WO1999042435A2 - Myxochelines - Google Patents

Abstract

The invention relates to compounds of general formula (A), where R is COOH, COOR1, CH2-OH, C(=O)NR2R3, CN, CH¿2NR?2R3, C(=O)-Z, CH¿2?-Z, or a substituent in accordance with formula (C), R?4¿ is COOH, COOR1, CH2-OH, C(=O)NR2R3CN, CH¿2NR?2R3 or a substituent in accordance with formula (D), where R1 is CxH2x+1 with x = 1,2,3,4,5, -CH2-C6H5 or -C6H5, R2, R3 independently of each other are H, C¿x?H2x+1 with x = 1,2,3,4,5, -CH2-C6H5 or -C6H5, Y independently of each other are benzoyl, formyl, acetyl, trifluoroacetyl, glycosyl or silyl; Z is an organic group linked via an O, N or S, and n is 1,2,3,4 or 5, and the absolute configuration at C* can be both S and R, as well as the salts of the compounds, especially alkali, alkaline-earth or ammonium salts, where R is not CH2NH2 or CN if n = 3 or 4 and R?4¿ = formula (D) with Y = H, and R is not formula (C) with Y = H if n = 2,3,4,5 and R4 = formula (D) with Y = H, and R is not CH¿2?-OH or COOH if R?4¿ = formula (D) with Y = H and n = 4 and the absolute configuration at the level of C* is S.

Description

 Mvxocheline

The present invention relates to compounds of the general formula A according to Claims 1 to 9, metal complexes, in particular iron complexes of these compounds according to Claim 10, processes for the preparation of the compounds according to Claim 11, compounds according to Claims 12 to 14, medicaments according to Claims 15 and 16, Use of the compounds according to the invention according to claim 17, methods for complexing metal ions and their use according to claims 18 to 20, and methods for the analysis of bacteria according to claim 21.

The isolation and synthesis of (S) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] hexanoic acid 7h was described as the first siderophore from the lysine series [JL Corbin and W. Bulen, Biochemistry 8 (3). 757 (1969)]. At the GBF (Society for Biotechnological Research mbH) in Braunschweig, the isolation of the siderophore, (iS) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] -hexan-l-ol (myxochelin A) 8h [B. Kunze, N. Bedorf, W. Kohl, G. Höfle and H. Reichenbach, Journal of Antibiotics, 41 (l 14, (1989)], and the isolation of the (S) -2,6-bis [(2,3 -dihydroxy-benzoyl) amino] -l-amino-hexane [Myxochelin B, W. Trowitzsch-Kienast, B. Kunze, H. Irschik, V. Wray, H. Reichenbach, G. Höfle, 9th Annual DECHEMA Conference of Biotechnologists , Berlin, (1991), Volume 382. Miller et al. Used, among others, the (S) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] -hexanoic acid 3h for the Synthesis of conjugates [MS Djarra, MC Lavoie, M. Jaques, I. Darwish, EK Dolence, JA. Dolence, A. Ghosh, M. Ghosh, MJ Miller and F. Malouin, Antimicrobial Agents and Chemotherapy, 40 f 111 2610, (1996)]. At the 25th Annual General Meeting of the Society of German Chemists from 10-16 In September 1995, compounds of the generic type were presented to the public in the form of myxochelin C, among other things (short presentations and list of participants at the 25th general meeting of the Society of German Chemists in Münster, 10 to 16 September 1995).

The international patent application PCT / EP 96/02796 reports on the synthetic access to myxochelin C and the homologous compounds. Regarding the biological effect, it is disclosed that these are tetra- and hexadentate siderophores, which are enormously effective. The uptake of the iron-loaded siderophores by enterobacteria apparently follows a mechanism dependent on the transport protein tonB.

The object of the present invention is to provide further siderophores.

The present invention relates to compounds of the general formula A.

Formula (A)

wobei

in which

R - COOH, COOR ¹ , CH ₂ -OH, C (= 0) NR ² R ³ , CN, CH ₂ NR ² R ³ , C (= 0) -Z, CH ₂ -Z or a substituent according to formula C.

CH,

Formula (C)

R ⁴ = COOH, COOR ¹ , CH ₂ -OH, C (= 0) NR ² R ³ CN, CH ₂ NR ² R ³ , or a substituent according to formula D.

Formula (D)

R ¹ = C _x H _{2x +} , with x = 1,2,3,4,5, -CH ₂ -C ₆ H ₅ or -C ₆ H ₅ ;

R ² , R ³ = independently of one another H, C _x H _{2x + 1} with x = 1,2,3, 4,5, -CH ₂ -C ₆ H ₅ , -

C ₆ H ₅ Y = independently of one another benzoyl, formyl, acetyl, trifluoroacetyl,

Glycosyl or silyl; Z = an organic group bonded via a 0, N, S and n = 1, 2, 3, 4 or 5

and the absolute configuration at C * can be both S and R.

and the salts of the compounds, especially alkali, alkaline earth or ammonium salts,

where R is not CH ₂ NH ₂ or CN if n = 3 or 4 and R ⁴ = formula D with Y = H

and R is not Formula C with Y = H when n = 2, 3, 4, 5 and R ⁴ = Formula D with Y = H

and R is not CH ₂ -OH or COOH if R ⁴ = formula D with Y = H and n = 4 and the absolute configuration at C * S

The following compounds according to general formula B are particularly suitable according to the invention.

Formula (B)

These are in particular the following compounds with Y = H:

if R = COOR, especially if R = CH ₃

(R) -2,3-bis - [(2,3-dihydroxy-benzoyl) amino] propanoic acid methyl ester 6a

(S) -2,3-bis - [(2,3-dihydroxy-benzoyl) amino] propanoic acid methyl ester 6b

(R) -2,4-bis - [(2,3-dihydroxy-benzoyl) amino] butanoic acid methyl ester 6c

(S) -2,4-bis - [(2,3-dihydroxybenzoyl) amino] butanoic acid methyl ester 6d

(R) -2,5-bis - [(2,3-dihydroxy-benzoyl) amino] pentanoic acid methyl ester 6e

(S) -2,5-bis - [(2,3-dihydroxy-benzoyl) amino] -pentanoic acid methyl ester 6f

(R) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] hexanoic acid methyl ester 6g

(S) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] hexanoic acid methyl ester 6h

if R = COOH

(R) -2,3-bis - [(2,3-dihydroxy-benzoyl) amino] propanoic acid 7a (S) -2,3-bis [(2,3-dihydroxy-benzoyl) amino] propanoic acid 7b (R) -2,4-bis - [(2,3-dihydroxybenzoyl) amino] butanoic acid 7c (S) -2,4-bis - [(2,3-dihydroxybenzoyl) amino] butanoic acid 7d (R) -2,5-bis - [(2,3-dihydroxybenzoyl) amino] pentanoic acid 7e (S) -2,5-bis - [(2,3-dihydroxybenzoyl) amino] pentanoic acid 7f (R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] hexanoic acid 7g

when R = CH ₂ -OH (A series cheline) (R) -2,3-bis - [(2,3-dihydroxy-benzoyl) amino] propan-l-ol 8a (S) -2,3 - bis - [(2,3-dihydroxy-benzoyl) amino] propane-1-ol 8b (R) -2,4-bis - [(2,3-dihydroxy-benzoyl) amino] -butan-l-ol 8c (S) -2, 4-bis- [(2,3-dihydroxy-benzoyl) amino] -butane-1 -ol 8d (R) -2,5-bis - [(2,3-dihydroxy-benzoyl) amino] -pentan-l-ol (myxochelin D _R -A) 8e (S) -2,5-bis - [(2,3-dihydroxy-benzoyl) amino] -pentan-l-ol (myxochelin DA) 8f ( R) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] hexan-l-ol (Myxochelin A _R ) 8g

if R = CONR ² R ³ , especially if R ² = R ³ = H

(R) -2,3-bis - [(2,3-dihydroxy-benzoyl) amino] propanoic acid amide 9a

(S) -2,3-bis - [(2,3-dihydroxy-benzoyl) amino] propanoic acid amide 9b

(R) -2,4-bis- [(2,3-dihydroxybenzoyl) amino] butanoic acid amide 9c

(S) -2,4-bis - [(2,3-dihydroxy-benzoyl) amino] butanoic acid 9d

(R) -2,5-bis - [(2,3-dihydroxybenzoyl) amino] pentanoic acid amide 9e

(S) -2, 5 -Bis- [(2,3-dihydroxy-benzoyl) amino] -pentanoic acid 9f

(R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] hexanoic acid amide 9g

(S) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] hexanoic acid 9h

The groups containing the mobile H atoms can also be present in the form of their salts. These can be represented by means of alkali, alkaline earth metals or can also be present as ammonium salts. According to the invention, the following compounds are suitable as intermediate compounds, the protective group Y being in particular benzyl:

(R) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propanoic acid methyl ester 2a (S) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propanoic acid methyl ester 2b ( R) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] -butanoic acid methyl ester 2c (S) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] -butanoic acid methyl ester 2d ( R) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] -pentanoic acid methyl ester 2e (S) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] -pentanoic acid methyl ester 2f ( R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] -hexanoic acid methyl ester 2g (S) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] -hexanoic acid methyl ester 2h ( R) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propanoic acid 3a (S) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propanoic acid 3b ( R) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] butanoic acid 3c (S) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] butanoic acid 3d ( R) -2,5-bis - [(2,3-dibenyloxybenzoyl) amino] pentanoic acid 3e (S) -2,5-bis - [(2,3-dibenzyloxybenzoyl) amino] pentanoic acid 3e ( R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexanoic acid 3g (R) -2, 3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propane-1-ol 4a (S) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propane-1 - ol 4b (R) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] butan-1-ol 4c (S) -2,4-bis - [(2,3-dibenzyloxy-benzoyl ) amino] -butane-1 -ol 4d (R) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] -pentane-1 -ol 4e (S) -2,5-bis- [ (2,3-dibenzyloxy-benzoyl) amino] -pentan-l-ol 4f (R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] -hexane-1-ol 4g (5) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexane-1-ol 4h (R) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propanoic acid amide 5a (<S) -2,3 -Bis- [(2,3-dibenzyloxy-benzoyl) amino] propanoic acid amide 5b (R) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] - butanoic acid amide 5c (S) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] butanoic acid 5d

(R) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] -pentanoic acid 5e

(S) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] pentanoic acid 5f

(R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexanoic acid 5g

(S) -2,6-bis - [(2,3-dibenzyloxybenzoyl) amino] hexanoic acid 5h

Intermediate compounds which can also be used are all customary derivatives which can be prepared in a generally known manner and which replace the mobile H atoms of the phenolic and amidic groups. The following are particularly worth mentioning: formyl, acetyl, trifluoroacetyl, glycosyl, silyl. These groups have the properties of being cleavable both in vitro and in vivo.

