CA1128507A

CA1128507A - Pharmacologically active substituted 1,2,4-triazines

Info

Publication number: CA1128507A
Application number: CA303,466A
Authority: CA
Inventors: James M. Gullo; Robert E. Moser; William P. Heilman; Robert J. Wayner
Original assignee: Diamond Shamrock Corp
Current assignee: Diamond Shamrock Corp
Priority date: 1977-05-17
Filing date: 1978-05-16
Publication date: 1982-07-27
Also published as: IL54728A; FR2391202B1; IT1105463B; GB1604084A; CH633541A5; IL54728A0; DE2821381A1; GB1604083A; GB1604085A; FR2391202A1; IT7849404A0; JPS5416491A

Abstract

ABSTRACT OF THE DISCLOSURE

Substituted 1,2,4-triazines, compositions thereof and methods of using same are described. The compounds of the invention exhibit a wide range of pharma-cological activity including anti-inflammatory, analgesic, anti-pyretic, hypotensive and central nervous system effects.

Description

5~7 PHARMACOLOG!CALLY ACTIVE SUBSTITUTED 1,2,4-TRIAZ11~1ES

BACKGROUND OF THE INVENTION

The present invention relates ~enerally to 1, 2, 4-triazine compounds and, more particularly, to certain substituted triazines evidencing anti-inflammatory, anal~esic, anti-pyretic, hypotensive and central nervous system activity in warm blooded animals.
Substituted 1, 2, 4-triazine compounds having various substituents thereon have heretofore been prepared and suggested for use in different ultimate applications. For example, Buu-hoi et al found that 3-rnercapto-5,6-dimethyl-1, 2, 4-tria~ine is tuberculostatic in vitro (J. Chem. Soc., 1956, 713-16). Likewise, 3-__ .
10 amino-6-alkyl (or 5-nitrofurylethenyl)-1, 2, ~triazines have been suggested as having antibacterial and antiviral activity (Cf. Chemical Abstracts, Vol. 60, 9278g and Vol.
62, 9155d). ~apanese Patent No. 69-08866 (April 24, 1969) also describes the bactericidal activity of 3-amino-5-alkoxy-6-methyl-1,2,4-triazines.
With respect to the anti-inflammatory activity oi as~triazine compounds, U.S. Patent No. 3,948,894 discloses 3-amino-5,6-diaryl-1,2,~triazine compounds and more specifically, 3-alkylamino, hydroxy-alkylamino, piperazino, piperidino, rnor-pholino or pyrrolidino-5,6disubstitu~ed phenyl, i.e., alkoxy, fluoro, dimethylamino or methylsulfinylphenyl triazine compounds and the treatment of inflammation, swell-ing, fever and ossification in warm-blooded animals therewith. The foregoing 20 compounds are indicated to be active upon oral or parenteral administration, whereas Belgian Patent No. 839,469 discloses 3-unsubstituted and ~C l-C8 alkyl, C7-C8 aralkyl, C3-Cs cycloalkyl, C4-C8 (cycloalkyl~alkyl or the corresponding oxy~en or thioethers, and halo-, Cl-C3 alkyl-, Cl-C3 alkoxy- or di(Cl-C3 alkyl) amine-5,~
substituted phenyl-1,2,4-triazines as anti-inflammatory agents which are ~opically ~.

~L~2l35~'~7 active. U.S. Patent No. 3,9~9,831 also discloses 3-chloro-5,6-diaryl-1,2,4-triazines as topically active anti-inflammatory compounds. U.S. Patent No. 3J644~358 describes a series of 3-and 6-alkoxycarbonyl or carboxamido substitutèd 1,2,4-triazines having anti-inflammatory activity.
In Japanese Patent No. 74-27874 (July, 1974), the patentees describe 3-amino, methylamino or 4-methyl-1-plperazinyl-5-(4'-pyridyl)-1,2,~triazines as having anti-inflammatory activity.
Other asymmetrical triazines have been suggested as having antihyperten-sive activity. For example, U.S. Patent No. 3,007,927 discloses 3,5-dihydrazino or 3, 5-dihydrazino-6-loweralkyl-1, 2,4-triazines as exhibiting a strong vasodilatory ef~ect. Similarly, 3-hydra~ino-5-pherlyl-1,

2,4-triazine is indicated to be a moderately active antihyper-tensive agent. See Burger, Medicinal Chemi stry, 3rd Ed o ~ 1027 Wi ley Interscience, 19 70) .
With respect to central nervous system activity, Trepanier et al, J. Med.
Chem. 9, 881-885 (1966) disclose certain substituted 1,4,5,6-tetrahydro-1,2,4,- 1 triazines as having anticonvulsant activity.
In addition to the foregoing, it is noted that 3-methylthio-5-phenyl-, 3-methylthio-5,6-dimethyl-,3-methoxy-5,~dimethyl-, 3-hydrazino-5,6-dimethyl-, and 3 methoxy-5-phenyl-1,2,4,-triazines are described in Paudler and Chen, J. Hetero.
Chem. 7, 767-771 (1970). Laakso describes the 3-ethoxy-S-phenyl-1,2,4-triazine (Tetrahedron, 1, 103 (1957)). 3-Hydroxy-5,6-diphenyl-1,2,4-triazine is described in Thiele, Ann. C:hem., 302, 299, i890. No biological or other utility for these com-pounds is mentioned in the foregoing literature publications.
SUMMARY OF THE INVENTION

It is, therefore, a primary object of ~he present invention to afford novel substi~uted 1,2,4,-triazine compounds which evidence unexpectedly superior pharma-cological activity or differen~ properties compared to previously proposed triazine compounds in warm-blooded anirnals.
A further object of the present invention is to provide ~nethods for in-ducing or obtaining antiphlogistic, analgesic, hypotensive and psychotropic effects in 7 i ~

mammals by the administration of preselec~ed dosages of active substituted 1,2,4-triazine compounds or pharmaceutically acceptable sal~s ~hereof in suitable non-toxic pharmaceutical dosa~e unit forms or c~mpositions.
A still further object of the present inven~ion is to provide stable, non-toxic dosage unit forms adapted for, e.g., oral, rectal, parenteral, etc. administration useful in the promotion of analgesia or central nervous system effects and the treat-ment7 management or mitigation of fever, ir~lammatory or hypertensive conditionsor disorders.
In one aspect of this invention there i8 provided a process for preparing a compound having the yeneral formula:
.' ~ .
~3~ ON
'~ R2--~N Rl wherein Rl i8 Cl-C4 hydroxy alkylamino, N-(Cl-C2 ~lkyl)-N-(hydroxy Cl-C4 alkyl)am~no, Cl-C~ alkyl, Cl-C10 alkoxy, C6-C10 aryloxy, C3-C6 cycloalkoxy, phenyl alkoxy, allyloxy, halophenoxy, Cl-C4 alkyl phenoxy, Cl-C4 alkoxy phenoxy, Cl-C10 alkylthio, C3-C6 cycloalkylthio, Cl-C4 alkyl sulfinyl, Cl-C4 alkyl sulfonyl, phenyl Cl-C4 alkylthio, di~e~hylpyrrolidyl, or hydrazino, Cl-C4 - al~yl hydrazino, O
NH-NH-I~-R
where R4 i8 Cl-CB alkyl, C~-C8 alkenyl, halo ~Cl-C~)alkyl, halo (C~-C8)alkenyl, C6-C10 cycloalkyl or R4 represents the group . -CH-NH -R7 where R~ iz ~, Cl-C4 alkyl cr benzyl and R7 is ~ or aarbobenzyloxy _ 4 -.~ ~, '.

R2 represents hydrogen, Cl-C4 alkyl, C3-C6 cycloalkyl, adamantyl, furyl, thienyl, benzofuryl, indolyl, pyridyl, halothienyl, phenyl or phenyl substituted with at least one substituent selected from h.alo, Cl-C~ alkyl, halo Cl-C6 alkyl, Cl-C5 alkoxy, acetamido, benzyloxy, diphenylmethyl, morpholino, methylene dioxy or nitro;
and R3 represents hydrogen, Cl-C6 alkyl, pyridyl, furyl, phenyl or phenyl substituted with at least one substituent selected ~ from halo, Cl-C6 alkyl, C~-C6 alkoxy, me~hylene dioxy or acetamido;
subject to the provisos that when R2 is hydrogen, R3 is also hydrogen; when Rl is alkyl, phenyl alkylthio, alkoxy, alkylthio, cycloalkylthio, cycloalkoxy, phenyl alkoxy, dimethylpyrrolidyl or hydroxy alkyl amino or said N-(alkyl)-N-(hydroxyalkyl)amino as defined be~ore, R2 and R3 can not both be halophenyl, Cl-C3 alkyl phenyl or Cl-C3 alkoxyphenyl; when Rl is hydrazino, methylthio, methoxy or ethoxy, R2 is other than phenyl and R2 and R3 cannot both be methyl; when Rl is hydrazino or Cl-C~
alkylhydrazino, R2 is other than Cl-C4 alkyl; and the ' pharmaceutically acceptable salts thereof;
wherein said process comprises: reacting a compound having the general formula R N ~

wherein R2 and R3 are as def.ined above, R6 is an alkylthio, substituted alkylthio, cycloalkylthio or halogen, with a compound having ~he general formula:

3~ B-Rl wherein Rl is as defined above and B is a base, and when the pharmaceutically acceptable salts are desired, further forming the salts.

4a-~.1% !3~7 In another aspact of this invention there is provided a process for preparing a co~pound having the general formuLa~

R3~o R2 N .R

whereln Rl is Cl-C10 alkylthio, C3-C6 cycloalkylthio or phenyl Cl-C4 alkylthio;
R2 represents hydrogen, Cl-C4 alkyl, C3 C6 cycloalkyl, adamantyl/
furyl, thienyl, benzofuryl, indolyl, pyridyl, halothienyl, phenyl or phenyl substituted with at least one substituent selected from halo, Cl-C6 alkyl, halo Cl-C6 alkyl, Cl-C6 alkoxy, acetamido, benzyloxy, diphenylmethyl, morpholino, me~hylene dioxy or nitro:
and R3 represents hydrogen, Cl-C6 alkyl, pyridyl, furyl, phenyl or phenyl substituted with at least one substituent selected from halo, Cl C6 alkyl, Cl-C6 alkoxy, methylene dioxy or acetamido;
with the provisos that when Rl is Cl-C10 alkylthio or C3-& :~
cycloalkylthio, R2 and R3 cannot both be halophenyl, Cl-C3 alkylphenyl or Cl-C3 alkoxyphenyl; and when Rl is methylthio, R2 is other than phenyl and R2 and R3 cannot both be methyl; and the pharmaceutically acceptable salts thereof;
wherein said process comprises reacting a ~ompound havlng the general formula: R2\ ~ O

R3 ~
wherein R2 and R3 are as defined above, with a semicarbazide hydrogen halide having the general formula SR
NH2N~C= NH.HX
wherein Rl is as defined above and X denotes a halogen atom, and when the pharmaceutically acceptable salts are ~esixed, further forming the salts~

- 4b -~2t 35~7 L

Thes~ and other similar object~, advantages, aspects and features are a~complished according to the methods, products and compositions of the invention compxised of substituted-1,2,4- triazines, comp~sitions derived therefrom a~d methods employing same.

DESCRIPTION OF THE PREFERRED EMaODIMENTS
. .

: It has now been found, in accordance with the present invention, that substituted 1,2,4-triazines of the ~eneral formula (I) z~N~ Rl :
wherein O
j Rl represents hydrazino, Cl-C4 alkylhydrazino, -NH-NH-C -R4 where R4 is C~l-C8 alkyl, C2-C8 alkenyl, halo (Cl-C8) alkyl, halo (C2-C8) alkenyl, C6-C10 cyclo-alkyl or a group of the formula where R5 is H, Cl-C4 alkyl or ben~yl and the corresponding N-amino carbobenzyloxy derivati~es thereof (i.e., O O
-NH-NH-C-CH-NH-C-OCH2-~), or hydroxy .~ R5 hydroxy Cl-C4 alkylamino, N-(Cl-C2 alkyl)-N-(hydroxy Cl-C4 alkyl) amino, Cl-ClO alkoxy, C6-C10 aryloxy, C3-C6 cycloalkoxy, phenylalkoxy, alkyl (Ci--- 4c --.

