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WO2008117079A1 - Composés antimicrobiens à base de 4-aminoquinoléine - Google Patents

Composés antimicrobiens à base de 4-aminoquinoléine Download PDF

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Publication number
WO2008117079A1
WO2008117079A1 PCT/GB2008/001127 GB2008001127W WO2008117079A1 WO 2008117079 A1 WO2008117079 A1 WO 2008117079A1 GB 2008001127 W GB2008001127 W GB 2008001127W WO 2008117079 A1 WO2008117079 A1 WO 2008117079A1
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Prior art keywords
formula
compound
alkyl
halo
infections
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WO2008117079B1 (fr
Inventor
Anthony Coates
Susan Mary Cramp
Hazel Joan Dyke
Yanmin Hu
Thomas David Pallin
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Helperby Therapeutics Ltd
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Helperby Therapeutics Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to certain 4-aminoquinoline-based compounds. As described herein, such compounds may be useful in medicine, such as in the killing of clinically latent microorganisms or the treatment of microbial infections.
  • tuberculosis Before the introduction of antibiotics, patients suffering from acute bacterial infections (e.g. tuberculosis or pneumonia) had a low chance of survival. For example, mortality from tuberculosis was around 50%.
  • acute bacterial infections e.g. tuberculosis or pneumonia
  • Antimicrobial agents target essential components of bacterial metabolism.
  • the ⁇ -lactams e.g. penicillins and cephalosporins
  • inhibit cell wall synthesis whereas other agents inhibit a diverse range of targets, such as DNA gyrase (quinolones) and protein synthesis (e.g. macrolides, aminoglycosides, tetracyclines and oxazolidinones).
  • DNA gyrase quinolones
  • protein synthesis e.g. macrolides, aminoglycosides, tetracyclines and oxazolidinones.
  • the range of organisms against which the antimicrobial agents are effective varies, depending upon which organisms are heavily reliant upon the metabolic step(s) that is/are inhibited.
  • the effect upon bacteria can vary from a mere inhibition of growth (i.e. a bacteriostatic effect, as seen with agents such as the tetracyclines) to full killing (i.e. a bactericidal
  • Bacteria have been growing on Earth for more than 3 billion years and, in that time, have needed to respond to vast numbers of environmental stresses. It is therefore perhaps not surprising that bacteria have developed a seemingly inexhaustible variety of mechanisms by which they can respond to the metabolic stresses imposed upon them by antibiotic agents. Indeed, mechanisms by which the bacteria can generate resistance include strategies as diverse as inactivation of the drug, modification of the site of action, modification of the permeability of the cell wall, overproduction of the target enzyme and bypass of the inhibited steps.
  • phenotypically resistant bacteria differ from those that are genotypically resistant in that they regain their susceptibility to antimicrobials when they return to a fast-growing state (e.g. when nutrients become more readily available to them).
  • phenotypically resistant bacteria in an infection leads to the need for prolonged courses of antimicrobial agents, comprising multiple doses. This is because the resistant, slowly multiplying bacteria provide a pool of "latent” organisms that can convert to a fast-growing state when the conditions allow (thereby effectively reinitiating the infection). Multiple doses over time deal with this issue by gradually killing off the "latent” bacteria that convert to "active" form.
  • a new approach to combating the problem of bacterial resistance might be to select and develop antimicrobial agents on the basis of their ability to kill "latent" microorganisms.
  • the production of such agents would allow, amongst other things, for the shortening of chemotherapy regimes in the treatment of microbial infections, thus reducing the frequency with which genotypical resistance arises in microorganisms.
  • 4-aminoquinoline compounds containing an N- substituent that is a bicyclic heterocycle may be used to kill clinically latent microorganisms.
  • a compound of formula I for the preparation of a medicament for killing clinically latent microorganisms, wherein the compound of formula I is represented by the structure
  • X 1 represents CH or N
  • X 2 represents N or O
  • A represents a fused benzene ring or a fused 5- or 6-membered, aromatic heterocycle containing from one to three heteroatoms selected from N, O and S;
  • R 2 represents
  • R 1 and R 3 independently represent H or one or more substituents on the fused benzene or heteroaromatic rings selected from
  • R 5a to R 5i , R 6a to R 6i , R 7a to R 7i and R 8a to R 8i independently represent, at each occurrence,
  • each aryl independently represents a C 6 .i 0 carbocyclic aromatic group, which group may comprise either one or two rings and may be substituted by one or more substituents selected from (a) halo,
  • Het 1 to Het 13 independently represent 4- to 14-membered heterocyclic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur, which heterocyclic groups may comprise one, two or three rings and may be substituted by one or more substituents selected from
  • R 11a to R 111 and R 12a to R 12 ' independently represent, at each occurrence
  • B 1 to B 16 independently represent a direct bond, O, S, NH or N(R 13 ); n, p, q, r, ⁇ , t, u, v and w independently represent O, 1 or 2;
  • R 13 represents (a) Ci -6 alkyl
  • alkyl, aikenyl, alkynyl, cycloalky!, and cycloalkenyl groups, as well as the alkyl part of alkoxy groups, may be substituted by one or more halo atoms, and (ii) cycloalkyl and cycloalkenyl groups may comprise one or two rings and may additionally be ring-fused to one or two benzene rings.
  • pharmaceutically-acceptable derivative includes references to: (a) pharmaceutically-acceptable salts with either acids or bases (e.g. acid addition salts); and/or
  • Acid addition salts that may be mentioned include carboxylate salts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate, heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate, propiolate, ascorbate, citrate, giucuronate, glutamate, glycolate, ⁇ -hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate, phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymaleate, hippurate, phthalate or ter
  • sulfonate salts e.g. benzenesulfonate, methyl-, bromo- or chloro-benzenesulfonate, xylenesulfonate, methanesuffonate, ethanesulfonate, propanesutfonate, hydroxyethanesulfonate, 1- or 2- naphthalene-sulfonate or 1 ,5-naphthalenedisulfonate salts) or sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, and the like.
  • sulfonate salts e.g. benzenesulfonate, methyl-, bromo- or chloro-benzenesulfonate, xylenesulfonate, methanesuffon
  • aryl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl and alkoxy groups apply, unless otherwise stated, at each usage of such terms herein.
  • the one or two benzene rings that may be fused to cycloalkyl groups may bear one or more of the substituents defined in respect of the relevant cycloalkyl group.
  • halo when used herein, includes fiuoro, chloro, bromo and iodo.
  • Heterocyclic (Het 1 to Het 13 and Hef to Hef) groups may be fully saturated, partly unsaturated, wholly aromatic or partly aromatic in character.
  • Het 1 to Het 13 and Hef to Hef are examples of heterocyclic (Het 1 to Het 13 and Hef to Hef) groups that may be mentioned include 1-azabicyclo[2.2.2]octanyl, benzimidazolyl, benzo[c]isoxazolidinyl, benzisoxazolyl, benzodioxanyl, benzodioxepanyl, benzodioxolyl, benzofuranyl, benzofurazanyl, benzomorpholinyl, 2,1 ,3-benzoxadiazolyl, benzoxazolidinyl, benzoxazolyl, benzopyrazolyl, benzo[e]pyrimidine, 2,1 ,3-benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, chromanyl, chromenyl, cinnolinyl, 2,3-dihydro- benzimidazolyl, 2,
  • Het 2 that may be mentioned include morpholinyl (e.g.morpholin-1-yl).
  • Het 4 examples include piperazinyl (e.g. piperazin-1-yl, such as 4-methylpiperazin-1 -yl) .
  • Het 9 examples include pyrimidinyl (e.g. pyrimidin-2-yl).
  • microorganisms means:
  • bacteria as defined below.
  • references herein to the terms “microbial”, “antimicrobiaf and “antimicrobially” shall be interpreted in accordance with the definition of “microorganisms”.
  • microbial' means fungal or, particularly, bacterial.
  • the term “clinically latent' includes references to microorganisms that are viable but non-culturable (e.g. bacteria that cannot be detected by standard culture techniques but that are detectable and quantifiable by techniques such as broth dilution counting, microscopy, or molecular techniques such as polymerase chain reaction).
  • microorganisms that are phenotypically tolerant, for example microorganisms that:
  • (b) possess drastically decreased susceptibility to drug-induced killing (e.g. microorganisms for which, with any given conventional antimicrobial agent, the ratio of minimum microbicidal concentration (e.g. minimum bactericidal concentration, MBC) to MIC is 10 or more).
  • drug-induced killing e.g. microorganisms for which, with any given conventional antimicrobial agent, the ratio of minimum microbicidal concentration (e.g. minimum bactericidal concentration, MBC) to MIC is 10 or more).
  • substantially unchanged refers to MIC values that are anywhere from 50 to 200% (e.g. 90 to 110%) of the value determined under standard conditions for the microorganism and conventional antimicrobial agent concerned.
  • threshold of infectious disease expression will be understood by those skilled in the art to include references to the growth rate threshold below which the symptoms of infectious disease (in a patient infected with the relevant microorganism) are absent.
  • metabolic activity of latent microorganisms can be determined by several methods known to those skilled in the art, for example by measuring mRNA levels in the microorganisms or by determining their rate of uridine uptake.
  • the term "clinically latent further includes references to microorganisms that, compared to the same number of microorganisms under logarithmic growth conditions (in vitro or in vivo), possess reduced but still significant levels of:
  • mRNA e.g. from 0.0001 to 50%, such as from 1 to 30, 5 to 25 or 10 to 20%, of the level of mRNA
  • uridine e.g. [ 3 H]uridine
  • uptake e.g. from 0.0005 to 50%, such as from 1 to 40, 15 to 35 or 20 to 30% of the level of [ 3 H]uridine uptake).
  • conventional antimicrobial agent(s) means: (a) conventional antifungal agents; and, particularly (b) conventional antibacterial agents, wherein each of (a) and (b) is as defined below.
  • conventional antibacterial agent(s) include references to bactericidal and bacteristatic agents that are known in the prior art (i.e. agents that have been selected and developed on the basis of their MICs - namely their ability to inhibit the growth of bacteria).
  • particular conventional antibiotic agents include any one or more of the following.
  • penicillin G penicillin V
  • phenethicillin phenoxymethylpeniciliinic acid
  • azlocillin carbenicillin
  • cloxacillin D-(-)-penicillamine
  • dicloxacillin nafciiiin and oxacillin
  • penicillinase-resistant penicillins e.g. fiucloxaciliin
  • broad-spectrum penicillins e.g. ampiciliin, amoxicillin, metampicillin and bacampicillin
  • antipseudomonal penicillins e.g. carboxypenicillins such as ticarciilin or ureidopenicillins such as piperacillin
  • carboxypenicillins such as ticarciilin or ureidopenicillins such as piperacillin
  • cephalosporins such as cefaclor, cefadroxil, cefalexin (cephalexin), cefcapene, cefcapene pivoxil, cefdinir, cefditoren, cefditoren pivoxil, cefixime, cefotaxime, cefpirome, cefpodoxime, cefpodoxime proxetil, cefprozii, cefradine, ceftazidime, cefteram, cefteram pivoxil, ceftriaxone, cefuroxime, cefuroxime axetil, cephaloridine, cephacetrile, cephamandole, cephaloglycine, ceftobiprole, PPI-0903 (TAK-599), 7- aminocephalosporanic acid, 7-aminodes-acetoxycephalosporanic acid, cefamandole, cefazolin, cefmetazole, cefopera
  • Tetracyclines such as tetracycline, demeclocycline, doxycycline, lymecycline, minocycline, oxytetracycline, chlortetracycline, meclocycline and methacycline, as well as glycylcyclines (e.g. tigecycline).
