FR2566410A1 - New diaminopimelic acid derivatives, a process for preparing them and their therapeutic application - Google Patents

Abstract

Diaminopimelic acid derivatives of general formula: in which (-A-B-) represents a chain R and R4 represent H, CHO, alkylcarbonyl, benzylcarbonyl, -CO-(CH2)n-COOR1, COCH(R5)NHR6 or a peptide chain; R1 = H or CH3, R2 and R3 represent OH, alkoxy, benzyloxy, NHCH(R5)COOR1 or a peptide chain; it being possible, in addition, for R and R3 to form together a simple bond when (-A-B-) represent ; as well as their isomers or their salts. These compounds are useful in particular as antibacterial agents.

Description

 The present invention relates to novel derivatives of diaminopimelic acid, their method of preparation and their therapeutic application.

dans laquelle - (-A-B-) représente l'un des enchainements suivants

- R et Rq, qui sont identiques ou différents, représentent chacun un atome
d'hydrogène ; un groupe formyle, aikylcarbonyle dans lequel le reste alkyle
a de 1 à 4 atomes de carbone ou benzylcarbonyle ; un enchaînement de structure
-C0-(CH2)n-COOR1 dans lequel n prend la valeur 1, 2 ou 3 et R1 représente
l'atome d'hydrogène ou le groupe méthyle ; ou un enchalnement de structure

où R5, R7 et R8 représentent chacun l'atome d'hydrogène, un groupe alkyle de 1 à 4 atomes de carbone, un groupe benzyle, (imidazolyl-4) méthyle, (indolyl-3) méthyle ou para-hydroxybenzyle, un groupe hydroxyalkyle, thioalkyle ou méthyl thicaîkyle dont les restes alkyle possèdent 1 ou 2 atomes de carbone, un groupe (amino-4) butyle ou (guanidino-3) propyle ou un groupe aminocarbonylalkyle dont le reste alkyle possède 1 à 3 atomes de carbone, R6 représente l'atome d'hydrogène ou le groupe formyle et m = 0 ou 1, R4 et R6 ne pouvant toutefois représenter le groupe formyle quand R= H - R 1 = H ou CH3 avec la restriction que lorsque R1 = CH3, (-A-B-) ne peut
représenter que (-CH=CH-) (E) ou (-CH2-CH2-) ;; -R2 et R3, qui sont identiques ou différents, représentent chacun-le groupe
hydroxyle, un groupe alkoxy de 1 à 4 atomes de carbone, un groupe benzyloxy ou un enchalnement de structure

The new derivatives of the invention more specifically correspond to the following general formula

in which - (-AB-) represents one of the following sequences

- R and Rq, which are identical or different, each represent an atom
hydrogen; a formyl, alkylcarbonyl group in which the alkyl radical
has 1 to 4 carbon atoms or benzylcarbonyl; a sequence of structures
-C0- (CH2) n-COOR1 wherein n is 1, 2 or 3 and R1 is
the hydrogen atom or the methyl group; or a structure chaining

where R5, R7 and R8 each represent a hydrogen atom, an alkyl group of 1 to 4 carbon atoms, a benzyl group, (4-imidazolyl) methyl, (3-indolyl) methyl or para-hydroxybenzyl, a group hydroxyalkyl, thioalkyl or methylthiaryl of which the alkyl radicals have 1 or 2 carbon atoms, a (4-amino) butyl or (3-guanidino) propyl group or an aminocarbonylalkyl group, the alkyl radical of which has 1 to 3 carbon atoms, R6 represents the hydrogen atom or the formyl group and m = 0 or 1, R4 and R6, however, not being able to represent the formyl group when R = H - R 1 = H or CH3 with the restriction that when R1 = CH3, (- AB-) can not
represent that (-CH = CH-) (E) or (-CH2-CH2-) ;; -R2 and R3, which are identical or different, each represent the group
hydroxyl, an alkoxy group of 1 to 4 carbon atoms, a benzyloxy group or a structural

auquel cas les composés (I) ont la structure

where R1, R5, R7, R8 and m have the same meanings as previously - R and R3 may further jointly form a single bond when (-AB-) is particular

in which case the compounds (I) have the structure

where R2 and R4 have the same meanings as previously the set (R, R1, R2, R3, R4) can not however take the following particular values: (H, H, OH, OH, H), (H, H, CH3O, CH3O, H), (H, CH3, OH, OH, H), (H, CH3, CH3O, CH3O, H) when (-AB-) represents (-CH2-CH2), or the following particular values: (H, H, OH, OH, H), (H, H, CH 3 O, CH 3 O, H) when (-AB-) represents

 It should be noted that formulas (I) and (I ') above contain several asymmetric carbon atoms. The present invention obviously extends as well to racemic as to diastereoisomers and enantiomers of formula (I) and (I '). It also extends to the addition salts of acids or bases, organic or inorganic, derivatives (I) and (I ') that they are in the form of racemic, diastereoisomers or enantiomers.

 Note also that when R and / or R4 = H and R2 and R3 = CH, the corresponding compounds of the invention may exist in the form of internal salts (zwitterions) which also fall within the scope of the invention.

 In what follows, the stereochemistry (R) or (S) is given (when it has been determined) according to Kahn-Ingold-Prelog rules. In addition, some coasts of diastereoisomers could be isolated by chromatographic techniques (in particular column chromatography on cellulose or silica) and when their exact stereochemistry is not indicated, they are called as the most polar or the least polar diastereoisomeric pair. .

dans lesquelles R' a les mêmes significations que R dans (I) excepté que R' ne peut pas représenter l'atome d'hydrogène ; R'2 et R'3 représentent chacun un groupe alkyloxy de 1 à 4 atomes de carbone ; R1 a les mêmes significations que dans (I) ; et R9 représente soit l'atome d'hydrogène [auquel cas la stéréochimie de la double liaison dans (Ia) est E : trans], soit l'atome de chlore [auquel cas la stéréochimie de la double liaison dans (la) est Z : cis], sont respectivement obtenus par réduction des composés de structures (II) et (IIa)

où R', R1,R'2, R'3 et R9 ont les mêmes significations que dans (Ia) et (Ib). The compounds (I) according to the invention, of particular structures (Ia) and (Ib)

in which R 'has the same meanings as R in (I) except that R' can not represent the hydrogen atom; R'2 and R'3 each represent an alkyloxy group of 1 to 4 carbon atoms; R1 has the same meanings as in (I); and R9 represents either the hydrogen atom [in which case the stereochemistry of the double bond in (Ia) is E: trans], or the chlorine atom [in which case the stereochemistry of the double bond in (la) is Z : cis], are respectively obtained by reduction of the compounds of structures (II) and (IIa)

where R ', R1, R'2, R'3 and R9 have the same meanings as in (Ia) and (Ib).

The reduction is preferably carried out either by the action of triphenylphosphine (P3), advantageously in an organic solvent such as tetrahydrofuran, on derivatives (II) and (IIa), followed by hydrolysis, or by catalytic reduction with hydrogen in the presence of the so-called catalyst of
LINDLAR compounds (II) and (IIa).

où R', R1, R'2, Rf3 et Rg ont les mêmes significations que dans-(II) et (IIa), par une synthèse en deux étapes qui consiste à traiter respectivement les composé sés (III) et (IIIa) par le chlorure de mésyle ou de tosyle notamment en milieu pyridinique, puis à condenser sur les mésylates ou tosylates intermédiaires ainsi obtenus, l'azoture de sodium notamment en solution dans le diméthylSor- mamide.The compounds (II) and (IIa) are respectively obtained from the hydroxyl compounds of formulas (III) and (IIIa)

where R ', R1, R'2, Rf3 and Rg have the same meanings as in- (II) and (IIa), by a two-step synthesis which consists of treating respectively the compounds ss (III) and (IIIa) by mesyl or tosyl chloride, in particular in a pyridine medium, and then on the intermediate mesylates or tosylates thus obtained, to be condensed, sodium azide, especially in solution in dimethyl-aminamide.

où R', R1, R'2 et R9 ont les mêmes significations que dans (III) et (IIIa), avec les composés de formule (V)
OCH - COR'3 (V) dans laquelle R'3 a les mêmes significations que dans (III) et (IIIa), cette condensation étant de préférence effectuée à température ambiante, dans un solvant aprotique (de préférence le chlorure de méthylène) en présence d'un acide de Lewis (de préférence le chlorure ferrique)
On notera ici que si les composés (IV) et (IVa) ont une stéréochimie bien définie (R) ou (S), la stéréochimie du carbone portant le substituant R1 des composés (I) issus de ces composés (IV) et (IVa) est alors également définie (R) ou (S).The compounds (III) and (IIIa) are respectively obtained by condensation of the compounds (IV) and (IVa)

where R ', R1, R'2 and R9 have the same meanings as in (III) and (IIIa), with the compounds of formula (V)
OCH - COR'3 (V) in which R'3 has the same meanings as in (III) and (IIIa), this condensation being preferably carried out at ambient temperature, in an aprotic solvent (preferably methylene chloride) in presence of a Lewis acid (preferably ferric chloride)
It will be noted here that if the compounds (IV) and (IVa) have a well-defined (R) or (S) stereochemistry, the stereochemistry of the carbon bearing the R1 substituent of the compounds (I) derived from these compounds (IV) and (IVa) ) is then also defined (R) or (S).

où R', R'2 et R'3 ont les mêmes significations que dans (Ia) ou (Ib) sont respectivement obtenus par déprotection des composés de formules (VI) et (VIa)

où R', R'2 et R'3 ont les mêmes significations que dans (Ic) et (Id), cette déprotection pouvant avantageusement être réalisée par action de l'acide formique.Compounds (I) of particular structures (Ic) and (Id)

where R ', R'2 and R'3 have the same meanings as in (Ia) or (Ib) are respectively obtained by deprotection of the compounds of formulas (VI) and (VIa)

where R ', R'2 and R'3 have the same meanings as in (Ic) and (Id), this deprotection may advantageously be carried out by the action of formic acid.

où RV, R'2 et R'3 ont les memes significations que dans (VI) et (VIa). Compounds (VI) and (VIa) are obtained by the action of sodium chloride in solution in a mixture of dimethylsulfoxide and water, respectively on the compounds of formulas (VII) and (VIIa)

where RV, R'2 and R'3 have the same meanings as in (VI) and (VIa).

 it should be noted that the compounds (VI) and (VIa) are each constituted by a mixture of two pairs of diastereoisomers, one more polar than the other and which may optionally be separated by column chromatography (preferably on a column of silica - medium pressure liquid chromatography MPLC), the corresponding compounds (Ic) and (Id) then also being each in the form of two pairs of diastereoisomers, one more polar than the other.

où R', R'2 et R'3 ont lesomêmes significations que dans (VII) et (VIIa).The compounds (VII) and (VIIa) are respectively obtained by the action of di-t-butyldicarbonate in an aprotic medium (preferably methylene chloride) on the compounds of formulas (VIII) and (VIIIa)

where R ', R'2 and R'3 have the same meanings as in (VII) and (VIIa).

où R', R'2 et R'3 ont les mêmes significations que dans (VIII) et (VIIIa).As for the compounds (VIII) and (VIIIa), they are obtained by carrying out the processes described above for obtaining the compounds (Ia) and - (Ib), but respectively from the compounds (IIb) and (tic)

where R ', R'2 and R'3 have the same meanings as in (VIII) and (VIIIa).

