MC1029A1 - Tetrahydropyridine and piperidine derivatives and process for their manufacture - Google Patents

Description

-1-

The present invention relates to novel tetrahydropyridine and piperidine derivatives which exhibit valuable pharmacological properties, a process for manufacturing these novel compounds and therapeutic preparations which contain them.

The novel compounds according to the present invention, derived from tetrahydropyridine and piperidine, correspond to the general formula I:

in which represents a hydrogen atom, an aliphatic hydrocarbon radical 20 with 1 to 12 carbon atoms or a cycloaliphatic hydrocarbon radical with 3 to 12 carbon atoms, these radicals being able to be substituted by hydroxyl groups or an oxo radical and/or interrupted by an oxygen atom, or represents a phenyl-(lower alkyl) radical 25 in the benzene ring of which at most three of the hydrogen atoms may be replaced by substituents from a halogen up to atomic number 33 of the lower alkyl or lower alkyl groups, the methylenedioxy and trifluoromethyl groups, and whose lower alkyl chain may be 30 substituted on a carbon atom by an oxo or hydroxyl group that is not directly attached to the cyclic nitrogen atom, or represents a cinnamyl radical correspondingly substituted possibly on the benzene ring, but which is not however not a methyl group, in the case where A represents an ethylene radical and B a methylene group, and at the same time R2, R1, R2 and R3 each represent a hydrogen atom, R1 represents a hydrogen atom or a lower alkyl group, R2 and R3 independently represent a hy- atom

-2-

drogen, a lower alkyl or lower alkoxy group, a halogen atom. Up to atomic number 35, benzyl-oxy or hydroxyl groups and R^ also represent a trifluoromethyl group, a 1-hydroxyalkyl (lower) group or an alc-5 1-enyl (lower) group, a 1-hydroxycycloalkyl group, cycloalc-

1-enyl or cycloalkoyl, each with 5 to 8 carbon atoms, or R^ and R^ together represent a trimethylene or tetramethylene radical, or correspondingly a condensed benzene ring, the 1,3-butadienylene radical; R^ represents an atom

10 of hydrogen or an alkyl group with at most 4 carbon atoms, and A and B represent saturated divalent aliphatic hydrocarbon radicals and one of these symbols may also represent a direct bond, and A and B also represent three chain elements and with R^ present at most 9 carbon atoms, X and Y each represent a hydrogen atom or together represent an additional bond.

Also part of the object of the present invention are addition salts, in particular pharma-20 ceutically acceptable addition salts of compounds of general formula I with mineral and organic acids, as well as the manufacture of these addition salts.

In compounds of general formula I, R^ represents an aliphatic or cycloaliphatic hydrocarbon radical, the 25 where appropriate substituted according to the definition or interrupted by an oxygen atom, for example an ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, 1-methylhexyl, octyl, nonyl, decyl, dodecyl, allyl, crotyl, 2-methylallyl, 2-propinyl, cyclopropyl, 30 cyclopropylmethyl, cyclobutylmethyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentylethyl, cyclohexylmethyl, 2-norbornanylmethyl, bicyclo[2,2,2]oct-2-ylmethyl, 1-adamantylmethyl, 3-cyclohexen-1-ylmethyl, 2-nor-bornen-5-ylmethyl,

2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxy-35 butyl, 2,3-dihydroxypropyl, acetonyl, 3-oxo-butyl, 2-hydroxy-

cyclohexyl, 2-oxo-cyclohexyl, 2-methoxyethyl, 2-ethoxyethyl, 2-isopropoxyethyl, 3-methoxypropyl, 2-butoxyethyl, 2,3-dimethoxypropyl, 3,3-diethoxybutyl, 2-(2-ethoxyethoxy)ethyl,

"f

-3-

2-cyclohexyloxyethyl, 2-(1-adamantyloxy)ethyl, furfuryl, tetrahydrofurfuryl, (2,2-dimethyl-1,3-dioxolan-4-yl)-methyl, or 2-(2-methyl-1,3-dioxolan-2-yl)-ethyl, or possibly a methyl group. If R is a substituted phenyl(lower alkyl) group as defined, it is advantageously one of those with 1 to 3 carbon atoms in the lower alkyl chain. The lower alkyl and alkoxy groups as substituents of the phenyl radical comprise from 1 to 7 carbon atoms, preferably 1 to 4, and are primarily methyl and methoxy groups. Examples of substituted phenyl-(lower alkyl) and cinnamyl radicals, possibly in accordance with the definition, may be cited as benzyl groups, p-fluoro-, o-, m- or p-chloro-, p-bromo-, 3,4-dichloro-, p-methyl-, p-isopropyl-, 15-o- or p-methoxy-, p-ethoxy-, p-isopropoxy, 3,4-dimethoxy-, 3,4-,5-trimethoxy-, 3,4-methylenedioxy and p-trifluoromethylbenzyl groups, as well as phenethyl, α-methylphenethyl, 2-phenylpropyl, p-hydroxyphenethyl, 3-hydroxy-3-phenylpropyl, phenacyl, 2-benzoylethyl or cinnamyl groups, which may, for example, be substituted in a manner analogous to the aforementioned benzyl groups.

As a lower alkyl group, it represents in particular one of those which have 1 to 4 carbon atoms, and especially the methyl group.

^e substituent R^ is for example as halogen atom, a fluorine, bromine and in particular chlorine atom, as lower alkyl or lower alkoxy group, one of those which have 1 to 7 carbon atoms, advantageously from 1 to 4 carbon atoms, for example an ethyl, isopropyl, tert-butyl, ethoxy, propoxy, isopropoxy, butoxy, or isobutoxy group, but especially a methyl or methoxy group. As a lower 1-hydroxyalkyl or alk-1-enyl group, R^ preferably contains 1 to 5 or 2 to 5 carbon atoms and are, for example, the hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxy-1-methylethyl, 1-hydroxybutyl, 1-hydroxy-1-methylpropyl, or 1-hydroxy-1-ethylbutyl groups, or the vinyl, prop-1-enyl, isopropenyl, but-1-enyl, 1-methylprop-1-enyl, or 1-ethylprop-1-enyl groups. As 1-hydroxycycloalkyl, cycloalc-1-enyl, or cycloalkyl groups with 5 to 8 carbon atoms, R^ represents

-4-

for example the 1-hydroxy-cycloheptyl, 1-hydroxy-cyclooctyl, cyclohept-1-enyl, cyclooct-1-enyl, cycloheptyl, or cyclooctyl groups, advantageously however, the 1-hydroxy-cyclopentyl, cyclopent-1-enyl, or cyclopentyl groups and especially the 5 1-hydroxy-cyclohexyl, the cyclohex-1-enyl or the cyclo-hexyl group.

Gum halogen atoms or lower alkyl or alkoxy groups, R^ represent in particular those which have been indicated above for the radicals cited for R^ as corresponding substitutes.

A methylene-dioxy group R^+R^ is advantageously located at position 5»6, and this also applies to trimethylene and tetramethylene radicals, while a condensed benzene ring Rj+R^ is found at position 5? 6- or 6,7- in particular, however at position 4,5.

R^ as a lower alkyl group is in particular an ethyl, propyl or n-butyl group or in particular a methyl group.

The saturated divalent hydrocarbon radicals A and B are methylene, ethylene, and trimethylene radicals and the corresponding lower alkyl radicals which, together with R^ or in the case where A and B represent the direct bond and R^ represents a hydrogen atom, individually have at most 9 carbon atoms, such as, for example, the ethylidene, propylidene, dimethylmethylene, and propylene groups.

1-ethylethylene, 1,1-dimethylethylene, 1-methyltrimethylene,

2-methyltrimethylethylene, 1-ethyltrimethylene, 1,1-dimethyltrimethylene, or 2,2-dimethyltrimethylene. In the case where A represents the direct bond or a radical with one or three elements

30 elements in the chain, such as the methylene and trimethylene groups, and B correspondingly represents a radical with two or three elements in the chain or direct bond, the symbols S and I advantageously represent a hydrogen atom, but they can possibly also represent an additional 35 bond.

Compounds of general formula I and their addition salts with organic and mineral acids possess valuable pharmacological properties. They delay in the Rat

-5-

and other types of experimental animals, after oral or subcutaneous administration in a dose range of 2 to 100 mg/kg, mono-aminooxidase in particular is selective against its A form, as evidenced by the results of isotopic determinations of enzymatic activity. At the same time, they delay the uptake of noradrenaline in the heart in rats, by oral or subcutaneous administration of 2 to 100 mg/kg, and also prevent serotonin from reaching the synaptosomes of the midbrain in rats. Furthermore, they delay the arrival of serotonin in human blood platelets in vitro, depending on the concentration. In addition, they are antagonistic, by intraperitoneal administration in rats, at doses between 2 and 40 mg/kg, to the effect of tetrabenazine. Together, with a favorable therapeutic index, the 15 compounds of general formula I and their pharmaceutically acceptable salts with mineral or organic acids are characterized as antidepressants, which can be administered, for example, orally or parenterally, for the treatment of mental depressions.

20 Particularly interesting compounds of formula I

are those in which R^ represents a hydrogen atom, while R^ represents a methyl group or advantageously a hydrogen atom, and Rj, E^, E^, A, B, X, and Y have the meanings given under formula I. Those of this group that are preferred 25 are also generally those of the compounds of general formula I in which R^ represents a hydrogen atom, a halogen up to atomic number 55, a lower alkyl or lower alkoxy group, the trifluoromethyl group, or a 1-hydroxycycloalkyl, cycloalc-1-enyl, or cycloalkyl group, each with 5 to 8 carbon atoms, preferably in position 5, and R^ represents a hydrogen atom or a lower alkyl group, the latter next to a lower alkyl group E^ in position 6, or R^ + R^ represents a condensed benzene ring in position 4, 5, or a trimethylene radical in position 5, 6. R^ re-35 presents a hydrogen atom or a methyl group, A and B represent a methylene, ethylidene, ethylene, propylene, or trimethylene radical, and direct bonding is possible provided that the sum of the chain elements is 3, and for X and Y a

additional bond or preferably especially when A does not represent a radical with two chain elements, contains hydrogen. Particularly important compounds are those in which R and R represent a hydrogen atom, R represents a hydrogen, chlorine, or bromine atom, or methyl or methoxy groups, advantageously at position 5, a hydrogen atom, or, especially next to the methyl group in R, the group R as the methyl group, hydrogen as R, a methylene group for A and an ethylene group for B, or preferably an ethylene group for A and a methylene group for B and an additional bond, or advantageously a hydrogen atom, for X and Y. Similarly, important compounds are those of general formula I in which R represents an alkyl group with at most 4 carbon atoms, especially the methyl group, and also allyl, 3-oxobutyl, or 3-hydroxybutyl groups, and especially those containing 2-propinyl or cyclopropylmethyl groups, while R2, R1, R1, A, B, X, and Y have the meanings given under formula I or advantageously, the preceding restricted meanings or especially the preceding specific meanings, to which it is appropriate to pay attention to the conditions indicated for the presence of a methyl group in R^. Particularly important compounds are for example 4-(2-benzofuranyl)-piperidine, 4-(5,6-dimethyl-2-benzofuranyl)-piperidine and 3-(2-benzofuranyl)-piperidine and their addition salts with pharmaceutically acceptable acids, such for example as hydrochloride.

The novel tetrahydropyridine and piperidine derivatives of general formula I and their addition salts with acids are manufactured according to the present invention in that

(a) the radical Ac is separated in a way known in itself in a compound of general formula II

-7-

5

10

15

20

25

30

35

in which Ac represents a separable radical and R2, Rj, and have the meanings given under formula I, and

(b) if desired, a compound obtained according to (a) or in another way of the formula la which enters into the general formula I is reacted

in which have the meanings given under the general formula I, with a reactive ester of a hydroxylated compound of general formula III

HO - R^ (III)

in which R^ has the meaning given for R^ of formula I excluding hydrogen, and represents the methyl group in the case where in the formula the ^5 represent a hydrogen atom, A represents an ethylene group and B a methylene group,

or under reducing conditions, with an oxo compound of general formula Illa

0 = . (IY)

in which R^ corresponds to a monovalent radical R^ and represents a divalent geminal radical, or else we add to a compound of general formula Illb

•pe -nd 'l 1

CH = C - CO - R° (Illb)

in which R°, R^", R® represent separate or bonded radicals, the -CH-CH-GO group entering the definition of R^ to complete the substituted oxo group, or else it is condensed with formaldehyde and a compound of general formula

-8-

15

IIIc s?

CH2 1

in which E^j and E^ represent separate or bonded radicals that complete the -CB^-CH-CO- group into an oxo-substituted radical that falls within the definition of , or

(c) the carbonyl or aeoxycarbonyl group is reduced in a compound of general formula IV

CO - Ei

(IIIc)

10

E,

N-CO-Et

(IV)

20 in which E^ represents a radical corresponding to the definition of E^ except the methylene group, or in the case where at least one of the symbols Ep, Rj, E^ and E^ do not represent a hydrogen atom and/or A does not represent an ethylene group and/or B does not represent a methylene group, can also represent -25 a lower alkoxycarbonyl group, or

(d) a compound of general formula V is reduced

30

E,

R„

R.

Rr y

- ES

Rr

©

on

35

in which Z ~ represents a monovalent anion or the normal equivalent of a polyvalent anion, Rg and Rr represent a hydrogen atom or an alkyl radical with together at most

_Q_ ✓

3.

6 carbon atoms, and E^, Ep, Rj and have the meanings given under formulas III or I, partially in a corresponding compound of general formula I in which X and Y represent an additional bond, or else, 5 (e) the hydrogenation of a compound of general formula V given above or a compound of general formula VI is carried out

E4 E,

6

15 in which Eg, Rj, R^, Rg and Rr have the meanings given under formula I or under formula V, or a compound of general formula Ib entering into general formula I

in which R^, E2, E^, E^, E^, A and B have the meanings given under formula I, by catalytic means in a compound of 30 piperidine, or

(f) cyclization of a compound of general formula VII is performed

-10-

in which Bg represents a lower alkoxy group or a lower (l-alkoxy-alkoxy) group; the two alkoxy groups can also be linked in a ring of 5 or 6 elements, E^ has the meaning given under formula III, and B^, B^, B^, A, B, 5 X and Y have the meanings given under formula I, or an alkali metal derivative of a compound of formula VII, by heating in acidic medium, or

(g) Hydrogenation is carried out on a compound of general formula I whose E^ group contains a double bond

10 or triple non-aromatic and/or is an oxo radical and in which X and Y represent a hydrogen atom, while B^, Bj, B^, B^, A and B have the meanings given under formula I, in the corresponding compound, whose E^ group does not contain a triple bond or no or a small number of double bonds

15 non-aromatic bonds and/or contains a primary or, in particular, secondary hydroxyl group, or

(h) a compound of general formula I is reduced whose group E^ contains an oxo radical while Ep, E^, R^, E^, A, B, X and Y have the meanings given under formula I, in

2.0 corresponding compound, whose group B^ contains a primary hydroxyl group or in particular a secondary hydroxyl group, or

(i) a compound of general formula I is hydrolyzed, in which R represents a benzyl group even-

25 actually substituted according to the definition, and/or E^ and/or R^ represent possibly inert substituted benzyloxy groups, and X and Y represent a hydrogen atom, while Rg, R^, A and B as well as where applicable R^_ and/or R^ have the meanings given under the formula I or

30 days) We heat until a certain amount is released

approximately equimolar of carbon dioxide a compound of general formula VIII

35

COOH

N - R,

(VIII)

-11-

in which E^, E^, E^, A, B, X and Y have the meanings given under the claim, or

'(k) a compound of general formula IX is reacted

10

R,

r:

R.

0

(IX)

in which Z represents a metal radical, Ea and E^ have the meanings given under formula I for E^ or E^ excluding hydroxyl groups and radicals substituted by hydroxyl groups, and E2 has the meaning given under formula I, with a reactive ester of a compound of general formula X

20

25

HO -

E'

h

(X)

in which E^ corresponds to a radical of the definition given under formula I excluding hydrogen as well as hydroxyl or oxo-substituted radicals and Aa and Ba have the meanings given under formula I for A or B excluding the direct bond for Aa and a radical with three elements of

Q

chain for B, and has the meaning given under the formula I or

(1) water is separated from a compound of general formula XI

Y

H R,

10

in which R25 ^3» % ^5 o11^ has the meanings given under formula I, Ra has the meaning given under formula III, and Aa and Ba have the meanings given under formula X, or from a compound of general formula I in which Rj represents a lower 1-hydroxyalkoyl group or a 1-hydroxycycloalkoyl group with 5 to 8 carbon atoms, while E^j has the meaning given under formula I excluding hydrogen, and R2, R^, E^, A, B, X, and Y have the meanings given under formula I, or,

20 (m) a chlorine or bromine atom is introduced at position 5 into a compound of general formula I in which E^ has the meaning given under formula I excluding hydrogen as well as radicals substituted by oxo and hydroxyl groups, B^, B^_, X and Y represent a hydrogen atom 25 and R2, A and B have the meanings given under formula I or in 1-methyl-4-(2-benzofuranyl)-pyridine, or

(n) a compound of general formula I in which E^ has the meaning given under formula I excluding hydrogen and radicals substituted by oxo or hydroxyl groups, and phenyl (lower alkyl) radicals substituted by a halogen atom, E^ represents a chlorine or bromine atom and a hydrogen atom or a lower alkyl group and B2, R^, A, B, X and Y have the meanings given under formula I, is transformed into a corresponding compound with a metal radical in place of R^ and this latter compound is reacted with an oxoalkane or an oxoalkanone with 5 to 8 carbon atoms, or

(0) a compound of general formula XII is treated with a strong acid

-13-

(XII)

10

15

20

in which E^ has the meaning given under formula III and E2, Rj and E^ have the meanings given under formula I or the crude product of the reaction of a compound of general formula XIII

(XIII)

of twice the molar quantity of formaldehyde and a compound of general formula XIV

H2ïï - E1 (XIV)

in which E^ has the meaning given under claim 1 and is used as an addition salt with a strong acid or together with one of them, and if desired a compound obtained in accordance with the processes indicated under (a) to (o) of general formula I is transformed into an addition salt with an organic or mineral acid.

The separable radical Ac is, in particular, an acyl radical. Its cleavage can be achieved, for example, by hydrolysis, solvolysis, hydrogenolysis, or reduction. In raw materials of general formula II, Ac can, for example, represent any acyl organic group, such as a lower alkanoyloxy group like the acetyl group, or an arene- group.

-14-

carbonyl groups, such as the benzoyl group, a iaene-sulfonyl or arene-sulfonyl group, such as methane-sulfonyl or p-toluene-sulfonyl groups, or even a mineral acyl group such as nitroso-NO. Among these, acyl groups are preferred because they ensure easy availability of the compounds containing them with general formula II and/or are relatively easy to separate. From these points of view, acyl groups are considered in particular, on the one hand, especially the acyl groups of semi-esters of carboxylic and thiocarboxy-10 leagues, in particular groups separable by hydrolysis, for example lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl groups, as well as phenoxycarbonyl and benzyloxycarbonyl groups, and also methoxythiocarbonyl and methylthiothiocarbonyl groups, 15 and on the other hand, acyl groups of other derivatives of carboxylic acids such as chlorocarbonyl groups and in particular cyano groups.

