US3168519A - 1-alkylphenyl-2, 2-di lower alkyl-4, 6-diimino-hexahydro-s-triazines - Google Patents

Description

.a hydroxy lower alkyl.

United States Patent O M 3,168,519 1-ALKYLPHENYL-2,2-Dl LQWER ALKYL-4,6-Dl- IMINO-HEXAHYDRO-s-TRIAZHNES Daniel Elmer Nagy, tamford, Corina, assignor to American Cyanamid ilompany, Stamford, Qonn, a carporation of Connecticut No Drawing. Filed Oct. 17, 1961, Sci". Na. rashes 6 Claims. ct. ass-249s This invention relates to new and useful alkylphenyl hexahydrotriazines and processes for their preparation. The invention is particularly concerned with the preparation of a new class of higher alkylated derivatives of phenyl hexahydrotriazine which demonstrate a high level of antibacterial, antitungal, and antialgal activity in a diversityof media. t t

The novel compounds of the present invention may be generally depicted as alkylated hexahydrotriazines of the following general structures embracing both tautomeric forms:

and acid addition salts and isomers thereofparticularly the isomeric forms: r H

wherein Rrepresents a substituent selected from the group consisting of a higher alkyl group having from 8 to about 18 carbon atoms and also an alkanoyl group; R represents a substituent selected from the group consisting of hydrogenand methyl; and R" represents a substituent selected from the group consisting of a lower In the tautomerie forms I, II, III, and IVYillustrat ed above, all forms are equally activebiocidal agents. However, the forms II and IV are generally considered to be the more stable forms although this is merely a matter" of degree. Y N By the term higher alkyl as it is employed to define.

the R substituent itgis intended to represent alkyl groups of the aliphatic series containing from C C carbon atoms which may be either in straight or branched chain conformation. This would, of course, embrace such substituents as octyl, nonyl, decyl, undecyl, dodecyl, tridecyl and branched chain isorners thereof. On the other hand, the term lower alkyl is intended to refer to the lower members of the series wherein C -C carbon atomsare contained either in straight or branched chain conformation. All of the well known members of this series such as methyl, ethyl, propyl, butyhpentyl, hexyl, and heptyli alkyl group having from 1 to about 7 carbon atoms and of both plant and animal origin.

3,168,519 Patented Feb. 2, 1965 would thus be included. In the case of the R substituent it is preferred that the substitution be in the para position in the phenyl ring although it is within the scope of the invention to effect substitution at any of the available positions in the phenyl ring.- V

By the term hydroXy lower alkyl it is intended to embrace polyhydroxy groups having from about 2 to 7 carbon atoms.

to refer to such carbonyl groups containing from about By the term alkanoyl it is intended 2 to 22 carbon atoms and includes such groups as propionyl, butyryl, pentanoyl, hexanoyl, octanoyl, dodec anoyl, octadecanoyl and the like.

It is known that a phenyl hexahydrotriazine has utility in pharmaceutical applications as an agent forthe treatment in humans of malaria and the like maladies of the blood. However, such compounds have never demonstrated any utility in the inhibition of bacterial, algal, or fungal growth and, in fact, when tested are found to be devoid of such activity. Quite unexpectedly, however, when one prepares the hithertounknown higher alkyl derivatives of a phenyl hexahydrotriazine as illustrated above this series of compounds is found to exhibit a high level of toxicity against a broad spectrum of degrading microorganisms which uncontrolled will rapidly deteriorate various materials and industrial systems which will tolerate their growth.

It is the principal object of the invention, "therefore, to provide the art with a novel class of alkylated phenyl hexahydrotriazines and a method for their manufacture.

It is a further object to provide as a novel antimicrobial agent the novel class of alkylated phenyl hexahydrotribiguanide hydrochloride with at least a molar equivalent of a ketone or aldehyde. The reaction is generally. con ducted in the presence of an inertsolventsucligasrntli anol or the like under reflux "conditions for thesolventi The product obtained is recovered by evaporation of the solvent after washing with saline solution to rernove inipmrities. It cairbe further purified by solution. in a recrystallization solvent mixture such as itolueneisopropanol and the like jto obtainthe' iiovel compounds of the invention. 1

In the case where it is desired. to prepare the isomeric form of the novelcompounds of this invention,. one first adds from 0.05-1 mole of hydrochloric acid to the alkylated phenylbiguanidehydrochloride. Itis preferred to remove any water. added with 'thehydrochloric acid prior to reactionwith the ketone bysuspending there; actants in benzene and azeo tropicallydistilling toremove any water present. Acetic acid is added as the solvent in place of methanol and the procedureis continuedas aboveindicated to obtain the 'pure .pro'duct.

