DD283389A5 - METHOD FOR PRODUCING NEW HYDRATED 1-BENZOOXACYCLOALKYLPYRIDINE CARBON ACID COMPOUNDS - Google Patents

Abstract

The invention relates to a process for the preparation of novel hydrogenated 1-Benzooxacycloalkylpyridincarbonsaeureverbindungen. According to the invention, 1-benzooxacycloalkylpyridinecarboxylic acid compounds of the formula (I) are prepared in which either R 1 is carboxy, lower alkoxycarbonyl, amidated carboxy or optionally acylated hydroxymethyl and R 2 is hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group or R 1 is hydrogen and R 2 is carboxy , Lower alkoxycarbonyl, amidated carboxy or optionally acylated hydroxymethyl and in which R 3 is lower or lower alkyl, R 5 is lower alkyl, alk is lower alkylene or lower alkylidene, ring A is unsubstituted or mono- or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, cyano, Halogen, lower alkyl and / or trifluoromethyl, which is intended to express the dashed line, that between the carbon atoms which carry the substituents R1 and R2 is a single or a double bond, m is 0 or 1 and in which either X is an oxygen atom or a methylene group and n is 0 or X is a direct bond and n is 1, and their tautomers and / or salts. These compounds can be used as pharmaceutical active ingredients and can be prepared in a conventional manner. Formula (I) {Production Method; 1-Benzooxacycloalkylpyridincarbonsaeureverbindungen; pharmaceutical agents; nootropic}

Description

A-1683A / +

Process for the preparation of further hydrogenated 1-benzooxacycloalkylpyridinecarboxylic acid compounds

Field of application of the invention

The invention relates to a process for the preparation of novel hydrogenated l-Benzooxacyloalkylpyridincarbonsäureverbindungen, the use of these compounds and a process for the preparation of pharmaceutical compositions.

Characteristic of the known state of the art

At present there are no solutions in the known prior art.

Object of the invention

The invention provides a process for the preparation of novel hydrogenated 1-benzooxacycloalkylpyridinecarboxylic acid compounds which are pharmacologically, primarily nootropic, effective and thus for the prophylactic and / or therapeutic treatment of the animal or human body, in particular as nootropics, e.g. for the treatment of cerebral insufficiency symptoms, in particular memory disorders, are applicable.

Explanation of the essence of the invention

The object of the invention is to provide a process for the preparation of new pharmacologically active compounds.

According to the invention the object is achieved in that 1-Benzooxacycloalkylpyridincarbonsäureverbindungen the formula

- 2 - 28J 333

IA II CCH ₂ ).

in which either Ri is carboxy, lower alkoxycarbonyl, amidiortes-carboxy or optionally acylated hydroxymethyl and R2 is hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group or Ri is hydrogen and R2 is carboxy, lower alkoxycarbonyl, amidated carboxy or optionally acylated Hydroxymethyl and wherein R3 is hydrogen or lower alkyl, Ri is lower alkyl, Rs is lower alkyl, alk is lower alkylene or lower alkylidene, the ring A is unsubstituted or mono- or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, cyano, halogen, lower alkyl and / or trifluoromethyl is intended to express the dashed line that between the carbon atoms bearing the substituents Rj and R2, is a single or a double bond, m is 0 or 1 and in which either X is an oxygen atom or a methylene group and η is 0 or V is a direct bond and η is 1, and their tautomers and / or salts and pharmaceutical compositions containing a compound of the formula I or a tautomer and / or a pharmaceutically acceptable salt thereof.

Amidated carboxy Ri or R2 has as amino, for example, unsubstituted or monosubstituted by lower aliphatic radicals amino and means, for example carbamyl, N-lower alkyl or N-N-di-lower alkylcarbamyl or N, N-lower alkylene or. N.N- (aza) -, N, N- (oxa) - or N.N-CThia-lower alkylene carbamyl.

Etherified hydroxy R 2 is, for example, lower alkoxy or optionally substituted phenyl-lower alkoxy.

389

Acyl in acylated hydroxymethyl Ri or R2 and in acylated hydroxy or acylated amino R ₂ is, for example, acyl derived from an organic carboxylic or sulfonic acid.

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.

Tautomeric forms of compounds of formula I exist, for example, when Rz is hydroxy or amino and the dotted line is intended to indicate that there is a double bond between the carbon atoms bearing the substituents Ri and R ₂ . The enols or enamines of formula I are then in equilibrium with the corresponding keto or ketimine tautomers of the formula

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 (the carbon atom having the radical R3), they can be present, for example, as pure enantiomers or enantiomer mixtures, such as racemates, and if at least one further chiral center is present (For example, the atom Ci, a different from hydrogen R ₂ 4-substituted piperidine radical and / or the atom C3 of a different hydrogen from Ri 3-substituted piperidine), as diastereomers, diastereomer or racemic mixtures. For example, with respect to Ri and R _2, geo-

metric isomers, such as cis and trans isomers, are formed if R 1 and R 2 are other than hydrogen and the dashed line indicates that there is a single bond between the carbon atoms bearing the substituents R 1 and R 2.

Salts of compounds of the formula I or their tautomers are, in particular, corresponding acid addition salts, preferably pharmaceutically usable acid addition salts. These are used, for example, with strong inorganic acids, such as mineral acids, e.g. Sulfuric acid, a phosphoric acid or a hydrochloric acid, with strong organic carboxylic acids, such as lower alkanecarboxylic acids, e.g. Acetic acid, such as optionally unsaturated dicarboxylic acids, e.g. Malonic, maleic or fumaric acid, or hydroxycarboxylic acids, e.g. Tartaric or citric acid, or with sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acids, e.g. Methane or p-toluenesulfonic acid formed. For example, when Ri or R2 is carboxy, corresponding compounds can form salts with bases. Suitable salts with bases include, for example, corresponding alkali metal or alkaline earth metal salts, e.g. 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. Tri-lower alkylamines, such as hydroxy-lower alkylamines, e.g. Mcno-, di- or trihydroxy-lower alkylamines, hydroxy-lower alkyl-lower alkylamines or polyhydroxy-lower alkylamines. Cyclic amines are e.g. Morpholine, thiomorpholine, piperidine or pyrrolidine. Examples of suitable mononized alkylamines are ethyl or t-butylamine, for example di-lower alkylamines, diethyl- or diisopropylamine, trin-lower alkylamines, for example trimethyl- or triethylamine. Hydroxy-lower alkylamines are e.g. Mono-, di- or triethanolamine; Hydroxy lower alkyl lower alkyl amines are e.g. Ν, Ν-dimethylamino or Ν, Ν-diethylaminoethanol; as the polyhydroxy-lower alkylamine, e.g. Glucosamine in question.

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

- 5 - Λ? Ι 389

Above and below, "residues" or compounds, unless defined otherwise, are understood as meaning, in particular, those which contain dis and 7, especially bis and 4, carbon atoms.

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

Lower alkyl is, for example, C 1 -C 4 -alkyl, such as methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl or tart-butyl, and further comprises C ₅ -C 7 -alkyl, ie pentyl, Hexyl or heptyl radicals.

Lower alkyl alkane is e.g. Ci-Ci, -Alkylen, which bridges the two ring systems drawn in formula I primarily by up to and with 3 C-atoms, and may, for. But can also be methylene, ethylene or 1,3-propylene, but also 1,2-propylene, 1,2- or 1,3- (2-methyl) -propylene or 1,2- or 1,3-butylene the two ring systems also by 4 C atoms bridge, ie Represent 1,4-butylene.

Lower alkylidene alk is e.g. Ci-Ci, -Alkyliden and can be used e.g. Methylene, ethylidene, 1,1- or 2,2-propylidene or 1,1- or 2,2-butylidene.

Lower alkanoyl is e.g. Cz-Cs alkanoyl, such as acetyl, propionyl, butyryl, isobutyryl or pivaloyl.

Lower alkanoyloxy is e.g. C2-C5 alkanoyloxy, such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy.