II, according to process (a), can be carried out in an alkaline medium or in an acidic medium. For example, it is carried out by prolonged heating with an alkali metal hydroxide, in particular sodium or potassium hydroxide, in a hydroxylated compound in the presence of a little water, at a temperature between about 80 and 200°C. A suitable reaction medium is in particular ethylene glycol or one of its lower monoalkyl ethers,

as well as, when carrying out hydrolysis in a closed container, also with a lower alkanool such as methanol, ethanol or butanol. In addition, compounds of general formula II in which Ac represents a cyano group, i.e. the acyl radical of cyanic acid or a chlorocarbonyl group, can be hydrolyzed in particular by heating with a mineral acid in an aqueous or hydro-organic solvent, for example by boiling for several hours in a mixture of 85% phosphoric acid and diformic acid, or by heating for several hours in 48% hydrobromic acid or in a mixture of hydrobromic acid and acetic acid at about 60-100°C, advantageously from 60 to 70°C.

the hydrolysis of compounds with a new general formula

Other separable groups Ac are groups formed

\

-15-

by adding a methyl group in place of Ac, from a lower dialcoyl ester of azodicarboxylic acids, which can be advantageously separated by hydrolysis in acidic medium, in particular by boiling in dilute 5 hydrochloric acid, for example 1 N with release of the lower dialcoyl ester of hydrazo-dicarboxylic acid.

An example of a group separable by solvolysis is the tert-butoxycarbonyl radical, which can be separated under anhydrous conditions by treatment with a suitable acid, such as trifluoroacetic acid.

Examples of Ac radicals that can be separated by reduction are α-aralkoxycarbonyl radicals, such as the benzyloxycarbonyl radical, which can be separated in the usual way by hydrogenolysis, in particular by catalytically activated hydrogen, such as hydrogen in the presence of a hydrogenation catalyst, for example palladium, platinum or nickel. Other radicals that can be separated by reduction are, for example, 2-halo-alkoxycarbonyl radicals, such as the 2,2,2-trichloroethoxycarbonyl radical or the 2-iodoethoxy-20 radical or the 2,2,2-tribromoethoxycarbonyl radical, which can be separated in the usual way, in particular by metallic reduction (what is referred to as nascent hydrogen). Nascent hydrogen can be obtained by the action of metals or metal alloys, such as amalgams, on hydrogen-producing agents, 25 such as carboxylic acids, alcohols, or water, taking into account in particular zinc or zinc alloys with acetic acid. The reduction of 2-halo-alkoxycarbonyl radicals can also be achieved by chromium(II) compounds such as chromium(II) chloride or chromium(II) acetate. 30 A reductively separable Ac radical can also be a sulfonyl group such as a lower alkane-sulfonyl or aryl-sulfonyl group, for example, the methane-sulfonyl or p-toluene-sulfonyl group, which can be separated in the usual way by reduction with nascent hydrogen, for example with an alkali metal such as lithium or sodium in liquid ammonia, or also by electrolysis.

The manufacture of raw materials of general formula II will be explained below.

-16-

Reactive esters of compounds of general formula III suitable for the reaction of compounds of general formula Ia according to process (b) include, for example, esters of hydrohalic acids, in particular chlorides, 5-bromines, and iodides, as well as esters of lower alkanesulfonic and arenesulfonic acids, such as esters of methanesulfonic acid or esters of benzenesulfonic acid and p-toluenesulfonic acid, and esters of other strong acids such as sulfuric acid esters like dimethyl sulfate and diethyl sulfate. Reactions with compounds of general formula Ia are preferably carried out in the presence of an acid-immobilizing agent in an inert organic solvent under the reaction conditions. Suitable acid immobilizers include, in particular, tertiary organic bases such as triethylamine, pyridine, symmetric collidine, and especially ethyl diisopropylamine, or basic mineral substances such as sodium or potassium carbonate. Suitable solvents include, for example, lower alkanols such as methanol, ethanol, isopropanol, or butanol; ethereal compounds such as dioxane, tetrahydrofuran, or 2-methoxyethanol; lower aliphatic ketones such as methyl ethyl ketone; and amides of N-substituted acids such as dimethylformamide or N,N,IP,N',N",N"-hexa-25-methylphosphoric acid triamide. The reaction temperature is between approximately 0 and 200°C, advantageously between room temperature and approximately 120°C. The reaction temperatures required for reactions with reactive esters of primary hydroxylated compounds are mainly within the lower part of the indicated range, whereas reactions with reactive esters of non-primary hydroxylated compounds are carried out at higher temperatures and, where appropriate, in closed reaction vessels, in which the introduction of a particularly effective acid immobilizing agent such as ethyl-diisopropylamine is advantageous.

Reactions of compounds with the general formula α with oxo compounds of the general formula α1 can take place, for example, in formic acid at temperatures between -

-17-

at approximately 70 and 100°C or, where appropriate, also under the action of hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum oxide, or palladium on carbon, at ambient temperature and pressure 5 or moderately elevated, in a suitable organic solvent such as ethanol or dioxane. Oxo compounds are considered in particular aliphatic aldehydes with at least two carbon atoms, aliphatic or cycloaliphatic ketones, benzaldehyde, and substituted benzaldehydes 10 according to the definition. But above all, they are particularly suitable insofar as a reaction component is used a compound of general formula la in which at least one of the radii R2, R^, R^ and R^ is different from hydrogen, and/or A is not ethylene and/or B is not methylene, formaldehyde is used which is advantageously applied with formic acid as a reducing agent.

unsaturated oxo of general formula Illb is carried out for example in an inert organic solvent such as benzene at 20 ambient temperature or, if necessary, by heating.

In raw materials of general formula Illb, at least one of the symbols preferably represents a hydrogen atom for R^ and R®; those of the compounds which are distinguished by a good reactivity and ease of obtaining are those in which 2> of the two symbols represent hydrogen.

The reaction of formaldehyde and a compound of general formula IIIc can be carried out under the usual conditions of the Mannnich reaction, for example by heating the hydrochloride of a compound 30 of general formula Ia with formaldehyde, which is advantageously introduced as an aqueous solution or as paraformaldehyde, and preferably in excess, in an organic solution at a temperature between approximately 70 and 140°C or at the boiling point of the reaction medium, if it is below 140°C. Suitable solvents include, in particular, lower alkanols such as ethanol, methanol, isopropanol, butanol, or isopentanol, as well as other water-miscible solvents such as dioxane.

The addition of compounds of formula la to compounds

The condensation of compounds of general formula la with

-18-

The reactive esters of hydroxyl compounds of general formula III, oxo compounds of general formula IIIa, and compounds of general formulas IIIb and IIIc are mostly known, and others are prepared in a manner analogous to that of the known compounds. The raw materials of general formula Ia are generally manufactured according to the process indicated in (a). Another advantageous manufacturing process for these compounds, in which X and Y represent a hydrogen atom, is the hydrogenation mentioned in (e), and further on, the hydrogenation indicated for substituted 2-, 3-, or 4-(2-benzofuranyl)-pyridines, possibly corresponding to the definitions for Rj, R^, Rg, and R,-?.

The reduction of amide groups of compounds of general formula IV according to (c) is carried out, for example, using lithium 15-tetrahydroaluminate or diborane in an ethereal solvent such as diethyl ether, tetrahydrofuran, dibutyl ether, or diethyl diethylene glycol ether, or mixtures thereof, at a temperature between approximately 20 and 100°C or at the boiling point of the reaction medium used, if it boils below 100°C. Diborane can be prepared and introduced either separately or formed in situ from sodium borohydride and boron trifluoride ether. The preparation of the raw materials of general formula IV will be explained below. 25 The partial reduction of compounds of general formula

V according to (d) is advantageously carried out using sodium or potassium borohydride in a hydro-organic medium, in that, for example, to a previously prepared solution of the raw material of general formula V in a water-miscible organic solvent 30, for example in a lower alkanool such as methanol or ethanol or their mixtures with water, an aqueous solution of sodium borohydride is gradually added and then a further reaction mixing time is allowed, maintaining a reaction temperature 35 between about 5 and 60°C, advantageously between ambient temperature and 35°C. The manufacture of the raw materials of general formula V will be explained below.

Catalytic hydrogenation of compounds with the following formulas

The hydrogenation of general formulas V, VI, and Ib can be carried out using common hydrogenation catalysts such as palladium on carbon or platinum oxide, rhodium catalysts such as rhodium on carbon or aluminum oxide, or alloy-skeleton catalysts such as Raney nickel, in an inert organic solvent such as methanol, ethanol, or dioxane, at room temperature and under normal pressure, or at moderately elevated temperatures up to approximately 100°C and under high pressure, for example, up to approximately 100 bar. The hydrogenation of tetrahydropyridine derivatives of general formula Ib is generally carried out under more moderate conditions than the hydrogenation of compounds of general formula VI, and particularly those of general formula V. For the hydrogenation of the latter, rhodium catalysts on aluminum oxide are considered in particular. The hydrogenation of compounds of general formula Ib, in which R represents a benzyl group, possibly substituted, whose cleavage must be avoided, is preferably carried out with one equivalent of hydrochloric gas, and after absorption of an equimolar quantity 20 of hydrogen, it is stopped. The manufacture of raw materials of general formula VI will be explained below. Raw materials of general formula Ib are manufactured, for example, according to one of the aforementioned processes for the manufacture of compounds of general formula I, advantageously by the partial reduction 25 indicated under (d) of the corresponding pyridinium salts.

For cyclization according to (f), a compound of general formula VII is transformed, for example, first by heating with an alkali metal amide or hydride, advantageously sodium hydride, in an inert solvent medium, such as dioxane, at a moderately high temperature, advantageously around 80°C, into an alkali metal derivative, in particular the sodium derivative. This can be precipitated, for example, by the addition of petroleum ether and separated by filtration, and then cyclized, for example, by boiling in 48% hydrobromic acid, into a compound of general formula I. The manufacture of raw materials of formula VII will be explained below.

-20-

Hydrogenation according to (g) can be carried out essentially as described for the preceding process (e) under the same reaction conditions and using the same catalysts indicated therein. In this way, the hydrogenation of a suitable R group can be performed in a single working step, as can hydrogenation according to process (e). Examples of hydrogenable R groups include allyl, 2-methylallyl, 2-propinyl-3-cyclohexen-1-ylmethyl, 5-norbornen-2-ylmethyl, cinnamyl, 3-oxobutyl, phenacyl, and 10-2-benzoylethyl.

The reduction according to (h) is carried out essentially like the partial reduction according to (d) indicated above, under the reaction conditions shown, advantageously using sodium borohydride, and can also be combined with the process indicated under (d). The appropriate reducible group R^ is, for example, the 3-oxobutyl, phenacyl, and 2-benzoylethyl group.

The separation by hydrogenolysis of a possibly substituted benzyl group R^ according to (i) is essentially carried out under the reaction conditions indicated in the preceding process (e) and using the catalysts specified therein. This step of the hydrogenolysis can also be carried out simultaneously with the hydrogenation according to (e); however, it can also be carried out separately as indicated, particularly for the selective hydrogenation of the cyclic double bond of compounds of general formula Ib, while retaining a benzyl group R^. Under the same reaction conditions as in process (e), the hydrogenolytic cleavage of inert substituted benzyloxy groups Rj and/or R^_ can also be carried out. "Inert" substituents are those which, during hydrogenolysis, are neither modified nor disruptive upon their removal. For these substituents, we mainly consider lower alkyl and lower alkoxy groups such as methyl and methoxy groups.

The decarboxylation of compounds of general formula 35 VIII, the manufacture of which will be described below according to process (j), is carried out, for example, by heating to approximately 250 to 300°C and above, advantageously in the presence of an alkaline earth metal oxide, in particular calcium oxide.

-21-

can also first transform carboxylic acids of general formula VIII into alkali or alkaline-earth metal salts, or into copper, mercury or silver salts and heat these salts to the indicated temperatures.

5 In the raw materials of general formula IX for process (k), the metal radical Z is a monovalent radical of a metallic compound or of a metal, for example, a magnesium halogen radical such as Cl-Mg, Br-Mg, or I-Mg, or the radical of an alkali metal, in particular lithium. The reaction 10 can be carried out in a manner known per se in an inert organic solvent, in particular in an ether or an ethereal solvent such as diethyl ether or tetrahydrofuran, advantageously at room temperature or at a slightly higher temperature up to the boiling point of the solvent used. 15 Advantageously, it is carried out in an inert gas atmosphere, for example, under nitrogen or argon. The reactive esters of compounds of general formula X are advantageously esters of strong acids, in particular of sulfonic acids for example arenesulfonic acids and lower alkanesulfonic acids 20 such as p-toluenesulfonic acid or methanesulfonic acid and of hydrohalic acids especially hydrochloric and hydrobromic acids.

The separation of water according to process (1) is carried out in a manner known in itself by heating the compound of general formula XI or compounds of general formula I suitable for the separation of water, advantageously removing the water formed and preferably in the presence of a strong acid, for example sulfuric acid, which can be used concentrated but in small quantity, or p-toluenesulfonic acid. The separation of water can also be carried out by heating in an inert organic solvent, for example in a water-miscible solvent such as benzene, toluene, or xylene, and advantageously removing the water.

The introduction of a chlorine or bromine atom according to "35 the process (m) can be done in the usual way in particular at a temperature which is not high or by cooling and in the presence of a catalyst such as iron, iodine, iron(III) chloride, aluminium chloride or the corresponding bromides.

-22-

In compounds suitable as starting materials for the process seion (11) of general formula I, the chlorine or bromine atom R^ is advantageously transformed, using activated magnesium, into a magnesium chlorinated radical or magnesium brominated radical 5, or using an alkali metal compound such as butyllithium, and replaced by an alkali metal radical, in particular the lithium radical, in which, for example, an ether or an ethereal solvent, such as diethyl ether or tetrahydrofuran, is used as a solvent. The following reaction can be carried out in the same medium or, where appropriate, with the addition of an inert solvent such as benzene, with lower oxoalkanes or cycloalkanones as defined, for example, at a temperature between -10°C and the boiling point of the reaction medium.

15. With process (o), strong acids are used, advantageously a mineral acid such as hydrochloric acid, in particular concentrated hydrochloric acid, or sulfuric acid, in particular moderately dilute sulfuric acid at 66%. The reaction temperature is between, after initial cooling for the regulation of the exothermic reaction,

between 60 and 110°G, advantageously between 90 and 100°G to obtain a reaction time of about 1 to 10 hours, advantageously 5 to 6 hours.

The raw materials of general formula XII are formed with substituted 4-(2-benzofuranyl)-4-piperidinols, which are part of general formula XI, by reacting compounds of general formula XIII with twice the molar amount of formaldehyde, for example, an aqueous solution of approximately 35%, and an equimolar amount of a mineral acid salt, in particular the hydrochloride of a compound of general formula XIV. Also included are the crude reaction products usable in place of compounds of general formula XII. The manufacture of the former is carried out essentially in the same way and under the same reaction conditions as for process 35(0); however, for a compound of general formula XIV, an equinormal amount of a strong acid such as concentrated hydrochloric acid is used, since it is not intended to use a compound of formula XIV as an advantageous addition salt.

•23

ment as hydrochloride. To finally carry out the rearrangement of the compound formed with general formula XII and simultaneously the dehydrogenation of the intermediate piperidinol, another mineral acid, such as concentrated sulfuric acid, is used, after gradual cooling, for example to 50-70°C, and the reaction is brought to completion by heating, for example, to 90-95°C. According to a distinctly less advantageous variant of the process, the formation of the crude reaction product and the simultaneous rearrangement or dehydrogenation of the same product can be carried out, in that an excess of a strong acid, in particular sulfuric acid or hydrochloric acid, is introduced at the outset. Compounds of general formula XIII can, for example, be prepared by reacting compounds of general formula IX with acetone, in a manner known in itself. 15 Compounds not already included in general formula I and not already being particularly indicated raw materials for the preceding processes can be manufactured in one or more steps from compounds of general formula VI given above. Among these latter compounds, unsubstituted 4-(2-benzofuranyl)-pyridine and 2-(2-benzofuranyl)-6-methylpyridine and other analogues substituted by a methyl group in the pyridine ring or in the benzene ring by a chlorine atom or a methyl group and their β-hydrochlorides have already been described by Swiss patent 451 963 25 (see also French patent no. 5337 M, United States patent no. 3 470 192). The manufacturing process indicated in the Swiss patent starts from possibly substituted salicylaldehyde which is first condensed by a process already known in itself [J. Org. Chem. 21_, 1039-1041 (1956)] with 4-pico-30 line, 2-picoline or suitable dimethylpyridines in acetic anhydride into acetic ester of o-[2-(4- or 2-pyridyl)~ vinyl]-phenol possibly substituted in a corresponding manner. By adding bromine, we obtain the corresponding compounds o-[1,2-dibromo-2-(4- or 2-pyridyl)-ethyl] which are cyclized 35 either directly with an alkali metal hydroxide or alkoxide, in an alcoholic solution, into corresponding compounds of general formula VI, or which are first transformed into the corresponding o-[2-bromo~2-(4- or 2-pyridyl)-vinyl] compound

-24-

with sodium acetate in acetic acid, which is cyclized in a completely analogous way into compounds of general formula VI.

According to a second series of reactions described in Swiss patent no. 501-610, the salicyl- is first transformed

aldehyde possibly substituted, first to its methyl ether, this is reduced to the corresponding alcohol, the latter is transformed via chloride into (o-methoxyphenyl)-acetonitrile possibly substituted, it is condensed with the ethyl ester of isonicotinic or picolinic acids,

optionally substituted with a methyl group to form the corresponding C-acylated (o-methoxyphenyl)acetonitrile, and finally, an alkali metal compound of this nitrile is cyclized by the action of concentrated hydrobromic acid to the desired 4- or 2-(2-benzofuranyl)pyri-15-idine, possibly substituted. In this reaction sequence, other esters of lower alkyl groups and isonicotinic acid and picolinic acid substituted with lower alkyl groups can be used, as well as, where appropriate, a lower alkyl ester of nicotinic acid substituted with lower alkyl groups.

However, the Applicant has discovered another series of reactions leading to the same raw materials of general formula VI, in which the 2-benzofuranyl radical is attached at position 2 or 4 to the pyridine ring, which, in the most important cases, may originate from a possibly substituted salicylaldehyde, but which is nevertheless simpler to carry out and shorter than the known series of reactions mentioned above. The new process is characterized in that a compound of general formula Via is transformed

30

in which R2, Rj and R^ have the meanings given under f

25

formula I, but preferably represents a hydrogen atom, in the presence of an acid immobilizing agent, with a 4-(halogeno-methyl)- or 2-(halogeno-methyl)-pyridine possibly substituted by lower alkyl groups, in particular with a 4- or 2-(chloromethyl)-pyridine or 4- or 2-(bromomethyl)-pyridine in an ether of general formula VIb,

formula in which Rg, Rj, R4' ^6 R7 on^ "1"es signify 51-tions given under formulas I or VI and this ether is cyclized by heating in the presence or absence of a condensing agent. The compounds thus obtained of general formula VI are new substances, excluding those already described in the aforementioned Swiss patents.

The reaction of compounds of general formula Via with 4- or 2-(chloromethyl)- or 4- or 2-(bromomethyl)-pyridines can be carried out, for example, in an inert organic solvent, such as dimethylformamide, in the presence of an acid-immobilizing agent, such as sodium or potassium carbonate, at a temperature between approximately 50 and 150°C, advantageously between 70 and 100°C, and, if desired, accelerated by the addition of a small amount of potassium or sodium iodide. The subsequent closing of the ring is achieved by heating the isolated, but not necessarily purified, compound of general formula VIb at a temperature between approximately 240 and 320°C. The closing of the cycle can however also be done possibly during the same working step as that of the formation of the ether and under the reaction conditions which are necessary or if necessary, by heating for a prolonged period and/or at a higher temperature, in the indicated range, with an excess of acid immobilizing agent acting as a condensation agent.

