GB2156818A

GB2156818A - Substituted alpha -amino acids, their preparation and pharmaceutical compositions containing them

Info

Publication number: GB2156818A
Application number: GB08507794A
Authority: GB
Inventors: Werner Muller; Paul Linus Herrling
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 1984-03-29
Filing date: 1985-03-26
Publication date: 1985-10-16
Also published as: PT80178B; FR2562076A1; ES8704957A1; HUT40447A; IT8547877A0; ES555560A0; IL74734A0; SE8501548D0; PT80178A; ES8802015A1; LU85826A1; GB2156818B; DK139185D0; SE8501548L; DE3510858A1; FI851234L; IT8547877A1; GR850770B; BE902040A; DK139185A

Abstract

Substituted alpha -amino acids useful for treating epilepsy, disorders associated with excess GH or LH secretion, schizophrenia, depression, CNS degenerative disorders and cerebral hypoxic conditions. The compounds are of formula <IMAGE> where R1 is H or an ester-forming group; A is an optionally substituted amino group; m and n are 1, 2 or 3; X is S, SO, SO2, O, NH, NR, CONH or CONR (where R is a hydrocarbyl group of at least 2 carbon atoms; Y is a phosphorus or sulphur containing acid or ester moiety, a carboxylic acid or ester or a tetrazolyl group.

Description

SPECIFICATION Substituted a-amino acids, their preparation and pharmaceutical compositions containing them The present invention relates to compounds of formula I,

wherein m and n are independently 1, 2 or 3, R1 is hydrogen or an ester forming radical, A is an optionally substituted amino group, X is sulfur, sulfinyl, sulfonyl, oxygen, imino, a substituted imino group, or an amido group substituted by a hydrocarbyl of at least 2 carbon atoms and Y is an optionally substituted tetrazolyl group, a phosphorus-containing acid group wherein phosphorus is attached directly to the -(CH2)n- moiety or an alkyl ester thereof optionally substituted by aryl or alicyclic or an alicyclic ester thereof; or X is sulfur, sulfinyl, sulfonyl, oxygen, imino or a substituted imino group, and Y is additionally also a sulfur-containing acid ester,-wherein sulfur is attached directly to the -(CH2)n- moiety, or X is sulfinyl, sulfonyl, oxygen or a substituted imino group, and Y is additionally also a sulfurcontaining acid group, wherein sulfur is attached directly to the -(CH2)n- moiety, or X is a substituted imino group or an amido group substituted by a hydrocarbyl of at least 2 carbon atoms and Y is additionally also a carboxylic acid group or an ester thereof, as well as to processes for their production and pharmaceutical compositions containing them.

The present invention includes salts of the compounds of formula I.

The present invention further includes bioprecursors or "pro-drugs" of the above defined compounds according to the invention, namely compounds that are converted in vivo into compounds of formula I stated above.

In particular the present invention provides a compound of formula 1',

wherein m and n are independently 1, 2 or 3, R1 is hydrogen, (C1-12)alkyl, (C1-12)alkylcarbonyloxy(C1-8)alkyl, (C1-12)alkoxycarbonyloxy(C1-8)alkyl, carboxy(C1-12)alkylcarbonyloxy(C1-8)alkyl, phenyl or phenyl(C, 8)alkyl or naphthyl or na phthyl(C, 8)alkyl, wherein each phenyl and naphthyl is optionally mono- or independently di- or trisubstituted by (C, 6)alkyl, (C1 6)alkoxy, halogen or hydroxy; pyridyl or pyridyl(C1-8)alkyl, R2 is hydrogen, (C1 ,2)alkyl, phenyl(C, 8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C, 6)alkyl, (C, 6)alkoxy, halogen or hydroxy; or pyridyl(C1-8)alkyl, R3 is hydrogen, (C, ,2)alkyl, phenyl(C, 8)alkyl, naphthyl(C, 8)alkyl, pyridyl(C1-8)alkyl, (C, ,2)al- kylcarbonyl, (C222)alkenylcarbonyl, (C4 22)alkadienylcarbonyl, (C622)alkatrienylcarbonyl, (C822)al- katetraenylcarbonyl, (C1-12)alkoxycarbonyl, phenylcarbonyl, naphthylcarbonyl, phenyl(C1-8)alkylcarbonyl, naphthyl(C, 8)alkylcarbonyl, phenoxycarbonyl, naphthyloxycarbonyl, phenyl(C1-8)alkox- ycarbonyl or naphthyl(C, 8)alkoxycarbonyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C, 6)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridylcarbonyl, pyridyl(C, 8)alkylcarbonyl, pyridyl(C, 8)alkoxycarbonyl; a group of formula II,

in which R4 is hydrogen, (C1-12)alkyl or phenyl(C, 6)alkyi, wherein phenyl optionally is mono- or independently disubstituted by (C1 6)alkyl, (C, 6)alkoxy, halogen or hydroxy, or a group of formula Ill or IV,

in which R5 and R5' are each, independently (C, 22)alkyl, (C2-22)alkenyl, (C4 22)alkadienyl, (C6-22)alkatrienyl, (C8-22)alkatetraenyl and v is independently of each other 0 or 1, X is -S-, -SO-, -SO2-, -O-, -NH-, -NR3'-, -CON(R)- or -N(R)CO-, R3' has the same significance as R3 except that it is not hydrogen, R is (C2-12)alkyl, phenyl or phenyl(C1-8)alkyl, wherein each phenyl optionally is monosubstituted by phenyl or phenyl(C, 4)alkyl or mono- or independently di- or tri-substituted by (C1-8)alkyl, (C1-6)alkoxy, (C1-6)alkylthio, halogen, hydroxy or trifluoromethyl, i) Y is one of the groups a), b), c), d), e) or f),

wherein R6 is (C1-22)alkyl, phenyl(C1-8)alkyl or naphthyl (C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (CI 6)alkoxy, halogen or hydroxy; pyridyl(C1-8)alkyl, R7 is (C1-22)alkyl, phenyl(C1-8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C1 6)alkoxy, halogen or hydroxy; pyridyl(C1 8)alkyl, or one of the groups p) or q)

in which u isO, 1,2, 3 or 4, R8 is is (C1-12)alkyl, phenyl or phenyl(C, 8)alkyl or naphthyl(C, 8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently disubstituted by (C, 6)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridyl or pyridyl(C1-8)alkyl, or ii) when X is -S-, -SO-, -SO2-, -O-, -NH- or -NR3'-, Y may additionally also be one of the groups g) or h)

wherein R7 is as defined above, or iii) when X is -SO-, -SO2, -O- or -NR3', Y may additionally also be one of the groups i) or i)

or iv) when X is -NR3'-, -CON(R)- or -N(R)CO-, Y may additionally also be a group k), -COOR9 k) wherein R9 is hydrogen, (C1 ,2)alkyl or phenyl(C, 8)alkyl or naphthyl(C, 8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)aikyl, (Ct 6)alkoxy, halogen or hydroxy; or pyridyl(C1 8)alkyl, or, when the compound of formula I' contains a salifiable group, a salt thereof.

