WO2011133104A1 - New ag(i) compounds with chelating ligands and their use in pharmaceutical compositions - Google Patents

New ag(i) compounds with chelating ligands and their use in pharmaceutical compositions Download PDF

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WO2011133104A1
WO2011133104A1 PCT/SE2011/050492 SE2011050492W WO2011133104A1 WO 2011133104 A1 WO2011133104 A1 WO 2011133104A1 SE 2011050492 W SE2011050492 W SE 2011050492W WO 2011133104 A1 WO2011133104 A1 WO 2011133104A1
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present
formula
compound
independently
optionally substituted
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PCT/SE2011/050492
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French (fr)
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Lars ÖHRSTRÖM
Vratislav Langer
Morsy Abu-Youssef
Gohar Yousry
Massoud Alshima A
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Oehrstroem Lars
Vratislav Langer
Morsy Abu-Youssef
Gohar Yousry
Massoud Alshima A
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Application filed by Oehrstroem Lars, Vratislav Langer, Morsy Abu-Youssef, Gohar Yousry, Massoud Alshima A filed Critical Oehrstroem Lars
Priority to EP11772330.4A priority Critical patent/EP2560977A4/en
Publication of WO2011133104A1 publication Critical patent/WO2011133104A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
    • C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic System without C-Metal linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • 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 new Ag(I) complexes with (E)-picolinaldehyde oxime, 4,5-diazafluorenone and their derivatives and related chelating pyridine based ligands, and their use in antimicrobial compositions.
  • Silver is recognised as a therapeutic agent used in the prevention of infection, and dilute solutions of silver nitrate and silver sulphadiazine have been among the most common preventive treatment for burns.
  • the interest in silver is largely attributed to its bactericidal efficacy at low concentration and its relatively limited toxicity to human cells.
  • Recently progress has led to an interest in dressings containing silver, which arises from advances in impregnation techniques and polymer technologies coupled with the increase in prevalence of bacterial resistance to antibiotics.
  • silver-based dressings on the market that aim to improve healing primarily by controlling the wound bioburden.
  • Kitamura, K. and Kondo, Y. JP 2000016906 describe a number of Ag(I) carboxylate complexes of nicotinic acid and related anionic ligands and their antibacterial properties.
  • Navarro describes l,10-phenanthroline-5,6-dione Ag(I) complexes and their effects on Leishmania parasites (Navarro, 2006) and McCann (McCann 2004) reported on Ag(l,10- phenanthroline-5,6-dione) 2 C10 4 and its effects on fungal and mammalian cells.
  • Yilmaz (Yilmaz 2008) reported antimicrobial activity studies on 5,5-Diethylbarbiturate complexes of silver with 2,2'-bipyridine and 3-(2-pyridyl)propanol and Zhu, (Zhu 2001) on the cytotoxicities of silver(I) complexes of 2,2'-bipyridines and 1,10-phenanthroline.
  • Onuegbu (Onuegbu 2007, Onuegbu 2008, Onuegbu 2009,) has reported a number of X-ray crystal structures of l,10-phenanthroline-5,6-dione Ag(I) complexes and Biju (Biju 2008) has reported on the structure of a 4,5-diazafluorenone silver(I) complex
  • Chen Chen (Chen, C-H, 2002) described the crystal structures of certain nicontinamide and nicotinic acid Ag(I) complexes with sulfonates counter anions
  • Balakrishna (Balakrishna, 2004) described the crystal structure of two Ag(I) isonicotinamide complexes. No biological data of any of these compounds were presented.
  • the present strategy to overcome the problems with solubility and photoinstability of Ag(I) compound is to investigate complexes having ligands that bind strongly to Ag(I), preventing premature release of "naked” Ag(I) and loss of efficiency as state above.
  • As the preferred coordination geometry of Ag (I) is linear two-coordinated and as it is known that ammonia dissolves precipitated AgCl(s) by forming a linear Ag(NH 3 ) 2 + complex, one should look at strongly binding nitrogen ligands enabling a linear coordination.
  • Pyridine is the most well known such example, but of course the toxicity of this ligand makes it unsuitable.
  • the Ag(I) complexes according to the invention are preferably complexes with neutral ligands, which are structurally and chemically different than the Ag(I) complexes described e.g. in (JP 2000016906), and are to have important advantages in terms of solubility, biological activity, bioavailability, and pharmacokinetics.
  • the present invention provides new Ag(I) complexes with (E)-picolinaldehyde oxime, 4,5- diazafluorenone and their derivatives and related chelating pyridine based ligands.
  • the present invention further provides methods for the use of Ag(I) complexes with these derivatives and related chelating pyridine ligands in the treatment, prevention and prophylaxis of infections.
  • the present invention provides a pharmaceutical preparation comprising, as an active ingredient, a compound according to Formula (I) or a pharmaceutical acceptable salt thereof together with a pharmaceutical acceptable carrier for the use in the treatment, prophylaxis and prevention of infections,
  • Rc and R D if present is or CH 2 CN
  • R 2 and R 3 independently are H, N0 2 , alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
  • X can be selected from N0 3 " , HS0 4 “ , S0 4 2” , HC0 3 “ , C0 3 2 , H 3 COO , CI “ , Br “ , ⁇ , BF 4 “ , H 3 P0 4 “ , H 2 P0 4 2” , and P0 4 3” .
  • the present invention provides a pharmaceutical preparation comprising, as an active ingredient, a compound comprising an ionic specie according to Formula (la) or a pharmaceutical acceptable salt thereof together with a pharmaceutical acceptable carrier for the use in the treatment, prophylaxis and prevention of infections,
  • Rc if present is or CH 2 CN
  • R 2 and R 3 independently are H, N0 2 , alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
  • the compound is selected from:
  • X can be selected from N0 3 " , HS0 4 “ , S0 4 2” , HC0 3 “ , C0 3 2” , H 3 COO “ , CI “ , Br “ , ⁇ , BF 4 “ , H 3 P0 4 “ , H 2 P0 4 2” , and P0 4 3” .
