WO2012153130A1 - Sels de 4-éthyl-1-(2-phényléthyl)-8-phénoxy-2,3-dihydro-1h-pyrrolo [3,2-c] quinoline et leur utilisation pour traiter des infections - Google Patents

Sels de 4-éthyl-1-(2-phényléthyl)-8-phénoxy-2,3-dihydro-1h-pyrrolo [3,2-c] quinoline et leur utilisation pour traiter des infections Download PDF

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Publication number
WO2012153130A1
WO2012153130A1 PCT/GB2012/051013 GB2012051013W WO2012153130A1 WO 2012153130 A1 WO2012153130 A1 WO 2012153130A1 GB 2012051013 W GB2012051013 W GB 2012051013W WO 2012153130 A1 WO2012153130 A1 WO 2012153130A1
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Prior art keywords
acid
phenoxy
dihydro
pyrrolo
phenylethyl
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PCT/GB2012/051013
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English (en)
Inventor
Yanmin Hu
Anthony Rm Coates
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Helperby Therapeutics Limited
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Publication of WO2012153130A1 publication Critical patent/WO2012153130A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to certain acid addition salts of 4-methyl-1-(2-phenylethyl)-8- phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline, including the methane sulphonic acid addition salt, to a process for the preparation of such compounds, and to the use of such compounds for the treatment of microbial infections.
  • APIs Pharmaceutically active ingredients with one or more basic centres may be prepared and formulated as acid addition salts.
  • the preparation of such salt forms may improve the physical and/or pharmaceutical properties of the basic API.
  • an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid, sulphuric acid and tartaric acid addition salts thereof, i.e.: 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline hydrobromide;
  • the acid addition salt of 4-methyl-1-(2- phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline is selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid and sulphuric acid addition salts thereof. These salts have been shown to possess particularly good thermal stability and purity profiles.
  • the acid addition salt of 4-methyl-1- (2-phenylethyl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline is selected from the group consisting of the methane sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts thereof. These salts have been shown to possess improved aqueous solubility compared to the corresponding free base and the hydrochloride acid addition salt.
  • the acid addition salt of 4-methyl-1-(2- phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline is selected from the group consisting of the methane sulphonic acid, succinic acid (preferably hemi-succinate) and tartaric acid (preferably hemi-tartrate) addition salts thereof.
  • the acid addition salt is the methane sulfonic acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H- pyrrolo[3,2-c]-quinoline.
  • a pharmaceutical composition comprising an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3- dihydro-1H-pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi- succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts, and a pharmaceutically acceptable carrier.
  • Such a composition may be used for treatment of a microbial infection, in particular for killing multiplying and/or clinically latent microorganisms associated with such an infection.
  • an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts, for the treatment of a microbial infection, in particular for killing multiplying and/or clinically latent microorganisms associated with such an infection.
  • a method of treating a microbial infection, in particular killing multiplying and/or clinically latent microorganisms associated with such an infection which comprises administering to a mammal, including man, an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H- pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts.
  • an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H- pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic
  • the acid addition salts of the present invention may be prepared by conventional methods in the art, for example as described in Berge, S. M. et al., J. Pharm. Sci., 1977, 66(1), 1 - 19; Stahl, P.H. and Wermuth, C.G., Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2011 , 2 nd Edition, Wiley-VCH, and references cited therein.
  • a process for preparing an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H- pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts, which process comprises: dissolving or suspending 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H- pyrrolo[3,2-c]-quinoline free base in a suitable solvent; treating the resulting solution or suspension with an acid selected from the group consisting of hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid, sulphuric acid or
  • an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H- pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts, which process comprises:
  • Suitable reaction solvents include esters, alcohols and mixtures thereof.
  • the solvent is de-gassed before use.
  • suitable esters include methyl acetate, ethyl acetate, n-propyl acetate, /so-propyl acetate, n-butyl acetate, /so-butyl acetate, fert-butyl acetate and sec-butyl acetate, and mixtures thereof.
  • suitable alcohols include methanol, ethanol, n-propanol, /so-propanol, n-butanol, /so-butanol, ferf-butanol and sec- butanol, and mixtures thereof.
  • the solvent is a mixture of ethyl acetate and methanol. More preferably, the ratio of ethyl acetate to methanol is from 5:1 to 10:1 , most preferably 10:1.
  • Suitable bases include alkali and alkaline earth metal carbonates, alkali metal hydroxides and alkali metal bicarbonates.
  • suitable alkali and alkaline earth metal carbonates include magnesium carbonate, calcium carbonate, lithium carbonate, sodium carbonate and potassium carbonate.
  • suitable alkali metal hydroxides include magnesium hydroxide and calcium hydroxide.
  • suitable alkali and alkaline earth metal bicarbonates include magnesium bicarbonate, calcium bicarbonate and sodium bicarbonate.