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

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

- 6 - 3,8s 583

Ν, Ν-di-lower alkylcarbamyl is e.g. N, N-di-C 1 -C -alkylcarbamyl, where in each case the two N-alkyl groups may be identical or different, such as Ν, Ν-dimethyl, N, N-diethyl, Ν, Ν-diisopropyl or N- butyl-N-methylcarban.yl.

Ν, Ν-Lower alkylene or NN- (Aza) -, NN- (Oxa) - or N, N- (Thia) -niederalkylencarbamyl has, for example 3 to and with 8, in particular 5 or 6, ring members and means, for example, pyrrolidino -, piperidino, piperazino or N'-lower alkyl, such as N'-methylpiperazino, morpholino or thiomorpholinocarbonyl.

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

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

Lower alkanesulfonyl is e.g. Ci-Ci, -Alkansulfonyl, such as methane or Aethansulfonyl.

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

The compounds of the formula I, their tautomers and / or their pharmaceutically acceptable salts have, for example, valuable pharmacological properties, in particular nootropic properties. For example, they effect in the Two-Compartment Passive Avoidance test model according to Mondadori and Classen, Acta Neurol. Scand. 6j), Suppl. 99, 125 (198A) at dose levels 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 formula I possess a considerable memory-improving effect in the step-down passive avoidance test according to M-> ndadori and Waser, Psythopharmacol. (> 3, 297 (1979)) from a dose of e '; wa 0.1 mg / kg i.p. as well as p.o.

- 7 - iSi 383

Similarly, the compounds of formula I or their tautomers and / or their pharmaceutically acceptable salts can be used as pharmaceuticals, e.g. Nootropics, for example, for the therapeutic and / or prophylactic treatment of cerebral insufficiency symptoms, in particular 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. In this case, the commercial preparation 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 ₁ in which either Ri carboxy, lower dialkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν-di-lower alkylcarbamyl, Ν, Ν-lower-alkylenecarbamyl, NN- (aza) -, NN- (Oxa) - or N, N- (Thia) niederalkylencarbamyl, hydroxymethyl, Niederalkanoyloxymethyl, Niederalkansulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl and R2 is hydrogen, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, lower alkanesulfonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino, lower alkanesulfonylamino, benzoylamino or Pyridoylamino or Ri is hydrogen and R2 is carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, Ν, Ν-di-lower alkylcarbamyl, Ν, Ν-lower alkylenecarbamyl, NN- (aza) -, NN- (oxa) - or N, N- ( Thia) lower alkylene carbamyl, hydroxymethyl, lower alkanoyloxymethyl, Niederalkansulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl and wherein R3 is hydrogen or lower alkyl, Ri ₁ is lower alkyl, Rs is lower alkyl, alk lower alkylene, which bridges the two ring systems shown in formula I by up to and with 3 C atoms, or lower alkylidene, the ring A is unsubstituted or mono-, di- or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, cyano, halo, lower alkyl and / or trifluoromethyl, the dotted line is intended to indicate that there is a single or a double bond between the carbon atoms bearing the substituents Ri and R2, m is 0 or 1 means and where either

- 8 - 283 383

X is an oxygenator or a methylene group and η is 0 or X is a direct bond and η is 1, and their tautomers and / or salts.

The invention relates, in particular, to a process for the preparation of compounds of the formula I in which R _{1 is} C ₁ -C ₁ -alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, or carbamyl, R 1 is hydrogen or hydroxyl, R 3 is hydrogen, R 1, Ci, alkyl, such as methyl, Rs is Ci-Ci, alkyl, such as methyl, alk for Ci-Ci.-alkylene which bridges the two ring systems shown in formula I by bis and with 3 C atoms, such as methylene or ethylene, the ring A is unsubstituted or, in particular in the 6-position, by Ci-Ci, -Alkoxy, such as methoxy, Ci-Ci, -Alkyl, such as methyl, halogen having an atomic number to and with 35, such as Fluorine or chlorine, cyano or trifluoromethyl, which is intended to indicate the dashed line, that between the carbon atoms carrying the substituents Ri and Rz is a single or a double bond, m is 1, X is an oxygen atom or a methylene group means and η stands for 0, and their dew Tomeren and / or salts.

The invention relates in particular to a process for preparing 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, R 1 is C 1 -C 4 -alkyl, such as methyl, R5 is Ci-Ci, alkyl, like methyl, alk stands for ethylene, the ring A unsubstituted or, in particular in the 6-position, simply by halogen with an atom number up to and with 35, like fluorine or chlorine, which is substituted dotted line between the carbon atoms carrying the substituents Ri and R2, a double bond is present, m is 1, X represents a methylene group and η is 0, and their salts.

The invention relates, in the first place, 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, R 1 is C 1 -C 4 -alkyl, such as methyl, R5 is Ci-Ci, -alkyl, such as methyl, alk represents ethylene, the ring A is unsubstituted, the

dashed line is to express that between the carbon atoms which carry the substituents Ri and R2, a double bond is present, m is 1, X represents a methylene group and η is 0, and their salts.

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

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

(Ha)

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

• - ·

HN ^ .y- ^R 2 < ^IIb >

• - t

Ri or a tautomer and / or salt thereof or

b) in a compound of the formula

or a tautomer and / or salt thereof, wherein X2 is a radical other than Ri convertible radical and X5 is a radical R

where R is hydrogen, an optionally etherified or a

acylated hydroxy group or an optionally acylated amino group

- 10 - 0.1h 383

X _{2 is converted} into hydrogen other than Ri or in a compound of formula III or a tautomer and / or salt thereof, wherein X _{2 is} hydrogen and X 5 is a radical convertible into R,

where R, is a radical R2 other than a radical R, X5 in b a

R, convicted or

c) for the preparation of a compound of formula I or a tautomer

and / or salt thereof, wherein Rz is hydroxy or amino and wherein Ri

is different from hydrogen and optionally acylated hydroxymethyl, a compound of the formula

-CH ₂ -Yi XaIk) -NT

IA II C) CH ₂ )

wherein Yi is a group of the formula -CH = R ₂ , -C (Yz) = R ₂ , -CH (Yz) -R ₂ or cyano, wherein R _{2 is} oxo or imino and Y _{2 represents} a leaving group, or a Salt thereof cyclized or

d) for the preparation of a compound of formula I ¹ , wherein Rz is oxo or imino and Ri is other than hydrogen, or a tautomer and / or salt thereof, a compound of formula

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

X ₃ -Ri (Vb)

or a salt thereof, wherein Ri is other than hydrogen and X3 is halogen or lower alkoxy, or

e) for the derivation of a compound of the formula I or of 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

/ \ / * ~ \ Ri CVD

or a salt thereof, wherein Xi, a radical convertible to R2, Xi _{1 converted} to R2 or

f) in a salt of the formula

where A is the anion of an acid, R "is Ri or etherified or protected hydroxymethyl, and R2 ^{1 is} R2, protected hydroxy, protected amino or etherified or protected hydroxymethyl which reduces excess double bonds to single bonds and, if R" of Ri and / or R 2 of R "in Ri and / or R2 ^1, R2 is different, converted in R2 or

g) for the preparation of a compound of the formula I or of a tautomer and / or salt thereof, in which R 2 is carboxy, amidated carboxy or lower alkoxycarbonyl and the dashed line is to indicate that between the carbon atoms bearing the substituents R 1 and R 2 Single bond is present, a compound of the formula

_ 12 - Q, 8 S ? <53

_ (alk) -l / ^N CH ₂ -R ₂

J / * X τη Χ

ΓΛ - CH (Y ₂ ) -Ri

(VIII)

wherein Y _{2 represents} a cleavable radical, or a salt thereof cyclized and each one optionally eliminates a protecting group and, if desired, a process according or otherwise obtainable compound of formula I converted into another compound of formula I, in each case an isomeric mixture obtainable according to the method in the Separates components, in each case an enantiomer or diastereomer mixture obtainable according to the method 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 in accordance with the method into the free compound of the formula I or into a converts other salt.

