NO170853B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 4-PHOSPHONOALKENYL PIPERIDINE-2-CARBOXYL ACIDS - Google Patents

Abstract

Compounds of the formula I <IMAGE> in which one or both of the acidic hydroxyl groups of the phosphonic acid part can be etherified, m is one or zero, R<1> denotes carboxyl, esterified carboxyl or amidated carboxyl, the heterocyclic five- or six-membered ring can additionally be substituted on the carbon and/or nitrogen, can have a carbon-carbon double bond or can be condensed with a carbocyclic 6-membered ring, starting from adjacent carbon atoms, A represents lower alkenylene; and salts thereof. These compounds are suitable as antagonists of the N-methyl-D-aspartate- sensitive amino acid stimulant receptor in mammals.

Description

The present invention relates to an analogous process for the production of therapeutically usable 4-phosphonopropenyl-piperidine-2-carboxylic acids of formula I

where Å means 1,3-propenylene, and their pharmaceutically usable salts.

The invention primarily relates to the preparation of compounds of formula I where the 2- and 4-substituents are in the cis position to each other and salts thereof.

Salts of the compounds produced according to the invention are preferably pharmaceutically acceptable salts, on the one hand metal or ammonium salts of compounds of formula I with a free phosphonic or carboxy group, especially alkali or alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, or advantageously crystallising ammonium salts, derived from ammonia or organic amines, such as methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris-(hydroxymethyl)aminomethane or benzyltrimethylammonium hydroxide. On the other hand, compounds produced according to the invention which are basic amines form acid addition salts with preferably pharmaceutically acceptable, inorganic or organic acids, such as with strong mineral acids, such as, for example, halogenated acids, e.g. hydrochloric or hydrobromic acid, sulfuric, phosphoric or nitric acid, aliphatic or aromatic carboxylic or sulphonic acids, e.g. acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, ascorbic acid, maleic acid, fumaric acid, pyruvic acid, pamoic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic or naphthalene sulfonic acid.

For isolation or purification purposes, salts can be obtained, which are not suitable for pharmaceutical purposes. However, pharmaceutically acceptable salts are preferably used for therapeutic purposes, and these salts are therefore preferred.

The compounds produced according to the invention exhibit valuable pharmacological properties, e.g. a selective blockade of N-methyl-D-aspartate-sensitive amino acid decoy receptors in mammals. The compounds are therefore suitable for the treatment of diseases involving an amino acid blockade in mammals, for example diseases of the nervous system, especially convulsive diseases (epilepsy) and anxiety states.

These effects can be demonstrated in in vitro experiments or in vivo animal experiments, whereby mammals or tissue or enzyme preparations from these are preferably used, e.g. mice, rats or monkeys. Said compounds can be administered enterally or parenterally, advantageously orally or transdermally, or also subcutaneously, intravenously or intraperitoneally, for example in gelatin capsules or in the form of aqueous suspensions or solutions. The administered in vivo dose may lie approximately between 0.01 and 100 mg/kg, preferably between 0.05 and 50 mg/kg and advantageously approximately between 0.1 and 10 mg/kg.

The inhibitory effect on the NMDA-type amino acid irritation receptors is demonstrated in vivo by the inhibition of NMDA-induced convulsions in mice.

Representative compounds of the invention prevent NMDA-induced seizures in mice at doses down to about 1.2 mg/kg i.p.

A further sign of the anticonvulsant activity consists in the fact that the compounds produced according to the invention effectively prevent audiogenically triggered seizures in DBÅ/2 mice [Chapman et al., Arzneim.-Forsch. 34» 1261, (1984)].

The effect is determined in the following way: 45 minutes after administration of the compound or the carrier, the mice enter individually into a soundproof chamber. After a habituation period of 30 seconds, the mice are exposed for 1 minute to a sound irritation of 110 db, or until a tonic-clonic seizure occurs. The control bouts consist of an initial Ise phase with a wild run. The prevention of the wild run is a sign of an anticonvulsant effect.

Test compounds are administered either as a solution in distilled water or as a suspension in a 3-#ig colloidal corn starch with 5 wt# polyethylene glycol 400 and 0.34# Tween 80 orally or intraperitoneally in an amount of 10 ml/kg body weight.

A sign of anxiolytic activity is the fact that the compounds produced according to the invention are effective in the Cook/Davidson conflict model [Psychopharmacologia 15, 159-168 (1969)].

