Beta-thiopropionyl-amino acid derivatives and their use as beta-

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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514381, 514383, 514397, 514445, 514563, 546335, 548253, 548255, 5482622, 5483351, 549 76, 564442, A61K 3144, C07D40102

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061567744

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BRIEF SUMMARY
This invention relates to chemical compounds having metallo-.beta.-lactamase inhibitory and antibacterial properties. The invention also relates to methods for the preparation of such compounds, to pharmaceutical compositions containing them, and to uses thereof.
Metallo-.beta.-lactamases confer resistance to the vast majority of .beta.-lactam based therapies, including carbapenems and jeopardise the future use of all such agents. As a result of the increased use of carbapenems and other .beta.-lactam antibiotics the clinical climate is becoming more favourable for the survival of clinical strains which produce metallo-.beta.-lactamases, and metallo-.beta.-lactamases have now been identified in common pathogens such as Bacillus fragilis, Klebsiella, Pseudomonas aeruginosa and Serratia marcescens. Emerging knowledge emphasises that metallo-.beta.-lactamases have the potential to present a crisis situation for antimicrobial chemotherapy.
U.S. Pat. No. 4,513,009 discloses amino derivatives including thiorphan having enkephalinase-inhibiting, antalgic, antidiarrhea and hypotensive. Analgesic effects are disclosed for thiorphan (B. P. Roques et al, Nature, 1980, 288, 286) and for other mercapto amino acid derivatives (JO 3002-117-A). Mercapto amino acid derivatives are disclosed as inhibitors of angiotensin-converting enzyme (ACE) (J. L. Stanton, et al., J. Med. Chem., 1983, 26, 1257, U.S. 4053-651 and GB 2090-591); as conferring antihypotensive effects (WO 9308162); as enkephalinase (neutral endopeptidase (NEP)) inhibitors (U.S. 4474-799 and Mimura et al., J. Med. Chem. 1992, 35, 602 and references cited therein); as dual inhibitors of ACE and NEP (fournie-Zaluski et al., J. Med. Chem., 1994, 37(8), 1070, WO 9417036 and Biiorg. Med. Chem. Lett., 1996, 6(17), 2097); as inhibitors of endothelian-converting enzyme (ECE) (WO 9311154, Burtenshaw, et al, Bioorg. Med. Chem. Lett., 1993, 3(10), 1953 and Deprez et al., Bioorg. Med. Chem. Lett., 1996, 6(19)); as metalloproteinase inhibitors (WO 9425435); and having radioprotective action and cytotoxicity (M. Hikita et al, J. Radiat. Res., 1975, 16(3), 162 and DE2,349,707). DE3819539 (Squibb) discloses amino acids and peptide derivatives as inhibitors of neutral endopeptidase and their use as antihypertensives and diuretics.
Other references to amino acid derivatives having the abovementioned activities include: Gordon et al., Life Sciences 1983, 33 (Supp. I), 113-6; Waller et al., J, Med. Chem. 1993, 36, 2390-2403; Saunders et al., J. Comp. Aided Mole. Des. 1987, 1, 133-42; Gomez-Monterrey et al., J. Med. Chem. 1993, 36, 87-94; Oya et al., Chem. Pharm. Bull. 1981, 29(4), 940-7; Trapani et al., Biochem. Mol. Biol. Int 1993, 31(5), 861-7; Baxter et al., J. Med. Chem. 1992, 35(20), 3718-20; Condon et al., J. Med. Chem. 1982, 25(3), 250-8; Cheung et al., J. Biol. Chem. 1980, 255(2), 401-7; Cushman et al., Biochemistry 1977, 16(25), 5484-91; EP0539848, EP0419327, EP0254032, EP0355784, EP0449523, EP0153755, U.S. Pat. No. 5,061,710, U.S. Pat. No. 4,339,600, U.S. Pat. No. 4,401,677, U.S. Pat. No. 4,199,512, DE2717548. DE2711225, JP54052073, JP54063017, JP54092937, JP55055165. JP54063017, WO9407481, WO8202890, BE890398, and WO97/24341 and WO97/24342 both published Jul. 10, 1997.
Other amino acid derivatives are described by: Fuchs et al., Arzneim.-Forsch. 1985, 35(9)1394-402, having mitochondrial dysfunction and postischemic myocardial damage activity; Rajkovic et al., Biochem. Pharmacol. 1984, 33(8), 1249-50, having enhancement of neutrophil response and modulation of superoxide and hydrogen peroxide production; Sakurai et al., Chem. Pharam. Bull. 1979, 27(12), 3022-8 forming a peptide/cytochrome P-450 heme system; and Sugiura et al., J. Am. Chem. Soc. 1977, 99(5), 1581-5, forming copper(II) and nickel(II) complexes.
WO97/30027 published Aug. 21, 1997 discloses certain amino acid derivatives which have metallo-.beta.-lactamase inhibitory properties.
A novel series of amino acid derivatives have now been discovered, which compounds have metallo-.beta.-lactamsae inhibitory proper

REFERENCES:
J.L. Stanton, et al., Angiotensin converting enzyme inhibitors: n-substituted monocyclic and bicylic amino acid derivatives, J. of Med. Chem., vol. 26(9), Sep. 1983, pp. 1267-1277.
M.C. Fournie-Zaluski, et al., New dual inhibitors of neutral endopeptidase and angiotension-converting enzyme: rational design, bioavailability, and pharmacological response in experimental hypertension, J. of Med. Chem., vol. 37(8), Apr. 15, 1994, pp. 1070-1083.
M. Ihara, et al., Synthesis of beta-lactam antibiotics by the sulpheno-cycloamination, J. of Amer. Chem. Soc., vol. 105(25), Dec. 14, 1983, pp. 7345-7352.
H. H. Wasserman, et al., The synthesis of beta-lactams by the cyclisation of beta-halopropionamides, Tetrahedron Letters, No. 6, Feb. 1979, pp. 549-552.

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