DD273837A5 - PROCESS FOR THE MANUFACTURE OF UNSATURATED PHOSPHONESE DERIVATIVES AND DERIVATIVES HEREVO - 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

Field of application of the invention

The invention relates to a process for the preparation of unsaturated phosphonic acids and derivatives thereof with valuable pharmacological properties.

The present invention further relates to methods of preparing pharmaceutical compositions containing these compounds, a method of blocking the N-methyl-D-aspartate sensitive amino acid receptor, and a method of treating conditions and diseases in mammals responsive to the action of an amino acid stimulant receptor antagonist by administration named compounds or pharmaceutical preparations in which the named compounds are enthaften.

The compounds of the present invention are effective and useful in mammals as selective antagonists of the N-methyl-D-aspartate-responsive (NMDA) amino acid reuptake receptor. Therefore, the compounds of the invention are also useful alone or in combination with mammals for the treatment of disorders responsive to blockade of the NMDA receptor, for example cerebral ischaemia, muscle spasms (spasticity), convulsive diseases (epilepsy) and anxiety. The compounds of the invention are also considered to be effective in the treatment of Huntington's disease (chorea hereditiva).

Characteristic of the known state of the art

It sir d no information is known about what connections responsive to exposure to a Aminosäurereizrezeptora ^r itagonisten and which are suitable for example for the treatment of diseases such as iviuskelspasmen cerebrate ischemia, convulsive disorders and anxiety

 There is also no information available about processes for the preparation of unsaturated phosphonic acids and derivatives thereof.

Object of the invention

The aim of the invention is the provision of novel compounds with valuable pharmacological properties, in particular having a blocking effect on the N-methyl-D-aspartate sensitive amino acid receptor, which are suitable for the treatment of cerebral ischaemia, muscle spasms, convulsive diseases and anxiety.

Explanation He * essence of the invention The invention has for its object to provide novel compounds with the desired properties and methods for their To find production. According to the invention, compounds of the formula I

(I)

wherein one or both of the acidic hydroxy groups of the phosphonic acid moiety can be etherified, m is one or zero, R 'is carboxy, esterified carboxy or amidated carboxy, the heterocyclic five- or six-membered ring additionally

Carbon and / or nitrogen may be substituted, having a carbon-carbon double bond or with a

carbocyclic six-membered ring, starting from adjacent carbon atoms, may be condensed, A is lower alkenylene; and salts thereof. These compounds are useful as antagonists of N-methyl-D-aspartate sensitive

Amino Acid Receptor in Mammals. Condensation starting from adjacent carbon atoms with a carbocyclic six-membered ring is a condensation

with, for example, cyclohexyl or phenyl, such that the conditoned heterocyclic ring in formula I is represented by a bicyclic ring system having 9 or 10 ring-forming atoms, depending on the value of m in formula I-

The heterocyclic ring system of the compounds of the formula I as defined above is used together with the Substituents R 'are represented, for example, by optionally substituted 2-carboxypyrrolidinyl, 2-carboxy-2,5-

dihydropyrrolyl, 2-carboxy-1,2,3,6-tetrahydropyridinyl, 2-carboxy-1,2,5,6-tetrahydropyridinyl, 2-carboxypiperidinyl, 2-

Carboxy-tetrahydroquinolinyl, 2-carboxyperhydroquinolinyl, 2-carboxy-2,3-dihydroindolyl or 2-carboxyperhydroindolyl,

wherein carboxy may be esterified or aminated.

Etherified hydroxy is represented, for example, by lower alkoxy, benzyloxy, benzyloxy, which on the phenyl part by Halogen, substituted by lower alkyl or lower alkoxy, by lower alkanoyloxymethyl or lower alkanoyloxynethyl,

which is substituted on the oxymethyl moiety by lower alkyl or cycloalkyl.

A preferred embodiment of the invention relates to the phosphonic acid derivatives of the formula I and derivatives thereof,

wherein the heterocyclic ring is optionally substituted 2-carboxypiperidinyl, 2-carboxy-1,2,3,6-tetrahydropyridinyl or 2-carboxy-1,2,5,6-tetrahydropyridinyl, especially the compounds of formula II,

(II)

and dio compounds of formula II having a double bond between C-3 and C-4 or between C-4 and C-5 of the piperidinyl ring, wherein the phosphono-containing chain is at the 3-, A- or 5-position of the piperidinyl or tetrahydropyridinyl ring R ¹ and R 'independently of one another are hydrogen, lower alkyl, benzyl or benzyl which is substituted on the phenyl moiety by halogen, lower alkyl or lower alkoxy, lower alkanoyloxymethyl or lower alkanoyloxymethyl which is substituted on the oxymethyl moiety by lower alkyl or cycloalkyl, R ^{1 is} carboxy or pharmaceutically acceptable esterified or amidated carboxy; R ^{2 is} hydrogen, lower alkyl, aryl lower alkyl or acyl; R ^{3 is} hydrogen, lower alkyl or aryl-lower alkyl; A is lower alkenylene; and salts thereof. Preference is given to the compounds of the formula II in which R and R 'independently of one another are hydrogen, lower alkyl, benzyl, lower alkanoyloxymethyl or lower alkancyloxymethyl which is substituted on the oxymethyl moiety by lower alkyl, cyclohexyl or cyclopentyl; R ^{1 is} carboxy, carbamoyl or pharmaceutically acceptable esterified carboxy as defined herein; R ² and R ^{3 are} hydrogen or lower alkyl; A is alkenylene of 2 to 4 carbon atoms; and pharmaceutically acceptable salts thereof.

Further preferred are the compounds of the formula II in which R and R 'independently of one another are hydrogen, lower alkanoyloxymethyl or lower alkanoyloxymethyl which is substituted on the oxymethyl part by lower alkyl; R 'is carboxy, carbamoyl or lower alkoxycarbonyl, lower alkanoyloxymethoxycarbonyl, straight chain

Di-lower alkylamino is C2-4-alko * ycarbonyl or pyridylmethoxycarbonyl, R ² and R ^{3 are} hydrogen; A is in the 4 position and is alkenylene having 3 or 4 carbon atoms and the double bond adjacent to the phosphono group; and pharmaceutically acceptable salts thereof

 Particularly preferred are the compounds of formula III

(III)

wherein A1,3 represents propenylene, preferably with the double bond adjacent to the phosphono group; R ^{1 represents} carboxy or pharmaceutically acceptable esterified carboxy as defined herein, as well as pharmaceutically acceptable salts thereof.

A preferred embodiment relates to the compounds of formula III wherein d'e are 2- and 4-substituents from each other

in cis-Steliung sieliön.

A v / eiterer subject of the invention are the phosphonic acid derivatives of formula I and the above-mentioned derivatives, wherein

the heterocyclic ring is optionally substituted 2-carboxy-1,2,3,4-tetrahydro- or -perhydroquinolinyl, wherein the phosphono-containing chain is preferably in the form of a tri- or tetra- or perhydroquinolinyl ring; H. the compounds of the formula IV

(IV)

or perhydro derivatives thereof, wherein R and R 'independently represent hydrogen, lower alkyl, benzyl or benzyl substituted on the phenyl moiety by halogen, lower alkyl or lower alkoxy, lower alkanoyloxymethyl, lower alkanoyloxymethyl substituted on the oxymethyl moiety by lower alkyl or cycloalkyl; R ^{1 is} carboxy or pharmaceutically acceptable esterified or amidated carboxy; R ^{2 is} hydrogen, lower alkyl, aryl-lower alkyl, or acyl; R ^{4 is} hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; A represents lower alkylene; and salts thereof

 The compounds of the formula V are preferred

I Il

Vv \.

VV

or perhydroquinoline derivatives thereof, wherein A represents 1,3-propenylene, having the double bond adjacent to the phosphono group; R ^{1 is} carboxy or pharmaceutically acceptable esterified carboxy as defined herein; and pharmaceutically acceptable salts of these compounds having a salt-forming functional group. Most preferred are the compounds of formula V wherein the 2- and 4-substituents are cis to each other.

Another object of the invention are the phosphonic acid derivatives of the formula I and the above-mentioned derivatives, wherein the heterocyclic ring denotes optionally substituted 2-carboxypyrrolidinyl, d. H. the compounds of formula Vl

R ³ -4- 4-A-P-OR '

(Vl)

YV Ar

and the compounds of formula VI having a double bond between C-3 and C-4 of the pyrrolidine / ring in which the phosphono-containing chain is preferably in the 3- or 4-position of the pyrrolidine ring and wherein R and R 'are independently from each other hydrogen, lower alkyl, benzyl or benzyl, which is substituted on the phenyl moiety by halogen, lower alkyl or Nioderalkoxy, Niederalkanoyloxymethy! or lower alkanoyloxymethyl which is substituted on the oxymethyl partil by lower alkyl or

Cycloalkyl substituted, mean; R ^{1 is} carboxy or pharmaceutically acceptable esterified or amidated carboxy; R ^{2 is} hydrogen, lower alkyl or acyl; R ^{3 is} hydrogen, lower alkyl or aryl-lower alkyl; A is lower alkenylene; and salts thereof.

Preference is given to the compounds of the formula VI in which the phosphono-bearing group is attached in position 3; R and R 'are hydrogen, R' is carboxy or pharmaceutically acceptable esterified carboxy, for example lower alkoxycarbonyl, lower alkanoyloxymethoxycarbonyl, di-lower alkyniamino-straight-chain C ₂ -4 -alkoxycarbonyl or pyridylmethoxycarbonyl; R ² and R ^{3 are} hydrogen; A is 1,3-propenylene having the double bond adjacent to the phosphono group; and pharmaceutically acceptable salts thereof.

The general definitions used herein have the following meaning in connection with the invention:

The term "lower" used above and below in connection with organic groups, radicals or compounds defines those having up to and including 7 carbon atoms, preferably those up to and including 4, and advantageously those having 1, 2 or 3 carbon atoms.

Lower alkyl preferably contains 1 to 4 carbon atoms and is for example ethyl, propyl, butyl or advantageously methyl.

Lower alkenylene in the meaning A preferably contains 2 to 4 carbon atoms and denotes z. For example, ethenylene, 1,3-propenylene, 1,4-but-1-enylene, or 1,4-but-2-enylene, preferably with the double bond adjacent to the phosphono group.

Lower alkoxy preferably contains 1 to 4 carbon atoms and denotes, for example, ethoxy, propoxy or advantageously methoxy.

Lower alkanoyl preferably contains from 2 to 7 carbon atoms and advantageously denotes acetyl, propionyl, n-butyryl, isobutyryl or pivaloyl, but may also be formyl.

Lower alkanoyloxy advantageously denotes acetoxy, propionyloxy, n- or i-butyryloxy or pivaloyloxy.

Cycloyalkyl preferably contains 3 to 8 carbon atoms and denotes, for example, cyclohexyl or cyclopentyl.