The cerebral anti-ischemic activity, i.e. the efficacy of the compounds of formula I in preventing or reducing brain damage in mammals resulting from transient cerebral ischaemia (such as in a stroke) can be determined using the Mongolian "Gerbil-Ischaemie" model, e.g. that model, which is described by T. Kirino in Brain Research 239, 57-69 (1982).

The inhibitory effect on the observed hyperactivity and on the degeneration of neurons in the Hippocampus area of the brain in connection with a five-minute ischemia is measured. The test compound is added i.p. 15 minutes before ischemia or 2, 4 and 5 hours after ischemia.

Representative compounds of the invention, administered before or after the ischemia episode at a dose of 10 mg/kg i.g., inhibit the ischemia-induced hyperactivity of gerbils and reduce the degeneration of cerebral neurons, as measured in the hippocampus region of the brain .

The above-mentioned advantageous properties show that the compounds produced according to the invention are usable as antagonists to the N-methyl-D-aspartate-sensitive amino acid irritation receptor in mammals and for the treatment of conditions in connection with this, such as for example anxiety states and convulsive disorders.

The above-mentioned advantageous properties mean that the compounds of formula I seem useful as antagonists of the N-methyl-D-aspartate-sensitive amino acid decoy receptor in mammals and for the treatment of corresponding conditions, such as anxiety states and convulsive disorders.

Corresponding 4-phosphonopropylpiperidine-2-carboxylic acids are known from the previously published Greek patent no. 861337. Compared to these, the compounds of formula I show a stronger and more prolonged anticonvulsant effect. Accordingly, comparative experiments with cis-4-(3-phosphonopropen-1-yl)piperidine-2-carboxylic acid (I) according to subsequent Example 3 with cis-4-(3-phosphonopropyl)piperidine-2-carboxylic acid (II) according to example 4f in GR-861337 on mice the following EDsø values for the protective effect against convulsions, experimentally induced by electroshock:

The compounds of formula I, i.e. those listed above, are prepared according to the invention by means of conventional methods, e.g. by

Using conventional methods, e.g. by

(a) condensation of an aldehyde of formula II

where means lower alkoxycarbonyl and R2 means lower alkanoyl or lower alkoxycarbonyl and A' means oxoethyl, with a tetralower alkyl ester of methylene diphosphonic acid under basic conditions or

(b) condensation of a compound of formula III

where A means 1,3-propenylene and where R^ means lower alkoxycarbonyl and R 2 means lower alkanoyl or lower alkoxycarbonyl and X stands for reactive esterified hydroxy, with a compound of formula where R' means lower alkyl, and transfer of the obtained compound of formula V

where A means 1,3-propenylene and where R and R' stand for lower alkyl, R^ means lower alkoxycarbonyl and R 2 means lower alkanoyl or lower alkoxycarbonyl, by treatment with an inorganic acid or with aqueous alkali, to the corresponding compound of formula I, and if the desired conversion of the free compound formed into a salt or a salt formed into the free compound or another salt.

Reactive, esterified hydroxide is esterified with a strong acid, especially a hydrohalic acid, for example hydrochloric acid, hydrobromic or hydroiodic acid or sulfuric acid or a strong organic acid, especially a strong organic sulphonic acid, such as an aliphatic or aromatic sulphonic acid, e.g. methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid. Said reactive, esterified hydroxy are particularly halogen, e.g. chloro-, bromo- or iodo-, or aliphatic or aromatically substituted sulphonyloxy, e.g. methanesulfonyloxy, phenylsulfonyloxy or 4-methylphenylsulfonyloxy (tosyloxy).

Therefore, in the starting compounds and intermediates, which are converted into the compounds of formula I in the manner described here, present functional groups such as carboxy, amino (including ring-NH) and hydroxy groups are protected if desired with conventional protecting groups, such as those commonly in preparative organic chemistry. Protected carboxy, amino and hydroxy groups are those which, under mild conditions, can be converted into free carboxy, amino and hydroxy groups, without the molecular skeleton being destroyed or other unwanted side reactions taking place.

The purpose of introducing protective groups is to protect the functional groups against unwanted reactions with the reaction components and under the conditions under which a desired chemical transformation is carried out. The necessity of protecting groups and their choice for a particular reaction is known to the person skilled in the art and depends on the nature of the functional groups to be protected (carboxy group, amino group, etc.), further on the structure and stability of the molecule, whose component the substituent is, and of the reaction conditions.