The reactions described above and below in the variants are carried out in a manner known per se, for example in a waste or usually in the presence of a suitable solvent or diluent or a mixture thereof, with cooling, at room temperature or with heating as required For example, in a temperature range of about -10 ° to the boiling point 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 Ha and Hb, III, IV, Va and Vb, VI, VII and VIII, which was developed for the preparation of the compounds of formula I. their tautomers and salts, is known in part or may also according to known methods, eg analogously to the process variants described above.

- 13 -

Starting material with basic centers can e.g. in the form of acid addition salts, for example with the acids listed above, while starting compounds with acidic groups, salts with bases, e.g. of the aforementioned type can form. Further, starting compounds may be in the form of tautomers, especially compounds of the formula Hb, wherein R 2 is hydroxy and the dashed line is intended to indicate that a double bond is present between the carbon atoms bearing the substituents R 1 and R 2.

Variant a) i

Reactive esterified hydroxy means, in particular, hydroxy esterified with a strong inorganic acid or organic sulfonic acid, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, e.g. Fluorosulfonyloxy, optionally, e.g. by halogen, substituted lower alkanesulphonyloxy, e.g. Methane or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g. Cyclohexanesulfonyloxy, or optionally, e.g. by lower alkyl or halogen, substituted benzenesulfonyloxy, e.g. 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. Suitable bases are, for example, alkali metal hydroxides, hydrides, amides, alkoxides, carbonates, triphenylmethylidene, -diliederalkylamides, -aminoloweralkylamides or lower alkylsilylamides, naphthalenamine, lower alkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines. Examples of these are sodium hydroxide, hydride, amide, ethylate, potassium tert-butoxide, carbonate, lithium triphenylmethylid, lithium diisopropylamide, potassium 3- (aminopropyl) amide, bis (trimethylsilyl) amide, dimethylaminonaphthalene, di or triethylamine, pyridine, benzyltrimethylanevonium hydroxide, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and 1,5-diaza-bicyclot5.4.0] undec-5-ene (DBU ) called.

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

- 14 - 2.83 3 * 3

Variant b)!

A radical X2 which can be converted into R 1 into a radical R and is, for example, a functionally modified carboxy other than R i or R, such as cyano, anhydridized carboxy, optionally substituted amidino, optionally esterified or anhydridized carboximidoyl, of esterified or amidated carboxy Ri or R ₂ different esterified or amidated carboxy, tri-lower alkoxy or trihalomethyl.

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 alkanoyloxycarbonyl, such as acetoxycarbonyl, or lower alkoxycarbonyloxycarbonyl, such as ethoxycarbonyloxycarbonyl.

Substituted amidino is exemplified by an aliphatic radical, e.g. Lower alkyl, substituted amidino, such as lower alkylamidino, e.g. Aethylamidino.

Among esterified or anhydrided carboximidoyl is e.g. Alkoxy, or Halogencarboximidoyl, for example, lower alkoxy, such as ethoxy, or chloro-carboximidoyl to understand.

Trinoweralkoxy or trihalomethyl is e.g. Trimethoxymethyl or trichloromethyl.

Radicals R ₁ are, for example, carboxy, lower alkoxycarbonyl, amidated carboxy or optionally acylated hydroxymethyl radicals R ₂ .

X ₂ can be converted, for example, by solvolysis into Ri other than hydrogen, just as Xs can be converted, for example, by solvolysis into a radical R 1. Solvolysemittel are, for example, water, the desired esterified carboxy Ri or R ₂ corresponding lower alkanols, ammonia or the desired amidated carboxy group Ri

- 15 -

or R ₂ corresponding amines. The treatment with a corresponding solvolysis agent is optionally carried out in the presence of an acid or base. Suitable acids are, for example, inorganic or organic protic acids, such as mineral acids, for example sulfuric acid or hydrogen halide, for example hydrochloric acid, such as sulfonic acids, for example lower alkane or optionally substituted benzenesulfonic acid, for example methane- or p-toluenesulfonic acid, or carboxylic acids, for example lower alkanecarboxylic acids, for example acetic acid, in question, while as bases, for example, those mentioned under variant a) can be used, in particular sodium or potassium hydroxide.

In the solvolysis, the cyano group, anhydridized carboxy, optionally substituted amidino, optionally esterified or anhydridised carboximidoyl, esterified or amidated carboxy, tri-lower alkoxy or trihalomethyl other than esterified or amidated carboxy Ri or R _{2 are} hydrolyzed to carboxy. In this case, optionally located on the ring A Niederalkanoyloxyreste be hydrolyzed in the course of the hydrolysis to hydroxy.

Cynno, 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 ammonia or an amidated carboxy Ri or R ₂ corresponding amine ammonia or aminolysed.

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

(Ua)

with a compound of the formula

- 16 -

^ .y ^Xs (HIa)

• - ·

X ₂

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

Compounds of the formula III in which X.sup.2 is a radical which is convertible into hydrogen other than hydrogen and X.sup.5 is hydroxyl or amino can advantageously also be obtained by cyclization of a compound of the formula ## STR5 ##

-CH ₂ -Y ₁ (alk) -NT

« ^{N N.} -Cn ₂ -X ₂

wherein Yi represents a group of the formula -CH = Ri, -C (Ya) = R ₂ , -CH (Y ₂ ) -R ₂ or cyano, wherein R _{2 is} oxo or imino, R _{2 is} hydroxy or amino and Y _{2 is} a can be cleavable radical, or a salt thereof can be prepared, wherein, for example, worked in an analogous manner as indicated under process variant c).

Variant c):

Cleavable radicals Y ₂ in groups of the formula -C (Y ₂ ) = R ₂ or -CH (Y ₂ ) -R ₂ 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, for example fluorosulfonyloxy, optionally substituted, for example by halogen, substituted lower alkanesulfonyloxy, eg methane- or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, eg cyclohexanesulfonyloxy, or benzenesulfonyloxy optionally substituted, for example by lower alkyl or halogen, eg Bromophenyl or p-Toluolsulfonylc \ y, or etherified hydroxy groups, for example lower alkoxy or optionally substituted Phenylniederaikoxy.

- 17 - 3S * 3 * 3

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

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

• - ·

(alk) -N ^ ^N CH = R ₂ m \

: ch ₂ )

wherein R ₂ ¹ oxo or imino, the treatment with one of said bases, in particular with an alkali metal lower alkoxide, eg with Natrijmmethanolat or sodium ethoxide, subject. In this case, the compound IVa cyclizes to a compound of formula I, wherein the dashed line indicates that between the carbon atoms, many carry the substituents Ri and R ₂ , there is a single bond, and wherein R _{2 is} hydroxy or amino. Starting materials IVa are obtained, for example, by reacting a reactive alkyl ester of the formula

IA II LCH ₂ )

-VV _x / "

Rs X

wherein Xi is reactive; esterified hydroxy, with a compound of the formula H ₂ N-CH ₂ -CH ₂ -RI (IVb) and the resulting intermediate of the formula

(alk) -N-CH ₂ CH ₂ -Ri

, Y / ^m A

IA l'l CCH ₂ )

VV · ⁷

- 18 - ώίϊ. 389

with acrolein or an optionally functionally modified aldehyde of the formula Yi-CH ₂ -CH ₂ -CH = R ₂ '(IVd; Y ₁ = reactive esterified hydroxy, R ₂ ¹ = oxo or imino).

In another preferred embodiment of variant c) is cyclized a compound of formula IV, wherein Yi and Ri Niederalkoxycarb ^ nyl mean, ie wherein Yi is a group of the formula -C (Y ₂ ) = R ₂ , in which ^{ρ is} ί oxo and the leaving group Y ₂ as etherified hydroxy having a Nieaeralkoxyg.uppe, to the corresponding compound of formula I ', wherein R _{2 is} oxo and Ri is lower alkoxycarbonyl.

