LU85826A1 - SUBSTITUTED ALPHA-AMINO ACIDS, THEIR MANUFACTURE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Description

* Μ i *

The present invention relates to compounds of

formula I

r R-jOOC

'T ^ CH-'CH2) n-X- (CH2) n-Y I

* 5 a / »in which m and n are independently 1, 2 or 3, 1 R- | is hydrogen or an ester group, A is an optionally substituted amino group, X is a sulfur or oxygen atom or a sulfinyl, sulfonyl, imino, substituted imino group, or an amido group substituted by a hydrocarbyl residue having at least 2 carbon atoms and Y is an optionally substituted tetrazolyl group, a phosphorus acid group in which the phosphorus is> directly connected to the residue or an alkyl ester of this group optionally substituted by an aryl or alicyclic residue or £ an alicyclic ester of this group; or X is a sulfur or oxygen atom or a substituted sulfinyl, sulfonyl, imino or imino group and Y is furthermore also 20 'a sulfur acid ester in which the sulfur is directly linked to the residue or X is an atom of oxygen or a substituted sulfinyl, sulfonyl or imino group and Y is also also a sulfur acid group in which the sulfur is directly linked to the residue "<CH2) n-, or X is a substituted imino group or an amido group substituted by a hydrocarbyl residue having at least 2 carbon atoms and Y s is also also a carboxylic acid group or an ester of this group, as well as processes for their manufacture and pharmaceutical compositions containing them.

* The present invention also encompasses the salts of the compounds of formula I.

AT

2

The present invention further relates to the bioprecursors of drugs or "pro-drugs" of the compounds according to the invention defined above / namely compounds which are trans-n formed in vivo into compounds of formula I above.

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

R100C

* ^ Nh-ich,) -x-ccho-y 1 '/ cm in R / in which m and n are independently 1, 2 or 3, Rj is a hydrogen atom or a C ^ -C ^ alkyl group / (C ^ jC ^ 15 carbonyloxy C ^ -Cg alkyl, (C ^ -C ^ alkoxy car-bonyloxy-C ^ -Cg alkyl, C ^ -C ^ carboxylalkyl carbonyloxy-alkyl C1-C6, phenyl or phenyl-C1-C6 alkyl or naphthyl or naphthyl-C1-C6, where each phenyl or naphthyl is optionally monosubstituted or independently di- or tri- substituted by C1-C6 alkoxy C ^, halogen or hydroxy; pyridyl or pyridyl C 1 -C 6 alkyl, R2 is hydrogen or C 1 -C 4 alkyl / · phenyl C 1 -C 6 alkyl or naphthyl C 1 -C 6 alkyl , wherein each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen or hydroxy; or pyridyl C 1 -C 6 alkyl,

Rj is hydrogen or phenyl-Cj-Cg alkyl, naphthyl-C ^ -Cg alkyl, pyridyl-Cj-Cg alkyl, (C> C alkyl]] “C -] ^“ carbonyl, (alkenyl in C2 ”C22carbonyLe / Calcadienyl in 30 C ^ -C225carbonyl, (alkatenyl in C ^ -C2 ^" carbonyl, Calca-tetraenyl in Cg-C22 ^ carbonyl, (alkoxy in C- | -C ^ 2 ^ carbony'-e / phenylcarbonyl, naphthylcarbonyl, phenyl- (C 1 / C 6 alkyl) -carbonyl, naphthyl- (C 1 -C alkyl - Cg) carbonyl, phenoxycarbonyl, naphthyloxycarbonyl, phenyl- (C 1 -C 6 alkoxy) carbonyl or r * 3 naphthyl - (C 1 -C 6 alkoxy) carbonyl, or each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C 1 -C 4 alkoxy, halogen or hydroxy; pyridylcarbonyl, pyridyl- C., - Cg) carbonyl,

C 5 pyridyUalkoxy (j-Cg) carbonyl; a group of formula II

R4 -CO ^^ N χ LJÛ 10 in which R ^ is hydrogen or an alkyl group in or phenyl-C ^ -C ^ alkyl, in which the phenyl group is optionally monosubstituted or independently disubstituted by C ^ alkyl - C ^, C ^ -C ^ alkoxy, halogen or hydroxy, or a group of formula III or IV, 15 ch2o (co) vr'5 ch2-o (C0) vR'5 -C00CH ch-o (co) vr5 CH20 (C0) vR5 -cooch2

III IV

wherein R5 and R ^ 'are each independently C 1 -C 22 alkyl, C 2 -C 22 alkenyl, C 1 -C 22 alkadienyl, C 1 -C 22 alkatenyl, C 1 -C 22 alkatetraenyl and v is independently each times 0 or 1, X is -s-, -SO-, S02-, -0-, -NH-, -NR-j'-, -CON (R) - or -N (R) CO-, "Rg has the same meaning as Rg, except that it is not hydrogen, R is a C2-C2-alkyl, phenyl or phenyl-C1-alkyl, in which each phenyl is optionally monosubstituted with phenyl or phenyl-C 1 -C 4 alkyl or monosubstituted or independently di- or tri-substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, π m "4 C 1 -C 4 alkylthio, halogen, hydroxy or trifluoromethyl, i) Y is one of the groups a), b), c), d), e) or f), 0 OH 0 OR, 0 OH 0 Rr

te II / Il / O II S II / O

~ v -P -P '-P

5 'Nw' S \ îR6 N) R7 ^ OH

a) b) c) d)

0 Λ // N‘N

<<i

X0R, N-N

o i

10 a.m.

e) f) sJ3 \. wherein R ^ is C ^ -C22 alkyl / phenyl-C ^ -Cg alkyl or naphthyl-C ^ -Cg alkyl in which each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C1-C6 alkyl, C1-C6 alkoxy, halogen or hydroxy; pyridyl C 1 -C 6 alkyl, R7 is C 1 -C 22 alkyl, phenyl C 1 -C 6 alkyl or naphthyl C 1 -C 3 alkyl where each phenyl or naphthyl is optionally monosubstituted or independently di- or tri- substituted with C1-C6 alkyl C1-C6 alkoxy haL ° 3èna or hydroxy; pyridyl-C1-C8 'alkyl or one of the groups p) or q)

* T

. "V P

25 P> q) in which u is equal to 0, 1, 2, 3 or 4, - 5 's

Rg is a C 1 -C 4 alkyl / phenyl or phenyl-C 1 -C 5 alkyl or naphthyl C 1 -C 6 alkyl, in which each phenyl or naphthyl is optionally monosubstituted or independently disubstituted by alkyl C ^ -C ^, C ^ -C ^ alkoxy, halogen or hydroxy; 5 pyridyl or pyridyl-C 1 -C 6 alkyl or ii) when X is -S-, -SO-, -SO27, -0-, -NH- or -NR ^ '-, Y can also be also one of the groups g) or h) 0 0

