GB2040941A - Dithienyl piperidines - Google Patents

Abstract

A compound corresponding to the following general formula (I): <IMAGE> wherein R1 represents hydrogen or hydroxy; R2 represents hydrogen; or R1 and R2 together represents a second bond between the carbon atoms to which they are attached. R3 represents hydrogen, C3-C8 cycloalkyl C1-C20 alkyl which may be substituted once or twice by hydroxy or -Alk-O-R8 wherein Alk represents C2-C6 alkylene and R8 represents C3-C8 cycloalkyl, C1-C6 alkyl, C1-C6 hydroxyalkyl or C2-C6 hydroxyalkyl or C1-C6 alkyl; and R4, R5, R6 and R7, which may be the same or different, each represents hydrogen, C1-C5 alkyl or halogen; at least one 3-thienyl radical being present when R3 represents unsubstituted C1-C6 alkyl; the N- oxides thereof, the quarternary salts thereof and the acid addition salts thereof are prepared. Inter alia, such compounds have an anti-ischaemic and blood pressure increasing effect or a bronchospasmolytic and anti- histamine/anti-serotonin effect.

Description

SPECIFICATION Dithienyl piperidines This invention relates to dithienyl piperidines.

US Patent No. 2,739,968 describes compounds showing spasmoíytic, analgesic and antihistamine activity. These compounds correspond to the following general formula:

wherein, for example, R2 represents a methyl group or even an ethyl group; R and R1 represent 2-thienyl radicals; R3 represents hydrogen; and Y represents hydrogen or a hydroxy group or, together with the piperidine ring, may even form a double bond.

German Offeníegungsschrift No. 2,12'8,808 relates to compounds corresponding to the following general formula:

wherein R represents a lower alkyl radical; and X represents an anionic radical of a pharmaceuticalíy acceptable acid. These compounds are also said to shown spasmolytic activity comparable with that of atropine sulphate.

In general terms, the present invention is concerned with compounds corresponding to the following general formula:

wherein Rt and R2 represent hydrogen or together form a second bond between the carbon atoms carrying the substituents R, and R2, in addition to which R1 may also represent a hydroxy group; R3 represents hydrogen, a C3C8 cycíoaíkyí group or a C,C20 alkyl group which may contain one or two hydroxyl groups, or wherein R3 represents a C2C6 hydroxyalkyl group substituted on the hydroxyl hydrogen by a C3C8 cycloalkyl group, by a C1C8 alkyl group, by a C1Css hydroxyaíkyl group or by a C2C" hydroxyaíkoxy-C,C6 alkyl group; and R4, R5, R8 and R7, which may be the same or different, represent hydrogen, C,C6 alkyl groups or halogen atoms; at least one 3-thienyl radical being present when R3 represents an unsubstituted C1C8 alkyl group; their N-oxides, their quaternary salts and their acid addition salts.

More particularly, in its broadest aspect, the present invention relates to a compound corresponding to the following general formula (I):

wherein R, represents hydrogen or hydroxy; R2 represents hydrogen; or R, and R2 together represent a second bond between the carbon atoms to which they are attached; R3 represents hydrogen, C3-C8 cycloalkyl, C1-C20 alkyl which may be substituted once or twice by hydroxy or -Alk-O-R8 wherein Alk represents C2-C6 alkylene and R8 represents C3-C8 cycloalkyl, Ci-Ca alkyl, C1-C,6 hydroxyalkyl or C2C6 hydroxyalkyl-C1-C6 alkyl; and R4, B5, B6, and R7, which may bathe same or different, each represents hydrogen, C1-C6 alkyl or halogen; at least one 3-thienyl radical being present when R3 represents unsubstituted C1-C6 alkyl; the N-oxides thereof, the quaternary salts thereof and the acid addition salts thereof.

In one embodiment, the present invention relates to a compound corresponding to the following general formula:

wherein R1 represents hydrogen or hydroxy; R2 represents hydrogen; or R, and R2 together represent a second bond between the carbon atoms to which they are attached; R3 represents hydrogen, C3-C8 cycloalkyl or C1-C20 alkyl which may be substituted once or twice by hydroxy; and R4, R5, R6 and R7, which may be the same or different, each represents hydrogen, C1-C6 alkyl or halogen; at least one 3thienyl radical being present when R3 represents unsubstituted C1-C8 alkyl; and the N-oxides thereof, the quaternary salts thereof and the acid addition salts thereof.

In another embodiment, the present invention relates to a compound corresponding to the following general formula:

wherein R1 represents hydrogen or hydroxy; R2 represents hydrogen; or R, and R2 together represent a second bond between the carbon atoms to which they are attached; Alk represents C2-C8 alkylene; R8 represents C3-C8 cycloalkyl, C,Ctl alkyl, C1-C8 hydroxyalkyl or C2-C6 hydroxyalkoxy-CtC, alkyl; and R4, Rs, B6 and R7, which may be the same or different, each represents hydrogen, C,--C, alkyl or halogen; and the N-oxides thereof, the quaternary salts thereof and the acid addition salts thereof.

The alkyl or alkoxy groups occurring in the compounds (I) and the C26 hydroxyalkyl group substituted on the hydroxyl hydrogen may be linear or branched and consist in particular of from 1 to 4 carbon atoms. When R4, R5, R6 and/or R, represent alkyl groups, these alkyl groups consist in particular of from 1 to 4 carbon atoms and are preferably methyl groups. When R4, R5, R6 and/or R7 represent halogen atoms, the halogen atoms in question are, for example, fluorine, chlorine or bromine. When R3 represents an alkyl group which contains a hydroxy group, this hydroxy group is preferably situated in the 2-position or the 3-position of the alkyl radical (the 1-position of the alkyl radical is where it is attached to the nitrogen atom of the piperidine ring).

The compounds according to the present invention show pharmacodynamic activity. Compounds (I) wherein R3 represents hydrogen, a C3-C8 cycloalkyl group or the C17C20 alkyl group optionally substituted by hydroxy groups have, for example, an anti-ischaemic and blood pressure-increasing effect. In addition, they increase peripheral circulation and frequently reduce heart rate (bradycardia).

Some of the compounds (I), particularly those wherein R3 represents a hydroxyalkyl group, for example a 2-hydroxyethyl group, also show analgesic activity. Compounds (I) wherein R3 represents a C2-C8 hydroxyalkyl group substituted on the hydroxyl hydrogen by a cycloalkyl group, by an alkyl group, by a hydroxyalkyl group or by a hydroxyalkoxyalkyl group are characterised, in particular, by a strong bronchospasmolytic effect. These compounds also show anti-histime/anti-serotonin activity and antianaphylactic activity (asthma-prophylactic activity).

Accordingly, an object of the present invention is to provide compounds having favourable pharmacodynamic properties which may be used as medicaments.

