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WO2005080549A2 - Trioxacarcins and their use against infections - Google Patents

Trioxacarcins and their use against infections 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)
French (fr)
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WO2005080549A3 (en
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/en
Publication of WO2005080549A3 publication Critical patent/WO2005080549A3/en

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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

The invention relates to the use of trioxacarcins as agents for treating infections caused by fungi, parasites, viruses or bacteria. The invention also relates to the novel trioxacarcin derivatives as such, to drugs containing them or the salts thereof and to the use thereof in the treatment of tumors and inflammatory diseases or in the treatment of infections that are caused by fungi, parasites, viruses or bacteria.

Description

Titel : Trioxacarcine und deren Verwendung Title: Trioxacarcine and its use
Beschreibungdescription
Die Erfindung betrifft Verwendung von Trioxacarcinen als Mittel zur Behandlung von Infektionskrankheiten verursacht durch Pilze, Parasiten, Viren und Bakterien sowie neueThe 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-Derivate als solche, ferner Arzneimittel die diese oder deren Salze enthalten und ferner deren Verwendung zur Behandlung von Tumoren sowie Entzündungserkrankungen oder zur Behandlung von Infektionskrankheiten verursacht durch Pilze, Parasiten, Viren und Bakterien.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.
Trioxacarcine sind Naturstoffe und können aus Streptomyceten isoliert werden.Trioxacarcins are natural products and can be isolated from Streptomycetes.
Einige Trioxacarcine, wie Trioxacarcin A, B und C sind bekannt (J. Antibiotics 1981 34(12) 1519). Eine anti-Tumor Aktivität gegen murine Tumoren wurde beschrieben (Fujimoto, K., Mori oto, M. Antitumor activity of trioxacarcin C. J Antibiot 36: 9, 1216-21. 1983 und 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).Some 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).
Überraschenderweise wurde nunmehr gefunden, dass Trioxacarcine und deren Derivate potente Arzneimittel zur Behandlung und Prophylaxe von Infektionskrankheiten verursacht durch Pilze, Parasiten, Viren und Bakterien darstellen. Darüber hinaus werden neue Trioxacarcine bereit gestellt, die neben ihrer Eignung zur Behandlung und Prophylaxe von Infektionskrankheiten verursacht durch Pilze, Parasiten, Viren und Bakterien eine Eignung zur Behandlung und Prophylaxe von Tumoren sowie Entzündungserkrankungen aufweisen.Surprisingly, it has now been found that trioxacarcins and their derivatives are potent medicaments for the treatment and prophylaxis of infectious diseases caused by fungi, parasites, viruses and bacteria. In addition, 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.
Die Erfindung betrifft daher die Verwendung von Trioxacarcinen der allgemeinen Formel I zur Herstellung von Arzneimitteln für die Behandlung und Prophylaxe von Infektionskrankheiten verursacht durch Pilze, Parasiten, Viren und Bakterien,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,
Figure imgf000003_0001
Figure imgf000003_0001
wobei jeweilswhere each
Rl H, Cι-Ci4-Alkyl, Cycloalkyl, Cι-C4-Alkyl-Cycloalkyl, Hetreocycloalkyl, C_.-C4-Alkyl-Heterocycloalkyl, C2-Cι_- Alkenyl, Aryl, Cι-C4-Alkyl-Aryl, Heteroaryl, Cι-C4-Alkyl- Heteroaryl, C (O) -Cι-Cι4-Alkyl, C (0) -Cycloalkyl, C(0)-Cι- C4-Alkyl-Cycloalkyl, C (0) -Hetreocycloalkyl, C(0)-Cι-C4- Alkyl-Heterocycloalkyl, C (0) -C2-Cι4-Alkenyl, C(0)-Aryl, C(0) -Cι-C4-Alkyl-Aryl, C (0) -Heteroaryl, C (0) -Cι-C4-Alkyl- Alkylheteroaryl, R2 H, Cι-Ci4-Alkyl, Cycloalkyl, Cι-C4-Alkyl-Cycloalkyl, Hetreocycloalkyl, Cι-C4-Alkyl-Heterocycloalkyl, C2-Cι4- Alkenyl, Aryl, Cι-C4-Alkyl-Aryl, Heteroaryl, Cι-C4-Alkyl- Heteroaryl, C (O) -Cι-Cι4-Alkyl, C (0) -Cycloalkyl, C (0) -Cx- C -Alkyl-Cycloalkyl, C (0) -Hetreocycloalkyl, C (0) -C1-C4- Alkyl-Heterocycloalkyl, C (0) -C2-Cι4-Alkenyl, C(0)-Aryl, C(0)-Cι-C4-Alkyl-Aryl, C (0) -Heteroaryl, C (0) -Cι-C4-Alkyl- Alkylheteroaryl,R1, C 1 -C 4 -alkyl, cycloalkyl, C 1 -C 4 -alkyl-cycloalkyl, heterocycloalkyl, C _.- C4-alkyl heterocycloalkyl, C 2 -Cι_- alkenyl, aryl, C 1 -C 4 -alkyl-aryl, Heteroaryl, -CC 4 alkyl heteroaryl, C (O) -Cι- 4 alkyl, C (0) cycloalkyl, C (0) -Cι- C 4 alkyl cycloalkyl, C (0) heterocycloalkyl , C (0) -Cι-C 4 - alkyl heterocycloalkyl, C (0) -C 2 -Cι 4 alkenyl, C (0) aryl, C (0) -Cι-C 4 alkyl aryl, C (0) heteroaryl, C (0) -C 1 -C 4 alkyl alkyl heteroaryl, R2 is H, Cι-Ci4-alkyl, cycloalkyl, Cι-C4 alkyl-cycloalkyl, Hetreocycloalkyl, Cι-C4-alkyl-heterocycloalkyl, C 2 -Cι 4 - alkenyl, aryl, Cι-C4 alkyl-aryl, heteroaryl C 1 -C 4 alkyl heteroaryl, C (O) -C 4 C 4 alkyl, C (0) cycloalkyl, C (0) -C x -C alkyl cycloalkyl, C (0) heterocycloalkyl, C (0) -C1-C 4 -alkyl heterocycloalkyl, C (0) -C 2 -Cι 4 alkenyl, C (0) aryl, C (0) -Cι-C 4 alkyl aryl, C ( 0) heteroaryl, C (0) -C 4 -alkyl alkyl heteroaryl,
R3 H, Cι-Cι4-Alkyl, Cycloalkyl, Cι-C4-Alkyl-Cycloalkyl, Hetreocycloalkyl, Cι-C4-Alkyl-Heterocycloalkyl, C2-Cι4- Alkenyl, Aryl, Cι-C4-Alkyl-Aryl, Heteroaryl, C_.-C -Alkyl- Heteroaryl, C (0) -Cι-Cι4-Alkyl, C (0) -Cycloalkyl, C(0)-C_- C-Alkyl-Cycloalkyl, C (0) -Hetreocycloalkyl, C(0)-Cι-C4- Alkyl-Heterocycloalkyl, C (0) -C2-Cι4-Alkenyl, C(0)-Aryl, C(0) -Cι-C4-Alkyl-Aryl, C (0) -Heteroaryl, C (0) -C_.-C4-Alkyl- Alkylheteroaryl,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) -Cι-Cι 4 -alkyl, C (0) -cycloalkyl, C (0) -C_- C-alkyl-cycloalkyl, C (0) -hetreocycloalkyl, C (0) -Cι-C 4 - alkyl heterocycloalkyl, C (0) -C 2 -Cι 4 alkenyl, C (0) aryl, C (0) -Cι-C 4 alkyl aryl, C ( 0) heteroaryl, C (0) -C _.- C 4 alkyl alkyl heteroaryl,
R4 H, C(0)H, C(0)-Cι-Ci4-Alkyl, C (0) -Cycloalkyl, C(0)-Cι-C4- Alkyl-Cycloalkyl, C (0) -Hetreocycloalkyl, C(0)-Cχ-C4- Alkyl-Heterocycloalkyl, C (0) -C2-Cι4-Alkenyl, C(0)-Aryl, C(0)-Cι-C4-Alkyl-Aryl, C (0) -Heteroaryl, C (0) -Cι-C4-Alkyl- Alkylheteroaryl,R4 H, C (0) H, C (0) -Cι-Ci4-alkyl, C (0) -cycloalkyl, C (0) -Cι-C 4 - alkyl-cycloalkyl, C (0) -hereocycloalkyl, C ( 0) -Cχ-C 4 - alkyl heterocycloalkyl, C (0) -C 2 -Cι 4 alkenyl, C (0) aryl, C (0) -Cι-C 4 alkyl aryl, C (0) Heteroaryl, C (0) -C 4 -alkyl alkyl heteroaryl,
R5 H, Cι-Ci4-Alkyl, Cycloalkyl, Cι-C4-Alkyl-Cycloalkyl, Hetreocycloalkyl, Cι-C4-Alkyl-Heterocycloalkyl, C2-Cι4- Alkenyl, Aryl, Cι-C-Alkyl-Aryl, Heteroaryl, C_-C4-Alkyl- Heteroaryl, C (0) -Cι-Cι4-Alkyl, C (0) -Cycloalkyl, C(0)-C!- C4-Alkyl-Cycloalkyl, C (0) -Hetreocycloalkyl, C(0)-Cι-C4- Alkyl-Heterocycloalkyl, C (0) -C2-C_4-Alkenyl, C(0)-Aryl, C(0)-Cι-C4-Alkyl-Aryl, C (0) -Heteroaryl, C (0) -C_.-C4-Alkyl-R5 is H, Cι-C 4 alkyl, cycloalkyl, Cι-C4 alkyl-cycloalkyl, Hetreocycloalkyl, Cι-C4-alkyl-heterocycloalkyl, C 2 -Cι 4 - alkenyl, aryl, Cι-C-alkyl-aryl, Heteroaryl, C_-C 4 alkyl heteroaryl, C (0) -Cι-Cι 4 alkyl, C (0) cycloalkyl, C (0) -C ! - C 4 -alkyl-cycloalkyl, C (0) -hetreocycloalkyl, C (0) -Cι-C 4 - alkyl-heterocycloalkyl, C (0) -C 2 -C_4-alkenyl, C (0) -aryl, C (0) -Cι-C 4 alkyl aryl, C (0) heteroaryl, C (0) -C _.- C 4 alkyl-
Alkylheteroaryl,
Figure imgf000005_0001
wobei Rll, R12 und R13 unabhängig voneinander und unabhängig von Rl eine der Bedeutungen von Rl annimmt, und X2 unabhängig von XI eine der Bedeutungen von XI annimmt,alkylheteroaryl,
Figure imgf000005_0001
