US 5,095,009 AGrant

NMDA Antagonists

Issue Date:1992-03-10

•20 Claims

Abstract

The present invention is directed to a new class of 4-(oxoalkyl)phosphono, 4(oxime alkyl)phosphono, or 4-(hydrazine alkyl)phosphono, 2-piperazine carboxylic derivatives that are useful as NMDA antagonists

Metadata

Assignee

Merrell Dow Pharmaceuticals Inc.

Inventors

Jeffrey P. Whitten
Bruce M. Baron

Application Information

Application Number:US 5534313

Filing Date:1990-07-20

Priority Date:1989-09-19

Art Unit:122

Classifications

IPC:

A61K 31675C07F 96509C07F 9653C07F 938C07F 940

Field of Search:

51454485337

Patent Drawings

This patent does not have any drawings.

Description

EXAMPLE I

The purpose of this Example is to demonstrate the preparation of the protected amino acids of Formula III using the methods disclosed in Step A of Reaction Scheme I and Method of V. J. Lee & K. L. Rinehart J. Am. Chem. Soc. 1978, 100, 4237.

A) N-Benzyloxycarbonyl-D-aspartic Acid

D-Aspartic acid (25.0 g, 0.188 mol) and benzyl chloroformate (34.3 ml, 0.282 mol) were added to sodium hydroxide (22.9 g, 0.564 mol) in water (600 ml). The resulting mixture was stirred at room temperature for 3 days. The mixture was then acidified with 6MHCl to pHl and extracted with ethyl acetate (3.times.250 ml). The extracts were combined, dried (MgSO.sub.4) and evaporated to a clear oil, wt 50.2 g. .sup.1 H NMR (90MH.sub.z, CDCl.sub.3): .delta.3.05 (2,bm), 4.65 (1,bm), 5.25 (2,s), 6.2 (1,bs), 7.4 (5,s), 10 (1,bs).

B) N-Benzyloxycarbonyl-3-methyl-D,L-aspartic Acid

Using a similar method to above 3-methyl-D,L-aspartic acid (10.0 g, 67 mmol), benzyl chloroformate (12 ml, 100 mmol) in 50% NaOH (16.7 g, 208 mmol) in water (125 ml) yielded N-benzyloxycarbonyl-3-methyl-D,L-aspartic acid 19.0g as a low melting solid. .sup.1 H NMR (90 MH.sub.z, CDCl.sub.3 /d.sub.6 DMSO): .delta.1.1 (3,d), 2.9 (1,dt), 4.4 (1,m), 4.95 (2,s) 5.9 (1,bd) 7.2 (5,6) 7.9 (1,bs).

C) N-Benzoylcarbonyl-D-2-Aminoadipic Acid

Using a similar method to above D-2-amino-adipic acid (4.0 g, 24.8 mmol), benzyl chloroformate (4.5 ml, 37.2 mmol) and 50% sodium hydroxide (6.0 g, 74.4 mmol) in water yielded N-benzoyl-carbonyl-D-2-amino adipic acid 7.5 g as a low melting solid. .sup.1 H NMR (300 MH.sub.z,CDCl.sub.3) .delta.1.65 (2,m) 1.78 (2,m) 2.41 (2,t) 3.8 (1, t) 5.1 (2,s) 7.4 (5,m).

EXAMPLE II

The purpose of this Example is to demonstrate the preparation of the oxazolone derivatives of Formula IV by the method disclosed in Step B of Reaction Scheme I and Method of M.ITOH Chem. Pharm. Bull. 1969, 17, 1679.

A) R-5-Oxo-4-acetic-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester

N-Benzyloxy carbonyl-D-aspartic acid (52 g, 195 mmol) was added to para-formaldehyde (16 g) and para-toluene sulphonic acid (1 g) in benzene (1 L). The resolving mixture was heated to the boil and refluxed for 41/2 hours with azaetropic removal of water (Dean & Starke trap). The mixture was then cooled and poured into 1 MHCl (500 ml). The resulting mixture was extracted with ethyl acetate (3.times.250 ml) and the extracts combined and washed with 5% sodium bicarbonate (2.times.500 ml). The bicarbonate extracts were combined, acidified with 6 MHCl then extracted with ethyl acetate (3.times.250ml). The ethyl acetate extracts were combined, dried (MgSO.sub.4) and evaporated to a low melting white solid, wt 25.9 g. .sup.1 H NMR (90 MH.sub.z, CDCl.sub.3) .delta.3.05 (2,m) 4.25 (1,t), 5.05 (2,s), 5.25 (2.dd), 7.2 (5,s), 7.5 (1,bs).