Halogen is preferably fluorine and chlorine, but may also be bromine or iodine.

Aroyl denotes; Arylcar) onyl, preferably benzoyl or benzoyl, substituted by 1 to 3 substituents selected from lower alkyl, Never deralkox ", trifluoromethyl and halogen; or pyridylcarbonyl, in particular nicotinoyl.

Aroyloxy bezeici ;;et preferably benzoyloxy, benzoyloxy, substituted on Pher.ylring by lower alkyl, halogen or lower alkoxy, z. Methyl, chloro or methoxy; or nicotinoyloxy.

Aryl preferably denotes optionally substituted phenyl, e.g. Phenyl or phenyl substituted by 1 to 3 substituents selected from lower alkyl, lower alkoxy, trifluoromethyl and halogen; or pyridyl, especially 3-pyridyl.

Aryl-lower alkyl preferably denotes aryl-C 1-4 -alkyl, where aryl has the meanings indicated above, advantageously benzyl or 2-phenylethyl.

Acyl refers to carboxy-derived acyl, preferably lower alkanoyl, aryl-nis-alkanoyl, aroyl, lower alkoxycarbonyl, aryl-lower alkoxycarbonyl, alpha-amino-lower alkanoyl or alpha-amino-aryl-lower alkanoyl.

Aryl-N or alkanoyl preferably denotes arylC 1-4 alkanoyl, advantageously phenylacetyl or 3-phenylpropionyl.

Lower alkoxycarbonyl preferably contains 1-4 carbon atoms in the alxoxy part and denotes, for example, methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or, preferably, ethoxycarbonyl.

Aryl-lower alkoxycarbonyl preferably denotes benzyloxycarbonyl.

Alpha-amino-lower alkanoyl and alpha-amino-aryl-lower alkanoyl refer to acyl groups of alpha-amino acids, e.g. B.

Alanyl, glycyl, leucyl, isoleucyl and pher.ylalanyl.

E-ine N-mono-lower alkyl-carbamoyl group preferably contains 1 to 4 carbon atoms in the alkyl part and is for example N-methylcarbamoyl, N-Propylcarbam jyl or advantageously N-ethylcarbamoyl.

An N, N-di-lower alkyl-carbamoyl group preferably contains 1 to 4 carbon atoms in each lower alkyl part and denotes e.g. B. Ν, Ν-dimethylcarbamoyl, N-ethyl-N-methylcarbamoyl and advantageously Ν, Ν-Diethylcarbamoyl.

Di-lower alkylcarbamoyl Niederalkylaminu M is preferably di-C ₁ _ ₄ alkylamino-NC !, wherein the two nitrogen atoms are separated by 2 to 4 carbon atoms ₂ -4-alkylcarbamoy, and designated z. N- (2-diethylaminoethyl) carbamoyl or N- (3-diethylaminopropyl) -carbamoyl.

Mono-lower alkylamino preferably contains 1 to 4 carbon atoms and denotes z. Methylamines), ethylamino, η- or i- (propylamino or butylamino).

Di-lower alkylamino preferably contains 1 to 4 carbon atoms in each lower alkyl group and denotes e.g. B.

Dimethylamino, diethylamino, di- (n-propyl) -amino and di- (n-butyl) -amino.

Di-lower alkylamino-lower alkoxycarbonyl preferably contains 2 to 4 carbon atoms in the A! Koxy part, the oxygen and nitrogen atoms are separated by 2 to 4 carbon atoms from each other, and denotes z. B.

N, N-DiethylaminoethoxycarbonyloderN.N-Diethylaminopropoxycarbonyl.

Pharmaceutically acceptable esterified carboxy in the context of the present invention denotes an esterified carboxy group R ¹ , preferably a carboxylic acid prodruyester, which can be converted into free carboxy under physiological conditions.

Pharmaceutically acceptable esterified carboxy preferably denotes e.g. B. lower alkoxycarbonyl; (amino, mono- or di-lower alkylamino) -substituted straight-chain C ₂ - ₅ -lower alkoxycarbonyl, carboxy-substituted Nioderalkoxycarbonyl, z. B.

ct-carboxy-substituted lower alkoxycarbonyl; lower alkoxycarbonyl-substituted lower alkoxycarbonyl, e.g. lower alkoxycarbonyl-substituted lower alkoxycarbonyl; aryl-substituted lower alkoxycarbonyl, e.g. B. unsubstituted or substituted ber.zyloxycarbonyl or pyridylmethoxycarbonyl; lower alkanoyloxy-substituted methoxycarbonyl, e.g.

pivaloyloxymethoxycarbonyl; (Lower alkanoyloxy or lower alkoxy) -substituted lower alkoxymethoxycarbonyl; Bicyclo [2.2.1] heptyloxycarbonyl-substituted methoxycarbonyl, e.g. B. bornyloxycarbonylmethoxycarbonyl; 3-phthalidoxycarbonyl; (Lower alkyl, lower alkoxy, halo) -substituted 3-phathalidoxycarbonyl; Lower alkoxycarbonyloxy-lower; e.g. 1- (methoxy or ethoxycarbonyloxy) ethoxycarbonyl.

The most preferred prodrug esters are e.g. the straight chain Ci-4-alkyl esters, z. Ethyl; the lower alkanoyloxymethyl esters, e.g. pivaloyloxymethyl; the di-lower alkylamino straight-chain C 1-4 alkyl esters, e.g. 2-diethylaminoethyl; the pyridylmethyl esters, e.g. 3-pyridylmethyl.

Pharmaceutically acceptable amidated carboxy in the context of the present invention denotes an amidated carboxy group R ¹ , preferably a carboxamide, which converts into free carboxy under physiological conditions

can be.

Preferred amidier.es carboxy is z. Carbamoyl, N-mono-lower alkylcarbamoyl, e.g. N-ethylcarbamoyl, N, N-di-lower alkylcarbamoyl, e.g. Ν, Ν-diethylcarbamoyl, or di-lower alkylamino-N-loweralkylcarbamoyl, e.g. N- (2-diethylaminoethylcarbamoyl or N- (3-diethylaminopropyl) carbamoyl.

Salts of the compounds according to the invention are preferably pharmaceutically acceptable salts, on the one hand metal or ammonium salts of the compounds according to the invention with a free phosphonic or carboxy group, in particular alkali metal or alkaline earth metal salts, for. For example, sodium, potassium, magnesium or calcium salts; or advantageously crystallizing ammonium salts derived from aminoniac or organic amines such as methylamine, diethylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) aminomethane or benzyltrimethylammonium hydroxide. On the other hand, the compounds of the invention, which are basic amines, acid addition salts with preferably pharmaceutically acceptable inorganic or organic acids such as strong mineral acids, such as Halogenwasse ^r dtoffsäuren, eg hydrochloric or hydrobromic acid; Sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonic acids, eg. Acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric, ascorbic, maleic, fumaric, pyruvic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic or naphthalenesulfonic acids.

For isolation or cleaning purposes salts can be recovered which are not suitable for pharmaceutical purposes. However, only pharmaceutically acceptable salts are used for therapeutic purposes, so salts are preferred. The compounds of the invention show valuable pharmacological properties, e.g. selective blocking of N-methyl-D-aspartate sensitive amino acid receptors in mammals. The compounds are therefore useful in the treatment of diseases responsive to amino acid irritation blockade in mammals, such as, for example, nervous system disorders, especially spasmodic disorders (epilepsy) and anxiety.

These effects can be demonstrated in in vitro or in vivo probing, advantageously using mammals of the tissue or enzyme preparations thereof, eg, mice, rats, or monkeys. Known compounds can be administered enterally or parenterally, advantageously orally or transdermally or subcutaneously, intravenously or intraperitoneally, for example in gelatin capsules or in the form of aqueous suspensions or solutions The in vivo dose administered may be between about 0.01 and 100 mg / kg, preferably between about 0.05 and 50 mg Named compounds may be administered in vitro in the form of, for example, aqueous solutions, the dose being approximately between ΙΟ " ⁴ and 10" ⁸ molar concentrations.

[Inhibitory action on NMDA-type amino acid reuptake receptors is determined in vitro by measuring the inhibition of MMDA-triggered ³ H-acetylcholine ( ³ H-ACh) release from rat brain corpus striatum tissue by J. Lehmann and B. Scatton, Brain Research 252, 77-89 (1982) and Nature 297, 422-424 (1982).

Antagonists of NMDA-type amino acid reuptake receptors competitively counteract NMDA-triggered ³ H-acetylcholine ( ³ H-ACh) release from brain corpus striatum tissue.

The inhibition of the NMDA induced ³ H-acetyl; choline ⁽³ H-ACh) release from Striatumgewebescheiben of rats by a urfindungsgemäße compound is expressed as a percentage of release of ³ H-ACh in response to stimulation with 50μΜ NMDA compared to control experiment. The experiments are two-tailed with a minimum of η = 4 in each group. The IC ₆₀ 's (Ie designate the concentration of test compound required to inhibit NMDA-enhanced ³ H-ACh release by 50%.

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

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

Another indication of anticonvulsant activity is that the compounds of the invention effectively prevent audiogenic seizures in DBA / 2 mice (Chapman et al., Arzneim.-Forsch., 34, 1261, [1984]). The effect is determined as follows: 45 minutes after administration of the compound or vehicle, the mice are individually placed in a soundproof chamber. After an accommodation time of 30s, the mice are exposed for 1 minute to a sound stimulation of 11OdB, or until a tonic-clonic seizure occurs. Control seizures consist of an initial phase of wild running. The prevention of wild running is an indication of aniikonvulsive effect. Test compounds are administered either as a solution in distilled water or as a suspension in a 3% colloidal corn starch with 5% by weight of polyoethylene glycol 400 and 0.34% Tween 80 orally or intraperitoneally in an amount of 10 ml / kg of body weight.

An indication of anxiolytic activity is the fact that the compounds of the invention are potent in the Cook / Davidson conflict model (Psychopharmacologia 15, 159-168 (1969)).

The cerebral anti-ischemic activity, that is, the effect of the compounds of the invention to prevent or reduce brain damage in mammals as a result of transient cerebral ischaemia (such as stroke) can be determined by the Mongolian model of gerbil-ischemia, e.g. The model described by T. Kirino in Brain Research 239, 57-69 (1982).

The inhibitory effect on the observed hyperactivity and degeneration of neurons in the hippocampal region of the brain is measured following a five minute ischemia. The test compound is i. p. Given 15 minutes before ischemia or 2,4 and 6 hours after ischaemia.

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

The above-mentioned advantageous properties make the compounds of the present invention useful as antagonists of N-methyl-D-aspartate sensitive amino acid reporter in mammals and for the treatment of related conditions such as anxiety and cramping disorders.

