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(12) United States Patent (10) Patent No.: US 9,181.233 B2 Heiser Et Al

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(12) United States Patent (10) Patent No.: US 9,181.233 B2 Heiser Et Al US009181233B2 (12) United States Patent (10) Patent No.: US 9,181.233 B2 Heiser et al. (45) Date of Patent: Nov. 10, 2015 2007/0191366 A1* 8, 2007 Hoffmann et al. ......... 514,235.5 (54) INHIBITORS OF GLUTAMINYLCYCLASE 2008/0214620 A1* 9, 2008 Heiser et al. ....... ... 514,338 (75) Inventors: Ulrich Heiser, Halle/Saale (DE); Daniel 2010.0040575 A1 2/2010 Hoffmann et al. ........... 424/85.2 Ramsbeck, Halle/Saale (DE); Torsten 2010 OO69381 A1 3, 2010 Itoh Hoffmann, Halle/Saale (DE); Livia FOREIGN PATENT DOCUMENTS Boehme, Halle/Saale (DE); Hans-Ulrich Demuth, Halle/Saale (DE) EP 1375486 1, 2004 WO WO 2004/005.283 1, 2004 (73) Assignee: PROBIODRUGAG. Halle/Saale (DE) WO WO 2004/O14881 2, 2004 WO WO 2004/031177 4/2004 WO WO2005/121132 12/2005 (*) Notice: Subject to any disclaimer, the term of this WO WO 2007/OO3961 1, 2007 patent is extended or adjusted under 35 WO WO 2008/O16123 2, 2008 U.S.C. 154(b) by 224 days. WO WO 2008/042571 4/2008 WO WO2008/065141 6, 2008 (21) Appl. No.: 13/040,159 WO WO 2008.154241 12/2008 WO WO 2008,157 273 12/2008 WO WO 2009/051705 4/2009 (22) Filed: Mar. 3, 2011 WO WO 2009, 111442 9, 2009 (65) Prior Publication Data OTHER PUBLICATIONS US 2011 FO224259 A1 Sep. 15, 2011 International Application Published as WO2005/121132 on Jun. 5, 2008, abstract in English only. Related U.S. Application Data Hess et al., 1-(5-Carboxy- and 5-carbamoylindol-lyl)propane-2- ones as inhibitors of human cytosolic phospholipase A2a: (60) Provisional application No. 61/309,951, filed on Mar. Bioisosteric replacement of the carboxylic acid and carboxamide 3, 2010. moiety, Bioorganic & Medicinal Chemistry, 2007, pp. 2883-2891, vol. 15, No. 8. Sawhney et al., Benzothiazole Derivatives: Part I—Synthesis of 2-(4- (51) Int. Cl. Thiazolyl)- & 6-(4- Thiazolyl)-benzothiazoles & Their Derivatives CO7D 235/04 (2006.01) as Potential Anthelmintics, Indian J. Of Chemistry, 1970, pp. 882 A6 IK3I/4I84 (2006.01) 884, vol. 8, No. 10. CO7D 417/04 (2006.01) Registry (STN) online). Apr. 19, 2002 (search date: Nov. 28, 2014) CO7D 403/04 (2006.01) CAS No. 406.189-44-4, 1 page. CO7D 413/04 (2006.01) (52) U.S. Cl. * cited by examiner CPC .......... C07D 417/04 (2013.01); A61 K3I/4184 (2013.01); C07D 235/04 (2013.01); C07D Primary Examiner — Theodore R West 403/04 (2013.01); C07D 413/04 (2013.01) (74) Attorney, Agent, or Firm — Dentons US LLP (58) Field of Classification Search None (57) ABSTRACT See application file for complete search history. The invention relates to novel heterocyclic derivatives as inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC cata (56) References Cited lyzes the intramolecular cyclization of N-terminal glutamine residues into pyroglutamic acid (5-oxo-prolyl, pGlu) under U.S. PATENT DOCUMENTS liberation of ammonia and the intramolecular cyclization of 4,746,669 A 5, 1988 Caldwell et al. N-terminal glutamate residues into pyroglutamic acid under 7,371,871 B2 * 5/2008 Schilling et al. ........... 548,346.1 liberation of water. 7,732,162 B2 * 6/2010 Hoffman et al. ................ 435/18 2006/0293334 A1* 12/2006 Fuji et al. ...................... 514,249 17 Claims, No Drawings US 9, 181,233 B2 1. 2 INHIBITORS OF GLUTAMINYL. CYCLASE pronounced sequence homology to bacterial aminopepti dases (Bateman, R. C. et al. 2001 Biochemistry 40, 11246 CROSS-REFERENCE TO RELATED 11250), leading to the conclusion that the QCs from plants APPLICATIONS and animals have different evolutionary origins. Recently, it was shown that recombinant human QC as well This application claims priority to U.S. Provisional Appli as QC-activity from brain extracts catalyze both, the N-ter cation Ser. No. 61/309,951, filed on Mar. 3, 2010, which is minal glutaminyl as well as glutamate cyclization. Most strik incorporated herein by reference in its entirety. ing is the finding, that cyclase-catalyzed Glu-conversion is favored around pH 6.0 while Gln-conversion to pGlu-deriva MATERIAL INCORPORATED-BY-REFERENCE 10 tives occurs with a pH-optimum of around 8.0. Since the formation of pClu-AB-related peptides can be suppressed by The Sequence Listing, which is a part of the present dis inhibition of recombinant human QC and QC-activity from closure, includes a computer readable form comprising pig pituitary extracts, the enzyme QC is a target in drug nucleotide and/or amino acid sequences of the present inven tion. The Subject matter of the Sequence Listing is incorpo 15 development for treatment of Alzheimer's disease. Inhibitors of QC are described in WO 2004/098625, WO rated herein by reference in its entirety. 