GB2314773A - Quinones for use in the inhibition of bacteria - Google Patents

Quinones for use in the inhibition of bacteria Download PDF

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GB2314773A
GB2314773A GB9713078A GB9713078A GB2314773A GB 2314773 A GB2314773 A GB 2314773A GB 9713078 A GB9713078 A GB 9713078A GB 9713078 A GB9713078 A GB 9713078A GB 2314773 A GB2314773 A GB 2314773A
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compound
bacteria
hereinbefore defined
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Stephen J Hodges
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University of Sheffield
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/12Ketones
    • A61K31/122Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67Vitamins

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  • Oral & Maxillofacial Surgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract

The use of quinones, preferably naphthoquinones, such as Vitamin K derivatives for the inhibition of bacteria in pharmaceuticals is described. In particular, the use of 2-methyl, 3-(2'methyl)-hexanoic acid-1,4-naphthoquinone (KCAT) is described and a toothpaste containing this compound is illustrated. In addition, processes for the preparation of certain naphthoquinones per se are described.

Description

OUINONE BACTERLAL INHIBITORS The present invention relates to a certain class of quinone compounds found to be active in inhibiting bacterial growth specifically to a class of naphthoquinones as inhibitors of, particularly but not exclusively, vitamin K dependant bacteria, to agents comprising these compounds, to their use as bacterial inhibitors, to compositions and growth media comprising these compounds, and to novel compounds of the class, synthetic or metabolic intermediates or precursors, metabolites or active fragments thereof and their preparation.
The quinone compounds to which this invention relates comprise certain analogues of vitamin K. Vitamin K was first discovered and reported in 1935 by H. Dam in Denmark who noted its anti-haemorrhagic properties and its occurrence as a nutritional factor. Vitamin K was thereafter isolated from plant and organism sources and two naturally occurring forms were determined, vitamin Kl (phylloquinone) and K2 (menaquinone) which compounds are characterised by a 2-methyl-1,4-naphthoquinone unit further substituted at the 3 position by a Cl6+ side chain comprising repeating isoprene units. A third synthetic vitamin K is now available known as K3 (menadione) comprising the further unsubstituted 2-methyl-1,4naphthoquinone. Other synthetic analogues of the K vitamins are now available. In view of the non toxic nature of the naturally occurring vitamins, synthetic naphthoquinone and benzoquinone compounds and metabolic derivatives of the parent vitamin K compounds are of great interest.
It is known that vitamin K is synthesised by intestinal bacteria in rats and other mammals. Hence vitamin K deficiency cannot readily be produced in healthy mammals although at least one antagonist is known which is believed to block the action of vitamin K and is used in clinical medicine to prevent clotting in the blood vessels, the compound dicumarol (3,31-methylenebis (4hydroxy-1,2-benzopyrone)) as described in Biochemistry, Albert Earl Lehninger, Worth Publishers Inc. New York, second edition page 358.
A further clinical use of vitamin K is reported in "A clinical re-evaluation of the effectiveness of vitamin Kl in oral surgery", D. H. Morgan et al, American Journal of Orthopedics, July 1963, 202-205, in which administration of vitamin K at the outset of oral surgery helped prevent much post-operative bleeding, oedema and oecchymosis with resultant avoidance of pain and rapid healing of surgical wounds.
More recent work has investigated the relationship of vitamin K with bacteria in mammals and the effects thereof. Two significant observations have resulted, firstly that certain bacteria occurring in mammals have an absolute requirement for vitamin K and when deprived of vitamin K their growth is curtailed or inhibited, and secondly that certain bacteria in mammals, as stated above synthesize vitamin K or analogues thereof.
The first of these observations has been reported in "Menaquinone is an obligatory component of the chain catalysing succinate respiration in Bacillus subtilis", E. Lemma et al, Arch. Microbiol (1990) 155:62-67 in which is disclosed the oxidation of succinate catalysed by the succinate enzyme dehydrogenase and vitamin K menaquinone and its analogues.
The second of these observations is expounded in "Vitamin K compounds in bacteria that are obligate anaerobes", R. J. Gibbons et al, Science, 146,1307 1309 in which the isolation of naphthoquinones, compounds of the vitamin K group, from various bacteria is reported. It was concluded that these compounds are present in a variety of obligately anaerobic chemoorganotrophic bacteria. The growth response was noted in addition to the vitamin K content in microbiologic assays of vitamin K in bacteria.
In "Relationships between periodontal health, salivary steroids, and Bacteroides intermedius in males, pregnant and non-pregnant women", R. Jonsson et al, J. Dent Res, August 1988, 67 (8), 1062-1068, and "Effects of estradiol and progesterone on Bacteroides melaninogenicus and Bacteroides gingivalis", K. S. Kornman et al, Infection and Immunity, January 1982, 35 (1), 256-263 the requirement of the black pigmented bacteria, Bacteroides (B. gingivalis now known as Porphyromonas gingivalis) for vitamin K for their growth is reported. The substitution of vitamin K by hormones as an essential growth factor of the black pigmented bacteria was investigated.