In general terms, the present invention provides a process for the preparation of such a compound which comprises: (a) reacting a compound corresponding to the following general formula (ill):

which may contain three conjugated ring double bonds; wherein R3 is as defined in claim 1 or is not present when the ring is a pyridine ring; and X represents; (A) -COZ, wherein Z represents halogen, C1-C6 alkoxy, or thienyl which may be substituted once or twice by halogen and/or C1-C6 alkyl; or (B) lithium or -MgHal wherein Hal represents chlorine, bromine or iodine; in case (A), with a compound corresponding to the following general formula (III):

wherein X' represents lithium or -MgHal; and the thienyl radical may be substituted once or twice by halogen and/or C1-C8 alkyl; or, in case (B) with a compound corresponding to the following general formula (IV):

at least one 3-thienyl radical being present in one of the above-mentioned starting materials when R3 in general formula (II) represents unsubstituted C1-C8 alkyl, and the r, jilting compounds is optionally treated with a reducing agent and/or a dehydrating agent and/or is alkylated through R3 and/or is converted into the N-oxide; or (b) the radical R3 as defined in claim 1 is introduced by alkylation on the N-atom in one or two steps into a compound corresponding to general formula (I) as defined in claim 1 wherein R3 represents hydrogen oran N-metal derivative thereof; R,, R2, R4, R,, R6 and R7 being as defined in claim 1; and the piperidine ring may contain three conjugated ring double bonds, and/or a compound corresponding to general formula (1) as defined in claim 1 wherein R3 represents lower alkyl; is dealkylated and the compound obtained is optionally treated with a reducing agent and/or a dehydrating agent and/or is converted into the Oxide.

In connection with the first-mentioned embodiment, the present invention provides a process for the preparation of such a compound which comprises: (a) reacting a compound corresponding to the following general formula

which may contain three conjugated ring double bonds; wherein R3 is as defined in claim 2 or is not present when the ring is a pyridine ring; and X represents: (A) -COZ, wherein Z represents halogen, C1-C6 alkoxy or thienyl which may be substituted once or twice by halogen and/or C1-C8 alkyl; or (B) an alkali metal or -MgHal wherein Hal represents chlorine, bromine or iodine; in case (A), with a compound corresponding to the following general formula

wherein X' represents an alkali metal or-MgHal; and the thienyl radical may be substituted once or twice by halogen and/or C1-C8 alkyl; or, in case (B), with a compound corresponding to the following general formula;

at least one 3-thienyl radical being present in one of the above-mentioned starting material when R3 represents unsubstituted C1-C6 alkyl; and the resulting compound is optionally treated with a reducing agent and/or a dehydrating agent and/or is alkylated through R3 and/or is converted into the N-oxide; or (b) treating a compound corresponding to the general formula defined in claim 2 wherein R1 represents hydroxy; and R2 represents hydrogen; with a dehydrating agent and/or a reducing agent and/or replacing R3 by another substituent R3; the resulting compound optionally being converted into the N-oxide.

In connection with the second-mentioned embodiment, the present invention provides a process for the preparation of such a compound which comprises: (a) introducing the radical -Alk-0-B8, wherein B8 is as defined in claim 3; into a compound corresponding to the following general formula:

or an N-metal derivative thereof; wherein R1, R2, R4, R5, R8 and R, are as defined in claim 3; and the piperidine ring may contain three conjugated ring double bonds; in one or more steps by alkylation on the N-atom; and the resulting compound is optionally treated with a reducing agent and/or a dehydrating agent and/or is converted into the N-oxide; or (b) reacting a compound corresponding to the following general formula:

which may contain three conjugated ring double bonds; wherein B8 is as defined in claim 3 or is not present in the case of a pyridine ring; and X represents: (A) -COZ wherein Z represents halogen, C,C alkoxy or thienyl which may be substituted once or twice by halogen and/or C1-C8 alkyl; or (B) an alkali metal or -MgHal wherein Hal represents chlorine, bromine or iodine; in case (A), with a compound correspondingto the following general formula:

wherein X represents an alkali metal -MgHal; and the thienyl radical may be substituted once or twice by halogen and/or C1-C8 alkyl; or, in case (B), with a compound corresponding to the following general formula:

and the resulting compound is optionally treated with a reducing agent and/or a dehydrating agent and/or is alkylated through the radical -Alk-0-B8 and/or is converted into the Oxide.

The resulting compound may be converted into an acid addition salt thereof or a quaternary salt thereof.

Embodiment (a) is generally carried out at temperatures of from -100 to +150 C, preferably from -75 to + 1 000C or up to +50 C. In cases where a 3-thienyl metal compound (particularly thienyl lithium) or a 3-thienyl Grignard compound is used, the reaction is preferably carried out at low temperatures, more particularly at temperatures below -500C, in an inert medium. In such cases, it is advantageous to carry out the reaction at temperatures of from -70 to -800C. Where 3-thienyl metal compounds are used, the reaction is carried out in particular at temperatures of from -70 to -800C.

Suitable solvents are, for example, saturated aliphatic symmetrical or asymmetrical diethyl ethers containing alkyl radicals of, for example, from 1 to 6 carbon atoms, C1-C8 alkyl ethers of unsaturated cycloalkanols and alkyl-substituted cycloalkanols, the cycloalkanol rings consisting in each case of 3,4, 5 or 6 carbon atoms; saturated C5Cg aliphatic or C3-C7 cycloaliphatic hydrocarbons, of which the C3-C7 cycioaliphatic hydrocarbons may advantageously be substituted from one to three times by C14 alkyl radicals; tetrahydrofuran; benzene; and benzene substituted by Cj3 alkyl radicals. The ethers and aliphatic or cycloaliphatic hydrocarbons used are, in particular, those which are liquid at temperatures of from -80 to +200C.

Examples of suitable solvents include: diethyl ether, diisopropyl ether, methyl cyclopentyl ether, hexane, cyclohexane, toluene, xylene, methyl cyclohexane, methyl cyclopentane, ethyl cyclohexane and dimethyl cyclohexane. The solvents mentioned may also be used in admixture with one another. For example, it is possible to use a solvent mixture consisting of a saturated ether and a benzene monosubstituted by C1-C3 alkyl. Such solvent mixtures are described, for example, in German Offenlegungsschrift No. 2,800,536.

A corresponding excess of organometallic compound is always necessary when the other reaction component contains active hydrogen (amino group, hydroxy group, salt). In general, however, it is frequently advisable to use an excess of organometallic compound because better yields may be obtained in this way.

When Z in the group -COZ (formula (II)) represents a halogen atom, the halogen atom in question is, in particular, chlorine, bromine or iodine.

Starting materials corresponding to the following general formula:

wherein the thienyl radical may even be substituted by halogen or lower alkyl groups; may be obtained, for example, by reacting the corresponding thienyl lithium or thienyl Grignard compound with a compound corresponding to the following general formula:

or by reacting the corresponding thienyl cyanide or thienyl carbonyl chloride with a compound corresponding to the following general formula:

(wherein Hal represents chlorine or bromine; R3 is not present in the case of a pyridine ring) in a solvent or suspending agent of the type normally used for Grignard reactions (for example lower saturated aliphatic ethers, benzene, methyl-substituted benzene) at temperatures from -80 to -+1000C.

In addition, starting materials of the type in question may also be obtained by reacting a compound corresponding to the following general formula:

and the corresponding thiophene in the presence of AICI3 on the Friedel-Crafts principle.

Starting materials (IV) may be obtained, for example, by subjecting a compound corresponding to the following general formula:

(wherein Hal represents chlorine or bromine) to Friedel-Crafts acylation with a compound corresponding to the following general formula:

in the presence of AICI3 in a solvent, such as dichloroethane or nitromethane, at temperatures of from 0 to +1000C.