B) S-5-Oxo-4-acetic-3-oxazolidinecarboxylic acid, 3 (phenylmethyl) ester

Using a similar method to above N-benzyloxycarbonyl-L-aspartic acid (10 g, 37 mmol), para-formaldehyde (3 g) and paratoluenesulphonic acid (0.25 g) in benzene (250 ml) yielded 10.1 g of a low melting solid. .sup.1 H NMR (90 MH.sub.z,CDCl.sub.3) .delta.3.05 (2,m), 4.25 (1,t) 5.05 (2,s) 5.25 (2,dd) 7.2 (5,s), 7.5 (1,bs).

C) R,S-5-Oxo-4-(.alpha.-methyl acetic acid)-3-oxazolidine carboxylic acid, 3-pheny(methyl) ester

Using a similar method to above N-benzyloxycarbonyl-3-methyl-D,L-aspartic acid (18.8 g, 67 mmol), para-formaldehyde (6 g) and para-toluenesulphonic acid (0.5 g) in benzene (500 ml) yielded 13.5 g of a low melting solid. .sup.1 H NMR (90 MH.sub.z, CDCl.sub.3) .delta.1.5 (3,d) 3.25 (1,m) 4.2 (1,D) 5.2 (2,s) 5.35 (2,dd), 7.2 (5,6), 9.2 (1,bs).

D) R-5-Oxo-4-butyric-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester

Using a similar method to above N-benzyloxycarbonyl-D-2-aminoadipic acid (7.5 g, 24.8 mmol), paraformaldehyde (5 g) and paratoluene sulphonic acid (0.5 g) in benzene yielded 5.83 g of a clear oil. .sup.1 H NMR (90 MH.sub.z,CDCl.sub.3) .delta.1.7 (2,m) 1.95 (2,m) 2.35 (2,m) 4.3 (1,m) 5.2 (2,s) 5.35 (2,dd) 7.4 (5,s).

EXAMPLE III

The purpose of this Example is to demonstrate the preparation of the acid chlorides of Formula V by the methods taught in Step C of Reaction Scheme I and Method of B. H. Lee & M. J. Miller Tetrahadron Lett. 1984, 25, 927.

A) R-5-Oxo-4-(acetyl chloride)-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester

Thionyl chloride (20 ml) was added to R-5-oxo-4-acetic-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester (9.8 g, 35.1 mmol) and refluxed for 10 minutes. The solution was then cooled and blown to a residue with a stream of dry N.sub.2. The residue was then concentrated under vacuum to yield a pale yellow oil (10.4 g). .sup.1 H NMR (90 MH.sub.z, CDCl.sub.3) .delta.3.5 (2,d) 4.2 .delta.(1,t) 5.1 (2,s) 5.25 (1,dd) 7.2 (5,s).

B) S-5-Oxo-4-(acetyl chloride)-3-oxazolidine carboxylic acid, 3-(phenylmethyl) ester

Using a similar method to above thionyl chloride (18 ml) and S-5-oxo-4-acetic-3-oxazolidine carboxylic acid, 3-(phenyl methyl) ester (10.1 g, 36 mmol) yielded 10.8 g of a yellow oil.

C) R,S-5-Oxo-4-(.alpha.-methyl-acetyl chloride)-3-oxazolidine carboxylic acid, 3-(phenylmethyl) ester

Using a similar method to above thionyl chloride (15 ml) 30 and R,S-5-oxo-4-(.alpha.-methyl-acetyl chloride)-3-oxazolidine carboxylic acid, 3-(phenylmethyl) ester yielded 7.4 g of a straw colored oil.

D) R-5-Oxo-4-(butryl chloride)-3-oxazolidine carboxylic acid, 3-(phenylmethyl)ester

Using a similar method to above thionyl chloride (8 ml) and R-5-oxo-4-butyric-3-oxazolidine carboxylic acid, 3-(phenylmethyl) ester (5.8 g, 18.9 mmol) yielded 6.1 of a colorless oil.

EXAMPLE IV

The purpose of this Example is to demonstrate the preparation of the protected beta Ketone phosphonates of Formula VII utilizing the coupling techniques taught in Step D of Reaction Scheme I and Method of J. M. Vaslet, N. Collignon & P. Savignac Can J. Chem. 1979, 57, 3216.

A) R-4-[3-(Diethoxyphosphinyl)-2-oxopropyl]-5-oxo-3-oxazolidine carboxylic acid, 3-(phenylmethyl) ester

Diethyl methylphosphonate (25.1 g, 165 mmol) was dissolved in THF (250 ml) under N.sub.2 and coded to -65.degree. C. 2.7M nBuLi (61 ml, 165 mmol) in hexanes was added dropwise over 15 minutes to the solution and stirred for a further 10 minutes while maintaining a temperature of -65.degree.. Copper I iodide (34.7 g, 182 mmol) was added and the resulting mixture warmed to -30.degree. C. and then stirred for an additional 1 h. R-5-Oxo-4-(acetyl chloride)-3-oxazolidine carboxylic acid, 3-(phenylmethyl) ester (54.2 g, 182 mmol) in ether (250 ml) was then added dropwise so as to maintain a temperature of -30.degree. C. and the resulting mixture stirred for a further 18 hours. The reaction was then poured into water (750 ml) and the aqueous mixture then extracted with dichloromethane (3.times.250 ml). The organic extracts were then combined, filtered through a bad of celite, dried (MgSO.sub.4) and evaporated to a pale yellow oil. Flash chromatography on silica gel with 100% ethyl acetate yielded a colorless oil wt. 31.9 g. .sup.1 H NMR (300 MH.sub.z, CDCl.sub.3) .delta.1.24 (6,t) 2.95 (2,d) 3.32 (2,m) 3.98 (4,m), 4.15 (1,m) 5.1 (2,s) 5.35 (2,dd) 7.28 (5,5); MS (CI), M/Z 414 (MH+).