Examples of a salt of a compound of formula l', when the compound contains a salifiable group, which is a free carboxylic acid group [i.e. R, is hydrogen or Y is group k) wherein R9 is hydrogen], a free phosphonic acid group [i.e. Y is one of the groups a), c) or d)], a free sulfonic acid group [i.e. Y is group i)], or a free sulfinyl acid group [e.g. Y is group j)] or the tetrazolyl group [Y is group f)] include cationic salts such as alkali metal salts, or optionally substituted ammonium salts. When in compounds of formula I' R3 is other than a carbonyl-containing group, acid addition salts can be formed, such as the hydrochloride, hydrobromide or maleinate Other acid addition salts are possible when X is NH or NR'3 wherein R'3 is other than a carbonyl-containing group.

Compounds of formula I have at least one chiral centre at the carbon atom bearing the amino group and therefore, can exist as enantiomers. Other chiral centres can appear e.g. at the phosphorus atom in the group e) and the sulfur atom in the group h). The present invention extends to the individual enantiomers, racemates, diastereoisomers as well as to mixtures thereof.

Wherein alkenyl groups are present, cis or trans isomers occur. These isomers are also included within the scope of the present invention.

In one group of compounds of formula 1', m and n are independently 1, 2 or 3, R1 is hydrogen, (C1 ,2)alkyl, (C1-12)alkylcarbonyloxy(C1-8)alkyl, phenyl or phenyl(C, 8)alkyl or naphthyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally being mono- or independently di- or trisubstituted by (C1-6)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridyl or pyridyl(C1-8)alkyl, R2 is hydrogen, (C1-12)alkyl, phenyl(C, 8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (C, 6)alkoxy, halogen or hydroxy; or pyridyl(C1-8)alkyl, R3 is hydrogen, (C1-12)alkyl, phenyl(C1-8)alkyl, naphthyl(C1-8)alkyl, pyridyl(C1-8)alkyl, (C-12)alkylcarbonyl, (C1-12)alkoxycarbonyl, phenylcarbonyl, naphthylcarbonyl, phenyl(C1-8)alkylcarbonyl, naphthyl(C1-8)alkylcarbonyl, phenoxycarbonyl, naphthyloxycarbonyl, phenyl(C1 8)alkoxycarbonyl or naphthyl(C1-8)alkoxycarbonyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (C 6)alkoxy, halogen or hydroxy; pyridylcarbonyl, pyridyl(C1-8)alkylcarbonyl, pyridyl(C1-8)alkoxycarbonyl; a group of formula II, in which R4 is hydrogen, X is -S-, -SO-, -SO2- or -0- and Y is one of the groups a), b), c), d), e), f) or g), or when X is -SO-, 502 or -O-, Y is additionally also group i), wherein R6 is (C1-22)alkyl, phenyl(C, 8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (C1 6)alkoxy, halogen or hydroxy; pyridyl(C1-8)alkyl, R7 is (C1-22)alkyl, phenyl(C1-8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridy(C1-8)alkyl, or one of the groups p) or q) in which u is 0, 1 or 2, R8 is (C1-12)alkyl, phenyl or phenyl(C1-8)alkyl or naphthyl or naphthyl(C1 8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-5)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridyl or pyridyl(C1 8)alkyl, or, when the compound of formula I' contains a salifiable group, a salt thereof.

In another group of compounds of formula l', mis 1,2 or 3, n is 1 or 2, R1 is hydrogen, (C, 12)alkyl, (C1-12)alkylcarbonyloxy(C1-8)alkyl, phenyl or phenyl(C1 8)alkyl or naphthyl or naphthyl(C1 8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C1 6)alkoxy, halogen or hydroxy; pyridyl or pyridyl(C1-8)alkyl, R2 is hydrogen, (C1-12)alkyl, phenyl(C1-8)alkyl or naphthyl(C1 8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C, 6)alkoxy, halogen or hydroxy; or pyridyl(C1-8)alkyl, R3 is hydrogen, (C1 12)alkyl, phenyl(C1 6)alkyl, naphthyl(C1 8)alkyl, pyridyl(C1 8)alkyl, (C1-12)al- kylcarbonyl, (C1-12)alkoxycarbonyl, phenylcarbonyl, naphthylcarbonyl, phenyl(C1 8)alkylcarbonyl, naphthyl(C1-8)alkylcarbonyl, phenoxycarbonyl, naphthyloxycarbonyl, phenyl(C1 8)alkoxycarbonyl or naphthyl(C1-8)alkoxycarbonyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C1 6)alkoxy, halogen or hydroxy; pyridylcarbonyl, pyridyl(C1 8)alkylcarbonyl, pyridyl(C1 8)alkoxycarbonyl; a group of formula II, in which R4 is hydrogen, X is -CON(R)-, R is phenyl optionally substituted by (C1 4)alkyl, (C1-4)alkoxy, (C1 4)alkylthio, halogen, trifluoromethyl or phenyl(C1 3)alkyl, Y is one of the groups a), b), c), d), e) or k) wherein R6 is (C1 22)alkyl, phenyl(C1-8)alkyl or naphthyl(C1 8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C1 6)alkoxy, halogen or hydroxy; pyridyl(C1-8)alkyl, R7 is (C1-22)alkyl, phenyl(C1-8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (C1-5)alkoxy, halogen or hydroxy; pyridyl(C1-8)alkyl, or one of the groups p) or q) in which u is 0, 1, 2, 3 or 4, R8 is (C1 12)alkyl, phenyl or phenyl(C1-8)alkyl or naphthyl or naphthyl(C1 8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridyl or pyridyl(C1-8)alkyl, R9 is hydrogen, (C1-12)alkyl, phenyl(C, 8)alkyl or naphthyl(C1 8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C1 6)alkoxy, halogen or hydroxy; or pyridyl(C1 8)alkyl, or, when the compound of formula I' contains a salifiable group, a salt thereof.

In still another group of compounds of formula I' m is 1 or 2, n is 3, R1 is hydrogen, R2 is hydrogen, R3 is hydrogen, (C1-12)alkoxycarbonyl, phenyl(C1-8)alkoxycarbonyl, a group of formula II, wherein R4 is hydrogen, or a group of formula III, wherein R5 and R5' are each (C, 22)alkyl especially (C1-12)alkyl and v is 0, , X is S, SO, SO2 and Y is the group a), a group c) wherein R7 is (C, 22)alkyl or the group p), wherein u is 2. In another group of compounds of formula I' m is 2, n is 1, R, is hydrogen, R2 is hydrogen, R3 is hydrogen, X is -CON(R)-, wherein R is phenyl, phenyl optionally being monosubstituted by halogen, and Y is a group k) wherein R9 is hydrogen.

