WO2003055843A1 - Agaricoglycerides et analogues - Google Patents

Agaricoglycerides et analogues Download PDF

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WO2003055843A1
WO2003055843A1 PCT/EP2002/014289 EP0214289W WO03055843A1 WO 2003055843 A1 WO2003055843 A1 WO 2003055843A1 EP 0214289 W EP0214289 W EP 0214289W WO 03055843 A1 WO03055843 A1 WO 03055843A1
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formula
compounds
dsm
hydroxy
alkyl
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PCT/EP2002/014289
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German (de)
English (en)
Inventor
Marc Stadler
Veronika Hellwig
Burkhardt Wiese
Nils Burkhardt
Dirk Denzer
Anke Mayer-Bartschmid
Swen Allerheiligen
Michael Gerisch
Stephan-Nicholas Wirtz
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Bayer Healthcare Ag
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Priority claimed from DE10238007A external-priority patent/DE10238007A1/de
Application filed by Bayer Healthcare Ag filed Critical Bayer Healthcare Ag
Priority to AU2002358719A priority Critical patent/AU2002358719A1/en
Publication of WO2003055843A1 publication Critical patent/WO2003055843A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/69—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/88—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/90—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with esterified hydroxyl and carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
    • C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
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    • 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
    • C12N1/14—Fungi; Culture media therefor
    • C12N1/145—Fungal isolates
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    • 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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters
    • C12P7/625—Polyesters of hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • 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
    • C12R2001/645—Fungi ; Processes using fungi

Definitions

  • the invention relates to agaricoglycerides and analogs, ner processes for their manufacture and their use for the manufacture of medicaments for treatment and / or
  • Oleurolysin (EC 3.4.24.16) is a Zn metalloprotease that inactivates a number of biologically active peptides such as ⁇ eurotensin and dynorphin A by cleavage (Shrimpton and Smith J Peptide Sci. 2000, 6, 251-263; Vincent et al. Brain Res. 1996, 709, 51-58).
  • dynorphin A As a ⁇ -opioid receptor agonist, dynorphin A has a strong analgesic effect, and when applied centrally, neurotensin also has an analgesic effect (Tyler et al. Brain Res. 1998, 792, 246-252).
  • Neurolysin inhibitors should therefore increase the analgesic effects of neurotensin and dynorphin A by inhibiting the inactivation of these peptides.
  • salicylic acid alkane polyol esters such as, for example, salicylic acid glycerol esters, which are synthesized or from molluscs of the genera Kelletia and
  • Buccinulum have been isolated, i.a. in Experientia 1996, 52, 812-817 as HIN-1 reverse transcriptase inhibitors with antiviral activity.
  • Non-medical applications for certain substituted benzoic acid diol esters are described: as starting materials for the production of polyesters (US-A-4,065,432, JP-A 60 094 942, JP-A 60 019 751, JP-A 51 033 187); as starting materials for the production of polycarbonate resins for electrophotographic photoconductors (US-B 6,187,492); as additives for a positive photoresist (DE-A 43 04 098); as additives for electrophotographic toners (JP-A 10 161 351).
  • the present invention relates to compounds of the formula
  • R, R, R, R, R and R independently of one another are radicals selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 -alkyl and C 1 -C 4 -alkoxy,
  • R, R and R independently of one another represent radicals selected from the group consisting of hydrogen, hydroxy, acetoxy, amino, carboxyl, halogen, cyano and C 1 -C 4 -alkyl,
  • radicals R 2 , R 5 and R 8 are hydroxy, acetoxy, amino or carboxyl
  • R 10 represents hydrogen or -CC 6 alkyl
  • R represents halogen or cyano
  • R represents hydroxy or acetoxy
  • R 3 , R 7 and R 9 independently of one another represent radicals selected from the group consisting of hydrogen, halogen and cyano,
  • R 8 represents hydrogen, hydroxy or acetoxy
  • R 2 and R 8 are each in the meta or para position of the benzoyl radicals
  • R 11 represents hydrogen or - alkyl
  • R 12 represents C 6 -C 10 aryl or 5- to 10-membered heteroaryl
  • Ce-Cio-aryl and 5- to 10-membered heteroaryl with up to 3 substituents selected independently from the group halogen, cyano, trifluoromethyl, Cr alkyl and C 1 -C 6 alkoxy may be substituted, or
  • R 11 and R 12 together with the carbon atom to which they are attached form a 4- to 6-membered cycloalkyl ring
  • R 1 represents halogen or cyano
  • R 2 represents hydroxy or acetoxy
  • R, R and R independently of one another for radicals selected from the group
  • R 8 represents hydrogen, hydroxy or acetoxy
  • R 2 and R 8 are each in the meta or para position of the benzoyl radicals
  • R 10 represents hydrogen or -CC 6 alkyl
  • R 13 represents phenyl, where phenyl can be substituted with up to 3 substituents independently of one another selected from the group consisting of halogen, cyano, trifluoromethyl, -Ce-alkyl, -CC 6 alkoxy and -CO 2 R 15 ,
  • R 15 represents Ci-C ⁇ -Al yl and benzyl.
  • the present invention further relates to the use of compounds of the formula (I)
  • R represents halogen or cyano
  • R 2 represents hydroxy or acetoxy
  • R 3 , R 7 and R 9 independently of one another for radicals selected from the group
  • R 8 represents hydrogen, hydroxy or acetoxy
  • R 2 and R 8 are each in the meta or para position of the benzoyl radicals
  • n 0 to 3
  • R 16 represents hydrogen, -CC 6 -alkyl or C 3 -C 8 -cycloalkyl
  • R 17 represents C 1 -C 6 -alkyl or C 3 -C 8 -cycloalkyl
  • C 1 -C 6 -alkyl may optionally be substituted by phenyl
  • the compounds according to the invention can also be in the form of their salts, solvates or
  • the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers).
  • the invention therefore relates both to the enantiomers or diastereomers and to their respective mixtures. These enantiomer and diastereomer mixtures can be separated into the stereoisomerically uniform constituents in a known manner.
  • preferred salts are physiologically acceptable salts of the compounds according to the invention.
  • Physiologically acceptable salts of the compounds according to the invention can be acid addition salts of the compounds with mineral acids, carboxylic acids or sulfonic acids.
  • mineral acids carboxylic acids or sulfonic acids.
  • particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ehanesulfonic acid,
  • Toluenesulfonic acid benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Physiologically and questionable salts can also be salts with conventional bases, such as, for example, alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example Calcium or magnesium salts) or ammonium salts, derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dmydroabieylamine, 1-ephenamine or methylpiperidine.
  • alkali metal salts for example sodium or potassium salts
  • alkaline earth metal salts for example Calcium or magnesium salts
  • ammonium salts derived from ammonia or organic amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine, dmydroabiey
  • solvates are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water.