B) S-4-[3-(Diethyoxyphosphinyl)-2-oxopropyl-5-oxo-3-oxazolidine carboxylic acid, 3-(phenylmethyl) ester

Using a similar method to above, S-5-oxo-4-(acetyl chloride)-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester (10.8 g, 36.3 mmol), methyl diethyl phosphonate (5.0 g, 33 mmol), 2.7 M nBuLi (12.2 ml, 33 mmol) and copper I iodide (6.91 g, 36.3 mmol) in THF (50 ml) and ether (50 ml) yielded a colorless oil wt 5.0 g .sup.1 H NMR (300 MH.sub.z, CDCl.sub.3) .delta.1.25 (6,t) 2.95 (2,d) 3.32 (2,m) 3.98 (4,m) 4.15 (1,m) 5.1 (2,s) 5.35 (2,dd) 7.28 (5,s): Ms (CI), M/Z 414 (MH+).

C) 4-[3-(Diethoxyphosphinyl)-1-methyl-2-oxopropyl]-5-oxo-3-diethyl phosphonate)-3-oxazolidine carboxylic acid, 3-(phenyl methyl) ester

Using a similar method to above, 5-oxo-4-(.alpha.-methyl acetyl chloride)-3-oxazolidine carboxylic acid, 3-(phenyl methyl) ester (7.4 g, 23.7 mmol), diethyl methyl phosphonate (3.28 g, 21.5 mmol), 2.7 M nBuLi (8.0 ml, 21.5 mmol) and copper I iodide (4.5 g, 23.7 mmol) in THF (40 ml) and ether (40 ml) yielded 3.17 g of a colorless oil. .sup.1 H NMR (90 MH.sub.z, CDCl.sub.3) .delta.1.2 (6,t) 1.4 (3,d) 2.95 (2,d) 4.1 (4,m) 5.1 (2,s) 5.25 (2,dd) 7.25 (5,s) MS CCZ), M/Z 428 (MH+).

D) 4-[3-(Diethoxyphosphinyl)-1,3-dimethyl-2-oxopropyl]-5-oxo-3-oxazolidinecar boxylic acid, 3-(phenylmethyl) ester

Using a similar method to above, 5-oxo-4-(.alpha.-methyl acetyl chloride)-3-oxazolidine carboxylic acid, 3-(phenyl methyl ester (6.9 g, 22 mmol), diethyl ethyl phosphonate (3.32 g, 20 mmol) and copper I iodide (4.19 g, 22 mmol) in THF (50 ml) and ether (50 m) yielded 2.19 of a colorless oil. .sup.1 H NMR (300 MH.sub.z, CDCl.sub.3) 1.1 (6,m) 1.12 (3,m) 1.96 (3,m) 3.4 (1,m) 3.6 (1,m) 4.25 (1,m) 5.2 (2,s) 5.35 (2,dd) 7.4 (5,s). MS (CI) M/Z 442 (MH+).

E) R-4-[3-(Diethoxyphosphinyl)-3-methyl-2-oxoproovl]-5-oxo-3-oxazolidine carboxylic acid, 3-(phenylmethyl) ester

Using a similar method to above R-5-oxo-4-(acetyl chloride)-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester (4.79 g, 16.1 mmol), ethyl diethyl phosphonate (2.43 g, 14.6 mmol), 2.7 M nBuLi (5.40 ml, 14.6 mmol) and copper I iodide (31 g, 16.1 mmol) in THF (30 ml) and ether (40 ml) yielded 2.1 g of a clear oil. .sup.1 H NMR (90 MH.sub.2, CDCl.sub.3) 1.2 (6,m) 1.25 (3,s) 3.1 (1,m) 3.8 (1,m) 4.05 (4,m) 5.1 (2,s) 5.25 (2,dd) 7.2 (5,s) MS CI M/Z 428 (MH+).

