DD295636A5 - NMDA Antagonists - Google Patents

Abstract

The invention relates to a new class of beta-ketophosphonates, beta-oxime phosphonates and beta-hydrazine phosphonates of the general formulas I and Ia, where R, R1, R2, A, B and M are as defined in claim 1. The compounds of general formulas I and Ia are useful in controlling the action of amino acids which are irritating to the NMDA receptor complex. Formula I u. I a {beta-ketophosphonates; beta-Oximphosphonate; beta-Hydrazinphosphonate; NMDA antagonists}

Description

Ph-CH = IT COOAlk

wherein R, R ₁ , X and A have the above meanings, Ph is a phenyl ring, and Y and Alk each independently represent a C ^ -alkyl radical, wherein the compounds of the general formula I are prepared, in which B is a radical of following formula

H ₂ N-CX-COOZ

R, Ri, A and X have the above meanings, and R ₂ and Z each represent a hydrogen atom, and that these compounds of general formula I are optionally esterified in a conventional manner for the preparation of the compounds of general formula I, wherein Z is C 1-4 alkyl, cycloalkyl, trialkylamino, alkylphenyl, phenyl or substituted phenyl, and R, Ri, R ₂ , A and B are as defined above; or E) compounds of general formula XV are condensed

H ₂ M (XV)

wherein M has the above meanings, with compounds of general formula I, wherein R, R ₁ , R ₂ , A and B have the above meanings, wherein the compounds of general formula I a are prepared in which R, R ₁ , R ₂ , A, Bund M have the above meanings.

12. Use of the compounds according to any one of claims 1 to 10 in combating the action of amino acids which are irritating to the NMDA receptor complex.

Use of the compounds according to any one of claims 1 to 10 for the treatment of epilepsy.

14. Use of the compounds according to any one of claims 1 to 10 for the treatment of diseases in which nerves degenerate.

Use of the compounds according to any one of claims 1 to 10 for the prevention of ischemic and / or hypoxic damage to the brain tissue.

16. Use of the compounds according to any one of claims 1 to 10 for the treatment of anxiety.

17. Use of the Verbindugnen according to one of claims 1 to 10 for the control of pain.

18. Use of the compounds according to any one of claims 1 to 10 for the treatment of muscle spasms.

19. A pharmaceutical composition comprising compounds according to any one of claims 1 to 10 in a pharmaceutically effective amount together with pharmaceutically acceptable carriers.

NMDA antagonists

The invention relates to a new class of beta-keto, beta-oxime and beta-hydrazine phosphates as NMDA antagonists. The invention also relates to their use in the treatment of epilepsy, nerve injuries resulting, for example, from strokes, cardiac arrest, hypoglycemia, corporal damage to the brain or spinal cord, diseases involving degeneration of nerves, anxiety and relieving pain. The invention further relates to pharmaceutical compositions containing these NMDA antagonists.

The invention relates to a new class of antagonists against irritating amino acids which act on the NMDA receptor complex. These antagonists have the following general formulas:

Ii II

HO-P-OR HO-P-OR

C = O C = M

A A

I 'I

B B

Formula I Formula Ia

in which R represents a hydrogen atom, a C 1-4 -alkyl radical or a trifluoromethyl group; Each of R ₁ and R ₂ independently represents a hydrogen atom, a C 1-4 alkyl, cycloalkyl, alkylphenyl, trifluoromethyl, phenyl or substituted phenyl group; M is a radical NOR ₃ or N-NH-R ₃ , where R _{3 is} a hydrogen atom, a C 1 -C 4 -alkyl or alkylphenyl radical; A represents a methylene or Trimethylenbrückengruppe, with up to two trifluoromethyl groups, C ₁ ^ ₄ -AIkVl-, cycloalkyl or alkylphenyl phenyl or substituted phenyl and / or may be optionally substituted; and B is one of the following radicals:

CO ₂ Z, I 'K ₂ N-CH-COOZ

odtx H ₂ N-CX-COOZ

wherein Z represents a hydrogen atom, a C 1-4 alkyl, cycloalkyl, trialkylamino, alkylphenyl, phenyl or substituted phenyl group; and X represents an alkyl, alkylphenyl or trifluoromethyl group; including their pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, tautomers, optical isomers and geometric isomers; with the following provisos: a) that the L-isomers of the compounds of general formula I are excluded when R, Ri and R _{3 are} hydrogen, A is unsubstituted methylene, and B is H ₂ N-CH-COOZ in which Z is a hydrogen atom; b) that at least one of R, R, and R _{2 is} a hydrogen atom; c) when B is either a piperazine derivative or an α-substituted amino acid, at least one of R ₁ and R _{2 is} hydrogen, and; d) that when B is an oxazolone derivative, R is a hydrogen atom.

(a) The terms "lower alkyl and d-4-alkyl" mean branched or straight chain alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, η-butyl or isobutyl groups and the like.

(b) The terms "lower alkoxy and C 1-4 alkoxy" mean branched or straight chain alkoxy groups, rrv-i to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and the like.

(c) The term "cycloalkyl" means a cyclohexyl or cyclopentyl group;

(d) The term "substituted phenyl ring" means a phenyl group (C ₆ H ₅ ) substituted with up to 3 isr wherein each moiety is independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, CF ₃ -, OCf-, OH-, CN-, NO ₂ -, COOR ₃ -, and CONR ₃ R ₄ -GrUpPCn in which R ₃ and R _{4 is} a hydrogen atom or a C, ^, - alkyl radical t> edeL-. These radicals may be the same or different and in the ortho, meta or para position.

(e) The term "alkylphenyl radical" means a - (CH ₂ ) _m -C ₆ H ₅ radical in which my number is from 1 to 3. This phenyl ring may be substituted as described above under (d).

(f) The term "piperazine derivative" means:

CO ₂ Z, ------

I

Hi

(g) The term "α-substituted amino acid" means H ₂ N-CX-COOZ.il

(h) The term "oxazolone" means "I

auk

(i) The term "trialkylamino" means -

AIk ₁

where η is an integer from 2 to 4 and Alk and Alk each independently represent a C 1-4 -alkyl radical, (j) The term "oxime" means compounds in which M is NO-R 3, (k) The term " Hydrazine "means a compound in which M is N-NH-R ₃ , (m) The term" halogen "means a chlorine, fluorine or bromine atom.

The term "pharmaceutically acceptable acid addition rate" means non-toxic organic or inorganic acid addition salts of the basic compounds of general formulas I and Ia or any of their intermediates Acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate Organic acids which form suitable salts include, for example, mono-, di- and tricarboxylic acids Such acids include, for example, acetic, glycol, lactic, benzene, malonic, succinic, glutaric, Fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymalein, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p -toluenesulfonic and sulfonic acids, such as methanesulfonic acid and 2-hydroxyethanesulfonic acid Such salts may be in either hydrated or substantially anhydrous form In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents and generally have higher melting points compared to their free base forms.

The term "pharmaceutically acceptable base addition salts" means any non-toxic organic or inorganic base addition salts of the compounds of general formulas I and Ia or any of their intermediates. [Bas Bas] Bases which form suitable salts include, for example, alkali metal or alkaline earth metal hydroxides such as sodium, potassium, calcium , Magnesium or barium hydroxides: ammonia and aliphatic, alicyclic or aromatic organic amines, such as methylamine, dimethylamine, trimethylamine and picoline.

Some of the compounds of general formulas I and Ia occur as optical isomers. Whenever one of the compounds of general formulas I or Ia is named, reference is made either to a specific optical isomer or to a mixture of optical isomers (unless expressly excluded). The specific optical isomers can be separated and recovered by conventional techniques such as chromatography on chiral stationary phases or cleavage via chiral salt formation followed by separation by selective crystallization. Another possibility for producing the relevant isomer as the end product is the use of a specific optical isomer as starting material.

The beta-ketophosphonates of general formula I are in a tautomeric equilibrium state in which the carbonyl group participates in a keto-enol equilibrium reaction. When the compound is in its enol form, R ₁ and R: are not both attached to the indicated carbon atom. Consequently, only these compounds show the tautomerism in which either R ₁ or R _{2 represents} a hydrogen atom. This tautomerism is explained below:

Il

HO-P-OR

HCR ₂ \

C = O

Il

HO-P-OR

CR2

C-OH

B Formula I, Keto

R ₁ = - H

B Formula I, Enol

The enol automer is due to the double formation as a geometric isomer. This enol is present as cis and trans isomer: _{0 0}

Il

P (OR) (OH) (OR) (OH) P

C-OH

C-OH

CIS

TRANS

In the case of the compounds of the general formula I in which A is a trimethylene group, another equilibrium reaction takes place, in which the compounds undergo an intramolecular condensation to form a cyclic imine. An example of such a ketone imine equilibrium reaction is explained below:

Il HO-P-OR

Ri -C-ro

C = O

(HCH) ₃

C-COOZ NH ₂

R ₂ -CP - OH

OR

K ^^^ ~ CO ₂ H

In the compounds of general formula Ia, where M is an oxime derivative, the oxime substituent may be either in syn or anti-configuration.

