WO1997049662A1 - Inhibiteurs bacteriens a base de quinone - Google Patents

Inhibiteurs bacteriens a base de quinone Download PDF

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Publication number
WO1997049662A1
WO1997049662A1 PCT/GB1997/001702 GB9701702W WO9749662A1 WO 1997049662 A1 WO1997049662 A1 WO 1997049662A1 GB 9701702 W GB9701702 W GB 9701702W WO 9749662 A1 WO9749662 A1 WO 9749662A1
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Prior art keywords
compound
bacteria
hereinbefore defined
composition
vitamin
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PCT/GB1997/001702
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English (en)
Inventor
Stephen John Hodges
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The University Of Sheffield
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Publication date
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Priority to AU32679/97A priority Critical patent/AU3267997A/en
Publication of WO1997049662A1 publication Critical patent/WO1997049662A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67—Vitamins

Definitions

  • 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 K, (phylloquinone) and K 2 (menaquinone) which compounds are characterised by a 2-methyl-l,4-naphthoquinone unit further substituted at the 3 position by a C j6 + side chain comprising repeating isoprene units.
  • K 3 (menadione) comprising the further unsubstituted 2 -methyl- 1,4- naphthoquinone.
  • Other synthetic analogues of the K vitamins are now available.
  • synthetic naphthoquinone and benzoquinone compounds and metabolic derivatives of the parent vitamin K compounds are of great interest.
  • vitamin K is synthesised by intestinal bacteria in rats and other mammals.
  • 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 (3,3 '-methy lenebis (4- hydroxy-l,2-benzopyrone)) as described in Biochemistry, Albert Earl Lehninger, Worth Publishers Inc. New York, second edition page 358.
  • vitamin K A further clinical use of vitamin K is reported in "A clinical re-evaluation of the effectiveness of vitamin K, 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.
  • 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.
  • 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.
  • 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.
  • gingivitis 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.
  • Vitamin K 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.
  • 3-epoxide metabolite of vitamin K was less active as an anti-inflammatory agent than was vitamin Ki and had no analgesic effect.
  • the observations were derived from intramuscular or intravenous injection of the vitamin K [ (analogues) in rats with an induced irritation of the paw. Nevertheless no conclusion was drawn on the mechanism of action of the vitamins.
  • Fibroblasts is Potently Inhibited by Naphthoquinine (Vitamin K) Compounds," K. Reddi et al, Cytokine, 7 (3) April 1995, 287-290 a synthetic product of vitamin K catabolism, 2-methyl, 3-(2'methyl)-hexanoic acid- 1,4- naphthoquinone (KCAT) was found to inhibit cytokine inflammatory mediator IL-6 production to a greater extent than the synthetic analogues menadione (K 3 ) and 2, 3-dimethoxy-l, 4-naphthoquinone (DMK) in turn to a greater extent than the naturally occurring vitamins K 2 and K, with an associated indication of their anti-inflammatory effects.
  • KCAT 2-methyl, 3-(2'methyl)-hexanoic acid- 1,4- naphthoquinone
  • 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.
  • 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.
  • the present invention relates to a class of compounds as inhibitors of bacteria, preferably of vitamin K dependant bacteria, comprising the quinone fragment:
  • the compounds may be any fused (hetero) aromatics comprising a 3- substituent which is functionally antagonistic, i.e. functionally inhibiting of bacterial growth.
  • 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.
  • R represents any lower aliphatic group or hydrogen
  • R 1 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 R 2 which are selected from any desired organic substituent.
  • 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.
  • 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.
  • R is methyl, ethyl or hydrogen, more preferably is methyl.
  • R 1 is a methylating acid function, for example is a C u20 carboxylic acid or ester, preferably selected from up to C 12 substantially straight chain carboxylic acid, methyl or ethyl ester, or metabolic precursor or fragment thereof.
