IE871694L

IE871694L - Pyridine derivatives and related intermediates

Info

Publication number: IE871694L
Application number: IE871694A
Authority: IE
Original assignee: Ciba Geigy
Priority date: 1986-06-26
Filing date: 1987-06-25
Publication date: 1987-12-26
Also published as: PT85157A; HU207061B; DK325587D0; AU8125587A; ES2044970T3; HUT48622A; ATE65084T1; GR3002308T3; FI91064C; FI91064B; DE3771280D1; EP0252005A1; JPS638382A; HK134994A; AU617988B2; FI872807A; JPH0699420B2; CA1322553C; IE59881B1; DD279674A5

Abstract

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

Description

The invention relates to novel hydrogenated l-benzooxa-cycloalkylpyridinec&rboxy1 ic acid compounds of the formula ,\ A ✓*' i a II K elk-SC .i—*J \ " / (C — Iff f Ri in which either represents carboxy, lower alkoxy-carbonyl, carbamoyl, M-lower alkylcarbaiaoyl, N,N-di-lower alkylcarbamoyl or optionally acylated hydroxymethyl and R2 represents hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group, or Ri represents hydrogen and R2 represents carboxy, lower alkoxycarbonyl, N~lower alkylcarbaiaoyl, N,N-di-lower alkylcarbamoyl or optionally acylated hydroxymethyl, R3 represents hydrogen or lower alkyl, alk represents lower aIkylens or lower alkylidene, the ring A is unsubstituted or is mono- or poly-substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or by trifluoromethyl, the dotted line is intended to indicate the presence of a single or a double bond between the carbon atosns carrying the radicals and $£2" an<^ either each of X and ¥ represents an oxygen atom and n represents 1, or X represents a methylene group , y represents an oxygen atom and n represents 1, or X represents an oxygen atom, ¥ represents a. methylene group and & represents l, or X represents a direct bond, Y represents an oxygen atom and n represents 2, and to their tautoraers and/or salts, to the use of these compounds, to processes for their Manufacture and to pharmaceutical compositions comprising a compound of the formula I or a tautomer and/or a pharmaceutical ly acceptable salt thereof.

Etherified hydroxy R2 is,, for example, lower alkoxy or optionally substituted phenyl-lower alkoxy.

Acyl in acylated hydroxymethyl and R2 and also in acylated hydroxy R2 and 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 radical of an aliphatic or monocyclic-aromatic carboxylic acid, such as lower alkanoyl or optionally substituted benzoyl, and also pvridoyl.

Acyl derived from an organic sulphonic acid is, for example, lower alkanesulphonyl.

The invention relates, for example, to compounds of the formula I in which R^ represents carboxy, lower alkoxy-carbonyl, carbamoyl, M-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R2 represents hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group, R3 represents hydrogen or lower alkyl,, alk represents lower alkylene or lower alkylidene, the ring A is unsubstituted or is mono- or poly-substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or by trifluoro™ methyl, the dotted line is intended to indicate the presence of a single or a double bond between the carbon atoms carrying the radicals R^ and R2f X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, and to their tautoiaers and/or salts, to the use of these compounds, to processes for their manufacture and to pharmaceutical compositions comprising such a compound of the formula I or a tautomer and/or a pharmaceutically acceptable salt thereof.

Tautomeric forms of compounds of the formula I exist, for example, when R2 represents hydroxy or amino and the dotted line is intended to indicate the presence of a double bond between the carbon atoms carrying the radicals % and R2- That is to say, the enols and enamines, respectively, of the formula I are in equilibrium mth the corresponding keto and ketimine tautoiaers, respectively, of the formula in which represents oxo or iiaino. Representatives of both tautomeric forms can be isolated.

The compounds according to the invention can also be in the form of stereoisomers. Since the compounds of the formula I have at least one chiral carbon atom (C-atosa) (the C-atom having the radical R3)t they may be, for example, in the form of pure enantiomers or enantiosaeric mixtures, such as racemates, and if,, also, there is at least one further chiral centre present (for example the C4-atoja of a. 4-substituted piperidine radical and/or the C3-ato» of a 3-substituted piperidine radical), they may also be in the for® of diastereoisomers* diastereo™ isomeric mixtures or Mixtures of racemates. Thus,, for example, geometrical isomers with respect to Ei and R2P such as cis- and trans-isomers, may be formed if % and /\ A /*> 0 n i» kl r2 are other than hydrogen.

Salts of compounds of the formula I and their tautomers are especially corresponding acid addition salts, preferably pharmaceuticalIv acceptable acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids. for example sulphuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as lower alkanecarboxvlic acidsf for example acetic acid,, optionally unsaturated dicarboxylic acids, for example malonic maleic or fumaric acid, or hydroxycarboxylic acids, for example tartaric or citric acid, or with sulphonic acids such as lower alkanesulphonic acids or optionally substituted benzenesulphonic acids, for example methane-or g-toluene-sulphonic acid. If, for example, R^ or R2 represents carboxy, corresponding compounds may form salts with bases. Suitable salts with bases are, for example, corresponding alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, pharmaceutically acceptable transition metal salts, such as zinc or copper salts, or salts with ammonia or organic amines, such as cyclic amines, mono-, di- or tri-lower alkvlamines, hydroxy-1 ower alkylamines, for example mono-, di- or tri-hydroxy-lower alkvlamines, hydroxy-lower alkyl-lower alkylamines or polyhydroxy-lower alkylamines. Cyclic amines are, for example, morpholine, thiomorpholine, piperidine or pyrrolidine,, As mono-lower alkylamines there come into consideration, for example, ethyl amine or tert«-butyl amine i* as di-lower alkylamines, for example, diethylamide or diisopropyl-amine, and as tri-lower alkylamines, for example, trimethylamine or triethylamine. Corresponding hydroxy-lower alkylamines are, for example, mono-, di- or tri- 6 ethanolamine? hydroxy-1oyer alkyl-lower alkylamines are, for example, N,N-dimethylamino- or N,N-diethylamino- ethanol; as polyhydroxy-lower alkylamine there comes into consideration, for example, glucosamine* v Also included are salts that are unsuitable for pharma ceutical uses, since they can be used, for example, for the isolation and purification of free compounds according to the invention and their pharmaceutically acceptable salts.

Hereinbefore and hereinafter, unless defined otherwise, radicals or compounds designated "»lo&?erw are to be understood as meaning those radicals or compounds which contain up to and including 7, especially up to and including 4, carbon atoms.

Lower alkoxy is C^-C^alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert.~ butoxy.

Lower alkyl is, for example, Ci~C4-alkyl, that is to say methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutvl, sec.-butyl or tert»-butyl, and also includes C5~C7~alkyl radicals, that is to say pentyl, hexyl and heptyl radicals „ Lower alkylene alk is Ci -C^-alkylene that bridges the two ring systems especially by up to and including 3 carbon atoms and may foe, for example, methylene, ethylene or 1,3-propylene , but may also be 1,, 2-propylene , 1,2- or * 1,3-(2-methyl)-propylene or 1,2- or 1,3-butylene, but may also bridge the two ring systems by 4 carbon atoms, that is to say it may be 1,4-butylene.

Lower alkylidene aIk is C x =C 4-a1ky1idene and may be, for example, methylene,, ethylidene, l£, 1- or 2,2-propylidene or 11- or 2,2-butylidene.

Lo%?er alkanoyl is C2-C5~alkanoyl, such as acetyl, propionyl, butyryl, isobutvryl or pivaloyl.

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

Lower alkoxycarbonyl is C1-C4~alkoxycarbonyl, such as methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, isobutoxy- or tert--butoxy-carbonyl.

N-lower alkylcarbamoyl is H-C1-C4-alkylcarbaiaoyl, such as N-methyl-, N-ethyl-, N-(n-propyl)-, M-isopropyl~, N-(n-butyl)-, N-isobutvl- or M-tert„-butyl-carbamoyl.

N,N-di-lower alkylcarbamoyl is MfM-di-C^-C^-alkyl-carbamoyl, in which the two M-alkyl groups may be the same or different, such as M,M-diiaethy 1-, N,N-diethyl-, N,N-diisopropyl- or N-butyl-N-methyl-carbamoyl.

Optionally substituted pheny1-1owar alkoxy is phenyl-C^-C^-alkoxy optionally substituted in the phenyl moiety, such as benzyloxy, jo-chlorobenzyloxy, 1-phenylethoxy or 1-(D-bromopheny1)-n-butoxy.

Optionally substituted benzoyl is,, for example, benzoyl, ©-chlorobenzoyl or D-nitrobenzoyl.

Lower alkanesulphonyl is C^-C^alkanesulphonyl, such as methane- or ethane-sulphonyl.

Halogen is especially halogen having an atomic number of up to and including 35, that is to say fluorine, chlorine or bromine, and also includes iodine.

The compounds of the formula I and their tautomers and/or their pharmaceutically acceptable salts have, for example, valuable pharmacological, especially nootropic, properties. Thus, for example£, in mice, in the Two-Compartiaent Passive Avoidance Test model according to Mondadori and Classen, Acta Neurol. Scand. 69,, Suppl. 99, 125 (1984), at dosages of approximately 0.1 mg/kg and above i.p. and p.o. they bring about a reduction in the amnesic effect of a cerebral electric shock.

The compounds according to the invention also exhibit a considerable memory-improving action which can be detected in mice in the Step-down Passive Avoidance Test according to Mondadori and Waser, Psychopharmacol. 63. 297 (1979) at a dose of approximately 0.1 mg/kg and above i.p. and p.o..

Accordingly, the compounds of the formula I and their tautomers and/or their pharmaceutically acceptable salts can be used as pharmaceuticals, for example nootropics, for example for the therapeutic and/or prophylactic treatment of the symptoms of cerebral insufficiency, especially memory disorders. The invention therefore relates also to the use of the compounds of the formula I and their tautomers and/or their pharmaceutically acceptable salts for the manufaicture of medicaments, especially nootropics, for the treatment of the symptoms of cerebral insufficiency, especially memory disorders The commercial formulation of the active ingredients may 0 also be included.

The invention relates especially to compounds of the formula I in which either % represents carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, N,M-5 di-lower alkylcarbaiaoyl, hydroxymethyl, C2-C5alkanoyloxy- methyl, lower alkanesulphonyloxymethyl, benzoyloxymefchyl or pyridoyloxymethyl and R2 represents hydrogen, hydroxyt, lower alkoxy, benzyloxy, C2~e5alkanoyloxy, lower alkane-sulphonyloxy, benzoyloxy, pyridoyloxy, ami no , C2-C5-10 alkanoylamino, lower alkanesulphonylamino, benzoylamino or pvridoylamino, or represents hydrogen and R2 represents carboxy, lower alkoxycarbonyl, H-lower alkylcarbamoyl, lower alkylcarbamoyl, hydroxy methyl , C2-*C5alkanoyloxyraethyl, lower alkanesulphonvloxy-15 methyl, ben2oy1oxvmethy1 or pyridoyloxymethyl, R3 represents hydrogen or C^-Cyalkyl, alk represents lower alkyl that bridges the two ring systems by up to and including 3 carbon atoms, or alk represents lower alkylidene, the ring A is unsubstituted or is mono-, di-20 or poly-substituted by hydroxy, lower alkoxy, C2-C5-alkanoyloxv^ halogen having an atomic number of up to and including 53, C^-Cyalkyl and/or by trifluoromethyl, the dotted line is intended to indicate the presence of a single or a double bond between the carbon atoms carrying 25 the radicals R]_ and R2, and either each of X and ¥ represents an oxygen atom and n represents 1, or X represents a methylene group,, Y represents an oxygen atom and a represents 1 or X represents an oxygen atom, Y represents a methylene group and n represents 1,, or X 4 30 represents a direct bond, Y represents an oxygen atom and n represents 2, radicals designated "lower" having from 1 * up to and including 4 carbon atoms, for example compounds of the formula I in which R^ represents carboxy, lower alkoxycarbonyl^ carbamoyl,, N~lover alkylcarbamoyl or N,N-di-lower alkylcarbaiaoyl, R2 represents hydrogen, hydroxy, lower alkoxy, benzyloxy, C2wC5alkanoyloxv, lower alkane-sulphonyloxy, benzoyloxy, pyridoyloxy, amino, C2"c5~ alkanoylamino, bensovlamino or pyridoylamino, R3 represents hydrogen or C1-C7alkyl, alk represents lower alkylene that bridges the two ring systems by up to and including 3 carbon atoms, or alk represents lower alkylidene, the ring A is unsubstituted or is mono-, di-or polv-substituted by hydroxy, lower alkoxy, C2-C5-alkanoyloxy, halogen having an atomic number of up to and including 53 , C^-Cyalkyl and/or by trifluoromethyl, the dotted line is intended to indicate the presence of a single or a double bond between the carbon atoms carrying the radicals R^ and R2, X represents an oxygen atom or a methylene group, ¥ represents an oxygen atom and n represents 1, radicals designated Mlower!S containing from 1 up to and including 4 carbon atoms, and to their tautomers and/or salts.

The invention relates more especially to compounds of the formula I in which either represents C1-CAalkoxy-carbonvl, such as methoxy- or ethoxy-carbonyl, carbamoyl, hydroxymethyl or C 2-C5aIkanov1oxymathy1, such as acetoxymethyl, and H2 represents hydrogen or hydroxy, or Rj represents hydrogen and R2 represents Ci~C4alkoxycarbonyl P such as ethoxycarbonyl, R3 represents hydrogen or Ci-C^alkyl, such as methyl, alk represents C3,-C4-alkylene that bridges the two ring systems by up to and including 3 carbon atoms, such as methylene or ethylene, the ring A is unsubstituted or is substituted, especially in the 7-position, by C^-^alkoxy, such as methoxy, the dotted line is intended to indicate the presence of a single or a double bond between the carbon atoms carrying S 1 the radicals Ri and R2 e cind either each of X and Y represents an oxygen atom and n represents 1, or X represents a Methylene groupY represents an oxygen atom and n represents 1, or X represents an oxygen atom,, Y 5 represents a methylene group and n represents 1, or X represents a direct bond, Y represents an oxygen atom and B. represents 2 , for example compounds of the formula I in which represents Ci-C4alkoxycarbonyl, such as methoxycarbonyl, R2 represents hydrogen or hydroxy, R3 10 represents hydrogen or alkyl , such as methyl , alk represents C^-C^alkylene that bridges the two ring systems by up to and including 3 carbon atoms, such as methylene or ethylene, the ring A is unsubstituted, the dotted line is intended to indicate the presence of a 15 single or a double bond between the carbon atoms carrying the radicals and R2, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, and their tautomers and/or salts.

The invention relates especially to compounds of the 20 formula I in which represents C^-C^alkoxycarhonyl, such as methoxy- or ethoxy-carbonyl, R2 represents hydrogen or hydroxy, R3 represents hydrogen, alk represents methylene or ethylene, the ring K is unsubstituted, the dotted line is intended to indicate the presence of a single or a double bond between the carbon atoms carrying the radicals Rx and R2, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, and their tautomers and/or salts.

The invention relates most especially to compounds of the 30 formula I in which R3 represents Ci-C^alkoxycarbonyl, such as methoxycarbonyl, R2 represents hydrogen, R3 represents hydrogen, alk represents methylene or ethylene, the ring A is unsubstituted, the dotted line is intended to indicate the presence of a single or a double bond between the carbon, atoms carrying the radicals and x represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents l, or in which Ri represents Cj-^alkoxy-carbonyl, such as methoxycarbonyl, R2 represents hydroxy, R3 represents hydrogen, alk represents methylene, the ring A is unsubstituted, the dotted line is intended to indicate the presence of a double bond between the carbon atoms carrying the radicals Ri_ and >1*2 «■ X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, and in each case their tautomers and/or salts.

The invention relates specifically to the novel compounds of the formula x mentioned in the Examples and their tautomers and/or salts and to processes for their manufacture.

The present invention relates also to a process for the manufacture of compounds of the formula I or their tautomers and/or their salts, for example characterised in that a) a compound of the formula /\ /*v IB ® ft, (Ila) alk-Xi or a salt thereof, in which Xi represents hydroxy or reactive esterified hydroxy, is reacted with a compound of the formula WJ-V 1 3 (lib) k or a tautomer and/or salt thereof , or b) in a compound of the formula /*\ z*1 (III) or a tautomer and/or salt thereof, in which X2 represents a radical that can be converted into Ri that is other than hydrogen, and X5 represents a radical Ra, and Ra represents hydrogen, hydroxy, lower alkoxy, fcenzyloxy, C2-C5alkanoyloxy, lower alkanesulphonvloxy, benzoyloxy, pyridoyloxy, amino, C2-C5alkanoylamino, lower alkane-su 1 phonylaiaino, benzoylamino or pyridoviamino„ X2 is converted into that is other than hydrogen, or in a compound of the fonaula III in which X2 represents hydrogen and X5 represents a radical that can be converted into R^j, and Rq represents a radical R2 other than a radical Ra, X5 is converted into E*0, or c) for the manufacture of a coiapound of the formula I or a tautomer and/or salt thereof, in which R2 represents hydroxy or amino and is other than hydrogen and represents especially lower alkoxycarbonyl, a compound of the formula A iB «• OB CH2R! in which represents a group of the formula ~CH= -C(¥2)=Rj>, -CH(Y2)-R2 or cyano, wherein R£ represents oxo 1 4 or iadno and ¥3 represents a removable radical^ or a salt thereof, is cyclised, or d) for the Manufacture of a compound of the formula or a tautomer and/or salt thereof, in which RJ represents oxo or imino and is other than hydrogen and represents especially lower alkoxycarbonyl ,, a compound of the formula /\ A > N.=*' / *2- (¥a) or a tautoiaer or a salt thereof, is reacted with a 10 compound of the formula X3-R1 (Vb) or a salt thereof, in which Ri|_ is other than hydrogen and X3 represents halogen or lower alkoxy, or e) for the manufacture of a coiapound of the formula I or 15 a tautoiaer and/or salt thereof, in which R2 represents hydroxy, lower alkoxy, bensvloxy, C2~C5alkanoyloxy, lower alkanesulphonyloxy, benzoyloxy, pyridoyloxy, amino, Co-^alkanoylamino # lower alkanesulphonylamino, benzoyl-amino or pyridoylamino, in a coiapound of the formula (VI) or in a salt thereof, in which X4 represents a radical that can be converted into converted into or f) especially for the manufacture of a compound of the formula I or a tautomer and/or salt thereof, in which R2 is hydrogen,, hydroxy, aminoe carboxy, lower alkoxycarbonyl , N-lower alkylcarbaiaoyl,, N,N-di-lower alkylcarbamoyl or hydroxviaethyl, in a compound of the formula represents hydrogen, lower alkoxy, benzyloxy, C2-C5-alkanoyloxy, lower aikanesulphonyloxv, benzoyloxy, pyridoyloxy, protected hydroxy, Cg-Csalkanoylamino, lower alkanesulphonylamino, benzoylaiaino, pyridoylamino, protected amino, carboxy,, lower alkoxycarbonyl, M-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, C2~C5~ alkanoyloxymethyl, lower alkanesulphonvloxymethylf benzcvloxymethyl, pyridoyloxymethyl or etherified or protected hydroxymethyl, the excess double bonds are reduced to single bonds, or g) for the manufacture of a compound of the formula I or a tautomer and/or salt thereof„ in which R2 represents carboxy, N~lover alkylcarbamoyl, N,N-di-lower alkylcarbamoyl ox" especially lower alkoxycarbonyl, a compound of the formula in which Y2 represents a removable radical, or a salt thereof, is cyclised, and in the case of each of /\ A /*» ® re /\ A /*' a • 1 6 processes a) to g)( a protecting group which may be present is removed , and.,, if desired.,, a compound of the forffiulei I obtainable in accordance with the process or by other means is converted into a different compound of the 5 formula I, an isomeric mixture obtainable in accordance with the process is separated into the components, an enantiomeric or diastereoisomeric mixture obtainable in accordance with the process is separated into the enantiomers or diastereoisomers, respectively, and/or a 10 free compound of the formula I obtainable in accordance with the process is converted into a salt or a salt obtainable in accordance with the process is converted into the free compound of the formula I or into a different salt, radicals designated ^ lower88 having from 1 15 up to and including 4 carbon atoms.