The compounds of the invention, d. H. those listed above can be prepared by conventional methods, e.g. B. djrch

a) condensation of an aldehyde or ketone of formula VII

(VII)

wherein m, R ¹ and the heterocyclic ring vvio are defined for formula I but wherein R ¹ and amino groups are in protected form, and A 'is nipderalkyl which is substituted by oxo and one carbon atom less than the alkenylene group A, having a Tetraester derivative of methylene diphosphonic acid, preferably with a tetra-lower alkyl ester of methylene-iphosphonic acid, and under basic conditions, and if necessary by deprotection of the product obtained, to give a compound of formula I wherein the double bond within group A is immediately adjacent to the phosphono group ; or h) condensation of a compound of the formula VIII,

(VIII)

wherein A, m, R ¹ and the heterocyclic ring are as defined for formula I and X is reactive esterified hydroxy, with a compound capable of introducing the phosphonic acid half and having one of the formulas IX or X,

Η-f-OR "(IX) P (R '") ₃

wherein R "denotes lower alkyl and R" 'represents halogen or lower alkoxy, and if necessary, converting the resulting phosphonic acid derivative into the phosphoric acid or other ester derivative thereof; or

c) conversion into R 'of a substituent other than R ¹ in position 2 on the heterocyclic ring in a compound which otherwise is identical to a compound according to the invention; further, by carrying out these processes with, if necessary, temporary protection of all interfering reactive groups and subsequent liberation of the resulting compound of the invention; if desired, converting a resulting compound of the invention into another compound of the invention and / or, if desired, converting the resulting free compound into a salt or a resulting salt into the free compound or other salt; and / or separating an isomer mixture or mixture of racemates into the individual isomers or racemates; and / or, if desired, separating a racemate into the optical antipodes.

Reactive esterified hydroxy in any of the methods listed herein, e.g. B. X in a compound of formula VIII is esterified by a strong acid, in particular a hydrohalic acid, for example hydrochloric acid, hydrogen bromide or hydroiodic acid or sulfuric acid or a strong organic Sä ·· "!, in particular a strong organic sulfonic acid, such as an aliphatic or aromatic sulfonic acid, eg methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid. Said reactive esterified hydroxy is, in particular, halogen, eg chlorine, bromine or iodine, or aliphatically or aromatically substituted sulphonyloxy, for example Methanesulfonyloxy, phenylsulfonyloxy or 4-methylphenylsulfonyloxy (tosyloxy).

Thus, in the starting compounds and intermediates that are converted to the compounds of the present invention as described herein, functional groups such as carboxy, amino (including ring NH), and hydroxy groups, if desired, are protected by conventional protecting groups as used in the preparative organic art Chemistry are common. Protected carboxy, amino and hydroxy groups are those that can be converted under mild conditions into free carboxy, amino and hydroxy groups without destroying the molecular skeleton or causing other unwanted side reactions.

The purpose of introducing protective groups is to protect the functional groups against undesired reactions with the reaction components and under the conditions under which a desired chemical transformation is carried out. The need for surfactants and the choice of them for a particular reaction is known to those skilled in the art and depends on the nature of the functional groups to be protected (carboxy group, amino group, etc.), structure and stability of the molecule , of which the substituent is a part, and of the reaction conditions. Well-known protecting groups that meet 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, TWGreene, "Protective Groups in Organic Synthesis", Wiley, New York 1981 and also "The Peptides", Vol. I, Schroeder and Luebke , Acaden lic Press, London, New York 1965 and in Houben-Weyl, "Methods of Organic Chemistry", Vol. 15/1, Georg Thieme Verlag, Stuttgart, 1974.

The preparation of the compounds of the invention in which the double bonds of the phosphono group are adjacent according to process (a), according to which an aldehyde or ketone is condensed with, for example, a lower alkyne of methylenediphosphonic acid, is carried out according to methods known to those skilled in the art for such condensations Presence of a strong anhydrous base, e.g. As butyllithium, in an inert polar solvent such as tetrahydrofuran, preferably with heating under reflux, the Ausgangsaldehyde or ketones of formula VII may, for. B.

weraen prepared by oxidation of the corresponding alcohols, for example with pyridinium chlorochromate, or according to other methods, such as. B. be illustrated in dan examples.

The respective alcohols can in turn be prepared in a known per se, for. By reduction of the corresponding aromatic alcohols using methods known to those skilled in the art for the reduction of pyrrole, pyridine, indole and quinoline compounds. For example, the reduction of pyrite. .1- or quinoline ring is preferably carried out with an organometallic reducing agent or by catalytic hydrogenation, for. Example, in the presence of platinum oxide and an acidic solvent such as acetic acid, so that the corresponding tetrahydropyridines, piperidines, 1,2,3,4-tetrahydroquinolines or perhydroquinolines are obtained according to the invention, for. B. according to formula II or IV and derivatives thereof. Quaternary quinolinium and pyridinium compounds, e.g. For example, those in which R ^{2 is} lower alkyl or aryl-Neraleralkyl can be reduced in a similar manner.

The alcohols, aldehydes or ketenes obtained in this way can also be converted into aldehydes or ketones of greater chain length, wherein conventional ancestors can be used, for. B. by a Wittig condensation of an aldehyde with methoxy-methyltriphenylphosphonium chloride, wherein the homoioge aldehyde is obtained, and by other per se hekannle reaction sequences, as described, for. B. in Beispic'en described.

The above-mentioned aromatic 2-carboxy-heterocycl, l-substituted lower alkanols, for example, the 2-carboxy pyridinyl or 2-carboxy-quinolinyl substituted lower alkanols or derivatives thereof, can in turn be prepared by reacting the 2-unsubstituted pyridinyl iodine 2-unsubstituted quinolinyl-substituted lower alkanols, in a suitably protected form, with, for example, a Pe; acid, such as m-chloroperbenzoic acid, to give the corresponding pyridine N-oxides or quinoline N-oxides. Condensation with a reactive cyanide, e.g. B. a Triaikyisiiyicyanid as Trimeihyisüyicydnid, preferably under basic conditions, for. In the presence of triethylamine, gives the corresponding 2-cyanopyridine or 2-cyanoquinoline derivatives, which are then converted into the 2-R '- (carboxy, esterified or amidated carboxyl-substituted pyridine), again in a manner known per se. and quinoline derivatives.

The condensation according to process (b) is advantageously used for the preparation of compounds of the formula I in which the double bond within the alkenylene group A is not immediately adjacent / ur phosphono group.

The condensation according to process b) of a compound of formula VIII with a compound of formula X, for. B.

Triethyl phosphite is carried out, for example, by heating in an inert solvent and under the conditions described for a Michaelis-Arbuzov reaction according to Angew. Chem. Int. Ed. 16,477 (1977) and Chem. Rev. 81,415 (1981). Similarly, a condensation z. B. with phosphorus trichloride and subsequent hydrolysis of a compound of formula I.

The condensation of a compound of formula VIII », ach process b) with a compound of formula IX, z. B.

Diethyl phosphonate (diethyl phosphite), for example, in a strongly basic medium, for. In the presence of an alkali metal such as sodium, an alkali metal hydride such as sodium hydride, an alkali metal alkoxide such as potassium t-butoxide in an inert solvent such as toluene or dimethylformamide.

Starting compounds of the formula VIII and reactive derivatives thereof can be prepared in a manner known per se, starting from intermediates of the formula VII in which A 'is oxo-substituted lower alkyl, the preparation of which is described above.

For example, the starting material of formula VIII, wherein A is propenylene, is prepared by condensing an aldehyde of formula VII wherein the group A 'is formyl (CH = O) with a suitable Wittig roughen, e.g. B. Formylmethylentriphenylphcsphoran. The resulting unsaturated aldehyde (in which the ketone has been extended by two carbon atoms) is reduced to the alcohol, e.g. With sodium borohydride, and the resulting unsaturated alcohol is converted into din reactive derivative, e.g. B. in the bromide with triphenylphosphine / N-bromosuccinimide.

Conversions according to method c) are carried out by generally known methods.

Examples of groups that can be converted to R ¹ are carboxy groups in the form of anhydrides or acid halides, cyano, amidino groups, including cyclic amidino groups such as 5-tetrazolyl, iminoether groups, including cyclic imino ether groups, for example dihydro 2-oxazolinyl or dihydro-2-oxazolinyl groups substituted by lower alkyl, and also hydroxymethyl, etherified hydroxymethyl, lower alkanoyloxymethyl, trialkoxymethyl, acetyl, trihaloacetyl, halomethyl, carboxycarbonyl (COCOOH), formyl (CHO), di (lower) alkoxymethyl, alkylenedioxymethyl or vinyl.

Some terms used in the methods have the meanings defined below.

Oxo-substituted lower alkyl is preferably formyl, formylmethyl, formylethyl or 2-oxo-propyl.

Trialkoxymethyl preferably refers to tri (lower alkoxy) methyl, especially triethoxy or trimethoxymethyl.

Etherified hydroxymethyl preferably denotes lower alkoxymethyl, lower alkoxyalkoxymethyl, e.g. B.

Methoxymethoxymethyl or 2-oxa- or 2-thiacyclo-alkoxymethyl, especially 2-TeVahydropyranyloxymethyl.

In particular, halomethyl refers to chloromethyl but may also be bromomethyl or iodomethyl.

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

Groups which are convertible into R 'meaning carboxy include esterified and amidated carboxy and are not limited to esterified and amidated carboxy as defined herein for R ¹ . A conversion to carboxy is usually carried out by solvolysis with an acid or base.

Benzyloxycarbonyl or nitrobenzyloxycarbonyl can also be converted to carboxy by catalytic hydrogenation, the latter group also with the aid of chemical reducing agents, eg. With sodium dithionite or with zinc and a carboxylic acid.

In addition, tert-butyloxycarbonyl can also be cleaved with trifluoroacetic acid.

Acetyl can be oxidatively converted to Cai boxy -Ji-rch conversion first into trihaloacetyl, z. B. tribromo- or Triiodacetyl, by

Treatment 2. B. with sodium hypobromite, then by splitting z. As an aqueous base, for example, sodium hydroxide.

Formyl, di- (lower) alkoxymethyl or alkylenedioxymothyl (formyl protected in the form of an acetal), ζ. Example, as dimethyl acetal, are oxidized, for example with silver nitrate, pyridinium dichromate or ozone to carboxy.

Vinyl can be converted to carboxy by ozonolysis to formyl, which in turn is oxidized to carboxy.

Hydrolysis of trialkoxymethyl to carboxy is advantageously carried out with inorganic acids, eg, hydrogen halide or sulfuric acid. Hydrolysis of Vf.rethertem hydroxymethyl to hydroxymethyl is best accomplished with solutions of inorganic acids, e.g. B. a hydrohalic acid. Hydroxymethyl is vviedei to oxidized to carboxy with an oxidizing agent, for example, with the first Pyridkmdichromat.

Halomethyl can be converted into the corresponding carboxaldehyde, for. B. with üimethylsulfoxid in the presence of triethylamine and silver tetrafluoroborate or mn chromium trioxide and pyridine in dichloromethane.