F) R-4-[5-(Diethoxyphosphinyl)-4-oxopentyl]-5-oxo-3-oxazolidine carboxylic acid, 3-(phenyl methyl) ester

Using a similar method to above R-5-oxo-4-(butryl chloride)-3-oxazolidinecarboxylic acid, 3-(phenyl methyl) ester (6.1 g, 18.7 mmol), methyl diethyl phosphonate (2.6 g, 17 mmol), 2.7 M nBuLi (6.3 ml, 17 mmol) and copper I iodide (3.6 g, 18.7 mmol) in THF (50 ml) and either (50 ml) yielded a clear oil, wt. 2.51 g. .sup.1 H NMR (300 MH.sub.z, CDCl.sub.3) .delta.1.32 (6,t) 1.59 (2,m) 1.80 (1,m) 1.99 (1,m) 2.61 (2,m) 3.04 (2,d) 4.13 (4,m) 4.35 (1,m) 5.2 (2,s) 5.35 (2,dd) 7.4 (5,s).

EXAMPLE V

The purpose of this Example is to demonstrate the preparation of the beta ketone phosphonates of Formula I via the methods taught in Step E of Reaction Scheme I.

A) R-4-oxo-5-phosphononorvaline

R-4-[3-(Diethoxyphosphinyl)-2-oxopropyl]-5-oxo-3-oxazolidinecarboxylic acid, 3-(phenylmethyl) ester (20.0 g, 48 mmol) was dissolved in CH.sub.2 Cl.sub.2 (750 ml) and acetonitrile (750 ml) and cooled under an atmosphere of dry N.sub.2 to 0.degree. C. Trimethyl silyl iodide (27.6 ml, 20.1 mmol) was added dropwise over 10 minutes and the resulting solution warmed to room temperature and stirred for 41/2 hours. Water (20ml) was than added and the reaction blown to a residue with a stream of N.sub.2. The residue was taken up in CH.sub.2 Cl.sub.2 (250 ml) and water (200 ml). The aqueous layer was then washed with CH.sub.2 Cl.sub.2 (10.times.20 ml) then washed with diethyl ether (3.times.300 ml) and then lyophylized to yield a yellow powder. The powder was taken up into a minimum volume of water and eluted on a BIORAD AG50W-X8 H+ form resin with water. The ninhydrin positive fractions were lyophylized to yield 6.2 g of an off white solid. The solid was taken back up in a minimum amount of water and reluted through a BIORAD Ag50W-X4 H+ form resin with water yielded 4.8 g of a white solid MP 154.degree. (with decomposition). .sup.1 H NMR (300 MH.sub.z, D.sub.2 O) 3.05 (2,dd) 3.35 (2,m) 4.2 (1,m); .sup.31 PNMR (121 MH.sub.2, D.sub.2 O) 12.4 (s); MS (FAB) M/Z 212 (MH+) Anal. Calcd. for C.sub.5 H.sub.10 NO.sub.6 P 1/2 H.sub.2 O: C,27.28; H, 5.04; N, 6.45. Found: C, 27.27; H, 4.82; N, 6.35. Weight loss by thermo gravimetry correlates with 4.8 wt. % water.

B) S-4-oxo-5-phosphononorvaline

Using a similar method to above S-4-[3-(Diethoxyphosphinyl)-2-oxopropyl]-5-oxo-3-oxazolidinecarboxylic acid, 3-(phenyl methyl) ester (5.0 g, 12 mmol) and trimethylsilyl iodide (6.9 ml, 48 mmol) in dichloromethane (250 ml) and acetonitrile (300 ml) to yield 0.28 g of a white solid. Mp 155.degree. C. (with decomposition). .sup.1 H NMR (300 MH.sub.2, D.sub.2 O) 3.05 (2,dd) 3.35 (2,m) 4.2 (1,m); .sup.31 PNMR (121 MH.sub.2, D.sub.2 O) 12.4 M S (FAB) m/z 212 (MH+). Anal. Calcd. for C.sub.5 H.sub.10 NO.sub.6 P 1/2 H.sub.2 O: C,27.28; H,5.04, N, 6.45. Found C, 27.07; H, 4.98; N, 6.37. Weight loss by thermo gravimetry correlates with 3.9 wt. % water.

C) 3,4-dimethyl-4-oxo-5-phosphononorvaline

Using a similar method to above 4-[3-(Diethoxyphosphinyl)-1,3-dimethyl-2-oxopropyl]-5-oxo-3-oxazolidine acid, 3-(phenylmethyl) ester (2.0 g, 4.5 mmol) and trimethyl silyiodide (2.6 ml, 18.1 mmol) in dichloromethane (100 ml) and acetonitrile (100 ml) yielded 21.4 mg of white solid m.p. 72.degree. with decomposition. .sup.1 H NMR 1.25 (6,m), 2.49 (1,m), 4.22 (1,m); .sup.31 PNMR (121 MH.sub.z, D.sub.2 O) 16.1 (s); Ms (FAB) m/z 240 (MH+). Anal. Calcd. for C.sub.7 H.sub.14 NO.sub.6 P 1/2 H.sub.2 O: C,35.15; H,5.90; N,5.86 Found: C,34.13; H,5.16, N, 5.22. Weight loss by thermo gravimetry correlates with 7.3% wt. % water.

