IE873149L - Unsaturated phosphonic 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

° r ^ A W W w "T 2 The present invention is concerned with the compounds of formula I, H®t—A—^ OR ' ( J- ) 1st—A—^ OR ' in which Het is a 2-R1~pyrrolidinyl, 2~R3-™2,5-dihydro-5 pyrrolvlp 2™R1~1,2,3,6-tetrahydropyridinyl» 2-R1-!,2,5,6~ tetrahydropyridinylf 2-R3--piperidinyl, 2-R1-tetrahydro-quinolinyl, 2 =R1 - per hy dr oqu i r? o 1 i ny 1, 2-R1-2, 3-dihydro-indolyl or 2-R^-perhydroindolyl group which also may be M-substituted by C1«-C4alkyl, phenyl~Ci -Chalky1, C2" 10 C7alkoxycarbonyl, benzyloxycarbonyl or by C2~C7alkanoyl and/or C-substituted in the heterocyclic 5- or 5-ring by C1-C4al!-cyl or by phenyl-Ci-C4alkyl and/or, in the fused benzo or cyclohexano radical that may b© present, by C^-C4alkyl, C1-C4alkoxy/ halogen or by trifluorouethyl, R1 15 is carboxy, C1-C4alkoxycarbonyl, carbamoyl or N-mono- or N,N~di-C^-c4alkylcarbamoyl, h is C2~C4alkenylene and R and R' are each independently hydrogen, C1-C4alkyl, benzyl t„ benzyl substituted in the phenyl moiety by halogen,, by Ci-C4alkyl or by C^-C^alkojq/^ C2-C7alkanoyl-20 oxymethyl, or Cj-Cyalkanoyloxymethyl substituted in the oxymethyl noiety by C^-C^alkyl or by C3~C8cycloalkyl ; and salts thereof™ These compounds are suitable as antagonists of the M-methyl-D-aspartate-sensitive excitatory amino acid receptor in mammals. 25 The present invention is further concerned with processes for preparing said compounds, with pharmaceutical compositions comprising said compounds, with processes for the manufacture of such pharmaceutical compositions and with the use of the compounds according to the 30 invention for the preparation of medicaments for treating conditions and diseases in mammals responsive to the effect of an excitatory amino acid receptor antagonist. 3 The compounds of the invention are active and useful in mammals as selective antagonists of the N-methyl-D~ aspartate (MMDA) sensitive excitatory amino acid receptor. The compounds of the invention are therefore 5 also useful, administered alone or in combination to mammals, for the treatment of disorders responsive to a blockade of the MMDA receptor, e.g. cerebral ischemia„ muscular spasms (spasticity), convulsive disorders (epilepsy) and anxiety. The compounds of the invention 10 are also considered effective in the treatment of Huntington1" s disease (Chorea hereditiva)* Fusion originating from adjacent carbon atoms with a six™ membered carbocyclic ring is fusion with e.g. cyclohexyl or phenyl such that the fused heterocyclic ring in 15 formula I is represented by a bicyclic ring system containing 9 or 10 ring-forming atoms,, depending on the value of the symbol a in formula I.

A preferred arrangement of the invention relates to compounds of the formula II />/-i ' (in ! °S Nji x and compounds of formula II with a double bond present between C-3 and c-4 or between C-4 and C~5 of the piperidinyl ring, wherein R and R' are each independently hydrogen,, Ci-C4&lkylt, benzyl, benzyl substituted in the 25 phenyl moiety by halogen,, by C^-C/jalkyl or by Ci-C4- alkoxy,, C2-C7alkanoyloxymethyl, or C2-C7aIkanoy 1 oxymethyl substituted in the oxymethyl moiety by C1-C4alkyl or by C3-Cacycl°alkyl, R1 is carboxy, Ci-C4alkoxycarbonyl, carbamoyl or N-mono- or N,N-di~C1-C4alkylcarbamoyl, R2 is 4 hydrogen, C1-C4alkyl, phenyl-C1-C4alkyl, C2-C7alkoxy= carbony1c ben2y1oxycarbony1 or C2~C7alkanoyl, R3 is hydrogen, c1~c4alkyl or phenyl-C1-C4alkyl, and A is C2-C4alkenyl@ne; and salts thereof. 5 Preferred are the compounds of formula II wherein R and R# are each independently hydrogen,, C1-C4alkyl, benssyl, C2~C7a1kanoy1oxyxne thy]. or C2-C7alksnoyloxymethyl substituted in the oxymethyl moiety by C^-C^alkyl, by cyclohexyl or by cvclopentyl, H1 is carboxy, carbamoyl or 10 C1-C4alkoxycarbonyl; R2 and R3 are hydrogen or Ci- C4alkyl, and A is alkenylene having from 2 to 4 carbon atomsand pharmaceutically acceptable salts thereof,, Further preferred are the compounds of formula II wherein R and R'? are each independently hydrogen, Co-15 C7alkanoyloxymethyl or C^-C^alkanoyloxyssethyl substituted in the oxymethyl moiety by C^-C^alkyl, R1 is carboxy,, carbamoyl or Ci-C4alkoxycarbonyl, B2 and R3 are hydrogen P and A is in the 4-position, and is alkenylene having 3 or 4 carbon atoms with the double bond adjacent to the 20 phosphono group; and pharmaceutically acceptable salts thereof.

Particularly preferred are the compounds of formula III Yv wherein A is 1,3-propenylene, preferably with the double 25 bond adjacent to the phosphono group, and R1 is carboxy or Ci-C4alkoxycarbonyl; and pharmaceutically acceptable salts thereof.

A preferred arrangement concerns the compounds of formula 5 III wherein the 2- and 4-substituents are cis to each other.

Another aspect of the invention relates to compounds of formula iv m A—OR' R'* —i- H i vyv (iv) i2 or perhydro derivatives thereof f wherein R and Rf are each independently hydrogenf, Ci--C4alkyl, benzyl, benzyl substituted ir# the phenyl moiety by halogen,, by Cj-C4alkyl or by C1-C4alkoxy, C2-C7alkanoyloxymethyl, or C2-10 C7alkanoyloxysiethyl substituted in the oxymethyl moiety by C1-c4alkyl or by C3~Cgcycloaikyl, R3- is carboxy, Ci_-C4alkoxycarbonyl, carbamoyl or N-mono~ or M^IP-di-Ci-C4alkylcarbaMoylc R2 is hydrogen, Cx-C4alkyl, phenyl-Cj-C4alkyl, C1-C7alkoxycarbonyl, benzyloxycarbonyl or C2~ 15 C7alkanoyl, R4 is hydrogen, Cx-C4alkyl, Ci-C4alkoxy, halogen or trifluorossethyl, and A is C2-C4alkenylene; and salts thereof.

Preferred are the compounds of formula ¥ (V) 20 or perhydroquinoline derivatives thereof, wherein A is 1,3-propenylene with the double bond adjacent to the phosphono group , and R~ is carboxy or Cx-C4alkoxy~ carbonyl; and pharmaceutically acceptable salts of said compounds having a salt-forming functional group. 6 Most preferred are the compounds of formula v wherein the 2- and 4~substituents are cis to each other.

A further aspect of the invention relates to compounds of formula VI R3—+ 4—A—P—OR ° 5 "y\i L I2 and the compounds of formula VI with a double bond present between C-3 and C-4 of the pyrrolidine1 ring, wherein R and R** are each independently hydrogen, Ci_-C4alkyl, benzyl, benzyl substituted in the phenyl moiety 10 by halogen, by -Chalky1 or by Ci-C4alJcoxy, C2-C7- alkanoyloxymethyl, or C^-C^alkanoyloxyaiethyl substituted in the oxymethyl moiety by Ci~C4alkyl or by C3~CQcycl©~ alkyl, R1 is carboxy, Cj-^alkoxycarbonyl, carbamoyl or M-aaono- or N,N-di-Cx-C4alkylcarbamoyl, R2 is hydrogen, 15 Cx-C4alkyl, Ci-Cyalkoxycarbonyl, benzyloxycarbonyl or €3-Cyalkanoyl, R3 is hydrogen, C1-C4alkyl or aryl-Ci-C4alkyl, and A is C2~C4alkenylene; and salts thereof.

Preferred are the compounds of formula VI wherein the phosphono-bearing group is attached at the 3-position? R 20 snd a* are hydrogen, R1 is carboxy or Ci -C4alk©3cy~ carbonyl, R2 and R3 are hydrogen,, and A is 1,3-propenyl- ene with the double borsd adjacent to the phosphono group? and pharmaceutically acceptable salts thereof.

The general definitions used herein have the following 25 Meaning in the context of the invention.

The term "lower" when used hereinbefore and hereinafter in connection with organic groups, radicals or compounds. 7 defines such groups, radicals or compounds having up to and including 7, preferably up to and including 4 and advantageously one, two or three carbon atoms„ C1-C4alkyl is, for example, ethyl, propyl, butyl or 5 advantageously methyl.

Cj-^alkenylene representing A denotes, for example, ethenylene, 1,3-propenylene, 1,4-but~l-enylene, 1,4-but-2-e.nylene, advantageously with the double bond adjacent to the phosphono grouping. 10 C1-C4alkoxy represents, for example, ethoxy, propoxy or advantageously methoxy.

C2~C7alkanoyl advantageously represents acetyl, propion-yl , n-butyryl, isobutyryl or pivaloyl, but may also be formyl- 15 C2~Cya1karsoy1oxy advantageously represents acetoxy, propionyloxy, n- or i-toutyryloxy or pivaloyloxy.

C3-Cgcycloalkyl represents, for example, cyclohexyl or cyclopentyl.

Halogen is preferably fluorine or chlorine., taut aiay also 20 represent bromine or iodine.

Phenyl-Ci -^alkyl advantageously represents benzyl or 2-phenethyl.

Ci-C7alkoxycarbonyl preferably contains 1 to 4 carbon atoms in the alkoxy moiety and represents,, for example, 25 methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl or advantageously ethoxycarbonvl.

H M-C1-C4alkylcarbam°yl is, for example, N-methylcarbamoyl, N-propylcarbamoyl or advantageously N-ethylcarbamoyl.

N^N-di-Cx-C^alkylcarbamoyl represents, for example, N,N-dimethylcarbaiaoyl, N-ethyl-N-aethylcarbamoyl and advant-5 ageously N,N-diethylcarbamoyl.