  • Aminoglycosides such as amikacin, gentamicin, netilmicin, neomycin, streptomycin, tobramycin, amastatin, butirosin, butirosin A 1 daunorubicin, dibekacin, dihydrostreptomycin, G 418, hygromycin B, kanamycin B, kanamycin, kirromycin, paromomycin, ribostamycin, sisomicin, spectinomycin, streptozocin and thiostrepton.
  • Aminoglycosides such as amikacin, gentamicin, netilmicin, neomycin, streptomycin, tobramycin, amastatin, butirosin, butirosin A 1 daunorubicin, dibekacin, dihydrostreptomycin, G 418, hygromycin B, kanamycin B, kanamycin, kirromycin, paromomycin
  • Macrolides such as azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin, amphotericins B (e.g. amphotericin B), bafilomycins (e.g. bafilomycin A1), brefeldins (e.g. brefeldin A), concanamycins (e.g. concanamycin A), filipin complex, josamycin, mepartricin, midecamycin, nonactin, nystatin, oleandomycin, oligomycins (e.g.
  • Macrolides such as azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin, amphotericins B (e.g. amphotericin B), bafilomycins (e.g. bafilomycin A1), brefeldins (e.g. brefeldin A), concanamycins (e.g. concanamycin A), filipin complex, josamycin
  • oligomycin A oligomycin A, oligomycin B and oligomycin C
  • pimaricin rifampicin, rifamycin, rosamicin, tylosin, virginiamycin and fosfomycin.
  • Ketolides such as telithromycin and cethromycin (ABT-773).
  • Lincosamines such as lincomycin.
  • Phenicois such as chloramphenicol and thiamphenicol.
  • Steroids such as fusidic acid (optionally in metal salt form, e.g. in salt form with an alkali metal such as sodium).
  • Giycopeptides such as vancomycin, teicoplanin, bleomycin, phleomycin, ristomycin, telavancin, dalbavancin and oritavancin.
  • Streptogramins such as quinupristin and dalfopristin, or a combination thereof.
  • Peptides such as polymyxins (e.g. colistin and polymyxin B),
  • ysostaphin duramycin, actinomycins (e.g. actinomycin C and actinomycin D), actinonin, 7-aminoactinomycin D, antimycin A, antipain, bacitracin, cyclosporin A, echinomycin, gramicidins (e.g. gramicidin A and gramicidin C), myxothiazoi, nisin, paracelsin, valinomycin and viomycin.
  • Lipopeptides such as daptomycin.
  • Lipoglycopeptides such as ramoplanin.
  • Sulfonamides such as sulfamethoxazole, sulfadiazine, sulfaquinoxaline, sulfathiazole (which latter two agents are optionally in metal salt form, e.g. in salt form with an alkali metal such as sodium), succinyisulfathiazole, sulfadimethoxine, sulfaguanidine, sulfamethazine, sulfamonomethoxine, sulfanilamide and sulfasalazine.
  • sulfamethoxazole such as sulfamethoxazole, sulfadiazine, sulfaquinoxaline, sulfathiazole (which latter two agents are optionally in metal salt form, e.g. in salt form with an alkali metal such as sodium), succinyisulfathiazole, sulfadimethoxine
  • Trimethoprim optionally in combination with a sulfonamide, such as sulfamethoxazole (e.g. the combination co-trimoxazole).
  • a sulfonamide such as sulfamethoxazole (e.g. the combination co-trimoxazole).
  • Antituberculous drugs such as isonia ⁇ id, rifampicin, rifabutin, pyrazinamide, ethambutol, streptomycin, amikacin, capreomycin, kanamycin, quinolones (e.g. those at (q) below), para-aminosalicylic acid, cycloserine and ethionamide.
  • Antileprotic drugs such as dapsone, rifampicin and clofazimine.
  • Nitroimidazoles such as metronidazole and tinidazole.
  • Nitrofurans such as nitrofurantoin.
  • Amino acid derivatives such as azaserine, bestatin, D-cycloserine, 1 ,10- phenanthroline, 6-diazo-5-oxo-L-norleucine and L-alanyl-L-1-aminoethyl- phosphonic acid.
  • Aureolic acids such as chromomycin A3, mithramycin A and mitomycin C.
  • Glucosamines such as 1-deoxymannojirimycin, 1-deoxynojirimycin and N- methyl-1 -deoxynojirimycin.
  • Macrolactams such as ascomycin.
  • Taxoids such as paclitaxel.
  • Peptidyl nucleosides such as blasticidine S, nikkomycin, nourseothricin and puromycin.
  • Nucleosides such as adenine 9- ⁇ -D-arabinofuranoside, 5-azacytidine, cordycepin, formycin A, tubercidin and tunicamycin.
  • Pleuromutilins such as GSK-565154, GSK-275833 and tiamulin.
  • (ak) Peptide deformylase inhibitors such as LBM415 (NVP PDF-713) and BB 83698.
  • Antibacterial agents for the skin such as fucidin, benzamycin, clindamycin, erythromycin, tetracycline, silver sulfadiazine, chlortetracycline, metronidazole, mupirocin, framycitin, gramicidin, neomycin sulfate, polymyxins (e.g. polymixin B) and gentamycin;
  • Miscellaneous agents such as methenamine (hexamine), doxorubicin, piericidin A, stigmatellin, actidione, anisomycin, apramycin, coumermycin A1 ,
  • cytochalasins e.g. cytochalasin B and cytochalasin D
  • emetine e.g. cytochalasin B
  • ionomycin e.g. cytochalasin D
  • antibiotics include those listed at (a) to (q) above, such as: the -cillins listed at (a)(i) above (e.g. amoxicillin, ampicillin, phenoxymethylpenicillin or, particularly, co-amoxiclav (co-amoxicillin)); the cephalosporins listed at (a)(ii) above (e.g. cefuroxime, cefaclor or cefalexin); the carbapenems listed at (a)(iii) above (e.g. ertapenem); the tetracyclines listed at (b) above (e.g. doxycycline or minocycline); the macrolides listed at (d)(i) above (e.g.
  • clarithromycin, erythromycin, roxithromycin or, particularly, azithromycin the ketolides listed at (d) (ii) above (e.g. telithromycin); the oxazolidinones listed at (i) above( e.g. linezolid); the lipopeptides listed at (k)(ii) above (e.g. daptomycin) trimethoprim and the combinations therewith (e.g. co-trimoxazol) listed at (m) above; the nitrofurans listed at (p) above (e.g. nitrofurantoin); and . the quinolones listed at (q) above (e.g.
  • the term "conventional antifungal agent(s)" include references to fungicidal and fungistatic agents that are known in the prior art (i.e. agents that have been selected and developed on the basis of their MICs - namely their ability to inhibit the growth of fungi).
  • particular conventional antifungal agents that may be mentioned include any one or more of the following.
  • azole antifungals such as imidazoles (e.g. clotrimazole, econazole, fenticonazole, ketoconazole, miconazole, suiconazole, and tioconazole) or triazoles (e.g. fluconazole, itraconazole and voriconazole);
  • imidazoles e.g. clotrimazole, econazole, fenticonazole, ketoconazole, miconazole, suiconazole, and tioconazole
  • triazoles e.g. fluconazole, itraconazole and voriconazole
  • polyene antifungals such as amphotericin and nystatin
  • miscellaneous antifungal agents such as griseofulvin, caspofungin or flucytosine, which latter two agents are optionally employed in combination
  • allylamine antifungals such as terbinafine.
  • R 3 does not represent a single substituent at the 6-position of the benzoxazole ring that is NH 2 or, particularly,
  • NHC(O)NHR 7 ' e.g. wherein R 7i represents phenyl substituted by two substituents selected from methyl, methoxy, trifluoromethy! and chloro;
  • R 2 is other than H
  • R 3 represents H.
  • A represents a fused benzene ring or a fused 6-membered, aromatic heterocycle containing one or two N-atoms
  • R 1 represents H or, particularly, one to four substituents on the fused benzene ring selected from halo (e.g. chloro), CN,
  • C 1-6 alkyl optionally substituted by one or more substituents selected from halo, CN, and OR 6a , OR 7a ,
  • R 2 represents C 1-6 alkyl optionally substituted by one or more substituents selected from halo, 0R Sa , N(R 5g )(R 5h ) and C(O)OR 51 , or R 2 represents H or Het 2 ;
  • R 3 one to four substituents on the fused benzene or heteroaromatic ring selected from halo (e.g. fluoro or chloro),
  • C 1-6 alkyl optionally substituted by one or more substituents selected from halo, CN, and OR 6a , 0R 7a ,
  • Het 4 or, particularly, R 3 represents H
  • R 4 when X 2 represents N, represents H or a substituent selected from Ci -6 alkyl and C 3 . 6 cycloalkyl, which latter two groups are optionally substituted by one or more substituents selected from halo, C 1-2 alkyl, 0-(Ci-2 alkyl), aryl and Het 5 ), or, when X 2 represents O, R 4 is absent;
  • R 5a to R 5i , R 6a to R 6 ', R 7a to R 7 ' and R 8a to R 8 ' independently represent, at each occurrence
  • Het 9 provided that R 5b , R 5b , R 7b or R 8b does not represent H when n, p, q or r, respectively is 1 or 2;
  • each aryl independently represents a C 6 - A o carbocyclic aromatic group, which group may comprise either one or two rings and may be substituted by one or more substituents selected from halo, CN 1
  • Ci-B alkyl optionally substituted by one or more substituents selected from halo, C 3-6 cycioalkyl (which latter groups is optionally substituted by one or more substituents selected from halo, C 1-4 aikyl and Ci -4 alkoxy), OR 9a , S(O) t R sb , S(O) 2 N(H)R 96 , N(H)S(O) 2 R 9f , N(R")(R 9h ), B 9 -C(O)-B 10 -R 9i , phenyl (which latter groups is optionally substituted by one or more substituents selected from OH, halo, methyl and methoxy) and Het 10 , OR 1Qa ,
  • R 9a to R 9i and R 1Oa to R 1Qi independently represent, at each occurrence, H,
  • C 1-6 alkyl C 3-6 cycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from halo, OH, C 1-4 alkyl, C 4-6 cycloalkyl
  • Het 1 to Het 13 independently represent 5- to 10-membered heterocyclic groups containing from one to four heteroatoms selected from oxygen, nitrogen and/or sulfur, which heterocyclic groups may comprise one or two rings and may be substituted by one or more substituents selected from halo,
  • C 1-6 alkyl, C 3-6 cycloalkyl, which latter two groups are optionally substituted by one or more substituents selected from halo, OH, C 1-4 alkyl, C 4-6 cycloalkyl (which latter group is optionally substituted by one or more substituents selected from halo, C 1 ⁇ alkyl and C f-4 alkoxy), C 1-4 alkoxy, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, methyl and methoxy) and Hef, 0R 12a , 0,
  • R 11a to R 11i and R 12a to R 12 ' independently represent, at each occurrence, H,
  • C- I-6 alky C 3 .6 cycloalkyl (which latter two groups are optionally substituted by one or more substituents selected from halo, OH, C- M alkyl, C 4-6 cycloalkyi (which latter group is optionally substituted by one or more substituents selected from halo, C 1-4 alkyl and C 1-4 alkoxy), C 1-4 alkoxy, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, methyl and methoxy) and Hef, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, methyl and methoxy) or Het d , provided that R 11b or R 12b does not represent H when v or w, respectively is 1 or
  • B 1 to B 16 independently represent a direct bond, O 1 S or NH;
  • R 13 represents Ci -4 alkyl or phenyl (which latter group is optionally substituted by one or more substituents selected from OH, halo, methyl and methoxy);
  • alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups, as well as the alkyl part of alkoxy groups, are unsubstituted;
  • cycloalkyl groups comprise one or (if sufficient number of C-atoms is present) two rings and are optionally ring-fused to a benzene ring (so as to form a group such as, for example, 1 ,2,3,4-tetrahydro- naphthyl or, particularly, indanyi).
