DD279674A5 - PROCESS FOR PREPARING HYDROGENATED 1-BENZOOXACYCLOALKYL-PYRIDINCARBONE ACID COMPOUNDS - Google Patents

Abstract

Novel hydrogenated 1-benzooxacycloalkylpyridinecarboxylic acid compounds of the formula <IMAGE> in which either R1 denotes carboxyl, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N,N-dilower alkylcarbamyl or optionally acylated hydroxymethyl and R2 denotes hydrogen, an optionally etherified or acylated hydroxyl group or an optionally acylated amino group or R1 denotes hydrogen and R2 represents carboxyl, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N,N-dilower alkylcarbamyl or optionally acylated hydroxymethyl, R3 denotes hydrogen or lower alkyl, alk denotes lower alkylene or lower alkylidene, the ring A is unsubstituted or mono- or polysubstituted by hydroxyl, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or trifluoromethyl, the dashed line is intended to express that a single bond or a double bond is present and either X and Y in each case denotes an oxygen atom and n represents 1 or X represents a methylene group, Y denotes an oxygen atom and n represents 1 or X represents an oxygen atom, Y denotes a methylene group and n represents 1 or X represents a direct bond, Y represents an oxygen atom and n represents 2, and their tautomers and/or salts are described. These compounds can be used as pharmaceutical active substances and can be prepared in a manner known per se.

Description

Explanation of the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

According to the invention, hydrogenated new I-Benzooxacycloalkylpyridincarbonsäureverbindungen the formula

> \ A / ^R3

in which either Ri is carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Din-di-lower alkylcarbamyl or optionally acylated hydroxymethyl and R _{2 is} hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylin amino group or R _{1 is} hydrogen and R _{2 is} Carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν-di-lower alkylcarbamyl or optionally acylated hydroxymethyl, R _{3 represents} hydrogen or lower alkyl, alk represents lower alkylene or lower alkylidene, ring A is unsubstituted or mono- or polysubstituted by hydroxy, N'-alkoxy, Lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl, which is intended to indicate the dotted line having a single or double bond and either X and Y are each oxygen and η is 1 or X is methylene, Y is Oxygen atom and η f r is 1, or X represents an oxygen atom, Y sine methyl group, and η represents 1, or X represents a direct bond, Y represents an oxygen atom, and η is 2, with the proviso that R ₂ of carbamyl is different, when Ri Is hydrogen, R _{3 is} hydrogen, alk is methylene, ethylene or 1,3-propylene, the ring A is unsubstituted or monosubstituted in the 6- or 7-position or disubstituted in 6- and 7-Ste! Ment, wherein the substituents of the group consisting of lower alkoxy, halogen, lower alkyl and trifluoromethyl, which is intended to express the dashed line, that between the carbon atoms carrying the substituents R, and R ₂ , a single bond, X and Y each represents an oxygen atom and η is 1 or when R _{1 is} hydrogen, R _{3 is} hydrogen, alk is ethylidene, ring A is unsubstituted, dashed line indicates that between the carbons fatomen, which carry the substituents Ri and R ₂ , a single bond is present, X and Y are each an oxygen atom and η is 1, and their tautomers and / or salts prepared. Furthermore, the invention relates to the use of the mentioned compounds of formula I, their tautomers and / or salts and a process for the preparation of pharmaceutical compositions containing one of the mentioned compounds of formula I or a tautomer and / or a pharmaceutically acceptable salt thereof.

Etherified hydroxy R ₂ is, for example, lower alkoxy or optionally substituted phenyl-lower alkoxy. Acyl in acylated hydroxymethyl R ₁ or R ₂ and in acylated hydroxy or acylated amino R ₂ is for example derived from an organic carboxylic or sulfonic acid 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 compounds of the formula I in which R _{1 is} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or N, N-di-lower alkylcarboxym, R _{2 is} hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group, R _{3 is} hydrogen or lower alkyl, aik 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, which is intended to indicate the dashed line that a simple or a double bond, X is an oxygen atom or a methylene group, Y is an oxygen atom and η is 1, their tautomers and / or salts, the use of these compounds and a process for the preparation of pharmaceutical compositions containing such a compound of formula I od a tautomer and / or a pharmaceutically acceptable salt thereof. Tautomeric forms of compounds of formula I exist for. B. when R _{2 is} hydroxy or amino and the dashed line is to express that a double bond is present. That is, the enols or enamines of the formula I are in equilibrium with the corresponding keto or ketimine tautomers of the formula

AA s ^R >

"i i

alk-N ^

wherein R _{2 is} oxo or imino. Representatives of both tautomeric forms can be isolated. The compounds of formula I may also be in the form of stereoisomers. Since the compounds of the formula I have at least one chiral carbon atom (C atom) (for example the carbon atom having the radical R ₃ ), they can, for example, For example, as pure enantiomers or enantiomer mixtures, such as racemates, and, if at least one further chiral center (e.g., as the atom a 4-substituted C4 Piperidinrestes and / or the C atom ₃ of a 3-substituted Piperidinrestes) is still present, and are present as diastereomers, diastereomer mixtures or racemate mixtures. So can

For example, with respect to R ₁ and R ₂ geometric isomers, such as cis- and trans-isomers formed, if Ri and R ₂ are different from hydrogen.

Salts of compounds of formula I hzw. their tautomers are in particular corresponding acid addition salts, preferably pharmaceutically acceptable acid addition salts. This we. For example, with strong inorganic acids such as mineral acids, eg. Sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids such as lower alkanecarboxylic acids, e.g. Acetic acid, such as optionally unsaturated dicarboxylic acids,

z. As malonic, maleic or fumaric acid, or as hydroxycarboxylic acids, eg. As tartaric acid or citric acid, or with sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acids, eg. As methane or p-toluenesulfonic acid formed.

For example, when R ₁ or R ₂ is 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 Triniederalkylamine, such as Hydroxiliederalkylamine, z. B. mono-, di- or

Trihydroxy-lower alkylamines, hydroxy-lower alkyl-lower alkyl-amines or polyhydroxy-lower alkylamines. Are cyclic amines

z. As 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 hydroxy-lower alkylamines are ζ. β. Mono-, di- or triethanolamine, and Hydroxyniederalkyl-lower alkyl amines are z. B. Ν, Ν-dimethylamino or N, N-diethylamino-ethanol, as Polyhydroxyniederalkylamin z. As 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 Forrr el I and their pharmaceutically acceptable salts.

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

Lower alkoxy is z. B. C ₁ -C ₄ -Akoxy, such as methoxy, ethoxy, n-propyloxy, isopropyioxy, n-butyloxy, isobutyloxy and tert-butyloxy.

Lower alkyl is z. B. C _: -C ₄ -AlkVl, such as methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl or tert-butyl and further comprises C ₅ -C ₇ -AlkVl-, d · '· Pentyl, hexyl or heptyl radicals.

Lower alkyl alk is z. B. C ₁ -C _t -alkylene, which bridges the two ring systems in the first place by up to and with 3 C-atoms, and identify, for example, methylene, Aetiiylen 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 bridge the two ring systems by 4 C-atoms, ie represent 1,4-butylene.

Niedoralkyliden alk is for example C | -C ₄ alkylidene and may, for. As methylene, ethylidene, 1,1- or 2,2-propylidene or 1,1- or 2,2-butylidene.

Lower alkanoyl is z. As Cr-C ₅ alkanoyl, such as acetyl, propionyl, butyryl, isobutyryl or pivaloyl.

Lower alkanoyloxy is e.g. B. C ^ s-alkanoyloxy, such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy.

Lower alkoxycarbonyl is z. As Cr-Cs-alkoxycarbonyl, such as methoxy, ethoxy n-propyloxy, Isopropyioxy-, n-butyloxy, isobutyloxy or tert-butyloxycarbonyl.

N-lower alkylcarbamyl is e.g. N-Ci-CrAlkylcarbamyl, such as N-methyl, N-ethyl, N- (n-propyl) -, N-isopropyl, N- (n-butyl) -, N-isobutyl - or N-tert. -Butylcarbamyl.

Ν, Ν-Diniederalkylcarbamyl is z. B. N, N-di-C, -CrAlkylcarbamyl, wherein each of the two N-alkyl groups may be the same or different, such as Ν, Ν-dimethyl, N, N-diethyl, Ν, Ν-diisopropyl- or N- butyl-N-methylcarbamyl.

Optionally substituted phenyl-lower alkoxy is e.g. B. optionally substituted in the phenyl moiety phenyl-C, -C ₄ alkoxy, such as benzyloxy, p-chlorobenzyloxy, 1-Phenyläthoxy or 1- (p-bromophenyl) -n-butyloxy.

Optionally substituted benzoyl is e.g. Benzoyl, p-chlorobenzoyl or p-nitrobenzoyl.

Lower alkanesulfinyl ϊε. ζ. B. Ci-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 formula 1 their tautomers and / or their pharmaceutically acceptable salts have, for example, valuable pharmacological, in particular nootropic. Properties on. So they cause z. In the two-compartment passive avoidance test model according to Mondadori and Classen, Acta Neurol. Scand. 69, Suppl. 99, 125 (1984) at doses above about 0.1 mg / kg i. p. as well as p.o. in the mouse a reduction of 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.

Accordingly, the compounds of formula I or their tautomers and / or their pharmaceutically acceptable salts as pharmaceuticals, for. As 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 thus the use of compounds of formula I, their tautomers and / or their pharmaceutically acceptable salts for the preparation of medicaments, in particular nootropics, for the treatment of cerebral Insuffizienzerscheinungen, in particular memory disorders. The commercial sealing of the active substances may also be included

The invention relates in the first place to a process for the preparation of compounds of the formula I wherein, taking into account the abovementioned proviso, either R _{1 is} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν-di-lower alkylcarbamyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulphonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl and R _{2 is} hydrogen, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, lower alkanesulfonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino, lower alkanesulfonylamino, benzoylamino or pyridoylamino, or R _{1 is} hydrogen and R _{2 is} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkyicarbamyl , Ν, Ν-Diniederalkylcarbamyl, hydroxymethyl, Niederalkanoyloxymethyl, Niederalkansulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, R _{3 is} hydrogen or lower alkyl, alk lower alkylene, which bridges the two ring systems by up to and with 3 C-atoms, or N lower alkylidene, the ring A is unsubstituted or monosubstituted, disubstituted or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl, which is intended to indicate the dashed line that a single or a double bond is present and either X and Y are each an oxygen atom and η is 1 or X is a methylene group, Y is

Is oxygen 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, for example a process for the preparation of compounds of formula I. wherein Ri is carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or Ν, Ν-Diniederalkylcarbaniyl, R _{2 is} hydrogen, hydroxy, lower alkoxy, benzyloxy, ι liederalkanoyloxy, Niederalkansulfonyloxy, benzoyloxy, pyridoyloxy, amino, Niederalkanoylamino, benzoylamino or pyridoylamino, Ra is hydrogen or Niedei alkyl, alk lower alkylene, which bridges the two ring systems by up to and with 3 C atoms, or lower alkylidene, the ring A is unsubstituted or mono-, di- or polysubstituted hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and or trifluoromethyl, which is intended to express the gestri - helte X is an oxygen atom or a methylene group, Y is an oxygen atom and η is 1, and their tautomers and / or salts. The invention relates above all to a process for the preparation of compounds of the formula I in which either R | C, -C ₄ alkoxycarbonyl, such as methoxy or ethoxycarbonyl, carbamyl, hydroxyethyl or C ₂ -C ₅ alkanoyloxymethyl, such as acetoxymethyl, and R _{2 is} hydrogen or hydroxy or R, is hydrogen and R _{2 is} Ci-Ci Alkoxycarbonyl, such as ethoxycarbonyl, Ra is hydrogen or C 1 -C ₄ -alkyl, such as methyl, alk for C 1 -C ₄ -alkylene, which bridges the two ring systems by up to and with 3 C atoms, such as methylene or Aethylene, the ring A is unsubstituted or, in particular in the 7-position, by C, -C ₄ alkoxy, such as methoxy, is substituted, the dashed line ^- 'm to express that a single or a double bond is present, and each of χ and Y is 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 stands, Y an oxygenato m and η is 2, for example a process for the preparation of compounds of formula I, wherein R, Ci-Cj-alkoxycarbonyl, such as methoxycarbonyl, R _{2 is} hydrogen or hydroxy, R _{3 is} hydrogen or C | -C ₄ - Alkyl, such as methyl, alk for ^ -C ^ alkylene, which bridges the two R.'ng systems by up to and with 3 C atoms, such as methylene or ethylene, is unsubstituted, the ring A, the dashed line to express Brinjen is intended to be a single or a double bond, X is an oxygen atom or a methylene group, Y is an oxygen atom and η is 1, and their tautomers and / or salts.

More particularly, the invention relates to a process for the preparation of compounds of the formula I in which R _{1 is} Ci-Cj-alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, R _{2 is} hydrogen or hydroxy, R _{3 is} hydrogen, alk is methylene or ethylene, the ring A is unsubstituted, the dotted line is intended to express that a single or a double bond is present, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and η is 1, and their tautomers and / or salts.

The invention relates first and foremost to a process for the preparation of compounds of the formula I in which R 1 is C 1 -C 4 -alkoxycarbonyl, such as methoxycarbonyl, R _{2 is} hydrogen, R _{3 is} hydrogen, alk is methylene or ethylene, ring A is unsubstituted, the dotted line is intended to express that a single or double bond is present, X is an oxygen atom or a methylene group, Y is an oxygen atom and π is 1, or wherein Ri Ci-C ^ alkoxycarbonyl, such as methoxycarbonyl, R _{2 is} hydroxy, R _{3 is} hydrogen, alk is methylene, the ring A is unsubstituted, the dashed line is intended to express that a double bond is present, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and η is 1, and in each case their Tautomeran and / or salts.

