EP1494682A2 - Polyphosphonate derivatives for toothpaste compositions - Google Patents

Polyphosphonate derivatives for toothpaste compositions

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Publication number
EP1494682A2
EP1494682A2 EP03740602A EP03740602A EP1494682A2 EP 1494682 A2 EP1494682 A2 EP 1494682A2 EP 03740602 A EP03740602 A EP 03740602A EP 03740602 A EP03740602 A EP 03740602A EP 1494682 A2 EP1494682 A2 EP 1494682A2
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
compound
formula
polyphosphonate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03740602A
Other languages
German (de)
French (fr)
Inventor
Benoít DENIZOT
Anne Denizot
François HINDRE
David Portet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universite dAngers
Institut National de la Sante et de la Recherche Medicale INSERM
Original Assignee
Universite dAngers
Institut National de la Sante et de la Recherche Medicale INSERM
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Filing date
Publication date
Application filed by Universite dAngers, Institut National de la Sante et de la Recherche Medicale INSERM filed Critical Universite dAngers
Publication of EP1494682A2 publication Critical patent/EP1494682A2/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K8/55Phosphorus compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents

Definitions

  • Polyphosphonate derivatives for toothpaste compositions are Polyphosphonate derivatives for toothpaste compositions.
  • the invention relates to a polyphosphonate compound used as a medicament, in particular for oral hygiene, an oral hygiene composition comprising such a bisphophonate compound, the use of such a compound for the preparation of a medicament more specifically intended for the prevention of the appearance and development of dental plaque.
  • the oral bacterial flora is made up of very many taxa in association, and organized in the form of a multigeneric biofilm commonly called dental plaque. This flora is associated with the development of carious and periodontal pathology. Certain species such as Streptococcus mutans, S. sobrinus and Lactobacillus, identifiable in this biofilm, are cariogenic and constitute the primary colonizing species of dental surfaces by interaction with molecules of salivary origin.
  • the bacterial species of the oral flora express virulence factors the effects of which are observable locally and certain from a distance: colonization factors (adhesins), persistence (aggressors, stress proteins ...), and tissue destruction (aggins, protease activities ).
  • Streptococci in the oral cavity colonize tooth surfaces via adhesins, which are protein components of the bacterial wall.
  • S. mutans plays a key role both in the initiation and the development of the carious process thanks to its homofermentative metabolism, but also to its capacity to produce homopolymers of glucose in particular (soluble dextrans), synthesized by glucosyltransferases (GTFs).
  • GTFs participate in the adhesion capacities of cariogenic streptococci via glucose polymers.
  • Decay can affect the enamel, dentin and pulp of the tooth. Symptoms can range from simple demineralization to complete destruction of the tooth.
  • Dental plaque adheres to the very thin layer that surrounds each tooth and that includes salivary proteins.
  • a 5-day plaque if not brushed off, can form a thick layer up to about 60 micrometers.
  • a cariogenic plaque can often include 2x10 8 S. mutans bacteria / mg of dry weight and can quickly releasing enough glucose and fructose by fermentation to generate an acidic plaque pH of 5.5 or less causing demineralization of dental surfaces.
  • chlorhexidine Certain substances have been identified as inhibiting the formation of dental plaque, such as chlorhexidine, when it is used twice a day in oral rinse at a concentration of 0.2%. Its prolonged persistence in the oral cavity makes it more effective. Chlorhexidine also has an affinity for hydroxyapatite (mineral component of enamel), but due to its side effects (staining of teeth, mucosa and composites), chlorhexidine is not suitable for long-term treatment .
  • Chlorhexidine in oral rinse remains one of the most recommended antiseptics in the prevention of dental plaque, being indicated when the mechanical methods must be suspended or temporarily reinforced.
  • Another non-ionic anti-bacterial agent, triclosan, mentioned for example in US Pat. No. 6,136,298, combined with a copolymer of polyvinyl methyl ether and maleic acid has the advantage of reducing plaque, gingivites, tartar and cavities, without side effects and without modifying the ecology of the oral flora.
  • Another approach is to act on the specific interactions that exist between microorganisms in the oral cavity and dental surfaces. Specific compounds can interfere with these interactions and constitute a means of preventing or controlling the formation of dental plaque.
  • Surfactants or polymers have thus been used intended to reduce or prevent salivary proteins from being adsorbed on the surface of the enamel. Surfactants naturally tend to adsorb on all surfaces, greatly reducing interfacial energy. The affinity of the molecule for an interface is generally affected by the properties of the hydrophobic and hydrophilic parts. Most surfactants adsorb on the surface in well-defined directions, and the action on protein adsorption and desorption can be closely associated with the orientation of the surfactants on the surface.
  • a dental composition comprises between 0.01 and 20% by weight of a surfactant, or of a mixture of surfactants, anionic, cationic, nonionic, and zwitterionic.
  • surfactants having an oral tolerance such as monoglycerides, glycerides, monoglycerides sulfonates, other fatty acid esters, alkyl sulfates, polysorbates, alkyl quaternary ammonium compounds, carboxylates, polyoxyethylenes, phosphonates, sodium alkyl sulfates, sodium lauryl sulfates.
  • the invention aims to overcome the drawbacks of the prior art by proposing a compound and a composition which is particularly effective and suitable for oral hygiene, according to different possible applications, in particular toothpaste pastes and gels, mouthwashes, chewing gums, gels. non-abrasive.
  • the invention also aims to provide oral hygiene compositions using an effective amount of active compound, capable of combating the bacterial agents causing alterations in the oral cavity which can be treated topically.
  • the invention aims in particular to obtain a composition
  • a composition comprising a compound capable of both being a good competitive inhibitor of the fixation of the proteins described above, of fixing effectively and sufficiently durably on the dental surface to be protected.
  • a polyphosphonate compound used as a medicament said compound being of general formula I:
  • R1, R2, R3, R5, R6, R7, R8 independently of one another represent a hydrogen atom or a C1-C6 alkyl or aryl group
  • X is a carbon atom C or a nitrogen atom N;
  • A, B and C represent a chemical bond, a C1-C6 alkyl or aryl group, a carbonyl group, or a hydrophilic group;
  • R4 represents: a) either a hydrogen atom, an OH group, a C1-C6 alkyl or aryl group, or a C1-C6 carboxylic acid, a free doublet (if X is nitrogen N); b) or a phosphonate of formula;
  • R9, R10 independently of one another represent a hydrogen atom, or a C1-C6 alkyl or aryl group; c) or a quaternary ammonium group of formula
  • R11, R12, R13 represent independently of each other a hydrogen atom, or a C1-C6 alkyl or aryl group
  • B represents a chemical bond, a C1-C6 alkyl group, a group carbonyl, or a hydrophilic group
  • R'1, R'2, R'3, R'5, R'6, R'7, R'8 independently of one another represent a hydrogen atom, or an alkyl or aryl group in C1-C6;
  • - A ', B' and C represent a chemical bond, a C1-C6 alkyl or aryl group, a carbonyl group, or a hydrophilic group;
  • R'4 represents a C1-C6 alkyl or aryl group, or a C1-C6 carboxylic acid; or a pharmaceutically acceptable salt of these polyphosphonate compounds of formula I or II.
  • This compound I is more especially intended to inhibit the appearance and the development of dental plaque.
  • this compound I is a bisphosphonate compound.
  • R1.R2.R3 are advantageously identical to each other and represent methyl or ethyl groups.
  • R5, R6, R7, R8 are advantageously identical to each other and represent hydrogen atoms or methyl groups.
  • hydrophilic group of 1 to 6 carbon atoms.
  • the hydrophilic group or groups are typically chosen from the groups of formula -LQ, in which L is a chemical bond or a linear or branched C1-C6 alkyl group, and Q is chosen from: a) a hydroxyl, amino or carboxyl group , sulfate, phosphate; b) a linear or branched C1-C6 alkyl group containing one or more hydroxyl, amino, carboxyl, sulfate, phosphate groups; c) a group M, OM, CONHM, NHCOM in which M is a hydrophilic group; d) a hydrophilic group according to points a), b) or c), protected by a group which again becomes a hydrophilic group after biological hydrolysis.
  • the invention relates to an oral composition, advantageously topical and intended for mouth hygiene, comprising a polyphosphonate compound I as described above, or a mixture of such polyphophonate compounds.
  • the composition comprises between 0.01 and 20%, advantageously between 0.05 and 5%, and even more advantageously between approximately 0.1 and 2% by weight of compound I.
  • the composition may also further comprise at least one of the elements chosen from an antibacterial agent, polishing agent, thickening agent, humectant, flavoring, sweetening agent, bleaching agent.
  • the composition is typically in the form of a mouthwash, a liquid to be sprayed, a toothpaste, a toothpaste gel or the like.
  • the subject of the invention is a polyphosphonate compound I as described above for the manufacture of an oral hygiene composition intended to inhibit the appearance and development of dental plaque.
  • alkyl group is meant in the sense of the present invention any alkyl group of 1 to 10 carbon atoms, linear or branched substituted or not, in particular the group CH 3 .
  • carboxylic acid is meant in the sense of the present invention any alkyl group as defined above to which is linked a carboxylic group (-COOH).
  • salts of the polyphosphonate compound I have the same general pharmacological properties as the free acid form and are acceptable from the point of view of toxicity.
  • the following salts are in particular included: acetate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, carbonate, chloride, citrate, lactate, isothionate, malate, methylbromide, methylnitrate, nitrate, ammonium salt , oleate, oxalate, palmitate, phosphate, diphosphate, stearate, sulfate, succinate, tartrate.
  • the bisphosphonate compound comprises a part comprising an acid group
  • pharmaceutically acceptable salt of alkali metal salts, such as the sodium or potassium salts, the calcium or magnesium salts, or the salts formed. with suitable organic ligands such as quaternary ammonium salts.
  • the present invention relates to a method for treating or preventing the development of dental plaque, comprising the administration of such a dentifrice composition, of polyphosphonate compounds in therapeutically effective amount, or of a salt pharmaceutically acceptable polyphosphonate.
  • therapeutically effective amount is meant that the amount of polyphosphonate administered makes it possible to limit and reduce the appearance and development of dental plaque. The invention will be particularly well understood on reading the detailed description which follows.
  • Bisphosphonate compounds characterized by phosphorus-carbon bonds (P-C-P), are stable compounds resistant to chemical or biological hydrolysis, as mentioned in document WO9836064.
  • the polyphosphonate compounds used have a behavior complementary to that of surfactants.
