ZA200201093B - Antibacterial agents. - Google Patents
Antibacterial agents. Download PDFInfo
- Publication number
- ZA200201093B ZA200201093B ZA200201093A ZA200201093A ZA200201093B ZA 200201093 B ZA200201093 B ZA 200201093B ZA 200201093 A ZA200201093 A ZA 200201093A ZA 200201093 A ZA200201093 A ZA 200201093A ZA 200201093 B ZA200201093 B ZA 200201093B
- Authority
- ZA
- South Africa
- Prior art keywords
- alkyl
- composition
- group
- compound
- hydroxy
- Prior art date
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- 239000003242 anti bacterial agent Substances 0.000 title description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 138
- -1 hydroxy, mercapto Chemical class 0.000 claims description 138
- 125000000217 alkyl group Chemical group 0.000 claims description 101
- 150000001875 compounds Chemical class 0.000 claims description 76
- 239000000203 mixture Substances 0.000 claims description 43
- 238000000034 method Methods 0.000 claims description 41
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 125000000623 heterocyclic group Chemical group 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 125000003342 alkenyl group Chemical group 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 125000003545 alkoxy group Chemical group 0.000 claims description 19
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000004429 atom Chemical group 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 125000004414 alkyl thio group Chemical group 0.000 claims description 14
- 230000000844 anti-bacterial effect Effects 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- KDGKTJGPFXIBEB-UHFFFAOYSA-N n-hydroxyformamide Chemical compound ONC=O KDGKTJGPFXIBEB-UHFFFAOYSA-N 0.000 claims description 11
- 230000001580 bacterial effect Effects 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 125000002837 carbocyclic group Chemical group 0.000 claims description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 229920006395 saturated elastomer Polymers 0.000 claims description 8
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 6
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 238000011109 contamination Methods 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000005059 halophenyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 208000035143 Bacterial infection Diseases 0.000 claims description 3
- 241000282412 Homo Species 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 150000001371 alpha-amino acids Chemical class 0.000 claims description 3
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- 150000001413 amino acids Chemical class 0.000 claims description 3
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 3
- 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000002346 iodo group Chemical group I* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 2
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 2
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 2
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims description 2
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 2
- 229940080818 propionamide Drugs 0.000 claims description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 19
- WYLSGWZVDHQRNX-UHFFFAOYSA-N 2-(3,4-dimethoxy-n-(4-methylphenyl)sulfonylanilino)-n-(2,4-dimethylpentan-3-yl)acetamide Chemical compound C1=C(OC)C(OC)=CC=C1N(CC(=O)NC(C(C)C)C(C)C)S(=O)(=O)C1=CC=C(C)C=C1 WYLSGWZVDHQRNX-UHFFFAOYSA-N 0.000 claims 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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Description
\
Antibacterial Agents
This invention relates to novel! hydroxamic acid and N-formyl hydroxylamine derivatives having antibacterial activity, to methods of treatment using such compounds, and to pharmaceutical and veterinary compositions comprising such compounds.
Many classes of antibacterial agents are known, including the penicillins and cephalosporins, tetracyclines, sulfonamides, monobactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol. The fundamental mechanisms of action of these antibacterial classes vary.
Bacterial resistance to many known antibacterials is a growing problem. Accordingly there is a continuing need in the art for alternative antibacterial agents, especially those which have mechanisms of action fundamentally different from the known - classes.
Amongst the Gram-positive pathogens, such as Staphylococci, Streptococci,
Mycobacteria and Enterococci, resistant strains have evolved/arisen which makes ) them particularly difficult to eradicate. Examples of such strains are methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant coagulase negative
Staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium.
Pathogenic bacteria are often resistant to the aminoglycoside, p-lactam (penicillins and cephalosporins), and chloramphenicol types of antibiotic. This resistance involves the enzymatic inactivation of the antibiotic by hydrolysis or by formation of inactive derivatives. The B-lactam (penicillin and cephalosporin) family of antibiotics are characterised by the presence of a p-lactam ring structure. Resistance to this family of antibiotics in clinical isolates is most commonly due to the production of a "penicillinase" (p-lactamase) enzyme by the resistant bacterium which hydrolyses the B-lactam ring thus eliminating its antibacterial activity.
Recently there has been an emergence of vancomycin-resistant strains of enterococci (Woodford N. 1998 Glycopeptide-resistant enterococci: a decade of experience. Journal of Medical Microbiology. 47(10):849-62). Vancomycin-resistant enterococci are particularly hazardous in that they are frequent causes of hospital based infections and are inherently resistant to most antibiotics. Vancomycin works by binding to the terminal D-Ala-D-Ala residues of the cell wall peptidioglycan precursor. The high-level resistance to vancomycin is known as VanA and is conferred by a genes located on a transposable element which alter the terminal residues to D-Ala-D-lac thus reducing the affinity for vancomycin. “ In view of the rapid emergence of multidrug-resistant bacteria, the development of antibacterial agents with novel modes of action that are effective against the growing ) number of resistant bacteria, particularly the vancomycin resistant enterococci and
B-lactam antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus ) aureus, is of utmost importance.
This invention is based on the finding that certain hydroxamic acid and N-formyl hydroxylamine derivatives have antibacterial activity, and makes available a new group of antibacterial agents. It has been found that the compounds with which this invention is concerned are antibacterial with respect to a range of bacteria, with potency against Gram-positive organisms generally being greater than against
Gram-negatives. Many of the compounds of the invention show activity against bacteria responsible for respratory infections, such as Streptococcus pneumoniae and Haemophilus influenzae.
Although it may be of interest to establish the mechanism of action of the compounds with which the invention is concerned, it is their ability to inhibit bacterial growth that makes them useful. However, itis presently believed that their antibacterial activity is due, at least in par, to intracellular inhibition of bacterial polypeptide deformylase (PDF; EC 3.5.1.31).
All ribosome-mediated synthesis of proteins starts with a methionine residue. In prokaryotes the methionyl moiety carried by the initiator tRNA is N-formylated prior to its incorporation into a polypeptide. Consequently, N-formylmethionine is always present at the N-terminus of a nascent bacterial polypeptide. However, most mature proteins do not retain the N-formyl group or the terminal methionine residue.
Deformylation is required prior to methionine removal, since methionine aminopeptidase does not recognise peptides with an N-terminal formylmethionine residue (Solbiati et al., J. Mol. Biol. 290:607-614, 1999). Deformylation is, therefore, a crucial step in bacterial protein biosynthesis and the enzyme responsible, PDF, is essential for normal bacterial growth. Although the gene encoding PDF (def) is present in all pathogenic bacteria for which sequences are known (Meinnel et al., J.
Mol. Biol, 266:939-49, 1997), it has no eukaryotic counterpart, making it an attractive target for antibacterial chemotherapy. : The isolation and characterisation of PDF has been facilitated by an understanding of the importance of the metal ion in the active site (Groche et al., Biophys.
Biochem. Res. Commun., 246:324-6, 1998). The Fe* form is highly active in vivo but is unstable when isolated due to oxidative degradation (Rajagopalan et al., J.
Biol. Chem. 273:22305-10, 1998). The Ni** form of the enzyme has specific activity comparable with the ferrous enzyme but is oxygen-insensitive (Ragusa et al., J. Mol.
Biol. 1998, 280:515-23, 1998). The Zn* enzyme is also stable but is almost devoid of catalytic activity (Rajagopalan et al., J. Am. Chem. Soc. 119:12418-12419, 1997).
Several X-ray crystal structures and NMR structures of E. coli PDF, with or without bound inhibitors, have been published (Chan et al., Biochemistry 36:13904-9, 1997;
Becker et al., Nature Struct. Biol. 5:1053-8, 1998; Becker et al., J. Biol. Chem.
® WO 01/10834 PCT/GB00/03078 273:11413-6, 1998; Hao et al., Biochemistry, 38:4712-9, 1999; Dardel et al., J. Mol.