  • GCRG-alky stand for a straight-chain or branched alkyl radical having 1 to 6, preferably 1 to 4, particularly preferably having 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
  • C 1 -C 6 -alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6, preferably 1 to 4, carbon atoms.
  • Non-limiting examples include methoxy,
  • Cfi-Cin-Aryl stands for an aromatic radical with 6 to 10 carbon atoms.
  • Preferred aryl radicals are phenyl and naphthyl.
  • 5- to 10-membered heteroaryl stands for 5- to 10-membered aromatic rings containing heteroatoms with at least one aromatic ring, which can contain 1 to 4 heteroatoms, which can be selected from O, S and N. Heteroaryl can in turn be added via C or N may be substituted.
  • Non-limiting examples include pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, Indolicenyl, indolyl, benzo [b] thienyl, benzo [b] furyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl and quinazolinyl.
  • 4- to 6-membered cycloalkyl ring represents a cycloalkyl group with 4 to 6 carbon atoms.
  • Non-limiting examples include cyclobutyl, cyclopentyl and
  • Halogen stands for fluorine, chlorine, bromine and iodine. Fluorine, chlorine and bromine are preferred, particularly preferably fluorine and chlorine.
  • radicals in the compounds according to the invention are optionally substituted, the radicals, unless otherwise specified, can be substituted one or more times in the same or different manner. A substitution with up to three identical or different substituents is preferred. Substitution with a substituent is very particularly preferred.
  • the present invention further relates to compounds of the formula (I)
  • R 1 , R 3 , R 4 , R 6 , R 7 and R 9 are independently selected for residues from the
  • R 2 , R 5 and R 8 independently of one another represent radicals selected from the group consisting of hydrogen, hydroxy, acetoxy, amino, carboxyl, halogen, cyano and C 1 -C 4 -alkyl,
  • radicals R, R and R are hydroxyl, acetoxy, amino or carboxyl
  • R, R and R are each in the meta or para position of the benzoyl radicals
  • R 10 represents hydrogen or -CC 6 alkyl.
  • R 1 represents halogen or cyano
  • R> 2 represents hydroxy, acetoxy, amino or carboxyl
  • R 3 , R 4 , R 6 , R 7 and R 9 independently of one another for radicals selected from the group
  • R 5 and R 8 independently of one another represent radicals selected from the group consisting of hydrogen, hydroxy, acetoxy, amino, carboxyl, halogen, cyano and C 1 -C 4 -alkyl,
  • R 2 , R 5 and R 8 are each in the meta or para position of the benzoyl radicals
  • R i ⁇ represents hydrogen or -CC 6 alkyl. Also preferred are compounds of formula (I) in which
  • R represents halogen or cyano
  • R 5 represents hydroxy, acetoxy, amino or carboxyl
  • R 1 , R 3 , R 6 , R 7 and R 9 independently of one another represent radicals selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 alkyl and C 1 -C 4 alkoxy,
  • R and R independently of one another represent radicals selected from the group consisting of hydrogen, hydroxy, acetoxy, amino, carboxyl, halogen, cyano and C 1 -C 4 -alkyl,
  • R and R are each in the meta or para position of the benzoyl radicals
  • R, 1 1 0 U represents hydrogen or -CC 6 alkyl. Also preferred are compounds of formula (I) in which
  • R 1 , R 3 , R 4 , R 6 , R 7 and R 9 are independently selected for residues from the
  • R 1 , R 3 , R 4 , R 6 , R 7 and R 9 are independently selected from the
  • R 2 , R 5 and R 8 independently of one another represent radicals selected from the group consisting of hydrogen, hydroxy, acetoxy, amino and carboxyl,
  • radicals R 2 , R 5 and R 8 are hydroxy, acetoxy, amino or carboxyl, and
  • R 1 , R 3 , R 4 , R 6 , R 7 , R 9 and R 10 have the meanings given above.
  • R 2 , R 5 and R 8 are each in the para position of the benzoyl radicals
  • R 1 , R 3 , R 4 , R 6 , R 7 , R 9 and R 10 have the meanings given above.
  • R 2 , R 5 and R 8 are selected independently of one another from the group hydrogen, hydroxy and acetoxy
  • R 2 , R 5 and R are each in the para position of the benzoyl radicals, and R 1 , R 3 , R 4 , R 6 , R 7 , R 9 and R 10 have the meanings given above.
  • R 10 represents hydrogen
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 have the meanings given above.
  • R 1 , R 3 , R 4 , R 6 , R 7 and R 9 independently of one another represent hydrogen or chlorine
  • radicals R 1 , R 3 , R 4 , R 6 , R 7 and R 9 is chlorine
  • R, R and R independently of one another represent radicals selected from the group consisting of hydrogen, hydroxy and acetoxy,
  • R 2 , R 5 and R 8 are each in the para position of the benzoyl radicals
  • R, 1 ⁇ 0 ⁇ stands for hydrogen.
  • R 1 represents chlorine
  • R 2 represents hydroxy or acetoxy
  • R 3 , R 4 , R 6 , R 7 and R 9 independently of one another represent hydrogen or chlorine
  • R 5 and R 8 independently of one another represent radicals selected from the group consisting of hydrogen, hydroxy and acetoxy
  • R, 2, R r> 5 and R are each in the para position of the benzoyl radicals
  • R .1 ⁇ 0 ⁇ stands for hydrogen.
  • R 4 represents chlorine
  • R 5 represents hydroxy or acetoxy
  • R 1 , R 3 , R 6 , R 7 and R 9 independently of one another represent hydrogen or chlorine
  • R 2 and R 8 independently of one another represent radicals selected from the group consisting of hydrogen, hydroxy and acetoxy,
  • R and R are each in the para position of the benzoyl radicals
  • R ⁇ stands for hydrogen
  • the present invention further relates to compounds of the formula (I)
  • E stands for -CR 1 1R12-, R 1 represents halogen or cyano,
  • R represents hydroxy or acetoxy
  • R, R and R independently of one another for radicals selected from the group
  • R 8 represents hydrogen, hydroxy or acetoxy
  • R 2 and R 8 are each in the meta or para position of the benzoyl radicals
  • R 11 represents hydrogen or -CC 4 alkyl
  • R 12 represents C 6 -C ⁇ o-aryl or 5- to 10-membered heteroaryl
  • Ce-Cio-aryl and 5- to 10-membered heteroaryl with up to 3 substituents independently selected from the group halogen, cyano, trifluoromethyl, C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy can be substituted
  • R 11 and R 12 together with the carbon atom to which they are attached form a 4- to 6-membered cycloalkyl ring.
