GB2390539A - Tri-substituted benzene & pyridine derivatives with 2 or 3 carboxy-comprising substituents for use as antibiotic or antibacterial agents - Google Patents
Tri-substituted benzene & pyridine derivatives with 2 or 3 carboxy-comprising substituents for use as antibiotic or antibacterial agents Download PDFInfo
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- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
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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
- C07C229/60—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 with amino and carboxyl groups bound in meta- or para- positions
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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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- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
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Description
COMPOUNDS AND THEIR THERAPEUTIC USE
Field of the Invention
This invention relates to di- and tricarboxylic acid analogues that inhibit bacterial chorismate synthase, and to their therapeutic use as antibiotics.
5 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 10 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 include, amongst others, trirnethoprim and the sulfonamide drugs.
Chorismate synthase, an enzyme in the shikimate pathway has been 15 shown to be essential for bacterial viability (EP0913480). Compounds that inhibit this enzyme could therefore be useful antibacterial agents.
The identification of compounds of the invention as inhibitors of bacterial charismata syntheses is novel and they are structurally distinct from previously synthesized antibiotics.
20 Summary of the Invention
This invention relates to compounds, and more specifically to di- and tri-
carboxylic acid analogues and to their pharmaceutical compositions defined by Formula 1, or a pharmaceutically acceptable salt thereof. The compounds and their pharmaceutically acceptable salts are claimed as the active ingredients in 25 medicines for the treatment of bacterial infection in man and animals.
zOH O Nf Q U R4 o Foanula 1
In Formula 1; Group V represents CH or N. W. X, Y and Z independently represent either bonds or spacer groups such that there are six bonds separating the carboxylic acid groups attached to 5 W and Z. Specifically, X and Y independently represent a bond or a group -CRT R2-, -C(=O)-, CR1(OR2), -CR1(NR1 R3)-, -CR1(NR1COR2)-, -O-, -S-,
-S(O)-, -SO2-, NR1-, or -NCOR1)-, wherein R1 R2 and R3 independently represent hydrogen or C,.6 branched, cyclic or straight-chain alkyl or alkenyl groups. W and Z can independently represent a bond or a group CRT R2-, 10 -C(=O)-,CR1(OR2),-CR1(NR1 R3)-,-CR1(NR1 COR2)-, wherein R1, R2 and R3 are as defined previously. Furthermore, W and X taken together can represent -CR1=CR2- (E or Z geometry) or -C triple bond C- if Y and Z each represent a bond. Group Q represents a bond or an -O-CH2- group.
15 Group U represents 0, NH or NR1 wherein R1 is as defined above.
R4 can represent a hydrogen, a C, I, branched, cyclic or straight-chain alkyl or alkenyl group, or an amino acid residue as shown below.
R5 R5 20::OH or /NH2 O O The (D or L) amino acid moiety can be selected from the following list; 25 alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine or valine.
Preferred compounds are those with the following combinations of Q. W. X, Y and Z: 30 W is CH2, X is 0, and Q. Y and Z each represent a bond W and X together are (E) CH=CH and Q. Y and Z each represent a bond W is -C(=O)- , X is NH and Q. Y and Z each represent a bond
W is CH2, X is O. Q is OCH2, Y and Z each represent a bond Particularly preferred compounds include those where W. X, Y and Z are as defined above, also that V = CH, U is O and R4 is H. Most favoured compounds include: 5 5-[(carboxycarbonyl) amino]isophthalic acid 5-((E)-2carboxyvinyl)isophthalic acid 5-(carboxymethoxy)isophthalic acid 3,5bis(carboxymethoxy)benzoic acid Compounds of the invention have therapeutic utility as antibacterial 10 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 charismata 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 15 medicines for the treatment of bacterial infection in man and animals.
Descriotion of the Invention Certain compounds of this invention are preferred.
The term "C,.6 alkyl" as used herein refers to straight and branched chain alkyl groups having up to 6 C atoms. Examples are methyl, ethyl, propyl, 20 isopropyl, n-butyl, sec-butyl and tert-butyl. "Alkyl" may have the same meaning.
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 25 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 30 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 5 subsequently be required to liberate the desired enantiomeric form.
Alternatively, specific enantiomers may be synthesized 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 10 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 crystal ligation 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.