Salts of the compounds of the invention are preferably pharmaceutically acceptable salts , on the one hand metal or ammonium salts of the compounds of the invention having a free phosphono or carboxy group, more par-10 ticularly alkali or alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts," or advantageously crystallising araraoniu® salts derived from ammonia or organic amines^ such as methylaaine, diethyl-amine, triethylaaine, dicyclohexylaaine, triethanolaaine, 15 ethylenediamine, tris-(hydroxymethy1)aainoaethane or benzyltrimethylaaaoniua hydroxide. On the other hand the compounds of the invention which are basic amines fora acid addition salts with preferably pharmaceutically acceptable inorganic or organic acids, such as strong 20 mineral acids, for example hydrohalic acids, e.g. hydrochloric or hydrobroaic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. acetic, propionic, succinic, glycolic, lactic, aalic, tartaric, gluconic, citric, 25 ascorbic, maleic, fuaaric, pyruvic, paaoic, nicotinic aethanesulfonic, ethanesulfonic, hydroxyeth&nesulfonic, benzenesulfonic, p-toluenesulfonic or naphthalenesulfonic acid.

Salts that are not suitable for pharmaceutical purposes 30 mey be obtained for isolation or purification purposes. However,, only pharmaceutically acceptable salts are used for therapeutic purposes and these salts, therefore, are preferred. 8 The compounds of the invention exhibit valuable pharmacological properties, e.g. selective blocking of the N-methyl-D-aspartate~s@nsitive excitatory amino acid receptors in mammals. The compounds are thus suitable 5 for treating diseases responsive to the blocking of excitatory amino acid in mammals,, e.g. nervous system disorders„ particularly convulsive disorders (epilepsy) and anxiety.

These effects can be demonstrated in in vitro tests or in vivo animal tests advantageously using mammals or tissues or enzyme preparations thereof,, e.g., mica, rats or monkeys. The said compounds can be administered enterally or parenterally, advantageously orally or transdermal ly, or subcutaneous ly,, intravenously or intra-peritoneally, for example,, within gelatin capsules, or in the form of aqueous suspension or solutions. The in vivo dosage administered may range between about Q.oi to 100 ®g/kg (3 preferably between about 0.05 and 50 mg/kg, advantageously between about 0.1 ©nd 10 Eg/kg. The said compounds can be administered jjj vitro in the form of e.g. aqueous solutions for which the dosage may range jjk 0 between about 10 "* solar and 10 molar concentrations.

The inhibitory effect on the HHDA-type excitatory amino acid receptors is determined in vitro by Measuring the 25 inhibition of NMD&-induced ^■-acetylcholine (3H-kCh) release from corpus striatum tissue of rat brain„ according to J. Lehasann and B. Scatton, Brain Research 252, 77-89 (198,2) and Mature 297 , 422-424 (1982) .

Antagonists of NHDA-type excitatory amino acid receptors 30 competitvely antagonize NMDA-induced 3H-acetylcholine (3H-ACh) release from corpus striatum tissue of the brain. 10 15 20 ■1 0 The inhibition of MMDA-induced ^-acetylcholine (3H—ACh) release from rat striatal tissue slices by a. compound of the invention is expressed as a percentage of the release of 3H-ACh in response to stimulation with 5 50 juM NMDA compared with a. control test™ Tests are two-tailed with a minimum of n = 4 in each group. IC50 values represent the concentration of test compound required to inhibit by 50 % the 3H~ACh release increased by NMDA. 1© The inhibitory effect on the NMDA-type excitatory amino acid receptors is demonstrated in vivo by inhibition of NMDA-induced convulsions in mice.

Representative compounds of the invention prevent NMDA-induced convulsions in mice at doses down to about 15 1-2 nig/kg i. p.

A further indication of the anticonvulsant activity is that compounds of tile invention are effective in preventing audiogenically induced seizures in DBA/2 Mice [Chapman mi-, Ar2neim--Forsch. 34; 1261, (1984)]. 20 2-Aaaino- -phosphonoalkenoic acids and functional derivatives thereof having NMDA-antagonistic properties are known from GB-A-2104079. The compounds prepared in accordance with the invention differ from those compounds by the structural feature of the heterocyclic group Hefc 25 in place of the ^CH-NH2 group- The activity is determined as follows: Forty five minutes following compound or vehicle administration, mice are placed individually in a soundproof chamber- After a 30 second accommodation period, the mice are 30 exposed to a sound stimulation of 110 dB for 1 minute or 1 1 until the appearance of a tonic-clonic seizure. Control seizures consist of an initial wild running phase. The prevention of wild running is indicative of an anticonvulsant activity.

Test compounds in either distilled water solution or in a 3 % colloidal cornstarch suspension containing 5 % by weight polyethyleneglycol 400 and 0.34 % Tween 80, are administered orally or intraperitoneally in a volume of 10 ml/kg body weight.

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

The cerebral antiischemic activity,, that is the effect of the compounds of the invention in preventing or reducing brain damage in mammals caused by a transient, cerebral ischemia (as in a stroke), can be determined in the mongolian gerbil ischemia model, e.g. the model described by T. Xirino in Brain Research 239, 57-69 (1982).

The inhibitory effect on the observed hyperactivity and on the degeneration of neurons in the hippocampus region of the brain following a 5-minute period of ischemia is measured. The test compound is administered i.p. 15 minutes before the ischemia or 2,, 4 and S hours post ischemia.

Representative compounds of the invention, administered at a dose of 10 mg/kg i.p. either before or after the ischemia episode, inhibit the ischemia-induced hyperactivity of the gerbil and reduce the degeneration of cerebral neurons as measured in the hippocampus region of 1 the brain.

The aforementioned advantageous properties render the compounds of the invention useful as antagonists of the N-methyl-D-aspartate-sensitive excitatory amino acid 5 receptor in mammals and for the treatment of conditions responsive thereto, such as anxiety and convulsive disorders.

The compounds of the invention, i.e. the compounds cited hereinabove,, may be prepared by conventional processes, 10 e.g. by a) condensing an aldehyde or ketone of formula vn Het-A' (vii) wherein Het and R1 are as defined for formula I but R1 and amino groups ar© in protected form, and A' is Ci« 15 C3alkyl substituted by oxo and containing one carbon atom less than the alkenylene group A, with a tetraaster derivative of methylenediphosphonic acid under basic conditions and, if required, removing protecting groups from the resulting product to obtain a compound of 20 formula I wherein the double bond within group A is directly adjacent to the phosphono group; or b) condensing a compound of formula VIII Het-A-X (VIII) wherein Met,,, A and R1 ar© as defined for formula I and 1 25 is reactive esterified hydroxy, with a compound capable of introducing the phosphonic acid moiety and having one of the formulae II and X «J .8 .i H—I—OR" (IX) ?(R"') 3 (X) 1r" wherein Rm is C^-^alkyl and R'*S! is halogen or Ci_-C4aXkoxy snd, if required, converting the resulting phosphonic acid derivative to the phosphorsic acid or 5 another ester derivative thereof; or c) converting to R1 a substituent other than R1 at position 2 of the heterocyclic ring in a compound otherwise identical to a compound of the invention; and carrying out the said processes with, if necessary,, 10 temporary protection of any interfering reactive groups,, and then freeing 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 j, converting a resulting free compound into a 15 salt or a resulting salt into the free compound or into another salt? and/or separating a mixture of isomers or of racemates into the individual isomers or racemates; and/or, if desired, resolving a racemate into the optical antipodes. 20 Reactive esterified hydroxy, in any of the herein-mentioned processes, e„g» X in a compound of formula viii, is esterified by a strong acid, especially a hydrohalic acid, e.g. hydrochloric, hydrobromic or hvdriodic acid, or sulfuric acid, or by a strong organic 25 acid, especially a strong organic sulfonic acid, such as an aliphatic or aromatic sulfonic acid, for example methanesulfonic acid, 4-nethylphenylsulfonic acid or 4-bromophenylsulfonic ©c.id„ The said reactive esterified hydroxy is especially halosulfonyioxy, for example 30 chloro-, broaso- or iodo-sulfonyloxy, or aliphatically or aromatically substituted sulfonyloxy, for example f 1 Jb -jj methanesulfonyloxy, phenylsulfonyloxy or 4-methylphenyl-sulfonyloxy (tosy1oxy).

In starting compounds and intermediates which are converted to the compounds of the invention in the manner 5 described herein,, functional groups present, such as carboxy„ amino (including ring MH) and hydroxy groups, are therefore optionally protected by conventional protecting groups that are common in preparative organic chemistry. Protected carboxy, amino and hydroxy groups 10 are those that can be converted under mild conditions into free carboxy, amino and hydroxy groups without the molecular framework being destroyed or other undesired side reactions taking place.

The purpose of introducing protecting groups is to 15 protect the functional groups from undesired reactions with reaction components and under the conditions used for carrying out ©. desired chemical transformation. The need and choice of protecting groups for a particular reaction is known to those skilled, in the art and depends 20 on the nature of the functional groups to be protected (carboxy group, amino group, etc.), the structure and stability of the molecule of which the substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions 25 and their introduction and removal are described,, for example, in J.F.W. McOmiet, "Protective Groups in Organic Chemistry", Plenum Press, London, Mew York 1973, T.W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, and also in "The Peptides", Vol.I, 30 Schroeder and Luebka,,, Academic Press, London, Mew York 1965, as well as in Houben-Weyl, "Hethoden der Organischen Chemie", Vol. 15/1, Georg Thieme Verlag, Stuttgart, 1974.

The preparation of the compounds of the invention wherein the double bond is adjacent to the phosphono grouping according to process (a) involving the condensation of an aldehyde or ketone with e.g. a lower alkyl ester of methylenediphosphonic acid is carried out according to processes known in the art for such condensations, in the presence of a strong anhydrous basee.g. butyl-lithium, in an inert polar solvent such as tetrahydro~ furan, preferably under reflux The starting aldehydes or ketones of formula VII can be prepared e.g., by oxidation of the corresponding alcohols, for example with pyridin-ium chlorochrornate, or by other methods, e.g. as illustrated in the Examples.

The respective alcohols can in turn b® prepared by methods that are known per gfi, 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 organometal1ic reducing agent or by catalytic hydrogenation, e.g. in the presence of platinum oxide and an acidic solvent, such as acetic acid, to give car-responding tetrahydropyridines, piperidines, 1,2,3,4-tetrahydroquinolines or perhydroquinolines of the invention, e.g. according to formula II or IV and derivatives thereof. Quaternary guinoliniua and pyridin-iu» compounds, e.g. those in which Eg is lower alkyl or aryl-lower alkyl, may be similarly reduced.

