SK46993A3 - New heterocyclic compounds as antagonists of excitatory amino acid receptors, process for their preparation and their use - Google Patents

Abstract

Compounds of formula (I), in which X is an imino, a methylene group, a benzylidine, an 1,1-allylidine, a 1,1-alkylidene group containing from two to seven carbons, or is a group D-E in which D, being part of the ring, is nitrogen and E is a straight or branched lower alkyl or acyl each containing one to seven carbons, an aroyl, a substituted or non-substituted allyl, benzyl or propargyl group; Y is a hydroxyl- or amino-bearing carbon or is a carbonyl group; Z is a group consisting of one to four methylene groups or is a 1,3-allylidene or 1,3-propargylidene group; W is a group P(O)(OR<1>)(OR<2>) wherein R<1> and R<2> is each independently hydrogen, C1-C2 alkyl, acyloxymetyl or -etyl; n, when X does not contain nitrogen in the ring, is 1 or 2, or, when X contains nitrogen, is 2; for use as analgetics, anticonvulsants and antiischemic agents, as well as methods for their preparation, their pharmaceutical preparations and their use.

Description

The present invention relates to novel piperazine, piperidine and pyrrolidine compounds, processes for their preparation, their use and pharmaceutical compositions containing them. These compounds are antagonists of N-methyl-D-aspartate (NMDA) receptors and are useful in the treatment of diseases known to be sensitive to NMDA-excited amino acid receptor blockade, especially in the treatment of disease states such as pain, anxiety and cerebral ischaemia.

BACKGROUND OF THE INVENTION

Amino acid excitation receptors (mainly L-glutamate and L-aspartate) are widely used! for treating the central non-metallic vertebrate system. Too much release of these acidic amino acids is due to a number of neuropathological conditions, and therefore possible receptor antagonists are sought as novel therapeutic agents. In animal animal models, NMDA antagonists have been shown to have an anticonvulsant effect (cf., for example, Lehmann et al., J. Pharmacol. Exp. Therap. 246, 65-75 (1988)), which results in NMDA antagonists. NMDA antagonists also provide protection against neuronal cell death due to inappropriate stimulation (Boast et al., Brain Res. 442, 345-348 (1982)) and can be used in the treatment of ischemic and hypoxic conditions as well as Intrathecal injection of NMDA antagonists has an analgesic effect (Cahusac et al., Neuropharmacology 23, 719-724 (1984)) and may also be useful in the treatment of migraine, anxiety and lutein hormone-related diseases. Compounds which are NMDA antagonists and belong to phosphonoalkyl substituted 2-piperidinecarboxylic acids group, are described, for example, in U.S. Pat.

746,653. Cis-4-phosphomethyl-2-piperidinecarboxylic acid is mentioned as an example of this class of compounds and is also disclosed in J. Med. Chem. 32, 827-833 (1989).

SUMMARY OF THE INVENTION

The present invention relates to a novel class of NMDA antagonists defined by Formula I

in which

X represents an imino group, a methylene group, benzylidene, 1,1-allylidene, a 2-7 carbon atom-1,1-alkylidene group or a group of formula DE, wherein D, which is part of a ring, represents a nitrogen atom and E represents a straight or branched lower an alkyl or acyl group each containing from 1 to 7 carbon atoms, an aroyl group or an optionally substituted allyl, benzyl or propargyl group,

Y 'means a carbon atom bearing a hydroxy or amino group or a carbonyl group,

Z represents a group containing 1 to 4 methylene groups or a 1,3-allylidene or 1,3-propargylidene group,

W represents a group of the formula P (O) (OR ¹ ) (OR ² ), wherein R ¹ and R ² are! independently of one another hydrogen, alkyl of 1 to 16 carbon atoms, alkyl of 1 or 2 carbon atoms substituted by phenyl, acyloxymethyl or acyloxyethyl, n when X does not contain a ring nitrogen atom, represents a number or 2 or if X contains a nitrogen atom represents the number 2 and in each of the compounds the carboxy group may be in the form of a pharmaceutically acceptable ester or amide.

Included within this class of heterocyclic amino acids of the invention are pharmaceutically acceptable salts and base addition salts such as metal salts. Hydrates are also included. This group further includes isomeric forms including the stereoisomer.

Particularly preferred are compounds of formula I wherein:

X is imino, C 1 -C 6 alkylimino, methylene, 1,1-ethylidene or 1,1-propylidene,

Y is a hydroxyl-bearing carbon atom or a carbonyl group,

Z represents a group consisting of 1 to 3 methylene groups or is a 1,3-allylidene or 1,3-propargylidene group,

W is P (O) (OR ¹ ) (OR ² ) wherein R ¹ and R ² are each independently hydrogen, C 1 -C 16 alkyl, C 1 -C 2 alkyl substituted with phenyl, acyloxymethyl or acyloxyethyl, n when X does not contain a ring nitrogen, is 1 or 2, or when X contains a nitrogen atom, is 2, and in each of the compounds the carboxy group may be in the form of a pharmaceutically acceptable ester or amide.

Included in this class of heterocyclic amino acids of the invention are pharmaceutically acceptable salts and base addition salts, such as metal salts. Hydrates are also included in this group. This group further includes isomeric forms including stereoisomers.

A more preferred class of compounds are those described by Formula II

in which

X is amino, C1-C4alkylimino, methylene, 1,1-ethylidene or 1,1-propylidene,

Y represents a carbon atom bearing a hydroxy group or represents a carbonyl group,

Z represents a group containing 1 to 3 methylene groups or represents a 1,3-allylidene or 1,3-propargylidene group,

W represents a group of the formula P (O) (OR ¹ ) (OR ² ), wherein R ¹ and R ² are! independently of one another a hydrogen atom, an alkyl group having 1 to 16 carbon atoms, an alkyl group having 1 or 2 carbon atoms substituted by phenyl, acyloxymethyl or acyloxyethyl.

This class of heterocyclic amino acids of the invention includes pharmaceutically acceptable salts and base addition salts such as metal salts. Hydrates are also included. This class of compounds further includes isomeric forms including the stereoisomer, some of which are preferred.

The term aroyl group, as used hereinabove, means optionally substituted benzoyl such as 2,6-dimethylbenzoyl or 4-bromobenzoyl, furancarbonyl, thiophenecarbonyl or pyridinecarbonyl.

Production methods

The compounds of this invention can be prepared by methods well known to those skilled in the art. One or more of the methods described below can be used

Method A involves the addition of α-metallized methanephosphonic acid dialkyl ester, β-metallized ethanephosphonic acid dialkyl ester or β-metallised ethene phosphonic acid dialkyl ester, i-metallised propanephosphonic acid dialkyl ester, and- or τ-metallised allylphosphonic acid dialkyl ester or metallised 1-dialkyl vinyl ester an inert solvent such as tetrahydrofuran at temperatures ranging from -75 ° C to room temperature to the unsaturated heterocyclic dicarboxylic derivatives of formula III

in which

X and n have the meanings given above,

R is an alkoxy or dialkylamino group containing up to 10 carbon atoms,

L represents a readily cleavable group such as a chlorine atom, a fluorine atom, an alkoxy group, an azido group or the like used to activate carboxylic acids against nucleophilic damage, or is a hydrido group, and

A indicates that the ring is aromatic or partially unsaturated; relieved.

The ring of the compound produced is then saturated by conventional means, such as catalytic hydrogenation, and the compounds of the invention are obtained by removing the protecting ester or amide groups or first removing the protecting groups and then hydrogenating the ring. The ketone functional groups of the intermediate can optionally be reduced to an alcohol using well known reducing agents, for example sodium borohydride. The intermediate or produced compound containing an alcohol function can also be oxidized to the ketone using standard techniques.

Method B: The metallized phosphonic acids listed in Method A can also be added to a heterocyclic compound of formula XV

in which

R, X, L and n have the meanings given above, using the same general conditions as previously described. The nitrogen in the ring can optionally be protected, for example, in the form of a carbamate ester. The alcohol and ketone functional groups may be interconverted as described in Method A. The compounds of the invention are obtained by removal of the ester and amide protecting groups.

Method C consists of reacting a halogenated ketone of formula V or VI

in which

X, n, R and A have the meanings given above,

Q represents a leaving group such as a chlorine atom of bromine or iodine, or a sulfonate such as tosyloxy, and m is 1 to 3, with a trialkylphosphite under the conditions commonly used in Arbuzo reaction or with dialkylsilylphosphite or trialkylsilylphosphite, preferably trimethylsilylphosphite or metallized. The nitrogen atom in the ring can optionally be protected, for example in the form of a carbamate ester. The ketone functionality can also be protected, for example, in the form of a ketal, for the duration of the reaction. The compounds of the invention are obtained. by removing protecting groups.

Method D consists of reacting a compound or partially protected intermediate produced according to Method A or B containing ketone functional groups in a phosphorus-containing side chain with ammonia or an ammonia source such as ammonium acetate under conditions known to introduce the primary amino group. Such conditions are usually called! as a condition of reductive amination, and for example, a reaction may be achieved in the presence of hydrogen and a catalyst such as palladium, or in the presence of a hydride source such as sodium cyanoborohydride in a suitable solvent such as ethanol.

The starting compounds of the formulas III, IV, v and vi are known or can be prepared by methods known to those skilled in the art. The reduction of the heteroaromatic or partially unsaturated ring is carried out by methods known in the art, for example for the reduction of pyrrole, pyridine or pirazine rings. For example, the pyridine ring reduction is preferably carried out by catalytic hydrogenation, such as in the presence of an Adams catalyst and in an acidic solvent such as acetic acid.

Protective groups are used whenever it is necessary to avoid side reactions and belongs to types well known in the art, such as tert-butoxycarbonyl or carbobenzyloxy for amines, straight or branched chain alkyl groups of 1 to 6 carbon atoms. , allyl or benzyl for carboxylic acids and a phosphonate group and silyl-based protecting or ketal type protecting groups for alcohols.

Certain terms used to describe the above methods have the following meanings:

An alkyl group refers to straight or branched alkyl chains containing an alkyl chain. from 1 to 8 carbon atoms and is preferably ethyl, butyl or isopropyl. Metallized means that the organometallic reagent is formed by processes such as reacting a carboxylic acid or a phosphonic acid dialkyl ester, i.e., weak acidic compounds, with a strong base such as butyllithium, sodium hydride or lithium diisopropylamide, or reacting the halide with a metal such as zinc, a zinc alloy and media, magnesium, lithium or sodium, in an inert or otherwise suitable solvent. The reagent thus formed can be further treated by the addition of another metal compound, for example, copper cyanide.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are intended to illustrate the invention and are not to be construed as limiting it in any way. ¹³ C-NMR spectral data are measured in D 2 O with tert-butanol (δ = 30.6 ppm) as an internal standard.

Example 1

Cis-3- (1-oxo-2-phosphonoethyl) -2-piperidinecarboxylic acid

Method A

A mixture of 0.415 g of cis-isopropyl- [1- (tert-butoxycarbonyl) -3- (2-dimethylphosphono-1-oxoethyl) -2-piperidinecarboxylate] and 0.38 ml of trimethylsilyl bromide was stirred in 3 ml of chloroform for 3 hours at room temperature. temperature 60 ° C. The solvent was evaporated under reduced pressure and the residue was dissolved in 5 ml of water and treated with 0.10 g of lithium hydroxide. The reaction mixture was stirred at room temperature for 3 hours and then eluted with water on Dovex 50Wx8H resin. Appropriate fractions were combined, water was evaporated under reduced pressure to give 3- (1-oxo-2-phosphonoethyl) -2-piperidinecarboxylic acid as a 3: 2 mixture of cis and trans isomer, which was crystallized from aqueous ethanol . 1 ³ C-NMR: 20.9, 22.5, 25.6, 27.1, 43.6,

45.2, 45.7, 46.6, 50.0, 50.5, 58.9, 59.7, 173.0, 173.8,

211.1, 211.2 ppm.

Further, trans-3- (1-oxo-2-phosphonoethyl) -2-piperidinecarboxylic acid is obtained, which crystal is from aqueous ethanol. This compound has a melting point of 184-186 ° C.

The starting compound is prepared as follows: Mix 12.5 ml

1,54-M-Butylithium in hexane and 2.1 ml of dimethyl methylphosphonate in 20 ml of tetrahydrofuran are added to 4.0 g of isopropyl (3-chlorocarbonyl-2-pyridinecarboxylate) in 20 ml of tetrahydrofuran at -78 ° C. After stirring for 15 minutes, saturated ammonium chloride solution was added to the reaction mixture, and the mixture was allowed to warm to room temperature. The reaction mixture was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue is chromatographed on silica gel using a mixture of ethyl acetate and acetone as eluent. Isopropyl 3- (2-dimethylphosphono-1-oxoethyl) -2-pyridinecarboxylate is obtained as an oil.

A mixture of 1.2 g of isopropyl [3- (2-dimethylphosphono-1-oxoethyl) -2-pyridinecarboxylate] and 0.2 g of 10% platinum on activated carbon in 15 ml of acetic acid is hydrogenated at 300 kPa at room temperature. for 3 hours. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in 10 ml of methylene chloride and potassium carbonate was added. After 15 minutes, 0.82 ml of di-tert-butyl dicarbonate was added to the reaction mixture, and the resulting mixture was stirred for 24 hours. The mixture was then filtered and chromatographed on silica gel with ethyl acetate as eluent. Cis-Isopropyl [1- (tert-butoxycarbonyl) -3- (2-dimethylphosphono-1-oxoethyl) -2-pyridinecarboxylate] is obtained as an oil.

Method B

A mixture of 0.425 g of cis-di-tert-butyl [3- (2-diethylphosphono-1-oxoethyl) -1,2-piperidinedicarboxylate] and 0.95 ml of trimethylsilyl bromide is stirred in 5 ml of chloroform for 3 hours at 60 ° C. ° C The solvent was evaporated under reduced pressure, the residue was dissolved in water and eluted on Dowex 50Wx8H resin to give cis-3- (1-oxo-2-phosphonoethyl) -2-piperidinecarboxylic acid, which was crystallized from aqueous ethanol. ¹³ C-NMR analysis: 19.3, 24.0, 42.2, 43.8, 45.0,

48.2, 57.8, 172.6, 210.0, 210.1 ppm.

The starting material is prepared as follows: A mixture of 19.6 g of tert-butyl (3-carboxy-2-pyridinecarboxylate) and 5 g of 10% palladium on charcoal in 250 ml of acetic acid is hydrogenated at 300 kPa for 6 hours. The mixture was filtered, the solvent was evaporated under reduced pressure to give cis-tert-butyl (3-carboxy-2-piperidinecarboxylate) as an oil.

To a mixture of 7.7 g of cis-tert-butyl (3-carboxy-2-piperidinecarboxylate) 5.2 ml of triethylamine, 100 ml of methanol and 50 ml of methylene chloride was added 8.3 g of di-tert-butyl dicarbonate. The mixture was stirred at room temperature overnight and then the solvent was evaporated under reduced pressure. In this way, the prepared compound is obtained which is in the form of an oil.

A mixture of 9.2 g of cis-tert-butyl- [1- (tert-butoxycarbonyl) -3-carboxy-2-piperidinecarboxylate] and 4.1 g of 1,1-carbonyldiimidazole in 50 ml of methylene chloride are stirred at room temperature over a room temperature. night. The solvent was evaporated under reduced pressure and the residue was dissolved in a mixture of 250 ml of toluene and 10 ml of methylene chloride and then washed successively with 75 ml of saturated citric acid, 75 ml of water and 75 ml of saturated sodium bicarbonate solution. After drying over sodium sulfate, the solvent was evaporated under reduced pressure to give the title compound as an oil.

To 1.3 g of cis-tert-butyl [1- (tert-butoxycarbonyl) -3-imidazolylcarbonyl-2-piperidinecarboxylate] in 10 ml of tetrahydrofuran at -78 ° C was added a mixture of 4.8 ml.

1.5-molar butyllithium in hexane, 1.1 ml diethyl methyl 13 phosphonate and 0.91 g magnesium bromide etherate in 10 ml tetrahydrofuran. After stirring for 15 minutes, saturated ammonium chloride solution was added to the reaction mixture, and the mixture was allowed to warm to room temperature. After drying with sodium sulfate, the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel using ethyl acetate / hexane (3: 2) as eluent. There was thus obtained cis-di-tert-butyl 1- (3- (2-diethylphosphono-1-oxoethyl) -1,2-piperidinedicarboxylate) which was in the form of an oil.

Example 2

3- (1-Oxo-3-phosphonopropyl) -2-piperidinecarboxylic acid

Similar to the above, 3- (1-oxo-3-phosphonopropyl) -2-piperidinecarboxylic acid is prepared in the form of a 4: 1 mixture of cis and trans isomer. C-NMR analysis: 19.0, 20.8, 21.2, 22.7, 24.3, 26.2, 35.3, 37.1,

44.4, 45.0, 46.5, 48.4, 58.2, 58.9, 172.5, 172.9, 214.9,

215.0 ppm.

The starting compound is prepared by introducing 2.3 g of isopropyl (3-chlorocarbonyl-2-pyridinecarboxylate) in 10 ml of toluene into a mixture of 1.5 g of zinc and medium, 10 ml of toluene, 2 ml of dimethylacetamide, 5 g of β- iodoethyl diethylphosphonate, 100 mg palladium chloride and 170 mg tri-o-tolylphosphine under sonication. The mixture was cooled in an ice bath over 10 minutes and then 50 mL of saturated sodium bicarbonate solution was added. The mixture was then filtered and extracted with ethyl acetate. After drying with sodium sulfate, the solvent was evaporated under reduced pressure. The residue is chromatographed on silica gel using a mixture of ethyl acetate and acetone as eluent. Cis-Isopropyl 3- (3-diethylphosphono-1-oxopropyl) -2-pyridinecarboxylate is obtained as an oil.

Example 3 cis-Isopropyl [3- (1-oxo-2-phosphonoethyl) -2-piperidinecarboxylate]

A mixture of 0.2 g of cis-isopropyl- [1- (tert-butoxycarbonyl) -3- (2-diethylphosphono-1-oxoethyl) -2-piperidinecarboxylate] and 0.3 ml of trimethylsilyl bromide was stirred in 3 ml of chloroform at 60 ° C. ° C for 3 hours. The solvent was evaporated from the reaction mixture under reduced pressure, the residue was dissolved in 4 ml of water and stirred for 30 minutes. The mixture was eluted with water on Dowex 50Wx8H resin to give cis-isopropyl- [3- (1-oxo-2-phosphonoethyl) -2-piperidinecarboxylate]. ¹³ C-NMR analysis: 20.9, 23.1, 23.2, 25.6, 43.3, 44.9, 46.7, 50.2,

58.7, 75.2, 171.1, 211.1, 211.2 ppm.

Example 4

3- (1-Oxo-2-phosphonoethyl) -2-piperidinecarboxylic acid

A mixture of 0.20 g of 3- (1-oxo-2-phosphonoethyl) -2-pyridine carboxylic acid and 0.20 g of 10% platinum on activated carbon in 10 ml of water was hydrogenated at 300 kPa at room temperature for 90 minutes. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was eluted with water on Dowex 50Wx8H resin to give 3- (1-oxo-2-phosphonoethyl) -2-piperidinecarboxylic acid as a 4: 1 mixture of cis and trans isomer.

Example 5

4-Methyl-3- (1-oxo-2-phosphonoethyl) -2-piperidinecarboxylic acid

A mixture of 0.08 g of di-tert-butyl [3- (2-diethylphosphono-1-oxo15-ethyl) -4-methyl-1,2-piperidinedicarboxylate] and 0.2 ml of trimethylsilyl bromide in 1 ml of chloroform is heated to a temperature of 64 C in a sealed container for 4 hours. The solvent was evaporated under reduced pressure, 0.3 ml of water was added to the residue and the sieves were allowed to stand for 1 hour. After evaporation, the residue was eluted with water on Dowex 50Wx8H cation exchange resin. The obtained substance is a mixture of stereoisomers in which the title compound can be distinguished as the main component with the following characteristic signals: ¹ H-NMR analysis (HDO at 4.74 ppm as reference standard): 3.82 (d, J = 4) Hz, H-2), 3.72 (t, H-3), 1.14 (d, 3H, 4-CH-1).

The starting material can be prepared as follows: 5.0 g of tert-butyl (3-carboxy-4-methyl-2-piridinecarboxylate), which was prepared from the corresponding acid anhydride and tert-butyl alcohol, is hydrogenated in acetic acid under pressure 300 kPa in the presence of 3 g of 10% palladium on activated carbon. After filtration and evaporation of the solvent, the residue, which is almost pure tert-butyl (3-carboxy-4-methylpiperidine-2-carboxylate), is treated with an equivalent amount of triethylamine in a 3: 1 mixture of dichloromethane and methanol and then added. 1 equivalent of di-tert-butyl dicarbonate. After a reaction time of 15 hours, the solvent was evaporated under reduced pressure to give almost pure triethylammonium di-tert-butyl (3-carboxy-4-methylpiperidine-1,2-dicarboxylate) salt which was in the form of a foam. 0.7 g of this compound was treated directly with cold 0.175 ml of oxalyl chloride and 5 drops of dimethylformamide in 25 ml of toluene over 45 minutes. The reaction mixture was then filtered through a sintered glass filter and the solvent was evaporated. In another embodiment, the acid can be purified by chromatography on silica gel using a 98: 2 mixture of dichloromethane and methanol as the eluent, and then converted to the acid fluoride by treatment with trifluorocyanidine. To a solution of the acid chloride in tetrahydrofuran, maintained at -70 ° C, was added a solution of 3 equivalents of lithiated diethyl methanephosphonate in tetrahydrofuran. The reaction mixture was stirred for 10 minutes and then treated with a saturated ammonium chloride solution. The mixture was allowed to warm to room temperature and extracted with ethyl acetate. Drying over sodium sulfate and evaporation of the solvent gave a residue which was chromatographed on silica gel using a 3: 2 mixture of ethyl acetate and hexane as eluent. 90 mg of di-tert-butyl [3- (2-diethylphosphono-1-oxoethyl) -4-methyl-1,2-piperidinedicarboxylate] are obtained in the form of an oil.

Example 6

Cis-3- (1-hydroxy-2-phosphonoethyl) -2-piperidinecarboxylic acid

A mixture of 0.35 g of the ammonium salt of cis-1-benzyloxycarbonyl-3- (1-hydroxy-2-phosphonoethyl) -2-piperidinecarboxylic acid and 0.30 g of palladium on activated carbon in 15 ml of water is hydrogenated at 300 kPa at a temperature of room for 2 hours. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was crystallized from aqueous ethanol to give the ammonium salt of cis-3- (1-hydroxy-2-phosphonoethyl) -2-piperidinecarboxylic acid. ¹³ C-NMR analysis: 20.6, 22.6, 34.1, 35.8, 38.5, 38.6, 44.9, 63.3, 70.4, 174.8 ppm.

The starting material was prepared as follows: Mix 22.6 ml

Butyllithium (1.37 mole) in hexane and diethyl methylphosphonate (4.7 g) in tetrahydrofuran (50 ml) was added to a mixture of isopropyl (3-formyl-2-pyridinecarboxylate) (5.45 g) in tetrahydrofuran (50 ml) at -60 ° C. The reaction mixture was stirred at -65 ° C for 1 hour, then 7 g of trimethylammonium chloride was added and the mixture was allowed to warm to room temperature. The solvent was removed in vacuo and the residue chromatographed on silica gel with _R acetone as eluent to give the lactone form of an oil get 3- (2-diethylphosphono-l-hydroxyethyl) -2-pyridine.

A mixture of 1.0 g of 3- (2-diethylphosphono-1-hydroxyethyl) -2-pyridinecarboxylic acid lactone and 0.2 g of platinum oxide in 20 ml of acetic acid is hydrogenated at 30 kPa at room temperature for 12 hours. The resulting mixture was filtered and the solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride (20 ml) and saturated sodium bicarbonate solution was added. The mixture was stirred at 0 ° C and then 0.61 ml of benzyl chloroformate was added. Stirring is continued at room temperature for 3 hours, the organic phase is separated and dried with sodium sulfate. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue is chromatographed on silica gel using ethyl acetate as eluent. This gives 1-benzyloxycarbonyl-3- (2-diethylphosphono-1-hydroxyethyl) -2-piperidinecarboxylic acid lactone which is in the form of an oil.

A mixture of 0.38 g of 1-benzyloxycarbonyl-3- (2-diethylphosphono-1-hydroxyethyl) -2-piperidinecarboxylic acid lactone and 0.65 ml of trimethylsilyl bromide is stirred in 4 ml of chloroform for 3 hours at 60 ° C. The solvent was then evaporated under reduced pressure and the residue was dissolved in 3 ml of water and treated with 0.10 g of lithium hydroxide. The reaction mixture was stirred at room temperature for 3 hours and then eluted with 1 molar ammonia on Dowex 50Wx8H resin. Thus, the ammonium salt of cis-1-benzyloxycarbonyl-3- (1-hydroxy-2-phosphonoethyl) -2-piperidinecarboxylic acid is obtained.

Example 7

3- (1-Oxo-2-phosphonoethyl) -2-piperazinecarboxylic acid

Mixture of 0.5 g of cis-methyl- [1,4-di- (tert-butoxycarbonyl) 18]

Of 3- (2-diethylphosphono-1-oxoethyl) -2-piperazinecarboxylate / and 1.25 ml of trimethylsilyl bromide were stirred in 5 ml of chloroform at 60 ° C for 3 hours. The solvent was then evaporated under reduced pressure and the residue was treated with 0.20 g of lithium hydroxide. The reaction mixture was stirred at room temperature for 3 hours and then eluted first with water and then with 1 molar ammonia on Dowex 50Wx8H resin. Thus, the ammonium salt of 3- (1-oxo-2-phosphonoethyl) -2-piperazinecarboxylic acid is obtained, which is a 3: 2 mixture of cis and trans isomers. ¹³ C-NMR analysis: 41.0, 41.5, 41.7, 42.2, 44.7, 46.1, 46.9, 48.3, 58.4, 59.4, 62.4, 63.2, 172.9, 173.0, 205.3,

206.7 ppm.

The starting material is prepared as follows: A mixture of 4.7 ml of 1,44-molar butyllithium in hexane and 1.0 g of diethyl 1-methylphosphonate in 10 ml of tetrahydrofuran is added to 2.0 g of cis-dimethyl- [1,4-di- of (tert-butoxycarbonyl) -2,3-piperazinedicarboxylate / in 20 ml of tetrahydrofuran at -78 ° C. After stirring for 30 minutes, saturated ammonium chloride solution was added. The reaction mixture was allowed to warm to room temperature and then extracted with chloroform. The extract was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with ethyl acetate / hexane. Cis-Methyl [1,4-di- (tert-butoxycarbonyl) -3- (2-diethylphosphon-1-oxoethyl) -2-piperazinecarboxylate] is obtained as an oil.

Pharmaceutical preparations

Pharmaceutical compositions containing a compound of formula (I) are prepared by known methods. If the compounds are used! As a pain-reducing agent, the compound of the invention is dissolved in a liquid diluent suitable for injection. It is particularly preferred to dissolve the compounds in isotonic sodium chloride solution. When used in the treatment of seizures, anxiety and cerebral ischemia, it is also possible for the compounds to be administered in the form of oral or rectal formulations such as tablets, capsules or lace. The preparation of pharmaceutical compositions containing a compound of formula I in the form of dosage units for oral administration may consist of mixing the selected compound with a solid excipient such as lactose or cellulose derivatives with a binder such as gelatin and a glidant such as magnesium stearate and then compressing them into tablets.

Dosage units for rectal administration may be solutions or suspensions or may be presented as a suppository.

Liquid compositions for oral administration may be in the form of syrups or suspensions, for example, solutions containing from about 0.2 to about 20% by weight of the active ingredient described herein.

s

Solutions for parenteral administration by injection may be prepared in aqueous solution from a pharmaceutically acceptable salt of the water-soluble active ingredient. These solutions may optionally contain stabilizing agents and / or buffers and may conveniently be in various ampoules containing dosage units.

Suitable dosage units of the compounds of the invention for the therapeutic treatment of adult humans are from 10 to 200 mg for oral administration and from 0.1 to 100 µg for intrathecal administration.

Biological evaluation

The compounds of the invention exhibit valuable pharmacological properties, for example, block the NMDA excited amino acid receptor in a mammal. Thus, the compounds are useful for the treatment of diseases susceptible to such blockade, especially convulsive diseases, anxiety states, cerebral ischemia and pain. These effects can be demonstrated in in vitro or in vivo tests, for example in mice, rats, dogs or monkeys. The compounds of this invention may be administered orally or parenterally to the mammal.

The inhibitory effect of the NMDA receptor excited by NMDA-type compounds is demonstrated in vitro by measuring inhibition

ABOUT

NMDA-induced H-acetylcholine, which is released from the striatum corpus tissue from rat brain, particularly as described by Lehmann and Scatton in Brain Research 252, 77-89 (1982). The inhibition of ³ H-acetylcholine induced by NMDA released from a thin section of corpus striatum tissue is expressed as a percentage of ³ H-acetylcholine released in response to stimulation with 50 pmol NMDA, as compared to the control assay.

The inhibitory effect of the NMDA receptor excited by compounds of the NMDA type is also determined by an in vitro assay, e.g. which measured the inhibition of ³ H-CGS 19755 binding to brain tissue preparations, particularly according to the data published by Lehmann et al. in J. Pharmacol. Exptl. Therap. 246, 65-75 (1988).

The antispasmodic effect of the compounds of the invention is determined in vivo by inhibiting convulsions caused by electric shock or NMDA in mice, particularly as described in the latter publication.

The analgesic effect of the compounds of the invention is determined in rats and mice by intrathecal injection, particularly as reported by Cahusac et al. in Neuropharmacoloyy 23, 719-724 (1984).

The best embodiment of the invention currently known is to use the compounds produced according to Example 1 or 6.

Claims (12)

Compounds of general formula I (D wherein: X represents an imino group, a methylene group, a benzylidene, a 1,1-allylidene, a 2-7 carbon atom-1,1-alkylidene group or a group of formula DE wherein D, which is part of a ring, represents a nitrogen atom and E represents a straight or branched lower an alkyl or acyl group, each containing from 1 to 7 carbon atoms, an aroyl group, or a substituted allyl, benzyl or propargyl group, Y represents a carbon atom bearing a hydroxy or amino group or represents a carbonyl group, Z represents a group containing 1 to 4 methylene groups or a 1,3-allylidene or 1,3-propargylidene group, W represents a group of the formula P (O) (OR ¹ ) (OR ² ), wherein R ¹ and R ² are! independently of one another a hydrogen atom, an alkyl group having 1 to 16 carbon atoms, an alkyl group having 1 or 2 carbon atoms substituted by phenyl, acyloxymethyl or acyloxyethyl; 1 or 2, or when X contains a nitrogen atom, it is 2 and in each of the compounds the carboxy group may be in the form of a pharmaceutically acceptable ester or amide, the same as hydrates, pharmaceutically acceptable salts and base addition salts such as metal salts and isomeric forms including the stereoisomer of these compounds. Compounds according to claim 1, wherein X is an imino group, an alkylimino group having from 1 to 2 6 carbon atoms, acylimino, methylene, 1,1-ethylidene or 1,1-propylidene, Y is a hydroxyl-bearing carbon atom or a carbonyl group, Z represents a group consisting of 1 to 3 methylene groups or is a 1,3-allylidene or 1,3-propargylidene group, W is P (O) (OR ¹ ) (OR ² ) wherein R ¹ and R ² are each independently hydrogen, C 1 -C 16 alkyl, phenyl substituted by 1 or 2 carbon atoms, acyloxymethyl or acyloxyethyl, n when X does not contain a ring nitrogen atom, is 1 or 2, or when X contains a nitrogen atom, it is 2, and in each compound the carboxy group may be in the form of a pharmaceutically acceptable ester or amide, pharmaceutically acceptable salts and base addition salts, such as metal salts, and isomeric forms, including stereoisomers of these compounds. Compounds according to claim 1, of the general formula II in which X is amino, C1-C4alkylimino, acylimino, methylene, 1,1-ethylidene or 1,1-propylidene, Y represents a carbon atom bearing a hydroxy group or represents a carbonyl group, Z represents a group containing 1 to 3 methylene groups or represents a 1,3-allylidene or 1,3-propargylidene group, W represents a group of the formula P (O) (OR ¹ ) (OR ² ), wherein R ¹ and R ² are each independently hydrogen, C 1 -C 16 alkyl, phenyl substituted by 1 or 2 carbon atoms, acyloxymethyl or acyloxyethyl, as well as hydrates, pharmaceutically acceptable salts and base addition salts such as metal salts, and isomeric forms including stereoisomers of these compounds. The compound of claim 1, wherein X represents a methylene group, Y represents a carbonyl group, Z represents a methylene group, W represents a group of formula P (O) (OR ¹ ) (OR ² ), wherein R ¹ and R ² are each hydrogen and n is 2. The compound of claim 1, wherein X represents a methylene group, Y represents a hydroxymethylene group, Z represents a methylene group, W represents a group of formula P (O) (OR ¹ ) (OR ² ), wherein R ¹ and R ² are each hydrogen and n is 2. A pharmaceutical composition having an anticonvulsant effect, comprising a compound according to claim 1. A pharmaceutical composition having an analgesic effect, comprising a compound according to claim 1. A pharmaceutical composition having a cerebral anti-ischemic effect comprising a compound according to claim 1. Use of a compound according to claim 1 for the manufacture of a pharmaceutical composition having an analgesic effect. Use of a compound according to claim 1 for the manufacture of a pharmaceutical composition having an anti-ischemic action. Use of a compound according to claim 1 for the production of a farm 26 A cerebral anticonvulsant agent. in which X, Y, Z, W and n have the meanings set forth in claim 1, as well as their hydrates, pharmaceutically acceptable salts, base addition salts and isomeric or stereoisomeric forms, characterized in that A) compounds of formula III wherein t X and n have the meanings given above, L represents a suitable leaving group, R is an alkoxy or dialkylamino group containing from 1 to 10 carbon atoms; and f denotes that the ring is aromatic or partially unsaturated, reacted with a metallated alkylphosphonic acid dialkyl ester, the resulting compounds are saturated in the usual way and the protecting groups are removed, B) compounds of formula IV (IV) wherein: X, L, R and n have the meanings given above, are reacted with a metallated alkylphosphonic acid and then deprotected, C) halogenated ketones of the general formula V or VI in which X, R, A and n have the meanings given above, Q is a leaving group and m is 1 to 3, reacted with a trialkyl phosphite or a metallated phosphonic dialkyl ester and then deprotects, or D) reacting the partially protected intermediates produced according to one of methods A and B containing ketone functional groups in a phosphorus-containing side chain with ammonia or an ammonia source. 13. A method of inducing analgesia, treating convulsions or cerebral ischemia, comprising administering to a mammal, including a human, in need of any of these treatments an effective amount of a compound of the invention.