Previous work by the present author has investigated the occurrence of vitamin Kl in gingival crevicular fluid (GCF) of patients suffering the disease periodontitis, which is linked to the vitamin K obligate black pigmented bacteria as pathogens. This work indicated that vitamin K may, in part, have a role to play as a marker of status of periodontal diseases, again subject to a significant amount of further work to understand the role of vitamin K in the metabolism of black pigmented bacteria. A further investigation into the growth promoting effects on gingivitis and black pigmented bacteria of low and high cigarette tobacco tars attributed the growth promotion to phylloquinone which is a significant component of these tars.
In "Mechanisms of Alveolar bone loss in periodontal disease", R. M Hopps et al, Periodontal Disease: Pathogens and Host Immune Responses, Ed. S.
Hamada et al, Quintessence Publishing Co. Ltd., Toyko, 1991, 307-320, is described one of the more serious features of advanced periodontal disease, the loss of alveolar bone which is the bone in the jaws which supports the teeth. The skeleton, of which the alveolar bone forms no exception, is remodelled throughout life and in the absence of disease by resorption of bone followed by associated deposition of new bone. Net loss of bone can occur when an increased rate of bone resorption is not accompanied by an increased rate of bone deposition. In the case of periodontal disease, alveolar bone loss leads to the loss of teeth and in the absence of the functional demand placed by the teeth on the alveolar bone, continued loss of the alveolar bone takes place leaving only basal bone which is functionally and metabolically different. This bone loss is irreversible and leads inevitably to the requirement for dentures with their associated inconvenience, embarrassment and discomfort and moreover the risk of further serious infection of the gums. Factors which are thought to be associated with periodontal bone loss can be classed as bacterial factors and host-derived factors. By host derived factors are understood inflammatory mediators which are released by the host cells as a result of the interaction of a range of different bacterial factors with host cells, in particular prostaglandins released by inflamed gingival tissue and crevicular fluid, cytokines also released by the gingiva and shown to stimulate bone resorption. As bacterial factors are understood agents which may contribute directly to bone loss in periodontal disease, since these may stimulate bone resorption directly, in particular the black pigmented bacteria or Bacteroides as hereinbefore mentioned. The authors acknowledge that it is unclear to what extent the bone resorbing activities of bacterial factors and host-derived factors contribute to the onset of periodontal disease.
It has been appreciated that periodontal destruction rarely occurs in the absence of gingivitis inflammation. The relation of the two conditions remains under study. Gingivitis is nevertheless more commonly occurring than periodontal disease and is evidenced by gingival tissue inflammation leading to high levels of bleeding, and the occurrence of lesions. The presence of black pigmented anaerobes in gingival fluid and gingival tissues has indicated a connection of the bacteria with gingivitis either as a consequence or as a cause.
In "Analgesic and Anti-Inflammatory Properties of Vitamins", A. Hanck et al, 189-206 is disclosed the anti-inflammatory properties of vitamins of the B complex, vitamin K and some of its metabolites and vitamin C. Two analogues of Vitamin K, comprising a shortened side chain ending with a carboxyl group and the ethyl ester derivative thereof reportedly demonstrated marked pharmacological effects but no anti-hemorrhagic properties. The 2, 3-epoxide metabolite of vitamin Kl was less active as an anti-inflammatory agent than was vitamin K1 and had no analgesic effect. The observations were derived from intramuscular or intravenous injection of the vitamin K1 (analogues) in rats with an induced irritation of the paw. Nevertheless no conclusion was drawn on the mechanism of action of the vitamins.
Most recently the foregoing observations have been most systematically investigated in respect of a vitamin K2 homologue, menatetrenone on bone resorption stimulated by certain cytokines, prostaglandins, hormones and vitamins and of the effect of a group of naphthoquinone vitamins (Vitamin K) on the production of inflammatory mediators such as cytokines.
In "Menatetrenone Inhibits Bone Resorption Partly Through Inhibition of PGE2 Synthesis In Vitro", Hara et al, Journal of Bone and Mineral Research, 8 (5) 1993, 535-542 the resorption effect was confirmed and the mechanism of inhibition of prostaglandin or cytokine stimulated resorption was proposed.
In "Interleukin 6 (IL-6) Production by Lipopolysaccharide-Stimulated Human Fibroblasts is Potently Inhibited by Naphthoquinine (Vitamin K) Compounds," K. Reddi et al, Cytokine, 2 (3) April 1995, 287-290 a synthetic product of vitamin K catabolism, 2-methyl, 3-(2'methyl)-hexanoic acid-1,4naphthoquinone (KCAT) was found to inhibit cytokine inflammatory mediator IL-6 production to a greater extent than the synthetic analogues menadione (K3) and 2, 3-dimethoxy-1, 4-naphthoquinone (DMK) in turn to a greater extent than the naturally occurring vitamins K2 and Kl with an associated indication of their anti-inflammatory effects. A mechanism was not concluded in explanation of these observations, although it was suggested that activity may be related to the redox capacity of the naphthoquinones. In view of the non toxicity of vitamin K it was considered that further investigation would be merited. The results were observed in cultures of gingival fibroblasts grown from human gingivi obtained during routine minor oral surgery, at an active level of 1 ,ug/ml of the analogues in culture.