When referring to compounds of general formulas I or Ia, the keto forms of these compounds are the enol forms of these compounds in the cis or trans configuration. the cyclic imine form of these compounds, the syn or anti-oxime derivative and the like. The claims also include these compounds. j

ι examples of the compounds of general formula I include:

a) R-4-oxo-5-phosphononorvaline i

b) R-2-amino-6-oxo-7-phosphonoheptanoic acid j

c) 4- (2-Oxo-3-phosphonopropyl) -2-piperazine-carboxylic acid

d) R-4- (2-oxo-3-phosphonopropyl) -5-oxo-3-oxazolidine

e) 4-oxo-5-phosphono-2-methylnorvaline

f) 4-oxo-5-phosphono-3-methylnorvaline.

g) R 1 -oxo-S-phosphono-S-methylnorvaline, yy h) 4-oxo-5-phosphono-3,5-dimethylnorvaline * i) 5- (hydroxymethoxyphosphinyl) -4-oxonorvaline 'j) 4-oxo 5-phosphono-2- (2-phenylethyl) norvaline , \ V) 4-oxo-5-phosphono-5- (2-phenylethyl) norvaline \ j I) R 1 -oxo-S-phosphononorvaline ethyl ester ; " m) R-2-amino-6-oxo-7-phosphonoheptanoic acid ethyl ester; n) 4-oxo-5-phosphono-2-methylnorvaline ethyl ester jS |

0) R 1 -oxo-S-phosphono-S-methylnorvalin benzyl ester

p) 4-Oxo-5-phosphono-2- (4'-trifluoromethylphenylethyl) -norvaline

q) 4- (2-Oxo-3'-phosphonopropyl) -2-piperazinecarboxylic acid ethyl ester

r) 4- (hydroxyimino) -5-phosphononorvaline

s) 4- (methoxyimino) -5-phosphononorvaline

t) 4- (ßenzylhydrazino) -5-phosphononorvaline

u) 4 - [(phenylmethoxy )iminol-5-phosphononorvaline

v) R-4-oxo-5-phosphonorvaline methyl ester

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

As with any class of medicinal drugs, certain compounds of general formulas I and II are preferred for their better effect, bioavailability and the like. Preferably, A is a methylene group and B is either a piperazine derivative or an amino acid, which may optionally be substituted in the α-position.

Preferred examples include:

a) R-4-oxo-5-phosphononorvaline

b) R-4-oxo-5-phosphononorvaline ethyl ester

c) R-4-oxo-5-phosphono-5-methylnorvaline

d) R 1 -oxo-S-phosphono-6-methylnorvaline ethyl ester

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

f) 4- (2-Oxo-3-phosphonopropyl O-2-piperazinecarboxylic acid ethyl ester

g) R-4-oxo-5-phosphono-2-methylnorvaline

h) fM-oxo-S-phosphono-methylnorvaline ethyl ester

1) 4- (hydroxyimino) -5-phosphononorvaline j) 4- (methoxyimino) -5-phosphononorvaline

k) 4- [(phenylmethoxv) -imino) -5-phosphononorvaline

I) R 1 -oxo-S-phosphononorvalin methyl ester

m) 4- [(2'-phenylethoxy) -iminol-5-phosphononorvaline.

The compounds of the general formula I can be prepared by customary processes. The compounds wherein B is an amino acid or a derivative of an amino acid (ie H ₂ N-CH-COOZ) and R is a Is hydrogen, can be prepared by the methods of Reaction Scheme I: REACTION SCHEME I

COOH

Step A A

Introduction of the protective group

E ₂ NC COOH

Forir.el II

COOH

PgNH-C-COOH

Formula III

COOH

Step B

PgNE-C-COOH

Formula III

Introduction of the protective group

paraformaldehyde

COOH

- "" - co

I o

Formula IV

PGN

COOH

Step C

Formula IV Preparation of the Acid Chloride

SOCl ₂

PGN

COCI

I A

CO

Formula V

-11- 295 6c

REACTIONS I CONTINUED

COCI

Step D ^A

PGN

+ M ⁺ CRiR ₂ -PO- (OY) ₂ - coupling CO►

YO-PO-OY I

RiCR ₂

CO

I A

Formula VI

Formula V

Step ε

YO-PO-OY

RlCR ₂ CO

PGN

 co

, 0

Formula VII PgN

CO

I ι

Formula VII

Cleavage of the protecting groups HO-PO-OH

RlCR ₂

CO

COOH

Formula I, R and Z = H

HO-PO-OH

Step F, optional

R ₁ CR ₂

Esterification HO-PO-OH

RlCR ₂

I co

H ₂ N

COOHH ₂ N

COOZ

In step A of Reaction Scheme I, an amino acid of general formula M in which A has the meanings of general formula I is provided on the free amine of the amino acid with a benzylcarbamate protecting group (Pg). This produces the protected amino acid of general formula II. In step B of the reaction scheme, the protected amino acid of general formula III is reacted with paraformaldehyde. This further protects the amino acid by forming an oxazolone derivative of general formula IV. In step C, the oxazolone is treated with thionyl chloride, which introduces an acid chloride group into the molecule. In this case, the acid chloride of the general formula V is formed. In step D, the acid chloride of the general formula V is subjected to a coupling reaction, optionally in the presence of a transition metal catalyst, with the phosphonate of the general formula VI, in which R ₁ and R ₂ are as defined in general formula I. and M is a suitable cation and each Y is independently a Ci_4-alkyl radical. This coupling reaction produces the protected beta-ketophosphonate of general formula VII wherein A, Ri, R ₂ and Y have the above meanings. In step E there is a deprotection reaction which serves to remove all protecting groups from the beta-ketophosphonate. This removes the benzyl carbamate and oxazolone protecting groups and the alkyl radicals identified as Y. In the optional step F, an ester group can be introduced on the phosphonic acid group of the end product of the general formula I. The appropriate starting material in step A of Reaction Scheme I is an amino acid in which A represents the same methylene or trimethylene group desired in the final product of general formula I. The introduction of the protecting group in step A can be carried out by conventional methods. Typically, the amino acid of the general formula limit 1 to 1.5 equivalents of benzyl chloroformate is added at about room temperature in about 0.05 to 0.2 M sodium hydroxide solution. The starting compounds are usually stirred for about 1 to 3 days. The protected amino acid of general formula III may be recovered from the mixture by known methods such as extraction with an organic solvent or by concentration.

The introduction of the protecting group after step B, wherein the protecting group is attached to the protected amino acid of the general formula III, can be carried out by conventional methods. The amino acid of the general formula III is usually mixed with about 2 to 3 equivalents of paraformaldehyde in the presence of an acid catalyst such as p-toluenesulfonic acid. The amount of catalyst in the reaction zone is about 1 to 3 wt% relative to the amino acid used. The starting compounds are usually stirred in an organic solvent such as benzene for about 1 to 4 hours at 40 ° C to reflux temperature.

The oxazolone of general formula IV may be obtained by conventional methods such as concentration or extraction from the reaction mixture. Optionally, the protected amino acid of general formula IV may be purified by selective extraction with acids, bases and organic solvents.

The next step in the reaction is the preparation of the acid chloride of general formula V shown in step C. This acid chloride can be prepared by conventional methods. Usually, the oxazolone of general formula IV is mixed with about 3 to 4 equivalents of thionyl chloride. The reaction can be carried out without a solvent or in a solvent such as chloroform. The reaction proceeds in 10 to 20 minutes at reflux. After the reaction, the acid chloride of the general formula V can be obtained from the reaction mixture by concentration under reduced pressure.

In step D of the reaction, the acid chloride of the general formula V is subjected to a coupling reaction with a phosphonate of the general formula VI. Suitable phosphonates have the same substituents as R 1 and R ₂ , such as the desired product of the general formula I. The alkyl radicals in the phosphonate designated Y do not remain in the end product. The cation denoted M is usually Li or Zn. The phosphonates of the general formula VI and processes for their preparation are known.

This coupling reaction can be carried out by conventional methods. Usually, equimolar amounts of the phosphonate are added with a suitable base, such as n-butyllithium, to form a cation of the phosphonate. This is then added with about a 10 mol% excess of the acid chloride in the presence of a transition metal catalyst such as copper iodide. The catalyst is usually present in the reaction zone in an equivalent amount. The reactants are usually contacted for 2 to 16 hours at a temperature of about -78 ° C to room temperature. The resulting protected beta-ketophosphonate of general formula VII can be obtained from the reaction zone either by concentration or extraction by conventional methods. Optionally, the beta-ketophosphonate may be purified by known chromatographic techniques, such as flash chromatography. The deprotection shown in step E can be carried out by conventional methods. This deprotection serves to remove the benzyl carbamate (Pg), the oxazolone moiety and the alkyl moieties denoted by Y. This produces some of the beta-ketophosphonates of general formula I. Typically, the protected beta-ketophosphonate of general formula VII is added with a stoichiometric amount of trimethylsilyl iodide (TMSI, about 4 equivalents) in a solvent such as methylene dichloride. The deprotection is usually carried out at room temperature for about 3 to 5 hours. The amount of trimethylsilyl iodide used is important. If the stoichiometric amounts of TSMI are not adhered to, a compound is obtained in which not all of the protective groups are split off.