  • a surfactant is a material which comprises both a non-polar hydrophobic part and a polar hydrophilic part, and which is capable of forming an interface between two surfaces of different polarities.
  • the term surface is commonly used for surfactants and can be both a solid surface or a liquid surface, or a non-solid surface and a liquid surface.
  • the non-polar part must be large enough to be sufficiently attached to a non-polar solid surface.
  • the polarity ratio between the hydrophilic part and the hydrophobic part must also be appropriate and optimized for each application.
  • Nonionic surfactants are generally defined as the product of the condensation of alkylene oxide groups (hydrophilic) with a hydrophobic compound which may be aliphatic or aromatic alkyl.
  • hydrophobic compound which may be aliphatic or aromatic alkyl.
  • polyoxyethylene sorbitan esters polyoxyethylene sorbitan esters, fatty alcohol ethoxylates, products resulting from the condensation of ethylene oxide and from the reaction product of propylene oxide and ethylene diamine.
  • Amphoteric surfactants are generally defined as derivatives of secondary and tertiary aliphatic amines in which the aliphatic radical can be linear or branched, in which one of the aliphatic substituents has 8 to about 18 carbon atoms, and in which one of the substituents aliphatics comprises an anionic group soluble in water such as a carboxylate, sulfonate, sulfate, phosphate, or phosphonate group. Mention may also be made of betaines.
  • Anionic surfactants typically include the water-soluble salts of alkyl sulfates having 8 to 20 carbon atoms in the alkyl radical (example: sodium alkyl sulfate) and the water-soluble salts of sulfonated monoglycerides fatty acids with 8 to 20 carbon atoms (example: sodium lauryl sulfate, coconut monoglyceride sulfonates, sarcosinates such as lauroyl sarcosinates, taurates, lauryl sulfoacetates, lauroyl isothionates, laureth carboxylates , dodecyl benzenesulfonates.
  • the compound I demonstrated a high efficiency, this compound comprising at least two phosphonic groups in order to ensure the fixing on the surface to be protected, and at least one quaternary ammonium group advantageously trimethyl.
  • the results are much better with two phosphonic groups than with one. It would seem that the presence of at least two phosphonic groups makes it possible to have at least two anchoring points for compound I on the surface to be protected.
  • the increase in stability seems to be linked to a steric parameter: the synergy of two close phosphonate functions brings better stability to the polyphosphonate compound and in particular to the bisphosphonate due to the single X atom which separates the two phosphorus atoms.
  • Compound I can also advantageously include: - two phosphonic groups (for good fixation) and two side chains of quaternary ammonium (for less repulsion during fixation) - or else two phosphonic groups (for good fixation), one quaternary ammonium chain (for less repulsion during fixing), and a bond with another polyphosphonic compound I, the adjacent compounds I then having a tendency to form a layer distributed over the surface to be protected.
  • the radical A and / or B of compound I can be an aryl group.
  • Aryl group means within the meaning of the present invention one or more aromatic rings having 5 to 8 carbon atoms, which can be joined or fused, substituted or not.
  • the aryl groups can be phenyl groups. But typically there will be no particular interest in having more than three carbon atoms or a phenyl radical on the substituents of compound I so as not to generate unwanted hydrophobic interactions.
  • the carbon chain of compound I can nevertheless typically contain up to six carbon atoms or hetero atoms.
  • the compound I advantageously comprises hydrophilic groups between the phosphonic group functionalities and the quaternary ammonium functionality or functionalities of the molecule.
  • the invention relates to the optical isomers of the polyphosphonate compound I.
  • TMADP 2,2-diphosphono-5-hydroxy-3-oxa-6-hexyltrimethylammonium chloride
  • HEDP hydroxyethylidene bisphosphonic acid
  • glycidyltrimethylammonium chloride 6-trimethyiammoniohexyl ⁇ 1, 1-bisphosphonic acid.
  • Compound I is incorporated into a composition for oral hygiene by topical route designated dentifrice composition typically comprising between 0.01 and 20%, advantageously between 0.05 and 5%, and even more advantageously between approximately 0.1 and 2% by weight of compound I.
  • dentifrice composition typically comprising between 0.01 and 20%, advantageously between 0.05 and 5%, and even more advantageously between approximately 0.1 and 2% by weight of compound I.
  • toothpaste means a composition for topical application to the teeth such as a liquid composition (for example mouthwash and rinsing) or a toothpaste (in the form of gel, powder or paste).
  • composition can be applied to the teeth by various suitable techniques including brushing, dyeing, spraying, mouthwash. Other possible means of application are known to those skilled in the art.
  • Various other ingredients can be incorporated into the composition, such as prophylactics, polishing agents, other surfactants, flavorings, suitable thickening or wetting agents. It must also be ensured that these agents do not prevent the desired fixation of the polyphosphonates on the dental surfaces.
  • prophylactic agents mention may be made of caries-limiting compounds such as sodium fluoride, potassium fluoride, hexylamine hydrofluoride.
  • these prophylactic agents are present in sufficient quantities to provide a concentration of fluoride ion of the order of 0.5 to 2% by weight of the dentifrice composition.
  • polishing agents there may be mentioned resins (product of condensation of urea and formaldehyde), particles of resins polymerized by heating (see US 3,070,510), silica xerogels (US 3,538,230), precipitated silica particles, calcium pyrophosphate, insoluble sodium metaphosphate, hydrated alumina, dicalcium orthophosphate, these agents being sufficiently non-abrasive not to undesirably alter the surface of the tooth or dentin. These agents can represent for example 5 to 95% by weight of the toothpaste composition.
  • the dentifrice composition is in the form of an oral liquid it typically contains an alcohol, a solubilizer, a non-abrasive cleaning agent, and when it is in the form of a gel it typically comprises a thickening agent.
  • the humectants glycerin, sorbitol, polyethylene glycol and other polyhydric alcohols, these humectants possibly representing up to approximately 35% of the weight of the toothpaste composition.
  • the toothpaste composition may comprise a liquid phase representing 10 to 99% by weight and comprising water and a humectant in variable proportion.
  • the flavors it is possible to use optionally associated mint oils, menthol, eugenol, orange, lemon, anise, vanillin, thymol, these agents generally representing less than 5% by weight of the toothpaste composition.
  • the composition can also comprise, for example, sweetening agents (sodium saccharinate), bleaching agents (titanium dioxide or zinc oxide), vitamins, other anti-plaque agents (zinc salts, including zinc citrate , copper salts, tin salts, strontinum salts, allantoin, chlorhexidine), antibacterial agents (triclosan: 2 ', 4,4'- trichloro-2-hydroxy-diphenyl ether), anti-calculus agents (pyrophosphates metal di and / or tetra alkali), pH adjusting agents, coloring agents, anti-caries agents (casein, urea, calcium glycerophosphates, sodium fluoride, monosodium fluorophosphate), stain-resistant compounds (silicone polymers ), anti-inflammatory agents (substituted salicylanilides), desensitizing agents (potassium nitrate, potassium citrate). Other agents are cited in US Pat. No. 5,258,173. The pH of the toothpaste
  • composition for a toothpaste or gel - polyphosphonate compound 1: 0.2 to 5%
  • Example of a non-abrasive gel composition such as a subgingival gel: - polyphosphonate compound 1: 0.2 to 5%
  • a dental solution will typically include 90 to 99% water.
  • a chewing gum type composition will typically include a base gum (about 50% to 99%), a flavoring agent (about 0.4% to 2%), a sweetening agent (about 0.01% to 20%).
  • humectants such as glycerin, propylene glycol
  • a mixer a mixer
  • humectants such as glycerin, propylene glycol
  • a pigment, a pH adjuster if necessary, an anti-caries agent is then added.
  • These ingredients are mixed until a homogeneous phase is obtained, to which a polishing agent is then mixed.
  • the mixture is then transferred to a high speed mixer, in which a thickening agent, an aroma, and the compound I are mixed, under reduced pressure from 20 to 100 mm of Hg.
  • the product obtained is a semi-solid and extrudable paste .
  • the toothpaste composition is typically applied regularly, every day or every two or three days, from one to three times a day, at a pH of about 5 to 9 or 10, generally between 5.5 and 8.
  • the compound obtained can be used in compositions according to the present invention.

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Abstract

The invention relates to a medicament containing the polyphosphonate compound of general formula (I) as an active ingredient.

Description

Dérivés poly-phosphonates pour compositions dentifrices. Polyphosphonate derivatives for toothpaste compositions.
L'invention concerne un composé polyphosphonate utilisé comme médicament, en particulier d'hygiène buccale, une composition d'hygiène buccale comprenant un tel composé bisphophonates, l'utilisation d'un tel composé pour la préparation d'un médicament plus spécifiquement destiné à la prévention de l'apparition et le développement de la plaque dentaire.The invention relates to a polyphosphonate compound used as a medicament, in particular for oral hygiene, an oral hygiene composition comprising such a bisphophonate compound, the use of such a compound for the preparation of a medicament more specifically intended for the prevention of the appearance and development of dental plaque.
La flore bactérienne buccale est constituée de très nombreux taxons en association, et organisée sous forme d'un biofilm multigénérique communément appelé plaque dentaire. Cette flore est associée au développement de la pathologie carieuse et parodontale. Certaines espèces telles que Streptococcus mutans, S. sobrinus et Lactobacillus, identifiables dans ce biofilm, sont cariogènes et constituent les espèces colonisatrices primaires des surfaces dentaires par interaction avec des molécules d'origine salivaire.The oral bacterial flora is made up of very many taxa in association, and organized in the form of a multigeneric biofilm commonly called dental plaque. This flora is associated with the development of carious and periodontal pathology. Certain species such as Streptococcus mutans, S. sobrinus and Lactobacillus, identifiable in this biofilm, are cariogenic and constitute the primary colonizing species of dental surfaces by interaction with molecules of salivary origin.
