| Use of cysteine derivatives for the preparation of a medicament intended to treat pathologies which result from the formation of the heterotrimeric g protein -> Monitor Keywords |
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  Use of cysteine derivatives for the preparation of a medicament intended to treat pathologies which result from the formation of the heterotrimeric g proteinUSPTO Application #: 20060035899Title: Use of cysteine derivatives for the preparation of a medicament intended to treat pathologies which result from the formation of the heterotrimeric g protein Abstract: The invention relates to the use of cysteine derivatives for preparing a medicament intended to treat diseases which result from the formation of the heterotrimeric G protein. These diseases include in particular diseases linked to the following biological functions or disorders: smell, taste, perception of the light, neurotransmission, neurodegeneration, endocrine and exocrine gland functions, autocrine and paracrine regulation, arterial tension, embryogenesis, benign cell proliferation, oncogenesis, viral infection, immunological functions, diabetes, obesity, and benign :and malign proliferative diseases. Said cysteine derivatives include in particular: bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine disulphide (I), and bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphtyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazin-7-yl) disulphide (II). (end of abstract)
Agent: Charles A. Muserlian C/o Hedman And Costigan - New York, NY, US Inventors: Gregoire Prevost, Marie-Odile Lonchampt, Thomas Gordon USPTO Applicaton #: 20060035899 - Class: 514249000 (USPTO) Related 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 Two Nitrogens And Four Carbon Atoms (e.g., Pyridazines, Etc.), 1,4-diazine As One Of The Cyclos The Patent Description & Claims data below is from USPTO Patent Application 20060035899. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] The present invention relates in particular to the use of derivatives of cysteine for the preparation of a medicament intended to treat pathologies which result from the formation of the heterotrimeric G protein. These diseases include in particular diseases linked to the following biological functions or disorders: smell, taste, perception of light, neurotransmission, neurodegeneration, endocrine and exocrine gland functions, autocrine and paracrine regulation, arterial tension, embryogenesis, benign cell proliferation, oncogenesis, viral infection, immunological functions, diabetes, obesity, and benign and malign proliferative diseases. [0002] The G proteins are in fact the structural association of three distinct sub-units called .alpha., .beta., and .gamma., but operate as dissociable entities constituted by .alpha. sub-units on the one hand and .beta./.gamma. dimers on the other hand. [0003] The G proteins participate in the transmission of signals outside the cell thanks to its interaction with receptors with seven transmembrane domains inside using different effectors including adenylate cyclase, phospholipase C or also the ionic channels. The adenylate cyclase enzyme generates cyclic AMP (cAMP) (cf. Gilman, A. G. Biosci. Rep. 15, 65-97 (1995)). Thus, it is known that, in order to activate the adenylate cyclase, it is necessary for the G proteins to be transitionally in a heterotrimeric form, in which form the monomer constituted by an .alpha. sub-unit is associated with the dimer constituted by the .beta. and .gamma. sub-units. It is only in this situation that the signal outside the cell can activate the .alpha. sub-unit of a G protein, which can, after disassociation, modulate the adenylate cyclase and modulate the production of cAMP. [0004] It is also known that the .beta./.gamma. dimers can directly activate the effectors leading to the activation of kinases regulated by extracellular signals (ERKs) or MAP kinases. A direct link between the .beta./.gamma. sub-units and the src or src like kinases has been demonstrated (cf. Gutkind, J. S. J. Biol. Chem. 273, 1839-1842 (1998)). [0005] Moreover, bacterial toxins such as Vibrio cholera and Bortella pertussis, peptides such as mastoparan and suramin have been presented as directly modulating the activity of the G proteins (cf. Freissmuth, M., Boehm, S., Beindl, W., et al. Mol. Pharmacol. 