NO885711L - HYDRATED 1-BENZOOXACYCLYLCYLPYRIDINE CARBOXYLIC ACID COMPOUNDS. - Google Patents

Abstract

A process for the preparation of novel hydrogenated 1-benzooxacycloalkylpyryldicarboxylic acid compounds of the formula is described. wherein either B represents carboxy, lower alkoxycarbonyl, salted carboxy or optionally acylated hydroxyethyl and Bj represents hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group or Si represents hydrogen and Sg represents carboxy, lower alkoxycarbonyl, salted carboxy or optionally acylated hydroxyethyl and wherein R represents hydrogen or lower alkyl, Ber represents lower alkyl. Thus lower alkylalk stands for lower alkylene or lower alkylene, the ring Å is unsubstituted or mono- or polysubstituted by hydroxy, lower alkoxy, lower alkanoylocay, cyano, halogen, lower alkyl and / or trifluoroethyl, the dotted line shall express that between the carbon bonds soa bare the subst1-tuents direct bond and n stands for 1, and their tautoærs and / or salts. These compounds can be used as pharmaceuticals and can be prepared in a manner known per se.

Description

The present invention relates to a method for the production of new hydrogenated 1-benzooxacycloalkylpyridine-carboxylic acid compounds of the formula

in which either R^ stands for carboxy, lower-alkoxycarbonyl, amidated carboxy or optionally acylated hydroxymethyl and R2 stands for hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group or Ri stands for hydrogen and R2 for carboxy, lower-alkoxycarbonyl, amidated carboxy or optionally acylated hydroxymethyl and in which R3 stands for hydrogen or lower-alkyl, R4 is lower-alkyl, R5 is lower-alkyl, alk stands for lower-alkylene or lower-alkylidene, ring A is unsubstituted or mono- or poly-substituted with hydroxy, lower-alkylidene, lower-alkanoyloxy, cyano, halogen, lower-alkyl and/or trifluoromethyl, the dotted line shall express that there is a single bond or a double bond between the carbon atoms carrying the substituents R^ and R2, m stands for 0 or 1 and in which either X stands for an oxygen atom or a methylene group and n stands for 0 or X stands for a direct bond and n stands for 1, and tautomers and/or salts thereof, use the solution of these compounds and a method for the preparation of pharmaceutical preparations containing a compound of formula I or a tautomer and/or a pharmaceutically usable salt thereof.

Amidated carboxy R^h.h.v. R2 shows as amino groups, for example, unsubstituted or with lower aliphatic residues mono- or dl-substituted amlno and means, for example, carbamyl, N-lower-alkyl- or N,N-di-lower-alkylcarbamyl or N,N-lower-alkylene-h.v. N,N-(aza)-, N,N-(oxa)- or N,N-(thia)lower alkylenecarbamoyl.

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

Acyl in acylated hydroxymethyl R^h.h.v. R2 as well as in acylated hydroxy or acylated amino R2 is, for example, acyl derived from an organic carboxylic or sulphonic acid.

Acyl derived from an organic carboxylic acid is, for example, the residue of an aliphatic or monocyclic-aromatic carboxylic acid, such as lower-alkanoyl or optionally substituted benzoyl, further pyridoyl.

Acyl derived from an organic sulfonic acid is, for example, lower-alkanesulfonyl.

Tautomeric forms of compounds of formula I exist e.g. when R 2 stands for hydroxy or amino and the dashed line expresses that there is a double bond between the carbon atoms carrying the substituents R 2 and . The enols or the enamines of formula I are then in equilibrium with the corresponding keto- or the ketimine tautomers of the formula in which R£ stands for oxo or imino. Representatives of both tautomeric forms can be isolated.

The compounds of formula I can also exist in the form of stereoisomers. Since the compounds of formula I have at least one chiral carbon atom (C atom) (e.g. the C atom that exhibits the residue R3), it can e.g. exist as pure enantiomers or mixtures of enantiomers, as racemates, and, as long as an additional chiral center is present (e.g. the C4 atom of a hydrogen-different R24-substituted piperidine residue and/or the C3 atom of a hydrogen-different R^3- substituted piperidine residue), also as diastereomers, diastereomer mixtures or racemate mixtures. Consequently, geometric isomers, such as els- and trans-isomers, can be formed, for example, with respect to R^ and R2, if R^ and R2 are different and the dashed line means that there is a single bond between the carbon atoms carrying the substituents R^ and R2.

Salts of the compounds of formula I or their tautomers are particularly corresponding acid addition salts, preferably pharmaceutically usable acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, e.g. sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as lower alkane carboxylic acids, e.g. acetic acid, as optionally unsaturated dicarboxylic acids, e.g. malonic, maleic or fumaric acid, or as hydroxycarboxylic acids, e.g. tartaric or citric acids, or with sulphonic acids, such as lower alkane or optionally substituted benzenesulphonic acids, e.g. methane or p-toluenesulfonic acids. If R1 and R2, for example, mean carboxy, corresponding compounds can form salts with bases. Suitable salts with bases are, for example, corresponding alkali metal or alkaline earth metal salts, e.g. sodium, potassium or magnesium salts, pharmaceutically usable 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. mono-, di- or trihydroxy-lower-alkylamines, hydroxy-lower-alkyl-lower-alkylamines or polyhydroxy-lower-alkylamines. Cyclic amines are e.g. morpholine, thiomorpholine, piperidine or pyrrolidine. As mono-lower alkylamines, e.g. ethyl or t-butylamine, as di-lower alkylamine e.g. diethyl or diisopropylamine, as tri-lower alkylamines e.g. trimethyl or triethylamine in consideration. Corresponding hydroxy-lower alkylamines are e.g. mono-, di-ll.h.v. triethanolamine, and hydroxy-lower-alkyl-lower-alkylamines are e.g. N,N-dimethylamino- or N,N-diethylamino-ethanol, as polyhydroxy-lower-alkylamine comes e.g. glycosamine in speech.

Also included are salts that are unsuitable for pharmaceutical applications, as these can for example be used for the isolation or the purification of the free compounds of formula I as well as their pharmaceutically usable salts.

In the above and following, residues or compounds denoted by "lower", unless otherwise defined, are especially those containing up to and including 7, preferably up to and including 4, carbon atoms.

Lower alkoxy is e.g. C1-C4-Alkoxy, such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy or tert-butyloxy.

Lower alkyl is e.g. C1-C4~alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and further includes Cs-Cy-alkyl-, i.e. pentyl, hexyl or heptyl residues.

Lower alkylene alk is e.g. Ci-C4~alkylene, which forms a bridge across the two ring systems in formula I primarily at up to 3 C atoms and can e.g. 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, but can also form a bridge over the ring systems with 4 C atoms, i.e. constitute 1,4-butylene.

Lower alkylidene alk is e.g. Ci-C4-alkylidene and can e.g. be methylene, ethylidene, 1,1- or 2,2-propylidene or 1,1- or 2,2-butylidene.

Lower alkanoyl is e.g. C 8 -C 8 alkanoyl, such as acetyl, propionyl, butyryl, isobutyryl or pvaloyl.

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

Lower alkoxycarbonyl is e.g. C 6 -C 6 alkoxycarbonyl, such as methoxy-, ethoxy-, n-propyloxy-, isopropyloxy, n-butyloxy-, isobutyloxy- or tert-butyloxycarbonyl.

N-lower alkylcarbamyl is e.g. N-C1-C4-alkylcarbamyl, such as N-methyl-, N-ethyl-, N-(n-propyl)-, N-isopropyl-, N-(n-butyl)-, N-isobutyl- or N-tert .-butylcarbamyl.

N,N-di-lower alkylcarbamyl is e.g. N,N-di-C1-C4-alkylcarbamyl, whereby the two N-alkyl groups may be the same or different, such as N,N-dimethyl-, N,N-diethyl-, N,N-diisopropyl- or N-butyl- N-methylcarbamyl.

N,N-lower-alkylene- or N,N-(aza)-, N.N-(oxa)- or N,N-(thia)-lower alkylenecarbamyl has, for example, 3 to 8, especially 5 or 6, ring members and means, for example, pyrrolidino-, piperidino-, piperazino- or N'-lower alkyl-, such as N<*->methylpiperazino-, morpholino- or thiomorpho-folinocarbonyl.

Optionally substituted phenyl-lower-alkoxy is e.g. optionally substituted in the phenyl part of phenyl-C 1 -C 1-6 alkoxy, such as benzyloxy, p-chlorobenzyloxy, 1-phenylethoxy or 1-(p-bromophenyl)-n-butyloxy.

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

Lower alkanesulfonyl are e.g. C 1 -C 4 -alkanesulfonyl, such as methane or ethanesulfonyl.

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

The compounds of formula I, their tautomers and/or their pharmaceutically usable salts exhibit, for example, valuable pharmacological, especially nootropic, properties. Accordingly, in the "Two-Compartment Passive Avoidance" experimental model according to Mondadori and Classen, Acta Neurol. Scand. 69, Suppl. 99, 125 (1984) in dose amounts" from about 0.1 mg/kg i.p. as well as p.o. in mice a reduction of the amnesic effect of a cerebral electroshock.

Furthermore, the compounds of formula I have a significant memory-enhancing effect, as can be determined by the "Step-down Passive Avoidance" test according to Mondadori and Waser, Psychopharmacol. 63, 297 (1979) from a dose of approx. 0.1 mg/kg i.p. as well as p.o. on mouse.

Consequently, the compounds of formula I or their tautomers and/or their pharmaceutically usable salts are used as pharmaceutical agents, e.g. nootropics, for example for therapeutic and/or prophylactic treatment of cerebral insufficiency conditions, especially memory disorders. A further object of the present invention is therefore the use of the compounds of formula I, their tautomers and/or their pharmaceutically usable salts for the preparation of drugs, especially of nootropics, for the treatment of cerebral insufficiency conditions, especially memory disorders. This may also include the industrial preparation of the active substances.

The invention primarily relates to a process for the preparation of compounds of formula I, in which either R^ stands for carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N,N-di-lower alkylcarbamyl, N,N-lower -alkylenecarbamyl, N.N-(aza)-, N-N-(oxa)- or N,N-(thia)-lower alkylenecarbamyl, hydroxymethyl, lower-alkanoyloxymethyl, lower-alkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl and R2 is hydrogen, hydroxy, lower -Alkoxy, benzyloxy, lower-alkanoyloxy, lower-alkanesulfonyloxy, benzoyloxy, pyridoyloxy, amino, lower-alkanoyl-amino, lower-alkanesulfonylamino, benzoylamino or pyri-doylamino or R^represents hydrogen and R2represents carboxy, lower-alkoxycarbonyl, carbamyl , N-lower-alkylcarbamyl, N,N-di-lower-alkylcarbamyl, N,N-lower-alkylenecarbamyl, N,N-(aza)-, N.N-(oxa)- or N,N-(thia)lower- alkylenecarbamyl, hydroxymethyl, lower-alkanoyloxymethyl, lower-alkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl and where in R3 stands for hydrogen or lower-alkyl, R4 is lower-alkyl, R5 is lower-alkyl, alk is lower-alkylene, which bridges the two ring systems entered in formula I by up to and including 3C atoms, or stands for the lower-alkylidene , the ring A is unsubstituted or singly, doubly or polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, cyano, halogen, lower alkyl and/or trifluoromethyl, the dotted line shall express that between the carbon atoms carrying the substituents R^ and R2 is a single or double bond, m stands for 0 or 1 and in which either X stands for an oxygen atom or a methylene group and n stands for 0 or X stands for a direct bond and n stands for 1, and their tautomers and/or salts.

