US2837463A - Therapeutic compositions comprising 5-amino hexahydropyrimidines or salts thereof - Google Patents

Therapeutic compositions comprising 5-amino hexahydropyrimidines or salts thereof Download PDF

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US2837463A
US2837463A US708072A US70807258A US2837463A US 2837463 A US2837463 A US 2837463A US 708072 A US708072 A US 708072A US 70807258 A US70807258 A US 70807258A US 2837463 A US2837463 A US 2837463A
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amino
methyl
bis
hexahydropyrimidine
acid
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Leonard S Fosdick
Roland R Read
Robert G Sanders
Robert B Edwards
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Warner Lambert Co LLC
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Warner Lambert Pharmaceutical Co
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    • 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

Definitions

  • This invention relates to therapeutic compositions and atent more particularly to therapeutic compositions containing certain S-amino hexahydro pyrimidine compounds.
  • compositions comprising a compound having the formula: H:
  • therapeutic compositions which are effective for various therapeutic purposes including, for example, the treatment of bovine mastitis, skin infections, fungus infections, scalp infections and other infections, both surface and systemic, caused by microorganisms; the provision of therapeutic compositions which are effective, for example, to inhibit the growth of microorganisms for which vitamin B is an essential metabolite or growth factor and certain enzyme systems in which cocarboxylase functions as an essential part; the provision of therapeutic compositions which are suitable, for example, for introduction into the oral cavity and for topical application to the skin and for parenteral administration; and the provision 'of therapeutic compositions of the class described which are nontoxic, nonsensitizing, nonirritating, and stable.
  • Other objects and features will be in part apparent and in part pointed out hereinafter.
  • compositions including a S-amino-hexahydropyrimidine compound having the following formula:
  • vitamin B is an essential metabolite, i. e., a necessary constituent of the normal metabolic processes, and growth factor for many microorganisms.
  • coenzyme, cocarboxylase which is a crystalline diphosphoric acid ester of vitamin B is required in order for the enzyme carboxylase to remove carbon dioxide from pyruvic acid and other organic acids formed from carbohydrates in the metabolism of such microorganisms. Accordingly, in the presence of vitamin 13,, the microorganisms grow and develop normally through the energy derived from the metabolic process described above.
  • the S-amino-hexahydropyrimidine component of the compositions of the invention acts as an antimetabolite or competitive antagonist for vitamin B in the metabolism of the microorganisms.
  • the S-amino-hexahydropyrimidine component is believed to form a complex with the enzyme carboxylase which, unlike the complex formed in the case of vitamin B is incapable of effecting the chemical changes characteristic of those occurring in the presence of cocarboxylase. Consequently, the decarboxylation of pyruvic acid, for example, as well as other organic acids ceases and the growth and development of. the microorganisms are thereby inhibited because of this interruption of their normal metabolic processes.
  • the compositions of the present invention are effective against certain enzyme systems of which cocarboxylase is an essential component.
  • compositions of the invention are markedly eflective in inhibiting the growth of microorganisms for which vitamin B is an essential metabolite or growth factor. 1
  • the measurement of antagonism between metabolite and antimetabolite may be expressed by a number known as the inhibition index.
  • the inhibition index is the quotient of the ratio of concentration of the two substances at which their effects are just counterbalanced, and represents the amount of antimetabolite which is needed to overcome the effect of a unit weight of metabolite. Thus, a low inhibition index is indicative of the high effectiveness of an antimetabolite.
  • the inhibition index in the case of vitamin B and the S-amino-hexahydropyrimidine compounds included in the compositions of the present invention is relatively low, and therefore, in general, it may be stated that ,only relatively small amounts of these compositions are required to offset the effect of relatively large amounts of vitamin B And since the antagonism between these pyrimidine compounds and vitamin B is competitive, the inhibition index is relatively constant with respect to all microorgan isms for which vitamin B is an essential metabolite.
  • compositions of the invention may be menorganisms isolated from acute and chronic bovine mastitis cases. Further, under therapeutic conditions induction of resistance in microorganisms to the compositions of the invention has not been found.
  • compositions of the invention are useful and effective in various therapeutic applications including, for example, the treatment of bovine mastitis, skin infections, fungus infections such as athletes foot, scalp infections, vaginal infections, nose and throat infections and other infections caused by microorganisms for which vitamin B is an essential metabolite or growth factor.
  • compositions of the invention are employed for dental purposes, their introduction into the oral cavity reduces acid formation on the tooth surface for prolonged periods of time and operates to maintain the pH well above the value of approximately 5.2. It is believed that the pyrimidine compound component of these therapeutic compositions operates by being effectively retained on dental plaques and, therefore, remains available over sustained periods of time to reduce acid production. These therapeutic compositions will exert a sufficiently persistent action in reducing acid production to be effective under the conditions of morning and evening use.
  • pyrimidine compounds specified herein are not only compatible with other components employed in therapeutic compositions, but they are also stable, nontoxic, nonirritating and nonsensitizing.
  • the pyrimidine compounds specified herein are not only compatible with other components employed in therapeutic compositions, but they are also stable, nontoxic, nonirritating and nonsensitizing.
  • the pyrimidine compounds specified herein are not only compatible with other components employed in therapeutic compositions, but they are also stable, nontoxic, nonirritating and nonsensitizing.
  • the pyrimidine compounds specified herein are not only compatible with other components employed in therapeutic compositions, but they are also stable, nontoxic, nonirritating and nonsensitizing.
  • the pyrimidine compounds specified herein are not only compatible with other components employed in therapeutic compositions, but they are also stable, nontoxic, nonirritating and nonsensitizing.
  • the pyrimidine compounds specified herein are not only compatible with other components employed in therapeutic compositions, but they are also stable, nontoxic
  • LD (a standard statistical value which corresponds to the single dose which is lethal to 50% of the test animals) for the compound 1,3-bis(beta-ethylhexyl)-5-methyl-S-amino-hexahydropyrimidine is 1630 mg./kg. orally in rats and 142 mg./kg. intraperitoneally in mice.
  • the maximum daily tolerated dose of this exemplary pyri midine compound in the rate is 75-l00 mg./kg.
  • the pyrimidine compounds of these novel therapeutic compositions have the formula:
  • R is an alkyl, aryl, aralkyl, alkaryl, hydroxyalkyl, aminoalkyl or cycloalkyl radical and R is hydrogen, or a lower alkyl or hydroxymethyl radical.