  • the compounds oi formula I are compounds of formula Ia
  • R 1a to R 1d all independently represents H or a substituent as defined above in respect of R 1 , and R 2 to R 4 , X 1 , X 2 and A are as hereinbefore defined.
  • Particular compounds of formula Ia that may be mentioned include those in which:
  • R 1a represents H
  • R 1b and/or R 1d represents a substituent as defined above in respect of R 1 .
  • R 1c represents H.
  • R 1a represents halo (e.g. chloro) or, particularly, H
  • R 1b represents H (e.g. when R 1c is other than H) or, particularly, a substituent selected from halo (e.g. chloro), CN, Ci-3 alkyl,
  • R 7a represents H or, particularly, Ci -3 alkyl (e.g. methyl or ethyl), which latter group is optionally substituted by phenyl, phenyl, which latter group is optionally susbstituted as defined above in respect of aryl (e.g. substituted by halo, such as chloro or, particularly, fluoro) or
  • R 7h represents H 1 Ci. 3 alkyl or, particularly, phenyl, which latter group is optionally susbstituted as defined above in respect of aryl, but is, in a particular embodiment, unsubstituted;
  • R 1c represents represents halo (e.g. chloro) or, particularly, H;
  • R 1d represents H or (e.g. when R 1b is other than H) a substituent selected from OR 7a (wherein R 7a is as hereinbefore defined) or, particularly, halo (e.g. chloro);
  • R 2 represents H, C 1 ⁇ alky! (e.g. methyl) or Het 2 ;
  • R 3 one to three substituents on the fused benzene or heteroaromatic ring selected from halo (e.g. fluoro or chloro), CN,
  • Het 1 to Het 13 independently represent 5- or 6-membered heterocyclic groups containing from one to three heteroatoms selected from oxygen, nitrogen and/or sulfur, which heterocyclic groups are partially unsaturated or, in particular embodiments, are either fully saturated or aromatic, and which heterocyclic groups may be substituted by one or more substituents selected from halo, C 1-3 alkyl and C 1-3 alkoxy (for example, Het 1 to Het 13 (such as Het 9 ) may independently represent aromatic 6-membered heterocyclic groups containing one or two nitrogen atoms, e.g.
  • pyrimidinyl such as pyrimidin-2-yl
  • Het 1 to Het 13 may independently represent fully saturated 6- membered heterocyclic groups containing one or two heteroatoms selected from oxygen and nitrogen, e.g. piperazinyi or morpholinyi, such as piperazin-1- yl or morpholin-1-yl, which groups are optionally substituted as described hereinbefore).
  • the compounds of formula are compounds of formula Ib
  • R 1a to R 1d , R 2 , X 1 , X 2 and R 4 are as hereinbefore defined.
  • X 1 represents CH; (2) X 2 represents N; (3) R 2 represents H or methyl; (4) R 1b represents H (e.g. when R 1c is other than H) or, particularly, a substituent selected from chloro, CN, OR 7a and N(H)R 7h ;
  • R /a represents phenylmethyj (i.e. benzyl) or phenyl, which latter group is optionally susbstituted by halo (e.g. fluoro, such as a single fluoro substituent in the 4-position);
  • halo e.g. fluoro, such as a single fluoro substituent in the 4-position
  • R 7h represents phenyl, which latter group is optionally susbstituted as defined above in respect of aryl, but is, in a particular embodiment, unsubstituted;
  • R 1G represents represents halo (e.g. chloro) or, particularly, H;
  • R 1d represents H;
  • R 4 represents H or, particularly, methyl.
  • R 1a , R 1c and R 1d all represent H and R 1b is other than H.
  • the medicament mentioned in the first aspect of the invention may be utilised in a method of medical treatment.
  • a method of killing clinically latent microorganisms in a mammal infected with such latent microorganisms comprising administering to said mammal a microbicidal ⁇ effective amount of compound of formula I, as hereinbefore
  • the compound of formula ! may be used to kill clinically latent microorganisms.
  • a compound of formula I as hereinbefore ' defined, to kill clinically latent microorganisms.
  • the use according to this aspect of the invention is an ex vivo use.
  • Compounds of formula I might also be employed to kill microorganisms of many different phenotypes, including growing microorganisms.
  • fourth, fifth and sixth aspects of the invention provide, respectively:
  • u treatment includes therapeutic and/or prophylactic treatment.
  • the uses according to the third and sixth aspects of the invention may be ex wVo uses, such as the use of a compound of formula I, as hereinbefore defined:
  • the compounds of formula 1 may be employed in methods of sterilisation or preservation, such as:
  • the object is preferably other than a human or animal body.
  • the materials that may be preserved according to the method described at (ii) above include polymers, lubricants, paints, fibres, leather, paper, foodstuffs, water and aqueous mixtures and solutions.
  • the compounds of formula I When used to kill clinically latent microorganisms or to treat a microbial infection, the compounds of formula I may be used either alone (i.e. as sole microbicidal or antimicrobial agents) or in combination with any one or more of the conventional antimicrobial agents described above.
  • the compounds of formula I when used as a sterilising agent, may be used either alone or in combination with a conventional sterilising agent.
  • conventional sterilising agent' when used herein, includes references to alcohols (e.g. industrial methylated spirits or ethanol), sodium chloride, thymol, chlorhexidine, cationic surfactants (e.g. cetrimide), iodine (optionally combined with povidone), phenolics (e.g. triclosan), oxidants (e.g. hydrogen peroxide, potassium permanganate or sodium hypochlorite) and any one or more of the conventional antimicrobial agents described above.
  • alcohols e.g. industrial methylated spirits or ethanol
  • sodium chloride thymol
  • chlorhexidine e.g. cetrimide
  • iodine optionally combined with povidone
  • phenolics e.g. triclosan
  • oxidants e.g. hydrogen peroxide, potassium permanganate
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier;
  • the combination product according to the seventh aspect of the invention provides for the administration of component (A) in conjunction with component (B), and may thus be presented either as separate formulations, wherein at least one of those formulations comprises component (A) and at least one comprises component (B), or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including component (A) and component (B)).
  • a pharmaceutical formulation including a compound of formula !, as hereinbefore defined and a conventional antimicrobial agent, as hereinbefore defined, or a pharmaceutically-acceptable derivative thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier (which formulation is hereinafter referred to as a "combined preparation"); and
  • Component (I) of the kit of parts is thus component (A) in admixture with a pharmaceuticaliy-acceptable adjuvant, diluent or carrier.
  • component (II) is component (B) in admixture with a pharmaceuticaliy-acceptable adjuvant, diluent or carrier.
  • a ninth aspect of the invention there is provided a method of making a kit of parts as defined above, which method comprises bringing a component (!), as defined above, into association with a component (U), as defined above, thus rendering the two components suitable for administration in conjunction with each other.
  • components (I) and (II) of the kit of parts may be: (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or (ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.
  • kit of parts comprising:
  • kits of parts described herein may comprise more than one formulation including an appropriate quantity/dose of component (A), and/or more than one formulation including an appropriate quantity/dose of component (B), in order to provide for repeat dosing. If more than one formulation (comprising either active compound) is present, such formulations may be the same, or may be different in terms of the dose of component (A) or component (B), chemical composition and/or physical form.
  • the combination product according to the seventh aspect of the invention may be used to kill clinically latent microorganisms and/or treat a microbial infection.
  • further aspects of the invention provide:
  • (H) a method of killing clinically latent microorganisms in a mammal, the method comprising administering to said mammal a microbicidally effective amount of a combination product according to the seventh aspect of the invention
  • the method of (iv) above provides for the advantage that the amount of conventional antimicrobial agent required to treat the microbial infection is reduced compared to that required in the absence of a compound of formula I.
  • bacteria and derivatives thereof, such as "bacterial infection”
  • organisms or infections due to organisms of the following classes and specific types: Gram-positive cocci, such as
  • Staphylococci e.g. Staph, aureus, Staph, epidermidis, Staph. saprophyticus, Staph, auricula ⁇ s, Staph, capitis capitis, Staph, c. ureolyticus, Staph, caprae, Staph, cohnii cohnii, Staph, c. urealyticus, Staph, equorum, Staph, gallinarum, Staph, haemolyticus, Staph, hominis hominis, Staph, h.
  • Staphylococci e.g. Staph, aureus, Staph, epidermidis, Staph. saprophyticus, Staph, auricula ⁇ s, Staph, capitis capitis, Staph, c. ureolyticus, Staph, caprae, Staph, cohnii cohnii, S
  • Streptococci e.g. beta-haemolytic, pyogenic streptococci (such as Strept. agalactiae, Strept canis, Strept. dysgalactiae dysgalactiae, Strept. dysgaiactiae equisimilis, Strept equi equi, Strept. equi zooepidemicus, Strept iniae, Strept. porcinus and Strept. pyogenes), microaerophilic, pyogenic streptococci (Streptococcus "milleri", such as Strept. anginosus, Strept. constellatus constellatus, Strept.
  • streptococci of the "mitis” alpha-haemolytic - Streptococcus "viridans", such as Strept. mitis, Strept. oralis, Strept. sanguinis, Strept. cristatus, Strept. gordonii and Strept. parasanguinis
  • "salivarius” non- haemofytic, such as Strept salivarius and Strept. vestibularis
  • mutans teeth-surface streptococci, such as Strept. criceti, Strept. mutans, Strept. ratti and Strept. sobrinus
  • Streptococci alternatively classified as Group A, B, C, D, E, G, L, P, U or V Streptococcus);
  • Gram-negative cocci such as Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria cinerea, Neisseria elongata, Neisseria flavescens, Neisseria lactamica, Neisseria mucosa, Neisseria sicca, Neisseria subflava and Neisseria weavers ' ;
  • Bacillaceae such as Bacillus anthracis, Bacillus subtilis, Bacillus thuringiensis, Bacillus stearothermophilus and Bacillus cereus;
  • Enterobacteriaceae such as Escherichia coli
  • Enterobacter e.g. Enterobacter aerogenes, Enterobacter agglomerans and Enterobacter cloacae
  • Citrobacter such as Citrob. freundii and Citrob. divernis
  • Hafnia e.g. Hafnia alvei
  • Erwinia e.g. Erwinia persicinus
  • Morganella morganii
  • Salmonella ⁇ Salmonella enterica and Salmonella typhi Salmonella ⁇ Salmonella enterica and Salmonella typhi
  • Shigella e.g. Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella sonnei
  • Klebsiella e.g. Klebs. pneumoniae, Klebs. oxytoca, Klebs. ornitholytica
  • Serratia e.g. Serratia marcescens and Serratia liquifaciens
  • Yersinia e.g. Yersinia enterocoiitica, Yersinia pestis and Yersinia pseudotuberculosis
  • Enterococci e.g. Enterococcus avium, Enterococcus casseiiflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus flavescens, Enterococcus gallinarum,
  • Enterococcus hirae Enterococcus ma/odoratus, Enterococcus mundtii, Enterococcus pseudoavium, Enterococcus raffinosus and Enterococcus solitarius;
  • Helicobacter e.g. Helicobacter pylori, Helicobacter cinaedi and Helicobacter fennelliae
  • Acinetobacter e.g. A. baumanii, A calcoaceticus, A. haemoly ⁇ cus, A. johnsonii, A. junii, A. Iwoffi and A. radioresistens
  • Acinetobacter e.g. A. baumanii, A calcoaceticus, A. haemoly ⁇ cus, A. johnsonii, A. junii, A. Iwoffi and A. radioresistens
  • Pseudomonas e.g. Ps. aeruginosa, Ps. maltophilia (Stenotrophomonas maltophilia), Ps. alcaligenes, Ps. chlororaphis, Ps. fluorescens, Ps. luteola. Ps. mendocina, Ps. monteilii, Ps. oryzihabitans, Ps. pertocinogena, Ps. pseudalcaiigenes, Ps. putida and Ps. stutzeri); Bacteriodes fragiiis; Peptococcus (e.g.