The invention relates above all to a process for the preparation of compounds of formula I in which R^ stands for C1-C4 alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, or carbamyl, R2 stands for hydrogen or hydroxy, R3 stands for hydrogen, R4 stands for C1-C4-alkyl , as methyl, R5 stands for Ci~C4-alkyl, as methyl, alk stands for the Ci~C4-alkylene, which bridges the ring systems with up to 3 C atoms entered in formula I, such as methylene or ethylene, the ring A is unsubstituted or specially substituted in the 6-position by C1-C4- alkoxy, such as methoxy, C1-C4-alkyl, such as methyl, halogen having an atomic number up to and including 35, such as fluorine or chlorine, cyano or trifluoromethyl, the dotted line shall express that there is a single or a double bond between the carbon atoms carrying the substituents R^ and Rg, m stands for 1, X stands for an oxygen atom or a methylene group and n stands for 0, and their tautomers and/or salts.

The invention relates in particular to a process for the preparation of compounds of formula I in which R^ stands for C1-C4-Alkoxycarbonyl, such as methoxycarbonyl, R2 stands for hydrogen, R3 stands for hydrogen, R4 stands for C1-C4-alkyl, such as methyl, R5 stands for C ^-C^-alkyl, such as methyl, alk stands for ethylene, the ring A may be unsubstituted or monosubstituted, especially in the 6-position, with halogen having an atomic number up to and including 35, such as fluorine or chlorine, the dotted line shall express that there is a double bond between the carbon atoms carrying the substituents R^ and Rg, m stands for 1, X stands for a methylene group and n stands for 0f and salts thereof.

The invention primarily relates to a process for the preparation of compounds of formula I, in which R^ stands for C 1 -C 4 alkoxycarbonyl, such as methoxycarbonyl, R 2 stands for hydrogen, R 3 stands for hydrogen, R 4 stands for C 1 -C 4 -alkyl, such as methyl . methylene group and n stands for 0, and salts thereof.

The invention relates in particular to a method for producing the new compounds of formula I and their salts mentioned in the examples.

The process according to the invention for preparing compounds of formula I and their tautomers and/or salts is, for example, characterized by the fact that man

a) reacts a compound of the formula

or a salt thereof, wherein X^ is hydroxy or reactively esterified hydroxy, with a compound of the formula

or a tautomer and/or a salt thereof, or

b) in a compound of the formula

or a tautomer and/or a salt thereof, wherein Xg is a residue that can be transferred to R^ which is different from hydrogen and X5 is a residue Ra, whereby Ra stands for hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group, Xg transfers to a residue R^ which is different from hydrogen or to a compound of formula III or a tautomer and/or a salt thereof, in which Xg is hydrogen and X5 represents a residue that can be transferred to R^ represents a residue Rg which is different from the residue Ra transfers X5 to R^, or c) for the preparation of a compound of formula I or a tautomer and/or a salt thereof, in which Rg stands for hydroxy or amino and in which R-^ is different from hydrogen and optionally acylated hydroxymethyl, ring-closes a compound of the formula in which Y-L stands for a group of the formula -CH=R^, -C(Y2)=R£, —CH(Y2)-R2 or cyano, whereby Rg" stands for oxo or imino and Y2 stands for a cleavable residue, or a salt thereof, or d) for the production of e n compound of formula I', in which R^ stands for oxo or imino and R^ is different from hydrogen, or a tautomer and/or a salt thereof, reacts a compound of the formula

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

or a salt thereof, in which R^ is different from hydrogen and X 3 stands for halogen or lower alkoxy, or e) for the preparation of a compound of formula I or a tautomer and/or a salt thereof, in which Rg stands for an optionally etherified or acylated hydroxy group or an optionally acylated amino group, in a compound of the formula

or a salt thereof, wherein X4 represents a residue that can be transferred to R2, transfers X4 to R2, or

f) in a salt of the formula

wherein A<®>represents the anion of an acid, Rf represents a residue R^or etherified or protected hydroxymethyl and R£J represents a residue R2, protected hydroxy, protected amino or etherified or protected hydroxymethyl, reduces the excess double bonds to the single bonds, if Rf is different from R1 and/or Rg from R2, Rf is transferred to R^ and/or Rg to R2, or g) for the preparation of a compound of formula I or a tautomer and/or a salt thereof, in which R2 stands for carboxy, amidated carboxy or lower alkoxycarbonyl and the dotted line shall express that there is a single bond between the carbon atoms bearing the substituents R^ and R 2 , ring-closing a compound of the formula

in which Y2 stands for a cleavable residue, or a salt thereof and cleaves off any protective group present, and if desired a compound of formula I according to the invention or obtained in another way is transferred to another compound of formula I, an isomer mixture obtained according to the invention is separated into the components , an enantiomer obtained according to the invention - or diastereomer mixture is split into the enantiomers or the diastereomers and/or a free compound of formula r obtained according to the invention is transferred to a salt or a salt obtained according to the invention to the free compound of formula I or to another salt.

The transactions mentioned above, and below in the variants, are carried out in a manner known per se, e.g. in the absence, or usually in the presence, of suitable solvents or diluents or a mixture of such, whereby one can, as required, work under cooling, at room temperature or under heating, e.g. in a temperature range from approx. -10°C to the boiling point of the reaction medium, preferably from approx. 20 to approx. 150°C and, if necessary, in a closed container, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.

The starting materials of the formulas Ia and Hb, III, IV, Va and Vb, VI, VII and VIII, which have been developed for the preparation of the compounds of the formula I, their tautomers and salts, are partly known or may also be is produced by methods known per se, e.g. analogously to the method variants indicated above.

Starting material with basic centers can e.g. exist in the form of acid addition salts, for example with the above-mentioned acids, while starting compounds with acidic groups can form salts with bases, e.g. of the above type. Furthermore, the starting compounds can exist in the form of tautomers, especially in the case of the compound of formula Hb, when Rg stands for hydroxy and the dotted line should express that there is a double bond between the carbon atoms, which carry the substituents, and Rg.

Variant a):

Reactively esterified hydroxy means in particular hydroxy esterified with a strong inorganic acid or organic sulphonic acid, for example halogen, such as chlorine, bromine or iodine, sulphonyloxy, such as hydroxysulphonyloxy, halogensulphonyloxy, e.g. fluorosulfonyloxy, optionally, e.g. with halogen, substituted lower-alkanesulfonyloxy, e.g. cyclohexanesulfonyloxy, or optionally, e.g. with lower alkyl or halogen, substituted benzenesulfonyloxy, e.g. p-bromopheyl or p-toluenesulfonyloxy. The N-alkylation is carried out in particular in the presence of a condensing agent, such as a suitable base. As bases, for example, alkali metal hydroxides, -hydrides, -amides, -alkanolates, -carbonates, -triphenylmethylides, -di-lower-alkylamides, -amino-lower-alkylamides or -lower-alkylsilylamides, naphthalene amines, lower-alkylamines, basic heterocyclic compounds, ammonium hydroxides and carbocyclic amines in question. Examples include sodium hydroxide, -hydride, -amide, -ethylate, potassium tert-butylate, -carbonate, lithium tri-phenylmethylide, lithium diisopropylamide, potassium 3-(amlnopropyl)-amide, -bis-(trimethylsilyl)-amide , dimethylaminonaphthalene, di- or triethylamine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5-diaza-bicyclo[4,3,0]non-5-ene (DBN) and 1,5-diaza-bicyclo[5,4 ,0]undec-5-ene (DBU).

The starting materials of the formulas Ila and Hb are partly known or can be prepared analogously to the known starting materials.

Variant b) ;

A residue Xg which can be transferred to a residue Ri different from hydrogen or a residue X5 which can be transferred to a residue R^ is, for example, functionally derived carboxy, different from R^h.h.v. Rfc, as cyano, anhydridized carboxy, optionally substituted amidino, optionally esterified or anhydridized carboxymldoyl, from esterified or amidated carboxy R-^h.h.v. R2 is different esterified or amidated carboxy, tri-lower alkoxy- or trihalomethyl.

Anhydridized carboxy is, for example, carboxy that is anhydridized with a mineral acid, such as hydrohalic acid, or with a carboxylic acid, such as an optionally substituted lower-alkane- or benzoic acid or a carbon halide lower alkyl half-ester. Examples include halocarbonyl, such as chlorocarbonyl, lower-alkanoyloxycarbonyl, such as acetyloxycarbonyl, or lower-alkoxycarbonyloxycarbonyl, such as ethoxycarbonyloxycarbonyl.

Substituted amidino is, for example, amidino which is substituted with an aliphatic residue, e.g. lower alkyl, such as lower alkylamidino, e.g. ethylamidino.

Under esterified or anhydridized carboxyl doyl is meant e.g. alkoxy-, e.g. halogenocarboxymidoyl, for example lower alkoxy-, such as ethoxy-, or chloro-carboxymidoyl.

Tri-lower-alkoxy- or trihalomethyl is e.g. tri-methoxymethyl or trichloromethyl.

Residues R 2 are, for example, carboxy, lower alkoxycarbonyl, amidated carboxy or optionally acylated hydroxymethyl residues R 2 .

X2 can, for example, be transferred to R^ which is different from hydrogen by solvolysis, in the same way as X5 is, for example, transferable by solvolysis to a residue R^. Solvolyzing agents are, for example, water, lower alkanols corresponding to the desired esterified carboxy R-^h.h.v. R2, ammonia or amines corresponding to the desired amidated carboxyl group R^h.h.v. R2. The treatment with a corresponding solvolytic agent is optionally carried out in the presence of an acid or base. Acids include, for example, inorganic or organic protonic acids, such as mineral acids, e.g. sulfuric acid or hydrogen halide acids, for example hydrochloric acid, such as sulphonic acids, e.g. lower-alkane- or optionally substituted benzenesulfonic acid, for example methane- or p-toluenesulfonic acid, or as carboxylic acids, e.g. lower-alkane carboxylic acids, for example acetic acid in question, while the bases under variant a) can for example be mentioned, especially sodium or potassium hydroxide.

During the solvolysis, the cyano group, anhydridized carboxy, optionally substituted amidino, optionally esterified or anhydridized carboxymldoyl, is hydrolyzed from esterified or amidated carboxy or R2 variously esterified or amidated carboxy, tri-lower alkoxy- or trihalomethyl to carboxy. Below this, lower alkanoyloxy acid residues which may be located on ring A during the course of the hydrolysis can be hydrolysed to hydroxy.

