AU617988B2 - Hydrogenated 1-benzooxacycloalkylpyridinecarboxylic acid compounds - Google Patents

Abstract

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

Description

COMMONWEALTH OF AUSTRALIA 6 1 I9SO PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class I t. Class Application Number: Lodged: Complete Specification Lodged- Accepted: Published: ~r~ckity Roleted Art

I

~.Name of Applicant: 4 'k Address of Applicant: Aciual Inventor: CIBA-GEIGY AG Klybeckstrasse 141, 4002 Basle, Switzerland WOLFGANG FROSTL VH PD C- co- -1DA3r- [3 Address for Service Complete Specification for the inven~tion entitled: HYDROGENATED 1-BENZOOXACYCLOALKYLPYRIDINECARBOXYLIC ACID COMPOUNDS The following statement is a full description of this invention, including the best method of performing it known to us 4-1 5969/+ Hlydrogenated 1 -benzooxacycloalkylpyridinecarboxylic acid compounds The invention relates to novel hydrogenated 1 -benzooxacycloalkylpyridinecarboxylic acid compounds of the formula 0 00 *00 0 0 00 0 0 0 0*4 0 04 0 0 0 0 0 00 000*00 00 0 00 0 0 0 op.

00 0 0 0 90 00004 *oo* 00 O 0 0 00 00 0 0000 04~* 00 0 0 x A fl ~alk- -2 R 1 in which either RI represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-dilower alkylcarbamoyl or optionally acylated hydroxymethyl and R 2 represents hydrogen, an optionally etherified or acylated hydroxy group or an optionally 2 acylated amino group, or R 1 represents hydrogen and

R

2 represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkyl carbamoyl or optionally acylated hydroxymethyl,

R

3 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 trifluoromethyl, the dotted line is intended j indicate the presence of a single or a double bond, 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 repre- S 5 sents a methylene group and n represents 1, or X represents a direct bond, Y represents an oxygen atom and n represents 2, and to their tautomers and/or *o.Ou salts, to the use of these compounds, to processes for their manufacture and to pharmaceutical compositions containing a compound of the formula I or a tautomer and/or a pharmaceutically acceptable salt thereof.

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

Acyl in acylated hydroxymethyl R 1 and R2, respectively, S and also in acylated hydroxy R 2 and acylated amino R2 respectively, is, for example, acyl derived from an organic Scarboxylic or sulphonic acid.

Acyl derived from an organic carboxylic acid is, for example, the radical of an aliphatic or monocyclic- 0 aromatic carboxylic acid, such as lower alkanoyl or optionally substituted benzoyl, and also pyridoyl.

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, 3 lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R 2 represents hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group, R 3 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 trifluoromethyl, the dotted line is intended to indicate the presence of a single or a double bond, X represents an oxygen atom or a methylene I group, Y represents an oxygen atom and n represents o ,o 1, and to their tautomers and/or salts, to the use of j these compounds, to processes for their manufacture and to pharmaceutical compositions containing such a compound of the formula I or i tautomer and/or a pharmaceutically acceptable salt thereof.

i Tautomeric forms of compounds of the formula I exist, for example, when R 2 represents hydroxy or amino and the dotted line is intended to indicate the ,it presence of a double bond. That is to say, the enols and enamines, respectively, of the formula I are in equilibrium with the corresponding keto and ketimine tautomers, respectively, of the formula i i i I A i Sa 1k-<

R

1

R

1 4 o o o o o 0 a o o 0 a 0 o o 0* 0 0 0 0O O 0 in which R' represents oxo or imino. 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-atom) (for example the C-atom having the radical

R

3 they may be, for example, in the form of pure enantiomers or enantiomeric mixtures, such as racemates, and if, also, there is at least one further chiral centre present (for example the C 4 -atom of a 4substituted piperidine radical and/or the C 3 -atom of a 3-substituted piperidine radical), they may also be in the form of diastereoisomers, diastereoisomeric mixtures or mixtures of racemates. Thus, for example, geometrical isomers with respect to R 1 and R 2 such as cis- and trans-isomers, may be formed if R 1 and R 2 are other than hydrogen.

Salts of compounds of the formula I and their tautomers are especially corresponding acid addition salts, preferably pharmaceutically 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 alkanecarboxylic acids, 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 P-toluene-sulphonic acid.

If, for example, R 1 or R 2 represents carboxy, corresponding compounds may form salts with bases.

Suitable salts with bases are, for example, correspond- 5 ing 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 alkylamines, hydroxy-lower alkylamines, for example mono-, di- or tri-hydroxy-lower alkylamines, hydroxy-lower alkyl-lower alkylamines or polyhydroxylower alkylamines. Cyclic amines are, for example, morpholine, thiomorpholine, piperidine or pyrrolidine.

As mono-lower alkylamines there come into consideration, for example, ethylamine or tert.butylamine; as di-lower alkylamines, for example, I diethylamine or diisopropylamine, and as tri-lower alkylamines, for example, trimethylamine or triethyl- Samine. Corresponding hydroxy-lower alkylamines are, Sfor example, mono-, di- or tri-ethanolamine, and Shydroxy-lower alkyl-lower alkylamines are, for example, N,N-dimethylamino- or N,N-diethylamino-ethanol, and as polyhydroxy-lower alkylamine there comes into consideration, for example, glucosamine.

i Also included are salts that are unsuitable for pharmaceutical 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 J otherwise, radicals or compounds designated "lower" are to be understood as meaning especially those radicals or compounds which contain up to and including 7, especially up to and including 4, carbon atoms.

Lower alkoxy is, for example, C 1

-C

4 -alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert.-butoxy.

Lower alkyl is, for example, CI-C 4 -alkyl, such 6 4

I

.4 i tg J1 a. a *e a at r Co a: C as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl or tert.-butyl, and also includes

C

5

-C

7 -alkyl radicals, that is to say pentyl, hexyl or heptyl radicals.

Lower alkylene alk is, for example, CI-C 4 alkylene that bridges the two ring systems especially by up to and including 3 carbon atoms and may be, 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.

Lowar alkylidene alk is, for example, C 1

-C

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

Lower alkanoyl is, for example, C 2

-C

5 alkanoyl, such as acetyl, propionyl, butyryl, isobutyryl or pivaloyl.

Lower alkanoyloxy is, for example, C 2

-C

5 alkanoyloxy, such as acetoxy, propionyloxy, butyryloxy, isobutyryloxy or pivaloyloxy.

Lower alkoxycarbonyl is, for example, C 2

-C

5 alkoxycarbonyl, such as methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, isobutoxy- or tert.-butoxycarbonyl.

N-lower alkylcarbamoyl is, for example, N-Cl-C 4 -alkylcarbamoyl, such as N-methyl-, N-ethyl-, N-(n-propyl)-, N-isopropyl-, N-(n-butyl)-, N-isobutyl- or N-tert.-butyl-carbamoyl.

N,N-di-lower alkylcarbamoyl is, for example, N,Ndi-C 1

-C

4 -alkylcarbamoyl, in which the two N-alkyl groups may be the same or different, such as N,Ndimethyl-, N,N-diethyl-, N,N-diisopropyl- or N-butyl- N-methyl-carbamoyl.

7 Optionally substituted phenyl-lower alkoxy is, for example, phenyl-C1-C 4 -alkoxy optionally substituted in the phenyl moiety, such as benzyloxy, p-chlorobenzyloxy, 1-phenylethoxy or 1-(p-bromophenyl)-nbutoxy.

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

Lower alkanesulphonyl is, for example, C 1

-C

4 alkanesulphonyl, such as methane- or ethane-sulphonyl.

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

The compounds of the formula I, their tautomers and/or their pharmaceutically acceptable salts have, for example, valuable pharmacological, especially nootropic, properties. Thus, for example, in mice, in S* the Two-Compartment Passive Avoidance Test model according to Mondadori and Classen, Acta Neurol.

Scand. 69, Suppl. 99, 125 (1984), at dosages of a oi" 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 symp'toms of cerebral insufficiency, especially memory disorders.

The invention therefore relates also to the use of -8- 8 compounds of the formula I, their tautomers and/or their pharmaceutically acceptable salts for the manufacture of medicaments, especially nootropics, for the treatment of the symptoms of cerebral insufficiency, especially memory disorders. The commercial formulation of the active ingredients may also be included.

The invention relates especially to compounds of the formula I in which either R, represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulphonyloxymethyl, Lenzoyloxymethyl or pyridoyloxymethyl and R 2 represents hydrogen, hydroxy, lower alkoxy, benzyloxy, S: lower alkanoyloxy, lower alkanesulphonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino, lower alkanesulphonylamino, benzoylamino or pyridoylamino, or R 1 represents hydrogen and R 2 Srepresents carboxy, lower alkoxycarbonyl, carbamoyl, N- Slower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulphonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, R 3 represents hydrogen or lower alkyl, alk represents lower alkylene that bridges the two ring systems by up to and including 3 carbon atoms, or alk Srepresents 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, 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 n represents 1, or X *I I 9 represents a direct bond, Y represents an oxygen atom and n represents 2, for example compounds of the formula I in which R 1 represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R 2 represents hydrogen, hydroxy, lower alkoxy, benzyloxy, lower alkanoyloxy, lower alkanesulphonyloxy, benzoyloxy, pyridoyloxy, amino, lower alkanoylamino, benzoylamino or pyridoylamino, R 3 represents hydrogen or lower alkyl, 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-, or poly-substituted by S" 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, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, and to their tautomers and/or salts.

The invention relates more especially to compounds o: of the formula I in which either RI represents

C

1

-C

4 -alkoxycarbonyl, such as methoxy- or ethoxycarbonyl, carbamoyl, hydroxymethyl or C2-C alkanoyloxymethyl, such as acetoxymethyl, and R S*represents hydrogen or hydroxy, or RI represents hydrogen and R 2 represents Cl-C 4 -alkoxycarbonyl, such as ethoxycarbonyl, R 3 represents hydrogen or

C

1

-C

4 -alkyl, such as methyl, alk represents SCl-C 4 -alkylene that bridges the two ring systems by I 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

1

-C

4 -alkoxy, such as methoxy, the dotted line is intended to indicate the presence of a single or a double bond, and either each of X and Y represents an 117i 10 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 2, for example compounds of the formula I in which R 1 represents C 1

-C

4 -alkoxycarbonyl, such as methoxycarbonyl, R 2 represents hydrogen or hydroxy, R 3 represents hydrogen or

C

1

-C

4 -alkyl, such as methyl, alk represents

C

1

-C

4 -alkylene that bridges the two ring systems by up to and including 3 carbon atoms, such as methylene rco or ethylene, the ring A is unsubstituted, the dotted line is intended to indicate the presence of a single or a double bond, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and o n represents 1, and to their tautomers and/or salts.

0* The invention relates especially to compounds of the formula I in which Ri represents Ci-C 4 alkoxycarbonyl, such as methoxy- or ethoxy-carbonyl,

R

2 represents hydrogen or hydroxy, R 3 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, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, and to o. their tautomers and/or salts.

The invention relates most especially to compounds of the formula I in which R 1 represents C 1

-C

4 alkoxycarbonyl, such as methoxycarbonyl, R 2 represents hydrogen, R 3 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, X represents an oxygen atom or a methylene group, Y represents an v oxygen atom and n represents 1, or in which R, Srepresents C 1

-C

4 -alkoxycarbonyl, such as methoxycarbonyl, R 2 represents hydroxy, R 3 represents hydrogen, alk represents methylene, the ring A is unsubstituted, the dotted line is intended to indicate the presence of a double bond, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, and in each case to their-tautomers 1 and/or salts.

