[go: up one dir, main page]

WO1999042435A2 - Myxochelines - Google Patents

Myxochelines Download PDF

Info

Publication number
WO1999042435A2
WO1999042435A2 PCT/EP1999/001131 EP9901131W WO9942435A2 WO 1999042435 A2 WO1999042435 A2 WO 1999042435A2 EP 9901131 W EP9901131 W EP 9901131W WO 9942435 A2 WO9942435 A2 WO 9942435A2
Authority
WO
WIPO (PCT)
Prior art keywords
amino
benzoyl
bis
dibenzyloxy
dihydroxy
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
Application number
PCT/EP1999/001131
Other languages
German (de)
English (en)
Other versions
WO1999042435A3 (fr
Inventor
Horst-Dieter Ambrosi
Kai Uwe Bindseil
Gerhard Jas
Lutz MÜLLER-KUHRT
Rolf Reissbrodt
Wolfram Trowitzsch-Kienast
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Analyticon AG Biotechnologie Pharmazie
Original Assignee
Analyticon AG Biotechnologie Pharmazie
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DE19807475A external-priority patent/DE19807475A1/de
Application filed by Analyticon AG Biotechnologie Pharmazie filed Critical Analyticon AG Biotechnologie Pharmazie
Priority to AU32536/99A priority Critical patent/AU3253699A/en
Publication of WO1999042435A2 publication Critical patent/WO1999042435A2/fr
Publication of WO1999042435A3 publication Critical patent/WO1999042435A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/547—Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent
    • 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
    • C07C235/52—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 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/12—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • C12Q1/04—Determining presence or kind of microorganism; Use of selective media for testing antibiotics or bacteriocides; Compositions containing a chemical indicator therefor
    • C12Q1/045—Culture media therefor

Definitions

  • 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 object of the present invention is to provide further siderophores.
  • the present invention relates to compounds of the general formula A.
  • C 6 H 5 Y independently of one another benzoyl, formyl, acetyl, trifluoroacetyl,
  • salts of the compounds especially alkali, alkaline earth or ammonium salts,
  • 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:
  • 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 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.
  • the following compounds are suitable as intermediate compounds, the protective group Y being in particular benzyl:
  • 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 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.
  • 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 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.
  • 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.
  • 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.
  • R can be a fluorescent marker bound via an N, O or S atom.
  • 7-chloro-4-nitrobenz-2-oxa-l, 3-diazole (NBD-Cl) or N-methylanthranilic acid (NMA) can be used as fluorescence markers.
  • 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 22
  • 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.
  • 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.
  • 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.
  • the sulfonic acid can be in the form of its alkali, alkaline earth or ammonium salts.
  • 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.
  • 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.
  • 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 ⁇ g to 100 g per day.
  • 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.
  • 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 absolute configuration at C * can be both S and R can be used to analyze bacteria.
  • the presence of pathogenic enterobacteria and / or tuberculosis-causing mycobacteria can be quickly analyzed.
  • samples contaminated with pathogenic enterobacteria and / or mycobacteria are incubated in an iron deficiency medium.
  • the representation is made from 5g analogously to the regulation for the synthesis of 6g.
  • the yield of 9g is 95%.
  • 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.
  • 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 ).
  • 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.
  • Salmonella stanleyville 36
  • Salmonella typhimurium enb-7 32
  • Salmonella typhimurium CL1509 aroA 38
  • Salmonella typhimurium AJB64 38
  • Morganella morganii SBK 3 355
  • 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.
  • CDMH Chemicaly defined medium - yeast extract
  • EDDHA ethylenediamine dihydroxyphenylacetic acid
  • 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 ⁇ M and 1.1 ⁇ M below that of myxochelin B R (1.8 ⁇ M - 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 ⁇ M) and 8h
  • the conjugates 23g and 23h showed an extremely selective effect in the antibiotic test (platelet test with 10 ⁇ l concentration 1 mg conjugate / 1 ml methanol).
  • platelet test with 10 ⁇ l concentration 1 mg conjugate / 1 ml methanol.
  • Pseudomonas aeruginosa ATCC 9027 21 or 18 mm - MIC values: 15.7 or 30.6 ⁇ g / ml
  • Proteus vulgaris 28 or 27 mm - MIC values: 505 or 980 ⁇ g / ml

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Zoology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Toxicology (AREA)
  • Microbiology (AREA)
  • Analytical Chemistry (AREA)
  • Biophysics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biotechnology (AREA)
  • Immunology (AREA)
  • Physics & Mathematics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un composé de formule générale (A) où R = COH, COOR1, CH2-OH, C(=O)NR2R3, CN, CH¿2NR?2R3, C(=O)-Z, CH¿2?-Z ou bien un substituant selon la formule (C), R?4¿ = COOH, COOR1, CH2-OH, C(=O)NR2R3CN, CH¿2NR?2R3, ou bien un substituant selon la formule (D), R1 = CxH2x+1 avec x = 1,2,3,4,5, -CH2-C6H5 ou bien -C6H5, R2, R3 = indépendamment l'un de l'autre H, C¿x?H2x+1 avec x = 1,2,3,4,5, -CH2-C6H5, -C6H5, Y = benzoyle, formyle, acétyle, trifluoracétyle, glycosyle ou silyle; Z = un groupe organique lié par l'intermédiaire d'un O, N, S, et n = 1,2,3,4, ou bien 5, et la configuration absolue au niveau de C* peut être aussi bien S que R, ainsi que les sels des composés, notamment des sels alcalins, alcalino-terreux, ou bien des sels d'ammonium. R n'est pas CH2NH2 ou CN si n = 3 ou 4 et R?4¿ = formule (D) avec Y = H, et R ne répond pas à la formule (C) avec Y = H si n = 2,3,4,5 et R4 = formule (D) avec Y = H, et R n'est pas CH¿2?-OH ou COOH si R?4¿ = formule (D) avec Y = H et n = 4 et la configuration absolue au niveau de C* est S.
PCT/EP1999/001131 1998-02-21 1999-02-22 Myxochelines Ceased WO1999042435A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU32536/99A AU3253699A (en) 1998-02-21 1999-02-22 Myxochelines

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19807360 1998-02-21
DE19807360.7 1998-02-21
DE19807475.0 1998-02-24
DE19807475A DE19807475A1 (de) 1998-02-24 1998-02-24 Myxocheline

Publications (2)

Publication Number Publication Date
WO1999042435A2 true WO1999042435A2 (fr) 1999-08-26
WO1999042435A3 WO1999042435A3 (fr) 1999-12-16

Family

ID=26044049

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/001131 Ceased WO1999042435A2 (fr) 1998-02-21 1999-02-22 Myxochelines

Country Status (2)

Country Link
AU (1) AU3253699A (fr)
WO (1) WO1999042435A2 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002070545A3 (fr) * 2001-03-01 2003-01-03 Gruenenthal Gmbh 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
US7169776B2 (en) * 2000-03-21 2007-01-30 Emisphere Technologies, Inc. Method of preparing alkylated salicylamides via a dicarboxylate intermediate
WO2008009655A3 (fr) * 2006-07-17 2008-05-29 Univ Muenster Wilhelms Utilisation médicale de dérivés d'acides n-phénylpropénoyl-aminés et de composés apparentés
JP2009215268A (ja) * 2008-03-12 2009-09-24 Shiseido Co Ltd グルタミン酸誘導体、不全角化抑制剤、毛穴縮小剤、肌荒れ防止・改善剤及び皮膚外用組成物
US20100137194A1 (en) * 2007-04-16 2010-06-03 The Regents Of The University Of Michigan Plasminogen Activator Inhibitor-1 Inhibitors and Methods of Use Thereof to Modulate Lipid Metabolism
US8410150B2 (en) 2007-03-09 2013-04-02 University Health Network Inhibitors of carnitine palmitoyltransferase and treating cancer
US8680282B2 (en) 2007-08-01 2014-03-25 University Health Network Cyclic inhibitors of carnitine palmitoyltransferase and treating cancer
US9718760B2 (en) 2012-10-31 2017-08-01 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 inhibitors and methods of use thereof
US11426368B2 (en) 2017-07-27 2022-08-30 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 (PAI-1) inhibitor and method of use
WO2023281063A1 (fr) * 2021-07-08 2023-01-12 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Médicaments antiviraux à large spectre

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
DE19654920A1 (de) * 1996-06-26 1998-01-08 Gruenenthal Gmbh Neue synthetische Catecholderivate, Verfahren zu ihrer Herstellung und ihre Verwendung

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7169776B2 (en) * 2000-03-21 2007-01-30 Emisphere Technologies, Inc. Method of preparing alkylated salicylamides via a dicarboxylate intermediate
WO2002070545A3 (fr) * 2001-03-01 2003-01-03 Gruenenthal Gmbh 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
WO2008009655A3 (fr) * 2006-07-17 2008-05-29 Univ Muenster Wilhelms Utilisation médicale de dérivés d'acides n-phénylpropénoyl-aminés et de composés apparentés
US8410150B2 (en) 2007-03-09 2013-04-02 University Health Network Inhibitors of carnitine palmitoyltransferase and treating cancer
US9527878B2 (en) 2007-04-16 2016-12-27 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 inhibitors and methods of use thereof to modulate lipid metabolism
US20100137194A1 (en) * 2007-04-16 2010-06-03 The Regents Of The University Of Michigan Plasminogen Activator Inhibitor-1 Inhibitors and Methods of Use Thereof to Modulate Lipid Metabolism
US9120744B2 (en) * 2007-04-16 2015-09-01 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 inhibitors and methods of use thereof to modulate lipid metabolism
US8680282B2 (en) 2007-08-01 2014-03-25 University Health Network Cyclic inhibitors of carnitine palmitoyltransferase and treating cancer
JP2009215268A (ja) * 2008-03-12 2009-09-24 Shiseido Co Ltd グルタミン酸誘導体、不全角化抑制剤、毛穴縮小剤、肌荒れ防止・改善剤及び皮膚外用組成物
US9718760B2 (en) 2012-10-31 2017-08-01 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 inhibitors and methods of use thereof
US11426368B2 (en) 2017-07-27 2022-08-30 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 (PAI-1) inhibitor and method of use
US12390427B2 (en) 2017-07-27 2025-08-19 Eastern Michigan University Plasminogen activator inhibitor-1 (PAI-1) inhibitor and method of use
WO2023281063A1 (fr) * 2021-07-08 2023-01-12 Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. Médicaments antiviraux à large spectre

Also Published As

Publication number Publication date
AU3253699A (en) 1999-09-06
WO1999042435A3 (fr) 1999-12-16

Similar Documents

Publication Publication Date Title
DE69426629T2 (de) Therapeutische verbindung - fettsäurekonjugate
DE69618600T2 (de) Colchicine derivate, deren verwendung und sie enthaltende formulierungen
AT393680B (de) Verfahren zur herstellung neuer n-(4-(3aminopropyl)-aminobutyl)-2-(w-guanidinofetts|ureamido)-2-substituierter ethanamide und ihrer salze
DE69832987T2 (de) Spingosinanaloga
DE2440956C3 (de) Kanamycin B-Derivate, Verfahren zu ihrer Herstellung und solche Derivate enthaltende Arzneimittel
EP0708640B1 (fr) Preparations pharmaceutiques avec un principe actif contenant des groupes amidine modifies
DD143902A5 (de) Verfahren zur herstellung von aminderivaten von glyzerin und propandiolen
WO1999042435A2 (fr) Myxochelines
DE69533267T2 (de) Colchicin-derivate sowie ihre therapeutische Verwendung
DE68909362T2 (de) (2R,3S,4S)-Alpha-(carboxycyclopropyl)glycin.
DE69516403T2 (de) Photodynamische konjugate mit biozide eigenschaften
DE69218222T2 (de) Neue ganglioside-derivaten
DE69812679T2 (de) Lipophile diester von komplexbildnern
DE19930177B4 (de) Intermolekular assoziierende Verbindungen und deren Verwendung
DE19507820A1 (de) Neuartig substituierte DTPA-Derivate, deren Metallkomplexe, diese Komplexe enthaltende pharmazeutische Mittel, deren Verwendung in der Diagnostik, sowie Verfahren zur Herstellung der Komplexe und Mittel
EP0413006A1 (fr) Derives d'acide carboxylique d'hydroxyalkane et leur emploi.
WO1997049669A1 (fr) Composes pouvant former des complexes avec des metaux
DE102017010898A1 (de) Neue Inhibitoren des Shikimisäurewegs
AT502145A1 (de) Glycosidase-hemmendes iminoalditol
EP0863139B1 (fr) Dérivés de benzoxazine, leur procédé de préparation et leur application
DE60000590T2 (de) Nitroimidazolderivate als Empfindlichkeitsverstärker für Chemotherapie und Radiotherapie
DE69031448T2 (de) Halbsynthetische Gangliosidanaloge
DE69318046T2 (de) Antikrebsbenzaldehydverbindungen
DE2641388B2 (de) 3',4'-Didesoxykanamycin B-N-methansulfonsäuren und deren Alkalimetallsalze sowie diese Verbindungen enthaltende pharmazeutische Präparate
DE69702158T2 (de) Carnitine-Bisalkanoylester mit bakterizider, fungizider und antiprotozoischer Wirkung

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AL AU BA BB BG BR CA CN CU CZ DE EE GD GE HR HU ID IL IN IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AL AU BA BB BG BR CA CN CU CZ DE EE GD GE HR HU ID IL IN IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

122 Ep: pct application non-entry in european phase