.
. . ~ ~ .",.. ~, ~28S~7 C4)aryloxy(aryl as before), allyloxy, halophenoxy, Cl-C4 alkyl-phenoxy, Cl-C4 alkoxyphenoxy, Cl-C10 alkylthio, Cl-C10 cycloalkyl-thio, Cl-C4 alkylsulfinyl, Cl-C4 alkylsulfonyl, phenylalkyl (e.g., Cl-C4 alkyl)thio, cis-dimethylpyrrolidyl or pyridyl;

R2 represents hydrogen, Cl-C4 alkyl, aryl (e.g., phenyl, naphthyl, anthracenyl), C3-C6 cycloalkyl, adamantyl, furyl, thieny~, benzofuryl, indolyl, pyridyl, halo-thienyl or phenyl substituted with at least one substituent selected from halo, Cl-C6 alkyl, halo (Cl-C6) alkyl, Cl-C6 alkoxy, acetamido, benzyloxy diphenyl-methyl, morpholino, methylenedioxy and nitro; ~ !
R3 represents hydrogen, Cl-C6 alkyl, aryl, pyridyl, furyl or phenyl substituted with at least one substituent selected from halo, Cl-C6 alkyl, Cl-C6 alkoxy, methyl-enedioxy and acetamido, with the proviso that when R2 is hydrogen R3 is also hydrogen; and the pharmaceutically acceptable acid addition salts thereof are useful anti-inflammatory, analgesic, anti-pyretic, hypotensive and psychotropic agents.
The substituted asymmetric triazine compounds of the present invention may be prepared by several alternative me~hods previously employed in the synthesis of 1,2,4-triazines or modifications thereof to obtain the Rl, R2 or F~3 substituents thereon as defined above. For example, 3-alkylthio, hydrazino or alkoxy-5-aryl-1,2,4,-triazines can be readily prepared according to the procedures set forth in W. W.
Paudler and T.K. Chen, J. Hetero. Chem. 7~ 767 (1970), wherein an appropriately substituted acetophenone is oxidized to the corresponding arylglyoxal by treatment with selenium dioxide. Condensation of S-methylthiosemicarbazide hydrogen iodide, obtained by the reation of thiosemicarbazide and methyl iodide, with an arylglyoxal affords the 3-methylthio-5-aryl-1,2,4,-triazine. The 3-methylthio5-aryl substituted triazine may then be used as an intermeàiate for the preparation of the ~hydrazino derivative by treatment with hydrazine hydrate or the 3-methoxy derivative by reaction with sodium methoxide. The foregoing general reaction scheme may be depicted as follows:
. .

~z~s~

R SeO R 11 l CH3 Aryl - C - CH3 2> Aryl - C - C}l + NH2NHC = NH Hl ~N ~ (NaHC03 ) Aryl NHNH2 NH2N 2 ~ V

/~O,~N

OCH3 ~

Compounds wherein R2 and R3 are as defined above may be synthesized - according to the methods described by Polonovski et al, Compt. Rend., 238, 695 (1954). An appropriately substituted alpha-diketone is condensed with semi-carbazide, followed by cyclization under basic conditions to form the 3-hydroxy-5,6-disubstituted-1,2,4-triazine. The last mentioned 3-hydroxy derivative is then chlorinated with phosphorus oxychloride to yield the 3-chloro-1,2,4-triazine which readily undergoes displacement by hydrazine or sodium methoxide ~o af~ord the ~
hydrazino-or ~methoxy-5,6-disubstituted-I,2,4-triazine compounds, as shown in the 2 0 following reaction scheme.

~C~ 1) ~ R~NO\N POC 13 ~ R¦O\N
R/ ~O 2) KOH R--N OH R N C 1 SCH
~ NH2 NHC=NH Q HI NaOCH3 / ¦ NH2NH2 ( NaHC03) l / I
'~ ~

~N~ R N"LoCH3 Rf~N NH2NH~

~7 It is noted that the alpha-diketone starting material may be directly converted to the 3-methylthio-5,6-disubstituted-1,2S4-triazine by cyclization with S-methylthiosemi-carbazide hydrogen iodide.
Reaction of the appropriate hydrazino triazine with the appropriate s anhydride, acyl chloride or carbobenzyloxy (CBZ) amino acid affords the correspond-ing acyl hydrazine triazines or ~-CBZ- amino acyl hydrazino triazines. Treatment of the CBZ: amino acyl hydrazino triazines with concentrated HBr/acetic acid affords the free amino acid HBr sal~.
Other substituents at the 3- position corresponding to Rl as set forth hereinabove are readily obtained by formation of the corresponding 3-chloro-5,~-disubs~ituted-1,2,4-triazine. Facile substitution of the 3-chloro starting material is carried out with a variety of amines, alcohols, phenols, thiols, and the like to yield the corresponding ~amino, alkoxy, phenoxy, alkylthio, etc. derivatives. Of course, similar substitution or displacement reactions may be carried out using the 3-methylthio reactant or intermediate.
Where necessary or desirable, the pharmaceutically or physiologically acceptable inorganic and organic acid addition salts of certain of the compounds of the present invention may be employed to, for instance, alter solubility properties or augment bioavailability. The criteria for selecting and methods for preparing salts suitable for administration are well known to those skilled in the art. Representative of acids for reaction with the sufficiently basic triazine compounds of the invention to form acceptable acid addition salts include hydrochloric, hydrobromic, hydroiodic, nitric, phosphoric, suîfuric, tartaric, citric, and the like. The expression '`pharma-ceutically acceptable'l as used herein is intended to include those salts capable of being formed with the basic triazine compounds of ~he invention without materially altering the chemical structure or pharmacological properties of the parent triazine compounds. Additionally, compounds of the . invention containing amino acid residues, i.e., an c~ -arnino acyl group, may be obtained as their hydrate salt orm, such as mono- or di- hydrobromide, hydrochloride, etc. hydrate and such compounds constitute particularly advantageous water-soluble derivatives of ~he invention.

- ~2~ 7 The synthesis methods described herein, in cer-tain instances, result in the preparation of mixtures of triazine isomers, e.g.~ 5,6-position isomers which can be separated employing conventional crystallization or chromatographic techniques.
As previously indicated, the compounds of the present invention possess anti-inflammatory, anti-pyretic, analgesic, antihypertensive and central nervoussystem te.g., hypnotic, sedative, antidepressant, muscle relaxant, spasmolytic, tran-quilizing, etc.) effects. Of course, it will be appreciated that the spedfic response elicited upon administration of the compounds of the present invention to an animal species will vary depending upon the specific structure of the administered compound, the unit dose, dosage regimen and mode of administration, as well as the mammalian species involved. Accordingly, as detailed hereinbelow, certain of the compounds of the invention are preferred over others relative to a predetermined pharmacological activity.
Thus, as preferred compounds for use in the anti-inflammatory compositl-ons and methods of the present invention, are those of Formula I wherein R
represents hydrazino, Cl-C4 alkyl hydrazino, -NH-NH-C-R4 (R4 as before) hydroxy Cl-C4 alkyl amino, ~1-(Cl-C2 alkyl)-N-(hydroxy Cl-C4 alkyl)amino, Cl-C10alkoxy, phenoxy, Cl-C4 alkylphenoxy, Cl-C4 alkoxyphenoxy, Cl-C10 alkylthio (preferably, Cl-C4 alkyl), or phenylalkyl (preferably, Cl-C4 alkyl) thio; R2 represents hydrogen, Cl-C4 alkyl, C3-C6 cycloalkyl, phenyl, naphthyl, adamantyl, furyl, thienyl, benzof uryl, indolyl~ pyridyl or phenyl substituted with at least one substituent selected from halo, Cl-C4 alkyl, halo or perhalo (Cl-C6) alkyl (e.g., trifluoromethyl, trifluoroethyl, e~c.), Cl-C6 alkoxy (including, e.g., 3', 4' -diaJkoxy), acetamido, morpholino or nitro; R3 represents hydrogen, Cl-C6 alkyl, phenyl, pyridyl or phenyl substi~uted with at leas~ one substituen~ selected from Cl-C4 alkyl, Cl-C6 alkoxy, halo or acetamido; provided that when R2 is hydro~en then R3 is also hydrogen orwhen Rl is hydroxyalkylamino or the group X-R6 wherein X=O, or S, and R6 is Cl-C8 alkyl, C7-C8 ara~kyl, C3-C8 cycloalkyl, C4-C8 cycloalkyl alkyl, R2 ancl R3 cannot simultaneously be halo-, alkyi-, or alkoxy-sulbsti tuted phenyl; and the pharma-~2~35~

ceutically acceptable acid addition salts thereo~. Particularly preferred compounds o~ Formula I are those wherein Rl is hydrazino, methylhydrazino, propionyl hydra^
zino, ~-aminoacetyl hydrazino, trifluoroacetyl hydrazino, hydroxy ~C2-C4) alkyl-amino, Cl-C4 alkoxy, allyloxy, Cl-C4 alkylthio or benzylthio; R2 is Cl-C4 alkyl,phenyl, furyl, thienyl, pyridyl, indolyl, adamantyl, C3-C6 cycloalkyl or phenyl sub-stituted with at least one substituent selected from halo (preferably, para-chloro, bromo or fluoro), halo Cl-C2 ~Ikyl (preferably, meta-trifluoromethyl), Cl-C4 alkyl, C1-C~ alkoxy (preferably 3', 4' -dimethoxy) and R3 is hydrogen; or wherein R2 and R3 are the same and represent Cl-C4 alkyl (preferably, methyl or ethyl~, phenyl or pyridyl provided E~l is selected from hydrazino, Cl-C4 alkoxy (preferably, methoxy), allyloxy, C l-C4 alkylthio or benzylthio. As specifically preferred compounds ofFormula 1, there may be mentioned 3-methylthio-5-phenyl-1,2,4-triazine, 3-hydra-zino-5-phenyl (or t-butyl)-1,2,4-triazine, 3-methylhydrazino-5-phenyl-1,2,4-triazine, 3-methoxy (or methylthio)-t-butyl-1,2,4-triazine, 3-methylthio-5-(2l-furyl or 2'-thi-enyl)-1,2,4-triazine, 3-trifluoroacetyl hydrazino-5-phenyl-1,2,~triazine, 3-methoxy-~(3'-trifluoromethyl phenyl)-1,2,4-triazine, 3-rnethylthio-5-(3'-trifluoromethylphenyl)- 1 ,2,4-triazine, 3-methoxy-5-(2'-f uryl)- 1 ,2,~triazine, 3-ethoxy-5-phenyl- 1,2,4-triazine, 3-propoxy-5-phenyl-1,2,4-triazine, 3-methylthio-5-cyclopropyl-1,2,4-tri-azine, 3-methoxy-5-cyclopropyl-1,2,4-triazine, 3-allyloxy-5-phenyl-1,2,~triazine, 3-2 0 methylthio-5,6-dimethyl- 1,2,4-triazine, 3-hydrazino-5,6-dimethyl- 1,2,4-triazine, 3-methoxy-5,6-dipyridyl- 1 ,2,4-triazine, 3-benzylthio-5,6-dimethly- 1 92,4-triazine and 3-methylthio-5-(3'-indolyl)-1,2,4-triazine.
Represen~ative of preferred compounds of Formula I for use in the analgesic compositions and methods of the present invention are those wherein ~1represents hydrazino, Cl-C4 alkyl hydrazillo, prop;onyl hydrazino, -arnino prop-ionylhydrazino, ~amino-phenylpropionyl (phenylalanine) hydrazino, haloacyl hydra-zino (preferably, tri~luoroacetyl hydrazino), Cl-C4 alkoxy or Cl-C4 alkythio, and R2 represents Cl-C4 alkyl ( preferably, ethyl, t-butyl), thienyl, phenyl or phenyl - substituted with at least one substituent selected from halo (preferably, meta-chloro), halo or perhalo (Cl-C4) alkyl (preferably, meta - halomethyl), or Cl-C4 alkoxy ~L~LZ8S~!7 (preferably, para-me~hoxy) when R3 is hydrogen; or compounds wherein Rl is as defined before and R2 and R3 are the same and represent Cl-C4 alkyl or Cl-C4 alkoxyphenyl (preferably, para-methoxyphenyl). Based upon presently definable dose-response relationships, especially preferred compounds falling within the aforesaid general Formula I are 3-hydrazino-5-phenyl (or meta-trifluoromethyl phenyl)-1,2,4-triazine, 3-methoxy-5-phenyl-1,2,4-triazine, 3-methoxy-S-t-butyl-ly2,4-triazine, 3-methylthio-5-(2'-thienyl)-1,2,4-triazine, 3-methyJhydrazino-5-phenyl-1,2,4-triazine, 3-trifluoroacetyl hydrazino-5-phenyl-1,2,4-triazine, 3-methoxy (or methylthio)-5-(3'-trifluoromethyl phenyl)-1,2,~triazine, 3-methoxy-5-(3'-chlorophenyl-1,2,4^triazine, 3-methylthio-5,6-dimethyl-1,2,4-triazine, 3-hydrazino-5,6-dimethyl-192,4-triazine and 3-methoxy (or methylthio)-5,6-(4'-methoxyphenyl)-1,2,4-triazine.
Inclusive of preferred compounds for use in the hypotensive compositions and methods of the present invention are compounds of Formula 1, wherein Rl rep-resents hydrazino, C 1-C4 alkyl hydrazino, ,~ 1 5 O

