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GB2404855A - Arylcarboxylic acid derivatives and their therapeutic use - Google Patents

Arylcarboxylic acid derivatives and their therapeutic use Download PDF

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Publication number
GB2404855A
GB2404855A GB0315878A GB0315878A GB2404855A GB 2404855 A GB2404855 A GB 2404855A GB 0315878 A GB0315878 A GB 0315878A GB 0315878 A GB0315878 A GB 0315878A GB 2404855 A GB2404855 A GB 2404855A
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United Kingdom
Prior art keywords
benzoic acid
acid
cyano
mmol
water
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Application number
GB0315878A
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GB0315878D0 (en
Inventor
Bruce W Leslie
Christopher Lawson
Christopher Woolley
Lihua Zhao
Michael Thomas
Richard Grant
Samantha Thomson
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Pantherix Ltd
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Pantherix Ltd
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Priority to GB0315878A priority Critical patent/GB2404855A/en
Publication of GB0315878D0 publication Critical patent/GB0315878D0/en
Publication of GB2404855A publication Critical patent/GB2404855A/en
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/64—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C233/56—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
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    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/62—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
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    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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    • C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
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Abstract

A compound, for therapeutic use, of Formula 1b, wherein R1, R2, and R3 independently represent a spacing group (Y)n where Y is independently selected from CH2, CH=CH, C(O), O, NH, S, S(O), S(O)2 and n = 0 to 2; Ar represents a carbocyclic or heterocyclic, single or fused aromatic ring, which may contain any degree of saturation or contain a carbonyl moiety, and is optionally substituted by CH3, OH, OCH3, CO2H, CONH2, SO2NH2, SO2CH3, SOCH3, SCH3, NH2, NO2, CN, halogen, CF3, phenyl or heterocycle; and wherein PG is a polar functional group, especially CO2H, CN or tetrazole. These compounds are useful in medicaments for the treatment of a bacterial infection. <EMI ID=1.1 HE=76 WI=78 LX=251 LY=945 TI=CF>

Description

ARYLCARBOXYLIC ACID DERIVATIVES AND THEIR TIIERAPEUTIC USE
Field of the Invention
This invention relates to arylcarboxylic acids which inhibit bacterial chorismate synthase, and to their therapeutic use as antibiotics.
Background to the invention
Several chemical classes of compound are known that possess considerable antibacterial activity, and these have proven of immense value in the treatment of bacterial diseases and infection. They include among others, the penicillins, the cephalosporins, the 0 aminoglycoside antibiotics, vancomycin analogues and the sulfonamide antibiotics.
The mechanism of action of a number of known antibiotics is by the direct inhibition of enzymes of essential bacterial biosynthetic pathways. These include, amongst others, trimethoprim and the sulfonamide antibiotics.
Chorismate synthase, an enzyme in the shikimate pathway has been shown to be essential for bacterial viability (EP0913480). Compounds that inhibit this enzyme could therefore be useful antibacterial agents.
Compounds such as Furosemide and Bumetanide are known diuretics; there is no report that they have potential as antibacterial agents.
Summary of the Invention
According to the present invention, arylcarboxylic acid derivatives and their pharmaceutically acceptable salts may be used as the active ingredients in medicines for the treatment of bacterial infection in man and animals. These compounds are of Formula
HOOCH R1
'R3-Ar HOOCR2 - Formula 1 In Formula 1: R1, R2 and R3 independently represent a spacing group (Y)n where Y is independently selected from CH2, CH=CH, C(O), O. NH, S. S(O) and S(O)2 and n = 0 to 2.
Ar represents a carbocyclic or heterocyclic, single or fused aromatic ring. This includes benzene, naphthalene and heterocycles containing one or more heteroatoms selected from O. N or S such as pyridine, pyrimidine, Fran, thiazole, indole, purine, acridine and the lo like. The bond to the Ar group may be from any ring atom. Additionally, the ring may contain any degree of saturation or may contain a carbonyl moiety.
Moreover, the Ar group is optionally substituted by one or more of: CH3, OH, OCH3, CO2H, CONH2, SO2NH2, SO2CH3, SOCH3, SCH3, NH2,, NO2,, CN, halogen, CF3, phenyl or heterocycle Furthermore, one or more of the terminal carboxylic acid groups may be replaced by a polar functional group, for example: CO2R4, CONR4R5, CONHOH, CN, SO2NR4R5, OR4, NR4COR5, NR4R5, NO2, NR4SO2R5, SO2R4, SOR4, SR4 and heterocyclyl, for example, tetrazolyl, triazolone or oxazolone.
R4 and R5 are independently defined as: H. C alkyl, Ct 4 alkylaryl, aryl or taken together R4 and R5 are C-6 alkylene; and aryl is defined as: Phenyl, or heterocyclyl optionally substituted by CH3, OH, OCH3, C02H, CONH2, SO2NH2, SO2CH3, SOCH3, SCH3, NH2,, NO2,, CN, halogen or CF3.
Preferred compounds are those where: R1, R2 and R3 are independently a bond, O. S. S(O), S(O) 2, CH=CH, NHCO or OCH2; the terminal groups are CO2H, CN or tetrazole; and Ar is phenyl or pyridyl, optionally substituted by one or more of: CH3, OH, OCH3, CO2H, CONH2, NO2,, CN, halogen, CF3 o or pyrazole.
Compounds of the invention have therapeutic utility as antibacterial agents. They are especially useful for the treatment of infections caused by gram positive organisms such as S. aureus. In particular, they exhibit inhibition of the enzyme chorismate synthase in the shikimate pathway which has been shown to be essential for bacterial viability (EP0913480). The compounds and their pharmaceutically acceptable salts are claimed as the active ingredients in medicines for the treatment of bacterial infection in man and animals.
Description of the invention
Compounds of Formula 1 may contain one or more chiral centres and exist in optically active forms. When a compound of Formula 1 or a salt thereof contains a single chiral centre (for example sec-butyl) it may exist in two enantiomeric forms. The present invention includes individual enantiomers and mixtures of these enantiomers. The enantiomers may be obtained by methods known to those skilled in the art. Such methods typically include resolution via formation of diastereomeric salts or complexes which may be separated, for example, by crystallisation; resolution via formation of diastereomeric derivatives or complexes which may be separated, for example, by crystallisation, gas- liquid or liquid chromatography; selective reaction with one enantiomer by reaction with an enantiomer-specific reagent, for example, enzymatic esterification, oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas liquid or liquid chromatography on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation processes described above, at least one further step will subsequently be required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesised by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into another by asymmetric transformation.
When a compound of Formula 1 or a salt thereof contains more than one chiral centre it may exist in diastereomeric forms. The diastereomeric pairs may be separated by lo methods known to those skilled in the art, for example, chromatography or crystallization and the individual enantiomers within each pair may be separated as described above.
The present invention includes each diastereomer of compounds of Formula 1 and mixtures thereof.
Some compounds of Formula 1 may exist in the form of solvates, for example, hydrates, which also fall within the scope of the present invention.
The compounds of Formula 1 may form organic or inorganic salts, for example, the compounds of Formula 1 may form addition salts with inorganic or organic acids, e.g. hydrochloric acid, hydrobromic acid, fumaric acid, tartaric acid, citric acid, sulfuric acid, hydiodic acid, maleic acid acetic acid, succinic acid, benzoic acid, pamoic acid, palmitic acid, dodecanoic acid and acidic amino-acids such as glutamic acid. Such compounds of Formula 1 may form base addition salts, for example, with alkali metal hydroxides e.g. sodium hydroxide, with amino- acids e.g. Iysine or arginine or with organic bases e.g. meglumaine. It will be appreciated that such salts, provided that they are pharmaceutically acceptable may be used in therapy in place of compounds of Formula 1.
Such salts are prepared by reacting the compound of Formula 1 with a suitable acid or base in a conventional manner. Such salts may also exist in the form of solvates, for example, hydrates. The present invention includes each salt and any solvate thereof.