He II

10 —S — OR-J ”-S-ORy

II

0 g) h) in which Ry is as defined above, ^ 15 or iii) when X is -SO-, -SO2, -0- or -NR ^ ', Y can also be one of the groups i) or j) '. 0 0 ri h

-S-OH -S-OH

20 0 i) j) or iv) when X is -NR ^ '-, -CQN (R) - or -N (R) C0-, Y can also be a group k), 25 -C00R9 k) “ wherein R 1 is hydrogen, C 1 -C 4 alkyl or phenyl C 1 -C 6 alkyl or naphthyl C 1 -C 6 alkyl, in which each phenyl or naphthyl is optionally monosubstituted or independently di- or tri- substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen or hydroxy; or pyridyl-C 1 -C 8 alkyl, or else, when the compound of formula 1 ′ contains a salifiable group, a salt of this compound.

c »6

Examples of the salts of a compound of formula I ′, when the compound contains a salifiable group, which is a free carboxylic acid group (that is to say Rj is hydrogen or Y is a group k) in which R is hydrogen], a phos acid group - ** 5 Free phonic acid (ie Y is one of the groups a), c) or d)], a free sulfonic acid group C is that is, ^ is a group i)] or a free sulfinic acid group [ie Y is a group j)] or the tetrazolyl group [Y is a group f)], include - cationic salts such as the alkali metal salts or the optionally substituted ammonium salts. When, in the compounds of formula I ', R3 is other than a group containing a carbonyl, it is possible to form acid addition salts such as hydrochloride, hydrobromide or maleate. Other acid addition salts are possible when X is NH or NR'3 in which R'3 is other than a group containing a carbonyl.

The compounds of formula I have at least one chiral center on the carbon atom carrying the amino group and can therefore exist in the form of enantiomers. Other chiral centers may appear, for example, on the phosphorus atom in group e) and the sulfur atom in group h). The present invention extends to individual enantiomers, racemates, dias-tereoisomers and mixtures thereof.

When alkenyl groups are present, there are cis or trans isomers. These isomers also fall within the scope of the present invention.

In a group of compounds of formula I ', m and n are independently 1, 2 or 3, R- | is hydrogen, (C1-C6 alkyl) carbonyloxy- C1-C6 alkyl, phenyl or phenyl-C1-C6 alkyl or naphthyl or naphthyl-C1-C8 alkyl, in which each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen or hydroxy; pyridyl or pyridyl C 1 -C 6 alkyl, R2 is hydrogen, phenyl C 1 alkyl -Cg or naphthyl-C 1 -C 6 alkyl in which each phenyl or naphthyl 7 is optionally monosubstituted or independently di or tri-substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen or hydroxy ; or pyridyl C1-C6 alkyl /

Rj is Hydrogen, C ^ -C ^ alkyl, phenyl-Cj-Cg alkyl,, 5 naphthyl-C <| -Cg alkyl, pyridyl-C ^ -Cg alkyl, C ^ -C ^ calkyl carbonyl, (C 1 -C 6 alkoxycarbonyl, phenylcarbonyl, naphthylcarbonyl, phenyl-C 1 -C 6 carbonyl) carbonyl, naphthyl- (C 1 -C 6 alkyl) carbonyl, phenoxycarbonyl, naphthyloxycar- * bonyl, phenylC 6 -C alkoxy) carbonyl or naphthyalkoxy (10 C, j-Cg) carbonyl in which each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C 1 -C 6 alkyl, C 1 -C alkoxy, halogen or hydroxy; pyridylcarbonyl, pyridyl- (C 1 -C 6 alkyl) carbonyl, pyridyl-Calcoxy (C 1 -C 6) carbonyl; A group of formula II, in which is hydrogen, X is -S-, -S0-, -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 -0-, Y is furthermore also a group i), in which R6 is an alkylphenyl-alkyl group C 1 -C 6 naphthyl C 1 -C 6 alkyl, in which each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen or hydroxy; pyridyl C 1 -C 6 alkyl, R 1 is C 1 -C 6 alkyl / phenyl C 1 -C 6 alkyl or naphthyl C 1 -C 6 alkyl in which each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted with C 1-6 alkyl, C 1-6 alkoxy or halogen or hydroxy; pyridyl-C 1 -C 6 alkyl, or one of the groups p) or q) xr in which u is equal to 0, 1 or 2,

Rg is a C 1 -C 4 alkyl / phenyl or phenyl C 1 -C 4 alkyl or naphthyl or naphthyl or C 1 -C 4 alkyl, in which each phenyl or naphthyl is optionally monosubstituted or independently di - or tri-substituted by c1 "c6" alkyl alkoxy

Ci “C6, halogen or hydroxy; pyridyl or pyridyl-C 1-6 -alkyl, δ or, when the compounds of formula 1 ′ contain a salifiable group, a salt of this compound.

In another group of compounds of formula I ′, - m is equal to 1, 2 or 3,; 5 n is equal to 1 or 2, Rl is hydrogen or a C1-C6 alkyl carbonyloxyalkyl, phenyl or phenyl C1-C8 alkyl or naphthyl or naphthyl-C 1 -C 6 alkyl, in which each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C 1 -C 4 alkyl, C 1 -C 6 alkoxy / halogen or hydroxy; pyridyl or pyridyl C 1 -C 6 alkyl, F * 2 is hydrogen or phenyl C 1 -C 6 alkyl or naphthyl C 1 -C 6 alkyl, in which each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen or hydroxy; or pyridyl-C 1 -C alkyl -C R 6 is hydrogen or a C 1 -C 4 alkyl group / phenyl-alkyl C 1 -C 6 naphthyl C 1 -C 6 alkyl, pyridyl C 1 -C 6 alkyl, (C 1 -C 12 alkyl ^ carbonyl / (C1-C12 carbonyl ^ carbonyl phenylcarbonyl, 20 naphthylcarbonyl, phenyl- (alkyl in Cj-Cg) carbonyl, naphthyl- (C ^ -CgJcarbonyl alkyl, phenoxycarbonyl, naphthyloxycarbonyl, phenyl-C, C, j-Cg) carbonyl or naphthyl- (-Cg> -alkoxy) carbonyl in which each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C ^ alkyl - C ^, (^ -C ^) alkoxy, halogen or hydroxy; pyridylcarbonyl, pyridyl- (C 1 -C 6 alkyl) carbonyl, pyridyl- (C 1 -C 6 alkoxy) carbonyl; or a group of formula II in which R ^ is hydrogen, X is a group -CON (R) -, R is phenyl optionally substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, alkylthio in halogen, trifluoromethyl or phenyl-alkyl in CjC ^, Y is one of the groups a), b), c), d), e) or k) in which / 5 9