The alcohols, aldehydes or ketones so obtained may also be converted to aldehydes or ketones of longer chain length using conventional processes, e.g. by a wittig condensation of an aldehyde with methoxy-methy1 -triphenylphosphonium chloride to yield the homologous ■ 1 6 aldehyde, and by other reaction sequences known per sa. e.g. as described in the Examples.

The aromatic 2~carboxy~heterocyclyl~substituted lower alkanols referred to above, for example the 2-carboxy-5 pyridinyl- or 2-carboxy-auino1iny1-substi tuted lower alkanols or derivatives thereof, can in turn be prepared by treatment of the 2-unsubstituted pyridinyl-substituted or 2-unsuhst.ituted quinolinyl-substituted lower alkanols in suitably protected form, with e.g. a peracid, such as 10 m-chloroperbenzoic acid, to give the corresponding pyridine-N~oxides or quinoline-N-oxides. 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 15 the corresponding 2~cyanopyridine or 2-cyanoquinoline derivatives which ©re then converted, again in a sanner known per se., to the 2-R1 (carboxy, esterified or amidated carboxy)-substituted pyridine and quinoline derivatives. 20 The condensation according to process (b) is advantageously used for the preparation of the compounds of forxaula 1 wherein, the double bond within the alJcenylene grouping & is not directly adjacent to the phosphono grouping. 25 The condensation according to process (b) of a compound of formula vixi with a compound of formula X, e„g„ triethyl phosphite, is carried out,, e.g. toy heating in an inert solvent, and under conditions that are known for a. Michaelis-Arbuzov reaction according to 30 Angew. Chem. Int. Ed. 16. 477 (1977) and Chem. Rev. 81,3 415 (1981). Similarly? condensation with e.g. phosphorus trichloride and subsequent hydrolysis gives a compound of formula I.

The condensation according to process (b) of a compound of formula VIII with a compound of formula IX„ e.g. diethylphosphonate (diethyl phosphite), is carried out e.g. in a strong basic medium, for instance in the presence of an alkali metal, e.g. sodium, an alkali metal hydrides, e.g. sodium hydride, an alkali metal alkoxides e.g. potassium t-butoxide5 in an inert solvent e.g. toluene or diraethylformamide.

The starting materials of formula VIII and reactive derivatives thereof can be prepared by methods well known in the art starting from intermediates of formula VII wherein A' represents oxo-substi-tuted lower alkyle the preparation of which is described above.

For example, the starting material of formula VIII wherein A represents propenylene is prepared by condensing an aldehyde of formula VII, wherein the grouping A9 represents formyl (CH~0), with a suitable Wit tig reagent, e.g. formylmethylene-triphenylphosphoran® ,s reducing the resulting unsaturated aldehyde (in which the chain has been lengthened by two carbon atoms) to the alcohol e.g. with sodium borohydride, and converting the resulting unsaturated alcohol to a reactive derivative, e.g. the bromide with triphenylphosphine/M-bromo-succinimide.

Interconversions according to process (c) are carried out by methods well-known in the art.

Groups convertible into R1 ares for example, carboxy groups inthe form of anhydrides or acid ha1ides„ eyano, amidino groups, including cyclic araidino groups such as 5-tetrazolyl» iminoether groups, including cyclic iminoether groups,, e.g. dihydro-2-oxasoliny 1 or dihydro-2-ojtazolinyl groups substituted by lower alkyl, and also hydroxymethyi„ etherified hydroxyiaethyls lower aIkanoyloxymethyl, I B trialkoxyraethyl, acetyl,, trihaloacetyl, halomethyl, carboxy carbonyl (COCOOH)s, formyl (CHO), di( lower)alkoxytnethvl, alkylenedioxymethyl or vinyl.

Certain terms used in the processes have the meanings as defined 5 below.

Oxo-substituted lower alkyl represents preferably formyl„ formyl-snethyl9 formylethyl or 2-oxo-propy 1, Trialkoxytnethyl represents preferably cri(lower alkoxy)methyl, particularly triethoxv- or trimethoxymethyl. 10 Etherified hydroxyraethyl represents preferably lower alkoxvmethy1, lower alkoxyalkoxymethyl, e.g. methoxymethoxymethyl or 2-oxa~ or 2-thiacyclo-alkoxymethyl, particularly 2~tetrahydropyranyloxy~ methyl.

Halomethyl represents especially chloromethyl but may also be 15 bromomethyl or iodomethyl.

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

Groups convertible into R1 representing carboxy include esterified and amidated carboxy and such are not limited to esterified and 20 amidated carboxy as defined herein for R'. Conversion to carboxy is generally accomplished by solvolysis, with acid or base.

Benzyloxycarbonyl or nitrobenzyloxycarbonyl may be converted into carboxy by catalytic hvdrogenation„ the latter also with chemical reducing agents, e.g. sodium dithionite or with zinc and a carboxy-25 lie acid. In addition^ tart-butyloxycarbonyl may also be cleaved with trifluoroacetic acid. 1 9 Acetyl niay be oxidacively cleaved to carboxy by conversion £irst to trihaloacetyl, e.g. tribrosno or triiodoacetvl, by treatment e.g. with sodium hypobromite, followed by cleavage with e.g. an aqueous base, e.g. sodium hydroxide.

Formyl, di( lower)-alkoxyraethyl or alkylenedioxymethyl (formyl protected in the form of an acetal), e.g. the dimethyl acetal, are oxidized with e.g. silver nitrate, pyridiniura dichromate or ozone to carboxy.

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

Hydrolysis of trialkoxymethyl to carboxy is advantageously carried out with inorganic acids, e.g. hydrohalic or sulfuric acid. Hydrolysis of etherified hydroxvaiethyl to hydroxyraethyl is preferably carried out with solutions of inorganic acids, e.g. a hydrohalic acido Hydroxymethyl is in turn oxidized to carboxy with an oxidizing agent, eg, pyridiniura dichromate.

Halomethyl may also be converted to the corresponding carboxalde-hydes with e.g. dimethylsulfoxide in the presence of triethylamine and silver tetrafluoroborate, or with chromium trioxide and pyridine in dichloromethane.

The conversion of cyano to lower aIkoxycarbonyl is advantageously carried out by treatment first with a lower alkanol, e.g. anhydrous ethanolj, in the presence of a strong acid, e.g. hydrochloric acid preferably at reflux temperature„ followed by hydrolysis with water.

Furthermore,, the conversion of cyano to carbamoyl is preferably carried out by treatment with an alkali metal hydroxide, e.g. dilute sodium hydroxide, and hydrogen peroxide, preferably at room terape- 2 0 Esterified carboxy such as lower aIkoxycarbonyl raay be amidated with ammonia, mono- or di~(lower)alkylamines, e.g. methylamine, dimethylamine, in an inert solvent, e.g. a lower alkanolf such as butanol, to unsubstituted, 5 mono- or di~(lower)alkylcarbamoyl.

The compounds of the invention may thus also be converted to other compounds of the invention e.g. by functional group conversions well-known in the art.

For example, conversion of carboxylie acid esters and 10 amides to carboxylie acids is advantageously carried out by hydrolysis with inorganic acids such as a hydrohalic or sulfuric acid or with aqueous alkalis, preferably alkali metal hydroxides such as lithium or sodium hydroxide. 15 Free carboxylic acids may be esterified with lower alkanols, such as ethanol, in the presence of a strong acid,, e.g. sulfuric acid, or with diazo (lower) alkanes, e.g. diazomethane, in a solvent such as ethyl ether, advantageously at room temperature,, to give the cor-20 responding lower alkyl esters.

Furthermore, the free carboxylic acids may be converted by treatment of a reactive derivative thereof, e.g. an acyl halide such as the acid chloride, or a mixed anhydride, e.g. one derived from a lo*»er alkyl halo-25 carbonate such as ethyl chlorocarbonate, with ammonia, mono- or di- (lower) alkylamines, in an inert solvent such as dichloromethane, preferably in the presence of a basic catalyst such as pyridine, to compounds wherein RA o 4 x represents unsubstituted, mono- or di-(lower)&lkyl~ carbamoyl.

Phosphor?,ic acid, esters are converted to the corresponding phosphonic acids by treatment with acid, such as aqueous 5 hydrochloric acid or hydrobromic acid in glacial acetic acid, or with bromotrimethylsilane according to J. Chen. Soc. Chem. Coram* 1979. 739. Benzyl esters may be converted to the acids by hydrogenolysis.

Phosphonic acids are converted to esters,, e.g. optionally 10 substituted lower alkyl esters, e„g» 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 15 formula I wherein Ket is N-substituted by C^-C^-alkanoyl or by C2-C7&lkoxycarbonyl, R and R* are Cr-C4alky 1, benzyl, bensyl substituted in the phenyl moiety by-halogen, by Ci-C4alkyl or by -C4alkoxy, C2~C7alkanoyl-oxymethyl, or C2-C7a 1 kanoy 1 oxymetry 1 substituted in the 20 oxymethyl moiety by Ci-C^alkyl or by C3-Cgcycloalkyl, and R1 is C1-C4alkoxycarbonyl, carbamoyl or N-mono- or N,N-di-C1-C4alkylcarbonyl, is converted into a corresponding N-unsubstituted compound of formula I in which R and R' are hydrogen and R3- is carboxy f by treatment with an 25 inorganic acid or with aqueous alkalis, there being suitable as inorganc acids hydrohalic acid or sulfuric acid, especially hydrochloric acid, and, as aqueous alkalis, alkali metal hydroxides, especially lithium or sodium hydroxide, preferably at elevated temperature. •> •> The above-mentioned reactions are carried out according to standard methods,, in the presence or absence of diluents,, preferably those that are inert to the reac-tants and are solvents therefor, of catalysts, of 5 condensing or said other agents and/or in an inert atmosphere, at low temperatures, room temperature or elevated temperatures, preferably ©t the boiling point of the solvents used, and at atmospheric or super-atmospheric pressure. The preferred solvents, catalysts and 10 reaction conditions are set forth in the following i1lustrative Examples.

The invention further includes any variant of the present processes in which an intermediate product obtainable at any stage thereof is used as starting material and the 15 remaining steps are carried out, or the process is discontinued at, any stage thereof,, or in which the starting materials are formed under the reaction conditions, or in which the reactants are used in the form of their salts or pur® antipodes.