- where R4 is Cl-C8 alkyl, C~-C8 alkenyl, halo (cl-c8j alkyl, halo (C2-C8) alkenyl, C6-C10 cycloalkyl or a group of the formula . -CH-NH2 . 20 R5 where R5 is H, Cl-C4 alkyl or benzyl and the corresponding N-amino carbobenzyloxy derivatives thereof; hydroxy (C2-C4) alkylamino, Cl-C4 alkoxy or Cl-C4 alkylthio;
R2 represents furyl, benzofuryl, phenyl or phenyl substituted with at least one sub-stituent selected from halo (preferably, meta or para-chloro), halo (Cl-C2) alkyl, Cl-2 5 C4 alkoxy (preferably, para-methoxy), methylenedioxy or morpholino when R3 represents hydrogen; or compounds whçrein Rl represents hydrazino, Cl-C4 alkyl hydrazino, acetyl hydrazino or Cl-C4 alkoxy and R2 and R3 are the same and sel-- ected from phenylJ substituted phenyl or furyl. As specifically preferred compounds of the foregoing descriptionJ there may be mentioned 3-rnethylhydrazino-5-phenyl-(or ;~ 30 5,6-diphenyl~1,2,4-~riazine, 3-me~hyl hydrazino-5,6-bis (4'-chlorophenyl)-1,2,4-triazine, 3-trifluoroacetylhydrazino-5-phenyl-1,2,4-triazine, 3-acetylhydrazino-5,6-35~!7 . .
diphenyl-1,2,4-triazine, 3-hydrazino-5-(3'-trifJuoromethyl phenyl)-1,2,4-triazine and 3-methoxy-5-(41-methoxyphenyl)-1~2,4-triazine.
Additionally, certain of the compounds in accordance with the present invention evidence psychotropic effects, i.e., preferential central nervous system activity including, for example, anti-depressant, muscle relaxant, hypnotic and seda-tive pharmacological properties. Compounds of General Formula I preferred in - connection with the compositions and methods of the present invention relative to such central nervous system activity are those wherein Rl represents hydrazino, N-(Cl-C2 alkyl)-N-(hydroxy Cl-C4 alkyl)amino, Cl-C4 alkoxy, allyloxy, hydroxy or Cl-C4 alkylthio and R2 represents Cl-C4 all<yl, phenyl or halo (Cl-C4) alkyl phenyl(preferably, trifluoromethyl) when R3 is hydrogen; or wherein Rl is hydroxy, methoxy, allyloxy, hydrazino or methylthio and R2 and R3 are the same and selected .i- from Cl-C4 alkyl, phenyl, furyl or pyridyl. Representative of such specifically pre-,' ferred compounds are 3-hydrazino-5-phenyl-1,2,~triazine, 3-methylthio-~t-butyl-,~
1,2,4-triazine and 3-methoxy-5,6-diphenyl- 1,2,4-triazine.
While certain of the substituted-1,2,4-triazine compounds set forth here-inabove in Formula I utilized in accordance with the practices of the present in-vention have heretofore been described without mention of any utility or in con-nection with utilities different from those described herein, the following compounds of the aforesaid General Formula I are considered novel pharmacologically activecompounds wherein correspondingly Rl is hydrazino, Cl-C4 alkylhydrazino, :~ o where R4 is Cl-C8 alkyl, Cj~-C8 alkenyl, halo (Cl-C8~ alkyl, halo ~C~-C8) alkenyl, - C6-C10 cycloalkyl or a group of the formula where R5 is H, Cl-C4 alkyl or benzyl and the corresponding N-amino carbobenzyloxy derivatives thereof, Cl-C4 hydroxyalkylamino, N-(Cl-C2 alkyl)-N-(hydroxy Cl-C4 alkyl amino, Cl-C4 alkyl, Cl-C10 alkoxy, C6-C10 aryloxy, C3-C6 cycloalkoxy, phenyl . 30 alkoxy, allyloxy, halophenoxy, Cl-C4 alkyl phenoxy, Cl-C4 alkoxy phenoxy, Cl-C10 ~85~7 alkylthio, Cl-C4 alkyl sulfinyl, Cl-C4 alkyl sulfonyl, phenyl Cl-C~ alkylthio, di-methylpyrrolidyl or pyridyl; R2 represents hydrogen, Cl-C4 alkyl, C3-C6 cycloalkyl, adamantyl, furyl, thienyl, benzofuryl, indolyl, pyridyl, halothienyl or phenyl sub-stituted with at least one substituent selected from halo, Cl-C6 alkyl, halo Cl-C6 alkyl, Cl-C6 alkoxy, acetamido, benzyloxy, diphenyl methyl, morpholino, methylene dioxy or nitro; and R3 represents hydrogen, Cl-C6 alkyl, pyridyl, furyl, phenyl or phenyl substituted with at least one substituent selected from halo, Cl-C6 alkyl, Cl-C6 alkoxy, methylene dioxy or acetamido; subject to the provisos that when R2 ishydrogen, R3 is also hydrogen; when Rl is alkoxy, alkylthio, cycloalkylthio, cycloalkoxy, phenyl alkoxy or hydroxy alkyl amino as defined before, R2 and R3 cannot both be halophenyl, Cl-C3 alkyl phenyl or Cl-C3 alkoxyphenyl; when Rl is hydroxy, hydrazino, methylthio, methoxy or ethoxy, R2 is other than phenyl and R2 and R3 cannot both be methyl; or when Rl is hydroxy or pyridyl, R2 and R3 cannotboth be phenyl; and the pharmaceutically acceptable salts thereof.
In accordance with the practices of the present invention, the active compounds of the invention may be administered alone or in combination with eachother or administered in admixture with pharmaceutical diluents, carriers, excipients or adjuvants suitably selected with respect to the intended route of administration and conventional pharmaceutical practices. For exarnple, for oral administration in the form of tablets or capsules, the active compound or compounds of the invention may be combined with such excipients as starch, lactose, sucrose, cellulose, talc, magnesium stearate, acacia, stearic acid and the like. Likewise, appropriate elixirs or suspensions may be formulated with preselected active compounds of the present invention in combination with suitable non-toxic solvents, flavorings, coloring agents, suspending agents and emulsifiers. Similarly, injectable dosage unit forrns may be utilized to accomplish intravenous, intramuscular or subcutaneous adrnirustration and, for such parenteral administration, suitable sterile aqueous or nonaqueous solutions or suspensions, optionally containing app~opria~e solut~s to effectuate isotonidty, will be employed. Other adjuvants and dosage forms will be apparent to those skilled in the art.

3~285~7 Compounds of the invention or compositions thereof may be administered to warm-blooded animals, i.e., mammals, including, for instance, mice, rats, guinea pigs, dogs and other domesticated animals, or humans. Dosages sufficient to elicit the above-indicated responses, i.e., analgesia, anti-inflammatory, etc., will generally ran~e between aoout 1 to 300 m~/kglday in laboratory mice based upon body weight, and preferably, between about 25 to 200 mg/kg/day. The foregoing dosages will normally be administered in three or four divided doses depending upon the desired dosage regimen. Of course, the actual effective dosage to be administered will vary depending upon the specif ic compound involved as well as the age, weigh~ and responsiveness of the particular animal species under consideration.
The compounds of the invention exhibit relatively low toxicities and the LD50 (lethal dose to 50 percent of mice treated intraperitoneally) will generally be greater than 300 mg/kg.
The following non-limiting examples are afforded in order that those lS skilled in the art may more readily understand the present invention and spedfic preferred embodiments thereof with respect to the preparation of starting materials, intermediates and compounds in accordance with the foregoing description.

EXAMPLE I

Preparation of 3-Methylthio-5-phenyl-1,2,4-Triazine Into a 1000 ml. flask equipped with a magnetic stirrer, heating mantle and condenser were placed S-methylthiosemicarbazide hydrogen iodide (170.1 g, 0.73 m.)t 430 ml. ethanol, phenylglyoxal (95.6 ~., 0.72 m.) and pyridine (S9.2 g, 0.75 m.~. The contents were heated at refllLx for two hours and the ethanol was recovered under vacuum. The resulting material was extracted with hexane to yield 3-methylthio-5-phenyl-1,2,4-triazine (109.7 g. - 74.9%), m.p. 99-100 C.
Analysis-calculated for C10 Hg N3 S (percen~): C, 59.09; H, 4.46, N, 20.67.
Found ~percenth C, 59.5~; H, 4.65; N, 20.91.
To minimize formation of the ~phenyl isomer and further optimize yield of the desired cyclic material phenylE~lyoxal hydrate can b~ utilized in lieu of phenyl-~2~S~7 glyoxal in the foregoing synthesis.

Preparation of 3-methoxy-5-Phenyl-1,2,4-Triazine Into a 2000 ml. flask equipped with a magnetic stirrer and condenser were placed methanol tllOO ml) and sodium (7.4 ~, 0.32 g.atm.). After the sodiurn reacted, 3-methylthio-5-phenyl- 1,2,4-triazine (61.0 g., 0.3 m.) was added and the contents warmed to 40 C with a hot water bath. After dissolution of the foregoing, the bath was removed and the contents allowed to stir at room temperature for 18 hours.
Then C02 gas was passed into the flask for 30 minutes. The precipitated materialwas filtered off and discarded. The filtrate was evaporated under vacuum. The remaining material was extracted with chloroform and the chloroform solution evaporated under the vacuum. The remaining material was then extracted with hexane. There was obtained from the hexane solution, 53.5 g (95.3% yield) of 3-methoxy-5-phenyl-1,2,4- triazine, m.p. 73-74 C.
Analysis-calculated for CloH9N30 (percent): C, 64.16; H, 4.85; N, 22.45.
Found (percent): C, 63.72; H, 4.90; N, 22.44.

:

Preparation of 3-Hydrazino-S-Phenyl-1,2,4-Triazine Into a 500 ml. flask equipped with a magnetic stirrer, heatin~ mantle and condenser were placed 3-methoxy-5-phenyl-1,2,4-triazine ~37.4 g, 0.2 m), 100 ml. of tetrahydrofuran, 95~ hydrazine t7.4 g, 0.22 m) and 20 ml. of absolute methanol. The contents were heated at reflux for 3.5 hours and poured into cold water. The precipitated material was filtered off, water washed, air dried and crystallized from 250 ml. of rnethanol. There was obtained 18.0 g (48.0% yield) of ~hydrazino~
phenyl-1,2,4-triazine, m.p. 144-14~ C. ~ ;~
Analysis-calculated for CgHgN5 (percent): C, ~7.74; H, 4.85; N, 37.41.
Found (percent): C:, $7.34; H, 4.87; N, 37.17.

112B5~7 Preparation of 3-Methylhydrazino-5-Phenyl-1,2,4-Triazine A solution of 3-methylthio-5-phenyl-1,2,4-triazine (5.0 g, 0.025 m), 10 ml.
of methylhydrazine and 100 ml of tetrahydrofuran was placed into a 500 ml flask 5equipped as before and the contents heated at reflux for 18 hours. 5 ml of additional methylhydrazine was added since thin layer chromatography showed the presence ofthe 3-methylthio-5-phenyl-1,2,4-triazine starting material. After heatin~ for 2 more hours, the reaction mixture was poured into 300 ml. of ice water. The yellow solid which formed ~as f iltered of f, washed with water and air dried. ~ollowing 10recrystallization from 300 ml of heptane, 1.8 g (36% yield) of the title cornpound was obtained, rn.p. 1 12-113 C.
Analysis-calculated for CloHllN5 (percent): C, 59.68; H, 5.51; N, 34.81.
Found (percent): C, 59.61; H, 5.55; N, 34.86.

15Preparation of 3-Methylhydrazino-5,6-(4'-Chloropheny~ 2~4-Triazine Into a 500 ml. round bottom flask was placed 3-methylthio 5,6-di (4'-chlorophenyl)-1,2,4-triazine (10.0 ~., 0.03 m.) dissolved in 95% ethanol (300 ml.). To this solution was added methylhydrazine (15 ml.) and the mixture was refluxed for 14 hours, cooled and concentrated. The crude solid was recrystallized from heptane, and 20then ether resulting in orange-yellow crystals of 3-methylhydrazino-5,6-(4'-chloro-phenyl)-i,2,~-triazine, rn.p. 147-148 C.
Analysis-calculated for C16H13N5C12 (percent~: C, 55.50; H, 3.78; N, 20.23. Found (percent): C, 55.1; H, 3.6; Ns 20.~.

"
2 5Preparation of 3~Acetylhydrazino-5,6-Diphenyl- 1,2,4-Triazine Into a 250 rnl. round bottom flask was placed,3-hydrazino-5$6-diphenyl-~12~35!~7 1,2,4-triazine tlO.O g., 0.04 m.) dissolved in warm dioxane (l50 ml.). To this stirring solution was added acetic anhydride tlO ml.) and the mixture was heated to 60 C for 1 hour. The mixture was cooled, diluted with water and the solid formed was collected and recrystallized from ethyl acetate, and slurri~ed with ether to afford the white solid 3-acetylhydrazino-5,6-diphenyl-1,2,4-triazine, rn.p. 166-168 C.
Analysis-calculated for C17 H15 N5 0 (percent): C, 66.87; H, 4.95; N, ~2.94. Found (percent~: C, 66.4; H, 4.8; N, 22.7.