In a preferred embodiment, R, R ⁴ = COOH, COOR ¹ , CH ₂ -OH, C (= 0) NR ² R ³ , CN or CH ₂ NR ² R ³ and the absolute configuration at C * is both S and R. can be.

The following compounds with Y = H are particularly suitable according to the invention:

if R, R ⁴ = COOR ¹ , in particular if R ¹ = CH ₃ (R) -2 - [(2,3-dihydroxybenzoyl) amino] -butane-1,4-disacid dimethyl ester 16a (S) -2- [ (2,3-Dihydroxy-benzoyl) amino] -butane-1,4-disacid dimethyl ester 16b (R) -2 - [(2,3-dihydroxy-benzoyl) amino] -pentane-1,5-disacid dimethyl ester 16c (S) -2 - [(2,3-Dihydroxy-benzoyl) amino] pentane-1, 5-diacid dimethyl ester 16d (R) -2 - [(2,3-dihydroxy-benzoyl) amino] hexane-1,6-diacetate dimethyl ester 16e (S) -2 - [(2,3-dihydroxybenzoyl) amino] hexane 1, 6-diacid dimethyl ester 16f (R) -2 - [(2,3-dihydroxybenzoyl) amino] heptane 1 , 7-Diacid dimethyl ester 16g (S) -2 - [(2,3-Dihydroxy-benzoyl) amino] -heptan- 1, 7-diacid dimethyl ester 16h if R, R ⁴ = COOH

(R) -2 - [(2,3-dihydroxybenzoyl) amino] butane 1, 4-diacid 17a (S) -2 - [(2,3-dihydroxybenzoyl) amino] butane 1, 4-diacid 17b (R) -2 - [(2,3-dihydroxybenzoyl) amino] pentane 1,5-diacid 17c (<S) -2 - [(2,3-dihydroxybenzoyl) amino] -pentane-1,5-diacid 17d (R) -2 - [(2,3-dihydroxy-benzoyl) amino] -hexane-1,6-diacid 17e (S) -2 - [(2,3-dihydroxy- benzoyl) amino] -hexane-1,6-diacid 17f (R) -2 - [(2,3-dihydroxy-benzoyl) amino] -heptane-1,7-diacid 17g (S) -2 - [(2, 3-Dihydroxy-benzoyl) amino] -heptan-1,7-diacid 17h

if R, R ⁴ = CH ₂ -OH

(R) -2 - [(2,3-dihydroxybenzoyl) amino] butane 1,4-diol 18a (S) -2 - [(2,3-dihydroxybenzoyl) amino] butane 1, 4-diol 18b (R) -2 - [(2,3-dihydroxy-benzoyl) amino] pentane-1,5-diol 18c (S) -2 - [(2,3-dihydroxy-benzoyl) amino] - pentane-1,5-diol 18d (R) -2 - [(2,3-dihydroxy-benzoyl) amino] -hexane 1,6-diol 18e (S) -2 - [(2,3-dihydroxy-benzoyl ) amino] -hexane-1,6-diol 18f (R) -2 - [(2,3-dihydroxy-benzoyl) amino] -heptane-1,7-diol 18g (iS) -2 - [(2,3 -Dihydroxy-benzoyl) amino] -heptane-1,7-diol 18h

if R, R ⁴ = C (= 0) NR ² R ³ , especially if R ² = R ³ = H (R) -2 - [(2,3-dihydroxy-benzoyl) amino] -butane 1, 4- diacid diamide 19a (S) -2 - [(2,3-dihydroxybenzoyl) amino] butane 1,4-diacid diamide 19b (R) -2 - [(2,3-dihydroxybenzoyl) amino] pentane 1, 5-diacid diamide 19c (S) -2 - [(2,3-dihydroxy-benzoyl) amino] pentane 1,5-diacid diamide 19d (R) -2 - [(2,3-dihydroxy-benzoyl) amino ] -hexane-1,6-diacid diamide 19e (S) -2 - [(2,3-dihydroxy-benzoyl) amino] -hexane-1,6-diacid diamide 19f (R) -2 - [(2,3-dihydroxy -benzoyl) amino] -heptane-1,7-diacid diamide 19 g (S) -2 - [(2,3-dihydroxy-benzoyl) amino] -heptane-1,7-di-acid diamide 19 h if R, R ⁴ = CN

(R) -2 - [(2,3-dihydroxybenzoyl) amino] butane 1,4-dinitrile 20a (S) -2 - [(2,3-dihydroxybenzoyl) amino] butane 1, 4-dinitrile 20b (R) -2 - [(2,3-dihydroxybenzoyl) amino] pentane 1,5-dinitrile 20c (S) -2 - [(2,3-dihydroxybenzoyl) amino] - pentane-1,5-dinitrile 20d (R) -2 - [(2,3-dihydroxy-benzoyl) amino] hexane-1,6-dinitrile 20e (S) -2 - [(2,3-dihydroxy-benzoyl ) amino] -hexane-1,6-dinitrile 20f (R) -2 - [(2,3-dihydroxy-benzoyl) amino] -heptane-1,7-dinitrile 20g (S) -2 - [(2,3 -Dihydroxy-benzoyl) amino] -heptane-1,7-dinitrile 20h

if R, R ⁴ = CH ₂ NR ² R ³ , in particular if R ² R ³ = H (R) - 1, 4-diamino-2 - [(2,3-dihydroxy-benzoyl) amino] -butane 21a (S ) - 1,4-diamino-2 - [(2,3-dihydroxy-benzoyl) amino] butane 21b (R) - 1,5-diammo-2 - [(2,3-dihydroxy-benzoyl) amino] - pentane 21c (S) - 1,5-diamino-2 - [(2,3-dihydroxy-benzoyl) amino] -pentane 21d (R) - 1,6-diamino-2 - [(2,3-dihydroxy-benzoyl ) amino] -hexane 21e (S) - 1, 6-diamino-2 - [(2,3-dihydroxy-benzoyl) amino] -hexane 21f (R) -l, 7-diamino-2 - [(2,3 -dihydroxy-benzoyl) amino] -heptane 21g (S) - 1, 7-diamino-2 - [(2,3-dihydroxy-benzoyl) amino] -heptane 21h

The groups containing the mobile H atoms can also be present in the form of their salts. These can be represented by means of alkali, alkaline earth metals or can also be present as ammonium salts.

According to the invention, the following compounds are suitable as intermediate compounds, the protective group Y being in particular benzyl:

(R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -butane-1,4-di-dimethyl ester 10a (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] butane-1,4-di-dimethyl ester 10b (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -pentane 1, 5-diacid dimethyl ester 10c (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] pentane-l, 5-disacid dimethyl ester 10D (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] - hexane-1,6-diacid dimethyl ester 10g (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] hexane-1,6-disacid dimethyl ester 10f (R) -2 - [(2,3-dibenzyloxy-benzoyl ) amino] -heptane-1,7-diacid dimethyl ester 10g (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane-1,7-di-acid dimethyl ester 10h (R) -2 - [(2,3 -Dibenzyloxy-benzoyl) amino] -butane-1,4-diacid 11a (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -butane-1,4-diacid 11b (R) -2- [ (2,3-dibenzyloxy-benzoyl) amino] -pentane-1,5-diacid 11c (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -pentane-1,5-diacid lld (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] hexane-1,6-diacid ll (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] hexane-1,6-diacid llf (R) -2 - [(2,3-dibenzyloxybenzoyl) amino] -heptan-1,7-diacid 11g (S) -2 - [(2,3- Dibenzyloxy-benzoyl) amino] -heptan-1,7-diacid 11h (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -butane-1,4-diol 12a (S) -2 - [( 2,3-dibenzyloxy-benzoyl) amino] butane-1,4-diol 12b (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -pentane-1,5-diol 12c (S) - 2 - [(2,3-dibenzyloxy-benzoyl) amino] pentane 1,5-diol 12d (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] hexane 1,6-diol 12e (5) -2 - [(2,3-dibenzyloxy-benzoyl) amino] hexane-1,6-diol 12f (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane-1, 7-diol 12g (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane-l, 7-diol 12h (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] - butane-1,4-diacid diamide 13a (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -butane-1,4-disacid diamide 13b (R) -2 - [(2,3-dibenzyloxy-benzoyl ) amino] -pentane-l, 5-diacid diamide 13c (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -pentane-1,5-diacid diamide 13d (R) -2 - [(2,3 -Dibenzyloxy-benzoyl) amino] -hexane-1,6-diacid diamide 13e (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -hexane-1,6-diacid diamide 13f (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptan-1,7-diacid diamide 13g (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane-1, 7-diacid diamide 13h (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] butane-1,4-dinitrile 14a (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] - butane-1,4-dinitrile 14b (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -pentane-1,5-dinitrile 14c (S) -2 - [(2,3-dibenzyloxy-benzoyl ) amino] -pentane-1,5-dinitrile 14d (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -hexane 1,6-dinitrile 14e (S) -2 - [(2,3 -Dibenzyloxy-benzoyl) amino] -hexane-1,6-dinitrile 14f (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane-1,7-dinitrile 14g (S) -2- [ (2,3-dibenzyloxy-benzoyl) amino] -heptane-l, 7-dinitrile 14h (R) -l, 4-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] -butane 15a (S) - 1,4-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] butane 15b (R) - 1,5-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] -pentane 15c (S) - 1,5-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] -pentane 15d (R) - 1,6-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] -hexane 15e (S) - 1, 6-diamino-2 - [(2,3-di benzyloxy-benzoyl) amino] -hexane 15f (R) -l, 7-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane 15g (S) - 1, 7-diamino-2 - [( 2,3-dibenzyloxy-benzoyl) amino] -heptane 15h

Intermediate compounds which can also be used are all customary derivatives which can be prepared in a generally known manner and which replace the mobile H atoms of the phenolic and amidic groups. The following are particularly worth mentioning: formyl, acetyl, trifluoroacetyl, glycosyl, silyl. These groups have the properties of being cleavable both in vitro and in vivo.