  • the compound is selected from
  • the present invention provides a pharmaceutical preparation comprising, as an active ingredient, a compound according to Formula (lb) or a pharmaceutical acceptable salt thereof together with a pharmaceutical acceptable carrier for the use in the treatment, prophylaxis and prevention of infections,
  • n 1 or 2
  • R c if present, independently are ,
  • R 2 and R3 independently are H, NO 2 , alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
  • the compound is selected from:
  • X can be selected from N0 3 " , HS0 4 “ , S0 4 2” , HC0 3 “ , C0 3 2 , H 3 COO , CI “ , Br “ , ⁇ , BF 4 “ , H 3 P0 4 “ , H 2 P0 4 2” , and P0 4 3” .
  • the present further provides a method for treatment, prophylaxis, or prevention of infection comprising administering to a mammal, including a human, in need thereof, a pharmaceutical effective amount of a compound according to Formula (I) or a
  • Rc and R D if present is or CH 2 CN
  • R 2 and R 3 independently are H, N0 2 , alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
  • X can be selected from N0 3 " , HS0 4 “ , S0 4 2” , HC0 3 “ , C0 3 2 , H 3 COO , CI “ , Br “ , ⁇ , BF 4 “ , H 3 P0 4 “ , H 2 P0 4 2” , and P0 4 3” .
  • the present invention provides a method for treatment, prophylaxis, or prevention of infection comprising administering to a mammal, including a human, in need thereof, a pharmaceutical effective amount of a compound comprising an ionic specie according to Formula (la) or a pharmaceutical acceptable salt thereof, Formula (la)
  • Rc if present is or CH 2 CN
  • R 2 and R 3 independently are H, N0 2 , alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
  • the compound is selected from:
  • X can be selected from N0 3 " , HS0 4 “ , S0 4 2” , HC0 3 “ , C0 3 2 , H 3 COO , CI “ , Br “ , ⁇ , BF 4 “ , H 3 P0 4 “ , H 2 P0 4 2” , and P0 4 3” .
  • the compound is selected from
  • the present invention provides a method for treatment, prophylaxis, or prevention of infection comprising administering to a mammal, including human, in need thereof, a pharmaceutical effective amount of a compound according to Formula (lb) or a pharmaceutical acceptable salt thereof, Formula (lb)
  • n 1 or 2 wherein Rc, if present, independently are ,
  • R 2 and R 3 independently are H, N0 2 , alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
  • the compound is selected from:
  • X can be selected from N0 3 " , HS0 4 “ , S0 4 2” , HC0 3 “ , C0 3 2 , H 3 COO , CI “ , Br “ , ⁇ , BF 4 “ , H 3 P0 4 “ , H 2 P0 4 2” , and P0 4 3” .
  • the present invention further provides use of a compound according to Formula (I) in the manufacture of a medicament for the use in the treatment, prophylaxis and prevention of infections,
  • R 2 and R 3 independently are H, N0 2 , alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
  • X can be selected from N0 3 " , HS0 4 “ , S0 4 2” , HC0 3 “ , C0 3 2 , H 3 COO , CI “ , Br “ , ⁇ , BF 4 “ , H 3 P0 4 “ , H 2 P0 4 2” , and P0 4 3” .
  • the present invention provides use of a compound comprising an ionic specie according to Formula (la) in the manufacture of a medicament for the use in the treatment prophylaxis and prevention of infections,
  • Rc if present is or CH 2 CN
  • R 2 and R 3 independently are H, N0 2 , alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen, [Ag(4,5-diazaflourenone)2]X,
  • X can be selected from N0 3 " , HS0 4 “ , S0 4 2” , HC0 3 “ , C0 3 2 , H 3 COO , CI “ , Br “ , ⁇ , BF 4 “ , H 3 P0 4 “ , H 2 P0 4 2” , and P0 4 3” .
  • the compound is selected from
  • the present invention provides use of a compound according to Formula (lb) in the manufacture of a medicament for the use in the treatment, prophylaxis and prevention of infections,
  • n 1 or 2
  • R c if present, independently are ,
  • R 2 and R 3 independently are H, NO 2 , alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
  • the compound is selected from:
  • X can be selected from N0 3 " , HS0 4 “ , S0 4 2” , HC0 3 “ , C0 3 2” , H 3 COO , CI “ , Br “ , ⁇ , BF 4 “ , H 3 P0 4 “ , H 2 P0 4 2” , and P0 4 3” .
  • the compound is
  • the present invention further provides novel compounds according to Formula (II),
  • Rc if present is or CH 2 CN
  • R 2 and R 3 independently are H, N0 2 , alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
  • X can be selected from N0 3 " , HS0 4 “ , S0 4 2” , HC0 3 “ , C0 3 2 , H 3 COO , CI “ , Br “ , ⁇ , BF 4 “ , H 3 P0 4 “ , H 2 P0 4 2” , and P0 4 3” .
  • the compounds of the present invention show strong antimicrobial activity and are useful in the treatment, prophylaxis and prevention of infections.
  • the infections to be treated or prevented are exemplified by, but not limited to, infections caused by bacteria, fungi, yeasts, or viruses, such as candidiasis, acne, herpes, and papilloma viral diseases.
  • the compounds of the present invention can be used in connection with treatment and prevention of pathological conditions of epithelial and dermal tissues, both intact and after lesion characterised by potential or acute infections sustained by pathogens., such as pathological conditions of the skin, of the mucosa and of the oral cavity, and external and internal genitals and ocular epithelia both intact and lesioned.
  • pathological conditions of epithelial and dermal tissues both intact and after lesion characterised by potential or acute infections sustained by pathogens.
  • pathological conditions of the skin, of the mucosa and of the oral cavity, and external and internal genitals and ocular epithelia both intact and lesioned can be used as therapeutic agents with disinfectant activity for the prevention, prophylaxis and treatment of the following pathological conditions:
  • Vascular tropic lesions ischemic ulcers, vascular ulcers, diabetic ulcers, stasis
  • the compounds of the present invention can have useful applications in paraphysiological conditions and for preventive purposes in dermoprotective, lenitive and cosmetic parapharmaceutical preparations.