In addition, they may be obtained by subjecting a compound corresponding to the following general formula:

(or-CO2B, wherein R represents a lower alkyl radical) to Grignard's reaction with a compound corresponding to the following general formula:

wherein M represents lithium; or MgCI or MgBr, in a solvent or suspending agent of the type normally used for Grignard reactions at temperatures of from -80 to + 1 000C.

Starting materials (II), wherein X represents the group --MgHal, may be obtained, for example, from compounds (II), wherein X represents chlorine, bromine or iodine, by the known Grignard or lithium-Grignard reaction using magnesium or metallic lithium in the solvents normally used (for example tetrahydrofuran, lower aliphatic ethers, lower alkyl benzenes) at temperatures of from 20 to 1200C. The Grignard reaction may have to be initiated with iodine + dibromoethane.

The elimination of water from compounds (I) wherein R, represents the hydroxy group and R2 hydrogen (the other symbols may be as defined above), is preferably carried out at elevated temperatures, for example at temperatures of from 20 to 1 500 C. It is preferred to use solvents, such as glacial acetic acid, benzene, dioxane and lower aliphatic alcohols.

Suitable dehydrating agents are, for example, mineral acids, such as sulphuric acid or hydrohalic acids; organic acids, such as oxalic acid, formic acid; thionyl chloride; zinc chloride; tin chlorlde; boron trifluoride; potassium hydrogen sulphate; aluminium chloride; phosphorus pentoxide; aluminium oxide; acid chlorides; red phosphorus + iodine in the presence of water.

In many cases, partial dehydration actually occurs during the working-up of the reaction products obtained by reacting compounds (II) with compounds (III) or (IV).

The reduction of compounds (I), wherein R1 and B2 form the double bond or Ri represents the hydroxy group and R2 hydrogen, and of products which contain three double bonds in the piperidine ring (the other symbols may be as defined above) may be carried out, for example, with hydrogen in the presence of hydrogenation catalysts, preferably in a solvent, such as alcohols, dioxane, tetrahydrofuran, benzene, acetic acid and ethyl acetate. Suitable hydrogenation catalysts are, in particular, noble metal catalysts, such as palladium and platinum, or sulphidic catalysts, such as palladium sulphide, platinum sulphide and rhenium heptasulphide. The catalysts may be used with or without supports. Suitable supports are, for example, barium sulphate and aluminium oxide. Hydrogenation is preferably carried out at temperatures of from 20 to 1 000C either under normal pressure or at elevated pressures of, for example, up to 100 bars. It is preferred to apply a pressure of from 2 to 20 bars.

Other suitable reducing agents are nascent hydrogen, for example metallic sodium in a lower alcohol (for example ethanol) with or without addition of water, sodium in liquid ammonia, sodium amalgam in the presence of an acid, such as dilute hydrochloric acid, dilute sulphuric acid or acetic acid. In this case, reduction is generally carried out either at room temperature or at elevated temperatures of up to 1 500C.

In addition, reduction may also be carried out, for example, electrolytically or with other hydrogen yielding agents, such as complex metal hydrides, for example alkali metal borohydrides, lithium alanate, sodium-bis-(2-methoxy ethoxy)-aluminium hydride in the presence of hydrogenation catalysts.

Halogen atoms in the 2,5-position on the thiophene ring may optionally be removed during reduction, particularly during catalytic hydrogenation (Pd-Ca CO3) or even electrolytic reduction. The selective elimination of halogen atoms in the thiophene ring is possibie, for example using zinc/glacial acetic acid.

Where compounds (I) wherein R, represents the hydroxy group and R2 hydrogen, used as starting materials, it is sometimes advisable simultaneously to add dehydrating agents. Suitable dehydrating agents are, for example, mineral acids, such as sulphuric acid or hydrohalic acids; organic acids, such as oxalic acid, formic acid: thionly chloride; aluminium chloride; zinc chloride; tin chloride; boron trifluoride; potassium hydrogen sulphate; aluminium oxide, phosphorus pentoxide: acid chlorides. It is particularly preferred to use nascent hydrogen in acid medium as the reducing agent.

Reduction may be carried out in solution or suspension. Suitable solvents are, for example, the solvents mentioned above.

In cases where the products contain three conjugated double bonds in the piperidine ring (pyridine ring), the nucleus hydrogenation of this pyridine ring is carried out above all in the presence of platinum, rhodium and ruthenium catalysts (PtO2; rhodium/carbon, ruthenium dioxide) at temperatures of from 20 to 500C and under pressures of from normal to 10 bars. Suitable solvents are, in particular, lower alcohols,dioxane, tetrahydrofuran, glacial acetic acid, alcoholic hydrochloric acid. It is often best to hydrogenate the corresponding hydrnchloddes. However, the pyridine ring may also be hydrogenated, for example, with alkali metals (e.g. sodium) in lower alcohols (e.g. ethanol) at temperatures of from 20 to 1500C.

The conversion of compounds (I) into the corresponding N-oxides may be carried out, for example, in inert solvents, such as chloroform or other chlorinated hydrocarbons, benzene, toluene, acetone or ethyl acetate, using hydrogen peroxide, a standard aliphatic or aromatic per-acid (peracetic acid, perbonzoic acid, m- perchlorobenzoic acid) or other monosubstitution products of hydrogen perioxide, such as alkyl peroxides (e.g. t-butyl peroxide) at temperatures of from 0 to 1 500C, preferably from 0 to 1000C.

Alkylation (embodiment (b)) is carried out by reacting a compound (I) wherein R3 represents hydrogen or an N-metal derivative thereof with a compound corresponding to the following general formula: B3-W (V) wherein R3 is as defined above; and W represents a halogen atom, such as chlorine, bromine or iodine, or the group RSO20, when R represents a C1-C8 alkyl radical or a phenyl or naphthyi radical optionally substituted by one or more lower alkyl radicals (for example a tosyl radical).

When R3 represents the substituted C2-C8 hydroxyalkyl group, alkylation may even be carried out in two steps by initially reacting the compound (I) wherein R3 represents hydrogen with a compound HOAlkW, wherein W may even form an ethylene oxide ring with the hydroxy group providing it is adjacent and Alk represents a C2-C8 alkylene group, for example the dimethylene group, and subsequently reacting the product of this reaction with a compound B3,-W, wherein W is as defined above and R3 represents a C3-C8 cycloalkyl group, a C1-C8 alkyl group, a C1-C6 hydroxyalkyl group or a C28 hydroxyalkoxy-C1-C8 alkyl group.

This alkylation reaction may be carried out in the presence or absence of solvents at tempertures of from 20 to 2000 C, preferably from 50 to 1 500 C. Suitable solvents or dispersants are, for example, aromatic hydrocarbons, such as benzene, toluene, xylene; aliphatic ketones, such as acetone, methyl ethyl ketone; halogenated hydrocarbons, such as chloroform, carbon tetrachloride, chlorobenzene, methylene chloride; aliphatic ethers such as butyl ether; cyclic ethers, such as tetrahydrofuran, dioxane; sulphoxides, such as dimethyl sulphoxide; tertiary acid asides, such as dimethyl formamide, N-methyl pyrrolidone; aliphatic alcohols, such as methanol, ethanol, isopropanol, amyl alcohol, tert.-butanol; and cycloaliphatic hydrocarbons, such as cyclohexane. Aqueous mixtures of the above-mentioned solvents may also be used. In many cases, the reaction is carried out at the reflux temperature of the solvent or dispersant used. In general, the alkylation reaction components are used in excess. The reaction may even be carried out in the presence of acid-binding agents, such as alkali metal carbonates (e.g. potash or soda), alkali metal hydroxides or tertiary amines (for example triethylamine). This applies, in particular, where the corresponding halides are used.