If Z is to mean a radical other than a hydrogen atom, it is necessary to carry out the esterification according to step F optionally. This esterification can be carried out by conventional methods. Suitable methods of esterification include boiling the beta-ketophosphonate with an alcohol at reflux in the presence of an acid. This alcohol should correspond in structure to the desired ester radical. Other common methods can also be used. The compounds of the general formula I in which R is a hydrogen atom and B is an oxazolone;

means can also be prepared by conventional methods. These compounds can be prepared by the method of Reaction Scheme I, except for a small change. The only change is that at step E, the protection group's abase, the amount of TSMI used is changed. With about 3 equivalents of TMSI, one can produce a β-ketophosphanate of general formula I in which the benzyl carbamate protecting group and the alkyl moiety denoted Y have been removed, but retaining the oxazolone moiety in the molecule. The compounds of the general formula I in which B represents a piperazine group may also be prepared by conventional methods. For example, they may be prepared by the process of the following Reaction Scheme III:

Step A

Reaction scheme III

OY OE

Br-A-C = C-PO (OY) N -alkylation

+ ι

COOY ^R l ^

Formula VIII

Schr ^ -t 3

ΥΟ-Ρ0-ΟΞ

COOY

Formula IX

Cleavage of the protecting groups

hydrolysis

Formula X

HO-PO-OR

IR ₁ CH

COOY

COOH

Formula X

formula

I, TO

Step C, optional

HO-PO-OR R ₁ CH

esterification

COOH

HO-PO-OR

RlCH

COOZ

In the first step of Reaction Scheme III, an N-alkylation is effected between a piperazine derivative of general formula VIII in which Y represents a C 1-8 -alkyl radical and a halo-enolphosphone derivative of general formula IX in which R ₁ and A are those of general formula I have meanings described, E is a C ^ -alkyl radical or a CF ₃ group and each Y is independently a Ci - «- alkyl radical. This N-alkylation produces the enol phosphonate derivative of the general formula X in which Y, E, R ₁ and A have the above meanings. The enol phosphonate derivative of general formula X is then subjected to hydrolysis which serves to remove the protecting groups designated by Y and convert the enol group to a carbonyl group. This hydrolysis can also remove the protecting group designated by E depending on the concentration of the acid used. When R represents a hydrogen atom in the desired compound of the general formula I, this entire hydrolysis is carried out. If Z is to represent an ester in the desired product of general formula I, then the optional esterification of step C is carried out.

One of the starting compounds is a piperazine of the general formula VIII in which Y is a C 1-4 -alkyl radical. This alkyl radical does not remain in the final product and its type is therefore of no importance. The other starting compound is a halo-enol phosphonate of the general formula IX in which each Y independently of one another is a Ci-4-alkyl radical, E is a C ^ -alkyl radical or a CF ₃ group and R ₁ and A are as defined in the have general formula I. The residues designated R ₁ and A remain in the final product; Therefore, the halo-enol phosphonate used should have the same radicals at these sites, as they are desired in the final product of general formula I. The alkyl radicals denoted Y do not remain in the final product and therefore their nature is irrelevant. The radicals designated E may remain in the final product, depending on whether partial or complete hydrolysis is carried out. If E is to mean either a CF ₃ group or a C 1-4 alkyl, then the halo enol phosphonate used should contain this residue in the E position. The piperazines of general formula VIII and the halo-enol phosphonates of general formula IX and the process for their preparation are known.

The N-alkylation can be carried out by conventional methods. Usually, approximately equimolar amounts of piperazine derivative and halo-enol phosphonate are combined for 0.5 to 18 hours in a polar solvent such as water. The N-alkylation is usually carried out at room temperature in the presence of a base such as sodium hydroxide. The base is usually present in an amount of about 1 to 3 equivalents. The enol piperazine derivative of the general formula X thus prepared can be obtained from the reaction zone by conventional methods such as extraction or concentration. Optionally, the enol piperazine derivative of general formula X may be purified by conventional chromatographic techniques, such as ion exchange chromatography.

The enol-piperazine of general formula X is then subjected to hydrolytic cleavage of the protecting groups which serves to remove the protecting groups designated Y and can remove the protecting group designated by E depending on the reaction conditions. In order to remove both the protecting groups indicated by Y and E, the enol-piperazine derivative of the general formula X is added with an about 6 molar solution of a mineral acid such as hydrochloric acid. This hydrolysis is carried out for about 1 to 18 hours at about 60 ^e C to the reflux temperature. Another way to remove the protecting groups is to add TMSI in the manner described above in Reaction Scheme !. The partial hydrolysis in which E is not removed from the molecule is carried out by adding the enol piperazine with a 1 M molar solution such as a mineral acid such as hydrochloric acid at 6O ⁰ C to reflux temperature for 1 to 8 hours. Regardless of the mode of deprotection, the desired compound of general formula I may be obtained from the reaction mixture either by concentration or extraction. It can then be purified by chromatography methods, such as ion exchange chromatography or recrystallization from a solvent system, such as water and alcohol.

When Z is an ester group, the esterification must be carried out to bring the desired residue to the Z position. This esterification can be carried out in the same manner as in the esterification step Fin reaction scheme I. The esterified product can also be obtained and purified in the same way.

15-295 63ί

The compounds of general formula I in which B represents an α-substituted amino acid (ie H ₂ N-CX-CC) OZ) may be prepared by the method set out below in Reaction Scheme IV;

Step A

H 3 Co

Reaction scheme IV

OY OE alkylation 1 I

CH ₃

Formula XI

Br-A-C = C-PO (OY) BuLi

Formula IX

H ₃ CO

CH ₃

YO-PO-OE

Step B

YO-PO-OE

R ₁ C

CH ₃ O

Cleavage of the protecting groups

hydrolysis

Step C, optional

HO-PO-OR

I RLCH

I co

esterification

H ₂ N

A X COOH

KO-PO-OR RLCH

CO

A X

COOH H ₂ N

Formula I, Z = H

HO-PO-OR

I RiCH

CO I

H ₂ N

COOZ

In step A of Reaction Scheme IV is an alkylation between a 3,6-dimethoxy-ptperazinderivat the general formula Xl in which X has the meanings given in formula I and a halo-enol phosphonate of the above-described general formula IX carried out in which R ₁ and A are as defined in general formula I, each Y is independently a C 1-4 alkyl radical and E is a C 1-4 alkyl group or a CF ₃ group. This alkylation produces the piperazine phosphonate derivative of the general formula XII in which X, A, R ₁ , E and Y have the above meanings. In step B, the piperazine phosphonate derivative of general formula XII is subjected to hydrolysis which eliminates the piperazine ring, removes the alkyl radicals indicated by Y, and can remove the radical indicated by E, depending on the manner in which the hydrolysis is carried out. As a result of this hydrolysis, a beta-ketophosphonate of the general formula I in which B is an α-substituted amino acid (ie H ₂ N-CX-COOZ) is obtained. If Z is to mean an ester radical, one must carry out the esterification of step C.

The 3,6-dimethoxypiperazine used as the starting compound should have the same radical in the X position, the desired end product of the general formula I is desired. The halo-enol phosphonate of the general formula IX used should have the same radical in the A and R positions as desired in the end product of the general formula I. The alkyl radicals indicated by Y do not remain in the end product and their particular similarity is not critical. If E represents a CF ₃ group or a C 1-8 -alkyl radical, then the halo-enol phosphonate used should contain this radical in the Ε-position. The halo-enol phosphonates of general formula IX and the 3,6-dimethoxypiperazines of general formula XII and the process for their preparation are known.

The alkylation described in step A can be carried out by conventional methods. Usually, the 3,6-dimethoxy-piperazine is first treated with an approximately equivalent amount of a base, such as n-butyllithium. They usually treat for about 0.5 to 8 hours at -78 ° C to 0 ° C in a solvent such as tetrahydrofuran brought together. The reaction zone is then heated to a temperature of about 30 ° C and an approximately equimolar amount d = s of halogen. The reaction partners are then stirred for about 1 to 18 hours, the reaction is then stopped with water and the piperazine phosphonate derivative of general formula XII is obtained from the reaction zone either by extraction or concentration. of the general formula XII are purified by customary chromatographic methods, such as flash chromatography or by recrystallization from a solvent system, such as ethyl acetate / hexane in the usual way.

The next step in the process sequence is the hydrolysis of the piperazine phosphonate derivative of general formula XI I, which is illustrated in step B. This hydrolysis can be carried out by conventional methods. When complete hydrolysis is desired (i.e., R is a hydrogen atom), the piperazine phosphonate is added with a 0.25 to 6 molar solution of a mineral acid such as hydrochloric acid. The deprotection is usually carried out at about 20 to 100 ° C for 1 to 18 hours.

If partial hydrolysis is desired (the residue designated by E is to be retained in the final product), the hydrolysis is carried out for 1 to 2 hours with a 0.2 to 1 molar solution of hydrochloric acid. The obtained beta-ketophosphonate of general formula I, which was prepared by one of the hydrolysis processes, can be obtained from the reaction mixture by concentration or extraction. The beta-ketophosphonate of general formula I can then be purified according to Schnr £ of Reaction Scheme III.

As in the other reaction schemes, the esterification must be carried out according to step C if Z is to represent an ester group.