Mainly those starting materials should be used in said reactions, that lead to the formation of those compounds indicated above as being especially preferred.

The invention also relates to any novel starting materials and processes for their manufacture.

Depending on the choice of starting saaterials and methods, the new compounds may be in the form of one of the possible isomers or mixtures thereof9 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 racernates or as mixtures of diastereoisomers or of geometric isomers- The aforesaid possible isomers esidmixtures thereof are within the scope of this invention; certain particular isomers are preferred as indicated above.

Any resulting mixtures of diastereoisomersormixtures of racernates can be separated on the basis of the physicochemical differences of the constituents9 in known manner, into the pure isomers, diastereoisomers j, racernates, or geometric isomers, for example by chromatography and/or fractional crystallization.

Any resulting racernates can be resolved into the optical antipodes by known methods, for example by reacting en acidic end produc with an optically active base that forms salts with the raceaic acid, and separating the salts obtained in this manner, for example by fractional crystallization, into the diastereoisomeric salts from which the optically active free carboxylic or phosphonic acid antipodes can be liberated on acidification. The basic racemic products can likewise be resolved into the optical antipodes, e.g. by separation of the diastereoisomeric salts thereof, with an optically active acid,, and liberating the optically active basic compound by treatment with a standard base. Racemic products of the invention can thus be resolved into their optical antipodes, e.g., by the fractional crystallisation of d- or £-(tartrates, mandelates. 2 4 camphor sulfonates) or of d- or-jKcs-raethylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietylamina, brucine or strychnine) salts. The acidic compounds of the invention can also be resolved by separating diastereomeric ester or amide derivatives prepared from an optically active alcohol or amine, and freeing the separated optically active compound. Advantageously,, the more active of the two antipodes is isolated.

Finally the compounds of the invention are obtained either in the free forai or as salts.. Any resulting base can be converted into a corresponding acid addition salt, preferably with the use of a therapeutically acceptable acid csranion exchange preparation, or resulting salts can be converted into the corresponding free bases, for example with the use of a stronger base, such as a metal or ammonium hydroxide or a basic salts, ® • g • an alkali metal hydroxide or carbonate, or a cation exchange preparation, or an alkylene oxide such as propylene oxide. A compound of the invention with a free carboxylic or phosphonic acid group can thus also be converted into the corresponding metal or ammonium salts. These or other salts, for exasaple9 the picrates5 can also be used for purification of th® 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 beween the free compounds and the compounds in the forsa of their salts,, whenever a compound is referred to in this contexts ® corresponding salt is also McLudadL, provided such is possible or appropriate under the circumstances.

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

The pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, for blocking the N-methyl-D-aspartate«sensitive excitatory amino acid receptor and for the treatment of diseases responsive to the blocking of the M-methyl-D-aspartate->sensitive excitatory amino acid receptor, such as cerebral ischemia, convulsive disorders and anxiety, comprising an effective amount of a pharmacologically active compound of the invention, alone or in combination with one or more pharmaceutical^ acceptable carriers„ The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an effective amount thereof in conjunction or admixture with carriers suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with a) diluents, e.g. lactose, dextrose, sucrose,, raannitol. sorbitol, cellulose and/or glycine* b) lubricants, e.g. silicas talcum, stearic acid, its magnesium or calcium salts and/or polyethyleneglycol; for tablets also c) binders e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium cErboxymethyIcellulose and/or polyvinylpyrrolidone? if desired d) disintegrants, e.g. starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners. Injectable compositions are preferably aqueous isotonic solutions or suspensions 5 and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilising, wetting or emulsifying agentss solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional sizing3 granulating or coating methods, and contain about 0„ 1 to 73 preferably about 1 to 50 %. of the active ingredient.

Suitable formulations for transdermal application include an effective amount of a compound of formula I *»ith carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. Characte- 2 G risCically, transdermal systems are in the form of a bandage comprising aprotective layer» a reservoir containing the compound optionally with carriers, optionally a rate—controlling means to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

The invention also relates to a method of blocking the N-methyl-D-aspartate—sensitive excitatory amino acid receptor in mammals, and to a" method of treatment of disorders in mammals, e.g.those responsive tto the bLocking of the N-methyl-D-aspartate excitatory amino acid receptor, such as cerebral ischemia, convulsive disorders and anxiety, using an effective amount of a compound of the invention as a pharmacologically active substance, preferably in the form of above-cited pharmaceutical compositions.

A particular embodiment thereof relates to a method of treating cerebral ischemia and of inhibiting brain damage resulting from cerebral ischemia (in a stroke) in mammals which comprises EdrairxLsear"-i&o; to a nannal in need o:t sactj. tx* A unit dosage for a mammal of about 50 to 70 kg may contain between about 5 and 100 sng of the active ingredient.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereof. Temperatures are given in degrees Centigrade. If not mentioned otherwise, all evaporations ©re performed under reduced pressure, preferably between about 2 and 13 kPa.

Example 1: Ethyl 4-[ l-( 3-diethylphosphonoprop-*-2-enyl) ]-l»tert~ butoxycarbonylpiperidina-2-carboxylata is hvdrolyzed with 6N hydrochloric acid to yield 4-[1~(3-phosphonoprop-2--enyl)]piperidine-2-carboxylic acid.

The starting material is prepared as follows; &-(2-hydroxyethyl)-pyridine is oxidized to 4-(2-hydroxyethyl)"pyridine-M~oxide which is in turn treated with trimethylsilyl cyanide to yield 4-(2-hydroxy-ethy1)-2-cyanopyridine which is converted to ethyl 4-(2-hydroxy~ ethyl)=2~pyridine carboxylate and then hydrogenated to yield ethyl 4-(2-hydroxyethy1)-piperidine-2-carboxylate.

A solution of 2=01 g of ethyl 4-(2-hydroxyethy1)-piperidine-2-carboxylate in 5 ml dichlororaethane is added to a solution of 2.20 g of di-tert-butyl dicarbonate in 10 ml dichloromethane. After standing for 10 minutes the solvent is evaporated and the residue is flash chromatographed with hexane/ethyl acetate ( "j z 1 ) to afford ethyl 4-(2-hydroxyethy1)-1-tart-butoxycarbonylpiperidine-2-carboxylate .

To a solution of 1.56 g of dimethyl sulfoxide in 10 ml dichloromethane is added 2.2 g of oxalyl chloride at ~78°C» After 20 minutes 2.4 g of ethyl 4~(2-hydroxyethyl)-I-tert-butoxycarbonyi--piperidina-2-carboxylata in 5 sal dichloromethane is added. The reaction Haxijurs is stirred for one hour and 2.2 g of triathylamine is add®d. The ice bath is removed, the solvent evaporated and the residue is flash chromatographed with hexane/ethyl acetate (7 s 3} co afford l-fcert-butoxycarbonvlpiperidine-2-© tnoxy carbonyl ->U—6ice-s®J.dehyde„ At -78°C„ 2.73 ml n-butyllithium is added to 2.02 g bis(diethyl~ phosphono)-methane in 20 ml anhydrous tetrahvdrofuran. After 5 minutes 2.08 g of 1 — tert—butoxycarfoonylpipesaLdine—2-e£fro:>sycar-» banyi-4-acetaldehyde in 5 ml tetrahydrofuran is added. The mixture is then refluxed for 16 hours. The cooled reaction mixture is concan- trated and flash chromatographed (95:5 dichlorosnethane/methanol) to yield ethyl 4~[l-(3~diethylphosphonoprop-2-enyl) ]-l-tert-butoxy-carbony1piperidine-2-carboxylate.

Example 2: The following compounds can be prepared according to methods generally illustrated in the previous examples (a) trans 3-( !-( 4-phosphonobut-3-enyl) ]-pyrrolidine-2~carboxylic acid; (b) trans 3-[l-(4-phosphonobut-2-enyl)]=pyrrolidine-2-carboxylie acid.

The starting material for compound (a) can be prepared as follows; Trans N-e thosycayboxiylpyrx-olidi:o.e~2—e thoxycarbonyl->»3~&ca^2Llde-» hyde is condensed with (C&Hs)3?=CHOCH3 under conditions of th® yittig reaction to afford trans N ~ Chcscyce^rbcaiylpyrroJidLn.e ~ 2— ethoEy~ carbonyl-3-propionaldehyde. Condensation with bis-(diethyiphos-phono)methane under conditions described herein (see Example 1) yields trans ethyl 3-[ l-(4-diethylphosphonobut-3-enyl) ]-pyrrolid.ine- 2-carboxylate.

The starting material for compound (b) can be prepared as follows: The alcohol9 trans ethyl N»ethoxycarbonyl--3-( 2-hydroxyethyl)-pyrrolidine-2-carboxylate is oxidized to the aldehyde „ trans M— © thoxy carbonyl pyr rol idirte -2 — @thoxycarbanyl-3~&ce t&ldehyd%*itjichj3 condensed with triphenylphosphoranylideneacetaldehyde under conditions of the Wittig reaction; the resulting et,^^unsaturated -aldehyde is reduced to the corresponding alcohol which is converted to the bromide. Condensation with triethyl phosphite yields ethyl 3-(l-(4-diethylphosphonobut-2-enyl)]-pyrrolldine-2-carboxylase.

Example 3° 4-»[1~(3-Phosphonoprop-l-enyl)]piperidine-2~carboxylic acid can be similarly prepared using ethyl 4-hydroxymethy1-K-ethoxycarbonyl- 30 piperidina-2-carboxylate as intermediate. 10 15 20 25 2 9-' Example 4; At ■=-78°C, 20.3 ml of butyllithium (1.64 M) is added to 8.5 ml of tetraethylmethylenediphosphonate (bis(diethylphosphono)-methane] in 100 ml anhydrous tetrahydrofuran. After 5 minutes. 9.26 g of 1 -(tex:t-butoxycarbonyl)-2-ethoxycarbonyl-piperidine-4-acetaldehyde in 125 ml anhydrous tetrahydrofuran is added. Mixture is refluxed 18 hours, cooled„ concentrated and purified by flash chromatography using ethyl acetate/hexane (75:25 to 9:1) to yield ethyl 4-[ l-( 3-diethylphosphonoprop-2-eny1)]-(1-tert-butoxycarbonyl)-piperidine-2-carboxylate.