où R', R'2 et R' 3 ont les mêmes significations que dans (nib) ou (IIc) et qui consiste à traiter respectivement les composés (IIIb) par le chlorure de tosyle ou de mésyle en milieu pyridinique, à faire réagir sur les composés intermé- diaires ainsi obtenus l'azoture de sodium dans le DXF, puis à séparer par chromatographie sur colonne de silice (MPLC) le mélange d'azides (nib) + (IIc) obtenu.The compounds (IIb) and (IIc) are obtained by a synthesis in three stages starting from the compounds (IIIb)

where R ', R'2 and R' 3 have the same meanings as in (nib) or (IIc) and which consists in treating the compounds (IIIb) respectively with tosyl chloride or mesyl in a pyridine medium, to be reacted on the intermediate compounds thus obtained, the sodium azide in the DXF, then to separate by chromatography on a silica column (MPLC) the mixture of azides (nib) + (IIc) obtained.

où R' et R'2 ont les mêmes significations que dans (IIIb), et des composés (V).The compounds (IIIb) are obtained for their part by carrying out the process described above for the synthesis of the compounds (III) and (IIIa), but respectively starting from the compounds (IVb).

where R 'and R'2 have the same meanings as in (IIIb), and compounds (V).

dans laquelle R10 représente l'atome d'hydrogène ou de chlore ou le groupe méthyle, sur les composés (X) ou (Xa)

où R'2 a les mêmes significations que dans (IV), (IVa) ou (IVb) et R11 désigne l'atome d'hydrogène, le groupe méthyle ou un groupe COR'2 dans lequel R'2 a
2 les mêmes significations que dans (IV), (IVa) ou (IVb). The compounds (IV), (IVa) and (IVb) are in turn obtained by condensation in the presence of a base (preferably K2CO3) in an aprotic solvent (preferably acetonitrile) and in the presence of a so-called catalyst. phase transfer, compounds of formula

in which R10 represents the hydrogen or chlorine atom or the methyl group, on the compounds (X) or (Xa)

where R'2 has the same meanings as in (IV), (IVa) or (IVb) and R11 designates the hydrogen atom, the methyl group or a COR'2 group in which R'2 has
2 the same meanings as in (IV), (IVa) or (IVb).

où R11 et R'2 ont les mêmes significations que dans (X) et R10 a les mêmes significations que dans (IX) sont ensuite éventuellement traités par l'acide chlorhydrique (#6N) pour donner les composes

où R10 a les mêmes significations que dans (IVc) et R1 représente un tome d'hydrogène ou le groupe méthyle.Compounds (IV), (IVa), (IVb) thus obtained and of particular structure:

where R11 and R'2 have the same meanings as in (X) and R10 has the same meanings as in (IX) are then optionally treated with hydrochloric acid (# 6N) to give the compounds

where R10 has the same meanings as in (IVc) and R1 represents a hydrogen or methyl group.

dans laquelle R" représente un groupe alkylcarbonyle où le reste alkyle possède 2 à 4 atomes de carbone, le groupe benzylcarbonyle, un enchaînement de structure -CO-(CH2)n-COOCH3, dans laquelle n prend la valeur 1, 2 ou 3, ou les enchaînements de structure

The compounds (IV ') are then treated with a mixture of thionyl chloride and an alcohol of formula
R'2 H. (XI) in which R'2 has the same meanings as in (ICc), then condensed
a) with formic acid in DMF,
(b) with acetic anhydride in solution in
methylene in the presence of triethylamine,
c) with the compounds of the formula

in which R "represents an alkylcarbonyl group where the alkyl radical has 2 to 4 carbon atoms, the benzylcarbonyl group, a structure -CO- (CH 2) n-COOCH 3 chain, in which n is 1, 2 or 3, or the structure sequences

dans lesquels R5, R7, R8 et m ont les mêmes significations que dans (I), le groupe protecteur

étant ensuite sélectivement hydrolysé par l'acide formique, ou
d) avec les composés de formule
R" - OH @ (XIII) dans laquelle R" a les mêmes significations que dans (XII), en présence de
DCCI (dicyclohexylcarbodiimide) en milieu aprotique, pour obtenir les composés (IV) et (IVa) correspondants.

in which R5, R7, R8 and m have the same meanings as in (I), the protecting group

then being selectively hydrolyzed with formic acid, or
d) with the compounds of the formula
R "- OH @ (XIII) in which R" has the same meanings as in (XII), in the presence of
DCCI (dicyclohexylcarbodiimide) in an aprotic medium, to obtain the corresponding compounds (IV) and (IVa).

dans laquelle R10 et R'2 ort les mêmes significations que dans (IVc) et obtenus par réaction des composés (IX) et des composés (Xa), sont traités par l'éthanol chlorhydrique (20,5N) pour donner les composés de formule

dans laquelle R'2 et R10 onties- mêmes significations que dans (IVd). Compounds (IVb) of particular formula

in which R10 and R'2 have the same meanings as in (IVc) and obtained by reaction of compounds (IX) and compounds (Xa), are treated with hydrochloric ethanol (20.5N) to give compounds of formula

in which R'2 and R10 have the same meanings as in (IVd).

 The compounds (IV ") are then condensed with the compounds of formula (XII) or with compounds (XIII) (according to the protocols described above) to give the corresponding compounds (IVb).

The compounds (XII) are, for their part, obtained by condensation in a tetrahydrofuranic medium or in a tetrahydrofuran-water mixture of the
N-hydroxysuccinimide with compounds (XIII) in the presence of DCCI.

dans laquelle R1, R', R'2, R'3 ont les mêmes significations que dans (Ia) et R12 représente l'atome d'hydrogène ou le groupe méthyle sont obtenus par hydrogénation catalytique, par exemple en présence de palladium sur charbon, en milieu alcoolique des composés (I) de formule particulière (Ia) pour lesquelles Rg = H, (Ib), (Ic) ou (Id).Compounds (I) of particular formula

in which R1, R ', R'2, R'3 have the same meanings as in (Ia) and R12 represents the hydrogen atom or the methyl group are obtained by catalytic hydrogenation, for example in the presence of palladium on carbon in an alcoholic medium compounds (I) of particular formula (Ia) for which Rg = H, (Ib), (Ic) or (Id).

dans laquelle R1 et (-A-B-) ont les mêmes significations que dans (I) et R' a les mêmes significations que dans (Ia) ou (Ib) sont obtenus par hydrolyse des composés (I) de formule particulière (Ia), (Ib), (Ic), (Id) ou (Ie) et notamment par action de lasoude aqueuse sur ces composés.Compounds (I) of particular formula

in which R1 and (-AB-) have the same meanings as in (I) and R 'has the same meanings as in (Ia) or (Ib) are obtained by hydrolysis of compounds (I) of particular formula (Ia), (Ib), (Ic), (Id) or (Ie) and in particular by aqueous lasoude action on these compounds.

dans laquelle R1 et (-A-B-) ont les mêmes significations que dans (I) et R'2 et R'3 ont les mêmes significations que dans (Ia) ou (Ib) sont obtenus par hydrolyse des composés (Ia), (Ib), (Ic), (Id) ou (Ie), dans lesquels R' représente le groupe formyle et notamment par action de l'éthanol chlorhydrique 0,5 N sur ces composés.Compounds (z) of particular formula

in which R1 and (-AB-) have the same meanings as in (I) and R'2 and R'3 have the same meanings as in (Ia) or (Ib) are obtained by hydrolysis of the compounds (Ia), ( Ib), (Ic), (Id) or (Ie), in which R 'represents the formyl group and especially by the action of 0.5 N hydrochloric ethanol on these compounds.

dans laquelle R1 et +A-B-) ont les mêmes significations que dans (I) et R' et R'2 ont les mêmes significations que dans (Ia) et (Ib) sont obtenus par chauffage dans l'eau des composés (Ia), (Ib), Cic), (Id) ou (Ie) correspondants.Compounds (I) of particular formula

in which R1 and + AB-) have the same meanings as in (I) and R 'and R'2 have the same meanings as in (Ia) and (Ib) are obtained by heating in water the compounds (Ia) , (Ib), Cic), (Id) or (Ie) corresponding.

dans laquelle R1 et CA-B-) ont les mêmes significations que dans (I) et R'2 a les mêmes significations que dans (la) sont obtenus par hydrolyse des composés (Ih) pour lesquels R' représente le groupe formyle et notamment par action de l'éthanol chlorhydrique 0,5 N sur ces composés.Compounds (I) of particular formula

in which R1 and CA-B-) have the same meanings as in (I) and R'2 has the same meanings as in (la) are obtained by hydrolysis of the compounds (Ih) for which R 'represents the formyl group and in particular by action of 0.5 N hydrochloric ethanol on these compounds.

dans laquelle R1 et (-A-B-) ont les mêmes significations que dans (I) sont obtenus par hydrolyse des composés (Ig) ou (Ii) correspondants et notamment par action de la soude aqueuse sur ces derniers.Compounds (I) of particular formula

in which R1 and (-AB-) have the same meanings as in (I) are obtained by hydrolysis of the corresponding compounds (Ig) or (Ii) and in particular by action of the aqueous sodium hydroxide on them.

dans laquelle R1, R3 et (-A-B-) ont les mêmes significations que dans (I), R' et R'2 ont les mêmes significations que dans (Ia) et R'4 a les mêmes significations que R4 dans (I) excepté que-R'4 ne peut représenter l'atome d'hydrogène, sont obtenus par condensation des composés (I) correspondants de formule (Ia), (Ib), (Ic), (Id), (Ie) ou (Ih)
avec l'acide formique de préférence dans le DMF pour donner les composés (Ik) dans lesquels R'4 représente le groupe formyle ;;
avec les composés de formule

dans laquelle R"4 a les mêmes significations que R" dans CXII)notamsent dans un solvant organique tel que le DMF, le THF ou le mélange THF-eau
avec les composés de formule
R"4 - OH (XIIIa) dans laquelle R"4 a les mêmes significations que R" dans (XIII), -en-milieu aprotique, en présence de DCCI ; ou
avec l'anhydride acétique, notamment en milieupyridinique ou dans le chlorure de méthylène ou le THF, en présence de triéthylamine.Compounds (I) of particular formula

in which R1, R3 and (-AB-) have the same meanings as in (I), R 'and R'2 have the same meanings as in (Ia) and R'4 has the same meanings as R4 in (I) except that R'4 can not represent the hydrogen atom, are obtained by condensation of the corresponding compounds (I) of formula (Ia), (Ib), (Ic), (Id), (Ie) or (Ih) )
with formic acid preferably in DMF to give the compounds (Ik) in which R'4 represents the formyl group;
with the formula compounds

wherein R "4 has the same meaning as R" in CXII) notamsent in an organic solvent such as DMF, THF or THF-water mixture
with the formula compounds
R "4-OH (XIIIa) in which R" 4 has the same meanings as R "in (XIII), in aprotic medium, in the presence of DCCI, or
with acetic anhydride, especially in pyridine medium or in methylene chloride or THF, in the presence of triethylamine.

dans laquelle R1 et (-A-B-) ont les mêmes significations que dans (I), R' a les mêmes significations que dans (Ia) et- R'4 a les mêmes significations que dans (Ik), sont obtenus par hydrolyse des composés (1k) correspondants et notamment par action de la soude aqueuse sur ces derniers.Compounds (I) of particular formula

in which R1 and (-AB-) have the same meanings as in (I), R 'has the same meanings as in (Ia) and R'4 has the same meanings as in (Ik), are obtained by hydrolysis of corresponding compounds (1k) and in particular by action of the aqueous sodium hydroxide on these.

