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GB1575915A - Pyridine derived fluorides and pharmaceutical compositions containing them - Google Patents

Pyridine derived fluorides and pharmaceutical compositions containing them Download PDF

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Publication number
GB1575915A
GB1575915A GB3083976A GB3083976A GB1575915A GB 1575915 A GB1575915 A GB 1575915A GB 3083976 A GB3083976 A GB 3083976A GB 3083976 A GB3083976 A GB 3083976A GB 1575915 A GB1575915 A GB 1575915A
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Prior art keywords
composition according
hydrofluoride
active ingredients
ethyl nicotinate
methylolpyridine
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GB3083976A
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Pierre Fabre SA
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Pierre Fabre SA
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Priority claimed from FR7523715A external-priority patent/FR2318632A1/en
Priority claimed from FR7533893A external-priority patent/FR2330394A2/en
Application filed by Pierre Fabre SA filed Critical Pierre Fabre SA
Publication of GB1575915A publication Critical patent/GB1575915A/en
Expired legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
    • 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
    • A61K8/69—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing fluorine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Birds (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

(54) PYRIDINE-DERIVED FLUORIDES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM (71) We, PIERRE FABRE S.A., a French Societe Anonyme, of 125, rue de la Faisanderie, Paris 16eme, France, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to pyridine-derived fluorides and to pharmaceutical compositions containing them.
Since the appearance of the work of MUHLEMAN et al. (Helv. odontol.
Acta, 1957), relating to the role of fluorides in the prevention of dental caries, numerous authors have experimented with amine fluorides and inorganic fluorides.
In general, the proposed complexes are unstable and are rapidly deactivated by hydrolysis; such is the case, for example with tin fluoride. Organic fluorides are frequently of low activity because their ionisation constants are low.
The compounds of the present invention have the advantages of being good carriers of fluorine, of being stable in aqueous solution, of having high ionisation constants and of being non-toxic. More especially, they combine the action of fluorine in the prevention of dental caries with a tonicising effect on the gums and the ability to inhibit the formation of dental plaque.
The present invention provides compounds of the general formula
in which R, is a hydrogen atom-or an alkyl group and R2 is CH2-OH, alkyl carboxylate (preferably methyl or ethyl carboxylate),
The compounds in accordance with the present invention can be prepared in known manner by treating the appropriate methylolpyridine, N-(2-hydroxyethyl)pyridinecarboxamide, alkyl pyridinecarboxylate or morpholinocarbonylpyridine with a stoichiometric amount of hydrogen fluoride or alkyl fluoride. Methylol pyridine and alkyl nicotinates can be readily prepared in known manner; N-(2hydroxyethyl)-nicotinamide and morpholinocarbonylpyridine can be prepared from alkyl nicotinates by reacting the latter with an excess of ethanolamine and an excess of morpholine, respectively.
It has been found that the compounds in accordance with the present invention possess inhibiting properties towards dental plaque in vitro, exert a protective action on tooth enamel and tonicise the gums by improving blood circulation. They can therefore be used in dental medicine, for the preventive and curative treatment of parodontopathies and odontopathies.
The present invention therefore also provides a pharmaceutical composition comprising, as an active ingredient, a compound as described above, in admixture or conjunction with a pharmaceutically suitable carrier.
The pharmaceutical compositions of the present invention preferably contain from 0. I to 10% by weight of active ingredient and preferably have a pH of less than 7.