The compounds of general formula I in which R has a meaning other than a hydrogen atom and B an amino acid or a derivative of an amino acid (ie H ₂ N-CH-COOZ) can also be prepared by the methods of Reaction Scheme IV. The only change to the reaction sequence is in the starting compounds used. The 3,6-dimethoxypiperazine of the general formula XII used should have a hydrogen atom in the X position. Since R represents a group other than a hydrogen atom, the deprotection after step B should be a partial hydrolysis.

The compounds of general formula I in which B represents an α-substituted amino acid can also be prepared by an alkylation between a halo-enol phosphonate of general formula IX above and an imine of general formula XIII shown below where X is as defined in general Formula I has τ. a phenyl ring and Alk means a C ₁ ^ -alkyl radical:

Ph-CH = N-CH formula XIII

COOAIk

This alkylation can be carried out in the same way as the alkylation of step A of Reaction Scheme IV. This alkylation gives an imine phosphonate of general formula XIV shown below, in which -, and A have the meanings as in general formula I and Ph and Alk are as defined above:

-17- 2951 HO-PO-OR

Il

Formula XIV

-CH = IT ^ (

Ph-CH = IT COOAk A beta-ketophosphonate of general formula I can then be prepared by subjecting the imine phosphonate of general formula XIV to acid hydrolysis in the same manner as the deprotection of step B in Reaction Scheme IV In other reaction schemes, esterification must be carried out when Z is an ester group. This esterification can be carried out on the same catfish as the esterification of step F in Reaction Scheme I.

The compounds of the formula Ia can likewise be prepared by customary processes. A process for preparing these compounds is shown below in Reaction Scheme V:

Reaction scheme V

O Il P-OR CONDENSATION RXN C = O XV 0 Il HO CR ₁ R ₂ H ₂ M HO-P-OR I formula CRiR A I B A I 13

C = M

Formula I Formula Ia

In Reaction Scheme V, one of the beta-ketophosphonates of general formula I is subjected to a condensation reaction with either an oxime or a hydrazine derivative of general formula XV in which M has the meanings of general formula Ia. One of the beta-hydrazones or beta-oximes of the general formula I a is obtained. <

The suitable reaction partners for the condensation reaction are beta-ketophosphonates in which A, B, R ₁ , R ₂ and R denote the same radicals desired in the final products and suitably substituted oximes or hydrazines in which M has the same meaning has, which is desired in the final product. The condensation reaction can be carried out by conventional methods. Usually, approximately equimolar amounts of the compound of general formula XV and the beta-ketophosphonate of general formula I are combined in a buffered solution. Sodium acetate is a suitable buffer. The reaction usually proceeds at 25 to 80 ° C for 1 to 24 hours. The desired compound of general formula Ia can then be obtained from the reaction mixture and purified by either gel filtration or ion exchange chromatography.

The compounds of the general formula I and Ia are antagonists against irritating amino acids. They counteract the effects that the irritating amino acids have on the NMDA receptor complex. They connect to the site on the NMDA receptor complex to which glutamate binds. They prove useful in the treatment of a number of disease states.

The compounds exhibit anticonvulsant properties and are useful in the treatment of epilepsy. They are also useful in the treatment of severe epileptic seizures, mild epileptic seizures, psychomotor seizures, and autoimmune seizures. One method of demonstrating its antiepileptic properties is through the ability of the compounds to inhibit sonic-induced convulsions in DBA / 2 mice. This test can be done in the following way.

Typically, a group of 6 to 8 male DBA / 2J sonic mice is administered from about 0.01 mg to about 100pg of the test compound. The test compound is administered intracerebrally into the lateral cerebral chamber. A second group of mice are given an equal amount of saline by the same route. 5 minutes later, the mice are individually placed in glass jars and exposed for 30 seconds to a sound stimulus of 110 decibels. Each mouse is observed during sonication for signs of seizure activity. The comparison group shows a statistically higher incidence of seizures than the group receiving the test compound.

Another method of demonstrating the properties of these compounds against epilepsy is performed because of their ability to inhibit the seizures caused by the administration of quinolinic acid. This test can be carried out in the following way.

To a group of 10 mice, 0.01 to 100 pg of test compound is administered into the cerebral cavity in a volume of 5 μL saline. A second control group from the same number of mice is given an equal volume of saline as a control. Approximately S minutes later, both groups are given 7.7 μg of quinolinic acid in a volume of 5μΙ saline in the cerebral cavity. The animals are observed 15 minutes later for signs of convulsive seizures. The comparison group has a statistically higher number of spasmodic seizures than the test group.

The compounds of general formulas I and Ia are found to be useful in preventing or minimizing the damage suffered by nerve tissues in the CNS due to the action of ischemic, hypoxic or hypoglycemic conditions. Representative examples of such ischemic, hypoxic or hypoglycemic conditions include strokes or disorders of cerebral vessels, carbon monoxide poisoning, hyperinsulinemia, cardiac arrest, drowning, asphyxiation and harm from hypoxia in neonates. The compounds should be administered to the patient within 24 hours of the onset of the hypoxic, ischemic or hypoglycemic condition, so that the compounds are effectively minimized to the damage to the CNS the patient suffers. The compounds also prove useful in the treatment of nerve degeneration disorders such as Huntington's disease, Alzheimer's disease, senile dementia, Type I glutaric acid acidemia, multiple infarct dementia, and nerve damage with uncontrolled convulsions. Administration of these compounds to a patient suffering from such a condition serves to protect the patient from suffering further degeneration of nerves, or reduces the rate at which degeneration of nerves occurs. The compounds, however, do not cause damage to the CNS caused by either disease or lack of oxygen or sugar. The term "treatment of" refers to the compound's ability to prevent further damage or reduce the rate at which further damage occurs.

The compounds exhibit anxiolytic activity and are therefore useful in the treatment of anxiety. These anxiolytic properties can be demonstrated by their ability. To inhibit emergency cries in very young rats. This test is based on the phenomenon that a very young rat is removed from their litter. Ultrasonic screams sent out. It has been found that anxiolytics inhibit these cries. The test procedures were described by C.R. Gardner, Distress vocalization in rat pups: a simple screening method for anxiolytic drugs. J. Pharmacol. Methods, 14: (1985), 181-187 and Insel et al., Rat pup ultrasonic isolation calls: Possible mediation by the benzodiapine receptor complex, Pharmacol. Biochem. Behav., 24: (1986), 1263-1267. The compounds also have an analgesic effect and are useful in controlling pain.

The compounds of general formulas I and Ia are muscle relaxants and therefore prove useful in the repair of muscle spasms. A method for demonstrating their usefulness as muscle relaxants is after the tail test after exercise. This assay method is based on the observation that the administration of morphine to mice causes a delayed contraction of their muscle to the coccyx and coccyx. This will make her cock in a wink! raised by about 90 °. A muscle-relaxing substance prevents the contraction of this muscle and inhibits the lifting of the tail. These assays have been described by K.O. Ellis and co-workers, Neuropharmacology, Vol. 13, (1974), pages 211-214.

In order to exhibit any of these therapeutic properties, the compounds must be administered in an amount sufficient to inhibit the effect that the irritating amino acids have on the NMDA receptor complex. The dose range at which these compounds exhibit this antagonistic effect can vary greatly and depends on the particular disease being treated, the severity of the patient's disease, the particular compound administered, the route of administration, or the presence of other underlying disease states Patients and the like. Typically, the compounds will exhibit their therapeutic effect at a dose range of about 1 mg / kg / day to about 500 mg / kg / day for any of the aforementioned diseases or conditions. Repeated daily administration may be required and depends on the above-mentioned conditions.

The compounds of the invention can be administered in a variety of ways. They are effective when given orally. The compounds may also be administered parenterally (i.e., subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally).

Pharmaceutical compositions can be prepared by conventional methods. Usually, an antagonistically effective amount of the compound is mixed with a pharmaceutically acceptable carrier. For oral administration, the compounds can be made into solid or liquid preparations such as capsules, pills, tablets, troches, melts, powders, suspensions or emulsions. Solid unit dosage forms may be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and corn starch, or they may be long-acting preparations. In another embodiment, the compounds of general formulas I and Ia can be mixed with conventional tablet bases such as lactose, sucrose and corn starch together with binders such as acacia, corn starch or gelatin, blasting agents such as potato starch or alginic acid and a lubricant such as stearic acid or magnesium stearate be tabletted. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or nonaqueous pharmaceutically acceptable solvent which may also contain conventional suspending agents, sweetening, flavoring and preservative agents. For parenteral administration, the compounds may be in a physiologically acceptable pharmaceutical carrier. be dissolved and administered either as a solution or suspension. Examples of suitable pharmaceutical carriers are water, saline, glucose solutions, fructose solutions, ethanol or oils of animal, vegetable or synthetic origin. The pharmaceutical carrier may also contain conventional preservatives, buffers and the like. When administered intrathecally, the compounds may be dissolved in common cerebrospinal fluid.

(a) The term patient refers to warm-blooded animals, such as guinea pigs. Mice, rats, cats, rabbits, dogs, monkeys, chimpanzees and humans.

(b) The term treating refers to the ability of the compounds to either prevent, ameliorate or slow the progression of the patient's disease.

(c) The term degeneration of nerves refers to the progressive death and disappearance of a population of neurons that characteristically occurs at a disease stage and results in brain damage.

