Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
  • C07D235/14—Radicals substituted by nitrogen 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
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
  • A61P33/06—Antimalarials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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
  • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • 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
  • C07D409/06—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 carbon chain containing only aliphatic carbon atoms

Definitions

• the present invention relates to novel enzyme inhibitors, more specifically to inhibitors of polypeptide deformylase useful in the treatment/prevention of infections and other diseases in which polypeptide deformylases are involved, especially in the treatment of bacterial and parasitic infections. More specifically the invention relates to benzimidazoles capable of inhibiting bacterial peptide deformylase, also known as PDF, an enzyme that catalyzes the deformylation of formyl-L-methionyl peptides.
• PDF BACKGROUND OF THE INVENTION Peptide deformylase (EC 3.4.1.88), also known as PDF, is an enzyme that catalyzes the deformylation of formyl-L-methionyl peptides.
• PDF removes the formyl group from the ⁇ /-terminal Met of newly synthesized proteins, i.e. catalyzes the conversion of formyl-L-methionyl peptide to methionyl peptide (Adams and Capecchi, 1966; Adams, 1968).
• PDF is essential to bacteria, and bacterial peptide deformylase (PDF) is now widely recognised as an attractive target for antibacterial chemotherapy (Giglione et. al., 2000; Giglione and Meinnel, 2001 ; Pei 2001 ; Yuan et al., 2001 ; Clements et. al., 2002).
• Deformylation is a crucial step in bacterial protein biosynthesis and PDF is an essential ingredient in bacterial growth, with the gene encoding PDF present in all sequenced pathogenic bacterial genomes.
• WO 02/41886A1 discloses hydroxamic acid or N-formyl hydroxylamine derivatives as inhibitors of bacterial polypeptide deformylase. Novel antibacterial compounds are urgently needed due to the growing resistance exhibited by both Gram-negative and Gram-positive bacteria and other microorganisms. Traditional antibiotics have targeted pathways unique to bacterial replication and maintenance. However, new pathways are not being targeted in a manner that outpaces the growth of bacterial resistance. Thus, novel compounds and strategies are greatly needed that can be used to eradicate resistant bacteria.
• the present invention relates to compounds of the general formula (I)
• R ⁇ R 2 , R 3 , and X are as defined in the detailed part of this description.
• the compounds of the invention are useful for the treatment of infections caused by bacteria or parasites. It is especially contemplated that the compounds of the present invention are useful for the treatment of infections fully or partly caused by Gram-positive or Gram-negative bacteria such as Escherichia coli and Staphylococcus aureus or by a parasite such as Plasmodium falciparum.
• peptide deformylase or "PDF” as used herein is intended to mean peptide deformylase (EC 3.4.1.88) also known as PDF, which catalyzes the conversion of the N-terminal formyl-L-methionyl peptide to methionyl peptide in newly synthesized proteins.
• treatment is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or the complications, or alleviating the symptoms or the complications, or eliminating the disease, condition, or disorder.
• C 1-6 alkyl denotes a straight or branched, saturated hydrocarbon chain having from one to six carbon atoms.
• C 1-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, iso-hexyl, 4-methylpentyl, neopentyl, 2,2-dimethylpropyl and the like.
• C 2-6 alkenyl denotes a straight or branched, unsaturated hydrocarbon chain having from two to six carbon atoms and at least one double bond.
• C 2-6 alkenyl groups include, but are not limited to, vinyl, 1- propenyl, allyl, iso-propenyl, n-butenyl, n-pentenyl, n-hexenyl and the like.
• C ⁇ alkoxy in the present context designates a group -O-C 1-6 alkyl used alone or in combination, wherein C 1-6 alkyl is as defined above.
• linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
• branched alkoxy are iso-propoxy, sec-butoxy, tert-butoxy, iso-pentoxy and iso-hexoxy.
• cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
• C 3-10 cycloalkyl denotes a radical of one or more saturated mono-, bi-, tri- or spirocyclic hydrocarbon having from three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like.
• C 3-10 cycloalkane refers to a saturated cyclic hydrocarbon having from three to ten carbon atoms. Examples include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane and the like.
• C 3-7 heterocycloalkyl denotes a radical of a totally saturated heterocycle like a cyclic hydrocarbon containing one or more heteroatoms selected from nitrogen, oxygen and sulphur independently in the cycle.