The compound (I) wherein R3 represents hydrogen, may also be used, for example, in the form of a metal salt, particularly an alkali metal salt (for example the sodium or potassium salt). This applies, in particular, where the other reaction component is a halide.

When carrying out the reaction, the ethylene oxide compound may even be replaced by the corresponding halogen hydrin or by a mixture of these two compounds (crude synthesis product) as the ethylene oxide starting compound.

Compounds (I) wherein R3 represents a lower alkyl group (in particular the methyl or ethyl group) may be converted in known manner by dealkylation into compounds wherein R3 represents hydrogen (cf. Houben-Weyl, Methoden der Organischen Chemie, Vol. Xl/l, pages 976 to 990 (1957); Tetrahedron Letters No. 18, pages 1567 to 1570 (1977); J. Org. Chem. 39, 1507 (1974); Helvetica Chimica Acta 59, 866 (1976).

Dealkylation may be carried out, for example, with chloroformic acid esters, such as chloroformic acid ethyl ester, chloroformic acid vinyl ester, chloroformic acid phenol ester, in an inert solvent, such as aromatic hydrocarbons (e.g. toluene, xylene, benzene), lower aliphatic halogenated hydrocarbons, such as 1,2-dichloroethane, at temperatures of from -50 to + I 000C, followed by acid or basic hydrolysis with, for example, alcoholic alkali (KOH/butanol) or alcoholic mineral acids (HCI, HBr, H2SO4) at temperatues of from 50 to 1 500C.

Reduction, treatment with dehydrating agents and conversion into a corresponding N-oxide may be carried out by the above-described methods.

The compounds according to the present invention are generally obtained in the form of racemates. The optically active antipodes are obtained either by using optically active starting materials or by racemate splitting via the salts of optically active acids, such as L-(+)-tartaric acid, D-(-)-tartaric acid, (+)-0,0'-dibenzoyl-D-tartaric acid, (-)-0,,O'-dibenzoyl-L-tartaric acid, (-)-O,O'-di-p-toloyl-L- tartaric acid, (+)-O,O'-di-p-toloyl-D-tartaric acid, (+)-camphor-10-sulphonic acid.

The compounds (I) may b sesame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, mono-, di- and triglycerides of saturated fatty acids C,2H2402 to C,8H3GO2 and mixtures thereof), pharmaceutically compatible monohydric or polyhydric alcohols and polyglycols, such as polyethylene glycols and derivatives thereof, esters of aliphatic saturated or unsaturated fatty acids (from 2 to 22 carbon atoms, especially from 10 to 1 8 carbon atoms) with monohydric aliphatic alcohols (from 1 to 20 carbon atoms) or polyhydric alcohols, such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol and mannitol, which optionally may even be etherified, benzyl benzoate, dioxolanes, glycerol formals, tetrahydrofurfuryl alcohol, polyglycol ethers with C1-C12 alcohols, dimethyl acetamide, lactamides, lactates, ethyl carbonates, silicones (especially medium viscosity dimethyl polysiloxanes) and magnesium carbonate.

Solutions may be prepared, for example, using water or phsiologically compatable organic solvents, such as ethanol, 1,2-propylene glycol, polyglycols and derivatives thereof, dimethyl sulphoxide, fatty alcohols, triglycerides, partial esters of glycerol and paraffins.

Conventional solution promoters and emulsifiers may be used in the preparation of the compositions. Examples of solution promoters and emulsifiers include: polyvinyl pyrrolidone, sorbitan fatty acid esters, such.as sorbitan trioleate, lecithin, acacia, tragacanth, poloxyethylated sorbitan monooleate, polyoxyethylated fats, polyoxyethylated oleotriglycerides, linolised oleotriglycerides, polyethylene oxide condensation products of fatty alcohols, alkyl phenols or fatty acids.

"Polyoxyethylated" in this context means that the substances in question contain polyoxyethylene chains having a degree of polymerisation of generally from 2 to 40, more particularly from 10 to 20.

Polyoxyethylated substances of this type may be obtained, for example, by reacting compounds containing hydroxyl groups (for example monoglycerides or diglycerides or unsaturated compounds, such as those containing oleic acid residues) with ethylene oxide (for example 40 moles of ethylene oxide per mole of glyceride).

Examples of oleotriglycerides include olive oil, peanut oil, castor oil, sesame oil, cottonseed oil, corn oil (see also Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete 1971, pages 191 to 195).

In addition, it is possible to add preservatives, stabilisers, buffers, for example calcium hydrogen phosphate, colloidal aluminium hydroxide, flavour correctants, antioxidants and complex-formers (for example ethylene diamino-tetraacetic acid). To stabilise the active principle, the pH may have to be, adjusted to a range of from 3 to 7 with physiologically compatible acids or buffers. A neutral to weakly acid (up to pH 5) pH is generally preferred.

Examples of suitable antioxidants include sodium metabisulphite, ascorbic acid, gallic acid, gallic acid alkyl esters, butyl hydroxy anisole, nordihydroguaiaretic acid, tocopherols and tocopherols + synergists (substances which bind heavy metals by complex formation, for example lecithin, ascorbic acid, phosphoric acid). Addition of the synergists greatly increases the antioxygenic effect of the tocopherols.

Examples of preservatives include sorbic acid, p-hyroxy benzoic acid esters (for example lower alkyl esters), benzoic acid, sodium benzoate, trichloroisobutyl alcohols, phenol, cresol, benzethonium chloride, and formalin derivatives.

The compounds according to the present invention are pharmocologically and galenically handled by the conventional methods. For example, active principle(s) and additives or excipients are thoroughly admixed by stirring or homogenisation (forexample in colloid mills, ball mills), generally at temperatures of from 20 to 800C, preferably from 20 to 500C.

The active principles or medicaments may be applied to the skin or mucosa or into the interior of the body, for example orally, enterally, pulmonarily, rectally, nasally, vaginally, lingually, intravenously, intra-arterially, intra-cardially, intramuscularly, intraperitoneally, intracutaneously and subcutaneously.

In particular, the addition of other active medicaments is also possible and favourable.

Compounds (I) wherein R3 represents hydrogen, a C3C8 cycloalkyl group or a C1C20 alkyl group optionally substituted by one or two hydroxy groups, have a good anti-anginous effect in anaestlietised and thoracotomised dogs in which constriction of a branch of the coronary artery produced a local disturbance in blood supply which may be detected exactly in space and time by means of epicardial electrocardiogram signals (ECG-signals). This effect is determined, for example. by the method of Skekares eft at J. Pharmacol. exper. Ther. 196, 15 (1976) with the following modification: the coronary vessel itself is stenosed. The effect of the compound is reflected in a reduction in the changes produced by the stenosis in the characteristic section of the ECG-signals derived from the surface of the heart. For example, in the test mentioned above, the variation in the electrocardiogram (ECG) In the ischaemia region is reduced by 62% after an intravenous dose of 3 mg/kg dog. This therapeutic effect is accompanied by a reduction in heart rate and a moderate increase in blood pressure.