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-Cι-Cι4-Alkyl, O-Cycloalkyl, 0-Cι-C4-Alkyl- Cycloalkyl, O-Hetreocycloalkyl, 0-Cι-C4-Alkyl- Heterocycloalkyl, 0-C2-Ci4-Alkenyl, O-Aryl, 0-C_-C4- Alkyl-Aryl, O-Heteroaryl, 0-Cι-C4-Alkyl-Heteroaryl, 0- C(0) -Cι-Ci4-Alkyl, 0-C (0) -Cycloalkyl, 0-C (0) -C_.-C4-Alkyl- Cycloalkyl, 0-C (0) -Hetreocycloalkyl, 0-C (0) -Ci-C.-Alkyl- Heterocycloalkyl, O-C (0) -C2-Cι4-Alkenyl, 0-C (0) -Aryl, 0- C(0) -Cι-C4-Alkyl-Aryl, 0-C (0) -Heteroaryl, 0-C (0) -C_-C4- Alkyl-Alkylheteroaryl,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-Cι-C 4 -alkyl heteroaryl, 0- C (0) -Cι-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 (0) -C 4 -C 4 alkyl aryl, 0-C (0) heteroaryl, 0-C (0) -C_ -C 4 - alkyl-alkyl heteroaryl,
R7 0H, O-Ci-C -Alkyl, 0-Cycloalkyl, 0-C_.-C4-Alkyl- Cycloalkyl, O-Hetreocycloalkyl, 0-Cι-C4-Alkyl- Heterocycloalkyl, 0-C2-Cι4-Alkenyl, 0-Aryl, 0-Cι-C4- Älkyl-Aryl, O-Heteroaryl, 0-Cι-C4-Alkyl-Heteroaryl, 0- C(0)-Cι-Ci4-Alkyl, 0-C (0) -Cycloalkyl, 0-C (0) -Cι-C4-Alkyl- Cycloalkyl, 0-C (0) -Hetreocycloalkyl, 0-C (0) -Cx-C4-Alkyl- Heterocycloalkyl, 0-C (0) -C2-Cι4-Alkenyl, 0-C (0) -Aryl, 0- C(0)-Cι-C4-Alkyl-Aryl, 0-C (0) -Heteroaryl, 0-C (0) -C1-C4- Alkyl-Alkylheteroaryl,R7 0H, O-Ci-C-alkyl, 0-cycloalkyl, 0-C _.- C 4 -alkyl-cycloalkyl, O-heterocycloalkyl, 0-Cι-C 4 -alkyl heterocycloalkyl, 0-C 2 -Cι 4 - Alkenyl, 0-aryl, 0-Cι-C 4 -alkyl-aryl, O-heteroaryl, 0-Cι-C 4 -alkyl heteroaryl, 0- C (0) -Cι-Ci4-alkyl, 0-C (0 ) -Cycloalkyl, 0-C (0) -Cι-C 4 -alkyl-cycloalkyl, 0-C (0) -hetreocycloalkyl, 0-C (0) -C x -C 4 -alkyl- heterocycloalkyl, 0-C ( 0) -C 2 -Cι 4 alkenyl, 0-C (0) aryl, 0- C (0) -Cι-C 4 alkyl aryl, 0-C (0) heteroaryl, 0-C (0 ) C 1 C 4 - alkyl heteroaryl,
oder R6 zusammen mit R7 eine 0-Brücke bildet R8 OH, 0-C_.-Cι -Alkyl, O-Cycloalkyl, 0-Cι-C4-Alkyl- Cycloalkyl, O-Hetreocycloalkyl, 0-C_.-C4-Alkyl- Heterocycloalkyl, 0-C2-Cι4-Alkenyl, O-Aryl, 0-C_.-C4- Alkyl-Aryl, O-Heteroaryl, 0-Cι-C4-Alkyl-Heteroaryl, 0- C (O) -Cι-Ci4-Alkyl, 0-C (0) -Cycloalkyl, 0-C (O) -Cι-C4-Alkyl- Cycloalkyl, 0-C (0) -Hetreocycloalkyl, O-C(O) -C1-C4-Alkyl- Heterocycloalkyl, 0-C (0) -C2-Cι4-Alkenyl, 0-C (0) -Aryl, 0- C(0)-Cι-C4-Alkyl-Aryl, 0-C (0) -Heteroaryl, 0-C (0) -Cι-C4- Älkyl-Alkylheteroaryl,or R6 forms a 0 bridge together with R7 R8 OH, 0-C_ . -Cι -alkyl, O-cycloalkyl, 0-Cι-C 4 alkyl-cycloalkyl, O-heterocycloalkyl, 0-C _.- C 4 -alkyl- heterocycloalkyl, 0-C 2 -Cι 4 -alkenyl, O-aryl, 0-C _.- C 4 -alkyl-aryl, O-heteroaryl, 0-Cι-C 4 -alkyl heteroaryl, 0-C (O) -Cι-Ci4-alkyl, 0-C (0) -cycloalkyl, 0 -C (O) -Cι-C 4 alkyl cycloalkyl, 0-C (0) -Hetreocycloalkyl, OC (O) -C 1 -C 4 alkyl heterocycloalkyl, 0-C (0) -C 2 -Cι 4- alkenyl, 0-C (0) -aryl, 0- C (0) -Cι-C 4 -alkyl-aryl, 0-C (0) -heteroaryl, 0-C (0) -Cι-C 4 - Älkyl-alkylheteroaryl,
R9 OH, 0-Cι-Ci4-Alkyl, O-Cycloalkyl, 0-Cx-C4-Alkyl- Cycloalkyl, O-Hetreocycloalkyl, 0-C_-C4-Alkyl- Heterocycloalkyl, 0-C2-Cι4-Alkenyl, O-Aryl, 0-C_-C4- Alkyl-Aryl, O-Heteroaryl, 0-Cι-C4-Alkyl-Heteroaryl, 0- C(0)-Cι-Ci4-Alkyl, 0-C (0) -Cycloalkyl, 0-C (0) -Cι-C4-Alkyl- Cycloalkyl, 0-C (0) -Hetreocycloalkyl, 0-C (0) -Cι-C4-Alkyl- Heterocycloalkyl, 0-C (0) -C2-Cι4-Alkenyl, 0-C (0) -Aryl, 0- C(0)-Cι-C4-Alkyl-Aryl, 0-C (0) -Heteroaryl, 0-C (0) -C1-C4- Alkyl-Al ylheteroaryl,R9 OH, 0-Cι-Ci4-alkyl, O-cycloalkyl, 0-C x -C 4 -alkyl- cycloalkyl, O-heterocycloalkyl, 0-C_-C 4 -alkyl- heterocycloalkyl, 0-C 2 -Cι 4 - Alkenyl, O-aryl, 0-C_-C 4 -alkyl-aryl, O-heteroaryl, 0-Cι-C 4 -alkyl heteroaryl, 0- C (0) -Cι-Ci4-alkyl, 0-C (0 ) -Cycloalkyl, 0-C (0) -Cι-C 4 -alkyl-cycloalkyl, 0-C (0) -hetreocycloalkyl, 0-C (0) -Cι-C 4 -alkyl-heterocycloalkyl, 0-C (0 ) -C 2 -Cι 4 alkenyl, 0-C (0) aryl, 0- C (0) -Cι-C 4 alkyl aryl, 0-C (0) heteroaryl, 0-C (0) -C1-C4- alkyl-al ylheteroaryl,
oder R8 zusammen mit R9 eine O-Brücke bildetor R8 forms an O-bridge together with R9
RIO H, HalogenRIO H, halogen
I 0, NOH, N0R31 , N0C0R31 , NOCH2CONR31R32 , NOCH ( CH3 ) CONR31R32 , NOC ( CH3 ) 2CONR31R32 , N-NHCO-R33 , N- NHCO-CH2NHCOR31 , N-0-CH2NHCOR31 , N-NHCS-R33 , NR31 , N-I 0, NOH, N0R31, N0C0R31, NOCH 2 CONR31R32, NOCH (CH 3 ) CONR31R32, NOC (CH 3 ) 2 CONR31R32, N-NHCO-R33, N- NHCO-CH 2 NHCOR31, N-0-CH 2 NHCOR31, N-NHCS-R33, NR31, N-
NR31R32 ,
Figure imgf000006_0001
(mit X' = NR315 , 0 , S und R311, R312, R313, R314, R315 unabhängig voneinander H oder Ci-Cβ-Alkyl) , N-NHS02-Aryl, N-NHS02-Heteroaryl,NR31R32,
Figure imgf000006_0001
(with X '= NR315, 0, S and R311, R312, R313, R314, R315 independently of one another H or Ci-Cβ-alkyl), N-NHS0 2 -aryl, N-NHS0 2 -heteroaryl,
R31, R32 unabhängig voneinander C_.-Cι4-Alkyl, Cι-Cι4-Alkanoyl, Ci-Ce-Alkylhydroxy, Ci-Cδ-Alkylamino, Ci-Cε- Alkylamino-Cι-C6-Alkyl, Cι-C6-Alkylamino-di-Cι-C6- Alkyl, Cycloalkyl, C_.-C4-Alkyl-Cycloalkyl, Heterocycloalkyl, C1-C -Alkyl-Heterocycloalkyl, Aryl, Aryloyl, Cι-C4-Alkyl-Aryl, Heteroaryl, Heteroaryloyl, Cι-C4-Alkyl-Heteroaryl, Cycloalkanoyl, Cι-C4-Alkanoyl-Cycloalkyl, Heterocycloalkanoyl, Cι-C4-Alkanoyl- Heterocycloalkyl, C_-C4-Alkanoyl-Aryl, C1-C4- Alkanoyl-Heteroaryl, Mono- und Di-Zuckerreste, die verknüpft sind über ein C-Atom, das im Zucker eine OH-Gruppe tragen würde, wobei die Zucker unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus Glucuronsäure und ihren Stereoisomeren an allen optischen C-Atomen, Aldopentosen, Aldohexosen einschließlich ihren Desoxyverbidungen (wie z.B. Glucose, Desoxyglucose, Ribose, Desoxyribose) ,R31, R32 independently of one another C _. -C 4 alkyl, C -C 4 alkanoyl, Ci-Ce alkylhydroxy, Ci-Cδ-alkylamino, Ci-Cε- alkylamino -CC 6 -alkyl, Cι-C6-alkylamino -di-Cι-C6- alkyl, cycloalkyl, C _.- C 4 -alkyl-cycloalkyl, heterocycloalkyl, C1-C -alkyl-heterocycloalkyl, aryl, aryloyl, Cι-C 4 -alkyl-aryl, heteroaryl, heteroaryloyl, Cι- C 4 -alkyl heteroaryl, cycloalkanoyl, -C-C 4 -alkanoyl-cycloalkyl, heterocycloalkanoyl, -C-C 4 -alkanoyl-heterocycloalkyl, C_-C 4 -alkanoyl-aryl, C1-C 4 - alkanoyl-heteroaryl, mono- and Di-sugar residues which are linked via a C atom which would have an OH group in the sugar, the sugars being selected independently of one another from the group consisting of glucuronic acid and its stereoisomers on all optical C atoms, including aldopentoses and aldohexoses their deoxy compounds (such as glucose, deoxyglucose, ribose, deoxyribose),
R33 unabhängig von R31, dieselben Bedeutungen wie R31 oder CH∑pyridinium-salze, CH∑tri-Ci-Cβ- a1ky1am onmium-salze,R33 independently of R31, the same meanings as R31 or CH∑pyridinium salts, CH∑tri-Ci-Cβ- a1ky1am onmium salts,
bedeutet, deren Stereoisomere, Tautomere und deren physiologisch verträglichen Salze.means, their stereoisomers, tautomers and their physiologically tolerable salts.
Außerdem betrifft die Erfindung neue Trioxacarcin Derivate der allgemeinen Formel I, wobei die Reste folgende Bedeutungen nicht gleichzeitig annehmen dürfen, und zwar mit Rl COCH3, R2 H, R3 H, XI 0, R4 H, R8 und R9 zusammen eine 0- Brücke, RIO H, und R5 bedeutet
Figure imgf000008_0001
darf R6 und R7 weder jeweils OH sein oder zusammen eine O-Brücke darstellen,In addition, 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
Figure imgf000008_0001
R6 and R7 must neither be OH or together represent an O bridge,
und falls R5 bedeutet
Figure imgf000008_0002
darf R6 und R7 keine 0 Brücke sein.and if R5 means
Figure imgf000008_0002
R6 and R7 must not be a 0 bridge.
Bevorzugte Stereoisomere sind die, die der folgenden räumlichen Struktur Ia mit der obigen Restebedeutung:Preferred stereoisomers are those of the following spatial structure Ia with the above meaning:
Figure imgf000008_0003
Figure imgf000008_0003
Besonders bevorzugte Stereoisomerie sind solche, deren Konfiguration der von natürlichem Trioxacarcin A entsprichtParticularly preferred stereoisomers are those whose configuration corresponds to that of natural trioxacarcin A.