To prepare the latter starting compounds of the formula IV, it is possible, for example, to obtain compounds of the formula

IaS \ h)

• ν · / η

Rs Κΐι

or salts thereof, which are e.g. are obtainable by reduction of the corresponding nitriles, and these? with at least 2 moles of a compound of the formula

/ \ (ivf)

to react.

Variant d):

The C-acylation according to the process 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

(aik) -X ₁ m

(Ha)

: ci ₂ ) ^

with a compound of the formula

^ ^ = R ₂ (Vc)

• - ·

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

Variant e):

In a radical R _{2 of} the specified type convertible radicals Xi are, for example, by solvolysis, ie reaction with a corresponding compound of formula R ₂ H or a salt thereof, in such a group R ₂ convertible radicals, for example halogen atoms, for example chlorine, bromine or iodine. Hydroxy X ₂ convertible radicals X u are also diazonium groups, for example of the formula -N ₂ A, where A is the anion of a strong acid, such as a mineral acid, for example the chloride or sulfate ion.

The solvolysis is carried out in a customary manner, for example in the presence of a base such as an alkali metal or alkaline earth metal hydroxide, for example sodium or potassium hydroxide, or a tertiary nitrogen base, for example a tri-lower alkylamine, such as triethylamine, or a heteroaromatic nitrogen base, such as pyridine, or a quaternary ammonium hydroxide, such as benzyltrimethylammonium hydroxide, or by using the compound R ₂ H in the form of a metal salt, for example of the formula R ₂ M, in which M is an alkali metal cation, such as the sodium ion. Advantageously, one works in the presence of a solvent or diluent, for example in an excess of the reaction component R ₂ H and / or a miscible inert solvent, if necessary, with cooling or heating, for example in the temperature range of about 0 ° to 120 ⁰ C, and / or under inert gas, such as nitrogen.

- 20 -

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

To prepare Ausgangeverbindungen of formula VI and salts thereof, for example, compounds of the formula Ha

and sets this with a corresponding connection of the F.ormel

• - ·

HN .y '~ ^x " ^(VIa)

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

In a preferred embodiment there are obtained compounds VI wherein Xi, is halogen and the dotted line indicates that there is a single bond between the carbon atoms bearing the substituents Ri and Xi and their salts by reacting a compound of the formula I, wherein R 2 signifies hydroxy and the dotted line indicates that there is a single bond between the carbon atoms bearing the substituents R 1 and R 2, or a salt thereof with a halogenating agent, such as phosphorus tri- or pentachloride or thionyl chloride; corresponding compounds I and their salts can be obtained, for example, in an analogous manner as described under process variant a) or c).

- 21 -

Variant f) t

The anion A is, for example, the anion of a strong protic acid, e.g. a halide ion such as chloride, bromide or iodide ion, or a sulfonation such as an optionally substituted lower alkane or benzenesulfonate ion, e.g. the methanesulfonate, ethanesulfonate or p-bromobenzenesulfonate or p-toluenesulfonate ion. Protected hydroxy is, for example, silyloxy, such as triphylene alkylsilyloxy, e.g. Trimethylsilyloxy, but may also be triphenyl-lower alkoxy, e.g. Trityloxy, his. Protected amino is, for example, silylamino, such as tri-lower alkylsilylamino, e.g. Trimethylsilylamino, but may also be phenyl, diphenyl or Triphenylniederalkylamino, such as benzylamino, diphenylamines or tritylamino. Etherified hydroxymethyl is, for example, lower alkoxymethyl, such as methoxy or ethoxymethyl, or optionally substituted phenyl-lower alkoxymethyl, e.g. in the phenyl moiety substituted phenyl Ci-Cit-alkoxymethyl, such as benzyloxy, p-chlorobenzyloxy, 1-Phenyläthyloxy- or l- (p-bromophenyl) -n-butyloxymethyl. Protected hydroxymethyl is, for example, silyloxymethyl, such as tri-lower alkylsilyl, e.g. Trimethylsilyloxymethyl, but can also Triphenylniederalkoxy-, e.g. Trityloxymethyl, be.

Process variant f) is particularly suitable for preparing a compound of the formula I or a tautomer and / or salt thereof in which either Ri is carboxy, lower alkoxycarbonyl, amidated carboxy or hydroxymethyl and Rz is hydrogen, hydroxy or amino or Ri is hydrogen and R2 is carboxy, lower alkoxycarbonyl, amidated carboxy or hydroxymethyl.

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-transferring reagent or by reduction with a metallic reduction system of metal and proton-releasing agent.

As hydrogenation catalysts there are e.g. Elements of Group VIII of the Periodic Table of the Elements or their derivatives, such as palladium, platinum, platinum oxide, ruthenium, rhodium, tris (triphenylphosphine) rhodium-1-halide, e.g. chloride, or Raney nickel, the

- 22 - .2 * 3 383

optionally coated on a support material, such as activated carbon, an alkali metal carbonate or sulfate or a silica gel. Suitable hydride-transferring reagents are, for example, suitable light metal hydrides, in particular alkali metal aluminum hydrides or borohydrides, such as lithium aluminum hydride, lithium triethyl borohydride, sodium borohydride, sodium cyanoborohydride, or tin hydrides, such as triethyl- or tributyltin hydride, or diborane. The metal component of the metallic reduction system is, for example, a non-noble metal such as alkali or alkaline earth metal, e.g. Lithium, sodium, potassium, magnesium or calcium, or transition metal, e.g. Zinc, tin, iron or titanium, while as proton-releasing agents e.g. Protonic 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 / salt or acetic acid or zinc / ethanol.

If R'i of Ri and / or RV is different from R2, the conversion of R "into Ri and / or R2 in R2, ie the removal of the protective groups and thus the release of the corresponding radicals Ri and / or R2, in the same or in a subsequent reaction step, which is carried out in a customary manner, for example as described in connection with process variant g).

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

(Ha),

wherein Xi is reactive esterified hydroxy, which in simply negatively charged form corresponds to the anion A, with compounds of the formula

(VIIa)

- 23 - äS5 383

or a salt thereof, e.g. in an analogous manner as described under process variant a).

Variant g):

Cleavable radicals Y2 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, e.g. Fluorosulfonyloxy, optionally, e.g. by halogen, substituted lower alkanesulphonyloxy, e.g. Methane or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g. Cyclohexanesulfonyloxy, or optionally, e.g. by lower alkyl or halogen, substituted benzenesulfonyloxy, e.g. p-bromophenyl or p-toluenesulfonyloxy, or etherified hydroxy groups, for example lower alkoxy or optionally substituted phenyl-lower alkoxy.

The cyclization can be carried out, for example, in the presence of one of the bases mentioned under variant a), in particular in the presence of an alkali metal lower alkanolate, e.g. with sodium methoxide or ethanolate.

The starting materials VIII were obtained, for example, by reacting a compound of the formula

_y (alk) _IjI-C

(IVh)

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

In the starting materials of the formulas Hb, III, IIIa, IV, IVg, VII and VIa, a hydroxy group R ₂ in etherified or a hydroxy or amino group R _{2 may} also be present in intermediate slotted form, as well as a hydroxymethyl group Ri or R ₂ may be present in etherified or intermediately protected form in compounds Hb, IVi, Vb, VI, VIa, VII, VIIa and VIII. Protected hydroxy is, for example, silyloxy, such as tri-

- 24 -. 2.83 383

lower alkylsilyloxy, e.g. Trimethylsilyloxy, but may also be triphenyl-lower alkoxy, e.g. Trityloxy, his. Protected amino is, for example, silyla. Ino, such as tri-lower alkylsilylamino, e.g. Trimethylsilylamino, but can 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, e.g. in the phenyl moiety substituted phenyl Ci-Cit-alkoxymethyl, such as benzyloxy, p-chlorobenzyloxy, 1-Phenyläthyloxy- or 1- (p-bromophenyl) -n-butyloxymethyl. Protected hydroxymethyl is, for example, silyloxymethyl, such as tri-lower alkylsilyl, e.g. Trimethylsilyloxymethyl, but can also Triphenylniederalkoxy-, e.g. Trityloxymethyl, be.