Les espèces bactériennes de la flore buccale expriment des facteurs de virulence dont les effets sont observables localement et certains à distance : facteurs de colonisation (adhésines), de persistance (agressines, protéines de stress...), et de destruction tissulaire (agressines, activités protéasiques...). Les streptocoques de la cavité buccale colonisent les surfaces dentaires par l'intermédiaire des adhésines qui sont de constituants protéiques de la paroi bactérienne. S. mutans joue un rôle-clé à la fois dans le déclenchement et le développement du processus carieux grâce à son métabolisme de type homofermentaire, mais aussi à sa capacité de produire des homopolymères de glucose en particulier (dextranes solubles), synthétisés par des glucosyltransférases (GTFs). Les GTFs participent aux capacités d'adhérence des streptocoques cariogènes par l'intermédiaire des polymères de glucose.The bacterial species of the oral flora express virulence factors the effects of which are observable locally and certain from a distance: colonization factors (adhesins), persistence (aggressors, stress proteins ...), and tissue destruction (aggins, protease activities ...). Streptococci in the oral cavity colonize tooth surfaces via adhesins, which are protein components of the bacterial wall. S. mutans plays a key role both in the initiation and the development of the carious process thanks to its homofermentative metabolism, but also to its capacity to produce homopolymers of glucose in particular (soluble dextrans), synthesized by glucosyltransferases (GTFs). GTFs participate in the adhesion capacities of cariogenic streptococci via glucose polymers.
La carie peut affecter l'émail, la dentine et la pulpe de la dent. Les symptômes peuvent aller de la simple déminéralisation jusqu'à la destruction totale de la dent.Decay can affect the enamel, dentin and pulp of the tooth. Symptoms can range from simple demineralization to complete destruction of the tooth.
La plaque dentaire adhère à la couche très mince qui entoure chaque dent et qui comprend des protéines salivaires. Une plaque dentaire de 5 jours, si elle n'est pas retirée par brossage, peut former une couche épaisse atteignant environ 60 micromètres. Une plaque cariogène peut souvent comprendre 2x108 bactéries S.mutans/mg de poids sec et peut rapidement libérer par fermentation du glucose et du fructose suffisamment pour générer un pH acide de la plaque de 5.5 ou moins provoquant une déminéralisation des surfaces dentaires.Dental plaque adheres to the very thin layer that surrounds each tooth and that includes salivary proteins. A 5-day plaque, if not brushed off, can form a thick layer up to about 60 micrometers. A cariogenic plaque can often include 2x10 8 S. mutans bacteria / mg of dry weight and can quickly releasing enough glucose and fructose by fermentation to generate an acidic plaque pH of 5.5 or less causing demineralization of dental surfaces.
L'apparition de la plaque dentaire et son développement peuvent être inhibés notamment par un brossage de dents rigoureux. Toutefois celui-ci présente un caractère fastidieux utilisé quotidiennement, durant toute la vie nécessitant une forte motivation, une certaine habileté et une bonne instruction. En outre une bonne hygiène buccale par brossage régulier ne suffit pas nécessairement pour éviter les gingivites et la formation de la plaque dentaire notamment.The appearance of dental plaque and its development can be inhibited in particular by rigorous brushing of teeth. However, it has a tedious nature used daily, throughout life requiring strong motivation, a certain skill and good instruction. In addition, good oral hygiene by regular brushing is not necessarily enough to avoid gingivitis and the formation of dental plaque in particular.
Par ailleurs, de nombreuses personnes sont incapables de mettre en œuvre correctement les techniques préconisées de brossage. En outre, l'utilisation d'antibiotiques est proscrite compte tenu de leurs effets secondaires de façon systématique dans la prophylaxie de la plaque dentaire. Les molécules à pouvoir bacteriolytique sont susceptibles d'entraîner la libération massive des constituants bactériens ou la dissémination de gènes de résistance aux antibiotiques. Le rôle des antiseptiques et des antibiotiques ne peut être que transitoire, additionnel ou supplétif.In addition, many people are unable to correctly implement the recommended brushing techniques. In addition, the use of antibiotics is prohibited given their side effects in a systematic way in the prophylaxis of dental plaque. The molecules with bacteriolytic power are capable of causing the massive release of the bacterial constituents or the dissemination of antibiotic resistance genes. The role of antiseptics and antibiotics can only be transient, additional or supplementary.
Certaines substances ont été identifiées comme inhibant la formation de la plaque dentaire, telles que la chlorhexidine, quand elle est utilisée deux fois par jour en rinçage buccal à une concentration de 0,2%. Sa rémanence prolongée dans la cavité buccale rend son efficacité plus grande. La chlorhexidine possède également une affinité pour l'hydroxyapatite (composant minéral de l'émail), mais du fait de ses effets secondaires (coloration des dents, de la muqueuse et des composites), la chlorhexidine ne convient pas pour un traitement de longue durée.Certain substances have been identified as inhibiting the formation of dental plaque, such as chlorhexidine, when it is used twice a day in oral rinse at a concentration of 0.2%. Its prolonged persistence in the oral cavity makes it more effective. Chlorhexidine also has an affinity for hydroxyapatite (mineral component of enamel), but due to its side effects (staining of teeth, mucosa and composites), chlorhexidine is not suitable for long-term treatment .
On a constaté que l'usage d'un vernis contenant de la chlorhexidine associée au thymol (Cervitec®, Vivadent) entraîne la réduction de la carie des sillons. Ce vernis semble particulièrement indiqué chez les jeunes patients porteurs d'appareils orthodontiques fixés.It has been found that the use of a varnish containing chlorhexidine associated with thymol (Cervitec®, Vivadent) leads to the reduction of cavity decay. This varnish seems particularly indicated in young patients with fixed orthodontic appliances.
La chlorhexidine en rinçage buccal reste un des antiseptiques les plus recommandés dans la prévention de la plaque dentaire, étant indiquée lorsque les méthodes mécaniques devront être suspendues ou temporairement renforcées. Un autre agent anti-bactérien, non ionique, le triclosan, mentionné par exemple dans le brevet US 6 136 298, associé à un copolymère d'éther polyvinyl méthyle et d'acide maléique présente l'avantage de réduire la plaque, les gingivites, le tartre et les caries, sans effet secondaire et sans modifier l'écologie de la flore buccale. Toutefois, on est toujours à la recherche de nouveaux composés renforçant l'efficacité du traitement contre la plaque dentaire.Chlorhexidine in oral rinse remains one of the most recommended antiseptics in the prevention of dental plaque, being indicated when the mechanical methods must be suspended or temporarily reinforced. Another non-ionic anti-bacterial agent, triclosan, mentioned for example in US Pat. No. 6,136,298, combined with a copolymer of polyvinyl methyl ether and maleic acid has the advantage of reducing plaque, gingivites, tartar and cavities, without side effects and without modifying the ecology of the oral flora. However, we are always on the lookout for new compounds that enhance the effectiveness of treatment against dental plaque.
Une autre approche consiste à agir sur les interactions spécifiques qui existent entre les micro-organismes de la cavité buccale et les surfaces dentaires. Des composés spécifiques peuvent interférer avec ces interactions et constituer un moyen de prévention ou de contrôle de la formation de la plaque dentaire. On a ainsi utilisé des surfactants ou des polymères destinés à réduire ou empêcher les protéines salivaires de s'adsorber à la surface de l'émail. Les surfactants tendent en effet naturellement à s'adsorber à toutes les surfaces réduisant fortement l'énergie interfaciale. L'affinité de la molécule pour une interface est généralement affectée par les propriétés des parties hydrophobes et hydrophiles. La plupart des surfactants s'adsorbent sur la surface selon des orientations bien définies, et l'action sur l'adsorption et la désorption des protéines peut être intimement associée à l'orientation des surfactants sur la surface.Another approach is to act on the specific interactions that exist between microorganisms in the oral cavity and dental surfaces. Specific compounds can interfere with these interactions and constitute a means of preventing or controlling the formation of dental plaque. Surfactants or polymers have thus been used intended to reduce or prevent salivary proteins from being adsorbed on the surface of the enamel. Surfactants naturally tend to adsorb on all surfaces, greatly reducing interfacial energy. The affinity of the molecule for an interface is generally affected by the properties of the hydrophobic and hydrophilic parts. Most surfactants adsorb on the surface in well-defined directions, and the action on protein adsorption and desorption can be closely associated with the orientation of the surfactants on the surface.
Il existe un très grand nombre de surfactants pouvant être utilisés, notamment pour améliorer l'hygiène buccale, dont certains sont mentionnés dans le brevet US 6,013,274. Par exemple une composition dentaire comprend entre 0,01 et 20% en poids d'un surfactant, ou d'un mélange de surfactants, anionique, cationique, non ionique, et zwittérionique. Par exemple on peut citer des surfactants ayant une tolérance orale tels que monoglycérides, des glycérides, des monoglycérides sulfonates, d'autres esters d'acides gras, des sulfates d'alkyles, des polysorbates, des composés alkyles ammonium quaternaire, des carboxylates, des polyoxyéthylènes, des phosphonates, des sulfates d'alkyles de sodium, des lauryl sulfates de sodium.There are a very large number of surfactants which can be used, in particular for improving oral hygiene, some of which are mentioned in US Patent 6,013,274. For example, a dental composition comprises between 0.01 and 20% by weight of a surfactant, or of a mixture of surfactants, anionic, cationic, nonionic, and zwitterionic. For example, mention may be made of surfactants having an oral tolerance such as monoglycerides, glycerides, monoglycerides sulfonates, other fatty acid esters, alkyl sulfates, polysorbates, alkyl quaternary ammonium compounds, carboxylates, polyoxyethylenes, phosphonates, sodium alkyl sulfates, sodium lauryl sulfates.
Les surfactants se fixent de manière compétitive à la surface dentaire, empêchant ainsi les protéines d'y adhérer. Toutefois, la difficulté réside dans l'identification d'un surfactant particulièrement approprié qui a une très bonne efficacité pour lutter contre la plaque dentaire. Par ailleurs, certains surfactants, comme cela est décrit dans le brevet US 5,993,784, ont un effet moussant excessif pour l'utilisateur.Surfactants attach competitively to the tooth surface, preventing proteins from sticking to it. However, the difficulty lies in identifying a particularly suitable surfactant which has very good efficacy in combating dental plaque. In addition, some surfactants, as described in US Patent 5,993,784, have an excessive foaming effect for the user.
On connaît également l'utilisation de molécules qui induisent une précipitation des protéines (précipitants), telles que des molécules polyioniques qui déplacent la pellicule de protéine de la dent et forment des ponts entre et avec les protéines (les gommes de xanthane, par exemple).The use of molecules which induce precipitation of proteins (precipitants) is also known, such as polyionic molecules which displace the protein film of the tooth and form bridges between and with proteins (for example xanthan gums). .
US 5,270,365 et EP 0 216681 décrivent l'utilisation de l'alendronateUS 5,270,365 and EP 0 216681 describe the use of alendronate
(acide 4-amino-1-hydroxybutilidène-1,1-biphosphonique) par voie orale ou par injection respectivement pour le traitement de la parodontite associée à la perte de l'os dentaire et contre le déchaussement des dents.(4-amino-1-hydroxybutilidene-1,1-biphosphonic acid) orally or by injection respectively for the treatment of periodontitis associated with the loss of dental bone and against tooth loosening.