dans laquelle R1, R3 et (-A-B-). ont les mêmes significations que dans (I),
R'1 a les mêmes significations que dans (Ia) et R'''4 a les mêmes significations que R4 dans (I) excepté que R"'4 ne peut représenter ni l'atome d'hydrogène ni le groupe formyle, sont obtenus par hydrolyse acide des composés (Ik) pour lesquels R' représente le groupe formyle et R'4 ne peut pas représenter le groupe formyle, cette hydrolyse pouvant notamment être réalisée par mise en oeuvre d'éthanol chlorhydrique 0,5 M. Compounds (I) of particular formula

wherein R1, R3 and (-AB-). have the same meanings as in (I),
R'1 has the same meanings as in (Ia) and R '''4 has the same meanings as R4 in (I) except that R "' 4 can not represent either the hydrogen atom or the formyl group, are obtained by acid hydrolysis of the compounds (Ik) for which R 'represents the formyl group and R'4 can not represent the formyl group, this hydrolysis may in particular be carried out using 0.5 M hydrochloric ethanol.

dans laquelle R1, (-A-B-) et R"14 ont les mêmes significations que dans (ils) sont obtenus par hydrolyse des composés (Im), notamment par action de la soude aqueuse sur ces derniers.Compounds (I) of particular formula

in which R 1, (-AB-) and R "14 have the same meanings as in (they) are obtained by hydrolysis of the compounds (Im), in particular by the action of the aqueous sodium hydroxide on them.

dans lesquelles R, R1, R4 et (-A-B-) ont les mêmes significations que dans (I)
et R2 et R3 sont identiques et ont les mêmes significations que R2 et R3 dans
(I) sans pouvoir toutefois représenter le groupe hydroxyle, sont obtenus à
partir des composés (If), (Ij), (Il) ou (In) correspondants par une synthèse
en deux stades et qui consiste
1) soit à traiter les composés (If), (Ij) ou (In) dont les groupes
-NH2 ont été protégés et les composés (It) avec le N-hydroxysuccinimide dans un solvant organique tel que le THFou lemélange THF-eau et en présence de DCCI, puis à con denser sur les composés intermédiaires ainsi obtenus les composés de formule
R"2H ou R"3H (XIIIb) où R"2 et R"3 ont les mêmes significations que dans (Io), (Ip) ou (Iq) ; soit à condenser les composés (If), (Ij) ou (In) dont les groupes -NH2 ont été protégés et les composés (It) avec les composés (XIIIb), en présence de
DCCI, en milieu aprotique, puis
2) à séparer par chromatographie notamment sur colonne de silice (MPLC) le mélange des composés (Io), (Ip) et (Iq) obtenu à l'étape précédente et à déprotéger les composés (Io), les composés (Ip) et les composés (Iq) ainsi séparés, par exemple par action de l'acide formique sur ces composés.Compounds (I) of particular formula

in which R, R1, R4 and (-AB-) have the same meanings as in (I)
and R2 and R3 are the same and have the same meanings as R2 and R3 in
(I) without however being able to represent the hydroxyl group, are obtained
from the corresponding compounds (If), (Ij), (II) or (In) by a synthesis
in two stages and that consists of
1) to treat the compounds (If), (Ij) or (In) whose groups
-NH2 were protected and the compounds (It) with N-hydroxysuccinimide in an organic solvent such as THF or THF-water mixture and in the presence of DCCI, and then to concentrate on the intermediate compounds thus obtained the compounds of formula
Where R "2H and R" 3 have the same meanings as in (Io), (Ip) or (Iq); or to condense the compounds (If), (Ij) or (In) whose -NH2 groups have been protected and the compounds (It) with the compounds (XIIIb), in the presence of
DCCI, in an aprotic environment, then
2) to be separated by chromatography, in particular on a silica column (MPLC), the mixture of the compounds (Io), (Ip) and (Iq) obtained in the preceding step and to deprotect the compounds (Io), the compounds (Ip) and the compounds (Iq) thus separated, for example by the action of formic acid on these compounds.

 The NH 2 groups of the compounds (If), (Ij) and (In) (see step 1 above) can be protected by the BOC group (# O-CO-), this protection being able in particular to be carried out by reacting said compounds with di-t-butyldicarbonate, in the presence of Et3N in bed or t-butanol.

et R = R4 = H, les composés (I) de formules particulières (Ip) et
(Iq) sont identiques.We note here that in the case where (-AB-) represents the group

and R = R4 = H, the compounds (I) of particular formulas (Ip) and
(Iq) are identical.

dans laquelle R, R1, R4 et (-A-B-) ont les mêmes significations que dans (I) et R"2 et R"3 ont les mêmes significations que dans (Io), (Ip) ou (Iq), mais sont différents, sont' obtenus par la synthèse mise en oeuvre pour la prépara tion des composés (Io), CIp) ou (Iq), mais à partir des composés (Ip), (Iq), (Ih) et (Ii) et des composés (Ik) et (Im) pour lesquels R3 = OH.Finally, the compounds (I) of particular formula

in which R, R1, R4 and (-AB-) have the same meanings as in (I) and R "2 and R" 3 have the same meanings as in (Io), (Ip) or (Iq), but are are obtained by the synthesis used for the preparation of the compounds (Io), ICp) or (Iq), but from the compounds (Ip), (Iq), (Ih) and (Ii) and compounds (Ik) and (Im) for which R3 = OH.

9 HCl] des composés (Ip) de structure particulière :

où R"2 et R4 ont les mêmes significations que dans (Ip), ce qui conduit aux composés (I') de structure particulière

où R"2 et R4 ont les mêmes significations que dans (Ip), les composés (I'a) pour lesquels R"2 = CH30 ou C2H50 étant ensuite éventuellement hydrolysés, notamment par action de la soude aqueuse, pour conduire aux composés (I') de formule particulière

The compounds (I ') are obtained by cyclization in the presence of WSC

9 HCl] compounds (Ip) of particular structure:

where R "2 and R4 have the same meanings as in (Ip), which leads to the compounds (I ') of particular structure

where R "2 and R4 have the same meanings as in (Ip), the compounds (I'a) for which R" 2 = CH30 or C2H50 are then optionally hydrolysed, in particular by the action of aqueous sodium hydroxide, to yield the compounds ( I ') of particular formula

 It will be noted that the cyclization mentioned above may advantageously be carried out in a water / THF mixture.

 The acid or base addition salts, organic or inorganic, of the compounds (I) can easily be obtained by using conventional salification techniques with an acid or a base.

 The following preparations are given by way of example to illustrate the invention.

EXAMPLE 1 Hydrochloride of E-amino-2-acetamido-6-heptenyl-ethyl dioate
[(Ia): R '= CH3CO, R1 = H, R'2 = R'3 = OC2H5; Code number: 2]
To a solution of 1.25 g of 2-azido-6-acetamido-6-hepten-6-ethyl dioate (E) [(II)] in 15 cm3 of THF is added all at once 1.31 g of triphenylphosphine. The mixture is stirred at room temperature, under a nitrogen or argon atmosphere, for 16 hours, then 0.23 ml of water is added and the mixture is stirred for a further 24 hours. Then the solvent is evaporated off, the residue is taken up in a hydrochloric acid solution (^ 2N). It is washed with methylene chloride and then the aqueous phase is evaporated. 1.2 g is thus obtained (Yield # 100%). of the expected compound whose physicochemical constants are collected in Table 1 + below.

 By the same process, but from the corresponding reagents, the other compounds (Ia) as well as the compounds (Ib), (VIII) and (VIIIa) are obtained.

Example 2: Ethyl ester of 2-amino-acid (2,2-bisthoycarbonyl-2-formamido)
4-ethyl-4-pentene [(VIII): R '= CHO, R 2 = R 3 = OC 2 H 5]
With stirring and under a hydrogen atmosphere, a mixture of 20 g of ethyl ester of azido acid is left behind. 2,2-bis (2-oxo-2-formamido) -4-ethyl-4-pentenoic acid (IIb) and 3 g of LINDLAR catalyst in 500 ml of alcohol. Then the catalyst is filtered, the filtrate is evaporated and the residue consisting of the expected product is used crude for the synthesis of the corresponding compound (VII).

 By the same process, but from the corresponding reagents, the compounds (Ia) and (Ib) are obtained, in particular that of code number 2 appearing in Table 1, as well as the compounds (VIIIa) and the other compounds (VIII). .

Example 3: ethyl ester of 2-azido acid (2,2-bisethoxycarbonyl)
formamido-2) ethyl-4-pentene-4-ol (IIb) and ethyl ester
2-azido-2-bisethoxycarbonyl-6, 6-formamido-4-methyl-4-acid
hexene-4-oic (IIc)
To a solution of 35.9 g of a mixture (not separated) of 2-hydroxy-2,2-bis (2-hydroxyethoxycarbonylformamido) ethyl-4-pentene-4-ethyl acid ester and ethyl ester of 2-Hydroxy-6-bisthoxycarbonyl-6-formamido-4-methyl-4-hexenic acid (tub) in 300 ml of pyridine is added 9.5 ml of mesyl chloride. Then after 3 hours at room temperature, it is diluted with ice water and acidified to pH # 2 with concentrated hydrochloric acid. Extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate (magnesium chloride), filtered and the filtrate is evaporated. 43.7 g of intermediate mesylate are obtained and dissolved in 400 ml of DMF. 7.8 g of sodium azide are then added, the mixture is left stirring for 15 hours at room temperature under an argon atmosphere, then the solvent is evaporated off under good vacuum, the residue is taken up in ethyl acetate and washed with water. dried over sodium sulfate Magnesium chloride), filtered and the filtrate evaporated. The residue is then chromatographed on a silica column (230-400 mesh) CMPLC). Elution with heptane mixture (70% ethyl acetate / 30%) gives 21 g (yield: 55%) of the expected compound (IIb) and then 6.5 g (yield: 20%) of the compound (IIc). ) which are used gross in the synthesis of the corresponding compounds (VIII) and (VIIIa).

 By the same method, but from the corresponding reagents, the compounds of formula (II) and (IIa) [respectively from compounds (III) and (IIIa)], as well as the other compounds (nib) and ( IIc).

EXAMPLE 4 Mixture of the Ethyl Ester of 2-Hydroxybutythoxycarbonyl
2,2-bonylformamido) 4-ethyl-4-pentene and ester
2-Hydroxybethoxycarbonyl-6,6-formamido-6-ethyl-ethyl
4-methyl-4-hexene (IIIb)
To a suspension of 64.9 g of ferric chloride in 150 ml of methylene chloride is added a solution of 20.5 g of ethyl glyoxylate (V) in 150 ml of methylene chloride. The mixture is left stirring for 15 minutes at ambient temperature, then the mixture is cooled to -100 ° C. and a solution of 25.8 g of α -formamido-α-methyl-2-propene is added thereto. -2) ethyl yl-1 malonate (IVb) in 150 ml of methylene chloride. It is left for 10 minutes at -100 ° C. and then the temperature is allowed to rise to room temperature. Ice water is added, the organic phase decanted, washed with 300 ml of 1N hydrochloric acid and then with twice 500 cm3 of water, dried over sodium sulfate (or magnesium), filtered and filtered. evaporate the filtrate. The residue thus obtained, which contains the expected compounds, is used crude in the synthesis of the corresponding compounds (IIb) and (IIc) (according to Example 3).