The compositions are suitably oral compositions, that is to say compositions which are not swallowed deliberately but which are normally retained in the mouth for a prolonged period of time and which contact the whole of the buccal and dental surfaces, for example a dentifrice, mouth wash, prophylactic paste, pastille, solution for topical application or chewing gum.
It has also been found that certain known bactericides capable of inhibiting the formation of dental plaque, especially biguanidine derivatives, for example chlorohexidine and its salts, and benzethonium chloride (described for example, in U.S. Patents Nos. 2684924, 2830006, 2863019 and 2990425), exhibit a boosting action on the compounds of the present invention, and that the compounds of the invention exhibit a similar boosting action on these bactericides. Thus, by including such bactericides in the compositions of the present invention, there is obtained a considerably improved inhibition of plaque formation. In addition, the biguanidine derivatives can be used in such small amounts that their previously observed property of causing teeth to turn brown, is suppressed.
The carriers used in the compositions of the present invention should be so selected that they optimise the activity of the active ingredients under conditions of maximum stability. In this respect, it has been demonstrated that the protection of ,teeth, determined by the E.S.R. (enamel solubility reduction) technique, is -practically zero if the fluorine-containing ingredient is applied at pH > 8. This point has been stressed by D. Comar at the 1974 Moscow congress on the applications of fluorine. The amount of fluorine fixed as a function of pH has been studied by Y: Ericsson (Acta Odont. Scand.). The compositions described below have been developed taking these requirements into account to ensure optimum inhibition of plaque formation and optimum protection of tooth enamel. The activity of the fluoride ions was increased by adjusting the pH to about 5, and removing all compounds capable of forming insoluble complexes with fluorine, for example silica and inorganic phosphates.
The synergistic compositions of the present invention makes it possible to obtain protection against dental plaque and caries far greater than that currently known.
The following Examples illustrate the invention.
Example 1.
3-Methylolpyridine hydrofluoride (product I)
The stoichiometric amount of 40% aqueous hydrofluoric acid was added to a solution of 3-methylolpyridine in methanol. The mixture was heated to 600C, and a homogeneous solution was obtained.
The solvents were evaporated off and 3-methylolpyridine hydrofluoride was obtained quantitatively.
Empirical formula: CeH8FNO.
Molecular weight: 129.13.
Translucent oil.
Fluorine content: 14.71%.
Refractive index: 2 = 1.5010.
Very soluble in water.
pH of 20% aqueous solution: 3.7.
Example 2.
N-(2-Hydroxyethyl)-nicotinamide hydrofluoride (product II) Methyl nicotinate was treated with an excess of ethanolamine and the reaction mixture was heated so as to distil off methanol at the rate at which it was formed.
The N-(2-hydroxyethyl)-nicotinamide thus obtained was treated with 40% aqueous hydrofluoric acid to give the derivative:
Empirical formula: C8H,1FN202.
Molecular weight: 186.19.
Thick yellow oil.
Soluble in water.
Fluorine content: 10.20%.
pH of 20% aqueous solution: 3.1.
Example 3.
Ethyl nicotinate hydrofluoride (product UI)
Empirical formula: CBH1oFNO2.
Molecular weight: 171.17.
Translucent oil.
Refractive index: nD2 = 1.4811.
Soluble in water.
Fluorine content: 11.10%.
pH of 20% aqueous solution: 2.5.
Absorption band: vC=O at 1,730 cm~'.
Salification band at 2,500 cm~'.
Example 4.
N- Dodecyl-3-methylolpyridine fluoride The stoichiometric amount of dodecyl fluoride was added to a solution of 3methylolpyridine in ethanol. The reaction mixture was heated under reflux for 8 hours. After evaporating off the solvent, the following compound was recovered quantitatively:
Empirical formula: C,8H32NOF. The following compounds were obtained in a similar manner: Example 5.
4-Nicotinoyl-morpholine hydrofluoride
Example 6.
2-Methylolpyridine hydrofluoride
Example 7 Methyl nicotinate hydrofluoride
Example 8.
