CA1312608C - Unsaturated phosphonic acids and derivatives - Google Patents

Abstract

4-16190/+/CGC 1135 Unsaturated Phosphonic Acids and Derivatives Abstract of the Disclosure The present invention is concerned with the compounds of formula I, (I) wherein one or both of the acidic hydroxy groups of the phosphonic acid moiety may be etherified, m represents one or zero, R1 is carboxy, esterified carboxy or amidated carboxy, wherein the five-or six-membered heterocyclic ring may be additionally substituted on carbon and/or nitrogen, may have present a carbon-carbon double bond or may be fused on .
adjacent carbon atoms with a six-membered carbocyclic ring, A represents lower alkenylene; and salts thereof. These compounds are useful for the treatment of nervous system disorders in mammals and as antagonists of the N-methyl-D-aspartate sensitive excitatory amino acid receptor.

Description

2 ~
_ 1 - 21~89-7279 4-16190/~/CGC 1135 Canada Unsaturatecl Phosphonic Acids and Derivatives The present invention is concerned with the formula I, R'O~
R i fH2)m ~I) wherein R and R' are each independently hydrogen, lower alkyl, benzyl, benzyl substituted in the phenyl moiety by lower alkyl, halogen or lowar alkoxy, lower alkanoyloxymethyl, lower alkanoyloxy methyl substituted in the oxymethyl moiety by lower alkyl or cycloalkyl, m represents one or zero, R1 is carboxy, lower alkoxycarbonyl carbamoyl or N-lswer or N,N-di-lower alkylcarbamoyl wherein the five-or six-membered heterocyclic ring represented by the partial formula / 4~
i 3 fH2 ) ( Ia) may have present a carbon-carbon double bond or may be fused on adjacent carbon atoms with a six-membered carbocyclic ring, and may be substituted on carbon by lower alkyl or phenyl-lower alkyl, and R2 denotes hydrogen by lower alkyl, phenyl-~ower alkyl, lower alkoxycarbonyl, benzyloxycar-bonyl or lower alkanoyl, and A represents lower alkenylene; or a salt thereof.

The instant invention is further concerned with processes for preparing said compounds 7 ~ith pharmaceutical compositions comprising said compounds, with a method of blocking the N-methyl~D-aspartate sensitive excitatory amino acid receptor, and with a method of treating conditions ~ and diseases in mammals responsive to the effect of an excitatory amino acid receptor antagonist by administration of said compounds or of pharmaceutical compositions comprising said compounds.

' 2 ~ ~ 8 The compounds of the invention are active and useEul in mammals as selective antagonists of the N-methyl-D-aspartate (NMDA) sensitive excitatory amino acid receptor. The compounds of the invention are therefore also useful, administered alone or in combination to mammals, for the treatment of disorders responsive to said blockade of the NMDA receptor, comprising e.g. cerebral ischaemia, muscular spasms (spasticity), convulsive disorders (epilepsy) and anxiety. The compounds of the invention are also contemplated to be useful for the treatment of Huntington's disease.

Fusion on adjacent carbon atoms with a six-membered carbocyclic ring isfusion with e.g. cyclohexyl or phenyl such that the fused heterocyclic ring of formula I is represented by a bicyclic ringsystem containing 9 or 10 ring-forming atoms, depending on the value of the symbol m of formula I.

The heterocyclic ringsystem of the compounds of formula I as defined hereinbefore, together with substituent Rl, is represented e.g. by optionally substituted 2-carboxypyrrolidinyl, 2-carboxy-2,5-dihydro-pyrrolyl, 2-carboxy-1,2,3,6-tetrahydropyridinyl, 2-carboxy-1,2,5,6-tetrahydropyridinyl, 2-carboxypiperidinyl, 2-carboxytetrahydroquino-linyl, 2-carboxyperhydroquinolinyl, 2-carboxy-2,3-dihydroindolyl or 2-carboxyperhydroindolyl, wherein carboxy may be esterified or amidated.

Etherified hydroxy RO or R'O, respectively is represented e.g. by loweralkoxy, benzyloxy, benzyloxy substituted on phenyl by halogen, by lower alkyl or lower alkoxy, lower alkanoyloxymethoxy or lower alkanoyloxy-me~hoxy substituted on oxymethyl by lower alkyl or cycloalkyl.

One preferred aspect of the invention relates to the phosphonic acid derivatives of formula I and derivatives thereof wherein the heterocyclic ring represents optionally substituted 2-carboxypiperidinyl, 2-carboxy-1,2,3,6-tetrahydropyridinyl or 2-carboxy-1,2,5,6-tetrahydropyridinyl, more specifically the compounds of the formula II

~i ~3~2~0~

- 3 ~ ~14~9-7279 ~ OR' 3 / R (II) or a compound 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, in which the phos-phono bearing chain is attached at the 3-, 4-, or 5-position of the piperidinyl or tetrahydropyridinyl ring, and wherein R and R' independently represent hydrogen, lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or lower alkoxy; lower alkanoyloxy-methyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl or cycloalkyl, R1 represents carboxy, lower alkoxycarbonyl, carbamoyl or N-lower or N,N-di-lower alkylcarbamoyl, R2 represents hydrogen, lower alkyl, phenyl-lower alkyl lower alkanoyl or lower alkoxycarbonyl; R3 re-presents hydrogen, lower alkyl or phenyl-lower alkyl; A represents lower alkenylene; or a salt thereof.

Preferred are the compounds of ~ormula II, wherein R and R' indepen-dently represent hydrogen, lower alkyl, benzyl, lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl, cyclohexyl or cyclopentyl; R1 represents carboxy, carbamoyl or pharma-ceutically acceptable esterified carboxy lower alkoxycarbonyl, carbamoyl or N-lower or N,N-di-lower alkylcarbamoyl, R2 and R~ represent hydrogen or lower alkyl; A represents alkenylene of 2 to 4 carbon atoms; and pharmaceutically acceptable salts thereof.

Further preferred are the compounds of formula II wherein R and R' independently represent hydrogen, lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl; R1 represents carboxy, carbamoyl or lower alkoxyca~bonyl, R2 and R3 represent hydrogen; A is at the 4-position and represents an alkenylene of 3 or 4 carbon atoms with double bond adjacent to phosphono grouping; and pharma-ceutically acceptable salts thereof.

a~

:l ~ L 2 ~

- 4 - 21~89-727g Particularly pref~rred aro the compounds of formula III

~ H (III~
T
y'Rl wherein A represents 1,3-propenylene, preferably with the double bond adjacent to the phosphono grouping; R1 represents carboxy, lower alkoxy-carbonyl, carbamoyl or N-lower or N,N-di-lower alkylcarbamoyl; and pharmaceutically acceptable salts of said compounds.

Most preferred are the compounds of formula III wherein the 2- and 4-substituents are cis to each other.

Another aspect of the invention relates to the phosphonic acid derivatives of formula I and derivatives cited above wherein the hetero-cyclic ring represents optionally substituted 2-carboxy-1,2,3,4-tetra-hydro- or perhydroquinolinyl in which the phosphono bearing chain is preferably locatad at the 3 or 4 position of the tetrahydro or perhydro-quinolinyl ring, i.e. the compounds of formula IV

- ~ OR' . . R (IV) ~./~ \Rl or a perhydro derivative thereof, wherein R and R' independently represent hydrogen, lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or lower alXoxy; lower alkanoyloxymethyl, lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl, or cycloalkyl;
R1 represents carboxy, lower alXoxycarbonyl, carbamoyl or N-lower or N,N-di-lower alkylcarbamoyl, R2 represents hydrogen, lower alkyl, phenyl-C

L3:~ 2~

- 5 - 21~89-7~79 lower alkyl, lower alkanoyl or lower alkoxycarbonyl, R4 represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; A
represents lower alkenylene; or a salt thersof.

Preferred are the compounds of ormula V

- OH
. .\ OH
il j (V) or a psrhydroquinoline derivative thereof wherein A represents 1,3-propenylene with the double bond adjacent to the phosphono grouping;
Rl represents carboxy or lower alkoxycarbonyl; or a pharmaceutically acceptabls salt of said compound.

Most preferred are the compounds of formula V wherein the 2- and 4-substituents are cis to each othsr.

A further aspect of the invention relates to the phosphonic acid derivativss of formula I and derivatives cited above wherein the hetero-cyclic ring represents optionally substituted 2-carboxypyrrolidinyl, i.e. the compounds of formula VI

R3-+ +~-A - 4_ OR' (VI) ~ ~l OR

and the compounds of formula VI with a double bond present between C-3 and C-4 of the pyrrolidinyl ring, wherein R and R' independently represent hydrogen, lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or lower alkoxyl lower alkanoyloxymethyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl, or cyclo-alkyl; Rl represents carboxy, lower alkoxycarbonyl, carbamoyl or N-lower or N,N-di-lower alkylcarbamoyl, R2 represents hydrogen, lower alkyl, lower alkanoyl or low~r al~oxycarbonyl, R3 represents hydrogen, lower alkyl or aryl-lower alkyl; A represents lower alkenylene; or a salt thereof.

Preferred are the compounds of formula VI wherein the phosphono bearinggroup is attached at the 3-position, R and R' represent hydrogen;
R1 represents carboxy, lower alkoxycarbonyl or lower alkanoyloxymethoxy-carbonyl; and R2 and R3 represent hydrogen; A represents 1,3-propenylene with double bond adjacent to the phosphono grouping or a salt thereof.

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

The term "lower", when referred to above and hereinafter in connection with organic groups, radicals or compounds respectively, defines such with up to and including 7, preferably up to and including 4 and advantageously one, two or three carbon atoms.

Lower alkyl contains l to 7, preferably 1 to 4 carbon atoms and represents for example ethyl, propyl, butyl or advantageously methyl.

Lower alkenylene representing A contains 2 to 4 carbon atoms and represents for example ethenylene, 1,3 propenylene, 1,4-but-1-enylene, 1,4-but-2-enylene, advantageously with double bond adjacent to phosphono grouping.

Lower alkoxy contains 1 to 7, preferably 1 to 4 carbon atoms and represents for example ethoxy, propoxy or advantageously methoxy.

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

Lower alkanoyloxy contains 2 to 5 carbon atoms and advantageously represents acetoxy, propionyloxy, n- or i-butyryloxy or pivaloyloxy.

~ 3 11 2~

Cycloalkyl contains preferably 3 to 8 carbon atoms and represents e.g. cyclohexyl or cyclopsntyl.

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

Aroyl represents arylcarbonyl, preferably benzoyl or benzoyl substituted by one to three substituents selected from lower alkyl, lower alkoxy, trifluoromethyl and halogen; or pyridylcarbonyl, particularly nicotinoyl.

Phenyl alkyl represents phenyl-Cl-4-alkyl, advantageously benzyl or 2-phenylethyl.

Lower alkoxycarbonyl contains 1 to 4 carbon atoms in the alkoxy portionand represents for example methoxycarbonyl, prop-oxycarbonyl, iso-propoxycarbonyl or advantageously ethoxycarbonyl.

An N-mono(lower alkyl)carbamoyl group contains 1 to 4 carbon atoms in the alkyl portion and is for example N-methylcarbamoyl, N-propylcarbamoyl or advantageously N-ethylcarbamoyl.

An N,N-di(lower alkyl)carbamoyl group contains 1 to 4 carbon atoms in each lower alkyl portion and represen~s for example N,N-dimethyl-carbamoyl, N-ethyl-N-methylcarbamoyl and advantageously N,N-diethyl-carbamoyl.

N-Mono-lower alkylcarbanoyl is, for example, N-ethylcarbamoyl and N,N-di-lower alkylcarbamoyl is, for example, N,N-diethylcarbamoyl.

Salts of the compounds of the invention are preferably pharmaceuticallyacceptable salts, on the one hand matal or ammonium salts of the compounds of the invention having a free phosphonic or carboxy group, more particularly alkali or alkaline earth metal salts, e.g. the sodium, potassium, magnesium or calcium salt; or advantageously crystallizing ammonium salts derived from ammonia or organic amines, such as methyl-~'.

~3~ 3~

amine7 diethylamine, triethylamine, dicyclohexylamine, triethanolamine,ethylenediamine, tris-(hydroxymethyl)aminomethane or benzyltrime~hyl-ammonium hydroxide. On the other hand the compounds of the invention which are basic amines form acid addition salts of preferably ph~rma-ceutically acceptabls inorganic or organic acids, such as of strong mineral acids, for example hydrohalic, e.g. hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitric acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. acetic, propionic, succinic, glycolic, lactic, malic, tartaric, gluconic, citric, ascorbic, maleic, fumaric, pyruvic, pamoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxy-ethanesulfonic, benzenesulfonic, p-toluenesulfonic or naphthalenesulfonic acid.

For isolation or purification purposes, salts may be obtained which might not be useful for pharmaceutical purposes. However, only pharmaceutically acceptable salts are used for therapeutic purposes and these salts, therefore, are preferred.

The compounds of the invention exhibit valuable pharmacological properties, e.g. by sslectively blocking the N-methyl-D-aspartate sensitive excitatory aminoacid receptors in mammals. The compounds are thus useful for treating diseases responsive to excitatory amino acid blockade in mammals, comprising e.g. nervous system disorders, particularly convulsive disorders (epilepsy) and anxiety.

These effects are demonstrable in in vitro tests or in vivo animal tests using advantageously mammals or tissues or enzyme preparations thereof, e.g. mice, rats, or monkeys. Said compounds can be administered to them enterally or parenterally, advantageously orally or transdermally, or subcutaneously, intravenously or intraperitoneally, for example, within gelatin capsules, or in the form of aqueous suspensions or solutions, respectively. The applied in vivo dosage may range between about 0.01 to 100 mg/kg, preferably between about 0.05 and 50 mglkg, advantageously between about O.l and 10 mg/kg. Said compounds can be applied in vitro in the form of e.g. aqueous solutions and the dosage may range between about 10 molar and 10 molar concentrations.

~'~j .

~3~2~
_ 9 _ The inhibitory effect on the NMDA-type excitatory amino acid receptors is determined in vitro by measuring the inhibition oE the NMDA-evoked 3H-acetylcholine (3H-ACh) release from corpus striatum tissue of rat brain, according to J. Lehmann and B. Scatton, ~rain Research 252, 77 - 89 (1982) and Nature 297, 422 - 424 (1982).

Antagonists of NMDA-type excitatory amino acid receptors competitively antagonize NMDA-evoked 3H-acetylcholine (3~1-ACh) release from corpus striatum tissue of the brain.

The inhibition of the NMDA-evoked 3H-acetylcholine (3~-ACh) release from rat striatal tissue slices by a compound of the invention is expressed as % of release of 3~-ACh in response to stimulation with 50 ~M NMDA
compared to control. Tests are two-tailed with a minimum of n = 4 in each group. ICso values represent the concentration of test compound required to inhibit thc NMDA-increased 3 H-ACh release by 50 %.

The inhi~itory effect on the NMDA-type excitatory amino acid receptors is demonstrated in vivo by inhibition of NMDA-induced convulsions in the mouse.

Illustrative compounds of the invention prevent NMDA-induced convulsions in the mouse at doses as low as about 1.2 mg/kg i.p.

Further indicative of the anticonvulsant activity, compounds of the invention are effective in preventing audiogenic-induced seizures in DBA/2 mice [Chapman et al., Arzneim.-Forsch. 34; 1261, (1984)].

The effect 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 exposed to a sound stimulation of 110 dB for 1 minute or 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 effect.

~;

~X~2~

Test compounds in either distilled water solution or in a 3 % (w/v) colloidal cornstarch suspension containing 5 % (w/v) polyethylene-glycol 400 and 0.34 % (w/v) Tween 80, are administered by oral intubation or intraperitoneally in a volume of 10 ml/kg of body weight.

Indicative of anxiolytic activity, 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 compoundsof the invention in preventing or reducing brain damage in mammals due to a transient cerebral ischemia (as in a stroke) cachemia (as in a stroke) can be determined in the mongolian gerbil ischemia model, e.g. the model described by T. Kirino, Brain Research 239, 57-69 (1982).

The inhibitory effect on the observed hyperactivity and on the degenera-tion 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 beEore the ischemia or 2, 4 and 6 hours pos~
ischemia.

