Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-14
2002-08-27
Shah, Mukand J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S298000, C544S123000, C544S295000, C514S252200, C514S235800, C514S272000, C514S252180
Reexamination Certificate
active
06440965
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel derivatives of a series of substituted pyrimidines, to pharmaceutical compositions which contain them, to methods for their preparation and to their use in therapy, particularly in the treatment of neurodegenerative or other neurological disorders of the central and peripheral systems.
Dementing disorders such as age-related cognitive disorders, e.g., senility or Alzheimer's disease are medical conditions for which there are currently only limited therapies. Although studies suggest that multiple neurotransmitter systems are involved in senile dementia, a loss of cholinergic neurons and a severe depletion of choline acetyltransferase appear to show the earliest and strongest correlations with functional cognitive impairment [see P. T. Francis, A. M. Palmer, N. R. Sims, D. M. Bowen, A. N. Davison, M. M. Esiri, D. Neary, J. S. Snowden and G. K. Wilcock, Neurochemical Studies of Early-onset Alzheimer's Disease. N. Engl. J. Med., 313, 7 (1985); R. T. Bartus, R. L. Dean, M. Pontecorvo and C. Flicker, The Cholinergic Hypothesis: A Historical Overview, Current Perspective, and Future Directions. Ann. N. Y. Acad. Sci., 444, 332 (1985); F. Hefti and L. S. Schneider, Nerve Growth Factor and Alzheimer's Disease, Clin. Neuropharmacol., 14, S62 (1991)]. Several groups have attempted to stimulate cholinergic activity by blocking the breakdown of acetylcholine with acetylcholine esterase inhibitors or by introducing muscarinic or nicotinic agonists [see R. T. Bartus, R. L. Dean III, B. Beer and A. S. Lippa, The Cholinergic Hypothesis of Geriatric Memory Dysfunction. Science, 217, 408 (1982); J. Varghese, I. Lieberburg and E. D. Thorsett, Chapter 21. Alzheimer's Disease: Current Therapeutic Approaches. Annu. Rep. Med. Chem., 28, 197 (1993)]. The approved drugs Cognex® and Aricept® are acetylcholine esterase inhibitors.
Nerve growth factor (NGF) is the best characterized neurotropic factor that is capable of inducing cell differentiation of neural cells and promoting neurite sprouting. The neurotrophic protein NGF primarily affects cholinergic neurons in the central nervous system and may be necessary for their survival [see F. Hefti and P. A. Lapchak, Pharmacology of Nerve Growth Factor in the Brain. Adv. Pharmacol., 24, 239 (1993)]. NGF is not systemically bioavailable, but if it is injected or infused directly into brain, it prevents neuronal cell loss and restores cognitive function in aged or lesioned rats or monkeys [see W. Fischer, A. Bjorklund, K. Chen and F. H. Gage, NGF Improves Spatial Memory in Aged Rodents as a Function of Age. J. Neurosci., 11, 1889 (1991)]. NGF effects ultimately result in the stimulation of choline acetyltransferase, the enzyme for biosynthesis of acetylcholine and the promotion of neurite growth. Consequently, small molecules that produce neurotrophic or “nerve growth factor-like” (NGF-like) properties in mammalian cell cultures have potential for use in the treatment of dementing disorders such as age-related senility or Alzheimer's disease and other neurodegenerative conditions such as peripheral neuropathies, Parkinson's, stroke damage, transient ischemic attacks or trauma-head injuries.
There are several reports of small molecules that exhibit various aspects of NGF-like activity. Isaxonine [2-(isopropylamino)pyrimidine] was developed as a neurotrophic pharmaceutical but the clinical application was withdrawn, possibly due to toxicological effects [see Neuropathies peripheriques et a l'isaxonine. Nouv. Presse Med., 11, 1189 (1982); S. Lehmann, C. Quirosa-Guillou, U. Becherer, C. Thai and J.-P. Zanetta, Neurite Outgrowth of Neurons of Rat Dorsal Root Ganglia Induced by New Neurotrophic Substances with Guanidine Group. Neurosci. Lett., 152, 57 (1993)]. Several 2-(piperazino)pyrimidine derivatives were reported to possess NGF-like activity and are being studied further for use in treating CNS degenerative diseases [see A. Awaya, H. Kobayashi, K. Horikomi, S. Tanaka, A. M. Kabir, K. Yokoyama, H. Ohna, K. Kato, T. Kitahara, I. Tomino, S. Isayama and S. Nakamura, Neurotrophic Pyrimidine Heterocyclic Compounds. I. The Newly Synthesized Pyrimidine Compounds Promote Neurite Outgrowth of GOTO and Neuro 2a Neuroblastoma Cell Lines, and Potentiate Nerve Growth Factor (NGF)-Induced Neurite Sprouting of PC-12 Cells. Biol. Pharm. Bull., 16, 248 (1993)]. AIT-082 (4[[3-(1,6-dihydro-6-oxo-9-purin-9-yl)-1-oxopropyl]amino]benzoic acid) is reported to enhance NGF action in cultured PC-12 cells and to restore age induced working memory deficits in mice [see P. J. Middlemiss, A. J. Glasky, M. P. Rathbone, E. Werstuik, S. Hindley and J. Gysbers, AIT-082, A Unique Purine Derivitive, Enhances Nerve Growth Factor Mediated Neurite Outgrowth from PC-12 cells, Neuroscience Let., 199, 131 (1995)]. In addition, U.S. Pat. No. 5,075,305 discloses 2-amino-5-bromo-4-(morpholino)pyrimidine as having NGF-like properties and its possible use in treating CNS degenerative diseases like Alzheimer's disease as well as peripheral neuropathies or other peripheral nervous system disorders.
