GB1597592A - Dithienyl alkylamines and alkenylamines having a hydroxy phenyl group - Google Patents

Description

(54) NEW DITHIENYL ALKYLAMINES AND ALKENYLAMINES HAVING A HYDROXY PHENYL GROUP (71) We, DEUTSCHE GOLD-UND SILBER-SCHEIDEANSTALT VORMALS ROESSLER, a body corporate oraganised under the laws of Germany of 9, Weissfrauenstrasse, 6 Frankfurt Main 1, Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: This invention repates to new dithienyl alkylamines and alkenylamines having a hydroxy phenyl group, and to a process for their production.

Compounds corresponding to the following formulae

are known. In these formulae, R3 and R1 represent hydrogen or a methyl group and R2 represents hydrogen, C1-C4-alkyl groups or a benzyl group or the entire group -NR2R2 forms a pyrrolidino group, a piperidino group, a morpholino group or a homopiperidino group. The main effect claimed for these compounds is a spasmolytic effect (Chimie Therapeutique 1973, pages 22-31).

U.K. Patent Specifications No. 1,296,112 and 1,328,545 disclose compounds corresponding to the general formula

in which the two thienyl radicals can each be substituted either one or more times by lower molecular weight alkyl radicals, the bridge member A-B has either the structure C(OH)-CHRfor the structure C=CR- in which both R" and Rf represents hydrogen atoms or one of R" and Rf represents a lower molecular weight alkyl group and the other represents a hydrogen atom; represents a hydrogen atom or a lower molecular weight alkyl group; Rb represents a hydrogen atom or a hydroxyl group; and the radicals Rc and Rd, which may be the same or different, each represent a hydrogen or halogen atom, a hydroxyl group, a lower molecular weight alkyl group, a lower molecular weight haloalkyl group or a lower molecular weight alkoxy group, their optically active or diastereomeric forms and their salts.

These compounds are effective for improving cerebral circulation.

Dithienyl alkylamines and alkenylamines having a hydroxy phenyl group are not specifically mentioned in U.K. Patent Nos. 1,296,112 and 1,328,545.

Furthermore the processes disclosed in the two patents can not produce the hydroxy phenyl derivatives in large yields, partly because many by-products are produced which are expensive and difficult to remove.

It has now surprisingly been found that the hydroxy phenyl derivatives have an extremely good pharmacological effect.

The present invention therefore relates to a compound corresponding to general formula:

wherein > AB represents either > C(OH)-CH2- or > C=CH-, Alk represents a straight-chain or branched-chain C1-C5-alkylene group, R represents a hydrogen atom or a C1-C4-alkyl group, and the phenolic hydroxy group may be substituted by a C2-C8 alkanoyl group, and the salts thereof.

One particular embodiment of such compounds is represented by compounds corresponding to the general formula

in which > A-B- has either the structure > C(OH)-CH2- or the structure > C=CH-- and R" represents a hydrogen atom or a C1-C4 alkyl group, and their salts.

[1,1-Dithienyl - (3) - yl - 1 - hydroxy - (3) - propyl] -[1 - hydroxy 1 - (p hydroxyphenyl - (2) - propyl] - amine and [1,1 - dithienyl - (3) - yl - 1 hydroxy - (3) - yl - ] - [1 - hydroxy - 1 - (p - hydroxyphenyl) - (2) - propyl] amine are particularly preferred compounds of the present invention.

The two thienyl radicals are preferably attached to > A-B- in the same position (bis-thien-(3)-yl or bis-thien-(2)-yl derivatives). It is also possible, however, for > A-B- to be simultaneously attached to a thien-(2)-yl and a thien-(3)-yl radical. The radical R in the structural moiety

is preferably methyl or ethyl. The hydroxy group on the phenyl ring may be in the ortho, para or meta posltion. if it is acylated, the aliphatic C2-C6-carboxylic acid on which it is based may be linear or branched and may consist in particular of 2 to 4 carbon atoms. The alkylene chain Alk is preferably straight and preferably consists of 1, 2 or 3 carbon atoms.

The compounds of formula (I) according to the present invention show pharmacodynamic activity, especially in disorders of the heart and circulation system. In particular, they produce an increase in peripheral and cerebral circulation and in this respect for example are considerably more active, especially in regard to peripheral circulation, than the known compounds according to UK Patent Nos. 1,296,112 and 1,328,545. In some cases, the compounds according to the present invention also dilate the coronary arteries and increase the power of the heart.