Commonly known protecting groups corresponding to these conditions, as well as their introduction and removal are described, for example, in J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, New York 1973, T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981 and also in "The Peptides", Vol. I, Schroeder und Luebke, Academic Press, London, New York 1965 as well as in Houben-Weyl, "The Method of Organischen Chemie", Vol. 15/1, Georg Thieme Verlag, Stuttgart, 1974.

The preparation of the compounds of formula I, in which the double bonds are close to the phosphono group, is carried out according to method (a), according to which an aldehyde is condensed with, for example, a lower alkyl ester of methylene diphosphonic acid, carried out according to the method, which is known to those skilled in the art for such condensations, in the presence of a strong, anhydrous base, e.g. butyllithium, in an inert, polar solvent, such as tetrahydrofuran, preferably under reflux. The starting aldehydes or ketones with formula VII can e.g. are produced by oxidation of the corresponding alcohols, for example with pyridinium chlorochromate, or according to other methods, as they are described, e.g. in the examples.

The alcohols in question can in turn be produced in a manner known per se, e.g. by reduction of the corresponding aromatic alcohols using methods known in the art for the reduction of pyrrole, pyridine, indole and quinoline compounds. For example, the reduction of the pyridine or quinoline ring is preferably carried out with an organometallic reducing agent or by catalytic hydrogenation, e.g. in the presence of platinum oxide and an acidic solvent, such as acetic acid, so that the corresponding piperidines of formula I are obtained.

The alcohols or aldehydes obtained in this way can also be transferred to aldehydes with a longer chain length, whereby conventional methods can be used, e.g. by means of a Wittig condensation of an aldehyde with methoxy-methyltriphenylphosphonium chloride, whereby the homologous aldehyde is obtained, and by other reaction sequences known in and of themselves, such as those e.g. are described in the examples.

The above-mentioned aromatic 2-carboxy-heterocyclyl-substituted lower alkanols, for example the 2-carboxy-pyridinyl-substituted lower alkanols or their derivatives can in turn be prepared by the 2-unsubstituted pyridinyl-substituted lower alkanols, which are present in suitable protected form, is treated, for example, with a peracid, such as m-chloroperbenzoic acid, so that the corresponding pyridine N-oxides are obtained. Condensation with a reactive cyanide, e.g. a trialkylsilyl cyanide such as trimethylsilyl cyanide, preferably under basic conditions, e.g. in the presence of triethylamine, gives the corresponding 2-cyanopyridine derivatives, which are then, again in a manner known per se, transferred to the 2-R<1->(carboxy, esterified or amidated carboxy)-substituted pyridine derivatives.

The condensation according to method b) of a compound of formula III with a compound of formula IV, e.g. triethyl phosphite, is carried out, for example, by heating in an inert solvent and under the conditions known for a Michaelis-Arbuzov reaction according to Angew. Chem. Int Ed. 16, 477 (1977) and Chem. Fox. 81. 415 (1981).

The starting compounds of formula III and reactive derivatives thereof can be prepared in a manner known per se, starting from intermediate products of formula II, as described above.

Some of the terms used in the methods have the meanings set out below.

Lower alkyl which is substituted by oxo preferably means formyl, formylmethyl, formylethyl or 2-oxo-propyl.

Trialkoxymethyl preferably denotes tri-(lower alkoxy)methyl, especially triethoxy or trimethoxymethyl.

Ethered hydroxymethyl preferably denotes lower alkyloxymethyl, lower alkoxyalkyloxymethyl, e.g. methoxymethoxymethyl or 2-oxa- or 2-thiacyclo-alkoxymethyl, especially 2-tetrahydropyranyloxymethyl.

Halomethyl refers in particular to chloromethyl, but can also be bromomethyl or iodomethyl.

An alkali metal preferably denotes lithium, but may also be potassium or sodium.

Thus, for example, the conversion of carboxylic acid esters to carboxylic acids is carried out advantageously by hydrolysis with inorganic acids such as, for example, a hydrohalic or sulfuric acid or with aqueous alkali, preferably alkali metal hydroxides such as lithium or sodium hydroxide. The phosphonic acid ester is converted to the corresponding phosphonic acids by treatment with an acid such as aqueous hydrochloric acid or hydrobromic acid in glacial acetic acid or with bromotrimethylsilane according to J. Chem. Soc. Chem. Comm. 1979. 739.