The compounds may also be mixed with any inert carrier and used in laboratory experiments to determine the concentration of the compounds in serum, urine and the like of the patient in the usual way. Disease with degeneration of nerves is usually associated with a loss of NMOA receptors. Therefore, the compounds of general formulas I and la prove useful in diagnostic procedures to aid physicians in the diagnosis of nerve degeneration disorders. The compounds of the invention may be labeled with isotope-containing compounds by conventional methods and used as scintigraphic agents. They may then be administered to a patient to determine if the patient has a reduced number of NMDA receptors and to determine the rate at which this loss occurs

 The following examples illustrate the invention.

example 1

In this example, the preparation of the protected amino acid of general formula III is carried out by the method of step A of Reaction Scheme I and the methods of V.J. Lee & K.L. Rinehart J. Am. Chem. Soc. 100 (1978), 4237

A) N-Benzyloxycarbonyl-D-aspartic acid

25 g (0.188 mol) of D-aspartic acid and 34.3 ml (0.222 mol) of benzyl chloroformate were added to 22.9 g (0.564 mol) of sodium hydroxide in 600 ml of water. The resulting mixture was stirred at room temperature for 3 days. The mixture was then acidified to pH 1 with 6 M HCl and extracted with 3x 250 mL of ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated. 50.2 g of a clear oil were obtained. ¹ H NMR (90MHz CDCl ₃ ): 53.05 (2, bm), 4.65 (1, bm), 5.25 (2, s), 6.2 (1, bs), 7.4 (5 , s>, 10 (1, bs).

B) N-Benzyloxycarboxyl-3-methyl-D, L-aspartic acid

Following a procedure similar to the procedure described above, 10.0 g (67 mmol) of 3-methyl-D, L-aspartic acid and 12 ml (10OmMoI) of benzyl chloroformate in 16.7 g (208 mmol) of 50% sodium hydroxide solution were reacted in 125 ml of water , This gave 19.0 g of N-benzyloxycarbonyl-S-methyl-DL-aspartic acid as a low-melting solid. ¹ H NMR (90 MHz, CDCl ₃ / d ₆ DMSO): δ 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 (I.

C) N-Benzoylcarbonyl-D-2-aminoadipic acid

Following a procedure similar to that described above, 4.0 g (24.8 mmol) of D-2-aminoadipic acid, 4.5 ml (37.2 mmol) of benzyl chloroformate and 6.0 g (74.4 mmol) of 50% sodium hydroxide solution were reacted. 7, N-benzoylcarbonyl-D-2-aminoadipic acid was obtained as a low-melting solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 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 2

In this example, the preparation of the oxazolone derivatives of general formula IV is described according to the procedures of step B of Reaction Scheme I and the methods of M. ITOH Chem. Pharm. Bull. 17, (1969), 1679.

A) R-S-oxo-4-acetic acid-3-oxazolidinecarboxylic acid-3-4phenylmethyl (-ester

16 g of paraformaldehyde and 1 g of p-toluenesulfonic acid in 1 liter of benzene were admixed with 52 g (195 mmol) of N-benzyloxycarbonyl-D-aspartic acid. The solubilizing mixture was heated to boiling and refluxed for four and a half hours with azetropic removal of water (with a Dean & Strong trap). The mixture was then cooled and poured into 500 ml of 1M HCl. The resulting mixture was extracted 3x with 25 ml of ethyl acetate and the combined extracts were washed with 2% SO 2 Cl 5% sodium bicarbonate. The bicarbonate extracts were combined, acidified with 6M HCl and extracted with 3x 250ml ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulfate and evaporated. 25.9 g of a low-melting white solid were obtained. ¹ H HMR (90MHz, CDCl ₃ ) 6 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 acid 3-oxazoline dinarboxylic acid 3- (phenylmethyl) ester

Following a procedure similar to that described above, 3 g of paraformaldehyde and 0.25 g of p-toluenesulfonic acid in 250 ml of benzene were added with 10 g (37 mmol) of N-benzyloxyearbonyl-L-aspartic acid. 10.1 g of a low-melting solid were obtained

Ή NMR (90MHz, CDCl ₃ ) δ 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-S-Oxo-t-methyl-acetic acid-S-oxazolidinecarboxylic acid S-phenylmethyl ester

Following a procedure similar to that described above, 6g of paraformaldehyde and 0.5g of p-toluenesulfonic acid in 500ml of benzene were added to 18.8g (67mmol) of N-benzyloxycarbonyl-3-methyl-D, L-aspartic acid. 13.5 g of a low-melting solid were obtained

¹ H NMR (90MHz, CDCl ₃ ) δ 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 acid 3-oxazolidinecarboxylic acid 3- (phenylmethyl) ester

Following a procedure similar to that described above, 5 g of paraformaldehyde and 0.5 g of p-toluenesulfonic acid in benzene were treated with 7.5 g (24.8 mmol) of N-benzyloxycarbonyl-D-2-aminoadipic acid to give 5.83 g of a clear oil , _:

¹ H NMR (90 MHz, CDCl ₃ ) δ 1.7 (2, m), 1.952.35 (2, m), 4.3 (1, m), 5.2 (2, s), 5.35 ( 2, dd), 7.4 (5, s). £

Example 3

In this example, the preparation of the acid chlorides of general formula V according to the procedures of step C of Reaction Scheme I and the method of B.H. Lee & M.J. Miller Tetrahedron Lett. 25 (1984) 927.

A) R-S-oxo-macetyl chloride J-S-oxazolidinecarboxylic acid S-phenylmethyl-O-ester

9.8 g (35.1 mmol) of R-50xo-4-acetic acid 3-oxazolidirrarbonsäure 3- (phenyl-ethyl) ester were added with 20 ml of thionyl chloride and refluxed for 10 minutes. The solution was cooled and treated with a dry stream of N ₂ blown. The residue was evaporated under reduced pressure to give 10.4 g of a pale yellow oil. ¹ H NMR (90MHz, CDCI ₃₎ δ3,5 (2, d), 4.2 α (1, t), 5.1 (2, s) (, 5.25 (1, dd), 7.2 5, s).

B) S-S-Oxo-A-iacetylchloride-S-oxazolidinecarboxylic acid S-phenylmethyl ester

Following a procedure similar to that described above, 10.1 g (36 mmol) of S-5-oxo-4-acetic acid-3-oxazolidinecarboxylic acid 3- (phenylmethyl) ester were added with 18 ml of thionyl chloride. 10.8 g of a yellow oil were obtained.

C) R.S-S-Oxo ^ -la-methyl-acetylchloro-S-oxazolidinecarboxylic acid S-iphenylmethyl-ester

Following a procedure similar to the procedure described above, R, S-5-oxo-4- (α-methyl-acetyl chloride) -3-oxazolidinecarboxylic acid 3- (phenylmethyl) ester was added with 15 ml of thionyl chloride. This gave 7.4 g of a straw-colored oil.

D) R-S-Oxo ^^ butyrylchloridl-S-oxazolidincarbonsäure S-fphenylmethyO ester

According to a procedure similar to that described above, 5.8 g (18.9 mmol) of R-5-oxo-4-butyric acid 3-oxazolidinecarboxylic acid 3- (phenylmethyl) ester were added with 8 ml of thionyl chloride. 6.1 g of a colorless oil were obtained.

Example 4

In this example, the preparation of the protected beta-ketophosphonate of general formula VII according to the coupling procedures of step D of Scheme I and the method of J.M. Vaslet, N. Collignon & P. Savignac Can J. Chem. 57 (1979), 3216.

A) R ^ -CS-iDiethoxyphosphinyD ^ -oxopropyll-S-oxo-S-oxazolidinecarboxylic acid a-tphenylmethyD ester

25.1 g (165 mmol) of diethyl methylphosphonate was dissolved in 25 mM THF under N ₂ and cooled to -65 ° C. The solution was then added dropwise to 61 ml (165 mmol) of 2,7 M "BuLi in hexane for 15 minutes and then for a further 10 minutes stirred at -65 °. 34.7 g (182 mmol) of copper (I) iodide were added and the resulting mixture was warmed to -30 ° C and then stirred for an additional hour. The mixture was added dropwise with 54.2 g (182 mmol) of R-5-oxo-4- (acetyl chloride) -3-oxazolidinecarboxylic acid 3- (phenylmethyl) ester in 250 ml of ether to maintain a temperature of -30 ° C was stirred and then for an additional 18 hours. The reaction mixture was then poured into 750 ml of water. The aqueous mixture was then extracted with 3x 250 ml of dichloromethane. The combined organic extracts were filtered through a celite pad, dried over magnesium sulfate and evaporated to a pale yellow oil. Flash chromatography on silica gel with 100% ethyl acetate gave 31.9 g of a colorless oil.

¹ HNMR (300MHz, CDCl ₃ ) δ 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 / Z414 (MH ⁺ ).

B) S-4- [3 (Diethyloxyphosphiny O-2-oxopropyl] -5-oxo-3-oxazoline-3-bis (phenylmethyl) ester

According to a procedure similar to the procedure described above, from 10,8g (36,3 mmol) of S-5-oxo-4- (acetyl chloride, S-oxazolidinecarboxylic acid S-phenylmethyl) ester, 5.0 g (33 mmol) of methyl diethylphosphonate was obtained , 12.2 ml (33 mmol) 2.7 M "BuLi and 6.91 g (36.3 mmol) copper (I) iodide in 50 ml THF and 50 ml ether 5.0 g of a colorless oil.