Die folgenden Ausführungen zu bevorzugten Verbindungen gelten für die Verbindungen als solche, als Arzneimittel und als Mittel zur Behandlung von Tumoren und Entzündungserkrankungen ausschließlich, falls Sie neu sind. Außerdem gilt die Bevorzugung für neue und bekannte Verbindungen bei der Verwendung als Mittel zur Behandlung und Prophylaxe von Infektionskrankheiten verursacht durch Pilze, Parasiten, Viren und Bakterien.The following comments on preferred compounds apply to the compounds as such, as medicaments and as Means to treat tumors and inflammatory diseases only if you are new. In addition, preference is given to new and known compounds when used as agents for the treatment and prophylaxis of infectious diseases caused by fungi, parasites, viruses and bacteria.
Bevorzugt sind daher die Verbindungen der Formel I, bei denen R2, R3, R4, Rll, R12 und R13 die gleiche Bedeutung annehmen, insbesondere alle gleich H sind.Preference is therefore given to the compounds of the formula I in which R2, R3, R4, R11, R12 and R13 have the same meaning, in particular all are H.
Außerdem bevorzugt sind Derivate bei denen XI und X2 die gleiche Bedeutung annehmen, insbesondere gleich 0 sind.Also preferred are derivatives in which XI and X2 have the same meaning, in particular are 0.
Rl ist bevorzugt H oder C (0) -Cι-Ci4-Alkyl, besonders bevorzugt H oder C (O) -Cι-C4-Alkyl, insbesondere H oder C(0)Me.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 ist bevorzugt H,
Figure imgf000009_0001
undR5 is preferably H,
Figure imgf000009_0001
and
R6 ist bevorzugt OH,
Figure imgf000009_0002
oder zusammen mit R7 eineR6 is preferably OH,
Figure imgf000009_0002
or together with R7
O-Brücke, besonders bevorzugt OH oder die O-Brücke, insbesondere die O-Brücke.O-bridge, particularly preferably OH or the O-bridge, in particular the O-bridge.
R7 ist bevorzugt OH, oder zusammen mit R6 eine O-Brücke, insbesondere die O-Brücke.R7 is preferably OH, or together with R6 an O bridge, in particular the O bridge.
R8 ist bevorzugt OH, oder zusammen mit R9 eine O-Brücke, insbesondere die O-Brücke. R9 ist bevorzugt OH, oder zusammen mit R8 eine O-Brücke, insbesondere die O-Brücke.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 ist bevorzugt H.RIO is preferably H.
Ganz besonders bevorzugt sind folgende neue Verbindungen:The following new compounds are very particularly preferred:
Figure imgf000010_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000011_0001
Als Mittel zur Prophylaxe und Behandlung von Infektionskrankheiten verursacht durch Pilze, Parasiten, Viren und Bakterien sind folgende Verbindungen ganz besonders bevorzugt : The following compounds are particularly preferred as agents for the prophylaxis and treatment of infectious diseases caused by fungi, parasites, viruses and bacteria:
Figure imgf000012_0001
Figure imgf000012_0001
und Ild, insbesondere Ha und Ild.and Ild, especially Ha and Ild.
Die Erfindung betrifft außerdem Arzneimittel enthaltend obige neue Verbindungen der Formel I neben den üblichen pharmazeutischen Trägern und Hilfs- und Zusatzstoffen. Bevorzugt sind auch die oben genannten Arzneimittel in Kombination mit weiteren Wirkstoffen zur Behandlung von Tumoren und Entzündungserkrankungen.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.
Alle erfindungsgemäßen Verbindungen (bekannte Verbindungen der Formel I und neue Verbindungen der Formel I) werden zur Herstellung von Arzneimitteln zur Behandlung und Prophylaxe von Infektionskrankheiten verursacht durch Pilze, Parasiten, Viren und Bakterien verwendet.All compounds according to the invention (known compounds of the formula I and new compounds of the formula I) are used for the preparation of medicaments for the treatment and prophylaxis of infectious diseases caused by fungi, parasites, viruses and bacteria.
Vorzugsweise sind die erfindungsgemäßen Verbindungen gegen ein- oder mehrzellige Parasiten wirksam, insbesondere gegen Erreger der Malaria und der Schlafkrankheit sowie der Chagas- Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmaniosen, der Trichomoniasis, der Pneumozystose, der Balantidiose, der Kryptosporidiose, der Sarkozystose, der Akanthamöbose, der Naeglerose, der Kokzidiose, der Giardiose und der Lambliose und zur Behandlung der resultierenden Infektionskrankheiten.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.
Ferner sind sie daher insbesondere als Malariaprophylaxe und als Prophylaxe der Schlafkrankheit sowie der Chagas- Krankheit, der Toxoplasmose, der Amöbenruhr, der Leishmaniosen, der Trichomoniasis, der Pneumozystose, der Balantidiose, der Kryptosporidiose, der Sarkozystose, derFurthermore, they are therefore in particular as malaria prophylaxis and as prophylaxis of sleeping sickness and Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, the
Akanthamöbose, der Naeglerose, der Kokzidiose, der Giardiose und der Lambliose geeignet.Akanthamöbose, Naeglerose, Coccidiosis, Giardiosis and Lambliosis suitable.
Die Behandlung und Prophylaxe von Malaria durch ein erfindungsgemäßes Arzneimittel ist bevorzugt.The treatment and prophylaxis of malaria by a medicament according to the invention is preferred.
Die erfindungsgemäßen Wirkstoffe sind insbesondere gegen die folgenden Bakterien einsetzbar:The active compounds according to the invention can be used in particular against the following bacteria:
Bakterien der Familie Propionibacteriaceae, insbesondere der Gattung Propionibacterium, insbesondere die Art Propionibacterium acnes; Bakterien der Familie Actinomycetaceae, insbesondere der Gattung Actinomyces; Bakterien der Gattung Corynebacterium, insbesondere die Arten Corynebacterium diphteriae und Corynebacterium pseudotuberculosis; Bakterien der Familie Mycobacteriaceae, der Gattung Mycobacterium, insbesondere die Arten Mycobacterium leprae; Mycobacterium tuberculosis . Mycobacterium bovis und Mycobacterium avium; Bakterien der Familie Chlamydiaceae, insbesondere die Spezies Chlamydia trachomatis und Chlamydia psittaci; Bakterien der Gattung Listeria, insbesondere die Art Listeria monocytogenes;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;
Bakterien der Art Erysipelthrix rhusiopathiae; Bakterien der Gattung Clostridilum; Bakterien der Gattung Yersinia, der Spezies Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica und Yersinia ruckeri Bakterien der Familie Mycoplasmataceae, der Gattungen Mycoplasma und Ureaplasma, insbesondere die Art Mycoplasma pneumoniae; Bakterien der Gattung Brucella; Bakterien der Gattung Bordetella; Bakterien der Familie Neiseriaceae, insbesondere der Gattungen Neisseria und Moraxella, insbesondere die Arten Neisseria meningitides, Neisseria gonorrhoeae und Moraxella bovis; Bakterien der Familie Vibrionaceae, insbesondere der Gattungen Vibrio, Aeromonas, Plesiomonas und Photobacterium, insbesondere die Arten Vibrio cholerae, Vibrio anguillarum und Aeromonas salmonicidas; Bakterien der Gattung Campylobacter, insbesondere die Arten Campylobacter jejuni, Campylobacter coli und Campylobacter fetus; Bakterien der Gattung Helicobacter, insbesondere die Art Helicobacter pylori; Bakterien der Familien Spirochaetaceae und der Leptospiraceae, insbesondere der Gattungen Treponema, Borrelia und Leptospira, insbesondere Borrelia burgdorferi; Bakterien der Gattung Actinobacillus; Bakterien der Familie Legionellaceae, der Gattung Legionella; Bakterien der Familie Rickettsiaceae und Familie Bartonellaceae; Bakterien der Gattungen Nocardia und Rhodococcus; Bakterien der Gattung Dernlatophilus; Bakterien der Familie Pseudomonadaceae, insbesondere der Gattungen Pseudomonas und Xanthomonas; Bakterien der Familie Enterobacteriaceae, insbesondere der Gattungen Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia und Shigella; Bakterien der Familie Pasteurellaceae, insbesondere der Gattung Haemophilus; Bakterien der Familie Micrococcaceae, insbesondere der Gattungen Micrococcus und Staphylococcus; Bakterien der Familie Streptococcaceae, insbesondere der Gattungen Streptococcus und Enterococcus und Bakterien der Familie Bacillaceae, insbesondere der Gattungen Bacillus und Clostridium.Bacteria of the species Erysipelthrix rhusiopathiae; Bacteria of the genus Clostridilum; Bacteria of the genus Yersinia, of the species Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri bacteria of the family Mycoplasmataceae, of the genera Mycoplasma and Ureaplasma, in particular the species Mycoplasma pneumoniae; Bacteria of the genus Brucella; Bacteria of the genus Bordetella; Bacteria of the family Neiseriaceae, in particular of the genera Neisseria and Moraxella, in particular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis; Bacteria of the Vibrionaceae family, in particular of the Vibrio, Aeromonas, Plesiomonas and Photobacterium genera, in particular the Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas species; Bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobacter fetus; Bacteria of the genus Helicobacter, in particular the species Helicobacter pylori; Bacteria of the Spirochaetaceae and Leptospiraceae families, in particular the Treponema, Borrelia and Leptospira genera, in particular Borrelia burgdorferi; Bacteria of the genus Actinobacillus; Bacteria of the family Legionellaceae, of the genus Legionella; Bacteria of the Rickettsiaceae family and Bartonellaceae family; Bacteria of the genera Nocardia and Rhodococcus; Bacteria of the genus Dernlatophilus; Bacteria of the family Pseudomonadaceae, especially of the genera Pseudomonas and Xanthomonas; Bacteria of the Enterobacteriaceae family, in particular of the genera Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella; Bacteria of the Pasteurellaceae family, especially of the genus Haemophilus; Bacteria of the Micrococcaceae family, in particular of the genera Micrococcus and Staphylococcus; Bacteria of the Streptococcaceae family, in particular of the genera Streptococcus and Enterococcus, and bacteria of the Bacillaceae family, in particular of the genera Bacillus and Clostridium.
Damit eignen sich die erfindungsgemäßen Verbindungen zur Behandlung der Diphterie, der Acne vulgaris, der Listeriosen, des Rotlaufs bei Tieren, der Gasbrand bei Mensch und Tier, Pararauschbrand bei Mensch und Tier, Tuberkulose bei Mensch und Tier, Lepra und weitere Mykobacteriosen bei Mensch und Tier, der Paratuberkulose der Tiere, Pest, mesenterialen Lymphadenitis und Pseudotuberkulose bei Mensch und Tier, Cholera, Legionärskrankheit, Borreliose bei Mensch und Tier, Leptospirosen bei Mensch und Tier, Syphilis, Campylobacter- Enteritiden bei Mensch und Tier, Moraxella-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
Keratokonjunctivitis und Serositis der Tiere, Brucellosen der Tiere und des Menschen, Milzbrand bei Mensch und Tier, Aktinomykose bei Mensch und Tier, Streptotrichosen, Psittakose/Ornithose bei Tieren, Q-Fieber, Ehrlichiose.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.
Weiter ist der Einsatz nützlich bei der Helicobacter- Eradikationstherapie bei Ulcera des Magendarmtraktes.The use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
Die Verbindungen sind ferner zur Behandlung und Prophylaxe von Pilzerkrankungen wirksam, solche wie Mykosen verursacht durch Dermatophyten, Hefen, Schimmelpilze (sog. DHS-System nach Rieth) . Daher betrifft die Erfindung ebenfalls ein Antimycotikum. Es können ebenfalls Kombinationen der erfindungsgemäßen Verbindungen mit einem weiteren Antibiotikum zur Behandlung der oben genannten Erkrankungen eingesetzt werden.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.