D) 3-methyl-4-oxo-5-phosphononorvaline

Using a similar method to above 4-[3-(Diethoxyphosphinyl)-1-methyl-2-oxopropyl]-5-oxo-3-oxazolidine carboxylic acid, 3-(phenylmethyl) ester (3.17 g, 7.4 mmol) and trimethylsilyl iodide (4.3 ml, 30.2 mmol) in dichloromethane (200 ml) and acetonitrile (200 ml) yielded 310 mg of a white solid m.p. 145.degree. (with decomposition). .sup.1 H NMR (300 MH.sub.z, D.sub.2 O) .delta.1.35 (3,d) 3.21 (2,dd) 3.61 (6,m) 4.35 (1,m); .sup.31 PNMR (121 MH.sub.z, D.sub.2 O) 11.90; (MS FAB) 226 (MH+). Anal. calcd. for C.sub.6 H.sub.12 NO.sub.6 P 1/2 H.sub.2 O: C,30.78; H, 5.60; N, 5.98. Found: C, 30.90; H, 5.48, N, 5.93. Weight loss by thermo gravimetry correlates with 4.3 wt. % water.

E) R-5-methyl-4-oxo-5-phosphononorvaline

Using a similar method to above R-4[3-Diethoxyphosphinyl)-3-methyl-2 oxopropyl]-5-oxo-3-oxazolidine carboxylic acid, 3-(phenyl methyl) ester (2.1 g, 4.9 mmol) and trimethylsilyl iodide (2.9 ml, 20.4 mmol) in dichloro-methane (150 ml) and acetonitrile (150 ml) yielded 70 mg of white solid m.p. 140.degree. (with decomposition). .sup.1 H NMR (300 MH.sub.2, D.sub.2 O) 1.35 (3,m) 3.31 (2,m) 3.54 (1,m) 4.28 (1,m) .sup.31 P NMR (121 MH.sub.2, D.sub.2 O) .delta.16.3 (s); M S (FAB) M/Z 226 (MH+) Anal. calcd for C.sub.6 H.sub.12 NO.sub.6 P 1/2 H.sub.2 O: C, 30.78; H, 5.60; N, 5.98. Found: C, 30.45, H, 5.24; N, 5.86. Weight loss by thermo gravimetry correlates with 5.2 mol% water.

F) R-2-Amino-6-oxo-7-phosphonoheptanoic acid

Using a similar method to above R-4-[5-(Diethoxyphosphinyl)-4-oxopentyl]-5-oxo-3-oxazolidine carboxylic acid, 3-(phenyl methyl) ester (2.5 g, 5.7 mmol) and trimethyl-silyl iodide (3.2 ml, 22.8 mmol) in dichloromethane (150 ml) and acetonitrile (150 ml) yielded 400 mg of a white solid m.p. 82.degree. with decomposition. .sup.1 H NMR (300 MH.sub.z, d.sub.6 DMSO) 1.65 (2,m) 1.90 (2,m) 2.8 (2,m) 3.1 (2,D) 4.1 Cl,M); .sup.31 P NMR (121 MH.sub.z, D.sub.2 O) ) 9.3 (s); M S (FAB) 240 (MH+). Anal calcd. for C.sub.7 H.sub.14 NO.sub.6 P. C, 35.15; H, 5.90; N, 5.86. Found: C, 35.38; H, 5.60, N, 5.80.

EXAMPLE VI

The purpose of this Example is to demonstrate the preparation of a beta ketone phosphonate of Formula I in which B is represented by a piperazine derivative using the methods taught in Reaction Scheme III.

4-(2-Oxo-3-phosphonopropyl)-2-piperazinecarboxylic acid

Piperazine-2-carboxylic acid hydrochloride 1.2 g (7.2 mmol) was dissolved in water (25 ml) and 80% sodium hydroxide (1.4 g), and dimethyl-1-bromo-2-methoxy propenyl phosphonate (2.4 g, 9.3 mmol) added. The resulting solution was stirred for 18 hours under a N.sub.2 atmosphere, then acidified to pH 3.0 with 1MHCl. The reaction was blown to a residue with a stream of N.sub.2 and then taken up in a minimum amount of water and eluted from a BIORAD Agl-X8 acetate form in resin with water. The ninhydrin positive fractions were lyophylized and hydrolysed with refluxing 6MHCl (50 ml) for 6 hours. The reaction was blown to a residue and eluted from a Amberlite CG-50 ion exchange resin with water hyphoylization yielded 71 mg of a white solid. .sup.1 H NMR (300 MH.sub.z, D.sub.2 O) .delta.3.02 (2,d) 3.3-3.6 (3,m) 3.6-3.8 (2,m) 3.7 (1,m) 3.71 (2,m). .sup.31 PNMR (121 MH.sub.z, D.sub.2 O) 12.25.