The reactions described in the variants hereinbefore and hereinafter are carried out in a manner known oar ss, for example in the absence, or customarily in the presence, of a suitable solvent or diluent or a mixture thereof, 20 the reactions being carried out, as necessary, while cooling, at room temperature or while heating, for example in a temperature range of from approximately -10° to the boiling temperature of the reaction medium, preferably at from approximately 20° to approximately 25 150°, and, if necessary, in a closed vessel, under pressure, in an inert gas atmosphere and/or under anhydrous conditions.

The starting materials of the formulae lis and lib, III, IV, Va and Vb, VI g vil and VIII, which are mentioned 30 hereinbefore and hereinafter and which were developed for the manufacture of the compounds of the formula I or their tautomers and/or salts, are in some cases known or they can be saanufactured likewise by methods known per se P for example analogously to the process variants described hereinbefore™ Starting materials having basic centres may, for example, be in the form of acid addition salts, for example with the acids listed hereinbefore, whilst starting compounds having acidic groups may form salts with bases, for example of the kind mentioned hereinbefore„ Starting compounds may also be in the form of tautomers, especially compounds of the formula lib wherein Rj represents hydroxy and the dotted line is intended to indicate the presence of a double bond between the carbon atoms carrying the radicals and Rj• Variant a)s Reactive esterified hydroxy is especially hydroxy esterified by a strong inorganic acid or organic sulphonic acid, for example halogen, such as chlorine, bromine or iodine, sulphonyloxy, such as hydroxy-sulphonyl oxy , halosulphonyloxy, for example fluoro-sulphonyloxy, lower alkanesulphonyloxy optionally substituted, for example, by halogen, for example methane- or trifluoromethane-sulphonyloxy, cycloalkane-sulphonyloxy, for example cvclohexanesulphonyloxy, or benzenesulphonyloxy optionally substituted, for example, by lower alkyl or by halogen e for example ;g-bromophenvl-or o-toluene-sulphonyloxy.

The N-alkylation is carried out especially in the presence of a condensation agent, such as a suitable base. Suitable bases are, for example, alkali metal hydroxides, hydrides, amides, alkoxides, carbonates, triphenylmethvlides, di-lower alkylamides, amino-lover t 8 alkylamides or lower alkylsilvlamides, or naphthalene-amines, lower alkylamines, basic heterocycles, ammonium hydroxides and carfooeyclic amines. There may be mentioned by way of examples sodium hydroxide, hydride, amide or etiioxide, potassium tert„-butoxide or carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium 3- (aminopropy 1)-amide or bis- (trimethylsilyl) -amide, or dimethvlaminonaphthalene, di- or tri-ethyl-amine, pyridine, benzyltrimethylamiaoniuja hydroxide, 1,5-diazabicyclo[4»3„0]non-5-ene (DBM) and 1,5-dieizabicyclo-[5„4„0]undec-5-ene (DBU).

The starting materials of the formula® Ila and lib are in some cases known or they can be manufactured analogously to the known starting materials™ Variant : A radical X2 that can be converted into Rj that is other than hydrogen, or a radical X5 that can be converted into a radical is, for example, functionally modified carboxy other than or Rj-,, respectively, such as cyano, anhydridised carboxy, optionally substituted amidino, optionally esterified or anhydridised carboximidoyl, esterified or amidated carboxy other than esterified or amidated carboxy tri-lower alkoxy- or trihalo-methyl.

Anhydridised carboxy is, for example, carboxy anhydridised with a mineral acid, such as a hydrohalic acid, or with a carboxylic acid, such as an optionally substituted lower alkanoic or benzoic acid or with a carbonic acid halide lower alkyl semi aster- As examples there may be mentioned: halocarbonyl, such as chlorocarbonyl, lower alkanoyloxycarbonyl, such as acetoxycarbonyl, or lower alkoxycarbonyloxvcarbonyl, such as ethoxycarbonyloxy- I 9 carhonyl.

Substituted amidino is, for example, amidino substituted by an aliphatic radical, for example lower alkyl, such as lower alkylamidino, for example ethylamidino.

^ Esterified or anhydridised carboximidoyl is to be understood as being, for example, alkoxy- or halo-carboximidoyl, for example lower alkoxy-, such as ethoxy-, or chloro-carhoximidoyl, respectively.

Tri-lower alkoxy- or trihalo-methyl is, for example, 10 trimethoxysnethyl or trichloromethyl, respectively™ Radicals R^ are, for example, carboxy, lower alkoxycarbonyl, carbamoyl, M-lower alkylcarbamoyl, M,M-di-lower alkylcarbamoyl or optionally acylated hydroxymethyl radicals R2• X2 can be converted into that is other than hydrogen, for example, by solvolysis, just as X5 can be converted into a radical R^, for example, by solvolysis.

Solvolysis agents are, for example, water, lower alkanols corresponding to the desired esterified carboxy Rt and 20 &2' smsaonia, or amines corresponding to the desired ami dared carboxy group and The treatment with a corresponding solvolysis agent is optionally carried out in the presence of an acid or base. Suitable acids are, for example, inorganic or organic protonic acids, such as 25 mineral acids, for example sulphuric acid or a hydrohalic acid, for example hydrochloric acid, sulphonic acids, for example lower alkanesulphonic or optionally substituted benzenesulphonic acids, for example methane- or k>™ toluene-sulphonic acid, or carboxylic acids, for example 2 0 lower alkanecarboxylic acids, for example acetic acid,, whilst as bases there ©ay be used, for example, those mentioned under Variant a), especially sodium or potassium hydroxide.

In the solvolysis with water (hydrolysis), the cya.no group, anhydridised carboxy, optionally substituted amidino, optionally esterified or anhydridised carboximidoyl, esterified or amidated carboxy other than esterified or amidated carboxy Ri or Rj, tri-lower alkoxvmethyl or trihalomethvl is hydrolysed to carboxy. Lower alkanoyloxy radicals which may be present at ring A may be hvdrolysed to hydroxy in the course of the hydrolysis.

Cyano, anhydridised carboxy, and esterified or amidated carboxy other than esterified or amidated carboxy or R2 are alcoholysed, for example with a suitable lower alkanol, to esterified carboxy R^ and K2, respectively, and cyano and anhydridised carboxy are asmonolysed or aminolysed, respectively, for example, with ammonia or with an amine corresponding to the amidated carboxy or R2, respectively.

The starting material of the formula III can be manufactured, for example, in a Banner analogous to that described under Variant a) by reacting a compound of the formula /\ A A « IB elk-X! (Ila) with a compound of the formula (Ilia) a tautoiaer and/or salt thereof, in the presence of one of the mentioned bases.

Compounds of the formula III in which X2 represents a radical that can be converted into Ri that is other than hydrogen and X5 represents hydroxy or amino, can advantageously be manufactured also by cyclisation of a coiapound of the formula in which Yj represents a group of the formula ~CH=R£, -C (Yp>) =R£ , -CH( Y2) -R2 or cvano, wherein R£ represents oxo or imino, R2 represents hydroxy or amino, and Y2 represents a removable radical, or a salt thereof, the operation being carried out, for example, in a manner analogous to that given in Process Variant c).

Variant c\: Removable radicals Y2 in groups of the formula ~C(Y2)=I*2 or —CH(Y2)~^2 £ref°r example, reactive esterified hydroxy groups, such as hydroxy esterified by a strong inorganic acid or organic sulphonic acid, for example halogen, such as chlorine, bromine or iodine, sulphonyl-oxy, such as hydroxysulphonyloxy, halosulphonyloxv, for example fluorosulphonvloxv„ lower alkanesulphonyloxy /n A /r B w optionally substituted, for example, by halogen, for example methane- or trifluoromethane-sulphonyloxy, cycloalkanesulphonyloxy, for example cyclohexane-sulphonyloxy, or ben2enesulphonyloxy optionally substituted, for example, by lower alkyl or by halogen, for example p-broaopheny1- or fi-toluene-sulphonyloxy, or etherified hydroxy groups, for example lower alkoxy or optionally substituted phenyl-lower alkoxy.

The cyclisation can be carried out, for example, analogously to the Dieckmann reactionP especially in the presence of one of the bases mentioned in Variant a) and with subsequent working-up by means of hydrolysis.

In a preferred embodiment, for example a compound of the formula in which represents oxo or imino, can be subjected to treatment with one of the mentioned bases, especially with an alkali metal lower alkoxide, for example with sodima methoxide or sodium ethoxide. During this treatment, the compound IV& cyclises to for® a compound of the formula I in which the dotted line indicates the presence of a single bond between the carbon atoms carrying the radicals lb and R2, and in which R2 represents hydroxy or amino. Starting materials of the formula iva are obtained, for example, by reacting a reactive alkyl- ester of the formula A /*■ 0) 01 »~CHg-Ra 2 3 (Ila) alk-Xj in which Xj_ is reactive esterified hydroxy, with a compound of the formula B21 -CH3-CH2-H(IVb) and reacting the resulting intermediate of the formula sv lk-^-C HsCHz~R% (1vc) with acrolein or with an optionally functionally modified aldehyde of the formula Y1-CH2-CH2~CH=R^ (ivd; Yx = reactive esterified hydroxy," R$ = oxo or imino).

In another preferred form of Variant c)p a compound of 10 the formula IV in which Y^ and represent lower alkoxycarbonyl, that is to say in which Yi represents a group of the formula -C(Y2, in which represents oxo and the removable radical ¥3 represents etherified hydroxy in the form of a lower alkoxy group, is cyclised 15 to form the corresponding compound of the formula I in which R£ represents oxo.

For the manufacture of the last-mentioned starting compounds of the formula iv, it is possible to use as starting materials, for example, compounds of the formula lAl .IX (IVe), ^alk-NHj or salts thereof, which ar© obtainable,, for example, by-reduction of the corresponding nitriles, and to react them with, at least 2 moles of a compound of the formula (IVf).

Variant d1): The O-acylation according to the process can be effected especially in the presence of one of the bases mentioned in Variant a), but especially advantageously by means of a metal base, such as lithiurn diisoprooylamine or n-butyllithium, optionally in the presence of chlorotri-metiiylsilane.

The reaction of a compound of the formula /n A A L (Vc), or ^ith a salt thereof, analogously to the N-alkylation according to Variant a) in the presence of on© of the mentioned bases, results in the starting material of the forms la Va« Variant els Radicals X4 that can be converted into R2 are* for example, radicals that car; be converted into a group R2 by solvolysis £, that is to say by reaction with a compound of the formula R2h or a salt thereof, for example reactive esterified hydroxy groups, such as halogen atoms, for example chlorine, bromine or iodine. Radicals x4 that can be converted into hydroxy R2 are also diasoniusi groups, for example of the formula ~M2®k© in which represents the anion of a strong acid, such as a mineral acidfor example the chloride or sulphate ion.

The solvolysis is effected in customary manner, for example in the presence of a base, such as an alkali metal or alkaline earth metal hydroxide, for example sodium or potassium hydroxide, or a tertiary nitrogen base, for example a tri-lower alkylamine, such as triethylamine, or a heteroaromatic nitrogen base, such as pyridine, or a quaternary ammonium hydroxide, such as benzyltrimethvlammonium hydroxide, or by using the compound R2H in the form of a metal salt, for example of the formula R2®M® (Vlb) in which m® represents an alkali metal cation, such as the sodium ion. The operation is advantageously carried out in the presence of a solvent or diluent, for example in an excess of the reactant R2H and/or in an inert solvent that is miscible with the latter, if necessary while cooling or heating, for example in a temperature range of approximately from 0° to 120°C, and/or under inert gas, such as nitrogen„ The solvolysis of radicals X4 to groups R2 can optionally be combined with the solvolytic conversion of solvolysable groups R^ into other groups R? according to the invention? for example in the amatonolysis of radicals X4 to amino R2 f if desired also lower alkoxycarbonyl groups Ri or other groups that can be solvolysed to carbamoyl Hi can toe asunonolysed to for®, carbamoyl groups Rjl at the same time.

For the manufacture of starting compounds of the formula VI and the salts thereof, for example compounds of the formula Ila (Ila) alk-Xi are used as starting materials and are reacted with a corresponding compound of the formula «< >~v.

(Via), ^Ri or with a salt thereof, in the presence of one of the bases mentioned above, the operation being carried out, for example, in a manner analogous to that described in Process Variant a).

In a preferred form, compounds of the formula VI in which X4 represents halogen and the dotted line indicates the presence of a single bond, and salts thereof, are obtained by reacting a compound of the formula I in which R2 represents hydroxy and the dotted line indicates the presence of a single bond, or a salt thereof, with a halogenating agent, such as phosphorus trichloride or pentachloride or thionyi chloride, it being possible to obtain the corresponding compounds of the formula I and their salts, for example, in a manner analogous to that 2 7 described under Process variant a) or c).

Variant: f)s The anion A® is, for example, the anion of a strong protonic acid, for example a halide ion, such as a 5 chloride, bromide or iodide ion, or a sulplionate ion, such as an optionally substituted lower alkane- or benzene-sulphonate ion, for example the methane-sulphonate, ethanesulphonate or a~»bromobenzenesulphonate or p-to 1 uenesulpb.onate ion„ is especially hydrogen, etherified hydroxy R2 or protected hydroxy, but may also be carboxy, lower alkoxycarbonyl, M-lower alkylcarbamoyl, H,M-di-lower alkylcarbamoyl R2 or etherified or protected hydroxysaethyl „ Protected hydroxy is, for example, silvloxy, such as tri-lower alkylsilyloxv, for example 15 trimethylsilyloxy, but may also be triphenyl-lower alkoxy, for example trityloxv* Protected amino is, for example, silvlamino, such as tri-lower alkylsilylamino, for example trimethylsilvlamino, but may also be phenyl-, diphenyl- or triphenyl-lower alkvlamino, such as benzvl-20 amino, diphenylamino or tritylamino. Etherified hydroxy-methyl is, for example, lower alkoxymethyl, such as methoxy- or ethoxy-methyl, or optionally substituted phenyl-lower alkoxymethyl, for example phenyl-Ci~C4~ alkoxymethyl substituted in the phenyl moiety, such as 25 benzyloxy-, o-chlorobenzyloxy-, 1-phenyXethoxy- or l-(o-bromophenyl)-n-butoxy-methyl. Protected hydroxymethvl is,, for example, silyloxymethyl, such as tri-lower alkylsilyloxy-, for example trimethylsilyloxy-methyl, but may also be triphenyl-lower alkoxy-, for example 30 trityloxv-methyl.

The reduction of the excess double bonds is effected by treatment with a suitable reducing agent, for example by 2 8 hydrogenation in the presence of a hydrogenation catalyst, by reduction with a hydride-transfer reagent or by reduction with a metallic reduction system consisting of metal and a proton-removing agent, Hydrogenation catalysts that co:aa into consideration are, for example; elements of sub-group VIII of the Periodic Table of Elements or derivatives thereof, such as palladium, platinum, platinum oxide, ruthenium„ rhodium, tris(triphenyIphosphane)rhodium(X) halide, for example 10 chloride, or Ranay nickel, which are optionally supported on a carrier, such as activated carbon, alkali metal carbonate or sulphate or a silica gel. Suitable as hydride-transfer reagents are, for example, suitable light metal hydrides, especially alkali metal aluminium 15 hydrides or borohydrides, such as lithium aluminium hydride, lithium triethylborohydride, sodium borohydride, sodium cyanoborohydride, or tin hydrides, such as triethyl- or tributyl-tin hydride, or diborane. The metal component of the metallic reduction system is, for 20 example, a base metal, such as an alkali metal or alkciline earth metal, for example lithium, sodium, potassium, magnesium or calcium, or a transition metal, for example sine, tin, iron or titanium, whilst as proton-removing agents there are suitable, for example, 25 protonic acids of the kind mentioned hereinbefore, such as hydrochloric or acetic acid, lower alkanols, such as ethanol, and/or amines or ammonia. Such systems are, for example, sodium/ammonia, sine/hydrochloric acid, sinc/-acetic acid or zinc/ethanol.

The manufacture of starting compounds of the formula VII is effected, for example, by reacting compounds of the formula f /\ A /*s W> » ® ! A ! ,£\ (Ila) alk-Xi in which X-i represents reactive esterified hydroxy corresponding to the anion frJP, with compounds of the formula Ai (Vila) f or with a salt thereof, the operation being carried out, for example, in a manner analogous to that described in Process variant a).

Variant ql: Removable radicals Y2 in coxa pounds VIII are, for example reactive esterified hydroxy groups, such as hydroxy esterified by a strong inorganic acid or organic sulphon ic acide for example halogen, such as chlorine, bromine or iodine, su1phony1oxy, such as hydroxysu1phonyloxyf halosulphonyloxyP for example fluorosulphonyloxy, lower alkanesulphonyloxy optionally substituted, for examplef by halogen, for example methane- or trifluoromethane-su 1 phony 1 oxy,, cycloalkanesulphonyloxy, for example cyclo hexanesxilphonyloxy, or benzenesulphonyloxy optionally substitutedt, for example,, by lower alkyl or by halogen, for example n-toroiaophenyl- or s-toluene-sulphonyloxy, or etherified hydroxy groups,, for example lower alkoxy or optionally substituted phenyl-lo«er alkoxy.

The cyclisation can be carried out f for example, in the 3 Q presence of one of the bases mentioned under Variant a) especially in the presence of an alkali netal lower alkoxide, for example with sodiusa aaethoxide or ethoxide The starting materials VII1 are obtained, for example, reacting a compound of the formula or a salt thereof, with a compound of the formula Y2~CH2~CH(Y2)~R1 (IVi)• In the starting materials of the formulae lib, III and Ilia, a hydroxy group &2 mEY be in etherified form and a hydroxy or amino group R2 may also be in intermediately protected form, just as a hydroxyraethy1 group Rj in compounds lib may be in etherified or intermediately protected form. Protected hydroxy is, for example, silyloxy, such as tri-lower alkylsilyloxy, for example trimethylsilyloxyt but nay also be txiphenyl-lower alkoxy, for example trityloxv- Protected asuim© is, for examplej. silylamiriOp such as tri-lower alkylsilylas&ino, for example trimethylsilylamino„ but aay also be phenyl-diphenyl- or triphenyl-lover alkylamino, such as benzyl-amino, diphenylmethylaaino or tritylamino. Etherified hydroxymethy1 is, for example , lower alkoxynethyl, such as methoxy- or ethoxy-methyl, or optionally substituted phenyl-lower alkoxymethyl, for example phenyl-cj-c^-alkoxymethyl substituted in the phenyl moiety, such as benzyloxy-, p-chlorobenzyloxy-, 1 -pbenylethoxy- or l-(s- /\ A / (IVh) bromophenyl) -n-butoxy~methyl. Protected bydroxymethyl is P for example, silyloxymethyl f such as tri-lower alkylsilylossy-, for example trimethylsilyloxy-methyl > but may also be triphenyl-lower alkoxy-, for example trityloxv-methyl.

The freeing of intermediately protected radicals Rj, that is to say the removal of the intermediate protecting groups, is effected in customary manner, for example by solvolysis, such as mild hydrolysis, for example treatment with water under neutral or slightly acidic conditions, for example by the action of dilute aqueous mineral or carboxylic acids, for example dilute hydrochloric or acetic acid- The freeing of intermediately protected hydroxy, amino or hydroxymethvl groups Rg in starting materials of the formula VI1 and Vila is effected in analogous manner.

Compounds of the formula I that are obtainable according to the process or by other means can be converted in customary manner into other compounds of the formula i.

For example, esterified or amidated carboxy groups Ri and R2 can be hydrolysed to carboxy and Rj, respectively, in customary manner , for example in the presence of a basic or acidic hydrolysis agent, such as an alkali metal hydroxide or carbonate, for example sodium hydroxide or potassium carbonate, or a mineral acid, for example hydrochloric acid or sulphuric acid. Esterified carboxy groups and R2 can also be converted into other esterified carboxy groups Rj and R?,. respectively, by transesterification, that is to say treatment with an alcohol in the presence of an acidic or basic solvolysis agent, such as a mineral acid, for example sulphuric 3 2 acid, or a corresponding alkali Hiatal alcoholate or an alkali matal hydroxide, or converted into amidated carboxy Ri and Ro, respectively, by reaction with ammonia or with a corresponding amine having at least one 5 hydrogen atom.