The present invention also relates to iron complexes of the compounds of the general formula A, the iron complexes having a UV / VIS absorption around λ = 570 nm. The compounds of general formula I according to the invention can be prepared by a process starting from commercially available ester dihydrochlorides of 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid and the amino acids ornithine and lysine. Using known coupling methods in organic chemistry and especially peptide chemistry, these are reacted with protected (preferably benzyl) 2,3-dihydroxybenzoic acids to give the corresponding diamides. These can now be hydrolyzed to the carboxylic acids in a basic or acidic medium, preferably with sodium hydroxide solution, and if necessary reduced to the alcohols using lithium aluminum hydride or reacted with gaseous ammonia to give the carboxylic acid amides. For the preferably benzyl-protected derivatives, the hydrogenolysis of the compounds leads to the free siderophores according to the invention of the general formula (A) with Y = H.

For example, starting from (R) -2,6-diamino-hexanoic acid methyl ester dihydrochloride Ig using methods known per se, for example by means of TBTU coupling [2- (1 H-benzotriazol-1-yl) - 1,1,3 , 3-tetramethyluronium tetrafluoroborate] den (R) -2,6-bis- [(2,3-dihydroxy-benzoyl) amino] -hexanoic acid methyl ester 6g, the (R) -2,6-bis - [(2,3-dihydroxy -benzoyl) amino] -hexanoic acid 7g, the (R) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] -hexan-l-ol (myxochelin A _R ) 8g and the (R) - Prepare 2,6-bis - [(2,3-dihydroxybenzoyl) amino] hexanoic acid 9g.

8g

First, the preferably benzyl-protected 2,3-dihydroxy-benzoic acid is bound amidically to the two NH ₂ groups. The methyl esters protected in this way can either be hydrolyzed to carboxylic acids under basic conditions, reduced to alcohols by means of LiAlH ₄ or converted into the carboxamides using NH ₃ . The hydrogenolysis of the 2,3-dibenzyloxy-benzoyl derivatives shown with Pd / C (10%) leads to the above-mentioned siderophoric products. Scheme 1 shows the reaction sequence for the synthesis of these siderophores.

The compounds according to the invention with R, R ⁴ = COOH, COOR ¹ , CH ₂ OH, C (= 0) NR ² R ³ , CN, CH ₂ NR ² R ^{3 are} carried out analogously, with the diester hydrochlorides being used accordingly the amino acids aspartic acid and glutamic acid as well as the 2-amino-hexane-l, 6-diacid and the 2-amino-heptane-l, 7-diacid. The carboxamides shown can be dehydrated to the dinitriles with triphosgene and these in turn can be reduced to the diamines with sodium borohydride. Scheme 2 shows the reaction sequence for the synthesis of these siderophores, shown on the basis of the synthesis of the aspartic acid derivatives.

The compounds according to the invention with a siderophoric structure are suitable for being taken up by bacteria. In doing so, they overcome the bacterial cell wall in an active transport process. In particular, the compounds (R) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] -hexanoic acid methyl ester 6g and (R) -2,6-bis - [(2,3-dihydroxy-benzoyl ) amino] -hexane carboxylic acid 7g are introduced particularly effectively by the bacteria. This allows substances with specific properties to be transported specifically to the inside of such bacteria. These can be, for example, pharmacologically or biologically active compounds, such as drugs or antibiotics, etc. However, they may also be higher molecular structures, e.g. Nucleic acids that are able to transform the corresponding bacterium in this way, or structures of antibodies that recognize, block or otherwise modify certain structures of the bacterium. The compounds to be introduced into the cell can, for example, be covalently attached as compound Z to certain functional groups of the compounds according to the invention or linked to one another via spacers and then brought into the cell of the bacterium. The covalent bond mentioned can also be unstable, see above. that this covalent bond is released again by intracellular processes and the active substance is then present in its free form in the cell (drug targeting). The advantage of such a coupling is that the active ingredients can be brought to the site of action in a targeted manner, so that high active concentrations can be reduced and risks from side effects can thus be reduced. The conjugates according to the invention can also be used to produce corresponding medicaments.

The siderophore and the biologically active compound can also be linked to one another via a spacer. The groups containing the mobile H atoms can also be present in the form of their salts. These can be represented by means of alkali, alkaline earth metals or can also be present as ammonium salts.

Furthermore, R can be a fluorescent marker bound via an N, O or S atom. With these conjugates it could be shown that the siderophores cross the cell membrane on "active transport routes". Furthermore, they enable kinetic detection of iron absorption.

Among other things, 7-chloro-4-nitrobenz-2-oxa-l, 3-diazole (NBD-Cl) or N-methylanthranilic acid (NMA) can be used as fluorescence markers.

The following conjugates are particularly suitable according to the invention:

(3S, 4S) -N ³ - {(R) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] -pentanoyl} -3-amino] -4-methyl-2-oxoazetidine-1 -sulfonic acid 23 e

(3S, 4 _* S) -N ³ - {(S) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] pentanoyl} -3-amino] -4-methyl-2-oxoazetidine - 1 -sulfonic acid 23f

(3S, 45) -N ³ - {(R) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] hexanoyl} -3-amino] -4-methyl-2-oxoazetidine-1 -sulfonic acid 23g

(3S, 4S) -N ³ - {(S) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] hexanoyl} -3-amino] -4-methyl-2-oxoazetidine-1 -sulfonic acid 23h.

These can be synthesized from the (3S, 4S) -3-amino-4-methyl-2-oxoazetidine-l-sulfonic acid and the (R) -2,5-bis - [(2,3-dibenyloxy-benzoyl) amino ] -pentanoic acid 3e, (S) -2,5-bis - [(2,3-di-benzyloxy-benzoyl) amino] -pentanoic acid 3f, (R) -2,6-bis - [(2,3-dibenzyloxy -benzoyl) amino] -hexanoic acid 3g and (S) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] -hexanoic acid 3h. The following conjugates are also possible:

(R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] -1 - [(2-N-methylbenzoyl) amino] hexane

25g

(S) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] -1 - [(2-N-methylbenzoyl) amino] hexane

25h

(R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] -1- [7- (4-nitrobenz-2-oxy-1,3-diazolyl) amino] hexane 26g

(S) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] - 1 - [7- (4-nitrobenz-2-oxy-1,3-diazolyl) amino] hexane 26h

The intermediates for this are the (3S, 4S) -N ³ - {(R) .- 2,6-bis - [(2,3-dibenzyloxybenzo-yl) amino] -pentanoyl} -3-amino] -4 -methyl-2-oxoacetide-1 -sulfonic acid 22e, (3S, 4S) -N ³ - {(S) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] -pentanoyl} -3- amino] -4-methyl-2-oxoazetidine-1 sulfonic acid 22f, (3S, 4S) -N ³ - {(R) -2,6-bis - [(2,3-dibenzyloxybenzoyl) amino] hexanoyl } -3-amino] -4-methyl-2-oxoazetidine-1 -sulfonic acid 22g or (3S, 4S) -N ³ - {(S) -2,6-bis - [(2,3-dibenzyloxy -benzoyl) amino] -hexanoyl} -3-amino] -4-methyl-2-oxoazetidine-l -sulfonic acid 22h, (R) -2,6-bis - [(2,3-dibenzyloxybenzoyl) amino] - l - [(2-N-methyl-benzoyl) amino] hexane 24 g or (S) -2,6-bis - [(2,3-dibenzyloxybenzoyl) amino] -l - [(2-N- methyl-benzoyl) amino] -hexane into consideration for 24 hours.

The conjugates 26g and 26h can be prepared directly by reaction of the (R) -2,6- bis - [(2,3-dihydroxybenzoyl) amino] - 1-amino-hexane or (S) -2,6-bis- [(2,3-di-hydroxybenzoyl) amino] -l-amino-hexane with NBD-Cl.

25 2fi

Intermediate compounds which can also be used are all customary derivatives which can be prepared in a generally known manner and which replace the mobile H atoms of the phenolic and amidic groups. The following are particularly worth mentioning: formyl, acetyl, trifluoroacetyl, glycosyl, silyl.

In addition, the sulfonic acid group can be esterified or amidated in a suitable manner, it being possible for these compounds to be prepared using generally known methods in organic chemistry. In addition, the sulfonic acid can be in the form of its alkali, alkaline earth or ammonium salts.

The groups mentioned have the properties of being able to be split off both in vitro and in vivo ((prodrug). Scheme 3 shows the synthesis of conjugate 23g.

The compounds according to the invention can be used as medicaments, it being advisable to provide an effective amount of at least one of the compounds of the formula A, mixtures thereof with pharmaceutical auxiliaries and / or carriers. The choice of aids is based, among other things, on galenical criteria, which in turn may depend on the application of the medicinal products. In principle, it is possible to apply the compounds in dissolved or solid form in appropriate dosage forms.

The drugs can be used in particular in therapeutic approaches in which the diseases are caused by defective metal ion metabolism. This can be indicated in particular in the event of an iron or aluminum metabolism error. The pharmaceuticals according to the invention complex the metal ions, in particular iron or aluminum ions, which can then be removed from the organism.

Furthermore, the compounds according to the invention are suitable as antibacterial, antiviral, antitumoral and / or antifungal agents. The medicaments according to the invention can therefore be used for the treatment of bacterial, viral and / or fungicidal infections. The medicaments according to the invention can also be used for parasitic diseases, for example malaria. However, the medicament according to the invention can also be used as a medicament in a form loaded with metal ions. The medicament according to the invention can remove iron and aluminum in various diseases of humans or animals, for example in hemosiderosis or thalassemia or also in Alzheimer's disease, in its metal ion-free form. A suitable dosage of the medicament according to the invention can be determined by the person skilled in the art by known tests and is preferably in the range from 0.1 μg to 100 g per day.

In the form with bound iron or other metal ions, the medicament according to the invention can also be used for tumor treatment. Iron complexes are able to generate oxygen radicals that can attack tumors in particular.

A method using the compounds according to the invention relates to the complexation of metal ions. Here, the metal ion-containing solution is brought into direct contact with solutions of the compounds according to the invention or the compounds according to the invention themselves. This method is therefore suitable for complexing, characterizing and / or removing metals from corresponding solutions containing these metal ions. Radioactive metal ions can also be complexed with the compounds according to the invention. This can serve as a starting point for an enrichment of radioactive isotopes and can be used in an analogous manner for the removal of radioactive isotopes.