The release etherified or intermediately protected residues Ri or R2ι ie cleavage of the intermediate protecting groups, in a conventional manner, for example by solvolysis, such as mild hydrolysis, eg treatment with water under neutral or weakly acidic conditions, for example by the action of dilute-aqueous mineral - or carboxylic acids, for example of dilute hydrochloric or acetic acid. In an analogous manner, the release of intermediately protected hydroxy and amino groups R ₂ and of etherified or protected hydroxymethyl groups R "and R'2 ¹ in starting materials of the formula VII or VIIa.

According to the method or otherwise available compounds of formula I can be converted in a conventional manner into other compounds of formula I.

For example, it is possible to add esterified or amidated carboxy groups R 1 and R ₂ in a customary manner, for example in the presence of a basic or acidic hydrolysis agent, such as an alkali metal hydroxide or carbonate, for example sodium hydroxide or potassium carbonate, or a mineral acid, for example hydrochloric acid or sulfuric acid Carboxy Ri or R ₂ hydrolyze. Esterified carboxy groups R 1 and R ₂ can furthermore be prepared by transesterification, ie treatment with an alcohol in the presence of an acidic or basic solvolysis agent, such as a mineral acid, for example of sulfuric acid, or of a corresponding alkali metal alcoholate or an alkali metal hydroxide, into other esterified carboxy groups R 1 and R _2.

- 25 -

R2 or converted by reaction with ammonia or a corresponding at least one hydrogen atom having amine in amidated carboxy Ri or R2.

Free carboxy Ri or R2 can be prepared in the usual way, for example by treatment with a corresponding alcohol in the presence of a mineral acid, e.g. of sulfuric acid, or by conversion to a halide and subsequent reaction with a corresponding alcohol, e.g. 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, are converted into esterified carboxy Ri or R2. Also, a carboxy compound can be esterified using a dehydrating agent such as Ν, Ν'-dicyclohexylcarbodiimide with a corresponding alcohol. Free or esterified carboxy Ri or R2 may also be prepared by reaction with ammonia or an amine having at least one hydrogen atom and dehydration of the intermediate ammonium salt, e.g. by heating or by means of a dehydrating agent, such as Ν, Ν'-dicyclohexylcarbodiimide, or by conversion: Ln the halide and subsequent reaction with ammonia or an amine having at least one hydrogen atom are converted into amidated carboxy Ri or R2.

Further, one may optionally esterify existing hydroxy groups, e.g. by treatment with a Niederalkancarbonsaureanhydrid or halide in Niederalkanoyloxy or convert by reaction with a reactive ester, in particular bromine or hydrochloric acid ester of a lower alkanol in corresponding etherified hydroxy. Conversely, from esterified or etherified hydroxy, such as lower alkanoyloxy or lower alkoxy, it is possible to release the hydroxy group solvolytically, preferably under acidic conditions. In an analogous manner, it is also possible to hydrolyze etherified or acylated hydroxy R2 to hydroxy.

Accordingly, one can continue to esterify hydroxymethyl Ri or R ₂ , for example, by treatment with a Niederalkancarbonsaureanhydrid or halide in Niederalkanoyloxymethyl Ri or R2 convert. Conversely, you can go out

- 26 - i * i 383

acylated hydroxymethyl, eg lower alkanoyloxymethyl, Ri or R ₂ solvolytically release the hydroxy group, preferably under acidic conditions.

Furthermore, hydroxymethyl Ri or R2 can be converted in the usual way in lower alkoxycarbonyl or amidated carboxy Ri or R ₂ , for example, in such a way that initially hydroxymethyl Ri or R ₂ in a conventional manner, for example in the presence of an oxidizing agent, such as Potassium permanganate or potassium dichromate, to carboxy oxidizes confused! and anichliessend the carboxy group in the usual manner, for example by treatment with an appropriate alcohol in the presence of a mineral acid, for example of sulfuric acid, or by conversion to a halide and subsequent reaction with an appropriate alcohol, for example in the presence of pyridine or triethylamine, or by conversion in an alkali metal salt and subsequent reaction with a reactive ester of the corresponding alcohol, such as a corresponding halide, or using a dehydrating agent, such as N, N'-dicyclohexylcarbodiimide, with a corresponding alcohol in lower alkoxycarbonyl Ri or R ₂ or by reaction with ammonia or a at least one hydrogen atom-containing amine and dehydration of the intermediate ammonium salt, for example by heating or by means of a dehydrating agent, such as Ν, Ν'-dicyclohexylcarbodiimide, or by conversion to the halide and subsequent reaction with ammonia or An amine having at least one hydrogen atom is converted into amidated carboxy Ri or R ₂ . It is likewise possible to convert acylated hydroxymethyl Ri or R ₂ into esterified or amidated carboxy Ri or R ₂ by first solvolytically liberating the acylated hydroxymethyl group, for example as described above, and then the resulting free hydroxymethyl group, as explained above, into a carboxyl group and the latter is further converted to an esterified or amidated carboxyl group. Conversely, esterified or amidated carboxy groups Ri and R _{2 can be converted} into optionally acylated hydroxymethyl Ri or R ₂ by first the esterified or amidated carboxy group Ri or R ₂ in a conventional manner, for example in the presence of a basic or acidic hydrolysis, such as an alkali metal hydroxide or carbonate, for example sodium hydroxide or potassium carbonate, or a mineral acid, for example hydrochloric acid or sulfuric acid,

- 27 - £ 3,383

hydrolyzed to carboxy and then the resulting carboxy group in the usual manner, e.g. in the presence of a reducing agent, for example of the type mentioned above, reduced to hydroxymethyl Ri or Ra, if desired, the latter, e.g. as described above, can then be converted into acylated hydroxymethyl Ri or R2.

In compounds of formula I in which the dotted line indicates that there is a double bond between the carbon atoms carrying the substituents Ri and R2, this may be e.g. in a manner known per se with the aid of a reducing agent, e.g. the species listed under variant f) are hydrogenated to a single bond.

Further, a compound of formula I in which the dotted line indicates that there is a double bond between the carbon atoms bearing the substituents Ri and R2, and R2 is hydrogen, e.g. in a conventional manner by addition of a compound R2-H in which Ra is an optionally vera'therte or acylated hydroxy group or an optionally acylated amino group, are converted into a corresponding piperidine compound. The addition is carried out in particular in the presence of a suitable base, e.g. the type listed under variant a) performed.

Compounds of formula i in which the dotted line indicates that there is a single bond between the carbon atoms carrying the substituents Ri and R2 can be reversed, for example by elimination of a compound R2-H in which R2 is optionally ethereal or acylated Represented hydroxy group or an optionally acylated amino group, in a conventional manner in corresponding tetrahydro-pyridine compounds in which R 2 is hydrogen, are transferred. For elimination, less suitable leaving groups R 2, for example hydroxy, can be converted beforehand, for example in situ , into more suitable leaving groups R 2, for example lower alkanesulphonyloxy, such as methanesulphonyloxy, or halogen, such as chlorine, bromine or iodine. The elimination takes place in particular in the presence of a suitable base, for example of the type listed under variant a).

- 28 - Λ83 383

Salts of compounds of the formula I or of their tautomers can be prepared in a manner known to them. Thus, for example, acid pronation salts of compounds of the formula I are obtained by treatment with an acid or a suitable ion exchange reagent. Salts may be converted in the usual way into the free compounds of formula I, acid addition salts e.g. by treating with a suitable basic agent.

Depending on the procedure or reaction conditions, the compounds of formula 1 can be obtained with salt-forming, in particular basic, properties in free form or in the form of salts.