The invention relates specifically to the novel compounds mentioned in the Examples and to processes for their manufacture.

i The present invention relates also to a process I for the manufacture of compounds of the formula I, I a i their tautomers and/or their salts, for example characii I\ a) a compound of the formula 0 .CH2 S/ (IIa), A 41 or a salt thereof, in which X 1 represents hydroxy or reactive esterified hydroxy, is reacted with a compound of the formula -12- HN R S\2 (IIb),

R

*a tautomer and/or salt thereof, i a or b) in a compound of the formula S a n alk- 'o 6 0 2 .a tautomer and/o r salt thereof, in which X, represents a radical that can be converted into R, that is other than hydrogen, and X 5 represents a radical Ra, and R a represents hydrogen, an optionally etherified or acylated hydroxy group or an optionally acylated amino group,

X

2 is converted into R1 that is other than hydrogen, or in a compound of the formula III in which X 2 represents hydrogen and X 5 represents a radical that

I_~

13 can be converted into Rb, and Rb represents a radical R 2 other than a radical Ra,

X

5 is converted into Rb, or c) for the manufacture of a compound of the formula I, a tautomer and/or salt thereof, in which R 2 represents hydroxy or amino, and in which R 1 is other than hydrogen and represents especially lower alkoxycarbonyl, a compound of the formula X R

A

(CH) CH -Y 0 6 .o CH2 n CH2-Y1 alk-N (IV), 0 a CH2R 1 in which Y1 represents a group of the formula -CH=R',

-C(Y

2

-CH(Y

2

)-R

2 or cyano, wherein R represents oxo or imino and Y 2 represents a removable radical, or a salt thereof, is cyclised, or d) for the manufacture of a compound of the formula SI', a tautomer and/or salt thereof, in which R 2 represents oxo or imino and the dotted line is intended to indicate the presence of a single bond, and in which as~rto .l R I is other than hydrogen and represents especially lower alkoxycarbonyl, a compound of the formula x (CH 2 (Va) alk-N 14 or a tautomer or a salt thereof, is reacted with a compound of the formula

X

3

-R

1 (Vb), or with a salt thereof, in which R 1 is other than hydrogen and X 3 represents halogen or lower alkoxy, or e) for the manufacture of a compound of the formula I, a tautomer and/or salt thereof, in which R 2 represents an optionally etherified or acylated hydroxy group or an optionally acylated amino group, in a compound of the formula A a k- (VI), 9. I I

R

•ee 11 I or in a salt thereof, in which X 4 represents a radical that can be converted into R 2

X

4 is converted into R 2 or f) especially for the manufacture of a compound of the formula I, a tautomer and/or salt thereof, in which R2 is other than etherified or acylated hydroxy, other than acylated amino and other than acylated hydroxymethyl, a compound of the formula 15 R (VII), in which A 0 represents the anion of an acid, and R" represents hydrogen, etherified, esterified or protected hydroxy or acylated or protected amino or carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or etherified, acylated or protected hydroxymethyl, the S**2 excess double bonds are teduced to single bonds, or g) for the manufacture of a compound of the formula 00 I, a tautomer and/or salt thereof, in which R 2 represents carboxy, carbamoyl, N-lower alkylcarbamoyl, SN,N-di-lower alkylcarbamoyl or especially lower alkoxyfcarbonyl, a compound of the formula 0

AJ

000(H H2) n a 1 a s Hhr-R2 (VIII), CH(Y2)-R 1 in which Y 2 represents a removable radical, or a salt thereof, is cyclised, and, in the case of each of processes a) to a ~16 protecting group which may be present is removed, and, if desired, a compound obtained in accordance with the process or by other means is converted into a different compound of the formula I, an isomeric mixture obtained in accordance with the process is separated into the components, an enantiomeric or diastereoisomeric mixture obtained in accordance with the process is separated into the enantiomers or diastereoisomers, respectively, a free compound of the formula I obtained in accordance with the process is converted into a salt, and/or a salt obtained in accordance with the process is converted into the free compound of the formula I or into a different salt.

The reactions described in the variants hereino before and hereinafter are carried out in a manner o* known per se, for example in the absence, or customarily in the presence, of a suitable solvent or diluent or a mixture thereof, 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 200 to approximately 1500, 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 IIa and IIb, III, IV, Va and Vb, VI, VII and VIII, which are mentioned hereinbefore and hereinafter and which were developed for the manufacture of the compounds of the formula I, their tautomers and salts, are in some cases known or they can be manufactured likewise by methods known per se, for example analogously to the process variants described hereinbefore.

Starting materials having basic centres may, for 17 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 in the case of compounds of the formula IIb when R 2 represents hydroxy and the dotted line is intended to indicate the presence of a double bond.

Variant a): Reactive esterified hydroxy is especially hydroxy 'esterified by a strong inorganic acid or organic sulphonic acid, for example halogen, such as chlorine, 0 bromine or iodine, sulphonyloxy, such as hydroxy- 909o9 sulphonyloxy, halosulphonyloxy, for example fluorosulphonyloxy, lower alkanesulphonyloxy optionally substituted, for example, by halogen, for example methane- or trifluoromethane-sulphonyloxy, cycloalkanesulphonyloxy, for example cyclohexanesulphonyloxy, or benzenesulphonyloxy optionally substituted, for example, by lower alkyl or by halogen, for example p- 0 •bromophenyl- or p-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, triphenylmethylides, di-lower alkylamides, amino-lower alkylamides or lower alkylsilylamides, or naphthaleneamines, lower alkylamines, basic heterocycles, ammonium 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-(aminopropyl)-amide or bis-(tri- 18 methylsilyl)-amide, or dimethylaminonaphthalene, di- or tri-ethylamine, pyridine, benzyltrimethylammonium hydroxide, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU).

The starting materials of the formulae IIa and IIb are in some cases known or they can be manufactured analogously to the known starting materials.

Variant b): A radical X 2 that can be converted into R 1 that is other than hydrogen, or a radical X5 that can be converted into a radical Rb, respectively, is, for example I functionally modified carboxy other than R 1 or Rb, .o9 respectively, such as cyano, anhydridised carboxy, optionally substituted amidino, optionally esterified or anhydridised carboximidoyl, esterified or amidated S 1carboxy other than esterified or amidated carboxy R 1 tri-lower alkoxy- or tri-halo-methyl.

Anhydridised carboxy is, for example, carboxy S' anhydridised with a mineral acid, such as a hydrohalic S'.r 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 Schlorocarbonyl, lower alkanoyloxycarbonyl, such as acetoxycarbonyl, or lower alkoxycarbonyloxycarbonyl, such as ethoxycarbonyloxycarbonyl.

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 halocarboximidoyl, for example lower alkoxy-, such as ethoxy-, or chloro-carboximidoyl, respectively.

-19- Tri-lower alkoxy- or tri-halo-methyl is, for example, trimethoxymethyl or trichloromethyl, respectively.

Radicals Rb are, for example, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,Ndi-lower alkylcarbamoyl or optionally acylated hydroxymethyl radicals R 2 X2 can be converted into RI that is other than hydrogen, for example, by solvolysis, just as Xg can be converted into a radical Rb, for example, by solvolysis. Solvolysis agents are, for example, water, lower alkanols corresponding to the desired esterified carboxy R and R 2 respectively, ammonia, or amines corresponding to the desired amidated carboxy group R 1 and R respectively. The treatment with a corresponding sol- S.volysis 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 mineral acids, for t- example sulphuric acid or a hydrohalic acid, for example hydrochloric acid, sulphonic acids, for example lower alkanesulphonic or optionally substituted benzene- 1 sulDhonic acids. for examnle methane- or n-tol-n ne- 4 4 *0.4 40 *r 4L It r .4.

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 especially sodium or potassium hydroxide.

In the solvolysis, the cyano group, anhydridised carboxy, optionally substituted amidino, optionally esterified or anhydridised carboximidoyl, esterified or amidated carboxy other than esterified or amidated carboxy R 1 and R 2 respectively, tri-lower alkoxymethyl or trihalomethyl is hydrolysed to carboxy. Lower alkanoyloxy radicals which may be present at ring A may also be hydrolysed to hydroxy in the course of the hydrolysis.

Cyano, anhydridised carboxy, and esterified or amidated carboxy other than esterified or amidated carboxy R and R 2 respectively, are alcoholysed, for example with a suitable lower alkanol, to esterified carboxy

R

1 and R2, respectively, and cyano and anhydridised carboxy are ammonolysed or aminolysed, respectively, for example, with ammonia or with an amine corresponding to the amidated carboxy R 1 or R2, respectively.

The starting material of the formula III can be manufactured, for example, in a manner analogous to that described under Variant a) by reacting a compound I of the formula S* *lk-X 1 with a compound of the formula 4R H 5 (IIIa) ii (CH) x 2 a tautomer and/or salt thereof, in the presence of one of the mentioned bases.

Compounds of the formula III in which X 2 represents a radical that can be converted into R| that is other than hydrogen and X 5 represents hydroxy or amino, can advantageously'be manufactured also by cyclisation of a compound of the formula HN X 5 (lia), a tautomer 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 R, that is other than hydrogen and X 5 represents hydroxy or amino, can advantageously 'be manufactured also by cyclisation of a compound of the formula i-A -21- A ._CH -Y S( 2 )n 2 1 alk- (IVg), in which Y 1 represents a group of the formula -CH=R',

-C(Y

2

-CH(Y

2

)-R

2 or cyano, wherein R' represents oxo or imino, R 2 represents hydroxy or amino, and Y represents a removable radical, or a salt thereof, the operation being carried out, for example, in a manner analogous to S o that given in Process Variant c) 9..

o o j 9 Variant c): Removable radicals Y2 in groups of the formula -C(Y or -CH(Y 2

)-R

2 are, for example, reactive ester- 2 2 ified hydroxy groups, such as hydroxy esterified by a strong inorganic acid or organic sulphonic acid, for example halogen, i- such as chlorine, bromine or iodine, sulphonyloxy, such as I hydroxysulphonyloxy, halosulphonyloxy, for example fluorosulphonyloxy, lower alkanesulphonyloxy optionally substituted, for example, by halogen, for example methane- or trifluoromethane-sulphonyloxy, cycloalkanesulphonyloxy, for example cyclohexanesulphonyloxy, or benzenesulphonyloxy optionally substituted, for example, by lower alkyl or by halogen, for example p-bromophenyl- or p-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 reaction, especially in the presence of one of the bases mentioned in Variant a) and with subsequent working-up by means of hydrolysis.

I~ i L IL I 22 In a preferred embodiment, for example a compound of the formula X R

IA

S (CH 2 (IVa) alk-N 2 -CH -R 1 62 1 in which R' 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 sodium methoxide or sodium ethoxide.

During this treatment, the compound IVa cyclises to form a compound of the formula I in which the dotted line indicates in this case that a double bond is not present and R 2 represents hydroxy or amino. Starting materials of the formula IVa are obtained, for example, S by reacting a reactive alkyl ester of the formula 1 t X R3

S

A (IIa), •Y 2 n alk-X 1 in which X, is reactive esterified hydroxy, with a P compound of the formula H2N-CH 2

-CH

2 -R (IVb) and reacting the resulting intermediate of the formula 23

H

2 n (IVc) alk- -CH2CH 2-R 1

H

with acrolein or with an optionally functionally modified aldehyde of the formula Y 1

-CH

2

-CH

2 -CH=R2 (IVd; Y, reactive esterified hydroxy; R' oxo or imino).

In another preferred form of Variant a 0 o 0 compound of the formula IV in which Yj and Ri represent *o lower alkoxycarbonyl,.that is to say in which Y 1 represents a group of the formula -C(Y in which group R' represents oxo and the removable radical Y 2 represents 02 etherified hydroxy in the form of a lower alkoxy group, is cyclised to form the corresponding compound of the 0 a formula I' in which R' represents oxo.

For the manufacture of the last-mentioned starting S .compounds of the formula IV, it is possible to use as starting materials, for example, compounds of the 0 formula o« X R 0 0 0 4 I L S(CHn (Ie), alk-NH 2 or salts thereof, which are obtainable, for example, by reduction of the corresponding nitriles, and to react them with at least 2 mols of a compound of the formula 24 (IVf) Variant d): The C-acylation according to the process can be effected especially in the presence of one of the bases mentioned in Variant but especially advantageously by means of a metal base, such as lithium diisopropylamine or n-butyllithium, optionally in the presence of chlorotrimethylsilane.

I The reaction of a compound of the formula .X R A I I a alk-X 1 S" with a compound of the formula S t 4i 4t 1 HN (Vc), I or with a salt thereof, analogously to the N-alkylation according to Variant a) in the presence of one of the mentioned bases, results in the starting material of the formula Va.

25 Variant e): Radicals X 4 that can be converted into R 2 are, for example, radicals that can be converted into a group R 2 by solvolysis, that is to say by reaction with a compound of the formula R 2 H or a salt thereof, for example reactive esterified hydroxy groups, such as halogen atoms, for example chlorine, bromine or iodine.

Radicals X 4 that can be converted into hydroxy R 2 are also diazonium groups, for example of the formula

G

-N

2 A in which A 0 represents the anion of a strong acid, such as a mineral acid, for example the chloride or sulphate ion.

I

o 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, S.4 such as pyridine, or a quaternary ammonium hydroxide, such as benzyltrimethylammonium hydroxide, or by using the compound VIa in the form of a metal salt, for example of the formula R 2 N (VIb) in which MG represents an alkali-metal cation, such as the sodium ion. The operation is advantageously carried out in o the presence of a solvent or diluent, for example in an excess of the reactant VIa 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 00 to 120 0 C, and/or under inert gas, such as nitrogen.

The solvolysis of radicals X4 to groups R 2 can optionally be combined with the solvolytic conversion of solvolysable groups R 1 into other groups R 1 according to the invention; for example in the ammonolysis of radicals X 4 to amino R 2 if desired

A

26 also lower alkoxycarbonyl groups R, or other groups Rq that can be solvolysed to carbamoyl R 1 can be ammonolysed to form carbamoyl groups R 1 at the same time.

For the manufacture of starting compounds of the formula VI and the salts thereof, for example compounds of the formula IIa Sy H2 (IIa) alk-X 1 0 I are used as starting materials and are reacted with a corresponding compound of the formula H 4 (VIa), a b& 1 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 X 4 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 R 2 represents hydroxy and the Sdotted line indicates the presence of a single bond, or a salt thereof, with a halogenating agent, such as phosphorus trichloride or pentachloride or thionyl i- -27chloride, it being possible to obtain the corresponding compounds of the formula I and their salts, for example, in a manner analogous to that described under Process Variant a) or c).

