Pyrrolidine and thiazole derivatives with...

Details Pyrrolidine and thiazole derivatives with... Pyrrolidine and thiazole derivatives with...

1999-08-17

2001-04-03

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S562000, C514S541000, C548S201000, C562S426000, C560S009000

Reexamination Certificate

active

06211212

ABSTRACT:

This invention relates to chemical compounds having metallo-&bgr;-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-&bgr;-lactamases confer resistance to the vast majority of &bgr;-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 &bgr;-lactam antibiotics the clinical climate is becoming more favourable for the survival of clinical strains which produce metallo-&bgr;-lactamases, and metallo-&bgr;-lactamases have now been identified in common pathogens such as
Bacillus fragilis
, Klebsiella,
Pseudomonas aeruginosa
and
Serratia marcescens
. Emerging knowledge emphasises that metallo-&bgr;-lactamases have the potential to present a crisis situation for antimicrobial chemotherapy.
U.S. Pat. No. 4,513,009 discloses amino acid 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. Pat. No. 4,053,651 and GB 2090-591); as conferring antihypotensive effects (WO 9308162); as enkephalinase (neutral endopeptidase (NEP)) inhibitors (U.S. Pat. No. 4,474,799 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
Bioorg. Med. Chem. Lett
., 1996, 6(17), 2097); as inhibitors of endothelin-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. U.S. Pat. No. 4,046,889, U.S. Pat. No. 4,105,776, U.S. Pat. No. 4,307,110, U.S. Pat. No. 4,316,906, BE868532, CH635087, J55057561, J55009060, U.S. Pat. No. 428,340 and EP0001978 disclose various substituted proline and thiazolidine compounds having anti-hypertensive activity.
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, WO940748 1, WO8202890 and BE890398.
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 P450 heme system; and Sugiura et al., J. Am. Chem. Soc. 1977, 99(5), 1581-5, forming copper(II) and nickel(II) complexes.
(1S, 2R, 5S)— and (1R, 2S, 5R)—isomers of [(2-mercapto-5-phenyl cyclopentanecarbonyl)-amino]-acetic acid are reported as inhibitors both of thermolysin and of neutral endopeptidase (Fillion et al, Biorg. Med. Chem. Lett, 1996, 6 (17), 2097-2102). N-(2-mercaptobenzoyl) derivatives of glycine and the L-amino acids are disclosed as possessing thymulin-like activity (Morita, et al, JP03176465 A2, 1991), as ACE inhibitors (Yun-Choi, et al, Yakhak Hoechi, 1988, 31 (1), 1-9) and as synthetic intermediates for the prepraration of disulphides (Lu. et al, Zhongguo Yaoke Daxue Xuebao, 1990, 21 (1), 1-5).
WO97/10225 (published 20.03.97) and WO97130027 (published 21.08.97) disclose certain amino acid derivatives which have metallo-&bgr;-lactamase inhibitory properties, and are useful for the treatment of infections in animals.
A further series of amino acid derivatives have now been discovered, which compounds have metallo-&bgr;-lactamase inhibitory properties, and are useful for the treatment of infections in animals.
According to the present invention there is provided a method of treatment of bacterial infections in humans or animals which comprises administering, in combination with a &bgr;-lactam antibiotic, a therapeutically effective amount of a compound of formula (IA), (IB) or (IC) or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof:
wherein:
R is hydrogen, a salt forming cation or an in vivo hydrolysable ester-forming group;
R
1
A
is hydrogen, (C
1-6
)alkyl optionally substituted by up to three halogen atoms or by a mercapto, (C
1-6
)alkoxy, hydroxy, amino, nitro, carboxy, (C
1-6
) alkylcarbonyloxy, (C
1-6
)alkoxycarbonyl, formyl or (C
1-6
)alkylcarbonyl group, (C
3-7
)cycloalkyl, (C
3-7
)cycloalkyl(C
2-6
)alkyl, (C
2-6
)alkenyl, (C
2-6
)alkynyl, aryl arly(C
1-6
)alkyl, heterocyclyl or heterocyclyl(C
1-6
)alkyl;
R
2
A
is hydrogen, (C
1-6
)alkyl or aryl(C
1-6
)alkyl;
R
1
B
and R
2
B
are each hydrogen or an organic substituent group;
R
1
C
is selected from
 in which A is a monocyclic aryl or heteroaryl ring and B is a monocyclic aryl, alicyclic or heterocyclic ring, C and D are independently —Z
p
-(CR
8
R
9
)
q
— or —(CR
8
R
9
)
q
—Z
p
where p is 0 or 1, q is 0 to 3 provided that p+q in C is not 0, R
8
and R
9
are independently hydrogen or (C
1-6
)alkyl or together represent oxo and Z is O, NR
10
or S(O)x where R
10
is hydrogen, (C
1-6
)alkyl or aryl(C
1-6
)alkyl and x is 0-2, and wherein C and D are linked ortho to one another on each of rings A and B in formula (b);
R
2
C
is hydrogen, (C
1-6
)alkyl or aryl(C
1-6
)alkyl;
R
3
and R
5
together complete a carbocyclic ring having 4 to 8 ring atoms, which may be saturated, unsaturated or aromatic, optionally fused to a phenyl ring, and optionally substituted by 1-3 halo, phenyl, (C
1-6
)alkoxy optionally substituted by 1-3 halo, hydroxy(C
1-6
)alkyl, mercapto(C
1-6
)alkyl, hydroxy, CO
2
R
7
, N(R
7
)
2
or CON(R
7
)
2
where each R
7
is independently hydrogen or (C
1-6
) alkyl, OCONH
2
, nitro, (C
1-6
) alkylcarbonyloxy, (C
1-6
)alkoxycarbonyl(C
1-6
)alkyl, formyl, or (C
1-6
)alkylcarbonyl groups; and
R
4
is hydrogen, or an in vivo hydrolysable acyl group.
The compounds of formulae (IA), (IB) and (IC), hereinafter ‘formula (I)’ may exist in a number of isomeric forms, all of which, including racemic and diastereoisomeric forms, are encompassed within the scope of the present invention.
It is preferred that the stereochemistry at the carbon atom marked * is D-.
The term ‘aryl’ includes phenyl and naphthyl, each optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, (C
1-6
)alkyl optionally substituted by 1-3 halo, phenyl, (C
1-6
)alkoxy optionally substituted by 1-3 halo, hydroxy(C
1-6
)alkyl, mercapto(C
1-6
)alkyl, hydroxy, CO
2
R
7
, N(R
7
)
2
or CON(R
7
)
2
where each R
7
is independently hydrogen or (C
1-6
)alkyl, OCONH
2
, nitro, (C
1-6
)alkylcarbonyloxy, (C
1-6
)alkoxycarbonyl(C
1-6
)alkyl, formyl, or (C
1-6
) alky

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