The compounds of general formula I and salts thereof, may be prepared by condensing a compound corresponding to the general formula:

in which Alk is a linear or branched C1-C5-alkylene group and X represents chlorine, bromine or iodine, with an amine corresponding to the general formula

wherein R is defined as above and the phenolic hydroxy group may be substituted by a C2-C5-alkanoyl group, and optionally converting compounds corresponding to general formula I, in which > A-B-= > C(OH)-CH2-, into the corresponding unsaturated compounds ( > AB-= > C=CH-) with a dehydrating agent by known methods and/or acylating them on the phenolic hydroxy group with an aliphatic C2-C6-carboxylic acid and optionally producing salts from the basic compounds obtained.

Unless otherwise indicated the term "lower" as used herein means having up to 6 carbon atoms, in particular having up to 4 carbon atoms.

This condensation reaction is carried out for example in the presence or absence of a solvent and at a temperature in the range from 0 to +1500C, and preferably at a temperature in the range from 20 to 1000C. Suitable inert solvents or suspending agents are, for example, saturated ethers, such as lower aliphatic dialkyl ethers, alkyl ethers or cycloalkanols and alkyl-substituted cycloalkanols; saturated liquid hydrocarbons, saturated cycloaliphatic hydrocarbons which may be substituted by lower alkyl radicals, cyclic ethers, such as tetrahydrofuran and dioxane; benzene; alkyl benzenes such as toluene; aliphatic saturated ketones; aliphatic and cycloaliphatic alcohols. The concentration of compound II in the solvent or suspending agent amounts for example to between 10 and 50%. The condensation reaction with compound III is best carried out in the presence of a base or hydrogen halide acceptor such as tertiary amines (triethylamine), alkali metal carbonates (potash) and alkali metal hydroxides. It is even possible to use compound III itself as hydrogen halide acceptor. The condensation reaction takes place with advantage in a stoichiometric ratio, although it is also possible to use any excess of compound III. The reaction time is governed by the reaction temperature. At temperatures in the range from 100 to 120"C for example, the reaction is over in 4 to 12 hours.

The elimination of water from compounds corresponding to general formula I, in which > A-B-= > C(OH)-CH2-, is best carried out at elevated temperatures, for example at a temperature in the range from 20 to 1500C. It is preferred to use a solvent such as dialkyl ethers, dioxane, glacial acetic acid, benzene, toluene, ethanol and isopropanol.

For carrying out this dehydrating reaction, there is no need initially to isolate the compound of formula I in which > A-B- represents the group > C(OH)- CH2-, instead the reaction mixture obtained after the reaction of compound II with compound III may for example be directly treated with the dehydrating agent, optionally after removal of the solvent. For example, isopropanolic or ethanolic hydrochloric acid may be directly added to the reaction mixture which is then heated for a few minutes to boiling point to obtain dehydration. The reaction product may be worked up in the usual way.

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

In the compounds of the present invention, the hydroxy group on the phenyl ring may optionally be subsequently acylated by a C2-C6-alkanoyl group.

Acylation may be carried out in inert solvents or suspending agents, such as dioxane, dimethyl formamide, benzene or toluene, at a temperature in the range from 0 to 2000 C. Suitable acylating agents are aliphatic C2-C6-ketenes and also acid halides, acid anhydrides or acid esters of aliphatic carboxylic acids containing from 2 to 5 C-atoms, optionally with addition of an acid-binding agent, such as potassium carbonate or sodium ethylate, or a tertiary amine, for example triethylamine. The esters in question are in particular those with lower aliphatic alcohols. Acylation may also be carried out by initially preparing an alkali metal salt by reacting a compound of formula I having a hydroxy group on the phenyl ring with an alkali metal alkali metal hydride or alkali metal amide (particularly sodium or sodium compounds) in an inert solvent, such as dioxane, dimethyl formamide, benzene or toluene, at a temperature of from 0 to 1500C and subsequently adding the acylating agent.

Instead of the acylating agents referred to, it is also possible to use other chemically equivalent agents (cf. for example L.F. and Mary Fieser "Reagents for Organic Synthesis", John Wiley and Sons, Inc. New York, 1967, Vol 1 pages 1303- 4 and Vols 2, page 471). Any acyl groups present in compounds of formula I may of course also be removed again, for example by hydrolysis in the presence of acids or basic substances at a temperature in the range of from 20 to 1500C.

Those compounds which contain asymmetrical carbon atoms and which are generally formed as racemates may be split into the optically active isomers by methods known per se, for example by means of an optically active acid. However, it is also possible to use optically active or even diastereomeric starting materials of general formula III from the outset, in which case a corresponding pure optically active form or diastereomeric configuration is obtained as the end product.

Where amines of formula III (which may be substituted in the phenyl ring by C2-C6 alkanoyloxy) are used as starting materials, they may be present in the erythro or threo configuration.