Free carboxy and R2 can be converted into esterified carboxy and H2, respectively, in customary mannert, for example by treatment with a corresponding alcohol in the presence of a mineral acid, for example sulphuric acid, 10 or by conversion into a halide and subsequent reaction with a corresponding alcohol, for example in the presence of pyridine or triethvlamine, or by conversion into an alkali metal salt and subsequent reaction with a reactive ester of the corresponding alcohol, such as a corres-15 ponding halide. Likewise, a carboxy compound can be esterified with a corresponding alcohol using a dehydrating agent, such as N,-dicyclohexyIcarbodiixaide. Free or esterified carboxy Hi and R2 can be converted into amidated carboxy and R2, respectively, also by 20 reaction with ammonia or an amine having at least one hydrogen atom and dehydration of the intermediately formed ammonium salt, for example by heating or by means of a dehydrating agent, such as N,M#-dicyclohexyl~ carbodiiaiide, or by conversion into the halide and 25 subsequent reaction with ammonia or with an amine having at least one hydrogen atom.

Furthermore, hydroxy groups which may be present can be esterified, for example converted by treatment with a lower alkanecarboacylic acid anhydride or halide into 30 lower alkanoyloxyor converted by reaction with a reactive ester, especially a hydrobromic or hydrochloric acid ester, of a lower alkanol into corresponding etherified hydroxy„ Conversely, in esterified or etherified hydroxy, such as lower alkanoyloxy or lower alkoxy, the hydroxy group(s) may be freed by solvolysis, preferably under acidic conditions- In em analogous manner, it is also possible to hydrolyse etherified or acylated hydroxy R2 to hydroxy™ In corresponding manner, furthermore hydroxyioethyl R^ and R2 can be esterified, for example converted by treatment with a lower alkanecarboxylic acid anhydride or halide into lower alkanoyloxymethvl Rj and R2, respectively-Conversely, the hydroxy group may be freed from acylated hydroxvmethyl Ri and R2, for example lower alkanovloxy-methvl, by solvolysis, preferably under acidic conditions.

Furthermore, hydroxvmethyl R^ and R2 can be converted in customary manner into lower alkoxycarbonyl, M-lower alkylcarbamoyl or N,N~di~lower alkylcarbamoyl and R2, respectively, or into carbamoyl Rlf the operation being carried out, for example, by first oxidising hydroxvmethyl and R2 to carboxy in customary manner, for example in the presence of an oxidising agent, such as potassium permanganate or potassium dichromate, and then : converting the carboxy group into lower alkoxycarbonyl Hi and R2f respectively, in customary manner, for example by treatment with a corresponding alcohol in the presence of a mineral acid, for example sulphuric acid, or by conversion into a halide and subsequent reaction with a corresponding alcohol, for example in the presence of pyridine or tri ethyl amine, or by conversion into an alkali metal salt and subsequent reaction with a reactive ester of the corresponding alcohol, such as a corresponding halide, or by using a dehydrating agentf such as 34 N j. 1*'' -dicyclohexy Icexbodiimids, with a corresponding alcohol; or converting the carboxy group into amidated carboxy % and R2, respectively, by reaction with ammonia or an amine having at least one hydrogen atosoa and 5 dehydration of the intermediately formed ammonium salt, for example by heating or by means of a dehydrating agent, such as M, M •" -dicyclohexylcarbodiimide f or by conversion into the halide and subsequent reaction with aiaiaonia or with an amine having at least one hydrogen 10 atom. It is also possible to convert acylated hydroxy-methyl Ri and R2 into esterified or amidated carboxy Ri and R2, respectively , by first freeing the acylated hydroxvmethyl group by solvolysis,, for example in the manner described above, and then converting the resulting 15 free hydroxymethyl group, in the manner described above, into a carboxy group and converting the latter further into an esterified or araidated carboxy group.

Conversely, esterified or amidated carboxy groups and R2 can be converted into optionally acylated hydroxy-20 methyl R^ and R2, respectively, by first hvdrolysing the esterified or amidated carboxy group R^ and R2 to carboxy in customary manner, for example in the presence of a basic or acidic hydrolysis agent, such as an alkali metal hydroxide or carbonate, for example sodium hydroxide or 25 potassium carbonate, or a mineral acid, for example hydrochloric acid or sulphuric acid, and then reducing the resulting carboxy group in customary manner, for example in the presence of a reducing agent, for example of the kind mentioned above, to hydroxymethyl Rt and R2„ 30 respectively, and, if desired, the latter can then be converted into acylated hydroxvmethyl Rj and R2, respectively, for example in the manner described above.

If the dotted line indicates the presence of a double bond between the carbon atoms carrying the radicals Hi and Ro in the compounds according to the invention,, this bond can be hydrogenated to a single bond,, for example in a manner known per se using a reducing agent, for example of the kind mentioned in variant f).

Furthermoree a compound according to the invention in which the dotted line indicates the presence of a double bond between the carbon atoms carrying the radicals R-j and R2 s' R2 represents hydrogen can be converted into a corresponding piperidine coiapound according to the invention, for example in a manner known oer se by the addition of a compound R2~H which R2 represents an optionally etherified or acylated hydroxy group or an optionally acylated amino group. The addition is carried out especially in the presence of a suitable base, for example of the kind mentioned under Variant a).

Conversely, compounds according to the invention in which the dotted line indicates the presence of a single bond between the carbon atoms carrying the radicals R^ and R2 can be converted in a manner known per se into corresponding tetrahydropyridine compounds according to the invention in which R2 represents hydrogen, for example by elimination of a compound R2-H in which R2 represents an optionally etherified or acylated hydroxy group or an optionally acylated amino group™ Leaving groups R2 that are less suitable for elimination, for example hydroxy, can first be converted£, for example in situ „ into more suitable leaving groups R2? for example lower alkane-sulphonyloxy, such as methanesulphonyloxy, or halogen, such as chlorine, bromine or iodine™ The elimination is effected especially in the presence of a suitable base, for example of the kind mentioned under Variant a)„ 3 8 Salts of compounds of the formula I and of their taut-.omers can be manufactured in a manner known p$r se.

Thus, for example, acid addition salts of compounds of the formula I are obtained by treatment with an acid or a 5 suitable ion exchange reagent. Salts can be converted into the free compounds of the formula I in customary manner; for example acid addition salts can be converted by treatment with a suitable basic agent- Depending upon the procedure and reaction conditions, the 10 compounds of the formula I according to the invention having salt-forming, especially basic, properties may be obtained in free form or in the form of salts.

As a result of the close relationship between the novel compound of the formula I in free form and in the form 15 of its salts, hereinbefore and hereinafter the free compound of the formula I or its salts should be understood as meaning optionally also the corresponding salts or the free compound of the formula I, respectively, where appropriate and expedient.

The novel compounds of the formula 11, including the salts of salt-forming compounds,, can also be obtained in the form of their hydrates or may include other solvents,, for example those used for the crystallisation of compounds in solid form.

Depending upon the starting materials and procedures chosen, the novel compounds of the formula I may be in the form of one of the possible isomers or in the form of a mixture thereof™ Depending upon the molecular symmetry, for example depending upon the number and the absolute and relative configuration of the chiral centres, such as asymmetric carbon atoms, there may be obtained as pure isomersfor example,, pure enantiomers and/or pure diastereoisomers , such as pure cis/trans-isomers or uneso-comioounds. Accordingly, as isomeric mixtures there may be obtained, for example,, enantiomeric mixtures, such as racemates, diastereoisomeric mixtures or mixtures of racemates.

Resulting diastareoisoiaeric mixtures and mixtures of racemates can be separated into the pure diastereoisomers or racemates in known manner on the basis of the physico-chemical differences between the constituents, for example by fractional crystallisation.

Resulting enantiomeric mixtures, such as racemates, can be separated into the enantiomers according to known methods, for example by recrvstallisation from an optically active solvent, by chromatography using chiral adsorbents, &?ith the aid of suitable microorganisms, by-cleaving with specific, immobilised enzymes, by means of the formation of inclusion compounds, for example using chiral Crown ethers, in which case only one enantiomer is complexed, or by conversion into diastereoisomeric salts, for example by reaction of a basic end product racemate with an optically active acid, such as a carboxylic acid, for example tartaric or malic acid, or a sulphonic acid, for example camphorsulphonic acid, and separation of the mixture of diastereoisomers obtained in this manner, for example on the basis of their different solubilities, into the diastereoisomers, from which the desired enantiomer can be freed by the action of suitable agents. Advantageously, the more active enantiomer is isolated- 3 8 The invention also relates to those forsas of the process according to which a compound obtainable as intermediate at any stag© of the process is used as starting material and the remaining steps are carried out, or a starting material is used in the for® of a derivative or salt and/or its racemates or enantiomers or, especially,, is formed under the reaction conditions- In the process of the present invention it is preferable to use those starting materials which result in the compounds of the formula I described at the beginning as being especially valuable. The invention relates also to novel starting materials which were developed specifically for the manufacture of the compounds of the formula I according to the invention, to their use and to processes for their manufacture, the variables , R2, R3, X, Y, n and alk and the substituents of the ring A and the dotted line having the meanings indicated for the groups of compounds of the formula I that are preferred in each case„ In this connection, special mention should be made of compounds of the formula alk-S-CHaCHz-Sl! H (IVc) and their salts. These likewise have nootropic properties in a degree of action comparable with that of the 39 corresponding compounds of the formulae 1 and I'" and can likewise be used as nootropic active ingredients in medicaments, Accordingly, the invention relates also to pharma-5 ceutical„ especially nootropic, preparations comprising as active ingredient a compound of the formula IVc in which R^ represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,, N,N-di~lower alkylcarbamoyl, hydroxymethyl, C 2 ~ C 5 a1fcanoy1 oxymethy 1, lower 10 alkanesulphonyloxyraethyl , ben soy 1 oxymethv 1 or pyridoyloxymethyl f R3 represents hydrogen or Ci~C7alkylf, alk represents lower alkylene or lower alkvlidene, the ring A is unsubstituted or is mono- or poly-substituted by hydroxy, lower alkoxy, C2-C5alkanoyloxy, halogen having 15 an atomic number of up to and including 53, C^-C^alkyl and/or by trifluoromethyl, and either each of X and Y represents an oxygen atom and n represents 1, or X represents a methylene group, ¥ represents an oxygen atom and n represents 1, or X represents an oxygen atom,, Y 20 represents a methylene group and n represents 1, or X represents a direct bond f Y represents an oxygen atom and n represents 2, or a pharmaceutically acceptable salt thereof, to the use of the mentioned compounds of the formula IVc or their pharmaceutically acceptable salts 25 for the manufacture of nootropic pharmaceutical preparations, to a method for the treatment of the symptoms of cerebral insufficiency, characterised in that one of the mentioned compounds of the formula IVc, or a pharmaceutically acceptable salt thereof,, is administered, and 30 to compounds of the formula IVc in which R^ represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,, MfM-»di-lo%?ar alkylcarbamoyl^ hydroxy-methyl, C2~C5alkanoyloxymethyl, lower alkanesulphonyloxv- 4.0 methyl,, bensoyloxvmethyl or pyridoyloxymethyl, R3 represents hydrogen or C^-C-^alkyl, alk represents lower alkylene or lower alkylidene,, the ring A is unsubstituted or is mono- or poly-substituted by hydroxy, lower alkoxy, 5 Cj^Cgalkanoyloxy, halogen having an atomic number of up to and including 53, C^-^alkyl and/or by trifluoromethyl, and either each of X and ¥ represents an. oxygen ©torn and n represents 1, or X represents a methylene group, ¥ represents an oxygen atom and n represents 1, or 10 X represents an oxygen atom, ¥ represents a methylene group and n represents 1, or X represents a direct bond, Y represents an oxygen atom and n represents 2, with the proviso that in compounds of the formula IVc in which the ring A is unsubstituted, each of X and Y represents 15 oxygen, n represents 1 and R3 represents hydrogen, alk is other than methylene if Ri represents carbamoyl or M-methyl-, N-ethyl~, N,N-dimethy1- or M^-diethyl-carbamoyl, and to their salts, and to a process for the manufacture of the latter , novel compounds of the formula 20 IVc and their salts, radicals designated "lower"" having from 1 up to and including 4 carbon atoms.

Accordingly, the invention relates, for example, also to pharmaceutical,, especially nootropic, preparations comprising as active ingredient a compound of the formula 25 IVc in which represents carboxy, lower alkoxycarbonyl, carbamoyl, M-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R3 represents hydrogen or C^-C^alkyl„ alk represents lower alkylena or lower alkylidene, the ring A is unsubstituted or is mono- or poly-substituted by 30 hydroxy, lower alkoxy,, C2-C5alkanoyloxy, halogen having an atomic number of up to and including 53, Ci~C7alkyl and/or by trif luoromethyl, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n 4 1 represents 1, or a pharmaceutically acceptable salt thereof, to the use of the mentioned compounds of the formula IVc or their pharmaceutically acceptable salts for the iaarmfacture of nootropic pharmaceutical prepare-5 tions, to a method for the treatment of the symptoms of cerebral insufficiency, characterised in that one of the mentioned compounds of the formula IVc, or a pharmaceutical ly acceptable salt thereof, is administered, and to compounds of the formula IVc in which represents 10 carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl or M,M-di-lower alkylcarbamoyl, R3 represents hydrogen or C^-Cyalkvl, alk represents lower alkylene or lower alkylidene, the ring A is unsubstituted or is mono- or poly-substituted by hydroxy, lower alkoxy, 15 C2~C5alkanoyloxy, halogen having an atomic number of up to and including 53, C^-Cyalkyl and/or by trifluoromethyl, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, with the proviso that in compounds of the formula IVc in which the 20 ring A is unsubstituted, each of X and Y represents oxygen, n represents 1 and R3 represents hydrogen, alk is other than methylene if represents carbamoyl or N~ methyl-, N-ethyl-, N,N-dimethyl- or N,N-diethyl-carbamoyland to their salts, and to a process for the 25 manufacture of the latter, novel compounds of the formula IVc and their salts, radicals designated 88lower™ having from 1 up to and including 4 carbon atoms.

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

The invention relates in this respect especially to pharmaceutical, especially nootropic, preparations and to the manufacture thereof and to methods of treatment, characterised in that there is selected a compound of the formula IVc in which % represents carboxy, lower alkoxycarbonyl, carbamoyl,, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbaiaoyl, hydroxymethyl» C2-C5alkanoyloxy-methyl, lower alkanesulphonyloxymethyl, ben2oy 1 oxvmethy 1 or pyridoyloxymethyl, R3 represents hydrogen or €^-€7-alkyl, alk represents lower alkylene that links the ring system with the MH group shown in formula IVc by up to and including 3 carbon atoms, or alk represents lower alkylidene, the ring A is unsubstituted or is mono-, di-or polv~substituted by hydroxy, lower alkoxy, C2-C5-alkanoyloxy, halogen having an atomic number of up to and including 53, c1-c7alkyl and/or by trif luoromethyl , and either each of X and Y represents an oxygen atom and n represents 1, or X represents a methylene group, Y represents an oxygen atom and n represents l, or X represents an oxygen atom , Y represents a methylene group and n represents 1, or X represents a direct bond, Y represents an oxygen atom and n represents 2, or one of the pharmaceutically acceptable salts thereof, and to compounds of the formula IVc in which represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, M,M-di~lower alkylcarbamoyl, hydroxy-methyl, C^-Cgalkanoyloxymethyl, lower alkanesulphonyl-oxvmethyl, benzoyloxymethyl or pyridoyloxymethyl, R3 represents hydrogen or Ci~C7alkyl, alk represents lower alkylene that links the ring system with the MH group shown in formula IVc by up to and including 3 carbon atoms, or alk represents lower alkylidene, the ring A is unsubstituted or is mono-, di- or poly-substituted by hydroxy, lower alkoxy, C2~c5alkanoyloxy, halogen having an atomic number of up to and including 53, c1-»c7alkyl and/or by trif luoromethyl, and either each of X and Y represents an oxygen atom and n represents 1, or X represents a Methylene group,, Y represents an oxygen atom and u represents 1, or 3E represents an oxygen atom, ¥ represents a methylene group and a represents 1, or X represents a direct bond, Y represents an oxygen atom and n represents 2, with the proviso that in compounds of the formula IVc in which the ring A is unsubstituted, each of X and Y represents oxygen , n represents 1 and R3 represents hydrogen, alk is other than methylene if E-L represents carbamoyl or M-methyl- , N-ethyl-, N,N-di-methyl- or M,M-diethyl-carbamoyl , and to their salts, and to a process for the manufacture of the latter, novel compounds of the formula IVc and their salts, radicals designated -lower88 having from 1 up to and including 4 carbon atoms, for example to pharmaceutical, especially nootropic, preparations and to the manufacture thereof and to methods of treatment, characterised in that there is selected a compound of the formula IVc in which R^ represents carboxy, lower alkoxycarbonyl, carbamoyl, M~ lower alkylcarbamoyl or N,N-di~lower alkylcarbamoyl, R3 represents hydrogen or C^-Cyalkyl, alk represents lower alkylene that links the ring system with the MH group shown in formula IVc by up to and including 3 carbon atoms, or alk represents lower alkylidene, the ring A is unsubstituted or is mono-, di- or poly-substituted by hydroxy, lower alkoxy, C2~C5alkanoyloxy, halogen having an atomic number of up to and including 53, C^-C7alkyl and/or by trifluoromethyl, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, or one of the pharmaceutically acceptable salts thereof, and to compounds of the formula IVc in which represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or M,M-di~lower alkylcarbamoyl, R3 represents hydrogen or C-^-Cyalkyl, alk represents lower alkylene that links the ring system 4 4 with the NH group shosm in formula IVc by up to and including 3 carbon atoms e or alk represents lower alkylidene, the rixsg A is unsubstituted or is n?ono~di-or poly-substituted by hydroxy , lower alkoxy, 5 C2-C5alkanoyloxy, halogen having an atomic number of up to and including 53, C1~C7alkyl and/or by trifluoromethyl,, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, with the proviso that in compounds of the formula IVc in which the 10 ring A is unsubstituted„ each of X and ¥ represents oxygen f n represents 1 and R3 represents hydrogen, alk is other than methylene if Ri represents carbamoyl or N-methyl-, N-ethyl~, N,N~dimethyl- or N,N-diethyl-carbamoyl, and to their salts, and to a process for the 15 manufacture of the latter, novel compounds of the formula I've and their salts, radicals designated "lower" having from 1 up to and including 4 carbon atoms.