Accordingly there is a need for a means to prevent the occurrence of, and/or progress of gingival infection and periodontal disease and indeed of other diseases such as osteoporosis which are caused by the disassociation of bone resorption and bone deposition. Moreover there is a need for agents which are capable of inhibiting the secretion of factors which enhance bone resorption in the instance of bone disease such as osteoporosis or periodontitis. Moreover there is a need for an agent which is capable of inhibiting the bacteria which are associated with diseased sites as pathogens for these diseases. Moreover there is a need for an agent which acts as an inhibitor of certain bacteria and enables the exclusion of such bacteria from growth media in the investigation of other bacteria. Moreover there is a need for the determination of the most effective anti-inflammatory agents which have been found to inhibit the secretion of inflammatory mediators such as cytokines and prostoglandins.
We have now surprisingly found that certain quinones, in particular certain naphthoquinones comprising a group of vitamin K like compounds, their analogues or metabolites or active fragments thereof are able to provide the needs hereinbefore defined. Accordingly in its broadest aspect the present invention relates to (naphtho) quinone compounds as inhibitors of bacteria, especially of vitamin K dependent bacteria. The present invention is of particular benefit in view of its application to pathogenic species of bacteria which utilise vitamin K in their energy transduction pathways and especially those which have an absolute requirement for vitamin K being unable to synthesise the compounds themselves. In a preferred aspect the present invention provides (naphtho) quinone compounds that are actively accumulated by these bacteria but which are not functional in the energy processes of the bacteria and which cannot be converted into useable compounds and thereby inhibit the ability of the bacteria to function, presenting a novel, directed antibiotic action.
Preferably therefore in its broadest aspect, the present invention relates to a class of compounds as inhibitors of bacteria, preferably of vitamin K dependant bacteria, comprising the quinone fragment:
wherein the compounds may be any fused (hetero) aromatics comprising a 3substituent which is functionally antagonistic, i.e. functionally inhibiting of bacterial growth. It is a particular advantage that the compound core structure is suitable for targeting or directing the compound to the active site of infection in any locus, for example the infected bone or periodontal pocket or the gut, and the 3-substituent is suitable for rendering the compound with anti-bacterial activity, suitably is a 3-substituent comprising a branched or unbranched aliphatic group or moiety which may be partially unsaturated.
More specifically the present invention relates to naphthoquinone compounds of formula I: (I)
as inhibitors of bacteria, preferably of vitamin K dependant bacteria, wherein R represents any lower aliphatic group or hydrogen; R' represents any side chain having acidic (precursor) or blocked (protected) acid functionality; and Ar represents a fused benzyne ring, or electronic equivalent thereof, and comprises optional substituents R2 which are selected from any desired organic substituent.
Preferably the compounds of formula I represent all active compounds having the vitamin K like structure which may be recognised by vitamin K dependant bacteria, and their analogues and metabolites, metabolic precursors thereof, or active fragments thereof. Preferably the compounds of formula I are selectively acquired by vitamin K dependant bacteria, in preference to naturally occurring vitamin K compounds or metabolic fragments thereof which enable the bacteria to thrive and grow.
Preferably R is methyl, ethyl or hydrogen, more preferably is methyl.
Preferably Rl is a methylating acid function, for example is a Cm 20 carboxylic acid or ester, preferably selected from up to C,2 substantially straight chain carboxylic acid, methyl or ethyl ester, or metabolic precursor or fragment thereof.
More preferably R' is a group selected from (CR3R4)n X wherein X equals COOR5, wherein R5 comprises hydrogen or hydrocarbon moieties, for example R5 is H, CH3 or C2H5 or chemical or electronic equivalent or metabolic precursor thereof or the like, and wherein any or each of R3 or/and R4 is hydrogen or a suitable functional group, for example halo, alkyl or the like, and (CR3R4)n is any carbon chain optionally including one or more isoprene units and heteroatoms such as oxygen, sulphur or the like in the form of (thio) ether units. As hereinbefore defined any acid group may be protected in suitable manner as known in the art.
Ar may suitably comprise heteroatoms and one or more substituents R2 as hereinbefore defined serving any particular desired purpose or function such as improving solubility, efficacy or other such factors. Preferably Ar is a benzyne ring and each R2 is hydrogen.
Most preferably the compound of Formula I is a synthetic catabolite of naturally occurring vitamin K wherein Ar is unsubstituted benzyne, R is methyl, Rl is (CR3R4)nX where each of R3 and R4 are hydrogen or methyl, n is 4 to 10 and X is COOH or COOCH3 for example having the structure 2methyl,3-(2'methyl)-hexanoic acid-1,4-naphthoquinone (KCAT), or the methyl ester thereof.
In a further aspect of the invention is provided novel compounds within formula (I) above, for example of formula (II):
wherein n = 1 to 20 and (CR3R4)n and X are as hereinbefore defined, and a process for the preparation thereof.
In a further aspect there is provided the use of a compound of formula I in an agent to inhibit the growth of a bacteria, preferably of a vitamin K dependant bacteria. A vitamin K dependant bacteria which may be inhibited according to the present invention may be selected from any bacteria which has an absolute requirement for vitamin K and is unable to synthesise a suitable source thereof selected from any suspected oral pathogen, for example a bacteria of the black-pigmented bacterial pathogens including the class Bacteroides, which are obligate anaerobes that have an absolute requirement for both hemin and vitamin K, and are found in mammalian body fluids for example in oral, gut or intestinal fluids, and the classes Porphyrymonas, Prevotella, Fusoba cterium, Actinobacillus, Campylobacter, Eubacterium, Eikenella, Peptostreptococcus, Selonomonas, and in particular Bfragilis, B.melaninogenicus, P. gingivalis, P. intermedia, or the like.