L'invention vise à palier les inconvénients de l'art antérieur en proposant un composé et une composition particulièrement efficace et adaptée à l'hygiène buccale, selon différentes applications possibles, notamment pâtes et gels dentifrices, bains de bouche, chewing-gums, gels non abrasifs. L'invention vise également à fournir des compositions d'hygiène buccale utilisant une quantité efficace de composé actif, apte à lutter contre les agents bactériens à l'origine d'altérations de la cavité buccale pouvant être traitées par voie topique.The invention aims to overcome the drawbacks of the prior art by proposing a compound and a composition which is particularly effective and suitable for oral hygiene, according to different possible applications, in particular toothpaste pastes and gels, mouthwashes, chewing gums, gels. non-abrasive. The invention also aims to provide oral hygiene compositions using an effective amount of active compound, capable of combating the bacterial agents causing alterations in the oral cavity which can be treated topically.
L'invention vise en particulier à obtenir une composition comprenant un composé capable à la fois d'être un bon inhibiteur compétitif de la fixation des protéines décrites ci-dessus, de se fixer efficacement et suffisamment durablement sur la surface dentaire à protéger.The invention aims in particular to obtain a composition comprising a compound capable of both being a good competitive inhibitor of the fixation of the proteins described above, of fixing effectively and sufficiently durably on the dental surface to be protected.
A cet effet, l'invention a pour objet selon un premier aspect un composé polyphosphonate utilisé comme médicament, ledit composé étant de formule générale I : To this end, the subject of the invention is, according to a first aspect, a polyphosphonate compound used as a medicament, said compound being of general formula I:
(i)(I)
Dans laquelle :In which :
1) R1,R2,R3,R5,R6,R7,R8 représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle ou aryle en C1-C6 ;1) R1, R2, R3, R5, R6, R7, R8 independently of one another represent a hydrogen atom or a C1-C6 alkyl or aryl group;
2) X est un atome de carbone C ou un atome d'azote N ;2) X is a carbon atom C or a nitrogen atom N;
3) A, B et C représentent une liaison chimique, un groupe alkyle ou aryle en C1-C6, un groupe carbonyle, ou un groupe hydrophile ;3) A, B and C represent a chemical bond, a C1-C6 alkyl or aryl group, a carbonyl group, or a hydrophilic group;
4) R4 représente : a) soit un atome d'hydrogène, un groupe OH, un groupe alkyle ou aryle en C1-C6, ou un acide carboxylique en C1-C6, un doublet libre (si X est un azote N) ; b) soit un phosphonate de formule ;4) R4 represents: a) either a hydrogen atom, an OH group, a C1-C6 alkyl or aryl group, or a C1-C6 carboxylic acid, a free doublet (if X is nitrogen N); b) or a phosphonate of formula;
O:O:
dans laquelle R9,R10 représentent indépendamment l'un de l'autre un atome d'hydrogène, ou un groupe alkyle ou aryle en C1-C6 ; c) soit un groupe ammonium quaternaire de formule wherein R9, R10 independently of one another represent a hydrogen atom, or a C1-C6 alkyl or aryl group; c) or a quaternary ammonium group of formula
dans laquelle R11,R12,R13 représentent indépendamment l'un de l'autre un atome d'hydrogène, ou un groupe alkyle ou aryle en C1-C6, et B représente une liaison chimique, un groupe alkyle en C1-C6, un groupe carbonyle, ou un groupe hydrophile ; d) soit un groupe hydrophile ; e) soit un composé polyphosphonate de formule générale II suivante :in which R11, R12, R13 represent independently of each other a hydrogen atom, or a C1-C6 alkyl or aryl group, and B represents a chemical bond, a C1-C6 alkyl group, a group carbonyl, or a hydrophilic group; d) either a hydrophilic group; e) or a polyphosphonate compound of general formula II below:
(II) dans laquelle :(II) in which:
- R'1,R'2,R'3,R'5,R'6,R'7,R'8 représentent indépendamment l'un de l'autre un atome d'hydrogène, ou un groupe alkyle ou aryle en C1-C6 ;- R'1, R'2, R'3, R'5, R'6, R'7, R'8 independently of one another represent a hydrogen atom, or an alkyl or aryl group in C1-C6;
- X' est un atome de C ou un atome de N ;- X 'is an atom of C or an atom of N;
- A', B' et C représentent une liaison chimique, un groupe alkyle ou aryle en C1-C6, un groupe carbonyle, ou un groupe hydrophile;- A ', B' and C represent a chemical bond, a C1-C6 alkyl or aryl group, a carbonyl group, or a hydrophilic group;
- et R'4 représente un groupe alkyle ou aryle en C1-C6, ou un acide carboxylique en C1-C6 ; ou un sel pharmaceutiquement acceptable de ces composés polyphosphonates de formule I ou II. Ce composé I est plus spécialement destiné à inhiber l'apparition et le développement de la plaque dentaire.- And R'4 represents a C1-C6 alkyl or aryl group, or a C1-C6 carboxylic acid; or a pharmaceutically acceptable salt of these polyphosphonate compounds of formula I or II. This compound I is more especially intended to inhibit the appearance and the development of dental plaque.
Avantageusement ce composé I est un composé bisphosphonate. R1.R2.R3 sont avantageusement identiques entre eux et représentent des groupes méthyle ou éthyle.Advantageously, this compound I is a bisphosphonate compound. R1.R2.R3 are advantageously identical to each other and represent methyl or ethyl groups.
R5,R6,R7,R8 sont avantageusement identiques entre eux et représentent des atomes d'hydrogène ou des groupes méthyle. Le groupeR5, R6, R7, R8 are advantageously identical to each other and represent hydrogen atoms or methyl groups. The group
BB
II
R4— X-A-R4— X-A-
II
CVS
est avantageusement un groupe hydrophile de 1 à 6 atomes de carbone.is advantageously a hydrophilic group of 1 to 6 carbon atoms.
Le ou les groupes hydrophiles sont typiquement choisis parmi les groupes de formule -L-Q, dans lesquels L est une liaison chimique ou un groupe alkyle en C1-C6 linéaire ou ramifié, et Q est choisi parmi : a) un groupement hydroxyle, aminé, carboxyle, sulfate, phosphate ; b) un groupe alkyle linéaire ou ramifié C1-Ç6 contenant un ou plusieurs groupements hydroxyle, aminé, carboxyle, sulfate, phosphate ; c) un groupement M, OM, CONHM, NHCOM dans lequel M est un groupement hydrophile ; d) un groupement hydrophile selon les points a), b) ou c), protégé par un groupement qui redevient un groupement hydrophile après une hydrolyse biologique.The hydrophilic group or groups are typically chosen from the groups of formula -LQ, in which L is a chemical bond or a linear or branched C1-C6 alkyl group, and Q is chosen from: a) a hydroxyl, amino or carboxyl group , sulfate, phosphate; b) a linear or branched C1-C6 alkyl group containing one or more hydroxyl, amino, carboxyl, sulfate, phosphate groups; c) a group M, OM, CONHM, NHCOM in which M is a hydrophilic group; d) a hydrophilic group according to points a), b) or c), protected by a group which again becomes a hydrophilic group after biological hydrolysis.
A représente de préférence un groupe alkyle en C1-C6 ou un groupe - O-(CH2)n- où n = 1 à 6, éventuellement substitué par un ou plusieurs groupes hydroxyles.A preferably represents a C1-C6 alkyl group or a group - O- (CH 2 ) n - where n = 1 to 6, optionally substituted by one or more hydroxyl groups.
Selon un deuxième aspect, l'invention a pour objet une composition buccale, avantageusement topique et destinée à l'hygiène de la bouche, comprenant un composé polyphosphonate I tel que décrit ci-dessus, ou un mélange de tels composés polyphophonates.According to a second aspect, the invention relates to an oral composition, advantageously topical and intended for mouth hygiene, comprising a polyphosphonate compound I as described above, or a mixture of such polyphophonate compounds.
Selon un mode de réalisation la composition comprend entre 0,01 et 20% , avantageusement entre 0,05 et 5 %, et encore plus avantageusement entre environ 0,1 et 2 % en poids de composé I. La composition peut également comprendre en outre au moins un des éléments choisis parmi un agent antibactérien, agent de polissage, agent épaississant, agent humectant, arôme, agent sucrant, agent de blanchiment.According to one embodiment, the composition comprises between 0.01 and 20%, advantageously between 0.05 and 5%, and even more advantageously between approximately 0.1 and 2% by weight of compound I. The composition may also further comprise at least one of the elements chosen from an antibacterial agent, polishing agent, thickening agent, humectant, flavoring, sweetening agent, bleaching agent.
La composition se présente typiquement sous la forme d'un bain de bouche, d'un liquide à pulvériser, d'une pâte dentifrice, d'un gel dentifrice ou analogue.The composition is typically in the form of a mouthwash, a liquid to be sprayed, a toothpaste, a toothpaste gel or the like.
Selon un autre aspect, l'invention a pour un objet un composé polyphosphonate I tel que décrit ci-dessus pour la fabrication d'une composition d'hygiène buccale destinée à inhiber l'apparition et le développement de la plaque dentaire.According to another aspect, the subject of the invention is a polyphosphonate compound I as described above for the manufacture of an oral hygiene composition intended to inhibit the appearance and development of dental plaque.
Par le terme « groupe alkyle », on entend au sens de la présente invention tout groupe alkyle de 1 à 10 atomes de carbones, linéaires ou ramifiés substitué ou non, en particulier, le groupe CH3.By the term "alkyl group" is meant in the sense of the present invention any alkyl group of 1 to 10 carbon atoms, linear or branched substituted or not, in particular the group CH 3 .
Par le terme « acide carboxylique », on entend au sens de la présente invention tout groupe alkyle tel que défini ci-dessus auquel est lié un groupe carboxylique (-COOH).By the term "carboxylic acid" is meant in the sense of the present invention any alkyl group as defined above to which is linked a carboxylic group (-COOH).
