AU629629B2

AU629629B2 - New unsaturated derivatives of 2,6-amino-heptanedioic acid, their preparation process and their application as medicaments

Info

Publication number: AU629629B2
Application number: AU53601/90A
Authority: AU
Inventors: Constantin Agouridas; Annie Martel; Nicole Tessot
Original assignee: Roussel Uclaf SA
Current assignee: Sanofi Aventis France
Priority date: 1989-04-18
Filing date: 1990-04-18
Publication date: 1992-10-08
Anticipated expiration: 2010-04-18
Also published as: FR2645858B1; HU902457D0; HU205066B; CA2014672A1; PT93790A; ZA902879B; AU5360190A; DE69009283T2; RU1836332C; ES2054286T3; EP0394118A1; IE65057B1; DE69009283D1; FR2645858A1; JP3009178B2; DK0394118T3; EP0394118B1; HUT54107A; IE901312L; ATE106384T1

Abstract

Novel derivatives of formula <IMAGE> in which, - the dotted lines represent an optional endo or exo double bond, - Y represents a (C2-18) alkyl, alkenyl or alkynyl or a (C1-18) alkyl substituted by one or several halogens, - X, X' and X1 represent hydrogen, an (-> C8) alkyl, alkenyl or alkynyl, an (-> C14) aryl, an (-> C18) aralkyl or an acyl derived from a fatty acid and/or an amino acid, and either n and/or n1 represents 1 and R and/or R1 represents an amino radical or an amino acid radical, or n and/or n1 represent 2 and R and R1 represent hydrogen, an (C1-8) alkyl or an (-> C14) aryl or an (-> C18) arylalkyl or a <IMAGE> radical, in which R2 represents a (C1-8) alkyl or an (-> C14) aryl, as well as their salts with acids or bases, a process for their preparation, their application as drugs and the compositions containing them.

Description

~-arrr~a~os.a~an.*r~auurnsiu~ 629629

CO]

Short Title: Int. Cl: Application Number; Lodged:

AUSTRALIA

PATENTS ACT 1952 MPLETE SPECIFICATION Form

(ORIGINAL)

FOR OFFICE USE Complete Specification Lodged: Accepted: Lapsed: Publishrr: riority: i Related Art: 9 Name of Applicant: Address of Applicant: 99 *9 Actual Inventors: Address for Service: TO BE COMPLETED BY APPLICANT

ROUSSEL-UCLAF

35, Boulevard des Invalides, 75007, Paris, France.

CONSTANTIN AGOURIDAS, NICOLE TESSOT and ANNIE

MARTEL

CALLINAN LAWRIE, Patent Attorneys, 278 High Street, Kew, Victoria 3101, Australia.

Complete Specification for the invention enitled: NEW UNSATURATED DERIVATIVES OF 2,6- AMINO-HEPTANEDIOIC ACID, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS The following statement is a full description of this invention, including the best method of performing it known to me:la New unsaturated derivatives of 2,6-amino-heptanedioic acid, their preparation process and their application as medicaments.

The present invention relates to new unsaturated derivatives of 2,6-diamino-heptanedioic acid, their preparation process and their application as mer 7aments.

A subject of the invention is the compounds general formula

X

N

*o 0 v C(O) nR C(0) (I) 15

R

1 (O)n C NHX1 1 in which, the dotted lines represent a double bond, optionally endo or exo, Y represents an alkyl, alkenyl or alkynyl radical containing from 2 to 18 carbon atoms, or an alkyl radical no 0 containing from 1 to 18 carbon atoms substituted by one or a more halogen atoms, X, X' and X 1 identical or different, represent a hydrogen atom, an alkyl, alkenyl or alkynyl radical containing up to 8 carbon atoms, an aryl radical containing up to 14 carbon atoms an aralkyl radical containing up to 18 carbon atoms, or an acyl radical derived from a fatty acidk&n from an alpha andar~o omega amino acid, and either n andteeL n 1 represents the number 1 and R andoaw

R

1 represents the remainder of an amine or an alpha or omega amino acid, or n andAen nI represents the number 2 and R and R 1 represent a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or an aryl radical containing up to 14 carbon atoms, or 1 an aralkyl radical containing up to 18 carbon atoms, or a 2

CH

2 0CR 2 radical, in which R 2 represents an alkyl radical containing up to 8 carbon atoms, or an aryl radical containing up to 14 carbon atoms, as well as their salts with organic or mineral acids or with bases.

When Y represents an alkyl radical, it is preferably an ethyl, propyl, isopropyl or butyl radical or an unsaturated radical such as the vinyl, allyl, ethynyl or propynyl radical.

When Y represents an alkyl radical substituted by one or more halogen atoms, it is preferably an alkyl radical substituted b' one or more fluorine or chlorine atoms, for S. example the radicals -CHF 2

-CH

2 F, -CHCl 2

-CH

2 C1.

"When X, X 1 R, R 1 or R 2 represents an alkyl radical, S. 15 it is preferably a methyl, ethyl, propyl, isopropyl or butyl radical.

When X, X' or X 1 represents an alkenyl radical, it is preferably a vinyl or allyl radical.

When X, X' or X 1 represents an alkynyl radical, it is preferably an ethynyl or propynyl radical.

When X, X 1 R, RI or R 2 represents an aryl radical, it is preferably a phenyl radical.

0° When X, X 1 R or R 1 represents an aralkyl radical, it is preferably a benzyl radical.

R

2 preferably represents a methyl, ethyl, n-propyi or phenyl radical.

When in the definition of substituents, it is a question of a fatty acid, it is preferably a saturated or unsaturatou aliphatic acid containing from 6 to 24 carbon atoms and preferably from 12 to 22 carbon atoms; for example the following acids can be cited: stearic, palmitic, lauric, caprylic, myristic, alpha or gamma linolenic, linoleic, arachidonic, docosapentaenoic or adamantane carboxylic.

When in the definition of substituents, it is a question of amines, it is preferably benzylamine, optionally substituted, methylamine, dimeLhylamine or any other secondary or tertiary amine.

When in the definition of substituents, it is a question 1 3 of amino acids, it is preferably an amino acid chosen from the group constituted by Ala, Val, Ival, Leu, Ile, Asp, Asn, Glu, Gin, Ser, Thr, Cys, Met, Lys, Arg, Phe, Tyr, Trp, His and Pro, Nva, Nle, Hyp, Orn, these acids being in the D or L form, as well as by Sar and Gly, all the previously mentioned acids capable of being N-acylated or N-alkylated.

