WO2002028829A2 - Inhibiteurs de peptide deformylase - Google Patents

Inhibiteurs de peptide deformylase Download PDF

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Publication number
WO2002028829A2
WO2002028829A2 PCT/US2001/029926 US0129926W WO0228829A2 WO 2002028829 A2 WO2002028829 A2 WO 2002028829A2 US 0129926 W US0129926 W US 0129926W WO 0228829 A2 WO0228829 A2 WO 0228829A2
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Prior art keywords
compound
phenyl
synthesis
formula
found
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PCT/US2001/029926
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English (en)
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WO2002028829A3 (fr
Inventor
Lee Chong
Roger Frechette
Carole Scott
Richard Tester
Whitney Smith
Katsumi Chiba
Masatoshi Sakamoto
Charles Gluchowski
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Questcor Pharmaceuticals, Inc.
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Priority to AU2002230385A priority Critical patent/AU2002230385A1/en
Publication of WO2002028829A2 publication Critical patent/WO2002028829A2/fr
Publication of WO2002028829A3 publication Critical patent/WO2002028829A3/fr

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • 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
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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    • 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
    • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • 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
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    • C07D295/182—Radicals derived from carboxylic acids
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    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
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Definitions

  • the present invention relates to a novel class of compounds, which inhibit peptide deformylase, pharmaceutical compositions containing compounds that inhibit peptide deformylase, and methods of treating various infections.
  • Staphylococcus aureus 15 bacterium Staphylococcus aureus, the most common cause of hospital-acquired infection.
  • penicillin killed bacteria led to the common use of penicillin during World War II in army hospitals. Soon after the debut of penicillin, strains of Staphylococcus aureus were isolated that were resistant to penicillin, hi fact, these resistant strains were commonly found in hospitals where penicillin was heavily used.
  • microorganisms is a manifestation of their short replication times and their ability to evolve in the face of the selective pressure exerted by antibiotics, hi order to survive, microorganisms have developed the ability to adapt quickly and effectively to changes in the environment such as changes in the light intensity, oxygen levels, acidity and exposure to antibiotics.
  • the emergence and spread of resistant bacteria is primarily caused by acquisition of drug resistance genes resulting in a broad spectrum of antibiotic resistance (e.g., extended-spectrum cephalosporin-resistant mutant beta-lactamases found in several bacterial organisms).
  • biochemical apparatus for the synthesis of polypeptides in bacteria and eukaryotes is strikingly different. It is preferable to have antimicrobial drugs that disrupt bacterial metabolism but that do not interfere with the host's metabolism. Antimicrobial drugs that interfere with the biochemical machinery of the host may cause the deleterious side effects associated with certain drugs. Thus, there is a need for antimicrobial drugs that specifically inhibit bacterial metabolism while not effecting eukaryotic biochemistry.
  • a significant difference between bacterial and eukaryotic protein synthesis is the use of formylated methionine as the first amino acid used during ribosome based synthesis of polypeptides.
  • eukaryotic protein biosynthesis is initiated with methionine whereas bacterial biosynthesis commences with ⁇ -formyl methionine.
  • Proper protein folding and function in bacteria usually occurs only after the ⁇ -formyl group is removed from the nascent polypeptide chain. This is accomplished by an enzyme called peptide deformylase (PDF).
  • PDF peptide deformylase
  • WO 99/59568 describes methods of using certain hydroxamic acid derivatives for antibacterial compositions. Large genera of compounds are disclosed yet only a few examples are given and the biological activities are not reported. It is not even know if the compounds disclosed therein are selective inhibitors of peptide deformylase.
  • R x is C r C 10 alkyl, aryl, heterocyclic, heteroalkyl or a substituted derivative thereof; R 2 and R 3 together with nitrogen represent a 4, 5, 6, or 7 membered heterocyclic ring optionally substituted with one of the following substituents -OH, -CH 2 OH,
  • R 3 is H, C r C 10 alkyl, aryl, heterocyclic, heteroalkyl or a substituted derivative thereof; or R 2 is methyl;
  • R 3 forms a ring with R 2 , or represents H, or is alkyl, heteroalkyl, aryl, heterocyclic, and substituted derivatives thereof;
  • R 3 when not in a ring with R 2 is alkyl, heteroalkyl, aryl, heterocyclic, and substituted derivatives thereof;
  • R 4 when not in a ring with R 2 is H, C r C 10 alkyl, aryl, heterocyclic, heteroalkyl or a substituted derivative thereof; or is together with R 2 and nitrogen as defined above to form a ring through a -CH 2 -CH 2 - linkage;
  • Rg is H, alkyl, heteroalkyl, heterocycyl, alkylaryl, alkylheterocyclic, or substituted derivatives thereof;
  • R 10 is H, alkyl, heteroalkyl, heterocycyl, alkylaryl, alkylheterocyclic, or substituted derivatives thereof.
  • antimicrobial drugs that are selective inhibitors of peptide deformylase are used to treat infection while reducing or avoiding deleterious side effects associated with therapeutic drugs that affect the host's biochemistry, h a preferred embodiment antimicrobial drugs of the invention are selective for peptide deformylase over other related enzymes such as angiotensin converting enzyme (ACE) thermolysm, collagenase and carboxypeptidase.
  • ACE angiotensin converting enzyme
  • Such selectivity minimizes the opportunity of adverse events associated with imbalances of these enzymes in the homostasis of tissue and organ functions affected by these metalloproteases.
  • a preferred embodiment of the invention involves the use of compounds or compositions of the invention therapeutically or prophylactically against bacteria that are resistant to other antibiotics such as ⁇ -lactam, quinolone and vancomycin resistant bacteria.
  • compounds of the invention may be used to treat contaminated or infected items, such as crops, wood, metal or plastic and the like, by methods such as, but not limited to, spraying or dusting of that agent onto the contaminated item, or impregnating that agent into the item.
  • compositions and therapies comprising a compound of the invention and a second antibacterial compound including antibiotics of the following groups consisting of, but not limited to, aminoglycosides, amphenicols, ansamycins, beta-lactams, cephalosporins, cephamycins, monolactams, oxacephems, penicillins, lincosamides, macrolides, polypeptide antibiotics, tetracyclines, 2,4-diaminopyrimidines, nitrofurans, quinolones, streptogramins, sulfonamides, sulfones, oxazolidinones and glycylcyclines.
  • antibiotics of the following groups consisting of, but not limited to, aminoglycosides, amphenicols, ansamycins, beta-lactams, cephalosporins, cephamycins, monolactams, oxacephems, penicillins, l
  • Z is NHOH or OR- j wherein Rg is H, alkyl or a biocleavable moiety;
  • Y is heteroalkyl, heterocyclic, or substituted derivatives thereof;
  • R j is C r C 10 alkyl, aryl, heterocyclic, heteroalkyl or a substituted derivative thereof;
  • R 3 forms a ring with R 2 , or represents H, or is alkyl, heteroalkyl, aryl, heterocyclic, and substituted derivatives thereof;
  • R 3 when not in a ring with R 2 is alkyl, heteroalkyl, aryl, heterocyclic, and substituted derivatives thereof;
  • R 4 when not in a ring with R 2 is H, C r C 10 alkyl, aryl, heterocyclic, heteroalkyl or a substituted derivative thereof; or is together with R 2 as defined above to form a ring through a -CH 2 -CH 2 - linkage.
  • Compounds of this subset may be represented Formulas X, XI, X ⁇ , and XIII.
  • Compounds of this set may be represented by Formula XV.
  • a subset of preferred compounds encompassed by Formula III is defined by Formulas XVI and XVII wherein R is selected from the group consisting of alkyl, heteroalkyl, aryl, heterocyclic, and substituted derivatives thereof. Compounds of this subset may be represented by Formulas XVI and XVII.
  • Compounds of this subset may be represented by Formula XVm.
  • a subset of preferred compounds encompassed by Formula IH is defined by Formula XXI, wherein M is 0 or 1, R is alkyl, the stereochemistry at the center indicated with * is R, or S, and Z is OH or NH-OH.
  • a subset of preferred compounds encompassed by Formula IV is defined by Formula XXII, wherein Rt, is selected from the group consisting of H, alkyl, heteroalkyl, aryl, heterocycyl, and alkylaryl; R 10 is selected from the group consisting of H, alkyl, heteroalkyl, aryl, heterocycle, and alkylaryl; and R n is selected from the group consisting of H, alkyl, heteroalkyl, aryl, heterocycle, and alkylaryl.
  • alkyl means a straight or branched chain alkyl moiety including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and isohexyl.
  • alkenyl means a straight or branched chain hydrocarbon moiety having one or more double bonds including, but not limited to, propene, 1-butene, 2-butene, iso-butene, 1-pentene, 2-pentene, iso-pentene, 1-hexene, 2-hexene, and 3-hexene.
  • cycloalkyl means a saturated alicyclic moiety having one or more fused ring systems with from 3-12 carbons including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • heteroalkyl means an optionally substituted alkyl chain containing one or more heteroatoms or their oxidized forms selected from nitrogen, sulfur, oxygen, or phosphorous.
  • heterocycle or “heterocyclic”, means a 5 to 7 member ring, either aromatic or non-aromatic, containing one or more heteroatoms selected from nitrogen, sulfur, and oxygen, and optionally substituted or fused to a benzene ring system examples, include but are not limited to, thiazolyl, imidazolyl, oxazolyl, indoyl, morpholinyl, pyridinyl, pyrrilidinyl, pyrimidinyl, thienyl, furyl, piperidinyl, and piperazinyl.
  • aryl refers to aromatic rings and substituted derivatives thereof including, but not limited to, phenyl and fused ring systems like napthyl.
  • biolabile or biocleavable moiety refers to a pharmaceutically acceptable, biologically degradable moiety or derivative of a compound of the invention, that is a prodrug which, upon administration to an animal or human being, is converted in the body to a compound of the invention.
  • biolabile or biocleavable moieties are particularly advantageous in providing compounds of the invention that are suitable for oral administration. The suitability of any particular biolabile or biocleavable group can be assessed by conventional in vivo animal or in vitro enzyme hydrolysis studies.
  • the IC 50 data is the concentration (nanomolar) of the compound that inhibits E coli peptide deformylase at 50%
  • the MIC data refers to the concentration of compound in micrograms per milliliters to achieve an inhibition of growth of a test organism such as E. coli.
  • stereocenter may be generated in racemic form, i.e., a mixture of R and S enantiomers or with the desired stereochemical orientation, i.e., the substantially or isolated R o ⁇ S enantiomer.
  • stereocenter may be generated in racemic form, i.e., a mixture of R and S enantiomers or with the desired c stereochemical orientation, i. e. , the substantially or isolated R S enantiomer.
  • stereocenter may be generated in racemic form, i.e., a mixture of R and S enantiomers or with the desired stereochemical orientation, i.e., the substantially or isolated R or S enantiomer.
  • stereochemistry at the 4-position of the thioproline ring is specified as the S enantiomer, one of ordinary skill in the art would readily recognize that the , , stereocenter may be generated in racemic form, i.e., a mixture of R and S enantiomers, or with the R stereochemical orientation.
  • stereocenter may be generated in racemic form, i.e., a mixture of R and S enantiomers or with the desired stereochemical orientation, i.e., the substantially or isolated R o ⁇ S enantiomer.
  • stereochemistry at the 2-position of the piperidine ring specified is as the S enantiomer
  • the stereocenter maybe generated in racemic form, i.e., a mixture of R and S enantiomers or as the R enantiomer.
  • stereocenter may be generated in racemic form, i.e., a mixture of R and S enantiomers or with the desired stereochemical orientation, i.e., the substantially or isolated R o ⁇ S enantiomer.
  • stereocenter may be generated in racemic form, i.e., a mixture of R and S enantiomers or with the desired stereochemical orientation, i.e., the substantially or isolated R o ⁇ S enantiomer.
  • the compounds of the invention have utility as agents effective against a variety of species of bacteria, including infectious pathogenic bacteria.
  • the invention also includes novel pharmaceutical compositions which comprise the compounds of the invention formulated in pharmaceutically acceptable formulations.
  • the invention features a method for treating a subject infected with an infectious agent by administering to that subject a therapeutically effective amount of a compound of the invention which causes PDF inhibition in the infectious agent as determined by the assays of the invention.
  • Veterinary uses are also included in this embodiment, as described below.
  • Such administration can be by any method known to those skilled in the art, for example, by topical application or by systemic administration. Additional antibacterial compounds may be adjunctively administered, as described below.
  • compounds of the invention can be used to treat contaminated or infected items, such as crops, wood, metal or plastic and the like, by methods such as, but not limited to, spraying or dusting of that agent onto the contaminated item, or impregnating that agent into the item.
  • terapéuticaally effective amount or “prophylactically effective” is meant an amount that relieves (to some extent) one or more symptoms of the disease or condition in the subject. Additionally, by “therapeutically effective amount” is meant an amount that returns to normal, either partially or completely, physiological or biochemical parameters associated with or causative of a bacterial disease or condition.
  • High through-put screens described in U.S. application number 09/449,419 filed November 29, 1999, which is incorporated by reference in its entirety, are used to determine the binding affinity of compounds to PDF in a novel assay that utilizes the enzyme's native iron metal center and the binding affinity to several other metalloproteases including thermolysm, carboxypeptidase, collagenase and angiotensin coverting enzyme.
  • the selectivity profile is then determined by calculating the ratio of the binding affinity of the inhibitor to: (1) peptide deformylase with it's native iron metal center and (2) other metalloproteases. It is preferred that compounds bind to PDF with a greater than or equal to 10-fold affinity relative to the other metalloproteases.
  • compoimds bind to PDF with a greater than or equal to 100-fold affinity relative to the other metalloproteases. In another embodiment, it is preferred that compoimds bind to PDF with a greater than or equal to 100-fold affinity relative to thermolysin and greater than or equal to 300-fold relative to carboxypeptidase, collagenase and angiotensin converting enzyme.
  • the screening methods of the invention are a substantial improvement over prior technologies in that: (1) the inhibition of peptide deformylase is determined using the enzyme's native iron catalytic metal center and (2) the risk of deleterious side effects can be minimized since the novel inhibitors identified by the means of the invention interact negligibly with important metalloproteases of the host's biochemical machinery.
  • the metalloproteases that are tested include thermolysin, carboxypeptidase, collagenase and angiotensin converting enzyme.
  • Initial high through-put assays are performed to determine the percent Fe-PDF inhibition at a particular concentration of test compound.
  • the concentration of test compound is typical between 1 ⁇ M - 5 mM. While the concentration may be varied, a preferred concentration of test compoimds is 300 ⁇ M.
  • the concentration of reagents described below reflects assays which contain 300 ⁇ M of test compound. However, the concentration of reagents can be easily adjusted to accommodate the concentration of test compound given the parameters provided by the invention in the disclosure below.
  • the reactions are set up in polypropylene plates. Preferred plates have 96- or 384- wells.
  • a preferred plate is a 96-well polypropylene plate with 12 columns and 8 rows. One column is reserved for the negative control (20% DMSO), one column is for the positive control (actinonin, Sigma, St. Louis, MO) and the rest are for test compounds.
  • the reaction mixture containing CHELEXTM 100 (Sigma, St.
  • the initial concentrations of the test compounds in the binding affinity assays are adjusted according to the results in the percent Fe-PDF inhibition studies.
  • Compounds are initially prepared in a 96-well working plate with 12 columns and 8 rows. Again, the invention is not limited to this size plate, one skilled in the art can choose plate size appropriate to ones needs.
  • One column is for the negative control (20% DMSO), another is reserved for the serial dilutions of the positive control, actinonin, and the rest are for the test compounds.
  • the test compounds are diluted from 1/5 to 1/640 fold. 85 ⁇ L of reaction mixture is added to each well along with 5 ⁇ L of the appropriately diluted test compound. The reactions are initiated by addition of 10 ⁇ L of 1/20,000 fold dilute Fe-PDF.
  • the plate After addition of the Fe-PDF the plate is immediately inserted into the spectrophotometer and monitored at 335-345 nanometers and preferably 340 nanometers. Analysis of the data provided from the spectrophotometer readings gives the binding affinities for the test compounds.
  • thermolysin assay is designed to detect compounds that have an inhibitory effect on the metalloprotease thermolysin.
  • the assay is based on the use of succinylated casein in conjunction with TNBSA (trinitrobenzene sulfonic acid)(Hatakeyama et al., (1992) Anal. Biochem. 204:181-184; Bubnis et al., (1992) Anal. Biochem. 207:129-133; Habeeb et al, (1996) Anal. Biochem. 14:328-336).
  • Native casein has been treated with succinic anhydride to block available primary amines on the surface of the protein.
  • Thermolysin acts to cleave the peptide bonds to expose primary amines.
  • TNBSA reacts with primary amines to produce a yellow-orange color that can be detected at A430 and quantitated.
  • a control well consisting of substrate, enzyme, and TNBSA with 1% DMSO is used to determine the basal signal level. Any test well with a relative signal lower than the control level would indicate that thermolysin activity has been disrupted.
  • the known inhibitor of thermolysin, phosphoramidon is added for the calculation IC 50 data (i.e., the concentration of test compound that results in a fifty percent reduction of enzyme activity).
  • the carboxypeptidase A assay is designed to detect compounds that have an inhibitory effect on carboxypeptidase A.
  • the assay is based on the use of a blue shift of the absorption spectrum that occurs upon the hydrolysis of a furanacryloyl peptide FAPP (FA-Phe-Phe-OH) by the enzyme (Peterson et al., (1982) Anal. Biochem. 125:420-426, which is incorporated by reference in its entirety).
  • Activity by the enzyme will produce a decrease in OD at A330 between an initial reading at time zero and a second reading after one hour.
  • a control- well consisting of enzyme, substrate, and 1% DMSO is used to determine a maximum OD. Any test well with an OD lower than the control well will indicate that the enzyme activity has been disrupted.
  • a known inhibitor of Carboxypeptidase A from potato tubers is added for the calculation of IC 50 data.
  • the collagenase assay is designed to detect compounds that have an inhibitory effect on bacterial collagenase.
  • the assay is based on the use of a blue shift of the absorption spectrum that occurs upon the hydrolysis of a furanacryloyl peptide FALGPA (FA-Leu-Gly-Pro-Ala-OH) by the enzyme (Van Wart et al., (1981) Anal. Biochem. 113:356-365, which is incorporated by reference in its entirety).
  • Activity by the enzyme will produce a decrease in OD at A330 between an initial reading at time zero and a second reading after twenty minutes.
  • a control- well consisting of enzyme, substrate, and 1% DMSO is used to determine a maximum OD. Any test well with a OD lower than the control well would indicate that the enzyme activity has been disrupted.
  • a peptide that is a known inhibitor of collagenase is used for calculation if IC50's.
  • the angiotensin converting enzyme (ACE) assay is designed to detect compounds that have an inhibitory effect on the enzyme ACE.
  • Angiotensin converting enzyme is a halide-activated peptidase that splits off hydrolytically the dipeptide His-Leu from the carboxyl end of the decapeptide angiotensin I (Asp-Arg-Val-Try-Ile-His-Pro-Phe-His-Leu), thereby converting it to the vasopressor octapeptide angiotensin II.
  • the assay utilizes the internally quenched fluorescent tripeptide derivative Abz-Gly-Phe(NO 2 )-Pro.
  • the fluorescent aminobenzoyl (Abz) group incorporated in this tripeptide can be excited in the 300-380 nm range upon cleavage of the peptide bond Gly-Phe(NO 2 )-Pro (Carmel and Yaron, (1978) Anal. Biochem. 87:265-273, which is incorporated by reference in its entirety). Fluorescence is proportional to the amount of liberated Abz-Gly, and a percent control value can be determined by comparing the fluorescence of a sample compound well to that of a control well containing only 1% DMSO.
  • MIC minimum inhibitory concentration
  • Methods known in the art may be used such as broth microdilution testing, using a range of concentrations of each test compound (1993, National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests For Bacteria That Grow Aerobically - Third Edition: Approved Standard, M7-A3, which is incorporated by reference herein in its entirety).
  • the MIC against a variety of pathogens are determined using the same method. Pathogenic species to be tested generally include, but are not limited to: E.
  • the compounds described above can be provided as pharmaceutically acceptable formulations using formulation methods known to those of ordinary skill in the art.
  • Administration as used in the invention includes those suitable for oral, ophthalmic, (including intravitreal or intracameral), topical, mucosal (including buccal, rectal, vaginal, nasal and sublingual), transdermal or parenteral (including subcutaneous, intramuscular, intravenous, bolus injection, intradermal, intratracheal, by implantabe pump, and epidural) administration.
  • the combinations may be incorporated into biodegradable polymers allowing for sustained release of the compound, the polymers being implanted in the vicinity of where drug delivery is desired. Biodegradable polymers and their use are described, for example, in detail in Brem et al., J. Neurosurg. 74:441-446 (1991).
  • the formulations include those suitable for oral, rectal, ophthalmic, (including intravitreal or intracameral) nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intratracheal, and epidural) administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by conventional pharmaceutical techniques. Such techniques include the step of bringing into association the active ingredient and the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into associate the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil emulsion and as a bolus, etc.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the ingredient to be administered in a suitable liquid carrier.
  • Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising the ingredient to be administered in a pharmaceutical acceptable carrier.
  • a preferred topical delivery system is a transdermal patch containing the ingredient to be administered.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of 20 to 500 microns which is. administered in the manner in which snuff is administered, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) conditions requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the administered ingredient.
  • formulations of the present invention may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents.
  • Oral dosage forms include tablets, capsules, dragees, and similar shaped, compressed pharmaceutical forms containing from about 1 ng to 500 mg of drag per unit dosage.
  • Isotonic saline solutions can be used for parenteral administration which includes intramuscular, intrathecal, intravenous and intra-arterial routes of administration. Rectal administration can be effected through the use of suppositories formulated from conventional carriers such as cocoa butter.
  • compositions thus comprise one or more compounds described above and are associated with at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the active ingredients are usually mixed with or diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule or sachet.
  • the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, carrier, or medium for the active ingredient.
  • the compositions can be in the form of tablets, pills, powders, elixirs, suspensions, emulsions, solutions, syrups, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • excipients include but are not limited to lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium silicate, microcrystalline cellulose, polyvinlypyrrolidinone, cellulose, water, syrup, and methyl cellulose
  • the formulations can additionally include lubricating agents such as talc, magnesium stearate and mineral oil, wetting agents, emulsifying and suspending agents, preserving agents such as methyl- and propylhydroxybenzoates, sweetening agents or flavoring agents.
  • compositions preferably are formulated in unit dosage form, meaning physically discrete units suitable as a unitary dosage, or a predetermined fraction of a unitary dose to be administered in a single or multiple dosage regimen to human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.
  • the compositions can be formulated so as to provide an immediate, sustained or delayed release of active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions of the present invention comprise an antibiotic compound as the active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients, for example antivirals.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic acids and bases, including inorganic and organic acids and bases.
  • Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of the invention are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as, but not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, formate, acetate, propionate, succinate, camphorsulfonate, citrate, acid citrate, fumarate, gluconate, isethionate, lactate, malate, mucate, gentisate, isonicotinate, saccharate, tartrate, bitartrate, para-toluenesulfonate, glycolate, glucuronate, maleate, furoate, glutamate, ascorbate, benzoate, anthranilate
  • pharmacologically acceptable anions such as, but not limited to, hydrochloride, hydrobromide, hydroi
  • bases that can be used to prepare pharmaceutically acceptable base addition salts of such acidic compounds of the invention are those that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations such as, but not limited to, alkali metal or alkaline earth metal salts and the calcium, magnesium, sodium or potassium salts in particular.
  • Suitable organic bases include, but are not limited to, N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumaine (N-methylglucamine), lysine, and procaine.
  • antibiotic compounds of the invention may be formulated in pharmaceutically acceptable compositions.
  • the compositions can be used alone or in combination with one another, or in combination with other therapeutic or diagnostic agents. These compositions can be utilized in vivo, ordinarily in a mammal, preferably in a human, or in vitro. In employing them in vivo, the compositions can be administered to the mammal in a variety of ways, including parenterally, intravenously, subcutaneously, intramuscularly, colonially, rectally, vaginally, nasally, orally, transdermally, topically, ocularly, or intraperitoneally.
  • the magnitude of a therapeutic dose of an antibiotic compound in the acute or chronic management of an infectious disease will vary with the severity of the infection or disease to be treated, the particular composition employed, and the route of administration.
  • the dose and dose frequency will also vary according to the species of animal, age, body weight, condition and response of the individual subject. Such dosing schemes can be readily selected by those skilled in the art with due consideration of such factors.
  • tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed.
  • tablets can be coated by standard aqueous or nonaqueous techniques, h addition to the common dosage forms set out above, an active ingredient can also be administered by controlled release means or delivery devices that are well known to . those of ordinary skill in the art, such as those described in U.S.
  • These dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
  • Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the pharmaceutical compositions of the invention.
  • the invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled-release. All controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled counterparts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drug substance being employed to cure or control the condition in a minimum amount of time.
  • controlled-release formulations include: 1) extended activity of the drug; 2) reduced dosage frequency; and 3) increased patient compliance, hi addition, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as blood levels of the drug, and thus can affect the occurrence of side effects.
  • Controlled-release of an active ingredient can be
  • compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules,
  • Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients, h general, the compositions are prepared by uniformly and intimately admixing the active
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules,
  • Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • Binders suitable for use in pharmaceutical compositions and dosage forms include,
  • 25 but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos. 2208,
  • Suitable forms of microcrystalline cellulose include, for example, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL RC-581, and AVICEL-PH-105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PATENT, U.S.A.).
  • An exemplary suitable binder is a mixture of microcrystalline cellulose
  • Suitable anhydrous or low moisture excipients or additives include AVICEL-PH-103TM and Starch 1500 LM.
  • suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.
  • the binder/filler in pharmaceutical compositions of the present invention is typically present in about 50 to about 99 weight percent of the pharmaceutical composition.
  • Disintegrants are used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant will produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) should be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used varies based upon the type of formulation and mode of administration, and is readily discernible to those of ordinary skill in the art.
  • Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.
  • Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof.
  • Additional lubricants include, for example, a syloid silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Piano, Texas), CAB-O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass), or mixtures thereof.
  • a lubricant can optionally be added, typically in an amount of less than about 1 weight percent of the pharmaceutical composition.
  • the methods of the invention also encompass combination therapy in which an antimicrobial compound of the invention or identified by means of the invention is administered as an admixture or sequentially with at least one other antimicrobial.
  • the second antibacterial compound may be naturally occurring or synthetic.
  • Suitable naturally occurring antibacterial compounds include, but are not limited to, aminoglycosides (including but not limited to dihydrostreptomycin, gentamycin, kanamycin, neomycin, paromycin and streptomycin); amphenicols (including but not limited to chloramphenicol); ansamycins (including but not limited to rifamycin); -lactams such as carbapems (including but not limited to imipenem), cephalosporins (including but not limited to cefazedone and cefroxadine), cephamycins (including but not limited to cefbuperazone); monobactams (including but not limited to aztreonam), oxacephems (including but not limited to flomoxef) or penicillins (including but not limited to ampicillin, carbencillin, methicillin, penicillin N, penicillin O and penicillin V); lincosamides (including but not limited to clindamycin and l
  • Suitable synthetic antibacterial compounds include 2,4-diaminopyrimidines (including but not limited to trimethoprim); nitrofurans (including but not limited to nifuradene); quinolones and quinolone analogs (including but not limited to enoxacin, lomefloxacin, nalidixic acid and ofloxacin); streptogramins; sulfonamides (including but not limited to sulfamoxole and sulfanilamide); sulfones (including but not limited to diathymosulfone); oxazolidinones (including but not limited to linezolid); and others such as glycylcyclines, clofoctol, hexedine, methenamine, and nitroxoline.
  • 2,4-diaminopyrimidines including but not limited to trimethoprim
  • nitrofurans including but not limited to nifuradene
  • a compound identified by the method of the invention and a second antibacterial compound means that the two are administered either as a mixture or sequentially.
  • the compound may be administered before or after the second antibacterial compound, so long as the initially administered compound is still providing antibacterial activity.
  • Any of the above described modes of administration can be used in combination to deliver the compound and the second antibacterial compound.
  • a compound identified by the method of the invention and a second antibacterial compound are administered adjunctively as a mixture, they are preferably given in the form of a pharmaceutical composition comprising both agents.
  • a pharmaceutical composition comprising a compound of the invention and a second antibacterial compound together with a pharmaceutically acceptable carrier.
  • the antibiotic compounds identified by the methods of the invention can be used to treat infectious diseases in animals, including humans, companion animals (e.g., dogs and cats), livestock animals (e.g., sheep, cattle, goats, pigs, and horses), laboratory animals (e.g., mice, rats, and rabbits), and captive or wild animals.
  • companion animals e.g., dogs and cats
  • livestock animals e.g., sheep, cattle, goats, pigs, and horses
  • laboratory animals e.g., mice, rats, and rabbits
  • captive or wild animals e.g., mice, rats, and rabbits
  • the antibiotics of the invention selectively target the invading microorganism and thus cause minimal adverse reactions common to many antibiotics such as gastrointestinal disturbances, allergies and hypersensitivities, blood disorders and central nervous system toxicities.
  • the compounds of the invention are expected to be particularly effective against pathogenic organisms found in the blood, muscle tissue (including heart), urinary tract, lower and upper respiratory tract, intestinal, skin and wound, genital tract, and mucosal tissue and include peripheral and central nervous system tissue but are not limited to, gram positive cocci, such as Staphylococci (e.g., S. aureus), Streptococci (e.g., S. pneumoniae, S. pyrogens, S. faecalis, S.
  • Staphylococci e.g., S. aureus
  • Streptococci e.g., S. pneumoniae, S. pyrogens, S. faecalis, S.
  • gram positive bacilli such as Bacillus (e.g., B. anthracis), Corynebacterium (e.g., C. diphtheriae), Listeria (e.g., L. monocytogenes); gram negative cocci, such as Neisseria (e.g., N. gonorrhoeae, N. Meningitidis); gram negative bacilli, such as Haemophilus (e.g., H. influenzae), Pasteurella (e.g., P. multocida), Proteus (e.g., P. mirabilis), Salmonella (e.g., S.
  • Bacillus e.g., B. anthracis
  • Corynebacterium e.g., C. diphtheriae
  • Listeria e.g., L. monocytogenes
  • gram negative cocci such as Neisseria (e.g., N. gonorrhoeae,
  • Shigella species Shigella species, Escherichia (e.g., E. coli), Klebsiella (e.g., K. pneumoniae), Serratia (e.g., S. marcescens), Yersinia ( e.g., Y. pestis), Providencia species, Enterobacter species, Bacteroides (e.g., fragilis), Acinetobacter species, Campylobacter (e.g., C. jejuni), Pseudomonas (e.g., P. aeruginosa), Bordetella (e.g. , B. pertussis), Brucella species, Fracisella (e.g., F.
  • Escherichia e.g., E. coli
  • Klebsiella e.g., K. pneumoniae
  • Serratia e.g., S. marcescens
  • Yersinia e.g., Y. pestis
  • Clostridia e.g., C. perfriugens
  • Helicobacter e.g., H. pylori
  • Vibrio e.g., V. cholerae
  • Mycoplasma e.g., M. pneumoniae
  • Legionella e.g., L. pneumophila
  • Spirochetes e.g., Treponema, Leptospira and Borrelia
  • Mycobacteria e.g., M. tuberculosis
  • Nocardia e.g., N. asteroides
  • Chlamydia e.g., C. trachomatis
  • Rickettsia species e.g., N. asteroides
  • compoimds of the invention can be prepared using commercially available starting materials and commercially available reagents using a variety of starting organic transformations. Nevertheless, specific synthetic routes and examples of syntheses are disclosed herein for illustrative purposes.
  • Boc tert-butoxycarbonyl
  • DCE 1,2-dichloroethane
  • DCM dichloromethane
  • TEA triethylamine
  • HOBt 1-hydroxybenzotriazole
  • DMAP dimethylaminopyridine
  • EDC 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • NHS N-Hydroxysuccinimide
  • DMF dimethylformamide
  • EtOAc ethyl acetate
  • MeOH methanol
  • THF tetrahydrofuran
  • TFA trifluoroacetic acid.
  • Array synthesis was conducted in 15 x 75 mm glass round bottom screw-cap vials contained in a custom 4 x 6 array aluminum synthesis block and sealed with a Teflon-lined rubber membrane. Reagents were added and aqueous extractions performed with single or multichannel pipettors. Filtrations were performed using Whatman/Polyfiltronics 24 well, 10 mL filtration blocks on a Whatman/Polyfiltronics UniVac filtration manifold modified to collect eluent in the custom synthesis block. Evaporation of volatile materials from the array was performed with a Labconco Vortex-Evaporator.
  • Step 1 To a solution of (R) tert-butyl (2-pentyl)succinate mono N-hydroxysuccinimide ester
  • the t-butyl ester (620 mg, 1.98 mmol) was subjected to 10 ml of 20% TFA/DCM solution for 4 h. The solvent was evaporated and dried under high vacuum to yield crude acid. The acid was dissolved in 3 ml of methanol and 6 ml of benzene, and trimethylsilyldiazomethane in hexanes (2.0 M, 6.0 ml, 12 mmol) was added slowly. Volatile material was removed under vacuum and the residue was purified by flash chromatography using 2% MeOH/EtOAc. Yield 480 mg, 90%.
  • Step 1 As in step 1 of the pyrrolidine carbamate I series, section 5.1.1.
  • Step 3 As in step 3 of pyrrolidine carbamate series I, section 5.1.1.
  • Lithium hexamethyldisilazide (118 ml, 1M in THF) was cooled to -78 °C under argon and a solution of an N-heptanoyloxazolidinone (31 g, 0.107 mol) in dry THF (5 ml/g) was added while maintaining the internal reaction temperature below -65 °C. After addition, the resulting solution was allowed to stir at -78 °C for 1 h. A solution of methyl bromoacetate (24.63g, 0.161 mol) in dry THF (1 ml/g) was added while the internal reaction temperature was maintained below -70 °C.
  • Step 1 and 2 Scheme HI.: l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.290 g, 1.52 mmol) and HOBT (0.256 g, 1.89 mmol) were added to a solution of Boc-thioproline (0.294 g, 1.26 mmol) in DMF (3.75 ml) and agitated for 1 h. Isobutylamine (0.159 ml, 1.6 mmol) was added and the solution was agitated overnight. Saturated ammonium chloride solution was added (5 mL) and the mixture was extracted with EtOAc.
  • EDC l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Step 3 The residue from Step 3 was dissolved in 2 ml of a solution prepared by mixing equal parts of cold 3 M KOH in methanol and cold 2 M NH 2 OH and filtering. This was allowed to shake for 15 min and Dowex H+ resin was added to reach a pH ⁇ 7. The solution was filtered, concentrated and purified by reverse phase HPLC to give 5.5 mg of Compound 57. Analyzed by HPLC/MS. Calculated weight 373.52, Found 341.1, 374.2, 396.1 (M-NHOH, M+H, M+Na).
  • Synthesis of compound 66 Synthesis of compound 66 was completed as described above for compound 57 using pyrrolidine in place of isobutylamine. Calculated weight 371.50, Found 339.2, 372.2, 394.1 (M-NHOH, M+H, M+Na).
  • Synthesis of compound 67 Synthesis of compound 67 was completed as described above for compound 57 using piperidine in place of isobutylamine. Calculated weight 385.53, Found 353.2, 386.2, 408.1 (M-NHOH, M+H, M+Na).
  • homoproline series was synthesized in an analogous fashion to the thioproline series, with Boc-thioproline replaced by Boc-pipecolic acid.
  • Synthesis of compound 84 Synthesis of compound 84 was completed as described above for compound 60 using Boc-pipecolic acid in place of Boc-thioproline. Calculated weight 397.52, Found 365.2, 420.0 (M-NHOH, M+Na).
  • Synthesis of compound 85 Synthesis of compound 85 was completed as described above for compound 61 using Boc-pipecolic acid in place of Boc-thioproline. Calculated weight 393.48, Found 361.2, 416.2 (M-NHOH, M+Na).
  • Synthesis of compound 92 Synthesis of compound 92 was completed as described above for compound 68 using Boc-pipecolic acid in place of Boc-thioproline. Calculated weight 395.54, Found 363.2, 418.2 (M-NHOH, M+Na).
  • Synthesis of compound 93 Synthesis of compound 93 was completed as described above for compound 69 using Boc-pipecolic acid in place of Boc-thioproline. Calculated weight 383.49, Found 406.2, (M+Na).
  • Synthesis of compound 96 was completed as described above for compound 57 using Boc-pipecolic acid in place of Boc-thioproline and N-methyl piperazine in place of isobutylamine. Calculated weight 396.53, Found 397.2, 420.2 (M+H, M+Na).
  • This amino amide HCl salt (1.48 g, 6.76 mmol) was added along with triethylamine (0.139 ml, 1.00 mmol) to a solution of (R) tert-butyl (2-pentyl)succinate mono acid (1.5 g, 6.15 mmol), EDC (1.41 g, 7.38 mmol) and HOBT (1.40 g, 10.36 mmol) which had been stirred in 50 ml of DMF for 30 min. The resulting mixture was allowed to stir overnight. A saturated solution of ammonium chloride (2.5 ml) was added and the mixture was extracted with EtOAc.
  • the tert-butyl ester (1.6 g, 3.92 mmol) was subjected to 15 ml of 20% TFA in DCM and stirred for 1 h. Evaporation and dried under high vacuum to yield crude acid which was dissolved in 6 ml of methanol and 12 ml of benzene, and trimethylsilyldiazomethane in hexanes (2.0 M, 12.0 ml, 24 mmol) was added slowly. Volatile material was removed in vacuo and the residue was purified by flash chromatography using EtOAc. Yield 1.05 g , 70%. Analyzed by LC/MS. Calculated weight 366.50; Found 296.3, 389.2 (M-C4H8N, M+Na).
  • Synthesis of compound 223 was completed as described above for compound 97 using D-Boc-pipecolic acid in place of L-Boc-pipecolic. Analyzed by HPLC/MS. Calculated weight 367.49, Found 297.2, 368.3 ( M-C4H8N, M+H ).
  • Synthesis of compound 98 was completed as described above for compound 97 using (R)-2-(t-butylcarboxymethyl)-3-(3,4-difluorophenyl)-propionic acid in place of (R) tert-butyl (2-pentyl) succinate mono acid. Analyzed by HPLC/MS. Calculated weight 423.46, Found 446.1 (M+Na).
  • Synthesis of compound 105 Synthesis of compound 105 was completed as described above for compoxmd 58 using Boc-nipecotic acid in place of Boc-thioproline. Calculated weight 381.52, Found 349.2, 382.3, 404.2 (M-NHOH, M+H, M+Na). 35 Synthesis of compound 106. Synthesis of compound 106 as completed as described above for compoxmd 59 using Boc-nipecotic acid in place of Boc-thioproline. Calculated weight 395.54, Found 363.3, 396.3, 418.0 (M-NHOH, M+H, M+Na).
  • Synthesis of compound 110 Synthesis of compound 110 was completed as described above for compoxmd 57 using Boc-nipecotic acid in place of Boc-thioproline and 2-aminomethylpyridine in place of isobutylamine. Calculated weight 404.51, Found 372.3, 25 405.2, 427.0 (M-NHOH, M+H, M+Na).
  • Synthesis of compound 111 was completed as described above for compoxmd 63 using Boc-nipecotic acid in place of Boc-thioproline.
  • Synthesis of compound 117 was completed as described above for compound 70 using Boc-nipecotic acid in place of Boc-thioproline.
  • Synthesis of compound 120 Synthesis of compound 120 was completed as ⁇ described above for compoxmd 57 using Boc-nipecotic acid in place of Boc-thioproline and N-methyl piperazine in place of isobutylamine. Calculated weight 396.53, Found 364.2, 397.2 (M-NHOH, M+H).
  • Synthesis of compound 124 Synthesis of compound 124 was completed as described for compoxmd 58 above for using Boc-isonipecotic acid in place of Boc-thioproline. Calculated weight 381.52, Found 349.2, 382.3 (M-NHOH, M+H).
  • Synthesis of compound 129 was completed as described for compoxmd 64 above for using Boc-isonipecotic acid in place of
  • Synthesis of compound 132 Synthesis of compound 132. Synthesis of compound 132 was completed as described for compound 67 above for using Boc-isonipecotic acid in place of Boc-thioproline. Calculated weight 381.52, Found 349.2, 382.3 (M-NHOH, M+H). Synthesis of compound 133. Synthesis of compound 133 was completed as described for compound 68 above for using Boc-isonipecotic acid in place of Boc-thioproline. Calculated weight 395.55, Found 363.3, 396.3 (M-NHOH, M+H).
  • Synthesis of compound 136 was completed as described for compoxmd 71 above for using Boc-isonipacotic acid in place of Boc-thioproline. Calculated weight 399.56, Found 367.3, 400.2 (M-NHOH, M+H).
  • Step 2 A methanolic solution of NH 2 OH HCl (2 M, 15 ml) was cooled to 0 °C. A methanolic solution of KOH (3 M, 15 ml) was added and the mixture was stirred for 30 min and filtered.
  • Step 1 Synthesis of compound 217. To a stirred solution of piperazine (6.1 g, 71 mmol) in CH 2 C1 2 (50 ml) was added a solution of benzoyl chloride(1.0 g, 7 mmol) in CH 2 C1 2 (50 ml) at 0°C. The reaction mixture was stirred overnight. After addition of H 2 O, the mixture was extracted with CHC1 3 , washed with H 2 O, then dried (MgSO 4 ) and concentrated. Purification of the residue by chromatography eluting with CHC1 3 / MeOH gave benzoyl piperazine (393 mg). Step 2 :
  • Step 3 The 4-((R)-tert-butyl (2-pentyl)succinate) benzoyl piperazine (378 mg, 1.0 mmol) was dissolved in CH 2 C1 2 (4 ml) and trifluoroacetic acid (1.6 ml) was added at 0°C. The reaction mixture was stirred at room temperature for 3 h and concentrated. After addition of H 2 O, the mixture was extracted with CH 2 C1 2 , dried(MgSO 4 ) and concentrated to give the acid (193mg).
  • Step 4 The 4-((R)-tert-butyl (2-pentyl)succinate) benzoyl piperazine (378 mg, 1.0 mmol) was dissolved in CH 2 C1 2 (4 ml) and trifluoroacetic acid (1.6 ml) was added at 0°C. The reaction mixture was stirred at room temperature for 3 h and concentrated. After addition of H 2 O, the mixture was extracted with CH 2 C1 2 , dried(MgSO
  • Steps 3-5 in the synthesis of compound 218 were completed as described above in Step 2-4 for the synthesis of compound 217 using the urea from step 2 in place of N-benzoylpiperazine.
  • Step 1 was completed as described above in Step 1 for the synthesis of compoxmd 217 using (3S)-(+)-l-benzyl-3-amino pyrrolidine in place of piperazine.
  • Step 2 :
  • Steps 3-5 in the synthesis of compound 219 were completed as described above in Step 2-4 for the synthesis of compound 217 using (3S)- 3-(N-benzoylamino) pyrrolidine in place of N-benzoylpiperazine.
  • Analyzed by ⁇ NMR (DMSO-d6) ⁇ : 10.55-10.45 (m, IH), 8.8 (s, IH), 8.65-8.5 (m, IH), 8.0-7.5 (m, 5H), 4.6-4.45 (m, IH), 4.0-3.8 (m, IH), 3.8-3.35 (m, 3H), 3.05-2.8 (m, IH), 2.4-1.8 (m, 5H), 1.6-1.0 (m, 8H), 0.95-0.75 (m, 3H).
  • HPLC MS Calculated weight 375.47, Found 343.4, 376.3, 398.2 (M-NHOH, M+H, M+Na).
  • Step l 15 Synthesis of compound 221. Step 1 was completed as described above in Step 2 of the synthesis of compound 219 using l-diphenyl-3-hydroxyazetidine in place of (3S)- 1 -benzyl-3-(N-benzoylamino) pyrrolidine. Step 2:
  • Step 2 was completed as described above in Step 3 of the synthesis of compound 20 218 using 3-hydroxyazetidine in place of benzoylpiperazine. Step 3:
  • Steps 4-5 30 Steps 4-5 in the synthesis of compound 221 were completed as described above in
  • Deprotection of the Boc-protected amino amides was accomplished by dissolving each product in 2 ml of 4 M HCl in dioxane, followed by shaking for 45 min, and evaporation of solvents. The vials were then placed under high vacuum overnight, weighed, and the amine hydrochlorides were analyzed by HPLC MS.
  • the tert-butyl esters were converted to the carboxylic acids by dissolving each in 2 ml of 4 M HCl in dioxane, shaken for 45 min, and evaporated. The vials were then placed under high vacuum overnight, weighed, and the acids were analyzed by HPLC/MS.
  • Synthesis of compound 143 was accomplished as described in the Section 5.6 calculated M.W. 355.48 found M.W. (M-NHOH, M+H, M+Na) 323.1, 356.3, 378.3.
  • Synthesis of compound 144 was accomplished as described in the Section 5.6 calculated M.W. 403.52 found M.W. (M-NHOH, M+H, M+Na) 371.2, 404.2, 426.2.
  • Synthesis of compound 157 was accomplished as described in the Section 5.6 calculated M.W. 423.58 found M.W. (M-NHOH, M+H, M+Na) 391.1, 424.1, 446.1.
  • Synthesis of compound 158 was accomplished as described in the Section 5.6 calculated M.W. 469.58 found M.W. (M-NHOH, M+H, M+Na) 437.2, 470.2, 492.3.
  • Synthesis of compound 170 was accomplished as described in the Section 5.6 calculated M.W. 296.34 found M.W. (M-NHOH, M+H, M+Na) 264.2, 297.2, 319.2
  • Synthesis of compound 171 was accomplished as described in the Section 5.6 calculated M.W. 357.25 found M.W. (M-NHOH, M+H, M+Na) 381.0, (Br isotopes) 324.2, 326.2, 357.2, 359.2, 379.0, 381.0.
  • Synthesis of compound 186 was accomplished as described in the Section 5.6 calculated M.W. 365.43 found M.W. (M-NHOH, M+H, M+Na) 333.3, 366.4.
  • Synthesis of compound 187 was accomplished as described in the Section 5.6 calculated M.W. 436.55 found M.W. (M-NHOH, M+H, M+Na) 437.3.
  • the series of 24 amines was added to each vial in a 4 x 6 array of tubes.
  • the mixtures were agitated for 18 h, diluted to 2.5 ml with DCM, washed twice with 10% NaHSO 4 (aqueous), once each with NaHCO 3 (saturated), and brine, filtered through Na 2 SO 4 and evaporated.
  • the resulting tert-butyl ester substituted amides were then weighed and analyzed by HPLC/MS.
  • Step 2 The tert-butyl esters were converted to the carboxylic acids by dissolving each in 2 ml of a solution of 100:5:1 TFA:water:DMS, followed by shaking for 45 min, and evaporation of solvents. The vials were then placed xmder high vacuum overnight, weighed, and the acids were analyzed by HPLC/MS.
  • Steps 3-4 Performed as in steps 5 and 6 in Section 5.6.1, as described above.
  • Step l Six Boc-protected amino acid NHS esters (Gly, b-Ala, Lys(Z), Ser(OBn), Asp(OBn,
  • Glu(OBn) were each dissolved in DCM to a concentration of 0.75 M, and 4 aliquots (0.48 ml, 0.36 mmol) of each were added to each column of the array, one per vial.
  • Three of the starting amine reagents pyrrolidine, piperidine, and benzylamine were each dissolved in DCM at 2.0 M. Dimethylamine was used as provided, in a 2 M THF solution (Aldrich).
  • Six aliquots (0.225 ml, 0.45 mmol) of each of the 4 amine solutions were added to each row of the array, one per vial.
  • the group of 24 amines used was: 3-hydroxypiperidine hydrochloride, 4-hydroxypiperidine, 2-piperidinemethanol, 3-piperidinemethanol, 2-piperidineethanol, 4-piperidineethanol, N-benzylethanolamine, diethanolamine, l-(2-hydroxyethyl)piperazine, N-methylhomoveratrylamine, nipecotamide, 2-(propylamino)ethanol, 2-(methylamino)ethanol, N-methylhydroxylamine hydrochloride, N,O-dimethylhydroxylamine hydrochloride, Boc-piperazine, 2-aminobenzyl alcohol, 3-aminobenzyl alcohol, 4-aminophenylethyl alcohol, N-benzylaspartic acid, DL-proline, isonipecotic acid, nipecotic acid Step 1:
  • the series of 24 amines (0.18 mmol) was added to each vial in a 4 x 6 array of tubes. To each was added 0.6 ml of DMF, DIEA (0.091 mL, 0.525 mmol), and chlorotrimethylsilane (0.040 ml, 3.15 mmol), and the array was agitated for 2.5 h.
  • D-Phenylalanine phenyl amide hydrochloride was prepared from Boc-Phe-NHS by standard procedures. This salt (54 mg, 0.20 mmol) was dissolved in 0.8 ml of DCM containing (R) tert-butyl (2-pentyl)succinate mono N-hydroxysuccinimide ester (740 mg, 0.19 mmol) and DIEA (37 ml, 0.21 mmol). The mixture was stirred at 35 °C for 24 h, diluted with DCM and washed once each with 0.2 M HCL, NaHCO 3 (saturated), and brine, filtered through MgSO 4 , and evaporated. The residue was analyzed by HPLC MS and NMR and carried on without further purification.
  • the succinyl tert-butyl ester (64 mg, 0.137 mmol) was dissolved in 1 ml of 100:5:1 TFA: water :DMS, stirred for 30 min, and evaporated. The residue was then dissolved in 2 ml 3:1 benzene:methanol and trimethylsilyldiazomethane in hexanes (2.0 M, 0.50 ml, 1.0 mmol) was added dropwise with stirring. After 20 min the color was discharged by dropwise addition of acetic acid and the solution was evaporated to yield approximately 75 mg of a pale yellow oil which was analyzed by HPLC/MS and carried on without further purification.
  • Synthesis of compound 275 was completed as described above for compound 274 using D-Boc-Nal-OSu in place of Boc-Nal-OSu. Analyzed by HPLC/MS. Calculated weight 349.43, Found 348.4 (M-H).
  • Step 5 A methanolic solution of NH 2 OH.HCl (2 M, 5 ml) was cooled to 0°C. A methanolic solution of KOH (3 M, 5 ml) was added dropwise over 10 min, the mixture was stirred for 30 min and filtered. An aliquot (1.5 ml, 1.5 mmol) of this solution was added to the methyl ester (60 mg, 0.16 mmol).
  • Methyl ester (60 mg, 0.16 mmol) from step 4 was treated with 1M LiOH/MeOH (2 ml) for 18 h.
  • the filtrate was collected and concentrated to dryness to give 45 mg (79%) of compound 279 as desired product. Analyzed by HPLC/MS. Calculated weight 348.45. Found 347.10 (M-H).
  • This resin was treated for 30 min with 20% piperidine in toluene for 30 minutes, washed repeatedly (3 X DMF, 1 X DCM, 1 X MeOH, 3 X DCM) and dried in vacuo to give the deprotected amino acid bound resin.
  • 1,2,3,4-Tetrahydro-l-napthylamine (0.057 ml, 0.375 mmol) was added to a suspension of the capped valine resin (0.050 g, 0.0375 mmol) in DMF (1 ml) and shaken overnight. The resin was then filtered and washed repeatedly (3 X DMF, 1 X DCM, 1 X MeOH, 3 X DCM) to give the compoxmd 224 bound resin. The damp resin was treated with 80% trifluoroacetic acid in DCM for 1 h and filtered. The resin was washed with DCM and the combined filtrate was dried in vacuo to give 4.4 mg of compound 224 which was analyzed by HPLC/MS. Calculated weight 449.64, Found 450 (M+H).
  • Synthesis of compound 233 was completed as described above for compoxmd 227 using 4-bromomethylbenzoic acid in place of 3-bromomethylbenzoic acid. Analyzed by HPLC/MS. Calculated weight 387.57, Found 388.3 (M+H). Synthesis of compound 234. Synthesis of compound 234 was completed as described above for compoxmd 228 using 4-bromomethylbenzoic acid in place of 3-bromomethylbenzoic acid. Analyzed by HPLC/MS. Calculated weight 403.57, Found 404.3 (M+H).
  • Synthesis of compound 206 Synthesis of compound 206 was completed as described above using bromomethyl cyclohexane in place of 1 -bromo-3-methyl butane.
  • Synthesis of compound 207 Synthesis of compound 207 was completed as described above using l-bromo-trans-2-butene in place of l-bromo-3 -methyl butane.
  • Synthesis of compound 208 was completed as described above using 1-bromobutane in place of l-bromo-3 -methyl butane.
  • Synthesis of compound 275 Synthesis of compound 275 was completed as described above for compoxmd 274 using D-Boc-Val-OSu in place of Boc-Val-OSu. Analyzed by HPLC/MS. Calculated weight 349.43, Found 348.4 (M-H).
  • Step 3 A methanolic solution of NH 2 OH.HCl (2.78 g in 34 ml) was cooled to 0°C. A methanolic solution of NaOH (3 g in 6 ml) was added, the mixture was stirred for 30 min and filtered. An aliquot (1 ml, 1.0 mmol NH 2 OH) of this solution was added to a vial containing hydantoin methyl ester product (57 mg, 0.16 mmol) of the previous reaction. The vial was shaken for 30 min then acidified to pH 5-6 with Dowex H+ resin. The solution was then filtered and concentrated to dryness. The crude material was purified by flash chromatography using 5% MeOH/DCM. Analyzed by HPLC/MS. Calculated molecular weight 337.40. Found 336.1 (M-H).
  • Synthesis of compound 244 was completed as described above for compound 300 using D,L-Leu in place of D,L-Phe. Analyzed by HPLC/MS. Calculated molecular weight 303.38. Found 302.1 (M-H).
  • Synthesis of compound 248 Synthesis of compoxmd 248 was completed as described above for compoxmd 300 using D,L-Nle in place of D,L-Phe. Analyzed by HPLC/MS. Calculated molecular weight 303.38. Found 302.1 (M-H).
  • Synthesis of compound 247 Synthesis of compound 247 was completed as described above for compound 300 using ethyl 2-isocyanato-3-phenylpropionate in place of ethyl 2-isocyanato-4-(methylthio)butyrate. Analyzed by HPLC/MS. Calculated molecular weight 321.42. Found 320.05 (M-H).
  • Step 1 EDC (1.03 g, 5.39 mmol) was added to a solution of Boc- Val (1.17 g, 5.39 mmol) in 8 ml of DCM and stirred for 30 min. At which time, pyrrolidine (0.45 ml, 7.42 mmol) was added and allowed the resulting mixture to stir for 18 h. After evaporation of solvent, the residue was taken up in EtOAc (10 ml) and extracted with IN HCl (5 ml), saturated aqueous NaHCO 3 (5 ml) then brine (5 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude Boc amide.
  • Boc amide (0.9 g, 3.3 mmol) was treated with 9 ml of 20% TFA in DCM for 3 h.
  • the volatile material W-S removed b vacuum to give the TFA salt of the amino amide.
  • Synthesis of compound 268 Synthesis of compound 268. Synthesis of compound 268 was completed as described above for compoxmd 301 using hexamethyleneimine in place of pyrrolidine. Analyzed by HPLC/MS. Calculated molecular weight 410.51. Found 409.20 (M-H). Synthesis of compound 269. Synthesis of compound 269 was completed as described above for compoxmd 301 using 2-isocyanato-3-propylbutyrate in place of 2-isocyanato-4-methylvalerate. Analyzed by HPLC/MS. Calculated molecular weight 410.51. Found 409.20 (M-H).
  • Step 1 A mixture of Boc-Phe-Osu (1.09 g, 2.8 mmol) and R-(-)-Prolinol (0.5 g, 4.9 mmol) was stirred in 5 ml THF for 18 h.. After evaporation of solvent, the residue was taken up in EtOAc (10 ml) and extracted with IN HCl (5 ml), saturated aqueous NaHCO 3 (5 ml) then brine (5 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give crude Boc amide.
  • Steps 2 and 3 Same as step 2 and step 3 in the synthesis of compound 301.
  • Step 4 Step 4:
  • Step 5 1M NaHMDS (139 ml, 0.14 mmol) was added to a solution of hydantoin (47.3 mg, 0.14 mmol) in 1 ml of THF at -78 °C. The solution was allowed to warm to 0°C then added chlorotrimethysilane (17.6 ml, 0.14 mmol). After stirring for 15 min, another equivalent of , NaHMDS (139 ml, 0.14 mmol) was added at 0°C followed by the addition of methylbromoacetate (19.7 ml, 0.21 mmol). The resulting mixture was allowed to warm to room temperature and stir for overnight.
  • Step 6 Same as step 6 in the synthesis of compound 301. Analyzed by HPLC/MS. Calculated molecular weight 460.53. Found 461.2 (M+H).
  • Synthesis of compound 270 Synthesis of compound 270. Synthesis of compound 270 was completed as described above for compoxmd 272 using Boc-Gly-OSu in place of Boc-Phe-OSu. Analyzed by HPLC/MS. Calculated molecular weight 370.41. Found 371 (M+H).
  • Step 1 t-Butyl bromoacetate (1.34 ml, 9.1 mmol) was added to a suspension solution of L-Leucine-methylester (3.3 g, 18.1 mmol) and triethylamine (2.52 ml, 18.1 mmol) in 40 ml DMF and stirred for 18 h. The resulting mixture was poured into 40 ml of saturated aqueous ammonium chloride and extracted with ether (2 X 50 ml). The combined ethereal layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude material was purified by flash chromatography using 20% EtOAc/hexane. Yield 2.3 g, 98%.
  • Step 2 A mixture of amine (1.6 g, 6.20 mmol) and methyl-3-isocyanato benzoate (1 g, 5.64 mmol) was stirred in 10 ml of DCM for 18 h. After removal of volatile material, the residue was taken up in EtOAc (30 ml) and washed with 1 N HCl (15 ml) then brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude material was carried to next step without purification.
  • Step 3 Triethylamine (0.8 ml, 5.7 mmol) was added to a solution of urea (2.4 g, 5.64 mmol) obtained from previous step and heated to reflux in 10 ml of THF for 14 h. Volatile material was then removed in vacuo and the residue was purified by flash chromatography using 30% EtOAc/Hexane. Analyzed by NMR.
  • Lithium diisopropylamide (3 ml, 6 mmol, 2M in hexane) was added to a solution of S-(+)- -trityloxymethyl- -butyrolactone (1.79 g, 5 mmol) in 15 ml THF at -78°C. After stirring for 30 min at -78°C, a solution of crotyl bromide (0.66 ml, 5.5 mmol) in 5 ml THF was added. The solution mixture was allowed to stir for 4 h at -78°C and then quenched with aqueous ammonium chloride (10 ml). After warming to room temperature, the resulting solution was extracted with EtOAc (2 X 30 ml).
  • Step 2 A mixture of (S)- -buten-2-yl- -trityloxymethyl- -butyrolactone (1.7 g, 4.13 mmol), 10% Pd/C (228 mg) and EtOAc (80 ml) was hydrogenated at 45 psi for 3 h. The Pd catalyst was removed by filtration through a celite pad and washed with EtOAc (40 ml). The filtrate was concentrated to give 1.68 g (99%) of title compoxmd. Analyzed by HPLC/MS. Calculated weight 414. Found 437 (M+Na). Step 3:
  • Lithium diisopropylamide (2.43 ml, 4.86 mmol, 2 M in hexane) was added to a solution of (S)- -butyl- -trityloxymethyl- -butyrolactone (1.69 g, 4.05 mmol) in 20 ml THF at -78°C. After stirring for 1 h at -78°C, a solution of allyl bromide (0.45 ml, 5.26 mmol) in 2 ml THF was added. The solution mixture was allowed to stir for 4 h at -78°C and then quenched with aqueous ammonium chloride (10 ml).
  • Trifluoroacetic acid (10 ml) was added to a solution of [S-(R*,R*)]- -butyl- -(propen-2-yl)- -trityloxymethyl- -butyrolactone (1.8 g, 3.96 mmol) in DCM (30 ml) at 0°C. The solution was stirred for 35 min at 0°C then concentrated to dryness. Saturated aqueous sodium chloride solution (30 ml) was poured into residue and extracted with DCM (2 x 20 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to dryness.
  • the selectivity of the inhibitors was calculated as the ratio of the IC50 for the compoxmd versus thermolysin (THERM) divided by the IC50 for the compound versus peptide deformylase (Fe-PDF).
  • the metalloproteases carboxypeptidase (CPEP), collagenase (COLL) and angiotensin converting enzyme (ACE) were also used in these studies but the IC50 for thermolysin (THERM) was generally the smallest for these enzymes.
  • inhibition is given as percent inhibition and for THERM, CPEP, COLL and ACE the inhibition values are the inhibition relative to confrols with no inhibitor (enzymatic reaction without test compound divided by reaction with test compound).

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Abstract

L'invention concerne une classe de composés qui inhibent la peptide déformylase, des compositions pharmaceutiques contenant des composés qui inhibent la peptide déformylase ainsi que des méthodes de traitement d'infections variées.
PCT/US2001/029926 2000-09-25 2001-09-24 Inhibiteurs de peptide deformylase WO2002028829A2 (fr)

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AU2002230385A AU2002230385A1 (en) 2000-09-25 2001-09-24 Peptide deformylase inhibitors

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002102791A1 (fr) * 2001-06-15 2002-12-27 Vicuron Pharmaceuticals Inc. Composés bicycliques de pyrrolidine
WO2003084947A1 (fr) * 2002-04-09 2003-10-16 Axxima Pharmaceuticals Ag Derives de 4,5,6,7-tetrahydrobenzo[b]thiophene et methodes d'intervention medicale contre les infections mycobacteriennes
EP1372692A2 (fr) * 2001-03-19 2004-01-02 Sloan Kettering Institute For Cancer Research Synthese asymetrique de (s,s,r)-(-)-actinonine, de ses analogues et ses utilisations
WO2004014425A1 (fr) * 2002-08-07 2004-02-19 Glaxo Group Limited Activateurs de canaux de potassium actives par calcium de conductance faible et utilisation associee
WO2004033441A1 (fr) * 2002-10-09 2004-04-22 British Biotech Pharmaceuticals Ltd Agents antibacteriens
WO2004099124A2 (fr) * 2003-05-08 2004-11-18 Morphochem Aktiengesellschaft für kombinatorische Chemie Nouveaux bioisosteres d'actinonine
WO2005092872A1 (fr) * 2004-03-26 2005-10-06 Arpida A/S Inhibiteurs de peptide deformylase
WO2006055663A2 (fr) 2004-11-17 2006-05-26 Smithkline Beecham Corporation Nouvelle utilisation
JP2006143667A (ja) * 2004-11-22 2006-06-08 Ube Ind Ltd ピペコリン酸アミド誘導体及び抗菌剤
WO2007068474A1 (fr) * 2005-12-14 2007-06-21 Medivir Ab Inhibiteurs de métalloprotéinase de type (2,5-dioxoimidazolidin-1-yl)-n-hydroxy-acétamides
US7465719B2 (en) 2003-01-17 2008-12-16 Topotarget Uk Limited Carbamic acid compounds comprising an ester or ketone linkage as HDAC inhibitors
JP2009505961A (ja) * 2005-07-29 2009-02-12 スミスクライン・ビーチャム・コーポレイション ペプチドデホルミラーゼ阻害剤
US7629343B2 (en) 2002-04-03 2009-12-08 Topotarget Uk Limited Carbamic acid compounds comprising a piperazine linkage as HDAC inhibitors
WO2010014943A2 (fr) * 2008-08-01 2010-02-04 Bioxiness Pharmaceutics, Inc. Analogues de méthionine, et procédés d'utilisation de ceux-ci
US7745637B2 (en) 2002-03-13 2010-06-29 Glaxosmithkline Llc Peptide deformylase inhibitors
US8349792B2 (en) 2006-12-19 2013-01-08 Cyclacel Limited Combination comprising CNDAC (2′-cyano-2′-deoxy-N4-palmitoyl-1-beta-D-arabinofuranosyl-cytosine) and a cytotoxic agent
US8530445B2 (en) 2008-06-09 2013-09-10 Cyclacel Limited Combinations of sapacitabine or CNDAC with DNA methyltransferase inhibitors such as decitabine and procaine
WO2013147161A1 (fr) 2012-03-29 2013-10-03 東レ株式会社 Dérivé d'acide nipécotique et son utilisation à des fins médicales
CN108610292A (zh) * 2018-06-12 2018-10-02 清华大学 一类3,5-二取代乙内酰脲类化合物及其制备方法与应用
US10226478B2 (en) 2011-04-14 2019-03-12 Cyclacel Limited Dosage regimen for sapacitabine and decitabine in combination for treating acute myeloid leukemia

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006031A1 (fr) * 1993-08-23 1995-03-02 Immunex Corporation Inhibiteurs de la secretion de facteur alpha de necrose tumorale
US5712300A (en) * 1996-03-08 1998-01-27 Pharmacia & Upjohn Company Hydroxamic acid derivatives useful for the treatment of diseases related to connective tissue degradation
US5840939A (en) * 1995-04-18 1998-11-24 British Biotech Pharmaceuticals, Ltd. Derivatives of succinamide and their use as metalloproteinase inhibitors
WO1999039704A1 (fr) * 1998-02-07 1999-08-12 British Biotech Pharmaceuticals Limited Agents antibacteriens
WO1999059568A1 (fr) * 1998-05-16 1999-11-25 British Biotech Pharmaceuticals Limited Derives de l'acide hydroxamique en tant qu'agents antibacteriens
WO2001038561A1 (fr) * 1999-11-29 2001-05-31 Questcor Pharmaceuticals, Inc. Methodes d'utilisation d'inhibiteurs de la peptide deformylase en tant que nouveaux agents antibacteriens
WO2001044179A1 (fr) * 1999-12-17 2001-06-21 Versicor, Inc. Nouveaux composes a base de succinate, compositions les contenant, et procedes d'utilisation et de preparation de ceux-ci

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0670019B2 (ja) * 1989-07-21 1994-09-07 明治製菓株式会社 新抗生物質ｓｆ２１９７ｃ物質およびその製造法
JPH03157372A (ja) * 1989-11-13 1991-07-05 Yamanouchi Pharmaceut Co Ltd Ｙｌ―０１８６９ｐ物質及びその製造法
JPH0625183A (ja) * 1991-12-04 1994-02-01 Banyu Pharmaceut Co Ltd 生理活性物質ｂｅ−１９０９３及びその製造法
JPH093094A (ja) * 1995-06-19 1997-01-07 Mercian Corp セラチオプロテアーゼ阻害剤

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006031A1 (fr) * 1993-08-23 1995-03-02 Immunex Corporation Inhibiteurs de la secretion de facteur alpha de necrose tumorale
US5840939A (en) * 1995-04-18 1998-11-24 British Biotech Pharmaceuticals, Ltd. Derivatives of succinamide and their use as metalloproteinase inhibitors
US5712300A (en) * 1996-03-08 1998-01-27 Pharmacia & Upjohn Company Hydroxamic acid derivatives useful for the treatment of diseases related to connective tissue degradation
WO1999039704A1 (fr) * 1998-02-07 1999-08-12 British Biotech Pharmaceuticals Limited Agents antibacteriens
WO1999059568A1 (fr) * 1998-05-16 1999-11-25 British Biotech Pharmaceuticals Limited Derives de l'acide hydroxamique en tant qu'agents antibacteriens
WO2001038561A1 (fr) * 1999-11-29 2001-05-31 Questcor Pharmaceuticals, Inc. Methodes d'utilisation d'inhibiteurs de la peptide deformylase en tant que nouveaux agents antibacteriens
WO2001044179A1 (fr) * 1999-12-17 2001-06-21 Versicor, Inc. Nouveaux composes a base de succinate, compositions les contenant, et procedes d'utilisation et de preparation de ceux-ci

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
"Antibiotic Actinonin. I to VIII" JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1, CHEMICAL SOCIETY. LETCHWORTH, GB, vol. 9, no. 9, 1975, pages 819-860, XP002119637 ISSN: 0300-922X cited in the application *
GHOSE A K ET AL: "DETERMINATION OF PHARMACOPHORIC GEOMETRY FOR COLLAGENASE INHIBITORS USING A NOVEL COMPUTATIONAL METHOD AND ITS VERIFICATION USING MOLECULAR DYNAMICS, NMR, AND X-RAY CRYSTALLOGRAPHY" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, WASHINGTON, DC, US, vol. 117, no. 16, 1995, pages 4671-4682, XP002051616 ISSN: 0002-7863 *
INAOKA Y ET AL: "PROPIOXATINS A AND B, NEW ENKEPHALINASE B INHIBITORS III. TOTAL SYNTHESIS OF PROPIOXATIN A" JOURNAL OF ANTIBIOTICS, JAPAN ANTIBIOTICS RESEARCH ASSOCIATION. TOKYO, JP, vol. 39, no. 10, October 1986 (1986-10), pages 1382-1385, XP000978947 ISSN: 0021-8820 *
INAOKA Y ET AL: "PROPIOXATINS A AND B, NEW ENKEPHALINASE B INHIBITORS. IV. CHARACTERIZATION OF THE ACTIVE SITE OF THE ENZYME USING SYNTHETIC PROPIOXATIN ANALOGUES" JOURNAL OF BIOCHEMISTRY, JAPANESE BIOCHEMICAL SOCIETY, TOKYO, JP, vol. 104, no. 5, November 1988 (1988-11), pages 706-711, XP000978993 ISSN: 0021-924X *
PATENT ABSTRACTS OF JAPAN vol. 015, no. 197 (C-0833), 21 May 1991 (1991-05-21) & JP 03 053891 A (MEIJI SEIKA KAISHA LTD), 7 March 1991 (1991-03-07) *
PATENT ABSTRACTS OF JAPAN vol. 015, no. 388 (C-0872), 2 October 1991 (1991-10-02) & JP 03 157372 A (YAMANOUCHI PHARMACEUT CO LTD), 5 July 1991 (1991-07-05) *
PATENT ABSTRACTS OF JAPAN vol. 018, no. 236 (C-1196), 6 May 1994 (1994-05-06) & JP 06 025183 A (BANYU PHARMACEUT CO LTD), 1 February 1994 (1994-02-01) *
PATENT ABSTRACTS OF JAPAN vol. 1997, no. 05, 30 May 1997 (1997-05-30) & JP 09 003094 A (MERCIAN CORP), 7 January 1997 (1997-01-07) *
SATO, TSUTOMU ET AL: "YM-24074, a new peptide antibiotic. II. Structural elucidation." JOURNAL OF ANTIBIOTICS (1996), 49(8), 811-814, XP002209585 *
TAMAKI KAZUHIKO ET AL: "Synthesis and structure-active relationships of gelatinase inhibitors derived from matlystatins" CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN. TOKYO, JP, vol. 43, no. 11, 1995, pages 1883-1893, XP002165817 ISSN: 0009-2363 *
TAMAKI, KAZUHIKO ET AL: "Total synthesis and inhibitory activity against gelatinase B of YL-01869P" J. ANTIBIOT. (1995), 48(1), 87-8, XP002209586 *

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EP1372692A2 (fr) * 2001-03-19 2004-01-02 Sloan Kettering Institute For Cancer Research Synthese asymetrique de (s,s,r)-(-)-actinonine, de ses analogues et ses utilisations
US7612059B2 (en) 2001-06-15 2009-11-03 Vicuron Pharmaceuticals, Inc. Pyrrolidine bicyclic compounds and its derivatives, compositions and methods of use
WO2002102791A1 (fr) * 2001-06-15 2002-12-27 Vicuron Pharmaceuticals Inc. Composés bicycliques de pyrrolidine
US6987104B2 (en) 2001-06-15 2006-01-17 Vicuron Pharmaceuticals Inc. Pyrrolidine bicyclic compounds and its derivatives, compositions and methods of use
US7745637B2 (en) 2002-03-13 2010-06-29 Glaxosmithkline Llc Peptide deformylase inhibitors
US7981895B2 (en) 2002-04-03 2011-07-19 Topotarget Uk Limited Carbamic acid compounds comprising a piperazine linkage as HDAC inhibitors
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US7629343B2 (en) 2002-04-03 2009-12-08 Topotarget Uk Limited Carbamic acid compounds comprising a piperazine linkage as HDAC inhibitors
WO2003084947A1 (fr) * 2002-04-09 2003-10-16 Axxima Pharmaceuticals Ag Derives de 4,5,6,7-tetrahydrobenzo[b]thiophene et methodes d'intervention medicale contre les infections mycobacteriennes
WO2004014425A1 (fr) * 2002-08-07 2004-02-19 Glaxo Group Limited Activateurs de canaux de potassium actives par calcium de conductance faible et utilisation associee
WO2004033441A1 (fr) * 2002-10-09 2004-04-22 British Biotech Pharmaceuticals Ltd Agents antibacteriens
US7465719B2 (en) 2003-01-17 2008-12-16 Topotarget Uk Limited Carbamic acid compounds comprising an ester or ketone linkage as HDAC inhibitors
WO2004099124A3 (fr) * 2003-05-08 2005-01-20 Morphochem Ag Komb Chemie Nouveaux bioisosteres d'actinonine
WO2004099124A2 (fr) * 2003-05-08 2004-11-18 Morphochem Aktiengesellschaft für kombinatorische Chemie Nouveaux bioisosteres d'actinonine
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WO2005092872A1 (fr) * 2004-03-26 2005-10-06 Arpida A/S Inhibiteurs de peptide deformylase
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