  • compositions According to the pathology and the degree of seriousness the compounds of the present invention can be used in Ag(I) concentrations of 2 ⁇ 10 "6 to 1 - 10 "1 mol/dm 3 in topical formulations and in combination with appropriate diluents and helping substances compatible with the planned usage.
  • the compounds of the present invention can be present encapsulated in nanospheres or microspheres, be in the form of liquids, semi-solids, solids, containing excipients or diluents of pharmaceutical or cosmetic grade (for example solutions and aqueous, non-aqueous, hydroalcoholic suspensions, drops, gels, emulsions, creams, ovules, powder sprays, sprays with or without propellants, foams), be these new or known materials.
  • pharmaceutical or cosmetic grade for example solutions and aqueous, non-aqueous, hydroalcoholic suspensions, drops, gels, emulsions, creams, ovules, powder sprays, sprays with or without propellants, foams
  • the compounds of the present invention can be supported, as they are or in any form mentioned above, upon inter biomaterials such as films, membranes, patches and dressings, also with slow release, or can be incorporated into biomaterials or into materials dissolving slowly or rapidly in aqueous environment.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl.
  • alkylcarbonyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • alkylcarbonyl include, but are not limited to, acetyl, 1- oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 6 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5- hexenyl.
  • halogen as used herein, means -CI, -Br, -I or -F.
  • the present compounds can exist as pharmaceutical acceptable salts.
  • “pharmaceutical acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.
  • the salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid.
  • Representative salts include acetate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetic, trifluoroacetic, glutamate, para- toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like.
  • the compounds (1) [Ag(4,5-diazaflourenone)2]N03 and (2) [Ag((E)-picolinaldehyde oxime)](N0 3 )., were prepared from an aqueous silver nitrate solution and the
  • Crystal 2 357 vs, 370 m, 391 m, 405 w, 412 w, 430 w, 517 m, 550 w, 620 m, 668 m, 684 m,716 s, 758 vs, 824 m, 833 m, 915 s, 1029 m, 1081 m, 1099 s, 1 149 m, 1260 s, 1271 s, 1384 vs, 1402 vs sh, 1462 s, 1559 vs, 1588 s, 1596 s, 1717 vs, 1831h w,2342 s, 2360 s, 2426 m, 2983 s, 3033 s, 3062 m.
  • Example 2 Antimicrobial activity
  • MICs Minimum inhibitory concentrations
  • the test materials were dissolved in DMSO. The highest concentration used was 256 ⁇ g/ml.
  • the inoculum was 10 5 CFU/ml for bacteria and 10 4 CFU/ml for the yeast.
  • Bacteria were cultured in Mueller Hinton Broth (MHB) for 24 h at 35 °C and the yeast in Glucose Peptone Broth (GPB) for 48 h at 30°C.
  • MIC value was corresponding to the lowest concentration that inhibited the bacterial growth. S pyogenes.
  • MICs values were determine Kd. and the antimicrobial activity is inversely proportional to this value.
  • Concentrations us i e pneumonaed in this screening were: 1, 2, 4, 8, 16, 32, 64, 128 and 256 ( ⁇ / ⁇ ). 1 ⁇ g/ml corresponds to a 10 "4 % solution and an b l P iii mras.
  • compound (1) was also found to have antifungal activity, measured as the ability to inhibit growth of Candida albicans.

Abstract

The present invention relates to new Ag(I) complexes with (E)-picolinaldehyde oxime, 4,5-diazafluorenone and their derivatives and related chelating pyridine based ligands, and their use in antimicrobial compositions.

Description

NEW Ag(I) COMPOUNDS WITH CHELATING LIGANDS AND THEIR USE IN PHARMACEUTICAL COMPOSITIONS.
Field of the invention
The present invention relates to new Ag(I) complexes with (E)-picolinaldehyde oxime, 4,5-diazafluorenone and their derivatives and related chelating pyridine based ligands, and their use in antimicrobial compositions.
Background
The growing problem of antibiotic resistant bacterial strains makes it necessary for us to find new ways to fight bacteria and to prevent infections. In wound care medicine this is especially relevant for large burns, where bacterial infections may be lethal, and for chronic infections, for example those infections affecting diabetes patients.
Silver is recognised as a therapeutic agent used in the prevention of infection, and dilute solutions of silver nitrate and silver sulphadiazine have been among the most common preventive treatment for burns. The interest in silver is largely attributed to its bactericidal efficacy at low concentration and its relatively limited toxicity to human cells. Recently progress has led to an interest in dressings containing silver, which arises from advances in impregnation techniques and polymer technologies coupled with the increase in prevalence of bacterial resistance to antibiotics. There are now a number of silver-based dressings on the market that aim to improve healing primarily by controlling the wound bioburden. Both the search for new more efficient antibacterial agents, and the concern for silver resistant bacteria, (Silver 2003, Silver 2006) make the development of new silver compounds as antibacterial agents an important challenge. Attention then needs to be directed to some of the possible limitations of the use of silver compounds, especially the precipitation of AgCl(s) when the agent comes into contact with the body fluids, and the photoinstability of many Ag (I) compounds. The reaction with serum albumin might also diminish the effectiveness of the Ag(I) compound.
Kitamura, K. and Kondo, Y. (JP 2000016906) describe a number of Ag(I) carboxylate complexes of nicotinic acid and related anionic ligands and their antibacterial properties. Navarro describes l,10-phenanthroline-5,6-dione Ag(I) complexes and their effects on Leishmania parasites (Navarro, 2006) and McCann (McCann 2004) reported on Ag(l,10- phenanthroline-5,6-dione)2C104 and its effects on fungal and mammalian cells. Yilmaz (Yilmaz 2008) reported antimicrobial activity studies on 5,5-Diethylbarbiturate complexes of silver with 2,2'-bipyridine and 3-(2-pyridyl)propanol and Zhu, (Zhu 2001) on the cytotoxicities of silver(I) complexes of 2,2'-bipyridines and 1,10-phenanthroline.
