Drechsleranol derivatives, processes for their preparation...

Details Drechsleranol derivatives, processes for their preparation... Drechsleranol derivatives, processes for their preparation...

2003-01-27

2004-09-21

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C252S404000, C252S407000, C426S545000, C435S126000, C549S456000

Reexamination Certificate

active

06794408

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel compounds called drechsleranols, which are formed by the microorganism
Drechslera australlensis
, ST 003360, DSM 14003, 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, their use as pharmaceutical compositions, and their use for the treatment and/or prophyloxis of degenerative neuropathies, for example, Alzheimer's disease, or psychiatric disorders, such as depression, sleep disturbances or seasonal affective disorder.
2. Description of the Art
Alzheimer's disease is a neuropsychiatric disorder which mainly occurs in elderly people. The disease is manifested by a multitude of symptoms which includes memory disorders, reduced perceptivity, orientation disorders, speech disorders, disorders of coordinated thought, etc. In Alzheimer's patients, characteristic neurohistological changes are found in the brain, such as, for example, deposits of “amyloid plaques” and also a degeneration of the neurofibrils in the nerve cells (“fibrillar bundles”). These neurohistological changes are characteristic, but nonspecific, since they also occur to a smaller extent in the normal aging process.
At present no causal treatment, but only symptomatic treatment, is possible for Alzheimer's disease. Currently available medicaments only delay the course of the disease, but they are not able to cure it. The group consisting of the centrally active 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 disease, cholinergic signal transmission plays a great role. These medicaments, however, can only be employed in the early and middle stages of the disease and they act to 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, these compounds are no longer effective. Other 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 needed.
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 in the biological cascade of apoptotic events should thus prevent apoptosis, and thereby counteract the development of Alzheimer's disease and halt the progress of the disease.
A further aspect of the present invention is the treatment and/or prohylaxis of psychiatric disorder. Circadian rhythms are generated by internal or endogenous timers (circadian clocks) which are present in a peat variety of organisms. The circadian clock is important for the maintenance of the biological rhythm. The circadian clock is self-sustaining and constant, even in total darkness, but it can be synchronized by external sign a, such as, for example, changes in the light or the temperature. The internal clock controls is the daily fluctuations of behavior, activity, food intake, the sleeping/walking cycle as well as physiological changes such as, for example, hormone secretion and change in the body temperature (Keesler at aL, Neuroreport (2000), 11(5). 951-955). Period (PER) is a central protein of this circadian clock, which is subject to daily variations with spec: to its concentration or its phosphorylation state. The phosphorylation of human PER1 (hPER1) by the enzyme human casein kinase 1 epsilon (hCK1&egr;) causes a decrease in the protein stability of hPER1. Phosphorylated hPER1 has a half life of approximately 12 hrs, whereas unphosphorylated hPER1 remains stable in cells for longer than 24 hours. Thus, modulation of hPER1 protein is clinically of importance especially in diseases which are associated with a disorder of the internal clock, such as, for example, depression (Souetre E. al., Annales medico-physiologiques, 1985, 143(9), 845-870). sleep disturbances or seasonal affective disorder. For the treatment of depression, monoamine oxidase inhibitors and inhibitors of the reuptake of noradrenaline and/or serotonin into the axoplasma (e.g. tricyclic antidepressants) are currently available; however, their exact mechanism of antidepressant action hitherto has not been clarified. With Inhibitor of hCK1&egr;, one would have available a now active principle for the treatment of psychiatric disorders, such as, for example, sleep disturbances, seasonal affective disorder and, in particular, depression.
SUMMARY OF THE INVENTION
The invention relates to a compound of the formula (I)
wherein:
R is H, or a group of the formula —(CH(OR
2
))
5
—CH
2
—OR
2
;
R
1
and R
2
independently are H, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl or C
6
-C
10
-aryl, wherein said C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl or C
6
-C
10
-aryl are optionally mono- or disubstituted by —OH, ═O, —O—C
1
-C
6
-alkyl, —O—C
2
-C
6
-alkenyl, C
6
-C
10
-aryl, —NH—C
1
-C
6
-alkyl, —NH—C
2-C
6
-alkenyl, —NH
2
or halogen, wherein said —O—C
1
-C
6
-alkyl, —O—C
2
-C
6
-alkenyl, C
6
-C
10
-aryl, —NH—C
1
-C
6
-alkyl and —NH—C
2
-C
6
-alkenyl substitutents are optionally substituted by —CN, —NH—C(O)—(C
1
-C
6
-alkyl) or ═NOH; or a stereoisomeric form thereof, or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
C
1
-C
6
-alkyl is a straight- or branched-chain alkyl having 1 to 6 C atoms, preferably having 1 to 4 C atoms, e.g. methyl, ethyl, i-propyl, tert-butyl and hexyl.
C
2
-C
6
-alkenyl is a straight- or branched-chain 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.
C
2
-C
6
-alkynyl is a straight- or branched-chain alkynyl having 2 to 6 C atoms, which is mono- or di-unsaturated, e.g. propynyl, butynyl and pentynyl.
C
6
-C
10
-aryl is an aryl group having 6 to 10 C atoms, e.g. phenyl, benzyl or 1- or 2-naphthyl, which can also be optionally substituted, for example by halogen, such as chlorine, bromine, or 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.
As used herein, the substituent —NH—C(O)—(C
1
-C
6
-alkyl) is defined as an amide wherein C
1
-C
6
-alkyl is a straight- or branched-chain alkyl having 1 to 6 C atoms, preferably having 1 to 4 C atoms, e.g. methyl, ethyl, i-propyl, tert-butyl and hexyl.
As used herein, ‘stereoisomer’ or ‘stereoisomeric form’ is a general term used for all isomers of individual molecules that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
As used herein, ‘R’ and ‘S’ are used as commonly used in organic chemistry to denote specific configuration of a chiral center. The term ‘R’ (rectus) refers

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