  • Peptococcus niger Peptostreptococcus
  • Clostridium e.g. C. perfringens, C. difficile, C. botuiinum, C. tetani, C. absonum, C. argentinense, C. baratii, C. biferrnentans, C. beijerinckii, C. butyricum, C. cadaveris, C. carnis, C. celatum, C. clostridioforme, C. cochlea ⁇ um, C. cocieatum, C. fa/lax, C. ghonii, C. glycolicum, C. haemolyticum, C. hastiforme, C.
  • Mycoplasma e.g. M. pneumoniae, M. hominis, M. genitalium and M. urealyticum
  • Mycobacteria e.g. Mycobacterium tuberculosis, Mycobacterium avium
  • Haemophilus e.g. Haemophilus influenzae, Haemophilus ducreyi, Haemophilus aegyptius, Haemophilus parainfluenzae, Haemophilus haemolyticus and Haemophilus parahaemolyticus
  • Haemophilus influenzae e.g. Haemophilus influenzae, Haemophilus ducreyi
  • Haemophilus aegyptius Haemophilus parainfluenzae
  • Haemophilus haemolyticus emophilus parahaemolyticus parahaemolyticus
  • Haemophilus parahaemolyticus e.g. Haemophilus influenzae, Haemophilus ducreyi, Haemophilus aegyptius, Haemophilus parainfluenzae, Haemophilus haemolyticus and Haemophilus parahaem
  • Actinobac ⁇ lus e.g. Actinobacillus actinomycetemcomitans, Actinobacillus equuli, Actinobaciiius hominis, Actinobacillus lignieresii, Actinobacillus suis and Actinobacillus ureae
  • Actinomyces e.g. Actinomyces israelii
  • Propionibacteria e.g. Propionibacterium acnes
  • Brucella e.g. Brucella abortus, Brucella canis, Brucella melintensis and Brucella suis
  • Brucella abortus e.g. Brucella abortus, Brucella canis, Brucella melintensis and Brucella suis
  • Campylobacter e.g. Campylobacter jejuni, Campylobacter coli, Campylobacter /a/7 and Campylobacter fetus
  • Campylobacter jejuni e.g. Campylobacter jejuni, Campylobacter coli, Campylobacter /a/7 and Campylobacter fetus
  • Listeria monocytogenes e.g. Campylobacter jejuni, Campylobacter coli, Campylobacter /a/7 and Campylobacter fetus
  • Vibrio e.g. Vibrio choierae and Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio carcharlae, Vibrio fluvialis, Vibrio furnissii, Vibrio hollisae, Vibrio metschnikovii, Vibrio mimicus and Vibrio vulnificus); Erysipelothrix rhusopathiae;
  • Corynebacteriaceae e.g. Coryneba ⁇ terium diphthen ' ae, Corynebacterium jeik ⁇ um and Corynebacterium urealyticum
  • Corynebacteriaceae e.g. Coryneba ⁇ terium diphthen ' ae, Corynebacterium jeik ⁇ um and Corynebacterium urealyticum
  • Spirochaetaceae such as Borrelia (e.g. Borrelia recurrentis, Borrelia burgdorferi, Borrelia afzelii, Borrelia andersonii, Borrelia bisseftii, Borrelia garinii, Borrelia japonica, Borrelia lusitaniae, Borrelia tanukii, Borrelia turdi, Borrelia valaisiana,
  • Borrelia e.g. Borrelia recurrentis, Borrelia burgdorferi, Borrelia afzelii, Borrelia andersonii, Borrelia bisseftii, Borrelia garinii, Borrelia japonica, Borrelia lusitaniae, Borrelia tanukii, Borrelia turdi, Borrelia valaisiana
  • Borrelia caucasica Borrelia crocidurae, Borrelia duttoni, Borrelia graingeri, Borrelia hermsii, Borrelia hispanica, Borrelia latyschewii, Borrelia mazzottii, Borrelia parkeri,
  • Treponema pallidum ssp. pallidum Treponema pallidum ssp. endemicum, Treponema pallidum ssp. perum and Treponema carateum
  • Pasteurella e.g. Pasteurella aerogenes, Pasteurella bettyae, Pasteurella canis, Pasteurella dagmatis, Pasteurella gallinarum, Pasteurella haemolytica, Pasteurella multocida multocida, Pasteurella multocida gallicida, Pasteurella multocida septica, Pasteurella pneumotropica and Pasteurella stomatis); Bordetella (e.g. Bordetella bronchiseptica, Bordetella hin ⁇ ii, Bordetella holmseii,
  • Nocardiaceae such as Nocardia (e.g. Nocardia asteroides and Nocardia brasiliensis);
  • Rickettsia e.g. Ricksettsii or Coxiella burnetii
  • Legionella e.g. Legionella anisa, Legionella birminghamensis, Legionalla bozemanii, Legionalla nunnatiensis, Legionalla dumoffii, Legionalla feeleii, Legionalla gormanii, Legionalla hackelia ⁇ , Legionalla israelensis, Legionalla jordanis, Legionalla lansingensis, Legionalla longbeachae, Legionella maceachernii, Legionalla micdadei, Legionalla oakridgensis, Legionalla pneumophila, Legionalla sainthelensi, Legionalla tucsonensis and Legionalla wadsworthii); Moraxella catarrhalis; Stenotrophomonas maltophilia; Burkholderia cepacia; Francisella tularensis; Gardnerella (e.g
  • Fiavobacteriaceae such as Capnocytophaga (e.g. Capnocytophaga canimorsus, Capnocytophaga cynodegmi, Capnocytophaga gingivalis, Capnocytophaga granulosa, Capnocytophaga haemolytica, Capnocytophaga ochracea and Capnocytophaga spillion);
  • Capnocytophaga e.g. Capnocytophaga canimorsus, Capnocytophaga cynodegmi, Capnocytophaga gingivalis, Capnocytophaga granulosa, Capnocytophaga haemolytica, Capnocytophaga ochracea and Capnocytophaga spumblea
  • Capnocytophaga e.g. Capnocytophaga canimorsus, Capnocytophaga cynodegmi, Capnocytophag
  • Bartonella Bartonella bacilliformis, Bartonella clar ⁇ dgeiae, Bartonella elizabethae, Bartonella henselae, Bartonella quintana and Bartonella vinsonii arupensis);
  • Leptospira e.g. Leptospira biflexa, Leptospira borgpetersenii, Leptospira inadai, Leptospira interrogans, Leptospira kirschneri, Leptospira noguchii, Leptospira santarosai and Leptospira we/7//;
  • Spirillium e.g. Spirillum minus
  • Baceteroides e.g. Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides merdae, Bacteroides ovatus, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides splanchinicus, Bacteroides stercoris, Bacteroides tectus, Bacteroides thetaiotao micron, Bacteroides uniformis, Bacteroides ureolyticus and Bacteroides vulgatus);
  • Baceteroides e.g. Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bac
  • Prevotella e.g. Prevotella bivia, Prevotella buccae, Prevotella corporis, Prevotella dentalis (Mitsuokella dentalis), Prevotella denticola, Prevotella disiens, Prevotella enoeca, Prevotella heparinolytica, Prevotella intermedia, Prevotella loeschii, Prevotella melaninogenica, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella oulora, Prevotella tannerae, Prevotella venoralis and Prevotella zoogleoformans); Porphyromonas (e.g. Prevotella bivia, Prevotella buccae, Prevotella corporis, Prevotella dentalis (Mitsuokella dentalis), Prevotella denticola, Prevotella disiens, Prevotella enoeca, Prevo
  • Fusobacterium e.g. F. gonadiaformans, F. mortiferum, F. naviforme, F. necrogenes, F. necrophorum necrophorum, F.
  • Chlamydia e.g. Chlamydia trachomatis
  • Chlamydophila e.g. Chlamydophila abortus (Chlamydia psittaci), Chlamydophiia pneumoniae (Chlamydia pneumoniae) and Chlamydophila psittaci (Chlamydia psittac ⁇ )
  • Chlamydia e.g. Chlamydia trachomatis
  • Chlamydophila e.g. Chlamydophila abortus (Chlamydia psittaci), Chlamydophiia pneumoniae (Chlamydia pneumoniae) and Chlamydophila psittaci (Chlamydia psittac ⁇ )
  • Leuconostoc e.g. Leuconostoc citreum, Leuconostoc cremoris, Leuconostoc dextranicum, Leuconostoc lactis, Leuconostoc mesenteroides and Leuconostoc pseudomesenteroides
  • Gemella e.g. Gemella bergeri, Gemella haemolysans, Gemella morbillorum and Gemella sanguinis
  • Gemella bergeri e.g. Gemella bergeri, Gemella haemolysans, Gemella morbillorum and Gemella sanguinis
  • Ureapiasma e.g. Ureaplasma parvum and Ureaplasma urealyticum.
  • Jbacferfa includes references to any of the above classes or specific types of organisms, except for Shigella (e.g. Shigella flexnerf) or Salmonella (e.g. Salmonella typhi).
  • Shigella e.g. Shigella flexnerf
  • Salmonella e.g. Salmonella typhi
  • fungf and derivatives thereof, such as “fungal infection”
  • organisms or infections due to organisms of the following classes and specific types:
  • Absidia e.g. Absidia corymbifera
  • Ajellomyces e.g. Ajellomyces capsulatus and Ajellomyces dermatitidis
  • Arthroderma e.g. Arthroderma benhamiae, Arthroderma fulvum, Arthroderma gypseum, Arthroderma incurvatum, Arthroderma otae and Arthroderma vanbreuseghemii
  • Arthroderma vanbreuseghemii e.g. Arthroderma benhamiae, Arthroderma fulvum, Arthroderma gypseum, Arthroderma incurvatum, Arthroderma otae and Arthroderma vanbreuseghemii
  • Aspergillus e.g. Aspergillus flavus, Aspergillus fumigatus and Aspergillus nige ⁇
  • Blastomyces e.g. Blastomyces dermatitidis
  • Candida e.g. Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei, Candida parapsilosis, Candida tropicalis and Candida pelliculosa
  • Cladophialophora e.g. Cladophialophora carrionii
  • Coccidioides e.g. Coccidioides immitis
  • Cryptococcus e.g. Cryptococcus ⁇ eoformans
  • Cunninghamella e.g. Cunninghamella sp.