  • R 1 is a group selected from (CR 3 R 4 ) n X wherein X equals COOR 5 , wherein R 5 comprises hydrogen or hydrocarbon moieties, for example R 5 is H, CH 3 or C 2 H 5 or chemical or electronic equivalent or metabolic precursor thereof or the like, and wherein any or each of R 3 or/and R 4 is hydrogen or a suitable functional group, for example halo, alkyl or the like, and (CR 3 R 4 ) 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.
  • any acid group may be protected in suitable manner as known in the art.
  • Ar may suitably comprise heteroatoms and one or more substituents R 2 as hereinbefore defined serving any particular desired purpose or function such as improving solubility, efficacy or other such factors.
  • R 2 substituents
  • Ar is a benzyne ring and each R 2 is hydrogen.
  • the compound of Formula I is a synthetic catabolite of naturally occurring vitamin K wherein Ar is unsubstituted benzyne, R is methyl, R 1 is (CR 3 R 4 ) n X where each of R 3 and R 4 are hydrogen or methyl, n is 4 to 10 and X is COOH or COOCH 3 for example having the structure 2- methyl,3-(2'methyl)-hexanoic acid-l,4-naphthoquinone (KCAT), or the methyl ester thereof.
  • KCAT 2- methyl,3-(2'methyl)-hexanoic acid-l,4-naphthoquinone
  • n 1 to 20 and (CR 3 R 4 ) n and X are as hereinbefore defined, and a process for the preparation thereof.
  • 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 Porphyry monas, Prevotella, Fusobacterium, Actinobacillus, Campylobacter, Eubacterium, Eikenella, Peptostreptococcus, brieflyomonas, and in particular B.fragilis, B.melaninogenicus, P. gingivalis, P. intermedia, or the like.
  • compounds as hereinbefore defined as anti-bacterial agents in particular for the haemin and vitamin K dependent bacteria.
  • 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.
  • compositions for systemic or site-specific administration comprising an effective amount of a compound as hereinbefore defined.
  • 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.
  • 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.
  • the compounds of formula I are non-toxic and can be orally administered.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a growth media comprising a compound of formula I as hereinbefore defined.
  • 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.
  • 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 IO "7 to 5 x 10 _1 % 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.
  • 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.
  • 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.
  • 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.
  • a process for the preparation of any composition for systemic, site-specific or other administrative purpose as herein before defined 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.
  • suitable diluents, dispersants, stabilisers, adjuvants, carriers, other active agents, or the like 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.
  • the intermediate (IV) comprising a fused ring system, which is further reacted with base and a starting material R'L (V) to introduce the side chain R 1 .
  • 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).
  • the starting material R'L (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-l-ol, which may be converted in suitable manner to introduce a leaving group L or alternatively depending on the nature of R 1 , 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 1 is generated (V).
  • 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.
  • terminal acid function may be functionalised as appropriate, for example for the conversion to the appropriate ester, whereafter any protecting group may be removed.
  • 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 CBr 4 and PPh 4 .
  • 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 starting material menadione (Aldrich Chemical Company, Ilia) was employed and reacted with cyclopentadiene at 25° C to generate the fused derivative thereof (IVa).
  • 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 (la).
  • the characterisation of this compound is given by Ruttimann et al as hereinbefore referred, which is incorporated herein by reference.
  • the laboratory maintained black-pigmented oral pathogen Porphorymonas gingivalis W50 was cultured in liquid media in the presence of phylloquinone (VK1, vitamin K,), menaquinone-4 (MK-4, a form of vitamin K 2 ), menadione (VK3), 2,3-dimethoxy-l, 4-naphthoquinone (DMO) and 2-methyl,-3-(2'- methyl)-hexanoic acid-l,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.
  • 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% (w/w) 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.
  • composition in liquid culture was found to be effective in inhibiting P. gingivalis growth at a concentration of 500ng/ml.
  • composition of the invention is thus effective in far lower amounts than would be required to maintain an oxidised environment through redox mechanism.