In a preferred embodiment of the invention, a compound of formula V is transferred by treatment with a hydrohalic acid or sulfuric acid, especially hydrochloric acid, or with aqueous alkali metal hydroxides, especially lithium or sodium hydroxide, preferably at elevated temperature, to a compound of formula I.

The aforementioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably those which are inert towards the reaction participants and are solvents for them, further by catalysts, by condensation or other mentioned agents and/or in an inert atmosphere, by low temperatures, room temperature or elevated temperatures, preferably at the boiling point of the solvent used and at atmospheric or above-atmospheric pressures. The preferred solvents, catalysts and reaction conditions are stated in the subsequent, clarifying examples.

Depending on the choice of starting materials and methods, the new compounds can exist in the form of a possible isomer or as a mixture thereof, for example depending on the number of asymmetric carbon atoms as pure optical isomers as antipodes or mixtures of optical isomers or racemates or as mixtures of diastereoisomers or geometric isomers . The aforementioned possible isomers and their mixtures belong to the scope of the present invention. Different, particular isomers are preferred, as already mentioned above.

Obtained mixtures of diastereoisomers or mixtures of racemates can, due to the physicochemical differences between the components, be divided into pure isomers, diastereoisomers, racemates or geometric isomers in a known manner, for example by chromatography and/or fractional crystallization.

Obtained racemates can be divided into the optical antipodes using known methods, for example by reaction between an acidic end product and an optically active base, which forms salts with the racemic acids, and division of the salts thus obtained, for example by fractional crystallization, into the the diastereoisomeric salts, from which the optically active, free carboxylic or phosphonic acid antipodes can be released after acidification. The basic, racemic products can also be divided into the optical antipodes, e.g. by splitting the diastereoisomeric salts thereof with an optically active acid and liberating the optically active basic compound by treatment with a standard base. Racemic products prepared according to the invention can also be divided into their optical antipodes, e.g. by fractional crystallization of d- or X-(tartrates, mandelates, camphor sulphonates) or d-or X-(a-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabiethylamine, brucine or strychnine) salts. The acidic compounds produced according to the invention can also be split by splitting the diastereomeric ester or amide derivatives, made from an optically active alcohol or an optically active amine, and releasing the split, optically active compound. Advantageously, the most active of the two antipodes is isolated.

Finally, the compounds produced according to the invention are obtained either in free form or as salts. Each base obtained can be converted into a corresponding acid addition salt, preferably using a therapeutically usable acid or anion exchange preparation or the salts obtained can be converted into the corresponding free bases, for example by using a stronger base, such as a metal or ammonium hydroxide or a basic salt, e.g. an alkali metal hydroxide or carbonate, or a cation exchange preparation or an alkylene oxide such as propylene oxide. A compound produced according to the invention with a free carboxylic or phosphonic acid group can also be converted into the corresponding metal or ammonium salts. These or other salts, for example the picrates, can also be used for purification of the obtained bases. The bases are converted into salts, the salts are split, and the bases are released from the salts.

In view of the close relationship between the free compounds and the compounds in the form of their salts, provided that a compound is listed in this context, the corresponding salt is also included, provided that this is possible or suitable under the relevant circumstances.

The compounds including their salts can also be obtained in the form of their hydrates or contain other solvents, which are used in their crystallization.

The pharmaceutical preparations are suitable for enteral, also for example oral or rectal, transdermal and parenteral administration to mammals including humans, for blocking the N-methyl-D-aspartate-sensitive amino acid irritation receptor and for the treatment of diseases associated with the blocking of the The N-methyl-D-aspartate-sensitive amino acid irritation receptor, i.e. for example in cerebral ischemia, convulsive diseases and anxiety states, and which contains an effective amount of a pharmacologically active compound produced according to the present invention alone or together with one or more pharmaceutically acceptable carriers.

Example 1:

4-pyridineacetic acid in 500 ml of anhydrous ethanol, containing 75 ml of concentrated sulfuric acid, is heated under reflux for 18 hours. The solution is cooled to 0°C and neutralized by adding sodium hydroxide solution and saturated aqueous sodium carbonate solution. Extraction with ethyl acetate gives, after evaporation in vacuo, the 4-pyridylacetic acid ethyl ester.