Certain compounds of Formula 1 or salts thereof may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof. s
"Pharmaceutically acceptable salts" are acid addition salts which can be prepared by any of the art recognised means. Typical acid addition salts include hydrochloride, hydrobromi de, hydro iodide, sulphate, phosphate, acetate, propionate, lactate, malate, succinate, tartrate, and cyclohexanesulphamates.
s As used hereinafter, the term "active compound" denotes a compound of Formula 1 including pharmaceutically acceptable salts thereof. In therapeutic use, the active compound may be administered orally, rectally, parenterally, topically, ocularly, aurally, nasally, intravaginally or to the buccal cavity, to give a local and/or systemic effect. Thus the therapeutic compositions of the present invention may take the form of any of the lo known pharmaceutical compositions for such methods of administration. The compositions may be formulated in a manner known to those skilled in the art so as to; give a controlled release, for example rapid release or sustained release, of the compounds of the present invention. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. The compositions of the invention l may contain 0.1-99% by weight of active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably the unit dosage of active ingredient is 1-500 ma. The excipients used in the preparation of these compositions are the excipients known in the pharmacist's art.
Compositions for oral administration are preferred compositions of the invention; and there are known pharmaceutical forms for such administration, for example tablets, capsules, granules, syrups and aqueous or oily suspensions.
Tablets may be prepared from a mixture of the active compound with fillers such as lactose or calcium phosphate, disintegrating agents, for example maize starch, lubricating agents, for example magnesium stearate, binders for example microcrystalline 2s cellulose or polyvinyl pyrrolidone and other optional ingredients known in the art to permit tableting the mixture by known methods. The tablets may, if desired, be coated! using known methods and excipients which may include enteric coating using for example hydroxypropylmethylcellulose phthalate. The tablets may be formulated in a; manner known to those skilled in the art so as to give a sustained release of the] compounds of the present invention. Such tablets may, if desired, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate.
Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by known methods and if desired, provided with enteric coatings in a known manner. The tablets and capsules may conveniently each contain 0.1 to 1000 mg (for example 10 ma, 50 ma, 100 ma, 200 ma, 400 ma, 600 ma, or 800 ma) of the active compound. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as lo sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example sunflower oil.
The active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or they may be added to a suitable liquid carrier (for example water) before ingestion. The granules may contain Is disintegrants (for example a pharmaceutically acceptable effervescent couple formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.
Compositions for topical administration are also preferred compositions of the invention. The pharmaceutically active compound may be dispersed in a Jo pharmaceutically acceptable cream, ointment or gel. A suitable cream may be prepared by incorporating the active compound in a topical vehicle such as petrolatum and/or light liquid paraffin, dispersed in an aqueous medium using surfactants. An ointment may be prepared by mixing the active compound with a topical vehicle such as a mineral oil, petrolatum and/or a wax e.g. paraffin wax or beeswax. A gel may be prepared by mixing the active compound with a topical vehicle comprising a gelling agent e.g. Gasified Carbomer BP, in the presence of water. Topically administrable compositions may also comprise a matrix in which the pharmaceutically active compounds of the present invention are dispersed so that the compounds are held in contact with the skin in order to administer the compounds transdermally. A suitable transdermal composition may be prepared by mixing the pharmaceutically active compound with a topical vehicle, such as described above, together with a potential transdermal accelerate such as dimethyl sulphoxide or propylene glycol.
Compositions of the invention suitable for rectal administration are known pharmaceutical forms for such administration, for example suppositories with hard fat, s synthetic glycerides or polyethylene glycol bases.
Compositions of the invention suitable for parenteral administration are known pharmaceutical forms for such administration, for example sterile suspensions or sterile solutions in a suitable solvent.
Compositions of the invention suitable for inhalation via the mouth and/or the nose are lo the known pharmaceutical forms for such administration, for example aerosols, nebulised solutions or powders. Metered dose systems, known to those skilled in the art, may be used.
Compositions suitable for application to the buccal cavity include slow dissolving tablets, troches, chewing gum, gels, pastes, powders, mouthwashes or rinses.
The compounds ofthe present invention may also be administered by continuous infusion either from an external source, for example by intravenous infusion, or from a source of the compound placed within the body, internal sources include implanted reservoirs containing the compound to be infused which is continuously released for example by osmosis and implants which may be a) liquid such as an oily solution or suspension of the go compound to be infused for example in the form of a very sparingly water-soluble derivative such as a dodecanoate salt or b) solid in the form of an implanted support for example of a synthetic resin of waxy material for the compound to be infused. The support may be a single body containing the entire compound or a series of several bodies each containing part of the compound to be delivered.
In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
The compounds of the invention can be prepared by a number of different routes.
Scheme 1 shows the preparation of compounds of Formula 1, where n = p+q, by reaction of a compound of Formula 2, in which the groups R1, R2 and Y are as defined previously and p = 0 to 2, and a compound of Formula 3 where Y is defined as previously, q = 0 to 2, and X represents a leaving group such as a halogen or sulfonate ester. The reaction can be carried out in an inert organic solvent such as ethanol, acetonitrile or DMF in the presence of a base such as an alkali metal carbonate or a tertiary amine base such as triethylamine in a temperature range between -80 C to 160 C.
HOOCR HOOCR
(Y)pH Y)qX (Y)n-Ar HOOCR2 Ar HOOCR2 Formula2 Formula 3 Formula 1 Schemel Compounds of Formula 3 are commercially available. Compounds of Formula 2 may be prepared by disconnection of R1 or R2, in a similar manner to the disconnection of R3 shown in Scheme 1 or 2, or are commercially available.
It is appreciated that where one or more of the carboxylic acid groups is replaced by a polar functional group, for example: CO2R4, CONR4R5, CONHOH, CN, SO2NR4R5, OR4, NR4COR5, NR4R5, NO2, NR4SO2R5, SO2R4, SOR4, SR4 and heterocyclyl, for example, tetrazolyl, triazolone or oxazolone, where R4 and R5 are as previously defined, that these functional groups are prepared by interconversion, at any stage of the synthesis, as generally understood by one of ordinary skill in the art, or are commercially available.
Preferably, carboxylic acids are protected as their esters before the coupling reaction and hydrolysed back to the carboxylic acids as the last step of the synthesis.
In addition, phenolic moieties not involved in the coupling process, are preferably purchased as anisoles and later deprotected according to methods generally understood by one of ordinary skill in the art, such as treatment with boron tribromide.
Alternatively compounds of Formula 1, where n = p+q, can be prepared by reaction of a compound of Formula 4, in which the groups R1, R2 and Y are as defined previously, p = O to 2, and X represents a leaving group such as a halogen or sulfonate ester, and a compound of Formula 5 where Y is defined as previously and q = 0 to 2. The reaction can be carried out in an inert organic solvent such as ethanol, acetonitrile or DMF in the presence of a base such as an alkali metal carbonate or a tertiary amine base such as triethylamine in a temperature range between -80 C to 160 C according to scheme 2.
HOOCR1 HOOCR 1 (Y)pX tY)qH (Y)n-Ar HOOCR2 Ar HOOCR2:} Formula 4 Formula 5 Formula 1 Scheme 2 Compounds of Formula 5 are commercially available. Compounds of Formula 4 may be prepared by disconnection of R1 or R2, in a similar manner to the disconnection of R3 shown in Scheme 1 or 2, or are commercially available.
The reactions described herein will be generally understood by one of ordinary skill in the art. The starting materials are available or can readily be prepared by one of ordinary skill in the art.
The following Preparations and Examples illustrate the invention. The intermediates and products gave satisfactory LCMS and 'H NMR results.
General Procedure for 4-ohenoxvisophthalic acids To a solution of dimethyl 4-bromoisophthalate (215 ma, 1.0 mmol) inDMF (10 mL) was added potassium carbonate (0.2 g), followed by the phenol (1.0 mmol) and the mixture heated to 120 C for 4 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the dimethyl 4 phenoxyisophthalate as a white solid (30 - 50%).
The solid was dissolved in methanol (10 mL), 1M NaOH (2 rnL) added and the mixture stirred at room temperature for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between 0 water (25 mL) and ethyl acetate (25 rnL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 4- phenoxyisophthalic acid as a white solid (90-100%).