 By the same method, but from the corresponding reagents, the other compounds (IIIb), as well as the compounds (III) and (IIIa), the stereochemistry (E) or (Z) of the compounds (III), (IIIa) are obtained. ), (II), (IIa), (IIb) and (IIc) being confirmed by the study of NMR spectra

EXAMPLE 5 Ethyl Ether of 2-Amino Acid (2-ethoxycarbonylformamido-2)
4-ethylpentenoic acid [(Ic); R '= CHO, R'2 = R'3 = OC2H5]
A mixture of 0.66 g of tert-butoxycarbonyl-2-amino-2- (2-ethoxycarbonyl-2-formamido) -ethyl-4-pentenoic acid (VI) is left at room temperature for 2 hours in 25 ml. of formic acid.

Then the formic acid is evaporated under good vacuum, the residue is taken up in water, lyophilized and the silica gel (MPLC) is lyophilized on the column.

Elution with 99% ethanol-1% ammonia gives 0.34 g (yield: 60%) of the expected compound.

 By the same method, but from the corresponding reagents, the other compounds (Ic) and the compounds (Id) are obtained.

Example 6: ethyl ester of tert-butoxycarbonylamino-2-acid (ethoxy-
2-carbonylformamido-4-ethyl-4-pentene (VI)
Under argon, a mixture of 18.3 g of tert-butoxycarbonylamino-2- (2-oxo-2-oxo-formyl-2-ethyl) -4-pentene-4-pentenecarboxylic acid is heated under argon for 8 hours at 1600 ° C. (VII), 2.34 g of sodium chloride and 1.5 ml of water in 45 ml of DMSO. Then the solvents are evaporated under good vacuum, the residue is taken up in 300 ml of ethyl acetate, dried over sodium sulfate, filtered and the filtrate evaporated. The residue is chromatographed on a silica column (MPLC). By elution with heptane 50% ethyl acetate 50%, 2 g (yield: 13%) of the most polar, di-isomeric pair and 2, are obtained. 4 g (Yield: 15.5%) of the least polar diastereoisomeric pair.

 By the same method, but from the corresponding reagents, the other compounds (VI) and the compounds (VIa) are obtained.

EXAMPLE 7 Tertiobutoxycarbonylamino-2 (bisethoxy) Ethyl Ester
2,2-carbonyl, 2-formamido) 4-ethyl-4-pentene (VII)
To a solution of 14.3 g of 2-amino-2- (2,2-bisethoxycarbonyl-2-formamido) -ethyl-4-pentene-4-enic acid (VIII) ethyl ester and 0.3 ml of triethylamine in 200 ml. 10.1 ml of diterbutyldicarbonate are added under methylene chloride under argon. We leave 18 hours in contact. Then the solvent is evaporated and the expected compound obtained is used crude in the synthesis of the corresponding compound (VI).

 By the same method, but from the corresponding reagents, the other compounds (VII) and the compounds (VIIa) are obtained.

Example 8: amino-2-amino-6-acetamido-6-methylheptane dioate hydrochloride
ethyl-1,7 [(Ie); R '= CH3CO, R'2 = R'3 = OC2H5, R1 = CH3, R12 = H]
To a solution of 4 g of ethyl E-amino-2-acetamido-6-methyl-6-heptene-4-yl dioate (Ia) in 100 ml of ethanol is added 0.5 g of 5% palladium on carbon and then the mixture is hydrogenated under normal pressure at ambient temperature for 16 hours. The mixture is then filtered, the filtrate is evaporated, the residue is taken up in hydrochloric ether (# 4, 5N) and the crystallized product is filtered off. 3.6 g (yield: 87%) of the expected product are obtained (mp> 260 ° C.).

 By the same method, but from the corresponding reagents, the other compounds (Ie) are obtained.

Example 9: amino-2-amino-2-amino-2-hydroxycarbonyl-4-ethylpenteneoxy
hydrated [(Ij); Code number 5]
To a solution of 1 g of 2-amino-amino (2-amino-2-ethoxycarbonyl) ethyl-4-pentene-4-ol (1-ethyl) dihydrochloride in 10 ml of water is added ml of concentrated soda (# 10N). The mixture is then stirred for 1 hour, acidified to pH -4.5 with concentrated hydrochloric acid, the solution is deposited on an Amberlite IR 120 resin column, washed on the column with 400 ml of water and then the product is eluted. with the aid of 0.5N ammonia. The solution obtained is evaporated, the residue is taken up in a mixture of 50% alcohol and 50% water and the precipitate obtained is filtered off. 0.32 g (yield: 51%) of the expected compound are thus obtained.

 By the same method, but from the corresponding reagents, the other compounds (Ij) and in particular those of code numbers 1, 3, 9, 12, 13, 20, 21, 27, 28, 29 and 39 are obtained. compounds (If), in particular those of code numbers 4, 7, 8, 11, 15, 17, 40 and 41, the compounds (II), in particular those of code numbers A6, 31, 42 and 43, the compounds ( In), in particular of code numbers 22, 24 and 30, as well as the compounds (I'b), in particular those of code numbers 14 and 36, the compounds having the code numbers listed above all being listed in FIG. Table 1 below.

EXAMPLE 10 Hydrochloride of cis-amino-6'-ethoxycarbonyl-2-exomethylene-4
caprolactam [(I'a); Code number 34]
A mixture of 0.37 g of cis formamido-6-ethoxycarbonyl-2-exomethylene-4-caprolactam [(Ia)) is heated for 5 minutes at 400 ° C.; Code number 32) in 20 ml of hydrochloric ethanol (# 0.5N). Then the solvent is evaporated under good vacuum, and the expected compound is thus obtained with a practically quantitative yield.

 By the same process, but from the corresponding reagents, the other compounds (a), in particular that of code number 35, the compounds (Ig) and in particular those with code numbers 18, 19 and 25, the compounds (Ii), the compounds (Im) in particular that of code number 23, as well as the compounds (IV ") necessary for the synthesis of the corresponding compounds (IVb), the compounds of code numbers 18, 19, 23, 25 and being listed in Table 1.

Example 11: Z-amino-2-acetamido-6-ethoxycarbonyl-6-methyl-4-hexene-4
oic (Ih)
A mixture of 0.5 g of ethyl ester of 2-amino-2-acetamido-6-ethoxycarbonyl-4-methyl-4-hexene-4-ol (Ib) in 10 ml of water is refluxed for 24 hours. the water is evaporated under good vacuum, the residue is taken up in ethyl acetate and the precipitate formed is filtered off. 0.3 g of the expected product is thus obtained.

Example 12 N (-L-Alanylamino) -2 Ethyl Ester (Formamido-2)
2-ethoxycarbonyl-4-ethyl-4-pentene

 A mixture of 0.01 mol of ethyl-2-amino-2- (2-formamido-2-ethoxy-2-enoxy) -4-ethylpentenol 4 (1-ol) -acetate and 0 ml of stirring are left stirring for 48 hours under argon. 0.1 mole of O- (N-tert-butoxycarbonyl-L-alanyl) hydroxysuccinimide (XIIa) in -30 ml of DMF. The solvent is then evaporated off under good vacuum, the residue is treated with formic acid as described in Example 5, and the residue is chromatographed on a silica column (MPLC). Elution with 90% ethyl acetate / ethanol mixture gives 74% of the expected product.

et N-[ amino-2( amino-2 méthoxyearbonyl-2) éthyl-4 pentène-4]oyl-L-alanilate de méthyle [(Ip) ou (Iq);

Example 13: N- [2-aminamino-2- (1-hydroxycarbonyl) ethylaminocarbonyl] -2
4-ethylpenten-4-yl-L-alanine (lo) and N- [amino-2 (2-amino)
hydroxycarbonyl (2) ethyl-4-pentene-1-yl-L-alanine [(Ip) # (Iq)
Code number :: 37]
A mixture of 3 g of N-tert-butoxycarbonylamino-2 (N-tert-butoxyearbonylamino-2-hydroxy-2-yl) -ethyl-4-pentene-4-olec acid (prepared from the compound (I)) is left stirring for 15 hours at room temperature with good stirring. ) of code number 5, according to the method described in Example 7, but by carrying out the reaction in water or tert-butanol, 3 g of L-alanine methyl ester hydrochloride, 2 g. 3 g of DCCI and 1.6 cm3 of triethylamine in 100 cm3 of THF0. Then, the mixture is filtered, the filtrate is evaporated, the residue is taken up in methyl acetate, the insoluble matter is filtered off and the filtrate is evaporated off. The residue is chromatographed on a silica column (MPLC). By elution with 80% ethyl acetate / 20% heptane, 35% of a diamidic derivative is obtained, followed by 22% of a monoamido derivative. These derivatives are treated with formic acid according to the protocol of the example To give respectively N- [2-aminamino-2 (L-methoxycarbonyl-1))
methyl ethylaminocarbonyl-2] ethyl-4-pentene-4} alkyl-L-alanilate [Clo]

and N- [methyl 2-amino-2- (2-aminodoxy-4-methoxycarbonyl) ethyl-4-pentenedioyl-L-alanilate [(Ip) or (Iq);

The latter, treated with aqueous sodium hydroxide # 2N according to the protocol of Example 9, respectively lead to the compound (Io) expected and the compound (Ip) or (Iq) code number 37 expected.

 By the same method, but from the corresponding reagents, are obtained the other compounds (Io) and (Ip), in particular those of code number 26, 44, 45 and 46 appearing in Table 1, the other compounds (Iq) as well as the compounds (Ir).

Example 14: i -formamido α - (2-methyl-2-propenyl) ethyl malonate (IVd)
A mixture of 24.4 g of ethyl α-formamido malonate (Xa) and 16.3 g of 2-methyl-3-chloropropene-2 is refluxed for 3 hours and 30 minutes, with good stirring. (IX), 16.6 g of potassium carbonate (ground) and 0.32 g of crown ether 18 CROwN-6 in 400 ml of acetonitrile, and then 5.4 g of 2-methyl-chloroacetate were added. 3 propene-2 and allowed to reflux for another 15 hours. Then filtered, evaporated the filtrate and chromatography the residue on a silica column (MPLC). Elution with 70% ethyl acetate / 30% heptane and then crystallization from heptane gives 27 g (yield: 87%) of the expected product.

 By the same method, but from the corresponding reagents, the other compounds (IVd) and the compounds (IVc) are obtained.

Example 15: 2-amino-4-pentenoic acid [(IV '; R1 = R10 = H]
A suspension of 2 g of ethyl acetate of 2-acetamido-4-pentenic acid (IVc) in 10 ml of 6N hydrochloric acid is heated at 1100 ° C. for 12 hours. Then the hydrochloric acid is evaporated, the residue is taken up several times with water, the lacquer solution is washed with ethyl acetate, then the aqueous phase is evaporated and the residue is dried under good vacuum.

This gives 80% of the expected product.

Example 16: ethyl ester of 2-formamido pentene-4-oic acid
[(IV); R1 = CHO; R1 = Rg = H]
To a solution cooled to 0 ° C. of 20.3 ml of thionyl chloride and 150 ml of ethanol, 6.4 g of 2-amino-4-pentene acid are added and the mixture is allowed to come to room temperature again. stir 12 hours, evaporate the solvents, repeated several times the residue in ethanol by evaporating the ethanol each time. The residue is then treated with formic acid in DMF at 1400 C for 1 hour and 30 minutes. After evaporation of the solvents, 9 g (Yield # 92%) of the expected product are obtained.

 By the methods of Examples 15 and 16, the other compounds (IV) as well as the compounds (IVa) are obtained from the corresponding reagents.