A solution of 23.8 g of 4-pyridylacetic acid ethyl ester in 100 ml of anhydrous tetrahydrofuran is added dropwise to 5.5 g of lithium aluminum hydride in 150 ml of anhydrous tetrahydrofuran under nitrogen. The mixture is heated for 40 minutes to 50°C (bath temperature), then cooled in an ice bath. Excess lithium aluminum hydride is decomposed by the addition of 6.6 ml of water, followed by 6.6 ml of 1596 aqueous sodium hydroxide and 20 ml of water. The solid is filtered off and the filtrate is evaporated in vacuo, in this way 4-pyridylethanol is obtained.

A solution of 16.3 g of 4-pyridylethanol, 21.8 g of chloro-tert-butyldimethylsilane and 10.9 g of imidazole in 150 ml of dimethylformamide is stirred for 1 hour at room temperature. The product is isolated by extraction in ethyl acetate/hexane (1:1) and washed four times with 400 ml of water. The extract is filtered through silica gel and evaporated in vacuo. In this way, 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine is obtained.

24 g of m-chloroperbenzoic acid is added to a stirred solution of 28.8 g of 4-(tert-butyl-dimethyl-silyloxyethyl)-pyridine in 300 ml of dichloromethane. After 4 hours, the solution is washed with aqueous sodium carbonate solution, then with water. The solution is dried over sodium sulphate, filtered and evaporated in vacuo. In this way, 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine-N-oxide is obtained.

A solution of 28.6 g of 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine-N-oxide, 60.3 ml of trimethylsilyl cyanide and 31.5 ml of triethylamine is heated and stirred under nitrogen for 3 hours to reflux. The dark solution is cooled in an ice bath, 30 ml of ethanol is added, then 400 ml of acetic acid and 200 ml of hexane. The solution is washed twice with 150 ml of water, dried over sodium sulfate, filtered, evaporated in vacuo and purified by flash chromatography using ethyl acetate/hexane (1:10). In this way, 4-(tert-butyl-dimethylsilyl-oxyethyl)-2-cyanopyridine is obtained.

A solution of 22.2 g of 4-(tert-butyl-dimethylsilyloxyethyl)-2-cyanopyridine in 220 ml of anhydrous ethanol, which contains 0.19 g of sodium, is stirred for 24 hours at room temperature. The solution is then cooled to 0°C and 22 ml of 6N hydrochloric acid is added. The solution is stirred for 16 hours at room temperature, cooled to 0°C, 7.5 ml of 6N sodium hydroxide is added, then 75 ml of saturated aqueous sodium bicarbonate. Extraction with dichloromethane and flash chromatography using ethyl acetate gives 4-(2-hydroxyethyl)-pyridine-2-carboxylic acid ethyl ester.

A mixture of 8.37 g of 4-(2-hydroxyethyl)-pyridine-2-carboxylic acid ethyl ester in 130 ml of acetic acid and 4 platinum oxide is hydrated at 345 kPa. Filtration, evaporation in vacuo, neutralization with potassium carbonate and extraction with dichloromethane gives an oil which is purified by flash chromatography using dichloromethane/methanol saturated with ammonia (20:1). In this way, 4-(2-hydroxyethyl)-piperidine-2-carboxylic acid ethyl ester is obtained.

A solution of 7.9 g of 4-(2-hydroxyethyl)-piperidine-2-carboxylic acid ethyl ester and 9.0 g of di-tert-butyl dicarbonate in 80 ml of dichloromethane is stirred for 2 hours at room temperature and then evaporated in vacuo. In this way, 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)-piperidine-2-carboxylic acid ethyl ester is obtained.

A solution of 11.8 g of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)-piperidine-2-carboxylic acid ethyl ester and 12.6 g of pyridinium chlorochromate in 175 ml of dichloromethane is stirred under nitrogen at room temperature for 80 minutes. The mixture is filtered and purified by flash chromatography using ethyl acetate/hexane (25:75). In this way, 1-(tert-butoxycarbonyl)-2-ethoxycarbonyl-piperidine-4-acetaldehyde is obtained.