Preparation of 3-Methylthio-5-t -Butyl- 1 ,2,4-Triazine Into a 1000 ml. flask equipped with a magnetic stirrer, heating mantle and condenser were placed S-methylthio semicarbazide hydrogen iodide (186.4 ~, 0.8 m), and 400 ml. of ethanol which were heated to 50C. A rnixture of t-butyl glyoxal ~87.8 g, 0.77 m) and pyridine ~63.3 g, 0.8 m~ was added to the flask over a 10 minute interval. The contents were stirred for 15 minutes and heated at reflux for 1.5 hours, cooled and the ethanol evaporated under vacuum. The resulting material was slurried with 500 ml. of water and the organic fraction extracted with chloroform. The chloroform was evaporated under vacuum and the resulting oil placed in a 300 ml.flask for vacuum distillatior~. There was obtained 84.8 g (60.0% yield) of 3-methylthio-5-t-butyl-1,2,4-triazine,m.p. 9l-93C at 0.1 mm. Hg.
Analysis-calculated for C8H13N3S (percent): C, 52.4~; H, 7.15; N, 22.93.
Found (percent): C, 51.57; H, 7.07; N, ~2.69.

Preparation of 3-Hydrazino-5-t-Butyl-1~2,4-Triazine Into a 250 ml. flask equipped with a magnetk stirrer, heating mant~e and condenser were placed 3-methylthio-5-t-butyl-1,29~triazine (18.3 ~, O.l m), lOû ml.
of tetrahydrofuran, 95~ hydrazine (3.9 ~, 0.11 m) and 10 ml. of absolute methanol.
The contents ~ere heated at reflux for 7.5 hours, cooled and the solvents were - `~
~2~3S~7 removed under vacuum. The resulting material was crystallized from 7.5 liters ofhexane. There was obtained 14.1 g (84.3% yield) of 3~hydrazino-5-t-butyl-1,2,4-triazine, m.p. 117-118C.
Analysis-calculated for C7H13N5 tpercent): C, 5û.28; H, 7.84; N, 41.89.
Found (percent): C, 49.88; H, 7.73; N, 41.46.

Preparation of 3-~ethylthio-5-12 -Fury~- 1,2,4-Triazine Into a 1000 ml. flask equipped as before were placed crude 2~thienyl glyoxal (126g, 0.9 m), 400 ml. of ethanol, S-methyithiosemicarbazide hydrogen iodide (210 g, 0.9 m) and pyridine (71.2 g, 0.9 m). The contents were heated at reflux for 1 hour, cooled and the ethanol evaporated under vacuum. The resulting material wasextracted with 3 liters of hexane. There was obtained 10.3 g (5.5% yield) of 3-methylthio-5-(2-thienyl)-172,4-triazine, m.p. 105-106 C.
Analysis-calculated for C8H7N3S 2 (percent): C, 45~91; H, 3.37; N, 20.08.
Found (percent): C, 45.54; H, 3.39; N, 20.05.

Preparation of 3-Trifluoroacetyl Hydrazino-5-Phenyl-1,2,4-Triazine To a stirred suspension of 3-hydrazino-5-phenyl-1,2,4-triazine (70 g, 0.374 m) in 1 liter of chloroform was added in portions 70 ml. of trifluoroacetic anhydride at 25 C to 30 C controlled by an ice water bath. When the addition was complete,the mixture was heated at 50C for 1~ hours. Upon cooling, the resulting precipitated solid was filtered off and dried. This dried solid was slurried with water, filtered, dried and recrystallized from chloroform to yield 60.û grams (56~6) oftrifluoracetyl hydrazino-5-phenyl-1,2,4-triazine as a.tan solid, m.p. 193 - 194 C.
Analysis-calculated for CllH8F3N50 (përcentk C, 46.65; H, 2.85; 1~1 24.73. Found (percent3: C, 46.72; H, 2~76; N, 25.09.

3L~LZ85~!~

Preparation o~ 3-Methoxy-5-~3'-Trifluoromethylphenyl~-1,2,4-Triazine Into a suitably equipped 500 ml. flask were placed 250 ml. of methanol and sodium (1.4 g, 0.05 g,atm.). Following reaction of the sodium, 10.8 g, 0.04 m 3-methylthio-5-(3'-trifluoromethylphenyl)-1,2,4-triazine (10.8 g, 0.04 m) was added to the flask and the contents allowed to stir at room temperature for I8 hours. Then carbon dioxide ~as was passed into the flask for 15 minutes and the precipitatedmaterial was filtered off and discarded. The filtrate was evaporated under vacuum and the resulting material extracted with 600 ml. of hexane. There was obtained 9.7 g (63.4% yield) of 3-methoxy-5-(3' trifluoromethylphenyl)-1,2,4-triazine, m.p. 95-97C.
Analysis-calculated for CllH8F3N3O (percent): C, 51.77; H, 3.16; N, 16.47. Found (percent): C, 51.58; H, 3.27; N, 16.28.

Preparation of 3-Me~hylthio-5-(2'-Furyl)-1,2,4-Tria~ine ::
Into a lOûO ml. ~lask suitably equipped with a magnetic stirrer, heating mantle and condenser were placed crude 2-furyl glyoxal (111.7 g, 0.9 m), 40û ml. of ethanol, S-methylthiosemicarbazide hydrogen iodide (210 g, 0.9) and pyridine (71.2 g, 0.9 m). The contents were heated ~t reflux for 1 hour, cooled and the ethanol evaporated under vacuum. The resultin~ material was extracted with 3 liters of hexane and there was obtained 20.0 g (11.5% yield) of 3-methylthio-~-(2'-furyl~-1,2,4-triazine, m.p. 88-90C.
.
Analysis-calculated for C8H7N30S ~percent): C, 49.72; H, 3.65; N, 21.75. Found (percenth C, 49.40; H, 3.69; 1~1, 21.87.

Preparation of 3-Methylthio-S,6-Dimethyl-1,2,~-Triazine Into a suitably equipped 2û0 ml f lask were placed S-methyl~hiosemi-- l?a -85~

carbazide hydrogen iodide (222.4 g, 0.954 m), and 700 ml. of ethanol which were heated to 60C. A mixture of diacetyl (82.1 g, 0.954 m~ and pyridine (75.9 g, 0.96m) was added to the flask oYer 15 minutes. The contents were heated at reflux for 2hours and the ethanol distilled off. About 1200 ml. of water was added to the flask and the resulting mixture extracted with chloroforrn. The chloroform was evaporated under vacuum and the resulting oil was placed in a 200 ml. flask for vacuum cfistillation. There was obtained 105.5 g (71.2% yield~ of 3-methylthio-5,6-dimethyl-1,2,4-triazine, b.p. 100-102C at 0.1 mm Hg.
Analysis-calculated for C~;H9N3S (percent): C, 46.42; H, 5.84; N, 27.07.
Found (percent): C, 47.03; H, 6.1~; N, 26.18.

.

Preparation of 3-Allyloxy-5,6-Dimethyl- 1,2,4-Triazine Into a 250 ml. ~lask equipped as preYiously described were placed 125 ml.
o~ allyl alcohol and sodium (1.8 g, 0.08 g.atm.). After completion of the sodillm reaction, 3-methylthio-5,6-dimethyl-1,2,4-triazine (10.8 g,~ 0.07 m~ was added to the flask and the contents allowed to stir at room temperature for 18 hours. Carbon dioxide gas was passed into the flask for 20 minutes and the contents poured into water. The solution was extracted with chloroform and the chloroform evaporated under vacuum and the resulting material placed in a 50 ml. flask for vacuum dis-tillation. There was obtained 8.5 g (73.5% yield) of 3-allyloxy-5,6-dimethyl-1,2,4-triazine, b.p. 84-86C at 0.08 mm Hg.
Analysis-calculated for C8HllN3O (percent): C, 58.16; H, 6.71; N, 25.44. Found (percent): C, 57.05; H, 6.73; N, 25.64.

Preparation of 3-Methylthio-S,6-(2'-Pyridyl) 1,2,4-Triazine To a solution of S-methylthiosemicarbazide hydrogen iodide (23 g, 0.1 m~
dissolved in ice water (200 ml.) was added a solution o~ 2,2'-pyridil (21 ~, 0.1 m) and - 17b -8S~7 sodium bicarbonate (9 g, 0.11 m) in 50% ethanol (250 ml.). Upon addition, gas was evolved and addition was carried out slowly while cooling. When gas evolution ceased, the mixture was stirred for 15 hours at rooM temperature. The mixture wàs diluted with about 200 ml. of water and repeatedly extracted with chloroform. The chloroform extracts were dried over anhydrous magnesium sulfate and concentratedto give a yellow solid which was recrystallized from hexane to yield 3-rnethylthio-5,6-(2'-pyridyl~1,2,4-triazine (8596), m.p. 122-123C.
,4nalysis-calculated for C14HllN5S (percent): C, 59.7~; H, 3.91; N, 24.910 Found (percent: t:, 5~.57; H, 3.90; N, 25.35.

Preparation of 3-M ethylthio-5-(3'-Indolyl)- l ,2,1~-Triazine Into a suitably equipped 1000 ml. flask were placed a solution of 3-indolyl glyoxal (27.0 g, 0.15 m~ dissolved in 200 ml of ethanol and sodium bicarbonate (13.2 g, 0.157 m) dissolved in 50 ml. of water to which was added a solution of S-methyl-thiosemicarbazide hydrogen iodide (36.5 g3 û.157 m) dissolved in 50 rnl. of water. l`he mixture was then heated at reflux for about 48 hours. Following reflux, the mixture was poured into ice water and the resulting solid was recrystallized twice from acetone. This solid was then slurried with water, filtered off and dried to yield 2.7 g of 3-methylthio-5-(3'-indolyl)-1,2,4-triazine, m.p. 232 - 234C.
Analysis-calculated ~or Cl2HloN4S (percent): C. 59.48; H, 4.i6, N, 23.12.
Found (percent): (:, S9.23; H, 4.17; N, 23.49.

EXAMPl E 14 Preparation of 3-Methylthio-5,6-(4'-Acetamido Phenyl)-1,234-Triazine Into a 100 ml ~iask was placed ~acetamidobenzil (10 g9 0.0285 m) dis-solved in dirnethylformamide (50 ml) and to this solution was added an aqueous solu-. .
tion of NaHC03 (1.0 g) and S-methylthiosemicarba~ide hydrogen iodide (7 g, 0.03 m~.
The mixture was stirred at room temperature for 15 hours9 then heated on a steam -- 17c --~2~ 7 bath for 1 hour, cooled and the precipitate which formed was collec$ed and washed with H2O, acetone, dried under reduced pressure to give 3-methylthio-5,6-(4'-acetamidophenyl)-1,2,4-triazine (70% yield), m.p. 300C.
Analysis-calculated for C2~HlgN5O2S (percent): C, 61.07; H~ 4.83; N, 17.27. Found (percent): C:, 60.69; H, 4.95; N, 17.76.

Preparation of 3-Methylthio-5-~3'-Chlorophenyl)-1,2,4-Triazine Into a suitably equipped 500 rnl. flask were placed selenium dioxide (34.4 g, 0.31 m), 250 ml. of dioxane and 10 ml. of water. The contents were heated to 6ûC
- and 3-chloroacetophenone (46.4 g, 0.3 m) was added in one portion. The conten~s were heated at reflux for 2 hours, cooled and filtered. The solvents were removed under vacuurn. The resulting 2-(3'-chlorophenyl) glyoxal was dissolved in 100 ml. of ethanol and additional selenium was filtered off.
Into a second 50û ml. f lask were placecl the crude 2-(3'-chlorophenyl) glyoxal (50.6 g, 0.3 m) thus obtained in lûO ml. of ethanol, pyridine (24.0 g, 0.3 m) and S-methylthiosemicarbazide hydrogen iodide (70. g, 0.3 m). The contents were heated at reflux for I hour and cooled. The precipitated material was filtered off and extracted with 1200 ml. of hexane. The hexane was evaporated off and the resulting material crystallized from methanol (200 ml.). There was obtained 26.0 g (36.5%
yield) of 3-methylthio-5-(3'-chlorophenyl)-1,2,4-triazine, m.p. 79-81C.
Analysis-calculated for ClOH8CllN35(percent): C, 50052; ~I, 3.39;
N, 17.68. Found (percent): C, 50.70; H, 3.32; N, 17.64.

"

, - 17d -~.~f~S~

Preparation of 3-Methylthio-5,6-Bis~3', 4'-Methylene Dioxy-Phenyl)-1,2,3-Triazine Into a 100 ml. round-bottomed flask was placed 3,4-methylene dioxy benzil (5 g, 0.016 m) dissolved in ethanol-dimethylformamide. To this solution was added S-methylthiosemicarbazide hydrogen iodide (4.0 g, 0018 m) and sodium bicar-bonate (2.0 g, 0.2 m). After gas evolution had ceased, the mixture was refluxed with stirring for 4 hours. Upon coolin~, a yellow solid formed which was collected, washed repeatedly with acetone and ether, and dried under reduced pressure to yield 3-methylthio-5,6-bis(3',4'-methylene dioxy-phenyl)-1,2,4-triazine (80% yield), m.p. 207-209C.
Analysis-calculated for C18H13N3O4S (percent): C, S8.86; H, 3.54; N, - 11.44. Found (percent): C, 58.80; H, 3.57; N, 11.31.