EXAMPLE VII

The purpose of this Example is to demonstrate the preparation of all of the beta-substituted beta ketone phosphonates at Formula I using the method disclosed in U. Schollkopf, V. Groth, K. O. Westphalen And C. Deng, Synthesis 1981, 969.

Synthesis of 2-methyl-4-oxo-5-phosphononorvaline

D,L-Alanine ethyl ester hydrochloride (10.0 g; 65.1 mmol) was added to benzaldehyde (6.6 ml; 65.1 mmol), magnesium sulfate (6 g) and triethylamine (20 ml) in dichloromethane (50 ml) and stirred at room temperature for 18 hours. The solids were filtered off and the filtrate partioned between ether (250ml) and water (250 ml). The organic layer was separated, dried and evaporated to yield a clear oil wt 11.3 g. .sup.1 H NMR (90 MH.sub.z, CDCl.sub.3) .delta.1.2 (3,t) 1.4 (3,d) 4.0 (1,m) 4.1 (2,q) 7.4 (5,m) 8.2 (1,s).

The oil (2.62 g; 12.8 mmol) was added to THF (200 ml) and cooled to -78.degree. for 1/2 hour. Lithium hexamethylsilylamine (1.0M in hexane; 12.8 mmol was added and stirred for 1/2 hour. Dimethyl-3-bromo 2-methoxy propenyl phosphonate (3.3 g, 12.8 mmol) in THF (75 ml) was added dropwise over 1/2 hour and the resulting solution stirred and warmed to room temperature over 18 hours. The reaction was then poured into water (500 m) and extracted with ethyl acetate (2.times.500 ml). The organic extracts were combined dried (MgSO.sub.4) and evaporated to a residue which was flash chromatographed on silica gel with ethyl acetate to yield 1.8 g of a clear oil. .sup.1 H NMR (300 MH.sub.z, CDCl.sub.3) 1.23 (3,6) 1.49 (3, s) 3.3-3.8 (11,m) 4.19 (1,q) 4.49 (1,D) 7.5 (m,5) 8.32 (1,s).

6MHCl (400 ml) was added to the oil (1.8 g, 4.6 mmol) and the mixture heated to the boil and refluxed under an atmosphere of N.sub.2 for 6 hours. The solution was then evaporated to a residue. The residue was taken up in ethanol (10 ml) and isopropyl alcohol (3 ml) and propylene oxide (1 ml) added. The resulting solid was filtered and dried wt. 0.75 g, m.p. 130.degree. with decomposition. .sup.1 H NMR (300 MH.sub.z, D.sub.2 O) 1.55 (3,s) 3.05 (1,ddd) 3.45 (1,dd): MS (FAB) M/Z 226 (MH+).

EXAMPLE VIII

The purpose of this Example is to demonstrate a partial hydrolysis in which the phosphonate ester moiety is retained in the final product.

5-(Hydroxymethoxyphosphinyl)-4-oxonorvaline

N-(Diphenylmethylene)glycine ethyl ester (3.1 g, 11.6 mmol) was dissolved in THF (50 ml) and cooled to -78.degree. under a dry atmosphere of N.sub.2. 1M Lithium hexamethylsilyamine in hexanes (12 ml, 12 mmol) was added and the resulting orange solution stirred at -78.degree. for 1/2 hour. Dimethyl-3-bromo-2-methoxypropenyl phosphate (3 g, 12 mmol) was added and the solution stirred and allowed to warm to room temperature over 18 hours. The reaction was then poured into water (200 ml) and extracted with ethyl acetate (2.times.250 ml). The organic extracts were combined, dried (MgSO.sub.4) and evaporated to a residue. Flash chromatography on silica gel with ethyl acetate, hexane (75:25) yielded 3.2 g of a light yellow oil. 1MHCL (50ml) was added to the oil (2.63 g); 5.9 mmol) and refluxed for 11/2 hours. The resulting solution was evaporated to a residue and eluted with water on a BIORAD 50W:X8H+ resin with water to yield 0.65 g of a white solid Mp 111.degree. (with decomposition). .sup.1 H NMR (300 MH.sub.z, D.sub.2 O) .delta.3.15 (1,d) 3.45 (1,m) 3.61 (3,d) 4.31 (1,m); MS (FAB) M/Z 226 (MH+) Anal. Calcd. for C.sub.6 H.sub.12 NO.sub.6 P 1/2 H.sub.2 O: C, 30.78; H, 5.60, N, 5.98. Found: C, 31.11; H, 5.57; N, 6.07.

EXAMPLE IX

This example demonstrates the preparation of the oximes of Formula Ia.