In particular a compound of formula I can be produced by a process which includes the steps of A) producing a compound of formula la,

wherein A, m and n are as defined above, R,' is R, other than hydrogen, X' is -S- and Y' is a phosphorus-containing acid ester group or a sulfur-containing acid ester group, by reacting a compound of formula V,

wherein R11, A and m are as defined above, with a compound of formula VI, W-(CH2)-Y1 VI wherein n and Y' are as defined above, and W is a leaving group, and as appropriate removing any amino-protecting group present B) producing a compound of formula Ib,

wherein m, n and Y' are as defined above and X" is -O-, by reacting a compound of formula VII,

wherein R10 is an acyl group and R,1 is (C1 4)alkyl, with a compound of formula VIII, W-(CH2)m-X''-(CH2)n-Y' VIII wherein X'', m, n, Y' and W are as defined above, under basic conditions, hydrolysing and decarboxylating the resulting product, C) producing a compound of formula Ic,

wherein R1, A, m, n and X are as defined above and Y" is a tetrazolyl group, by reacting a compound of formula IX,

wherein R,, A, X, m and n are as defined above, with a hydrazoic acid salt and as appropriate removing any amino-protecting group present, D) producing a compound of formula Id,

wherein R" A, m, n and Y are as defined above, and X"' is -SO- or -SO2-, by oxidizing a compound of formula lab,

wherein R1, A, m, n, X' and Y are as defined above, and as appropriate removing any aminoprotecting group present, E) producing a compound of formula le,

wherein R,', m and n are as defined above, xiV is -NH- or -NR31-, Y''' is a phosphoruscontaining acid ester group, a sulfur-containing acid ester group and when xiV is -NR3,-, Y"' may additionally also be a carboxylic acid group or an ester thereof, by reacting a compound of formula X,

wherein R,' is as defined above, with a compound of formula XI

wherein m, n, W and Y"' are as defined above and R3" is as defined for R3' above but may also be an amino-protecting group, under basic conditions, hydrolysing the resulting compound and as appropriate removing any amino-protecting group present, F) producing a compound of formula If,

wherein R,', A, m and n are as defined above, Xv is an amido group substituted by a hydrocarbyl of at least 2 carbon atoms and yiv is a phosphorus-containing acid ester group or a carboxylic acid group or an ester thereof, by reacting a compound of formula XII,

with a compound of formula XIII U'-(CH,),-Y'" XIII wherein RX', A, yiv, m and n are as defined above, and either one of U and U' is -CO-Z and the other is an amino group substituted by a hydrocarbyl of at least 2 carbon atoms and Z is a reactive carboxylic acid residue and as appropriate removing any amino-protecting group present and if desired interconverting one compound of formula I into another and optionally introducing substituents which are different from hydrogen e.g. substituting group A or esterifying acid groups, or converting esters to the corresponding acids, or when the compound of formula I contains a salifiable group, forming a salt thereof.

Process A) may be effected in conventional manner. The compound of formula V may be prepared in situ e.g. by cleavage of the corresponding symmetrical disulfide for example with a compound of formula HS-(CH2)n-OH. The reaction is suitably carried out in an organic solvent, such as methanol, ethanol or dioxan at room temperature. The reaction is carried out under an oxygen free atmosphere. The subsequent reaction with a compound of formula VI, wherein W is e.g. halogen, especially bromine, methylsulfonyloxy or p-methylphenylsulfonyloxy, is conveniently carried out in the presence of an acid binding agent, such as triethyl amine.If the process is to be carried out in order to obtain a compound of formula la wherein A is an unsubstituted amino group or monosubstituted with a group that is other than a carbonyl-containing group, it is convenient to use a compound of formula V, wherein A is protected by an amino protecting group. Conventional amino-protecting groups such as benzyloxycarbonyl or tert.-butyloxycarbonyl can be used. The deprotection can be carried out using conventional procedure, e.g. by hydrolysis. The benzyloxycarbonyl group can also be removed by hydrogenolysis.

Process B) may be performed in conventional manner. The reaction can be carried out in an organic solvent such as methanol, ethanol or toluene in the presence of sodium methoxide or sodium ethoxide at a temperature between 40 and 110 . The subsequent hydrolysis and decarboxylation can be effected with e.g. mineral acid. In compounds of formula VII R10 is for example formyl, acetyl, benzoyl or benzylcarbonyl.

Process C) may be effected in manner known for the synthesis of a tetrazole ring. The hydrazoic acid salts include alkali metal salts, such as sodium azide, alkaline earth metal salts, such as magnesium azide, other metal salts such as aluminium azide. These salts can be employed alone or in combination with ammonium chloride or a Lewis acid such as aluminium chloride. The reaction can be carried out in a solvent such as tetrahydrofurane, dioxane or dimethylformamide at the reflux temperature of the solution. In compound of formula IX A is conveniently protected by an amino-protecting group, when compounds of formula Ic are to be prepared, wherein A is an unsubstituted amino group or monosubstituted with a group that is other than a carbonyl-containing group. The deprotection can be effected as described in process A).

Process D) can be carried out in known manner. Any conventional method for oxidizing a thioether to a sulfoxide or sulfone can be utilized to carry out this reaction. For example for the preparation of sulfoxides sodium periodate, NaBO3 or tetra(n-butyl)periodate can be used.

Sulfones can be obtained using NaBO3, H202 in formic acid or KHSO5 as oxidizing agent. The reaction can be carried out in a solvent such as aqueous methanol or aqueous ethanol. For the production of a compound of formula Id, wherein A is an unsubstituted amino group or monosubstituted with a group that is other than a carbonyl-containing group, conveniently a compound of formula lab, wherein A is protected by an amino-protecting group as described hereinbefore, is employed.

Process E) can be performed in conventional manner. The reaction can for example be carried out in a basic two phase system, e.g. a water-immiscible solvent such as dichloromethane and solid or aqueous sodium hydroxide using a phase-transfer catalyst e.g. benzyltriethylammonium chloride. Suitable temperatures range from 0" to room temperature. Alternatively the reaction can also be carried out in an organic solvent, such as methanol, ethanol or toluene in the presence of e.g. sodium ethoxide or sodium methoxide at a temperature between 40" and 110'.

The subsequent hydrolysis of the resulting product can be effected with e.g. hydrochloric acid.

When a compound of formula le, wherein xiV is -NH- is desired, R3" is conveniently an amino protecting group as defined in process A).

Process F) may be effected in conventional manner. Z is e.g. halogen, especially chlorine or bromine, or a group -O-COOR11, wherein R,1 is (C1 4)alkyl. The reaction is suitable carried out in an organic solvent, such as methylene chloride at room temperature. Conveniently an acid binding agent, such as triethylamine, is present. In compounds of formula XII A is conveniently protected by an amino-protecting group when compounds of formula If are desired, wherein A is an unsubstituted amino group or monosubstituted with a group other than a carbonyl-containing group. The deprotection can be carried out in known manner.

