AU2003201963B2 - Drechslera anole derivatives, method for the production and use thereof - Google Patents
Drechslera anole derivatives, method for the production and use thereof Download PDFInfo
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- AU2003201963B2 AU2003201963B2 AU2003201963A AU2003201963A AU2003201963B2 AU 2003201963 B2 AU2003201963 B2 AU 2003201963B2 AU 2003201963 A AU2003201963 A AU 2003201963A AU 2003201963 A AU2003201963 A AU 2003201963A AU 2003201963 B2 AU2003201963 B2 AU 2003201963B2
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- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000012631 food intake Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 210000001682 neurofibril Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 235000019319 peptone Nutrition 0.000 description 1
- 229940066779 peptones Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000001965 potato dextrose agar Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000013587 production medium Substances 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000027765 speech disease Diseases 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000011573 trace mineral Substances 0.000 description 1
- 235000013619 trace mineral Nutrition 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 108010046845 tryptones Proteins 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/04—Chelating agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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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
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/04—Oxygen as only ring hetero atoms containing a five-membered hetero ring, e.g. griseofulvin, vitamin C
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- 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
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Description
WO 03/064405 PCT/EP03/00487 Drechsleranol derivatives, processes for their preparation and their use The present invention relates to novel compounds called drechsleranols, which are formed by the microorganism Drechslera australiensis, ST 003360, DSM 14093, or a fungus ST 004112, DSM 14524 which has not been determined more closely taxonomically, during fermentation, a process for the preparation of these compounds and their use for the production of pharmaceuticals, in particular for the treatment and/or prophylaxis of degenerative neuropathies, for example of Alzheimer's disease, or psychic disorders, such as depression, sleep disturbances or seasonally related affective disorders.
Alzheimer's disease is a neuropsychiatric disorder which mainly occurs in elderly people. The disease is manifested in a symptom complex which includes memory disorders, reduced perceptivity, orientation disorders, speech disorders, disorders of coordinated thought, etc. In Alzheimer patients, characteristic neurohistological changes are found in the brain, such as, for example, the deposits of "amyloid plaques" and also a degeneration of the neurofibrils in the nerve cells ("fibrillar bundles"). These changes are admittedly characteristic, but nonspecific, since they also occur to a smaller extent in the normal ageing process.
At present no causal treatment, but only symptomatic treatment, is possible. So far there are medicaments which only delay the course of the disease, but they are not able to cure it. The group consisting of the cerebral acetylcholinesterase inhibitors (Tacrin®, Donepezil®, Rivastigmin®, Galantamin®), currently offers the most important therapeutic approach, since for the memory-relevant structures, which are impaired to a considerable extent in Alzheimer's, cholinergic signal transmission plays a great role. The medicaments, however, can only be employed in the mild and middle stages of the disease. They increase the concentration of acetylcholine in the information-transmitting synapses of the brain. If there is too severe damage to the neurons, i.e. in the late stage of the disease, they are no longer effective. Further substances whose use has been investigated are estrogens, nonsteroidal analgesics, antioxidants and nerve growth factors (NGF).
It is estimated that at present there are approximately one million people in the Federal Republic of Germany who are suffering from Alzheimer's disease. This figure will presumably increase still further in the next few years on account of the increasing life expectancy of the population. Novel substances for the treatment of this disorder are therefore urgently necessary.
The group consisting of the c-Jun N-terminal kinases (JNKs) are protein kinases which are activated by oxidative stress. So far, it is known that only JNK-3 (in contrast to JNK-1 and JNK-2) is expressed in the neurons of the human brain. There are indications that the JNKs have an influence on cell death. This cell death (or apoptosis) is probably the causal mechanism of the death of the neurons in the brain of Alzheimer's patients (Kumagae et al., Mol. Brain Res. (1999), 67(1), 10-7). The activation of c-Jun N-terminal kinase is one step in this mechanism. Inhibition at this position should thus prevent apoptosis, and thereby counteract the development of the Alzheimer's disorder and halt its progress.
A further aspect of the present invention is the treatment and/or prophylaxis of psychic disorders. Circadian rhythms are generated by endogenous timers which are present in a great variety of organisms. The circadian clock is important for the maintenance of the biological rhythm. It is self-sustaining and constant, even in total darkness, but it can be synchronized by external signals, such as, for example, changes in the light or the temperature. The internal clock controls the daily fluctuations of behavior, activity, food intake, the sleeping/waking cycle just as physiological changes such as, for example, hormone secretion and changes in the body temperature (Keesler et al., Neuroreport (2000), 11(5), 951-955).
Period (PER) is a central protein of this circadian clock, which is subject to daily variations with respect to its concentration or its phosphorylation state. The phosphorylation of human PER1 (hPER1) by the enzyme human casein kinase 1 epsilon (hCK1E) causes a decrease in the protein stability with hPER1.
Phosphorylated hPER1 has a half life of approximately 12 hours, whereas unphosphorylated hPER1 remains stable in cells for longer than 24 hours. An influencing of this central protein hPER1 is clinically of importance especially in diseases which are connected with a disorder of the internal clock, such as, for example, depression (Souetre E. et al., Annales medico-physiologiques, 1985, 143(9), 845-870), sleep disturbances or seasonally related affective disorders. For the treatment of depression, so far monoamine oxidase inhibitors and inhibitors of the reuptake of noradrenalin and/or serotonin into the axoplasma tricyclic antidepressants) are available, the exact mechanism of action hitherto not being clarified. With an inhibitor of hCK1E, one would have available a new active principle for the treatment of psychic disorders, such as, for example, of sleep disturbances, seasonally related affective disorders and in particular of depression.
