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Aminophenoxyacetamide derivatives and pharmaceutical composition containing thereofRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Piperidines, Additional Ring ContainingAminophenoxyacetamide derivatives and pharmaceutical composition containing thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060178401, Aminophenoxyacetamide derivatives and pharmaceutical composition containing thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATION DATA [0001] This application is a continuation application of U.S. patent application Ser. No. 10/009,566, filed Dec. 12, 2001, which is a .sctn.371 application of PCT/JP01/03198 filed Apr. 13, 2001, which claims priority to JP 2000-112100 filed Apr. 13, 2000. The entire contents of each of these applications is incorporated herein by reference. TECHNICAL FIELD [0002] The present invention relates to cerebral functional or organic disorders improving and treating agents containing aminophenoxyacetamide derivatives and pharmaceutically acceptable salt thereof as an active ingredient, having neuroprotective effect by inducing the production of CalbindinD-28k, one of Ca.sup.2+-binding proteins, and to the methods for selecting these neuroprotective aminophenoxyacetamide derivatives. More specifically, the present invention relates to the therapeutic and improving agents for various cerebral dysfunction due to various ischemic disorders such as cerebral infarction, intracerebral hemorrhage and cerebral arteriosclerosis. Furthermore, the present invention relates to therapeutic and improving agents for various cerebral organic disorders due to senile dementia, sequelae of cerebral injury, or surgical operation, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and Huntington's disease, etc. BACKGROUND ART [0003] It is considered that the progressive and delayed death of nerve cells, observed in cerebral injury and cerebrovascular disease such as intracerebral hemorrhage, transient cerebral ischemia, and cerebral infarction, is mainly caused by the increase of the intracellular Ca.sup.2+ concentration, the various factors of which are related to signal transduction to cause, for example, the abnormal activation of receptors by over releasing glutamate which is internal excitability, the activation of ion channels, and the induction of reactive oxygen species/free radicals. [F. B. Meyer, Brain Res. Rev., 14, 227 (1989); E. Boddeke et al., Trends Pharmacol. Sci., 10, 397 (1989); J. M. McCall et al., Ann. Rep. Med. Chem., 27, 31 (1992)]. [0004] From these points of view, antagonists for glutamate receptors, calcium channel blockers, antioxidants and so on have been applied for medicaments of preventing or suppressing the neurodegeneration. However, these clinically used medicaments suppress only a few pathways relating to the increase of the cellular Ca.sup.2+ concentration, and therefore are not yet sufficient enough for preventing or suppressing the neurodegeneration. [0005] On the contrary, the internal production of CalbindinD-28k is induced by activation of receptors for many physiologically active substance's such as FGF, NT-3, NT-4/5, BDNF, IGF-I/II, PDGF, estrogen and so on, and as well as by activation of FGF receptor, which is one of nerve growth factor receptors [C. V.-Abejon et el., Neuron, 15, 105 (1995); A. Silva et al., Brain Res. Bull., 1, 35 (2000)]. And CalbindinD-28k, one of Ca.sup.2+-binding proteins and mainly distributed in vulnerable site against ischemic disorders in the central nervous system, which is known to show buffer action against the increase of intracellular Ca.sup.2+ concentration. [A. M. Lacopino et al., Neurodegeneration, 3, 1 (1994); M. P. Mattson et al., Neuron, 6, 41 (1991)] [0006] Accordingly, it is expected to achieve sufficient neuroprotective effects against the increase of intracellular Ca.sup.2+ concentration caused by any kinds of pathways if CalbindinD-28k, one of the Ca.sup.2+-binding proteins per se, can be supplied in a cell. Namely, it is expected that medicaments containing CalbindinD-28k would be extremely effective therapeutic and improving agents against cerebral functional and due to various ischemic disorders such as cerebral infarction, intracerebral hemorrhage and cerebral arteriosclerosis. It is also expected to be effective against cerebral dysfunction due to cerebral ischemic disorders due to sequelae of senile dementia, cerebral injury and surgical operation, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and