Rg is a phenyl-C1-C6 alkyl or naphthyl-C1-C6 alkyl group, in which each phenyl or naphthyl is I o optionally monosubstituted or independently di- or tri- substituted by C ^ alkyl - C1, halogenated alkoxy or - 5 hydroxy; or pyridÿl-alkyl in C -CQ, I o R-j. is a C 1 -C 22 alkyl / phenyl-C 1 -C 6 alkyl or naphthyl C 1 -C 6 alkyl group in which each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C 1 -C 4 alkyl, C1-C6 alkoxy, halogen or hydroxy; pyridyl-C 1 -C alkyl or one of the groups p) or q) in which u is equal to 0, 1, 2, 3 or 4,

R 8 is a phenyl or phenyl-C 1 -C 6 alkyl or naphthyl or naphthyl or C 1 -C 6 alkyl group in which each phenyl or naphthyl is optionally monosubstituted or independently - di- or tri-substituted by alkyl C ^ -C ^, C ^ -C ^ alkoxy, halogen or hydroxy; pyridyl or pyridyl-C ^ -Cg alkyl, ^ Rç is hydrogen or a C * | -C <| 2 / phenyl-C ^ -Cg alkyl or naphthyl-C ^ -Cg alkyl group, in wherein each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen or hydroxy; or pyridyl-C 1 -C 6 alkyl, or alternatively, when the compound of formula 1 ′ contains a salifiable group, a salt of this compound.

In yet another group of compounds of formula I ', m is 1 or 2, n is 3, R <| is hydrogen, R2 is hydrogen, Rg is hydrogen or a group (C1-C6 alkoxycarbonyl, phenylC1-C6alkoxy) carbonyl, a group of formula II in which R ^ is hydrogen or a group of formula III in which Rg and Rg 'are each C1-6 alkyl / especially v-alkyl is 0, X is S, SO, SO2 and Y is

group a), a group c) in which R ^ is C 1 -C 4 alkyl ^ u the group p) in which u is equal to 2. In another group of compounds of formula I ′, m is equal to 2, n is 1, Rj is hydrogen, R2 is hydrogen, Rg is hydrogen, X is -CON (R) -, wherein R is phenyl, optionally monohalogenated, and Y

10 is a group k) in Which is Hydrogen.

In particular, a compound of formula I can be produced by a process which comprises the following stages: A) production of a compound of formula la,

5 R-, OOC

** ^ H-CCHO-X'-CCHO-Y 'la v · c. m c n br in which A, m and n are as defined above, R-j1 is R <| other than hydrogen, X 'is -S- and Y' is an acid ester group

10 sulfur by reaction of a compound of formula V

'OOC

^ CH-ICHO -SH V

/ 2 m 15 in which R'-j, A and m are as defined above, with a compound of formula VI,

W_ (CH2) n "Y 'VI

in which n and Y ′ are as defined above and W is an eliminable group, and if necessary elimination of the amino-protective groups which may be present, B) production of a compound of formula Ib,

HOOC

^ CH- (CHO-X "- (CH-,) -Y 'Ib s c. M en h2n ^ î 25 wherein m, n and Y' are as defined above and X" is -0-,

5 by reaction of a compound of formula VII

C00R - / 1

R10HN-CH VII

VOOR ^ a.

11 in which R ^ Q is an acyl group and is a C 1 -C 4 alkyl group, with a compound of formula VIII,

W— (CHOm "" X "- (CHO —Y 'VIII

dm dn.; r in which X ", m, n, Y 'and W are as defined above, under 5 basic conditions, hydrolysis and decarboxylation of the resulting product, C) production of a compound of formula le, R- OOC 1 \ ^ CH- (CHp) -X- (CHp) -Y "le ✓ dmdnf /

In which R ^, A, m, n and X are as defined above and Y "is a tetrazolyl group, by reaction of a compound of formula IX

R-OOC 1 \

CH-CCHOm-X- <CH->) -CN IX

s dm dn "15 in which R ^, A, X, m and n are as defined above with a salt of hydrazoic acid and elimination, if necessary, of the amino-protecting groups possibly present, D) production of a composed of formula Id,

R-jOOC

20 NsCH- (CHOm-X, "- (CH?) - Y Id yr dm dn A 'in which R ^, A, m, n and Y are as defined above and X"' is -S0- or - SO2-, by oxidation of a compound "of formula Iab,

R-jOOC

25 ^ CH-CCH,) -X'-CCH,) -Y Iab - ydmdn î p / in which R ^, A, m, n, X 'and Y are as defined above, and elimination, if necessary groups amino protectors possibly present, 12 E) production of a compound of the formula lyooc \: H- (CH?) m-X1V- (CH?) -Y "'the y cm in ♦ H2rr

In which R ^ ', m and n are as defined above, X1V is -NH- or -NR ^' -, Y '"is a phosphorus acid ester group, a sulfur acid ester group '' and when X1V

is -NRj1-, Y1 "can also be also a carboxylic acid group or its ester, by reaction of a compound of formula X

10

R1’OOC

^ CH, X

<c6h5) 2C = n /

in which R <| 1 is as defined above, with a compound of formula XI

15 Rtz "

W- (CHp) -N- (CHp) -Y "'XI

cm en in which m, n, W and Y "'are as defined above and Rj" is as defined for R ^' above / but can also be an amino-protective group, under basic conditions, hydrolysis of compound 20 resulting and elimination, if necessary / of the amino-protecting groups possibly present, F) production of a compound of formula If,

Rl'OOC

^ CH- (CH ·,) -XV- (CH,> -Y1V If y 2 m 2 n A '25 in which R ^', A, m and n are as defined above, Xv is a substituted amido group with a hydrocarbyl residue having at least two carbon atoms and Y1V is a phosphorus acid ester group or a carboxylic acid group or its ester, by reaction of a y compound of formula XII, 13

R1 OOC

ΎΗ- (ΟΗ,) -U CXII

2 ”.4

7 with a compound of formula XIII

'- 5 U'-CCH,) -Y1V ΧΠΙ 2 n in which R, j', A, Y1V, m and n are as defined above and either of the residues U and U 'is -CO -Z and the other is an amino group substituted by a hydrocarbyl residue having at least 2 carbon atoms and Z is a reactive carboxylic acid residue 10 and elimination, if necessary, of the no-protective friend groups possibly present and / if desired / conversion of one compound of formula I to another and optional introduction of substituents which are different from hydrogen, e.g. substitution of group A or esterification of acid groups, conversion of esters to corresponding acids or, when the compound of formula I contains a salifiable group, formation of a salt of the salifiable compound.