Variant f): The anion AP is, for example, the anion of a strong protonic acid, for example a halide ion, such as a chloride, bromide or iodide ion, or a sulphonate ion, such as an optionally substituted lower alkane- or benzene-sulphonate ion, for example the methanesulphonate, ethanesulphonate or E-bromophenylsulphonate or p-toluenesulphonate ion. R" is especially hydrogen, etherified hydroxy R 2 or protected hydroxy, but may S* also be carboxy, lower alkoxycarbonyl, carbamoyl, Nlower .alkylcarbamoyl, N,N-di-lower alkylcarbamoyl R 2 or etherified or protected hydroxymethyl. Protected hydroxy is, for example, silyloxy, such as tri-lower alkylsilyloxy, for example trimethylsilyloxy, but may also be triphenyl-lower alkoxy, for example trityloxy.

Protected amino is, for example, silylamino, such as tri-lower alkylsilylamino, for example trimethylsilylamino, but may also be phenyl-, diphenyl- or triphenyllower alkylamino, such as benzylamino, diphenylamino or *i tritylamino. Etherified hydroxymethyl is, for example, lower alkoxymethyl, such as methoxy- or ethoxy-methyl, S t or optionally substituted phenyl-lower alkoxymethyl, i for example phenyl-C 1

-C

4 -alkoxymethyl substituted in the phenyl moiety, such as benzyloxy-, E-chlorobenzyloxy-, '-phenylethoxy- or 1-(p-bromophenyl)n-butoxy-methyl. Protected hydroxymethyl is, for example, silyloxymethyl, such as tri-lower alkylsilyloxy-, for example trimethylsilyloxy-methyl, but may also be triphenyl-lower alkoxy-, for example trityloxy-methyl.

28- The reduction of the excess double bonds is effected by treatment with a suitable reducing agent, for example by hydrogenation in the presence of a hydrogenation catalyst, by reduction with a hydridetransfer reagent or by reduction with a metallic reduction system consisting of metal and a protonremoving agent.

Hydrogenation catalysts that come 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(triphenylphosphine)rhodium(I) halide, for example chloride, or Raney nickel, which are optionally supported on a carrier, such as activated carbon, o alkali metal carbonate or sulphate or a silica gel.

Suitable as hydride-transfer reagents are, for example, a *o0 suitable light metal hydrides, especially alkali metal aluminium hydrides or borohydrides, such as lithium aluminium hydride, lithium triethylborohydride, sodium borohydride, sodium cyanoborohydride, or tin hydrides, oo such as triethyl- or tributyl-tin hydride, or diborane.

The metal component of the metallic reduction system is, for example, a base metal, such as an alkali metal or alkaline earth metal, for example lithium, sodium, potassium, magnesium or calcium, or a transition metal, for example zinc, tin, iron or titanium, whilst as proton-removing agents there are suitable, for example, protonic acids of the kind mentioned hereinbefore, such as hydrochloric or acetic acid, lower Salkanols, such as ethanol, and/or amines or ammonia.

Such systems are, for example, sodium/ammonia, zinc/hydrochloric acid, zinc/acetic acid or zinc/ethanol.

The manufacture of starting compounds of the formula VII is effected, for example, by reacting compounds of the formula 29 X R

I

A

(CH

2 alk-X

I

a) in which Xi represents reactive esterified hydroxy 4 corresponding to the anion A with compounds of the formula S **0 (VIIa), e* or with a salt thereof, the operation being carried o out, for example, in a manner analogous to that described in Process Variant a).

I .Variant g): Removable radicals Y2 in compounds VIII are, for II 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, sulphonyloxy, such as hydroxysulphonyloxy, halosulphonyloxy, for example 1 fluorosulphonyloxy, lower alkanesulphonyloxy optionally substituted, for example, by halogen, for example methane- or trifluoromethane-sulphonyloxy, cycloalkanesulphonyloxy, for example cyclohexanesulphonyloxy, or benzenesulphonyloxy optionally substituted, for 30 example, by lower alkyl or by halogen, for example p-bromophenyl- or E-toluene-sulphonyloxy, or etherified hydroxy groups, for example lower alkoxy or optionally substituted phenyl-lower alkoxy.

The cyclisation can be carried out, for example, in the presence of one of the bases mentioned under Variant especially in the presence of an alkali metal lower alkoxide, for example with sodium methoxide or ethoxide.

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

I

R

CH2n \y (IVh), alk-N-CH 2

CH

2

CH

2

-R

2

H

to *or a salt thereof, with a compound of the formula Y2-CH2-CH(Y2

)-R

I (IVi).

In the starting materials of the formulae IIb, III j and IIIa, a hydroxy group R 2 may be in etherified form and a hydroxy or amino group R 2 may also be in intermediately protected form, just as a hydroxymethyl group R 2 in compounds IIb may be in etherified or intermediately protected form. Protected hydroxy is, for example, silyloxy, such as tri-lower alkylsilyloxy, for example trimethylsilyloxy, but may also be triphenyl-lower alkoxy, for example trityloxy.

Protected amino is for example, silylamino, such as trilower alkyl silylamino, for example trimethylsilylamino, but may also be phenyl-, diphenyl- or triphenyl-lower alkylamino, such as benzylamino, 31 diphenylmethylamino or tritylamino. Etherified hydroxymethyl is, for example, lower alkoxymethyl, such as methoxy- or ethoxy-methyl, or optionally substituted phenyl-lower alkoxymethyl, for example phenyl-Ci-C 4 alkoxymethyl optionally substituted in the phenyl moiety, such as benzyloxy-, p-chlorobenzyloxy-, 1phenylethoxy- or 1--(p-bromophenyl)-n-butoxy-methyl.

Protected hydroxymethyl is, for example, silyloxymethyl, such as tri-lower alkylsilyloxy-, for example trimethylsilyloxy-methyl, but may also be triphenyllower alkoxy-, for example trityloxy-methyl.

The freeing of intermediately protected radicals

R

2 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 interi. mediately protected hydroxy, amino or hydroxymethyl groups R" in starting materials of the formula VII and VIIa, respectively, 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 Sthe formula I.

For example, esterified or amidated carboxy groups R S1 1 and R2, respectively, can be hydrolysed to carboxy R1 and R2, 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

R

1 and R2, respectively, can also be converted into other esterified carboxy groups R 1 and 32

R

2 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 acid, or a corresponding alkali metal alcoholate or an alkali metal hydroxide, or converted into amidated carboxy R and R 2 respectively, by reaction with ammonia or with a corresponding amine having at least one hydrogen atom.

Free carboxy R 1 and R 2 respectively, can be converted into esterified carboxy R 1 and R 2 respectively, in customary manner, for example by treatment with a corresponding alcohol in the presence of a mineral acid, for exampli sulphuric acid, or by conversion into a halide and subsequent reaction with a correspcoding alcohol, for example in the presence of pyridine or triethylamine, or by conversion into an alkali metal salt and subsequent reaction with a reactive ester of the corresponding alcohol, such as a corresponding halide.

o Likewise, a carboxy compound can be esterified with a corresponding alcohol using a dehydrating agent, such as N,N'-dicyclohexylcarbodiimide. Free or esterified carboxy R 1 and R 2 respectively, can be converted into amidated carboxy R 1 and R 2 respectively, also by reaction with ammonia or an amine having at least one hydrogen atom and dehydration of the intermediately formed ammonium Ssalt, for example by heating or by means of a dehydrating Sagent, such as N,N'-dicyclohexylcarbodiimide, or by l conversion into the halide and 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 alkanecarboxylic acid anhydride or halide into lower alkanoyloxy or converted by reaction with a reactive ester, especially a hydrobromic or hydro-

A

_ZZZ= 1 33chloric 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 an analogous manner, it is also possible to hydrolyse etherified or acylated hydroxy R 2 to hydroxy.

In corresponding manner, furthermore hydroxymethyl

R

1 and R 2 respectively, can be esterified, for example converted by treatment with a lower alkanecarboxylic acid Sanhydride or halide into lower alkanoyloxymethyl R 1 and R 2 respectively. Conversely, the hydroxy group may be freed from acylated hydroxymethyl R 1 and R 2 respectively, for example lower alkanoyloxymethyl, by solvolysis, preferably under acidic conditions.

Furthermore, hydroxymethyl R 1 and R 2 respectively, can be converted in customary manner into lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N,N-dilower alkylcarbamoyl R 1 and R 2 respectively, the operation Sbeing carried out, for example, by first oxidising hydroxymethyl R 1 and R 2 respectively, to carboxy in customary I 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 alkoxy- I «carbonyl R and R 2 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 triethylamine, or by conversion into an alkali metal salt and subsequent reaction with a reactive ester of the corresponding alcohol, such as a corresponding halide, or by using a dehydrating agent, such as N;N'-dicyclohexylcarbodiimide, with a corresponding alcohol; or converting the 34 carboxy group into amidated carboxy R 1 and R 2 respectively, by 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,N'-dicyclohexylcarbodiimide, or by conversion into the halide and subsequent reaction with ammonia or with an amine having at least one hydrogen atom. It is also possible to convert acylated hydroxymethyl R 1 and R2, respectively, into esterified or amidated carboxy R 1 and R 2 respectively, by first freeing the acylated hydroxymethyl group by solvolysis, for example in the manner described above, and then converting the resulting free hydroxymethyl group, in the manner described above, into a carboxy group and converting the latter further into an esterified or amidated carboxy group. Conversely, esterified or amidated carboxy groups R 1 and R 2 respectively, can be converted into optionally acylated hydroxymethyl R 1 and R 2 respectively, by first hydrolysing the esterified or amidated carboxy group R 1 and R 2 respectively, 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 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 i agent, for example of the kind mentioned above, to hydroxymethyl R 1 and R 2 respectively, and, if desired, the latter can then be converted into acylated hydroxymethyl R 1 and R 2 respectively, for example in the manner described above.

If the dotted line indicates the presence of a double bond 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).

Furthermore, a compound according to the invention in which the dotted line indicates the presence of a double bond and R 2 represents hydrogen can be converted into a corresponding piperidine compound according to the invention, for example in a manner known per se by the addition of a compound R 2 -H in which R 2 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 S. mentioned under Variant a).

SConversely, compounds according to the invention S' in which the dotted line indicates the presence of a single bond can be converted in a manner known per se into corresponding tetrahydropyridine compounds according to the invention in which R 2 represents hydrogen, for example by elimination of a compound

R

2 -H in which R 2 represents an optionally etherified or acylated hydroxy group or an optionally acylated amino group. Leaving groups R 2 that are less suitable for elimination, for example hydroxy, can first be converted, for example in situ, into more suitable leaving groups R 2 for example lower alkanesulphonyloxy, such as methanesulphonyloxy, or halogen, t" such as chlorine, bromine or iodine. The elimination is effected especially in the presence of a suitable u base, for example of the kind mentioned under Variant a).

Salts of compounds of the formula I and of their tautomers can be manufactured in a manner known per se. Thus, for example, acid addition salts of compounds of the formula I are obtained by treatment with an acid or a suitable ion exchange reagent. Salts 36 can be converted into the free compounds 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 compounds 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 in free form and in the form of its salts, hereinbefore and hereinafter the free compound or its salts should be understood as meaning optionally i also the corresponding'salts or the free compound, respectively, where appropriate and expedient.

The novel compounds, including the salts of salto 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 may be in the S° form of one of the possible isomers or in the form of a 1 mixture thereof. Depending upon the molecular I 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 I r obtained as pure isomers, for example, pure enantiomers and/or pure diastereoisomers, such as pure cis/trans- I isomers or meso-compounds. Accordingly, as isomeric mixtures there may be obtained, for example, enantiomeric mixtures, such as racemates, diastereoisomeric mixtures or mixtures of racemates.

Resulting diastereoisomeric 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 con- 37 stituents, for example by fractional crystallisation.

Resulting enantiomeric mixtures, such as racemates, can also be separated into the enantiomers according to known methods, for example by recrystallisation from an optically active solvent, by chromatography using chiral adsorbents, with the aid of f 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 4 0 acid, for example tartaric or malic acid, or a *o sulphonic acid, for example camphorsulphonic acid, and *I separa.tion 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 o* enantiomer is isolated.