The invention relates to a compound of the formula (I) 0 0
II
R
1
R
1 where R is H, or a group of the formula -(CH(OR 2 5
-CH
2
-OR
2 and
R
1 and R 2 independently of one another are Hor a C1-C6-alkyl, C2-C6-alkenyl, C 2
-C
6 -alkynyl or C5-C10-aryl group, in which alkyl, alkenyl and alkynyl are straight-chain or branched, and in which the groups are optionally mono- or disubstituted by: 2.1-OH, 2.2=0, 2.3-O-C 1
-C
6 -alkyl, in which alkyl is straight-chain or branched, 2.4-O-C 2
-C
6 -alkenyl, in which alkenyl is straight-chain or branched, 2.6-NH-C1-C 6 -alkyl, in which alkyl is straight-chain or branched, 2.7-NH-C2-C6-alkenyl, in which alkenyl is straight-chain or branched, 2.8-NH 2 or 2.9 halogen, in which the substituents 2.3 to 2.7 can be further substituted by -CN, -amide or -oxime functions, or a stereoisomeric form of the compound of the formula or a physiologically tolerable salt of the compound of the formula or a physiologically tolerable salt of a stereoisomeric form of a compound of the formula
C
1 -C6-alkyl is a straight-chain or branched alkyl having 1 to 6 C atoms, preferably having 1 to 4 C atoms, e.g. methyl, ethyl, i-propyl, tert-butyl and hexyl.
C2-C6-alkenyl is a straight-chain or branched alkenyl having 2 to 6 C atoms, which is mono-, di- or triunsaturated, e.g. allyl, crotyl, 1-propenyl, penta-1,3-dienyl and pentenyl.
C2-C6-alkynyl is a straight-chain or branched alkynyl having 2 to 6 C atoms, which is mono- or diunsaturated, e.g. propynyl, butynyl and pentynyl.
C5-C10-aryl is an aryl group having 5 to 10 C atoms, e.g. phenyl, benzyl or 1- or 2naphthyl, which can also be further substituted, for example by halogen, such as chlorine, bromine, fluorine, by alkyl having 1-4 C atoms, preferably methyl, by hydroxyl, by alkoxy having 1-4 C atoms, in particular methoxy, or by trifluoromethyl.
The invention preferably relates to a compound of the formula in which R is H or a group of the formula -(CH(OR 2 5
-CH
2
-OR
2
R
1 and R 2 independently of one another are H or C 1
-C
6 -alkyl, or a stereoisomeric form and/or a physiologically tolerable salt of this preferred compound.
The invention particularly preferably relates to a compound of the formula in which R is a group of the formula -(CH(OR 2 5
-CH
2
-OR
2 and R 1 and R 2 are H, or a stereoisomeric form and/or a physiologically tolerable salt of this particularly preferred compound. Such a compound is described by formula (II):
OH
OH
HO
OH
HO
(II)
HO OH HO A further particularly preferred subject of the invention is a compound of the formula in which R and R 1 are H, or a stereoisomeric form and/or a physiologically tolerable salt of this compound. Such a compound is described by formula (III): OH HO Chiral centers in the compounds of the formula and (II) can be present, if not stated otherwise, in the R or in the S configuration. The invention relates both to the optically pure compounds and to mixtures of stereoisomers, such as mixtures of enantiomers and mixtures of diastereomers, in any ratio.
The invention furthermore relates to obvious chemical equivalents of the compounds of the formulae (II) or (III).
Obvious chemical equivalents of the compounds according to the invention are compounds which have the same activity as the compounds according to the invention and exhibit a slight chemical difference or are converted into the compounds according to the invention under mild conditions. The equivalents mentioned include, for example, ethers, esters, reduction products and complexes of the compounds according to the invention.
For example, one or more hydroxyl groups of the compounds of the formula (11) or (111) can be etherified, for example with a C1-C6-alcohol with addition of acid, or esterified with, for example, an activated acid, for example acid chlorides or other acid derivatives. It is further possible, for example, for one or more double bonds of the compound of the formula (11) or (111) to be reduced using a reductant, double bonds, for example, being reduced using H 2 /Pd.
The phenol groups of the compounds according to the invention can furthermore form chelates with mono- or polyvalent cations. Compounds which contain chelateforming phenol groups moreover have an antioxidant effect Sugihara et al., Journal of Health Science 2001, 47(2), 99-106). Antioxidants (oxidation inhibitors) are organic compounds which inhibit or prevent undesired changes in the substances to be protected caused by the effects of oxygen. Antioxidants are needed, for example, in plastics for protection against ageing, in fats for protection against rancidity, in oils against resinification, in aromatic substances against deterioration in odor, in foodstuffs, in pharmaceuticals, etc. The action of the antioxidants is usually that they act as radical scavengers for the free radicals occurring in the oxidation. The compounds of the formula (11) and (111) can therefore also be used as chelating agents and as antioxidants.
The abovementioned methods for derivatization are described in textbooks such as Jerry March, Advanced Organic Chemistry, John Wiley Sons, 4 th Edition, 1992. In order to carry out reactions selectively, it can be advantageous to introduce suitable protective groups in a manner known per se before the reaction. The protective groups are removed after the reaction, then the reaction product is purified.
The compounds of the formulae (11) and (111), and the obvious chemical equivalents thereof, can be converted into the corresponding pharmaceutically tolerable salts according to methods known to the person skilled in the art.
Pharmacologically tolerable salts of the compounds according to the invention are understood as meaning both inorganic and organic salts, such as are described in Remingtons Pharmaceutical Sciences (17th edition, page 1418 [1985]). Possible salts are, in particular, alkali metal, ammonium and alkaline earth metal salts, salts with physiologically tolerable amines and salts with inorganic or organic acids such as, for example, HCI, HBr, H 2
SO
4 maleic acid, fumaric acid.
The invention additionally relates to a compound of the empirical formula
C
2 6
H
2 4 0 9 characterized by the 1 H-NMR and 13 C-NMR data according to table 2 (vide infra), or a stereoisomeric form and/or a physiologically tolerable salt.