Example 17 cis and trans formamido-6 ethoxycarbonyl-2-exomethylene-4-capro
lactam [(I'a); R4 = CHO, R "2 = OC2H5; Code numbers 32 and 333
To a solution of 3.8 g of 2-formamido acid (2-amino-2-ethoxycarbonyl) ethyl-4-pentene-4-oscan (Ip) in 200 ml of THF and 200 ml of water is added in 5 minutes. 5.63 g of WSC

Then allowed to stir at room temperature for 24 hours. The solvents are then evaporated, the residue is taken up in a mixture of 100 ml of water and 100 ml of chloroform, acidified to pH # with concentrated hydrochloric acid, the organic phase decanted, dried over sodium sulphate or of magnesium, filter and evaporate the filtrate. The residue is chromatographed on a silica column (MPLC). By elution with a 60% ethyl acetate / 40% heptane mixture, 0.37 g (yield: 10%) of the cis derivative (the least polar) of code number 32, then 0.3 g (yield: 8.5%) of trans derivative (the most polar) of code number 33.

By the same method, but from the corresponding reagents, are obtained the other compounds (I'a) and especially those of code numbers 34 and 35 appearing in Table 1. These two particular compounds can also be obtained by treating respectively compounds (Ia) of code numbers 32 and 33 for which R4 = CHO by 0.5N hydrochloric ethanol according to the protocol of Example 10 TABLE 1

<SEP> No. <SEP> Weight <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> OR
<tb><SEP> of <SEP> Formula <SEP> Form <SEP> Formula <SEP> Raw <SEP> Molecule
Code <SEP> SPECTRUM <SEP> NMR, <SEP> IR <SEP> OR <SEP>[&alpha;] D20
<tb><SEP>
<tb><SEP> diHCl <SEP> +
<tb><SEP> C <SEP> H <SEP> N
<tb><SEP> 7, <SEP> 45% <SEP> H2O
<tb><SEP> Base <SEP> C7H12N2O4 <SEP> 188.19
<tb><SEP> 1 <SEP>#<SEP> (E) <SEP> 2 <SEP> HCl <SEP> Cal. <SEP>% <SEP> 29.80 <SEP> 5.83 <SEP> 9.93
<tb><SEP> + <SEP> C7H14Cl2N2O4 <SEP> 280.56
<tb><SEP> 7.45% <SEP> H2O <SEP> + <SEP> 7.45 <SEP>% <SEP> H2O <SEP> Tr. <SEP>% <SEP> 29.76 <SEP> 5.67 <SEP> 9.74
<tb><SEP> Base <SEP> C12H22N2O5 <SEP> 274.32 <SEP> NMR <SEP> (1H) - <SEP>#<SEP>ppm; CH3OD <SEP> - <SEP> basis
<tb><SEP> 2 <SEP>#<SEP> (SE) <SEP> HCl <SEP> C12H23ClN2O5 <SEP> 310.78 <SEP> 1.3, t <SEP> (-CH3) <SEP>;<SEP> 2, <SEP> 0, <SEP> s <SEP> (CH3 <SEP> CON) <SEP>;<SEP> 2, <SEP> 7,
<tb><SEP> m <SEP> (CH-2) <SEP>;<SEP> 4.3, q <SEP> (O-CH 2); 5.8, m (-CH = CH-)
<tb><SEP> Base <SEP> C8H14N2O4 <SEP> 202.21 <SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm <SEP> D2O <SEP> - <SEP> based
<tb><SEP> 3 <SEP>#<SEP> (E) <SEP> 2 <SEP> HCl <SEP> C8H16Cl2N2O4 <SEP> 275.13 <SEP> 2.7, <SEP> (2, CH) <SEP>;<SEP> 40.9 <SEP> (-CH2) <SEP>;<SEP> 16.7
<tb><SEP> (CH3) <SEP>;<SEP> 142 <SEP> and <SEP> 142.2 <SEP>(> C =) <SEP>;<SEP> 171.5 <SEP> and
<tb><SEP> 172, <SEP> 1 <SEP> (-COOH) <SEP>;<SEP> 120, <SEP> 7 <SEP> (-C =)
<tb><SEP> 3/4 <SEP> NH <SEP> +
<tb><SEP> Base <SEP> C10H16N2O5 <SEP> 244.25 <SEP> C <SEP> H <SEP> N
<tb><SEP> 3 / 4H2O3
<tb><SEP> 4 <SEP>#<SEP> 3/4 <SEP> NH3 <SEP> C10H16N2O5 <SEP> 270.53 <SEP> Cal. <SEP>% <SEP> 44.4 <SEP> 7.36 <SEP> 14.23
<tb><SEP> + <SEP> 3/4 <SEP> H2O <SEP> + <SEP> 3 / 4NH3 + 3 / 4H2O <SEP> Tr. <SEP>% <SEP> 44.24 <SEP> 7 , 80 <SEP> 13.94
<tb> TABLE 1 (continued)

<SEP> No. <SEP> Weight <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> OR
<tb><SEP> of <SEP> Formula <SEP> Form <SEP> Formula <SEP> Raw <SEP> Molecule
Code <SEP> SPECTRUM <SEP> NMR, <SEP> IR <SEP> OR <SEP>[&alpha;] D20
<tb><SEP>
<tb><SEP> HCl <SEP> + <SEP> H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C8H14N2O4 <SEP> 202.21
<tb><SEP> 5 <SEP>#<SEP> HCl <SEP> + <SEP> H2O <SEP> C8H15ClN2O4 <SEP> 256.68 <SEP> Cal. <SEP>% <SEP> 37.43 <SEP> 6 , 68 <SEP> 10.91
<tb><SEP> + <SEP> H2O <SEP> Tr. <SEP>% <SEP> 37.50 <SEP> 6.62 <SEP> 11.04
<tb><SEP> Base <SEP> C10H16N2O5 <SEP> 244.25 <SEP> + <SEP> H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> 7 <SEP>#<SEP> (E) <SEP> + <SEP> H2O <SEP> + <SEP> H2O <SEP> 262,27 <SEP> Cal. <SEP>% <SEP> 45.79 <SEP> 6.92 <SEP> 10.68
<tb><SEP> Tr. <SEP>% <SEP> 45.54 <SEP> 6.88 <SE> 10.62
<tb><SEP> Base <SEP> C10H18N2O5 <SEP> 264.26 <SEP> + <SEP> 1.6 <SEP> H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> 8 <SEP>#<SEP> + <SEP> 1.6 <SEP> H2O <SEP> + <SEP> 1.6 <SEP> H2O <SEP> 275.31 <SEP> Cal. <SEP>% <SEP> 43.62 <SEP> 7.70 <SEP> 10.17
<tb><SEP> Tr. <SEP>% <SEP> 43.19 <SEP> 7.57 <SEP> 9.93
<tb> TABLE 1 (continued)

<SEP> No. <SEP> Weight <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> OR
<tb><SEP> of <SEP> Formula <SEP> Form <SEP> Formula <SEP> Raw <SEP> Molecule
Code <SEP> SPECTRUM <SEP> NMR, <SEP> IR <SEP> OR <SEP>[&alpha;] D20
<tb><SEP>
<tb><SEP> NMR <SEP> (1H) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> Base <SEP> C8H14N2O4
<tb><SEP> 9 <SEP>#<SEP> 220.21 <SEP> 1.6, <SEP> s <SEP> (-CH3) <SEP>;<SEP> 2.6, <SEP> m <SEP> (-CH2) <SEP>;<SEP> 3.8
<tb><SEP> + <SEP> 1 <SEP> H2O <SEP> + <SEP> 1 <SEP> H2O
<tb><SEP> (-CH) <SEP>;<SEP> 5.8, m <SEP> (-CH = CH-)
<tb><SEP> NMR <SEP> (1H) <SEP> - <SEP>#<SEP> ppm, <SEP> CDCl3
<tb><SEP> 1.8, s <SEP> (CH3) <SEP>;<SEP> 2.6, m <SEP> (-CH2) <SEP>;<SEP> 3.8, m <SEP> (CH)
<tb><SEP> 10 <SEP>#<SEP> (Z) <SEP> Base <SEP> C14H24N2O5 <SEP> 300.35 <SEP> 4.2, q <SEP> (O-CH2) <SEP>;<SEP> 1.2, t <SEP> (-CH3) <SEP>;<SEP> 5.2, m
<tb><SEP> (-CH = <SEP> and <SEP> - # - H) <SEP>;<SEP> 2, s <SEP> (COCH3)
<tb><SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> Base <SEP> C10H16N2O5 <SEP> 262.26 <SEP> 52.6-52.9 <SEP> (-CH) <SEP>;<SEP> 34.2 <SEP> (-CH2) <SEP>;<SEP> 22.6
<tb><SEP> 11 <SEP>#<SEP> (Z) <SEP> + <SEP> 1 <SEP> H2O <SEP> + <SEP> 1 <SEP> H2O <SEP> (-CH3) <SEP ><SEP> 137.8 <SEP>(> C <SEP> =) <SEP>;<SEP> 124, <SEP> 7 <SEP> (-CH =) <SEP>;
<tb><SEP> 174.4-176.2 <SEP> (-C <SEP> = <SEP> O)
<tb><SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> Base <SEP> C8H14N2O4 <SEP> 53.3-53.5 <SEP> (- # H) <SEP>;<SEP> 34.7 <SEP> (-CH2) <SEP>;<SEP> 22.5
<tb><SEP> 12 <SEP>#<SEP> (Z) <SEP> + <SEP> 1.33 <SEP> H2O <SEP> + <SEP> 1.33 <SEP> H2O <SEP> 226, 17 <SEP> (-CH3) <SEP>;<SEP> 140, <SEP> 4 <SEP>(> C =) <SEP>;<SEP> 122, <SEP> 3 <SEP> (-CH =) <SEP>;
<tb><SEP> 173, <SEP> 7-175, <SEP> 1 (C = O)
<tb> TABLE 1 (continued)

<SEP> No. <SEP> Weight <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> OR
<tb><SEP> of <SEP> Formula <SEP> Form <SEP> Formula <SEP> Raw <SEP> Molecule
Code <SEP> SPECTRUM <SEP> NMR, <SEP> IR <SEP> OR <SEP>[&alpha;] D20
<tb><SEP>
<tb><SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> 52.8-55.1 <SEP> (-CH) <SEP>;<SEP> 33.3 <SEP> (-CH2) <SEP>;<SEP> 133.4
<tb><SEP> 13 <SEP>#<SEP> (E) <SEP> Base <SEP> C7H12N2O4 <SEP> 188.19
<tb><SEP> 126.4 <SEP> (-CH = CH-) <SEP>;<SEP> 170.7-171.5 <SEP> (-C = O) <SEP>;
<tb><SEP>[&alpha;] D20 <SEP> = <SEP> -3.3 <SEP> [C = 1, <SEP> H2O]
<tb><SEP> 1 <SEP> H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> 14 <SEP>#<SEP> Acid <SEP> C10H14N2O4 <SEP> 244.24 <SEP> Cal. <SEP>% <SEP> 49.17 <SEP> 6.60 <SEP> 11 47
<tb><SEP> + <SEP> 1 <SEP> H2O <SEP> + <SEP> 1 <SEP> H2O <SEP> Tr. <SEP>% <SEP> 49.17 <SEP> 6.74 <SEP > 11.49
<tb><SEP> NMR <SEP> (1H) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> 1.6, s <SEP> (-CH3) <SEP>;<SEP> 2.2, <SEP> s <SEP> (COCH3) 2.8, m
<tb><SEP> 15 <SEP>#<SEP> (E) <SEP> Base <SEP> C10H16N2O5 <SEP> 244.24
<tb><SEP> (-CH2) <SEP>;<SEP> 4.0, m <SEP> (-CH) <SEP>;<SEP> 6.2 <SEP> and <SEP> 5.7, <SEP> M
<tb><SEP> J <SEP> = <SEP> 15 <SEP> Hz <SEP> (-CH <SEP> = <SEP> CH-)
<tb><SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> Salt <SEP> C13H19N3Na2O6 <SEP> 386.30 <SEP> 50.8-53.9 <SEP> (CH) <SEP>;<SEP> 38.6-38.9 <SEP> (CH2) <SEP>;
<tb><SEP> 16 <SEP>#<SEP> (E) <SEP> Disodium <SEP> + <SEP> 1.5H20 <SEP> 20.8-21, <SEP> 1 <SEP>(<SEP> CH3) <SEP>;<SEP> 142.3 <SEP> (C =) 2;
<tb><SEP> + <SEP> 1.5 <SEP> H2O <SEP> 115, <SEP> 6 <SEP> (= CH2); <SEP> 22.8 <SEP> (COCH3)
<tb><SEP>[&alpha;] D20 = + <SEP> 4.6 <SEP> (C = 1, <SEP> H2O)
<tb> TABLE 1 (continued)