Biol. 280:501-13, 1998; O'Connell et al., J. Biomol. NMR, 13:311-24, 1999), indicating similarities in active site geometry to metalloproteinases such as thermolysin and the metzincins.
Recently the substrate specificity of PDF has been extensively studied (Ragusa et al., J. Mol. Biol. 289:1445-57, 1999; Hu et al., Biochemistry 38:643-50, 1999;
Meinnel et al., Biochemistry, 38:4287-95, 1999). These authors conclude that an unbranched hydrophobic chain is preferred at P1’, while a wide variety of P2’ substituents are acceptable and an aromatic substituent may be advantageous at the P3’ position. There have also been reports that small peptidic compounds containing an H-phosphonate (Hu et al., Bioorg. Med. Chem. Lett., 8:2479-82, 1998) or thiol (Meinnel et al., Biochemistry, 38:4287-85, 1999) metal binding group are = micromolar inhibitors of PDF. Peptide aldehydes such as calpeptin (N-Cbz-Leu-
AF norleucinal) have also been shown to inhibit PDF (Durand et al., Arch. Biochem. -
Biophys., 367:297-302, 1999). However, the identity of the metal binding group and - its spacing from the rest of the molecule (“recognition fragment”) has not been studied extensively. Furthermore, non-peptidic PDF inhibitors, which may be k desirable from the point of view of bacterial cell wall permeability or oral } bioavailability in the host species, have not been identified.
Related Prior Art
Certain N-formyl hydroxylamine derivatives have previously been claimed in the patent publications listed below, although very few examples of such compounds have been specifically made and described:
EP-B-0236872 (Roche)
WO 92/09563 (Glycomed)
WO 92/04735 (Syntex)
WO 95/19965 (Glycomed)
WO 95/22966 (Sanofi Winthrop)
WO 96/16027 (Syntex/Agouron)
WO 97/03783 (British Biotech)
WO 97/18207 (DuPont Merck)
WO 98/38179 (GlaxoWelicome)
WO 98/47863 (Labs Jaques Logeais)
The pharmaceutical utility ascribed to the N-formyl hydroxylamine derivatives in those publications is the ability to inhibit matrix metalloproteinases (MMPs) and in some cases release of tumour necrosis factor (TNF), and hence the treatment of diseases or conditions mediated by those enzymes, such as cancer and rheumatoid arthritis.
In addition to these, US-A-4,738,803 (Roques et al.) also discloses N-formyl hydroxylamine derivatives, however, these compounds are disclosed as enkephalinase inhibitors and are proposed for use as antidepressants and hypotensive agents. Also, WO 97/38705 (Bristol-Myers Squibb) discloses certain N- formyl hydroxylamine derivatives as enkephalinase and angiotensin converting enzyme inhibitors.
Our copending International Patent Application No. WO 99/39704 describes and claims, inter alia, the use of a compound of formula (i) or a pharmaceutically or veterinarily acceptable salt thereof in the preparation of an antibacterial composition: on
H N A hig 0) 0] R, oO wherein R, represents hydrogen, C,-C, alkyl or C,-C, alkyl substituted by one or more halogen atoms; R, represents a substituted or unsubstituted C,-C, alkyl,
tL, 6 cycloalkyl(C,-C; alkyl)- or aryl(C,-C; alkyl)- group; and A represents a group of formula (IA), or (1B): : 0]
R ah > on $= NReR,
Ry Re (1A) (1B) wherein R, represents the side chain of a natural or non-natural alpha amino acid, and R, and R, when taken together with the nitrogen atom to which they are attached form an optionally substituted saturated heterocyclic ring of 3 to 8 atoms which ring is optionally fused to a carbocyclic or second heterocyclic ring.
Very many hydroxamic acid derivatives are known. Many have been disclosed as having matrix metalloproteinase (MMP) inhibitory activity, and thus to be potentially useful for the treatment of diseases mediated by MMPs, for example cancer, arthritides, and conditions involving tissue remodeling such as wound healing, and restenosis. In addition our International Patent Application No. WO 99/59568 describes the use of analogues of the N-formylhydroxylamine derivatives of WO 99/39704 (wherein the N-formylhydroxylamine group is replaced by a hydroxamic acid group) in the preparation of an antibacterial composition.
This invention relates to a group of antibacterially active hydroxamic acid and and N- formyl hydroxylamine compounds which differ in structure from those of Intemational
Patent Applications Nos. WO 99/59568 and WO 99/39704, principally in the nature of the -NR,R, group (see formulae (1), (IA) and (IB) above and the hydroxamic acid analogues thereof). In those applications, the term "optionally substituted” as used in relation to the saturated heterocyclic ring formed by Rs, Rs and the nitrogen to which they are attached is defined as meaning certain specific substituents. In the present compounds, the group -NR;R; is also an optionally substituted saturated heterocyclic ring of 3 to 8 atoms which ring is optionally fused to a carbocyclic or second heterocyclic ring, but the substituents are different from those permitted by
WO 99/59568 and WO 99/39704. The group -NR;R, of the N-formyl hydroxylamines and hydroxamic acids of the invention is also believed to distinguish the present compounds from those known in the MMP, TNF, ACE, and enkephalinase inhibitor art.
The present invention provides a compound of formula (11), or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof
R, O a AA A (0)
R, wherein
Q represents a radical of formula -N(OH)CH(=0) or formula -C(=0)NH(OH);
R, represents hydrogen, C,-C, alkyl or C,-C; alkyl substituted by one or more halogen atoms, or, except when Q is a radical of formula -N(OH)CH(=0), a hydroxy,
C,-C, alkoxy, C,-C, alkenyloxy, amino, C,-C, alkylamino, or di-( C,-C, alkyl)amino group;
R, represents a substituted or unsubstituted C,-C; alkyl, cycloalkyl(C,-C; alkyl)- or aryl(C,-C; alkyl)- group; and A represents a group of formula (IIA), or (IIB):
® WO 01/10834 PCT/GB00/03078 0
R
Ns
X ro + NR:Rg
Ry Rs (IIA) (1B) wherein R, represents the side chain of a natural or non-natural alpha amino acid, and R; and Rg when taken together with the nitrogen atom to which they are attached form a saturated heterocyclic first ring of 5 to 7 atoms which is optionally fused to a saturated or unsaturated carbocyclic or heterocyclic second ring of 5to 7 atoms; characterised in that (a) the said second ring is substituted by (C,-C;)alkyl, (C,-Cg)alkenyl, . (C,-Cilalkynyl, (C,-C,)alkoxy, hydroxy, mercapto, (C,-Cs)alkylthio, halo, amino, trifluoromethyl, oxo, nitro, -COOH, -CONH, -COR?*, -COOR?, -NHCOR?*, -CONHR*, - -NHRA, -NR*R®, or -CONR"R® wherein R* and R® are independently a (C,-Cg)alkyl group; and/or (b) the said first or second ring is substituted by a group of formula (liC), ; provided that the first ring is not substituted by phenoxy, benzyl or benzyl substituted by (C,-C,)alkyl, (C,-C¢)alkoxy, phenoxy, hydroxy, mercapto, (C,-Cs)alkylthio, amino, halo, trifluoromethyl, nitro, -COOH, -CONH, -COR?, -COOR"*, -NHCOR?*, -CONHRA, -
NHR”, -NR*R®, or -CONR"R® wherein R* and R® are independently a (C,-C)alky! group, —HAlK )m=(X)p-(Alk2)—2Z (IC) wherein m, p and n are independently 0 or 1;
Z represents, a hydroxy group, or a phenyl or heterocyclic ring of 5 to 7 atoms which is optionally fused to a saturated or unsaturated carbocyclic or heterocyclic second ring of 5 to 7 atoms
AJk' and Alk? independently represent divalent C,-C, alkylene radicals;
X represents -O-, -S-, -S(0)-, -S(0,)-, -C(=0)-, -NH-, -NR,- where R, is C,-C, alkyl; and wherein
Alk', Alk? and Z when Z is not a hydroxy group independently are optionally substituted by (C,-Cs)alkyl, (C,-C¢)alkenyl, or (C,-Cg)alkynyl, phenyl, or halophenyl, trifluoromethyl, . monocyclic 5 or 6-membered hetrocyclic, benzyl, or halophenylmethyl, hydroxy, phenoxy, (C,-Ce)alkoxy, or hydroxy(C,-Cg)alkyl, mercapto, (C,-C;)alkylthio or mercapto(C,-Cg)alkyl, - 0X0, nitro, ’ cyano (-CN) halo (bromo, chloro, fluoro, or iodo) -COOH, or -COOR#, -CONH, -CONHR?, or -CONR*R® -COR?, -SO,RA, -NHCOR?, : -NH,, -NHR?, or -NR*R®, wherein R* and R® are independently a (C,-C,) alkyl group, R* and R® taken together with the nitrogen atom to which they are attached form a 5- or 6-
® WO 01/10834 PCT/GB00/03078 membered heterocyclic ring which may be substituted by (C,C;)alkyl, hydroxy, or hydroxy(C,-C,)alkyl.