Preferably there is provided according to the present invention use of compounds as hereinbefore defined as anti-bacterial agents, in particular for the haemin and vitamin K dependent bacteria. Whilst certain compounds as hereinbefore defined may function as bacteriostatic agents it is desirable in certain applications to be able to eradicate the bacterial pathogens entirely and in such instance there is preference for compounds as hereinbefore defined which are bacteriocidal compounds capable of achieving this end.
In a further aspect of the invention there is provided a composition for systemic or site-specific administration comprising an effective amount of a compound as hereinbefore defined. Preferably there is provided a composition for systemic or site-specific administration comprising an effective amount of the compound KCAT as hereinbefore defined. It is a particular advantage that site-specific compositions may require very low effective amounts in comparison with effective amounts for systemic compositions.
Preferably a composition as herein before defined is formulated for oral administration, for example is a health care product comprising a toothpaste, paste, emulsion, mouthwash, gum, lozenge, tablet, chewable mint or the like or is incorporated in an edible, chewable or inhalable product such as smoking or chewing tobacco or any product comprising tobacco, tobacco derived tars, tobacco substitutes; or is suited for animal administration and is in the form of a paste, solution, tablet, emulsion or the like. In a particular advantage of the present invention, the compounds of formula I are non-toxic and can be orally administered. It will be appreciated that the administration of compounds of formula I in association with tobacco, tobacco-derived tars, or tobacco substitutes will help significantly to counteract the oral bacterial growth promoting effect of these tars. It is also of partcular advantage that oral compositions for animal administration may effectively combat periodontitis also known as "broken mouth" disorder which is prevalent in sheep.
Preferably the composition for oral administration as hereinbefore defined is a cosmetic product comprising a tooth whitener, emulsion for painting on or about the tooth or gums, for example to conceal or enhance blemishes or defects, wash or spray for suppressing odours, or the like.
Alternatively a composition is hereinbefore defined is formulated for systemic administration in the form of an infusion, suppository, pessary, spray, solution, cream, concentrate, solid, soluble granules or the like.
Alternatively the composition for site-specific application as hereinbefore defined is formulated as a dressing or the like to be applied to the human or animal body, including sanitary dressings and the like, impregnated with a compound of the invention, or is a disinfectant product comprising a spray, solution, cream, concentrate, soluble granules or the like, which may be applied to any animate or non-animate surface to inhibit bacterial growth, preferably of vitamin K dependant bacteria. In a particular advantage a disinfectant composition as hereinbefore defined, finds application in health care environments such as hospitals, clinics, infirmaries or the like where the risk of infection by bacterial pathogens is to be avoided. Alternatively the composition may be provided in the form of a dressing or cleaning element which has been impregnated with the compound as hereinbefore defined in convenient manner for ease of application, for example a sanitary towel or dressing, a nappy cloth, sponge, cotton swab. A cleaning element may be comprised as part of a self cleaning element of a health care appliance.
In a further aspect of the invention there is provided a growth media comprising a compound of formula I as hereinbefore defined. Preferably the growth media is adapted for use in supporting the growth of certain bacteria other than vitamin K dependant bacteria as hereinbefore defined. The growth media of the present invention is of particular advantage in conducting clinical tests which are highly susceptible to contamination by the vitamin K dependant bacteria as herein before defined.
Reference herein to an effective amount or concentration of a compound as hereinbefore defined is to any amount or concentration which may be applied which is sufficient to provide an effective concentration or amount of the active agent at the site of infection or target site, for example the periodontal pocket in order to achieve the object of inhibiting the vitamin K dependant bacteria as herein before defined. Preferably an effective amount or concentration is sufficient to eradicate the bacteria. An effective concentration or amount may be less than 5% w/w in a site-specific composition as herein before defined, for example in an amount of 1 to 2 % w/w or less, for example in an amount of 5 x 10-7 to 5 x 10-l% w/w; or may be more than 5% w/w in a systemic composition as hereinbefore defined, for example in an amount of 5-95% w/w. Preferably an effective concentration or amount in a disinfectant composition as hereinbefore defined may be determined by known methods according to the nature of the vehicle and efficacy of directing the compound to the periodontal pocket. It is a particular advantage that the compound may be orally administered to an amount of 10 mg per day or greater by virtue of its effective non-toxicity.
In a further aspect the present invention provides a dual purpose composition having both anti-inflammatory properties and properties which inhibit bacteria, preferably vitamin K dependant bacteria as hereinbefore defined comprising an effective amount of a compound of formula I as hereinbefore defined. Preferably a dual purpose composition comprises an effective amount of the compound KCAT as herein before defined.
The dual purpose composition of the present invention is of particular advantage in its application to disorders comprising both inflammation and bacterial infection for example periodontitis where inflammation follows initial bacterial infection. The compositions of the invention may thus be able to function by both limiting the infection and curbing the host mediated response to the disease and thereby accelerate healing.
In a further aspect there is provided according to the present invention a process for the preparation of any composition for systemic, site-specific or other administrative purpose as herein before defined which process comprises admixing an effective amount of a compound of formula I as hereinbefore defined with one or more suitable diluents, dispersants, stabilisers, adjuvants, carriers, other active agents, or the like.