The invention relates in particular to a process for the preparation of the novel compounds of the formula I and their tautomers and / or salts mentioned in the examples.

The process of the present invention for the preparation of compounds of formula I, their tautomers and / or their salts is e.g. Example, characterized in that a) a compound of formula

(Ma),

or a salt thereof, wherein X, hydroxy or reactive esterified hydroxy, with a compound of the formula

• - ·

HK ^V «-R ₂

a tautomer and / or salt thereof or b) in a compound of the formula

alk-N ^

a tautomer and / or salt thereof, in which X _{2 is} a radical convertible into hydrogen R ₁ and X _{5 is} a radical R ₀ , where R _{a is} hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group, X ₂ converted to hydrogen different Ri or more compound of formula III wherein X ₂ is hydrogen and X ₅ a can be converted into R _b radical, wherein R _b is a other than a radical R _a R _2, X ₅ in R _b transferred or

c) for preparing a compound of formula I, a tautomer and / or salt thereof, wherein R _{2 is} hydroxy or amino, ur.d wherein R _{1 is} other than hydrogen and in particular Niederaikoxycarbonyi means, a compound of the formula

(IV),

\ / s / " ^{z /} n \ -CH ₂ -Y ₁

alk-N ^

--CH ₂ R ₁

wherein Y _{1 represents} a group of the formula -CH = Rj, -C (Y ₂ I = R ₂ , -CH (Y ₂ IR ₂ or cyano, wherein R _{2 is} oxo or imino and Y _{2 represents} a cleavable radical, or a Salt thereof cyclized or

d) for the preparation of a compound of formula Γ, a tautomer and / or salt thereof, wherein R _{2 is} oxo or imino and the dashed line zl · η means expressing that a single bond is present, and wherein R _{1 is} different from hydrogen and in particular Niederaikoxycarbonyi means a compound of the formula

y \ .A / ^Rl

(Va)

or a tautomer or a salt thereof with a compound of the formula

X ₃ -R ₁ (Vb),

or a salt thereof, wherein R ₁ is other than hydrogen and X _{3 is} halogen or lower alkoxy, or e) for the preparation of a compound of formula I, a tautomer and / or salt thereof, wherein R _{2 is} an optionally etherified or acylated hydroxy group or an optionally acylated amino group, in a compound of the formula

(Vl),

\ .A / ^H2 "

or a salt thereof, wherein X ₄ is a radical that can be converted into R ₂ group, X ₄ is converted into R _2, or f) uiner particular for producing compound of formula I, a tautomer and / or salt thereof, wherein R ₂ of etherified or acylated hydroxy , is different from acylated amino and acylated hydroxymethyl, a compound of the formula

AÄ / ^Rl

® alk-N ^

wherein Α ^{Θ is} the anion of an acid and R ' _{2 is} hydrogen, etherified, esterified or protected hydroxy or acylated or protected amino or carboxy, Niederaikoxycarbonyi, carbamyl, N-lower alkylcarbamyl, N, N-di-lower alkylcarbamyl or etherified, acylated or protected hydroxymethyl that reduces excess double bonds to single bonds or

g) for preparing a compound of formula I, a tautomer and / or salt thereof, wherein R _{2 is} carboxy, carbamyl, N-lower alkylcarbamyl, Ν, Ν-di-lower alkylcarbamyl or in particular Niederaikoxycarbonyi, a compound of formula

(VIII)

alk-κ'CH2-R2

^X. -CH (Y ₂ ) -Ri

in which Y 2 is a cleavable radical, or a salt thereof is cyclized and in each case splits off an optionally present protective group and, if desired, a process according or otherwise obtainable compound of formula I converted into another compound of formula I, in each case a method according to the invention obtainable isomer mixture in the components separates, in each case an enantiomer or diastereomer mixture obtainable by the process into the enantiomers or diastereomers and / or converts in each case a free available compound of the formula I into a salt or a salt obtainable according to the process into the free compound of the formula I or into another Salt is converted.

Dio reactions described above and below in the variants are carried out in a conventional manner, for. B.

in Ab- or usually in the presence of a suitable solvent or diluent or a mixture thereof, wherein, as required, with cooling, at room temperature or with heating z. Example, in a temperature range of about -10 ° to the boiling temperature of the reaction medium, preferably from about 20 ° to about 150 ⁰ C, and, if necessary, working in a closed vessel, under pressure, in an inert gas atmosphere and / or under anhydrous conditions ,

The above and below listed starting material of the formulas Il a and Il b. III, IV, Va and Vb, Vl, VM jnd VIII, which was developed for the preparation of the compounds of formula I, their tautomers and acids, 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. Example, in the form of acid addition salts, for example with the abovementioned acids, while starting compounds with acidic groups, salts with bases, for. B. of the aforementioned type can form. Furthermore, starting compounds in the form of tautomers may be present, in particular in the case of compounds of the formula Mb, when R _{2 is} hydroxyl and the dashed line is intended to indicate that a double bond is present.

Option A):

Reactive esterified hydroxy means especially with a strong inorganic acid or organic sulfonic acid esterified hydroxy, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, haloculfonyloxy, z. For example, fluorosulfonyloxy, optionally, z. B. by halogen, substituted Niederalkansulfonyloxy, z. B.

Methane or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g. B. cyclohexanesulfonyloxy, or optionally, for. B. by lower alkyl or halogen, substituted benzenesulfonyloxy, z. For example, p-bromophenyl or p-toluenesulfonyloxy.

The N-alkylation is carried out in particular in the presence of a condensing agent, such as a suitable base. Examples of suitable bases are alkali metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylidene, lower alkylamides, -aminoloweralkylaminde or lower alkylsilylamides, naphthalenamine, lower alkylamine, 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, dimethylaminonapthalene, di - or triethylamine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and IS-diaza-bicyclolBAOlundec-S-ene (DBU) called.

The starting materials of the formulas Ma and Mb are known in some cases or can be prepared in analogy to the known starting materials.

Variant b):

A radical X _{2 which can be passed} over into hydrogen Ri or a radical X _{5 which} can be converted into a radical R _b is, for example, a functionally modified carboxy other than R 1 or R _b , such as cyano, anhydrided carboxy, optionally substituted amidino, optionally esterified or anhydridised carboximidoyl , esterified or amidated carboxy, tri-lower alkoxy or trihalomethyl, other than esterified or amidated carboxy R i.

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 alkanoyloxycarbonyi, such as acetyloxycarbonyl, 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. ethylamidirio.

Under esterified 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.

Radicals R _b are, for example, carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν-di-dirkylalkylcarbamyl or optionally acylated hydroxymethyl radicals R ₇ .

For example, X ₂ can be converted into Ri other than hydrogen by solvolysis, just as X _{5 can be converted,} for example, by solvolysis, into a radical R _b . Solvolysemittel are, for example, water, the desired esterified carboxy Ri or R ₂ corresponding lower alkanols, ammonia or the desired amidated carboxy group Ri or R ₂ corresponding amines. The treatment with a corresponding solvolysis agent is optionally carried out in the presence of an acid or base. As acids, for example, inorganic or organic protic acids, such as mineral acids, eg. For example, sulfuric acid or hydrohalic acids, such as hydrochloric acid, such as sulfonic acids, for example, lower alkane or optionally substituted benzenesulfonic acid, beispielsweisu 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 the solvolysis, the cyano group, anhydrided carboxy, optionally substituted amidines optionally vsrestertes or

anhydridized carboximidoyl, esterified or amidated carboxy, tri-lower alkoxy or Trihalogenmethyi of carboxy or esterified or amidated carboxy Ri or R ₂ hydrolyzed to carboxy. In this case, optionally located on the ring A Niederalkanoyloxyreste be hydrolyzed in the course of the hydrolysis to hydroxy.

Cyaiio, anhydridized carboxy, esterified or amidated carboxy other than esterified or amidated carboxy Ri or R ₂ are, for example, alcoholysed with a suitable lower alkanol to esterified carboxy Ri or R ₂ and cyano and anhydridized carboxy, for example with amrone or an amidated carboxy R ₍ or R ₂ corresponding amine ammono- or ar.iinolysiert.

The starting material of formula II, for example, in analogy to the manner described under variant a) by reacting a compound of formula

(Ha),

with a compound of the formula

(IIIa)

a tautomer and / or salt thereof in the presence of one of said bases.

Compounds of the formula III where worm X _{2 is} an R different from hydrogen ₍ meaning a convertible radical and X _{5 represents} hydroxy or amino, may advantageously also be obtained by cyclization of a compound of the formula

.AA / ³

(Jh ^ V- ^(IVg) '

^A A ^ \

Λ / \ / n \ --CH ₂ -Y ₁

-CH ₂ -X ₂

wherein Y ₁ e'ne group of the formula -CH = R ₂ , -C (Y ₂ I = R ₂ , -CH (Y ₂ JR ₂ or cyano, wherein R _{2 is} oxo or Immo, R _{2 is} hydroxy or amino and Y _{2 represents} a cleavable residue, or a salt thereof are prepared, wherein, for example, worked in an analogous manner as indicated under process variant c).

Variant c):

Cleavable radicals Y ₂ in groups de. Formula -C (Y ₂ I-Hi or -CH (Y ₂ JR ₂₎ are, for example, reactive esterified hydroxy groups such as hydroxy esterified with a strong anoic acid or organic sulfonic acid, for example halogen, such as chloro, bromo or iodo, sulfonyloxy, such as hydroxysulfonyloxy , Halosulfonyloxy, for example fluorosulfonyloxy, optionally substituted by halogen, for example, niaderalkarisulfonyloxy, for example methane or trifluoromethanesulfonyloxy, cyrloalkanesulfonyloxy, for example cyclohexanesulfonyloxy, or optionally, for example by lower alkyl or halogen, substituted bonsulosulfonyloxy, for example p-bromophenyl- or p-toluenesulfonyloxy, or rather etherified hydroxy groups, for example lower alkoxy or optionally substituted phenyl-lower-alkoxy.

The cyclization can be carried out, for example, in analogy to the Dieckmann reaction, in particular in the presence of one of the i'ntor of variant a) mentioned bases and with subsequent hydrolytic workup.

In a preferred embodiment, for example, a compound of the formula

alk-N CH = R

-CH ₂ -Ri

wherein R _{2 is} oxo or imino, the treatment with one of said bases, in particular with a Alkalimetallniederalkanolat, z. B. with Natriummethbnolat or Natriumäth jnolat subject. In this case, the compound IVa cycüsiert to a compound of formula I, wherein the dashed line indicates that no double bond. or R _{2 is} hydroxy or amino. Starting materials IVa be ?. 8. Obtained by using a reactive Alkvlesier of formula

(Mal, a Ik-Xi

wherein Xi is a reactive esterified hydroxy, with a compound of the formula H ₂ N-CH ₂ -CH ₂ -R, (IV b) and the resulting intermediate of the formula

.A.A / ·

(IVc),

with acrolein or an optionally functionally modified aldehyde of the formula Yi-CH ₂ -CH ₂ -CH = R ₂ (IVd; Yi = reactive esterified hydroxy, R ₂ = oxo or imino).

In another preferred embodiment of variant c) to cyclize a compound of formula IV, wherein Yi and Ri are lower alkoxycarbonyl, ie wherein Yi is a group of the formula -C (Y ₂ J = R ₂ in which R _{2 is} oxo and the cleavable radical Y ₂ as etherified hydroxy has a lower alkoxy group, to the corresponding compound of formula Γ, wherein R _{2 is} oxo.

For the preparation of the latter starting compounds of the formula IV can be, for example, compounds of the formula

/ \ A AA I

^ H ₂ ) \ ν '^ y η \

aIk-NH ζ

or whose salts go out, which z. B. are obtainable by reduction of the corresponding nitriles, and these with at least 2 moles of a compound of formula

• ^ ^X Rj (IVf),

to react.

Varianted):

The C-acylation according to the invention can be carried out in particular in the presence of one of the bases mentioned under variant a), but particularly advantageously by means of a metal base, such as lithium diisopropylamine or n-butyllithium, optionally in the presence of chlorotrimethylsilane.

The reaction of a compound of the formula

(Ha),

^ aIk-X ₁ with a compound of the formula

Hn () · = 0 (Vc).

• - ·

or a salt thereof in analogy to the N-alkylation according to variant a) in the presence of one of the bases mentioned to <'τη starting material of the formula Va

Variant e):

R ₂ convertible radicals X ₄ are, for example, by solvolysis, ie reaction with a compound of formula R ₂ H or a salt thereof, in a group R ₂ überführhare radicals, for example, reactive esterified hydroxy groups, such as halogen atoms, ζ. 8. Chlorine, bromine or iodine. In hydroxy R ₂ convertible radicals X ₄ are also diazonium groups, z. B. the formula -Ν ₂ ®Α ^Θ , wherein Α ^Θ the anion of a strong acid, such as a mineral acid, eg. As the chloride or sulfate, means. SolvOlyse in the usual manner, for example in the presence of a base such as an alkali metal or alkaline earth metal hydroxide, z. As sodium or potassium hydroxide, or a tertiary St: kstoff base, z. Example, a Triniederalkylamins, such as triethylamine, or a heteroaromatic nitrogen base, such as pyridine, or a quaternary ammonium hydroxide, such as benzyl-trimethyl-ammonium hydroxide, or ^r by the compound Vl a in the form of a metal salt, for. B. the formula R ₂ ®M® (Vl b), wherein Μ ^{Θ is} an alkali metal cation, such as the sodium ion, is used. Advantageously, one works in the presence of a solvent or diluent, for. Example, in a copyright of the Reaktionskc components Vl a and / or a miscible with this inert solvent, if necessary, with cooling or heating, for. D. in the temperature range of about ^{0 0} C to 120 ° C, and / or under inert gas, such as nitrogen.