A) 4-(Hydroxyimino)-5-phosphononorvaline

0.25g of R-4-Oxo-5-phosphononorvaline (1.1 mmol) were stirred overnight at 40.degree. C. with 1.0 g sodium acetate (12.2 mmol) and 0.50 g hydroxylamine HCl (7.2 mmol) in 5 ml water. Disappearance of starting material by HPLC indicated completion of the reaction. The reaction mixture was eluted through a column of Sephadex.RTM. G-10 with D.I. water. The ninhydrin positive fractions were then combined and condensed by freeze drying to yield 153 mg (59%) of 4-(hydroxyimino)-5-phosphononorvaline as white hygroscopic solid, m.p. 128.degree. C. (with decomposition). Calculated as anhydrous: C, 26.56; H, 4.90; N, 12.39. Found: C, 21.13; H, 4.45, N, 9.85. TGA: 9.7% loss. FAB MS M+H 227.1; 300 MHz NMR in D.sub.2 O .sup.1 H: 4.25 M, 4.15 M (total 1 H) 30 M(2H), 3.1 M(2H) 31p(1H decoupled): 14.8, 15.75; .sup.13 C: 32-34 D, 38, 55, 157D, 177.

B) 4-(Methoxyimino)-5-phosphononorvaline

0.21 g of R-4-Oxo-5-phosphononorvaline and 0.5 g of O-methyl hydroxylamine HCl, were reacted as in Example IX(A) and 4-(methoxyimino)-5-phosphononorvaline was obtained as a white hydroscopic solid, m.p. 170.degree. C. (with decomposition). (52%) Calcd: C, 30.01; H, 5.46; N, 11.67. Found: C, 21.22; H, 4.48; N, 8.10 and 6.1% loss on Tg analysis. FAB MS: M+H of 241.1. 300 MH.sub.z :.sup.1 H(D.sub.2 O): 4.1 M(1H), 3.85 D syn/anti(3H), 3.0 M(2H) 2.9M(2H) 31P(1H decoupled) 15+16.4 (syn/anti)

C) 4-[(Phenylmethoxy)imino]-5-phosphononorvaline

0.2 g R-4-Oxo-5-phosphononorvaline, 0.5 g O-Benzyl hydroxyamine HCl were reacted as in Example IX(A) and 4-[(phenylmethoxy)imino]-5-phosphononorvaline was obtained as a white hygroscopic powder, m.p. 153.degree. (with decomposition), 100 mg (33%). Calcd: C 45.58; H 5.42; N, 8.86. Found: C, 40.08; H, 4.81;N, 7.67,; and 9.8% loss on Tg analysis. FAB MS: M+H 317.1. 300 MHz .sup.1 H (D20) 7.45 M (5 H) 5.15 D (2H) 4.1 M (1H), 3.0 M (2H), 2.9 M (2H).

D) 4-[(2'-phenylethoxy)imino]-5-phosphononorvaline

4-[(2'-phenylethoxy)imino]-5-phosphononorvaline may be prepared using the methodology described in Example IX (A-C) but substituting R-4-oxo-5-phosphononorvaline and O-(2-phenylethyl)hydroxylamine hydrochloride as the starting materials.

EXAMPLE X

This example demonstrates the preparation of a compound of Formula Ia in which M is hydrazone.

4-(Benzylhydrazino)-5-phosphononorvaline may be prepared using the methodology of Examples IX (A-C) but substituting R-4-oxo-5-phosphononorvaline and benzylhydrazine dihydrochloride as the starting material.

EXAMPLE XI

This example demonstrates the preparation of the esters of Formula Ia.

A) R-4-Oxo-5-phosphononorvaline methyl ester

Freshly distilled acetyl chloride (25 ml) was added dropwise to dry methanol (500 ml) at 0.degree. C. under N.sub.2 over 15 minutes. R-4-Oxo-5-phosphononorvaline (1.25 g) was added and the resulting mixture heated to the boil and refluxed for 16 hours. The resulting solution was condensed to an oil which was taken up in dry methanol (500 ml) and a slow stream of HCl passed through the solution while refluxing the solution for a further 16 hours. The resulting solution was cooled, blown to a residue with a stream of N.sub.2 and then the residue eluted through a Biorad AGlX8 200-400 mesh resin (acetate form) with water. The fractions containing the desired product were freeze dried to yield 590 mg of a white solid, m.p. 88.degree. C. (with decomposition). Anal. Calcd, C, 32.01; H, 5.37; N, 6.22. Found, C, 30/17%; H, 5.90 %; N, 5.87 %. TGA loss 5.7 mol %. MS(FAB) M/Z 226 (MH+). 300 MHz .sup.1 H NMR (D20) 4.42 (1H, e) 3.82 (3H, S, 3.51 (2H, m) 3.14 (2H, dd). .sup.31 P NMR (D.sub.2 O.sub.1, .sup.1 H decoupled) 11.4 ppm.