The invention also relates to those forms of the 0 process according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried t, out, or a starting material is used in the form of a S 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 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 -38 according to the invention, to their use and to processes for their manufacture, the variables R 1

R

2

R

3 X, Y, n and alk and the substituents of the ring A 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 X R3 (CH 2 I(I

VC)

a lk-N-CH2CH2-R1 and their salts. These likewise have nootropic properties in a degree of action comparable with that I of the corresponding compounds of the formulae I and I' I and can likewise be used as nootropic active ingredients in medicaments.

t Accordingly, the invention relates also to pharmaceutical, especially nootropic, preparations containing as active ingredient a compound of the formula IVc in which R 1 represents carboxy, lower alkoxycarbonyl, I carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or optionally acylated hydroxymethyl,

R

3 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 trifluoromethyl, and either each of X and Y represents an oxygen atom and n represents 39 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 2, or a pharmaceutically acceptable salt thereof, to the use of the mentioned compounds of the formula IVc or their pharmaceutically acceptable salts 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 to e0 0 oo compounds of the formula IVc in which R 1 represents Scarboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl or optionally acylated hydroxymethyl, R 3 represents hydrogen or lower alkyl, alk represents lower alkylene or lower alkylidene, the ring A is unsubsti- S0 o. tuted or is mono- or poly-substituted by hydroxy, lower b fo u alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or by trifluoromethyl, and either each of X and Y S represents an oxygen atom and n represents 1, or X Srepresents a methylene group, Y represents an oxygen atom and n represents 1, or X represents an oxygen Si.t atom, Y represents a methylene group and n represents S*p'4 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 R 3 represents hydrogen, alk is other than methylene if R 1 represents carbamoyl or Nmethyl-, N-ethyl-, N,N-dimethyl- or N,N-diethylcarbamoyl, and to their salts, and to a process for the manufacture of the latter, novel compounds of the

I

40 40 formula iVc and their salts.

Accordingly, the invention relates, for example, also to pharmaceutical, especially nootropic, preparations containing as active ingredient a compound of the formula IVc in which R 1 represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R 3 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 ii trifluoromethyl, X represents an oxygen atom or a S: methylene group, Y represents an oxygen atom and n represents 1, or a pharmaceutically acceptable salt thereof, to the use of the mentioned compounds of the S formula IVc or their pharmaceutically acceptable salts i for the manufacture of nootropic pharmaceutical preparations, to a method for the treatment of the I symptoms of cerebral insufficiency, characterised in Ii that one of the mentioned compounds of the formula IVc, f or a pharmaceutically acceptable salt thereof, is administered, and to compounds of the formula IVc in which R 1 represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower j alkylcarbamoyl, R 3 represents hydrogen or lower I alkyl, alk represents lower alkylene or lower alkylidene, the ring A is unsubstituted or is mono- or I poly-substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl 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 ring A is unsubstituted, each of X and Y represents oxygen, n represents 1 and R 3 represents hydrogen, alk is other than methylene if Ri 1 -41 )1 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 manufacture of the latter, novel compounds of the formula IVc and their salts.

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

The invention relates in this respect especially I 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 1 represents i carboxy, lower alkoxycarbonyl, carbamoyl, N-lower Salkylcarbamoyl, N,N-di-lower alkylcarbamoyl, hydroxy- A methyl, lower alkanoyloxymethyl, lower alkanesulphonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, I R 3 represents hydrogen or lower alkyl, 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 I alkylidene, the ring A is unsubstituted or is mono-, di- I or poly-substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or by it S* trifluoromethyl, 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 Irepresents 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 S4 and n represents 2, or one of the pharmaceutically acceptable salts thereof, and to compounds of the formula IVc in which R 1 represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,Ndi-lower alkylcarbamoyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulphonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, R 3 represents 42 hydrogen or lower alkyl, 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 .I is unsubstituted or is mono-, di- or poly-substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower 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, Y represents an oxygen atom and n represents 1, or X represents an oxygen atom, Y represents a methylene group and n i 0, represents 1, or X represents a direct bond, Y Srepresents an oxygen atom and n represents 2, with

S

t the proviso that in compounds of the formula IVc in ST which the ring A is unsubstituted, each of X and Y F represents oxygen, n represents I and R 3 represents I *hydrogen, alk is other than methylene if RI represents carbamoyl or N-methyl-, N-ethyl-, N,Ndimethyl- or N,N-diethyl-carbamoyl, and to their salts, a xt and to a process for the manufacture of the latter, i novel compounds of the formula IVc and their salts, for example to pharmaceutical, especially nootropic, prepara- Stions and to the manufacture thereof and..to methods of ttreatment, characterised in that there is selected a compound of the formula IVc in which R 1 represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R 3 represents hydrogen or lower alkyl, 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 polysubstituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or by trifluoromethyl, X represents an oxygen atom or a methylene 43 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

R

1 represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R 3 represents hydrogen or lower alkyl, 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 oe alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or by trifluoromethyl, X represents an oxygen atom or a o o' 1" methylene group, Y represents an oxygen atom and n 0, represents 1, with the proviso that in compounds of the o9 formula IVc in which the ring A is unsubstituted, each Seo* of X and Y represents oxygen, n represents 1 and R 3 represents hydrogen, alk is other than methylene if R, represents carbamoyl or N-methyl-, N-ethyl-, N,Ndimethyl- or N,N-diethylcarbamoyl, and to their salts, and o, a to a process for the manufacture of the latter, novel compounds of the formula IVc and their salts.

aBo In this respect the invention relates more 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 R 1 represents carboxy, hydroxymethyl, C 2

-C

5 -alkanoyloxymethyl, such as acetoxymethyl, Cj-C 4 -alkoxycarbonyl, such as methoxycarbonyl, or carbamoyl, R 3 represents hydrogen or CI-C 4 -alkyl, such as methyl, alk represents C 1

-C

4 -alkylene that 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 c 44 substituted, especially in the 7-position, by

C

1

-C

4 -alkoxy, such as methoxy, 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 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 RI represents carboxy, hydroxymethyl,

C

2

-C

5 alkanoyloxymethyl, such as acetoxymethyl, C 1

-C

4 99 alkoxycarbonyl, such as methoxycarbonyl, or carbamoyl,

R

3 represents hydrogen or C 1

-C

4 -alkyl, such as methyl, alk represents C 1

-C

4 -alkylene that links the ring system with the NH group shown in formula IVc by up to and including 3 carbon atoms, such as oo methylene or ethylene, the ring A is unsubstituted or is substituted, especially in the 7-position, by C -C 4 S alkoxy, such as methoxy, and either each of X and Y represents an oxygen atom and n represents 1, or X II represents a methylene group, Y represents an oxygen atom and n represents 1, or X represents an oxygen tr atom, Y represents a methylene group and n represents 1, or X represents a direct bond, Y represents an I 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 R 3 represents hydrogen, alk is other than methylene if R 1 represents carbamoyl, and to their salts, and to a process for the manufacture of the latter, novel compounds of the formula IVc and their salts, for example pharmaceutical, especially to nootropic, preparations and to the manufacture thereof, and to methods of treatment, characterised in that 45 there is selected a compound of the formula IVc in which R 1 represents C 1

-C

4 -alkoxycarbonyl, such as methoxycarbonyl, R 3 represents hydrogen or C1-C 4 alkyl, such as methyl, alk represents C1-C 4 alkylene that links the ring system with the NH group 4 shown in formula IVc by up to and including 3 carbon atoms, such as methylene or ethylene, the ring A is unsubstituted, X represents an oxygen atom or a 4 methylene group, Y represents an oxygen atom and n represents 1, or one of the pharmaceutically acceptable Si salts thereof, and to compounds of the formula IVc in which R 1 represents C 1

-C

4 -alkoxycarbonyl, such as I methoxycarbonyl,

R

3 represents hydrogen or C1-C 4 *409 alkyl, such as methyl, alk represents CI-C 4 i. alkylene that links the ring system with the NH group shown.in formula IVc by up to and including 3 carbon Satoms, 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 n represents 1, and to their salts, and to a process for the manufacture of the latter, novel compounds of the formula IVc and their salts.

In this respect the invention relates most especially to pharmaceutical, especially nootropic, .c 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 RI represents C 1

-C

4 -alkoxycarbonyl, such as methoxycarbonyl, R 3 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 one of the pharmaceutically acceptable salts thereof, and to compounds of the formula IVc in which R 1 represents C 1

-C

4 -alkoxycarbonyl, such as -46 methoxycarbonyl, R 3 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, and to their salts, and to a process for the manufacture of the latter, novel compounds of the formula IVc and their salts.

In this respect the invention relates specifically to pharmaceutical, especially nootropic, preparations and to the manufacture thereof and to methods of S. treatment, characterised in that there is selected one S. 'of the novel compounds of the formula IVc mentioned in j the Examples, or one of the pharmaceutically acceptable o 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, S novel compounds of the formula IVc and their salts.

The present invention relates also to a process for the manufacture of compounds of the formula IVc and 1 their salts, for example characterised in that V h) compounds of the formulae S X R 3 (VIIIa) (VIIIb), in which one of the radicals and Z 2 represents reactive esterified hydroxy and the other represents amino, and Z 3 represents hydrogen, or Z 1 represents amino, and Z 2 and Z 3 together represent an 47 additional bond, or optionally salts of these compounds, are reacted with one another, or i) in a compound of the formula X R3 A CH2'\ (IX) Y'alk-N-CH 2

CH

2

-X

6

H

in which X 6 represents a radical that can be converted into R 1 or in a salt thereof, Xg is converted into R 1 and, if desired, in the case of each of processes h) and a compound obtained in accordance with the process or by other means is converted into a different compound of the formula IVc, an isomeric mixture obtained in accordance with the process is separated into the components, an enantiomeric or diastereo- S.isomeric mixture obtained in accordance with the process is separated into the enantiomers or diastereoisomers, respectively, a free compound of the formula IVc obtained in accordance with the process is converted into a salt and/or a salt obtained in accordance with the process is converted into the free compound of the formula IVc or into a different salt.

Variant h): Reactive esterified hydroxy Z 1 and Z 2 respectively, is especially hydroxy esterified by a strong inorganic acid or organic sulphonic acid, for example halogen, 48 such as chlorine, bromine or iodine, sulphonyloxy, such as hydroxysulphonyloxy, halosulphonyloxy, for example fluorosulphonyloxy, lower alkanesulphonyloxy optionally substituted, for example, by halogen, for example methane- or trifluoromethane-sulphonyloxy, cycloalkanesulphonyloxy, for example cyclohexanesulphonyloxy, or benzenesulphonyloxy optionally substituted, for example, by lower alkyl or by halogen, for example pbromophenyl- or j-toluene-sulphonyloxy.

The reaction is in this case carried out especially in the presence of a condensation agent, such as a suitable base. Suitable bases are, for S"example, alkali metal hydroxides, hydrides, amides, I alkoxides, carbonates, triphenylmethylides, di-lower alkylamides, amino-lower alkylamides or lower alkylsilylamides, or naphthaleneamines, lower alkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines. There may be mentioned by way of example: i sodium hydroxide, hydride, amide or ethoxide, potassium tert.-butoxide or carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium 3-(aminopropyl)amide or bis-(trimethylsilyl)-amide, or dimethylaminonaphthalene, di- or tri-ethylamine, pyridine, benzyl- S'It trimethylammonium hydroxide, 1,5-diazabicyclo[4.3.0]nonjl 5-ene (DBN) and 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU). The reaction of amines VIIIa (ZI amino) with acrylic acid compounds VIIIb (Z 2 3 bond) is effected, for example, while heating, for example at approximately 60-120 0

C.

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

Variant i): A radical X6 that can be converted into R 1 is, -49 for example, functionally modified carboxy other than

R

1 such as cyano, anhydridised carboxy, optionally substituted amidino, optionally esterified or anhydridised carboximidoyl, esterified or amidated carboxy other than esterified or amidated carboxy R 1 trilower 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 S, substituted lower alkanoic or benzoic acid or with a 1 carbonic acid halide lower alkyl semiester. As examples there may be mentioned: halocarbonyl, such as i$ chlorocarbonyl, lower alkanoyloxycarbonyl, such as acetoxycarbonyl, or lower alkoxycarbonyloxycarbonyl, such as ethoxycarbonyloxycarbonyl.

Substituted amidino is, for example, amidino substituted by an aliphatic radical, for example lower i alkyl, such as lower alkylamidino, for example ethyl- I o* amidino.

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

Tri-lower alkoxy- or tri-halo-methyl is, i for example, trimethoxymethyl or trichloromethyl, respectively.

X6 can be converted into R 1 for example, by solvolysis. Solvolysis agents are, for example, water, lower alkanols corresponding to the desired esterified carboxy RI, ammonia, or amines corresponding to the desired amidated carboxy group R 1 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 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 2-toluenesulphonic 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 especially sodium or potassium hydroxide.

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

o .Cyano, anhydridised carboxy, and esterified or *amidated carboxy other than esterified or amidated carboxy R, are alcoholysed, for example with a suitable lower alkanol, to esterified carboxy R 1 and cyano and anhydridised carboxy are ammonlysed or aminolysed, for example with ammonia or with an amine ft corresponding to the amidated carboxy R1, respect- Sively.

The starting material of the formula IX can be obtained, for example, by reaction of compounds of the formulae XAkZ C A (CH2 alk-NH 2 and Z 2

-CH

2

-CH(Z

3

)-X

6 (IXa) (IXb), 51 in which Z 2 represents reactive esterified hydroxy and Z 3 represents hydrogen, or Z 2 and Z 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 for example in the presence of a basic agent.