At -78°C, 20.3 ml of butyllithium (1.64 M) is added to 8.5 ml of tetraethyl methylene diphosphonate [bis(diethylphosphono)-methane] in 100 ml of anhydrous tetrahydrofuran. After 5 minutes, 9.26 g of 1-(tert.-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-acetaldehyde in 125 ml of anhydrous tetrahydrofuran are added. The mixture is heated for 18 hours under reflux, cooled, evaporated and purified by flash chromatography, whereby acetate/hexane (75:25 to 9:1) is used. In this way, 4-[1-(3-diethylphosphonoprop-2-enyl)]-1-(tert-butoxycarbonyl)-piperidine-2-carboxylic acid ethyl ester is obtained.

A mixture of 4.67 g of 4-[1-(3-diethylphosphonoprop-3-enyl)]-1-(tert-butoxycarbonyl)-piperidine-2-carboxylic acid ethyl ester and 75 ml of 6N hydrochloric acid is heated for 12 hours under reflux. The solution is evaporated to dryness in vacuo. The remainder is taken up in 50 ml of ethanol, and 3.8 ml of propylene oxide is added. The solid that is separated is filtered off and dried in a vacuum. In this way, cis-4-[1-(3-phosphonoprop-2-enyl)]-piperidine-2-carboxylic acid is obtained, freezing point 163-165°C.

Example 2:

At 0°C, 9.4 ml of acetic anhydride are added to a stirred solution of 13.5 g of 4-(2-hydroxyethyl)-piperidine-2-carboxylic acid ethyl ester in 75 ml of pyridine. After stirring at room temperature for 30 minutes, the solution is evaporated in vacuo and acetic acid (300 ml) is added. The solution is washed twice with 2N hydrochloric acid, once with water and once with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated in vacuo. The residue is taken up in 100 ml of ethanol, 5 g of powdered potassium carbonate is added, and the mixture is stirred for 1 hour at room temperature. The solution is filtered, evaporated in vacuo and purified by flash chromatography using dichloromethane/methanol (95:5). In this way trans 1-acetyl-4-(2-hydroxyethyl)-piperidine-2-carboxylic acid ethyl ester is obtained.

A mixture of 3.7 g of trans 1-acetyl-4-(2-hydroxyethyl)-piperidine-2-carboxylic acid ethyl ester and 5.4 g of pyridinium chlorochromate in 75 ml of dichloromethane is stirred under nitrogen for 2 hours. The mixture is filtered and purified by flash chromatography using ethyl acetate/hexane (7:3 to 8:2). Trans 1-acetylpiperidine-2-ethoxycarbonyl-4-acetaldehyde is obtained in this way.

At -78°C, 6.9 ml of butyllithium (1.6 M) is added to 2.9 ml of tetraethylmethylene diphosphonate in 30 ml of anhydrous tetrahydrofuran. After 5 minutes, 2.47 g of trans 1-acetylpiperidine-2-ethoxycarbonyl-4-acetaldehyde in 55 ml of anhydrous tetrahydrofuran are added. The mixture is heated for 18 hours under reflux, cooled, evaporated and purified by flash chromatography using dichloromethane/ethanol (100:3). In this way, trans 4-[1-(3-diethylphosphonoprop-2-enyl)]-1-acetyl-piperidine-2-carboxylic acid ethyl ester is obtained.

A mixture of 2.5 g of trans 4-[1-(3-diethylphosphonoprop-2-enyl)]1-acetylpiperidine-2-carboxylic acid ethyl ester and 40 ml of 6N hydrochloric acid is heated for 12 hours under reflux. The solution is evaporated to dryness in vacuo. The residue is taken up in 20 ml of ethanol and 2.3 ml of propylene oxide is added. The solid that separates is filtered off and dried in a vacuum. In this way, trans 4-[1- (3-phosphonoprop-2-enyl)]-piper is obtained in din-2-carboxylic acid, freezing point 132-140<0>C.

Example 3:

A solution of 20 g of 4-pyridylcarbinol, 28.9 g of chloro-tert-butyl-dimethylsilane and 14.4 g of imidazole in 200 ml of dimethylformamide is stirred for 3 hours at room temperature. The product is isolated by extraction in ethyl acetate/hexane (1:1), and the extract is washed four times with 400 ml of water. The solution is filtered over silica gel and evaporated in vacuo. In this way, 4-(tert-butyl-dimethylsilyloxymethyl)-pyridine is obtained.