The compounds with the general formula A, wherein

R = COOH, COOR ¹ , CH ₂ -OH, C (= 0) NR ² R ³ , CN, CH ₂ NR ² R ³ , C (= 0) -Z,

CH ₂ -Z or a substituent according to formula C.

R ⁴ = COOH, COOR ¹ , CH ₂ -OH, C (= 0) NR ² R ³ CN, CH ₂ NR ² R ³ , or a substituent according to formula D.

R ¹ = C _x H _{2x + 1} with x = 1, 2,3,4,5, -CH ₂ -C ₆ H ₅ or - H ₅ ;

R ² , R ³ = independently of one another H, C _x H _{2x +} j with x = 1,2,3, 4,5, -CH ₂ -C ₆ H ₅ , - H ₅ Y = independently of one another benzoyl, formyl, acetyl, trifluoroacetyl,

Glycosyl or silyl; Z = an organic group bonded via a 0, N, S and n = 1, 2, 3, 4 or 5

and the absolute configuration at C * can be both S and R can be used to analyze bacteria. In particular, the presence of pathogenic enterobacteria and / or tuberculosis-causing mycobacteria can be quickly analyzed. For this purpose, for example, samples contaminated with pathogenic enterobacteria and / or mycobacteria are incubated in an iron deficiency medium. By adding the compounds according to the invention, it is possible to selectively excite only one pathogenic bacterial strain for rapid growth.

The invention is illustrated by the following examples.

example 1

(R) -2,6-diamino-hexanoic acid methyl ester dihydrochloride (lg)

5 g (27.08 nmole) of commercially available H- (R) -Lys-OHxHCl (from Bachern) are suspended in 50 ml of freshly dried methanol. Gaseous HC1 is passed through the reaction solution with ice / salt cooling (duration 30 min.), A clear solution being formed. The reaction mixture is left to stand at room temperature for 2 days, then the methanol is spun in in vacuo. The remaining white solid is washed with diethyl ether. 6.0 g (94%), (DC: R _f = 0.35, n-

Butanol / water / glacial acetic acid = 4: 1: 1). - [α] _D ²⁰ = -22.44 (c = 0.5, CH ₃ OH). -

'H NMR (CD ₃ OD): δ (ppm) = 8.8 (br., 3 H, NH ₃ ⁺ ), 8.3 (br., 3 H, NH ₃ ⁺ ), 3.96 (m , 1 H,

2-H), 3.7 (s, 3 H, 0-CH ₃ ), 2.71 (m, 2 H, 6-H ₂ ), 1.8 (m, 2 H, 3- H ₂ ), 1.55 (m, 2 H, 4-

H ₂ ), 1.4 (m, 2 H, 5- H ₂ ). (+) - CI MS: m / z - 161 [M + H ⁺ - 2 x HCl], - C ₇ H ₁₈ C1 ₂ N ₂ 0 ₂ (233.1): calcd. C 36.06 H 7.78 , N 12.02, Cl 30.42, found. C 35.94, H 7.88 N 11.87, Cl 30.34.

Example 2

(R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexanoic acid methyl ester (2g)

1 g (4.29 mmol) lg are suspended in 50 ml of dried dichloromethane. 8.87 g (8.58 mmol) of 2,3-dibenzyloxy-benzoic acid, [Mp = 123EC, shown according to literature procedure: F. Kanai, K. Isshiki, H. Nagawana, T. Takita, T. Takeuchi, H Umezawa, "J. Antibio", 37, 3987, (1985), m.p. = 124EC], 2.76 g (8.58 mmol) of TBTU and 4.38 ml (25.74 mmol) of Hunig's base to the reaction solution given. The reaction solution is stirred for 5 days at room temperature, a clear solution being formed. It is extracted with 5% HCl, saturated aqueous solutions of NaHC0 ₃ and NaCl and the organic phase is dried over NaS0 ₄ . After evaporation in vacuo, a syrupy residue remains, which is purified by means of flash chromatography (ethyl acetate / n-heptane = 1: 1). 2.7 g (90.1%) of a slightly yellow colored syrup are obtained. (TLC: R _f = 0.75, ethyl acetate). [α] _D ²⁰ = + 16.98 (c = 0.38 in chloroform).

Η NMR (CDC1 ₃ ): δ (ppm) = 8.44 (d, J = 7.6 Hz, 1H, 2-NH), 7.83 (t, J = 5.5 Hz, 1 H, 6 -NH), 7.48 -7.18 (m, 2 ^* 6 H, arom. = CH-), 5.17-5.02 (m, 8 H, 4 x OCH ₂ -phe), 4.55 (ddd , J _! = 5.5 Hz, J ₂ = 7.6 Hz, J ₃ = 3.1 Hz, 1 H, 2-H), 3.64 (s, 3 H, 0-CH ₃ ), 3, 15 (dt, J, = 7.0 Hz, J ₂ = 13.1 Hz, 2 H, 6- H ₂ ), 1.58 (m, 2 H, 3-H ₂ ), 1.35-1, 08 (m, 4 H, 4 and 5 H ₂ ). -

¹³ H-NMR (CDC1 ₃ ): δ (ppm) = 23 (t, C-5), 28 (t, C-3), 33 (t, C-4), 39 (t, C-6), 53 (d, C-2), 54 (q, O-CH ₃ ), 71, 71.5, 76 and 76.5 (t, 0-CH ₂ -phe), 117, 117.5, 123, 123 , 5, 124, 124.5 (d, arom. = CH, benzoyl), 126.5, 127.3 (s, quart. Arom. = C-, benzoyl), 127.5- 128.5 (d, 20 x arom. = C-, phe), 136.5, 136.7 (s, quart.arom. C, phe), 146.5 147 (s, arom. = C-, phe), 151.5 151.7 (s, arom. = C-0), 165, 165 (sec. amide-C = 0), 172.5

(Ester-C = 0).

C ₄₉ H ₄₈ N ₂ 0 ₈ (792.9).

Example 3

(S) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexanoic acid methyl ester (2h)

The presentation is analogous to 2 g, whereby commercially available H-Lys-OMe x 2 HCl can be used for this. (TLC: R _f = 0.75, ethyl acetate). [α] _D ²⁰ = - 13.79 (c = 0.38 in chloroform).

Example 4

(R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] hexanoic acid methyl ester (6g)

100 mg (0.13 mmol) of the methyl ester 2g are dissolved in 5 ml of THF and 20 ml of methanol and 50 mg of Pd / C (10%) are added. The stirred reaction solution is at 1.0 bar and room temperature for 30 min. hydrated. The mixture is then filtered through kieselguhr and Chelex 100 (Merck) and the filtrate is concentrated in vacuo. 49 mg (88%) of vitreous methyl ester remain. (TLC: R _f = 0.35, dichloromethane with 10% methanol, sudden blue coloring with FeCl ₃ ).

Η NMR (CD ₃ OD): δ (ppm) = 7.3 (dd, 1 H, benzoyl-, 1 x 6-H), 7.2 (dd, 1 H, benzoyl-, 1 x 6-H ) 6.95 (dd, 1 H, benzoyl-, 1 x 4-H), 6.9 (dd, 1 H, benzoyl-, 1 x 4-H), 6.65 (dd, 1 H, benzoyl- , 1 x 5-H), 6.6 (dd, 1 H, benzoyl-, 1 x 5-H), 4.65 (dd, 1 H, 2-H), 3.7 (s, 3 H, 0-CH ₃ ), 3.4 (dd, 2 H, 6-H ₂ ), 2.0 (m, 1 H, 3-H ₂ ), 1.9 (m, 1 H, 3-H ₂ ) , 1.7 (m, 2 H, 4-H ₂ ), 1.5 (m, 2 H, 5-H ₂ ). C _2I H ₂₄ N ₂ 0 ₈ (432.4). Example 5

(S) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] -hexanoic acid methyl ester (6h) The representation is made from 2h analogously to the instructions for the synthesis of 6g. The yield is 91%. The DC behavior and the 'H NMR spectrum are identical to 6g.

C ₂₁ H ₂₄ N ₂ 0 ₈ (432.4).

Example 6

(R) -2,6-bis - [(2,3-dibenzyloxybenzoyl) amino] hexane carboxylic acid (3g)

500 mg (0.63 mmol) of the methyl ester 2g are dissolved in 20 ml of dioxane. 20 ml of a 0.1 N NaOH solution are added to this solution and the mixture is stirred vigorously for 1.5 h at room temperature. The dioxane is evaporated down in vacuo and the remaining aqueous phase is extracted twice with diethyl ether. The aqueous phase is acidified with 5% HCl, which is then extracted twice with diethyl ether. The organic diethyl ether phases are dried over Na ₂ S0 ₄ and evaporated in vacuo after filtration. 450 mg of 3 g (92%) are obtained as a colorless oil.

[α] _D ²⁰ = +16.5 (c = 0.65 in chloroform). Miller et al. [Bioconjugate Chem., Vol. 2, No. 4, 281, (1991)] give a rotation value for the enantiomeric compound 3h of [α] ²² _D = + 8.8 (c = 1, CHC1 ₃ ). From 3 batches shown, however, we determined [α] ²⁰ _D = - 16.9E (c = 0.58, CHC1 ₃ ) for ₃ hours!

'H NMR (CDC1 ₃ ): δ (ppm) = 8.57 (d, 1H, 2-NH), 7.92 (t, 1 H, 6-NH), 7.71 -7.11 (m , 26 H, aroma = CH-), 5.15-5.03 (m, 8 H, 4 x OCH ₂ -phe), 4.50 (ddd, 1 H, 2-H), 3.11 ( m, 2-H, 6-H ₂ ), 1.69 (m, 1 H, 3-H ₂ ), 1.39 (m, 1-H, 3-H ₂ ), 1.17 (m, 4 -H, 4-H ₂ and 5-H ₂ ). - C ₄₈ H ₄₆ N ₂ 0 ₈ (778.9). Example 7

(R) -2,6-bis- [(2,3-dihydroxy-benzoyl) amino] hexane carboxylic acid (7g)

The representation is made from 3g analogously to the regulation for the synthesis of 6g. The yield of 7g is 93%. - Glassy oil. (TLC: R _f = 0.25, dichloromethane with 10%) methanol, sudden blue coloring with FeCl ₃ ).

'H NMR (CD ₃ OD): δ (ppm) = 7.35 (dd, J - 1.5 and 8.1 Hz, 1 H, benzoyl, 1 x 6-H), 7.20 (dd , J = 1.5 and 8.1 Hz, 1 H, benzoyl-, 1 x 6-H) 6.88-6.92 (m, 2 H, benzoyl-, 2 x 4-H), 6.65 -6.73 (m, 2 H, benzoyl-, 2 x 5-H), 4.62 (m, 1 H, 2-H), 3.40 (m, 2 H, 6-H ₂ ), 2 , 05 (m, 1H, 3-H ₂ ), 1.90 (m, 1-H, 3-H ₂ ), 1.70 (m, 2H, 4-H ₂ ) and 1.55 (m, 2H) , 5-H ₂ ). - C ₂₀ H ₂₂ N ₂ O ₈ (418.4). - calculated C 57.41 H 5.30 N 6.70 found C 57.47 H 5.43 N 6.84.

Example 8

(R) -2,6-bis - [(2,3-dibenzyloxybenzoyl) amino] hexan-l-ol (4g)

500 mg (0.63 mmol) 2g are dissolved in 20 ml of diethyl ether and 50 mg of LiAlH ₄ (1.4 mmol) are added in portions with stirring. After 2 h, 5% HCl is carefully added and the HCl phase is extracted several times with diethyl ether. The ether phases are washed with sat. Washed NaCl solution, dried over NaS0 ₄ and evaporated in vacuo. The residue is purified by means of flash chromatography (n-heptane / ethyl acetate = 1: 3). 350 mg (73%) 4g are obtained as a colorless oil. [α] _D ²⁰ = + 25.5 (c = 0.65 in chloroform).

'H NMR (CDC1 ₃ ): δ (ppm) = 8.21 (d, 1H, 2-NH), 7.91 (t, 1 H, 6-NH), 7.71 -7.12 (m , 26 H, aroma = CH-), 5.17-5.02 (m, 8 H, 4 x OCH ₂ -phe), 3.93 (ddd, 1 H, 2-H), 3.54 (dd, 1 H, CH ₂ -OH) 3.42 (dd, 1 H, CH ₂ -OH) 3.22 (m, 1-H, 6-H ₂ ), 3.13 (m, 1-H, 6- H ₂ ), 1.47 (m, 2 H, 3-H ₂ ), 1.23 (m, 2-H, 6-H ₄ ) (m, 2-H, 5-H ₂ ). - ¹³ H-NMR (CDCI ₃ ): δ (ppm) = 23.2 (C-5), 29.1 (C-3), 30.2 (C-4), 39.0 (C-6), 52.4 (C- 2), 71.4 71.5, 76.2 and 76.4 (0-CH ₂ -phe), 117.0 117.3, 123.3 123.4, 124.3 124 , 4 (aroma = CH, benzoyl), 127.0, 128.2 (quart. Aroma. = C-, benzoyl), 127.3-128.7 (20 x aroma. = C-, phe), 136 , 4 136.5 (quart. Aroma. C, phe), 146.8 147.0 (aroma. = C-, phe), 151.6 151.7 (aroma. = C-0), 165.1, 165.9 (sec amide-C = 0). - C ₄₈ H ₄₈ N ₂ 0 ₇ (764.9).

Example 9

(S) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] -hexan-1-ol (4h)

The representation takes place from 2 h analogously to the regulation for the synthesis of 4 g. The 4h yield is 75%. - [α] _D ²⁰ = - 21.8 (c = 0.6 in chloroform).

Example 10

(R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] hexan-l-ol (myxochelin A _R ) (8g)

The representation is made from 4g analogously to the regulation for the synthesis of 6g. The yield of 8g is 90%. - Glassy oil. (TLC: R _f = 0.25, dichloromethane with 10% methanol, sudden blue coloring with FeCl ₃ ).

'H NMR (CD ₃ OD): δ (ppm) = 7.35 (dd, J = 1.5 and 8.1 Hz, 1 H, benzoyl, 1 x 6-H), 7.20 (dd , J = 1.5 and 8.1 Hz, 1 H, benzoyl-, 1 x 6-H) 6.88-6.95 (m, 2 H, benzoyl-, 2 x 4-H), 6.65 -6.75 (m, 2 H, benzoyl-, 2 x 5-H), 4.20 (m, 1 H, 2-H), 3.65 (m, 2-H, CH ₂ - OH), 3.40 (m, 2 H, 6-H ₂ ), 1.45-1.80 (m, 6 H, 3-H ₂ , 4-H ₂ and 5-H ₂ ). C ₂₀ H ₂₄ N ₂ O ₇ (404.4). - Example 11

(R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) aminoJ-hexanoic acid amide (5g)

1 g (1.26 mmol) 2g are dissolved in 10 ml of tetrahydrofuran and 150 ml of methanol. The reaction solution is kept at OEC with ice / NaCl, gaseous ammonia is passed through for 1 h. The cooled reaction solution is then immediately placed in an autoclave which is kept closed for 3 d at room temperature. After carefully opening the autoclave, the reaction solution is spun in. The remaining white solid is pure for analysis. - (TLC: R _f = 0.60, ethyl acetate), F _p = 120 ° C, [α] ²⁵ _D = + 9.2 (c = 0.5 in acetone), [for 5h is [α] ²⁵ _D = - 9, 0 (c = 0.5 in acetone)!]. - IR (KBr): v = 3371 (NH), 3032 (aromatic CH), 2930 (aliphatic CH), 1651 (amide-I), 1526 (amide-II) cm ^" '. - Η-NMR (300 MHz, CDC1 ₃ ): δ (ppm) - 8.31 (d, J = 7.4 Hz, IH, N ² -H), 7.90 (t, J = 5.4 Hz, IH, N ⁶ -H), 7.67 (m, 4H , 2 x benzoyl-4-H and 2 x benzoyl-6-H), 7.30 (m, 20 H, aromatic H), 7.15 (m, 2H, 2 x benzoyl-5-H), 6.37 (s, IH , primary amide-H, 5.30 (s, IH, primary amide-H _b ), 5.16 (m, 8H, 0-CH ₂ -phe), 4.42 (dd, J, = 7.5 Hz, J ₂ = 7.6 Hz , IH, 2-H), 3.16 (dd, Jj = 6.6 Hz, J ₂ - 5.4 Hz, 2H, 6-CHr), 1.74 (m, IH, 3-CH, -), 1.34 (m, 2H, 4 -CH ₂ -), 1.21 (m, 3H, 3- CH _b -, 5-CH ₂ -). - ¹³ C-NMR (75.4 MHz, CDC1 ₃ ): δ (ppm) = 22.8 (t, C-4 ), 28.7 (t, C-3), 30.6 (t, C-5), 39.0 (t, C-6), 53.0 (d, C-2), 71.2, 71.3, 76.2, 76.3 (t, 0- CH ₂ -phe), 116.9, 117.4 (d, arom. = CH-), 123.0, 123.3 (d, arom. = CH-), 124.4, 124.4 (d, arom. = CH-), 126.7, 127.3 (see , quart. aroma. C); 127.7-128.9 (d, 20 x aroma. = CH-), 136.2, 136.4 (s, quart. aroma. C), 146.8, 146.9 (s, quart. aroma. = C-0 -), 151.7, 151.7 (s, quart. Aroma. = C- 0), 165.0, 165.6 (s, sec. Amide-CO), 173.7 (s, prim. Amide CO). - C ₄₈ H ₄₇ N ₃ 0 ₇ (777.3): calc. C 74.16 H 6.10 N 5.41; found C 73.76 H 5.99 N 5.33. - Example 12

(R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] hexanoic acid amide (9g)

The representation is made from 5g analogously to the regulation for the synthesis of 6g. The yield of 9g is 95%. - Glassy oil. (TLC: R _f = 0.30, dichloromethane with 10% methanol, sudden blue coloring with FeCl ₃ ).

'H NMR (CD ₃ OD): δ (ppm) = 7.3 (dd, 1 H, benzoyl-, 1 x 6-H), 7.15 (dd, 1 H, benzoyl-, 1 x 6- H) 6.95 (dd, 1 H, benzoyl-, 1 x 4-H), 6.85 (dd, 1 H, benzoyl-, 1 x 4-H), 6.70 (dd, 1 H, benzoyl -, 1 x 5-H), 6.63 (dd, 1 H, benzoyl-, 1 x 5-H), 4.58 (dd, 1 H, 2-H), 3.37 (dd, 2 H) , 6-H ₂ ), 1.95 (m, 1 H, 3-H ₂ ), 1.85 (m, 1 H, 3-H ₂ ), 1.65 (m, 2 H, 4-H ₂ ), 1.5 (m, 2 H, 5-H ₂ ). - ¹³ C NMR (75.4 MHz, CDC1 ₃ ): δ (ppm) = 24.3 (t, C-4), 30.05 (t, C-3), 32.96 (t, C-5) , 40.21 (t, C-6), 54.57 (d, C-2), 116.92, 117.36 (s, benzoyl, 2 x Cl), 118.77, 119.72, 119.90 , 119.95 (d, arom. = CH-), 147.39, 147.52, 149.80, 150.44 (s, benzoyl-, 2 x C-2 and C-3), 171.09, (s, sec amide-C = 0), 171.77 (s, primary amide-C = 0), 177.32 (s, CONH ₂ ). C ₂₀ H ₂₃ N ₃ O ₇ (417.4).

Example 13

(S) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] hexanoic acid 9h

The preparation takes place from (S) -2,6-bis - [(2,3-dibenzyloxybenzoyl) amino] - hexanoic acid amide 5h (for the representation see international patent application PCT / EP 96/02796) analogously to the instructions for the synthesis of 6g. The yield of 9h is 89%. The DC behavior and the 'H NMR spectrum are identical to 9 g.

C ₂₀ H ₂₃ N ₃ O ₇ (417.4). Example 14

Myxochelin-iron complex:

If the solutions of 6g, 6h, 7g, 8g, 9g or 9h in methanol are mixed with dilute iron (III) chloride solution - also methanolic - an immediate blue coloration occurs: λ _max around 570 nm.

Example 15

The enantiomerically pure R- and S-ornithine methyl ester dihydrochloride le and lf can be used to prepare the compounds 6e, 6f, 7e, 7f, 8e, 8f, 9e or 9f, which are shorter by one CH ₂ group, while maintaining all reaction conditions.