The conversion of cyano into lower alkoxycarbonyl is advantageously carried out by treatment first with a niedcralkanoyl, z. Anhydrous ethanol, in the presence of a strong acid, e.g. Hydrochloric acid, preferably at the recycle temperature, followed by hydrolysis with water.

Moreover, the conversion of cyan to carbamoyl is preferably carried out by treatment with an alkali metal hydroxide, e.g. For example, dilute sodium hydroxide, and hydrogen peroxide, preferably at room temperature.

Esterified carboxy, such as lower alkoxycarbonyl, may be amidated with ammonia, mono- or di (lower) alkylamines, such as methylamine, dimethylamine, in an inert solvent, e.g. As a Niederalkancl, such as butanol, to unsubstituted, mono- or di (lower) alkylcarbamoyl.

The compounds of the invention can therefore be converted into other Vorbindungen invention, for example by conversion of functional groups as is well known.

Thus, for example, the conversion of carboxylic esters ν id -amides into carboxylic acids is advantageously carried out by hydrolysis with inorganic acids such as, for example, a hydrogen halide or sulfuric acid or with aqueous alkali: preferably alkali metal hydroxides such as lithium or sodium hydroxide.

Free carboxylic acids can be esterified with lower alkanols, such as ethanol, in the presence of a strong acid, for example sulfuric acid, or with diazo (lower) alkanes, e.g. As diazomethane, in a solvent such as ethyl ether, and advantageously at room temperature, whereby the corresponding lower alkyl arise.

In addition, the free carboxylic acids can be prepared by treating a reactive derivative thereof, e.g. an acyl halide such as the acid chloride or a mixed anhydride, e.g. For example, one that is derived from a lower alkyl halo carbonate, such as ethyl chloroformate, with ammonia, mono- or di (lower) alkylamines, in an inert solution, such as dichloromethane, preferably in the presence of a basic catalyst, such as pyridine, in compounds in which R 'denotes unsubstituted, mono- or di- (N-halo) alkylcarbamoyl.

Phosphonic acid esters are 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.

Benzyl esters can be converted into the acids by hydrogenolysis.

Phosphonic acids are converted to esters, e.g. In optionally substituted lower alkyl esters, for example by condensation with an optionally substituted lower alkyl halide, preferably in a basic non-aqueous medium such as in the presence of triethylamine.

In a preferred embodiment of the invention, a compound of formula II, IV and VI, wherein R and R 'are lower alkyl, benzyl or benzyl substituted on the phenyl moiety by halogen, lower alkyl or lower alkoxy, is lower alkanoyloxy or lower alkanoyloxymethyl at the oxymethyl moiety is substituted by lower alkyl or cycloalkyl, preferably lower alkyl, R ^{1 is} pharmaceutically acceptable esterified or amidated carboxy, preferably lower alkoxycarbonyl, and R ^{2 is} acyl, preferably lower alkoxycarbonyl, by treatment with an inorganic acid such as a hydrohalic acid or sulfuric acid, in particular hydrochloric acid, or with aqueous alkalis, preferably alkali metal hydroxides, in particular lithium or sodium hydroxide, preferably at elevated temperature, converted into a compound of formula II, IV or Vl, wherein R and R 'are hydrogen, R ^{1 is} carboxy means and R ² stands for hydrogen.

The abovementioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably those which are inert to the reactants and solvents thereof, further catalysts, condensates or other named agents and / or in an inert atmosphere, at low Temperatures, room temperature or elevated temperatures, preferably at the boiling point of the solvents used and at atmospheric or superatmospheric pressure. The preferred solvents, catalysts and reaction conditions are given in the following illustrative examples.

The invention further extends to all variants of the present methods in which an intermediate product obtainable at any stage thereof is used as the starting material and the remaining stages are carried out, or where the process is terminated at any stage thereof or where the starting materials occur under the reaction conditions, or wc d'e reaction components are used in the form of their salts or pure antipodes.

In the main, such starting materials should be used in the named reactions which lead to the formation of the compound as they have been listed above as being particularly preferred.

The C.-invention also relates to all novel starting materials and processes for their preparation.

Depending on the choice of starting materials and methods, the new compounds may be in the form of one of the possible isomers or mixtures thereof, for example, depending on the number of asymmetric carbon atoms as pure optical isomers such as antipodes or as mixtures of optical isomers such as racemates or as mixtures of diastereoisomers or geometric isomers. The mentioned possible isomers and their mixtures are within the scope of the present invention; various specific isomers are preferred, as previously mentioned.

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

Resulting racemates can be separated by known methods in the optical antipodes, for example by reaction of an acidic end product with an optically active base which forms salts with dor rncemischen acid, and separating the salts thus obtained, for example by fractional crystallization, in the diastersoisomeren salts from which the optically active free carboxylic or Phosphorsäureantipoden can be released after acidification. The basic racemic products can also be resolved into the optical antipodes, e.g. By separating the diastereoisomeric salts thereof with an optically active acid and releasing the optically active basic compound by treatment with a standard base. Racemic products of the invention can thus be separated into their optical antipodes, z. B. by fractional crystallization of d- or MTartraten, almonds, camphorsulfonites) or d- or X- (a-methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamine, brucine or strychnine) salts. The acidic compounds of the invention can also be resolved by separating the diastereoisomeric ester or amide derivatives prepared from an optically active alcohol or amine and liberating the separated optically active compound. Advantageously, the more active of the two antipodes is isolated.

Finally, the compounds according to the invention are obtained either in free form or as salts. Any resulting base may be converted to a corresponding acid addition salt, preferably using a therapeutically acceptable acid or anion exchange preparation, or the resulting salts may be converted to the corresponding free bases, for example by using a stronger base such as a metal or ammonium hydroxide or a basic salt, e.g. Example, an alkali metal hydroxides or carbonatr, or a cation exchange preparation or an alkylene oxides such as propylene oxide. A compound according to the invention having a free carboxylic or phosphonic acid group can therefore be converted into the corresponding metal or ammonium salts. These or other salts, for example the Picrate, can also be used for the purification of the bases obtained; the bases are converted into salts, the salts are separated, and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, so far as a compound is mentioned in this context, the corresponding salt is also included, provided that this is possible or appropriate under the particular circumstances.

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

Dii3 pharmaceutical preparations according to the vorliegendon invention are those which are suitable for an enteral, ie for example oral or rectalo, transdermal and parenteral administration to mammals including humans, for blocking the N-methyl-D-aspaitatsensitive amino acid receptor and for the treatment of diseases, which are responsive to blocking of the N-methyl-D-aspartate sensitive amino acid receptor, such as cereal ischaemia, convulsive disorders and anxiety, and which contain an effective amount of a pharmacologically active compound of the present invention alone or in association with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the present invention are useful in the preparation of pharmaceutical compositions containing an effective amount thereof, with the addition or admixture of excipients suitable for enteral or parenteral administration. Preferred are tablets and gelatin capsules containing the active ingredient together with a) diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, e.g. Silica, talc, stearic acid, their magnesium or calcium salts and / or polyethylene glycol; for tablets also c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcollulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if desired, d) disintegrating agents, for example starches, agar-agar, alginic acid or its sodium salt or foaming mixtures; and / or e) absorbents, colorants, flavorings and sweeteners. Injectable preparations are preferably aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. Named preparations may be sterilized and / or contain adjuvants, for example preservatives, stabilizing, wetting or emulsifying agents, solubilization mif. Salts for regulating the osmotic pressure and / or buffer. In addition, they may also contain orally therapeutically valuable substances. These preparations are prepared by conventional mixing, granulation or coating methods and contain about 0.1 to 76%, preferably about 1 to 50% of the active components.

Suitable formulations for transdermic administration include an effective amount of a compound of formula I with carrier. Advantageous carriers are absorbable pharmacologically acceptable solvents which assist passage through the skin of the host. In the characteristic case, transdermal systems are in the form of a plaster having a protective layer, a drug reservoir, optionally with carriers, optionally a flow rate control device which delivers the active agent to the skin of the host at a controlled and predetermined level over an extended period of time, and adjuvants Attach the system to the skin. The invention also relates to a method for blocking the mammalian N-methyl-D-aspartate sensitive amino acid reuptake receptor and to a method of treating mammalian diseases such as those responsive to blocking of the N-methyl-D-aspartate sensitive amino acid reuptake receptor, for example cerebral ischaemia, convulsive diseases and anxiety states, wherein an effective amount of a compound of the invention is used as the pharmacologically active substance, and preferably in the form of the above-mentioned pharmaceutical preparations. A particular embodiment dwon commits to a method for the treatment of cerebral ischaomie and for the prevention of brain damage as ^I: olge of cerebral ischaemia (a stroke) in mammals, which consists in applying an effective amount of an N-methyl-D-aspartate blocking compound of the invention or a pharmaceutical preparation containing such Vorbindung, administered to a mammal, which requires a self-treatment.

The dosage of the active compound administered depends on the genus of the warm-blooded animal (mammal), the body weight, the age, the individual condition and the mode of administration.

A unit dosage for a mammal of about 50 to 70 kg may contain between about 5 and 100 mg of the active component.

embodiment

The invention will be explained in more detail below with reference to some examples.

The following examples are intended to illustrate the invention and are not intended to be limiting of the same. The temperatures are given in degrees Celsius. Unless otherwise specified, all evaporations are carried out under reduced pressure, preferably approximately between 2 and 13 kPa.

Example 1 Ethyl 4-l1- (3-diethylphosphonoprop-2-enyl) -1-tert-butoxy-carb-n-pyridine-2-carboxylate is hydrolyzed with 6N hydrochloric acid. This gives 4- [1- (3-phosphonoprop-2-enyl) -1-piperidine-2-carboxylic acid.

The starting material is prepared as follows: 4- (2-Hydroxyethyl) pyridine is oxidized to 4- (2-hydroxyethyl) pyridine N-oxide, which in turn is treated with trimethylsilyl cyanide to give 4- (2-hydroxyethyl) -2 cyanopyridine is obtained.

The latter is converted into the 4- (2-Hydroxyethy!) - 2-pyridincarbonsäureethylester and then hydrogenated to 4- (2-hydroxyethyl) -piperidine -? - Carbonsäureethylester.

A solution of 2.01 g of 4- (2-hydroxyethyl) -piperidine-2-carboxylic acid ethyl ester in 5 ml of dichloromethane is added to a solution of 2.20 g of di-tert-butyl dicarbonate in 10 ml of dichloromethane. After standing for 10 minutes, the solvent is removed and the residue is subjected to flash chromatography with hexane / ethyl acetate (1: 1). This gives the 4- (2-hydroxyethyl) -1-tert-butoxycarbonylpiperidiit-2-carboxylic acid ethyl ester.

