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(12) Patent Application Publication (10) Pub. No.: US 2009/0156582 A1 Tsukamoto Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0156582 A1 Tsukamoto Et Al US 20090156582A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0156582 A1 Tsukamoto et al. (43) Pub. Date: Jun. 18, 2009 (54) PYRAZOLE COMPOUND Publication Classification (76) Inventors: Tetsuya Tsukamoto, Osaka-shi, (51) Int. Cl. Osaka (JP); Takeshi Yamamoto, A6II 3/55 (2006.01) Osaka-shi,Osaka (JP); Ryosuke A63L/454 (2006.01) Tokunoh, Osaka-shi, Osaka (JP); A63L/462 (2006.01) Tomohiro Kawamoto, Osaka-shi, C07D 403/02 (2006.01) Osaka (JP); Masahiro Okura, Osaka-shi, Osaka (JP); Masakumi (52) U.S. Cl. .................... 514/217.09: 514/406; 514/326; Kori, Osaka-shi, Osaka (JP); 548/364.1: 548/368.4: 546/211; 540/603 Katsuhito Murase, Osaka-shi, Osaka (JP) (57) ABSTRACT Correspondence Address: The present invention provides a pyrazole compound repre WENDEROTH, LIND & PONACK, L.L.P. sented by the formula (I): 1030 15th Street, N.W., Suite 400 East Washington, DC 20005-1503 (US) b (Io) (21) Appl. No.: 11/884,054 Ra R (22) PCT Filed: Feb. 9, 2006 (86). PCT No.: PCT/UP2006/302686 S371 (c)(1), wherein ring Ao is a pyrazole ring optionally further having 1 (2), (4) Date: Sep. 14, 2007 or 2 substituents; R is a substituted carbamoyl group; and R' (30) Foreign Application Priority Data is an optionally Substituted acylamino group, or a salt thereof or a prodrug thereof, which is useful as an agent for the Feb. 9, 2005 (JP) .................................. O333562005 prophylaxis or treatment of GSK-3? related pathology or Dec. 22, 2005 (JP) .................................. 3709622005 disease, and a GSK-3? inhibitor including same. US 2009/0156582 A1 Jun. 18, 2009 PYRAZOLE COMPOUND activated during nerve cell death. Accordingly, GSK-3 inhibi tor is expected to not only Suppress neurodegeneration but TECHNICAL FIELD also suppress two major pathological findings of Alzheimer's 0001. The present invention relates to pyrazole com disease. As our own findings, we have clarified that PI3 pounds having a Glycogen Synthase Kinase 3 (GSK-3) kinase-Akt system signal transduction plays a key role in inhibitory activity, which are useful as pharmaceutical neuropoiesis and nerve regeneration and found that inhibition agents, and use thereof. of GSK-3 located downstream thereof can facilitate neu ropoiesis. Considering our new findings in combination, BACKGROUND ART there is a possibility that GSK-3 inhibitor suppresses two major pathological findings of Alzheimer's disease and addi 0002 GSK-3 was found to be a kinase that phosphorylates tionally Suppresses neurodegeneration, induces neuropoiesis and deactivates glycogen synthase. It has been clarified at present that it is involved in the oxidation and synthesis of and achieves regeneration of function. It is assumed that fatty acid, or abnormality in insulin signaling pathway via GSK-3 inhibitor having the above-mentioned properties can phosphates of various protein groups related to metabolism be an ultimate therapeutic drug for Alzheimer's disease, and and signal transduction Such as AcylCoA carboxylase, ATP can also be effective as a therapeutic drug for neurodegenera citrate lyase. Insulin receptor substrate-1 and the like. More tive diseases Such as Parkinson's syndrome and the like, cere over, GSK-3 is known to phosphorylate various structural brovascular disorders and the like. Since a report has recently proteins and regulate functions thereof. Particularly, phos documented that Akt System signal transduction decreases in phorylation of tau protein has been attracting attention in schizophrenia, GSK-3 inhibitor may become a completely relation to the onset of Alzheimer's disease. In addition, new type of therapeutic drug for Schizophrenia. GSK-3 is involved in phosphorylation of various transcrip 0005. The following compounds are known as compounds tion factors, and particularly, activates activator protein-1, having a GSK-3 inhibitory activity. cyclic AMP response element binding protein, nuclear factor (1) Purine, pyrimidine derivatives of activated T cells, heat shock factor-1, b-catenin, Myc. C/EBP, NFK-b or the like. Therefore, its inhibitor is expected The compounds described in WO200220495 such as to be a therapeutic drug for Alzheimer's disease, cerebral apoplexy, manic-depressive illness, Schizophrenia, cancer, type II diabetes and obesity. 0003. In insulin signaling pathway, GSK-3 is negatively H regulated by phosphorylation via Akt (protein kinase B: also C C C described as PKB). In diabetic patients, increased activity of GSK-3 and synthesis of fatty acids and/or insulin resistance S.