Subsequent operations which may, if desired, be carried out on resulting compounds of the formula IVc are especially conversions of R, and of substituents of the ring A, separations of enantiomers and dia- I .stereoisomers and conversions into one another of salts "and free compounds, analogous to those indicated for .I the compounds of the formula I and are carried out in 'analogous manner.

The invention relates also to the use of compounds of the formula I or IVc, respectively, their tautomers and/or pharmaceutically acceptable salts of such compounds V having salt-forming properties, especially as pharmacological, especially nootropically active, active ingredients. They can be used, preferably in J the form of pharmaceutically acceptable preparations, in a method for the prophylactic and/or therapeutic I 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 contain as active ingredient a compound of the formula I or IVc, respectively, or, where appropriate, a tautomer and/or pharmaceutically acceptable salt thereof, and to processes for their manufacture.

The pharmaceutical preparations according to the invention, which contain a compound of the formula I or i 52 IVc, respectively, or,.where appropriate, a tautomer and/or pharmaceutically acceptable salt thereof, are for enteral, such as oral and also rectal, and parenteral administration to warm-blooded animal(s), the preparations containing the pharmacological active jingredient alone or together with customary pharmaceutical adjuncts.

SThe novel pharmaceutical preparations contain, for example, from approximately 10% to approximately preferably from approximately 20% to approximately of active ingredient. Pharmaceutical preparations .2 according to the invention for enteral and parenteral 1 l administration are, for example, those in dosage unit i forms, such as dragees, tablets, capsules or suppositories, and also ampoules. They are I manufactured in a manner known per se, for example i by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.

i Thus, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid a carriers, optionally granulating a resulting mixture, rIt and processing the mixture or granulate, if desired or necessary after the addition of suitable adjuncts, to i C Aform tablets or dragee cores.

|I Suitable carriers are, especially, fillers, such I as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium j hydrogen phosphate, also binders, such as starch pastes Iusing, for example, corn, wheat, 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 F ,2-1 -53 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 that may be resistant to gastric juices, there being used, inter alia, concentrated sugar solutions that may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or lacquer solutions in suitable organic solvents or solvent mixtures, or, for the manufacture of coatings resistant to gastric juices, Ssolutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethyloe cellulose phthalate. Colourings or pigments may be i added to the tablets or dragee coatings, for example for identification purposes or to indicate different Sdoses of active ingredient.

Further orally administrable pharmaceutical preparations are dry-filled capsules consisting of i gelatine, and also soft, sealed capsules consisting of gelatine and a plasticiser, such as glycerine or sorbitol. The dry-filled capsules may contain the j active ingredient in the form of a granulate, for iI example in admixture with fillers, such as lactose, i binders, such as starches, and/or glidants, such as talc or magnesium stearate, and optionally j stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable i I 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

A"

54 suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatine rectal capsules that contain 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 t r corresponding oily injection suspensions, there being used suitable lipophilic 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 .dium carboxymethylcellulose, sorbitol and/or dextran and, optionally, also stabilisers.

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

The following Examples illustrate the invention described above but are not intended to limit the scope thereof in any way. Temperatures are given in degrees Celsius.

As a result of the close relationship between a 55 compound of the formula I and the corresponding tautomeric compound of the formula in the Examples a compound of the formula I should be understood as meaning optionally also the tautomeric compound of the formula I' where appropriate and expedient. The same applies to a compound of the formula I' and to salts of compounds of the formulae I and I'.

4 0 r 4 1 a 9 .4115 i 56 Example 1: First 5.55 g (25 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrobromide (guvacoline hydrobromide) and then 11.31 g (87.5 mmol) of N-ethy?-N,N-diisopropylamine are added to a solution of 7.96 g (25 mmol) of 3-(p-toluenesulphonyloxymethyl)chroman in 100 ml of dimethylformamide. The mixture is stirred for 15 hours at 500 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 washed with water and extracted with 2N hydrochloric acid. The hydrochloric acid extracts are t I ,combined, rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with ii dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 5.92 g of 1-(chroman-3-ylmethyl)i 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl i ester are obtained in the form of a pale yellow oil.

The 1-(chxoman-3-ylmethyl)-1,2,5,6-tetrahydropyridine-3- Scarboxylic acid methyl ester hydrochloride produced I therefrom using hydrochloric acid in diethyl ether melts at 158-1590 after crystallisation from methanol/diethyl ether.

I3-(p-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-metho-ycarbonylchroman (US i 4,178,380) in 200 ml of absolut ahydrofuran is added dropwise within a period 0 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 rb~ 57 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 of oily 3-hydroxymethylchroman, which crystallises from diethyl ether/pentane and melts at 60-61°, are obtained.

46.14 g (242 mmol) of p-toluenesulphonyl 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 Sexothermic 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 of 3- (-toluenesulphonyloxymethyl)chroman having a melting point of 86-870 are obtained.

Example 2: At room temperature and while stirring, 0.75 g (15.6 mmol) of sodium hydride dispersion in mineral oil is added within a period of minutes to a solution of 4.36 g (13 mmol) of N,N-bis- (2-methoxycarbonylethyl)-N-(chroman-3-ylmethyl)-amine in 50 ml of absolute dimethylformamide. 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 2N 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.

58 There are obtained 3.8 g of crystalline 4-hydroxy- 1-(chroman-3-ylmethyl)-1,2,5,6-tetrahydropyridine-3carboxylic acid methyl ester hydrochloride or l-(chroman- 3-ylmethyl)-4-oxo-piperidine-3-carboxylic acid methyl ester hydrochloride, respectively, which, after recrystallisation from methanol/diethyl ether has a decomposition point of 167-1680.

N,N-bis(2-methoxycarbonylethyl)-N-(chroman-3ylmethyl)-amine can be manufactured, for example, St t ,in the following manner: First 1.77 g (13.32 mmol) of aluminium chloride in 4,t 50 ml of absolute diethyl ether are added dropwise while stirring at room temperature to a suspension of I 3.04 g (80 mmol) of lithium aluminium hydride in 100 ml of absolute diethyl ether. Then 6.29 g (40 mmol) of 3i cyanochromene Gupta et al., Ind. J. Chem.

21B, 344 (1982)] in 50 ml of absolute tetrahydrofuran S, are added dropwise within a period of 20 minutes. The I reaction mixture is boiled under reflux for 16 hours.

After it has cooled, it is carefully decomposed with 3.1 ml of water, 3.1 ml of sodium hydroxide solution strength) and 9.3 ml of water. The precipitate Sformed is filtered off with suction, the filtrate is Sconcentrated by evaporation in vacuo and the oily i residue is dissolved in diethyl ether. The organic phase is 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 by shaking with dichloromethane. After drying the combined organic phases over sodium sulphate and concentrating in vacuo, 3.5 g of 3-aminomethylchroman are obtained in the form of a yellow oil.

The 3-aminomethylchroman hydrochloride produced therefrom using hydrochloric acid in diethyl ether is 59 recrystallised from methanol/diethyl ether and melts at 218-2190.

3.03 g (35.2 mmol) of acrylic acid methyl ester are added to a solution of 2.61 g (16 mmol) of 3-aminomethylchroman in 20 ml of methanol. The reaction solution is stirred for 16 hours at 500 and, after cooling, is concentrated by evaporation in vacuo.

5.1 g of N,N-bis(2-methoxycarbonylethyl)-N- (chroman-3-ylmethyl)-amine are obtained in the form of i a reddish oil.

a I I Example 3: A solution of 10.48 g (30 mmol) of N-[2- (chroman-3-yl)ethyl]-N,N-bis(2-methoxycarbonylethyl)amine in 35 ml of absolute dimethylformamide is added dropwise at room temperature and while stirring to a I suspension of 2.16 g (40 mmol) of sodium methoxide in ml of dimethylformamide within a period of minutes. The reaction mixture is stirred for 16 hours at room temperature and then concentrated to dryness by evaporation under a high vacuum. Diethyl ether is I "added to the residue and extraction is carried out with cold 2N hydrochloric acid. The combined hydrochloric acid extracts are extracted by shaking with dichloro- ,methane and the dichloromethane phases are dried over ,sodium sulphate and concentrated by evaporation in vacuo. There are obtained 4.25 g of 1-[2- (chroman-3-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride or 1-[2-(chroman-3-yl)ethyl]- 4 -oxopiperidine-3-carboxylic acid methyl ester.hydrochloride, respectively, which after recrystallisation from methanol/diethyl ether, has a decomposition point of 175-1770.

N-[2-(chroman-3-yl)ethyl]-N,N-bis(2-methoxycarbonylethyl)-amine can be manufactured, for example, in the following manner: 60 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-(D-toluenesulphonyloxymethyl)chroman (for manufacture see Example 1) in 300 ml of dimethyl sulphoxide and the whole is heated to 600 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 I concentrated by evaporation in vacuo. 26.75 g of 3-cyanomethylchroman are obtained in the form of a pale yellow oil which crystallises from Sdiethyl ether/pentane. The crystals melt at 630.

First 4.44 g (33.3 mmol) of aluminium chloride in c 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) I of 3-cyanomethylchroman, dissolved in 200 ml of tetrahydrofuran, are added dropwise within a period of minutes. The reaction mixture is stirred for 16 I <>hours at room temperature and then decomposed with 7.6 ;ml of water, 7.6 ml of sodium hydroxide solution Sstrength) and 22.8 ml of water. The precipitate formed j is filtered off with suction and the filtrate is Vi concentrated by evaporation in vacuo. The oily I residue is dissolved in diethyl ether and washed with i water. The organic phase is then extracted by shaking j 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 organic phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 15.95 g of 3-(2-aminoethyl)chroman are obtained in the form of a colourless 61 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 244-2450.

6.63 g (77 mmol) of acrylic acid methyl ester are added at room temperature to a solution of 6.2 g mmol) of 3-(2-aminoethyl)chroman 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]-N,N-bis(2-methoxycarbonyli ethyl)-amine in the form of a reddish oil.

Example 4: In a manner analogous to that described S in Example 3, by reacting 3-(2-aminoethyl)chroman with I 1 equivalent of acrylic acid methyl ester, it is i possible to manufacture the corresponding N-[2i (chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine whose hydrochloride melts at 190-1920 i Example 5: In a manner analogous to that described in Examples 3 and 4, by reacting 3-aminomethylchroman with I equivalent of acrylic acid methyl ester, it is possible to manufacture N-(2-methoxycarbonylethyl)-N- I y I' (chroman-3-ylmethyl)-amine or its hydrochloride.

Example 6: First 3.3 g (14.8 mmol) of 1,2,5,6- I rtetrahydropyridine-3-carboxylic acid methyl ester Shydrobromide (guvacoline hydrobromide) and then 6.1 g (47.3 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 4.5 g (13.5 mmol) of toluenesulphonyloxy)ethyl]chroman in 70 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 600 and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the 4 4 62 oily residue and extraction 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 combined dichloromethane phases are dried over sodium sulphate and concentrated by Sevaporation in vacuo. 3.97 g of 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3carboxylic acid methyl ester are obtained in the form of a yellow oil. The 1-[2-(chroman-3-yl)ethyl]-

'E

i 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from t methanol/diethyl ether and melts at 175-177 0 jl 3-[2-(p-toluenesulphonyloxy)ethyl]chroman can be Smanufactured, for example, as follows: ml of 2N sodium hydroxide solution are added to Sa solution of 7.8 g (45 mmol) of 3-cyanomethylchroman i in 150 ml of ethanol and the whole is boiled under I reflux for 16 hours. After cooling, the reaction mixture is concentrated by evaporation in vacuo.

The residue is dissolved in water and extracted with Sdiethyl ether. The aqueous phase is acidified with I hydrochloric acid (36% strength) and extracted by I shaking with dichloromethane. The combined dichloromethane extracts are dried over sodium sulphate and concentrated by evaporation in vacuo. 8.3 g of 3-carboxymethylchroman are obtained in the form of colourless crystals which melt at 106-107°.

ml of sulphuric acid (100% strength) are added to a solution of 7.69 g (40 mmol) of 3-carboxymethylchroman 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 -63residue 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 of 3-methoxycarbonylmethylchroman 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 o (35 mmol) of lithium aluminium hydride in 50 ml of e" absolute diethyl ether. Stirring is continued at room .o temperature for a further 16 hours and then the whole I 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 I 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 2-toluenesulphonyl chloride are added while stirring at room temperature to a S. solution of 5.35 g (30 mmol) 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 of 3-[2-(E-toluenesulphonyloxy)ethyl]chroman, which melts at 91-930, are obtained.

64 Example 7: First 11.1 g (50 mmol) of 1,2,5,6tetrahydropyridine-3-carboxylic 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- 1,4-dioxan (US 2,366,102) in 100 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 500 and then concentrated by evaporation under a high vacuum. Water is added to the residue and extraction is carried out with diethyl ether. The SIorganic phases are washed with water and extracted by S' shaking with 2N hydrochloric acid. The combined

I(

I hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and Sextracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 10.75 g of 1-(benzo-1,4-dioxan-2-ylmethyl)-1,2,5,6tetrahydropyridine-3-carboxylic acid methyl ester are obtained in the form of a yellow oil. The 1-(benzo-1,4dioxan-2-ylmethyl)-1,2,5,6-tetrahydropyridine-3carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and decomposes at 215-2170.