Owing to the close relationship between the novel compound of the formula I in free form and in the form of their salts, the corresponding salts or the free compound of the formula ## STR5 ## are optionally present and subsequent below the free compound of the formula I or its salts I understand.

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

Depending on the choice of starting materials and procedures, the novel compounds of the formula I can be present in the form of one of the possible isomers or as a mixture thereof. In this case, depending on the molecular symmetry, e.g. 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 Kacemate, Diastereomerengemische or racemic mixtures are present.

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.

- 29 -

Enantiomer mixtures obtained, such as racemates, can be decomposed according to 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, on the formation of inclusion compounds, eg using chiral crown ether, wherein only one enantiomer is complexed, or by conversion to diastereomeric salts, e.g. by reacting a basic end-product racemate with an optically active acid such as carboxylic acid, e.g. Tartaric or malic acid, or sulphonic acid, e.g. Camphorsulfonic acid, and separation of the thus obtained diastereomeric mixture, e.g. due to their different solubilities, into the diastereomers from which the desired enantiomer can be released by the action of suitable means. Advantageously, one isolates the more effective enantiomer.

The invention also relates to those embodiments of the process according to which one starts from an intermediate obtainable 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 especially under the reaction conditions ev.

The process of the present invention preferably uses those starting materials which lead to the compounds of the formula I described above as being particularly valuable. The process for the preparation of novel starting materials which have been specially developed for the preparation of the compounds of formula I and their use also form an object of the invention, wherein the variables R ₁ , R a, R ₃ , Ri ₁ , Rs, X, m, η and alk and the substituents of the ring A and the dashed line have the meanings given for the respective preferred compound groups of the formula I.

The invention also relates to the use of compounds of the formula I or of their tautomers and of pharmaceutically usable salts of such compounds having salt-forming properties, in particular as a pharmacological, primarily nootropic, effective active ingredient.

- 30 -

punch. They may be used, preferably in the form of pharmaceutically acceptable preparations, in a process for the prophylactic and / or therapeutic treatment of the animal or human body, in particular as nootropics, e.g. for the treatment of cerebral insufficiency symptoms, in particular memory disorders.

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

The pharmaceutical preparations obtainable according to the invention and containing a compound of the formula I or a tautomer and / or a pharmaceutically acceptable salt thereof are those for enteral, such as oral, rectal, and pare.iteral administration to warm-blooded animals; phaimakologische drug is contained 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 for enteral or parenteral administration obtainable according to the invention are e.g. those in unit dosage forms such as dragees, tablets, capsules or suppositories, and also ampoules. These are produced in a manner known per se, e.g. produced 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 dragee cores ,

Suitable carriers are, in particular, fillers, such as sugars, e.g. Lactose, sucrose, m-indite or sorbitol, cellulose prep., And / or calcium phosphate, e.g. Tricalcium phosphate or calcium hydrogen phosphate, also binders such as starch pastes using e.g. corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and / or polyvinylpyrrolidone, if desired, disintegrants such as

- 31 -

above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Auxiliaries are primarily flow regulators and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable, possibly gastric juice-resistant coatings, which u.a. concentrated sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. for the identification or labeling of different doses of active substance.

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 Fon., A granule, 2.B. in admixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible for stabilizers to be added.

As rectally applicable pharmaceutical preparations are e.g. Suppositories which consist of a combination of the active ingredient with a suppository base. As suppository base, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polystylene glycols or higher alkanols. Fernor may also be used gelatin rectal capsules containing a combination of the active ingredient with a basic bulking agent. As basic materials there are e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.

- 32 - Asa 123

For parenteral administration, aqueous solutions of an active ingredient in water-soluble form, e.g. a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, whereby suitable lipophilic solvents or vehicles such as fatty oils, e.g. Sesame oil, or synthetic fatty acid esters, e.g. Ethyl oleate or triglycerides, or aqueous injection suspensions containing viscosity increasing agents, e.g. Nntriumcarboxymethylceilulose, sorbitol and / or dextran, and optionally also contain stabilizers.

The dosage of the active ingredient may depend on various factors, such as mode of administration, species of warm-blooded animals, age and / or individual condition. In the normal case, for an approximately 75 kg of warm-blooded animals when administered orally, an approximate daily dose of about 20 to about 500 i.ig, in particular from about 25 to about 250 mg, advantageously in several equal sub-doses to estimate.

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.

AusführungsbeispieIe

As a result of the close relationship between a compound of the formula I and the corresponding tautomeric compound of the formula I ¹ , in the examples a compound of the formula I is to be understood as meaningful and expedient, if appropriate, also the tautomeric compound of the formula I '. The same applies to a compound of the formula I ¹ and to salts of compounds of the formulas I and I '.

Example 1: A solution of 9 g (25 mmol) of 2,2-dimethyl-3- [2- (4-toluenesulfonyloxy) ethyl] -chroman in 100 ml of N, N-dimethylformamide is first mixed with 5.55 g (25 mmol ) 1,2, So-tetrahydro-pyridine-ß-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then with 11.31 g (87.5 mmol) of N-ethyl-NN-diisopropyl-amine. The solution is stirred for 15 hours at 60 ° and then evaporated in a high vacuum. The residue is mixed with water and extracted with diethyl ether.

- 33 -

The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline while cooling with sodium hydroxide solution (30%) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. This gives 5.52 g (67% of theory) of 1- [2- (2,2-dimethylchroman-3-yl) ethyl] -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester as pale yellow Oei. The l- [2- (2,2-dimethylchroman-3-yl) ethyl] -l, 2,5,6-tetrahydro-pyridine-S-carboxylic acid methyl ester hydrochloride prepared therefrom with hydrochloric acid in diethyl ether crystallizes from methanol / diethyl ether and melts at 196-197 °.

The 2,2-dimethyl-3- [2- (4-toluenesulfonyloxy) ethyl] -chroman can be e.g. recovered as follows:

25 g (0.6 mol) of sodium hydride dispersion (57% in mineral oil) are extensively freed from mineral oil by repeated washing with η-hexane and then covered with 500 ml of dried tetrahydrofuran. Under nitrogen and cooling in an ice bath, 134 g (0.6 mol) of phosphonoacetic acid of the formula (H5C20) ₂ P (OO) CH ₂ C (OO) OC ₂ H 5 are added dropwise within 1 hour. The mixture is stirred for a further hour at 0 °. To the homogeneous solution, a solution of 88.57 g (0.5 mol) of 2,2-dimethyl-3-oxo-chroman [F. Camps et al., J. Heterocyclic Chem. 2g, 1421 (1985)] in 300 ml of tetrahydrofuran. It is stirred overnight at room temperature. Then, the solution is concentrated in vacuo to about 350 ml and poured onto 3 l of ice-cold Phophatpufferlösung _r (pH = 6). The mixture is extracted with diethyl ether. The washed with water and dried over sodium sulfate combined organic phases are evaporated in vacuo. The yellow residue is chromatographed on 4 kg of silica gel (0.040-0.063 mm) with toluene as the eluent. This gives 60.3 g (49% of theory) of 3-ethoxycarbonylmethyl-2,2-dimethyl-2H-chromene as pale yellow oil.

A solution of 59.1 g (0.24 mol) of 3-ethoxycarbonylmethyl-2,2-dimethyl-2H-chromene in 400 ml of absolute ethanol is mixed with 3 g of palladium on carbon (5%) and in a PARR apparatus at Room temperature during

_ 34 -

Hydrogenated for 2 hours. The reaction mixture is then filtered through diatomaceous earth. The filtrate is evaporated to dryness. The oily residue consists of pure 3-ethoxycarbonylmethyl-2,2-dimethylchroman.