A subset of compounds of the invention consists of those of formula (ll) as defined above wherein : (a) the said second ring is substituted by (C,-Cg)alkyt, (C,-Cg)alkenyl, (C,-Cslalkynyl, (C,-C;)alkoxy, hydroxy, mercapto, (C,-Cg)alkylthio, amino, trifluoromethyl, oxo, nitro, -COOH, -CONH, -COR*, -COOR*, -NHCOR*, -CONHRA, -NHR?, -NR”R®, or -CONR*R® wherein R* and R® are independently a (C,-C)alkyl group; and/or (b) the said first or second ring is substituted by a group of formula (I1C), provided that the first ring is not substituted by phenoxy, benzyl or benzyl substituted - by (C,-Cs)alkyl, (C,-Cs)alkoxy, phenoxy, hydroxy, mercapto, (C,-Ce)alkylthio, amino, halo, trifluoromethyl, nitro, -COOH, -CONH, -COR?*, -COOR?*, -NHCOR?, -CONHR?, - - NHRA, -NR*R®, or -CONR*R® wherein R* and R® are independently a (C,-C;)alkyl group, ] —HAK Yo (Xp (AlKRT—Z (1C) wherein m, p and n are independently O or 1;
Z represents, a hydroxy group, or a phenyl or heterocyclic ring of 5 to 7 atoms which is optionally fused to a saturated or unsaturated carbocyclic or heterocyclic second ring of 5 to 7 atoms
Alk' and Alk? independently represent divalent C,-C; alkylene radicals;
X represents -O-, -S-, -S(0)-, -S(0,)-, -C(=0)-, -NH-, -NR;- where R, is C.-C, alkyl; and wherein
Ak', Alk? and Z when Z is not a hydroxy group independently are optionally substituted by (C,-Cg)alkyl, (C,-Ce)alkenyl, or (C,-C¢)alkynyl, phenyl, or halophenyl, trifluoromethyl, monocyclic 5 or 6-membered hetrocyclic, benzyl, hydroxy, phenoxy, or (C,-Cg)alkoxy, mercapto, or (C,-C¢)alkylthio, oxo, nitro, -COOH, or -COOR", . -CONH, -CONHR*, or -CONR"R® -CORA, - -NHCORA, -NH,, -NHR", or -NR*R®, : wherein R* and R® are independently a (C,-C,) alkyl group,
In another aspect, the invention provides a method for the treatment of bacterial infections in humans and non-human mammals, which comprises administering to a subject suffering such infection an antibacterially effective dose of a compound of formula (I) as defined above. in a further aspect of the invention there is provided a method for the treatment of bacterial contamination by applying an antibacterially effective amount of a compound of formula (ll) as defined above to the site of contamination.
The compounds of formula (Il) as defined above may be used as component(s) of
® WO 01/10834 PCT/GB00/03078 antibacterial cleaning or disinfecting materials.
On the hypothesis that the compounds (ll) act by inhibition of intracellular PDF, the most potent antibacterial effect may be achieved by using compounds which efficiently pass through the bacterial cell wall. Thus, compounds which are highly active as inhibitors of PDF in vitro and which penetrate bacterial cells are preferred for use in accordance with the invention. It is to be expected that the antibacterial potency of compounds which are potent inhibitors of the PDF enzyme in vitro, but are poorly cell penetrant, may be improved by their use in the form of a prodrug, ie a structurally modified analogue which is converted to the parent molecule of formula (I), for example by enzymic action, after it has passed through the bacterial cell wall.
As used herein the term “(C,-C;)alkyl” means a straight or branched chain alkyl moiety having from 1 to 6 carbon atoms, including for example, methyl, ethyl, n- : propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl. i As used herein the term "divalent (C,-C,)alkylene radical” means a saturated hydrocarbon chain having from 1 to 3 carbon atoms and two unsatisfied valencies.
As used herein the term “(C,-C;)alkenyl” means a straight or branched chain alkenyl moiety having from 2 to 6 carbon atoms having at least one double bond of either E or Z stereochemistry where applicable. The term includes, for example, vinyl, allyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
As used herein the term "C,-C, alkynyl" refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2- butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl and 5-hexynyl.
As used herein the term “cycloalkyl” means a saturated alicyclic moiety having from
3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein the term "heteroaryl" refers to a 5- or 6- membered aromatic ring containing one or more heteroatoms;. Illustrative of such groups are thienyl, fury, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl.
As used herein the unqualified term “heterocyclyl” or “heterocyclic” includes "heteroaryl" as defined above, and in particular means a 5-7 membered aromatic or non-aromatic heterocyclic ring containing one or more heteroatoms selected from S,
N and O, including for example, pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyi, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzofuranyl, pyranyl, . isoxazolyl, benzimidazolyl, methylenedioxyphenyl, maleimido and succinimido groups. -
Unless otherwise specified in the context in which it occurs, the term “substituted” as i applied to any moiety herein means substituted with up to four substituents, each of which independently may be (C,-C¢)alkyl, (C,-C¢)alkoxy, hydroxy, mercapto, (C,-
C,)alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), trifluoromethyl, nitro, -COOH, -CONH, -COR?, -COOR*, -NHCOR?, -CONHR?, -NHR”, -NR*R®, or -
CONRAR? wherein R* and R® are independently a (C,-C;)alkyl group
As used herein the terms “side chain of a natural alpha-amino acid” and “side chain of a non-natural alpha-amino acid” mean the group R* in respectively a natural and non-natural amino acid of formula NH,-CH(R*)-COOH.
Examples of side chains of natural alpha amino acids include those of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, histidine, 5-
® WO 01/10834 PCT/GB00/03078 hydroxylysine, 4-hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, a-aminoadipic acid, a-amino-n-butyric acid, 3,4-dihydroxyphenylalanine, homoserine, a- methylserine, omithine, pipecolic acid, and thyroxine.
In natural alpha-amino acid side chains which contain functional substituents, for example amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl, or indolyl groups as in arginine, lysine, glutamic acid, aspartic acid, tryptophan, histidine, serine, threonine, tyrosine, and cysteine, such functional substituents may optionally be protected.