<SEP> No. <SEP> Weight <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> OR
<tb><SEP> of <SEP> Formula <SEP> Form <SEP> Formula <SEP> Raw <SEP> Molecule
Code <SEP> SPECTRUM <SEP> NMR, <SEP> IR <SEP> OR <SEP>[&alpha;] D20
<tb><SEP>
<tb><SEP> NMR <SEP> (1H) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> 1,3, s <SEP> (CH3) <SEP>;<SEP> 1.5, s <SEP> (CH3) <SEP>;<SEP> 2.6, m
<tb><SEP> 17 <SEP>#<SEP> Base <SEP> C10H17N3O5 <SEP> 259.26
<tb><SEP> (CH2) <SEP>;<SEP> 3.8, m <SEP> (CH) <SEP>;<SEQ> 5.7, m <SEP> (CH = CH)
<tb><SEP>[&alpha;] D20 = <SEP> -2.5 <SEP> (C = 1, <SEP> H2O)
<tb><SEP> 2HCl <SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C12H22N2O4 <SEP> 258.31
<tb><SEP> 18 <SEP>#<SEP> Cal. <SEP>% <SEP> 43.51 <SEP> 7.30 <SEP> 8.46
<tb><SEP> 2 <SEP> HCl <SEP> C12H24Cl2N2O4 <SEP> 331.24
<tb><SEP> Tr. <SEP>% <SEP> 43.10 <SEP> 7.29 <SEP> 8.38
<tb><SEP> 2HCl <SEP> +
<tb><SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C12H22N2O4 <SEP> 258.31 <SEP> 3/4 <SEP> H2O
<tb><SEP> 19 <SEP>#<SEP> 2HCl <SEP> C12H24Cl2N2O4 <SEP> Cal. <SEP>% <SEP> 41.80 <SEP> 7.45 <SEP> 8.12
<tb><SEP> + <SEP> 3/4 <SEP> H2O <SEP> + <SEP> 3/4 <SEP> H2O <SEP> 344.75 <SEP> Tr. <SEP>% <SEP> 41 , 83 <SEP> 7.22 <SEP> 8.21
<tb><SEP> 1/4 <SEP> H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C8H14N2O4 <SEP> 206.71
<tb><SEP> 20 <SEP>#<SEP> Cal. <SEP>% <SEP> 46.48 <SEP> 7.07 <SEP> 13.55
<tb><SEP> + <SEP> 1/4 <SEP> H2O <SEP> + <SEP> 1/4 <SEP> H2O
<tb><SEP> Tr. <SEP>% <SEP> 46.66 <SEP> 7.17 <SEP> 13.43
<tb> TABLE 1 (continued)

<SEP> No. <SEP> Weight <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> OR
<tb><SEP> of <SEP> Formula <SEP> Form <SEP> Formula <SEP> Raw <SEP> Molecule
Code <SEP> SPECTRUM <SEP> NMR, <SEP> IR <SEP> OR <SEP>[&alpha;] D20
<tb><SEP>
<tb><SEP> 1/4 <SEP> H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> 21 <SEP>#<SEP> Base <SEP> C8H14N2O4 <SEP> 206.71 <SEP> Cal. <SEP>% <SEP> 46.48 <SEP> 7.07 <SEP> 13.55
<tb><SEP> Tr. <SEP>% <SEP> 46.49 <SEP> 7.19 <SEP> 13.35
<tb><SEP> 1.75 <SEP> H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C10H17N3O5 <SEP> 290.79 <SEP> Cal. <SEP>% <SEP> 41.18 <SEP> 7.10 <SEQ> 14.45
<tb><SEP> 22 <SEP>#<SEP> + <SEP> 1.75H2O <SEP> + <SEP> 1.75 <SEP> H2O <SEP> Tr. <SEP>% <SEP> 41.18 <SEP> 6.94 <SEP> 14.40
<tb><SEP>[&alpha;] D20 = <SEP> + <SEP> 10.4 <SEP> (C <SEP> = <SEP> 1, <SEP> H2O)
<tb><SEP> 1.25 <SEP> H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C13H23N3O5 <SEP> 323.86 <SEP> Cal. <SEP>% <SEP> 48.21 <SEP> 7.93 <SEP> 12.97
<tb><SEP> 23 <SEP>#<SEP> + <SEP> 1,25H2O <SEP> + <SEP> 1,25 <SEP> H2O <SEP> Tr. <SEP>% <SEP> 48,05 <SEP> 7.77 <SEP> 12.93
<tb><SEP>[&alpha;] D20 = <SEP> + <SEP> 9.2 <SEP> (C <SEP> = <SEP> 1, <SEP> H2O)
<tb><SEP> 2 <SEP> H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C11H19N3O5 <SEP> 309.32 <SEP> Cal. <SEP>% <SEP> 42.71 <SEP> 7.49 <SEP> 13.58
<tb><SEP> 24 <SEP>#<SEP> + <SEP> 2 <SEP> H2O <SEP> + <SEP> 2 <SEP> H2O <SEP> Tr. <SEP>% <SEP> 42,52 <SEP> 7.34 <SEP> 13.51
<tb><SEP>[&alpha;] D20 <SEP> = <SEP> + <SEP> 8.9 <SEP> (C <SEP> = <SEP> 1, <SEP> H2O)
<tb> TABLE 1 (continued)

<SEP> No. <SEP> Weight <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> OR
<tb><SEP> of <SEP> Formula <SEP> Form <SEP> Formula <SEP> Raw <SEP> Molecule
Code <SEP> SPECTRUM <SEP> NMR, <SEP> IR <SEP> OR <SEP>[&alpha;] D20
<tb><SEP>
<tb><SEP> 2.25 <SEP> HCl <SEP> +
<tb><SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C10H18N2O4 <SEP> 230.26 <SEP> 1.8 <SEP>% <SEP> H2O
<tb><SEP> 25 <SEP>#<SEP> 2.25 <SEP> Hcl <SEP> 312.31 <SEP> Cal. <SEP>% <SEP> 37.76 <SEP> 6.62 <SEP> 8.81
<tb><SEP> + <SEP> 1.8 <SEP>% <SEP> H2O <SEP> + <SEP> 1.8 <SEP>% <SEP> H2O <SEP> 318.03 <SEP> Tr. <SEP>% <SEP> 37.35 <SEP> 6.64 <SE> 8.99
<tb><SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm <SEP> - <SEP> D2O
<tb><SEP> 54.7, <SEP> 55.4, <SEP> 55.6, <SEP> 58.2 <SEP> (CH), 34.2 <SEP>(CH2);
<tb><SEP> 26 <SEP>#<SEP> Base <SEP> C10H17N3O5 <SEP> 259.26
<tb><SEP> 128.6,134.5, <SEQ> 134.9 <SEP> (-CH = CH-); <SEP> 58.2
<tb><SEP> (- # -); <SEP> 19 <SEP> (CH)
<tb><SEP>[&alpha;] D20 = -19, <SEP> 8 <SEP> 3 <SEP> (C <SEP> = <SEP> 1, <SEP> H2O)
<tb><SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> Base <SEP> C7H12N2O4 <SEP> 206.20 <SEP> 52.8, <SEP> 55.1 <SEP> (CH) <SEP>;<SEP> 33.3 <SEP> (CH2) <SEP>;<SEP> 133.4,
<tb><SEP> 27 <SEP>#<SEP> + <SEP> 1 <SEP> H2O <SEP> + <SEP> 1 <SEP> H2O <SEP> 126.4 <SEP> (CH = CH) <SEP>;<SEP> 170.7, <SEP> 171.5 <SEP>(#)
<tb><SEP>[&alpha;] D20 = <SEP> + <SEP> 1.9 <SEP> (C <SEP> = <SEP> 1, <SEP> HCl <SEP> 1N)
<tb><SEP> NMR <SEP> (1H) <SEP> - <SEP>#<SEP> ppm <SEP> - <SEP> D2O-DCl
<tb><SEP> Base <SEP> C8H14N2O4 <SEP> 202.21
<tb><SEP> 28 <SEP>#<SEP> 5.3, s <SEP> (= CH2)
<tb><SEP> Couple <SEP> of <SEP> diastereoisomers <SEP><SEP> 2 <SEP> HCl <SEP> C8H16Cl2N2O4 <SEP> 275.14
<tb><SEP> minus <SEP> polar <SEP> (cellulose) <SEP>[&alpha;] D20 = <SEP> - <SEP> 18.2 <SEP> (C <SEP> = <SEP> 0, 19, <SEP> H2O)
<tb><SEP> levorotatory
<tb> TABLE 1 (continued)

<SEP> No. <SEP> Weight <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> OR
<tb><SEP> of <SEP> Formula <SEP> Form <SEP> Formula <SEP> Raw <SEP> Molecule
Code <SEP> SPECTRUM <SEP> NMR, <SEP> IR <SEP> OR <SEP>[&alpha;] D20
<tb><SEP>
<tb><SEP> NMR <SEP> (1H) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O-DCl
<tb><SEP> 29 <SEP>#<SEP> Base <SEP> C6H14N2O4 <SEP> 202.21 <SEP> 5.3, s <SEP> (-CH2)
<tb><SEP> Couple <SEP> of <SEP> diastereoiscomers <SEP> 2 <SEP> HCI <SEP> C8H16Cl2N2O4 <SEP> 275,14 <SEP>[&alpha;] D20 = <SEP> + <SEP> 14 , 1 <SEP> (C <SEP> = <SEP> 0.17, <SEP> H2O)
<tb><SEP><SEP> plus <SEP> polar <SEP> (cellulose)
<tb><SEP> Dextrorotatory
<tb><SEP> 1NH3 <SEP> +
<tb><SEP> C <SEP> H <SEP> N
<tb><SEP> 1H2O
<tb><SEP> Base <SEP> C16H20N2O5 <SEP> 320.34 <SEP> Cal. <SEP>% <SEP> 54.07 <SEP> 7.09 <SEP> 11.62
<tb><SEP> 30 <SEP>#<SEP> 1NH3 + 1H2O <SEP> C16H23N3O5 <SEP> 355.38 <SEP> Tr. <SEP>% <SEP> 54.36 <SEP> 6.86 <SEP > 11.36
<tb><SEP> + <SEP> 1 <SEP> H2O <SEP> 1/2 <SEP> H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C24H26N2O6 <SEP> 447.47 <SEP> Cal. <SEP>% <SEP> 64.41 <SEP> 6.08 <SEP> 6.26
<tb><SEP> 31 <SEP>#<SEP> + <SEP> 1/2 <SEP> H2O <SEP> Tr. <SEP>% <SEP> 64.88 <SE> 6,18 <SEP> 6 46
<tb><SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> CDCl3
<tb><SEP> Base <SEP> 117.2 <SEP> (-CH2) <SEP>;<SEP> 141.7 <SEP> (C) <SEP>;<SEP> 40.41.9
<tb><SEP> 32 <SEP>#<SEP> C11H16N2O4 <SEP> 240.25
<tb><SEP> Couple <SEP> of <SEP> diastereoisomers <SEP> (2CH2) <SEP>;<SEP> 51, <SEP> 54.5 <SEP> (2CH) <SEP>;<SEP> 62.7 <SEP>(OCH2);
<tb><SEP> the <SEP> less <SEP> polar <SEP> (es) <SEP> 14.1 <SEP> (CH2-CH3) <SEP>;<SEP> 160.2 <SEP> (NCHO)
<tb> TABLE 1 (continued)