Illustrative compounds of the invention, at a dose of 10 mg/kg i.p.
administsred 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 the brain.

The aforementioned advantageous properties render the compoun~s of the invention useful as antagonists of the N-methyl-D-aspartate excitatory amino acid 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, e.g. by ~s~

a~ condensing an aldehyde or ketone of the formula VII

z)m (~II) ~ R

wherein m, R1, R2 and the heterocyclic ring are as defined for formula I
with R1 and amino groups in protected form, and A' represents oxo substituted lower alkyl having 1 carbon less than the alkenylene group A, with a tetra ester derivative of methylenediphosphonic acid, preferably with a tetra-lower alkyl ester of methylenediphosphonic acid, in the presence of a strong anhydrous base and in an inert polar solvent and if required deprotecting the resul~ing product to obtain a compound of formula I wherein the double bond within the grouping A is adjacent to the phosphono grouping; or b) condensing a compound o the ~ormula VIII

k3~ (VIII) --Rl wherein A, m, R1, R2 and the heterocyclic ring are as defined for formula I, and X represents reactive esterified hydroxy, with a compound capa~le of introducing the phosphonic acid moiety, having one of formulae IX or X

H - ~- OR" (IX) P(R"')3 (X) R"
wherein R" represents lower alkyl and R"' represents halogen or lower alkoxy and, i~ required, converting the resulting phosphonic acid derivative to the phosphonic acid or other ester derivative thereof; or ~2~3~3 - 12 - 21~89-7279 c) hydrolysis to carbamoyl or carboxy R1 a cyano group at position 2 of the heterocycllc ring in a compound otherwise identical to a compound of the invention; and carrying ou~ the said processes while, if necessary, temporarily protecting any interfering reactive group(s) in these processes, and then liberating the resulting compound of the invention;
and, if required, converting a resulting compound of ~he invention into another compound of the invention, and, if required, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt; and if a single isomer or racemate is required, separating a mixture of isomers or racemates obtained into the single isomers or racemates; and, if an individual optical antipodes is required, resolving a racemate obtained into the optical antipodes.

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 hydrohalic, e.g. hydrochloric9 hydrobromic or hydroiodic acid, or sulphuric acid, or by a strong organic acid, especially a strong organic sulfonic acid, such as an aliphatic O'f aromatic sulfonic acid, for example methanesulfonic acid, 4-methylphenylsulfonic acid or 4-bromophenylsulfonic acid. Said reactive esterified hydroxy is especially halo, for example chloro, bromo or iodo, or aliphatically or aromatically substituted sulfonyloxy, for example methanesulfonyloxy, phenylsulfonyloxy or 4-methylphenylsulfonyloxy (tosyloxy).

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

The purpose of introducing protecting groups is to protect the functional groups ~rom undesired reactions with reaction components and under the conditions used for carrying out a desired chemical transformation. The r~

2 ~ ~ ~
- 13 - 21~89-7279 need and choice of protecting groups for a particular reaction is known to those skilled in the art and depends on the nature of the functional group to be protected (carboxy group, amino group, stc.), the structure and stability of the molecule of which th~ substituent is a pa~t, and the reaction conditions.

Well-knQwn protecting groups that meet these conditions and their introduction and removal are described, for example, in J.F.W. McOmie, "Protective Groups in Organic Chemistryl', Plenum Press, London, New York 1973, T.U. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981, and also in "The Peptides", Vol. I, Schroeder and Luebke, Academic Press, London, New York 1965, as well as in Houben-Weyl, "Methoden 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 keton~ with e.gO a tstra lower alkyl ester of methylenediphosphonic acid is carried out according to procedure known in the art for such condensations, in the presence of a strong anhydrous base, e~g. butyl lithium, in an inert polar solvent such as tetrahydrofuran9 prefsrably at reflux temperat~re. The starting aldehydes or ketones of formula VII can be prepared e.g. by oxidation of the corresponding alcohols for example with pyridinium chlorochromate, or other methods e.g. as illustrated in the examples.

The respective alcohols can in turn be prepared by methods generally known in the art, e.g. by reduction of the corresponding aromatic alcohols using methods known in the art for the reduction of pyrrole, pyridine, indole and quinoline rings. For example, the reduction of the pyridine or quinoline ring is advantageously carried out with an organo-metallic reducing agent or by catalytic hydrogenation, e.g. in the presence of platinum oxide and an acidic solvent such as acetic acid to give corresponding tetrahydropyridines, piperidines, 1,2,3,4-tetra-hydroquinolines or perhydroquinolines of the invention, i.e. of :L 3 ~

formula II, IV and derivatives thereoE. Quaternary quinolinium and pyridinium compounds, e.g. in which R2 is lower alkyl or aryl-lower alkyl, may be similarly reduced.

The alcohols, aldehydes or ketones so obtained may also be converted toaldehydes or ketones of longer chain length using conventional methodology, e.g. by a Wittig condensation of an aldehyde with methoxy-methyl-triphenylphosphonium chloride to yield the homologous aldehyde, and by other well-known sequences of reactions described in the examples.

Ths aromatic 2-carboxy-heterocycle-substituted lower alkanols referred to above, for example the 2-carboxypyridinyl- or 2-carboxy-quinolinyl-substituted lower alkanols or derivatives thereof can in turn be prepared by treatment of the 2-unsubstituted pyridinyl- or 2-unsubstituted quinolinyl-substituted lower alkanols in suitably protected form, wi~h e.g. a peracid, such as 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 the corresponding 2-cyanopyridine or 2-cyano-quinoline derivatives which are then converted, by methods known in the art, to the 2-R1 (carboxy, esterified or amidated carboxy) substituted pyridine and quinoline derivatives.

The condensation according to process (b) is advantageously used for the preparation of the compounds of formula I wherein the double bond within the alkenylene grouping A is not adjacent to the phosphono grouping.

The condensation according to process (b) of a compound of formula VIIIwith a compound of formula X, e.g. triethyl phosphite, is carried out, e.g. by heating in an inert solvent, and under conditions known in the art for a Michaelis-Arbuzov reaction according to Angew. Chem. Int.
~d. 16, 477 (1977) and Chem. Rev. 81, 415 (1981). Similarly, condensation with e.g. phosphorus trichloride and subsequent hydrolysis gives a compound of formula I.

- 15 - 2l489-727g The condensation according to process (b) of a rompound of formula VIIIwith a compound of formula IX, e.g. diothylphosphonate (diethyl phosphite), is carried ous e.g. in a strong basic medium, for instance in the presence of an alkali metal, e.g. sodium, an alkali metal hydride, e.g. sodium hydride, an alkali metal alkoxide, e.g. potassium t-butoxide, in an inert solvent e.g. toluene or dimethylformamide.

The starting materials of formula VIII and reactive derivatives thereofcan be prepared by methods well known in the art starting from inter-mediates of formula VII wherein A' represents o~o-substituted lower alkyl, the ~reparation of which is described above.

For example, the starting material of formula VIII wherein A representspropenylene is prepared by condensing an aldehyde of formula VII, wherein the grouping A' represents formyl (CH=O), with a suitable Uittig reagent, e.g. formylmethylene-triphenylphosphoran, reducing the resulting un-saturated 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 triphenylphosphinelN-bromo-succinimideO

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

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

:~3:~2~
- l6 - 21~89-7279 Oxo substituted lower alkyl represents preferably formyl, formylmethyl,formylethyl or 2-oxo-propyl.

Trialkoxymethyl re,oresents preferably tri(lower alkoxy)methyl, particularly triethoxy- or trimethoxymethyl.

Etherified hydroxymethyl represents preferably lower alkoxymethyl, lower alkoxyalkoxymethyl, e.g. methoxymathoxymethyl or 2-oxa- or 2-thiacyclo-alkoxymethyl, particularly 2-tetrahydropyranyloxymethyl.

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

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

Conversion of cyano to carboxy is gsnerally accomplished by solvolysis,with acid or base.

- 17 - ~ 3 .~ 2 ~ ~ ~ 21489-7279 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 temperature.

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

For example, conversion of carboxylic acid esters and amides to carboxylic acids is advantageously carried out by hydrolysis with inorganic acids such as a hydrohalic or sulfuric acid or with aqueous lL3 ~2~

alkalies, preferably alkali metal hydroxides such as lithium or sodium hydroxide.

~ree 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 corresponding lower alkyl esters.

Furthermore, ths free carboxylic acids may be converted via treatment of a reactive intermediate thereof, e.g. an acyl halide such as the acid chloride, or a mixed anhydride, e.g. such derived from a lower alkyl halocarbonate such as ethyl chloroformate, 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 R1 represents unsubstituted, mono or di-~lower)alkyl-carbamoyl.

Phosphonic acid esters are converted to the corresponding phosphonic acids by treatment with 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 may be converted to the acids by hydrogenolysis.

Phosphonic acids are converted to esters, e.g. optionally 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 ~riethylamine.

In a preferred embodiment of the invention a compound of formula II, IVor VI7 wherein R and R' represent lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or lower alkoxy; lower alkanoyloxy-methyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl or cycloalkyl, preferably lower alkyl, R1 is pharmaceutically acceptable esterified or amidated carboxy, preferably lower alkoxy-carbonyl, and R2 represents acyl, preferably lower alkoxycarbonyl, is ``" ~3:~ 2~

~ ,9 converted into a compound of formula II, IV or VI, respectively, wherein R and R' are hydrogen, Rl is carboxy and R2 is hydrogen, by treatment with an inorganic acid, such as a hydrohalic acid or sulfuric acid, preferably hydrochloric acid, or with aqueous alkalies, preferably alkali metal hydroxides, such as lithium or sodium hydroxidas, preferably at elevated temperatures.

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such that are inert to the reagents and are solvents thereof, of catalysts, of condensing or said other agents respectively and/or in inert atmospheres, at low temperatures, room temperature or elevated temperatures, preferably at the boiling point of the solvents used, and at atmospheric or super-atmospheric pressure. The preferred solvents, catalysts and reaction conditions are set forth in the appended illustrative 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 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 reaction components are used in the form of their salts or optically pure 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 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 asymmetrical carbon atoms, as pure optical isomers, such as antipodes, or as mixtures of optical isomers such as racemates or as mixtures of diastereoisomers or ~,'~

of geometric îsomers. The aforesaid possible isomers or mixtures thereoE
are within the purview of this invention; certain particular isomers are preferred as indicated above.

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

Any resulting racemates can be resolved into the optical antipodes by known methods, for example by e.g. reacting an acidic end product with an optically active base that forms salts with the racemic 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 diastereo-isomeric salts thereof, with an optically ac~ive 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 crystallization of d- or ~-(tartrates, mandelates, camphorsulfonates) or of d- or~ -methylbenzylamine, cinchonidine, cinchonine, quinine, quinidine, ephedrine, dehydroabietyl-amine, 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 regenerating the resolved optically active compound. Advantageously, the more active of the two antipodes is isolated.

Finally the compounds of the invention are either obtained in the free form, or as a salt thereof. Any resulting base can be converted into a corresponding acid addition salt, preferably with the use of a thera-peutically useful acid or anion 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 motal or ammonium hydroxide or a basic ~"

~2~

saltg e.g. an alkali metal hydroxide or carbonate, or a cae:ion exchange preparation, or an alkylene oxide such as propylene oxide. ~ 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 example, the picrates, can also be used for purifica-tion 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 beween the free compounds and the compounds in the form of their salts, whenever a compound is referred to in this context, a corresponding salt is also intended, 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 blockade of the N-methyl-D-aspartate sensitive excitatory amino acid receptor and for the treatment of diseases responsive to blockade of the N-methyl-D-aspartate sensitive excitatory amino acid receptor, such as cerebral ischemia, convulsive disorders and anxiety, comprising an effectiv~ amount of a pharma-cologically active compound of the invention, alone or in combination with one or more pharmaceutically acceptable carriers.

The phasmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising an e~fective amount thereof in conjunction or admixture with excipients or 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, mannitol, sorbitol~ cellulose and/or glycine b) lubricants, e.g. siliça, talcum, stearic acid, its magnesium or calciu~ salt and/or polyethyleneglycol; for tablets also c) binders e.g. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or ~ 3 ~ 8 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, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other tharapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75 %, preferably about 1 to 5Q %, of the active ingredient.

Suitable formulations for transdermal application include an effective amount of a compound of formula I with carrier. Advantageous carriers include absorbable pharmacologically acceptable solvents to assist passage throught the skin of the host. Characteristically, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier 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 of 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. such responsive to blockade 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 the administration to a mammal .

:: .

~ 3 ~

in need thereof of an effective amount of an N-methyl-D-aspartate blocking compound of the invention or of a pharmaceutical composition comprising a said compound.

The dosage of active compound administered is dependent on the species of warm-blooded animal (mammal), the body weight, age and individual condition, and on the form 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 ingredient.

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

Example 1: Ethyl 4-[1-(3-diethylphosphonoprop-2-enyl)]-1-tert-butoxy-carbonylpiperidine-2-carboxylate is hydrolyzed with 6N hydrochloric acid to yield 4-[1-(3-phosphonoprop-2-enyl)]piperidine-2-carboxylic acid.

The starting material is prepared as follows: 4-(2-hydroxyethyl)-pyridine is oxidized to 4-(2-hydroxyethyl)-pyridine-~-oxide which is in turn treated with trimethylsilyl cyanide to yield 4-(2-hydroxyethyl)-2-cyanopyridine which is converted to ethyl 4-(2-hydroxyethylj-2-pyridine carboxylate and then hydrogenated to yield ethyl 4-(2-hydroxyethyl)-piperidine-2-carboxylate.

A solution of 2.01 g of ethyl 4-(2-hydroxyethyl)-piperidine-2-carboxylate in 5 ml dichloromethane is added to a solution o 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 (50:50) to afford ethyl 4-(2-hydroxyethyl)-1-tert-butoxycarbonylpiperidine-2-carboxylate.

~,1 ` L3~2~

- 2~ -To a solution of 1.56 g of dimethyl sulfoxide in 10 ml dichloromethane is added 2.2 g of oxalyl chloride at -78C. After 20 minutes 2.4 g of ethyl 4-(2-hydroxyethyl)-1-tert-butoxycarbonyl-piperidine-2-carboxylate in 5 ml dichloromethane is added. The reaction is stirred for one hour and 2.2 g of triethylamine is added. l'he ice bath is removed, the solvent evaporated and the residue is flash chromatographed with hexane/ethyl acetate (70:30) to afford ethyl 1-tert-butoxycarbonylpiperidine-2-carboxylate-4-acetaldehyde.

At -78C, 2.73 ml n-butyllithium is added to 2.02 g bis(diethyl-phosphono)-methane in 20 ml anhydrous tetrahydrofuran. After 5 minutes 2.08 g ethyl 1-tert-butoxycarbonylpiperidine-2-carboxylate-4-acet-aldehyde in 5 ml tetrahydrofuran is added. The mixture is then refluxed for 16 hours. The cooled reaction mixture is concentrated and flash chromatographed (95:5 dichloromethane/methanol) to yield ethyl 4-[1-(3-diethylphosphonoprop-2-enyl)]-1-tert-butoxycarbonylpiperidine-2-carboxylate.

Example 2: The following compounds can be prepared according to methods generally illustrated in the previous example:

(a) trans 3-[1-(4-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 ethyl N-ethoxycarbonyl-pyrrolidine-2-carboxylate-3-acetaldehyde is condensed with (C6Hs)3P=CHOCH3 under conditions of the Wittig reaction to afford trans ethyl N-ethoxycarbonylpyrrolidine-2-carboxylate-3-propion-aldehyde. Condensation with bis-(diethylphosphono)methane under conditions described herein (e.g. example 1) yields trans ethyl 3-[1-(4-diethylphosphonobut-3-enyl)]-pyrrolidine-2-carboxylate.