In this respect the invention relates more especially to pharmaceutical, especially nootropic, preparations and to 20 the manufacture thereof and to methods of treatment, characterised in that there is selected a compound of the formula IVc in which represents carboxy* hydroxy-methyl, C2™C5alkanoyloq/iaathyl, such as acetoxymethyl ,, Ci-C4aIkoxycarbonv1, such as methoxycarbony1, or 25 carbamoyl R3 represents hydrogen or C^-^alkyl, such as methyl, alk represents C^-^alkylene that links the ring system with the MH group shown in formula IVc by up to and including 3 carbon atoms, such as methylene or ethylenethe ring h is unsubstituted or is substituted,, 30 especially in the 7-position, by C^C^alkoxy such as methoxy, and either each of X and V represents an oxygen atom and n represents 1, or X represents a methylene group, Y represents an oxygen atom and n represents lf or X represents an oxygen atom t, Y represents a methylene group and n represents 1, or X represents a direct bond, Y represents an oxygen atom and n represents 2, or one of the pharmaceutical ly acceptable salts thereof,, and to 5 compounds of the formula IVc in which Ri represents carboxy, hydroxymethyl, C2*-C5alkanoyloxymethyl, such as acetoxymethyl, Ci -^alkoxycarbonyl, such as methoxy-carbonylf or carbamoylt R3 represents hydrogen or C1-C4-alkyl,, such as methyl f alk represents C i -C4 a Iky 1 ene that 10 links the ring system with the NH group shown in formula IVc by up to and including 3 carbon atoms, such as methylene or ethylene, the ring A is unsubstituted or is substituted, especially in the 7-position, by €^-€4-alkoxy, such as methoxy, and either each of X and Y 15 represents an oxygen atom and n represents 1, or X represents a methylene group, Y represents an oxygen atom and n represents 1, or X represents an oxygen atom, Y represents a methylene group and n represents 1, or X represents a direct bond, Y represents an oxygen atom and 20 n represents 2, with the proviso that in compounds of the formula IVc in which the ring A is unsubstituted, each of X and Y represents oxygen, n represents 1 and R3 represents hydrogen, alk is other than methylene if R^ represents carbamoyl, and to their salts, and to a 25 process for the manufacture of the lattert> novel compounds of the formula IVc arid their salts, for example to pharmaceutical, especially nootropic, preparations and to the manufacture thereof, and to methods of treatment, characterised in that there is selected a 30 compound of the formula IVc in which represents C^-C^-alkoxycarbonyl, such as methoxycarbonyl, R3 represents hydrogen or C1~C4alkyl, such as methyl, alk represents Ci-C4alkylene that links the ring system with the group shown in formula IVc by up to and including 3 4 0 carbon atoms, such as methylene or ethylene,, the ring a is unsubstituted, X represents an oxygen atom or a methylene group,, Y represents an oxygen atom and a represents 1;, or one of the pharmaceutical ly acceptable 5 salts thereof, and to compounds of the formula IVc in which represents Ci«C4alkoxycarbonyl, such as methoxycarbonyl, R3 represents hydrogen or alkyl„ such as methyl, alk represents C1-C4a.lky3.ene that links the ring system with the MB group shown in formula IVc by 10 up to and including 3 carbon atoms, such as methylene or ethylene, the ring A is unsubstituted, X represents an oxygen atom or a methylene group f Y represents an oxygen atom and n represents 1, and to their salts, and to a process for the manufacture of the latter, novel 15 compounds of the formula IVc and their salts„ In this respect the invention relates most especially to pharmaceutical, especially nootropic, preparations and to the manufacture thereof, and to methods of treatment, characterised in that there is selected a compound of the 20 formula IVc in which represents C-^-C^alkoxycarbonyl, such as methoxycarbonyl, R3 represents hydrogen, alk represents methylene or ethylene, the ring A is unsubstituted, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, or 25 one of the pharmaceutically acceptable salts thereof, and to compounds of the formula IVc in which represents C^C^alkoxycarbonylt, such as methoxycarbonyl, R3 represents hydrogen, alk represents methylene or ethylene, the ring A is unsubstituted,, X represents an 30 oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1 f, and to their salts,, and to a process for the manufacture of the latter, novel compounds of the formula IVc and their salts. 4 7 In this respect the invention relates specifically to pharmaceutical, especially nootropic, preparations arid to the manufacture thereof and to methods of treatment, characterised in that there is selected one of the novel 5 compounds of the formula IVc mentioned in the Examples, or one of the pharmaceutically acceptable salts thereof, and to the novel compounds of the formula IVc mentioned in the Examples and to their salts, and to processes for the manufacture of the latter, novel compounds of the 10 formula IVc and their salts.

The present invention relates also to a process for the manufacture of compounds of the formula IVc and their salts, for example characterised in that h) compounds of the formulae /\ A a>' a * I A I l\ and 22~CH2~CH(23)~Ri 1 aik=Zi (villa) (Vlllb), in which one of the radicals and Sj represents reactive esterified hydroxy and the other represents amino and Z3 represents hydrogen, or 2h represents amino and I2 anc^ 23 together represent an additional bond, or 20 optionally salts of these compounds, are reacted with one another, or i) in a compound of the formula /\ A /*» «• * « 4 R in which Xg represents a radical that can be converted into Rlf or in a salt thereof, X5 is converted into Rlif, and, if desired, in the case of each of processes Li) and i), a compound of the formula IVc obtainable in 5 accordance with the process or by other means is converted into a different compound of the formula IVc, an isomeric mixture obtainable in accordance with the process is separated into the components, an enantiomeric or diastereoisomeric mixture obtainable in accordance 10 with the process is separated into the enantiomers or diastereoisomers, respectively, and/or a free compound of the formula IVc obtainable in accordance with the process is converted into a salt or a salt obtainable in accordance with the process is converted into the free 15 compound of the formula IVc or into a different salt.

Variant h*>: Reactive esterified hydroxy Zi and Z2 is especially hydroxy esterified by a strong inorganic acid or organic sulphonic acid, for example halogen, such as chlorine, 20 bromine or iodine, sulphonyloxy, such as hydroxy- sulphonyloxy, halosulphonyloxy, for example fluoro-sulphonyloxy, lower alkanesulphonyloxv optionally substituted, for example, by halogen, for example methane- or trifluoromethane-sulphonyloxy, cycloalkane-25 sulphonyloxy, for example cyclohexanesulphonyloxy, or benzenesulphonyloxy optionally substituted, for example, by lower alkyl or by halogen, for example jj-broruophenyl-or o-toluene-sulplionyloxy - The reaction is in this case carried out especially in 30 the presence of a condensation agent, such as a suitable base. Suitable bases are, for example, alkali metal hydroxides,, hydrides, amides, alkoxides, carbonates, triphenylmethylides, di-lower alkylamides, amino-lower alkylamides or lower alkylsilylamides, or naphthalene-amines , lower alkylamines, basic heterocycles, asHaonium hydroxides and carbocyclic amines. There may be mentioned by way of example: sodium hydroxide,, hydride, amide or ethoxide, potassium tert.-butoxide or carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium 3= (aaiinopropyl) -amide or bis-(trimethylsilyl)-aiaide, or dimethylaminonaphthalene, di- or tri-ethyl-amine, pyridine, hen sy 1 tr iiaethy 1 ammon ium hydroxide, 1,5-diazabicyclo[4„3.0]non-5-ene {DBM) and 1,5-dia2abicyclo-[5.4.0]undec-5-ene (DBU). The reaction of amines Villa (Zi = amino) with acrylic acid compounds VIIlb (Z2 + Z3 = bond) is effected, for example, while heating, for example at approximately 50-120°C.

The starting materials of the formulae villa and VIIlb are known or they can be manufactured analogously to known methods.

Variant i)s h radical Xg that can be converted into R^ is,, for example, functionally modified carboxy other than Ri , such as cvano, anhydridised carboxy, optionally substituted amidino, optionally esterified or anhydridised carboximidoyl, esterified or amidated carboxy other than esterified or amidated carboxy , tri-lower alkoxymethyl or trihalomethyl.

Anhydridised carboxy is, for example, carboxy anhydridised with a mineral acid, such as a hydrohalic acid, or with a carboxylic acid, such as an optionally substituted lower alkanoic or benzoic acid, or with a carbonic acid halide lower alkyl semiester. As examples there may be mentioned" halocarbonyl, such as chlorocarhonyl, lower alkanoyloxycarbonyl t, such as acetoxycarbonyl or lower alkoxycarbonyloxycarbonyl, such as efchoxycarbonyloxy ~ carbonyl.

Esterified or anhydridised carboximidoyl is to be understood as being, for example, alkoxy- or halo-carboximidoyl, for example lower alkoxy-, such as ethoxy-, or chloro-carboximidoyl, respectively.

Tri-lower alkoxy- or trihalo-methyl is,, for example, trimethoxymethyl or trichloromethyl, respectively.

Xg can be converted into R^, for excimple, by solvolysis. Solvolysis agents are, for example, water, lower alkanols corresponding to the desired esterified carboxy Hi , ammonia, or amines corresponding to the desired amidated carboxy group Ri. The treatment with a corresponding solvolysis agent is optionally carried out in the presence of an acid or baseSuitable acids are, for example, inorganic or organic protonic acids, such as mineral acids, for example sulphuric acid or a hydrohalic acid, for example hydrochloric acid, sulphonic acids, for example lower alkanesulphonic or optionally substituted benzenesulphonic acid,, for example methane- or ^-toluene-sulphonic acid, or carboxylic acids, for example lower alkanecarboxylic acids, for example acetic acid, whilst as bases there may be used, for example, those mentioned under Variant h), especially sodium or potassium hydroxide.

In the solvolysis with water (hydrolysis), the cyano group, anhydridised carboxy, optionally substituted amidino, optionally esterified or anhydridised carboximidoyl, esterified or amidated carboxy other than esterified or amidated carboxy R^e tri-lower alkoxymethyl or trihalomethyl is hydrolysed to carboxy. Lower alkanoyloxy radicals which, may be present at the ring A xaay be hydrolysed to hydroxy in the course of the hydrolysis.

Cyano, anhydridised carboxy, and esterified or amidated carboxy other than esterified or amidated carboxy Rt_ are alcoholysed, for example with a suitable lower alkanol, to esterified carboxy Ri, and cyano and anhydridised carboxy are anunonolysed or aminolvsed, for example with ammonia or with an amine corresponding to the amidated carboxy , respectively.

The starting material of the formula IX can be obtained, for example, by reaction of compounds of the formulae in which represents reactive esterified hydroxy and 23 represents hydrogen, or an<^ ^3 together represent an additional bond, or optionally salts of these compounds, the operation being carried out in a manner analogous to that described under Process Variant c)„ for example in the presence of a basic agent* y\ A A ® ® Sl 'alk-NHa (IXa) Zz-C&z—CH( Zj)—X& (IXb) s Subsequent operations which may, if desired, b© carried out on compounds of the formula IVc obtainable in accordance with the process are especially conversions of Hi and of substituents of the ring A, separations of 5 enantioraers and diastereoisomers and conversions into one another of salts and free compounds, analogous to those indicated for the compounds of the formula I and are carried out in analogous manner- The invention relates also to the use of compounds of the 10 formula I or IVc and, where appropriate, their tautomers and/or pharmaceutically acceptable salts of such compounds having salt-forming propertiest especially as pharmacological, especially nootropically active, active ingredients» They can be used, preferably in the form of 15 pharmaceutical^ acceptable preparations, in a method for the prophylactic and/or therapeutic treatment of the animal or human body, especially as nootropics, for example for the treatment of the symptoms of cerebral insufficiency, especially memory disorders.

The invention relates also to pharmaceutical preparations that comprise as active ingredient a compound of the formula I or IVc or, where appropriate, a tautomer and/or pharmaceutical ly acceptable salt thereof,, and to processes for their manufacture„ The pharmaceutical preparations according to the invention, which comprise a compound of the formula I or IVc or, where appropriate, a tautomer and/or pharmaceutical ly acceptable salt thereof, are for enteral, such as oral and also rectal, and parenteral administration to a warm-30 blooded animal, the preparations comprising the pharmacological active ingredient alone or together with customary pharmaceutical adjuncts™ The novel pharmaceutical preparations comprise, for example, from approximately 10% to approximately 80%, preferably from approximately 20% to approximately 60%, active ingredient. Pharmaceutical preparations according to the invention for enteral and parenteral administration are, for example, those in dosage unit forms, such as drag^es, tablets, capsules or suppositories,, and also ampoules. They are manufactured in a manner known per se. for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, to form tablets or dragee cores.

Suitable carriers are, especially, fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphate, for example tricalcium phosphate or calcium hydrogen phosphate, also binders, such as starch pastes using, for example, corn, s^heat, rice or potato starch, gelatine, tragacanth, methylcellulose and/or polyvinylpyrrolidone, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate- Adjuncts are especially flow-regulating agents and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings 4 that may foe resistant to gastric juices, there being used? inter alia, concentrated sugar solutions that may contain gum arahic, talc, polyvinylpyrrolidone^ polyethylene glycol and/or titanium dioxide,, or lacquer 5 solutions in suitable organic solvents or solvent mixtures, or, for the manufacture of coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulos® phthalate or hvdroxypropvImethyIce1lulose phthalate. Colourings or 1 o pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient- Further orally administrable pharmaceutical preparations are dry-filled capsules consisting of gelatine, and also soft,, sealed capsules consisting of gelatine and a plasticiser, such as glycerine or sorbitol- The dry-filled capsules may contain the active ingredient in the form of a granulate,, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers may also be added- There come into consideration as rectally administrable pharmaceutical preparations,, for example, suppositories that consist of a combination of the active ingredient and a suppository base. Suitable as suppository bases, 30 are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatine rectal (1*3 bjJb capsules that comprise a combination of the active ingredient and a base material. Suitable base materials are? for example, liquid triglycerides,, polyethylene glycols or paraffin hydrocarbons„ Suitable for parenteral administration are especially aqueous solutions of an active ingredient in water-soluble form, for example a water-soluble salt, also suspensions of the active ingredient, such as corresponding oily injection suspensions, there being used suitable 10 liphophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, 15 sorbitol and/or dextran, and, optionally, also stabilisers .

The dosage of the active ingredent can depend upon various factors, such as the method of administration, the species of warm-blooded animal, age and/or individual 20 condition. In normal cases, the estimated approximate daily dose for a warm-blooded animal weighing approximately 75 kg is, in the case of oral administration, from approximately 20 mg to approximately 500 mgt, especially from approximately 25 mg to approximately 250 mg, 25 advantageously in several equal partial doses.

The following Examples illustrate the invention described above but are not intended to iiaait the scope thereof in any way. Temperatures are given in degrees Celsius„ As a result of the close relationship between a compound 30 of the formula I and the corresponding tautomeric .5 & compound of the formula l'„ in the Examples a compound of the formula I should be understood as meaning optionally also the tautomeric compound of the formula 1-" where appropriate and expedient. The same applies to a 5 compound of the formula I' and to salts of compounds of the formulae I and I'.

Example 1: First 5.55 g (25 ramol) of 1,2,5,6-tetra-hydropyr idine-3-carboxylie acid methyl ester hydrobromide (guvacoline hydrobromide) and then 11,31 g (87.5 mmol) of 10 N-ethyl-N,N-diisopropylamine are added to a solution of 7.96 g (25 mmol) of 3-(D~toluenesulphonyloxyaiethyl)~ chromai) in 100 ml of dime thy Iformamide. The mixture is stirred for 15 hours at 50° and then concentrated by evaporation under a high vacuum. Water is added to the 15 residue and extraction is carried out with diethyl ether. The organic phases are washed with water and extracted with 2M hydrochloric acid. The hydrochloric acid extracts are combined, rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and 20 extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 5.92 g (83%) of l-(c.hroraan-3~ ylmethyl)-1,2,5,6-tetrahydropyridine-3~carfaoxylic acid methyl ester are obtained in the form of a pale yellow 25 oil. The l-(chroman-3-ylinethyl)--l,2,5,6-tetrahydro-pyridine-3-carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether melts at 158-159° after crystallisation from methanol/diethyl ether. 3-(jD-toluenesulphonyloxymethyl)chroman can be manufactured, for example, as follows: At room temperature and while stirring, a solution of 50.0 g (260 mmol) of 3~methoxycarbonylchroman (US 4 , 178f,380) in 200 ml of absolute tetrahydrofuran is added drop«dse within a period of 40 minutes to a suspension of 9.86 g (260 mmol) of lithium aluminium hydride in 300 ml of absolute diethyl ether» After stirring for 16 hours at room temperature, the reaction mixture is decomposed with 9.9 ml of water, 9.9 ml of sodium hydroxide solution (15% strength) and 30 ml of water. The precipitate formed is filtered off with suction and the filtrate is concentrated to dryness by evaporation in vacuo„ The oily residue is dissolved in diethyl ether and the solution is washed with water, dried over sodium sulphate and concentrated to dryness by evaporation. 36.71 g (86%) of oily 3~hvdroxyinethyl-chroman, which crystallises from diethyl ether/pentane and melts at 60-61*, are obtained. 46»14 g (242 mmol) of D-toluenesuiphonyl chloride are added while stirring at room temperature to a solution of 36.12 g (220 mmol) of 3-hydroxymethylchroman in 100 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. The reaction mixture is stirred for a further 3 hours at room temperature and then poured onto ice-water- The crystals formed are filtered off with suction, washed with water and dried in vacuo. 65*84 g (94%) of 3- (jo-toluenesulphonyloxymethyl )chroman having a melting point of 86-87* are obtained.

Example 2^ At room temperature and while stirring, 0.75 g (15.6 mmol) of sodium hydride dispersion in mineral oil (50%) is added within a period of 30 minutes to a solution of 4.36 g (13 raaol) of II,M-bis(2-methoxy- carhonylethyl) ~M~ (chroinan~3-yl:raathyl) -amine in 50 nil of absolute dimethylfonaamide „ The reaction mixture is stirred for a further 1 hour at room temperature and then concentrated by evaporation under a high vacuum. Diethyl ether is added to the resulting residue and extraction is carried out with cold 2H hydrochloric acid. The combined hydrochloric acid extracts are extracted by shaking with dichloromethane and the combined dichloromethane extracts are dried over sodium sulphate and concentrated by evaporation. There are obtained 3.8 g (85.8%) of crystalline 4 ~hydr oxy ~1~(chroman-3-ylmethyl)-1,2 s5,6~ tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride or 1-(chroman-3-ylxttethyl)-4-oxo-piperidine~ 3-carboxylic acid methyl ester hydrochloride which, after recrystal1isation from methanol/diethyl ether, has a decomposition point of 167-158 °„ N,N-bis(2-methoxycarbonvlethyl)-N-(chroman-3-ylmethyl)-amine can be manufactured, for example, in the following manner: First 1-77 g (13.32 mmol) of aluminium chloride in 50 ml of absolute diethyl ether are added dropwise while stirring at room temperature to a suspension of 3.04 g (80 mmol) of lithium aluminium hydride in 100 ml of absolute diethyl ether. Then 6.29 g (40 mmol) of 3-cyanochromene [R.C. Gupta ajc ai„, Ind. J. Chem. 213, 344 (1S82)] in 50 ml of absolute tetrahydrofuran are added dropwise within a period of 20 minutes- The reaction mixture is boiled under reflux for 16 hours. After it has cooled, the reaction mixture is carefully decomposed with 3.1 ml of water, 3.1 ml of sodium hydroxide solution (15% strength) and 9.3 ml of water. The precipitate formed is filtered off with suction, the filtrate is ,5.8 concentrated by evaporation in vacuo and the oily residue is dissolved in diethyl ether. The organic phase is Mashed with water and extracted with 2N hydrochloric acid- The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted by shaking with dichloromethane. After drying the combined organic phases over sodium sulphate and concentrating in vacuo. 3.5 g (53.6%) of 3-aminomethylchroman are obtained in the form of a yellow oil. The 3-aininontethylchrosian hydrochloride produced therefrom using hydrochloric acid in diethyl ether is recrvstallised from methanol/diethyl ether and melts at 218-219*. 3.03 g (35.2 mmol) of acrylic acid methyl ester are added to a solution of 2.61 g (15 mmol) of 3-aminomethylchroman in 20 ml of methanol. The reaction solution is stirred for 15 hours at 50° and, after cooling, is concentrated by evaporation in vacuo. 5„1 g (95%) of M,M~bis(2«-methoxycarbony1ethyl)-N~(chroman-3~vlmethyl)-amine are obtained in the form of a reddish oil.

Example 3: A solution of 10,48 g (30 mmol) of M-[2-(chroman-3-vl)-ethyl]-N,M-bis(2-methoxycarbonylethyl)-amine in 35 ml of absolute dimethylformamide is added dropwise at room temperature and while stirring to a suspension of 2.15 g (40 mmol) of sodium metlioxide in 25 ml of dimethylformamide within a period of 15 minutes. The reaction mixture is stirred for 15 hours at room temperature and then concentrated to dryness by evaporation under a high vacuum. Diethyl ether is added to the residue and extraction is carried out with cold 2M hydrochloric acid. The combined hydrochloric acid extracts are extracted by shaking with dichloromethane 6 0 and. the dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. There are obtained 4.25 g (40%) of l-[2-(chroman-3-yl)ethyl]-4-hydrosjy-l , 2,5, S-tetrahydropyridine-S-carboxylic acid methyl ester hydrochloride or X-[2~(chroman-3~y1)ethyl]-4-oxopiperidine-3-carboxylic acid methyl ester hydrochloride which, after recrystallisation from methanol/-diethyl ether t, has a decomposition point of 175-177°.

N-[2-(chroman-3-yl) ethyl ] -N t, N-bis (2-methoxycarbonylethyl)-amine can be manufactured, for example, in the following manner: 12.53 g (192.5 mmol) of potassium cyanide are added at room temperature to a solution of 55.72 g (175 mmol) of 3~(©-toluenesulphonyloxysiethyl )chroman (for manufacture see Example 1) in 300 ml of dimethyl sulphoxide and the whole is heated to 60° while stirring. After 3 hours, ice-water is added to the reaction mixture, the whole is extracted with diethyl ether and washed thoroughly with water. The combined organic phases are dried over sodium sulphate and concentrated by evaporation An vacuo. 25,75 g (88.3%) of 3~cyanomethylchroman are obtained in the form of a pale yellow oil which crystallises from diethyl ether/pentane. The crystals melt at 63*.