Likewise, in the side chains of non-natural alpha amino acids which contain functional substituents, for example amino, carboxyl, hydroxy, mercapto, guanidyl, imidazolyl, or indolyl groups, such functional substituents may optionally be - protected. ) The term “protected” when used in relation to a functional substituent in a side chain of a natural or non-natural alpha-amino acid means a derivative of such a ) substituent which is substantially non-functional. The widely used handbook by T. W. . Greene and P. G. Wuts "Protective Groups in Organic Synthesis" Second Edition,
Wiley, New York, 1991 reviews the subject. For example, carboxyl groups may be esterified (for example as a C,-C, alkyl ester), amino groups may be converted to amides (for example as a NHCOC,-C; alkyl amide) or carbamates (for example as an NHC(=0)0C,-C; alkyl or NHC(=O)OCH,Ph carbamate), hydroxyl groups may be converted to ethers (for example an OC,-C, alkyl or a O(C,-C, alkyl)pheny! ether) or esters (for example a OC(=0)C,-C; alkyl ester) and thiol groups may be converted to thioethers (for example a tert-butyl or benzyl thioether) or thioesters (for example a
SC(=0)C,-C, alky! thioester).
There are several actual or potential chiral centres in the compounds according to the invention because of the presence of asymmetric carbon atoms. The presence of several asymmetric carbon atoms gives rise to a number of diastereoisomers with
R or S stereochemistry at each chiral centre. The invention includes all such diastereoisomers and mixtures thereof. Currently, the preferred stereoconfiguration of the carbon atom carrying the R, group is R; that of the carbon atom carrying the
R, group (when asymmetric) is S; and that of the carbon atom carrying the R, group (when asymmetric) is R.
In the compounds of the invention:
R, may be, for example, hydrogen, methyl, or trifuoromethyl. Hydrogen is currently preferred.
R, may be, for example: optionally substituted C,-C; alkyl, C,-C, alkenyl, C;-C, alkynyl or cycloalkyl; phenyl(C,-C, alkyl)-, phenyl(C,-C, alkenyl)- or phenyl(C,-Cg alkynyl)- optionally substituted in the phenyl ring; ) cycloalkyl(C,-Cs alkyl)-, cycloalkyl(C,-C; alkenyl)- or cycloalkyl(C,-C4 alkynyl) i optionally substituted in the cycloalkyl ring; heterocyclyl(C,-C; alkyl)-, heterocyclyl(C;-C; alkenyl)- or heterocyclyl(C,-Cs alkynyl)- optionally substituted in the heterocyclyl ring; or
CH,(CH,),0(CH,),- or CH,(CH,),S(CH,),-, wherein pis 0,1,2or3 and q is 1, 2o0r3.
Specific examples of R, groups include methyl, ethyl, n- and iso-propyl, n- and iso-butyl, n-pentyl, iso-pentyl 3-methyl- but-1-yl, n-hexyl, n-heptyl, n-acetyl, n-octyl, methylsulfanylethyi, ethylsulfanylmethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-ethoxymethyl, 3-
® WO 01/10834 PCT/GB00/03078 hydroxypropyl, allyl, 3-phenylprop-3-en-1-yl, prop-2-yn-1-yl, 3-phenylprop-2- yn-1-yl, 3-(2-chlorophenyl)prop-2-yn-1-yl, but-2-yn-1-yl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyi, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, furan-2-yimethyl, furan-3- methy|, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-yimethyi, piperidinylmethyl, phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4-methoxyphenylpropyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl, and 4- methoxybenzyl.
Presently preferred groups at R, are (C,-Cg)alkyl-, cycloalkylmethyl-, (C,-
C.)alkyl-S-(C,-C,)alkyl-, or (C,-C,)alkyl-O-(C,-C,)alkyl-, especially n-propyl, n- butyl, n-pentyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl. ! R, may be, for example the characterising group of a natural « amino acid, for example benzyl, or 4- ) methoxyphenylmethyl, in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated; or a group -[Alk],R, where Alk is a (C,-C¢)alkylene or (C,-C)alkenylene group optionally interrupted by one or more -O-, or -S- atoms or -N(R,,)- groups [where R,, is a hydrogen atom or a (C,-Cg)alkyl group], nis 0 or 1, and R, is hydrogen or an optionally substituted phenyl, aryl, heterocyclyl, cycloalkyl or cycloalkenyl group or (only when n is 1) R, may additionally be hydroxy, mercapto, (C,-C,)alkyithio, amino, halo, trifluoromethyl, nitro, -COOH, -
CONH, -COOR*, -NHCOR*, -CONHR?*, -NHR*, -NR*R®, or -CONRR® wherein R* and R® are independently a (C,-C;)alkyl group; or a benzyl group substituted in the phenyl ring by a group of formula -
OCH,COR, where R; is hydroxyl, amino, (C,-Cs)alkoxy, phenyl(C,-C)alkoxy,
(C,-Cs)alkylamino, di((C,-C¢)alkyl)amino, phenyl(C,-C¢)alkylamino; or a heterocyclic(C,-C¢)alkyl group, either being unsubstituted or mono- or di- substituted in the heterocyclic ring with halo, nitro, carboxy, (C,-C;)alkoxy, cyano, (C,-Ce)alkanoyl, trifluoromethyl! (C,-C;)alkyl, hydroxy, formyl, amino, (C,-Cq)alkylamino, di-(C,-C;)alkylamino, mercapto, (C,-Ce)alkylthio, hydroxy(C,-C¢)alkyl, mercapto(C,-Cg)alky! or (C,-Cg)alkylphenylmethyl; or a group -CR,R,R. in which: each of R,, R, and R; is independently hydrogen, (C,-C;)alkyl, (C,-
C,)alkenyl, (C,-C;)alkynyl, phenyl(C,-Cg)alkyl, (C,-C,)cycloalkyl; or
R. is hydrogen and R, and R, are independently phenyl or heteroaryl such as pyridyl; or
R. is hydrogen, (C,-C;)alkyl, (C,-C;)alkenyt, (C,-C)alkynyl, phenyl(C,-
C¢)alkyl, or (C;-C;)cycloalkyl, and R, and R, together with the carbon } atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; or r
R., R, and R together with the carbon atom to which they are attached ] form a tricyclic ring (for example adamantyl); or
R, and R, are each independently (C,-Cg)alkyl, (C,-C¢)alkenyl, (C,-
C,)alkynyl, phenyl(C,-C;)alkyl, or a group as defined for R_ below other than hydrogen, or R, and R, together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic ring, and R, is hydrogen, -OH, -SH, halogen, -CN, -CO,H, (C,-C,)perfluoroalkyl, -
CH,OH, -CO,(C,-C;)alkyl, -O(C,-C,)alkyl, -O(C,-C,)alkenyl, -S(C,-
C,)alkyl, -SO(C,-C;)alkyl, -SO,(C,-C,) alkyl, -S(C,-Cg)alkenyl, -SO(C,-
C,)alkenyl, -SO,(C,-C)alkenyl or a group -Q-W wherein Q represents a
® WO 01/10834 PCT/GB00/03078 bond or -O-, -S-, -SO- or -SO,- and W represents a phenyl, phenylalkyl, (C,-C,)cycloalkyl, (C,-Cg)cycloalkylalkyl, (C,-
C;)cycloalkenyl, (C,-C,)cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, -CN, -
CO,H, -CO,(C,-C;)alkyl, -CONH,, -CONH(C,-C;)alkyl, -CONH(C,-
Csalkyl),, -CHO, -CH,OH, (C,-C,)perfluoroalkyl, -O(C,-Cg)alkyl, -S(C,-
C,)alkyl, -SO(C,-Cg)alkyl, -SO,(C,-Cg)alkyl, -NO,, -NH,, -NH(C,-C;)alkyl, -N((C,-C;)alkyl),, -NHCO(C,-Cs)alkyl, (C,-Cg)alkyl, (C,-Cqlalkenyl, (C.-
Cs)alkynyl, (C,-C,)cycloalkyl, (C,-C,)cycloalkenyl, phenyl or benzyl.