The solvolysis of radicals X ₄ to form groups R ₂ can optionally be combined with the solvolytic conversion of solvolyzable groups R 1 into other groups R 1 according to the invention; for example, in the ammonolysis of radicals X ₄ to amino R ₂ , lower alkoxycarbonyl groups R 1 or other may also be added Carbamyl Ri solvolyzable groups Ri are simultaneously ammonolyzed to carbamyl groups Ri.

For the preparation of starting compounds of formula VI and salts thereof, for example, compounds of the formula Ha

slide),

^N alk-Xj

and sets this with a corresponding compound of the formula

• -

""Nile

or a salt thereof in the presence of one of the abovementioned bases, z. B. in an analogous manner as described under process variant a).

In a preferred embodiment compounds Vl are obtained in which X _{4 is} halogen and the dotted line is a single bond, and salts thereof are prepared by reacting a compound of formula I wherein R _{2 is} hydroxy and the dotted line represents a single bond, or a salt thereof with a halogenating agent, such as phosphorus tri- or pentachloride or thionyl chloride, wherein the corresponding compounds I and their salts can be obtained, for example, in an analogous manner as described under process variant a) or c).

Variant f):

The anion Α ^Θ is, for example, the anion of a strong protic acid, z. A halide such as chloride, bromide or iodide ion, or a sulfonation such as an optionally substituted lower alkane or benzene sulfonation, e.g. As the methanesulfonate, Äthansulfonat- or p-Bromophenylsulfonat- or p-Toluolsulfonation. In particular, P'i is hydrogen, etherified hydroxy R ₂ or protected hydroxy, but may also be carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Μ, Ν-di-lower alkylcarbamyl R ₂ or etherified or protected hydroxymethyl. Protected hydroxy is, for example, silyloxy, such as tri-lower alkylsilyloxy, e.g. B. trimethylsilyloxy, but can also TriphenylniederalKoxy, z. B. trityloxy. Protected imino is, for example, silylamino, such as tri-lower alkylsilylamino, e.g. As trimethylsilylamino, but may also be phenyl, diphenyl or Ti iptvjnylniederalkylamino, such as benzyiamino, diphenylamino or tritylamino. Etherified hydroxymethyl is, for example, lower alkoxymethyl, such as methoxy or ethoxymethyl, or optionally substituted phenyl-lower alkoxymethyl, eg. B. substituted in the phenyl moiety phenyl-Ci-C ^ alkoxymethyl, such as benzyloxy, p-Chlorbenzyioxy-, 1-Phonyläthyloxy- or 1- (p-Bn mphenyl) -n-butyloxymethyl. Protected hydroxymethyl is, for example, silyloxymethyl, such as tri-lower alkylsilyl, e.g. Triniethylsilyloxymethyl, but also run triphenyl-lower alkoxy, e.g. Trityloxymethyl. The reduction of the excess double bonds is carried out by treatment with a suitable reducing agent, for example by hydrogenation in the presence of a hydrogenation catalyst, by reduction with a hydride-transferred reagent or by reduction with a metallic reduction system of metal and proton-releasing agent. Suitable hydrogenation catalysts are, for example, elements of subgroup VIII of the Periodic Table of the Elements or derivatives thereof, such as palladium, platinum, platinum oxide, ruthenium, rhodium, tris (triphenylphosphine) rhodium-1-halide, eg. B. chloride, or Raney nickel, optionally on a support material, such as activated carbon. Alkali metal carbonate or sulfate or a silica gel are applied. As hybrid-transferring reagents, for example, suitable light metal, insbeso ⁿ de.-e Allalimetallaluminiumhydride or -borhydride such as lithium aluminum Lithiumtriäthylborhydrid, Natriumborhydri'J, sodium cyanoborohydride, or tin hydrides, such as triethyl- or Tributylzinnnydrid, or diborane are suitable. The metal component of the metallic reduction system is, for example, a non-noble metal, such as alkali or alkaline earth metal, z. As lithium, sodium, potassium. Magnesium or calcium, or transition metal, e.g. As zinc, tin, iron or titanium, while as proton-releasing agent z. As protic acids of the aforementioned type, such as hydrochloric or acetic acid, lower alkanols, such as ethanol, and / or amines or ammonia come into question. Such systems are, for example, sodium / ammonia, zinc / hydrochloric acid or acetic acid or zinc / ethanol.

The preparation of starting compounds of the formula VII is carried out, for example, by reacting compounds of the formula

slide),

^% alk-Xi wherein X; corresponding to the anion Α® corresponding reactive esterified hydroxy, with compounds of the formula

/) - R2 V / (Vila),

or a salt thereof, wherein z. B. in an analogous manner as described under process variant a). Variant g):

Cleavable radicals Y ₂ in compounds VIII are, for example, reactive esterified hydroxy groups, such as 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, ζ. B. fluorosulfonyloxy, optionally, ζ. B. by halogen, substituted Niederalkansulfonyloxy, z. B. Met'.ian- or Trifluormethansulfonyloxy, Cycloalkansulfonyloxy, z. B. cyclohexanesulfonyloxy, or optionally, ι. B. by lower alkyl or halogen, substituted benzenesulfonyloxy, z. For example, p-bromophenyl or p-toluenesulfonyloxy, odei etherified hydroxy groups, for example, lower alkoxy or optionally substituted Phenylniederalkoxy.

The cyclization can be carried out, for example, in the presence of one of the bases mentioned under variant e), in particular in the presence of an alkali metal lower alkanolate, eg. Q. be carried out with sodium methoxide or ethanolate. The starting materials VIII are obtained, for example, by reacting a compound of the formula

" ^VhJ

alk-K-CH ₂ CH ₂ CH ₂ -R ₂ H

or a salt thereof with a compound of the formula Y ₂ -CH ₂ -CH (Y ₂ I-Ri (IVi)).

In the starting materials of the formulas II b, III and III a, a hydroxy group R ₂ in etherified or a hydroxy or amino group R _{2 can} also be present in intermediately protected form, as well as a hydroxymethyl group R ₂ in compounds II b in etherified or intermediately protected Form can be present. Protected hydroxy is, for example, silyloxy, such as tri-lower alkylsilyloxy, e.g. B. trimethylsilyloxy, but can also Triphenylniederalkoxy, z. B. trityloxy. For example, protected amino is silylamino, such as tri-lower alkylsilylamino, e.g. B. trimethylsilylamino, but may also be phenyl, diphenyl or Triphenylniederalkylamino, such as benzylamino, diphenylmethylamino or tritylamino.

Etherified hydroxymethyl is, for example, lower alkoxymethyl, such as methoxy- or ethoxymethyl, or optionally substituted phenyl-lower alkoxymethyl, eg phenyl-C 1 -C ₄ -alkoxymethyl substituted in the phenyl moiety, such as benzyloxy, p-chlorobenzyloxy, 1-phenylethyloxy or 1 - (p- bromophenyl) -n-butyloxymethyl. Protected hydroxymethyl is, for example, silyloxymethyl, such as tri-lower alkylsilyl, e.g. B. trimethylsilyloxymethyl, but can also Triphenylniederalkoxy-, z. Trityloxymethyl.

The release of intermediately protected radicals R ₂ , ie cleavage of the intermediate protecting groups, is carried out in customary manner, for example by solvolysis, such as mild hydrolysis, eg. B. treatment with water under neutral or weakly acidic conditions, eg. B. by the action of dilute aqueous mineral or carboxylic acids, eg. B. of dilute hydrochloric or acetic acid. In an analogous manner, the release of intermediately protected hydroxy, amino or hydroxymethyl groups R ₂ in starting materials of the formula VII or Vila.

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 amidiorten carboxy groups R ₁ and R ₂ in a conventional manner, 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. As hydrochloric acid or sulfuric acid, to Carboxy Ri or R ₂ hydrolyze. Esterified carboxy groups R ₁ and R ₂ can also be diTch transesterification, ie treatment with an alcohol in the presence of an acidic or basic Solvolysemittels, such as a. ' Mineral acid, e.g. B. of sulfuric acid, or a corresponding alkali metal alkoxide or an alkali metal hydroxide, in other esterified carboxy groups R ₁ or R ₂ or by reaction with ammonia or a corresponding mindiistens having a hydrogen atom amine are converted into amidated carboxy R ₁ or R ₂ .

Free carboxy Ri or R ₂ can in the usual manner, for example by treatment with a corresponding alcohol in the presence of a mineral acid, for example of sulfuric acid, or by conversion into 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 gepereitertes carboxy R ₁ or R ₂ are converted. Likewise, a carboxy bond may be esterified with a corresponding alcohol using a dehydrating agent such as N, N'-dicyclohexylcarbodiimide. Free or esterified carboxy R ₁ or R ₂ may also be prepared by reaction with ammonia or an amine having at least one hydrogen atom and dehydration of the ammonium salt formed intermediately, for. B. by 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 having at least one hydrogen-containing amine are converted into amidated carboxy R ₁ or R ₂ .

Further, one can optionally esterify existing hydroxy groups, for. B. by treating with a Niederalkancarbonsäureanhydrid or halide in Niederalkanoyloxy convert odor convert by reaction with a reactive ester, in particular bromine or hydrochloric acid ester, a lower alkanol into corresponding etherified hydroxy. Conversely, one can solvolytically release the hydroxy group (s) from esterified or etherified hydroxy, such as lower alkanoyloxy or lower alkoxy, preferably under acidic conditions. In an analogous manner, it is also possible to hydrolyze etherified or acylated hydroxy R ₂ to hydroxy.

Accordingly, one can continue to esterify hydroxymethyl R ₁ or R ₂ , z. Transferring example, by treatment with a lower alkanecarboxylic or lower alkanoyloxymethyl halide in R _(or R _2. Conversely, as lower alkanoyloxymethyl, Ri or R ₂ may be made of acylation-IEM hydroxymethyl, z. Liberate the hydroxy group by solvolysis, preferably under acidic conditions ,

Furthermore, hydroxymethyl R | or R ₂ in usually lower alkoxycarbonyl, carbamyl, N-Niederalkylcarbarnyl or N ₁ N 'Diniederalkylcarbamyl Ri or R ₂ convert, wherein z. B. is moved in such a way that first hydroxymethyl R ₁ or R ₂ 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 Wuise, z. B. by treatment with a corresponding alcohol in the presence of a mineral acid, for. B. of sulfuric acid, or by conversion into a halide and subsequent

Reaction with a corresponding alcohol, for. In the presence of pyridine or triethylamine, or by conversion to an alkali metal salt followed by reaction with a reactive ester of the corresponding alcohol, such as a corresponding halide, or using a dehydrating agent, such as Ν, Ν'-dicyclohexylcarbodiimide, with an appropriate alcohol Lower alkoxycarbonyl R ₁ or R ₂ or by reaction with ammonia or an amine having at least one hydrogen atom and dehydration of the ammonium salt formed intermediately, for. B. by 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 having at least one hydrogen-containing amine is converted into amidated carboxy Ri or R2. It is likewise possible to convert acylated hydroxymethyl R ₁ or R ₂ into esterified or amidated carboxy R ₁ or R ₂ by first solvolytically liberating the acylated hydroxymethyl group, eg. As described above, and then the resulting free hydroxymethyl group, 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 ₁ and R _{2 can be} in optionally acylated hydroxymethyl R ₁ or R ₂ in a conventional manner, for example in the presence of a basic or acidic Hyrolysemittels, 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, hydrolyzed to carboxy and then the resulting carboxy group in the usual manner, for. B. in the presence of a reducing agent, for example of the type mentioned above, reduced to hydroxymethyl R ₁ or R ₂ , wherein, if desired, the latter, for. B. as described above, then still in acylated hydroxymethyl R ₁ or Ri can be converted. If the dashed line indicates that a double bond is present in the compounds obtainable in accordance with the process, this can be achieved, for example, with B. in a conventional manner with the aid of a reducing agent, for. As the variant listed under variant f) are hydrogenated to a single bond.

Furthermore, a compound obtainable by the process in which the dashed line represents a double bond and R _{2 is} hydrogen, z. B. in a conventional manner by addition of a compound R ₂ -H in which R _{2 is} an optionally etherified or acylated hydroxy group or an optionally acylated amino group, are converted into a corresponding piperidine compound according to the process. The addition is in particular in the presence of a suitable 3ase, z. B. the variant listed under a) performed.

Compounds obtainable by the process in which the dashed line stands for a single bond can be reversed z. B. by elimination of a compound R ₂ -H, in which R _{2 represents} an optionally etherified or acylated hydroxy group or an optionally acylated amino group, in a conventional manner in corresponding process tetrahydro-pyridine compounds in which R _{2 is} hydrogen, transferred become. For elimination poorer leaving groups R ₂ , z. As hydroxy, can previously, for example, in situ, in more suitable leaving groups R ₂ , z. Lower alkanesulfonyloxy, such as methanesulfonyloxy, or halogen, such as chlorine, bromine or iodine. The elimination takes place in particular in the presence of a suitable base, for. B. of the species listed under variant a). Salts of compounds of formula I or of their tautomers can be prepared in a conventional manner. 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 in the free compounds, acid addition salts z. By treating with a suitable basic agent.

Depending on the procedure or Reakticnsbedingungen the compounds obtainable by the process can be obtained with salt-forming, in particular basic properties, in pure form or in the form of salts. 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 new compounds according to the method available, including their salts of salt-forming compounds can also be obtained in Fo ^r n of their hydrates, or other, for example for crystallization of the present compounds used in solid form. Include solvent.