15 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 20 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. 25 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 30 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.
"Pharmaceutically acceptable salts" are acid addition salts which can be 5 prepared by any of the art recognised means. Typical acid addition salts include hydrochloride, hydrobromide, hydrolodide, sulphate, phosphate, acetate, prop ionate, lactate, ma l ate, succi nate, tartrate, and cyclohexanesul phamates.
As used hereinafter, the term "active compound" denotes a compound of Formula 1 including pharmaceutically acceptable salts thereof. In therapeutic 10 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 known pharmaceutical compositions for such methods of administration. The compositions may be Formulated in a 15 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 20 of the invention are generally prepared in unit dosage form. Preferably the unit dosage of active ingredient is 1500 mg. 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 25 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 30 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 5 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 10 mg (for example 10 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, or 800 mg) 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 15 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 20 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 25 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 30 topical vehicle comprising a gelling agent e.g. basified 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 administerthe 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 5 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, synthetic glycerides or polyethylene glycol bases.
Compositions of the invention suitable for parenteral administration are 10 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, 15 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 20 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 compound to be infused 25 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.
30 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 by hydrolysis of ester-protected compounds of Formula 2. In Formula 2, Q. U. V, 5 X, Y and Z are as defined previously for Formula 1. R4 is as defined previously but if an amino-acid group is present, its acid or terminal amide group may be covalently linked to Wang or RINK resin. R6 and R7 can be independently hydrogen, C, 6 alkyl, an optionally substituted benzyl group, or a resin such as Wang or Merrifield resin. Basic hydrolysis of compounds of Formula 2 may be
10 achieved by reaction with an alkali metal hydroxide in water or an alcohol (with or without organic co-solvents) at a temperature range between 0 C and 1 00 C.
Acidic ester hydrolysis may be necessary if the starting material contains t-butyl ester or if there is an ester linkage to Wang resin. These may be cleaved using trifluoroacetic acid either neat or in combination with a co-solvent such as 15 dichloromethane. The reaction may be performed at between 0 C and 1 00 C.
17 at-R6 Y' CO2H O H OH I O HO kR4 Act:: R4 or TFA-DCM Wat U Formula 2 Formula 1 Scheme 1 Scheme 2 shows the preparation of compounds of Formula 2 wherein W 20 is CR1R2, X is O. and Q. Y and Z each represent a bond. Dimethyl 5-
hydroxyisophthalate is reacted with alkyl 2-haloacetate or 2-haloacetic acid and a base in an inert organic solvent at a temperature range between 0 C and 150 C. Suitable solvents include such as ethanol, dimethyl sulfoxide or DMF.
Suitable bases include alkali metal hydroxides or carbonates or tertiary amine 25 base such as triethylamine or Hunigs base.
0 R6
MeO OH H I _ O Jest 0 Soled R1 R.? Hal = Cl, Br or I O OMe: O OMe Fomala 2 Scheme2 Scheme 3 shows the preparation of compounds of Formula 2 wherein W 5 is CH2, X is 0, Q is OCH2, Y and Z each represent a bond. Methyl 3,5-
dihydroxybenzoic acid is reamed with alkyl 2-haloacetate or 2-haloacetic acid and a base in an inert organic solvent at a temperature range between 0 C and 150 C. Suitable solvents include such as ethanol, dimethyl sulfoxide or DMF.
Suitable bases include alkali metal hydroxides or carbonates or tertiary amine 10 base such as triethylamine or Hunigs base.
Scheme 4 shows the preparation of compounds of Formula 2 wherein W and X are together -CR1=CH-, and Q. Y and Z each represent a bond. 5-
Bromoisophthalic acid is reacted with an acrylate CH2=CR1CO2R6 in the presence of a palladium (O) or palladium (II) catalyst, triphenyl phosphine and 15 a base in a suitable organic solvent at between 0 C and 150 C. Suitable catalysts for the Heck reaction include PdCI2, Pd(OAc)2, Pd(Ph)4 and the like.