Onuegbu (Onuegbu 2007, Onuegbu 2008, Onuegbu 2009,) has reported a number of X-ray crystal structures of l,10-phenanthroline-5,6-dione Ag(I) complexes and Biju (Biju 2008) has reported on the structure of a 4,5-diazafluorenone silver(I) complex, Chen (Chen, C-H, 2002) described the crystal structures of certain nicontinamide and nicotinic acid Ag(I) complexes with sulfonates counter anions, , Balakrishna (Balakrishna, 2004) described the crystal structure of two Ag(I) isonicotinamide complexes. No biological data of any of these compounds were presented.
Brief description of the invention
The present strategy to overcome the problems with solubility and photoinstability of Ag(I) compound is to investigate complexes having ligands that bind strongly to Ag(I), preventing premature release of "naked" Ag(I) and loss of efficiency as state above. As the preferred coordination geometry of Ag (I) is linear two-coordinated and as it is known that ammonia dissolves precipitated AgCl(s) by forming a linear Ag(NH3)2 + complex, one should look at strongly binding nitrogen ligands enabling a linear coordination. Pyridine is the most well known such example, but of course the toxicity of this ligand makes it unsuitable.
The related compounds nicotinic acid, nicotinamide (Vitamin B3) and their derivatives are known for their many beneficial uses and silver(I) compounds containing these ligands are the subject of a recent patent application (PCT/EP2008/056773). In the present patent application we extend this concept to chelating ligands, where we take advantage of the greater thermodynamic stability of coordination compounds with bidentate ligands.
The Ag(I) complexes according to the invention are preferably complexes with neutral ligands, which are structurally and chemically different than the Ag(I) complexes described e.g. in (JP 2000016906), and are to have important advantages in terms of solubility, biological activity, bioavailability, and pharmacokinetics.
The present invention provides new Ag(I) complexes with (E)-picolinaldehyde oxime, 4,5- diazafluorenone and their derivatives and related chelating pyridine based ligands.
The present invention further provides methods for the use of Ag(I) complexes with these derivatives and related chelating pyridine ligands in the treatment, prevention and prophylaxis of infections.
Detailed description of the invention
The present invention provides a pharmaceutical preparation comprising, as an active ingredient, a compound according to Formula (I) or a pharmaceutical acceptable salt thereof together with a pharmaceutical acceptable carrier for the use in the treatment, prophylaxis and prevention of infections,
AgpXq
Figure imgf000004_0001
Formula (I)
wherein dashed bonds are single, double, triple, delocalized or aromatic, a,b = 0 to 2, p=l to 4, and q=l to 4, RA is H, OH or a (CH)r(NH)s(N)t unit (r+s+t = 3 or 4, in any order) giving a five or six member aromatic ring attached at point Al (in which case RD is not present), optionally substituted with Rc, and RB if present is a (C=0)u or (C(OH)2)u unit (u=l or 2) attached to RA.
Rc and RD if present is
Figure imgf000004_0002
or CH2CN
where Ri is N or O,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
and where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion.
X can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2 , H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3".
In one preferred embodiment the present invention provides a pharmaceutical preparation comprising, as an active ingredient, a compound comprising an ionic specie according to Formula (la) or a pharmaceutical acceptable salt thereof together with a pharmaceutical acceptable carrier for the use in the treatment, prophylaxis and prevention of infections,
Formula (la)
Figure imgf000005_0001
Rc if present is or CH2CN
where Ri is N or O,
u=l or 2,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
Preferably the compound is selected from
[Ag(4,5-diazaflourenone)2]X,
[Ag( 1 , 10-phenanthroline-5 ,6-dione)2]X,
where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion.
X can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2", H3COO", CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3". Most preferably the compound is selected from
Compound 1 [Ag(4,5-diazaflourenone)2]N03,
Compound 2 [Ag(l , 10-phenanthroline-5,6-dione)2]NO3,
In another preferred embodiment the present invention provides a pharmaceutical preparation comprising, as an active ingredient, a compound according to Formula (lb) or a pharmaceutical acceptable salt thereof together with a pharmaceutical acceptable carrier for the use in the treatment, prophylaxis and prevention of infections,
Figure imgf000006_0001
Formula (lb)
n= 1 or 2, wherein Rc, if present, independently are
Figure imgf000006_0002
,
where Ri is N or O,
and, if present, R2 and R3 independently are H, NO2, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
Preferably the compound is selected from
[Ag((E)-picolinaldehyde oxime)]X,
where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion.
X can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2 , H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3".
Most preferably the compound is
compound (3) [Ag((E)-picolinaldehyde oxime)](N03).
The present further provides a method for treatment, prophylaxis, or prevention of infection comprising administering to a mammal, including a human, in need thereof, a pharmaceutical effective amount of a compound according to Formula (I) or a
pharmaceutical acceptable salt thereof,
AgpXq
Figure imgf000007_0001
Formula (I)
wherein dashed bonds are single, double, triple, delocalized or aromatic, a,b = 0 to 2, p=l to 4, and q=l to 4, RA is H, OH or a (CH)r(NH)s(N)t unit (r+s+t = 3 or 4, in any order) giving a five or six member aromatic ring attached at point Al (in which case RD is not present), optionally substituted with Rc, and RB if present is a (C=0)u or (C(OH)2)u unit (u=l or 2) attached to RA-
Rc and RD if present is
Figure imgf000007_0002
or CH2CN
where Ri is N or O,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
and where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion.
X can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2 , H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3".
In one preferred embodiment the present invention provides a method for treatment, prophylaxis, or prevention of infection comprising administering to a mammal, including a human, in need thereof, a pharmaceutical effective amount of a compound comprising an ionic specie according to Formula (la) or a pharmaceutical acceptable salt thereof, Formula (la)
Figure imgf000008_0001
Rc if present is or CH2CN
where Ri is N or O,
u=l or 2,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
Preferably the compound is selected from
[Ag(4,5-diazaflourenone)2]X,
[Ag(l,10-phenanthroline-5,6-dione)2]X, where X is a negative counter-ion bonded or non bonded to the Ag(I) ion.
X can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2 , H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3".