Cyano, anhydridized carboxy, from esterified or amidated carboxy R^h.h.v. R2differently esterified or amidated carboxy is alcoholized, for example, with a suitable lower alkanol to esterified carboxy R^h.h.v. R2 and cyano and anhydridized carboxy amono- or is aminolyzed, for example, with ammonia or an amine corresponding to amidated carboxy R^h.h.v. R2.

The starting material of formula III can, for example, be prepared analogously to the method specified under variant a) by reacting a compound of the formula with a compound of the formula

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

Compounds of formula III, in which Xg stands for a residue that can be transferred to R^ which is different from hydrogen ■ and X5 stands for hydroxy or amino, can advantageously also be prepared by the addition of a compound of the formula in which Yi stands for a group of the formula - CH=R^, -C(Y2)=r£,~CHCYg)—R2or cyano, whereby Rg" stands for oxo or imino, Rg stands for hydroxy or amino and Yg stands for a cleavable residue, or a salt thereof, whereby for example, work is done analogously to the method described under method variant

c).

Variant c) :

Cleavable residues Yg in the groups of the formula -C(Y2)=R^ or —CH(Y2)-R2 are, for example, reactively esterified hydroxy groups, such as hydroxy esterified with strong inorganic acids or organic sulphonic acid, for example halogen, such as chlorine, bromine or iodo, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, e.g. fluorosulfonyloxy, optionally, e.g. with halogen, substituted lower-alkanesulfonyloxy, e.g. methane- or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g. cyclohexanesulfonyloxy, or optionally, e.g. with 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 coupling can, for example, be carried out analogously to Dieckmann reactions, especially in the presence of one of the bases mentioned under variant a), and during subsequent hydrolytic work-up.

In a preferred embodiment, one can for example submit a compound of the formula

in which Rg" stands for oxo or imino, treatment with one of the mentioned bases, especially with an alkali metal lower alkanolate, e.g. sodium methanolate or sodium ethanolate. The compound IVa is thereby cyclized to a compound of formula I in which the dotted line indicates that between the carbon atoms, which carry the substituents R^ and Rg, there is a single bond and Rg stands for hydroxy or amino. Starting substances IVa are obtained, for example, by reacting a reactive alkyl ester of the formula in which Xi stands for reactively esterified hydroxy, with a compound of the formula HgN-CHg-CHg-Ri (IVb) and the obtained intermediate of the formula

is reacted with acrolein or an optionally functionally derived aldehyde of the formula Y1-CH2-CH2-CH=R^ (IVd; = reactive esterified hydroxy; R<g>* = oxo or imino).

In another preferred embodiment of variant c) a compound of formula IV is ring-closed, in which Y^ and R^ stand for lower-alkoxycarbonyl, i.e. in which Y^ stands for a group of the formula -CÉYg^R<g>*, in which R£ is oxo and the cleavable residue Yg exhibits as etherified hydroxy a lower-alkoxy group, to the corresponding compound of formula I', in which R£ is oxo and R^ stands for lower-alkoxycarbonyl.

For the production of the latter starting compounds of formula IV, one can for example proceed from compounds of the formula

or salts thereof, such as e.g. can be obtained by reducing the corresponding nitriles, and reacting these with at least 2 mol of a compound of the formula

Variant d):

The C-acylation according to the invention can especially take place in the presence of the bases mentioned under variant a), particularly advantageously with the help of a metal base, such as lithium diisopropylamine or n-butyllithium, optionally in the presence of chlorotrimethylsilane.

The turnover of a compound of the formula

with a compound of the formula

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

Variant e) :

For a residue Rg of the indicated type of transferable residues X4 are, for example, residues that can be transferred to such groups Rg, e.g. by reaction with a corresponding compound of formula R2H or a salt thereof, for example halogen atoms, e.g. chlorine, bromine or iodine. Residues X4 which can be transferred to hydroxy R2 are further diazonium groups, e.g. of the formula

—N2<®>A<®>, where A<®> is the anion of a strong acid, e.g. a mineral acid, such as chloride or sulfation.

The solvolysis takes place in the usual way, for example in the presence of a base, such as an alkali metal or alkaline earth metal hydroxide, e.g. sodium or potassium hydroxide, or a tertiary nitrogen base, e.g. a tri-lower alkylamine, such as triethylamine, or a heteroaromatic nitrogen base, such as pyridine, or a quaternary ammonium hydroxide, such as benzyl trimethyl ammonium hydroxide, or by using the compound R 2 H in the form of a metal salt, e.g. of the formula R2<®>M<®>, where M<®> is an alkali metal cation, such as the sodium ion. It is advantageous to work in the presence of a solvent or diluent, e.g. in an excess of the reaction components R2H and/or an inert solvent miscible with this, if necessary during cooling or heating, e.g. in the temperature range from approx. 0 to 120°C, and/or under inert gas, such as nitrogen.

The solvolysis of residues X4 to such groups R2 can optionally be combined with the solvolytic transfer of solvolysable groups R^ to other groups R^ according to the invention, for example, in the ammonolysis of the residues X4 to amino R2, lower alkoxycarbonyl groups R^ or other carbamyl R^ solvolysable groups R ^simultaneously ammono-lyzed to carbamyl groups R^.

For the preparation of starting compounds of formula VI and salts thereof, one starts, for example, from compounds of formula IIa and reacts these with a corresponding compound of the formula

or a salt thereof in the presence of one of the above-mentioned bases, whereby it e.g. proceeds analogously to method variant a).

In a preferred embodiment, compound VI is obtained, in which X4 stands for halogen and the dotted line is to express that there is a single bond between the carbon atoms, which carry the substituents Ri and X4, and salts thereof by reacting a compound of formula I in which R2 stands for hydroxy and the dotted line should express that between the carbon atoms, which carry the substituents R^ and R2 , there is a single bond, or a salt thereof with a halogenating agent, such as phosphorus tri- or -pentachloride or thionyl chloride, whereby the corresponding compounds I and their salts, for example, can is achieved analogously to the method described under method items a) or c).

Variant f):

The anion A<®> is, for example, the anion of a strong protonic acid, e.g. a halide ion, such as chloride, bromide or iodide ion, or a sulfate ion, such as an optionally substituted lower alkane or benzene sulfonation, e.g. the methanesulfonate, ethanesulfonate or p-bromophenylsulfonate or p-toluenesulfonation. Protected hydroxy is, for example, silyloxy, such as tri-lower alkylsilyloxy, e.g. trimethylsilyloxy, but can also be triphenyl-lower-alkoxy, e.g. trityloxy. Protected amino is, for example, silylamino, such as tri-lower alkylsilylamino, e.g. trimethylsilylamino, but can also be phenyl-, diphenyl- or triphenyl-lower alkylamino, such as benzylamino, diphenylamino or tritylamino. Etherated hydroxymethyl is, for example, lower alkoxymethyl, such as methoxy- or ethoxymethyl, or optionally substituted phenyl lower alkoxymethyl, e.g. in the phenyl part substituted phenyl-Cy-C4-Alkoxymethyl, 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. trimethylsilyloxymethyl, but can also be triphenyl-lower-alkoxy-, e.g. trityloxymethyl.

Particularly suitable is the process variant f) for the preparation of a compound of formula I or a tautomer and/or a salt thereof, in which either R^ stands for carboxy, lower alkoxycarbonyl, amidated carboxy or hydroxymethyl and R 2 stands for hydrogen, hydroxy or amino or in which R 2 stands for hydrogen and R 2 stands for carboxy, lower alkoxycarbonyl, amidated carboxy or hydroxymethyl.

The reduction of the excess double bonds takes place 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 hydration catalysts, e.g. elements from the VIII side group of the periodic table above the elements or their derivatives under consideration, such as palladium, platinum, platinum oxide, ruthenium, rhodium, tris(triphenylphosphane)-rhodium-I-halide, e.g. -chloride, or Raney nickel, which is optionally applied to carrier material, such as activated carbon, an alkali metal carbonate or -sulphate or a silica gel. Suitable hydride-transferring reagents include, for example, light metal hydrides, especially alkali metal aluminum hydrides or -borohydrides, such as lithium aluminum hydride, lithium triethylborohydride, sodium borohydride, sodium cyanoborohydride, or tin hydrides, such as triethyl or tributyltin hydride, or diborane in question. The metal component of the metallic reduction system is, for example, a base metal, such as alkali or alkaline earth metal, e.g. lithium, sodium, potassium, magnesium or calcium, or transition metal1, e.g. zinc, tin, iron or titanium, while as a proton-releasing agent, e.g. protonic acids of the above-mentioned type, such as hydrochloric acid or acetic acid, lower alkanols, such as ethanol, and/or amines or ammonia in speech. Such systems are, for example, sodium/ammonia, zinc/hydrochloric or acetic acid or zinc/ethanol.

If Rf is different from R^ and/or Rg is different from R2, the transfer of Rf to R^ and/or Rg to R2 takes place, i.e. the removal of the protective groups and thus the release of the corresponding residues R^ and/or R2, in the same or in successive reaction steps, whereby work is carried out in the usual way, e.g. as described in connection with method variant g).

The preparation of the starting compounds of formula VII usually takes place by reacting compounds of the formula in which stands for reactive esterified hydroxy, which in single negatively charged form corresponds to the anion A<®>, with compounds of the formula

or a salt thereof, whereby it e.g. work in an analogous way as described under method variant a).

Variant g) ;

Cleavable residues Yg in compound VIII are, for example, reactively 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, halogensulfonyloxy, e.g. fluorosulfonyloxy, optionally e.g. with halogen, substituted lower-alkanesulfonyloxy, e.g. methane- or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g. cyclohexanesulfonyloxy, or optionally, e.g. with 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 ring closure can, for example, be carried out in the presence of one of the bases mentioned under variant a), especially in the presence of an alkali metal lower alkanolate, e.g. with sodium methanolate or -ethanolate.

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

or a salt thereof with a compound of the formula Y2-CH2-CH(Y2)-Ri (IVi).

In the starting substances of the formulas Hb, III, Illa, IV, IVg, VII and Vila, a hydroxy group R2 can be present in the ether or a hydroxy or amino group R 2 also in intermediate protected form, in the same way as a hydroxymethyl group R 2 h.h.v. R2i compounds Hb, IVi, Vb, VI, Via, VII, Vila and VIII can exist in etherified or intermediate protected form. Protected hydroxy is, for example, silyloxy, such as tri-lower alkylsilyloxy, e.g. trimethylsilyloxy, but can also be triphenyl-lower-alkoxy, e.g. trityloxy. Protected amino is, for example, silylamino, such as tri-lower alkylsilylamino, e.g. trimethylsilylamino, but can also be phenyl-, diphenyl- or triphenyl-lower-alkylamino, such as benzylamino, diphenyl-methylamino or tritylamino. Ethered hydroxymethyl is, for example, lower alkoxymethyl, such as methoxy- or ethoxy methyl, or optionally substituted phenyl-lower-alkyloxymethyl, e.g. in the phenyl part substituted phenyl-C 1 -C 4 -alkoxymethyl, 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. trimethylsilyloxymethyl, but can also be triphenyl-lower-alkoxy-, e.g. trityloxymethyl.