Suitable bases include tertiary amine bases such as Hunigs base, or alkali metal carbonates. DMF, water or DMSO may be used as solvent. Compounds of Formula 2 wherein W and X are together-CHR1CH2-, and Q. Y and Z each 20 represent a bond can be prepared from the above compound by reduction using hydrogen and a palladium or platinum catalyst in an alcoholic solvent.
o MeO/UOH R1 RZ R6 ' 1 ( I RC OH Hal = Cl B. Or I I I OW:O'R6
FOrmUb 2 A R1 R2 Scheme 3 HO2C 6F ' " HO,C,,
O SOhent V: R1 R6 CO2H I
CO2H FOb 2 Scheme 4 5 Scheme 5 shows the preparation of compounds of Formula 2 wherein W is CO, X is NR1, and Q. Y and Z each represent a bond. Commercially available methyl 5-amino isophthalate is reacted with alkyl oxalyl chloride and a base in an organic solvent at a temperature between O and 50 C. Sutable solvents and bases include respectively THF and DMF, and pyridine or triethylamine.
O R1 /R6
M O 1H O R6 MCO 1 O
So J OMe FOmUa 2 O OMe 10 Scheme 5
Compounds of Formula 2 wherein V is N. W is CR1 R2, X is S. and Q. Y and Z each represent a bond may be prepared according to Scheme 6. 2,6-
dimethoxycarbonyl-4-halopyridine is heated with a base at between 50-1 50 C in an inert solvent. Suitable bases include alkali metal carbonates and the 5 solvents can be DMF or toluene. Compounds of Formula 2 wherein X is -SO- or -S02- can be prepared from the corresponding sulfide X = S by treatment with one or two equivalents of an oxidant such as metachloroperbenzoic acid.
O Hal C D ORB OMe Hal = F or Cl Formed 2 O OMe Scheme 6 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.
Preparation of Examples 15 A. Synthesis of 5-((E)-2-carboxyvinyl) isophthalic acid 1. Preparation of 5-((1E)-3-ethoxy-3-oxyprop-1-enyl) isophthalic acid HO2C CO2CH2CH3
HO2C A mixture of 5-bromoisophthalic acid (1.79 9, 7.33 mmol), ethyl acrylate (1.32 mL, 14.65 mmol), triphenylphosphine (0.58 9, 2.2 mmol), triethylamine 25 (3.06 mL, 22 mmol), and palladium acetate (164 mg, 0.733 mmol) in DMF (50 mL) was stirred at 140 C under nitrogen for 16 hours. The reaction mixture was
poured into water, and extracted with ethyl acetate to remove triphenylphosphine oxide. The aqueous layer was acidified with 2M hydrochloric acid, and extracted with ethyl acetate. The combined ethyl acetate extracts were dried and concentrated to give a brown solid which was further purified by trituration from 5 minimum ethyl acetate to afford a yellow solid (1.53 9, 79% yield).
LC/MS: ES+ 265 (M+H), ES- 263 (M-H)
HNMR(CD3OD, 400 MHz) d 8.44 (s, 1H, ArH), 8.22 (s, 2H, ArH), 7.58 (d, 1H, J=16 Hz), 6.45 (d, 1H, J=16Hz), 4.07 (q, 2H, CH2),1.15 (t, 3H, CH3).
2.Preparation of 5-((E)-2-carboxyvinyl)isophthalic acid 1 0 HO2C
CO2H HO2C A solution of 5-((1E)-3-ethoxy-3-oxyprop-1-enyl)isophthalic acid (0.1 9, 0.38 mmol), 50% sodium hydroxide aqueous solution (0.6 mL) in methanol (15 mL) was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue is acidified with 2M hydrochloride solution, then extracted with 20 ethyl acetate. The combined extracts were dried and concentrated to give a yellow solid (95 mg, 98% yield).
LC/MS: 100% by Sedex ELSD, ES- 235 (M-H) -I 1HNMR (d6 DMSO, 400 MHz) d 13. 10 (broad s, 3H, COOH), 8.46 (s, 1H), 8.40 (s, 2H), 7.74 (d, J=16, 1H), 6. 66 (d, 1H, J=16 Hz).