To a solution of 1.56 g of dimethyl sulfoxide in 10 ml of dichloromethane are added at -78 ⁰ C, 2.2 g of oxalyl chloride. After 20 minutes, 2.4 g of 4- (2-hydroxyethyl) -1-tert-butoxycarbonylpiperidine-2-carboxylic acid ethyl ester in 5 ml of dichloromethane are added. The batch is stirred for one hour and 2.2 g of triethylamine are added. The ice bath is removed, the solvents are stripped off and the residue is flash chromatographed with hexane / ethyl acetate (7: 3). Is obtained as en ι i-tert-butoxycarbonylpiperidin ^ -ethoxy-carbonyl ^ acetaldehyde.

At -78 ° i, 2.73 ml of m-butyllithium are added to 2.02 g of (diethyl-phosphono) methane in 20 ml of anhydrous tetrahydrofuran. After 5 minutes, 2.08 g of i-tert-butoxycarbonyl-piperidine-ethoxy-carbonyl-M-acetaldehyde in 5 ml of tetrahydrofuran are added. The mixture is then refluxed for 16 hours. The cooled mixture is concentrated and subjected to flash chromatography (95: 5 dichloromethane / methanol). This gives the 4- [1- (3-Diethylphosphonoprop ^ -enyOl-i-tert-butoxycarbonylpiperidiri ^ -carboxylic acid ethyl ester.

Example 2: The following compounds can be prepared according to the procedures described in general terms in the preceding example:

(a) trans3-i1-i4-phosphonobut-3-enyl)] - pyrrolidine-2-carboxylic acid;

(b) trans 3- | 1 - (4-phosphonobut-2-enyl)) - pyrrolidine-2-carboxylic acid.

The starting material for compound (a) can be prepared as follows: trans N -ethoxycarbonylpyrrolidine -ethoxycarbonyl-S-acetaldehyde is condensed with (C ₆ Hs) SP = CHOCH ₃ under the conditions of the Wittig reaction to give trans N-ethoxycarbonyl-pyrrolidine ^ -ethoxycarbonyl-S-propionaldehyde. Condensation with bis (diethylphosphono) methane under the conditions described above (see Example 1) gives the trans 3- [1- (4-diethylphosphonobut-3-enyl)] - pyrrolidine-2-carboxylic acid ethyl ester.

The starting material for compound (b) can be prepared as follows: the alcohol trans N-ethoxycarbonyl-3- (2-hydroxyethyl) -pyrrolidine-2-carboxylic acid ethyl ester is oxidized to the aldehyde trans N-ethoxycarbonylpyrrolidine -ethoxycarbonyl-S-acetaldehyde, which is condensed with triphenylphosphoranylidene acetaldehyde under conditions of the Wittig reaction; the resulting α, β-unsaturated-C ^ Ädehyde is reduced to the corresponding alcohol, which is converted into the bromide. Condensation with triethyl phosphite gives ethyl 3- [1- (4-diethylphosphonobut-2-enyl)] pyrrolidine-2-carboxylate.

Example 3: 4- [1- (3-phosphonoprop-1-enyl)] - piperidine-2-carboxylic acid can be prepared in a similar manner by using the 4-hydroxy-methyl-N-ethoxycarbonyl-piperidine-2-carboxylic acid ethyl ester as an intermediate ,

Example 4: At -78 ° C, 20.3 ml of butyllithium (1.64 M) are added to 8.5 ml of tetraethylmethylenediphosphonate 1b (diethylphosphono) methane] in 100 ml of anhydrous tetrahydrofuran. For 5 minutes 9.26 g of 1- (tert-butoxycarbonyl) -2-ethoxycarbonylpiperidine-4-acetaldehyde in 125 ml of anhydrous tetrahydrofuran are added. The mixture is refluxed for 18 hours, cooled, concentrated and purified by flash chromatography using ethyl acetate / hexane (75:25 to 9: 1). This gives 4- [1- (3-diethylphosphonoprop-2-enyl)] - 1- (tert-butoxycarbonyl) -piperidine-2-carboxylic acid, ethyl ester.

The starting material is prepared as follows: A solution of 4-pyridylacetic acid in 500 ml of anhydrous ethanol containing 75 ml of concentrated succinic acid is refluxed for 18 hours. The solution is cooled to ⁰ ° C. and neutralized by addition of sodium hydroxide solution and saturated aqueous sodium carbonate solution. Extraction with ethyl acetate yields after concentration in vacuo 4-pyridylacetic acid ethyl ester.

A solution of 23.0 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 40 minutes for 5O ⁰ 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 15% aqueous sodium hydroxide and 20 ml of water. The solid is filtered off and the filtrate is concentrated under reduced pressure, thus obtaining 4-pyridylethanol.

A solution of 16.3 g of 4-pyridylethanol, 21.8 g of chloro-tert-butyl-dimethylsilane 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 concentrated in vacuo. This gives 4- (tert-butyldimethylsilyloxy-ethyl) -pyridine.

To a stirred solution of 28.8 g of 4- (tert-butyldimethylsilyl-oxyethyl) -pvridine in 300 ml of dichloromethane is added 24 g of m-chlorobenzoic acid. After 4 hours, the solution is washed with aqueous Natriumcarbonatlösuny, then with water. The solution is dried over sodium sulfate, filtered and concentrated in vacuo. This gives the 4- (tert-butyldimethylsily! Oxyethyl, -pyridine N-oxide.

A solution of 28, eg 4- (tert-butyl-dimethylsilyloxyethyl) -fyridin-N-oxide, 60.3 ml of trimethylsilyl cyanide and 31.5 ml of triethylamine is refluxed under nitrogen for 3 hours and stirred. The dark solution is cooled in an ice bath, 30 ml of ethanol was added, then 400 ml of ethyl acetate and 200 ml of hexane. The solution is washed twice with 150 ml of water, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using ethyl acetate / hexane (1:10). This gives 4- (tert-butyl-dimethylsilyloxyethyl) -2-cyanopyr din.

A solution 22.2 g of 4- (tert-butyl-dimethylsilyloxyethyl) -2-cyano-pyridine in 220 ml of anhydrous ethanol containing 0.10 g of sodium is stirred for 24 hours at room temperature. The solution is then cooled to ⁰ ° C. and 22 ml of 6 N hydrochloric acid are added. The solution is stirred at room temperature for 16 hours, cooled to ⁰ ° C., 7.5 ml of 6N sodium hydroxide are added, then 75 ml of saturated aqueous sodium carbonate. Extraction with dichloromethane and flash chromatography using tsiqester imposes the 4- (2-hydroxyethyl) -pyridin-2-c ». ά onsäureethylester.

A mixture of 8.371 4- (2-hydroxyethyl) -pyridine-2-carboxylic acid ethyl ester in 130 ml of acetic acid and 4 g of platinum oxide is hydrogenated at 345kPa. Filtration, concentration in vacuo, neutralization with potassium carbonate and extraction with dichloromethane gives an oil which is purified by flash chromatography, wounded with dichloromethane / methanol saturated with ammonia (20: 1). This gives the 4- (2-hydroxyethvi) -piperidine-2-carboxylic acid ethyl ester.

A solution of 7.9 g of ethyl 4- (2-hydroxyethyl) -piperidine-2-carboxylate and 9.0 g of di-tert-butyl dicarbonate in 80 ml of dichloromethane is added. Stirred for hours at room temperature and concentrated in vacuo. This gives 1 - (vert-Butoxycarbonyli-4- (2-hydroxy-ethyl) -piperidine-2-carboxylic acid ethyl ester.

A solution of 11.3 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). This gives the 1- (tert-butoxycarbonyl) -2-ethoxy-carbonyl-piperidine-4-acetaldehyde.

Example 5: A Gsmisch 4,67g of 4-I1- (3-Diethylphosphonoprop-2-enyl)] - 1- '(tert-butoxycarbonyl) -piper _l din-2-carboxylate und75ml6N hydrochloric acid is heated under reflux for 12 hours. The solution is concentrated to dryness in vacuo. The residue is taken up in 50 ml of ethanol and 3.8 ml of propylene oxide are added. The solid which separates is filtered off and dried in vacuo. This gives the cis-4- [1- (3-phosphonoprop-2-unyl) -1-piperidine-2-carboxylic acid, mp. 163-165 ° C.

Example 6 At -78 ⁰ C 6,9rr.l butyllithium (1.6M) are added to 2.9ml tetraethyl somi in anhydrous tetrahydrofuran. After 5 minutes, 2.47 g of trans i-acetylpiperidine-ethoxycarbonyl-acetaldehyde in 55 ml of anhydrous tetrahydrofuran are added. The mixture is refluxed for 18 hours, cooled, concentrated and purified by flash chromatography using dichloromethane / ethanol (100: 3). This gives the trans 4- [1- (3-Diethylphosphonoprop ^ -enyDJ-i-acetyl-piperidin ^ -carboxylic acid ethyl ester.

The starting material is prepared as follows: At 0 ⁰ C 9,4ml acetic anhydride to a stirred solution of 13.5 g 4- (2-hydroxyethyl) piperidine-2-carbonsäureethylestor in 75ml of pyridine are added. After stirring at room temperature for 30 minutes, the solution is concentrated in vacuo and ethyl acetate (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 concentrated in vacuo. The residue is taken up in 100 ml of ethanol, 5 g of powdered potassium carbonate are added and the mixture is stirred for one hour at room temperature. The solution is filtered, concentrated in vacuo and purified by flash chromatography using dichloromethane / ethanol (95: 5). This gives the trans 1-acetyl-4- (2-hydroxyethyl) -piperidine-2-carboxylic acid ethyl ester. 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 chlorochromai 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). This gives the trans 1-acetylpiperidine-2-ethoxycarbonyl-4-acetaldehyde.

Example 7: A mixture of 2.5 g of ethyl 4- [1- (3-diethylphosphono-prop-2-enyl)] - 1-acetylpiperidine-2-carboxylate and 40 ml of 6 N hydrochloric acid is refluxed for 12 hours. The solution is concentrated to dryness in vacuo. The residue is taken up in 20 ml of ethanol and 2.3 ml of propylene oxide are added. The solid which separates out is filtered off and dried in vacuo. This gives the trans 4-i1- (3-phosphonoprop-2-enyl) -1-piperidine-2-carboxylic acid, mp. 132-14O ⁰ C.

Example 8: A solution of 0.334 g of trans ^ .M-O-bromoprop-i-enylH-i-tert-butoxycarbonyD-piperidine-ethylcarboxylate and 3.5 ml of triethylphosphite is refluxed under nitrogen for 70 minutes. The cooled solution is concentrated in vacuo and purified by flash chromatography using dichloromethane / methanol (100: 3). This gives the trans 4- [1- (3-diethylphosphonoprop-1-enyl)] - 1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid ethyl ester.

The starting material is prepared as follows: 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 through silica gel and concentrated in vacuo. This gives 4- (tert-butyl-dimethylsilyl-oxymethyl) pyridine.