The invention additionally relates to a compound of the empirical formula
C
2 0
H
1 2 0 3 characterized by the 1 H-NMR and 13 C-NMR data according to table 3 (vide infra), or a stereoisomeric form and/or a physiologically tolerable salt. The invention additionally relates to a compound formula obtainable by fermentation of ST 003360 (DSM 14093) or of a variant and/or mutants of ST 003360 (DSM 14093) in a culture medium until the compound of the formula (11) accumulates in the culture broth, subsequent isolation of the compound of the formula and, if appropriate, conversion into a pharmacologically tolerable salt.
The invention additionally relates to a compound formula (111), obtainable by fermentation of ST 004112 (DSM 14524) or of a variant and/or mutants of ST 004112 (DSM 14524) in a culture medium until the compound of the formula (111) accumulates in the culture medium, subsequent isolation of the compound of the formula (111), and, if appropriate, conversion into a pharmacologically tolerable salt.
The invention moreover relates to a compound of the formula obtainable by fermentation of ST 003360 (DSM 14093) or of a variant and/or mutants of ST 003360 (DSM 14093) in a culture medium until the compound of the formula (11) accumulates in the culture broth, subsequent isolation of the compound of the formula or fermentation of ST 004112 (DSM 14524) or of a variant and/or mutants of ST 004112 (DSM 14524) in a culture medium until the compound of the formula (111) accumulates in the culture medium, subsequent isolation of the compound of the formula (111), and subsequent conversion into a compound of the formula and, if appropriate, conversion into a pharmacologically tolerable salt.
An isolate of Drechslera australiensis, ST 003360, was deposited in the Deutsche Sammlung von Mikroorganismen und Zellkulturen (German Collection of Microorganisms and Cell Cultures) GmbH (DSM), Mascheroder Weg 1B, 38124 Brunswick, Germany according to the rules of the Budapest convention on the 02.28.
2001 under the following number: DSM 14093.
The strain Drechslera australiensis, ST 003360, DSM 14093, has a dark black-brown mycelium and has no further characteristic features.
An isolate of a hitherto taxonomically undetermined fungus, ST 004112, was deposited in the Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH (DSM), Mascheroder Weg 1B, 38124 Brunswick, Germany according to the rules of the Budapest convention under the following number: DSM 14524.
The strain ST 004112, DSM 14524, is gray to black on malt agar. The strain was isolated from a soil sample from French Guyana.
The invention furthermore relates to a process for the preparation of the compound of the formula which comprises culturing the microorganism ST 003360 (DSM 14093) or a variant and/or mutant of ST 003360 (DSM 14093) in an aqueous nutrient medium, isolating and purifying a compound of the formula and converting it, if appropriate, into an obvious chemical equivalent and/or a pharmacologically tolerable salt.
The invention furthermore relates to a process for the preparation of the compound of the formula (111), which comprises culturing the microorganism ST 004112 (DSM 14524) or a variant and/or mutant of ST 004112 (DSM 14524) in an aqueous nutrient medium, isolating and purifying a compound of the formula (III), and converting it, if appropriate, into an obvious chemical equivalent and/or a pharmacologically tolerable salt.
The invention furthermore relates to a process for the preparation of a compound of the formula which comprises a) culturing the microorganism ST 003360 (DSM 14093) or a variant and/or mutants of ST 003360 (DSM 14093) in an aqueous culture medium, and isolating and purifying the compound of the formula or culturing the microorganism ST 004112 (DSM 14524) or a variant and/or mutants of ST 004112 (DSM 14524) in a culture medium, and isolating and purifying the compound of the formula (III), and b) converting a compound of the formula (II) or a compound of the formula (III) into a compound of the formula and c) converting the compound of the formula if appropriate, into a pharmacologically tolerable salt.
Instead of the strain Drechslera australiensis, DSM 14093, or of the strain ST 004112, DSM 14524, their respective mutants and/or variants can also be employed.
A mutant is a microorganism in which one or more genes of the genome have been modified, the gene or the genes being functionally and hereditarily retained which are responsible for the capability of the organism to produce the inventive compound.
Such mutants can be produced in a manner known per se by physical means, for example irradiation, such as using ultraviolet rays or X-rays, or chemical mutagens, such as, for example, ethyl methanesulfonate (EMS); 2-hydroxy-4-methoxybenzophenone (MOB) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), or as described by Brock et al. in "Biology of Microorganisms", Prentice Hall, pages 238- 247 (1984).
A variant is a phenotype of the microorganism. The microorganisms have the ability to adapt to their environment and therefore show marked physiological flexibility. In the phenotypic adaptation, cells of the microorganism are involved, the nature of the modification not being genetically conditioned and being reversible under modified conditions Stolp, Microbial ecology: organisms, habitats, activities. Cambridge University Press, Cambridge, GB, page 180, 1988).
The screening for mutants and variants which produce the antibiotic according to the invention can be carried out by determination of the biological activity of the active compound accumulated in the culture broth, for example by determination of the JNK-3- or hCK1E-inhibiting action, or by detection of compounds, which are known as JNK-3- or hCK1E-inhibiting, in the fermentation broth by, for example, HPLC or LC-MS methods.
The fermentation course and the formation of the compounds according to the invention can be monitored according to methods known to the person skilled in the art, such as, for example, by testing the biological activity in bioassays or by chromatographic methods such as thin-layer chromatography (TLC) or highperformance liquid chromatography (HPLC).
In a nutrient medium which contains at least one carbon and nitrogen source and also the customary inorganic salts, under aerobic conditions the strain Drechslera australiensis, ST 003360, DSM 14093, produces the compound of the formula (11) according to the invention, and the strain ST 004112, DSM 14542, produces the compound of the formula (111) according to the invention.
The fermentation conditions described below apply for the strain Drechslera australiensis, ST 003360, DSM 14093, and for the strain ST 004112, DSM 14524.