• heterocycles include, but are not limited to, pyrrolidine (1-pyrrolidine, 2-pyrrolidine, 3- pyrrolidine, 4-pyrrolidine, 5-pyrrolidine), pyrazolidine (1-pyrazolidine, 2-pyrazolidine, 3- pyrazolidine, 4-pyrazolidine, 5-pyrazolidine), imidazolidine (1-imidazolidine, 2- imidazolidine, 3-imidazolidine, 4-imidazolidine, 5-imidazolidine), thiazolidine (2- thiazolidine, 3-thiazolidine, 4-thiazolidine, 5-thiazolidine), piperidine (1-piperidine, 2- piperidine, 3-piperidine, 4-piperidine, 5-piperidine, 6-piperidine), piperazine (1- piperaz
• C ⁇ -6 alkyl-C 3-1 ocycloalkyr refers to a cycloalkyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
• C 1 . 6 alkyl-C 3- heterocycloalky refers to a heterocycloalkyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
• aryl as used herein is intended to include carbocyclic aromatic ring systems. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated below.
• heteroaryl as used herein includes heterocyclic unsaturated ring systems containing one or more heteroatoms selected among nitrogen, oxygen and sulphur, such as furyl, thienyl, pyrrolyl, and is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.
• aryl and “heteroaryl” include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N- hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), phenanthrenyl, fluorenyl, pentalenyl, azulenyl, biphenylenyl, thiophenyl (1 -thienyl, 2- thienyl), furyl (1-furyl, 2-furyl), furanyl, thiophenyl, isoxazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, pyranyl, pyridazinyl, pyraziny
• Non-limiting examples of partially hydrogenated derivatives are 1 ,2,3,4- tetrahydronaphthyl, 1 ,4-dihydronaphthyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
• C 1-6 alkylaryl refers to an aryl group as defined above attached through a C 1-6 alkyl group as defined above having one, two, three, four, five or six carbon atoms; it is to be understood that the term includes unsubstituted or substituted C 1-6 alkylaryl.
• C ⁇ -6 alkylheteroaryl refers to a heteroaryl group as defined above attached through a C-i -6 alkyl group as defined above having one, two, three, four, five or six carbon atoms; it is to be understood that the term includes unsubstituted or substituted C 1-6 alkylheteroaryl.
• thioC 1-6 -alkyl in the present context designates a group -S-C 1-6 -alkyl, wherein C 1-6 -alkyl is as defined above.
• Representative examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, butylthio, isobutylthio, sec- butylthio, tert-butylthio, n-pentylthio, isopentylthio, neopentylthio, tert-pentylthio, n- hexylthio, isohexylthio and the like.
• C ⁇ -6 alkylthio-C 1-6 alkyl in the present context designates a group -C 1-6 alkyl- S- C 1-6 alkyl, wherein C 1-6 -alkyl is as defined above.
• Representative examples include, but are not limited to, methylthio methyl, ethylthio methyl (i.e.
• n- propylthio methyl isopropylthio methyl, butylthio methyl, isobutylthio methyl, sec- butylthio methyl, tert-butylthio methyl, n-pentylthio methyl, isopentylthio methyl, neopentylthio methyl, tert-pentylthio methyl, methylthio ethyl, methylthio propyl, methylthio isopropyl, methylthio butyl, methylthio isobutyl, methylthio pentyl, methylthio isopentyl, methylthio hexyl, methylthio isohexyl and the like.
• C 1-6 -alkylmercapto in the present context designates a group -C 1-6 -alkyl-SH, wherein C ⁇ -6 -alkyl is as defined above.
• Representative examples include, but are not limited to mercapto methyl (i.e.
• C 1-6 -alkylhydroxy in the present context designates a group -C 1-6 -alkyl-OH wherein C ⁇ -6 -alkyl is as defined above.
• Representative examples include, but are not limited to, methylhydroxy (i.e. -CH 2 -OH), ethylhydroxy, n-propylhydroxy, isopropylhydroxy, butylhydroxy, isobutylhydroxy, sec-butylhydroxy, tert-butylhydroxy, n- pentylhydroxy, isopentylhydroxy, neopentylhydroxy, tert-pentylhydroxy, n-hexylhydroxy, isohexyl hydroxy and the like.
• C 1-6 alkylcarboxy in the present context designates a group -C 1-6 -alkyl- COOH wherein C 1-6 -alkyl is as defined above.
• Representative examples include, but are not limited to, carboxymethyl (i.e. -CH 2 -COOH), carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, carboxyhexyl and the like
• C 1-6 alkylamide in the present context designates a group -C 1-6 alkyl-CONH 2 , wherein C 1-6 -alkyl is as defined above.