  • S-amino-hexahydropyrimidine compounds which have been found elfectivc may be mentioned l,3-bismethyl-5-methyl-5-amino-hexahydropyrimidine, 1,3-bis(beta-ethylhexyl -5-methyl-5-amine-hexahydropyrimidine, l,3-bispropyl-S-rnethyl-S-amino-hexahydropyrimidine, 1,3-bisisopropyl-5-methyl-S-amino-hexahydropyrimidine, l,3-bisbutyl-5-methyl-5-aminohexahydropyrimidine, 1,3-bis(second ary butyl)-5-methyl- 5-amino-hexahydropyrimidine, l,3-bis(tertiary butyl)-5' methyl-S-amino-hexahydropyrimidine, 1,3-bishexyl-5- methyl 5 amino
  • salts of these amine compounds may also be utilized. Salts are readily formed with acids such as, for example, acetic acid, phosphoric acid, boric acid, hydrochloric acid, maleic acid, benzoic acid, citric acid, malic acid, oxalic acid, tartaric acid, succinic acid, glutaric acid, gentisic acid, Valerie acid, gallic acid, ,S-resorcylic acid, acetyl salicylic acid and salicylic acid, as well as perchloric acid, barbituric acid, sulfanilic acid, phytic acid and p-nitro benzoic acid. These amines also form useful salts with long chain aliphatic acids such as stearic acid, palmitic acid, oleic acid, myristie acid, and lauric acid.
  • the trihydrochloride for example, is highly water soluble.
  • compositions of the present invention comprise a pyrimidine compound of the class described above and a pharmaceutical carrier which may be either a liquid or solid material.
  • a pharmaceutical carrier which may be either a liquid or solid material.
  • these compositions include not only paste, powder and liquid dentifrices, but also mouthwashes, chewing gum, tablets, lozenges and troches.
  • compositions include water washable ointments, non-water washable ointments, ophthalmic ointments, scalp lotions, nasal preparations including nasal jellies, nasal sprays and nasal drops, aerosols (for topical application in the treatment of fungi, for example), powders including foot powders and insufilation powders tablets and vaginal preparations including vaginal suppositories and suitable compositions for parenteral administration.
  • solid pharmaceutical carriers include starch, gelatin, lactose, talc, boric acid and the like. Any of the conventional pharmaceutical carriers used in pharmaceutical practice may be utilized herein where such materials are compatible with the aforementioned pyrimidine compounds.
  • These novel compositions may include a liquid pharmaceutical carrier and be in the form of solutions, dispersions, suspensions and the like. Although these pyrimidine compounds are relatively insoluble in water,
  • any surface active agent which is a solvent for the pyrimidine compounds or in any such agent, which, when added to water, gives a semi-' colloidal solution, for example, ethanolamine salts, polyvinylpyrrolidone and the complex sorbitol etherester sold under the trade-designation Tween 20 are satisfactory dispersing agents.
  • these pyrimidine compounds are soluble in oils such as peanut oil and organic solvents.
  • the percentage of the pyrimidine compound incorporated in the therapeutic compositions of the invention may be varied considerably, but we prefer to use an amount between approximately 0.01% by weight and 1% by weight. Amounts smaller than 0.01% by weight of one of the pyrimidine compounds may also be used in the practice of the invention.
  • the dental compositions of the invention may include a water-soluble oxalate component, such as, for example, sodium, potassium and ammonium oxalates and the urea salts of oxalic acid.
  • a water-soluble oxalate component such as, for example, sodium, potassium and ammonium oxalates and the urea salts of oxalic acid.
  • the amounts of oxalate component, when included in these compositions may be varied considerably, but a range of approximately 0.25% to approximately 1.5% by weight is preferred.
  • Example 1 A dentifrice composition was prepared by mixing 99.5 parts by weight of a paste having the following components:
  • the resulting product was a paste dentifrice composition containing 0.1% by weight of 1,3-bis(beta-ethylhexvl)-5- methyl-5-amino-hexahydropyrimidine.
  • Example 2 A dentifrice composition was prepared from the following components:
  • Example 5 was repeated employing 1,3-bis(hydro xy Water (q. s. to 100%) 23.464 1 tertiary butyl) 5 ethyl 5 amino hexahydropyrimi-
  • Tween Example 12 v I 20 1,3-bis(hydro xy Water (q. s. to 100%) 23.464 1 tertiary butyl) 5 ethyl 5 amino hexahydropyrimi-
  • a dentifrice composition as described in Example-12' was prepared except that 0.01% of 1,3-bis(beta-ethylhexyl)-5 methyl-5-amino-hexahydropyrimidine was employed. The percentage by Weight of the water component was adjusted to compensate for the decreased percentage of the pyrimidine compound.
  • Example 4 A mouthwash was prepared from the following components:
  • Example 6 Example 5 was repeated employing 1,3-bisdodecy1-5- methyl-5-amino-hexahydropyrimidine in a concentration of 0.1 mg./ml. saliva. At this concentration, it was found that inhibition of acid formation was attained.
  • Example 7 Example 5 was repeated employing 1,3-bistetradecyl- 5-methyl-5-amino hexahydropyrimidine in a concentration of 2 mg./ml. saliva. At this concentration, it was found that 100% inhibition of acid formation was at- I tained.
  • Example 8 Example 5 was repeated employing 1,3-bishexadecyl- 5-methyl-5-amino-hexahydropyrimidine in a concentration of 0.1 mg./ml. saliva. At this concentration, it was found that 100% inhibition of acid formation was attained.
  • Example 9 Example 5 was repeated employing 1,3-bis(dicyclohexyl)-5-methyl-S-amino-hexahydropyrimidine in a concentration of 0.1 mg./ml. saliva. At this concentration, it was found that 100% inhibition of acid formation was attained.
  • Example 13 Example was repeated employing 1,3 bis(cyclohexyl)-5-ethyl-5-amino-hexahydropyrimidine in a concentration of 2 mg./ml. saliva. At this concentration, it was found that 100% inhibition of acid formation was attained.
  • Example 14 A therapeutic foot powder was prepared from the following components:
  • a water washable therapeutic ointment was prepared from the following components:
  • Example 16 A nonwater washable therapeutic ointment was prepared'from the following components:
  • Example 17 A therapeutic ophthalmic ointment was prepared from the following components:
  • Example 18 A therapeutic nasal drop composition was prepared from the following components:
  • Example 19 A therapeutic nasal spray was prepared from the following components:
  • Example 20 Atherapeutic nasal jelly was prepared from the following components:
  • Example 21 A therapeutic vaginal insulfiation powder was prepared from the following components:
  • Example 22 A therapeutic vaginal tablet was prepared from the following components:
  • Example 23 The therapeutic vaginal suppository was prepared from the following components:
  • the suppository was prepared in accordance with the procedure set forth on page 764 of the United States Pharmacopeia (fourteenth revision).
  • Example 24 A therapeutic scalp lotion was prepared from the following components:
  • Example 25 A therapeutic soap was prepared by compressing the following components into soap cakes:
  • compositions of the invention analogous to the above-described compositions and containing comparable amounts of the pyrimidine compounds specifically enumerated above may be prepared and are effective in the practice of the invention.