  • the ratio of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]- quinoline (free base) to acid employed is from 1 :1 to 1 :5 equivalents, such as 1 :1, 1 :1.5, 1 :2, 1 :3, 1 :4 or 1 :5 equivalents.
  • the ratio is 1 :1.
  • the acid addition salts of the present invention may be isolated from solution using conventional means, for example by filtration, followed by washing and/or drying.
  • the acid addition salts of the present invention possess antimicrobial activity and may in particular be used to kill multiplying and/or clinically latent microorganisms associated with microbial infections.
  • an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]- quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts, to kill clinically latent microorganisms associated with a microbial infection.
  • "kill” means a loss of viability as assessed by a lack of metabolic activity.
  • clinical latent microorganism means a microorganism that is metabolically active but has a growth rate that is below the threshold of infectious disease expression.
  • the threshold of infectious disease expression refers to the growth rate threshold below which symptoms of infectious disease in a host are absent.
  • the metabolic activity of clinically 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.
  • clinically latent microorganisms when compared to 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.
  • Clinically latent microorganisms typically possess a number of identifiable characteristics. For example, they may be viable but non-culturable; i.e. they cannot typically be detected by standard culture techniques, but are detectable and quantifiable by techniques such as broth dilution counting, microscopy, or molecular techniques such as polymerase chain reaction.
  • clinically latent microorganisms are phenotypically tolerant, and as such are sensitive (in log phase) to the biostatic effects of conventional antimicrobial agents (i.e.
  • microorganisms for which the minimum inhibitory concentration (MIC) of a conventional antimicrobial is substantially unchanged); but possess drastically decreased susceptibility to drug-induced killing e.g. microorganisms for which, with any given conventional antimicrobial agent, the ratio of minimum microbiocidal concentration (e.g. minimum bactericidal concentration, MBC) to MIC is 10 or more).
  • microorganisms means fungi and bacteria. References herein to “microbiaf, “antimicrobiaf and “ antimicrobial ⁇ ' shall be interpreted accordingly.
  • microbiaf means fungal or bacterial
  • microbial infection means any fungal or bacterial infection.
  • bacteria includes, but is not limited to, references to 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, saprophytics, Staph, auricularis, 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.
  • Streptococci e.g.beta-haemolytic, pyogenic streptococci (such as Strept. agalactiae, Strept. cam ' s, Strept. dysgalactiae dysgalactiae, Strept. dysgalactiae 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 constellatus pharyngidis and Strept. intermedius
  • oral 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-haemolytic, such as Strept. salivarius and Strept. vestibularis
  • mutans teeth-surface streptococci, such as Strept criceti, Strept. mutans
  • Strept. ratti and Strept. sobrinus groups, Strept. acidominimus, Strept. bovis, Strept faecalis,
  • Strept equinus Strept. pneumoniae and Strept. suis, or 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 weaveri;
  • 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), Shigella (e.g. Shigella dysenteriae, Shigella flexneri, Shigella boydii and Shigella sonnei), Klebsiella (e.g. Klebs.
  • Escherichia coli Enterobacter aerogenes, Enterobacter agglomerans and Enterobacter cloacae
  • Citrobacter such as Citrob. freundii and Citrob. divernis
  • Hafnia
  • pneumoniae Klebs. oxytoca, Klebs. ornitholytica, Klebs. planticola, Klebs. ozaenae, Klebs. terrigena, Klebs. granulomatis (Calymmatobacterium granulomatis) and Klebs. rhinoscleromatis), Proteus (e.g. Pr. mirabilis, Pr. rettgeri and Pr. vulgaris), Providencia (e.g. Providencia alcalifaciens, Providencia rettgeri and Providencia stuartii), Serratia (e.g.
  • Serratia marcescens and Serratia liquifaciens e.g. Yersinia enterocolitica, Yersinia pestis and Yersinia pseudotuberculosis
  • Yersinia e.g. Yersinia enterocolitica, Yersinia pestis and Yersinia pseudotuberculosis
  • Enterococci e.g. Enterococcus avium, Enterococcus casseliflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus flavescens, Enterococcus gallinarum, Enterococcus hirae, Enterococcus malodoratus, Enterococcus mundtii, Enterococcus pseudoavium, Enterococcus raffinosus and Enterococcus solitarius);
  • Enterococci e.g. Enterococcus avium, Enterococcus casseliflavus, Enterococcus cecorum, Enterococcus dispar, Enterococcus durans, Enterococcus faecalis, Enterococcus faecium, Enterococcus flavescens, Enter
  • Helicobacter e.g. Helicobacter pylori, Helicobacter cinaedi and Helicobacter fennelliae
  • Acinetobacter e.g. A. baumanii, A. calcoaceticus, A. haemolyticus, 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. pseudalcaligenes Ps. putida and Ps. stutzeri
  • Peptococcus e.g. Peptococcus niger
  • Clostridium e.g. C. perfringens, C. difficile, C. botulinum, C. tetani, C. absonum, C. argentinense, C. baratii, C. bifermentans, C. beijerinckii, C. butyricum, C. cadaveris, C. carnis, C. celatum, C. clostridioforme, C. cochlearium, C. cocleatum, C. fallax, C. ghonii, C. glycolicum, C. haemolyticum, C. hastiforme, C. histolyticu , C. indolis, C. innocuum, C. irregulare, C.
