Abstract:
Novel N-(phenyl)-1,4,5,6-tetrahydro-1,2,4-triazine-3-methanamines are disclosed which are useful as herbicides, insecticides, and antimicrobial agents. Various member compounds are also pharmacologically active.

Description:
SUMMARY OF THE INVENTION 
     This invention relates to novel N-(phenyl)-1,4,5,6-tetrahydro-1,2,4-triazine-3-methanamines corresponding to the formula: ##STR1## and the addition salts thereof. In the present specification and claims R and R 1  independently represent hydrogen or a lower alkyl of from 1 to 3 carbon atoms and R 2 , R 3 , R 4 , and R 5  independently represent hydrogen, methyl, trihalomethyl, or a halogen. 
     Operable addition salts of the above triazine compounds are those having anionic moieties which have no substantial detrimental effects upon the herbicidal, compounds are those having anionic moieties which have no substantial detrimental effects upon the herbicidal, insecticidal, or antimicrobial activity of the compounds. Representative salts include acid addition salts formed by addition to the triazine compounds inorganic acids such as hydrochloric, hydrobromic, sulfuric, and nitric acid or of organic acids such as acetic, lactic, maleic, succinic, fumaric, glutaric, citric, malic, sulfonic, tartaric, and the like. 
     The compounds of the present invention are crystalline solids which are of varying degrees of solubility in water and various organic solvents such as ether, alcohols, chlorinated hydrocarbons, lower alkanes, and esters. The compounds of the present invention exhibit herbicidal, insecticidal, and antimicrobial activities, however a given compound may not show activity in all of the above-mentioned areas. In addition, some of the compounds are pharmacologically active. 
     DESCRIPTION OF THE PRIOR ART 
     1,2,4-Triazines which are related in structure to the compounds of the present invention, but lack the amino linkage to the phenyl group, are disclosed in U.S. Pat. No. 3,471,486. Other 1,2,4-triazines are disclosed in U.S. Pat. Nos. 3,021,328; 3,135,737; 3,426,635; 3,428,635; 3,463,777; 3,471,485; 3,471,487 and 3,471,488. The condensation of β-aminoalkylhydrazines with iminoesters and orthoesters to yield 1,4,5,6-tetrahydro-1,2,4-triazines is disclosed in Trepanier et al., Jour. of Medicinal Chem., 10, 228 (1967). 
     Herbicidal activity has been shown for 2-alkylthio-4,6-diamino-s-triazine compounds. German Auslegenschriften 141,633. 
     DETAILED DESCRIPTION OF THE INVENTION 
     In general compounds of the present invention are prepared by the reaction of a selected N-(cyanomethyl)-aniline with methanol at room temperature in the presence of a catalytic amount of sodium methoxide to yield the phenylaminomethylimidate. See Schaefer et al., J. Org. Chem, 26, 412 (1961). The imidate formed in this manner is caused to react with a 2-aminoethylhydrazine to yield the desired 1,2,4-triazine of the present invention. The two step reaction may be represented as follows: ##STR2## wherein R 1 , R 2 , R 3 , R 4  and R 5  represent the same substitutions indicated above. If unavailable, N-(cyanomethyl)aniline used as a starting material in (I) above is prepared by reacting a substituted or unsubstituted aniline with a selected aldehyde, sodium hydrogen sulfate, and potassium cyanide. The reaction may be carried out on a steambath. 
     The following examples illustrate the preparation of compounds that are the subject of the present invention, but are not to be construed as a limitation thereon. 
    