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. These are, 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 / trans isomers or meso compounds. Accordingly, as isomeric mixtures, e.g. Enantiomerengemische, 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. By reacting a basic end-product racemate with an optically active acid such as carboxylic acid, e.g. 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 solubility wedges, 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 specially developed for the preparation of the compound according to the invention and their use also form one

The invention relates to the variables R ₁ , R ₂ , R a, X, Y, η and alk and the substituents of ring A having the meanings given for the respective preferred compound groups of formula I.

The invention also relates to the use of compounds of the formula I, their tautomers and / or pharmaceutically acceptable salts of such compounds having salt-forming properties, in particular as pharmacological, primarily nootropic effective, active substances. In this case, they can, preferably in the form of pharmaceutically acceptable preparations, in a method for the prophylactic and / or therapeutic treatment of the animal or human body, especially as nootropics, z. 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 optionally a tautomer and / or pharmaceutically acceptable salt thereof as an active ingredient. The preparations obtainable by the process which comprise a compound of the formula I or, where appropriate, a tautomer and / or pharmaceutically acceptable salt thereof, are those for enteral, such as oral, rectal, and parenteral administration to warm-blooded animals, the pharmacologically active substance being alone or together with conventional pharmaceutical excipients.

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 e.g. As such in dosage unit forms, such as dragees, tablets, capsules or suppositories, further ampoules. These are in a known manner, for. B. by conventional mixing, granulation, coating, solution or lyophilization process. Thus, one can obtain pharmaceutical preparations for oral use by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and the mixture or granules, if desired or necessary, after addition of suitable excipients, processed into tablets or Dragoe cores , Suitable carriers are in particular fillers, such as sugars, for. As lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphate, z. As tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch pastes, using z. Corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone, if desired, disintegrating agents such as the above-mentioned starches, furthermore carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate , Auxiliaries are primarily flow, regulators and lubricants, eg. 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 Lösungsmitteige, niche or, for the manufacture of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropylmethyl cellulose phthalate used. 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 gelatine capsules, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules may contain the active ingredient in the form of granules, e.g. 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 come z. As suppositories into consideration, 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, polyethylene glycols or higher alkenols. Furthermore, gelatin rectal capsules containing a combination of the active ingredient with a basic bulking agent may also be used. As basic materials come z. As 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 solvents or vehicles, such as fatty oils, eg. As sesame oil, or synthetic fatty acid esters, eg. As ethyl oleate or triglycerides, used or aqueous injection suspensions, which viscosity-increasing 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 the mode of administration, warm-blooded species, age and / or individual condition. Normally, an approximate daily dose of about 20 to 500 mg, in particular from about 25 to about 250 mg, advantageously in several equal divided doses, is to be estimated for a warm-blooded animal weighing about 75 kg when administered orally.

embodiment

The following examples illustrate the invention described above; however, they are not intended to limit their scope in any way. Temperatures are given in degrees centigrade.

Due to the close relationship between a compound of formula I and the corresponding tautomeric compound of the formula I 'in the examples by a compound of formula I meaningful and appropriate, if appropriate, to understand the tautomeric compound of formula Γ. The same applies to a compound of the formula Γ and to salts of compounds of the formulas I and Γ.

Example 1: A solution of 7.96 g (25 mmol) of 3- (p-toluenesulfonyloxymethyl) chroman in 100 ml of dimethylformamide is first treated with 5.55 g (25 mmol) of 1: 0 ^ -tetrahydro-pyridine-S-carboxylic acid methyl ester hydrobromide (guavacoline). hydrobromide) and then admixed with 11.31 g (87.5 mmol) of N-ethyl-N, N-diisopropylamine. The mixture is stirred for 15 hours at 50 ° C and then evaporated in a high vacuum. The residue is mixed with water and extracted with diethyl ether. The organic phases are washed with water and extracted with 2N hydrochloric acid. The hydrochloric acid extracts are combined, made alkaline with sodium hydroxide solution (30%) and extracted with dichloromethane. The combined organic phases are over

Dried sodium sulfate and evaporated in vacuo. This gives 5.92 g (83%) of i-I pyridine-3-carboxylic acid methyl ester as a light yellow oil. The resulting from hydrochloric acid in diethyl ether 1- (chroman-3-ylmethylM ^ .b.e-tetrahydro-pyridine-S-carboxylic acid methyl ester hydrochloride melts after crystallization from methanol / diethyl ether at 158-159 "C.

3- (p-toluenesulfonyloxymethyl) 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 within 40 minutes 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 decomposed 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 while stirring at room temperature with 46.14g (242mmo!) P-Toluolsulfonsäurechlorid, 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 precipitated crystals are filtered off, washed with water and dried in vacuo. This gives 65.84 g (94%) of 3- (p-Toluolsu'fonyloxymethyl) -chroman of mp. 86-87 ° C.

EXAMPLE 2 A solution of 4.36 g (13 mmol) of N, N-bis (2-methoxycarbonylethyl) -N- (3-chloro-3-ylmethyl) -amine in 50 ml of absolute dimethylformamide is stirred at room temperature with stirring within 30 minutes. 75 g (15.6 mmol) sodium hydride dispersion in mineral oil (50%) registered. The reaction mixture is stirred for 1 hour at room temperature and then evaporated in a high vacuum. The residue obtained is combined with diethyl ether and extracted with cold 2N hydrochloric acid. The combined hydrochloric acid extracts are extracted by shaking with dichloromethane and the combined dichloromethane extracts are dried over sodium sulfate and evaporated. This gives 3.8 g (85.8%) of crystalline 4-hydroxy-1 - (chroman-3-ylmethyl) -1,2,5,6-tetrahydro-pyridine-S-carboxylic acid methyl ester hydrochloride or 1- (chroman- 3-ylmethyl) -4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride, which has a decomposition point of 167-168 ⁰ C after recrystallization from methanol / diethyl ether.

N, N-bis (2-methoxycarbonylethyl) -N- (chroman-3-ylmethyl) -amine can be, for. To prepare a suspension of 3.04 g (80 mmol) of lithium aluminum hydride in 100 ml of absolute diethyl ether first with stirring at room temperature 1.77 g (13,32mmol) Aluminiumchiorid in 50 ml of absolute diethyl ether are added dropwise. Subsequently, 6.29 g (40 mmol) of 3-cyanochromes (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 Phae is washed with water and extracted with 2 N hydrochloric acid. The combined hydrochloric acid 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 resulting from hydrochloric acid in diethyl ether S-Aminomethylchroman hydrochloride is recrystallized from methanol / diethyl ether and melts at 218-219 ° C.

A solution of 2.61 g (16 mmol) of 3-aminomethylchroman in 20 ml of Methai oil is admixed with 3.03 g (35.2 mmol) of methyl acrylate. The reaction solution is stirred for 16 hours at 5O ⁰ C and evaporated after cooling in vacuo. This gives 5.1 g (95%) of N, N-bis (2-methoxycarbonylethyl) -N- (chroman-3-ylmethyl) -amine in the form of a reddish oil.

Example 3: A solution of 10.48 g (30 mmol) of N- [2- (chroman-3-yl) ethyl] -N, N-bis (2-methoxycarbonylethyl) amine in 35 ml of absolute dimethylformamide is added at room temperature with stirring a suspension of 2.16 g (40 mmol) of sodium methoxide in 25 ml of dimethylformamide is added dropwise within 15 minutes. The reaction mixture is stirred for 16 hours at room temperature and then evaporated to dryness in a high vacuum. The residue is treated with diethyl ether and extracted with cold 2N hydrochloric acid. The combined hydrochloric acid extracts are extracted by shaking with dichloromethane and the dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. This gives 4.25 g (40%) of 1- [2- (chroman-3-yl) ethyl] -4-hydroxy-1 ^, o-tetrariydro-pyridine-S-carboxylic acid methyl ester hydrochloride biw. 1 - [2- (chroman-3-yl) ethyl-4-oxopiperidine-3-carboxylate hydrochloride, which has a decomposition point of 175-177 ° C after recrystallization from methanol / diethyl ether.

N- [2- (chroman-3-yl) ethyl] -N, N-bis (2-methoxycarbonylethyl) -amine may e.g. For example, a solution of 55.72 g (175 mmol) of 3- (p-toluenesulfonyloxymethyl) chroman (preparation see Example 1) in 300 ml of dimethyl sulfoxide is treated at room temperature with 12.53 g (192.5 mmol) of potassium cyanide and heated to 60 ° C with stirring. After 3 hours, the reaction mixture is treated with ice-water, extracted with diethyl ether and washed thoroughly with water. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. 26.75 g (88.3%) of 3-cyanomethylchroman are obtained in the form of a light yellow oil which crystallises from diethyl ether / pentane. The crystals melt at 63 °.

4.44 g (33.3 mmol) of aluminum chloride in 150 ml of absolute diethyl ether are first added dropwise with stirring at room temperature to a suspension of 7.59 g (200 mmol) of lithium aluminum hydride in 300 ml of absolute diethyl ether. Then 17.32 g OOOmmol) 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 combined 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 15.95 g (90%) of 3- (2-aminoethyl) chroman as a colorless oil. The 3- (2-AminoäthyOchroman hydrochloride prepared therefrom with hydrochloric acid in diethyl ether crystallized from methanol / diethyl ether and has a mp. Of 244-245 ° C.

A solution of 6.2 g (35 mmol) of 3- (2-aminoethyl) chroman in 50 ml of methanol is added at room temperature with 6.63 g (77 mmol) of methyl acrylate and stirred for 16 hours at room temperature. The reaction mixture is then evaporated in vacuo to yield 12.23 g (100%) of N- [2- (chroman-3-yl) ethyl-N, N-bis (2-methoxycarbonylethyl) -amine as a reddish oil.

Example 4: A solution of 4.5 g (13.5 mmol) of 3- [2- (p-toluenesulfonyloxy) ethyl] chroman in 7 μM of absolute dimethylformamide is first extracted with 3.3 g (14.8 mmol) of 1S-5-TG-tetrahydro-pyridine S-carboxylic acid methyl ester hydrobromide (G avacolin hydrobromide) and then treated with 6.1 g (47.3 mmol) of N-ethyl-N, N-diisopropyl-amine. The mixture is stirred for 16 hours at 6O ⁰ C and evaporated after cooling in a high vacuum. The oily residue is mixed with water and extracted with üiäthyläther. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline with caustic soda (30%) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. This gives 3.97 g (97.7%) of methyl 1- [2- (chroman-3-yl) ethyl] -1,2,5,6-etrahydro-pyridine-3-carboxylate as a yellow oil. The produced therefrom with hydrochloric acid in diethyl 1- (2- (Chroman-S-ylJäthyll-i ^ .ö.e-tetrahydro-pyridin-S-carbonsäuremethylester hydrochloride crystallized from methanol / diethyl ether and melts at 175-177 ⁰ C.

3- [2- (p-toluenesulfonyloxy) ethyhlene can be z. B. prepare 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 exiracts are dried over sodium sulfate and evaporated in vacuo. 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-carboxymethylchroman 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 1.33g (35mmol) of lithium aluminum hydride in 50ml of absolute diethyl ether wild at room temperature. a solution of 7.22g (35mmol) of 3-Methoxycarbonylmethylchroman in 50ml of absolute tetrahydrofuran within 30 minutes with stirring added dropwise. 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, wherein the slightly exothermic reaction is maintained with an ice bath at room temperature , After 3 hours of stirring at room temperature, the reaction mixture is poured onto ice-water. The precipitated crystals are filtered off, washed with water and dried in vacuo. This gives 5.9 g (59.2%) of 3- [2- (p-Toluolsulfony! Oxy) ethyllehroman, which melts at S1-93 ° C.

Example 5: A solution of 11.45 g (50 mmol) of 2-bromomethyl-benzo-1,4-dioxane (US 2,366,102) in 100 ml of absolute dimethylformamide is added first with 11.1 g (50 mmol) of 1,1-triethanol -pyridine-S-carboxylic acid methyl ester hydrobromide (Guvacolin hydrobromide) and then treated with 22.6 g (175 mmol) of N-ethyl-N, N-diisopropylamine. The mixture is stirred for 16 hours at 5O ⁰ C and then evaporated in a high vacuum. The residue is mixed with water and extracted with diethyl ether. The organic phases are washed with water and shaken out with 2 N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline with caustic soda (30%) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. This gives 10.75 g (74.4%) of i-IBenzo-IAdioxan ^ -ylmethylM ^ .ö.e-tetrahydropyidin-S-carboxylic acid methyl ester in the form of a yellow oil. The 1- (benzo-1,4-dioxan-2-ylmethyl) -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride prepared therefrom with hydrochloric acid in diethyl ether crystallizes from methanol / diethyl ether and decomposes at 215 to 217 ⁰ C.

Example 6: A solution of 4.88 g (15 mmol) of 1- (benzo-1,4-dioxan-2-yl-methyl) -1,2,5,6-tetrahydr-1-pyridine-3-carboxylate hydrochloride in 100 ml Methanol is treated with 0.5 g of palladium on carbon (5 ' Ό) and hydrogenated at room temperature and atmospheric pressure for 6 hours. Thereafter, the catalyst is filtered off with suction and the filtrate is evaporated in vacuo. The oily residue is dissolved in hot acetone and treated until cloudy with diethyl ether. There are crystallized from 4.08 g (83%) of i-IBenzo-i ^ -dioxan ^ -ylmethyll-piperidine-S-carboxylic acid methyl ester hydrochloride, mp 186-188 ⁰ C from.

