WO2005097100A2 - Antibacterial agents - Google Patents

Antibacterial agents Download PDF

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Publication number
WO2005097100A2
WO2005097100A2 PCT/GB2005/001295 GB2005001295W WO2005097100A2 WO 2005097100 A2 WO2005097100 A2 WO 2005097100A2 GB 2005001295 W GB2005001295 W GB 2005001295W WO 2005097100 A2 WO2005097100 A2 WO 2005097100A2
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Prior art keywords
benzyl
methyl
hplc
purity
amino
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PCT/GB2005/001295
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French (fr)
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WO2005097100A3 (en
Inventor
Edward Andrew Boyd
Stuart Hatcher
Lloyd Czaplewski
Jeffrey Errington
David Brown
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Prolysis Ltd.
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Publication of WO2005097100A2 publication Critical patent/WO2005097100A2/en
Publication of WO2005097100A3 publication Critical patent/WO2005097100A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/32—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • This invention relates to the use of a class of beta arnino acids, di-substituted on the amino group, as antibacterial agents, to novel members of that class perse, and to pharmaceutical compositions comprising such compounds.
  • antibacterial agents including the penicillins and cephalosporins, tetracyclines, sulfona ides, monobactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol.
  • penicillins and cephalosporins including the penicillins and cephalosporins, tetracyclines, sulfona ides, monobactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol.
  • penicillins and cephalosporins tetracyclines
  • sulfona ides monobactams
  • fluoroquinolones and quinolones aminoglycosides
  • MRSA methicillin resistant Staphylococcus aureus
  • MRCNS methicillin resistant coagulase negative Staphylococci
  • Penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium.
  • Vancomycin-resistant enterococci are particularly hazardous in that they are frequent causes of hospital based infections and are inherently resistant to most antibiotics. Vancomycin works by binding to the terminal D-Ala-D-Ala residues of the cell wall peptidoglycan precursor.
  • the high-level resistance to vancomycin is known as VanA and is conferred by a genes located on a transposable element which alter the terminal residues to D-Ala-D-lac thus reducing the affinity for vancomycin.
  • This invention is based on the finding that a class of di-substituted beta-amino acids, and carboxyl isosteres thereof, have antibacterial activity as evidenced b-y inhibition of bacterial growth by members of that class.
  • ring A is an optionally substituted monocyclic aryl, heteroaryl or cycloalkyl radical
  • ring B is a monocyclic aryl, heteroaryl or cycloalkyl radical
  • R is (i) an optionally substituted monocyclic aryl, heteroaryl or cycloalkyl radical, or an optionally substituted cycloalkyl(CrC 6 alkyl)- radical in which the cycloalkyl moiety is monocyclic, or (ii) an optionally substituted CrC 6 alkyl radical which may be interrupted by -O-, -S-, or -NR 2 - wherein R 2 hydrogen or is C C 6 alkyl.
  • the invention includes (i) a method of treating bacterial infection in a subject suffering such infection comprising administering to the subject an amount of a compound of formula (I) as defined above, sufficient to inhibit bacterial growth, and (ii) a method of treating bacterial contamination of a substrate comprising applying to the site of such contamination an amount of a compound of formula (I) as defined above, sufficient to inhibit bacterial growth.
  • Carboxyl bioisostere radical is a substituent or group which has chemical or physical similarities to a carboxylic acid group.
  • (C a -C )alkyl wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms.
  • a 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
  • Carbocyclic refers to a cyclic radical whose ring atoms are all carbon, and includes monocyclic aryl and cycloalkyl
  • cycloalkyl refers to a saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • aryl refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical. Illustrative of such radicals are phenyl, biphenyl and napthyl.
  • heteroaryl refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O.
  • Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.
  • heterocyclyl or “heterocyclic” includes “heteroaryl” as defined above, and in particular means a mono-, bi- or tri-cyclic non- aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical.
  • radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups.
  • substituted as applied to any moiety herein means substituted with up to four compatible substituents, each of which is independently selected from (C ⁇ -C 6 )alkyl, (C C 6 )alkoxy, hydroxy, hydroxy(CrC 6 )alkyl, mercapto, mercapto(CrC 6 )alkyl, (C C 6 )alkylthio, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), oxo, phenyl, -COOH, -COOR A , -COR A , -SO 2 R A , -CONH 2 , -SO 2 NH 2 , -CONHR A , -SO 2 NHR A , -CONR A R B , -SO 2 NR A R B , -NH 2 , -
  • salt includes base addition, acid addition and quaternary salts.
  • Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyi-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
  • bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyi-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N
  • Those compounds (I) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesunfonic, glutamic, lactic, and mandelic acids and the like.
  • hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
  • organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzo
  • Radicals which are carboxyl isosteres are known in the art of medicinal chemistry and include those referrred to above.
  • a preferred such isostere is the 1 H-tetrazol-5-yl radical:
  • Preferred carboxyl esters include the methyl, ethyl and cyclopentyl esters.
  • Ring A is an optionally substituted monocyclic aryl, heteroaryl or cycloalkyl radical.
  • examples include optionally substituted cyclopentyl, cyclohexyl, 2-, 3-, or 4-pyridyl, and (currently preferred) optionally substituted phenyl, 2- or 3-furyl, or 2- or 3-thienyl radicals.
  • Optional substituents in ring A may be any of those specified above, and in particular may be selected from methyl, ethyl, n- and iso-propyl, n-, sec- and tert- butyl, trifluoromethyl, hydroxy, methoxy, mercapto, methylthio, fluoro, chloro, bromo, nitro, cyano, methylenedioxy and ethylenedioxy.
  • Ring B is a monocyclic aryl, heteroaryl or cycloalkyl radical.
  • examples include cyclopentyl, cyclohexyl, 2-, 3-, or 4-pyridyl, 2- or 3-furyl, or 2- or 3-thienyl radicals and (currently preferred) phenyl.
  • R ⁇ be hydrogen or methyl.
  • B is phenyl, it is currently preferred that X be -O-, -S-, -(CH 2 )-,
  • R is (i) an optionally substituted monocyclic aryl, heteroaryl, or cycloalkyl radical, or an optionally susbtituted cycloalky d-Ce alkyl)- radical in which the cycloalkyl moiety is monocyclic or (ii) an optionally substituted C C 6 alkyl radical which may be interrupted by -O-, -S-, or -NR 2 - wherein R 2 hydrogen or is C C 6 alkyl.
  • R may be, for example, an optionally substituted cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, 2-, 3-, or 4-pyridyl or (currently preferred) phenyl, 2- or 3-furyl, or 2- or 3-thienyl radical.
  • Optional substituents may be any of those listed above, for example selected from methylenedioxy, ethylenedioxy and (currently preferred) methyl, ethyl, n- and iso- propyl, n-, sec- and tert-butyl, trifluoromethyl, hydroxy, methoxy, mercapto, methylthio, fluoro, chloro, bromo, nitro, cyano.
  • R may be, for example, methyl, ethyl, n- or iso- propyl, n-, sec- or tert-butyl, CH 3 -O-CH 2 -, CH 3 -S-CH 2 -, CH 3 -NH-CH 2 -, CH 3 -N(CH 3 )- CH 2 -, CH 3 -O-CH 2 -, CH 3 -S-CH 2 -, CH 3 -NH-CH 2 -,
  • Compounds of formula (I) wherein Z is a carboxyl radical may be prepared by alkylation of a disubstituted amino compound of formula (II) wherein P is a hydroxyl protecting group, using an aldehyde (III) and removal of the protecting group P.
  • the protecting group may be a resin, for solid support synthesis.
  • Compounds (II) may be prepared by a Michael addition reaction of a compound (IV) and the mono-substituted amino compound (V).
  • Compounds of formula (I) wherein Z is a 1 H-tetrazol-5-yl radical may be prepared by the cycloaddition reaction of the nitrile compound (VI) with azidotrimethyltin.
  • the nitrile (VI) may be prepared by reaction of a disubstituted amino compound (VII) with bromoacetonitrile.
  • the disubstituted amino compound (VII) may be prepared by alkylation of a monosubstituted amino compound of formula (VIII) using aldehyde (III) above.
  • HPLC-MS instrument comprises: Hewlett Packard 1312A binary pump Hewlett Packard 1314A variable wavelength detector (set at 215nm) Gilson 215 autosampler fitted with a 1 ml syringe Polymer Labs PL1000 Evaporative Light Scattering Detector (where fitted) Micromass ZMD mass spectrometer operating in Electrospray positive ionisation mode.
  • the LC eluent is split, after flowing through the VWD uv detector, and approximately 200 ⁇ l/min enters the mass spectrometer, 800 ⁇ l/min to the ELS (where fitted).
  • the instruments were controlled using Micromass MassLynx 3.5 software under Windows NT4.0
  • Step 3 Cleavage of ⁇ -Amino Acid from resin : 3-[(3-Methyl-benzyl)-(3-phenoxy- benzyl)-amino]-propionic acid (Compound 1)
  • Step 2 Alkylation: [(3-Methyl-benzyl)-(3-phenoxybenzyl)-amino]-acetonitrile
  • Step 3 Cycloaddition: (3-Methyl-benzyl)-(3-phenoxy-benzyl )-(1 H-tetrazol-5-ylmethyl)-amine (Compound 2)
  • the aqueous phase was then diluted with EtOAc (2.5ml) and this biphasic solution was stirred for 2mins before the organic layer was removed. This process was repeated.
  • the aqueous phase was acidified using aq. HCI (2M) and diluted with EtOAc (2.5ml). This mixture was stirred for 1 hr and then the organic layer was separated. This extraction procedure was repeated a further two times. The post-acidification organic fractions were combined, dried (MgSO 4 ), filtered and the solvent was concentrated in vacuo.
  • the crude product was purified by column chromatography on SiO 2 using 5% EtOAc/hexanes as the eluent to provide the desired product as a colourless oil (35mg, 31 % yield).
  • Example 104 3- ⁇ (3-Fluoro-benzyl)-[3-(1 -phenyl-vinyl)-benzyl]-amino ⁇ -propionic acid
  • Example 170 3-[(3-Cyclohexylmethoxy-benzyl)-(5-methyl-furan-2- ylmethyl)-amino]-propionic acid
  • Example 202 3-[(2-Chloro-5-trif luoromethyl-benzyl)-(4-methyl-th_ iophen-2- ylmethyl)-amino]-propionic acid
  • the compounds of the above examples were tested in the following antibacterial assay as one estimate of their activity.
  • Microtitre plates containing 100 ⁇ l volumes of the test compounds (standard concentration range: 1 -128 ⁇ g/ml) in 1.6% dimethyl sulfoxide were inoculated with 10 ⁇ l inocula of Bacillus subtilis 168 CA with A 600 n m measuring 0.06 in S medium + 3% CH (Sharpe et al, 1998. J. Bacteriol. 180, 547- 555). Plates were incubated at 37°C with agitation until A 6 oo ⁇ m measured between 0.25 and 0.30 in the control (no compound) samples.
  • volumes (20 ⁇ l) were sampled on to poly-L-lysine treated slides and cells were examined by phase-microscopy at 100 x magnification under oil-immersion. The tested compounds were observed to inhibit bacterial cell division, and to produce a filamentous phenotype, ie having an average cell length in cultures greater than or equal to twice the average cell length in control culture.
  • MICs minimum inhibitory concentrations
  • Bacillus subtilis 168 CA - MICS were determined by the broth microdilution method (National Committee for Olinical Laboratory Standards. 2000. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard - 5th ed.).
  • Microtitre plates containing the test compounds were inoculated with a starting inoculum of 5x10 5 cfu/ml.
  • Mueller-Hinton broth (Oxoid) was used as a growth medium The MIC was defined as the lowest concentration of compound inhibiting visible growth. Activities were scored as 'A' if the MIC was single digit eg. ⁇ 8 microgrammes/ml, 'B' if the MIC was 16 to 64 microgrammes/ml and 'C if the MIC was greater than 64 microgrammes/ml.

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Abstract

Use of compounds of formula (I) as antibacterial agents: Formula (I), wherein Z is a carboxyl radical HOC (∼O)-, a carboxyl ester radical, or a carboxyl isostere radical; ring A is an optionally substituted monocyclic aryl, heteroaryl or cycloalkyl radical; ring B is a monocyclic aryl, heteroaryl or cycloalkyl radical; X is çO-, -S-, -(CH2)-, ç(CH=CH)-, -C (=C?2)-, -CH (CH3)-, -C(=O)-, -C(=S)-, -C(=NR1)-, orçNR1-wherein R1 is hydrogen or C1-C6 alkyl; R is (i) an optionally substituted monocyclic aryl, heteroaryl, or cycloalkyl radical, or an optionally substituted cycloalkyl(C1-C6 alkyl)- radical in which the cycloalkyl moiety is monocyclic, or (ii) an optionally substituted C1-C6 alkyl radical which may be interrupted by çO-, -S-, or -çNR2-wherein R2 hydrogen or is C1-C6 alkyl.