<SEP> No. <SEP> Weight <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> OR
<tb><SEP> of <SEP> Formula <SEP> Form <SEP> Formula <SEP> Raw <SEP> Molecule
Code <SEP> SPECTRUM <SEP> NMR, <SEP> IR <SEP> OR <SEP>[&alpha;] D20
<tb><SEP>
<tb><SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> CDCl3
<tb><SEP> 117.6 <SEP> (= CH2); 140.5 <SEP> (C) <SEP>;<SEP> 38,7,39,8
<tb><SEP> 33 <SEP>#<SEP> Base <SEP> C11H16N2O4 <SEP> 240.25
<tb><SEP> Couple <SEP> of <SEP> diastereoisomers <SEP>(2CH2);<SEP> 52, <SEP> 54.6 <SEP> (2CH) <SEP>;<SEP> 61.9 <SEP> (OCH2) <SEP>;
<tb><SEP> the <SEP> more <SEP> polar <SEP> (trans) <SEP> 14.2 <SEP> (CH2-CH3) <SEP>;<SEP> 160.3 <SEP> (NCHO)
<tb><SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> Base <SEP> C10H16N2O3 <SEP> 212.24 <SEP> 118.6 <SEP> (= CH2) <SEP>;<SEP> 141, <SEP> 1 <SEP> (C =) <SEP>;<SEP> 37, <SEP> 40.9
<tb><SEP> 34 <SEP>#<SEP> 1 <SEP> BCl <SEP> C10H17ClN2O3 <SEP> 248.71 <SEP> (2CH2) <SEP>;<SEP> 53.1, <SEP> 55.1 <SEP> (2CH) <SEP>;<SEP> 64.3 (OCH2)
<tb><SEP> Couple <SEP> of <SEP> diastereoisomers <SEP> 14.2 <SEP> (CH2-CH3)
<tb><SEP> cis <SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> Base <SEP> C10H16N2O3 <SEP> 212.24 <SEP> 119.4 <SEP> (= CH2) <SEP>;<SEP> 140.1 <SEP> (C =) <SEP>;<SEP> 36.9, <SEP> 39.8
<tb><SEP> 35 <SEP>#<SEP> 1 <SEP> HCl <SEP> C10H17ClN2O3 <SEP> 248.71 <SEP> (2CH2) <SEP>;<SEP> 54.7, <SEP> 55.3 <SEP> (2CH) <SEP>;<SEP> 63.9 <SEP> (OCH2) <SEP>;
<tb><SEP> Couple <SEP> of <SEP> diastereoisomers <SEP> tans <SEP> 14.5 <SEP> (CH2CH3)
<tb><SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> 118.8 <SEP> (= CH2) <SEP>;<SEP> 140.6 <SEP> (-C =) <SEP>;<SEP> 37 <SEP> AND <SEP> 39.8
<tb><SEP> Base <SEP> C8H12N2O3 <SEP> 184.19
<tb><SEP> (CH2) <SEP>;<SEP> 54.6 <SEP> AT <SEP> 56.3 <SEP> (-CH)
<tb><SEP> 36 <SEP>#<SEP> HCl <SEP> C8H13ClN2O3 <SEP> 220.66
<tb><SEP> Couple <SEP> of <SEP> diastereoisomers <SEP> IR <SEP>: <SEP> CONH <SEP> to <SEP> 1670 <SEP> CM-1
<tb><SEP> trans
<tb> TABLE 1 (continued)

<SEP> No. <SEP> Weight <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> OR
<tb><SEP> of <SEP> Formula <SEP> Form <SEP> Formula <SEP> Raw <SEP> Molecule
Code <SEP> SPECTRUM <SEP> NMR, <SEP> IR <SEP> OR <SEP>[&alpha;] D20
<tb><SEP>
<tb><SEP> + <SEP> 2,3H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C11H19N3O5 <SEP> 314.72 <SEP> Cal. <SEP>% <SEP> 41.98 <SEP> 7.56 <SEP> 13.35
<tb><SEP> 37 <SEP>#<SEP> + <SEP> 2,3 <SEP> H2O <SEP> + <SEP> 2,3 <SEP> H2O <SEP> Tr. <SEP>% <SEP > 41.82 <SEP> 7.39 <SEP> 13.93
<tb><SEP>[&alpha;] D20 <SEP> = <SEP> - <SEP> 18.6 <SEP> (C <SEP> = <SEP> 1, <SEP> H2O)
<tb><SEP> 2HCl <SEP> +
<tb><SEP> C <SEP> H <SEP> N
<tb><SEP> 1/2 <SEP> H2O
<tb><SEP> Base <SEP> C22H26N2O4 <SEP> 382.44
<tb><SEP> Cal. <SEP>% <SEP> 56.89 <SEP> 6.29 <SEP> 6.03
<tb><SEP> 38 <SEP>#<SEP> 2HCl <SEP> C22H28Cl2N2O4 <SEP> 464.38
<tb><SEP> + <SEP> 1/2 <SEP> H2O <SEP> + <SEP> 1/2 <SEP> H2O <SEP> Tr. <SEP>% <SEP> 56.95 <SEP> 6 , 45 <SEP> 6.22
<tb><SEP> 2HCl <SEP> +
<tb><SEP> C <SEP> H <SEP> N
<tb><SEP> 2 <SEP> H2O
<tb><SEP> Base <SEP> C7H11ClN2O4 <SEP> 222.64
<tb><SEP> Cal. <SEP>% <SEP> 56.89 <SEP> 6.29 <SEP> 6.03
<tb><SEP> 39 <SEP>#<SEP> 2HCl <SEP> + <SEP> 2H2O <SEP> C7H13Cl2N2O4 <SEP> 328.64
<tb><SEP> + <SEP> 2 <SEP> H2O <SEP> Tr. <SEP>% <SEP> 25.58 <SEP> 5.15 <SEP> 8.60
<tb><SEP> 2NH3 <SEP> + <SEP> 1.5H2O <SEP>;<SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> Base <SEP> C12H18N2O7 <SEP> 302.28
<tb><SEP> 117, <SEP> s <SEP> (= CH2) <SEP>;<SEP> 141.7 <SEP>(# C =) <SEP>;<SEP> 33.2-33.9
<tb><SEP> 40 <SEP>#<SEP> 2NH3 <SEP> C12H24N4O7 <SEP> 363.37
<tb><SEP> + <SEP> 1.5H2O <SEP> + <SEP> 1.5 <SEP> H2O <SEP> (-CH2-CH2-CO) <SEP>;<SEP> 38.7-39.8 <SEP> (CH2) <SEP>;<SEP> 54.4
<tb><SEP> (-CH2)
<tb> TABLE 1 (continued)

<SEP> No. <SEP> Weight <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> OR
<tb><SEP> of <SEP> Formula <SEP> Form <SEP> Formula <SEP> Raw <SEP> Molecule
Code <SEP> SPECTRUM <SEP> NMR, <SEP> IR <SEP> OR <SEP>[&alpha;] D20
<tb><SEP>
<tb><SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> 118.3-118.8 <SEP> (= CH2) <SEP>;<SEP> 140, <SEP> 3 <SEP>(# C =) <SEP>;
<tb><SEP> 41 <SEP>#<SEP> Base <SEP> C13H22N2O5 <SEP> 286.32 <SEP> 53.6-53.8-54.1-54.3 <SEP> (-CH) <SEP>;<SEP> 36.3
<tb><SEP> (-CH2-CO) <SEP>;<SEP> 13.9 <SEP> (CH3-)
<tb><SEP> + <SEP> 2H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C14H24NO6 <SEP> 380.39 <SEP> Cal. <SEP>% <SEP> 44.20 <SEP> 7.42 <SEP> 14.72
<tb><SEP> + <SEP> 2H2O <SEP> + <SEP> 2 <SEP> H2O <SEP> Tr. <SEP>% <SEP> 44.26 <SEP> 7.21 <SEP> 14.43
<tb><SEP> 42 <SEP>[&alpha;] D20 <SEP> = <SEP> + <SEP> 34.6 <SEP> (C <SEP> = <SEP> 1, <SEP> H2O)
<tb><SEP> 2.5H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C14H24N4O6 <SEP> 389.40 <SEP> Cal. <SEP>% <SEP> 43.18 <SEP> 7.51 <SEP> 14.39
<tb><SEP> 43 <SEP> + <SEP> 2H2O <SEP> + <SEP> 2H2O <SEP> Tr. <SEP>% <SEP> 43.43 <SEP> 7.55 <SEQ> 14.67
<tb><SEP>[&alpha;] D20 <SEP> = <SEP> + <SEP> 9.9 <SEP> (C <SEP> = <SEP> 1, <SEP> H2O)
<tb><SEP> + <SEP> 2H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C11H19N3O6 <SEP> 325.32 <SEP> Cal. <SEP>% <SEP> 40.60 <SEP> 7.12 <SEP> 12.91
SEP> 44 SEP> + , 81 <SEP> 12.78
<tb> TABLE 1 (continued)

<SEP> No. <SEP> Weight <SEP> ANALYSIS <SEP> ELEMENTARY <SEP> OR
<tb><SEP> of <SEP> Formula <SEP> Form <SEP> Formula <SEP> Raw <SEP> Molecule
Code <SEP> SPECTRUM <SEP> NMR, <SEP> IR <SEP> OR <SEP>[&alpha;] D20
<tb><SEP>
<tb><SEP> NMR <SEP> (13C) <SEP> - <SEP>#<SEP> ppm, <SEP> D2O
<tb><SEP> 121.8 <SEP> and <SEP> 121, <SEP> 4 <SEP> (= CH2) <SEP>;<SEP> 137.5 <SEP>(# C =) <SEP>;<SEP> 17.5 <SEP> and
<tb><SEP> 45 <SEP>#<SEP> Base <SEP> C14H24N4O6 <SEP> 344.36 <SEP> 18.3 <SEP> (CH3) <SEP>;<SEP> 170.3 <SEP> AND <SEP> 174 (NHCO) <SEP>;<SEP> 174.7 <SEP> and
<tb><SEP> 180.5 <SEP>(#)<SEP>;<SEP> 37.1 <SEP> and <SEP> 37.8 <SEP> (-CH2)
<tb><SEP> + <SEP> 2.5H2O <SEP> C <SEP> H <SEP> N
<tb><SEP> Base <SEP> C10H17N3O5 <SEP> 304.3 <SEP> Cal. <SEP>% <SEP> 39.46 <SEP> 7.28 <SEP> 13.81
<tb><SEP> 46 <SEP>#<SEP> + <SEP> 2.5H2O <SEP> + <SEP> 2.5 <SEP> H2O <SEP> Tr. <SEP>% <SEP> 39.32 <SEP> 7.16 <SEP> 13.64
<Tb>
The derivatives (I) and their pharmaceutically acceptable salts have in particular revealed antibacterial properties. These properties have been demonstrated, in vitro, by studying the inhibition of the growth of various bacterial strains, in particular by the agar dilution method, using the apparatus of STEERS (Methods for antimicrobial dilution). tests for Bacteria that grow aerobically - Volume 3 (2), pp. 30-93. Standard Trial National Committee for Clinical Laboratory Standards (NCCLS), Clyde Thornsberry et al.
The compounds according to the invention have been used at concentrations ranging from 0.5 to 128 g per ml.

