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WO2005080549A2 - Trioxacarcine et son utilisation - Google Patents

Trioxacarcine et son utilisation Download PDF

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Publication number
WO2005080549A2
WO2005080549A2 PCT/EP2005/001696 EP2005001696W WO2005080549A2 WO 2005080549 A2 WO2005080549 A2 WO 2005080549A2 EP 2005001696 W EP2005001696 W EP 2005001696W WO 2005080549 A2 WO2005080549 A2 WO 2005080549A2
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WIPO (PCT)
Prior art keywords
alkyl
aryl
cycloalkyl
heteroaryl
heterocycloalkyl
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PCT/EP2005/001696
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German (de)
English (en)
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WO2005080549A3 (fr
Inventor
Oliver Kayser
Hartmut Laatsch
Rajendra Prasad Maskey
Friedrich Hansske
Iris GRÜN-WOLLNY
Elisabeth Helmke
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Biofrontera Discovery Gmbh
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Publication of WO2005080549A2 publication Critical patent/WO2005080549A2/fr
Publication of WO2005080549A3 publication Critical patent/WO2005080549A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/44—Preparation of O-glycosides, e.g. glucosides
    • C12P19/60—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin
    • C12P19/62—Preparation of O-glycosides, e.g. glucosides having an oxygen of the saccharide radical directly bound to a non-saccharide heterocyclic ring or a condensed ring system containing a non-saccharide heterocyclic ring, e.g. coumermycin, novobiocin the hetero ring having eight or more ring members and only oxygen as ring hetero atoms, e.g. erythromycin, spiramycin, nystatin
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
    • C12R2001/465—Streptomyces
    • 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 invention relates to the use of trioxacarcines as agents for the treatment of infectious diseases caused by fungi, parasites, viruses and bacteria and new ones
  • Trioxacarcine derivatives as such, furthermore medicaments containing these or their salts and furthermore their use for the treatment of tumors and inflammatory diseases or for the treatment of infectious diseases caused by fungi, parasites, viruses and bacteria.
  • Trioxacarcins are natural products and can be isolated from Streptomycetes.
  • trioxacarcins such as trioxacarcin A, B and C are known (J. Antibiotics 1981 34 (12) 1519). Anti-tumor activity against murine tumors has been described (Fujimoto, K., Mori oto, M. Antitumor activity of trioxacarcin C. J Antibiot 36: 9, 1216-21. 1983 and Tamaoki, T., Shirahata, K., Iida , T. Tomita, F. Trioxacarcins, novel antitumor antibiotics. II. Isolation, physico-chemical properties and mode of action. J Antibiot 34: 12, 1525-30. 1981).
  • trioxacarcins and their derivatives are potent medicaments for the treatment and prophylaxis of infectious diseases caused by fungi, parasites, viruses and bacteria.
  • new trioxacarcins are made available which, in addition to their suitability for the treatment and prophylaxis of infectious diseases caused by fungi, parasites, viruses and bacteria, are also suitable for treatment and prophylaxis of tumors and inflammatory diseases.
  • the invention therefore relates to the use of trioxacarcines of the general formula I for the manufacture of medicaments for the treatment and prophylaxis of infectious diseases caused by fungi, parasites, viruses and bacteria,