    
     EXAMPLE 1 
     Preparation of 3-(anilinomethyl)-1,4,5,6-tetrahydro-1-methyl-1,2,4-triazine 
     To 110 ml. of methyl alcohol 16.5 grams (0.125 mol.) of N-(cyanomethyl)aniline was added along with 0.68 grams (0.0125 mol.) of sodium methoxide as a catalyst. The reaction mixture was stirred at room temperature overnight. The following day 0.75 ml. of acetic acid was added to the mixture. The reaction mixture was evaporated to dryness and the semicrystalline imidate was recovered. 
     The recovered imidate (17 grams) was added to 100 ml. of anhydrous ethanol and 11.2 grams of 1-(2-aminoethyl)-1-methylhydrazine. This mixture was stirred at room temperature for 2 hours and refluxed overnight. The reaction mixture was cooled and evaporated to yield a gummy solid. Ether (150 ml.) was added and the crystals that formed were filtered off. The crude 3-(anilinomethyl)-1,4,5,6-tetrahydro-1-methyl-1,2,4-triazine was recrystallized from isopropyl alcohol. The melting point of the product was 124°-125° C. 
     Elemental analysis gave carbon 64.42%, hydrogen 7.99%, and nitrogen 27.14%. Theoretical calculated is carbon 64.67%, hydrogen 7.89%, and nitrogen 27.42%. 
     EXAMPLE 2 
     Preparation of 1,4,5,6-tetrahydro-N-(2-(trifluoromethyl)-phenyl)-1,2,4-triazine-3-methanamine 
     A solution containing 16 grams of N-(cyanomethyl)-2-(trifluoromethyl)aniline in 45 ml. of ethyl alcohol was cooled to about 5° C. To this solution 0.4 grams of sodium methoxide was added. The reaction mixture was stirred for 24 hours. Acetic acid (0.45 ml.) was added to the reaction mixture and it was cooled for 2 hours in ice water. 
     2-Aminoethylhydrazine was added to the mixture and it was refluxed for 2 hours. The mixture that resulted was diluted with about 150 ml. of benzene and the sodium acetate that separated was filtered off. The filtrate was concentrated by evaporation and about 100 ml. of hexane was added and the mass chilled. Beige crystals of 1,4,5,6-tetrahydro-N-(2-(trifluoromethyl)-phenyl)-1,2,4-triazine-3-methanamine formed. The product was recrystallized from warm benzene to which hexane was added. The product had a melting point of 97°-98° C. 
     The structure was substantiated by ir, nmr and elemental analyses. 
     Using the general procedure described above other 1,2,4-triazine-3-methanamines corresponding to the formula ##STR3## were prepared. These compounds are listed in Table I. 
     
                                           TABLE I__________________________________________________________________________Compound                RecrystallizationExample No.  R  R.sub.1        R.sub.2           R.sub.3              R.sub.4                 R.sub.5                     Solvent Mp°, C.__________________________________________________________________________ 3     H  H  CF.sub.3           H  F  H C.sub.6 H.sub.6 /hexane                             97-98 4     CH.sub.3     H  CF.sub.3           H  F  H C.sub.6 H.sub.6 /hexane                             112-114 5     H  H  H  CF.sub.3              F  H ethanol/H.sub.2 O                             156-158 6     CH.sub.3     H  H  CF.sub.3               Cl                 H C.sub.6 H.sub.6 /hexane                             149-150 7     CH.sub.3     H  CH.sub.3           H  H  H C.sub.6 H.sub.6 /hexane                             79-80 8     H  H  CH.sub.3           H  H  H C.sub.6 H.sub.6 /hexane                             105-106 9     CH.sub.3     CH.sub.3        H  CF.sub.3              H  H C.sub.6 H.sub.6 /hexane                             126-12710     H  CH.sub.3        H  CF.sub.3              H  H C.sub.6 H.sub.6 /hexane                             123-12411     H  H  H  CF.sub.3               Cl                 H CH.sub.3 CCl.sub.3                             171-17212     CH.sub.3     H  CF.sub.3           H  H  H C.sub.6 H.sub.6 /hexane                              98-10013     CH.sub.3     H  H  H  CH.sub.3                 H isopropanol/C.sub.6 H.sub.6                             126-12714     CH.sub.3     H  H  CH.sub.3              H  H ethanol/C.sub.6 H.sub.6                             87-8815     H  H  H  H  CH.sub.3                 H C.sub.6 H.sub.6                             135-13616     H  H  H  CH.sub.3              H  H C.sub.6 H.sub.6 /hexane                             106-10717     CH.sub.3     H  F  H  F  H C.sub.6 H.sub.6 /hexane                             81-8318     CH.sub.3     H  F  H  F  H isopropanol/ethanol                             113-11419     H  H  F  H  H  H C.sub.6 H.sub.6 /hexane                             104-10620     H  H  F  H  F  H C.sub.6 H.sub.6                             132-13321     H  H  H  H  H  H C.sub.6 H.sub.6 /hexane                             110-11122     CH.sub.3     H  H  CF.sub.3              H  H ethyl ether/hexane                             107-10823     H  H  H  CF.sub.3              H  H ethanol   165-16624     H  H  F  H  H  F C.sub.6 H.sub.6 /hexane                             121-12225     CH.sub.3     H  F  H  H  F C.sub.6 H.sub.6 /hexane                             97-98__________________________________________________________________________ 
    