The end products of formula I may be obtained in the free form or in the form of their salts, depending upon the process conditions and starting materials used.

The salts of the end products may be converted back into the bases by methods known per se, for example with alkali or ion exchangers. Salts may be obtained from the bases by reaction with organic or inorganic acids, especially those which are suitable for the formation of therapeutically valuable salts. Acids such as these are, for example, hydrohalic acids, sulphuric acids, acids of phosphorus, nitric acid, perchloric acid, organic mono-, di- or tri-carboxylic acids of the aliphatic, alicyclic, aromatic or heterocyclic series and sulphonic acids. Examples of these acids are formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, hydroxy maleic acid, pyruvic acid, phenyl acetic acid, benzoic acid, p-amino benzoic acid, anthranilic acid, p-hydroxy benzoic acid, salicylic acid, p-amino salicylic acid, embonic acid, methane sulphonic acid, ethane sulphonic acid, hydroxyethane sulphonic acid, ethylene sulphonic acid; halogen benzene sulphonic acid, toluene sulphonic acid, naphthalene sulphonic acid or sulphanilic acid.

The compounds according to the present invention are suitable for the preparation ofpharmaceutical compositions and preparations. The pharmaceutical compositions or medicaments contain as active principle one or more of the compounds according to the invention, optionally in admixture with other phamacologically or pharmaceutically active substances. The medicaments are prepared in known manner with the usual pharmaceutical additives and other conventional excipients and diluents.

Examples of excipients and additives of this kind are the substances recommended and specified in the following literature references as additives for pharmacy, cosmetic and related fields: Ullmanns Encyklopadie der technischen Chemie, Vol. 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), pages 918 et seq, H.v. Czetsch-Lindenwald, Hilfsstoffe fur Pharmazie and angrenzende Gebeite; Pharm. Ind., No. 2, 1961, pages 72 et seq; Dr. H. P. Fiedler Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete Cantor KG. Aulendorf (Wurtt). 1971.

Examples include gelatin, natural sugars, such as cane sugar or lactose, lecithin, pectin, starch (for example corn starch), alginic acid, tylose, talcum, lycopodium, silica (for example colloidal silica), cellulose, cellulose derivatives (for example cellulose ethers in which the cellulose hydroxy groups are partly etherified with lower saturated aliphatic alcohols and/or lower saturated aliphatic hydroxy alcohols, for example methyl hydroxy propyl cellulose), stearates, magnesium and calcium salts of fatty acids with 12 to 22 carbon atoms, especially the saturated fatty acids (for example stearates), emulsifiers, oils and fats, especially vegetable oils and fats (for example eanut oil, caster oil, olive oil, seasame oil, cottonseed oil, corn oil, wheat germ oil, sunflower seed oil, cod liver oil, mono-, di- and tri-glycerides of saturated fatty acids C,2H2402 to C18H36O2 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 (2 to 22 carbon atoms, especially- 10 to 18 carbon atoms) with monohydric aliphatic alcohols (1 to 20 carbon atoms) or polyhydric alcohols, such as glycols, glycerol, diethylene glycol, pentaerythritol, sorbitol, and mannitol which optionally may be etherified, benzyl benzoate, dioxolanes, glycerol formals, tetrahydrofurfuryl alcohol, polyglycol ethers with C1-C12-alcohols, dimethyl acetamide, lactamides, lactates, ethyl carbonates, silicones (especially mediumviscosity dimethyl polysiloxanes) and magnesium carbonate.

Solutions can be prepared, for example, with water or physiologically compatible organic solvents, such as for example 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 ester, such as sorbitan trioleate, lecithin, acacia, tragacanth, polyoxyethylated 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 with a degree of polymerisation of from 2 to 40, more particularly from 10 to 20.

Polyoxyethylated substances of this kind can be obtained for example by reacting compounds containing hydroxyl groups (for example monoglycerides of 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, and corn oil (see also Dr. H. P. Fiedler "Lexikon" der Hilfsstoffe fur Pharmazie, Kosmetic and 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, anti-oxidants and complex formers (for example ethylene diaminotetraacetic acid).

To stabilise the active principle molecule, 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-value 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, ascorbin acid, phosphoric acid). Addition of the synergists greatly increases the antioxygenic effect of the tocopherols.

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

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

The active principles or medicaments may be applied to the skin or mucosa or into the interior of the body, for example orally, enterally, polmonarily, rectally, nasally, vaginally, lingually, intravenously, intraarterially, intracardially, intramuscularly, intraperitoneally, intracutaneously or subcutaneously.