Example 7: A solution of 10.12 g (30 mmol) of N, N-bis (2-methoxycarbonylethyl) -N- (benzo-1,4-dioxan-2-ylmethyl) -amine in 25 ml of absolute dimethylformamide is added at room temperature with stirring The reaction mixture is stirred for a further 3 hours at room temperature and then evaporated to dryness in a high vacuum combined hydrochloric acid extracts are extracted with dichloromethane and the dichloromethane phases dried over sodium sulfate and evaporated in vacuo to give 4.5 g (44.4%) of 4-hydroxy-1 · (benzo-M-dioxane ^ -ylmethyl) -I ^. Ethyl O-tetrahydro-pyridine-S-carboxylate hydrochloride or methyl 1- (benzo-1,4-dioxan-2-ylmethyl) -4-oxo-piperidine-3-carboxylate hydrochloride, which is recrystallized from methanol / diethyl ether and a decomposition point of 185-187 ° C ,

N, N-bis (2-methoxycarbonylethyl) -N- (benzo-1,4-dioxan-2-ylmethyl) -amine is ζ. Β. A solution of 6.61 g (40 mmol) of 2-aminomethylbenzo-1,4-dioxane (J. Augustin et al., J.Med.Chem. 8,44611965) in 80 ml of methanol is designated 7, 57g (88mmol) was added methyl acrylate and stirred for 16 hours at 5O ⁰ C. After cooling, the reaction mixture is evaporated in vacuo. This gives 12.82 g (95%) of N, N-bis (2-methoxycarbonylethyl) -N- (benzo-1,4-dioxan-2-ylmethyD-amine as a reddish oil.

Example 8: Analogously to Example 7, 4-hydroxy-1- (2-methylbenzo-1,4-dioxan-2-ylmethyl-1-yl-e-tetra-hydro-pyridine -S-carboxylic acid methyl ester hydrochloride or the 1- (2-methylbenzo-1,4-dioxan-2-ylmethylM-oxo-piperidine-S-carhonsäuremethylesterhydrochlorid produce.

Example: A solution of 52.7 g (0.15 mol) of N, N-bis (2-methoxycarbonylethyl) -N- (2- (benzo-1,4-dioxan-2-yl) ethyl) amine in 150 ml of absolute dimethylformamide is added dropwise at room temperature with stirring to a suspension of 10.8 g (0.20 mol) of sodium methoxide in 100 ml of absolute dimethylformamide within 10 minutes.The reaction mixture is stirred for 15 hours at room temperature and then evaporated to dryness in a high vacuum.The residue obtained is treated with diethyl ether extracted with cold 2N hydrochloric acid and the combined hydrochloric acid extracts are extracted by shaking with dichloromethane, the dichloromethane phases are dried over sodium sulphate and evaporated in vacuo to give 34.0 g (63.7%) of benzo-1-adioxane ethyl-D-ät-ethyl---hydroxy-I ^, -Se-tetrahydro-pyridine-a-carboxylic acid hydrochloride or Hk-JSenzo-IAdioxan ^ -yOäthylM-oxo-piperidine-S-carboxylic acid methyl ester hydrochloride, which is recrystallized from methanol / diethyl ether and a Decomposition point v on 165-166 ⁰ C. N, N-bis (2-methoxycarbonylethyl) -N- [2- (benzo-1,4-dicxan-2-yl) ethyl] amine can be prepared, for example, in the following manner: A solution of 32.25 g (0.18 mol) 2- (2-aminoethyl) benzo-1,4-dioxane [J. Augustin et al., J. Med. Chem. 8,446 (19651) in 250 ml of methanol is mixed at room temperature with 34.1 g (0.396 mol) of methyl acrylate. The reaction mixture is stirred for 6 hours at 50 ° C and evaporated after cooling in vacuo. This gives 57.9 g (91.5%) of N, N-bis (2-methoxycarbonylethyl) -N- [2- (benzo-1,4-dioxan-2-yl) ethyl] amine as a red oil.

Example 10: A solution of 12.45 g (35 mmol) of 1-I2- (benzo-1,4-dioxan-2-yl) ethyl-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride or 1 - [2- (benzo-1-adioxan-1-yl-yl) -oxopiperidine-S-carboxylic acid methylene chloride in 250 ml of methanol is treated with 1.25 g of platinum oxide and hydrogenated at room temperature and atmospheric pressure The filtrate was evaporated in vacuo and the oily residue was dissolved in hot acetone, cooled to give 4.87 g (38.9%) of cis-1- (2- (benzo-1,4-dioxan-2-y-ethyl) -hydroxy -piperidine-S-carboxylic acid methyl ester hydrochloride of mp. 182-185 ⁰ C from.

Example 11: A suspension of 12.45 g (35 mmol) of methyl 1-1- (benzo-1,4-dioxan-2-yl) ethyl] -4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride or 1 - [2- (benzo-1 Adioxan ^ -yD-ethylM-oxo-piperidine-S-carboxylic acid methyl ester hydrochloride in 250 ml of methanol for 1 hour with stirring at -15 ° C in portions with 2.65 g (70 mmol) of sodium borohydride added. It is at -1O ⁰ C stirred and then the reaction mixture for 4 hours evaporated in vacuo and taken up in water / ethyl acetate. the ethyl acetate extracts are washed with water, dried over sodium sulfate and evaporated. this gives 11.2 g (100% Crude product which is chromatographed over 560 g of silica gel (0.040 g, 063 mm) with ethyl acetate as eluent, giving 5.41 g (48.2%) of trans-1 - [2- (benzo-1,4-dioxane-2 -yl) ethyl] -4-hydroxypiperidine-3-carboxylic acid methyl ester as a light yellow oil The trans-1- [2-benzo-1,4-dioxan-2-yl) ethyl] -4-hydroxy-piperidine prepared therefrom with fumaric acid -3-car Bonsäuremethylester fumarate crystallized from methanol / Uiäthyläther as hemihydrate with a mp. Of 150-152 ⁰ C.

Example 12: A solution of 8.03 g (25 mmol) of a mixture of cis- and trans-1- [2- (benzo-1,4-dioxan-2-yl) ethyl-4-hydroxypiperidine-3-carboxylic acid methyl ester in 100 ml Toluene is first treated with 19.03 g (125 mmol) of IS-DiazabicycloIöAOlundec-ö-en and then added dropwise with stirring at 0-5 ⁰ C with a solution of 3.44 g (30 mmol) of methanesulfonyl chloride in 20 ml of toluene. Then allowed to warm to room temperature and stirred for a further 16 hours. The reaction mixture is then treated with ice-water and the organic phase extracted with 2 N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline with sodium hydroxide solution (30%) and shaken out with dichloromethane. The combined organic phases are washed with water, dried over sodium sulfate and evaporated in vacuo. This gives 5.8 g (76.5%) of crude product which is chromatographed over 300 g of silica gel (0.040-0.063 mm) with toluene / ethyl acetate (1: 1) as the eluent. This gives 4.13 g (54.5%) of ethyl 1- [2- (benzo-1,4-dioxan-2-yl) ethyl] -1,2,5,6-tetrahydro-pyridine-3-carboxylate as a yellow oil , The 1- [2- (benzo-1,4-dioxan-2-yl) ethyl] -i ^^ e-tetrahydro-pyridine-S-carboxylic acid methyl ester hydrochloride prepared therefrom with hydrochloric acid in diethyl ether crystallizes on? Methanol / diethyl ether and decomposes at 205-206 ° C.

Example 13: A solution of 3.32 g (10 mmol) of 3- (2- (p-toluenesulfonyl-cxy) ethyl) chroman in 50 ml of absolute dimethylformamide is first treated with 2.1 g (11 mmol) of 1,4-tetrahydropyridine. S-Carbonsaureathylester hydrochloride and then with 4.53g (35mmol) of N-ethyl-N, N-diisopropylamine added. The mixture is stirred for 16 hours at 6O ⁰ C and evaporated after cooling in a high vacuum. The oily residue is mixed with water and extracted with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline with caustic soda (30%) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. 1.65 g (52.3%) of ethyl i-f-chroman-S-y-ethyl-1-methyl-tetrahydro-pyridine-S-carboxylate are obtained as yellow oil. The resulting from this with hydrochloric acid in Diäthy, jther prepared * - [2- (chroman-3-yl) ethyl] -1,2,5,6-tetrahydro-pyridine-S-carboxylic acid ethyl ester hydrochloride crystallized from acetone / Diäthyläti he and melts at 177-178 ⁰ C.

Example 14: A solution of 2.54 g (7.5 mmol) of 1- [2- (chroman-3-yl) ethyl] -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride in 170 mL of absolute ethanol 3.4 ml of sulfuric acid (100%) and boiled under reflux for 35 hours. After cooling, the reaction mixture is evaporated in vacuo. The residue is dissolved cold in water and

extracted with diethyl ether. The aqueous phase is made alkaline with sodium hydroxide solution (30%) and extracted with dichloromethane. The combined dichloromethane extracts are dried over sodium sulfate and evaporated in vacuo. This gives 2.30 g (97.4%) of 1- [2- (chroman-3-yl) ethyl-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid ethyl ester as a yellow oil. The resulting prepared with hydrochloric acid in diethyl ether 1- [2- (chroman-3-yl) ethyl | -1,2,5,6-tetrahydro-pyridine-3-carbonsäureäthylesterhydrochlorid crystallized from acetone / diethyl ether and melts at 177-178 ° C. ,

Example 15: A solution of 3.98 g (12 mmol) of 3- | 2- (p-toluenesulfonyloxy) ethyl] chroman in 50 ml of absolute dimethylformamide is first treated with 3.76 g (24 mmol) of piperidine-3-carboxylic acid ethyl ester and then with 3.1 g 624 mmol) of N-ethyl-N, N-diisopropylamine. The mixture is stirred for 16 hours at 6O ⁰ C and evaporated after cooling in a high vacuum. The oily residue is mixed with water and extracted with diethyl ether. The vert-organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are made cold with sodium hydroxide solution (30%) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. This gives 3.7 g (97.3%) of 1- [2- (chroman-3-yl) ethyl] -piperidine-3-carboxylic acid ethyl ester as a yellow oil. The hydrochloric acid in diethyl ether prepared therefrom 1- (2- (chroman-3-yl) ethyl-3-piperidinylcarboxylate hydrochloride from acetone / diethyl ether with 0.18 equivalents of water of crystallization urd melts at 140-143 ⁰ C.

Example 16: A solution of 3.98 g (12 mmol) of 3- [2- (p-toluenesulfonyloxy) ethyl] chroman in 50 mL of absolute dimethylformamide is added first with 3.76 g (24 mmol) of piperidine-4-carboxylic acid ethyl ester followed by 3.1 g (24mmol) N-ethyl-N, N-diisopropylamine added. The mixture is stirred for 16 hours at 6O ⁰ C and evaporated after cooling in a high vacuum. The oily residue is mixed with water and shaken out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline with caustic soda (30%) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. This gives 3.8 g (100%) of crude product which is chromatographed over 200 g of silica gel (0.040-0.063 mmol) with Äthylar.etat as the eluent. Thereafter, 3.7 g (97.3%) of 1- [2- (chroman-3-yl) ethyl] -piperidine-4-carboxylic acid ethyl ester as a colorless oil. The hioraus prepared with hydrochloric acid in diethyl ether 1- [2- (chroman-3-yl) ethyl] piperidine-4-carbonsäureäthylesterhydrochlorid crystallized from ethanol / diethyl ether and melts at 182-186 ° C.

Example 17: A solution of 3.34 g (10 mmol) of 2- [2- (p-toluenesulfonyloxy) ethyl] benzo-1,4-dioxane in 50 ml of absolute dimethylformamide is first charged with 1.96 g (12.5 mmol) of piperidine-3 Carboxylic acid ethyl ester and then with 2.58g (20mmol) of N-ethyl-N, N-diisopropyl-am η added. The mixture is stirred for 16 hours at 6O ⁰ C and evaporated after cooling in a high vacuum. The oily land is mixed with water and extracted with diethyl ether. The combined organic phases were washed with water and treated with 2N gum. extracted acid. The combined hydrochloric acid extracts are made alkaline with caustic soda (30%) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. It contains 3.82 g (100%) of crude product which is filtered through 190 g of silica gel (0.040-0.063 mm) with ethyl acetate and eluent. This gives 3.70 g (96.6%) of ethyl 1- [2- (benzo-1,4-dioxan-2-yl-yl-ethyl) -piperidine-3-carboxylate as a light-yellow oil, the resulting 1-hydrochloric acid prepared in diethyl ether - [2- (benzo-1,4-dioxan-2-yl) ethyl] -piperidine-3-carboxylic acid ethyl ester hydrochloride is crystallized from ethanol / Diäthyiäther and melts at 162-165 ⁰ C. The 2- [2- (p For example, toluenesulfonyloxy) ethyl] benzo-1,4-dioxane can be prepared as follows: In a solution of 15.76 g (90 mmol) of 2-cyano-ethyl-benzo-1,4-dioxane (BE-613,211) in 200ml of absolute methanol is actuation introduced at 5-1O ⁰ C with stirring, hydrogen chloride until &!. then allowed to thaw the reaction mixture to Raumtemperetur and stirred for 16 hours at room temperature. the reaction mixture is then refluxed for 2 hours. after cooling, The gomish is evaporated in vacuo, and the oily residue is mixed with ice-water and extracted with diethyl ether, giving the combined, organic phases cold with water, saturated Natriumhydrogencerbonetlösung and washed again with water, dried over sodium sulfate and evaporated in vacuo. This gives 18.2 g (97.3%) of 2-Methoxycaibonylmethyl-benzo-1,4-dioxan ice pale yellow oil. To a suspension of 2.85 g (75 mmol) of lithium aluminum hydride in 120 ml of absolute diethyl ether, a solution of 15.61 g (75 mmol) of 2-methoxycarbonylmethyl-benzo-1,4-dioxane in 120 ml of absolute tetrahydrofuran is added dropwise while stirring at room temperature for 30 minutes , The reaction mixture is stirred for 2 hours at room temperature. Then, the reaction mixture is carefully decomposed with 2.85 ml of water, 2.85 ml of sodium hydroxide solution (15%) and 8.55 nl 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 thoroughly with water, dried over sodium sulfate and evaporated in vacuo. This gives 12.37 g (91.6%) of 2- (2-hydroxyethyl) benzo-1,4-dioxane ice colorless oil.