-26-

From the compounds of general formula VI, by quaternization with reactive esters of hydroxylated compounds of general formula III, the compounds of general formula V are obtained. Quaternization can be carried out in the usual way in an inert organic solvent medium, for example in a lower alkanool which can also be the basis of the reactive ester, as well as for example in ethyl acetate, tetrahydrofuran or dioxane, at room temperature or at moderately high temperature, up to about 100°C. 10 Raw materials of general formula II, in which Ac represents a semi-ester of carboxylic or thiocarboxylic acid or a cyano radical or a chlorocarbonyl radical, can be obtained, for example, from the corresponding compounds of general formula I in which represents an easily separable group such as allyl or benzyl groups, and especially the methyl group, by reaction with esters or thioesters of chloroformic acid, especially the ethyl ester, the tert-butyl ester, the benzyl ester, the phenyl ester of chloroformic acid or the S-methyl ester of chloro-20 thioformic acid or with cyanogen bromide or phosgene,

in a hot, inert organic solvent, for example, in toluene at its boiling point. Instead of suitable compounds of general formula I, 1-methyl-4-(2-benzofuranyl)-1,2,3,6-25-tetrahydropyridine and 1-methyl-4-(2-benzofuranyl)-piperidine can also be used for this reaction. In place of the aforementioned carboxylic acid derivatives, carboxylic acid halides such as acetyl bromide or benzoyl chloride can also be used; however, the corresponding reaction for the cleavage of the 30 E^j group requires more vigorous conditions and is less complete than, for example, the use of ethyl ester of chloroformic acid, and in particular cyanogen bromide. The reaction is also interesting between suitable compounds of general formula I with esters of chloroformic acid, cyanogen bromide, or similar reagents, and the associated hydrolysis in the reaction sequence according to (a) is important

I

-27-

in particular for the manufacture of the final substances of general formula I in which R^ represents a hydrogen atom and X and Y together form an additional bond. Thus, for the preparation of the raw materials of general formula II, one starts, in particular, from compounds of the more restricted general formula Ib, in which R^ represents a methyl, allyl, or benzyl group. Similarly, starting from compounds of general formula Ib in which R^ represents a methyl group, one prepares, by reaction with lower dialcoyl esters of azodicarboxylic acids, such as azodicarboxylic acid diethyl ether, for example in methanol, or preferably by several hours of boiling in cyclohexane, the corresponding addition products; see on this subject Liebigs Ann. Ohem. 590, 57-54 (1954) and J. prakt. Chem. (4), 26, 218-224 15 (1964). Among the raw materials of general formula II with a -NO group as Ac radical, those which are of particular interest are those which relate to the carbon atom adjacent to the nitrogen atom to be acylated, a methyl group or another lower alkyl group which can be introduced into the corresponding compounds in these groups by metallization and then reaction with a lower alkyl halide.

The raw materials of formula V for reduction according to (c), especially those which have an additional bond in place of X and Y, are manufactured according to or analogously to the manufacture described previously for raw materials of general formula II using suitable carboxylic acid halides from corresponding compounds of general formula I, especially those of the narrower formula Ib with a methyl group for R^ or from 50 1-methyl-4-(2-benzofuranyl)-1,2,5,6-tetrahydropyridine. However, it is particularly advantageous for the fabrication of compounds of general formula IV with hydrogen atoms for X and Y, of compounds of general formula Ia, in particular of compounds readily available by hydrogenation according to the procedure (e) of this formula with hydrogen atoms for X and Y and of acylizing the imino group in the usual way, for example by reaction with suitable carboxylic acid halides, i.e. corresponding to the definition for R^ in pre-

-28-

presence of an acid immobilizing agent for example potassium carbonate, in an inert organic solvent medium, such as dioxane or in pyridine or in mixture with organic solvents at room temperature or at moderately elevated temperature.

The raw materials of general formula VII can be manufactured, for example, in a manner analogous to that previously indicated according to the sequence of reactions described in Swiss patent no. 501 610 using an ethyl ester of 10 1,2,5,6-tetrahydro-isonicotinic acid or an ethyl ester of isonicotinic acid possibly substituted at position 1 in accordance with the definition for Ra and possibly on the ring by lower alkyl groups or corresponding hydrogenated derivatives of the nicotinic acid series or of pic-o-15 Unique acid.

In particular, one can manufacture in a simple way those of the raw materials of general formula VIII in which Rj represents a 5-hydroxyl group in that one condenses, in a way analogous to that which is described for the sequence of reactions published by A.N. Grinev and his collaborators for example in J. Gen. Ghem. USSR 27, English translation S 897 (1957) by condensation of p-benzoquinone with the ethyl ester of isonicotinoyl-acetic acid into ethyl ester of 2-(4-pyridyl)-5-iiyâ.roxy-3-benzofuran-carboxylic acid, the latter is transformed 25 for example in a manner analogous to the processes indicated under (b), (d) and (e) into ethyl ester of 2-(1,2,3,6-tetrahydro-4-pyridyl)- or 2-(4-piperidyl)-5-hydroxy-3-benzo-furan-carboxylic acid, substituted on the nitrogen atom according to the definition given for , and the latter is hydrolyzed into free acid 30.

For example, compounds of general formula IX are obtained from corresponding compounds substituted by a halogen atom at position 2 with magnesium, or in particular from corresponding unsubstituted compounds at position 2, 35 of which are known, with alkali metal compounds, such as butyl-lithium, in situ, that is to say, using the medium serving for the following reaction with reactive esters of compounds of general formula X. In the

i |

I

-29-

of the latter raw materials, some are known and others can be prepared in a similar way from corresponding known compounds of general formula X.

The raw materials of general formula 5 XI are obtained in particular by reaction of compounds of general formula IX given above with substituted 4-piperidones and 3-piperidones Aa and Ba with the corresponding definition for Ra and possibly corresponding to the definitions for R^, some of which are known, and others can be manufactured in a manner analogous to the known compounds.

The present invention also relates to those variants of the processes indicated under (a) to (o) and their preliminary steps in which a process is interrupted at any stage, or in which a compound 15 obtained as an intermediate product in any stage is used, and the missing steps are carried out, or a raw material is formed under the reaction conditions, or, where appropriate, is used in the form of a salt. In the case where the necessary materials are optically active, either racemates or isolated antipodes 20 may be used, or, in the presence of diastereomerism, either the racemic mixture or specific racemates or isolated antipodes are used. Likewise, these substances may, where appropriate, be used in the form of their salts. Advantageously, 25 of the raw materials are used to carry out the reactions according to the present invention that lead to the final substances of the groups particularly indicated.

Depending on the process conditions and the raw materials, the raw materials are obtained in their free form 30 or in a form that forms part of the present invention, as well as their addition salts with acids or, where applicable, also in the form of their hydrates. The addition salts with acids of the new compounds of general formula I can be transformed into free bases in a manner known per se, for example 35 with basic agents such as alkalis or ion exchangers. On the other hand, the compounds of general formula I obtained according to the process of the present invention can, if desired, be transformed in the usual way into their "f

-30-

Addition salts with organic or mineral acids. For example, a solution of a compound of general formula I is mixed in an organic solvent with the acid desired for the salt component. Advantageously, an organic solvent is used for the reaction in which the salt formed is only slightly soluble so that it can be separated by filtration. These solvents are, for example, ethyl acetate, methanol, ether, acetone, methyl ethyl ketone, acetone-ether, acetone-ethanol, methanol-ether, or ethanol-ether mixtures. For applications as medicines, one can use

Instead of free bases, addition salts are formed with pharmaceutically acceptable acids, that is, salts with those acids whose anions are not toxic in the doses required. It is also advantageous that the salts used as medications be readily crystallizable or only slightly or not at all hygroscopic. For the formation of salts with compounds of general formula I, one can use, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, methane-tallow, ethane-tallow, 2-hydroxyethane-sulfonic, acetic, lactic, succinic, fumaric, maleic, malic, tartaric, citric, benzoic, salicylic, phenylacetic, mandelic, and pamoic acids.

Depending on the choice of raw materials and the type of work, the new compounds can be presented as optical an-25 types or racemates, or, insofar as they contain at least two asymmetric carbon atoms, also as mixtures of isomers (racemic mixtures). The resulting isomeric mixtures (racemic mixtures) can be separated, based on their differences in physical and chemical properties, into their constituent parts, in a manner known in itself, into pure racemates of the two stereoisomers (diastereomers), for example by chromatography or fractional crystallization.

The racemates obtained can be separated by processes known in themselves, for example by recrystallization at 35°C from an optically active solvent medium, using microorganisms, or by reaction with an optically active acid forming a salt of the racemic compound, and the separation of the salts obtained in this way, for example, based on their solubility

-31-

Different compounds, in diastereomers, from which the antipodals can be released by the action of suitable agents. Optically active acids particularly suitable for this purpose include, for example, the D and L forms of tartaric acid, D-o-toluyl-5-tartaric acid, malic acid, mandelic acid, camphosulfonic acid, and quinic acid. Advantageously, the more active of the two antipodals is isolated.

The novel substances are administered orally, rectally, or parenterally. Doses depend on the type of application, the medication, age, and individual condition. Daily doses of the free base, its 5-oxide, or pharmaceutically acceptable salts of the free bases range from 0.1 mg/kg to 10 mg/kg for warm-blooded animals. Suitable unit-dose forms, such as coated tablets, tablets, suppositories, or ampoules, preferably contain 5 to 100 mg of an active substance according to the present invention.

Unit-dose formulations for oral administration preferably contain as an active substance between 5 and 90% of a compound of formula I or one of its pharmaceutically acceptable salts. For their manufacture, the active substance is combined, for example, with powdered solid vehicles such as lactose, sucrose, sorbitol, mannitol, starches such as potato starch, maize starch or amylopectin, as well as kelp powder or lemon pulp powder, cellulose derivatives or gelatin, possibly with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols, in tablets or coated tablet cores. The centers of sugar-coated dragees, for example, are coated with concentrated sugar solutions which may also contain gum arabic, talc, and/or titanium dioxide, or with a varnish dissolved in an organic solvent or a mixture of readily volatile solvents. These coatings may contain colorants, for example, to distinguish different doses of the active substance. Gelatin capsules and sealed soft gelatin capsules with an emollient such as glycerin are suitable alternative forms of unit-dose oral administration. The capsules advantageously contain the active substance in granulated form.

-32-

For example, it can be mixed with fillers such as corn starch and/or lubricants such as talc or magnesium stearate, and, where appropriate, stabilizers such as sodium metabisulfite (Na2S2O) or ascorbic acid. With soft soot-based caps, the active substance is preferably dissolved or suspended in suitable liquids, such as liquid polyethylene glycols, to which stabilizers may also be added.

As a unit dose form for rectal administration, suppositories are considered, for example, which consist of a combination of an active substance and a suppository base. Suitable suppository bases include, for example, natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols, or higher alkanols. Similarly, rectal gelatin capsules are suitable, which consist of a combination of the active substance and a base. Suitable base bases include, for example, liquid triglycerides, polyethylene glycols, or paraffinic hydrocarbons. Ampoules for parenteral administration, particularly intramuscular administration, preferably contain a water-soluble salt of an active substance at a concentration advantageously ranging from 0.5 to 5%, possibly with appropriate stabilizing agents and buffering agents, in aqueous solution. 25 The following instructions explain the preparation of tablets, dragees, capsules, suppositories and ampoules:

a) 250 g of 4-(2-benzofuranyl)piperidine hydrochloride is mixed with 175.80 g of lactose and 169.70 g of potato starch, and the mixture is moistened with a solution

30 alcoholic solution of 10 g of stearic acid and granulated through a sieve. After drying, 160 g of potato starch, 200 g of talc, 2.50 g of magnesium stearate and 32 g of colloidal silica are mixed together and the mixture is pressed into 10,000 tablets, each weighing 100 mg and containing 25 mg of active substance, which may, if necessary, have scoring lines to accommodate more precise dosing.

b) A granule is prepared from 250 g of 4-(5,6-dimethyl-2-benzofuranyl)-piperidine hydrochloride, 175.90 g

-33-

lactose and the alcoholic solution of 10 g of stearic acid which is mixed after drying with 56.60 g of colloidal silica, 165 g of talc, 20 g of potato starch and 2.50 g of magnesium stearate and is compressed to give 10,000 dragees.

5. They are then coated with a concentrated syrup containing 502.28 g of crystallized sucrose, 6 g of shellac, 10 g of gum arabic, 0.22 g of coloring, and 1.5 g of titanium dioxide. The resulting coated tablets each weigh 120 mg and each contain 25 mg of the active substance.

10 c) To prepare 1000 capsules, each containing 10 mg of the active substance, 10 g of 4-(5-methoxy-2-benzofuranyl)-piperidine hydrochloride is mixed with 248 g of lactose, the mixture is moistened uniformly with an aqueous solution of 2 g of gelatin, and the mixture is granulated through a suitable sieve (per

15 example the Sieve III of Ph. Helv. V). The granule is mixed with 10.0 g of dry corn starch and 15.0 g of talc and 1000 hard gelatin capsules of size 1 are filled uniformly.

d) A base mass for suppositories is prepared from 2.5 g of 1-methyl-4-(5-chloro-2-

20 benzofuranyl)-piperidine and 167.5 g of solid paraffin and 100 suppositories are poured, each containing 25 mg of active substance.

e) 1000 ampoules are filled with a solution of 10.0 g of 3-(2-benzofuranyl)-piperidine hydrochloride in one liter

Add 25 ml of water and sterilize. Each ampoule contains a 1% solution of 10 mg of active substance.

The invention also relates, as new industrial products, to the compounds obtained by implementing the process defined above; however, these products are not protected by this patent for their therapeutic uses.

-34-

The following examples explain the manufacture of new compounds of general formula I, as well as intermediate products not yet described, without, however, restricting the scope of the present invention to them. Temperatures are given in degrees Celsius.

EXAMPLE 1

81.0 g of 4-(2-benzofuranyl)-pyridine is dissolved in 1.5 liters of ethanol and hydrogenation is carried out in the presence of 10.0 g of palladium on carbon (5%) at a temperature between 70 and 80°C and an initial pressure of 80 bars. After

At 3 p.m., 25.8 liters of hydrogen were absorbed. The hydrogenation was stopped, the catalyst was separated for filtration, and the filtrate was evaporated under vacuum. The residue was fractionated under high vacuum by distillation. The fraction that distills between 15,122, and 129°C at 0.10 mmHg is 4-(2-benzofuranyl)-piperidine. The hydrochloride, prepared with a hydrochloric acid gas solution in ethyl acetate, melts after recrystallization in acetone at 228–230°C.

The 4-(2-benzofuranyl)pyridine used as a raw material can be manufactured in the following way:

a) 146.4 g of salicylaldehyde, 196.8 g of 4-(chloromethyl)pyridine hydrochloride, 750 g of potassium carbonate, and 2 g of potassium iodide are heated to 80-90°C with stirring for 15 hours in 3 liters of d-imethylformamide. The mixture is then filtered.

25. Next, the solution is aspirated, and the filter cake is washed again with 1 liter of chloroform. The combined filtrates are evaporated under vacuum, and the evaporation residue is dissolved in 1 liter of chloroform. The organic phase is first washed with 1 liter of 2 N sodium hydroxide, then with 1 liter of water. 30. It is dried over sodium sulfate, filtered by aspirate, and...

evaporates. The crude residual o-[(4-pyridyl)-methoxy]-benzaldehyde is used without further purification.

b) It is heated under nitrogen at 300°C for 30 minutes

290 g of o-[(4-pyridyl)-methoxy]-benzaldehyde. After cooling, the residue is dissolved in a small amount of methylene chloride and chromatographed over 3 kg of aluminum oxide (activity II, neutral). The first fraction eluted with 4 liters of methylene chloride is 4-(2-benzofuranyl)-pyridine. The compound melts after recrystallization in ethanol at 132–133°C.

-35-

EXAMPLE 2

11 g of 4-(5-methoxy-2-benzofuranyl)-pyridine is dissolved in 240 mL of methanol and hydrogenated in the presence of 5 g of rhodium catalyst on carbon (5%) at a temperature between 40 and 50°C and an initial pressure of 4 bar. After 90 hours, 3.3 liters of hydrogen have been absorbed. The hydrogenation is stopped, the catalyst is separated by filtration, and the filtrate is evaporated under vacuum. The residue is fractionated by distillation under high vacuum. The fraction that distills between 120 and 128°C and under 0.10 mmHg is 4-(5-methoxy-2-benzofuranyl)-piperidine. The hydrochloride prepared from a solution of hydrochloric acid gas in ethyl acetate melts after recrystallization in acetone at 220-222°C. The 4-(5-methoxy-2-benzofuranyl)-15-pyridine used as a raw material can be prepared as follows: a) 65.6 g of 5-methoxysalicylaldehyde, 7 g of 4-(chloromethyl)pyridine hydrochloride, 280 g of potassium carbonate, and 2 g of potassium iodide are heated in 800 mL of dimethylformamide at 100°C for 20 hours. The solution is then filtered by aspiration, and the filter cake is washed with 1 liter of chloroform. The combined filtrates are evaporated under vacuum, and the residue is dissolved in 1 liter of chloroform. The organic phase is first washed with 500 ml of 2 N sodium hydroxide solution, then with one liter of water, dried over sodium sulfate, filtered, and evaporated. The residual 4-(5-methoxy)-2-benzofuranyl)-pyridine melts after recrystallization in ethyl acetate at 123°C. The hydrochloride prepared from a hydrochloric acid gas solution in ethyl acetate is recrystallized in ethyl acetate and melts at 228°C. 30 EXAMPLE 3

Similar to that of example 2, 11 g of 4-(7-methoxy-2-benzofuranyl)-pyridine is hydrogenated and 4-(7-methoxy-2-benzofuranyl)-piperidine is obtained, which is transformed into its hydrochloride in a similar manner to that of example 2. Melting point 174-°C.

Similarly, in a manner analogous to that of example 2, 4-(5,6-dimethoxy-2-benzofuranyl)-pyridine is obtained by hydrogenation of 12.5 g of 4-(5,6-dimethoxy-2-benzofuranyl)-piperidine

-36-

melting point 98°C and its hydrochloride melting point 227-229°C.

The 4-(7-methoxy-2-benzofuranyl)-pyridine used as a raw material can be prepared as follows: 5 a) Heat 106.5 g of o-vanxlline, 116 g of 4-(chloromethyl)-pyridine hydrochloride, 420 g of sodium carbonate, and 2 g of sodium iodide in 1000 ml of dimethylformamide at 90-95°C for 15 hours. Filter the mixture by aspiration, and wash the filter cake with 1 liter of chloroform. Evaporate the combined filtrates under vacuum, and dissolve the residue in 1 liter of chloroform. Wash the organic phase first with 500 ml of 2 N sodium hydroxide solution, then with 1 liter of water. Dry over sodium sulfate, filter, and evaporate. The residue from evaporation represents a mixture of 4-(7-methoxy-15 2-benzofuranyl)-pyridine and 2-[(4-pyridyl)-methoxy]-3-methoxy-* benzaldehyde and is used without further purification.

b) 140 g of the mixture obtained according to (a) is heated under nitrogen for 4 minutes at 250°C. After cooling, the residue is dissolved in a little methylene chloride, and chromatography is performed on 2000 g of aluminum oxide (activity II,

neutral). The first fraction eluted with 4 liters of methylene chloride is 4-(7-methoxy-2-benzofuranyl)-pyridine. The compound melts after recrystallization in ether at 138–141°C. The hydrochloride prepared with a solution of hydrochloric acid gas in ethyl acetate melts at 240–242°C.

In a manner analogous to (a), starting from 127.5 g of 4,5-dimethoxy-salicylaldehyde, a crude mixture of 2-[(4-pyridyl)-methoxy]-4,5-dimethoxy-benzaldehyde and its ring-closing product is obtained.