25 B. Svnthesis of 5-(carboxymethoxy)isonhthalic acid HOO Oo:OH 30 OH O
To a solution of dimethyl 5-hydroxyisophthalate (2.1 9, 10 mmol) in acetonitrile (25 mL) was added potassium carbonate (2.0 9), followed by ethyl bromoacetate (1.1mL,10 mmol). The reaction mixture was heated under reflux overnight. The solvent was removed by rotary evaporation and the residue was 5 partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was washed twice with brine (25 mL), then evaporated. The product crystallized on standing. The solid was then triturated with hexane, filtered and dried to yield 2.20 9 (74%) of dimethyl 5-(2oxyethoxy)isophthalate, with 100% purity.
LC/MS: ES+ 297 (M+H), 319 (M+Na) 10 'H NMR (CDCI3, 400 MHz) d 8.34 (t, 1 H. J = 2Hz), 7.78 (d, 2H, J = 2Hz), 4.73 (s, 2H), 4.31 (q, 2H, J = THE), 3.95 (s, 6H),1.32 (t, 3H, J = 7Hz).
To a warm solution of dimethyl 5-(2-oxyethoxy)isophthalate (2.20 9, 7.4 mmol) in methanol (20 mL) was added 1 M NaOH (22 mL,22 mmol,3 eq) and the solution was stirred over the weekend. The methanol was removed by rotary 15 evaporation and then 2M HCI (15 mL) was added. The solid was filtered, washed with water, and then dried to give (carboxymethoxy)isophthalic acid (1.559, 82%), with 100% purity.
H NMR (d6 DMSO, 400 MHz) d 13.38 (broad s, 31), 8.18 (s,1 H), 7.70 (s, 2H) , 4.94 (s, 2H) 20 Synthesis of 3,5-bis(carboxymethoxy)benzaic acid HOjO Oq'OOO 25 OH OH
To a solution of 3,5-dihydroxybenzaic acid (1.68 9, 10 mmol) in acetonitrile (25 mL) was added potassium carbonate (3 9), followed by ethyl bromoacetate (3.3 mL,30 mmol,3 eq). The reaction mixture was heated to reflux 30 overnight. The solvent was removed by rotary evaporation and the residue was partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was washed twice with brine (25 mL), then evaporated. The product crystallised
on standing. The solid was then triturated with hexane, filtered and dried to yield methyl 3,5-bis(2-ethoxy-2-oxoethoxy)benzoate (3.1 9, 91%), with 100% purity.
LC/MS: ES+ 341 (M+H), 363 (M+Na) H NMR (CDCI3, 400 MHz) d 7.12 (d, 2H, J= 2Hz), 6.65 (t,1 H. J = 2Hz), 4.55 (s, 5 4H), 4.19 (q, 4H, J = 7Hz), 3.81 (s, 3H),1.22 (t, OH, J = 7Hz).
A suspension of methyl 3,5-bis(2-ethoxy-2-oxoethoxy)benzoate (1.70 9, 5 mmol) in 1 M NaOH (15 mL, 15 mmol, 3 eq) was heated at 100 C for 4 hours, causing dissolution. The reaction was left to stand overnight and then acidified the next day with 2M HCI (10 mL). The solid was filtered, washed with water, 10 then dried to yield 3,5-bis (carboxymethoxy)benzoic acid (1.28 9, 95%), with 100% purity.
LC/MS: ES- 269 (M-H), 291 (M-2H+Na) H NMR (d6 DMSO, 400 MHz) d 13.1 (br s, 3H), 7.03 (d, 2H, J= 2Hz), 6.75 t,1 H. J= 2Hz), 4.74 (s, 4H).
15 C. Svnthesis of 5-l(carboxvcarbonyl) aminolisophthalic acid 1. Dimethyl 5{[(ethoxy(oxo)acetyl]amino}-isophthalate o HN CO2CH2CH3
20 H3CO2CJ-CO2CH3
Dimethyl 5-aminoisophthalate (59, 24mmol), ethyl oxalyl chloride (3.2 9, 25 24 mmol), and pyridine (1.95 mL, 24 mmol) were stirred together in DMF for 72 hours. Water was added to the reaction mixture followed by ethyl acetate. The precipitated solid was filtered off and washed with water to give a pure white solid (5.77 9, 78%).
LCIMS: ES- 308 (M-H); ES 310 (M+H), 332 (M+Na).
30 'H NMR (d6 DMSO, 400 MHz) d 1.3 (t, 3H), 3.9 (s, 6H), 4.3 (q, 2H), 8.2 (t, 3H), 8.7 (d,1H), 11.2 (s,1H).