Description

Antibacterial Agents
This invention relates to the use of a class of beta arnino acids, di-substituted on the amino group, as antibacterial agents, to novel members of that class perse, and to pharmaceutical compositions comprising such compounds.
Background to the Invention
Many classes of antibacterial agents are known, including the penicillins and cephalosporins, tetracyclines, sulfona ides, monobactams, fluoroquinolones and quinolones, aminoglycosides, glycopeptides, macrolides, polymyxins, lincosamides, trimethoprim and chloramphenicol. The fundamental mechanisms of action of these antibacterial classes vary.
Bacterial resistance to many known antibacterials is a growing problem. Accordingly there is a continuing need in the art for alternative antibacterial agents, especially those that have mechanisms of action fundamentally different from the known classes.
Amongst the Gram-positive pathogens, such as Staphylococci, Streptococci, Mycobacteria and Enterococci, resistant strains have evolved/arisen which makes them particularly difficult to eradicate. Examples of such strains are methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant coagulase negative Staphylococci (MRCNS), penicillin resistant Streptococcus pneumoniae and multiply resistant Enterococcus faecium.
Recently there has been an emergence of vancomycin-resistant strains of enterococci (Woodford N., 1998. Glycopeptide-resistant enterococci: a decade of experience. Journal of Medical Microbiology. 47: 849-62). Vancomycin-resistant enterococci are particularly hazardous in that they are frequent causes of hospital based infections and are inherently resistant to most antibiotics. Vancomycin works by binding to the terminal D-Ala-D-Ala residues of the cell wall peptidoglycan precursor. The high-level resistance to vancomycin is known as VanA and is conferred by a genes located on a transposable element which alter the terminal residues to D-Ala-D-lac thus reducing the affinity for vancomycin.
In view of the rapid emergence of multidrug-resistant bacteria, the development of antibacterial agents with novel modes of action that are effective against the growing number of resistant bacteria, particularly the vancomycin resistant enterococci and beta-lactam antibiotic-resistant bacteria, such as methicillin-resistant Sta/ohylococcus aureus, is of utmost importance.
Brief Description of the Invention
This invention is based on the finding that a class of di-substituted beta-amino acids, and carboxyl isosteres thereof, have antibacterial activity as evidenced b-y inhibition of bacterial growth by members of that class.
Detailed Description of the Invention
According to a broad aspect of the invention, there is provided the use of a compound of formula (I), or a salt, hydrate, or solvate thereof, in the man ufacture of an antibacterial composition:
Figure imgf000003_0001
wherein
Z is a carboxyl radical HOC(=O)-, a carboxyl ester radical, or a carboxyl i sostere radical;
ring A is an optionally substituted monocyclic aryl, heteroaryl or cycloalkyl radical;
ring B is a monocyclic aryl, heteroaryl or cycloalkyl radical;
X is -O-, -S-, -(CH2)-, -(CH=CH)-, -C(=CH2)- , -CH(CH3)-, -C(=O)-, -C(=S)-, - C(=NR1)-, or -NRr wherein R is hydrogen or C-ι-C6 alkyl;
R is (i) an optionally substituted monocyclic aryl, heteroaryl or cycloalkyl radical, or an optionally substituted cycloalkyl(CrC6 alkyl)- radical in which the cycloalkyl moiety is monocyclic, or (ii) an optionally substituted CrC6 alkyl radical which may be interrupted by -O-, -S-, or -NR2- wherein R2 hydrogen or is C C6 alkyl. In another broad aspect, the invention includes (i) a method of treating bacterial infection in a subject suffering such infection comprising administering to the subject an amount of a compound of formula (I) as defined above, sufficient to inhibit bacterial growth, and (ii) a method of treating bacterial contamination of a substrate comprising applying to the site of such contamination an amount of a compound of formula (I) as defined above, sufficient to inhibit bacterial growth.
Members of the class of compounds defined by formula (I) above are believed novel in their own right, apart from those of formula (IX) and (IX) below, and the invention includes such novel members of the class, as more fully elaborated below. The compounds (IX) and (X)
Figure imgf000004_0001
are disclosed, without any attribution of biological activity, in Mclean et. al., J. Chem. Soc. Perkin Transactions 1 : Organic and Bio-Organic Chemistry, 1973, (10), 1084-8 and Caputo et. al., EU. J. Org. Chem., (2002), (17), 3050-3054.
Definitions
As used herein, a "carboxyl bioisostere radical" is a substituent or group which has chemical or physical similarities to a carboxylic acid group. Carboxyl bioisosteres include -SO2OH, -P(=O)(NH2)OH, -C(=O)NHCN, -SO2NHR and -P(=O)(OR)OH, wherein R is methyl or ethyl, and cyclic radicals such as:
Figure imgf000004_0002
As used herein, the term "(Ca-C )alkyl" wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms. Thus when a is 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.
As used herein the term "carbocyclic" refers to a cyclic radical whose ring atoms are all carbon, and includes monocyclic aryl and cycloalkyl
As used herein the term "cycloalkyl" refers to a saturated carbocyclic radical having from 3-8 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
As used herein the unqualified term "aryl" refers to a mono-, bi- or tri-cyclic carbocyclic aromatic radical. Illustrative of such radicals are phenyl, biphenyl and napthyl.
As used herein the unqualified term "heteroaryl" refers to a mono-, bi- or tri-cyclic aromatic radical containing one or more heteroatoms selected from S, N and O. Illustrative of such radicals are thienyl, benzthienyl, furyl, benzfuryl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl, benzthiazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, oxazolyl, benzoxazolyl, isoxazolyl, benzisoxazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl and indazolyl.
As used herein the unqualified term "heterocyclyl" or "heterocyclic" includes "heteroaryl" as defined above, and in particular means a mono-, bi- or tri-cyclic non- aromatic radical containing one or more heteroatoms selected from S, N and O, and to groups consisting of a monocyclic non-aromatic radical containing one or more such heteroatoms which is covalently linked to another such radical or to a monocyclic carbocyclic radical. Illustrative of such radicals are pyrrolyl, furanyl, thienyl, piperidinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl, morpholinyl, benzfuranyl, pyranyl, isoxazolyl, benzimidazolyl, methylenedioxyphenyl, ethylenedioxyphenyl, maleimido and succinimido groups. Unless otherwise specified in the context in which it occurs, the term "substituted" as applied to any moiety herein means substituted with up to four compatible substituents, each of which is independently selected from (Cι-C6)alkyl, (C C6)alkoxy, hydroxy, hydroxy(CrC6)alkyl, mercapto, mercapto(CrC6)alkyl, (C C6)alkylthio, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitrile (-CN), oxo, phenyl, -COOH, -COORA, -CORA, -SO2RA, -CONH2, -SO2NH2, -CONHRA, -SO2NHRA, -CONRARB, -SO2NRARB, -NH2, -NHRA, -NRARB, -OCONH2, -OCONHRA ,-OCONRARB, -NHCORA, -NHCOORA, -NRBCOORA, -NHSO2ORA, -NRBSO2OH, -NRBSO2ORA,-NHCONH2, -NRACONH2, -NHCONHRB -NRACONHRB, -NHCONRARB , and -NRACONRARB wherein RA and RB are independently a (CrC6)alkyl group. An "optional substituent" is one of the foregoing substituent groups.
As used herein the term "salt" includes base addition, acid addition and quaternary salts. Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyi-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like. Those compounds (I) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesunfonic, glutamic, lactic, and mandelic acids and the like.
Compounds of the invention which contain one or more actual or potential chiral centres, because of the presence of asymmetric carbon atoms, can exist as a number of diastereoisomers with R or S stereochemistry at each chiral centre. The invention includes all such diastereoisomers and mixtures thereof.
The radical Z
Z is a carboxyl HOC(=O)-, carboxyl ester, or a carboxyl isostere radical. Radicals which are carboxyl isosteres are known in the art of medicinal chemistry and include those referrred to above. A preferred such isostere is the 1 H-tetrazol-5-yl radical:
Figure imgf000007_0001
Preferred carboxyl esters include the methyl, ethyl and cyclopentyl esters.
The ring A
Ring A is an optionally substituted monocyclic aryl, heteroaryl or cycloalkyl radical. Examples include optionally substituted cyclopentyl, cyclohexyl, 2-, 3-, or 4-pyridyl, and (currently preferred) optionally substituted phenyl, 2- or 3-furyl, or 2- or 3-thienyl radicals. Optional substituents in ring A may be any of those specified above, and in particular may be selected from methyl, ethyl, n- and iso-propyl, n-, sec- and tert- butyl, trifluoromethyl, hydroxy, methoxy, mercapto, methylthio, fluoro, chloro, bromo, nitro, cyano, methylenedioxy and ethylenedioxy.
The ring B
Ring B is a monocyclic aryl, heteroaryl or cycloalkyl radical. Examples include cyclopentyl, cyclohexyl, 2-, 3-, or 4-pyridyl, 2- or 3-furyl, or 2- or 3-thienyl radicals and (currently preferred) phenyl.
The radical X
X is -O-, -S-, -(CH2)-, -(CH=CH)-, -C(=CH2)- , -CH(CH3)-, -C(=O)-, -C(=S)-,
-C(=NR1)-, or -NRr wherein R is hydrogen or C C6 alkyl. When X is
-C(=NR1)-, or -NRr it is currently preferred that R^ be hydrogen or methyl. When B is phenyl, it is currently preferred that X be -O-, -S-, -(CH2)-,
-C(=CH2)- or -(CH=CH)- preferably in the 3- or 4-position of the phenyl ring B.
The radical R
R is (i) an optionally substituted monocyclic aryl, heteroaryl, or cycloalkyl radical, or an optionally susbtituted cycloalky d-Ce alkyl)- radical in which the cycloalkyl moiety is monocyclic or (ii) an optionally substituted C C6 alkyl radical which may be interrupted by -O-, -S-, or -NR2- wherein R2 hydrogen or is C C6 alkyl.
In the case of the first option (i) R may be, for example, an optionally substituted cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, 2-, 3-, or 4-pyridyl or (currently preferred) phenyl, 2- or 3-furyl, or 2- or 3-thienyl radical. Optional substituents may be any of those listed above, for example selected from methylenedioxy, ethylenedioxy and (currently preferred) methyl, ethyl, n- and iso- propyl, n-, sec- and tert-butyl, trifluoromethyl, hydroxy, methoxy, mercapto, methylthio, fluoro, chloro, bromo, nitro, cyano.
In the case of the second option (ii) R may be, for example, methyl, ethyl, n- or iso- propyl, n-, sec- or tert-butyl, CH3-O-CH2-, CH3-S-CH2-, CH3-NH-CH2-, CH3-N(CH3)- CH2-, CH3-O-CH2-, CH3-S-CH2-, CH3-NH-CH2-,
CH3-N(CH3)-CH2-, CH3CH2-O-CH2-, CH3CH2-S-CH2-, CH3CH2-NH-CH2-, CH3CH2- N(CH3)-CH2-, CH3-O-CH2CH2-, CH3-S-CH2CH2-, CH3-NH-CH2CH2-, or CH3-N(CH3)- CH2CH2- radical. Optional substituents may again be selected from any of those listed above. Currently preferred R radicals are methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl.
A specific subset of compounds of formula (I) with which the invention is concerned consists of those wherein ring A is optionally substituted phenyl, 2- or 3-thienyl, or 2- or 3-furyl; ring B is phenyl; X is -O-, -S-, -(CH2)-, -C(=CH2)- or -(CH=CH)- in the 3- or 4-position of the phenyl ring B; R is methyl, ethyl, n- or iso-propyl, n-, sec- or tert- butyl, or optionally substituted phenyl, cyclohexyl, 2- or 3-thienyl, 2- or 3-furyl; and wherein any optional substituents are selected from methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, trifluoromethyl, hydroxy, methoxy, mercapto, methylthio, fluoro, chloro, bromo, nitro, or cyano, and of course the salts, prodrugs, hydrates and solvates thereof.
Specific compounds with which the invention is concerned include those of the Examples below.
Compounds of formula (I) wherein Z is a carboxyl radical may be prepared by alkylation of a disubstituted amino compound of formula (II) wherein P is a hydroxyl protecting group, using an aldehyde (III) and removal of the protecting group P. The protecting group may be a resin, for solid support synthesis.
Figure imgf000009_0001
(ll) (III)
Compounds (II) may be prepared by a Michael addition reaction of a compound (IV) and the mono-substituted amino compound (V).
Figure imgf000009_0002
Details of the foregoing route are further elaborated in the Examples herein.
Compounds of formula (I) wherein Z is a 1 H-tetrazol-5-yl radical may be prepared by the cycloaddition reaction of the nitrile compound (VI) with azidotrimethyltin.
Figure imgf000009_0003
The nitrile (VI) may be prepared by reaction of a disubstituted amino compound (VII) with bromoacetonitrile.
Figure imgf000010_0001
The disubstituted amino compound (VII) may be prepared by alkylation of a monosubstituted amino compound of formula (VIII) using aldehyde (III) above.