The release of preferred or intermediate protected residues R^h.h.v. R2 , i.e. the removal of the intermediate protective groups, takes place in the usual way, for example by solvolysis, as mild hydrolysis, e.g. treatment with water under neutral or slightly acidic conditions, e.g. by the influence of dilute aqueous mineral or carboxylic acids, e.g. of dilute hydrochloric or acetic acid. In a similar way, the release of intermediately protected hydroxy and amino groups Rg and of etherified or protected hydroxymethyl groups R^ and R£ takes place in starting substances of the formulas VII and/or Vila.

According to the invention or otherwise obtained compounds of formula I can be transferred in the usual way to other compounds of formula I.

Consequently, one can e.g. hydrolyze esterified or amidated carboxy groups R^h.h.v. R 2 in the usual way, for example in the presence of a basic or acidic hydrolysis agent, such as an alkali metal hydroxide or carbonate, e.g. of sodium hydroxide or potassium carbonate, or a mineral acid, e.g. of hydrochloric or sulfuric acid, to carboxy R^h.h.v. R2. Esterified carboxy groups R^h.h.v. R2 can further be transferred by reaction, i.e. treatment with an alcohol in the presence of an acidic or basic solvolytic agent, such as a mineral acid, e.g. sulfuric acid, or a corresponding alkali metal alcoholate or an alkali metal hydroxide, to other esterified carboxy groups Rj[h.h.v. R2or by reaction with ammonia or a corresponding amine which exhibits at least one hydrogen atom to amidated carboxy R^h.h.v. R2.

Free carboxy R^h.h.v. R2 can be transferred to esterified carboxy R^h.h.v. R2 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 transfer to a halide and subsequent reaction with a corresponding alcohol, e.g. in the presence of pyridine or triethylamine, or by transfer to an alkali metal salt and subsequent reaction with a reactive ester of a corresponding alcohol, as a corresponding halide. Furthermore, a carboxy compound can be esterified using a dehydrating agent, such as N,N'-dicyclohexylcarbodiimide with a corresponding alcohol. Free or esterified carboxy R^h.h.v. R2 can also be transferred to amidated carboxy R^h.h.v. R2 by reaction with ammonia or an amine that has at least one hydrogen atom and dehydration of the intermediately formed ammonium salt, e.g. by heating or by means of a dehydrating agent, such as N,N'-dicyclohexylcarbodiimide, or by transfer to the halide and subsequent reaction with ammonia or an amine exhibiting at least one hydrogen atom.

Furthermore, optionally present hydroxy groups can be esterified, e.g. transfer to lower-alkanoyloxy by treatment with a lower-alkanecarboxylic acid anhydride or —halide or by reaction with a reactive ester, especially bromine or hydrogen chloride ester, transfer a lower alkanol to the corresponding etherified hydroxy. Conversely, from esterified or etherified hydroxy, such as lower alkanoyloxy or lower alkoxy, the hydroxy groups can be set free solvo-reductively, preferably under acidic conditions. In a similar way, etherified or acylated hydroxy R2 can also be hydrolysed to hydroxy.

Correspondingly, one can further esterify hydroxymethyl R-^ or Rg» e.g. by treatment with a lower alkanecarboxylic acid anhydride or -halide transfer to lower-alkanoyloxymethyl R^h.h.v. Rg. Conversely, one can from acylated hydroxymethyl, e.g. lower-alkanoyloxymethyl R^h.h.v. R2 release the hydroxy groups solvolytically, preferably under acidic conditions.

Furthermore, hydroxymethyl R^h.h.v. R 2 is in the usual way transferred to lower alkoxycarbonyl or amidated carboxy R 2 , respectively. R2, whereby it e.g. proceed in such a way that hydroxymethyl R^h.h.v. R2 is usually first oxidized to carboxy, e.g. in the presence of an oxidizing agent, such as potassium permanganate or potassium dichromate and then the carboxy groups are transferred to the lower carboxycarbonyl R^h.h.v. R2 in the usual way, e.g. by treatment with a corresponding alcohol in the presence of a mineral acid, e.g. sulfuric acid, or by transfer to a halide and subsequent reaction with a corresponding alcohol, e.g. 1 the presence of pyridine or triethylamine, or by transfer to an alkali metal salt and subsequent reaction with a reactive ester of the corresponding alcohol, as a corresponding halide, or using a dehydrating agent, such as N,N'-dicyclohexylcarbodiimide, with a corresponding alcohol or is transferred to amidated carboxy R^h.h.v. R2 by reaction with ammonia or an amine which exhibits at least one hydrogen atom and dehydration of the intermediately formed ammonium salt, e.g. by heating or by means of a dehydrating agent, such as N,N'-dicyclohexylcarbodiimide, or by transfer to the halide and subsequent reaction with ammonia or an amine exhibiting at least one hydrogen atom. Likewise, one can transfer acylated hydroxymethyl R^h.h.v. R2 to esterified or amidated carboxy R^h.h.v. R2 by first setting the acylated hydroxymethyl group free solvolytically, e.g. as described above, and then transfers the obtained free hydroxymethyl groups, as described above, to a carboxyl group and further transfers the latter to an esterified or amidated carboxyl group. Conversely, esterified or amidated carboxy groups R^h.h.v. Rg is transferred to optionally acylated hydroxymethyl R^ h.h.v. Rg, by first hydrolysing the esterified or amidated carboxyl groups R^h.h.v. Rg in the usual way to carboxy, for example in the presence of a basic or acidic hydrolysis agent, such as an alkali metal hydroxide or carbonate, e.g. sodium hydroxide or potassium carbonate, or a mineral acid, e.g. hydrochloric or sulfuric acid, and then, reducing the obtained carboxyl group in the usual way, e.g. in the presence of a reducing agent, for example of the type mentioned above, to hydroxymethyl R^h.h.v. Rg, whereby if desired the latter is transferred to acylated hydroxymethyl R^h.h.v. Rg, e.g. as described above.

In compounds of formula I in which the dotted line is to express that there is a double bond between the carbon atoms, which carry the substituents Ri and Rg, this can be hydrogenated to a single bond, e.g. in a manner known per se by means of a reducing agent, e.g. of the type specified under method variant f).

Furthermore, a compound of formula I in which the dotted line should express that between carbon atoms carrying the substituents R^ and Rg, there is a double bond and Rg stands for hydrogen, e.g. in a manner known per se by addition of a compound R2-H, in which Rg stands for an optionally etherified or acylated hydroxy group or an optionally acylated amino group, is transferred to a corresponding piperidine compound. The addition is thereby carried out especially in the presence of suitable bases, e.g. of the type specified under variant a).

Compounds of formula I, in which the dotted line expresses that there is a single bond between the carbon atoms, which carry the substituents R^ and Rg, can be reversed, e.g. by eliminating a compound Rg-H, in which Rg stands for an optionally etherified or acylated hydroxy group or an optionally acylated amino group, in 1 and per se known manner is transferred to corresponding tetrahydro-pyridine compounds, in which Rg stands for hydrogen. For an elimination of poorly suitable leaving groups Rg, e.g. hydroxy, these can beforehand, e.g. In situ, are transferred to more suitable cleavable groups Rg, e.g. lower alkanesulfonyloxy, such as methanesulfonyloxy, or halogen, such as chlorine, bromine or iodine. The elimination thereby takes place particularly in the presence of suitable bases, e.g. of the type specified under variant a).

Salts of compounds of formula I or their tautomers can be prepared in a manner known per se. Consequently, one obtains, for example, acid addition salts of compounds of formula I by treatment with an acid or a suitable ion-exchange reagent. Salts can be transferred in the usual way to the free compounds of formula I, acid addition salts e.g. by treatment with suitable basic agents.

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

Due to the close relationship between the new compounds of formula I in free form and in the form of salts, in the preceding and following free compounds of formula I and their salts are also understood to mean the corresponding salts or the free compounds of formula I.

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

The new compounds of formula I can, depending on the choice of starting materials and working methods, exist in the form of one of the possible isomers or as mixtures thereof. Hereby, depending on the molecular symmetry, e.g. depending on the number, absolute and relative configuration of the chirality centers, such as asymmetric C atoms, pure isomers are obtained, e.g. pure enantiomers and/or pure diastereomers, such as pure cis/trans isomers or meso compounds. Consequently, it can exist as isomer mixtures, e.g. enantiomeric mixtures, such as racemates, diastereomer mixtures or racemate mixtures.

Obtained diastereomer mixtures and racemate mixtures can, on the basis of the physico-chemical differences between the components, be separated into the pure diastereomers or racemates in a known manner, for example by fractional crystallization.

Obtained enantiomer mixtures, such as racemates, can be decomposed into the enantiomers by known methods, for example by recrystallization from an optically active solvent, chromatography on chiral adsorbents, with the help of suitable microorganisms, by cleavage with specific, immobilized enzymes, or the formation of inclusion compounds, e.g. using chiral crown ethers, whereby only a complex with one enantiomer is formed, or by transfer to diastereomeric salts, e.g. by reacting a basic final racemate with an optically active acid, such as carboxylic acid, e.g. tartaric or malic acid, or sulphonic acid, e.g. camphorsulphonic acid, and the separation of the diastereomer mixture thus obtained, e.g. on the basis of different solubilities, to the diastereomers, from which the desired enantiomer can be set free by the action of its own means. Preferably, the most effective enantiomer is isolated.

The invention also relates to those embodiments of the method where one starts from an obtained compound that is obtained at any step of the method as an intermediate product and carries out the missing steps or uses a starting substance in the form of a derivative or salt and/or its racemate or enantiomers, or especially form this under the reaction conditions.

In the method according to the present invention, starting materials are preferably used which lead to the compounds of formula I which are indicated at the outset as particularly valuable. The process for the production of new starting materials, which has been developed specifically for the production of the compounds of formula I and their use also constitutes an object of the invention, whereby the substituents , Rg, R3, R4, R5, X, m, n and alk as well as the substituents on the ring A and the dotted line have the meanings indicated for the preferred connecting groups of formula I in each case.

In this context, the connection of formula should in particular

and salts thereof are mentioned. These also have nootropic properties in comparable potency as the corresponding compounds of formula I or I', and can also find use as nootropic drug active ingredients.