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

A solution of 23.8 g of ethyl 4-pyridylacetate 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 at 50°C (bath) for 40 minutes? then cooled in an ice bath, and the excess lithium aluminum hydride is decomposed by additiosi 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 concentrated in vacuo to yield 4-pyridy1-ethanol.

A solution of 16.3 g of 4-pyridvlethanol, 21.8 g of chloro-terebut yl-dimet hyl si lana and 10.9 g of imidazole in 150 sal of dimethyl-formamide is stirred 1 hour at room temperature. The product is isolated by extraction in ethyl acetate/hexane (1:1) and washed 4 times with 400 ml of water; the extract is filtered through silica gel and concentrated in vacuo to yield 4-(tert-butyl-dimathylsilyl-oxyethyl)-pyridine . 3 fll To a stirred solution of 28.8 g of 4~(tert-butyl-dimethylsilyloxy-ethyl)-pyridine in 300 ml of dichioromethane is added 24 g of m-chloroperbenzoic acid. After 4 hours the solution is washed with aqueous sodium carbonate solution and water. The solution is dried over sodium sulfate, filtered and concentrated in vacuo to yield 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine-N-oxide.

A solution of 28.6 g of 4-(tert-butyl-diiaethylsilyloxyethyl)-pyridine-N-oxide, 60.3 ml of trimethylsilyl cyanide and 31.5 ml triethylainine is stirred under nitrogen at reflux for 3 hours. The dark solution is cooled in an ice bath. 30 ml of ethanol added;, followed by 400 ml ethyl acetate and 200 ml 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) to yield 4-(tert-butyl-diiaethyi-silyloxyethyl)-2--cyanopyridine» A solution of 22.2 g of 4-( tert-butyi-=dimethylsilyloxyethyl)~2-cyanopyridine in 220 ml anhydrous ethanol containing 0.19 g of sodium is stirred at room temperature for 24 hours. The solution is then cooled to 0°C and 22 ml of 6N hydrochloric acid added. The solution is stirred at room temperature for 16 hourss cooled to 0°C and 7.5 ml 6N sodium hydroxide added followed by 75 mi saturated aqueous sodium bicarbonate. Extraction with dichioromethane and flash chromatography using ethyl acetate yields ethyl 4-(2-hydroxy™ ethyl)-pyridine-2-carboxylate.

A mixture of 8.37 g of ethyl 4-(2-hydroxyethyl)-pyridine-2-carboxylate in 130 ml acetic acid and 4 g platinum oxide is hydro-genated at 345 kPa. Filtration, concentration in vacuo, neutralization with potassium carbonate and extraction with dichioromethane yields an oil that is purified by flash chromatography using dichioromethane/methanol saturated with ammonia (20:1) to yield ethyl 4-(2-hydroxyethy!)-piperidina-2-carboxylate. 3 1 A solution of 7.9 g of ethyl-4-(2-hydroxysthy1)-piperldine-2-carboxylate, 9.0 g di~tert-butyl dicarbonate in 80 ml of dichioromethane is stirred for 2 hours at room temperature and then concentrated in vacuo to yield ethyl l-(tert-butoxycarbonyl)-4-(2-hydroxy-5 ethyl)-piperidine-2-carboxylate.

A solution of 11.8 g of ethyl(l-tert-butoxycarbonyl)-4~(2"hydroxy-ethyl)-piperidine-2-carboxylate and 12.6 g of pyridinium chloro-chromate in 175 sal dichioromethane is stirred under nitrogen at room temperature for 80 minutes. Mixture is filtered and purified by 10 flash chromatography using ethyl acetate/hexane (25;75) to yield l-(tert-buto xyc ar bony 1)-2-e thoxy car bony 1-piperidine-4-ace'c aldehyde.

Example 5; A mixture of 4.67 g of ethyl 4-[l-(3-diethylphosphono-prop-2-enyl]-l-(tert-butoxycarbonyl)-~piperidine-2-carboxylate and 75 ml 6M hydrochloric acid is refluxed 12 hours. The solution is •j 5 concentrated in vacuo to dryness. The residue is taken up in 50 ml ethanol and 3.8 ml of propylene oxide added. The solid that separates is filtered off and dried in vacuo to yield cis-4-[ ].-(3-phosphonoprop-2-enyl) ]-piperidine-2-carboxylic acids ra.p. 1S3-165°C.

Example 6; At ~78°Ca 5.9 snl of butyllithium (1.6 M) is added to 2.9 sal of tetraethylmethylene diphosphonate in 30 ml anhydrous tetrahydrofuran. After 5 minutes, 2„&7 g of trans 1 —acetyIpipsr-±d±ne~2—eftioaeyc&rboayl~li™&o&tgi]dehyde in 55"2- of anhydrous tstra™ hydrafur&jj. is added. The mixture is refluxed 18 hours, cooled, concentrated and purified by flash chromatography using dichloro-aethane/ethanol (100:3) to yield trans ethyl 4-[l-(3-diethylphos-phonoprop-2-enyl) 3~i~acetyl~piperidine-2-carboxylate.

The starting raaterial is prepared as follows: At 0°C? 9.4 ml acetic anhydride is added to a stirred solution of 13.5 g of ethyl 4~( 2-hydroxyethyI)-piperidine-2-carboxylate in 75 ml pyridine. After 30 stirring at room temperature for 30 minutes the solution is concentrated in vacuo and ethyl acetate (300 ®1) is added; the solution is washed twice vith 2M hydrochloric acid;, once with water and once 20 25 with saturated sodium bicarbonate, dried over sodiura sulfate, filtered and concentrated in vacuo. The residue is taken up in 100 ml ethanol, S g of powdered potassium carbonate is added and the mixture stirred 1 hour at room temperature. The solution is filtered, concentrated in vacuo and purified by flash chromatography using dichioromethane/methanol (95:5) to yield trans ethyl 1 — ece tyl—k- (2~hydroxy0 thyl) —piperidine~2~carbo3:ylate.

A mixture of 3.7 g of trans ethyl l-acetyl-4-(2-hydroxyethyl)-piperidina-2-carboxylate and 5.4 g of pyridinium chlorochromate in 75 ml dichioromethane 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) to yield trans 1 ~ace tyl pi peri dine—2 ~ a thos:ycarbonyl«L;.-acs teldehyde Example 7; A mixture of 2.5 g of trans ethyl 4-[l-(3-diethylphos-phonoprop~2-enyl)]~l-acetylpiperidine-2-carboxylate and 40 ml 6N hydrochloric acid is refluxed for 12 hours. Th© solution is concentrated in vacuo to dryness. The residue is taken up in 20 ml of ethanol and 2.3 ml of propylene oxide added. The solid that separates is filtered off and dried in vacuo to yield trans 4-(l-(3-phosphonoprop-2-euyl)]-piperidine-2-carboxylie acid, ra.p. 132-140°C- Example 8; A solution of 0.334 g of trans ethyl 4-fl-(3-bromoprop-l~ enyl) ]-J.-(tart-butoxycarbonyl)~pip®ridine~2-carboxyl&te and 3.5 ml of triethylphosphit® is refluxed under nitrogen for 70 minutes. The cooled solution is concentrated in vacuo and purified by flash chromatography using dichlorotnethana/methanol (100;3) to yield trans ethyl 4~(X~(3-diethylphosphonoprop-l-enyl)]-l~(tert-butoxycarbonyl)~ pi peridine-2~carboxylase.

The starting material is prepared as follows; A solution of 20 g 4-pyridvlcarbinol, 28.9 g of chloro-tert-butyl-diraethylsilan® and 14.4 g imidazole in 200 ml disaathylforraasaide is stirred 3 hours at room temperature. Product is isolated by extraction in ethyl **3^ ' m"y tjjft acetate/hexane (Is!) and the extract is cashed h tirres witii lujonl of water. The solution is filtered through silica gel and concentrated in vacuo to yield 4-(tert-butyl-dimathylsilvloxymethyl)-pyridine.

A solution of 40.6 g of 4-(eert-butyl-dimethy1silyloxyraethyl)-pyridine and 40 g of m-chloroperbenzoic acid in 500 ml dichioromethane is stirred 16 hours at room temperature. Solution is washed with 2M sodium hydroxide and water, dried over sodium sulfate, filtered and concentrated in vacuo to yield 4~(tert-butvldimethyl-silyloxyicnethyl)~pyridine~N-*oxide.

A solution of 37„9 g of 4-(tert-butyl-dimethylsilyloxymethyl)-pyridine-M-oxide, 84 ml of trimethyIsilyl cyanide and 44 ml tri-ethylamine is stirred under nitrogen at reflux for 2 1/2 hours. Dark solution is cooled in an ice bacht then 40 ml of ethanol added followed by 500 ml of ethyl acetate. The solution is washed twice with waters dried over sodium sulfates filtered9 concentrated in vacuo and purified by flash chromatography using ethyl acetate/hexane (Is 10) to yield 4-(tert-butyl-diraethylsilvloxy-aathyi)-2-cyanopyridine.

A solution of 21.7 g of 4-(tert-butyl-dimethylsilyloxymethyl)-2~ cyanopyridine in 220 ml anhydrous ethanol containing 0.2 g of sodium is stirred at room temperature for 18 hours, cooled to 0°C and 22 al 6N hydrochloric acid is then added. The solution is stirred at room temperature for 18 hours,, cooled to 0°C8 7.5 ml SN sodium hydroxide added followed by 20 ml saturated aqueous sodium carbonate. Extraction with dichioromethane, then drying, filtering and concentrating the extract yields an oil which crystallizes from ether to yield ethyl 4-(hydroxymethyl)-pyridine-2~carboxylate. a mixture of 13.9 g of ethyl a-(hydroxymethyl)~pyridine-=2-carfooxy-lates 5 g platinum oxide in 250 ml acetic acid is hydrogenated at 34h kPa. Filtration, concentration in vacuo, and neutralisation with potassium carbonate in dichioromethane yields an oil is «> >s £ -dl purified by flash chromatography using dichlororaethane/snethanol saturated with ammonia (20:1) to yield ethyl 4-(hydroxymethyl)-piperidine-2-carboxylata.

A solution of 5.16 g of ethyl 4-(hydroxymethyl)-piperidine-2-5 carboxylate and 6.33 g di-tert-butyl dicarbonate in 100 ml of dichioromethane is stirred at room temperature for 18 hours. The solution is concentrated in vacuo to yield ethyl l-(tert-butoxy-carbony1)-4-(hydroxyraethyl)-piperidine-2-carboxylate.