The compounds and compositions of the present invention as hereinbefore defined may be of particular application in combating bacteria as herein before defined which are implicated in oral diseases and complications, including bone disorders, following oral surgery, in bone resorption disfunctions such as periodontitis and osteoporosis or the like, and in diseases of the intestinal tract or gut.
Where compounds of formula I are known naturally occurring or previously synthesised compounds, the preparation thereof should be well known to a man skilled in the art. The known and novel compounds of the invention may be prepared as follows, with reference to Synthesis disclosed by Ruttimann et al, "Chimica" (1986) 40 (9), 290-306, and Gerorkzan et al, "Chem. Heterocyclic Compd." (Engl. Trans.) (1989) 2, 269, and the Figures hereinbelow. In particular Ruttimann et al disclose the synthesis of the compound KCAT.
The process as described in Figure 1 relates to reaction of menadione (K3, Aldrich Chemical Company) with cyclopentadiene with the application of heat thereby generating the intermediate (IV) comprising a fused ring system, which is further reacted with base and a starting material RlL (V) to introduce the side chain R'. L denotes any leaving group which renders the terminal carbon of R1 as electron poor and open to nucleophilic attack, for example L = halo or the like, preferably bromo (Br). The intermediate compound (VI) thus formed is further reacted at elevated temperature for example in excess of 50"C to cause regeneration of cyclopentadiene and reconjugation of the aromatic system, thereby generating the final product (I).
As a novel further stage the group R' may be modified for example to convert the ester to the carboxylic acid derivative, i.e. X = COOCH3 or C2H5 to X = COOH, typically by means of base hydrolysis and subsequent acid treatment.
The starting material R1L (V) may be obtained by any suitable known means, for example as disclosed by Gerorkzan et al starting from the commercially available prenyl bromide (Aldrich Chemical Company) or a precursor thereof, for example 3-methyl, but-2-ene-1-ol, which may be converted in suitable manner to introduce a leaving group L or alternatively depending on the nature of R', to introduce a protecting group, Pg which may be any known protecting group, for example benzyl or the like. A protecting group is suitably introduced by means of nucleophilic substitution employing silver oxide as additional reagent, for example reaction with PgBr or the like.
Defunctionalised or protected starting material (VII) is reacted to form the epoxide (VIII) for example with use of mCPBA, subsequently the application of heat causes opening of the epoxy ring to introduce a hydroxy group alpha to the rearranged unsaturated bond. The compound (IX) is reacted with a suitable acylating agent to produce compound (X) or like precursor to a rearrangement, typically employing a Klausen reagent whereby the structure R' is generated (V). It will be apparent that appropriate choice of acylating agent enables the variation of chain length, substituents and saturation or unsaturation thereof in this stage, whereby for example any desired analogue may be prepared. Finally the terminal acid function may be functionalised as appropriate, for example for the conversion to the appropriate ester, whereafter any protecting group may be removed. Suitably a protecting group comprising benzoyl may be removed by cleavage of benzyl with use of a suitable reagent such as Pd, C, H, and subsequent introduction of the desired leaving group L, for example introduction of bromo by the reaction with CBr4 and PPh4.
In a further aspect of the present invention there is provided novel compounds, synthetic or metabolic intermediates or precursors, metabolites, or active fragments thereof and a process for the preparation thereof as hereinbefore defined, and in particular with reference to the attached Figures and the following examples.
The invention is herein below illustrated in non limiting manner with reference to the following examples.
Example 1 - Preparation and characterisation of methyl ester of KCAT The starting material menadione (Aldrich Chemical Company, IIIa) was employed and reacted with cyclopentadiene at 25"C to generate the fused derivative thereof (IVa). Treatment with base, O-K+ and subsequent treatment with methyl 4-methyl, 6-bromo hex4-eneoate (Va), introduced the 3substituent (VIa). The intermediate was further reacted by application of heat in the range 70"C to 110"C causing the elimination of cyclopentadiene with the resultant isolation of the product methyl ester of KCAT as hereinbefore defined (it). The characterisation of this compound is given by Ruttimann et al as hereinbefore referred, which is incorporated herein by reference.
Example 2 - Preparation and characterisation of KCAT The compound (Ia) of example 1 was converted to the corresponding carboxylic acid by means of base hydrolysis, for examp generating KCAT (Ib). The characterisation of this compound is given by Ruttimann et al as hereinbefore referred, which disclosure is incorporated herein by reference.
Example 3 - Preparation of intermediate (va) Prenyl bromide (Aldrich Chemical Company) (VII wherein L = Br) was converted to the epoxide using mCPBA, which was subsequently heated to derive the intermediate (IX) wherein L = Br. Treatment with Ac2O-DMAP generated the ester (X) wherein L = Br, which was then subject to Klausen rearrangement using standard reagents such as LDA and TMFU. The rearranged product thereof (V) wherein L = Br was converted to the methyl ester (Va) by reaction with CH2N2 for use in the preparation of KCAT as hereinbefore defined.
The characterisation thereof is provided by Gerorkzan et al as hereinbefore referred, which disclosure is incorporated herein by reference.