Example 8: 0.5 g of palladium-on-carbon is added to a solution of 4.88 g (15 mmol) of 1-(benzo- 1,4-dioxan-2-ylmethyl)-1,2,5,6-tetrahydropyridine-3carboxylic 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 65 diethyl ether is added until the solution becomes turbid. 4.08 g of 1-(benzo-1,4-dioxan-2ylmethyl)-piperidine-3-carboxylic acid methyl ester hydrochloride having a melting point of 186-1880 crystallise out.

Example 9: At room temperature and while stirring, a solution of 10.12 g (30 mmol) of N,N-bis(2-methoxycarbonylethyl)-N-(benzo-1,4-dioxan-2-ylmethyl)-amine in ml of absolute dimethylformamide 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 dimethylt ,formamide. The reaction mixture is stirred for a further 3 hours at room temperature and then Sconcentrated to dryness by evaporation under a high vacuum. Diethyl ether is added to the residue and extraction by shaking is carried out with cold 2N i hydrochloric acid. The combined hydrochloric acid Sextracts are extracted with dichloromethane and the dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. There are obtained 4.5 g of 4-hydrcxy-l-(benzo-1,4-dioxan- 2-ylmethyl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid i methyl ester hydrochloride or 1-(benzo-1,4-dioxan-2-yl- Smethyl)-4-oxopiperidine-3-carboxylic acid methyl ester H .hydrochloride, respectively, which is recrystallised from methanol/diethyl ether and has a decomposition point of 185-1870.

r N,N-bis(2-methoxycarbonylethyl)-N- (benzo-1,4-dioxan- 2-ylmethyl)-amine can be manufactured, for example, as follows: 7.57 g (88 mmol) of acrylic acid methyl ester are added to a solution of 6.61 g (40 mmol) of 2-aminomethylbenzo-1,4-dioxan Augustin et al., J. Med.

Chem. 8, 446 (1965)] in 80 ml of methanol and the whole is stirred for 16 hours at 500. After cooling, the reaction mixture is concentrated by evaporation in vacuo. 12.82 g of N,N-bis(2-methoxycarbonyljl_ 66 ethyl)-N-(benzo-1,4-dioxan-2-ylmethyl)-amine are obtained in the form of a reddish oil.

Example 10: In a manner analogous to that described in Example 9, by reacting 2-aminomethylbenzo-1,4-dioxan with 1 equivalent of acrylic acid methyl ester, it is possible to manufacture the corresponding N-(2methoxycarbonylethyl)-N-(benzo-1,4-dioxan-2-ylmethyl)amine whose hydrochloride melts at 153-1550 Example In a manner analogous to that described in Example 9, it is also possible to manufacture 4hydroxy-1-(2-methylbenzo-1,4-dioxan-2-ylmethyl)- 1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride or 1-(2-methylbenzo-1,4-dioxan- 2-ylmethyl)-4-oxopiperidine-3-carboxylic acid methyl ester hydrochloride, respectively.

Example 12: In a manner analogous to that described It itt in Examples 9 and 10, by reacting 2-(2-aminoethyl)benzo-1,4-dioxan with 1 equivalent of acrylic acid I. lit methyl ester, it is possible to manufacture N-[2- (benzo-1 ,4-dioxan-2-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine and its hydrochloride, and by reacting 2-aminomethyl-2-methylbenzo-1,4-dioxan with 1 equivalent of acrylic acid methyl ester, it is possible to manufacture N-(2-methoxycarbonylethyl)-N-(2methylbenzo-1,4-dioxan-2-ylmethyl)-amine and its hydrochloride.

Example 13: A solution of 52.7 g (0.15 mol) of N,Nbis(2-methoxycarbonylethyl)-N-[2-(benzo-1,4-dioxan-2yl)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 67 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 with cold 2N hydrochloric acid. The combined hydrochloric acid extracts are extracted by shaking with dichloromethane.

The dichloromethane phases are dried over sodium Ssulphate and concentrated by evaporation in vacuo.

i There are obtained 34.0 g of 1-[2-(benzo-1,4j'|4 dioxan-2-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydrot' pyridine-3-carboxylic acid methyl ester hydrochloride S. or 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-oxopiperidine- S3-carboxylic acid methyl ester hydrochloride, respectively, which is recrystallised from methanol/diethyl ether and has a decomposition point of 165-1660.

N,N-bis(2-methoxycarbonylethyl)-N-[2-(benzo-1,4- \dioxan-2-yl)ethyl]-amine can be manufactured, for Sexample, 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-aminoethyl)-benzo-1,4-dioxan [J.

Augustin et al., J. Med. Chem. 8, 446 (1965)] in 250 ml of methanol. The reaction mixture is stirred for 6 hours at 500 and, after cooling, is concentrated by evaporation in vacuo. 57.9 g of N,N-bis(2-methoxycarbonylethyl)-N-[2-(benzo-1,4-dioxan- S2-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 1-[2-(benzo-1,4dioxan-2-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride I

I

68 or 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-oxopiperidine-3carboxylic acid methyl ester hydrochloride, respectively, 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 taken 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 of cis-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylic acid methyl ester hydrochloride having a melting point of 182-1850 crystallise out.

S* Example 15: At -15° and while stirring, 2.65 g (70 mmol) of sodium borohydride are added in portions over a period of one hour to a suspension of 12.45 g mmol) of 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylic acid 9 methyl ester hydrochloride or 1-[2-(benzo-1,4-dioxan-2yl)ethyl]-4-oxopiperidine-3-carboxylic acid methyl ester hydrochloride, respectively, in 250 ml of methanol. Stirring is i. continued for a further 4 hours at -100 and then the reaction mixture is concentrated by evaporation in vacuo and taken up in water/ethyl 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 chromatographed on 560 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 5.41 g of trans---[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylic acid methyl ester are obtained in the form of a pale yellow oil. The trans-1-[2- (benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3carboxylic acid methyl ester fumarate produced therefrom using fumaric acid crystallises from r .r t r It? A d S it It 4 Irr S Sd I i) 4 t It t 69 methanol/diethyl ether in the form of the hemihydrate having a melting point of 150-1520.

Example 16: First 19.03 g (125 mmol) of bicyclo[5.4.0]undec-5-ene and then, dropwise and while stirring at a solution of 3.44 g (30 mmol) of methanesulphonyl chloride in 20 ml of toluene are added to a solution of 8.03 g (25 mmol) of a mixture of cis- and trans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]- 4-hydroxypiperidine--carboxylic acid methyl ester in 100 ml of toluene. The whole is then allowed to warm up to room temperature and is stirred for a further 16 hours. Ice-water is then added to the reaction mixture and the organic phase is 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. The combined organic phases are washed with water, dried over sodium sulphate and concentrated by evaporation in vacuc. 5.8 g (76.5%) of crude product are obtained and are chromatographed on 300 g of silica gel (0.040-0.063 mm) using toluene/ethyl acetate as the eluant. 4.13 g of 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester are obtained in the form of a yellow oil. The 1-[2-(benzo-1,4-dioxan-2yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and decomposes at 205-2060.

Example 17: First 2.1 g (11 mmol) of 1,2,5,6-tetrahydropyridine-3-carboxylic acid ethyl ester hydrochloride and then 4.53 g (35 mmol) of N-ethyl- N,N-diisopropylamine are added to a solution of 3.32 g .1 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 600 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 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium j hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by i| evaporation in vacuo. 1.65 g of 1-[2i (chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine-3- C carboxylic acid ethyl ester are obtained in the form of I a yellow oil. The 1-[2-(chroman-3-yl)ethyl]-1,2,5,6j tetrahydropyridine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in r 'diethyl ether crystallises from acetone/diethyl ether j and melts at 177-1780 S*'i 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]-1,2,5,6-tetrahydropyridine-3carboxylic acid methyl ester hydrochloride in 170 ml of I 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, while cold, with sodium hydroxide solution strength) and extracted with dichloromethane. The combined dichloromethane extracts are dried over sodium sulphate and concentrated by evaporation in vacuo.

2.30 g of 1-[2-(chroman-3-yl)ethyl]-1,2,5,6- I1 71- I i

I

tetrahydropyridine-3-carboxylic acid ethyl ester are obtained in the form of a yellow oil. The 1-[2-(chroman-3-yl)ethyl]-1,2,5,6-tetrahydropyridine- 3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from acetone/diethyl ether and melts at 177-178°.

Example 19: First 3.76 g (24 mmol) of piperidine-3carboxylic acid ethyl ester and then 3.1 g (24 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.98 g (12 mmol) of 3-[2-(p-toluenesulphonyloxy)- I ethyl]chroman in 50 ml of absolute dimethylformamide.

The mixture is stirred for 16 hours at 600 and, after I O 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 Scombined organic phases are extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium S*hydroxide solution (30% strength) and extracted with 4 dichloromethane. The combined dichloromethane phases 4, are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.7 g of 1-[2-(chroman-3-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester are obtained in the form of a yellow oil.

The 1-[2-(chroman-3-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from acetone/diethyl ether using 0.18 equivalent of water of crystallisation and melts at 140-1430.

Example 20: First 3.76 g (24 mmol) of piperidine-4carboxylic acid ethyl ester and then 3.1 g (24 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of i

A

i:l i -72 3.98 g (12 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 50 ml of absolute dimethylformamide.

The mixture is stirred for 16 hours at 600 and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction by shaking 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 ec r hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases S' 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 mm) using ethyl acetate as the eluant. 3.7 g of 1-[2-(chroman-3-yl)ethyl]i piperidine-4-carboxylic acid ethyl ester are then ,t obtained in the form of a colourless oil. The 1-[2chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced thereform using hydrochloric acid in diethyl ether crystallises from i ethanol/diethyl ether and melts at 182-1860.

4 Example 21: First 1.96 g (12.5 mmol) of piperidinei 3-carboxylic acid ethyl ester and then 2.58 g (20 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.34 g (10 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at i 600 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 73o 4 t 44 1-

I

I

tt 4 t 1o

II

*441r alkaline, while cold, with sodium hydroxide solution 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 of 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]piperidine-3-carboxylic acid ethyl ester are then obtained in the form of a pale yellow oil. The 1-[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 ethanol/diethyl ether and melts at 162-1650.

The 2-[2-(p-toluenesulphonyloxy)ethyl]-benzo- 1,4-dioxan can be obtained, for example, in the following manner: Hydrogen chloride is introduced at 5-100, while stirring, into a solution of 15.76 g (90 mmol) of 2cyanomethylbenzo-1,4-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 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 again with water, and then dried over sodium sulphate and concentrated by evaporation in vacuo. 18.2 g of 2-methoxycarbonylmethylbenzo-1,4-dioxan are obtained in the form of a pale yellow oil.

At room temperature and while stirring, a solution 74 of 15.61 g (75 mmol) of 2-methoxycarbonylmethylbenzo- 1,4-dioxan in 120 ml of absolute tetrahydrofuran 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 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 strengh) and 8.55 ml of water. The precipitate S, 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 in vacuo.

tI c:, 12.37 g of 2-(2-hydroxyethyl)-benzo-1,4-dioxan f are obtained in the form of a colourless oil.

A 12.20 g (64 mmol) of E-toluenesulphonyl chloride i are added at room temperature and while stirring to a f solution of 10.81 g (60 mmol) of 2-(2-hydroxyethyl)benzo-1,4-dioxan in 35 ml of absolute pyridine, the slightly exothermic reaction being maintained at room i temperature by means of an ice bath. The reaction mixture is stirred for a further 3 hours at room ttemperature and then poured onto ice-water. The S' crystals formed are filtered off with suction, washed with water and dried in vacuo. 15.50 g of 2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan, ji which melts at 82-84o, are obtained.

Example 22: First 1.96 g (12.5 mmol) of piperidine- 4-carboxylic acid ethyl ester and then 2.58 g (20 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.34 g (10 mmol) of 2 2 -(.-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 75 600 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 sadium hydroxide solution strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium Ssulphate and concentrated by evaporation in vacuo.

S3.80 g 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. 3.7 g of 4 t 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-4carboxylic acid ethyl ester are then obtained in the form of a yellow oil. The 1-[2-(benzo-1,4-dioxan-2yl)ethyl]-piperidine-4-carboxylic acid ethyl ester o hydrochloride produced therefrom using hydrochloric 44 acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 165-1680.

Example 23: 21 ml (42 mmol) of 2N sodium hydroxide t solution are added at room temperature while stirring to a solution of 2.99 g (10 mmol) of N-[2-(chroman-3yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride in 60 ml of methanol. After 5 minutes, ml of water are added to the reaction mixture which is then stirred for 30 minutes at 50-600. 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 off with suction. 2.5 g of N-[2-(chroman-3-yl)ethyl]-N- (2-carboxyethyl)-amine hydrochloride are obtained (m.p.