Suitable preferred carbon sources for the aerobic fermentation are assimilable carbohydrates and sugar alcohols, such as glucose, lactose, sucrose or D-mannitol and carbohydrate-containing natural products, such as, for example, malt extract.
Suitable nitrogen-containing nutrients are: amino acids, peptides and proteins and their degradation products, such as peptones or tryptones, furthermore meat extracts, yeast extracts, ground seeds, for example of corn, wheat, beans, soy or of the cotton plant, distillation residues from alcohol production, meat meals or yeast extracts, but also ammonium salts and nitrates. Organic salts which the nutrient solution can contain are, for example, chlorides, carbonates, sulfates or phosphates of the alkali metals or alkaline earth metals, iron, zinc, cobalt and manganese. Trace elements which the nutrient solution can contain are, for example, molybdenum, copper, nickel or selenium.
The formation of the compound (11) according to the invention proceeds particularly well in a nutrient solution which contains approximately 0.1 to preferably 0.5% to of potato dextrose and 0.2 to preferably 0.5 to of yeast extract. The details in percent are in each case based on the weight of the entire nutrient solution.
The formation of the compound (111) according to the invention proceeds particularly well in a nutrient solution which contains approximately 0.1 to preferably 0.5% to of malt extract and 0.2 to preferably 0.5 to of yeast extract. The details in percent are in each case based on the weight of the entire nutrient solution.
The culturing of the microorganism is carried out aerobically, for example, submerse with shaking and stirring in shaker flasks or fermenters, optionally with introduction of air or oxygen or on solid media. It can be carried out in a temperature range from approximately 18 to 350C, preferably at approximately 20 to 300C, in particular at 22 to 280C. The pH range should be between 4 and 8, preferably between 5 and 6. The microorganism is cultured under these conditions, in general, over a period of 24 to 300 hours, preferably 36 to 168 hours.
Culturing is advantageously carried out in a number of stages, i.e. one or more precultures are first prepared in a liquid nutrient medium, which are then inoculated into the actual production medium, the main culture, for example in the volume ratio 1:10 to 1:100. The preculture is obtained, for example, by inoculating a mycelium into a nutrient medium and allowing it to grow for approximately 36 to 120 hours, preferably 48 to 72 hours. The mycelium can be obtained, for example, by allowing the strain to grow for approximately 3 to 40 days, preferably 4 to 10 days, on a solid or liquid nutrient medium, for example malt-yeast agar or potato dextrose agar.
The invention is illustrated further in the following examples. Percentage details relate to the weight. Mixing ratios in the case of liquids relate to the volume, if no other details have been given.
The inventive compounds occur both in the mycelium and in the culture filtrate. It is therefore expedient to separate the fermentation solution into the culture filtrate and the mycelium by filtration and to dry them separately. The dried culture filtrate and the dried mycelium are expediently separately extracted using an organic solvent, for example methanol or propan-2-ol.
If a culture has been applied to solid medium, the inventive compounds are present both in the mycelium and in the solid agar medium. The entire culture is expediently lyophilized and the lyophilizate is extracted with an organic solvent, for example methanol or propan-2-ol.
The extraction can be carried out in a wide pH range, but it is expedient to work in a neutral or weakly alkaline medium, preferably between pH 7 and pH 10. The extract can be concentrated and dried, for example, in vacuo.
One method of the isolation of the compounds according to the invention is carried out by the separation principle of the different polarities in a manner known per se.
A further method of purification is chromatography on adsorption resins such as, for example, on Diaion® HP-20 (Mitsubishi Casei Corp., Tokyo), on Amberlite® XAD 7 (Rohm and Haas, USA), on Amberchrom® CG, (Toso Haas, Philadelphia, USA) or on the like. Moreover suitable are numerous reversed-phase supports, e.g. RP 8 and
RP
18 such as have become generally known, for example, in the context of highpressure liquid chromatography (HPLC).
A further possibility of purification of the compounds according to the invention consists in the use of "normal-phase" chromatographic supports, such as, for example, silica gel or A1 2 0 3 or others in a manner known per se.
An alternative isolation process is the use of molecular sieves, such as, for example, Fractogel@ TSK HW-40 (Merck, Germany) and others, in a manner known per se. It is moreover possible to recover the compounds according to the invention from enriched material by crystallization. Suitable for this purpose are, for example, organic solvents and their mixtures, anhydrous or with the addition of water. An additional process for the isolation and purification of the antibiotics according to the invention consists in the use of anion exchangers, preferably in the pH range from 4 to 10. Particularly suitable for this purpose is the use of buffer solutions to which portions of organic solvents have been added.
It has surprisingly been found that the compounds of the formula according to the invention are inhibitors of JNK-3 and CK-I. Table 1 summarizes the activity data of the inventive compounds by way of example: Table 1: Activity data of the compounds of the formula (11) and (111) Receptor (11) (111) JNK-3 1.1 pM 2.8 /M hCK1E 2.9 pM not determined The present invention therefore also relates to the use of one or more of the compounds of the formula (11) or (111) according to the invention as pharmaceuticals, and to the use of one or more of the compounds of the formula (11) or (111) according to the invention for the production of pharmaceuticals, in particular for the treatment and/or for the prophylaxis of degenerative neuropathies, for example of Alzheimer's disease, or psychic disorders, for example of depression, sleep disturbances or seasonally related affective disorders.
The present invention additionally relates to a pharmaceutical containing one or more compounds according to the invention.
Said pharmaceutical containing a compound of the formula (11) and/or (111) is prepared using one or more physiologically suitable excipients and brought into a suitable administration form.
The pharmaceuticals according to the invention can be administered enterally (orally), parenterally (intramuscularly or intravenously), rectally or locally (topically).
They can be administered in the form of solutions, powders (tablets, capsules including microcapsules), ointments (creams or gel), or suppositories. Possible physiologically suitable excipients or formulations of this type are the pharmaceutically customary liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavor corrigents, colorants and/or buffer substances. As an expedient dose, 0.1 1000, preferably 0.2 100, mg/kg of body weight are administered. They are expediently administered in dose units which contain at least the effective daily amount of the compounds according to the invention, e.g. 30 3000, preferably 50 1000, mg.