Most preferably the compound is selected from
Compound 1 [Ag(4,5-diazaflourenone)2]N03,
Compound 2 [Ag(l,10-phenanthroline-5,6-dione)2]NO3,
In another preferred embodiment the present invention provides a method for treatment, prophylaxis, or prevention of infection comprising administering to a mammal, including human, in need thereof, a pharmaceutical effective amount of a compound according to Formula (lb) or a pharmaceutical acceptable salt thereof, Formula (lb)
n = 1 or 2, wherein Rc, if present, independently are
Figure imgf000009_0002
,
where Ri is N or O,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
Preferably the compound is selected from
[Ag((E)-picolinaldehyde oxime)]X,
where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion.
X can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2 , H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3".
Most preferably the compound is
compound (3) [Ag((E)-picolinaldehyde oxime)](N03).
The present invention further provides use of a compound according to Formula (I) in the manufacture of a medicament for the use in the treatment, prophylaxis and prevention of infections,
AgpXq
Figure imgf000009_0003
Formula (I)
wherein dashed bonds are single, double, triple, delocalized or aromatic, a,b = 0 to 2, p=l to 4, and q=l to 4, RA is H, OH or a (CH)r(NH)s(N)t unit (r+s+t = 3 or 4, in any order) giving a five or six member aromatic ring attached at point Al (in which case RD is not present), optionally substituted with Rc, and RB if present is a (C=0)u or (C(OH)2)u unit (u=l or 2) attached to RA.
Rc and RD if present
Figure imgf000010_0001
where Ri is N or O,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
and where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion.
X can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2 , H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3".
In one preferred embodiment the present invention provides use of a compound comprising an ionic specie according to Formula (la) in the manufacture of a medicament for the use in the treatment prophylaxis and prevention of infections,
Formula (la)
Figure imgf000010_0002
Rc if present is or CH2CN
where Ri is N or O,
u=l or 2,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen, [Ag(4,5-diazaflourenone)2]X,
[Ag( 1 , 10-phenanthroline-5 ,6-dione)2]X,
where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion.
X can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2 , H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3".
Most preferably the compound is selected from
Compound 1 [Ag(4,5-diazaflourenone)2]N03,
Compound 2 [Ag(l , 10-phenanthroline-5,6-dione)2]NO3,
In one preferred embodiment the present invention provides use of a compound according to Formula (lb) in the manufacture of a medicament for the use in the treatment, prophylaxis and prevention of infections,
Figure imgf000011_0001
Formula (lb)
n= 1 or 2, wherein Rc, if present, independently are
Figure imgf000011_0002
,
where Ri is N or O,
and, if present, R2 and R3 independently are H, NO2, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
Preferably the compound is selected from
[Ag((E)-picolinaldehyde oxime)]X,
where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion.
X can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2", H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3". Most preferably the compound is
compound (3) [Ag((E)-picolinaldehyde oxime)](N03).
The present invention further provides novel compounds according to Formula (II),
Figure imgf000012_0001
Formula (II) wherein n=l to 4, m=0 to 3, p=l to 4, and q=l to 4,
Rc if present is
Figure imgf000012_0002
or CH2CN
where Ri is N or O,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
and where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion.,
X can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2 , H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3".
Pharmaceutical use As evidenced in Example 2, the compounds of the present invention show strong antimicrobial activity and are useful in the treatment, prophylaxis and prevention of infections.
According to the present invention the infections to be treated or prevented are exemplified by, but not limited to, infections caused by bacteria, fungi, yeasts, or viruses, such as candidiasis, acne, herpes, and papilloma viral diseases.
The compounds of the present invention can be used in connection with treatment and prevention of pathological conditions of epithelial and dermal tissues, both intact and after lesion characterised by potential or acute infections sustained by pathogens., such as pathological conditions of the skin, of the mucosa and of the oral cavity, and external and internal genitals and ocular epithelia both intact and lesioned. In particular the compounds of the present invention can be used as therapeutic agents with disinfectant activity for the prevention, prophylaxis and treatment of the following pathological conditions:
• Infections of the skin both intact and lesioned, of the oral mucosa, and external and internal genitals and ocular epithelia, brought about by bacteria, fungi, yeasts or viruses
• Superficial or deep wounds, internal or external, grazes and abrasions, lacerated or contused wounds, wounds with soft tissue loss, strongly exudating wounds, both chronic and acute, surgical wounds, traumatic wounds
• Superficial and deep burns
• Vascular tropic lesions ischemic ulcers, vascular ulcers, diabetic ulcers, stasis
ulcers, corneal ulcers
• Bedsores
• Athletes foot
• Abscesses
In order to achieve a broad spectrum antimicrobial effect a mixture of two or more of the compounds of the present invention can be used.
In addition the compounds of the present invention can have useful applications in paraphysiological conditions and for preventive purposes in dermoprotective, lenitive and cosmetic parapharmaceutical preparations.
Pharmaceutical formulations According to the pathology and the degree of seriousness the compounds of the present invention can be used in Ag(I) concentrations of 2· 10"6 to 1 - 10"1 mol/dm3 in topical formulations and in combination with appropriate diluents and helping substances compatible with the planned usage.
For all mentioned applications the compounds of the present invention can be present encapsulated in nanospheres or microspheres, be in the form of liquids, semi-solids, solids, containing excipients or diluents of pharmaceutical or cosmetic grade (for example solutions and aqueous, non-aqueous, hydroalcoholic suspensions, drops, gels, emulsions, creams, ovules, powder sprays, sprays with or without propellants, foams), be these new or known materials. Moreover, the compounds of the present invention can be supported, as they are or in any form mentioned above, upon inter biomaterials such as films, membranes, patches and dressings, also with slow release, or can be incorporated into biomaterials or into materials dissolving slowly or rapidly in aqueous environment.
Definitions
As used throughout this specification and the appended claims, the following terms have the following meanings:
The term "alkyl" as used herein, means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl. The term "alkylcarbonyl" as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1- oxopropyl, 2,2-dimethyl-l-oxopropyl, 1-oxobutyl, and 1-oxopentyl.