European Patent Applicaton EP 0 626 674 A1 discloses a group of 4-substituted amino-5-substituted phenoxy pyrimidine derivatives and their use as psychotropic drugs. European Patent Application 0 459 819 A2 describes a group of 4-substituted amino-5-substituted phenyl pyrimidine derivatives and their use in the treatment of neurological disorders. Document DE 23 44 611 A discloses a group of 4-substituted amino -5-substituted phenoxy pyrimidine derivatives.
The compound 2-p-chloroanilino-4-&bgr;-diethylaminoethylamino-5-phenoxypyrimidine, and its use as antimalarial agent, has been disclosed (See Curd et al., Journal of the Chemical Society, 378-384 (1946). The compounds, 2-amino-4-&bgr;-diethylaminoethylamino-5-phenoxypyrimidine and 2-amino-4-y-diethylaminopropylamino-5-phenoxypyrimidine, and their use as antimalarial agents, have also been disclosed (See Hull et al., Journal of the Chemical Society, 41-52 (1947).
SUMMARY OF THE INVENTION
We have now discovered a series of substituted pyrimidines that demonstrate NGF-like activity and/or enhancement of NGF activity in PC12 cells. The compounds stimulated both neurite outgrowth and choline acetyltransferase activity in In vitro experiments. Such activities are predictive for causing increased choline acetyltransferase activity in rat striatum and improving cognitative performance in animal models of age-induced working memory deficits by potentiating the activity of endogenous NGF in the brain. [P. J. Middlemiss. A. J. Glasky, M. P. Rathbone, E. Werstuik, S. Hindley and J. Gysbers, AIT-082, A Unique Purine Derivitive, Enhances Nerve Growth Factor Mediated Neurite Outgrowth from PC12 cells. Neuroscience Let. 199, 131 (1995); A. J. Glasky, C. L. Melchior, S. Pirzadeh, N. Heydari and R. F. Ritzmannn, Effect of AIT-082, a Purine Analog, on Working Memory in Normal and Aged Mice. Pharmacol. Biochem. Behav., 47, 325 (1994); R. Morris. Developments of a Water-maze Procedure for Studying Spatial Learning in the Rat. J. Neurosci. Methods, 11, 47 (1984)].
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, there are provided novel compounds of Formula I;
wherein
W is O, CH2, CH2CH2, OCH2, or CH2CH2CH2;
R
1
is hydroxyC1-6alkyamino, morpholino, piperidino, piperazino, piperazinoamino, homopiperazino, homopiperidino, homomorpholino, benzoxazino, indolino, 1,2,3,4-tetrahydroquinolino, benzylamino, wherein C or N atoms may be substituted with one or more substituents selected from the group consisting of:
NR4R5 (wherein R4 and R5 may be the same or different and are H, C1-6alkyl, hydroxyC1-6alkyl, C3-8cycloalkyl, C6-10aryl, C6-10arylCC1-6alkyl, C1-6alkoxy, C6-10aryloxy or C6-10arylC1-6alkoxy);
NR4R5carbonyC1-6alkyl (wherein R4 and R5 may be the same or different);
OH;
CN;
C1-6alkyl;
C2-7alkenyl;
C2-7alkenyl;
C6-10aryl;
C6-10heteroaryl;
hydroxy
Beauchamp Lilia M.
Kelley James L.
Krenitsky Thomas A.
Alston & Bird LLP
Krenitsky Pharmaceuticals, Inc.
Liu Hang
Shah Mukand J.
LandOfFree
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