The following examples are intended to serve for the illustration of the invention in greater detail, without wishing to restrict the breadth of the invention in any manner.
Example 1: Preparation of a glycerol culture of Drechslera australiensis, ST 003360, DSM 14093.
100 ml of nutrient solution (malt extract yeast extract glucose
(NH
4 2 HP0 4 0.05%, pH 6.0) in a sterile 300 ml Erlenmeyer flask were inoculated with the strain Drechslera australiensis, ST 003360, DSM 14093, and incubated on a rotating shaker for 7 days at 25 0 C and 140 rpm. 1.5 ml of this culture were then diluted with 2.5 ml of 50% strength glycerol and stored at -135 0
C.
Example 2: Preparation of a main culture in the Erlenmeyer flask of Drechslera australiensis, ST 003360, DSM 14093.
A sterile 300 ml Erlenmeyer flask containing 100 ml of the following nutrient solution: 2.4 g/l of potato dextrose, 0.2 g/l of yeast extract, was inoculated with a culture grown in a slant tube (same nutrient solution, but with 2% agar) or with 1 ml of a glycerol culture (see example 1) and incubated at 180 rpm and 25 0 C on a shaker.
The maximum production of the drechsleranol of the formula (II) according to the invention was achieved after about 144 hours. For the inoculation of 10 I fermenters, a 48 to 96 hour-old submerse culture (inoculation amount about 10%) from the same nutrient solution sufficed.
Example 3: Preparation of the compound of the formula (II) in a 10 1 fermenter.
A 10 I fermenter was operated under the following conditions: Nutrient medium: 2.4 g/l of potato dextrose 0.2 g/l of yeast extract pH 5.1 (before sterilization) Incubation time: 115 hours Incubation temperature: 250 C Stirrer speed: 200 rpm Aeration: 15 /min It was possible to suppress foam formation by repeated addition of ethanolic polyol solution. The production maximum was achieved after about 96 to 144 hours.
Example 4: Isolation of the compound of the formula (II).
A fermentation batch from a glass fermenter having a nominal volume of 10 I was lyophilized and extracted 3x with 3 I of methanol in each case. The methanol extract was reduced to about 500 ml in vacuo and diluted with water to a methanol content of 10%. The diluted extract (5 I) was then applied to a prepared glass column (BPG 100, 4 I internal volume, Pharmacia Biotech), which was packed with about 0.5 liter of MCI-Gel® CHP-20P material (adsorber resin from Mitsubishi Chemicals, Japan).
The column was then eluted using a gradient of 100% water to 100% acetonitrile in 60 min. The column flow (50 ml min) was collected in fractions (50 ml each). All fractions were tested in the JNK-3 assay and the active fractions (fractions 26-44) were combined. Concentration in vacuo and subsequent lyophilization afforded 1.21 g of a brown powder.
This powder was applied to a LUNA® 10 p C18 column (size: 50 mm x 250 mm; Phenomenex, Germany) with a LUNA® 10 p C18 precolumn (size: 21.2 mm x mm) and chromatographed using a gradient of 0% to 50% acetonitrile in 0.1% ammonium acetate/water over the course of 50 minutes. The flow of the eluent was 125 ml/min, the fraction size 250 ml. Fraction 17 showed the greatest activity in the subsequent bioassay. It was lyophilized (220 mg) and subsequently investigated by means of mass spectrometry. It was seen that the fraction consisted of a single substance (purity Example 5: Characterization of the compound of the formula (II).
The physicochemical and spectroscopic properties of the compound isolated according to example 4 can be summarized as follows: Empirical formula: C 2 6
H
24 0 9 Molecular weight: 480 UV maxima: 226, 236, 260, 312, 340 nm 1 H- and 13 C-NMR: see table 2 Table 2: NMR chemical at 300 K shifts 6 (ppm) of the compound of the formula (II) in DMSO Position 'H 1C 1 152.57 2 118.06 3 7.45 129.9 (broad) 4 124.95 -134.57 6 7.62 115.83 7 7.26 125.99 8 6.75 107.91 9 154.76 115.27 11 152.27 12 119.16 13 7.38 130.13 14 7.30 117.58 135.66 16 7.28 118.72 17 7.25 126.37 18 6.75 108.19 19 154.50 115.15 21 4.62 78.4 (broad) 22 3.62 73.43 Position 1'H C 23 3.39 78.91 24 3.25 70.47 3.34 81.29 26 3.69, 3.45 61.37 Example 6: Preparation of a glycerol culture of ST 004112, DSM 14524.
100 ml of nutrient solution (malt extract yeast extract glucose
(NH
4 2 HP0 4 0.05%, pH 6.0) in a sterile 300 ml Erlenmeyer flask were inoculated with the strain DSM 14524 and incubated on a rotating shaker for 7 days at 250C and 140 rpm. 1.5 ml of this culture were then diluted with 2.5 ml of 50% strength glycerol and stored at -135°C.
Example 7: Preparation of a main culture of ST 004112, DSM 14524, on solid medium (plates).
sterile 25 x 25 cm 2 plates were poured using 200 ml of a nutrient solution containing 20 g/I of malt extract, 2 g/l of yeast extract and 2% agar and having a pH of 7.0 in each case. These plates were inoculated with 2 ml of a preculture and incubated at 250C. The maximum production of the compound of the formula (111) was achieved after about 360 hours.
Example 8: Preparation of a main culture in the Erlenmeyer flask of ST 004112, DSM 14524.
A sterile 300 ml Erlenmeyer flask containing 100 ml of the following nutrient solution: 2.4 g/ of potato dextrose, 0.2 g/ of yeast extract, was inoculated with a culture grown in a slant tube (same nutrient solution, but with 2% agar) or with 1 ml of a glycerol culture (see example 6) and incubated at 180 rpm and 25°C on a shaker.
