GB1604083A - Substituted 1,2,4-triazines - Google Patents

Abstract

The new substituted triazines of formula I, whose symbols are defined in Claim 1, have pharmacological properties such as antiinflammatory, analgesic, antipyretic and hypotensive effects and act on the central nervous system. <IMAGE>

Description

(54) IMPROVEMENTS IN OR RELATING TO SUBSTITUTED 1,2,4-TRIAZINES (71) We, DIAMOND SHAMROCK CORPORATION, of 1100 Superior Avenue, Cleveland, Ohio 44114, United States of America, a corporation organised and existing under the laws of the State of Delaware, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates generally to 1,2,4-triazine compounds and, more particularly, to certain substituted triazines evidencing anti-inflammatory, analgesic, anti-pyretic, hypotensive and central nervous system activity in warmblooded animals.

Substituted 1,2,4-triazine compounds having various substituents thereon have previously been prepared and suggested for use in different ultimate applications.

For example, Buu-hoi et al found that 3 - mercapto - 5,6 - dimethyl - 1,2,4 triazine is tuberculostatic in vitro (J. Chem. Soc., 1956, 713-16). Likewise, 3 amino - 6 - alkyl(or 5 - nitrofurylethenyl) - 1,2,4 - triazines have been suggested as having antibacterial and antiviral activity (Cf. Chemical Abstracts, Vol. 60, 9278 g and Vol. 62, 9155d). Japanese 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 of as-triazine compounds, U.S.

Patent No. 3,948,894 discloses 3 - amino - 5,6 - diaryl - 1,2,4 - triazine compounds and, more specifically, 3- alkylamino, hydroxy-alkylamino, piperazino, piperidino, morpholino or pyrrolidino - 5,6 sdisubstituted phenyl, i.e., alkoxy, fluoro, dimethylamino or methylsulphinylphenyl triazine compounds and the treatment of inflammation, swelling, fever and ossification in warm-blooded animals therewith. The foregoing compounds are indicated to be active upon oral or parenteral administration, whereas Belgian Patent No. 839,469 discloses 3 unsubstituted and 3 - C1-C8 - alkyl, C7-C8 - aralkyl, C3-C8 - cycloalkyl, C4- C8 - (cycloalkyl)alkyl or the corresponding ethers or thioethers, and halogen, C1- C3 - alkyl - , C1-C3 - alkoxy - or di(C1-C3 - alkyl) - amine - 5,6 - substituted phenyl - 1,2,4 - triazines as anti - inflammatory agents, which are topically active.

U.S. Patent No. 3,989,831 also discloses 3 - chloro - 5,6 - diaryl - 1,2,4 - triazines as topically active anti - inflammatory compounds. U.S. Patent No. 3,644,358 describes a series of 3- and 6 - alkòxyearbonyl or carbamoyl substituted 1,2,4triazines having anti-inflammatory activity.

In Japanese Patent No. 74-27874 (July, 1974), the patentees describe 3 amino, methylamino or 4 - methyl - 1 - piperazinyl - 5 - (4' - pyridyl) - 1,2,4 triazines as having anti - inflammatory activity.

Other asymmetrical triazines have been suggested as having antihypertensive activity. For example, U.S. Patent No. 3,007,927 discloses 3,5 - dihydrazino or 3,5 -- dihydrazino - 6 - lower - alkyl - 1,2,4 - triazines as exhibiting a strong vasodilatory effect. Similarly, 3 - hydrazino - 5 - phenyl - 1,2,4 - triazine is indicated to be a moderately active antihypertensive agent. See Burger, Medicinal Chemistry, 3rd Ed., 1027, (Wiley Interscience, 1970).

With respect to central nervous system activity, Trepanier et al, J. Med. Chem.

9, 881-885 (1966) disclose certain subtituted 1,4,5,6 - tetrahydro - 1,2,4 triazines as having anticonvulsant activity.

In addition to the foregoing, 3 - methylthio - 5 - phenyl -, 3 - methylthio 5,6 - dimethyl -, 3 - methoxy - 5,6 - 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 3 - ethoxy - 5 - phenyl 1,2,4 - triazine (Tetrahedron, 1, 103 (1957). 3 - Hydroxy - 5,6 - diphenyl - 1,2,4 triazine is described in Thiele, Ann. Chem., 302, 299, 1890. No biological or other utility for these compounds is mentioned in the foregoing literature publications.

It has now been discovered that a large class of substituted 1,2,4 - triazine compound, many of which are new, evidence unexpectedly superior pharmacological activity or different properties compared to previously proposed triazine compounds in warm-blooded animals.

In accordance with one aspect of the present invention, substituted 1,2,4 triazines are provided, each being a compound of the formula:

wherein: R, represents a hydrazino, N' - (C1-C4 - alkyl) - hydrazino or

group, where R4 is a C1-C8 - alkyl, C2-C8 - alkenyl, halo - (C1-C8 alkyl), halo - (C2C8 - alkenyl), C6-C10 - cycloalkyl or

group, R5 being a hydrogen atom or a C1-C4 -alkyl or benzyl group and Z being a hydrogen atom or a benzyloxy - carbonyl group, or R1 represents a hydroxy - (C1-C4 - alkyl) - amino, N - (C1-C2 - alkyl) N - (hydroxy - C1-C4 - alkyl) - amino, C1-C10 - alkoxy, C6-C10 aryloxy, C3-C6 - cycloalkoxy, phenylalkoxy, allyloxy, halophenoxy, C1 c4 - alkylphenoxy, C1-C4 - alkoxyphenoxy, C1-C10 - alkylthio, C3 C6 - cycloalkylthio, C1-C4 - alkylsulphinyl, C1-C4 - alkylsulphonyl, phenyl - (C1-C4 - alkyl) - thio, cis - dimethylpyrrolidyl or pyridyl group; R2 represents a hydrogen atom or a C1-C4 - alkyl, C3-C6 - cycloalkyl, adamantly, furylm thienyl, benzofuryl, indolyl, pyridyl, halothienyl, or phenyl group or a phenyl group substituted with at least one substituent selected from halogen, C1-C6 - alkyl, halo - (C1-C6 - alkyl), C1-C6 alkoxy, acetamido, benzyloxy, diphenylmethyl, morpholino, methylenedioxy and nitro substituents; and R3 represents a hydrogen atom or a C1-C6 - alkyl, pyridyl, furyl or phenyl group or a phenyl group substituted with at least one substituent selected from halogen, C1-C6 - alkyl, C1-C6 - alkoxy, methylenedioxy and acetamido substituents; subject to the provisos that; (i) when R2 is a hydrogen atom, R3 is also a hydrogen atom; (ii) when R1 is a phenylalkylthio, alkoxy, alkylthio, cycloalkylthio, cycloalkoxy or phenylalkoxy group, R2 and R3 are not selected from halophenyl, C1-C3 alkylphenyl or C1-C3 - alkoxyphenyl groups; (iii) when R1 is a dimethylpyrrolidyl, hydroxyalkylamino or N - (C1C2 alkyl) - N - (hydroxy - C1-C4 - alkyl) - amino group, R2 and R3 are not both halophenyl, both C1-C3 - alkylphenyl or both C1-C3 - alkoxyphenyl groups; (iv) when R1 is a hydrazino, alkylthio, methoxy or ethoxy group, R2 is other than a phenyl group and R2 and R3 are not both methyl groups; (v) when R1 is a hydrazino or N' - (C1-C4 - alkyl) - hydrazino group, R2 is other than a C1-C4 - alkyl group; and (vi) when Rl is an alkoxy group, R2 is other than a pyridyl group; and the pharmaceutically-acceptable salts thereof.

It has been discovered that these compounds and other related compounds known per se within the general class of substituted 1,2,4-triazines are useful antiinflammatory, analgesic, anti-pyretic, hypotensive and psychotropic agents.