Toothpaste: 3-methylolpyridine hydrofluoride 0.1 to 2% chlorohexidine hydrochloride 0.01 to 0.1% glycerol 5 to 30% hydroxyethylcellulose 2 to 4% sorbitol 25% sweetener and flavouring q.s.
Example 9.
Toothpaste: Ethyl nicotinate hydrofluoride 0.1 to 2% benzethonium chloride 0.01 to 0.2% ethylene oxide/propylene glycol complex 4% hydroxyethylcellulose 2 to 4% sweetener and flavouring q.s.
Example 10.
Mouth wash: (pH = 5) Ethyl nicotinate hydrofluoride 0.1 to 2% benzethonium chloride 0.01 to 0.2% pyrrolidone carboxylic acid 0.5 to 5% hydroxyethylcellulose 0.5 to 2% sweetener and flavouring q.s.
Example 11.
Dentifrice gel: Ethyl nicotinate hydrofluoride 0.1 to 2% chlorohexidine dihydrochloride 0.01 to 0.1% Carbopol 934 ('Carbopol' is a registered Trade Mark)0.5 to 4% propylene glycol 1 to 10% ethanol 1 to 5% ethylene oxide/polypropylene glycol complex 4% sweetener and flavouring q.s.
Example 12.
The anti-plaque activity was determined in accordance with the method described by Plissier et al. (Le Chirurgien Dentiste, 16th October 1974, page 63) and is expressed as the inhibitory concentration in ,ug/ml of solution.
A very marked boosting action was demonstrated by using the combination of benzethonium chloride + ethyl nicotinate hydrofluoride, relative to each active ingredient used separately. The same is true in the case of- the combination of chlorohexidine with ethyl nicotinate hydrofluoride.
TABLE I
Minimum inhibitory dose for plaque formation in vitro Benzethonium chloride 15.6 yg/ml Ethyl nicotinate hydrofluoride 15.6 llg/ml 20% of benzethonium chloride + 7.8 llgiml (*) 80% of ethyl nicotinate hydrofluoride (*) total weight of the 2 active principles.
TABLE II
Inhibitory dose for plaque formation in vitro yg/ml Chlorohexidine hydrochloride 7.80 Ethyl nicotinate hydrofluoride 15.6 80% of chlorohexidine + 3.9 (*) 20% of ethyl nicotinate hydrofluoride 20% of chlorohexidine + 7.8 (*) 80% of ethyl nicotinate hydrofluoride (*) total weight of the 2 active principles.
Pharmacological tests (a) Protective action on dental enamel The properties of the compounds of Examples 1, 2 and 3 were studied in vitro in accordance with the ESR (Enamel Solubility Reduction) test.
Batches of healthy human teeth were treated, after protection of the roots with acid-resistant varnishes, with aqueous solutions of the compounds of the invention at 37"C. Comparison teeth were treated with solutions of sodium chloride. The teeth were then decalcified by means of a phthalate buffer solution of pH 4.
The results were assessed by complexometric determination of the calcium by the SCHWARZENBACH method and colorimetric determination of the phosphorus by the FISKE and SUBVAROW method.
The concentration of active fluorides, the contact time and the pH were varied in turn.
The comparison of the amounts of calcium and of phosphorus extracted in the case of the treated teeth and of the comparison teeth made it possible to assess the protective action on the enamel (Tables III and IV).
TABLE III Determination of calcium
Amount of Ca extracted* protection Product I 0.18 mg 95.5 Product II 0.19 mg 95.3 Product III 0.11 mg 97.2 Comparison 4.03 mg 0 *Mean of 14 measurements on various batches of teeth.
TABLE IV Determination of phosphorus
Amount of P extracted* protection Product I 0.17 93.3 Product II 0.20 92.1 Product III 0.14 94.5 Comparison 2.55 0 *Mean of 14 measurements on various batches of teeth; -(b) Inhibiting action on dental plaque in vitro The activity in vitro was measured by adapting the method of OLSON, BLEI WEIS and SMALL (Infection and Immunity 1972, 5, 419), in which the plaque is obtained on the wall of test tubes and its extent is assessed spectrophotometrically as the optical density 10-2 at 540 nanometres.
The reading was taken after washing the tubes with water and detaching the plaque with 20 ml of 0.5 N sodium hydroxide solution; the results were compared with the comparison tubes of a culture in Jordan medium, containing 5% of sucrose, without inhibitor.
TABLE V
15 yg/ml 7 /lga'ml % % OD inhibition OD inhibition Comparison 105 0 105 0 Product I 0 100% 10 80% Product II 15 85% 70 30% Product III 0 100% 30 L 70% (c) Bactericidal activity The minimum bactericidal concentrations (MBC) were determined for various microbial strains; the results are expressed in Mg/ml.