In particular, the addition of other medicinally active principles, above all cardiac glycosides, xanthines, thrombocyte aggregation blockers or nicotinic acid, is also possible and favourable.

In anaesthetised, mixed-breed dogs, the compounds according to the invention produce a marked and lasting increase in peripheral circulation, as measured with electromagnetic flow meters. At the same time, the heart rate volume (cold dilution method) is considerably increased. In the above-mentioned test, a dose of for example 0.1 mg per kg of dog body weight produced an average increase in circulation through the Arteria femoralis of 47% over a period of 1 hour. In the same test, the heart rate volume increased by 39% on an hourly average. This vasodilating effect is comparable with the effect of the known medicament Isoxsuprine.

The lowest effective vasolidating dose in the animal test mentioned above is 0.05 mg/kg (if the compounds are applied intravenously) and 1 mg/kg (if the compounds are given orally).

General dose ranges for the vasolidating effect (in the above animal test) are for example from 1 to 30 mg/kg (oral), particularly 10 mg/kg and from 0.1 to 3.0 mg/kg (intravenous), particularly 0.3 mg/kg.

Indications for which the compounds according to the invention may be considered include peripheral circulation disorders such as: Morbus Raynaud, arteriosclerotic vascular diseases, Ulcus cruris Claudicatio intermittens, diabetic angiopathy, apoplexy and post-apoplectic conditions, tropic disorders attributable to ageing: also hypertonia, particularly in conjunction with diuretics.

The pharmaceutical preparations generally contain from 5 to 50 mg of the active component(s) according to the invention.

The active component(s) according to the invention may be administered in the form of tablets, capsules, pills, dragees, suppositories, ointments, jellies, 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 from 10 to 50 mg or solutions containing from 1 to 5% of active substance.

The individual dose of the active components according to the invention may amount, for example, to a) from 10 to 50 mg in the case of oral formulations b) from 5 to 20 mg in the case of parenteral formulations (for example intravenous or intramuscular) c) from 3 to 10 mg in the case of formulations intended for inhalation (solutions or aerosols) (in each case the doses are based on the free base).

For example, 1 to 3 tablets containing from 20 to 100 mg of active substance may be prescribed three times daily or, in the case of intravenous injection for example a 1 to 10 ml ampoule containing from 3 to 30 mg of substance may be prescribed 1 to 3 times daily. In the case of oral administration, the minimum daily dose is 50 mg for example whilst the maximum daily dose should not exceed 2 g.

In the treatment of dogs and cats, the oral individual dose is generally from 5 to 20 mg/kg of body weight; the parenteral dose is from 0.3 to 1.0 mg/kg of body weight.

The acute toxicity of the compounds according to the invention in mice (expressed by the LD 50 mg/kg; Miller and Tainter's method: Proc. Soc. Exper.

Biol. a. Med. 57 1944) 261) is from 200 to 800 mg/kg for example in the case of oral application (in some cases it is above 1200 mg/kg.) The medicaments may be used in human medicine, veterinary medicine and agricultural medicine either on their own or in admixture with other phamacologically active substances.

The starting compounds of formula II may be obtained by reacting thien (3) - yl or thien - (2) - yl lithium with a compound corresponding to the formula

in which Alk is a linear or branched C1-C5-alkylene group, preferably a linear C1-C3-alkylene group, Z is an alkoxy group having up to 6 carbon atoms, preferably upto 4 carbon atoms, chlorine, bromine, iodine, or a thienyl radical, and Hal is chlorine, bromine or iodine, in an inert medium at a low temperature, preferably below -50"C. The compounds of formula II is formed in a yield of, for example 96% of the theoretical.

By contrast, hitherto known reactions of this type, for example of thien - (3) yl lithium with a) - phenylethylamino - propionic acid esters (see German Patent Specification No. 1,921,453) do not take the place uniformly and the required dithien - (3 - yl compound can only be isolated in yields of at most 30 /O. In particular, other thienyl isomers are always formed in relatively large quantities. In addition, separation of the required dithienyl compound from the other reaction products and its purification are extremely difficult and can only be carried out, for example, by complicated and elaborate recrystallisation several times in combination with treatment with active carbon.

In one embodiment of the process of the present invention, a compound corresponding to the general formula

in which X represents chlorine, bromine or iodine, is condensed with a hydroxy phenyl aklanolamine corresponding to the general formula

in which R" is as defined above and the phenolic hydroxy group may be substituted by a C2-C6-alkanoyl group, and optionally the compounds corresponding te general formula (IA) in which > A-B-= > C(OH)-CH2-, are converted into the corresponding unsaturated compounds ( > A-B-= > C-CH-) with a dehydrating agent and optionally a salt is produced from the basic compound obtained.