  • Example 26 A therapeutic foot powder was prepared from the following components:
  • the trihydrochloride is also useful in this composition.
  • Example 27 A therapeutic throat lozenge is prepared by subjecting a mixture of the following components to compression molding, the amounts given being suflicient for the preparation of 1000 tablets weighing one gram each:
  • Example 28 A therapeutic vaginal gel is prepared from the following components:
  • the lactic acid present is in stoichiometric excess to form the lactate of the amine base.
  • Example 29 A therapeutic vaginal gel preparation is formulated by combining the following:
  • Example 30 A therapeutic shampoo is prepared from the followin components:
  • Example 31 An antifugal nail preparation is formulated from the following:
  • Example 32 A non-water washable ointment was prepared from the following components:
  • the above ointment can be converted to a water washable ointment by substituting hydrophilic ointment, U. S. P., in place of the petrolatum.
  • Example 33 A therapeutic suspension of the trihydrochloride of 1,3 bis(beta ethylhexyl) 5 methyl 5 amino hexahydropyrirnidine is obtained by adding 6.5 g. of the trihydrochloride salt to 15 cc. of distilled water, adding the solution obtained to a solution of 40 g. of polyvinylpyrrolidone in 40 cc. of distilled water, adjusting the pH to 6.8-7.2 by adding aqueous 30% sodium hydroxide solution, then adding a solution of 20 g. of sodium carboxymethyl cellulose in 600 cc. of distilled water and finally bringing the total volume to 1000 ml. by adding the'necessary amount of distilled water.
  • Example 34 A mouthwash was prepared from the following components:
  • a therapeutic shampoo is obtained by combining the following components:
  • a therapeutic vaginal suppository was prepared by molding a mixture of the following components into suppositories weighing one gram, each:
  • a therapeutic composition effective to'inhibit the growth of microorganisms, free of undesirable toxic effects comprising a pharmaceutical carrier and a substantial amount, less than 1% by weight, of a compound of the group consisting of those having the formula:
  • R represents a radical selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, hydroxy-alkyl, aminoalkyl, and cycloalkyl and R is selected from the group consisting of hydrogen, lower alkyl and hydroxymethyl radicals and the salts of said compounds.
  • composition set forth in claim 1 wherein the compound is l,3-bis(1-methyl heptyD-S-methyl-S-amino- 5-aminohexahydropyrimidine.
  • composition set forth in claim 1 wherein the compound is 1,3-bis(beta ethylhexyl)-5-methyl-5-aminohexahydropyrimidine.
  • composition set forth in claim 1 wherein the compound is 1,3-bis(1-methyl heptyD-S-methyl-S- aminohexahydropyrimidine.
  • composition set forth in claim 1 wherein the compound is 1,3-bisheptyl-5-methyl-5-amino-hexahydropyrimidine.
  • composition set forth in claim 1 wherein the compound is 1,3-bisoctyl-5-methyl-S-amino-hexahydropyrimidine.
  • composition set forth in claim 1 wherein the compound is 1,3 bis(methyl-benzyl)-5-m thyl-i-atninc hexahydropyrimidine.
  • a dental composition comprising a tooth cleaning component and a substantial amount, less than 1% by weight, of 1,3-bis(beta-ethylhexyl)-5-methyl-5-aminohexahydropyrimidine.
  • a dental composition comprising a tooth cleaning component and a substantal amount, less than 1% by weight, of a salt of 1,3-bis(beta-ethylhexyl)-5-methyl-5- amino-hexahydropyrimidine.
  • a mouthwash composition comprising an aqueous alcoholic vehicle and a substantial amount, less than 1% by weight, of l,3-bis(beta-ethylhexyl)-5-methyl-5- amino-hexahydropyrimidine.
  • a mouthwash composition comprising an aqueous alcoholic vehicle and a substantial amount, less than 1% by weight, of a salt of 1,3-bis(beta-ethylhexyU-S- methyl-5-amino-hexahydropyrimidine.
  • a water-washable ointment comprising a hydrophilic ointment base and a substantial amount, less than 1% by weight, of 1,3-bis(beta-ethylhexyl)-S-methyl- 5-amino-hexahydropyrimidine.
  • a water-washable ointment comprising a hydro philic ointment base and a substantial amount, less than 1% by weight, of a salt of 1,3-bis(beta-cthylhexyD-S- methyl-S-amino-hexahydropyrimidine.
  • a vaginal suppository comprising a glycerinated gelatin base and a substantial amount, less than 1% by weight, of l,3-bis(beta-ethylhexyl)-5-methyl-5-aminohexahydropyrimidine.
  • a soap composition comprising a soap base and a substantial amount, less than 1% by weight, of 1.3- bis(beta ethylhexyl) 5 methyl 5 amino hexahydropyrimidine.

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Description

United States 2,837,463 THERAPEUTIC coMrosrrroNs COMPRISING S-AMINO HEXAHYDROPINES OR SALTS THEREOF No Drawing. Application January 10, 1958 Serial No. 708,072
21 Claims. (Cl. 167-93) This invention relates to therapeutic compositions and atent more particularly to therapeutic compositions containing certain S-amino hexahydro pyrimidine compounds.
This application is a continuation-in-part of our copending applications Serial No. 393,247, filed November 19, 1953, now abandoned, Serial No. 447,408, filed August 2, 1954, now abandoned, and Serial No. 547,332, filed November 16, 1955, now abandoned.
Briefly, the present invention is directed to therapeutic compositions comprising a compound having the formula: H:
C RN NR \C 111 \NH: wherein R is an alkyl, aryl, aralkyl, alkaryl, hydroxyalkyl, aminoalkyl or cycloalkyl radical and R is hydrogen, or a lower alkyl or hydroxymethyl radical, and a pharmaceutical carrier. In lieu of employing the above -amino-hexahydropyrimidines in the form of their free bases, the salts of these amine compounds may also be utilized.
Among .the several objects of the invention may be noted the provision of therapeutic compositions which are effective for various therapeutic purposes including, for example, the treatment of bovine mastitis, skin infections, fungus infections, scalp infections and other infections, both surface and systemic, caused by microorganisms; the provision of therapeutic compositions which are effective, for example, to inhibit the growth of microorganisms for which vitamin B is an essential metabolite or growth factor and certain enzyme systems in which cocarboxylase functions as an essential part; the provision of therapeutic compositions which are suitable, for example, for introduction into the oral cavity and for topical application to the skin and for parenteral administration; and the provision 'of therapeutic compositions of the class described which are nontoxic, nonsensitizing, nonirritating, and stable. Other objects and features will be in part apparent and in part pointed out hereinafter.
The invention accordingly comprises the products hereinafter described, the scope of the invention being indicated in. the following claims.