     The compounds of the present invention were tested for use as pre-emergent and as post-emergent herbicides on various selected plant species. 
     EXAMPLE 26 
     Use of Compounds as a Pre-emergent Herbicide 
     An aqueous composition consisting of a predetermined amount of one of the compounds of the present invention was dispersed in water and employed as a pre-emergent herbicide. The compositions were employed to treat separate pots filled to within one inch of the top with a medium-textured soil wherein each pot contained good, viable seeds of one of a predetermined plant species. Each pot was maintained so as to prevent any interaction with test compounds in different pots. Each pot was treated with one of the compositions as a soil drench in sufficient volume to wet the top 11/2 to 2 inches of soil. The compositions were applied to the pots so that the respective pots of a given plant species were treated with a different test compound. Another pot was treated only with water to serve as a control. After treatment, the pots were maintained for two weeks under greenhouse conditions conducive for good plant germination and growth and watered as necessary. The specific plant species, test compound, dosage, and results are set forth below in Table II. Numbers in the column below the plant species indicate herbicidal activity and shows the concentration of compound used expressed in terms of pounds/acre. 
     
                                           TABLE II__________________________________________________________________________Compound                    Wild Mustard                                  YellowEx. No. Cotton     Wild Oats           Pig Weeds                 Bind Weed                       Charlock                              Beans                                  Fox Tail__________________________________________________________________________ 5    1010    10  1013              2018              20    2020              20          20     2022              20    20    20         2023              20    20    2024                                 10__________________________________________________________________________ 
    
     EXAMPLE 27 
     Use of Compounds as a Post-Emergent Herbicide 
     A series of aqueous compositions each consisting of a predetermined amount of one of the compounds of the present invention dispersed in water were employed as post-emergent herbicides. The respective compositions were employed to treat separate stands of a predetermined plant species grown to a height of 2 to 4 inches in pots containing sandy loam soil. Each pot was maintained so as to prevent any interaction with test compounds in different pots. Each pot was treated with one of the compositions as a spray applied to the plants to run off. The compositions were applied to the pots so that respective pots of a given plant species were treated with one of each of the test compounds. Another pot was treated only with water to serve as a control. After treatment the pots were maintained for two weeks under greenhouse conditions conducive for good plant growth and watered as necessary. The specific plant species, test compounds, dosage, and results are set forth below in Table III. Numbers in the columns under the plant species indicate herbicidal activity and show the concentration of compound used in parts per million. 
     
                                           TABLE III__________________________________________________________________________Compound Yellow                      Wild MustardEx. No. Fox Tail      Crabgrass           Velvet Leaf                 Pig Weeds                       Bind Weed                             Charlock                                    Beans__________________________________________________________________________ 4    4000 5    4000 4000 9    4000 4000 400013    4000            400014    4000            400015    400018                          4000  400019    4000            400022    4000 4000       4000        4000   4000__________________________________________________________________________ 
    
     Various compounds of the present invention have also shown insecticidal activity. Table IV lists compounds having such activity and gives the concentrations at which they were found to be effective in parts per million in an aqueous solution. 
     
