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Title:
BACTERIAL ENZYME INHIBITORS
Document Type and Number:
WIPO Patent Application WO/2003/048115
Kind Code:
A1
Abstract:
Compounds of formula (I) are antibacterial agents: wherein: Z is −N(OH)CH(=O) or −C(=O)NH(OH)&semi R1 represents hydrogen, methyl or trifluoromethyl or, except when Z is a radical of formula −N(OH)CH(=O), a hydroxy, halo or amino group&semi R2, R3 and R4 independently represents hydrogen or a group R10−(D)n−(ALK)m− wherein R10 , D, n, m and ALK are as defined in the claims&semi or R3 and R4 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic heterocyclic ring containing from 5 to 7 ring atoms, one of which is the nitrogen atom to which R4 and R5 are attached and the remaining ring atoms being selected from compatible combinations of carbon, oxygen, sulfur and nitrogen.

Inventors:
GANE PAUL (GB)
PORTER BARRY (GB)
WILLEMS HENRIETTE (GB)
BECKETT RAYMOND PAUL (US)
KEAVEY KENNETH (GB)
Application Number:
PCT/GB2002/005350
Publication Date:
June 12, 2003
Filing Date:
November 27, 2002
Export Citation:
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Assignee:
NOVO PHARMACEUTICALS LTD DE (GB)
GANE PAUL (GB)
PORTER BARRY (GB)
WILLEMS HENRIETTE (GB)
BECKETT RAYMOND PAUL (US)
KEAVEY KENNETH (GB)
International Classes:
A61P31/04; C07C275/24; C07D213/40; C07D295/215; (IPC1-7): C07C275/14; C07C275/12; C07C275/24; C07D213/75; C07D295/20; A61K31/17; A61P31/04
Domestic Patent References:
WO1999039704A11999-08-12
WO1999059568A11999-11-25
Foreign References:
US4025622A1977-05-24
Other References:
CHEN ET AL: "Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor", BIOCHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, PA, US, vol. 39, 15 February 2000 (2000-02-15), pages 1256 - 1262, XP002158085, ISSN: 0006-2960
Attorney, Agent or Firm:
Walls, Alan J. (Watlington Road, Oxford OX4 6LY, GB)
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Claims:
Claims :
1. A compound of formula (I), or a salt or hydrate thereof: wherein: Z represents a radical of formulaN (OH) CH (=O) or formulaC (=O) NH (OH); R1 represents hydrogen, methyl or trifluoromethyl or, except when Z is a radical of formulaN (OH) CH (=O), a hydroxy, halo or amino group R2 represents hydrogen or a group Rio (D) n (ALK) m wherein Rio represents an optionally substituted CiC6 alkyl, C2C6 alkenyl, C2C6 alkynyl, cycloalkyl, aryl, or heterocyclyl group and ALK represents a straight or branched divalent C1C6 alkylene, C2C6 alkenylene, or C2C6 alkynylene radical, and may be interrupted by one or more nonadjacentNH,OorSlinkages, D representsNH,OorS, and n is 0 or 1 ; R3 and R4 independently represent hydrogen or a group R10(D)n(ALK)m as defined for R2, or R3 and R4 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic heterocyclic ring containing from 5 to 7 ring atoms, one of which is the nitrogen atom to which R4 and Rs are attached and the remaining ring atoms being selected from compatible combinations of carbon, oxygen, sulfur and nitrogen.
2. A method for the treatment of bacterial infections in humans and nonhuman mammals, which comprises administering to a subject suffering such infection an antibacterially effective dose of a compound as claimed in claim 1.
3. A composition compriosing a compound as claimed in claim 1 and a pharmaceutical acceptable carrier.
4. A compound as claimed in claim, a method as claimed in claim 2 or a composition as claimed in claim 3 wherein Z is a radical of formulaN (OH) CH (=O), andf R1 is hydrogen, methyl or trifluoromethyl.
5. A compound as claimed in claim, a method as claimed in claim 2 or a composition as claimed in claim 3 wherein Z is a radical of formulaC (=O) NH (OH), and Pi is hydrogen, methyl, trifluoromethyl, hydroxy, halo or amino.
6. A compound as claimed in claim, a method as claimed in claim 2 or a composition as claimed in claim 3 wherein Ri is hydrogen.
7. A compound, method or composition as claimed in any of claims 4 to 6 wherein R2 is: : optionally substituted C1C8 alkyl, C3C6 alkenyl, C3C6 alkynyl or cycloalkyl ; phenyl (C1C6 alkyl), phenyl (C3C6 alkenyl)or phenyl (C3C6 alkynyl) optionally substituted in the phenyl ring; cycloalkyl (C1C6 alkyl), cycloalkyl (C3C6 alkenyl)or cycloalkyl (C3C6 alkynyl) optionally substituted in the cycloalkyl ring; heterocyclyl (C1C6 alkyl), heterocyclyl (C3C6 alkenyl)or heterocyclyl (C3C6 alkynyl)optionally substituted in the heterocyclyl ring; or CH3 (CH2) pO (CH2) q or CH3 (CH2) pS (CH2) q, wherein p is 0,1, 2 or 3 and q is 1, 2 or 3.
8. A compound, method or composition as claimed in claim 7 wherein R2 is methyl, ethyl, nor isopropyl, nand isobutyl, npentyl, isopentyl 3methylbut1yl, nhexyl, nheptyl, noctyl, methylsulfanylethyl, ethylsulfanylmethyl, 2methoxyethyl, 2 ethoxyethyl, ethoxymethyl, 3hydroxypropyl, allyl, 3phenylprop3en1yl, prop2yn 1yl, 3phenylprop2yn1yl, 3(2chlorophenyl) prop2yn1yl, but2yn1yl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, furan2ylmethyl, furan3 ylmethyl, tetrahydrofuran2ylmethyl, tetrahydrofuran2ylmethyl, piperidinylmethyl, <BR> <BR> <BR> phenylpropyl, 4chlorophenylpropyl, 4methylphenylpropyl, 4methoxyphenylpropyl, benzyl, 4chlorobenzyl, 4methylbenzyl, or 4methoxybenzyl.
9. A compound, method or composition as claimed in wherein R2 is (C1C6) alkyl, cycloalkylmethyl, (CiC3) alkylS(C1C3) alkyl, or (CiC3) alkylO(C1C3) alkyl, especially npropyl, nbutyl, npentyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.
10. A compound, method or composition as claimed in any of claims 4 to 8 wherein R3 is any of the R2 groups psecified in claim 7, 8 or 9.
11. A compound, method or composition as claimed in any of claims 4 to 8 wherein R3 is hydrogen.
12. A compound, method or composition as claimed in any of claims 4 to 11 wherein R4 is methyl, ethyl, nor isopropyl, nor isobutyl, npentyl, isopentyl, 3 methylbut1yl, nhexyl, nheptyl, noctyl, hydroxymethyl, 2hydroxymethyl, methoxymethyl, 2methoxyethyl, 2ethoxyethyl, 2ethoxymethyl, 3hydroxypropyl, <BR> <BR> <BR> allyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl,<BR> <BR> <BR> <BR> <BR> cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, furan2ylmethyl, furan3methyl,<BR> <BR> <BR> <BR> <BR> tetrahydrofuran2ylmethyl, tetrahydrofuran2ylmethyl,, piperidinyl, piperazinyl, piperidinylmethyl, piperazinylmethyl, phenyl, 4chlorophenyl, 4methylphenyl 4 methoxyphenyl, 4hydroxyphenyl, 4aminophenyl, benzyl, 4chlorobenzyl, 4 methylbenzyl, 4methoxybenzyl, 4hydroxybenzy, 4aminobenzyl, naphthyl, naphthylmethyl and naphthyl and naphthylmethyl substituted in the naphthyl rings by methyl, methoxy, hydroxy, chloro, or amino.
13. A compound, method or composition as claimed in any of claims 4 to 11 wherein R3 and R4 taken together with the nitrogen to which they are attached form a piperidino, piperazino, morpholino, pyridyl, oxazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl ring, any of which may be substituted.
Description:
Bacterial Enzyme Inhibitors This invention relates to hydroxamic acid and N-formyl hydroxylamine compounds which inhibit the activity of the bacterial enzyme known as peptide deformylase.

Since bacterial growth is known to be inhibited by inhibitors of peptide deformylase, the compounds of the invention are expected to include antibacterial agents.

Background to the Invention The compounds of the invention are inhibitors 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. 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). Although a deformylase homologue has recently been cloned from the mitochondria of human cells (Giglione et. el. EMBO Journal, 19,5916-5929, 2000) it has not been shown to be functional, and its relevance is unknown. Since a number of currently used antibiotics are known to act on both bacteria and mitochondria, PDF is still considered to be a target for antibacterial chemotherapy (for a review see Giglione et al., Mol Microbiol., 36: 1197-1205,2000).

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 Ni2+ 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 Zn2+ 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.

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.

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 amide 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: 4287-95,1999 ; Huntingdon et al., Biochemistry, 39: 4543-51,2000 ; Wei et al, J. Combinatorial Chem. , 2: 650-57,2000) metal binding group are micromolar inhibitors of PDF. Peptide aldehydes such as calpeptin (N- Cbz-Leu-norleucinal) have also been shown to inhibit PDF (Durand et al., Arch.

Biochem. Biophys. , 367: 297-302,1999). Recently, the naturally occurring hydroxamic acid antibiotic actinonin, for which the target of its antibacterial activity was previously unknown, was shown to be a potent inhibitor of polypeptide deformylase (WO 99/39704, and Chen et al, Biochemistry, 39: 1256-62,2000).

Examples of non-peptidic PDF inhibitors with carboxylic acid (Green et al., Arch.

Biochem. Biophys. 375: 355-8,2000 ; Jayasekera et al., ibid. , 381: 313-6,2000) or hydroxamic acid (Apfel et al., J. Med. Chem. , 43: 2324-31,2000) metal binding groups are also known.

It has been reported that PDF is present in eukaryotic parasites such as Plasmodium falciparum (Meinnel, Parasitology Today, 16: 165-8,2000). Those authors also found evidence for the presence of PDF in other parasites of humans, such as the kinetoplastid protozoan parasites Trypanosoma brucei and Leishmania major. Based on these findings, it is anticipated that the hydroxamic acid and N-formyl hydroxylamine compounds with which this invention is concerned have antiprotozoal activity, and are useful in the treatment of malaria and other protozoal diseases.

Several patent applications describe antibacterial hydroxamic acid and N-formyl hydroxylamine agents whose activity has been attributed to inhibition of PDF. These publications include our copending International patent applications nos. WO 99/39704, WO 99/59568, WO 00/35440, WO 00/44373, WO 00/58294 and WO 00/61134, as well as WO 01/40198 (Aventis), WO 01/44179 (Versicor), WO 01/44178 (Versicor), and WO 01/38561 (Questcor).

Further, actinonin is a naturally occurring antibacterial agent having a hydroxamic acid group, and certain derivatives of actinonin are also known to have antibacterial activity. (see for example Bouboutou et al, Colloq. INSERM (1989) 174 (Forum Pept.

2nd, 1988), 341-4; Lelevre et. al. Pathol. Biol. (1989), 37 (1), 43-46; Broughton et. al.

J. Chem. Soc. Perkin Trans. 1 (1975) (9), 857-60. The antibacterial activity of actinonin has been shown to be due, at least in part, to inhibition of PDF (WO 99/39704 and other publications) Brief Description of the Invention This invention is based on the discovery of a class of hydroxamic acid and N-formyl hydroxylamine derivatives which are inhibitors of the activity of PDF. Compounds in that class are therefore expected to have antibacterial activity. The class includes novel structures which form part of the invention. Also within the scope of the invention is a method of identifying antibacterial agents from within the class of PDF inhibitors of the invention.

Detailed Description of the Invention According to the invention there is provided a compound of formula (I), or a salt or hydrate thereof: wherein: Z represents a radical of formula-N (OH) CH (=O) or formula-C (=O) NH (OH); R1 represents hydrogen, methyl or trifluoromethyl or, except when Z is a radical of formula-N (OH) CH (=O), a hydroxy, halo or amino group R2 represents hydrogen or a group Rio- (D) n- (ALK) m- wherein Rio represents an optionally substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, aryl, or heterocyclyl group and ALK represents a straight or branched divalent Ci-C6 alkylene, C2-C6 alkenylene, or C2-C6 alkynylene radical, and may be interrupted by one or more non-adjacent-NH-,-O-or-S-linkages, D represents-NH-,-O-or-S-, and n is 0 or 1 ; R3 and R4 independently represent hydrogen or a group Rio- (D) n- (ALK) m- as defined for R2, or R3 and R4 taken together with the nitrogen atom to which they are attached form an optionally substituted monocyclic heterocyclic ring containing from 5 to 7 ring atoms, one of which is the nitrogen atom to which R4 and R5 are attached and the remaining ring atoms being selected from compatible combinations of carbon, oxygen, sulfur and nitrogen.

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 (I) as defined above to the site of contamination.

The compounds of formula (I) as defined above may be used as component (s) of antibacterial cleaning or disinfecting materials.

As used herein the term"(C1-C6) 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.

As used herein the term" (C2-C6) 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"C2-C6 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"aryl"refers to a mono-, bi-or tri-cyclic carbocyclic aromatic group, and to groups consisting of two covalently linked monocyclic carbocyclic aromatic groups. Illustrative of such groups are phenyl, biphenyl and napthyl.

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, furyl, 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, pyridinyl, 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 applied to any moiety herein means substituted with up to four substituents, each of which independently may be (Cl-C,) alkyl, phenyl, benzyl, (C,-C6) alkoxy, hydroxy, mercapto, (C,-C6) alkylthio, amino, halo (including fluoro, chloro, bromo and iodo), cyano, trifluoromethyl, nitro,-COOH,-CONH2-CORA,-COORA,-NHCORA,-CONHRA, -NHRA,-NRARB, or-CONRARB wherein RA and RB are independently a (Cl-C,) alkyl group. In the case where the substituent is phenyl or benzyl, the phenyl ring may be substituted with any of the foregoing except phenyl or benzyl.

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 R2 group is R; and that of the carbon atom carrying the Pi group (when asymmetric) is R.

In the compounds of the invention: When Z is a radical of formula-N (OH) CH (=O), R1 is hydrogen, methyl or trifluoromethyl. When Z is a radical of formula-C (=O) NH (OH), R1 is hydrogen, methyl, trifluoromethyl, hydroxy, halo (e. g. chloro, bromo or especially fluoro) or amino. Hydrogen is currently preferred in both cases.

R2 may be, for example : optionally substituted C1-C8 alkyl, C3-C6 alkenyl, C3-C6 alkynyl or cycloalkyl ; phenyl (C1-C6 alkyl)-, phenyl (C3-C6 alkenyl)-or phenyl (C3-C6 alkynyl)- optionally substituted in the phenyl ring; cycloalkyl (C1-C6 alkyl)-, cycloalkyl (C3-C6 alkenyl)-or cycloalkyl (C3-C6 alkynyl)- optionally substituted in the cycloalkyl ring; heterocyclyl (C1-C6 alkyl)-, heterocyclyl (C3-C6 alkenyl)-or heterocyclyl (C3-C6 alkynyl)-optionally substituted in the heterocyclyl ring; or CH3 (CH2) pO (CH2) q- or CH3 (CH2) pS (CH2) q-, wherein p is 0,1, 2 or 3 and q is 1, 2 or 3.

Specific examples of R2 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-octyl, methylsulfanylethyl, ethylsulfanylmethyl, 2- methoxyethyl, 2-ethoxyethyl, ethoxymethyl, 3-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, <BR> <BR> <BR> cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl,<BR> <BR> <BR> <BR> <BR> <BR> cyclohexylethyl, cyclohexylpropyl, furan-2-ylmethyl, furan-3-ylmethyl,<BR> <BR> <BR> <BR> <BR> <BR> <BR> tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-ylmethyl, piperidinylmethyl, phenylpropyl, 4-chlorophenylpropyl, 4-methylphenylpropyl, 4- methoxyphenylpropyl, benzyl, 4-chlorobenzyl, 4-methylbenzyl, and 4- methoxybenzyl.

Presently preferred groups at R2 are (C1-C6) alkyl-, cycloalkylmethyl-, (C1- C3) alkyl-S-(C1-C3) alkyl-, or (Ci-C3) alkyl-O-(C1-C3) alkyl-, especially n-propyl, n- butyl, n-pentyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl or cyclohexylethyl.

R3 may be any of the groups discussed in relation to R2, but presently it is preferred that R3 is hydrogen.

Examples of groups R4 are methyl, ethyl, n-and iso-propyl, n-and iso-butyl, n- pentyl, iso-pentyl, 3-methyl-but-1-yl, n-hexyl, n-heptyl, n-octyl, hydroxymethyl, 2-hydroxymethyl, methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2- ethoxymethyl, 3-hydroxypropyl, allyl, cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, furan-2-ylmethyl, furan-3-methyl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-2-ylmethyl,, piperidinyl, piperazinyl, piperidinylmethyl, piperazinylmethyl, phenyl, 4-chlorophenyl, 4- methylphenyl 4-methoxyphenyl, 4-hydroxyphenyl, 4-aminophenyl, benzyl, 4- chlorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-hydroxybenzy, 4- aminobenzyl, naphthyl, naphthylmethyl and naphthyl and naphthylmethyl substituted in the naphthyl rings by methyl, methoxy, hydroxy, chloro, or amino.

When R3 and R4 taken together with the nitrogen to which they are attached form a heterocyclic ring, that ring may be, for example piperidino, piperazino, morpholino, pyridyl, oxazolyl, thiazolyl, oxadiazolyl, or thiadiazolyl, any of which may be substituted, for example by methyl, methoxy, hydroxy, chloro, or amino.

Specific examples of compounds of the invention include N-hydroxy-N [2R- (3-naphthalen-1-ylmethyl-ureido)-hexyl]-formamide, N- [2R- (3-Benzyl-ureido)-hexyl]-N-hydroxy-formamide,<BR> <BR> <BR> <BR> <BR> <BR> <BR> N-{3-Cyclopentyl-2R- [3- (3, 4-dimethoxy-benzyl)-ureido]-propyl}-N-hydroxy- formamide, N-{3-Cyclopentyl-2R- [3-pyridin-4-ylmethyl-ureido)-propyl]-N-hydroxy- formamide, N- {3-Cyclopentyl-2R- [3- (4-methoxy-benzyl)-ureido]-propyl-N-hydroxy- formamide, N- {3-Cyclopentyl-2R- [3- (4-methoxy-benzyl)- ureido]-propyl-N-hydroxy- formamide and 4-Phenyl-piperazine-1-carboxylic acid [1 R-cyclopentylmethyl-2- (formyl- hydroxy-amino)-ethyl]-amide as well as the corresponding compounds in which the N-hydroxy formylamino group is replaced by a hydroxamic acid group.

Compounds of the invention in which Z is an N-formylhydroxyamino group may be prepared by deprotecting an 0-protected N-formyl-N-hydroxyamino compound of formula (II) : in which R,, R2, R3, and R4 are as defined for general formula (I) and P, is a hydroxy protecting group removable to leave a hydroxy group by hydrogenolysis or hydrolysis. Benzyl is a preferred P, group for removal by hydrogenolysis, and tert- butyl and tetrahydropyranyl are preferred groups for removal by acid hydrolysis.

Compounds of formula (II) may be prepared by reaction of a compound of formula (IVA) with diphenylphosphoryl azide to form an intermediate compound of formula (IVB) then reacting compound (IVB) with an amine of formula R3R4NH.

Compounds of formula (II) may also be prepared by N-formylation, for example using acetic anhydride and formic acid, or 1-formylbenzotriazole, of compounds of formula (111) wherein R1, R2, R3 and R4 and P1 are as defined in relation to formula (II).

Compounds (III) may be prepared by reaction of a carboxylic acid of formula (IV) with diphenylphosphoryl azide to form an intermediate compound of formula (IVC) then reacting compound (IVC) with an amine of formula R3R4NH. Compounds of the invention in which Z is a hydroxamic acid group may be prepared by reacting the parent compound wherein Z is a carboxylic acid group (IIA) with hydroxylamine or an N-and/or 0-protected hydroxylamine, and thereafter removing any O-or N-protecting groups.

Compounds of formula (IIA) may be prepared by reaction of a carboxylic acid of formula (V) with diphenylphosphoryl azide to form an intermediate compound of formula (VA) then reacting compound (VA) with an amine of formula R3R4NH, then removing the protecting group P1 Further details of the preparation of compounds of the invention are presented in the following Example, wherein the following abreviations are used: Bn Benzyl DPPA Diphenylphosphoryl azide HPLC High performance liquid chromatography LRMS Low resolution mass spectrometry RT Retention time TFA Trifluoroacetic acid Analytical HPLC was run on a Beckman System Gold, using Waters Symmetry C18 column (50 mm, 4.6 mm) with 20 to 90 % solvent B gradient (1.5 ml/min) as the mobile phase. [Solvent A: 0.05% TFA in 10% water 90% MeCN ; Solvent B: 0.05% TFA in 10% MeCN 90% water, 5 min gradient time], detection wavelength at 214 nm.

Preparative HPLC was run on a Gilson autoprep instrument using a C18 Waters delta pak (151lm, 300 A, 25 mm, 10 mm) with 20 to 90 % solvent B gradient (6 ml/min) as the mobile phase. [Solvent A 10% MeCN/water; Solvent B: 10% water/MeCN, 13 min gradient time], UV detection was at 214 nm. Reagents were purified and dried where necessary by standard techniques.

Example 1 The preparation of N-hydroxy-N-[2R-(3-naphthalen-1-ylmethyl-ureido)-heXyl]- formamide is outlined in Scheme 1. 2R-[(Benzyloxy-formyl-amino)-methyl]-hexanoic acid was prepared by analogy with methods in international patent application WO 99/39704.

Scheme 1 OBn Step A OBn H OH Hymn N in il O O O Unisolated intermediate Step A Reagent 1 OBn OII B nj I H H Step B Step C OBn O H H y H ouzo Reagents and Conditions: A. DPPA, Et3N, reagent 1, toluene, heat 80 C; B. Formyl-acetic anhydride, CH2Cl2, Et3N ; C. H2, Pd/C, EtOH Step A: 1- [l R- (benzyloxyamino-methyl)-pentyl]-3-naphthalen-1-ylmethyl-urea A mixture of 2R-[(bezyloxy-formyl-amino)-metyl]-hexanoic acid (360 mg, 1.3 mmol), DPPA (273 pI, 1.3 mmol) and triethylamine (180 pI, 1.3 mmol) in a solution of toluene (12 ml) were heated to 80 °C. After 0.5 h 1-naphthylmetylamine (433 µl, 2.6 mmol) was added and the reaction mixture was stirred for 18 h at 80 °C. The mixture was allowed to cool and the solvent was removed in vacuo to yield an oily residue which was taken up in dichloromethane (20 ml). The organic phase was washed with 1 M hydrochloric acid (2 x 20 ml), 1 M sodium carbonate (2 x 20 ml), brine (1 x 20 ml), dried over anhydrous magnesium sulphate and the solvent was removed in vacuo to yield 1.0 g of a brown oil. Flash chromatography (dichloromethane, 3% methanol) yielded the title compound as a cloudy oil (100mg, 18%). LRMS +ve: 406 (M+1, 100%). HPLC: RT 5. 8 min (100%) ; 1H-NMR (CDCI3) â : 8.04 (1 H, d, J = 8. 1 Hz), 7.88- 7. 84 (1H, m), 7.77-7. 75 (1H, m), 7.52-7. 47 (2H, m), 7.39-7. 13 (7H, m), 5.72 (1H, brs), 5.15 (1 H, brs), 4.77 (2H, d, J = 5. 3 Hz), 4.40-4. 38 (3H, m) 3.69 (1 H, s), 2.98 (1 H, dd, J = 13.5 & 2.8 Hz), 2.70-2. 66 (1 H, m), 1.42-1. 22 (6H, m), 0.95 (3H, t, J 12.5 Hz).

Step B: N-Benzyloxy-N [2R- (3-naphthalen-1-ylmethyl-ureido)-hexyl]-formamide To a solution of 1- [l R- (benzyloxyamino-methyl)-pentyl]-3-naphthalen-1-ylmethyl-urea (94 mg, 0.24 mmol) in dichloromethane (5 ml) was added formyl-acetic anhydride (63 ul, 0.72 mmol) and triethylamine (99 ti, 0.72 mmol) and the reaction mixture was stirred for 18 h at room temperature. The solvent was removed in vacuo to yield the title compound as a clear oil (100 mg, 100%). No further purification was attempted.

LRMS +ve: 434 (M+1, 90%), 456 (M-1,70%). HPLC: RT 6.2 min (95%).

Step C : N-hydroxy-N-[2R-(3-naphthalen-1-ylmethyl-ureido)-heXyl]-form amide To a solution of N-benzylOxy-N-[2R-(3-naphthalen-1-ylmethyl-ureido)-heXyl]- formamide (100 mg, 0.43 mmol) in ethanol (6 ml) was added Pd/C (25% w/w, 15 mg) and one drop of formic acid and this suspension was then blanketed with hydrogen.

The reaction mixture was stirred at room temperature for 18 h. The catalyst was filtered off and the solvent was removed under reduced pressure to yield an oil (77 mg). Preparative HPLC yielded the title compound as a clear oil (43 mg, 54%). HPLC: Rt 5.9 min (99%); LRMS, +ve ion 344 (M+1, 100%), 366 (M+Na, 80%);-ve ion 342 (M-1,90%) ; 1H-NMR (CDCI3) 6 : 10.00 (1H, brs, OH), 8.14 (1H, s, CHO), 7.91 (1H, d, J = 8.4 Hz, ArH), 7.81 (1H, d, J=7.9 Hz, ArH), 7.71 (1H, d, J = 8.1 Hz, ArH), 7.53-7. 45 (2H, m, ArH), 7.37-7. 26 (2H, m, ArH), 5.71 (1H, brs, NH), 5.37 (1H, d, J = 8.4Hz, NH), 4.70 (2H, ddd, J = 20.8 Hz, 15. 1 Hz & 5.6 Hz), 4.06-4. 01 (1H, m), 3.76 (1 H, dd, J 13. 5Hz & 11.6Hz), 1.77-1. 65 (1 H, m), 1.53-1. 26 (6H, m), 0.89 (3H, J = 7.0 Hz, m); 13C-NMR ; # (CD03) : 14.2, 22.8, 28.6, 32.2, 42.5, 47.1, 51.1, 123.5, 125.7, 125.8, 126.3, 126.8, 128.6, 129.2, 131.5, 134.2, 134.5, 160.6, 163.4.

The following compounds may also be prepared by the method of Example 1