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Abstract

On décrit un composé utile en tant qu'inhibiteur de bactéries qui comprend un fragment de quinone; un procédé de préparation de ce composé; une composition contenant ledit composé et la préparation de cette dernière ainsi que l'utilisation dudit composé pour combattre les bactéries, plus particulièrement les bactéries dépendant de la vitamine K.
PCT/GB1997/001702 1996-06-25 1997-06-25 Inhibiteurs bacteriens a base de quinone WO1997049662A1 (fr)

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AU32679/97A AU3267997A (en) 1996-06-25 1997-06-25 Quinone bacterial inhibitors

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GBGB9613309.5A GB9613309D0 (en) 1996-06-25 1996-06-25 Quinone bacterial inhibitors
GB9613309.5 1996-06-25

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003037284A1 (fr) * 2001-10-31 2003-05-08 Smithkline Beecham P.L.C. Composition pour hygiene buccale
KR100866008B1 (ko) * 1999-10-19 2008-10-29 메이지 데어리즈 코포레이션 대사성 골질환의 예방 치료약
JP2013515712A (ja) * 2009-12-23 2013-05-09 ハオマメディカ・リミテッド 骨粗鬆症の治療
JP2013515711A (ja) * 2009-12-23 2013-05-09 ハオマメディカ・リミテッド 抗凝血薬化合物およびその使用

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012162496A1 (fr) * 2011-05-24 2012-11-29 Northeastern University Facteurs de croissance microbiens
FR2996755B1 (fr) * 2012-10-15 2015-04-24 Oreal Utilisation cosmetique d'une menaquinone comme actif deodorant

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2104871A1 (fr) * 1970-02-07 1971-08-26
DE2431198A1 (de) * 1973-07-02 1975-01-23 Takeda Chemical Industries Ltd Chinonderivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittelzubereitungen
JPS55153739A (en) * 1979-05-18 1980-11-29 Takeda Chem Ind Ltd Quinone compound and its preparation
EP0038160A1 (fr) * 1980-04-14 1981-10-21 Takeda Chemical Industries, Ltd. Dérivés des quinones, leur préparation et leur utilisation
DE3035279A1 (de) * 1980-09-18 1982-04-01 Zyma GmbH, 8000 München Verfahren zur herstellung von 2-methyl-5-hydroxy-1,4-naphthochinon
DE3427383A1 (de) * 1984-07-25 1986-01-30 Eckart Prof. Dr. 6500 Mainz Eich Avaron und avaron-derivate, verfahren zu ihrer herstellung, sie enthaltende arzneimittel und deren verwendung
US4818441A (en) * 1979-07-02 1989-04-04 Takeda Chemical Industries, Ltd. Quinine derivatines
EP0339442A2 (fr) * 1988-04-27 1989-11-02 Hoechst Aktiengesellschaft Angucyclinones d'après des streptomyces, procédé pour leur obtention et leur utilisation
EP0657412A1 (fr) * 1992-12-01 1995-06-14 Kyowa Hakko Kogyo Co., Ltd. Derive de saintopine

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4963565A (en) * 1986-07-30 1990-10-16 National Jewish Center For Immunology And Respiratory Medicine In vivo treatment of mycobacterial infections with 6-cyclo octylamino-5,8-quinoline quinone
US5223430A (en) * 1988-08-04 1993-06-29 American Cyanamid Company Subspecies of micromonospora citrea which produces antibiotic ll-e19085 alpha
EP0362996B1 (fr) * 1988-08-16 1994-04-27 The Wellcome Foundation Limited Naphtoquinones pour le traitement et prophylaxe des infections de pneumocystis carinii
GB8923254D0 (en) * 1989-10-16 1989-12-06 Wellcome Found Medicaments
ES2119086T3 (es) * 1993-09-21 1998-10-01 Takeda Chemical Industries Ltd Uso de quinonas para la fabricacion de un medicamento para el tratamiento y prevencion de una rinitis alergica.