Le terme « pharmaceutiquement acceptable » signifie que les sels du composé polyphosphonate I ont les mêmes propriétés pharmacologiques générales que la forme acide libre et sont acceptables d'un point de vue de la toxicité. Parmi les sels possibles, on inclut notamment les sels suivants : acétate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromure, calcium, carbonate, chlorure, citrate, lactate, isothionate, malate, méthylbromure, méthylnitrate, nitrate, sel d'ammonium, oléate, oxalate, palmitate, phosphate, diphosphate, stéarate, sulfate, succinate, tartrate. En outre, lorsque le composé bisphosphonate comprend une partie comprenant un groupement acide, on peut citer comme sel pharmaceutiquement acceptable des sels de métaux alcalins, tels que les sels du sodium ou de potassium, les sels de calcium ou de magnésium, ou des sels formés par des ligands organiques appropriés tels que des sels d'ammonium quaternaire. Selon un mode de réalisation, la présente invention concerne une méthode pour traiter ou prévenir le développement de la plaque dentaire, comprenant l'administration d'une telle composition dentifrice, de composés polyphosphonates en quantité thérapeutiquement efficace, ou d'un sel pharmaceutiquement acceptable de polyphosphonate. Par le terme « quantité thérapeutiquement efficace », on entend que la quantité de polyphosphonate administrée permet de limiter et réduire l'apparition et le développement de la plaque dentaire. L'invention sera particulièrement bien comprise à la lecture de la description détaillée qui suit.The term "pharmaceutically acceptable" means that the salts of the polyphosphonate compound I have the same general pharmacological properties as the free acid form and are acceptable from the point of view of toxicity. Among the possible salts, the following salts are in particular included: acetate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, carbonate, chloride, citrate, lactate, isothionate, malate, methylbromide, methylnitrate, nitrate, ammonium salt , oleate, oxalate, palmitate, phosphate, diphosphate, stearate, sulfate, succinate, tartrate. In addition, when the bisphosphonate compound comprises a part comprising an acid group, mention may be made, as pharmaceutically acceptable salt, of alkali metal salts, such as the sodium or potassium salts, the calcium or magnesium salts, or the salts formed. with suitable organic ligands such as quaternary ammonium salts. According to one embodiment, the present invention relates to a method for treating or preventing the development of dental plaque, comprising the administration of such a dentifrice composition, of polyphosphonate compounds in therapeutically effective amount, or of a salt pharmaceutically acceptable polyphosphonate. By the term "therapeutically effective amount" is meant that the amount of polyphosphonate administered makes it possible to limit and reduce the appearance and development of dental plaque. The invention will be particularly well understood on reading the detailed description which follows.
Les composés bisphosphonates, caractérisés par des liaisons phosphore-carbone (P-C-P), sont des composés stables résistants à des hydrolyses chimiques ou biologiques, comme rappelé dans le document WO9836064.Bisphosphonate compounds, characterized by phosphorus-carbon bonds (P-C-P), are stable compounds resistant to chemical or biological hydrolysis, as mentioned in document WO9836064.
La demanderesse a réussi à démontrer que le composé I est particulièrement efficace pour empêcher la fixation des protéines sur des surfaces notamment dentaires. Une difficulté toute particulière réside dans l'identification de composés ayant un comportement particulièrement efficace pour l'application recherchée.The Applicant has successfully demonstrated that compound I is particularly effective in preventing the attachment of proteins to surfaces, in particular dental surfaces. A very particular difficulty lies in the identification of compounds having a particularly effective behavior for the desired application.
Les composés polyphosphonates utilisés ont un comportement complémentaire par rapport à celui des surfactants.The polyphosphonate compounds used have a behavior complementary to that of surfactants.
Un surfactant est un matériau qui comprend à la fois une partie hydrophobe non polaire et une partie hydrophile polaire, et qui est capable de former une interface entre deux surfaces de différentes polarités. Le terme surface est utilisé couramment pour les surfactants et peut être à la fois une surface solide ou une surface liquide, ou une surface non solide et une surface liquide. Toutefois, tous les matériaux qui comprennent une partie polaire et une partie non polaire ne sont pas des surfactants efficaces. Par exemple, la partie non polaire doit être suffisamment grande pour être suffisamment attachée à une surface solide non polaire. Le rapport de polarité entre la partie hydrophile et la partie hydrophobe doit également être approprié et optimisé pour chaque application.A surfactant is a material which comprises both a non-polar hydrophobic part and a polar hydrophilic part, and which is capable of forming an interface between two surfaces of different polarities. The term surface is commonly used for surfactants and can be both a solid surface or a liquid surface, or a non-solid surface and a liquid surface. However, not all materials that include a polar portion and a non-polar portion are effective surfactants. For example, the non-polar part must be large enough to be sufficiently attached to a non-polar solid surface. The polarity ratio between the hydrophilic part and the hydrophobic part must also be appropriate and optimized for each application.
Les surfactants non ioniques sont généralement définis comme le produit de la condensation de groupes oxyde d'alkylènes (hydrophiles) avec un composé hydrophobe qui peut être aliphatique ou alkyle aromatique. Par exemple, on peut citer les esters de polyoxyéthylène sorbitan, des éthoxylates d'alcools gras, des produits issus de la condensation de l'éthylène oxyde et du produit de la réaction de l'oxyde de propylène et de l'éthylène diamine. Les surfactants amphotériques sont généralement définis comme des dérivés d'aminés aliphatiques secondaires et tertiaires dans lesquels le radical aliphatique peut être linéaire ou ramifié, dont l'un des substituants aliphatiques possède 8 à environ 18 atomes de carbone, et dont l'un des substituants aliphatiques comprend un groupe anionique soluble dans l'eau tel qu'un groupement carboxylate, sulfonate, sulfate, phosphate, ou phosphonate. On peut citer également les bétaines.Nonionic surfactants are generally defined as the product of the condensation of alkylene oxide groups (hydrophilic) with a hydrophobic compound which may be aliphatic or aromatic alkyl. For example, there may be mentioned polyoxyethylene sorbitan esters, fatty alcohol ethoxylates, products resulting from the condensation of ethylene oxide and from the reaction product of propylene oxide and ethylene diamine. Amphoteric surfactants are generally defined as derivatives of secondary and tertiary aliphatic amines in which the aliphatic radical can be linear or branched, in which one of the aliphatic substituents has 8 to about 18 carbon atoms, and in which one of the substituents aliphatics comprises an anionic group soluble in water such as a carboxylate, sulfonate, sulfate, phosphate, or phosphonate group. Mention may also be made of betaines.
Les surfactants anioniques incluent typiquement les sels solubles dans l'eau de sulfates d'alkyles comprenant 8 à 20 atomes de carbone dans le radical alkyle (exemple : sulfate d'alkyle de sodium) et les sels solubles dans l'eau de monoglycérides sulfonés d'acides gras ayant 8 à 20 atomes de carbone (exemple : le lauryl sulfate de sodium, les sulfonates de monoglyceride de noix de coco, les sarcosinates tels que les lauroyl sarcosinates, les taurates, les lauryl sulfoacétates, les lauroyl isothionates, les laureth carboxylates, les dodécyl benzènesulfonates.Anionic surfactants typically include the water-soluble salts of alkyl sulfates having 8 to 20 carbon atoms in the alkyl radical (example: sodium alkyl sulfate) and the water-soluble salts of sulfonated monoglycerides fatty acids with 8 to 20 carbon atoms (example: sodium lauryl sulfate, coconut monoglyceride sulfonates, sarcosinates such as lauroyl sarcosinates, taurates, lauryl sulfoacetates, lauroyl isothionates, laureth carboxylates , dodecyl benzenesulfonates.
La demanderesse a démontré que le composé I faisait preuve d'une grande efficacité, ce composé comportant au moins deux groupes phosphoniques afin d'assurer la fixation sur la surface à protéger, et au moins un groupe ammonium quaternaire avantageusement triméthyle. En ce qui concerne le nombre de groupements phosphoniques, les résultats sont bien meilleurs avec deux groupements phosphoniques qu'avec un seul. Il semblerait que la présence d'au moins deux groupes phosphoniques permette d'avoir au moins deux points d'ancrage du composé I sur la surface à protéger. En outre, l'augmentation de stabilité semble être liée à un paramètre stérique : la synergie de deux fonctions phosphonates proches apporte une meilleure stabilité au composé polyphosphonate et en particulier au bisphosphonate due à l'unique atome X qui sépare les deux atomes de phosphore.The Applicant has demonstrated that the compound I demonstrated a high efficiency, this compound comprising at least two phosphonic groups in order to ensure the fixing on the surface to be protected, and at least one quaternary ammonium group advantageously trimethyl. With regard to the number of phosphonic groups, the results are much better with two phosphonic groups than with one. It would seem that the presence of at least two phosphonic groups makes it possible to have at least two anchoring points for compound I on the surface to be protected. In addition, the increase in stability seems to be linked to a steric parameter: the synergy of two close phosphonate functions brings better stability to the polyphosphonate compound and in particular to the bisphosphonate due to the single X atom which separates the two phosphorus atoms.
La demanderesse a démontré que la présence d'un groupe ammonium quaternaire améliore très nettement les résultats de fixation à la surface à protéger. L'explication de cette efficacité n'est pas évidente, il semblerait que la présence de cet ammonium quaternaire limite la charge globale du composé I ce qui entraînerait une moindre répulsion de ce composé sur la surface, en l'occurrence dentaire, à protéger, et donc une meilleure fixation de ce composé sur le support. Le composé I peut également comporter avantageusement: - deux groupes phosphoniques (pour une bonne fixation) et deux chaînes latérales d'ammonium quaternaire (pour une moindre répulsion lors de la fixation) - ou bien deux groupes phosphoniques (pour une bonne fixation), une chaîne d'ammonium quaternaire (pour une moindre répulsion lors de la fixation), et une liaison avec un autre composé polyphosphonique I, les composés I adjacents ayant alors tendance à former une couche répartie sur la surface à protéger. Le radical A et/ou B du composé I peut être un groupe aryle. Par le termeThe Applicant has demonstrated that the presence of a quaternary ammonium group very clearly improves the results of attachment to the surface to be protected. The explanation for this effectiveness is not obvious, it would seem that the presence of this quaternary ammonium limits the overall charge of compound I which would cause less repulsion of this compound on the surface, in this case dental, to protect, and therefore better fixation of this compound on the support. Compound I can also advantageously include: - two phosphonic groups (for good fixation) and two side chains of quaternary ammonium (for less repulsion during fixation) - or else two phosphonic groups (for good fixation), one quaternary ammonium chain (for less repulsion during fixing), and a bond with another polyphosphonic compound I, the adjacent compounds I then having a tendency to form a layer distributed over the surface to be protected. The radical A and / or B of compound I can be an aryl group. By the term
« groupe aryle », on entend au sens de la présente invention un ou plusieurs cycles aromatiques ayant 5 à 8 atomes de carbones, pouvant être accolés ou fusionnés, substitués ou non. En particulier, les groupes aryles peuvent être des groupes phényle. Mais typiquement il n'y aura pas d'intérêt particulier à avoir plus de trois atomes de carbone ou un radical phényle sur les substituants du composé I afin de ne pas générer des interactions hydrophobes non souhaitées."Aryl group" means within the meaning of the present invention one or more aromatic rings having 5 to 8 carbon atoms, which can be joined or fused, substituted or not. In particular, the aryl groups can be phenyl groups. But typically there will be no particular interest in having more than three carbon atoms or a phenyl radical on the substituents of compound I so as not to generate unwanted hydrophobic interactions.