This anti-anginous effect is comparable with that of the known medicament nitroglycerine.

The lowest dose with which an anti-anginous effect may be obtained in the above-mentioned animal test is, for example, 1 mg/kgoral, 1 mg/ky sublingual, 0.1 mg/kg intravenous.

The general dosage range for the anti-anglinous effect (in the above-mentioned animal test) is, for example, from 1 to 50 mg/l < g, more particularly from 3 to 30 mg/kg, oral, from 1 to 50 mg/kg, more particularly from 3 to 30 mg/kg, sublingual, from 0.1 to 20 mg/kg, more particularly from 1 to 10 mg/kg, intravenous.

Indications for which the anti-anginous compounds may be considered include angina pectoris, cardiac infarct, tachycardial rhythm disturbances.

The pharmaceutical preparations may contain, for example, from 10 to 500 mg of the active components according to the present invention.

The active components according to the present invention may be made up, for example, in the form of tablets, capsules, pills, dragees, suppositories, ointments, gels, creams, powders, dusting powders. aerosols or in liquid form. Suitable liquid formulations are, for example, oily or alcoholic and aqueous solutions, suspensions and emulsions. Preferred formulations are tablets containing, for example from 50 to 500 mg or solutions containing, for example, from 1 to 5% of active substance.

The individual dose of the active components according to the present invention may amount to, for example: (a) from 200 to 500 mg for oral formulations; (b) from 1 00 to 300 mg of parenteral formulations (for example intravenous, intramuscular); (c) from 200 to 500 mg of formulations intended for rectal or vaginal application; (d) from 1 to 5% for formulations intended for local application to the skin and mucosa (for example in the form of solutions, lotions, emulsions and ointments); (the doses being based on the free base in each case).

For example, it is possible to prescribe from 1 to 3 tablets containing from 100 to 200 mg of active substance three times a day or, in the case of intravenous injection, for example, one from 2 to 10 ml ampoule containing from 50 to 100 nig of substance from one to three times a day. In the case of oral administration, the minimum daily dose is, for example, 200 mg, whilst the maximum daily dose should not exceed 1.5 g.

The acute toxicity of the anti-anginous compounds in mice (expressed by the LD mg/kg; Miller and Tainter's method: Proc. Soc. Exper. Biol. a. Med. 57(1944) 261), for example in the case of oral application, amounts to from 300 to 1000 mg/kg.

Compounds (I) wherein R3 represents a C2-C8 hydroxyalkyl group substituted on the hydroxyl hydrogen by a C3-C5 cycloalkyl group, a C1-C8 alkyl group, a C1-C8 hydroxyalkyl group or a C28 hydroxyalkoxy-C1-C8 alkyl group, have a good broncholytic-spasmolytic effect, a papaverine-like effect, an anti-histamine/anti-serotonin effect and an anti-anaphylactic effect (asthma-prophylactic effect).

These effects may be determined, for example, by the following test methods: Determination of the papaverine-like effect: Magnus's method, cf. Pflugers Acrch. Physiol., 102, 123 (1904) and Pharmacological Experiments on Isolated Preparation 2nd Edition, E and S. Livingstone, Edinburgh and London, 1 970.

Determination of the bronchospasmolytic effect on the isolated tracheal spiral by J.W. Constantine's method, cf. J. Pharm. Pharmacol. 17, 384 (1965), and in vivo in dogs and guinea pigs by Konzett Rossler's method, Arch. exper. Pathol. Pharmacol. 195, 71(1940).

Determination of the anti-histamine/anti-serotonin and asthma-prophylactic effect by asthma tests (histamine spasm, acetyl choline spasm, serotonin spasm, ovalbumin spasm) on non-anaesthetised guinea pigs in accordance with Kallos and Pagel, Acta med. cand. 91, 292 (1937), and by the method of Niemegeers eft at Arch. Int. Pharmacodyn. 234, 164 (1978).

For example, in the above-mentioned test (Konzett and Rosslefs bronchospasmolvsis test), the histamine-induced bronchospasm is on average completely suppressed with a dose of 0.1 mg/kg guinea pig body weight.

This anti-histaminic broncholytic effect is comparable with the effect of the known medicament clemastin.

The lowest bronchospasmolytically active dose in the above-mentioned animal test is, for example, 0.1 mg/kg oral, 0.01 mg/kg intravenous.

The general dosage range of this bronchospasmolytic effect (in the above-described animal test) is, for example, from 0.1 to 3 mg/kg, more particularly 1 mg/kg, oral and from 0.01 to 0.3 mg/kg, more particularly 0.1 mg/kg, intravenous.

Indications for which the bronchospasmolytic compounds maybe considered include antiallergicum (histamine-serotonin antagonist), allergic reactions of the skin and mucosa, asthma prophylaxis.

The pharmaceutical preparations containing the bronchospasmolytic compounds may contain, for example, from 1 to 10 mg of the active component(s) according to the present invention.

The active component(s) according to the present invention may be made up in the form of tablets, capsules, pills, dragees, suppositories, ointments, gels, creams, powders, dusting powders, aerosols or in liquid form. Suitable liquid formulations are, for example, oily or alcoholic and aqueous solutions, suspensions and emulsions. Preferred formulations are tablets containing, for example, from 2 to 10 mg or solutions containing, for example, from 0.5 to 2% of active substance.

The individual dose of the bronchospasmolytically active components may amount to, for example: (a) from 1 to 10 mg for oral formulations; (b) from 0.5 to 2 mg for parenteral formulations (for example intravenous, intramuscular); (c) from 0.3 to 1 mg for formulations intended for inhalation (solutions or aerosols).

For example, it is possible to prescribe from 1 to 3 tablets containing from 2 to 20 mg of active substance three times daily or, in the case of intravenous injection, for example, one from 1 to 10 ml ampoule containing from 0.3 to 3 mg of substance from one to three times a day. In the case of oral administration, the minimum daily dose is, for example, 5 mg, whilst the maximum daily dose should not exceed 200 mg.

In the treatment of cats and dogs, the individual oral dose is, for example, from 0.5 to 2 mg/kg body weight; the parenteral dose is from 0.1 to 1 mg/kg body weight The acute toxicity of the bronchospasmolytic compounds in mice (expressed by the LD 50 mg/kg; Miller and Tainter's method: Proc. Soc. Exper. Biol. a. Med. 57 (1944) 261), for example in the case of peroral adminstration, is above 500 mg/kg.

The medicaments may be used in human medicine, in veterinary medicine and in agricultural medicine either on their own or in admixture with other pharmaceutically active substances.

The following Examples iilustrate the present invention: EXAMPLE 1 (Di-3-thienyl)-(N-methyl-4-piperidyl)-ca rbinol

(a) 4.86 g (0.2 g-atom) of magnesium are covered with absolute tetrahydrofuran, followed by-the addition of one grain of iodine and 0.5 ml of dibromethane. Once the reaction has started, 26.9 g (0.198 mole) of 4-chloro-N-methyl piperidine dissolved in 30 ml of absolute tetrahydrofuran are added dropwise over a period of 1 5 minutes. After heating under reflux for 2 hours, the solution is diluted with 120 ml of absolute tetrahydrofuran. 19.4 g (0.1 mole) of p-dithienyl ketone are then added in small portions at room temperature.