A solution of 40.6 g of 4- (tert-butyl-dimethylsilyloxymethyl) -pyridine and 40 g of m-chloroperbenioic acid in 500 ml of dichloromethane is stirred for 16 hours at room temperature. The solution is washed with 2N sodium hydroxide solution and water, dried over sodium sulfate, filtered and concentrated in vacuo. This gives 4- (tert-butyldimethylsilyloxymethyl) pyridine N-oxides.

A solution of 37.9 g of 4- (tert-butyldimethylsilyloxymethyl) pyridine N-oxides, 8 ml of trimethylsilyl cyanide and 44 ml of triethylamine is refluxed under nitrogen for 2 hours and stirred. The dark solution is cooled in an ice bath, then 40 ml of ethanol zugegebcin, then 500 ml of ethyl acetate. The solution is washed twice with water, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromatography using ethyl acetate / hexane (1:10). This gives 4- (tert-butyldimethylsilyloxymethyl) -2-cyanopyridine.

A solution of 21g of 4- (tert -butyl-dimethylsilyloxymethyl) -2-cyanopyridine in 220ml of anhydrous ethanol containing 0.2g of sodium was stirred wild at room temperature for 18 hours, cooled to 0 ° C, then 22ml of 6N hydrochloric acid was added , The solution is stirred at room temperature for 18 hours, cooled to 0 ° C, 7.5 ml of 6N sodium hydroxide are added, then 20 ml of saturated aqueous sodium carbonate solution. Extraction with dichloromethane, then drying, filtration and concentration of the extract gives an oil. which crystallized from ether. This gives the 4- (hydroxy-methyl) pyridine-2-carboxylic acid ethyl ester.

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 hydrogenated at 344 kPa. Filtration, concentration in vacuo and neutralization with potassium carbonate in dichloromethane yields an oil which is purified by flash chromatography using dichloromethane / methanol saturated with ammonia (20: 1).

This gives ethyl 4- (hydroxymethyl) piperidine-2-carboxylate.

A solution of 5.16 g of ethyl 4- (hydroxymethyl) piperidine-2-carboxylate 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 concentrated in vacuo to give 1- (tert-ButoxycarbonylM-lhydroxymethylJ-piperidine ^ -carboxylic acid ethyl ester.

A solution of 7.9 g of tert-butoxycarbonylM-1-hydroxymethyl-piperidine -carboxylic acid ethyl ester and 9,9 g of pyridinium chlorochromate in 175 ml of dichloromethane is passed at room temperature for 3 hours. The mixture is filtered and purified by flash chromatography using ethyl acetate / hexane (25:75). This gives 1 (1G-t- butoxy- carbonyl- U-ethoxycarbonyl-piperidine-carboxaldehyde.

A solution of 1 g of tert-butoxycarbonyl-ethoxycarbonyl-piperidinecarboxaldehyde and 2 g offorrimethylenetriphenylphosphorane in 16 ml of toluene is heated for 2 hours at 100 ° C. (bath temperature). The solution is cooled and purified by flash chromatography using ethyl acetate / hexane (25:75). This gives the 1- (tert-butoxycarbonyl) -2-ethoxycarbonylpiperidine-4-acrylaldehyde.

A solution of 0.83 g of 1- (tert-butoxycarbonyl) -1-ethoxycarbonyl-piperidine-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 are added, then ice-cold water The mixture is extracted with dichloromethane, the extract is dried over sodium sulfate, filtered and concentrated in vacuo Purification by flash chromatography using ethyl acetate / hexane (25:75) gives the trans 1- (tert -butyl) carbonyl). 4- [1- (3-h / droxyprop-l-enyl) J-piperidine-2-carboxylic acid ethyl ester.

A solution of 0.387 g of trans -butoxycarbonylM-MO-hydroxyprop-i-enyUl-piperidine ^ -carboxylic acid ethyl ester, 0.35 g of triphenylphosphine and 0.23 g of bromosuccinimide in 8 ml of dichloromethane is stirred initially at ⁰ ° C. and then at room temperature for 40 minutes , Purification by flash chromatography using ethyl acetate / hexane (1: 9) gives dan 4- [1- (3-bromoprop-1-enyl)] - 1- (tert-butoxycarbonyl) -piperidine-2-carboxylic acid ethyl ester.

Example 9: A solution of 0.39 g of ethyl 4- [1- (3-diethylphosphonoprop-1-enyl)] - 1- (tert-butoxycarbonyl) -piperidine-2-carboxylate and 2.3 ml of trifluoroacetic acid in 8 ml of dichloromethane is added Room temperature stirred 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 J gives the trans 4- [1- (3-diethylphosphonoprop-1-enyl)] - piperidine-2-carboxylic acid ethyl ester.

Example 10: A solution of 0.265 g of 4- [1- (3-diethyiphosphonoprop-enyl) -J-piperidine-2-carboxylic acid ethyl ester in 5 ml of anhydrous ethanol containing 0.074 ml of butyl lithium (1.6M) becomes 72 Hours to 80 ^c C (Badternperatur) heated. After cooling, 0.025 ml of acetic acid is added, then excess saturated sodium bicarbonate solution, and the mixture is extracted with dichloromethane. Concentrating the dichloromethane extract using dichloromethane / isopropanol saturated with ammonia (20: 1); Ice 4 - [(1- (3-diethylphosphonoprop-1-enyl)] - piperidine-2-carboxylic acid ethyl ester.

Example 11:

a) A mixture of 0,142g ice of 4- [1- (3-Diethylphosphonoprop-1-enyl)] - piperidine-2-carboxylic acid ethyl ester and 2.5 ml of 6N ⁱ .Salzsäure is heated under reflux for 12 hours. The solution is concentrated to dryness in vacuo. The residue is taken up in 2 ml of ethanol, and 0.15 m! Propylene oxide is added. The solid that separates out is filtered off and stored in the

Vacuum dried. This gives the ice 4- | 1- (3-PiVjst> honoprop-1-enyl)] - piperidine-2-carboxylic acid, mp. 175 ° C (decomposition).

b) In an analogous manner, the hydrolysis of the trans-ester of Example 9 gives the corresponding trans-acid, mp 130-135 ° C.

c) A solution of ice 4- [1- (3-phosphonoprop-1-enyl) -1-piperidine 2-carboxylic acid in ethanol saturated with hydrogen chloride is heated at reflux overnight. The solvent is removed in vacuo. A solution of the residue in ethanol is treated with propylene oxide and concentrated to dryness. This gives the ethyl 4- [1- (3-phosphonoprop-1-enyl)] piperidine-2-carboxylate.

Example 12: To a solution of 0,234g trans-i ^ Ethox caiiJonyl ^ -ethoxycarbonyl-pyrrolidin-S-propionaldehyde in 5 ml of anhydrous tetrahydrofuran under nitrogen cooled to -78 ⁰ C, is slowly added a solution of tetraethyl 0,23ml and 0, 57ml butyllithium (1.6M) in 5ml anhydrous tetrahydrofuran, also at -78 ° C. The solution is refluxed for 14 hours, cooled and treated with 0.15 ml of acetic acid. The reaction is concentrated, diluted with water and extracted with dichloromethane. The extract is dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography using fissigester gives the trans 1-ethoxycarbonyl-3- [1- (4-diethylphosphonobut-3-enyl)] - pyrrolidine-2-carboxylic acid ethyl ester.

The starting material is prepared as follows: A mixture of 50 g of N- (2-cyanoethyl) glycine in 300 ml of ethanol saturated with hydrochloric acid gas is stirred for 1 hour at room temperature, then heated under reflux for 1 hour. After cooling, the solid is filtered off and the filtrate is neutralized with Nairnmbicarbonat, filtered again and concentrated. This gives N- (ethoxycarbonylmethyl) -β-alaninothylestei.

To a mixture of 49g of N- (ethoxycarbonylmethyl) -ß-n aninethylester and 30ml water, cooled to -1O ⁰ C! Is added dropwise 27,6ml Chlorkohlensäureethylestcr, followed by a solution of 12.7 g of sodium carbonate in 50ml of water. The mixture is warmed to room temperature, then heated to 55 ° C for 50 minutes. The mixture is cooled, extracted with toluene, the extract is washed with 2 N hydrochloric acid and water. The extract is dried over sodium sulfate, filtered, concentrated and distilled in vacuo. This gives N-iethoxycarbonylmothyO-N-lethoxycarbonyO-β-alsiiinethylesier.

A solution of 53.9 g of N-IEthoxycarbonylmethyl-N-ethoxycarbonyO-β-alanine ethyl ester in 100 ml of toluene is added dropwise to a stirred solution of potassium hexanediamine disilazide (429 ml, 0.653M) in 125 ml of toluene under nitrogen and cooled to CC. After 45 minutes at U ⁰ C, 21.6 ml of acetic acid are added, followed by a solution of 100 g of sodium phosphate (monobasic) in 1 uter water. The phases are separated, the organic phase is washed with a pH 7 buffer, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography using ethyl acetate / hexane (3: 7). This gives i-ethoxyrarbonyl-S-oxopyrrolidin ^ -carboxylic acid ethyl ester.

Cooled to a stirred suspension of 24g Benzyloxycarbonylmethyltriphenylphosphoniumbromid in 225 ml of anhydrous tetrahydrofuran under nitrogen and cooled to 0 ⁰ C, potassium hexamethyldisilazide 73ml! 0,652M) are added. After 1 minute, a solution of 11 g of i-ethoxycarbonyl-S-oxo-pyrrolidine -carboxylic acid ethyl ester in 50 ml of tetrahydrofuran is added, and the mixture is refluxed for 2 hours. After cooling, the mixture is filtered and concentrated in vacuo. The residue is taken up in ethyl acetate, washed with water, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography using ethyl acetate / hexane (1: 4). This gives an oil which is hydrogenated in 200 ml of ethanol with 5 g of 10% palladium on carbon. After filtration and concentration of the filtrate, i-ethoxycarbonyl-ethoxycarbonylpyrrolidine-S-acetic acid is obtained.

A solution of 10 g of 1-ethoxycarbonyl-ethoxycarbonylpyrrolidine-S-acetic acid in 50 ml of tetrahydrofuran is cooled to ⁰ ° C. and 55 ml of borane / tetrahydrofuran (1 M) are added dropwise. After 2 hours stirring at ^{0 0} C 200 ml of water are added, the mixture is extracted with ethyl acetate, washed twice with water and dried over sodium sulfate. The solution is filtered, concentrated and purified by flash chromatography using ethyl acetate / hexane (1: 1 to 7: 3).

This gives ice-1-ethoxycarbonyl-ethoxycarbonylpyrrolidine-S-ethanol.

