Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-26
2004-09-07
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S544000
Reexamination Certificate
active
06787564
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to some new optically active clausenamide derivatives, process of the preparation thereof, a pharmaceutical composition containing the same and their medical use, particularly their use in the respects of hypoxia protective, nootropic and neurodegenerative disease such as cerebral ischemia, Alzheimer disease and vascular dementia.
BACKGROUND OF THE INVENTION
The average life span in Chinese population is now over 70 years of age.It increased by 100% as compared with before foundation of P.R. China. A scientific of study in abroad estimates that the proportion of the population over 65 years of age will increase to 18.8% by the 2025, when it will just exceed the proportion of children (18.6%). It means that one of 5 population in about 20 years later will be senile. Alzheimer's disease(AD) and vascular damentia(VD) refer to the presenile and senile form of the disease. i.e. under age 65 vs age 65 and over. Therefore, with the aging of population, the incidence of AD and VD will certainly be increased. The old men and their related neurodegenerative diseases especially various dementia have to undergoing two kinds of death, firstly the psychological death and then physical death. This is a heavy load for not only patients but also families and society. The aging of population is considered as a disadvantage factor, next to the war, pestilence, farming and shortage of resource and energy, to society's development and stability.
There are many drugs for prevention and treatment of senile dementia, such as cerebral vasodilators which can increase cognition function through improvement of blood flow and energy. However, a real valuable cerebral vasodilator should have high selectivity with no effect on brain metabolism and no “blood steal” phenomenon, it needs also to have antiplatelet aggregation and antithrombosis actions. Calcium channel blocker nimodipine accords with some demands as mentioned above, it acts on L-type but not the N- and T-type voltage dependent calcium channel. The drugs for central cholinergic system, the precoursor of acetyecholine(Ach) has weak therapeutic effect. Ach receptor agonists and cholinesterase inhibitors have certain sympmatically therapeutic effect, but its effect is short, and more important is that they can not affect athogenesis of dementia. Many neuropeptides and neurotrophine factors were considered as promising antidementia agents, but its clinical therapeutic effect is not good. The main reason for this is that these large molecules could not pass through the blood-brain barrier. Piracetam or 2-oxo-1 pyrolidine acetamide is usually considered as the prototype nootropic drug. In recent years, clinical studies indicated that the effect of piratcetam in improving memory impairment was mild or obscure. In addition, its mechanism of action is not fully understood, although it has been studied for nearly 30 years.
Racemic clausenamide was isolated from the aqueous extract of leaves of Rutoceae Clausena lausium(Lour) Skeels and had been claimed to have pronounced cerebal hypoxia protective and antiamnestic effect. Its potential medical use and processes of preparation from the plant had been granted a patent right for Chinese Academy of Medical Sciences and Bayer AG(EU patent No. 072514, U.S. Pat. No. 4,879,391 and Chinese patent No. 90107309). Methods for chemical synthesis of racemic clausenamide also had been applied for patent protection (German patent No. 3927370, EP No. 0414120).
SUMMARY OF THE INVENTION
The object of the present invention is to provide a new compound for the prevention and/or treatment of neurodegenerative disease such as cerebral ischemia, Alzheimer disease and vascular dementia.
Levoclausenamide as one of the active enantiomer of the racemic clausenamide is generally believed that an optically active clausenamide is the double of that of racemic clausenamide in respect to a biological activity or no any activity. The present inventors have now unexpectedly found that the biological activity of Levoclausenamides is significantly stronger than double of that of racemic clausenmide and is at 5-10 times more potent than that of racemic clausenamide in respect of said activity.
Furthermore, in both behavioral and electrophysiological studies. Levoclausen amide showed to facilitate learning and memory and increase neuronal plasticity. Besides,(−)clausenamide could antagonize A&bgr; induced neurotoxicity, inhibit neuron's apoptosis and tau protein over phosphorerytion, and therefore (−) clausenamide may be used as drug for prevention and/or treatment of dementia in early stage. The nootropic and antidementia tests of (−) clausenamide have been carried out in biochemical, molecular biological and morphological fields. For example, (−) clausenamide has been indicated to increase synapses of dentate gyrus in adult rats.