The interconversions of one compound of formula I to another may be effected in conventional manner and may be used e.g. to reintroduce any group which have been removed in the above mentioned processes.

The optional introduction of substituents into an amino group can be effected in conventional manner. For example the alkylation of the amino group may be carried out with alkyl halides or alkyl sulfates. If only one alkyl group has to be introduced suitably dialkylation is prevented by application of known methods, e.g. N-acylation, alkylation via N-acyl anion, removal of the acyl group. When the compound to be alkylated contains a free carboxy group, (e.g. R1 is hydrogen) it is preferably blocked by a protecting group e.g. benzyl removable by selective hydrogenolysis.

The acylation of the amino group can be effected by reaction with the appropriate acid or a reactive derivative thereof. The urethane can be prepared by reaction with a halo-formic acid ester.

The optional esterification can be carried out using conventional methods. When a phosphonic acid monoester [V is a group c)] is desired the esterification can for example be effected in pyridine in the presence of trichloroacetonitrile at a temperature of about 100 . When in the starting material to be esterified A is an amino group which is unsubstituted or monosubstituted with a group that is other than a carbonyl-containing group, such amino group is suitably protected by an amino-protecting group as described above.

The optional conversion of an ester to the corresponding acid can be effected by any conventional method, e.g. by hydrolysis. Using selective methods, e.g. hydrogenolysis, compounds of formula I can be prepared wherein either the phosphonic diester or the carboxylic acid ester is converted into the corresponding acid.

The optional formation of a salt, when the resulting compound of formula I contains a salifiable group may be carried out conventionally.

Compounds of formula I not embraced by formula I' may be produced in manner analogous to similar compounds of formula I' or by methods known and conventional in the art.

Insofar as the production of the starting materials for the above processes is not particularly described, these may be produced in analogous manner to known compounds or to processes described herein.

The racemates may be separated by conventional means, e.g., by fractional crystallizations of optically active salt forms. Alternatively, a pure enantiomeric or diastereoisomeric form may be produced by utilizing optically active resp. diastereoisomeric starting materials. The cis-trans mixture can be separated in a known manner into the corresponding cis and trans components.

In the following examples all temperatures are given in degrees centigrade and are uncorrected. The [a]D20 values are also uncorrected.

Example 1: ( + )-S-(3- Ph osph on opropyl)-D-cystein e The pH of a solution of 1 3.2 g di-benzyloxycarbonyl-D-cystine-diethylester in 240 ml methanol/water (10:1) is adjusted to 8 by addition of conc. ammonia. 4.5 ml 2-mercaptoethanol are added under nitrogen and the mixture is stirred for 5 hours at room temperature.

The mixture is then evaporated in vacuum, and the residue dissolved in 50 ml triethyl amine.

14.2 g 3-bromo-propanephosphonic acid diethylester are then added dropwise under nitrogen and the mixture is stirred at room temperature overnight. The solvent is removed in vacuum and the residue dissolved in ether/toluene (1:1). The solution is washed with water and brine solution. After drying over anhydrous sodium sulfate, the solvent is removed under vacuum. The residue is refluxed with 100 ml 7N hydrochloric acid for 10 hours. The mixture is evaporated under vacuum, the residue dissolved in ethanol (94%), treated with propylene oxide and evaporated under vacuum to afford the title compound, which is crystallized from etha nol/water, m.p. 203-205 (decomp.), [a]D20 + 14.8 (C = 0.7 water).

Example 2: S-(3-Phosphonopropyl)-D, L-cysteine In manner analogous to Example 1 but starting from di-benzyloxycarbonyl-D,L-cystine- diethylester there is obtained the title compound, m.p. 215-218" (decomp.).

Example 3: S-(2-Phosphonoethyl)-D, L-homocysreine In manner analogous to Example 1 the title compound is obtained in amorphous form.

Example 4: N-Benzyloxycarbonyl-S-(3-phosphonopropyl)-D, L-cysteine 4.8 ml Benzyl chloroformate are added dropwise at 5 to 10" to a stirred suspension of 3.7 g S-(3-phosphonopropyl)-D,Lcysteine and 2.5 g magnesiumoxide in 25 ml of water and 10 ml of ether. The mixture is stirred at room temperature for 24 hours. The mixture is then made acidic with concentrated hydrochloric acid (ice cooling) and extracted with acetic acid ethyl ester. The organic phase is dried and evaporated. The residue is recrystallised from ether/acetic acid ethyl ester to give the heading compound, m.p. 102-105".

Example 5: S-f3-r(Dodecyloxy)hydroxyphosphinyl]propyl]-D,L-crsteine A mixture of 2.1 g N-Benzyloxycarbonyl-S-(3-phosphonopropyl)-D,L-cysteine, 1.25 ml 1dodecanol, 0,55 ml trichloroacetonitrile and 20 ml absolute pyridine is stirred at 1 00" for 6 hours. The mixture is then evaporated in vacuo and the residue partitioned between diluted aqueous sodium carbonate and ether. The aqueous phase is acidified with hydrochloric acid and extracted with acetic acid ethyl ester. The organic phase is dried and evaporated. The residue is treated with 1 5 ml of a solution of HBr in trifluoroacetic acid and stirred for 2 hours at room temperature. The mixture is then evaporated in vacuo and the residue partitioned between diluted hydrochloric acid and acetic acid ethyl ester.The aqueous phase is evaporated in vacuo, the residue dissolved in ethanol (94%), treated with propylene oxide and evaporated under vacuum. The residue is crystallized from ether to give the heading compound, m.p. 1 60-1 63".

Example 6: In manner analogous following compounds of formula I' are prepared wherein R1 and R2 are each hydrogen, m is 1 and n is 3:

Analogous Ex. R3 X V Conf. m. p. to Ex. a) H S 0 L 203-205 1 P(OH)2 decomp. SOH b) H S P' D.L 168-172 5 \ (cli 0,2 H c) C00 CO S D 0 4 P(OH)2 d) CO 0nC12H25 S 0 D,L 123-126 4 N P( H)2 e) COOCH(CH20-nC4Hg)2 S O D,L *) 4 N P(OH)2

*) Rf = 0.73 [CH3COOC2H5/CH3COOH/H2O (5:2:2)] Example 7: (- )-N-(Carboxymethyl)-N-phenyl-D-glutamine A solution of 7.4 g N-benzyloxycarbonyl-D-glutaminic-acid-a-benzyl ester in 1 20 ml methylene chloride and 2.7 ml triethylamine is stirred at 0" and 1.9 ml ethyl chloroformate is added dropwise. The mixture is stirred at about 10" for 1+ hours, then 3.3 g N-phenyl-glycine are added in portions. The reaction mixture is then stirred for 48 hours allowing the temperature to come to ambient. The mixture is extracted with cold dilute sodium hydroxide solution, the extract is acidified with 2N hydrochloric acid (ice cooling) and extracted with methylene chloride.