• Representative examples include, but are not limited to, carbamoylmethyl (i.e. -CH 2 -CONH 2 ), carbamoylethyl, carbamoylpropyl, carbamoylbutyl, carbamoylpentyl, carbamoylhexyl and the like.
• C ⁇ -6 -alkylamino in the present context designates a group -C 1-6 -alkyl-NH 2 wherein C -6 -alkyl is as defined above.
• Representative examples include, but are not limited to, methylamino (i.e.
• alkylamino-C 1-6 -alkyl in the present context designates a group -C 1-6 -alkyl- NH-C 1-6 -alkyl wherein C 1-6 -alkyl is as defined above.
• Representative examples include, but are not limited to, methylamino methyl, ethylamino methyl (i.e -CH 2 -NH-C 2 H 5 ), n- propylamino methyl, isopropylamino methyl, butylamino methyl, isobutylamino methyl, sec-butylamino methyl, tert-butylamino methyl, n-pentylamino methyl, isopentylamino methyl, neopentylamino methyl, tert-pentylamino methyl, n-hexylamino methyl, isohexylamino methyl, methylamino ethyl, methylamino propyl, methylamino isopropyl, methylamino butyl, methylamino isobutyl, methylamino pentyl, methylamino isopentyl, methylamino
• dialkylamino-C 1-6 -alkyl in the present context designates a group (C 1-6 - alkyl) 2 -N-C 1-6 -alkyl wherein C 1-6 -alkyl is as defined above.
• Representative examples include, but are not limited to, dimethylamino methyl, diethylamino methyl (i.e.
• Representative examples include, but are not limited to, methylamidine, ethylamidine, propylamidine, butylamidine, pentylamidine, hexylamidine and the like.
• Representative examples include, but are not limited to, 1-methylguanidine, 1-ethylguanidine,
• Halogen designates an atom selected from the group consisting of F, CI, Br and I.
• unsubstituted or substituted as used herein means that the groups in question are optionally unsubstituted or substituted with one, two or three substituents independently of each other selected from halogen, hydroxy, amino, mercapto, nitro, cyano, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, C 1-6 alkyl, C 1-6 alkoxy, thioC-,. 6 alkyl, C 1-6 alkylamino, alkylamino-C 1-6 alkyl and dialkylamino-C 1-6 alkyl.
• substituents may be the same or different.
• amino acid refers to the D- or L- isomers of the more than 20 standard amino acid residues including alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gin), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (lie), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), praline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr) and valine (Val).
• amino acid is a monomer containing an amino group and a carboxyl group that can be polymerized to form peptide and protein chains.
• peptide/protein-forming amino acids have the amino and carboxyl groups attached to the same carbon atom (the alpha carbon) and are designated alpha amino acids.
• side chain of an alpha amino acid denotes the substituent on the alpha carbon.
• Variable substituents generate different amino acids with different chemical properties.
• An amino acid residue is the portion of the amino acid that remains after incorporation into a polypeptide chain. The residue includes the alpha- carbon and the nitrogen/carbonyl moieties.
• a functional group which can be converted to hydrogen in vivo is intended to include any group which upon administering the present compounds to the subjects in need thereof can be converted to hydrogen e.g. enzymatically or by the acidic environment in the stomach.
• Non-limiting examples of such groups are acyl, carbamoyl, monoalkylated carbamoyl, dialkylated carbamoyl, alkoxycarbonyl, alkoxyalkyl groups and the like such as C 1-6 -alkylcarbonyl, aroyl, C 1-6 - alkylcarbamoyl, di-C 1-6 alkyl-alkylcarbamoyl, C -6 -alkoxycarbonyl and C 1-6 -alkoxy-C 1-6 - alkyl.
• diseases and disorders related to peptide deformylase is intended to include any disease or disorder in which an effect, preferably an inhibiting effect, on peptide deformylase is beneficial, especially on the bacterial peptide deformylase.
• IC 50 denotes the concentration required for 50% inhibition of PDF in a binding assay.
• t-Bu refers to the tertiary butyl radical
• Boc refers to the t-butyloxycarbonyl radical
• Fmoc refers to the fluorenylmethoxycarbonyl radical
• Ph refers to the phenyl radical
• Cbz refers to the benzyloxycarbonyl radical.
• the present invention relates to compounds of the general formula (I) 20
• X is -CONHOH, -COOH, -OH, or -SH;
• Ri is selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkylmercapto, C 1-6 alkylthio-C 1-6 alkyl, C 1-6 alkylhydroxy, C 1-6 alkylcarboxy, C 1-6 alkylamide, C 1-6 alkylamino, alkylamino-C 1-6 alkyl, dialkylamino-C 1 .
• R 2 is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 3- ⁇ o cycloalkyl, C 1-6 alkyl-C 3- ⁇ o cycloalkyl, C 3-7 heterocycloalkyl, C 1-6 alkoxy, C ⁇ -6 alkylamino, C 1-6 alkylmercapto, C 1-6 alkylhydroxy, thioC 1-6 alkyl, alkylamino-C 1-6 alkyl, dial
• R 4 is selected from the group consisting of hydrogen and a side chain of a natural alpha amino acid
• R 5 is amino, hydroxy, C ⁇ -6 alkoxy or -NH-C 1-6 alkyl
• R 6 and R 7 are identical or different and are independently of each other selected from the group consisting of C 3-7 heterocycloalkyl, an unsubstituted or substituted C 1-6 alkyl- C 3-7 heterocycloalkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C 1-6 alkylaryl group and an unsubstituted or substituted C -6 alkylheteroaryl group; wherein a substituted group is substituted with one, two or three substituents independently selected from halogen, hydroxy, amino, mercapto, nitro, cyano, trifluoromethyl, C 1-6 alkyl, C 1-6 alkoxy, thioC 1-6 alkyl, C-i -6 alkylhydroxy, C 1-6 alkylamino, alkylamino-C 1-6 alkyl and dialkylamino-C 1-6 alkyl.
• X is -CONHOH or -COOH.
• X is-OH or -SH.
• R- is a side chain of a natural alpha amino acid such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine and valine, or alternatively, R ⁇ is selected from the group consisting of d -6 alkyl, C 3-10 cycloalkyl, d-e alkylmercapto, C 1-6 alkylthio-C 1-6 alkyl, C 1-6 alkylhydroxy, C 1-6 alkylcarboxy, C 1-6 alkylamide, C 1-6 alkylamino, alkylamino-C 1-6 alkyl, dialkylamino-d.
• a natural alpha amino acid such as alanine, arginine, asparagine, aspartic acid,
• R-i is ethyl, isobutyl, 2-(methylsulfanyl)ethyl, 4-aminobutyl, benzyl, 4- hydroxybenzyl, 2-phenylethyl and naphth-1-yl-methyl.
• R 2 is preferably selected from the group consisting of C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 alkyl-C 3-10 cycloalkyl, C 1-6 alkylamino, C 1-6 alkylhydroxy, an unsubstituted or substituted C 1-6 alkylaryl group and an unsubstituted or substituted C 1-6 alkylheteroaryl group, wherein a substituted group is substituted with one, two or three substituents independently selected from halogen, hydroxy, amino, mercapto, nitro, cyano, trifluoromethyl, C 1-6 alkyl, d -6 alkoxy and thioC 1-6 alkyl.
• R 2 is selected from the group consisting of ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclohexyl methyl, cyclohexylethyl, aminoethyl, aminopropyl, aminobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, an phenyl, fluorosubstituted phenyl, chlorosubstituted phenyl, benzyl, fluorosubstituted benzyl, chlorosubstituted benzyl, thiophenylethyl and furany I methyl.
• R 2 may be selected from butyl, cyclopropyl, cyclohexylmethyl, 2- aminoethyl, 2-hydroxyethyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2,6-difluorobenzyl, 2-thiophen-2-ylethyl or furan-2-ylmethyl.
• R 3 is -NHCH(R 4 )COR 5 , in which R 4 is hydrogen or a side chain of a natural alpha amino acid, such as a side chain of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine or valine, preferably R 4 is hydrogen; and R 5 is C -6 alkoxy, preferably methoxy, ethoxy, propoxy or butoxy.
• R 4 is hydrogen or a side chain of a natural alpha amino acid, such as a side chain of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, me
• R 3 is a group -NHR 7 , a group - NR 6 R 7 or a group -OR 7 , in which R 6 or R 7 is C 3-7 heterocycloalkyl or an unsubstituted or substituted C 1-6 alkyl-C 3-7 heterocycloalkyl group.
• R 6 or R 7 is an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, an unsubstituted or substituted C 1-6 alkylaryl group or an unsubstituted or substituted d -6 alkylheteroaryl group.
• Preferred compounds of the invention are:
• the compounds of the invention may exist as geometric isomers or optical isomers or stereoisomers as well as tautomers. Accordingly, the invention includes all geometric isomers and tautomers including mixtures and racemic mixtures of these and a pharmaceutically acceptable salt thereof, especially all R- and S- isomers.
• the compounds of the invention may also exist as solvent complexes as well as in different morphological forms.
• the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
• Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
• Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
• suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
• compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
• metal salts include lithium, sodium, potassium, magnesium salts and the like.
• ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
• pharmaceutically acceptable acid addition salts are the hydrates and solvent complexes, which the present compounds are able to form.
• the acid addition salts may be obtained as the direct products of compound synthesis.
• the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
• the compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention.
• the invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
• prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the Formula I.
• Prodrugs are any covalently bonded compounds, which release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
• Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
• both the cis (Z) and trans (E) isomers are within the scope of this invention.
• compounds may exist in tautomeric forms, such as keto- enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
• Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
• the invention also encompasses active metabolites of the present compounds.
• the present invention includes all complexes of the compounds of this invention.
• the meaning of any substituent at any one occurrence in Formula I or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.
• the compounds of Formula I exhibit in a bacterial PDF assay (see below) an IC 50 value of less than 500 /M, preferably less than 100 ⁇ M, more preferably less than 50 ⁇ M, even more preferably less than 1 ⁇ M, especially less than 500 nM, particularly 300 nM or less.
• the compounds of the present invention having the general Formula I may be prepared by the methods set forth in the scheme A and scheme B in 'Materials and Method' below.
• R 3 is -NHCH(R 4 )COR 5
• the aromatic core is coupled to the resin by standard procedures (step 1).
• Nucleophilic aromatic substitution by the proper amine affords the desired substituted aminonitrobenzoic acid bound to the resin (step 2).
• Reduction of the nitro functionality is achieved by using SnCI 2 in a suitable solvent like DMF (step 3).
• Amino acid coupling to the diaminobenzoic acid is achived by standard procedures (HATU, HOAt) to afford the desired product (step 4). Ring closure to produce the benzimidazole is obtained by heating the resin in neat acetic acid (step 5).
• the amino acid residue is deprotected by standard procedures, and coupling of the respective end functionality (CONHOH, COOH, OH or SH) is achieved by standard coupling procedures (TBTU, DIEA) (step 6). Finally the target molecule is cleaved off the resin by treatment with base (step 7).
• R 3 is -NHR 7 , -NR 6 R 7 or -OR
• Nucleophilic aromatic substitution by the proper amine affords the desired substituted aminonitrobenzoic acid ester (step 1 ).
• Reduction of the nitro functionality is achieved by using NaBH 4 /Cu(acac) 2 (step 2).
• Amino acid coupling to the diaminobenzoic acid ester is achived by standard procedures (HATU, HOAt) to afford the desired product (step 3). Ring closure to produce the benzimidazole is obtained by heating in neat acetic acid (step 4).
• the amino acid residue is deprotected by standard procedures, and coupling of the respective end functionality (CONHOH, COOH, OH or SH) is achieved by standard coupling procedures (TBTU, DIEA) (step 5).
• the corresponding primary amides are produced by aminolysis in NH 3 /MeOH (step 6).
• the corresponding esters or amides are produced by basic hydrolysis of the methylester and subsequent coupling of amines using standard procedure (TBTU, NEM) or esterification by coupling of alcohols using standard procedure (MSNT, Methylimidazole) (step 7).
• Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions, which may be acceptable.
• Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine.
• Cations such as Li + , Na + , K + , Ca ++ , Mg ++ and NH 4 + are specific examples of cations present in pharmaceutically acceptable salts.
• Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
• a pharmaceutical composition comprising, as an active ingredient, a compound of the present invention together with a pharmaceutically acceptable carrier or diluent.
• This composition may be in unit dosage form and may comprise from about 1 ⁇ g to about 1000 mg such as, e.g., from about 10 ⁇ g to about 500 mg, from about 0.05 to about 100 mg or from about 0.1 to about 50 mg, of the compound of the invention or a pharmaceutically acceptable salt or ester thereof.
• the composition of the invention may be used for oral, nasal, transdermal, pulmonal or parenteral administration. It is contemplated that the pharmaceutical composition of the invention is useful for treatment of bacterial and/or parasitic infections.
• the compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament.
• the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19.sup.th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.
• compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intrapehtoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
• compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.
• Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
• compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
• Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
• a typical oral dosage is in the range of from about 0.001 to about 50 mg/kg body weight per day, preferably from about 0.01 to about 30 mg/kg body weight per day, and more preferred from about 0.05 to about 20 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
• the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
• a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from about 1 ⁇ g to about 1000 mg such as, e.g., from about 10 ⁇ g to about 500 mg, 0.05 to about 500 mg, preferably from about 0.05 to about 100 mg, more preferably from about 0.1 to about 50 mg.
• parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
• typically doses are in the order of about half the dose employed for oral administration.
• the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
• One example is an acid addition salt of a compound having the utility of a free base.
• a compound of the Formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the Formula (I) with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids.
• Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
• solutions of the novel compounds of the Formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed.
• aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
• the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
• the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
• Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
• solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
• liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.
• the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
• the pharmaceutical compositions formed by combining the novel compounds of the Formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
• the formulations may conveniently be presented in unit dosage form by methods known in the art of
• Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. If a solid carrier is used for oral administration, the preparation may be tableted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
• a typical tablet which may be prepared by conventional tabletting techniques, may contain: Core: Active compound (free compound or salt) 5.0 mg Lactosum Ph. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg Amberlite 1.0 mg Magnesii stearas q.s. Coating: Hydroxypropyl methylcellulose approx. 9 mg Acylated monoglyceride approx. 0.9 mg
• the pharmaceutical composition of the invention may comprise the compound of the Formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.
• the compounds of Formula I are useful as protease inhibitors, particularly as inhibitors of metallo proteases, more particularly as inhibitors of peptide deformylase, even more particularly as inhibitors of bacterial peptide deformylase.
• the present invention provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds.
• the compounds of the present invention may be especially useful for the treatment or prevention of diseases caused by a variety of bacterial or prokaryotic organisms.
• examples include Gram-positive and Gram-negative aerobic and anaerobic bacteria such as, Staphylococci, for example S. aureus and S. epidermidis; Enterococci, for example E. faecium and E. faecalis; Streptococci, for example S. pneumoniae; Haemophilus, for example H. influenzae; Moraxella, for example M. catarrhalis Escherichia, for example E. coli; Mycobacteria, for example M. tuberculosis and M. ranae; Mycoplasma, for example M.
• pneumoniae Pseudomonas, for example P. aeruginosa; intercellular microbes, for example Chlamydia and Rickettsiae.
• Other examples include Klebsiella pneumoniae, Shigella flexneri, Salmonella typhimurium, Bordetella pertussis, Clostridia perfringens, Helicobacter pylori, Campylobacterjejuni, Legionella pneumophila and Neisseria gonorrhoeae. It is further contemplated that the compounds of the present invention are useful for the treatment of parasitic infections, for example infections caused by Plasmodium falciparum and the like.
• the present invention relates to a method for the treatment of ailments, the method comprising administering to a subject in need thereof an effective amount of a compound or a composition of this invention.
• an effective amount of a compound or a composition of this invention corresponds to an amount of active ingredient, i.e. active compound or a pharmaceutically acceptable salt or ester thereof, in the range of from about 1 ⁇ g to about 1000 mg such as, e.g., from about 10 ⁇ g to about 500 mg, from about 0.05 to about 100 mg or from about 0.1 to about 50 mg.
• the present invention relates to use of a compound of this invention for the preparation of a medicament, preferably a medicament for the treatment of infections caused by Gram-positive or Gram-negative aerobic or anaerobic bacteria, or by parasites.
• Klebsiella pneumoniae Shigella flexneri, Salmonella typhimurium, Bordetella pertussis, Clostridia perringens, Helicobacter pylori, Campylobacter jejuni, Legionella pneumophila and Neisseria gonorrhoeae.
• the compounds of the present invention are useful for the treatment of parasitic infections, for example infections caused by Plasmodium falciparum and the like.
• an intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients is most effective, although an intramuscular bone injection is also useful.
• the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit PDF.
• the compounds may be administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.
• the precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.
• the compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein.
• a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient.
• the oral dose would be about 0.5 to about 50 mg/kg. No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.
• the compounds of the present invention fully or partly inhibit bacterial PDF, and are thus useful for the treatment and/or prevention of a wide variety of conditions and disorders in which inhibition of PDF is beneficial.
• the present invention relates to a compound of the general Formula (I) or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for use as a pharmaceutical composition.
• the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the Formula (I) or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents.
• the starting materials used herein are commercially available or can be prepared according to procedures previously reported in the literature. Unless otherwise stated commercial starting materials were used without further purification. All solvents were HPLC grade. Anhydrous solvents were obtained by storing over 4 A activated molecular sieves. Synthetic methods to prepare the compounds of this invention might employ protective groups to mask a reactive functionality or minimize unwanted side reactions. Such protective groups are described generally in Green et al. (1999).
• Piperidine was obtained from Fluka (98%); 3-fluoro-4-nitrobenzoic acid was obtained from Aldrich (98%); SnCI 2 was obtained from Fluka (98%); succinic anhydride was obtained from Aldrich (97%); 3-mercaptopropionic acid was obtained from aldrich (98%); MaOMe was obtained from Aldrich (95%).
• Step 7 X CONHOH or COOH or OH or SH Scheme A Method A Step 1 :
• Resin Typically 5.0 g of Fmoc protected glycine linked to POEPOP 5 oo-resin (Renil et al. (1996)) (loading ⁇ 1.0 mmol/g) was swelled in DMF. Fmoc-deprotection was made by treatment with a 20% solution of piperidine in DMF. A solution of 4-fluoro-3- nitrobenzoic acid (15.0 mmol, 2.8 g, 3 eq.) was dissolved in DMF and activated with TBTU (14.0 mmol, 4.50 g, 2.8 eq) and NEM (20.0 mmol, 2.30 g, 4 eq). The acid was activated for 15 min prior to being added to the swelled resin. Reaction was run over night at room temperature. The resin was then rinsed with DMF (10 times), DCM (10 times) and finally MeCN (10 times). The resin was lyophilized.
• Step 5 The resin was washed with AcOH (3 times) and finally AcOH was added to the resin and warmed to 80 degrees C for 48h. The resin was then washed with DMF (10 times) and used directly in the next step.
• Step 6 The resin was treated with 20% piperidine in DMF for 30 min at room temperature and then rinsed with DMF (8 times).
• the desired benzimidazoles were cleaved off the resin by treatment of 0.1 M NaOMe in methanol. The products were collected and lyophilized. Analyses of the products were made by LC-MS (Liquid Chromatography-Mass Spectrometry).
• Step l
• step 1 The product from step 1 (typically 1 mmol) was dissolved in DCM/MeOH (50:50, typically 3 ml). In a separate MeOH solution (typically 20 ml) NaBH 4 (10 equiv.) and Cu(acac) 2 (0.6 equiv.). To the borohydride/Cu(acac) 2 solution was added the product from step 1. The reaction mixture was stirred at room temperature for 2h. The solvent was removed. Water was added and the aqueous solution was extracted with EtOAc. Drying and removal of the solvent yields the desired product used directly in the next step.
• MeOH solution typically 20 ml
• NaBH 4 10 equiv.
• Cu(acac) 2 0.6 equiv.
• step 3 The product from step 3 was dissolved in AcOH and warmed to 60C over night. The solvent was removed in vacuo and the product used directly in the next reaction step.
• Step 5 The product from step 4 was treated with 20% piperidine in DMF for 30 min at room temperature. The solvent was removed in vacuo, and was then alternatively treated with:
• step 5 The respective product from step 5 were dissolved in NH 3 /MeOH (7M) and stirred at room temp, over night. The solvent was removed in vacuo and the product purified by prep. HPLC.
• BIOLOGICAL ASSAYS The compounds of this invention may be tested in the following biological assay in order to determine the concentration of compound (IC 50 ) required for exhibiting the desired pharmacological effect.
• PDF Peptide Deformylase
• the IC 50 value of a compound of the invention as a bacterial PDF inhibitor was determined using the following assay.
• Assay buffer 0.1 M MOPS pH was adjusted to 7.2 with NaOH, containing 0.25 M NaCI, 100 ⁇ g/mL catalase and 1 mg/mL BSA.
• E.coli enzyme (2.5 mg/ml) 10 ⁇ l + 290 ⁇ l Assay buffer, 1 ⁇ l per ml enzyme mix.
• Substrate mix 10 mM f-Met-Ala was made up from 200 mM f-Met-Ala in methanol with assay buffer.
• TNBS solution Freshly dilute 1 M TNBS stock solution diluted 1 :10 with water.
• Buffer C 0.5 M borate buffer adjusted to pH 9.5 with NaOH.
• Buffer D 0.2 ml of freshly prepared 0.5 M Na 2 SO 3 was mixed with 9.8 mL of 0.5M NaH 2 PO 4 .
• Inhibitor solution 2 mM Sodium 4-(hydroxymercurio) benzoate in assay buffer.
• Compound mix Compound of formula I dissolved in DMSO in a 10 mg/mL stock solution. Further dilutions were made in DMSO in the concentration range between 0.05 to 100 mM.
• the assay was performed in a 96 Microtiter plate containing test compound. To each well containing test compound mix was added 75 microliter of enzyme mix from E. coli followed by the addition of 25 microliter of substrate mix. The resulting mix was incubated for 30 minutes at room temperature with shaking. TNBS solution (50 microliter/well) was added and the resulting mixture was incubated for 15 minutes under shaking. Buffer C was then added (20 microliter/well). After incubating at room temperature for 15 minutes under shaking, buffer D was added (50 microliter/well). The optical diffraction was then measured at 420 nm, thereby determining the IC 50 value.
• the assay was repeated using enzyme mix from S. aureus.
• the title compound was prepared according to Method A using 4-chlorobenzyl amine in step 2, phenylalanine acid in step 4 and S-trityl protected mercaptopropionic acid in step 6.
• IC 50 (microM): 22.1 (enzyme from E.coli) 6.1 (enzyme from S. aureus).
• IC 50 (microM): 12.9 (enzyme from E.coli) 1.6 (enzyme from S. aureus).
• IC 50 (microM): 2.6 (enzyme from E.coli) 2.7 (enzyme from S. aureus).
• IC 50 (microM): 5.6 (enzyme from E.coli) 0.023 (enzyme from S. aureus).
• IC 50 (microM): 4.8 (enzyme from E.coli) 0.068 (enzyme from S. aureus).
• IC 50 (microM): 3.3 (enzyme from E.coli) 4.0 (enzyme from S. aureus).
• IC S0 microM: 0.071 (enzyme from E.coli) 0.099 (enzyme from S. aureus).
• IC 50 > 200 (enzyme from E.coli) > 200 (enzyme from S. aureus).
• IC 50 (microM): 0.3 (enzyme from E.coli) 0.3 (enzyme from S. aureus).
• IC 50 (microM): 13.1 (enzyme from E.coli) 1.4 (enzyme from S. aureus).
• IC- 50 (microM): 35.2 (enzyme from E.coli) 25.0 (enzyme from S. aureus).
• the title compound was prepared according to Method A using aminoethanol in step 2, phenylalanine in step 4 and succinicacid anhydride in step 6.
• IC 50 (microM): 41.8 (enzyme from E.coli) 27.7 (enzyme from S. aureus).
• IC 50 > 200 (enzyme from E.coli) 34.4 (enzyme from S. aureus).
• the title compound was prepared according to Method A using cyclopropyl amine in step 2, alpha-aminobutyric acid in step 4 and O-trityl succinicacid hydroxamide in step 6.
• IC 50 (microM): 7.0 (enzyme from E.coli) 0.3 (enzyme from S. aureus).
• the title compound was prepared according to Method A using benzyl amine amine in step 2, alpha-aminobutyric acid in step 4 and O-trityl succinicacid hydroxamide in step 6.
• IC 50 (microM): 0.3 (enzyme from E.coli) 0.496 (enzyme from S. aureus).
• IC 50 (microM): 0.3 (enzyme from E.coli) 2.266 (enzyme from S. aureus).
• IC 50 (microM): 0.3 (enzyme from E.coli) 0.3 (enzyme from S. aureus).
• IC 50 (microM): 6.5 (enzyme from E.coli) 0.9 (enzyme from S. aureus).
• IC 5 o microM: 3.6 (enzyme from E.coli) 2.0 (enzyme from S. aureus).
• IC 50 (microM): 5.2 (enzyme from E.coli) 2.4 (enzyme from S. aureus).
• IC 5 o microM: 0.3 (enzyme from E.coli) 0.3 (enzyme from S. aureus).
• IC 50 (microM): 0.3 (enzyme from E.coli) 0.3 (enzyme from S. aureus).
• IC-5 0 microM: 0.3 (enzyme from E.coli) 0.3 (enzyme from S. aureus).
• IC 50 (microM): 0.3 (enzyme from E.coli) 0.3 (enzyme from S. aureus).
• Gennaro A. R.; Gennaro A. L. Remington, The Science and Practice of Pharmacy, 19th ed., Mack Publishing Co., Easton, Pa., 1995.

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