  • Clostridium e.g. C. perfringens, C. difficile, C. botulinum, C. tetani, C. absonum, C. argentinense, C. baratii, C. bifermentans, C.
  • leptum leptum, C. limosum, C. malenominatum, C. novyi, C. oroticum, C. paraputrificum, C. piliforme, C. putrefasciens, C. ramosu , C. septicum, C. sordelii, C. sphenoides, C. sporogenes, C. subterminale, C. symbiosum and C. tertium);
  • Mycoplasma e.g. M. pneumoniae, M. hominis, M. genitalium and M. urealyticum
  • Mycobacteria e.g. Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium fortuitum, Mycobacterium marinum, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium leprae, Mycobacterium smegmitis, Mycobacterium africanum, Mycobacterium alvei, Mycobacterium asiaticum, Mycobacterium aurum, Mycobacterium bohemicum, Mycobacterium bovis, Mycobacterium branded, Mycobacterium brumae, Mycobacterium celatum, Mycobacterium chubense, Mycobacterium confluentis, Mycobacterium conspicuum, Mycobacterium cookii, Mycobacterium flavescens, Mycobacterium gadium, Mycobacterium gastri, Mycobacterium genavense, Mycobacterium gordonae, Mycobacterium goodii
  • Haemophilus influenzae Haemophilus ducreyi, Haemophilus aegyptius, Haemophilus parainfluenzae, Haemophilus haemolyticus and Haemophilus parahaemolyticus);
  • Actinobacillus e.g. Actinobacillus actinomycetemcomitans, Actinobacillus equuli, Actinobacillus hominis, Actinobacillus lignieresii, Actinobacillus suis and Actinobacillus ureae
  • Actinobacillus e.g. Actinobacillus actinomycetemcomitans, Actinobacillus equuli, Actinobacillus hominis, Actinobacillus lignieresii, Actinobacillus suis and Actinobacillus ureae
  • Actinomyces e.g. Actinomyces israelii
  • 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 lari and Campylobacter fetus
  • Vibrio e.g. Vibrio cholerae and Vibrio parahaemolyticus, Vibrio alginolyticus, Vibrio carchariae, Vibrio fluvialis. Vibrio furnissii, Vibrio hollisae, Vibrio metschnikovii, Vibrio mimicus and Vibrio vulnificus);
  • Corynebacteriaceae e.g. Corynebacterium diphtheriae, Corynebacterium jeikeum and Corynebacterium urealyticum
  • Corynebacteriaceae e.g. Corynebacterium diphtheriae, Corynebacterium jeikeum and Corynebacterium urealyticum
  • Spirochaetaceae such as Borrelia (e.g. Borrelia recurrentis, Borrelia burgdorferi, Borrelia afzelii, Borrelia andersonii, Borrelia bissettii, 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, Borrelia persica, Borrelia turicatae and Borrelia venezuelensis) and Treponema (Treponema pallidum ssp.
  • Borrelia e.g. Borrelia recurrentis, Bor
  • 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
  • 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 hinzii, Bordetella holmseii, Bordetella parapertussis, Bordetella pertussis and Bordetella trematum
  • Nocardiaceae such as Nocardia (e.g. Nocardia asteroides and Nocardia brasiliensis);
  • Rickettsia e.g. Ricksettsii or Coxiella burnetii
  • Legionella e.g. Legionalla anisa, Legionalla birminghamensis, Legionalla bozemanii
  • Gardnerella e.g. Gardneralla vaginalis and Gardneralla mobiluncus
  • Flavobacteriaceae such as Capnocytophaga (e.g. Capnocytophaga canimorsus,
  • Capnocytophaga cynodegmi Capnocytophaga gingivalis, Capnocytophaga granulosa,
  • Bartonella Bartonella bacilliformis, Bartonella clarridgeiae, 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 wellii;
  • 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 thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus and Bacteroides vulgatus); Prevotella (e.g. Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides
  • Porphyromonas e.g. Porphyromonas asaccharolytica, Porphyromonas cangingivalis, Porphyromonas canoris, Porphyromonas cansulci, Porphyromonas catoniae, Porphyromonas circumdentaria, Porphyromonas crevioricanis, Porphyromonas endodontalis, Porphyromonas gingivalis, Porphyromonas gingivicanis, Porphyromonas levli and Porphyromonas macacae);
  • Porphyromonas e.g. Porphyromonas asaccharolytica, Porphyromonas cangingivalis, Porphyromonas canoris, Porphyromonas cansulci, Porphyromonas catoniae, Porphyromonas circumdentaria, Porphyromonas crevioricanis, Porphyromonas endodontalis, Porphy
  • Fusobacterium e.g. F. gonadiaformans, F. mortiferum, F. naviforme, F. necrogenes, F. necrophorum necrophorum, F. necrophorum fundiliforme, F. nucleatum nucleatum, F. nucleatum fusiforme, F. nucleatum polymorphum, F. nucleatum vincentii, F. periodonticum, F. russii, F. ulcerans and F. varium);
  • Chlamydia e.g. Chlamydia trachomatis
  • Cryptosporidium e.g. C. parvum, C. hominis, C. canis, C. felis, C. meleagridis and C. muris
  • Chlamydophila e.g. Chlamydophila abortus (Chlamydia psittaci), Chlamydophila pneumoniae ⁇ Chlamydia pneumoniae) and Chlamydophila psittaci ⁇ Chlamydia psittaci
  • Chlamydophila e.g. Chlamydophila abortus (Chlamydia psittaci), Chlamydophila pneumoniae ⁇ Chlamydia pneumoniae
  • Chlamydophila psittaci Chlamydophila psittaci ⁇ Chlamydia psittaci
  • 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
  • Ureaplasma e.g. Ureaplasma parvum and Ureaplasma urealyticum.
