DD291555A5 - METHOD FOR PRODUCING BENZOOXACYCLOALKYL-SUBSTITUTED AMINOSAEUREDERIVATES - Google Patents

Abstract

The invention relates to a process for the preparation of novel benzooxacycloalkyl-substituted amino acid derivatives of the formula wherein R 1 is carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N, N-di-lower alkylcarbamyl or optionally acylated hydroxymethyl, R 3 is hydrogen or lower alkyl, alk is lower alkylene or lower alkylidene which is unsubstituted or monosubstituted or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl and either X and Y are each an oxygen atom and n is 1 or X is a methylene group, Y is an oxygen atom and n is 1 or X is an oxygen atom, Y is a methylene group and n is 1 or X is a direct bond, Y is an oxygen atom and n is 2, with the addition in the compounds of the formula I in which the ring A is unsubstituted, X and Y are each oxygen ellen, n is 1 and R3 is hydrogen, alk is different from methylene, when R1 is carbamyl or N-methyl, N-ethyl, N, N-dimethyl or N, N-Diaethylcarbamyl, and their salts. These compounds and salts can be used as pharmaceutical active ingredients and can be prepared in a conventional manner. Formula (I) {Benzooxacycloalkyl-substituted amino acid derivative preparation; pharmaceuticals}

Description

Field of application of the invention

The invention relates to processes for the preparation of Benzooxacycloalkyl-substituted amino acid derivatives, which are used for the preparation of nootropotropic pharmaceutical preparations.

Characteristic of the known state of the art

From the US National Library of Medicine, a publication is known in which five compounds of the formula, 0 CH ₂ -NH-CH ₂ -CH ₂ -C (= O) -N (R ₁ ) -R ₂

(R ₁ = R ₂ = H, CH ₃ or C ₂ H ₆ or R, = H, R ₂ = CH ₃ or C ₂ H ₆ ).

No information is available on the use or the effect of these five compounds, in particular, no information is given on any nootropo activity.

Object of the invention

According to the invention, novel benzooxacycloalkyl-substituted amino acid derivatives of the formula I having valuable pharmacological properties are made available.

In particular, the compounds according to the invention have nootropic activity.

Explanation of the nature of the invention

The present invention is based on the object to find pharmaceutically active compounds and to provide processes for their preparation.

The invention relates to a process for the preparation of benzooxacycloalkyl-substituted amino acid derivatives of the formula

^x Λ

² * Ik

where R | R _{3 is} hydrogen or lower alkyl, alk is lower alkylene or lower alkylidene, the ring A is unsubstituted or mono- or polysubstituted by hydroxyl, lower alkoxy, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamoyl, N-lower alkylcarbamyl or optionally acylated hydroxymethyl, Halo, lower alkyl and / or trifluoromethyl is substituted and either X and Y each represent an oxygen atom and η is 1 or X represents a methylene group, Y is an oxygen atom and η is 1 or X represents an oxygen atom, Y is a methylene group and η is 1 or X is a direct bond, Y is an oxygen atom and η is 2, or a pharmaceutically acceptable salt thereof, the use of said compounds of formula I or their pharmaceutically acceptable salts to prepare nootropic pharmaceutical preparations, with the proviso in that in compounds of the formula I in which the ring A is unsubstituted, X and Y are each oxygen, η is 1 and R _{3 is} hydrogen, alk is different from methylene, when Ri is carbamyl or N-methyl, N-ethyl, N, N-dimethyl - or Ν, Ν-diethylcarbamyl, and their salts.

Acyl in acylated hydroxymethyl R _1, for example, derived from an organic carboxylic or sulfonic acyl. Acyl derived from an organic carboxylic acid is, for example, the radical of an aliphatic or monocyclic aromatic carboxylic acid, such as lower alkanoyl or optionally substituted benzoyl, and also pyridoyl. For example, acyl derived from an organic sulfonic acid is lower alkanesulfonyl.

The invention relates, for example, to a process for the preparation of a pharmaceutical, in particular nootropone, preparation containing as active ingredient a compound of the formula I in which R 1 is carboxy, lower-alkoxycarbonyl, carbamyl, N-lower-alkylcarbamyl or N, N-dineroera-carbamyl, R _{3 is} hydrogen or Lower alkyl, alk is lower alkylene or lower alkylidene, the ring A is unsubstituted or monosubstituted or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and η is 1, or a pharmaceutically acceptable salt thereof, the use of said compounds of formula I or their pharmaceutically acceptable salts for the preparation of nootropic pharmaceutical preparations, a process for the treatment of cerebral insufficiency symptoms, characterized in that one of the compounds of For mel I or a pharmaceutically acceptable salt thereof, and a process for the preparation of compounds of formula i, wherein Ri is carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or Ν, Ν-di-lower carbamyl, R _{3 is} hydrogen or lower alkyl, alk is lower alkylene or Lower alkylidene, the ring A is unsubstituted or mono- or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl, X represents an oxygen atom or a methylene group, Y is an oxygen atom and η is 1, with the proviso in compounds of the formula I in which the ring A is unsubstituted, X and Y are each oxygen, η is 1 and R _{3 is} hydrogen, alk is different from methylene, when R _{1 is} carbamyl or N-methyl, N-ethyl -, Ν, Ν-dimethyl or Ν, Ν-diethylcarbamyl, and their salts.

The compounds of formula I may be in the form of stereoisomers. Since the compounds of the formula I have at least one chiral carbon atom (C atom) (the carbon atom having the radical R ₃ ), they can be used, for example, as pure enantiomers or

Enantiomer mixtures, such as racemates, and, if at least one further chiral center is present (eg in the group alk), also present as diastereomers, diastereomer mixtures or racemate mixtures.

Salts of compounds of the formula I are, in particular, corresponding acid addition salts, preferably pharmaceutically usable acid addition salts. These are, for example, with strong inorganic acids such as mineral acids, eg. B.

Sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as lower alkanecarboxylic acids, eg. Acetic acid such as optionally unsaturated dicarboxylic acids, e.g. Malonic, maleic or fumaric acid, or hydroxycarboxylic acids, e.g. B tartaric acid or citric acid, or with sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acids, for. As methane or p-toluenesulfonic acid formed. If R, for example carboxy, corresponding compounds can form salts with bases. Suitable salts with bases are, for example, corresponding alkali metal or alkaline earth metal salts, eg. As sodium, potassium or magnesium salts, pharmaceutically acceptable transition metal salts, such as zinc or copper salts, or salts with ammonia or organic amines such as cyclic amines, such as mono-, di- or Triniedöralkylamine, such as Hydroxiliederalkylamine, z. B. mono-, di- or

Trihydroxy-lower alkylamines, hydroxy-lower alkyl-lower alkyl-amines or polyhydroxy-lower alkylamines. Cyclic amines are e.g. Morpholine, thiomorpholine, piperidine or pyrrolidine. Examples of suitable mono-lower alkylamines are ethyl or tert-butylamine, for example diethyl- or diisopropylamine as di-lower alkylamine, trimethyl- or triethylamine, for example, as tri-lower alkylamines. Corresponding Hydroxyniederalkylamine are z. Mono-, di- or triethanolamine, and hydroxy-lower alkyl-lower alkyl-amino are e.g. Ν, Ν-dimethylamino or Ν, Ν-diethylaminoethanol, as Pol ^ hydroxy lower alkylamine is e.g. Glucosamine in question.

Also included are unsuitable for pharmaceutical uses salts, since these can be used for example for the isolation or purification of free compounds of formula I and their pharmaceutically usable salts.

Above and below, "residues" or compounds, unless otherwise defined, are understood as meaning, in particular, those containing up to and including 7, above to and below 4, carbon atoms.

Lower alkoxy is, for example, C 1 -C ₄ -alkoxy, such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy and tert-butyloxy.

Lower alkyl is for example C ₁ -C ₄ -AlkVl, such as methyl, ethyl, n-propyl, isopropyl, η-butyl, I: obutyl, sec-Butvl or tert-Buiyl and further comprises C ₆ -C ₇ -AlkYl-, ie Pentyl, hexyl or heptyl radicals.

Lower alkyl alk is z. B. C, -C ₄ -alkylene, which links the ring system with the drawn in formula I NH group primarily by up to and with 3 C-atoms, and may, for. As methylene. Methylene or 1,3-propylene, but also 1,2-propylene, 1,2- or 1,3- (2-methyl) -propylene or 1,2- or 1,3-butylene, but can also be the ring system with the drawn in formula I NH group also by 4C atoms, ie 1,4-butylene represent.

Lower alkylidene alk is, for example, C 1 -C ₄ -alkylidene and may be, for example, methylene, ethylidene, 1,1- or 2,2-propylidene or 1,1- or 2,2-butylidene.

Lower alkanoyl is z. B. Cj-Cj alkanoyl, such as acetyl, propionyl, butyryl, isobutyryl or pivaloyl.