Die erfindungsgemäßen Wirkstoffe sind ferner insbesondere bei Infektionen mit folgenden Viren einsetzbar: Parvoviridae : Parvoviren, Dependoviren, Densoviren; Adenoviridae : Adenoviren, Mastadenoviren, Aviadenoviren; Papovaviridae: Papovaviren, insbesondere Papillomaviren (so genannte Warzenviren) , Polyomaviren, insbesondere JC-Virus, BK-Virus, und Miopapovaviren; Herpesviridae : AlleThe 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
Herpesviren, insbesondere Herpes-Simplex-Viren, der Varizellen/Zoster- Viren, menschlicher Zytomegalievirus, Epstein-Barr- Viren, alle humanen Herpesviren, humanes Herpesvirus 6, humanes Herpesvirus 7, humanes Herpesvirus 8; Poxviridae: Pockenviren, Orthopox-, Parapox-, Molluscum- Contagiosum- Virus, Aviviren, Capriviren, Leporipoxviren; alle primär hepatotropen Viren, Hepatitisviren: Hepatitis-AViren, Hepatitis-B- Viren, Hepatitis-C- Viren, Hepatitis-D- Viren, Hepatitis-E- Viren, Hepatitis-F- Viren, Hepatits- G- Viren; Hepadnaviren: sämtliche Hepatitisviren, Hepatitis-B-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
Virus, Hepatitis-D- Viren; Picornaviridae: Picornaviren, alle Enteroviren, alle Polioviren, alle Coxsackieviren, alle Echoviren, alle Rhinoviren, Hepatitis-A- Virus, Aphthoviren; Calciviridae: Hepatitis-E- Viren; Reoviridae: Reoviren, Orbiviren, Rotaviren; Togaviridae: Togaviren, Alphaviren Rubiviren, Pestiviren, Rubellavirus; Flaviviridae : Flaviviren, FSME- Virus; Orthomyxoviridae : Influenzaviren; Paramyxoviridae : Paramyxoviren, Morbillivirus, Pneumovirus, Masernvirus, Mumpsvirus; Rhabdoviridae : Rhabdoviren, Rabiesvirus, Lyssavirus, viskuläres Stomatitisvirus; Coronaviridae: Coronaviren; Bunyaviridae: Bunyaviren, Nairovirus, Phlebovirus, üukuvirus, Hantavirus; Arenaviridae: Arenaviren, Iymphozytäres Choriomeningitis- Virus; Retroviridae: Retroviren, alle HTL- Viren, humanes T -cell leukämie- Virus, Oncornaviren, Spumaviren, Lentiviren, HI- Viren; Filoviridae: Marburg- und Ebolavirus; Slowvirus- Infektionen; Onkoviren, Leukämie-Viren.Virus, hepatitis D virus; Picornaviridae: Picornaviruses, all enteroviruses, all polioviruses, all Coxsackieviruses, all echoviruses, all rhinoviruses, hepatitis A virus, aphthoviruses; Calciviridae: hepatitis E viruses; Reoviridae: reoviruses, orbiviruses, rotaviruses; Togaviridae: Togaviruses, Alphaviruses, Rubiviruses, Pestiviruses, Rubellavirus; Flaviviridae: flaviviruses, TBE virus; Orthomyxoviridae: influenza viruses; Paramyxoviridae: paramyxoviruses, morbillivirus, pneumovirus, measles virus, mumps virus; Rhabdoviridae: rhabdoviruses, rabies virus, lyssavirus, viscous stomatitis virus; Coronaviridae: Coronaviruses; Bunyaviridae: Bunyaviren, Nairovirus, Phlebovirus, üukuvirus, Hantavirus; Arenaviridae: Arenaviruses, Iymphocytic choriomeningitis virus; Retroviridae: retroviruses, all HTL viruses, human T-cell leukemia virus, oncornaviruses, spumaviruses, lentiviruses, HI- viruses; Filoviridae: Marburg and Ebola viruses; Slow virus infections; Oncoviruses, leukemia viruses.
Die erfindungsgemäßen Verbindungen sind daher zur Behandlung folgender viraler Infekte geeignet:The compounds according to the invention are therefore suitable for the treatment of the following viral infections:
Eradikation von Papillomaviren zur Vorbeugung von Tumoren, insbesondere von Tumoren der Geschlechtsorgane, verursacht durch Papillomaviren beim Menschen, Eradikation von JC-Viren und BK- Viren, Eradikation von Herpesviren, Eradikation humaner Herpesviren 8 zur Behandlung der Kaposi-Sarkoma, Eradikation von Zytomegalie- Viren vor Transplantationen, Eradikation von Eppstein-Barr- Viren vor Transplantation und zur Vorbeugung von Eppstein- Barr- Viren-assozierten Tumoren, Eradikation von Hepatitisviren zur Behandlung von chronischen Leber-Erkrankungen und zur Vorbeugung von Lebertumoren und Leberzirrhosen, Eradikation von Coxsackieviren bei Kardiomyopathien, Eradikation von Coxsackieviren bei Diabetes-mellitus-Patienten, Eradikation von Immunschwäche- Viren in Mensch und Tier, Behandlung von Begleitinfektionen in AIDS-Patienten, Behandlung von Entzündungen viraler Genese des Respirationstraktes (Larynxpapillome, Hyberplasien, Rhinitis, Pharyngitis, Bronchitis, Pneumonien) , der Sinnesorgane (Keratokonjunktivitis ) , des Nervensystems (Poliomyelitis, Meningoenzephalitis, Enzephalitis, subakute sklerosierende Panenzephalitis, SSPE, progressive multifokale Leukoenzephalopathie, Lymphozytäre Chorio eningitis) , des Magen-Darm- Traktes (Stomatitis, Gingivostomatitis, Ösophagitis, Gastritis, Gastroenteritis, Durchfallerkrankungen) , der Leber und des Gallensystems (Hepatitis, Cholangitis, hepatozelluläres Karzinom) , des lymphatischen Gewebes (Mononukleose, Lymphadenitis) , des hämatopoetischen Systems, der Geschlechtsorgane (Mumpsorchitis) , der Haut (Warzen, Dermatitis, Herpes labialis, Fieberbläschen, Herpes Zoster, Gürtelrose), der Schleimhäute (Papillome, Konjunktivapapillome, Hyperplasien, Dysplasien) , des Herz-Blutgefaß-Systems (Arteriitis, Myokarditis, Endokarditis, Perikarditis) , des Nieren-Harnweg- Systems, der Geschlechtsorgane (Anogenitale Läsionen, Warzen, Genitalwarzen, spitzen Kondylome, Dysplasien, Papillome, Zervixdysplasien, Condylomata acuminata, Epidermodysplasia verruciformis) , der Bewegungsorgane (Myositis, Myalgien), Behandlung der Maul- und Klauenseuche der Paarhufer, des Colorado-Zeckenfiebers, des Dengue-Syndroms, des hämorrhagisches Fiebers, der Frühsommermeningoenzephalitis (FSME) und des Gelbfiebers.Eradication of papillomaviruses for the prevention of tumors, in particular tumors of the genital organs, caused by papillomaviruses in humans, eradication of JC viruses and BK viruses, eradication of herpes viruses, eradication of human herpes viruses 8 for the treatment of Kaposi's sarcoma, eradication of cytomegaloviruses before transplants, eradication of Eppstein-Barr viruses before transplantation and for the prevention of Eppstein-Barr virus-associated tumors, eradication of hepatitis viruses for the treatment of chronic liver diseases and for the prevention of liver tumors and liver cirrhosis, eradication of Coxsackieviruses in cardiomyopathies, eradication of Coxsackieviruses in diabetes mellitus patients, eradication of immunodeficiency viruses in humans and animals, treatment of concomitant infections in AIDS patients, treatment of inflammation of the viral genesis of the respiratory tract (laryngeal papillomas, hyberplasias, rhinitis, pharyngitis, bronchitis, pneumonia), the sensory organ ane (keratoconjunctivitis), of the nervous system (poliomyelitis, meningoencephalitis, encephalitis, subacute sclerosing panencephalitis, SSPE, progressive multifocal leukoencephalopathy, lymphocytic Chorio eningitis), of the gastrointestinal tract (stomatitis, gingivostomatitis, oesophagitis, gastritis, gastroenteritis, diarrhea), of the Liver and the biliary system (hepatitis, cholangitis, hepatocellular carcinoma), the lymphatic tissue (mononucleosis, lymphadenitis), the hematopoietic system, the genital organs (mumpsorchitis), the skin (warts, dermatitis, herpes labialis, cold sores, herpes zoster, herpes zoster of the mucous membranes (papillomas, conjunctive apapillomas, hyperplasias, dysplasias), the cardiovascular system (arteritis, Myocarditis, endocarditis, pericarditis), the kidney-urinary system, the genital organs (anogenital lesions, warts, genital warts, acute condylomas, dysplasias, papillomas, cervical dysplasias, condylomata acuminata, epidermodysplasia verruciformis), the movement organs (myalgia) Foot and mouth disease of cloven hoofed animals, Colorado tick fever, Dengue syndrome, hemorrhagic fever, early summer meningoencephalitis (TBE) and yellow fever.
Die neuen Verbindungen sind ferner geeignet für die Behandlung und Prophylaxe von Tumoren undThe new compounds are also suitable for the treatment and prophylaxis of tumors and
Entzündungserkrankungen, insbesondere solche ausgewählt aus der Gruppe „neoplastische Tumoren, inflammatorische Erkrankungen, Autoimmunerkrankungen, degenerative Gelenkserkrankungen, Erkrankungen des rheumatischen Formenkreises mit Knorpelabbau, chronische Polyarthritis, Gelenktrauma, immobilisierungsbedingter Knorpelschwund, septischer Schock, Erkrankungen mit gestörter Leukozyten-Adhäsion, Erkrankungen durch erhöhte TNFalphaInflammatory 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
Konzentrationen, Cachexie, Morbus Crohn, Abstoßungsreaktionen nach Transplantationen"Concentrations, cachexia, Crohn's disease, rejection after transplantation "
Alle genannten Indikationen sind im Pschyrembel®, de Gruyter, Berlin beschrieben.All mentioned indications are described in Pschyrembel®, de Gruyter, Berlin.
Des weiteren betrifft die Erfindung den hinterlegten Streptomyces DSM 16185. Der Mikroorganismus wurde am 23. Januar 2004 gemäß Budapester Vertrag bei der DSMZ (d.h. Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg lb, 38124 Braunschweig, Deutschland) hinterlegt.Furthermore, 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).
Die Erfindung betrifft' außerdem ein Verfahren zur Herstellung der oben genannten Verbindungen, wobei die Verbindungen entweder direkt aus Streptomyceten, insbesondere aus dem 1. hinterlegten Streptomyces DSM 16185, isoliert werden können oder aus solchen Verbindungen und bekannten Trioxacarcinen semisynthetisch zugänglich sind. In der Beschreibung und den Ansprüchen gelten für die einzelnen Substituenten folgende Definitionen: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:
Der Term „Alkyl" für sich oder als Teil eines anderen Substituenten bedeutet ein lineares oder verzweigtes Alkylketten-Radikal der jeweils angegebenen Länge. Bevorzugt sind Alkyle mit 1 bis 6 Kohlenstoffatomen, insbesondere mit 1 bis 4 Kohlenstoffatomen. So bedeutet Ci-.-Alkyl z.B. Methyl, Ethyl, 1-Propyl, 2-Propyl, 2-Methyl-2-propyl, 2-Methyl-l- propyl, 1-Butyl, 2-Butyl, C_-6-Alkyl z.B. Cι-4-Alkyl, Pentyl, 1-Pentyl, 2-Pentyl, 3-Pentyl, 1-Hexyl, 2-Hexyl, 3-Hexyl, 4- Methyl-1-pentyl oder 3, 3-Dimethyl-butyl . Die Alkyle können substituiert sein mit bis zu 3 Substituenten, bevorzugt bis zu 1 Substituenten, wobei die Substituenten unabhängig voneinander die Bedeutung OH, N02, CN, CF3, OR5, SH, SR5, COOH, COOR5, NH2, NHR5, NR5R6, Halogen, Aryl, Heteroaryl, Heterocycloalkyl haben können, wobei die Reste R5 und R6 unabhängig von einander Cι-Cιo-Alkyl, Cycloalkyl, Cι-C4~Alkyl- Cycloalkyl bedeuten können. Bevorzugt sind die Alkyle nicht substituiert .The term “alkyl” by itself or as part of another substituent means a linear or branched alkyl chain radical of the length given in each case. Preferred are alkyls with 1 to 6 carbon atoms, in particular with 1 to 4 carbon atoms Methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl, C_- 6 -alkyl, for example Cι- 4 -alkyl, pentyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 4-methyl-1-pentyl or 3, 3-dimethyl-butyl 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, NH 2 , NHR5, NR5R6, halogen, aryl, heteroaryl, heterocycloalkyl where the radicals R5 and R6 can independently of one another be C 1 -C 8 -alkyl, cycloalkyl, C 1 -C 4 -alkyl-cycloalkyl, and the alkyls are preferably unsubstituted.
