Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1998-06-15
2000-03-28
Fonda, Kathleen K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514 2, 514309, A61K 31195
Patent
active
060432780
DESCRIPTION:
BRIEF SUMMARY
This invention concerns perfluoro-lower-alkyl derivatives of amino acids. A new synthetic route is provided for preparing .alpha.-aminotrifluoromethylketones. Fluorinated derivatives of amino acids and peptides are shown to have a new property of inhibiting or inactivating certain enzymes. Certain of the trifluoromethyl derivatives of amino acids are new compounds per se.
The catalytic action of a number of proteases is associated with disease processes, e.g. cancer, thrombosis. The inhibition of these protease enzymes is thus of potential therapeutic importance. Trifluoromethylketones including, but not exclusively, trifluoromethylketone derivatives of .alpha.-amino acids and peptides are documented inhibitors of proteases in vitro and are currently being developed by the pharmaceutical industry.
.beta.-lactamases are bacterial enzymes which confer resistance to .beta.-lactam antibiotics. They may be divided into four groups on the basis of their primary structure and mechanism [Ambler, R. P., Phil. Trans. R.
Soc. Lond. B., 289, 321-331 (1980)]. Classes A, C and D contain a nucleophilic serine residue at their active sites. Class B enzymes do not, but are metalloproteins which require a bivalent transition metal ion (normally zinc) for activity. The class B enzymes are produced by a range of bacteria. Bacteria which produce .beta.-lactamases are able to hydrolyse and thereby inactivate a wide range of .beta.-lactam antibiotics (including those of medicinal and commercial interest, e.g. penicillins, cephalosporins, carbapenems and others). Resistance to .beta.-lactam antibiotics mediated by metallo .beta.-lactamases is becoming an increasing clinical problem [Payne, D., J. Med. Microbiol., 39, 93, 1993.]
The so-called "combination" therapy in which a mixture of a .beta.-lactam antibiotic and an inhibitor of a serine .beta.-lactamase is administered in order to overcome the problem of resistance mediated by the serine .beta.-lactamases, has led to useful and highly effective medications. This approach is exemplified by the pharmaceutical product Augmentin (a Smithkline Beecham product) which is a combination of amoxycillin, an antibiotic and clavulanic acid [Cartwright, S. J. and Coulson, A. F. W., Nature, 278, 360-361 (1979) and references therein.], a .beta.-lactamase inhibitor. To the best of our knowledge there are no literature reports of inhibitors of the class B metallo-.beta.-lactamases, hence a combination therapy approach cannot be used, and thus resistance to them is a particular problem.
This invention is partly based on the discovery that perfluoro-lower-alkyl (i.e. C.sub.n F.sub.2n+1 where n is 1-4) e.g. trifluoromethyl derivatives of .alpha.-amino acids can act as metallo-.beta.-lactamase enzyme inhibitors. Thus, in this aspect the invention provides use of a trifluoromethyl derivative of an amino acid or peptide or a fluorinated .beta.-lactam substrate analogue as a metallo-.beta.-lactamase enzyme inhibitor, or in the preparation of an antibacterial formulation. The invention also provides an antibacterial formulation comprising a mixture of a .beta.-lactam antibiotic and a perfluoro-lower-alkyl derivative of an amino acid or a peptide or a fluorinated .beta.-lactam substrate analogue. A substrate analogue is a compound having a similar shape and binding properties to a .beta.-lactam substrate peptide.
Preferably the perfluoro-lower-alkyl derivative of the amino acid has the formula (I) or (II) ##STR1## where either R.sup.4 is OH and R.sup.5 is H, or C.sub.1 -C.sub.12 hydrocarbon; or R.sup.5 is OH and R.sup.4 is H or C.sub.1 -C.sub.12 hydrocarbon; or each of R.sup.4 and R.sup.5 is H; or R.sup.4 and R.sup.5 together are .dbd.O, hydrocarbon which is either unsubstituted or which carries an acidic or a basic substituent, the free base and acid salts thereof.
The hydrocarbon groups R, R.sup.1, R.sup.4 and R.sup.5 may be alkyl, alkenyl, alkynyl, straight chained or branched, cyclic, aromatic, heterocyclic or alicyclic. Examples of acidic and basic substituents include carboxylate, sulphonate, hyd
REFERENCES:
patent: 2521902 (1950-09-01), Coover et al.
patent: 5338856 (1994-08-01), Ricks et al.
Chemical Abstracts, 124(1), abstract No. 9415a (Jan. 1996).
Chemical Abstracts, 122(19), abstract No. 234109g (May 1995).
Chemical Abstracts, 121(23), abstract No. 281229k (Dec. 1994).
Chemical Abstracts, 113(17), abstract No. 147802y (Oct. 1990).
K. Brady et al., Biochemistry, 29(33), 7608-7617 (1990).
K. Brady et al., Biochemistry, 29(33), 7600-7607 (1990).
Chemical Abstracts, 112(13), abstract No. 11520v (Mar. 1990).
M. Kolb et al., Liebigs Ann. Chem., (1), 1-6 (1990).
N. Peet, J. Med. Chem., 33(1), 394-407 (1990).
M. Kolb et al., Tetrahedron Lett., 27(14), 1579-1582 (1986).
Chemical Abstracts, 106(11), abstract No. 85059f (Mar. 1987).
B. Imperiali et al., Biochemistry, 25(13), 3760-3767 (1986).
Chemical Abstracts, 66(21), abstract No. 95004d (May 1967).
M. Walter et al., Tetrahedron Lett, 36(42), 7761-7764 (Oct. 1995).
M. Gilpin et al., J. Antibiot., 48(10), 1081-1085 (1995).
C. Derstine et al., J. Am. Chem. Soc., 118(35), 8485-8486 (1996).
M. Walter et al., Bioorg. Med. Chem. Lett., 6(20), 2455-2458 (1996).
Adlington Robert M
Antonio Felici
Baldwin Jack E
Frere Jean-Marie
Schofield Christopher Joseph
Fonda Kathleen K.
Isis Innovation Limited
LandOfFree
Perfluoralkyl substituted metallo-beta-lactamase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Perfluoralkyl substituted metallo-beta-lactamase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Perfluoralkyl substituted metallo-beta-lactamase inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1326445