Lower alkanoyloxy is e.g. Cj-Cj alkanoyloxy such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy.

Lower alkoxycarbonyl is e.g. Cz-Cs-alkoxycarbonyl, such as methoxy, aothoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxycarbonyl,

N-lower alkylcarbamyl is e.g. N-d-C ^ alkylcarbamyl. such as N-methyl, N-ethyl, N- (n-propyl) -, N-isopropyl, N- (n-butyl) -, N-bobutyl- or N-tert-butylcarbamyl.

Ν, Ν-Diniederalkylcarbamyl is, for example, N, N-di-C _t -C4-alkylcarbamyl, wherein each of the two N-alkyl groups may be the same or different, such as N, N-dimethyl, Ν, Ν-diethyl, Ν, Ν-diisopropyl- or N-butyl-N-methylcarbamyl.

Optionally% substituted benzoyl is z. As benzoyl, p-chlorobenzoyl or p-nitrobenzoyl.

Lower alkanesulfonyl is z. As C, -C ₄ alkanesulfonyl, such as methane or Aethansulfonyl.

Halogen is especially halogen having an atomic number up to and including 35, such as fluorine, chlorine or bromine, and further includes iodine.

The compounds of the formula I and their pharmaceutically acceptable salts have, for example, valuable pharmacological properties, in particular nootropic properties. For example, they effect in the Two Compartmont Passive Avoidance test model after Mondadori and Classen, Acta Neurol. Scand. 69, Suppl. 99, 125 (1984) in doses above about 0.1 mg / kg i. p.

as well as p. o. In the mouse, a reduction in the amnesic effect of a cerebral electric shock.

Likewise, the compounds of the formula I have a considerable memory-improving effect, which in the step-down passive avoidance test according to Mondadori and Waser, Psychopharmacol. 63,297 (1979) from a dose of about 0.1 mg / kg i. p. as well as p. O.

on the mouse.

Similarly, the compounds of formula I and their pharmaceutically acceptable salts can be used as pharmaceuticals, e.g.

Nootropics, for example, for the therapeutic and / or prophylactic treatment of cerebral insufficiency symptoms, especially memory disorders, are used. Another object of the invention is therefore the use of compounds of formula I and their pharmaceutically acceptable salts for the preparation of medicaments, in particular of nootropics, for the treatment of cerebral insufficiency symptoms, in particular memory disorders. In this case, the commercial preparation of the active substances may be included.

The invention relates in the first place to a process for the preparation of pharmaceutical, in particular nootropic, preparations or a treatment process, which comprises reacting a compound of the formula I in which R ₍ carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν- Diniederalkylcarbamyl, hydroxymethyl, Niederalkanoyloxymethyl, Niederalkansulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, R _{3 is} hydrogen or lower alkyl, alk lower alkylene, which links the ring system with the drawn in formula I NH group through to and with 3C atoms, or lower alkylidene, the ring A is unsubstituted or monosubstituted, disubstituted or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl and either X and Y are each an oxygen atom and η is 1 or X is a methylene group, Y is an oxygen atom means and η is 1 or X is an oxygen represents an atom, Y is a methylene group and η is 1 or X is a direct bond, Y is an oxygen atom and η is 2, or selects one of its pharmaceutically acceptable salts, and processes for the preparation of compounds of formula I, wherein Ri Carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, NN-di-lower alkylcarbamyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulphonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, R _{3 represents} hydrogen or lower alkyl,

Alk lower alkylene which links the Ringsyqtem with the drawn in formula I NH group through to and with 3C atoms, or lower alkylidene, the ring A is unsubstituted or mono-, di- or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, Is lower alkyl and / or trifluoromethyl and either X and Y each represent an oxygen atom and η is 1 or X represents a methylene group, Y is an oxygen atom and η is 1 or X represents an oxygen atom, Y is a methylene group and η is 1 or X is a direct bond, Y is an oxygen atom and η is 2, with the proviso that in compounds of formula I wherein the ring A is unsubstituted, X and Y are each oxygen, η is 1 and R _{3 is} hydrogen, alk is different from methylene, when R _{1 is} carbamyl or N-methyl, N-ethyl, Ν, Ν-dimethyl or Ν, Ν-diethylcarbamyl, and their salts, for example, a process for the preparation of pharmaceutical, especially nootropic, preparations or a treatment process, characterized in that a compound of formula I, wherein R _{1 is} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or Ν, Din-Diniederalkylcarbamyl, R ₃ Is hydrogen or lower alkyl, alk lower alkylene, which links the ring system with the drawn in formula I NH group by up to and 3C atoms, or lower alkylidene, the ring A is unsubstituted or mono-, di- or polysubstituted by hydroxy, lower alkoxy , Lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and η stands for 1, or selects one of its pharmaceutically soluble salts, and a process for the preparation of compounds of formula I, wherein R, carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or , Ν-di-lower alkylcarbamoyl group, R ₃ represents hydrogen or lower alkyl, alk is lower alkylene that links the ring system with the drawn in formula I is NH group by up to and including 3C atoms, or represents lower alkylidene, which is unsubstituted Ring A or mono-, is substituted twice or more by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and η is 1, with the proviso that in compounds of the formula I, wherein the ring A is unsubstituted, X and Y are each oxygen, η is 1 and R _{3 is} hydrogen, alk is different from methylene when R | Carbamyl or N-methyl, N-ethyl, Ν, Ν-dimethyl or Ν, Ν-diethylcarbamyl, and their salts.

The invention relates above all to a process for the preparation of pharmaceutical, in particular nootropic, preparations or a treatment process, which comprises reacting a compound of the formula I in which R 1 represents carboxy, hydroxymethyl, C 1 -C 5 -alkanoyloxymethyl, such as acetoxymethyl, C 1 -C 4 ^ Alkoxycarbonyl, such as methoxycarbonyl, or carbamyl, R _{3 is} hydrogen or C ₁ -C ₄ alkyl, such as methyl, alk for Ct-C ^ alkylene, which is the ring system having the NH group shown in formula I by bis and with 3C atoms linked, such as methylene or ethylene, is the ring A is unsubstituted or substituted, in particular in the 7-position, by C ₁ -C ₄ -alkoxy, such as methoxy, and either X and Y each represent an oxygen atom and η is 1 is or X is a methylene group, Y is an oxygen atom and η is 1 or X is an oxygen atom, Y is a methylene group and η is 1 or X is a direct bond, Y is an oxygen fatom there. and η is 2, or one of its pharmaceutically acceptable salts, and a process for the preparation of compounds of formula I, wherein R-, carboxy, hydroxymethyl, Cj-Cs-alkanoyloxymethyl, such as acetoxymethyl, Ct-t ^ alkoxycarbonyl, as Methoxycarbonyl, or carbamyl, R _{3 is} hydrogen or C ₁ -C ₄ -Alkyl, such as methyl, is alk for C ₁ -C ₄ -AlkYlBn, which is the ring system with the drawn in formula I NH group by bis and with 3 C atoms linked, such as methylene or ethylene, is the ring A is unsubstituted or substituted, in particular in the 7-position, by C ₁ -C ₄ -alkoxy, such as methoxy, and either X and Y are each eir. Is oxygen and η is 1 or X is a methylene group, Y is an oxygen atom and r is 1 or X is an oxygen atom, Y is a methylene group and η is 1 or X is a direct bond, Y is an oxygen atom and η is 2, with the proviso that in compounds of formula I wherein the ring A is unsubstituted, X and Y are each oxygen, η is 1 and R _{3 is} hydrogen, alk is different from methylene when R | Carbamyl, and their salts, for example a process for the preparation of pharmaceutical, especially nootropic, preparations or a treatment process, characterized in that one is a compound of formula I, wherein R ₁ CHVAikox / earbonyl, such as methoxycarbonyl, R _{3 is} hydrogen or C ₁ -C ₄ -alkyl, such as methyl, is alk for C ₁ -C ₄ -alkyl bound to the ring system with the NH group shown in formula I by up to and with 3C atoms, such as methylene or ethylene, wherein ring A is unsubstituted, X is an oxygen atom or a methylene group, Y is an oxygen atom and η is 1, or one of its pharmaceutically acceptable salts, and a process for the preparation of compounds of formula I, wherein C ₁ -C ₄ -Aikoxycarbonyl, such as methoxycarbonyl, R _{3 is} hydrogen or C ₁ -C ₄ -AlkVl, such as methyl, alk for dC ^ alkylene, which is the ring system with the drawn in formula I NH group by bi s and 3C-linked atoms, such as methylene or ethylene, is unsubstituted, the ring A is an oxygen atom or a methylene group, Y is an oxygen atom and η is 1, and their salts.