De préférence, A et/ou B représentent un groupe alkyle en C1-C3 ou un groupe -0-(CH2)n- où n= 1 à 3, éventuellement substitué par un ou plusieurs groupe hydroxyles.Preferably, A and / or B represent a C1-C3 alkyl group or a group -0- (CH 2 ) n - where n = 1 to 3, optionally substituted by one or more hydroxyl groups.
La chaîne carbonée du composé I peut néanmoins comporter typiquement jusqu'à six atomes de carbone ou hétéro-atomes. Afin d'éviter de telles interactions hydrophobes, le composé I comporte avantageusement des groupements hydrophiles entre les fonctionnalités groupe phosphonique et la ou les fonctionnalités ammonium quaternaire de la molécule.The carbon chain of compound I can nevertheless typically contain up to six carbon atoms or hetero atoms. In order to avoid such hydrophobic interactions, the compound I advantageously comprises hydrophilic groups between the phosphonic group functionalities and the quaternary ammonium functionality or functionalities of the molecule.
Grâce à l'efficacité du composé I, une faible quantité dans la composition d'hygiène buccale de ce composé suffit pour être efficace, d'où une économie de composé. Par ailleurs, il est entendu que l'invention concerne les isomères optiques du composé polyphosphonate I.Thanks to the effectiveness of compound I, a small amount in the oral hygiene composition of this compound is sufficient to be effective, hence a saving in compound. Furthermore, it is understood that the invention relates to the optical isomers of the polyphosphonate compound I.
Les essais effectués ont démontré l'efficacité supérieure des composés polyphosphonates I par rapport à d'autres composés en particulier les esters diphosphoniques, les sulfonates, les phosphates, les carboxylates, les diphosphates. Parmi les bisphosphonates, des résultats pariculièrement concluants ont été obtenus avec le chlorure de 2,2-diphosphono-5-hydroxy-3-oxa-6- hexyltriméthylammonium (TMADP) et l'acide 6-triméthyiammoniohexyl~1 ,1- bisphosphonique. Ce composé TMADP a été synthétisé en une seule étape en utilisant l'acide hydroxyéthylidène bisphosphonique (HEDP), et le chlorure de glycidyltriméthylammonium. La réaction a été effectuée dans le DMSO conservé au préalable sur tamis moléculaire. Après dissolution de HEDP (2 g ; 14,5.10 ° mol) à 50°C dans 30 ml de DMSO, l'époxyde (2,2 g ; 14.5.10-3 mol) est ajouté et la température portée à 110°C pendant 24 heures. Le DMSO est ensuite évaporé sous pression réduite et le produit brut est repris dans un minimum d'eau distillée. Le produit TMADP est alors chromatographié sur résine échangeuse de cations (DOWEX 50WX8-20/50 Mesh, H + form). La colonne est éluée à l'eau distillée et le produit pur est recueilli entre pH = 3,0 et 3,5. La demanderesse, soucieuse de réaliser un modèle expliquant la fixation des composés polyphosphonates, a notamment démontré qu'une plaque présentant des propriétés de fixation s'apparentant à une surface dentaire, telle qu'une plaque inox, était efficacement recouverte et protégée contre la fixation de protéines (contamination par les protéines inférieure à 10%), pour une concentration de seulement 2,86x10"4 mol.1-1 de TMADP après 10 minutes d'incubation de cette plaque avec TMAPD (contamination à environ 50% pour une concentration d'environ 1 ,4x10^ mol.1-1) . La quantité suffisante de recouvrement de molécules TMADP sur ce modèle est de 4x103 molécules par nm2 de surface de plaque. Le composé I est intégré dans une composition pour hygiène buccale par voie topique désignée composition dentifrice comprenant typiquement entre 0,01 et 20 %, avantageusement entre 0,05 et 5 %, et encore plus avantageusement entre environ 0,1 et 2 % en poids de composé I. Par le terme dentifrice, on entend une composition pour une application topique sur les dents telle qu'une composition liquide (par exemple bain de bouche et de rinçage) ou une pâte dentifrice (sous la forme de gel, de poudre ou de pâte).The tests carried out have demonstrated the higher efficiency of the polyphosphonate compounds I compared to other compounds in particular the diphosphonic esters, the sulfonates, the phosphates, the carboxylates, the diphosphates. Among the bisphosphonates, particularly conclusive results have been obtained with 2,2-diphosphono-5-hydroxy-3-oxa-6-hexyltrimethylammonium chloride (TMADP) and 6-trimethyiammoniohexyl ~ 1, 1-bisphosphonic acid. This TMADP compound was synthesized in a single step using hydroxyethylidene bisphosphonic acid (HEDP), and glycidyltrimethylammonium chloride. The reaction was carried out in DMSO previously stored on a molecular sieve. After dissolving HEDP (2 g; 14.5.10 ° mol) at 50 ° C in 30 ml of DMSO, the epoxide (2.2 g; 14.5.10- 3 mol) is added and the temperature brought to 110 ° C for 24 hours. The DMSO is then evaporated under reduced pressure and the crude product is taken up in a minimum of distilled water. The TMADP product is then chromatographed on cation exchange resin (DOWEX 50WX8-20 / 50 Mesh, H + form). The column is eluted with distilled water and the pure product is collected between pH = 3.0 and 3.5. The Applicant, anxious to produce a model explaining the fixation of polyphosphonate compounds, has in particular demonstrated that a plate having fixing properties resembling a dental surface, such as a stainless steel plate, was effectively covered and protected against fixation. of proteins (contamination by proteins less than 10%), for a concentration of only 2.86x10 "4 mol.1-1 of TMADP after 10 minutes of incubation of this plate with TMAPD (contamination at about 50% for a concentration about 1, 4x10 ^ mol.1-1). The sufficient amount of covering of TMADP molecules on this model is 4x10 3 molecules per nm 2 of plate surface. Compound I is incorporated into a composition for oral hygiene by topical route designated dentifrice composition typically comprising between 0.01 and 20%, advantageously between 0.05 and 5%, and even more advantageously between approximately 0.1 and 2% by weight of compound I. Pa r the term toothpaste means a composition for topical application to the teeth such as a liquid composition (for example mouthwash and rinsing) or a toothpaste (in the form of gel, powder or paste).
La composition peut être appliquée sur les dents par diverses techniques appropriées notamment le brossage, la teinture, la pulvérisation, le bain de bouche. D'autres moyens d'application possibles sont connus de l'homme du métier. Divers autres ingrédients peuvent être incorporés dans la composition, tels que des agents prophylactiques, des agents de polissage, d'autres surfactants, des arômes, des agents d'épaississement ou d'humectation appropriés. Il faut en outre s'assurer que ces agents n'empêchent pas la fixation souhaitée des polyphosphonates sur les surfaces dentaires.The composition can be applied to the teeth by various suitable techniques including brushing, dyeing, spraying, mouthwash. Other possible means of application are known to those skilled in the art. Various other ingredients can be incorporated into the composition, such as prophylactics, polishing agents, other surfactants, flavorings, suitable thickening or wetting agents. It must also be ensured that these agents do not prevent the desired fixation of the polyphosphonates on the dental surfaces.
Parmi les agents prophylactiques on peut citer des composés limitant les caries tels que du fluorure de sodium, du fluorure de potassium, de l'hydrofluorure d'hexylamine. Typiquement, ces agents prophylactiques sont présents en quantités suffisantes pour fournir une concentration en ion fluorure de l'ordre de 0,5 à 2 % en poids de la composition dentifrice.Among the prophylactic agents, mention may be made of caries-limiting compounds such as sodium fluoride, potassium fluoride, hexylamine hydrofluoride. Typically, these prophylactic agents are present in sufficient quantities to provide a concentration of fluoride ion of the order of 0.5 to 2% by weight of the dentifrice composition.
Parmi les agents de polissage on peut citer des résines (produit de condensation de l'urée et du formaldéhyde), des particules de résines polymérisées par chauffage (voir US 3 070 510), des xérogels de silice (US 3 538 230), des particules de silice précipitées, le pyrophosphate de calcium, le métaphosphate insoluble de sodium, l'alumine hydratée, l'orthophosphate dicalcium, ces agents étant suffisamment peu abrasifs pour ne pas altérer de manière non souhaitée la surface de la dent ou de la dentine. Ces agents peuvent représenter par exemple 5 à 95 % en poids de la composition dentifrice.Among the polishing agents there may be mentioned resins (product of condensation of urea and formaldehyde), particles of resins polymerized by heating (see US 3,070,510), silica xerogels (US 3,538,230), precipitated silica particles, calcium pyrophosphate, insoluble sodium metaphosphate, hydrated alumina, dicalcium orthophosphate, these agents being sufficiently non-abrasive not to undesirably alter the surface of the tooth or dentin. These agents can represent for example 5 to 95% by weight of the toothpaste composition.
Parmi les agents de gélification ou d'épaississement, on peut citer des gommes naturelles, telle que la gomme arabique, la sodium carboxyle cellulose, l'hydroxyéthyl cellulose, représentant généralement 0,5 à 10 % de la composition du dentifrice en poids. Lorsque la composition dentifrice est sous forme d'un liquide buccal elle contient typiquement un alcool, un solubilisant, un agent de nettoyage non abrasif, et lorsqu'elle est sous forme d'un gel elle comprend typiquement un agent épaississant.Among the gelling or thickening agents, there may be mentioned natural gums, such as gum arabic, sodium carboxyl cellulose, hydroxyethyl cellulose, generally representing 0.5 to 10% of the composition of the toothpaste by weight. When the dentifrice composition is in the form of an oral liquid it typically contains an alcohol, a solubilizer, a non-abrasive cleaning agent, and when it is in the form of a gel it typically comprises a thickening agent.