The starting material for compound (b) can be prepared as follows: The alcohol, trans ethyl N-ethoxycarbonyl-3-~2-hydroxyethyl)-pyrrolidine-2-carboxylate is oxidized to the aldehyde, trans ethyl N-ethoxycarbonyl-pyrrolidine-2-carboxylate-3-acetaldehyde, which is condensed with 2 ~ ~ ~

triphenylphosphoranylideneacetaldehyde under conditions of the Wittig reaction; the resulting ~,~-unsaturated C4-aldehyde is reduced -to the corresponding alcohol which is converted to the bromide. Condensation with triethyl phosphite yields ethyl 3-[1-t4-diethylphosphonobut-2-enyl)]-pyrrolidine-2-carboxylate.

Example 3:
4-[1-(3-Phosphonoprop-l-enyl)]piperidine-2-carboxylic acid can be similarly prepared using ethyl 4-hydroxymethyl-N-ethoxycarbonyl-piperidine-2-carboxylate as intermediate.

Example 4: At -78C, 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-(tert-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-[1-(3-diethylphosphono-prop-2-enyl)]-(1-tert-butoxycarbonyl)-piperidine-2-carboxylate.

The starting material is prepared as follows: A solution of 4-pyridyl-acetic acid in 500 ml of anhydrous ethanol containing 75 ml of concentrated sulfuric acid is refluxed 18 hours. The solution is cooled to 0C 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 50C (bath) for 40 minutes, then cooled in an ice bath, and the excess lithium aluminum hydride is decomposed by 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 concsntrated in vacuo to yield 4-pyridylethanol.

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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 1 hour at room temperature. The product is isolated by extraction into athyl acetate/hexane (l:l) and washed 4 times with 400 ml of water;
the extract is ~iltered through silica gel and concentrated in vacuo to yield 4-(tert-butyl-dimethylsilyl-oxyethyl)-pyridine.

To a stirred solution of 28.8 g of 4-(tert-butyl-dimethylsilyloxy-ethyl)-pyridine in 300 ml of dichloromethane is added 24 g of m-chloro-perbenzoic 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-dimethylsilyl-oxyethyl)-pyridine-N-oxide.

A solution of 28.6 g of 4-(tert-butyl-dimethylsilyloxyethyl)-pyridine-N-oxide, 60.3 ml of trimethylsilyl cyanide and 31.5 ml triethylamine 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 aceeate/hexane (l:10) to yield 4-~tert-butyl-dimethylsilyloxyethyl)-2-cyanopyridine.

A solution of 22.2 g of 4-(tert-butyl-dimethylsilyloxyethyl)-2-cyano-pyridine 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 0C and 22 ml of 6N hydrochloric acid added. The solution is stirred at room temperature for 16 hours, cooled to 0C and 7.5 ml 6N sodium hydroxide added followed by 75 ml saturated aqueous sodium bicarbonate.
Extraction with dichloromethane and flash chromatography using ethyl acetate yields ethyl 4-(2-hydroxyethyl)-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 hydrogenated at 345 kPa.
Filtration, concentration in vacuo, neutralization with potassium carbonate and extraction with dichloromethane yields an oil that is ~.

~S~ ~2S~, purified by flash chromatography using dichloromethane/methanol saturated with ammonia (20:1) to yield ethyl 4-(2-hydroxyethyl~-piperidine-2-carboxylate.

A solution of 7.9 g of ethyl-4-(2-hydroxyethyl)-piperidine-2-carboxylate, 9.0 g di-tsrt-butyl dicarbonate in 80 ml of dichloromethane is stirred for 2 hours at room temperature and then concentrated in vacuo to yield ethyl 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)-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 chlorochromate in 175 ml dichloromethane is stirred under nitrogen at room temperature for 80 minutes. Mixture is filtered an l purified by flash chromatography using ethyl acetate/hexane (25:75) to yield 1-(tert-butoxycarbonyl)-2-ethoxycarboDyl-piperidine-4-acetaldehyde.

Example S: A mixture of 4.~7 g o~ ethyl 4-[1-(3-diethylphosphonoprop-2-enyl]-l-(tert-butoxycarbonyl)-piperidine-2-carboxylate and 75 ml 6N
hydrochloric acid is refluxed 12 hours. The solution is concentrated in vacuo to dryness. The residue is dissolved 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-[1-(3-phosphonoprop-2-enyl)]-piperidine-2-carboxylic acid, m.p. 163-165C.

Example 6: At -78C, 6.9 ml of butyllithium (1.6 M) is added to 2.9 ml of tetraethylmethylene diphosphonate in 30 ml anhydrous tetrahydrofuran.
After 5 minutes~ 2.47 g oE trans ethyl l-acetyl-piperidine-2-carboxylate-4-acetaldehyde in 55 ml tetrahydrofuran (anhydrous) is added. The mixture is refluxed 18 hours, cooled, concentrated and purified by flash chromatography using dichloromethane/ethanol (100:3) to yield trans ethyl 4-[1-(3-diethylphosphonoprop-2-enyl)]-1-acetyl-piperidine-2-carboxylate.

~ 3~2~

The starting material is prepared as follo~s: At 0C, 9.4 ml acetic anhydride is added to a stirred solution of 13.5 g of ethyl 4-(2-hydroxy-ethyl)-piperidine-2-carboxylate in 75 ml pyridine. 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, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in 100 ml ethanol t 5 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 dichloromethane/methanol (95:5) to yield trans ethyl 1-acetyl-4-(2-hydroxyethyl)-piperidine-2-carboxylate.

A mixture of 3.7 g of trans ethyl 1-acetyl-4-(2-hydroxyethyl)-piperidine-2-carboxylate and 5.4 g of pyridinium chlorochromate in 75 ml dichloro-methane 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 ethyl 1-acetylpiperidine-2-carboxylate-4-acet-aldehyde.

Example 7: A mixture of 2.5 g of trans ethyl 4-[1-(3-diethylphosphono-prop-2-enyl)]-1-acetylpiperidine-2-carboxylate and 40 ml 6N hydrochloric acid is refluxed for 12 hours. The solution is concentrated in vacuo to dryness. The residue is dissolved 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-[1-(3-phosphonoprop-2-enyl)]-piperidine-2-carboxylic acid, m.p. 132-140C.

Example 8: A solution of 0.334 g of trans ethyl 4-[1-(3-bromoprop-1--enyl)]-l-(tert-butoxycarbonyl)-piperidine-2-carboxylate 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) to yield trans ethyl 4-[1-(3-di-ethylphosphonoprop-l-enyl)]~l-(tert-butoxycarbonyl)-piperidine-2-carboxylate.

~ 3 ~
-- ?9 -The starting material is prepared as follows: A solution of 20 g 4-pyridylcarbinol, 28.9 g of chloro-tert-butyl-dimethylsilane and 14.4 g imidazole in 200 ml dimethylformamide is stirred 3 hours at room temperature. Product is isolated by extraction into ethyl acetate/hexane (1:1) and washing extract 4 times with 400 ml of water. The solution is filtered through silica gel and concentrated in vacuo to yield 4-(tert-butyl-dimethylsilyloxymethyl)-pyridine.

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

A solution of 37.9 g of 4-(tert-butyl-dimethylsilyloxymethyl)-pyridine-N-oxide, 84 ml of trimethylsilyl cyanide and 44 ml triethylamine is stirred under nitrogen at reflux for 2 1/2 hours. Dark solution is cooled in an ice bath, then 40 ml of ethanol added followed by 500 ml of ethyl acetate. The solution is washed twice with water, dried over sodium sulfate, filtered, concentrated in vacuo and purified by flash chromato-graphy using ethyl acetatethexane (1:10) to yield 4-(tert-butyl-dimethyl-silyloxymethyl)-2-cyanopyridine.

A solution of 21.7 g of 4-(tert-butyl-dimethylsilyloxymethyl)-2-cyano-pyridine in 220 ml anhydrous ethanol containing 0.2 g of sodium is stirred at room temperature for 18 hours, cooled to 0C and 22 ml 6N
hydrochloric acid is then added. The solution is stirred at room temperature for 18 hours, cooled to 0C, 7.5 ml 6N sodium hydroxide added followed by 20 ml saturated aqueous sodium carbonate. Extraction with dichloromethane, then drying, filtering and concentrating the extract yields an oil which crystallizes from ether to yield ethyl 4-(hydroxy-methyl)-pyridine-2-carboxylate.

A mixture of 13.9 g of ethyl 4-(hydroxymethyl)-pyridine-2-carboxylate, 5 g platinum oxide in 250 ml acetic acid is hydrogenated at 345 kPa.
Filtration, concent}ation in vacuo, and neutralization with potassium ~r .~
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carbonate in dichloromethane yields an oil that is purifled by flash chromatography using dichloromethane/methanol saturated with ammonia ~20:1) to yield ethyl 4-(hydroxymethyl)-piperidine-2-carboxylate.

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

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

A solution of 1 g of 1-(tert-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-carboxaldehyde and 2 g of formylmethylene-triphenylphosphoran in 16 ml oE toluene is heated to 100C (bath) for 2 hours. The soluticn is cooled and purified by flash chromatography using ethyl acetate/hexane (25:75) to yield l-(tert-butoxycarbonyl)-2-ethoxycarbonyl-piperidine-4-acryl-aldehyde.

A sol~tion of 0.83 g of 1-(tert-butoxycarbonyl)-2-ethoxycarbonyl-piperidine-4-acrylaldehyde and 0.11 g of sodium borohydride in ~ ml of ethanol is stirred at 0C for 30 minutes; 0.2 ml of acetic acid is added followed by ice cold water and the mixture is extracted with dichloro-methane. The extract is dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography using ethylacetate/hexane (25:75) yields trans ethyl l-(tert-butoxycarbonyl)-4-[1-(3-hydroxyprop-1-enyl)]-piperidine-2-carboxylate.

A solution of 0.367 g of trans ethyl 1-(tert-butoxycarbonyl)-4 [1-(3-hydroxyprop-l-enyl)]-piperidine-2-carboxylate, 0.35 g triphenylphosphine and 0.23 g of bromosuccinimide in 8 ml of dichloromethane is stirred ~ 3 ~ ?~

initially at 0C and then at room tamperature for 40 minutes. Purifica-tion by flash chromatography using ethyl acetate/hexane (1:9) yields trans ethyl 4-[1- (3-bromoprop-1-enyl)]-1-(tert-butoxycarbonyl)-piperidine-2-carboxylate.

Example 9: A solution of 0.39 g o~ trans ethyl 4-[1-(3-diethylphos-phonoprop-l-enyl)]-l-(tert-butoxycarbonyl)-piperidine-2-carboxylate and 2.3 ml of trifluoroacetic acid in ~ ml of dichloromethane is stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate is added and the mixture extracted with dichloromethane. Purification by flash chromatography using dichloromethane/methanol saturated with ammonia (20:1) yields trans ethyl 4-[1-(3-diethylphosphonoprop-1-enyl)]-piperidine-2-carboxylate.

Example 10: A solution of 0.265 g of trans ethyl 4-[1-(3-diethyl-phosphonoprop-l-enyl)]-piperidine-2-carboxylate in 5 ml of anhydrous ethanol containing 0.074 ml of butyl lithium (1.6 M) is heated at 80C
(bath) for 72 hours. After cooling, 0.025 ml acetic acid is added, followed by excess saturated sodium bicarbonate, and the mixture is extracted with dichloromethane. The dichloromethane extract on concentration in vacuo yields an oil; purification by flash chromato-graphy using dichloromethane/isopropanol saturatèd with ammonia (20:1) yields cis ethyl 4-[1-(3-diethylphosphonoprop-1-enyl)]-piperidine-2-carboxylate.

Example 11:
a) A mixture of 0.142 g of cis ethyl 4-[1 (3-diethylphosphonoprop-1-enyl)]-piperidine-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 dissolved in 2 ml of ethanol and O.lS ml of propylene oxide is added. The solid that separates is filtered off and dried in vacuo to yield cis 4-[1-(3-phosphonoprop-1-enyl)]-piperidine-2-carboxylic acid, m.p. 175C dec.

b) Similarly, hydrolysis of the trans ester of example 9 yields the corresponding trans acid, m.p. 130-135C.

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~L 3 ~ g c) A solution of cis 4-[1-(3-phosphonoprop-1-enyl)]-piperidine-2-carboxylic 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-1-enyl)]-piperidine-2-carboxylate.

Example 12: To a solution of 0.234 g of trans 1-ethoxycarbonyl-2-ethoxy-carbonyl-pyrrolidine-3-propionaldehyde in 5 ml of anhydrous tetra-hydrofuran under nitrogen, cooled to -78C9 is added slowly a solution of 0.23 ml of tetraethylmethylenediphosphonate and 0.57 ml of butyllithium (1.6 M) in 5 ml of anhydrous tetrahydrofuran also at -78C. Solution is refluxed for 14 hours, cooled and treated with 0.15 ml of acetic acid;
the reaction mixture is concentra~ed, diluted with water and extracted with dichloromethane. The extrac~ is dried over sodium sulfate, filtered and concentrated; purification by flash chromatography using ethyl acetate yields trans ethyl l-ethoxycarbonyl-3-[1-(~-diethylphosphonobut-3-enyl)]-pyrrolidine-2-carboxylate.

The starting material is prepared as follows: A mixture of 50 g of N-(2-cyanoethyl)glycine in 300 ml of ethanol saturated with hydrogen chloride gas is stirred 1 hour at room temperature then refluxed for 1 hour. After cooling the solid is filtered off and the filtrate neutralized with sodium bicarbonate, filtered again and concentrated to yield ethyl N-(ethoxycarbonylmethyl)-B-alaninate.

To a mixture of 49 g of ethyl N-(ethoxycarbonylmethyl)-B-alaninate and 30 ml of water cooled to -10C is added dropwise 27.6 ml of ethyl -chloroformate followed by a solution of 12.7 g of sodium carbonate in 50 ml of water. The mixture is warmed to room temperature then heated at 55C for 50 minutes. The mixture is cooled, extracted with toluene, the extract is washed with 2N hydrochloric acid and water. The extract is dried over sodium sulfate, filtered, concentrated and distilled in vacuo to yield ethyl N-(ethoxycarbonylmethyl)-N-(ethoxycarbonyl)-B-alaninate.

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A solution of 53.9 g of ethyl N-(ethoxycarbonylmethyl)-N-(ethoxy-carbonyl)-~-alaninate in 200 ml of toluene is a~ded dropwise to a stirred solution of potassium hexamethyldisilazide (429 ml, 0.653 M) in 125 ml of toluene under nitrogen and cooled to 0C. After 45 minutes at 0C, 21.6 ml of acetic acid is added followed by a solution of 100 g of sodium phosphate (monobasic) in 1 liter of water. The layers are separated, the organic layer 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-ethoxycarbonyl-3-oxo-pyrrolidine-2-carboxylate.

To a stirred suspension of 24 g of benzyloxycarbonylmethyl-triphenyl-phosphonium bromide in 225 ml of anhydrous tetrahydrofuran under nitrogen and cooled to 0C is added 73 ml of potassium hsxamethyldisilazide (0.652 M). After 10 minutes a solution of 11 g of ethyl 1-ethoxycarbonyl-3-oxopyrrolidine-2-carboxylate in 50 ml of tetrahydrofuran is added and the mixture refluxed 2 1/2 hours. Aftsr 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 yield, after filtering and concentrating the filtrate, 1-~thoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetic acid.

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

A solution of 6 g o~ cis 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol in 75 ml of dichloromethane containing 7.3 ml of diisopropyl-ethylamine, to which is added 5.1 ml of 85 Y0 benzyloxymethyl chloride, ~- .

~ L~8 is seirred 3 1/2 hours a~ room tempera~urs. The solution is washed with water and saturated aqueous sodium bicarbonate. The solution is then dried over sodium sulfata, filtered, concentrated and purified by ~lash 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 1-ethoxycarbonyl-3-[2-(benzyloxy-methoxy)-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 lN hydrochloric acid is added, the solution is concentrated in vacuo, cold water added and mixture extracted with dichloromethane. The extract is dried over sodium sulfate, filtered, concentrated and purified by high pressure liquid chromatography using ethyl acetate/hexane (15:85) to yield trans ethyl 1-ethoxycarbonyl-3-[2-(benzyloxymethoxy)-ethyl]-pyrrolidine-2-carboxylate.

A mixture of 1.64 g of trans ethyl 1-ethoxycarbonyl-3-[(2-benzyloxy-methoxy)-ethyl]-pyrrolidine-2-carboxylate and 2 g o~ 10 ~/0 palladium on carbon in 35 ml of acetic acid is hydrogenated at 311 kPa. 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~ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-ethanol.

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

To 0.4 g of trans 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acet-aldehyde in 5 ml anhydrous tetrahydrofuran under nitrogen, cooled to -78C, is added dropwise a solution of 1.17 g of methoxymethyl-tri-phenylphosphonium chloride in 15 ml of anhydrous tetrahydrofuran to which is added 1.55 ml of potassium tert-butoxide/tetrahydrofuran :~ 3 ~

(1.6 M). Solution ls stirred at room temperature for 4 hours. 2N hydro-chloric acid (11 ml) is added and the mixture is stirred ~or 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) to yield trans 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-propionaldehyde.

Example 13: A mixture of 0.193 g of trans ethyl 1-ethoxycarbonyl-3-[1-(4-diethylphosphonobut-3-enyl)]-pyrrolidine-2-carboxylate and 4 ml 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-[1-(4-phosphonobut-3-enyl)]-pyrrolidine-2-carboxylic acid, m.p. 110-115C dec.

Exam~le 14: To a solution of 0.426 g cis 1-ethoxycarbonyl-2-ethoxy-carbonylpyrrolidine-3-propionaldehyde in 10 ml of anhydrous tetra-hydrofuran under nitrogen, cooled to -78C, is added slowly a solution of 0.45 ml of tetraethylmethylenediphosphonate and 1.06 ml of butyllithium (1.6 M) in 10 ml of anhydrous tetrahydro-furan also at -78C. Solution is refluxed 14 hours, cooled and 0.3 ml acetic acid is added; the reaction mixture 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 ethyl acetate to yield cis ethyl l-ethoxycarbonyl-3-[1~(4-diethylphosphonobut-3-enyl)]-pyrrolidine-2carboxylate.

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

~.1 ~ 3 ~ 3 ~

To d.663 g of cis l-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde in 10 ml anhydrous tetrahydrofuran und~r nitrogen, cooled to 78C, is added dropwise a solution of 2.21 g of methoxymethyl-triphenyl-phosphonium chloride in 20 ml of anhydrous tetrahydrofuran to which is added 2.6 ml of potassium tert-butoxide/tetrahydrofuran (1.6 M). Solution is stirred at room temperature for 4 hours 15 ml of 2N hydrochloric acid is added and the mixture 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) yields cis 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-propionaldehyde.

Example 15: A mixture of 0.176 g of cis ethyl 1-ethoxycarbonyl-3-[1-(4-diethylphosphonobut-3-enyl)]-pyrrolidine-2-carboxylate and 3.5 ml of concentrated hydrochloric acid is refluxed 18 hours. The solution is concentrated in vacuo to dryness, the residue dissolved in 1.5 ml of isopropanol/methanol (5:1) and 0.2 ml of propylene oxide is added. The solid that separates is filtered off and dried in vacuo to yield cis 3-[1-(4-phosphonobut-3-enyl)]-pyrrolidine-2-carboxylic acid, m.p. 132-140C.

~xample 16: A solution of 0.0655 g of trans ethyl 1-ethoxycarbonyl-3-[1-(4-bromobut-2-enyl~]-pyrrolidine-2-carboxylate in 0.75 ml o triethyl-phosphite is refluxed 20 minutes. The solutlon is concentrated in vacuo and the residue purified by flash chromatography using dichloro-methane/ethanol (30:1) to yield trans ethyl 1-ethoxycarbonyl-3-[1-(4-di-ethylphosphonobut-2-enyl)]-pyrrolidine-2-carboxylate.

The starting material is prepared as follows: A solution of 0.225 g of trans 1-ethoxycarbonyl-2-ethoxycarbonylpyrrolidine-3-acetaldehyde and 0.4 g of (formylmethylene)-triphenylphosphoran in 2 ml of dichloromethane 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 1-ethoxycarbonyl-3-[1-(4-oxobut-2-enyl)]-pyrrolidine-2-carboxylate.

:~ 3 ~

To a stirred solution of 0.102 ~ of trans ethyl 1-ethoxycarbonyl-3-[1-(4-oxobut-2-enyl)]-pyrrolidine-2-carboxylate in 2 ml of ethanol cooled to 0C is added 0.035 g of sodium borohydride. After 30 minutes at 0C and 30 minutes at room temperature 0.05 ml of acetic acid is added, the solution concentrated, water added and mixture extracted with dichloro-methane. The solution is dried over sodium sulfate, filtered and concentrated in vacuo to yield trans ethyl l-ethoxycarbonyl-3-[1-(4-hydroxybut-2-enyl)]-pyrrolidine-2carboxylate.

To a stirred solution of 0.0937 g of trans ethyl 1-ethoxycarbonyl-3-[1-(4-hydroxybut-2-enyl)]-pyrrolidine-2-carboxylate and 0.1 g of triphenyl-phosphine in 2 ml of dichloromethane at 0C is added 0.067 g of N-bromo-succinimide. 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-[1-(4-bromobut-2-enyl)]-pyrrolidine-2-carboxylate.

Example 17: A mixture of 0.053 g oE trans ethyl l-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 is concentrated to dryness in vacuo, the residue is dissolved 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 eluating with O.lN ammonium hydroxide to yield trans 3-[1-(4-phosphono-but-2-enyl)]-pyrrolidine-2-carboxylic acid, m.p. 138-145C.

Example 18: Prsparation of an injectable formulation containing 10 mg of the active ingredient per 5 ml of solution ha~ing a formula as follows:

cis 4-[1-(3-phosphonoprop-1-enyl)]-piperidine-2-carboxylic acid 10.0 g Propylparaben 0.5 g Uater for injection q.s. 5000.0 ml ~. .. .

12$~

The active ingredient and preservative ar0 dissolved in 3500 ml of water for injection and the solution is diluted to 5000 ml. The solution is filtered through a sterile filter and filled into injection vials under sterile conditions each vial containing 5 ml of the solution.

Example 19:
a) Preparation of 10,000 tablets each containing 10 mg of the active ingredient, having the formula as follows:

cis 4-[1-(3-phosphonoprop-1-enyl)]-piperidine-2-carboxylic acidlO0.00 g Lactose 2,535.00 g Corn starch 125.00 g Polyethylens glycol 6,000150.00 g Magnesium stearate 40.00 g Purified water q.s.

Procedure: All the powders are passed through a screen with openings of0.6 mm. The the drug substance, 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 the boiling solution of the polyethylene glycol in 260 ml of water. The paste formed is added to the powders, which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35C
broken on a screen with 1.2 mm openings and compressed into tablets, using concave punches uppers bisected.

Analogously tablets are prepared, containing about 1-50 mg of one of the other compounds disclosed and exemplified herein.

b) Preparation o 1,000 capsules each containing 5 mg of the active ingredient, having the formula as follows:

,~J ?.

~3~2~8 cis h-[1-(3-phosphonoprop-l-enyl)]-piperidine-2-carboxylic acid 5.0 g Lactose 212.0 g Modifled starch 80.0 g Magnesium stearate 3.0 g Procedure: All the powders are passed through a screen with openings of0.6 mm. Then the drug substance is placed in a suitable mixer and mixed first with the magnesium stearate, then with the lactose and starch until homogeneous. No. 2 hard gelatin capsules are filled with 300 mg of said mixture each, using a capsule filling machine.

Analogously capsules are prepared, containing about 1-50 mg of the other compounds disclosed and exemplified herein.

Claims (18)

1. A compound of the formula I, (I) wherein R and R' are each independently hydrogen, lower alkyl, benzyl, benzyl substituted in the phenyl moiety by lower alkyl, halogen or lower alkoxy, lower alkanoyloxymethyl, lower alkanoyloxy methyl substituted in the oxymethyl moiety by lower alkyl or cycloalkyl, m represents one or zero, R1 is carboxy, lower alkoxycarbonyl carbamoyl or N-lower or N,N-di-lower alkylcarbamoyl wherein the five-or six-membered heterocyclic ring represented by the partial formula (Ia) may have present a carbon-carbon double bond or may be fused on adjacent carbon atoms with a six-membered carbocyclic ring, and may be substituted on carbon by lower alkyl or phenyl-lower alkyl, and R2 denotes hydrogen, by lower alkyl, phenyl-lower alkyl, lower alkoxycarbonyl, benzyloxycar-bonyl or lower alkanoyl, and A represents lower alkenylene: or a salt thereof.

2. A compound as claimed in claim 1, wherein the heterocyclic ring-system, together with substituent R1, is represented by 2-carboxy-pyrrolidinyl, 2-carboxy-2,5-dihydropyrrolyl, 2-carboxy-1,2,3,6-tetra-hydropyridinyl, 2-carboxy-1,2,5,6-tetrahydropyridinyl, 2-carboxy-piperidinyl, 2-carboxytetrahydroquinolinyl, 2-carboxyperhydroquinolinyl, 2-carboxy-2,3-dihydroindolyl or 2-carboxyperhydroindolyl, which may be substituted on carbon or lower alkyl or phenyl-lower allyl and at nitrogen by lower allyl, phenyl-lower alkyl, lower alkoxycarbonyl, benzyloxycarbonyl or lower alkanoyl and wherein carboxy may be esterified or amidated as indicated in claim 1, or a salt thereof.

3. A compound as claimed in claim 1, of the formula II

(II) or a compound 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, in which the phos-phono bearing chain is attached at the 3-, 4-, or 5-position of the piperidinyl or tetrahydropyridinyl ring, and wherein R and R' independently represent hydrogen, lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or lower alkoxy; lower alkanoyloxy-methyl or lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl or cycloalkyl, R1 represents carboxy, lower alkoxycarbonyl, carbamoyl or N-lower or N,N-di-lower alkylcarbamoyl, R2 represents hydrogen, lower alkyl, phenyl-lower alkyl, lower alkanoyl or lower alkoxycarbonyl R3 re-presents hydrogen, lower alkyl or phenyl-lower alkyl; A represents lower alkenylene; or a salt thereof.

4. A compound as claimed in claim 1, of the formula III

(III) wherein A represents 1,3-propenylene, R1 represents carboxy, lower alkoxycarbonyl, carbamoyl or N-lower or N,N-di-lower alkylcarbamoyl; or a pharmaceutically acceptable salt of said compound.

5. A compound as claimed in claim 1, of the formula III

(III) wherein wherein A represents 1,3-propenylene with the double bond adjacent to the phosphono grouping; R1 represents carboxy, lower alkoxy-carbonyl, carbamoyl or N-lower or N,N-di-lower alkylcarbamoyl; or a pharmaceutically acceptable salt of said compound.

6. 4-[1-(3-phosphonoprop-2-enyl)]piperidine-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

7.4-[1-(3-phosphonoprop-1-enyl)]piperidine-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

8. A compound as claimed in claim 1, of the formula IV

(IV) or a perhydro derivative thereof, wherein R and R' independently represent hydrogen, lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or lower alkoxy; lower alkanoyloxymethyl, lower alkanoyloxymethyl substituted on oxymethyl by lower alkyl, or cycloalkyl;
R1 represents carboxy, lower alkoxycarbonyl, carbamoyl or N-lower or N,N-di-lower alkylcarbamoyl, R2 represents hydrogen, lower alkyl, phenyl-lower alkyl, lower alkanoyl or lower alkoxycarbonyl, R4 represents hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl; A
represents lower alkenylene; or a salt thereof.

9. A compound as claimed in claim 1, of the formula V

(V) or a perhydroquinoline derivative thereof wherein A represents 1,3-propenylene with the double bond adjacent to the phosphono grouping;
R1 represents carboxy or lower alkoxycarbonyl; or a pharmaceutically acceptable salt of said compound.

10. A compound as claimed in claim 1, of the formula VI

(VI) or a compound of formula VI with a double bond present between C-3 and C-4 of the pyrrolidinyl ring, wherein R and R' independently represent hydrogen, lower alkyl, benzyl, benzyl substituted on phenyl by halogen, lower alkyl or lower alkoxy, lower alkanoyloxymethyl or lower alkanoyl-oxymethyl substituted on oxymethyl by lower alkyl, or cycloalkyl R1 represents carboxy, lower alkoxycarbonyl, carbamoyl or N-lower or N,N-di-lower alkylcarbamoyl, R2 represents hydrogen, lower alkyl, lower alkanoyl or lower alkoxycarbonyl, R3 represents hydrogen, lower alkyl or aryl-lower alkyl; A represents lower alkenylene; or a salt thereof.

11. A compound as claimed in claim 1, wherein the phosphono bearing group is attached at the 3-position, R and R' represent hydrogen; R1 represents carboxy, lower alkoxycarbonyl or lower alkanoyloxymethoxycarbonyl; and R2 and R3 represent hydrogen; A represents 1,3-propenylene with double bond adjacent to the phosphono grouping or a salt thereof.

12. trans 3-[1-(4-phosphonobut-3-enyl)]-pyrrolidine-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

13. trans 3-[1-(4-phosphonobut-2-enyl)]-pyrrolidine-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

14. cis-4-[1-(3-phosphonoprop-2-enyl)]-piperidine-2-carboxylic acid, trans 4-[1-(3-phosphonoprop-2-enyl)]-piperidine-2-carboxylic acid, cis 4-[1-(3-phosphonoprop-1-enyl)]-piperidine-2-carboxylic acid or trans 4-[1-(3-phosphonoprop-1-enyl)]-piperidine-2-carboxylic acid or a pharma-ceutically acceptable salt thereof.

15. cis 3-[1-(4-phosphonobut-3-enyl)]-pyrrolidine-2-carboxylic acid or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition for the treatment of disorders responsive to said blockade of the NMDA receptor containing a compound according to any one of claims 1 to 13 together with at least one customary pharmaceutical excipients.

17. Process for the manufacture of compounds according to claim 1, which consists in a) condensing an aldehyde or ketone of the formula VII

(VII) wherein m, R1 and the heterocyclic ring are as defined for formula I
with R1 and amino groups in protected form, and A' represents oxo substi-tuted lower alkyl having 1 carbon less than the alkenylene group A, with a tetra ester derivative of methylenediphosphonic acid, under basic conditions, and if required deprotecting the resulting product to obtain a compound of formula I wherein the double bond within the grouping A is adjacent to the phosphono grouping; or b) condensing a compound of the formula VIII

(VIII) wherein A, m, R1 and the heterocyclic ring are as defined for formula I, and X represents reactive esterified hydroxy, with a compound capable of introducing the phosphonic acid moiety, having one of formulae IX or X, (IX) P(R"')3 (X) wherein R" represents lower alkyl and R"' represents halogen or lower alkoxy and, if required, converting the resulting phosphonic acid derivative to the phosphonic acid or other ester derivative thereof; or c) hydrolysis to carbamoyl or carboxy R1 of a cyano group at position 2 of the heterocyclic ring in a compound otherwise identical to a compound of the invention; and carrying out the said processes while, if necessary, temporarily protecting any interfering reactive group(s) in these pro-cesses, and then liberating the resulting compound of the invention and, if required, converting a resulting compound of the invention into another compound of the invention, and, if required, converting a resulting free compound into a salt or a resulting salt into the free compound or into another salt; and if a single isomer or racemate is required, separating a mixture of isomers or racemates obtained into the single isomers or racemates; and, if an individual optical antipodes is required, resolving a racemate obtained into the optical antipodes.

18. Process according to claim 16 wherein a compound of the formula I
wherein at least one of R and R' denotes lower alkyl, benzyl, benzyl substituted in the phenyl moiety by lower alkyl, halogen or lower alkoxy, lower alkanoyloxymethyl, lower alkanoyloxy methyl substituted in the oxymethyl moiety by lower alkyl or cycloalkyl, R1 denotes lower alkoxy-carbonyl, carbamoyl or N-lower or N,N-di-lower alkylcarbamoyl and which is N-substituted by lower alkanoyl or lower alkoxycarbonyl, is converted by treatment with an inorganic and or with aqueous alkalies into the corresponding N-substituted compound of the formula I, wherein R and R' are hydrogen and R1 denotes carboxy, or into a salt thereof.

FD 4.4/KVB/bg*/ms