Preferably, a mixture obtained by reacting thien - (3) - yl or thien - (2) - yl lithium with a compound corresponding to the formula

in which Z is a lower alkoxy group, chlorine, bromine, iodine, or a thienyl radical, and Hal is chlorine, bromine or iodine, optionally after removal of solvent, is used as the starting material (IIA).

In general formula IV, the radical Z is in particular an alkoxy group with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms, which may be branched or chlorine or bromine. However, Z can also be a thien - (2) - yl radical or a thien (3) - yl radical.

The reaction of the thienyl lithium compound, especially thien - (3) - yl lithium, with compound IV preferably takes place in an inert solvent mixture liquid at -800C consisting of a saturated ether and a saturated hydrocarbon and/or a mono- or di- C1-C4-alkyl benzene. Suitable halogen C3-C7-alkane carboxylic acid esters are for example halogen propionic acid esters, butyric acid esters or valeric acid esters.

If the solvent mixture consists of an ether and a saturated hydrocarbon, from 0,3 to 3 parts bv volume and preferably from 0.8 to 3 parts by volume of ether are used for example to 1 part by volume of hydrocarbon. If the solvent mixture consists of an ether and a monoalkyl or dialkyl benzene, from 0.1 to 3 parts by volume and preferably from 0.2 to 1 part by volume of ether are used for example to 1 part by volume of alkyl benzene. If the solvent mixture consists of the three components ether, saturated hydrocarbon and alkyl benzene, the ratio in which the three components are mixed is, for example 0.l-0.9:0.l-0.9:0.l-0.9.

Suitable saturated ethers are, in particular, aliphatic symmetrical or asymmetrical dialkyl ethers, the alkyl groups preferably consisting of 1 to 6 carbon atoms and being, for example, methyl, ethyl isopropyl, propyl, isobutyl or butyl.

Other suitable ethers are, for example, C1-C6-alkyl ethers of saturated cycloalkanols and alkyl-substituted cycloalkanols, the cycloalkanol rings each consisting of 3, 4, 5 or 6 carbon atoms. The ethers are preferably liquid at temperatures in the range from -80 to +200 C.

The saturated hydocarbons are preferably aliphatic or cycloaliphatic hydrocarbons which are liquid at temperatures in the range from -80 to +200C and which may contain for example from 5 to 9 and preferably 6 or 7 carbon atoms and may be branched. The cycloaliphatic hydrocarbons are preferably substituted once or even several times (twice, three times), by C1-C4-alkyl radicals, especially methyl, ethyl or propyl radicals, the number of ring atoms amounting to 3, 4, 5, 6 or 7. The saturated alkyl radicals which may be used as substituents for the benzene are methyl, ethyl propyl, isopropyl, butyl, isobutyl, tert.-butyl, I-methyl propyl.

Examples of the solvents which may be used are diethyl ether, diisopropyl ether, methyl cyclopentyl ether, hexane, cyclohexane, toluene, xylene, methyl cyclohexane, methyl cyclopentane, ethyl cyclohexane and dimethyl cyclohexane.

It is of advantage to add compound (IV), particularly when it is a halogen alkane carboxylic acid ester, as such or in the form of a solution in the hydrocarbon and/or ether (for example diisopropyl ether and/or toluene) to the thienyl lithium, such a thien - (3) - yl lithium, precooled to the reaction temperature and then to keep the reaction mixture at the reaction temperature for about 1 to 4 hours.

Thereafter water for example is added to the reaction solution, optionally after heating to -20 to +200 C. The organic phase is dried (MgSO4 or NaSO4) and concentrated by evaporation under reduced pressure. The crude l,l-bis[thien-(3or 2)-yl]-3-halogenoalkanol thus obtained may be used without further purification for the reaction with the amine of formula III. The thienyl lithium compound, for example thien-(3 or 2)-yl lithium, is generally produced beforehand from 3-bromo or 2-bromothiophene or from 3-iodo or 2-iodothiophene in an ether and a C1-C5- alkyl lithium or aryf fithium compound in an ether/hydrocarbon mixture, the ethers and hydrocarbons already mentioned (including the alkyl benzenes) being suitable for this purpose (dialkyl ether being particularly preferred as the ether component.

The alkyl radical of the alkyl lithium compound may be linear or branched.

Examples of 1--1.5:1 or ether and alkylbenzene in a ratio of 0.2--0.5:1 (coricentration of the lithium compound from 5 to 30 /O by weight) and cooled to a temperature below 700 C, in such a way that the temperature does not exceed -70"C. The reaction component of formula (IV) is then added, for example, in the form of a 10 to 100% solution (% by weight) in one of the above-mentioned dialkyl ethers or alkyl benzenes, again in such a way that the temperature does not exceed -70"C.