[Although methanoliis the preferred solventyfor the .re-

action, a number of equally useful inert, solvents suchas ethanol, cellosolve land the like; may be also employed. The time ot reaction will yary with the reflux conditions and inert solvent employed; but generally speaking the. I

reaction will be completed within 8 to 24 hours for most,

if not all, of the reactants employed.

Moreover, it is an important aspect of the present invention that in the preparation of the novel compounds a ketone such as acetone when employed in excess as a reactant has a dual function of performing as a solvent. Other ketones which may be employed in the same manner are methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, and the like which demonstrate excellent solvent properties.

It is also Within the scope of the general preparation to add a substituted aniline salt and dicyandiamide to the ketone to form the alkyl substituted phenylbiguanide in situ and effect a reaction with the ketone. illustrated by reference to the following general equation wherein the ketone employed is dimethyl ketone and methanol is employed as an additional solvent. The values for R are, of course the same as its values indicated above. The use of this particular variant of the general procedure will be dictated by the choice and availability of reagents.

CH3 CH3 We prefer to prepare our noval compounds by the general reaction:

cose andthe like as Well as aldehydic sugars or'ketoses such as fructose or the like. In the latter case the R" as illustratedabove will represent apolyhydroxy function onthe final product prepared.

A. typical preparation of 1-dodecylphenyl-2,Z-dimethyl- 4,6-diimino-hexahydro-s-triazine (1-dodecylphenyl-2,2-dimethyl-4,6-diamino-1,Z-dihydro-s-triazine) hydrochloride is conducted as follows. Dodecylphenylbiguanide hydrochloride, (24.6 grams) is mixed with concentrated HCl (3.3 ml.) and 125 mlgof acetone. These components are refluxed overnightand the'crystalline material formed re- This may be covered by crystallization. -A 10 gram yield of the; final after application on a given surface. In addition to this for those paint formulations which contain casein and latex and are thus surbject to decomposition while in the container in st orage theiinstant compounds will preserve thesefrom such de gradation when added at the same dosage levels as indicated above.

The instant novel antimicrobial agents may be added to or incorporated in the material they are destined to preserve by means of dipping, dusting, spraying or the like or alternatively by direct addition into the formula or system to be protected.

While it is preferred to employ the novel comp unds of the invention in an aqueous or alcohol carrier vehicle, since they are both water and alcohol soluble they may, in a given instance, be admixed with other ingredients such as diluents, carriers and the like. Or if desired they may be placed in a formulation containing a surface active agent such as any of a number of such well known anionic, cationic, or nonionic agents.

The invention will be further illustrated by the following examples of specific methods of preparation of some of the representative members of the series. Also, a brief view of the relative antimicrobial activityof a few representative members of applicants class of compounds as compared to the known unsubstituted phenyl hexahydrotriazines of the prior art will be presented. This will further demonstrate the truly unexpected nature of applicants discovery.

It must be borne in mind that these several examples are intended only to illustrate the invention in more specific terms and are not intended to limit its scope in any manner. For a proper definition of the scope of applicants invention, reference may be had to the several appended claims.

EXAMPLE 1 1 -dodecylphenyl-2-n-hexyl4,6-diiminohexahydro-s-trz'azine hydrochloride Reflux 0.128 mole of l-dodecylphenylbiguanide hydrochloride, 0.2 mole of heptaldehyde and 2 ml. of concentrated hydrochloric acid in 150 ml. of methanol for about 30 hours. Filter 01f the crystals which form when the solution is cooled to a temperature of 0-5 C. Collect and recrystallize from isopropanol to obtain the product of this example. M.P. above 300 C. in yield about 70%.

. EXAMPLE 2 V J -d0decylphenyl-2,2-dimethyl-4,6-diimin0- hexahydro-s-triazine hydrochloride Heat 0.0428 mole of dodecylphenylbiguanide hydrochloride, 0.145 mole of acetone and 1ml. of concentrated hydrochloric acid at 5060 C. in 100 ml. of methanol for 8 hours with constant stirring. The solution is concentrated by evaporation to about 50 ml. at reduced presthe reaction mixture at C. and add 0.0525 mole dicyandiamide in small portions over a one half hour period. After addition of the dicyandiamide, increase-the temperature to C. and maintain for 3 hours. Cool the solution slowly to about 50 C. and add 0.10 mole of acetone.v Heat this reaction mixture to 70 C. for 8 hours following the addition of the acetone. Cool-the solution and separate out a finely divided white powder which is the product of this example. M.P. 200202 C.

