GB2386892A - Carboxy containing (phenyl-/heterocyclyl-)methylene substituted azole & azine derivatives and their therapeutic use as antibacterials - Google Patents
Carboxy containing (phenyl-/heterocyclyl-)methylene substituted azole & azine derivatives and their therapeutic use as antibacterials Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/66—Thiobarbituric acids
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- 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
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
Abstract
Compounds of Formula 1 <EMI ID=1.1 HE=37 WI=55 LX=383 LY=650 TI=CF> <EMI ID=1.2 HE=37 WI=54 LX=1195 LY=654 TI=CF> <PC>[wherein W is S or O; X is NH, S or O; Z is one or more phenyl or heterocyclyl rings (optionally substituted by C1-6 alkyl, halogen, hydroxy, alkoxy, nitro and trifluoromethyl) optionally separated by a spacing group (Y)n where Y is selected from CH2, O, NH, S, S(O), S(O)2 and n = 0 to 6; and R is hydrogen, a phenyl or heterocyclyl ring (optionally substituted by C1-6 alkyl, halogen, hydroxy, alkoxy, nitro and trifluoromethyl) optionally separated by a spacing group (Y)n where Y is selected from CH2, O, NH, S, S(O), S(O)2 and n = 0 to 6, alternatively, R is of the form (Y)nCOOH] inhibit the phosphopantetheine adenylyltransferase enzyme and may be used as antibacterial agents, eg to treat infections caused by gram positive organisms such as S. aureus.
Description
COMPOUNDS AND TEIEIR THERAPEUTIC USE
Field of the Invention
This invention relates to compounds, and more specifically to azole or barbiturate analogues, and to their therapeutic use,.
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 aminoglycoside antibiotics, vancomycin analogues and the sulfonamide drugs.
The mechanism of action of a number of known antibiotics is by the direct inhibition of enzymes of essential bacterial biosynthetic pathways. These indude, amongst others, trimethoprim and the sulfonamide drugs.
An enzyme of the Coenzyme A biosynthetic pathway, phosphopantetheine adenylyltransferase (PPAT), has been shown to be essential for bacterial viability (WO/ 0017387) and a compound that could inhibit such au enzyme in viva would be likely to be of use as an antibacterial agent.
The compounds described in the invention are structurally distinct from previously prescribed antibiotics, and their mode of action is also dissimilar.
Summary of the Invention
This invention relates to compounds, and more specifically to azole or barbiturate analogues defined by Formula la and lb and to their therapeutic use. The compounds and their pharmaceutically acceptable salts are claimed as the active ingredients in medicines for the treahnent of bacterial infection in man and animals. O O R-NZ,COOH RN JZ'COOH
MAX WAX O
W Formula la Formula lb wherein W is S or O; X is NH, S or O; Z is one or more phenyl or heterocyclyl rings (optionally substituted by C, aLkyl, halogen, hydroxy, alkoxy, nitro and trifluoromethyl) optionally separated by a spacing group (Y)n where Y is selected from CH2, O. NH, S. S(O), S(0) 2 and n = 0 to 6; and R is hydrogen, a phenyl or heterocyclyl ring (optionally substituted by Can aLkyl, halogen, hydroxy, aLcoxy, nitro and trifluoromethyl) optionally separated by a spacing group (Y)n where Y is selected from CH2, O. NH, S. S(O), S(0)2 and n = O to 6, alternatively, R is of the form (Y)nCOOH Compounds of the invention include salts thereof.
Preferred compounds are where R is benzothiazole, m-chlorophenyl, p(trifluoromethyl)benzyl, benzimidazole, hydrogen or CH2COOH; X is NH, S or O; W is S or O and Z-COOH is:
OHHO -:0 \ó> AH\O tOH CON> -OH o Compounds of the invention, most of which are new, have therapeutic utility. In particular, they exhibit inhibition of the enzyme phosphopantetheine adenylyltransferase. The compounds are useful as active ingredients in medicines, for the treatment of bacterial infection in man and animals.