The invention therefore also relates to a process for the preparation of compounds of formula IVc, in which R^ stands for carboxy, lower alkoxycarbonyl, amidated carboxy or optionally acylated hydroxymethyl, R 3 stands for hydrogen or lower alkyl, R 4 stands for lower alkyl, R 5 stands for lower alkyl, alk stands for lower-alkylene or lower-alkylidene, ring A is unsubstituted or mono- or poly-substituted with hydroxy, lower-alkoxy, lower-alkanoyloxy, cyano, halogen, lower-alkyl and/or trifluoromethyl, m stands for 0 or 1, and in which either X represents an oxygen atom or a methylene group and n represents 0 or X represents a direct bond and n represents 1, and their salts, the use of said compounds of formula IVc and a method for the preparation of pharmaceutical preparations containing a compound of formula IVc or a pharmaceutically usable salt thereof.

The variables in formula IVc have, for example, the preferred meanings specified under formula I.

The invention therefore primarily relates to a process for the preparation of compounds of formula IVc, in which stands for carboxy, lower alkoxycarbonyl, carbamyl, N-lower alkylcarbamyl, N,N-di-lower alkylcarbamyl, N,N-lower alkylenecarbamyl , N,N-(aza)-, N.N-(oxa)- or N,N-(thia)lower-alkylenecarbamyl, hydroxymethyl, lower-alkanoyloxymethyl, lower-alkanesulfonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, R3 stands for hydrogen or lower-alkyl, R4 stands for lower alkyl, R5 stands for lower alkyl, alk stands for lower alkylene, which connects the ring system with the NH group entered in formula IVc with up to 3 C atoms, or stands for lower alkylidene, the ring A is unsubstituted or mono-, di- or poly-substituted with hydroxy, lower alkoxy, lower alkanoyloxy, cyano, halogen, lower alkyl and/or trifluoromethyl, m stands for 0 or 1 and in which either X is an oxygen atom or a methylene group and n stands for 0 or X stands for a direct bond and n stands for f or 1, and salts thereof.

Accordingly, the invention relates above all to a process for the preparation of compounds of formula IVc in which R^ stands for C1~C4-alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, carbamyl, N,N-lower-alkylenecarbamyl, such as piper-idlnocarbonyl, N,N- (aza)lower alkylenecarbamyl, as piper-azlnocarbonyl, N,N-(oxa)lower alkylenecarbamyl, as morpho-1inocarbonyl, or N,N-(tla)lower alkylenecarbamyl, as tlomorpholinocarbonyl, R3 stands for hydrogen, R4 for C] —C4-alkyl, such as methyl, R5 stands for Ci-C4~alkyl, such as methyl, alk stands for the Ci-C4-alkyl which connects the rlng system with the I formula IVc Inscribed NH group with up to 3 C-atoms, such as methylene or ethylene, the ring A". is unsubstituted or substituted in the 6-position, with C 1 -C 4 ~ alkoxy, such as methoxy, C 1 -C 4 alkyl, such as methyl, halogen with an atomic number up to and including 35, such as fluorine or chlorine, cyano or trifluoromethyl, m represents 0 or 1, X represents an oxygen atom or a methylene group and n represents 0, and salts thereof.

Accordingly, the invention relates in particular to a process for the preparation of compounds of formula IVc, in which R^ stands for C1-C4-alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or carbamyl, R3 stands for hydrogen, R4 stands for C1-C4-alkyl, such as methyl, R5 stands for Ci-C4-alkyl, alk stands for Ci-C4~alkylene t which binds the ring system together with the NH group entered in formula IVc with up to 3 C atoms, such as methylene or ethylene, the ring A is unsubstituted or, especially in 6-position singly substituted with halogen of atomic number up to and including 35, such as fluorine or chlorine, m is 1, X is a methylene group and n is 0, and salts thereof.

Consequently, the invention primarily relates to a process for the preparation of compounds of formula IVc in which R} stands for C1-C4-alkoxycarbonyl, such as methoxycarbonyl, or carbamyl, R3 stands for hydrogen, R4 stands for C1-C4-alkyl, such as methyl, R5 stands for for C 1 -C 4 alkyl, such as methyl, alk stands for ethylene, ring A is unsubstituted, m stands for 1, X stands for a methylene group and n stands for 0 and salts thereof.

The invention primarily relates to a method for producing the 1 examples mentioned new compounds of formula IVc and salts thereof.

The method according to the invention for producing compounds of formula IVc or salts thereof is e.g. characterized by the fact that man

h) reacts compounds of the formulas

in which one of the residues Z^ and Zg stands for reactively esterified

hydroxy, the other for amino and Z3 stands for hydrogen or Z-L is amino and Zg and Z3 together constitute an additional bond, or possibly salts of these compounds or

i) in a compound of the formula

in which Xfc stands for a residue that can be transferred to R^ , or a salt thereof, transfers X^ to R^ and cleaves off a possibly present protecting group or, if desired, transfers

a compound of formula IVc according to the invention or obtained in another way to another compound of formula IVc, separates an isomer mixture obtained according to the invention into its components, splits an enantiomer obtained according to the invention, or diastereomer mixture in the enantiomers or the diastereomers and/or transfers a free compound of formula IVc obtained according to the invention to a salt or a salt obtained according to the invention to the free compound of formula IVc or to another salt.

Variant h):

Reactive esterified hydroxy or Z2 means in particular hydroxy esterified with a strong inorganic acid or organic sulphonic acid, for example halogen, such as chlorine, bromine or iodine, sulphonyloxy, such as hydroxysulphonyloxy, halogensulphonyloxy, e.g. fluorosulfonyloxy, optionally, e.g. with halogen, substituted lower-alkanesulfonyloxy, e.g. methane- or trifluoromethanesulfonyloxy, cycloalkanesulfonyloxy, e.g. cyclohexanesulfonyloxy, or optionally, e.g. with lower alkyl or halogen, substituted benzenesulfonyloxy, e.g. p-bromophenyl- or p-toluenesulfonyloxy.

The reaction is carried out in this case in particular in the presence of a condensation agent, such as a suitable base. Examples of bases include alkali metal hydroxides,

— hydrides, -amides, -alkanolates, -carbonates, -triphenylmethylides, -di-lower-alkylamides, -amino-lower-alkylamides or -lower-alkylsilylamides, naphthalene amines, lower-alkylamines, basic heterocyclic compounds, ammonium hydroxides and carbocyclic amines. Examples include sodium hydroxide, hydride, amide, ethylate, potassium tert-butylate, carbonate, lithium triphenylmethylamide, lithium diisopropylamide, potassium 3-(aminopropyl)amide, bis-(trimethylsilyl)- amide, dimethylaminonaphthalene, di- or triethylamine, pyridine, benzyl-trimethyl-ammonium hydroxide, 1,5-diaza-bicyclo[4,3,0]non-5-ene (DBN) and 1,5-diaza-bicyclo[5, 4,0]-undec-5-ene (DBU). The turnover of amines Villa (Z^- amino)

with acrylic acid compounds VHIb (Z2+ Z3= bond) takes place, for example, during heating, e.g. to approx. 60-120°C.

The starting material of the formulas Villa and VHIb is known or can be prepared analogously to known methods.

Variant in ) ;

A residue X^ which can be transferred to is, for example, functionally derived carboxy different from R^, such as cyano, anhydridized carboxy, optionally substituted amidino, optionally esterified or anhydridized carboxymldoyl, from esterified or amidated carboxy R^differently esterified or amidated carboxy, tri -lower alkoxy- or trihalomethyl .

Anhydridized carboxy is, for example, with a mineral acid, such as hydrogen halide acids, or with a carboxylic acid, such as an optionally substituted lower-alkane- or benzoic acid or a carboxylic acid halide lower alkyl half-ester anhydrided carboxy. Examples include halocarbonyl, such as chlorocarbonyl, lower-alkanoyloxycarbonyl, such as acetyloxycarbonyl, or lower-alkoxycarbonyloxycarbonyl, such as ethoxycarbonyloxycarbonyl.

Substituted amidino is, for example, amidino substituted with an aliphatic residue, e.g. lower alkyl, such as lower alkylamidino, e.g. ethylamidino.

By esterified or anhydridized carboxymldoyl is meant e.g. alkoxy- or halogenocarboxymidoyl, for example lower alkoxy-, such as ethoxy-, or chlorocarboxymidoyl.

Tri-lower-alkoxy- or trihalomethyl is e.g. tri-methoxymethyl or trichloromethyl.

Xfc can, for example, be transferred to R^ by solvolysis. Solvolytic agents are, for example, water, lower alkanols corresponding to the desired esterified carboxy, ammonia or amines corresponding to the desired amidated carboxy group R . The treatment with a corresponding solvolytic agent is possibly carried out in the presence of an acid or base. Examples of acids include inorganic or organic protonic acids, such as mineral acids, e.g. sulfuric acid or hydrogen halide acids, for example hydrochloric acid, such as sulphonic acids, e.g. lower-alkane- or optionally substituted benzenesulfonic acid, for example methane- or p-toluenesulfonic acid, or as carboxylic acids, e.g. lower-alkane carboxylic acids, for example acetic acid, while the bases mentioned under variant h) can be used, in particular sodium or potassium hydroxide.

In the solvolysis, the cyano group, anhydridized carboxy, optionally substituted amidino, optionally esterified or anhydridized carboxymldoyl, from esterified or amidated carboxy R^differently esterified or amidated carboxy, tri-lower-alkyl or trihalomethyl, is hydrolyzed to carboxy. Below this, any lower-alkanoyloxy acid residues present on ring A during the course of the hydrolysis can be hydrolysed to hydroxy.

Cyano, anhydridized carboxy, from esterified or amidated carboxy R^ different esterified or amidated carboxy is, for example, alcoholized with a suitable lower alkanol to esterified carboxy R^ and cyano and anhydridized carboxy, for example, amono- or aminolyzed with ammonia or with an amine corresponding to amidated carboxy R^.

The starting material of formula IX can e.g. obtained by reacting compounds of the formulas in which one of the residues Z^ and Zg stands for reactively esterified hydroxy, the other for amino and Z3 stands for hydrogen or Z± stands for amino and Zg and Z3 together form an additional bond, or possibly salts of these compounds , whereby work is carried out in an analogous manner as described under method variant h), for example in the presence of a basic agent. Reactive esterified hydroxy Z^h.h.v. Zg thereby has, for example, one of the meanings specified under method variant h).

In the starting materials of the formula VHIb, a hydroxymethyl group Ri can be present in an etherified or intermediately protected form. Etherated hydroxymethyl is, for example, lower alkoxymethyl, such as methoxy- or ethoxymethyl, or optionally substituted phenyl-lower-alkyloxymethyl, e.g. in the phenyl part substituted phenyl-C 1 -C 4 -alkyloxymethyl, such as benzyloxy-, p-chlorobenzyloxy-, 1-phenylethyloxy- or 1-(p-bromophenyl)-n-butyloxymethyl. Protected hydroxymethyl is, for example, silyloxymethyl, such as trl-lower-alkylsilyl-, e.g. trimethylsilyloxymethyl, but can also be triphenyl-lower-alkoxy-, e.g. trityloxymethyl.