To a suspension of 7.6 g (0.2 mol) of lithium aluminum hydride in 200 ml of absolute diethyl ether is under ice-cooling, a solution of 50 g (0.2 mol) of 3-Aethoxycarbonylmethyl-2,2-dimethyl-chroman in 250 ml of absolute diethyl ether added dropwise within 1 hour. The reaction mixture is

Stirred for 3 hours at room temperature and then carefully decomposed with 7.5 ml of water, 7.5 ml of sodium hydroxide solution (15%) and 23 ml of water. The precipitate is filtered off. The filtrate, dried over sodium sulphate, is evaporated in vacuo. This gives 39.5 g (95% of theory) of 2,2-dimethyl-3- (2-hydroxyethyl) -chroman in the form of a colorless oil.

A solution of 37.1 g (0.18 mol) of 2,2-dimethyl-3- (2-hydroxyethyl) -chroman in 150 ml of pyridine is added at room temperature with stirring with 38 g (0.2 mol) of 4-toluenesulfonyl chloride wherein the slightly exothermic reaction is maintained at room temperature with an ice bath. The mixture is stirred for 4 hours at room temperature. The reaction mixture is then poured into ice-water and extracted with diethyl ether. The combined ethereal phases are washed three times with 150 ml of citric acid solution (5 %) and three times with 150 ml of water, dried over sodium sulfate and evaporated. This gives 59.1 g (89% of theory) of 2,2-dimethyl-3- [2- (4-toluenesulfonyloxy) ethyl] -chroman as yellow OeI, which is used in this form.

Example 2: In a solution of 5.66 g (15 mmol) of N- [2- (2,2-dimethylchroman-3-yl) ethyl] -N, N-bis (2-methoxycarbonylethyl) -amine in 50 ml of absolute Bei, Ν-dimethylformamide are added at room temperature with stirring within 30 minutes 0.87 g (18 mmol) of sodium hydride dispersion in mineral oil (50%). The reaction mixture is stirred for 1 hour 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 1.95 g (34% of theory) of 1- [2- (2,2-dimethylchroman-3-yl) ethyl] -4-hydroxy-l, 2,5,6-tetrahydropyridine-3 -carboxylic

- 35 -

acid methyl ester hydrochloride or 1- [2- (2,2-dimethylchroman-3-yl) ethyl] -4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride which, after recrystallization from methanol / diethyl ether, has a decomposition range of 168-170 ° owns.

N- [2- (2,2-dimethylchroman-3-yl) ethyl] -N, N-bis (2-methoxycarbonylethyl) -amine can e.g. be prepared in the following way:

A solution of 14.4 g (40 mmol) of 2,2-dimethyl-3- [2- (4-toluenesulfonyloxy) -a'-thyl] -chroman (prepared as described in Example 1) in 200 ml of ethanol is treated with a solution of 3.9 g (60 mmol) of sodium azide in 10 ml of water. The mixture is refluxed for 18 hours. After cooling, the ethanol is evaporated in vacuo and the residue is treated with water and extracted with dichloromethane. The dichloromethane phase is washed with water, dried over sodium sulfate and evaporated. 8.7 g (94% of theory) of 3- (2-azidoethyl) -2,2-dimethylchroman are obtained in the form of a yellow oil.

A solution of 6.94 g (30 mmol) of 3 ~ (2-azidoethyl) -2,2-dimethylchroman in 100 ml of absolute tetrahydrofuran is added to a stirred in a nitrogen atmosphere suspension of 1.14 g (30 mmol) of lithium aluminum hydride 100 ml of absolute diethyl ether added dropwise within 1 hour at room temperature. After stirring for a further 2 hours, the reaction mixture is hydrolyzed with 1.14 ml of water, 1.14 ml of sodium hydroxide solution (15%) and 3.4 ml of water. The resulting precipitate is filtered off with suction and the filtrate is completely evaporated in vacuo. The OeI obtained as residue is dissolved in 150 ml of diethyl ether and the solution is extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline with concentrated sodium hydroxide solution under ice-cooling and extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. This gives 5.6 g (91% of theory) of 3- (2-aminoethyl) -2,2-dimethyl-chroman as a yellow oil whose hydrochloride melts at 245-248 ° with decomposition.

A solution of 5.13 g (25 mmol) of 3- (2-aminoethyl) -2,2-dimethylchroman in 50 ml of methanol is admixed at room temperature with 4.74 g (55 mmol) of methyl acrylate. The mixture is allowed to stand at room temperature for 16 hours

- 36 -

stirred and then evaporated in vacuo. This gives 9, A3 g (100% of theory) of N- [2- (2,2-dimethylchroman-3-yl) ethyl] -N, N-bis (2-methoxycarbonylethyl) -amine as pale yellow oil, that will continue to be used in this form.

Example 3: In an analogous manner as described in Examples 1 and 2, it is also possible to prepare the following compounds or in each case a salt thereof:

1- [2- (2,2-dimethyl-6-fluorochroman-3-yl) ethyl] -1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester and

methyl 1- [2- (6-cyano-2,2-dimethylchroman-3-yl) ethyl] -4-hydroxy-1,2,5-tetrahydro-pyridine-3-carboxylate or the [2- (6-cyano-2,2-dimethyl-chroman-3-yl) ethyl] -A-oxo-piperidin-3-carbonsäuremethylester.

Example A: Tablets containing 25 mg of the active ingredient, for example, 1- [2- (2,2-dimethylchroman-3-yl) ethyl] -1,2'-o-tetrahydro-pyridine-S-carboxylic acid methyl ester hydrochloride be prepared as follows:

Ingredients (for 1000 tablets):

Active ingredient 25.0 g

Lactose 100.7 g

Wheat starch 7.5g

Polyethylene glycol 6000 5.0 g

Talc 5.0 g

Magnesium stearate 1.8 g

demineralised water q.s.

Preparation: All solid ingredients are first driven through a sieve of 0.6 mm 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 AO ml of water and added to this suspension to a boiling solution of polyethylene glycol in 100 ml of water. The resulting starch paste is added to the bulk and the mixture, if necessary with the addition of

- 37 -

Water, granulated. The granules are dried overnight at 35 °, forced through a sieve of 1.2 mm mesh size and pressed on both sides concave tablets of about 6 mm in diameter.

Example 5 Tablets containing 50 mg of the active ingredient, for example 1- [2- (2,2-dimethylchroman-3-yl) ethyl] -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride made as follows:

Composition (for 10 000 tablets):

Active ingredient 500.00 g

Lactose 140.80 g

Potato starch 274.70 g

Stearic acid 10.00 g

Talc 50.00 g

Magnesium stearate 2.50 g

Colloidal Silica 32.00 g

Ethanol q.s.

A mixture of the active ingredient, the lactose and 194.70 g potato starch is moistened with an ethanolic solution of stearic acid and granulated through a sieve. After drying, the remainder of the potato starch, talc, magnesium stearate and colloidal silica are mixed, and the mixture is compressed to 0.1 gram weight tablets, which may optionally be provided with partial grooves for finer dosage adjustment.

In an analogous manner, 100 mg of active ingredient can be incorporated.

Example 6: Capsules containing 0.025 g of the active ingredient, for example l- [2- (2,2-dimethylchroman-3-yl) ethyl] -1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride be prepared as follows:

- 38 - ^ J

Composition (for 1000 capsules):

Active ingredient 25.00 g

Lactose 249.00 g

Gelatin 2.00 g

Cornstarch 10.00 g

Talc 15.00 g

Water q.s.

The active substance is mixed with the lactose, the mixture is moistened evenly with an aqueous solution of the 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 talc and filled with portions of 300 mg into hard gelatine capsules (size 1).

Example 7 : 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 3, can also be prepared in an analogous manner as in Examples 4 to 6.