The reaction mixture is then left to after-react for 2 hours at boiling temperature. For hydrolysis, the reaction mixture is poured onto ice/ammonium chloride (250 9/259). The organicphase is separated off and the aqueous phase is repeatedly extracted by shaking with chloroform. After drying and removal of the solvent by distillation in vacua, the required product is isolated by dry column chromatography on silica gel (eluent: ether/methanol = 90%/1 0%). For salt formation, the free base obtained is dissolved in ethanol, followed by addition of an equimolar quantity of maleic acid also dissolved in ethanol. The maleate is recrystallised from ethanol. M.p. of the maleate: 189-191 OC. Yield: 259/0 (based on dithienyl ketone).

(b) 63.5 g (0.38 mole) of 3-bromothiophene dissolved in 100 ml of diisopropyl ether are added dropwise at -750C to a mixture consisting of 350 ml of diisopropyl ether and 200-ml of butyl lithium (20% solution in hexane). On completion of the addition, the mixture is stirred for 2 hours before a solution of 33 g (0.1 9 mole) of N-methyl-4-piperidine carboxylic acid ethyl ester in 50 ml of diisopropyl ether is added dropwise at -750C. In all operations, the reaction temperature of -700C should not be exceeded. Hydrolysis is obtained by the addition of 250 ml of water. The aqueous phase is repeatedly extracted with chloroform. After drying in the conventional way, the solution is concentrated and cooled. The carbinol which crystallises out is filtered off under suction, dried and used without further purification for dehydration (see Example 2). Yield: 73%.

EXAMPLE 2 4-(di-3-thienyl methylene)-N-methyl piperidine

14 g (0.048 mole) of (di-3qhienyl)-(N-methyl-4-piperidyl)-carbinol (crude product) are dissolved in 200 ml of methanol, followed by the addition of 20 ml of 8 N isopropanolic hydrochloric acid. After heating for 1 hour, the solvent is removed under reduced pressure and the hydrochloride obtained is recrystallised from isopropanol. M.p. of the hydrochloride: 2300 C. Yield: 79%.

The starting carbinol is obtained in the same way as in Example 1 (b).

EXAMPLE 3 4-[3-thienyl-(2,5-dimethyl-3-thienyl)-methylenej-N-methyl piperidine

4 g of (2,5-dimethyl-3-thienyl)-(N-methyl-4-piperidyl)-3-thienyl)-carbinoi are dehydrated with 10 ml of 8 N isopropanolic HCI in 50 ml of methanol in the same way as in Example 2. For purification, the base is first liberated from the oily hydrochloride obtained with ammonia. The base is isolated by dry column chromatography on silica gel (eluent: ether/methanol = 95%/5%) and dissolved in acetone, followed by the addition of an equimolar quantity of oxalic acid. The oxalate obtained is recrystallised from ethyl acetate/ethanol. Mp. of the oxalate 1 55-1 570C. Yield 56%.

The starting carbinol is obtained as in Example 1 (a) from 1 2.2 g (0.055 mole) of (2,5-dimethyl-3thienyl)-3-thienyl ketone, 14.7 g (0.1 1 mole) of 4-chloro-N-methyl piperidine and 2.67 g (0.11 g-atom) of magnesium.

EXAMPLE 4 4-(di-3-thienyi-methylene)-N-cyclohexyl piperidine

5 g of (di-3-thienyl)-(N-cyclohexyl-4-piperidyl)-carbinol are dehydrated with 10 ml of 8 N isopropanolic HCI in 50 ml of methanol and worked-up in the same way as in Example 2. The hydrochloride is recrystallised from isopropanol. M.p. of the hydrochloride: 2320C. Yield 41%.

The starting carbinol is produced in the same way as in Example 1 (b).

EXAMPLE 5 4-(di-3-thienyl-methylene)-piperidine

A solution of 122 g (0.443 mole) of 4-(di-3-thienyl-methylene)-N-methyl piperidine in 400 ml of toluene is added dropwise at 800C to a mixture of 1 00 g (0.886'mole) of chloroformic acid ethyl ester and 200 ml of toluene. On completion of the addition, the reaction mixture is stirred for 3 hours at 800C and concentrated by distilling off the solvent in vacua. The 4-(di-3-thienyl-methylene)-N-carbethoxy piperidine crystallises out and is recrystallised from isopropanol (yield: 98%; m.p.: 109-111 OC).

A mixture of 163 g (0.484 mole) of this carbethoxy compbund, 120 g (2.2 moles) of potassium hydroxide and 1200 ml of n-butanol is boiled under reflux until the starting compound has been completely reacted, as confirmed by thin layer chromatography. The butanol is removed in vacuo and water added to the residue which is then repeatedly extracted by shaping with methylene chloride. Salt formation is carried out with maleic acid in acetone as solvent. Yield 68%. M.p. of the maleate: 1 73 to 1740C.

EXAMPLE 6 4-(di-2-thienyl-methylene)-N-(2-hydroxyethyl)-piperidine

6.8 g (0.026 mole) of 4-(di-2-thienyl-methylene)-piperidine and 12.6 g (0.1 56 mole) of 2chloroethanol are dissolved in 100 ml of xylene and the resulting solution heated under reflux for 10 hours in the presence of 21.6 g (0.156 mole) of potassium carbonate. After the addition of water, separation of the organic phase, repeated extraction of the aqueous phase with chloroform, combination and drying of the organic phases, the solvent is distilled off in vacuo and the hydrochloride obtained with isopropanolic hydrochloric acid and acetone as solvent. It is recrystallised from isopropanol. M.p. of the hydrochloride 196 C. Yield 63%.

The thienyl starting compound is prepared in the same way as in Example 5.

EXAMPLE 7 4-(di-3-thienyl-methylene)-N-(2-hydroxyethyl)-pipe ridine Preparation as in Example 6 from 6.8 g of 4-(di-3-thienyl-methylene)-piperidine and 1 2.6 g of 2 chloro-cthanol. M.p. of the hydrochloride: 170-171 0C (from isopropanol). Yield 48%.

EXAMPLE 8 4-(di-3-thienyl-methylene)-N-[2-hydroxy-( 1 )-propyl]-piperidine Preparation as in Example 6 from 6.8 g of 4-(di-3-thienyl-methylene)-piperidine and 4.9 9 of 1chloro-2-hydroxypropane. M.p. of the hydrochloride (from isopropanol) 209 CC. Yield 22%.

EXAMPLE 9 4-[di-2-thienyl-rnethylene]-N-[2,3-dihydroxy-( 1 )-propyl]-piperidine

lOg (0.038 mole) of 4-(di-2-thienyl-methylene)piperidine and 5.6 g (0.076 mole) of glycidol are dissolved in 50 ml of ethanol and the resulting solution heated under reflux for 8 hours. The solvent is then removed and the required glycidyl compound is isolated by dry column chromatography on silica gel (eluent: chioroform). For further purification, the hydrochloride is prepared and recrystallised twice from isopropanol. M.p. of the hydrochloride 1 41--1 43 OC. Yield 33%.