In accordance with the present invention, it has now I been found that compositions including a S-amino-hexahydropyrimidine compound having the following formula:
2,837,463 Patented June s, 1958 wherein R is an alkyl, aryl, aralkyl, alkaryl, hydroxyalkyl, aminoalkyl or cycloalkyl radical and R represents hydrogen or a lower alkyl or hydroxymethyl radical and the salts thereof, are useful therapeutic compositions for various applications. For example, we have found that the growth and development of microorganisms for which vitamin B is an essential metabolite or growth factor and the activity of certain enzyme systems in which cocarboxylase is an essential component can be effectively inhibited by the use of the novel therapeutic compositions of the present inventtion.
It is known that vitamin B is an essential metabolite, i. e., a necessary constituent of the normal metabolic processes, and growth factor for many microorganisms. The presence of the coenzyme, cocarboxylase, which is a crystalline diphosphoric acid ester of vitamin B is required in order for the enzyme carboxylase to remove carbon dioxide from pyruvic acid and other organic acids formed from carbohydrates in the metabolism of such microorganisms. Accordingly, in the presence of vitamin 13,, the microorganisms grow and develop normally through the energy derived from the metabolic process described above.
Without limiting in any way the scope of the invention with respect to the mode in which these novel therapeutic compositions operate when used for various therapeutic purposes, it is believed that the S-amino-hexahydropyrimidine component of the compositions of the invention acts as an antimetabolite or competitive antagonist for vitamin B in the metabolism of the microorganisms. The S-amino-hexahydropyrimidine component is believed to form a complex with the enzyme carboxylase which, unlike the complex formed in the case of vitamin B is incapable of effecting the chemical changes characteristic of those occurring in the presence of cocarboxylase. Consequently, the decarboxylation of pyruvic acid, for example, as well as other organic acids ceases and the growth and development of. the microorganisms are thereby inhibited because of this interruption of their normal metabolic processes. Likewise, the compositions of the present invention are effective against certain enzyme systems of which cocarboxylase is an essential component.
The compositions of the invention are markedly eflective in inhibiting the growth of microorganisms for which vitamin B is an essential metabolite or growth factor. 1
The measurement of antagonism between metabolite and antimetabolite may be expressed by a number known as the inhibition index. The inhibition index is the quotient of the ratio of concentration of the two substances at which their effects are just counterbalanced, and represents the amount of antimetabolite which is needed to overcome the effect of a unit weight of metabolite. Thus, a low inhibition index is indicative of the high effectiveness of an antimetabolite. The inhibition index in the case of vitamin B and the S-amino-hexahydropyrimidine compounds included in the compositions of the present invention is relatively low, and therefore, in general, it may be stated that ,only relatively small amounts of these compositions are required to offset the effect of relatively large amounts of vitamin B And since the antagonism between these pyrimidine compounds and vitamin B is competitive, the inhibition index is relatively constant with respect to all microorgan isms for which vitamin B is an essential metabolite.
Among the many microorganisms against which the compositions of the invention are effective may be menorganisms isolated from acute and chronic bovine mastitis cases. Further, under therapeutic conditions induction of resistance in microorganisms to the compositions of the invention has not been found.
The therapeutic compositions of the invention are useful and effective in various therapeutic applications including, for example, the treatment of bovine mastitis, skin infections, fungus infections such as athletes foot, scalp infections, vaginal infections, nose and throat infections and other infections caused by microorganisms for which vitamin B is an essential metabolite or growth factor.
Where the compositions of the invention are employed for dental purposes, their introduction into the oral cavity reduces acid formation on the tooth surface for prolonged periods of time and operates to maintain the pH well above the value of approximately 5.2. It is believed that the pyrimidine compound component of these therapeutic compositions operates by being effectively retained on dental plaques and, therefore, remains available over sustained periods of time to reduce acid production. These therapeutic compositions will exert a sufficiently persistent action in reducing acid production to be effective under the conditions of morning and evening use.
The pyrimidine compounds specified herein are not only compatible with other components employed in therapeutic compositions, but they are also stable, nontoxic, nonirritating and nonsensitizing. For example, the
LD (a standard statistical value which corresponds to the single dose which is lethal to 50% of the test animals) for the compound 1,3-bis(beta-ethylhexyl)-5-methyl-S-amino-hexahydropyrimidine is 1630 mg./kg. orally in rats and 142 mg./kg. intraperitoneally in mice. The maximum daily tolerated dose of this exemplary pyri midine compound in the rate is 75-l00 mg./kg. Three groups of twenty rats each were given 0.02%, 0.05% and 0.1% by weight of l,3-bis(beta-ethylhexyl)-5-methyl-5- aminohexahydropyrimidine in their diet for a period of forty-eight weeks. No mortalities were observed in any of the three groups. Histopathology of these animals at six months showed no pathological lesions attributed to l,3-bis(beta-ethylhexyl) -5-methyl-5-arnino-hexahydropyrimidine. Further, repeated instillation of a saturated aqueous solution of 1,3-bis(beta-ethylhexyl)-S-methyl-5- amino-hexahydropyrimidine into rabbits eyes showed that this exemplary pyrimidine compound is not a primary irritant to delicate tissues.