  • Epidermophyton e.g. Epidermophyton floccosum
  • Exophiala e.g. Exophiala dermatitidis
  • Filobasidiella e.g. Filobasidiella neoformans
  • Fonsecaea e.g. Fonsecaea pedrosoi
  • Fusarium e.g. Fusarium solani
  • Geotrichum e.g. Geotrichum candidum
  • Histoplasma e.g. Histoplasma capsuiatum
  • Hortaea e.g. Hortaea wasneckii
  • lssatschenkia e.g. lssatschenkia orientalis
  • Madurella e.g. Madurella grisae
  • Malassezia e.g. Malassezia furfur, Malassezia globosa, Malassezia obtusa, Malassezia pachydermatis, Malassezia rest ⁇ cta, Malassezia slooffiae and Malassezia sympodialis
  • Microsporum e.g. Microsporum canis, Microsporum fulvum and Microsporum gypseum
  • Mucor e.g. Mucor circinelioides
  • Nectria e.g. Nectria haematococca
  • Paecilomyces e.g. Paecilomyces variotii
  • Paracoccidioides e.g. Paracoccidioides brasiliensis
  • Penicillium e.g. Penicillium marneffei
  • Pichia e.g. P/c/i/a anomala and P/cft/a guilliermondii
  • Pneumocystis e.g. Pneumocystis jiroveci ⁇ Pneumocystis carinii
  • Pseudallescheria e.g. Pseudaliescheha boydii
  • Rhizopus e.g. Rhizopus oryzae
  • Rhodotorula e.g. Rhodotorula rubra
  • Scedosporium e.g. Scedosporium apiospermum
  • Schizophyllum e.g. Schizophyilum commune
  • Sporothrix e.g. Sporothrix schenckii
  • Trichophyton e.g. Trichophyton mentagrophytes, Trichophyton rubrum
  • Trichosporon e.g. Trichosporon asahii, Trichosporon cutaneum, Trichosporon inkin and Trichosporon mucoides.
  • compounds of formula I 1 or combination products comprising compounds of formula I may be used to kill any of the above-mentioned bacterial or fungal organisms (clinically latent or otherwise).
  • Staphylococci such as Staph, aureus (either Methicillin-se ⁇ sitive (i.e. MSSA) or Methicillin-resistant (i.e. MRSA)) and Staph, epidermidis;
  • Streptococci such as Strept. agalactiae and Strept. pyogenes
  • Bacillaceae such as Bacillus anthracis
  • E ⁇ terobacteriaceae such as Escherichia coli
  • Klebsiella e.g. Klebs. pneumoniae and Klebs. oxytoca
  • Proteus e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris
  • Enterococci such as Enterococcus faecalis and Enterococcus faecium
  • Mycobacteria such as Mycobacterium tuberculosis
  • Propionibacteria such as Propionibacterium acnes.
  • fungi that may also be mentioned in this respect include Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum and Pneumocystis jiroveci.
  • Particular bacterial or fungal infections that may be mentioned in relation to (i) the use according to the fourth aspect of the invention, (ii) the method according to the sixth aspect of the invention and (iii) the above-described use and method involving the combination product according to the seventh aspect of the invention (i.e. use (iii) above or method (iv) above), include infections with
  • Staph aureus (either Methicillin-sensitive (i.e. MSSA) or Methicillin-resistant (i.e. MRSA)) and Staph, epidermidis,
  • Streptococci such as Strept. agalactiae and Strept. pyogenes, Bacillaceae, such as Bacillus anthracis,
  • Enterobacteriaceae such as Escherichia coli, Klebsiella (e.g. Klebs. pneumoniae and Klebs. oxytoca) and Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris),
  • Klebsiella e.g. Klebs. pneumoniae and Klebs. oxytoca
  • Proteus e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris
  • Enterococci such as Enterococcus faecalis and Enterococcus faecium
  • Mycobacteria such as Mycobacterium tuberculosis or fungi such as Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum and Pneumocystis jiroveci.
  • tuberculosis e.g.
  • pulmonary tuberculosis non-pulmonary tuberculosis (such as tuberculosis lymph glands, genito-urinary tuberculosis, tuberculosis of bone and joints, tuberculosis meningitis) and miliary tuberculosis), anthrax, abscesses, acne vulgaris, actinomycosis, bacilliary dysentry, bacterial conjunctivitis, bacterial keratitis, botulism, Buruli ulcer, bone and joint infections, bronchitis (acute or chronic), brucellosis, burn wounds, cat scratch fever, cellulitis, chancroid, cholangitis, cholecystitis, cutaneous diphtheria, cystic fibrosis, cystitis, diffuse panbronchioiitis, diphtheria, dental caries, diseases of the upper respiratory tract, empymea, endocarditis, endometritis, enteric fever, enter
  • otitis e.g. otitis externa and otitis media
  • orchitis pancreatitis, paronychia, pelveoperitonitis, peritonitis, peritonitis with appendicitis, pharyngitis, phlegmons, pinta, plague, pleural effusion, pneumonia, postoperative wound infections, postoperative gas gangrene, prostatitis, pseudo-membranous colitis, psittacosis, pulmonary emphysema, pyelonephritis, pyoderma (e.g.
  • oropharyngeal candidiasis vaginal candidiasis or balanitis
  • cryptococcosis favus, histoplasmosis, intertrigo, mucormycosis
  • tinea e.g. tinea corporis, tinea capitis, tinea cruris, tinea pedis and tinea unguium
  • onychomycosis pityriasis versicolor
  • ringworm and sporotrichosis e.g. tinea corporis, tinea capitis, tinea cruris, tinea pedis and tinea unguium
  • a further aspect of the invention provides a compound of formula Ic for use in medicine, wherein compounds of formula Ic take the same definition as compounds of formula I, as hereinbefore defined, provided that: (a) when X 1 represents N and R 2 represents H and A represents a fused benzene ring, then
  • R 3 does not represent a single substituent at the 6-position of the benzoxazole ring that is NH 2 or NHC(O)NHR 71 (e.g. wherein R 7i represents phenyl substituted by two substituents selected from methyl, methoxy, trifluoromethyl and chloro), and (U) when R 1 represents two halo substituents at the 6- and 8-positions of the quinazoline ring, X 2 represents N and R 4 represents CH 3 , then R 3 does not represent H; and (b) when X 1 represents CH, R 2 represents H and X 2 represents N, then
  • R 4 when R 4 represents H and A represents a fused benzene ring (and, for example, R 3 represents H), then R 1 does not represents a single halo (e.g. chloro) substituent (e.g. in the 7-position of the quinoline ring), and (ii) when R 4 represents H or tetrahydrofuran-2-y!, which latter group is substituted by OH and hydroxymethyi, A represents a fused pyrimidinyl ring and R 1 represents H, then R 3 does not represent two substituents that are OH and NH 2 .
  • halo e.g. chloro
  • Particular compounds of formula Ic that may be mentioned include relevant compounds of formula Ia and Ib, as hereinbefore defined. Still further compounds of formula Ic that may be mentioned include those in which:
  • X 1 represents CH
  • protozoa and derivatives thereof, such as “protozoal disease” includes references to organisms (or infections due to organisms) of the following classes and specific types: Leishmania (e.g. Leishmania donovanii);
  • amoeba e.g. Entamoeba, such as Entamoeba histolytica, Entamoeba coli, Entamoeba hartmanni and Entamoeba polecki
  • amoeba e.g. Entamoeba, such as Entamoeba histolytica, Entamoeba coli, Entamoeba hartmanni and Entamoeba polecki
  • Microsporidia e.g. Enterocylozoon bieneusi, Encephalitozoon hel/em, Encephalitozoon cunicu Ii and Septata intestinalis.
  • Particular conditions that the compounds of formula I, Ia, Ib or Ic can be used to treat include Leishmaniasis, malaria, trypanosomiasis, toxoplasmosis, giardiasis, balantidiasis, amoebiasis (amoebic dysentery), cryptosporidiosis, isosporiasis and microsporidiosis.
  • L 1 represents a suitable leaving group (e.g. halo, such as chloro) and R 1 , R 2 and X 1 are as hereinbefore defined, with a compound of formula III,
  • R 3 , R 4 and A are as hereinbefore defined, for example under coupling conditions known to those skilled in the art (e.g. at room temperature or above (such as at from 120 to 180 0 C) in the presence of a suitable solvent (e.g. an organic solvent such as toluene, tetrahydrofuran, ⁇ /, ⁇ /-dimethy)formamide, 1 ,2-dimethoxyethane, or mixtures thereof), a base (for example, an alkali metal alkoxide, such as a sodium or potassium tertiary alkoxide (e.g.
  • a suitable solvent e.g. an organic solvent such as toluene, tetrahydrofuran, ⁇ /, ⁇ /-dimethy)formamide, 1 ,2-dimethoxyethane, or mixtures thereof
  • a base for example, an alkali metal alkoxide, such as a sodium or potassium tertiary alkoxide (e.g.
  • a tertiary amine base such as triethylamine or diisopropylethylamine
  • an appropriate coupling agent for example a phosphine-containing palladium(H) complex, such as 1 ,1 ' ⁇ b/s ⁇ (diphenylphosphino)ferrocine palladium(ll) chloride or the complex formed between 2- dicyclohexylphosphino ⁇ '-dimethylaminobiphenyl and f ⁇ s-(dibenzylideneacetone)- dipalladiurn
  • an appropriate coupling agent for example a phosphine-containing palladium(H) complex, such as 1 ,1 ' ⁇ b/s ⁇ (diphenylphosphino)ferrocine palladium(ll) chloride or the complex formed between 2- dicyclohexylphosphino ⁇ '-dimethylaminobiphenyl and f ⁇ s-(dibenzylideneacetone)- dipallad
  • R ⁇ R 2 and X 1 are as hereinbefore defined, with a compound of formula V wherein R 3 , A and L 1 are as hereinbefore defined, for example under coupling conditions known to those skilled in the art (e.g. at room temperature or above in the presence of a suitable solvent (e.g. an organic solvent such as N,N- dimethylformamide) and a base (for example, an alkali metal hydride, such as sodium hydride)).
  • a suitable solvent e.g. an organic solvent such as N,N- dimethylformamide
  • a base for example, an alkali metal hydride, such as sodium hydride
  • R 1 , R 2 and X 1 are as hereinbefore defined, using a suitable halogenating agent (for example, a th/onyl halide, a phosphorous trihalide (e.g. PCi 3 ), a phosphorous pentahalide (e.g. PCI 5 ) or, particularly, a phosphorous oxyhalide (e.g. P(O)CI 3 )), for example at elevated temperature (such as from 70 to 120 0 C).
  • a suitable halogenating agent for example, a th/onyl halide, a phosphorous trihalide (e.g. PCi 3 ), a phosphorous pentahalide (e.g. PCI 5 ) or, particularly, a phosphorous oxyhalide (e.g. P(O)CI 3 )
  • elevated temperature such as from 70 to 120 0 C.
  • Compounds of formula IV may be prepared according to, or by analogy with, methods known to those skilled in the art.
  • compounds of formula IV may be prepared by reaction of a corresponding compound of formula Ii with ammonia, or a protected derivative thereof (e.g. benzylamine, optionally bearing one or more substituents (e.g. substituents selected from the group comprising methyl, metnoxy, halo and nitro) on the phenyl ring, thus forming compounds such as 2,4- dimethoxybenzylamine).
  • a protected derivative of ammonia is employed, the protecting group is removed from the resulting protected intermediate (e.g. under standard conditions, such as acid-catalysed cleavage or catalytic hydrogenation) in order to form the compound of formula IV.