The term "alkenyl" as used herein, means a straight or branched chain hydrocarbon containing from 2 to 6 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5- hexenyl.
The term "carbonyl" as used herein, means a -C(=0)- group. The term "halogen," as used herein, means -CI, -Br, -I or -F.
The present compounds can exist as pharmaceutical acceptable salts. The term
"pharmaceutical acceptable salt," refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. Representative salts include acetate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetic, trifluoroacetic, glutamate, para- toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric, and the like.
EXAMPLES
Example 1. Synthesis of Ag(I) compounds
The compounds (1) [Ag(4,5-diazaflourenone)2]N03 and (2) [Ag((E)-picolinaldehyde oxime)](N03)., were prepared from an aqueous silver nitrate solution and the
corresponding free ligand dissolved in ethanol. The compounds were characterised by single crystal X-ray diffraction unambiguously proving structures in accordance with formulas (la, lb) and (2), respectively.
(1) [Ag(4,5-diazaflourenone)2lNQ3, To an aqueous solution (4 cm ) of AgN03 (0.170 g, 1 mmol), an ethanolic solution (4 cm ) of 4,5-diazafluoren-9-one ligand, (dafone), (0.182 g, 1 mmol) was added. The turbid yellow solution was then heated to boiling with continuous stirring until clear. Yellowish crystals, suitable for X-ray diffraction, of crystal form a [Ag(4,5-diazafluoren-9-one)2N03], were filtered off after slow cooling of the solution to room temperature. Yellow needles of crystal form b [Ag(4,5-diazafluoren-9- one)2]N03-H20 were collected one day later from the former filtrate with a yield % (85 %) with respect to the metal. FTIR, KBr (cm 1) (v, very; s, strong; m, medium; w, weak; br, broad; sh, shoulder): crystal 1 : 361 s, 370 m, 392 s, 412 w, 422 w, 429 w, 518 m, 551 w, 620 m, 633 m, 668 m, 685 m, 717 s, 759 vs, 806 m, 824 m, 834 s, 915 s, 1030 m, 1081 s, 1099 s, 1 150 m, 1258 s, 1308 s br, 1384 vs br, 1402 vs br, 1463 s, 1558 vs, 1588 vs, 1716 vs, 1832 m, 2359 s, 3035 vs, 3418 s br. Crystal 2: 357 vs, 370 m, 391 m, 405 w, 412 w, 430 w, 517 m, 550 w, 620 m, 668 m, 684 m,716 s, 758 vs, 824 m, 833 m, 915 s, 1029 m, 1081 m, 1099 s, 1 149 m, 1260 s, 1271 s, 1384 vs, 1402 vs sh, 1462 s, 1559 vs, 1588 s, 1596 s, 1717 vs, 1831h w,2342 s, 2360 s, 2426 m, 2983 s, 3033 s, 3062 m.
(2) [Ag((E)-picolinaldehyde oxime)l(NQ3).To a solution of AgN03 (0.17 g, 1.0 mmol) in 10 ml deionized water an ethanolic solution of 2-amino-3-methylpyridine (0.108 g, 1.0 mmol) was added drop by drop with stirring for about 20 min. the clear solution is placed in refrigerator at 4°C for couple of days to give colorless plated crystals suitable for X-ray measurements. The crystals were filtered off, washed with small amount of ethanol and dried in air. Yield: 0.015 g, 76% with respect to the ligand. Analytical data (%): Calc: C, 37.29; H, 4.14; N, 18.13; Ag, 27.93. Found: C, 37.33; H, 4.33; N, 18.06; Ag, 28.16. 1H NMR (DMSO- 6): 2.057 (s, 3H, CH3 at m-position of Py ), 6.27 (s, 2H, NH2 at o-positin of Py), 6.54 (t, 1H , m-H of Py), 7.37 (d, 1H , p-H of Py), (d, 1H , o-H of Py),
Example 2. Antimicrobial activity Their antimicrobial activity was established according to the recommendations of NCCLS, (National Committee for Clinical Laboratory Standards 1999) by the use of a broth microdilution method. Minimum inhibitory concentrations (MICs) for the tested compound were conducted using different pathogens. The test materials were dissolved in DMSO. The highest concentration used was 256 μg/ml. The inoculum was 105 CFU/ml for bacteria and 104 CFU/ml for the yeast. Bacteria were cultured in Mueller Hinton Broth (MHB) for 24 h at 35 °C and the yeast in Glucose Peptone Broth (GPB) for 48 h at 30°C.
S aureus.
MIC value was corresponding to the lowest concentration that inhibited the bacterial growth. S pyogenes.
For the following seven samples, MICs values were determine Kd. and the antimicrobial activity is inversely proportional to this value. Concentrations usie pneumonaed in this screening were: 1, 2, 4, 8, 16, 32, 64, 128 and 256 (μ§/ηύ). 1 μg/ml corresponds to a 10"4 % solution and an bl Piii mras.
Ag(I) concentration of about 2- 10"6 mol/dm3.
Sit enerca.
Table 1. Minimum inhibitory concentration (MIC) for compound 1 against some diabetic
foot bacteria compared with some antibiotics of choice
Test Organisms / MIC ( g/ml) Ps.
i aerugnosa
Antibiotic group Antibiotic
Amoxicillin >256 >256 >256 >256 >256 2
Ampicillin/ sulbactam 4 >256 >256 >256 >256 4
Penicillin
Ultracillin (cyclocillin) 3 >256 >256 >256 >256 3
Imipenem 3 >256 >256 >256 >256 6
Cephradine 2 >256 >256 >256 >256 4
Cefuroxime 6 >256 >256 >256 >256 5
Cephalosporines Cefotaxime t >256 >256 200 >256 ! t
Ceftazidime 3 128 4 : 72 96 8
Cefoperazone 16 >256 200 >256 128 2
Amikacin 6 128 12 200 >256 12
Aminoglycoside
Streptomycin 3 72 >256 128 200 3
Figure imgf000018_0001
Table 2. Minimum inhibitory concentration (MIC) for compound 2 against some diabetic foot bacteria compared with some antibiotics of choice
Figure imgf000019_0001
In a preliminary experiment compound (1) was also found to have antifungal activity, measured as the ability to inhibit growth of Candida albicans.