The invention relates first and foremost to a process for the preparation of pharmaceutical, in particular nootropic, preparations or a treatment process, which comprises reacting a compound of the formula I in which R _{1 is} C ₁ -C ₄ -alkoxycarbonyl, such as methoxycarbonyl, R _{3 is} hydrogen, alk is methylene or ethylene, ring A is unsubstituted, X is an oxygen atom or a methylene group, Y is an oxygen atom and η is 1, or one of its pharmaceutically acceptable salts, and a process for the preparation of compounds of formula I, wherein R ₁ ^ -C ^ alkoxycarbonyl, such as methoxycarbonyl, R _{3 is} hydrogen, alk is methylene or ethylene, the ring A is unsubstituted, X represents an oxygen atom or a methylene group, Y is an oxygen atom and η stands for 1, and their salts,

The invention relates in particular to a process for the preparation of pharmaceutical, especially nootropic, preparations or a treatment process, characterized in that one of the novel compounds of the formula I mentioned in the examples or one of its pharmaceutically acceptable salts, and a process for the preparation of in the examples mentioned new compounds of formula I and their salts.

The present invention is a process for the preparation of compounds of formula I and their salts, for. B. characterized in that one

a) Compounds of the formulas

'(VIII a) and Zr-C; VCH (Z ₃ JR ₁ (VIIIb)

alk-Zi

wherein one of the radicals Z ₁ and Z _{2 is} reactive esterified hydroxy, the other amino and Z _{3 is} hydrogen or Zi is amino and Z ₂ and Z ₃ together represent an additional bond, or optionally salts of these compounds with one another or b) in a compound the formula

.AA ./ '1 * 1 ₍

LOLOK . ^(IXI ·

wherein X _{6 is} a radical convertible into R ₁ , or a salt thereof X ₆ in R | if desired, in each case a compound I obtained in accordance with the method or in another manner is converted into a different compound of the formula I, in each case an isomer mixture obtainable according to the process is separated into the components, a respective enantiomer or diastereomer mixture obtainable according to the process is split into the enantiomers or diastereomers and / or or in each case a free compound of the formula I obtainable in accordance with the process is converted into a salt or a salt obtainable according to the process is converted into the free compound of the formula I or into another salt.

The reactions described above and below in the processes are carried out in a manner known per se, for. B. in Ab or usually in the presence of a suitable solvent or Verdünngsmittels or a mixture thereof, wherein, as required, with cooling, at room temperature or with heating z. Example, in a temperature range of about -1O ⁰ C to the boiling temperature of the reaction medium, preferably from about 20 ⁰ C to about 150 ° C, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and / or under anhydrous Conditions works. The above and below listed starting material, which was developed for the preparation of the compound of formula I and its salts, is known in part or can also by known methods, for. B. analogously to the process variants described above, are produced.

Starting material with basic centers can, for. ß. in the form of acid addition salts, for example with the acids listed above, while starting compounds with acidic groups, salts with bases, e.g. of the aforementioned type can form.

Option A):

Reactive esterified hydroxy Z ₁ or Z ₂ means, in particular, hydroxy esterified with a strong inorganic acid or organic sulfonic acid, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, for example fluorosulfonyloxy, optionally substituted, for example by halogen, lower alkanesulfonyloxy for example, methane or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g. B. cyclohexanesulfonyloxy, or optionally, for. B. by lower alkyl or halogen, substituted benzenesulfonyloxy, z. B. p-bromophenyl or p-Toluolsufonyloxy.

The reaction is carried out in particular in the presence of a condensing agent, such as a suitable base. Suitable bases are, for example, alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylidene, diniederalkylamides, aminoloweralkylamides or lower alkylsilylamides, naphthalenamine, lower alkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines. Examples of these are sodium hydroxide, hydride, amide, ethylate, potassium tert-butoxide, carbonate, lithium triphenylmethylid, lithium diisopropylamide, potassium 3- (aminopropyl) amide, bis (trimethylsilyl) amide, dimethylaminonaphthalene, di - or triethylamine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1, S-diazabicyclo [4.3.0lnone-5-ene (DBN) and IS-diaza-bicyclojB ^ .Olundec-G-ene (DBU).

The reaction of amines VIII a (Z ₁ = amino) with acrylic acid compounds VIII b (Z ₂ + Z ₃ = bond) takes place, for example, with heating, for. B. to about 60-120 ° C.

The starting materials of the formulas VIII a and VIII b are known or can be prepared in analogy to the known starting materials.

Variant b):

One that can be converted in R _t radical X ₉ is _(for example, of R different functionally modified carboxy, such as cyano, anhydridised carboxy jebenenfalls substituted amidino, optionally esterified or anhydridised carboximidoyl, esterified or amidated carboxy R _t various esterified or amidated carboxy, Triniederalkoxy-oderTrihalogenmethyl.

Anhydridized carboxy is, for example, anhydrided carboxy with a mineral acid such as hydrohalic acid, or with a carboxylic acid such as an optionally substituted lower alkanoic or benzoic acid or a lower alkyl halide halide. Examples which may be mentioned are halocarbonyl, such as chlorocarbonyl, lower alkanoyloxy-carbonyl, such as acetoxycarbonyl, or lower alkoxycarbonyloxycarbonyl, such as ethoxycarbonyloxycarbonyl.

Substituted amidino is, for example, an aliphatic radical, for. Lower alkyl, substituted amidino such as lower alkylamidino, e.g. B. ethylamidino.

Under vürestertem or anhydridisiertem Carboximidoyl z. As alkoxy or Halogencarboximidoyl, for example, lower alkoxy, such as ethoxy, or chloro-carboximidoyl to understand.

Triniederalkoxy- or trihalomethyl is z. B. trimethoxymethyl or trichloromethyl.

Xe can be converted into R ₁ , for example, by solvolysis. Solvolysemittel are, for example, water, the desired veri / esterified carboxy Ri corresponding lower alkanols, ammonia or the desired amidiorten carboxy group Ri according to '/ amines. The treatment with a corresponding solvolysis agent is optionally carried out in the presence of an acid or base. Suitable acids are, for example, inorganic or organic protic acids, such as mineral acids, for example sulfuric acid or halohydroic acids, for example hydrochloric acid, such as sulphonic acids,

z. B. Niederalkan- Her grafted substituted benzenesulfonic acid, for example methane or p-toluenesulfonic acid, or as carboxylic acids, eg. As lower alkanecarboxylic acids, such as acetic acid, in question, while as bases, for example, those mentioned under variant a) may be used, in particular sodium or potassium hydroxide.

In solvolysis, the cyano group, anhydridized carboxy, optionally substituted amidino, optionally esterified or anhydridised carboximidoyl, esterified or amidated carboxy, tri-lower alkoxy or trihalomethyl are different from esterified or amidated carboxy Ri to carboxy hydrolyzed. In this case, optionally located on the ring A Niederalkanoyloxyreste be hydrolyzed in the course of the hydrolysis to hydroxy.

Cyano, anhydridized carboxy, esterified or amidated carboxylic acid other than esterified or amidated carboxy Ri are alcoholized, for example, with a suitable lower alkanol to give esterified carboxy R !, and ammonia or anhydridized carboxy, for example, with ammonia or an amine corresponding to the amidated carboxy R _t aminolysed.

The starting material of Formal IX may e.g. by reacting compounds of the formulas

(IXa) and Zr-CH ₇ -CH (Z ₃ IX ₈ (IXb),

wherein Z _{2 is} reactive esterified hydroxy and Z _{3 is} hydrogen or Z ₂ and Z ₃ together represent an additional bond, or optionally salts of these compounds are obtained, wherein, for example, in analogy to the Dieckmann reaction, especially in the presence of one of the variant a) said bases and subsequent hydrolytic workup, is carried out.

Starting compounds of the formula IXa can be obtained, for example, by reduction of the corresponding nitriles. According to the method or otherwise available compounds of formula I can be converted in a conventional manner into other compounds of formula I.

So you can z. B. esterified or amidated carboxy groups Ri in customary, for example in the presence of a basic or acidic hydrolysis agent, such as an alkali metal hydroxide or carbonate, ζ. Example of sodium hydroxide or potassium carbonate, or a mineral acid, eg. As hydrochloric acid or sulfuric acid, hydrolyze to carboxy Ri. Esterified carboxy groups R _t can also be obtained by transesterification, ie treatment with an alcohol in the presence of an acidic or basic solvolysis agent, such as a mineral acid, e.g. B, of sulfuric acid, or of a corresponding alkali metal alkoxide or of an alkali metal hydroxide into other esterified carboxy groups R) or by reaction with ammonia or a corresponding amine having at least one hydrogen atom are converted into amidated carboxy Ri. Free. Carboxy R, in a conventional manner, for example by treatment with a corresponding alcohol in the presence of a mineral acid, for. B. of sulfuric acid, or by conversion to a halide and subsequent reaction with a corresponding alcohol, for. B. in the presence of pyridine or triethylamine, or by conversion into an alkali metal salt and subsequent reaction with a reactive ester of the corresponding alcohol, such as a corresponding halide, in esterified carboxy R, are transferred. Likewise, a carboxy compound can be esterified using a dehydrating agent such as N, N'-dicyclohexylcarbodiimide with a corresponding Al'ohol. Free or esterified carboxy R) may also be prepared by reaction with ammonia cder an amine having at least one hydrogen atom and dehydration of the ammonium salt formed intermediately, for. 8. be converted into amidated carboxy Rt by heating or by means of a dehydrating agent, such as N.N'Dicyclohexylcarbodiimid, or by conversion into the halide and subsequent reaction with ammonia or an amine having at least one hydrogen atom.