TABLE VI
Strains Salmonella Strepto- Citro- Achromo brancaster coque Hafnia bacter bacter MBC X ProductI 15 15 30 15 7 Product II 30 30 60 30 30 Product III 30 15 30 15 15 The minimum inhibitory concentrations for plaque are of the same order as the bactericidal concentrations for Streptococcus mutans, namely 15 ,ug/ml for products I and III; taken overall, product II is less active.
(d) Tolerance in vivo Cutaneous tolerance The tolerance was investigated for each product on 5 adult albino guineapigs.
Application of the undiluted product 3 times per week for 2 weeks to the previously shaven flank of the animal did not produce any significant cutaneous reaction.
Ocular tolerance The ocular tolerance was tested on albino rabbits and on mice. After instilling 2 drops of solution (concentration varying from 1 to 5%) into the conjunctival sac, the behaviour of the animal was observed for 3 minutes; in the case of all the compounds tested, no difference was observed relative to a comparison batch of animals.
Epicutaneous tolerance Epicutaneous tests were carried out on New Zealand rabbits. After having shaved the flanks of the animal, the stratum corneum was scratched. The results evaluated on the Draize scale showed that in the case of the majority of the products, the irritation index was very low.
lntra-dermal tolerance The intra-dermal tests were carried out by injecting 0.1 ml of a 1% solution of product in olive oil. The injections are repeated every day, on the flanks of previously shaven guineapigs. After an interval of 2 weeks, a similar injection was given above the preceding injection zone and the height, diameter and colour of the reactions was observed. All the observations made showed that there was neither primary irritation nor sensitisation.
(e) Using the methods described above, tests were carried out on the combination of compounds of the invention and bactericide. Perfect tolerance in respect of the mucous membranes was confirmed.
These compositions exhibit the properties required for use in the cosmetic field. The effect of the teeth turning brown, due to the biguanidines, was not detected. On the other hand, a trophic action on the gums was established, attributable to the presence of nicotinic acid derivatives and of pyroglutamic acid.
The latter was used to acidify the compositions to pH 5. It was chosen in view of its perfect local tolerance and its harmlessness.
The results of clinical tests were encouraging. A significantly increased efficacy in the prevention of dental diseases, especially caries and gingivites caused by dental plaque, was established.
WHAT WE CLAIM IS: l. A compound of the general formula
in which R, is a hydrogen atom or an alkyl group and R2 is CH2OH, alkyl carboxylate,
2. 3-Methylolpyridirre hydrofluoride.
3. N-(2-Hydroxyethyl)-nicotinamide hydrofluoride.
4. Ethyl nicotinate hydrofluoride.
5. N-Dodecyl-3-methylolpyridine fluoride.
6. 2-Methylolpyridine hydrofluoride.
7. A pharmaceutical composition comprising, as an active ingredient, a compound according to claim 1 in admixture or conjunction with a pharmaceutically suitable carrier.
8. A composition according to claim 7, which also contains a known bactericide capable of inhibiting dental plaque.
9. A composition according to claim 8, wherein the bactericide is a biguanidine derivative or benzethonium chloride.
10. A composition according to claim 9, wherein the active ingredients are ethyl nicotinate hydrofluoride and chlorohexidine or a salt thereof.
11. A composition according to claim 9, wherein the active ingredients are ethyl nicotinate hydrofluoride and benzethonium chloride.
12. A composition according to claim 9, wherein the active ingredients are 3methylolpyridine and chlorohexidine or a salt thereof.
13. A composition according to any one of claims 7 to 12 in the form of a dentifrice, mouth wash, prophylactic paste, solutions for topical application or chewing gum.
14. A composition according to any one of claims 7 to 13, containing from 0.1% to 10% by weight of the active ingredients.
15. A composition according to any one of claims 7 to 14, of which the pH is less than 7.
**WARNING** end of DESC field may overlap start of CLMS **.