  • R1 C 1 -C 4 -alkyl, cycloalkyl, C 1 -C 4 -alkyl-cycloalkyl, heterocycloalkyl, C _.- C4-alkyl heterocycloalkyl, C 2 -C ⁇ _- alkenyl, aryl, C 1 -C 4 -alkyl-aryl, Heteroaryl, -CC 4 alkyl heteroaryl, C (O) -C ⁇ - 4 alkyl, C (0) cycloalkyl, C (0) -C ⁇ - C 4 alkyl cycloalkyl, C (0) heterocycloalkyl , C (0) -C ⁇ -C 4 - alkyl heterocycloalkyl, C (0) -C 2 -C ⁇ 4 alkenyl, C (0) aryl, C (0) -C ⁇ -C 4 alkyl aryl, C (0) heteroaryl, C (0) -C 1 -C 4 alkyl alky
  • R3 H -CC 4 -alkyl, cycloalkyl, -CC 4 -alkyl-cycloalkyl, heterocycloalkyl, -C-C4-alkyl heterocycloalkyl, C 2 -C 4 -alkenyl, aryl, C 1 -C 4 -alkyl-aryl, Heteroaryl, C _.- C -alkyl- heteroaryl, C (0) -C ⁇ -C ⁇ 4 -alkyl, C (0) -cycloalkyl, C (0) -C_- C-alkyl-cycloalkyl, C (0) -hetreocycloalkyl, C (0) -C ⁇ -C 4 - alkyl heterocycloalkyl, C (0) -C 2 -C ⁇ 4 alkenyl, C (0) aryl, C (0) -C ⁇ -C 4 alkyl aryl, C ( 0) heteroaryl, C (0) -C
  • R4 H C (0) H, C (0) -C ⁇ -Ci4-alkyl, C (0) -cycloalkyl, C (0) -C ⁇ -C 4 - alkyl-cycloalkyl, C (0) -hereocycloalkyl, C ( 0) -C ⁇ -C 4 - alkyl heterocycloalkyl, C (0) -C 2 -C ⁇ 4 alkenyl, C (0) aryl, C (0) -C ⁇ -C 4 alkyl aryl, C (0) Heteroaryl, C (0) -C 4 -alkyl alkyl heteroaryl,
  • R5 is H, C ⁇ -C 4 alkyl, cycloalkyl, C ⁇ -C4 alkyl-cycloalkyl, Hetreocycloalkyl, C ⁇ -C4-alkyl-heterocycloalkyl, C 2 -C ⁇ 4 - alkenyl, aryl, C ⁇ -C-alkyl-aryl, Heteroaryl, C_-C 4 alkyl heteroaryl, C (0) -C ⁇ -C ⁇ 4 alkyl, C (0) cycloalkyl, C (0) -C !
  • alkylheteroaryl where R11, R12 and R13 independently of one another and independently of Rl assume one of the meanings of Rl, and X2 independently of XI assume one of the meanings of XI,
  • R6 OH, 0 -CC 4 alkyl, O-cycloalkyl, 0 -C 4 alkyl cycloalkyl, O-heterocycloalkyl, 0 -C 4 alkyl heterocycloalkyl, 0-C 2 -Ci4 alkenyl , O-aryl, 0-C_-C 4 -alkyl-aryl, O-heteroaryl, 0-C ⁇ -C 4 -alkyl heteroaryl, 0- C (0) -C ⁇ -Ci4-alkyl, 0-C (0) -Cycloalkyl, 0-C (0) -C _.- C 4 -alkyl-cycloalkyl, 0-C (0) -hetreocycloalkyl, 0-C (0) -Ci-C-alkyl-heterocycloalkyl, OC (0) - C 2 -C 4 alkenyl, 0-C (0) aryl, 0-C
  • R7 0H, O-Ci-C-alkyl, 0-cycloalkyl, 0-C _.- C 4 -alkyl-cycloalkyl, O-heterocycloalkyl, 0-C ⁇ -C 4 -alkyl heterocycloalkyl, 0-C 2 -C ⁇ 4 - Alkenyl, 0-aryl, 0-C ⁇ -C 4 -alkyl-aryl, O-heteroaryl, 0-C ⁇ -C 4 -alkyl heteroaryl, 0- C (0) -C ⁇ -Ci4-alkyl, 0-C (0 ) -Cycloalkyl, 0-C (0) -C ⁇ -C 4 -alkyl-cycloalkyl, 0-C (0) -hetreocycloalkyl, 0-C (0) -C x -C 4 -alkyl- heterocycloalkyl, 0-C ( 0) -C 2 -C ⁇ 4 al
  • R6 forms a 0 bridge together with R7 R8 OH, 0-C_ . -C ⁇ -alkyl, O-cycloalkyl, 0-C ⁇ -C 4 alkyl-cycloalkyl, O-heterocycloalkyl, 0-C _.- C 4 -alkyl- heterocycloalkyl, 0-C 2 -C ⁇ 4 -alkenyl, O-aryl, 0-C _.- C 4 -alkyl-aryl, O-heteroaryl, 0-C ⁇ -C 4 -alkyl heteroaryl, 0-C (O) -C ⁇ -Ci4-alkyl, 0-C (0) -cycloalkyl, 0 -C (O) -C ⁇ -C 4 alkyl cycloalkyl, 0-C (0) -Hetreocycloalkyl, OC (O) -C 1 -C 4 alkyl heterocycloalkyl, 0-C
  • R9 OH, 0-C ⁇ -Ci4-alkyl, O-cycloalkyl, 0-C x -C 4 -alkyl- cycloalkyl, O-heterocycloalkyl, 0-C_-C 4 -alkyl- heterocycloalkyl, 0-C 2 -C ⁇ 4 - Alkenyl, O-aryl, 0-C_-C 4 -alkyl-aryl, O-heteroaryl, 0-C ⁇ -C 4 -alkyl heteroaryl, 0- C (0) -C ⁇ -Ci4-alkyl, 0-C (0 ) -Cycloalkyl, 0-C (0) -C ⁇ -C 4 -alkyl-cycloalkyl, 0-C (0) -hetreocycloalkyl, 0-C (0) -C ⁇ -C 4 -alkyl-heterocycloalkyl, 0-C (0 ) -C 2 -C ⁇
  • R8 forms an O-bridge together with R9