: ~ EXAMPLES 17-111 lS The following compounds were prepared using the foregoing synthesis procedures with appropriate selection of the substituted glyoxal reactant for con-densation with S-methylthiosemicarbazide hydrogen iodide and conversion of the resulting 3-methylthio-1,2,4-tria2ine derivative or, where appropriate, by selection of a substituted alpha beta diketone for condensation with semicarbazide, cyclization and chlorination to obtain the 3-chloro-1,2,4-triazine derivative for conversion into the desired 3-substituted-5-mono or 5,6-disubstituted-1,2,4-triazines~
Example 17- 3-methoxy-5-methyl-1,2,4-triazine, m.p. 87-~9 C.
Example 18- 3-methoxy-5-t-butyl-1,2,4-triazine, m.p. 45-46 C~
Ex~mple 19 - 3-methylthio-5-(3'-trifluoromethyl phenyl)-1,2,4-triazine, m.p.
1~3-125 C.
Example 20- ~methoxy-5-(?'-~uryl)~ 94-triazine, m.p. 96-97C.
Example 21 - 3-ethoxy-5-phenyl-1,2,4-triazine, m.p. 48-49 C.
Example 22 - 3-methoxy-5-(2'-napthyl)-1,2,4-triazine9 m.p. 130-131 C.

8~;~7 Example 23 - 3-methoxy-5,6-dimethyl-1,2,4-triazine, b.p. 55-57 C at 0.05 mm Hg.
Example 24 - 3-isopropoxy-5,6-dimethyl-1,2,4-triazine, b.p. 75-78 C at 0.5 mm Hg.
Example 25 - 3-hydrazino-5,6-dimethyl-1,2,4-triazine, m.p. 126-127C.
O Example 26 - 3-methoxy-5,6-di(4'-methylphenoxy)-1,2,4-triazine, m.p. 128-Example 27 - 3-methoxy-5,6-di(2'-pyridyl)-1,2,4-triazine, m.p. 132-133C.
Example 28 - 3-B-hydroxyethyl amino-5-phenyl-1,2,4-triazine, m.p. 152-153C.
Example 29 - 3-methoxy-5-(1'-naphthyl)-1,2,4-triazine, m.p. 76-77 C.
Example 30 - 3-methoxy-5-(2'-naphthyl)-1,2,4-triazine, m.p. 130~ 131C.
Example 31 - 3-n-propoxy-5-phenyl-1,2,4-triazine, m.p. 44-45 C.
Exa2;ple 32- 3~methylthio-5-(3'-methoxy-4'-hydroxyphenyl)-1,2,4-triazine, m.p.
190-191.5 C.
O Example 33 - 3-rnethylthio-5-(3',4'-dimethoxyphenyl)-1,2,4-triazine, m.p. 148-Example 34 - 3-methylthio-5-(1'-adamantyl)-1,2,4-triazine, m.p. 140-141C.
Example 35 3-methylthio-5-(2'-benzofuryl)-1,2,4-triazine, m.p. 134-135 C.
Example 36- 3-methoxy-5-(1'-adamantyl)-1,2,4-triazine, m.p. 101-102 C.
Example 37 - 3-methylthio-5-cyclopropyl-1,2,4-triazine, m.p. 44-46 C.
O Example 38 - 3-methoxy-5-(3',4'-dimethoxyphenyl)-1,2,4-triazine, m.p. 167-169 C.
O Example 39 - 3-methylthio-5-(2',4',6'-trimethylphenyl)-1,2,4-triazine, m.p. 97-O Example 40 - 3-methylthio-5-(4'-morpholino phenyl)-1,2,4-triazine, m.p. 127-Exalrple 41 - ~methoxy-5-cyclopropyl-1,2,4-triazine, b.p. 119-121 C at 1.8-2.1 mrn Hg.
Example 42 - ~methyl~hio-5-(2',4'-difluorophenyl)-1,2,4-triazine, m.p. 79-80C.
Example 43 - 3-meehylthio-5-(4'-bromophenyl~1,2,4-triazine, m.p. 153-154C.
O Example 44 - 3-methylthio-5-(4'-methoxyphenyl3-1,2,4-triazine, m.p. 118-Example 45 - 3-methoxy-5-(4'-bromophenyl)- 1,2,4-triazine, m.p. 108-109 C.
Example 46 - 3-rnethoxy-5-(4'-methoxyphenyl)-1,2,4-triazine, m.p. 106-107 C.

Example 47 - 3-allyloxy-5-phenyl-1,2,4-triazine, b.p. 155C at 0.3 mm Hg.

5!~7 Example 48- 3-methoxy-5,6-diphenyl-1,2,4-triazine, m.p. 78-79C.
Example 49 - No Example.
Example 50 - 3-(N-met~l-N-(B-hydroxyethyl)amino~-5,6-bis-(4'-methoxy-phenyl)-1,2,4-triazine, m.p. 108-110 C.
Example 51 - 3-chloro-5,6-diphenyl-1,2,4-triazine, m.p. 152-155 C.
E~rnple 52 - 3-(cis-2',5'-dimethyl pyrrolidyl)-5,6-diphenyl-1,2,4-triazine, m.p.
131-134 C.
Example 53- 3-phenoxy-5,6-diphenyl-1,2,4-triazine, m.p. 123-125 C.
O Example 54 - 3-methylthio-5,6-bis(4'-chlorophenyl)-1,2,4-triazine, m.p. 142-143 C.
Exampl& 55 - 3-(N-methyl-N-B-hydroxyethyl amino~5,6-diphenyl-1,2,4-triazine, m.p. 101-104 C.
Example 56- 3-benzylthio-5,6-dimethyl-1,2,4-triazine, m.p. 47-48C.
Example 57 - 3-methylthio-5-(4'-nitrophenyl)-1,2,4-triazine, m.p. 218-219C.
Example 58 - 3-methoxy-5-(2',4'-difluorophenyl)-1,2,4-triazine, m.p. 91-93C.
E~mple 59 - 3-methylthio-5-phenyl-1,2,4-triazine (hydrogen iodide salt), m.p.
191-192 C.
Example 60- 3-~4'-methylphenoxy)-5,6-diphenyl-1,2,4-triazine, m.p. 154-157 C.
Example 61 - 3-ethoxy-5,6-diphenyl-1,2,4-triazine, m.p. 73-74 C.
Example 62 - 3-methylthio-5-(4'-e~hylphenyl)-1,2,4-triazine, m.p. 71-72 C.
Example 63- 3-(4'-methoxyphenoxy)-5-phenyl-1,2,4-triazine, m.p. 149-151 C.
Example 64 - 3-n-pentoxy-5-phenyl-1,2,4-triazine, m.p. 36-3S C.
Example 65 - 3-n-butoxy-1,2,4-triazine, b.p. 129-138 at 13 mm Hg.
Example 66- 3-methoxy-5-(2'-thienyl)-1,2,4-triazine, m.p. 129-130 C.
O Example 67 - ~hydrazino-5-(3'-trifluoromethylphenyl)-1,2,4-triazine, m.p. 140-Example 68 - ~methylthio-5-(3'-methoxyphenyl)-1,2,4-triazine, m.p. 96-97 C.
Example 69 - 3-methoxy-5-(3'-methoxyphenyl)-1,2,4-triazine, rn.p. 106-107C.
Example 70 - ~methylthio-5-(5'-chloro-2'-thienyl)-1,2,4 triazine, m.p. 149-15~C.
Example 71 - ~melhylthio-5-(1'-naphthyl)~ ,4-triazine, m.p. 116.5-118 C.
Example 72 - 3-methylthio-(4'-methylphenyl)- 1,,2,4-triazine, m.p. 160-161 C.
Exam~le 73 - 3-(N-methyl-N-(B-hydroxyethyl)amino)-5-phenyl-1,2,4-triazine, m.p. 90-91 C.

Exarnple 74 - 3-methylthio-$-(4'-chlorophenyl)-1,2,4-triazine, m.p. 165-166 C.
Example 75- 3-methoxy-5 (3'-chlorophenyl)-1,2,4-triazine, m.p. ~3-94 C~
Example 76- 3-methylthio-5,6-bis-(~'-furyl~-1,2,4-triazine, m.p. 92-92 C.
Exarnple 77 - 3-hydrazino-5,6-bis-(2'-furyl)-1,2,4-triazine, m.p. 168-169 C.
O Example 78 - 3-methyl-5,6-bis-(4'-methylphenyl)-1,2,4-triazine, m.p. 166-S Example 79 - 3-methylsulfonyl-5,6-dimethyl-1,2,4-triazine, m.p. 97-98C.
ExOample 80 - 3-methylthio-5,6-bis(3',4'-dimethoxyphenyl)-1,2,4-triazine, m.p.

Example 81 - 3-(2'-pyridyl)-5,6-diphenyl-1,2,4-triazine, m.p. 191-193 C.
Example 82 - 3-methoxy-6-phenyl-1,2,4-triazine, m.p. 94-95C.
Exampl~ 83 - 3-methylthio-5-(3'-methoxy-4'-benzyloxyphenyl)-1,2,4-triazine, m.p. 158-159 C.
Example 84 - 3-methylthio-5-(9'-anthracenyl)-1,2,4-triazine, m.p. 181-184 C.
Example 85- 3-methoxy-5-(9'-anthracenyl)-1,2,4-triazine, m.p. 195-195C.
Ext~ample 86 - 3-methylthio-5-(3',4'-methylene dioxyphenyl)-1,2,4-triazine, m.p.
Example 87- ~methylthio-5-diphenylmethyl-1,2,4-triazine, m.p. 162-163C.
Example 88 - 3-methylthio-5-(4'-ethoxyphenyl)-1,2,4-triazine, m.p. 119-120C.
O Example 89 - 3-methoxy-5-(2',4',6'-~rimethylphenyl)-1,2,4-triazin~, m.p. 96-Example 90- 3-hydroxy-5-phenyl-1,2,4-triazine, m.p. 235-237C.
Example 91 - 3-methoxy-5-(4'-methoxyphenyl~-1,2,4-triazine, m.p. 106-107C.
O Example 92 - 3-methoxy-5,6-bis(3',4'-dimethoxyphenyl)-1,2,4-triazine, m.p. 83-84 C.
O Example 93 - 3-me~hylthio-S,6-bis(4'-methoxyphenyl~-1,2,4-~riazine, m.p. 152-153 C.
Example 94 No Example Example 95 - ~isopropoxy-5~6-diphenyl-1,2,4-triazine, m.p. 96-98C.
Example 96 - 3-methoxy-S,6-bis(4'-chlorophenyl)-192,4-triazine, m.p. 146-147C.
Example 97 - No Example .
Example 98- ~methoxy-S-(4'-chlorophenyl~-1,2,4-triazine, m.p. 131-133C.
Example 99 No Example ~L2~35g~7 Example 100- 3-methoxy-5-(2'-benzofuryl)-1,2,4-triazine, m.p. 139-140 C.
Example 101 - ~methoxy-5-~3',4'-methylene dioxyphenyl)-1,2,4-triazine, m.p.
129` 130C.
Example 102 - 3-methoxy-5-(4'-morpholinophenyl)-1,2,4--triazine, m.p. 122-123C.
Example 103 - 3-methylthio-5-(2'-chlorophenyl)-1,2,4-triazine, m.p. 68-69C.
Example 104 - 3-methoxy-`5,6-bis~2'^furyl)-1,2,4-triazine, m.p. 105-107 C.
Example 105- 3-methoxy-5-phenyl-6-methyl-1,2,4-triazine, m.p. 72-74 C.
Example 106- ~n-nonyithio-5-phenyl-1,2,4-triazine, m~p. 47-49 C.
O Example 107 - 3-adamantanoyl hydrazino-5-phenyl-1,2,4-triazine, m.p. 218-220 C.
ExOample 108 - 3-propionylhydra~ino-5-(4'-chlorophenyl)-1,2,4-triazine, m.p.
213-214 C.
Example 109 - 3-acetylhydrazino-5-phenyl-1,2,4-triazine, m.p. 181-183C.
O example 110 - 3-cyclohexanoylhydrazino-S-phenyl-1,2,4-triazine, m.p. 208-209 C.
Example 111 - 3-hexanoylhydrazino-5-phenyl-1,2,4-triazine, m.p. 198-200C.
The following examples further illustrate the preparation of carbobenzyl-oxy N-protected ~aminoacylhydrazino and ~-aminoacylhydrazino derivatives of the present invention.

Preparation of Glycine-N-Carboben~yloxy-2-(5-Phenyl-1,2,4-Triazin-3-yl)-Hydrazide Carbohenzyloxy glycine (2.1 g., 0.01 m.) was dissolved in pyridine (dried over Ba O) and chilled to -10 C under inert atmosphere. Dicyclohexyl-carbodiimide (2.1 g., 0.01 m.) was dissolved in warm pyridine and added by syringe. 3-Hydrazino-~
phenyl-1,2,4-triazin (1.9 g., 0.01 m.) was dissolved in pyridine and added dropwise by syringe to the stirring mixture at -lG C. The ice bath was removed and ~he mixture allowed to s~ir at room temperature for S hours. The precipitate which formed was removed by filtration and identified as dicyclohexyl urea and discarded. The solution was concentrated and the Yiscous oil taken up in hot ethyl acetate. Acldition of small amounts of pet ether and coolin~ resulted in the formation of the title compound as a yellow powder, m.p. 166-167 C.
Analysis-calculated for C19 H18 N6 3 (perc:ent): C9 60,82; H, 4.7;'; N, 22.22. Found (percent): C, 61.05; H, 5.25; N, 21.91.