Der Term „Alkenyl" für sich oder als Teil eines anderen Substituenten bedeutet ein lineares oder verzweigtes Alkylketten-Radikal mit eine oder mehreren C=C- Doppelbindungen der jeweils angegebenen Länge, wobei mehrere Doppelbindungen bevorzugt konjugiert sind. Bevorzugt sind Alkylene mit 1 bis 6 Kohlenstoffatomen, insbesondere mit 1 bis 4 Kohlenstoffatomen. So bedeutet C2-6-Alkenyl z.B. 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-The term "alkenyl" alone or as part of another substituent means a linear or branched alkyl chain radical with one or more C = C double bonds of the length indicated in each case, with a plurality of double bonds preferably being conjugated. 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-l-pentenyl oder 3, 3-Dimethyl- butenyl. Die Alkenyle können substituiert sein mit bis zu 3 Substituenten, bevorzugt bis zu 1 Substituenten, wobei die Substituenten unabhängig voneinander die Bedeutung OH, N02, CN, CF3, OR5, SH, SR5, COOH, COOR5, NH2, NHR5, NR5R6, Halogen, Aryl, Heteroaryl, Heterocycloalkyl haben können, wobei die Reste R5 und R6 unabhängig von einander C_-Cιo- Alkyl, Cycloalkyl, Cι-C4-Alkyl-Cycloalkyl bedeuten können. Bevorzugt sind die Alkenyle nicht substituiert.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_-Cιo-alkyl, cycloalkyl, Cι-C 4 alkyl-cycloalkyl. The alkenyls are preferably not substituted.
Der Term „Halogen" steht für Fluor, Chlor, Brom, Jod, bevorzugt Brom und Chlor.The term "halogen" stands for fluorine, chlorine, bromine, iodine, preferably bromine and chlorine.
Der Term „Cycloalkyl" für sich oder als Teil eines anderen Substituenten beinhaltet ungesättigte (einfach oder mehrfach, bevorzugt einfach) oder gesättigte, cyclische Kohlenwasserstoffgruppen, mit 3 bis 10 C-Atomen, bevorzugt 3 bis 8 C-Atomen, wie z.B. Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cyclohex-2-enyl, Cyclohex-3-enyl, Cyclohex-2, 4-dienyl, 4-Methyl-cyclohexyl, 3-Methyl- cyclohexyl, Cycloheptyl oder Cyclooctyl . Gesättigte Cycloalkyle sind bevorzugt. Die Cycloalkyle können substituiert sein mit bis zu 3 Substituenten, bevorzugt bis zu 1 Substituenten, wobei die Substituenten unabhängig voneinander die Bedeutung Ci-Cβ-Alkyl, OH, N02, CN, CF3, OR5, SH, SR5, Ci-Ce-Alkylhydroxy, Cι-C6-Alkyl-OR5, COOH, COOR5, NH2, NHR5, NR5R6, Halogen, Aryl, Cι-C4-Alkylaryl, Heteroaryl, Cχ-C4-Heteroalkylaryl haben können, wobei die Reste R5 und R6 unabhängig von einander C_-Cιo-Alkyl, Cycloalkyl, Cχ-C4-Alkyl- Cycloalkyl bedeuten können.The term "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-Cβ-alkyl, OH, N0 2 , CN, CF 3 , OR5, SH, SR5, Ci-Ce-alkylhydroxy, Cι- 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_ -Cιo-alkyl, cycloalkyl, Cχ-C 4 alkyl-cycloalkyl can mean.
Der Term „Heterocycloalkyl" für sich oder als Teil eines anderen Substituenten beinhaltet Cycloalkylgruppen worin bis zu zwei CH2-Gruppen durch Sauerstoff-, Schwefel- oder Stickstoffatome ersetzt sein können und eine oder zwei weitere CH2-gruppe durch eine oder zwei Carbonylfunktio (en) , Carbothionylfunktion (en) oder eine Carbonylfunktion und eine Carbothionylfunktion ersetzt sein kann, z.B. Pyrrolidin, Piperidin, Morpholin oderThe term "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
Figure imgf000021_0001
Die Heterocycloalkyle können wie die Cycloalkyle substituiert sein .
Figure imgf000021_0001
The heterocycloalkyls can be substituted like the cycloalkyls.
Der Term „Aryl" für sich oder als Teil eines anderen Substituenten beinhaltet aromatische Ringsysteme mit bis zu 3 Ringen, bei denen mindestens 1 Ringsystem aromatisch ist und die mit bis zu 3 Substituenten, bevorzugt bis zu 1 Substituenten substituiert sind, wobei die Substituenten unabhängig voneinander die Bedeutung Ci-Ce-Alkyl, OH, N02, CN, CF3, 0R5, SH, SR5, Cι-C5-Alkylhydroxy, Cι-C6-Alkyl-OR5, COOH, C00R5, NH2, NHR11, NR5R6, Halogen haben können, wobei die Reste R5 und R6 unabhängig von einander C_.-Cιo-Alkyl, Cycloalkyl, Cι-C4-Alkyl-Cycloalkyl bedeuten können, substituiert sind.The term "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.
Bevorzugte Aryle sind neben Phenyl und 1-Naphtyl und 2- Naphtyl :In addition to phenyl and 1-naphthyl and 2-naphthyl, preferred aryls are:
Figure imgf000021_0002
Figure imgf000022_0002
Der Term „Heteroaryl" für sich oder als Teil eines anderen Substituenten beinhaltet aromatische Ringsysteme mit bis zu 3 Ringen, und bis zu 3 gleichen oder verschiedenen Heteroatomen N, S, 0, bei denen mindestens 1 Ringsystem aromatisch ist und die mit bis zu 3 Substituenten, bevorzugt bis zu 1 Substituenten substituiert sind, wobei die Substituenten unabhängig voneinander die Bedeutung Ci-Cδ-Alkyl, OH, N02, CN, CF3, OR5, SH, SR6, Cι-C6-Alkylhydroxy, Cι-C6-Alkyl-OR5, COOH, COOR5, NH2, NHR5, NR5R6, Halogen haben können, wobei die Reste R5, R6 unabhängig von einander die oben angegebenen Bedeutungen haben können.
Figure imgf000021_0002
Figure imgf000022_0002
The term "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-Cδ-alkyl, OH, N0 2 , CN, CF 3 , OR5, SH, SR6, Cι-C 6 -alkylhydroxy, Cι-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.
Bevorzugte Heteroaryle sind:Preferred heteroaryls are:
Figure imgf000022_0001
Der Term „Ringsystem" bezieht sich im Allgemeinen auf 3, 4, 5, 6, 7, 8, 9 oder 10 gliedrige Ringe. Bevorzugt sind 5 und 6 gliedrige Ringe. Des weiteren sind Ringsysteme mit einem oder 2 anellierten Ringen bevorzugt.
Figure imgf000022_0001
The term “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.
Die Verbindungen der Formeln I und Subfor eln können als solche oder falls sie acidische oder basische Gruppen aufweisen in Form ihrer Salze mit physiologisch verträglichen Basen oder Säuren vorliegen. Beispiele für solche Säuren sind: Salzsäure, Zitronensäure, Trifluoressigsäure,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. Examples of such acids are: hydrochloric acid, citric acid, trifluoroacetic acid,
Weinsäure, Milchsäure, Phosphorsäure, Methansulfonsäure, Essigsäure, Ameisensäure, Maleinsäure, Fumarsäure, Bernsteinsäure, Hydroxybernsteinsäure, Schwefelsäure, Glutarsäure, Asparaginsäure, Brenztraubensäure, Benzoesäure, Glucuronsäure, Oxalsäure, Ascorbinsäure und Acetylglycin. Beispiele für Basen sind Alkaliionen, bevorzugt Na, K, Erdalkaliionen, bevorzugt Ca, Mg, Ammoniumionen.Tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, succinic acid, hydroxy succinic acid, sulfuric acid, glutaric acid, aspartic acid, pyruvic acid, benzoic acid, glucuronic acid, oxalic acid, ascorbic acid and acetylglycine. Examples of bases are alkali ions, preferably Na, K, alkaline earth ions, preferably Ca, Mg, ammonium ions.
Die erfindungsgemäßen Verbindungen können in üblicher Weise oral verabfolgt werden. Die Applikation kann auch i.V., i.m., mit Dämpfen oder Sprays durch den Nasen-Rachenraum erfolgen.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.
Die Dosierung hängt vom Alter, Zustand und Gewicht des Patienten sowie von der Applikationsart ab. In der Regel beträgt die tägliche Wirkstoffdosis pro Person zwischen etwa 0.1 μg/kg, insbesondere 1 mg/kg und 1 g/kg bei oraler Gabe. Diese Dosis kann in 2 bis 4 Einzeldosen oder einmalig am Tag insbesondere als Slow-release-Form gegeben werden.The dosage depends on the age, condition and weight of the patient as well as the type of application. As a rule, the daily dose of active ingredient per person is between about 0.1 μg / 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.
Die neuen Verbindungen können in den gebräuchlichen galenischen Applikationsformen fest oder flüssig angewendet werden, z.B. als Tabletten, Filmtabletten, Kapseln, Pulver, Granulate, Dragees, Lösungen, oder Sprays. Diese werden in üblicher Weise hergestellt. Die Wirkstoffe können dabei mit den üblichen galenischen Hilfsmitteln wie Tablettenbindern, Füllstoffen, Konservierungsmitteln, Tablettensprengmitteln, Fließreguliermitteln, Weichmachern, Netzmitteln, Dispergiermitteln, Emulgatoren, Lösungsmitteln, Retardierungsmitteln, Antioxidantien und/oder Treibgasen verarbeitet werden (vgl. H. Sucker et al.: Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). Die so erhaltenen Applikationsformen enthalten den Wirkstoff normalerweise in einer Menge von 0,1 bis 99 Gew.-%.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.
Beispiele : Nachstehende Beispiele dienen zur näheren Erläuterung der Erfindung, ohne die Erfindung auf diese zu beschränken.Examples: The following examples serve to explain the invention in more detail without restricting the invention thereto.
Die Verbindungen der Formeln I können prinzipiell vollsynthetisch nach bekannten Methoden hergestellt werden. Einfacher lassen sie sich aus zugänglichenIn principle, the compounds of the formulas I can be prepared fully synthetically by known methods. They are easier to access
Ausgangssubstanzen, wie der Verbindung von Beispiel 1 bis 8 nach an sich bekannten Methoden semisynthetisch herstellen.Starting substances, such as the compound from Examples 1 to 8, are prepared semisynthetically by methods known per se.
Beispiel 1example 1
Die Verbindung 1 kann nach folgender Methode isoliert werden.Compound 1 can be isolated using the following method.