EXAMPLE 3 1-0ctadecylphenyl-ZJ-dimethyl-4,6-diimino-hexahydr0- a s-triazine Dissolve 1.0 mole of octadecylaniline in 200 ml. of isopropanol and treat with 1.10 mole of hydrogen chloride gas over a period of one half hour. Increase the temperature to 80 C. and add 1.05 mole dicyandiamide in small portions over a period of one half hour. Increase the temperature to 90 C., maintain for 3 hours and reduce to about 50 C. Add 1.05 mole of acetone and raise the temperature to 75 C. where it is maintained for about 8 hours. Dilute the reaction mixture with isopropanol and crystallize by removing about half of the solvent under vacuum to yield the hydrochloride salt of the compound. Careful. addition of 1.10 mole of ammonium hydroxide dropwise at room temperature yields the free base which is the product of this example.

EXAMPLE 4 2,2-dimethyl-4-dodecylphenylimin0-6-imino-hexahydro-s-triazine hydrochloride A. Dodecylphenylbiguanide hydr0chl0ride.Dilute 0.5 mole of concentrated hydrochloric acid (50 grams); .to 100 ml. with Water. Suspend 0.4 mole dodecylaniline and 0.6 mole dicyandiamide in 100 ml. of a 50% Water-isopropanol mixture. Heat to 90 C. and add the dilute acid solution slowly over 1% hours. Heat the solution for 2 hours longer. Cool the solution and dilute with 100 ml. of benzene and 75 ml. of isopropanol in a separatory funnel after Washing with 20% saline solution to remove impurities. Add additional i'sopropanol during the washing procedure to insure the separation of the layers in the funnel. Separate off the upper layer containing 436 m1. of the mixture which contains the dodecylphenylbiguanide hydrochloride starting material for use in Part B of the example.

B. 2,2 diniethyl 4 clodecyIphenylimino-6-imino-hexahydro-s-triazine hydrochloride.-Evaporate 0.1 mole of dodecylphenylbiguanide hydrochloride of Part A (1 ml.) to remove the solvent. Add 100 mls. of benzene and 2.0 ml. of hydrochloric acid and azeotrope to remove water. Distillthe benzene off and take up the residue in 200 ml. of acetic acid and ml. of acetone. Heat this solution at 90 C. for about 16 hours. Remove the solvents by evaporation, and take the product up in a mixture of toluene and isopropanol and wash with ml. of saline solution. The upper layer is removed and vacuum dis tilled to give 4.4 grams of the product of this example. M.P. -86-88 C. The product formed is referred to as the normal form and is soluble in acetone, benzene and slightly soluble in water.

" ample. Add 100 ml. of benzene and azeotrope to remove 2.5 ml. of water. Then add 2.0 ml. of concentrated hydrochloric acid and azeotropically distill to remove 1.6 ml. of Water. The benzeneis then distilled off. Add 100 ml. of methanol and 22 ml. of acetone and reflux at 64 C. for 18 hours. Vacuum distill oif the methanol and suspend the product recovered in 250 ml. of acetone. The insoluble residue weighs 9.5 grams. Distill oil the acetone and take the product up in benzene and precipitate with hexane. A second fraction of insolubles of 9.1 grams is obtained. Both fractions exhibit a melting point of 195-202 C. and are the product of this example in its isomeric form.

EXAMPLE 6 Z-methyZ-Z-isobdryl-4-dodecylphenylimino-6-iminohexahydro-s-triazin'e hydrochloride tion of the solvents. It is only very slightly soluble in.

water and readily soluble in isopropanol. During vacuum drying at C. it is a thick liquid but upon cooling becomes a glassy solid.

EXAMPLE 7 1 -0clylphenyl-2,2-dimethyl-4,6-diimirio-hexahydr0- s-triazine hydrochloride EXAMPLE 8 1-octanoylphenyl-2,2-dimethyl-4,6-diimino-hexahydro-s-triazine hydrochloride Stir for 18 hours a mixture of 0.025 mole (6.4 grams) of 4-n-octanoylaniline hydrochloride; 0.027 mole (2.3

grams) of dicyandiamide and 30ml. of acetone in 15 m1. of methanol at room temperature until the solution turns orange color and a precipitate forms. The overall stirring time is about 24 hours. Chill the mixture to obtain 1.9 grams of product in tWocrops and spontaneous evaporation of the solvent yields another 5.4 grams for a total yield of 7.3 grams (77%). Recrystallize this crude product twice from a 1 to 3 mixture of methanolether and once from water to recover the product of this example. M.P. 1841 86 C.

