(12) United States Patent (10) Patent No.: US 6,958,358 B2 Quibell Et Al
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USOO695.8358B2 (12) United States Patent (10) Patent No.: US 6,958,358 B2 Quibell et al. (45) Date of Patent: Oct. 25, 2005 (54) INHIBITORS OF CRUZIPAIN AND OTHER FOREIGN PATENT DOCUMENTS CYSTEINE PROTEASES WO 98/O5336 2/1998 WO 98/08802 3/1998 (75) Inventors: Martin Quibell, Cambridge (GB); WO 98/28268 7/1998 Manoj Kumar Ramjee, Cambridge WO 98/50533 11/1998 (GB) WO 99/53039 10/1999 WO OO/294.08 5/2000 (73) Assignee: Amura Therapeutics Limited (GB) WO O2/O40462 5/2000 WO OO/69855 11/2000 (*) Notice: Subject to any disclaimer, the term of this WO O2/O51983 7/2002 patent is extended or adjusted under 35 U.S.C. 154(b) by 49 days. OTHER PUBLICATIONS (21) Appl. No.: 10/466,385 Fenwick, et al., “Diastereoselective Synthesis, Activity and Chiral Stability of Cyclic Alkoxyketone Inhibitors of Cathe (22) PCT Filed: Jan. 17, 2002 psin K,” Bioorganic & Medicinal Chemistry Letters, vol. 11, pp. 199-202 (2001). (86) PCT No.: PCT/GB02/00194 Marquis, et al., “Conformationally Constrained 1, S371 (c)(1), 3-Diamino Ketones: A Series of Potent Inhibitors of the (2), (4) Date: Jan. 8, 2004 Cysteine Protease Cathepsin K. J. Med. Chem., vol. 41, pp. 3563-3567 (1998). (87) PCT Pub. No.: WO02/057246 Primary Examiner Taofiq Solola PCT Pub. Date:Jul. 25, 2002 (74) Attorney, Agent, or Firm Wilmer Cutler Pickering (65) Prior Publication Data Hale and Dorr LLP US 2004/0106805 A1 Jun. 3, 2004 (57) ABSTRACT Related U.S. Application Data Compounds of general formula (I): (60) Provisional application No. 60/275,506, filed on Mar. 13, 2001. (I) (30) Foreign Application Priority Data Jan. 17, 2001 (GB) ............................................. O101.204 51) Int.nt. Cl.Cl." .................... A61K 31/343; A61K 31/381 CO7D 307/93; CO7D 495/00 - (V)V)m (52) U.S. Cl. ......................... 514,443; 514/470; 549/33; 549/465; 549/466 (58) Field of Search ................................. 514/443, 470; wherein R', Y, (X), (W), (V), Z and U are as defined in 549/33, 465, 466 the Specification, are inhibitors of cruzipain and other cyS teine protease inhibitors and are useful as therapeutic agents, (56) References Cited for example in Chagas disease, or for validating therapeutic target compounds. U.S. PATENT DOCUMENTS 3.652,574 A 3/1972 Garmaise .................... 260/296 35 Claims, No Drawings US 6,958,358 B2 1 2 INHIBITORS OF CRUZPAN AND OTHER within the myriad of proteins found in nature. This hydro CYSTEINE PROTEASES lytic action is performed by initially recognising, then bind ing to, particular three-dimensional electronic Surfaces dis THIS INVENTION relates to compounds which are played by a protein, which aligns the bond for cleavage inhibitors of the protease cruzipain, a gene product of the precisely within the protease catalytic Site. Catalytic TrypanoSoma Cruzi parasite. In particular, the invention hydrolysis then commences through nucleophilic attack of provides compounds that are useful for the therapeutic the amide bond to be cleaved either via an amino acid treatment of TrypanoSoma Cruzi infection, to the use of these Side-chain of the protease itself, or through the action of a compounds, and to pharmaceutical compositions compris water molecule that is bound to and activated by the pro ing them. Furthermore, this invention relates to compounds tease. Proteases in which the attacking nucleophile is the which are inhibitors acroSS a broad range of cysteine thiol Side-chain of a CyS residue are known as cysteine proteases, to the use of these compounds, and to pharma proteases. The general classification of cysteine protease ceutical compositions comprising them. Such compounds contains many members found acroSS a wide range of are useful for the therapeutic treatment of diseases in which organisms from Viruses, bacteria, protozoa, plants and fungi participation of a cysteine protease is implicated. 15 to mammals. The trypanoSomal family of parasites have a Substantial Biological investigation of TrypanoSoma Cruzi infection Worldwide impact on human and animal healthcare has highlighted a number of Specific enzymes that are (McKerrow, J. H., et al, Ann. Rev. Microbiol. 47821–853, crucial for the progression of the parasite's life cycle. One 1993). One parasite of this family, Trypanosoma cruzi, is the Such enzyme, cruzipain, a cathepsin L-like cysteine causative agent of Chagas disease, which affects in exceSS protease, is a clear therapeutic target for the treatment of of twenty million people annually in Latin and South Chagas disease ((a) CaZZulo, J. J. et al, Curr. Pharm. Des. America, is the leading cause of heart disease in these 7, 1143–1156, 2001; (b) Caffrey, C. R. et al, Curr. Drug regions and results in more than 45,000 deaths per annum Targets, 1, 155-162, 2000). Although the precise biological (Centers for Disease Control and prevention website). In role of cruzipain within the parasite's life cycle remains addition, with the increase in migration of the infected 25 unclear, elevated cruzipain messenger RNA levels in the