Further, one can optionally esterify existing hydroxy groups, for. B. by treatment with a Niederalkancarbonsäureanhydrid or halide in Niedoralkanoyloxy or convert by reaction with a reactive ester, in particular bromine or hydrochloric acid ester, a lower alkanol in corresponding etherified hydroxy. Inversely, esterified or etherified hydroxy, such as lower alkanoyloxy or lower alkoxy, may solvolytically release the hydroxy group (s), preferably under acidic conditions. Accordingly, it is also possible to esterify hydroxymethyl R _t , for example by treating it with a lower alkanecarboxylic acid anhydride or halide in lower alkanoyloxymethyl Ri. Conversely, the hydroxy group can be released solvolytically from acylated hydroxymethyl, eg lower alkanoyloxymethyl, R 1, preferably under acidic conditions.

Furthermore, hydroxymethyl Ri can usually be converted into lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or N, N-D; lower alkylcarbamyl Ri, where z. B. in the manner that initially hydroxymethyl Ri in a conventional manner, for. B. in the presence of an oxidizing agent, such as potassium permanganate or potassium dichromate, is oxidized to carboxy and then the carboxy group in the usual manner, for. B. by treatment with a ensprechenden alcohol in the presence of a mineral acid, eg. B. of sulfuric acid, or by conversion to a halide and subsequent reaction with a corresponding alcohol, for. B. in the presence of pyridine or triethylamine, or by conversion iln an alkali metal salt and subsequent reaction with a reactive ester of the corresponding alcohol, such as a corresponding

Halide, or using a dehydrating agent, such as N.N'-dicyclohexylcarbodiimide, with a corresponding alcohol in lower alkoxycarbonyl Rt or by reaction with ammonia or an amine having at least one hydrogen atom and dehydration of the intermediate ammonium salt, eg. B. dur h heating

or by means of a dehydrating agent, such as Ν, Ν'-dicyclohexylcarbodiimide, or by conversion into the halide and subsequent reaction with ammonia or an amine having at least one hydrogen atom is converted into amidated carboxy Ri. It is also possible to convert acylated hydroxymethyl Ri into esterified or amidated carboxy R, by first solvolytically releasing the acylated hydroxymethyl group, eg. As described above, and then the resulting free hydroxymethylgruppa, as explained above, converted into a carboxyl group and the latter further into an esterified or amidated carboxyl group. Conversely, esterified or amidated carboxy groups R, can be converted into optionally hydroxymethyl R ₁ , by first esterifying the esterified or amidated carboxy group R i in the usual way, for example in the presence of a basic or acidic hydrolyzing agent, such as an alkali metal hydroxide or carbonate, ζ , Example of sodium hydroxide or potassium carbonate, or a mineral acid, eg. B. of hydrochloric acid or sulfuric acid, hydrolyzed to carboxy and then the resulting carboxy group in customary, for example in the presence of a reducing agent, for example of the type mentioned above, iu hydroxymethyl R ₁ , where desired, the latter, for example, as described above, then still in acylated hydroxymethyl R _t can be transferred.

Salts of compounds of the formula I can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of the formula I are obtained by treatment with an acid or a suitable ion exchange reagent. Salts can be converted in the usual way into the free compounds, acid addition salts z, B. by treatment with a suitable basic agent.

Depending on the procedure or conditions of the reaction, the process can be obtained in accordance with available compounds having salt-forming, in particular basic properties, in free form or in the form of saline.

As a result of the close relationship between the new compound in free form and in the form of their salts, the corresponding salts or the free compound are to be understood in the preceding and following by the free compound or its salts.

The novel compounds obtainable by the process, including their salts of salt-forming compounds, can also be obtained in the form of their hydrates or include other solvents used, for example, for the crystallization of compounds present in solid form.

The novel compounds obtainable in accordance with the process can be in the form of one of the possible isomers or as a mixture thereof, depending on the choice of starting materials and procedures. Depending on the molecular symmetry,

z. Depending on the number, absolute and relative configuration of the chiral centers, such as asymmetric C atoms, as pure isomers e.g. pure enantiomers and / or pure diastereomers, such as pure cis / tmns isomers or meso compounds.

Accordingly, as isomer mixtures z. B. enantiomer mixtures, such as racemates, diastereomer mixtures or racemate mixtures.

Resulting diastereomer mixtures and mixtures of racemates can be separated in a known manner in the pure diastereomers or racemates due to the physico-chemical differences of the constituents, for example by fractional crystallization.

Resulting mixtures of enantiomers, such as racemates, can be resolved into the enantiomers by known methods, for example by recrystallization from an optically active solvent, chromatography on chiral adsorbents, with the aid of suitable microorganisms, by cleavage with specific immobilized enzymes, via the formation of inclusion compounds, z. Example, using chiral crown ether, wherein only one enantiomer is complexed, or by conversion into diastereomeric salts, eg. Example, by reacting a basic Enderacemats with an optically active acid, v »ie carboxylic acid, for. As tartaric or malic acid, or sulfonic acid, eg. B. camphorsulfonic acid, and separation of the thus obtained diastereomer mixture, for. Due to their different solubilities, into the diastereomers from which the desired enantiomer can be released by the action of suitable means. Advantageously, one isolates the more effective enantiomer.

The invention also relates to those embodiments of the process according to which one proceeds from a compound obtainable as an intermediate at any stage of the process and performs the missing steps or uses a starting material in the form of a derivative or salt and / or its racemates or enantiomers, or in particular forms under the reaction conditions.

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described at the outset as being particularly valuable. The process for the preparation of novel starting materials which have been developed specifically for the preparation of the compounds according to the invention and their use likewise form an object of the invention, the variables R), R3, X, Y, η and alk and the substituents of the ring A have the meanings given for the particular preferred compound groups of the formula I.

The invention also relates to the use of compounds of the formula I and pharmaceutically acceptable salts of such compounds having salt-forming properties, in particular as pharmacological, primarily nootropic effective, active substances. In this case, they can be used, preferably in the form of pharmaceutically usable preparations, in a process for the prophylactic and / or therapeutic treatment of the animal or human body, in particular as nootropics, for example. B. for the treatment of cerebral insufficiency symptoms, especially memory disorders apply.

The invention also relates to a process for the preparation of pharmaceutical preparations containing a compound of formula I or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical preparations according to the invention which contain a compound of the formula I or a pharmaceutically acceptable salt thereof are those for enteral, such as oral, rectal rectal, and parenteral administration to warm-blooded animals, the pharmacological Active ingredient alone or together with conventional pharmaceutical excipients is included.

The new pharmaceutical preparations contain e.g. from about 10% to about 80%, preferably from about 20% to about 60%, of the active ingredient. Pharmaceutical preparations according to the invention for enteral or parenteral administration are ϊ. Β. such

In dosage unit forms, wio dragees, tablets, capsules or suppositories, also ampoules. These are in a manner known per se, ζ. B. by conventional mixing, granulation, coating, solution or l.yophilisierungsverfahren. Thus, pharmaceutical preparations for oral administration can be obtained by combining the active substance with solid carriers, optionally granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable auxiliaries, to form tablet dragee cores. Suitable carriers are in particular fillers, such as sugars, for. As lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphate, z. Tricalcium phosphate or calcium hydrogen phosphate, forer binders such as starch pastes, using e.g. Corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulore and / or polyvinylpyrrolidone, if desired, blastters such as the above-mentioned starches, furthermore carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, wio sodium alginate , Auxiliaries are primarily flow, regulators and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragoe cores are provided with suitable, optionally gastric juice-resistant coatings, which u.a. concentrated sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or gastric juice-resistant coatings, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. As for the identification or labeling of different doses of active ingredients, be attached.

Other orally applicable pharmaceutical preparations are gelatin capsules and soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules can be the active ingredient in the form of granules, eg. As in admixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible for stabilizers to be added.