By convention it will be acknowledged that the symbols for the alpha-amino carboxylic acids represent these acids in their D or L configuration (for example, the term Ala signifies Alanine in the D form or in the L form).

The addition salts with mineral or organic acids can be, for example, the salts formed with the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, 2 15 succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic such as methane- or ethanesulphonic, S arylsulphonic such as benzene- or paratoluenesulphonic, or arylcarboxylic.

The salts of the derivatives of the invention can be formed with organic or mineral bases. Among the mineral bases, the alkali and alkaline-earth hydroxides can be cited, such as for example, sodium, potassium, lithium and calcium hydroxides, magnesium or ammonium hydroxide. Among the organic bases, the substituted or non-substituted alkylated 25 amines can be cited, such as for example, trimethylamine, methylamine, propylamine, N,N-diethylethanolamine or tris(hydroxymethyl) methylamine; basic amino acids can also S" be cited, such as for example, lysine or arginine; also other bases can be cited, such as for example, glucosamine or procaine.

Among the preferred compounds of the invention, there can be cited the compounds of formula in which the dotted lines represent an exo double bond, those in which x i represents a hydrogen atom, those in which X, X' and X 1 represent a hydrogen atom, those in which X'represents a hydrogen atom or a methyl radical, X represents a methyl or benzyl radical and X 1 represents a hydrogen atom and those in which R and R 1 each represent a hydrogen atom, as well as 4 their addition salts with organic or mineral acids or with bases.

Among the preferred compounds of the invention, there can be cited the compounds in which Y represents an acetylene radical, those in which Y represents an ethylene radical or also those in which Y represents an ethyl radical.

A quite particular subject of the invention is the compounds the preparation of which is given hereafter in the experimental part, such as for example the compounds of Examples 4, 7 and The derivatives which are a subject of the present invention possess very interesting pharmacological properties, they are notably endowed with interesting antibacterial properties.

15 These properties are illustrated further on in the S experimental part.

These properties justify the use of the products of the invention as well as their salts, as medicaments.

Therefore a subject of the present Application is also the use, as medicaments, of the derivatives of formula as well as their pharmaceutically acceptable addition salts.

The medicaments according to the invention find their 000 use, for example, in antibiotherapy vis-a-vis bacterial germs, yeasts, fungi (candida albicans....) in anti-viral therapy, and in anti-cancer chemotherapy, by themselves or in combination, and lastly as adjuvants to a standard antibiotherapy or to vaccination.

Finally a subject of the invention is the pharmaceutical compositions which contain at least one aforementioned derivative or one of its addition salts with pharmaceutically acceptable acids or bases, as active principle.

As medicaments, the derivatives cor:responding to formula and their addition salts with phartaceutically acceptable acids or bases can be incorporated in pharmaceutical compositions intended to be taken by digestive or parenteral route.

These pharmaceutical compositions can be, for example, solid or liquid and can be presented in the pharmaceutical forms currently used in human medicine, such as for example, simple or sugar-coated tablets, capsules, granules, suppositories, injectable preparations; they are prepared according to usual methods. The active principle or principles can be incorporated in the excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.

Also a subject of the invention is a preparation process characterised in that a compound of general formula (II): o' OSO 2 al K C(O) R'

Y

R' 0 )on C NHX' o 0 00 0 in which alk represents an alkyl radical containing from 1 to 8 carbon atoms optionally substituted by one or more halogen atoms, n, nI and the dotted lines r'etain the same meaning as S* previously, Y' represents either Y, or X'l, R' and R' 1 have the same meaning as X 1 R and R 1 with the exception of the hydrogen, is subjected to the action of a reagent capable of providing a precursor of the amino function or of an amine of formula

HN/X

X"

in which X'has the meaning indicated previously and X' has Pyl AU the meaning indicated for X with the exception of the hydrogen, so as to obtain, if appropriate, after suitable Streatment, the compound of formula which, if desired, is 6 subjected to all or part oi the following operations in any order: deprotection of the amine functions, functionalistion of the amine functions, hydrolysis of the ester functions, the treatment of Y' so as to obtain Y, total or selective reduction of the Y substituent when this is unsaturated, -salification.

In a preferred embodiment, alk represents a methyl, ethyl or n-propyl radical or a CF 3 radical, the reagent capable of providing a precursor of the amino S. function is sodium nitride, potassium phthalamide or 15 hydroxylamine.

The amine is obtained by methods known to the expert, Sfor example by hydrolysis in the case of the phthalamide.

the hydrolysis agent of the phthalamide in this case can be a mineral base followed by an acid hydrolysis or hydrazine, the deprotection of the amine function is effected ooe preferably by the action of a diluted mineral acid such as 0 hydrochloric acid, or an organic acid such as trifluoroacetic acid, the hydrolysis of the ester functions is effected 25 preferably by saponification using a wi.neral base such as soda or potash, optionally followed by a treatment by an acid resin, the salification is effected by the addition of an acid or base to the reaction medium.

A quite particular subject of the invention is a process characterised in that a compound of formula (II) as defined previously is subjected to the action of sodium nitride so as to obtain the compound of formula (III): 7

N

3 C(O) R' y,

(III)

SR'l(o)nlC

NHX

1 which is subjected to a reducing agent of the N 3 group, so as to obtain the compound of formula (IV): NH2 C R' n

(IV)

n C NHX' 1 which is subjected either to all or part of the operations mentioned previously.

In a preferred embodiment: the reducing agent which is reacted with the compound of formula (III) is triphenylphosphine, followed by an acid hydrolysis, equally the procedure can be catalytic hydrogenation, for example in the presence of palladium on 2 5 activated charcoal poisoned by quinoline.

A more particular subject of the invention is a process characterised in that a compound of formula (IIA)

OSO

2 alK H3C CO 2

R'

H3C-- Si-C=C

H

3 C R' 1 0 2 C NHX' 1 (IIA) 8 is subjected either to the action of sodium nitride so as to obtain the compound of formula (IIIA):

N

3 3 C C

O

2

R'

H3C Si-CsC

(IIIA)

H

3 C R' 1 0 2 C NHX' 1 which is subjected to the action of a reducing agent of the nitride so as to obtain the compound of formula (IVA):

NH

2

CH

3 i- rCO2R' H3C Si-CC.U SH3C

R'

1 2C NHX 1

(IVA)

or to the action of an amine of formula

X'

in which X'and X" have the meaning indicated previously so 25 as to obtain the compound of formula (IVB):

XII

N1 H3C CO2R'

H

3 C Si-C-C

(IVB)

H

3 C'

R'

1 0 2 C

NHX'