 The medium used is the minimum agar medium described by DAVIS and MINGIOLI in J. Bacteriol., 60, 17 (1950).

 The results obtained with some compounds according to the invention and expressed by the minimum inhibitory concentration, are summarized in Table 2 below.

TABLE 2

<tb><SEP> Concentration <SEP> minimum <SEP> inhibitory <SEP> (g / ml)
<tb> SEP compounds tested
<tb><SEP> bacterial strain <SEP>
<tb><SEP> Numbers <SEP> of <SEP> code
<tb><SEP> E. <SEP> Coli <SEP> ATCC <SEP> 9637 <SEP> Pseudomonas <SEP> aeruginosa
<tb><SEP> A-22
<tb><SEP> 5 <SEP> 2 <SEP> 16
<tb><SEP> 21 <SEP> 2 <SEP> 4
<tb><SEP> 42 <SEP> 1 <SEP>> 128
<tb><SEP> 37 <SEP> 4 <SEP> 4
<tb><SEP> 40 <SEP>> 128 <SEP> 2
<tb><SEP> 23 <SEP> 2 <SEP> 128
<Tb>
The acute toxicity of the derivatives (I) and their pharmaceutically acceptable salts has also been studied according to the method of MILLER and TAINTER (Proc.Soc.Expl.Biol Med (1944), 57, 261. Thus, for example, the LD 50 of the code number derivative (I) orally in the mouse is greater than 5 g / kg.

It can be seen from Table 2 and from the toxicological study that the large difference between active and toxic doses makes it possible to use, as medicaments, derivatives (I) and their pharmaceutically acceptable salts, in particular for the treatment of diseases caused by bacteria and in particular for the treatment of colibacillosis and
Pseudomonas aeruginosa.

 The present invention therefore also relates, as medicaments, and especially as antibiotic drugs, the derivatives (I) and their pharmaceutically acceptable salts.

 The invention finally extends to pharmaceutical compositions containing, as active principle, at least one of the above-defined drugs in combination with a suitable vehicle. These compositions may be adapted (a) to oral administration and may then be for example in the form of dragees, capsules or tablets, or (b) to parenteral (intravenous or intramuscular) administration and then present as injectable solutions.

 The administered dose of active ingredient is variable depending on the condition being treated, the subject and the route of administration. Thus, in the case of oral administration, this dose can reach 5 g per day in one or more doses and in the case of parenteral administration, it can reach 4 g per day in at least two doses. The dose administered may however be increased to 15 g per day per day and 12 g per day parenterally in case of severe infections.

Claims (17)

 1. Derivatives of diaminopimelic acid, corresponding to the general formula

 in which - (-A-B-) represents one of the following concatenations

 - R and R4, which are identical or different, each represent an atom  hydrogen; a formyl, alkylcarbonyl group in which the alkyl radical  has 1 to 4 carbon atoms or benzylcarbonyl; a sequence of structures  -CO- (CH2) n-COOR1 wherein n is 1, 2 or 3 and R1 is  the hydrogen atom or the methyl group

 where R5, R7 and R8 each represents a hydrogen atom, an alkyl group of 1 to 4 carbon atoms, a benzyl group, (4-imidazolyl) methyl, (indolyl 3) methyl or para-hydroxybenzyl, a hydroxyalkyl group , the thioalkyl or methylthioalkyl whose alkyl radicals have 1 or 2 carbon atoms, a (4-amino) butyl or (3-guanidino) propyl group or an aminocarbonylalkyl group, the alkyl radical of which has 1 to 3 carbon atoms, R6 represents hydrogen atom or the formyl group and m = 0 or 1, R4 and R6, however, can not represent the formyl group when R = H - R1 = H or CH3 with the restriction that when R1 = CH3, (-AB-) can not  represent that (-CH = CH-) (E) or (-CH2-CH2-) - R2 and R3, which are identical or different, each represent the group  hydroxyl, an alkoxy group of 1 to 4 carbon atoms, a benzyloxy group or a chain of structure

 in which case the compounds (I) have the structure

 where R1, R5, R7, R8 and m have the same meanings as above; - R and R3 can additionally form a siple binding when (-A-B-) is particular  as well as their diastereoisomers and enantiomers, the mineral or organic acid or base addition salts and the possible internal salts of the derivatives (I) and (I ') in the form of racemic, diastereoisomers or enantiomers.

 where R2 and R4 have the same meanings as previously the set (R, R1, R2, R3, R4) can not however take the following particular values: (H, H, OH, OH, H), (H, H, CH3O, CH3O, H), (H, CH3, OH, OH, H), (H, CH3, CH3O, CH3O, H) when (-AB-) represents (-CH2-CH2-), nor the following particular values (H, H, OH, OH, H), (H, H, CH 3 O, CH 3 O, H) when (-AB-) represents  2. Compounds according to claim 1, for which at least one of the groups R or R4 represents a chain

 and at least one of R2 or R3 is the hydroxyl group.  3. Compounds according to claim 1, for which at least one of the groups R2 or R3 represents a sequence

 and at least one of R or R4 is hydrogen.  4. The compound according to claim 1, wherein R and R4 simultaneously represent hydrogen and R2 and R3 simultaneously represent the hydroxyl group.  5. Medicament in particular antibacterial activity, characterized in that it is constituted by one of the compounds according to any one of claims 1 to 4.  6. Pharmaceutical composition, characterized in that it comprises at least one of the medicaments according to claim 5, in association with a pharmaceutically acceptable carrier,  7. Process for the preparation of the compounds according to claim 1 and of particular formula ::

 where R 'has the same meanings as R in claim 1, without however being able to represent the hydrogen atom, R2, and R3 represent an alkyloxy group of 1 to 4 carbon atoms, R1 has the same meanings as in the claim 1 and Rg represents the hydrogen or chlorine atom, as well as corresponding salts, characterized in that it consists in reducing respectively the compounds of formula

  where B ', R1, R'2, R'3 and Rg have the same meanings as in (Ia) and (Ib), and then optionally to salify the products obtained.  8. Process for the preparation of the compounds according to claim 1 and of particular formula

 where RT, R'2 and R'3 have the same meanings as in claim 7, as well as corresponding salts, characterized in that it consists in deprotecting the amino groups respectively of compounds of formula

 where R ', R! and R'3 have the same meanings as in (Ic) and (Id), then possibly to salify the products obtained.  9. Process for the preparation of the compounds according to claim 1 and of particular formula

 wherein R, B2, and 23 have the same meanings as in claim 7, and R12 denotes hydrogen atom or methyl group and corresponding salts, characterized in that it consists in catalytically hydrogenating the compounds (Ia) , (Ib), (Ic) or (Id) corresponding defined in claims 7 and 8, and optionally to salify the products obtained.  10. Process for the preparation of the compounds according to claim 1, for R2 = R3 = OH with the exception of those for which R = H and R4 = CHO, characterized in that it consists in hydrolyzing in basic medium the corresponding derivatives (I) according to claim 1 for which R2 and R3 represent an alkoxy group of 1 to 4 carbon atoms, and then optionally salify the obtemis products.  11. Process for the preparation of the compounds according to claim 1 for which  R2 = R3 = OH and R = R4 = H. characterized in that it consists in hydrolyzing in basic medium the  corresponding derivatives (I) according to claim 1, for which R2 or R3 represents a group  alkoxy of 1 to 4 carbon atoms, then optionally to salify the products obtained.  12. Process for the preparation of compounds according to claim 1, for which R = R4 = H, R2 = alkoxy of 1 to 4 carbon atoms and R3 = OH or alkoxy of 1 to 4 carbon atoms, characterized in that consists in hydrolyzing in acid medium the corresponding derivatives (I) for which R = formyl, and then optionally salifying the products obtained.  13. A process for the preparation of the compounds according to claim 1, for which R = H, R4 has the same meaning as in claim 1 without however being able to represent hydrogen atom or the formyl group and R2 = alkoxy of 1 to 4 carbon atoms. carbon, characterized in that it consists in hydrolyzing in acid medium the corresponding derivatives (I) for which R = formyl.  14. Process for the preparation of the compounds according to claim 1, for which R and R4 have the same meaning as in claim 1 but can not however represent the hydrogen atom and R2 = alkoxy of 1 to 4 carbon atoms, characterized in that it consists in treating the corresponding derivatives (I) for which R can not represent a hydrogen atom, R4 = H, R2 = alkoxy of 1 to 4 carbon atoms and R3 = alkoxy of 1 to 4 carbon atoms or OH, with formic acid, acetic anhydride or compounds of formula

 where R "4 = (C 1 -C 4) alkylcarbonyl, benzylcarbonyl or a CO-(CH 2n) -COOCH 3 structure where n = 1, 2 or 3,

 where R5, R7, R8 and m have the same meanings as in claim 1.

 15. Process for the preparation of the compounds according to claim 1, for which R2 and / or R3 are other than OH, characterized in that it consists in (a) treating the corresponding derivatives (I) for which R2 and / or R3 represent a hydroxyl group and whose optional NH 2 groups have been protected by the BOC group, or by N-hydroxysuccinimide in the presence of DCCI, then to condense on the compounds thus obtained, the compounds of formula  R2H or Rf3H CXIIIb) where R "2 and R" 3 respectively have the same meanings as R2 and R3 in claim 1 but can not represent a hydroxyl group, either directly by the compounds (XIIIb) in the presence of DCCI, (b) in the case where in the starting compounds R2 = R3 = OH, to be separated by chromatography the mixture of three compounds obtained in step (a), (c) to possibly deprotect the compounds thus separated, then (d) to possibly salify the products thus obtained.  16. Process for the preparation of the derivatives according to claim 1 of particular formula

 in which R4 and R "2 respectively have the same meanings as R4 and B2 in (I) except that R2 can not represent the hydroxyl group as well as their salts, characterized in that it consists in treating the compounds of formula

 in which B4 and R "2 have the same meanings as in (I'a), by the W.S.C. (Et-N = C = N- (CH2) 3

HCl), then possibly to salify the products obtained.  17. As original intermediates necessary for the synthesis of the compounds (I) according to claim 1, the compounds of the formula

 in which R 1 and R 'respectively have the same meanings as R 1 and R in claim 1, R' not however being able to represent the hydrogen atom, and R '2 and R' 3 represent an alkoxy group of 1 to 4 atoms of carbon, as well as the compounds of formula

 in which R ', R'2 and R'3 have the same meanings as in (III), (IIIa) or (IIIb).