As rectally applicable pharmaceutical preparations are e.g. Suppositories which consist of a combination of the active ingredient with a suppository base. As suppository base are z. As natural or synthetic triglycerides, paraffin hydrocarbons, Polyäthylenqlykolo or higher alkenols. Furthermore, gelatin rectal capsules containing a combination of the active ingredient with a basic bulking agent can also be used. As basic materials there are e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question. For parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, eg. As a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, wherein suitable lipophilic solvent or vehicle such as fatty oils, eg. As sesame oil, or synthetic fatty acid esters, eg. As ethyloleate or triglycerides, used or aqueous injection suspensions, which viskositätser'iöhende substances, eg. As sodium carboxymethyl cellulose, sorbitol and / or dextran, and optionally also contain stabilizers. The dosage of the active ingredient may depend on various factors, such as mode of administration, species of warm-blooded animals, age and / or individual condition. Normally, for an approximately 75 kg warm-blooded animal when administered orally, an approximate daily dose of about 20 to about 500 mg, in particular from about 25 to about 250 mg, advantageously in several identical Toildosen to estimate.

embodiments

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are in Celsiusgr & den specified.

example 1

A solution of 6.2 g {35 mmol) of 3- (2-aminoethyl) chroman in 50 ml of methanol is mixed at room temperature with 3.32 g (39 mmol) of methyl acrylate and stirred for 16 hours at room temperature. The reaction mixture is then evaporated in vacuo to give the N- (2- (chroman-3-yl) ethyl) -N- (2-methoxycarbonylethyl) -amine as a reddish oil whose

Hydrochloride at 190-192 ⁰ C melts.

The 3- (2-aminoethyl) chroman may, for. B. be prepared as follows:

A solution of 50.0 g (260 mmol) of 3-methoxycarbonylchroman (US Pat. No. 4,178,380) in 200 ml of absolute tetrahydrofuran is added dropwise while stirring at room temperature to a suspension of 9.85 g (260 mmol) of lithium aluminum hydride in 300 ml of absolute diethyl ether. After stirring at room temperature for 16 hours, the reaction mixture is added with 9.9 ml of water, 9.9 ml of sodium hydroxide solution (15%) and 30 ml of water. The precipitate is filtered off with suction and the filtrate is evaporated to dryness in vacuo. The oily residue is dissolved in diethyl ether and the solution washed with water, dried over sodium sulfate and evaporated to dryness. This gives 36.71 g (86%) of oily 3-hydroxymethylchroman, which crystallized from diethyl ether / pentane and melts at 60-61 ⁰ C.

A solution of 36.12 g (220 mmol) of 3-hydroxymethylchroman in 100 ml of absolute pyridine is added with stirring at room temperature with 46.14g (242 mmol) of p-toluenesulfonyl chloride, wherein the slightly exothermic reaction is maintained with an ice bath at room temperature. The reaction mixture is stirred for 3 hours at room temperature and then poured into ice-water The precipitated crystals are filtered off with suction, washed with water and dried in vacuo to give 65.84 g (94%) of 3- (p-toluenesulfonyloxymethyl) -chromane of the mp 86-87 ° C.

A solution of 55.72 g (USmmoDS-fp-tri-sulfonyloxymethyltrichroman in 300 ml of dimethyl sulfoxide is treated at room temperature with 12.53 g (192 mmol) of potassium cyanide and heated with stirring to 60 ° C. After 3 hours, the reaction mixture is mixed with ice-water The combined organic phases are dried over sodium sulphate and evaporated in vacuo to give 26.75 g (88.3%) of 3-cyanomethylchroman in the form of a light yellow oil which crystallises from diethyl ether / pentane melt at 63 ° C.

To a suspension of 7.59 g (200 mmol) of lithium aluminum hydride in 300 ml of absolute diethyl ether are first added dropwise while stirring at room temperature 4.44 g (33f, 3mmol) of aluminum chloride in 150 ml of absolute diethyl ether. Subsequently, 17.32 g (100 mmol) of 3-cyanomethylchroman dissolved in 200 ml of tetrahydrofuran are added dropwise within 15 minutes. The reaction mixture is stirred for 16 hours at room temperature and then decomposed with 7.6 ml of water, 7.6 ml of sodium hydroxide solution (15%) and 22.8 ml of water. The precipitate is filtered off with suction and the filtrate is evaporated in vacuo. The oily residue is dissolved in diethyl ether and washed with water. The organic phase is then extracted by shaking with 2N hydrochloric acid. The admixed hydrochloric acid extracts are made alkaline with caustic soda (30%) and extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. This gives "." 95g (90%) of 3- (2-aminoethyl) chroman as a colorless oil. The 3- (2-aminoethyl) produced therefrom with hydrochloric acid in diethyl ether chroman hydrochloride crystallized from methanol / diethyl ether, and has a mp. 244-245 ⁰ C.

Example 2

In anloger way as described in Example 1, can be prepared by reacting 3-Aminomethylchroman with 1 equivalent of methyl acrylate, the N- (2-methoxycarbonylethyl) -N- (chroman-3-ylmethyl) -amine or its hydrochloride.

The 3-aminomethylchroman is broken down e.g. to produce the following catfish:

To a suspension of 3.04 g (80 mmol) of lithium aluminum hydride in 100 ml of absolute diethyl ether are first added dropwise, with stirring at room temperature, 1.77 g (13.32 mmol) of aluminum chloride in 50 ml of precipitated diethyl ether. Subsequently, 6.29 g (40 mmol) of 3-cyanochroman (R.C. Gupta et al., Ind. J. Chem. 21B, 344 [1982]) are added dropwise in 50 ml of absolute tetrahydrofuran within 20 minutes. The reaction mixture is refluxed for 16 hours. After cooling, the reaction mixture is carefully decomposed with 3.1 ml of water, 3.1 ml of sodium hydroxide solution (15%) and 9.3 ml of water. The precipitate is filtered off with suction, the filtrate is evaporated in vacuo and the oily residue is dissolved in diethyl ether. The organic phase is washed with water and extracted with 2N hydrochloric acid. The combined extracts are made alkaline with sodium hydroxide solution (30%) and shaken out with dichloromethane. After drying the combined organic phases over sodium sulfate and concentration in vacuo, 3.5 g (53.6%) of 3-aminomethylchroman are obtained as a yellow oil. The 3-Aminomethylchroman hydrochloride prepared therefrom with hydrochloric acid in diethyl ether is recrystallized from methanol / diethyl ether and melts at 218-219 ° C.

Example 3

A solution of 6.61 g (40 mmol) of 2-aminomethyl-benzo-1,4-dioxane (Augustin J. et al., J. Med. Chem. 8, [196D]) in 80 ml of methanol is charged with 3.79 g (44mmol) methyl acrylate and stirred for 16 hours at 5O ⁰ C stirred. After cooling, the reaction mixture is evaporated in vacuo. The N- (2-methoxycarbonylethyl) -N- (benzo-1,4-dioxan-2-ylmethyl) -amine is obtained as a reddish oil whose hydrochloride melts at 153.degree.-55.degree.

Example 4

In a manner analogous to that described in Example 3, reaction of 2- (2-aminoethyl) benzo-1,4-dioxane (J. Augustin et al., J. Med. Chem. 8,44611965]) with 1 equivalent Methyl acrylate, the N- (2- (benzo-1,4-dioxan-2-yl) ethyl] -N- (2-methoxycarbonylithyl) amine or its hydrochloride and by reacting 2-aminomethyl-2-methyl-benzoyl 1,4-dioxane with 1 equivalent of methyl acrylate, the N- (2-methoxycarbonylethyl) -N- (2-methyl-benzo-1,4-dioxan-2-ylm ' ⁱ * hyl) amine or its hydrochloride produce.

Example 5

A solution of 2.99 g of dOmmol) N- [2- (chroman-3-yl) ethyl] -N- (2-methoxycarbonylethyl) -amine hydrochloride in 60 ml of methanol is stirred at room temperature while stirring with 21 ml (42 mmol) of 2N Liquified sodium hydroxide solution. After 5 minutes, added to the reaction mixture to 40ml Wcsser and the mixture is stirred then for 30 minutes at 50-60 ⁰ C. After cooling, the mixture is evaporated in vacuo. The residue is dissolved in 30 ml of water, treated with 10 ml of hydrochloric acid (36%) and cooled in an ice bath. The precipitated crystals are sucked off. This gives 2.5 g (87%) of N- [2- (chroman-3-yl) ethyl] -N- (2 - '. Arboxyäthyl) -amine hydrochloride (mp 186-188 ⁰ C).