The maximum production of the compound of the formula (111) was achieved after about 144 hours. For the inoculation of 10 1 fermenters, a 48 to 96 hour-old submerse culture (inoculation amount about 10%) of the same nutrient solution sufficed.
Example 9: Isolation of the compound of the formula (111).
plate cultures (20 x 20 cm each plate) were lyophilized and extracted 2x with 10 I of methanol in each case. The methanol extract was reduced to about 500 ml in vacuo and diluted to a methanol content of 10% with water. The diluted extract (5 I) was then applied to a prepared glass column (BPG 100, 4 I internal volume, Pharmacia Biotech), which was packed with about 0.5 liter of MCI-Gel® material (adsorber resin of Mitsubishi Chemicals, Japan). The column was eluted using a gradient of 100% water to 100% acetonitrile in 30 min. The column flow ml/min) was collected in fractions (50 ml each). All fractions were tested in the JNK-3 assay and the active fractions (fractions 30-44) were combined.
Concentration in vacuo and subsequent lyophilization afforded a brown gummy residue.
The residue was dissolved in water/acetonitrile centrifuged and applied to a LUNA® 10 p C18 column (size: 21 mm x 250 mm; Phenomenex, Germany) and chromatographed using a gradient of 0% to 100% acetonitrile in 0.1% ammonium acetate/water over the course of 60 minutes. The flow of the eluent was 33 ml/min, the fraction size 33 ml. Fractions 28-32 showed the greatest activity in the subsequent bioassay. They were lyophilized and then further purified. For this, the substance was chromatographed on a LUNA® 5p C18 column (size: 10 mm x 250 mm; Phenomenex, Germany) using a gradient of 30% to 60% acetonitrile in 0.1% ammonium acetate/water over the course of 45 minutes. The flow of the eluent was 6.5 ml/min, the fraction size 6.5 ml. Fractions 18-24 showed the greatest activity in the subsequent bioassay. After freeze-drying (yield: 10 mg), subsequent analysis by means of analytical HPLC and MS spectrometry showed that it was a homogeneous compound (purity Example 10: Characterization of the compound of the formula (III).
The physicochemical and spectroscopic properties of the compound isolated according to example 9 can be summarized as follows: Empirical formula: C 20
H
12 0 3 Molecular weight: 300 UV maxima: 226, 236, 260, 312, 340 nm 1 H- and 13C-NMR: see table 3 Table 3: NMR chemical shifts 6 (ppm) of the compound of the formula (III) in MeOD at 300 K.
Position 1H 1C 1 154.3 (a) 2 -121.3 (a) 3 7.46 130.63 4 7.31 119.55 137.60 6 7.24 119.55 7 7.22 127.52 8 6.69 109.20 9 157.0 -117.5 (a) For these carbon atoms, no (or an extremely broad) signal is observed in the 13C spectrum. The chemical shifts were therefore determined by means of correlations in the HMBC spectrum.
Example 11: Demonstration of the activity of the compounds of the formulae (II) and (III) in the JNK-3 assay The assay is carried out on a CyBio pipetter system in a 384-hole plate format. The assay contains 10 pl of sample (extract or pure substance, for example a compound of the formula (II) or of the formula (III)) in 3% DMSO, 10 pl of an enzyme/substrate mixture (JNK-3 /GST-ATF2) and 10 pl of ATP in a final volume of 30 p1. After incubation at 370C for 20 minutes, 50 pl of the HTRF antibody mixture (XL665-anti- GST/ (Eu)cryptate anti-P-ATF2) are added. After 120 minutes at room temperature, the signal emission of the energy transfer and of europium at 665 and 615 nm is measured after the samples have been stimulated at 340 nm in a Victor 2
(WALLAC).
Buffer I for the dilution of JNK3, GST-ATF2, ATP: mM HEPES, pH 100 /M MgCI 2 0.03% TRITON X 100 mM DTT Glycerol Buffer II for the dilution of the HTRF reagents: 100 mM HEPES, pH 100 mM KF 133 mM EDTA 1 g/I BSA Reagents: Supplier: Final concentration: JNK3 Kinase Biotech, Vitry 8 ng well GST-ATF2 Biotech, Vitry 88 ng well ATP Sigma, A7699 15 pM Anti-GST-XL665 CisBio 125 ng well Anti-P-ATF2-(Eu)cryptate NEB/CisBio 6 ng well Each plate contains 16 positive controls (maximum energy transfer, buffer I instead of samples), 8 blank controls (minimum energy transfer, buffer II instead of ATP) and 8 holes which contain EDTA 200 pM.
The results are calculated as follows: Firstly, the signal ratio (intensity (665nm) /intensity (615nm)) is determined. A blank correction is then carried out in which the following formula is used: delta F (ratio (sample) ratio (min)) (ratio (min) x 100) The activity of the samples is then calculated in the following manner: Inhibition 100 x 1 (delta F(sample) delta F(max)) Example 12: Demonstration of the activity of the compound of the formula (II) in the hCK1s assay The assay is carried out in a Jobi-Well (CyBio) and Biomek 2000 pipetter system in the 384-hole plate format. The 384-hole plates are coated with 50 pl per well of a casein solution of the concentration 100 pg/ml in coating buffer (corresponds to 5 pg of casein per well, casein Sigma) and is stored overnight at 4 0 C. Washing four times with 90 pl of wash solution 1 (50 mM HEPES pH 7.4 and 150 mM NaCI) is then carried out. The reaction is carried out in a final volume of 50 pl. During the course of this, 10 pl of dilute natural substance extract in each case, for example a compound of the formula (II) or a compound of the formula (111), 20 pl of hCK1E enzyme solution (corresponds to 29 ng of casein per well) and 20 p1 of ATP solution (final concentration: 0.4 pCi of 33 P-y-ATP radiolabeled and 0.4 /M of cold ATP per well) are pipetted onto the coated plates. The plates are then incubated at 37°C for one hour. The plates are then washed four times with 75 p1 of wash solution 2 (phosphoric acid, and measured for 30 seconds in a MicroBeta Trilux counter
(WALLAC).