The methylene chloride extract is dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 120 ml methanol and water (1:1) and hydrogenated under normal conditions over palladium on carbon catalyst (10%). The mixture is then heated to dissolve the precipitate and the catalyst is filtered off. The filtrate is evaporated to afford the title compound, which recrystallized from ethanol/water, m.p. 207-208 (decomp); [a]D20 - 33,7" (c = 0,6 in 0.2 N HCI). When recrystallisation from ethanol/water is repeated several times the title compound has m.p. 220-222 (decomp.); [a]D20 - 55.1" (c = 0.6 in 0.2 N HCI).

Example 8: In manner analogous to Example 7 the following compounds of formula I' are obtained: a) (+ )-N-(Carboxymethyl)-N-phenyl-L-glutamine, m.p. 209-211" (decomp.); [a]D20 + 34.2" (c = 0.6 in 0.2 N HCI), b) (- )-N-(Carboxymethyl)-N-(4-chlorophenyl)-D-glutamine, decomp. from 1 50": [a]D20 - 20.5" (c = 0.6 in 0.2 N HCI).

Example 9: (- )-3-f(3-Phosphonopropyl)sulfinylj-D-alanine To a solution of 1.5 g (-- )-S-(3-phosphonopropyl)-D-cysteine in 60 ml water is added at 0" under stirring dropwise a solution of 1.25 g sodium periodate in 10 ml water. The mixture is stirred at 0" for 1 5 minutes and thereafter evaporated in vacuo. The residue is dissolved in water and passed through an ion exchange column filled with Dowex 50W X8 (16-40 mash) and the column is eluted with water. The eluate is evaporated in vacuo to give the heading compound, which recrystallized from water/ethanol has a m.p. of 180-190" (decomp.).

Example 10: (+ )-3-U3-Phosphonopropyl)sulfonylj-D-alanine To a stirred solution of 1 g (- )-S-(3-Phosphonoprnpyl)-D-cysteine in 30 ml formic acid are added at room temperature dropwise 8.8 ml 30% H2O2. The mixture is stirred 48 hours at room temperature. The cristalline precipitate is filtered off, washed with ethanol and then ether to give the heading compound, m.p. 201-204" (decomp.).

The compounds of formula I exhibit pharmacological activity and are therefore indicated for use as pharmaceuticals e.g. for therapy. In particular, the compounds exhibit central nervous system activity as indicated in standard tests. For example, the compounds inhibit the locomotion in mice. In this test groups of 3 male mice (18-24 g, OF-1, Sandoz Basle) receive 3.2, 10, 32, 100 and 320 mg i.p. of the test drug. 1 hour after drug administration the mice are observed individually and their locomotion compared with that of control mice concurrently treated with vehicle. The locomotion is judged to be either unaffected, definitely more or less than controls, strongly more or less than controls, or completely inhibited.

The compounds of formula I additionally exhibit anticonvulsant activity as indicated in standard tests. In a first test, the compounds inhibit the electroshock-induced convulsions in the mouse [E. Swinyard, J. Am. Pharm. Soc. 38, 201 (1949) and J. Pharm. Exp. Therap. 106, 319 (1 952)]. In this test groups of 3 mice (18-26 g, OF-1, Sandoz Basle) receive the test substance in a dosage of 3.2-320 mg/kg i.p.. After 60 minutes a 50 mA, 200 ms long shock is applied with corneal electrodes smeared with electrolyte jelly. This supra-threshold shock produces tonic extensor convulsions of all extremities. Inhibition of the hind-limb extension is taken as a protective action. After investigation of several dose-levels an EDm,n is estimated.

In a second test the compounds further inhibit 3-mercaptopropionic acid-induced convulsions in the mouse. In this test groups of 6 female mice (18-26 g, OF-1, Sandoz Basle) were pretreated with the test substance in a dosage of 0.1-100 mg/kg i.p. 30 minutes later they are challenged with 100 mg/kg s.c. 3-mercaptopropionic acid and observed for 30 minutes. The latencies for the appearance of the first signs of convulsions, for the first tonic convulsions and for the occurrence of death are noted. The significance of any differences is observed using the Mann-Whitney U-test [S. Siegel, Non-parametric Statistics, McGraw-Hill, New York 1956].

The compounds of formula I interact with excitatory amino acid systems, in particular they are competitive antagonists of NMDA (N-Methyl-D-aspartic acid) receptors, as indicated by an inhibitory effect on NMDA-induced depolarizations of the isolated amphibian spinal cord. This may be shown in the test performed in conventional manner (see for example D.R. Curtis et al., J. Physiol. (London) 150, 656-682, (1961) and R.H. Evans et al., Br. J. Pharmac. 67, 591-603 (1979) as follows: A hemisected proximal part of the spinal cord of a toad or frog lies in a recording chamber perfused by a Ringer solution (111 mM NaCI, 2 mM KCI, 2 mM CaCI2, 1 2 mM Glucose, Trisbuffer (pH 7,5, 10 mM)). The dorsal root is pulled into the stimulating chambers, the ventral root into the recording chambers. A stimulator connected to the stimulating chambers is used.A DC high impedance preamplifier measures the DC potential between the ground lead sampling the main chamber and one of the recording chambers. The signal from the preamplifier is monitored on a CRO to display stimulated synaptic activity (dorsal root-ventral root potential, DR-VRP) or to a chart recorder to display slow changes in potential. A copy of the preamplifier signal is fed into an integrator that calculates the area under the curve.

The excitatory amino acid agonists are applied at increasing doses of from 1 ,um to 1 mM to determine dose response curves (DRC). After each dose, usually applied for 30 s to 1 min, the drug is washed out until control values of the VRP are reached. To measure the effect of each dose, the following procedure is used: the area under the curve measured by the integrator is sampled continuously at 1 min interval; the values for the last 5 min before the drug application are added to the values of the first 5 min after the VRP-slope has returned to control values and averaged. This average represents the control VRP and is deducted from the averaged values of the first 5 min after drug application. The effect of increasing doses are then measured and the numbers fed into a computer which constructs a dose response curve (DRC).From such DRCs EC50 values are then determined graphically.

Antagonists are tested in two stages. The first stage consists of applying the agonist 3-5 times at a constant concentration near the EC75 and repeating the procedure in presence of the antagonist. After a washout period the agonist alone is retested 3-5 times in order to evaluate recovery. The values obtained in such experiments are again fed into the computer which plots bar-diagrams, calculates the means of the control-, drug- and recovery groups and tests statistically the difference between control and drug group. If a test drug shows inhibition in the first stage, competitive antagonism is tested in the second stage. This is done by determining a four point DRC of the agonist in the linear range and then repeating the DRC in presence of the putative antagonist at a constant concentration. Recovery is tested by repeating the DRC after the washout of the test drug.A first indication of competitive antagonism is given by a parallel shift to the right of the DRC in presence of the antagonist, e.g. compounds of the present invention at a concentration from 1 to about 300 ym. In such cases pA2-values are calculated according to the formula pA2 = -log I + log (A50 - (B50 where I is the concentration of the antagonist, A50 is the EC50 for the agonist in presence of the antagonist and B50 the EC50 of the agonist alone before the application of the test drug.