Figure imgf000010_0002
Details of this route to tetrazolyl compounds of formula (I) are elaborated in the Examples herein.
The following examples illustrate the synthesis of compounds with which the invention is concerned. In these examples, the analytical methods used to characterise compounds comprised HPLC-MS and 1H and 13C NMR.
Abbreviations
DBU 1 ,8-Diazabicyclo[5.4.0]undec-7-ene
DMF Λ/,Λ/-Dimethylformamide
HPLC High performance liquid chromatography
MS Mass spectrometry
NMR Nuclear magnetic resonance
Rt Retention Time
TBME tert-Butyl methyl ether
TFA Trifluoroacetic acid
THF Tetrahydrofuran
HPLC-MS instrument comprises: Hewlett Packard 1312A binary pump Hewlett Packard 1314A variable wavelength detector (set at 215nm) Gilson 215 autosampler fitted with a 1 ml syringe Polymer Labs PL1000 Evaporative Light Scattering Detector (where fitted) Micromass ZMD mass spectrometer operating in Electrospray positive ionisation mode.
The LC eluent is split, after flowing through the VWD uv detector, and approximately 200μl/min enters the mass spectrometer, 800μl/min to the ELS (where fitted). The instruments were controlled using Micromass MassLynx 3.5 software under Windows NT4.0
HPLC Conditions
Mobile Phase: Aqueous - Water + 0.1 % Trifluoroacetic acid Organic - Acetonitrile + 0.1 % Trifluoroacetic acid
Gradient:
Figure imgf000011_0001
Run time: 2.4 mins Flow rate: 1 ml/min Injection vol: 3 μl
Column temperature: ambient (20°C)
Column: 50 x 2.0mm Hypersil C18 BDS; 5μm UV Detector Variable wavelength detector set at 215nm ELS Detector Nebuliser Temperature 80°C Evaporation temperature 90°C Gas Flow 1.5 l/hr
MS Detector m/z 150-800 @ 0.5secs/scan, 0.1 second interscan delay Cone voltage 25V, Source Temp. 140°C Drying Gas 350 l/hr Using these conditions the error bar for the retention time was + 0.15 min. NMR
1 H NMR spectra were recorded on a 400MHz Bruker NMR machine.
Example 1 : Preparation of 3-[(3-Methyl-benzyl)-(3-phenoxy-benzyl)-amino]- propionic acid
stepl
Figure imgf000012_0001
Figure imgf000012_0003
Figure imgf000012_0002
Scheme 1
Step 1 Michael addition
To a round-bottomed flask containing Wang acrylate (25g, 29.25mmol, 1.17mmol/g) and DMF (250ml) was added 3-methylbenzylamine (17.7g, 146.5mmol, 5eq) and DBU (22.2g, 146.5mmol, 22ml, 5eq). The mixture was agitated for 72hrs and the resin collected by filtration. The resin was washed with [DMF (3 x 50ml), MeOH (3 x 50ml)] x 3; [DCM (3 x 50ml), MeOH (3 x 50ml)] x 3; 50ml CH2CI2 and TBME (3 x 50ml) and dried in a vacuum oven overnight (31.13g recovered, 1.05mmol/g). To check that the reaction was complete 0.01 g of resin was cleaved (1 ml of 50% TFA/CH2CI2 for 20 mins), filtered and the filtrate concentrated in vacuo to give an oil. HPLC-MS: O.δOmin t77/z 193 [ +H]+.
Step 2 Reductive Alkyl ation
To a round bottomed flask containing the resin from step 1 (31.13g, 29.25mmol) in DMF (250ml) was added 3-phenoxybenzaldehyde (57.9g, 292.5mmol, 10eq) and acetic acid (17.55g, 292.5mmol, 16.7ml, 10eq). After shaking for 15mins sodium tnacetoxyborohydride (62.0g, 292.5mmol, 10eq) was added and the resulting mixture was agitated for 20hrs.The resin was then collected by filtration and washed with [DMF (3 x 100ml), MeOH (3 x 100ml)] x 3; [DCM (3 x 100ml), MeOH (3 x 100ml)] x 3; 100ml CH2CI2 and TBME (3 x 100ml) and dried in the vacuum oven overnight (41.56g recovered, 0.70mmol/g). To check that the reaction was complete 0.01 g of resin was cleaved (1 ml of 50% TFA/CH2CI2 for 20 mins), filtered and the filtrate concentrated in vacuo to give an oil. HPLC-MS: 1.69min m/z375 [M+H]+.
Step 3 Cleavage of β-Amino Acid from resin : 3-[(3-Methyl-benzyl)-(3-phenoxy- benzyl)-amino]-propionic acid (Compound 1)
To a round bottomed flask containing the resin from step 2 in CH2CI2 (150ml) was added TFA (130ml). After shaking for 30 mins, the resin (that was now purple in colour) was collected by filtration and washed with CH2CI2 (100ml). The filtrate was concentrated in vacuo to give the crude product as a yellow oil that was purified by column chromatography on SiO2 using 3% MeOH/CH2CI2 as eluent to give the desired TFA adduct as a yellow oil (1 1.55g, 80% yield) 1H NMR (CDCI3): 7.34 (m, 3H), 7.26 (m, 2H), 7.15 (m, 4H), 7.00 (m, 4H), 4.23 (bm, 4H), 3.35 (2H, bt), 2.83 (2H, bt), 2.33 (s, 3H).
Example 2: Preparation of (3-Methyl-benzyl)-(3-phenoxy-benzyl)-(1 H-tetrazol- 5-ylmethyl)-amine stepl
Figure imgf000013_0001
Figure imgf000013_0002
step2
Figure imgf000013_0003
Scheme 2 Step 1 - Reductive Alkylation: (3-Methyl-benzyl)-(3-phenoxy-benzyl)-amine
To a solution of 3-methylbenzylamine (5.0g, 41.3mmol, 1.1 eq) in THF (50ml) at room temperature under nitrogen was added 3-phenoxybenzaldehyde (7.5g, 37.8mmol, 1 eq) followed by acetic acid (3.4g, 56.6rπmol, 1.5eq). The mixture was stirred for 16hrs and then cooled to 0°C before sodium borohy ride (2.14g, 56.6mmol, 1.5eq) was introduced in portions. The resulting suspension was stirred for 15mins at 0°C and then warmed to room temperature where it was maintained for 4hrs. After this time the reaction was cooled to 0°C and quenched by the addition of water (50ml). The mixture was extracted with EtOAc (3 x 50ml) and the combined extracts were washed with brine, dried (MgSO4), filtered and the solvent was concentrated in vacuo. The crude product was purified by column c romatography on SiO2 using 40% EtOAc/hexanes as the eluent to give the desired product as a colourless oil (6.45g, 56% yield). HPLC-MS: 1.36min tπ/z 304 [M+H]+. 1H NMR (CDCI3) 7.38-6.95 (m, 13H), 3.82 (s, 2H), 3.79 (s, 2H), 2.38 (s, 3H).
Step 2 - Alkylation: [(3-Methyl-benzyl)-(3-phenoxybenzyl)-amino]-acetonitrile
To a solution of (3-methyl-benzyl)-(3-phenoxy-benzyl)-amine from stepl (1 g, 3.3mmol, 1 eq) in DMF (2.5ml) at room temperature under nitrogen was added bromoacetonitrile (435mg, 3.63mmol, 1.1 eq) followed by caesium carbonate (1.61g, 4.94mmol, 1.5eq) and sodium iodide (49mg, 0.33mmol, 0.1 eq). The reaction was stirred at room temperature for 16hrs and then diluted with EtOAc (10ml) and washed with brine (3 x 10ml). The aqueous washings were extracted with EtOAc (1 x 10ml) and the organic layers were combined, dried (MgSO4), filtered and the solvent was concentrated in vacuo. The crude product was purified by column chromatography on SiO2 using 20% EtOAc/hexanes as the eluent to provide the desired product as a colourless oil (920mg, 81 % yield). HPLC-MS: 1.94rrιin m/z 343 [M+H]+. 1H NMR (CDCI3) 7.40-6.99 (m, 13H), 3.76 (s, 2H), 3.72 (s, 2H), 3.42 (s, 2H), 2.39 (s, 3H).
Step 3 - Cycloaddition: (3-Methyl-benzyl)-(3-phenoxy-benzyl )-(1 H-tetrazol-5-ylmethyl)-amine (Compound 2)
To a solution of [(3-methyl-benzyl)-(3-phenoxy-benzyl)-amino]-acetonitrile from step2 (100mg, 0.29mmol, 1 eq) in toluene (5ml) at room temperature under nitrogen was added azidotrimethyltin (71.6mg, 0.35mmol, 1.2eq). The resulting mixture was heated to reflux where it was maintained for 20hrs. After this time, the reaction was cooled to room temperature and partitioned between NaOH (0.2ml of a 2M solution) and hexanes (0.5ml). The mixture was stirred for lOrnins and then the organic layer was removed. The aqueous phase was then diluted with EtOAc (2.5ml) and this biphasic solution was stirred for 2mins before the organic layer was removed. This process was repeated. The aqueous phase was acidified using aq. HCI (2M) and diluted with EtOAc (2.5ml). This mixture was stirred for 1 hr and then the organic layer was separated. This extraction procedure was repeated a further two times. The post-acidification organic fractions were combined, dried (MgSO4), filtered and the solvent was concentrated in vacuo. The crude product was purified by column chromatography on SiO2 using 5% EtOAc/hexanes as the eluent to provide the desired product as a colourless oil (35mg, 31 % yield). HPLC-MS: 1.45min m z 386 [M+H]+. 1H NMR (CDCI3) 7.27-6.86 (m, 13H), 4.03 (s, 2H), 3.70 (s, 2H), 3.68 (s, 2H), 2.24 (s, 3H).
The following further compounds were synthesised by the route described in Example 1.
Example 3 3-[(3-Methyl-benzyl)-(4-phenoxy-benzyl)-amino]-propionic acid
Figure imgf000015_0001
Mono TFA salt. HPLC-MS: m/z 376 [M+H]+. Rt = 1.44 min. Purity 98%
Example 4 3-[[3-(4-tet?-Butyl-phenoxy)-benzyl]-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000015_0002
Mono TFA salt. HPLC-MS: m/z 432 [M+H]+. Rt = 2.01 min. Purity 91 %
Example 5 3-[[3-(4-Methoxy-phenoxy)-benzyl]-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000015_0003
Mono TFA salt. HPLC-MS: m/z 406 [M+H]+. Rt = 1.77 min. Purity 100% Example 6 3-[(3-Methyl-benzyl)-(3-p-tolyloxy-benzyl)-amino]-propionic acid
Figure imgf000016_0001
Mono TFA salt. HPLC-MS: m z 390 [M+H]+. Rt = 1.68 min. Purity 95%
Example 7 3-[(3-Fluoro-benzyl)-(4-phenoxy-benzyl)-amino]-propionic acid
Figure imgf000016_0002
Mono TFA salt. HPLC-MS: m/z 380 [M+H]+. Rt = 1.71 min. Purity 100%
Example 8 3-[(3-Fluoro-benzyl)-(3-phenoxy-benzyl)-amino]-propionic acid
Figure imgf000016_0003
Mono TFA salt. HPLC-MS: m/z 380 [M+H]+. Rt = 1.71 min. Purity 100%
Example 9 3-{(3-Fluoro-benzyl)-[3-(4-methoxy-phenoxy)-benzyl]-amino}-propionic acid
Figure imgf000016_0004
Mono TFA salt. HPLC-MS: m/z 410 [M+H]+. Rt = 1.71 min. Purity 100% Example 10 3-[(2,5-Dimethyl-ber_ zyl)-(3-phenoxy-benzyl)-amino]-propionic acid
Figure imgf000017_0001
Mono TFA salt. HPLC-MS: m/z 390 [M+H]+. Rt = 1.46 min. Purity 100%
Example 11 3-[(2,6-Difluoro-3-methyl-benzyl)-(3-phenoxy-benzyl)-amino]-propionic acid
Figure imgf000017_0002
Mono TFA salt. HPLC-MS: m/z412 [M+H]+. Rt = 1.34min. Purity 96%
Example 12 3-[(2,6-Difluoro-3-methyl-benzyl)-(4-phenoxy-benzyl)-amino]-propionic acid
Figure imgf000017_0003
Mono TFA salt. HPLC-MS: m/z412 [M+H . Rt = 1.42min. Purity 98%
Example 13 3-[(3-Benzyl-benzyl)-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000017_0004
Mono TFA salt. HPLC-MS: m/z 374 [M+H]+. Rt = 1.43min. Purity 100% Example 14 3-[(3-Benzyl-benzyl)-(2,5-dimethyl-benzyl)-amino]-propionic acid
Figure imgf000018_0001
Mono TFA salt. HPLC-MS: m/z 388 [M+Hf. Rt = 1.47min. Purity 91 %
Example 15 3-.(3-Benzvl-benzvl.-.4-fluoro-3-methvl-benzvlVamino]-propionic acid
Figure imgf000018_0002
Mono TFA salt. HPLC-MS: m/z 392 [M+H]+. Rt = 1.44min. Purity 100%
Example 16 3-[(3-Benzyl-benzyl)-(5-methyl-furan-2-ylmethyl)-amino]-propionic acid
Figure imgf000018_0003
Mono TFA salt. HPLC-MS: m/z 364 [M+Hf". Rt = 1.37min. Purity 92%
Example 17 3-[(3-Methyl-benzyl)-(3-phenylsulfanyl-benzyl)-amino]-propionic acid
Figure imgf000018_0004
Mono TFA salt. HPLC-MS: m/z 392 [M+Hf. Rt = 1.44min. Purity 98% Example 18 3-[(2,5-Dimethyl-benzyl)-(3-phenylsulfanyl-benzyl)-amino]-propionic acid
Figure imgf000019_0001
Mono TFA salt. HPLC-MS: m/z 406 [M+H]+. Rt = 1.48min. Purity 98%
Example 19 3-[(5-Methyl-furan-2-ylmethyl)-(3-phenylsulfanyl-benzyl)-amino]- propionic acid
Figure imgf000019_0002
Mono TFA salt. HPLC-MS: m/z 382 [M+Hj+. Rt = 1.38min. Purity 98%
Example 20 3-[(3-Benzyl-benzyl)-(2,6-difluoro-3-methyl-ben__:yl)-amino]-propionic acid
Figure imgf000019_0003
Mono TFA salt. HPLC-MS: m/z410 [M+H]+. Rt = 1.43min. Purity 97%
Example 21 3-[(3-Benzyl-benzyl)-(2-chloro-6-fluoro-3-methyl-benzyl)-amino]- propionic acid
Figure imgf000019_0004
Mono TFA salt. HPLC-MS: m/z 426 [M+H]+. Rt = 1.47min. Purity 96% Example 22 3-[(3-Benzyl-benzyl)-(6-chloro-2-fluoro-3-methyI -benzyl)-amino]- propionic acid
Figure imgf000020_0001
Mono TFA salt. HPLC-MS: m/z 426 [M+H]+. Rt = 1.45min. Purity 95%
Example 23 3-[(2,6-Difluoro-3-methyl-benzyl)-(3-phenylsulfanyl-benzyl)-amino]- propionic acid
Figure imgf000020_0002
Mono TFA salt. HPLC-MS: m/z 428 [M+H]+. Rt = 1.45min. Purity 90%
Example 24 3-[[3-(3-Chloro-phenoxy)-benzyl]-(3-methyl-ben_zyl)-amino]-propionic acid
Figure imgf000020_0003
Mono HCI salt. HPLC-MS: m/z 410 [M+H]+. Rt = 1.38min. Purity 90%
Example 25 3-[[3-(4-Fluoro-phenoxy)-benzyl]-(3-methyl-ben_?:yl)-amino]-propionic acid
Figure imgf000020_0004
Mono HCI salt. HPLC-MS: m/z 394 [M+H]+. Rt = 1.48min. Purity 96% Example 26 3-{(3-Methyl-benzyl)-[3-(4-nitro-phenoxy)-benzyl]-amino}-propionic acid
Figure imgf000021_0001
Mono TFA salt. HPLC-MS: m/z 421 [M+H]+. Rt = 1.81 min. Purity 94%
Example 27 3-[[3-(4-Cyano-phenoxy)-benzyl]-(3-methyl-benzyl)-amino]-propi nic acid
Figure imgf000021_0002
Mono HCI salt. HPLC-MS: m/z 401 [M+Hf. Rt = 1.73min. Purity 99%
Example 28 3-{(3-Methyl-benzyl)-[3-(thiophen-3-yloxy)-benzyl]-amino}-propio nic acid
Figure imgf000021_0003
Mono HCI salt. HPLC-MS: m/z 382 [M+Hf. Rt = 1.72min. Purity 85%
Example 29 3-[(3-Cyclohexyloxy-benzyl)-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000021_0004
Mono TFA salt. HPLC-MS: m/z 382 [M+Hf. Rt = 1.85min. Purity 93% Example 30 3-[(6-Chloro-2-fluoro-3-methyl-benzyl)-(3-cyclohexyloxy-benzyl)- aminofpropionic acid
Figure imgf000022_0001
Mono TFA salt. HPLC-MS: m/z 434 [M+Hf. Rt = 1.89min. Purity 92%
Example 31 3-[(3-Cyclohexyloxy-benzyl)-(2,6-difluoro-3-methyl-benzyl)-amino]- propionic acid
Figure imgf000022_0002
Mono TFA salt. HPLC-MS: m/z 418 [M+Hf. Rt = 1.85min. Purity 94%
Example 32 3-[(3-Cyclohexyloxy-benzyl)-(5-methyl-furan-2-ylmethyl)-amino]- propionic acid
Figure imgf000022_0003
Mono TFA salt. HPLC-MS: m/z 372 [M+Hf. Rt = 1.79min. Purity 89%
Example 33 3-[(4-Benzyl-benzyl)-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000022_0004
Mono TFA salt. HPLC-MS: m/z 374 [M+Hf. Rt = 1.85min. Purity 95% Example 34 3-[(4-Benzyl-benzyl)-(6-chloro-2-fluoro-3-methyl-benzyl)-amino]- propionic acid
Figure imgf000023_0001
Mono TFA salt. HPLC-MS: m/z 426 [M+Hf. Rt = 1.88min. Purity 94%
Example 35 3-[(4-Benzyl-benzyl)-(3-fluoro-benzyl)-amino]-propionic acid
Figure imgf000023_0002
Mono TFA salt. HPLC-MS: m/z 378 [M+Hf. Rt = 1.81 min. Purity 97% Example 36 3-[(3-Butoxy-benzyl)-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000023_0003
Mono TFA salt. HPLC-MS: m/z 356 [M+Hf. Rt = 1.81 min. Purity 88%
Example 37 3-[(3-Butoxy-benzyl)-(6-chloro-2-fluoro-3-methyl-benzyl)-amino]- propionic acid
Figure imgf000023_0004
Mono TFA salt. HPLC-MS: m/z 408 [M+Hf. Rt = 1.87 min. Purity 83%. Example 38 3-[(3-Butoxy-benzyl)-(2,6-difluoro-3-methyl-benzyl)-amino]-propionic acid
Figure imgf000024_0001
Mono TFA salt. HPLC-MS: m/z 392 [M+Hf. Rt = 1.83 min. Purity 90%.
Example 39 3-[(2,5-Dimethyl-benzyl)-(3-isobutoxy-benzyl)-amino]-propionic acid
Figure imgf000024_0002
Mono TFA salt. HPLC-MS: m/z 370 [M+Hf. Rt = 1.84 min. Purity 88%.
Example 40 3-[(2,6-Difluoro-3-methyl-benzyl)-(3-isobutoxy-benzyl)-amino]- propionic acid
Figure imgf000024_0003
Mono TFA salt. HPLC-MS: m/z 392 [M+Hf. Rt = 1.79 min. Purity 83%.
Example 41 3-[[3-(4-Methoxy-benzyl)-benzyl]-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000024_0004
Mono TFA salt. HPLC-MS: m/z 404 [M+Hf. Rt = 1.35 min. Purity 97%. Example 42 3-[[3-(2-Methoxy-benzyl)-benzyl]-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000025_0001
Mono TFA salt. HPLC-MS: m/z 404 [M+Hf. Rt = 1.85 min. Purity 100%.
Example 43 3-{(3-Methyl-benzyl)-[3-(2-methyl-benzyl)-benzyl]-amino}-propionic acid
Figure imgf000025_0002
Mono TFA salt. HPLC-MS: m/z 388 [M+Hf. Rt = 1.41 min. Purity 98%.
Example 44 3-{(3-Methyl-benzyl)-[3-(4-methyl-benzyl)-benzyl]-amino}-propionic acid
Figure imgf000025_0003
Mono TFA salt. HPLC-MS: m/z 388 [M+Hf. Rt = 1.43 min. Purity 97%.
Example 45 3-[[3-(3-Methoxy-benzyl)-benzyl]-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000025_0004
Mono TFA salt. HPLC-MS: m/z 404 [M+Hf. Rt = 1.36 min. Purity 95%. Example 46 3-[[3-(4-Fluoro-benzyl)-benzyl]-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000026_0001
Mono TFA salt. HPLC-MS: m/z 392 [M+Hf. Rt = 1.37 min. Purity 98%.
Example 47 3-[[3-(3-Fluoro-benzyl)-benzyl]-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000026_0002
Mono TFA salt. HPLC-MS: m/z 392 [M+Hf. Rt = 1.81 min. Purity 98%.
Example 48 3-[[3-(3-Chloro-benzyl)-benzyl]-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000026_0003
Mono TFA salt. HPLC-MS: m/z 408 [M+Hf. Rt = 1.92 min. Purity 99%.
Example 49 3-[[3-(3,5-Difluoro-benzyl)-benzyl]-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000026_0004
Mono TFA salt. HPLC-MS: m/z410 [M+Hf. Rt = 1.85 min. Purity 98%. Example 50 3-[[3-(3,4-Difluoro-benzyl)-benzyl]-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000027_0001
Mono TFA salt. HPLC-MS: m/z 410 [M+Hf. Rt = 1.85 min. Purity 96%.
Example 51 3-[(2-Chloro-6-fluoro-3-methyl-benzyl)-(3-isobutoxy-benzyl)-amino]- propionic acid
Figure imgf000027_0002
Mono TFA salt. HPLC-MS: m/z 408 [M+Hf. Rt = 1.86 min. Purity 100%.
Example 52 3-[(2-Fluoro-5-methyl-benzyl)-(3-phenylsulfanyl-benzyl)-amino]- propionic acid
Figure imgf000027_0003
Mono TFA salt. HPLC-MS: m/z 410 [M+Hf. Rt = 1.81 min. Purity 96%.
Example 53 3-[(3-Benzyl-benzyl)-(2-fluoro-5-methyl-benzyl)-amino]-propionic acid
Figure imgf000027_0004
Mono TFA salt. HPLC-MS: m/z 392 [M+Hf. Rt = 1.79 min. Purity 98%. Example 54 3-[(3-Benzyl-benzyl)-(3-ethyl-benzyl)-amino]-propionic acid
Figure imgf000028_0001
Mono TFA salt. HPLC-MS: m/z 388 [M+Hf. Rt = 1.87 min. Purity 89%.
Example 55 3-[(2-Fluoro-5-methyl-benzyl)-(3-phenoxy-benzyl)-amino]-propionic acid
Figure imgf000028_0002
Mono TFA salt. HPLC-MS: m/z 394 [M+Hf. Rt = 1.77 min. Purity 95%.
Example 56 3-[[3-(3-Methoxy-phenylsulfanyl)-benzyl]-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000028_0003
Mono TFA salt. HPLC-MS: m/z 422 [M+Hf. Rt = 1.45 min. Purity 95%.
Example 57 3-{(3-Methyl-benzyl)-[3-(4-methylsulfanyl-phenylsulfanyl)-benzyl]- amino}-propionic acid
Figure imgf000028_0004
Mono TFA salt. HPLC-MS: m/z 438 [M+Hf. Rt = 1.57 min. Purity 99%. Example 58 3-[[3-(2,4-Difluoro-phenylsulfanyl)-benzyl]-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000029_0001
Mono TFA salt. HPLC-MS: m/z 428 [M+Hf. Rt = 1.46 min. Purity 98%.
Example 59 3-[[3-(2-Chloro-4-fluoro-phenoxy)-benzyl]-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000029_0002
Mono TFA salt. HPLC-MS: m/z 444 [M+Hf. Rt = 1.50 min. Purity 97%.
Example 60 3-[[3-(3-Fluoro-phenylsulfanyl)-benzyl]-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000029_0003
Mono TFA salt. HPLC-MS: m/z 410 [M+Hf. Rt = 1.85 min. Purity 100%.
Example 61 3-[[3-(3-Chloro-phenylsulfanyl)-benzyl]-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000029_0004
Mono TFA salt. HPLC-MS: m/z 426 [M+Hf. Rt = 1.92 min. Purity 100%. Example 62 3-[[3-(2-Fluoro-phenylsulfanyl)-benzyl]-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000030_0001
Mono TFA salt. HPLC-MS: m/z 410 [M+Hf. Rt = 1 .85 min. Purity 96%.
Example 63 3-[[3-(2,6-Dimethyl-phenylsulfanyl)-benzyl]-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000030_0002
Mono TFA salt. HPLC-MS: m/z 420 [M+Hf. Rt = 1.93 min. Purity 100%.
Example 64 3-[[3-(4-Fluoro-phenylsulfanyl)-benzyl]-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000030_0003
Mono TFA salt. HPLC-MS: m/z 410 [M+Hf. Rt = 1.88 min. Purity 96%.
Example 65 3-[[3-(4-Chloro-phenylsulfanyl)-benzyl]-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000030_0004
Mono TFA salt. HPLC-MS: m/z 426 [M+Hf. Rt = 1.88 min. Purity 96%. Example 66 3-[(3-Methyl-benzyl)-(3-o-tolylsulfanyl-benzyl)-amino]-propionic acid
Figure imgf000031_0001
Mono TFA salt. HPLC-MS: m/z 406 [M+Hf. Rt = 1.92 min. Purity 100%.
Example 67 3-[[3-(2,6-Dichloro-phenylsulfanyl)-benzyl]-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000031_0002
Mono TFA salt. HPLC-MS: m/z 460 [M+Hf. Rt = 1.91 min. Purity 100%.
Example 68 3-[[3-(4-Cyano-phenylsulfanyl)-benzyl]-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000031_0003
Mono TFA salt. HPLC-MS: m/z417 [M+Hf. Rt = 1.80 min. Purity 98%.
Example 69 3-{(3-Methyl-benzyl)-[3-(4-nitro-phenylsulfanyl)-benzyl]-amino}- propionic acid
Figure imgf000031_0004
Mono TFA salt. HPLC-MS: m/z 437 [M+Hf. Rt = 1.80 min. Purity 96%. Example 70 3-[(3-Cyclohexylsulfanyl-benzyl)-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000032_0001
Mono TFA salt. HPLC-MS: m/z 398 [M+Hf. Rt = 1.97 min. Purity 87%.
Example 71 3-[(2-Chloro-5-methyl-benzyl)-(3-phenylsulfanyl-benzyl)-amino]- propionic acid
Figure imgf000032_0002
Mono TFA salt. HPLC-MS: m/z 426 [M+Hf. Rt = 1.40 min. Purity 98%.
Example 72 3-[(3-Benzyl-benzyl)-(2-chloro-5-methyl-benzyl)-amino]-propionic acid
Figure imgf000032_0003
Mono TFA salt. HPLC-MS: m/z 408 [M+Hf. Rt = 1.39 min. Purity 86%.
Example 73 3-[(2-Chloro-5-methyl-benzyl)-(3-phenoxy-benzyl)-amino]-propionic acid
Figure imgf000032_0004
Mono TFA salt. HPLC-MS: m/z410 [M+Hf. Rt = 1.35 min. Purity 98%. Example 74 3-[(4-Fluoro-3-methyl-benzyl)-(3-phenoxy-cyclohexylmethyl)-amino]- propionic acid
Figure imgf000033_0001
Mono TFA salt. HPLC-MS: m/z 400 [M+Hf. Rt = 1.81 min. Purity 83%.
Example 75 3-[(2,5-Dimethyl-benzyl)-(4-phenylsulfanyl-benzyl)-amino]-propionic acid
Figure imgf000033_0002
Mono TFA salt. HPLC-MS: m/z 406 [M+Hf. Rt = 1 .88 min. Purity 91 %.
Example 76 3-[(4-Fluoro-3-methyl-benzyl)-(4-phenylsulfanyl-benzyl)-amino]- propionic acid
Figure imgf000033_0003
Mono TFA salt. HPLC-MS: m/z 410 [M+Hf. Rt = 1.86 min. Purity 92%.
Example 77 3-[(6-Chloro-2-flιιoro-3-methyl-benzyl)-(4-phenylsulfanyl-benzyl)- aminofpropionic acid
Figure imgf000033_0004
Mono TFA salt. HPLC-MS: m/z 444 [M+Hf. Rt = 1.88 min. Purity 83%. Example 78 3-[(2,6-Difluoro-3-methyl-benzyl)-(4-phenylsulfanyl-benzyl)-amino]- propionic acid
Figure imgf000034_0001
Mono TFA salt. HPLC-MS: m/z 428 [M+Hf. Rt = 1.84 min. Purity 88%.
Example 79 3-[(2-Chloro-6-fluoro-3-methyl-benzyl)-(4-phenylsulfanyl-benzyl)- aminofpropionic acid
Figure imgf000034_0002
Mono TFA salt. HPLC-MS: m/z 444 [M+Hf. Rt = 1.88 min. Purity 82%.
Example 80 3-[(5-Methyl-furan-2-ylmethyl)-(4-phenylsulfanyl-benzyl)-amino]- propionic acid
Figure imgf000034_0003
Mono TFA salt. HPLC-MS: m/z 382 [M+Hf. Rt = 1.79 min. Purity 91 %.
Example 81 3-[(3-Fluoro-ben_zyl)-(4-phenylsulfanyl-benzyl)-amino]-propionic acid
Figure imgf000034_0004
Mono TFA salt. HPLC-MS: m/z 396 [M+Hf. Rt = 1.79 min. Purity 94%. Example 82 3-[Benzyl-(4-styryl-benzyl)-amino]-propionic acid
Figure imgf000035_0001
Mono TFA salt. HPLC-MS: m/z 372 [M+Hf. Rt = 1.78 min. Purity 91 %. Example 83 3-[(3-Methyl-benzyl)-(4-styryl-benzyl)-amino]-propionic acid
Figure imgf000035_0002
Mono TFA salt. HPLC-MS: m/z 386 [M+Hf. Rt = 1.34 min. Purity 89%.
Example 84 3-[(4-Fluoro-3-methyl-benzyl)-(4-styryl-benzyl)-amino]-propionic acid
Figure imgf000035_0003
Mono TFA salt. HPLC-MS: m/z 404 [M+Hf. Rt = 1.86 min. Purity 92%.
Example 85 3-[(5-Methyl-furan-2-ylmethyl)-(4-styryl-benzyl)-amino]-propionic acid
Figure imgf000035_0004
Mono TFA salt. HPLC-MS: m/z 376 [M+Hf. Rt = 1.80 min. Purity 84%. Example 86 3-[(3-Fluoro-benzyl)-(4-styryl-benzyl)-arrιino]-propionic acid
Figure imgf000036_0001
Mono TFA salt. HPLC-MS: m/z 390 [M+Hf. Rt = 1.79 rnin. Purity 89%. Example 87 3-[(3-Butoxy-benzyl)-(2,5-dimethyl-benzyl)-amino]-propionic acid
Figure imgf000036_0002
Mono TFA salt. HPLC-MS: m/z 370 [M+Hf. Rt = 1.87 rnin. Purity 87%.
Example 88 3-[(3-Butoxy-benzyl)-(5-methyl-furan-2-ylmethyl)-amino]-propionic acid
Figure imgf000036_0003
Mono TFA salt. HPLC-MS: m/z 346 [M+Hf. Rt = 1.76 rnin. Purity 83%.
Example 89 3-[(4-Fluoro-3-methyl-benzyl)-(3-isobutoxy-benzyl)-amino]-propionic acid
Figure imgf000036_0004
Mono TFA salt. HPLC-MS: m/z 374 [M+Hf. Rt = 1.80 rnin. Purity 88%. Example 90 3-[(6-ChIoro-2-fluoro-3-methyl-benzyl)-(4-styryl-benzyl)-amino]- propionic acid
Figure imgf000037_0001
Mono TFA salt. HPLC-MS: m/z 438 [M+Hf. Rt = 1 .90 min. Purity 100%.
Example 91 3-[(2-Chloro-6-fluoro-3-methyl-benzyl)-(4-styryl-benzyl)-amino]- propionic acid
Figure imgf000037_0002
Mono TFA salt. HPLC-MS: m/z 438 [M+Hf. Rt = 1.91 min. Purity 100%.
Example 92 3-[(3-Benzyl-benzyl)-(5-methyl-thiophen-2-ylmethyl)-amino]-propionic acid
Figure imgf000037_0003
Mono TFA salt. HPLC-MS: m/z 380 [M+Hf. Rt = 1.77 min. Purity 100%.
Example 93 3-[(5-Methyl-thiophen-2-ylmethyl)-(3-phenoxy-ben___yl)-amino]- propionic acid
Figure imgf000037_0004
Mono TFA salt. HPLC-MS: m/z 382 [M+Hf. Rt = 1.77 min. Purity 100%. Example 94 3-[Furan-2-ylmethyl-(3-phenylsulfanyl-benzyl)-amino]-propionic acid
Figure imgf000038_0001
Mono TFA salt. HPLC-MS: m/z 368 [M+Hf. Rt = 1.25 min. Purity 98%. Example 95 3-[(3-Benzyl-benzyl)-furan-2-ylmethyl-amino]-propionic acid
Figure imgf000038_0002
Mono TFA salt. HPLC-MS: m/z 350 [M+Hf. Rt = 1.23 min. Purity 96%.
Example 96 3-[(3-Benzyl-benzyl)-(4-hydroxy-3-methyl-benzyl)-amino]-propionic acid
Figure imgf000038_0003
Mono TFA salt. HPLC-MS: m/z 390 [M+Hf. Rt = 1.25 min. Purity 91 %.
Example 97 3-[(4-Hydroxy-3-methyl-benzyl)-(3-phenoxy-benzyl)-amino]-propionic; acid
Figure imgf000038_0004
Mono TFA salt. HPLC-MS: m/z 392 [M+Hf. Rt = 1.23 min. Purity 91 %. Example 98 3-[(2-Hydroxy-3-methyl-benzyl)-(3-phenylsulfanyl-benzyl)-Amino]- propionic acid
Figure imgf000039_0001
Mono TFA salt. HPLC-MS: m/z 408 [M+Hf. Rt = 1.82 min. Purity 100%.
Example 99 3-[(4-Methyl-thiophen-2-ylmethyl)-(3-phenylsulfanyl-benzyl)-amino]- Propionic acid
Figure imgf000039_0002
Mono TFA salt. HPLC-MS: m/z 398 [M+Hf. Rt = 1.83 min. Purity 100%.
Example 100 3-[(3-Benzyl-benzyl)-(4-methyl-thiophen-2-ylmethyl)-amino]-propionic acid
Figure imgf000039_0003
Mono TFA salt. HPLC-MS: m/z 380 [M+Hf. Rt = 1.81 min. Purity 100%.
Example 101 3-[(4-Methyl-thiophen-2-ylmethyl)-(3-phenoxy-benzyl)-amino]- propionic acid
Figure imgf000039_0004
Mono TFA salt. HPLC-MS: m/z 382 [M+Hf. Rt = 1.78 min. Purity 100%. Example 102 3-{(3-Methyl-benzyl)-[3-(1 -phenyl-vinyl)-benzyl]-amino}-propionic acid
Figure imgf000040_0001
Mono TFA salt. HPLC-MS: m/z 386 [M+Hf. Rt = 1.87 min. Purity 100%.
Example 103 3-{(2,6-Difluoro-3-methyl-benzyl)-[3-(1 -phenyl-vinyl)-benzyl]-amino}- propionic acid
Figure imgf000040_0002
Mono TFA salt. HPLC-MS: m/z 422 [M+Hf. Rt = 1.87 min. Purity 100%.
Example 104 3-{(3-Fluoro-benzyl)-[3-(1 -phenyl-vinyl)-benzyl]-amino}-propionic acid
Figure imgf000040_0003
Mono TFA salt. HPLC-MS: m/z 390 [M+Hf. Rt = 1.86 min. Purity 100%.
Example 105 3-[(3-Benzyl-benzyl)-(5-methyl-thiophen-3-ylmethyl)-amino]-propionic acid
Figure imgf000040_0004
Mono TFA salt. HPLC-MS: m/z 380 [M+Hf. Rt = 1.34 min. Purity 98%. Example 106 3-[(5-Methyl-thiophen-3-ylmethyl)-(3-phenoxy-benzyl)-amino]- propionic acid
Figure imgf000041_0001
Mono TFA salt. HPLC-MS: m/z 382 [M+Hf. Rt = 1.31 min. Purity 95%.
Example 107 3-[(5-Methyl-thiophen-3-ylmethyl)-(3-phenylsulfanyl-benzyl)-amino]- propionic acid
Figure imgf000041_0002
Mono TFA salt. HPLC-MS: m/z 398 [M+Hf. Rt = 1.36 min. Purity 98%.
Example 108 3-{(3-Methyl-benzyl)-[3-(1 -phenyl-ethyl)-benzyl]-amino}-propionic acid
Figure imgf000041_0003
Mono TFA salt. HPLC-MS: m/z 388 [M+Hf. Rt = 1.90 min. Purity 94%.
Example 109 3-[(3-Benzyl-benzyl)-(3-fluoro-benzyl)-amino]-propionic acid
Figure imgf000041_0004
Mono TFA salt. HPLC-MS: m/z 378 [M+Hf. Rt = 1.32 min. Purity 91 %. Example 110 3-[(3-Cyclohexylmethyl-benzyl)-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000042_0001
Mono TFA salt. HPLC-MS: m/z 380 [M+Hf. Rt = 1.74 min. Purity 94%.
Example 111 3-[(3-Cyclopentylmethoxy-benzyl)-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000042_0002
Mono TFA salt. HPLC-MS: m/z 382 [M+Hf. Rt = 1.65 min. Purity 92%.
Example 112 3-[[3-(2-Ethyl-butoxy)-benzyl]-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000042_0003
Mono TFA salt. HPLC-MS: m/z 384 [M+Hf. Rt = 1.69 min. Purity 81 %.
Example 113 3-[[3-(2-Methoxy-ethoxy)-benzyl]-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000042_0004
Mono TFA salt. HPLC-MS: m/z 358 [M+Hf. Rt = 1.39 min. Purity 89%. Example 114 3-[(2-Chloro-5-methyl-benzyl)-(3-cyclopentylmethoxy-benzyl)-amino]- propionic acid
Figure imgf000043_0001
Mono TFA salt. HPLC-MS: m/z 416 [M+Hf. Rt = 1.69 min. Purity 80%.
Example 115 3-[(2-Chloro-5-methyl-benzyl)-(3-cyclopentyloxy-benzyl)-amino]- propionic acid
Figure imgf000043_0002
Mono TFA salt. HPLC-MS: m/z 402 [M+Hf. Rt = 1.58 min. Purity 90%.
Example 116 3-{(2-Chloro-5-methyl-benzyl)-[3-(2-ethyl-butoxy)-benzyl]-amino}- propionic acid
Figure imgf000043_0003
Mono TFA salt. HPLC-MS: m/z 418 [M+Hf. Rt = 1 .72 min. Purity 85%.
Example 117 3-[(3-Cyclohexylmethyl-benzyl)-(2-fluoro-5-methyl-benzyl)-amino]- propionic acid
Figure imgf000043_0004
Mono TFA salt. HPLC-MS: m/z 398 [M+Hf. Rt = 1.74 min. Purity 89%. Example 118 3-[(3-Cyclopentylmethoxy-benzyl)-(2-fluoro-5-methyl-benzyl)-amino]- propionic acid
Figure imgf000044_0001
Mono TFA salt. HPLC-MS: m/z 400 [M+Hf. Rt = 1.66 min. Purity 93%.
Example 119 3-[(3-Cyclopentyloxy-benzyl)-(2-fluoro-5-methyl-benzyl)-amino]- propionic acid
Figure imgf000044_0002
Mono TFA salt. HPLC-MS: m/z 386 [M+Hf. Rt = 1.55 min. Purity 94%.
Example 120 3-[[3-(2-Ethyl-butoxy)-benzyl]-(2-fluoro-5-methyl-benzyl)-amino] propionic acid
Figure imgf000044_0003
Mono TFA salt. HPLC-MS: m/z 402 [M+Hf. Rt = 1.70 min. Purity 95%.
Example 121 3-[(2-Fluoro-5-methyl-benzyl)-(3-hexyloxy-benzyl)-amino]-propionic acid
Figure imgf000044_0004
Mono TFA salt. HPLC-MS: m/z 402 [M+Hf. Rt = 1.71 min. Purity 91 %. Example 122 3-{(2-Fluoro-5-methyl-benzyl)-[3-(2-methyl-butoxy)-benzyl]-amino}- propionic acid
Figure imgf000045_0001
Mono TFA salt. HPLC-MS: m/z 388 [M+Hf. Rt = 1.62 min. Purity 86%.
Example 123 3-[(2-Fluoro-5-methyl-benzyl)-(3-pentyl-benzyl)-amino]-propionic acid
Figure imgf000045_0002
Mono TFA salt. HPLC-MS: m/z 372 [M+Hf. Rt = 1.70 min. Purity 95%.
Example 124 3-[(3-Cyclohexylmethyl-benzyl)-(2,6-difluoro-3-methyl-benzyl)-amino]- propionic acid
Figure imgf000045_0003
Mono TFA salt. HPLC-MS: m/z 416 [M+Hf. Rt = 1.74 min. Purity 84%.
Example 125 3-[(3-Cyclopentylmethoxy-benzyl)-(2,6-difluoro-3-methyl-benzyl)- aminofpropionic acid
Figure imgf000045_0004
Mono TFA salt. HPLC-MS: m/z 418 [M+Hf. Rt = 1.66 min. Purity 90%. Example 126 3-{(2,6-Difluoro-3-methyl-benzyl)-[3-(2-ethyl-butoxy)-benzyl]-amino}- propionic acid
Figure imgf000046_0001
Mono TFA salt. HPLC-MS: m/z 420 [M+H]+. Rt = 1 .70 min. Purity 95%.
Example 127 3-{(2,6-Difluoro-3-methyl-benzyl)-[3-(2-methyl-butoxy)-benzyl]-amino}- propionic acid
Figure imgf000046_0002
Mono TFA salt. HPLC-MS: m/z 406 [M+H]+. Rt = 1 .40 min. Purity 90%.
Example 128 3-[(2,6-Difluoro-3-methyl-benzyl)-(3-pentyl-benzyl)-amino]-propionic acid
Figure imgf000046_0003
Mono TFA salt. HPLC-MS: m/z 390 [M+H]+. Rt = 1.69 min. Purity 92%.
Example 129 3-{(3-Ethyl-benzyl)-[3-(2-methyl-butoxy)-benzyl]-amino}-propionic acid
Figure imgf000046_0004
Mono TFA salt. HPLC-MS: m/z 384 [M+H]+. Rt = 1.69 min. Purity 83%. Example 130 3-[(3-Ethyl-benzyl)-(3-pentyl-benzyl)-amino]-propionic acid
Figure imgf000047_0001
Mono TFA salt. HPLC-MS: m/z 368 [M+Hf. Rt = 1.75 min. Purity 93%. Example 131 3-[Benzyl-(3-benzyl-benzyl)-amino]-propionic acid
Figure imgf000047_0002
Mono TFA salt. HPLC-MS: m/z 360 [M+Hf. Rt = 1.29 min. Purity 98%.
Example 132 3-[(2-Chloro-5-methyl-benzyl)-(3-pentyl-benzyl)-amino]- propionic acid
Figure imgf000047_0003
Mono TFA salt. HPLC-MS: m/z 388 [M+Hf. Rt = 1 .92 min. Purity 100%.
Example 133 3-[(3-Cyclopentylmethoxy-benzyl)- (4-methyl-thiophen-2- ylmethyl)-amino]-propionic acid
Figure imgf000047_0004
Mono TFA salt. HPLC-MS: m/z 388 [M+Hf. Rt = 1 .85 min. Purity 100%. Example 134 3-{(3-Methyl-benzyl)-[3-(2-methyl-butoxy)-benzyl]-amino}- propionic acid
Figure imgf000048_0001
Mono TFA salt. HPLC-MS: m/z 370 [M+Hf. Rt = 1.85 min. Purity 100%.
Example 135 3-[(3-Cyclopentyloxy-benzyl)-(4-methyl-thiophen-2-ylmethyl)- aminofpropionic acid
Figure imgf000048_0002
Mono TFA salt. HPLC-MS: m/z 374 [M+Hf. Rt = 1.84 min. Purity 100%. Example 136 3-[(3-Methyl-benzyl)-(3-pentyl-benzyl)-amino]-propionic acid
Figure imgf000048_0003
Mono TFA salt. HPLC-MS: m/z 354 [M+Hf. Rt = 1.97 min. Purity 100%.
Example 137 3-[[3-(2-Ethyl-butoxy)-benzyl]-(4-methyl-thiophen-2- ylmethyl)-amino]-propionic acid
Figure imgf000048_0004
Mono TFA salt. HPLC-MS: m/z 390 [M+Hf. Rt = 1.98 min. Purity 100%. Example 138 3-[(2-Chloro-5-methyl-benzyl)-(3-cyclohexylmethyl-benzyl)- aminofpropionic acid
Figure imgf000049_0001
Mono TFA salt. HPLC-MS: m/z 414 [M+Hf. Rt = 2.09 min. Purity 100%.
Example 139 3-[(3-Cyclohexylmethyl-benzyl)-(4-methyl-thiophen-2- ylmethyl)-amino]-propionic acid
Figure imgf000049_0002
Mono TFA salt. HPLC-MS: m/z 386 [M+Hf. Rt = 2.01 min. Purity 100%. Example 140 3-[[3-(2-Methyl-butoxy)-benzyl]-(4-methyl-thiophen-2- ylmethyl)-amino]-propionic acid
Figure imgf000049_0003
Mono TFA salt. HPLC-MS: m/z 376 [M+Hf. Rt = 1.85 min. Purity 100%.
Example 141 3-[(4-Butyl-benzyl)-(4-methyl-thiophen-2-ylmethyl)-amino] propionic acid
Figure imgf000049_0004
Mono TFA salt. HPLC-MS: m/z 346 [M+Hf. Rt = 1.82 min. Purity 100%. Example 142 3-[(4-Methyl-thiophen-2-ylmethyl)-(3-pentyl-benzyl)-amino]- propionic acid
Figure imgf000050_0001
Mono TFA salt. HPLC-MS: m/z 360 [M+Hf. Rt = 1.88 min. Purity 100%.
Example 143 3-{(2-Chloro-5-methyl-benzyl)-[3-(2-methyl-butoxy)-benzyl]- amino}-propionic acid
Figure imgf000050_0002
Mono TFA salt. HPLC-MS: m/z 404 [M+Hf. Rt = 1.91 min. Purity 100%. Example 144 3-[(3-Butyl-benzyl)-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000050_0003
Mono TFA salt. HPLC-MS: m/z 340 [M+Hf. Rt = 1.82 min. Purity 97%. Example 145 3-[(3-Hexyl-benzyl)-(3-methyl-benzyl)-amino]-propionic acid
Figure imgf000050_0004
Mono TFA salt. HPLC-MS: m/z 369 [M+Hf. Rt = 1.98 min. Purity 93%. Example 146 3-{(3-Met yI-benzyl)-[3-(3-methyl-butyl)-benzyl]-amino}- propionic acid
Figure imgf000051_0001
Mono TFA salt. HPLC-MS: m/z 355 [M+Hf. Rt = 1.89 min. Purity 100%.
Example 147 3-[(3-Butylsulfanyl-benzyl)-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000051_0002
Mono TFA salt. HPLC-MS: m/z 373 [M+Hf. Rt = 1.84 min. Purity 95%.
Example 148 3-[(3-Cyclopentylsulfanyl-benzyl)-(3-methyl-benzyl)-amino]- propionic acid
Figure imgf000051_0003
Mono TFA salt. HPLC-MS: m/z 385 [M+Hf. Rt = 1.85 min. Purity 97%. Example 149 3-[(3-Butyl-benzyl)-(2-chloro-5-methyl-benzyl)-amino]- propionic acid
Figure imgf000052_0001
Mono TFA salt. HPLC-MS: m/z 375 [M+Hf. Rt = 1.94 min. Purity 87%.
Example 150 3-[(2-Chlo ro-5-methyl-benzyl)-(3-hexyl-benzyl)-amino]- propionic acid
Figure imgf000052_0002
Mono TFA salt. HPLC-MS: m/z 403 [M+Hf. Rt = 2.12 min. Purity 87%.
Example 151 3-[(3-Butylsulfanyl-benzyl)-(2-chloro-5-methyl-benzyl)- aminofpropionic acid
Figure imgf000052_0003
Mono TFA salt. HPLC-MS: m/z 406 [M+Hf. Rt = 1.98 min. Purity 88%.
Example 152 3-[(2-Chloro-5-methyl-benzyl)-(3-cyclopentylsulfanyl-benzyl)- aminoj-propionic acid
Figure imgf000053_0001
Mono TFA salt. HPLC-MS: m/z 418 [M+Hf. Rt = 1.98 min. Purity 86%.
Example 153 3-[(2-Chloro-5-methyl-benzyl)-(3-cyclohexylmethoxy-benzyl)- aminofpropionic acid
Figure imgf000053_0002
Mono TFA salt. HPLC-MS: m/z 430 [M+Hf. Rt = 2.09 min. Purity 87%.
Example 154 3-[(3-Butyl-benzyl)-(2-fluoro-5-methyl-benzyl)-amino]- propionic acid
Figure imgf000053_0003
Mono TFA salt. HPLC-MS: m/z 358 [M+Hf. Rt = 1.84 min. Purity 91 %. Example 155 3-[(2-Fluoro-5-methyl-benzyl)-(3-h_ exyl-benzyl)-amino]- propionic acid
Figure imgf000054_0001
Mono TFA salt. HPLC-MS: m/z 386 [M+Hf. Rt = 1.99 min. Purity 94%.
Example 156 3-{(2-Fluoro-5-methyl-benzyl)-[3-(3-methyl-butyl)-benzyl]- amino}-propionic acid
Figure imgf000054_0002
Mono TFA salt. HPLC-MS: m/z 373 [M+Hf. Rt = 1.90 min. Purity 97%.
Example 157 3-[(3-Butylsulfanyl-benzyl)-(2-fluoro-5-methyl-benzyl)- aminofpropionic acid
Mono TFA salt. HPLC-MS: m/z 390 [M+Hf. Rt = 1.86 min. Purity 98%, Example 158 3-[(3-Cyclopentylsulfanyl-benzyl)-(2-fluoro-5-methyl-benzyl)- aminofpropionic acid
Figure imgf000055_0001
Mono TFA salt. HPLC-MS: m/z 402 [M+Hf. Rt = 1.87 min. Purity 98%.
Example 159 3-[(3-Butyl-benzyl)-(2,6-difluoro-3-methyl-benzyl)-amino]- propionic acid
Figure imgf000055_0002
Mono TFA salt. HPLC-MS: m/z 376 [M+Hf. Rt = 1.86 min. Purity 91 %.
Example 160 3-[(2,6-Difluoro-3-methyl-benzyl)-(3-hexyl-benzyl)-amino]- propionic acid
Figure imgf000055_0003
Mono TFA salt. HPLC-MS: m/z 404 [M+Hf. Rt = 2.01 min. Purity 97%.
Example 161 3-{(2,6-Difluoro-3-methyl-benzyl)-[3-(3-methyl-butyl)-benzyl]- amino}-propionic acid
Figure imgf000055_0004
Mono TFA salt. HPLC-MS: m/z 390 [M+Hf. Rt = 1.91 min. Purity 95%.
Example 162 3-[(3-Butylsulfanyl-benzyl)-(2,6-difluoro-3-methyl-benzyl)- aminofpropionic acid
Figure imgf000056_0001
Mono TFA salt. HPLC-MS: m/z 408 [M+Hf. Rt = 1.87 min. Purity 98%.
Example 163 3-[(3-Cyclopentylsulfanyl-benzyl)-(2,6-difluoro-3-methyl- benzyl)-amino]-propionic acid
Figure imgf000056_0002
Mono TFA salt. HPLC-MS: m/z 420 [M+Hf. Rt = 1.88 min. Purity 95%. Example 164 3-[(3-Cyclohexylmethoxy-benzyl)-(2,6-difluoro-3-methyl-benzyl)- aminofpropionic acid
Figure imgf000056_0003
Mono TFA salt. HPLC-MS: m/z 432 [M+Hf. Rt = 1.98 min. Purity 93%. Example 165 3-[(3-Butyl-benzyl)-(5-methyl-f uran-2-ylmeth yl)-amino]- propionic acid
Figure imgf000057_0001
Mono TFA salt. HPLC-MS: m/z 330 [M+Hf. Rt = 1.80 min. Purity 94%.
Example 166 3-[(3-Hexyl-benzyl)-(5-methyl-furan-2-ylmethyl)-amino]- propionic acid
Figure imgf000057_0002
Mono TFA salt. HPLC-MS: m/z 358 [M+Hf. Rt = 1.97 min. Purity 92%.
Example 167 3-[[3-(3-Methyl-butyl)-benzyl]-(5-methyl-f ura rι-2-ylmethyl)- aminofpropionic acid
Figure imgf000057_0003
Mono TFA salt. HPLC-MS: m/z 344 [M+Hf. Rt = 1.88 min. Purity 94%. zyl)-(5-methyl-furan-2-ylmethyl)-
Figure imgf000058_0001
Mono TFA salt. HPLC-MS: m/z 362 [M+Hf. Rt = 1.83 min. Purity 93%.
Example 169 3-[(3-CycIopentylsulf anyl-benzyl)-(5-methyl-f uran-2 - ylmethyl)-amino]-propionic acid
Figure imgf000058_0002
Mono TFA salt. HPLC-MS: m/z 374 [M+Hf. Rt = 1.84 min. Purity 94%.
Example 170 3-[(3-Cyclohexylmethoxy-benzyl)-(5-methyl-furan-2- ylmethyl)-amino]-propionic acid
Figure imgf000058_0003
Mono TFA salt. HPLC-MS: m/z 386 [M+Hf. Rt = 1.95 min. Purity 92%. Example 171 3-[(3-Butyl-benzyl)-(3-ethyl-benzyl)-amino]-propion ic acid
Figure imgf000058_0004
Mono TFA salt. HPLC-MS: m/z 354 [M+Hf. Rt = 1.93 min. Purity 94%. Example 172 3-[(3-Butylsulfanyl-benzyl)-(3-ethyl-benzyl)-amino]-propionic acid
Figure imgf000059_0001
Mono TFA salt. HPLC-MS: m/z 386 [M+Hf. Rt = 1.95 min. Purity 94%.
Example 173 3-[(3-Butyl-benzyl)-(2,5-dimethyl-benzyl)-amino]-propionic acid
Figure imgf000059_0002
Mono TFA salt. HPLC-MS: m/z 354 [M+Hf. Rt = 1.90 min. Purity 96%.
Example 174 3-{(2,5-Dimethyl-benzyl)-[3-(3-methyl-butyl)-benzyl]-amino}- propionic acid
Figure imgf000059_0003
Mono TFA salt. HPLC-MS: m/z 368 [M+Hf. Rt = 1.98 min. Purity 94%. Example 175 3-[(3-Butylsulfanyl-benzyl)-(2,5-dimethyl-benzyl)-amino]- propionic acid
Figure imgf000060_0001
Mono TFA salt. HPLC-MS: m/z 386 [M+Hf. Rt = 1.94 min. P urity 98%.
Example 176 3-[(3-Cyclopentylsulfanyl-benzyl)-(2,5-dimethyl-benzyl)- aminofpropionc acid
Figure imgf000060_0002
Mono TFA salt. HPLC-MS: m/z 398 [M+Hf. Rt = 1.95 min. P urity 95%.
Example 177 3-[(3-Cyclohexylmethyl-benzyl)-(5-methyl-fura-n-2-ylmethyl)- aminofpropionic acid
Figure imgf000060_0003
Mono TFA salt. HPLC-MS: m/z 370 [M+Hf. Rt = 1.90 min. P urity 94%.
Example 178 3-[[3-(2-Ethyl-butoxy)-benzyl]-(5-methyl-furan-2-ylmethyl)- aminofpropionic acid
Figure imgf000060_0004
Mono TFA salt. HPLC-MS: m/z 374 [M+Hf. Rt = 1.92 min. P urity 94%. Example 179 3-[[3-(2-Methyl-butoxy)-benzyl]-(5-methyl-furan-2-ylmet ιyl)- aminofpropionic acid
Figure imgf000061_0001
Mono TFA salt. HPLC-MS: m/z 360 [M+Hf. Rt = 1.90 min. Purity 85%.
Example 180 3-[(5-Methyl-furan-2-ylmethyl)-(3-pentyl-benzyl)-amino]- propionic acid
Figure imgf000061_0002
Mono TFA salt. HPLC-MS: m/z 344 [M+Hf. Rt = 1.87 min. Purity 94%.
Example 181 3-{(2-Chloro-5-methyl-benzyl)-[3-(3-methyl-butyl)-benzyl]- amino}-propionic acid
Figure imgf000061_0003
Mono TFA salt. HPLC-MS: m/z 389 [M+Hf. Rt = 2.02 min. Purity 87%.
Example 182 3-[(3-Butyl-benzyl)-(4-methyl-thiophen-2-ylmethyl)-amino]- propionic acid
Figure imgf000061_0004
Mono TFA salt. HPLC-MS: m/z 346 [M+Hf. Rt = 1.36 min. Purity 100%, Example 183 3-[[3-(3-Methyl-butyl)-benzyl]-(4-methyl-thiophen-2- ylmethyl)-amino]-propionic acid
Figure imgf000062_0001
Mono TFA salt. HPLC-MS: m/z 360 [M+Hf. Rt = 1.43 min. Purity 100%.
Example 184 3-[(3-Butylsulfanyl-benzyl)-(4-methyl-thiophen-2-ylmeth,yl)-
Figure imgf000062_0002
Mono TFA salt. HPLC-MS: m/z 378 [M+Hf. Rt = 1.38 min. Purity 100%.
Example 185 3-[(3-Cyclopentylsulfanyl-benzyl)-(4-methyl-thiophen-2- ylmethyl)-amino]-propionic acid
Figure imgf000062_0003
Mono TFA salt. HPLC-MS: m/z 390 [M+Hf. Rt = 1.38 min. Purity 100%.
Example 186 3-[(2-Chloro-5-methyl-benzyl)-naphthalen-2-ylmethyl-amino]- propionic acid
Figure imgf000062_0004
Mono TFA salt. HPLC-MS: m/z 368 [M+Hf. Rt = 1.74 min. Purity 96%. Example 187 3-[(3-Benzyl-benzyl)-(3-cyano-benzyl)-amino]-propionic acid
Figure imgf000063_0001
Mono TFA salt. HPLC-MS: m/z 385 [M+Hf. Rt = 1.78 min. Purity 81 %. Example 188 3-[(3-Benzyl-benzyl)-(2-fluoro-benzyl)-amino]-propionic acid
Figure imgf000063_0002
Mono TFA salt. HPLC-MS: m/z 378 [M+Hf. Rt = 1.82 min. Purity 95%.
Example 189 3-[(3-Benzyl-benzyl)-(2-methyl-benzyl)-amino]-propionic acid
Figure imgf000063_0003
Mono TFA salt. HPLC-MS: m/z 374 [M+Hf. Rt = 1.86 min. Purity 94%.
Example 190 3-[(3-Benzyl-benzyl)-(3-difluoromethoxy-benzyl)-amϊ no]- propionic acid
Figure imgf000063_0004
Mono TFA salt. HPLC-MS: m/z 426 [M+Hf. Rt = 1.88 min. Purity 97%. Example 191 3-[(3-Benzyl-benzyl)-(2-chloro-benzyl)-amino]-propionic acid
Figure imgf000064_0001
Mono TFA salt. HPLC-MS: m/z 394 [M+Hf. Rt = 1.85 min. Purity 92%.
Example 192 3-[(3-Benzyl-benzyl)-(3-bromo-benzyl)-amino]-propionic acid
Figure imgf000064_0002
Mono TFA salt. HPLC-MS: m/z 439 [M+Hf. Rt = 1.89 min. Purity 98%.
Example 193 3-[(3-Bromo-benzyl)-(2-chloro-5-methyl-benzyl)-amino]- propionic acid
Figure imgf000064_0003
Mono TFA salt. HPLC-MS: m/z 397 [M+Hf. Rt = 1.70 min. Purity 92%.
Example 194 3-[(3-Methyl-benzyl)-(3-trifluoromethyl-benzyl)-amino]- propionic acid
Figure imgf000064_0004
Mono TFA salt. HPLC-MS: m/z 352 [M+Hf. Rt = 1.69 min. Purity 97%. Example 195 3-[(2-Chloro-5-methyl-benzyl)-(3-trifluoromethyl-benzyl)- aminofpropionic acid
Figure imgf000065_0001
Mono TFA salt. HPLC-MS: m/z 386 [M+Hf. Rt = 1.73 min. Purity 95%.
Example 196 3-[(3-Methyl-benzyl)-(3-trifluoromethoxy-benzyl)-amino]- propionic acid
Figure imgf000065_0002
Mono TFA salt. HPLC-MS: m/z 368 [M+Hf. Rt = 1.74 min. Purity 100%.
Example 197 3-[(2-Chloro-5-methyl-benzyl)-(3-trifluoromethoxy-benzyl)- aminofpropionic acid
Figure imgf000065_0003
Mono TFA salt. HPLC-MS: m/z 402 [M+Hf. Rt = 1.76 min. Purity 94%.
Example 198 3-[(3-Benzyl-benzyl)-(5-ethyl-furan-2-ylmethyl)-amino]- propionic acid
Figure imgf000065_0004
Mono TFA salt. HPLC-MS: m/z 378 [M+Hf. Rt = 1.87 min. Purity 94%. methyl-
Figure imgf000066_0001
Mono TFA salt. HPLC-MS: m/z 340 [M+Hf. Rt = 1.23 min. Purity 100%.
Example 200 3-[(4-Methyl-thiophen-2-ylmethyl)-(3-trifluoromethoxy- benzyl)-amino]-propionic acid
Figure imgf000066_0002
Mono TFA salt. HPLC-MS: m/z 374 [M+Hf. Rt = 1.26 min. Purity 97%.
Example 201 3-[Benzo[1 ,3]dioxol-4-ylmethyl-(3-benzyl-benzyI)-smino]- propionic acid
Figure imgf000066_0003
Mono TFA salt. HPLC-MS: m/z 538 [M+Hf. Rt = 1.63 min. Purity 100%.
Example 202 3-[(2-Chloro-5-trif luoromethyl-benzyl)-(4-methyl-th_ iophen-2- ylmethyl)-amino]-propionic acid
Figure imgf000066_0004
Mono TFA salt. HPLC-MS: m/z 420 [M+Hf. Rt = 1.59 min. Purity 100%. Example 203 3-[(3-Benzyl-benzyl)-(3-vinyl-benzyl)-amino]-propionic acid
Figure imgf000067_0001
Mono TFA salt. HPLC-MS: m/z 362 [M+Hf. Rt = 1.60 min. Purity 93%.
Example 204 3-[(2-Fluoro-5-methyl-benzyl)-(3-trifluoromethyl-benzyl)- aminofpropionic acid
Figure imgf000067_0002
Mono TFA salt. HPLC-MS: m/z 370 [M+Hf. Rt = 1.71 min. Purity 96%.
Example 205 3-[(2-Fluoro-5-methyl-benzyl)-(3-trifluoromethoxy-benzyl)- aminofpropionic acid
Figure imgf000067_0003
Mono TFA salt. HPLC-MS: m/z 386 [M+Hf. Rt = 1.75 min. Purity 95%.
Example 206 3-[[3-(2-Ethyl-butoxy)-benzyl]-(2-methyl-thiazol-4-ylmethyl)- aminofpropionic acid
Figure imgf000067_0004
Mono TFA salt. HPLC-MS: m/z 391 [M+Hf. Rt = 1.51 min. Purity 90%. Example 207 3-[(3-Benzyl-benzyl)-(2,5-difluoro-benzyl)-amino]-propionic acid
Figure imgf000068_0001
Mono TFA salt. HPLC-MS: m/z 396 [M+Hf. Rt = 1.39 rnin. Purity 96%.
Example 208 3-[(3-Benzyl-benzyl)-(2,3-difluoro-benzyl>amino]-propionic acid
Figure imgf000068_0002
Mono TFA salt. HPLC-MS: m/z 396 [M+Hf. Rt = 1.39 rnin. Purity 96%.
Example 209 3-[(3-Benzyl-benzyl)-(2,5-dichloro-benzyl)-amino]-propionic acid
Figure imgf000068_0003
Mono TFA salt. HPLC-MS: m/z 428 [M+Hf. Rt = 1.50 rnin. Purity 94%.
Example 210 3-[(3-Benzyl-benzyl)-(5-bromo-2-f luoro-b enzyl)-amino]- propionic acid
Figure imgf000068_0004
Mono TFA salt. HPLC-MS: m/z 446 [M+Hf. Rt = 1.45 rnin. Purity 97%. Example 211 3-[(3-Benzyl-benzyl)-thiophen-2-ylmethyl-amino]-propionic acid
Figure imgf000069_0001
Mono TFA salt. HPLC-MS: m/z 366 [M+Hf. Rt = 1.78 min. P urity 97%.
Example 212 3-[(3-Benzy!-benzyl)-thiophen-3-ylmethyl-amino]-propionic acid
Figure imgf000069_0002
Mono TFA salt. HPLC-MS: m/z 366 [M+Hf. Rt = 1.79 min. P urity 97%.
Example 213 3-[(4-Butyl-benzyl)-(2-chloro-5-methyl-benzyl)-amino]- propionic acid
Figure imgf000069_0003
Mono TFA salt. HPLC-MS: m/z 374 [M+Hf. Rt = 1.63 min. P urity 88%.
Example 214 3-[(4-Butyl-benzyl)-(2-fluoro-5-methyl-benzyl)-amino]- propionic acid
Figure imgf000069_0004
Mono TFA salt. HPLC-MS: m/z 358 [M+Hf. Rt = 1.59 min. P urity 95%.
Example 215 3-[(2-Fluoro-5-methyl-benzyl)-(4-pentyl-benzyl)-amino]- propionic acid
Figure imgf000069_0005
Mono TFA salt. HPLC-MS: m/z 372 [M+Hf. Rt = 1.68 min. Purity 94%.
Example 216 3-[(4-Butyl-benzyl)-(2,6-difluoro-3-methyl-benzyl)-amino]- propionic acid
Figure imgf000070_0001
Mono TFA salt. HPLC-MS: m/z 376 [M+Hf. Rt = 1.60 min. Purity 94%.
Example 217 3-[(2,6-Difluoro-3-methyl-benryl)-(4-pentyl-benzyl)-amino]- propionic acid
Figure imgf000070_0002
Mono TFA salt. HPLC-MS: m/z 390 [M+Hf. Rt = 1.68 min. Purity 994%.
Example 218 3-[(4-Butyl-benzyl)-(2,5-dimet yl-benzyl)-amino]-propionic acid
Figure imgf000070_0003
Mono TFA salt. HPLC-MS: m/z 354 [M+Hf. Rt = 1.66 min. Purity 93%.
Example 219 3-[(2,5-Dimethyl-benzyl)-(4-pe ntyl-benzyl)-amino]-propionic acid
Figure imgf000070_0004
Mono TFA salt. HPLC-MS: m/z 368 [M+Hf. Rt = 1.74 min. Purity 93%.
Assay Methods
The compounds of the above examples were tested in the following antibacterial assay as one estimate of their activity. Microtitre plates containing 100 μl volumes of the test compounds (standard concentration range: 1 -128 μg/ml) in 1.6% dimethyl sulfoxide were inoculated with 10 μl inocula of Bacillus subtilis 168CA with A600nm measuring 0.06 in S medium + 3% CH (Sharpe et al, 1998. J. Bacteriol. 180, 547- 555). Plates were incubated at 37°C with agitation until A6ooπm measured between 0.25 and 0.30 in the control (no compound) samples. Volumes (20 μl) were sampled on to poly-L-lysine treated slides and cells were examined by phase-microscopy at 100 x magnification under oil-immersion. The tested compounds were observed to inhibit bacterial cell division, and to produce a filamentous phenotype, ie having an average cell length in cultures greater than or equal to twice the average cell length in control culture.
In addition, the compounds were tested to determine minimum inhibitory concentrations (MICs) against Bacillus subtilis 168CA- MICS were determined by the broth microdilution method (National Committee for Olinical Laboratory Standards. 2000. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard - 5th ed.). Microtitre plates containing the test compounds were inoculated with a starting inoculum of 5x105 cfu/ml. Mueller-Hinton broth (Oxoid) was used as a growth medium The MIC was defined as the lowest concentration of compound inhibiting visible growth. Activities were scored as 'A' if the MIC was single digit eg. <8 microgrammes/ml, 'B' if the MIC was 16 to 64 microgrammes/ml and 'C if the MIC was greater than 64 microgrammes/ml.
Results:
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001

Claims

Claims:
1. The use of a compound of formula (I), or a salt, hydrate, solvate or prodrug thereof, in the manufacture of an antibacterial composition:
Figure imgf000075_0001
wherein
Z is a carboxyl radical HOC(=0)-, a carboxyl ester radical, or a carboxyl isostere radical;
ring A is an optionally substituted monocyclic aryl, heteroaryl or cycloalkyl radical;
ring B is a monocyclic aryl, heteroaryl or cycloalkyl radical;
X is -O-, -S-, -(CHa)-, -(CH=CH)-, -C(=CH2)-, -CH(CH3)-, -C(=O)-, -C(=S)-, -C NR,)- , or -NR wherein Ri is hydrogen or C-ι-C6 alkyl;
R is (i) an optionally substituted monocyclic aryl, heteroaryl, or cycloalkyl radical, or an optionally susbtituted cycloal kyl(Cι-C6 alkyl)- radical in which the cycloalkyl moeity is monocyclic, or (ii) an optionally substituted Cι-C6 alkyl radical which may be interrupted by -O-, -S-, or -NR2- wherein R2 hydrogen or is C C6 alkyl.
2. The use as claimed in claim 1 wherein Z is a 1 H-tetrazol-5-yl radical:
Figure imgf000075_0002
3. The use as claimed in claim 1 or claim 2 wherein ring A is a cyclopentyl, cyclohexyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-furyl, or 2- or 3-thienyl ring.
4. The use as claimed in any of claims 1 to 3 wherein optional substituents in ring A are selected from methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, trifluoromethyl, hydroxy, methoxy, mercapto, methylthio, fluoro, chloro, bromo, nitro, cyano, methylenedioxy and ethylenedioxy.
5. The use as claimed in any of the preceding claims wherein ring B is a cyclopentyl, cyclohexyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-furyl, or 2- or 3-thienyl ring.
6. The use as claimed in any of the preceding claims wherein X is -NR or - C(=NR.)wherein Ri is hydrogen or methyl.
7. The use as claimed in any of the preceding claims wherein R is an optionally substituted cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, 2-, 3-, or 4-pyridyl, 2- or 3-furyl, or 2- or 3-thienyl radical.
8. The use as claimed in claim 7 wherein optional substituents in R are selected from methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl, trifluoromethyl, hydroxy, methoxy, mercapto, methylthio, fluoro, chloro, bromo, nitro, cyano, methylenedioxy and ethylenedioxy.
9. The use as claimed in any of claims 1 to 6 wherein R is an optionally substituted methyl, ethyl, n- or iso-propyl, n-, sec- or tert-butyl, CH3-O-CH2-, CH3-S- CH2-, CH3-NH-CH2-, CH3-N(CH3)-CH2-, CH3-O-CH2-, CH3-S-CH2-, CH3-NH-CH2-, CH3-N(CH3)-CH2-, CH3CH2-0-CH2-, CH3CH2-S-CH2-,
CH3CH2-NH-CH2-, CH3CH2-N(CH3)-CH2-, CH3-O-CH2CH2-, CH3-S-CH2CH2-, CH3- NH-CH2CH2-, or CH3-N(CH3)- CH2CH2- radical.
10. The use as claimed in claim 9 wherein optional substituents in R are selected from methyl, trifluoromethyl, hydroxy, methoxy, mercapto, methylthio, fluoro, chloro, bromo, nitro, or cyano.
1 1. The use as claimed in claim 1 wherein ring A is optionally substituted phenyl, 2- or 3-thienyl, or 2- or 3-furyl; ring B is phenyl; X is -O-, -S-, -(CH2)-, -C(=CH2)- or - (CH=CH)- in the 3- or 4-position of the phenyl ring B; R is methyl, ethyl, n- or iso- propyl, n-, sec- or tert-butyl, or optionally substituted phenyl, cyclohexyl, 2- or 3- thienyl, 2- or 3-furyl; and wherein any optional substituents are selected from methyl, ethyl, n- and iso-propyl, n-, sec- and tert-butyl,, trifluoromethyl, hydroxy, methoxy, mercapto, methylthio, fluoro, chloro, bromo, nitro, or cyano.
12. A method of treating bacterial infection in a subject suffering such infection comprising administering to the subject an amount of a compound as defined in any of the preceding claims sufficient to inhibit bacterial growth.
13. A method of treating bacterial contamination o'f a substrate comprising applying to the site of such contamination an amount of a compound as defined in any of claims 1 to 11 sufficient to inhibit bacterial growth
14. A compound of formula (I) as defined in any of claims 1 to 11 , or a pharmaceutically acceptable salt, hydrate or solvate thereof, PROVIDED THAT the compound is not one of formula (IX) or (X)
Figure imgf000077_0001
or a salt hydrate or solvate thereof.
15. A pharmaceutical composition comprising compound as claimed in claim 14, together with a pharmaceutically acceptable carrier.
PCT/GB2005/001295 2004-04-06 2005-04-01 Antibacterial agents WO2005097100A2 (en)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009125606A1 (en) * 2008-04-11 2009-10-15 株式会社医薬分子設計研究所 Pai-1 inhibitor
CN102137837A (en) * 2008-04-11 2011-07-27 株式会社医药分子设计研究所 PAI-1 inhibitor
JPWO2009125606A1 (en) * 2008-04-11 2011-08-04 株式会社医薬分子設計研究所 PAI-1 inhibitor
US8633245B2 (en) 2008-04-11 2014-01-21 Institute Of Medicinal Molecular Design, Inc. PAI-1 inhibitor
WO2010123599A2 (en) * 2009-01-23 2010-10-28 The Board Of Trustees Of The University Of Illinois Anti-bacterial compositions and methods including targeting virulence factors of staphylococcus aureus
WO2010123599A3 (en) * 2009-01-23 2011-01-20 The Board Of Trustees Of The University Of Illinois Anti-bacterial compositions and methods including targeting virulence factors of staphylococcus aureus
US9822108B2 (en) 2012-01-13 2017-11-21 Rutgers, The State University Of New Jersey Antimicrobial agents
US9475783B2 (en) 2012-03-21 2016-10-25 Rutgers, The State University Of New Jersey Antimicrobial agents
US9458150B2 (en) 2013-11-08 2016-10-04 Rutgers, The State University Of New Jersey Antimicrobial agents
US10071082B2 (en) 2013-11-08 2018-09-11 Rutgers, The State University Of New Jersey Antimicrobial agents
US11129814B2 (en) 2013-11-08 2021-09-28 Taxis Pharmaceuticals, Inc. Antimicrobial agents
WO2015112902A3 (en) * 2014-01-23 2015-11-05 Sova Pharmaceuticals, Inc. CYSTATHIONINE-(gamma)-LYASE (CSE) INHIBITORS FOR TREATING PAIN
US10513528B2 (en) 2016-02-25 2019-12-24 Taxis Pharmaceuticals, Inc. Synthetic processes and intermediates
US10774093B2 (en) 2017-03-30 2020-09-15 Taxis Pharmaceuticals, Inc. Synthetic processes and synthetic intermediates

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