Compounds prepared by this method: 4-(2-methoxyphenoxy)isophthalic acid 4-[4-(aminocarbonyl)phenoxy]isophthalic acid General Procedure for 4(phenvlthio)isonhthalic acids Prepared as for the General Procedure for 4phenoxyisophthalic acids by substituting a benzenethiol for the phenol.
Compounds prepared by this method: 4-[(3-chlorophenyl)thio]isophthalic acid General Procedure for 4-anilino- 3-nitrobenzoic acids To a solution of methyl 4-chloro-3-nitrobenzoate (195 ma, 1.0 mmol) in DMF (10 mL) was added potassium carbonate (0.2 g), followed by the aniline (1.0 mmol) and the mixture heated to 120 C for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the methyl 4-anilino-3- nitrobenzoate as a yellow solid (60%).
The solid was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture stirred at room temperature for 18 hr. The solvent was evaporated under vacuum, then the lo residue partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 4-anilino-3 nitrobenzoic acid as a yellow solid (20%).
Compounds prepared by this method: 4-anilino-3-nitrobenzoic acid General Procedure for 4-(benzYlamino)-3- cvanobenzoic acids To a solution of methyl 3-cyano-4-fluorobenzoate (179 ma, 1.0 mmol) in DMSO (10 mL) was added diisopropylethylamine (0.35 mL, 2. 0 mmol), followed by the benzylamine (3.0 mmol) and the mixture stirred for 36 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the methyl 4-(benzylamino)-3-cyanobenzoate as a white solid (80%).
The solid was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture stirred at room temperature for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 4-(benzylamino)-3-cyanobenzoic acid as a yellow solid (80%).
0 Compounds prepared by this method: 4-(benzylamino)-3-cyanobenzoic acid General Procedure for 3-nitro-4- ohenoxvLenzoic acids To a solution of methyl 4-chloro-3-nitrobenzoate (215 ma, 1.0 mmol) in DMF (10 mL) was added potassium carbonate (0.2 g), followed by the phenol (1.0 mmol) and the mixture heated to 100 C for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the methyl 3-nitro 4-phenoxybenzoate as a yellow solid (90%).
The solid was dissolved in methanol (10 mL), 1M NaOH (1 mL) added and the mixture stirred at room temperature for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 3-nitro-4 phenoxybenzoic acid as a yellow solid (90%).
Compounds prepared by this method: 4-(2-methoxyphenoxy)-3-nitrobenzoic acid General Procedure for 3-nitro-4- (ohenvlthio)benzoic acids Prepared as for the General Procedure for 3- nitro-4-phenoxybenzoic acids by substituting a benzenethiol for the phenol.
0 Compounds prepared by this method: 4-[(3-chlorophenyl)thio]-3-nitrobenzoic acid General Procedure for 3amino-4-phenoxYbenzoic acids A mixture of the methyl 3-nitro-4phenoxybenzoate (1.0 mmol), ammonium formate (0.5 g) and 5% palladium on carbon (5 ma) in ethanol (5 mL) and THE (5 mL) were stirred for 18 hr.
The catalyst was removed by filtration through celite, then the solvent removed under vacuum and the residue partitioned between water (25 mL) and ethyl acetate (25 mL).
The organic layer was separated, washed with brine (25 mL), dried (MgSO4), filtered, then evaporated to give the methyl 3-amino-4 phenoxybenzoate as a yellow oil (50-100%).
The solid was dissolved in methanol (10 mL), NaOH pellets (0.4g, 10 mmol) added and the solution stirred for 18 hr. The solid was collected, washed with methanol, then dried to give the 3-amino-4-phenoxybenzoic acid sodium salt as an off-white solid (70%).
Compounds prepared by this method: 3-amino-4-(2-methoxyphenoxy)benzoic acid General Procedure for 3- l(carboxYcarbonvl)aminol-4-nhenoxYbenzoic acids To a solution of the methyl 3-amino-4-phenoxybenzoate (1.0 mmol) and pyridine (1 mL) in DMF (10 mL) was added ethyl oxalyl chloride (0.22 mL. 2.0 mmol) and the reaction! stirred for 18 hr. The solvent removed under vacuum and the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with brine (25 mL), dried (MgSO4), filtered, then evaporated to give the methyl 3 {[ethoxy(oxo)acetyl]amino}-4-phenoxybenzoate as a yellow oil (50-100%).
0 The oil was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture stirred for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 is mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 3 [(carboxycarbonyl)amino]-4-phenoxybenzoic acid as a white solid (20-100%).
Compounds prepared by this method: 3-[(carboxycarbonyl)amino]-4-(3-methoxyphenoxy)benzoic acid 3-[(carboxycarbonyl)amino]-4-(2-methoxyphenoxy)benzoic acid 3-[(carboxycarbonyl)amino]-4-(4-methoxyphenoxy)benzoic acid 3-[(carboxycarbonyl)amino]-4-(3-carboxyphenoxy)benzoic acid 3-[(carboxycarbonyl)amino]-4-(4-carboxyphenoxy)benzoic acid General Procedure for l(5-cYano-2-nhenoxYPhenyl)aminol(ozo)acetic acids Prepared as for the General Procedure for 3-[(carboxycarbonyl)amino]-4phenoxybenzoic acids via the General Procedure for 3-amino-4phenoxybenzoic acids and the General Procedure for 3-nitro-4-phenoxybenzoic acids but replacing methyl 4-chloro-3nitrobenzoate by 4- chloro-3 -nitrobenzonitrile.
Compounds prepared by this method: ({ 5-cyano-2-[2-(lH-pyrazol-5-yl)phenoxy]phenyl} amino)(oxo)acetic acid General Procedure for 3-amino-4-(benzvl)oxYbenzeic acids lo A mixture of methyl 4-hydroxy-3-nitrobenzoate (1.97 g, 10 mmol), the benzyl bromide (10 mmol) and cesium fluoride (7.55g, 50 mmol) in DMF (25 mL) was stirred for 18 hr.
The solvent was evaporated under vacuum and the residue triturated with water. The solid was collected, washed with water, then dried over P205 to give the methyl 4 benzyloxy-3-nitrobenzoate as a yellow solid (75-100%) .
A mixture of the solid, sodium hydrosulfide hydrate (3.0 g) and triethylamine (2.7 mL, 20 mmol) in DMF (50 mL) was stirred at 110 C for 18 hr under nitrogen. After cooling, water (100 mL) was added, followed by acidification with 2M hydrochloric acid. The solid was collected then recrystallized from toluene to give the 3-amino-4-(benzyl)oxybenzoic acid as yellow solid (20-30%).
Compounds prepared by this method: 3-amino-4-(benzyl)oxybenzoic acid 3-amino-4-[(2-methoxybenzyl)oxy]benzoic acid 3-amino-4-[(3-methoxybenzyl)oxy]benzoic acid 3-amino-4-[(4-methoxybenzyl)oxy]benzoic acid 3-amino-4-{[4-(trifluoromethyl)benzyl]oxy}benzoic acid 3-amino-4-{[3-(trifluoromethyl)benzyl]oxy}benzoic acid 3-amino-4-{ [2-(trifluoromethyl)benzyl]oxy} benzoic acid 3-amino-4-[(4-fluorobenzyl)oxy]benzoic acid 3-amino-4-[(3-fluorobenzyl)oxy]benzoic acid General Procedure for 4(benzvloxv)-3-l(carboxvcarbonvl)aminolbenzeic acids s To a solution ofthe 3-amino-4-(benzyl)oxybenzoic acid (1.0 mmol) and pyridine (1 mL) in DMF (10 mL) was added ethyl oxalyl chloride (0.1 1 rnL. 1.0 mmol) and the reaction stirred for 18 hr.
Water (100 mL) was added, followed by acidification with 2M hydrochloric acid. The solid was collected, washed with water, then dried over P2O5 to give the 0 4-(benzyl)oxy-3-{[ethoxy(oxo)acetyl]amino}benzoic acid as a pale yellow solid (60 80%).
The solid was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture stirred for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 4- (benzyloxy)-3-[(carboxycarbonyl)amino]benzoic acid as a white solid (20- 100%).