First 4.44 g (33,.3 mmol) of aluminium chloride in 150 ml of absolute diethyl ether are added dropwise while stirring at room temperature to a suspension of 7.59 g (200 mMol) of lithium aluminium hydride in 300 ml of absolute diethyl ether™ Then 17.32 g (100 mmol) of 3-cyanomethyIchroman, dissolved in 200 ml of tetrahvdro-furan, are added dropwise within a period of 15 minutes -The reaction mixture is stirred for 16 hours at room temperature and then decomposed with 7-S ml of water, 7.6 ml of sodiuiE hydroxide solution (15% strength) and 22.8 ml of water. The precipitate formed is filtered off with suetiob and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether and washed with water. The organic phase is then extracted by shaking with 2M hydrochloric acid,, The combined hydrochloric acid extracts are rendered alkaline, while cold,, with sodium hydroxide solution (30% strength.) and extracted with dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated by evaporation ia vacuo. 15.95 g (90%) of 3~(2-aminoethyl)chroman are obtained in the form of a colourless oil. The 3-(2-aminoethyl)chroman hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and has a melting point of 244-245°. 6.63 g (77 mmol) of acrylic acid methyl ester are added at room temperature to a solution of 6.2 g (35 mmol) of 3 - (2-aminoethyl) ciiroman in 50 ml of methanol and the whole is stirred for 16 hours at room temperature. The reaction mixture is then concentrated by evaporation in vacuo and yields 12.23 g (100%) of N-[2~(chroman-3-yl)ethyl]~M,M-bis(2-methoxycarbonvletb:yl)-amine in the form of a reddish oil.

Example 4: In a manner analogous to that described in Example 3, by reacting 3-(2-aminoethyl)chroman with 1 equivalent of acrylic acid methyl ester, it is possible to manufacture the corresponding Ii-[2-(chroman~3~yl)-ethy1]-N-(2-methoxycarbonvlethy1)-amine whose hydrochloride melts at 190-192°.

B2 Example 5; In a manner analogous to that described in Examples 3 and 4, by reacting 3-aminomethylchroman with 1 equivalent of acrylic acid methyl ester, it is possible to manufacture N- (2-methoxycarbonylethyl) —H- (chroman-3 -5 ylmethyl)-amine or its hydrochloride.

Example 6; First 3„3 g (14.8 mmol) of 1,2,5,6-tetra-hydropvridine-3-carboxy1ic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 6.1 g (47»3 mmol) of M-ethyl-NeM-diisopropylamine are added to a solution of 10 4.5 g (13.5 mmol) of 3-[2-(jj-toluenesulphonyloxy)ethyl]-chroman in 70 ml of absolute dimethylfonaamide„ The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Mater is added to the oily residue and extrac-15 tion is carried out with diethyl ether. The combined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The 20 combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.97 g (97»7%) of 1~[2~(chroman~3-yl)ethyl]-1,2,5,6~ tetrahydropyridine-3-carboxy1 ic acid methyl ester are obtained in the form of a yellow oil- The 1-[2-(chroman-25 3~yl)ethyl3-l,2,5,S-tetrahydropyridine~3~carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and melts at 175-177*. 3-[2-(s-toluenesulphonyloxy)ethyl]chroman can be manufactured, for example,, as follows; 50 ml of 2N sodium hydroxide solution are added to a solution of 7.8 g (45 mmol) of 3-cyanoaethyIchroman in 150 ml of ethanol and the whole is boiled under reflux for 15 hours. After cooling, the reaction Mixture is concentrated by evaporation in vacuo- The residue is dissolved in water and extracted with diethyl ether. The aqueous phase is acidified with hydrochloric acid (36% strength) and extracted by shaking with dichloromethane. The combined dichloromethane extracts are dried over sodium sulphate and concentrated by evaporation in vacuo. 8.3 g (96%) of 3-carboxymethylchroman are obtained in the form of colourless crystals which melt at 106-107°. 1.5 ial of sulphuric acid (100% strength) are added to a solution of 7.69 g (40 miaol) of 3-carboxyraethylchroman in 150 ml of methanol and the whole is boiled under reflux for 3 hours, after cooling,, the reaction mixture is concentrated by evaporation in vacuo. The residue is dissolved in diethyl ether and washed, while cold,, with water, sodium hydrogen carbonate and again with water. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 8.08 g (98%) of 3~metho>jycarbonylmethylchroman are obtained in the form of a pale yellow oil.

At room temperature and while stirring, a solution of 7.22 g (35 mmol) of 3-methoxycarbonylmethylchroman in 50 ml of absolute tetrahydrofuran is added dropwise within a period of 30 minutes to a suspension of 1.33 g (35 mmol) of lithium aluminium hydride in 50 ml of absolute diethyl ether. Stirring is continued at room temperature for a further 16 hours and then the whole is carefully decomposed with 1.33 ml of water,, 1.33 ml of sodium hydroxide solution (15% strength) and 4.0 ml of water- The precipitate formed is filtered off with suction and. the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether. The solution is washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 6.23 g (100%) of 3-(2-hydroxyethyl)chroman are obtained in the form of a yellow oil. 6.29 g (33 mmol) of s-toluenesulphonyl chloride are added while stirring at room temperature to a solution of 5.35 g (30 suaol) of 3 -(2-hydroxyethyl)chroman in 30 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. After ^stirring for a further three hours at room temperature, the reaction mixture is poured onto ice-water. The crystals formed are filtered off with suction, washed with water and dried in vacuo. 5.9 g (59.2%) of 3-[2-(o™ toluenesulphonyloxy)ethyl]chroman, which melts at 91-93", are obtained.

Example. 7: First 11.1 g (50 mmol) of 1,2,5,6-tetrahydro-pyridine-3-carboxylie acid methyl ester hydrobromide (guvacoline hydrobromide) and then 22.6 g (175 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 11®45 g (50 mmol) of 2-bromomethylbenzo-l,4-dioxan (US 2,366,102) in 100 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 50° and then concentrated by evaporation under a high vacuum. Water is added to the residue and extraction is carried out with diethyl ether. The organic phases are cashed with water and extracted by shaking with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The 8 5 combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation la vacuo. 10.75 g (74.4%) of 1~( benzoyl, 4»dioxan-,2~ylai@thyl)-1,2,5, S-tetrahydropyridine-3-carboxylic acid methyl ester are obtained in the form of a yellow oil. The l-(benzo~ 1,4~dioxan™2~ylniethyl )-l„ 2... 5 , 6~tetrahydropyridi«e-3~ carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and decomposes at 215-217°.

Example 8; 0„5 g of palladium-on-carbon (5%) is added to a solution of 4.88 g (15 mmol) of l-(benzo-l,4-dioxan~ 2-ylmethyl )~1,2 f 5 f 6 ~tetrahydropyr idi ne- 3-carboxylie acid methyl ester hydrochloride in 100 ml of methanol and the whole is hydrogenated for 6 hours at room temperature and at normal pressure. The catalyst is then filtered off with suction and the filtrate is concentrated by evaporation in vacuo« The oily residue is dissolved in hot acetone and diethyl ether is added until the solution becomes turbid. 4,08 g (83%) of l~(benzo-l,4-dioxan-2~ ylmethvl) *-piperidine-3-~carboxylic acid methyl ester hydrochloride having a melting point of 186-188° crystallise out.

Example 9 ° At room temperature and while stirring, a solution of 10.12 g (30 mmol) of N,N-bis(2-methoxy-carbony1ethy1)-N~(benzo-1,4-dioxan-2-yljnethyl)-amine in 25 ml of absolute dimethylrormamide is added dropwise within a period of 15 minutes to a suspension of 2.16 g (40 mmol) of sodium methoxide in 25 ml of dimethyl-formamide. The reaction mixture is stirred for a further 3 hours at room temperature and then concentrated to dryness by evaporation under a high vacuum. Diethyl 6 6 ether is added to the residue and extraction by shaking is carried out with cold 2H hydrochloric acid. The combined hydrochloric acid extracts are extracted with dichloroiaethane and the dichloromethane phases are dried 5 over sodium sulphate and concentrated by evaporation in vacuo. There are obtained 4*5 g (44.4%) of 4"hydroxy-1-(benzo-1... 4-dioxan~2*-ylinethyl) ~i,, 2,, 56-tetrahydropyridine-3-carboxy 1 ic acid methyl ester hydrochloride or l"(be:aso-1,4-dioxan-2-yl;oethyl) -4-oxopiperi d ine-3-carboxy3,ic acid 10 methyl ester hydrochloride which is recrystallised from methanol/diethyl ether and has a decomposition point of 185—187 *.

N,N-bis(2-Methoxycarbonylethyl)-N*~(benso-lf4-dioxan-2-y liaethy 1)-amine can be manufactured,, for example„ as 15 followss 7„57 g (88 mmol) of acrylic acid methyl ester are added to a solution of 5. 61 g (40 raaol) of a-aminomethylbenso-1,4-dioxan [J. August in gfc &1-, J- Med. Chexa. 446 (1965)] in 80 ml of methanol and the whole is stirred for 20 16 hours at 50°. After cooling, the reaction mixture is concentrated by evaporation jyj vacuo. 12.82 g (95%) of M, N-bis (2 -methoxycarbonyl ethyl) ~M~ (benzo-l, 4-dioxan-2~ ylmethyl)-amine are obtained in the form of a reddish oil* Example 10 - In a maimer analogous to that described in Example 9 P by reacting 2-a»ino»ethylbenzo-l,4-dioxan with 1 equivalent of acrylic acid methyl ester, it is possible to manufacture the corresponding (2-methoxycarbonyl-ethyl)-N-(benso-l,4-dioxan-2-ylmethyl)-amine whose 30 hydrochloride melts at 153-155°. 6 7 ExaB.nla lis in a manner analogous to that described in Example 9, it is also possible to manufacture 4-hydroxy-I- (2-methylbenzo-l, 4-dioxan-2-yImethy 1) -1,2,5 „ 6-tetra-hydropyridine-3-carboxylic acid methyl ester hydrochloride or 1-(2-methylbenzo-l,4-dioxan-2-ylmethyl)-4-oxopiperidine-3-carboxylic acid methyl ester hydrochloride .

Example 12: In a manner analogous to that described in Examples 9 and 10, by reacting 2-(2-aminoethyl)~benzo-1,4-dioxan with 1 equivalent of acrylic acid methyl ester, it is possible to manufacture H-[2-(benzo~l,4-dioxan-2-yl)ethyl]~N~(2-methoxyc arbony1 e thy1)-amine and its hydrochloride , and by reacting 2~aminomethyl~2~ raethylbenzo-l,4-dioxan with 1 equivalent of acrylic acid methyl ester s it is possible to manufacture M- (2-methoxy-carbony1ethy1)-N-(2-methylbenso-le4-dioxan-2-ylmethyl)-amine and its hydrochloride.

Example 13: A solution of 52.7 g (0.15 mol) of bis(2-methoxycarbony1ethy1)-N-[2-(benzo-1,4-dioxan-2-yl)ethyl]-amine in 150 ml of absolute dimethylformamide is added dropwise at room temperature while stirring to a suspension of 10.8 g (0.20 mol) of sodium methoxide in 100 ml of absolute dimethylformamide within a period of 10 minutes™ The reaction mixture is stirred for a further 15 hours at room temperature and then concentrated to dryness by evaporation under a high vacuum. Diethyl ether is added to the resulting residue and extraction is carried out sith cold 2N hydrochloric acid. The combined hydrochloric acid extracts are extracted by shaking with dichloromethane. The dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. There are obtained 34.0 g (53.7%) 6 8 of l- [ 2-(bensso~l, 4-d.ioxan~2~yl) ethyl ] ~4~hydroxy«l, 2 f 5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride or l-[2~(foenzo-l,4-dioxan-2-yl)-ethyl]-4-oxopiperidine-3-carboxylic acid methyl ester Hydrochloride femich is recrystal1ised. from methanol/diethyl ether and has a decomposition point of 155-165°.

N „M~bis( 2-methoxycarbonylethyl) [ 2- (benao-l, 4-dioxan- 2~ yl) -ethyl]-amine can be manufactured,. for example, in the following manner* 34.1 g (0.396 mol) of acrylic acid methyl ester are added at room temperature to a solution of 32.25 g (0,18 mol) of 2~( 2-arainoethy 1)-benzoyl, 4-dioxan [J-Augustin at mi- , J. Med. Chem„ 8, 446 (1965)] in 250 ml of methanol- The reaction mixture is stirred for 6 hours at 50° and, after cooling, is concentrated by evaporation in vacuo. 57.9 g (91.5%) of N,N-bis(2-methoxycarbonylethyl)-N-[2-(benso-l,4~dioxan~2-yl)ethyl]-amine are obtained in the form of a red oil- Example 14; 1.25 g of platinum oxide are added to a solution of 12.45 g (35 mmol) of l-[2-(ben20-l,4-dioxan-2-yl)ethyl]-4-hydroxy-1,215,6-tetrahydropyridine-3~ carboxylic acid methyl ester hydrochloride or 1-J2-(benzo-1,4-dioxan-2 -y 1)ethy1]-4-oxop iperidine~ 3-carboxylic acid methyl ester hydrochloride in 250 ml of methanol and the whole is hydrogenated at room temperature and at normal pressure. After the theoretically necessary amount of hydrogen has been ta&en up*, the catalyst is separated off,, the filtrate is concentrated by evaporation in vacuo and the oily residue is dissolved in hot acetone. After cooling, 4.87 g (38.9%) of cis~l~ [2-(henzo-i s4-dioxan-2-yl)-ethyl]-4-hydroxypiperidine-3- carboxylic acid methyl ester hydrochloride having a melting point of 182-185" crystallise out.

Example 15; At -15° and while stirring, 2.65 g (70 nuaol) of sodium borohvdride are added in portions over a period of one hour to a suspension of 12.45 g (35 mnol) of 1-[2-(benso-X, 4-dioxan-2~yl) ethyl ] -4-hydroxy-l P2e5 f. 6~tetra~ hydropyridine-3-carboxylic acid methyl ester hydrochloride or 1-[2-(benzo-1,4-dioxan-2-yl)ethyl] -4-oxopiperidine-3-carboxy1ic acid methyl ester hydrochloride in 250 ail of methanol. Stirring is continued for a further 4 hours at -10" and then the reaction mixture is concentrated by evaporation in vacuo and taken up in water/ethvl acetate. The ethyl acetate extracts are washed with water, dried over sodium sulphate and concentrated by evaporation. 11.2 g (100%) of crude product are obtained which are chroiaatographed on 560 g of silica gel (0.040-0.063 sum) using ethyl acetate as the eluant. 5.41 g (48.2%) of trans-1-f2-(benzo-1.4-dioxan-2-y1)ethyl]-4-hydroxypiperidine-3-carboxylic acid methyl ester are obtained in the form of a pale yellow oil. The trans-1-T2-fbenzo-1,4-dioxan-2-vl)ethyl1-4-hvdroxy-piperidine-3-carboxylie acid methyl ester fuaiarate produced therefrom using fumaric acid crystallises from methanol/diethyl ether in the form of the hemihydrate having a melting point of 150-152°.

Example 16; First 19.03 g (125 mnol) of 1„5-diaisa-bicyclo[5.4.0]undec-5-ene and then,, dropwise and while stirring at 0-5°, a solution of 3.44 g (30 mmol) of wethanesulphonyl chloride in 20 ml of toluene are added to a solution of 8.03 g (25 miaol) of a mixture of cis-and trans-1- [ 2- (benso-l „ 4~dioxan-2~yl) -ethyl ]-4~hydroxy-piperidine-3-carboxylic acid methyl ester in 100 ml of 7 Q toluene. The whole is then allowed to warm up to rooia temperature and is stirred for a further 16 hours. Ice-water is then added to the reaction fixture and the organic phase is extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold( Mi til sodium hydroxide solution (30% strength) and extracted by shaking with dichloro-methane- The combined organic phases are washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo„ 5.8 g (75.5%) of crude product are obtained and are chromatographed on 300 g of silica gel (0»040-0*063 mm) using toluene/ethyl acetate (1:1) as the eluant. 4.13 g (54.5%) of 1-[2-(benzo-l,4-dioxan-2-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylie acid methyl ester are obtained in the form of a yellow oil» The 1~[2~(benzo-1,4-dioxan-2~y 1)ethyl]-1,2,5,6-tetra-hydropyridine-3-carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and decomposes at 205-206*.

Example 17s First 2.1 g (11 mmol) of 1,2,5,S-tetrahydro-pyridine-3-carboxylic acid ethyl ester hydrochloride and then 4.53 g (35 mmol) of N-ethyl~N„N-diisopropylainine are added to a solution of 3.32 g (10 mmol) of 3~[2~(g-toluenesulphonyloxy)ethyl]-chroman in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60* and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with, diethyl ether. The combined organic phases are extracted with 2M hydrochloric acid- The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloro- 7 i methane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation jjj vacuo. 1.65 g (52-3%) of l-[2-(chrojman-3~yl)ethyl ]~ l f 2,5, 6-tetrahydropyridine-3-carboxylic acid ethyl ester 5 are obtained in the form of a yellow oil. The 1~[ 2- (chroman-3-yl)ethyl3-1,2,5,6-tetrahydropyridine-3-carboxylie acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from acetone/diethyl ether and rue Its at 10 177-178 *.

Example 18: 3.4 ml of sulphuric acid (100% strength) are added to a solution of 2„54 g (7.5 mmol) of 1~[2~ (chroman-3-yl)ethyl]-l,2,5,6-tetrahydropvridine-3™ carboxylic acid methyl ester hydrochloride in 170 ml of 15 absolute ethanol and the whole is boiled under reflux for 35 hours. After cooling, the reaction mixture is concentrated by evaporation in vacuo. The residue is dissolved in water while cold and is extracted with diethyl ether. The aqueous phase is rendered alkaline, 20 while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane extracts are dried over sodium sulphate and concentrated by evaporation in vacuo. 2.30 g (97.4%) of 1-[2-(chroman-3 ~v 1)ethyl]-1,2,5,S-tetrahydropyridine~ 25 3-carboxylic acid ethyl ester are obtained in the form of a yellow oil. The l-[2-(ehroman-3-yl)ethyl]-1,2*5,6-tetrahydropyridine-3-carboxylic acid ethyl ester hydrochloride produced thereform using hydrochloric acid in diethyl ether crystallises from acetone/diethyl ether and 30 melts at 177-178*.

Example 19: First 3.76 g (24 mmol) of piperidine-3-carboxylic acid ethyl ester and then 3.1 g (24 mmol) of 7 2 N-ethyl-NfN-diisopropylainine are added to © solution of 3.98 g (12 Moaol) of 3-[2"(2~tolu@nesulphottyloxy)ethyl]-chroasan in 50 ml of absolute dimethylformamide. Tb.& mixture is stirred for 16 hours at 60° ©:acf.after 5 cooling, is concentrated by evaporation under a high vacuum Mater is added to the oily residue and extraction is carried out &?ith diethyl ether.. The combined organic phases are extracted with 2¥. hydrochloric acid. The combined hydrochloric acid extracts are rendered 10 alkaline,, while cold, with sodium hydroxide solution (30% strength) and extracted %?ith dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.7 g (97.3%) of 1-[2-(chroman~ 3-y1)ethy1]~piperidine~ 3-15 carboxylic acid ethyl ester are obtained in the form of a yellow oil- The l~[2-(chroman-3~yl)ethyl3~piperidine~3~ carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from acetone/diethyl ether using 0«18 20 equivalent of water of crystallisation and melts at 140-143* .

Example 20; First 3„75 g (24 mmol) of piperidine-4-carboxylic acid ethyl ester and then 3.1 g (24 mmol) of &'~ethy 1 -'?!M-diisopropy1 amine ©re added to a solution of 25 3.98 g (12 mmol) of 3-[2-(D™toluenesulphonyloxy)-ethyl]~ chroman in 50 ml of absolute dimetftylformamide*, The mixture is stirred for IS hours at 60" and# after cooling, is concentrated by evaporation under a high vacuum- Mater is added to the oily residue and eartrac-30 tion by shaking is carried out with diethyl ether. The combined organic phases are extracted with 2M hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3,8 g (100%) of crude product are obtained which are chromatographed on 200 g of silica gel (0.040-0.063 mo) using ethyl acetate as the eluant. 3.7 g (97,3%) of i-[2~(chroman-3~yl)ethyl]-piperidine-4-carboxylic acid ethyl ester are then obtained in the form of a colourless oil. The l~[2-(chroman-3-yl)ethyl]~ pipe:cidine-4~carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 182-186°.