The compounds listed in Table 1 below, which correspond to the following general formula:

are prepared in the same way as in Example 9. In each case, 0.038 mole of 4-(di-3-thienyl-methylene)piperidine are reacted with 0.076 mole of the glycidol corresponding to the alcohol B3-OH.

TABLE 1

Example Recrystal I isation No. R3 Yield M.p. medium OH 10 -CH2-CH-CH2-OH 15 % 130-132"C isopropanol (hydrochloride) OH 11(*) -CH2-CH-(CH2)3CH1 31 % 69-710C isopropanol (base) OH 12 (*) -CH3-CH-(CH3),CH3 76 % 82-830C ethanol (base) OH 13(t) -CH2-CHCH2)15CH3 78 78 % 9293 C ethanol (base) (*) Ethanol is replaced by isopropanol as solvent. In addition, purification by column chromato graphy may be left out.

5.5 g (0.02 mole) of 4-(di-3-thienyl-methylene)-N-methyl piperidine are dissolved in 50 ml of ethanol, 7.2 g of 30% hydrogen peroxide are added dropwise while cooling with ice and the mixture left standing for 8 days at room temperature. Excess hydrogen peroxide is destroyed by the addition of Ptcarbon. After filtration and removal of the solvent at room temperature, the amine oxide is crystallised in ethyl acetate, M.p. 92-960C. Yield 77%.

EXAMPLE 16 4-{di-3 thienyl-methyl)-N-methyl piperidine

9.5 g (0.03 mole) of 4-(di-3-thienyl-methylene)-N-methyl piperidine hydrochloride are dissolved in 270 ml of methanol and the resulting solution is hydrogenated at 650C/5 bars in the presence of 9.5 g of Pd BaSO4 (9.25% Pd). Purification is carried out by dry column chromatography on solica gel (eluent: chloroform/petroleum ether. M.p. of the hydrochloride 251-2530C. Yield 11%.

EXAMPLE 17 4-(di-3-thierlyl-methylene)-N-(2-methoxyethyl)-piperidine

8.9 g (0.034 mole) of 4-(di-3-thienyl-methylene)-piperidine and 18 g (0.17 mole) of 2-chloroethyl methyl ether are dissolved in 100 ml of xylene and the resulting solution is heated under reflux for 10 hours in the presence of 22.4 g of sodium carbonate. After the addition of water, separation of the organic phase, repeated extraction of the aqueous phase with chloroform, combination and drying of the organic phases, the solvent is distilled off in vacuo and the hydrochloride is obtained with isopropanolic hydrochloric acid and acetone as solvent. Recrystallisation is carried out from acetone.

M.p. of the hydrochloride 1 800C. Yield 30%.

The thienyl starting compound is obtained as follows: A solution of 1 22 g (0.443 mole) of 4-(di-3-thienyl-methylene)-N-methyl piperidine (obtained, for example, by method (b)) in 400 ml of toluene is added dropwise at 800C to a mixture of 100 g (0.886 mole) of chloroformic acid ethyl ester and 200 ml of toluene. On completion of the addition, the reaction mixture is stirred for 3 hours at 800C and concentrated by distilling off the solvent in vacuo. The 4-(di-3 thienyl-methylene)-N-carbethoxy piperidine crystallises out and is recrystallised from isopropanol (yield: 98%, m.p.: 109-111 0C).

A mixture of 1 63 g (0.484 mole) of this carbethoxy compound, 1 20 g (2.2 moles) of potassium hydroxide and 1200 ml of n-butanol is boiled under reflux until the starting compound has been completely reacted, as confirmed by thin layer chromatography. The butanol is removed in vacuo and water added to the residue which is then repeately extracted by shaking with methylene chloride. Salt formation is carried out with maleic acid in acetone as solvent. Yield: 68%, m.p. of the maleate: 173-1740C.

The compounds listed in Table 2 below, which correspond to the following general formula

are prepared in the same way as in Example 17. In each case, 0.034 mole of the corresponding 4 (dithienyl-methylene)-pyridine is reacted with 0.17 mole of the compound Cl-CH2-CH2-OB3. The hydrochlorides of the end products obtained are each recrystallised from isopropanol.

TABLE 2 Example Position of the two M.p. of the No. thienyl radicals R Yield hydrochloride 18 3-position -(CH2)2-OH 31 % 178"C 19 3-position -(CH2)2-O-(CH2)2OH 46 % 128"C 20(t) 2-position -CH3 18 % 169-170"C 21 2-position -(CH2)2-OH 20 % 1450C (*) In this Example, salt formation was preceded by purification by column chromatography on silica gel (eluent: chloroform/methanol 98 %: 2 %3.

EXAMPLE 22 4-(di-2-thienyl-methylene)-N-(2-cyclopenyloxyethyl)-piperidine

6 g (0.0175 mole) of 4-(di-2-thienylmethylene)-N-(2-hydroxyethyl)-piperidine hydrochloride are added in portions to a suspension of 1.3 g of NaH (80%) in 100 ml of dried xylene. The mixture is then boiled until the evolution of hydrogen is over. 5.3 g of cyclopentyl bromide dissolved in 10 ml of xylene are added dropwise at boiling temperature. After a reaction time of 1 6 hours, the reaction mixture is hydrolysed in the cold, the xylene phase is separated off, followed by drying and concentration. For purification, the product is chromatographed on silica gel for dry column chromatography using ethyl acetate as eluent and the oxalate is precipitated from acetone solution. M.p. of the oxaiate 193-1 950C, yield 32%.

EXAMPLE 23 Tablets: 8 kg of active principle (compound of Example 6) are mixed with 5 kg of lactose and 3 kg of microcrystalline cellulose and the resulting mixture granulated in the conventional way with a solution of 0.3 kg of polyvinyl pyrrolidone in 1.2 kg of water.

After the addition and mixing of 3.45 kg of microcrystalline cellulose, 2 kg of corn starch, 0.05 kg of highly disperse silica and 0.2 kg of magnesium stearate, tablets having a weight of 220 mg, a diameter of 9 mm and a radius of curvature of 1 3.5 mm are pressed. The tablets have a hardness of from 5 to 7 kg (Heberlein harness tester). Each tablet contains 80 mg of active principle.

Ampoules: 400 g of active principle (compound of Example 7) are dissolved in a mixture of 4 kg of 1,2propylene glycol and 1 5 kg of water for injection purposes, the resulting solution is made up to 20 litres with water for injection purposes and filtered. After the solution has been introduced into 2 ml ampoules, the ampoules are sterilised in the conventional way for 20 minutes at 1 200C/1 bar. Each ampoule contains 40 mg of active principle in 2 ml.

Tablets: 1 kg of active principle (compound of Example 18) is mixed with 5 kg of lactose and 3 kg of microcrystalline cellulose and the resulting mixture granulated in the conventional way with a solution of 0.3 kg of polyvinyl pyrrolidone in 1.2 kg of water.