A solution of 40.6 g of 4-(tert.-butyl-dimethylsilyl-oxymethyl)-pyridine and 40 g of m-chloroperbenzoic acid in 50 ml of dichloromethane is stirred for 16 hours at room temperature. The solution is washed with 2N caustic soda and water, dried over sodium sulphate, filtered and evaporated in vacuo. In this way, 4-(tert-butyldimethylsilyloxymethyl)-pyridine-N-oxide is obtained.

A solution of 37.9 g of 4-(tert-butyldimethylsilyloxymethyl)-pyridine-N-oxide, 84 ml of trimethylsilyl cyanide and 44 ml of triethylamine is heated under nitrogen for 2 1/2 hours under reflux and stirred. The dark solution is cooled in an ice bath, then 40 ml of ethanol, then 500 ml of acetic acid are added. The solution is washed twice with water, dried over sodium sulphate, filtered, evaporated in vacuo and purified by flash chromatography using ethyl acetate/hexane (1:10). In this way, 4-(tert-butyl-dimethylsilyloxymethyl)-2-cyanopyridine is obtained.

A solution of 21.7 g of 4-(tert-butyl-dimethylsilyl-oxymethyl)-2-cyanopyridine in 220 ml of anhydrous ethanol, containing 0.2 g of sodium, is stirred at room temperature for 18 hours, cooled to 0°C, then add 22 ml of 6N hydrochloric acid. The solution is stirred at room temperature for 18 hours, cooled to 0°C, 7.5 ml of 6N sodium hydroxide solution is added, then 20 ml of saturated aqueous sodium carbonate solution. Extraction with dichloromethane, then drying, filtering and evaporating the extract gives an oil which crystallizes from ether. On in this way 4-(hydroxymethyl)pyridine-2-carboxylic acid ethyl ester is obtained.

A mixture of 13.9 g of 4-(hydroxymethyl)pyridine-2-carboxylic acid ethyl ester and 5 g of platinum oxide in 250 ml of acetic acid is hydrated at 344 kPa. Filtration, evaporation in vacuum and neutralization with potassium carbonate in dichloromethane gives an oil which is purified by flash chromatography using dichloromethane/methanol saturated with ammonia (20:1). In this way, 4-(hydroxymethyl)piperidine-2-carboxylic acid ethyl ester is obtained.

A solution of 5.16 g of 4-(hydroxymethyl)piperidine-2-carboxylic acid ethyl ester and 6.33 g of di-tert-butyl dicarbonate in 100 ml of dichloromethane is stirred at room temperature for 18 hours. The solution is evaporated in vacuo, in this way 1-(tert-butoxycarbonyl)-4-(hydroxymethyl)-piperidine-2-carboxylic acid ethyl ester is obtained.

A solution of 7.9 g of 1-(tert.-butoxycarbonyl)-4-(hydroxymethyl)-piperidine-2-carboxylic acid ethyl ester and 9.9 g of pyridinium chlorochromate in 175 ml of dichloromethane is stirred at room temperature for 3 hours. The mixture is filtered and purified by flash chromatography using ethyl acetate/hexane (25:75). In this way, 1-(tert-butoxycarbonyl)-2-ethoxycarbonyl-piperidine-4-carboxaldehyde is obtained.

A solution of 1 g of 1-(tert.-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-carboxaldehyde and 2 g of formylmethylenetriphenylphosphorane in 16 ml of toluene is heated for 2 hours to 100° C. (bath temperature). The solution is cooled and purified by flash chromatography using ethyl acetate/hexane (25:75). In this way, 1-(tert-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-acrylaldehyde is obtained.

A solution of 0.83 g of 1-(tert-butoxycarbonyl)-2-ethoxy-carbonylpiperidine-4-acrylaldehyde and 0.11 g of sodium borohydride in 8 ml of ethanol is stirred at 0°C for 30 minutes. 0.2 ml of acetic acid is added, then ice-cold water, and the mixture is extracted with dichloromethane. The extract is dried over sodium sulphate, filtered and evaporated in vacuo. Purification by flash chromatography using acetate/hexane (25:75) gives trans 1-(tert-butoxycarbonyl)-4-[1-(3-hydroxyprop-1-enyl)]-piperidine-2-carboxylic acid ethyl ester.