Claims (9)

- 39 - j, 8i 383 Patent claim e 1. A process for preparing novel hydrogenated 1-Benzooxacycloalkyl pyridincarbonsäureverbindungen the formula R ₅ wherein either Ri is carboxy, lower alkoxycarbonyl, amidated carboxy or optionally acylated hydroxymethyl and R2 is hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group or Ri is hydrogen and R2 is carboxy, lower alkoxycarbonyl, amidated carboxy or optionally acylated hydroxymethyl and wherein R3 is hydrogen or lower alkyl, Ri is lower alkyl, R5 is lower alkyl, alk is lower alkylene or lower alkylidene, Ring A is unsubstituted or monosubstituted or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, cyano, halo, lower alkyl and / or trifluoromethyl dotted line is intended to mean that between the carbon atoms carrying the substituents Ri and R2 is a single or a double bond, m is 0 or 1 and in which either X represents an oxygen atom or a methylene group and η is 0 or X is a direct bond and η is 1, or of tautomers and / or salts thereof, characterized in that a) a compound of formula (Ha) or a salt thereof, wherein Xi is hydroxy or reactive esterified hydroxy, with a compound of the formula - AO - A83 383 // - R ₂ (lib) \ y / 'X or a tautomer and / or salt thereof or b) in a compound of the formula X ₂ (in) or a tautomer and / or salt thereof, wherein X2 is a radical other than Ri convertible radical and X5 is a radical R where R is hydrogen, an optionally etherified or a is an acylated hydroxy group or an optionally acylated amino group, X2 is converted into hydrogen other than Ri or in a compound of formula III or a tautomer and / or salt thereof, wherein X2 is hydrogen and X5 is an R, convertible radical, where R, is a radical R2 other than a radical R, X5 in b a R, convicted or c) for the preparation of a compound of the formula I or of a tautomer and / or salt thereof in which R 2 is hydroxy or amino and in which R 1 is different from hydrogen and optionally acylated hydroxymethyl, a compound of the formula -CH ₂ -Yi
(Alk) _- N ^ (IV), wherein Yi is a group of the formula -CH = R ₂ , -C (Y ₂ ) = R ₂ , -CH (Y ₂ ) -R ₂ or cyano, where R _{2 is} oxo or imino and Y _{2 is} a leaving group, or a salt thereof cyclized or d) for the preparation of a compound of formula I ¹ , wherein R _{2 is} oxo or imino and Ri is other than hydrogen, or a tautomer and / or salt thereof, a compound of formula IAM LCH ₂ ) W / " or a tautomer and / or a salt thereof with a compound of the formula X ₃ -Ri (Vb) or a salt thereof, wherein Ri is other than hydrogen and X3 is halogen or lower alkoxy, or e) for preparing a compound of the formula I or 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 i A ii C ^CH z) SV ⁿ or a salt thereof, wherein Xu represents a convertible into R ₂ radical, Xu converted into R _2, or f) in a salt of the formula IA II LCH ₂ ) 0-v - 42 - where A is the anion of an acid, R "is Ri or etherified or protected hydroxymethyl, and R2 ^{1 is} R2, protected hydroxy, protected amino or etherified or protected hydroxymethyl which reduces excess double bonds to single bonds and, if R" is different from R] and / or R'2 from R2, R "converted into Ri and / or RV in R2 or g) for the preparation of a compound of the formula I or of a tautomer and / or salt thereof, in which R 2 is carboxy, amidated carboxy or lower alkoxycarbonyl and the dashed line is to indicate that between the carbon atoms bearing the substituents R 1 and R 2 Single bond is present, a compound of the formula • - t (alk) -1 / ^X CH ₂ -R ₂
^m \ _ch (Y ₂ ) - _Ri (Viii) in which Y 2 is a cleavable radical, or a salt thereof is cyclized and in each case splits off an optional 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 a mixture of isomers available in the components separates, in each case a method according ErVialtliches Enantiomeren- or diastereomeric mixture splits into the enantiomers or diastereomers and / or in each case a free solution of the formula I available in a salt converted or a salt according to the process obtainable in the free compound of formula I or in another Salt is converted. 2. The method according to claim 1, characterized in that a compound of formula I is prepared in which Entwoder Ri carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N, N-di-lower alkylcarbamyl, Ν, Ν-Niederalkylencarbamyl, N, N- (Aza ), N, N- (oxa) - or N, N- (thia) lower alkylene carbamyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl and R2 denotes hydrogen, hydroxy, lower alkoxy, benzyloxy, lower - A3 - alkanoyloxy, lower alkanesulfonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino, lower alkanesulfonylamino, benzoylamino or pyridoylamino or Ri is hydrogen and R2 is carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N, N-di-lower alkylcarbamyl, Ν, Ν-lower alkylenecarbamyl, NN- Aza) -, NN- (Oxa) - or N, N- (thia) lower alkylene carbamyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl and wherein R3 is hydrogen or lower alkyl, Ri ₁ is lower alkyl, R 5 is lower alkyl, alk is lower alkylene, which bridges the two ring systems shown in formula I by up to and with 3 C atoms, or lower alkylidene, the ring A is unsubstituted or mono-, di- or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, cyano, halogen, lower alkyl and / or Trifluoromethyl is substituted, which is intended to express the dashed line between the carbon atoms which bear the substituents R 1 and R 2, a single bond or a double bond is present, m is 0 or 1 and in which either X is an oxygen atom or a methylene group and η is 0 or X is a direct bond and η is 1 , or a tautomer and / or salt thereof. 3. The method according to claim 1, characterized in that a compound of formula I is prepared wherein Ri is Ci-Ci, alkoxycarbonyl or carbamyl, R2 is hydrogen or hydroxy, R3 is hydrogen, Ri, Ci-Ci _1- alkyl , R _{5 is} Ci-Ci, alkyl, alk is Ci-Ci.-alkylene, which bridges the two ring systems drawn in formula I by up to and with 3 C atoms, the ring A is unsubstituted or, in particular in 6- Substituted by Ci-Ci ₁ -alkoxy, Ci-Ci _1- Alkyl, halogen with an atomic number up to and with 35, cyano or trifluoromethyl, the dashed line is to express that between the carbon atoms, the substituents Ri and R2, a single or a double bond is present, m is 1, X is an oxygen atom or a methylene group and η is 0, or a lautomeres and / or salt thereof. 4. The method according to claim 1, characterized in that a compound of formula I is prepared, wherein Ri is Ci-Ci, alkoxycarbonyl, R2 is hydrogen, R3 is hydrogen, Ri, Ci-Ci, alkyl - 44 - R _{5 is} Ci-Ci ₁ -AIlCyI, alk is ethylene, the ring A is unsubstituted or, in particular in the 6-position, is simply substituted by halogen with an atomic number up to and including 35, which is intended to express the dashed line, in that a double bond is present between the carbon atoms which carry the substituents R 1 and R 2, m is 1, X represents a methylene group and η is 0, or a salt thereof. 5. The method according to claim 1, characterized in that a compound of formula I is prepared wherein Ri is Ci-Ci, alkoxycarbonyl, R2 is hydrogen, R3 is hydrogen, Ri, Ci-Ci, alkyl, R ₅ Ci -Ci ₁ alkyl, alk is ethylene, the ring A is unsubstituted, which is intended to indicate the dashed line, that between the carbon atoms bearing the substituents Ri and R2, a double bond, m is 1, X is one Represents methylene group and η is 0, or a salt Javon. 6. The method according to claim 1, characterized in that l- [2- (2,2-dimethylchroman-3-yl) ethyl] -l, 2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester or a salt there "on. 7. The method according to claim 1, characterized in that l- [2- (2,2-dimethylchroman-3-yl) ethyl] -4-hydroxy-l, 2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester or methyl l- [2- (2,2-dimethylchroman-3-yl) ethyl] -4-oxo-piperidine-3-carboxylate or a salt thereof. 8. The method according to claim 1, characterized in that l- [2- (2,2-dimethyl-6-fluoro-chroman-3-yl) ethyl] -1, 2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester or a salt thereof. 9. The method according to claim 1, characterized in that one 1-t 2- (6-cyano-2,2-dimethyl-chroman-3-yl) ethyl] -4-hydroxy-l, 2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester or l- [2 - (6-cyano-2,2-dimethylchroman-S-yDä'thyll-'i-oxo-piperidine-S-carboxylic acid methyl ester or a salt thereof.
FO 7.4 GR / sm *