  • R 1 , R 3 , R 7 and R 9 represent chlorine
  • R 1 , R 3 , R 7 and R 9 are each in the meta position of the benzoyl radicals
  • R 2 and R 8 represent hydroxy
  • R 2 and R 8 are each in the para position of the benzoyl radicals
  • R n represents hydrogen or methyl
  • R 12 represents phenyl, pyridyl or quinolinyl
  • the present invention further relates to compounds of the formula (I)
  • R 1 represents halogen or cyano
  • R 2 represents hydroxy or acetoxy
  • R, R and R independently of one another are radicals selected from the group consisting of hydrogen, halogen, C 1 -C 4 -alkyl and cyano,
  • R represents hydrogen, hydroxy or acetoxy
  • R »1 ⁇ 0 ⁇ represents hydrogen or CC 6 alkyl
  • R 13 represents phenyl
  • R 15 is -Ce-alkyl and benzyl.
  • R 1 , R 3 , R 7 and R 9 represent chlorine
  • R 1 , R 3 , R 7 and R 9 are each in the meta position of the benzoyl radicals
  • R 9 and R R represent hydroxy
  • R 2 and R 8 are each in the para position of the benzoyl radicals
  • R 14 represents hydrogen
  • R 13 represents phenyl
  • phenyl can be substituted with up to 3 substituents independently selected from the group consisting of chlorine, fluorine, bromine, trifluoromethyl, C 1 -C 4 alkyl, methoxy and -CO 2 benzyl.
  • the present invention further relates to the following compounds
  • the present invention further preferably relates to the use of compounds of the formula (I)
  • R 2 represents hydroxy or acetoxy
  • R 3 , R 7 and R 9 independently of one another represent hydrogen or chlorine
  • R » stands for hydrogen, hydroxy or acetoxy
  • n 1 to 3
  • R 16 represents hydrogen or methyl
  • R 17 represents C 1 -C 4 -alkyl
  • dC 4 alkyl can optionally be substituted with phenyl
  • the invention further relates to processes for the preparation of the compounds of
  • R, ⁇ to R, R to R and R 10 have the meanings given above,
  • X 1 represents halogen, preferably bromine or chlorine, or hydroxy
  • R, 1 to R, 10 have the meanings given above,
  • X rl represents halogen, preferably bromine or chlorine, or hydroxy
  • R to R, R to R, R and R have the meanings given above,
  • R to R, R to R and R have the meanings given above,
  • Formula (I) comprises the compounds (Ia), (Ib) and (Ic).
  • the hydroxyl group of the radicals R, R and R optionally carries a protective group, such as. B. benzyl, which can be split off by methods known to those skilled in the art.
  • R 1 , R 2 , R 3 and R 10 have the meanings given above,
  • R 10 has the meanings given above,
  • X 3 represents halogen, preferably bromine or chlorine, or hydroxy
  • R 10 to R 13 , R 16 and R 7 have the meanings given above,
  • R, 10 has the meanings given above,
  • R 13 has the meanings given above, and X 4 represents halogen, preferably bromine or chlorine, hydroxy or methoxy,
  • R 10 and R 13 have the meanings given above,
  • Formula (X) includes compounds (Xa).
  • Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether,
  • hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or
  • Bases are, for example, alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, or amides such as lithium diisopropylamide, or organic amines such as DBU, triethylamine or diisopropylethylamine, preferably diisopropylethylamine or triethylamine.
  • alkali metal hydroxides such as sodium or potassium hydroxide
  • alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate
  • amides such as lithium diisopropylamide
  • organic amines such as DBU, triethylamine or diisopropylethylamine, preferably diisopropylethylamine or triethylamine.
  • Preferred inert solvents are tetrahydrofuran, dimethylformamide, 1,2-dichloroethane or methylene chloride. •
  • Typical condensing agents are, for example, carbodiimides such as, for example, N, N'-diethyl, N, N, '- dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexyl-carbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl- 1, 2-oxazolium-3 sulfate or 2-tert.
  • carbodiimides such as, for example, N, N'-diethyl, N, N, '- dipropyl, N, N'-diiso
  • acylamino compounds such as 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryloxy or benzotriazoloxy -tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-l-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1 - (2H) -pyridyl) - 1, 1, 3,3 -tetramethyl- uronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-l-yl) -N, N, N ', N'-t
  • Bases are, for example, alkali carbonates, e.g. Sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • alkali carbonates e.g. Sodium or potassium carbonate
  • hydrogen carbonate or organic bases
  • organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.
  • N- (3-dimethylaminoisopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt) and triethylamine in dimethylformamide or carbonyldiimidazole in 1,2-dichloroethane is particularly preferred.
  • Additional reagents are customary additional reagents for Mitsunobu reaction conditions, such as triphenylphosphine, diphenyl- (2-pyridyl) -phosphine or (4-dimethylaminophenyl) -diphenylphosphine, triphenylphosphine is preferred.
  • Azodicarboxylates are, for example, diethyl azodicarboxylate, dimethyl azodicarboxylate, diisopropyl azodicarboxylate or di-tert-butyl azodicarboxylate, diethylazodicarboxylate is preferred.
  • Inert solvents are, for example, halogenated hydrocarbons such as chloroform, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as benzene, xylene or toluene, nitroaromatics such as nitrobenzene, carboxylic acid amides such as dimethylformamide or dimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide, aliphatic nitrile nitrate, such as acetonitrile nitrile , Esters such as ethyl benzoate or other solvents such as N-methylpyrrolidone, preference is given to tetrahydrofuran.
  • halogenated hydrocarbons such as chloroform
  • ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane
  • hydrocarbons such as benzene, xylene
  • the compounds of the formula (II), (IV) and (VII) can, if appropriate, be obtained from the reaction mixtures by chromatography.
  • the invention further relates to processes for the preparation of the compounds of
  • R 2 represents hydroxy or acetoxy
  • R 6 and R 9 independently of one another represent hydrogen or chlorine
  • the compounds of formula (Id) are obtained by fermentation of microorganisms and the subsequent isolation of the compound from the culture broth.
  • the compounds of the formula (Id) are particularly preferably prepared by fermentation of Basidiomycetes, organisms of the genus Agaricus are particularly preferably used here.
  • Inoculum has been prepared in this way, this is aseptically into further shaking bottles or other suitable equipment for the fermentation of the
  • a vegetative inoculum is preferably used for large-volume fermentations.
  • the vegetative inoculum is made by inoculating a small volume of the culture medium with mycelium fragments.
  • the vegetative inoculum is then transferred to a fermentation vessel in which, after a suitable incubation period, the compounds according to the invention are produced in an optimal yield.
  • the medium in which the vegetative Inoculum produced can be identical or different to that medium which is used for the preparation of the compounds according to the invention, as long as it ensures sufficient microorganism growth.