The pyrimidine compounds of these novel therapeutic compositions have the formula:
wherein R is an alkyl, aryl, aralkyl, alkaryl, hydroxyalkyl, aminoalkyl or cycloalkyl radical and R is hydrogen, or a lower alkyl or hydroxymethyl radical. These compounds may be prepared by the method described in U. S. Patent 2,387,043. Among the S-amino-hexahydropyrimidine compounds which have been found elfectivc may be mentioned l,3-bismethyl-5-methyl-5-amino-hexahydropyrimidine, 1,3-bis(beta-ethylhexyl -5-methyl-5-amine-hexahydropyrimidine, l,3-bispropyl-S-rnethyl-S-amino-hexahydropyrimidine, 1,3-bisisopropyl-5-methyl-S-amino-hexahydropyrimidine, l,3-bisbutyl-5-methyl-5-aminohexahydropyrimidine, 1,3-bis(second ary butyl)-5-methyl- 5-amino-hexahydropyrimidine, l,3-bis(tertiary butyl)-5' methyl-S-amino-hexahydropyrimidine, 1,3-bishexyl-5- methyl 5 amino hexahydropyrimidine, 1,3-bisheptyl- 5 -methyl-S -arnino-hexahydropyrirnidine, l ,3-bisocty1-5- methyl-5-amino-hexahydropyrimidine, 1,3-bisdecyl5 methyl-5-amino-hexahydropyrimidine, l,3-bisdodccyl-5- methyl-S-amino-hexahydropyrimidine, 1,3-bistetradecyl-S- methyl-5-amino-hexahydropyrimidine, 1,3-bishexadecyl-5- methyl-5 -amino-hexahydropyrimidine, 1,3-bis( 1 -methylheptyl -5-methyl-5-amino-hexahydropyrimidine, 1,3-bis (1,3 dimethylbutyl) 5 methyl 5 amino hexahydropyrimidine, l,3-bis(tertiary butyl-Z-methyl)-5methyl-5- amino-hexahydropyrimidine, 1,3-bis (isopropyl-Z-methyl S-methyl-amino-hexahydropyrimidine, 1,3-bis (hydroxy tertiary butyl)-S-methyl-S-amino-hexahydropyrimidine, l, 3 bis(isopropyl) 5 hydroxymethyl 5 amino hexahydropyrimidine, 1 ,3-bis fi-hydroxyethylaminopropyl) -5- methyl-5-amino-hexahydropyrimidine, l,3-bis( 1,1-dimethyl 2 hydroxyethyl) 5 methyl 5 amino hexahydropyrimidine, l,3-bis(butylaminopropyl)-5-methyl-5-amino-hexahydropyrimidine, 1 ,3-bis (beta-ethylhexyl) -5-amino-hexahydropyrimidine, 1-,3-bis (beta-ethylhcxyl) -5 hydroxymethyl-S-amino-hexahydropyrimidine, 1,3-bis (cyclohexyl)-5methyl-S-amino-hexahydropyrimidine, 1,3- bis(dicyclohexyl) 5 methyl 5 amino hexahydropyrimidine, 1,3-bistolyl-5methyl-5-amino-hexahydropyrimidine, 1,3-bisbenzyl-5-methyl-Samino-hexahydropyrimh dine, l ,3-bis (methylbenzyl) -5 -methyl-S-amino-hexahydropyrimidine, 1,3-bisphenyl-5-methyl-5-amino-hexahydropyrimidine, 1 ,3-bis (phenylethyl) -5-methyl-5-amino-hexahydropyrimidine, 1,3-bis (beta-ethylhexyl) -5-ethyl-5-amino-hexahydropyrirnidine, l,3-bis-dodecyl-5-cthyl-5-aminohexahydropyrimidine, l,3-bis(hydroxy tertiary butyl)-5- ethyl-5-amino-hexahydropyrimidine, 1,3-bis(beta-ethylhexyl)-5-propyl-S-amino-hexahydropyrimidine, and 1,3- bis(beta ethylhexyl) 5 butyl 5 amino hexahydropyrimidine. It will be understood that other S-aminohexahydropyrirnidine compounds of the above-noted classes are also suitable for use in the compositions of the invention.
As stated above, in lieu of employing the S-aminohexahydropyrimidines above in the form of their free.
bases, the salts of these amine compounds may also be utilized. Salts are readily formed with acids such as, for example, acetic acid, phosphoric acid, boric acid, hydrochloric acid, maleic acid, benzoic acid, citric acid, malic acid, oxalic acid, tartaric acid, succinic acid, glutaric acid, gentisic acid, Valerie acid, gallic acid, ,S-resorcylic acid, acetyl salicylic acid and salicylic acid, as well as perchloric acid, barbituric acid, sulfanilic acid, phytic acid and p-nitro benzoic acid. These amines also form useful salts with long chain aliphatic acids such as stearic acid, palmitic acid, oleic acid, myristie acid, and lauric acid. The trihydrochloride, for example, is highly water soluble.
The therapeutic compositions of the present invention comprise a pyrimidine compound of the class described above and a pharmaceutical carrier which may be either a liquid or solid material. When used for dental purposes, these compositions include not only paste, powder and liquid dentifrices, but also mouthwashes, chewing gum, tablets, lozenges and troches. For other uses, these compositions include water washable ointments, non-water washable ointments, ophthalmic ointments, scalp lotions, nasal preparations including nasal jellies, nasal sprays and nasal drops, aerosols (for topical application in the treatment of fungi, for example), powders including foot powders and insufilation powders tablets and vaginal preparations including vaginal suppositories and suitable compositions for parenteral administration. Examples of solid pharmaceutical carriers include starch, gelatin, lactose, talc, boric acid and the like. Any of the conventional pharmaceutical carriers used in pharmaceutical practice may be utilized herein where such materials are compatible with the aforementioned pyrimidine compounds. These novel compositions may include a liquid pharmaceutical carrier and be in the form of solutions, dispersions, suspensions and the like. Although these pyrimidine compounds are relatively insoluble in water,
they may be readily dispersed in any surface active agent which is a solvent for the pyrimidine compounds or in any such agent, which, when added to water, gives a semi-' colloidal solution, for example, ethanolamine salts, polyvinylpyrrolidone and the complex sorbitol etherester sold under the trade-designation Tween 20 are satisfactory dispersing agents. Also, these pyrimidine compounds are soluble in oils such as peanut oil and organic solvents.
The percentage of the pyrimidine compound incorporated in the therapeutic compositions of the invention may be varied considerably, but we prefer to use an amount between approximately 0.01% by weight and 1% by weight. Amounts smaller than 0.01% by weight of one of the pyrimidine compounds may also be used in the practice of the invention.
In addition to one of the above-noted pyrimidine compounds, the dental compositions of the invention may include a water-soluble oxalate component, such as, for example, sodium, potassium and ammonium oxalates and the urea salts of oxalic acid. The amounts of oxalate component, when included in these compositions may be varied considerably, but a range of approximately 0.25% to approximately 1.5% by weight is preferred.
The following examples illustrate the invention.
Example 1 A dentifrice composition was prepared by mixing 99.5 parts by weight of a paste having the following components:
and 0.5 part by weight. of a concentrate having the following components:
Components: Percent by weight 1,3-bis(beta-ethylhexyl)-5methyl 5 aminohexahydropyrimidine 20.0 Complex sorbitol ether-ester dispersing agent (sold under the trade designation Tween Water 40.0
The resulting product was a paste dentifrice composition containing 0.1% by weight of 1,3-bis(beta-ethylhexvl)-5- methyl-5-amino-hexahydropyrimidine.