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2104871A1 (fr) * 1970-02-07 1971-08-26
DE2431198A1 (de) * 1973-07-02 1975-01-23 Takeda Chemical Industries Ltd Chinonderivate, verfahren zu ihrer herstellung und sie enthaltende arzneimittelzubereitungen
JPS55153739A (en) * 1979-05-18 1980-11-29 Takeda Chem Ind Ltd Quinone compound and its preparation
US4818441A (en) * 1979-07-02 1989-04-04 Takeda Chemical Industries, Ltd. Quinine derivatines
EP0038160A1 (fr) * 1980-04-14 1981-10-21 Takeda Chemical Industries, Ltd. Dérivés des quinones, leur préparation et leur utilisation
US4393075A (en) * 1980-04-14 1983-07-12 Takeda Chemical Industries, Ltd. Quinone compounds and their use in suppressing the production of SRS-A in mammals
US4393075B1 (fr) * 1980-04-14 1989-07-04
DE3035279A1 (de) * 1980-09-18 1982-04-01 Zyma GmbH, 8000 München Verfahren zur herstellung von 2-methyl-5-hydroxy-1,4-naphthochinon
DE3427383A1 (de) * 1984-07-25 1986-01-30 Eckart Prof. Dr. 6500 Mainz Eich Avaron und avaron-derivate, verfahren zu ihrer herstellung, sie enthaltende arzneimittel und deren verwendung
EP0339442A2 (fr) * 1988-04-27 1989-11-02 Hoechst Aktiengesellschaft Angucyclinones d'après des streptomyces, procédé pour leur obtention et leur utilisation
EP0657412A1 (fr) * 1992-12-01 1995-06-14 Kyowa Hakko Kogyo Co., Ltd. Derive de saintopine

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
A. RÜTTIMANN: "Recent Advances in the Synthesis of K-Vitamins", CHIMICA, vol. 40, no. 9, 1986, pages 290 - 306, XP002041421 *
BEILSTEIN INFORMATION SEVICE: FILE CROSSFIRE, XP002041425 *
I. AZUMA ET AL.: "The Effect of Ubiquinone-7 and its Metabolites on the Immune Response", INTERNAT. J. VIT. NUTR. RES., vol. 48, 1978, pages 255 - 261, XP002041423 *
M. K. DHAON ET AL.: "Derivatives of 2-Methyl-1,4-naphthoquinone ...", J. MED. CHEM., vol. 27, 1984, pages 1196 - 1201, XP002041422 *
M. WATANABE: "Ubiquinone and related Compounds. XXVIII. Effect of the ...", CHEM. PHARM. BULL., vol. 22, no. 1, 1974, pages 183 - 188, XP002041424 *
PATENT ABSTRACTS OF JAPAN vol. 005, no. 028 (C - 044) 20 February 1981 (1981-02-20) *
REDDI, K. ET AL.: "Interleukin 6 production", CYTOKINE, vol. 7, no. 3, 1995, pages 287 - 290, XP002041420 *
V. AMBROGI ET AL.: "Studies on the antibacterial and antifungal properties of 1,4-naphthoquinones", BR. J. PHARMAC., vol. 40, 1970, pages 871 - 880, XP002041760 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100866008B1 (ko) * 1999-10-19 2008-10-29 메이지 데어리즈 코포레이션 대사성 골질환의 예방 치료약
WO2003037284A1 (fr) * 2001-10-31 2003-05-08 Smithkline Beecham P.L.C. Composition pour hygiene buccale
JP2013515712A (ja) * 2009-12-23 2013-05-09 ハオマメディカ・リミテッド 骨粗鬆症の治療
JP2013515711A (ja) * 2009-12-23 2013-05-09 ハオマメディカ・リミテッド 抗凝血薬化合物およびその使用
US9622989B2 (en) 2009-12-23 2017-04-18 Haoma Medica Limited Treatment of osteoporosis

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GB2314773B (en) 2001-04-11
AU3267997A (en) 1998-01-14
GB9613309D0 (en) 1996-08-28
GB9713078D0 (en) 1997-08-27

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