In one preferred embodiment of the above process the reaction is carried out in a solvent mixture of toluene and diisopropyl either and, after the reaction mixture has been hydrolysed, the organic phase is subjected to fractional vacuum distillation, the low-boiling constituents of the mixture, such as diisopropyl ether, thiophene and butyl bromide, together with some of the toluene used being removed overhead, whilst a solution of 1,1 - bis[thien - (3 or 2) - yl]-w-halogenoalkano1 in toluene is recovered as sump residue and is directly introduced into the next stage of the process.

The reactants may be used for example in the following molar ratios: thienyl lithium: compound (IV)=2.04.0: 1.

Based on lithium alkyl and bromo- or iodothiophene, the following molar ratio for example may be applied: alkyl lithium compound: bromo(iodo)thiophene: compound (IV=2.5-5.0:2.04.0: 1, more especially 2.Q--5.0:2.00-4.0:1.

The reaction temperature should never exceed -50"C. It is of advantage to carry out the reaction at a temperature of from -65"C to -750C, the reaction preferably being carried out at a temperature below -70"C, for example at a temperature of from -80 C to 700 C.

The resulting l,l-bis[thien-(3 or 2)-yl-o-halogenalkanol of formula II may be reacted with compound III directly, i.e. without further purification. This reaction may be carried out in the presence or absence of solvent or suspending agent.

Suitable inert solvents or suspending agents are for example, the same solvents or suspending agents which are used for the reaction of the thienyl lithium with compound IV, for example diisopropyl ether and toluene. In addition it is also possible for example to use other alkyl and dialkyl benzenes, dialkyl ethers, aliphatic ketones and aliphatic and cycloaliphatic alcohols. It is also possible directly to react the reaction mixture, in which the compound of formula II is formed with compound III. Since a reaction mixture such as this still contains the alkyl halide formed during the reaction, it may be necessary to use a corresponding excess of compound III.

The derivatives obtained from the intermediate compound of formula II produced as described above are substantially isomer-free and are obtained in satisfactorily pure form after a single recrystallisation.

The invention is illustrated by the following Examples.

EXAMPLE I [1,1 -Dithien-3-yl- 1 -hydroxy-3-propyl]-[ 1 ,hydroxy- 1 (p-hydroxyphenyl)-2-propyl] -amine 25 g (0.15 mole) of p-hydroxy norephedrin, 22.5 ml of triethylamine and 45.5 g (0.15 mole) of l,l-dithien-3-yl-3-bromo-l-propanol are heated with stirring for 8 hours to 1000C in 80 ml of dioxane. The mixture is then largely concentrated in a rotary evaporator, 150 ml of water are added to the residue which is then extracted by shaking three times with 100 ml of diethyl ether. The combined ethereal extracts are dried with magnesium sulphate. After a few hours at OOC, a pale coloured substance crystallises out and is recrystallised from acetone. 15 g of colourless crystalline substance are obtained. M.p.: 174--175"C.

Hydrogen maleate To prepare this salt, 5.0 g of the base are suspended in 30 ml of ethyl acetate.

Following the addition of 1.5 g of maleic acid, a clear solution is formed to which diethyl ether is added until it just begins to cloud. After standing for 12 hours, the crystallisate is filtered off under suction, washed with ethyl acetate and dried: 4.0 g of hydrogen maleate. M.p.: 108--109"C.

Production of the starting material 1, l-dithien-3-yl-3-bromo- l-propanol: In a 1.5 litre four-necked flask equipped with a dropping funnel, a drying tube, a stirrer, a thermometer and an inlet for nitrogen, 300 ml of absolute diisopropyl ether are cooled under nitrogen with a cooling bath of methanol and dry ice.

During cooling a 15% solution of 335.2 ml of n-butyl lithium in hexane (0.55 mole) is added and the mixture cooled to -750C. A solution of 81.5 g of 3-bromothiophene (0.5 mole in 100 ml of absolute diisopropyl ether is then added dropwise over a period of 90 minutes in such a way thata temperature of 700C is not exceeded. The reaction mixture is then left to afterreact for 1 hour at -700C to -750C. A solution of 36.2 g of p-bromopropionic acid ethyl ester (0.2 mole) in 60 ml of absolute diisopropyl ether is then added dropwise over a period of 90 minutes in such a way that a temperature of -70"C is not exceeded. The reaction mixture is then left to react for another 4 hours. The cooling bath is then removed and 160 ml of water are added to the reaction mixture. The temperature rises to --200C. The reaction mixture is then stirred for a while until the temperature has risen above 0 C, after which the organic phase is separated off, dried with MgSO4, filtered and all the lowboiling constituents are distilled off in vacuo in a rotary evaporator. A light oil is obtained as residue. Yield: 54 G (96% of the theoretical, based on the bromopropionic acid ester).