Analysis.-Calcd for C H N OCl: C, 60.07; H, 7.96; N, 18.44; Cl, 9.34. Found: C, 60,03, 59.94; H, 8.10, 7.98; N, 18.30, 18.05; Cl, 9.18, 9.12.

EXAMPLE 9 4-d0decanoylphenylimino-Z-methyl-Z-isobutyl-6-iminohexahydro-s-triazine hydrochloride To 0.1 mole (39.5 grams) of dodecanoyl phenyl biguanide hydrochloride and ml. of benzene add 2.0 ml. of concentrated hydrochloric acid. Azeotropically distill this mixture until 1.6 ml. of material is removed. After distilling the benzene add 50 ml. of methyl isobutyl ketone and 200 m1. of glacial acetic acid, and heat the solution at 96 C. overnight. The test for the presence of biguanides, using copper sulfate and alkali as test reagents, will give a negative reaction indicating the absence of the starting biguanide.

Vacuum evaporate the above solution to obtain a quantitative yield of the crude product of the examplewhich is an armorphous solid, soluble in isopropanol from which it is purified by recrystallization.

EXAMPLE 10 4-octodecanoyl phenylimino-Z-melhyl-2-isobutyl-fi-iminohexahydro-s-triazine hydrochloride While only a few of the alkanoyl substituted members.

of the novel group of substituted hexahydro-s-triazines have been shown, it is believed that these are representative of the broad class of such substituted derivatives included within the concept of the invention.

EXAMPLE 1 1 As an example of the importance of the R substitution on the hexahydro s-triazine molecule, the following brief tabulation indicates the relative activity of a substituted and unsubstituted compound as'rclated to the prevention of growth of industrial degrading microorganisms:

TABLE I V NHR4 IN Rg-N -NHg-H C1 Industrial 1 R1 R R4 Autimicrobial Activity H 11C3H7 CuHs H NOHG. H DQ 11 51.-- 4C1zH2;\CaH4 H .1 Good.

as it will be noted from the above table the compound wherein a dodecyl function is attached to the phenyl ring exhibited strong antimicrobial activity, yet a compound absent the said function has no such activity.

' It-rnust, vof course, be understood that While the aforesaid illustrative examples disclose the preparation of the hydrochloride salt, other inorganic acids such as nitric or sulfuric or organic acids such as picric or paratoluene sulfonic may be employed to yield a large number of corresponding salts either inorganic or organic.

I claim: I

1. A compound selected from the group consisting of thoseof the formulae:

and acid addition salts thereof wherein R represents a substituent selected from the group consisting of a higher alkyl and an alkanoyl; R represents a substituent selected from the group consisting of hydrogen and methyl and R" represents a substituent selected from the group consisting of lower alkyl and hydroxyl lower alkyl.

2. 1 dodecylphenyl 2 n hexyl 4,6 diiminohexahydro-s-triazine hydrochloride.

3. 1 dodecylphenyl 2,2 dimethyl 4,6 diiminohexahydro-s-triazine hydrochloride.

4. l octadecylphenyl 2,2 dimethyl 4,6 diirninohexahydrostriazine.

5. 1 octylphenyl 2,2 dimethyl 4,6 diimino hexahydro-s-triazine hydrochloride.

6. 1'- octanoylphenyl 2,2-dimethyl-4,6-diirnino-hexahydro-s-triazine hydrochloride.

References Cited in the file of this patent UNITED STATES PATENTS 2,515,116 Dudley July 11, 1950 2,734,807 Chenicek et a1. Feb. 14, 1956 2,803,628 Crowther Aug. 20', 1957 2,900,385 Modest Aug. 18, 1959 OTHER REFERENCES Smolin et a1.: s-Triazine and Derivatives, pub. by Interscience Pub. Inc, 1959, pp. 258-265.

Modest et al.: Journal of the American Chemical So ciety, vol. 74 (1952), pp. 8556.

Stedmens' Medical Dictionary, 17th Edition (1949), pp. 72, 734, 737and 1309, pub. by Williams & Wilkins Co.

Claims (1)

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE OF THE FORMULAE: