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WO2002070545A2 - Analogues de siderophores en tant que chelateurs du fer a 4 ou 6 dents, a base d'acides amines ou de peptides, procedes de production et utilisations associes - Google Patents

Analogues de siderophores en tant que chelateurs du fer a 4 ou 6 dents, a base d'acides amines ou de peptides, procedes de production et utilisations associes Download PDF

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Publication number
WO2002070545A2
WO2002070545A2 PCT/EP2002/002073 EP0202073W WO02070545A2 WO 2002070545 A2 WO2002070545 A2 WO 2002070545A2 EP 0202073 W EP0202073 W EP 0202073W WO 02070545 A2 WO02070545 A2 WO 02070545A2
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WO
WIPO (PCT)
Prior art keywords
formula
compounds
alkyl
coch
bis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2002/002073
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German (de)
English (en)
Other versions
WO2002070545A3 (fr
Inventor
Steffen Wittmann
Lothar Heinisch
Ina Scherlitz-Hofmann
Ute Möllmann
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Gruenenthal GmbH
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Gruenenthal GmbH
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Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Priority to AU2002251026A priority Critical patent/AU2002251026A1/en
Publication of WO2002070545A2 publication Critical patent/WO2002070545A2/fr
Publication of WO2002070545A3 publication Critical patent/WO2002070545A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to new siderophore analogs derived from amino acids or peptides.
  • the compounds represent 4- or 6-toothed iron chelators or their derivatives masked with acyl groups, at least 4 chelating groups being formed from catechol units.
  • the compounds are effective as siderophores in Gram-negative bacteria and mycobacteria, ie they can supply bacteria with iron ions. The effects on mycobacteria for which no synthetic siderophores are known are of particular importance.
  • conjugates with active ingredients for example with antibiotics (as "siderophore-antibiotic conjugates"
  • they can be introduced into the bacterial cell via iron transport routes and thus improve or expand their effectiveness more than previous compounds of this type.
  • N- (2,3-dihydroxybenzoyl) glycine has been found as a siderophore in B. subtilis (Ito.T., Neilands, JB, J.Amer.Chem Soc. 80 (1958), 4645).
  • Some catechol-substituted amino acid derivatives have already been prepared synthetically, e.g. N- (2,3-dihydroxybenzoyl) -L-threonine (Kanai, F .; Kaneko, T., Morishima, H., Isshiki, K., Takita, T., Takeuchi, T., Umezawa, H. , J. Antibiot.
  • siderophores as iron chelators are potentially able to influence the biological iron metabolism and related diseases in various ways.
  • the siderophore desferrioxamine B (desferral) is successfully used in diseases based on iron overload (eg thalassemia).
  • Other effects of siderophores or siderophor analogues are also such as the anti-tumor activity of an analog of mycobactin (Tsunakawa M., Li-Ping Chang, Mamber SW, Bursuker I, Hugill R .; US Patent 5811440, 1998).
  • the invention serves to find new siderophore analogs derived from amino acids or peptides and to their use. These compounds represent 4- and 6-toothed iron chelators or their derivatives masked with acyl groups, at least 4 chelating groups being formed by catechol units.
  • the aim of the invention is to find new compounds which act as siderophores in Gram-negative bacteria and mycobacteria and which outperform the compounds of this type described hitherto in their siderophore activity or are also effective for the first time as siderophores in mycobacteria.
  • suitable compounds for introducing active substances, e.g. of antibiotics, via bacterial iron transport pathways into the bacterial cell that exceed the compounds of this type described so far.
  • these compounds are intended to find new precursors or prodrug forms for iron chelators which can influence the biological iron metabolism and related diseases in various ways.
  • the aim of acylated catechol compounds or the incorporation of the catechol structure into the heterocyclic benzoxazinedione structure is to give the compounds improved pharmacological properties or to serve as pharmacological forms of transport for the catechol compounds which actually promote penetration.
  • the invention has for its object to find new siderophore analogs as 4- and 6-toothed iron chelators or their acylated derivatives, derived from amino acids or peptides, of the general formula I, which can act as siderophores in bacteria.
  • R 6 H, alkyl, hydroxyalkyl, alkyloxyalkyl, acyloxyalkyl, carboxy,
  • R 7 H, alkyl, alkyl, alkyloxycarbonylalkyl
  • R 5 H, CO in combination with R 10
  • R 2 H, COalkyl, COOAlkyl
  • R 5 H or R 5 together with one of the radicals R 2 or R 10 represents a group -CO-
  • R 3 H, COAlkyl, COOAlkyl
  • R 4 H, alkyl, substituted alkyl, aryl, substituted aryl, halogen, alkoxy, substituted alkoxy, in all possible positions, also occurring several times,
  • asymmetric carbon atoms are present, the corresponding D and L forms, enantiomers and diastereomers and the racemates or mixtures of enantiomers and diastereomers are likewise the subject of the invention.
  • the compounds mentioned can be present as free acids, in the form of their salts or as easily cleavable esters which can be cleaved under physiological conditions.
  • 2,3-dihydroxybenzoic acid for example 2,3-diacyloxybenzoyl chloride
  • the compounds of formula I with a carboxyl group can be present as free acids, in the form of their salts or as easily cleavable esters, in particular cleavable under physiological conditions.
  • the compounds can be further purified by customary methods known from the prior art, for example by recrystallization or by means of chromatographic methods.
  • the compounds of the formula I according to the invention show siderophore activity in various Gram-negative bacterial strains and also in mycobacteria. As a result, these compounds can be used as growth factors for certain bacterial cultures.
  • the test for siderophore effectiveness was carried out with various bacterial strains which showed very little growth under the test conditions in the case of iron deficiency.
  • the following test strains were used: Pseudomonas aeruginosa ATCC 27853, SG 137, NCTC 10662, ATCC 9027 and Escherichia coli ATCC 25922.
  • the mutant enb7 from Salmonella typhimurium was used for the test, which is described in the Biosynthesis of the siderophore enterobactin is blocked and its iron supply is disturbed.
  • the test was carried out in an agar diffusion test, whereby growth promotion means that the test substances enable the iron supply of the bacteria and are therefore effective as siderophores.
  • the growth promotion was evaluated as the diameter of the growth zones in mm.
  • Desferal was used for the pseudomonas, for the E. coli strain ferricrocin and for the mutant enb7 enterobactin.
  • the test substances were applied in an amount of 5 ⁇ g / test leaflet in each case.
  • the growth promotion of mycobacteria was also examined under iron deficiency.
  • the following indicator strains were used: The wild strains M. smegmatis SG 987 and mc 2 155 and their mutants M10 (exochelin-) and M24 (mycobactin) obtained by chemical mutagenesis, as well as the genetically generated mutants of M. smegmatis mc 2 155 B1 ( Biosynthesis of exochelin), B3 (biosynthesis of exochelin and mycobactin) and U3 (recording system for exochelin) (Schumann G., Möllmann U., Heinemann I .; DE 19817021 A1). The results are shown in Table 2, the natural siderophore mycobactin served as a control for all test strains.
  • the compounds are effective as siderophores in most strains of mycobacteria, usually better than the mycobactin used as a control. It should be emphasized that several compounds also promote bacterial growth in the two mutants B3 (exochelin, mycobactin) and U3 (uptake system for exochelin). Examples
  • the cloudy solution formed after one hour was filtered and the tetrahydrofuran was largely distilled off in vacuo.
  • the aqueous solution was cooled to 0 ° C, reacted with hydrochloric acid to about pH 2 ', and extracted with 40 ml of ethyl acetate three times.
  • the organic phase was washed three times with aqueous sodium chloride solution, dried with sodium sulfate and evaporated.
  • the title compound was obtained in 50% yield in the form of a colorless solid foam.
  • the preparation was carried out analogously to Example 2 from N, N'-bis (2,3-diacetoxybenzoyl) -L-ornithine and O-benzyl-D-serine, the title compound in 30% yield in the form of a colorless solid foam was obtained 1 H NMR (DMSO-d6):.
  • Step 1
  • Step 2 N-N'.N "-bis ( ' 2.3-diacetoxybenzoyl ' ) -D-ornithyll-L- ⁇ lutamic acid-3- (N-hvdroxy-N-decvQ-amide
  • Step 1
  • Example 15 The preparation was carried out analogously to Example 15 by hydrogenation of the product from stage 1, the title compound being obtained in 90% yield in the form of a solid foam.
  • Step 1
  • Example 15 The preparation was carried out analogously to Example 15 by hydrogenation of the product from stage 1, the title compound being obtained in 90% yield in the form of a solid foam.
  • Step 1
  • Example 15 The preparation was carried out analogously to Example 15 by hydrogenation of the product from stage 1, the title compound being obtained in 70% yield in the form of a solid foam.
  • Example 15 The preparation was carried out analogously to Example 15 by hydrogenation of the product from Example 19, the title compound being obtained in 90% yield in the form of a solid foam.
  • Step 1
  • Stage 1 the title compound being obtained in 90% yield in the form of a colorless, solid foam.
  • Step 1 L-glutamic acid-1-benzyl ester-5- (N'-benzoyloxy-N'-cvclohexyl) amide
  • stage 3 The title compound was prepared by catalytic hydrogenolysis of the product from stage 1 analogously to example 15, stage 2. stage 3:
  • N N-bis- (2,3-diacetoxybenzoyl) -D-omithin
  • 0.112 ml of N-methylmorpholine 10 ml of anhydrous tetrahydrofuran
  • N 2 -r N'-benzoyloxy-N'-methyl-amido-qlutarov ⁇ -N 6 - (NN -bis-2,3-diacetoxybenzov ⁇ -L-lysyll-L-lysine
  • N-BenzovIoxy-N-cylohexyl-glutaric acid monoamide The title compound was prepared analogously to Example 24 from glutaric anhydride and N-cyclohexyl-O-benzoylhydroxylamine (see Example 19). Level 2: N 2 - (N'-Benzoyl-N'-cvclohexyl-amidoglutaroyl) -L-lvsin
  • the title compound was prepared analogously to Example 24 from N 2 - [4- (N'-benzoyloxy-N'-cyclohexyl-amidoyl) -n-butanoyl] -N ⁇ -ZL-lysine and N 2 , N 6 -Bis- ( 2,3-di-acetoxybenzoyl) -D-omithin in a 50% yield in the form of a colorless solid foam.
  • Step 1
  • N 6 -L-Lvsyl-N 2 - (aminocaprovO-L-lvsin) To a solution of 0.265 g (1 mmol) ⁇ -Z-aminocaproic acid and 0.112 ml of N-methylmorpholine in 10 ml of anhydrous tetrahydrofuran were at -20 ° C with stirring 0.130 ml (1 mmol) of butyl chloroformate were added, the mixture was stirred for 45 minutes at -10 ° C.
  • the aqueous solution obtained was cooled to 0 ° C., brought to about pH 2 with hydrochloric acid and extracted three times with in each case 30 ml of ethyl acetate.
  • the organic phase was washed three times with aqueous sodium chloride solution, dried over sodium sulfate and evaporated. After drying in a high vacuum, the product was taken up in 10 ml of acetonitrile and triethylamine was added dropwise until the mixture had reached pH 8. Then the mixture was stirred at 20 ° C. for one hour. In order to maintain the pH 8, triethylamine was optionally added.
  • Table 1 Growth promotion of the compounds according to the invention in Gram-negative bacterial strains under iron deficiency (growth zones in mm)
  • Table 2 Growth promotion of the compounds according to the invention in mycobacteria (growth zones in mm)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux analogues de sidérophores en tant que chélateurs du fer à 4 ou 6 dents et leurs dérivés acylés à base d'acides aminés ou de peptides de formule générale (I). Les composés selon l'invention sont actifs comme sidérophores sur les mycobactéries et sur les souches bactériennes Gram négatif, notamment les pseudomonades et les souches E.coli et Salmonella. Ils peuvent servir de véhicules pour introduire des agents actifs, par ex. des antibiotiques (en tant que 'conjugués antibiotiques-sidérophores '), dans des cellules bactériennes, dont ils améliorent et élargissent l'efficacité antibactérienne et surmontent les résistances. En outre, les composés susmentionnés sont des promédicaments potentiels pour chélateurs du fer, pouvant être utilisés en cas de maladies associées à des troubles du métabolisme du fer. Formule (I), où R1 = OH ou une deuxième molécule d'acide aminé ou différents groupes substituants contenant du catéchol ou de l'hydroxamate en tant qu'autres groupes chélate, R2 = H, acyle ou -CO- en liaison avec R5, R3 = H ou acyle, R4 = H, halogène ou différents groupes substituants contenant C ou O, R5 = H ou -CO- en liaison avec R2, les liaisons comme acides libres se présentant sous forme de leurs sels ou de leurs esters facilement fissibles.
PCT/EP2002/002073 2001-03-01 2002-02-27 Analogues de siderophores en tant que chelateurs du fer a 4 ou 6 dents, a base d'acides amines ou de peptides, procedes de production et utilisations associes Ceased WO2002070545A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002251026A AU2002251026A1 (en) 2001-03-01 2002-02-27 Siderophore analogues as tetra- or hexadentate iron chelators on the basis of amino acids or peptides, method for producing them and the use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10111161A DE10111161A1 (de) 2001-03-01 2001-03-01 Neue Siderophoranaloga als 4- oder 6-zähnige Eisenchelatoren auf der Basis von Aminosäuren oder Peptiden, Verfahren zu ihrer Herstellung und ihre Anwendung
DE10111161.4 2001-03-01

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WO2002070545A2 true WO2002070545A2 (fr) 2002-09-12
WO2002070545A3 WO2002070545A3 (fr) 2003-01-03

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008151288A3 (fr) * 2007-06-05 2009-09-24 Xenon Pharmaceuticals Inc. Composés aromatiques et hétéroaromatiques utiles dans le traitement de troubles du métabolisme du fer
JP2015166329A (ja) * 2014-03-04 2015-09-24 公益財団法人微生物化学研究会 新規生物活性物質

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4447374A1 (de) * 1994-12-22 1996-06-27 Trowitzsch Kienast Wolfram Pro Myxochelin C und verwandte Verbindungen, neue Syntheseprodukte als Metalltransporteure und als chemo-therapeutische Mittel
WO1999042435A2 (fr) * 1998-02-21 1999-08-26 Analyticon Ag Biotechnologie Pharmazie Myxochelines

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008151288A3 (fr) * 2007-06-05 2009-09-24 Xenon Pharmaceuticals Inc. Composés aromatiques et hétéroaromatiques utiles dans le traitement de troubles du métabolisme du fer
JP2015166329A (ja) * 2014-03-04 2015-09-24 公益財団法人微生物化学研究会 新規生物活性物質

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AU2002251026A1 (en) 2002-09-19
DE10111161A1 (de) 2002-09-05
WO2002070545A3 (fr) 2003-01-03

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