hCK1E enzyme solution: 1.45 pg of recombinant hCK1E per ml of kinase buffer Kinase buffer: M HEPES pH 7.4 mM MgCl2 0.25 mM DTT 0.6 mM EGTA Coating buffer: 27.5 mM Na 2 C0 3 22.5 mM NaHCO 3 (pH 9.6) in 0.9% NaCI ATP solution: 20 pCi/ml of 33 P-y-ATP and 1 pM of cold ATP On each plate, 16 holes are used in order to determine the total enzyme activity.
(without inhibitor addition) and a further 16 without enzyme addition in order to determine the nonspecific reaction.
00
O
CI The inhibition of a sample can be calculated according to the following formula: S[1-(CPM(sample)- CPM(nonspec.)) (CPM(enzyme concentration) CPM (nonspec.))] x 100 0 CPM counts per minute S The results of the JNK-3 and hCK1e assays are summarized in table 1 (vide c( supra).
0 c Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
Claims (17)
- 2.0 a C 1 -C 6 -alkyl, C2-C 6 -alkenyl, C2-C 6 -alkynyl or C 5 -C10-aryl group, in which alkyl, alkenyl and alkynyl are straight-chain or branched, and in which the groups are optionally mono- or disubstituted by: 2.1 -OH, 2.2 =0, 2.3 -O-C 1 -C 6 -alkyl, in which alkyl is straight-chain or branched, 2.4 -O-C 2 -C 6 -alkenyl, in which alkenyl is straight-chain or branched, -aryl, 2.6 -NH-C 1 -C 6 -alky l in which alkyl is straight-chain or branched, 2.7 -NH-C 2 -C 6 -alkenyl, in which alkenyl is straight-chain or branched, 2.8-NH 2 or 2.9 halogen, in which the substituents 2.3 to 2.7 can further be substituted by -CN, -amide or -oxime functions, 00 O O (N a O O \O (N, or a stereoisomeric form of the compound of the formula or a physiologically tolerable salt of the compound of the formula or a physiologically tolerable salt of a stereoisomeric form of a compound of the formula 2. A compound of the formula as claimed in claim 1, where R is H or a group of the formula -(CH(OR 2 5 -CH 2 -OR 2 R 1 and R 2 independently of one another are H or C 1 -C 6 -alkyl, in which C 1 -C 6 -alkyl is straight-chain or branched and optionally mono- or disubstituted by the radicals 2.1 to 2.9.
- 3. A compound of the formula as claimed in claim 1, characterized in that it has the formula (II) OH OH HO HO HO' or a stereoisomeric form of the compound of the formula (II) or a physiologically tolerable salt of the compound of the formula (II) or a physiologically tolerable salt of a stereoisomeric form of a compound of the formula (II).
- 4. A compound of the formula as claimed in claim 1, characterized in that it has the formula (III) I 00 6noo cO N: OH HO or a stereoisomeric form of the compound of the formula (111) or a physiologically tolerable salt of the compound of the formula (I11) or a physiologically tolerable 0 5 salt of a stereoisomeric form of a compound of the formula (111). A compound of the formula (11) as claimed in claim 3 or a pharmacologically tolerable salt of a compound of the formula obtainable by fermentation of ST 003360 (DSM 14093) or of a variant or mutant of ST 003360 (DSM 14093) in a culture medium until the compound of the formula (11) accumulates in the culture broth, subsequent isolation of the compound of the formula and, if appropriate, conversion into a pharmacologically tolerable salt of the compound of the formula (11).
- 6. A compound of the formula (111) as claimed in claim 4 or a pharmacologically tolerable salt of a compound of the formula (111), obtainable by fermentation of ST 004112 (DSM 14524) or of a variant or mutant of ST 004112 (DSM 14524) in a culture medium until the compound of the formula (111) accumulates in the culture medium, subsequent isolation of the compound of the formula (111), and, if appropriate, conversion into a pharmacologically tolerable salt of the compound of the formula (111).
- 7. A compound of the formula as claimed:in claim 1 or a pharmacologically tolerable salt of a compound of the formula bbtainable by fermentation of ST 003360 (DSM 14093) or of a variant or mutant of ST 003360 (DSM 14093) in a culture medium until the compound of the formula (11) accumulates in the culture broth, subsequent isolation of the compound of the formula or fermentation of ST 004112 (DSM 14524) or of a variant or mutant of ST 004112 (DSM 14524) in a culture medium until the compound of the formula (111) accumulates in the 00 0 culture medium, subsequent isolation of the compound of the formula (111), and cI subsequent conversion into a compound of theformula and, if appropriate, conversion into a pharmacologically tolerable salt. of the compound of the formula MI.
- 8. A process for the preparation of the compound of the formula (11) as Sclaimed in claim 3 or pharmacologically tolerable salt of a compound of the formula (11I), characterized in that it comprises Sa) culturing the microorganism ST 003360 (DSM 14093) or a variant or t' mutant of ST 003360 (DSM 14093), 10 b) isolating and purifying a compound of the formula and (Ni c) converting the compound of the formula if appropriate, into an obvious chemical equivalent or a pharmacologically tolerable salt.