30 In a manner analogous to (b) this mixture is completely transformed into 4-(5,5-dimethoxy-2-benzofuranyl)-pyridine with a melting point of 129-133, the hydrochloride 241-242°C.

EXAMPLE 4

20 g of 4-(5-methyl-2-benzofuranyl)-pyridine 35 is dissolved in 350 ml of ethanol and hydrogenated in the presence of an equivalent of hydrochloric acid gas and 4 g of palladium on 5% carbon at a temperature between 70 and 80°C and an initial pressure of 80 bar. After 15 hours, the theoretical quantity

T

-37-

Hydrogen was absorbed. The hydrogenation was stopped, the catalyst was separated by filtration, and the filtrate was evaporated under vacuum. The residue was dissolved in 500 mL of a 10% aqueous solution of methane-tissunic acid, and the acidic solution was extracted with ether. The aqueous solution was then adjusted by adding 30% sodium hydroxide to a pH of 12 and extracted with one liter of chloroform. The chloroform solution was dried over sodium sulfate, filtered, and evaporated. The residue was distilled by fractionation under high vacuum. The fraction that distilled at 120–125°C under 0.1 mmHg was 4-(5-methyl-2-benzofuranyl)-piperidine, which, after recrystallization in pentane, melted at 51–53°C. Hydrochloride prepared from a solution of hydrochloric gas in ethyl acetate melts at 158-161°0.

15. The 4-(5-methyl-2-benzofuranyl)-pyridine used as a raw material can be prepared in the following way:

a) 173.8 g of 5-methylsalicylaldehyde, 210 g of 4-(chloromethyl)pyridine hydrochloride, 620 g of potassium carbonate, and 207 g of potassium iodide are heated in 1000 mL of dimethylformamide at 80-90°C for 20 hours with stirring. The solution is then filtered by aspiration, and the filter cake is washed with 500 mL of dimethylformamide. The mixture is evaporated under vacuum, and the evaporation residue is dissolved in 1 liter of chloroform. The organic phase is first washed with 1 liter of 1 N sodium hydroxide solution, then with 1 liter of water, dried over sodium sulfate, filtered by aspiration, and evaporated. The residual oil is a mixture of 2-[(4-pyridyl)methoxy]-5-methylbenzaldehyde and 4-(5-methyl-2-benzofuranyl)pyridine and is distilled under high vacuum. The fraction that distills at 170-190°C and 0.1 mmHg is dissolved for further purification in a small amount of methylene chloride and chromatographed over 3 kg of aluminum oxide (activity II, neutral). The first fraction eluted with 4 liters of methylene chloride is 4-(5-methylbenzofuranyl)pyridine. The compound melts after recrystallization in pentane at 160-162°C.

EXAMPLE 5

10.0 g of 4-(2-benzofuranyl)-piperidine (see example 1) and 6.0 g of 3-bromo- are dissolved in 200 ml of methanol.

-38-

Propine is mixed with 50 g of potassium carbonate and stirred at room temperature for 30 hours. The reaction mixture is then filtered by aspiration, the filter cake is washed with 500 mL of chloroform, and the five combined filtrates are evaporated under vacuum. The residue is dissolved in a small amount of methylene chloride and chromatographed over 300 g of aluminum oxide (activity II, neutral). The first fractions eluted with a total of one liter of methylene chloride contain 1-(2-propinyl)-4-(2-benzofuranyl)-piperidine. The base is recrystallized in hexane and melts at 75–77°C. The hydrochloride, prepared with hydrochloric acid gas in ethyl acetate and recrystallized in ethyl acetate, melts at 203–205°C.

In a similar way, starting from 11.4 g of 4-(5,6-dimethyl-2-benzofuranyl)-piperidine (see example 31) 15, we obtain 1-(2-propinyl)-4-(5,6-dimethyl-2-benzofuranyl)-piperidine with a melting point of 104-106°C, whose hydrochloride melts at 231-233°C.

EXAMPLE 6

5.8 g of 4-(2-20 benzofuranyl)-piperidine (see example 1), 27 mL of N,N-di-isopropylamine, and 27 g of isopropyl bromide are refluxed in 100 mL of isopropanol for 15 hours. The solution is then evaporated under vacuum, the residue is dissolved in 500 mL of chloroform, and the organic phase is washed first with 500 mL of 1 N sodium hydroxide solution and then with 500 mL of water. It is dried over sodium sulfate, filtered, and evaporated. From the residual crude base, the hydrochloride of 1-isopropyl-^-^-benzofuranyl)-piperidine is prepared with a hydrochloric gas solution in ethyl acetate, which melts after recrystallization in ethyl acetate at 186-188°C.

EXAMPLE 7

Dissolve 10.0 g of 4-(2-benzofuranyl)-piperidine (see Example 1) and 6.0 g of allyl bromide in 250 mL of methanol. After adding 50 g of sodium carbonate, stir at room temperature for 48 hours. The reaction solution is then filtered by aspiration, and the filter cake is washed with 500 mL of chloroform. The combined filtrates are washed with 300 mL of 2 N sodium hydroxide solution and dried.

-39-

and evaporate. The residue is dissolved in a small amount of methylene chloride and chromatographed over 500 g of aluminum oxide (activity II, neutral). The first fractions eluted with a total of 2 liters of methylene chloride contain 1,5-allyl-4-(2-benzofuranyl)-piperidine. The hydrochloride, prepared with a hydrochloric acid gas solution in ethyl acetate, is recrystallized in ethyl acetate and then melts at 224°C.

EXAMPLE 8

A solution of 6.0 g of 4-(2-benzofuranyl)piperidine (see Example 1) and 6.0 g of methyl vinyl ketone in 100 mL of benzene is stirred for 24 hours at room temperature. The solvent is then evaporated under vacuum (maximum bath temperature 45°C). The evaporation residue is mixed with a solution of hydrochloric acid gas in ethyl acetate, and the resulting 1-(5-oxobutyl)-4-(2-benzofuranyl)piperidine hydrochloride, or [2-4-(2-benzofuranyl)piperidino]ethyl]methyl ketone hydrochloride, is separated by filtration. It melts at 184–186°C.

• EXAMPLE 9

A solution of 14.5 g of 1,20 (cyclopropylcarbonyl)-4-(2-benzofuranyl)piperidine in 100 mL of tetrahydrofuran is added dropwise to a refluxing solution of 15.5 g of lithium tetrahydroaluminate in 200 mL of tetrahydrofuran. After 15 hours of refluxing, the reaction mixture is cooled, and the excess lithium tetrahydroaluminate is destroyed at -10°C with 15 mL of water, 15 mL of 10% sodium hydroxide solution, and 45 mL of water. The reaction solution is filtered by aspiration, the filter cake is washed with 1 liter of chloroform, and the combined filtrates are evaporated under vacuum. The residue is dissolved in 500 mL of 2 N hydrochloric acid, and the acid solution is washed with ether. The aqueous solution is then adjusted to pH 12 by adding 10% sodium hydroxide solution and extracted with one liter of chloroform. The chloroform solution is dried over sodium sulfate, filtered by aspiration, and evaporated, yielding crude 1-(cyclopropylmethyl)-4-(2-55 benzofuranyl)-piperidine. After recrystallization in hexane, the free base melts at 68°C. The hydrochloride is prepared with hydrochloric acid gas in ethyl acetate and recrystallized in ethyl acetate, melting at 223–225°C.

-40-

1-(cyclopropylcarbonyl)-4-(5,6-dimethyl-2-benzofuranyl)-piperidine is obtained in a similar manner by reducing 16.0 g of 1-(cyclopropylmethyl)-4-(5,6-dimethyl-2-benzofuranyl)-piperidine. Its melting point is 80-83°C, and its hydrochloride has a melting point of 184-186°C.

The 1-(cyclopropylcarbonyl)-4-(2-benzofuranyl)piperidine used as a raw material can be prepared in the following way:

12.1 g of 4-(2-benzofuranyl)-piperidine 10 is dissolved in 250 mL of dioxane, and a solution of 7.35 g of cyclopropane-carbonyl chloride and 50 g of potassium carbonate is added. The reaction solution is stirred for 15 hours at room temperature. It is then filtered by aspiration, the residue is washed over a filter with 15 L of chloroform, and the combined filtrates are evaporated under vacuum. The residue is dissolved in 250 mL of ethyl acetate, and the solution is successively washed with 2 N hydrochloric acid, water, 2 N ammonium hydroxide, and water. It is dried over sodium sulfate, filtered, and evaporated. The oily residue 20 from evaporation is, according to chromatographic analysis, unitary 1-(cyclopropylcarbonyl)-4-(2-benzofuranyl)-piperidine, which can be used for reduction with lithium tetrahydroaluminate.

Similarly, starting from 13.7 g of 4-(5,6-25-dimethyl-2-benzofuranyl)-pipei,idine (see example 31) the 1-

(cyclopropylcarbonyl)-4-(5,6-dimethyl-2-benzofuranyl)-piperidine.

EXAMPLE 10

A solution of 27.6 g of 1-(3,4,5-trimethoxybenzoyl.l)-4,30 (2-benzofuranyl)-piperidine in 150 mL of tetrahydrofuran is added dropwise to a refluxing solution of 4.0 g of lithium tetrahydroaluminate in 120 mL of tetrahydrofuran. After 4 hours of refluxing, the reaction mixture is cooled, and the excess sodium tetrahydroaluminate is destroyed at -10°C with 4 mL of water. The reaction solution is filtered by aspiration, the filter cake is washed with 1 L of chloroform, and the combined filtrates are evaporated under vacuum. The residue is dissolved in 500 mL of a 10% aqueous solution of methanesulfonic acid, and the solution is washed.

-41-

The acid is dissolved in ether. The aqueous phase is then adjusted by adding 30% sodium hydroxide solution to pH 12 and extracted with one liter of chloroform. The chloroform solution is dried over sodium sulfate, filtered, and evaporated, yielding crude 1-(3,4,5-trimethoxybenzyl)-2-(2-benzofuranyl)-piperidine. The hydrochloride is prepared with hydrochloric acid gas in ethyl acetate and recrystallized in ethyl acetate; it melts at 212°C.

The 1-(3,4,5-trimethoxybenzoyl)-4~(2-10 benzofuranyl)-piperidine used as a raw material can be prepared in the following way.

a) To a solution of 72.0 g of 4-(2-benzofuranyl)t-piperidine (see Example 1) and 50 g of sodium carbonate in 100 mL of dioxane, a solution of 18.4 g of 3,4,5-trimethoxybenzoyl chloride is added dropwise, stirring and cooling from 15°C outside the container, ensuring that the reaction temperature does not exceed 50°C. The reaction solution is then stirred for 15 hours at room temperature. The reaction solution is filtered by aspiration, the residue is washed through 20 filters with 500 mL of chloroform, and the combined filtrates are evaporated under vacuum. The residue is dissolved in 250 ml of ethyl acetate and the solution is successively washed with 2 F hydrochloric acid, water, 2 N aqueous ammonia, and water. It is then dried over sodium sulfate, filtered, and evaporated. The resulting 1-(3,4,5-trimethoxybenzoyl)-4-(2-benzofuranyl)-piperidine melts after recrystallization in hexane at 131–134°C.

EXAMPLE 11

Similar to Example 10, 8.0 g of 1-acetyl-4-(2-benzofuranyl)-piperidine in 100 mL of tetrahydrofuran is reduced with 12.0 g of lithium tetrahydruroaluminate in 150 mL of tetrahydrofuran, and the reaction mixture is then refluxed for 15 hours. The crude 1-ethyl-4-(2-benzofuranyl)-piperidine obtained is trans-35 formed to the hydrochloride, which, after recrystallization in ethyl acetate, melts at 198°G.

The raw material is prepared as follows:

a) A solution of 7.0 g of 4-(2-benzofura-

-42-

1-Acetyl-4-(2-benzofuranyl)piperidine (see Example 1) in 100 ml of pyridine with 150 ml of acetic anhydride and stirred first for 15 hours at room temperature and then for 2 hours at 45°C. After which, the reaction mixture is evaporated under vacuum, the residue is dissolved in ethyl acetate, and this solution is washed successively twice with 2 N hydrochloric acid, 2 N aqueous ammonia, and water, dried over sodium sulfate, and evaporated. The residual crude 1-Acetyl-4-(2-benzofuranyl)piperidine can be used directly. A sample of the substance recrystallized in pentane melts at

95-97°C.

EXAMPLE 12

A solution of 70 g of 1-methyl-4-(5-chloro-2-benzofuranyl)pyridinium diiodide in 500 mL of methanol is added dropwise to a solution of 70 g of sodium borohydride in 150 mL of water, stirring and cooling from the outside, ensuring that the reaction temperature does not exceed 35°C. The solution is then stirred for 20 hours at room temperature. The methanol is then evaporated under vacuum, and the residual aqueous phase is extracted twice with 500 mL of chloroform each time. The chloroform solution is dried over sodium sulfate, filtered, and evaporated. 1-methyl-4-(5-chloro-2-benzofuranyl)-1,2,3,6-tetrahydropyridine is recrystallized in hexane and melts at 108–118°C. Chlor-25 hydrate prepared from a hydrochloric gas solution in ethyl acetate melts after recrystallization in ethyl acetate at 266°C.

In a similar manner, using 78.2 g of 1-methyl~4-(5-bromo-2-benzofuranyl)-pyrid.inium iodide, 30 1-methyl-4-(5~bromo-2-benzofuranyl)-1,2,3,6-tetrahydropyridine, melting point 129°C, is obtained.

The raw materials can be prepared as follows: a) Heat 210 g of 5-chlorosalicylaldehyde, 220 g of 4-35 (chloromethyl)pyridine hydrochloride, and 750 g of potassium carbonate to 80°C while stirring for 20 hours.

3.3 g of potassium iodide in 2 liters of dimethylformamide. The solution is then filtered by aspiration, and the filter residue is washed again with 1 liter of chloroform. The solution is evaporated under

-43-

The filtrates are collected, and the residue from the first evaporation is dissolved in one liter of chloroform. The organic phase is washed twice, first with one liter of 2 N sodium hydroxide solution and then with one liter of water. It is dried over sodium sulfate, filtered, and evaporated. The remaining crude 2-(4-pyridyl)-methoxy-5-chlorobenzal-dehyde is used in further purification.

b) 272 g of 2-[_ (4-pyridyl)-methoxy]->-chlorobenzaldehyde is heated under nitrogen at 300°C for 30 minutes. After cooling, the residue is dissolved in a small amount of chloride

10 of methylene and chromatography on 2 kg of aluminum oxide (activity II, neutral). The first fraction eluted with 5 liters of methylene chloride is 4-(5-chloro-2-benzofuranyl)-pyridine. The compound melts after recrystallization in ethanol at 132-133°C. The hydrochloride prepared from a solution of 15 hydrochloric acid in ethyl acetate melts after recrystallization in ethyl acetate at 265°C.

c) 142 g of 4-(5-chloro-2-benzofuranyl)-pyridine is dissolved in 430 ml of methanol and stirred with 300 ml of methyl iodide for 13 hours at 40-45°C. The mixture is then cooled to

20. The solution is cooled to 0°C and the precipitated salt is separated by aspiration. The filter cake is washed with 50 ml of isopropanol. After recrystallization in isopropanol, 1-methyl-3-(5-chlorobenzofuranyl)pyridinium iodide melts at 258-260°C.

In a manner analogous to (a) using 25,269 g of 3-bromosalicylaldehyde, 2~[_ (4-pyridyl) -methoxy]-5-bromo-salicylaldehyde is obtained, and then, starting from 320 g of this crude product, in a manner analogous to (b), 4-(5-bromo-2-benzofuranyl)-pyridine with a melting point of 136-158°C is obtained.

And finally, similarly to (c) starting from 168 g 30 of 4-(3-bromo-2-benzofuranyl)-pyridine, the iodide of 1-methyl-4~ (5-bromo-2-benzofuranyl)-pyridinium with a melting point of 266-270°C.

EXAMPLE 13

A solution of 40 g of sodium borohydride in 100 ml of water is added dropwise to a solution of 44.3 g of 1-methyl-35-4-(5-methoxy-2-benzofuranyl)-pyridinium iodide in 350 ml of methanol, while stirring and cooling from the outside, so that the reaction temperature does not exceed 35°C.

-44-

Next, the solution is stirred for 20 hours at room temperature. The methanol is then evaporated under vacuum, and the residual aqueous phase is extracted twice, each time with 500 mL of chloroform. The chloroform solution is dried over sodium sulfate, filtered, and evaporated. 1-Methyl-4-(5-methoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyridine is recrystallized in cyclohexane and melts at 99–101°C. Chlorhethylate, prepared from a hydrochloric acid gas solution in ethyl acetate, melts after recrystallization in ethyl acetate at 10,258°C.

Starting from 47.9 g of 1-methyl-4-(5,6-dimethoxy-2-benzofuranyl)-pyridinium iodide, we obtain 1-methyl-4-(5,6-dimethoxy-2-benzofuranyl)-1,2,5,6-tetrahydropyridine, with a melting point of 139-141°C, and its hydrochloride, with a melting point of 234-236°C.

The raw materials can be prepared as follows: a) Dissolve 29.4 g of 4-(5-methoxy-2-benzofuranyl)-pyridine (see Example 2a) in 250 mL of methanol and stir for 15 hours at 40–45°C with 100 mL of methyl iodide. Then cool the solution to 20°C, stir with activated carbon, and filter through purified diatomaceous earth. Evaporate the filtrate under vacuum and recrystallize the residue in isopropanol. The resulting 1-methyl-4-(5-methoxy-2-benzofuranyl)-pyridinium iodide melts at 210–212°C.

25 In a similar manner, using 33.3 g of 4-(5,6-dimethoxy-2-benzofuranyl)-pyridine (see example 3b), we obtain the iodide of 1~methyl-4~(5,6-dimethoxy-2-benzofuranyl)-pyridinium with a melting point of 268-270°C.

EXAMPLE 14

30. A solution of 91.0 g of 1-methyl- iodide is added

4-(7-methoxy-2-benzofuranyl)-pyridinium in 1500 ml of methanol, by stirring and cooling from the outside, a solution of 40.0 g of sodium borohydride in 160 ml of water, dropwise so that the temperature does not exceed 35°C. The solution is then stirred for 20 hours at room temperature. The methanol is then evaporated under vacuum, the residual aqueous phase is extracted twice, each time with 500 ml of methylene chloride, the chloride solution is dried

-45-

Methylene chloride is eluted over sodium sulfate, filtered, and evaporated. The residue from the evaporation is dissolved in a small amount of methylene chloride and chromatographed over 900 g of aluminum oxide (activity II, neutral). The first fraction eluted with 3.5 liters of methylene chloride is 1-methyl-4-(7-methoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyrianine. The free base melts after recrystallization in pentane at 89–92°C. The hydrochloride, prepared from a hydrochloric acid gas solution in ethyl acetate, melts after recrystallization in ethyl acetate at 246–248°C.

The raw material can be prepared in the following way:

a) 60 g of 4-(7-methoxy-2-benzofuranyl)~pyridine (see example 3b) is dissolved in 750 ml of methanol and stirred with 150 ml of methyl iodide for 15 hours at 40-45°C,

The solution is then cooled to 0°C and the crystals are separated by aspiration. 1-Methyl-4-(7-methoxy-2-benzofuranyl)-pyridinium iodide melts after recrystallization in ethanol at 219°C.