Example 2 A dentifrice composition was prepared from the following components:
Components: Percent by weight Alumina hydrate 40.0 Example 10 7 Titanium dioxide 1.0 Example was repeated employin 1,3-bis(beta-ethyl- Sodium saccharin 0.15 hexyl)-5-ethyl-S-amino-hexahydropyrimidine in a concen- Detergent 3.0 trationof 0.1 mg./ml. saliva. At this concentration, it Gum tragacanth 1.5 was .found that 100% inhibition of acid formation was Sodium oxalate 0.5 65 attained. Glycerine 12.0 d-Sorbitol solutions 17.0 Example 11 Phosphoric acid 5% 03 Ex mple 5 was repeated employing 1,3-bisdodecyl-5- Flavor 5 ethyl-5-amino-hexahydropyrimidine in a concentration of 1,3 bis(beta ethylhexyl) 5 methyl 70 0.1 mg./ml. sal iv a At this concentration, it was found hexahydmpyrimidine 00333 that 100% inhibition of acid formation was attainedw 1 Complex sorbitol ether-ester dispersing agent (sold under the trade designation Tween Example 12 v I 20") 0.0667 Example 5 was repeated employing 1,3-bis(hydro xy Water (q. s. to 100%) 23.464 1 tertiary butyl) 5 ethyl 5 amino hexahydropyrimi- Example 3 A dentifrice composition as described in Example-12' was prepared except that 0.01% of 1,3-bis(beta-ethylhexyl)-5 methyl-5-amino-hexahydropyrimidine was employed. The percentage by Weight of the water component was adjusted to compensate for the decreased percentage of the pyrimidine compound.
Example 4 A mouthwash was prepared from the following components:
Water q. s. 1000.00 ml. 7
Example 5 Thetechniques described in Fancher, O. E. Fosdick,
L. S., and Calandra, J. C., J. Dental Res. 23: 23 (1944),
Calandra, J. C., and Fosdick, L. S., J. Dental Res. 26: 303 1947), and Calandra, J. C., and Fosdick, L. S., J. Dental Res. 26: 309 (1947), were employed to determine acid formation in saliva-enamel-sugar mixtures. When tested by these techniques, 1,3-bis(cyclohexyl)-5- methyl-S-amino-hexahydropyrimidine in a concentration of 2 mg./ml. saliva was found to reduce acid formation. 2
Example 6 Example 5 was repeated employing 1,3-bisdodecy1-5- methyl-5-amino-hexahydropyrimidine in a concentration of 0.1 mg./ml. saliva. At this concentration, it was found that inhibition of acid formation was attained.
Example 7 Example 5 was repeated employing 1,3-bistetradecyl- 5-methyl-5-amino hexahydropyrimidine in a concentration of 2 mg./ml. saliva. At this concentration, it was found that 100% inhibition of acid formation was at- I tained.
Example 8 Example 5 was repeated employing 1,3-bishexadecyl- 5-methyl-5-amino-hexahydropyrimidine in a concentration of 0.1 mg./ml. saliva. At this concentration, it was found that 100% inhibition of acid formation was attained.
Example 9 Example 5 was repeated employing 1,3-bis(dicyclohexyl)-5-methyl-S-amino-hexahydropyrimidine in a concentration of 0.1 mg./ml. saliva. At this concentration, it was found that 100% inhibition of acid formation was attained.
7 dine in a concentration of 0.1 mg./m1. saliva. At this concentration, it was found that 100% inhibition of acid formation was attained.
Example 13 Example was repeated employing 1,3 bis(cyclohexyl)-5-ethyl-5-amino-hexahydropyrimidine in a concentration of 2 mg./ml. saliva. At this concentration, it was found that 100% inhibition of acid formation was attained.
Example 14 A therapeutic foot powder was prepared from the following components:
A water washable therapeutic ointment was prepared from the following components:
1,3 bis(beta-ethylhexyl) 5 methyl 5 -arninoheXahydro-pyrimidine g Hydrophilic ointment (USP), q. s. to 100.0 g.
Example 16 A nonwater washable therapeutic ointment was prepared'from the following components:
1,3 bis(beta-ethy1hexyl) 5 methyl 5 -amino hexahydro-pyrimidine g White ointment (USP), q. s. to 100.0 g.
Example 17 A therapeutic ophthalmic ointment was prepared from the following components:
G. 1,3 bis(beta-ethylhexyl) 5 methyl 5 -aminohexahydro-pyrirnidine 0.10 Mineral oil 8.50 Wool fat 9.15
Petrolatum, q. s. to 100.00 g.
Example 18 A therapeutic nasal drop composition was prepared from the following components:
G. 1,3 bis(beta-ethylhexyl) 5 methyl 5 -aminohexahydro-pyrimidine 0.1 Complex sorbitol ether-ester dispersing agent (sold under the trade designation Tween 20) 1.4 Sodium chloride 0.9
Distilled water, q. s. to 100.00 ml.
Example 19 A therapeutic nasal spray was prepared from the following components:
1,3 bis(beta-ethylhexyl) 5 methyl 5 -ami.no-
hexahydro-pyrirnidine 0.1 Menthol 0.5
Light mineral oil (US P), q. s. to 100.0 ml.
Example 20 Atherapeutic nasal jelly was prepared from the following components:
G. 1,3 bis(beta-ethylhexyl) 5 methyl 5 -aminohexahydro-pyrimidine 0.1
8 Glycerine Tragacanth Distilled water, q. s. to 100.0 g.
Example 21 A therapeutic vaginal insulfiation powder was prepared from the following components:
1,3 bis(beta-ethylhexyl) 5 methyl 5 -aminohexahydro-pyrimidine 0.1 Boric acid 5.0 Lactose 20.0
Kaolin, q. s. to 100.0 g.
Example 22 A therapeutic vaginal tablet was prepared from the following components:
a G. 1,3 bis(beta-ethylhexyl) 5 methyl 5 -aminohexahydro-pyrimidine 0.01 Boric acid 0.50
Lactose 0.50
Example 23 The therapeutic vaginal suppository was prepared from the following components:
1,3 bis (beta ethylhexyl) 5 methyl 5 aminohexahydropyrimidine 0.01 Glycerinated gelatin base 10.00
The suppository was prepared in accordance with the procedure set forth on page 764 of the United States Pharmacopeia (fourteenth revision).
Example 24 A therapeutic scalp lotion was prepared from the following components:
1,3 bis (beta ethylhexyl) 5 methyl 5 aminohexahydropyrimidine g 0.1 Ethyl alcohol ml 65.0
- Distilled water, q. s. to 100.0 m1.
Example 25 A therapeutic soap was prepared by compressing the following components into soap cakes:
1,3 bis(beta-ethylhexyl) 5 methyl 5 aminohexahydropyrimidine g.. 0.2 Soap granules (Ivory"), q. s. to 100.0 g.
Other compositions of the invention analogous to the above-described compositions and containing comparable amounts of the pyrimidine compounds specifically enumerated above may be prepared and are effective in the practice of the invention.
Example 26 A therapeutic foot powder was prepared from the following components:
Components: Parts by weight, g.
1,3 bistbeta ethylhexyl) 5 methyl 5- amino-hexahydropyrimidine salicylate 0.142
Boric acid 10.0
Starch 20.0
Talc, q. s. to 100.0 g.
The trihydrochloride is also useful in this composition.
Example 27 A therapeutic throat lozenge is prepared by subjecting a mixture of the following components to compression molding, the amounts given being suflicient for the preparation of 1000 tablets weighing one gram each:
Components: Parts by weight, g.