Example 21: First 1.96 g (12.5 mmol) of piperidine-3-carboxylic acid ethyl ester and then 2.58 g (20 mmol) of H-ethyl~M,N~diisopropylamine are added to a solution of 3.34 g (10 mmol) of 2~[2-(D»toluenesulphonyloxy)ethvlj-benzo-1,4-dioxan in 50 ml of absolute dimethylf ormaxnide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum* Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo... 3.82 g (100%) of crude product are obtained which are filtered over 190 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant.. 3.70 g (96.6%) of 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester are then 7 4 obtained in the form of a pale yellow oil- The l-[2-(benzo-1„4-dioxan-2~yl)ethyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from 5 ethanol/diethyl ether and melts at 162-165°.

The 2- [ 2-(g)~toluenesulphonyloxy) ethyl ]-benso-1,4-dioxan cars be obtained, for exampleL, in the following manner; Hydrogen chloride is introduced at 5-10°, %?hile stirring,, into a solution of 15.76 g (90 mmol) of 2-cyanomethyl-10 foen20-l,4-dioxan (BE 613,211) in 200 ml of absolute methanol until saturation is reached,. The reaction mixture is then thawed to room temperature and is stirred for a further 16 hours at that temperature, The reaction mixture is then boiled under reflux for 2 hours. After 15 cooling„ the mixture is concentrated by evaporation in vacuo. Ice-water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed, while cold, with water, saturated sodium hydrogen carbonate solution and 20 again with water,, and then dried over sodium sulphate and concentrated by evaporation in vacuo. 10-2 g (97.3%) of 2-methoxycarbonylmefchylbenzo-le4-dioxan are obtained in the form of a pale yellow oil- At room temperature and while stirring, a solution of 25 15.61 g (75 rase!) of 2~methoxycarbonyliaethylbenzo~l, dioxan in 120 ail of absolute tefcrahydrofuran is added dropwise within a period of 30 minutes to a suspension of 2-85 g (75 mmol) of lithium aluminium hydride in 120 ml of absolute diethyl ether- The reaction mixture is 30 stirred for a further 2 hours at room temperature. It is then carefully decomposed with 2-85 ml of water, 2.85 ml of sodium hydroxide solution (15% strength) and 8.55 ml of 'water. The precipitate formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether. The solution is washed thoroughly with water, dried over sodium sulphate and concentrated by evaporation 2M vacuo„ 12.37 g (91.6%) of 2~(2-hydroxyethyl)-benzo-1,4-dioxan are obtained in the form of a colourless oil. 12.20 g (64 mmol) of D-toluenesulphonyl chloride are added at room temperature and while stirring to a solution of 10.81 g (60 mmol) of 2-(2-hydroxyethyl)benzole 4-dioxan in 35 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. The reaction mixture is stirred for a further 3 hours at room temperature and then poured onto ice-water. The crystals formed are filtered off with suction, washed with water and dried in vacuo. 15.50 g (77„2%) of 2~[2-(o~*toluenesulphonyloxy)ethyl]~ benzo-1,4-dioxan, which malts at 82-84°, are obtained.

Example 22; First 1.96 g (12.5 mmol) of piperidine-4-carboxylic acid ethyl ester and then 2.58 g (20 msaol) of N-ethyl~M,N~diisopropylamine are added to a solution of 3.34 g (10 mmol) of 2-[2-(g-toluenesulphonyloxy)ethyl]-benzo~l, 4-dioxan in 50 ml of absolute dixaethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline,, while cold, with sodium 7 6 hydroxide solution (30% strength) end extracted with di chlorosis thane., The combined dichloromethane phases ©re dried over sodium sulphate and concentrated by evaporation 1b vacuo. 3.80 g (99.2%) of crude product are 5 obtained which are filtered over 190 g of silica gel (0„040—0.0S3 mm) using ethyl acetate as the eluant. 3.7 g (96-6%) of 1-[2~(benzoyl,4-dioxan-2~yl)ethyl]-piperidine-4~carboxylic acid ethyl ester are then obtained in the form of a yellow oil- The l~[2-(ben2o-10 1 ^-dioxan-^-yl)ethyl ]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 155-168*.

Example 23; 21 ml (42 auaol) of 2N sodium hydroxide 15 solution are added at room temperature while stirring to a solution of 2.99 g (10 mmol) of M~[2~(chroman-3~ yl)ethyl] -N—(2-methoxycarbonylethyl)-amine hydrochloride in SO ml of methanol. After 5 minutes, 40 ml of water are added to tine reaction mixture which is then stirred 20 for 30 minutes at 50-60°. After cooling, the mixture is concentrated by evaporation in vacuo. The residue is dissolved in 30 ml of water,, and then 10 ml of hydrochloric acid (36% strength) are added and the whole is cooled in an ice bath. The crystals formed are filtered 25 off with suction- 2.5 g (87.5%) of M-[2-(chroman--3- yl)ethyl]-M-(2-carboxyethyl)-amine hydrochloride are obtained (m„p. 186-188°).

The N- [ 2- (chroman-3~yl) ethy 13 -N- (2-Methoxycarbonylethy 1) -amine hydrochloride can be manufactured, for example, as described in Example 4.

Example 24: First 1„57 g (10 Hmiol) of piperidine-3-carboxylic acid ethyl ester and then 2.07 g (16 aiol) of N~ethyl~N„N-diisopropylamine are added to a solution of 2.66 g (8 mmol) of 2~[2"(s~toluenesulphonylo3£y)ethyl]« chroman in 35 ml of absolute dimethyl fonaamide. The mixture is stirred for 16 hours at SO* and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 2-28 g (90.1%) of crude product are obtained and are chromatographed on 120 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 1.82 g (72.2%) of 1-[2-(chroman-2-yl)ethyl]-piperidine-3-carfooxylic acid ethyl ester are then obtained in the form of a yellow oil. The 1~[2-(chroman~2-yl)ethyl]-piperidine-3-carboxylie acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 148-151°. 2-[2-(a*"toluenesulphonyloxy)ethyl]chroman can be manufactured, for example, in the following manner: 14.2 ml of sulphuric acid (100% strength) are added to a solution of 70.34 g (0.39 mol) of 2-carhoxycliroman in 1400 ml of methanol and the whole is boiled under reflux for 4 hours. After cooling, the reaction mixture is concentrated by evaporation in vacuo and the residue is 7 8 dissolved in diethyl ether and washed with water, cold saturated sodiura hydrogen cs.vbo.oata solution and again with water ,, The ethereal phase is dried over sodium sulphate and concentrated by evaporation .in vacuo. 5 72.8 g (96%) of 2methoxycarbonylchroman are obtained in the fona of a pale yellow oil.

At room temperature and while stirring, a solution of 36.4 g (0.19 mol) of a-methoxycarbonylchroman in 400 ml of absolute tetrahydrofuran is added dropwise within a 10 period of 1 hour to a suspension of 7.2 g (0»19 mol) of lithium aluminium hydride in 400 ml of absolute diethyl ether. After continuing to stir for a further 16 hours at room temperaturef the reaction mixture is carefully decomposed with 7.2 ml of tester, 1.1 ml of sodium 15 hydroxide solution (15% strength) and 21»6 ml of water« The precipitate formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether. The ethereal solution is washed with aater, dried over sodium 20 sulphate and concentrated by evaporation in vacuo. 31 g (99.3%) of 2-hydroxymethylchroinan are thus obtained in the form of a colourless oil. 38.16 g (0.2 mol) of o-to1uenesulpeony1 chloride are added at room temperature while stirring to a solution of 25 31 g (0.189 mol) of 2-hydroxymethylchroman in 110 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. The reaction mixture is sti.rred for a further 3 hours at room temperature and then poured onto ice-water. The oil 30 which separates out is rexaoved by decanting the aqueous phase f dissolved in diethyl ether and washed with ice-cold 2N hydrochloric acid and ice-water. The ethereal 7 3 phases are dz"ied over sodium sulphate and concentrated by evaporation in vacuo. 58„15 g (96S%) of 2~(a-toluene~ sulphonyloxymethyl)chroman are obtained in the form of a colourless oil. .6 g (0.216 mol) of sodium cyanide are added to a solution of 57.31 g (0.18 mol) of 2-(;o-toluerie-su 1 phonyloxymethy 1) chroman in 800 ml of absolute dimethyl fox-mamide and the whole is heated, while stirring, to 60°. After 10 hours,, ice-water is added to the reaction mixture and extraction is carried out with diethyl ether. The combined ethereal phases are washed thoroughly with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 30«0 g (96.2%) of crude product are obtained and are chromatographed on 1000 g of silica gel (0.040-0.063 mm) using toluene as the eluant. 18„16 g (58.2%) of 2-cyanomethylchroman are thus obtained in the form of a yellow oil.

Hydrogen chloride gas is introduced at 5-10° into a solution of 17.32 g (0.1 mol) of 2-cyanomethylchroman in 200 ml of absolute methanol until saturation is reached. The reaction mixture is then thawed to room temperature and is stirred for a further 16 hours at that temperature. The reaction mixture is then boiled under reflux for 2 hours. It is then cooled and the mixture is concentrated by evaporation in vacuo. Ice-water is added to the residue and extraction is carried out with diethyl ether. The combined organic phases are washed, while cold t, with water, sodium hydrogen carbonate solution and again with water, and then dried over sodium sulphate and concentrated by evaporation in vacuo. 18.58 g (90.1%) of crude product are obtained and are filtered over 460 g of silica gel (0.040-0.063 mm) using toluene as the eluant.

B © 17 SO g (86.3%) of 2-methoKycarbony isaathy 1chroman are obtained in the form of © pale yellow oil.

At room temperature and while stirring,• a solution of 16.91 g (82 mmol) of 2-iaetiioxycerbonyliaethylcliroaian in 150 sal of absolute tetrahydrofuran is added dropwise within a period of 30 minutes to a suspension of 3.11 g (82 mmol) of lithium aluminium hydride in 150 ml of absolute diethyl ether. Stirring is continued for a further 16 hours at room temperature and then the whole is carefully decomposed with 3„1 nil of water, 3.1 ml of sodium hydroxide solution (15% strength) and 9.3 ml of water» The precipitate formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether. The ethereal solution is cashed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 14.36 g (98.3%) of 2-(2-hydroxyethyl)chroman are obtained in the form of a colourless oil. .73 g (82.5 mmol) of o-toluenesulphonvl chloride are added at room temperature while stirring to a solution of 13.36 g (75 bjieoI) of 2-(2-hydroxvethyl)chroman in 90 ail of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath, After stirring for a further 3 hours at room temperature„ the reaction mixture is poured onto ice-water. The crystals formed are filtered off with suction,, washed with water and dried in vacuo. There are obtained 8„S8 g (34.7%) of 2-[2-(2>-toluenesulphonyloxy)-ethyl ]chrosaan which melts at 57-59".

Example 25; first 1.57 g (10 saaol) of piperidine~4~ carboxylie acid ethyl ester and then 2.07 g (16 mmol) of 8 I N-ethyX-N, N-di isopropy1amine are added to a solution of 2.66 g (8 mmoi) of 2- [ 2-(a-toluenesulphonyloty)ethy3, ]-chroman in 35 ial of absolute dimethylforsaamide. The mixture is stirred for 16 hours at SO* and then,, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2M hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline,, while coldf with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 2-17 g (85,7%) of crude product are obtained and are chromatographed on 110 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 1,90 g (75.1%) of l~[2-(chroman~2-yl)~ ethvl]-piperidine-4-carboxylie acid ethyl ester are thus obtained in the form of a yellow oil, The 1-[2-(chroman-2-yl)ethyl ]~piperidine~4~carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 190-192° .

Example 26: 3.01 g (35 msaol) of acrylic acid methyl ester are added at 0-5°, while stirring,, to a solution of 6.2 g (35 mmol) of 2-(2-aminoethyi)chroman in 200 ml of methanols Stirring is continued for a further 16 hours at 0-5° and the mixture is then concentrated by evaporation in vacuo. 8.76 g (95.2%) of crude product are obtained and are chromatographed on 250 g of silica gel (0.040-0.063 am) using ethyl acetate as the eluant. 5.10 g (55.4%) of H-[2~(chroman-2-yl)ethyl]-M-(2-methoxy-carbonylethyl)-amine are thus obtained in the form of a 8 2 yellow oil. The N-[2-(chroman-2-yl)ethyl]-N~(2-methoxycarbonyl ethy1)-amine hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and melts at 152-153°. 2-(2~aminoethyl)chroman can be manufacturedf for example, in the following manner* First, at room temperature and %?hila stirringt, 2.2 g (16.5 simoI) of aluminium chloride in 70 sal of absolute diethyl ether are added dropwise to a suspension of 3.8 g (100 mmol) of lithium aluminium hydride in 150 ml of absolute diethyl ether. Then 8.SS g (50 mmol) of 2~ cyanomethylchroman in 70 ml of absolute tetrahydrofuran are added dropwise within a period of 20 minutes. The reaction mixture is stirred for a further IS hours at room temperature and then carefully decomposed with 3.8 ml of water, 3.8 ml of sodium hydroxide solution (15% strength) and 11.4 ml of water. The precipitate formed is filtered off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved in diethyl ether. The ethereal phase is washed with ^ater, dried over sodium sulphate and concentrated by evaporation. 8.75 g (98.8%) of 2~~(2~ aminoethyl) chroman are obtained in the form of a colourless oil.

Example 27 s 1«5 ail of concentrated hydrochloric acid are added to a solution of 4.81 g (0.015 mol) of 1~[2~ (chroman~3~yl) -ethyl ] - 3 -cyano- 4 -hydroxy-1,2,5,6-tefra-hydropyridine hydrochloride or !-[2-(chroman-3 ~y 1)ethy1]-3~cyano~4~oxopiperidine hydrochloride in 100 ml of methanol (55% strength) and the whole is boiled under reflux for 15 hours. After cooling,, the reaction 83 mixture is concentrated to a volume of approximately 30 ml under reduced pressure and the solution is poured into a mixture of 80 ml of 5N hydrochloric acid and 20 ml of toluene, whereupon,, s?hil@ stirring and cooling,, X~[2-(chroman™3-y1)ethyl]-4-hydroxy-l,2,5,6~tetrahydro~ pvridine-3-carfooxylic acid methyl ester hydrochloride or 1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine-3-carboxylic acid methyl ester hydrochloride, respectively,, having a melting point of 175-177° (decomposition) crystallises out.

The 1~[ 2-(chroraan-3~yl )ethyl ]-3-cyano-4-hydroxy~l ,2,5,6-tetrahvdropyridine hydrochloride or l-[ 2-(chrotaan-3-yl)ethyl]-3~cyano-4-oxopiperidine hydrochloride can be manufactured, for example, in the following manner: g (0.1 mol) of M-[2~(chroman-3-yl)ethyl]-M-(2-methoxy-carbonylethyl)-amine hydrochloride are dissolved in 100 ml of methanol, and then 10.5 g (0.1 mol) of triethylaiaine and 5.84 g (0.11 raol) of acrylonitrile are added to the solution and the whole is stirred for 15 hours at room temperature. The reaction mixture is then concentrated under a water-jet vacuum, the residue is taken up in diethyl ether and the ethereal solution is washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation. H~ [ 2 - (chroman- 3 -v 1) -ethyl ] -N- (2-cyano-ethyl) --M- (2-methoxycarbony 1 ethyl) -aaiine is thus obtained in the form of a yellow oil.

A solution of 13.07 g (41„3 mmol) of N—[2-(chroman—3- yl) ethyl ] -M- (2-cyanoethyl) -N- (2-methoxycarfoonylethyl) -amine in 200 ml of tetrahydrofuran is added dropwise under a nitrogen atmosphere to a suspension of 5.73 g of 8 4 sodium hydride (55% suspension in mineral oil) in 100 ml of tetrahydrofuran and the whole is stirred for 16 hours at room temperature. After adding 70 ml of 2M sulphuric acida yellow solution is obtained - 300 ml of diethyl 5 ether and 100 ml of water are added thereto to form two phases. The aqueous phase is extracted three times with 100 ml of diethyl ether each time. The combined organic phases are dried over sodium sulphate, concentrated to approximately 100 ml under reduced pressure and then 10 poured into a mixture of 80 ml of 5N hydrochloric acid and 20 ml of toluene, whereupon, while stirring and cooling, 1~[2-(chroman-3-yl)ethyl]-3-cyano-4-hydroxy-1,2,5,6-tetrahydropyridine hydrochloride or l~[2~ (chroman-3~yl)ethyl]-3-cyano-4-oxopiperidine hydro-15 chloride crystallises out,, Example 28s 17.4 ml of n-butvllithium in hexana are added at 0-5* to a solution of 2,,,81 g of diisopropylamine in 30 ml of dry tetrahydrofuran. The whole is stirred for 30 minutes at room temperature, then cooled to -15* 20 and a solution of 6.24 g (25 mmol) of 1-[2-(chroman-3- yl)ethyl]-4~oxopiperidine in 30 ml of tetrahydrofuran is added. After 15 minutes, a solution of 3.05 g (28 mmol) of chlorotrimethylsilane in 15 ml of tetrahydrofuran is added dropwise- The whole is stirred overnight at room 25 temperature, the solution is filtered and the filtrate is concentrated to dryness by evaporation under reduced pressure. l-[2-(chroman~3-yl) ethyl 3*-4-trimethylsilyloxy-1,2„5,6-tetrahydropyridine is thus obtained in the form of a pale yellow oil. 6.63 g (20 mmol) of the X~[2~ 30 (chroman-3-yl) -ethyl ] -4-trimethylsilyloxy-l 2 p 5 „ 6- tetrahydropyridine obtained are dissolved in 50 ml of dichloromethane and the solution is added dropwise to a solution, cooled to 0°, of 2*3 g (24 mmol) of chloro- 8 5 formic acid methyl ester and 50 mg (2.4 mmol) of anhydrous sine bromide in 50 ml of absolute dichloromethane . After warming up to room temperature,, the reaction solution is stirred for one hour and then poured onto 150 ml of saturated sodium hydrogen carbonate solution,, Extraction is carried out with dichloromethane, and the combined organic phases are dried over sodium sulphate and then concentrated by evaporation-The residue is dissolved in 70 ml of ethanol and the solution is acidified with ethanolic hydrochloric acid. After adding diethyl ether and after cooling,, 1-[ 2-(chroman-3-yl)ethyl]-4-hydroxy-l,2,5,6-tetrahvdro-pvri d i ne-3-carboxy!ic acid methyl ester hydrochloride or 1- [ 2- (chroman-3-yl) -ethyl ]-4~oxopiperidine-3--carboxylic acid methyl ester hydrochloride having a melting point of 175-177° crystallises out.

The 1- [ 2- (chroman-3-vl)ethyl ] ~4--oxopiperidine can be manufactured, for example, in the following manner: First 8.45 g (55 mmol) of piperidone hydrochloride monohydrate and then 22.62 g (175 mmol) of M-ethyl-MeN-diisopropylamine are added to a solution of 16.62 g (50 mmol) of 3-[2~(p-toluenesulphonyloxy)ethyl3chroman in 100 ml of dimethylformamide. The mixture is stirred for 18 hours at 80° and,, after cooling, is concentrated to dryness by evaporation under reduced pressure. The residue is dissolved in diethyl ether and washed with water. The organic phase is separated off and extracted with 211 hydrochloric acid. The hydrochloric acid extracts are combined, rendered alkaline,, while cold,, with concentrated sodium hydroxide solution and extracted with dichloromethane. The dichloromethane phases are combined, dried over sodium sulphate and concentrated to 8 6 dryness by evaporation under reduced pressure. A dark bro%m resin is obtained %?hich is purified by chromatography on 350 g of silica gel (0»040-0»GS3 am) using toluene/ethyl acetate (1:1) as the eluant, l-(2-(chroman-3-yl)ethyl]~4~oxopiperidine is obtained in the form of a pale yellow oil.