EXAMPLE 15

20. Adding to a solution of 125 g of 1-methyl- iodide

4-(5-methyl-2-benzofuranyl)-pyridinium is reacted in 750 mL of methanol by stirring and externally cooling a solution of 60 g of sodium borohydride in 150 mL of water, dropwise, so that the reaction temperature does not exceed 35°C. The solution is then stirred for 20 hours at room temperature. The methanol is then evaporated under vacuum, and the residual aqueous phase is extracted twice with 500 mL of chloroform each time. The chloroform solutions are dried over sodium sulfate, filtered, and evaporated. 1-Methyl-4-(5-30-methyl-2-benzofuranyl)-1,2,3,6-tetrahydropyridine is recrystallized in diisopropyl ether and melts at 102°C. The hydrochloride prepared from a hydrochloric acid gas solution in ethyl acetate melts after recrystallization in ethyl acetate at 243°.

35 The raw material can be prepared as follows from the compound in example 4a).

a) Dissolve 80 g of 4-(5-methyl-2-benzofuranyl)-pyridine in 150 ml of deciethanol and stir for 15 hours at 40-45°C with 150 ml of methyl iodide. Then cool.

—46—

The solution is at 0°C and the precipitated salt is separated by aspiration. The filter cake is washed with 500 ml of ethanol. After recrystallization in methanol, 1-methyl-4-(5-methyl-2-benzofuranyl)-pyridinium iodide melts at 198-200°C.

5 EXAMPLE 16

To a solution of 65.5 g of 1-methyl-4-(naphtho[2,1-b]furan-2-yl)pyridinium iodide in 900 mL of methanol, while stirring and cooling from the outside, a solution of 27.0 g of sodium borohydride in 110 mL of water is added dropwise, ensuring that the reaction temperature does not exceed 30°C. The solution is then stirred for 15 hours at room temperature. The methanol is then evaporated under vacuum, and the aqueous phase is extracted twice with 500 mL of chloroform each time. The chloroform solutions are dried over sodium sulfate, filtered, and evaporated. The resulting oil is dissolved in 150 mL of methylene chloride and chromatographed over 1 kg of aluminum oxide (activity II, neutral). The first fractions eluted with 2 liters of methylene chloride contain 1-methyl-4-(naphtho[2,1-b]~20 furan-2-yl)-1,2,3,6-tetrahydropyridine. The free base is recrystallized in hexane and melts at 120-122°C. The hydrochloride prepared from a hydrochloric acid gas solution in ethyl acetate melts after recrystallization in ethyl acetate at 277°C.

25. The raw material can be prepared as follows:

a) 85.4 g of 2-hydroxy-naphtaldehyde, 79.3 g of 4-(chloromethyl)-pyridine hydrochloride, 300 g of potassium carbonate and 2.5 g of potassium iodide are heated at 100°G for 20 hours while stirring in 800 ml of dimethylformamide.

30 The solution is then filtered by aspiration, and the residue is washed again on the filter with one liter of chloroform. The combined filtrates are evaporated under vacuum, and the evaporation residue is dissolved in one liter of chloroform. The organic phase is first washed twice, each time with one liter of 2 N sodium hydroxide solution and then with one liter of water. It is dried over sodium sulfate, filtered, and evaporated. The remaining crude 2-[(4-pyridyl)-methoxy]-1-naphtaldehyde is used without further purification.

b) 93.0 g of 2-[(4-

-47-

pyridyl)-methoxy]-1-naphtaldehyde for 30 minutes. After cooling, the residue is dissolved in a small amount of methylene chloride and chromatographed over 2 kg of aluminum oxide (activity II, neutral). The first fraction eluted with 3 liters of methylene chloride is 4-(naphthol-2,1-b]-furan-2-yl)-pyridin. The compound melts after recrystallization in ethyl acetate at 137-139°C. The hydrochloride prepared from a hydrochloric acid gas solution in ethyl acetate melts after recrystallization in ethyl acetate at 295-300°C. 10 c) 51*0 g of 4-(naphtho[2,1-b]-furan-2-yl)-

Pyridine is dissolved in 750 ml of methanol and stirred for 20 hours at 40-45°C with 100 ml of methyl iodide. The solution is then cooled to 0°C and the precipitated salt is separated by aspiration and washed with 150 ml of isopropanol. After recrystallization in isopropanol, 1-methyl-4-(naphtho[2,1-b-furan-2-yl)-pyridinium iodide melts at 310-315°C (with decomposition).

EXCELLENT 17

To a solution of 75 g of 1-benzyl-4-(2-benzofuranyl)pyridinium bromide in 500 mL of benzene, a solution of 75 g of sodium borohydride in 150 mL of water is added dropwise, stirring continuously and cooling from the outside, ensuring that the reaction temperature does not exceed 35°C. The mixture is then stirred for 20 hours at room temperature. The methanol is then evaporated under vacuum, and the residual aqueous phase is extracted twice with 500 mL of chloroform each time. The chloroform solution is dried over sodium sulfate, filtered, and evaporated. The resulting 1-benzyl-4-(2-benzofuranyl)-1,2,3,6-tetrahydropyridine melts after recrystallization in aethyl ether at 138°C. The hydrochloride prepared at 30 from a hydrochloric gas solution in methyl acetate melts after recrystallization in the acetone-isopropanol mixture at 237-238°C.

The raw material can be prepared in the following way:

35 a) 99 g of 4-(2-benzofuranyl)-pyridine are dissolved

(see example 1b) in 1600 ml of methanol and reflux for 15 hours with 120 g of benzyl bromide. The solution is then cooled to 20°C and stirred for 10 minutes.

-48-

with 50 g of activated charcoal and filtered through purified diatomaceous earth. The filtrate is evaporated under vacuum and the evaporation residue is recrystallized in acetone. The resulting 1-benzyl-4-(2-benzofuranyl)-pyridinium bromide melts at 213-215°G.

5 EXAMPLE 18

A solution of 70.0 g of sodium borohydride in 150 mL of water is added dropwise to a solution of 100.0 g of 1-methyl-4-(3-methyl-2-benzofuranyl)pyridinium iodide in 500 mL of methanol, while stirring and cooling from the outside, so that the reaction temperature does not exceed 35°C. The solution is then stirred for 20 hours at room temperature. The methanol is then evaporated under vacuum, and the residual aqueous phase is extracted twice with 500 mL of chloroform each time. The chloroform solution is dried over sodium sulfate, filtered, and evaporated. The evaporation residue is dissolved in a small amount of methylene chloride and chromatographed over 1000 g of aluminum oxide (activity II, neutral). The first fraction eluted with one liter of methylene chloride is 1-methyl-4-(3-methyl-2-benzo-20 furanyl)-1,2,3,6-tetrahydropyridine. The compound melts after recrystallization in pentane at 56–58°C. The hydrochloride prepared from a hydrochloric acid gas solution in methyl acetate melts after recrystallization in ethyl acetate at 284–286°C.

25. The raw material can be prepared in the following way:

a) 64.0 g of o-hydroxyacetophenone, 64.6 g of 4-(chloromethyl)pyridine hydrochloride, 250 g of sodium carbonate, and 3.3 g of potassium iodide are heated in one liter of dimethylformamide at 120°C with stirring for 20 hours. The solution is then filtered by aspiration, and the residue is washed again on a filter with 500 mL of dimethylformamide. The combined filtrates are evaporated under vacuum, and the evaporation residue is dissolved in one liter of chloroform. The organic phase is washed twice, first with one liter of 2 N sodium hydroxide solution each time, and then with one liter of water. It is dried over sodium sulfate, filtered, and evaporated. The residual crude 2-[(4-pyridyl)-methoxy]-acetophenone is used without further purification.

-49-

b) It is heated to 300°C under nitrogen for 40 minutes,

80 g of 2-[(4-pyridyl)-methoxyl-acetophenone] are used. After cooling, the residue is dissolved in a small amount of methylene chloride and chromatographed over 1000 g of aluminum oxide (activity 5 II, neutral). The first fraction eluted with 1.5 liters of methylene chloride is 4-(3-methyl-2-benzofuranyl)-pyridine. The compound melts after recrystallization in hexane at 55–57°C. The hydrochloride, prepared from a hydrochloric acid gas solution in ethyl acetate, melts after recrystallization in ethyl acetate at 280°C.

c) 58.0 g of 4-(3-methyl-2-benzylfuranyl)-pyridine is dissolved in 350 ml of methanol and stirred for 20 hours at 40-45°C with 75 ml of methyl chloride. The solution is then cooled to 0°C and the pre-salt is separated by aspiration.

15. The filter cake is washed again with ethanol. After recrystallization in methanol, 1-methyl-4-(3-methyl-2~benzofuranyl)-pyridinium iodide melts at 236-238°C.

EXAMPLE 19

112 g of 1-methyl-4-(5-chloro-2-benzofuranyl) 20-1,2,3,6-tetrahydropyridine (see Example 12) is dissolved in 2.3 liters of methanol and hydrogenation is carried out in the presence of 11 g of platinum oxide at a temperature between 20 and 30°C and under normal pressure. After 9 hours, 9.87 liters of hydrogen have been absorbed, which corresponds exactly to the theoretical amount of hydrogen absorption. The hydrogenation is stopped, the catalyst is separated by filtration, and the filtrate is evaporated under vacuum. The residue is dissolved in a small amount of chloroform and chromatographed on 600 g of aluminum oxide (activity II, neutral). The first fraction eluted with 230 liters of chloroform is 1-methyl-4-(5-chloro-2-benzofuranyl)-piperidine. This melts after recrystallization in hexane at 107°C. The hydrochloride prepared from a solution of the base with a solution of hydrochloric acid gas in ethyl acetate melts at 260°C.

35. A similar approach is obtained starting from 132 g of 1-

methyl-4-(5-bromo-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (see example 12) the 1-methyl-4-(5-bromo-2-benzofuranyl)-piperiidine with a melting point of 116-119°C and whose hydrochloride melts at 272-275°C.

-50-

EXAMPLE 20

22.0 g of 1-methyl-4-(5-methoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (see Example 13) is dissolved in 220 mL of methanol and hydrogenated in the presence of 4 g of a palladium catalyst on carbon (5% Pd), at 40–50°C and under normal pressure. The hydrogenation is stopped after 11 hours, the catalyst is separated by filtration, and the filtrate is evaporated under vacuum. The residue is dissolved in a small amount of chloroform and chromatographed on 400 g of aluminum oxide (activity II, neutral). The first fraction eluted with 2 L of chloroform is 1-methyl-4-(5-methoxy-2-benzofuranyl)piperidine. It melts after recrystallization in hexane at 68°G. The hydrochloride prepared from a solution of the base with a solution of hydrochloric gas in 15% ethyl acetate melts at 282-284°C.

1-methyl-4-(5,6-dimethoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyridine is obtained in a similar manner by hydrogenation of 24.7 g of 1-methyl-4-(5,6-dimethoxy-2-benz ofuranyl)-piperidine with a melting point of 73-75°0 and its hydrochloride with a melting point of 20,228-231°C.

EXAMPLE 21

24.2 g of 1-methyl-4-(7-methoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (see Example 14) is dissolved in 200 mL of methanol and hydrogenated in the presence of 4 g of palladium on carbon (5% Pd) at 40–50°C and under normal pressure. The hydrogenation is stopped after 15 hours, the catalyst is separated by filtration, and the filtrate is evaporated under vacuum. 1-Methyl-4-(7-methoxy-2-benzofuranyl)-piperidine melts after recrystallization in pentane at 76–78°C. The hydrochloride, prepared from a hydrochloric acid gas solution in ethyl acetate, melts at 172–173°C.

EXAMPLE 22

28.5 g of 1-methyl-4-(5-methyl-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (see Example 15) is dissolved in 150 mL of methanol and hydrogenation is carried out in the presence of 60 g of Raney nickel at a temperature between 90 and 95°C and with an initial pressure of 100 bar. After exactly 15 hours, the theoretical amount of hydrogen was absorbed.

-51-

The hydrogenation process is interrupted, the catalyst is separated by filtration, and the filtrate is evaporated. 1-Methyl-4-(5-methyl-2-benzofuranyl)-piperidine melts after recrystallization in hexane at 88-90°C. The hydrochloride, prepared from a solution of 5-hydrochloric acid gas in 1-ethyl acetate, melts at 186-189°C.

EXAMPLE 23

26.0 g of 1-methyl-4-(naphtho[2,1-b]furan-2-yl)-1,2,3,6-tetrahydropyridine is dissolved in 300 mL of methanol and hydrogenated in the presence of 3 g of 10-palladium catalyst on carbon (5% Pd) at a temperature between 40 and 50°C and under normal pressure. After 2 hours, 2.27 liters of hydrogen have been absorbed, which corresponds exactly to the theoretical amount of hydrogen consumed. The hydrogenation is stopped, the catalyst is separated by filtration, and the filtrate is evaporated under vacuum. The residue is 1-methyl-4-(naphtho[2,1-b]furan-2-yl)-piperidine. This melts after recrystallization in pentane at 83–85°C. The hydrochloride prepared from a solution of the base and a solution of hydrochloric acid gas in ethyl acetate melts at 243°C. The raw material is prepared according to the example.

16.

EXAMPLE 24

77.5 g of 1-benzyl-4-(2-benzofuranyl)~1,2,3,6-tetrahydropyridine (see Example 17) is dissolved in 200 mL of methanol. Hydrogenation is carried out after the addition of 53 mL of a 4.56% (w/v) methanolic solution, hydrochloric acid (corresponding to one equivalent of HCl), and 0.9 g of palladium on carbon (5%), at a temperature between 20 and 30°C and under normal pressure. After 17 hours, 30 ± 1.36 liters of hydrogen have been absorbed, which corresponds exactly to the theoretical amount of hydrogen consumed for one equivalent. The hydrogenation is stopped, the catalyst is separated by filtration, and the filtrate is evaporated under vacuum. The residue is 1-benzyl-4-(2-benzofuranyl)-piperidine. It melts after recrystallization in hexane at 77-79°C. The hydrochloride prepared from a solution of the base and a solution of hydrochloric gas in ethyl acetate melts at 217-218°C.

-52-

EXAMPLE 25

50.5 g of 1-methyl-4-(3-methyl-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (see Example 18) is dissolved in 500 ml of methanol and, in the presence of 1 g of platinum oxide, hydrogenation is carried out at a temperature between 20 and 30°C and under normal pressure. After 31 hours, 4.98 liters of hydrogen have been absorbed, which corresponds exactly to the theoretical amount of hydrogen. The hydrogenation is stopped, the catalyst is separated by filtration, and the filtrate is evaporated under vacuum. The residue is dissolved in methylene chloride and chromatographed on 800 g of aluminum oxide (neutral, activity II). The first fraction eluted with 3 liters of methylene chloride is the 1-Methyl-4-(3-methyl-2-benzofuranyl)-piperidine. The hydrochloride prepared from a solution of the base and a solution of hydrochloric gas in ethyl acetate melts at 228-230°C.

EXAMPLE 26

15.0 g of 1-methyl-4-(5-chloro-2-benzofuranyl)piperidine (see Example 19) is dissolved in 150 mL of toluene, and 20 to 40 g of chloroformic acid ethyl ester is added. The mixture is brought to a boil for 15 hours with stirring, and during the first hour, a small amount of toluene is removed by distillation to rapidly eliminate the released methylene chloride and ensure complete reflux of the toluene. The solution is then cooled to 20°C, filtered by aspiration, and the residue is washed again with 800 mL of toluene. The collected filtrates are successively washed with 500 ml of water, 1 liter of a 10% methanesulfonic acid solution in water, 1 liter of water, 500 ml of a 2 N sodium hydroxide solution, and 30, then 500 ml of water. They are dried over sodium sulfate, filtered, and then...

evaporates. The residual crude ethyl ester of 4-(5-chloro-2-benzofuranyl)-1-piperidine-carboxylic acid is used without further purification.

11.5 g of ethyl ester of 4-(5-35-chloro-2-benzofuranyl)-1-piperidine carboxylic acid is dissolved in 75 ml of ethylene glycol. After adding 50 ml of a 50% aqueous potassium hydroxide solution, the mixture is heated at 160°C for 15 hours, with vigorous stirring of the cloudy solution.

-53-

The reaction solution is cooled to 20°C and extracted twice, each time with 500 mL of ethyl acetate. The organic phases are washed five times, each time with 1 liter of water, dried over sodium sulfate, filtered, and evaporated. The residue is dissolved in 300 mL of a 10% methanesulfonic acid solution in water, and the acidic solution is extracted with ether. The aqueous solution is then adjusted to pH 12 by adding a 10% caustic soda solution and extracted with 1 liter of chloroform. The chloroform solution is dried over sodium sulfate, filtered, and evaporated, yielding 4-(5-chloro-2-benzofuranyl)-piperidine. After recrystallization in hexane, the free base melts at 77-78°G. The hydrochloride is prepared with hydrochloric acid gas in ethyl acetate and recrystallized in ethyl acetate, melting at 252-254°G. 15 EXAMPLE 27

Similar to Example 26, starting from 14.4 g of 1-methyl-4-(5-methyl-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (see Example 15), we obtain the crude ethyl ester of 4-(5-methyl-2-benzofuranyl)-3,6-dihydro-1(2H)-pyridine-carboxy-20 acid, which can be used directly for hydrolysis. A sample of the substance recrystallized in pentane melts at 85°G.

The above ester is hydrolyzed in a manner analogous to that of example 26 and 4-(5~methyl~2-benzofura~ 25 nyl)-1,2,3,6-tetrahydropyridine is obtained, which is transformed in a manner analogous to example 26 into its hydrochloride.

Similarly, in a manner analogous to that of example 26, we obtain

- starting from 14.9 g of 1-methyl-4-(5-chloro-2-benzofuranyl)-30 1,2,3,6-tetrahydropyridine (see example 12), the ethyl ester of 4-(5-chloro-2-benzofuranyl)-3,6-dihydro-1(2H)~ pyridine-carboxylic acid and from this the 4-(5-chloro-2-benzofuranyl)-1,2,3,6-tetrahydropyridine and its hydrochloride,

- starting from 12.3 g of 1-methyl-4-(2-benzofuranyl)-1,2,3,6-35 tetrahydropyridine, the crude ethyl ester of 4-(2~

benzofuranyl)-3,6-dihydro-1(2H)-pyridine carboxylic acid and from this the 4-(2-benzofuranyl)-1,2,3,6-tetrahydro-pyridine and its hydrochloride,

-54-

- starting from 14.6 g of 1-methyl-4-(5-methoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (see example 13), the ethyl ester of 4-(5-methoxy-2-benzofuranyl)-3,6-dihydro-

crude 1(2H)-pyridine-carboxylic acid, and from this the 5-4-(5-methoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyridine and its hydrochloride,

- starting from 14.6 g of 1-methyl-4-(7-methoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (see example 14), the ethyl ester of 4-(7-methoxy-2-benzofuranyl)-3,6-dihydro-

10 crude 1(2H)-pyridine-carboxylic acid and from this the

4-(7-methoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyridine and its hydrochloride,

- starting from 14.4 g of 1-methyl-4-(3-methyl-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (see example 18), the ethy- ester

15 lique of 4-(3-methyl-2-benzofuranyl)-3,6-dihydro-

crude 1(2H)-pyridine-carboxylic acid and from this, 4-(3-methyl-2-benzofuranyl)-1,2,3,6-tetrahydropyridine and its hydrochloride,

- starting from 14.5 g of 1-methyl~4-(3-methyl-benzofuranyl)-

20 piperidine (see example 25), the crude carboxylic ethyl ester of 4-(3-methyl~ 2-benzofuranyl)-1-piperidine and from this the 1-(3-methyl-2-benzofuranyl)-piperidine and its hydrochloride.

EXAMPLE 28

25. 12.0 g of 1-methyl-4-(naphtho[2,1-b]furan-2-

yl)-piperidine (see example 23) is dissolved in 150 ml of toluene, and 40.0 g of ethyl ester of chloroformic acid is slowly added dropwise under a strong stream of nitrogen to rapidly remove the released methylene chloride.