Figure imgf000024_0001
Der marine Stamm Streptomyces sp. B8652 oder DSM 16185 wurde unter Standardbedingungen fermentiert und mit Essigsäureethylester extrahiert. Das Rohextrakt (16g), wurde flashchromatographisch an Kieselgel mit einem Gradienten aus CHCl3/MeOH ( 1300ml CHC13, 1000ml CHCl3/l%MeOH, 1000ml CHCl3/2%MeOH, 1000mlCHCl3/3%MeOH, 500mlCHCl3/5%MeOH, 500ml CHCl3/7%MeOH, 400ml CHCl3/10%MeOH, 300ml CHCl3/MeOH 13%, 300ml CHCl3/20% MeOH und 200ml MeOH ) aufgetrennt . Die Fraktion I enthielt ausschließlich Fett und wurde nicht weiter untersucht. Die Fraktionen III - V waren hoch aktiv im Agar Diffusionstest gegen Staphylococcus a ureus, Escherichia colx , Ba cill us subtilϊs und Streptomyces viridochromogenes (Tu 57). Die weitere Aufreinigung an Sephadex LH-20 (4x100cm, CHCl3/40% MeOH und präparative Schichtchromatographie (PTLC, Kieselgel, CHCl3/7%MeOH) sowie nochmals Auftrennung an Sephadex lieferte aus Fraktion III (1.57g) hauptsächlich Trioxacarcin A (257mg) als gelben Feststoff.
Figure imgf000024_0001
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 subtilϊs 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.
Beispiele 2 bis 7:Examples 2 to 7:
Durch weitere chromatographische Auftrennung in CH3Cl/MeOH an Silicagel konnten nach zunehmender Polarität geordnet Trioxacarcin EBy further chromatographic separation in CH3Cl / MeOH on silica gel, trioxacarcin E
Figure imgf000025_0001
und Trioxacarcin F
Figure imgf000025_0001
and trioxacarcin F
Figure imgf000026_0001
isoliert werden,
Figure imgf000026_0001
be isolated
Aus einer weiteren Fraktion konnten Trioxacarcin BTrioxacarcin B
Figure imgf000026_0002
Figure imgf000026_0002
Trioxacarcin D Trioxacarcin D
Figure imgf000027_0001
und Trioxacarcin C
Figure imgf000027_0001
and trioxacarcin C
Figure imgf000027_0002
isoliert werden,
Figure imgf000027_0002
be isolated
Aus der polarsten Fraktion wurde das Derivat Ilg isoliert The derivative Ilg was isolated from the most polar fraction
Figure imgf000028_0001
Figure imgf000028_0001
Die Strukturen der Verbindungen wurden durch verschiedene spektroskopische Methoden (1H-NMR, ESI-MS) bestimmt.The structures of the compounds were determined by various spectroscopic methods (1H-NMR, ESI-MS).
Die physikalischen Daten der Verbindungen Ild, Ile und Ilf sind wie folgt.The physical data of the compounds Ild, Ile and Ilf are as follows.
Tabelle 1: Physikalisch-chemische Eigenschaften der Verbindung Ild, Ile, IlfTable 1: Physico-chemical properties of the compound Ild, Ile, Ilf
Verbindung Iid Verbindung Ile Verbindung IldConnection Iid Connection Ile Connection Ild
Zustand Gelber gelber gelber Feststoff Feststoff FeststoffState Yellow Yellow Yellow Solid Solid Solid
Rf 0.40 0.45 0.55Rf 0.40 0.45 0.55
(CHCl3/10%MeOH)(CHCl 3 /10% MeOH)
(+) -ESI MS: 1691 763 ([M+Na+1] 1847 ( [2M+Na+1] , 857 ([2M+Na+1], 935 ( [M+Na+1] ( [M+Na+1](+) -ESI MS: 1691 763 ([M + Na +1 ] 1847 ([2M + Na +1 ], 857 ([2M + Na +1 ], 935 ([M + Na +1 ] ([M + Na +1 ]
(-)-ESI MS: 1668
Figure imgf000028_0002
911 [M-H]"1 834 [M]"1 740 [M]"1 (-) - ESI MS: 1668
Figure imgf000028_0002
911 [MH] "1 834 [M] " 1 740 [M] "1
Summenformel C40H50O19 C34H440i8 C 2H58θ22
Figure imgf000029_0001
Molecular formula C40H50O19 C34H4 4 0i8 C 2 H58θ 2 2
Figure imgf000029_0001
Tabelle 2. Antimikrobielle Aktivität [Hemmhof in mm] von Verbindung II a-e und Ilg im Agar Diffusionstest 30-40μg/9mm Papierscheibe gegen verschiedene Organismen.Table 2. Antimicrobial activity [inhibitory zone in mm] of compound II a-e and Ilg in the agar diffusion test 30-40μg / 9mm paper disk against different organisms.
EC BS SV SA MM CA CV CS SS Verbindung Ha 34 40 25 24 k.A. k.A. k.A. k.A. k.A. Verbindung Ilb 32 38 27 22 k.A. k.A. k.A. k.A. k.A. Verbindung IIc 30 38 24 22 k.A. k.A. k.A. k.A. k.A. Verbindung Ild 33 39 28 23 k.A. k.A. k.A. k.A. k.A. Verbindung Ile 30 37 24 20 k.A. k.A. k.A. k.A. k.A. Verbindung Ilg 28 30 25 21 k.A. k.A. k.A. k.A. k.A. k.A. keine Aktivität, Bacillus subtilis (BS) , Streptomyces viridochromogenes (Tu 57), Staphylococcus aureus (SA), Escherichia coli (EC) , Candida albicans (CA) , Mucor miehei (MM), Chlorella vulgaris (CV) , Chlorella sorokiniana (CS) and Scenedesmus subspicatus (SS) Anti-plasmodia TestEC BS SV SA MM CA CV CS SS connection Ha 34 40 25 24 kAkAkAkAkA connection Ilb 32 38 27 22 kAkAkAkAkA connection IIc 30 38 24 22 kAkAkAkAkA connection Ild 33 39 28 23 kAkAkAkAkA connection Ile 30 37 24 20 kAkAkAkAkA 25A connection Ilg 28 kAkAkAkAkAkA no activity, Bacillus subtilis (BS), Streptomyces viridochromogenes (Tu 57), Staphylococcus aureus (SA), Escherichia coli (EC), Candida albicans (CA), Mucor miehei (MM), Chlorella vulgaris (CV), Chlorella sorokin CS) and Scenedesmus subspicatus (SS) Anti-plasmodia test
Die Antiplasmodienwirkung von Ha, Ilb und Ild wurde bestimmt unter Verwendung des NF54 Stammes P. falciparum unbekannter Herkunft. Dieser Stamm wurde erstmals am Amsterdamer Flughafen isoliert. Als zweiter Teststamm diente der Kl Stamm aus Thailand. NF54 zeigt normale Sensitivität zu allen bekannten Antileishmania Medikamenten. Der Stamm ist hingegen resisten gegen Chloroquin und Pyriή'iethamin. Ein modifizierter [3H] Hypoxanthin Inkorporationsassay wurde für die Bestimmung der Intra-erythrocytischen Inhibition des Parasitenwachstums verwendet. P. falciparum infizierte menschliche rote Blutzellen im hypoxanthinarmen Kulturmedium wurden mit verschiedenen Medikamentenverdünnungen in Microtiterplatten für 48h bei 37°C in 4%iger feuchter C02-Atmosphäre inkorporiert. Nach der Zugabe von [ H] -Hypoxanthin wurde das Parasitenwachstum bestimmt. Der ICso-Wert wurde zwischen den beiden Wirkstof konzentrationen interpoliert. Antiplasmodienwirkung von Trioxacarcin A (Ha) gegenThe 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 pyriή'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. Anti-plasmodic action of trioxacarcin A (Ha) against
Plasmodium falciparum . Die Verbindung Ild ist ebenfalls aktiv. Plasmodium falciparum. The Ild connection is also active.
Figure imgf000031_0001
Figure imgf000031_0001

Claims

Patentansprüche claims
1. Verwendung von Trioxacarcinen der allgemeinen Formel I zur Herstellung eines Arzneimittels für die Behandlung und Prophylaxe von Infektionskrankheiten verursacht durch Pilze, Parasiten, Viren und Bakterien,1. Use of trioxacarcines of the general formula I for the manufacture of a medicament for the treatment and prophylaxis of infectious diseases caused by fungi, parasites, viruses and bacteria,
Figure imgf000032_0001
wobei jeweils
Figure imgf000032_0001
where each
Rl H, Cι-Ci4-Alkyl, Cycloalkyl, C_-C4-Alkyl-Cycloalkyl, Hetreocycloalkyl, Cι-C4-Alkyl-Heterocycloalkyl, C2-Cι4- Alkenyl, Aryl, C_-C4-Alkyl-Aryl, Heteroaryl, C_-C4-Alkyl- Heteroaryl, C (0) -Cι-Cι4-Alkyl, C (0) -Cycloalkyl, C(0)-Cι- C4-Alkyl-Cycloalkyl, C (0) -Hetreocycloalkyl, C(0)-Cι-C4- Alkyl-Heterocycloalkyl, C (0) -C2-Cι4-Alkenyl, C(0)-Aryl, C(0)-Cι-C4-Alkyl-Aryl, C (0) -Heteroaryl, C (0) -C_.-C4-Alkyl- Alkylheteroaryl,R1, C 1 -C 4 -alkyl, cycloalkyl, C_-C 4 -alkyl-cycloalkyl, heterocycloalkyl, Cι-C 4 -alkyl heterocycloalkyl, C 2 -Cι 4 - alkenyl, aryl, C_-C 4 -alkyl-aryl, Heteroaryl, C_-C 4 alkyl heteroaryl, C (0) -Cι-Cι 4 alkyl, C (0) cycloalkyl, C (0) -Cι- C 4 alkyl cycloalkyl, C (0) heterocycloalkyl , C (0) -Cι-C 4 - alkyl heterocycloalkyl, C (0) -C 2 -Cι 4 alkenyl, C (0) aryl, C (0) -Cι-C 4 alkyl aryl, C (0) heteroaryl, C (0) -C _.- C 4 alkyl alkyl heteroaryl,
R2 H, Cι-Ci4-Alkyl, Cycloalkyl, C_.-C4-Alkyl-Cycloalkyl, Hetreocycloalkyl, Cι-C4-Alkyl-Heterocycloalkyl, C2-Cι - Alkenyl, Aryl, C_-C4-Alkyl-Aryl, Heteroaryl, C_-C4-Alkyl- Heteroaryl, C (0) -Cι-C14-Alkyl, C (0) -Cycloalkyl, C(0)-Cι- C4-Alkyl-Cycloalkyl, C (0) -Hetreocycloalkyl, C (0) -C_.-C4- Alkyl-Heterocycloalkyl, C (0) -C2-Cι4-Alkenyl, C(0)-Aryl, C(0)-C_.-C4-Alkyl-Aryl, C (0) -Heteroaryl, C (0) -C1-C4-Alkyl- Alkylheteroaryl,R2 H, -C-Ci4-alkyl, cycloalkyl, C _.- C 4 alkyl-cycloalkyl, heterocycloalkyl, Cι-C4-alkyl heterocycloalkyl, C 2 -Cι - alkenyl, aryl, C_-C 4 -alkyl aryl, heteroaryl , C_-C 4 alkyl heteroaryl, C (0) -Cι-C 14 alkyl, C (0) cycloalkyl, C (0) -Cι- C 4 alkyl cycloalkyl, C (0) heterocycloalkyl, C (0) -C _.- C 4 - alkyl heterocycloalkyl, C (0) -C 2 -Cι 4 alkenyl, C (0) aryl, C (0) -C _.- C 4 alkyl aryl, C (0) heteroaryl, C (0) -C 1 -C 4 alkyl alkyl heteroaryl,