- 9. A process for the preparation of the compound of the formula (111) as claimed in claim 4 or of a pharmacologically tolerable salt of a compound of the formula (111), characterized in that it comprises a) culturing the microorganism ST 004112 (DSM 14524) or a variant or mutant of ST 004112 (DSM 14524), b) isolating and purifying a compound of the formula (111), and c) converting the compound of the formula (111), if appropriate, into an obvious chemical equivalent or a pharmacologically tolerable salt. A process for the preparation of a compound of the formula as claimed in claim 1 or of a pharmacologically tolerable salt of a compound of the formula characterized in that it comprises a) culturing the microorganism ST 003360 (DSM 14093) or a variant or mutant of ST 003360 (DSM 14093) in a culture medium, and isolating and purifying the compound of the formula (11), 00 O or culturing the microorganism ST 004112 (DSM 14524) or a variant or Smutant of ST 004112 (DSM 14524) in a culture medium, and isolating and purifying the compound of the formula (111), and b) converting a compound of the formula (11) or a compound of the formula (111) into a compound of the formula and c) converting the compound of the formula if appropriate, into a pharmacologically tolerable salt.
- 11. The use of a compound as claimed in one of claims 1 to 7 for the production of a pharmaceutical.
- 12. The use of a compound as claimed in one of claims 1 to 7 for the production of a pharmaceutical for the therapy or prophylaxis of degenerative neuropathies.
- 13. The use of a compound as claimed in one of claims 1 to 7 for the production of a pharmaceutical for the therapy or prophylaxis of Alzheimer's disease.
- 14. The use of a compound as claimed in one of claims 1 to 7 for the production of a pharmaceutical for the therapy or prophylaxis of psychological disorders.
- 15. The use of a compound as claimed in one of claims 1 to 7 for the production of a pharmaceutical for the therapy or prophylaxis of depressions, sleep disturbances or seasonally related affective disorders.
- 16. The use of a compound as claimed in one of claims 1 to 7 as a chelating agent or antioxidant.
- 17. A pharmaceutical containing at least one compound as claimed in any one of claims 1 to 7 and one or more physiologically suitable excipients.
- 18. The strain Drechslera australiensis, ST 003360, DSM 14093.
- 19. The strain ST 004112, DSM 14524. A compound substantially as hereinbefore described according to example 4 or
- 21. A method of therapy or prophylaxis of a condition described in any one of claims 12 to 15 by the administration of an effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable derivative thereof to a subject in need. Sanofi-Aventis Deutschlahd GmbH WATERMARK PATENT TRADE MARK ATTORNEYS P24231AU00
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| DE10203557.1 | 2002-01-29 | ||
| DE10203557A DE10203557A1 (en) | 2002-01-29 | 2002-01-29 | Drechsleranol derivatives, process for their preparation and their use |
| PCT/EP2003/000487 WO2003064405A1 (en) | 2002-01-29 | 2003-01-20 | Drechslera anole derivatives, method for the production and use thereof |
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| EP (1) | EP1472240B1 (en) |
| JP (1) | JP4436134B2 (en) |
| AR (1) | AR038233A1 (en) |
| AT (1) | ATE466848T1 (en) |
| AU (1) | AU2003201963B2 (en) |
| BR (1) | BR0307199A (en) |
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| DE (2) | DE10203557A1 (en) |
| IL (1) | IL163166A (en) |
| MX (1) | MXPA04006358A (en) |
| PE (1) | PE20030815A1 (en) |
| WO (1) | WO2003064405A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105339362B (en) * | 2013-06-26 | 2017-09-01 | Dic株式会社 | Compound containing phenolic hydroxyl group, phenolic resin, solidification compound, its solidfied material, semiconductor-encapsulating material and tellite |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3068706B2 (en) * | 1992-02-26 | 2000-07-24 | 塩野義製薬株式会社 | Aldose reductase inhibitor |
-
2002
- 2002-01-29 DE DE10203557A patent/DE10203557A1/en not_active Withdrawn
-
2003
- 2003-01-20 DE DE50312692T patent/DE50312692D1/en not_active Expired - Lifetime
- 2003-01-20 AU AU2003201963A patent/AU2003201963B2/en not_active Ceased
- 2003-01-20 JP JP2003564028A patent/JP4436134B2/en not_active Expired - Fee Related
- 2003-01-20 AT AT03700811T patent/ATE466848T1/en not_active IP Right Cessation
- 2003-01-20 EP EP03700811A patent/EP1472240B1/en not_active Expired - Lifetime
- 2003-01-20 CA CA2473988A patent/CA2473988C/en not_active Expired - Fee Related
- 2003-01-20 WO PCT/EP2003/000487 patent/WO2003064405A1/en active Application Filing
- 2003-01-20 MX MXPA04006358A patent/MXPA04006358A/en active IP Right Grant
- 2003-01-20 BR BR0307199-5A patent/BR0307199A/en not_active Application Discontinuation
- 2003-01-27 AR ARP030100225A patent/AR038233A1/en not_active Application Discontinuation
- 2003-01-29 PE PE2003000091A patent/PE20030815A1/en not_active Application Discontinuation
-
2004
- 2004-07-22 IL IL163166A patent/IL163166A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1472240B1 (en) | 2010-05-05 |
| EP1472240A1 (en) | 2004-11-03 |
| CA2473988A1 (en) | 2003-08-07 |
| AR038233A1 (en) | 2005-01-05 |
| DE50312692D1 (en) | 2010-06-17 |
| BR0307199A (en) | 2004-11-03 |
| JP4436134B2 (en) | 2010-03-24 |
| MXPA04006358A (en) | 2004-10-04 |
| WO2003064405A1 (en) | 2003-08-07 |
| ATE466848T1 (en) | 2010-05-15 |
| PE20030815A1 (en) | 2003-10-10 |
| CA2473988C (en) | 2011-05-03 |
| DE10203557A1 (en) | 2003-08-07 |
| IL163166A (en) | 2008-08-07 |
| JP2006503797A (en) | 2006-02-02 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| TC | Change of applicant's name (sec. 104) |
Owner name: SANOFI-AVENTIS DEUTSCHLAND GMBH Free format text: FORMER NAME: AVENTIS PHARMA DEUTSCHLAND GMBH |
|
| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |