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  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
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  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
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  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
  • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/14—Nitrogen atoms not forming part of a nitro radical
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  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

• This invention is directed to novel succinate compounds. This invention is also directed to uses of these compounds in various medicinal applications, including treating disorders amenable to treatment by peptidyl deformylase inhibitors. This invention is still further directed to pharmaceutical compounds comprising these compounds and methods of synthesis thereof. State of the Art
• Penicillin is an extremely well known example of such an agent. Penicillin acts by inhibiting biosynthesis of bacterial cell walls. Since mammalian cells do not require cell walls for survival, administration of penicillin to a human infected with bacteria can kill the bacteria without killing human cells. However, the use of antibiotics and antimicrobials has also resulted in increased resistance to these agents. As bacteria become resistant to older, more widely used antimicrobial agents, new antimicrobials must be developed in order to provide effective treatments for human and non-human animals suffering from microbial infection.
• Peptide deformylase is a metallopeptidase found in prokaryotic organisms such as bacteria. Protein synthesis in prokaryotic organisms begins with N-formyl methionine (fMet). After initiation of protein synthesis, the formyl group is removed by the enzyme peptide deformylase (PDF); this activity is essential for maturation of proteins. It has been shown that PDF is required for bacterial growth (Chang et al. J. Bacteriol. 171 :4071-4072 (1989); Meinnel T, Blanquet S, J. Bacteriol. 176(23):7387- 90 (1994); Mazel D et al., EMBOJ. 13(4):914-23 (1994 )).
• PDF peptide deformylase
• Prokaryotic organisms including disease-causing prokaryotes, are described in Balows, A., H.G. Truper, M. Dworkin, W. Harder, and K.-H. Schleifer (eds.), The Prokaryotes, 2nd ed., New York: Springer-Verlag, 1992; and Holt, J.G. (editor-in- chief). Bergey's Manual of Systematic Bacteriology, Vols. 1-4, Baltimore: Williams & Wilkins, 1982, 1986, 1989.
• PDF is part of the metalloproteinase superfamily. While PDF clearly shares many of the features which characterize metalloproteinases, it differs from other members of the superfamily in several important respects.
• the metal ion in the active enzyme appears to be Fe (II), or possibly another divalent cationic metal, instead of the zinc ion more commonly encountered. Rajagopalan et al, J. Am. Chem. Soc, 119:12418-19 (1997).
• the divalent ion appears to play an important role, not only in catalysis, but also in the structural integrity of the protein.
• the third ligand of the divalent ion is a cysteine, rather than a histidine or a glutamate, as in other metalloproteinases and is not located at the C-terminal side of the HEXXH motif but far away along the amino acid sequence and N-terminal to the motif.
• the solution structure shows significant differences in the secondary and tertiary structure of PDF compared to other prototypical metalloproteinases see Meinnel et al. J. Mol Biol 262:375-386 (1996).
• PDF from E. coli, Bacillus stear other mophilus, and Thermus thermophilus have been characterized see Meinnel et al., J Mol Biol 267:749-761 (1997).
• MMPs matrix metalloproteinases
• this invention is directed to a compound of Formula (I):
• R 2 is independently hydrogen or -R 9 wherein R 9 is as defined above;
• the compound of Formula (I) inhibits peptidyl deformylase at an IC 50 of less than or equal to about 100 nm, preferably of less than or equal to 10 nm, more preferably of less than or equal to 1 nm.
• the compound of Formula (I) displays a selectivity for peptidyl deformylase over at least one metalloproteinase selected from the group consisting of ACE and Matrilysin of greater than or equal to about 10 times, more preferably of greater than or equal to about 100 times, still more preferably of greater than or equal to about 1000 times.
• this invention is directed to pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
• this invention is directed to a method of treatment of a disease in a mammal treatable by administration of a peptidyl deformylase inhibitor which method comprises administration of a therapeutically effective amount of a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient either alone or in combination with other pharmacologically active agents.
• the compounds of this invention are useful in treating microbial diseases.
• the microbial infection can be due to bacteria, other prokaryotes, or other organisms, including parasites, dependent on peptide deformylase for growth or survival.
• this invention is directed to the use of a compound of Formula (I) or a pharmaceutically acceptable salts thereof in the preparation of a medicament for use in the treatment of diseases mediated by peptidyl deformylase enzyme.
• this invention is directed to a method for identifying compounds useful in treating microbial infections, comprising performing an assay to identify compounds which meet the criterion of either i) an IC 50 for peptide deformylase of less than or equal to about 1 ⁇ M, or ii) an MIC for a disease-causing pathogen of less than or equal to about 32 ⁇ g/ml; performing an assay to identify compounds which meet the criterion of iii) displaying a selectivity for peptide deformylase over at least one metalloproteinase selected from the group consisting of Angiotensin Converting Enzyme (ACE) and Matrilysin of greater than or equal to about 10 times; and selecting compounds which meet either both criteria i) and iii), or both criteria ii) and iii).
• ACE Angiotensin Converting Enzyme
• the compounds so identified meet the criterion of either i) an IC 50 for peptide deformylase of less than or equal to about 100 nM, or ii) an MIC for a disease-causing pathogen of less than or equal to about 10 ⁇ g/ml.
• alkyl refers to saturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms.
• alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmefhyl, cyclopentylethyl, and adamantyl.
• Cyclic alkyl groups can consist of one ring, including, but not limited to, groups such as cycloheptyl, or multiple fused rings, including, but not limited to, groups such as adamantyl or norbornyl.
• alkylene means a saturated divalent aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, e.g., methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methyl- propylene, butylene, pentylene, cyclopentylmethylene, and the like.
• substituted alkyl means an alkyl group as defined above that is substituted with one or more substituents, preferably one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
• substituents preferably one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkyla
• the phenyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide.
• substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and
• substituted alkyl groups include, but are not limited to, -CF 3 , -CF 2 -CF 3 , hydroxymethyl, 1- or 2-hydroxyethyl, methoxymethyl, 1- or 2-ethoxyethyl, carboxymethyl, 1- or 2- carboxyethyl, methoxycarbonylmethyl, 1- or 2-methoxycarbonyl ethyl, benzyl, and the like.
• substituted alkylene means an alkylene group as defined above that is substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
• substituents preferably one to three substituents, selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dial
• the phenyl group may optionally be substituted with one to three substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide.
• substituents selected from the group consisting of halogen (fluoro, chloro, bromo, and iodo, preferably fluoro, chloro, or bromo), alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and
• substituted alkyl groups include, but are not limited to, -CF 2 -, -CF 2 -CF 2 -, hydroxymefhylene, 1- or 2-hydroxyethylene, methoxymethylene, 1- or 2-ethoxyethylene, carboxymethylene, 1- or 2-carboxy- ethylene, and the like.
• alkynyl refers to unsaturated aliphatic groups including straight- chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, which contain at least one triple bond ( -C ⁇ C-).
• alkynyl groups include, but are not limited to, acetylene, 2-butynyl, and the like.
• alkynylene refers to unsaturated divalent aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms, which contain at least one triple bond ( -C ⁇ C-).
• alkynylene groups include, but are not limited to, -C ⁇ C-, -C ⁇ C-CH 2 -, and the like.
• substituted alkenyl or “substituted alkynyl,” refers to the alkenyl and alkynyl groups as defined above that are substituted with one or more substituents, selected from the group consisting of halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
• substituents selected from the group consisting of halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked
• substituted alkenylene or “substituted alkynylene,” refers to the alkenylene and alkynylene groups as defined above that are substituted with one or more substituents, selected from the group consisting of halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
• substituents selected from the group consisting of halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked
• aryl refers to an aromatic carbocyclic group of 6 to 14 carbon atoms having a single ring (including, but not limited to, groups such as phenyl) or multiple condensed rings (including, but not limited to, groups such as naphthyl or anthryl), and includes both unsubstituted and substituted aryl groups.
• Substituted aryl is an aryl group that is substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, aryloxy, benzyl, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
• substituents preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl,
• arylene refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1 ,2-phenylene, 1,3- phenylene, 1 ,4-phenylene, 1,2-naphthylene and the like.
• amino refers to the group -NH 2 .
• thioalkoxy means a radical -SR where R is an alkyl as defined above e.g., methylthio, ethylthio, propylthio, butylthio, and the like.
• dialkylamino means a radical -NHR and -NRR' respectively where R and R' independently represent an alkyl group as defined herein.
• Representative examples include, but are not limited to dimethylamino, methylethylamino, di(l-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)- amino, (cyclohexylmethyl)(ethyl)amino, and the like.
• acyloxy means a radical -OC(O)R, where R is hydrogen, alkyl, aryl, heteroaryl or substituted alkyl wherein alkyl, aryl, heteroaryl, and substituted alkyl are as defined herein.
• Representative examples include, but are not limited to formyl, acetyloxy, cylcohexylcarbonyloxy, cyclohexylmethylcarbonyloxy, benzoyloxy, benzylcarbonyloxy, and the like.
• heteroalkyl refers to alkyl, alkenyl, and alkynyl groups respectively as defined above, that contain the number of carbon atoms specified (or if no number is specified, having 1 to 12 carbon atoms) which contain one or more heteroatoms, preferably one to three heteroatoms, as part of the main, branched, or cyclic chains in the group.
• Heteroatoms are independently selected from the group consisting of-NR-, -NRR, (where each R is hydrogen or alkyl), -S-, -O-, -SR (R is hydrogen or alkyl), -OR (R is hydrogen or alkyl), and P; preferably -NR where R is hydrogen or alkyl and/or O.
• Heteroalkyl, heteroalkenyl, and heteroalkynyl groups may be attached to the remainder of the molecule either at a heteroatom (if a valence is available) or at a carbon atom.
• heteroalkyl groups include, but are not limited to, groups such as -O-CH 3 , -CH 2 -O-CH 3 , -CH 2 -CH 2 -O-CH 3 , -S-CH 2 -CH 2 -CH 3 , -CH 2 -CH(CH 3 )-S-CH 3 , -CH 2 -CH 2 -NH-CH 2 -CH 3 , 1 -ethyl-6-propylpiperidino, 2-ethylthiophenyl, piperazino, pyrrolidino, piperidino, morpholino, and the like.
• carboalkoxy means -C(O)OR where R is alkyl as defined above and include groups such as methoxycarbonyl, ethoxycarbonyl, and the like.
• Carboxamide means -C(O)NHR or -C(O)NRR'where R and R' are independently hydrogen or alkyl as defined above. Representative examples include groups such as aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, and the like.
• heteroaryl or “HetAr” refers to an aromatic carbocyclic group of 3 to 9 ring atoms forming a single ring and having at least one hetero atom, preferably one to three heteroatoms including, but not limited to, heteroatoms such as N, O, P, or S, within the ring.
• Representative examples include, but are not limited to single ring such as imidazolyl, pyrazolyl, pyrazinyl, pyridazinyl, pyrimidinly, pyrrolyl, pyridyl, thiophene, and the like, or multiple condensed rings such as indolyl, quinoline, quinazoline, benzimidazolyl, indolizinyl, benzothienyl, and the like.
• heteroalkyl, heteroalkenyl, heteroalkynyl and heteroaryl groups can be unsubstituted or substituted with one or more substituents, preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, benzyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl, mercapto, carboxy, benzyloxy, phenyl, aryloxy, cyano, nitro, thioalkoxy, carboxaldehyde, carboalkoxy and carboxamide, or a functionality that can be suitably blocked, if necessary for purposes of the invention, with a protecting group.
• substituents preferably one to three substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, benzyl, halogen, alkoxy, acyloxy, amino, mono or dialkylamino, hydroxyl,
• the heteroatom(s) as well as the carbon atoms of the group can be substituted.
• the heteroatom(s) can also be in oxidized form.
• heteroarylene refers to the diradical group derived from heteroaryl
• heteroalkylene refers to the diradical group derived from heteroalkyl, heteroalkenyl, and heteroalkynyl (including substituted heteroalkyl, heteroalkenyl, and heteroalkynyl), as defined above.
• alkylaryl refers to an alkyl group having the number of carbon atoms designated, appended to one, two, or three aryl groups.
• alkoxy refers to an alkyl, alkenyl, or alkynyl linked to an oxygen atom and having the number of carbon atoms specified, or if no number is specified, having 1 to 12 carbon atoms.
• alkoxy groups include, but are not limited to, groups such as methoxy, ethoxy, tert-butoxy, and allyloxy.
• aryloxy refers to an aryl group linked to an oxygen atom at one of the ring carbons.
• alkoxy groups include, but are not limited to, groups such as phenoxy, 2-, 3-, or 4-methylphenoxy, and the like.
• halogen refers to Cl, Br, F or I substituents, preferably fluoro or chloro.
• -(C ⁇ -C ⁇ 2 ) alkyl, substituted alkyl, or heteroalkyl means an alkyl, substituted alkyl or heteroalkyl group respectively as defined above and having 1 to 12 carbon atoms.
• Ri when Ri is -(C]-C ⁇ 2 ) alkyl, substituted alkyl, or heteroalkyl it means that Ri can be -(C ⁇ -C ⁇ 2 ) alkyl or -(C ⁇ -C 12 )substituted alkyl, or - (C,-C ⁇ 2 )heteroalkyl.
• alkenyl, substituted alkenyl, or heteroalkenyl means an alkenyl, substituted alkenyl, or heteroalkenyl group as defined above and having 1 to 12 carbon atoms.
• alkynyl, substituted alkynyl, or heteroalkynyl means an alkynyl, substituted alkynyl, or heteroalkynyl group as defined above and having 1 to 12 carbon atoms.
• -(C ⁇ -C ⁇ 2 ) alkylene, substituted alkylene, or heteroalkylene means an alkylene, substituted alkylene, or heteroalkylene group as defined above and havingl to 12 carbon atoms.
• -(C]-C ⁇ 2 ) alkenylene, substituted alkenylene, or heteroalkenylene means that the alkenylene, substituted alkenylene, or heteroalkenylene group as defined above and having 1 to 12 carbon atoms.
• -(C ⁇ -C ⁇ 2 ) alkynylene, substituted alkynylene, or heteroalkynylene means an alkynylene, substituted alkynylene, or heteroalkynylene group as defined above and having 1 to 12 carbon atoms.
• -(C 3 -C ⁇ 2 arylene or heteroarylene)- means that the arylene has 6 to 12 carbon atoms (e.g., phenylene, naphtylene, and the like) and heteroaryl ene groups have 3 to 12 carbons atoms and additionally contain one to three heteroatoms including, but not limited to, heteroatoms such as N, O, P, or S, within the ring (e.g., 2,6-pyridylene, 2,4-pyridinylene, 1 ,2-quinolinylene, 1,8- quinolinylene, 1 ,4-benzofi ⁇ ranylene, 2,5-pyridylene, 2,5-indolenyl, and the like) in accordance with the definition of the heteroaryl ene above.
• heteroatoms such as N, O, P, or S
• Protecting group refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions.
• protecting groups can be found in Greene et al. (1991) Protective Groups in Organic Synthesis, 2nd Ed. (John Wiley & Sons, Inc., New York).
• Preferred amino protecting groups include, but are not limited to, benzyloxycarbonyl (CBz), t-butyl- oxycarbonyl (Boc), t-butyldimethylsilyl (TBDIMS), 9-fluorenylmethyl-oxycarbonyl (Fmoc), or suitable photolabile protecting groups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, dimethyl dimethoxybenzil, 5-bromo-7-nitroindolinyl, and the like.
• Preferred hydroxyl protecting groups include Fmoc, TBDIMS, photolabile protecting groups (such as nitroveratryl oxymethyl ether (Nvom)), Mom (methoxy methyl ether), and Mem (methoxy ethoxy methyl ether).
• Particularly preferred protecting groups include NPEOC (4-nitrophenethyloxycarbonyl) and NPEOM (4-nitrophenethyloxy- methyloxycarbonyl).
• “Inhibitor” refers to a compound that interferes with the interaction between a target and its respective substrate(s) or endogenous ligand(s).
• Target molecules include, but are not limited to, enzymes and receptors.
• Enzyme inhibitors have been extensively studied from kinetic and mechanistic standpoints; see, e.g., Fersht, A., Enzyme Structure and Mechanism, 2nd Ed., New York, W.H. Freeman, 1985.
• a useful measure of the effectiveness of a compound at inhibiting enzyme catalysis is the IC 50 of that compound.
• Useful inhibitors have an IC 50 equal to or less than about 10 TM, preferably equal to or less than about 1 TM. More preferably, the inhibitor has an IC 50 equal to or less than about 100 nM, still more preferably equal to or less than about 10 nM, even more preferably equal to or less than about lnM.
• inhibitors have an IC 50 equal to or less than about 100 pM, or equal to or less than about 10 pM.
• a selective inhibitor refers to an inhibitor that will inhibit the activity of one macromolecule, typically an enzyme, while exhibiting little or no inhibitory effect on another macromolecule, typically another enzyme.
• the compounds of the invention are particularly useful in that they display selective inhibition of peptidyl deformylase while exhibiting much lower inhibitory activity towards metalloproteinases such as matrilysin.
• the selectivity of an enzyme inhibitor can be indicated by dividing the IC 50 of the compound for the enzyme which is not intended to be inhibited, by the IC 50 of the compound for the enzyme which is intended to be inhibited.
• a compound has an IC 50 for matrilysin of 1 ⁇ M, and an IC 50 for peptidyl deformylase of 0.01 ⁇ M, the compound displays a 100-fold (or 100 times) selectivity for peptidyl deformylase over matrilysin, or alternatively is said to be 100 times more selective for peptidyl deformylase compared to matrilysin.
• Useful compounds display a selectivity of greater than or equal to about 10 times, preferably greater than or equal to about 100 times, more preferably greater than or equal to about 1000 times, still more preferably greater than or equal to about 10,000, for peptidyl deformylase over one or more other metalloproteinases, for example for peptidyl deformylase over matrilysin.
• the compounds of the invention are intended for use in eukaryotic animals.
• the animal is a vertebrate; more preferably, the animal is a mammal; most preferably, the animal is a human.
• isomers Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
• stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
• enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
• An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
• a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
• the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
• R 6 substituent in a compound of Formula (I) is 2-hydroxyethyl
• the carbon to which the hydroxy group is attached is an asymmetric center and therefore the compound of Formula (I) can exist as an (R)- or (S)-stereoisomer.
• the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
• a “pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
• a “pharmaceutically acceptable excipient” as used in the specification and claims includes both one and more than one such excipient.
• a “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
• Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesul
• a compound of Formula (I) may act as a pro-drug.
• Prodrug means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject.
• Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound.
• Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
• prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylamino-carbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
• esters e.g., acetate, formate, and benzoate derivatives
• carbamates e.g., N,N-dimethylamino-carbonyl
• Treatment includes:
• a “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
• the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
• a preferred group of compounds is that wherein Ri is hydrogen or hydroxy, preferably hydroxy.
• the stereochemistry at the carbon carrying the Ri group is (R) or (S).
• Ri is halo; preferably chloro or fluoro; more preferably fluoro.
• the stereochemistry at the carbon carrying the Ri group is (R) or (S), preferably (S) when Rj is fluoro.
• R 3 is hydrogen or R ⁇ where Rn is -C ⁇ -C ⁇ alkyl or -(C ⁇ -C 8 alkylene) n7 -(C 3 -C ⁇ 2 aryl or heteroaryl), preferably methyl, ethyl, n-propyl, wo-propyl, w-butyl, iso-buty ⁇ , tert-butyl, w-pentyl, zY-pentyl, ⁇ e ⁇ -pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4-dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl.
• the stereochemistry at the carbon carrying the R 3 group is (R) or (S), preferably (R).
• R 7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1 , 1 -dimethylpropylaminocarbonyl, 2-(cyclohexen- 1 -yl)- ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2-ylamino- carbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl-aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4-ylmethylamino- carbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxy-phenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3- phenylamin
• R 7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol- 2-ylaminocarbonyl.
• R is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl or thiazol-2-ylaminocarbonyl.
• the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R group is either (R) or (S), preferably (S); or
• R 14 is hydrogen, -(C ⁇ -C 12 ) alkyl, substituted alkyl, or heteroalkyl, -(C ⁇ -C] 2 ) alkenyl, substituted alkenyl, or heteroalkenyl, -(C]-C ⁇ ) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(C C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n ⁇ 0 where n9 and nlO are independently 0 or 1.
• R 7 is hydrogen or -(
• R 2 is hydrogen or -R 9 where R 9 is as defined above;
• a preferred group of compounds is that wherein Ri is hydrogen or hydroxy and the stereochemistry at the carbon carrying the Ri group is (R) or (S), preferably (S).
• R 3 is hydrogen or R where R 9 is -C ⁇ -C ⁇ 2 alkyl or -(C ⁇ -C 8 alkylene) n7 -(C 3 -C ⁇ 2 aryl or heteroaryl) where n7, preferably methyl, ethyl, n-propyl, wo-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4- dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl.
• the stereochemistry at the carbon carrying the R 3 group is (R) or (S), preferably (R).
• n 1 or 2, preferably 1 ; and R 7 is:
• R ]4 and R 15 are independently selected from the group consisting of hydrogen, -(C ⁇ -C ⁇ 2 ) alkyl, substituted alkyl, or heteroalkyl, -(Ci- C ⁇ 2 ) alkenyl, substituted alkenyl, or heteroalkenyl, -(C ⁇ -C ⁇ 2 ) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and -(C ⁇ -C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or hetero arylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n 10 where n9 and nlO are independently 0 or 1.
• R 7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1 , 1 -dimethylpropylaminocarbonyl, 2-(cyclohexen- 1 -yl)- ethylaminocarbonyl, indan-5 -ylaminocarbonyl, 4,5-dimethylthiazol-2-ylamino- carbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethylaminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3 -ylaminocarbonyl, pyridin-4-ylmethyl- aminocarbonyl, 3,4-methylenedioxyphenylaminocarbonyl, quinolin-3- ylaminocarbonyl, methylaminocarbonyl, 4-biphenylaminocarbonyl, 3 -phenoxyphenylaminocarbonyl, 3 -phen
• R 7 is ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2- ylaminocarbonyl, or thiazol-2 -ylaminocarbonyl. More particularly, R 7 is phenylaminocarbonyl or pyrimidin-2-ylaminocarbonyl.
• the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R 7 group is either (R) or (S), preferably (S); or
• Rj 4 is hydrogen, -(C ⁇ -C ⁇ 2 ) alkyl, substituted alkyl, or heteroalkyl, -(C ⁇ -C ⁇ 2 ) alkenyl, substituted alkenyl, or heteroalkenyl, -(C ⁇ -C 12 ) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(C ⁇ -C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ! -C 8 alkyl or substituted alkyl) nl o where n9 and nlO are independently 0 or 1.
• the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R 7 group is either (R) or (S), preferably (S).
• R 2 is -H or -R 9 where R 9 is as defined above;
• R ⁇ 2 is selected from the group consisting of-C]-C ⁇ 2 alkylene, substituted alkylene, or heteroalkylene, -C ⁇ -C ⁇ 2 alkenylene, substituted alkenylene, or heteroalkenylene, -C ⁇ -C ⁇ 2 alkynylene, substituted alkynylene, or heteroalkynylene, and -(C ⁇ -C 8 alkylene or substituted alkylene) n5 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n6 where n5 and n6 are independently 0 or 1 ; and Ri 1, R ⁇ a , and R ⁇ are independently selected from the group consisting of -C ⁇ -C ⁇ 2 alkyl, substituted alkyl, or heteroalkyl, -C)-C ⁇ 2 alkenyl, substituted alkyn
• R 1 ⁇ is hydrogen or -Ri 1 where Ri 1 is as defined above;
• a preferred group of compounds is that wherein Ri is hydroxy and the stereochemistry at the carbon carrying the Ri group is (R) or (S), preferably (S).
• R 2 is hydrogen.
• R 3 is hydrogen or R where R is -C 1 -C 12 alkyl or -(C ⁇ -C 8 alkylene) n5 -(C -C ⁇ 2 aryl or heteroaryl) where n5 is 0 or 1, preferably methyl, ethyl, n-propyl, w ⁇ -propyl, n-butyl, iso-bulyl, tert-butyl, n-pentyl, zso-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4- dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl.
• the stereochemistry at the carbon carrying the R 3 group is (R) or
• R is selected from the group consisting of -(Ci- C ⁇ 2 ) alkyl, substituted alkyl, or heteroalkyl, -(C ⁇ -C] 2 ) alkenyl, substituted alkenyl, or heteroalkenyl, -(C ⁇ -C ⁇ 2 ) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, and - (C ⁇ -C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n 10 where n9 and nlO are independently 0 or 1.
• R 7 is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1 , 1 -dimethylpropylaminocarbonyl, 2-(cyclohexen- 1 -yl)- ethylaminocarbonyl, indan- 5 -ylaminocarbonyl, 4,5-dimethylthiazol-2- ylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl- aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4- ylmefhylaminocarbonyl, morpholin-4-ylcarbonyl, 3,4-methylenedioxy- phenylaminocarbonyl, quinolin-3-ylaminocarbonyl, methylaminocarbonyl, 4- biphenylaminocarbonyl,
• R 7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-yl- aminocarbonyl, or thiazol-2-ylaminocarbonyl.
• R 7 is phenylaminocarbonyl or pyrimidin-2-ylamino- carbonyl.
• the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R 7 group is either (R) or (S), preferably (S); or
• the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R 7 group is either (R) or (S), preferably (S).
• Ri is -OH, -OR , -SH or -SR 9 wherein R is selected from the group consisting of -C 1 -C 12 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) nl -(C -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n2 where nl and n2 are independently O or 1;
• R 2 is hydrogen;
• R 3 is -Rn, -OH, -OR, ⁇ , -R 12 OR 11 , -SH, -SRn, -NH 2 , -NHRn,
• Ri is -OH or -OR 9 .
• R 3 is -C ⁇ -C ⁇ 2 alkyl, such as C 4 alkyl and R 4 is H.
• R is -Rn where Rn is selected from the group consisting of -C ⁇ -C ⁇ 2 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C1-C 12 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n7 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n8 where n7 and n8 are independently 0 or 1; and
• R 3 is -(C ⁇ -C ⁇ 2 )alkyl, preferably n-butyl.
• R is -C(O)O-C ⁇ -C ⁇ 2 alkyl, such as -C(O)O-C i -C 4 alkyl, for example -C(O)O-tert-butyl.
• R 3 is -Rn where -Rn is selected from the group consisting of -C ⁇ -C ⁇ 2 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ alkenyl, substituted alkenyl, or heteroalkenyl, -C 1 -C 12 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n7 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n8 where n7 and n8 are independently 0 or 1 ;
• R 7 is -NH 2 , -NHR ⁇ 3 , or -NHR ⁇ 4 R ⁇ 5 where R ⁇ 3 , R ]4 and R 15 are independently selected from the group consisting of -C 1 -C 12 alkyl, substituted alkyl, or heteroalkyl, - C ⁇ -C ⁇ 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -C] 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(Cj-C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n ⁇ 0 where n9 and nlO are independently 0 or 1; or where R) 4 and R 15 combine to form a substituted or unsubstituted C 4 -C] 0 cyclic alkyl, cyclic heteroalkyl,
• R 3 is C ⁇ -C ⁇ 2 alkyl, preferably n-butyl. In another embodiment of this series of compounds, R is -NHR ⁇ 3 where R ⁇ is as defined above.
• R 3 is -Rn wherein Rn is selected from the group consisting of hydrogen
• n7 and n8 are independently 0 or 1 ;
• R 7a , R 7b , R 7c and R 7 a are independently selected from the group consisting of hydrogen, -C ⁇ -C 12 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n7 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n8 where n7 and n8 are independently 0 or 1 ;
• R 7a , R 7b , R 7c and R 7 a are independently selected from the group consisting of hydrogen, -C ⁇ -C 12 alkyl, substituted alkyl, or heteroalky
• R 3 is n-butyl.
• R 3 is -Rn where R is selected from the group consisting of hydrogen, -Ci- C 12 alkyl, substituted alkyl, or heteroalkyl, -C 1 -C 12 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n7 -(C 3 -C] 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n8 where n7 and n8 are independently 0 or 1 ; and
• R 7a is selected from the group consisting of hydrogen, -C ⁇ -C ⁇ 2 alkyl, substituted alkyl, or heteroalkyl, -C 1 -C 12 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n -(C 3 -C] 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) radical ⁇ 0 where n9 and nlO are independently 0 or 1; or a pharmaceutically acceptable salt thereof.
• R 7a is -CH 2 -R ⁇ j where R d is selected from the group consisting of H, -C 1 -C 12 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -Cj 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -Cn alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n ⁇ 0 where n9 and nlO are independently 0 or 1.
• R 3 is -Rn where Rn is selected from the group consisting of hydrogen, -Ci- C 12 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C ⁇ -C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n7 -(C -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n8 where n7 and n8 are independently 0 or 1 ; and
• R 7 is selected from the group consisting of-R ⁇ 4 or -OR ⁇ 4 where R ⁇ 4 is selected from the group consisting of -C 1 -C 12 alkyl, substituted alkyl, or heteroalkyl, - C 1 -C 12 alkenyl, substituted alkenyl, or heteroalkenyl, -C]-C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, and -(C ⁇ -C 8 alkyl or substituted alkyl) n9 -(C -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n ⁇ 0 where n9 and nlO are independently 0 or 1 ; or a pharmaceutically acceptable salt thereof.
• R is n-butyl.
• R 7 is -OCH 3 or -O-tert-butyl.
• R 3 is -Rn where Rn is hydrogen, -C ⁇ -C ⁇ 2 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ 2 alkenyl, substituted alkenyl, or heteroalkenyl, -C]-C ⁇ 2 alkynyl, substituted alkynyl, or heteroalkynyl, or -(C ⁇ -C 8 alkyl or substituted alkyl) n7 -(C 3 -C] 2 arylene or heteroaryl ene)-(C ⁇ -C 8 alkyl or substituted alkyl) n8 where n7 and n8 are independently 0 or 1 ; and 30a, R 30b , R 30C R30d, and R 30e are independently selected from the group consisting of hydrogen, -C1-C12 alkyl, substituted alkyl, or heteroalkyl, -C ⁇ -C ⁇ alkenyl, substituted alkenyl, or heteroalkenyl,
• Ri is halo
• a preferred group of compounds is that wherein the embodiments of (i) - (iii) defined below are employed either singularly or in any combination: (i) A preferred group of compounds is that wherein R t is fluoro.
• the stereochemistry at the carbon carrying the Ri group is (R) or (S), preferably (S).
• R 3 is hydrogen or R 9 where R 9 is -C ⁇ -C ⁇ 2 alkyl or -( -C 8 alkylene) n5 -(C 3 -C 12 aryl or heteroaryl) where n5 is 0 or 1, preferably methyl, ethyl, n-propyl, ts ⁇ -propyl, n-butyl, wo-butyl, tert-butyl, n-pentyl, wo-pentyl, neo-pentyl, n-hexyl, 2-, 3-, 4-, or 5-methylpentyl, 4,4- dimethylbutyl, benzyl, 3-phenylpropyl, 2-phenylethyl, or 4-phenylbutyl, more preferably n-butyl.
• the stereochemistry at the carbon carrying the R 3 group is (R) or (S), preferably (R); and (iii) R 7 is:
• R H and R ]5 are independently hydrogen, -(Ci- C 12 ) alkyl, substituted alkyl, or heteroalkyl, -(C 1 -C 12 ) alkenyl, substituted alkenyl, or heteroalkenyl, -(C ⁇ -C ⁇ 2 ) alkynyl, substituted alkynyl, or heteroalkynyl, alkoxy, or -(C ⁇ -C 8 alkyl or substituted alkyl) n9 -(C 3 -C ⁇ 2 arylene or heteroarylene)-(C ⁇ -C 8 alkyl or substituted alkyl) n 10 where n9 and nlO are independently 0 or 1 ; or Rj 4 and R ⁇ 5 combine to form a substituted or unsubstituted -(C 4 -C ⁇ o)cyclic alkyl, cyclic heteroalkyl, aryl or heteroaryl group
• R is n-butylaminocarbonyl, tert-butylaminocarbonyl, benzylaminocarbonyl, 1,1-dimethylprop ylaminocarbonyl, 2-(cyclohexen-l-yl)- ethylaminocarbonyl, indan-5-ylaminocarbonyl, 4,5-dimethylthiazol-2- ylaminocarbonyl, 4-phenoxyphenylaminocarbonyl, cyclopropylmethyl- aminocarbonyl, pyridin-2-ylaminocarbonyl, pyridin-3-ylaminocarbonyl, pyridin-4- ylmethylaminocarbonyl, mo ⁇ holin-4-ylcarbonyl, 3 ,4-methylenedioxy- phenylaminocarbonyl, quinolin-3 -ylaminocarbonyl, methylaminocarbonyl, 4- biphenylaminocarbonyl, 3 -phenoxy
• R 7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, pyrimidin-2-ylaminocarbonyl, or thiazol- 2-ylaminocarbonyl.
• R 7 is piperidin- 1 -ylcarbonyl, azetidin-1 -ylcarbonyl, ethylaminocarbonyl or thiazol-2-ylaminocarbonyl.
• the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R 7 group is either (R) or (S), preferably (S); or
• the stereochemistry at the C2 carbon atom of the pyrrolidine ring, i.e., carbon carrying the R 7 group is either (R) or (S), preferably (S).
• Preferred compounds of the Invention are:
• the starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co.,
• the starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
• a compound of Formula (I) where Ri, R , and R 4 are hydrogen, and R 3 , R ⁇ , R 7 , Y, and n are as defined in the Summary of the Invention can be prepared as described in Scheme A below.
• Amines of formula 2 are commercially available or they can be prepared by methods well known in the art.
• N, N-dialkylamines such as pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperidine, homopiperazine, proline tert-butyl ester, Z-proline-2-methylamide, (S)-(+)-2-(methoxymethyl)- pyrrolidine, Z-proline-N-methoxy-N-methylamide, (S)-2-(pyrrolidinylmethyl)- pyrrolidine, Z-proline-N-morpholineamide, -proline-NN-dimethylamide, homoproline methyl ester, E-homoproline tert-butylester, 3-(R)- tert-butoxy-L- proline-O- t-butyl ester, pipecolinic acid, 1, 2,3, 4-tetrahydroquino line, 1- hydroxyethylpiperazine, 2-hydroxye
• ⁇ , ⁇ -dialkylamines 2 such as 2-acetylaminomethylpyrrolidine can be prepared from N-5 ⁇ c-Z-prolinol as described in Example 16 below.
• trans-3-Acetoxy-Z, -proline O- tert-butyl ester can be prepared from Cbz protected trans-3-hydroxy-Z,-proline as described in Example 17 below which can then be converted to trans 3-hydroxy-Z- proline O-tert-butyl ester, if desired, by hydrolysis of the acetoxy group in trans-3- acetoxy- -proline O-tert-butyl ester as described in Example 17 below.
• Compound 3 can optionally be converted to a compound of formula 4 where prior to converting it to a compound of Formula (I). This would be desirable if certain group(s) in compound 3, e.g., R 3 , Re, and/or R 7 had to transformed to other group(s) within the scope of the invention prior to introducing the hydroxamate group in the molecule.
• a compound of formula 3 where Re or R 7 is a tert- butoxyamino group can be converted to a corresponding compound of formula 4 where R 6 or R 7 is an acetylamino group by first treating 3 with an acid such as diluted hydrochloric acid at ambient temperature to provide a corresponding compound of formula 3 where R or R 7 is an amino group, followed by treatment with an acetylating agent such as acetic anhydride in the present of an organic base such as pyridine.
• an acid such as diluted hydrochloric acid at ambient temperature
• an acetylating agent such as acetic anhydride
• a compound of formula 3 where R and ⁇ or R 7 is a hydroxy can be converted to a compound of formula 4 where R 6 and ⁇ or R is a sulfonamido group (i.e., - NHSO 2 R ⁇ 5 where R ⁇ 5 is as defined in the Summary of the Invention) by first converting the hydroxy group into amino group, followed by treatment with a sulfonylating agent.
• R 6 and ⁇ or R is a sulfonamido group
• a compound of formula 3 where R 6 and ⁇ or R 7 is a suitably protected carboxyl group can be converted to a compound of formula 4 where R 6 and ⁇ or R 7 is an aminocarbonyl group (i.e., -CONHRj 4 or -CONR ] R ⁇ 5 where R[ 4 and R ]5 is as defined in the Summary of the Invention) by first deprotecting the carboxy group and then treating with an amine of formula -NHR) 4 or -NR ⁇ 4 R ⁇ 5 (where R ⁇ 4 and R ⁇ 5 is as defined in the Summary of the Invention). Briefly, the reaction conditions for deprotecting of the carboxy group will depend on the nature of the protecting group.
• amination reaction is typically carried out in the presence of an inert, polar aprotic solvent (e.g. DMF, dioxane, etc.) with a non-nucleophilic base (e.g. triethylamine, diisopropylethylamine, etc.) and a coupling reagent (e.g. EDCI, PyBOP, DIC, etc.).
• an inert, polar aprotic solvent e.g. DMF, dioxane, etc.
• a non-nucleophilic base e.g. triethylamine, diisopropylethylamine, etc.
• a coupling reagent e.g. EDCI, PyBOP, DIC, etc.
• NHR t and NHR] 4 Ri 5 are available commercially, or can be readily prepared by methods well known in the art.
• methylamine, aniline, 2-aminothiazole, etc. are commercially available.
• Others can be prepared, for example, via reductive amination of an aldehyde, or Fukuyama alkylation of a suitable nitroaryl sulfonamide followed by cleavage of the sulfonamide to liberate the desired amine.
• Compound 3 or 4 is then converted to a hydroxamate compound of Formula (I) by treating it at 0 °C with aqueous 50 % hydroxylamine in a polar organic solvent such as dioxane and the like. After the reaction is complete the mixture is then purified by preparative reverse-phase (C18) HPLC to afford compound of Formula (I). If desirable, suitable O-protected hydroxylamine such as O-benzylhydroxyl- amine can also be used to give an O-protectedhydroxamate compound. Removal of the protecting group will provide a compound of Formula (I).
• a compound of Formula (I) can be converted to other compounds of Formula (I) by methods well known in the art. Some such methods are described below.
• Compounds of Formula (I) containing a hydroxy group may be prepared by de- alkylation/benzylation of an alkyloxy/benzyloxy substituent; and those containing an acid group, by hydrolysis of an ester group.
• a compound of Formula (I) having an alkenyl or alkynyl group can be prepared by reacting a corresponding compound of Formula (I) containing a bromine or iodine atom with trimethylsilylacetylene under the Castro-Stephens reaction conditions.
• a compound of Formula (I) containing an alkoxy group may be prepared by alkylation of hydroxy substituent.
• a compound of Formula (I) containing a carboxy group can be prepared by hydrolyzing an ester group in a corresponding compound of Formula (I) under acid hydrolysis reaction conditions.
• the resulting carboxy group can optionally be converted to an amido group, if desired, by first converting the carboxy group to an activated ester derivative e.g., treating the carboxy compound with dicyclohexyl carbodiimide, DEAD and the like, followed by treatment with an amine. It will be recognized by a person skilled in the art that some of these transformations can be carried out prior to converting the compound of formula 5 to a compound of Formula (I).
• R 3 X Treatment of dimethyl malate 5 under strongly basic conditions with an appropriate alkylhalide R 3 X (where R 3 is alkyl, alkenyl, alkynyl, substituted, heteroalkyl and X is halo such as chloro, bromo, or iodo) provides 2-substituted dimethyl malate 6.
• the reaction is typically carried out in a polar aprotic solvent such as THF, and the base is typically lithium diisopropylamide (LDA).
• LDA lithium diisopropylamide
• the reaction is initially carried out at a low temperature, preferably at about - 78 °C, and then allowed to slowly warm to room temperature. The reaction is then stirred for several hours. The reaction is typically higher yielding when R 3 X is an allylic halide.
• the resulting olefin can be reduced, if desired, to provide a compound of formula 6 where R 3 is alkyl.
• the typically reduction procedure involves a suspension of 6 and a catalyst (e.g., 10 % palladium on carbon) in a solvent such as ethylacetate and would be stirred under a hydrogen atmosphere for several hours to afford the corresponding compound of formula 6 where R 3 is alkyl.
• a catalyst e.g. 10 % palladium on carbon
• Many compounds of formula R 3 X are commercially available or they can be prepared by methods well known in the art. For example, iodomethane, benzylbromide, crotylbromide, allylbromide, vinylbromide are commercially available.
• Others can be prepared from the corresponding alcohol by first activating the hydroxy group as ap- toluenesulfonate ester (tosyl ester), followed by tosylate displaced with a halide ion in a modified Finkelstein procedure to afford an alkylhalide as described in working examples below.
• Treatment of 6 with a base affords a malic acid derivative of formula 7.
• the base can be an inorganic base such as lithium hydroxide or potassium hydroxide, and is most preferably sodium hydroxide. This reaction is usually performed in a polar, protic solvent such as methanol.
• an orthoester 8 (R a is -Ph and R b is -OMe).
• This reaction is ideally performed with a co-solvent, preferably in a mixture of toluene.
• the reaction is ideally performed at a higher temperature, most preferably at 110 °C.
• the catalyst is typically a sulfonic acid, such as/7-toluenesulfonic acid, or most preferably camphorsulfonic acid.
• Compound 10 is then optionally converted to a compound of formula 11 for reasons discussed in Scheme A such as derivatizing the R 3 , R and/or R 7 groups prior to converting it to a compound of Formula (I).
• compound 10 it can be directly converted to a compound of Formula (I) as described in Scheme A above.
• the hydroxy group in compound 10 can be replaced by various other Ri groups as defined in the Summary of the Invention prior to converting it to a compound of Formula (I).
• Some representative examples are discussed below: (i) the hydroxy group in compound 10 can be replaced by a fluoro group prior to converting it to a compound of Formula (I) as shown below.
• the hydroxyl group at the C2 carbon in compound 10 can be replaced by a fluoro group by first converting the hydroxyl group into an active ester followed by displaced with fluorine to afford compound 12.
• the reaction is performed in a halogenated solvent, such as dichloromethane (DCM), in the presence of an organic base, such as pyridine.
• DCM dichloromethane
• the alcohol is typically activated as a sulfonate ester, preferably the trifluoromethane-sulfonate. This esterification reaction is typically earned out at a low temperature, preferably about -20 °C.
• the active ester is then reacted with a fluoride ion, typically derived from tris(dimethylamino)sulfur- (trimethylsilyl)difluoride (TAS-F).
• a fluoride ion typically derived from tris(dimethylamino)sulfur- (trimethylsilyl)difluoride (TAS-F).
• TAS-F tris(dimethylamino)sulfur- (trimethylsilyl)difluoride
• the stereochemistry at the C2 carbon atom is inverted during this transformation, (ii) the hydroxy group in compound 10 can be converted to an alkoxy under alkylation reaction conditions such as treatment of 10 with an alkyl halide such as methyl iodide, ethyl iodide, benzyl bromide, and the like, in the presence of a strong base such as sodium hydride and in a polar solvent such as dimethylformamide.
• an alkyl halide such as methyl iodide, ethyl iodide, benzyl bromide, and the like
• the hydroxy group in compound 10 can be converted to benzoyloxy group by first converting it into an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate, followed by treatment with tetrabutyl ammomium benzoate.
• an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate
• the hydroxy group in compound 10 can be converted to thiol group by first converting it into an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate, followed by treatment potassium thioacetate.
• Example 48 Detailed description of this procedure is provided in Example 48 below.
• the hydroxy group in compound 10 can be converted to an azido or amino group or it's derivatives by first converting it into an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate, followed by treatment with sodium azide.
• an activated ester such as a sulfonate ester, preferably the trifluoromethanesulfonate
• the azide group can optionally reducted under catalytic hydrogenation reaction conditions to give an amino group which can be further derivatized by methods well known in the art. Detailed description of this procedure is provided in Example 49 and 34 below.
• the hydroxyl at the C-2 carbon of intermediate 10 is converted to an active ester as described above in (i) above.
• Nucleophilic substitution with a variety of nucleophiles such as acetate anion, or more preferably, tetrabutylammonium benzoate, provides intermediate 14. This reaction proceeds in a hydrocarbon solvent, preferably in toluene.
• a hydrocarbon solvent preferably in toluene.
• Compound 14 is treated with a base to afford hydroxy derivative 15.
• This base 0 is preferably the salt of an alcohol such as sodium methoxide, sodium ethoxide and the like, and more preferably sodium methoxide.
• the reaction proceeds in an alcoholic solvent such as methanol, ethanol and the like, most preferably in methanol.
• Compound 15 is re-activated as a sulfonate ester, preferably a trifluoromethane sulfonate as described above and then treated with a fluorination 5 reagent, preferably TAS-F, to afford the corresponding fluoro intermediate 16 which has the same stereochemistry at the C-2 carbon as in intermediate 10.
• a fluorination 5 reagent preferably TAS-F
• Compound 16 or 17 is then converted to a compound of Formula (I) as discussed above.
• a compound of Formula (I) can also be prepared as illustrated in Scheme C below.
• a compound of Formula (I) where Ri & R 2 are fluoro and R 2 , R 3 , Re, Ri, Y and n are as defined in summary of the invention can be prepared as illustrated in Scheme D below.
• Treatment of 22 with a base such as sodium methoxide in methanol provides 2-hydroxysuccinate derivative of formula 23.
• Compound 23 is then converted to a trifluoromethanesulfonate ester derivative 24 using triflic anhydride in the presence of a base such as triethyamine, pyridine and the like.
• compositions which comprise a bioactive hydroxamic acid compound or derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• compositions of the invention include those in a form adapted for oral, topical or parenteral use and can be used for the treatment of bacterial infection in animals, preferably mammals, more preferably humans.
• antibiotic compounds also referred to herein as antimicrobial compounds, according to the invention can be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.
• Such methods are known in the art (see, e.g., Remington's Pharmaceutical Sciences, Easton, PA: Mack Publishing Co.) and are not described in detail herein.
• compositions can be formulated for administration by any route known in the art, such as subdermal, inhalation, oral, topical or parenteral.
• the compositions can be in any form known in the art, including but not limited to tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
• the compounds can also be administered in liposome formulations.
• the compounds can also be administered as prodrugs, where the prodrug administered undergoes biotransformation in the treated mammal to a form which is biologically active.
• topical formulations of the present invention can be presented as, for instance, ointments, creams or lotions, solutions, salves, emulsions, plasters, eye ointments and eye or ear drops, impregnated dressings and aerosols, and can contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
• the formulations can also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
• Such carriers can be present, for example, from about 1% up to about 99% of the formulation. For example, they can form up to about 80% of the formulation.
• Tablets and capsules for oral administration can be in unit dose presentation form, and can contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, 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 can be coated according to methods well known in standard pharmaceutical practice.
• Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for reconstitution with water or another suitable vehicle before use.
• Such liquid preparations can contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.
• suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats
• emulsifying agents for example lecithin, sorbitan monooleate, or
• fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being prefened.
• the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle or other suitable solvent.
• the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
• agents such as a local anesthetic preservative and buffering agents can be dissolved in the vehicle.
• the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection can be supplied to reconstitute the liquid prior to use.
• Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration.
• the compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
• a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
• compositions can contain, for example, from about 0.1% by weight to about 99%o by weight, e.g., from about 10-60%> by weight, of the active material, depending on the method of administration.
• each unit will contain, for example, from about 1-500 mg of the active ingredient.
• the dosage as employed for adult human treatment will range, for example, from about 1 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to about 0.015 to 50 mg/kg per day.
• the dosage is, for example, from about 5 to 20 mg/kg per day.
• the hydroxamate compounds of the present invention can be used for the treatment or prevention of infectious disorders caused by a variety of bacterial or prokaryotic organisms.
• infectious disorders caused by a variety of bacterial or prokaryotic organisms.
• examples include Gram positive and Gram negative aerobic and anaerobic bacteria, including Staphylococci, for example S. aureus and S. epidermidis; Enterococci, for example E. faecalis and E. faecium; Streptococci, for example S pneumoniae; Haemophilus, for example H. influenza; Moraxella, for example M. catarrhalis; and Escherichia, for example E. coli.
• Other examples include Mycobacteria, for example M.
• compositions, for treating or preventing infectious disorders comprising a hydroxamic acid compound or derivative as disclosed herein in combination with a pharmaceutically acceptable carrier.
• a dosage amount of a hydroxamic acid compound or derivative as disclosed herein in an effective amount for the treatment, prevention or alleviation of a disorder, such as an infectious disorder can be screened for activity against different microbial agents and appropriate dosages can be determined using methods available in the art.
• the compounds can be used to treat a subject to treat, prevent, or reduce the severity of an infection.
• Subjects include animals, plants, blood products, cultures and surfaces such as those of medical or research equipment, such as glass, needles, surgical equipment and tubing, and objects intended for temporary or permanent implantation into an organism.
• Treating a subject includes, but is not limited to, preventing, reducing, or eliminating the clinical symptoms caused by an infection of a subject by a microorganism; preventing, reducing, or eliminating an infection of a subject by a microorganism; or preventing, reducing, or eliminating contamination of a subject by a microorganism.
• the microorganism involved is preferably a prokaryote, more preferably a bacterium.
• an infectious disorder in a subject such as a human or other animal subject
• methods of treating or preventing an infectious disorder in a subject are provided, by administering an effective amount of a hydroxamic acid compound or derivative as disclosed herein to the subject.
• the compound is administered in a pharmaceutically acceptable form optionally in a pharmaceutically acceptable carrier.
• infectious disorder is any disorder characterized by the presence of a microbial infection, such as the presence of bacteria.
• infectious disorders include, for example central nervous system infections, external ear infections, infections of the middle ear, such as acute otitis media, infections of the cranial sinuses, eye infections, infections of the oral cavity, such as infections of the teeth, gums and mucosa, upper respiratory tract infections, lower respiratory tract infections, genitourinary infections, gastrointestinal infections, gynecological infections, septicemia, bone and joint infections, skin and skin structure infections, bacterial endocarditis, burns, antibacterial prophylaxis of surgery, and antibacterial prophylaxis in immunosuppressed patients, such as patients receiving cancer chemotherapy, or organ transplant patients.
• the compounds and compositions comprising the compounds can be administered by routes such as topically, locally or systemically.
• Systemic application includes any method of introducing the compound into the tissues of the body, e.g., intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, nasal, vaginal, rectal, and oral administration.
• the specific dosage of antimicrobial to be administered, as well as the duration of treatment, can be adjusted as needed.
• the compounds of this invention can also be used to prepare a composition in an inert diluent which is useful in inhibiting bacterial growth.
• An "inert diluent" means an excipient that is useful in preparing a composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable.
• DIAD diisopropylazodicarboxylate
• Fmoc, FMOC 9-fluorenylmethyloxycarbonyl
• HATU O-(7-aza-benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
• HBTU O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
• HHMPA (4-hydroxymethyl-3-methoxyphenoxy)-alkanoic acid
• HMP resin hydroxymethylphenoxy resin
• HOAt 1 -hydroxy-7-azabenzotriazole
• HOBt 1 -hydroxybenzotriazole
• MeOH methanol
• MMP matrix metalloproteinase
• NMM N-methyl morpholine
• NPEOC 4-nitrophenethyloxycarbonyl
• NPEOM 4-nitrophenethylmethyloxycarbonyl
• NVOC 6-nitroveratryloxycarbonyl
• NVOM nitroveratryloxymethyl ether
• PS-PS resins or PS-PEG resin polyethylene glycol-polystyrene graft copolymer resins
• PFP-OTFA pentafluorophenyl trifluoroacetate
• PyBOP benzotriazole-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate
• PyBROP bromotripyrrolidinophosphonium hexafluorophosphate
• TBP tributylphosphate
• TGS resin TENTAGEL S resin
• TGS NH 2 resin TENTAGEL S NH 2 resin
• THF tetrahydrofuran
• THP 2-tetrahydropyranyl
• TM AD N,N,N',N'-tetramethylazodicarboxamide (1,1 '- Azobis(N,N- dimethylformamide))
• TMOF trimethylorthoformate
• TPP triphenyl phosphine
• TsCl tosyl chloride
• TsOH toluenesulfonic acid
• Trt trityl
• Step 2 To methyl-3-(i?)-butyl-3-(2-(S)-carboxycarbonylpyrrolidin- 1 -ylcarbonyl)- propionate E-2 (100 mg) in DMF (1 mL) was added an amine (1 equivalent), DIEA (2.5 equivalents) and HATU (1 equivalent) and the reaction stirred for 4 h. The solution was then cooled to 0 °C, 50 %> aqueous hydroxylamine was added (400 ⁇ L), and the reaction stined at 4 °C for 4 hours to 3 days, depending upon the succinate.
• Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (5 mmol) and the solution allowed to warm to rt.
• the reaction mixture was washed with aqueous sodium bicarbonate and brine, dried (Na 2 SO 4 ) and concentrated then purified on silica gel (ethylacetate/hexanes) to afford 2.3 mmol (45 %>) of methyl 3-(S)-n- butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl-carbonyl)-2-(/?)-fluoropropionate
• Step 2 To methyl 3-(i?)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl- carbonyl)-2-(i?)-benzoyloxypropionate H-2 (8.7 mmol) in methanol (25 mL) at 0 °C was added sodium methoxide (catalytic; pH adjusted to 10) and the solution stirred for 2 h.
• Step 3 To methyl 3-(i?)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl- carbonyl)-2-(i?)-hydroxypropionate H-3 (8.7 mmol) in DCM (10 mL) was added pyridine (25 mmol), the reaction was cooled to -20 °C, then triflic anhydride (12.5 mmol) was added. The solution was stirred for 1 hour, then worked up as described above. The intermediate triflate was resuspended in DCM and cooled to -50 °C.
• Tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TAS-F) was added (8.7 mmol) and the solution allowed to warm to rt.
• the reaction mixture was washed with aqueous sodium bicarbonate and brine, dried (Na 2 SO 4 ) and concentrated, then purified on silica gel (ethylacetate/hexanes) to afford 4.3 mmol (50 %>) of methyl 3- (S)-n-butyl-3-[2-(S)-tert-butoxycarbonylpyrrolidin-l-yl-carbonyl)-2-(S)- fluoropropionate H-4.
• N-Boc-(2-methylaminocarbonyl)pynolidine (3.3 g, 63%>).
• Step 2 N-Boc-(2-methylaminocarbonyl)pyrrolidine (3.3 g, 14.5 mmol) was treated with HCl (4 N in dioxane, 10 mL) for 1 h.
• Step 3 To mono t-butyl 2-(i?)-(n-butyl)-3-( ⁇ S)-methylsuccinic acid (680 mg, 1.39 mmol, prepared in step 2 above) in DCM (15 mL) was added L-proline methyl ester hydrochloride (3.34 mmol, 554 mg), DIEA (1.28 mL, 7.34 mmol) and then PyBOP (1.74 g, 3.34 mmol).
• the t-butyl group was removed from mono t-butyl 3-( ?)-(n-butyl)-3-[2-(S)- methoxycarbonyl)pyrrolidin-l -ylcarbonyl] -2-(S)-methylpropionate (260 mg, 732 ⁇ mol) using 1 :2 TFA/DCM, followed by evaporation of the TFA and solvent.
• Step 4 Phenylsulfonyl chloride (2 eq.) was added slowly to a solution of methyl 3- (i?)-(n-butyl)-3-[2-(S)-tert-butoxycarbonyl)-4-(S)-azido-pyrrolidin-l-ylcarbonyl]- propionate (ca. 0.1 g) in DCM (lmL) and pyridine (0.1 mL) at 0 °C. The solution was allowed to warm to rt and then stined an additional 2 h. The solvent was removed in vacuo, the residue dissolved in EtOAc (5 mL) and washed with HCl solution (5%), NaHCO 3 (sat.) and brine.
• Step 1 To l-(2,2-dimethyl-4-oxo-l,3-dioxolan-5-yl)-l-(2-(S)-tert- butoxycarbonylpyrrolidin-l-ylcarbonyl)pentane (4 mmol; prepared as described previously using, tert-butyl ester of compound F-6, General Procedure F) in methanol
• TPP triphenylphosphine
• DIAD diisopropylazodicarboxylate
• Methyl 3-(i?)-(n-butyl)-3-[(2-(S)-(tert-butoxycarbonyl)pyrrolidin- 1 -ylcarbonyl] -2-(i?)-benzoyloxypropionate (prepared as described in Example 37) was de- O-benzoylated by treatment with methanolic sodium methoxide at 0°C for 2 hours.
• Step 2 To methyl 3-(i?)-(n-butyl)-3-[(2-(S)-(carboxy)pynolidin-l-yl- carbonyl]propionate (0.2 mmol) in dioxane (1 mL) was added 2-(l-cyclohexenyl)- ethyl amine (0.22 mmol), DIEA (0.22 mmol) and HATU (0.22 mmol) and the reaction stined for 2 h. Aqueous 50 %> hydroxylamine was then added (1 mL), and the reaction stined an additional 24 h. The reaction mixture was purified by preparative reverse-phase (C18) HPLC to afford the title compound. MS (APCI) m/z 394 [M+H].
• reaction was stined for 16 h, then diluted with ethylacetate, washed with water, saturated aqueous sodium bicarbonate, and brine, then dried ( ⁇ a 2 SO 4 ) and puriifed on silica gel (ethylacetate/hexanes) to afford methyl 3-(#)-(n-butyl)-3-[(2-(S)-(tert- butoxycarbonyl)-pynolidin-l-ylcarbonyl]-2-(R)-azidopropionate.

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