Method A can be implemented in a conventional manner. The compound of formula V can be prepared in situ, for example by cleavage of the corresponding symmetrical disulfide / for example by a compound of formula HS- (CH2) n-OH. The reaction is advantageously carried out in an organic solvent such as methanol, ethanol or dioxane at room temperature. The reaction is carried out in an oxygen-free atmosphere. The subsequent reaction with a compound of formula VI, in which W is for example a halogen, especially bromine, or a methylsulfonyloxy or p-methylphenylsulfonyloxy group, is suitably carried out in the presence of an acceptor agent. acids such as triethylamine. If the process is to be carried out to obtain a compound of formula la in which A is an amino group unsubstituted or monosubstituted by a group other than a group containing a carbonyl residue, a compound of 14 should be used. formula V, in which A is protected by an amino-protecting group. Conventional amino protecting groups such as benzyloxycarbonyl or terbutyloxycarbonyl can be used. Removal of the protecting groups (deprotection) can be carried out using a conventional technique, for example by hydrolysis. The benzyloxycarbonyl group can also be removed by hydrogenolysis.

Method B) can be implemented in a conventional manner. The reaction can be carried out in an organic solvent such as methanol, ethanol or toluene in the presence of sodium methylate or sodium ethylate at a temperature between 40 and 110 °. Subsequent hydrolysis and decarboxylation can be carried out, for example, with a mineral acid. In the compounds of formula VII, is, for example, a formyl, acetyl, benzoyl or benzyloxycarbonyl group.

Process C) can be implemented in a known manner for the synthesis of a tetrazole ring. Salts of hydrazo acids include alkali metal salts such as sodium azide, alkaline earth metal salts such as magnesium azide, other metal salts such as aluminum azide . These salts can be used alone or in combination with ammonium chloride or a Lewis acid such as aluminum chloride. The reaction can be carried out in a solvent such as tetrahydrofuran, dioxane or dimethyl-formamide at the reflux temperature of the solution. In the compound of formula IX, A is suitably protected by an amino-protecting group, when compounds of formula le are to be prepared in which A is an unsubstituted amino group or monosubstituted by a group other than a group containing an i 30 remains carbonyl. Deprotection can be performed as? described in method A).

jt15

Method D) can be implemented in a known manner. Any conventional technique for the oxidation of a thioether to the sulfoxide or sulfone can be used to carry out this reaction. For example, for the preparation of? 5 sulfoxides can be used sodium periodate, NaBO ^ or tetra (n-butyl) ammoniumperiodate. The sulfones can be obtained by using NaBOj, 1 ^ 2 in formic acid or KHSO, - as an 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, in which A is an amino group unsubstituted or monosubstituted by a group other than a group containing a carbonyl, advantageously is used a compound of formula Iab in which A is protected by a amino protecting group as previously described.

The process E) can be carried out in a conventional manner. The reaction can be carried out, for example, in a basic two-phase system, for example a water immiscible solvent such as dichloromethane and solid or aqueous sodium hydroxide, using a phase transfer catalyst $ per 20 example benzyltriethylammonium chloride. Suitable temperatures are between 0 ° and room temperature.

Alternatively, the reaction can also be carried out in an organic solvent such as methanol, ethanol or toluene in the presence, for example, of sodium ethylate or sodium methylate at a temperature between 40 and 110 °. The subsequent hydrolysis of the resulting product can be carried out, for example, by hydrochloric acid. When a compound of formula Ie in which X1V is -NH- is desired, R ^ "is advantageously an amino-protecting group as defined in process A).

The method F) can be implemented in a conventional manner. For example, Z is a halogen, especially chlorine or bromine, or a group -O-COOR ^ in which R ^ is C <j-C ^ alkyl. The reaction is conveniently carried out in an organic solvent such as methylene chloride at room temperature. Advantageously, the operation is carried out in the presence of an acid acceptor, such as triethylamine. In the compounds of formula XII, A is suitably protected by an amino-protecting group when compounds of formula If are desired in which A j is an amino group unsubstituted or monosubstituted by a group r 5 other than a carbonyl group . The removal of the protective group is carried out in a known manner.

Mutual conversions from one compound of formula I to another can be carried out in a conventional manner and can be used * for example ^ to reintroduce a group which has been removed in the above-mentioned methods.

The optional introduction of substituents into an amino group can be carried out in a conventional manner. For example, the alkylation of the amino group can be carried out by alkyl halides or alkyl sulfates. If only one alkyl group is to be introduced, dialkylation is suitably avoided by the application of known techniques, for example N-acylation, alkylation via an N-acylated anion, removal of the "acyl group. When the compound to be alkylated contains a free carboxy group (for example is hydrogen), it is preferably blocked by a protective group, for example benzyl which can be removed by selective hydrogenolysis. The acylation of the amino group can be carried out by reaction with the appropriate acid or a reactive derivative thereof. Urea can be prepared by reaction with an ester of haloformic acid.

The optional esterification can be carried out using conventional techniques. When it is desired a phosphonic acid monoester CY is a group cl esterification can be carried out for example 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 unsubstituted or monosubstituted by a group other than a carbonyl group, this 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 carried out by any conventional technique, for example by hydrolysis. Using selective techniques, for example hydrogenolysis, compounds of formula I can be prepared in which either the phosphonic diester, z or the carboxylic ester is converted to the corresponding acid.

The optional formation of a salt, when the resulting compound of formula I contains a salifiable group, can be carried out in a conventional manner.

Compounds of formula I not corresponding to formula 1 'can be produced in a similar manner to similar compounds of formula 1' or by known and conventional techniques.

Insofar as the production of the starting materials for the above processes is not particularly described, these can be produced analogously to known compounds or to the processes described here.

^ The racemates can be separated by conventional means, for example by fractional crystallization of optically active salt forms. Alternatively, a pure enantiomeric or diastereoisomeric form can be produced using optically active starting materials or diastereoisomers. The cis-trans mixture can be separated in known manner into the corresponding cis and trans components.

In the following examples, all temperatures are given in degrees Celsius and are not corrected. The Ccü ^ values are also uncorrected.

Example 1: (+) - S- (3-phosphonopropyl) -D-cysteine.

A solution of 13.2 g of di-benzyloxycarbonyl-D-cystine diethyl ester in 240 ml of methanol / water mixture (10: 1) is adjusted to pH 8 by adding concentrated ammonia.

4.5 ml of 2-mercapto-ethanol are added under nitrogen and the mixture is stirred for 5 h at room temperature. The mixture is then evaporated in vacuo and the residue is dissolved in 50 ml of triethylamine. Then added dropwise under nitrogen 14.2 g of diethyl 3-bromo-propanephosphonate and the mixture is stirred at room temperature overnight. The solvent is removed under vacuum 4 "'·" 18 and the residue is dissolved in the ether / toluene mixture (1 1).

The solution is washed with water and with a brine solution.

After drying over anhydrous sodium sulfate, the solvent is removed in vacuo. The residue is heated to reflux with 100 ml of 7N hydrochloric acid for 10 h. The mixture is evaporated in vacuo, the residue is dissolved in ethanol (94%), treated with propylene oxide and evaporated in vacuo to give the desired compound which is recrystallized from the ethanol mixture / water, F. 203-205 C decomp.), Zal ^ ° = + 14.8 ° (c = 0.7 in water).