76 186 188 0).

The N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride can be manufactured, for example, as described in Example 4.

Example 24: First 1.57 g (10 mmol) of piperidine-3carboxylic acid ethyl ester and then 2.07 g (16 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution I of 2.66 g (8 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]chroman in 35 ml of absolute dimethylformamide.

VI r The mixture is stirred for 16 hours at 600 and, after Scooling, 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 Shydrochloric acid extracts are rendered alkaline, while I ,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 I 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 of 1-[2- (chroman-2-yl)ethyl]-piperidine-3-carboxylic acid ethyl ester are then obtained in the form of a yellow oil. The 1-[2-(chroman-2-yl)ethyl]-piperidine-3carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 148-1510.

(-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-carboxy-

^II

77 chroman 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 dissolved in diethyl ether and washed with water, cold saturated sodium hydrogen carbonate solution and again with water. The ethereal phase is dried over sodium sulphate and concentrated by evaporation in vacuo. 72.8 g of 2-methoxycarbonylchroman are obtained in the form of a pale f yellow oil.

At room temperature and while stirring, a solution I of 36.4 g (0.19 mol) of 2-methoxycarbonylchroman in 400 i ml of absolute tetrahydrofuran is added dropwise S*r within a period of I 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 temperature, the reaction mixture is carefully decomposed with 7.2 ml of water, 7.2 ml of sodium hydroxide solution (15% strength) and 21.6 ml of water. The precipitate formed is filtered I off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved S in diethyl ether. The ethereal solution is washed with 1 water, dried over sodium sulphate and concentrated by I evaporation in vacuo. 31 g of 2-hydroxymethylchroman are thus obtained in the form of a colourless oil.

38.16 g (0.2 mol) of o-toluenesulphonyl chloride are added at room temperature while stirring to a solution of 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 stirred for a further 3 hours at room temperature and then poured onto ice-water. The oil which separates out is removed 78 by decanting the aqueous phase, dissolved in diethyl ether and washed with ice-cold 2N hydrochloric acid and ice-water. The ethereal phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 58.15 g of 2-(p-toluenesulphonyloxymethyl)chroman are obtained in the form of a colourless oil.

10.6 g (0.216 mol) of sodium cyanide are added to a solution of 57.31 g (0.18 mol) of 2-(p-toluenesulphonyloxymethyl)chroman in 800 ml of absolute S' dimethylformamide and the whole is heated, while stir- Sring, to 600. After 10 hours, ice-water is added to the reaction mixture and extraction is carried out with I diethyl ether. The combined ethereal phases are washed Sthoroughly with water, dried over sodium sulphate and Sconcentrated by evaporation in vacuo. 30.0 g (96.2%) |i of crude product are obtained and are chromatographed 1000 g of silica gel (0.040-0.063 mm) using toluene as the eluant. 18.16 g of 2-cyanomethylchroman 1 are thus obtained in the form of a yellow oil.

Hydrogen chloride gas is introduced at 5-100 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 i 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, 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 of crude product are obtained and are filtered 79 over 460 g of silica gel (0.040-0.063 mm) using toluene as the eluant. 17.80 g of 2-methoxycarbonylmethylchroman are obtained in the form of a pale yellow oil.

At room temperature and while stirring, a solution of 16.91 g (82 mmol) of 2-methoxycarbonylmethylchroman in 150 ml 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 I| tof absolute diethyl ether. Stirring is continued for t a further 16 hours at room temperature and then the Swhole is carefully decomposed with 3.1 ml of water, i 3.1 ml of sodium hydroxide solution (15% strength) and i i 9.3 ml of water. The precipitate formed is filtered S off with suction and the filtrate is concentrated by evaporation in vacuo. The oily residue is dissolved I in diethyl ether. The ethereal solution is washed with water, dried over sodium sulphate and concentrated by evaporation in vacuo. 14.36 g of 2-(2hydroxyethyl)chroman are obtained in the form of a colourless oil.

15.73 g (82.5 mmol) of 2-toluenesulphonyl S''chlo"-' are added at room temperature while stirring Ito a solution of 13.36 g (75 mmol) of 2-(2-hydroxyethyl)chroman in 90 ml 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 8.68 g of 2-[2-(P-toluenesulphonyloxy)ethyl]chroman which melts at 57-590 80 Example 25: First 1.57 g (10 mmol) of piperidine-4carboxylic acid ethyl ester and then 2.07 g (16 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 2.66 g (8 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]chroman in 35 ml of absolute dimethylformamide.

The mixture is stirred for 16 hours at 600 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 Sr extracted with 2N hydrochloric acid. The combined S< hydrochloric acid extracts are rendered alkaline, while Scold, with sodium hydroxide solution (30% strength) SL and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 2.17 g of crude product are obtained and are chromato- I' graphed on 110 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 1.90 g of 1-[2- .(chroman-2-yl)ethyl]-piperidine-4-carboxylic 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 j hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 190-1920.

Example 26: 3.01 g (35 mmol) of acrylic acid methyl ester are added at 0-50, while stirring, to a solution of 6.2 g (35 mmol) of 2-(2-aminoethyl)chroman in 200 ml of methanol. Stirring is continued for a further 16 hours at 0-50 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 mm) using ethyl acetate as the eluant. 5.10 g of N-[2-(chroman- 81 2-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine are thus obtained in the form of a yellow oil. The N-[2- (chroman-2-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from methanol/diethyl ether and melts at 152-1530.

S2-(2-aminoethyl)chroman can be manufactured, for example, in the following manner: First, at room temperature and while stirring, S2.2 g (16.5 mmol) of aluminium chloride in 70 ml of Sabsolute diethyl ether are added dropwise to a suspension of 3.8 g (100 mmol) of lithium aluminium Shydride in 150 ml of absolute diethyl ether. Then S8.66 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 I for a further 16 hours at room temperature and then carefully decomposed with 3.8 ml of water, 3.8 ml of 1. t, 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 I in vacuo. The oily residue is dissolved in diethyl ether. The ethereal phase is washed with water, dried Sover sodium sulphate and concentrated by evaporation.

8.75 g of 2-(2-aminoethyl)chroman are obtained in the form of a colourless oil.

Example 27: 1.5 ml of concentrated hydrochloric acid Sare 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-tetrahydropyridine hydrochloride or 1-[2-(chroman-3-yl)ethyl]-3-cyano-4-oxopiperidine hydrochloride, respectively, in 100 ml of methanol (95% strength) and the whole is boiled under reflux for 15 hours. After cooling, the reaction mixture is concentrated to a volume of approximetely -82ml under reduced pressure and the solution is poured into a mixture of 80 ml of 5N hydrochloric acid and ml of toluene, whereupon, while stirring and cooling, 1- [2-(chroman-3-yl)ethyl]-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylic 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 175-1770 (decomposition) crystallises out.

SThe 1-[2-(chroman-3-yl)ethyl]-3-cyano-4-hydroxy-

I-

1,2,5,6-tetrahydropyridine hydrochloride or 1-[2- S" (chroman-3-yl)ethyl]-3-cyano-4-oxopiperidine hydro- Schloride, respectively, can be manufactured; for example, Sin the following manner: g (0.1 mol) of N-[2-(chroman-3-yl)ethyl]-N- (2-methoxycarbonylethyl)-amine hydrochloride are dissolved in 100 ml of methanol, and then 10.5 g (0.1 S, mol) of triethylamine and 5.84 g (0.11 mol) 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. N-[2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-N-(2-methoxycarbonylethyl)amine is thus obtained in the form of a yellow oil.

A solution of 13.07 g (41.3 mmol) of N-[2- I (chroman-3-yl)ethyl]-N-(2-cyanoethyl)-N-(2-methoxycarbonylethyl)-amine in 200 ml of tetrahydrofuran is added dropwise under a nitrogen atmosphere to a suspension of 5.73 g of 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 2N sulphuric acid, a yellow a- 83 solution is obtained. 300 ml of diethyl 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 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)ethyll-3-cyano-4-hydroxyt 1,2,5,6-tetrahydropyridine hydrochloride or 1-[2- 4 (chroman-3-yl)ethyll-3-cyano-4-oxopiperidine hydrochloride, respectively, crystallises out.

S, Example 28: 17.4 ml of n-butyllithium in hexane are added at 0-50 to a solution of 2.81 g of diisopropylamine in 30 ml of dry tetrahydrofuran. The whole is Sstirred for 30 minutes at room temperature, then cooled to -150 and a solution of 6.24 g (25 mmol) of 1-[2- K (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 Sstirred overnight at room temperature, the solution is filtered and the filtrate is concentrated to dryness by evaporation under reduced pressure. 1-[2-(chroman-3yl)ethyl]-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 1-[2-(chroman-3-yl)ethyl]-4-trimethylsilyloxy-1,2,5,6-tetrahydropyridine obtained are dissolved in 50 ml of dichloromethane and the solution is added dropwise to a solution, cooled to of 2.3 g (24 mmol) of chloroformic acid methyl ester and 60 mg (2.4 mmol) of anhydrous zinc bromide in ml of absolute dichloromethane. After warming up to room temperature, the reaction solution is stirred for I 84 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]-4hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride or 1-[2-(chroman-3-yl)- V ethyl]-4-oxopiperidine-3-carboxylic acid methyl ester hydrochloride, respectively, having a melting point of 175-177° crystallises out.

SThe 1-[2-(chroman-3-yl)ethyl]-4-oxopiperidine can be manufactured, for example, in the following manner: First 8.45 g (55 mmol) of piperidone hydro- Schloride monohydrate and then 22.62 g (175 mmol) of *N-ethyl-N,N-diisopropylamine are added to a solution of 4 16.62 g (50 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman in 100 ml of dimethylformamide. The mixture is stirred for 18 hours at 800 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 2N hydrochloric acid. The hydrochloric acid extracts are combined, rendered alkaline, while cold, with concentrated I sodium hydroxide solution and extracted with dichloromethane. The dichloromethane phases are combined, dried over sodium sulphate and concentrated to dryness by evaporation under reduced pressure. A dark brown resin is obtained which is purified by chromatography on 350 g of silica gel (0.040-0.063 mm) using toluene/ethyl acetate as the eluant. 1-[2- 85 I (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, I a solution of 8.5 g (25 mmol) of 1-[2-(benzo-1,4dioxan-2-yl)ethyl]-1,2,5,6-tetrahydropyridine-3- ,carboxylic acid methyl ester in 50 ml of Stetrahydrofuran 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-.1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4i benzyloxypiperidine-3-carboxylic acid methyl ester is obtained in the form of an oil.

I E SExample 30: At -100 and while stirring, 1.41 g of sodium borohydride are introduced within a period of minutes into a suspension of 8.45 g (18 mmol) of 1-[2- V f (chroman-3-yl)ethyl]-3-methoxycarbonylpyridinium j- I toluenesulphonate in 43 ml of methanol. Stirring is continued for 1 hour at 00 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) using ethyl acetate as the eluant. The main eluate, which is concentrated by evaporation, is treated with ethereal hydrochloric acid to yield 1-[2-(chroman-3ii; 86 yl)ethyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester hydrochloride having a melting point of 175-1770.

The 1-[2-(chroman-3-yl)ethyl]-3-methoxycarbonylpyridinium p-toluenesulphonate can be manufactured, for example, in the following manner: 16.6 g (50 mmol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman and 9.3 g (67.5 mmol) of pyridine-3carboxylic 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 1-[2-(chroman- S3-yl)ethyl]-3-methoxycarbonylpyridinium E-toluenesulphonate is thus obtained in the form of a white I foam.

Example 31: 33.2 g (0.1 mol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman, 14.0 g of N-(2-methoxyt carbonylethyl)-amine hydrochloride and 39 g of N-ethyl- N,N-diisopropylamine are dissolved under nitrogen in S750 ml of dimethylformamide and the solution is stirred Sfor 16 hours at room temperature. The reaction mixture Li is subsequently concentrated to approximately 200 ml under reduced pressure, 500 ml of water are then added 1 and the whole is extracted by shaking three times with I 150 ml of dichloromethane each time. The combined 1organic phases are dried over sodium sulphate and concentrated to dryness by evaporation. By adding ethanolic hydrochloric acid and cooling, N-[2-(chroman- 3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydro- Schloride having a melting point of 190-192o is obtained.

Example 32: 6 ml of concentrated hydrochloric acid are added to a solution of 11.5 g (0.05 mmol) of N- 87 [2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-amine in 100 ml 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, N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride having a melting point of 190-192° is obtained (yield: 82%).

The N-[2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)amine can be manufactured, for example, in the S' following manner: 17.7 g (0.1 mol) of 3-(2-aminoethyl)chroman are 1 dissolved in 100 ml of methanol, and then 10.5 g (0.1 s mol) of triethylamine and 5.84 g (0.11 mol) of acrylo.nitrile 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 S' with ice-water. The ethereal phase is dried over .potassium carbonate and concentrated by evaporation. N- S [2-(chroman-3-yl)ethyl]-N-(2-cyanoethyl)-amine is thus I? obtained in the form of a pale yellow oil.