30. The solution is then refluxed for 20 hours, cooled, filtered by aspiration, and the residue on the filter is washed again with 500 ml of toluene. The combined filtrates are then successively washed with 500 ml of water, one liter of a 10% methane-tallow solution in water, 500 ml of water, and 500 ml of lye.

35 ml of 2 N sodium hydroxide and 500 ml of water are mixed, dried over sodium sulfate, filtered, and evaporated. The residual ethyl ester of 4-(naphtho-r.[2,1-b]-furan-2-yl)-1-piperidine-carboxylic acid melts after recrystallization in pentane at 89-92°C.

-55-

7.8 g of ethyl ester of 4-(naphtho-) acid are dissolved

[2,1-b]-furan-2-yl)-1-piperidine-carboxylic acid is reacted in 60 mL of ethylene glycol. After adding 40 mL of a 50% aqueous potassium hydroxide solution, the mixture is heated for 15 hours at 160°C, with vigorous stirring of the resulting cloudy solution. The reaction solution is then cooled to 20°C and extracted twice, each time with 500 mL of ethyl acetate. The organic phases are washed five times, each time with 1 liter of water, dried over sodium sulfate, filtered, and evaporated.

10. The residue is dissolved in 400 ml of 2 N hydrochloric acid and the acidic solution is extracted with toluene. The aqueous solution is then adjusted to pH 12 by adding 10% sodium hydroxide solution and extracted with one liter of chloroform. The chloroform solution is dried over sodium sulfate, filtered, and evaporated.

15 and we obtain 4-(naphtho[2,1-b]-furan-2-yl)-piperidine. The hydrochloride is prepared with hydrochloric gas in ethyl acetate and recrystallized in ethyl acetate and it melts at 225°G.

20 - Starting from 15.8 g of 1-methyl-4-(naphtho[2,1-b]furan-2-yl)-1-,2,3,6-tetrahydropyridine (see example 16), the ethyl ester of crude 4-(naphtho[2,1-b]furan-2-yl)-3,6-dihydro-1(2H)-pyridine-carboxylic acid and from this, 4-(naphtho-[2,1-b]furan-2-yl)-1,2,3,6-tetrahydropyridine. 25 EXAMPLE 29

1,2,3,6-Tetrahydropyridine (see Example 17) is dissolved in 900 mL of methanol and hydrogenated in the presence of 9.0 g of palladium on carbon (5% Pd) at a temperature between 30 and 40°C and under normal pressure. After 22 hours, 12.2 liters of hydrogen have been absorbed, which corresponds exactly to the theoretical consumption of 2 equivalents. The hydrogenation is stopped, the catalyst is separated by filtration, and the filtrate is evaporated under vacuum. The residue is distilled under high vacuum by fractionation. The fraction that distills at 108–110°C under 0.06 mmHg is 4-(2-benzofuranyl)-piperidine, identical to the compound described in Example 1.

Similarly, we obtain:

88.8 g of 1-benzyl-4-(2-benzofuranyl)- are dissolved

-56-

EXAMPLE 50

To a solution of 6.0 g of 1-(3-oxobutyl)-4-(2-benzofuranyl)-piperidine (see Example 8) in 150 mL of methanol, a solution of 6.0 g of sodium borohydride in 25 mL of water is added dropwise, at a rate of 5 drops, ensuring that the reaction temperature does not exceed 30°C. The mixture is then stirred for 15 hours at room temperature. The methanol is then evaporated under vacuum. The residual aqueous phase is extracted twice, each time with 250 mL of chloroform. The chloroform solution is dried over sodium sulfate, filtered, and evaporated. The residue is dissolved in 500 mL of 2 N hydrochloric acid, and the acid solution is washed with ether. Next, the aqueous solution is adjusted to pH 12 by adding 10% sodium hydroxide solution and extracted with 15 liters of chloroform. The chloroform solution is dried over magnesium sulfate, filtered, and evaporated, yielding crude 1-(3-hydroxybutyl)-4-(2-benzofuranyl)-piperidine or 4-(2-benzofuranyl)-α-methyl-1-piperidine-propanol. Its hydrochloride is prepared with hydrochloric acid gas in 20-ethyl acetate and recrystallized in ethyl acetate, melting at 194-195°C.

EXAMPLE 31

A solution of 45.0 g of sodium borohydride in 190 ml of water is added to a solution of 99 g of 1-methyl-4-(5,6-dimethyl-2-benzofuranyl)-pyridinium iodide in 1500 ml of 25-methoxyl, while stirring and cooling from the outside.

Add the solution dropwise, ensuring the reaction mixture temperature does not exceed 35°C. The solution is then stirred for 15 hours at room temperature. The methanol is then evaporated under vacuum. The residual aqueous phase is extracted twice, each time with 750 mL of chloroform. The chloroform solution is dried over sodium sulfate, filtered, and evaporated. The oily residue is recrystallized from cyclohexane, yielding 1-methyl-4-(5,6-dimethyl-2-benzofuranyl)-1,2,3,6-35 tetrahydropyridine with a melting point of 124-126°C. The hydrochloride, prepared with hydrochloric acid gas in ethyl acetate, melts after recrystallization from acetone at 231-233°C.

-57-

Similarly, from 99 g of 1-methyl-4-(4,7-dimethyl-2-benzofuranyl)-pyridinium iodide, we obtain 1-methyl-4-(4,7-dimethyl-2-benzofuranyl)-1,2,3,6-tetrahydropyridine, whose melting point is 69-71°C, hydrochloride, melting point 281-283°C,

- starting from 99 g of 1-methyl-4-(5,7-dimethyl-2-benzofuranyl)-pyridinium iodide, 1-methyl-4-(5,7-dimethyl-2-benzofuranyl)-1,2,3,6-tetrahydropyridine with a melting point of 99-102°C, hydrochloride, melting point: 250-252°C,

10 - starting from 110 g of 1-methyl-4-[5-(tri-

fluoromethyl)-2-benzofuranyl]-pyridinium, 1-methyl-4—[5-(tri-fluoromethyl)-2-benzofuranyl]-1,2,3,6-tetrahydropyridine and its hydrochloride,

- starting from 102 g of 1-methyl-4- [5,6-

15 (trimethylene)-2-benzofuranyl]-pyridinium, 1-methyl-4— [3,6-(trimethylene)-2-benzofuranyl]-1,2,3,6-tetrahydropyridine and its hydrochloride.

The raw materials can be prepared in the following way:

20 a) Heat to 150-170°C while stirring for 20 hours,

58.5 g of 4-,5-dimethylsalicylaldehyde, 64.0 g of 4-(chloromethyl)pyridine hydrochloride, 24.0 g of potassium carbonate, and 2.0 g of potassium iodide in 500 ml of dimethylformamide. The reaction mixture is then filtered by aspiration and

25. The filter residue is washed with one liter of chloroform. The combined filtrates are evaporated under vacuum, and the evaporation residue is dissolved in 150 ml of methylene chloride and chromatographed on 2000 g of aluminum oxide (activity II, neutral). The first fraction eluted with 2.8 liters of methylene chloride...

30-lene is 4-(5,6-dimethyl-2-(benzofuranyl)-pyridine. The compound melts after recrystallization in hexane at 168-170°C. The hydrochloride prepared with a hydrochloric acid gas solution in methyl acetate melts after recrystallization in ethyl acetate at 278-280°C.

35. We prepare in a similar way starting from 58.5 g of

3,6-Dimethyl-salicylaldehyde, 4-(4,7-dimethyl-2-benzofuranyl)-pyridine with a melting point of 78-80°C, hydrated hydrochloride, melting point 266-269°C,

-58-

- starting from 58.5 g of 3,5-dimethyl-salicylaldehyde, 4-(5,7-diraethyl-2-benzofuranyl)-pyridine, melting point -107-109°C Hydrochloride, melting point 285°C,

- starting from 74.2 g of 5-(trifluoromethyl)-salicyl-5 aldehyde or aaa-trifluoro~2,5-cresot-aldehyde, the ^—[^-(trifluoromethyl) -2 -"benz of uranyl] -pyridine and

- starting from 62.8 g of 4,5-(trimethylene)-salicyl-aldehyde (or 6-hydroxy-5-indan-carboxaldehyde, see J. Amer.

Chem. Soc. 77, 2466-75), the 4-[5,6-trimethylen)-2-benzofuranyl]-

10 pyridine, melting point 90-92°C.

b) 79.0 g of 4-(5,6-dimethyl-2-benzofuranyl)-pyridine is dissolved in 750 mL of methanol and stirred for 20 hours at 40–45°C with 100 mL of methyl iodide. The solution is then cooled to -20°C and the precipitated salt is separated by aspiration and washed with 150 mL of isopropanol. After recrystallization in isopropanol, the resulting 1-methyl-4-(5,6-dimethyl-2-benzofuranyl)-pyridinium iodide melts at 219–221°C.

A similar result can be obtained using:

79.0 g of 4-(4,7-dimethyl-2-benzofuranyl)-pyridine, 20 g of 1-methyl-4-(4,7-dimethyl-2-benzofuranyl)-pyridinium iodide, melting point 316-320°C,

79.0 g of 4-[5,7-dimethyl-2-benzofuranyl)-pyridine, 1~methyl-4-(5,7-dimethyl-2-benzofuranyl)-pyridinium iodide, melting point 268-270°C,

25 93.2 g of 4-[5-(trifluoromethyl)-2-benzofuranyl]-pyri-

dine, 1-methyl-4-[5-(trifluoromethyl)-2-benzofuranyl]-pyridinium iodide and

83.4 g of 4-[5,6-(trimethylen)-2-benzofuranyl]-pyridine, 1-methyl1-4-[5,6-(trimethylen)-2-benzofuranyl]-pyridi-30 nium iodide, melting point 194-197°0.

EXAMPLE 32

139 g of 1-methyl-4-(5,6-dimethyl-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (see Example 31) is dissolved in 1500 ml of methanol and hydrogenation is carried out in the presence of 14 g of palladium catalyst on carbon (containing 5% palladium), at a temperature between 20 and 25°C and under normal pressure. After 8 hours, the theoretical required quantity of 13 liters of hydrogen has been absorbed. The hydrogenation is stopped.

-59-

The catalyst is separated by filtration and the filtrate is evaporated under vacuum. Crude 1-methyl-4-(5,6-dimethyl-2-benzofuranyl)-piperidine is recrystallized in cyclohexane and melts at 122-124°C. The hydrochloride prepared from a solution of the base with a solution of hydrochloric acid gas in ethyl acetate melts at 205-207°C.

In a similar manner, with identical quantities of 1-methyl-4-(4-,7-dimethyl-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (see example 31), we obtain 1-methyl-4-(4-,7-dimethyl-10 2-benzofuranyl)-piperidine, and its hydrochloride which melts at 242°C,

of 1-methyl-4-(5,7-dimethyl-2-benzofuranyl)-1,2,3,6-tetrahydropyridine (see example 31) 1-methyl-4-(5,7-dimethyl-2~benzo-furanyl)-piperidine and its hydrochloride with a melting point of 210-13 212°G.

Similarly, hydrogenation in the presence of 8 g of catalyst in 800 ml of methanol is obtained until 5 liters of hydrogen are absorbed, and analogously overall: from 62.2 g of 1-methyl-4-[5-(trifluoromethyl)-20 2-benzofuranyl]-1,2,3,6-tetrahydropyridine (see example 31) 1-methyl-4-[5-(trifluoromethyl)-2-benzofuranyl]-piperidine and its hydrochloride and

from 56.0 g of 1-methyl-4-[5,6~trimethylen)~2-benzofuranyl]-1,2,3,6-tetrahydropyridine (see example 31) the 25 1-methyl-4-[5,6-(trimethylen)-2-benzofuranyl]-piperidine and its hydrochloride.

EXAMPLE 35

43 g of 1-methyl-4-(5,6-dimethyl-2-benzofuranyl)piperidine (see Example 32) is dissolved in 800 mL of toluene, and 80 g of chloroformic acid ethyl ester is added. The solution is boiled for 15 hours with stirring, and during the first hour, a small portion of the toluene is removed by distillation to rapidly eliminate the released methyl chloride and ensure complete reflux of the toluene. The solution is then cooled to 20°C, filtered by aspiration, and the residue is washed again on the filter with 100 mL of toluene. The combined filtrates are then washed successively with 500 mL of water, 1000 mL of a 10% methanesulfonic acid solution, 1000 mL of water, and 500 mL of...

-60-

From an aqueous solution of sodium hydroxide 2 5T and 500 ml of water, the mixture is dried over sodium sulfate, filtered, and evaporated. The crude residual ethyl ester of 4-(5,6-dimethyl-2-benzofuranyl)-1-piperidine-carboxylic acid melts after recrystallization in pentane at 96-97°G.

36.5 g of ethyl ester of 4-(5,6-dimethyl-1-2-benzofuranyl)-1-piperidine carboxylic acid is dissolved in 150 mL of ethylene glycol. After adding 70 g of solid sodium hydroxide, the cloudy solution is heated by vigorous stirring for 15 hours at 160°C. The reaction solution is then cooled to 20°C and extracted twice with 500 mL of ethyl acetate each time. The organic phases are washed five times with 1 liter of water each time, dried over sodium sulfate, filtered, and evaporated. The residue is dissolved in 15,300 mL of a 10% methanesulfonic acid solution in water, and the acid solution is extracted with ether. The aqueous solution is adjusted to pH 12 by adding 10% sodium hydroxide solution and extracted with one liter of chloroform. The chloroform solution is dried over sodium sulfate, filtered, and evaporated, yielding crude 4-(5,6-dimethyl-2-benzofuranyl)-piperidine. The hydrochloride is prepared with hydrochloric acid gas in ethyl acetate and recrystallized in ethyl acetate, where it forms as a hydrate that melts at 230–233°C.

In a similar way, we obtain,

25 - starting from 43 g of 1-methyl-4-(4,7-dimethyl-2-

benzofuranyl)-piperidine (see example 32), the ethyl ester of crude 4-(4,7-dimethyl-2-benzofuranyl)-1-piperidine carboxylic acid and from there, 4-(4,7-dimethyl-2-benzofuranyl)-piperidine and its hydrochloride with a melting point of 266°C, 30 - starting from 43 g of 1-methyl-4-(5,7-dimethyl-2-

benzo-furanyl)-piperidine (see example 32), the ethyl ester of crude 4-(5,7-dimethyl-2-benzofuranyl)-1-piperidine carboxylic acid and from there, 4-(5,7-dimethyl-2-benzofuranyl)-piperidine and its hydrochloride with a melting point of 215-218°C, 35 - starting from 50 g of 1-methyl-4-[5-(trifluoromethyl)-

2-benzofuranyl]-piperidine (see example 32), the ethyl ester of crude 4-[5-(trifluoromethyl)-2-benzofuranyl]-1-piperidine-carboxylic acid and from there, 4-[5-(trifluoromethyl)-2-benzofuranyl]-1-piperidine and its hydrochloride and

-61-

- starting from 45 g of 1-methyl~4-[5,6-trimethylen)-2-benzofuranyl]-piperidine (see example 32), the ethyl ester of 4-[5,6-(trimethylen-2-benzofuranyl]-1-piperidine-carboxy-lic acid and from there, 4-[5,6-(trimethylen)-2-benzofuranyl]-piperidine-5 dine and its hydrochloride.

EXAMPLE 34

One hundred grams of 4-(5,6-dimethyl-2-benzofuranyl)-piperidine (see Example 33) are dissolved in 50 mL of formic acid. Six mL of a 40% aqueous formaldehyde solution are added dropwise to this solution while stirring. The reaction mixture is heated to 95–100°C for 5 hours and then stirred at room temperature for 15 hours. The mixture is then made strongly acidic by adding 10 mL of concentrated hydrochloric acid, and the solvent is removed by evaporation. The evaporation residue is dissolved in 100 mL of water, non-basic substances are extracted with toluene, the aqueous phase is adjusted to pH 12 by adding a 10% aqueous sodium hydroxide solution, and the solution is extracted three times, each time with 300 mL of chloroform. The organic phases are combined, dried over sodium sulfate, filtered, and evaporated. The residue is chromatographed.

Evaporation over 500 g of aluminum oxide (activity II neutral). The first fraction eluted with 500 mL of methylene chloride is not unitary by thin-layer chromatography and is not repeated. The second fraction eluted with 500 mL of methylene chloride is pure 1-methyl-4-(5,6-dimethyl-2-benzofuranyl)-piperidine. The compound melts after recrystallization in cyclohexane at 122–124°C and is identical to the compound in Example 32.

EXAMPLE 35

30. 7.0 g of 4-(2-benzofuranyl)~1,3- are brought to reflux

Dimethyl-4-piperidinol was dissolved in 100 mL of crystallizable acetic acid and 30 mL of hydrochloric acid for 10 hours. The solution was cooled and extracted three times, each time with 200 mL of chloroform. The organic phases were washed with 2 N acetone lye, dried over sodium sulfate, filtered, and evaporated. Crude 4-(2-benzofuranyl)-1,5-dimethyl-1,2,3,6-tetrahydropiperidinol melted after recrystallization in ethyl acetate at 242–244°C.

-62-

The raw material is prepared as follows:

Over 30 minutes, 50 mL of a dipolar solution of n-butyllithium in hexane is added dropwise to a solution of 11.8 g of benzofuran in 100 mL of diethyl ether at a reaction temperature of -5°C. The solution is then stirred for one hour at 0°C. Next, a solution of 1,3-dimethyl-4-piperidone in 50 mL of absolute diethyl ether is added dropwise over 15 minutes. The reaction temperature is maintained at 0°C by external cooling. The reaction solution is stirred for

15 hours at room temperature. Then, while stirring, pour the mixture onto 200 g of ice and extract the aqueous phase three times, each time with 500 ml of ethyl acetate. The combined organic extracts are dried over sodium sulfate, filtered, and evaporated. The residue is dissolved in 500 ml of 2 N hydrochloric acid, and the acid solution is washed with ether. The pH of the aqueous solution is then adjusted to 12 by adding 10% sodium hydroxide solution, and the mixture is extracted with one liter of chloroform. The chloroform solution is dried over sodium sulfate, filtered by aspiration, and evaporated, yielding 4-(2-benzophenylamine)-1,3-dimethyl-4-piperidinol, which, after recrystallization in hexane, melts at 128-130°C.

EXAMPLE 56

To a solution of 60 g of 25 1-methyl-zt--(5-bromo-2-benzofuranyl)-piperidine (see Example 19) in 300 mL of diethyl ether at -5°C, 4-80 mL of a 1.35 N solution of n-butyllithium in absolute diethyl ether is added dropwise over 30 minutes. The reaction temperature is maintained between -5 and 0°C during the dropwise addition by external cooling. The solution is then stirred for a further 90 minutes at 5-10°C. Next, a solution of 85 mL of cyclchexanone in 100 mL of absolute diethyl ether is added dropwise over 30 minutes, maintaining the reaction temperature by external cooling between 35°C and 5°C. The reaction solution is then stirred for 15 hours at room temperature. Afterward, while stirring, it is poured onto 300 g of ice, and the aqueous phase is extracted three times, each time with 500 mL of ethyl acetate. The

-63-

Organic extracts are combined on sodium sulfate, filtered, and evaporated. The residue is dissolved in 300 mL of 2 N hydrochloric acid, and the acid solution is washed with ether. The aqueous solution is then adjusted to pH 12 by adding 10% sodium hydroxide solution and extracted with 1000 mL of chloroform. The chloroform solution is dried on sodium sulfate, filtered, and evaporated, yielding 1-methyl-4-[5-(1-hydroxycyclohexyl)-2-benzofuranyl-piperidine. After recrystallization in cyclohexane, the free base melts at 155–157°C. The hydrochloride is prepared with hydrochloric acid gas in ethyl acetate and recrystallized in acetone, melting at 226–229°C.

