The present invention relates to new chemical compounds which can be used as inhibitors of dental plaque, and orally-acceptable compositions thereof, combinations thereof with known compounds having an inhibitory action on the formation of dental plaque, such as biguanidines, and method of treating therewith for the prevention of dental plaque or tartar and dental caries.
The new compounds have the general formula ##STR1## in which R1 =H or alkyl
R2 =CH2 OH, alkyl carboxylate, ##STR2## and R2 is in 2 or 3 position.
Compositions containing these active principles are useful in particular in the preventive treatment of periodontopathies and odontopathies and in the field of oral-dental hydgiene.
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1. A compound of formula ##STR14## in which R1 =H or alkyl
R2 =CH2 OH, in 2 or 3 position on the pyridyl ring, "alkyl" containing a maximum of twelve carbon atoms.
2. A compound of
3-pyridylmethanol hydrofluoride, N-dodecyl 3-pyridylmethanol fluoride, and 2-pyridylmethanol hydrofluoride.
6. An oral and dental hygiene composition suitable for use in the inhibition of dental plaque and protection of the tooth enamel comprising a compound of
7. An oral and dental hygiene composition suitable for use in the inhibition of dental plaque and protection of the tooth enamel comprising a compound of
8. An antiplaque and tooth enamel protective dentrifice preparation containing, as active principle, an effective amount of a product according to
9. An antiplaque and tooth enamel protective dentrifice preparation containing, as active principle, an effective amount of a product according to
10. Orally-acceptable antiplaque and tooth enamel protective composition containing an effective amount of a compound of
11. An anti-plaque and tooth enamel protective composition according to
12. A composition according to
13. A composition according to
14. An anti-plaque and tooth enamel protective composition according to
15. A composition according to
16. A composition according to
17. An anti-plaque and tooth enamel protective composition according to
18. An orally-acceptable antiplaque and tooth enamel protective composition according to
19. An orally-acceptable antiplaque and tooth enamel protective composition according to
20. An oral and dental hygiene composition suitable for use in the inhibition of dental plaque and protection of the tooth enamel comprising a composition of
21. Method for the inhibition of dental plaque and protection of the tooth enamel, comprising the step of contacting a tooth or the oral cavity containing said tooth with a compound of
22. Method for the inhibition of dental plaque and protection of the tooth enamel, comprising the step of contacting a tooth or the oral cavity containing said tooth with a compound of
23. Method for the inhibition of dental plaque and protection of the tooth enamel, comprising the step of contacting a tooth or the oral cavity containing said tooth with a composition of
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1. Field of the Invention
Certain novel pyridine compounds and fluoride salts thereof; antiplaque, anticaries and antiperiodontitis compounds; oral and dental hygiene compositions thereof, method of treating therewith, and combinations with known antiplaque compounds such as biguanidines.
2. Prior Art
The oral diseases periodontitis and dental caries are plaque-related problems of a complex nature and origin, which have until the present been most successfully treated or obviated by the mechanical removal of plaque, since the chemical approach to plaque inhibition has not been successful. The present invention, however, provides compounds having relatively low toxicity and which have been shown to be effective for the inhibition of dental plaque and, accordingly, also for the inhibition of dental caries and periodontitis, which problems or ailments are caused by undue buildup of dental plaque and resulting complications.
Since the appearance of the work of Muhleman et al. (Helv. odontol. Acta, 1957), concerning the role of fluorides in the prevention of dental caries, many authors have experimented on amine fluorides or inorganic fluorides.
In general, the complexes recommended are unstable and are deactivated by rapid hydrolysis; this is true of tin fluoride. The organic fluorides are frequently less active, since the ionization constant is low.
All established more or less useful compounds of the prior art have been found to be characterized by serious shortcomings and/or side effects, and there exists a clear and ever-growing demand for more specific and advantageous compounds or treatments in this activity and utility area, especially for antiplaque, anticaries, and anti-peridontitis products and methods. The fulfillment of this demand is one of the objects of the present invention, as will become more fully apparent hereinafter.
The new compounds which are the object of the invention have the advantage of being good carriers of fluorine which have the following properties:
fluorides stable in aqueous solution
high ionization constant
nontoxic organic molecule
and in particular of combining the action of fluorine in the prevention of dental caries with a tonifying effect on the gums and a power of inhibition with respect to the formation of dental plaque.
This is the first time that these three beneficial actions are combined in the same molecule.
This invention relates to novel pyridine compounds, fluoride salts thereof, orally-acceptable compositions containing the same, a method of using the same for their antiplaque or anticaries properties, and combinations with known antiplaque compounds such as biguanidines.