The present invention is directed to a new pharmacologically active chiral compound a substituted &dgr;-butyrolactan (hereinafter called as levoclausenamide or (−) clausenamide) with the absolute configuration of 3S4R5R6S with levo rotation as shown in formula 1.
The present invention provides to some new optically active stereoisomeric clausenamide derivatives of formula II,
wherein said optically active clausenamide derivatives of formula II is selected from one of the following compound:
*3S4R5R6R (−)epiclausenamide,
*3R4S5S6S (+)epiclausenamide
**3S4R5S6R (−)neoclausenamide,
**3R4S5R6S (+)neoclausenamide
**3S4R5S6S(−)epineoclausenamide,
**3R4S5R6R(+)epineoclausen amide
*3S4S5S6R (+)cisclausenamide,
*3R4R5R6S (−)cisclausenamide
*3S4S5S6S (+)cisepiclausenamide,
*3R4R5R6R (−)cisepiclausenamide
*3S4S5R6S (−)cisneoclausenamide,
*3R4R5S6R (+)cisneoclausenamide
*3S4S5R6R(−)cisepineoclausenamide, and
*3R4R5S6S(+)cisepineoclausen-amide
wherein “*” indicates new optically active clausenamide compounds;
“**” indicates that racemic compounds of which is known but some biological activities thereof concerning noortropic, neurodegenerative disease have not been reported up to now.
The invention provides to some optically active clausenamide derivatives of formula I selected from one of the following compounds for the prevention and/or treatment of neurodegenerative diseases:
3S, 4R, 5R, 6S (−) Levoclausenamide,
3S4R5R6R (−) epiclausenamide,
3R4S5S6S (+)epiclausenamide,
3S4R5S6R (−)neoclausenamide,
3R4S5R6S (+)neoclausenamide,
3S4R5S6S(−)epineoclausenamide,
3R4S5R6R(+)epineoclausen amide,
3S4S5S6R (+)cisclausenamide,
3R4R5R6S (−)cisclausenamide,
3S4S5S6S (+)cisepiclausenamide,
3R4R5R6R (−)cisepiclausenamide,
3S4S5R6S (−)cisneoclausenamide,
3R4R5S6R (+)cisneoclausenamide,
3S4S5R6R(−)cisepineoclausenamide, and
3R4R5S6S(+)cisepineoclausen-amide.
The invention provides to a pharmaceutical composition comprising some optically active compounds of formula I and/or II and pharmaceutically carrier or excipient.
The invention provides to a pharmaceutical composition for the prevention and/or treatment of neurodegenerative diseases comprising any one of the optically active compounds of formula I and pharmaceutically carrier or excipient.
The invention provides to a use of any one of the optically active compounds of formula I and/or II for the manufacture of medicament for the prevention and/or treatment of neurodeganerative diseases.
The invention provides a method for the prevention and/or treatment of neurodegenerative disease comprising administrating to a patient suffered with neurodegenerative disease or high risk of neurodegenrative disease an effective prevention and/or treatment amount of any one of the optically active compounds of formula I and/or II.
The invention provides to a process for the preparation of levoclausenamide, which characterized in that:
1. De novo synthesis by using intramoleuclar inductive asymmetrical Dargen reaction to prepare compound (2*);
2. B
Chen Shiming
Huang Liang
Wu Kemei
Zhang Juntian
Darby & Darby
Institute of Materia Medica, Chinese Academy of Medical Sciences
McKane Joseph K.
Saeed Kamal
LandOfFree
Optically active clausenamides, process of the preparation... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Optically active clausenamides, process of the preparation..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Optically active clausenamides, process of the preparation... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3211631