The release of intermediately protected residues R^, i.e. cleavage of the intermediate protecting groups takes place in the usual way, for example by solvolysis, as mild hydrolysis, e.g. treatment with water under neutral or slightly acidic conditions, e.g. by the influence of dilute aqueous mineral or carboxylic acids, e.g. of dilute hydrochloric or acetic acid.

After operations which, if desired, can be carried out on compounds IVc obtained according to the method or in other ways, particularly analogous conversion reactions of R^ and of substituents on ring A, enantiomer and diastereomer separation and mutual conversions of salts and free compounds of formula IVc as indicated for the compound of formula I and which is carried out in an analogous manner.

The invention also relates to the use of compounds of formula I or IVc, possibly its tautomers and/or pharmaceutically usable salts of such compounds with salt-forming properties, especially as pharmacological, primarily nootropically active, active substances. Hereby, they can, preferably in the form of pharmaceutical preparations, be used in a method for prophylactic and/or therapeutic treatment of humans or animals, especially as nootropics, e.g. for the treatment of cerebral insufficiency conditions, especially memory disorders.

The invention also relates to a method for the production of pharmaceutical preparations containing a compound of formula I or IVc or optionally a tautomer and/or a pharmaceutically usable salt thereof as active substance.

In the pharmaceutical preparations obtained according to the invention, which contain a compound of formula I or IVc or possibly a tautomer and/or a pharmaceutically usable salt thereof, these are preparations for enteral, such as oral, further rectal and parenteral administration to warm-blooded animals, whereby the pharmacologically active substance is present alone or together with usual pharmaceutical excipients.

The new pharmaceutical preparations contain e.g. from approx. 10% to approx. 80%, preferably from approx. 20% to approx. b0% of the active substance. According to the invention, pharmaceutical preparations for enteral or parenteral administration is e.g. preparations In dosage unit forms such as dragées, tablets, capsules or suppositories, further ampoules. These are produced in a manner known per se, e.g. by means of conventional mixing, granulating, coating, dissolving or lyophilization methods. Consequently, pharmaceutical preparations for oral use can be obtained by mixing the active substance with solid carriers, an obtained mixture is optionally granulated and the mixture or the granulate is processed into tablets or dragee cores, if desired or necessary, after adding suitable excipients.

Suitable carriers are especially fillers, such as sugar, e.g. lactose, sucrose, mannitol is sorbitol, cellulose preparations and/or calcium phosphate, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders, such as starch glue, using e.g. maize, wheat, rice or potato starch, gelatin, tragacanth, methyl cellulose and/or polyvinylpyrrolidone, if desired, explosives, such as the above-mentioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Aids are primarily flow control agents and lubricants, e.g. silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragé core is equipped with suitable, possibly gastric juice-resistant covers, whereby one e.g. use concentrated sugar solutions which possibly contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, varnish solution in the suitable organic solvents or solvent mixtures or, for the production of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. The tablets or dragé coatings may have added dyes or pigments, e.g. for identification or to indicate different doses of active substance.

Further orally usable pharmaceutical preparations are capsules made of gelatin, as well as soft, closed capsules made of gelatin and a plasticizer, such as glycerin or sorbitol. Stik capsules can contain the active substance in the form of a granule, e.g. in a mixture 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 substance is dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, whereby stabilizers may be added if necessary.

As rectally applicable pharmaceutical preparations, e.g. suppositories in consideration, these consist of a combination of the active substance with a suppository base. As suppository bases, e.g. natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules can also be used which contain a combination of the active substance with a base substance. As base materials come e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in question.

For parenteral administration, primarily aqueous solutions of an active substance in water-soluble form are suitable, e.g. a water-soluble salt, further suspensions of the active substance, such as corresponding oily injection suspensions, whereby suitable lipophilic solvents or carriers, 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 substances, e.g. sodium carboxymethylcellulose, sorbitol and/or dextran, and optionally also stabilizer.

The dosage of the active substance depends on various factors, such as method of administration, species of warm-blooded animal, age and/or individual condition. In the normal case, for a warm-blooded animal of approx. 75 kg by oral administration, an estimated daily dose of approx. 20 to approx. 500 mg reasonable, especially from approx. 25 to about 250 mg, preferably in several, equally large partial doses.

The following examples illustrate the above-mentioned invention without limiting its scope.

Due to the close relationship between a compound of formula I and the corresponding tautomeric compound of formula I', in the compounds a compound of formula I must also be understood as the tautomeric compound of formula I'. The same applies to a compound of formula I' as well as to salts of the compounds of 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) of 1, 2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrobromide (guvacolin hydrobromide) and then with 11.31 g (87.5 mmol) of N-ethyl-N,N-diisopropylamine. The solution is stirred for 15 hours at 60°C and evaporated under high vacuum. The 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 while cooling with caustic soda (30$) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. 5.52 g (67$ of theoretical) of l-[2-(2,2-dimethylchroman-3) are obtained -yl)ethyl]-1,2,5,6-tetrahydro-pyrridine-3-carboxylic acid methyl ester as a clear yellow oil.This with hydrochloric acid in diethyl ether gave 1-[2-(2,2-dimethylchroman-3-yl )ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride is crystallized from methanol/diethyl ether and melts at 196-197°C.

2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)ethyl]-chroman can e.g. is prepared in the following way: 25 g (0.6 mol) of sodium hydride suspension (57$ in mineral oil) is freed by washing several times with n-hexane largely from mineral oil and then covered with 500 ml of dry tetrahydrofuran. Under nitrogen and cooling in an ice bath, 134 g (0.6 mol) phosphonoacetic acid triethyl ester of the formula (H5C20)2P(=0)CH2C(=0)0C2H5 is added dropwise over the course of 1 hour. It is stirred for a further hour at 0°C. A solution of 88.57 g (0.5 mol) of 2,2-dimethyl-3-oxochromane [F. Camps et al., J. Heterocyclic Chem. 22, 1421

(1985)] 1300 ml of tetrahydrofuran. It is stirred overnight at room temperature. The solution is then concentrated in a vacuum to approx. 350 ml and poured onto 3 1 of ice-cold phosphate buffer solution (pH = 6). The mixture is extracted with diethyl ether. The combined organic phases which have been washed with water and dried over sodium sulphate are evaporated in vacuo. The yellow residue is chromatographed on 4 kg of silica gel (0.040-0.063 mm) with toluene as eluent. 60.3 g (49% of theory) of 3-ethoxycarbonylmethyl-2,2-dimethyl-2H-chrome are obtained in this way as a clear yellow oil.

A solution of 59.1 g (0.24 mol) of 3-ethoxycarbonylmethyl-2,2-dlmethyl-2H-chrome in 400 ml of absolute ethanol is mixed with 3 g of palladium on charcoal (5$) and hydrated in a PARR apparatus at room temperature for 2 hours. The reaction mixture is then filtered over 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 1 lithium aluminum hydride in 200 ml of absolute diethyl ether, a solution of 50 g (0.2 mol) of 3-ethoxycarbonyl-methyl-2,2-dimethyl-chroman is added dropwise under ice-cooling in 250 ml of absolute diethyl ether during 1 hour. The reaction mixture is stirred for 13 hours at room temperature and is then carefully mixed with 7.5 ml of water, 7.5 ml of caustic soda ($15) and 23 ml of water. The precipitated precipitate from Utreres. The filtrate dried over sodium sulfate is evaporated in vacuo. 39.5 g (95% of theory) of 2,2-dimethyl-3-(2-hydroxyethyl)-chroman are obtained in the form of a colorless oil.

A solution of 37.1 g (0.18 mol) of 2,2-dlmethyl-3-(2-hydroxyethyl)-chroman in 150 ml of pyridine is mixed at room temperature with stirring with 38 g (0.2 mol) of 4- toluenesulfonyl chloride, whereby the slightly exothermic reaction is kept at room temperature by means of an ice bath. It is stirred for 14 hours at room temperature. The reaction mixture is then poured onto ice water and extracted with diethyl ether. The combined ether-containing phases are washed three times, each time with 150 ml of citric acid solution (5$) and three times, each time with 150 ml of water, dried over sodium sulfate and evaporated. In this way, 59.1 g (89$ of theoretical) of 2,2-dimethyl-3-[2-(4-toluenesulfonyloxy)ethyl]-chroman are obtained as a yellow oil, which is further used in this form.

Example 2

In a solution of 5.66 g (15 mmol) of N-[2-(2,2-dimethyl-chroman-3-yl)ethyl]-N,N-bis(2-methoxycarbonylethyl)-amine in 50 ml of absolute N ,N-dimethylformamide 0.87 g (18 mmol) sodium hydride suspension in mineral oil (50$) is introduced at room temperature with stirring over the course of 30 minutes. The reaction mixture is stirred for 1 hour at room temperature and then evaporated to dryness under high vacuum. The residue is mixed with diethyl ether and extracted with cold 2N hydrochloric acid. The combined hydrochloric acid extracts are decanted with dichloromethane and the dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. 1.95 g (34$ of theoretical) 1-[2-(2,2-dimethylchroman-3-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydro-pyridine-3-carboxyl are obtained -acid methyl ester hydrochloride or 1-[2-(2,2-dimethylchroman-3-yl)-ethyl]-4-oxo-piperidine-S-carboxylic acid methyl ester hydrochloride, which after recrystallization from methanol/diethyl ether has a decomposition range of 168-170°C.

N-[2-(2,2-dlmethylchroman-3-yl)ethyl]-N,N-bis(2-methoxycarbonyl-ethyl)-amine can e.g. produced in the following way:

A solution of 14.4 g (40 mmol) of 2,2-dlmethyl-3-[2-(4-toluenesulfonyloxy)ethyl]-chromane (prepared as described in example 1) in 200 ml of ethanol is mixed with a solution of 3, 9 g (60 mmol) of sodium azide in 10 ml of water. The mixture is boiled for 18 hours under reflux. After cooling, the ethanol is evaporated under vacuum and the residue is mixed 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-dlmethylchroman are obtained in the form of a yellow oil.

A solution of 6.94 g (30 mmol) of 3-(2-azidoethyl)-2,2-dlmethylchromane in 100 ml of absolute tetrahydrofuran is added dropwise in a nitrogen atmosphere to a stirred suspension of 1.14 g (30 mmol) of lithium aluminum hydride in 100 ml of absolute diethyl ether during 1 hour at room temperature. After a further 2 hours of stirring, the reaction mixture is hydrolysed with 1.14 ml of water, 1.14 ml of caustic soda (15$) and 3.4 ml of water. The formed precipitate is filtered off, and the filtrate is completely evaporated in vacuo. The oil obtained as a 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 under ice-cooling with concentrated caustic soda and extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated in vacuo. 5.6 g (91% of theory) of 3-(2-aminoethyl)-2,2-dimethylchroman are obtained as a yellow oil, the hydrochloride of which melts with decomposition at 245-248°C.

A solution of 5.13 g (25 mmol) of 3-(2-aminoethyl)-2,2-dimethylchroman in 50 ml of methanol is mixed at room temperature with 4.74 g (55 mmol) of acrylic acid methyl ester. The mixture is stirred for 16 hours at room temperature and then evaporated in vacuo. 9.43 g (100$ of theory) of N-[2-(2,2-dimethylchroman-3-yl)ethyl]-N,N-bls(2-methoxycarbonylethyl)-amine are obtained in this way as clear yellow oil , which is further used in this form.

Example 3

To a solution of 3.08 g (15 mmol) 3-(2-aminoethyl)-2,2-dimethylchroman (prepared as described in example 2) in 75 ml of methanol is added dropwise under ice-cooling over the course of 15 minutes a solution of 1.3 g (15 mmol) of acrylic acid methyl ester in 25 ml of methanol. The reaction mixture is stirred at 0°C for 6 hours and then evaporated in vacuo. The oily residue is chromatographed on 300 g of silica gel (0.040-0.063 mm) with ethyl acetate as eluent. 2.75 g (63% of theory) of N-[2-(2,2-dimethylchroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)amine are obtained in this way as a clear yellow oil whose hydrochloride melts at 132-134"C.

Example 4

A solution of 2.91 g (10 mmol) of N-[2-(2,2-dimethylchroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)amine (prepared as described in example 3) is mixed in 20 ml of methanol with 15 ml of a 5N solution of ammonia in methanol and the reaction mixture is allowed to react in a closed container for 6 days at room temperature. The mixture is then evaporated, and N-(2-aminocarbonylethyl)-N-[2-(2,2-dimethyl-chroman-3-yl)ethyl]-amine hydrochloride is prepared from the residue with methanolic hydrochloric acid, which exhibits a melting range at 194-196"C.

Example 5

To a solution of 2.23 g (10 mmol) 3-(2-aminoethyl)-2,2-dimethyl-6-fluorochroman in 50 ml of methanol is added dropwise over 15 minutes, and while stirring, at a temperature of 0 to 5°C a solution of 0.86 g (9.9 mmol) of acrylic acid methyl ester in 10 ml of methanol. The reaction mixture is then stirred for 16 hours at 0 to 5°C and then evaporated in vacuo. The oily residue is chromatographed on 200 g of silica gel (0.040-0.063 mm) with ethyl acetate as eluent. 1.9 g (61.4$ of theoretical) N-[2-(2,2-dimethyl-6-fluoro-chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)- amine as clear yellow oil. The N-[2-(2,2-dimethyl-6-fluoro-chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride prepared from this with hydrochloric acid in diethyl ether is crystallized from acetone/diethyl ether and melts at 129-131°C.

The 3-(2-aminoethyl)-2,2-dimethyl-6-fluoro-chroman can e.g. is prepared as follows: A solution of 28.0 g (0.2 mol) of 5-fluoro-2-hydroxy-benzaldehyde [prepared according to Y. Suzuki and H. Takahashi, Chem. Pharm. Bull. 31, 1751 (1983)] in 500 ml of N,N-dimethylformamide is mixed with stirring with 83.1 g (0.2 mol) of potassium carbonate. The resulting viscous suspension is mixed with 36.3 g (0.2 mol) of 3,3-dimethylacrylic acid ethyl ester. The reaction mixture is then stirred for 16 hours at 150°C, and evaporated in vacuo after cooling to room temperature. The solid residue obtained is mixed with water, and the aqueous mixture is extracted with diethyl ether. The combined ether-containing phases are washed step by step with water, 2N hydrochloric acid, 2N caustic soda and once again with water, dried over sodium sulfate and evaporated in vacuo. The oily residue obtained is chromatographed on 1,000 g of silica gel (0.040-0.063 mm) with toluene as eluent. In this way, 19.5 g (55% of theory) of 2,2-dimethyl-6-fluoro-2H-chrome are obtained as clear yellow oil.

A solution of 17.8 g (0.1 mol) of 2,2-dimethyl-6-fluoro-2H-chrome in 300 ml of trichloromethane is mixed with stirring at 15 to 20° C with 40.6 g (0.2 mol) m-chloroperbenzoic acid. To the suspension obtained, 17.1 g (0.15 mol) of trifluoroacetic acid are quickly added at room temperature. The reaction mixture is stirred for 2 hours at room temperature and is then mixed with an aqueous solution of sodium sulphite/sodium hydrogen carbonate (1:1). The organic phase is separated, washed step by step with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue obtained is subjected to high vacuum at 160°C ball tube distillation. The distillate is dissolved in diethyl ether and the solution is washed step by step with sodium bicarbonate solution and saturated sodium chloride solution, dried over sodium sulfate and re-evaporated in vacuum. The resulting oily residue is chromatographed on 500 g of silica gel (0.040-0.063 mm) with toluene as eluent, thus obtaining 7.76 g (40% of theory) of 2,2-dimethyl-6-fluoro-3-oxo-chroman as a clear yellow oil.

A solution of 5.7 g (29 mmol) of 2,2-dimethyl-6-fluoro-3-oxo-chroman in 100 ml of absolute tetrahydrofuran is added over 30 minutes with stirring at 0 to 5°C dropwise to a suspension of 1.69 g (35 mmol) of sodium hydride dispersion (55% in mineral oil), which has previously been largely freed of mineral oil by washing several times with n-hexane, in 100 ml of absolute tetrahydrofuran. It is then stirred for 30 minutes at 0 to 5°C, and a solution of 7.9 g (35 mmol) of phosphonoacetic acid triethyl ester of the formula (H5C20)2P(=0)CH2C(=0)0C2H5 in 70 ml of absolute tetrahydrofuran is then added dropwise. during 30 minutes at 0 to 5°C. The reaction mixture is further stirred for 30 minutes at 0 to 5°C and then for 16 hours at room temperature and preferably then in 700 ml of cold phosphate buffer solution (pH=6). The resulting mixture is extracted with diethyl ether. The combined organic phases are washed successively with phosphate buffer solution (pH=7) and water, dried over sodium sulphate and evaporated. The red oil obtained is chromatographed on 400 g of silica gel (0.040-0.063 mm) with toluene as eluent. 5.76 g (75% of theory) of 3-ethoxycarbonylmethyl-2,2-dimethyl-6-fluoro-2H-chromium 1 are obtained in the form of an orange colored oil.

A solution of 3.4 g (13 mmol) of 3-ethoxycarbonylmethyl-2,2-dimethyl-6-fluoro-2H-crora in 30 ml of absolute ethanol is mixed with 140 ml of palladium on charcoal (5$) and hydrated at normal pressure and room temperature for 90 minutes. The catalyst is then filtered off, and the filtrate is evaporated in vacuo. In this way, 3.47 g of 3-ethoxycarbonylmethyl-2,2-dimethyl-6-fluorochroman are obtained as a clear yellow oil.

To a suspension of 0.97 g (25.5 mmol.) 1 lithium aluminum hydride in 30 ml absolute diethyl ether, a solution of 3.4 g (12.7 mmol) 3-ethoxycarbonylmethyl-2 ,2-dimethyl-6-fluoro-chroman in 40 ml of absolute diethyl ether. The reaction mixture is stirred for 2 hours at room temperature and then carefully mixed with 1 ml of water, 1 ml of caustic soda ($15) and 3 ml of water. The formed precipitate is suctioned off, and the filtrate dried over sodium sulphate is evaporated in vacuo. 2.75 g (96% of theory) of 2,2-dimethyl-6-fluoro-3-(2-hydroxy-ethyl)-chroman are obtained in this way as a clear yellow oil.

A solution of 4.48 g (20 mmol) of 2,2-dimethyl-6-fluoro-3-(2-hydroxy-ethyl)-chroman in 30 ml of absolute pyridine is mixed at room temperature with stirring with 4.01 g (21 mmol ) 4-toluenesulfonyl chloride, whereby the slightly exothermic reaction with an ice bath is kept at room temperature. The reaction mixture is stirred for 2 hours at room temperature, then poured onto ice water and the mixture is extracted with diethyl ether. The combined organic phases are washed cold with 2N hydrochloric acid and then with water, dried over sodium sulphate and evaporated in vacuo. In this way, 6.5 g (85.8% of theory) of 2,2-dimethyl-6-fluoro-3-[2-(4-toluenesulfonyloxy)ethyl]-chroman are obtained as clear yellow oil.

A solution of 6.3 g (16.6 mmol) of 2,2-dimethyl-6-fluoro-3-[2-(4-toluenesulfonyloxy)ethyl]-chroman in 100 ml of ethanol is mixed with a solution of 1.62 g (24.9 mmol) of sodium azide in 10 ml of water. The mixture is boiled for 1-18 hours under reflux. After cooling, the ethanol is evaporated and the residue is mixed with water. The aqueous mixture is extracted with diethyl ether. The combined organic phases are washed with water, dried over sodium sulphate and evaporated in vacuo. 4.13 g (100% of theory) of 3-(2-azidoethyl)-2,2-dimethyl-6-fluorochroman are obtained in this way as a clear yellow oil.

To a suspension of 0.61 g (16 mmol) of lithium aluminum hydride in 30 ml of absolute diethyl ether, a solution of 4.0 g (16 mmol) of 3-(2-azidoethyl)-2,2-dimethyl is added dropwise over the course of 30 minutes -6-fluorochroman in 30 ml of absolute tetrahydrofuran. The reaction mixture is stirred for 2 hours at room temperature and then carefully mixed with 0.61 ml of water, 0.61 ml of caustic soda ($15) and 1.83 ml of water. The formed precipitate is suctioned off and the filtrate is evaporated in vacuo. The oily residue is dissolved in diethyl ether and the solution is extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are made alkaline under ice-cooling with caustic soda (30$) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulfate and evaporated in vacuo. 3.21 g (90$ of theory) of 3-(2-aminoethyl)-2,2-dimethyl-6-fluorochroman are obtained in this way as a yellow oil. The 3-(2-aminoethyl)-2,2-dimethyl-6-fluorochroman hydrochloride prepared from this with hydrochloric acid in diethyl ether is crystallized from methanol/diethyl ether and has a melting range from 249 to 251°C.

Example 7

Tablets Containing 25 mg of the active substance, e.g. N-[2-(2,2-dimethylchroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amino-hydrochlorid, can be prepared in the following way:

Ingredients (for 1,000 tablets):

Manufacturing:

All solid components are first passed through a sieve with a mesh size of 0.6 mm. The active substance, lactose, talc, magnesium stearate and half of the starch are then mixed. The other half of the starch is suspended in 40 ml of water, and this suspension is added to a boiling solution of polyethylene glycol in 100 ml of water. The obtained starch paste is added to the main quantity and the mixture is granulated, if necessary with the addition of water. The granulate is dried overnight at 35°C, driven through a sieve with a mesh size of 1.2 mm and pressed into tablets that are concave on both sides and have a diameter of approx. 6 mm.

