NEW HETEROCYCLIC COMPOUNDS AS ANTAGONISTS OF EXCITATORY AMINO ACID RECEPTORS, PROCESSES FOR THEIR PREPARATION AND THEIR USE

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: NEW HETEROCYCLIC COMPOUNDS AS ANTAGONISTS OF EXCITATORY AMINO ACID RECEPTORS, PROCESSES FOR THEIR PREPARATION AND THEIR USE Field of the invention The present invention relates to new piperazine, piperidine, and pyrrolidine compounds, to methods for their preparation, their use, and their pharmaceutical preparation. The compounds are antagonists of N-methyl- D-aspartate (NMDA) receptors and are useful in the treatment of disorders known to be responsive to blockade of the NMDA excitatory amino acid receptor, especially in the treatment of disorders such as pain, anxiety and cerebral ischemia. Background of the invention Receptors for excitatory amino acids (mainly L- glutamate and L-aspartate) are widespread in the vertebrate central nervous system. Excessive release of these acidic amino acids is implicated in a number of neuropathological conditions and hence a potential for receptor antagonists as new therapeutic agents. In animal models of human disorders it has been shown that NMDA antagonists have anticonvulsant activity cf. e.g. Lehmann et al. J. Pharmacol. Exp. Therap. 1988, 246, 65-75. This implicates the usefulness of NMDA antagonists as new antiepileptic agents. NMDA antagonists also give protection against neuronal cell death caused by excessive stimulation (Boast et al. Brain Res. 1982, 442, 345-348) and may be used in the treatment of ischemic and hypoxic conditions and also of neurodegenerative disorders e.g. Alzheimer's disease. By intrathecal injection NMDA antagonists have analgetic activity (Cahusac et al. Neuropharmacology 1984, 22, 719-724) These antagonists may also be beneficial in the treatment of migraine, anxiety, and illness linked to luteinizing hormone secretion. Compounds that are NMDA antagonists and are phosphonoalkyl-substituted 2-piperidine carboxylic acids have been described in e.g. U.S. Patent 4,746,653. cis-4-Phosphonomethyl-2-piperidinecarboxylic acid is mentioned as an example of this class of compounds. They are also mentioned in J. Med. Chem. 1989, 32, 827-833. Description of the invention The present invention is a new class of NMDA antagonists defined by formula I in which X is an imino, a methylene group, a benzylidene, an 1,1-allylidene, an 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-allγlidene or 1,3- propargylidene group; 1 2 1 2 W is a group P(0)(OR ) (OR ) wherein R and R is each independently hydrogen, c ι" c ιg alkyl, phenyl- substituted C--C 2 alkyl, acyloxymethyl or -ethyl; n, when X does not contain nitrogen in the ring, is 1 or 2, or, when X contains nitrogen, is 2; and in each of which compounds the carboxy group may be functionalized in form of a pharmaceutically acceptable ester or amide. Within this class of heterocyclic amino acids of the invention the pharmaceutically acceptable salts and base addition salts such as metal salts are included. The hydrates are also included. Further included are isomeric forms including stereoisomers. Especially preferred are the compounds of formula I wherein X is imino, C--Cg alkylimino, methylene, 1,1-ethylidene or 1,1-propylidene; Y is a hydroxyl-bearing carbon or is a carbonyl group; Z is a group consisting of one to three methylene groups or is a 1,3-allylidene or 1,3-propargylidene group; W is a group P(0)(OR 1)(OR2) wherein R1 and R2 is each independently hydrogen, C.-C-g alkyl, phenyl- substituted C--C 2 alkyl, acyloxymethyl or -ethyl; n, when X does not contain nitrogen in the ring, is 1 or 2, or, when X contains nitrogen, is 2; and in each of which compounds the carboxy group may be functionalized in form of a pharmaceutically acceptable ester or amide. Within this class of heterocyclic amino acids of the invention the pharmaceutically acceptable salts and base addition salts such as metal salts are included. The hydrates are also included. Further included within this class of compounds are isomeric forms including stereoisomers. An even more preferred class of compounds is described by formula II wherein X is imino, C--C. alkylimino, methylene, 1,1-ethylidene or 1,1-propylidene; Y is a hydroxyl-bearing carbon or is a carbonyl group; Z is a group consisting of one to three methylene groups or is a 1,3-allylidene or 1,3-propargylidene group; W is a group P(O) (OR 1)(OR2) wherein R1 and R2 is each independently hydrogen, C-i-C-g alkyl, phenyl- substituted C.-C- alkyl, acyloxymethyl or -ethyl; Within this class of heterocyclic amino acids of the invention are the pharmaceutically acceptable salts and base addition salts such as metal salts. The hydrates are also included; further included within this class of compounds are isomeric forms including stereoisomers of which some are preferred. The term "aroyl" used above has the meaning benzoyl or substituted benzoyl such as 2,6-dimethylbenzoyl or 4- bromobenzoyl, furancarbonyl, thiophenecarbonyl or pyridinecarbonyl. Preparations The compounds of the present invention may be prepared by procedures well known to those skilled in the art. One or several of the following methods can be used. Method A involves addition of either alpha-metallated methanephosponic acid dialkylester, beta-metallated ethane- or ethenephosphonic acid dialkyl ester, gamma- metallated propanephosphonic acid dialkylester, alpha- or gamma-metallated allylphosphonic acid dialkyl ester or metallated 1-propynylphosphonic acid dialkyl ester, in an inert solvent such as tetrahydrofuran at temperatures ranging from -75°C to room temperature, to an unsaturated heterocyclic dicarboxylic derivative III, in which X and n have the meaning as defined above, R is alkoxy or dialkylamino containing up to ten carbon atoms, L is a suitable leaving group such as chloro, fluoro, alkoxy, azido or similar groups used to activate carboxylic acids towards nucleophilic attack, or is hydrido; and A denotes that the ring is aromatic or partly unsaturated. The ring of the product is then saturated by conventional means such as catalytic hydrogenation, and the compounds of the invention are obtained by removal of the protecting ester or amido groups or by first removing the protecting groups and then hydrogenate the ring. An intermediate containing a ketone function may be optionally reduced to an alcohol using well known reducing agents e.g. sodium borohydride and an intermediate or product containing an alcohol function may also be oxidized to a ketone using standard techniques. Method B. The metallated phosphonic acids mentioned in Method A can also be added to a heterocyclic compound of formula IV in which R, X, L and n are as defined above using the same general conditions mentioned. The nitrogen in the ring can be optionally protected for example in the form of a carbamate ester. Alcohol and ketone functions may be interconverted as described in Method A. The compounds of the invention are obtained by removal of the protecting ester or amido groups. Method C. Reacting a halogenated ketone of formula V or VI VI in which X, n, R, and A are as defined above, Q represents a leaving group such as chloro, bromo, iodo or a sulphonate ester such as tosyloxy, and m is 1-3; with a trialkyl phosphite under conditions usually employed in the Arbuzov reaction or with a dialkyl trialkylsilyl, preferrably trimethylsilyl, phosphite or with a metallated dialkyl ester of phosphonic acid. The nitrogen in the ring may be optionally protected for example in the form of a carbamate ester. The ketone functionality may also require temporary protection for example in the form of a ketal. The compounds of the invention are obtained by removal of the protecting groups. Method D. Reacting a product or partly protected inter¬ mediate from Methods A or B containing a ketone functionality in the side chain that contains phosphorus, with ammonia or a source of ammonia such as ammonium acetate under conditions known to lead to introduction of a primary amino group. Such conditions are usually referred to as reductive amination conditions and can be exemplified by reacting 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 e.g. ethanol. The starting compounds of formulas III, IV, V, and VI are known or can be prepared by processes known to those skilled in the art. Reduction of heteroaromatic or parly unsaturated rings is carried out by methods known in the art for the reduction of pyrrole, pyridine or pyrazin rings. For example, the reduction of the pyridine ring is advantageously carried out by catalytic hydrogenation e.g. in the presence of Adams catalyst and in an acidic solvent such as acetic acid. Protecting groups are used whenever necessary to hinder side-reactions and are of types well known to the art such as tert-butoxycarbonyl or carbobenzoxy for amines, C- to Cg straight or branched alkyl, allyl or benzyl esters for carboxylic acids and the phosphonate group, and silyl-based or ketal type protecting groups for alcohols. Certain terms used in the above methods have the meaning as defined below. "Alkyl" means straight or branched alkyl chains containing from one to eight carbon atoms and is advantageously ethyl, butyl or isopropyl. "Metallated" means that an organometallic reagent is formed by methods such as reacting a carbon acid or a dialkyl ester of phosphonic acid, i.e. slightly acidic compounds, with a strong base such as butyllithium, sodium hydride or lithium diisopropylamide or by recting a halide with a metal such as e.g. zinc, a zinc-copper couple, magnesium, lithium or sodium in an inert and otherwise suitable solvent. The so formed reagent may be further modified by addition of other metal compounds e.g. cuprous cyanide. Examples The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. 13C-NMR spectra are measured in D 2 0 with tert-butanol (δ=30.6 ppm) as internal standard. Example 1; cis-3-(l-Oxo-2-phosphonoethyl)-2- piperidinecarboxylic acid. METHOD A A mixture of 0.415 g of cis-isopropyl l-(tert- butyloxycarbonyl)-3-(2-dimethylphosphono-l-oxoethyl)-2- piperidinecarboxylate and 0.38 ml of trimethyl- silylbromide was stirred in 3 ml of chloroform for 3 hours at 60°C. Then the solvent was removed in vacuo and the residue was dissolved in 5 ml of water and treated with 0.10 g of lithium hydroxide. After stir¬ ring for 3 hours at room temperature the mixture was eluted with water through Dowex 50Wx8H. Fractions were collected and water was removed in vacuo to afford a 3:2 cis/trans mixture of 3-(l-oxo-2-phosphonoethyl)-2- piperidinecarboxylic acid which crystallized from water/ethanol. 13 C-NMR (ppm) : 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, and trans 3-(l-oxo-2-phosphono- ethyl)-2-piperidinecarboxylic acid which crystallized from water/ethanol, melting at 184-186°C. The starting material was prepared as follows. A mix¬ ture of 12.5 ml of butyllithium (1.54 M in hexane) and 2.1 ml of dimethyl methylphosphonate in 20 ml of tetra- hydrofuran (THF) was added to 4.0 g of isopropyl 3- chlorocarbonyl-2-pyridinecarboxylate in 20 ml of THF at -78°C. After stirring for 15 minutes saturated ammonium chloride was added and the mixture was allowed to warm to room temperature. After drying over sodium sulfate the solvent was removed in vacuo. The residue was chro- matographed on silica gel with ethyl acetate/acetone as the eluent to give isopropyl 3-(2-dimethylphosphono-l- oxoethyl)-2-pyridinecarboxγlate as an oil. A mixture of 1.2 g of isopropyl 3-(2-dimethylphosphono- -l-oxoethyl)-2-pyridinecarboxylate and 0.2 g of 10 % platinum on charcoal in 15 ml of acetic acid was hydro- genated at 300 kPa at room temperature for 3 hours. The mixture was filtered and the solvent was removed in vacuo. 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 and the mixture was stirred for 24 hours. The mixture was filtered and chromatographed on silica gel with ethyl acetate as the eluent to give cis-isopropyl 1- (tert-butyloxycarbonyl)-3-(2-dimethylphosphono-l-oxo- ethγl)-2-piperidinecarboxylate as an oil. METHOD B A mixture of 0.425 g of cis-di-tert-butyl 3-(2-diethyl- phosphono-1-oxoethyl)-1,2-piperidinedicarboxylate and 0.95 ml of trimethylsilylbromide was stirred in 5 ml of chloroform for 3 hours at 60°C. The solvent was removed in vacuo and the residue was dissolved in water and eluted through Dowex 50Wx8H to afford cis-3-(l-oxo-2- phosphonoethyl)-2-piperιdmecarboxylιc acid which crys- tallized from water/ethanol. 13C-NMR (ppm) : 19.3, 24.0, 42.2, 43.8, 45.0, 48.2, 57.8, 172.6, 210.0, 210.1. The starting material was prepared as follows. A mix¬ ture of 19.6 g of tert-butyl 3-carboxy-2-pyridinecarbo- xylate and 5 g of 10 % palladium on charcoal in 250 ml of acetic acid was hydrogenated at 300 kPa for 6 hours. The mixture was filtered and the solvent was removed in vacuo to afford cis-tert-butyl 3-carboxy-2-piperidine- carboxylate as an oil. To a mixture of 7.7 g of cis-tert-butyl 3-carboxγ-2- piperidinecarboxylate, 5.2 ml of triethylamine, 100 ml of methanol and 50 ml of methylene chloride 8.3 g of di-tert-butyl dicarbonate was added. The mixture was stirred at room temperature over night and then the solvent was removed in vacuo to give the product as an oil. A mixture of 9.2 g of cis-tertbutyl l-(tert-butγloxo- carbonyl)-3-carboxy-2-piperidinecarboxylate and 4.1 g of 1,1-carbonyldiimidazole in 50 ml of methylene chlo¬ ride was stirred over night at room temperature. The solvent was removed in vacuo and the residue was dis¬ solved in 250 ml of toluene and 10 ml of methylene chloride and washed in order with 75 ml of saturated citric acid, 75 ml of water and 75 ml of saturated sodium hydrogen carbonate. After drying over sodium sulfate the solvent was removed in vacuo to afford the product as an oil. A mixture of 4.8 ml of butyllithium (1.5 M in hexane) and 1.1 ml of diethyl methylphosphonate and 0.91 g of magnesiumbromide etherate in 10 ml of THF was added to 1.3 g of cis-tert-butyl l-(tert-butyloxycarbonyl)-3- imidazolylcarbonyl-2-piperidinecarboxylate in 10 ml of THF at -78°C. After stirring for 15 minutes saturated ammonium chloride was added and the mixture was allowed to warm to room temperature. After drying over sodium sulfate the solvent was removed in vacuo. The residue was chromatographed on silica gel with ethyl acetate/- hexane 3:2 as the eluent to give cis-di-tert-butγl 3- (2-diethylphosphono-l-oxoethγl)-1,2-piperidinedicar- boxylate as an oil. Example 2: 3-(l-Oxo-3-phosphonopropyl)-2-piperidinecarboxylic acid. Similarly prepared was a 4:1 cis/trans mixture of 3-(l- oxo-3-phosphonopropyl)-2-piperidinecarboxylie acid. 13 C-NMR (pp ): 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. The starting material was prepared by adding 2.3 g of isopropyl 3-chlorocarbonyl-2-pyridinecarboxylate in 10 ml of toluene to a mixture of 1.5 g of Zn-Cu, 10 ml of toluene, 2 ml of dimethylacetamide, 5 g of beta-iodo- ethyl diethylphosphonate, 100 mg of palladium chloride and 170 mg of tri-o-tolylphosphine under ultrasonic activation. The mixture was cooled on ice bath after 10 minutes and 50 ml of saturated sodium hydrogen carbo¬ nate was added. The mixture was filtered and extracted with ethyl acetate. After drying over sodium sulfate the solvent was removed in vacuo. The residue was chro- matographed on silica gel with ethyl acetate/acetone as the eluent to give cis-isopropyl 3-(3-diethyl- phosphono-l-oxopropyl)-2-pyridinecarboxγlate as an oil. Example 3: Cis-isopropyl 3-(l-oxo-2-phosphonoethγl)-2- piperidine-carboxylate. A mixture of 0.2 g of cis-isopropyl 1-(tert-butyloxy- carbonyl)-3-(2-diethγlphosphono-l-oxoethyl)-2-piperi- dinecarboxylate and 0.3 ml of trimethylsilylbromide was stirred in 3 ml of chloroform for 3 hours at 60°C. Then the solvent was removed in vacuo and the residue was dissolved in 4 ml of water and stirred for 0.5 hour. The mixture was eluted with water through Dowex 50Wx8H to give cis-isopropyl 3-(l-oxo-2-phosphonoethyl)-2- piperidinecarboxylate, 13C-NMR (ppm) : 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. Example 4: 3-(l-Oxo-2-phosphonoethyl)-2-piperidinecar- boxylic acid. A mixture of 0.20 g of 3-(l-oxo-2-phosphonoethyl)-2- pyridinecarboxylic acid and 0.20 g of 10 % platinum on charcoal in 10 ml of water was hydrogenated at 300 kPa at room temperature for 1.5 hours. The mixture was fil¬ tered and the solvent was removed in vacuo. The residue was eluted with water through Dowex 50Wx8H to afford a 4:1 cis/trans mixture of 3-(l-oxo-2-phosphonoethyl)-2- piperidinecarboxylic acid. Example 5: 4-Methyl-3-(l-oxo-2-phosphonoethyl)-2-piperidinecar- boxylic acid. A mixture of 0.08 g of di-tert-butyl 3-(2-dietyl- phosphono-1-oxoethγl)-4-methγl-l,2-piperidinedicar- boxylate and 0.2 ml of trimethylsilylbromide in 1 ml of chloroform was heated at 64 °C in a closed vial for 4 h. The solvent was removed in vacuo and 0.3 ml of water was added and the mixture was left for 1 h. After evaporation the residue was eluted with water through a cation exchange resin (Dowex 50Wx8H) . The product was a mixture of stereisomers in which it was possible to discern the title compound as a major component having the following characteristic H-NMR signals (HDO at 4.74 ppm as reference): 3.82 (d,J 4Hz,H-2), 3.72 (t, H-3), 1.14 (d, 3H, 4-Me). The starting material was prepared as follows, tert- Butyl 3-carboxy-4-methyl-2-pyridinecarboxylate (5.0 g), which was prepared from the corresponding anhydride and tert-butyl alcohol, was hydrogenated in acetic acid at 300 kPa in the presence of 10 % Pd-C (3 g). After fil- tration and evaporation of solvent the residue, which was almost pure tert-butyl 3-carboxy-4-methylpiperi- dine-2-carboxylate, was treated with an equivalent of triethylamine in a mixture of dichloromethane and methanol (3:1) and one equivalent of di-tert-butyl dicarbonate was added. After a reaction time of 15 h solvents were evaporated in vacuo leaving almost pure di-tert-butyl 3-carboxy-4-methylpiperidine-l,2-dicarbo- xylate triethylammonium salt as a foam. This material (0.7 g) was treated directly in the cold with oxalyl chloride (0.175 ml) and 5 drops of DMF in toluene (25 ml) for 45 in followed by filtration through a glass sinter filter and evaporation of solvent. Alternatively the acid can be purified by silica gel chromatography using dichloromethane/methanol (98/2) as an eluent, and then be converted to the acid fluoride by treatment with cyanuric fluoride. To a solution of the acid chlo- ride in THF, kept at -70 °C, a solution of 3 equiva¬ lents of lithiated diethyl ethanephosphonate in THF was added. After stirring for 10 min saturated ammonium chloride was added, the mixture was allowed to reach room temperature and was extracted with ethyl acetate. Drying over sodium sulfate and removal of solvent gave a residue which was chromatographed on silica gel with ethyl acetate/hexane 3:2 as the eluent to give di-tert- butyl 3-(diethylphosphono-1-oxoethyl)-4-methγl- piperidine-l,2-dicarboxylate as an oil (90 mg) . Example 6: Cis-3-(l-hydroxy-2-phosphonoethyl)-2-piperi- dinecarboxylic acid. A mixture of 0.35 g of cis-l-benzyloxycarbonyl-3-(1- hydroxγ-2-phosphonoethyl)-2-piperidinecarboxylie acid ammonium salt and 0.30 g of palladium on charcoal in 15 ml of water was hydrogenated at 300 kPa at room tempe¬ rature for 2 hours. The mixture was filtered and the solvent was removed in vacuo. The residue was crystal¬ lized from water/ethanol to yield cis-3-(l-hydroxy-2- phosphonoethγl)-2-piperidinecarboxylic acid ammonium ssaalltt.. 1133 CC--NNMMRR ((ppppmm)):: 2200..66,, 222..6, 34.1, 35.8, 38.5, 38.6, 44.9, 63.3, 70.4, 174.8 The starting material was prepared as follows. A mix¬ ture of 22.6 ml of butyllithium (1.37 M in hexane) and 4.7 g of diethyl methylphosphonate in 50 ml of THF was added to 5.45 g of isopropyl 3-formyl-2-pyridine- carboxylate in 50 ml of THF at -60°C. After stirring for 1 hour at -65°C 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 was chromatographed on silica gel with acetone as eluent to give 3-(2-diethγlphosphono-l-hydroxy- ethyl)-2-pyridinecarboxylic acid lactone as an oil. A mixture of 1.0 g of 3-(2-diethylphosphono-l- hydroxy)-2-pyridinecarboxylic lactone and 0.2 g of pla¬ tinum oxide in 20 ml of acetic acid was hydrogenated at 300 kPa at room temperature for 12 hours. The mixture was filtered and the solvent was removed in vacuo. The residue was dissolved in 20 ml of methylene chloride and saturated sodium hydrogen carbonate was added. The mixture was stirred at 0°C and 0.61 ml of benzyl chlo- roformiate was added. After stirring for 3 hours at room temperature the organic phase was separated and dried over sodium sulfate. The mixture was filtered and the solvent was removed in vacuo. The residue was chro¬ matographed on silica gel with ethyl acetate as eluent to afford l-benzγloxycarbonyl-3-(2-diethγlphosphono-l- hydroxyethyl)-2-piperidinecarboxylic lactone as an oil. A mixture of 0.38 g of l-benzyloxycarbonyl-3-(2-di- ethylphosphono-1-hydroxyethyl)-2-piperidinecarboxylie lactone and 0.65 ml of trimethylsilylbromide was stir¬ red in 4 ml of chloroform for 3 hours at 60°C. Then the solvent was removed in vacuo and the residue was dis¬ solved in 3 ml of water and treated with 0.10 g of lithium hydroxide. After stirring for 3 hours at room temperature the mixture was eluted with 1 M NH 3 through Dowex 50Wx8H to give cis-l-benzyloxycarbonyl-3-(1-hyd- roxy-2-phosphonoethyl)-2-piperidinecarboxγlic acid ammonium salt. Example 7: 3-(l-Oxo-2-phosphonoethyl)-2-piperazinecar- boxylic acid. A mixture of 0.5 g of cis-methyl 1,4-di-(tert-butyloxy- carbonyl)-3-(2-diethylphosphono-l-oxoethyl)-2-pipera- zinecarboxylate and 1.25 ml of trimethylsilylbromide was stirred in 5 ml of chloroform for 3 hours at 60°C. Then the solvent was removed in vacuo and the residue was treated with 0.20 g of lithium hydroxide. After stirring for 3 hours at room temperature the mixture was eluted first with water and then with 1 M NH 3 thro¬ ugh Dowex 50Wx8H to give a 3:2 cis/trans mixture of 3- (l-oxo-2-phosphonoethyl)-2-piperazinecarboxylic acid ammonium salt. 13C-NMR (ppm): 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. The starting material was prepared as follows. A mix¬ ture of 4.7 ml of butyllithium ( 1.44 M in hexane ) and 1.0 g of diethyl methylphosphonate in 10 ml of THF was added to 2.0 g of cis-dimethyl 1,4-di-(tert-butyloxy- σarbonyl)-2,3-piperazinedicarboxylate in 20 ml of THF at -78°C. After stirring for 30 minutes saturated ammo¬ nium chloride was added and the mixture was allowed to warm to room temperature and extracted with chloroform. After drying over sodium sulfate the solvent was re¬ moved in vacuo. The residue was chromatographed on si¬ lica gel with ethyl acetate/hexane as the eluent to give cis-methyl 1,4-di-(tert-butyloxycarbonyl)-3-(2- diethylphosphono-l-oxoethyl)-2-piperazinecarboxylate as an oil. Pharmaceutical preparations Pharmaceutical preparations containing a compound of the formula I are made according to known methods. When the compounds are used as analgesics a compound accor- ding to the invention is dissolved in a liquid diluent suitable for injection. It is especially preferred to dissolve the compounds in isotonic sodium chloride solution. When the compounds are used in the treatment of convulsive disorders, anxiety and cerebral ischemia it is also possible to adminster them in form of an oral or rectal preparation such as tablets, capsules or suppositories. To produce pharmaceutical preparations containing a compound of the formula I in the form of dosage units for oral administration the selected com¬ pound may be mixed with a solid excipient, e.g. lactose or cellulose derivatives, a binder such as gelatine, and a lubricant such as magnesium stearate, and then compressed into tablets. Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of supposi¬ tories. Liquid preparations for oral application may be in the form of syrups or suspensions e.g. solutions containing from about 0.2 % to about 20 % by weight of the active substance herein described. Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active sub¬ stance. These solutions may optionally contain stabili¬ zing agents and/or buffering agents and may con- veniently be provided in various dosage unit ampoules. Suitable unit dosages of the compounds of the invention in therapeutical treatment of human adults are 10 to 200 mg at peroral administration and 0.1 to 100 μg at intrathecal administration. Biological evaluation The compounds of the invention exhibit valuable pharma¬ cological properties, e.g. blocking the NMDA excitatory amino acid receptor in mammals. The compounds are thus useful for treating disorders responsive to such block¬ ade particularly convulsive disorders, anxiety, cereb¬ ral ischemia, and pain. These effects are demonstrable in tests in vitro or in vivo e.g. in mice, rats, dogs or monkeys. Said compounds can be administered to them orally or parenterally. The inhibitory effect on the NMDA-type excitatory amino acid receptors is determined in vitro by measuring the 3 inhibition of the NMDA-evoked H-acetylcholine release from corpus striatum tissue of rat brain essentially as described by Lehmann and Scatton, Brain Research 1982, 252, 77-89. The inhibition of the NMDA-evoked 3 H-ace- tylcholine release from striatal tissue slices is ex- 3 pressed as % of release of H-acetylcholine in responsi to stimulation with 50 μM NMDA compared to control. The inhibitory effect on the NMDA-type excitatory amino acid receptors is determined also by an in vitro assay that measures the inhibition of binding of H-CGS 19755 to brain tissue preparations essentially according to Lehmann et al J. Pharmacol. Exptl. Therap. 1988, 246, 65-75. The anticonvulsive effect of the compounds of the in¬ vention is determined in vivo by inhibition of electro- shock- or NMDA-induced convulsions in the mouse essen¬ tially as described in the last mentioned reference. The analgetic effect of said compounds is determined in the rat and the mouse by intrathecal injection essen- tially according to Cahusac et al. Neuropharmacology 1984, 23, 719-24. The best mode of carrying out the invention known at present is to use the compounds acccording to examples 1 or 6.

Claims: CLAIMS 1. Compounds of the formula I in which X is an imino, a methylene group, a benzylidene, an 1,1-allylidene, an 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 con¬ taining 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)(OR2) wherein R1 and R2 is each independently hydrogen, C ^ -C-g alkyl, phenyl-substi¬ tuted --C 2 alkyl, acyloxymethyl or -ethyl; n, when X does not contain nitrogen in the ring, is 1 or 2, or, when X contains nitrogen, is 2; and in each of which compounds the carboxy group may be functiona¬ lized in form of a pharmaceutically acceptable ester or amide, as well as the hydrates, pharmaceutically accep¬ table salts and base addition salts, such as metal salts, and isomeric forms including stereoisomers. 2. Compounds according to claim 1, wherein X is imino, C^-Cg alkylimino, acylimino, methylene, 1,1-ethylidene or 1,1-propylidene; Y is a hydroxyl-bearing carbon or is a carbonyl group; Z is a group consisting of one to three methylene groups or is a 1,3-allylidene or 1,3-propargylidene group; W is a group P(0)(OR 1)(OR2) wherein R1 and R2 is independently hydrogen, C η -C η g alkyl, phenyl-substitu- ted Cx -C- alkyl, acyloxymethyl or -ethyl; n, when X does not contain nitrogen in the ring, is 1 or 2, or, when X contains nitrogen, is 2; and in each of which compounds the carboxy group may be functiona¬ lized in form of a pharmaceutically acceptable ester or amide, as well as the hydrates, the pharmaceutically acceptable salts and base addition salts, such as metal salts and isomeric forms including stereoisomers. 3. Compounds according to claim 1 of the formula II, wherein X is imino, C-.-C. alkylimino, acylimino, methylene, 1,1-ethylidene or 1,1-propylene; Y is a hydroxyl-bearing carbon or is a carbonyl group; Z is a group consisting of one to three methylene groups or is a 1,3-allγlidene or 1.3-propargylidene group; W is a group P(0)(OR 1)(OR2) wherein R1 and R2 is independently hydrogen, C- j -C.g alkyl, phenyl- substituted 1 ~C 2 alkyl, acyloxymethyl or -ethyl; as well as hydrates, pharmaceutically acceptable salts and base addition salts, such as metal salts and isomeric forms including stereoisomers. 4. A compound according to claim 1 wherein X is a methylene group, Y is a carbonyl group Z is methylene group W W iiss PP((00))((OORR 11 ))((OORR 22 )),, wherein R 1 and R 2 are both hydrogen, and n is 2. 5. A compound according to claim 1 wherein X is a methylene group, Y is a hydroxymethylene group Z is a methylene group W W iiss PPffOOHHOORR^^--MMOORR 22 )),, wherein R 1 and R 2 are both hydrogen, and n is 2. 6. A pharmaceutical preparation with anticonvulsant effect containing a compound according to claim 1. 7. A pharmaceutical preparation with analgetic effect containing a compound according to claim 1. 8. A pharmaceutical preparation with cerebral anti- ischemic effect containing a compound according to claim 1. 9. Use of a compound according to claim 1 for the manufacture of a pharmaceutical preparation with analgetic effect. 10. Use of a compound according to claim 1 for the manufacture of a pharmaceutical preparation with antiischemic effect. 11. Use of a compound according to claim 1 for the manufacture of a pharmaceutical preparation with cere¬ bral anticonvulsant effect. 12. A process for the preparation of a compound of the formula I the hydrates, pharmaceutically acceptable salts base addition salts isomeric or stereoisomeric forms, wherein X, Y, Z, W and n are as defined in claim 1 wherein A) a compound of the formula III wherein X and n are as defined above; L is a suitable leaving group R is alkoxy or dialkylamino with up to 10 carbon atoms and A denotes that the ring is aromatic or partly unsaturated is reacted with a metallated dialkyl ester of an alkylphoshonic acid, the formed compound is saturated by conventional methods and the protecting groups are removed; or B) a compound of the formula wherein X, L, R and n are as defined above is reacted with a metallated alkylphosphonic acid, whereafter the protecting groups are removed; or C) a halogenated ketone of the formula V or VI wherein X, R, A and n are as defined above and Q is a leaving group is reacted with a trialkyl phosphite or with a metallated dialkyl ester of phosphonic acid, whereafter the protecting groups are removed; or D) a partly protected intermediate from one of the methods A) or B) containing a ketone functionality in the side chain that contains phosphorus is reacted with ammonia or a source of ammonia. 13. A method for inducing analgesia, treating convul¬ sions or cerebral ischemia comprising administering to mammals including man needing any of these treatments an effective amount of a compound according to claim 1.

Inventors: CLAESSON ALF, SWAHN BRITT-MARIE, CLAESSON, ALF, SWAHN, BRITT-MARIE
Applicants: ASTRA AB, AKTIEBOLAGET ASTRA
Application year: 1991
Main classification: C07F9
IPC codes: A61K31, A61P9, A61P25, C07F9