                                           TABLE IV__________________________________________________________________________                                          Southern             Southern          Yellow Fever                                          HouseCompound Cabbage      Beet Army             Army              Mosquito                                      House                                          MosquitoEx. No. Looper      Worm Larvae             Worm Boll Weevil                         Boll Worm                               Adult  Fly Larvae__________________________________________________________________________ 1    400 6         40010    40023                500  500    400   10.024                                         50025                                         500 1.00__________________________________________________________________________ 
    
     Member compounds have also shown antimicrobial activity at concentrations of about 500 parts per million when used against various species such as for example, Bacillus subtilis, Staphylococcus aureus, Salmonella typhosa, Mycobacterium phlei, Trichoderm sp Madison P-42, Escherichia coli, Trichophton mentogrophytes, Pullularia pullulans, and Candida pelliculosa. The following compounds were found to be effective against one or more of the above species. 
     N-(4-fluoro-3-(trifluoromethyl)-phenyl)-1,4,5,6-tetrahydro-1-methyl-1,2,4-triazine-3-methanamine (Example 4). 
     N-(4-fluoro-3-(trifluoromethyl)phenyl)-1,4,5,6-tetrahydro-1,2,4-triazine-3-methanamine (Example 5). 
     N-(4-chloro-3-(trifluoromethyl)phenyl)-1,4,5,6-tetrahydro-1-methyl-1,2,4-triazine-3-methanamine (Example 6). 
     1,4,5,6-tetrahydro-N-(2-methylphenyl)-1,2,4-triazine-3-methanamine (Example 8). 
     1,4,5,6-tetrahydro-α-methyl-N-(trifluoromethylphenyl)-1,2,4-triazine-3-methanamine (Example 10). 
     N-(4-chloro-3-(trifluoromethyl)phenyl)-1,4,5,6-tetrahydro-1,2,4-triazine-3-methanamine (Example 11). 
     1,4,5,6-tetrahydro-1-methyl-N-2-(trifluoromethylphenyl)-1,2,4-triazine-3-methanamine (Example 12). 
     1,4,5,6-tetrahydro-N-(4-methylphenyl)-1,2,4-triazine-3-methanamine (Example 15). 
     1,4,5,6-tetrahydro-N-(3-methylphenyl)-1,2,4-triazine-3-methanamine (Example 16). 
     N-(2-fluorophenyl)-1,4,5,6-tetrahydro-1,2,4-triazine-3-methanamine (Example 19). 
     N-(2,4-difluorophenyl)-1,4,5,6-tetrahydro-1,2,4-triazine-3-methanamine (Example 20). 
     N-(2,5-difluorophenyl)-1,4,5,6-tetrahydro-1,2,4-triazine-3-methanamine (Example 24). 
     Some of the compounds also display various pharmacological activity. For instance the compounds of Example 2 and Example 7 have been shown to enhance learning and memory in mice by increasing the ability of mice fed on diets containing 0.125% of these compounds to avoid electric shocks. 
     The compound of Example 3 has been shown to prevent the formation of clots in rabbit serum that has been sensitized to the split products of mouse fibrin. The compounds therefore have demonstrated thromolysis activity and are useful in the treatment of various conditions that cause clots to form within the vascular system of a mammal. 
     Central Nervous System stimulant and antidepressant activity has been recognized in several member compounds as for example, compounds Examples 16 and 21. Mice injected with about 60 mg/kg body weight of these compounds have been shown to be protected against reserpine induced ptosis. In addition, compounds Examples 17 and 21 have been shown to be effective in the treatment of hypertension in rats when administered orally at a dosage of 30 mg/kg of body weight.