  • fungf and derivatives thereof, such as “fungal infection” includes, but is not limited to, references to organisms (or infections due to organisms) of the following classes and specific types:
  • Absidia e.g. Absidia corymbifera
  • Ajeilomyces e.g. Ajellomyces capsulatus and Ajellomyces dermatitidis
  • Arthroderma e.g. Arthroderma benhamiae, Arthroderma fulvum, Arthroderma gypseum,
  • Aspergillus e.g. Aspergillus flavus, Aspergillus fumigatus and Aspergillus niger
  • Aspergillus flavus e.g. Aspergillus flavus, Aspergillus fumigatus and Aspergillus niger
  • Blastomyces e.g. Blastomyces dermatitidis
  • Candida e.g. Candida albicans, Candida glabrata, Candida guilliermondii, Candida krusei,
  • Candida parapsilosis, Candida tropicalis and Candida pelliculosa Candida parapsilosis, Candida tropicalis and Candida pelliculosa
  • Cladophialophora e.g. Cladophialophora carrionii
  • Coccidioides e.g. Coccidioides immitis and Coccidioides posadasii
  • Cryptococcus e.g. Cryptococcus neoformans
  • Cunninghamella e.g. Cunninghamella sp.
  • Epidermophyton e.g. Epidermophyton floccosurn
  • Exophiala e.g. Exophiaia 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 capsulatum
  • Hortaea e.g. Hortaea wasneckii
  • Issatschenkia e.g. Issatschenkia orientalis
  • Madurella e.g. Madurella grisae
  • Malassezia e.g. Malassezia furfur, Malassezia giobosa, Malassezia obtusa, Malassezia pachydermatis, Malassezia restricta, Malassezia slooffiae and Malassezia sympodialis
  • Malassezia e.g. Malassezia furfur, Malassezia giobosa, Malassezia obtusa, Malassezia pachydermatis, Malassezia restricta, Malassezia slooffiae and Malassezia sympodialis
  • Microsporum e.g. Microsporum canis, Microsporum fulvum and Microsporum gypseum
  • Mucor e.g. Mucor circinelloides
  • Nectria e.g. Nectria haematococca
  • Paecilomyces e.g. Paecilomyces variotii
  • Paracoccidioides e.g. Paracoccidioides brasiliensis
  • Penicillium e.g. Penicillium marneffei
  • P/cft/a e.g. P/ch/a anomala and P/cft/a guilliermondii
  • Pneumocystis e.g. Pneumocystis jiroveci (Pneumocystis carinii)
  • Pneumocystis jiroveci Pneumocystis carinii
  • Pseudallescheria e.g. Pseudallescheria boydii
  • Rhizopus e.g. Rhizopus oryzae
  • Rhodotorula e.g. Rhodotorula rubra
  • Scedosporium e.g. Scedosporium apiospermum
  • Schizophyllum e.g. Schizophyllum commune
  • Sporothrix e.g. Sporothrix schenckii
  • Trichophyton e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton verrucosum and Trichophyton violaceum
  • Trichosporon e.g. Trichosporon asahii, Trichosporon cutaneum, Trichosporon inkin and Trichosporon mucoides.
  • Particular bacteria that may be treated using the acid addition salts of the present invention include:
  • Staphylococci such as 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.
  • the bacterium is Staph. Aureus; either MSSA or MRSA.
  • an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts thereof, for nasal decolonisation of MSSA or MRSA, preferably MRSA.