  • the mushrooms are fermented successfully in NMG media (e.g. glucose:
  • malt extract media 0.4%, malt extract: 1.0%, yeast extract: 0.4%) or malt extract media (malt extract 1.0% to 4.0%).
  • other culture media such as medium Q6 / 2, ZM / 2, MGP medium (all see example 1), as well as oatmeal medium, potato dextrose nutrient solution, CMG nutrient solution and commeal medium (the latter culture media see ATCC Media Handbook , American Type Culture Collection, Rockville, Md., USA
  • a strain from the genus Agaricus is fermented in an aqueous nutrient medium under aerobic conditions, e.g. in a nutrient medium containing a source of coblene and possibly a proteinaceous material.
  • a source of coblene and possibly a proteinaceous material include glucose, brown sugar, sucrose, glycerin, starch, corn starch, lactose, dextrin, molasses, etc.
  • Preferred nitrogen sources include cottonseed flour, yeast, autolysed baker's yeast, solid milk components, soybean meal, corn flour, pancreatic or papainically digested casein breakdown products, solid distillation components , Animal broths
  • the preparation of the compounds of the formula (Id) can be induced at any temperature which ensures sufficient growth of the microorganisms.
  • the temperature is preferably between 21 ° C. and 32 ° C., particularly preferably approximately 24 ° C.
  • sterile air is usually passed through the culture medium.
  • the volume of air used is in the range from approximately 0.25 to approximately 0.5 volume of air per volume of culture medium per minute (wm).
  • An optimal ratio in a 10 L boiler is approximately 0.2 wm with movement generated by a conventional propeller rotating at approximately 200-500 rpm, preferably 100 rpm.
  • the addition of a small amount, such as 1 ml / l, of an anti-foaming agent, such as silicone, to the fermentation medium is necessary if foaming is a problem.
  • a further possibility for the preparation of the compounds of formula (Id) consists in the cultivation of microorganisms of the genus Agaricus on solid substrates, by adding gelatinizing materials such as agar-agar nutrient solutions or in liquid media in standing culture, for which purpose all common substrates including the liquid media specified above can be used.
  • optimal production of the compounds of formula (Id) is obtained within 8 to 25 days, preferably in about 11 days.
  • the fermentation broth usually becomes acidic during the fermentation (pH
  • the final pH is partly dependent on the buffer that may be used and partly on the initial pH of the culture medium.
  • the pH is preferably adjusted to approximately 6.0 to 7.0 before sterilization, particularly preferably to pH 6.3.
  • the compounds according to the invention are mainly present in the mycelium of the fermented microorganisms, but they can also occur, generally in smaller amounts, in the culture supernatant of the microorganisms.
  • the culture broth can be easily obtained by filtering through a filter press or a nutsche.
  • the production of the compounds according to the invention can be followed during the fermentation with the aid of analytical HPLC (UV or mass spectrometric detection), the compounds according to the invention being detectable directly in the crude extract.
  • analytical HPLC UV or mass spectrometric detection
  • extracts from freeze-dried culture broths as well as extracts made with the help of liquid-liquid extraction from smaller amounts of mycelium or culture broth removed during the fermentation can be used.
  • the production of the compounds according to the invention can be increased by sterile addition of potential biogenetic precursors such as glycerol and 3,5-dichloro-4-hydroxybenzoic acid to the fermentation medium.
  • the compounds according to the invention are suitable for use as medicaments for the treatment and / or prophylaxis of diseases in humans and / or animals.
  • the compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity.
  • the compounds according to the invention can be used alone or in combination with other medicaments for the prophylaxis and treatment of acute and / or chronic pain (for a classification see "Classification of Chronic Pain,
  • Chronic Pain Syndromes and Definitions of Pain Terms ", 2nd ed., Meskey and Begduk, eds .; IASP-Press, Seattle, 1994), in particular for the treatment of cancer-induced pain and chronic neuropathic Pain such as diabetic neuropathy, post-herpetic neuralgia, peripheral nerve damage, central pain (e.g. as a result of cerebral ischemia) and trigeminal neuralgia, and other chronic pain such as lumbago, low back pain, inflammatory or rheumatic Pain.
  • cancer-induced pain and chronic neuropathic Pain such as diabetic neuropathy, post-herpetic neuralgia, peripheral nerve damage, central pain (e.g. as a result of cerebral ischemia) and trigeminal neuralgia, and other chronic pain such as lumbago, low back pain, inflammatory or rheumatic Pain.
  • the invention also relates to eight new strains (WP 4080, WP 4105,
  • This invention also includes the use of any mutants capable of producing agaricoglycerides, including natural mutants and artificial mutants, which can be obtained in a manner known per se from the said microorganisms by conventional means, e.g. by radiation with X-rays, ultraviolet radiation, treatment with N-methyl-N'-nitro-N-nitrosoguanidine, 2-aminopurine and the like or by methods of genetic engineering.
  • test substances are dissolved in 100% DMSO and serially diluted. Typically, dilution series from 500 ⁇ M to 3.9 ⁇ M are produced (resulting final concentrations in the test: 10 ⁇ M to 0.078 ⁇ M). 2 ⁇ L of the diluted substance solutions are placed in the wells of microtiter plates (OptiPlate-96; Packard) submitted. Then 50 ⁇ L of a diluted neurolysin solution are added.
  • the enzyme reaction is finally started by adding 50 ⁇ L of diluted peptide substrate.
  • Thermal hyperalgesia can be determined by measuring the latency time within which a rat removes a paw from the area of a radiant heat source (Plantartest, Ugo Basile (Comerio, Italy)).
  • the substance is administered at different points before the pain test via different application routes (i.V., i.p., p.o., i.t, i.c.v., s.c, transdermal).
  • the difference between the von Frey pressures and the latency times in the plantart test is first determined between sham-operated and vehicle-treated axotomized rats. This difference represents the maximum achievable effect of the tibial axotomy.
  • the effect of an analgesic is shown as a percentage change in pain parameters related to the maximum effect.
  • the new active ingredients can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the Total mixture must be present, ie in amounts sufficient to achieve the dosage range indicated.
  • the formulations are, for example, by stretching the active ingredients with solvents and or carriers, optionally using
  • Emulsifiers and / or dispersants e.g. in the case of the use of water as a diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally, transdermally or parenterally, in particular perlingually or intravenously. However, it can also be done by inhalation through the mouth or nose, for example with the aid of a spray, or topically via the skin.
  • the amount is approximately 0.1 to 30 mg / kg, preferably approximately 0.5 to 10 mg / kg body weight.