1 then either the compound (IV

A

or (IVB) is subjected to the action of a selective cleaving agent of the ester functions and of the trimethylsilyl radical so as to obtain the compound of formula (IA): C~ Ym~~ll~_ ~1~1~1~ 9-

(IA)

HO

2C NHX' 1 that, if appropriate, is subjected to the action of a cleaving agent of the am.ne protector group so as to obtain the compound of formula (IB):

XII

Nl' O x CO 2

H

(IB)

HO2C

NH

2 or the compound of formula (IVA) or (IVB) is subjected to the action of a cleaving agent of the trimethylsilyl so as to obtain the compound of formula (IC):

CO

2

R'

(TC)

HC=C AA 1 2C then if desired, the compound of formula (IA) (IB) or (IC) is subjected to the action of a partial reducing agent so as obtain the corresponding compound of formula (ID) in which Y represents an ethenyl radical, or to the action of a total reducing agent of the triple bond so as to obtain the 1 10 corresponding compound of formula (IE) in which Y is an ethyl radical, then, if appropriate, the compounds of formula thus obtained are subjected to all or part of the operations mentioned previously.

In a preferred embodiment of the process: the cleaving agent of the trimethylsilyl group is potassium fluoride or tetrabutylammonium fluoride.

The products of formula in which R and/or R 1 represent the remainder of an amine can be obtained by amidification of the acid functions of the product of formula (IA) the amidification is effected in the presence of condensation agents such as dicyclohexylcarbodiimide, N, N'carbonyldiimidazole, or the bis-alkyl amides of sulphurated acids such as N, N'-sulphinyl-bis(dimethylamine),

SO[N(CH

3 3 2 or also by the formation of the mixed anhydride with isobutyl chloroformate.

Certain starting products of formula (II) are described and claimed in the European Pacent Application 88 402741.8 filed on 2.11.1988, their preparation is mentioned hereafter.

The compounds of formula (II) and (IIA) can be prepared, S for example, according to the processes described hereafter in the experimental part, for example, according to the diagram:

Y

LDA/THF H8--CO 2

R

X

1 N CO 2 R i H Y C 2

R

1 FeCl 3

/CH

2 Cl 2

NHX

1 OH

OSO

2 alK

CO

2 R 4 CO 2

R

Y n T?

NHX

1

NHX

11 The compounds of formula (II) in whi.ch Y' represents a alkynyl trimethylsilyl radical are new and are themselves a cabject of the invention.

The products A are known and can, for example, be prepared according to the process described by USP 4088667 or in Tet. Lett, CASARA et al. 1978 p.

1581 and fol.

The compounds of formula (III) and (IIIA) are new and are themselves a subject of the present invention.

0 4 0 a a Fl o 12 The following examples illustrate the invention however limiting it.

EXAMPLE 1 6-amino-2-ethynyl-2-[(methoxycarbonyl)-amino]-4methylene heptanedioic acid.

STAGE A 7-ethyl-l-methyl 6-azido-2-[(methoxycarbonyl)amino]-4-methylene-2-[2-(trimethylsilyl)-ethynyl] heptanedicate.

0.498 g of sodium nitride is added to a solution containing 3.32 g of 7-ethyl-l-methyl 6- (methanesulphonyloxy)-2-[(methoxycarbonyl)-amino-4-methylene- 2-[2-(trimethyl)-ethynyl -heptanedioate prepared as indicated S0 after example 1, and 30 cm 3 of dimethylformamide. The reaction medium is maintained under agitation for 16 hours.

0 It is filtered, diluted with water, extracted with ether and 15 the extracts are dried and evaporated to dryness. 3.7 g of S* product is obtained which is purified by chromatography on 0 silica eluting with a cyclohexane-ethyl acetate (6-4) g00 I mixture. 2.28 g of sought product is obtained. Rf 0.35.

SPAGE B 7-ethyl-l-methyl C-amino-2-[(methoxycarbonylN- 0 amino]-4-methylene-2-[2-trimethylsilyl)-ethynyl]- So"° heptanedioate.

519 mg of the product obtained in the previous stage is dissolved in 6 cm 3 of tetrahydrofuran. 341 mg of triphenylphosphine is added and the whole is agitated for 16 hours at ambient temperature. 0.65 cm 3 of water is added and agitation takes place for 30 hours. The prodict obtained is diluted with ether, extracted with a normal solution of hydrochloric acid, the aqueous phase is washed with ether. Sodium bicarbonate is added and extraction takes place with ether, followed by washing, drying and bringing to dryness. 433 mg of sought product is obtained.

Rf 0.4 (eluant ethyl acetate) STAGE C 6-amino-2-ethynyl-2-[(methoxycarbonyl)-amino]- 4-methylene heptanedioic acid.

1.23 g of product prepared as in the previous stage is dissolved in 12 cm 3 of etha The mixture is cooled to +4 0 o and 5 cm 3 of a 2N solution of soda is added. The solution obtained is allowed to rise to ambient temperature and ;IZIL~YILI 13 maintained under agitation for 38 hours, 50 W x 8 Dowex resin is added. The mixture is filtered, rinsed with water, eluted with dilute ammonium hydroxide and evaporated to dryness.

709 mg of product is obtained which is chromatographed on silica eluting with an ethanol-ammonium hydroxide mixture (8- 600 mg of sought product is obtained.

Rf 0.2.

PREPARATION 1 7-ethyl-l-methyl 6-(methanesulphonyloxy)-2- [(methoxycarbonyl)-amino]-4-methylene-2-[2-trimethylsilyl)ethynyi]-heptanedioate.

A solution containing 183.4 g of diisopropylamine in 5570 cm 3 of tetrahydrofuran is cooled to -60 0 C. 1135 cm 3 of butyllithium in he3.ane is introduced at between -50 0 C and 0 C. The temperature is allowed to rise to 0 0 C and agitation takes place for 15 minutes, followed by cooling to -66 0 /-k;50C and a solution containing 147 g of methyl 2- [(methoxycarbonyl)-amino]-4-(trimethyliilyl)-3-butynoate, (prepared as indicated for the same ethyl carbonate in Tetrahedron Letters No. 18 p.1581 (1978)), in 1100 cm 3 of etrahydrofuran is added over 50 minutes. Agitation takes place for 45 minutes at -65 0 /-70 0 C and at this temperature 558.6 cm 3 of hexanemethylphL photri...ide is added. Agitation takes pacr for 15 minutes at this temperature and 81.6 g of methallyl bromide in solution in 1100 cm 3 of tetrahydrofuran is added. Agitation takes place for 2 hours at -67 0 /-70 0 C and 186 cm 3 of acetic acid diluted 10 times in tetrahiydrofuran is added. The temperature of the mixture is allowed to rise to it is then filtered, washed with tetrahydrofuran and distilled to dryness under reduced pressure. The dry extract is taken up in methylene chloride and washed with water. The organic phasey are dried, washed with methylene chloride and brought to dryness. 587,5 g of crude product is obtained which is chromatographed on silica, eluting with a cyclohexane-ethyl acetate mixture The sought product is rbtained. Rf 0.4.

STAGE B 7-ethyl-l-methyl 6-hydroxy-2-[methoxycarbonyl)amino]-4-methylene-2-[2-(trimethylsilyl)-ethynyl]heptanedioate.

I 1 14 9.72 g of ferric chloride is put in suspension in cm 3 of methylene chloride, in the presence of siliporite.

The mixture is cooled to 0°C and 3.1 g of ethyl glyoxylate in solution in 40 cm 3 of methylene chloride is introduced over 30 minutes. Then agitation takes place for 30 minutes at ambient temperature, the solution is cooled to -60 0 C and g of product prepared in the previous stage, in solution in 40 cm 3 of methylene chloride, is introduced over minute The reaction medium is agitated at -60°C for 2 hours. It is poured over an excess of sodium bicarbonate (the medium remaining basic), followed by filtering, rinsing, washing with water, drying and evaporating to dryness. 6.4 g S of product is obtained which is purified by chromatography on silica eluting with a cyclohexane-ethyl acetate mixture a0a0 a15 3.64 g of sought product is obtaineH, Rf 0.37.

a°0a a STAGE C: 7-ethyl-l-methyl 6-(methanesulphonyloxy)-2a o S°'0 [(methoxycarbonyl)-amino]-4-methylene-2-[ 2-trimethylsilyl)ethynyl]-heptanedioate.

8.43 g of the product prepared as in the previous Stage in 70 cm 3 of pyridine is cooled to 0°C. 1.7 cm 3 of mesyl a'"o chloride is introduced. The mixture is agitated for 5 hours 00000 at ambient temperature. The pyridine is evaporated off at ambient temperature under reduced pressure. The residue 0° obtained is taken up in ether, the ether solution is washed with a normal solution of hydrochloric acid until an acid pH is obtained, then is washed with salt water until neutral.

i' The organic phase is dried and evaporated to dryness at a temperature lower than 30°C. 11 g of desired product is obtained which is chromatographed by eluting with a cyclohexane ethyl acetate mixture 8.28 g of desired product is obtained. Rf 0.35.

EXAMPLE 2: 2,6-diamino-2-ethynyl-4-methylene heptanedioic acid.

A mixture comprising 246 mg of the product obtained in Stage B of Example 1, and 5 cm 3 of 5N soda is heated for hours at 120 0 C. The mixture is ice-cooled, brought to pH 6 with concentrated hydrochloric acid and evaporated to dryness. The product is passed over an ion-exchange resin, 1AW9=4'_ t~ 15 W x 8 Dowex. Elution is carried out with water, then with a 2N ammonium hydroxide solution and the fractions containing the product are brought to dryness. After lyophilization, mg of desired product is obtained. Rf 0.24 (eluant: butanol ethyl acetate water EXAMPLE 3: 6-amino-2-ethenyl-2-[(methoxycarbonyl)-amino]-4methylene heptanedioic acid.

STAGE A: 7-ethyl-l-methyl 6-amino-2-ethynyl-2-[(methoxycarbonyl)-amino]-4-methylene heptanedioate.

99 mg of potassium fluoride is added to a solution comprising 338 mg of product obtained in Stage B of Example 1 in 4 cm 3 of dimethylformamide. The mixture is agitated at ambient temperature for 16 hours, then diluted with ether, washed with water, dried and evaporated to dryness. 320 mg 15 of product is obtained which is chromatographed on silica, o°0 eluting with a cyclohexane ethyl acetate mixture S. then eluting with ethyl acetate. 182 mg of desired product is obtained. Rf 0.3.

STAGE B: 7-ethyl-l-methyl 6-amino-2-ethenyl-2-[(methoxycarbonyl)-amino]-4-methylene heptanedioate.

S494 mg of product prepared in the previous stage is dissolved in 50 cm 3 of ethanol, 99 microlitres of quinoline and 250 mg of 5% palladium on barium sulphate are added.

Hydrogenation (P 1200 mm/hg) is carried out until absorption of 34 cm 3 followed by filtering, rinsing with ethanol and evaporating to dryness. 560 mg of product is obtained which is purified by chromatography on silica, eluting with ethyl acetate. 433 mg of desired product is obtained. Rf 0.3.

STAGE C: 6-amino-2-ethynyl-2-[(methoxycarbonyl)-amino]-4methylene heptanedioic acid.

400 mg of product prepared in the previous stage is dissolved in 2.5 cm 3 of ethanol. The solution is ice-cooled Sand 2.5 cm 3 of 2N soda is introduced. Agitation is carried out for 24 hours at ambient temperature. 1 cm 3 of caustic soda lye is added, with agitation for 3 hours at ambient temperature. The solution is diluted with water, and 50 x 8 Dowex resin is added until a pH of 2 is obtained.

Filtration is carried out, followed Ly rinsing with water, eluting with N ammonium hydroxide then with 40% ammonium hydroxide, and evaporating to dryness. 208 mg of desired product is obtained. Rf 0.25 (eluant: EtOH NH 4 0H EXAMPLE 4: 2,6-diamino-2-ethenyl-4-methylene heptanedioic acid.

220 mg of product obtained in Stage C of Example 3 is dissolved in 2.5 cm 3 of water and 2.5 cm 3 of caustic soda lye. The solution is taken to 100 0 C for 5 hours; it is left to return to ambient temperature, ice is added, and it is acidified with 50 W x 8 Dowex resin. Filtration is carried out, followed by rinsing with water then with diluted ammonium hydroxide, and evaporating to dryness. 190 mg of product is obtained which is chromatographed on silica, 15 eluting with an ethanol ammonium hydroxide mixture o 76 mg of desired product is obtained. Rf 0°0°0 EXAMPLE 5: 1-methyl 6-amino-2-ethyl-2-[(methoxycarbonyl)amino]-4-methylene heptanodioate.

STAGE A: 7-ethyl-l-methyl 6-amino-2-ethyl-2-[(methoxycarbonyl)-amino]-4-methylene heptanedioate.

1.17 g of product obt4ined in Stags A of Example 3 is dissolved in 100 cm 3 of ethanol. 1.1 g of 5% palladium on barium sulphate and 0.1 cm 3 of quinoline are added.

Hydrogenation is carried out until saturation is reached, followed by filtering, rinsing with ethanol and evaporating to dryness. 1.32 g of product is obtained which is purified by chromatography on silica, eluting with ethyl acetate.

1.1 g of desired product is obtained. Rf 0.35.

STAGE B: 1-methyl 6-amino-2-ethyl-2-[(methoxycarbonyl)amino]-4-methylene heptanedioate.

200 mg of product obtained in Stage A is dissolved in 2 cm 3 of ethanol. 0.55 cm 3 of N soda is added drop by drop at ambient temperature. The mixture is maintained under agitation at ambiezt temperature for one hour 30 minutes, then diluted with uater and acidified to pH 3 with 50 W x 8 Dowex resin. Filtration is carried out, thAn rinsing with water and the amino fraction is extracted by washing the resin with ammonium hydroxide diluted to one tenth. After i1 17 evaporation to dryness, the residue is taken up in water, filtered and lyophilized. 131 mg of product is obtained which is purified by chromatography on silica, eluting with a methylene chloride methanol mixture Rf 0.25. The product obtained is purified by being passed over resin. In this way the desired product is obtained, (yield 44%).

EXAMPLE 6: 6-amino-2-ethyl-2-[(methoxycarbonyl)-amino]-4methylene heptanedioic acid.

2.25 cm 3 of 2N soda is introduced, at 0°C, to a solution comprising 225 mg of product obtained in Stage A of Example in 2.25 cm 3 of ethanol. The solution obtained is left to S return to ambient temperature, and maintained under agitation for 16 hours. It is diluted with water and 50 W x 8 Dowex Sresin is added. After agitation for 30 minutes, filtration 15 is carried out, and the filtrate is rinsed with water.

00 Elution is done with one tenth ammonium hydroxide, followed 0 o0 by evaporation to dryness. 180 mg of product is obtained, which is purified by chromatography on silica, eluting with an ethanol ammonium hydroxide mixture In this way the desired product is obtained. Rf 0.6.

o° .o EXAMPLE 7: 2,6-diamino-2-ethyl-4-methylene heptanedioic acid.

0 \300 mg of product obtained in Stage A of Example 5 is Sdissolved in 3 cm 3 of ethanol. 3 cm 3 of caustic soda lye is added to the solution thus obtained. It is maintained at 90°C for 13 hours. Ice is added and acidification to pH 2 is carried out by adding 50 W x 8 Dowex resin, followed by filtration and rinsing with water. Elution is done with diluted ammonium hydroxide, followed by evaporation to dryness. 230 mg of product is obtained, which is purified by chromatography on silica, eluting with an ethanol ammonium hydroxide mixture 125 mg of desired product is obtained. Rf 0.3 (eluant: butanol acetic acid water EXAMPLE 8: 2,6-diamino-2-(difluoromethyl)-4-methylene heptanedioic acid.

STAGE A: Diethyl 6-azido-2-difluoromethyl-2-formyl-amino-4methylene heptanedioate.

0.131 g of sodium nitride is added to e solution UVY i. ~Cplr;~;*LX~-Y L- ~-611_?1I~NI~Yi 18 comprising 0.700 g of diethyl 2-(difluoromethyl)-2- (formylamino)-4-methylene-6-[(methanesulphonyl)-oxy]heptanedioate in 15 cm 3 of dimethylformamide. The solution obtained is agitated for 16 hours at ambient temperature.

The dimethylformamide is evaporated off at 35 0 C under reduced pressure. The residue is taken up in methylene chloride and washed with a 10% aqueous solution of sodium acid carbonate, then with brine, dried and evaporated to dryness. 655 mg of desired product is obtained. Rf 0.65 (eluant: CHC1 2 AcOEt STAGE B: Diethyl 6-amino-2-difluoromethyl-2-formyl-amino-4methylene heptanedioate.

310 mg of triphenylphosphine is added at 0°C to a solution comprising 350 mg of product prepared in the 15 previous stage and 20 cm 3 of tetrahydrofuran. The solution S obtained is allowed to return to ambient temperature and maintained under agitation for 16 hours. 0.5 cm 3 of water is added, and the reaction mixture is maintained under agitation for 24 hours.

The tetrahydrofuran is evaporated off and the residue is S taken up in methylene chloride. Extraction is done with a 2N hydrochloric acid solution, followed by neutralizing with a solution of sodium acid carbonate, and extraction with ethyl acetate. The extracts are washed, dried and evaporated to dryness. 250 mg of desired product is obtained. Rf 0.15.

STAGE C: 2,6-diamino-2-(difluoromethyl)-4-methyleno heptanedioic acid.

a) De-formylation A solution comprising 140 mg of product prepared in the previous stage in 5 cm 3 of ethanol and 0.5 cm 3 of 12N hydrochloric acid is taken to reflux for one hour. It is neutralized with sodium acid carbonate, evaporated to dryness and the residue is taken up in water. Extraction is done Swith ethyl acetate, the extracts are washed with water, dried and evaporated to dryness. 100 mg of product is obtained.

b) Saponification The product obtained in Stage a) is taken up in 3 cm 3 of ethanol, and 1.5 cm 3 of an N solution of soda is added. The 19 reaction mixture is maintained under agitation for 16 hours at ambient temperature, then neutralized with a solution of hydrochloric acid to a pH of about 5. After evaporation to dryness, the residue is taken up in water. The product is placed on an ion-exchange resin (50 W x 8 Dowex). Elution is done with water, then with a 0.7N solution of ammonium hydroxide. After reuniting, the fractions containing the desired product are brought to dryness. In this way 80 mg of desired product is obtained, which is lyophilized. Rf 0.25 in BuOH, AcOH, H 2 0 PREPARATION 2: Diethyl 2-(difluoromethyl)-2-formylamino-4- Smethylene-6-[(methylsulphonyl)-oxy]-heptanedioate.

STAGE A: (2-methyl-2-propenyl)-propane~ioate of (1,1dimethylethyl) and of ethyl.

o 15 33 g of ethyl tertbutyl malonate is dissolved in 400 cm 3 of acetonitrile, 29 g of potassium carbonate, 0.5 g of crown ether (18-6) and 300 g of 3-chloro-2-methyl-l-propene are added while agitating, and the whole is agitated for 16 hours at 65 0 C. The insoluble part is filtered off and the filtrate is evaporated to dryness. The residue is chromatographed on silica, eluting with a cyclohexane ethyl acetate mixture Sooo (95-5) and 18 g of pure product and 22 g of mixture are isolated. This is chromatographed on silica, eluting with a cyclohexane ethyl acetate mixture (97.5-2.5) and a further 11 g of product is isolated.

Rf 0.35 in cyclohexane ethyl acetate (95-5).

STAGE B: (Difluoromethyl) (2-methyl-2-propenyl)-propanedioate of (1,1-dimethylethyl) and of ethyl.

2.8 g of sodium hydride is put in suspension in 100 cm 3 of tetrahydrofuran, 11.1 g of product obtained in Stage A in 100 cm 3 of tetrahydrofuran is added drop by drop, and the whole is agitated for one hour at 42 0 C. Freon 22 is bubbled through for 15 minutes while agitating at 45 0 C, and agitation is continued for one hour at 45 0 C and for one hour at ambient temperature under a Freon 22 atmosphere. The reaction medium is hydrolysed with salt water, extracted with methylene chloride, the organic phase is washed with salt water, dried and concentrated to dryness. 13 g of expected product is obtained.

Rf 0.4 in cyclohexane ethyl acetate (95-5).

STAGE C: Monoethyl (difluoromethyl) (2-methyl-2-pro.c propanedioate.

13 g of product obtained above is dissolved in 100 cm 3 of methylene chloride, 70 cm 3 of trifluoroacetic acid is added and agitation is carried out for one hour 30 minutes at ambient temperature. After concentrating to dryness under reduced pressure, the residue is taken up in methylene chloride and extracted with a 10% aqueous solution of sodium bicarbonate. The aqueous phase is washed with methylene chloride and neutralized with concentrated hydrochloric acid.

Extraction is done with methylene chloride, the extracts are washed with salt water, dried and concentrated to dryness, and 5.3 g of expected product is obtained.

°0 Rf 0.5 in CH 2 Cl 2 MeOH AcOH STAGE D: Ethyl 2-(difluoromethyl)-2-(formylamino)-4-methyl-4pentenoate.

10.5 g of product obtained above is agitated in 60 cm 3 of thionyl chloride and heated under reflux for 3 hours.

o After evaporating to dryness, the residue is taken up in toluene and dried under reduced pressure, and 10.5 g of acid chloride is obtained. The latter is dissolved in 50 cm 3 of acetone, cooled to 0°C, and a solution of 3.35 g of sodium nitride in 20 cm 3 of water is added drop by drop, followed by agitation for one hour at 0°C. The acetone is evaporated off, extraction is done with ether, the extracts are washed with salt water, dried, evaporated to dryness and 10 g of Lnitride is obtained. The latter is dissolved in 100 cm 3 of formic acid and heated under reflux for one hour 30 minutes.

It is allowed to return to ambient temperature and 40 cm 3 of acetic anhydride is added drop by drop, with agitation for 3 hours at ambient temperature. 40 cm 3 of ice-cooled water is added slowly, followed by evaporation to dryness. The residue is taken up in a water methylene chloride mixture, extracted with methylene chloride, and the extracts are washed with a 10% aqueous solution of sodium bicarbonate, then with salt water, dried and concentrated to dryness. The 21 residue is chromatographed on silica, eluting with a cyclohexane ethyl acetate mixture (85-15) and 5 g of expected product is isolated.

STAGE E: Diethyl 2-(fluoromethyl)-2-(formylamino)-6-hydroxy- 4-methylene heptanedioate.

9.65 g of ferric chloride is put in suspension in 50 cm 3 of methylene chloride, 3.03 g of ethyl glyoxylate in 50 cm 3 of methylene chloride is added drop by drop and agitation is carried out for 30 minutes at ambient temperature. The mixture is cooled to -60 0 C and 3.5 g of product obtained in Stage 7 in 50 cm 3 of methylene chloride is added drop by drop. Agitation is carried out for one hour at 30 0 C and then for one hour at -20 0 C. The reaction mixture is poured into ice-cooled water, extracted with methylene chloride, the extracts are washed with salt water, then with a 10% aqueous solution of sodium bicarbonate, then with salt water, dried and evaporated to dryness. The residue is chromatographed on silica, eluting with a cyclohexane ethyl acetate mixture and 0.590 g of product B (4-i.,dthyl heptene and 1.7 g of product C (4-methylene heptane and 1 g of mixture are obtained.

Product B: Rf. 0.32 in cyclohexane ethyl acetate Product C: Rf. 0.35 (1 1) STAGE F: Diethyl 2-(difluoromethyl)-2-(formylamino)-4methylene-6-[(methylsulphonyl)-oxy]-heptanedioate.

1.65 g of product C obtained above is dissolved in cm 3 of pyridine, cooled to 0 0 C and 0.725 g of methanesulphonyl chloride is added. Agitation is carried out for minutes at 0 0 C and for 5 hours at ambient temperature. The reaction mixture is poured into ice-cooled 6N hydrochloric acid, uxtracted with methylene chloride, the organic phase is washed with 6N hydrochloric acid and then with a 10% aqueous solution of sodium bicarbonate and finally with salt water, dried and evaporated to dryness. The residue is chromatographed on silica, eluting with a methylene chloride ethyl acetate mixture and 1.55 g of expected product is isolated. Rf. 0.45 in CH 2 C12 AcOEt 22 EXAMPLE 9: 2-ethynyl-2-[(methoxycarbonyl)-amino]-4-methylene- 6-[(phenylmethyl)-amino]-heptanedioic acid.

STAGE A: 7-methyl-i-methyl 2-[(methoxycarbonyl)-amino]-4methvlene-6-[(phenylmethyl)-amino]-2-[2-(trimethylsilyl)ethynyl]-heptanedioate.

A solution comprising 1.6 g of product prepared in preparation 3 in 40 cm 3 of methylene chloride is added to a solution comprising 387 mg of triethylamine, 393 mg of benzylamine in 80 cm 3 of methylene chloride. The mixture is agitated for 6 hours at ambient temperature, washed with a solution of N hydrochloric acid, then with a solution of sodium bicarbonate, dried and evaporated to dryness. 1.54 g of crude desired product is obtained which is purified by chromatography on silica, eluting with a methylene chloride 15 ethyl acetate mixture 1.2 g of desired product is ,o obtained. Rf. 0.28 (CH 2 C1 2 AcOEt i STAGE B: 7-ethyl-l-methyl 2-ethynyl-2[(methoxycarbonyl)amino]-4-methylene-6-[(phenylmethyl)-amino]-heptanedioate.

0.23 g of potassium fluoride is added to 1.23 g of product prepared as in Stage A, in solution in 30 cm 3 of o dimethylformamide. The mixture is agitated for 16 hours at ambient temperature, then diluted in 200 cm 3 of ethyl ether.

S Washing, drying and evaporation to dryness are carried out.

S 1.02 g of desired product is obtained.

Rf. 0.6 (cyclohexane ethyl acetate STAGE C: 2-ethynyl-2-[(methoxycarbonyl)-amino]-4-methylene-6- [(phenylmethyl)-amino]-heptanedioic acid.

cm 3 of 2N soda is added to a solution comprising 140 mg of product prepared in the previous stage and 15 cm 3 of ethanol. The mixture is agitated at ambient temperature for 3 days. It is neutralized with 50 W x 8 Dowex resin, then filtered. The filtrate is washed with water then eluted with 100 cm 3 of 0.5N ammonium hydroxide. After evaporating to dryness, the residue is taken up ii water, filtered and lyophilized. 106 mg of desired product is obtained.

Rf. 0.25 (EtOH, NH 4 0H PREPARATION 3: 7-ethyl-l-methyl 2-[(methoxycarbonyl)-amino]- 4-methylene-6-[(trifluoromethylsulphonyl)-oxy]-2-r2- I1 -23 (trimethylb.lyl)-ethynyl]-heptanedioate.

1.015 g of trifluoromethane sulphonic anhydride is added at 0°C to a solution comprising 594 mg of pyridine and 6 cm 3 of methylene chloride. The solution obtained is agitated for 10 minutes at 0°C. The solution obtained is poured into a solution comprising 1.2 g of product prepared in Stage B of preparation 1 in solution in 30 cm 3 of methylene chloride.

Agitation is carried out for 15 minutes at 0°C. Washing is carried out with N hydrochloric acid, then with a solution of sodium acid carbonate, followed bj drying and evaporation to dryness at 30 0 C. 1.6 g of desired product is obtained.

Rf. 0.45 ?cyclohexane ethyl acetate EXAMPLE 10: 2-amino-2-ethynyl-4-methylene-6-[(phenylmethyl)amino]-heptanedioic acid.

A solution comprising 400 mg of product prepared in Example 9 in 35 cm 3 of 6N soda is heated for 2 hours minutes at 90 0 C. The solution is neutralized with 12N hydrochloric acid until a pH of about 5 is obtained. After partial concentration, it is placed on 50 W x 8 Dowex resin.

1 20 After rinsing with water and eluting with 0.5N ammonium hydroxide, the fractions containing the product are I reunited. After evaporation to dryness 320 mg of product is S obtained which is purified on silica, eluting with a methylene chloride methanol. acetic acid mixture 150 mg of product is obtained which is purified again by chromatography on s'.ica, eluting with a CH 2 Cl MeOH i mixture then with a CH 2 C12 MeOH NH 4 0H mixture In this way the desired pure product is obtained which is lyophilized.

Rf. 0.35 (eluant: BeOH AcOH H20 EXAMPLE 11: 2-amino-6-(dimethylamino)-2-ethynyl-4-methylene heptanedioic acid.

STAGE A: 7-ethyl-l-methyl 2-[(methoxycarbonyl)-amino]-6- S(dimethylamino)-4-methylene-2-(2-trimethylsilyl)-ethynyl]heptanedioate.

1.44 g of 7-ethyl-l-methyl 2-[(methoxycarbonyl)-amino]- 4-methylene-6-((trifluoromethyldulphonyl)-oxy]-2-[ 2 (trimethylsilyl)-ethynyl heptanedioate prepared as in rr uu rul I- U l s 24 preparation 3 in 40 cm 3 of tetrahydrofuran is cooled to 0 0

C.

Dimethylamine is bubbled through for 5 minutes, followed by agitation for 30 minutes at 0°C. The solvent is evaporated off, the residue taken up in methylene chloride, washed with a 10% aqueous solution of sodium bicarbonate, concentrated to dryness, and 1.2 g of crude product is recovered which is purified by chromatography on silica (eluant: methylene chloride ethyl acetate 440 mg of expected product is obtained.

Rf. 0.33 (methylene chloride ethyl acetate 6-4).

STAGE B: 2-amino-6-(dimethylamino)-2-ethynyl-4-methylene heptanedioic acid.

108 mg of potassium fluoride is added to 400 mg of product obtained in Stage A in solution in 15 cm 3 of dimethylformamide and the mixture is agitated for 16 hours at ambient temperature. After concentration to dryness, the residue is taken up in methylene chloride, washed with salt water, and the solvents are dried and evaporated to dryness.

330 mg of 2-ethynyl intermediate is obtained. 300 mg of this .1'20 product is dissolved in 10 cm 3 of ethanol, 1.7 cm 3 of 2N soda is added, with agitation for 16 hours at ambient temperature.

The solvent is evaporated off, the residue is taken up in 4 cm 3 of 6N soda, with agitation for 4 hours at 90 0

C.

Neutralization is effected by treatment on Dowex resin for one hour. Filtration is carried out and the filtrate is waaned with water, then with 0.5N ammonium hydroxide. 270 mg of crude product is obtained which is chromatographed on silica (eluant: ethanol ammonium hydroxide 9-1, 8-2 then 7- Treatment is carried out again on Dowex resin, followed by elution with 0.5N ammonium hydroxide, and the residue is taken up in 10 cm 3 of water and lyophilizd 135 mg of expected product is obtained.

Rf. 0.25 (ethanol ammonium hydroxide 8-2).

SEXAMPLE 12: 2-ethynyl-2- (methoxycarbonyl) -amino methylene- 6-(methylaiiino)-heptanedioic acid.

STAGE A: 7-ethyl-l-methyl 2-[(methoxycarbcnyl)-amino]-6methylamino)-4-methylene-2-2-(timethysil -ethynyl heptanedioate.

p ~Lcrs~R;saro~imace~~+r~i oeea

O

OOu 25 1,4 cm 3 of methylamine in ethanol solution (8.06 M/1.) is added to a solution comprising 0.96 g of 7-ethyl-l-methyl 2-[(methoxycarbonyl)-amino] -4-methylene-6-[(trifluoromethyleulphonyl)-oxy -2-[2-(trimethyliilyl) -ethynyl] -1eptanedioate prepared as in preparation 3 in 25 cm 3 of tetrahydrofuran, and the whole is agitated for 15 minutes at ambient temperature. The solvent ij evaporated off, the residue is taken up in methylene chloride, washed with a 10% aqueous solution of sodium bicarbonate, dried and concentrated tc dryness. 770 mg of product is obtained which is chromatographed on silica (eluant: methylene chloride ethyl acetate 530 mg of expected product is collected.

Rf. 0.15 (methylene chloride ethyl acetate 6-4).

STAGE B: 7-ethyl-l-methyl 2-ethynyl-2-[(methoxycarbonyl)amino]-6-(methylamino)-4-methyl.-ne heptanedioate.

The operation is carried out as in Stage B of Example 9 using 5C mg of product prepared as in Stage A in 30 cm 3 of dimethylformamide and 260 mg of potassium fluoride. 620 mg of expected product is obtained.

Rf. 0.5 (methylene chloride ethyl acetate STAGE C: 2-ethynyl-2-[(methoxycarbonyl)-amino]-4-methylene-6- (methylamino)-heptanedioic acid.

The operation is carried out as in Stage C of Example 9 using at the start 200 mg of product obtained in Stage B in 13 cm 3 of ethanol and 0.9 cm 3 of 2N soda. 156 mg of expt-ted product is obtained.

Rf. 0.3 (ethanol ammonium hydroxide 8-2).

EXAMPLE 13: 2-amino-6-(methylamino)-2-ethynyl-4-methylene heptanedioic acid.

A solution comprising 320 mg of product obtained as in Example 12 in 35 cm 3 Df 6N soda is heated for 3 hours at 0 C. The solution is washed with 12N hydrochloric acid until a pH of 3 is obtained, then treated on 50 W x 8 Dowex Sresin, rinsed with water and eluted with 0.5N ammonium hydroxide, then the fractions containing the product are reunited. 220 mg of product is collected which is purified on silica (eluant: ethanol ammonium hydroxide 95-5, 90-10 then 85-15). After another treatment on Amberlyst 15 resin, i 26 washing with water, eluting with 0.5N ammonium hydroxide and lyophilizing, 53 mg of expected pure product is obtained.

Rf. 0.2 (ethanol ammonium hydroxide 85-15).

EXAMPLE 14: Tablets were prepared corresponding to the formula: Product of Example 2 50 mg Excipient q.s. for a tablet completed at 250 mg (detail of excipient: lactose, starch, talc, magnesium stearate).

EXAMPLE Capsules were prepared corresponding to the formula: Product of Example 3 100 mg 0 Standard excipient for capsules.

S 15 Anti-bacterial activity (in vitro) W The anti-bacterial activity of th-i products claimed was determined by the method of diffusion in Davis Mingioli medium having added to it 1% of agar. The geloses used are poured into Petri dishes at 48 0 C, after sowing with 5 x 10 J° 20 germs/ml by means of the control bacterial strain. The 0 o 0 inoculations com-. from a pre-culture for 24 hours in Davis Mingioli medium. After hardening of the geioses, the aqueous I solutions of the products studied are introduced into the wells (9 mm) hollowed into the medium with a punch. The areas of inhibition observed (ii r in mm) are measured after incubation for 24 hours at 37°C.

Product of Product of Product of Exarrple 4 Example I Example (100 (100 mg/l) (100 mg/1) Escherichia Coli 078 17.5 18 Salmonella typhimurium MZ11 31 34 19 Enterobacter cloacae '321E 26 29 Provide ia sp. DU48 29 28

Claims

2-amino-2-ethvnyl-4-methylene-6-(phenylmethyl)-amino heptanedioic acid. 11) As medicaments, the compounds of formula as defined in any one of claims 1 to 9, as well as their salts with pharmaceutically acceptable organic or mineral acids or bases. 12) As medicaments, the compounds of formula as defined i A 29 in claim 10, as well as their salts with pharmaceutically acceptable organic or mineral acids or bases. 13) Process fo the preparation of compounds of formula (I) as defined in any one of claims 1 to 10, characterized in that a compound of general formula (II): OSO 2 alK C(0) R' Y NHX R' 1 (O)n C NHX' (II) o i o r o e 0 e o e o 0 o a in which alk represents an alkyl radical containing from 1 to 8 carbon atoms optionally substituted by one or more halogen atoms, n, n 1 and the dotted lines retain the same eai as previously, Y' represents either Y, or E X'I, R' and R' 1 have the same meaning as X1, R and R 1 with the exception of the hydrogen, is subjected to the action of a reagent capable of providing a precursor of the amino function or of an amine of formula HN in which X'has the meaning indicated in claim 1 and X' has the meaning indicated for X with the exception of the hydrogen, so as to obtain, if appropriate, after suitable treatment, the compound of formula which, if desired, is subjected to all or part of the following operations in any order: deprotection of the amine functions, functionalistion of the amine functions, hydrolysis of the ester functions, the treatment of Y' so as to obtain Y, total or selective reduction of the Y substituent when this is unsaturated, -salification. 14) Process according to claim 13, characterized in that the reagent capable of providing a precursor of the amino function is sodium nitride, potassium phthalamide or hydroxylamine. Process according to claim 13, characterized in that a compound of formula (II) defined as in claim 13 is subjected to the action of sodium nitride so as to obtain the compound of formula (III): 3 C(O) 0y C NHX' 1 1. which is subjected to the action of a reducing agent of the N 3 group, so as to obtain the compound of formula (IV): NH 2 C (O)nR' (IV) R'1(O)n C NHX' 1 which is subjected to all or part of the operations mentioned at the end of claim 13. 16) Process according to claim 13, characterized in that a compound of formula (IIA): OSO 2 alK 2R H 3 C (IIA) H 3 C- Si-C.C H3C R 102 NHX'1 is subjected either to the action of sodium nitride so as to -77 obtain the compound of formula (IIIA): -31 H C~ CO 2 R' (IIIA) H 3 C R 1 0 2 C NHX' which is subjected to the action of a reducing agent of the nitride so as to obtain the compound of formula (IVA): NH 2 H3 R'0 2 I-X 4> as to obai the copoIVoAorul)IV xi asthe eiter the compound (oVf forml (IVB) i ujctdt h compnd ofhe foema n (IA(oIA):ssbjce t h 0 r p 32 (IA) HO 2 that, if appropriate, is subjected to the action of a cleaving agent of the amine protector group so as to obtain the compound of formula (IB): 00 00 000 Don 0 o0 0 0 6 00 .0 0 0 0"0 000 n0 0 00 000 00 o 0 (IB) HC=C HO 2 C or the compound of formula (IVA) or (IVB) is subjected to the action of a cleaving agent of the trimethylsilyl so as to obtain the compound of formula (IC): NH X1 (Ic) HC=C R' then if desired, the compound of formula (IB) or (Ic) is subjected to the action of a partial reducing agent so as to obtain the corresponding compound of formula (ID) in which Y represents an ethenyl radical, or to the action of a total reducing agent of the triple bond so as to obtain the corresponding compound of formula (IE) in which Y is an ethyl