It is an object of the present invention to provide certain compounds and fluorides thereof, which are useful in the chemical inhibition of dental plaque and resulting problems or ailments, a process for producing the same, orally-acceptable compositions thereof, a method of treating therewith, and combinations with known antiplaque compounds such as biguanidines. Additional objects will become apparent hereinafter and still other objects will be obvious to one skilled in the art.
The present invention, made at the Pierre Fabre Research Center, concerns new chemical compounds and their use in therapy. They may be used in particular for the prevention and treatment of periodontopathies, caries, and dental plaque.
These new chemical compounds have the general formula ##STR3## in which: R1 =H, alkyl
R2 =CH2 --OH, alkyl carboxylate, ##STR4##
and R2 is in the 2 or 3 position.
The R1 and alkyl carboxylate "alkyl" groups are, independently, an alkyl group, straight or branched, having one to twenty carbon atoms, inclusive, and is preferably an alkyl group, straight or branched, of no more than twelve carbon atoms, but especially such alkyl groups having one to eight carbon atoms, inclusive, including such usual and representative groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl, tert. butyl, amyl, hexyl, heptyl, octyl, decyl, dodecyl, octadecyl, nonadecyl, et cetera, as well as corresponding unsaturated, doubly unsaturated, and triply unsaturated radicals, e.g., alkynl, alkenyl, and alkadienyl radicals.
These novel compounds of Formula A have valuable pharmacological properties, especially as inhibitors of dental plaque as further elucidated hereinafter, which makes them useful not only as antiplaque, but also as anticaries and anti-periodontitis, products.
The following Examples are given by way of illustration only and are not to be construed as limiting.
To a methanolic solution of 3-pyridyl methanol add the stoichiometric quantity of hydrofluoric acid in 40% aqueous solution.
Heat the reaction mixture to 60°C A homogeneous solution is obtained.
The solvents are evaporated to dryness; the 3-pyridyl methanol hydrofluoride is obtained quantitatively.
Empirical formula: C6 H8 FNO
Molecular weight: 129.13
Translucent oil
Fluorine content: 14.71
Index of refraction: nD21 =1.5010
Very soluble in water.
pH of 20% aqueous solution: 3.7.
Methyl nicotinate is treated with an excess of ethanolamine, the reaction mixture is heated so as to distill the methanol as it is formed.
The N-hydroxy ethyl nicotinamide thus obtained is treated with a 40% aqueous solution of hydrofluoric acid to produce the derivative ##STR6## Empirical formula: C8 H11 FN2 O2 Molecular Weight: 186.19
Organoleptic characteristics: thick yellow oil
Solubility characteristics: soluble in water
Fluorine content: 10.20%
pH of 20% aqueous solution: 3.1
Organoleptic characteristics: translucent oil
Index of refraction: nD22 =1.4811
Solubility characteristics: soluble in water
Fluorine content: 11.10%
pH of a 20% aqueous solution: 2.5
Absorption band: vC═0 at 1730 cm-1
Salification band at 2500 cm-1
This compound was obtained by: Treatment of ethyl-3-nicotinate with a solution of fluorhydric acid in a stoichiometric quantity.
Compounds wherein the ethyl group is replaced by another alkyl group, such as methyl, octyl, or dodecyl, or octadecyl are prepared in the same manner, namely by: Treatment of the nicotinic esters with a solution of fluorhydric acid in stoichiometric quantity.
To an ethanolic solution of 3-pyridyl methanol there is added a stoichiometric amount of dodecyl fluoride.
The reaction mixture is heated under reflux for 8 hours.
After evaporation of the solvent to dryness, there is quantitatively recovered the compound: ##STR8## Empirical formula: C18 H32 NOF
Compounds wherein the dodecyl group is replaced by another alkyl group, e.g., methyl, ethyl, octyl, or octadecyl, are obtained in the same manner using the selected alkyl fluoride instead of dodecyl fluoride.
There were also obtained:
3-nicotinoyl morpholine hydrofluoride: ##STR9## 2-pyridyl methanol hydrofluoride ##STR10##
These compounds were obtained, respectively, by:
(V) Treatment of 3-nicotinyl morpholine with a solution of fluorhydric acid in stoichiometric quantity.
(VI) Treatment of 2-pyridyl methanol with a solution of fluorhydric acid in stoichiometric tropic trophic action at the level of the gums, imputable to the presence of nicotine derivatives and the presence of pyroglutamic acid. The latter was used to acidify the compositions to a pH of 5. It was selected because of its excellent local tolerance and its innocuousness. The results of the clinical experiments are encouraging. There was found substantially increased effectiveness of the pharmaceutical preparations for the prevention of dental diseases, particularly caries and gingivitis caused by dental plaque.