Parmi les humectants, on peut citer la glycérine, le sorbitol, le polyéthylène glycol et d'autres alcools polyhydriques, ces humectants pouvant représenter jusqu'à environ 35 % du poids de la composition dentifrice. Typiquement la composition dentifrice peut comprendre une phase liquide représentant 10 à 99% en poids et comprenant de l'eau et un humectant en proportion variable. Parmi les arômes, on peut utiliser éventuellement associés les huiles de menthe, le menthol, l'eugénol, l'orange, le citron, l'anis, la vanilline, le thymol, ces agents représentant généralement moins de 5 % en poids de la composition dentifrice. La composition peut comprendre en outre par exemple des agents sucrants (saccharinate de sodium), des agents de blanchiment (dioxyde de titane ou oxyde de zinc), des vitamines , d'autres agents anti-plaque ( sels de zinc, dont citrate de zinc, sels de cuivre, sels d'étain, sels de strontinum, allantoïne, chlorhexidine), des agents antibactériens (triclosan : 2',4,4'- trichloro-2-hydroxy-diphényl éther), des agents anti-calculs (pyrophosphates de métal di et/ou tétra alcalins), des agents ajusteurs de pH, des agents colorants, des agents anti-caries (caséine, urée, glycérophosphates de calcium, fluorure de sodium, fluorophosphate de monosodium), des composés antitaches (polymères de silicone), des agents anti-inflammatoires (salicylanilides substitués), des agents désensibilisants (nitrate de potassium, citrate de potassium). D'autres agents sont cités dans le brevet US 5 258 173. Le pH de la composition dentifrice est typiquement compris entre 6 et 10.Among the humectants, mention may be made of glycerin, sorbitol, polyethylene glycol and other polyhydric alcohols, these humectants possibly representing up to approximately 35% of the weight of the toothpaste composition. Typically the toothpaste composition may comprise a liquid phase representing 10 to 99% by weight and comprising water and a humectant in variable proportion. Among the flavors, it is possible to use optionally associated mint oils, menthol, eugenol, orange, lemon, anise, vanillin, thymol, these agents generally representing less than 5% by weight of the toothpaste composition. The composition can also comprise, for example, sweetening agents (sodium saccharinate), bleaching agents (titanium dioxide or zinc oxide), vitamins, other anti-plaque agents (zinc salts, including zinc citrate , copper salts, tin salts, strontinum salts, allantoin, chlorhexidine), antibacterial agents (triclosan: 2 ', 4,4'- trichloro-2-hydroxy-diphenyl ether), anti-calculus agents (pyrophosphates metal di and / or tetra alkali), pH adjusting agents, coloring agents, anti-caries agents (casein, urea, calcium glycerophosphates, sodium fluoride, monosodium fluorophosphate), stain-resistant compounds (silicone polymers ), anti-inflammatory agents (substituted salicylanilides), desensitizing agents (potassium nitrate, potassium citrate). Other agents are cited in US Pat. No. 5,258,173. The pH of the toothpaste composition is typically between 6 and 10.
Exemple de composition pour une pâte ou un gel dentifrice : - composé polyphosphonate 1 : 0,2 à 5%Example of composition for a toothpaste or gel: - polyphosphonate compound 1: 0.2 to 5%
- agent abrasif : 10% à 50%- abrasive agent: 10% to 50%
- agent épaississant : 0,1% à 5%- thickening agent: 0.1% to 5%
- agent humectant : 10% à 55%- humectant: 10% to 55%
- agent arôme : 0,04% à 2% - agent sucrant : 0,1% à 3%- flavoring agent: 0.04% to 2% - sweetening agent: 0.1% to 3%
- agent colorant : 0,01% à 0,5%- coloring agent: 0.01% to 0.5%
- eau : 2 à 45%.- water: 2 to 45%.
Exemple de composition de gel non abrasif tel qu'un gel subgingival : - composé polyphosphonate 1 : 0,2 à 5%Example of a non-abrasive gel composition such as a subgingival gel: - polyphosphonate compound 1: 0.2 to 5%
- agent épaississant : 0,1% à 20%- thickening agent: 0.1% to 20%
- agent humectant : 10% à 55%- humectant: 10% to 55%
- agent arôme : 0,04% à 2%- flavoring agent: 0.04% to 2%
- agent sucrant : 0,1% à 3% - agent colorant : 0,01% à 0,5% - eau : 2 à 45%.- sweetening agent: 0.1% to 3% - coloring agent: 0.01% to 0.5% - water: 2 to 45%.
Exemple de composition de bain de bouche :Example of mouthwash composition:
- composé polyphosphonate 1 : 0,2 à 5% - agent humectant : 0 à 50%- polyphosphonate compound 1: 0.2 to 5% - humectant: 0 to 50%
- agent arôme : 0,04% à 2%- flavoring agent: 0.04% to 2%
- agent sucrant : 0,1% à 3%- sweetening agent: 0.1% to 3%
- agent colorant : 0,01% à 0,5%- coloring agent: 0.01% to 0.5%
- eau : 45 à 95 % - ethanol : 0 à 25%- water: 45 to 95% - ethanol: 0 to 25%
Une solution dentaire comprendra typiquement 90 à 99% d'eau. Une composition de type chewing gum comprendra typiquement une gomme de base (environ 50% à 99%), un agent arôme (environ 0,4% à 2%), un agent sucrant (environ 0,01% à 20%).A dental solution will typically include 90 to 99% water. A chewing gum type composition will typically include a base gum (about 50% to 99%), a flavoring agent (about 0.4% to 2%), a sweetening agent (about 0.01% to 20%).
L'homme du métier incorporera de manière appropriée et sans effort excessif différents agents tels que cela est décrit dans le brevet US 6 132 702.Those skilled in the art will appropriately incorporate and without excessive effort various agents as described in US Pat. No. 6,132,702.
Pour préparer une composition dentifrice on procède par exemple comme suit : les humectants tels que la glycérine, le propylène glycol, sont dispersés avec l'agent sucrant et l'eau dans un mélangeur, jusqu'à ce que le mélange devienne un gel homogène. On ajoute alors un pigment, un ajusteur de pH le cas échéant, un agent anti-caries. Ces ingrédients sont mélangés jusqu'à obtenir une phase homogène, à laquelle on mélange alors un agent de polissage. Le mélange est alors transféré dans un mélangeur à haute vitesse, dans lequel un agent épaississant, un arôme, et le composé I sont mélangés, sous pression réduite de 20 à 100 mm de Hg. Le produit obtenu est une pâte semi-solide et extrudable.To prepare a toothpaste composition, the procedure is for example as follows: humectants such as glycerin, propylene glycol, are dispersed with the sweetening agent and water in a mixer, until the mixture becomes a homogeneous gel. A pigment, a pH adjuster if necessary, an anti-caries agent is then added. These ingredients are mixed until a homogeneous phase is obtained, to which a polishing agent is then mixed. The mixture is then transferred to a high speed mixer, in which a thickening agent, an aroma, and the compound I are mixed, under reduced pressure from 20 to 100 mm of Hg. The product obtained is a semi-solid and extrudable paste .
La composition dentifrice est typiquement appliquée régulièrement, chaque jour ou tous les deux ou trois jours, d'une à trois fois par jour, à un pH d'environ 5 à 9 ou 10, en général entre 5,5 et 8.The toothpaste composition is typically applied regularly, every day or every two or three days, from one to three times a day, at a pH of about 5 to 9 or 10, generally between 5.5 and 8.
Synthèse de l'acide 6-triméthviammoniohexyM,1- bisphosphoniqueSynthesis of 6-trimethviammoniohexyM, 1- bisphosphonic acid
(CH3)3-N+-(CH2)5-COOH + H3P03 + PCI3 >- (CH3)3-N+-(CH2)5-C(P03H2)2OH Mode opératoire(CH 3 ) 3 -N + - (CH 2 ) 5 -COOH + H 3 P0 3 + PCI 3 > - (CH 3 ) 3 -N + - (CH 2 ) 5 -C (P0 3 H 2 ) 2 OH Procedure
Dans un tricol, sont mélangés 1 équivalent d'acide 6-trimethylammonio caproïque et 6 équivalents H3PO3 Le mélange est chauffé à 85°C pendant 10 minutes. 3 équivalents de PCI3 sont ajoutés goutte à goutte et le mélange agité pendant deux heures. Le produit obtenu est traité avec 4ml d'eau et porté à reflux pendant 12 heures. Après passage sur charbon actif, le solvant est évaporé sous vide et le produit de la réaction est repris dans un minimum d'eau. Le produit désiré est obtenu après précipitation dans un excès d'éthanol.In a three-necked flask, 1 equivalent of 6-trimethylammonio caproic acid and 6 equivalents H 3 PO 3 are mixed. The mixture is heated at 85 ° C. for 10 minutes. 3 equivalents of PCI3 are added dropwise and the mixture stirred for two hours. The product obtained is treated with 4 ml of water and brought to reflux for 12 hours. After passing over active carbon, the solvent is evaporated under vacuum and the reaction product is taken up in a minimum of water. The desired product is obtained after precipitation in an excess of ethanol.
Rendement = 35%Yield = 35%
RMN 1H, 500MHz, d (ppm) : 3,27 m, CH2-N+ (2H) ; 3,05 s, (CH3)3N+ (9H); 1 ,91 m, CH2-C-P (2H) ; 1 ,77 m, CH2 (2H) ; 1 ,61 m, CH2 (2H) ; 1 ,36 m, CH2 (2H) 1 H NMR, 500 MHz, d (ppm): 3.27 m, CH 2 -N + (2H); 3.05 s, (CH 3 ) 3 N + (9H); 1.91 m, CH 2 -CP (2H); 1.77 m, CH 2 (2H); 1.61 m, CH 2 (2H); 1.36 m, CH 2 (2H)
RMN 31P, 500MHz, d (ppm) : 19,44 ppm 31 P NMR, 500 MHz, d (ppm): 19.44 ppm
Le composé obtenu peut être utilisé dans des compositions selon la présente invention. The compound obtained can be used in compositions according to the present invention.