Preparation of N -(5-Phenyl-1,2,4-Triazin-3-yl) Glycine Hydraz~de (I:)ihydrobromide Hydrate) Into 500 ml. erlenmeyer flask was placed glycine -N-carbobenzyloxy-~-(5-phenyl-1,2,~triazin-3-yl)-hydrazide (16.0 g., 0.045 m.~ dissolved in glacial acetic acid (100 ml.). To this solution was added 100 ml. of 4 N H~r/AcOH and the flask stored for 1 hour at room temperature with intermittent stirring. The reaction mixture was diluted with excess anhydrous ether (300 ml.) and stored at 5C for 12 hours, forming a red solid which was collected and slurried in ether several times. Upon drying in a vacuum oven for 10 hours, the title compound was recovered as a pale yellow solid, m.p. 220-221C.
Analysis-calculated for Cll H12 N~; O; 21~Br . H2O (percent): C, 31.I3;
H, 3.77; N, 19.81. Found (percent): C, 31.1; H, 3,9: N, 20.1.

The following compounds were similarly prepared usin~ the foregoing synthesis methods with appropriate selection of the N-carbobenzyloxy amino acid reactant and cleavage of the N-protecting group.
Example 114 - N -(5-p-chloro~henyl-1,2,4-triazin-3-yl) alanine hydrazide (di-hydrobromide hydrate), ~.p. 252-254 C.
Example 115 - N -(5-phenyl-1,2,4-triazin-3-yl) valine hydrazide (dihydrobromide hydrate), m.p. 274_275i3C.
Example 116 - N -~5-phenyl-O1 ~2,4-triazin-3-yl~ phenylalanine hydrazide (di-hydrobromide hydrate), r~.p. 264-~65 C.

PHARMACOl OGICAL ACTIYITY

The results of studies demonstrating the indicated anti inflammatory, anal~esic, hypotensive and central nervous system effects observed upon admini-stration of effec~ive dosages of typical preferred compounds in accordance with the ~Z13~37 present invention and the procedures utilized to evaluate pharmacological actlv;ty are set forth below.

A. Anti-inflammatory Assay Anti-inflammatory activity, i.e., effectiveness in the prevention and inhibition of granuloma tissue formation, is demonstrated by relative inhibition of carrageenin-induced edema as determined by the diminution of experimental edema induced in the hind paw of a rat by the injection of carrageenin. The procedure employed is a modification of the method of Winter et al, Proc. Soc. Exptl. Biol.
Med. 111:544 (1962). The device used for measurement of the paw volume is an adaptation of the water displacement procedure described by Adamkiewicz et al, Can. J. Biochem. Physiol. 33:332 (1955). Test compounds were administered orally, one hou~ prior to the intraplantar injection of 0.05 ml. of sterile 1.0 per cent solution of carrageenin into the left hind paw of male rats (Long Evans strain) weighing between about 130-200 grams. At peak swelling time (3 hours) the volume of edemawas calculated by differential paw volumes.
Table I sets forth the results obtained (indicated as percent reduction OI
edema compared to phenylbuta~one control values) at the indicated dosages for each of the identified compounds.

2 0 TABLE I - Carrageenin Assay Compound Exarnple No.Dose (mg/k~)% Reduc~ion of Edema

4 150 57 9 ~00 39 11 200 6~

TABLE I - Carrageenin Assay (Continued) Compound Example No. Dose (mg/k~) % Reduction of Edema 18 ~00 64 21 20û 96 ~2 200 7 4~

29 200 2~

3g 200 52 43 ~oo 20 l~4 200 18 4~ 200 17 50 (1) 200 67 4 58 150 . 36 113 50 3~
.
l-Comparative Example - See U.S. Pat. No. 3948,894 B. Analgesic Assay The phenylquinone writhing test was érnployed to evaluate analgesic activity according to the following procedure:
Phenylquinone (phenyl-p-benzoquinone, No. 7104, Eas~rnan Organic Chem-~2~7 icals) is made up as a 0.02% aqueous solution in 5~6 ethyl alcohol. Phenylquinone solutions are made up fresh twice daily. 5tandard reference agents and ~he tes~
compounds are dissolved or suspended in a .25% methylcellulose solution. A control group consisting o~ ten mice (Carworth CFl male mice) are administered the .02~6phenylquinone solution at a dose o~ 0.25 ml/mouse. The rnice are housed individually and observed closely for ten minutes for exhibition of writhing. The onset of writhing occurs within three minutes and 100% of the mice must writhe within ten minutes.Test compounds are administered orally to groups of ten mice. The volume given is .01 ml/gram of body wei~ht. Activity can be studied at 15, 30, 60, and 120 minutes after oral administration. After the designated time interval of a dose group has elapsed, the mice are challenged with phenylquinone intraperitoneally. Complete blocking of the writhing syndrom for the ten minute observation period in any one mouse is considered a positive analgesic response ~or that mouse. Conversely, if any mouse writhes definitely once it is considered not to be protected. The number of mice not writhing in a group multiplied by ten equals percent analgesia for that dose at that time interval.
The compounds tested, dose administered, and analgesic response are sumrnarized in Table 11.
TA~LE 11 - Phenylquinone Writhing Assay (% Control) Ccar~ound Dose E~le ~. (m~/k~) 15 Min. 30 Min. 60 Min - (1) _ 1~0 - 10 2 12.5 lQ 30 30 3 30 _ 30 2~ 7 TABLE 11 - Phenylquinone WrithinR Assay (% Control (Continued Dose Com o~n- ~2]~ehL~Y9~ (m~/k~ lS Min. 30 Min~ 60 Min ~0 10 - - :
18 50 - ~0 19 30 _ 20 22 100 20 ~L0 10 24 70 ~ 10 12.5 - 20 26 25 10 ~lO 10 : 38 100 - 20 10 39 100 1~ _ 10 53 100 ~0 - 10 100 - 10 20 ~0 72 10~ 20 73 100 10 - - :

77 25 20 'I20 20 78(2~ 50 20 20 20 79 100 _ .30 30 ~0 1~0 10 10' ~LZ~35~7 LE II - Phen~l~one Writh~ Assay (% Control) (Continued~

Example N~. ~L~ 15 Min. 30 Min. 60 Min 81 100 1~ 20 8~ 100 - 10 20 86 100 ~0 so 1 oo - . - ~o 93 100 20 30 30 ;, .
1- Indicates not tested at indicated time ~nterval 2 - See Belgiun Pat. No. 839,469 C. Anti-Hypertensive Assay Spontaneously hypertensive rats, 12 to 16 weeks of age, were used in this assay. Systolic blood pressures were determined by the tail cuff method, utilizing capacitance transducers for the detection of pressure, an aneroid manometer for measuring pressure, and an oscilloscope for visualizin~ the disappearance and/orappearance of the pressure pulse. Heart rate was measured by a biotachometer.
Groups of five rats having systolic blood pressures of 170 mmH~ or ~reater were chosen and the test compounds administered at the doses indicated below (oral) as a solution or suspension in .25% methylcellulose (MC~ at a volume of 5 ml/kg. One group served as the control and received the vehicle. Twen~y-four hours aEter dosing, systolic blood pressure and heart rate were recorded. A second dose of cornpound was administered and blood pressure and heart rate deterrnined at 4 and 24 hours after the second dose.
The results observed are set forth in Table II1 below:

,~ ~

~ 85~

TA~LE 111- SHR Assay Dose Mean Drop - mm/H~.
Compound Example No.(mF,/hF,) -- 24 hr. 4 hr. 24 hr 28 hr. 48 hr._ _ _ _ 3 50 30 43 S8 6û - -3A 1 ûO 0 49 '56 92 3C 100 55 70 ~. 90 2~ 100 10 2 lO 2 61 100 2 4 1~ 11 78 lO0 8 ~ 5 11 12 100 - 50 + 1 0 a 1l - -103 1~0 2 10 10 13 107 100 ~9 86 41 36 108 100 ~7 79 107 111 109 100 40 94 106 10~

D. Psychotropic Effects The central nervous system activity of certain of the preferred compounds in accordance with the present invention were determined using the following neuro-pharmacological profile assay procedures.
White male mice of the Carworth Farm Strain (C~-l) weighing 18 - 22 grams were used in these determinations. The test compound, re~ardless of solu-bility, is suspended in a 0.2556 aqlJeous methylcellulose solution. Intraperitoneal injections were adminis~ered in logarithmic progression and sequen~ially. The dose levels employed routinely are 10, 30, 100, and 300 mg/kg, using four male rnice at each dase level. Since this test was conducted in a sequential manner, the first dose administered was at 30~ mg/kg. The mice were injected at this dose level and ~2~35~

observed for gross changes produced by the drug, such as behavioral, neurological, autonomic, and toxic effects.
The animals were observed continuously for one hour and if no signs of pharmacological or toxicological activity were present at the end of the first hour, they were in~ermittently checked for activity every fifteen minutes ~hereafter for two consecutive hours. At the end of the third hour of observation, if no demon-strable change had occurred in the behavior of the mice, the compound was con-ditionally considered inactive and the animals were checked intermittently for forty-eight hours. Subsequent dose levels below 300 mg/kg were not administered in this case. Alternatively, if demonstrable pharmacological changes occurred within thefirst three hours after adminis~ration of the drug at 300 mg/kg, the subsequent doses were administered and the animals observed for changes in overt behavior. The observation period begins immediately followin~ the injection and the animals are then continuously observed for three hours and intermittently checked thereafter for ` forty-eight hours. The animals were observed and signs and symptoms of pharma-cological activity were recorded continuously until no further symptoms developed and until the symptoms that had appeared were no longer present. The animals were observed in a fixed environment consisting of a 15 inch square in which their movements were not restricted. It was very important that the animals were free to move about for evaluation of spacial orientation, alertness, and spontaneous motor activity. The animals were systematically observed and manipulated to measure the onset~ peak effect, duration and character of drug action.
The major characteristics observed relative to central nervous system actiYity for the compounds indicated are summarized in the following Table IV.

-- 30 ~

~1285~7 TABLE IV - Neuropharmacological Profile Compound Example No.Dose ~mg/k~e) CNS Activity 3 300,100,30,10 Antidepressant 4 300,100,30 "
s 5 300,100,30,10 "
300~100,30 "
11 300, 100 Hypnotic 12 300,100,30 "
19 300,100,30,10 , 3 Sedative 300,100,30,10 An~ depressant 48 300,100,30 Muscle Relaxant 300,100,30 Antidepressant 73 30Q,100 Hypnotic 104 300, 100l30 "

15As a consequence of the levels of activity in the carrageenin anti-inf~am-matory assay, certain of the compounds of the invention were subjected to more advanced evaluation utilizing the adjuvant-induced arthritis test. This test requires one month (from day 0 to day 31) for completion. In the first 17 days (0-17), the disease is in the developing stage, while ~or the remainder of the month (18-31) the 20disease is fully developed. The results of this assay procedure, given in terms of percent reduction of swelling in the hind paw of the rat are shown in table V.
The method employed is essentially that of Newbould, Brit. ~. Pharmacol.
21:127, 1963. The test compounds were studied in the developing arthritis state and in the established arthritic state. Separate groups of 12 rats were orally administered 2Sthe compounds using methylcellulose as the vehicle. In the study of the developing disease, administration of the test compounds begins on day 1 and on day 2 each animal is injected with 0.5 ml/kg of a O.S% suspension of heat-killed Mycobacterium Tuberculosis into the plantar surface of the left hind paw. Foot volumes were mea^
sured by a water displacement device on the day of administration of the Mycrobac-30terium and again on days 3, lû and 17. The test compounds were administered once daily. At the same time, body wei~hts were recorded daily and the animals examined for the spread of .he inflammation and degree of secondary lesions. For study in ~he established disease, another group of rats were injected with the Mycrobacteriurn and - foot volumes were measured. After 20 days volumes were again measured and 35administration of the test compounds began and continued for 11 days. Foot volume ~lZ~S~

measurements were repeated on day 27 and day 31. The extent of the spread of in-flammation and degree of lesions were recorded daily as were the body weights. The effect of the test compounds is measured by the percentage reduction in left hind paw volumes as compared to the hind paw volumes of the control groups.

TABLE V - Adjuvant-Arthritis Assay (% R~eduction) Compound Dose Day Day Day Day Day Day Example No. (m~/kg) 3 10 i7 20 27 3i 7 50 30 30 39 4 24 ~9 As indicated previously, certain of the compounds of the invention also display excellent antipyretic activity. As shown by the following cornparative data, 3-methoxy-5-phenyl-1,2,4-triazine (compound of exampJe 2), for instance, is com-lS parable in activity to Aspirin. Antipyretic activity was measured utilizing the con ventional yeast induced fever assay procedure (15% yeast solution injected at two sites).