A solution of 10.81 g (60 mmol) of 2- (2-hydroxyethyl) benzo-1,4-dioxane in 35 ml of absolute pyridine is added at room temperature while stirring with 12.20 g (64 mmol) of p-toluenesulfonic chloride 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 15.50 g (77.2%) of 2- [2- (p-toluenesulfonyloxy) ethyl) benzo-1,4-dioxane, which melts at 82-84 ° C.

Example 18: A solution of 3.34 g (10 mmol) of 2- [2- (p-toluenesulfonyloxy) ethyl) benzo-1,4-dioxane in 50 mL of absolute dimethylformamide is charged first with 1.96 g (12.5 mmol) of piperidine-4 Carboxylic acid ethyl ester and then with 2.58g (20mmol) of N-ethyl-N, N-diisopropylamine added. The mixture is stirred for 16 hours at 6O ⁰ C and evaporated after cooling in a high vacuum. The oily residue is mixed with water and extracted with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline with sodium hydroxide solution (30%) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. This gives 3.80 g (99.2%) of crude product which is filtered through 190 g of silica gel (0.040-0.063 mm) with ethyl acetate as the eluent. Thereafter, 3.7 g (96.6%) of 1 - | 2- (benzo-1,4-dioxan-2-yl) ethyl] -piperidine-4-carboxylic acid ethyl ester as a yellow oil. The 1- (2- (benzo-1,4-dioxan-2-yl) ethyl | - piperidine-4-carboxylic acid ethyl ester hydrochloride prepared from this with hydrochloric acid in diethyl ether crystallizes from ethanol / diethyl ether and melts at 165-168 ° C.

Example 19: A solution of 2.66g (8mmol),? - [2- (p-toluenesulfonyloxy) ethyl chloromethane in 35ml absolute dimethylformamide is first charged with 1.57g (10mmol) piperidiri-S-cirbayl ethyl ester followed by 2.07g (16mmol). N-ethyl-N, N-diisopropyl-smin added. The mixture is stirred for 16 hours at 60 ^° C. and, after cooling, evaporated in a high vacuum. The oily residue is mixed with water and extracted with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline with sodium hydroxide solution (30%) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. This gives 2.28 g (90.1%) of crude product which is chromatographed over 120 g of silica gel (0.040-0.063 mm) with ethyl acetate as the eluent. Thereafter, 1.82 g (72.2%) of 1- [2- (chroman-2-yl) ethyl) -piperidine-3-carboxylic acid ethyl ester are obtained as a yellow oil. The 1 - [2-chroman-2-yl) ethyl] -piperidine-3-carboxylic acid ethyl ester hydrochloride prepared therefrom with hydrochloric acid in diethyl ether crystallizes from ethanol / diethyl ether and melts at 148-151 ° C. 2- [2- (p-toluenesulfonyloxy) ethyl] chroman can be prepared, for example, in the following manner:

A solution of 70.34 g (0.39 mol) of 2-carhoxychroman in 1400 ml of methanol is mixed with 14.2 ml of sulfuric acid (100% and refluxed for 4 hours.) After cooling, the reaction mixture is evaporated in vacuo and the residue is dissolved in diethyl ether The ethereal phase was dried wild over sodium sulfate and evaporated in vacuo to give 72.8 g (96%) of 2-methoxycarbonylchroman a's light yellow oil.

To a suspension of 7.2 g (0.19 mol) of lithium aluminum hydride in 400 ml of absolute diethyl ether is added dropwise a solution of 36.4 g (0.19 mol) of 2-Methoxycarbonylchrcman in 400 ml of absolute tetrahydrofuran for 1 hour with stirring at room temperature. After 16 hours Nachrüiiren 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 is evaporated in vacuo. 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-Hydrolxymetliylchroman in the form of a colorless oil.

A solution of 31 g (0.189 mol) of 2-hydroxymethylchi imane 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 decanting the aqueous phase, dissolved in diethyl ether and washed with ice cold 2N hydrochloric acid and ice water. The ethereal phases were dried over sodium sulfate and evaporated in vacuo. One receives 17,15g (96,6%) ^ - (p-ToluolsulfonyloxymethyDchroman as colorless oil.

A solution of 57.31 g (0.18 mol) of 2- (p-toluenesulfonyloxymethyl) chroman in 80PmI absolute dimethylformamide is treated with 10.6 g (0.216 mol) of sodium cyanide and heated with stirring to 6O ⁰ 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. This gives 30.0 g (96.2%) of crude product, which is chromatographed over 1000 g of Kie gel. (0.040-0.063 mm) with toluene as the eluent. In this way 18.16 g (58.2%) of 2-cyanomethylchroman are obtained as a yellow oil.

In a solution of 17.32 g (0.1 mol) of 2-Cyanomethylchroman in 200 ml of absolute methanol is introduced at 5-1O ⁰ C hydrogen chloride gas to saturation. Then allowed to thaw the reaction mixture to room temperature and stirred for 16 hours at room temperature. Thereafter, the reaction mixture is refluxed for 2 hours.

Then allowed to cool and evaporated the mixture in vacuo e'n. The residue is mixed with ice-water and extracted with diethyl ether. The combined organic phases are washed in the cold with water, sodium bicarbonate and once again water, dried over sodium sulfate and evaporated in vacuo. This gives 18.58 g (90.1%) of crude product, which is filtered through 460 g of silica gel (0.040-0.063 mm) with toluene as the eluent. 17.80 g (86.3%) of 2-methoxycarbonylmethylchroman are obtained as a light yellow oil.

To a suspension of 3.11 g (82 mmol) of lithium aluminum hydride in 150 ml of absolute diethyl ether is added dropwise at room temperature, a solution of 16.91 g (82 mmol) of 2-Methoxycarbonylmethylchroman in 150 ml of absolute tetrahydrofuran for 30 minutes with stirring. It is stirred for 16 hours at room temperature and then 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 and the filtrate is evaporated in vacuo. 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 14.36 g (98.3%) of 2- (2-hydroxyethyl) chroman in the form of a colorless oil.

A solution of 13.36 g (75 mmol) of 2- (2-hydroxyethyl) chroman in 90 ml of absolute pyridine is added at room temperature while stirring with 15.73 g (82.5 mmol) of p-toluenesulfonyl chloride, wherein the slightly exothermic reaction with an ice bath at room temperature is held. After 3 hours of stirring at room temperature, the reaction mixture is poured onto ice-water. The precipitated crystals are filtered off, washed with water and dried in vacuo. This gives 8.68 g (34.7%) of 2-l2- (p-Toluolaulfonyloxy) ethyl] chroman, which melts at 57-59 ⁰ C.

Example 20: A solution of 2.66 g (8 mmol) of 2- [2- (p-toluenesulfonyloxy) ethyl] chroman in 35 ml of absolute dimethylformamide is first treated with 1.57 g (10 mmol) of piperidine-4-carboxylic acid ethyl ester followed by 2.07 g ( 16 mmol) of N-ethyl-N, N-diisopropylamine. The mixture is stirred for 16 hours at 6O ⁰ C and then evaporated after cooling under high vacuum. The oily residue is mi '. Water and extracted with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline with sodium hydroxide solution (30%) and extracted with dichloromethane. The combined dichloromethane Phdsen are dried over sodium sulfate and evaporated in vacuo'n. This gives 2.17 g (85.7%) of crude product which is chromatographed over 110 g of silica gel (0.040-0.063 mm) with ethyl acetate as eluant, to give 1.90 g (75.1%) of 1- [2- (Chroman-2-yl) -ethyl-piperidine-4-carboxylic acid ethyl ester, al., Yellow oil The 1 - [2- (chroman-2-yl-1-yl-piperidine] -carboxylic acid ethyl ester prepared therefrom with hydrochloric acid in diethyl ether hydrochloride crystallizes from ethanol / diethyl ether and melts at 190-192 ° C.

Example 21: A solution of 4.81 g (0.015 mol) of 1- [2-chronan-3-yl) ethyl] -3-cyano-4-hydroxy-1,2,5,6-tetr-i-pyrrolidine hydrochloride or i-ß-fChroman-S-yUhyl-S-cyano ^ -oxo-piperidine hydrochloride in 100 ml of methanol (95%) is added with 1.5 ml of concentrated hydrochloric acid and refluxed for 15 hours. After cooling, the reaction mixture is concentrated under reduced pressure to a volume of about 30 ml and this solution is poured into a mixture of 80 ml of 5N hydrochloric acid and 20 ml of toluene, followed by stirring and cooling 1 - ^ - (chroman-S-yOätriyll ^ -hydroxy-i, 2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl-ester hydrochloride or methyl 1- [2- (chroman-3-yl) ethyl] -4-oxo-piperidine-3-carboxylate hydrochloric) crystallized from mp 175-177 ° C (dec.).

Das1- [2- (chroman-3-yl) ät'iyll-3-cyano-4-hydroxy-1,2,5,6-tetrahydropyridin-hydrochloridbzw. 1- [2- (Chroman-3-y ') ethyl] -3-cyano ^ oxo-piperidine hydrochloride may e.g. produce as follows:

In an analogous manner as described in Example 3, by reaction of 3- (2-aminoethyl) chroman with 1 equivalent of ethyl acrylate, the corresponding M- [2- (3-chronian-3-yl) ethyl] -N- (2-methoxycarbonyläthyl) - amine, whose hydrochloride melts at 130-192 ° C.

30 g (0.1 mol) of N-l2- (chroman-3-yl) ethyl] -N- (2-methoxycarbonylethyl) amine hydrochloride are dissolved in 100 ml of methanol and the solution is washed with 10.5 g (0.1 mol) triylsyl and 5.84 g (C, 11 mol) of acrylonitrile were added and the mixture was stirred at room temperature for 15 hours. Thereafter, the reaction mixture is concentrated in Wasserstrahlvdk ti, the residue taken up in diethyl ether and washed the ethereal solution with egg water neutral. The ethereal phase is dried over potassium carbonate and evaporated. This gives the N-I2- (chroman-3-yl) ethyl] -N (2-cyanoethyl) -N- (2-methoxycarbonylethyl) -amine in the form of a yellow oil.

A suspension of 5.73 g of nartrium hydride (55% suspension in mineral oil) in 100 ml of tetrahydrofuran is added dropwise under a nitrogen atmosphere with a solution of 13.07 g (41.3 mmol) of N- [2- (2- (chroman-3-yl)]. ethyl-N- (2-cyanoethyl) -N- (2-methoxycarbonylethyl) -amine in 200 ml of tetrahydrofuran and stirred for 16 hours at room temperature, and after addition of 70 ml of 2 N sulfuric acid, a yellow solution is obtained 300 ml of diethether, lather and 100 ml of water, two phases being obtained The aqueous phase is extracted three times with 100 ml of diethyl ether each time The combined organic phases are dried over sodium sulphate, concentrated under reduced pressure to about 100 ml and then into a mixture of 00 ml 5N hydrochloric acid and 20 ml of toluene are poured into the reaction and the cooling is followed by crystallization of the 1- [2- (chroman-3-yl) -äthyll-3-cyano-4-oxo-pip'.indin hydrochloride.

Example 22: A solution of 2.81 g Diisopropylarrv ^Λ i'.i 30ml dry tetrahydrofuran at 0-5 ° is mi: 17.4 mi n-ßutyllithium. in hexane. The mixture is left to stir for 30 minutes, then cooled to -15 ° and a solution of 6.24 g (25 mmol) of 1- [2- (chroman-3-yl) -ethyl] - is added. jxo-piperidine ί · ι 30m! Tetrahydrofuran ϊ j. After 15 minutes, a solution of 3.03 g (28 mmol) of chlorotrinsilane in 15 ml of tetrahydrofuran is added in. The mixture is allowed to rinse overnight at room temperature, the solution is filtered and the filtrate is evaporated to drunk in vacuo to give a T.O. Thus, the 1 - [2- (chroman-3-yl) ethyl] -4-trimethyl-silyloxy-1,2,5,6-tetrahydropyridine in the form of a pale yellow oil C, 63g (20 mmcl) of the retained 1- [ 2-Chromanan-3-yl) ethyl) -4-trimethyl-silyloxy-1,2,5,6-tetrahydropyridine are dissolved in 50 ml of dichloromethane and this solution is added to a solution of 2.3 g (24 mmol) cooled to 0 °. Chloroformic acid and 60mg (2.4 mmol) of anhydrous zinc bromide in 50 ml of absolute dichloromethane was added dropwise. After warming to room temperature, the reaction solution is stirred for 1 hour and then poured onto 150 ml of saturated Natriumhydrogencarbcnatlösung. It is extracted with dichloromethane, the combined organic phases are dried over sodium sulfate and evaporated. The residue is dissolved in 70 ml of ethanol and the solution is acidified with ethanolic hydrochloric acid. After addition of diethyl ether and cooling, the 1- [2- (chroman-3-yl) ethyl] -4-hydroxy-1,2,5,6-tetrahydro-pyridine-3-carbonsäi; remethylef * .er hydrochlcrid or The 1- (2 (chromdn-3-yl-ethylM-oxo-piperidine-S-methyl carbonate hydrochloride, mp 176-177 ° ^C.) The 1 - [2- (chroman-3-yl) ethy! j-4rxo. For example, piperidine can be prepared as follows.

A solution of 16.62 g (50 mmol) of 3- [2- (p-toluenesulfonyloxy) ethyl] -chroman in 100 ml of dimethylformamide is first charged with 8.45 g (55 mmol) piperidone hydrochloride monocydrate and then with 22.62 g (175 mmol) N-ethyl-N, N'-diisopropyl-amir; added. The mixture is stirred for 18 hours bt 80 ° C and evaporated after cooling under reduced pressure to dryness. The residue is dissolved in diethyl ether and washed with water. The organic phase is separated and extracted with 2 N hydrochloric acid. The hydrochloric acid extracts are ve. ah > .. made alkaline with concentrated sodium hydroxide solution and extracted with dichloromethane. The dichloromethane phases were ve agreed, dried over sodium sulfate and evaporated to dryness under reduced pressure. One receives a dark brown Hr.rc.rc. which is purified by chromatography on toluene / ethyl acotate (1: 1) as eluant on 350 g of silica gel (0.040-0.063 mm). The 1- | 2- (chroman-3-yl) ethyl] -4-oxo-piperidine is obtained in the form of a pale yellow oil.

Example 23: Before suspension of 1.2 g of sodium hydride (50% igc suspension in mineral oil) in 25 ml of dry tetrahydrofuran is combined with a solution of 2.7 g (25 mmol) of benzyl alcohol in 25m! Tetrahydrofuran and heated after decay by gas evolution for 30 minutes under reflux. After cooling, a solution of 8.5 g (25 mmol) of 1- (2- (Ben20-1,4-dioxan-2-yl) ethyl] -1,2,5,6-tetrahydropyridine-3 is added dropwise 5-tetrahydrofuran tetrahydrofuran is added and refluxed again for 5 hours, after cooling, the solvent is removed, giving a mixture of γ and γ- [2- (benzo-1,4-dioxan-2-yl) ethyl] Methyl 4-benzyloxy-piperidine-3-carboxylate in the form of an oil.

Step Example! 24: In a suspension of 8.45 g (18 mmol) of 1 - [2- (chroman-3-yl) ethyl) -3-methoxycarbonyl-pyridinium p-toluene-3-tertonate in 43 ml of methanol are stirred at -10 ° within 90 Minutes of 1.41 g sodium borohydride. The reaction mixture is stirred with 50 ml of water and extracted twice with 100 ml of dichloromethane each time, and the dichloromethane phases are combined, dried over magnesium sulfate and evaporated to dryness. The crude product is chromatographed on 150 g of rocket (0.063-0.2 mm) with ethyl acetate as La jfmitiel purified by treating the evaporated main eluate with ethereal hydrochloric acid, the 1- [2 (chroman-3-yl) ethyl-1,2, 5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride of mp. 175-177 °.

The 1 - [2- (chroman-yl) ethyl] -3-methoxycarbonyl-pyridinium-p-toluene-sulfonate can, for. B. be prepared as follows. 16.6 g (50 mmol) of 3- [2- (p-toluenesulfonyloxy) ethyl] chroman and 9.3 g (67.5 mmol) of pyridine-3-carboxylic acid methyl ester are suspended in 50 ml of butan-2-one and the suspension is placed under 72 hours Stirring heated to the boiling point. It is allowed to cool, the reaction mixture is concentrated under reduced pressure, and thus obtains the i-ß-IChroman-S-ylJäthyll-S-methoxycarbonyl-pyridinium-p-toluenesulfonate in the form of a white foam.

Example 25: 5.2 g of a mixture of cis- and trans-1- [2- (benzo-1,4-dioxan-2-yl) ethyl] -4-benzyloxy-piperidine-3-carboxylic acid methyl ester are dissolved in 100 ml of methanol, with 2 g of palladium on carbon (10%) and hydrogenated in a Parr apparatus for 12 hours at room temperature. The reaction mixture is then filtered through diatomaceous earth and the filtrate is evaporated to dryness. The crude oily evaporation residue is chromatographed on silica gel with toluene / ethyl acetate (9: 1) as the eluent. First, the trans-i - ^ - IBenzo-i ^ -dioxan ^ -yDäthyll-A-hydroxy-piperidine-S-carboxylic acid methyl ester and then the cis-1- [2- (benzo-1,4-dioxan-2-yi ) ethyl] -4-hydroxy-piperidine-3-carboxylic acid methyl ester. The purified fractions are each combined and evaporated. The residue containing the trans product is treated with fumaric acid in methanol / diethyl ether to give the trans-1- [2- (benzo-1,4-dioxan-2-yl) ethyl] -4-hydroxy-piperidine 3-carboxylic acid methyl ester fumarate, which crystallized as hemihydrate and melts at 150-152 ⁰ C. The residue, which contains the cis product, is treated with ethereal hydrochloric acid to yield cis-1 - | 2- (benzo-1,4-dioxan-2-yl) ethyl) -4-hydroxypiperidine-3-carboxylic acid methyl ester. hydrochloride of mp. 182-185 ⁰ C.

Example 26: 6.8 g (20 mmol) of a mixture of cis- and trans-1-l2- (benzo-1,4-dioxan-2-yl) ethyl] -4-chloro-piperidine-3-carboxylic acid methyl ester are dissolved in 20 ml Dissolved methanol. At room temperature, 40 ml (140 mmol) of 3.5 N soldering of ammonia in methanol are added dropwise. The mixture is 24h. allowed to stand at room temperature. Then the solvent is removed under reduced pressure. The residue obtained is dissolved in dichloromethane, the solution is extracted by shaking with 2N hydrochloric acid and the acidic aqueous phase is separated, made alkaline with sodium bicarbonate and extracted with diethyl ether / dichloromethane (2: 1). The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and freed from the solvent under reduced pressure. The residue obtained is chromatographed on basic silica gel with dichloromethane / methanol (99: 1) as the eluent. The eluates are combined and evaporated to dryness. The oily residue consists of pure 4-amino-1- [2- (benzo-1,4-dioxan-2-yl) ethyl] -piperidine-3-carboxamide (cis / trans mixture).

A mixture of methyl and trans-1- [2- (benzo-1,4-dioxan-2-yl) ethyl-4-chloro-piperidine-3-carboxylate can be obtained, for example, as follows:

9.7 g (30 mmol) of a mixture of cis- and trans-1 - [2- (benzo-1,4-dioxan-2-yl) ethyl] -4-hydroxy-piperidine-3-carboxylic acid methyl ester (preparation see example 25) and 3.6 g (36 mmol) of triethylamine are dissolved in 100 ml of dichloromethane. At room temperature, 3.92 g (33 mmol) of thionyl chloride are added dropwise with stirring. The mixture is 4h. stirred at room temperature. Then it is filtered off from the precipitated triethylamine hydrochloride and the filtrate is shaken cold with saturated sodium bicarbonate solution. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate and freed from the solvent under reduced pressure. The resulting mixture of cis- and trans-1- [2- (benzo-1,4-dioxan-2-yl) ethyl] -4-chloro-piperidine-3-carboxylic acid methyl ester is further used crude.

Example 27: A solution of 11.94 g (30 mmol) of N-) 3-ethoxycarbonylpropyl) -N- (2-bromoethyl) -N- [2- (chroman-3-yl) ethyl] -amine in 40 ml of absolute dimethylformamide while stirring at room temperature to a suspension of 2.72 g (40 mmol) of sodium ethanol in 30 ml of dimethylformamide was added dropwise inert 20 minutes. The reaction mixture is stirred for 16 hours at room temperature and then evaporated to dryness in a high vacuum. The residue is combined with diethyl ether and extracted with cold 2N hydrochloric acid. The combined hydrochloric acid extracts are extracted by shaking with dichloromethane and the dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. The residue obtained is the crude product, which is chromatographed over 500 g of silica gel (0.040-0.063 mm) with ethyl acetate as the eluent. Evaporation of the eluate gives the 1- [2- (chroman-3-yl) ethyl j-piperidine-4-carboxylic acid ethyl ester as a colorless oil. The produced therefrom with hydrochloric acid in diethyl ether 1 - [2- (chroman-3-yl) ethyl] -piperidine-4-carboxylic acid ethyl ester hydrochloride is crystallized from ethanol / diethyl ether and melts at 182-186 ⁰ C.

The N- (3-ethoxycaibonylpropyl) -N- (2-bromoethyl) -N- [2- (chroman-3-yl) -ethyl] amine may be e.g. as follows. 17.7 g (0.1 mol) of 3- (2-aminoethyl) chroman are dissolved in 100 ml of methanol and the solution is mixed with 10.5 g (0.1 mol) of triethylamine and 19.5 g (0.1 mol) of 4-bromobutyric acid ethyl ester , The mixture is stirred for 15 hours at room temperature and then concentrated the reaction mixture in a water jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice water. The ethereal phase is dried over potassium carbonate and evaporated. This gives the oily N- (3-ethoxycarbonylpropyl) -N- [2- (chrorrian-3-yl) ethyl] amine, which can be reused in crude form. 29.1 g (0.1 mol) of N- (3-ethoxycarbonylpropyl) -N- [2- (chroman-3-yl) ethyl] -amine are dissolved in 200 ml of methanol and the solution is washed with 10.5 g (0.1 mol) triethylamine and 18.8 g (0.1 mol) of 1,2-Dibromäthan vc.setzt. The mixture is stirred for 16 hours at room temperature and then the reaction mixture is concentrated in a water-jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice water. The ethereal phase is dried over potassium carbonate and evaporated. This gives the N- (3-ethoxycarbonylpropyl) -N- (2-bromoethyl-N- [2- (chroman-3-yl) ethyl] -amine in the form of an oil, which can be used further crude.

Example 28: In an analogous manner as described in Examples 1 to 27 can also be 1- [2- (chroman-4-yl) ethyl | -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester and its Hydrochloride and the 1- [2- (chroman-4-yl) ethyl-ethyl-3-ethylhexylcarboxylate and its hydrochloride.

Example 29: Tablets containing 25mg of active ingredient, e.g. 1- (Benzo-1,4-dioxan-2-ylmethyl) -ciperidine-3-carboxylic acid methyl ester hydrochloride can be prepared as follows:

Ingredients (for 1000 tablets): 25.0 g active substance 100.7 g lactose 7.5 g wheat starch 5.0 g Polyethylene glycol 6000 5.0 g talc 1.8g magnesium stearate q.s. demineralized water

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 added to the suspension to a boiling solution of the polyethylene glycol in 100 ml of water. The resulting starch paste is added to the bulk and the mixture is granulated, if necessary with the addition of water. The granules are dried overnight at 35 ⁰ C, driven through a sieve with 1.2 mm mesh size and compressed to both sides concave tablets of about 6mm diameter.

Example 30: Tablets containing 50 mg of the active ingredient, e.g. B. 1 - (Benzo-1,4-dioxan-2-ylmethyl) -piperidine-3-carboxylic acid methyl ester hydrochloride are prepared as follows:

Composition (for 10000 tablets):

Active ingredient 500.00 g

Lactose 140.80 g

Potato starch 274.70 g

Stearic acid 10.00g

Talc 50.00 g

Magnesium stoate 2.50 g

Colloidal Silica 32.00 g

Ethanol q.s.

A mixture of the active ingredient, lactose and de ^r 194,70g potato starch is moistened with an ethanolic solution of the 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 optionally be provided with partial scores for finer adjustment of dosage. In an analogous manner, 100 mg of active ingredient can be incorporated.

Example 31: Capsules containing 0.025 g of the active ingredient, e.g. Methyl 1- (benzo-1,4-dioxan-2-ylmethyl) -piperidine-3-carboxylate hydrochloride may 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 15.00g

Water q.s.

The active ingredient 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 capsules (size 1) from.