-->'s H are considered to be synergistically induced by the over Na2 N lapped occurrence of promoted GSK-3 gene expression and insulin dysfunction. Since GSK-3 positively regulates the process of adipocyte differentiation and/or maturation via phosphorylation of C/EBP, increased GSK-3 activity triggers obesity, which in turn aggravates diabetes. In fact, it has been and the like, reported that administration of GSK-3 inhibitor improves the compounds described in EP 1136099-A1 such as insulin resistance of model animals of TYPE II diabetes. We have additionally elucidated as our own findings that GSK-3 inhibitor Suppresses adipocyte differentiation and/or matura R3 tion, expresses an antiobesity effect, as well as promotes Sugar-dependent insulin secretory action of pancreatic re- N1 N cells. Given these findings in combination, GSK-3 is consid ered to be additively and/or synergistically involved in the M l onset of diabetes in the insulin targeting tissues such as liver, (rs1-no skeletal muscle, fat, pancreas and the like, and GSK-3 inhibi N R2 tor can be an effective therapeutic drug for obesity and/or A diabetes because it eliminates these factors. RI 0004 Activation of GSK-3 in Alzheimer's brain has been reported, and therefore, GSK-3 is considered to be involved in neuritic plaque and neurofibrillary change, which are the two major pathological findings in Alzheimer's disease. In the metabolism of amyloid precursor proteins, GSK-3 is linked to Y Secretase to positively regulate the production off amyloid HN protein, a main constituent component of neuritic plaque. As Cl for tau protein, which is a main constituent component of -----, R2 neurofibrillary change, GSK-3 is considered to facilitate R!: R2: H, alkyl phosphorylation of the protein, prevent axonal transport, and R. 2.3 or 4-Py finally induce neurodegeneration. It is also known that R; H, alkyl, halo, halo-alkyl, OH, alkoxy, NO2, CN GSK-3 is located downstream of the PI3 kinase Akt system signal transduction important for the nerve cell Survival, and US 2009/0156582 A1 Jun. 18, 2009 and the like, the compounds described in EP 1136482-A1. EP the compounds described in WO 01/56567-A1 such as 1136483, EP 1136486-A1 and WO2002/18386-A1 such as p–CIOS n E-A N NH2 O S HN { N NH2 and the like, and the like. (2) Azole derivatives The compounds described in WO2002057259-A2 such as A: alkylene, CO or bond B: CO, SO, SO2, CFNOR or bond D: OH, halo, CN, NO2, alkoxy, E: alk(en)yl, alkynyl, alkylthio, alkoxy, CO2H, alkoxycarbonyl, subs-Ph, Py, R2 CH R2 e e and the like. NH NH N / N / (3) Maleimide derivatives HN N HN N The compounds described in WO200021927, Rx WO200038675 and WO2001 74771 Such as ls R1 ls RI H Ry s s1 s s1 O N O and the like, o C the compounds described in WO2003004478 such as o-Clu Me C and the like, the compounds described in WO2002/10158 such as and the like, the compounds described in WO200224694-A1 and H WO20025.0073-A1 Such as O N O O -(RI 21 Sx ( ) (/ NN R N RG-1- Yn N R5 s H H O O N O 21 * CH Y. 3 N N1 N Y: CH or N R': alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, R2. aryl or hetroaryl and the like, and the like. US 2009/0156582 A1 Jun. 18, 2009 (4) Other heterocyclic compounds (2) The following compounds have been reported as phos The compounds described in Chemistry & Biology 2000, 7, phodiesterase IV inhibitors (Journal of Computer-Aided 51-63 such as Molecular Design, vol. 15, No. 9, pages 767-785, 2001). N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-1,4-diaz epino.6.7.1-hiindol-3-yl)-4-acetylamino-2,5-dimethyl-2H pyrazole-3-carboxamide. N Me H and the like, Ph the compounds described in WO 01/60374-A1 such as Me NHAC O H N (3) The following compounds have been reported as antibac CC terial agents (Pamazie, Vol. 53, No. 5, pages 346-348, 1998): 0009 (a) N-phenyl-4-benzoylamino-2-ethyl-5-methyl 2H-pyrazole-3-carboxamide, 0010 (b) N-phenyl-2-ethyl-5-methyl-4-(2-nitrobenzoy C lamino)-2H-pyrazole-3-carboxamide, and the like. 0011 (c) N-(4-chlorophenyl)-2-ethyl-5-methyl-4-(4-ni (5) As ATP noncompetitive compounds, the compound trobenzoylamino)-2H-pyrazole-3-carboxamide, and described in J. Med. Chem., 2002,45(6), 1292-1299 which is 0012 (d) N-phenyl-2-ethyl-5-methyl-4-(4-methylben a thiadiazolidinone derivative Zoylamino)-2H-pyrazole-3-carboxamide. Me 2 N N1 Et -N -Nip. O o N\ f Ph-C-NH -Nin M NY O Me CFO and the like. 0006. On the other hand, the following compounds are known as the pyrazole compounds. (1) The following compounds have been reported as antibac terial agents or antifungal agents (WO02/094793). 0007 (a) N-methyl-2,5-dimethyl-4-2-4-(4-nitrophe noxy)phenyl)acetylamino-2H-pyrazole-3-carboxamide, C and Et O 0008 (b) N-methyl-4-2-4-(4-chlorophenoxy)phenyl 1. C-NH acetylamino-2,5-dimethyl-2H-pyrazole-3-carboxamide. US 2009/0156582 A1 Jun.
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