In the field of oral-dental hygiene, the preparations forming an object of the invention have given very satisfactory results. They meet the criteria and standards required for cosmetic oral-dental application, exerting a cleaning action on the teeth and the mucous membranes.
The foregoing composition Examples may also omit the chlorhexidine or benzethonium compound, but the amount of remaining active ingredient is then preferably doubled in amount.
In use, the compounds may be employed as chewable or dissolvable tablets in which they are present together with usual orally-acceptable carriers, excipients, binders, and the like. For example, tablets may be prepared conventionally by compounding one of the new compounds with customary carriers and adjuvants, e.g., talc, magnesium stearate, starch, lactose, gelatin, gums, and the like.
In their most advantageous form, then, the compositions of the present invention will contain a non-toxic orally-acceptable carrier in addition to the active ingredient, i.e., a compound of Formula A. Exemplary carriers are: solids--lactose, magnesium stearate, calcium stearate, starch, terra alba, dicalcium phosphate, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia, or the like; liquids--elixir, solution, or suspensions in water or the like. When sugars are employed, the inert or non-plaque-forming sugars are of course preferred. The active agents of the invention can be conveniently employed in the form of such compositions containing in their broadest aspects 0.01 to 67 percent, especially 0.04 to 12.15 percent, by weight of active ingredient, although 0.1 to 5% is definitely preferred. Such formulations and oral hygiene compositions are representatively illustrated in U.S. Pat. No. 3,751,561, with or without, but preferably without, the enzyme components as therein disclosed.
A wide variety of forms suitable for orally-acceptable usage and dosages may accordingly be employed. The active inredient and orally-acceptable carrier may, for example, in its broader aspects take the form of a gum, granule, pill, tablet, lozenge, elixir, syrup, toothpaste, mouthwash, gargle, chewable tablet, or other liquid suspension or emulsion.
The method of using the compounds of the present invention comprises exposing a tooth or teeth, or the oral cavity in which the tooth or teeth are located, to the antidental plaque activity of a compound of Formula I, preferably admixed with an orally-acceptable carrier, for example, in the form of any of the abovementioned compositions, or filled into a capsule, for the purpose of inhibiting formation of dental plaque on the tooth, and thereby also inhibiting complications which normally result therefrom, including dental caries and periodontitis. The compounds and their fluoride salts, expecially the alkyl fluorides and hydrofluorides, may be advantageously employed in any desirable form and in amounts approximating those employed in the representative compositions of the Examples hereof. Illustratively, they may be used in an amount of from about 0.1 to 100 milligrams per treatment, preferably from about 0.2 to 10 milligrams per treatment, depending upon the exact mode employed. The treatment is preferably given or undertaken a suitable number of times daily so that the daily treatment provides an effective amount of the active compound for the intended purpose, namely, inhibition of dental plaque and its resultant problems or complications as aforesaid, as already stated in the foregoing.
In addition, the active ingredients of the present invention or compositions containing the same may either be administered together with or include other active materials and/or medicaments, e.g., buffering agents, antacids, flavors anesthetics, antiseptics, surface-active agents, or the like. The compositions may take the form of impregnated dental floss mouthwashes, gargles, candies, masticable candies, lozenges, tablets, toothpowders, sprays, toothpastes, dragees, creams, salves, ointments denture cements or aids, breath purifiers, or other similar oral hygiene compositions.
The preceding formulations are representative and may be employed for incorporation of any of the pharmacologically-active compounds of the invention, but have been particularly designed to embody as active ingredient the particular compounds embodied therein, especially in the form of a pharmacologically-acceptable fluoride salt thereof, e.g., the alkyl fluoride or hydrofluoride.
Various modifications in the compounds, compositions, and methods of the invention will be apparent to one skilled in the art and may be made without departing from the spirit or scope thereof, and it is therefore to be understood that the invention is to be limited only by the scope of the appended claims.
Dubois, Jacques, Mouzin, Gilbert, Cousse, Henri, Vezin, Jean-Claude, D'Hinterland, Lucien D.
| Patent | Priority | Assignee | Title |
| 4996042, | Mar 06 1989 | Procter & Gamble Company, The | Toothpaste |
| 5174989, | Nov 25 1987 | Shiseido Company Ltd. | Oral composition |
| Patent | Priority | Assignee | Title |
| 3914406, | |||
| CA673101, |
| Executed on | Assignor | Assignee | Conveyance | Frame | Reel | Doc |
| Mar 15 1979 | Pierre Fabre S.A. | (assignment on the face of the patent) | / |
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