B) R-4-Oxo-5-phosphononorvaline ethyl ester

R-4-Oxo-5-phosphononorvaline (0.5 g) was added to anhydrous ethanol (250 ml) and the resulting mixture saturated with anhydrous HCl. The mixture was refluxed for 5 hours then cooled and evaporated to a residue. The resulting residue was taken up in water (100 ml) and then freeze dried to yield a white solid m.p. 98.degree. C. (with decomposition). Anal Calcd C, 30.50; H, 5.49; N, 5.08. Found, C, 29.51; H, 5.69; N, 5.04. TGA loss 0.4 mol % loss. MS(FAB) M/Z 240 (MH+). 300 MHz .sup.1 H NMR (CD.sub.2 O) 4.42 (1H, t) 4.29 (2H, q) 3.51 (2H, m) 3.25 (2M, d) 1.28 (3H, t). hu 31P NMR (D.sub.2 O , .sup.1 H decoupled) 14.6 ppm.

Claims

What is claimed is:

1. A compound of the formulae: ##STR15## in which R is represented by hydrogen, C.sub.1-4 alkyl, or --CF.sub.3 ; R.sub.1 and R.sub.2 are each independently represented by hydrogen, C.sub.1-4 alkyl, C.sub.5-6 cycloalkyl, C.sub.1-3 alkylphenyl in which the phenyl ring may be optionally substituted, --CF.sub.3, phenyl or substituted phenyl; M is represented by N--O--R.sub.3 or N--NH--R.sub.3, in which R.sub.3 is represented by hydrogen, C.sub.1-4 alkyl or C.sub.1-3 alkylphenyl in which the phenyl ring may be optionally substituted; A is represented by a methylene or a trimethylene bridging group, either of which may be optionally substituted with up to 2 substituents selected from the group consisting of --CF.sub.3 C.sub.1-4 alkyl, C.sub.5-6 cycloalkyl, C.sub.1-3 alkylphenyl in which the phenyl ring may be optionally substituted, phenyl, substituted phenyl; and B is represented by: ##STR16## in which Z is represented by hydrogen, C.sub.1-4 alkyl, C.sub.5-6 cycloalkyl, C.sub.2-4 trialkylamino, C.sub.1-3 alkylphenyl in which the phenyl ring may be optionally substituted, phenyl, or substituted phenyl; the pharmaceutically acceptable acid addition salts thereof; the pharmaceutically acceptable basic addition salts thereof, the optical isomers thereof; the geometric isomers thereof and tautomers thereof, with the following proviso's a) at least one the substituents represented by R, R.sub.1 and R.sub.2 must be a hydrogen atom, and b) when B is represented by a piperazine derivative then at least one of the substituents represented by an oxazolone derivative then R must be a hydrogen atom.

2. A compound according to claim 1, wherein A is represented by methylene.

3. A compound according to claim 1 wherein A is represented by trimethylene.

4. A compound according to claim 2 wherein R is represented by hydrogen or a C.sub.1-4 alkyl.

5. A compound according to claim 4 wherein R.sub.1 is represented by hydrogen or a C.sub.1-4 alkyl.

6. A compound according to claim 1 wherein said methylene is substituted with a C.sub.1-4 alkyl.

7. A compound according to claim 1 in which R.sub.1 and R.sub.2 are hydrogen.

8. A compound according to claim 1 in which Z is hydrogen.

9. A compound according to claim 1 of the formula: ##STR17##

10. A compound according to claim 1 of the formula: ##STR18##

11. A compound according to claim 1 in which said compound is 4-(2-Oxo-3-phosphonopropyl)-2-piperazine carboxylic acid.

12. A compound according to claim 1 in which said compound is 4(2-Oxo-3-phosphonopropyl)-2-piperazine carboxylic acid ethyl ester.

13. A method for the treatment of epilepsy comprising administering to a patient in need thereof an anti-epileptic amount of a compound according to claim 1.

14. A method for preventing ischemic/hypoxic damage to cerebral tissue comprising administering to a patient in need thereof an effective amount of a compound according to claim 1.

15. A method according to claim 14 in which said hypoxic/ischemic damage is due to a stroke or a cerebrovascular accident.

16. A method for the treatment of anxiety comprising administering an anxiolytic amount of a compound according to claim 1.

17. A method for producing an analgesic effect comprising administering to a patient in need thereof an analgesic amount of a compound according to claim 1.

18. A method for treating muscle spasms comprising administering an anti-spasmodic amount of a compound according to claim 1.

19. A method for antagonizing the effects of excitatory amino acids upon the NMDA receptor complex comprising administering to a patient in need thereof an NMDA antagonistic amount of a compound according to claim 1.

20. A pharmaceutical composition comprising a compound according to claim 1 which is present in an NMDA antagonistic amount in admixture with a pharmaceutically acceptable carrier.

Patent Citations (2)

Patent	Date	Inventor	Cited By
US4705781	1987-11-01	Boast
EPX159889	1985-04-01

Non-Patent Literature (3)

Derwent Abstract 88-251354/36 (Abstract of DE 3804-936-A).
Bennett et al., Life Sciences, vol. 39, pp. 2455-2461.
Pike et al., Biochimica et Biophysica Acta. 708 (1982) 203-209.