Example 16

(3S, 4S) -N ³ - {(R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexanoyl} -3-amino] -4-methyl-2-oxoazetidine-1 -sulfonic acid 22g

73 mg (0.094 mmol) 3g, 30 mg (0.094 mmol) TBTU and 32μl (0.18 mmol) Hünig base are dissolved in 10 ml absolute dichloromethane and stirred at room temperature. In parallel, 17 μl (0.094 mmol) (3S, 4S) -3-amino-4-methyl-2-oxoazetidin-1-sulfonic acid in 10 ml absolute dichloromethane are mixed with 16 μl (0.094 mmol) Hünig base and stirred at room temperature . After one hour, the two solutions are combined and the mixture is stirred for a further 48 h at room temperature, a clear reaction solution being formed. This is extracted with 5% HCl, saturated aqueous solutions of NaHC0 ₃ and NaCl. The organic phase is dried over NaSO ₄ . The residue that remains after being rotated in a vacuum The crude product is purified by means of flash chromatography (dichloromethane / methanol = 10: 1). 25 mg of 22 g (55%) are obtained as a colorless syrup. (TLC: R _f = 0.2, dichloromethane / methanol = 10: 1). - C ₅₂ H ₅₂ N ₄ O _n S (941.1).

Example 17

(3S, 4S) -N ³ - {(S) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexanoyl} -3-amino] -4-methyl-2-oxoazetidine-1 -sulfonic acid 22h

The display is analogous to 22g, assuming 3h. Yield 58% of 22h as a colorless syrup (TLC: R _f = 0.2, dichloromethane / methanol = 10: 1). - C ₅₂ H ₅₂ N ₄ O _π S (941.1).

Example 18

(3S, 4S) -N ³ - {(R) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] hexanoyl} -3-amino] -4-methyl-2-oxoazetidine-1 -sulfonic acid 23g

The representation is made from 22g analogously to the regulation for the synthesis of 6g. The yield of 23g is δl%. - Glassy oil. (TLC: R _f = 0.25, dichloromethane with 30% methanol, sudden blue coloring with FeCl ₃ ). -

C ₂₄ H ₂₈ N ₄ O _n S (580.6). -

Example 19

(3S, 4S) -N ³ - {(S) -2,6-bis - [(2,3-dihydroxy-benzoyl) ammo] hexanoyl} -3-amino] -4-methyl-2-oxoazetidine-1 -sulfonic acid 23h

The display takes place from 22h analogous to the regulation for the synthesis of 6g. The yield of 23h is 83%. - Glassy oil. (TLC: R _f = 0.25, dichloromethane with 30% methanol, sudden blue coloring with FeCl ₃ ). - C ₂₄ H ₂₈ N ₄ 0 "S (580.6).

Example 20

(R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] -1- [7- (4-nitrobenz-2-oxy-1,3-diazolyl) amino] hexane 26g

40 mg (0.1 mmol) of (R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] -l-amino-hexane and 21 mg (0.1 mmol) of 7-chloro-4-nitrobenz -2-oxa-l, 3-diazole are stirred in 5 ml of methanol for 5 hours at room temperature. The reaction solution is spun in iV. There remain 51 mg (91%) of a glassy solid. TLC (RP 18): R _F = 0.8, MeOH / H ₂ 0).

At an excitation wavelength of λ = 480 nm, the conjugate shows strong fluorescence at λ = 540 nm, which is coupled to a release of the iron. C ₂₆ H ₂₆ N ₆ 0 ₉ (566.5)

Biological effects

The effect of the siderophores 6g, 6h, Tg, 8g, 9g, 9h and 16a, 16b, l £ a, 19b, 19c, 19d, 20a, 20b, 20c. 20d, 21a, 21b is proven by means of a bioassay. The following strains of enterobacteria (gram-negative bacteria) and mycobacteria, which have a defect in the iron transport system and therefore cannot absorb the iron, are identified by the siderophores 6g, 6h, 7g, 8g, 9g, 9h and 16a, 16b. 19a, 19b. 19c. 19d. 20a. 20b. 20c. 20d, 21a, 21b in the concentration of 5 μg / disc so well supplied with iron that the strains nevertheless show enormous growth zones in an iron-depleted medium. The growth zones obtained are larger than those caused by the siderophores protected in the international patent application PCT / EP 96/02796. Compound 9g shows the following growth zones (in mm):

Salmonella stanleyville (36), Salmonella typhimurium enb-7 (32), Salmonella typhimurium CL1509 aroA (38), Salmonella typhimurium AJB64 (38), Morganella morganii SBK 3 (35) and Mycobacterium smegmatis (25).

Table 1 shows an overview of growth zones which were achieved with the substances according to the invention in comparison with known compounds.

(S) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] hexanitrile (myxochelin C-nitrile), (R) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] hexanitrile (myxochelin C _R -nitrile), (S) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] - 1-amino-hexane (myxochelin B), (R) -2, 6-bis - [(2,3-dihydroxy-benzoyl) amino] -1-amino-hexane (myxochelin B _R ), (S) -l, 2,6-tris - [(2,3-dihydroxy-benzoyl) amino] hexane (myxochelin C), (R) -l, 2,6-tris - [(2,3-dihydroxy-benzoyl) amino] hexane (myxochelin C _R )

Table: Feeding test using Enterobacteriaceae strains, p. aeruginosa PAO 6609 and M. smegmatis 987 with various "myxochelins"

m

>

DJ

H H m O m r- to σ>

Legend for table 1:

TRIS: Tris (hydroxymethyl) aminomethane

VB: Vogelbonner medium

Dip: Dipryridyl

CDMH: Chemicaly defined medium - yeast extract

EDDHA: ethylenediamine dihydroxyphenylacetic acid

HZ: inhibition zone

The test conditions are published in R. Reissbrodt, L. Heinisch, U. Möllmann, W. Rabsch, H. Ulbricht, "Biometais", 6, pages 155 to 162 (1993) and R. Reissbrodt and W. Rabsch, "Zbl. Bakt. Hyg. ", A 268, pages 306 to 317, (1988).

Furthermore, the siderophores 6g, 6h, 7g, 8g, 9g and 9h have improved antiviral activities, in particular against cytomegaloviruses from strain AD-169. The IC ₅₀ values for the active ingredients 8g and 8h are 1.7 μM and 1.1 μM below that of myxochelin B _R (1.8 μM - the best effect so far!).

The antitumor effect of the Myxocheline 6g, 8g and 8h on neuroblastoma cells is surprisingly better than that of the already known compounds. So far the best TC are ₅₀ - values from Myxochelin- C _R nitrile (0.98 uM) and Myxochelin- C (0.91 uM) is worse than that of the compounds 6g '(0.86 .mu.M), 8g (0.63 μM) and 8h

(0.77 µM).

The conjugates 23g and 23h showed an extremely selective effect in the antibiotic test (platelet test with 10 μl concentration 1 mg conjugate / 1 ml methanol). Among the many strains tested, only the multi-resistant strain Pseudomonas aeruginosa ATCC 9027 (21 or 18 mm - MIC values: 15.7 or 30.6 μg / ml) and Proteus vulgaris (28 or 27 mm - MIC values: 505 or 980 μg / ml) zones of inhibition.

Claims

claims Compound of the general formula (A) Formula (A)

in which R COOH, COOR ¹ , CH ₂ -OH, C (= 0) NR ² R ³ , CN, CH ₂ NR ² R ³ , C (= 0) -Z, CH ₂ -Z or a substituent according to formula C.

Formula (C) R ⁴ COOH, COOR ¹ , CH ₂ -OH, C (= 0) NR ² R ³ CN, CH ₂ NR ² R ³ , or a substituent according to formula D.

Formula (D) R ¹ C _x H _{2x + 1} with x = 1,2,3,4,5, -CH ₂ -C ₆ H ₅ or -C ₆ H ₅ ; R ² , R ³ independently of one another H, C _x H _{2x + 1} with x = 1,2,3, 4,5, -CH ₂ - C ₆ H ₅ , -C ₆ H ₅ Y independently of one another benzoyl, formyl, acetyl, trifluoroacetyl, Glycosyl or silyl; Z is an organic group bonded via a 0, N, S and n is 1, 2, 3, 4 or 5 and the absolute configuration at C * can be both S and R. and the salts of the compounds, especially alkali, alkaline earth or ammonium salts, where R is not CH ₂ NH ₂ or CN if n = 3 or 4 and R ⁴ = formula D with Y = H and R is not Formula C with Y = H when n = 2, 3, 4, 5 and R ⁴ = Formula D with Y = H and R is not CH ₂ -OH or COOH if R ⁴ = formula D with Y = H and n = 4 and the absolute configuration at C * S 2. Compound according to claim 1 with the formula (B)