  • Particular fungi that may be treated with the acid addition salts of the present invention include 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, asthma, bacilliary dysentry, bacterial conjunctivitis, bacterial keratitis, bacterial vaginosis, 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 panbronchiolitis, diph
  • the acid addition salts of the present invention may be administered alone or in combination with another antimicrobial compound.
  • a combination comprising an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3- dihydro-1 H-pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi- succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts thereof, and another antimicrobial agent.
  • the invention provides the use of an acid addition salt of 4-methyl-1- (2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi- tartrate) addition salts thereof, in combination with another antimicrobial agent for the treatment of a microbial infection, preferably for killing clinically latent microorganisms associated with a microbial infection.
  • an acid addition salt of 4-methyl-1- (2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably
  • the term "in combination with” covers both separate and sequential administration of an antimicrobial agent and an anesthetic agent.
  • the agents are administered sequentially, either the antimicrobial agent or the anesthetic agent may be administered first.
  • the agents may be administered either in the same or a different pharmaceutical composition.
  • Adjunctive therapy i.e. where one agent is used as a primary treatment and the other agent is used to assist that primary treatment, is also an embodiment of the present invention.
  • a product comprising an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1H-pyrrolo[3,2-c]- quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts thereof and another antimicrobial agent as a combined preparation for simultaneous, separate or sequential use in the treatment of a microbial infection.
  • Suitable antimicrobial compounds for use in combination with the acid addition salts of the present invention include one or more compounds selected from the following:
  • penicillinase-resistant penicillins e.g. flucloxacillin
  • antipseudomonal penicillins e.g. carboxypenicillins such as ticarcillin or ureidopenicillins such as piperacillin
  • carboxypenicillins such as ticarcillin 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, cefprozil, 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, cef
  • ⁇ -lactams such as monobactams (e.g. aztreonam), carbapenems (e.g. imipenem (optionally in combination with a renal enzyme inhibitor such as cilastatin), meropenem, ertapenem, doripenem (S-4661) and RO4908463 (CS-023)), penems (e.g. faropenem) and 1-oxa-P-lactams (e.g. moxalactam).
  • monobactams e.g. aztreonam
  • carbapenems e.g. imipenem (optionally in combination with a renal enzyme inhibitor such as cilastatin), meropenem, ertapenem, doripenem (S-4661) and RO4908463 (CS-023)
  • penems e.g. faropenem
  • 1-oxa-P-lactams e.g. moxalactam
  • 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, 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, 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. oligomycin A, oligomycin B and oligomycin C), pimaricin, rifampicin, rifamycin, rosamicin, tylosin, virginiamycin and fosfomycin.
  • amphotericins B e.g. amphotericin B
  • bafilomycins e.g. bafilomycin A1
  • brefeldins e.g.
  • Ketolides such as telithromycin and cethromycin (ABT-773).
  • Lincosamines such as lincomycin.
  • Phenicols 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).
  • Glycopeptides such as vancomycin, teicoplanin, bleomycin, phleomycin, ristomycin, telavancin, dalbavancin and oritavancin.
  • Oxazolidinones such as linezolid and AZD2563.
  • Streptogramins such as quinupristin and dalfopristin, or a combination thereof.
  • Peptides such as polymyxins (e.g. colistin and polymyxin B), lysostaphin, 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), myxothiazol, nisin, paracelsin, valinomycin and viomycin.
  • polymyxins e.g. colistin and polymyxin B
  • actinomycins e.g. actinomycin C and actinomycin D
  • actinonin 7- aminoactinomycin D
  • antimycin A antipain
  • bacitracin cyclosporin A
  • gramicidins e.g. gramicidin A and gramicidin C
  • 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), succinylsulfathiazole, sulfadimethoxine, sulfaguanidine, sulfamethazine, sulfamonomethoxine, sulfanilamide and sulfasalazine.
  • sulfamethoxazole sulfadiazine
  • sulfaquinoxaline e.g. in salt form with an alkali metal such as sodium
  • succinylsulfathiazole sulfadimethoxine
  • sulfaguanidine sulfamethazine
  • sulfamonomethoxine s
  • 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 isoniazid, 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.
  • Nitrofurans such as nitrofurantoin.
  • Quinolones such as nalidixic acid, norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, gatifloxacin, gemifloxacin, garenoxacin, DX-619, WCK 771 (the arginine salt of S-(-)-nadifloxacin), 8-quinolinol, cinoxacin, enrofloxacin, flumequine, lomefloxacin, oxolinic acid and pipemidic acid.
  • 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 /V-methyl-1- deoxynojirimycin.
  • Indole derivatives such as staurosporine.
  • Diaminopyrimidines such as iclaprim (AR-100).
  • Taxoids such as paclitaxel.
  • Statins such as mevastatin.
  • Polyethers such as lasalocid A, lonomycin A, monensin, nigericin and salinomycin.
  • 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.