  • the strains WP 4080 and WP 4105 were made using medium 2 from in Wuppertal in summer 1999, each on meadows by Dr. M. Stadler found and identified fruiting bodies of Basidiomycetes isolated. While the WP 4080 strain was isolated from the spore imprint of a Basidiomycete fruiting body, the WP4105 strain was successfully extracted from the sterile context of the
  • Basidiomycete fruiting body To take hat of another Basidiomycete fruiting body in culture.
  • the fruiting bodies showed a similar morphology and, according to the available knowledge, belong to the same species. They were divided into stems and hats and initially had pink-colored, later black-colored lamellas, on which the basidia with the basidiospores were formed. The spore dust was black.
  • boys In boys, the fruiting bodies showed a similar morphology and, according to the available knowledge, belong to the same species. They were divided into stems and hats and initially had pink-colored, later black-colored lamellas, on which the basidia with the basidiospores were formed. The spore dust was black.
  • boys In boys
  • a velum was observed in the fruiting bodies, and the adult fruiting bodies accordingly had a simple ring on the stem, which originated from the remnants of the velum.
  • the stem was 1-2 cm in diameter and up to 7 cm long, and the initially hemispherical hat, spread out in older specimens, reached a diameter of up to 8 cm.
  • a characteristic yellowing was observed on the outside of the entire fruiting body under pressure.
  • the fungal cultures were grown on YMG agar (medium la). After a week, the mycelium reached about 7 cm in diameter on an agar plate of 9 cm. The substrate discolored after about 10 days brownish, whereas the mycelium remained white-felted. Buckles were observed on the septa of the hyphae.
  • WP 4105 (the filing date is 31.10.2001 in both cases) under the Budapest Treaty with the DSMZ, German Collection of Microorganisms and Cell Cultures GmbH, Mascheroder Weg lb, D-38124 Braunschweig, Germany.
  • the strain MUCL 35030 was created in 1992 by Dr. C. Decock in Warcoing (Belgium) found in a garden and called Agaricus arvensis Schaeff.:Fr. identified fruiting bodies isolated and supplied to Bayer AG by MUCL (BCCMTM / MUCL, Mycotheque de l'Universite catholique de Louvain, Place Croix du Sud 3, B-1348 Louvain-la-Neuve, Belgium). The strain was again deposited with the DSMZ under the Budapest contract under the number DSM 14892. The filing date is March 8, 2002.
  • the WP 0058 strain was developed by Dr. H. Müller (Bayer AG) in September 1994 isolated from the spores of fruiting bodies of Agaricus bisporus (Lange) Imbach found in Wuppertal in September 1991. The strain was deposited with the DSMZ under the number DSM 14900 under the Budapest contract.
  • the filing date is March 18, 2002.
  • the fruiting bodies of the herbarium STMA 98023 were developed on May 9, 1998 by Dr. M. Stadler in Hamburg near the Hyundaiparkstadion found on a meadow and as Agaricus bitorquis (Quel.) Sacc. identified.
  • the culture (strain WP 4385) was created from the context of the hat.
  • the trunk was numbered
  • the strain MUCL 28516 was created in 1984 by Prof. Dr. G. L. Hennebert in Kapellen (Belgium) and found as Agaricus bitorquis (Quel.) Sacc. identified fruiting bodies isolated and supplied to Bayer AG by MUCL (BCCMTM / MUCL, Mycotheque de l'Universite catholique de Louvain, Place Croix du Sud 3, B-1348 Louvain-la-Neuve, Belgium). The strain was again deposited with the DSMZ under the Budapest contract under the number DSM 14893. The filing date is March 8, 2002.
  • the fruiting bodies of the STMA 97106 herbarium were obtained on September 9, 1997 in Wuppertal (Pahlkestrasse) from Dr. M. Stadler found on the edge of a paved walkway and as Agaricus bitorquis (Quel.) Sacc. identified.
  • the culture (strain WP 4140) was created from the context of the hat. The strain was deposited with the DSMZ under number DSM 14894. The filing date is March 8, 2002.
  • the strain MUCL 29004 was created in 1986 by Prof. Dr. GL Hennebert in Louvain-la-Neuve (Belgium) found on a meadow and called Agaricus campestris var. Campestris L.:Fr. identified fruiting bodies isolated and supplied to Bayer AG by MUCL (BCCMTM / MUCL, Mycotheque de l'Universite catholique de Louvain, Place Croix du Sud 3, B-1348 Louvain-la-Neuve, Belgium). The strain was again deposited with the DSMZ under the Budapest contract under the number DSM 14896. The filing date is March 8, 2002. The strain MUCL 28242 was created in 1993 by Prof. Dr.
  • strain CBS 585.76 was developed in September 1976 in Empolder near Embrugge (Netherlands) by Prof. Dr. W. Garns found and as Agaricus macrosporus
  • the WP 0059 strain was developed by Dr. H. Müller (Bayer AG) in September 1994 from the spores of fruiting bodies of Agaricus xanthoderma Genev found in Wuppertal in September 1991. isolated. The strain was deposited with the DSMZ under the number DSM 14901 under the Budapest contract. The filing date is March 18, 2002.
  • the fruiting bodies of the herbarium STMA 00034 were grown on September 9, 1997 in Wuppertal by Dr. M. Stadler in the Finsterbruimertal district (Schopp, Rhineland-Palatinate) found on wood from Pseudotsuga and identified as Hypholoma marginatum (Pers.:Fr.) J. Schrot.
  • the culture (strain FU41954) was created from the context of the hat. The strain was numbered DSM
  • the WP 0360 strain was obtained from Prof. R. Seeger on September 25, 1992 from fruiting bodies of a Hypholoma sp. Found near Coburg. isolated and to the Bayer AG delivered. The strain was deposited with the DSMZ under the number DSM 14902 under the Budapest contract. The filing date is March 18, 2002.
  • the strain FU 40473 was developed by Dr. H. Dörfelt isolated on October 3, 1999 from fruiting bodies of Psathyrella prona (Fr.) Gillet found on a cattle pasture in Neuengönna (Thuringia) and delivered to Bayer AG. The strain was deposited with the DSMZ under the number DSM 14903 under the Budapest contract. The filing date is March 18, 2002.
  • the strain DSM 11373 was supplied by the DSMZ as Stropharia rugosoannulata Farlow ex Murrill to Bayer AG and again deposited with the DSMZ under the Budapest contract under the number DSM 14904. The filing date is March 18, 2002.
  • the fruiting bodies of the herbarium STMA 97126 were harvested on September 22, 1997 near Johannisnch / Pfalz near Burgalbspring by Dr. M. Stadler found and as Stropharia squamosa (Pers.:Fr.) Pav. identified.
  • the culture (strain WP 4121) was created from the basidiospores. The strain was deposited with the DSMZ under the number DSM 14899 under the Budapest contract.