A solution of 7.9 g of ethyl 1™(tert-butoxycarbonyl)-4~(hydroxys 10 methyl)-piperidine-2-carboxylate and 9.9 g of pyridinium chloro- chromate in 175 ml of dichioromethane is stirred at room temperature for 3 hours. The mixture is filtered and purified by flash chromatography using ethyl acetate/hexane (25?75) to yield l-(tert-butoxy-carbony!)-2-ethoxvcarbonylpiperidine-4-carboxaldehyde- A solution of 1 g of l-( tert-butojcycarbonyl)-2=ethoxycarbony 1-piperidina-4~casboxaldshyde and 2 g of forraylmethylene-triphenyl-phosphoran irs 16 ml of toluene is heated to 100°C (bath temp« ) lbr 2 hours. The solution is cooled and purified by flash chromatography using ethyl acetate/hexane (25?75) to yield X-(tert-butoxycarbonyl)-2-eehoxycarbonyl--piperidine-4™scrylaldehyde. h solution of 0.83 g of l-(tesT-butojcycarbonyl)-2-ethoxycarbonyI~ piperidi«®-4-acryialdehyde 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 followed by ice cold water and the mixture is extracted 25 with dichioromethane. The extract is dried over sodium sulfates filtered and concentrated in vacuo. Purification by flash chromatography using ethylacetate/hexane (25s75) yields trans ethyl l-(tert-butoxycarbonvl)-4-[l-(3-hydroxyprop-I-enyl)]-piperidine-2~carboxy™ late. 15 20 try o b A solution of 0.367 g of trans ethyl 1 - (tert-butoxycarbonyl)-4-[i-(3-hydroxyprop-I-enyl)]-piperidine~2~carboxylate , 0.35 g triphenyl-phosphin® and 0.23 g of bromosuccinimide in 8 ml of dichioromethane is stirred initially at 0°C and then at room temperature for 40 minutes. Purification by flash chromatography using ethyl acetate/hexane (1:9) yields trans ethyl 4-{l-(3-bromoprop-l-enyl) ]-1~(tert-butoxycarbony1)-piperidine-2-carboxylate.

Example 9; A solution of 0.39 g of trans ethyl 4-[l-(3-diethvlphos-phonoprop-l-enyl) ]-l-( tert-butoxvcarbonyl)-piperidine-2-carboxylate and 2»3 ml of trifluoroacetic acid in 8 ml of dichioromethane is stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate is added and the mixture extracted with dichioromethane. Purification by flash chromatography using dichioromethane/methanol saturated with ammonia (20;!) yields trans ethyl 4-[l-(3-diethyl-phosphonoprop-l-enyl)]-piperidine-2-carboxy late.

Example 10; A solution of 0.265 g of trans ethyl 4-[1~(3-diethyl-phosphonoprop-l-enyl) ]-pipe xridine-2-car boxy late in 5 ml of anhydrous ethanol containing 0.074 ml of butyl lithium (1.6 M) is heated at &D°C (bath tempi') for 72 hours. After coolings 0.025 ml acetic acid is addeds followed by excess saturated sodium bicarbonate, and the mixture is extracted with dichioromethane. The dichioromethane extract on concentration in vacuo yields an oil; purification by flash chromatography using dichlororaethane/isopropanol saturated with ammonia (20:1) yields cis ethyl 4-[l-(3~diethylphosphonoprop-X-> enyl)]-piperidine~2~carboxylate.

Example 11; a) A mixture of 0.142 g of cis ethyl 4-[ 1~( 3-diethylphosphonoprop-1-enyl)]-pipsridine-2-carboxylate and 2.5 ml of 6N hydrochloric acid is refluxed for 12 hours. The solution is concentrated in vacuo to dryness. The residue is 'fcaken. up in 2 mi of ethanol and 0.15 tal of propylene oxide is added- The solid that separates is filtered off and dried in vacuo to yield cis «-[ l-( 3~phosphonoprop~X~ex>yl) ]-piperidine~2-carboxylic ®cid9 m.p. 175°C (decomposition)» 3 6 b) Similarly, hydrolysis of the trans ester of Example 9 yields the corresponding trans acid, a.p. 130-135°C. c) A solution of cis &-[l-(3-phosphonoprop-l-enyi)]-piperidine~2-casrboxylie acid in saturated ethanolic hydrochloric acid is heated under reflux overnight. The solvent is removed in vacuo. A solution of the residue in ethanol is treated with propylene oxide and evaporated to dryness to yield cis ethyl 4~[1~(3-phosphonoprop-l-enyl)]-piperidine-2-carboxylate.

Example 12; To a solution of 0.234 g of trans 1-ethoxycarbony1=2-ethoxycarbonyl-pyrrolidine-3-propionaldehyde in 5 ml of anhydrous tetrahydrofuran under nitrogen, cooled to -78°C3 is added slowly a solution of 0.23 ml of tetraethylmethylenediphosphonate and 0.57 sal of butyllithium (1.6 H) in 5 sal of anhydrous tetrahydrofuran also at -78°C, Solution is refluxed for 14 hours, cooled and treated with 0.15 ml of acetic acid; the reaction mixture is concentrated, diluted with water and extracted with dichioromethane. The extract is dried over sodium sulfate, filtered and concentrated9* purification by flash chromatography using ethyl acetate yields trans ethyl l-ethoxvcarbonyl-3-fl-(4-diethylphosphonobut-3-enyl)]-pyrrolidine-2-carboxylate.

The starting material is prepared as follows: A mixture of 50 g of M~(2-cys.noathyl)glycine in 300 sal of ethanol saturated with hydrogen chloride gas is stirred 1 hour at room tesaperatur® then refluxed for 1 hour. After cooling the solid is filtered off and the filtrate neutralised with sodium bicarbonate,, filtered again and concentrated to yield ethyl M-(ethoxycarbonylmethyl)-B-alaninat:e.

To a mixture of 49 g of ethyl !3-(ethoxycarbonyiinethyl)-g™©laninate and 30 ml of water cooled to ~10°C is added dropwise 27.6 s>l of ethyl chlorocssrbooatBfollowed by a solution, of 12.7 g of sodiusa carbonate in 50 ml of water. The mixture is warmed to room tempera-ture then heated at 55°C for 50 minutes. The saixxure is cooled, extracted with toluene6 the extract is washed with 2H hydrochloric 3 7 acid and water. The extract is dried over sodium sulfate, filtered, concentrated and distilled in vacuo to yield ethyl N-(ethoxycar-bonylmethyl)-N-(ethoxycarbonyl)~g~alaninate.

A solution of 53.9 g of ethyl N-(ethoxycarbonylmethyl)-N-(ethoxy-carbonyl)-g-alaninate in 200 ml of toluene is added dropwise to a stirred solution of potassium hexamethyldisilazide (429 ml, 0.653 M) in 125 sal of toluene under nitrogen and cooled to 0°C. After 45 minutes at 0°C, 21.6 sal of acetic acid is added followed by a solution of 100 g of sodium phosphate (monobasic) in 1 liter of water. The phases are separated, the organic phase is washed with pH 7 buffer, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane (3:7) to yield ethyl 1 -e'choxycarbonyl-3-oxo-pyrrolIdine-2-carboxylace.

To a stirred suspension of 24 g of benzyloxycarbonylmeehyl~tri-phenylphosphonium bromide in 225 ml of anhydrous tetrahydrofuran under nitrogen and cooled to 0°C is added 73 ml of potassium hexamethyldisilazide (0.652 M). After 10 minutes a solution of 11 g of ethyl l~ethoxycarbonyl-3-oxopyrrolidine-2~carboxylate in 50 ml of tetrahydrofuran is added and the mixture refluxed 2 1/2 hours. After cooling the mixture is filtered and concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with water, dried over sodium sulfate, filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane (1:4) to yield an oil;; this is hydrogenated in 200 ml of ethanol and 5 g of 10 % palladium on carbon to yield9 after filtering and concentrating the filtrate, l~ethoxycarbonyl~2--ethoxycarbonylpyrrolidine-3~acetic acid.

A solution of 10 g of l-ethoxycarbonyl--2~ethoxvcarbonyl-pyrrolidine-3~acetic acid in 50 ml tetrahydrofuran is cooled to 0°C and 55 ml of borane/tetrahydrofuran (1 M) is added dropwise. After stirring 2 hours at 0°CS 20 ml of water is 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 3 8 flash chromatography using ethyl acetate/hexane (1:1 to 7:3) to yield cis 1-ethoxycarbonyl~2-echoxycarbonylpyrrolidine~3-ethanol.

A solution of 6 g of cis 1-ethoxycarbony1-2-ethoxycarbonyl-pyrrolidine-3-ethanol in 75 ml of dichioromethane containing 7.3 ml of diisopropylethylamine, to which is added 5.1 ml of 85 % benzyl-oxymethyl chlorides is stirred 3 1/2 hours at room temperature. The solution is washed with water and saturated aqueous sodium bicarbonate. The solution is then dried over sodium sulfate, filtered, concentrated and purified by flash chromatography using ethyl acetate/hexane (1:4) to yield cis ethyl l-ethoxycarbonyl-3-[2-(benzyloxymethoxy)-ethyl]-pyrrolidine-2-carboxylate.

A solution of 6.2 g of cis ethyl l~ethoxycarbonyl~3~[2-(benzyloxy-raethoxy)-ethyl]-pyrrolidine-2-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 IN hydrochloric acid is added, the solution is concentrated in vacuo, cold water added and mixture extracted with dichioromethane. The extract, is dried over sodium sulfate, filtereds concentrated and purified by high pressure liquid chromatography using ethyl acetate/hexane (15:85) t yield trans ethyl 1~ethoxycarbonyl-3-[ 2=(benzyloxymethoxy)-ethyl ]-pyrrolidine-2-carboxylace.

A mixture of 1.64 g of trans ethyl l-ethoxycarbonyl-3-f(2-benzyi-oxymethoxy)-ethyl]-pyrrolidine-2-carboxylate and 2 g of 10 % palladium on carbon in 35 &1 of acetic acid is hydrogenated at 310 k'Pa. The Mixture is filtered, concentrated in vacuo and purified by flash chromatography using ethyl acetate/hexane (6:4 to 7:3) to yield trans l-ethoxvcarbonyl-2-ethoxycarbonylpyrroli-dine-3-ethanol.