EXAMPLE 37

20 g of 1-methyl-4-[5-(1-hydroxy-cyclohexyl)-2-benzofuranyl]-piperidine is brought to reflux in 60 ml of crystallizable acetic acid and 15 ml of hydrochloric acid for

48 hours. The reaction solution is cooled to room temperature and evaporated under vacuum. The evaporation residue is suspended in 1000 mL of chloroform and washed with 2 N sodium hydroxide solution. The organic phase is dried over sodium sulfate, filtered, and chromatographed over 700 g of aluminum oxide (activity II, neutral). The first fractions eluted with 3000 mL of chloroform yield crude 1-methyl-4-[5-(1-cyclohexyl)-2-benzofuranyl]-piperidine after evaporation. After recrystallization in hexane, the compound melts at 81–85°C. The hydrochloride prepared with a hydrochloric acid gas solution in ethyl acetate melts after recrystallization in ethyl acetate at 227–229°C.

EXAMPLE 38

2.0 g of 1-methyl-4-(5-cyclohexyl)-2-benzofuranyl)piperidine is dissolved in 30 ml of methanol and hydrogenated in the presence of 0.2 g of a palladium catalyst on carbon (5% Pd) at 20-25°C and under normal pressure. Hydrogenation is stopped after 3 hours, after 100% hydrogen absorption. The catalyst is separated by filtration and the filtrate is evaporated under vacuum. The residual 1-methyl-4-(5-cyclohexyl-2-benzofuranyl)piperidine is then collected.

melts after recrystallization in hexane at 89-90°C. The hydrochloride prepared with a hydrochloric acid gas solution melts after recrystallization in ethyl acetate at 238-240°C.

-64-

EXAMPLE 39

To a 0% iodide solution, 1-methyl-3-(2-benzofuranyl)pyridinium pyridinium is added dropwise to 600 mL of methanol, with stirring and external cooling. A solution of 50 g of sodium borohydride in 100 mL of water is then added dropwise, ensuring that the reaction temperature does not exceed 35°C. The solution is then stirred for 15 hours, and another 50 g solution of sodium borohydride in 100 mL of water is added dropwise, again ensuring that the reaction temperature does not exceed 35°C. The methanol is then evaporated under vacuum, and the residual aqueous phase is extracted twice, each time with 300 mL of chloroform. The chloroform solution is dried over sodium sulfate, filtered, and evaporated. The 1-methyl-3-(2-benzofuranyl)-1,2,5,6-tetrahydropyridine obtained 15 is recrystallized in diisopropyl ether and melts at 63°C. The hydrochloride prepared with a hydrochloric acid gas solution in ethyl acetate melts after recrystallization in ethyl acetate at 244-246°C.

The raw material can be prepared in the following way:

20 sales:

40 g of 3-(2-benzofuranyl)-pyridine [Chim. Ther. 6, 159-166 (1971)] is dissolved in 300 ml of methanol and stirred for 15 hours at 40-45°C with 100 ml of methyl iodide. The solution is then cooled to between 0 and -5°C and the salt formed is separated by aspiration. The filter cake is washed again with

300 ml of isopropanol. After recrystallization in isopropanol, 1-methyl-3-(2-benzofuranyl)-pyridinium iodide melts at 222°C.

EXAMPLE 40

20.2 g of 1-methyl-3-(2-benzofuranyl)-30 1,2,5,6-tetrahydropyridine (see example 39) is dissolved in 300 ml of methanol and hydrogenation is carried out in the presence of 6 g of palladium catalyst on carbon (5% Pd), at a temperature between 40 and 50°C and under normal pressure. After 4 hours, 2.1 liters of hydrogen have been absorbed, which corresponds exactly to the theoretical hydrogen consumption. The hydrogenation is stopped, the catalyst is separated by filtration, and the filtrate is evaporated under vacuum. The residue from evaporation is distilled by fractionation under high vacuum.

-65-

The fraction that distills between 108 and 110°G under 0.09 mm Hg is 1-methyl-3-(2-benzofuranyl)-piperidine. The hydrochloride prepared from a solution of the base with a solution of hydrochloric acid gas in ethyl acetate melts at 193-195°G.

5 EXAMPLE 41

11.2 g of 1-methyl-3-(2-benzofuranyl)-piperidine (see Example 40) is dissolved in 100 mL of toluene, and 22.5 g of chloroformic acid ethyl ester is added. The mixture is heated to boiling for 15 hours with stirring, and during the first 10 hours, a small amount of toluene is distilled off to rapidly remove the released methyl chloride and then to ensure complete reflux of the toluene. The solution is then cooled to 70°C, separated by aspiration, and the residue is washed through a filter with 500 mL of toluene. The collected filtrates are successively washed with 500 ml of water, one liter of a 10% aqueous solution of methanesulfonic acid, one liter of water, 500 ml of 2 N sodium hydroxide solution, and 500 ml of water. The mixture is then dried with sodium sulfate, filtered, and evaporated. The remaining crude ethyl ester of 3-(2-benzo-20 furanyl)-1-piperidine carboxylic acid is used without further purification.

12.2 g of ethyl ester of 3-(2-benzofuranyl)-1-piperidine carboxylic acid is dissolved in 150 mL of ethylene glycol. After adding 50 g of solid sodium hydroxide, the resulting cloudy solution is heated by vigorous stirring for 25 to 15 hours at 160°C. The reaction solution is then cooled to 20°C and extracted twice, each time with 500 mL of toluene. The organic phases are washed five times with 1 liter of water, dried over sodium sulfate, filtered, and evaporated. The residue is dissolved in 300 mL of a 10% aqueous solution of methanesulfonic acid, and the acid solution is extracted with ether. The aqueous solution is then adjusted to pH 12 by adding 10% sodium hydroxide solution, and the extraction is performed with 1 liter of chloroform. The chloroform solution is dried with sodium sulfate, filtered, and evaporated. The evaporation residue is distilled under high vacuum, and 3(2-benzofuranyl)piperidine is distilled under 0.2 mmHg at 160-166°C. The hydrochloride is prepared from this base with hydrochloric acid gas in ethyl acetate and recrystallized in ethyl acetate, melting at 216-218°C.

-66-

EXAMPLE 42

17.4 g of 2-(2-benzofuranyl)-pyridine is dissolved in 180 mL of methanol and hydrogenated in the presence of 1.8 g of palladium on carbon (5% Pd) at a temperature of 40–50°C and an initial pressure of 3 bar (Paar apparatus). After 26 hours, 5.06 liters of hydrogen have been absorbed. The hydrogenation is stopped, the catalyst is separated by filtration, and the filtrate is evaporated under vacuum. The evaporation residue is dissolved in 400 mL of 102 N hydrochloric acid, and the acidic solution is extracted with ether. The aqueous phase is then adjusted to pH 12 by the addition of 10% sodium hydroxide solution, and the solution is extracted with 1 liter of chloroform. The chloroform solution over sodium sulfate is dried, filtered, evaporated, and the residue is distilled by fractionation under high vacuum. The fraction that distills between 112 and 116°C at 0.15 mmHg is 2-(2-benzofuranyl)-piperidine. The hydrochloride, prepared with a hydrochloric acid gas solution in ethyl acetate, melts after recrystallization in acetone at 222–225°C.

The raw material can be prepared according to the example

20 43 a).

EXAMPLE 43

To a solution of 18.2 g of 1-methyl-2-(2-benzofuranyl)pyridinium iodide in 150 mL of methanol, 6.15 g of sodium borohydride dissolved in 50 mL of water is added dropwise over 30 minutes, while stirring and cooling with ice-cold water. The solution is stirred for one hour at room temperature and the pale yellow solution is poured into 1000 mL of water. The oil, which separates with chloroform, is extracted. The chloroform extracts are dried over anhydrous sodium sulfate, and the solvent is removed by vacuum distillation. The oily residue is resuspended in a small amount of methylene chloride and chromatographed over 150 g of aluminum oxide (2% water). Methylene chloride eluates, upon evaporation, yielded 13.2 g of 1-methyl-2-(2-benzofuranyl)-1,4,5,6-tetrahydropyridine as a yellow oil. This was hydrogenated in 130 mL of ethyl acetate after the addition of 1 g of a 10% palladium-carbon catalyst at room temperature. After the absorption of 935 mL of hydrogen, the hydrogenation ceased within 19 hours.

-67-

The catalyst is separated by filtration, the filtrate is evaporated under vacuum, and the residue is distilled under high vacuum. 1-Methyl-2-(2-benzofuranyl)-piperidine is obtained as a colorless oil with a boiling point (0.02 mm Hg) of 93-97°C. 5-Hydroxyl-5-drate is obtained as colorless crystals with a melting point of 188-189°C by dissolving the distilled base in five times the amount of acetone and neutralizing it with a 2 N solution of hydrochloric acid gas in ethyl acetate.

The raw material can be prepared in the following way:

10 sales:

a) 12.2 g of salicylaldehyde and 16.4 g of 2-(chloromethyl)pyridine hydrochloride are brought to a boil with the addition of 55.2 g of potassium carbonate and 0.2 g of potassium iodide in 200 ml of isopropanol, under good stirring.

15. The reaction mixture is heated for 12 hours under reflux. The reaction mixture is filtered and evaporated under vacuum. The residue is dissolved in 100 mL of chloroform and washed with a 2N sodium hydroxide solution, then extracted with water. The chloroform solution is then dried over anhydrous sodium sulfate and evaporated under vacuum. 20. The residual oil is dissolved in benzene and filtered over 200 g of aluminum oxide (2% water). The filtrates are evaporated and the residue is distilled under high vacuum. 2-(2-pyridyl-methoxy)-benzaldehyde is obtained as a colorless, viscous oil with a boiling point of 135-164°C/0.04 mmHg, which, after solidifying, melts at 69-71°C. This substance is heated for

After 30 minutes under a nitrogen atmosphere at 300°C, it is dissolved after cooling in methylene chloride and the solution is filtered through aluminum oxide (2% water). The filtrate yields 2-(2-benzofuranyl)-pyridine as yellow crystals with a melting point of 86-87°C (in isopropanol).

b) 19.5 g of 2-(2-benzofuranyl)-pyridine is dissolved in 150 ml of methanol and heated in an autoclave for

17 hours at 120°C with 4-2.9 g of methyl iodide. After cooling, the crystallized 1-methyl-2-(2-35benzofuranyl)pyridinium iodide is separated by aspiration and washed with isopropanol. To purify it, it is recrystallized in methanol-ether, yielding dark orange crystals with a melting point of 179-180°C.

Claims (1)