  • R31, R32 independently of one another C _. -C 4 alkyl, C -C 4 alkanoyl, Ci-Ce alkylhydroxy, Ci-C ⁇ -alkylamino, Ci-C ⁇ - alkylamino -CC 6 -alkyl, C ⁇ -C6-alkylamino -di-C ⁇ -C6- alkyl, cycloalkyl, C _.- C 4 -alkyl-cycloalkyl, heterocycloalkyl, C1-C -alkyl-heterocycloalkyl, aryl, aryloyl, C ⁇ -C 4 -alkyl-aryl, heteroaryl, heteroaryloyl, C ⁇ - C 4 -alkyl heteroaryl, cycloalkanoyl, -C-C 4 -alkanoyl-cycloalkyl, heterocycloalkanoyl, -C-C 4 -alkanoyl-cyclo
  • R33 independently of R31, the same meanings as R31 or CH ⁇ pyridinium salts, CH ⁇ tri-Ci-C ⁇ - a1ky1am onmium salts,
  • the invention relates to new trioxacarcin derivatives of the general formula I, the radicals not being allowed to assume the following meanings simultaneously, namely with R 1 COCH 3, R 2 H, R 3 H, XI 0, R 4 H, R 8 and R 9 together a 0- Bridge, RIO H, and R5 means R6 and R7 must neither be OH or together represent an O bridge,
  • R5 means R6 and R7 must not be a 0 bridge.
  • Preferred stereoisomers are those of the following spatial structure Ia with the above meaning:
  • Particularly preferred stereoisomers are those whose configuration corresponds to that of natural trioxacarcin A.
  • Rl is preferably H or C (0) -C 1 -C 4 -alkyl, particularly preferably H or C (O) -C 1 -C 4 alkyl, in particular H or C (0) Me.
  • R5 is preferably H
  • R6 is preferably OH, or together with R7
  • O-bridge particularly preferably OH or the O-bridge, in particular the O-bridge.
  • R7 is preferably OH, or together with R6 an O bridge, in particular the O bridge.
  • R8 is preferably OH, or together with R9 an O bridge, in particular the O bridge.
  • R9 is preferably OH, or together with R8 an O bridge, in particular the O bridge.
  • RIO is preferably H.
  • the following compounds are particularly preferred as agents for the prophylaxis and treatment of infectious diseases caused by fungi, parasites, viruses and bacteria:
  • the invention also relates to medicaments containing the above new compounds of formula I in addition to the usual pharmaceutical carriers and auxiliaries and additives.
  • the above-mentioned medicinal products are also preferred in combination with further active substances for the treatment of tumors and inflammatory diseases.
  • All compounds according to the invention are used for the preparation of medicaments for the treatment and prophylaxis of infectious diseases caused by fungi, parasites, viruses and bacteria.
  • the compounds according to the invention are preferably active against single- or multicellular parasites, in particular against pathogens of malaria and sleeping sickness as well as Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, and sarcolocystosis , Akanthamöbose, Naeglerose, Coccidiosis, Giardiose and Lambliose and for the treatment of the resulting infectious diseases.
  • malaria prophylaxis and as prophylaxis of sleeping sickness and Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, the
  • the treatment and prophylaxis of malaria by a medicament according to the invention is preferred.
  • the active compounds according to the invention can be used in particular against the following bacteria:
  • Bacteria of the Propionibacteriaceae family in particular of the Propionibacterium genus, in particular the Propionibacterium acnes species; Bacteria of the family Actinomycetaceae, especially the genus Actinomyces; Bacteria of the genus Corynebacterium, in particular the species Corynebacterium diphteriae and Corynebacterium pseudotuberculosis; Bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, in particular the species Mycobacterium leprae; Mycobacterium tuberculosis.
  • Mycobacterium bovis and Mycobacterium avium Bacteria of the Chlamydiaceae family, in particular the species Chlamydia trachomatis and Chlamydia psittaci; Bacteria of the genus Listeria, in particular the species Listeria monocytogenes;
  • the compounds according to the invention are therefore suitable for the treatment of diphtheria, acne vulgaris, listeriosis, erysipelas in animals, gas burns in humans and animals, para-burns in humans and animals, tuberculosis in humans and animals, leprosy and other mycobacteriosis in humans and animals , paratuberculosis of animals, plague, mesenteric lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease, Lyme disease in humans and animals, leptospirosis in humans and animals, syphilis, Campylobacter enteritis in humans and animals, Moraxella
  • Keratoconjunctivitis and serositis of animals Keratoconjunctivitis and serositis of animals, brucellosis of animals and humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis / ornithosis in animals, Q fever, Ehrlichiosis.
  • the use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
  • the compounds are also effective for the treatment and prophylaxis of fungal diseases, such as mycoses caused by dermatophytes, yeasts, molds (so-called DHS system according to Rieth).
  • the invention therefore also relates to an antimycotic.
  • Combinations of the compounds according to the invention with a further antibiotic can also be used for the treatment of the abovementioned diseases.
  • the active compounds according to the invention can also be used in particular for infections with the following viruses: Parvoviridae: Parvoviruses, Dependoviruses, Densoviruses; Adenoviridae: adenoviruses, mastadenoviruses, aviadenoviruses; Papovaviridae: papovaviruses, in particular papillomaviruses (so-called wart viruses), polyomaviruses, in particular JC virus, BK virus, and miopapovavirus; Herpesviridae: All
  • Herpes viruses in particular herpes simplex viruses, the varicella / zoster viruses, human cytomegalovirus, Epstein-Barr viruses, all human herpes viruses, human herpes virus 6, human herpes virus 7, human herpes virus 8; Poxviridae: smallpox viruses, Orthopox, Parapox, Molluscum Contagiosum virus, Aviviruses, Capriviruses, Leporipoxviruses; all primarily hepatotropic viruses, hepatitis viruses: hepatitis AV viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses, hepatitis E viruses, hepatitis F viruses, hepatitis G viruses; Hepadnaviruses: all hepatitis viruses, hepatitis B
  • the compounds according to the invention are therefore suitable for the treatment of the following viral infections:
  • the new compounds are also suitable for the treatment and prophylaxis of tumors and
  • Inflammatory diseases especially those selected from the group “neoplastic tumors, inflammatory diseases, autoimmune diseases, degenerative joint diseases, diseases of the rheumatic type with cartilage breakdown, chronic polyarthritis, joint trauma, immobilization-related cartilage loss, septic shock, diseases with disturbed leukocyte adhesion, TNF
  • the invention relates to the deposited Streptomyces DSM 16185.
  • the microorganism was deposited on January 23, 2004 in accordance with the Budapest Treaty with the DSMZ (i.e. German Collection of Microorganisms and Cell Cultures GmbH, Mascheroder Weg lb, 38124 Braunschweig, Germany).
  • the invention also relates to 'a method of preparing the above mentioned compounds, wherein the compounds either directly from Streptomyces, in particular from the 1. deposited Streptomyces DSM 16185, can be isolated or are semisynthetically accessible from such compounds and known trioxacarcines.
  • the following definitions apply to the individual substituents in the description and the claims:
  • alkyl by itself or as part of another substituent means a linear or branched alkyl chain radical of the length given in each case.
  • the alkyls can be substituted with up to 3 substituents , preferably up to 1 substituent, where the substituents can independently be OH, N0 2 , CN, CF 3 , OR5, SH, SR5, COOH, COOR5,
  • Alkylenes having 1 to 6 carbon atoms are preferred , in particular with 1 to 4 carbon atoms, for example C 2 -6-alkenyl means, for example, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl , 1, 3-butdienyl, 2,4-butdienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1,3-
  • Pentdienyl 2, 4-pentdienyl, 1, 4-pentdienyl, 1-hexenyl, 2- Hexenyl, 1, 3-hediexyl, 4-methyl-1-pentenyl or 3, 3-dimethyl-butenyl.
  • the alkenyls can be substituted with up to 3 substituents, preferably up to 1 substituent, the substituents independently of one another meaning OH, N0 2 , CN, CF 3 , OR5, SH, SR5, COOH, COOR5, NH 2 , NHR5, NR5R6 , Halogen, aryl, heteroaryl, heterocycloalkyl can have, where the radicals R5 and R6 independently of one another can mean C_-C ⁇ o-alkyl, cycloalkyl, C ⁇ -C 4 alkyl-cycloalkyl.
  • the alkenyls are preferably not substituted.
  • halogen stands for fluorine, chlorine, bromine, iodine, preferably bromine and chlorine.
  • cycloalkyl by itself or as part of another substituent includes unsaturated (single or multiple, preferably single) or saturated, cyclic hydrocarbon groups with 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, cyclohex-2-enyl, cyclohex-3-enyl, cyclohex-2, 4-dienyl, 4-methyl-cyclohexyl, 3-methylcyclohexyl, cycloheptyl or cyclooctyl. Saturated cycloalkyls are preferred.
  • the cycloalkyls can be substituted be with up to 3 substituents, preferably up to 1 substituent, the substituents independently of one another being Ci-C ⁇ -alkyl, OH, N0 2 , CN, CF 3 , OR5, SH, SR5, Ci-Ce-alkylhydroxy, C ⁇ - C 6 alkyl OR5, COOH, COOR5, NH 2 , NHR5, NR5R6, halogen, aryl, C 1 -C 4 alkylaryl, heteroaryl, Cl-C 4 heteroalkylaryl, where the radicals R5 and R6 independently of one another C_ -C ⁇ o-alkyl, cycloalkyl, C ⁇ -C 4 alkyl-cycloalkyl can mean.
  • heterocycloalkyl by itself or as part of another substituent includes cycloalkyl groups in which up to two CH 2 groups can be replaced by oxygen, sulfur or nitrogen atoms and one or two further CH 2 groups by one or two carbonyl functions ), Carbothionyl function (s) or a carbonyl function and a carbothionyl function can be replaced, for example pyrrolidine, piperidine, morpholine or
  • heterocycloalkyls can be substituted like the cycloalkyls.
  • aryl by itself or as part of another substituent includes aromatic ring systems with up to 3 rings, in which at least 1 ring system is aromatic and which are substituted with up to 3 substituents, preferably up to 1 substituent, the substituents being independent of one another the meaning Ci-Ce-alkyl, OH, N0 2 , CN, CF 3 , 0R5, SH, SR5, -C-C 5 -alkylhydroxy, -C-C 6 -alkyl-OR5, COOH, C00R5, NH 2 , NHR11, NR5R6 May have halogen, where the radicals R5 and R6 may independently of one another be C 1 -C 8 -alkyl, cycloalkyl, C 1 -C 4 -alkyl-cycloalkyl, are substituted.
  • aryl and 1-naphthyl and 2-naphthyl preferred aryls are:
  • heteroaryl by itself or as part of another substituent includes aromatic ring systems with up to 3 rings, and up to 3 identical or different heteroatoms N, S, 0, in which at least 1 ring system is aromatic and those with up to 3 substituents , preferably up to 1 substituents are substituted, the substituents independently of one another being Ci-C ⁇ -alkyl, OH, N0 2 , CN, CF 3 , OR5, SH, SR6, C ⁇ -C 6 -alkylhydroxy, C ⁇ -C 6 - Alkyl-OR5, COOH, COOR5, NH 2 , NHR5, NR5R6, halogen can have, where the radicals R5, R6 can independently of one another have the meanings given above.
  • Preferred heteroaryls are:
  • ring system generally refers to 3, 4, 5, 6, 7, 8, 9 or 10-membered rings. 5 and 6-membered rings are preferred. In addition, ring systems with one or 2 fused rings are preferred.
  • the compounds of the formulas I and Subfor eln can be present as such or, if they have acidic or basic groups, in the form of their salts with physiologically compatible bases or acids.
  • acids are: hydrochloric acid, citric acid, trifluoroacetic acid,
  • bases are alkali ions, preferably Na, K, alkaline earth ions, preferably Ca, Mg, ammonium ions.
  • the compounds of the invention can be administered orally in a conventional manner.
  • the application can also be done i.V., i.m., with vapors or sprays through the nasopharynx.
  • the dosage depends on the age, condition and weight of the patient as well as the type of application.
  • the daily dose of active ingredient per person is between about 0.1 ⁇ g / kg, in particular 1 mg / kg and 1 g / kg when administered orally. This dose can be given in 2 to 4 single doses or once a day, especially as a slow-release form.
  • the new compounds can be used in the customary pharmaceutical application forms in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, dragees, solutions or sprays. These are manufactured in the usual way.
  • the active ingredients can be combined with the usual pharmaceutical auxiliaries such as tablet binders, fillers, preservatives, tablet disintegrants, Flow regulators, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retardants, antioxidants and / or propellants are processed (see H. Sucker et al .: Pharmaceutical Technology, Thieme-Verlag, Stuttgart, 1978).
  • the application forms thus obtained normally contain the active ingredient in an amount of 0.1 to 99% by weight.
  • the compounds of the formulas I can be prepared fully synthetically by known methods. They are easier to access
  • Compound 1 can be isolated using the following method.
  • the marine strain Streptomyces sp. B8652 or DSM 16185 was fermented under standard conditions and extracted with ethyl acetate.
  • the crude extract (16g) was purified by flash chromatography on silica gel with a gradient of CHCl 3 / MeOH (1300 ml CHC1 3, 1000ml CHCl 3 / l% MeOH, 1000 ml CHCl 3/2% MeOH, 1000mlCHCl 3/3% MeOH, 500mlCHCl 3/5 % MeOH, 500ml CHCl 3 /7% MeOH, 400ml CHCl 3 /10% MeOH, 300ml CHCl 3 / MeOH 13%, 300ml CHCl 3 /20% MeOH and 200ml MeOH).
  • Fraction I contained only fat and was not examined further.
  • Fractions III - V were highly active in the agar diffusion test against Staphylococcus a ureus, Escherichia colx, Bacillus subtil ⁇ s and Streptomyces viridochromogenes (Tu 57).
  • Further purification on Sephadex LH-20 (4x100cm, CHCl 3 /40% MeOH and preparative layer chromatography (PTLC, silica gel, CHCl 3 /7% MeOH) as well as further separation on Sephadex gave mainly trioxacarcin A (257mg ) as a yellow solid.
  • the antiplasmodic activity of Ha, Ilb and Ild was determined using the NF54 strain P. falciparum of unknown origin. This strain was first isolated at Amsterdam Airport. The Kl strain from Thailand served as the second test strain. NF54 shows normal sensitivity to all known antileishmania drugs. The strain, however, is resistant to chloroquine and pyri ⁇ 'iethamin.
  • a modified [ 3 H] hypoxanthine incorporation assay was used to determine intra-erythrocytic inhibition of parasite growth.
  • P. falciparum infected human red blood cells in the hypoxanthine-poor culture medium were incorporated with various medication dilutions in microtiter plates for 48 h at 37 ° C. in a 4% moist CO 2 atmosphere. Parasite growth was determined after the addition of [H] -hypoxanthine. The ICso value was interpolated between the two drug concentrations.

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Abstract

L'invention concerne l'utilisation de trioxacarcines afin de traiter des maladies infectieuses provoquées par des champignons, des parasites, des virus ou des bactéries, ainsi que de nouveaux dérivés de trioxacarcine, des médicaments contenant ces trioxacarcines ou leurs sels et l'utilisation de celles-ci afin de traiter des tumeurs, des maladies inflammatoires ou des maladies infectieuses provoquées par des champignons, des parasites, des virus ou des bactéries.
PCT/EP2005/001696 2004-02-21 2005-02-18 Trioxacarcine et son utilisation WO2005080549A2 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7781577B2 (en) 2006-09-29 2010-08-24 Lexicon Pharmaceuticals, Inc. Inhibitors of sodium glucose co-transporter 2 and methods of their use
US7846945B2 (en) 2007-03-08 2010-12-07 Lexicon Pharmaceuticals, Inc. Piperdine-based inhibitors of sodium glucose co-transporter 2 and methods of their use
WO2011119549A1 (fr) * 2010-03-22 2011-09-29 President And Fellows Of Harvard College Trioxacarcines et utilisations de celles-ci
US9775915B2 (en) 2012-11-26 2017-10-03 President And Fellows Of Harvard College Trioxacarcins, trioxacarcin-antibody conjugates, and uses thereof
WO2019036537A1 (fr) * 2017-08-17 2019-02-21 William Marsh Rice University Analogues et dimères de trioxacarcine en tant qu'agents anticancéreux puissants

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EP0071428A1 (fr) * 1981-07-22 1983-02-09 Kyowa Hakko Kogyo Kabushiki Kaisha Dérivés à activité antibiotique pouvant être obtenus à partir d'une culture de Streptomyces bottropensis
US4511560A (en) * 1979-10-26 1985-04-16 Kyowa Hakko Kogyo Kabushiki Kaisha Antibiotic substances DC-45, and their use as medicaments

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EP0157203A3 (fr) * 1984-04-04 1986-10-01 American Cyanamid Company Agents antitumoraux LL-D49194 alpha 1, LL-D49194 bêta 1, LL-D49194 bêta 2, LL-D49194 bêta 3, LL-D49194 gamma, LL-D49194 delta, LL-D49194 epsilon, LL-D49194 dzéta, LL-D49194 êta LL-D499194 oméga 1, LL-D49194 oméga 2 et LL-D49194 oméga 3

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US4511560A (en) * 1979-10-26 1985-04-16 Kyowa Hakko Kogyo Kabushiki Kaisha Antibiotic substances DC-45, and their use as medicaments
EP0071428A1 (fr) * 1981-07-22 1983-02-09 Kyowa Hakko Kogyo Kabushiki Kaisha Dérivés à activité antibiotique pouvant être obtenus à partir d'une culture de Streptomyces bottropensis

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FUJIMOTO, KAZUHISA ET AL: "Antitumor activity of trioxacarcin C" JOURNAL OF ANTIBIOTICS , 36(9), 1216-21 CODEN: JANTAJ; ISSN: 0021-8820, 1983, XP008048950 *
MASKEY, RAJENDRA P. ET AL: "Anti-cancer and antibacterial trioxacarcins with high anti-malaria activity from a marine Streptomycete and their absolute stereochemistry" JOURNAL OF ANTIBIOTICS , 57(12), 771-779 CODEN: JANTAJ; ISSN: 0021-8820, 2004, XP008048955 *
TAMAOKI, TATSUYA ET AL: "Trioxacarcins, novel antitumor antibiotics. II. Isolation, physicochemical properties and mode of action" JOURNAL OF ANTIBIOTICS , 34(12), 1525-30 CODEN: JANTAJ; ISSN: 0021-8820, 1981, XP008048951 *
TOMITA, FUSAO ET AL: "Trioxacarcins, novel antitumor antibiotics. I. Producing organism, fermentation and biological activities" JOURNAL OF ANTIBIOTICS , 34(12), 1519-24 CODEN: JANTAJ; ISSN: 0021-8820, 1981, XP008048954 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7781577B2 (en) 2006-09-29 2010-08-24 Lexicon Pharmaceuticals, Inc. Inhibitors of sodium glucose co-transporter 2 and methods of their use
US8476413B2 (en) 2006-09-29 2013-07-02 Lexicon Pharmaceuticals, Inc. Sulfanyl-tetrahydropyran-based compounds and methods of their use
US7846945B2 (en) 2007-03-08 2010-12-07 Lexicon Pharmaceuticals, Inc. Piperdine-based inhibitors of sodium glucose co-transporter 2 and methods of their use
WO2011119549A1 (fr) * 2010-03-22 2011-09-29 President And Fellows Of Harvard College Trioxacarcines et utilisations de celles-ci
US9102697B2 (en) 2010-03-22 2015-08-11 President And Fellows Of Harvard College Trioxacarcins and uses thereof
US9611287B2 (en) 2010-03-22 2017-04-04 President And Fellows Of Harvard College Trioxacarcins and uses thereof
US9775915B2 (en) 2012-11-26 2017-10-03 President And Fellows Of Harvard College Trioxacarcins, trioxacarcin-antibody conjugates, and uses thereof
US20180221504A1 (en) * 2012-11-26 2018-08-09 President And Fellows Of Harvard College Trioxacarcins, trioxacarcin-antibody conjugates, and uses thereof
US10639381B2 (en) 2012-11-26 2020-05-05 President And Fellows Of Harvard College Trioxacarcins, trioxacarcin#antibody conjugates, and uses thereof
WO2019036537A1 (fr) * 2017-08-17 2019-02-21 William Marsh Rice University Analogues et dimères de trioxacarcine en tant qu'agents anticancéreux puissants

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