1,3 bis(beta ethylhexyl) methyl 5- amino hexahydropyrimidine trihydrochloride 1.5 Benzocaine 5.0 Sodium citrate 10.0 Synthetic sweetener (sodium saccharin and sodium cyclamate) 10.5 Sugar, powdered 656.0 Magnesium stearate 5.0 Flavor 4.5 Color 0.05 Polyethylene glycol 6000, q. s. to 1000.0 g.
Example 28 A therapeutic vaginal gel is prepared from the following components:
Components: Parts by weight 1,3 bis(beta ethylhexyl) 5 methyl 5- amino-hexahydropyrimidine g 1.00 Lactic acid, U. S. P. cc 2.50 Polysorbate 80 (polyoxyethylene sorbitan monooleate) g 14.00 Polyethylene glycol 400 g 50.00 Sodium carboxymethyl cellulose g 20.00 Sodium chloride g 8.00 Sodium benzoate g 3.00
Water, potable, q. s. to 1000.00 cc.
The lactic acid present is in stoichiometric excess to form the lactate of the amine base.
Example 29 A therapeutic vaginal gel preparation is formulated by combining the following:
Components: Parts by weight, g.
1,3 bis(beta ethylhexyl) 5 methyl 5- amino hexahydropyrimidine trihydrochloride 1.33 Polyethylene glycol 400 50.00 Sodium carboxymethyl cellulose (type 70 HV) 20.00 Sodium chloride 8.00 Sodium benzoate 3.00
Water, potable, q. s. to 1000.00 ml.
Example 30 A therapeutic shampoo is prepared from the followin components:
Components: Parts by weight 1,3 bis(beta ethylhexyl) 5 methyl 5- Diethanolamine amide of lauric acid kg 3.000 Hydrochloric acid (20% w./v.) 1iters 1.800 Formaldehyde solution, U. S. P. do Water, potable, q. s. to 100.000 liters.
Example 31 An antifugal nail preparation is formulated from the following:
Components: Parts by weight, g.
1,3 bis (beta ethylhexyl) 5 methyl 5 amino hexahydropyrimidine salicylate n 5 hydroxide.
'10 Polysorbate 15 Sodium carboxymethyl cellulose 10 Sodium benzoate 3 Water, q. s. to 1000 cc.
Example 32 'A non-water washable ointment was prepared from the following components:
Components: Parts by weight, g. 1,3-bis(beta-ethylhexyl)-5-methyl-5-amino hexahydropyrimidine valerate 0.1
Benzocaine 0.5
Petrolatum, U. S. P., q. s. to 100.0 g.
The above ointment can be converted to a water washable ointment by substituting hydrophilic ointment, U. S. P., in place of the petrolatum.
Example 33 A therapeutic suspension of the trihydrochloride of 1,3 bis(beta ethylhexyl) 5 methyl 5 amino hexahydropyrirnidine is obtained by adding 6.5 g. of the trihydrochloride salt to 15 cc. of distilled water, adding the solution obtained to a solution of 40 g. of polyvinylpyrrolidone in 40 cc. of distilled water, adjusting the pH to 6.8-7.2 by adding aqueous 30% sodium hydroxide solution, then adding a solution of 20 g. of sodium carboxymethyl cellulose in 600 cc. of distilled water and finally bringing the total volume to 1000 ml. by adding the'necessary amount of distilled water.
Example 34 A mouthwash was prepared from the following components:
A therapeutic shampoo is obtained by combining the following components:
Components: Parts by weight 1,3 bis(beta ethylhexyl) 5 methyl 5- amino hexahydropyrimidine trihydrochloride 3 1.33 Distearate of polyethylene glycol 400 g 16.7 Ammonium lauryl sulfate (27% solution) g 500.0 Distilled water cc 20.0 Ethyl alcohol, q. s. to cc 1000.00 Perfume cc 1.8
The pH is adjusted to 6.5 with aqueous 10% sodium Example 36 A therapeutic vaginal suppository was prepared by molding a mixture of the following components into suppositories weighing one gram, each:
Components: Parts by weight, g.
1,3 bis(beta ethylhexyl) 5 methyl 5- amino-hexahydropyrimidine trihydrochloride 1.50 Gramicidin 0.05 Neomycin sulfate 1.00 Polyethylene glycol 6000..- 650.0
Beta-lactose 430.0
"11 Example 37 A dentrifice composition was prepared from the following components:
Components: Percent by weight Alumina hydrate 40.0 Titanium dioxide 1.0 Sodium saccharin 0.15 Detergent 3.0 Gum tragacanth 1.5 Sodium oxalate 0.5 Glycerine 12.0 d-Sorbitol solution 17.0 Phosphoric acid 85% 0.3 Flavor 0.986
1,3 bis(beta ethylhexyl) methyl 5- amino-hexahydropyrimidine trihydrochloride 0.283 Complex sorbitol ether-ester dispersing agent (sold under the trade designation Tween 20) 0.0667 Water (q. s. to 100%) 23.214
In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.
As various changes could be made in the above products without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.
We claim:
1. A therapeutic composition effective to'inhibit the growth of microorganisms, free of undesirable toxic effects, comprising a pharmaceutical carrier and a substantial amount, less than 1% by weight, of a compound of the group consisting of those having the formula:
wherein R represents a radical selected from the group consisting of alkyl, aryl, aralkyl, alkaryl, hydroxy-alkyl, aminoalkyl, and cycloalkyl and R is selected from the group consisting of hydrogen, lower alkyl and hydroxymethyl radicals and the salts of said compounds.
2. The composition set forth in claim 1 wherein the compound is l,3-bis(1-methyl heptyD-S-methyl-S-amino- 5-aminohexahydropyrimidine.
3. The composition set forth in claim 1 wherein the compound is 1,3-bis(beta ethylhexyl)-5-methyl-5-aminohexahydropyrimidine.
4. The composition set forth in claim 1 wherein the compound is 1,3-bis(1-methyl heptyD-S-methyl-S- aminohexahydropyrimidine.
5. The composition set forth in claim 1 wherein the compound is 1,3-bisheptyl-5-methyl-5-amino-hexahydropyrimidine.
6. The composition set forth in claim 1 wherein the compound is 1,3-bisoctyl-5-methyl-S-amino-hexahydropyrimidine.
7. The composition set forth in claim 1 wherein the compound is 1,3 bis(methyl-benzyl)-5-m thyl-i-atninc hexahydropyrimidine.
8. A dental composition comprising a tooth cleaning component and a substantial amount, less than 1% by weight, of 1,3-bis(beta-ethylhexyl)-5-methyl-5-aminohexahydropyrimidine.
9. A dental composition comprising a tooth cleaning component and a substantal amount, less than 1% by weight, of a salt of 1,3-bis(beta-ethylhexyl)-5-methyl-5- amino-hexahydropyrimidine.