Example β

A solution of 6.2 g (35 mmol) of 2- (2-aminoethyl) chroman in 200ml of methanol at 0-5 "C under stirring with 3.01 g (35 mmol) was added methyl acrylate. It is stirred for 16 hours at 0-5 ⁰ C., and the mixture is then evaporated in vacuo, giving 8.76 g (95.2%) of crude product which is chromatographed over 250 g of silica gel (0.040-0.063 mm) with ethyl acetate as eluent. 10 g (55.4%) of N- [2- (chroman-2-yl) ethyl-N- (2-methoxycarbonylethyl) -amine as a yellow oil The Hiaraur prepared with hydrochloric acid in diethyl ether N- [2- (chroman-2 -yl) ethyl] -N- (2-methoxycarbonylethyl) -amine hydrochloride crystallized from Met! anol / diethyl ether and melts at 152-153 ⁰ C.

2- (2-Aminoisyl) chroman can be e.g. produce as follows:

A solution of 70.34 g (0.33rnc!) 2-Carboxychroman in 1400ml of methanol is added with 14.2ml sulfuric acid (100%) and boiled for 4 hours under reflux. After cooling, the reaction mixture is evaporated in vacuo and the residue dissolved in diethyl ether and washed with water, cold saturated sodium bicarbonate solution and water again. The ethereal phase is dried over sodium sulfate and evaporated in vacuo. This gives 72.8 g (96%) of 2-methoxycarbonylchroman as a light yellow oil.

To a suspension of 7.2 g (0.19 mol) of lithium aluminum hydride in 400 ml of absolute diethyl ether, a solution of 36.4 g (0.19 mol) of 2-Methoxycarbonylchroman in 400 ml of absolute tetrahydrofuran is added dropwise within 1 hour with stirring at room temperature. After stirring for 16 hours at room temperature, the reaction mixture is carefully decomposed with 7.2 ml of water, 7.2 ml of sodium hydroxide solution (15%) and 21.6 ml of water. The precipitate is filtered off with suction and the filtrate in vacuo

evaporated. The oily residue is dissolved in diethyl ether. The ethereal solution is washed with water, dried over sodium sulfate and evaporated in vacuo. This gives 31 g (99.3%) of 2-hydroxymethylchroman in the form of a colorless oil.

A solution of 31 g (0.189 mol) of 2-hydroxymethylchroman in 110 ml of absolute pyridine is added at room temperature with stirring with 38.16g (0.2 mol) of p-toluenesulfonyl chloride, wherein the slightly exothermic reaction is maintained with an ice bath at room temperature. The reaction mixture is stirred for 3 hours at room temperature and then poured onto ice-water. The separated oil is separated by decantation of the aqueous phase, dissolved in diethyl ether and washed with ice-cold 2 N hydrochloric acid and ice water. The ethereal phases are dried over sodium sulfate and evaporated in vacuo. 58.15 g (96.6%) of 2- (p-toluenesulfonyloxymethyl! Chroman as a colorless oil are obtained. A solution of 57.31 g (0.18 mol) of 2- (p-toluenesulfonyloxymethyl) chroman in 800 ml of absolute dimethylformamide is added with 10 , 6 g (0.216 mol) of sodium cyanide and heated with stirring to 60 ° C. After 10 hours, the reaction mixture is mixed with ice-water and extracted with diethyl ether.The combined ethereal phases are washed thoroughly with water, dried over sodium sulfate and evaporated in vacuo receives 30.0 g (96.2%) of crude product which is chromatographed over 1000 g of silica gel (0.040-0.063 mm) with toluene as eluant to give 18.16 g (58.2%) of 2-cyanomethylchroman as a yellow oil.

To a suspension of 3.8 g (100 mmol) of lithium aluminum hydride in 150 ml of absolute diethyl ether, 2.2 g (16.5 mmol) of aluminum chloride in 70 ml of absolute diethyl ether are first added dropwise with stirring at room temperature. Subsequently, 8.66 g (50 mmol) of 2-cyanomethylchroman in 70 ml of absolute tetrahydrofuran are added dropwise within 20 minutes. The reaction mixture is stirred for 16 hours at room temperature and then carefully decomposed with 3.8 ml of water, 3.8 ml of sodium hydroxide solution (15%) and 11.4 ml of water. The precipitate is filtered off with suction and the filtrate is evaporated in vacuo. The oily residue is dissolved in diethyl ether. The ethereal phase is washed with water, dried over sodium sulfate and evaporated. This gives 8.75 g (98.8%) of 2- (2-aminoethyl) chroman as a colorless oil.

Example 7

33.2 g (0.1 mol) of 3- [2- (p-toluenesulfonyloxy) ethyl] chroman, 14.0 g of N-fZ-Methoxycarbonyla'thyOamin hydrochloride and 39 g of N-ethyl-N, N-diisopropyl-amine are under Dissolved nitrogen in 760ml dimethylformamide and the solution stirred for 16 hours at room temperature. Thereafter, the reaction mixture is concentrated under reduced pressure to about 200 ml, then treated with 500 ml of water and extracted by shaking three times with 150 ml of dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated to dryness. By addition of ethanolic hydrochloric acid and cooling, the N-12- (chroman-3-yl) -ethyl] -N- (2-methoxycarbonylethyl) -amine hydrochloride of mp 190-192 ° C. is obtained.

3- [2- (p-Toluolsuifonyloxy) ethyl] chroman can be z. B. produce as follows:

A solution of 7.8 g (45 mmol) of 3-cyanomethylchroman in 150 ml of ethanol is mixed with 50 ml of 2N sodium hydroxide solution and boiled under reflux for 16 hours. After cooling, the reaction mixture is evaporated in vacuo. The residue is dissolved in water and extracted with diethyl ether. The aqueous phase is acidified with hydrochloric acid (36%) and extracted by shaking with dichloromethane. The combined dichloromethane extracts are dried over sodium sulfate and evaporated in. Vacuum. This gives 8.3 g (96%) of 3-carboxymethylchroman in the form of colorless crystals which melt at 106-107 ⁰ C.

A solution of 7.69 g (40 mmol) of 3-carboxymethylehroman in 150 ml of methanol is added with 1.5 ml of sulfuric acid (100%) and refluxed for 3 hours. After cooling, the reaction mixture is evaporated in vacuo. The residue is dissolved in diethyl ether and washed cold with water, sodium bicarbonate and water again. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. This gives 8.08 g (98%) of 3-methoxycarbonylmethylchroman as a light yellow oil.

To a suspension of 1.33 g (35 mmol) of lithium aluminum hydride in 50 ml of absolute diethyl ether, a solution of 7.22 g (35 mmol) of 3-methoxycarbonylmethylchroman in 50 ml of absolute tetrahydrofuran is added dropwise at room temperature while stirring for 30 minutes. The mixture is stirred for 16 hours at room temperature and carefully decomposed with 1.33 ml of water, 1.33 ml of sodium hydroxide solution (15%) and 4.0 ml of water. The precipitate is filtered off with suction and the filtrate is evaporated in vacuo. The oily residue is dissolved in diethyl ether. The solution is washed with water, dried over sodium sulfate and evaporated in vacuo. This gives 6.23 g (100%) of 3- (2-hydroxyethyl) chroman as a yellow oil.

A solution of 5.35 g (30 mmol) of 3- (2-hydroxyethyl) chroman in 30 ml of absolute pyridine is added at room temperature while stirring with 6.29 g (33 mmol) of p-toluenesulfonyl chloride, keeping the slightly exothermic reaction with an ice bath at room temperature , After stirring for 3 hours at room temperature, the reaction mixture is poured into water. The fancy crystals we. Suck off with suction, washed with water and dried in vacuo. This gives 5.9 g (59.2%) of 3- [2- (p-toluenesulfonyloxy) ethyl] chroman, which melts at 91-93 ° C.

Example 8

A solution of 11.5 g (0.05 mmol) of N- [2- (chroman-3-yl) ethyl] -N- (2-cyanoethyl) -amine in 100 ml of methanol is treated with 6 ml of concentrated hydrochloric acid. The reaction mixture is refluxed for 15 hours. After being obtained, the solvent is removed under reduced pressure and the residue is crystallized from methanol / acetone. After recrystallization from methanol / acetone, the N- | 2- (chroman-3-yl) ethyl] -N- (2-methoxycarbonyläthyl) -amine hydrochloride, mp. 190-192 ° (yield: 82%).

The N- [2- (chroman-3-yl) ethyl] -N- (2-cyanoethyl) -amine can be z. B. produce as follows:

17.7 g (0.1 mol) of 3- (2-aminoethyl) chroman are dissolved in 100 ml of methanol and the solution is admixed with 10.5 g (0.1 mol of triethylamine and 5.84 g (0.11 mol) of acrylonitrile stirred for 15 hours at room temperature and then the reaction mixture concentrated in a water jet vacuum a. the residue is taken up in diethyl ether and washed with ice water neutral. the ätherir, oi ^ ^p hase is dried over potassium carbonate and evaporated. thus obtained the N- [2- ( Chroman-3-yl) ethyl) -N- (2-cyanoäthyD-amine in the form of a pale yellow oil.