A solution of 0.991 g of trans l-ethoxycarbonyl-2-ethoxycarbonyl-pyrrolidine-3-ethanol and 1.24 g pyridinium chlorochromate in 20 ml of dichioromethane is stirred under nitrogen for 4 hours. Mixture i 39 filtered and purified by flash chromatography using ethyl acetate/hexane (1:1) to yield trans l-ethoxycarbonyl-2-ethoxvcarbo-nyIpyrrolidine-3-acetaldehyde.

To 0.4 g of trans 1-ethoxycarbony1-2-ethoxycarbonylpyrrolidine-3-scetaldehvde in 5 snl anhydrous tetrahydrofuran under nitrogen, cooled to -78°C, is added dropwise a solution of 1.17 g of raethoxy-methyl-triphenylphosphoniura chloride in 15 ml of anhydrous tetrahydrofuran, which contains 1.55 ml of potassium tert-butoxide/tetrahydrofuran (1.6 M), Solution is stirred at room temperature for 4 hours. 2N hydrochloric acid (11 ml) is added and the mixture is stirred for 45 minutes. The solution is concentrated and then extracted with dichioromethane. 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) to yield trans l~ethoxycarbonyl-2~ethoxycarbonylpyrrolidine-3-propionaldehvde.

Example 13: A mixture of 0.193 g of trans ethyl 1-ethoxycarbonyl-3-[ l-(4-diethylphosphonobut~3-enyl) ]~pyrrolidine-2--carboxylate and 4 snl of concentrated hydrochloric acid is refluxed for 16 hours. The solution is cooled and concentrated to dryness in vacuo. The solid that separates is filtered off and dried in vacuo to yield trans 3"[ l-(4-phosphonobut-3-enyl) ]-pyrrolidine-2-carboxylic acid, to.p. 110-115°C (decomposition) Example 14; To a solution of 0.426 g cis l-athoxycarbonvl-2-ethoxy™ car bony lpyrrolidine-3-propi one Idehyde in 10 ml of anhydrous tetrahydrofuran under nitrogen, cooled to -78°C, is added slowly a solution of 0.45 ml of tetraethylmethylenediphosphonate and 1.06 ml of butyl lithium (1.6 M) in 10 ml of anhydrous tetrahydrofuran also at ~78°C. Solution is refluxed 14 hours, cooled and 0.3 si! acetic acid is added; the reaction mixture is concentrated, water is added and the mixture is extracted with dichioromethane. The extract is dried over sodium sulfate, filtered, concentrated and purified by 4"0 flash chromatography using ethyl acetate to yield cis ethyl l-ethoxycarbonyl-3-[l-(4-diethylphosphonobut-3-enyl)]-pyrrolidine-2-carboxylate.

The starting material is prepared as follows: A solution of 0.908 g 5 of cis l-ethoxycarbonyl-2~ethoxycarbonylpyrrolidine~3~ethanol and 1.14 g pyridinium chlorochroiaate in 20 ml of dichioromethane is stirred under nitrogen for 4 hours. Mixture is filtered and purified by flash chromatography using ethyl acetate/hexane (1:1) to yield cis 1-ethoxvcarbonyl-2-ethoxycarbonylpyrrolidine~3-acetaldehyde.

To 0.663 g of cis l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde in 10 ml anhydrous tetrahydrofuran under nitrogen, cooled to -78°C„ is added dropwise a solution of 2.21 g of tnethoxy-methyl-triphenvlphosphonium chloride in 20 ail of anhydrous tetrahydrofuran which contains 2.6 sal of potassium tert-butoxide/tetrahydrofuran (1.6 M). Solution is stirred at room temperature for k hours; 15 ml of 2N hydrochloric acid is added and the mixture stirred for 45 minutes. The solution is concentrated and then extracted with dichioromethane. The extract is dried over sodium sulfate„ filtered and concentratedi purification by flash chromatography using ethyl acetate/hexane (1:5 to 3:7) yields cis l~ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-propionaidehyde.

Example 15: A mixture of 0.176 g of cis ethyl l-ethoxycarbonyl-3-[1-(4~diethylphosphonobut-3-enyl)]-pyrrolidine~2-carboxylate and 3.5 ml of concentrated hydrochloric acid is refluxed 18 hours. The 25 solution is concentrated in vacuo to dryness, the residue talcsn up in 1.5 al of isopropanol/methanol (5:1) and 0.2 nil of propylene oxide is added. The solid that separates is filtered off and dried in vacuo to yield cis 3-(l-(4-phosphonobut-3-enyl)]-pyrrolidine-2-carboxylic acid, si.p. 132=140°C. 10 15 20 4 I Example 16: A solution of 0=0665 g of trans ethyl 1-ethoxycarbonyl-3-[ l-(4-brotnobut-2-enyl) ]-pyrrolidine-2-carboxylate in 0.75 ral of triethylphosphite is refluxed 20 minutes. The solution is concentrated in vacuo and the residue purified by flash chromatography using dichloromethane/ethanol (30:1) to yield trans ethyl I-ethoxy-carbonyl-3-[1=(4-diethylphosphonobut-2-enyl)]™pyrrolidine~2~carboxy~ late.

The starting material is prepared as follows: A solution of 0.225 g of trans 1-ethoxycarbonv1-2-ethoxycarbonyIpyrro1idine-3-acetaldehyde and 0.4 g of (formyImethyleine)-1riphenylphosphoran in 2 ml of dichioromethane is refluxed 44 hours. The solution is concentrated and the residue is purified by flash chromatography using ethyl acetate/hexane (2:3) to yield trans ethyl l-ethoxycarbonyl~3-*[ l-(4-oxobut~2~enyl)]-pyrrolidine-2-carboxylate.

To a stirred solution of 0.102 g of trans ethyl l-ethoxycarbonyl™3~ (l-(4-oxobut-2-enyl)]-pyrrolidine-2~carboxylats in 2 ral 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 is added, the solution concentrated, water added and the mixture extracted with dichioromethane. The solution is dried over sodium sulfate, filtered and concentrated in vacuo to yield trans ethyl l-ethoxycarbonvl=3-[l-(4-hydroxybut-2-enyl)]-pyrrolidine-2-carboxylate.

To a stirred solution of 0.0937 g of trans ethyl 1-ethoxycarbonyl-3-[!-(4-hydroxybut~2-enyl)]~pyrrolidine-2-carboxylate and 0.1 g of triphenylphosphine in 2 ml of dichioromethane at 0°C is added 0.067 g of M-bromosuccinisnide• After 30 minutes at room temperature the mixture is purified by flash chromatography using ethyl acetate/hexane (1:3) to yield trans ethyl l-ethoxycarbonyl-3-ll-(4~ bromobut-2-enyl)]-pyrrolidine=2-carboxylate. 4 2 Example 17; A mixture of 0.053 g of trans ethyl 1-ethoxycarbonyl-3-[1-(4~diethylphosphonobut-2-enyl)]-pyrrolidine-2~carboxylate and 1.5 ml of concentrated hydrochloric acid is refluxed for 16 hours. The solution 5 is concentrated to dryness in vacuo, the residue is taken up in 1 ml of methanol, 0.2 ml of propylene oxide is added and the solution is concentrated. The residue is purified by ion exchange chromatography eluting with 0.1M ammonium hydroxide solution to yield trans 3-[l-(4~ 10 phosphonobut-2-enyl) ]-pyrrolidine-2-carboxylie acid,, ra.p. 138-145°C.

Example 18: preparation of an injectable formulation containing 10 mg of the active ingredient per 5 ml of solutions 15 ' cis 4-[l-(3-phospiionoprop~l~enyl) ]- piperidine-2-carboxylic acid 10.0 g propylparaben 0.5 g water ad 5000,0 ml The active ingredient and preservative are dissolved in 20 3500 ml of water for injection purposes and the solution is diluted to 5000 ml. The solution is filtered through a sterile filter and filled into injection ampoules under sterile conditions» each ampoule containing 5 ml of the solution. 25 Example 19s a) Preparation of 10,000 tablets each containing 10 mg of the active ingredients cis 4-[l—(3-phosphonoprop-1-enyl)]~ piperidine~2~carboxylic acid 100.00 g 30 lactose 2,535.00 g cornstarch 125,00 g polyethylene glycol magnesium stearate water (sterile) 6000 150.00 g 40.00 g q.s.

Procedure: All the powders are passed through a sieve with openings of 0.6 mm. Then the active compound, lactose, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 65 ml of water and the suspension added to a boiling solution of the polyethylene glycol in 260 ml of water. The paste formed is added to the powder mixture,, which if necessary is granulated with additional water. The granulate is dried overnight at 35°C, forced through a sieve with 1.2 mm openings and compressed into concave tablets with upper breaking notches.

Tablets containing about 1-50 mg of one of the other compounds disclosed hereinbefore are prepared in an analogous manner- b) Preparation of 1,000 capsules each containing 5 mg of the active ingredient: cis 4-[l-(3-phosphonoprop~1-eny1)]- piperidine-2-carboxylic acid 5-0 g lactose 212.0 g starch 80-0 g magnesium stearate 3.0 g Procedure: Each powder is passed through a sieve with openings of 0.6 ami. Than the active compound is placed in a mixer and mixed first with the magnesium stearate, then with the lactose and starch until a homogeneous mass is obtained. B?o. 2 hard gelatin capsules are each filled with 300 mg of the prepared mixture.