Examples of particular R, groups include methyl, ethyl, benzyl, 4-chlorobenzyl, 4- hydroxybenzyl, phenyl, cyclohexyl, cyclohexylmethyl, pyridin-3-yimethyl, tert- butoxymethyl, naphthylmethyi, iso-butyl, sec-butyl, tert-butyl, 1-benzylthio-1- ) methylethyl, 1-methylthio-1-methylethyl, 1-mercapto-1-methylethyl, 1-methoxy-1- methylethyl, 1-hydroxy-1-methylethyl, 1-fluoro-1-methylethyl, hydroxymethyl, 2- ) hydroxethyl, 2-carboxyethyl, 2-methylcarbamoylethyl, 2-carbamoylethyl, and 4- aminobutyl. Presently preferred R, groups include tert-butyl, iso-butyl, benzyl, isopropyl and methyl.
R; and R, taken together with the nitrogen atom to which they are attached form a saturated 5- to 7-membered monocyclic N-heterocyclic first ring which is attached via the N atom, and which is optionally fused to a saturated or unsaturated carbocyclic or heterocyclic second ring of 5 to 7 atoms. One or more additional ring hetero atoms such as nitrogen may be present in the first ring. Examples of such first rings are 1-pyrrolidinyl, piperidin-1-yl, 1-piperazinyl, hexahydro-1-pyridazinyl, morpholin-4-yl, tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-thiazin-4-yl 1-oxide, tetrahydro-1,4-thiazin4-yl 1,1-dioxide, hexahydroazipino, thiomorpholino, diazepino, thiazolidinyl or octahydroazocino. Presently preferred are piperidin-1-yl and 1- piperazinyl. The substituent (IC) may be present on a ring carbon atom or a ring nitrogen atom of the first or second rings.
In the substituent (IIC) (from whose definition benzyl, certain substituted benzyis, and phenoxy are excluded) Alk' and Alk? may independently represent, for example -(CH,)- or -(CH,CH,)-. In the case where mis 0 and p is 1, X may be, for example -
C(=0)- or -S(O,)-. In such cases n may be 0 or 1, and when the -NR;R; first ring contains a second ring nitrogen, the -C(=0)- or -S(O,)- of (IC) may be linked to that ring nitrogen in an amide or sulphonamide bond.
In the substituent (IIC) m, n and p may all be 0, so that the group Z is directly linked to the -NR,R; first ring.
In a preferred subset of the compounds of the invention, the substituent (IC) has the formula -CH,Z, -OZ, or -(C=0)Z wherein (subject to the exclusion of benzyl, certain substituted benzyls, and phenoxy) Z is a phenyl, 3,4-methylenedioxyphenyl, morpholinyl, pyrimidinyl, 1,2,3-thiadiazolyl, 1,4-thiazolyl, benzofuranyl, furanyl, . thienyl, pyranyl, pyrrolyt, pyrazolyl, isoxazolyl, or pyridyl ring which may optionally be substituted as specified. In particular, Z may be a phenyl, 3,4-methylenedioxyphenyl, morpholinyl, pyrimidin-2-yi, 1,2,3-thiadiazol-5-yl, 1,4-thiazol-5-yl, benzofuran-2-yl, 2- or 3-furanyl, 2- or 3-thienyl, 2- or 3-pyranyil, 2-, 3- or 4-pyrrolyl, 3-, 4- or 5-pyazolyl, i 3-, 4- or 5-isoxazolyl, or 2-, 3- or 4-pyridyl ring any of which may optionally be substituted as specified in the broad description of the compounds of the invention.
In the compounds of formula (11) as defined above wherein Q is a radical of formula -
C(=O)NH(OH) the radicals R,, R., and A may be any of those discussed ubove in relation to compounds (Il) wherein Q is a radical of formula -N(OH)CH(=0).
However, in addition, R, may be, for example, a hydroxy, methoxy, ethoxy, n- propyloxy, allyloxy, amino, methylamino, dimethylamino, ethylamino, or diethylamino group.
Specific examples of substituents (liC) include those present in the compounds specifically named, and/or exemplified herein.
® WO 01/10834 PCT/GB00/03078
Examples of specific compounds of the invention are those of the Examples herein.
In those Examples, where a compound of formula (Il) above wherein Q is an N- formylhydroxylamine radical -N(OH)CH(=0) is disclosed, it is to be understood that the equivalent compound wherein Q is a hydroxamate radical -C(=O)NH(OH) is also a specific compound of the invention, and vice versa.
Preferred compounds of the invention include those selected from the group consisting of compounds of formulae (IID) - (IG) and (IW) - (112): \ o) 0 R AN 0 0 R, ~z 4 a Z
H N N
H 0 N OH R 0]
OH R, 0) 2 (IID) (IIE)
Y 0 R rr N72 . 0) R, ~z y 4 PP \ - N ~ N HO N
HO N 4 3 (IF) (1G)
0] 0 1 0
OH R, y AZ OH R, Ln, Zz (Iw) (1X)
J PP
0] R, v Zz 0) R, Ln, Zz (ny) (12) wherein
R, is n-propyl, n-butyl, n-pentyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexyiethyl;
R, is tert-butyl, iso-buty!, benzyl or methyl;
Y is -CH,-, -O- or -(C=0)-, and )
Z is a phenyl, 3,4-methylenedioxyphenyl, morpholinyl, pyrimidinyl, 1,2,3-thiadiazolyl, . 1,4-thiazolyl, benzofuranyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrazolyl, isoxazolyl, or pyridyl ring; in particular, a phenyl, 3,4-methylenedioxyphenyl, morpholinyl, . pyrimidin-2-yl, 1,2,3-thiadiazol-5-yl, 1,4-thiazol-5-yl, benzofuran-2-yl, 2-or 3-furanyl, 2- or 3-thienyl, 2- or 3-pyranyl, 2-, 3- or 4-pyrrolyl, 3-, 4- or 5-pyazolyl, 3-, 4- or 5- - isoxazolyl, or 2-, 3- or 4-pyridyl ring, which may optionally be substituted as specified in the general description of compounds of the invention.
Particular compounds of the invention, preferred for their potency against organisms which infect the respiratory system, include N-[1S-(4-benzo[1,3]dioxol-5-yimethyl- piperazine-1-carbonyl)-2,2-dimethyl-propyl}-2R-cyclopentylmethyl-3-(formyl-hydroxy- amino)-propionamide and N-[1S-(4-Benzo[1 ,3]dioxol-5-ylimethyl-piperazine-1- carbonyl)-2,2-dimethyl-propyll-2R-cyclopentylmethyl-N-hydroxy-succinamide
® WO 01/10834 PCT/GB00/03078
Compounds of the invention in which Q is an N-formylhydroxyamino group may be prepared by deprotecting an O-protected N-formyl-N-hydroxyamino compound of formula (lll):
Pres R;
H N A hid any 0) R, Oo in which R,, R,, and A are as defined in general formula (I) and Rs is a hydroxy protecting group removable to leave a hydroxy group by hydrogenolysis or hydrolysis. Benzyl is a preferred Ry; group for removal by hydrogenolysis, and tert- butyl and tetrahydropyranyl are preferred groups for removal by acid hydrolysis.
A Compounds of the invention in which Q is a hydroxamic acid group may be prepared by reacting the parent compound wherein Q is a carboxylic acid group (IliA) . R, ) HOOC A (INA) rR, © with hydroxylamine or an N- and/or O-protected hydroxylamine, and thereafter removing any O- or N-protecting groups
Compounds of formula (111) or (IIIA) may be prepared by causing an acid of formula (IV) or (IVC) or an activated derivative thereof to react with an amine of formula (IVA) or (IVB)
ORys Re R
H,N Rs ~~ OH N HNR4R,
R Rs oO R, oO 4 (Iv) (IVA) (vB)
R,
R2500C OH (IVC) (0)
R, wherein R, R,, R,, Rs, and R; are as defined in general formula (Il) except that any substituents in R, R,, R,, Rs, and Rg which are potentially reactive in the coupling reaction may themselves be protected from such reaction, and Ry is as defined in relation to formula (lll) above, and optionally removing protecting groups R, R,, R,,
R,, and R,.
Compounds of formula (IVA), (IVB) and (IVC) are prepared by standard literature methods, and many are commercially available.
Compounds of formula (IV) may be prepared by N-formylation, for example using acetic anhydride and formic acid, or 1-formylbenzotriazole, of compounds of formula i v)
PRas R oA v)
R, © wherein R;, R, and R,; are as defined in relation to formula (lif) and Y is either a chiral auxiliary or an OR, group wherein R,; is hydrogen or a hydroxy protecting group. In the case where Y is an OR, group or a chiral auxiliary the hydroxy protecting group or auxiliary is removed after the formylation step to provide the compound of formula (IV). Suitable chiral auxiliaries include substituted oxazolidinones which may be removed by hydrolysis in the presence of base.
® WO 01/10834 PCT/GB00/03078
A compound of general formula (V) may be prepared by reduction of an oxime of general formula (VII)
Pre R,
SAN vin
Oo
R wherein R,, R,, and R,; are as defined above, and Y is either an OR, group as defined above or a chiral auxiliary. Reducing agents include certain metal hydrides (eg sodium cyanoborohydride in acetic acid, triethylsilane or borane/pyridine) and hydrogen in the presence of a suitable catalyst. Following the reduction when the group Y is a chiral auxiliary it may be optionally converted to a OR; group.
A compound of general formula (VII) can be prepared by reaction of a -keto : carbonyl compound of general formula (Vil) - R,
Ny Y (vil)
R, © wherein R,, R,, and Y are as defined above, with an O-protected hydroxylamine.
B-keto carbonyl compounds (VIII) may be prepared in racemic form by formylation or acylation of a carbonyl compound of general formula (IX)
Ry ”
Oo wherein R, and Y are as defined above, with a compound of general formula (X) he
X
(X) wherein R, is as defined above and Q is a leaving group such as halogen or alkoxy, in the presence of a base.
The Examples herein provide further details of routes and methods for the preparation of compounds of the invention.
Salts of the compounds of the invention include physiologically acceptable acid addition salts for example hydrochlorides, hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates, phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates. Salts may also be formed with bases, ) for example sodium, potassium, magnesium, and calcium salts.
Compositions with which the invention is concerned may be prepared for administration by any route consistent with the pharmacokinetic properties of the - active ingredient(s).
Orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyi-pyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral
Claims (27)
1. A compound of formula (Il), or a pharmaceutically or veterinarily acceptable salt, hydrate or solvate thereof R, ©O R, wherein Q represents a radical of formula -N(OH)CH(=0) or formula -C(=O)NH(OH); R, represents hydrogen, C,-C; alkyl or C,-C, alkyl substituted by one or more halogen atoms, or, except when Q is a radical of formula -N(OH)CH(=0), a hydroxy, C,-C, alkoxy, C,-C, alkenyloxy, amino, C,-C; alkylamino, or di-( C,-C, alkyl)amino group; R, represents a substituted or unsubstituted C,-C; alkyl, cycloalkyl(C,-C; alkyl) or aryl(C,-C, alkyl)- group; A and A represents a group of formula (1A), or (liB): - : 0 R ~~ 5 x on + NRR; R; Rg (NA) (1B) wherein R, represents the side chain of a natural or non-natural alpha amino acid, and R; and R; when taken together with the nitrogen atom to which they are attached form a saturated heterocyclic first ring of 5 to 7 atoms which is optionally fused to a saturated or unsaturated carbocyclic or heterocyclic second ring of 5to 7 atoms; characterised in that
(a) the said second ring is substituted by (C,-Cs)alkyl, (C,-C¢)alkenyl, (C,- Ce)alkynyl, (C,-C;)alkoxy, hydroxy, mercapto, (C,-Cs)alkylthio, halo, amino, trifluoromethyl, oxo, nitro, -COOH, -CONH, -COR*, -COORA, - NHCOR?*, -CONHR*, -NHR”, -NR*R®, or -CONR"R® wherein R* and R® are independently a (C,-C,)alkyl group; and/or
(b) the said first or second ring is substituted by a group of formula (liC),
provided that the first ring is not substituted by phenoxy, benzyl or benzyl substituted by (C,-Cs)alkyl, (C,-C;)alkoxy, phenoxy, hydroxy, mercapto, (C,-Cs)alkylthio, amino,
halo, trifluoromethyl, nitro, -COOH, -CONH, -COR*, -COOR*, -NHCOR", -CONHR?", -
NHRA, -NR*R®, or -CONR*RE wherein R* and R® are independently a (C,-C;)alkyl group,
—HAIK) i (X), (AlKP—Z (IC) . wherein m, p and n are independently 0 or 1;
Z represents, a hydroxy group, or a phenyl or heterocyclic ring of 5 to 7 atoms which is optionally fused to a saturated or unsaturated carbocyclic or heterocyclic second ring of 5 to 7 atoms
Alk' and Alk? independently represent divalent C,-C, alkylene radicals;
X represents -O-, -S-, -S(0)-, -S(0,)-, -C(=0)-, -NH-, -NR;- where R; is C,-C, alkyl;
and wherein
AlK', Alk? and Z when Z is not a hydroxy group independently are optionally substituted by (C,-Cpalkyl, (C,-C,)alkenyl, or (C-C,)alkynyl, phenyl, or halophenyl, trifluoromethyl, monocyclic 5 or 6-membered hetrocyclic, benzyl, or halophenylmethyl, hydroxy, phenoxy, (C,-Cs)alkoxy, or hydroxy(C,-C)alkyl, mercapto, (C,-C;)alkylthio or mercapto(C,-C¢)alkyl, 0X0, nitro, cyano (-CN) halo (bromo, chloro, fluoro, or iodo) -COOH, or -COOR?, -CONH, -CONHR?, or -CONR"R® -COR*, -SO,RA, § -NHCOR?", -NH,, -NHR", or -NRR®, - wherein R* and R® are independently a (C,-C,) alkyl group, R* and R® taken together with the nitrogen - atom to which they are attached form a 5- or 6- membered heterocyclic ring which may be substituted by (C,C,)alkyl, hydroxy, or hydroxy(C,-C,)atkyl.
2. A compound as claimed in claim 1 wherein (@) the said second ring is substituted by (C,-Ce)alkyl, (C,-C¢)alkenyl, (C,-Cs)alkynyl, (C,-Ce)alkoxy, hydroxy, mercapto, (C,-C)alkylthio, amino, trifluoromethyl, oxo, nitro, -COOH, -CONH, -COR*, -COOR?, -NHCOR", -CONHR?, -NHR*, -NR*R®, or -CONR*R® wherein R* and R® are independently a (C,-C¢)alkyl group; and/or g N i ~ ". Fl ® WO 01/10834 EAN PCT/GB00/03078 ( Lo 94 (b) the said first or second ring is substituted by a group of formula (lIC), provided that the first ring is not substituted by phenoxy, benzyl or benzyl substituted by (C,-Cq)alkyl, (C,-Cg)alkoxy, phenoxy, hydroxy, mercapto, (C,-C¢)alkylthio, amino, halo, trifluoromethyl, nitro, -COOH, -CONH, -COR?*, -COOR?*, -NHCOR*, -CONHR?, - NHRA, -NR*R®, ar -CONR*R® wherein R* and R® are independently a (C,-C,)alky! group, SHAK (Xp (AR—Z (IC) wherein m, p and n are independently 0 or 1; Z represents, a hydroxy group, or a phenyl or heterocyclic ring of 5 to 7 atoms which ) is optionally fused to a saturated or unsaturated carbocyclic or heterocyclic second ] ring of 5 to 7 atoms Alk' and Alk? independently represent divalent C,-C; alkylene radicals; - X represents -O-, -S-, -S(O)-, -S(0,)-, -C(=0)-, -NH-, -NR;- where R; is C,-C, alkyl; "and wherein AIK’, Alk? and Z when Z is not a hydroxy group independently are optionally substituted by (C,-Cy)alkyl, (C,-Cs)alkenyl, or (C,-Cg)alkynyl, phenyl, or halophenyl, trifluoromethyl, monocyclic 5 or 6-membered hetrocyclic, benzyl, hydroxy, phenoxy, or (C,-C;)alkoxy,
4 } PCT/GB00/03078 = 95 mercapto, or (C1-Cglalkylthio, 0X0, nitro, -COOH, or -COORA, -CONH,, -CONHRA, or -CONRARB -CORA, -NHCORA, -NH,, -NHRA, or -NRARB, wherein RA and RB are independently a (C4-Cg) alkyl group.
3. Use of a compound as claimed in claim 1 or claim 2, in the manufacture of a medicament for the treatment of bacterial infections in humans and non-human mammals. i
4. A method for the treatment of bacterial contamination by applying an : antibacterially effective amount of a compound as claimed in claim 1 or claim 2 to the site of contamination.
5. The use of a compound as claimed in claim 1 or claim 2 in the manufacture of an antibacterial composition.
6. A pharmaceutical or veterinary composition comprising a compound as claimed in claim 1 or claim 2 together with a pharmaceutically or veterinarily acceptable carrier.
7. A substance or composition for use in a method for treating bacterial infections in humans and non-human mammals, said substance or composition comprising a compound as claimed in claim 1 or claim 2, and said method comprising administering said substance or composition to a subject suffering such infection.
8. A compound as claimed in claim 1 or claim 2, a method as claimed in claim 4, a use as claimed in claim 3 or claim 5, or a composition as claimed in claim 6, or a substance or composition for use in a method of treatment, as claimed in claim 7, wherein R4 is hydrogen. AMENDED SHEET
) - { PCT/GB00/03078
9. A compound, method, use, composition, or substance or composition for use in a method of treatment, as claimed in claim 8, where R, is (C,-Cg)alkyl-, cycloalkylmethyl-, (C,-Cj)alkyl-S-(C,-C,)alkyl-, or (C,-Cj)alkyl-O-(C,-C;)alkyi-.
10. A compound, method, use, composition, or substance or composition for use in a method of treatment, as claimed in claim 8 wherein R, is n-propyl, n-butyl, n- . pentyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.
11. A compound as claimed in claim 1 or claim 2, a method as claimed in claim 4, a use as claimed in claim 3 or claim 5, a composition as claimed in claim 6, or a substance or composition for use in a method of treatment, as claimed in claim 7, wherein R, is the characterising group of a natural a amino acid, for example benzyl, or 4- : methoxyphenylmethyl, in which any functional group may be protected, any amino group may be acylated and any carboxyl group present may be amidated; or a group -[AlK],R, where Alk is a (C,-C¢)alkylene or (C,-Cg)alkylene group optionally interrupted by one or more -O-, or -S- atoms or -N(R,,)- groups [where R,, is a hydrogen atom or a (C,-Cg)alkyl group], nis 0 or 1, and Ry is hydrogen or an optionally substituted phenyl, aryl, heterocyclyl, cycloalkyl or cycloalkenyl group or (only when n is 1) Ry may additionally be hydroxy, mercapto, (C,-Cg)alkylthio, amino, halo, trifluoromethyl, nitro, -COOH, -CONH,, -COORA, -NHCOR?, -CONHR* -NHR* -NR*R®, or -CONR"R® wherein R* and R® are independently a (C,-C;)alkyl group; or a benzyl group substituted in the phenyl ring by a group of formula -OCH,COR; where Ry is hydroxyl, amino, ((C,-Ce)alkoxy, phenyl (C,-C¢)alkoxy, (C,-Cs)alkylamino, di((C,-C¢)alkyl)amino, phenyl (C,-Cg)alkylamino; or a heterocyclic(C;-C¢)alkyl group, either being unsubstituted or mono- or di- substituted in the heterocyclic ring with halo, nitro, carboxy, (C,-Cg)alkoxy, cyano, (C,-Cg)alkanoyl, trifluoromethyl (C,-Cg)alkyl, hydroxy, formyl, amino, AMENDED SHEET on 97 (C,-C¢)alkylamino, di-(C,-C;)alkylamino, mercapto, (C;-Cs)alkylthio, hydroxy(C,-C¢)alkyl, mercapto(C,-Cg)alkyl! or (C,-C)alkylphenylmethyl; or a group -CR,R,R. in which: each of R,, R, and R_ is independently hydrogen, (C,-C;)alkyl, (C,- C,)alkenyl, (C,-Cglalkynyl, phenyl(C,-Cq)alkyl, (C5-Cg)cycloalkyl; or
R. is hydrogen and R, and R, are independently phenyl or heteroaryl such as pyridyl; or R, is hydrogen, (C,-C¢)alkyl, (C,-C¢)alkenyl, (C.-C)alkynyl, phenyl(C,- C,)alkyl, or (C;-C;)cycloalkyl, and R, and R, together with the carbon atom to which they are attached form a 3 to 8 membered cycloalkyl or a 5- to 6-membered heterocyclic ring; or
R.. R, and R, together with the carbon atom to which they are attached form a tricyclic ring (for example adamantyl); or - R, and R, are each independently (C,-Cs)alkyl, (C,-C¢)alkenyl, (C,- - Cs )alkynyl, phenyl(C,-Cs)alkyl, or a group as defined for R, below other than hydrogen, or R, and R, together with the carbon atom to which ) they are attached form a cycloalkyl! or heterocyclic ring, and R; is hydrogen, -OH, -SH, halogen, -CN, -CO,H, (C,-C,)perfluoroalkyl, - CH,OH, -CO,(C,-C¢)alkyl, -O(C,-Cg)alkyl, -O(C,-C¢)alkenyl, -S(C,- Cy)alkyl, -SO(C,-Cy)alkyl, -SO,(C,-C,) alkyl, -S(C,-Cg)alkenyl, -SO(C,- Cy)alkenyl, -SO,(C,-C;)alkenyl or a group -Q-W wherein Q represents a bond or -O-, -S-, -SO- or -SO,- and W represents a phenyl, phenylalkyl, (C;-Cg)cycloalkyl, (C,-Cg)cycloalkylalkyl, (C,- Cs cycloalkenyl, (C,-Cs)cycloalkenylalkyl, heteroaryl or heteroarylalkyl group, which group W may optionally be substituted by one or more substituents independently selected from, hydroxyl, halogen, -CN, -
PCT/GB00/03078 CO,H, -CO,(C,-Cq)alkyl, -CONH,, -CONH(C,-Cs)alkyl -CONH(C;- Cealkyl),, -CHO, -CH,OH, (C,-C,)perfluoroalkyl, -O(C;-C)alkyl, - S(C,-Cg)alkyl, -SO(C,-Cg)alkyl, -SO,(C,-Cg)alkyl, -NO,, -NH,, -NH(C;- Ce)alkyl, -N((C,-C¢)alkyl),, -NHCO(C,-C¢)alkyl, (C,-Cglalkyl, (C,- Cs)alkenyl, (C,-Cg)alkynyl, (C5-Cg)cycloalkyl, (C,-Cg)cycloalkenyl, phenyl or benzyl.
12. A compound, method, use, composition, or substance or composition for use in a method of treatment, as claimed in claim 10 or claim 11 wherein R, is methyl, ethyl, n-propyl, n-butyl, benzyl, 4-chlorobenzyl, 4-hydrobenzyl, phenyl, cyclohexyl, cyclohexylmethyl, pyridin-3-yimethyl, tert-butoxymethyl, naphthylmethyl, iso-butyl, sec-butyl, tert-butyl, 1-benzylthio-1-methylethyl, 1-methylthio-1-methylethyl, 1- : | mercapto-1-methylethyl, 1-methoxy-1-methylethyl, 1-hydroxy-1-methylethyl, 1-fluoro- 1-methylethyl, hydroxymethyl, 2-hydroxethyl, 2-carboxyethyl, 2-methylcarbamoylethyl, 2-carbamoylethyl, or 4-aminobutyl.