Example 2: S-C3-phosphonopropyl) -D.L-cysteine.

Analogously to Example 1, but starting from the diethyl ester of di-benzyloxycarbonyl-D, L-cystine, the desired compound F 215-218 ° (decomp.) Is obtained.

- Example 3: S- (2-phosphonoethvl) -D.L-homocysteine.

Analogously to Example 1, the desired compound - is obtained in amorphous form.

Example 4: N-benzyloxycarbonyl-S- (3-phosphonopropyl) -D, L-cysteine.

4.8 ml of benzyl chloroformate at 5-10 ° C are added dropwise to a stirred suspension of 3.7 g of S- (3-20 phosphonopropyl) -D, L-cysteine and 2.5 g of magnesium oxide in 25 ml of water and 10 ml of ether. The mixture is stirred at room temperature for 24 h. The mixture is then acidified with concentrated hydrochloric acid (ice cooling) and extracted with ethyl acetate. The organic phase is dried and evaporated. The residue is recrystallized from an ether / ethyl acetate mixture to give the title compound, mp 102-105 °.

Example 5: S-C3-C (dodecyloxy) hydroxyphosphinyl3propyl] -D.L-cysteine.

A mixture of 2.1 g N-benzyloxycarbonyl-S- (3-phosphonopropyl) -D, L-cysteine, 1.25 ml of 1-dodecanol, 0.55 ml of trichloroacetonitrile is stirred at 100 ° for 6 h. 20 ml of anhydrous pyridine. The mixture is then evaporated under vacuum and the residue is partitioned between the dilute aqueous sodium carbonate and the ether.

The aqueous phase is acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase v is dried and evaporated. The residue is treated with 15 ml of a solution of HBr in trifluoroacetic acid and the mixture is stirred for 2 h at room temperature. The mixture is then evaporated in vacuo and the residue is partitioned between dilute hydrochloric acid and ethyl acetate.

The aqueous phase is evaporated in vacuo, the residue is dissolved in ethanol (94%), treated with propylene oxide and evaporated in vacuo. The residue is recrystallized from ether to give the title compound * F 160-163 °.

Example 6:

In an analogous manner, the following compounds of formula 1 ′ are prepared in which and R 1 are each hydrogen, i - 15 m is equal to 1 and n is equal to 3:

Configu- Analogous to

Example R3 X Y "tlon P.F. Example a) H S 0 L 203-205 1 P (OH) 2 decomp.

»» H s * ycH2, JP ° ’L 168'172 5

H

; c) = ° ηΑο so ο 4 P (0H) 2 20

Configu- Analogue

Example R, X Y ration P.F. in example d) C0 0nCi2H25 s 0 D »L 123-126 4

II

p (oh) 2 5 e) C00CH (CH20-nC4H9) 2 S0 0, L 1) 4

II

p (oh) 2

Rf = 0.73 CCH3COOC2H5 / CH3COOH / H2O (5: 2: 2)] s

Example 7: (-O-N-Ccarboxvmethyl) -N-phenyl-D-qlutannne.

A solution of 7.4 g of α-benzyl N-benzyl-10-oxycarbonyl-D-glutamate in 120 ml of methylene chloride and 2.7 ml of triethylamine is stirred at 0 ° and 1 drop is added. , 9 ml of ethyl chloroformate. The mixture is stirred at approximately 10 ° for 1 1/2 hours, then 3.3 g of N-phenylglycine are added in portions. The reaction mixture is then stirred for 48 h while allowing to warm to room temperature. The mixture is extracted with a cold dilute solution of sodium hydroxide, the extract is acidified with 2N hydrochloric acid (ice cooling) and extracted with methylene chloride. The chloromethylenic extract is dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 120 ml of methanol-water mixture (1: 1) and hydrogenated under normal conditions on a palladium carbon catalyst (10%). The mixture is then heated to dissolve the precipitate and the catalyst is filtered off.

The filtrate is evaporated to obtain the title compound, which is recrystallized from a methanol / water mixture, F 207-208 (decomp.); [a] ^ = -33.7 ° (c = 0.6 in 0.2 N HCl). After repeating the recrystallization from ethanol / water several times, the title compound has an F of 220-222 (decomp); Calli ^ = -55.1 °

îr U

5 (c = 0.6 in 0.2 N HCl).

Example 8:

The following compounds of formula 1 'are obtained in an analogous manner to Example 7: a) (+) - N- (carboxymethyl) -N-phenyl-L-glutamine, mp 209-211 ° (decomp.); 10 [oüp0 = + 34.2 ° (c = 0.6 in 0.2 N HCl), b) (-) - N- (carboxymethyl) -N- (4-chlorophenyl) -D-glutamine, decomp. from 150 °: Ca ^ ° = -20.5 ° (c = 0.6 in 0.2 N HCl).

Example 9: (-) - 3-E (3-ohosphonopropyl) sulfinyU-D-alanine. i, To a solution of 1.5 g of (-) - S- (3-phosphonopropyl) - 15 D-cysteine in 60 ml of water, a solution of 1 is added dropwise at 0 ° with stirring. 25 g of sodium periodate in 10 ml of water. The mixture is stirred at 0 ° for 15 min and then evaporated in vacuo. The residue is dissolved in water and passed through an ion exchange column packed with Dowex 50W X8 20 (0.42-1.19 mm) and the column is eluted with water. The eluate is evaporated in vacuo to give the title compound which is recrystallized from a water / ethanol mixture, mp 180-190 ° (decomp.).

Example 10: (H -) - 3-E (3-phosphonopropyl) sulfonyU-D-alanine.

To a stirred solution of 1 g of (-) - S- (3-phosphono-25-propyl) -D-cysteine in 30 ml of formic acid, 8.8 ml of H 2 are added dropwise at room temperature O-, at 30%. The mixture is stirred at room temperature for 48 h. The crystalline precipitate is filtered off, washed with ethanol and then with ether to give the compound mentioned, titrating at 30 ° 201-204 ° (decomp.).

The compounds of formula I exhibit pharmacological activity and are therefore indicated for use in therapy as medicaments. In particular,

The compounds exhibit activity on the central nervous system as indicated in standardized tests. For example, the compounds inhibit locomotion in mice. In this test, 5 of the groups of three male mice (18-24 g, OF-1, Sandoz Basel) receive 3.2 mg 10 mg, 32 mg, 100 mg and 320 mg of the drug tested i.p. 1 hour after administration of the drug, the mice are observed individually and their locomotion is compared with that of control mice treated concurrently with the vehicle. It is estimated that the locomotion is either unchanged, markedly superior or inferior to that of the controls, strongly above or below that of the controls, or totally inhibited.

The compounds of formula I also exhibit an anticonvulsant activity, indicated in standardized tests.