A solution of 6 g of i-ethoxycarbonyl-ethoxycarbonylpyrrolidine-S-ethanol in 75 ml of dichloromethane containing 7.3 ml of diisopropylethylamine to which 5.1 ml of 85% benzyloxymethyl chloride is added is stirred for 3 hours at room temperature. The solution is washed with water and with saturated aqueous sodium carbonate solution. The solution is then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography using ethyl acetate / hexane (1: 4). 1-Ethoxycarbonyl-3- [2- (benzyloxymethoxy) -ethyl] -pyrrolidine-2-carboxylic acid ethyl ester is thus obtained.

A solution of 5.2 g of ethyl-i-ethoxycarbonyl-S-U-fbenzyloxymethoxy-ethyl-pyrrolidine -carboxylate in 75 mL of anhydrous ethanol containing 1 mL of butyllithium (1.6 M) is refluxed under nitrogen for 6 days. After cooling, 1.7 ml of 1N hydrochloric acid are added, the solution is concentrated in vacuo, cold water is added, and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, concentrated and purified by high performance liquid chromatography using ethyl acetate / hexane (15:85). This gives trans-1-ethoxycarbonyl-3- [2- (benzyloxymethoxy) -ethyl] -pyrrolidin-2-carboxylic acid ethyl ester.

A mixture of 1.64 g of ethyl 1-ethoxycarbonyl-3- [2- (benzyloxymethoxy) ethyl] -pyrrolidine-2-carboxylate 10 g of palladium on carbon in 35 ml of acetic acid is hydrogenated at 31OkPa. The mixture is filtered, concentrated in vacuo and purified by flash chromatography using ethyl acetate / hexane (6: 4 to 7: 3). This gives trans 1-ethoxycarbonyl-ethoxycarbonyl-pyrrolidine-S-ethanol.

A solution of 0.991 g of trans i-ethoxycarbonyl-ethoxycarbonyl-pyrrolidine-S-ethanol and 1.24 g of pyridinium chlorochrornate in 20 ml of dichloromethane is stirred under nitrogen for 4 hours. The mixture is filtered and purified by flash chromatography using ethyl acetate / hexane (1: 1). This gives the trans I-ethoxy-carbonyl ^ -ethoxycarbonylpyrrolidine-S-acetaldehyde.

To 0.4 g of trans i-ethoxycarbonyl-ethoxycarbonylpyrrolidine-S-acetaldehyde in 5 ml of anhydrous tetrahydrofuran under nitrogen, cooled to -78 ° C, is added dropwise a solution of 1.17 g of methoxymethyl-triphenylphosphonniumchlorid in 15 ml of anhydrous tetrahydrofuran, which 1 Contains 55 ml of potassium tert-butoxide / T6-tetrahydrofuran (1.6M). The solution is stirred at room temperature for 4 hours. 11 ml of 2 N hydrochloric acid are added and the mixture is stirred for 45 minutes. The solution is concentrated and then extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, concentrated, and the residue is purified by flash chromatography using ethyl acetate / hexane (1: 5 to 3: 7).

This gives the trans i-ethoxycarbonyl-ethoxycarbonyl-pyrrolidine-S-propionaldehyde.

Example 13: A mixture of 0.193 g of trans 1-ethoxycarbonyl-3- [1- (4-diethylphosphonobut-3-enyl)] -pyrrolidine-2-carboxylic acid ethyl ester and 4 ml of concentrated hydrochloric acid is refluxed for 16 hours. The solution is cooled and concentrated to dryness in vacuo. The solid which separates out is filtered off and dried in vacuo. This gives the trans 3- [1- (4-phosphonobut-3-enyl)] - pyrrolidine-2-carboxylic acid, mp. 110-115 ⁰ C (decomposition).

Example 14: To a solution of 0,426g ice i-ethoxycarbonyl-S ^ -ethoxycarbonylpyrrolidin-propionaldehyde in 10 ml of anhydrous tetrahydrofuran under nitrogen and cooled to -78 ⁰ C, is slowly added a solution of 0.45 mL Tetraethylmethyler.diphosphonat and 1, 06ml Butyllithium (1.6M) in 10ml anhydrous tetrahydrofuran, also at -78 ⁰ C, given. The solution is heated under reflux for 14 hours, cooled and treated with 0.3 ml of acetic acid. The reaction is concentrated, water is added and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, concentrated and purified by flash chromatography using f-.ssiafister. This gives ice-i-ethoxycarbonyl-SMM-diethylphosphonobut-S-enyl-1-pyrrolidinocarboxylic acid ethyl ester.

The starting mixture is prepared as follows: A solution of O, S08g icethoxycarbonyl-ethoxycarbonylpyrrolidine-S-ethanol and 1.14 g of pyridinium chlorochromate in 20 ml of dichloromethane is stirred for 4 hours under nitrogen. The mixture is filtered and purified by flash chromatography using Ess'gester / hexane (1: 1). This gives the ice 1-ethoxycarbonyl ^ -ethoxycarbonylpyrrolidine-S-acelaldehyde.

To 0,663g ice-i ^ Ethoxyrarbonyl -ethoxycarbonylpyrrolidin-S-acetaldehyde in 10 ml of anhydrous tetrahydrofuran under nitrogen cooled to -78 ⁰ C, a solution of 2.21 g of methoxymethyl-triphenylphosphonium chloride is added dropwise in 20 ml of anhydrous tetrahydrofuran, 2.6 ml which Potassium tert-butoxide / tetrahydrofuran (1.6M) contains. The solution is stirred for 4 hours at room temperature. 15 ml of 2 N hydrochloric acid are added and the mixture is stirred for 45 minutes. The solution is concentrated and then extracted with dichloromethane. The extract is dried over sodium sulfate, filtered and concentrated. Purification by flash chromatography using ethyl acetate / hexane (1: 5 to 3: 7) affords the 1-ethoxycarbonyl-ethoxycarbonylpyrrolidine-S-propionaldehyde.

Example 15: A mixture of 0.176 g of ethyl 1-ethoxycarhonyl-3- [1- (4-diethylphosphonobut-3-enyl) -l-pyrrolidine-2-carboxylate and 3.5 ml of concentrated hydrochloric acid is refluxed for 18 hours. The solution is in vacuo to ι ru ..! ::; ⁰ concentrated, the residue is in 1.5 m! ! Sopropanol / Mcthanol (5: 1), and 0.2 ml of propylene oxide are added. The solid which separates out is filtered off and dried in vacuo. Thus obtained ice 3- [1- (4-Phosphonobut-3-enyl)] - pyrrolidine-2-carboxylic acid, Fp.132-140 ⁰ C.

Example 16: A solution of 0.0665 g of trans 1-ethoxycarbonyl-3- [1- (4-bromobut-2-ethyl)] -pyrrolidine-2-carboxylic acid ethyl ester in 0.75 ml of triethyl phosphite is heated at reflux for 20 minutes. The solution is concentrated in vacuo and the residue is purified by flash chromatography using dichloromethane / ethanol (30: 1). This gives the trans 1-ethoxycarbonyl-3- [1- (4-diethylphosphonobut-2-enyl)] - pyrrolidine-2-carboxylic acid ethyl ester.

The starting material is prepared as follows: A solution of 0.225 g of trans 1 -ethoxycarbonyl-ethoxycarbonylpyrrolidine-S-acetaldehyde and 0.4 g of (formylmethylene) -triphenylphosphorane in 2 ml of dichloromethane is refluxed for 44 hours. The solution is concentrated and the reflux is purified by flash chromatography using ethyl acetate / hexane (2: 3). This gives the trans 1-ethoxycarbonyl-3-t1- (4-oxobut-2-enyl) | -pyrrolidine-2-carboxylic acid ethyl ester.

To a stirred solution of 0.102 g of trans 1-ethoxycarbonyl-3- [1- (4-oxobut-2enyl)] -pyrrolidine-2-carboxylic acid ethyl ester in 2 mL of ethanol, cooled to ⁰ ° C, is added 0.035 g of sodium borohydride. After 30 minutes at ⁰ ° C. and 30 minutes at room temperature, 0.05 ml of acetic acid are added, the solution is concentrated, water is added and the mixture is extracted with dichloromethane. The solution is dried over sodium sulfate, filtered and concentrated in vacuo. This gives the trans 1-ethoxycarbonyi-3- (1- (4-hydroxybut-2-enyl)] - pyrrolidine-2-carDonsäureethylester.

To a stirred solution of 0.0937 g of trans 1-ethoxycarbonyl-3- [1- (4-hydroxybut-2-enyl) -pyrrolidine-2-carboxylic acid ethyl ester and 0.1 g of triphenylphosphine in 2 ml of dichloromethane at 0 ° C, 0.067 g of N- Given bromosuccinimide. Purified: After 30 minutes at room temperature, the mixture is purified by flash chromatography using Essigester / hexane (1: 3). This gives the trans 1-ethoxyoiubonyl-3- [1- (4-bromobut-2-enyl)] - pyrrolidine-2-carborisauric acid diethyl ester.

Example 17: A mixture before. 0.053 g of trans-1-ethoxycarbonyl-3- (1- (4-diethylphosphonobut-2-enyl)] -pyrrolidine-2-carboxylic acid ethyl ester and 1.5 ml of concentrated hydrochloric acid are refluxed for 16 hours, the solution is concentrated to dryness in vacuo, the residue is taken up in 1 ml of methanol, 0.2 ml of propylene oxide are added and the solution is concentrated, the residue is purified by ion exchange chromatography eluting with 0.1 N aluminum hydroxide solution to give the trans 3- [1- ( 4-Phosphonobut-2-enyl)] - pyrrolidine-2-carboxylic acid, mp 138-145 ⁰ C..

Example 18 Preparation of an Injectable Formulation Containing 10 mg of the Active Compound per 5 ml of Solution:

composition

cis4- [1- (3-Phosphonoprop-1-enyl)] -

piperidine-2-carboxylic acid 10.0 g

Propylparaben 0.5 g

Water ad 5 000 ml

The active ingredient and ingredients are dissolved in 3 500 ml of water for injection, and the solution is diluted to 5000 ml. The solution is filtered through a sterile filter and filled under sterile conditions into injection vials, each vial containing 5 ml of the solution.

-is- 273 337

Example 19:

a) Preparation of 10000 tablets each with 10.0 mg active ingredient: ingredients

Ice 4- [1 - (3-phosphonoprop-i-enyl)] -

piperidine-2-carboxylic acid 100.00 g

Lactose 2535.00 g

Cornstarch 125,00 g

Polyethylene glycol 6000 150.00 g

Magnesium stearate 40.00g

VVasssr (sterile) q.s.

The powdery material is forced through a sieve with openings of 0,6rnm. The mixture is then mixed with the lactose, the magnesium stearate and half the amount of starch in a mixer. The other half amount of starch is suspended in 65 ml of water, and this suspension is added to the boiling solution of the polyethylene glycol in 260 ml of water. The formed paste is added to the powder mixture, which is optionally granulated with further water. The granules are dried overnight at 35 ° C, this drives through a sieve with 1.2 mm wide openings and compressed to concave tablets with upper Brurhkerbe.