Example 9

The N- [2- (chroman-4-yl) ethyl] -N- (2-methoxycarbonylethoxy) amine and its hydrochloric acid can also be obtained in an analogous manner as described in Examples 1 to 8.

Example 10

Tablets containing 25mg of active ingredient, e.g. N- [2- (chroman-3-yl) ethyl-N- (2-methoxycarbonylethyl) -amine hydrochloride can be prepared as follows:

Ingredients (for 1000 tablets): 25.0 g 'Active ingredient 100.7 g lactose 7.5 g wheat starch 5.0 g PolyäthylenglykoieoOO 5.0 g talc 1.8g magnesium stearate

demineralised water q.s.

Preparation: All solid ingredients are first driven through a sieve of 0.6mm mesh size. Then the active ingredient, the lactose, the talc, the magnesium stearate and half of the starch are mixed. The other half of the starch is suspended in 40 ml of water and this suspension is added to a boiling solution of polyethylene glycol in 100 ml of water. The obtained starch pulp is added to the bulk and the mixture is granulated, if necessary adding water. The granules are dried overnight at 35 °, driven through a sieve with 1.2 mm Masci.enweite and pressed on both sides concave tablets of about 6mm diameter.

Example 11

Tablets containing 50 mg of the active ingredient, e.g. B. N- | 2- (chroman-3-yl) ethyl-N- (2-methoxycarbonylethyl) -amine hydrochloride are prepared as follows:

Composition (for 10000 tablets): 500.00 g active substance 140.80 g lactose 274.70 g potato starch 10.00 g stearic acid 50.00 g talc 2.50 g magnesium stearate 32.00 g Colloidal silica q.s. ethanol

A mixture of the active ingredient, the lactose and 194.70 g of potato starch is moistened with an ethanolic solution of stearic acid and granulated through a sieve. After drying, the remainder of the potato starch, talc, magnesium stearate and colloidal silica are mixed, and the mixture is compressed into tablets of 0.1 g each, which may, if desired, be provided with partial grooves for finer dosage adjustment. In an analogous manner, 100 mg of active ingredient can be incorporated.

Example 12

Capsules containing 0.025 g of the active ingredient, e.g. N- [2- (chroman-3-yl) ethyl] -N- (2-methoxycarbonylethyl) amine hydrochloride can be prepared as follows:

Composition (for 1000 capsules):

Active ingredient 25.00 g

Lactose 249.00 g

Gelatin 2.00 g

Cornstarch 10.00 g

Talc 15.00 g

Water q.s.

The active substance is mixed with the lactose, the mixture is moistened evenly with an aqueous solution of gelatin and granulated through a sieve with a mesh size of 1.2 to 1.5 mm. The granules are mixed with the dried corn starch and the talc and filled with portions of 300 mg in hard gelatin capsules (size 1) from.

Example 13

In a manner analogous to those described in Examples 10 to 12, it is also possible to prepare pharmaceutical preparations containing as active ingredient another compound of the formula I or a pharmaceutically acceptable salt thereof, for example according to Examples 1 to 9.

Claims (33)