-68- - DEMANDS - 1 - Process for manufacturing new tetrahydropyridine and piperidine derivatives of general formula I: 10 N - R, (I) in which R^ represents a hydrogen atom, an aliphatic hydrocarbon radical with 1 to 12 carbon atoms or a cycloaliphatic hydrocarbon radical with 3 to 12 carbon atoms, radicals which may be substituted by hydroxyl groups or an oxo radical and/or interrupted by an oxygen atom, or represents a phenyl-(lower alkyl) radical in which the benzene ring with at most three hydrogen atoms may be replaced by substituents from halogen atoms up to atomic number 55, lower alkyl or lower alkoxy groups, methylenedioxy and trifluoromethyl groups, and whose lower alkyl chain may be substituted on one of the carbon atoms not directly bonded to the cyclic nitrogen atom, by an oxo radical or a hydroxyl group, or represents a substituted cinnamyl radical correspondingly possibly in the benzene ring but which must not however be a methyl group, in the case where A represents the ethylene radical and B the methylene radical and at the same time R2, R^, R^ and R^ each represent a hydrogen atom, R2 represents a hydrogen atom or a lower alkyl group, R^ and R^ independently represent a hydrogen atom, a lower alkyl group 35 or lower alkoxy, halogen atoms up to atomic number 35, benzyloxy or hydroxyl groups and R^ also a trifluoromethylene group, a lower 1-hydroxyalkyl group or lower alk-1-enyl group, a 1-hydroxycycloalkyl group, -69- cycloalc-1-enyl or cycloalcoyl, each with 5 to 8 carbon atoms, or R^ and R^ together represent a trimethylene or tetramethylene radical, or corresponding to a condensed benzene ring, the 1,3-butadienyl radical, R^ represents a hydrogen atom or an alkyl group with at most M carbon atoms, and A and B represent saturated aliphatic divalent hydrocarbon radicals, and one of these symbols may also represent the direct bond, A and B together representing three chain elements and together with R^ present at most 10⁹ carbon atoms, X and T each represent a hydrogen atom or together an additional bond, and their addition salts with organic and mineral acids, characterized in that a) the Ac radical is separated in a compound of general formula II: 25 in which Ac represents a separable radical and R2, R^, R^ and R^ have the meanings given under formula I, and b) if desired, a compound obtained according to (a) or in another way of general formula is reacted, encompassed in general formula I -70- 10 20 25 30 in which R2, R4, R5 have the meanings given under the general formula I, with a reactive ester of a hydroxyl compound of general formula III >a HO - R; (III) Q in which R^ has the meaning given under formula I for R^ excluding hydrogen and, represents the methyl group in the case where in the formula Rj» R4 and R^ represent a hydrogen atom, A represents the ethylene group and B the methylene group. or "under reducing conditions, with an oxo compound of general formula Illa 0 = Rj (Illa) in which R^ which corresponds to a monovalent radical R,j represents a divalent geminal radical, or "we add to a 15 composed of general formula Illb RÎ R? CH = C - CO - Ri (Illb) That in which R^, R^, Rxi represent separate radicals or 'If linked together, the -CH-CH-CO- group entering' into one of the definitions of R^ completing an oxo-substituted radical, or else it is condensed with formaldehyde and a compound of general formula IIIc R® *1 CH, CO - Ri (IIIc) in which R^ and R^ represent separate or bonded groups, the -CT^-CH-CO- group falling within one of the definitions given for Ry| completes an oxo-substituted radical, or c) it is reduced to a compound of general formula IV R- N-CO-R; (IV) -71- in which R^ represents a radical corresponding to the definition of IL] except a methylene group or in the case where at least one of the symbols ï^j ^5 does not represent a hydrogen atom and/or A does not represent an ethylene group and/or B 5 does not represent a methylene group, can also represent an alkoxycarbonyl group, the carbonyl or alkoxycarbonyl groups are reduced or d) a compound of general formula V is reduced 10 15 E, E, 0 Rr R, ^ © N ^ y R„ - R has oh (V) in which Z® represents a monovalent anion or the normal equivalent of a polyvalent anion, R^ and R^ represent a hydrogen atom or an alkyl radical with together at most 6 carbon atoms and R^", R3 e"k have the meanings given under formulas III or I, partially in corresponding compounds of general formula I in which X and Y have an additional bond or e) hydrogenation is carried out of a compound of general formula V given above or a compound of general formula VI Rr 30 35 (VI) in which R^, R^, R^, Rg and R^ have the meanings given under formulas I or V, or a compound of general formula -72- Ib entering into the general formula I in which R1, R2, R1, R1, R1, A and B have the meanings given under formula I, by catalytic means to the corresponding piperidine compound, or 15 f) a compound of general formula VII is cyclized 25 in which Rg represents a lower alkoxy group or a lower 1-alkoxy-alkoxy group, whose two alkoxy groups can be linked in a 5- or 6-membered ring, R^ has the meaning given under formula III and R^, R^_, R^, A, B, X and Y 30 have the meanings given under formula I or a derivative of alkali metal of a compound of general formula VII by heating in an acidic medium or g) hydrogenation is carried out of a compound of general formula I whose group R^ does not contain a non-aromatic double or triple bond and/or contains an oxo radical and in which X and Y represent a hydrogen atom, while R^, Rj, R^ and Ey A and B have the meanings given under formula I, into a corresponding compound whose group R^ does not contain -73- no triple bond or no or a small number of non-aromatic double bonds and/or contains a primary or, in particular, secondary hydroxyl group or h) a compound of general formula I is reduced in which the 5th group [IL] contains an oxo radical, while ^ ■> ^5* A, B, X, and Y have the meanings given under formula I, in corresponding compounds whose group R^ contains a primary or, in particular, secondary hydroxyl group, or i) a compound of general formula I is subjected to hydrogenolysis, in which R^ represents a benzyl group, possibly substituted according to the definition, and/or R^ and/or R^ represent inert, possibly substituted benzyloxy groups, and X and Y represent a hydrogen atom, while Rg, R^, A and B, as well as possibly R^ and/or R^, have the meanings given under formula I, or j) a compound of general formula VIII is heated 20 25 30 35 COOH R- R, R. (VIII) in which R^, R^, R^, R^, A, B, X and Y have the meanings given under formula I until the release of an approximately equimolar quantity of carbon dioxide or k) a compound of general formula IX is reacted RF HE 0 (IX) R has In which Z represents a metallic radical, R^ and R^; have -74- The meanings given for R^ or R^ exclude hydroxyl groups and hydroxy-substituted radicals, and R^ has the meaning given under formula I, with a reactive ester of a compound of general formula X 10 HO - c: N - R (X) 15 20 11 in which R^ corresponds to a radical of given definition under the formula I excluding hydrogen as well as the' cl 3. Hydroxyl and oxo-substituted radicals, and A and B, have the meanings given under formula I for A or B, excluding a direct bond for Aa and a radical with three chain elements for Ba, and R- represents the meaning given under formula I, or 1) Water is separated from a compound with the general formula XI 25 30 R has (XI) in which R£, R^, R^ and R^ have the meanings given under formula I, R^ that given under formula III and Aa and Ba that given under formula X, or from a compound of 35 general formula I, in which R^ represents a group 1-hydroxyalcohol or a 1-hydroxycycloalcohol group with 5 to 8 carbon atoms, while R^ has the meaning given in formula I excluding hydrogen and R~, R^, , -75- A, B, X, and Y have the meanings given under formula I, or m) into a compound of general formula I, in which R^ has the meaning given under formula I, excluding hydrogen and oxo- or hydroxy-substituted radicals, R^, R^, X, and Y represent a hydrogen atom and R2, R^, A, and B have the meanings given under formula I, or chlorine or bromine is introduced at position 5 into 1-methyl-4-(2-benzofuranyl)piperidine, or n) a compound of general formula I is transformed in which R^ has the meaning given under formula I, excluding hydrogen and oxo- and hydroxy-substituted radicals and phenyl-(lower alkyl) radicals, substituted by a halogen atom, R^ represents a chlorine or bromine atom and R^ represents a hydrogen atom, or a lower alkyl group and R2, R^, A, B, X and Y have the meanings given under formula I, in the corresponding compound with a metal radical in place of R^ and this latter compound is reacted with a lower oxoalkane or a cycloalkanone with 20 5 to 8 carbon atoms or 0) A compound of general formula XII is treated with a strong acid 25 R3 5.R2 ,oh3 C' CH, E4 ~0Ho N 2 / 2\ \ 0 CH0 (XII) \ ^ d 30 Ra 3. ' in which R^ has the meaning given under formula III and R2, R^ and R^ have the meanings given under formula 35 I, or the crude product of the reaction of a compound of general formula XIII -76- R 3 Z"2 CH. 3 Cr=CH (XIII) '2 R, a double molar quantity of formaldehyde and a compound with general formula XIV in which R^ has the meaning given under formula I and which is used as an addition salt with a strong acid or 15 together with one of these, and if desired, a compound obtained according to one of the processes indicated under (a) to (o) of general formula I is transformed into an addition salt with organic or mineral acids. 20 that we manufacture compounds of general formula I in which R,, represents a hydrogen atom, R2» R^ » R^, R^, A, B, X and I have the meanings given under claim 1, and their addition salts with acids, according to one of the processes (a), (e), (i) or (j). 25 3 - A process according to claim 1, characterized in that compounds of general formula 1 are manufactured, wherein R1 and R2 represent a hydrogen atom, R1 represents a hydrogen atom, a halogen up to atomic number 35, a lower alkyl group or a lower alkoxy group, a trifluoromethyl group or a 1-hydroxyalkyl, cycloalkyl-1-enyl or cycloalkyl group, each with 5 to 8 carbon atoms, R1 represents a hydrogen atom or a lower alkyl group, or R1 and R2 together form a condensed benzene ring at position 4, 5, or a trimethylene radical at position 5, 6, 35 represents a hydrogen atom or a methyl group, A and B represent a methylene, ethylidene, ethylene, propylene or trimethylene radical, and the direct bond is provided that the sum of the chain members is three, and X and Y re- T H2N - R1 (XIV) 2 - Method according to claim 1, characterized in -77- each contain an additional hydrogen atom or together an additional bond, and their addition salts according to one of the processes (a), (e), (i) or (j). 4 - A process according to claim 1, characterized in 5 that compounds of general formula I are manufactured, in which and B-2 represent a hydrogen atom, R^ represents a hydrogen, chlorine, bromine, methyl or methoxy group, R^ represents a hydrogen atom or the methyl group, A represents the methylene group and B the ethylene group or A represents the ethylene group and B the methylene group and X and Y each represent a hydrogen atom or together an additional bond, and their addition salts with acids according to any one of the processes (a), (e), (i) or (j). 15 5 - Process according to claim 1, characterized in that compounds of general formula I are manufactured in which R^ and R2 represent a hydrogen atom, R^ represents a hydrogen, chlorine, bromine, methyl or methoxy group, R^ represents a hydrogen atom or the methoxy group, A represents the methylene group and B the ethylene group or A represents the ethylene group and B the methylene group and X and Y each represent a hydrogen atom, and their addition salts with acids according to any one of the processes (a), (e), (i) or (J). 25 6 - A process according to claim 1, characterized in that compounds of general formula I are manufactured, wherein R^ has the meaning given in claim 1, excluding hydrogen, and, where A represents an ethylene radical and B a methylene radical, and where R^, R1, R^, and R^ each represent a hydrogen atom or the methyl group, and R2, R^, R^, R^, A, B, X, and Y have the meanings given in claim 1, and their addition salts with acids are manufactured according to any one of the processes (b), (c), (d), (e), (f), (g), (h), (i), (g), (o), (l), (m), (n), or (o). 35 7 - A process according to claim 1, characterized in that compounds of general formula I are manufactured, wherein R' has the meaning given in claim 1, at f the exclusion of hydrogen, and in the case where A represents the -78- ethylene radical and B the methylene radical and that at the same time and R^ each represent a hydrogen atom, a the methyl group, represents a hydrogen atom, R* represents a hydrogen atom, up to atomic number 35, a lower alkyl or lower alkoxy group, the trifluoromethyl group or a 1-hydroxycycloalcohol, 1-cycloalc-1-enyl or cycloalcohol group, each with 5 to 8 carbon atoms, R^ represents a hydrogen atom or a lower alkyl group or R^ and R^ together represent a dense benzene ring at position 4,5 or a trimethylene radical at position 5,6, represents a hydrogen atom or a methyl group, A and B represent a methylene, ethylidene, ethylene, propylene or trimethylene radical and the direct bond on the condition that the sum of the chain members is equal to 3, 15 and X and Y each represent a hydrogen atom or together represent an additional bond, and their salts add with acids according to one of the processes (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (1), (m), (n) or (o). 8 - Process according to claim 1, characterized in 20 that compounds of general formula I are manufactured in which R^ has the meaning given under claim 1 excluding hydrogen and, in the case where A represents the ethylene group and B the methylene radical and that at the same time R2, R^, R4. and R^ each represent a hydrogen atom, a 25 the methyl group, R2 and R^ represent a hydrogen atom, R^ represents a hydrogen, chlorine, bromine, methyl or methoxy atom, R^ represents a hydrogen atom or the methyl group, A represents the methylene group and B the ethylene group or A represents the ethylene group and B the methylene group and X and Y each represent a hydrogen atom or together represent an additional bond, and their addition salts with acids, according to one of the processes (b), (c), (d), (e), (f), (g), (h), (j), (k), (1), (m) or (0). 35 9 - A process according to claim 1, characterized in that it produces compounds of general formula I in which R^| represents an alkyl group with at most 4 carbon atoms excluding the methyl group, in the case where A represents -79- R^ represents the ethylene radical and B the methylene radical, and at the same time R^ and R^ each represent a hydrogen atom, the allyl, 3-oxobutyl, 3-hydroxybutyl, 2-propinyl or cyclopropylmethyl groups, R^ represents a hydrogen atom, R^ represents a halogen up to atomic number 35, a lower alkyl or lower alkoxy group, the trifluoromethyl group or a 1-hydroxy cycloalkyl, 1-cycloalkyl-1-enyl or cycloalkyl group, each with 5 to 8 carbon atoms, R^ represents a hydrogen atom or a lower alkyl group, or R^ and R^ together represent a benzene ring condensed at position 4,5 or a trimethylene radical at position 5,6, R^ represents a hydrogen atom or a methyl group, A and B represent the methylene, ethylidene radicals, ethylene, propylene, or trimethylene and the direct bond 15, provided that the sum of the chain members is 3, and X and Y each represent a hydrogen atom or together an additional bond and their addition salts with acids, according to one of the processes (b), (c), (d), (e), (f), (g), (h), (j), (k), (l), (m), or (o). 20 10 - Process according to claim 1, characterized in that compounds of general formula I are manufactured in which R^ represents an alkyl group with at most 4 carbon atoms excluding the methyl group, in the case where A represents the ethylene radical and B the methylene radical and that at the same time R2, R^, R4. and R^ each represent a hydrogen atom, the allyl, 3-oxobutyl, 3-hydroxybutyl, 2-propinyl or cyclopropylmethyl groups, R^ and R^ represent a hydrogen atom, R^ represents a hydrogen atom, of chlorine, bromine, the methyl or methoxy group, R^ represents a hydrogen atom or 30 the methyl group, A represents the methylene group and B the ethylene group or A represents the ethylene group and B the methylene group and X and Y each represent a hydrogen atom or together represent an additional bond, and their addition salts with acids according to one of the 35 processes (b), (c), (d), (e), (f), (g), (h), (j), (k), (1), (m) or (o). 11 - A process according to claim 1, characterized in that compounds of general formula I are manufactured in the- f -80- Which R^ represents an alkyl group with at most 4 carbon atoms, excluding the methyl group? In the case where A represents the ethylene radical and B the methylene radical, and at the same time R2 and R^^5 each represent a 5-hydroxyl atom, the allyl, 3-oxobutyl, 3-hydroxybutyl, 2-propinyl, or cyclopropylmethyl groups, R2 and R^ represent a hydrogen atom, R^ represents a hydrogen, chlorine, or bromine atom, the methyl or methoxy groups, R^ represents a hydrogen atom or the methyl group, A represents the methyl-10 group and B the ethylene group, or A represents the group ethylene and B the methylene group and X and Y each represent a hydrogen atom and their addition salts with acids according to one of the processes (b), (c), (e), (f), (g), (h), (j), (k), (m) or (o). 15 12 - Process according to claim 1, characterized in that compounds of general formula I are manufactured in which R^ represents the methyl, 2-propinyl or cyclopropylmethyl groups, R2 and R^ represent a hydrogen atom, R^ represents a chlorine, bromine, methyl or methoxy atom, R^ represents a hydrogen atom or the methyl group, A represents the methylene group and B the ethylene group or A represents the ethylene group and B the methylene group and X and Y each represent a hydrogen atom or together represent an additional bond, and their addition salts 25 with acids, according to any one of the processes (b), (c), (d), (e), (f), (j), (k), (l), or (m). 13 - A process according to claim 1, characterized in that the compounds described in the examples, of general formula I and their addition salts, are manufactured with acids, 30 in accordance with one of the processes (a) to (o). 14 - Process according to claim 1, characterized in that 4-(2-benzofuranyl)-piperidine and its addition salts are manufactured with pharmaceutically acceptable acids, in accordance with one of the processes (a)', (e), (i) or (j). 35 15 - Process according to claim 1, characterized in that 4-(5,6-dimethyl-2-benzofuranyl)-piperidine and its addition salts are manufactured with pharmaceutically acceptable acids, according to one of the processes (a), (e), (i) or (j). -81- 16 - Process according to claim 1, characterized in that 3-(2-benzofuranyl)-piperidine and its addition salts are manufactured with pharmaceutically acceptable acids in accordance with one of the processes (a), (e), (i) or (j). 5 17 - Process according to claim 1, characterized in that 4~(5-chloro-2-benzofuranyl)-piperidine and its addition salts are manufactured with pharmaceutically acceptable acids in accordance with one of the processes (a), (e), (i) or (j). 18 - Process according to claim 1, characterized in 10 that 4-(5-methoxy-2-benzofuranyl)-piperidine and its addition salts are manufactured with pharmaceutically acceptable acids, according to one of the processes (a), (e), (i) or (j) 19 - A method for manufacturing compounds of general formula VI given under claim 1, wherein the radical 15 2-benzofuranyl is fixed in position 4- or 2 of the pyridine ring and R2J R^ ' ^4-' ^7 on^ -^es meanings given under claim 1, characterized in that an ether of general formula VIb in which R2, Rj > ^4* Rg and Rr, have the meanings given under claim 1, is cyclized by heating in the presence or absence of a condensation agent. 20 - Process according to claim 1, characterized in that one of the processes indicated under (a) to (o) is interrupted at any step or that a compound obtained as an intermediate product at any step is started and the missing steps are carried out or a raw material is formed under the reaction conditions or possibly used in the form of a salt. -82- 21 - A method according to claim 1, characterized in that the racemate or one of the isolated antipodes of an optically active raw material is used, or, in the presence of diastereoisomerism, a racemic mixture, a par- racemate 5 particular or likewise an isolated antipode, if necessary in the form of a salt. 22 - A method according to claim 1, characterized in that a mixture of isomers obtained (racemic mixture) is separated in a manner known in itself into its two stereo- racemates 10 isomers and/or which are separated according to processes known in themselves, the racemate obtained in antipodes. 23 - Compounds of general formula I given under claim 1, wherein R^, R2, Rj, R^, R^, A, B, X and Y have the meanings given under claim 1, and their 15 salts of addition with acids. 24 - Compounds of general formula I given under claim 1, in which R^ represents a hydrogen atom and R2, Rj, R^, A, B, X and Y have the meanings given under claim 1, and their addition salts with aci- 20 of. 25 - Compounds of general formula I given under claim 1 in which R1 and R2 represent a hydrogen atom, R1 represents a hydrogen atom, a halogen up to atomic number 35) a lower alkyl group or lower alkoxy group 25th, the trifluoromethyl group or a 1-hydroxycyclo-alkyl, cycloalk-1-enyl or cycloalkyl group, each with 5 to 8 carbon atoms, R^ represents a hydrogen atom or a lower alkyl group, or R^ and R^ together represent a benzene ring condensed at position 4,5 or a tri-' radical 30 methylene in position 5)6, R^ represents a methyl group, A and B represent a methylene, ethylidene, ethylene, propylene, or trimethylene group, and the direct bond, provided that the sum of the chain members is 3, and X and Y each represent a hydrogen atom or group representing 35 attempt an additional bond, and their addition salts with acids. 26 - Compounds of formula I given under claim f, in which R^, R2 and R^ represent a hydrogen atom, -83- 10 R^ represents a hydrogen, chlorine, bromine atom, methyl or methoxy groups, R^ represents a hydrogen atom or the methyl group, A represents the methylene group and B the ethylene group or A represents the ethylene group and B the methylene group, and X and Y each represent a hydrogen atom or together represent an additional bond, and their addition salts with acids. 27 - Compounds of general formula I given under claim 1, wherein R and R represent a hydrogen atom, R represents a hydrogen, chlorine, bromine, methyl or methoxy group, R represents a hydrogen atom or the methyl group, A represents the methylene group and B the ethylene group, or A represents the ethylene group and B the methylene group, and X and Y each represent 15 a hydrogen atom, and their addition salts with acids-. 28 - Compounds of general formula I given under claim 1, wherein R^ has the meaning given under claim 1 excluding hydrogen and in the case where A represents the ethylene radical and B the methylene radical and 20 that at the same time R£, R^, R^ and R^ each represent a hydrogen atom, or the methyl group, and R2, R^, R^, R^, A, B, X and Y have the meanings given under claim 1, and their addition salts with acids. 29 - Compounds of general formula I given under claim 1, wherein R^ has the meaning given under claim 1 excluding hydrogen and, where A represents an ethylene radical and B a methylene radical and R1, R1, R1 and R2 each represent a hydrogen atom or the methyl group, R2 represents a hydrogen atom, R1 represents a hydrogen atom, a halogen up to atomic number 35, a lower alkyl or lower alkoxy group, the trifluoromethyl group or a 1-hydroxycyclo-alkyl, 1-cyclo-alkyl-1-enyl or cycloalkyl group each with 5 to 8 carbon atoms, R1 represents a hydrogen atom or a lower alkyl group or R1 and R2 together represent a benzene ring condensed at position 4,5 or a trimethylene radical at position 35 5,6, represents a hydrogen atom or "a methyl group", A and B represent a methylene radical, -84- ethylidene, ethylene, propylene or trimethylene and direct bonding provided that the sum of the chain members is 3, and X and Y each represent a hydrogen atom or together an additional bond, and their addition salts 5 with acids. 30 - Compounds of general formula I given in claim 1, wherein R^ has the meaning given in claim 1 excluding hydrogen and, where A represents an ethylene radical and B a methylene radical 10 and that at the same time R^, R^ and R^ each represent a hydrogen atom, or the ethyl group, R2 and R^ represent a hydrogen atom, R^ represents a hydrogen, chlorine, bromine, methyl or methoxy group atom, R^_ represents a hydrogen atom or the methyl group, A represents the methylene group and B the ethylene group or A represents the ethylene group and B the methylene group and X and Y each represent a hydrogen atom or together represent an additional bond, and their addition salts with acids. 31 - Compounds of general formula I given under claim 1, in which R represents an alkyl group with at most 4 carbon atoms excluding the methyl group, in the case where A represents an ethylene radical and B the methylene radical and at the same time R2, R3, R4 and R5 each represent a hydrogen atom, the allyl group, 3-oxobutyl, 3-hydro-2-hydroxybutyl, 2-propinyl or cyclopropyl-methyl, R2 and R3 represent a hydrogen atom, R5 represents a hydrogen atom, a halogen up to atomic number 35, a lower alkyl or lower alkoxy group, the trifluoromethyl group or a 1-hydroxycycloalkyl, 1-cycloalkyl-1-enyl or cycloalkyl group 30 with 5 to 8 carbon atoms each, R5 represents a hydrogen atom or a lower alkyl group or R^ and R^ together represent a condensed benzene ring in position 4,5 or a trimethylene radical in position 5,6, represents a hydrogen atom or a methyl group, A and B represent a 35 methylene, ethylidene, ethylene, propylene or trimethylene radical and the direct bonding provided that the sum of the chain members is 3, and X and Y each represent a hydrogen atom or together represent an additional bond, and their addition salts with acids. -85- 32 - Compounds of general formula I given under claim 1, wherein R^ represents an alkyl group with at most 4 carbon atoms excluding the methyl group, in the case where A represents the ethylene radical and B the methylene radical and at the same time R£, R^, R^ and R^ each represent a hydrogen atom, the allyl, 3-oxobutyl, 3-hydroxybutyl, 2-propinyl or cyclopropylmethyl groups, R2 and R^ represent a hydrogen atom, R^ represents a hydrogen, chlorine, bromine or methyl or methoxy group, R^ represents a hydrogen atom or the methyl group, A represents the methylene group and B the ethylene group or A represents the ethylene group and B the methylene group and X and Y each represent a hydrogen atom or together represent an additional bond, and their addition salts with acids. 15 33 - Compounds of general formula I given under claim 1 in which R^ represents an alkyl group with at most 4 carbon atoms excluding the methyl group, in the case where A represents the ethylene radical and B the methylene radical and at the same time R2? R^ > R4. and R^ each represent a hydrogen atom, the allyl, 3-oxobutyl, 3-hydroxybutyl, 2-propinyl, or cyclopropylmethyl groups, -R^ e-t; R5 represent a hydrogen atom, R^ represents a hydrogen, chlorine, bromine, methyl or methoxy group, R^ represents a hydrogen atom, or the methyl group, A represents the methylene group and B the ethylene group or A represents the ethylene group and B the methylene group, and X and Y each represent a hydrogen atom, and their addition salts with acids. 34 - Compounds of general formula I given under claim 1, characterized in that R^ represents the methyl, 2-propinyl, or cyclopropylmethyl groups, R£ and R^ represent a hydrogen atom, R^ represents a chlorine, bromine, methyl or methoxy atom, R^ represents a hydrogen atom or the methyl group, A represents the methylene group and B the ethylene group or A represents the ethylene group and B the methylene group and X and Y each represent a hydrogen atom or together represent an additional bond, and their addition salts with acids. -86- 35 - Compounds of general formula I given under claim 1, wherein R^ represents the 2-propinyl or cyclopropylmethyl group, e"t represent a hydrogen atom, R- represents a hydrogen, chlorine, or bromine atom, 5 the methyl or methoxy group, R^ represents a hydrogen atom or the methyl group, A represents the ethylene group and B the methylene group, or A represents the methylene group and B the ethylene group, and X and Y each represent a hydrogen atom, and their addition salts with acids. 10 56 - The compounds of general formula I given under claim 1 described in the examples and their addition salts with acids. 37 - Ba 4-(2-benzofuranyl)-piperidine and its addition salts with pharmaceutically acceptable acids. 15 38 - La 4-(5,6-dimethyl-2-benzofuranyl)-piperidine and its addition salts with pharmaceutically acceptable acids. 39 - 3-(2-benzofuranyl)-piperidine and its addition salts with pharmaceutically acceptable acids. 20 4-0 - 4-(5-chloro-2-benzofuranyl)-piperidine and its addition salts with pharmaceutically acceptable acids. 4-1 - 4-(5-methoxy-2-benzofuranyl)-piperidine and its addition salts with pharmaceutically acceptable acids. 4-2 - 1-(2-propinyl)-4— (2-benzofuranyl)-piperidine and 25 of its addition salts with pharmaceutically acceptable acids. 4-3 - 1-(cyclopropylmethyl)-4--(2-benzofuranyl)-piperidine and its addition salts with pharmaceutically acceptable acids. 30 44- - 1-(3-oxobutyl)-4-(2-benzofuranyl)-piperidine and its addition salts with pharmaceutically acceptable acids. 45 - 1-(3-hydrobutyl)-4-(2-benzofuranyl)-piperidine and its addition salts with pharmaceutically acceptable acids. 46 - 1-(2-propinyl)-4-(5,6-dimethyl-2-benzofuranyl)-35 piperidine and its addition salts with pharmaceutically acceptable acids. 47 - 1-(cyclopropylmethyl)-4-(5,6-dimethyl-2-benzofuranyl)-piperidine and its addition salts with pharmaceutically acceptable acids. -87- 48 - The hydrochlorides of the compounds according to claims 23 to 47. Number of pages Word crossed out: null Word added: null 87 By Power of Attorney of CIBA-GEIGY AG.