Competitive antagonism can be confirmed by repeating the experiment with a double dose of the test drugs, if approximately the same pA2 results there is a reasonable certainty that the antagonist is competitive (0. Arunlakshana et a., Brit. J. Pharmacol. 19, 48-58 (1959); M.

Wenke, Drug receptor interactions. In BACO ZM (ed) Fundamentals of biochemical pharmacology, Pergamon Press, Oxford, 357-381 (1971)).

The compounds of formula I' wherein X is S, SO, SO2, NH or NR3, are also selective as indicated in that quisqualate induced depolarisations are not significantly effected in the above test wherein NMDA is replaced by quisqualic acid.

The compounds of formula I' wherein X is CON(R) or N(R)CO are broad spectrum antagonists as indicated in that quisqualate and kainate induced depolarisations are also inhibited.

On the basis of the above mentioned CNS activities the compounds of formula I are indicated for use for the treatment of CNS diseases. As a result of their anti-convulsant activity the compounds are indicated for use for the treatment of epilepsy. For this use an indicated daily dosage is in the range from about 25 to about 800 mg of the compound conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing for example from about 6 to about 400 mg of the compound or in sustained release form.

As a result of their NMDA receptor antagonism the compounds are indicated for the use i) in the treatment of disorders having an aetiology comprising or associated with excess GHsecretion e.g. in the treatment of diabetes mellitus and angiopathy as well as of acromegaly and ii) in the treatment of disorders having an aetiology associated with or modulated by excess LHsecretion e.g. in the treatment of prostate hypertrophy or in the treatment of menopausal syndrome.

For this use an indicated daily dosage is in the range from about 1 to about 800 mg of the compound conveniently given in divided doses 2 to 4 times a day in unit dosage form containing for example from about 0.2 to about 400 mg of the compound or in sustained release form.

As a result of their NMDA receptor antagonism the compounds of formula I are further indicated for use for the treatment of schizophrenia and depression or of CNS degenerative disorders, such as Huntington's disease or Alzheimer's disease. For these uses an indicated daily dosage is in the range from about 25 to about 800 mg of the compound conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing for example from about 6 to about 400 mg of the compound or in sustained release form.

The compounds of formula I protect further against hypoxia-induced degeneration of rat hippocampal neurons in vitro at concentrations ranging from 1 ym to 3 mM [method of S.

Rothman, J. Neurosci. 4, 1884-1891(1984)]. The compounds are therefore indicated for use for the treatment of cerebral hypoxic conditions, e.g. stroke.

For this use an indicated daily dosage is in the range of from about 10 to about 800 mg of the compound conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing for example from about 2 to about 400 mg of the compound or in sustained release form.

The anticonvulsant indication and the protection against hypoxic conditions are the preferred indications. The Examples 1, 2 and 7 compounds are the preferred compounds. The Example 7 compound is most preferred.

The compounds of formula I may be administered as such or as their pharmaceutically acceptable salts. Such salts exhibits the same order of activity as the compounds of the invention in free base or free acid form. The present invention also provides a pharmaceutical composition comprising a compound of formula I us such or in salt form in association with a pharmaceutically acceptable diluent or carrier. Such compositions may be formulated in conventional manner. The compounds may be administered by any conventional route in particular enterally preferably orally e.g. in the form of tablets or capsules, or parenterally e.g. in form of injectable solutions or suspensions.

In a first group of compounds X is -S-.

In a second group of compounds X is -SO-.

In a third group of compounds X is -SO2-.

In a fourth group of compounds X is -O-.

In a fifth group of compounds X is -NH-.

In a sixth group of compounds X is -NR3'-.

In a seventh group of compounds X is -CON(R)-.

In an eight group of compounds X is -N(R)CO-.

In a ninth group of compounds R is phenyl.

In a tenth group of compounds R is phenyl substituted by phenyl.

In an eleventh group of compounds Y is group a).

In a twelth group of compounds Y is a group c).

In a thirteenth group of compounds Y is a group k).

Other groups may be formed individually from each of the significances of Y, R, R1, R2, R3, R4, R5, R5, R7, R8 and R9..

Claims

1. A process for the production of a compound of formula I,

wherein m and n are independently 1, 2 or 3, R, is hydrogen or an ester forming radical, A is an optionally substituted amino group, X is sulfur, sulfinyl, sulfonyl, oxygen, imino, a substituted imino group or an amido group substituted by a hydrocarbyl of at least 2 carbon atoms and Y is an optionally substituted tetrazolyl group, a phosphorus-containing acid group, wherein phosphorus is attached directly to the -(CH2)n- moiety or an alkyl ester thereof optionally substituted by aryl or alicyclic or an alicyclic ester thereof; or X is sulfur, sulfinyl, sulfonyl, oxygen, imino or a substituted imino group, and Y is additionally also a sulfur-containing acid ester, wherein sulfur is attached directly to the -(CH2),,- moiety, or X is sulfinyl, sulfonyl, oxygen or a substituted imino group, and Y is additionally also a sulfurcontaining acid group, wherein sulfur is attached directly to the -(CH2),,- moiety, or X is a substituted imino group or an amido group substituted by a hydrocarbyl of at least 2 carbon atoms and Y is additionally also a carboxylic acid group or an ester thereof, or an salt thereof which includes the step of A) producing a compound of formula la,

wherein A, m and n are as defined above, R1, is R, other than hydrogen, X' is -S- and Y' is a phosphorus-containing acid ester group or a sulfur-containing acid ester group, by reacting a compound of formula V,

wherein R'1, A and m are as defined above, with a compound of formula VI, W-(CH2)n-Y' VI wherein n and Y' are as defined above, and W is a leaving group, and as appropriate removing any amino-protecting group present B) producing a compound of formula Ib,

wherein R10 is an acyl group and R11 is (Cr 4)alkyl, with a compound of formula VIII, W-(CH2)m-X''-(CH2)n-Y' VIII wherein X", m, n, Y' and W are as defined above, under basic conditions, hydrolysing and decarboxylating the resulting product, C) producing a compound of formula Ic,

wherein R1, A, X, m and n are as defined above, with a hydrazoic acid salt and as appropriate removing any amino-protecting group present, D) producing a compound of formula Id,

wherein R1, A, m, n and Y are as defined above, and X"' is -SO- or -SO2-, by oxidizing a compound of formula lab,

wherein R1,, m and n are as defined above, Xv is -NH- or -NR3'-, Y"' is a phosphorus containing acid ester group, a sulfur-containing acid ester group and when X IV is is -NR3'-, Y"' may additionally also be a carboxylic acid group or an ester thereof, by reacting a compound of formula X,

wherein R1, is as defined above, with a compound of formula Xl

wherein R,', A, m and n are as defined above, Xv is an amido group substituted by a hydrocarbyl of at least 2 carbon atoms and Y is a phosphorus-containing acid ester group or a carboxylic acid group or an ester thereof, by reacting a compound of formula Xll,

with a compound of formula XIII U'-(CH2)n-Y IV XIII wherein R1', A, yiv, m and n are as defined above, and either one of U and U' is -CO-Z and the other is an amino group substituted by a hydrocarbyl of at least 2 carbon atoms and Z is a reactive carboxylic acid residue and as appropriate removing any amino-protecting group present and if desired interconverting one compound of formula I into another, and when the compound of formula I contains salifiable group, forming a salt thereof.