Capsules containing 1-50 rag of one of the other compounds disclosed hereinbefore are prepared in an analogous manner»

Claims (32)

a-s Patent Claims

1. Compounds of formula I, Hse—A—|—OR' 1 1 } OR in which Het is a 2-RJ-pyrro1idiny1, 2-Ri-2,5-dihvdro-pyrrolyl, 2-Ri-1,2,3,6-tetrahydropyridiny1, 2-Ri-1,2,5,6-tetrahydropyridiny1, 2-Ri-piper idiny1 , 2-Ri-tetrahydro-quinolinyl, 2-R*-perhydroquino 1iny1, 2-Ri-2,3-dihydro-indolyl or 2-Ri-perhydroindolyl group which also may be N-substituted by Ci -Ct a 1ky1, pheny1~Ci-C^a Iky 1 , C2-C?aIkoxycarbonvI. benzyloxycarbonyl or by Cz-Cya 1kanoy1 and/or C-substituted in the heterocyclic 5- or 6-ring by Cj—Chalky1 or by pheny1-Ci-C*alky 1 and/or, in the fused benzo or cyclohexano radical that may be present, by Cx-Chalky!s C! -C<, a 1 koxy e halogen or by trif1uoromethy1, Ri is carboxy. C| -C«, alkoxvcarbony 1 , carbamoyl or N-mono- or N,N-di-Ci-Cfea Iky1carbamoyI , A is C2-C4a 1keny1ene and R and R* are each independently hydrogen, Cn-C$alkylf benzyle benzyl substituted in the phenyl moiety by halogen, by C 3 -C

2. Compounds according to claim 1 of formula II s F—OR' ./ K U (ll) a3-r 1 N^/' and compounds of formula II with a double bond present between C-3 and C-4 or between C-4 and C-5 of the piperidinyl ring, wherein R and R' are each iudependent1y hydrogen, Ct -C

3. Compounds of formula II according to claim 2, wherein R and R' are each independently hydrogen, C1-C4alkyl, benzyl, C2-C7a 1kanoy1oxymethyI, or Co-C7 a 1kenoy1oxymet hy1 substituted in the oxymethyl moiety by C3-C4alkyl, by cyclohejcvl or by eye lopenty 1 „ Ri is carboxy „ carbamoyl or C«-C$© 1koxycarbony1; R2 and R3 are hydrogen or C1 -C4©!ky16 and A is alkenylene having from 2 to 4 carbon atoms; and pharmaceutical^ acceptable salts thereof. 4 „ Compounds of formula II according to claim 2, wherein R and R* are each independently hydrogen , Cj-C7a 1kanoy1-oxymethyl or C2 —C7alkanoyloxymethy1 substituted in the oxymethyl moiety by Cj™C

4. 7

5. Compounds according to claim 4 of formula III a 1—oh ' OH / \ I (III) T v wherein A is 1.3-propeny1ene, preferably with the double bond adjacent to the phosphono group, and Ri is carboxy or Cj—alkoxycarbonyI; and pharmaceutica11y acceptable salts thereof.

6. [1-(3~Phosphonoprop-2-eny1)]-piper idine-2-carboxy1i c acid according to claim 1 and pharmaceuticaIly acceptable salts thereof.

7. 4-[1-(3-Phosphonoprop-1-env1)]-piperidine-2-carboxylic ecid according to claim 1 and pharmaceutica11y acceptable salts thereof.

8. Compounds according to claim 1 of formula IV or perhydro derivatives thereof, wherein R and R' are each independently hydrogen- Cj~C*a 1ky1. benzyl, benzyl substituted in the phenyl moiety by halogen, by Ci-C^alkvl or by C* -C«, a 1 koxy, C3 -C7 a 1 kanoy 1 oxyme t hy 1 , or C?-C7alkanoyloxymethy1 substituted in the oxymethyl moiety bv Ct -Ca, a 1 ky 1 or by C3 -Cq eye I oa Iky 1 , R* is carboxy. Ci-C^a 1koxycarbony1, carbamoyl or N-mono- or N,N'-di-Cj-C

9. Compounds according to claim 8 of formula V ^ j—OH e ® Aw jf \/ \ i ij I \ /" (V) " T * or perhydroquino1ine derivatives thereor, wherein A is 1 s 3-propenj/lene with the double bond adjacent to the phosphono group, and Hi is carboxy or C1 -C« a 1koxycarbony 1; and pharmaceutically acceptable salts of said compounds having a salt-forming functional group.

10. Compounds according to claim 1 of formula VI OR' Y'v L l? and the compounds of formula ¥1 with a double bond present between C-3 and C-4 of the pyrrolidinyl ring, wherein R and B' are each independently hydrogen, Ci-C^alkyls benzyl, benzyl substituted in the phenyl moiety by halogen,, by Cj-C&alkyl or by C* -C4 & 1 koxy, C2-C7-a1kanoy1oxymethyl , or Ci -C7a 1kanoy1oxymethy1 substituted in the oxymethyl moiety by Ct-C^alkyl or by C3-Cqeye 1o-alkyls RS is carboxy, Cj -C*5 a 1 koxycarbony 1 , carbamoyl or W-mono- or N,N-di-Cia 1kyIcarbamoy1, R- is hydrogen, Cj-ChalkylB C3 -C7 a 1koxycarbony1, benzv1oxycarbony1 or C^■ C7a 1kanoy1e R3 is hydrogen. Cj-C^alkyl or erv1~C\-C ^ a!ky1„ and h is C;»-C&aIkeny1ene; and salts thereof. ft o

11. Compounds of formula VI according to claim 10, wherein the phosphono-bearing group is attached at the 3-position; R and R' are hydrogen, Ri is carboxy or Ci- C/» a 1 koxycarbony 1 , R2 and R3 are hydrogen, and A is 1,3-propenylene with the double bond adjacent to rht phosphono group; and pharmaceutica1ly acceptable salts thereof.

12. trans-3-[I-(4-Phosphonobu t-3-eny1)]-pyrrolidine-2-carboxylic acid according to claim 1 and pharmaceutica1ly acceptable salts thereof.

13. trans-3-[1-(4-Phosphonobut-2-eny1)]-pyrro1idine-2-carboxwlie ecid according to claim 1 and pharmaceutica1ly acceptable salts thereof.

14. The compounds mentioned in claims I to 13 for use in a method for the therapeutic treatment of the human or animal body.

15. Pharmaceutical preparations containing © compound according to any one of claims 1 to 14 together with a pharmaceutically suitable carrier.

16. The compounds mentioned in claims 1 to 14 as NMDA-antagonists.

17. The use of the compounds mentioned in claims 1 to 14 for the manufacture of pharmaceutica1 preparations.

18. The use of the compounds mentioned in claims 1 to 14 for the manufacture of pharmaceutical preparations for use as NMDA-antagonists.

19. Compounds according to claim 5B selected from the group consisting of ci_s-4-[ 1-( 3~phosphonoprop-2-eny 1 ) ]-piper idine-2-carboxyl 5. c acid, tra.ns-4 - [ 1 - ( 3-phosphono-prop-2-eny1)]-piperidine-2-carboxy1ic acid, cis-fe-f1~(3-phosphonoprop-1 -eny1)]-p iperidine-2-carboxy1ic acid and trans- 4 - [ JL- ( 3-phosphonoprop-JL-eny 1 )]-piperidine-2-carboxy1ic acid, and pharmaceutic©11v acceptable salts thereof.

20. Compounds according to claim 10, selected from cis-3-[i - (4-phosphonobut-3-enyI)]-pyrrol idine-2-carboxy Ii c acid and pharmaceutica11y acceptable salts thereof.

21. Pharmaceutical preparations containing a compound according to claim 19 or 20 together with a pharmaceuti-cally suitable carrier.

22. The compounds mentioned in claims 19 and 20 for use in a method for the therapeutic treatment of the human or animaI body.

23. The compounds mentioned in claims 19 and 20 as NMDA-antagoni sts„

24. „ The us® of the compounds mentioned in claims 19 and 20 for the manufacture of pharmaceutica 1 preparations.

25. The use of the compounds mentioned in claims 19 and 20 for the manufacture of pharmaceutical preparations for use as NMDA-antagonists.

26. A process for the manufacture of compounds according to claim 1 of formula 1 in which all of the symbols have the meanings given in claim 1, and salts thereof, which comprises a) condensifsg an aldehyde or ketone of formula VII Het-A' (VII ) wherein Het and R1 are as defined for formula I but Ri and amino groups are in protected form, and A' is C]-C3alkyl substituted by oxo and containing one carbon atom less than the alkenvlene group AB with a tetraester derivative of methylenediphosphonic acid under basic conditions and, if required, removing protecting groups from the resulting product to obtain a compound of formula I wherein the double bond within group A is directly adjacent to the phosphono group; or b) condensing a compound of formula VIII Het-A-X (VIII) wherein Het, A and R* 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 the formulae IX and X | H—f—OR" (IX) P(R"") 3 (X) OR" wherein B" is Ci~C*alkyl and R'" is halogen or Ci~ C^elkoxy and, if required v converting the resulting phosphonic acid derivative to the phosphonic acid or another ester derivative thereof: or c) converting to R* a substituent other than R« at position 2 of the heterocyclic ring in a compound otherwise identical to a compound of the invention; and carrying out the said processes with, if necessary, temporary protection of any interfering reactive groups, and then freeing the resulting cosnpound of the invention: if desired converting a resulting compound of the invention into another compound o£ the invention and/or, if desired, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt; and/or separating a mixture of isomers or of racernates into the individual isomers or raceniates; and/or, if desired, resolving a racemate into the optical ant ipodes .

27. 21. A process according to claim 26, which comprises converting a compound of formula I in which Het is N-substituted by Ci-C7 a 1kanoy1 or by C%-C7a 1koxycarbony1 , R and R' are Ci-C^alkyl, benzyl, benzyl substituted in the phenyl moiety by halogen, by Ci-C*alkyl or by C1-Ci,-alkoxy, Ci -C7 a 1 kanoy 1 oxymethy 1 , or Co -C7 a 1 kanoy 1 oxymethy 1 substituted in the oxymethyl moiety by Cj-C^alkyl or by C3-C3cvc1oa 1 ky 1 „ and Ri is Cj ~C<, a 1 koxycarbony 1 , carbamoyl or N-mono- or N , N-di-Ci-C4a Iky1carbonyl, into a corresponding N-unsubsrituted compound of formula I in which R and R' are hydrogen and R1 is carbosy, by treatment with an inorganic acid or with aqueous alkalis.

28. A process according to claisn 269 which comprises converting a compound of formula I in which Het is N-subst .i tuted by C2 -C7 a 1 kanoy 1 or by Co-C7a 1koxycarbony1 , R and R* are Ci-C*alkyl and RJ is C1-C4a1koxycarbony1, into a corresponding N-unsubstituted compound of formula I in which R and R' ©re hydrogen and R* is carboxy, by treatment with en inorganic acid or with aqueous alkalis.

29. A compound according to claim 1, substantially as hereinbefore described and exemplified.

30. h process for the manufacture of a compound according to claim 1, substantially as hereinbefore described and exemplified.

31. A compound according to claim 1, whenever manufactured by process claimed in a preceding claim.

32. A pharmaceutical preparation according to claim 15, substantially as hereinbefore described and exemplified. F-.R. KELLY A CO.f AGEHTS FOR THE APPLICANTS„