Example A - Bacterial Cultures The laboratory maintained black-pigmented oral pathogen Porphorymonas gingtvalis W50 was cultured in liquid media in the presence of phylloquinone (VK1, vitamin Kl), menaquinone-4 (MK-4, a form of vitamin K2), menadione (VK3), 2,3-dimethoxy-1, 4-naphthoquinone (DMO) and 2-methyl,-3-(2'methyl)-hexanoic acid- ,4-naphthoquinone (KCAT, a natural product of mammalian phylloquinone catabolism (McBurney et al, 1980)) 4ml total volume. All the compounds were used at a concentration of 500ng/ml and growth was monitored as a function of change in the conductivity of the culture broth with time. The cultures were grown under anaerobic conditions.
The bacterial growth observed in each of these experiments in shown in Figure 1.
It is clear that P. gingivalis can efficiently use vitamins Kl, K2, K3 and DMO, but the growth of this bacteria in the presence of KCAT was curtailed after an initially normal growth curve. It is likely that the cultured bacteria contain an internal store of vitamin K and that this may maintain the initial metabolic requirements until the reserves are exhausted and the effects of KCAT can be seen after this point.
Example B - Recovery of bacterial cultures The liquid cultures of P. gingivalis from Example A were subsequently cultured anaerobically under ideal growth conditions on blood agar plates but in the absence of any further compounds of formula I to which they had initially been exposed. All the cultures, including those exposed to KCAT, were shown to be viable. Growth was monitored as a function of an increase in the number of coloured colonies with distinctive odours of the blackpigmented bacteria.
Results are shown in Figure 2 of the anaerobic culture of Examples A and B in the presence and absence of menadione (VK3) (500ng/ml).
Example B shows that KCAT is not bacteriocidal when administered in amount of 500ng/ml as in Example A to the culture of Example A.
Example C - Composition According to the Invention An antibacterial toothpaste was prepared by admixing KCAT at 1-2% (wlw) in a standard toothpaste composition having the commonly employed constituents and ratios. The composition is suitably placed in a light-resistant packaging or container to ensure compound stability.
The composition in liquid culture was found to be effective in inhibiting P.
gingivalis growth at a concentration of 500ng/ml.
The composition of the invention is thus effective in far lower amounts than would be required to maintain an oxidised environment through redox mechanism.

Claims (23)

1. A compound as an inhibitor of bacteria comprising a quinone fragment.
2. A compound according to Claim 1 wherein the quinone fragment is of the formula:
wherein the compound is a fused (hetero) aromatic comprising a 3-substituent which is functionally antagonistic.
3. A compound as claimed in any of Claims 1 and 2 wherein the 3substituent is a branched or unbranched aliphatic group or moiety which may be partially unsaturated.
4. A compound as inhibitor of bacteria comprising a naphthoquinone compound of formula I:
wherein R represents any lower aliphatic group or hydrogen; Rl represents any side chain having acidic (precursor) or blocked (protected) acid functionality; and Ar represents a fused benzyne ring, or electronic equivalent thereof, and comprises optional substituents R2 which are selected from an organic substituent.
5. A compound as claimed in Claim 4 wherein R is methyl, ethyl or hydrogen.
6. A compound as claimed in any of Claims 4 and 5 wherein Rl is a methylating acid function, for example is a C,20 carboxylic acid or ester, preferably selected from up to C12 substantially straight chain carboxylic acid, methyl or ethyl ester, or metabolic precursor or fragment thereof.
7. A compound as claimed in Claim 6 wherein Rl is a group selected from (CR3R4)n X wherein X equals COOR5, wherein R5 comprises hydrogen or hydrocarbon moieties, for example R5 is H, CH3 or C2H5 or chemical or electronic equivalent or metabolic precursor thereof or the like, and wherein any or each of R3 or/and R4 is hydrogen or a suitable functional group, for example halo, alkyl or the like, and (CR3R4)n is any carbon chain optionally including one or more isoprene units and heteroatoms such as oxygen, sulphur or the like in the form of (thio) ether units.
8. A compound as claimed in any one of Claims 4-7 wherein Ar optionally comprises heteroatoms and one or more substituents R2 as hereinbefore defined in Claims 4 or 5 with reference to R; preferably Ar is a benzyne ring and each R2 is hydrogen.
9. A compound as claimed in any one of Claims 4-8 which is a synthetic catabolite of naturally occurring vitamin K wherein Ar is unsubstituted benzyne, R is methyl, R' is (CR3R4)nX where each of R3 and R4 are hydrogen or methyl, n is 4 to 10 and X is COOH or COOCH3 for example having the structure 2-methyl,3-(2'methyl)-hexanoic acid- 1,4-naphthoquinone (KCAT), or the methyl ester thereof.
10. A compound of formula (II):
wherein n = 1 to 20; X equals COOR5, wherein R5 comprises hydrogen or hydrocarbon moieties, for example R5 is H, CH3 or C2H5 or chemical or electronic equivalent or metabolic precursor thereof or the like; any or each of R3 or/and R4 is hydrogen or a suitable functional group, for example halo, alkyl or the like, and (CR3R4)n is any carbon chain optionally including one or more isoprene units and heteroatoms such as oxygen, sulphur or the like in the form of (thio) ether units.
11. A composition for systemic or site-specific administration comprising an effective amount of a compound as hereinbefore defined with reference to any of Claims 1-10.
12. A composition as claimed in Claim 11 which is formulated for oral administration, for example is a health care product comprising a toothpaste, paste, emulsion, mouthwash, gum, lozenge, tablet, chewable mint or the like or is incorporated in an edible, chewable or inhalable product such as smoking or chewing tobacco or any product comprising tobacco, tobacco derived tars, tobacco substitutes; or is suited for animal administration and is in the form of a paste, solution, tablet, emulsion or the like.
13. A composition as claimed in Claim 11 which is for site-specific application as hereinbefore defined and is formulated as a dressing or the like to be applied to the human or animal body, including sanitary dressings and the like, impregnated with a compound of the invention, or is a disinfectant product comprising a spray, solution, cream, concentrate, soluble granules or the like, which may be applied to any animate or non-animate surface to inhibit bacterial growth.
14. A composition as claimed in Claim 11 which is formulated for systemic administration in the form of an infusion, suppository, pessary, spray, solution, cream, concentrate, solid, soluble granules or the like.
15. A dual purpose composition having both anti-inflammatory properties and properties which inhibit bacteria comprising an effective amount of a compound as hereinbefore defined with reference to any of Claims 1-10.
16. A process for the preparation of a composition for systemic, sitespecific or other administrative purpose as hereinbefore defined with reference to any of Claims 11-15 which process comprising admixing an effective amount of a compound as hereinbefore defined with reference to any of Claims 1-10, with one or more suitable diluents, dispersants, stabilisers, adjuvants, carriers, other active agents or the like.
17. A compound or composition as hereinbefore defined with reference to any of Claims 1-15 for use in combating bacteria implicated in oral disease or complications, including bone disorders, following oral surgery, in bone resorption disfunctions such as periodontitis and osteoporosis or the like and in diseases of the intestinal tract or gut.
18. A compound, composition or use thereof as hereinbefore defined with reference to any of Claims 1-17 as inhibitor of bacteria wherein the bacteria is vitamin K dependent, for example black pigmented bacteria including the class Bacteroides, and bacteria of the classes Porphyrymonas, Prevotella, Fusobacterium, Actinobacillus, Campylobacter, Eubacterium, Eikenella, Peptostreptococcus, Selonomonas, and in particular B.fragilis, B.melaninogenicus, P. gingivalis, P. intermedia, or the like..
19. A compound, composition or preparation thereof as claimed in any of Claims 1-18 with reference to the description, Figures or examples.
20. A growth media comprising a compound as hereinbefore defined with reference to any of Claims 1-10.
21. A process for the preparation of any novel compound as claimed in any of Claims 1-10.
22. A process for the preparation of a compound as an inhibitor of bacteria as claimed in any of Claims 1-10 comprising: the reaction of menadione with cyclopentadiene at elevated temperature to generate intermediate of formula IV or IVa as hereinbefore defined; the reaction of intermediate of formula IV or IVa with base and intermediate of formula V or Va as hereinbefore defined; and elimination of cyclopentadiene at elevated temperature to generate product compound of formula I wherein Rl is an ester; and optionally subjecting the compound of formula I wherein Rl is an ester to hydrolysis with subsequent acid treatment to obtain the corresponding acid.
23. Novel intermediates of the process as claimed in Claims 20 or 21.
23. A process as claimed in Claims 21 or 22 with reference to the description, Examples and/or Figures.
24. Novel intermediates of the process as claimed in Claims 21 or 22.
Amendments to the claims have been filed as follows ~CILAXMS 1. A compound as an inhibitor of bacteria comprising a quinone fragment.
wherein the quinone fragrrzent is of the formula:
wherein the compound is a fused (hetero) aromatic comprising a 3-substituent which is functionally antagonistic.
2. A compound as claimed in Claim 1 wherein the 3-substituent is a branched or unbranched aliphatic group or moiety which may be partially unsaturated.
3. A compound as inhibitor of bacteria comprising a naphthoquinone compound of formula I:
wherein R represents any lower aliphatic group or hydrogen; R' represents any side chain having acidic (precursor) or blocked (protected) acid functionality; and Ar represents a fused benzyne ring, or electronic equivalent thereof, and comprises optional substituents R2 which are selected from an organic substituent.
4. A compound as claimed in Claim 3 wherein R is methyl, ethyl or hydrogen.
5. A compound as claimed in any of Claims 3 and 4 wherein R' is a methylating acid function, for example is a Cm 20 carboxylic acid or ester, preferably selected from up to C,2 substantially straight chain carboxylic acid, methyl or ethyl ester, or metabolic precursor or fragment thereof.
6. A compound as claimed in Claim 5 wherein R' is a group selected from (CR3R4)n X wherein X equals COOR5, wherein R5 comprises hydrogen or hydrocarbon moieties, for example R5 is H, CH3 or C2H5 or chemical or electronic equivalent or metabolic precursor thereof or the like, and wherein any or each of R3 or/and R4 is hydrogen or a suitable functional group, for example halo, alkyl or the like, and (CR3R4)n is any carbon chain optionally including one or more isoprene units and heteroatoms such as oxygen, sulphur or the like in the form of (thio) ether units.
7. A compound as claimed in any one of Claims 3-6 wherein Ar optionally comprises heteroatoms and one or more substituents R2 as hereinbefore defined in Claims 3 or 4 with reference to R; preferably Ar is a benzyne ring and each R2 is hydrogen.
8. A compound as claimed in any one of Claims 3-7 which is a synthetic catabolite of naturally occurring vitamin K wherein Ar is unsubstituted benzyne, R is methyl, Rl is (CR3R4)nX where each of R3 and R4 are hydrogen or methyl, n is 4 to 10 and X is COOH or COOCH3 for example having the structure 2 methyl,3-(2'methyl)-hexanoic acid- 1 ,4naphthoquinone (KCAT), or the methyl ester thereof.