1.1 -dithien-3-yl-4-bromo- 1 -butanol and 1,1 -dithien-3-yl-5-bromo- 1 -pentanol are similarly obtained in the form of light oils.

EXAMPLE 2 Preparation of [1, l-dithien-3-yl-l -hydroxy-3-propyl] [I -hydroxy-l -p- hydroxyphenyl)-2-propyll-amine (compound code 14020) corresponding to the formula:

The compound is obtained as follows: 0.1 mole of 1,1 -dithien-3-yl-3-bromo- l-propanol, 0.11 mole of triethylamine and 0.1 mole of primary amine are heated under reflux with stirring for 12-15 hours in 60 ml of diisopropylether. After cooling, the crystallisate is filtered off under suction, washed with diisopropyl ether and dried. The product is then suspended in water, filtered under suction, washed with water, dried, recrystallised and the maleic acid salt optionally produced in the same way as in Example 1. The solvent from which the salt was recrystallised was methanol.

Compound 14020 was obtained in a yield of 42%. (M.p. of base: 165166 ) EXAMPLE 3 [1,1 -dithien-3-yl- 1 -propen-3-yl]-[ 1 -hydroxy- 1 -(p-hydroxy phenyl)-2-propyl]-amine 25 g (0.15 mole) ofp-hydroxy norephedrine, 22.5 ml of triethylamine and 45.5 g (0.15 mole) of 1,1-dithien-3-yl-3-bromo-(1)-propanol are heated with stirring for 8 hours to 100"C in 80 ml of dioxane. The mixture is then largely concentrated in a rotary evaporator and the syrupy residue is digested twice with 250 ml. of diethyl ether. The combined ethereal solutions are acidified with isopropanolic HCI, as a result of which a highly viscous product is precipitated. After the solvent has been poured off, the residue is taken up in 100 ml of ethanol, followed by boiling under reflux for 10 minutes. The solution is then concentrated in a rotary evaporator. The residue is dissolved in 100 ml of warm acetone from which the substance slowly crystallises out after cooling. Recrystallisation from isopropanol gives the hydrochloride of the compound in the form of colourless crystals. M.p. of the hydrochloride: 138--140"C. Yield: 10.2 g.

EXAMPLE 4 Preparation of 1,1 -dithien-3-yl-alklene-yl-amines corresponding to the formula

For meaning of -Q and Alk, see Table 1 The compounds listed in Table 1 are obtained as follows: 0.1 mole of the following amine

For meaning of -Q and Alk, see Table 1 are dissolved in 50 ml. of methanol, followed by the addition of a 10% excess of the quantity of isopropanolic HCI required for salt formation, of which the concentration should be between 5 and 7 moles per litre. The reaction mixture, is heated under reflux for 20 to 30 minutes. After cooling, the compounds crystallise out in abundance. Should this not happen, diethyl ether is added to the solution until permanent clouding occurs. The reaction product then separates out, generally in crystalline form.

Preferred solvents for recrystallisation are methanol, ethanol and isopropanol.

TABLE 1

M a oo Irr 70 1 1 which the t7aw Amine component salt was m.p. of ,.

Code -Q Alk Salt recrystallised salt CH3 13800 -N 'HMOH HCl methanol 2l2ll0 68 OH CH2)2 CH3 N -NH-cH-cH/\oH -(CH2)3- HCl methanol l77l780 15 I- diethyl ether OH w 1 Pharmaceutical compositions including compounds according to the invention are illustrated by the following Examples.

EXAMPLE A (Capsules) The following raw materials are required for a batch of 500,000 capsules: 1. Active compound 10.0 kg Lactose 60.0 kg Microcrystalline cellulose 58.8 kg Magnesium stearate 1.2 kg 130.0 kg II. 500,000 gelatine capsules, size 2 Production 1) An active compound is size-reduced in an air-jet mill with dust protection to such an extent that the particles have the following particle size: at least 50% 5 ,am the rest 10 ym the active compound micronised.

2) All the raw materials required for producing the capsule material are passed through a 1.5 mm mesh screen. Thereafter 58.8 kg of microcrystalline cellulose and 10 kg of an active compound (micronised) are mixed for 1 hour in a Turbula mixer rotating at 10 r.p.m. 60 kg of lactose and 1.2 kg of magnesium stearate are added to the mixture, followed by mixing another 45 minutes.= capsule filing.