D

Claims (19)

1. A compound corresponding to the following general formula (I):

wherein R represents hydrogen or hydroxy; R2 represents hydrogen; or R1 and R2 together represent a second bond between the carbon atoms to which they are attached; R3 represents hydrogen, C3-C8 cycioalkyl, C1-C20 alkyl which may be substituted once or twice by hydroxy or -Alk-O-B8 wherein Alk represents C2-C8 alkylene and B8 represents C3-C8 cycloalkyl. C1-C8 alkyl, C1-C8 hydroxyalkyl- or C2-C8 hydroxyalkyl -C1-L'8 alkyl: and R4, Rs, R6 and R7, which may be the same or different. each represents hydrogen, C1-C8 alkyl or halogen; at least one 3-thienyl radical being present when R3 represents unsubstituted C1-C8 alkyl; the N-oxides Thereof, the quaternary salts thereof and the acid addition salts thereof.

2. A compound corresponding to the following general formula:

wherein R, represents hydrogen or hydroxy; R2 represents hydrogen; or R, and R2 together represent a second bond between the carbon atoms to which they are attached; R3 represents hydrogen, C3-C6 cycloalkyl or C1-C20 alkyl which may be substituted once or twice by hydroxy; and R4, R5, R6 and R7, which may be the same or different, each represents hydrogen, C1-C6 alkyl or halogen; at least one 3thienyl radical being present when R3 represents unsubstituted C1-C8 alkyl; and the N-oxides thereof, the quaternary salts thereof and the acid addition salts thereof.

3. A compound corresponding to the following general formula:

wherein R1 represents hydrogen or hydroxy; R2 represents hydrogen; or R1 and R2 together represent a second bond between the carbon atoms to which they are attached; alk represents C28 alkylene; R6 represents C3-C8 cycloalkyl, C1-C8 alkyl C1-C8 hydroxyalkyl or C2-C8 hydroxyalkoxy-C1-C8 alkyl; and R4, R5, R6 and R7, which may be the same or different, each represents hydrogen, C1-C8 alkyl or halogen; and the N-oxides thereof, the quaternary salts thereof and the acid addition salts thereof.

4. A compound as claimed in any one of claims 1 to 3 substantially as herein described.

5. A compound as claimed in any of claims 1 to 3 substantially as herein described with reference to the Examples.

6. A process for the preparation of a compound as claimed in claim 1 which comprises: (a) reacting a compound corresponding to the following general formula (ill):

which may contain three conjugated ring double bonds; wherein R3 is as defined in claim 1 or is not present when the ring is a pyridine ring, and X represents; (A) -COZ, wherein Z represents halogen, C1-C8 alkoxy, or thienyl which may be substituted once or twice by halogen and/or C16 alkyl; or (B) lithium or -MgHal wherein Hal represents chlorine, bromine or iodine; in case (A), with a compound corresponding to the following general formula (III):

wherein X' represents lithium or -MgHal; and the thienyl radical may be substituted once or twice by halogen and/or C1-C8 alkyl; or, in case (B) with a compound corresponding to the following general formula (IV):

at least one 3-thienyI radical being present in one of the above-mentioned starting materials when R3 in general formula (II) represents unsubstituted C1-C6 alkyl, and the resulting compounds is optionally treated with a reducing agent and/or a dehydrating agent and/or is alkylated through R3 and/or is converted into the N-oxide; or (b) the radical R3 as defined in claim 1 is introduced by alkylation on the N-atom in one or two steps into a compound corresponding to general formula (I) as defined in claim 1 wherein R3 represents hydrogen or an N-metal derivative thereof; R1, R2, R4, R5, B8 and R7 being as defined in claim 1; and the piperidine ring may contain three conjugated ring double bonds, and/or a compound corresponding to general formula (I) as defined in claim 1 wherein R3 represents lower alkyl; is dealkylated and the compound obtained is optionally treated with a reducing agent and/or a dehydrating agent and/or is converted into the N-oxide.

7. A process for the preparation of a compound as claimed in claim 2 which comprises: (a) reacting a compound corresponding to the following general formula:

which may contain three conjugated ring double bonds; wherein R3 is as defined in claim? or is not present when the ring is a pyridine ring; and X represents: (A) -COZ, wherein Z represents halogen, C1-C6 alkoxy or thienyl which may be substituted once or twice by halogen and/or C1-C8 alkyl; or (B) an alkali metal or --MgHal wherein Hal represents chlorine, bromine or iodine: in case (A), with a compound corresponding to the following general formula

wherein X represents an alkali metal or-MgHaI; and the thienyl radical may be substituted once or twice by halogen and/or C1-C8 alkyl; or, in case (B), with a compound corresponding to the following general formula

at least one 3-thienyl radical being present in one of the above-mentioned starting materials when R3 represents unsubstituted C1-C8 alkyl; and the resulting compound is optionally treated with a reducing agent and/or a dehydrating agent and/or is alkylated through R3 and/or is converted into the N-oxide; or (b) treating a compound corresponding to the general formula defined in claim 2 wherein R1 represents hydroxy; and R2 represents hydrogen; with a dehydrating agent and/or a reducing agent and/or replacing R3 by another substituent R3; the resulting compound optionally being converted into the N-oxide.

8. A process for the preparation of a compound as claimed in claim 3 which comprises: (a) introducing the radical -AIk-O-B8, wherein RB is as defined in claim 3; into a compound corresponding to the following general formula:

or an N-metal derivative thereof; wherein R1, R2, R4, R5, R8 and R7 are as defined in claim 3; and the piperidine ring may contain three conjugated ring double bonds; in one or more steps by alkylation on the N-atom; and the resulting compound is optionally treated with a reducing agent and/or a dehydrating agent and/or is converted into the N-oxide; or (b) reacting a compound corresponding to the following general formula

which may contain three conjugated ring double bonds; wherein RB is as defined in claim 3 or is not present in the case of a pyridine ring; and X represents: (A) rOZ wherein Z represents halogen, C1-C6 alkoxy or thienyl which may be substituted once or twice by halogen and/or C1-C6 alkyl; or (B) an alkali metal or -MgHal wherein Hal represents chlorine, bromine or iodine; in case (A), with a compound corresponding to the following general formula:

wherein X' represents an alkali metal --MgHal; and the thienyl radical may be substituted once or twice by halogen and/or C1-C6 alkyl; or, in case (B), with a compound corresponding to the following general formula

and the resulting compound is optionally treated with a reducing agent and/or a dehydrating agent and/or is alkylated through the radical -Alk-O-R6 and/or is converted into the N-oxide.

9. A process as claimed in any of claims 6 to 8 in which the resulting compound is converted into an acid addition salt thereof or a quarternary salt thereof.

10. A process as claimed in any of claims 6 to 8 substantially as herein described.

11. A process as claimed in any of claims 6 to 8 substantially as herein described with reference to the Examples.

12. A compound as claimed in any of claims 1 to 3 when prepared by a process as claimed in any of claims 6 to 11.

13. A composition which comprises a compound as claimed in any of claims 1 to 5 or 12 and a pharmacological excipient and/or a diluent.

14. A composition as claimed in claim 13 substantially as herein described.

1 5. A composition as claimed in claim 13 substantially as herein described with reference to the Examples.

1 6. A process for the preparation of a composition as claimed in claim 1 3 which comprises formulating the compound as claimed in any of claims 1 to 5 or 12 and the pharmacological excipient and/or diluent.

17. A process as claimed in claim 16 substantially as herein described.

1 8. A process as claimed in claim 1 6 substantially as herein described with reference to the Examples.

19. A composition as claimed in claim 13 when prepared by a process as claimed in any of claims 16to 18.