Example 33: 5.2 g of a mixture of cis- and trans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4benzyloxypiperidine-3-carboxylic acid methyl ester are dissolved in 100 ml of methanol, and then 2 g of palladium-on-carbon are added and the whole is hydrogenated in a Parr apparatus for 12 hours at room temperature. The reaction mixture 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 as the eluant. First the 88 trans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylic acid methyl ester and then the cis-l-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylic acid 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-1-[2- (benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3carboxylic acid methyl ester fumarate which crystallises out in the form of the hemihydrate and Smelts at 150-1520. The residue that contains the cis product is treated with ethereal hydrochloric

S

t acid and thus yields cis-1-[2-(benzo-1,4-dioxan-2yl)ethyl]-4-hydroxypiperidine-3-carboxylic acid methyl t ester hydrochloride which has a melting point of 182-1850.

Example 34: 6.8 g (20 mmol) of a mixture of cisand trans-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4chloropiperidine-3-carboxylic acid methyl ester are dissolved in 20 ml of methanol. 40 ml (140 mmol) of a S'I" 3.5N solution of ammonia in methanol are added dropwise at room temperature. The mixture is left to stand at Sroom 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 2N hydrochloric acid and the acidic aqueous phase is separated off, rendered alkaline with sodium hydrogen carbonate and extracted with diethyl ether/dichloromethane The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulphate and freed of the solvent under reduced pressure. The resulting residue is chromatographed on basic silica gel using 89 dichloromethane/methanol (99:1) as the eluant. The eluates are combined and concentrated to dryness by evaporation. The oily residue consists of pure 4amino-1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine- 3-carboxylic acid amide (cis/trans mixture).

A mixture of cis- and trans-1-[2-(benzo-1,4dioxan-2-yl)ethyl]-4-chloropiperidine-3-carboxylic acid methyl ester can be obtained, for example, as follows: trans-'-[2-(benzo-1,4-dioxan-2-yl)ethyl]-4-hydroxypiperidine-3-carboxylic acid methyl ester (for t manufacture see Example 33) and 3.6 g (36 mmol) of Striethylamine are dissolved in 100 ml of dichloromethane. 3.92 g (33 mmol) of thionyl chloride are Sadded 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-[2-(benzo- 1,4-dioxan-2-yl)ethyl]-4-chloropiperidine-3-carboxylic acid methyl ester is used further in the crude state.

Example 35: At room temperature and while stirring, Ia solution of 11.94 g (30 mmol) of N-(3-ethoxycarbonylpropyl)-N-(2-bromoethyl)-N-[2-(chroman-3-yl)ethyl]amine in 40 ml of absolute dimethylformamide is added dropwise within a period of 20 minutes to a suspension of 2.72 g (40 mmol) of sodium ethoxide in 30 ml of dimethylformamide. The reaction mixture is stirred for 16 hours at room temperature and then concentrated to dryness by evaporation under a high vacuum. Diethyl

I--

90 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-yl)ethyl]-piperidine-4-carboxylic S' acid ethyl ester in the form of a colourless oil. The 1-[2-(chroman-3-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced therefrom using i hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 182-1860.

SThe N-(3-ethoxycarbonylpropyl)-N-(2-bromoethyl)-Ni [2-(chroman-3-yl)ethyl]-amine can be manufactured, for S example, in the following manner: S17.7 g (0.1 mol) of 3-(2-aminoethyl)chroman are ji dissolved in 100 ml of methanol, and then 10.5 g (0.1 i mol) of triethylamine and 19.5 g (0.1 mol) of 4-bromobutyric acid ethyl ester are added to the solution.

The 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. Oily N-(3-ethoxycarbonylpropyl)-N-[2- (chroman-3-yl)ethyl]-amine is thus obtained and can be used further in crude form.

1 29.1 g (0.1 mol) of N-(3-ethoxycarbonylpropyl)-N- [2-(chroman-3-yl)ethyl]-amine are dissolved in 200 ml of methanol, and 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 91 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-ethoxycarbonylpropyl)-N-(2-bromoethyl)-N-[2-(chroman-3-yl)ethyl]amine is thus obtained in the form of an oil which can be used further in the crude state.

SExample 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 N-[2-(chroman-4-yl)ethyl]-N-(2methoxycarbonylethyl)-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 and 33 to 35 it is also possible to obtain 1-[2- (chroman-4-yl)ethyl]-1,2,5,6-cetrahydropyridine-3carboxylic acid methyl ester and its hydrochloride and 1-[2-(chroman-4-yl)ethyl]-piperidine-3-carboxylic acid I ethyl ester and its hydrochloride.

Example 38: Tablets, each containing 25 mg of active *ingredient, for example 1-(benzo-1,4-dioxan-2ylmethyl)-piperidine-3-carboxylic acid methyl ester hydrochloride, can be manufactured in the following manner: 1 t 92 Constituents (for 1000 tablets): active ingredient 25.0 g lactose 100.7 g wheat starch 7.5 g polyethylene glycol 6000 5.0 g talcum 5.0 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 mm.

Sf The active ingredient, the lactose, the talcum, the j magnesium stearate and half of the starch are then i mixed together. The other half of the starch is i suspended in 40 ml of water and the suspension is added i to a boiling solution of the polyethylene glycol in 100 ml of water. The starch paste formed is added to S*the main mixture which is then granulated, if necessary i with the addition of water. The granulate is dried i overnight at 350, forced through a sieve having a I mesh width of 1.2 mm and compressed to form tablets !1 approximately 6 mm in diameter which are concave on both sides.

i Example 39: Tablets, each containing 50 mg of the active ingredient, for example 1-(benzo-1,4-dioxan-2ylmethyl)-piperidine-3-carboxylic acid methyl ester hydrochloride, are manufactured as follows: 93 Composition (for 10,000 tablets): active ingredient lactose potato starch stearic acid talc magnesium stearate colloidal silica ethanol 500.00 g 140.80 g 274.70 g 10.00 g 50.00 g 2.50 g 32.00 g q.s.

I I

L

i fl Pr r

I:

A mixture of the active ingredient, the lactose and 194.70 g of the potato starch is moistened -ith 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 may, if desired, be provided with dividing notches for finer adjustment of the dosage.

100 mg of active ingredient can be incorporated in an analogous mcnner.

Example 40: Capsules, each containing 0.025 g of the active ingredient, for example 1-(benzo-1,4-dioxan-2ylmethyl)-piperidine-3-carboxylic acid methyl ester hydrochloride, can be manufactured as follows: Composition (for 1000 capsules): active ingredient lactose gelatine corn starch talc water 25.00 g 249.00 g 2.00 g 10.00 g 15.00 g q.s.

94 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 mm. The granulate is mixed with the dried corn starch and the talc and 300 mg portions are filled into hard gelatine capsules (size 1).

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

Example 42: In a manner analogous to that described o* in Examples 38 to 41, it is also possible to manufacture pharmaceutical preparations that contain S as active ingredient a different compound of the formula I or a tautomer and/or a pharmaceutically acceptable salt thereof or a different compound of the formula IVc or a pharmaceutically acceptable salt thereof, for example according to Examples 1 to 37.

I.

-4

Claims (12)

1. A compound of the formula X 3 A 11 AH 2\ (IVc) alk-N-CH 2 CH -R 1 H in which R 1 represents carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N- di-lower alkylcarbamoyl, hydroxymethyl, lower alkanoyloxymethyl, lower alkanesulphonyloxymethyl, benzoyloxymethyl or pyridoyloxymethyl, R 3 represents hydrogen or lower alkyl, Salk represents lower alkylene that links the ring system with I 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 in mono-, di- or poly-substituted by i hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl and/or by trifluoromethyl, and either each of X and Y represents an oxygen atom and n represents 1, or X represents Sa 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 S 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 R 3 represents hydrogen, alk is other than methylene if R 1 represents carbamoyl or N-methyl-, N-ethyl-, N,N- dimethyl- or N,N-diethyl-carbamoyl, or a salt thereof.

2. A compound of the formula IVc according to claim 1 in which R 1 represents carboxy, lower alkoxy-carbonyl, carbamoyl, N-lower alkylcarbamoyl or N,N-di-lower alkylcarbamoyl, R 3 represents hydrogen or lower alkyl, alk 0 Yb377e/VMJ L r i.r; I i i ii. i 96 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 in mono-, di- or poly-substituted by hydroxy, lower alkoxy, lower alkanoyloxy, halogen, lower alkyl 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 ring A is unsubstituted, each of X and Y represents oxygen, n represents 1 and R 3 represents hydrogen, alk is other than methylene if R 1 represents carbamoyl or N-methyl-, N-ethyl-, N,N-dimethyl- or N,N-diethyl-carbamoyl, or a salt thereof.

3. A compound of the formula IVc according to claim 1 in S which R 1 represents carboxy, hydroxymethyl, C -C4a l koxycarbonyl or carbamoyl, R 3 represents hydrogen or C -C 4 -alkyl, alk represents C 1 -c 4 -alkylene that links the ring system with the NH group shown in formula IVc by up to and including 3 carbon atoms, the ring A is unsubstituted or is substituted, 1 especially in the 7-position, by C 1 -C 4 -alkoxy, 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 SE' 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 S 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 R 3 represents hydrogen, alk is other than methylene if R 1 represents carbamoyl, or a salt thereof.

4. A compound of the formula IVc according to claim 1 in which R 1 represents C 1 -C 4 -alkoxycarbonyl, R 3 represents hydrogen or C 1 -C 4 -alkyl, alk represents S 377e/VMJ 377e/VMJ r -97 C1- 4 -alkylene that links the ring system with the NH group shown in formula IVc by up to and including 3 carbon atoms, the ring A is unsubstituted, X represents an oxygen atom or a methylene group, Y represents an oxygen atom and n represents 1, or a salt thereof. I A compound of the formula IVc according to claim 1 in which R 1 represents C 1 -C 4 alkoxycarbonyl, R 3 I represents hydrogen, .aTh 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 a salt thereof.

6. N-f 2-(chroman-.3-yl)-ethyl]-N-(2-methoxycarbonyl-ethyl) amine or a salt thereof.

7. 2-methoxycarbonylethyl) (benzo-1, 4-dioxan-2-ylmethyl) "fit, amine or a salt thereof. a. N-(2-methoxycarbonylethyl) -N-(chroman-3-ylmethyl) -amine carbonylethyl)-amine or a salt thereof. 1% iu~1. N-( 2 -methoxycarbonyethyl)N-2methylbenzo -,4dioxa..2- ylmethyl)-amine or a salt thereof.

11. N-2(hoa--l-ty]N(-abxehl-mn or a If salt thereof.

12. N-2(hoa--l-ty]N-2mtoyabnlehl- amine or a salt thereof.

13. N-f 2 -(chroman- 4 -yl)-ethyl]-N-(2-methoxycarbonyl.ethyl) amine or a salt thereof. ;i I I I -r 98

14. Process for the manufacture of a compound of the formula IVc, or a salt thereof, according to any one of claims 1 to 13, characterised in that h) compounds of the formulae X R A S (CH Y alk-Z 1 and Z 2 -CH 2 -CH(Z 3 )-R 1 (VIIIa) (VIIIb) in which one of the radicals Z 1 and Z 2 represents reactive S. esterified hydroxy and the other represents amino, and Z Srepresents hydrogen, or Z 1 represents amino, and Z2 and Z together represent an additional bond, or optionally salts of these compounds, are reacted with one another, or i) in a compound of the formula 3 y• (2 n (IX) alk-N-CCH 2 CH- in which X 6 represents a radical that can be converted into R1, or in a salt thereof, X 6 is converted into R1' and, if desired, in the case of each of processes h) and a compound obtained in accordance with the process or by other means is converted into a different compound of the formula IVc, an isomeric mixture obtained in accordance with the process is separated into the components, an enantiomeric or N 77e/VMJ No' -99 diastereo-isomeric mixture obtained in accordance with the process is separated into the enantiomers or diastereo-isomers, respectively, a free compound obtained in accordance with the process is converted into a salt and/or a salt obtained in accordance with the process is converted into the free compound or into a different salt. A pharmaceutical preparation containing as active ingredient a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, together with customary pharmaceutical adjuncts.

16. Process for the manufacture of a pharmaceutical preparation according to claim 15, characterised in that a E: pharmaceutically acceptable salt thereof, together with "customary pharmaceutical adjuncts, is admixed and processed to form a pharmaceutical preparation. I r 17. A nootropic pharmaceutical preparation according to claim S. 15, characterised in that a nootropic active ingredient is tttti j selected. I 18. Method for the treatment of the symptoms of cerebral .t insufficiency, characterised in that a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable I salt thereof or a pharmaceutical preparation according to claim 15 or 17 is administered.

19. A compound as defined in claim 1, substantially as herein described with reference to any one of the Examples that describe said compound. DATED this 3rd day of October, 1991. RBy Their Patent Attorneys S\ ARTHUR S. CAVE CO. 0377e/VMJ A