  • L 1 represents a suitable leaving group (e.g. O-C 1 . 4 alkyl)
  • R 1 and R 2 are as hereinbefore defined, for example at elevated temperature (e.g. at reflux temperature) in the presence of a suitable solvent (such as dioxane) and optionally in the presence of an acid, such as polyphosphoric acid.
  • a suitable solvent such as dioxane
  • R 1 and R 2 are as hereinbefore defined, for example at elevated temperature (such as reflux temperature) in the presence of a suitable solvent (e.g. an alcohol such as ethanol, water, or mixtures thereof) and optionally in the presence of a base such as sodium carbonate.
  • a suitable solvent e.g. an alcohol such as ethanol, water, or mixtures thereof
  • a base such as sodium carbonate
  • R 1 and R 2 are as hereinbefore defined, for example at elevated temperature (such as from 180 to 22O 0 C) in the presence of a suitable solvent (e.g. 1 ,2- dichlorobenzene).
  • a suitable solvent e.g. 1 ,2- dichlorobenzene
  • Compounds of formula Vl in which X 1 represents N may be prepared by cyclisation of a corresponding a compound of formula X, wherein R 1 and R 2 are as hereinbefore defined, for example at elevated temperature in the presence of a base (e.g. an alkali metal hydroxide, such as sodium hydroxide) and an appropriate solvent (e.g. water).
  • a base e.g. an alkali metal hydroxide, such as sodium hydroxide
  • an appropriate solvent e.g. water
  • R 1 is as hereinbefore defined, with a compound of formula XII,
  • R 2 and L 2 are as hereinbefore defined, for example under conditions known to those skilled in the art (e.g. under conditions described hereinbefore in respect of the preparation of compounds of formula Vl).
  • Compounds of formula VIII may be prepared according to, or by analogy with, methods known to those skilled in the art, such as by reduction of a corresponding compound of formula XIII 1 wherein R 1 and R 2 are as hereinbefore defined, in the presence of a reducing agent (such as tin(ll) chloride), for example under conditions known to those skilled in the art (such as, when the reducing agent is tin(ll) chloride, by reaction at elevated temperature (e.g. reflux temperature) in the presence of an acid (such as concentrated hydrochloric acid) and a suitable solvent (e.g. an alcohol such as ethanol, water, or mixtures thereof).
  • a reducing agent such as tin(ll) chloride
  • an acid such as concentrated hydrochloric acid
  • a suitable solvent e.g. an alcohol such as ethanol, water, or mixtures thereof.
  • L 3 represents O-C M alkyl
  • L 2 is as hereinbefore defined (and may or may not take the same definition as L 3 )
  • R 1 and R 2 are as hereinbefore defined, for example under conditions known to those skilled in the art (e.g. at elevated temperature (such as from 180 to 22O 0 C) in the presence of a suitable solvent (e.g. 1 ,2-dichlorobenzene)), followed by hydrolysis of ihe resulting ester of formula XiVA, wherein R 1 , R 2 and L 3 are as hereinbefore defined, for example under conditions known to those skilled in the art (e.g. at elevated temperature (such as reflux temperature) in the presence of a suitable alkali (such as sodium hydroxide) and an appropriate solvent (such as water)).
  • a suitable solvent e.g. 1 ,2-dichlorobenzene
  • L 2 and L 3 are as hereinbefore defined, and wherein the two L 3 groups may be the same as or different from each other, for example under conditions known to those skilled in the art (e.g. a ⁇ elevated temperature, such as from 80 to 100 0 C).
  • Substituents on alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclic groups in compounds of formulae I 1 H, 111, IV, V, Vl, VII, VIII 1 IX, X, Xl, XII, XIII, XIV and XiVA may be introduced and/or interconverted using techniques well known to those skilled in the art by way of standard functional groups intercon versions, in • accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions.
  • benzyloxy may be converted to hydroxy
  • hydroxy may be converted to alkoxy
  • phenyl may be halogenated to give halophenyl
  • halo may be displaced by cyano, etc.
  • Compounds of formula I may be isolated from their reaction mixtures using conventional techniques.
  • compounds of formula I may be isolated by conversion to an acid (e.g. hydrochloric acid) salt (e.g. by way of addition of acid to the crude product) and then recrystallisation of the salt from a suitable solvent (e.g. methanol or, particularly, ethanol).
  • a suitable solvent e.g. methanol or, particularly, ethanol
  • the salt can simply be washed with or slurried in the presence such a suitable solvent in order to isolate the pure acid salt of the compound of formula I.
  • pharmaceutically acceptable derivatives of compounds of formula ! also include “protected” derivatives, and/or compounds that act as prodrugs, of compounds of formula I.
  • Compounds of formula I may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. HPLC techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica). All stereoisomers are included within the scope of the invention.
  • Functional groups that it is desirable to protect include hydroxy, amino and carboxylic acid.
  • Suitable protecting groups for hydroxy include optionally substituted and/or unsaturated alky! groups (e.g. methyl, ally], benzyl or ferf-butyl), trialkylsilyl or diarylalkylsilyl groups (e.g. f-butyldimethylsilyi, f-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl.
  • Suitable protecting groups for carboxylic acid include Ci -6 alky] or benzyl esters.
  • the protection and deprotection of functional groups may take place before or after coupling, or before or after any other reaction in the above-mentioned schemes.
  • Protected derivatives of compounds of formula I may be converted chemically to compounds of the invention using standard deprotection techniques (e.g. hydrogenation). The skilled person will also appreciate that certain compounds of formula I may also be referred to as being "protected derivatives" of other compounds of formula I.
  • the compounds of formula I When used in the above-described method of treatment, the compounds of formula I may be formulated for administration to a patient.
  • a pharmaceutical formulation including a compound of formula I (e.g. a compound of formula Ia, Ib or Ic), in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the above-mentioned medicaments, (components of) combination products and pharmaceutical formulations may be prepared according to methods known to those skilled in the art, for example by mixing a compounds of formula I (e.g. a compound of formula Ia, Ib or Ic) with excipient or excipients.
  • a compounds of formula I e.g. a compound of formula Ia, Ib or Ic
  • the compound of formula I When formulated with excipients, the compound of formula I may be present in the above-mentioned medicaments, (components of) combination products and pharmaceutical formulations in a concentration from 0.1 to 99.5% (such as from 0.5 to 95%) by weight of the total mixture.
  • the compound of formula When administered to patients by way of any of the above-mentioned medicaments, (components of) combination products and pharmaceutical formulations, the compound of formula will normally be administered orally, by any parenteral route or via inhalation.
  • compounds of formula I e.g. compounds of formula Ia, Ib or Ic
  • compounds of formula Ia, Ib or Ic can also be administered by incorporation of the compound of formulae I into feed or drinking water.
  • Preferred route of administration of compounds of the invention are oral.
  • Suitable daily doses of the compounds of the invention in prophylactic and/or therapeutic treatment of mammals include, for example, 0.001-100 mg/kg body weight at peroral administration and 0.001-50 mg/kg body weight at parenteral administration.
  • a topical pharmaceutical composition comprising a compound of formula I (e.g. a compound of formula Ia 1 Ib or Ic) in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier;
  • a combination product for topical administration comprising
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • the combination product provides for the administration of component (A) in conjunction with component (B), and may thus be presented either as separate topical formulations, wherein at least one of those formulations comprises component (A) and at least one comprises component (B), or may be presented (i.e. formulated) as a combined topical preparation (i.e. presented as a single topical formulation including component (A) and component (B)).
  • Topical compositions which are useful for treating disorders of the skin or of membranes accessible by digitation (such as membrane of the mouth, vagina, cervix, anus and rectum), include creams, ointments, lotions, sprays, gels and sterile aqueous solutions or suspensions.
  • topical compositions include those in which the active ingredient(s) is (are) dissolved or dispersed in a dermatological vehicle known in the art (e.g. aqueous or non-aqueous gels, ointments, water-in-oil or oil-in-water emulsions).
  • Constituents of such vehicles may comprise water, aqueous buffer solutions, non-aqueous solvents (such as ethanol, isopropanol, benzyl alcohol, 2-(2- ethoxyethoxy)ethanoi, propylene glycol, propylene glycol monolaurate, glycofuroi or glycerol), oils (e.g. a mineral oil such as a liquid paraffin, natural or synthetic triglycerides such as MiglyolTM, or silicone oils such as dimethicone).
  • the dermatological vehicle employed may contain one or more components selected from the following list: a solubilising agent or solvent (e.g.
  • a ⁇ -cyclodextrin such as hydroxypropyi ⁇ - cyclodextrin, or an alcohol or polyol such as ethanol, propylene glycol or glycerol
  • a thickening agent e.g. hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylceDulose or carbomer
  • a gelling agent e.g. a polyoxyethylene-polyoxypropylene copolymer
  • a preservative e.g.
  • benzyl alcohol benzalkonium chloride, chiorhexidine, chforbutol, a benzoate, potassium sorbate or EDTA or salt thereof
  • pH buffering agent(s) such as a mixture of dihydrogen phosphate and hydrogen phosphate salts, or a mixture of citric acid and a hydrogen phosphate salt.
  • the amount of compound of formula I used in topical compositions or combination products will depend, inter alia, upon the particular nature of the composition or combination product, as well as its intended use. In any event, those skilled in the art will be able to determine, by routine and non-inventive methods, amounts of compound of formula I that can be employed. Typically, however, the compound of formula I will be present in the topical composition or combination product at from 0.01 to 25% by weight (e.g. from 0.1 to 10% by weight, such as from 0.1 to 5% by weight or, particularly, from 0.5 to 3% (e.g. 2%) by weight) of the composition or product.
  • 0.01 to 25% by weight e.g. from 0.1 to 10% by weight, such as from 0.1 to 5% by weight or, particularly, from 0.5 to 3% (e.g. 2%) by weight
  • topical pharmaceutical compositions such as creams, ointments, lotions, sprays and sterile aqueous solutions or suspensions are well known in the art. Suitable methods of preparing topical pharmaceutical compositions are described, for example in WO 95/10999, US 6,974,585, WO 2006/048747, as well as in documents cited in any of these references.
  • Topical pharmaceutical compositions and combination products according to the present invention may be used to treat a variety of skin or membrane disorders, such as infections of the skin or membranes (e.g. e.g. infections of nasal membranes, axilla, groin, perineum, rectum, dermatitic skin, skin ulcers, and sites of insertion of medical equipment such as i.v. needles, catheters and tracheostomy or feeding tubes) with any of the bacteria, fungi described hereinbefore, (e.g. any of the Staphylococci, Streptococci, Mycobacteria or Pseudomonas organisms mentioned hereinbefore, such as S. aureus (e.g. Methiciltin resistant S. aureus (MRSA))).
  • infections of the skin or membranes e.g. e. infections of nasal membranes, axilla, groin, perineum, rectum, dermatitic skin, skin ulcers, and sites of insertion of medical equipment such as
  • Particular bacterial conditions that may be treated by topical pharmaceutical compositions and combination products according to the present invention also include the skin- and membrane-related conditions disclosed hereinbefore, as well as: acne vulgaris; rosacea (including eiythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea and ocular rosacea); erysipelas; erythrasma; ecthyma; ecthyma gangrenosum; impetigo; paronychia; cellulitis; folliculitis (including hoi tub folliculitis); furunculosis; carbunculosis; staphylococcal scalded skin syndrome; surgical scarlet fever; streptococcal peri-anal disease; streptococcal toxic shock syndrome; pitted keratolysis; trichomycosis axillaris; pyoderma; external canal ear infections;
  • kansasii M. malmoense, M. szulgai, M. simiae, M. gordonae, M. haemophilum, M. avium, M. intracetlulare, M. chelonae (including M. abscessus) or M. fortuitum infections, swimming pool (or fish tank) granuloma, lymphadenitis and Buruli ulcer (Baimsdale ulcer, Searles' ulcer, Kakerifu ulcer or Toro ulcer)); intertrigo; as well as infected eczma, bums, abrasions and skin wounds.