so on. [0007] However, it is very difficult and therefore it is not likely to administer the CalbindinD-28k protein directly into the desirable site in the central nervous system of a body in view of the limitations existing in the pharmacological and pharmaceutical methodology because CalbindinD-28k itself is an unstable macro molecular weight protein having 28 Kd (Kilo Dalton) of molecular weight. [0008] On the other hand, the lower molecular weight compounds capable of including the production of CalbindinD-28k protein can be easily prepared into the various kinds of pharmaceutical compositions by the conventional technique. Therefore, these lower molecular weight compounds would induce the production of the neuroprotective CalbindinD-28k protein once easily administered into a body, showing the buffering action against the increase of the intracellular Ca.sup.2+ concentration. That is, these lower molecular weight compounds can be effective pharmaceutical compounds for improving and treating cerebral functional and organic disorders. [0009] Under these circumstances, one objective of the present invention is to select and to provide the lower molecular-weight neuroprotective compounds capable of inducing the production of CalbindinD-28k, one kind of Ca.sup.2+-binding proteins, via phosphorylation of receptors of various physiologically active substances, as well as to provide the pharmaceutical compositions of low toxicity in suitable preparations such as intravenous injectable solution. [0010] The other objective of the present invention is to provide the therapeutic and improving agents for cerebral functional disorders due to various ischemic disorders such as cerebral infarction, intracerebral hemorrhage and cerebral arteriosclerosis, as well as cerebral organic disorders such as sequelae of senile dementia, cerebral injury, or surgical operation, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. DISCLOSURE OF THE INVENTION [0011] As one aspect of the present invention, it is provided aminophenoxyacetamide derivatives represented by the following formula (I): wherein, [0012] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are, independent from each other, hydrogen atom or lower alkyl group which may be substituted; [0013] R.sup.5, R.sup.6, R.sup.7 and R.sup.8 are, independent from each other, hydrogen atom or lower alkyl group which may be substituted; [0014] E.sup.1 is group --NR.sup.9 (in which, R.sup.9 is hydrogen atom or alkyl group which may be substituted); [0015] E.sup.2 is oxygen atom or group --NR.sup.10 (in which, R.sup.10 is hydrogen atom; alkyl group which may be substituted; aryl group which may be substituted or aralkyl group which may be substituted); Q is a group of --X--Y-Q', in which X is a connecting bond, lower alkyl group, lower alkenyl group or lower alkynyl group; Y is a connecting bond, or a group selected from the groups consisting of C.dbd.O, C(.dbd.O)NH, NHC(.dbd.O), --O--, --S--, CH(OH), --O--CH(OH), and --O--CH.sub.2--CH(OH), in which hydrogen atom of amido group may be substituted with lower alkyl group; and Q' is hydrogen atom or a cyclic group selected from the groups consisting of aryl group, heteroaryl group, saturated or unsaturated cyclic hydrocarbon group, and saturated or unsaturated heterocyclic group, wherein one or more of the hydrogen atom in the cyclic group of Q' may be substituted; [0016] provided that X and Y are both connecting bond then Q' is not hydrogen atom; or provided that one of X and Y is other than connecting bond then E.sup.2 is the group --O-- and all of the groups of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are not hydrogen atom; or a pharmaceutically acceptable salt thereof. [0017] In the description of a lower alkyl group may be specifically a straight or branched alkyl group of the number of carbon atoms from C.sub.1 to C.sub.6, for example, methyl, ethyl, n-propyl, isopropyl and so on and more preferably, methyl or ethyl. In the description of lower alkenyl group may be specifically C.sub.1 to C.sub.6 alkenyl group, and lower alkynyl may be specifically C.sub.1 to C.sub.6 alkynyl group. [0018] Furthermore, the present invention provides the aminophenoxyacetamide derivatives of the formula (I), in which; [0019] R.sup.1, R.sup.2, R.sup.3 and R.sup.4 all are methyl group; Continue reading about Aminophenoxyacetamide derivatives and pharmaceutical composition containing thereof... 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