9. A compound of formula (II):
wherein n = 1 to 20; X equals COOR5, wherein R5 comprises hydrogen or hydrocarbon moieties, for example R5 is H, CH3 or C2H5 or chemical or electronic equivalent or metabolic precursor thereof or the like; any or each of R3 or/and R4 is hydrogen or a suitable functional group, for example halo, alkyl or the like, and (CR3R4)n is any carbon chain optionally including one or more isoprene units and heteroatoms such as oxygen, sulphur or the like in the form of (thio) ether units.
10. A composition for systemic or site-specific administration comprising an effective amount of a compound as hereinbefore defined with reference to any of Claims 1-9.
11. A composition as claimed in Claim 10 which is formulated for oral administration, for example is a health care product comprising a toothpaste, paste, emulsion, mouthwash, gum, lozenge, tablet, chewable mint or the like or is incorporated in an edible, chewable or inhalable product such as smoking or chewing tobacco or any product comprising tobacco, tobacco derived tars, tobacco substitutes; or is suited for animal administration and is in the form of a paste, solution, tablet, emulsion or the like.
12. A composition as claimed in Claim 10 which is for site-specific application as hereinbefore defined and is formulated as a dressing or the like to be applied to the human or animal body, including sanitary dressings and the like, impregnated with a compound of the invention, or is a disinfectant product comprising a spray, solution, cream, concentrate, soluble granules or the like, which may be applied to any animate or non-animate surface to inhibit bacterial growth.
13. A composition as claimed in Claim 10 which is formulated for systemic administration in the form of an infusion, suppository, pessary, spray, solution, cream, concentrate, solid, soluble granules or the like.
14. A dual purpose composition having both anti-inflammatory properties and properties which inhibit bacteria comprising an effective amount of a compound as hereinbefore defined with reference to any of Claims 1-9.
15. A process for the preparation of a composition for systemic, site-specific or other administrative purpose as hereinbefore defined with reference to any of Claims 10-14 which process comprising admixing an effective amount of a compound as hereinbefore defined with reference to any of Claims 1-9, with one or more suitable diluents, dispersants, stabilisers, adjuvants, carriers, other active agents or the like.
16. A compound or composition as hereinbefore defined with reference to any of Claims 1 - 14 for use in combating bacteria implicated in oral disease or complications, including bone disorders, following oral surgery, in bone resorption disfunctions such as periodontitis and osteoporosis or the like and in diseases of the intestinal tract or gut.
17. A compound, composition or use thereof as hereinbefore defined with reference to any of Claims 1-16 as inhibitor of bacteria wherein the bacteria is vitamin K dependent, for example black pigmented bacteria including the class Bacteroides, and bacteria of the classes Porphyrymonas, Prevotella, Fusobacterium, Actinobacillus, Campylobacter, Eubacterium, Eikenella, Peptostreptococcus, Selonomonas, and in particular B.fragilis, B.melaninogenicus, P. gin givalis, P. intemzedia, or the like..
18. A compound, composition or preparation thereof as claimed in any of Claims 1-17 with reference to the description, Figures or examples.
19. A growth media comprising a compound as hereinbefore defined with reference to any of Claims 1-9.
20. A process for the preparation of any novel compound as claimed in any of Claims 1-9.
21. A process for the preparation of a compound as an inhibitor of bacteria as claimed in any of Claims 1-9 comprising: the reaction of menadione with cyclopentadiene at elevated temperature to generate intermediate of formula IV or IVa as hereinbefore defined; the reaction of intermediate of formula IV or IVa with base and intermediate of formula V or Va as hereinbefore defined; and elimination of cyclopentadiene at elevated temperature to generate product compound of formula I wherein R' is an ester; and optionally subjecting the compound of formula I wherein R' is an ester to hydrolysis with subsequent acid treatment to obtain the corresponding acid.
22. A process as claimed in Claims 20 or 21 with reference to the description, Examples and/or Figures.
GB9713078A 1996-06-25 1997-06-23 Quinones for use in the inhibition of bacteria Expired - Fee Related GB2314773B (en)

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EP1230920A4 (en) * 1999-10-19 2004-09-29 Meiji Dairies Corp Food materials useful in preventing and ameliorating metabolic bone diseases and preventives/remedies for metabolic bone diseases comprising these materials
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WO2011077159A1 (en) 2009-12-23 2011-06-30 Haomamedica Limited Treatment of osteoporosis
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WO2011077158A1 (en) 2009-12-23 2011-06-30 Haomamedica Limited Anticoagulant compounds and their use
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CN103002888B (en) * 2009-12-23 2016-10-26 豪马药物有限公司 Anticoagulant compounds and application thereof
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CN103002886B (en) * 2009-12-23 2016-10-26 豪马药物有限公司 Osteoporotic treatment
US20140199372A1 (en) * 2011-05-24 2014-07-17 Northeastern University Microbial growth factors
FR2996755A1 (en) * 2012-10-15 2014-04-18 Oreal Cosmetic use of menaquinone or vitamin K2 as active deodorant for treating and/or preventing human body odor

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AU3267997A (en) 1998-01-14

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