2. A process for the production of a compound of formula I or an salt thereof as hereinbefore described with reference to any of the Examples.

3. A compound of formula I or a salt thereof whenever produced by a process according to claim 1.

4. A compound of formula I or a salt thereof.

5. A compound of claim 4 of formula 1',

wherein m and n are independently 1, 2 or 3, R1 is hydrogen, (C1 12)alkyl, (C1 -12)alkylcarbonyloxy(C1 8)alkyl, (C1-12)alkoxycarbonyloxy(C1-8)al- kyl, carboxy(C1-12)alkylcarbonyloxy(C1-8)alkyl, phenyl or phenyl(C1 8)alkyl or naphthyl or na phthyl(C1 8)alkyl, wherein each phenyl and naphthyl is optionally mono- or independently di- or trisubstituted by (C1-6)alkyl, (C1-6)alkoxy, halogen or hydroxy; pyridyl or pyridyl(C1-8)alkyl R2 is hydrogen, (C1 12)alkyl, phenyl(C1-8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C1 6)alkoxy, halogen or hydroxy; or pyridyl(C1-8)alkyl, R3 is hydrogen, (C1-12)alkyl, phenyl(C1 8)alkyl, naphthyl(C1 8)alkyl, pyridyl(C1-8)alkyl, (C, ,2)al- kylcarbonyl, (C2-22)alkenylcarbonyl, (C4-22)alkadienylcarbonyl, (C6-22)alkatrienylcarbonyl, (C8-22) alkatetraenylcarbonyl, (C1-12)alkoxycarbonyl, phenylcarbonyl, naphthylcarbonyl, phenyl(C, 8)alkyl- carbonyl, naphthyl(C1 8)alkylcarbonyl, phenoxycarbonyl, naphthyloxycarbonyl, phenyl(C1 8)alkoxycarbonyl or naphthyl(C1 8)alkoxycarbonyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C, 6)alkyl, (C1 6)alkoxy, halogen or hydroxy; pyridylcarbonyl, pyridyl(C1 8)alkylcarbonyl, pyridyl(C, 8)alkoxycarbonyl; a group of formula II,

in which R4 is hydrogen, (C, ,2)alkyl or phenyl(C, 6)alkyl, wherein phenyl optionally is mono- or independently disubstituted by (C, 6)alkyl, (C, 6)alkoxy, halogen or hydroxy, or a group of formula Ill or IV,

in which R5 and R5, are each, independently (C, 22)alkyl, (C2-22)alkenyl, (C4 22)alkadienyl, (C622)alkatrienyl, (C8-22)alkatetraenyl and v is independently of each other 0 or 1, X is -S-, -SO-, -SO2-, -O-, -NH-, -NR3'-, -CON(R)- or -N(R)CO-, R3' has the same significance as R3 except that it is not hydrogen, R is (C2 ,2)alkyl, phenyl or phenyl(C1 8)alkyl, wherein each phenyl optionally is monosubstituted by phenyl or phenyl(C1-4)alkyl or mono- or independently di- or tri-substituted by (C1-6)alkyl, (C1-6)alkoxy, (C1-6)alkylthio, halogen, hydroxy or trifluoromethyl, i) Y is one of the groups a), b), c), d), e) or f),

wherein R6 is (C1 22)alkyl, phenyl(C1-8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C1 6)alkoxy, halogen or hydroxy; pyridyl(C1-8)alkyl, R7 is (C1 22)alkyl, phenyl(C1-8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridyl(C1-8)alkyl, or one of the groups p) or q)

in which u is 0, 1, 2, 3 or 4, R8 is (C, 12)alkyl, phenyl or phenyl(C1-8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently disubstituted by (C1-6)alkyl, (C1 6)alkoxy, halogen or hydroxy; pyridyl or pyridyl(C1 8)alkyl, or ii) when X is -S-, -SO-, -SO2-, -O-, -NH- or -NR3,-, Y may additionally also be one of the groups g) or h)

wherein R7 is as defined above, or iii) when X is -SO-, -SO2-, -O- or -NR3'-, Y may additionally also be one of the groups i) or j)

or iv) when X is -NR3'-, -CON(R)- or -N(R)CO-, Y may additionally also be a group k), -COOR9 k) wherein R9 is hydrogen, (C1-12)alkyl or phenyl(C, 8)alkyl or naphthyl(C1 8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (C1 6)alkoxy, halogen or hydroxy; or pyridyl(C1-8)alkyl, or a salt thereof.

6. A compound of claim 5 wherein m and n are independently 1, 2 or 3, R, is hydrogen, (C1-12)alkyl, (C1-12)alkylcarbonyloxy(C1 8)alkyl, phenyl or phenyl(C, 8)alkyl or naphthyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridyl or pyridyl(C1-8)alkyl, R2 is hydrogen, (C1-12)alkyl, phenyl(C, 8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (C, 6)alkoxy, halogen or hydroxy; or pyridyl(C1-8)alkyl, R3 is hydrogen, (C1 12)alkyl, phenyl(C1-8)alkyl, naphthyl(C, 8)alkyl, pyridyl(C, 8)alkyl, (C1-12)al- kylcarbonyl, (C1-12)alkoxycarbonyl, phenylcarbonyl, naphthylcarbonyl, phenyl(C, 8)alkylcarbonyl, naphthyl(C, 8)alkylcarbonyl, phenoxycarbonyl, naphthyloxycarbonyl, phenyl(C, 8)alkoxycarbonyl or naphthyl(C1-8)alkoxycarbonyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridylcarbonyl, pyridyl(C1-8) alkylcarbonyl, pyridyl(C1-8)alkoxycarbonyl; a group of formula II, in which R4 is hydrogen, X is -S-, -SO-, -SO2- or -0- and Y is one of the groups a), b), c), d), e), f) or g), or when X is -SO-, -SO2- or -O-, Y is additionally also group i), wherein R6 is (C1 22)alkyl, phenyl(C, 8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (C1-6)alkoxy, halogen or hydroxy; pyridyl(C1-8)alkyl, R7 is (C1 22)alkyl, phenyl(C, 8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C1 6)alkoxy, halogen or hydroxy; pyridyl(C1 8)alkyl, or one of the groups p) or q) in which u is 0, 1 or 2, R8 is (C1 12)alkyl, phenyl or phenyl(C1-8)alkyl or naphthyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridyl or pyridyl(C1-8)alkyl, or a salt thereof.