13. A compound, method, use, composition, or substance or composition for use in a method of treatment, as claimed in claim 10 or claim 11 wherein R, is tert-butyl, iso-butyl, benzyl, isopropyl or methyl.
14. A compound, method, use, composition, or substance or composition for use in a method of treatment, as claimed in claim 13 wherein Rs and R; taken together with the nitrogen atom to which they are attached form a piperidin-1-yl or 1-piperazin- 4-yl ring.
15. A compound, method, use, composition, or substance or composition for use in a method of treatment, as claimed in any of claim 10, 13 or 14 wherein the substituent (IC) has the formula -CH,Z, -OZ, or -(C=0)Z wherein Z is defined in claim 1 or claim 2. AMENDED SHEET
PCT/GB00/03078
16. A compound, method, use, composition, or substance or composition for use in a method of treatment, as claimed in any of claims 10 or 13 - 15 wherein in the substituent (IIC) Z is a phenyl, 3,4-methylenedioxyphenyl, morpholiny!, pyrimidinyl, 1,2,3-thiadiazolyl, 1,4-thiazolyl, benzofuranyl, furanyl, thienyl, pyranyl, pyrrolyl, pyrazolyl, isoxazolyl, or pyridyl ring which may optionally be substituted as specified in the definition of Z in claim 1 or claim 2. :
17. A compound, method, use, composition, or substance or composition for use in a method of treatment, as claimed in any of claims 10 or 13 - 15 wherein in the substituent (IIC) Z is a phenyl, 3,4-methylenedioxyphenyl, morphololinyl, pyrimidin-2- yl, 1,2,3-thiadiazol-5-yl, 1,4-thiazol-5-yl, benzofuran-2-yl, 2- or 3-furanyl, 2-or 3- thienyl, 2- or 3-pyranyl, 2-, 3- or 4-pyrrolyl, 3-, 4- or 5-pyazolyl, 3-, 4- or 5-isoxazolyl, or 2-, 3- or 4-pyridyl ring which may optionally be substituted as specified in the definition of Z in claim 1 or claim 2.
18. A compound as claimed in claim 1 or claim 2, a method as claimed in claim 4, a use as claimed in claim 3 or claim 5, a composition as claimed in claim 6, or a substance or composition for use in a method of treatment, as claimed in claim 7, wherein R, is hydrogen; R, is n-propyl, n-butyl, n-pentyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl; R, is tert-butyl, iso-butyl, benzyl or methyl; Rs and R, taken together with the nitrogen atom to which they are attached form a piperidin-1-yl or 1-piperazin-4-yl ring; the substituent (lIC) has the formula -CH,Z, -OZ, or -(C=0)Z wherein Z is as defined in claim 16 or claim 17.
19. A compound as claimed in claim 1 or claim 2 a method as claimed in claim 4, a use as claimed in claim 3 or claim 5, a composition as claimed in claim 6, or a substance or composition for use in a method of treatment, as claimed in claim 7, wherein the compound is one selected from the group consisting of compounds of formula (IID)-(IIG) and (lIW) - (IZ): AMENDED SHEET
“a $ PCT/GB00/03078
Y NAN 0 oO R, ~z 0 0 a z A | oy N HY N | : OH R, 3 OH R, o) (IID) (HE) Y NTT oO R, ~z oR, 7 z K N By NS HO” N HO N 0 R, o) °c Rr o (IF) (1G) 0 0 Jy 0 OH R, y Zz OH R, NG Zz (IW) (1X) : : 0 | | J 0 0 R, AZ oO R, PR ~Z - Y Y (ny) - (1g) wherein R, is n-propyl, n-butyl, n-pentyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethy! or cyclohexylethyl; R, is tert-butyl, iso-butyl, benzyl or methyl; Y is -CH,-, -O- or -(C=0)-; and ’ Z is as defined in claim 16 or 17. AMENDED SHEET
PCT/GB00/03078
20. A compound as claimed in claim 1 or claim 2, a method as claimed in claim 4, a use as claimed in claim 3 or 5, a composition as claimed in claim 6, or a substance or composition for use in a method of treatment, as claimed in claim 7, wherein the compound is one specifically named and/or exemplified herein, or is the hydroxamate (Q represents a radical of formula -C(=O)NH(OH)) or N-formylhydroxylamine (Q represents a radical of formula -N(OH)CH(=0)) analogue thereof, as the case may be.
21. A compound as claimed in claim 1 or claim 2, a method as claimed in claim 4, a use as claimed in claim 3 or 5, a composition as claimed in claim 6, or a substance or composition for use in a method of treatment, as claimed in claim 7, wherein the compound is N-(1S-(4-benzo[1,3]dioxol-5-ylmethyl-piperazine-1-carbonyl)-2,2- dimethyl-propyl]-2R-cyclopentylmethyl-3-(formyl-hydroxy-amino)-propionamide or N- [1S-(4-benzo[1,3]dioxol-5-yImethyl-piperazine-1-carbonyl)-2,2-dimethyl-propyl}-2R- cyclopentylmethyl-N-hydroxy-succinamide.
22. A compound as claimed in claim 1, substantially as herein described and - illustrated. :
23. Use as claimed in claim 3 or claim 5, substantially as herein described and illustrated.
24. A method as claimed in claim 4, substantially as herein described and illustrated.
25. A composition as claimed in claim 6, substantially as herein described and illustrated.
26. A substance or composition for use in a method of treatment as claimed in claim 7, substantially as herein described and illustrated. AMENDED SHEET
PCT/GB00/03078
27. Anew compound, a new use of a compound as claimed in claim 1 or claim 2, a new method for treating contamination, a new composition, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9918869.0A GB9918869D0 (en) | 1999-08-10 | 1999-08-10 | Antibacterial agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200201093B true ZA200201093B (en) | 2003-07-30 |
Family
ID=10858920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200201093A ZA200201093B (en) | 1999-08-10 | 2002-02-07 | Antibacterial agents. |
Country Status (3)
| Country | Link |
|---|---|
| CN (2) | CN101007784A (en) |
| GB (1) | GB9918869D0 (en) |
| ZA (1) | ZA200201093B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100451002C (en) * | 2006-03-10 | 2009-01-14 | 中山大学 | Derivatives of 2,6-dipyridylene cyclohexanone, and its application in preparing antibacterial medicine |
| CN106928096A (en) * | 2017-02-07 | 2017-07-07 | 河南师范大学 | A kind of synthetic method of metal protease inhibitors key intermediate |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10500986A (en) * | 1994-05-28 | 1998-01-27 | ブリテッシュ バイオテック ファーマシューティカルズ リミテッド | Metalloproteinase inhibitors |
| NZ322553A (en) * | 1995-11-23 | 1998-12-23 | British Biotech Pharm | Metalloproteinase inhibitors |
| PL335378A1 (en) * | 1997-02-26 | 2000-04-25 | Glaxo Group Ltd | Derivatives of inverse hydroxamates as metaloprotease inhibitors |
-
1999
- 1999-08-10 GB GBGB9918869.0A patent/GB9918869D0/en not_active Ceased
-
2000
- 2000-08-10 CN CN 200710007364 patent/CN101007784A/en active Pending
- 2000-08-10 CN CNB2005100811981A patent/CN1330634C/en not_active Expired - Fee Related
-
2002
- 2002-02-07 ZA ZA200201093A patent/ZA200201093B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN1704402A (en) | 2005-12-07 |
| CN1330634C (en) | 2007-08-08 |
| GB9918869D0 (en) | 1999-10-13 |
| CN101007784A (en) | 2007-08-01 |
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