Formula (B) wherein R, Y and n are as defined in claim 1 and the absolute configuration at C * can be both S and R. 3. Compound according to claim 2, characterized in that Y - H, R = COOR ¹ , in particular with R ¹ = CH ₃ , or Y = H, R = COOH, o <ter Y = H, R = CH ₂ -OH , or Y = H, R = CONR ² R ³ . Compounds according to claim 3, characterized in that it is (R) -2,3-bis - [(2,3-dihydroxy-benzoyl) amino] propanoic acid methyl ester 6a, n = 1 (S) -2,3-bis - [(2,3-dihydroxy-benzoyl) amino ] -propanoic acid methyl ester 6b, n = 1 (R) -2,4-bis - [(2,3-dihydroxy-benzoyl) amino] -butanoic acid methyl ester 6c, n = 2 (S) -2,4-bis - [(2nd , 3-dihydroxy-benzoyl) amino] -butanoic acid 6d, n = 2 (R) -2,5-bis - [(2,3-dihydroxy-benzoyl) amino] -pentanoic acid methyl ester 6e, n = 3 (S) -2 , 5-bis - [(2,3-dihydroxy-benzoyl) amino] -pentanoic acid methyl ester 6f, n = 3 (R) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino) -hexanoic acid methyl ester 6g, n = 4 (S) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] -hexanoic acid methyl ester 6h, n = 4 or (R) -2,3-bis - [(2,3-dihydroxy-benzoyl) amino] propanoic acid 7a, n = 1; (S) -2,3-bis- [(2,3-dihydroxy-benzoyl) amino] propanoic acid 7b, n = 1; (R) -2,4-bis - [(2; 3-dihydroxy-benzoyl) amino] butanoic acid 7c, n - 2; (S) -2,4-bis - [(2,3-dihydroxybenzoyl) amino] butanoic acid 7d, n = 2; (R) -2,5-bis - [(2,3-dihydroxybenzoyl) amino] pentanoic acid 7e, n = 3; (S) -2,5-bis - [(2,3-dihydroxybenzoyl) amino] pentanoic acid 7f, n = 3; (R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] hexanoic acid 7g, n = 4 or (R) -2,3-bis - [(2,3-dihydroxybenzoyl) amino] propah-l-ol 8a, n = 1; (S) -2,3-bis- [(2,3-dihydroxybenzoyl) amino] propan-l-ol 8b, n = 1; (R) -2,4-bis - [(2,3-dihydroxy-benzoyl) amino] butan-l-ol 8c, n = 2; (S) -2,4-bis - [(2,3-dihydroxybenzoyl) amino] butan-l-ol 8d, n = 2; (R) -2,5-bis - [(2,3-dihydroxybenzoyl) amino] pentane-1-oil (myxochelin D _R -A) 8e, n = 3; (S) -2,5-bis - [(2,3-dihydroxy-benzoyl) amino] -pentan-l-ol (Myxochelin DA) 8f, n = 3; (R) -2,6- bis - [(2,3-dihydroxy-benzoyl) amino] hexan-l-ol (myxochelin A _R ) 8g, n = 4 or (R) -2,3-bis - [(2,3-dihydroxy-benzoyl) amino] propanoic acid amide 9a, n = 1; (S) - 2,3-bis - [(2,3-dihydroxy-benzoyl) amino] propanoic acid amide 9b, n = 1; (R) -2,4- bis - [(2,3-dihydroxy-benzoyl) amino] butanoic acid amide 9c, n = 2; (S) -2, 4-bis- [(2,3-dihydroxy-benzoyl) amino] butanoic acid 9d, n = 2; (R) -2,5-bis - [(2,3-dihydroxy-benzoyl) amino] pentanoic acid amide 9e, n = 3; (S) -2,5-bis - [(2,3-dihydroxy-benzoyl) amino] -pentanoic acid 9f, n = 3; (R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] hexanoic acid amide 9g, n = 4; (S) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] hexanoic acid 9h, n = 4. 5. Compounds according to claim 2, in which Y = benzyl as in (R) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propanoic acid methyl ester 2a (S) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propanoic acid methyl ester 2b (R) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] butanoic acid methyl ester 2c (S) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] butanoic acid methyl ester 2d (R) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] pentanoic acid methyl ester 2e (S) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] pentanoic acid methyl ester 2f (R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexanoic acid methyl ester 2g (S) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexanoic acid methyl ester 2h (R) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propanoic acid 3a (<S) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propanoic acid 3b (R) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] butanoic acid 3c (S) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] butanoic acid 3d (R) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] pentanoic acid 3e (S) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] pentanoic acid 3f (R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexanoic acid 3g (R) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propane-1-ol 4a (<S) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propan-l-ol 4b (R) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] butan-1-ol 4c (S) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] butan-1-ol 4d (R) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] pentane-1-ol 4e (S) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] pentane-1-ol 4f (R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexane-1-ol 4g (S) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexane-1-ol 4h (R) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propanoic acid amide 5a (S) -2,3-bis - [(2,3-dibenzyloxy-benzoyl) amino] propanoic acid amide 5b (R) -2,4-bis - [(2,3-dibenzyloxybenzoyl) amino] butanoic acid 5c (S) -2,4-bis - [(2,3-dibenzyloxy-benzoyl) amino] butanoic acid 5d (R) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] -pentanoic acid 5e (S) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] pentanoic acid 5f (R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexanoic acid 5g (<S) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexanoic acid 5h 6. A compound according to claim 1, characterized in that R ⁴ = COOH, COOR ¹ , CH ₂ OH, C (= 0) NR ² R ³ , CN, CH ₂ NR ² R ³ and R, n, R ¹ , R ² , R ³ , Y are as defined in claim 1. 7. Compounds according to claim 6, characterized in that Y = H, R, R ⁴ = COOR ¹ , in particular with R ¹ = CH ₃ , or Y = H, R, R ⁴ = COOH, or Y = H, R, R ⁴ = CH ₂ -OH, or Y = H, R, R ⁴ = CONR ² R ³ , in particular with R ² R ³ = H, or Y = H, R, R ⁴ = CN, or Y = H, R , R ⁴ = CH ₂ NR ² R ³ , especially when R ² , R ³ = H. 8. Compounds according to claim 7, characterized in that it is (R) -2 - [(2,3-dihydroxybenzoyl) amino] butane-l, 4-dimethyl disate 16a, n = 1; (S) -2 - [(2,3-dihydroxybenzoyl) amino] butane-l, 4-dimethyl disate 16b, n = 1; (R) -2 - [(2,3-di-hydroxy-benzoyl) amino] pentane-1,5-disacid dimethyl ester 16c, n = 2; (S) -2 - [(2,3-Dihydroxy-benzoyl) amino] pentane-l, 5-diacid dimethyl 16d. n = 2; (R) -2 - [(2,3-dihydroxybenzoyl) amino] hexane-1,6-disacid dimethyl ester 16e, n = 3, (S) -2 - [(2,3-dihydroxybenzoyl) amino] hexane-l, 6-diacid dimethyl ester 16f. n = 3; (R) -2 - [(2,3-Dihydroxy-benzoyl) amino] -heptane-l, 7-dimethyl dimer 16g, n = 4; (S) -2 - [(2,3-Dihydroxybenzoyl) amino] -heptan- 1, 7-diacid dimethylester 16h, n = 4 or (R) -2 - [(2,3-Dihydroxy-benzoyl) amino] butane-1,4-diacid 17a. n = 1; (S) -2- [(2,3-dihydroxybenzoyl) amino] butane-1,4-diacid 17b, n = 1; (R) -2 - [(2,3-dihydroxybenzoyl) amino] pentane-1,5-diacid 17c, n = 2; (S) -2 - [(2,3-dihydroxy-benzoyl) amino] pentane-1,5-diacid 17d, n = 2; (R) -2 - [(2,3-dihydroxybenzoyl) amino] hexane-1, 6-diacid 17e, n = 3; (S) -2 - [(2,3-Dihydroxybenzoyl) amino] hexane-1,6-diacid 17f. n = 3; (R) -2 - [(2,3-Dihydroxybenzoyl) amino] heptane-1,7-diacid 17g. n = 4; (S) -2 - [(2,3-Dihydroxy-benzoyl) amino] -heptane-l, 7-diacid 17h, n = 4 or (R) -2 - [(2,3-dihydroxybenzoyl) amino] butane-1,4-diol 18a, n = 1; (S) -2 - [(2,3-dihydroxybenzoyl) amino] butane-1,4-diol 18b, n = 1; (R) -2 - [(2,3-dihydroxybenzoyl) amino] pentane-1,5-diol 18c, n = 2; (S) -2 - [(2,3-dihydroxybenzoyl) amino] pentane-1,5-diol 18d. n = 2; (R) -2 - [(2,3-dihydroxybenzoyl) amino] hexane-1, 6-diol 18e, n = 3; ( ₁ S) -2 - [(2,3-Dihydroxy-benzoyl) amino] - hexane-1,6-diol 18f. n = 3; (R) -2 - [(2,3-dihydroxybenzoyl) amino] -heptane-l, 7-diol 18g, n = 4; (S) -2 - [(2,3-Dihydroxy-benzoyl) amino] -heptane-l, 7-diol 18h, n = 4 or (RV2 - [(2,3-dihydroxybenzoyl) amino] butane-1,4-diacid diamide 19a, n = 1; (S) - 2 - [(2,3-dihydroxybenzoyl) amino] butane-l, 4-diacid diamide 19b, n = 1; (R) -2- [(2,3-dihydroxy-benzo-yl) amino] pentane-l, 5-diacid diamide 19c, n = 2; (S) -2- [ (2,3-Dihydroxy-benzoyl) amino] -pentane-l, 5-diacid diamide 19d. N = 2; (R) -2- [(2,3-dihydroxy-benzoyl) amino] -hexane-l, 6- diacid diamide 19e, _* n = 3; (S) -2- [(2,3-dihydroxybenzoyl) amino] hexane-l, 6-diacid diamide 19f, n = 3; (R) -2- [( 2,3-dihydroxy-benzoyl) amino] -heptane-l, 7-diacid diamide 19 g, n = 4; (S) -2- [(2,3-dihydroxy-benzoyl) amino] -heptane-1,7-di-acid diamide 19h, n = 4 or (R) -2 - [(2,3-dihydroxybenzoyl) amino] butane-1,4-dinitrile 20a, n = 1; (S) -2 - [(2,3- Dihydroxy-benzoyl) amino] -butane-1,4-dinitrile 20b. n = 1; (R) -2 - [(2,3- Dihydroxy-benzoyl) amino] pentane-1,5-dinitrile 20c. n = 2; (<S) -2 - [(2,3- Dihydroxy-benzoyl) amino] -pentane-1,5-dinitrile 20d, n = 2; (R) -2 - [(2,3- Dihydroxy-benzoyl) amino] -hexane-1,6-dinitrile 20e, n = 3; (S) -2 - [(2,3- Dihydroxy-benzoyl) amino] -hexane-1,6-dinitrile 20f, n = 3; (R) -2 - [(2,3- Dihydroxy-benzoyl) amino] -heptane-l, 7-dinitrile 20g. n = 4; (<S) -2 - [(2,3-Dihydroxy-benzoyl) amino] -heptane-l, 7-dinitrile 20h. n = 4 or (R) -1,4-diamino-2 - [(2,3-dihydroxy-benzoyl) amino] butane 21a, n = 1; (<S) -1,4-diamino-2 - [(2,3-dihydroxy-benzoyl) amino] butane 21b, n = 1; (R) -1,5-diamino-2 - [(2,3-dihydroxy-benzo-yl) amino] pentane 21c, n = 2; (5) -1,5-diamino-2 - [(2,3-dihydroxybenzoyl) amino] pentane 21d. n = 2; (R) -l, 6-diamino-2 - [(2,3-dihydroxy-benzoyl) amino] hexane 21e, n = 3; (S) -l, 6-diamino-2 - [(2,3-dihydroxy-benzoyl) amino] hexane 21f. n = 3; (R) -l, 7-diamino-2 - [(2,3-dihydroxy-benzoyl) amino] -heptane 21g, n = 4; (S) -l, 7-diamino-2 - [(2,3-dihydroxy-benzoyl) amino] -heptane 21h. n = 4. 