¹ H NMR (300MHz, CDCl ₃ ) δ 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 (Cl), M / 2 (MH *).

C) 4- [3- (Diethoxyphosphinyl) -1-methyl-2-oxopropyl] -5-oxo-3-diethylphosphonate) -3-oxazolidinecarboxylic acid 3- (phenylmethyl) ester

Following a procedure similar to that described above, 7.4 g (23.7 mmol) 5-oxo-4- (amethylacetylchloride-S-oxazolidine carboxylic acid S-phenylmethyl ester, 3.28 g (21.5 mmol) diethyl methylphosphonate was obtained , 8.0 ml (21.5 mmol) of 2.7 M "BuLi and 4.5 g (23.7 mmol) of copper (l) iodide in 40 ml of THF and 40 ml ether 3,17g of a colorless oil. ¹ H NMR ( 90MHz, CDCI ₃ ) δ 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-oxazolidinecarboxylic acid 3- (phenylmethyl) ester

By a method similar to the procedure described above, from 5.9 g (22 mmol) of 5-oo-4- (α-methylacetyl chloride) S-oxazolidine carboxylic acid S-phenylmethyl ester, 3.32 g (20 mmol) of diethyl ethyl phosphonate and 4 , 19 g (22 mmol) of copper (I) iodide in 50 ml of THF and 50 ml of ether 2.1 g of a colorless oil.

¹ HNMR (300MHz, CDCl 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 ^ -p-iDiethoxyphosphinyO-S-methyl-Z-oxo-propyl-S-oxo-S-oxazolidinecarboxylic acid S-phenylmethyl ester

Following a procedure similar to that described above, from 4.79 g (16.1 mmol) of R-5-oxo-4'-acetyl chloride (S-oxazolidinecarboxylic acid S-phenylmethyl) ester (14.6 mmol) was obtained ) Ethyl diethylphosphonate, 5.4 mL (14.6 mmol) 2.7 M "BuLi and 31 g (16.1 mmol) copper (I) iodide in 30 mL THF and 40 mL ether 2.1 g of a clear oil. ¹ H NMR (90 MH ₂ , CDCl 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 (Cl) M / Z 428 (MH ⁺ ).

  "·

F) R-4-t5- (diethoxyphosphinyl) -4-oxopentyl] -5-oxo-3-oxo-din-1-ol) o-acid, 3- (phenyllidyl) ester Following a procedure similar to that described above, 6.1 g (18.7 mmol) of R-5-oxo-4- was obtained.

(butyryl chloride) -3-oxazolidinecarboxylic acid, 3-phenytmethyl ester, Z6g (17 mmol) methyl diethylphosphonate, 6.3 ml (17 mmol)

2.7Mn BuLi and 3.6g (18.7 mmol) copper iodide in 50 mL THF and 50 mL ether 2.51 g of a clear oil.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.32 (6, t), 1.59 (2, m), 1.80 <1, m). 1.99 (1.rn), 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 5 In this example, the preparation of the beta-ketophosphonate of the general formula I by the method of step E

of Reaction Scheme I

A) R ^ oxo-S-phosphononorvaline

20.0 g (48 mmol) of R ^ - (3-IDiethoxyphosphiny1) -2-oxopropyl] -5-oxo-3K} xazolidine-arbonic acid 3- (phenylmethyl) ester were dissolved in 750 ml of dichloromethane and 750 ml of acetonitrile in an atmosphere cooled from dry N ₂ to 0 ° C. 27.6 ml (20.1 mmol) of trimethyl-ethyl iodide were added dropwise for 10 minutes. The resulting solution was warmed to room temperature and stirred for 4 hours. Thereafter, 20 ml of water were added and the reaction mixture with a

Blow nitrogen stream through. The resulting residue was taken up in 250 ml of dichloromethane and 200 ml of water. The

aqueous phase was washed with 10x 20ml dichloromethane and then with 3x 300ml diethyl ether and then freeze-dried. A yellow powder was obtained which was taken up in the required minimum volume of water and eluted from a BIORAD AG50W-X8 resin in H * form with water. The ninhydrin positive fractions were freeze dried. This gave 6.2 g of a dirty white solid. The solid was in the required minimum amount

Water and eluted from a BIORAD AG50W-X4 resin in H ~ form with water. 4.8 g of a white one were obtained Solid with mp 154 C (with decomposition).

¹ H NMR (300MHz, D ₂ O) 3.05 (2, dd), 3.35 (2, m) 4.2 (1.m); ³¹ PNMR (121MH ₂ , D ₂ O) 12.4 (s); MS (FAB) M / 2 212 (MH ⁺ )

CsH ₁₀ NO ₆ P V2H _? 0: CHN

calculated: 27.28 5.04 6.45

Filled: 27.27 4.82 6.35

The weight loss by thermogravimetry corresponds to 4.8% by weight of water. B) S-4-oxo-5-phosphononorvaline By a method similar to the procedure described above, from 5.0 g (12 mmol) S-4-I3-

(Diethoxyphosphinyl) -D -oxopropyl-S-oxo-S-oxazolidincerboxylic acid S-phenylmethyl ester and 6.9 ml (48 mmol)

Trimethylsilyljodid in 250ml dichloromethane and 300ml acetonitrile 0.28g of a white solid, mp 155 ° C (under Decomposition).

¹ H NMR (300MH ₂ , D ₂ O) 3.05 (2, dd), 3 _r 35 (2, m), 4.2 <1, m); ⁵¹ PNMR (121 NM ₂ , D ₂ O) 12.4 MS (FAB) m / z212 (MH *).

C ₅ H ₁₀ NO ₆ PV ₂ H ₂ O: CHN

calculated: 27.28 5.04 6.45

Filled: 27.07 4.98 6.37.

The weight loss by thermogravimetry corresponds to 3.9 wt .-% water. C) 3,4-dimethyl-4-oxo-5-phosphononorvaline Following a procedure similar to that described above, 2.0 g (4.5 mmol) of 4- (3

(Diethoxyphosphinyl) -1,3-dimethyl-2-oxopropyl-S-oxo-3-oxazolidinecarboxylic acid 3- (phenylmethyl) ester and 2.6ml (18.1mmol)

Trimethylsilyl iodide in 100 ml dichloromethane and 100 ml acetonitrile 21.4 mg of a white solid of mp 72 "C (under Decomposition).

¹ H NMR 1.25 (6, m), 2.49 (1, m), 4.22 (1, m); ³¹ PNMR (121 MHz, D ₂ O) 16.1 (s); Ms (FAB) m / z 240 (MH *).

C ₇ H ₁₄ NO ₆ PVjH ₂ O: CHN

calculated: 35.15 5.90 5.86

found: 34.13 5.16 5.22-

The weight loss by thermogravimetry corresponds to 7.3% by weight of water. D) 3-methyl-4-oxo-5-phosphononorvaline A procedure similar to that described above gave 3.17 g (7.4 mmol) of 4- [3

(Diethoxyphosphinyl) -D-methyl-oxopropyll-O-oxo-S-oxazolidinecarboxylic acid S-phenylethyl ester and 4.3 ml (30.2 mmol)

Trimethylsilyl iodide in 200 ml of dichloromethane and 200 ml of acetonitrile 310 mg of a white solid of mp 145 "C (under Decomposition).

¹ H NMR (300MHz, D ₂ O) δ 135 (3, d), 3.21 (2, dd), 3.61 <6, ml, 4.35 (1, m); ³¹ PNMR (121 MHz, D ₂ O) 11.90; ! MS FAB) 226 (MH *).

C ₆ H ₁₂ NOePVzH ₂ O: CHN

calculated: 30.78 5.60 5.98

Filled: 30.90 5.4S 5.93.

The weight loss by thermogravimetry corresponds to 4.3% by weight of water. E) R-S-methyl-oxo-O-phosphononorvaline Another method, similar to that described above, gave 2.1 g (4.9 mmol) of R-4- [3-

(Diethoxyphosphinyl-S-methyl-O-propyl-S-oxo-S-oxazolidinecarboxylic acid S-phenylmethyl ester and 2.9 ml (20.4 mmol)

Trimethylsilyl iodide in 150 ml of dichloromethane and ISOmI acetonitrile 70 mg of a white solid of mp 140 ^e C (under Decomposition).

¹ H NMR (300MH ₂ , D ₂ O) 1.35 (3, m), 3.31 (2, m), 3.54 (1, m), 4.28 (1, m), ³¹ P NMR (121MH ,, D ₂ O) δ 16.3 (s); MS (FAB) M / Z 226 (MH *)

C ₆ H ₁₂ NO ₆ VjH ₂ O: CHN

calculated: 30.78 5.60 5.98

Filled: 30.45 5.24 5.86.

The weight loss by thermogravimetry corresponds to 5.2 mol% water.

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

Following a procedure similar to the method described above was obtained from 2.5 g (5.7 mmol) R-4- [5- \ (^ DiethoxyphosphinyO -oxopentyll-E-oxo-S-oxazolidinecarboxylic acid, 3- (phenylmethyl) -ester and 3,2ml (22,8mmol)

Trimethylsilyl iodide in 150 ml of dichloromethane and 150 ml of acetonitrile 400 mg of a white solid of mp 82 ° C (with decomposition).

