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(12) United States Patent (10) Patent No.: US 8,541,596 B2 Heiser Et Al

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(12) United States Patent (10) Patent No.: US 8,541,596 B2 Heiser Et Al USOO854.1596B2 (12) United States Patent (10) Patent No.: US 8,541,596 B2 Heiser et al. (45) Date of Patent: Sep. 24, 2013 (54) INHIBITORS OTHER PUBLICATIONS (75) Inventors: Ulrich Heiser, Halle/Saale (DE); Daniel Souillac, et al., Characterization of Delivery Systems, Differential Scanning Calorimetry in Encyclopedia of Controlled Drug Delivery, Ramsbeck, Halle/Saale (DE); Torsten 1999, John Wiley & Sons, pp. 212-227.* Hoffmann, Halle/Saale (DE); Livia Vippagunta et al., Advanced Drug Delivery Reviews, 48 (2001), pp. Boehme, Halle/Saale (DE) 3-26. Abuzar et al., Synthesis of N-Aryl- & N-Heteroaryl-benzimidazoles (73) Assignee: Probiodrug AG, Halle/Saale (DE) as Potential Anthelmintics, Indian Journal of Chemistry, 1980, pp. 599-600, vol. 19B. (*) Notice: Subject to any disclaimer, the term of this Brauniger et al., Darstellung von DesaZaanalogen des Kinetins, patent is extended or adjusted under 35 Archiv der Pharmazie, 1966, pp. 13 and 194-196, vol. 299. No. 3, in U.S.C. 154(b) by 0 days. German. Chemical Abstracts Service Registration No. (CAS RN) 1069857 (21) Appl. No.: 13/091,276 25-5, entered Nov. 2, 2008, 1 page. Chemical Abstracts Service Registration No. (CAS RN) 1137428 (22) Filed: Apr. 21, 2011 36-4, entered Apr. 21, 2009, 1 page. Gallagher et al., Synthesis and photolysis of azido (65) Prior Publication Data benzobthiophens, -benzothiazoles, -benzimidazoles, and -inda Zoles: Novel 6,7-Diamino-benzothiazoles, -benzimidazoles, and -in US 2011 FO262388A1 Oct. 27, 2011 dazoles and 6-Diethylamino-8H-thiazolo-5,4-c azepines, J Chem Soc Perkin I, 1980, pp. 2362-2370. Related U.S. Application Data JP62-024244 published Feb. 2, 1987, English abstract, downloaded Provisional application No. 61/326,401, filed on Apr. from PAJ, 1 page. (60) JP63-250385 published Oct. 18, 1988, English abstract, downloaded 21, 2010. from PAJ, 1 page. Int. C. Molnar, In 4.5-Stellung ungleich substituierte o-Nitraniline, (51) Helvectica Chemica Acta, 1963, pp. 1779-1783, vol. 63, in German. A6 IK3I/484 (2006.01) Roy et al., Syntheses of 4,6-Dinitro-5-substituted-amino CO7D 235/08 (2006.01) benzimidazoles & 4,6-Dinitro-2-methyl-5-substituted (52) U.S. C. aminobenzimidazoles, Indian J Chem, 1979, pp. 164-166, vol. 17B. USPC ........ 548/304.4; 546/176: 548/126; 548/156; Soskic et al., Sythesis of N-n-Propyl-N-(2-arylethyl)-5-(1H 514/314: 514/362; 514/367: 514/394 benzimidazol-2-thione)-ethylamines and Related Compounds as (58) Field of Classification Search Potential Dopaminergic Ligands, Arzneim.-Forsch./Drug Res., USPC ....................................................... 548/304.4 1996, pp. 741-746, vol. 46. See application file for complete search history. * cited by examiner (56) References Cited Primary Examiner — Laura L. Stockton U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Dentons US LLP 5,106,862 A * 4/1992 Briving et al. ................ 514,394 6,582,351 B1* 6/2003 Sawada et al. ................ 546,118 (57) ABSTRACT FOREIGN PATENT DOCUMENTS JP 62-024244 2, 1987 Novel heterocyclic derivatives as inhibitors of glutaminyl JP 62,055644. A * 3, 1987 cyclase (QC, EC 2.3.2.5). QC catalyzes the intramolecular JP 63-250385 10, 1988 cyclization of N-terminal glutamine residues into pyro WO WOOOf 42022 A1 T 2000 glutamic acid (5-oxo-prolyl, pClu) under liberation of WO WOO1/O577O A1 1, 2001 WO WOO3,O77914 A1 9, 2003 ammonia and the intramolecular cyclization of N-terminal WO WO-2007/002092 A1 * 1, 2007 glutamate residues into pyroglutamic acid under liberation of WO WO2007/053.131 A2 5/2007 Water. WO WO2007/053.131 A3 5/2007 WO WO2008/O5595.0 A1 5, 2008 WO WO2008/128985 A1 10, 2008 18 Claims, No Drawings US 8,541,596 B2 1. 2 INHIBITORS Recently, it was shown that recombinant human QC as well as QC-activity from brain extracts catalyze both, the N-ter CROSS-REFERENCE TO RELATED minal glutaminyl as well as glutamate cyclization. Most strik APPLICATIONS ing is the finding, that cyclase-catalyzed Glu-conversion is favored around pH 6.0 while Gln-conversion to pGlu-deriva This application claims priority to U.S. Provisional Appli tives occurs with a pH-optimum of around 8.0. Since the cation Ser. No. 61/326,401, filed on Apr. 21, 2010, which is formation of pClu-AB-related peptides can be suppressed by incorporated herein by reference in its entirety. inhibition of recombinant human QC and QC-activity from pig pituitary extracts, the enzyme QC is a target in drug MATERIAL INCORPORATED-BY-REFERENCE 10 development for treatment of Alzheimer's disease. Inhibitors of QC are described in WO 2004/098625, WO The Sequence Listing, which is a part of the present dis 2004/098591, WO 2005/039548, WO 2005/075436, WO closure, includes a computer