Compounds prepared by this method: 3-[(carboxycarbonyl)amino]-4-[(2-chlorobenzyl)oxy]benzoic acid 3-[(carboxycarbonyl)amino]-4-[(3-chlorobenzyl)oxy]benzoic acid 3-[(carboxycarbonyl)amino]-4-[(4-chlorobenzyl)oxy]benzoic acid 3-[(carboxycarbonyl)amino]-4-[(3-methylbenzyl)oxy]benzoic acid 3-[(carboxycarbonyl)amino]-4-[(3-methoxybenzyl)oxy]benzoic acid 3-[(carboxycarbonyl)amino]-4- { [4-(trifluoromethyl)benzyl]oxy} benzoic acid 3-[(carboxycarbonyl)amino]-4-(benzyloxy)benzoic acid 3-[(carboxycarbonyl)amino]-4-[(2-methoxybenzyl)oxy]benzoic acid 3 -[(carboxycarbonyl)amino]-4- { [3 -(trifluoromethyl)benzyl]oxy} benzoic acid 3-[(carboxycarbonyl)amino]-4- { [2-(trifluoromethyl)benzyl]oxy}benzoic acid 3-[(carboxycarbonyl)amino]-4-[(4-fluorobenzyl)oxy]benzoic acid3-[(carboxycarbonyl)amino]-4-[(4-methoxybenzyl)oxy]benzoic acid 3-[(carboxycarbonyl)amino]-4-[(3-fluorobenzyl)oxy]benzoic acid General Procedure for 3-(aroYlamino)-4-(benzvl)oxvlbenzoic acids To a solution of the 3-amino-4-(benzyl)oxybenzoate (1.0 mmol) and pyridine (1 mL) in DMF (10 mL) was added the aroyl chloride (0.11 mL. 1.0 mmol) and the reaction stirred for 18 hr. Water (100 mL) was added, followed by acidification with 2M hydrochloric lo acid. The solid was collected, washed with water, then dried over P2O5 to give the 3-(aroylamino)-4-[(benzyl)oxy]benzoic acid as a pale yellow solid (30-60%) .
Compounds prepared by this method: 3-(benzoylamino)-4-[(2-methoxybenzyl)oxy]benzoic acid 4-[(2-methoxybenzyl)oxy]-3-[(4-nitrobenzoyl)amino]benzoic acid 3-[(3-cyanobenzoyl)amino]-4-[(2-methoxybenzyl)oxy]benzoic acid 3-[(4-cyanobenzoyl)amino]-4-[(2-methoxybenzyl)oxy]benzoic acid 4-[(2-methoxybenzyl)oxy]-3-[(thien-2-ylcarbonyl)amino]benzoic acid 3-(2-furoylamino)-4-[(2-methoxybenzyl)oxy]benzoic acid 4-[(2-methoxybenzyl)oxy]-3-[(pyridin-3-ylcarbonyl)amino]benzoic acid hydrochloride 4-[(2-methoxybenzyl)oxy]-3-[(pyridin-4-ylcarbonyl)amino]benzoic acid hydrochloride 3-[(4-carboxybenzoyl)amino]-4-[(2-methoxybenzyl)oxy]benzoic acid General Procedure for 4-(benzvloxY)-3-cyanobenzoic acid A mixture of methyl 3- cyano-4-hydroxybenzoate (177 ma, 1.0 mmol), the benzyl bromide (1.0 mmol) and cesium fluoride (0.755g, 5.0 mmol) in DMF (25 mL) was stirred for 18 hr. The solvent was evaporated under vacuum and the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the methyl 4-(benzyloxy)-3- cyanobenzoate as a white solid (50 - 100%).
The solid was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture stirred at room temperature for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 4-(benzyloxy) 0 3-cyanobenzoic acid as a pale yellow solid (20-50%).
Compounds prepared by this method: 4-(benzyloxy)-3-cyanobenzoic acid 3-cyano-4-[(3-nitrobenzyl)oxy]benzoic acid 3-cyano-4-{ [4-(trifluoromethyl)benzyl]oxy} benzoic acid 3-cyano-4-[(2-fluorobenzyl)oxy]benzoic acid 3-cyano-4-[(2-nitrobenzyl)oxy]benzoic acid 3-cyano-4-[(4-fluorobenzyl)oxy]benzoic acid General Procedure for 3-cvano4-ohenoxYbenzoic acids To a solution of methyl 4-chloro-3-cyanobenzoate (195 ma, 1.0 mmol) in DMF (10 mL) was added potassium carbonate (0.2 g), followed by the phenol (1.0 mmol) and the mixture heated to 120 C for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the methyl 3 cyano-4phenoxybenzoate as a white solid (50 - 100%).
The solid was dissolved in methanol (10 mL), 1M NaOH (1 mL) added and the mixture stirred at room temperature for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 3-cyano-4- phenoxybenzoic acid as a white solid (20-100%).
Compounds prepared by this method: 3-cyano-4-(2-methylphenoxy)benzoic acid lo 3-cyano-4-(2-methoxyphenoxy) benzoic acid 3-cyano-4-(4-methoxyphenoxy)benzoic acid Alternative General Procedure for 3-cvano-4-ohenoxvbenzoic acids To a solution of 2-fluoro-5formylbenzonitrile (149 ma, 1.0 mmol) in DMF (10 mL) was added potassium carbonate (0.2 g), followed by the phenol (1.0 mmol) and the mixture heated to 120 C for 18 hr under nitrogen. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 5-formyl-2 phenoxybenzonitrile as a white solid (60 - 90%).
To a solution ofthe solid (1.0 mmol) in acetonitrile (5 mL) and acetone (5 mL) was added a solution of 2KHSOs.KHSO4.K2SO4 (1.2 g, 2.0 mmol) in water (5 mL) and the mixture stirred for 18 hr. The solvent was evaporated under vacuum and the residue triturated with water. The solid was collected, washed with water, then dried over P205 to give the 3 cyano-4-phenoxybenzoic acid as a white solid (30-80%).
Compounds prepared by this method: 3 - c y a n o - 4 - (3 - m e t h o x y p h e n o x y) b e n z o i c a c i d 4-[4-(aminocarbonyl)phenoxy]-3-cyanobenzoic acid 3-cyano-4-[3-(dimethylamino)phenoxy]benzoic acid 4-(4-chlorophenoxy)-3-cyanobenzoic acid 3-cyano-4-[4-(methoxycarbonyl)phenoxy]benzoic acid 3-cyano-4-[3-(methoxycarbonyl)phenoxy]benzoic acid s 3-cyano-4-(pyridin-3yloxy)benzoic acid 4-(4-carboxyphenoxy)-3-cyanobenzoic acid 4-(3-carboxyphenoxy)-3-cyanobenzoic acid 3-cyano-4-phenoxybenzoic acid 3-cyano-4-(2-fluorophenoxy)benzoic acid lo 3-cyano-4-(3-cyanophenoxy) benzoic acid 3-cyano-4-(2,6-dimethylphenoxy)benzoic acid 3-cyano-4-(2-ethylphenoxy)benzoic acid 3-cyano-4-[2-(methylsulfonyl)phenoxy]benzoic acid 3-cyano-4-(2-cyanophenoxy)benzoic acid 4-[2-(aminocarbonyl)phenoxy]-3-cyanobenzoic acid 3-cyano-4-(4-cyanophenoxy)benzoic acid 4-(2-chlorophenoxy)-3-cyanobenzoic acid 4-(4-amino-3-nitrophenoxy)-3-cyanobenzoic acid 3-cyano-4-(3-methylphenoxy)benzoic acid 4-(3-chlorophenoxy)-3-cyanobenzoic acid 3-cyano-4-(4-hydroxyphenoxy)benzoic acid 4-[3-(aminocarbonyl)phenoxy]-3-cyanobenzoic acid 4-[4-(acetylamino)phenoxy]-3-cyanobenzoic acid 4-[4-(2-amino-2-oxoethyl)phenoxy]-3-cyanobenzoic acid 3-cyano-4-[2-(lH-pyrazol-3-yl)phenoxy]benzoic acid 4-(1, 1'-biphenyl-2-yloxy)-3-cyanobenzoic acid 3-cyano-4-(2-pyridin-3-ylphenoxy)benzoic acid 3-cyano-4-(2-pyridin-4-ylphenoxy)benzoic acid 3-cyano-4-(2-morpholin-4-ylphenoxy)benzoic acid 4-[2-(6-aminopyridin-3-yl)phenoxy]-3-cyanobenzoic acid 3-cyano-4-(2-isoxazol-5-ylphenoxy)benzoic acid 3-cyano-4-[3-methoxy-2-(lH-pyrazol-5-yl)phenoxy]benzoic acid 3-cyano-4-[3-hydroxy-2-( lH-pyrazol-5-yl)phenoxy]benzoic acid 5-[2-(4-carboxy-2-cyanophenoxy)phenyl]-2-furoic acid 3-cyano-4-(2-isoxazol-5-yl-3-methoxyphenoxy)benzoic acid 3-cyano-4-[2-( 1 -phenyl- lH-pyrazol-3-yl)phenoxy]benzoic acid 3 -cyano-4- { 2-[5-(2-hydroxyethyl)isoxazol-3 -yl]phenoxy} benzoic acid 3-cyano-4-(2-piperazin-1-ylphenoxy)benzoic acid 5-[2-(4-carboxy-2-cyanophenoxy)phenyl]nicotinic acid 4-(2-carboxyphenoxy)-3-cyanobenzoic acid lo 3-cyano-4-[5-methoxy-2-( lHpyrazol-5-yl)phenoxy]benzoic acid 3-cyano-4-[(2-methyl-1,3-benzothiazol-5-yl)oxy]benzoic acid 3-cyano-4-{2-[(propylamino)carbonyl]phenoxy}benzoic acid 3 -cyano-4-[5 -hydroxy-2-( 1 H-pyrazol-5-yl)phenoxy]benzoic acid 3-cyano-4-[4-fluoro-2-(lH-pyrazol-3-yl)phenoxy]benzoic acid 4-[4-chloro-2-( 1 H-pyrazol-3 -yl)phenoxy]-3 -cyanobenzoic acid 4-(9H-carbazol-2-yloxy)-3-cyanobenzoic acid 3-cyano-4-(3-{ [(2-furylmethyl)amino]carbonyl}phenoxy)benzoic acid 3-cyano-4-[4-methoxy-2-(lH-pyrazol-5-yl)phenoxy]benzoic acid 3-cyano-4{3-[(propylamino)carbonyl]phenoxy} benzoic acid 3-cyano-4-[4-hydroxy-2-(lH-pyrazol-5-yl)phenoxy]benzoic acid 4-(2-{[(4-chlorophenyl)amino]carbonyl}phenoxy)-3-cyanobenzoic acid 4-(2-{ [(3-chlorophenyl)amino]carbonyl}phenoxy)-3-cyanobenzoic acid 4-(2- { [(2-chlorophenyl)amino]carbonyl}phenoxy)-3-cyanobenzoic acid 4-{4-[carboxy(hydroxy)methyl]phenoxy}-3-cyanobenzoic acid 2s 3 -cyano-4-(2- { [(3 -methoxyphenyl)amino]carbonyl} phenoxy)benzoic acid 3-cyano-4-(2-{ [(4-methoxyphenyl)amino]carbonyl} phenoxy)benzoic acid 3 -cyano-4-[4-( 1 H-imidazol- 1 -yl)phenoxy]benzoic acid 3-cyano-4-(2-{[(2-methoxyphenyl)amino]carbonyl}phenoxy)benzoic acid General Procedure for 4-(arvlthio)-3-cvanobenzoic acids Prepared as for the General Procedure for 3-cyano-4-phenoxybenzoic acids by substituting an arylthiol for the phenol.
Compounds prepared by this method: 3-cyano-4-[(4-methoxyphenyl)thio]benzoic acid 2-[(4-carboxy-2-cyanophenyl)thio]nicotinic acid 6-[(4-carboxy-2-cyanophenyl)thio]nicotinic acid 4-[(3-carboxyphenyl)thio]-3-cyanobenzoic acid lo 4-[(4-carboxyphenyl)thio] -3-cyanobenzoic acid 3-cyano-4-(pyridin-2-ylthio)benzoic acid 3-cyano-4-[(3-methylphenyl)thio]benzoic acid 3-cyano-4-[(2-methoxyphenyl)thio]benzoic acid 3-cyano-4-[(3-methoxyphenyl)thio]benzoic acid 4-[(3-chlorophenyl)thio]-3-cyanobenzoic acid 4-[(4-chlorophenyl)thio]-3-cyanobenzoic acid 3-cyano-4-[(2-hydroxyphenyl)thio]benzoic acid 3-cyano-4-(phenylthio)benzoic acid 3-cyano-4-[(2-methylphenyl)thio]benzoic acid 3-cyano-4-[(4-methylphenyl)thio]benzoic acid 3-cyano-4-[(3,4-dimethylphenyl)thio]benzoic acid 3-cyano-4-[(3,5-dimethylphenyl)thio]benzoic acid 3-cyano-4-[(4-fluorophenyl)thio]benzoic acid 3-cyano-4-[(3,4-dichlorophenyl)thio]benzoic acid 3-cyano-4-(2-naphthylthio)benzoic acid 4- { [4-(aminocarbonyl)phenyl]thio} -3 -cyanobenzoic acid 4-[(2-chlorophenyl)thio]-3-cyanobenzoic acid 3-cyano-4-[(3,5-dichlorophenyl)thio]benzoic acid 3-cyano-4-[(2,6-dichlorophenyl)thio]benzoic acid 3-cyano-4-[(2,6-dimethylphenyl)thio]benzoic acid 3-cyano-4-[( l -methyllH-imidazol-2-yl)thio]benzoic acid 4-(benzylthio)-3-cyanobenzoic acid 3-cyano-4-{[2-(hydroxymethyl)phenyl]thio}benzoic acid 4-(1,3-benzothiazol-2-ylthio)-3-cyanobenzoic acid 3-cyano-4-[(4,6-dimethylpyrimidin-2-yl)thio]benzoic acid 3-cyano-4-[(4-phenyl-1,3-thiazol-2-yl)thio]benzoic acid General Procedure for 4-l(arYl)sulfonvll-3-cYanobenzoic acids To a solution ofthe 4(arylthio)-3-cyanobenzoic acid (1.0 mmol) in acetic acid (5 mL) lo was added 30% aqueous hydrogen peroxide (1 mL) and the solution stirred for 18 hr. Water (20 mL) was added and the solution extracted with ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 4-[(aryl)sulfonyl]-3-cyanobenzoic acid as a pale yellow solid (50 100%).
Compounds prepared by this method: 3-cyano-4-[(4-methoxyphenyl)sulfonyl]benzoic acid 4-[(3-carboxyphenyl)sulfonyl]-3-cyanobenzoic acid 3-cyano-4-(pyridin-2-ylsulfonyl)benzoic acid 6-[(4-carboxy-2-cyanophenyl)sulfonyl]nicotinic acid 3-cyano-4-(pyridin-4-ylsulfonyl)benzoic acid 3-cyano-4-[(3-methylphenyl)sulfonyl]benzoic acid 3-cyano-4-[(2-methoxyphenyl)sulfonyl]benzoic acid 3-cyano-4-[(3-methoxyphenyl)sulfonyl]benzoic acid 4-[(3-chlorophenyl)sulfonyl]-3-cyanobenzoic acid 4-[(4-chlorophenyl)sulfonyl]-3-cyanobenzoic acid 3-cyano-4-[(4-nitrophenyl)sulfonyl]benzoic acid General Procedure for 4l(arYl)sulDlnvll-3-cYanobenzoic acids To a solution ofthe 4-(arylthio)-3cyanobenzoic acid (1.0 mmol) in acetonitrile (5 mL) and acetone (5 mL) was added a solution of 2KHSO5.KHSO4.K2SO4 (1.2 g, 2.0 mmol) in water (5 mL) and the mixture stirred for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL).
The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the lo 4-[(aryl)sulfinyl]-3-cyanobenzoic acid as a pale yellow solid (50 - 60%).
Compounds prepared by this method: 4-[(3-carboxyphenyl)sulfinyl]-3-cyanobenzoic acid 6-[(4-carboxy-2-cyanophenyl)sulfinyl]nicotinic acid 3-cyano-4-[(4-methoxyphenyl)sulfinyl]benzoic acid 3-cyano-4-[(2-methoxyphenyl)sulfinyl]benzoic acid 3-cyano-4-[(3-methoxyphenyl)sulfinyl]benzoic acid 4-[(4-carboxyphenyl)sulfinyl]-3-cyanobenzoic acid 3-cyano-4-(pyridin-2-ylsulfinyl)benzoic acid General Procedure for 4ohenoxv-3-(lH-tetrazol-S-yl)benzeic acids To a solution of the methyl 3cyano-4-phenoxybenzoate (1.0 mmol) [see General Procedure for 3-cyano-4-phenoxybenzoic acids] in DMF (10 mL) was added sodium azide (65 ma, 1.0 mmol), followed by ammonium chloride (53.5 ma, 1.0 mmol) and lithium chloride (5 ma) and the mixture heated to 150 C for 40 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the methyl 4-phenoxy-3-(lH-tetrazol-5-yl)benzoate as a white solid (50 - 100%).
The solid was dissolved in methanol (10 mL), IM NaOH (1 mL) added and the mixture stirred at room temperature for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 4-phenoxy-3-(lH-tetrazol-5-yl)benzoic acid as a white solid (20-100%).
Compounds prepared by this method: 4-[3-(dimethylamino)phenoxy]-3-(1H-tetrazol-5-yl)benzoic acid 4-(2-methylphenoxy)-3-( lH-tetrazol-5-yl)benzoic acid General Procedure for 4-(arvlthio)-3-(lH-tetrazol-S-vl)benzoic acids Prepared as for the General Procedure for 4-phenoxy-3-(lH-tetrazol-5-yl)benzoic acids by substituting an arylthiol for the phenol.
Compounds prepared by this method: 4-[(3 -chlorophenyl)thio)]-3-( 1 H-tetrazol-5-yl)benzoic acid 4-[(3 -methylphenyl)thio)]-3-( 1 H-tetrazol-5-yl)benzoic acid General Procedure for 2-l(nhenvl)thiol-5-(5-oxo-2,5-dihvdroisoxazol-3- vl)benzonitriles To a solution ofthe 5-formyl-2-(phenylthio)benzonitrile (1.0 mmol) [prepared in the same manner as for 5-formyl-2-phenoxybenzonitriles (see Alternative General Procedure for 3- cyano-4 phenoxybenzoic acids) by substituting a benzenethiol for the phenol] in dichloromethane (10 mL) was added ethyl diazoacetate (0.21 mL, 2.0 mmol) followed by SnCl2 (189 ma, 1.0 mmol) and the mixture stirred for 18 hr. The mixture was filtered through silica, eluting with 15% EtOAc:hexane to remove impurities, followed by eluting with 20% EtOAc:hexane to isolate the product. Evaporation gave the ethyl 3-[3-cyano-4-(phenylthio)phenyl]-3- oxopropanoate as an oil (30-60%).
To a solution of the oil (0.5 mmol) in ethanol (10 mL) was added 0 hydroxylamine hydrochloride (69.5 ma, 1.0 mmol) and sodium acetate (82 ma, 1.0 mmol) and the solution heated to reflux for 2 hr. The solution was cooled, then poured into water (25 mL) and extracted with ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 2-[(phenyl)thio]-5-(5-oxo-2,5-dihydroisoxazol-3-yl)benzonitrile as a pale yellow solid (so%) Compounds prepared by this method: 2-[(4-methoxyphenyl)thio]-5-(5-oxo-2,5-dihydroisoxazol-3-yl)benzonitrile 2-[(3 -methylphenyl)thio] -5 -(5 -oxo-4, 5 -dihydroisoxazol-3 -yl) benzonitrile General Procedure for 5-(5-ozo-4,5-dihydro-lH-1,2,4-triazol3-vl)-2 (ohenylthio)benzonitriles To a solution ofthe 5-formyl-2-(phenylthio) benzonitrile (1.0 mmol) [prepared in the same manner as for 5-formyl-2-phenoxybenzonitriles (see Alternative General Procedure for 3- cyano-4 phenoxybenzoic acids) by substituting a benzenethiol for the phenol] in ethanol (10 mL) was added semicarbazide hydrochloride (111 ma, 1.0 mmol) and sodium acetate (82 ma, 1.0 mmol) and the solution heated to reflux for 1 hr. The solution was cooled, poured into water (25 mL) then the solid was collected, washed with water, then dried over P2O5 to give the S-{(E)-[(aminocarbonyl)hydrazono]methyl}-2-(phenylthio)benzonitrile as a white solid (80-100%).
To the solid in acetic acid (10 mL) was added sodium acetate (82 ma, 1.0 mmol), followed by bromine (160 ma, 1.0 mmol) and the mixture stirred for 1 hr. The mixture was partitioned between lo water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 5-(5-oKo-4,5-dihydro-lH-1,2,4-triazol-3-yl)-2-(phenylthio)benzonitrile as a white solid (30-40%).
Compounds prepared by this method: 2-[(4-methoxyphenyl)thio]-5-(5-oxo-4,5-dihydro- 1H- 1,2,4-triazol-3-yl) benzonitrile 2-[(3-methylphenyl)thio]-5-(5-oxo-4,5-dihydro- 1H1,2,4-triazol-3-yl) benzonitrile 2-[(3 -chlorophenyl)thio]-5 -(5 -oxo-4,5 -dihydro- 1 H- 1,2,4-triazol-3 - yl)benzonitrile General Procedure for 3-l(E)-2-carboxvvinvll-4- phenoxvbenzoic acids To a solution of 3-bromo-4-fluorobenzonitrile (200 ma, 1.0 mmol) in DMF (to mL) was added potassium carbonate (0.2 g), followed by the phenol (1.0 mmol) and the mixture heated to 80 C for 6 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 3-bromo-4- phenoxybenzonitrile as a white solid (60 - 100%).
A mixture of the 3-bromo-4-phenoxybenzonitrile, ethyl acrylate (0.9 mL, 1 mmol), palladium acetate (23 ma, 0.1 mmol), triphenylphosphine (80 ma, 0. 3 mmol), and triethylamine (0.2 mL, 1.5 mmol) in DMF (25 mL) was thoroughly degassed then stirred at 140 C for 18 hr under nitrogen. The catalyst was removed by filtration through celite, then the DM:F removed under vacuum. The residue was purified by silica chromatography, elating with 50% hexane:ethyl acetate to give the ethyl (2E)-3-(5-cyano 2-phenoxyphenyl)acrylate as a colourless oil (50 - 100%).
The oil was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture heated to reflux for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 3 [(E)-2-carboxyvinyl]-4-phenoxybenzoic acid as a white solid (20-100%).
Compounds prepared by this method: 4-(3-carboxyphenoxy)-3-[(E)-2-carboxyvinyl]benzoic acid 4-(4-carboxyphenoxy)-3-[(E)-2-carboxyvinyl]benzoic acid 3-[(E)-2-carboxyvinyl]-4-(2-methoxyphenoxy)benzoic acid 3-[(E)-2-carboxyvinyl]-4-phenoxybenzoic acid General Procedure for (2E)-3(5-cvano-2-ohenoxvphenvl)acrvlic acids The ethyl (2E)-3-(5-cyano-2phenoxyphenyl)acrylate (1.0 mmol) [see General Procedure for 3-[(E)-2-carboxyvinyl]-4-phenoxybenzoic acids] was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture stirred for 18 hr. The methanol was evaporated under vacuum then the solution acidified with 2M hydrochloric acid (25 mL). The solid was collected, washed with water, then dried over P2Os to give the (2E)-3-(5-cyano-2 phenoxyphenyl)acrylic acid as a white solid (50%).
Compounds prepared by this method: (2E)-3-(5-cyano-2-phenoxyphenyl)acrylic acid 0 (2E)-3 - { 5 -cyano-2-[3 -(dimethylamino)phenoxy]phenyl} acrylic acid (2E)-3-[5-cyano-2-(4-hydroxyphenoxy)phenyl]acrylic acid (2E)-3-[5-cyano-2-(2-methoxyphenoxy)phenyl]acrylic acid General Procedure for 3-l(E)-2-arvlvinvll-4-nhenoxYbenzoic acids A mixture ofthe 3-bromo-4phenoxybenzonitrile (1.0 mmol)[see General Procedure for 3-[(E)-2-carboxyvinyl]-4-phenoxybenzoic acids], vinylarene (1.0 mmol), palladium acetate (23 ma, 0.1 mmol), triphenylphosphine (80 ma, 0.3 mmol), and triethylamine (0.2 mL, 1.5 mmol) in DMF (25 mL) was thoroughly degassed then stirred at 140 C for 18 hr under nitrogen. The catalyst was removed by filtration through celite, then the DMF removed under vacuum. The residue was purified by silica chromatography, eluting with 50% hexane:dichloromethane to give the 3-[(E)-2 arylvinyl]-4phenoxybenzonitrile as a colourless oil (50 - 100%).
The oil was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture heated to reflux for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 3 [(E)-2-arylvinyl]-4-phenoxybenzoic acid as a white solid (20-100%).
Compounds prepared by this method: 4-(2-methoxyphenoxy)-3-[(E)-2-pyridin-4-ylvinyl]benzoic acid 4-(2-methoxyphenoxy)-3-[(E)-2-pyridin-2-ylvinyl]benzoic acid General Procedure for 3-arvl-4-ohenoxvbenzoic acids A mixture of the 3-bromo-4phenoxybenzonitrile (0.5 mmol)[see General Procedure for 3-[(E)-2-carboxyvinyl]-4-phenoxybenzoic acids], arylboronic acid (0.5 mmol), 0 palladium tetrakis(triphenylphosphine) (23 ma, 0.1 mmol) and sodium acetate (123 ma, 1.5 mmol) in THE (3 mL), propan-l-ol ( 1.5 mL) and water (1 mL) was thoroughly degassed then heated to reflux for 18 hr under nitrogen. The catalyst was removed by filtration through celite, then the solvent removed under vacuum. The residue was partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), then evaporated. The residue was purified by silica chromatography, eluting with hexane:dichloromethane to give the 3-aryl-4- phenoxybenzonitrile as a colourless oil (20 - 50%).
The oil was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture heated to reflux for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 3 aryl-4-phenoxybenzoic acid as a white solid (60-80%).
Compounds prepared by this method: 4-(2-methylphenoxy)-3 -thien-3 -ylbenzoic acid 3-(2-furyl)-4-(2-methylphenoxy)benzoic acid 4-(2-methylphenoxy)-3-thien-2-ylbenzoic acid General Procedure for 4(benzvloxv)-3-(carboxvmethoxv)benzoic acids To a solution of ethyl 3,4dihydroxybenzoate (1.8 g, 10 mmol) in acetonitrile (25 mL) was added sodium bicarbonate (0.84 g, 10 mmol) followed by the benzyl bromide (10 mmol) and the mixture heated to reflux for 18 hr. The solvent was evaporated under vacuum and the residue partitioned between ethyl acetate (25 mL) and 2M hydrochloric acid (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), then evaporated to give the ethyl 4-(benzyloxy)-3-hydroxybenzoate as a colourless oil (100%).
To a solution ofthe oil in in acetonitrile (25 mL) was added potassium carbonate (2.5 g), followed by ethyl bromoacetate (1.67 g, 10 mmol) and the mixture heated to reflux for 18 hr. The solvent was evaporated under vacuum and the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), then evaporated to give the ethyl 4-(benzyloxy)-3-(2-ethoxy-2-oxoethoxy)benzoate as a colourless oil (90%).
The oil was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture stirred at room temperature for 18 hr. The methanol was evaporated under vacuum then the solution acidified with 2M hydrochloric acid (25 mL). The solid was collected, washed with water, then dried over P2Os to give the 4-(benzyloxy)-3-(carboxymethoxy)benzoic acid as a white solid (80%).
Compounds prepared by this method: 4-(benzyloxy)-3-(carboxymethoxy)benzoic acid General Procedure for 2- (benzvlezv)-5-(carboxvmethoxv)benzoic acids As for the General Procedure for 4-(benzyloxy)-3-(carboxymethoxy)benzoic acids but replacing ethyl 3,4- dihydroxybenzoate by methyl 2,5-dihydroxybenzoate.
Compounds prepared by this method: 2-(benzyloxy)-5-(carboxymethoxy)benzoic acid 5-(carboxymethoxy)-2-[(3-methoxybenzyl)oxy]benzoic acid 5-(carboxymethoxy)-2-[(4-methoxybenzyl)oxy]benzoic acid 0 2-[(4-carboxybenzyl)oxy]-5-(carboxymethoxy)benzoic acid 5-(carboxymethoxy)-2-[(2-methylbenzyl)oxy]benzoic acid General Procedure for 2-(benzvloxv)-5-(E)-2-carboxwinvllbenzoic acids To a solution of methyl 5-formyl-2-hydroxybenzoate (1.8 g, 10 mmol) in THF (10 mL) was added a solution of methyl (triphenylphosphorylidene)acetate (3.34 g, 10 mmol) in THF (10 mL) and the solution stirred, under nitrogen, for 18 hr. The solvent was removed under vacuum and the residue purified by silica chromatography, eluting with hexane:EtOAc. Evaporation gave methyl 2-hydroxy-5-[(lE)-3-methoxy-3-oxoprop-1-enyl]benzoate as a white solid (80%).
A mixture of methyl 2-hydroxy-5-[(lE)-3-methoxy-3-oxoprop-1-enyl]benzoate (236 ma, 1.0 mmol), the benzyl bromide (1.0 mmol) and potassium carbonate (0.2 g) in DMF (25 mL) was stirred 140 C for 18 hr. The mixture was cooled, then poured into water (25 mL). The solid was collected, washed with water, then dried over P2Os to give the methyl 2-(benzyloxy)-5-[(lE)-3-methoxy-3-oxoprop-1-enyl]benzoate as a white solid (30 100%).
The oil was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture stirred at room temperature for 18 hr. The methanol was evaporated under vacuum then the solution acidified with 2M hydrochloric acid (25 mL). The solid was collected, washed with water, then dried over P20s to give the 2-(benzyloxy)-5-[(E)-2-carboxyvinyl] benzoic acid as a white solid (90- 1 00%), Compounds prepared by this method: 2-(benzyloxy)-5-[(E)-2-carboxyvinyl]benzoic acid 5-[(E)-2-carboxyvinyl]-2-[(4-methoxybenzyl)oxy]benzoic acid 2-[(4-carboxybenzyl)oxy]-5-[(E)-2-carboxyvinyl]benzoic acid lo 5-[(E)-2carboxyvinyl]-2-[(3-methoxybenzyl)oxy]benzoic acid General Procedure for (2E)-3-3-cvano-4-(ohenylthio)ohenvllacrvlic acids To a solution ofthe 5formyl-2-(phenylthio)benzonitrile (1.0 mmol) [prepared in the same manner as for 5-formyl-2-phenoxybenzonitriles (see Alternative General Procedure for 3- cyano-4- phenoxybenzoic acids) by substituting a benzenethiol for the phenol] in THF (5 mL) containing triethylamine (1 mL) was added a solution of methyl (triphenylphosphorylidene)acetate (0.334 g, 1.0 mmol) in THF (5 mL) and the solution stirred for 1 hr. The solvent was evaporated to give an oil which was used without purification.
The oil was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture stirred at room temperature for 18 hr. The methanol was evaporated under vacuum then the solution acidified with 2M hydrochloric acid (25 mL). The solid was collected, washed with water, then dried over P20s to give the (2E)-3-[3-cyano-4-(phenylthio)phenyl] acrylic acid as a white solid (60%).
Compounds prepared by this method: 4-({4-[(E)-2-carboxyvinyl]-2-cyanophenyl}thio)benzoic acid (2E)-3{3-cyano-4-[(2-methylphenyl)thio]phenyl} acrylic acid General Procedure for (2E)-3-(3-cvano-4-nhenoxYphenvl)acrylic acids To a solution of methyl (2E)-3-(3-cyano-4-fluorophenyl)acrylate (205 ma, 1.0 mmol) in DMF (10 mL) was added potassium carbonate (0.2 g), followed by the phenol (1.0 mmol) and the mixture heated to 120 C for 18 hr under nitrogen. The solvent was evaporated 0 under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the methyl (2E)-3-(3-cyano-4-phenoxyphenyl)acrylate as a white solid (70%).
The oil was dissolved in methanol (10 mL), 1M NaOH (2 mL) added and the mixture stirred for 18 hr. The solvent was evaporated under vacuum, then the residue partitioned between water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated, acidified with 2M HCI (2 mL) and extracted with ethyl acetate. The organic layer was separated, washed with water (25 mL), then brine (25 mL), treated with charcoal, filtered, then evaporated to yield the 3 aryl-4-phenoxybenzoic acid as a white solid (90%).
Compounds prepared by this method: (2E)-3- { 3-cyano-4-[2-( lH-pyrazol-3-yl)phenoxy]phenyl} acrylic acid (2E)-3-[5-cyano-2-(4-methoxyphenoxy)phenyl]acrylic acid Measurement ofICso Phosphate release from the chorismate synthase catalysed reaction, was measured using the spectrophotometric assay as disclosed in Webb, Proc. Nat. Acad. Sci. (USA), 1992; 89: 4884-4887.
The reaction assay solution comprised 0.005 units of chorismate synthase (where 1 unit is sufficient to catalyse the turnover of 1,umole of substrate per minute), FMN at a concentration of 10 AM and dimethyl sulfoxide (10% v/v). The substrate for chorismate synthase was EPSP (112 t1M). An immiscible layer of mineral oil (24% v/v) was placed over the aqueous assay solution and sodium dithionite added below the mineral oil layer to initiate the enzymatic reaction. The sodium dithionite concentration was 1.5 mM although concentrations smaller than or greater than 1.5 mM may be used.
The inhibitory effect of a compound can be described by an Icso value, that is the lo concentration of inhibitor at which half (50%) inhibition of the maximal (100%) inhibition occurs. Icso values were determined by measuring the extent of inhibition over a range of concentrations of the compound, preferably a range where the degree of inhibition varied from no inhibition (0%) to complete inhibition (100%). The IC50 value can be estimated from a plot of % inhibition against concentration of inhibitor, or can be calculated using data fitting programs, such Grafit (Elsevier) or EnzFitter (Biosoft).
An inhibitor's Icso value was determined from the rate of phosphate release in the presence of various concentrations of inhibitor compared to the base rate measured in the absence ofinhibitor (3.261lmole/l/min).

Claims (8)

  1. Claims I. A compound, for therapeutic use, of Formula 1
    HOOCH R1
    HOOC R2J Formula 1 wherein R1, R2 and R3 independently represent a spacing group (Y)n where Y is independently selected from CH2, CH=CH, C(O) , O. NH, S. S(O), S(0)2 and n = 0 to 2; Ar represents a carbocyclic or heterocyclic, single or fused aromatic ring containing any degree of saturation or a carbonyl moiety, and optionally substituted by 0 CH3, OH, OCH3, CO2H, CONH2, SO2NH2, SO2CH3, SOCH3, SCH3, NH2,, NO2,, CN, halogen, CF3, phenyl or heterocycle, and wherein one or more of the terminal carboxylic acid groups may be replaced by a polar functional group.
  2. 2. A compound of claim 1, wherein the polar group is CO2R4, CONR4R5, CONHOH, CN, SO2NR4R5, OR4, NR4COR5, NR4R5, NO2, NR4SO2R5, SO2R4, SOR4, SR4 or heterocyclyl; R4 and R5 are independently H. C alkyl, C, 4 alkylaryl or aryl or taken together R4 and R5 are C, alkylene; and aryl is phenyl, or heterocyclyl optionally substituted by one or more of CH3, OH, OCH3, CO2H, CONH2, SO2NH2, SO2CH3, SOCH3, SCH3, NH2, NO2, CN, halogen or CF3.
  3. 3. A compound of claim 1, wherein R1, R2 and R3 are independently a bond, O. S. S(O), S(O) 2, CH=CH, NHCO or OCH2; the terminal groups are CO2H, CN or tetrazole; and Ar is phenyl or pyridyl, optionally substituted by one or more of CH3, OH, OCH3, 2s CO2H, CONH2, NO2,, CN, halogen, CF3 or pyrazole.
  4. 4. A pharmaceutical composition comprising as an active ingredient a compound of any preceding claim, together with a carrier or diluent.
  5. 5. Use of a compound of any of claims 1 to 3, for the manufacture of a medicament for the treatment of a bacterial infection.
  6. 6. The use of claim 5, wherein the infection is caused by a gram positive organism.
  7. 7. The use of claim 6, wherein the organism is
  8. S. aureus.
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US20070225332A1 (en) * 2006-02-15 2007-09-27 Yu Gui Gu Novel acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome
US7622486B2 (en) 2004-09-23 2009-11-24 Reddy Us Therapeutics, Inc. Pyridine compounds, process for their preparation and compositions containing them
US8735595B2 (en) 2006-02-15 2014-05-27 Abbvie Inc. Acetyl-CoA carboxylase (ACC) inhibitors and their use in diabetes, obesity and metabolic syndrome
WO2020236907A1 (en) * 2019-05-20 2020-11-26 Albert Einstein College Of Medicine Compounds and methods for treatment of bacterial infections

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CN109705057B (en) * 2017-10-25 2023-05-30 成都先导药物开发股份有限公司 Histone deacetylase inhibitor and preparation method and application thereof

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WO2001023347A1 (en) * 1999-09-29 2001-04-05 Novo Nordisk A/S Novel aromatic compounds
WO2001092273A2 (en) * 2000-05-30 2001-12-06 Guilford Pharmaceuticals Inc. Benzenedicarboxylic acid derivatives
GB2365426A (en) * 2000-08-01 2002-02-20 Pantherix Ltd Bactericidal benzamide derivatives
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GB2378179A (en) * 2001-08-03 2003-02-05 Pantherix Ltd Aromatic sulfonamides and their use in treating bacterial diseases
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WO2000076969A1 (en) * 1999-06-10 2000-12-21 Warner-Lambert Company Method of inhibiting amyloid protein aggregation and imaging amyloid deposits using isoindoline derivatives
WO2001023347A1 (en) * 1999-09-29 2001-04-05 Novo Nordisk A/S Novel aromatic compounds
WO2001092273A2 (en) * 2000-05-30 2001-12-06 Guilford Pharmaceuticals Inc. Benzenedicarboxylic acid derivatives
GB2365426A (en) * 2000-08-01 2002-02-20 Pantherix Ltd Bactericidal benzamide derivatives
WO2003000262A1 (en) * 2001-06-26 2003-01-03 Astrazeneca Ab Vinyl phenyl derivatives as glk activators
GB2378179A (en) * 2001-08-03 2003-02-05 Pantherix Ltd Aromatic sulfonamides and their use in treating bacterial diseases
WO2004029239A1 (en) * 2002-09-27 2004-04-08 Pantherix Ltd. Crystal structure of chorismate synthase and uses thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7622486B2 (en) 2004-09-23 2009-11-24 Reddy Us Therapeutics, Inc. Pyridine compounds, process for their preparation and compositions containing them
US20070225332A1 (en) * 2006-02-15 2007-09-27 Yu Gui Gu Novel acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome
US8735595B2 (en) 2006-02-15 2014-05-27 Abbvie Inc. Acetyl-CoA carboxylase (ACC) inhibitors and their use in diabetes, obesity and metabolic syndrome
US8748627B2 (en) * 2006-02-15 2014-06-10 Abbvie Inc. Acetyl-CoA carboxylase (ACC) inhibitors and their use in diabetes, obesity and metabolic syndrome
WO2020236907A1 (en) * 2019-05-20 2020-11-26 Albert Einstein College Of Medicine Compounds and methods for treatment of bacterial infections

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