3) The capsule filling is introduced into size 2 gelatine capsules. Quantity of filling per capsule: 260 mg.

EXAMPLE B (suppositories) Production 20 g of an active compound are incorporated into 1980 g of molten suppository material (for example solid fat DAB 7) after which the melt is introduced in known manner into moulds for 2.0 g suppositories. 1 suppository contains 20 mg of the active compound.

Claims (17)

WHAT WE CLAIM IS:

1. A compound corresponding to the general formula:

wherein > AB represents either > C(OHCH2- or > C=CH-, Alk represents a straight-chain or branched-chain C1-C5-alkylene group, R represents a hydrogen atom or a C1-C4-alkyl group, and the phenolic hydroxy group may be substituted by a C2-C6 alkanoyl group, and the salts thereof.

2. A compound corresponding to the general formula:

wherein > A-B- represents either > C(OH)-CH2- or > C=CH- and R" represents a hydrogen atom or a C1-C4 alkyl group and the salts thereof.

3.[l,l -Dithien -(3) -yl -l -hydroxy -(3) -propyl]-[l hydroxy -l -(p - hydroxyphenyl) - (2) - propyl] - amine.

4 [1,1 - Dithien - (3) - yl - 1 - propen - (3) - yl - ] - [hydroxy - 1 - (p hydroxy phenyl) - (2) - propyl] - amine.

5. A compound as claimed in claim 1 substantially as described with particular reference to any one of the Examples.

6. A process for the production of compounds corresponding to the general formula (1) as defined in claim 1, or a salt thereof, which comprises condensing a compound corresponding to the general formula

in which Alk is a straight chain or branched-chain C1-C5-alkylene group and X is chlorine, bromine or iodine, with an amine corresponding to the general formula:

wherein R is defined as in Claim 1 and the phenolic hydroxy group may be substituted by a C2-C6-alkanoyl group and compounds corresponding to general formula (I), in which > A-B= > C(OHCH2-, are optionally converted into the corresponding unsaturated compounds ( > A-B-= > C=CH-) by reaction with a dehydrating agent or are acylated on the phenolic hydroxy group by reaction with an aliphatic C2-C6-carboxylic acid and a salt is optionally produced from the basic compounds obtained.

7. A process as claimed in Claim 6, wherein a reaction mixture obtained by reacting thien - (3) - yl or thien - (2) - yl lithium with a compound corresponding to the formula

in which Alk is a linear or branched C1-C5-alkylene group, Z is an alkoxy group having upto 6 carbon atoms, chlorine bromine, iodine or a thienyl radical, and Hal is chlorine, bromine or iodine, optionally after removal of solvent, is used as starting material (II).

8. A process for the production of a compound as claimed in claim 2 or a salt thereof which comprises condensing a compound corresponding to the general formula

in which X represents chlorine, bromine or iodine, with a hydroxy phenyl alkanolamine corresponding to the general formula

in which R" is as defined in claim 2 and the phenolic hydroxy group may be substituted by a C2-C6-alkanoyl group, and optionally converting compounds as claimed in claim 2 in which > A-B-= > C(OH)-CH2-, into the corresponding unsaturated compounds ( > A-B-= > C-CH-) with a dehydrating agent and optionally producing a salt from the basic compound obtained.

9. A process as claimed in claim 8 wherein a mixture obtained by reacting thien - (3) - yl or thien - (2) - yl lithium with a compound corresponding to the formula

in which Z is a lower alkoxy group, chlorine, bromine, iodine, or a thienyl radical, and Hal is chlorine, bromine or iodine, optionally after removal of solvent, is used as starting material (IIA).

10. A process as claimed in claim 6 substantially as herein described with particular reference to any one of the Examples.

11. A process as claimed in claim 8 substantially as herein described with particular- reference to either Example 1 or 3.

12. A compound of formula (I) as defined in claim I when produced by a process as claimed in claim 6, 7 or 10.

13. A compound as claimed in claim 2 when produced by a process as claimed in claim 8, 9 or 11.

14. A medicament containing as active principle a compound as claimed in claim 1 or 12 together with at least one pharmacologically acceptable excipient and/or diluent.

15. A medicament containing as active principle a compound as claimed in any of claims 2 to 5 or 13 together with at least one pharmacologically acceptable excipient and/or diluent.

16. A process for producing a medicament which comprises processing a compound as claimed in claim 1 or 12 with at least one pharmaceutically acceptable excipient and/or diluent to form a pharmaceutical preparation.

17. A process for producing a medicament which comprises processing a compound as claimed in any of claims 2 to 5 or 13 with at least one pharmaceutically acceptable excipient and/or diluent to form a pharmaceutical preparation.