Claims (17)

  1. **WARNING** start of CLMS field may overlap end of DESC **.
    product in olive oil. The injections are repeated every day, on the flanks of previously shaven guineapigs. After an interval of 2 weeks, a similar injection was given above the preceding injection zone and the height, diameter and colour of the reactions was observed. All the observations made showed that there was neither primary irritation nor sensitisation.
    (e) Using the methods described above, tests were carried out on the combination of compounds of the invention and bactericide. Perfect tolerance in respect of the mucous membranes was confirmed.
    These compositions exhibit the properties required for use in the cosmetic field. The effect of the teeth turning brown, due to the biguanidines, was not detected. On the other hand, a trophic action on the gums was established, attributable to the presence of nicotinic acid derivatives and of pyroglutamic acid.
    The latter was used to acidify the compositions to pH 5. It was chosen in view of its perfect local tolerance and its harmlessness.
    The results of clinical tests were encouraging. A significantly increased efficacy in the prevention of dental diseases, especially caries and gingivites caused by dental plaque, was established.
    WHAT WE CLAIM IS: l. A compound of the general formula
    in which R, is a hydrogen atom or an alkyl group and R2 is CH2OH, alkyl carboxylate,
  2. 2. 3-Methylolpyridirre hydrofluoride.
  3. 3. N-(2-Hydroxyethyl)-nicotinamide hydrofluoride.
  4. 4. Ethyl nicotinate hydrofluoride.
  5. 5. N-Dodecyl-3-methylolpyridine fluoride.
  6. 6. 2-Methylolpyridine hydrofluoride.
  7. 7. A pharmaceutical composition comprising, as an active ingredient, a compound according to claim 1 in admixture or conjunction with a pharmaceutically suitable carrier.
  8. 8. A composition according to claim 7, which also contains a known bactericide capable of inhibiting dental plaque.
  9. 9. A composition according to claim 8, wherein the bactericide is a biguanidine derivative or benzethonium chloride.
  10. 10. A composition according to claim 9, wherein the active ingredients are ethyl nicotinate hydrofluoride and chlorohexidine or a salt thereof.
  11. 11. A composition according to claim 9, wherein the active ingredients are ethyl nicotinate hydrofluoride and benzethonium chloride.
  12. 12. A composition according to claim 9, wherein the active ingredients are 3methylolpyridine and chlorohexidine or a salt thereof.
  13. 13. A composition according to any one of claims 7 to 12 in the form of a dentifrice, mouth wash, prophylactic paste, solutions for topical application or chewing gum.
  14. 14. A composition according to any one of claims 7 to 13, containing from 0.1% to 10% by weight of the active ingredients.
  15. 15. A composition according to any one of claims 7 to 14, of which the pH is less than 7.
  16. 16. A composition according to any one of claims 7 to 15, wherein the
    acidifying agent is pyroglutamic acid.
  17. 17. A pharmaceutical composition substantially as described in any one of Examples 8 to 11 herein.
GB3083976A 1975-07-25 1976-07-23 Pyridine derived fluorides and pharmaceutical compositions containing them Expired GB1575915A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7523715A FR2318632A1 (en) 1975-07-25 1975-07-25 SUBSTD. PYRIDINIUM FLUORIDE SALTS - esp. useful for treating and preventing dental caries
FR7533893A FR2330394A2 (en) 1975-11-04 1975-11-04 ORAL ANTICARIA AND ANTI-SCALE COMPOSITIONS

Publications (1)

Publication Number Publication Date
GB1575915A true GB1575915A (en) 1980-10-01

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DE (1) DE2633028A1 (en)
GB (1) GB1575915A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL229538A (en) * 1957-07-13
NL239622A (en) * 1958-05-29

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DE2633028A1 (en) 1977-02-10
DE2633028C2 (en) 1989-03-16

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PS Patent sealed
704A Declaration that licence is not available as of right for an excepted use (par. 4a/1977)
PE20 Patent expired after termination of 20 years

Effective date: 19960722