A solution of 0.367 g of trans l-(tert-butoxycarbonyl)-4-[1-(3-hydroxyprop-l-enyl)]piperidine-2-carboxyl acid ethyl ester, 0.35 g of triphenylphosphine and 0.23 g of bromosuccinimide in 8 ml of dichloromethane is stirred first at 0°C and then at room temperature for 40 minutes. Purification by flash chromatography using ethyl acetate/hexane (1:9) gives trans 4-[1-(3-bromoprop-1-enyl]-1-(tert.-butoxycarbonyl)-piperidine-2-carboxylic acid ethyl ester.

A solution of 0.334 g of trans 4-[1-(3-bromoprop-1-enyl)]-1-(tert-butoxycarbonyl)-piperidine-2-carboxylic acid ethyl ester and 3.5 ml of triethyl phosphite is heated under nitrogen for 70 minutes to reflux. The cooled solution is evaporated in vacuo and purified by flash chromatography using dichloromethane/methanol (100:3). Trans 4-[1-(3-diethylphosphonoprop-1-enyl)]-1-(tert-butoxycarbonyl)-piperidine-2-carboxylic acid ethyl ester is obtained in this way.

A solution of 0.39 g of trans 4-[1-(3-diethylphosphonoprop-1-enyl)]-1-(tert.butoxycarbonyl)-piperidine-2-carboxylic acid ethyl ester and 2.3 ml of trifluoroacetic acid in 8 ml of dichloromethane is stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate solution is added and the mixture is extracted with dichloromethane. Purification by flash chromatography using dichloromethane/methanol saturated with ammonia (20:1) gives trans 4-[3-diethylphosphonoprop-1-enyl]-piperidine-2-carboxylic acid ethyl ester.

A solution of 0.265 g of trans 4-[1-(3-diethylphosphonoprop-1-enyl)]-piperidine-2-carboxylic acid ethyl ester in 5 ml of anhydrous ethanol, containing 0.074 ml of butyllithium (1.6 M) is heated for 72 hours at 80 °C (bath temperature). After cooling, 0.025 ml of acetic acid is added, then excess saturated sodium bicarbonate solution, and the mixture is extracted with dichloromethane. Evaporation of the dichloromethane extract in vacuo gives an oil. Purification of this by flash chromatography using dichloromethane/isopropanol saturated with ammonia (20:1) gives cis 4-[1-(3-diethylphosphonoprop-1-enyl)]-piperidine-2-carboxylic acid ethyl ester.

A mixture of 0.142 g of cis 4-[1-(3-diethylphosphonoprop-1-enyl)]-piperidine-2-carboxylic acid ethyl ester and 2.5 ml of 6N hydrochloric acid is heated for 12 hours under reflux. The solution is evaporated in vacuo to dryness. The residue is taken up in 2 ml of ethanol, and 0.15 ml of propylene oxide is added. Solids that are separated are filtered off and dried in a vacuum. In this way, cis 4 — [l-(3~phos f onopr op-1-enyl)] — piper is obtained in di-2-carboxylic acid, freezing point 175°C (decomposition). (b) In an analogous manner, the hydrolysis of the trans-ester gives the corresponding trans-acid, freezing point 130-135°C.

Claims (2)

1. Analogous process for the preparation of therapeutically useful 4-phosphonopropenylpiperidine-2-carboxylic acids with formula I where A means 1,3-propenylene, and pharmaceutically usable salts thereof, characterized by (a) condensation of an aldehyde of formula II wherein R^ means lower alkoxycarbonyl and R 2 means lower alkanoyl or lower alkoxycarbonyl and A' means oxoethyl, with a tetralower alkyl ester of methylene diphosphonic acid under basic conditions or (b) condensation of a compound of formula III wherein A means 1,3-propenylene and where R^ means lower alkoxycarbonyl and R2 means lower alkanoyl or lower alkoxycarbonyl and X stands for reactive esterified hydroxy, with a connection with formula where R' means lower alkyl, and transfer of the obtained compound of formula V where A means 1,3-propenylene and where R and R' stand for lower alkyl, R^ means lower alkoxycarbonyl and R 2 means lower alkanoyl or lower alkoxycarbonyl, by treatment with an inorganic acid or with aqueous alkali, to the corresponding compound of formula I, and if the desired conversion of the free compound formed into a salt or a salt formed into the free compound or another salt. 2. Process according to claim 1 for the production of cis-4-(phosphonoprop-1-enyl)piperidine-2-carboxylic acid or a salt thereof, characterized in that corresponding, substituted starting materials are used.