  • Peptide deformylase inhibitors such as LBM415 (NVP PDF-713) and BB 83698 (38)
  • 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 , L(+)-lactic acid, cytochalasins (e.g. cytochalasin B and cytochalasin D), emetine and ionomycin.
  • Antiseptic agents such as chlorhexidine, phenol derivatives (e.g. thymol and triclosan), quarternary ammonium compounds (e.g. benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, cetrimonium bromide, cetrimonium chloride and cetrimonium stearate), octenidine dihydrochloride, and terpenes (e.g. terpinen-4-ol).
  • chlorhexidine phenol derivatives (e.g. thymol and triclosan)
  • quarternary ammonium compounds e.g. benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, cetrimonium bromide, cetrimonium chloride and cetrimonium stearate
  • octenidine dihydrochloride e.g. terpinen-4-ol
  • an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts thereof, as a sterilising agent or as a preservative.
  • the acid addition salts of the present invention may be employed in methods of sterilisation or preservation, such as: (i) a method of sterilising an object, the method comprising applying to said an acid addition salt of object 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H- pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi- succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts thereof; or
  • a method of preserving an inorganic or, preferably, an organic material comprising contacting, combining or mixing said material with an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts thereof.
  • 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 compound of the invention when used as a sterilising agent, may be used either alone or in combination with a conventional sterilising agent.
  • the term "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, chlorhe
  • the acid addition salts of the present invention may be administered as the raw material but the active ingredients are preferably provided in the form of pharmaceutical compositions.
  • the active ingredients may be used either as separate formulations or as a single combined formulation. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation.
  • Formulations of the invention include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) or in a form suitable for administration by inhalation or insufflation administration. The most suitable route of administration may depend upon the condition and disorder of the patient.
  • compositions of the invention are preferably formulated for oral or topical administration, most preferably for topical administration.
  • a topical composition comprising an acid addition salt of 4- methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi- tartrate) addition salts thereof, for intra-nasal application.
  • formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy e.g. as described in "Remington: The Science and Practice of Pharmacy", Lippincott Williams and Wilkins, 21 st Edition, (2005). Suitable methods include the step of bringing into association to active ingredients with a carrier which constitutes one or more excipients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation. It will be appreciated that when the two active ingredients are administered independently, each may be administered by a different means.
  • the active ingredients When formulated with excipients, the active ingredients may be present in a concentration from 0.1 to 99.5% (such as from 0.5 to 95%) by weight of the total mixture; conveniently from 30 to 95% for tablets and capsules and 0.01 to 50% (such as from 3 to 50%) for liquid preparations.
  • a suitable concentration for the acid addition salts of the present invention is from 0.1 to 5% (w/v) of the total mixture.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration), each containing a predetermined amount of active ingredient; as powder or granules; as a solution or suspension in an aqueous liquid or non-aqueous liquid; or as an oil-in-water liquid emulsion or water-in-oil liquid emulsion.
  • the active ingredients may also be presented a bolus, electuary or paste.
  • a tablet may be made by compression or moulding, optionally with one or more excipients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with other conventional excipients such as binding agents (e.g. syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, polyvinylpyrrolidone and/or hydroxymethyl cellulose), fillers (e.g. lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate and/or sorbitol), lubricants (e.g. magnesium stearate, stearic acid, talc, polyethylene glycol and/or silica), disintegrants (e.g.
  • binding agents e.g. syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, polyvinylpyrrolidone and/or hydroxymethyl cellulose
  • fillers e.g. lactos
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered active ingredient with an inert liquid diluent.
  • the tablets may be optionally coated or scored and may be formulated so as to provide controlled release (e.g. delayed, sustained, or pulsed release, or a combination of immediate release and controlled release) of the active ingredients.
  • the active ingredients may be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs.
  • Formulations containing the active ingredients may also be presented as a dry product for constitution with water or another suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel and/or hydrogenated edible fats), emulsifying agents (e.g. lecithin, sorbitan mono-oleate and/or acacia), non-aqueous vehicles (e.g. edible oils, such as almond oil, fractionated coconut oil, oily esters, propylene glycol and/or ethyl alcohol), and preservatives (e.g. methyl or propyl p-hydroxybenzoates and/or sorbic acid).
  • suspending agents e.g. sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium ste
  • 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 ingredients are dissolved or dispersed in a dermatological vehicle known in the art (e.g. aqueous or nonaqueous 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)ethanol, propylene glycol, propylene glycol monolaurate, glycofurol 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).
  • a solubilising agent or solvent e.g.
  • Topical formulations may also be formulated as a transdermal patch.