R3 H, Cι-Ci4-Alkyl, Cycloalkyl, Cι-C4-Alkyl-Cycloalkyl, Hetreocycloalkyl, Cι-C4-Alkyl-Heterocycloalkyl, C2-Cι4- Alkenyl, Aryl, Cι-C4-Alkyl-Aryl, Heteroaryl, Cι-C4-Alkyl- Heteroaryl, C (0) -Cι-Cι4-Alkyl, C (0) -Cycloalkyl, C (0) -Ci- C4-Alkyl-Cycloalkyl, C (0) -Hetreocycloalkyl, C (0) -C1-C4- Alkyl-Heterocycloalkyl, C (0) -C2-C_.4-Alkenyl, C(0)-Aryl, C(0) -Cι-C-Alkyl-Aryl, C (0) -Heteroaryl, C (0) -Cι-C4-Alkyl- Alkylheteroaryl,R3 is H, Cι-Ci4-alkyl, cycloalkyl, Cι-C4 alkyl-cycloalkyl, Hetreocycloalkyl, Cι-C4-alkyl-heterocycloalkyl, C 2 -Cι 4 - alkenyl, aryl, Cι-C 4 -alkyl-aryl, Heteroaryl, -CC 4 -alkyl heteroaryl, C (0) -C -CC 4 -alkyl, C (0) -cycloalkyl, C (0) -Ci- C 4 -alkyl-cycloalkyl, C (0) -hetreocycloalkyl , C (0) -C1-C4-alkyl heterocycloalkyl, C (0) -C 2 -C_. 4- alkenyl, C (0) aryl, C (0) -Cι-alkyl aryl, C (0) heteroaryl, C (0) -Cι-C 4 alkyl alkyl heteroaryl,
R4 H, C(0)H, C(0) -Cι-Ci4-Alkyl, C (0) -Cycloalkyl, C(0)- Cι-C4-Alkyl-Cycloalkyl, C (0) -Hetreocycloalkyl, C(0)-C_- C4-Alkyl-Heterocycloalkyl, C (0) -C2-Cι4-Alkenyl, C(0)- Aryl, C(0)-Cι-C4-Alkyl-Aryl, C (0) -Heteroaryl, C(0)-Cχ-C4- Alkyl-Alkylheteroaryl,R 4 is H, C (0) H, C (0) -Cι-Ci4-alkyl, C (0) -cycloalkyl, C (0) - Cι-C4-alkyl-cycloalkyl, C (0) -Hetreocycloalkyl, C ( 0) -C_- C 4 alkyl heterocycloalkyl, C (0) -C 2 -Cι 4 alkenyl, C (0) - aryl, C (0) -Cι-C 4 alkyl aryl, C (0) -Heteroaryl, C (0) -Cχ-C 4 - alkyl-alkylheteroaryl,
R5 H, Cι-Ci4-Alkyl, Cycloalkyl, C1-C4-Alkyl-Cycloalkyl, Hetreocycloalkyl, Cι-C4-Alkyl-Heterocycloalkyl, C2-Cι4- Alkenyl, Aryl, Cι-C-Alkyl-Aryl, Heteroaryl, Cι-C4-Alkyl- Heteroaryl, C (0) -Cι-C1 -Alkyl, C (0) -Cycloalkyl, C(0)-C_- C4-Alkyl-Cycloalkyl, C (0) -Hetreocycloalkyl, C (0) -Cx-C4- Alkyl-Heterocycloalkyl, C (0) -C2-Cι4-Alkenyl, C(0)-Aryl, C(0) -Cι-C4-Alkyl-Aryl, C (0) -Heteroaryl, C (0) -Cι-C4-Alkyl-R5 is H, Cι-Ci4-alkyl, cycloalkyl, C 1 -C 4 alkyl-cycloalkyl, Hetreocycloalkyl, Cι-C4-alkyl-heterocycloalkyl, C 2 -Cι 4 - alkenyl, aryl, Cι-C-alkyl-aryl, Heteroaryl, C 1 -C 4 alkyl heteroaryl, C (0) -C 1 C 1 alkyl, C (0) cycloalkyl, C (0) -C 4 C 4 alkyl cycloalkyl, C (0) heterocycloalkyl , C (0) -C x -C 4 alkyl heterocycloalkyl, C (0) -C 2 -Cι 4 alkenyl, C (0) aryl, C (0) -Cι-C 4 alkyl aryl, C (0) heteroaryl, C (0) -Cι-C 4 alkyl-
Alkylheteroaryl,
Figure imgf000033_0001
, wobei Rll, R12 und R13 unabhängig voneinander und unabhängig von Rl eine der Bedeutungen von Rl annimmt, und X2 unabhängig von XI eine der Bedeutungen von XI annimmt, R6 OH, 0-Cι-Ci4-Alkyl, O-Cycloalkyl, 0-C1-C4-Alkyl- Cycloalkyl, O-Hetreocycloalkyl, 0-Cχ-C -Alkyl- Heterocycloalkyl, 0-C2-Cι4-Alkenyl , O-Aryl, 0-Cχ-C- Alkyl-Aryl, O-Heteroaryl, 0-Cι-C4-Alkyl-Heteroaryl, 0- C(O) -Cι-Ci4-Alkyl, O-C (0) -Cycloalkyl, O-C (0) -Cχ-C-Alkyl- Cycloalkyl, O-C (0) -Hetreocycloalkyl, 0-C (0) -Cχ-C4-Alkyl- Heterocycloalkyl, O-C (0) -C2-Cι4-Alkenyl, 0-C (0) -Aryl, 0- C(0) -Cι-C4-Alkyl-Aryl, 0-C (0) -Heteroaryl, 0-C (0) -Cχ-C4- Alkyl-Alkylheteroaryl,alkylheteroaryl,
Figure imgf000033_0001
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-Cι-Ci 4 -alkyl, O-cycloalkyl, 0-C 1 -C 4 -alkyl-cycloalkyl, O-heterocycloalkyl, 0-Cχ-C -alkyl-heterocycloalkyl, 0-C 2 -Cι 4 - Alkenyl, O-aryl, 0-Cχ-C-alkyl-aryl, O-heteroaryl, 0-Cι-C 4 -alkyl-heteroaryl, 0- C (O) -Cι-Ci 4 -alkyl, OC (0) - Cycloalkyl, OC (0) -Cχ-C-alkyl- cycloalkyl, OC (0) -hetreocycloalkyl, 0-C (0) -Cχ-C 4 alkyl- heterocycloalkyl, OC (0) -C 2 -Cι 4 alkenyl , 0-C (0) aryl, 0-C (0) -Cι-C 4 alkyl aryl, 0-C (0) heteroaryl, 0-C (0) -Cχ-C 4 - alkyl-alkyl heteroaryl .
R7 OH, 0-Cι-Ci4-Alkyl, O-Cycloalkyl, 0-Cχ-C4-Alkyl- Cycloalkyl, O-Hetreocycloalkyl, 0-C_.-C4-Alkyl- Heterocycloalkyl, 0-C2-Cι4-Alkenyl, O-Aryl, 0-Cχ-C4- Alkyl-Aryl, O-Heteroaryl, 0-Cχ-C4-Alkyl-Heteroaryl, 0-R7 OH, 0-Cι-Ci4-alkyl, O-cycloalkyl, 0-Cχ-C 4 -alkyl- cycloalkyl, O-heterocycloalkyl, 0-C _.- C 4 -alkyl- heterocycloalkyl, 0-C 2 -Cι 4 - Alkenyl, O-aryl, 0-Cχ-C 4 - alkyl-aryl, O-heteroaryl, 0-Cχ-C 4 -alkyl-heteroaryl, 0-
C(0) -Cι-Ci4-Alkyl, O-C (0) -Cycloalkyl, 0-C (0) -Cχ-C4-Alkyl- Cycloalkyl, 0-C (0) -Hetreocycloalkyl, 0-C (0) -C_-C4-Alkyl- Heterocycloalkyl, O-C (0) -C2-Cι4-Alkenyl, O-C (0) -Aryl, 0- C(0)-Cι-C4-Alkyl-Aryl, 0-C (0) -Heteroaryl, 0-C (0) -Cχ-C4- Alkyl-Alkylheteroaryl,C (0) -Cι-Ci4-alkyl, OC (0) -cycloalkyl, 0-C (0) -Cχ-C 4 -alkyl-cycloalkyl, 0-C (0) -hetreocycloalkyl, 0-C (0) - C_-C 4 alkyl heterocycloalkyl, OC (0) -C 2 -Cι 4 alkenyl, OC (0) aryl, 0- C (0) -Cι-C 4 alkyl aryl, 0-C (0 ) Heteroaryl, 0-C (0) -Cχ-C 4 - alkyl-alkylheteroaryl,
oder R6 zusammen mit R7 eine O-Brücke bildetor R6 forms an O-bridge together with R7
R8 OH, 0-Cι-Ci4-Alkyl, O-Cycloalkyl, 0-Cι-C4-Alkyl- Cycloalkyl, O-Hetreocycloalkyl, 0-Cι-C4-Alkyl-R8 OH, 0-C 1 -C 4 -alkyl, O-cycloalkyl, 0-C 1 -C 4 alkyl-cycloalkyl, O-hetreocycloalkyl, 0-C 1 -C 4 alkyl-
Heterocycloalkyl, 0-C2-Cι4-Alkenyl, O-Aryl, 0-Cχ-C4- Alkyl-Aryl, O-Heteroaryl, 0-Cχ-C4-Alkyl-Heteroaryl, 0- C(0) -Cχ-Cχ4-Alkyl, 0-C (0) -Cycloalkyl, 0-C (0) -Cχ-C4-Alkyl- Cycloalkyl, O-C (0) -Hetreocycloalkyl, 0-C (0) -Cχ-C-Alkyl- Heterocycloalkyl, O-C(O) -C2-Cι4-Alkenyl, 0-C (0) -Aryl, 0- C(0)-Cι-C4-Alkyl-Aryl, 0-C (0) -Heteroaryl, 0-C (0) -Cχ-C4- Alkyl-Alkylheteroaryl,Heterocycloalkyl, 0-C 2 -C 4 -alkenyl, O-aryl, 0-Cχ-C 4 -alkyl-aryl, O-heteroaryl, 0-C C-C 4 -alkyl heteroaryl, 0- C (0) -Cχ -Cχ 4 alkyl, 0-C (0) cycloalkyl, 0-C (0) -Cχ-C 4 alkyl cycloalkyl, OC (0) heterocycloalkyl, 0-C (0) -Cχ-C alkyl Heterocycloalkyl, OC (O) -C 2 -C 4 alkenyl, 0-C (0) aryl, 0 -C (0) -C 4 alkyl aryl, 0-C (0) heteroaryl, 0-C (0) -Cχ-C 4 - alkyl-alkylheteroaryl,
R9 OH, 0-Cχ-Cχ4-Alkyl, O-Cycloalkyl, 0-Cχ-C4-Alkyl- Cycloalkyl, O-Hetreocycloalkyl, 0-Cχ-C-Alkyl-R9 OH, 0-Cχ-Cχ 4 alkyl, O-cycloalkyl, 0-Cχ-C 4 alkyl-cycloalkyl, O-hetreocycloalkyl, 0-Cχ-C-alkyl-
Heterocycloalkyl, 0-C2-Cι4-Alkenyl, O-Aryl, 0-Cχ-C4- Alkyl-Aryl, O-Heteroaryl, 0-Cχ-C4-Alkyl-Heteroaryl, 0- C(0)-Cχ-Cχ4-Alkyl, O-C (0) -Cycloalkyl, O-C (0) -Cχ-C4-Alkyl- Cycloalkyl, O-C (0) -Hetreocycloalkyl, O-C (0) -C_.-C4-Alkyl- Heterocycloalkyl, O-C (0) -C2-C14-Alkenyl, 0-C (0) -Aryl, 0- C(0)-Cχ-C4-Alkyl-Aryl, 0-C (0) -Heteroaryl, O-C (0) -Cχ-C4-Heterocycloalkyl, 0-C 2 -C 4 alkenyl, O-aryl, 0-Cχ-C 4 - Alkyl-aryl, O-heteroaryl, 0-Cχ-C 4 -alkyl heteroaryl, 0- C (0) -Cχ-Cχ 4 -alkyl, OC (0) -cycloalkyl, OC (0) -Cχ-C 4 - Alkyl-cycloalkyl, OC (0) -hetreocycloalkyl, OC (0) -C _.- C 4 -alkyl- heterocycloalkyl, OC (0) -C 2 -C 14 -alkenyl, 0-C (0) -aryl, 0- C (0) -Cχ-C 4 alkyl aryl, 0-C (0) heteroaryl, OC (0) -Cχ-C 4 -
Alkyl-Alkylheteroaryl, oder R8 zusammen mit R9 eine O-Brücke bildetAlkyl-alkylheteroaryl, or R8 together with R9 forms an O-bridge
RIO H, HalogenRIO H, halogen
XI 0 , NOH , N0R31 , N0C0R31 , NOCH CONR31R32 , NOCH ( CH3 ) CONR31R32 , NOC ( CH3 ) 2CONR31R32 , N-NHCO-R33 , N- NHCO-CH2NHCOR31 , N-0-CH2NHCOR31 , N-NHCS -R33 , NR31 , N-XI 0, NOH, N0R31, N0C0R31, NOCH CONR31R32, NOCH (CH 3 ) CONR31R32, NOC (CH 3 ) 2 CONR31R32, N-NHCO-R33, N- NHCO-CH 2 NHCOR31, N-0-CH 2 NHCOR31, N -NHCS -R33, NR31, N-
NR31R32,
Figure imgf000035_0001
(mit X' = NR315, 0, S und R311, R312, R313, R314, R315 unabhängig voneinander H oder Cχ-C6-Alkyl) , N-NHS02-Aryl, N-NHS02-Heteroaryl,NR31R32,
Figure imgf000035_0001
(with X '= NR315, 0, S and R311, R312, R313, R314, R315 independently of one another H or Cχ-C 6 -alkyl), N-NHS0 2 -aryl, N-NHS0 2 -heteroaryl,
R31, R32 unabhängig voneinander Cχ-Cχ4-Alkyl, Cχ-Cχ4- Alkanoyl, Cχ-C6-Alkylhydroxy, Cχ-C6-Alkylamino, Cχ-C6- Alkylamino-Cχ-C6-Alkyl, Cχ-C6-Alkylamino-di-Cχ-C6-Alkyl,R31, R32 independently of one another Cχ-Cχ 4- alkyl, Cχ-Cχ 4 -alkanoyl, Cχ-C6-alkylhydroxy, Cχ-C 6 -alkylamino, Cχ-C6- alkylamino-Cχ-C 6 -alkyl, Cχ-C 6 - alkylamino-di-Cχ-C6 alkyl,
Cycloalkyl, Cχ-C4-Alkyl-Cycloalkyl, Heterocycloalkyl, Cχ~ C4-Alkyl-Heterocycloalkyl, Aryl, Aryloyl, Cχ-C4-Alkyl- Aryl, Heteroaryl, Heteroaryloyl, Cχ-C4-Alkyl-Heteroaryl, Cycloalkanoyl, Cχ-C4-Alkanoyl-Cycloalkyl, Heterocycloalkanoyl, Cχ-C4-Alkanoyl-Heterocycloalkyl,Cycloalkyl, Cχ-C 4 -alkyl-cycloalkyl, heterocycloalkyl, Cχ ~ C4-alkyl-heterocycloalkyl, aryl, aryloyl, Cχ-C4-alkyl-aryl, heteroaryl, heteroaryloyl, Cχ-C4-alkyl-heteroaryl, cycloalkanoyl, Cχ -Alkanoyl-cycloalkyl, heterocycloalkanoyl, Cχ-C4-alkanoyl-heterocycloalkyl,