readable form comprising 2008/055945, WO 2008/055947, WO 2008/055950 and nucleotide and/or amino acid sequences of the present inven WO2008/0651.41. tion. The Subject matter of the Sequence Listing is incorpo 15 EP 02011 349.4 discloses polynucleotides encoding insect rated herein by reference in its entirety. glutaminyl cyclase, as well as polypeptides encoded thereby and their use in methods of Screening for agents that reduce FIELD OF THE INVENTION glutaminyl cyclase activity. Such agents are useful as pesti cides. The invention relates to inhibitors of glutaminyl cyclase WOOO/42022 discloses a series of MEK inhibitors which (QC, EC 2.3.2.5). QC catalyzes the intramolecular cycliza are claimed to be useful in the treatment of proliferative tion of N-terminal glutamine residues into pyroglutamic acid diseases such as cancer. WO 03/077914 discloses a series of (5-oxo-prolyl, pClu) under liberation of ammonia and the MEK inhibitors which are claimed to be useful in the treat intramolecular cyclization of N-terminal glutamate residues ment of hyperproliferative diseases Such as cancer and into pyroglutamic acid under liberation of water. inflammation. Roy and Bhaduri (1979) Indian J Chem 17B. 25 164-166 discloses the synthesis of 4,6-dinitro-5-substituted BACKGROUND OF THE INVENTION amino-benzoimidazole compounds. Soskic et al (1996) Arz neimittel-Forschung 46(8), 741-746 discloses the synthesis Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the of benzoimidazole ethylamine compounds which are claimed intramolecular cyclization of N-terminal glutamine residues to be useful as dopaminergic ligands. Braeuniger etal (1966) into pyroglutamic acid (pGlu) liberating ammonia. A QC 30 Archiv der Pharmazie 299(3), 193-196 discloses a series of was first isolated by Messer from the latex of the tropical plant benzimidazole compounds which are claimed to be useful as Carica papaya in 1963 (Messer, M. 1963 Nature 4874, 1299). stimulants for plant growth. WO 2007/053131 discloses a 24 years later, a corresponding enzymatic activity was dis series of acrylamide derivatives which are claimed to be use covered in animal pituitary (Busby, W. H. J. etal. 1987J Biol ful as antibiotic agents. WO 01/05770 discloses a series of Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 35 benzoimidazolone derivatives which are claimed to be useful Proc Natl AcadSci USA 84,3628-3632). For the mammalian as cCMP-PDE inhibitors. QC, the conversion of Gln into pGlu by QC could be shown Definitions for the precursors of TRH and GnRH (Busby, W. H. J. et al. The terms “k,” or “K” and “K” are binding constants, 1987J Biol Chem 262,8532-8536; Fischer, W. H. and Spiess, which describe the binding of an inhibitor to and the subse J. 1987 Proc Natl AcadSci USA 84,3628-3632). In addition, 40 quent release from an enzyme. Another measure is the “ICso initial localization experiments of QC revealed a co-localiza value, which reflects the inhibitor concentration, which at a tion with its putative products of catalysis in bovine pituitary, given substrate concentration results in 50% enzyme activity. further improving the Suggested function in peptide hormone The term “DP IV-inhibitor” or “dipeptidyl peptidase IV synthesis (Bockers, T. M. et al. 1995 J Neuroendocrinol 7, inhibitor' is generally known to a person skilled in the art and 445-453). In contrast, the physiological function of the plant means enzyme inhibitors, which inhibit the catalytic activity QC is less clear. In the case of the enzyme from C. papaya, a 45 of DP IV or DPIV-like enzymes. role in the plant defense against pathogenic microorganisms “DP IV-activity” is defined as the catalytic activity of was suggested (El Moussaoui, A. etal. 2001 Cell Mol LifeSci dipeptidyl peptidase IV (DP IV) and DP IV-like enzymes. 58, 556-570). Putative QCs from other plants were identified These enzymes are post-proline (to a lesser extent post-ala by sequence comparisons recently (Dahl, S. W. et al. 2000 nine, post-serine or post-glycine) cleaving serine proteases Protein Expr Purif 20, 27-36). The physiological function of 50 found in various tissues of the body of a mammal including these enzymes, however, is still ambiguous. kidney, liver, and intestine, where they remove dipeptides The QCs known from plants and animals show a strict from the N-terminus of biologically active peptides with a specificity for L-Glutamine in the N-terminal position of the high specificity when proline oralanine form the residues that substrates and their kinetic behavior was found to obey the are adjacent to the N-terminal amino acid in their sequence. Michaelis-Menten equation (Pohl, T. et al. 1991 Proc Natl 55 The term “PEP-inhibitor” or “prolyl endopeptidase inhibi Acad Sci USA 88, 10059-10063: Consalvo, A. P. et al. 1988 tor” is generally known to a person skilled in the art and Anal Biochem 175, 131-138; Gololobov, M.Y.
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