Example 29% A solution of 2.7 g (25 mmol) of benzyl alcohol in 25 ml of tetrahydrofuran is added to a suspension of 1.2 g of sodium hydride (50% suspension in mineral oil) in 25 ml of dry tetrahydrofuran and, when the evolution of gas has subsided, the whole is heated under reflux for 30 minutes. After cooling, a solution of 8.5 g (25 iftinol) of 1-[2-(benzo-1,4~dioxan-2-yl)~ ethyl]-1,2,5,6~tetrahydropyridine-3-carboxylie acid methyl ester in 50 nil of tetrahydrof uran is added dropwise and the whole is heated under reflux again for 5 hours. After cooling, the solvent is removed. A mixture of cis~ and trans-l-f 2~(benzo-1„4-dioxan--2-yl)ethyl]~4-benzyloxypiperidine~3-carboxylic acid methyl ester is obtained in the form of an oil.

Example 30; At -10* and while stirring,, 1.41 g of sodium borohydride are introduced within a period of 90 minutes into a suspension of 8.45 g (18 mmol) of 1-[2-(chroman-3-yl) ethyl ] ~3-methoxycarbony1pyridinium |>-toluenesulphonate in 43 ml of methanol. Stirring is continued for 1 hour at 0° and for 2 hours at room temperature and then 50 ml of water are added to the reaction mixture and extraction by shaking is carried out twice with 100 ml of dichloromethane each time. The dichloromethane phases are combined,, dried over magnesium sulphate and concentrated to dryness by evaporation. The crude product is purified by chromatography on 150 g of silica gel (0.063-0.2 mm) 8 7 using ethyl acetate as the eluant. The main eluate, which is concentrated by evaporation,, is treated with ethereal hydrochloric acid to yield X-[2-(chroman-3-yl)ethyl]~1,2,5,6-tetrahydropyridine~3-carlx>xylic acid methyl ester hydrochloride having a melting point of 175-177°.

The 1- [ 2- (chroman-3~yl) ethyl 3~3-methoxycarbonylpyridiniuia o-tolusnesulphonate can be manufactured t, for example , in the following manners 16.6 g (50 mmol) of 3~[2-(D~toluenesulphonyloxy)ethvl]~ chroman and 9.3 g (67.5 mmol) of pyridine-3-carboxylie acid methyl ester are suspended in 50 ml of butan-2-one and the suspension is boiled for 72 hours while stirring. It is cooled, the reaction mixture is concentrated under reduced pressure, and l-[2-(chroman-3~yl)ethyl]~3-methoxycarbonylpvridinium o-toluenesulphonate is thus obtained in the form of a white foam.

Example 31i 33.2 g (0,1 mol) of 3-[2-(p-toluene-sulphonyloxy)ethyl]chroman, 14,0 g of S-(2-methoxycarbonyl ethyl )-amine hydrochloride and 39 g of M-ethyl-M,M-diisopropylamina are dissolved under nitrogen in 750 ml of dimethylformamide and the solution is stirred for 16 hours at room temperature. The reactions mixture is subsequently concentrated to approximately 200 ml under reduced pressure, 500 ml of water are then added and the whole is extracted by shaking three times with 150 ml of dichloromethane each time. The combined organic phases are dried over sodiuaa sulphate and concentrated to dryness by evaporation. By adding ethanolic hydrochloric acid and cooling, '$-[2-(chroman-3-y1)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride 8 8 having a melting point of 190-192* is obtained.

Example 32; 6 sal of concentrated hydrochloric acid are added to a solution of 11.5 g (0.05 »1) of M-[2-(chroman-3-yl) ethyl ]-M-(2-cyanoethyl) -amine in 100 ial of methanol. The reaction mixture is boiled under reflux for 15 hours. After cooling, the solvent is removed under reduced pressure and the residue is crystallised from methanol/acetone. After recrystallisation from methanol/acetone, M-[2-(chroman-3-yl)ethyl]~M~(2-methoxy-carbonylethyl)-amine hydrochloride having a melting point of 190-192* is obtained (yield* 82%).

The N-[2-(chroman-3-yl)ethyl]-N-(2-cvanoethyl)-amine can be manufactured, for example, in the following manners 17.7 g (0.1 mol) of 3-(2-aittinoethyl)chroman are dissolved in 100 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 584 g (0.11 mol) of acrylonitrile are added to the solution. The reaction mixture is stirred for 15 hours at room temperature and then concentrated under a water-jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice-^ater» The ethereal phase is dried over potassium carbonate and concentrated by evaporation. M-[2-(chroman-3-yl)ethyl]-M-(2-cyanoethyl)amine is thus obtained in the form of a pale yellow oil.

Example 33: 5.2 g of a mixture of cis- and trans-l-f2-(benso-l„4-dioxan~2-yl)ethyl]-4~benzyloxypiperidine~3- carboxylic acid methyl ester are dissolved in 100 ml of methanol, and then 2 g of palladium-on-carbon (10%) are added and the whole is hydrogenated in a Parr apparatus for 12 hours at room temperature. The reaction mixture 8 9 is then filtered over diatomaceous earth and the filtrate is concentrated to dryness by evaporation. The crude oily residue is chromatographed on silica gel using toluene/ethyl acetate (9:1) as the eluant. First the trans-1-[2-(benzo-1,4-dioxan~2-yl)ethyl]-4-hydroxy-piperid i ne<~ 3-carboxy1ic acid methyl ester and then the cis-1-[2-(benzo-1,4-dioxan~2-yl)ethyl]-4-hydroxy-piperidine-3-carboxvlic cicid methyl ester is eluted. In each case the purified fractions are combined and concentrated by evaporation. The residue that contains the trans product is treated with fumaric acid in methanol/diethyl ether and thus yields trans-l-f 2-(benzo-1,4-dioxan-2-yl) ethyl ]-4-hydroxypiperidine~3-carboxylic acid methyl ester furaarate which crystallises out in the form of the hemihvdrate and melts at 150-152°. The residue that contains the cis product is treated with ethereal hydrochloric acid and thus yields cis-1-[2-(benzo-l,, 4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylie acid methyl ester hydrochloride which has a melting point of 182-185°.

Example 34 t S „ 8 g (20 rruaol) of a mixture of cis- and trans-l-f2-(benzo-1,4-dioxan-2-yl)ethyl]-4-ehloro-piperidine-3-carboxylic acid methyl ester are dissolved in 20 ml of methanol. 40 ml (140 mmol) of a 3.5M solution of ammonia in methanol are added dropwise at room temperature. The mixture is left to stand at room temperature for 24 hours. The solvent is then removed under reduced pressure. The resulting residue is dissolved in dichloromethane, the solution is extracted by shaking with 21? hydrochloric acid and the acidic aqueous phase is separated off ^ rendered alkaline sith sodium hydrogen carbonate and extracted with diethyl ether/dichloromethane (2:1)- The organic extracts are S 0 washed "with saturated sodium chloride solution, dried over magnesium sulphate and freed of the solvent under reduced pressureThe resulting residue is chromatographed on basic silica gel using dichloromethane/-methanol (99s1) as the eluant. The eluates are combined and concentrated to dryness by evaporation. The oily residue consists of pure 4-amino-l-[2-(ban20-l,4-dioxan-2-vl)ethyl]-piperidine~3-carboxylic acid amide (cis/trans mixture).

A mixture of cis- and trans-1-[2-(benzo-1,, 4-dioxan~2™yl)-ethyl]-4-chloropiperidine~3-carboxylic acid methyl ester can be obtained, for example,, as follows: 9.7 g (30 mmol) of a mixture of cis- and trans-l-f2-(benso-l,4-dioxan~2-yl)ethyl]-4-hydroxypiperidine-3-carboxylic acid methyl ester (for manufacture see Example 33) and 3.6 g (36 mmol) of triethylamine are dissolved in 100 ml of dichloromethane. 3,92 g (33 mmol) of thionyl chloride are added dropwise while stirring at room temperature. The mixture is stirred for 4 hours at room temperature. The triethylamine hydrochloride formed is then filtered off and the filtrate, while cold, is extracted by shaking with saturated sodium hydrogen carbonate solution. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and freed of the solvent under reduced pressure. The resulting mixture of cis- and trans-1-f 2-(benzo-l* 4-dioxan-2-yl)ethyl ] ~4~chloropiperidine~3-car.boxylic acid methyl aster is used further in the crude state.

Example 35: At room temperature and while stirring, a solution of 11.94 g (30 mmol) of N-(3-ethoxvcarbonyl-propvl)-N~(2-bromoethyl)-M-[2-{chroman-3-yl)ethyl]-amine in 40 at! of absolute dimethyl formamide is added dropwise within a period of 20 minutes to a suspension of 2.72 g (40 aoaol) of sodiua ethoxide in 30 ml of dimethyl-formamide- The reaction mixture is stirred for IS hours at room temperature and then concentrated to dryness by evaporation under a high vacuum- Diethyl ether is added to the residue and extraction is carried out with cold 2N hydrochloric acid* The combined hydrochloric acid extracts are extracted by shaking with dichloromethane and the dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. The crude product is obtained as the residue and is chromatographed on 500 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. The eluate is concentrated by evaporation to yield 1-[2-(chroman-3-vl)ethyl]-piperidine-4~carboxylie acid ethyl ester in the form of a colourless oil. The l-[2~(chroman-3-yl)ethyl]~ piperidine-4-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 182-186°.

The M~(3-ethoxvcarbonylpropyl)-N-(2-bromoethyl)-N-[ 2-(chroman-3-yl)ethyl]-amine can be manufactured{, for example, in the following manner: 17,7 g (0„l mol) of 3-(2~aminoethyl)chroman are dissolved in 100 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 19,5 g (0.1 mol) of 4-bromobutyric acid ethyl ester are added to the solution. Tile reaction mixture is stirred for 15 hours at room temperature and is then concentrated under a water-jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation.

Oi ly N- (3-ethoacycarbonylpropyl) -N- [ 2~(chroman- 3-yl)-ethyl ] -amine is thus obtained and can be used further in crude form* 29.1 g (0.1 mol) of K~(3-ethoxycarbonylpropyl)-S-[2-(chroman-3-yl)ethyl]-amine are dissolved in 200 ml of methanol, and then 10.5 g (0.1 mol) of triethylamine and 18,8 g (0.1 mol) of 1,2-dibromoethane are added to the solution. The reaction mixture is stirred for 16 hours at room temperature and then concentrated under a water-jet vacuum. The residue is taken up in diethyl ether and washed neutral with ice-water. The ethereal phase is dried over potassium carbonate and concentrated by evaporation. N~(3-ethoxycarbonvlpropyl)-N-(2-bromoethyl )-M-[ 2- (chroman-3-yl)ethyl]-amine is thus obtained in the form of an oil which can be used further in the crude state.

Example 36: In a manner analogous to that described in Examples 4, 5, 10, 12, 23, 26, 31 and 32, it is also possible to obtain [ 2- (chroman-4-yl) ethyl ]-W~ (2-methoxycarbonylethyl)-amine and its hydrochloride.

Example 37: In a manner analogous to that described in Examples 1 to 3, 6 to 9, 11, 13 to 22, 24, 25, 27 to 30 and 33 to 35 it is also possible to obtain 1-(2-(chroman-4-yl)ethyl]-1,2,5,S~tetrahydropyridine-3~carboxylie acid methyl ester and its hydrochloride and l-[2-(chrom©n-4~ yl)ethyl]-piperidine-3-carboxylic acid ethyl ester and its hydrochloride. 9 3 Example 38: Tablets, each comprising 25 sag of active ingredientfor example l-(benso~l ,4-dioxan-2-yl»iethyl)-piperidine-3-carboxylic acid methyl ester hydrochloride, can be manufactured in the following manner: Constituents (for 1000 tablets!: active ingredient .0 g lactose 100 .7 g wheat starch 7 .5 g polyethylene glycol 6000 .0 g talcum .0 g magnesium stearate 1 .8 g demineralised water q • s • Preparation: All the solid ingredients are first forced through a sieve having a mesh width of 0.6 noa. The active ingredient, the lactose, the talcum, the magnesium stearate and half of the starch are then mixed together, The other half of the starch is suspended in 40 ml of water and the suspension is added to a boiling solution of the polyethylene glycol in 100 ml of water. The starch paste formed is added to the main mixture which is then granulated, if necessary with the addition of water. The granulate is dried overnight at 35", forced through a sieve having a mesh width of 1.2 asm and compressed to form tablets approximately 6 aim in diameter which are concave on both sides. 3 4 Example 39: Tablets, each comprising 50 ag of the active ingredient, for example 1-(benzo-1,4-dioxan-2-ylmethyl) -piperidine-3-carboxylie acid methyl aster hydrochloridej, are manufactured as follows: Composition C for 10 ,000 tablets): active ingredient 500 .00 g lactose 140 »80 q potato starch 274 .70 g stearic acid .00 g talc 50 .00 g magnesium stearate 2 .50 g colloidal silica 32 „00 g ethanol q .s.

A mixture of the active ingredient„ the lactose and 194.70 g of the potato starch is moistened &dth an ethanolic solution of the stearic acid and granulated through a sieve. After drying, the remainder of the potato starch, the talc, the magnesium stearate and the colloidal silica are admixed and the mixture is compressed to form tablets that each weigh 0.1 g and that mays if desired, foe provided with dividing notches for finer adjustment of the dosage„ 100 mg of active ingredient can be incorporated in an 25 analogous manner» Example 401 Capsules,, each comprising 0„025 g of the active ingredient, for example l~(benzo-1,4-dioxan-2- ylmethyl)-piperidine-3~carboxylic acid methyl ester hydrochloride, can be manufactured as follows: Composition Cfor 1000 capsules): active ingredient 25.00 g lactose 249.00 g gelatine 2.00 g corn starch 10.00 g talc 15.00 g water q-s.

The active ingredient is mixed with the lactose and the mixture is moistened uniformly with an aqueous solution of the gelatine and is granulated by being passed through a sieve having a mesh width of from 1.2 to 1„5 ram. The granulate is mixed with the dried corn starch and the talc and 300 mg portions are filled into hard gelatine capsules (sise 1).

Example 41: In a manner analogous to that described in Examples 38 to 40, it is also possible to manufacture pharmaceutical preparations that comprise N-[2-(chroman-3—yl)ethyl]-M-(2-methoxycarbonylethy1)-amine hydrochloride as active ingredient.

Example 42: In a manner analogous to that described in Examples 38 to <1, it is also possible to manufacture pharmaceutical preparations that comprise as active ingredient a different compound of the formula I or a tautoiaer and/or a pharmaceutical ly acceptable salt thereof or a different compound of the formula IVc or a 8 6 pharmaceutically acceptable salt thereof, for example according to Examples 1 to 3/

Claims

S 7 Patent plains

1. A coapouad of the forsmla < k (i), in which either Ri represents carboxylower alkoxycarbonyl, carbamoyl., M-lower alkylcarbamoyl, N,N-di-lover alkylcarbamoyl, hydroxymethylf C^-^alkanoyloxymethylf lower alkanesulphonyloxymethyl, benzoylcxymethyl or pyridoyloxymethyl and R2 represents hydrogen, hydroxy, lower alkoxy, benzyl oxyt, C^-Cgalkanovloxyf lower alkane-sulphonyloxy, benzoyloxv, pyridoyloxy, amino, C2-C5-alkanoylamino, lower alkanesulphonvlamino, benzoylamino or pyridoylaaino, or represents hydrogen and R2 represents carboxy, lower alkoxycarbonyl, N-lower alkylcarbamoyl, H,N-di-lower alkylcarbaiaoyl, hydroxv-methyl, C2~C5alkanoyloxymethyl, lower alkanesulphonvloxy-methyl, benzoy 1 oxymethy 1 or pyridoyloxymethyl f r3 represents hydrogen or Ci-C^&lkyl f. alk represents lower alkylene that bridges the tvo ring systems by up to and including 3 carbon atoms, or alk represents lower alkylidene, the ring A is unsubstituted or is mono-, di-or poly-substituted by hydroxy, lower alkoxy, c2~c5~ alkanoyloxy, halogen having an atomic number of up to and including 53, 0^-07alkyl and/or by trif luoromethyl, the dotted line is intended to indicate the presence of a single or a double bond between the carbon atoms carrying the radicals and Rj, and either each of X and Y represents an oxygen atom and n represents 1, or X represents a methylene group, Y represents an oxygen atom and n represents 1, or X represents an oxygen atom, Y represents a methylene group and m represents 1, or X represents a direct bond, Y represents am oxygen ataia arsd a represents 2, radicals designated "lower" containing froa 1 up to and including 4 carbon atoms, ©r a tatatomer and/or salt thereof.

2. A compound of the formula 1 according to claim 1 in which Ei represents carboxy, lower alkoxycarbonyl, carbamoyl , H-lover alkylcarbamoyl or JJ,H-di-lower alkylcarbamoyl, R2 represents hydrogen, hydroxy, lower alkoxy, benzyloxy, c2~C5alkanoyloxy, lower alkane-sulphonyloxy, bensoyloxy, pyridoyloxy, aminof C2-C5-alkanoylamino, benzoylamino or pyridoylaiaino, H3 represents hydrogen or C^~Cyalkyl, alk represents lever alkylene that bridges the tvo ring systems by up to and including 3 carbon atoms, or elk represents lower alkylidene, the ring A is unsubstituted or is aono-, di~ or poly-substituted by hydroxy, lower alkoxy, C2-C5-™ alkanoyloxy, halogen having an atomic number of up to and including 53, Ci-Chalky 1 and/or by trifluoromethyl, the dotted line is intended to indicate the presence of a single or a double bond between the carbon atoms carrying the radicals Hi and R2, x represents an oxygen atom or a Methylene group, Y represents an oxygen atom and n represents l, radicals designated *lower" containing from 1 up to and including 4 carbon atoms, or a tautoiaer and/or salt thereof.

3.„ A compound of the forsmla 1 according to claim 1 i;n which either represents -^alkoxycarbonyl, carbamoyl, hydroxymethy 1 or ^-Cgalkanoyloxymethyl and R? represents hydrogen or hydroxy, or R^ represents hydrogen and R2 represents C^K^alkoxycarbonylf R3 represents hydrogen or C^-C^alkyl, alk represents C^-^alkylene that bridges the two ring systems by up to and including 3 carbon ato^is, the ring A is unsubstituted or is sub stituted, especially in the 7-position, by alkoxy, the dotted line is intended to indicate the presence of a single or as double bond between the carbon atoas carrying the radicals Rj_ and Eg, and either each of X and Y represents an oxygen atora and n represents 1, or 3C represents a methylene group, Y represents an oxygen atom and a represents l, or X represents an oxygen atoa,, Y represents a methylene group and n represents if or K represents a direct bond, Y represents an oxygen atom and a represents 2, or a tautoiaer and/or salt thereof.

4.- A compound of the formula I according to claim 1 in which represents Ci-C^alkoxycarbonyl, R2 represents hydrogen or hydroxy, R3 represents hydrogen or €^-€4" alkyl, alk represents C^~C4alkylene that bridges the two ring systems by up to and including 3 carbon atomsP the ring A is unsubstituted, the dotted line is intended to indicate the presence of a single or a double bond between the carbon atoms carrying the radicals Ri and R2, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, or a tautoiaer and/or salt thereof,

5. A compound of the formula I according to claim 1 in which represents Ci-C^alkoxycarbonyl, R2 represents hydrogen or hydroxy, R3 represents hydrogen, alk represents Methylene or ethylene, the ring A is unsubstituted, the dotted line is intended to indicate the presence of a single or a double bond between the carbon atoras carrying the radicals and R2, X represents an oxygen atom or a Methylene group, Y represents an oxygen atom and n represents 1, or a tautouer and/or salt thereof.

6. 4-Hydroxy-l~ (chroman-3-ylmethyl) -1,2, 5,6-tetrahydro- pvridine~3-carboxylic acid methyl ester or 1-(chroman-3-ylmethyl) -4-oxo~piperidine~3~carboxylic acid methyl 1 0 0 ester, l-[2-fehroman-3-yl|-ethyl3 ™1,2,5,6-tetrahydro-pyridine-3-carboxylic acid aethyl ester, x~(benso-i,4-dioxan-2-yliaethyl)~piperidine~3~carboxylic acid ae-thyl ester or 4-hydroxy-l-(b«n2o-l, 4-di©xars-2-ylaet&yl) -X,2,5,6-tetrahydropyridine-3-carboxylie ac id ©ethy1 ester or X-(benzo-1,4-dioxan~2~ylmethyl) ~4~oxopip

7.„ 1- [2- (Chroman-3~yl)-ethyl 3 -1, 2, 5, 6-tetrahydropyridine- 3-carboxylic acid, ethyl ester or a salt thereof.