10. A mouthwash composition comprising an aqueous alcoholic vehicle and a substantial amount, less than 1% by weight, of l,3-bis(beta-ethylhexyl)-5-methyl-5- amino-hexahydropyrimidine.
11. A mouthwash composition comprising an aqueous alcoholic vehicle and a substantial amount, less than 1% by weight, of a salt of 1,3-bis(beta-ethylhexyU-S- methyl-5-amino-hexahydropyrimidine.
12. A water-washable ointment comprising a hydrophilic ointment base and a substantial amount, less than 1% by weight, of 1,3-bis(beta-ethylhexyl)-S-methyl- 5-amino-hexahydropyrimidine.
13. A water-washable ointment comprising a hydro philic ointment base and a substantial amount, less than 1% by weight, of a salt of 1,3-bis(beta-cthylhexyD-S- methyl-S-amino-hexahydropyrimidine.
14. A vaginal suppository comprising a glycerinated gelatin base and a substantial amount, less than 1% by weight, of l,3-bis(beta-ethylhexyl)-5-methyl-5-aminohexahydropyrimidine.
15. A soap composition comprising a soap base and a substantial amount, less than 1% by weight, of 1.3- bis(beta ethylhexyl) 5 methyl 5 amino hexahydropyrimidine.
16. The method of treating humans and animals to inhibit the growth of microorganisms which comprises topically administering to said humans and animals a composition of claim 1.
17. The method of treating humans and animals to inhibit the growth of microorganisms which comprises systemically administering to said humans and animals a composition of claim 1. I
18. The method of treating humans and animals to inhibit the growth of microorganisms which comprises topically administering to said humans and animals -a composition of claim 2.
19. The method of treating humans and animals to inhibit the growth of microorganisms which comprises systemically administering to said humans and animals a composition of claim 2.
20. The method. of treating humans and animals to inhibit the growth of microorganisms which comprises topically administering to said humans and animals a composition of claim 3.
21. The method of treating humans and animals to inhibit the growth of microorganisms which comprises systemically administering to said humans and animals a composition of claim 3.
OTHER REFERENCES Fosdick et al.: J. D. R., vol. 32, No. 4, August 1953, pp. 486-496.

Claims (1)

1. A THERAPEUTIC COMPOSITION EFFECTIVE TO INHIBIT THE GROWTH OF MICROORGANISMS, FREE OF UNDESIRABLE TOXIC EFFECTS, COMPRISING A PHARMACEUTICAL CARRIER AND A SUBSTANTIAL AMOUNT, LESS THAN 1% BY WEIGHT, OF A COMPOUND OF THE GROUP CONSISTING OF THOSE HAVING THE FORMULA:
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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3072529A (en) * 1957-07-19 1963-01-08 Warner Lambert Pharmaceutical Therapeutic composition of a 5-aminohexahydro-pyrimidine and selected chelating agents
US3087891A (en) * 1961-04-10 1963-04-30 Commercial Solvents Corp Process for the control of bacteria in water flooding operations
US3135656A (en) * 1964-03-23 1964-06-02 Armour & Co Method of controlling bacterial fire blight disease in living plants
US3248243A (en) * 1962-05-17 1966-04-26 Commerical Solvents Corp Aminohexahydropyrimidine-stabilized adhesive compositions
US4088752A (en) * 1974-05-31 1978-05-09 Gaba Ag Oral composition for plaque and caries inhibition
US4141968A (en) * 1976-06-16 1979-02-27 Doll Gmbh Novel salts of 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine in compositions having bacteriostatic activity
US4142050A (en) * 1975-11-06 1979-02-27 Doll Gmbh Salts of 1,3-bis(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine
US4515771A (en) * 1983-04-11 1985-05-07 Fine Daniel H Composition and method for the preventative treatment of dental disease and apparatus for dispensing said composition
US4666517A (en) * 1986-06-04 1987-05-19 Colgate-Palmolive Co. Antiplaque oral composition
AT390368B (en) * 1986-10-06 1990-04-25 Colgate Palmolive Co STABLE DENTAL CARE FOR PREVENTING DENTAL COATING
US6685919B2 (en) 2000-04-11 2004-02-03 Henkel Kommanditgesellschaft Auf Aktien Plaque-controlling liquid tooth cleaning gel
US20090004305A1 (en) * 2005-07-26 2009-01-01 William Chandler Antimicrobial and antiviral composition

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Publication number Priority date Publication date Assignee Title
US2415047A (en) * 1945-08-04 1947-01-28 Commercial Solvents Corp Insect-controlling compositions and method for controlling insects thereby

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2415047A (en) * 1945-08-04 1947-01-28 Commercial Solvents Corp Insect-controlling compositions and method for controlling insects thereby

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3072529A (en) * 1957-07-19 1963-01-08 Warner Lambert Pharmaceutical Therapeutic composition of a 5-aminohexahydro-pyrimidine and selected chelating agents
US3087891A (en) * 1961-04-10 1963-04-30 Commercial Solvents Corp Process for the control of bacteria in water flooding operations
US3248243A (en) * 1962-05-17 1966-04-26 Commerical Solvents Corp Aminohexahydropyrimidine-stabilized adhesive compositions
US3135656A (en) * 1964-03-23 1964-06-02 Armour & Co Method of controlling bacterial fire blight disease in living plants
US4088752A (en) * 1974-05-31 1978-05-09 Gaba Ag Oral composition for plaque and caries inhibition
US4142050A (en) * 1975-11-06 1979-02-27 Doll Gmbh Salts of 1,3-bis(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine
US4141968A (en) * 1976-06-16 1979-02-27 Doll Gmbh Novel salts of 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine in compositions having bacteriostatic activity
US4515771A (en) * 1983-04-11 1985-05-07 Fine Daniel H Composition and method for the preventative treatment of dental disease and apparatus for dispensing said composition
US4666517A (en) * 1986-06-04 1987-05-19 Colgate-Palmolive Co. Antiplaque oral composition
AT390367B (en) * 1986-06-04 1990-04-25 Colgate Palmolive Co ORAL CARE PRODUCTS
AT390368B (en) * 1986-10-06 1990-04-25 Colgate Palmolive Co STABLE DENTAL CARE FOR PREVENTING DENTAL COATING
US6685919B2 (en) 2000-04-11 2004-02-03 Henkel Kommanditgesellschaft Auf Aktien Plaque-controlling liquid tooth cleaning gel
US20090004305A1 (en) * 2005-07-26 2009-01-01 William Chandler Antimicrobial and antiviral composition
US7638147B2 (en) * 2005-07-26 2009-12-29 Global Life Technologies Corp. Antimicrobial and antiviral composition

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