Claims

REVENDICATIONS
1. Médicament contenant en tant que principe actif le composé polyphosphonate de formule générale I :1. Medicament containing as active principle the polyphosphonate compound of general formula I:
Dans laquelle :In which :
1) R1, R2, R3, R5, R6, R7, R8 représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe alkyle ou aryle en C1-C6 ;1) R1, R2, R3, R5, R6, R7, R8 independently of one another represent a hydrogen atom or a C1-C6 alkyl or aryl group;
2) X est un atome de carbone C ou un atome d'azote N ; 3) A représente un groupe alkyle ou aryle en C1-C6, un groupe carbonyle ou un groupe hydrophile, B et C représentent une liaison chimique, un groupe alkyle ou aryle en C1-C6, un groupe carbonyle, ou un groupe hydrophile ; 4) R4 représente : a) soit un atome d'hydrogène, un groupe OH, un groupe alkyle ou aryle en C1-C6, ou un acide carboxylique en C1-C6, un doublet libre (si X est un azote N) ; b) soit un phosphonate de formule :2) X is a carbon atom C or a nitrogen atom N; 3) A represents a C1-C6 alkyl or aryl group, a carbonyl group or a hydrophilic group, B and C represent a chemical bond, a C1-C6 alkyl or aryl group, a carbonyl group, or a hydrophilic group; 4) R4 represents: a) either a hydrogen atom, an OH group, a C1-C6 alkyl or aryl group, or a C1-C6 carboxylic acid, a free doublet (if X is nitrogen N); b) or a phosphonate of formula:
dans laquelle R9, R10 représentent indépendamment l'une de l'autre un atome d'hydrogène, ou un groupe alkyle ou aryle en C1-C6 ; c) soit un groupe ammonium quaternaire de formule dans laquelle R11, R12, R13 représentent indépendamment l'un de l'autre un atome d'hydrogène, ou un groupe alkyle ou aryle en C1-C6, et B représente un liaison chimique, un groupe alkyle en C1-C6, un groupe carbonyle, ou un groupe hydrophile ; d) soit un groupe hydrophile ; e) soit un composé polyphosphonate de formule générale II suivante : wherein R9, R10 independently of one another represent a hydrogen atom, or a C1-C6 alkyl or aryl group; c) or a quaternary ammonium group of formula in which R11, R12, R13 represent, independently of one another, a hydrogen atom, or a C1-C6 alkyl or aryl group, and B represents a chemical bond, a C1-C6 alkyl group, a group carbonyl, or a hydrophilic group; d) either a hydrophilic group; e) or a polyphosphonate compound of general formula II below:
dans laquelle : in which :
- R'1 R'2, R'3, R'5, R'6, R'7, R'8 représentent indépendamment l'un de l'autre un atome d'hydrogène, ou un groupe alkyle ou aryle en C1-C6 ;- R'1 R'2, R'3, R'5, R'6, R'7, R'8 independently of one another represent a hydrogen atom, or a C1 or C aryl group -C6;
- X' est un atome de C ou un atome de N ;- X 'is an atom of C or an atom of N;
- A', B' et C représentent une liaison chimique, un groupe alkyle ou aryle en C1-C6, un groupe carbonyle, ou un groupe hydrophile ;- A ', B' and C represent a chemical bond, a C1-C6 alkyl or aryl group, a carbonyl group, or a hydrophilic group;
- et R'4 représente un groupe alkyle ou aryle en C1-C6, ou un acide carboxylique en C1-C6, ou un sel pharmaceutiquement acceptable de ces composés polyphosphonates de formule I et II, à l'exception de l'acide 4-amino-1-hydroxybutylidène-1 ,1-biphosphonique. - and R'4 represents a C1-C6 alkyl or aryl group, or a C1-C6 carboxylic acid, or a pharmaceutically acceptable salt of these polyphosphonate compounds of formula I and II, with the exception of 4- amino-1-hydroxybutylidene-1, 1-biphosphonic.
2. Médicament selon la revendication 1, caractérisé en ce que R1, R2, R3 sont avantageusement identiques entre eux et représentent des groupes méthyle ou éthyle.2. Medicament according to claim 1, characterized in that R1, R2, R3 are advantageously identical to each other and represent methyl or ethyl groups.
3. Médicament selon l'une quelconque des revendications 1 et 2, caractérisé en ce que R5, R6, R7, R8 sont avantageusement identiques entre eux et représentent des atomes d'hydrogène ou des groupes méthyle.3. Medicament according to any one of claims 1 and 2, characterized in that R5, R6, R7, R8 are advantageously identical to each other and represent hydrogen atoms or methyl groups.
4. Médicament selon l'une quelconque des revendications 1 à 3, caractérisé en ce que le groupe4. Medicament according to any one of claims 1 to 3, characterized in that the group
BB
II
R4— X-A-R4— X-A-
II
CVS
est avantageusement un groupe hydrophile de 1 à 6 atomes de carbone.is advantageously a hydrophilic group of 1 to 6 carbon atoms.
5. Médicament selon l'une quelconque des revendications 1 à 4, caractérisé en ce que le ou les groupes hydrophiles sont choisis parmi les groupes de formule -L-Q, dans lesquels L est une liaison chimique ou un groupe alkyle en C1-C6 linéaire ou ramifié, et Q est choisi parmi : a) un groupement hydroxyle, aminé, carboxyle, sulfate, phosphate ; b) un groupe alkyle linéaire ou ramifié C1-C6 contenant un ou plusieurs groupements hydroxyle, aminé, carboxyle, sulfate, phosphate ; c) un groupement M, OM, CONHM, NHCOM dans lequel M est un groupement hydrophile ; d) un groupement hydrophile selon les points a), b) ou c), protégé par un groupement qui redevient un groupement hydrophile après une hydrolyse biologique. 5. Medicament according to any one of claims 1 to 4, characterized in that the hydrophilic group or groups are chosen from the groups of formula -LQ, in which L is a chemical bond or a linear C1-C6 alkyl group or branched, and Q is chosen from: a) a hydroxyl, amino, carboxyl, sulphate, phosphate group; b) a linear or branched C1-C6 alkyl group containing one or more hydroxyl, amino, carboxyl, sulfate, phosphate groups; c) a group M, OM, CONHM, NHCOM in which M is a hydrophilic group; d) a hydrophilic group according to points a), b) or c), protected by a group which again becomes a hydrophilic group after biological hydrolysis.
6. Médicament selon l'une quelconque des revendications 1 à 6, caractérisé en ce que le composé de formule I comporte deux groupements phosphoniques et un groupement ammonium quaternaire.6. Medicament according to any one of claims 1 to 6, characterized in that the compound of formula I comprises two phosphonic groups and a quaternary ammonium group.
7. Chlorure de 2,2-diphosphono-5-hydroxy-3-oxa-6-hexyltriméthylammonium à titre de médicament.7. 2,2-Diphosphono-5-hydroxy-3-oxa-6-hexyltrimethylammonium chloride as a medicament.
8. Composition pour hygiène buccale par voie topique caractérisée en ce qu'elle comprend un composé polyphosphonate de formule I :8. Composition for oral hygiene by topical route, characterized in that it comprises a polyphosphonate compound of formula I:
( dans laquelle R1 , R2, R3, R4, R5, R6, R7, R8, X, A, B et C sont tels que définis à la revendication 1 , ou un de ses sels pharmaceutiquement acceptables, ou un mélange de tels composés polyphosphonates.(in which R1, R2, R3, R4, R5, R6, R7, R8, X, A, B and C are as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a mixture of such polyphosphonate compounds .
9. Composition selon la revendication 8, caractérisée en ce qu'elle comprend entre 0,01 et 20 %, avantageusement entre 0,05 et 5 %, et encore plus avantageusement entre environ 0,1 et 2 % en poids de composé I.9. Composition according to claim 8, characterized in that it comprises between 0.01 and 20%, advantageously between 0.05 and 5%, and even more advantageously between approximately 0.1 and 2% by weight of compound I.
10. Composition selon la revendication 8 ou 9, caractérisée en ce qu'elle comprend en outre au moins un des éléments choisi parmi un agent antibactérien, agent de polissage, agent épaississant, agent humectant, arôme, agent sucrant, agent de blanchiment. 10. Composition according to claim 8 or 9, characterized in that it further comprises at least one of the elements chosen from an antibacterial agent, polishing agent, thickening agent, humectant, flavoring, sweetening agent, bleaching agent.
11. Composition selon l'une quelconque des revendications 8 à 10, caractérisée en ce qu'elle se présente sous la forme d'un bain de bouche, d'un liquide à pulvériser, d'une pâte dentifrice, d'un gel dentifrice.11. Composition according to any one of claims 8 to 10, characterized in that it is in the form of a mouthwash, a liquid to be sprayed, a toothpaste, a toothpaste gel .
12. Utilisation d'un composé polyphosphonate de formule (I)12. Use of a polyphosphonate compound of formula (I)
(D dans laquelle R1, R2, R3, R4, R5, R6, R7, R8, X, A, B et C sont tels que définis à la revendication 1 , ou un de ses sels pharmaceutiquement acceptables, pour la fabrication d'un médicament destiné à inhiber l'apparition et le développement de la plaque dentaire.(D in which R1, R2, R3, R4, R5, R6, R7, R8, X, A, B and C are as defined in claim 1, or one of its pharmaceutically acceptable salts, for the manufacture of a medicine to inhibit the onset and development of dental plaque.
13. Utilisation selon la revendication 12 caractérisée en ce que le composé I est choisi parmi : - le chlorure de 2, 2-diphosphono-5-hydroxy-3-oxa-6- hexyltriméthylammonium et, l'acide 6-trimethylammoniohexyl-1 , 1 - bisphosphonique. 13. Use according to claim 12 characterized in that the compound I is chosen from: - 2, 2-diphosphono-5-hydroxy-3-oxa-6-hexyltrimethylammonium chloride and, 6-trimethylammoniohexyl-1 acid, 1 - bisphosphonic.
EP03740602A 2002-04-12 2003-04-14 Polyphosphonate derivatives for toothpaste compositions Withdrawn EP1494682A2 (en)

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FR0204596A FR2838339B1 (en) 2002-04-12 2002-04-12 POLYPHOSPHONATE DERIVATIVES FOR DENTIFRING COMPOSITIONS
FR0204596 2002-04-12
PCT/FR2003/001178 WO2003086412A2 (en) 2002-04-12 2003-04-14 Polyphosphonate derivatives for toothpaste compositions

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WO2003086412B1 (en) 2004-05-27
WO2003086412A3 (en) 2004-04-01
FR2838339A1 (en) 2003-10-17
AU2003262154A8 (en) 2003-10-27
AU2003262154A1 (en) 2003-10-27
CA2482230A1 (en) 2003-10-23
US20050153938A1 (en) 2005-07-14
FR2838339B1 (en) 2005-06-24
WO2003086412A2 (en) 2003-10-23
JP2005529107A (en) 2005-09-29

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