In an analogous manner, the tablets containing dwt 1-50 mg of one of the other compounds disclosed above are prepared.

b) Preparation of 1000 capsules each containing 5 mg of active ingredient: excipients

cis4- [1- (3-Phosphonoprop-1-enyl)] - 5.00 g piperidine-2-carboxylic acid 212.00 g lactose 80.00 g Strength 3.00 g Magnesiumsteariit

Each powder win ι printed through a sieve with openings of 0.6mm diameter. The mixture is then mixed with the magnesium stearate in a mixer, then with the lactose and the starch until a homogeneous mass is obtained. Fill in No. 2 Hartgslatini. Capsules with 300mg each of the prepared mixture

 Analogously, capsules containing 1-50 mg of one of the other compounds disclosed above can be prepared.

Claims (16)

X CCH,) (D wherein one or both of the acidic hydroxy groups of the phosphonic acid moiety may be etherified, m is one or zero, R ^{1 is} carboxy, esterified carboxy or amidated carboxy, the heterocyclic five- or six-membered ring may additionally be substituted on the carbon and / or 3r is nitrogen, a carbon Have carbon double bond or may be condensed with a carbocyclic six-membered ring starting from adjacent carbon atoms, A is lower alkenylene; and salts thereof, characterized by a) condensation of an aldehyde or ketone of formula VII (VII) wherein m, R ¹ and the heterocyclic ring are as defined for formula I, but wherein R ¹ and amino groups are in protected form, and A 'is lower alkyl which is substituted by oxo and has one carbon atom less than the alkenylene group A, with a Tetraester derivative of methylene diphosphonic acid, and under basic conditions and, if necessary, by deprotection of the product obtained, to give a compound of formula I wherein the double bond within group A is immediately adjacent to the phosphono group; or
b) condensation of a compound of the formula VIII, X- ß (VIII) wherein A, m, R ¹ and the heterocyclic ring are as defined for formula I and X is reactive esterified hydroxy, with a compound capable of introducing the phosphonic acid moiety and having one of formula IX or X, - OR "(IX) P (R '') ₃ (X) wherein R "denotes lower alkyl and R" 'represents halogen or lower alkoxy, and if necessary, converting the resulting phosphonic acid derivative into the phosphonic acid or other ester derivative thereof; or c) conversion into R ^{1 of} a substituent other than R ¹ in position 2 on the heterocyclic ring in a compound which is sonromatic identical to a compound according to the invention; further, by carrying out these methods with, if necessary, temporary protection of all disordering reactive groups and subsequent liberation of the resulting compound of the invention; if desired, conversion of a resulting compound of the invention into a another compound of the invention and / or, if desired, conversion of the resulting free compound into a salt or a resulting salt in the free compound or another salt; and / or separating an isomer mixture or mixture of racemates into the individual isomers or racemates ⁴ and / or, if desired, separating a racemate into the optical antipodes. 2. The method according to claim 1, characterized in that the heterocyclic ring system, together with the substituent R ^{1 is} represented by gegeoenenfalls substituted 2-carboxypyrrolidinyl, 2-carboxy-2,5-dihydropyrrolyl, 2-carboxy-1,2, 3,6-tetrahydropyridinyl, 2-carboxy-1,2-F, 6-tetrahydropyridinyl, 2-carboxypiperidinyl, 2-carboxy-tetrahydroquinolinyl, 2-carboxy-perhydroquinolinyl, 2-carboxy-2,3-di-hydroindolyl or 2-carboxy-perhydroindolyl, wherein carboxy may be esterified or amidiort. 3. The method according to claim 1, characterized in that compounds of the formula il 4 Α- Ρ -OR ^{1 0R} ₂ V and compounds of formula II having a double bond between C-3 and C-4 or between C-4 and C-5 of the piperidinyl ring, wherein the phosphone-containing chain is attached to the 3, 4 or 5 position of the piperidinyl or tetrahydropyridinyl ring and R and R 'are independently hydrogen, lower alkyl, benzyl, or benzyl substituted on the phenyl moiety by halogen, lower alkyl or lower alkoxy, lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted on the oxymethyl moiety by lower alkyl or cycloalkyl, R ^{1 is} carboxy or pharmaceutically acceptable esterified or amidated carboxy; R ^{2 is} hydrogen, lower alkyl, aryl-lower alkyl or acyl; R ^{3 is} hydrogen, lower alkyl or aryl-lower alkyl; A is lower alkenylene; and salts thereof. 4. An ancestor according to claim 3, characterized in that R and R 'are independently hydrogen, lower alkyl, benzyl, Niederalkanoyloxymethyl or Niederalkanoyloxymethyl, which is substituted on the oxymethyl moiety by lower alkyl, cyclohexyl or cyclopentyl; R "carboxy, carbamoyl-o-1" is pharmaceutically acceptable esterified carboxy as defined herein; R ² and R ^{3 are} hydrogen or lower alkyl; A is alkenylene of 2 to 4 carbon atoms. 5. The method according to claim 3, characterized {, ekennzeichnet that R and R 'are independently hydrogen, lower alkanoyloxymethyl or lower alkanoyloxymethyl, which is substituted on the oxymethyl moiety by lower alkyl; R ^{1 is} carboxy, carbamoyl or lower alkoxycarbonyl, lower alkanoyloxymethoxycarbonyl, straight chain di-lower alkylamino C ₂ -4 alkoxycarbonyl or pyridylmethoxycarbonyl; R ² and R ^{3 are} hydrogen; A is in the 4-position and is alkenylene having 3 or 4 carbon atoms and the double bond adjacent to the phosphono group. 6. The method according to claim 3, characterized in that compounds of the formula III X ⁸ \ O
U
- P - OH OH wherein A is 1,3-propenylene, preferably having the double bond adjacent to the phosphono group; R ^{1 represents} carboxy or pharmaceutically acceptable esterified carboxy as defined herein, as well as pharmaceutically acceptable salts thereof. Process according to claim 1, characterized in that 4- [1- (3-phosphono-prop-2-enyl)] - piperidine-2-carboxylic acid and pharmaceutically acceptable salts thereof are prepared. 8. The method according to claim 1, characterized in that 4- [1- (3-phosphono-prop-1-enyl)] - _v oiperidin-2-carboxylic acid and pharmaceutically acceptable salts thereof are prepared. 8. The method according to claim 1, characterized in that compounds of the formula IV or perhydro derivatives thereof, wherein R and R 'independently represent hydrogen, lower alkyl, benzyl or benzyl substituted on the phenyl moiety by halogen, lower alkyl or lower alkoxy, lower alkanoyloxymethyl, lower alkanoyloxymethyl substituted on the oxymethyl moiety by lower alkyl or cycloalkyl; R ^{1 is} carboxy or pharmaceutically acceptable esterified or amidated carboxy; R ^{2 is} hydrogen, lower alkyl, aryl-lower alkyl or acyl; R ^{4 is} hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; A represents lower alkenylene; and salts thereof. 10. The method according to claim 9, characterized in that compounds of the formula V (V) or perhydroquinoline derivatives thereof wherein A is 1,3-propenylene having the double bond adjacent to the phosphono group; R ^{1 is} carboxy or pharmaceutically acceptable esterified carboxy as defined herein; and pharmaceutically acceptable salts of these compounds having a salt-forming functional group. 11. The method according to claim 1, characterized in that compounds of the formula Vl O
'.A - P - OR ¹ N ^{κ x} _D l OR u ^R (Vl) and compounds of formula VI are prepared with a double bond between C-3 and C-4 of the pyrrolidinyl ring, and wherein R and R 'are independently hydrogen, lower alkyl, benzyl or benzyl substituted at the phenyl moiety by halogen, lower alkyl or lower alkoxy, lower alkanoyloxymethyl or lower alkanoyloxymethyl which substituted on the oxymethyl part by Niec eralkyl or cycloalkyl, bedsuten; R ^{1 is} carboxy or pharmaceutically acceptable s esterified or amidated carboxy; R ^{2 is} hydrogen, lower alkyl or acyl; R ^{3 is} hydrogen, lower alkyl or aryl-lower alkyl; A is lower alkenylene; and salts thereof. 12. The method according to claim 11 _1, characterized in that the phosphono-ent.; Nde group is attached in the position 3; R and R 'are hydrogen; R ^{1 is} carboxy, lower-N-carbonyl, lower-alkanoyloxymethoxycarbonyl, di-lower alkylamino-straight chain C 1 -C 4 -alkoxycarbonyl or pyridylmethoxycarbonyl; R ² and R ^{3 are} hydrogen; A represents 1,3-propenyl with the double bond adjacent to the phosphono group. 13. The method according to claim 1, characterized in that trans 3- [1- (4-phosphonobut-3-enyl) lpyrrolidin-2-carboxylic acid and pharmaceutically acceptable salts thereof are prepared. 14. The method according to claim 1, characterized in that trans 3- [1- (4-phosphonobut-2-enyl)] - pyrrolidine-2-carboxylic acid and pharmaceutically acceptable salts thereof are prepared. 15. The method according to claim 1, characterized in that compounds selected from the group consisting of cis- ^ ti-IS-phosphonoprop ^ -enyljJ-piperidine ^ -carboxylic acid, tra: is 4- [1- (3-phosphonoprop-2- enyl)] - piperidine-2-carboxylic acid, cis4- [1- (3-phosphonoprop-1-enyl)] piperidine-2-carboxylic acid and trans 4- [1- (3-phosphonoprop-1-enyl)] - piperidine 2-carboxylic acid and pharmaceutically acceptable salts thereof. 16. The method according to claim 1, characterized in that compounds selected from ice 3- [1- (4-phosphonobut-3-enyl)] - pyrrolidine-2-carboxylic acid and pharmaceutically acceptable salts thereof are prepared. 17. The method according to claim 1, characterized in that a compound of formula II, IV or Vl, wherein R and R 'is lower alkyl, benzyl or benzyl which is substituted on the phenyl moiety by halogen, lower alkyl or lower alkoxy, lower alkanoyloxymethyl or lower alkanoyloxymethyl, which is substituted on the oxymethyl part by lower alkyl or cycloalkyl, R ^{1 is} pharmaceutically acceptable esterified or amidated carboxy, and R ^{2 is} acyl, by treatment with an inorganic acid, or with aqueous alkalis, in a compound of formula II, IV or Vl wherein R and R 'are hydrogen, R ^{1 is} carboxy and R ^{2 is} hydrogen. 18. The method according to claim 17, characterized in that a compound of formula II, IV or Vl, wherein R and R 'are lower alkyl and R ¹ and R ^{2 are} niaderalkoxycarbonyl, by treatment with an inorganic acid, or with aqueous alkalis, into a compound of formula II, IV or Vl wherein R and R 'are hydrogen, R ^{1 is} carboxy and R ^{2 is} hydrogen.