8. X-(Chroman~3-ylmethyl)-1,2, 5,S-tetrahvdropyridine-3-> carboxylic acid aethyl esterP l-[2-(chrosan-3~yl)-ethyl) - 4-hydroxy-i,2,5,6-tetrahydropyridine~3-carboicylic acid aethyl ester or l-[2-(chroman-3-yl)-ethyl]-4-oxo-piperidine-3~carboxylic acid aethyl ester, 1-(bengo-l,4-dioxan-2-ylmethyl) -1,2,5, 6~tetrahydropyridine-3-carboxyiic acid methyl ester, 4-hydroxy-1-(2-methyl-ben20-l,4-dioxan-2-ylmethyl)-1,2,5, 5~tetrahydropyridine~ 3-carboxylic acid methyl ester or 1-(2-methyl-benzo-1,4-dioxan-2-ylmethyl)~4-oxopiperidine~3~carboj

9. 1-F 2- (Chroman-3-yl)-ethyl 3-piperidine-3-carboxylic acid ethyl ester, l~[2~(chroman~3~yl)-ethyl]-piperidine™ 4-carboxyl ic acid ethyl ester,, X-[2-(feenzo-l, 4-dioxan-2- 1 0 1 yl)-ethyl 3-piper idIiie-3-carboxylic acid ethyl ester, 1-[2-(benzo-1,4-dioxan-2-yl)-ethyl]-piperidine-4-carboxylic acid ethyl ester,, l-(2-(chroBasi-2-yl)-ethyl]-piperldine-3~carboxy3Lic acid ethyl ester, l-[2-(chro3aan-2-yl)-ethyl]-piperidine-4-carboxylic acid ethyl ester, cis-1-[2-(benzo-1,4-dioxan~2-yl)-ethyl]-4-benzyloxy-piperidine-3-carboxylie acid use thy 1 ester, trans-1-[2~(benzo-1,4-dioxan-2-yl)-ethyl]-4-benzyloxy-piperidine-3-carboxylic acid methyl ester,, cis-4-a®ino-l-£2-(benzo-1,4-dioxan-2-yl)-ethyl]-piperidine-3-carboxylic acid a»ide, trans-4-amino-!-[2-(benzo-1,4-dioxan~2-yl)-ethyl]-piperidine-3-carboxylic acid amide, l-[2-(chroman-4~yl)-ethyl]-1,2,5,6-tetrshydropyridine-3-carboxylic acid laethyl ester or l-[2-(chroman-4-yl)-ethyl]-piperidine-3-carboxylic acid ethyl ester or, respectively, a salt thereof.

10. A process for the manufacture of a compound of the formula I, or a tautoiaer and/or salt thereof, according to any one of claims 1 to 9, characterised in that a) a compound of the formula or a salt thereof, in which Xi represents hydroxy or reactive esterified hydroxy, is reacted with a compound of the formula /\ /\ « ID (Ila) (lib) or a tautomer and/or salt thereof,, or h) in a compound of the formula /\ J*\ « * {in) or a tautomer and/or salt: thereof, in which represents a radical that cam be converted into that is other than hydrogen,, and X5 represents a radical Ra, and Ha represents hydrogen,, hydroxyt lower alkoxy, benzyloxv, C2-C5alkanoyloxy, lower alkaneswlphonyloxy, benzoyloxy, pyridoyloxy<, amino,, Cj-Cgalkanoylamino,, lower alkane-su 1 phenyl amino £, benzoylamino or p }/r i doy 1 ast i no e X2 is converted into Ri that is other than hydrogen, or in a compound of the formula III in which X2 represents hydrogen and X5 represents a radical that: can be converted into R-jjf and represents a radical R2 other than a radical Ra, X5 is converted into R-D, or c) for the manufacture of a compound of the formula I or a tautoiaer and/or salt thereof, in which R2 represents hydroxy or amino and is other than hydrogen and represents especially lower alkoxycarbonyl, a compound of the formula in which represents a grow of the formula -CH=Rj, ~C (Y?) =R«>c -~C3I("?2) -2*2 or cyano^ wherein represents oxo or imino and represents a removable radical, or a salt thereof f is cvclised, or d) for the Manufacture of a compound of the formula 11 or a tautoiaer and/or salt, thereof, in which represents oxo or i3oino and R^ other than hydrogen and represents especially lower alkoxycarbonyl, a compound of the formula /x /\ y w a chjrj 10 3 /\ A /** AS j>> x s *■» or a tautoiaer, or in each esse a salt thereof,, is reacted with a compound of the forsnula X3-RX (Vb> or a salt thereof, in which is other than hydrogen and X3 represents halogen or lower alkoxy, or e) for the manufacture of a compound of the formula I or a tautoiaer and/or salt thereof, in which H2 represents hydroxy, lower alkoxy, benzyloxy, C2~C5alkanovloxy, lower alkanesulphonyloxy, benzoyloxy, pyridoyloxy, amino, C2-C5alkanoylamino, lower alkanesulphonvlamino, benzoyl-amino or pyridoylamino, in a compound of the formula " \ V (¥I) ii or in a salt thereof, in which represents a radical that can be converted into , X\* is converted into # or f) especially for the manufacture of a compound of the formula I or a tautomer ancl/or salt thereof,, in 'which H2 is hydrogen, hydroxy, amino, carboxy, lower alkoxycarbonyl , M-lower alkylcarbasioyl, N,N-di-lower alkylcarbamoyl or hydrorymethylism a coiapound of the formula 10 4 A/s »lk-^ """>-rsa® (vii5 * kl in which A® represents the anion of an acid and Eg represents hydrogen, lower alkoxy, benzyloxy, Cg-Cg-alkanoyloxy, lower alkanesulphonyloxy, henz©y1oscy? pyridoyloxy, protected hydroxy,, C^-Cgalleanoylamino, lower alkanesulphonylamino„ benzoylaaino, pyridoylamiino, protected amino, carboy/, lower alkoxycarbonyl, fc?-lower alkylcarbaiaoyl, M,N~di-lower alkylcarbamoyl, C2-C3-a1kanoy1oxyiaethy1, lower alkanesulphonyloxyiaethyl, benzcyloxyinethyl, pyridoyloxymethyl or etherified or protected hydroxviaethyl, the excess double bonds are reduced to single bonds, or g) for the manufacture of a compound of the formula I or a tautoiaer and/or salt thereof, in which represents carboxy, M-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or especially lower alkoxycarbonyl, a compound of the formula /\ /\ ^ in * i a jj h v/ (¥111) a «*. ® alk-js^ \li2-rj; —CH< in which Y2 represents a removable radical, or a salt thereof, is cyclised, and in the case of each of processes a) to g), a protecting group which may be present is removed, and, if desired, a compound of the formula I obtainable in accordance with the process or by other means is converted into a different compound of the formula I, an isomeric mixture obtainable in accordance with the process is separated into the components, an enantiomeric or diastereoisoxaeric mixture obtainable in 1 ©5 accordance with the process is separated into the enantiomers or diastereoisomers, respectively,, and/or a free compound o£ the formula I obtainable in accordance with the process is converted into a salt or a salt obtainable in accordance with the process is converted into the free compound of the formula I or into a different salt, radicals designated "lower" containing fro® 1 up to and including 4 carbon atoms.

11. h compound of the formula in which represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, hydroxymethyl, C2~C5alkanoylcxymethyl, lower alkanesulphonylcxymethyl, bansoyloxymethyl or pyridoyloxymethyl, R3 represents hydrogen or C^-^aikyl, alk represents lower alkylene or lower alkylidene, the ring A is unsubstituted or is mono- or poly-substituted by hydroxy, lover alkoxy, C2-053lkanoyloxy, halogen having an atomic number ©f up to and including 53, Cn-C^alkyl and/or by trif luoromethyl, and either each of 3£ and Y represents an oxygen atom and n represents 1„ or X represents a methylene group, Y represents an oxygen atom and n represents 1, or X represents an oxygen atom, Y represents a methylene group and n represents 1, or X represents a direct bond,, Y represents an oxygen atom and n represents 2e, with the proviso that in compounds of the formula I've in which the ring A is unsubstituted , each of X and Y represents oxygen, n represents 1 and H3 represents hydrogen„ alk is other than methylene if represents carbamoyl or N-methyl-, N-ethyl-, N,N-di-methyl- or N,N~diethyl-carbamoyl, radicals designated A A A Y « ® 'alk-^-CH2CH;-Ri fl (IVc) 10 8 "lower" containing from 1 up to and including 4 carbon atoms,, or as salt thereof.

12. A compound of the formal a IVc according to elaia 11 in which represents carboxy, lover alkoxycarbonyl, 5 carbamoyl, M-lower alkylcarbasaoyl or H^N-di-lower alkylcarbaiaoylR3 represents hydrogen or Ci~C7&lkyl,, alk represents lower alkylene or lower alkylidene, the ring A is unsubstituted or is ®omo~ or polv-substituted by hydroxy, lower alkoxy, C2-C5alkanoyloxy, halogen having 10 an atomic number of up to and including 53 e C^-Gj&l'kyl and/or by trifluoromethvX^ X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, with the proviso that in compounds of the formula IVc in which the ring A is unsubstituted, each 15 of X and ¥ represents oxygen, n represents 1 and R3 represents hydrogen, alk is other than methylene if represents carbamoyl or N-methyl-f M™ethyl~, N,M~di~ methyl- or N,N-diethyl-carbamoyl, radicals designated "lower" containing from 1 up to and including 4 carbon 20 atoms, or a salt thereof,

13. A compound of the formula IVc according to claim 11 in which Ri represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl , hydroxyjeethyl, C2-C5alkanoyloxyiaethyl, lower 25 alkanesulphonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl , :r3 represents hydrogen or C^-^alkyi , alk represents lower alkylene that links the ring ©yste® with the MH group shown in foraula IVc by «p to and including 3 carbon atoms, or alk represents lower alkylidene, the 30 ring A is unsubstituted or is Bono-, di- or poly- substituted by hydroxy, lover alkoxy, C2-C5alkanoyloxy, halogen having an atomic number of up to and including 53 ? Cj-e-yfelkyl and/or by trifluoromethyl^ and either each of X and Y represents an oxygen atoh and n repre 1 ©7 sents 1, or X represents a methylene group, ¥ represents an oxygen atom and a represents 1, or X represents an oxygen atom, Y represents a methylene group and jj represents 1, or 1 represents a direct bond,, Y represents an oxygen atom and a represents 2, with the proviso that in compounds of the formula IVc in which the ring A is unsubstituted, each of X and Y represents oxygen, n represents 1 and R3 represents hydrogen , alk is other than methylene if % represents carbamoyl or K-methyl- , N-ethyl-, PfM-dimethyl- or N,N~diethyl-carbamoyl, radicals designated "lower" containing from 1 up to and including 4 carbon atoms, or a salt thereof.

14. A compound of the formula IVc according to claim 11 in which Ri_ represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbaiaoyl, R3 represents hydrogen or C1-C7alkyl, alk represents lower alkylene that links the ring system with the NH group shown in formula IVc by up to and including 3 carbon atoms, or alk represents lower alkylidene, the ring A is unsubstituted or is mono-, di- or poly-substituted by hydroxy,, lower alkoxy, C2-^alkanoy loxy, halogen having an atomic number of up to and including 53 „ C1-C7alkyl and/or by trif luoromethyl, J, represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, with the proviso that in compounds of the formula IVc in which the ring A is unsubstitutedj, each of X and Y represents oxygen, n represents 1 and R3 represents hydrogen, alk is other than methylene if % represents carbamoyl or HHnethyl-, N-ethyl-, N,li-diaethyl- or N,N-diethyl-carbamoyl, radicals designated "lower" containing frosa 1 up to and. including 4 carbon atoms, or a salt thereof -

15. A compound of the formula IVc according to claim 11 in which % represents carboxy, hydroxymethyl, Cp-Cj- 1 © 8 alkanoyloxyaettoyl, C^-C.^alkoxycarbonyl or carbamoyl, R3 represents hydrogen or CjH^alfcyl, alk represents C1-C4al3cylene that links the ring systems with the »H group shown in forewla IVc by up to and including 3 5 carbon atoms„ the ring A is unsubstituted or is sub stituted, especially in the 7-position, by c^-X^alfcoxy, and either each of X and Y represents an oxygen atom and U represents l, or 3C represents a methylene group, V represents an oxygen aton and s represents 1, or X 10 represents an oxygen atom, ¥ represents a methylene group and n represents 1„ or X represents a direct bond, ¥ represents an oxygen atom and n represents 2, with the proviso that in compounds of the formula IVc in which the ring A is unsubstituted, each of X and ¥ represents 15 oxygen, n represents 1 and R3 represents hydrogen, alk is other than methylene if Rt_ represents carbamoyl s or a salt thereof.

16., A compound of the formula IVc according to claim 11 in which represents C1-C4alkoxycarbonyl, R3 represents 20 hydrogen or Cj-C^ialkyl, a 13c represents C^-^alkylene that links the ring system with the MH group shown in formula IVc by up to and including 3 carbon atoms, the ring A is unsubstituted,, X represents an oxygen atoia or a methylene group., ¥ represents an oxygen atom and n represents lf or 25 a salt thereof.

17. A compound of the formula IVc according to claim 11 in which represent© C^-C^alkoxycarbonyl,, H3 represents hydrogen, alk represents methylene or ethylene, the ring A is unsubstituted, X represents ar» oxygen atom or a 30 methylene group, ¥ represents an oxygen atom and n represents 1, or a salt thereof.

18. N-[2-(Chroman-3~yl)-ethyl]-N~{2-methoxycarbonyl-ethyl)-amine or a salt thereof,, t 0 9

19. K-(2~Jiet.hoxycarbonyle"thyl) (benzo-1,4-dioxan-2~ ylmethyl)-amine or a salt thereof.

20.- N-(2-Methoxycarbonylethyl) -H- (chroman-3-ylsaethyl) -amine, N~[2~(benao-l,4-dioxan-2-yl>-ethyl]-H-(2-methoxy~ carbonylethyl)-smine or H-(2-»et3boxycarbonylethyl)-N~(2-methylbenzo~l,4-dioxan-2-ylmethyl)-amine or, respectively, a salt thereof™

21. N-[2~(Chro*an-3-yl)-ethyl]-N-(2-carboxyethyl)-amine, N~[2—(chroman-2-yl)-ethyl]-N-(2-methoxycarbonylethyl)-amine or N-[2-(chroman-4-y 1)-ethyl]-N-(2-methoxycarbonyl- ethyl)-amine or, respectively, a salt thereof.

22. A process for the manufacture of a compound of the formula IVc, or a salt thereof, according to any one of claims 11 to 21, characterised in that h) compounds of the formulae in which one of the radicals and represents reactive esterified hydroxy and the other represents amino and S3 represents hydrogen, or Z^ represents amino and end Z3 together represent am additional bond, or optionally salts of these compounds, are reacted, with one another, or i) in a compound of the formula /\ /\ ✓*» al k~2 (Villa) (VIIlb) , /N A /* #1' » » alk-N-CH2CH:-X6 (IX) 11© in which % represents a radical "that cam be converted into Rj_, ©r In a salt thereof, 3% is converted into R1# and, if desired,, in the case of each of processes h) and i), a comparand of the formula IVc obtainable is 5 accordance with the process or by other seans is converted into a different compound of the formula IVc, an isomeric mixture obtainable in accordance with the process is separated into the components, an enantiomeric or diastereoisoaeric saixture obtainable in accordance 10 with the process is separated into the enantiomers ©r diastereoisomers, respectively., and/or a free compound of the formula IVc obtainable in accordance with the process is converted into a salt or a salt obtainable in accordance with the process is converted into the free 15 compound of the formula IVc or into a different salt„

23. A compound of the formula (IVc) slk-^i^chzchz—ri in which Hi represents carboxy, lower alkoxycarbonyl,, carbamoyl, N~lower alkylcarbamoyl, H,N-di-lover alkyl-20 carbamoyl, hydroxymethyl, Cg-Csalkanoyloacymetiiyl, lower alkanesulphonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl , H3 represents hydrogen or Ci-C7alkylt, alk represents lower alkylene or lower alkylidene, the ring A is unsubstituted or is saono- or poly-substituted by 25 hydroxy, lower alkoxy, C2~C5alkanoylQxy, halogen having an atomic number of up to and including 53, C^-Oyalkyl and/or by tri fluoromethyl, and either each of X and Tf represents an oxygen atom and n represents 1, or X represents a methylene group, Y represents an oxygen atom 30 and n represents l, or X represents an oxygen atom, Y represents a methylene group and n represents l, or X 11 1 represents a direct bond, Y represents an oxygen ato» and a represents 2, radicals designated "lover1* containing fro© 1 up t© and including 4 carbon, atons, or' a pharToa-ceutically acceptable salt thereof, for use in a method for the therapeutic and/or prophylactic treat-sent, of the human or ania&I body-

24. A compound of the formula in which Ri represents carboxy, lover alkoxycarbonyl, carbamoyl, N-lover alkylcarbamoyl or N,N-di-lower alkylcarbamoyl,, R3 represents hydrogen or C^-^alkyl, alk represents lover alkylene or lower alkylidene, the ring A is unsubstituted or is mono- or poly-substituted by hydroxy, lower alkoxy, C2-C5&lkanoyloxy, halogen having an atomic number of up to arsd including 53, C1~C7alkyl and/or by trif luoromethyl, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, radicals designated "lower" containing from 1 up to and including 4 carbon atoms, or a. pharmaceutical ly acceptable salt thereof, for use in a method for the therapeutic and/or prophylactic treatment of the human or animal body,

25.,. a compound according to any one of claims 1 to 9 and 11 to 21 or if appropriate a tautoiaer arx2/or a pharmaceutical ly acceptable salt thereof for use in a method for the therapeutic and/or prophylactic treatment of the human or animal body „ A A, /■' \* d> m alk-J-CH2CH2-Ri n (I¥c)

26. A compound according to any one of claims 2f 4, 6f 8, 12, 14 and IS to 20 or if appropriate a tautoiaer and/or a pharsaaceutically acceptable salt thereof for use in a method for the therapeutic and/or prophylactic treatment of the human or aniaal body.

27.„ • h compound of the formula I've according to claim 23 in which % represents carbamoyl or N~aethyl-, N-ethyl-, N„N-diiaethyl- or N,N-diethyl-carbamoyl, R3 represents hydrogen, alk represents methylene, the ring A is unsubstituted, each of X and I represent© an oxygen aton and a represents 1, or a pharmaceutic&lly acceptable salt thereof, for us© in a method for the therapeutic and/or prophylactic treatment of the human or animal body.

28. A pharmaceutical preparation comprising as active ingredient a compound according to any one of claims i to 9„ 11 to 21, 23 and 25 or if appropriate a tautomer and/or a pharmaceutical ly acceptable salt thereof,, optionally together with customary pharmaceutical adjuncts.

29. h pharmaceutical preparation comprising as active ingredient a compound according to any one of claims 2, 4, 6„ S, 12, 14, 16 to 20, 24, 26 and 27 or if appropriate a tautomer and/or a pharmaceutics.lly acceptable salt thereof,, optionally together with customary pharmaceutical adjuncts.

30.- The use of a compound according to any one of claims 1 to 9, 11 to 21, 23 and 25, or if appropriate a tautomer and/or a pharmaceutically acceptable salt thereof, for the manufacture of a pharmaceutical preparation., for example a nootropic.

31. A compound according to claim 1, substantial1y as hereinbefore described and exemplified.

32. A process for the manufacture of a compound according to claim 1, substantially as hereinbefore described and exemplified.

33. A compound according to claim 1, whenever manufactured by process claimed in claim 10 or 32.

34. A compound according to claim 11, substantially as hereinbefore described and exemplified.

35. A pharmaceutical preparation according to claim 28 or 29, substantially as hereinbefore described and exemplified. f. r. kelly & co., agents for the applicants