  • YMG yeast-malt-glucose medium
  • glucose 0.4%
  • yeast extract 0.4%
  • malt extract 1.0% made up with 1 L tap water.
  • pH was adjusted to 6.3 with 0.1 M HC1.
  • Medium la 1.5% Difco Bacto Agar was added to Medium 1 as described above before autoclaving. After cooling, slanted tubes or agar plates were poured from it.
  • Mycorrhiza Medium malt extract 0.8%, glucose 0.7%, asparagine 0.05%, casein hydrolyzate 0.1%, KH 2 PO4 0.05%, MgSO 4 0.05%, yeast extract 0.1%, Difco Bacto Agar 1.5% ad 1 L deionized water, pH Set 5.05 with 1 N hydrochloric acid before autoclaving for 30 min at 121 ° C and 1 bar
  • MGP medium glucose 1%, maltose 2%, soy peptone 0.2%, yeast extract 0.1%, KH 2 PO 4 0.1%, MgSO 4 x 7 H 2 O 0.05%, FeCl 3 (10 mM), 1 ml , ZnSO (1.78 g / 1) 1 ml, CaCl 2 (0.1 mM) 1 ml).
  • the above information applies to media in shake cultures and agar plates.
  • the fermenters were generally sterilized with steam and with the addition of small amounts of defoamer, as described below in the corresponding examples.
  • the fermentation was carried out using 1 L Erlenmeyer flasks, each containing 300 ml of medium 1, which was inoculated with 10 pieces of agar from a well-covered plate of medium la, each about 1 cm in diameter.
  • the fermentation was carried out at an incubation temperature of 23 ° C. on a rotary shaker at 140 rpm for 192 hours.
  • the mycelium was separated from the rest of the culture broth by centrifugation (15 min at 1000 x g) and then extracted as described in general procedure C.
  • Analogous fermentations in media 2 - 5 also led to the formation of the agaricoglyceride after a fermentation period of 192 h. This was determined with the help of HPLC analyzes to quantify the agaricoglyceride (see Table 2). With media M4 and M5, the fermentation time can be extended cause an increase in the agaricoglyceride content up to 300 h, so that these media have been selected for the fermentations on a 30 L scale.
  • strain Agaricus sp. WP 4080 is characterized by better production rates and was therefore selected for the production in the stirred tank, which is described in the following
  • the strain Agaricus sp. WP 4080 in medium 1 (see under fermentation media), as described under general procedure A, is grown.
  • the fermentation was carried out either in medium 4 or medium 5.
  • 1 x 200 ml (for main culture in medium 4) or 3 x 200 ml (for main culture in medium 5) of a preculture was used as an inoculum for 30 L medium 4 or medium 5.
  • SAG 5693 (Union Carbide, USA) added per L, and sterilized with steam for 60 min at 1.1 bar. This production culture was incubated for 115 hours at 24 ° C., aeration of 0.2 wm and a stirrer speed of 100 rpm.
  • HPLC parameters Two different analytical HPLC methods with UN / visual (HPLC-UV / Vis) and with mass spectrometric detection (HPLC-MS) were used to characterize the agaricoglycerides.
  • HPLC-UN / Nis analyzes were carried out using a Hewlett Packard Series 1100 analytical HPLC system (HP, Waldbronn, Germany), consisting of a G 1312A binary pump system, a G 1315A diode array detector, a G 1316A column temperature control system, a G 1322A degassing system and one
  • HPLC-MS was carried out on an HP 1100 HPLC system, coupled to a Micromass-LCT mass spectrometer (Micromass, Manchester, Great Britain) in ESI + mode and in ESIneg mode. Mass spectra were recorded in the range between 200 and 1200.
  • the HP100 system used operated with the following parameters: Stationary phase: Waters Symmetry C18, 3.5 around 2.1x50mm column, mobile phase: gradient water (A), acetonitrile (B) + 0.1% formic acid (0-1 min 100% A; 1-5 min linear gradient to 10% A / 90% B; 5-6 min 10% A / 90% B, 6-6.10 min 90% B - 100% B). The results were saved and evaluated using the integrated Micromass OpenLynx Browser Version software
  • the qualitative detection was carried out by comparing the characteristic HPLC-UV and HPLC-MS data (retention times, UV and ESI-LC-MS spectra).
  • the content determination for the agaricoglyceride A and the detection of the other compounds was carried out using external and internal standards of methanolic solutions of the agaricoglycerides.
  • the retention times of the compounds are shown in Table 1 and the amounts of agaricoglyceride A formed during the fermentation in Table 2. Since the secondary components (examples 2 and 3) were difficult to detect from the crude extracts, they were not quantified.
  • Table 2 Content of agaricoglyceride A in the mycelial extracts of WP 4080 from shake cultures in different media and with different fermentation times
  • Method A Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm,
  • HPLC-MS is connected to an HP 1100 HPLC system, coupled to a micromass
  • Method 2 Instrument: Micromass ZMD, HP1100; Column: Nucleosil, 50 mm x 2.1 mm, 5 ⁇ m;
  • 4- (Benzyloxy) -3-chloro-5-fluorobenzoic acid chloride can be prepared analogously to 4- (benzyloxy) -3,5-dichlorobenzoic acid chloride (Example 12A) starting from 4- (hydroxy) -3-chloro-5-fluorobenzoic acid (cf. : J Org. Chem. 1952, 17, 1425-1430).
  • 4- (Benzyloxy) -3-cyanobenzoic acid chloride can be prepared analogously to 4- (benzyloxy) -3,5-dichlorobenzoic acid chloride (Example 12A) starting from 4- (hydroxy) -3-cyano-benzoic acid (cf. US Pat. No. 4,151,297) , Example 7A
  • 4- (Benzyloxy) -3-fluorobenzoic acid chloride can be prepared analogously to 4- (benzyloxy) -3,5-dichlorobenzoic acid chloride (Example 12A) starting from 4- (hydroxy) -3-fluoro-benzoic acid (cf. Lit. J Org. Chem. 1952, 17, 1425-1430).
  • Example 12A 3,5-dichlorobenzoic acid chloride (Example 12A) starting from 4- (hydroxy) -5-chloro-2,3-difluorobenzoic acid, obtainable from l-chloro-2,3,4-trifluoro-5- (trifluoromethyl) benzene (cf. DE-A 3 736089) in analogy to 3-chloro-2,5,6-trifluoro-4-hydroxybenzoic acid, which is obtained by heating l-chloro-2,3,4,6-tetrafluoro-5- (trifluoro - Methyl) benzene can be obtained with sodium hydroxide solution (cf. DE-A 3 804 288).