In a first test, the compounds inhibit convulsions induced by EC electroshocks in mice. Suinyard, in J. Am. Pharm. Soc. 38. p 201 (1949) and J. Pharm. Exp. Therap. 106 # p 319 (1952) 1. In this test, groups of three mice (18.26 g 0F-1, Sandoz Basel) receive the test substance at a dose of 3.2-20 320 mg / kg i.p. After 60 min, a shock of 50 mA is applied for 200 ms by corneal electrodes coated with an electrolyte jelly. This shock above the threshold produces convulsions of the tonic extender from all extremities. The inhibition of the extension of the hind leg is taken as a protective effect. 25 After studying several doses, an EDmin is evaluated.

In a second test, the compounds also inhibit convulsions induced by 3-mercaptopropionic acid in mice. In this test, groups of six female mice (18-26 g, 0F-1, Sandoz Basel) are pretreated with the test substance at a dose of 0.1-100 mg / kg i.p. 30 min after receiving 100 mg / kg s.c. of 3-mercaptopropionic acid ^ they are observed for 30 min. We note the waiting times for the appearance of the first signs of convulsions, for the first tonic convulsions and for death. The significance of possible differences is observed using the Mann-Whitney ES U test. Siegel, Non-parametric Statistics, McGrawHill, New York 1956], 5 23

The compounds of formula I act on excitatory amino acid systems, and are in particular competitive antagonists of NMDA receptors (N-methyl-D-aspartic acid), v as indicated by an inhibitory effect on depolarizations of 5 NMDA-induced amphibian-isolated spinal cord. This can be shown in the test carried out in a conventional manner (see for example DR Curtis et al., J. Physiol. (London) 150, p 656-682, (1961) and RH Evans et al., Br. J. Pharmac. 67 , p 591-603 (1979)) as follows: a proximal part cut in half of the spinal cord of a toad or a frog is placed in a recording chamber, with infusion by a Ringer solution (NaCl 111 mM, 2 mM KCl, 1 mM CaCl2, 12 mM glucose, Tris buffer (pH 7.5, 10 mM) The dorsal root is drawn into the stimulation chambers, the ventral root into the recording chambers.

We use a stimulator connected to the stimulation chambers. A high impedance DC preamplifier measures the DC potential between the sample ground wire of the main chamber and one of the recording chambers.

The signal from the preamplifier is followed on a CRO to display the stimulated synaptic activity (dorsal root potential - ventral root, RD-PRV) or on a graphic recorder to indicate slow variations in potential. A copy of the preamplifier signal is introduced into an integrator which calculates the area under the curve.

The excitatory amino acid agonists are »applied at increasing doses from 1 μΜ to 1 mM to determine the dose-response curves (CDR). After each dose, usually applied for 30 sec to 1 min, the drug is washed away until the PRV control values are reached. s, To measure the effect of each dose, the following technique is used: the area under the curve measured by the integrator is taken continuously at 1 min intervals; the values for the last 5 min before the application of the drug are added to the values for the first 5 min after the slope of the PRV has returned to the control values and the average is taken. This average represents the control PRV and it is deduced from the average values of the first 5 min after the application of the drug. The effect of increasing doses is then measured and the numbers are entered into a computer 5 which constructs a dose-response curve (CDR). The values of CE ^ q are then determined graphically from these CDRs.

The antagonists are tested in two stages. The first step is to apply the agonist 3-5 times at a constant concentration close to EC. ^ And repeat the procedure in the presence of the antagonist. After a period of elimination by washing, the agonist alone is again tried 3-5 times to assess recovery. The values obtained in these experiments are again entered into the computer which draws bar diagrams, calculates the means of the control, drug and recovery groups and statistically assesses the difference between the control group and the drug group. If a drug tried causes inibition in the first stage, we try in the second stage competitive antagonism. This is achieved by determining a 4-point CDR of the antagonist in the linear section and then repeating the CDR in the presence of the supposed antagonist at a constant concentration. Recovery is attempted by repeating the CDR after washing away the tested drug. A first indication of competitive antagonism is given by a parallel shift towards <.e. right 25 of CDR in the presence of the antagonist, for example of the compounds of the present invention at a concentration of 1 to approximately 300 μΜ. In such cases, the pA2 values are calculated according to the form pA2 = - Log I + Log (A50.) (B50 ~ ') 30 in which I is the concentration of the antagonist, A50 is the EC, jq for L The agonist in the presence of the antagonist and B50 is the ECj-q of the agonist only before the application of the drug tested.

25

One can confirm competitive antagonism by repeating the experiment with a double dose of the drugs tested, if one obtains roughly the same pA2, there is a good probability that the antagonist is competitive (0. Arunlakshana and others , Brit. J.

5 Pharmacol. .19, p 48-58 (1959); M. Wenke, Drug receptor interactions, BACQ ZM (ed) Fundamentals of biochemical pharmacology, Pergamon Press, Oxford, p 357-381 (1971)).

The compounds of formula 1 'in which X is S, SO, SOg, NH or NR ^ i are also selective as indicated by the fact that the depolarizations induced by quisqualate are not significantly affected in the above test. above in which we replace the NMDA with quisqualic acid.

The compounds of formula 1 'in which X is CON (R) or N (R) C0 are broad spectrum antagonists as indicated by the fact that depolarizations induced by quisqualate and kainate are also inhibited.

Based on the activities mentioned above on the CNS, the compounds of formula I are indicated for use in the treatment of CNS diseases. It results from their anticonvulsant activity that the compounds are indicated for use in the treatment of epilepsy. For this use, a daily dose indicated is in the range of about 25 to about 800 mg of the compound, suitably administered in divided doses 2 to 4 times a day in the form of unit doses containing, for example, from approximately 25 6 to approximately 400 mg of the compound or in prolonged-release form,

As a result of their NMDA receptor antagonism, the compounds are indicated for use i) in the treatment of disorders having an etiology comprising or associated with excess GH secretion, for example in the treatment of diabetes mellitus and angiopathy, as well as acromegaly, and ii) in the treatment of disorders having an etiology associated with ^ or modulated by an excess of LH secretion / for example in the treatment of prostatic hypertrophy or in the treatment menopause syndrome.

* 26

For this use / a daily dose indicated is in the range of approximately 1 to approximately 800 mg of the compound / · suitably administered in divided doses 2 to 4 times per day in the form of unit doses containing for example approximately 0/25 5 at about 400 mg of the compound or in sustained release form.

it?

Due to their NMDA receptor antagonism / the compounds of formula I are still indicated for use in the treatment of schizophrenia and depression or degenerative diseases of the CNS, such as Huntington's disease or dementia. 'Alzheimer's. For these uses / a daily dose indicated is in the range of about 25 to about 800 mg of the compound suitably administered in divided doses 2 to 4 times per day in the form of unit doses containing for example from about 6 to about 400 mg of the compound or sustained release form, The compounds of formula I further protect against degeneration of neurons of the rat hippocampus induced by hypoxia / in vitro at varying concentrations from 1 to 3 μΜ „[S method Rothman, J. Neurosci. 4, p 1884-1891 (1984) 3. The compounds are therefore indicated for use in the treatment of conditions of cerebral hypoxia, for example, stroke.

For this use, a daily dose indicated is in the range of about 10 to about 800 mg of the compound suitably administered in divided doses 2 to 4 times a day in the form of unit doses containing for example from about 2 to about 25,400 mg of the compound or in sustained release form.

The indication as anticonvulsant and protection against hypoxia states are the preferred indications. The compounds of Examples 1, 2 and 7 are the preferred compounds. The compound of Example 7 is very particularly recommended.

The compounds of formula I can be administered as such or in the form of their pharmaceutically acceptable salts.

* These salts have the same type of activity as the compounds of the invention in the form of free base or free acid. The present invention also provides a pharmaceutical composition comprising a compound of formula I, as such or in salt form / in combination with a pharmaceutically acceptable diluent or carrier. These compositions V 27 can be prepared in a conventional manner. The compounds can be administered by any conventional route / in particular by enteral route / preferably by oral route, for example in the form of tablets or capsules, or by parenteral route, for example in the form of solutions or injectable suspensions.

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

'- In a second group of compounds, X is -S0-.

In a third group of compounds, X is -SC ^ - · * In a fourth group of compounds, X is -0-.

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

In a sixth group of compounds, X is -NR ^ '-.

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

In an eighth group of compounds, X is -N (R) C0-.

In a ninth group of compounds, R is phenyl.

In a tenth group of compounds, R is phenyl substituted with phenyl.

In an eleventh group of compounds, Y is a group a), g In a twelfth group of compounds, Y is a group c).

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

Other groups can be formed individually from each of the meanings of Y, R, R ^, R £, R ^, R ^, R ^ a R ^ a R- ^ a Rg and Rç.

L

> "

Claims (6)

1. A process for the production of a compound of formula I / · "- R ^ OOC ^ CH-CCH2) mX- (CH2) nY I 5 wherein m and n are independently 1, 2 or 3, is hydrogen or a radical forming an ester group, A is an optionally substituted amino group, 10. is a sulfur or oxygen atom or a sulfinyl, sulfonyl, imino, substituted imino group, or an amido group substituted by a hydrocarbyl residue having at least 2 carbon atoms and ** Y is an optionally substituted tetrazolyl group, a * - phosphorus acid group in which the phosphorus is linked directly to the residue or an alkyl ester of this group optionally substituted by an aryl or alicyclic residue or an alicyclic ester of this group; or X is a sulfur or oxygen atom or a substituted sulfinyl, sulfonyl, imino or imino group and Y is furthermore also a sulfur acid ester in which the sulfur is bound directly to the rest - (CH-) -, where 2 n X is an oxygen atom or a g substituted sulfinyl, sulfonyl or imino group and Y is furthermore also a sulfur acid group in which the sulfur is directly linked to the residue “^ CH2) n“, where X is a substituted imino group or an amido group substituted by ^. a hydrocarbyl residue having at least 2 carbon atoms and Y * is also also a carboxylic acid group or its ester, or one of its salts which comprises the following steps: 29 il,. A) production of a compound of formula la, 2. A compound "of formula I, as defined in claim 1, or a salt thereof. 3. A compound according to claim 2, of formula Γ R., OOC 'NîH-CCHO -x-ccho-Y 1' / 2m 2 n, in which m and n are independently 1, 2 or 3, 25 R 1 is a hydrogen atom or a C 1 -C 4 alkyl / C 1 -C 4 alkylkyl A carbonyloxy-C 1 -C 4 alkyl / (2 4 -carboxy- bonyloxy-C 1 -C 6 alkyl / C ^ -C <carboxylalkyl <j2 ^ cart, onyLoxy-C ^ -Cg alkyl / phenyl or phenyl-C <j-Cg or naphthyl or naphthyl-C ^ -Cg alkyl / where each phenyl or naphthyl is y _ 1 *> J. 33 optionally monosubstituted or independently di- or tri-substituted by C -] - C6 alkyl, Cj-C6 alkoxy, halogen or hydroxy; pyridyl or pyridyl C-alkyl "j-Cg, ^ R2 is hydrogen or a C1-C4 alkyl phenyl-alkyl group 4. A compound according to claim 2 or 3, for use as a medicament. 5. A medicament, characterized in that it contains a compound according to claim 2 or 3, or one of its pharmaceutically acceptable salts. 5 C.j ~ Cg or naPhtyL-C ^ -Cg alkyl, or each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C ^ c ^ alkyl, C alkoxy, - C6 /. halogen or hydroxy; or pyridyl-Cj-Cg alkyl, R3 is hydrogen or CjC ^ alkyl phenyl-Cj-Cg alkyl, naphthyl-Cj-Cg alkyl, pyridyl-Cj-Cg alkyl, ^ -Ck calkyl ^ carbonyl, (C2-C22 alkenyl ^ carbonyl, (C4 alkadienyl ~ C22 ^ car * 30ny * 'e' ialcatrienyl C ^ -C2 ^ -carbonyl, Calca-tetraenyl Cg-C22 ^ carb ° nyl / (alkoxy at C ^ -C ^^ carbonyl / phenylcarbonyl, naphthylcarbonyl, phenyl- (C ^ -Cg alkyl) -15 carbonyl, naphtyl- (C <j-Cg alkyl) carbonyl, phenoxycarbonyl, ^ naphthyloxycarbonyl, phenyl- (alkoxy Cj-Cg) carbonyl or naphthyl- (C ^ -C6 alkoxycarbonyl, olT each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by C ^ -C ^ alkyl, C ^ -C ^ alkoxy, halogen or 20 hydroxy; pyridylcarbonyl, C 1- -C pyridyl-Calkyl, C 1 -C pyridylCalkoxy) carbonyl; a group of formula II R4 -C0 \ ^ N \ 25. QO II 10 in which R ^ is hydrogen or a C1-C12 alkyl or phenyl-C1-C6 alkyl group, in which the phenyl group is optionally monosubstituted or independently disubstituted k by C1-C4 alkyl , Cj-Cg alkoxy, halogen or hydroxy,! - 30 or a group of formula III or IV, 34 Γ ch2o (co) vr * 5 ch2-o (co) vR'5 -COQCH CH-O (CO) Rc : II CH20CC0) vR5 -cooch2 III IV 5 in which and R ^ 'are each, independently, a C 1 -C 22 alkyl group, C 2 -C 22 alkenyl, C 1 -C 22 alkadienyl, C 1 -C 22 alkatrienyl / Cg-C22 alkatetraenyl and v is independently 0 or 1, X 'is -S-, -SO-, SO2-, -0-, -NH-, -NRj'-, -CON (R) - or - N (R) CO-, w 10 Rg 'has the same meaning as R ^ except that it is not hydrogen, R is a C2 ~ C- | 2 alkyl group, phenyl or phenyl-Cj alkyl -Cg, ζ in which each phenyl is optionally monosubstituted by phenyl or phenyl-C 1 -C alkyl or monosubstituted or independently di- or tri-substituted by C 1 alkyl jC ^, C ^ -C ^ alkoxy, (^ -C ^ alkylthio, halogen, hydroxy or trifluoromethyl, i) Y is one of the groups a), b), c), d), e) or f), 0 .OH 0 OR, 0 OH 0 R0 X0H N) R6 \ r7 \ oh 20 a) b) c) d): y * yj S ^ OR, Nh O, H e) f) 35 in which is a C1-C4 alkyl, phenyl-C1-C6 alkyl or naphthyl-C1-C8 alkyl group in which each phenyl or naphthyl is optionally monosubstituted or independently di- or tri ”^ 5 substituted by alkyl C1-C0, C1 ”C6 alkoxy, halogen or hydroxy; pyridyl C 1 -C 6 alkyl, R7 is C 1 -C 4 alkyl phenyl C 1 -C 6 alkyl or naphthyl C 1 -C 6 alkyl or each phenyl or naphthyl is optionally monosubstituted or independently di- or tri -substituted by alkyl C1 "C6 'C1-C6 alkoxy C6' halogen or hydroxy; pyridyl-C1-C8 alkyl or one of the groups p) or q): - ,, v P 10 p) q) in which u is equal to 0, 1, 2, 3 or 4, Rg-is a C 1 -C 4 alkyl / phenyl or phenyl C 1 -C 6 alkyl group or naphthyl C 1 -C 4 alkyl group, in which each phenyl or naphthyl is optionally monosubstituted or independently di-substituted by (C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen or hydroxy; pyridyl or pyridyl C 1 -C 6 alkyl, or ii) when X is -S-, -SO-, -SO27, -0-, -NH- or -NRj'-, Y - can also be one of the groups g) or h) 0 0, lt II £ .0 ; -s-or7 -s-or7 II m% 0 g) h) 2S in which R7 is as defined above, or iii) when X is -SO-, -SO2, “0- or" NR-j1, In addition, there can also be one groups i) or 3) 36 Ο Ο II Μ -S-OH -S-ΟH II O i) J> 5 or iv) When X is -NRj'-, -CONCR) - or -NCRKO-, Y can besides also being a group k), -C00R9 k) in which R 1 is hydrogen, C 1 -C 4 alkyl or phenyl-10 C 1 -C 6 alkyl or naphthyl C 1 -C 6 alkyl, in which each phenyl or naphthyl is optionally monosubstituted or independently di- or tri-substituted by alkyl to alkoxy to halogen or hydroxy; or pyridyl C1-C8 alkyl or a salt thereof. 5 U '- (CH,) -Y1V XIII 2 n in which lesR, j', A, Y, m and n are as defined above and either of the residues U and U 'is -CO -Z and the other is an amino group substituted by a hydrocarbyl residue having at least 2 carbon atoms and Z is a residue of reactive carboxylic acid and elimination if necessary, amino-protecting groups possibly present and if desired conversion of a compound of formula I into another ^ and / when the compound of formula I contains a salifiable group / * formation of a salt of this salifiable group, 5 R- | ’OOC i. 'SyCH-CCH->) -X' - (CH?) N-Y 'la yr £ m c. n *> tr in which A, m and n are as defined above, 'is other than hydrogen, X' is -S- and Y 'is an ester group of ΊΟ phosphorus acid or an ester group of sulfur acid, by reaction of a compound of formula V lyooc 'CH- (CH ^) -SH V / cmv 15 in which R' ^, A and m are as defined above, with a »compound of formula VI, W-CCH2) nY 'VI in which n and Y' are as defined above and W is an eliminable group, and if necessary elimination of the amino-protecting groups 2o which may be present, B) production of a compound of formula Ib, H00C 'CH- (CHO “X" - (CHp) _- Y' Ib / £ m cm, in which m, n and Y 'are as defined above and X "is -0-, by reaction of a compound of formula VII v COOR ^ * R10HN-CH VII Γ VoOR ^ 30 in which R, j0 is an acyl group and R ^ is an alkyl group with a compound of formula VIII, VIII cmcni in which X ", m, n, Y 'and W are as defined above, under r 5 basic conditions ^ hydrolysis and decarboxylation of the resulting product, C) production of a compound of formula le, R-OOC 1 \ ^ CH- (CHp) -X- (CHp) -Y "le ✓ cmtnp / 10 in which Rj, A, m, n and X are as defined above and Y "is a tetrazolyl group, by reaction of a compound of formula IX R.OOC. v 1 \ ^ CH-CCH2) -X-CCH2) n-CN IX * a / 15 in which R ^, A, X, m and n are as defined above, with a salt of hydrazoic acid and elimination, if necessary, amino-protecting groups which may be present, D) production of a compound of formula Id, R-jOOC 20 NsCH- (CHp) mX "'- CCHp) -Y Id y cm cnh' - in which R ^, A, m, n and Y are as defined above and X '" is -S0- or -S02- , by oxidation of a compound of formula Iab, R-jOOC ^ 25 XCH- (CH,) -X '- (CHO -Y Iab y 2 mcn * ka / in which R <j, A, m, n, X 'and Y are as defined above, and elimination, if necessary, of the amino-protective groups which may be present, /' 31 E) production of a compound of the formula lyooc r, NlH-CCHO-X ^ -CCHO -Y "'le ^ y dm dn H2tr v 5 in which R ^', m and n are as defined above, X1V is -NH- or -NR ^ '-, Y"' is an acid ester group phosphorus, a "sulfur acid ester group and when X1V is -NR ^ '", Y "' may also be also a carboxylic acid group or its ester, by reaction of a compound of formula X 10 R ^ OOC ^ CH, X / 2 (C6H5) 2C = N / in which R ^ 'is as defined above, with a compound of formula XI' 15? 3 "w“ CCH2) m "N ~ (CH2) n“ Y " 'XI in which m, n, W and Y "' are as defined below sus and Rj "is as defined for R ^ 'above, but can also be an amino-protecting group, under basic conditions - hydrolysis of the resulting compound and elimination, if necessary, of the amino-protecting groups possibly present, F) production of a compound of formula If, Rl'ooc ^ CH-CCH-,) -XV-CCHO -Y1V If y 2 m 2 n 25 A> · in which R ^ ', A, m and n are as defined above, Xv is 2 an amido group substituted by a hydrocarbyl residue having at least two carbon atoms and Y1V is an ester group of phosphorus acid or a carboxylic acid group or its ester, by reaction of a compound of formula XII, 32 R1 OOC -U XII 2 'with a compound of formula XIII J. · »« 6. A pharmaceutical composition comprising a compound according to claim 2 or 3 or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable diluent or vehicle.