Compounds of similar structure to those of the invention have been described before as antibacterial agents.
However, these compounds do not contain a carboxylic acid moiety and possess only weak activity. For this reason, the increased antibacterial potency of azole or barbiturate analogues containing a catboxylic acid moiety could not have been predicted and is therefore novel. A number of these compound have been purchased and found to be inactive in our phosphopantetheine adenylyltransferase and only feebly active in our antibacterial screens.
Descrintion of the Invention The term "Clot aLkyl" as used herein refers to straight and branched chain alkyl groups having up to 6 C atoms. Examples are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl and tert-butyl. "AUcyl" may have the same meaning. "Halogen" means F. Cl, Br or I. "Alkoxy" means Can alkyd-. "Heterocyclyl" means a saturated, unsaturated or aromatic ring of 5 to 8 atoms containing one or more heteroatoms such as 0, S or N. and which may be bonded via any C or ring atom.
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 an Such methods typically include resolution via formation of diastereomeric salts or complexes which may be separated, for example, by crystallization; resolution via formation of diastereomeric derivatives or complexes which may be separated, for example, by crystallization, 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 mto 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 methods known to those skilled in the art, for example, chromatography or crystalhsation 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 I may exist in the form of solvates, for example, hydrates, which also fall within the scope of the present invention.
The compounds of formula l may form organic or inorganic salts, for example, the compounds of formula l 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. lysine or arginine or with orgamc 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 l 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.
"Phannaccutically acceptable salts" are acid addition salts which can be prepared by any of the art recognised means. Typical acid addition salts include hydrochloride, hydrobrornide, hydroiodide, sulphate, phosphate, acetate, propionate, lactate, malate, succinate, tatrate, cyclohexanesulphamates, methanesulphonates, ethanesulphonates, benzenesulphonates, toluenesulphonates, fumarates ard other pharmaceutically acceptable counter ions for amines.
The preferred procedure for preparing compounds of the invention comprises reacting a azole or barbiturate analogue of the formula 2a or 2b with an aldehyde of formula 3, wherein W. X Z and R are as defined in previously. The reaction can be carried out at a temperature range between -80 to 250 C, optionally in the presence of an acid, base or dehydrating agent, and optionally in the presence of an inert organic solvent. It is appreciated that work-up procedures may involve the use of an acid or base.
In a preferred method, the reaction is carried out in boiling acetic anLydride as solvent, containing a catalytic amount of sodimn acetate.
O O R-N>X W4OCO2H
W Formula 2a Formula 2bFormula 3 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
Compounds of this 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. Without wishing to be bound by theory, their activity may be due to their ability to inhibit an enzyme of the Coenzyme A biosynthetic pathway, phosphopantetheine adenylyltransferase (PPAT). This enzyme has been shown to be essential for bacterial viability (WO-A-00/17387). An assay for activity against PPAT is described below.
The present invention also provides pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I including pharmaceutically acceptable salts thereof together with a pharmaceutically acceptable diluent or carrier As used hereinafter, the term "active compound" denotes a compound of formula I including pharmaceutically acceptable salts thereof. In therapeutic use, the active compound may be administered orally, rectally, parenterally, topically, ocularly, aurally, nasally, intravaFin:lly 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 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 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 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 phtbalate.
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 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 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 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 ueous medium using surfactants. An ointment
may be prepared by mixing the active compound with a topical vehicle such as a mir eral 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. basified Carbomer BP, in the presence of water. Topically admit istrable 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 fonns for such adnunistration, for example suppositories with hard fat, 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 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 of the 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 with n 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 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 all the 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 fonn of particles of very small size, for example as obtained by fluid energy milling.
The following examples illustrate the invention. The intermediates illustrate the preparation of precursors.
Where intermediates are novel, they also form part of the patent.
Intermediate 1. 3-(3-FormvlphenoxY1methllbenzoic acid To a suspension of 60% sodium hydride in paraffin (2.4 g, 60 mmol) in DMF (15 rnL) was added a solution of 3-hydroxybenzaldehyde (3.65 g, 30 mmol) in Dim (15 mL) with effervescence, followed by a solution of 3-(chloromethyl)benzoic acid (5. 4 g, 32 mmol) in DMF (15 mL) with effervescence, and the mixture stirred overnight Water (50 mL) was added and the mixture washed with ethyl acetate (50 mL) to remove the paraffin. The aqueous layer was made acidic with 2M hydrochloric acid (50 mL) and extracted with ethyl acetate (50 mL) . The organic layer was washed with brine (2 x 25 mL), then evaporated, to give 3-[(3-fonnylphenoxy)methyl]benzoic acid (7.4 g, 96% yield).
m/z 279(M+Na), 255(M-H).
Intermediate 2. 3-(5-Formvlthionhen-2-yl)benzoic acid To a degassed solution of 5-formylthiophene-2-boronic acid (1.56 g, 10 mmol), 3bromobenzoic acid (2.0 g, 10 mmol) and sodium acetate (4.0 g, 30 mmol) in 50% aqueous propan-1-ol (20 mL) was added Pd 03Ph3)4 (1.3 g), the mixture degassed then heated to reflux overnight under nitrogen. The mixture was
evaporated, and the residue partitioned between 2M hydrochloric acid (25 mL) and ethyl acetate (25 mL).
The mixture was filtered, then the organic layer extracted with 1M sodium hydroxide (25 mL). The aqueous layer was made acidic with 2M hydrochloric acid (25 rnL) and extracted with ethyl acetate (25 mL) then filtered. The organic layer was washed with brine (2 x 25 mL), then evaporated, to give 3-(5-formylthiophen-2-yl)benzoic acid (1.1 g, 53% yield).
m/z 233 (M+), 231 (M-H).
Intermediate 3. 3-(5-Formylfuran-2-vl)benzeic acid 3-(5-Formylfuran-2yl) benzoic acid was prepared from 5-formylfuran-2-boronic acid and 3bromobenzoic acid according to the method for Intermediate 2.
m/z 217 (M+H), 215 (M-H).
Intermediate 4. 5-(5-FormvlthioDhen-2-Yl)-2-hydroxybenzoic acid 5-(5Formylthiophen-2-yl)-2-hydroxybenzoic acid was prepared from 5formylfuran-2-boronic acid and 5-bromo-2-hydroxybenoic acid according to the method for Intermediate 2.
m/z 249 (M+H), 247 (M-H).
Intermediate 5. 2-(5-Por nvlfuran-2-vUhio)nicotinic acid To a suspension of 2-mercaptonicotinic acid (8.85 g,57 mmol) in DMF (50 mL), under nitrogen, was added a solution of potassium hydroxide (6.38 g 114 mmol) in water (10 mL) and the mixture heated to 90 C to give a solution. A solution of 5-bromo-2-furaldehyde (10.0 g, 57 mmol) in DMF (50 mL) was added and heating continued overnight. The solution was evaporated, the residue dissolved in water (50 rnL) and 2M hydrochloric acid added to pH 3. The resulting solid was collected, washed with water, then dried overnight in a desiccator over P2Os to give 2-(5-formylfuran-2-ylthio) nicotinic acid (13.0 g, 92% yield). m/z 250 (M+H), 248 (M-H).
Intermediate 6. 6-(5-Formvlfuran-2-Ylthio)nicotinic acid 6-(5-Formylfiran2-ylthio)nicotinic acid was prepared from 6-mercaptonicotinic acid and 5bromo-2-
furaldehyde according to the method for Intermediate 5.
m/z 250 (M+H), 248 (M-H).
General Procedure for the Prenaration of Examules.
To a solution of the azole or barbiturate analogue of formula 2 (1.0 mmol) in boiling acetic anhydride (0.5 ml) was added NaOAc (5 mg), followed by a solution of the aldehyde of fornula 3 (1.0 rnmol) in hot acetic anhydride (0.5 ml). The solution was heated for 10 minutes, then cooled. The residue was triturated with diethyl ether, the solid collected, washed with diethyl ether ard dried. The solid was suspended in water (1 ml) overnight, collected, washed with water and dried overnight in a desiccator over P2O5 to give the target compound of formula 1. Compoumds were analysed by LCMS and H N
Examples O H OH O H H N N OH
S So 0 Ct Cl Sit n HO Ex4 Cl Si EN IN 1D-0(>CO2H 7 O IS:H
HE AH i_;CO2H O POOH,1 1
S iOH HO tooth HO: POOH HE j
Procedure for determining concentration of compound necessary to reduce the measured enzymatic activ ty of phosphopantetheine adenylyltransferase to half its control activity (ICsu) The inhibitory effect of a compound on PPAT can be measured by determining the difference in the amount of the product of the reaction released in the absence and presence of the compound The reaction catalysed by PPAT is the transfer of the adenosine monophosphate moiety of ATP to 4-phosphopantetheine or an analogue thereof, generating the products dephosphoCoenzyme A, or an analogue thereof, and inorganic pyrophosphate.
In Webb, Proc. Nat. Acad. Sci. (USA), 1992; 89: 4884 - 4887, there is described an assay for the measurement of phosphate using the chromogenic substrate 2-amino-mercapto-7-methylaminopurine ribonucleoside (methyl thioguanosine). Phosphate was found to cleave this nucleoside in a reaction catalysed by purine nucleoside phosphorylase, generating ribose 1-phosphate and the corresponding free base, 2-amino-6-mercapto-7methylaminopurine (methylthioguanine, MTG). Conversion of the nucleoside to MTG generates a readily monitored spectrophotometric signal at 360 nm. This assay was later extended by Lloyd et al, Nucleic Acids Research, 1995: 23: 2886-2892, to measure inorganic pyrophosphate by incorporating inorganic pyrophosphatase in the assay to generate inorganic phosphate which can then be assayed as described above.
A Preparation of enzyme (PPAI) Staphylococcus aureus PPAT may be prepared from an overproducing strain of E. cold that harbours the gene encoding Staphylococcal PPAT on a multicopy plasmid. After growth, cells are harvested by centrifugation, and resuspended in 20 mM Tris-HCI buffer pH 8.0 containing 5 mM dithiothreitol (Buffer 1). Cells are broken by sonication and cell debris is removed by centrifugation. Ammonium sulphate (5.24 g/20 ml) is added to the supernatant to give 45% saturation, and the insoluble material is removed by centrifugation. More ammonium sulphate (1.38 g/20 ml) is added to the supernatant to give 55% saturation. The resulting precipitate is collected by centrifugation, re- dissolved in Buffer l and dialysed against Buffer 1.
The dialysed supernatant is then applied to a HiLoad_ Q (Arnersham Pharmacia Biotech) ion-exchange column. PPAT is eluted by applying a gradient of NaCI (from O M to l M in Buffer 1. Fractions containing PPAT activity are combined, ammonium sulphate is added to give a final concentartion of 1.2 M, then the solution is applied to a HiLoad7M PhenylSepharose (Amersham Phannacia Biotech) hydrophobic interaction chromatography column. PPAT is eluted by applying a decreasing gradient (from 1.2 M to O M) of ammonium sulphate. Fractions containing PPAT activity are combined, then dialysed against 20 mM citrate buffer pH 5.5 containing 5 mM dithiothreitol (Buffer 2). The solution is then applied to a Sephacyl7M S-lOO gel filtration column (Amersham Pharmacia Biotech) and eluted in Buffer 2.
Fractions containing PPAT activity are dialysed into Buffer 1 for storage.
B Measurement of enzymatic activity A reaction was carried out to measure phosphate production from the enzyme-coupled system, in the presence and absence of compounds. The reaction assay comprised 0.0023 units PPAT (where 1 unit is sufficient to catalyse the conversion of l micromole of substrate per minute per ml). The substrate for PPAT was 4phosphopantetheine (100 -) and ATP was also present in the reaction mix at a concentration of 100. If present, the compound was added as a DMSO solution, so that the final DMSO concentration is 1% vh.
Phosphate release was measured using the spectrophotometric assay as disclosed in Webb, vice supra.
C Measurement of ICso The inhibitory effect of a compound can be described by an IC50 value, that is the concentration of inhibitor at which half (50 /0) 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 /O) 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).
Results of ICso determinations Example Siaphylococcusaureus PPAT ICE (EMS 2 3.3 3 4.7 4 13.2
5 11.2
6 1.6 7, 0.68
8 12.9
1.8 10 15.2
11 7.0
12 3.7
13 7.7.
14 7.3
15 1.2
16 9.4
Claims (9)
1.A compound, for therapeutic use, of Formula 1 O O R-N)\z, COOH RNJTz'COOH NIX WHO
W Formula la Formula lb wherein W is S or O; X is NH, S or O; Z is one or more phenyl or heterocyclyl rings (optionally substituted by C.6 alkyl, halogen, hydroxy, alkoxy, nitro and trifluoromethyl) optionally separated by a spacing group (Y)n where Y is selected from CH2, O. NH, S. S(O), S(0)
2 and n = 0 to 6; and R is hydrogen, a phenyl or heterocyclyl ring (optionally substituted by Cry aLkyl, halogen, hydroxy, aLicoxy, nitro and trifluoromethyl) optionally separated by a spacing group (Y)n where Y is selected from CH2, O. NH, S. S(O), S(O)2 and n = 0 to 6, alternatively, R is of the form (Y)nCOOH. 2.A compound of claim 1, independent of use, excluding: 3-(5-{(E)-[3-(3-chlorophenyl) 4-oxo-2-thioxo-1,3-thiazolidin-5ylidene]methyl}-2-furyl)benzoic acid
3. A compound of claim 1 where R is benzothiazole, m-chlorophenyl, p-(trifluoromethyl)benzyl, benzimidazole, hydrogen or CH2COOH; X is NH, S or O; W is S or O and Z = phenyl, thiophene directly bound to phenyl, furan directly bound to phenyl, furanSph or phOCH2ph.
4. A compound of claim 1, selected from: 3-{(Z)-[3-(lH-benzimidazol-2-yl)4-oxo-2-thioKo-1,3-thiazolidin-5-ylidene]methyl}benzaic acid 3-({3-[(Z)(3-[lH-benzimidazol-2-yl]-4-oxo-2-thioKo-1,3-thiazolidin-
5 ylidene)methyl] phenoxy}methyl)benzaic acid 3-[(3-{(E)-[1-(3achlorophenyl)-4,6ioxo-2thioxotetrahydropyrimidin-5(2H) ylidene]methyl}phenoxy)methyl]benzoic acid 3-(5-{ (E)-[1-(3-chlorophenyl)-4,6-dioxo-2-thioxotetrahydropyrinudin5(2H) ylidene]methyl}thien-2-yl)benzoic acid 3-(5-{(Z)-[ 1-(3chlorophenyl)-5-oxo-2-thioxcimidazolidin-4-ylidene]methyl}thien-2-yl) benzoic acid 3-{(Z)-[3-(1,3-benzothiazol-2-yl)a4-oxo-2-thioxo-1,3thiazolidin-Sylidene]methyl}benzoic acid 2-({5-[(Z)-(4-oxo-2-thioxo-1,3oxazolidin-5-ylidene)methyl]-2-furyl}thio)nicotinic acid 2-({5-[(2,4,6trioKotetrahydropyrinudin-5(2H)-ylidene)methyl]-2-furyl}thio)nicotinic acid 2-({5-[(Z)-(5-oxo-2-thioxoimidazolidin '1-ylidene)methyl]-2-furyl} thio)nicotinic acid 3-{ 5-[(Z)-(4aoxo-2-thioxo-1,3-thiazolidin-5-ylidene) methyl]-2-furyl}benzoic acid
2-({5-[(4,6-dioKo-2-thioxotetrahydropyrimidin-5(2H)-ylidene)methyl]-2furylithio)nicotinic acid 2-({S-[(Z)-(2,Wioxo-1,3-thiazolidin-5-ylidene) methyl]-2-furyl}thio)nicotinic acid 5-(S-{ (Z)-[3-(carboxymethyl)-4-oxo-2tbioxo-1,3-thiazolidin-5-ylidene]methyl}-2-fulyl)-2 hydroxybenzoic acid 6[(5-{(Z)-[3 -(carboxymethyl)-4-oxo-2-thioxo-1,3-thiazolidin-5-ylidene] methyl}-2 furyl)thio]nicotinic acid 6-({5-[(Z)-(4-oxo-2-thioXo-1,3oxazolidin-5-ylidene)methyl]-2-furyl}thio)nicotinic acid 3 -[5-((Z)-{4oxo-2-thioXo-3-[4-(trifluoromethyl)benzyl]-1,3-thiazolidin-5-ylidene} methyl)-2 filryllbenzoic acid A procedure for preparing compounds of the invention comprising the reaction of a azole or barbiturate analogue of the formula 2a or 2b with an aldehyde of formula 3, wherein W. X, Z and R are as defined previously, preferably in boiling acetic anhydride as solvent, containing a catalytic amount of sodium acetate.
O O R-N:X WHO ZcO H W Formula 2a Formula 2b Formula 3
6. A pharmaceutical composition comprising as an active ingredient a compound of any preceding claim, together with a canter or diluent
7. Use of a compound of any of claims 1 to 4, for the manufacture of a medicament for the treatment of a bacterial infection.
8. The use of claim 7, wherein the infection is caused by a gram positive organism.
9. The use of claim 8, wherein the organism is S. oureus.
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| GB0207410A GB2386892A (en) | 2002-03-28 | 2002-03-28 | Carboxy containing (phenyl-/heterocyclyl-)methylene substituted azole & azine derivatives and their therapeutic use as antibacterials |
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| GB0207410A GB2386892A (en) | 2002-03-28 | 2002-03-28 | Carboxy containing (phenyl-/heterocyclyl-)methylene substituted azole & azine derivatives and their therapeutic use as antibacterials |
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| GB2386892A true GB2386892A (en) | 2003-10-01 |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004043955A1 (en) * | 2002-11-13 | 2004-05-27 | Rigel Pharmaceuticals, Inc. | Rhodanine derivatives and pharmaceutical compositions containing them |
| WO2005020990A1 (en) * | 2003-07-30 | 2005-03-10 | Centre National De La Recherche Scientifique | Antibiotic thiazolidines |
| WO2005041951A2 (en) * | 2003-10-28 | 2005-05-12 | Rigel Pharmaceuticals, Inc. | Rhodanine derivatives for use as antiviral agents |
| WO2005016227A3 (en) * | 2003-08-14 | 2005-11-17 | Insight Biopharmaceuticals Ltd | Methods and pharmaceutical compositions for modulating heparanase activation and uses thereof |
| EP1802297A2 (en) * | 2004-10-21 | 2007-07-04 | The Burnham Institute | Compositions and methods for treatment of disease caused by yersinia spp infection |
| EP1834642A2 (en) * | 2006-03-08 | 2007-09-19 | National Institute of Immunology | 2-thioxothiazolidin-4-one compounds and compositions as antimicrobial and antimalarial agents targeting enoyl-ACP reductase of type II fatty acid synthesis pathway and other cell growth pathways |
| JP2008516999A (en) * | 2004-10-21 | 2008-05-22 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Heterocyclic carbonyl compounds |
| WO2008134840A2 (en) * | 2007-05-03 | 2008-11-13 | Universidade Federal De Pernambuco - Ufpe | Compound with anesthetics activity, methods for its production an pharmaceutical compositions comprising the same |
| WO2010136804A1 (en) * | 2009-05-28 | 2010-12-02 | Aston University | Pyrimidine derivatives for use as antibiotics |
| US9056862B2 (en) | 2011-05-10 | 2015-06-16 | National University Corporation Kobe University | Thioxothiazolidine derivative having Ras function inhibitory effect |
| US9517230B2 (en) * | 2011-01-26 | 2016-12-13 | University Of Rochester | Small molecule RNase inhibitors and methods of use |
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| WO2001093841A2 (en) * | 2000-06-05 | 2001-12-13 | Novuspharma S.P.A. | Barbituric acid analogs as therapeutic agents |
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Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004043955A1 (en) * | 2002-11-13 | 2004-05-27 | Rigel Pharmaceuticals, Inc. | Rhodanine derivatives and pharmaceutical compositions containing them |
| WO2005020990A1 (en) * | 2003-07-30 | 2005-03-10 | Centre National De La Recherche Scientifique | Antibiotic thiazolidines |
| WO2005016227A3 (en) * | 2003-08-14 | 2005-11-17 | Insight Biopharmaceuticals Ltd | Methods and pharmaceutical compositions for modulating heparanase activation and uses thereof |
| US7566732B2 (en) | 2003-10-28 | 2009-07-28 | Rigel Pharmaceuticals, Inc. | Rhodanine compositions for use as antiviral agents |
| WO2005041951A3 (en) * | 2003-10-28 | 2005-10-06 | Rigel Pharmaceuticals Inc | Rhodanine derivatives for use as antiviral agents |
| WO2005041951A2 (en) * | 2003-10-28 | 2005-05-12 | Rigel Pharmaceuticals, Inc. | Rhodanine derivatives for use as antiviral agents |
| EP1802297A4 (en) * | 2004-10-21 | 2008-05-28 | Burnham Inst | Compositions and methods for treatment of disease caused by yersinia spp infection |
| EP1802297A2 (en) * | 2004-10-21 | 2007-07-04 | The Burnham Institute | Compositions and methods for treatment of disease caused by yersinia spp infection |
| JP2008516999A (en) * | 2004-10-21 | 2008-05-22 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | Heterocyclic carbonyl compounds |
| AU2007201027B2 (en) * | 2006-03-08 | 2009-10-22 | National Institute Of Immunology | 2-thioxothiazolidin-4-one compounds and compositions as antimicrobial and antimalarial agents targeting enoyl-acp reductase of type II fatty acid synthesis pathway and other cell growth pathways |
| EP1834642A3 (en) * | 2006-03-08 | 2007-10-03 | National Institute of Immunology | 2-thioxothiazolidin-4-one compounds and compositions as antimicrobial and antimalarial agents targeting enoyl-ACP reductase of type II fatty acid synthesis pathway and other cell growth pathways |
| EP1834642A2 (en) * | 2006-03-08 | 2007-09-19 | National Institute of Immunology | 2-thioxothiazolidin-4-one compounds and compositions as antimicrobial and antimalarial agents targeting enoyl-ACP reductase of type II fatty acid synthesis pathway and other cell growth pathways |
| WO2008134840A2 (en) * | 2007-05-03 | 2008-11-13 | Universidade Federal De Pernambuco - Ufpe | Compound with anesthetics activity, methods for its production an pharmaceutical compositions comprising the same |
| WO2008134840A3 (en) * | 2007-05-03 | 2009-01-29 | Univ Fed De Pernambuco Ufpe | Compound with anesthetics activity, methods for its production an pharmaceutical compositions comprising the same |
| US8217068B2 (en) | 2007-05-03 | 2012-07-10 | Universidade Federal de Pernambuco—UFPE | Compound with anesthetics activity, methods for its production and pharmaceutical compositions comprising the same |
| WO2010136804A1 (en) * | 2009-05-28 | 2010-12-02 | Aston University | Pyrimidine derivatives for use as antibiotics |
| US9517230B2 (en) * | 2011-01-26 | 2016-12-13 | University Of Rochester | Small molecule RNase inhibitors and methods of use |
| US9056862B2 (en) | 2011-05-10 | 2015-06-16 | National University Corporation Kobe University | Thioxothiazolidine derivative having Ras function inhibitory effect |
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| GB0207410D0 (en) | 2002-05-08 |
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