9. Compounds according to claim 6 with Y = benzyl as in (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -butane-1,4-disacid dimethyl ester 10a (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -butane-1, 4-diacid dimethyl ester 10b (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] pentane 1,5-disacid dimethyl ester 10c (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] pentane 1,5-disacid dimethyl ester lOd (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] hexane 1,6-disacid dimethyl ester lOe (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] - hexane-1,6-diacid dimethyl ester 10F (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane-1,7-di-acid dimethyl ester 10 g (S) -2 - [(2,3-dibenzyloxy-benzoyl ) amino] -heptane-l, 7-diacid dimethyl ester 10 h (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -butane 1,4-diacid 11a (S) -2 - [(2,3- Dibenzyloxy-benzoyl) amino] -butane-1,4-diacid 11b (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -pentane-1,5-diacid 11c (S) -2 - [( 2,3-dibenzyloxy-benzoyl) amino] -pentane-1,5-diacid lld (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -hexane-1,6-diacid (S) - 2 - [(2,3-dibenzyloxy-benzoyl) amino] hexane 1,6-diacid llf ( R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane-1,7-diacid 11g (<S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane-1, 7-diacid 11h (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] butane-1,4-diol 12a (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] - butane-1,4-diol 12b (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] pentane-1,5-diol 12c (S) -2 - [(2,3-dibenzyloxy-benzoyl ) amino] -pentane-1,5-diol 12d (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -hexane-1,6-diol 12e (S) -2- [(2,3 -Dibenzyloxy-benzoyl) amino] -hexane-1,6-diol 12f (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane-1,7-diol 12g (S) -2- [ (2,3-dibenzyloxy-benzoyl) amino] -heptane-1,7-diol 12h (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -butane-1,4-diacid diamide 13a (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] butane-1,4-diacid diamide 13b (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -pentane-1,5-diacid diamide 13c (S) -2 - [(2,3-dibenzyloxybenzoyl) amino] pentane 1,5-diacid diamide 13d (R) -2 - [(2,3-dibenzyloxybenzoyl) amino] hexane 1 , 6-diacid diamide 13e (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] hexane 1, 6-diacid diamide 13f (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane 1, 7-diacid diamide 13g (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptan-l, 7-diacid diamide 13h (R) -2 - [(2,3-dibenzyloxy-benzoyl) amino] - butane-1,4-dinitrile 14a (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] butane-1,4-dinitrile 14b (R) -2 - [(2,3-dibenzyloxy-benzoyl ) amino] -pentane-1,5-dinitrile 14c (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -pentane-1,5-dinitrile 14d (R) -2 - [(2,3 -Dibenzyloxy-benzoyl) amino] -hexane-1,6-dinitrile 14e (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -hexane-1,6-dinitrile 14f (R) -2- [ (2,3-dibenzyloxy-benzoyl) amino] -heptane-1,7-dinitrile 14g (S) -2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane-1,7-dinitrile 14h (R) - 1,4-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] butane 15a (S) - 1,4-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] butane 15b (R) - 1,5-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] pentane 15c (S) - 1,5-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] pentane 15d (R) - 1, 6-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] hexane 15e (S) -l, 6-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] hexane 5f (R) - 1, 7 -Diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane 15g (S) - 1,7-diamino-2 - [(2,3-dibenzyloxy-benzoyl) amino] -heptane 15h 10. Blue iron complexes of the compounds according to one of claims 1 to 4 and 6 to 8, characterized in that the iron complexes have a UV / VIS absorption by λ ^ _ax . Have 570 nm. 11. A process for the preparation of the compounds according to any one of claims 1 to 9, wherein the ester dihydrochlorides of 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid, the amino acids ornithine and lysine or the diester hydrochloride of the amino acids aspartic acid and glutamic acid as well as the 2-amino-hexane-1,6-dioic acid and 2-amino-heptane-l, 7-dioic acid with coupling methods of the ^'organic chemistry, or specifically the peptide chemistry with protected 2,3- Dihydroxybenzoic acids are converted to the di- or monoamides - These are hydrolyzed to the carboxylic acids with sodium hydroxide solution, reduced to the alcohols using lithium aluminum hydride or amminolyzed to the carboxylic acid amides with gaseous ammonia - The carboxylic acid diamides can be dehydrated to the dinitriles with triphosgene and these in turn can be reduced to the diamines with sodium borohydride. 12. A compound according to claim 1, characterized in that Z is an active ingredient, in particular an antibiotic or a dye, in particular a fluorescent dye. 13. A compound according to claim 12, in which n = 3 or 4 and Z = 2-oxoazetidine-l-sulfonic acid or 7-chloro-4-nitrobenz-2-oxa-l, 3-diazole (NBD) or 2-N- Methylamino-benzoyl is like with (3S, 4S) -N ³ - {(R) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] pentanoyl} -3-amino] - 4-methyl-2-oxoazetidine-l -sulfonic acid 23e and (3S, 4S) -N ³ - {(5) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] -pentanoyl} -3-amino] -4τmethyl-2-oxoazetidine -l- sulfonic acid 23 f. (3S, 4S) -N ³ - {(R) -2,6-bis - [(2,3-dihydroxy-benzoyl) amino] hexanoyl} -3-amino] - 4-methyl-2-oxoazetidine-l -sulfonic acid 23g and (3S, 4S) -N ³ - {(S) -2,6-bis - [(2,3- dihydroxy-benzoyl) amino] -hexanoyl} -3-amino] -4-methyl-2-oxoazetidine-1-sulfonic acid 23h. (R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] -l - [(2-N-methylbenzoyl) amino] hexane 25g (S) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] -l - [(2-N-methyl-benzoyl) amino] - hexane 25h (R) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] - 1 - [7- (4-nitrobenz-2-oxy-1,3-diazolyl) amino] hexane 26g (S) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] -1- [7- (4-nitrobenz-2-oxy-1,3-diazolyl) amino] hexane 26h 14. Compounds according to claim 12 with Y = benzoyl as ^(3ιS, 4S) -N ³ - {(R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] pentanoyl} -3- amino] -4-methyl-2-oxoazetidin- l -sulfonic acid 22e, the (3S, 4S) -N ³ - {(S) -2,6-bis- [(2,3-dibenzyloxy-benzo-yl) amino] -pentanoyl} -3-amino] -4 -methyl-2-oxoazetidine-1 -sulfonic acid 22f, (3S, 4S) -N ³ - {(R) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] -hexanoyl} -3- amino] -4-methyl-2-oxoazetidine-1 -sulfonic acid 22g or (3S, 4S) -N ³ - {(S) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] - hexanoyl} -3-amino] -4-methyl-2-oxoazetidine-l -sulfonic acid 22h. (R) -2,6-bis - [(2,3-dibenzyloxybenzoyl) amino] - 1 - [(2-N-methyl-benzoyl) amino] -hexane 24g, (S) - 2,6-bis- [ (2,3-Dibenzyloxybenzoyl) amino] - 1 - [(2-N-methyl-benzoyl) amino] - hexane 24h. 15. A process for the preparation of the compound according to any one of claims 12 to 14, which by synthesis from the (3S, 4S) -3-amino-4-methyl-2-oxoazetidine-l-sulfonic acid and the (R) -2, 5-bis - [(2,3-dibenzyloxy-benzoyl) amino] pentanoic acid 3e. (S) -2,5-bis - [(2,3-dibenzyloxy-benzoyl) amino] pentanoic acid 3f, (R) -2,6-bis- [(2,3-dibenzyloxy-benzoyl) amino] hexanoic acid 3g and (S) -2,6-bis - [(2,3-dibenzyloxy-benzoyl) amino] hexanoic acid 3h or by reacting (R) -2,6-bis- [(2,3-dibenzyloxybenzoyl) amino] -l -amino-hexane or (S) -2,6-bis - [(2,3-dibenzyloxybenzoyl) amino] -l - amino-hexane can be prepared with N-methylanthranilic acid and, if appropriate, the benzyl-protected compounds are then reacted by hydrogenolysis on the catalyst to give the conjugates according to one of claims 12 to 14 or, in the case of conjugates 26g and 26h, by direct reaction of the (R) 2,6-bis - [(2,3-dihydroxybenzoyl) amino] -l-amino-hexane or (S) -2,6-bis - [(2,3-dihydroxybenzoyl) amino] - 1-amino-hexane with NBD-Cl. 16. Medicaments containing, in addition to conventional pharmaceutical auxiliaries and / or carriers, an effective amount of at least one of the compounds according to Claims 1 to 10 and / or 12 to 14. 17. Use of a compound according to at least one of claims 1 to 9 and / or 12 to 14 for the manufacture of a medicament for the treatment of diseases which are correlated with defective metal ion metabolism, in particular iron or aluminum metabolism, or for the discharge of metal ions, in particular iron or Aluminum ions, from body fluid and / or for the treatment of bacterial, viral, fungicidal and / or parasitic infections (eg malaria) and for the treatment of tumors. 18. A method for complexing metal ions, in particular iron ions, by adding a solution containing metal ions to a compound as claimed in at least one of claims 1 to 9. 19. Use of a compound according to at least one of claims 1 to 9 for complexing, characterizing and / or removing metals from the solutions containing the corresponding metal ions. 20. Use according to claim 19, wherein the metal ions are radioactive metal ions. 21. A method for the analysis of bacteria, in particular pathogenic enterobacteria and mycobacteria, wherein the samples contaminated with bacteria are incubated in an iron deficiency medium and by adding a compound having the general formula (A) R = COOH, COOR ¹ , CH ₂ -OH, C (= 0) NR ² R ³ , CN, CH ₂ NR ² R ³ , C (= 0) -Z, CH ₂ -Z or a substituent according to formula CR ⁴ = COOH, COOR ¹ , CH ₂ -OH, C (= 0) NR ² R ³ CN, CH ₂ NR ² R ³ , or a Substituent according to formula DR ¹ = C _x H _{2x + 1} with x = 1,2,3,4,5, -CH ₂ -C ₆ H ₅ or -C ₆ H ₅ ; R ² , R ³ = independently of one another H, C _x H _{2x + 1} with x = 1,2,3, 4,5, -CH ₂ - C ₆ H ₅ , -C ₆ H ₅ Y = independently of one another benzoyl, formyl, acetyl, trifluoroacetyl, Glycosyl or silyl; Z = an organic group bonded via a 0, N, S and n = 1, 2, 3, 4 or 5 and the absolute configuration at C * can be both S and R, selectively growing only the bacteria that can accept these compounds.