TABLE Vl - Antipyretic Assay Test Compounds 2 0 Administered temps. @ 0 hr. temps. @ 18 hrs. temps. ~ I9Y2 hrs.
Compound of Example 2 @ 100 mg/kg 38.1 39.0 35.3 Controls (methylcellulose) 38.2 39.4 39.6 Aspirin @ 100 mg/kg 38.0 38.8 37.8 As indicated by the test data presented hereinabove~ the compounds of the present invention evidence a high degree of pharmacologlcal activity. Moreover, the present compounds possess certain ad~antageous properties which make them particularly interesting for use in the aforementioned methods and compositions of the invention. For example, the preferred substituted 1,2,4-triazine compounds of the invention, as a consequence of the absense of any acid forming groups thereon,are presently considered non-ulcerogenic. Moreover, the present compounds are non-steroidal and, accordingly, are devoid of the adverse side effects often associated ~, -- 3 2 8~7 with steroids. Some of the preferred hypotensive compounds of the present mvention, e.g., the compound of example 7, demonstrate both advantageous rapid onset of action as well as a long duration o~ activity which are particularly valuable properties in the chemotherapeutic management of hypertension. It is also important to notethat the preferred 5-substituted compounds of the invention are relatively more soluble in water and organic solvents than previously suggested 5,6-disubstituted compounds which is specifically advantageous from a formulation standpoint.
While the invention has been ~escribed and illustrated with reference to certain preIerred embodiments thereof, those skilled in the art will appreciate that various changes~ modif ications, and substitutions can be made therein without department from the spirit of the invention. For example, effective dosages other than the preferred ranges set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal treated, severity of observed conditions, i.e., inflammation, fever, pain, etc., dosage related adverse effects, if any, observed and analogous considerations. Likewise, the spedfic pharmacological responses observed may vary depending upon the particular active compound selected or whether different active compounds are used in combination or in the presence of suitable pharmaceutical carriers as well as the type of formulation and mode of administration employed and such expected variations or differences in results are contemplated in accordance with the objects and practices of the present invention.
It is intended, therefore, that the invention be limited only by the scope of the claims which follow.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound having the general formula:
wherein R1 is C1-C4 hydroxy alkylamino, N-(C1-C2 alkyl)-N-(hydroxy C1-C4 alkyl)amino, C1-C4 alkyl, C1-C10 alkoxy, C6-C10 aryloxy, C3-C6 cycloalkoxy, phenyl alkoxy, allyloxy, halophenoxy, C1-C4 alkyl phenoxy, C1-C4 alkoxy phenoxy, C1-C10 alkylthio, C3-C6 cycloalkylthio, C1-C4 alkyl sulfinyl, C1-C4 alkyl sulfonyl, phenyl C1-C4 alkylthio, dimethylpyrrolidyl, or hydrazino, C1-C4 alkyl hydrazino, -NH-NH-?-R4 where R4 is C1-C8 alkyl, C2-C8 alkenyl, halo (C1-C8)alkyl, halo (C2-C8)alkenyl, C6-C10 cycloalkyl or R4 represents the group where R5 is H, C1-C4 alkyl or benzyl and R7 is H or carbobenzyloxy;
R2 represents hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, adamantyl, furyl, thienyl, benzofuryl, indolyl, pyridyl, halothienyl, phenyl or phenyl substituted with at.
least one substituent selected from halo, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, acetamido, benzyloxy, diphenylmethyl, morpholino, methylene dioxy or nitro;
and R3 represents hydrogen,C1-C6 alkyl, pyridyl, furyl, phenyl or phenyl substituted with at least one substituent selected from halo, C1-C6 alkyl, C1-C6 alkoxy, methylene dioxy or acetamido;

subject to the proviso that when R2 is hydrogen, R3 is also hydrogen; when R1 is alkyl, phenyl alkylthio, alkyoxy, alkylthio, cycloalkylthio, cycloalkoxy, phenyl alkoxy dimethyl pyrrolidyl, or hydroxy alkyl amino or said N-(alkyl)-N-(hydroxyalkyl)amino as defined before, R2 and R3 cannot both be halophenyl, C1-C3 alkyl phenyl or C1-C3 alkoxyphenyl; when R1 is hydrazino, methylthio, methoxy or ethoxy, R2 is other than phenyl and R2 and R3 cannot both be alkyl;
when R1 is hydrazino or C1-C4 alkylhydrazino, R2 is other than C1-C4 alkyl;
and the pharmaceutically acceptable salts thereof;
wherein said process comprises: reacting a compound having the general formula wherein R2 and R3 are as defined above, R6 is an alkylthio, substituted alkylthio, cycloalkylthio or halogen, with a compound having the general formula:

wherein R1 is as defined above and B is a base, and when the pharmaceutically acceptable salts are desired, further forming the salts.

2. The process according to claim 1, further comprising converting the compound having the formula:

wherein R1, R2 and R3 are as defined in claim 1, to a compound of the same general formula wherein at least one of the substituents R1, R2 and R3 is different from its respective group in the starting compound.

3 . The process according to claim 1 for preparing a compound having the general formula:
wherein R2 and R3 are as defined in claim 1, R1 is C1-C10 alkoxy, C3-C6 cycloalkoxy, phenyl alkoxy, alloyloxy, halophenoxy, C1-C4 alkyl phenoxy or C1-C4 alkoxy phenoxy; with the provisos that when R1 is alkoxy, cycloalkoxy, phenyl alkoxy as defined above, R2 and R3 cannot both be halophenyl, C1-C3 alkylphenyl or C1-C3 alkoxyphenyl; and when R1 is methoxy or ethoxy, R2 is other than phenyl and R2 and R3 cannot both he methyl;
and the pharmaceutically acceptable salts thereof, wherein said process comprises reacting the compound having the general formula wherein R2, R3 and R6 are as defined in claim 1, with a compound having the general formula:

wherein R1 is as defined above and B is as defined in claim 1, and when the pharmaceutically acceptable salts are desired, further forming the salts.

4 . The process according to claim 3, wherein R6 is methylthio.

5 . The process according to claim 3, wherein R6 is chlorine.

6 . The process according to claim 3, wherein B is sodium or hydrogen.

7 . The process according to claim 1 for preparing a compound having the general formula:
wherein R2 and R3 are as defined in claim 1; R1 is hydrazino, C1-C4 alkylhydrazino, or -NH-NH-?-R4 where R4 is as defined in claim 1, with the provisos that when R1 is hydrazino, R2 is other than phenyl and R2 and R3 cannot both be methyl; and when R1 is hydrazino or C1-C10 alkylhydrazino, R2 is other than C1-C4 alkyl; and pharmaceutically acceptable salts thereof, wherein said process comprises reacting a compound having the general formula wherein R2, R3 and R6 are as defined in claim 1 with a compound having the general formula: B-R1 wherein R1 is as defined above and B is as defined in claim l;
or when a compound of the formula where R2 and R3 are as defined in claim 1; R1 is C1-C4 alkyl hydrazino or -NH-NH-?-R4 where R4 is as defined in claim 1, is desired, said process comprises reacting a compound of the formula:

with a salt of its corresponding C1-C4 alkyl and a base, or its corresponding aldehyde of the formula: R4-CHO wherein R4 is as defined in claim 1; and when the pharmaceutically acceptable salts are desired, further forming the salts.

8 . The process according to claim 7 wherein R6 is methylthio.

9 . The process according to claim 7 wherein R6 is chlorine.

10 . The process according to claim 7 wherein B is hydrogen or sodium.

11 . The process according to claim 8, 9 or 10, wherein the reaction is carried out in the presence of tetrahydro-furan and methanol.

12 . The process according to claim 7, for preparing a carbobenzyloxy N-protected .alpha.-aminoacylhydrazino or .alpha.-amino-acylhydrazino derivative of the hydrazino compound, wherein the process further comprises reacting said hydrazino compound with a corresponding N-carbobenzyloxy amino acid.

13 . The process according to claim 3 wherein R1 is C1-C3 alkoxy or allyloxy, R2 is C3-C6 cycloalkyl, thienyl, furyl, pyridyl, indolyl, phenyl, meta-halophenyl, methoxyphenyl, dimethoxyphenyl or trifluoromethylphenyl; and R3 is hydrogen, C1-C4 alkyl, pyridyl or furyl.

14 . The process according to claim 13 wherein R3 is hydrogen.

15 . The process according to claim 7 wherein R1 is hydrazino, methylhydrazino or haloacetyl hydrazino; R2 is C3-C6 cycloalkyl, thienyl, furyl, pyridyl, indolyl, phenyl, meta-halophenyl, methoxyphenyl, dimethoxyphenyl or trifluoromethyl-phenyl; and R3 is hydrogen, C1-C4 alkyl, pyridyl or furyl.

16 . The process according to claim 15 wherein R3 is hydrogen.

17. A process for preparing 3-methoxy-5-t-butyl-1,2,4-triazine wherein 3-methylthio-5-t-butyl-1,2,4-triazine is reacted with sodium methylate.

18. A process for preparing 3-methoxy-5-t-butyl-1,2,4-triazine wherein 3-chloro-5-t-butyl-1, 2,4-triazine is reacted with sodium methylate.

19. A process for preparing 3-methoxy-5-(3'-trifluoromethyl-phenyl)-1,2,4-triazine wherein 3-methylthio-5-(3'-trifluoromethylphenyl)-1,2,4-triazine is reacted with sodium methylate.

20. A process for preparing 3-methoxy-5-(3'-trifluoromethylphenyl)-1,2,4-triazine wherein 3-chloro-5-(3'-trifluoromethylphenyl)-1,2,4-triazine is reacted with sodium methylate.

21. A process for preparing 3-methoxy-5,6-di(2'-pyridyl)-1,2,4-triazine wherein 3-methylthio-5,6-di(2'-pyridyl)-1,2,4-triazine is reacted with sodium methylate.

22. A process for preparing 3-methoxy-5,6-di(2'-pyridyl)-1,2,4-triazine wherein 3-chloro-5,6-di(2'-pyridyl)-1,2,4-triazine is reacted with sodium methylate.

23, A process for preparing 3-n-propoxy-5-phenyl-1,2,4-triazine wherein 3-methylthio-5-phenyl-1,2,4-triazine is reacted with sodium n-propylate.

24. A process for preparing 3-n propoxy-5-phenyl-1,2,4-triazine wherein 3-chloro-5-phenyl-1, 2,4-triazine is reacted with sodium n-propylate.

25. A process for preparing 3-methoxy-5-cyclopropyl-1,2,4-triazine wherein 3-methylthio-5-cyclopropyl-1,2,4-triazine is reacted with sodium methylate.

26. A process for preparing 3-methoxy-5-cyclopropyl-1,2,4-triazine wherein 3-chloro-5-cyclopropyl-1,2,4-triazine is reacted with sodium methylate.

27. A process for preparing 3-allyloxy-5-phenyl-1,2,4-triazine wherein 3-methylthio-5-phenyl-1,2,4-triazine is reacted with sodium 3-allylate.

28, A process for preparing 3-allyloxy-5-phenyl-1,2,4-triazine wherein 3-chloro-5-phenyl-1, 2,4-triazine is reacted with sodium 3-allylate.

29. A process for preparing 3-allyloxy-5,6-dimethyl-1,2,4-triazine wherein 3-methylthio-5, 6-dimethyl-1,2,4-triazine is reacted with sodium allylate.

30. A process for preparing 3-allyloxy-5,6-dimethyl-1,2,4-triazine wherein 3-chloro-5,6-dimethyl-l,2,4-triazine is reacted with sodium allylate.

31. A process for preparing 3-methoxy-5-(4'-morpholinophenyl)-1,2,4-triazine wherein 3-methylthio-5-(4'-morpholinophenyl)-1,2,4-triazine is reacted with sodium methylate.

32. A process for preparing 3-methoxy-5-t4'-morpholinophenyl)-1,2,4-triazine wherein 3-chloro-5-(4'-morpholinophenyl)-1,2,4-triazine is reacted with sodium methylate.

33. A process for preparing 3-methoxy-5-(3'-chloro-phenyl)-1,2,4-triazine wherein 3-methylthio 5-(3'-chlorophenyl)-1,2,4-triazine is reacted with sodium methylate.

34. A process for preparing 3-methoxy-5-(3'-chloro-phenyl)-1,2,4-triazine wherein 3-chloro-5-(3'-chlorophenyl)-1,2,4-triazine is reacted with sodium methylate.

35. A process for preparing 3-acetylhydrazino-5-phenyl-1,2,4-triazine wherein 3-methylthio-5-phenyl-1,2,4-txiazine is reacted with acetylhydrazine.

36. A process for preparing 3-acetylhydrazino-5-phenyl-1,2,4-triazine wherein 3-chloro-5-phenyl-1,2,4-triazine is reacted with acetylhydrazine.

37. A process for preparing 3-acetylhydrazino-5-phenyl-1,2,4-triazine wherein 3-hydrazino-5-phenyl-1,2,4-triazine is reacted with acetic acid anhydride.