Example 32: Pharmaceutical preparations containing, as active ingredient, another compound of the formula I or a tautomer and / or a pharmaceutically acceptable salt thereof, for example according to Examples 1 to 28, can also be prepared analogously to Examples 29 to 31 ,

Claims (33)

wherein either R _{1 is} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν-di-lower alkylcarbamyl or optionally acylated hydroxymethyl and R _{2 is} hydrogen, an optionally etherified or acylated hydroxy group or a givenfells acylated amino group or R _{1 is} hydrogen and R _{2 is} Carboxy, Niedoralkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν-Diniederalkylcarbamyl 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, Halo, lower alkyl and / or trifluoromethyl is substituted, the dotted line is to express that a single or a double bond is present and either X and Y each represents an oxygen atom and η is 1 or X represents a methylene group, Y represents an oxygen atom and η for r is 1 or X is oxygen, Y is methylene and η is 1 or X is a direct bond, Y is oxygen and η is 2, with the proviso that R _{2 is} different from carbamyl when R is _{1 is} hydrogen, R3 is hydrogen, alk is Methvlen, ethylene or 1,3-propylene, the ring A is unsubstituted or monosubstituted in the 6- or 7-position or disubstituted in the 6- and 7-position, wherein the substituents from the group consisting of lower alkoxy, halogen, lower alkyl and trifluoromethyl, which is intended to express the dashed line, that between the carbon atoms carrying the substituents R ₁ and R ₂ , a single bond is present, X and Y are each an oxygen atom, and η is 1 or when R _{1 is} hydrogen, R _{3 is} hydrogen, alk is ethylidene, the ring A is unsubstituted, the dashed line is intended to express that between the carbons fatomen, which carry the substituents R ₁ and R ₂ , a single bond is present, X and Y are each an oxygen atom and η is 1, or a tautomer and / or salt thereof, characterized in that
a) a compound of the formula (Ma) alk-Xi or a salt thereof, wherein X _{1 is} hydroxy or reactive esterified hydroxy, with a compound of the formula • - · a tautomer and / or salt thereof or b) in a compound of the formula I ₂ a tai'tomer and / or salt thereof, wherein X _{2 is} a radical other than hydrogen other than R ₁ and X _{5 is} a radical % , where R _{3 is} hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group, X ₂ converted into R ₁ different from hydrogen or in a compound of the formula III, wherein X _{2 is} hydrogen and X _{5 is} a radical convertible into R _b , wherein R _{h is} a radical R ₂ different from a radical R ₂ , X ₅ in Rb is converted or c) for preparing a compound of formula I, a tautomer and / or salt thereof, wherein R _{2 is} hydroxy or amino, and wherein R _{1 is} different from hydrogen and in particular lower alkoxycarbonyl, a compound of formula • -CH2R1 wherein Y _{1 represents} a group of the formula -CH = R ₂ , -C (Y ₂ J = R ₂ , -CH (Y ₂ JR ₂ or cyano, wherein R _{2 is} oxo or imino and Y _{2 represents} a cleavable radical, or a salt of which is cyclized or d) for the preparation of a compound of formula Γ, a tautomer and / or salt thereof, wherein R _{2 is} oxo or imino and the dashed line is to indicate that a single bond is present, and wherein R _{1 is} other than hydrogen and in particular lower alkoxycarbonyl, a compound of the formula (Va)  alk - <^ \ = 0 or a tautomer or each a salt thereof with a compound of the formula X3-R1 (Vb) or a salt thereof, wherein R _{1 is} other than hydrogen and X _{3 is} halogen or lower alkoxy, or e) for the preparation of a compound of the formula I, a tautomer and / or salt thereof, wherein R _{2 is} an optionally etherified or acylated hydroxy group or an optionally acylated amino group, in a compound of the formula .Λ.Λ / ¹ (Vl), or a salt thereof, wherein X ₄ represents a convertible into R ₂ residue, X4 converted into R _2, or f) in particular for preparing a compound of formula I, a tautomer and / or salt thereof, wherein R _{2 is} different from etherified or acylated hydroxy, acylated amino and acylated hydroxymethyl, a compound of formula (VII) \ Θ .'- R ₂ A wherein Α ^{θ is} the anion of an acid and R _{2 is} hydrogen, etherified, esterified or protected hydroxy or acylated or protected amino or carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν-di-lower alkylcarbamyl or etherified, acylated or protected hydroxymethyl that reduces excess double bonds to single bonds or g) for the preparation of a compound of formula I, a tautomer and / or salt thereof, wherein R _{2 is} carboxy, carbamyl, N-Niederalkylcarbamyi, Ν, Ν-Diniederalkylcarbamyl or especially lower alkoxycarbonyl, a compound of formula Y \ A / ^J (VIII) ^ CH ₂ -R ₂
^N. -CH (Yv) -Ri in which Y _{2 represents} a cleavable radical, or a salt thereof cyclized and in each case splits off an optionally present protective group and, if desired, a compound according to the method or otherwise obtainable compound of formula I converted into another compound of formula I, in each case an isomer mixture obtainable according to the method in the Separates components, in each case an enantiomer or diastereomer mixture obtainable by the process into the enantiomers or diastereomers and / or in each case converts a free compound of the formula I obtainable according to the process into a salt or a salt obtainable according to the process into the free compound of the formula I or into a converts other salt. 2. The method according to claim 1, characterized in that a compound of formula I, wherein Ri is carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or Ν, Ν-Diniederalkylcarbamyl, R _{2 is} hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group, R _{3 is} hydrogen or Niederalky! alk means lower alkylene or lower alkylidene, the ring A is unsubstituted or monosubstituted or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, halo, lower alkyl and / or trifluoromethyl, which is intended to indicate that a single or double bond is present in the dotted line X represents an oxygen atom or a methylene group, Y represents an oxygen atom and η represents 1, or produces a tautomer and / or salt thereof. 3. The method according to claim 1, characterized in that one obtains a compound of formula I, wherein, taking into account the proviso mentioned in claim 1, either Ri carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν-Diniederalkylcarbamyl, hydroxymethyl, Niederalkanoyloxymethyl , Lower alkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl and R _{2 represents} hydrogen, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, lower alkanesulfonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino, lower alkanesulfonylamino, benzoylamino or pyridoylamino or Ri denotes hydrogen and R _{2 represents} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν-di-lower alkylcarbamyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, R _{3 represents} hydrogen or lower alkyl, alk lower alkylene which bridges the two ring systems through to and with 3 C atoms, or Never represents the alkylidene, the ring A is unsubstituted or mono-, or substituted several times by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl, which is intended to indicate that a dinuclear or a double bond is present, 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, or a tautomer and / or salt thereof. 4. The method according to claim 1, characterized in that a compound of formula I, wherein R _{1 is} carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl or Ν, Ν-Diniederalkylcarbamyl, R _{2 is} hydrogen, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, Lower alkanesulfonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino, benzoylamino or pyridoylamino, R _{3 is} hydrogen or lower alkyl, alk lower alkylene, which bridges the two ring systems by bis and m ^: t 3 carbon atoms, or lower alkylidene, the ring A is unsubstituted or is monosubstituted, disubstituted or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and / or trifluoromethyl, which is intended to indicate the dashed line representing a single or double bond, X represents an oxygen atom or a methylene group, Y. Means oxygen and η is 1, or produces a tautomer and / or salt thereof. 5. The method according to claim 1, characterized in that one is a compound of formula I, wherein either Fi _{1 is} C ₁ -C ₄ -AlkOXyCaI bonyl, carbamyl, hydroxymethyl or C ₂ -C ₅ alkanoyloxyme'chyl and R _{2 is} hydrogen or R _{1 is} hydrogen or R _{1 is} hydrogen and R ₂ is C ₁ -C ₄ -alkoxycarbonyl, R _{3 is} hydrogen or C ₁ -C ₄ -alkyl, alk is C ₁ -C ₄ -alkylene, which comprises the two ring systems by up to and including 3 C atoms is bridged, the ring A is unsubstituted or, in particular in the 7-position, is substituted by C ₁ -C ₄ -alkoxy, which is intended to express the dashed line that a single or a double bond is present, 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 Represents oxygen atom and η is 2, or produces a tautomer and / or salt thereof. 6. The method according to claim 1, characterized in that a compound of formula I, wherein R _{1 is} CHV alkoxycarbonyl, R _{2 is} hydrogen or hydroxy, R _{3 is} hydrogen or C ₁ -C ₄ -A ^ yI, alk for d- Cj-alkylene, which bridges the two ring systems through to and with 3 C atoms, is unsubstituted, the ring A is intended to express the silicated line, that a single or a double bond is present, X represents an oxygen atom or a methylene group , Y represents an oxygen atom and η is 1, or produces a tautomer and / or salt thereof. 7. The method according to claim 1, characterized in that a compound of formula I, wherein R _{1 is} dC ^ alkoxycarbonyl, R _{2 is} hydrogen or hydroxy, R _{3 is} hydrogen, alk is methylene or ethylene, the ring A is unsubstituted in which the dashed line is intended to express that there is a single bond or a double bond, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and η is 1, or produces a tautomer and / or salt thereof. 8. The method according to claim 1, characterized in that one is a compound of formula I, wherein R ₁ is d-Cj-alkoxycarbonyl, R _{2 is} hydrogen, R _{3 is} hydrogen, alk is methylene or ethylene, the ring A is unsubstituted in which the dashed line is intended to express that a single bond or a double bond is present, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and η is 1, or wherein R ₁ denotes d-Gj-alkoxycarbonyl, R ₂ denotes hydroxy , R ₃ is hydrogen, alkfür methylene, the ring a is unsubstituted, the dotted line is intended to indicate that a double bond is present, X represents an oxygen atom or a methylene group, Y represents an oxygen atom, and η is 1, or in each case produces a tautomer and / or salt thereof. 9. The method according to claim 1, characterized in that one prepares 1- (Chrornan-3-ylmethyl) -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester or a salt thereof. Process according to Claim 1, characterized in that methyl 4-hydroxy-1- (chroman-3-ylmethyloxy) -1,4-diethyrropyridine-S-carboxylic acid or 1- (chroman-3-ylmethyl) -4- oxo-piperidine-3-carboxylic acid methyl ester or a salt thereof. 11. The method according to claim 1, characterized in that 1- [2- (chroman-3-yl) ethyl J-4-hydroxy-I ^ B ^ tetrahydro-pyridine-S-carboxylic acid methylesterbzw. Methyl 1- [2- (chroman-3-yl) ethyl] -4-oxo-piperidine-3-carboxylate or a salt thereof. 12. The method according to claim 1, characterized in that one prepares 1- [2- (chroman-3-yl) ethyl] -i ^ ö.e-tetrahydro-pyridine-S-carboxylic acid methyl ester or a salt thereof. 13. The method according to claim 1, characterized in that one prepares 1- (benzo-1,4-dioxan-2-ylmethyO-i ^ .e-tetrahydro-pyridine-S-carboxylic acid methyl ester or a salt thereof. 14. The method according to claim 1, characterized in that one prepares 1- (benzo-1,4-dioxan-2-ylmethyl) piperidine-3-carboxylic acid methyl ester or a salt thereof. 15. The method according to claim 1, characterized in that Λ-hydroxy-I - (benzo-1,4-dioxan-2-ylmethyl) -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester or. 1- (benzo-l, 4-dioxan-2-ylmethyl) -4-oxopiperidine-3-carboxylic acid methyl ester or a salt thereof. 16. The method according to claim 1, characterized in that 4-hydroxy-1- (2-methyl-benzo-1,4-dioxan-2-ylmethyl) -1 ^, Se tetrahydropyridine-S-carboxylic acid methyl ester or 1 - (2-Methylberizo-M-dioxane ^ -ylmethylM-oxo-piperidine-S-carboxylic acid methyl ester or a salt thereof. 17. Process according to Claim 1, characterized in that 1- [2- (benzo-1,4-dioxan-2-yl-ethyl-1H-hydroxy-1H-o-tetrahydro-pyridine-S-carboxylic acid methyl ester or 1- [2- - (Benzo-1,4-dioxan-2-yl) ethyl] -4-oxo-piperidine-3-carboxylic acid methyl ester or a salt thereof. 18. The method according to claim 1, characterized in that one prepares cis-1- [2- (benzo-1,4-dioxan-2-yl) ethyl] -4-hydroxy-piperidine-3-carboxylic acid methyl ester or a salt thereof. 19. Process according to Claim 1, characterized in that trans-1- [2- (benzo-1,4-dioxan-2-yl) ethyl] -4-hydroxy-piperidine-3-carboxylic acid methyl ester or a salt thereof is prepared. 20. The method according to claim 1, characterized in that one prepares 1- [2- (benzo-1,4-dioxan-2-yljäthyl] -i ^ ..e.e-tetrahydro-pyridine-S-carboxylic acid methyl ester or a salt thereof , 21. The method according to claim 1, characterized in that one prepares 1- [2- (chroman-3-yl) ethyl] -i ^^ e-tetrahydro-pyridine-S-carboxylic acid ethyl ester or a salt thereof. 22. The method according to claim 1, characterized in that one prepares 1- [2- (chroman-3-yl) ethyl] -piperidin-3-carboxylic acid ethyl ester or a salt thereof. 22. The method according to claim 1, characterized in that one prepares 1- [2- (chroman-3-yl) ethyl J-piperidine-4-carboxylic acid ethyl ester or a salt thereof. 24. The method according to claim 1, characterized in that one produces 1- [2- (benzo-1,4-dioxan-2-yDäthyl] -piperidine-3-carboxylic acid ethyl ester or a salt thereof. 25. The method according to claim 1, characterized in that one produces 1- [2- (benzo-1,4-diox3n-2-yOäthylJ-piperidine-4-carboxylic acid ethyl ester or a salt thereof. 26. The method according to claim 1, characterized in that one prepares 1- [2- (chroman-2-yl) ethylnyl] piperidine-3-carboxylic acid ethyl ester or a salt thereof. 27. The method according to claim 1, characterized in that one prepares 1- [2- (chroman-2-yl) ethyl] -piperidin-4-carboxylic acid ethyl ester or a salt thereof. 28. The method according to claim 1, characterized in that one prepares cis-1- [2- (benzo-1,4-dioxan-2-yl) ethyl] -4-benzyloxy-piperidine-3-carboxylic acid methyl ester or a salt thereof. 29. The method according to claim 1, characterized in that one produces trans-1- [2- (benzo-1,4-dioxan-2-yl) ethyl] -4-benzyloxy-piperidine-3-carboxylic acid methyl ester or a salt thereof. 30. Process according to Claim 1, characterized in that cis-4-amino-1- [2- (benzo-1,4-dioxan-2-yl) ethyl] -piperidine-3-carboxamide or a salt thereof is prepared. 31. The method according to claim 1, characterized in that trans-4-amino-1 - [2- (benzo-1,4-dioxan-2-yl) ethyl] - prepared piperidine-3-carboxamide or a salt thereof , 32. The method according to claim 1, characterized in that one prepares 1- [2- (chromo-4-yl) ethyl] -i ^ ö.e-tetrahydro-pyridine-S-carboxylic acid methyl ester or a salt thereof. 33. The method according to claim 1, characterized in that one produces 1- [2-chroman-4-yl) ethyl] piperidine-3-carboxylic acid ethyl ester or a salt thereof.