2004/098591, WO 2005/039548, WO 2005/075436, WO FIELD OF THE INVENTION 2008/055945, WO 2008/055947, WO 2008/055950 and WO2008/0651.41. The invention relates to novel heterocyclic derivatives as EP 02011 349.4 discloses polynucleotides encoding insect inhibitors of glutaminyl cyclase (QC, EC 2.3.2.5). QC cata glutaminyl cyclase, as well as polypeptides encoded thereby lyzes the intramolecular cyclization of N-terminal glutamine and their use in methods of Screening for agents that reduce residues into pyroglutamic acid (5-oxo-prolyl, pGlu) under glutaminyl cyclase activity. Such agents are useful as pesti liberation of ammonia and the intramolecular cyclization of cides. N-terminal glutamate residues into pyroglutamic acid under 25 liberation of water. DEFINITIONS BACKGROUND OF THE INVENTION The terms “k, or “K” and “K” are binding constants, which describe the binding of an inhibitor to and the subse Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzes the 30 quent release from an enzyme. Another measure is the “ICso intramolecular cyclization of N-terminal glutamine residues value, which reflects the inhibitor concentration, which at a into pyroglutamic acid (pGlu) liberating ammonia. A QC given substrate concentration results in 50% enzyme activity. was first isolated by Messer from the latex of the tropical plant The term “DP IV-inhibitor” or “dipeptidyl peptidase IV Carica papaya in 1963 (Messer, M. 1963 Nature 4874, 1299). inhibitor' is generally known to a person skilled in the art and 24 years later, a corresponding enzymatic activity was dis 35 means enzyme inhibitors, which inhibit the catalytic activity covered in animal pituitary (Busby, W. H. J. etal. 1987J Biol of DP IV or DPIV-like enzymes. Chem 262, 8532-8536; Fischer, W. H. and Spiess, J. 1987 “DP IV-activity” is defined as the catalytic activity of Proc Natl AcadSci USA 84,3628-3632). For the mammalian dipeptidyl peptidase IV (DP IV) and DP IV-like enzymes. QC, the conversion of Gln into pGlu by QC could be shown These enzymes are post-proline (to a lesser extent post-ala for the precursors of TRH and GnRH (Busby, W. H. J. et al. 40 nine, post-serine or post-glycine) cleaving serine proteases 1987J Biol Chem 262,8532-8536; Fischer, W. H. and Spiess, found in various tissues of the body of a mammal including J. 1987 Proc Natl AcadSci USA 84,3628-3632). In addition, kidney, liver, and intestine, where they remove dipeptides initial localization experiments of QC revealed a co-localiza from the N-terminus of biologically active peptides with a tion with its putative products of catalysis in bovine pituitary, high specificity when proline oralanine form the residues that further improving the Suggested function in peptide hormone 45 are adjacent to the N-terminal amino acid in their sequence. synthesis (Bockers, T. M. et al. 1995 J Neuroendocrinol 7, The term “PEP-inhibitor” or “prolyl endopeptidase inhibi 445-453). In contrast, the physiological function of the plant tor” is generally known to a person skilled in the art and QC is less clear. In the case of the enzyme from C. papaya, a means enzyme inhibitors, which inhibit the catalytic activity role in the plant defense against pathogenic microorganisms of prolyl endopeptidase (PEP prolyl oligopeptidase, POP). was suggested (El Moussaoui, A. etal. 2001 Cell Mol LifeSci 50 “PEP-activity” is defined as the catalytic activity of an 58, 556-570). Putative QCs from other plants were identified endoprotease that is capable to hydrolyze post proline bonds by sequence comparisons recently (Dahl, S. W. et al. 2000 in peptides or proteins where the proline is in amino acid Protein Expr Purif 20, 27-36). The physiological function of position 3 or higher counted from the N-terminus of a peptide these enzymes, however, is still ambiguous. or protein Substrate. The QCs known from plants and animals show a strict 55 The term “QC as used herein comprises glutaminyl specificity for L-Glutamine in the N-terminal position of the cyclase (QC) and QC-like enzymes. QC and QC-like substrates and their kinetic behavior was found to obey the enzymes have identical or similar enzymatic activity, further Michaelis-Menten equation (Pohl, T. et al. 1991 Proc Natl defined as QC activity. In this regard, QC-like enzymes can Acad Sci USA 88, 10059-10063: Consalvo, A. P. et al. 1988 fundamentally differ in their molecular structure from QC. Anal Biochem 175, 131-138; Gololobov, M.Y. et al. 1996 60 Examples of QC-like enzymes are the glutaminyl-peptide Biol Chem Hoppe Seyler 377,395-398). A comparison of the cyclotransferase-like proteins (QPCTLs) from human (Gen primary structures of the QCs from C. papaya and that of the Bank NM 017659), mouse (GenBank BC058181), Macaca highly conserved QC from mammals, however, did not reveal fascicularis (GenBank AB168255), Macaca mulatta (Gen any sequence homology (Dahl, S.W. et al. 2000 Protein Expr Bank XM 001110995), Purif 20, 27-36).
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