  • Example 1A 15.0 mg (16.1 ⁇ mol) of Example 1A are dissolved in a mixture of 2 ml of methanol and 2 ml of tetrahydrofuran. After adding 5.0 mg of Lindlar catalyst, the mixture is hydrogenated for one hour at room temperature and RT. The suspension is filtered through Celite and washed with methanol. The filtrate is concentrated and the residue is purified on silica gel 60 (mobile phase: dichloromethane-methanol 100: 0, 100: 1, 100: 2). 2.8 mg (25.0% of theory) of product are obtained.
  • the mycelium from 10 YMG shake flasks was separated from the supernatant by centrifugation and combined. The moist mycelium was then twice with each
  • the yield was 16 mg of the title compound from the mycelium of 1 L culture.
  • Nerfahren 3 Representation from the mycelium of a fermentation on a 30 L scale (MGP medium)
  • the mycelium from a fermentation in 200 L MGP medium was removed from the supernatant
  • the total yield was 291 mg of the title compound from the mycelium of 30 L culture.
  • Nerfahren 4 Representation from the mycelium of a fermentation on a 200 L scale (Q6 medium)
  • the material to 50 g was C j g ftmmiealupperem silica gel (Sigma Aldrich 37.763 to 5) adsorbed.
  • the solvent was evaporated in vacuo and the dry extract / silica gel mixture was applied to a chromatography column consisting of the same cig chromatography material that had been equilibrated with 50% acetonitrile (column size
  • the title compound was highly enriched from the column with a retention time (R t ) of 99-112 min in an intermediate 2.
  • This intermediate product 2 (together 3.2 g from 32 grams of intermediate product 1) was portioned into aliquots of approximately 250 mg and again using a Merck
  • Hydroxybenzoic acid increased to 18.2 - 19.0 mg.
  • Example 10 Preparation of Example 10 can be isolated as a by-product.
  • Example 31 can be prepared analogously to example 39 from the corresponding starting compounds.
  • MS (ESIneg): mz 683 (MH) " ;
  • LC / MS (Method 1): R t 7.1 min;
  • Phenols can be prepared analogously to the synthesis of Example 1:
  • Example 2A 130 mg (0.2 mmol) of Example 2A, 50.0 mg (0.22 mmol) of benzyl p-hydroxybenzoate and 67.9 mg (0.26 mmol) of triphenylphosphine are successively dissolved in 5 ml of abs. Dissolved tetrahydrofuran and stirred at 0 ° C for ten minutes. Then 34.5 ⁇ l (0.22 mmol) of diethyl azodicarboxylate are added dropwise. The reaction mixture is warmed to RT in an ice bath, stirred for 3 days and then concentrated.
  • Example 37 can be produced analogously to example 36 from the corresponding starting compounds.
  • Example 38 can be prepared analogously to example 32 from the corresponding starting compounds.
  • MS (ESIneg): m / z 687 (MH) " ;
  • Example 39 can be prepared by reacting 2 - [(3,5-dichlorobenzoyl) oxy] -1- (hydroxymethyl) ethyl-3,5-dichlorobenzoate (Example 3A) with 4- (benzyloxy) -3,5-dichlorobenzo- Acid chloride (Example 12A) can be obtained analogously to Example 1.
  • 1H-NMR 500 MHz, d 6 -DMSO
  • ⁇ ca.ll.3 (s, broad, OH), 7.95 (s, IH), 7.93 (s, IH), 7.89 (s, 2H), 7.83 (s, 2H), 7.81 (s, 2H), 5.72 (m, IH), 4.79-4.63 (m, 4H).
  • Example 40
  • Example 40 can be prepared analogously to example 39 from the corresponding starting compounds.
  • the information below relates to the microorganism and / or other biological material mentioned in the description -1 page 49 -2 line 30 -3 information regarding deposit -3-1 name of the depository DSMZ-German collection of microorganisms and cell cultures GmbH -3-2 Address of the depository Mascheroder Weg lb, D-38124 Braunschweig, Germany -3-3 Date of deposit 18 March 2002 (03/18/2002) -3-4 Receipt number DSMZ 14900 -4 Further information NONE -5 Destination states , for which all destinations are given special information -6 separately submitted information NONE
  • the following information relates to the microorganism and / or other biological material mentioned in the description -1 page 50 -2 line 6 -3 Information regarding deposit -3-1 Name of the depository DSMZ-German Collection of Microorganisms and Cell Cultures GmbH -3-2 Address of the depository Mascheroder Weg lb, D-38124 Braunschweig, Germany -3-3 Date of deposit 08 March 2002 ( 08.03.2002) -3-4 Entry number DSMZ 14895 -4 Further information NONE -5 Destination states for which all destination states are given special information -6 Separately submitted information NONE
  • This international depository accepts the microorganism designated under 1, which it received on 2 001 - 10 -3 1 (date of first deposit) 1 .
  • microorganism referred to under I was received by this International Depository on (date of first deposit) and an application for the conversion of this initial deposit into a deposit under the Budapest Treaty was received on (date of receipt of the application for conversion).
  • This international depository accepts the microorganism designated under 1, which it received on 2001 - 1 0 - 31 (date of first filing).
  • microorganism referred to in 1 has been received by this International Depository on (date of first deposit) and an application for conversion of this first deposit into a deposit under the Budapest Treaty has been received on (date of receipt of the application for conversion).
  • This international depository accepts the microorganism referred to under I, which it received on 2002-03-08 (date 'first deposit)'.
  • microorganism designated under I was received by this depository on (date of first deposit) and an application for the conversion of this first deposit into a deposit according to the Budapest Treaty was received on (date of receipt of the request for conversion).
  • microorganism referred to under I was received by this International Depository on (date of first deposit) and an application for the conversion of this initial deposit into a deposit under the Budapest Treaty was received on (date of receipt of the request for conversion).
  • This international depository accepts the microorganism designated I, which it received on 2002-03-08 (date of first deposit).
  • microorganism referred to under I was received by this international depository on (date of first deposit) and an application for the conversion of this first deposit into a deposit under the Budapest Treaty was received on (date of receipt of the request for conversion).
  • This international depository accepts the microorganism designated under I, which it received on 2002-03-08 (date of first deposit).
  • microorganism referred to under I was received by this international depository on (date of first deposit) and an application for conversion of this initial deposit into a deposit under the Budapest Treaty was received on (date of receipt of the application for conversion).
  • microorganism referred to in 1 has been received by this international depository on (date of first filing) and an application for conversion of this first deposit into a deposit under the Budapest Treaty has been received on (date of receipt of the request for conversion).
  • This international depository accepts the microorganism referred to under I, which it received on 2002-03-08 (date of first deposit).
  • microorganism referred to under I was received by this international depository on (date of first deposit) and an application for the conversion of this first deposit into a deposit under the Budapest Treaty was received on (date of receipt of the request for conversion).