1. A process for the preparation of Benzooxacycloalkyl-substituted amino acid derivatives of the formula Ik-N-CH ₀ CH ₀ -R ₁
ι c. 2 1 wherein R _{1 is} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N, N-di-lower alkylcarbamyl or optionally acylated hydroxymethyl, R _{3 is} hydrogen or lower alkyl, alk is lower alkylene or lower alkylidene, ring A is unsubstituted or mono- or polysubstituted by hydroxy, lower alkoxy , Lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl, and either X and Y are each an oxygen atom and η is 1 or X is a methylene group, Y is an oxygen atom and η is 1 or X is an oxygen atom, Y is a methylene group and η is 1 or X is a direct bond, Y is an oxygen atom and η is 2, with the proviso that in compounds of the formula I in which the ring A is unsubstituted, X and Y are each oxygen, η is 1 and R _{3 is} hydrogen, alk is different from methylene when R _{1 is} carbamyl or N-methyl, N-Aet hyl-, Ν, Ν-dimethyl- or Ν, Ν-Diäthylcarbamyl, or a salt thereof, characterized in that
a) Compounds of the formulas (VIIIb) wherein one of the radicals Z ₁ and Z _{2 is} reactive esterified hydroxy, the other amino and Z _{3 is} hydrogen or Z _{1 is} amino and Z ₂ and Z ₃ together represent an additional bond, or optionally salts of these compounds with one another or b) in one Compound of the formula '^, /' ^ Y ^ ² VXaIk-N-CH ₂ CH ₂ -X ₆ wherein Xe represents a convertible into R ₁ radical, or a salt thereof Χβ in R ₁ above and, if desired, respectively a method according to, or obtainable in other ways compound I into another compound of the form ^'1' I, respectively A method according mixture of isomers obtainable in the Separates components, each ent in accordance with the procedure available Enantiomeren- or diastereomeric mixture splits into the enantiomers or diastereomers and / or in each case a process according to available free compound I converted into a salt or a salt according to the process converts into the free compound I or into another salt. 2. The method according to claim 1, characterized in that a compound of formula I is prepared wherein R _{1 is} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or Ν, Ν-Diniederalkylcarbamyl, R _{3 is} hydrogen or lower alkyl, alk lower alkylene or lower alkylidene the ring A is unsubstituted or mono- or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and η is 1 with the proviso that in compounds of formula I wherein the ring A is unsubstituted, X and Y are each oxygen, η is 1 and R _{3 is} hydrogen, alk is different from methylene when Ri is carbamyl or N-methyl -, N-ethyl, Ν, Ν-dimethyl or N ₁ N-Diäthylcarbamyl, or a salt thereof. 3. The method according to claim 1, characterized in that a compound of formula I is prepared in which R _{1 is} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N, N-di-lower alkylcarbamyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, R _{3 is} hydrogen or lower alkyl, alk lower alkylene, which links the ring system with the drawn in formula I NH group by up to and 3 C atoms, or lower alkylidene, the ring A is unsubstituted or one, two or more times Hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl and either X and Y are each an oxygen atom and η is 1 or X is a methylene group, Y is an oxygen atom and η is 1 or X is an oxygen atom, Y is a methylene group and η is 1 or X is a direct bond, Y is an oxygen atom and η is 2, with the proviso that in compounds of formula I wherein the ring A is unsubstituted, X and Y jewe.is oxygen, η is 1 and R _{3 is} hydrogen, alk is different from methylene when R _{1 is} carbamyl or N-methyl, N-ethyl, Ν, Ν-dimethyl or Ν, Ν-diethylcarbamyl, or a salt thereof. 4. The method according to claim 1, characterized in that a compound of formula I is prepared wherein Ri is carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or Ν, Ν-Diniederalkylcarbamyl, R _{3 is} hydrogen or lower alkyl, alk lower alkylene, which is the Ping system with the drawn in formula I NH group linked by up to 3 C atoms, or lower alkylidene, the ring A is unsubstituted or mono-, di- or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or Trifluoromethyl is substituted, X is an oxygen atom or a methylene group represents '' an oxygen atom and η is 1, with the proviso that in compounds of formula I, wherein the ring A is unsubstituted, X and Y are each oxygen, η for 1 and R _{3 is} hydrogen, alk is different from methylene, if Ri is carbamyl or N-methyl, N-ethyl, Ν, Ν-dimethyl or Ν, Ν-diethylcarba means myl, or a salt thereof. 5. The method according to claim 1, characterized in that a compound of formula I is prepared wherein R _{1 is} carboxy, hydroxymethyl, C ^ CB alkanoyloxymethyl, C ₁ -C ₄ alkoxycarbonyl or carbamyl, R _{3 is} hydrogen or C ₁ -C ₄ -AlkYl is, alkfürC ^ d-alkylene, which is the ring system with the attached in formula I NH-Gn: ppe connected by up to and with 3 C-atoms, the ring A is unsubstituted or, in particular in the 7-position, by C ₁ -C ₄ -alkoxy is substituted and either X and Y are each an oxygen atom and η is 1 or X is a methylene group, Y is an oxygen atom and η is 1 or X is an oxygen atom, Y is a methylene group and η is 1 or X is a direct bond, Y is an oxygen atom and η is 2, with the proviso that in compounds of formula I wherein the ring A is unsubstituted, X and Y are each oxygen, η is 1 and R ₃ hydrogen ff, alk is different from methylene when R _{1 is} carbamyl, or e ^? salt of it. 6. The method according to Ans, ji u h h 1, characterized in that a compound of formula I is prepared wherein R _{1 is} Cr-Gj-alkoxycarbonyl, R _{3 is} hydrogen and C ₁ -C ₄ -AlkYl, alk for C is C 1 -C 4 alkylene, which links the ring system with the NH group drawn in formula I by up to and with 3 C atoms, is unsubstituted, ring A is an oxygen atom or a methylene group, Y is an oxygen atom and η is 1, or a salt thereof. 7. The method according to claim 1, characterized in that a compound of formula I is prepared wherein R _{1 is} dC ^ alkoxycarbonyl, R _{3 is} hydrogen, alk is methylene or ethylene, the ring A is unsubstituted, X is an oxygen atom or a Represents methylene group, Y represents an oxygen atom and η is 1, or a salt thereof. 8. The method according to claim 1, characterized in that one prepares N- (2- (chroman-3-yl) ethyl) -N- (2-methoxycarbonyläthyl) amine or a salt thereof. 9. The method according to claim 1, characterized in that one prepares N- (2-Mothoxycarbonyläthyl) -N- (benzo-1,4-dioxan-2-ylmethyl) -amine or a salt thereof. 10. The method according to claim 1, characterized in that one prepares N- (2-methoxycarbonylethyl) -N- (chroman-3-ylmethyl) -amine or a salt thereof. 11. The method according to claim 1, characterized in that one prepares N- (2- (benzo-1,4-dioxan-2-yl) ethyl) -N- (2-methoxycarbonyläthyl) amine or a salt thereof. 12. The method according to claim 1, characterized in that one prepares N- (2-methoxycarbonylethyl) -N- (2-methyl-benzo-1,4-dioxan-2-ylmethyl) -fimin or a salt thereof. 13. The method according to claim 1, characterized in that one prepares N- (2- (chroman-3-yl) ethyl) -N- (2-carboxyäthyO-amine or a salt thereof. 14. The method according to claim 1, characterized in that one prepares N- (2- (chroman-2-yl) ethyl) -N- (2-methoxycarbonyläthyl) amine or a Saiz thereof. 15. The method according to claim 1, characterized in that one prepares N- (2- (chroman-4-yl) ethyl) -N- (2-methoxycarbonyläthyl) amine or a salt thereof. 16. A compound of the formula alk-N-CH ₂ CH ₂ -Ri wherein R _{1 is} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Din-di-lower alkylcarbamyl or optionally acylated hydroxymethyl, R _{3 is} hydrogen or lower alkyl, alk is lower alkylene or lower alkylidene, the ring A is unsubstituted or mono- or polysubstituted by hydroxy, lower alkoxy , Lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl, and either X and Y are each an oxygen atom and η is 1 or X is a methylene group, Y is an oxygen atom and η is 1 or X is an oxygen atom, Y is a methylene group and η is 1 or X is a direct bond, Y is an oxygen atom and η is 2, with the proviso that in compounds of the formula I in which the ring A is unsubstituted, X and Y are each oxygen, η is 1 and R _{3 is} hydrogen, alk is different from methylene, when R _{1 is} carbamyl or N-methyl, N- Aethyl, Ν, Ν-dimethyl or Ν, Ν-diethylcarbamyl, or a salt thereof. 17. A compound according to claim 16 of the formula I in which R _{1 is} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or Ν, Ν-di-lower alkylcarbamyl, R _{3 is} hydrogen or lower alkyl, alk is lower alkylene or lower alkylidene, the ring A is unsubstituted or or is polysubstituted by hydroxy, niaderalkoxy, lower alkanoyloxy, halogen, lower alkyl, or trifluoromethyl, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and η is 1, with the proviso that in compounds of the formula I in which Ring A is unsubstituted, X and Y are each oxygen, η is 1 and R _{3 is} hydrogen, alk is different from methylene, when R ₁ carbamyl or N-methyl, N-ethyl, Ν, Ν-dimethyl or Ν, Ν-diethylcarbamyl, or a salt thereof. 18. A compound according to claim 16 of the formula I, wherein R _{1 is} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν-di-lower alkylcarbamyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, R _{3 is} hydrogen or lower alkyl, alk lower alkylene which connects the ring system with the NH group drawn in formula I by up to and with 3C atoms, or lower alkylidene, the ring A is unsubstituted or monosubstituted, disubstituted or polysubstituted by hydroxyl, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or either trifluoromethyl and X and Y are each an oxygen atom and η is 1 or X is a methylene group, Y is an oxygen atom and η is 1 or X is an oxygen atom, Y is a methylene group and η is 1 or X is is a direct bond, Y represents an oxygen atom and η is 2, with de r proviso that in compounds of the formula I in which the ring A is unsubstituted, X and Y are each oxygen, η is 1 and R _{3 is} hydrogen, alk is different from methylene, if R _{1 is} carbamyl or N-methyl, N-ethyl, Ν, Ν-dimethyl or Ν, Ν-diethylcarbamyl, or a salt thereof. -4- 291 5B5 19. A compound according to claim 16 of formula I, wherein Ri is carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or Ν, Ν-Diniederalkylcarbamyl, R _{3 is} hydrogen or lower alkyl, alk lower alkylene, which is the ring system with the drawn in formula I. NH Group through to and with 3C ^: atoms attached, or lower alkylidene, the ring A is unsubstituted or mono-, di- or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl, X is an oxygen atom or a Represents methylene, Y is an oxygen atom and η is 1, with the proviso that in compounds of formula I wherein the ring A is unsubstituted, X and Y are each oxygen, η is 1 and R3 is hydrogen, alk of methylene is different when Ri is carbamyl or N-methyl, N-ethyl, Ν, Ν-dimethyl or N, N-diethylcarbamyl, or a salt thereof. 20. A compound according to claim 16 of the formula I, wherein R _{1 is} carboxy, hydroxymethyl, C ₂ -C ₅ alkanoyloxymethyl, Ci-C ^ alkoxycarbonyl or carbamyl, R _{3 is} hydrogen or C ₁ -C ₄ alkyl, alk for C, -C ₄ -alkylene, which links the ring system with the NH group drawn in formula I by up to and with 3 C atoms, the ring A is unsubstituted or, in particular in the 7-position, by C ₁ -C ₄ -AlkOXy is substituted and either X and Y each represent an oxygen atom and η is 1 or X represents a methylene group, Y is an oxygen atom and η is 1 or X represents an oxygen atom, Y is a methylene group and η is 1 or X is is a direct bond, Y is an oxygen atom and η is 2, with the proviso that in compounds of formula I wherein the ring A is unsubstituted, X and Y are each oxygen, η is 1 and R _{3 is} hydrogen , alk is different from methylene, w when R _{1 is} carbamyl, or a salt thereof. 21. A compound according to claim 16 of the formula I, in which R _{1 is} C ₁ -C ₄ -alkoxycarbony I, R _{3 is} hydrogen or C ₁ -C ₄ -alkyl, alk is C ₁ -C ₄ -alkyl, which is the Ring system with the drawn in formula I NH group linked by up to and 3 C atoms, is, the ring A is unsubstituted, X is an oxygen atom or a methylene group, Y is an oxygen atom and η is 1, or a salt thereof , 22. A compound according to claim 13 of the formula I, wherein R _{1 is} C ₁ -C ₄ -alkoxyCaTbOnYl, R _{3 is} hydrogen, alk is methylene or ethylene, the ring A is unsubstituted, X represents an oxygen atom or a methylene group, Y is an oxygen atom and η is 1, or a salt thereof. 23. N- [2- (chroman-3-yl) ethyl] -N- (2-methoxycarbonylethyl) -amine or a salt thereof. 24. N- (2-Methoxycarbonylethyl) -N- (benzo-1,4-dioxan-2-ylmethyl) -amine or a salt thereof. 25. N- (2-Methoxycarbonylethyl) -N- (chroman-3-ylmethyl) -amine or a salt thereof. 26. N- [2- (benzo-1,4-dioxan-2-yl) ethyl] -N- (2-methoxycarbonylethyl) -amine or a salt thereof. 27. N- (2-Methoxycarbonylethyl) -N- (2-methyl-benzo-1,4-dioxan-2-ylmethyl) -amine or a salt thereof. 28. N- [2- (chroman-3-yl) ethyl] -N- (2-carboxyethyl) -amine or a salt thereof. 29. N ^ -chromanyoxyethyl-N, N-methoxycarbonylethoxyamine or a salt thereof. 30. N- [2- (chroman-4-yl) ethyl] -N- (2-methoxycarbonylethyl) -amine or a salt thereof. 31. A pharmaceutical preparation containing as active ingredient a compound according to any one of Claims 16 to 30 of the formula I or a compound of the formula I obtainable according to one of Claims 1 to 15 or in each case a pharmaceutically acceptable salt thereof, optionally in addition to customary pharmaceutical excipients. 32. A process for the preparation of a pharmaceutical preparation according to claim 31, characterized in that the active ingredient, optionally together with conventional pharmaceutical excipients, processed into a pharmaceutical preparation. 33. Use of a compound according to any one of claims 16 to 30 of the formula I or a obtainable according to any one of claims 1 to 15 compound of formula I or each of a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical preparation, for. B. a nootropic.