  • a ⁇ -cyclodextrin such as hydroxypropyl ⁇ -cyclodextrin, or an alcohol or polyol such as ethanol, propylene glycol or glycerol
  • a thickening agent e.g. hydroxymethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose or carbomer
  • a gelling agent e.g. a polyoxyethylene- polyoxypropylene copolymer
  • a preservative e.g. benzyl alcohol, benzalkonium chloride, chlorhexidine, chlorbutol, a benzoate, potassium sorbate or EDTA or salt thereof
  • pH buffering agent(s) e.g. a mixture of dihydrogen phosphate and hydrogen phosphate salts, or a mixture of citric acid and a hydrogen phosphate salt.
  • Topical formulations may also be formulated as a transdermal patch.
  • 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, e.g. in WO9510999, US6974585, WO2006048747, as well as in documents cited in any of these references.
  • Topical pharmaceutical compositions 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. 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 above, (e.g. any of the Staphylococci, Streptococci, Mycobacteria or Pseudomonas organisms mentioned hereinbefore, such as S. aureus (e.g. Methicillin resistant S. aureus (MRSA))).
  • infections of the skin or membranes 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 tracheosto
  • Particular bacterial conditions that may be treated by topical pharmaceutical compositions of the present invention also include the skin- and membrane-related conditions disclosed hereinbefore, as well as: acne vulgaris; rosacea (including erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea and ocular rosacea); erysipelas; erythrasma; ecthyma; ecthyma gangrenosum; impetigo; paronychia; cellulitis; folliculitis (including hot tub folliculitis); furunculosis; carbunculosis; staphylococcal scalded skin syndrome; surgical scarlet fever; streptococcal peri-anal disease; streptococcal toxic shock syndr ome; pitted keratolysis; trichomycosis axillaris; pyoderma; external canal ear infections; green nail syndrome
  • kansasii M. malmoense, M. szulgai, M. simiae, M. gordonae, M. haemophilum, M. avium, M. intracellulare, M. chelonae (including M. abscessus) or M. fortuitum infections, swimming pool (or fish tank) granuloma, lymphadenitis and Buruli ulcer (Bairnsdale ulcer, Searles' ulcer, Kakerifu ulcer or Toro ulcer)); as well as infected eczma, burns, abrasions and skin wounds.
  • Particular fungal conditions that may be treated by topical pharmaceutical compositions of the present invention also include include the skin- and membrane-related conditions disclosed hereinbefore, as well as: candidiasis; 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.
  • compositions for use according to the invention may be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients.
  • the pack may, e.g. comprise metal or plastic foil, such as a blister pack.
  • compositions are intended for administration as two separate compositions these may be presented in the form of a twin pack.
  • compositions may also be prescribed to the patient in "patient packs" containing the whole course of treatment in a single package, usually a blister pack.
  • Patient packs have an advantage over traditional prescriptions, where a pharmacist divides a patients' supply of a pharmaceutical from a bulk supply, in that the patient always has access to the package insert contained in the patient pack, normally missing in traditional prescriptions. The inclusion of the package insert has been shown to improve patient compliance with the physician's instructions.
  • a patient pack comprising an acid addition salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H- pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi-tartrate) addition salts thereof, and an information insert containing directions on the use of the combination of the invention.
  • a double pack comprising in association for separate administration, an antimicrobial agent, preferably having biological activity against clinically latent microorganisms, and an acid addition salt of 4-methyl-1-(2- phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline selected from the group consisting of the hydrobromic acid, methane sulphonic acid, p-toluene sulphonic acid, succinic acid (preferably hemi-succinate), sulphuric acid and tartaric acid (preferably hemi- tartrate) addition salts thereof.
  • doses employed for adult human treatment will typically be in the range of 0.02 to 5000 mg per day, preferably 1 to 1500 mg per day.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, e.g. as two, three, four or more sub- does per day.
  • X-Ray Powder Diffraction patterns were collected on a PANalytical diffractometer using Cu Ka radiation (45kV, 40mA), . ⁇ - ⁇ goniometer, focusing mirror, divergence slit (1/2"), soller slits at both incident and divergent beam (4mm) and a PIXcel detector.
  • the software used for data collection was X'Pert Data Collector, version 2.2f and the data was presented using X'Pert Data Viewer, version 1.2d.
  • DSC data was collected on a PerkinElmer Pyris 4000 DSC.
  • the instrument was verified for energy and temperature calibration using certified indium. A predefined amount in milligrams (mg) of the sample was placed in a pin holed aluminium pan and typically heated at 20° C.min "1 from 30°C to 350° C, or varied as experimentation dictated.
  • the instrument control and data analysis was Pyris Software v9.0.1.0174.
  • Sorption isotherms were obtained using a Hiden Isochema moisture sorption analyser (model IGAsorp), controlled by IGAsorp Systems Software V6.50.48.
  • the sample was maintained at a constant temperature (25 °C) by the instrument controls.
  • the humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow of 250 ml. min "1 .
  • the instrument was verified for relative humidity content by measuring three calibrated Rotronic salt solutions (10 - 50 - 88%).
  • the weight change of the sample was monitored as a function of humidity by a microbalance (accuracy +/- 0.005 mg).