7. A compound of claim 5 wherein m and n are independently 1, 2 or 3, R1 is hydrogen, (C1 12)alkyl, (C1-12)alkylcarbonyloxy(C1-8)alkyl, phenyl or phenyl(C1-8)alkyl or naphthyl or naphthyl(C1 8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C1 6)alkoxy, halogen or hydroxy; pyridyl or pyridyl(C1 8)alkyl, R2 is hydrogen, (C1 12)alkyl, phenyl(C1-8)alkyl or naphthyl(C1 8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C, 6)alkyl, (C, 6)alkoxy, halogen or hydroxy; or pyridyl(C1 8)alkyl, R3 is hydrogen, (C1 12)alkyl, phenyl(C1 8)alkyl, naphthyl(C1 8)alkyl, pyridyl(C1 8)alkyl, (C1 ,2)al- kylcarbonyl, (C1-12)alkylcarbonyl, (C1 2)alkoxycarbonyl, phenylcarbonyl, naphthylcarbonyl, phenyl(C1-8)alkylcarbonyl, naphthyl(C1-8)alkylcarbonyl, phenoxycarbonyl, naphthyloxycarbonyl, phenyl(C1-8)alkoxycarbonyl or naphthyl(C1-8)alkoxycarbonyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C, 6)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridylcarbonyl, pyridyl(C1-8)alkylcarbonyl, pyridyl(C, 8)alkoxycarbonyl; a group of formula II, in which R4 is hydrogen, X is -CON(R)-, R is phenyl optionally substituted by (C1-4)alkyl, (C1 4)alkoxy, (C1 4)alkylthio or halogen, Y is one of the groups a), b), c), d), e) or k) wherein R6 is (C1 22)alkyl, phenyl(C1-8)alkyl or naphthyl(C1 8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1 6)alkyl, (C1 6)alkoxy, halogen or hydroxy;; pyridyl(C1 8)alkyl, R7 is (C1 22)alkyl, phenyl(C1-8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C, 6)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridyl(C1 8)alkyl, or one of the groups p) or q) in which u is 0, 1 or 2, R8 is (C1 12)alkyl, phenyl or phenyl(C, 8)alkyl or naphthyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C, 6)alkyl, (C, 6)alkoxy, halogen or hydroxy; pyridyl or pyridyl(C1-8)alkyl, R9 is hydrogen, (C, ,2)alkyl, phenyl(C, 8)alkyl or naphthyl(C1-8)alkyl, wherein each phenyl and naphthyl optionally is mono- or independently di- or trisubstituted by (C1-6)alkyl, (C, 6)alkoxy, halogen or hydroxy; or pyridyl(C1-8)alkyl, or a salt thereof.

8. A compound of claim 5, wherein m and n are independently 1, 2 or 3, R, is hydrogen, R2 is hydrogen, R3 is hydrogen, (C1-12)alkoxycarbonyl, phenyl(C1-8)alkoxycarbonyl, a group of formula II, wherein R4 is hydrogen, or a group of formula III, wherein R5 and R5' are each (C1 22)alkyl and v is O,, X is S, SO or SO2 and Y is the group a), a group c) wherein R7 is (C1 22)alkyl or the group p), wherein u is 2 or a salt thereof.

9. A compound of claim 5, wherein m is 2, n is 1, R1 is hydrogen, R2 is hydrogen, R3 is hydrogen, X is -CON(R)-, wherein R is phenyl, phenyl optionally being monosubstituted by halogen, and Y is a group k) wherein R9 is hydrogen or a salt thereof.

10. A compound of claim 5 which is (+ )-S-(3-phosphonopropyl)-D-cysteine or a salt thereof.

11. A compound of claim 5 which is S-(3-phosphonopropyl)-D,L-cysteine or a salt thereof.

12. A compound of claim 5 which is S-(2-phosphonoethyl)-D,L-homocysteine or a salt thereof.

13. A compound of claim 5 which is N-benzyloxycarbonyl-S-(3-phosphonopropyl)-D,L-cys- teine or a salt thereof.

14. A compound of claim 5 which is S-[3-[(dodecyloxy)hydroxyphosphinyl]propyl]-D,L cysteine or a salt thereof.

15. A compound of claim 5 which is (- )-N-(carboxymethyl)-N-phenyl-D-glutamine or a salt thereof.

16. A compound of claim 5 which is (+ )-N-(carboxymethyl)-N-phenyl-L-glutamine or a salt thereof.

17. A compound of claim 5 which is (- )-N-(carboxymethyl)-N-(4-chlorophenyl)-D-glutamine or a salt thereof.

18. A compound of claim 5 wherein R, and R2 are each hydrogen, m is 1 and n is 3 or a salt thereof.

19. A compound of claim 18 wherein R3 is hydrogen, X is S and Y is group a) or a salt thereof.

20. A compound of claim 18 wherein R3 is hydrogen, X is S and Y is group c) wherein R7 is group p) in which u is 2 or a salt thereof.

21. A compound of claim 18 wherein R3 is a group of formula II wherein R4 is hydrogen, X is S and Y is group a) or a salt thereof.

22. A compound of claim 18 wherein R3 is COOnC,2H2s, X is Sand Y is group a) or a salt thereof.

23. A compound of claim 18 wherein R3 is a group of formula III, wherein R5 and R5' are each nC4H9 and v is O, X is S and Y is group a) or a salt thereof.

24. A compound of claim 5 which is (- )-3-((3.phosphonopropyl)sulfinyl]-D-alanine or a salt thereof.

25. A compound of claim 5 which is (+ )-3-((3-phosphonopropyl)sulfonyl-D-alanine or a salt thereof.

26. A compound according to any one of claims 5 to 25 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

27. A compound according to any one of claims 5 to 25 or a pharmaceutically acceptable salt thereof for use for the treatment or epilepsy, disorders associated with excess GH or LH secretion, schizophrenia, depression, CNS degenerative disorders and cerebral hypoxic conditions.

28. A pharmaceutical composition which comprises a compound of any one of claims 5 to 25 or a pharmaceutically acceptable salt thereof in association with a pharmaceutical carrier or diluent.

29. A method of treating epilepsy, disorders associated with excess GH or LH secretion, schizophrenia, depression, CNS degenerative disorders and cerebral hypoxic conditions, which comprises administering a therapeutically effective amount of a compound of any one of claims 5 to 25 or a pharmaceutically acceptable salt thereof to a subject in need of such treatment.