49, 602-611 (1996); Boehm, S., Huck, S., Motejlek, A., et al. Journal of Neurochemistry 66, 1019-1026 (1996); Cachero, T. G., Rigual, R., Rocher, A. & Gonzalez, C. Eur. J. Neurosci. 8, 2320-2327 (1996); Danilenko, M., Worland, P., Carlson, B., Sausville, E. A. & Sharoni, Y. Biochem. Biophys. Res. Commun. 196, 1296-1302 (1993); Beindl, W., Mitterauer, T., Hohenegger, M., Ijzerman, A. P., Nanoff, C. & Freissmuth, M. Mol. Pharmacol. 50, 415-423 (1996)). [0006] For example, the choleric toxin modifies the as sub-unit of the G protein by adding an ADP-ribose originating from the NAD to an arginine-specific acceptor site. This completely blocks the activity of the GTPase, provoking persistent stimulation of its next effector, adenylate cyclase and leading to overproduction of cAMP. [0007] The harmful effects of an abnormal cAMP level are also known and occur in particular at the level of the following biological functions or disorders: smell, taste, perception of light, neurotransmission, neurodegeneration, endocrine and exocrine gland functions, autocrine and paracrine regulation, arterial tension, embryogenesis, benign cell proliferation, oncogenesis, viral infection and immunological functions, diabetes and obesity. [0008] The Applicant has just discovered that certain derivatives of cysteine, namely the compounds of general formula (A) corresponding to sub-formulae (A1) or (A2): in which: [0009] X represents R.sub.12 and Y represents R.sub.8, or X and Y complete a ring with 6 members, the X-Y set representing the --CH(R.sub.8)--CH(R.sub.9)-radical; [0010] R.sub.1 represents H, a lower alkyl or alkylthio radical; [0011] R.sub.2 and R.sub.3 represent independently H or a lower alkyl radical; [0012] R.sub.4 represents H.sub.2 or O; [0013] R.sub.5 represents H, or one of the lower alkyl, lower alkenyl, lower alkynyl, aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle radicals, these radicals being optionally substituted by radicals chosen from the group comprising a lower alkyl radical, --O--R.sub.10, --S(O).sub.mR.sub.10 (m representing 0, 1, or 2), --N(R.sub.10)(R.sub.11), --N--C(O)--R.sub.10, --NH--(SO.sub.2)--R.sub.10, --CO.sub.2--R.sub.10, C(O)--N(R.sub.10)(R.sub.11), and --(SO.sub.2)--N(R.sub.10)(R.sub.11); [0014] R.sub.6 and R.sub.7 represent independently H, a --C(O)--NH--CHR.sub.13--CO.sub.2R.sub.14 radical, or one of the lower alkyl, aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle radicals, these radicals being optionally substituted by radicals chosen from the group comprising the OH, alkyl or lower alkoxy, N(R.sub.10)(R.sub.11), COOH, CON(R.sub.10)(R.sub.11), and halo radicals, or R.sub.6 and R.sub.7 form together an aryl radical or a heterocycle; [0015] R.sub.8 and R.sub.9 represent independently, H, or one of the lower alkyl, aryl, lower arylalkyl, heterocycle or lower alkyl heterocycle radicals, these radicals being optionally substituted by radicals chosen from the group comprising the OH, alkyl or lower alkoxy, N(R.sub.10)(R.sub.11), COOH, CON(R.sub.10)(R.sub.11) and halo radicals, or R.sub.8 and R.sub.9 together form an aryl radical or a heterocycle; [0016] R.sub.10 and R.sub.11 represent independently H, an aryl radical or a heterocycle, or an alkyl, arylalkyl or lower alkyl heterocycle radical; [0017] R.sub.12 represents NR.sub.9, S, or O; [0018] R.sub.13 represents a lower alkyl radical optionally substituted by a radical chosen from the lower alkyl, --OR.sub.10, S(O).sub.mR.sub.10 (m representing 0, 1, or 2) and --N(R.sub.10)(R.sub.11) radicals; [0019] R.sub.14 represents H or a lower alkyl radical; or the compounds of general formula (B): W.sub.1--Ar--W.sub.2 (B) in which: [0020] W.sub.1 represents a remainder originating from a cysteine in reduced or non reduced form; [0021] Ar represents a radical derived from an aminobenzoic acid, the aromatic ring of which is optionally substituted; Continue reading... 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