  • a defined amount of sample was placed in a tarred mesh stainless steel basket under ambient conditions.
  • Example 1 A full experimental cycle consisted of two scans (sorption and desorption) at a constant temperature (25 °C) and 10 % RH intervals over a 10 - 90 % range (90 minutes for each humidity level). This type of experiment should demonstrate the ability of samples studied to absorb moisture (or not) over a set of well determined humidity ranges.
  • the following non-limiting examples illustrate the present invention.
  • Potassium carbonate (1638 g) was dissolved in water (2453 mL) at room temperature. Ethyl acetate (4095 mL) and methanol (410 mL) were added and the solvents were degassed. 4- methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline hydrochloride (450 g) was added and the reaction mixture stirred until two clear phases were achieved (-20 minutes). The phases were separated and the organic phase was dried over magnesium sulfate filtered and placed under nitrogen.
  • 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline p-toluene sulphonate was prepared by mixing 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1H- pyrrolo[3,2-c]-quinoline (0.6 g) with p-toluene sulphonic acid (1.75 ml / 1 M) in 5 volumes of ethyl acetate using an analogous method to that described in Example 4. Melting point by DSC: 176 °C (onset).
  • 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline sulphate was prepared by mixing 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]- quinoline (0.64 g) with sulphuric acid (1.79 ml / 1 M) in 5 volumes of iso-propyl alcohol using an analogous method to that described in Example 4. Melting point by DSC: 285 °C (main peak); 150 °C (small endotherm).
  • 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline hemi-tartrate was prepared by mixing 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]- quinoline (100 mg) with tartaric acid (0.6 eq. / 1 M) in 5 volumes of ethyl acetate using an analogous method to that described in Example 4. Melting point by DSC: 181 °C (main peak); 108 °C (small endotherm).
  • hydrobromide, methane sulphonate, sulphate and p-toluene sulphonate salts of 4- methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline were analysed by GVS according to the general protocol described herein to monitor their ability to adsorb moisture.
  • 4-methyl-1 -(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H-pyrrolo[3,2-c]-quinoline hydrochloride was employed as a reference material. None of the salts tested were found to be hygroscopic.
  • MSSA methicilin sensitive Staphylococcus aureus
  • Bacteria were grown in 10 ml of nutrient broth (No. 2, (Oxoid)) overnight at 37°C with continuous shaking at 120 rpm. The overnight cultures were diluted 1000 X with iso-sensitest broth. The cultures were incubated at 37°C with shaking for 1-2 hours to reach log CFU 6. Viability of the bacteria was estimated by colony forming unit (CFU) counts. From serial 10- fold dilutions of the experimental cultures, 100 ⁇ samples were added to triplicate plates of nutrient agar plates (Oxoid) or blood agar plates (Oxoid). CFUs were counted after incubation of the plates at 37°C for 24 hours.
  • CFU colony forming unit
  • Bacterial cultures 10 ⁇ of overnight cultures was added to 10 ml of fresh iso-sensitest broth to make the inoculation to 10 6 CFU/ml. 290 ⁇ of the cell suspension was added to each well of the 96 well plate, which was incubated at 37°C for 24 hours. 300 ⁇ of iso-sensitest broth without bacterial cells were added to wells of the plate as a no bacterial control.
  • the optical density of the bacterial cells was read at 405 nm using a plate reader (Bio TEK).
  • the MIC concentration was determined as the lowest concentration of drug which inhibits the bacterial growth.
  • the methane sulphonate salt of 4-methyl-1-(2-phenylethyl)-8-phenoxy-2,3-dihydro-1 H- pyrrolo[3,2-c]-quinoline was found to have the same MIC (8 Mg/ml) as the free base and the hydrochloride salt.

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Abstract

L'invention concerne certains sels d'addition d'acide de 4-méthyl-1-(2-phényléthyI)-8- phénoxy-2,3-dihydro-1H-pyrrolo[3,2-c]-quinoline comprenant les sels associés d'addition d'acide sulfonique de méthane, un procédé de préparation de ces composés et leur utilisation pour traiter les infections microbiennes.
PCT/GB2012/051013 2011-05-10 2012-05-09 Sels de 4-éthyl-1-(2-phényléthyl)-8-phénoxy-2,3-dihydro-1h-pyrrolo [3,2-c] quinoline et leur utilisation pour traiter des infections WO2012153130A1 (fr)

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WO1995010999A1 (fr) 1993-10-22 1995-04-27 Smithkline Beecham Corporation Nouvelle composition
US6974585B2 (en) 2001-08-01 2005-12-13 Medlogic Global Limited Durable multi-component antibiotic formulation for topical use
WO2006048747A1 (fr) 2004-11-08 2006-05-11 Glenmark Pharmaceuticals Limited Compositions pharmaceutiques topiques contenant un compose anti-acne et un compose antibiotique
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