5-[(carboxycarbonyl) amino]-isophthalic acid o HN CO2H
HO2C CO2H
Aqueous sodium hydroxide (0.26 g, 6.4 mmol) was added to a stirred 10 methanolic solution of dimethyl 51[(ethoxy(oxo)acetyl]amino}- isophthalate (0.5 9, 1.6 mmol) at room temperature. After 6 hours, LC/MS analysis indicated that only hydrolysis of the ethyl ester had taken place. Heating the reaction mixture at 80 C for 4 hours with a further 10 equivalents of NaOH completed hydrolysis of all three esters. The reaction mixture was acidified and product was extracted 15 with ethyl acetate. The combined ethyl acetate layers were dried over magnesium sulphate and the solvent was evaporated to give impure product.
The aqueous layers were also evaporated and the residual solid was washed with ethyl acetate. The ethyl acetate filtrate was evaporated to give a white solid (0.13 9, 32%) of 98% pure by'H NMR.
20 LC/MS: ES-252 (M-H).
H NMR (d6 DMSO, 400 MHz): 8.1 (s, 1 H), 8.5 (d, 2H), 1 1 (s, 1 H), 13.25 (s, 2H).
Measurement of IC60 Phosphate release from the chorismate synthase catalysed reaction, was measured using the spectrophotometric assay as disclosed in Webb, Proc. Nat.
25 Acad. Sci. (USA), 1992; 89: 4884887.
The reaction assay solution comprised 0.005 units of chorismate synthase (where 1 unit is sufficient to catalyse 1 mM of substrate per minute), FMN at a concentration of 10 mM and dimethyl sulfoxide (10% v/v). The substrate for chorismate synthase was EPSP (112 mM). An immiscible layer of mineral oil 30 (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.
An inhibitor's IC50 value can be determined from the rate of phosphate 5 release in the presence of various concentrations of inhibitor compared to the base rate measured in the absence of inhibitor (3.26 mmole/l/min).
Results of IC60 determinations Especially favoured compounds 5[(carboxycarbonyl) amino]isophthalic acid 10 5-((E)-2-carboxyvinyl) isophthalic acid 5-(carboxymethoxy)isophthalic acid 3,5bis(carboxymethoxy)benzoic acid gave IC50 values against isolated Streptococcus pneumonias chorismate synthase in the range 20-1000 mM.
Claims (8)
1. A compound, for therapeutic use, of Formula 1 zOH 5 v O HO::W QU'
o Formula 1 10 wherein V represents CH or N; W. X, Y and Z independently represent either bonds or spacer groups such that there are six bonds separating the carboxylic acid groups attached to W and Z: specifically, X and Y independently represent a bond or a group -CRT R2-, -C(=O)-, CR1(OR2), -CR1(NR1 R3)-, -CR1(NR1 COR2)-, -O-, -S-,
15 -S(0)-, -SO2-, NR1-, or-NCOR1)-, wherein R1, R? and R3 independently represent hydrogen or C,.6 branched, cyclic or straight-chain alkyl or alkenyl groups. W and Z can independently represent a bond or a group CRT R2-, -C(=O)-, CR1(OR2),-CR1(NR1 R3)-,-CR1(NR1 COR2)-, wherein R1, R2 and R3 are as defined previously; or W and X taken together can represent -CR1=CR2 20 (E or Z geometry) or -C-C- if Y and Z each represent a bond; Q represents a bond or a -O-CH2- group; U represents O. NH or NR1 wherein R1 is as defined above; and R4 can represent a hydrogen, a C, 6 branched, cyclic or straight-chain alkyl or alkenyl group, or an amino acid residue as shown below R5 R5 OH or /NH2 O O 30 the (D or L) amino acid moiety can be selected from the following list; alanine, arginine, asparagine, aspartic acid, glutamic acid, glutamine, glycine, histidine,
isoleucine, leucine, methionine, phenylalanine, praline, serine, threonine, tryptophan, tyrosine or valine.