Example 8

Tablets, containing 50 mg of the active substance, e.g. N-[2-(2,2-Dimethylchroman-3-yl)ethyl]-N-(2-methoxy-carbonylethyl)-amine hydrochloride is prepared as follows:

Composition (for 10,000 tablets):

A mixture of the active substance, the lactose and 194.70 g of potato starch is moistened with an ethanolic solution of the stearic acid and granulated through a sieve. After drying, the remaining potato starch, talc, magnesium stearate and colloidal silicon dioxide are added and the mixture is pressed into tablets, each weighing 0.1 g, which can optionally be equipped with dividing lines for finer adjustment of the dosage.

In a similar way, 100 mg of active substance can be incorporated.

Example 9

Capsules containing 0.025 g of active substance, e.g. N-[2-(2,2-dimethylchroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)amine hydrochloride can be prepared in the following way:

Composition (for 1,000 capsules):

The active substance is mixed with the lactose, the mixture is evenly moistened 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 talc and filled in portions of 300 mg in hair gelatin capsules (size 1).

Example 10

In a similar way as described in examples 7 to 9, pharmaceutical preparations can also be prepared which, as active ingredient, contain a compound of formula I or a tautomer and/or a pharmaceutically usable salt thereof or another compound of formula IVc or a pharmaceutically usable salt hence, for example according to examples 1 to 6.

Claims (10)

1. Process for preparing a compound of the formula in which either R^ stands for carboxy, lower-alkoxycarbonyl, amidated carboxy or optionally acylated hydroxymethyl and R2 stands for hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group or Ri stands for hydrogen and R2 for carboxy, lower-alkoxycarbonyl, amidated carboxy or optionally acylated hydroxymethyl and in which R3 stands for hydrogen or lower alkyl, R4 is lower alkyl, R5 is lower alkyl, alk stands for lower alkylene or lower alkylidene, ring A is unsubstituted or mono- or polysubstituted with hydroxy , lower-alkoxy, lower-alkanoyloxy, cyano, halogen, lower-alkyl and/or trifluoromethyl, the dotted line shall express that there is a single or a double bond between the carbon atoms carrying the substituents R^ and R2, m stands for 0 or 1, and in which either X stands for an oxygen atom or a methylene group and n stands for 0 or X stands for a direct bond and n stands for 1, or a tautomer and/or a salt thereof, characterized by a) reacting a compound of the formula or a salt thereof, wherein stands for hydroxy or reactively esterified hydroxy, with a compound of the formula or a tautomer and/or a salt thereof orb) in a compound of the formula or a tautomer and/or a salt thereof, wherein X2 represents a residue that can be transferred to R^ which is different from hydrogen and X5 represents a residue Ra, whereby Ra represents hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amlno group, Xg transfers to a residue Ri which is different from hydrogen or 1 a compound of formula III or a tautomer and/or a salt thereof, in which Xg is hydrogen and X5 is a residue that can be transferred to Rb , in which R^ stands for a residue Rg different from the residue Ra transfers X5 to Rb or c) for the preparation of a compound of formula I or a tautomer and/or a salt thereof, in which Rg stands for hydroxy or amino and in which R^ is different from hydrogen and optionally acylated hydroxymethyl, or a compound of the formula in which Yi stands for a group of the formula -CH=Rg* , -C(Yg)=R£, —CH(Yg)-Rg or cyano, whereby Rg1 stands for oxo or imino and Yg stands for a cleavable residue, or a salt thereof or d) for the preparation of a compound of formula I', in which R-J stands for oxo or imino and Ri is different from hydrogen, or a tautomer and/or a salt thereof, reacts a compound of the formula or a tautomer and/or a salt thereof with a compound of the formula or a salt thereof, wherein is different from hydrogen and X 3 represents halogen or lower alkoxy, or e) for the preparation of a compound of formula I or a tautomer and/or a salt thereof, in which Rg stands for an optionally etherified or acylated hydroxy group or a optionally acylated amino group, in a compound of the formula or a salt thereof, in which X4 stands for a residue which can be transferred to Rg, transfers X4 to Rg, orf) in a salt of the formula where A <®> represents the anion of an acid, Rf represents a residue R^ or etherified or protected hydroxymethyl and Rg <1> represents a residue Rg, protected hydroxy, protected amino or etherified or protected hydroxymethyl, reduces the excess double bonds to single bonds and, if Rf is different from R^ and/or Rg" is different from Rg, transfer Rf to R1 and/or Rg" to Rg or g) for the preparation of a compound of formula I or a tautomer and/or a salt thereof, in which Rg is large for carboxy, amidated carboxy or lower carboxycarbonyl and the dotted line shall express that between the carbon atoms carrying the substituents R^ and Rg a single bond, ring- concludes a compound of the formula in which Yg stands for a cleavable residue, or a salt thereof and cleaves off any protective group present and, if desired, transfers a compound of formula I obtained by the method or in another way to another compound of formula I, divides an isomer mixture obtained according to the invention into its components , splits an enantiomer obtained according to the invention - or diastereomer mixture in the enantiomers or the diastereomers and/or transfers a free compound of formula I obtained by the process to a salt or a salt obtained by the process to the free compound of formula I or to another salt. 2. Method according to claim 1, characterized in that a compound of formula I is prepared in which Ri stands for C1~C4 alkoxycarbonyl or carbamyl, Rg stands for hydrogen or hydroxy, R3 stands for hydrogen, R4 stands for C1-C4 alkyl, R5 stands for for C1-C4-alkyl, alk stands for C1-C4-alkylene, which binds together the ring systems shown in formula I with up to 3 C-atoms, the ring A is unsubstituted or substituted, especially in the 6-position, with Ci - C4~ alkoxy, Ci-C4 -alkyl, halogen with atomic number up to and including 35, cyano or trifluoromethyl, the dotted line shall express that there is a single or a double bond between the carbon atoms carrying the substituents Ri and Rg, m stands for 1, X stands for an oxygen atom or a methylene group and n stands for 0, or a tautomer and/or a salt thereof. 3. Process according to claim 1, characterized in that a compound of formula I is prepared in which Ri stands for Ci~C4 -Alkoxycarbonyl, Rg stands for hydrogen, R3 stands for hydrogen, R4 stands for Ci~C4 -alkyl, R5 stands for Ci~C4 ~ alkyl, alk stands for ethylene, the ring A can be unsubstituted or singly substituted, especially in the 6-position, with halogen with an atomic number up to and including 35, the dotted line shall express that there is a double bond between the carbon atoms carrying the substituents Ri and R2 , m stands for 1, X stands for a methylene group and n stands for 0, or a salt thereof. 4. Method According to claim 1, characterized in that a compound of formula I is prepared in which Ri stands for C1-C4 alkoxycarbonyl, Rg stands for hydrogen, R3 stands for hydrogen, R4 stands for C1-C4 alkyl, R5 stands for C]_ —C4~alkyl, alk stands for ethylene, the ring A is unsubstituted, the dotted line shall express that there is a double bond between the carbon atoms carrying the substituents Ri and Rg, m stands for 1, X stands for a methylene group and n stands for 0, or a salt thereof. 5 . Process according to claim 1, characterized in that one prepares 1-[2-(2,2-dimethylchroman-3-yl)-ethyl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester or a salt thereof. 6. Process for preparing a compound of the formula in which R 1 stands for carboxy, lower alkoxycarbonyl, amidated carboxy or optionally acylated hydroxymethyl, R 3 stands for hydrogen or lower alkyl, R 4 is lower alkyl, R 5 is lower alkyl, alk is lower alkylene or lower alkylidene, the ring A is unsubstituted or mono- or poly-substituted with hydroxy, lower-alkoxy, lower-alkanoyloxy, cyano, halogen, lower-alkyl and/or trifluoromethyl, ra stands for 0 or 1 and in which either X is an oxygen atom or a methylene group and n stands for 0 or X stands for a direct bond and n stands for 1, or a salt thereof, characterized by manh) Converts compounds of the formulas with each other, in which one of the residues Z± and Zg stands for reactively esterified hydroxy, the other for amino and Z3 stands for hydrogen or Z^ is amino and Zg and Z3 together form a further bond, or possibly salts of these compounds, ori) in a connection of the formula wherein Xfc is a residue which can be transferred to R-^ , or a salt thereof, transfers X^, to R^ and, in either case, cleaves off any protecting group present and, if desired, transfers one by the process or otherwise obtained compound of formula IVc to another compound of formula IVc, divides an isomer mixture obtained by the method into its components, splits an enantiomer obtained by the method, or diastereomer mixture in the enantiomers or the diastereomers, and/or transfers a free compound of formula IVc obtained by the process to a salt or converts a salt obtained by the process to the free compound of formula IVc or to another salt. 7. Process according to claim 6, characterized in that a compound of formula IVc is prepared in which Ri stands for C1 -C4 -Alkoxycarbonyl, carbamyl, N,N-lower alkylenecarbamyl, N,N-(aza)lower alkylenecarbamyl, N,N- (oxa)lower alkylenecarbamyl or N,N-(thia)lower alkylenecarbamyl, R3 stands for hydrogen, R4 stands for Ci -C4~ alkyl, R5 stands for Ci -C4~ alkyl, alk stands for Ci -C4 - the alkyl that connects the ring system with the NH group entered in formula IVc with up to 3 C atoms, the ring A is unsubstituted or, especially in the 1 6-position, substituted with Ci~C4 -Alkoxy, Ci-C4 -Alkyl, halogen with atomic number to and with 35, cyano or trifluoromethyl, m represents 0 or 1, X represents an oxygen atom or a methylene group and n represents 0, or a salt thereof. 8. Method According to claim 6, characterized in that a compound of formula IVc is prepared in which Ri stands for Ci-C4 alkoxycarbonyl or carbamyl, R3 stands for hydrogen, R4 stands for Ci-C4 alkyl, R5 stands for Ci-C4 alkyl, alk stands for the Ci -C4 -alkylene, which connects the ring system with the NH group entered in formula IVc with up to 3 C atoms, the ring A is unsubstituted or, especially in the 6-position, singly substituted with halogen with an atomic number up to and including 35 , m stands for 1, X stands for a methylene group and n stands for 0, or a salt thereof. 9. Method according to claim 6, characterized in that a compound of formula IVc is prepared, in which Ri stands for C1-C4 alkoxycarbonyl or carbamyl, R3 is hydrogen, R4 stands for C1-C4 alkyl, R5 stands for C1-C4 alkyl, alk stands for ethylene, ring A is unsubstituted, m stands for 1, X stands for a methylene group and n stands for 0, or a salt thereof. 10. Process according to claim 6, characterized in that N-[2-(2,2-dimethylchroman-3-yl)-ethyl]-N-(2-methoxycarbonylethyl)-amln, N-(2-aminocarbonyl ethyl)- N-[2-(2,2-dimethylchroman-3-yl)ethyl]-amln or N-[2-(2,2-dimethyl-6-fluoro-chroman-3-yl)ethyl]-N-(2 -methoxycarbonyl-ethyl)-amine or salts thereof.