  • Particular fungal conditions that may be treated by topical pharmaceutical compositions and combination products according to the present invention also include include the skin- and membrane-related conditions disclosed hereinbefore, as well as: candidiasis (e.g. oropharyngeal candidiasis, vaginal candidiasis or balanitis); sporotrichosis; ringworm (e.g. tinea pedis, tinea cruris, tinea capitis, tinea unguium or tinea corporis); tinea versicolor; and infections with Trichophyton, Microsporum, Epidermophyton or Pityrosporum ovale fungi.
  • candidiasis e.g. oropharyngeal candidiasis, vaginal candidiasis or balanitis
  • sporotrichosis e.g. tinea pedis, tinea cruris, tinea capitis, tinea unguium or tinea corporis
  • tinea versicolor e.g. Trichophyton
  • the compound of formula I when employed to treat a microbial infection, is preferably administered in a smaller number of doses than is necessary for the treatment of the same microbial infection utilising conventional antimicrobial agents only (e.g. in less than 7, 6, 5, 4, or 3 doses, such as in 2 doses or, particularly, 1 dose).
  • a still further aspect of the invention provides a method of reducing the dose of conventional antimicrobial agent required to treat a microbial infection, the method comprising co-administering a compound of formula I.
  • Compounds of formulae I have the advantage that they may be used to kill- clinically latent microorganisms. Further, in treating microbial infections, compounds of formulae I may possess the further advantage that they allow for a shorter period of therapy (either alone or in combination with a conventional antimicrobial agent), thus increasing patient compliance (through, for example, the need to take fewer or smaller closes of antimicrobial agents) and/or minimising the risk of generating sub-populations of microorganisms that are (genetically) resistant to conventional antimicrobial agents.
  • compounds according to the invention may have the advantage that they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, or have other useful pharmacological properties over compounds known in the prior art.
  • Test procedures that may be employed to determine the biological (e.g. bactericidal or antibacterial) activity of the compounds of formula I include those known to persons skilled in the art for determining:
  • methods for determining activity against log phase bacteria include a determination, under standard conditions (i.e. conditions known to those skilled in the art, such as those descried in WO 2005/014585, the disclosures of which document are hereby incorporated by reference), of Minimum Inhibitory Concentration ("MIC”) or Minimum Bactericidal Concentration (“MBC”) for a test compound.
  • MIC Minimum Inhibitory Concentration
  • MBC Minimum Bactericidal Concentration
  • methods for determining activity against clinically latent bacteria include a determination, under conditions known to those skilled in the art (such as those described in Nature Reviews, Drug Discovery 1 , 895-910 (2002), the disclosures of which are hereby incorporated by reference), of Minimum Stationary- cidal Concentration ("MSC”) or Minimum Dormicidal Concentration (“MDC”) for a test compound. Specific examples of such methods are described below. Protocol for Pyogenic Bacteria
  • strains used for screening are shown in the following table.
  • the bacteria except for streptococci and H. influenzae were grown in 10 mL of nutrient broth (No. 2 (Oxoid)) overnight at 37 0 C, with continuous shaking at 120 rpm. Streptococci and H. influenzae were grown overnight in Todd-Hewitt broth (Sigma) without shaking. The overnight cultures were diluted (1000 X) in 100 mL of growth medium and then incubated with or without shaking for 10 days. Viability of the bacteria was estimated by colony forming unit (CFU) counts at 2 hours intervals at the first 24 hours and at 12-24 hours afterwards.
  • CFU colony forming unit
  • Log-phase cultures The above-described overnight cultures were diluted (1000 X) with iso-sensitest broth. The cultures were then incubated at 37°C with shaking for 1-2 hours to reach log CFU 6, which served as log-phase cultures.
  • Stationary phase cultures Cultures incubated for more than 24 hours are in stationary phase. For drug screening, 5-6 day old stationary phase cultures are used as shown in Rg. 1 (the periods between two arrows).
  • An antibiotic e.g. gentamicin
  • PBS phosphate buffered saline
  • CFU counts CFU counts
  • test compound Different concentrations of each test compound were incubated with the (persister) cell suspension in 96 well plates for various periods of time (24 and 48 hours). Bactericidal activity was then determined by taking CFU counts of the resulting cultures, as described above.
  • M. tuberculosis H37Rv was grown in 10 mL of Middlebrook 7H9 broth containing
  • clumps in the cultures were broken up by vortexing the cultures in the presence of 2 mm glass beads (Philip Harris Scientific, Staffordshire, UK) for 2 minutes, followed by so ⁇ ication in a water bath sonicator (Branson Ultrasonic B. V.) for 5 minutes.
  • the numbers of viable M. tuberculosis in the cultures were determined by colony forming unit (CFU) counts on Middlebrook 7H11 agar. Serials of 10-fold dilutions of the cultures are made in Middlebrook 7H9 broth with 0.05% (v/v) Tween 80 but without ADC. Then, 100 ⁇ l_ of samples was added to one-third segments of the agar plates in duplicate. The plates were incubated in polythene bags for 3 weeks at 37°C.
  • Model 1 Stationary-phase cultures. Different concentrations of each test compound were incubated with the sonicated 100-day cultures, each concentration to a separate 10 m!_ culture. After incubation for 5 days, counts of viable CFU were determined by inoculating a pair of 7H11 plates with 100 ⁇ L of 10-fold serial dilutions of the resulting cultures.
  • Wlodel 2 - Persistent bacteria selected by rifampicin The Wlodel 2 - Persistent bacteria selected by rifampicin.
  • Rifampicin 100 mg/L was added to each of a set of sonicated 100-day cultures, which cultures were then incubated for 5 days. After the first day of incubation, no colonies could be obtained on plates inoculated from the culture. After washing twice with PBS by centrifugation, fresh (and rifampicin-free) 7H9 medium was added to make up the volume to 10 ml_ and the test compound was added in the same concentrations as in mode! 1. After further incubation for 7 days, CFU counts were determined by inoculating 1 niL from each container onto a 7H11 plate.
  • compounds of formulae I 1 Ia, Ib and Ic may also be tested in various in vivo models, including those known to those skilled in the art.
  • protocols that may be followed include those described in Antimicrobial Agents and Chemotherapy 49(8), 3435-41 (2005), as well as the following.
  • mice ICR or BALB/c mice aged 6-8 weeks are obtained from Harlan UK.
  • the mice are anesthetized by intraperitoneal injection of 200 ⁇ l_ of Ketamine hydrochloride/Xylazine solution. Fur on the back of the mouse is removed using an electrical clipper.
  • a 2 cm 2 (2 cm x 1 cm) area of skin is marked with a marker pen.
  • the marked skin area is swabbed using a disposable swab for 3 times in order to examine the bacterial numbers on the skin.
  • the bacteria on the swab will spread on blood agar plates (OxoidTM).
  • Log-phase or stationary phase bacterial cultures will be used. The cultures will be concentrated by centrifugation to obtain 10 9 to 10 10 CFU/mL The cell pellet will be resuspended with nutrient broth or PBS and glycerol (50%). 15-20 ⁇ l_ of the cell suspension is added to the skin area (2 cm 2 ) which gives 10 6"7 CFU on the skin. The skin is allowed to dry for about 15 min. Solutions of test compound at different concentrations will be applied on the skin area for different periods of time.
  • Bacterial numbers on the skin will be estimated as follows: After the mouse has been euthanised, the skin at the marked area will be cut and added into a 2 mL tube containing 1 mL water and glass beads (1 mm). The skin will be homogenised using a reciprocal shaker (Hybaid Ltd, UK) for 45 seconds (speed setting 6.5) or votexing for 1 tnin. Residual test compound will be removed by washing 3 times with water or PBS (if the test compound precipitates in the buffer system, water alone is used for washing). CFU counts will be performed after a serial of 10 fold dilution of the homogenates. 100 ⁇ l_ samples will be added to one third of blood agar plates (OxoidTM) in duplicate. Colony forming units (CFU) will then be counted using aCoLye (a colony counter) after incubation of the plates at 37 0 C for 24 hours.
  • a reciprocal shaker Hybaid Ltd, UK
  • PBS
  • mice ICR or BALB/c mice aged 6-8 weeks are obtained from Harlan UK.
  • the mice are anesthetized by intraperitoneal injection of 200 ⁇ l_ of Ketamine hydrochloride/Xylazine solution.
  • the fur of the mice on the back will be removed by electric clipper.
  • An area of 2 cm 2 skin is tape-stripped using autoclave tape.
  • the skin will be striped 10 times in succession. After this procedure, the skin become visibly damaged and is characterized by reddening and glistening but no regular bleeding. Buprenorphine will be given during the anaesthetic period and every 12 hours for up to 3 days to reduce prolonged pain.
  • a bacterial infection is initiated by placing a 10 ⁇ L of bacterial cell suspension containing 10 7 cells from overnight or stationary phase cultures on the damaged skin area. At 0 and 4 hours after infection, 3 mice will be killed to estimate the CFU counts on the skin. After 24 hours, solutions of test compound at different concentrations will be applied on the skin area for different periods of time. The experiments will be terminated 18 h after the last topical treatment.
  • Bacterial numbers of the wounds will be estimated as follow: After the mouse has been euthanised, the wounds, approximately 2 cm 2 will be cut and added to a 2 ml_ tube containing 1 mL water and glass beads (1 mm). The skin will be homogenised using a reciprocal shaker (Hybaid Ltd, UK) for 45 seconds (speed setting 6.5).
  • Residual test compound will be removed by washing 3 times with water. CFU counts will be performed after a serial of 10 fold dilution of the homogenises. 100 ⁇ L samples are added to one third of blood agar plates (OxoidTM) in duplicate. Colony forming units
  • Method A Experiments performed on a Micromass Platform LCT spectrometer with positive ion electrospray and single wavelength UV 254 nm detection using a Higgins Clipeus C18 5 ⁇ m 100 x 3.0 mm column and a 1 mL / minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitriie containing 0.1 % formic acid (solvent B) for the first minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes.
  • the final solvent system was held constant for a further 5 minutes.
  • Method B Experiments performed on a Micromass Platform ZQ Quadrupole spectrometer with positive ion eiectrospray and single wavelength UV 254 nm detection using a Higgins Clipeus C18 5 ⁇ m 100 x 3.0 mm column and a 1 mL / minute flow rate.
  • the initial solvent system was 95% solvent A and 5% solvent B for the first minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes.
  • the final solvent system was held constant for a further 5 minutes.
  • Method C Experiments performed on a Micromass Platform LC spectrometer with positive and negative ion electrospray and ELS/Diode array detection using a
  • Microwave experiments were carried out using either a Personal Chemistry Smith SynthesizerTM or Emrys OptimizerTM which use a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperatures from 40-250 0 C can be achieved, and pressures of up to 20 bar can be reached.
  • Preparative HPLC was carried out using a 150x20.6 mm 7 micron Genesis Ci 8 column eluting at 10 mL/min with a gradient of water/MeCN (+0.1 % formic acid or 0.1% trifluoroacetic acid). The fractions containing the desired product were concentrated. In some cases the compound was then converted to the hydrochloride salt by treatment with 1 M hydrochloric acid, followed by evaporation.