¹ H NMR (300 MHz, d ₆ DMSO) 1.65 (2, m), 1.90 (2, m), 2.8 (2, m), 3.1 (2, D), 4.4 ( 1, m); ³¹ P NMR (121 MHz, D ₂ O), 9.3 (s); MS (FAB) 240 (ΜΗ *).

C ₇ H ₁₁ NO ₆ P: CHN

calculated: 35.15 5.90 5.86

Filled: 35,38 5,60 5,80.

Example 6

In this example, the preparation of the beta-ketophosphonate of general formula I in which B is a piperazine derivative is illustrated by the methods of Reaction Scheme III.

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

 1.2 g (7.2 mmol) of piperazine -carboxylic acid hydrochloride was dissolved in 25 ml of water and 1.4 g of 80% sodium hydroxide

J and 2.4 g (9.3 mmol) of dimethyl-i-bromo-2-methoxypropenyl-phosphonate. The resulting mixture was 18 hours

under an N ₂ atmosphere and then acidified to pH 3.0 with 1M HCl. The reaction mixture was washed with a

, ! Blown through N ₂ stream. The resulting mixture was taken up in the required minimum volume of water and from

. a BIORAD Ag 1-X8 resin in acetate form with water eluted. The ninhydrin-positive fractions were

; j freeze-dried and refluxed for 6 hours with 50 ml of 6M HCl. The reaction mixture became a residue

and eluted from an Amberlite CG-SO ion exchange resin with water. After freeze-drying, 71 mg of a white solid were obtained,

j ¹ H NMR (300MHz, D ₂ O) 63.02 (2, d), 3.3-3.6 (3, m), 3.6-3.8 (2, m), 3.7 ( 1.0m), 3.71 (2, m). ³¹ PNMR (121 MHz, D ₂ O) 12.25.

Example 7

In this example, the preparation of the beta-substituted beta-ketophosphonates of the general formula I is explained by the method of U. Schollkopf, V.Groth, K.-O.Westphalen and C.Deng, in Synthesis (1981), 969.

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

6.6 ml (65.1 mmol) of benzaldehyde, 6 g of magnesium sulfate and 20 ml of triethylamine in 50 ml of dichloromethane were admixed with 10.0 g (65.1 mmol) of D.L-alanine ethyl ester hydrochloride and stirred at room temperature for 18 hours. The solids were filtered off and the filtrate was partitioned between 250 mL of ether and 250 mL of water. The organic phase was separated, dried and evaporated. It received 11.3g of a clarified oil.

¹ H NMR (90MHz, CDCl ₃ ) δ 1.2 (3, t), 1.4 (3, d), 4.0 (1, m) 4.1 (2, q), 7.4 (5 , 0), 8,2 (1, s).

2.62 g (12.8 mmol) of the oil prepared above was cooled to 200 ml THFgegeben and V2 hour to -78 ^e C. 12.8 mmol of 1.0 M lithium hexamethylsirylamine in hexane was added and stirred for 2 hours. The mixture was added dropwise with 3.3 g (12.8 mmol) of dimethyl 3-bromo-2-methoxypropenyl phosphonate in 75 ml of THF for 2 hours, and the resulting solution was warmed to room temperature for 18 hours. The reaction mixture was then poured into 500 ml of water and extracted 2x with 500 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated to a residue which was flash chromatographed through silica gel with ethyl acetate. One received 1.8g of a clarified oil. ¹ H NMR (300 MHz, CDCl 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).

The 1.8 g (4.6 mmol) of the oil prepared above was admixed with 400 ml of 6M HCl. The mixture was heated to boiling and refluxed for 6 hours in an N ₂ atmosphere. The solution was then evaporated to a residue. The residue was taken up in 10 ml of ethanol and admixed with 3 ml of isopropanol and 1 ml of propylene oxide. The resulting solid was filtered and dried. 0.75g of mp 130X was obtained (with decomposition).

¹ H NMR (300MHz, D ₂ O) 1.55 (3, s), 3.05t1, ddd), 3.45 (1, dd); MS (FAB) M / Z 226 (MH ⁺ ).

Examples

In this example, the partial hydrolysis is explained, in which the phosphonate ester group is retained in the final product. - '

5- (Hydroxymethoxyphosphinyl) -4-oxonorvalin

3.1 g (11.6 mmol) of N- (diphenylmethylene) -glycine ethyl ester were dissolved in 50 ml of THF and cooled in a dry N ₂ atmosphere at -78 ° C. 12 ml (12 mmol) of IM lithium hexamethylsilylamine in hexane was added and the resulting orange solution was stirred at -78 ° C for one hour. 3 g (12 mmol) of dimethyl 3-bromo-2-methoxypropenyl phosphate was added.

The solution was stirred and warmed to room temperature in 18 hours. The reaction mixture was then poured into 200 ml of water and extracted 2 χ with 250 ml of ethyl acetate. The combined organic extracts were dried over magnesium sulfate and evaporated to a residue. After flash chromatography through silica gel with

Ethyl acetate / hexane (75:25) gave 3.2 g of a light yellow oil.

2.63 g (5.9 mmol) of the oil obtained above were admixed with 50 ml of 1 M HCl and heated under reflux for 1.5 hours. The resulting solution was evaporated to a residue and eluted with water from a BIORAD 50 W: X8 resin in H + form.

0.65 g of a white solid of F.111X (with decomposition) was obtained.

¹ H NMR (300MHz, D ₂ O) 53.15 (1, d), 3.45 (1, m). 3.61 (3, d), 4.31 (1, m); MS (FA) M / Z 226 (MH *).

CeH ₁ JNO ₆ PViH ₂ O: C H N calc .: 30.78 5.60 5.98 Found .: 31.11 5.57 6.07.

Example 9 In this example, the preparation of the oximes of the general formula Ia is explained. A) 4- (Hydroxyimino) -5-phosphononorvaline

0.25 g (1.1 mmol) of R ~ 4 ~ oxo-5-phosphononorvaline were incubated overnight at 40 ° C with 1.0 g (12.2 mmol) of sodium acetate and 0.5 g (7.2 mmol) of hydroxylamine hydrochloride The disappearance of the starting compound on HPLC indicated completion of the reaction, the reaction mixture was eluted through a Sephadex * 6-10 with deionized water, and fractions positive with ninhydrin were combined and dehydrated by freeze-drying 153 mg (59%) of 4- (hydroxyimino) -5-phosphononorvaline as a white hygroscopic solid, mp 128 ° C (dec) FAB MS M + H 227.1; 300MHz NMR in O ₂ O ¹ H: 4, 25M, 4.15m (total 1 H) 30 M (2H), 3.1 m (2H) ³¹ P (IH decoupled): 14.8, 15.75; ¹³ C: 32-340.38, 55.1570, 177th

CHN

as anhydrous: 26.56 4.90 12.39

F .: 21.13 4.45 9.85

Thermogravimetry: 9.7% loss. B) 4- (methoxyimino) -5-phosphononorvaline

0.21 g of R-4-oxo-5-phosphononorvaline and 0.5 g of O-methylhydroxylamine hydrochloride were reacted as in Example 9 (A).

This gave 52% of 4- (methoxyimino) -5-phosphononorvaline as a white hygroscopic solid, mp 170 * C (under Decomposition). FABMS: M + yard 241.1; 300MHz ¹ H (D ₂ O): 4.1 M (1H), 3,85Dsyn / anti (3H), 3.0 M (2H) 2.9M (2H) ^3l P (1Hentkoppelt) 15 + 16.4

(Syn / anti).

CHN: 30.01 5.46 11.67

Filled: 21,22 4,48 8,10

Thermogravimetry: 6.1% loss. C) 4 - [(phenylmethoxy) -imino] -5-phosphononorvaline

0.2 g of R-4-oxo-5-phosphononorvaline and 0.5 g of O-benzylhydroxylamine hydrochloride were reacted as in Example 9 (A). 100 gm (33%) of 4 - [(phenylmethoxy )iminol-5-phosphononorvaline was obtained as white hygroscopic powder, from F.153 ° C (under

Decomposition). FAB MS: M + H317.1; 300MHz ¹ H (D ₂ O) 7.45M (5H), 5.15D (2H), 4.1 M (1H), 3, OM (2H) 2.9M (2H).

CHN: 45.58 5.42 8.86

Filled: 40.08 4.81 7.67

Thermogravimetry: 9.8% loss. D) 4 - [(2'-phenylethoxy) -imino] -5-phosphononorvaline

4 - [(2'-phenylethoxy) -imino) -5-phosphononorvaline can be prepared by following the procedure of Example 9 (AC), substituting 0- (2-phenylethyl) -hydroxylamine for R-4-oxo-5-phosphononorvaline hydrochloride replaced as starting compound.

Example 10

This example illustrates the preparation of a compound of the formula Ia, where M is a hydrazone group. 4- (Benzylhydrazino) -5-phosphononorvaline can be prepared according to the method of Examples 9 (A-C) by substituting benzylhydrazine dihydrochloride starting compound for R-4-oxo-S-phosphononorvaline

Example 11 In this example, the preparation of the esters of the general formula Ia is explained. A) R-4-oxo-5-phosphononorvaline methyl ester

25ml of freshly distilled acetyl chloride were added dropwise for 15 minutes at 0 ^e CunterN ₂ to 500 ml of dry methanol.

1.25 g of R-4-oxo-S-phosphononorvaline was added and the resulting mixture was heated to boiling and refluxed for 16 hours. The resulting solution was evaporated to an oil, which was taken up in 500 ml of dry methanol. Through this solution, a slow stream of HCl was passed. At the same time, the solution was submerged for a further 16 hours

Reflux cooked. The resulting solution was cooled, bubbled with N 2 flow to a residue which was passed through BIORAD Ag 1-X8 200-400mesh resin was eluted in acetate form with water. The fractions with the desired product

were freeze-dried. 590 mg of a white solid of mp 88 ° C. (with decomposition) were obtained.

MS (FAB) M / Z 226 (MH *); 300 MHz ¹ H NMR (D ₂ O) 4.42 (1H, e), 3.82 (3H.S), 3.51 (2Hm), 3.14 (2H.dd). ³¹ P NMR (D ₂ O), ¹ H decoupled

CHN: 32.01 5.37 6.22

Filled: 30.17 5.90 5.87.

Thermogravimetry: 5.7 mol% loss.

β) R-4-oxo-5-phosphononorvaline ethyl ester 0.5 g of R 1 -oxo-5-phosphononorvaline was added to 250 ml of anhydrous ethanol and the resulting mixture was saturated with anhydrous HCl. The resulting mixture was refluxed for S hours, then cooled and evaporated.

The residue obtained was taken up in 100 ml of water and freeze-dried. A white solid was obtained from F.98 ° C (with decomposition). MS (FAB) M / 2240 (MH ⁺ ); 300 MHz ¹ H NMR (D ₂ O) 4.42 (1H, t), 4.29 (2H, q), 3.51 (2H, m), 3.25 (2M, d), 1.28 ( 3H, t); ³¹ P NMR (D ₂ O), ¹ H NMR (D ₂ O), ¹ H decoupled 14.6 ppm.

CHN calculated: 30.50 5.49 5.08

Filled: 29.51 5.69 5.04

Thermogravimetry: 0.4 mol% loss.

Claims (9)

1. Compounds of the general formulas I and Ia:
OO Il HO-P-OR HO-P-OR CR1R2 CR1R2 C = O C = M I i B (D B in which R represents a hydrogen atom, a C 1-4 -alkyl radical or a trifluoromethyl group; Each of R ₁ and R ₂ independently represents a hydrogen atom, a C 1-4 -alkyl, cycloalkyl, alkylphenyl, trifluoromethyl, phenyl or substituted phenyl group; M is a radical NO-R3 or N-NH-R ₃ , where R _{3 is} a hydrogen atom "a C ₁ -C 18 -alkyl or alkylphenyl radical; A represents a methylene or trimethylene bridge group which may optionally be substituted with up to 2 trifluoromethyl groups, C 1-4 alkyl, cycloalkyl or alkylphenyl radicals and / or phenyl or substituted phenyl groups; and 6 means one of the following radicals: CO ₂ Z or H ₂ N-CX-COOZ wherein Z represents a hydrogen atom, a C 1-4 alkyl, cycloalkyl, trialkylamino, alkylphenyl, phenyl or substituted phenyl group; and X represents an alkyl, alkylphenyl or trifluoromethyl group; including their pharmaceutically acceptable acid addition salts, pharmaceutically acceptable β-acid addition salts and their optical isomers, geometric isomers and tautomers; with the following provisos: a) that the L isomers of the compounds of general formula I are excluded if R ₁ , R ₁ and R _{2 are} each hydrogen, A is unsubstituted methylene and B is H ₂ N-CX-COOZ, wherein Z and X represent a hydrogen atom; b) that at least one of R, Ri and R _{2 is} a hydrogen atom; c) when B is either a piperazine derivative or an α-substituted amino acid, at least one of R ₁ and R _{2 is} hydrogen, and d) when B is an oxazolone derivative, R is a hydrogen atom. 2. Compounds according to claim 1, wherein A is a methylene group 3. Compounds according to claim 1, wherein A is a trimethylene group 4. Compounds according to any one of claims 1 to 3, wherein R represents a hydrogen atom or a C ₁ ^ - alkyl radical. 5. Compounds according to any one of claims 1 to 4, wherein Ri represents a hydrogen atom or a C ₁ ^ - alkyl radical. 6. Compounds according to one of claims 1 to 5, wherein B is a H ₂ N-CX-COOZ-ReSt. 7. Compounds according to any one of claims 1 to 5, wherein B is a radical means.
8. Compounds according to one of claims 1 to 5, wherein B is the group means.
9. Compounds according to one of claims 1 to 7, wherein Z is a hydrogen atom. 10. A compound according to any one of claims 2oder4bis9, wherein the methylene group is substituted with a C ₁ ^ ₄ -Al ky I rest. 11. Process for the preparation of compounds of the general formulas I and Ia O O "ii HO-P-OR HO-P-OR I i CRiR ₂ CRiR ₂ C = O C = M A A i i B B Formula I Formula Ia in which R denotes a hydrogen atom, a C ₁ -j-alkyl radical or a trifluoromethyl group; Each of R ₁ and R ₂ independently represents a hydrogen atom, a C 1-4 -alkyl, cycloalkyl, alkylphenyl, trifluoromethyl, phenyl or substituted phenyl group; M is a radical NO-R3 or N-NH-R ₃ is -R, wherein R ₃ is a hydrogen atom, an alkyl- C ₁ ^ ₄ -alkyl or represents alkylphenyl; A represents a methylene or trimethylene bridge group which may be optionally substituted with up to 2 trifluoromethyl groups, C 1-6 alkyl, cycloalkyl, alkylphenyl and / or phenyl or substituted phenyl groups; and B is one of the radicals of the formulas below: CO₂Z. j I H₂N-CH-COOZ for H ₂ N-CX-COOZ wherein Z represents a hydrogen atom, a C 1-4 alkyl, cycloalkyl, trialkylamino, alkylphenyl, phenyl or substituted phenyl group; and X represents an alkyl, alkylphenyl or trifluoromethyl group; including their pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, tautomers, optical isomers and geometric isomers; with the following provisos: a) that the L-isomers of the compounds of the general formula I are excluded if R, R ₁ and R _{2 are} a hydrogen atom, A is an unsubstituted methylene group and B is a radical H ₂ N-CH-COOZ in which Z is a hydrogen atom; b) that at least one of R, R ₁ and R _{2 is} a hydrogen atom; c) that when B is either a piperazine derivative or an α-substituted amino acid, at least one of R ₁ and R _{2 represents} a hydrogen atom; and d) when B is an oxazolone radical, R is a hydrogen atom, characterized in that A) protecting groups in a conventional manner of compounds of general formula VII | be split off, YO-PO-OY RlCR ₂ CO (VII) wherein R ₁ , R ₂ and A have the above meanings, Y is a C ₁ _ ₄ alkyl radical and Pg is a Benzylcarbamatschutzgruppe, wherein the compounds of the general || Formula I are prepared, in the B one of the radicals of the following formulas H2N-CH-COOZ R ₁ , R ₂ and A have the above meanings, and R and Z each represent a hydrogen atom, and that these compounds of general formula I are optionally esterified in a conventional manner for the preparation of the compounds of general formula I, wherein Z is a C ₁ ^ -alkyl, cycloalkyl, trialkylamino, alkylphenyl radical, a phenyl or substituted phenyl group and R, R ₁ , R ₂ , A and B have the above meanings; or
B) compounds of general formula X are hydrolyzed in a conventional manner YO-PO-OE 1 R ₁ C II C-OY (X) , COOY wherein R ₁ and A have the above meanings, each Y is independently a C ^ alkyl radical and E is a C ₁ ^ -alkyl radical or a CF ₃ group, wherein the compounds of general formula I are prepared, in the B den Remainder of the formula · - ι CO ₂ Z R, Ri and A have the above meanings and R ₂ and Z each represent a hydrogen atom, and that these compounds of general formula I are optionally esterified in a conventional manner for the preparation of the compounds of general formula I, wherein Z is a C ₁ ^ ₄ -AlkVl-, cycloalkyl, trialkylamino, alkylphenyl radical, a phenyl or substituted phenyl group and R, R ₁ , R ₂ , A and B have the above meanings; or
Compounds of the general formula XII are hydrolyzed in a manner known per se, YO-PO-OE CH ₃ O (XII) OCH ₃ CH ₃ wherein R ₁ , A and X have the above meanings, each Y is independently C 1 -C 4 alkyl and E is C ₁ -C 4 alkyl or -CF ₃ -GrUpPe, the compounds of general formula I being prepared, in the B is the rest of the formula H ₂ N-CX-COOZ R, R ₁ , A and X have the above meanings and R ₂ and Z each represent a hydrogen atom, and that these compounds of the general formula I are optionally esterified in a manner known per se for the preparation of the compound of general formula I, wherein Z is C 1 -C 4 alkyl, cycloalkyl, trialkylamino, alkylphenyl, phenyl or substituted phenyl, and R, R ₁ , R ₂ , A, B and X are as defined above; or D) compounds of general formula XIV are hydrolyzed in a conventional manner HO-PO-OR RLC ii C-OY
Formula XIV