Cχ-C4-Alkanoyl-Aryl, Cχ-C4-Alkanoyl-Heteroaryl, Mono- und Di-Zuckerreste, die verknüpft sind über ein C-Atom, das im Zucker eine OH-Gruppe tragen würde, wobei die Zucker unabhängig voneinander ausgewählt sind aus der Gruppe bestehend aus Glucuronsäure und ihren Stereoisomeren an allen optischen C-Atomen, Aldopentosen, Aldohexosen einschließlich ihren Desoxyverbindungen, R33 unabhängig von R31, dieselben Bedeutungen wie R31 oder CH2pyridinium-salze, CH2tri-Cχ-C6- alkylamirionmium-salze,Cχ-C 4 -alkanoyl-aryl, Cχ-C4-alkanoyl heteroaryl, mono- and di-sugar residues, which are linked via a C atom which would carry an OH group in the sugar, the sugars being selected independently of one another from the group consisting of glucuronic acid and its stereoisomers on all optical carbon atoms, aldopentoses, aldohexoses including their deoxy compounds, R33 independently of R31, the same meanings as R31 or CH 2 pyridinium salts, CH 2 tri-Cχ-C6-alkylamirionmium salts,
bedeutet, deren Stereoisomere, Tautomere und deren physiologisch verträglichen Salze.means, their stereoisomers, tautomers and their physiologically tolerable salts.
Verwendung von Trioxacarcinen der allgemeinen Formel I nach Anspruch 1, wobei R2, R3, R4, Rll, R12 und R13 die gleiche Bedeutung annehmen, insbesondere alle gleich H sind .Use of trioxacarcines of the general formula I according to claim 1, wherein R2, R3, R4, R11, R12 and R13 have the same meaning, in particular all are H.
Verwendung von Trioxacarcinen der allgemeinen Formel I nach Anspruch 1 oder 2, wobei XI und X2 die gleiche Bedeutung annehmen, insbesondere gleich 0 sind.Use of trioxacarcines of the general formula I according to claim 1 or 2, where XI and X2 have the same meaning, in particular are 0.
Verwendung von Trioxacarcinen der allgemeinen Formel I nach einem der Ansprüche 1 bis 3, wobei Rl H oder C(O)- Cχ-Cχ4-Alkyl ist, insbesondere C(0)Me.Use of trioxacarcines of the general formula I according to one of claims 1 to 3, wherein Rl is H or C (O) - Cχ-Cχ 4 alkyl, in particular C (0) Me.
Verwendung von Trioxacarcinen der allgemeinen Formel I nach einem der Ansprüche 1 bis 4, wobei R5 H,Use of trioxacarcines of the general formula I according to one of claims 1 to 4, where R5 is H,
Figure imgf000036_0001
erwendung von Trioxacarcinen der allgemeinen Formel I nach einem der Ansprüche 1 bis 5, wobei R6 OH,
Figure imgf000036_0001
Use of trioxacarcines of the general formula I according to one of claims 1 to 5, where R6 OH,
Figure imgf000036_0002
oder zusammen mit R7 eine O-Brücke ist Verwendung von Trioxacarcinen der allgemeinen Formel I nach einem der Ansprüche 1 bis 6, wobei R7 ist OH, oder zusammen mit R6 eine O-Brücke ist.
Figure imgf000036_0002
or together with R7 is an O-bridge Use of trioxacarcines of the general formula I according to one of claims 1 to 6, wherein R7 is OH, or together with R6 is an O-bridge.
Verwendung von Trioxacarcinen der allgemeinen Formel I nach einem der Ansprüche 1 bis 7, wobei R8 OH oder zusammen mit R9 eine O-Brücke ist.Use of trioxacarcines of the general formula I according to one of claims 1 to 7, wherein R8 is OH or together with R9 is an O-bridge.
Verwendung von Trioxacarcinen der allgemeinen Formel I nach einem der Ansprüche 1 bis 8, wobei R9 OH oder zusammen mit R8 eine O-Brücke ist.Use of trioxacarcines of the general formula I according to one of claims 1 to 8, wherein R9 is OH or together with R8 is an O-bridge.
10. Verwendung von Trioxacarcinen der allgemeinen Formel I nach einem der Ansprüche 1 bis 8, wobei RIO H ist.10. Use of trioxacarcines of the general formula I according to one of claims 1 to 8, wherein RIO is H.
11. Verbindungen der allgemeinen Formel I nach Anspruch 1, wobei die Reste folgende Bedeutungen nicht gleichzeitig annehmen dürfen: Mit Rl COCH3, R2 H, R3 H, XI O, R4 H, R8 und R9 zusammen eine O-Brücke, RIO H, und11. Compounds of general formula I according to claim 1, wherein the radicals must not assume the following meanings simultaneously: With Rl COCH3, R2 H, R3 H, XI O, R4 H, R8 and R9 together an O-bridge, RIO H, and
a . ) R5 bedeutet
Figure imgf000037_0001
darf Rβ und R7 weder jeweils OH sein oder zusammen eine O-Brücke darstellen, und fallsa. ) R5 means
Figure imgf000037_0001
Rβ and R7 must neither each be OH or together represent an O bridge, and if
Figure imgf000037_0002
darf Rβ und R7 keine 0 Brücke sein.
Figure imgf000037_0002
Rβ and R7 must not be a 0 bridge.
12. Verbindungen oder deren Salze ausgewählt aus der Gruppe12. Compounds or their salts selected from the group
Figure imgf000038_0001
Figure imgf000038_0001
13. Arzneimittel enthaltend mindestens eine Verbindung nach Anspruch 11 oder 12.13. Medicament containing at least one compound according to claim 11 or 12.
14. Arzneimittel nach Anspruch 13 zur Behandlung und Prophylaxe von Tumoren und Entzündungserkrankungen, insbesondere ausgewählt aus der Gruppe neoplastische Tumoren, inflammatorische Erkrankungen, Autoimmunerkrankungen, degenerative Gelenkserkrankungen, Erkrankungen des rheumatischen Formenkreises mit Knorpelabbau, chronische Polyarthritis , Gelenktrauma, immobilisierungsbedingter Knorpelschwund, septischer Schock, Erkrankungen mit gestörter Leukozyten-Adhäsion, Erkrankungen durch erhöhte TNF-alpha Konzentrationen, Cachexie, Morbus Crohn, Abstoßungsreaktionen nach Transplantationen und zur Behandlung und Prophylaxe von Infektionskrankheiten verursacht durch Pilze, Parasiten, Viren und Bakterien.14. Medicament according to claim 13 for the treatment and prophylaxis of tumors and inflammatory diseases, in particular 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 impaired leukocyte adhesion, diseases due to increased TNF-alpha concentrations, cachexia, Crohn's disease and transplantation after rejection and transplantation, rejection reactions Prevention of infectious diseases caused by fungi, parasites, viruses and bacteria.
15. Verwendung nach einem der Ansprüche 1 bis 10 oder einem Arzneimittel nach Anspruch 14 zur Behandlung und Prophylaxe von Malaria, Schlafkrankheit, Chagas- Krankheit, Toxoplasmose, Amobenruhr, Leishmaniosen, Trichomoniasis, Pneumozystose, Balantidiose, Kryptosporidiose, Sarkozystose, Akanthamöbose, Naeglerose, Kokzidiose, Giardiose und Lambliose.15. Use according to one of claims 1 to 10 or a medicament according to claim 14 for the treatment and prophylaxis of malaria, sleeping sickness, Chagas disease, toxoplasmosis, amoic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, acanthamoebosis, naeglerosis, coccidiosis , Giardiosis and lambliosis.
16. Pharmazeutische Zusammensetzung enthaltend mindestens eine Verbindung nach einem der Ansprüche 1 bis 12 oder ein Arzneimittel nach einem der Ansprüche 13 bis 14 und ggfs in Kombination mit mindestens einem weiteren geeigneten Arzneimittel und einen pharmazeutischen Trager, samt Hilfs- und Zusatzstoffe.16. Pharmaceutical composition containing at least one compound according to one of claims 1 to 12 or a medicament according to one of claims 13 to 14 and possibly in combination with at least one other suitable medicament and a pharmaceutical carrier, together with auxiliaries and additives.
17. DSM 16185.17. DSM 16185.
18. Verwendung von Streptomyceten, insbesondere eines Streptomyces nach Anspruch 14 zur Herstellung von Trioxacarcinen der allgemeinen Formel I nach Anspruch 1. 18. Use of Streptomycetes, in particular a Streptomyces according to claim 14 for the preparation of trioxacarcines of the general formula I according to claim 1.
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WO2011119549A1 (en) * 2010-03-22 2011-09-29 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
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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 (en) * 2010-03-22 2011-09-29 President And Fellows Of Harvard College Trioxacarcins and uses thereof
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 (en) * 2017-08-17 2019-02-21 William Marsh Rice University Trioxacarcin analogs and dimers as potent anticancer agents

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