population from rural to urban Sites and movements from epimastigote developmental Stage indicate a role in the South and Central America into North America, the infec nutritional degradation of host-molecules in lySOSomal-like tion is spreading via blood transfusions, and at birth. The vesicles (Engel, J. C. et al., J. Cell. Sci, 111,597–606, 1998). present treatments of choice for Trypanosoma Cruzi The validation of cruzipain as a viable therapeutic target has infection, nifurtimox and benznidazole (an NADH fumarate been achieved with increasing levels of complexity. Addi reductase inhibitor, Turrens, J. F., et al, Mol Biochem tion of a general cysteine protease inhibitor, Z-Phe-Ala Parasitol., 82(1), 125-9, 1996) are at best moderately FMK to Trypanosoma cruzi-infected mammalian cell cul Successful, achieving ~60% cure during the acute phase of tures blocked replication and differentiation of the parasite, infection (see Docampo, R. Curr: Pharm. Design, 7, thus arresting the parasite life cycle (Harth, G., et al, Mol. 1157–1164, 2001 for a general discussion) whilst not being 35 Biochem. Parasitol. 58, 17-24, 1993). Administration of a prescribed at all during the chronic phase where cardiomy Vinyl Sulphone-based inhibitor in a TrypanoSoma Cruzi opathy associated heart failure often occurs (Kirchhoff, L. V. infected murine animal model not only rescued the mice New Engl. J. Med.,329, 639-644, 1993). Additionally, these from lethal infections, but also produced a complete recov two drugs have Serious adverse toxic effects, requiring close ery (Engel, J. C. et al., J. Exp. Med, 188(4), 725-734, 1998). medical Supervision during treatment, and have been shown 40 Numerous other in vivo studies have confirmed that infec to induce chromosomal damage in chagastic infants (Gorla, tions with alternative parasites Such as Leishmania major N. B. et al, Mutat. Res. 206, 217-220, 1988). Therefore, a (Selzer, P. M. et al, Proc. Natl. Acad. Sci. U.S.A., 96, Strong medical need exists for new effective drugs for the 11015-11022, 1999), Schistosoma mansoni and Plasmo chemotherapeutic treatment of TrypanoSoma Cruzi infection. dium falciparium (Olson, J. E. et al, Bioorg. Med. Chem., 7, Classically, the identification of enzymes found to be crucial 45 633-638, 1999) can be halted or cured by treatment with for the establishment or propagation of an infectious disease cysteine protease inhibitors. has been instrumental in the development of Successful A variety of Synthetic approaches have been described drugs such as antivirals (e.g. HIV aspartyl protease towards the design of cruzipain inhibitors. However, inhibitors) and anti-bacterials (e.g. f-lactam antibiotics). although providing a biological proof-of-principle for the The Search for a similar Achilles heel in parasitic infections 50 treatment of TrypanoSoma Cruzi infection, current inhibitors has examined numerous enzymes (e.g. parasitic dihydro exhibit a number of biochemical and physical properties that folate reductase, see Chowdhury, S. F. et al., J. Med. Chem., may preclude their clinical development. (e.g. See (a) 42(21), 4300-4312, 1999; trypanothione reductase, see Li, Brinen, L. S. et al, Structure, 8,831-840, 2000, peptidomi Z. et al, Bioorg. Med Chem. Lett., 11(2), 251-254, 2001; metic vinyl Sulphones, possible adverse mammalian cell parasitic glyceraldehydes-3-phosphate dehydrogenase, See 55 toxicity (see McKerrow, J. H. and Engel, J. unpublished Aranov, A. M. et al., J. Med. Chem., 41(24), 4790-4799, results cited in Scheidt, K. A. et al, Bioorg. Med. Chem, 6, 1998). A particularly promising area of research has iden 2477-2494, 1998); (b) Du, X. etal, Chem. Biol.., 7, 733–742, tified the role of cysteine proteases, encoded by the parasite, 2000, aryl ureas, generally with low uM activity, and high that play a pivotal role during the life cycle of the parasite ClogP values, thus poor aqueous Solubility and probably low (McKerrow, J. H., et al, Bioorg. Med. Chem., 7, 639-644, 60 oral bioavailability; (c) Roush, W. R. et al, Tetrahedron, 56, 1999). Proteases form a substantial group of biological 9747-9762, 2000, peptidyl epoxysuccinates, irreversible molecules which to date constitute approximately 2% of all inhibitors, with potent activity verses house-keeping mam the gene products identified following analysis of Several malian proteases Such as cathepsin B; (d) Li, R. etal, BioOrg. genome Sequencing programmes (e.g. See Southan, C. J. Med. Chem. 4(9), 1421-1427, 1996, bisarylacylhydrazides Pept. Sci, 6, 453-458, 2000). Proteases have evolved to 65 and chalcones, polyhydroxylated aromatics; (e) U.S. Pat. participate in an enormous range of biological processes, No. 6,143.931, WO 9846559, non-peptide O-ketoamides). mediating their effect by cleavage of peptide amide bonds Of the many different approaches to enzyme inhibition to US 6,958,358 B2 3 4 date, only the cruzipain protease inhibitors have proven aspartic acid (158 to 163, residue number varies between effective in curing disease-related animal models of Trypa proteases) and an inhibitor (N-H) is often observed, where noSoma Cruzi infection.