  • This international depository accepts the microorganism referred to under I, which it received on 2002-03-08 (date of first deposit) 1 .
  • microorganism referred to under I was received by this international depository on (date of first deposit) and an application for the conversion of this first deposit into a deposit under the Budapest Treaty was received on (date of receipt of the request for conversion).
  • microorganism referred to under I has been received by this International Depository on (date of first filing) and an application for conversion of this first deposit into a deposit under the Budapest Treaty has been received on (date of receipt of the application for conversion).
  • microorganism referred to under I has been received by this International Depositary on (date of first deposit) and an application for the conversion of this first deposit into a deposit under the Budapest Treaty has been received on (date of receipt of the request for conversion).
  • microorganism referred to under I was received by this international depository on (date of first deposit) and an application for the conversion of this first deposit into a deposit under the Budapest Treaty was received on (date of receipt of the request for conversion).

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Abstract

Agaricoglycérides et analogues, procédé de production de ces substances, ainsi que leur utilisation pour la fabrication de médicaments destinés au traitement et / ou à la prophylaxie de maladies, en particulier d'états de douleur.
PCT/EP2002/014289 2001-12-27 2002-12-16 Agaricoglycerides et analogues WO2003055843A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002358719A AU2002358719A1 (en) 2001-12-27 2002-12-16 Agaricoglycerides and analogs

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE10164141.9 2001-12-27
DE10164141 2001-12-27
DE10238007.4 2002-08-20
DE10238007A DE10238007A1 (de) 2001-12-27 2002-08-20 Agaricoglyceride und Analoga

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WO2003055843A1 true WO2003055843A1 (fr) 2003-07-10

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PCT/EP2002/014289 WO2003055843A1 (fr) 2001-12-27 2002-12-16 Agaricoglycerides et analogues

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AU (1) AU2002358719A1 (fr)
WO (1) WO2003055843A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006225386A (ja) * 2005-02-14 2006-08-31 Merck Patent Gmbh メソゲン化合物、液晶媒体および液晶ディスプレイ
WO2007112505A1 (fr) * 2006-04-05 2007-10-11 Nufarm Australia Limited Derives esters de type glyceride de composes herbicides et compositions les comprenant
US20100137194A1 (en) * 2007-04-16 2010-06-03 The Regents Of The University Of Michigan Plasminogen Activator Inhibitor-1 Inhibitors and Methods of Use Thereof to Modulate Lipid Metabolism
US9096501B2 (en) 2007-04-16 2015-08-04 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 inhibitors and methods of use thereof to modulate lipid metabolism
US9718760B2 (en) 2012-10-31 2017-08-01 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 inhibitors and methods of use thereof
US11426368B2 (en) 2017-07-27 2022-08-30 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 (PAI-1) inhibitor and method of use

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO1992018459A1 (fr) * 1991-04-18 1992-10-29 Yoshitomi Pharmaceutical Industries, Ltd. Compose d'ester benzoique et procede de production

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WO1992018459A1 (fr) * 1991-04-18 1992-10-29 Yoshitomi Pharmaceutical Industries, Ltd. Compose d'ester benzoique et procede de production

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A. LESPAGNOL ET AL.: "A propos quelques nouveaux dérivés de l'aspirine", BULLETIN DE LA SOCIETE DE PHARMACIE DE LILLE., vol. 1, - 1969, LILLE., FR, pages 33 - 41, XP008015051, ISSN: 0366-3507 *
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HANAYAMA, NAOKI ET AL: "Preparation of glycol mono- or dibenzoate esters", XP002234889, retrieved from STN Database accession no. 118:212685 *
E. DE JONG, J. A. FIELD: "Sulfur Tuft and Turkey Tail", ANNUAL REVIEW OF MICROBIOLOGY., vol. 51, 1997, ANNUAL REVIEWS INC., PALO ALTO, CA., US, pages 375 - 414, XP008014950, ISSN: 0066-4227 *
JIRACEK J ET AL: "DEVELOPMENT OF THE FIRST POTENT AND SELECTIVE INHIBITOR OF THE ZINCENDOPEPTIDASE NEUROLYSIN USING A SYSTEMATIC APPROACH BASED ON COMBINATORIAL CHEMISTRY OF PHOSPHINIC PEPTIDES", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY OF BIOLOGICAL CHEMISTS, BALTIMORE, MD, US, vol. 271, no. 32, 9 August 1996 (1996-08-09), pages 19606 - 19611, XP000677097, ISSN: 0021-9258 *
M. COVELLO, G. CIAMPA ET AL.: "Synthesis and properties of 2-hydroxy- and 2-acetoxy-5-iodobezoic acid polyesters of short-chain aliphatic polyalcohols", LA RICERCA SCIENTIFICA, vol. 38, no. 10, 1968, pages 933 - 936, XP008015073 *
M. H. PORCHER, G. RIMMINGTON: "Sorting Agaricus Names", INTERNET ARTICLE, - 8 March 1999 (1999-03-08), XP002234888, Retrieved from the Internet <URL:http://gmr.landfood.unimelb.edu.au/Plantnames/Sorting/Agaricus.html> [retrieved on 20030312] *
TH. SABALITSCHKA: "Synthesische Studien über die Beziehung zwischen chemischer Konstitution und antimikrobischer Wirkung X", ARCHIV DER PHARMAZIE., 1931, VCH VERLAGSGESELLSCHAFT MBH, WEINHEIM., DE, pages 228 - 246, XP008015074, ISSN: 0365-6233 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006225386A (ja) * 2005-02-14 2006-08-31 Merck Patent Gmbh メソゲン化合物、液晶媒体および液晶ディスプレイ
WO2007112505A1 (fr) * 2006-04-05 2007-10-11 Nufarm Australia Limited Derives esters de type glyceride de composes herbicides et compositions les comprenant
US20100137194A1 (en) * 2007-04-16 2010-06-03 The Regents Of The University Of Michigan Plasminogen Activator Inhibitor-1 Inhibitors and Methods of Use Thereof to Modulate Lipid Metabolism
US9096501B2 (en) 2007-04-16 2015-08-04 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 inhibitors and methods of use thereof to modulate lipid metabolism
US9120744B2 (en) * 2007-04-16 2015-09-01 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 inhibitors and methods of use thereof to modulate lipid metabolism
US9527878B2 (en) 2007-04-16 2016-12-27 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 inhibitors and methods of use thereof to modulate lipid metabolism
US9718760B2 (en) 2012-10-31 2017-08-01 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 inhibitors and methods of use thereof
US11426368B2 (en) 2017-07-27 2022-08-30 The Regents Of The University Of Michigan Plasminogen activator inhibitor-1 (PAI-1) inhibitor and method of use

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