2. A compound of claim 1, having any of the following combinations of Q. W. X, Y and Z: 5 W is CH2, X is O. and Q. Y and Z each represent a bond; W and X together are (E) CH=CH and Q. Y and Z each represent a bond; W isC(=O)-, X is NH and Q. Y and Z each represent a bond; and W is CH2, X is O. Q is OCH2, Y and Z each represent a bond.
3. A compound of claim 2, wherein V = CH, U is O and R4 is H. 10
4. A compound of claim 1, selected from: 5-l(carboxycarbonyl) amino] isophthalic acid; 5-((E)-2-carboxyvinyl)isophthalic acid; 5(carboxymethoxy)isophthalic acid; and 3,5-bis(carboxymethoxy)benzoic acid.
15
5. A pharmaceutical composition comprising as an active ingredient a compound of any preceding claim, together with a carrier or diluent.
6. Use of a compound of any of claims 1 to 4, for the manufacture of a medicament for the treatment of a bacterial infection.
? j The use of claim 6, wherein the infection is caused by a grampositive 20 organism.
8. The use of claim 7, wherein the organism is S. avreus.
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|---|---|---|---|
| GB0215773A GB2390539A (en) | 2002-07-08 | 2002-07-08 | Tri-substituted benzene & pyridine derivatives with 2 or 3 carboxy-comprising substituents for use as antibiotic or antibacterial agents |
| GB0315876A GB2390976A (en) | 2002-07-08 | 2003-07-07 | Aryl and heteroaryl carboxylic acid derivatives and their therapeutic use |
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| GB0215773A GB2390539A (en) | 2002-07-08 | 2002-07-08 | Tri-substituted benzene & pyridine derivatives with 2 or 3 carboxy-comprising substituents for use as antibiotic or antibacterial agents |
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| GB0315876A Withdrawn GB2390976A (en) | 2002-07-08 | 2003-07-07 | Aryl and heteroaryl carboxylic acid derivatives and their therapeutic use |
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| CN101450915B (en) * | 2007-11-30 | 2013-01-23 | 山东轩竹医药科技有限公司 | Cyclohexene substituted benzoic acid derivatives |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5261219A (en) * | 1975-11-14 | 1977-05-20 | Tokyo Yuuki Kagaku Kougiyou Kk | Nonnmedical germcide for noxious organism |
| BE898614A (en) * | 1984-01-05 | 1984-05-02 | Abello Quimicos Farma Prod Sa | Antitumour and antiparasitic platinum complexes - contg. 1,2-di:amino-cyclohexane ligand |
| WO2001092274A2 (en) * | 2000-05-30 | 2001-12-06 | Guilford Pharmaceuticals Inc. | Naaladase inhibitors for treating retinal disorders and glaucoma |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001091738A2 (en) * | 2000-05-30 | 2001-12-06 | Guilford Pharmaceuticals Inc. | Naaladase inhibitors for treating amyotrophic lateral sclerosis |
| AU2002364743A1 (en) * | 2001-12-28 | 2003-07-24 | Guildford Pharmaceuticals Inc. | Naaladase inhibitors for treating huntington's disease |
-
2002
- 2002-07-08 GB GB0215773A patent/GB2390539A/en not_active Withdrawn
-
2003
- 2003-07-07 GB GB0315876A patent/GB2390976A/en not_active Withdrawn
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5261219A (en) * | 1975-11-14 | 1977-05-20 | Tokyo Yuuki Kagaku Kougiyou Kk | Nonnmedical germcide for noxious organism |
| BE898614A (en) * | 1984-01-05 | 1984-05-02 | Abello Quimicos Farma Prod Sa | Antitumour and antiparasitic platinum complexes - contg. 1,2-di:amino-cyclohexane ligand |
| WO2001092274A2 (en) * | 2000-05-30 | 2001-12-06 | Guilford Pharmaceuticals Inc. | Naaladase inhibitors for treating retinal disorders and glaucoma |
Non-Patent Citations (1)
| Title |
|---|
| CHEMICAL ABSTRACTS, Abstr. No. 87:97391; & JP 52 061219 A (TOKYO YUUKI KAGAKU KOUGIYOU KK) (20-05-1977) * |
Also Published As
| Publication number | Publication date |
|---|---|
| GB0215773D0 (en) | 2002-08-14 |
| GB2390976A (en) | 2004-01-28 |
| GB0315876D0 (en) | 2003-08-13 |
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