The above cited micro-organisms are provided as examples only and this list is not intended to define the scope and limits of the use of compounds of the present invention. These results demonstrate that the tested compounds have strong antimicrobial activity, and furthermore demonstrate a specificity against certain strains, but also show that an appropriate mixture of the tested compounds could be used in blind chemotherapy against resistant bacteria.
Reference list
Balakrishna, R. Bhogala, P.K. et al (2004) "1 :2 and 1 : 1 Ag(I)-isonicotinamide compounds : Five-fold interpenetrated CdS04 network and the first example of (pyridine)N-Ag- O(amide) bonds" Crystal Growth & Design 4:215-218
A. R. Biju and M. V. Rajasekharan (2008), Polyhedron, 27, 2065-2068
Bowmaker, G.A., Effendy, et al. (2005). "Syntheses, structures and vibrational
spectroscopy of some 1 : 2 and 1 : 3 adducts of silver(I) oxyanion salts with pyridine and piperidine bases containing non-coordinating 2(,6)-substituents" Inorganica Chimica Acta 358, 4342-4370.
Chen, C-H, Cai, J. et al. (2002). "Assembly via H-bonds and Ag-Ag attractions of one- dimensional silver(I) complexes of nicotinamide and nicotinic acid with sulfonate counter- anions" Polyhedron 21 : 689-695
McCann, M., Coyle, B., Mckay, S., McCormack, P., Kavanagh, K., Devereux, M., McKee, V., Kinsella, P., O'Connor, R. & Clynes, M. (2004). Synthesis and X-ray crystal structure of Ag(phendio)(2) C104 (phendio=l,10-phenanthroline-5,6-dione) and its effects on fungal and mammalian cells. Biometals, 17, 635-645.
National Committee for Clinical Laboratory Standards (1999). "Performance standards for antimicrobial susceptibility testing. NCCLS approved standard M100-S9" Wayne, PA
Navarro, M., Cisneros-Fajardo, E. J. & Marchan, E. 2006. New silver polypyridyl complexes: Synthesis, characterization and biological activity on Leishmania mexicana. Arzneimittel- Forschung-Drug Research, 56, 600-604.
Onuegbu, J., Butcher, R. J., Hosten, C, Udeochu, U. C. & Bakare, O. 2009. Bis(l,10- phenanthroline-5,6-dione -kappa N-2,N ')silver(I) tetrafluoridoborate. Acta Crystallographica Section E-Structure Reports Online, 65, Ml 119-U954.
Onuegbu, J., Butcher, R. J., Hosten, C, Udeochu, U. C. & Bakare, O. 2007. Bis(l,10- phenanthroline-5,6-dione -kappa N-2,N ')silver(I) perchlorate. Acta Crystallographica Section E- Structure Reports Online, 63, M2309-U576.
Onuegbu, J., Butcher, R. J., Hosten, C, Udeochu, U. C. & Bakare, O. 2008. Acetato(l,10- phenanthroline-5,6-dione)silver(I) trihydrate. Acta Crystallographica Section E-Structure Reports Online, 64, M403-U1185.
Silver, S. (2003). "Bacterial silver resistance: molecular biology and uses and misuses of silver compounds." Ferns Microbiology Reviews 27(2-3): 341-353.
Silver, S., L.T. Phung et al. (2006) "Silver as biocide in burns and wound dressing and bacterial resistance to silver compounds" Ind. Microbiol. Biotechnol. 2006, 33, 627-634.
Yilmaz, F., Yilmaz, V. T., Karakaya, H. & Bueyuekguengoer, O. 2008. 5,5-
Diethylbarbiturate complexes of silver with 2,2'-bipyridine and 3-(2-pyridyl)propanol: syntheses, crystal structures, spectroscopic, thermal and antimicrobial activity studies. Z. Naturforsch., B Chem. Sci, 63, 134-138.
Zhu, H.-L., Chen, Q., Peng, W.-L., Qi, S.-J., Xu, A.-L. & Chen, X.-M. 2001. Syntheses, crystal structures and cytotoxicities of silver(I) complexes of 2,2'-bipyridines and 1,10- phenanthroline. Chin. J. Chem., 19, 263-267.

Claims

1. A pharmaceutical preparation comprising, as an active ingredient, a compound according to Formula (I) or a pharmaceutical acceptable salt thereof together with a pharmaceutical acceptable carrier for the use in the treatment, prophylaxis and prevention infections,
AgpXq
Figure imgf000023_0001
Formula (I)
wherein dashed bonds are single, double, triple, delocalized or aromatic, a,b = 0 to 2, p=l to 4, and q=l to 4, RA is H, OH or a (CH)r(NH)s(N)t unit (r+s+t = 3 or 4, in any order) giving a five or six member aromatic ring attached at point Al (in which case RD is not present), optionally substituted with Rc, and RB if present is a (C=0)u or (C(OH)2)u unit (u=l or 2) attached to RA.
Rc and RD if present is
Figure imgf000023_0002
or CH2CN
where Ri is N or O,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
and where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion, which can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2 , H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3".
2. A pharmaceutical preparation according to claim 1 where the active ingredient is a compound comprising an ionic specie according to Formula (la), Formula (la)
Figure imgf000024_0001
Rc if present is or CH2CN
where Ri is N or O,
u=l or 2,
and, if present, R2 and R? independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
3. A pharmaceutical preparation according to claim 1 the active ingredient is a compound accordin to Formula (lb),
Figure imgf000024_0002
Formula (lb)
n= 1 or 2, wherein Rc, if present, independently are
Figure imgf000024_0003
,
where Ri is N or O,
and, if present, R2 and R? independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
4. A method for treatment, prophylaxis, or prevention of infection comprising
administering to a mammal, including a human, in need thereof, a pharmaceutical effective amount of a compound according to Formula (I) or a pharmaceutical acceptable salt thereof,
AgpXq
Figure imgf000025_0001
Formula (I)
wherein dashed bonds are single, double, triple, delocalized or aromatic, a,b = 0 to 2, p=l to 4, and q=l to 4, RA is H, OH or a (CH)r(NH)s(N)t unit (r+s+t = 3 or 4, in any order) giving a five or six member aromatic ring attached at point Al (in which case RD is not present), optionally substituted with Rc, and RB if present is a (C=0)u or (C(OH)2)u unit (u=l or 2) attached to RA.