38. A process for preparing 3-propionylhydrazino-5-(4'-chlorophenyl)-1,2,4-triazine wherein 3-methylthio-5-(4'-chlorophenyl)-1,2,4-triazine is reacted with propionylhydrazine.

39. A process for preparing 3-propionylhydrazino-5-(4'-chlorophenyl)-1,2,4-triazine wherein 3-chloro-5-(4'-chloro phenyl)-1,2,4-triazine is reacted with propionylhydrazine.

40. A process for preparing 3-propionylhydrazino-5-(4'-chlorophenyl)-1,2,4-triazine wherein 3-hydrazino-5- (4'-chlorophenyl)-1,2,4-triazine is reacted with propionic acid anhydride.

41. A process for preparing 3-methylhydrazino-5-phenyl-1,2,4-triazine wherein 3-methylthio-5-phenyl-1,2,4-triazine is reacted with methylhydrazine.

42. A process for preparing 3-methylhydrazino-5-phenyl-1,2,4-triazine wherein 3-chloro-5-phenyl-1,2,4-triazine is reacted with methylhydrazine.

43. A process for preparing 3-methylhydrazino-5-phenyl-1,2,4-triazine wherein 3-hydrazino-5-phenyl-1,2,4-triazine is reacted with a methylhalide.

44. A process for preparing 3-acetylhydrazino-5,6-diphenyl-1,2,4-triazine wherein 3-methylthio-5,6-diphenyl-1,2,4-triazine is reacted with acetylhydrazine.

45. A process for preparing 3-acetylhydrazino-5,6-di-phenyl-1,2,4-triazine wherein 3-chloro-5,6-diphenyl-1,2,4-triazine is reacted with acetylhydrazine.

46. A process for preparing 3-acetylhydrazino-5,6-di-phenyl-1,2,4-triazine wherein 3-hydrazino-5,6-diphenyl-1,2,4-triazine is reacted with acetic acid anhydride.

47. A process for preparing 3-methylhydrazino-5,6-bis (4'-chlorophenyl)-1,2,4-triazine wherein 3-methylthio-5,6-bis (4'-chlorophenyl)-1,2,4-triazine is reacted with methylhydrazine.

48. A process for preparing 3-methylhydrazino-5,6-bis(4'-chloropheny1)-1,2,4-triazine wherein 3-chloro-5,6 bis (4'-chlorophenyl)-1,2,4-triazine is reacted with methylhydrazine.

49. A process for preparing 3-methylhydrazino-5,6-bis(4'-chlorophenyl)-1,2,4-triazine wherein 3-hydrazino-5,6-bis(4'-chlorophenyl)-1,2,4-triazine is reacted with a methyl-halide.

50. A process for preparing 3-trifluoroacetylhydrazine-5-phenyl-1,2,4-triazine wherein 3-methylthio-5-phenyl-1,2,4-triazine is reacted with trifluoroacetylhydrazine.

51. A process or preparing 3-trifluoroacetylhydrazino-5-phenyl-1,2,4-triazine wherein 3-chloro-5-phenyl-1 t 2,4-triazine is reacted with trifluoroacetylhydrazine.

52. A process for preparing 3-trifluoroacetylhydrazino-5-phenyl-1,2,4-triazine wherein 3-hydrazino-5-phenyl-1,2,4-triazine is reacted with trif1uoroacetic acid anhydride.

53. A process for preparing 3-hydrazino-5-(3'-tri-fluoromethylphenyl)-1,2,4-triazine wherein 3-methylthio-5-(3'-trifluoromethylphenyl)-1,2,4-triazine is reacted with hydrazine.

54. A process for preparing 3-hydrazino-5-(3'-tri-fluoromethylphenyl)-1,2,4-triazine wherein 3-chloro-5-(3'-tri-fluoromethylphenyl)-1,2,4-triazine is reacted with hydrazine.

55. A compound having the general formula:

wherein R1 is C1-C4 hydroxy alkylamino, N-(C1-C2 alkyl) -N-(hydroxy C1-C4 alkyl) amino, C1-C4 alkyl, C1-C10 alkoxy, C6-C10 aryloxy, C3-C6 cycloalkoxy, phenyl alkoxy, allyloxy, halophenoxy, C1-C4 alkyl phenoxy, C1-C4 alkoxy phenoxy, C1-C10 alkylthio, C3-C6 cyclo-alkylthio, C1-C4 alkyl sulfinyl, C1-C4 alkyl sulfonyl, phenyl C1-C4 alkylthio, dimethylpyrrolidyl, or hydrazino, C1-C4 alkyl hydrazino, -NH-NH-?-R4 where R4 is C1-C8 alkyl, C2-C8 alkenyl, halo (Cl-C8) alkyl, halo (C2-C8) alkenyl, C6-C10 cycloalkyl or R4 represents the group where R5 is H, C1-C4 alkyl or benzyl and R7 is H or carbobenzyloxy;
R2 represents hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, adamantyl, furyl, thienyl, benzofuryl, indolyl, pyridyl, halothienyl, phenyl or phenyl substituted with at least one substituent selected from halo, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, acetamido, benzyloxy, diphenylmethyl, morpholino, methylene dioxy or nitro;
and R3 represents hydrogen, C1-C6 alkyl, pyridyl, furyl, phenyl or phenyl substituted with at least one substituent selected from halo, C1-C6 alkyl, C1-C6 alkoxy, methylene dioxy or acetamido;
subject to the provisos that when R2 is hydrogen, R3 is also hydrogen; when R1 is alkyl, phenyl alkylthio, alkoxy, alkylthio, cycloalkylthio, cycloalkoxy, phenyl alkoxy, dimethylpyrroledyl or hydroxy alkyl amino or said N-(alkyl)-N-(hydroxyalkyl) amino as defined before, R2 and R3 cannot both be halophenyl, C1-C3 alkyl phenyl or C1-C3 alkoxyphenyl; when R1 is hydrazino, methylthio, methoxy or ethoxy, R2 is other than phenyl and R2 and R3 cannot both be methyl; when R1 is hydrazino or C1-C4 alkylhydrazino, R2 is other than C1-C4 alkyl; and the pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 1 or 2, or by an obvious chemical equivalent thereof.

56. A compound having the general formula:

wherein R1 is C1-C10 alkoxy, C3-C6 cycloalkoxy, phenylalkoxy, alloyloxy, halophenoxy, C1-C4 alkyl phenoxy or C1-C4 alkoxy phenoxy; R2 represents hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, adamantyl, furyl, thiehyl, benzofuryl, indolyl, pyridyl, halothienyl, phenyl or phenyl substituted with at least one substituent selected from halo, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, acetamido, benzyloxy, diphenylmethyl, morpholino, methylene dioxy or nitro; and R3 represents hydrogen, C1-C6 alkyl, pyridyl, furyl, phenyl or phenyl substituted with at least one substituent selected from halo, C1-C6 alkyl, C1-C6 alkoxy, methylene dioxy or acetamido; with the provisos that when R1 is alkoxy, cycloalkoxy, phenyl alkoxy as defined above, R2 and R3 cannot both be halophenyl, C1-C3 alkylphenyl or C1-C3 alkoxy-phenyl; and when R1 is methoxy or ethoxy, R2 is other than phenyl and R2 and R3 cannot both be methyl; and pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 3, 4 or 5 or by an obvious chemical equivalent thereof.

57. A compound having the general formula:

wherein R1 is hydrazino, C1-C4 alkylhydrazino, or -NH-NH-?-R4 where R4 is C1-C8 alkyl, C2-C8 alkenyl, halo(C1-C8)alkyl, halo(C2-C8)alkenyl, C6-C10 cycloalkyl or a group of the formula where R5 is H, C1-C4 alkyl or benzyl; R2 represents hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, adamantyl, furyl, thienyl, benzofuryl, indolyl, pyridyl, halothienyl, phenyl or phenyl substituted with at least one substituent selected from halo, C1-C6 alkyl, halo C1-C6 alkyl, C1-C6 alkoxy, acetamido, benzyloxy, diphenylmethyl, morpholino, methylene dioxy or nitro; and R3 represents hydrogen, C1-C6 alkyl, pyridyl, furyl, phenyl or phenyl substituted with at least one substituent selected from halo, C1-C6 alkyl, C1-C6 alkoxy, methylene dioxy or acetamido;
with the provisos that when R1 is hydrazino, R2 is other than phenyl and R2 and R3 cannot both be methyl; and when R1 is hydrazino or C1-C4 alkylhydrazino, R2 is other than C1-C4 alkyl;
and pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 7, 8 or 9 or by an obvious chemical equivalent thereof.

58. A compound having the general formula:

wherein R1 is C1-C3 alkoxy or allyloxy; R2 is C3-C6 cycloalkyl, thienyl, furyl, pyridyl, indolyl, phenyl, meta-halophenyl, methoxyphenyl, dimethoxyphenyl or trifluoromethylphenyl, and R3 is hydrogen, C1-C4 alkyl, pyridyl or furyl; and pharmaceutically acceptable salts thereof whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.

59. A compound having the general formula:

wherein R1 is C1-C3 alkoxy or allyloxy; and R2 is C3-C6 cyclo-alkyl, thienyl, furyl, pyridyl, indolyl, phenyl, meta-halophenyl, methoxyphenyl, dimethylphenyl or trifluoromethylphenyl; and pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.

60. A compound having the general formula:

wherein R1 is hydrazino, methylhydrazino or haloacetylhydrazino;
R2 is C3-C6 cycloalkyl, thienyl, furyl, pyridyl, indolyl, phenyl, meta-halophenyl, methoxyphenyl, dimethoxyphenyl, or trifluoro-methylphenyl; and R3 is hydrogen, C1-C4 alkyl, pyridyl or furyl;
and pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 15 or by an obvious chemical equivalent thereof.

61. A compound having the general formula:

wherein R1 is hydrazino, methylhydrazino or haloacetylhydrazino;
and R2 is C3-C6 cycloalkyl, thienyl, furyl, pyridyl, indolyl, phenyl, meta-halophenyl, methoxyphenyl, dimethoxyphenyl or trifluoromethylphenyl; and pharmaceutically acceptable salts thereof, whenever prepared by the process of claim 16 or by an obvious chemical equivalent thereof.

62. 3-Methoxy-5-t-butyl-1,2,4-triazine whenever prepared by the process of claim 17 or 18, or by an obvious chemical equivalent thereof.

63. 3-Methoxy-5-(3'-trifluorsmethylphenyl)-1,2,4-triazine whenever prepared by the process of claim 19 or 20 or by an obvious chemical equivalent thereof.

64. 3-Methoxy-5,6-(2'-dipyridyl)-1,2,4-triazine whenever prepared by the process of claim 21 or 22 or by an obvious chemical equivalent thereof.

65. 3-n-propoxy-5-phenyl-l,2,4-triazine whenever prepared by the process of claim 23 or 24 or by an obvious chemical equivalent thereof.

66. 3-Methoxy-5-cyclopropyl-1,2,4-triazine whenever prepared by the process of claim 25 or 26 or by an obvious chemical equivalent thereof.

67. 3-Allyloxy-5-phenyl-1,2,4-triazine whenever prepared by the process of claim 27 or 28 or by an obvious chemical equivalent thereof.

68. 3-Allyloxy-5,6-dimethyl-1,2,4-triazine whenever prepared by the process of claim 29 or 30 or by an obvious chemical equivalent thereof.

69. 3-Methoxy-5-(4'-morpholinophenyl)-1,2,4-triazine whenever prepared by the process of claim 31 or 32 or by an obvious chemical equivalent thereof.

70. 3-Methoxy-5-(3'-chlorophenyl)-1,2,4-triazine whenever prepared by the process of claim 33 or 34 or by an obvious chemical equivalent thereof.

71. 3-Acetylhydrazino-5-phenyl-1,2,4-triazine whenever prepared by the process of claim 35 , 36 or 37 or by an obvious chemical equivalent thereof.

72. 3-Propionyl-hydrazino 5-(4'-chlorophenyl)-1,2,4-triazine whenever prepared by the process of claim 38, 39 or 40 or by an obvious chemical equivalent thereof.

73. 3-Methylhydrazino-5-phenyl-1,2,4-triazine whenever prepared by the process of claim 41 , 42 or 43 or by an obvious chemical equivalent thereof.

74. 3-Acetylhydrazino-5,6-diphenyl-1,2,4-triazine whenever prepared by the process of claim 44 , 45 or 46 or by an obvious chemical equivalent thereof.

75. 3-Methylhydrazino-5, 6-bis (4'-chlorophenyl)-1,2,4-triazine whenever prepared by the process of claim 47, 48 or 49 or by an obvious chemical equivalent thereof.

76. 3-Trifluoroacetylhydrazino-5-phenyl-1,2,4-triazine whenever prepared by the process of claim 50 , 51 or 52 or by an obvious chemical equivalent thereof.

77. 3-Hydrazino-5-(3'-trifluoromethylphenyl)-1,2,4-triazine whenever prepared by the process of claim 53 or 54 or by an obvious chemical equivalent thereof.