  • a crude cream-coloured solid prepared (from 3-chloroaniiine) as a mixture with 5-chloro-4-hydroxy-2-methy!quinoline.
  • the crude product was used without further purification.
  • a cream-coloured solid prepared from 2,4-dichloroaniline. The crude product was used without further purification.
  • a brown solid prepared from 4-phenylaminoaniiine and ethyl acetoacetate.
  • 2,3-Dichlorobenzaldehyde (10.5 g) was added to a cooled mixture of concentrated sulphuric acid (20 mL) and concentrated nitric acid (20 mL). The resultant mixture was stirred and heated at 9O 0 C overnight. The mixture was poured carefully into a mixture of ice and water and the resultant white solid was collected by filtration. The solid was dissolved in diethyl ether, dried (MgSO 4 ) and filtered.
  • Oxalyl chloride (11.0 ml_) was added dropwise to a solution of 2,3-dichloro-6- nitrobenzoic acid (1.5 g; see step (i) above) in dichloromethane (50 mL) containing a few drops of ⁇ /, ⁇ /-dimethylformamide. The resultant mixture was stirred at room temperature for 2 hours then evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (1 :4) to give the sub-title compound (1.3 g) as a pale yellow oil.
  • 1H NMR (CDCI 3 ) ⁇ 8.2 (d, 1 H), 7.8 (d, 1 H).
  • the sub-title compound was prepared by a procedure analogous to that described in Preparation 3 above, utilising 4-(4-methylpiperazin-1-yl)phenylamine in place of 4-phenoxyaniline, and ethyl acetoacetate in place of diethyl ethoxymethylenemalonate.
  • the filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and dichloromethane (0:100 gradually increasing to 1 :9) and collecting the major, yellow product.
  • the product was further purified by preparative HPLC and the major component was converted to the hydrochloride salt to give the title compound (0.07 g) as a bright yellow solid.
  • a bright yellow solid prepared from 4-chloro-6-cyano-2-methyiquinoline (see
  • a bright yellow solid (isolated as the free base), prepared from 4-chloro-6 ⁇ benzyloxy-2- methylquinoline (see Preparation 11 (iv) above).
  • a bright yellow solid prepared from 4,7-dichloro-2-methylquinoline (see Preparation 11 (vi) above).
  • a bright yellow solid (isolated by preparative HPLC, without conversion to the hydrochloride salt), prepared from 4-chloro-6-(4-fluorophenoxy)-2-methylquinoline (see Preparation 1 1 (ix) above).
  • the resultant mixture was diluted with ethyl acetate and washed with water and saturated brine solution then dried (Na 2 SO 4 ) and filtered.
  • the filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, methanol, acetic acid and water (600:20:3:2 gradually increasing to 120:20:3:2) to give a major, yellow component, which was converted to the hydrochloride salt.
  • the resulting yellow solid was recrystallised from ethanol and then triturated with diethyl ether to give the title compound (0.054 g) as a yellow solid.
  • the filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and dichloromethane (1 :20) and collecting the major, yellow component. This was further purified by chromatography on silica, eluting with a mixture of methanol and ethyl acetate (1 :20 increasing to 1 :10), collecting the major component, which was converted to the hydrochloride salt to give the title compound (0.025 g) as a yellow solid.
  • the mixture was partitioned between water and ethyl acetate and the organic layer was washed with saturated brine solution, dried (MgSO 4 ) and filtered.
  • the filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of methanol and dichioromethane (5:95, gradually increasing to 20:80), coiiecting the major product.
  • the filtrate was evaporated to dryness and the residue was purified by chromatography on silica eiuting with a mixture of 2 M ammonia in methanol and ethyl acetate (5:95, gradually increasing to 20:80).
  • the desired fractions were concentrated, hydrochloric acid was added, and the solvent evaporated to give the title compound (0.009 g) as a bright yellow solid.
  • Bio activity that was determined included a log kill, at 20 ⁇ g/mL of test compound, of above 0.5 (e.g. from 0.5 to 7) against stationary phase and/or persister bacteria of the types Enterococcus, Staphylococcus aureus, Streptococcus pyogenes and Mycobacterium tuberculosis.
  • Example 2 demonstrated a log kill, at 20 ⁇ g/mL of test compound, from 5.87 to 7.05 for stationary phase bacteria of the types Enterococcus, Staphylococcus aureus (including MRSA), Streptococcus pyogenes, Streptococcus agalactiae and Mycobacterium tuberculosis.
  • Example 3(iv) demonstrated a log kill, at 20 ⁇ g/mL of test compound, , from 5.90 to 6.51 for stationary phase bacteria of the types Enterococcus, Staphylococcus aureus (including MRSA), Streptococcus pyogenes, Streptococcus agalactiae and Mycobacterium tuberculosis.
  • EDTA ethylenediaminetetraacetic acid
  • MRSA methici ⁇ in-resistant Staphylococcus aureus
  • n-, s-, /-, t- and tert- have their usual meanings: normal, secondary, iso, and tertiary.

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Abstract

L'invention porte sur des composés de formule I dans laquelle R1, R2, R3, R4, X1, X2 jusqu'à A ont les significations données dans la description. L'invention porte également sur des utilisations médicales de ces composés, telles que la destruction de micro-organismes cliniquement latents ou le traitement d'infections microbiennes.
PCT/GB2008/001127 2007-03-28 2008-03-27 Composés antimicrobiens à base de 4-aminoquinoléine Ceased WO2008117079A1 (fr)

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RU2376989C1 (ru) * 2008-10-09 2009-12-27 Фатима Якубовна Богатырева Способ лечения больных бесплодием, обусловленным ановуляцией на фоне хронического и острого воспаления органов малого таза
DE102009004959A1 (de) * 2009-01-14 2010-07-15 Justus-Liebig-Universität Giessen Mittel zur Vorbeugung und Behandlung der Pityriasis versicolor
WO2011121345A1 (fr) 2010-03-30 2011-10-06 Helperby Therapeutics Limited Nouveau traitement combiné et utilisation associée
WO2012017215A1 (fr) 2010-08-05 2012-02-09 Helperby Therapeutics Limited Combinaison d'une pyrroquinoléine et d'un agent antimicrobien de type bêta-lactame, de mupirocine ou de chlorhexidine
WO2012017216A1 (fr) 2010-08-05 2012-02-09 Helperby Therapeutics Limited Combinaison d'une pyrroloquinoléine et d'un agent antimicrobien de type aminoglycoside
WO2012032360A2 (fr) 2010-09-10 2012-03-15 Helperby Therapeutics Limited Nouvelle utilisation de composés biologiquement actifs
RU2466746C1 (ru) * 2011-05-31 2012-11-20 Фатима Якубовна Богатырева Способ лечения больных бесплодием, обусловленным непроходимостью маточных труб и ановуляторным менструальным циклом
RU2475244C1 (ru) * 2012-02-09 2013-02-20 Ринат Файзутдинович Билалов Средство для лечения актиномикоза и некробактериоза сельскохозяйственных животных "антиактиномициллин"
US8765712B2 (en) 2009-01-14 2014-07-01 Justus-Liebig-Universitaet Giessen Agent for preventing and treating pityriasis versicolor
WO2016166515A1 (fr) 2015-04-11 2016-10-20 Helperby Therapeutics Limited Composition pour voie orale
WO2017072488A1 (fr) 2015-10-27 2017-05-04 Helperby Therapeutics Limited Triple combinaison
WO2017091661A1 (fr) * 2015-11-25 2017-06-01 Strovel Jeffrey William Inhibiteurs de bromodomaines bet bicycliques et leurs utilisations
FR3057774A1 (fr) * 2016-10-21 2018-04-27 Museum National D'histoire Naturelle Derives de la purine pour leur utilisation dans le traitement ou la prevention de maladies dues a une mutation non-sens
WO2018162928A1 (fr) 2017-03-10 2018-09-13 Helperby Therapeutics Limited Procédé de restauration de l'efficacité d'un agent antibactérien
WO2018172250A1 (fr) 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-méthyl-quinazolines
US10266536B2 (en) 2013-03-14 2019-04-23 Convergene Llc Methods and compositions for inhibition of bromodomain-containing proteins
WO2019201848A1 (fr) 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-méthyl-aza-quinazolines
KR102058623B1 (ko) 2019-08-27 2019-12-23 주식회사 아미코스메틱 여드름 유발 피부상재균에 대한 항균활성을 갖는 류코노스톡 시트리움
CN110963967A (zh) * 2019-11-25 2020-04-07 武汉智顿科技发展有限公司 一种2-甲基-4-氨基喹啉的制备方法
CN111018777A (zh) * 2019-11-25 2020-04-17 武汉智顿科技发展有限公司 一种地喹氯铵的制备方法
CN111087390A (zh) * 2017-11-10 2020-05-01 西南大学 氟喹诺酮类胺基衍生物及其用途
CN111537633A (zh) * 2020-04-29 2020-08-14 上海应用技术大学 一种头孢类抗生素的液相色谱-质谱联用的检测方法
CN113528388A (zh) * 2021-07-19 2021-10-22 海南大学 珊瑚共生链霉菌、发酵生产放线菌素d的方法及应用
CN116751163A (zh) * 2023-06-07 2023-09-15 辽宁大学 一种4-氯喹啉类化合物及合成方法
US12497395B2 (en) 2019-04-24 2025-12-16 Convergene, Llc Small molecule bromodomain inhibitors and uses therof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2623878A (en) * 1948-02-09 1952-12-30 Ciba Pharm Prod Inc 2, 4-disubstituted amino quinazolines
WO2006034235A2 (fr) * 2004-09-20 2006-03-30 Serenex, Inc. Inhibiteurs quinoline et quinazoline a substitution inhibant la quinone reductase 2

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2623878A (en) * 1948-02-09 1952-12-30 Ciba Pharm Prod Inc 2, 4-disubstituted amino quinazolines
WO2006034235A2 (fr) * 2004-09-20 2006-03-30 Serenex, Inc. Inhibiteurs quinoline et quinazoline a substitution inhibant la quinone reductase 2

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY Chemical Abstracts Service, Columbus, Ohio, US; 20 April 2006 (2006-04-20), XP002489798 *
MOHAMED, MOSAAD SAYED ET AL: "Synthesis and anti-inflammatory evaluation of some new quinazoline derivatives", INTERNATIONAL JOURNAL OF PHARMACOLOGY , 1(3), 261-266 CODEN: IJPNGZ; ISSN: 1811-7775, 2005, XP002489797 *

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DE102009004959A1 (de) * 2009-01-14 2010-07-15 Justus-Liebig-Universität Giessen Mittel zur Vorbeugung und Behandlung der Pityriasis versicolor
US8765712B2 (en) 2009-01-14 2014-07-01 Justus-Liebig-Universitaet Giessen Agent for preventing and treating pityriasis versicolor
WO2011121345A1 (fr) 2010-03-30 2011-10-06 Helperby Therapeutics Limited Nouveau traitement combiné et utilisation associée
JP2013523707A (ja) * 2010-03-30 2013-06-17 ヘルパービー セラピューティクス リミテッド 新規な組み合わせおよび使用
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RU2475244C1 (ru) * 2012-02-09 2013-02-20 Ринат Файзутдинович Билалов Средство для лечения актиномикоза и некробактериоза сельскохозяйственных животных "антиактиномициллин"
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US11028079B2 (en) 2015-11-25 2021-06-08 Convergene, Llc Small molecule BET bromodomain inhibitors and uses thereof
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