Rc and RD if present is
Figure imgf000025_0002
or CH2CN
where Ri is N or O,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
and where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion, which can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2 , H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3".
5. A method according to claim 4 where the compound is a compound comprising an ionic specie according to Formula (la), Formula (la)
Figure imgf000026_0001
Rc if present is or CH2CN
where Ri is N or O,
u=l or 2,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
6. A method according to claim 4 where the compound is a compound according to Formula lb) ,
Figure imgf000026_0002
Formula (lb)
n= 1 or 2, wherein Rc, if present, independently are
Figure imgf000026_0003
,
where Ri is N or O,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
7. Use of a compound according to Formula (I) in the manufacture of a medicament for the use in the treatment, prophylaxis and prevention of infections, AgpXq
Figure imgf000027_0001
Formula (I)
wherein dashed bonds are single, double, triple, delocalized or aromatic, a,b = 0 to 2, p=l to 4, and q=l to 4, RA is H, OH or a (CH)r(NH)s(N)t unit (r+s+t = 3 or 4, in any order) giving a five or six member aromatic ring attached at point Al (in which case RD is not present), optionally substituted with Rc, and RB if present is a (C=0)u or (C(OH)2)u unit (u=l or 2) attached to RA.
Rc and RD if present is
Figure imgf000027_0002
or CH2CN
where Ri is N or O,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
and where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion, which can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2 , H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3".
8. Use according the claim 7 where the compounds is a compound comprising an ionic specie according to Formula (la),
Figure imgf000027_0003
Formula (la) Rc if present is
Figure imgf000028_0001
or CH2CN
where Ri is N or O,
u=l or 2,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
9. Use according the claim 7 where the compound is a compound according to
Formula (lb),
Figure imgf000028_0002
Formula (lb)
n= 1 or 2, wherein Rc, if present, independently are
Figure imgf000028_0003
,
where Ri is N or O,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
10. A compound according to Formula I
AgpXq
Figure imgf000028_0004
Formula (I)
wherein dashed bonds are single, double, triple, delocalized or aromatic, a,b = 0 to 2, p=l to 4, and q=l to 4, RA is H, OH or a (CH)r(NH)s(N)t unit (r+s+t = 3 or 4, in any order) giving a five or six member aromatic ring attached at point Al (in which case RD is not present), optionally substituted with Rc, and RB if present is a (C=0)u or (C(OH)2)u unit (u=l or 2) attached to RA.
Rc if present is
Figure imgf000029_0001
or CH2CN
where Ri is N or O,
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen,
and where X is a negative counter-ion bonded or non-bonded to the Ag(I) ion, which can be selected from N03 ", HS04 ", S04 2", HC03 ", C03 2 , H3COO , CI", Br", Γ, BF4 ", H3P04 ", H2P04 2", and P04 3";
with the proviso that said compound is not [Ag(4,5-diazafluoren-9-one) ]N03 · H20, or bis(l,10-phenanthroline-5,6-dione-K Ν,Ν') silver(I) tetrafluoridoborate.
11. A compound according to claim 10, comprising an ionic specie according to Formula la
Formula (la)
Figure imgf000029_0002
Rc if present is or CH CN
where Ri is N or O;
u=l or 2;
and, if present, R2 and R3 independently are H, N02, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
12. A compound according to claim 1 1 , wherein said compound is selected from the group consisting of:
Compound 1 [Ag(4,5-diazaflourenone)2]N03, and
Compound 2 [Ag(l , 10-phenanthroline-5,6-dione)2]NO3.
13. A compound according to Formula (lib)
Figure imgf000030_0001
Formula (lb)
n= 1 or 2, wherein Rc, if present, independently are
Figure imgf000030_0002
,
where Ri is N or O,
and, if present, R2 and R3 independently are H, NO2, alkyl, alkenyl, alkylcarbonyl, each optionally substituted with halogen.
14. A compound according to claim 13 which is
Compound (3) [Ag((E)-picolinaldehyde oxime)](N03).
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005023760A2 (en) * 2003-09-05 2005-03-17 The University Of Akron Metal complexes of n-heterocyclic carbenes as radiopharmaceuticals and antibiotics
WO2008145759A1 (en) * 2007-05-31 2008-12-04 Cse Incubation Ab New silver(i) compounds and their use in pharmaceutical compositions for the treatment, prophylaxis and prevention of infections

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005023760A2 (en) * 2003-09-05 2005-03-17 The University Of Akron Metal complexes of n-heterocyclic carbenes as radiopharmaceuticals and antibiotics
WO2008145759A1 (en) * 2007-05-31 2008-12-04 Cse Incubation Ab New silver(i) compounds and their use in pharmaceutical compositions for the treatment, prophylaxis and prevention of infections

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BIJU, A.R. ET AL.: "Unusual coordination geometris of silver(I) 4,5- diazafluoren-9-one compexes", POLYHEDRON, vol. 27, 2008, pages 2065 - 2068, XP022706132 *
MASSOUD, ALSHIMA'A A ET AL.: "Bis 4,5-diazafluoren-9-one silver(I) nitrate: Synthesis, X-ray structures, solution chemistry, hydrogel loading, DNA coupling and anti-bacterial screening", NEW JOURNAL OF CHEMISTRY, vol. 35, no. 3, 2011, pages 640 - 648, XP008167151 *
ONUEGBU, JONATHAN ET AL.: "Bis(1,10-phenanthroline-5,6-dione- kappa2 N,N')silver(I) tetrafluoridoborate", ACTA CRYSTALLOGRAPHICA, SECTION E: STRUCTURE REPORTS, vol. E65, no. 9, 2009, pages M1119 - M1120, XP055099988 *
See also references of EP2560977A4 *

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