The substituted asymmetric triazine compounds of the present invention may be prepared by several alternative methods previously employed in the synthesis of 1,2,4 - triazines or modifications thereof to obtain the R1, R2 or R3 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 by 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 reaction of thiosemicarbazide and methyl iodide, with an arylglyoxal affords the 3 methylthio - 5 - aryl - 1,2,4 - triazine. The 3 - methylthio - 5 - aryl - substituted triazine may then be used as an intermediate in the preparation of the 3 - 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:

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 semicarbazide, 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 to afford the 3 - hydrazino - or 3 - methoxy - 5,6 - disubstituted - 1,2,4 - triazine compounds, as shown in the following reaction scheme.

It is noted that the alpha-diketone starting material may be directly converted to the 3 - methylthio - 5,6 - disubstituted - 1,2,4 - triazine by cyclization with S methylthiosemicarbazide hydrogen iodide.

Reaction of the appropriate hydrazino triazine with the appropriate anhydride, acyl chloride or carbobenzyloxy (CBZ) amino acid affords the corresponding acyl hydrazine triazines or a - CBZ - amino acyl hydrazino triazines. Treatment of the CBZ amino acyl hydrazino triazines with concentrated HBr/acetic acid affords the free amino acid HBr salt.

Other substituents at the 3-position corresponding to R, as set forth hereinabove are readily obtained by formation of the corresponding 3 - chloro 5,6 - disubstituted - 1,2,4 - triazine. Facile substitution of the 3 - chloro starting material is carried out with a variety of amines, alcohols, phenols and thiols, to yield the corresponding 3 - amino, alkoxy, phenoxy and alkylthio 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, for instance, to 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, sulphuric, tartaric and citric. The expression "pharmaceutically acceptable" as used herein is intended to include those salts capable of being formed with the basic triazine compounds of the 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 a-amino acyl group, may be obtained as their hydrate salt form, such as mono- or di-hydrobromide or hydrochloride hydrate and such compounds constitute particularly advantageous water-soluble derivatives of the invention.

The synthesis methods described herein, in certain instances, result in the preparation of mixtures of triazine isomers, e.g., 5,6-position isomers which can be separated by employing conventional crystallization or chromatographic techniques.

As previously indicated, the compounds of the present invention possess antiinflammatory, anti-pyretic, analgesic, antihypertensive and central nervous system (e.g., hypnotic, sedative, antidepressant. muscle relaxant, spasmolytic and tranquilizing) effects. Of course, it will be appreciated that the specific 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, preferred compounds for use in anti-inflammatory compositions and methods according to a preferred aspect of the present invention, are compounds of formula I wherein: R, represents a hydrazino, N' - (C1-C4 - alkyl) - hydrazino or

group, where R4 is a C1-C8 - alkyl, halo - (C1-C8 - alkyl) or

group, R5 being a C1-C4 - alkyl group; or R1 represents a hydroxy - (C1-C4 - alkyl) - amino, N - (C1-C2 - alkyl) N - (hydroxy - C1-C4 - alkyl) - amino, C1-C10 - alkoxy, halophenoxy, C1-C4 - alkylphenoxy, C1-C4 - alkoxyphenoxy, C1-C10 - alkylthio or phenyl - (C1-C4 - alkyl) - thio group; R2 represents a hydrogen atom or a C1-C4 - alkyl, C3-C6 - cycloalkyl, adamantyl, furyl, thienyl, benzofuryl, indolyl, pyridyl or phenyl group or a phenyl group substituted with at least one substituent selected from haligen, C1-C4 - alkyl, halo - (C1-C6 - alkyl), C1-C6 - alkoxy, acetamido, morpholino and nitro substituents; and R3 represents a hydrogen atom or C1-C6 - alkyl, phenyl or pyridinyl group or a phenyl group substituted with at least one substituent selected from halogen, C1-C4 - alkyl, C1-C6 - alkoxy and acetamido substituents; subject to the provisos (i) to (v) inclusive as contained in the first definition of the formula given above; or at least one pharmaceutically-acceptable acid addition salt of a compound of the formula; and a pharmaceutical carrier.

The preferred anti - inflammatory compositions are preferably used in the form of pharmaceutical preparations in dosage unit form, comprising per dosage unit from 1 to 300 milligrams of at least one such compound, together with a pharmaceutical carrier. Such preparations are preferably formulated for oral administration. Particularly preferred compounds are those of Formula I as just defined wherein R1 is hydrazino, N' - methylhydrazino, N' - propionylhydrazino, N' - &alpha; - aminoacetylhydrazino, N' - trifluoroacetylhydrazino, hydroxy(C2-C4 alkyl) - amino, C1-C4 - alkoxy, C1-C4 - alkylthio or benzylthio; R2 is C1-C4 alkyl, phenyl, furyl, thienyl, pyridyl, indolyl, adamantyl, C3-C6 - cycloalkyl or phenyl substituted with at least one substituent selected from halogen (preferably para-chloro, bromo or fluoro), halo - (C1-C2 - alkyl) (preferably meta trifluoromethyl), C1-C4 - alkoxy (preferably 3',4' - dimethoxy) and R3 is hydrogen; or wherein R2 and R3 are the same and each represents C,C4 - alkyl (preferably methyl or ethyl), phenyl or pyridyl, provided R, is selected from hydrazino, C1-C4 - alkoxy (preferably methoxy), allyloxy, C1-C4 - alkylthio or benzylthio. As specifically preferred compounds of Formula I, there may be mentioned 3 - (N' - methyl - hydrazino) - 5 - phenyl - 1,2,4 - triazine, 3 methoxy - (or methylthio) - t - butyl - 1,2,4 - triezine, 3 - methylthio - 5 - (2' furyl) - (or 2' - thienyl) - 1,2,4 - triazine, 3 - (N' - trifluoroacetylhydrazino) - 5 phenyl - 1,2,4 - triazine, 3 - methoxy - 5 - (3' - trifluoromethylphenyl) - 1,2,4 triazine, 3 - methylthio - 5 - (3' - trifluoromethyl - phenyl) - 1,2,4 - triazine, 3 methoxy - 5 - (2' - furyl) - 1,2,4 - triazine, 3 - propoxy - 5 - phenyl - 1,2,4 triazine, 3 - methylthio - 5 - cyclopropyl - 1,2,4 - triazine, 3 - methoxy - 5 cyclopropyl - 1,2,4 - triazine, 3 - allyloxy - 5 - phenyl - 1,2,4 - triazine, 3 benzylthio - 5,6 - dimethyl - 1,2,4 - triazine and 3 - methylthio - 5 - (3' indolyl) - 1,2,4 - triazine.

Representative of preferred compounds of Formula I for use in the analgesic compositions and methods of the present invention are those wherein R, represents hydrazine, N' - (C1-C4 - alkyl) - hydrazino, N' - (trifluoroacetyl - hydrazino, C1-C4 - alkoxy or C1-C4 - alkylthio and R2 represents a C1-C4 - alkyl (preferably ethyl or t - butyl), thienyl or phenyl group or a phenyl group substituted with at least one substituent selected from halogen (preferably-meta-chloro), halo (C1-C4 - alkyl) (preferably meta-halomethyl) or C1-C4 - alkoxy (preferably paramethoxy) when R3 is a hydrogen atom; or compounds wherein R1 is as defined before and R2 and R3 are the same and each represents a C1-C4 - alkyl or a butoxy phenyl group; subject to the above-mentioned provisos (iii) and (iv). Based upon currently definable dose-response relationships, especially preferred compounds falling within the aforesaid general Formula I are 3 - hydrazino - (meta trifluoromethylphenyl) - 1,2,4 - triazine, 3 - methoxy - 5 - t - butyl - 1,2,4 triazine, 3 - methylthio - 5 - (2' - thienyl) - 1,2,4 - triazine, 3 - (N' methylhydrazino) - 5 - - phenyl - 1,2,4 - triazine, 3 - (N' trifluoroacetylhydrazino) - 5 phenyl - 1,2,4 - triazene, 3 - methoxy - (or methylthio) - 5 - (3' - trifluoromethylphenyl) - 1,2,4 - triazine and 3 - methoxy 5 - (3' - chlorophenyl) - 1,2,4 - triazine. Inclusive of preferred compounds for use in the hypotensive compositions and methods of the present invention are compounds of Formula I, wherein R, represents a hydrazino, N'-(C1-C4 - alkyl) hydrazino or

group, where R4 is a C1-C8 - alkyl, C2-C8 - alkenyl, halo - (C1-C8 - alkyl), halo - (C2-C8 - alkenyl), C6-C10 - cycloalkyl or

where R5 is a hydrogen atom or a C1-C4 - alkyl or benzyl group and Z is a hydrogen atom or a benzyloxycarbonyl group or R1 represents a hydroxy - (C1 C4 - alkyl) - amino, C1-C4 - alkoxy or C1-C4 - alkylthio group; R2 represents a furyl, benzofurl or phenyl group or a phenyl group substituted with at least one substituent selected from halogen (preferably meta or para - chloro), halo - (C1 C2 - alkyl), C1-C4 - alkoxy (preferably para - methoxy), methylenedioxy and morpholino substituents, when R3 represents a hydrogen atom; or wherein R1 represents a hydrazino, (C1-C4 - alkyl) - hydrazino, N' - (acetyl) - hydrazino or C1-C4 - alkoxy group and R2 and R3 are the same and each represents a furyl, phenyl, methylenedioxyphenyl or morpholino - phenyl group; subject to the proviso that when R1, is a hydrazino, alkylthio, methoxy or ethoxy group, R2 is other than a phensI group. As specifically preferred compounds of the foregoing description, there may be mentioned 3 - (N' - methylhydrazino) - 5 - phenyl - (or 5,6 - diphenyl) - 1,2,4 - triazine, 3 - (N' - methylhydrazino) - 5,6 - bis(4' chlorophenyl) - 1,2,4 - triazine, 3 - (N' - trifluoroacetylhydrazino) - 5 - phenyl 1,2,4 - triazine, 3(N' - acetylhydrazino) - 5,6 - diphenyl - 1,2,4 - triazine, 3 hydrazino - 5 - (3' - trifluoromethylphenyl) - 1,2,4 - triazine and 3 - methoxy 5 - (4' - methoxyphenyl) - 1,2,4 - tnazine.

Additionally, certain of the compounds in accordance with the present invention evidence sychotropic effects, i.e., preferential central nervous system activity including, for example, anti-depressant, muscle relaxant, hypnotic and sedative 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 R1 represents a hydrazino, N' - (C1C2 - alkyl) - N - (hydroxy - C1C4 - alkyl) - amino, C1- C4 - alkoxy, allyloxy or C1-C4 - alkylthio group and R2 represents a C1-C4 alkyl, phenyl or halo - (C1-C4 - alkyl) - phenyl group (preferably trifluoromethyl) when R3 is a hydrogen atom; or wherein R1 is a methoxy, allyloxy, hydrazino or methylthio group and R3 and R3 are the same and each represents a C1-C4 - alkyl, phenyl, furyl or pyridyl group, subject to the provisos that; (a) when R, is a hydrazino, alkylthio, methoxy or ethoxy group, R2 is other than a phenyl group and R2 and R3 are not both methyl group; (b) when R1 is a hydrazino group, R2 is other than a C1-C4 - alkyl group; and (c) when R1 is an alkoxy group, R2 is other than a pyridyl group.

In accordance with the present invention, the active compounds of the invention may be administered alone or in combination with each other or they may be 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 example, for oral administration in the form of tablets or capsules, the active compound or compounds of the invention may be combined with conventional excipients, such as starch, lactose, sucrose, cellulose, talc, magnesium stearate, acacia and stearic acid. Likewise, appropriate elixirs or suspensions may be formulated with preselected active compounds of the present invention in combination with suitable non-toxic solvents, flavourings, colouring agents, suspending agents and emulsifiers. Similarly, injectable dosage unit forms may be made up for intravenous, intramuscular or subcutaneous administration and, for such parenteral administration, suitable sterile aqueous or nonaqueous solutions or suspensions, optionally containing appropriate solutes to provide isotonicity, may be employed. Other adjuvants and dosage forms will be apparent to those skilled in the art.

Compounds of the invention or compositions containing such compounds 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 effect etc., generally range from I to 300 mg/kglday in laboratory mice based upon body weight, and preferably, from 25 to 200 mg/kg/day. The foregoing dosages are normally administered in three or four divided doses depending upon the desired dosage regimen. Of course, the actual effective dosage to be aministered will vary depending upon the specific compound involved as well as the age, weight and responsiveness of the particular animal species under consideration.

The compounds of the invention exhibit relatively low toxicities and the LD,,, (lethal dose to 50 percent of mice treated intraperitoneally) generally is greater than 300 mg/kg.

The following non-limiting Examples are afforded in order that those skilled in the art may more readily understand the present invention and specific preferred embodiments thereof with respect to the preparation of starting materials, intermediates and compounds in accordance with the foregoing description.

Reference is also made to Applications Nos. 8033940 and 8033941 (Serial Nos.

1604084 and 1604085), covering matter divided from this application and concerned with closely-related pharmaceutical preparations and compositions containing various known substituted 1,2,4-triazine compounds.

EXAMPLE 1 Preparation of 3-(N'-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 methylhydrazino and 100 ml of tetrahydrofuran was placed into a 500 ml flask equipped 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 of the 3 - methylthio - 5 - phenyl - 1,2,4 - triazine starting material.

After heating for 2 more hours, the reaction mixture was poured into 300 ml. of ice water. The yellow solid which formed was filtered off, washed with water and air dried. Following recrystallization from 300 ml of heptane, 1.8 g (36% yield) of the title compound was obtained, m.p. 112"--113"C.

Analysis: calculated for C,oH1,Ns (percent): C, 59.68; H, 5.51;N, 34.81. Found (percent): C, 59.61; H, 5.55; N, 34.86.

EXAMPLE 2 Preparation of 3-(N'-Methylhydrazino)-5,6-bis(4'-Chlorophenyl)-1,2,4-Triazine Into a 500 ml. round bottom flask was placed 3-methylthio-5,6-di(4' chlorophenyl)-l,2,4-triazine (10.0 g., 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 then ether resulting in orange-yellow crystals of 3- (N' methylhydrazino)- 5,6 - bis(4' - chlorophenyl) - 1,2,4 - triazine, m.p. 147C 1480C.

Analysis: calculated for C,eH,3N5CI2 (percent): C, 55.50; H, 3.78; N, 20.23.

Found (percent): C, 55.1; H, 3.6; N, 20.2.

EXAMPLE 3 Preparation of 3-(N'-Acetylhydrazino)-5,6-Diphenyl-1,2,4-Triazine Into a 250 ml. round bottom flask was placed 3 - hydrazino - 5,6 - diphenyl 1,2,4 - triazine (10.0 g., 0.04 m.) dissolved in warm dioxane (150 ml.). To this stirring solution was added acetic anhydride (10 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 slurried with ether to afford the white solid 3 - (N' - acetylhydrazino) - 5,6 - diphenyl - 1,2,4 - triazine, m.p. 1660-l680C.

Analysis: calculated for C,7H,5NSO (percent): C, 66.87; H, 4.95; N, 22.94.

Found (percent): C, 66.4; H, 4.8; N, 22.7.

EXAMPLE 4 Preparation of 3-Methylthio-5-t-B utyl- 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 g, 0.8 m), and 400 ml. of ethanol which were heated to 500 C. A mixture 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 aistillation. There was obtained 84.8 g (60.0 O yield) of 3 - methylthio - 5 - t - butyl - 1,2,4 - triazine, m.p. 91-930C at 0.1 mm.

Hg.

Analysis: calculated for C"H,3N3S (percent): C, 52.42; H, 7.15; N, 22.93. Found (percent): C, 51.57; H, 7.07; N, 22.69.

EXAMPLE 5 Preparation of 3-Methylthio-5(2'-ThienylY 1, 2,4-Triazine Into a 1000 ml. flask equipped as before were placed crude 2 - thienylglyoxal (126 g, 0.9 m), 400 ml. of ethanol, S - methylthiosemicarbazide 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 was extracted with 3 liters of hexane. There was obtained 10.3 g (5.5% yield of 3 methylthio - 5 - (2' - thienyl) - 1,2,4 - triazine, m.p. 1050--1060C.

Analysis: calculated for C8H7N3S2 (percent): C, 45.91; H, 3.37; N, 20.08. Found (percent): C, 45.54; H, 3.39; N, 20.05.

EXAMPLE 6 Preparation of 3-(N'-Trifluoroacetylhydrazino)-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 litre of chloroform was added in portions 70 ml. of trifluoroacetic anhydride at 250C to 300C controlled by an ice water bath. When the addition was complete, the mixture was heated at 500C 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 60.0 grams (56 ) of 3 - (N' - trifluoroacetylhydrazino) - 5 - phenyl - 1,2,4 - triazine as a tan solid, m.p. 193"--194"C.

Analysis: calculated for Cr1H8F3N5O (percent): C, 46.65; H, 2.85; N, 24.73.

Found (percent): C, 46.72; H, 2.76; N, 25.09.

EXAMPLE 7 Pre hexane and there was obtained 20.0 g (11.5% yield) of 3 - methylthio - 5 - (2 furyl) - 1,2,4 - triazine, m.p. 880-900C.

Analysis: calculated for C8H7N3OS (percent): C, 49.72; H, 3.65; N, 21.75.

Found (percent): C, 49.40; H, 3.69; N, 21.87.

EXAMPLE 9 Preparation of 3-Allyloxy-5,6-Dimethyl-1,2,4-Triazine Into a 250 ml. flask equipped as previously described were placed 125 ml. of allyl alcohol and sodium (1.8 g, 0.08 g.atm.). After completion of the sodium 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 distillation. There was obtained 8.5 g (73.5% yield) of 3 - allyloxy - 5,6 dimethyl - 1,2,4 - triazine, b.p. 840--860C at 0.08 mm Hg.

Analysis: calculated for C8H,1N3O (percent): C, 58.16; H, 6.71; N, 25.44.

Found (percent): C, 57.05; H, 6.73; N, 25.64.

EXAMPLE 10 Preparation of 3-Methyithio-5,6-(2'-Pyridyl)-l ,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 of 2,2' - pyridyl (21 g, 0.1 m) and sodium bicarbonate (9 g, 0.11 m) in 50 /O 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 was diluted with about 200 ml. of water and repeatedly extracted with chloroform. The chloroform extracts were dried over anhydrous magnesium sulfate and concentrated to give a yellow solid which was recrystallized from hexane to yield 3 - methylthio - 5,6 - (2' - pyridyl) - 1,2,4 - triazine (85%), m.p. 122"--123"C.

Analysis: calculated for C,4Ht1N5S (percent): C, 59.79; H, 3.91; N, 24.91.

Found (percent): C, 59.57; H, 3,90; N, 25.35.

EXAMPLE 11 Preparation of 3-Methylthio-5-(3'-Indolyl)- 1 ,2,4-Triazine Into a suitably equipped 1000 ml. flask were placed a solution of 3' indollglyoxal(27.0 g, 0.15 m) dissolved in 200 ml of ethanol and sodium bicarionate (13.2 g, 0.157 m) dissolved in 50 ml. of water to which was added a solution of S - methylthiosemicarbazide hydrogen iodide (36.5 g, 0.157 m) dissolved in 50 ml. of water. The 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. 2320--234"C.

Analysis: calculated for Cl2HloN4S (percent): C, 59.48; H, 4.16, N, 23.12.

Found (percent): C, 59.23: H, 4.17; N, 23.49.

EXAMPLE 12 Preparation of 3-Methylthio-5,6-bis(4'-Acetamidophenyl)-1,2,4-Triazine Into a 100 ml flask was placed p - acetamidobenzil (lOg, 0.0285 m) dissolved in dimethylformamide (50 ml) and to this solution was added an aqueous solution of NaHCO3 (1.0 g) and S - methylthiosemicarbazide hydrogen iodide (7 g, D.03 m).

The mixture was stirred at room temperature for 15 hours, then heated on a steam bath for 1 hour, cooled and the precipitate which formed was collected and washed with H2O, acetone, dried under reduced pressure to give 3 - methylthio - 5,6 bis(4' - acetamidophenyl) - 1,2,4 - triazine (70% yield), m.p. 300"C.

Analysis: calculated for C20H18N5O2S (percent): C, 61.07; H, 4.83; N, 17.27.

Found (percent): C, 60.69; H, 4.95; N, 17.76.

EXAMPLE 13 Preparation of 3-Methylthio-5-(3'-Chlorophenyl)- 1 ,2,4-Triazine In a suitably equipped 500 ml. 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 600C and 3' - chloroacetophenone (46.4 g, 0.3 m) was added in one portion. The contents were heated at reflux for 2 hours, cooled and filtered. The solvents were removed under vacuum. The resulting 2 - (3' - chlorophenyl) glyoxal was dissolved in 100 ml. of ethanol and additional selenium was filtered off.

Into a second 500 ml. flask were placed the crude 2 - (3' - chlorophenyl) glyoxal (50.6 g, 0.3 m) thus obtained in 100 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 1 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 -81 C.

Analysis: calculated for CroH8CtN3S (percent): C, 50.52; H, 3.39; N, 17.68.

Found (percent): C, 50.70; H, 3.32; N, 17.64.

EXAMPLE 14 Preparation of 3-Methylthio-5,6-bis(3',4'-Methylenedioxyphenyl) 1,2,3-Triazine Into a 100 ml. round-bottomed flask was placed 3,4 - methylenedioxy benzil (5 g, 0.016 m) dissolved in ethanoldimethylformamide. To this solution was added S methylthiosemicarbazide hydrogen iodide (4.0 g, 0.18 m) and sodium bicarbonate (2.0 g, 0.2 m). After gas evolution had ceased, the mixture was refluxed with stirring for 4 hours. Upon cooling, 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' - methylenedioxyphenyl) - 1,2,4 - triazine (80% yield), m.p. 207 -209 C.

Analysis: calculated for C,6H,3N304S (percent): C, 58.86; H, 3.54; N, 11.44.

Found (percent): C, 58.80; H, 3.57; N, 11.31.

EXAMPLES 1584 The following compounds were prepared using the foregoing synthesis procedures with appropriate selection of the substituted glyoxal reactant for condensation with S - methylthiosemicarbazide hydrogen iodide and conversion of the resulting 3 - methylthio - 1,2,4 - triazine 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 15-3 - methoxy - 5 - methyl - 1,2,4 - triazine, m.p. 87 -89 C.

Example 16-3 - methoxy - 5 - t - butyl - 1,2,4 - triazine, m.p. 45 -46 C.

Example 17-3 - methylthio - 5 - (3' - trifluoromethylphenyl) - 1,2,4 triazine, m.p. 123 -125 C.

Example 18-3 - methoxy - 5 - (2' - furyl) - 1,2,4 - triazine, m.p. 96 -97 C.

Example 19-3 - isopropoxy - 5,6 - dimethyl - 1,2,4 - triazine, b.p. 75 78 C at 0.5 mm Hg.

Example 20-3 - methylthio - 5 - (3',4' - dimethoxyphenyl) - 1,2,4 - triazine, m.p. 148 -151 C.

Example 21-3 - ss - hydroxyethylamino - 5 - pheyl - 1,2,4 - triazine, m.p.

152 -153 C.

Example 22-3 - n - propoxy - 5 - phenyl - 1,2,4 - triazine, m.p. 44 -45 C.

Example 23-3 - methylthio - 5 - (1' - adamantyl) - 1,2,4 - triazine, m.p.

140 -141 C.

Example 24-3 - methylthio - 5 - )2 - benzofuryl) - 1,2,4 - triazine, m.p.

134 -135 C.

Example 25-3 - methoxy - 5 - (1' - adamantly) - 1,2,4 - triazine, m.p.

101 -102 C.

Example 26-3 - methylthio - 5 - cyclopropyl - 1,2,4 - triazine - triazine, m.p. 44 460C.

Example 27-3 - methylthio- 5 - (2',4',6' - trimethylphenyl)- 1,2,4triazine, m.p. 97 -98 C.

Example 28-3 - methylthio - 5 - (4' - morpholinophenyl) - 1,2,4 - triazine, m.p. 127 -128 C.

Example 29-3 - methoxy - 5 - cyclopropyl - 1,2,4 - triazine, b.p. 119 121 C at 1.8-2.1 mm Hg.

Example 30-3 - methylthio - 5 - (2',4' - difluorophenyl) - 1,2,4 - triazine, m.p. 79 -80 C.

Example 31-3 - methylthio - 5 - (4' - bromophenyl) - 1,2,4 - triazine, m.p.

153 -154 C.

Example 32-2 - methylthio - 5 - (4' - methoxyphenyl) - 1,2,4 - triazine, m.p. 118 -119 C.

Example 33-3 - methoxy - 5 - (4' - bromophenyl) - 1,2,4 - triazine, m.p.

108 -109 C.

Example 33 - methoxy - 5 - (4' - methoxyphenyl) - 1,2,4 - triazine, m.p.

106 -107 C.

Example 35-3 - allyloxy - 5 - phenyl - 1,2,4 - triazine, b.p. 155 C at 0.3 mm Hg.

Example 36-3 - (N - methyl - N - (p - hydroxyethyl)amino) - 5,6 - bis (4' - methoxyphenyl) - 1,2,4 - triazine, m.p. 108 -110 C.

Example 37-3 - methoxy - 5 - (3',4' - dimethoxyphenyl) - 1,2,4 - triazine, m.p. 167 -169 C.

Example 38-3 - (cis - 2',5' - dimethylpyrrolidinyl) - 5,6 - diphenyl - 1,2,4 triazine, m.p. 131 -134 C.

Example 39-3 - phenoxy - 5,6 - diphenyl - 1,2,4 - triazine, m.p. 123 - 125 C.

Example 40-3 - (N - methyl - N - (ss - hydroxyethyl) - (amino) - 5,6 diphenyl - 1,2,4 - triazine, m.p. 101 -104 C.

Example 41-3 - benzylthio - 5,6 - dimethyl - 1,2,4 - triazine, m.p. 47 48 C.

Example 42-3 - methylthio - 5 - (4' - nitrophenyl) - 1,2,4 - triazine, m.p.

218 -219 C.

Example 43-3 - methoxy - 5 - (2',4' - difluorophenyl) - 1,2,4 - triazine, m.p.

91 -93 C.

Example 45-3 - (4' - methylphenoxy) - 5,6 - diphenyl - 1,2,4 - triazine, m.p.

154 -157 C.

Example 46-3 - methylthio - 5 - (4' - ethylphenyl) - 1,2,4 - triazine, m.p.

71 -72 C.

Example 47-3 - (4' - methoxyphenoxy) - 5 - phenyl - 1,2,4 - triazine, m.p.

149 -151 C.

Example 48-3 - n - pentoxy - 5 - phenyl - 1,2,4 - triazine, m.p. 36 -38 C.

Example 49-3 - n - butoxy - 1,2,4 - triazine, b.p. 129 -138 at 13 mm Hg.

Example 50-3 - methoxy - 5 (2' - thienyl) - 1,2,4 - triazine, m.p. 129 130 C.

Example 51-3 - hydrazino - 5 - (3' - trifluoromethylphenyl) - 1,2,4 triazine, m.p. 140 -142 C.

Example 52-3 - methylthio - 5 - (3' - methoxyphenyl) - 1,2,4 - triazine, m.p. 96 -97 C.

Example 53-3 - methoxy - 5 - (3' - methoxyphenyl) - 1,2,4 - triazine, m.p.

106 -107 C.

Example 54-3 - methylthio - 5 - (5' - chloro - 2' - thienyl ) - 1,2,4 - triazine, m.p. 149 -150 C.

Example 55-3 - methylthio - 5 - (4' - methylphenyl) - 1,2,4 - triazine, m.p.

160 -161 C.

Example 56-3 - (N - methyl - N - (ss - hydroxyethyl)amino - 5 - phenyl 1,2,4 - triazine, m.p. 90 -91 C.

Example 57-3 - methylthio - 5 - (4' - chlorophenyl) - 1,2,4 - triazine, m.p.

165 -166 C.

Example 58-3 - methoxy - 5 - (3' - chlorphenyl) - 1,2,4 - triazine, m.p.

930-940C.

Example 59-3 - methylthio - 5,6 - bis - (2' - furyl) - 1,2,4 - triazine, m.p.

920-930C.

Example 60-3 - hydrazino - 5,6 - bis - (2' - furyl) - 1,2,4 - triazine, m.p.

168 -169 C.

Example 61-3 - methyl - 5,6 - bis - (4' - methylphenyl) - 1,2,4 - triazine, m.p. 1660-1670C.

Example 62-3 - methylsulfonyl - 5,6 - dimethyl - 1,2,4 - triazine, m.p. 97 - 980C.

Example 63-3 - methylthio - 5,6 - bis(3',4' - dimethoxyphenyl)- 1,2,4 - triazine, m.p. 130 -131 C.

Example 64-3 - (2' - pyridyl) - 5,6 - diphenyl - 1,2,4 - triazine, m.p. 191 - 193 C.

Example 663 - methylthio - 5 - (3' - methoxy - 4' - benzyloxyphenyl) - 1,2,4 - triazine, m.p. 1580-1590C.

Example 67-3 - methylthio - 5 - (3',4' - methylenedioxyphenyl) - 1,2,4 triazine, m.p. 166 -167 C.

Example 69-3 - methylthio - 5 - (4' - ethoxyphenyl) - 1,2,4 - triazine m.p.

Example 69-3 - methylthio Example 70-3 - methoxy - 5 - (2',4',6' - trimethylphenyl) - 1,2,4 - triazine, m.p. 960-970C.

Example 71-3 - methoxy - 5 - (4' - methoxyphenyl) - 1,2,4 - triazine, m.p.

106 -107 C.

Example 72-3 - methoxy - 5,6 - bis(3',4' - dimethoxyphenyl) - 1,2,4 triazine, m.p. 83 -84 C.

Example 733 - isopropoxy - 5,6 - diphenyl - 1,2,4 - triazine, m.p. 96 - 980C.

Example 74-3 - methoxy - 5 - (4' - chlorophenyl) - 1,2,4 - triazine, m.p.

131 -133 C.

Example 753 - methoxy - 5 - (2' - benzofuryl)- 1,2,4 - triazine, m.p.

139 -140 C.

Example 76-3 - methoxy - 5 - (3',4' - methylenedioxyphenyl) - 1,2,4 triazine, m.p. 129 -130 C.

Example 77-3 - methoxy - 5 - (4' - morpholinophenyl) - 1,2,4 - triazine, m.p. 122 -123 C.

Example 783 - methylthio - 5 - (2' - chlorophenyl) - 1,2,4 - triazine, m.p.

68 -69 C.

Example 79-3 - methoxy - 5,6 - bis(2' - furyl) - 1,2,4 - triazine, m.p. 105 1070C.

Example 80-3 - (N' - adamantan - 1" - oylhydrazino) - 5 - phenyl - 1,2,4 triazine, m.p. 218 -220 C.

Example 81-3 - (N' - propionylhydrazino) - 5 - (4' - chlorophenyl) - 1,2,4 triazine, m.p. 2130-2140C.

Example 82-3 - (N' - acetylhydrazino) - 5 - phenyl - 1,2,4 - triazine, m.p.

181 -183 C.

Example 83-3 - (N' - cyclohexynoylhydrazino) - 5 - phenyl - 1,2,4 triazine, m.p. 208 -209 C.

Example 843 - hexanoylhydrazino - 5- phenyl - 1,2,4 - triazine, m.p.

1980-2000C.

The following Examples further illustrate the preparation of carhohenzyloxy N - protected a - aminoacylhydrazino and a - aminoacylhydrazino derivatives of the present invention.

EXAMPLE 85 Preparation of N-(Benzyloxycarbonylglycyl)-2' (5-Phenyl-1,2,4-Triazin-3-yl)-Hydrazide N - Benzyloxycarbonylglycine (2.1 g., 0.01 m.) was dissolved in pyridine (dried over BaO) and chilled to -10 C under inert atmosphere.

Dicyclohexylcarbodimide (2.1 g., 0.01 m.) was dissolved in warm pyridine and added by syringe. 3 - hydrazino - 5 - phenyl - 1,2,4 - triazine (1.9 g., 0.01 m.) was dissolved in pyridine and added dropwise by syringe to the stirring mixture at -10 C. The ice bath was removed and the mixture allowed to stir at room temperature for 5 hours. The precipitate which formed was removed by filtration and identified as dicyclohexylurea and discarded. The solution was concentrated and the viscous oil taken up in hot ethyl acetate. Addition of small amounts of pet. ether and cooling resulted in the formation of the title compound as a yellow powder, m.p. 166 -167 C.

Analysis: calculated for C19H18N6O3 (percent): C, 60.82; H, 4.77; N, 22.22.

Found (percent): C, 61.05; H, 5.25; N, 21.91.

EXAMPLE 86 Preparation of N'-(5-Phenyl-1,2,4-Triazin-3-yl)glycyl-hydrazide (dihydrobromide Hydrate) Into 500 ml. erlenmeyer flask was placed (N - carbobenzyloxyglycyl) - 2' (5 - phenyl - 1,2,4 - 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 HBr/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 5 C for 12 hours, forming a red solid which was collected and slurried in ether several times. Upon drying in a vacuum over for 10 hours, the title compound was recovered as a pale yellow solid, m.p. 220 221 C.

Analysis: calculated for C11H12N6O .2HBr. H2O (percent): C, 31.13; H, 3.77; N, 19.81. Found (percent): C, 31.1; H, 3.9; N, 20.1.

The following compounds were similarly prepared using the foregoing synthesis methods with appropriate selection of the N-carbobenzyloxy amino acid reactant and cleavage of the N-protecting group.

Example 87-N' - (5 - p - chlorophenyl - 1,2,4 - triazin - 3 yl)alanylhydrazide (di - hydrobromide hydrate), m.p. 252 -254 C.

Example 88-N' - (5 - phenyl - 1,2,4 - triazin - 3 - yl) valyl hydrazide (dihydrobromide hydrate), m.p. 274 -275 C.

Example 89-N' - (5 - phenyl - 1,2,4 - triazin - 3 - yl)phenylalanyl hydrazide (di - hydrobromide hydrate), m.p. 2640--265"C.

Pharmacological Activity The results of studies demonstrating the indicated anti-inflammatory, analgesic, hypotensive and central nervous system effects observed upon administration of effective dosages of typical preferred compounds in accordance with the present invention and the procedures utilized to evaluate pharmacological activity 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 hour 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 l3(200 grams. At peak swelling time (3 hours) the volume of edema was calculated by differential paw volumes.

Table I sets forth the results obtained (indicated as percent reduction of edema compared to phenylbutazone control values) at the indicated dosages for each of the identified compounds.

TABLE I Carrageenin Assay Compound Dose % Reduction Example No. (mg/kg) of Edema 100 76 4 150 57 5 200 51 6 150 41 7 100 77 8 200 39 9 200 63 10 200 19 11 200 71 12 200 12 15 200 8 16 200 64 17 200 51 18 175 70 19 200 37 21 200 43 22 200 51 23 200 17 24 200 2 25 150 30 26 200 86 27 200 7 TABLE I (cont.) Carrageenin Assay Compound Dose % Reduction Example No. (mglkg) of Edema 28 200 19 29 200 57 30 150 10 31 200 20 32 200 18 33 200 33 34 200 17 35 200 67 36(1) 200 67 38 200 22 39 200 7 40 200 23 41 200 52 42 200 16 43 150 36 45 200 18 46 200 33 47 200 15 48 200 29 81 100 40 86 50 32 (1) Comparative Example-See U.S. Pat. No. 3948,894.

B. Analgesic Assay The phenylquinone writhing test was employed to evaluate analgesic activity according to the following procedure: Phenylquinone (phenyl - p - benzoquinone), No. 7104, Eastman Organic Chemicals is made up as a 0.02% aqueous solution in 5% ethyl alcohol.

Phenylquinone solutions are made up fresh twice daily. Standard reference agents and the test compounds are dissolved or suspended in a .25% methylcellulose solution. A control group consisting of ten mice (Carworth CF1 male mice) are administered the .02% phenylquinone solution at a dose of 0.25 mVmouse. The mice 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 mVgram of body weight. 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 syndrome for the ten minute observation period in any one mouse is considered a positive analgesic response for 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 summarized in Table II.

TABLE II Phenylquinone Writhing Assay (% Control) Compound Dose Example No. (mg1l:g) 15 Min. 30 Min. 60 Min.

1 100 60 30 30 4 100 - 20 - 5 25 20 - - 50 - 70 - 100 - 10 - 6 100 - 50 - 7 15 50 - 10 8 70 - 10 - 9 100 - 30 - 10 100 - 10 20 TABLE II (cont.) Phenylquinone Writhing Assay (% Control) Compound Dose Example No. (mkg) 15 Min. 30 Min. 60 Min.

13 60 10 - 16 50 - 40 17 30 - 20 - 18 30 - 10 19 70 - 10 21 100 30 10 10 22 100 10 - 23 100 30 10 24 100 10 10 10 26 100 20 - 27 100 10 - 10 28 100 30 10 30 100 20 10 31 100 10 10 10 32 100 10 10 20 36 25 30 40 20 50 60 50 40 100 70 100 80 38 100 - 30 10 39 100 20 - 10 40 100 20 - 49 50 - 10 50 25 20 10 50 80 50 20 60 100 80 40 51 25 - 20 10 50 70 30 30 100 10 60 40 52 30 10 - 53 50 10 20 20 100 10 20 10 54 50 10 20 10 100 10 20 10 55 100 20 - 56 100 10 - 57 100 10 - 58 60 100 90 70 59 30 10 - 60 25 20 20 20 75 20 10 10 61(1) 50 20 20 20 100 50 80 50 62 100 - 30 30 63 100 10 10 64 100 10 20 66 100 10 - 67 100 20 - 69 100 10 - 70 100 10 - 10 71 100 30 10 72 100 10 10 73 100 10 10 20 81 25 30 50 50 87 50 50 50 60 89 100 30 60 60 (1) Comparative Example-See Belgian 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 visualizing the disappearance and/or appearance of the pressure pulse. Heart rate was measured by a biotachometer.

Groups of five rats having systolic blood pressures of 170 mmHg or greater were chosen and the test compounds administered at the dose 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. Twenty-four hours after dosing, systolic blood pressure and heart rate were recorded. A second dose of compound was administered and blood pressure and heart rate determined at 4 and 24 hours after the second dose.

The results observed are set forth in Table III below: TABLE III SHR Assay Compound Dose Mean Drop-mm/Hg Example No. (mg/hg) 4:hr. 24 hr. 4 hr. 24 hr. 28 hr. 48 hr.

1 100 0 49 56 92 2 100 0 41 48 73 3 100 55 70 - 90 6 50 0 25 56 59 100 51 29 70 88 63 4t 18 100 30 0 54 38 21 100 10 2 10 2 - 29 100 28 9 1 8 - - 34 100 17 22 12 19 - - 51 100 26 0 48 40 61 100 8 +5 11 12 74 100 0 0 37 29 - - 75 50 +1 0 0 11 - - 76 50 3 7 9 3 - - 77 100 11 4 7 12 - - 78 100 2 10 10 13 - - 80 100 49 86 41 36 81 100 47 79 107 111 83 100 40 94 106 104 84 100 53 53 81 68 85 100 32 37 47 36 86 50 41 35 105 91 87 100 44 58 91 103 88 100 23 17 37 44 89 100 26 38 75 82 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 (CF-I) weighing 18-22 grams were used in these determinations. The test compound, regardless of solubility, is suspended in a 0.25% aqueous methylcellulose solution. Intraperitoneal injections were administered in logarithmic progression and sequentially. The dose levels employed routinely are 10, 30, 100, and 300 mg/kg, using four male mice at each dose level. Since this test was conducted in a sequential manner, the first dose administered was at 300 mg/kg. The mice were injected at this dose level and observed for gross changes produced by the drug, such as behavioural, 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 intermittently checked for activity every fifteen minutes thereafter for two consecutive hours. At the end of the third hour of observation, if no demonstrable change had occurred in the behaviour of the mice, the compound was conditionally 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 the first three hours after administration of the drug at 300 mg/kg, the subsequent doses were administered and the animals observed for changes in overt behaviour. The observation period begins immediately following 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 pharmacological 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 activity for the compounds indicated are summarized in the following Table IV.

TABLE IV Neuropharmacological Profile Compound Example No. Dose (mg/kg) CNS Activity 4 300,100,30 Antidepressant 9 300,100 Hypnotic 10 300,100,30 Hypnotic 17 300,100,30,10,3 Sedative 49 300,100,30 Antidepressant 56 300,100 Hypnotic 79 300,100,30 Hypnotic As a consequence of the levels of activity in the carrageenin anti-inflammatory 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 (017), the disease is in the developing stage, while for the remainder of the month (18-31) the disease 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. J. 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 the 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 mVkg of a 0.5% suspension of heat-killed Mycobacterium Tuberculosis into the plantar surface of the left hind paw. Foot volumes were measured by a water displacement device on the day of administration of the Mycobacterium and again on days 3, 10 and 17. The test compounds were administered once daily. At the same time, body weights were recorded daily and the animals examined for the spread of the inflammation and degree of secondary lesions. For study in the established disease, another group of rats were injected with the Mycobacterium and foot volumes were measured. After 20 days volumes were again measured and administration of the test compounds began and continued for 11 days. Foot volume measurements were repeated on day 27 and day 31. The extent of the spread of inflammation and degree of lesions were recorded daily as were the body weights. The effect of the te the invention, as a consequence of the absence 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 with steroids. Some of the preferred hypotensive compounds of the present invention, e.g., the compound of example 6, demonstrate both advantageous rapid onset of action as well as a long duration of activity which are particularly valuable properties in the chemotherapeutic management of hypertension. It is also important to note that 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 described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications, and substitutions can be made therein. 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, e.g. inflammation, fever or pain, dosage-related adverse effects, if any, observed and analogous considerations.

Likewise, the specific 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 present invention.

Claims (19)

WHAT WE CLAIM IS:

1. A compound of the formula:

wherein: R1 represents a hydrazino, N' - (C1-C4 - alkyl) - hydrazino or

group, where R4 is a C18 - alkyl, C2-C8 - alkenyl, halo - (C alkyl), halo - (C248 - alkenyl), C6-C10 - cycloalkyl or

group, R6 being a hydrogen atom or a C14 - alkyl or benzyl group and Z being a hydrogen atom or a benzyloxy - carbonyl group, or R1 represents a hydroxy - (C1-C4 - alkyl) - amino, N - (C1-C2 - alkyl) N - (hydroxy - C1-C4 - alkyl) - amino, C1-C10 - alkoxy, C6-C10 aryloxy, C3-C6 - cycloalkoxy, phenylalkoxy, allyloxy, halophenoxy, C1 C4 - alkylphenoxy, C1-C4 - alkoxyphenoxy, C1-C10 - alkylthio, C3 C6 - cycloalkylthio, C1-C4 - alkylsulphinyl, C1-C4 - alkylsulphonyl, phenyl - (C1-C4 - alkyl) - thio, cis - dimethylpyrrolidyl or pyridyl group; R2 represents a hydrogen atom or a C1-C4 - alkyl, C3-C6 - cycloalkyl, adamantyl, furyl, thienyl, benzofuryl, indolyl, pyridyl, halothienyl or phenyl group or a phenyl group substituted with at least one substituent selected from halogen, C1-C6 - alkyl, halo - (C1-C6 - alkyl), C1-C6 alkoxy, acetamido, benzyloxy, diphenylmethyl, morpholino, methylenedioxy and nitro substituents; and R3 represents a hydrogen atom or a C1-C6 - alkyl, pyridyl, furyl or phenyl group or a phenyl group substituted with at least one substituent selected from halogen, C1-C6 - alkyl, C1-C6 - alkoxy, methylenedioxy and acetamido substituents; subject to the provisos that; (i) when R2 is a hydrogen atom, R3 is also a hydrogen atom; (ii) when R1 is a phenylalkylthio, alkoxy, alkylthio, cycloalkylthio, cycloalkoxy or phenylalkoxy group, R2 and R3 are not selected from halophenyl, C1-C3 alkylphenyl and C1-C3 - alkoxyphenyl groups; (iii) when R1 is a dimethylpyrrolidyl, hydroxyalkylamino or N - (C1C2 alkyl) - N - (hydroxy - C1-C4 - alkyl) - amino group, R2 and R3 are not both halophenyl, both C1-C3 - alkylphenyl or both C1-C3 - alkoxyphenyl groups; (iv) when R1 is a hydrazino, alkylthio, methoxy or ethoxy group, R2 is other than a phenyl group and R2 and R3 are not both methyl groups; (v) when R1 is a hydrazino or N' - (C1-C4 - alkyl) - hydrazino group, R2 is other than a C1-C4 - alkyl group; and (vi) when R, is an alkoxy group, R2 is other than a pyridyl group; and the pharmaceutically - acceptable salts thereof.

2. A compound as claimed in Claim 1, wherein RX represents a hydrazino, N' methylhydrazino, N' - haloacetylhydrazino, C1-C3 - alkoxy, allyloxy, C1-C3 alkylthio or benzylthio group; R2 represents a C3-C6 - cycloalkyl, thienyl, furyl, pyridyl, indolyl, phenyl, meta - halophenyl, methoxyphenyl, dimethoxyphenyl or trifluoromethylphenyl group; and R3 represents a hydrogen atom or a C1-C4 alkyl, pyridyl or furyl group.

3. A compound as claimed in Claim 2, wherein R3 represents a hydrogen atom.

4. A compound as claimed in Claim 1, selected from 3 - (N' - acetylhydrazino)- 5- phenyl- 1,2,4 - triazine, 3 - (N' - propionyl hydrazino) - 5 - (4' - chlorophenyl) - 1,24 - triazme, 3 - (N' methylhydrazino) - 5 - phenyl - 1,2,4 - triazine, 3 - (N' - acetylhydrazino) - 5,6 diphenyl - 1,2,4 - triazine, 3 - (N' - methyl) - hydrazino - 5,6 - bis(4' chlorophenyl) - 1,2,4 - triazine, 3 - (N' - trifluoroacetylhydrazino) - 5 - phenyl 1,2,4 - triazine, 3 - methoxy - 5 - t - butyl - 1,2,4 - triazine, 3 - methoxy - 5 (3' - trifluoromethylphenyl) - 1,2,4 - triazine, 3 - methoxy - 5,6 - di(2' - pyridyl) 1,2,4 - triazine, 3 - methylthio - 5 - t - butyl - 1,2,4 - triazine, 3 - methylthio - 5 (2' - furyl) - 1,2,4 - triazine, 3 - methylthio - 5 - (2' - thienyl) - 1,2,4 - triazine, 3 - methylthio - 5 - (3' - trifluoromethylphenyl) - 1,2,4 - triazine, 3 - n - propoxy - 5 - phenyl - 1,2,4 - triazine, 3 - methylthio - 5 - (3' - indolyl) - 1,2,4 triazine, 3 - methylthio - 5 - cyclopropyl - 1,2,4 - triazine, 3 - methoxy - 5 cyclopropyl - 1,2,4 - triazine, 3 - allyloxy - 5 - phenyl - 1,2,4 - triazine, 3 allyloxy - 5,6 - dimethyl - 1,2,4 - triazine, 3 - hydrazino - 5 - (3' - trifluoromethylphenyl) - 1,2,4 - triazine, 3 - methoxy - 5 - (3' - chlorophenyl) 1,2,4 - triazine, 3 - (N' - a - aminoacetylhydrazino) - 5 - phenyl - 1,2,4 - triazine, and 3 - (N' - a - aminopropionylhydrazino) - 5 - (4' - chlorophenyl) - 1,2,4 triazine.

5. A compound according to claim 1, substantially as hereinbefore described.

6. A compound according to any preceding claim, when prepared by a method as hereinbefore described.

7. A composition comprising one or more compounds of the formula defined in claim 1, in conjunction with at least one pharmaceutical carrier.

8. A pharmaceutical composition in dosage unit form, for administration to obtain an anti-inflammatory effect, comprising, per dosage unit, an amount within the range from 1 to 300 milligrams of at least one compound of the formula:

wherein R1 represents a hydrazino, N' - (C1-C4 - alkyl) - hydrazino or

group, where R4 is a C1-C8 - alkyl, halo - (C1-C8 - alkyl) or

group, R5 being a C1-C4 - alkyl group; or R1 represents a hydroxy - (C1-C4 - alkyl) - amino, N - (C1-C2 - alkyl) N - (hydroxy - C1-C4 - alkyl) - amino, C1-C10 - alkoxy, phenoxy, C1 C4 - alkylphenoxy, C1-C4 - alkoxyphenoxy, C1-C10 - alkylthio or phenyl - (C1-C4 - alkyl) - thio group; R2 represents a hydrogen atom or a C1-C4 - alkyl, C3-C6 - cycloalkyl, adamantyl, furyl, thienyl, benzofuryl, indolyl, pyridyl or phenyl group or a phenyl group substituted with at least one substituent selected from halogen, C,C4 - alkyl, halo - (C,C- - alkyl), C1-C6 - alkoxy, acetamido, morpholino and nitro substituents; and R3 represents a hydrogen atom or a C1-C6 - alkyl, phenyl or pyridyl group or a phenyl group substituted with at least one substituent selected from halogen, C1-C4 - alkyl, C1-C6 - alkoxy and acetamido substituents; subject to provisos (i) to (v) inclusive as defined in claim 1; or at least one pharmaceutically-acceptable acid addition salt of a compound of the formula; and a pharmaceutical carrier.

9. A pharmaceutical composition in dosage unit form as claimed in claim 8, formulated for oral administration.

10. A pharmaceutical composition in dosage unit form as claimed in claim 8 or 9, wherein the compound is 3 - (N' - methylhydrazino) - 5 - phenyl - 1,2,4 triazine.

11. A pharmaceutical composition in dosage unit form, for administration to obtain an analgesic effect, comprising, per dosage unit, an amount within the range from 1 to 300 milligrams of at least one compound of the formula:

wherein R1 represents a hydrazino, N' - (C1-C4 - alkly) - hydrazino, N' (trifluoroacetyl) - hydrazino, C1-C4 - alkoxy or C1-C4 - alkylthio group and R2 represents as C1-C4 - alkyl, thienyl or phenyl group or a phenyl group substituted with at least one substituent selected from halogen, halo - (C1-C4 - alkyl) and C1-C4 - alkoxy substituents, when R3 represents a hydrogen atom, or wherein R1 is as defined above and R2 and R3 are the same and each represents a C1-C4 alkyl or a butoxyphenyl group; subject to provisos (iii) and (iv) as defined in claim l; or at least one pharmaceutically - acceptable salt of a compound of the formula; and a pharmaceutical carrier.

12. A hypotensive composition, comprising at least one compound of the formula:

wherein: R, represents a hydrazino, N' - (C1-C4 - alkyl) - hydrazino or

group, where R4 is a C1-C8 - alkyl, C2-C8 - alkenyl, halo - (c1-C8 alkyl), halo - (C2-C8 - alkenyl), C6-C10 - cycloalkyl or

group, R5 being a hydrogen atom or a C1-C4 - alkyl or benzyl group and Z being a hydrogen atom or a benzyloxycarbonyl group; or R, represents a hydroxy - (C1-C4 - alkyl) - amino, C1-C4 - alkoxy or C1- C4 - alkylthio group; R2 represents a furyl, benzofuryl or phenyl group or a phenyl group substituted with at least one substituent selected from halogen, halo - (C1-C2 alkyl), C1-C4 - alkoxy, methylene dioxy and morpholino substituents, when R3 represents a hydrogen atom, or wherein: R, represents a hydrazino, C1-C4 - alkoxy or

group, where R4 and R5 are as above defined and R2 and R3 are the same and each represents a furyl, phenyl, methylenedioxyphenyl or morpholino-phenyl group; subject to the proviso that when R, is a hydrazino, alkylthio, methoxy or ethoxy group, R2 is other than a phenyl group, or at least one pharmaceutically-acceptable salt of a compound of the formula; and a pharmaceutical carrier.

13. A hypotensive composition as claimed in claim 12, wherein the one or more compounds are selected from 3 - (N' - methylhydrazino) - 5 - phenyl 1,2,4 - triazine, 3 - (N' - a - aminoacetylhydrazino) - 5 - phenyl - 1,2,4 - triazine, 3 - (N' - a - aminopropionylhydrazino) - 5 - (4' - chlorophenyl) - 1,2,4 - triazine, 3 - (N' - trifluoroacetylhydrazino) - 5 - phenyl - 1,2,4 - triazine, 3 - (N' propionylhydrazino) - 5 - phenyl - 1,2,4 - triazine, 3 - hydrazino - 5 - (3' trifluoromethylphenyl) - 1,2,4 - triazine and 3 - methoxy - 5 - (4' methoxyphenyl) - 1,2,4 - triazine.

14. A pharmaceutical preparation in dosage unit form, for administration to obtain a central nervous system effect, comprising, per dosage unit, an amount within the range from I to 300 milligrams of at least one compound of the formula:

wherein R, represents a hydrazino, N' - (C1-C2 - alkyl) - N - (hydroxy - C2- C4 - alkyl) - amino, C14 - alkoxy, allyloxy or C14 - alkylthio group and R2 represents a C1-C4 - alkyl, phenyl or halo - (C1-C4 - alkyl) - phenyl group when R3 represents a hydrogen atom; or wherein R, represents a methoxy, allyloxy, hydrazino or methylthio group and R2 and R3 are the same and each represents a C1-C4 - alkyl, phenyl, furyl or pyridyl group; subject to the provisos that; (a) when R1 is a hydrazino, alkylthio, methoxy or ethoxy group, R2 is other than a phenyl group and R2 and R3 are not both methyl groups; (b) when R, is a hydrazino group, R2 is other than a C1-C4 - alkyl group; and (c) when R, is an alkoxy group, R2 is other than a pyridyl group; or at least one pharmaceutically - acceptable salt of a compound of the formula; and a pharmaceutical carrier.

15. A composition according to any of claims 7 to 14, substantially as hereinbefore described.

16. A method of promoting an anti-inflammatory, analgesic, hypotensive or central nervous system effect in a non-human animal, which comprises administering thereto a therapeutically-sufficient amount of at least one compound according to any of claims 1 to 6 or a composition according to any of claims 7 to 15.

17. A method as claimed in claim 16, wherein the compound is selected from 3 - (N' - trifluoroacetylhydrazino) - 5 - phenyl - 1,2,4 - triazine, 3 - methoxy 5 - t - butyl - 1,2,4 - triazine, 3 - methoxy - 5 - (3' - trifluoromethyl) - 1,2,4 triazine, 3 - methylthio - 5 - (2' - furyl) - 1,2,4 - triazine, 3 - methylthio - 5 - (2' thienyl)- 1,2,4 - triazine, 3 - methylthio - 5 - (3' - trifluoromethylphenyl) 1,2,4 - triazine, 3 - n - propoxy - 5 - phenyl - 1,2,4 - triazine, 3 - methylthio - 5 (3' - indolyl) - 1,2,4 - triazine, 3 - methylthio - 5 - cyclopropyl - 1,2,4 - triazine, 3 - methoxy - 5 - cyclopropyl - 1,2,4 - triazine, 3 - allyloxy - 5 - phenyl - 1,2,4 triazine, 3 - allyloxy - 5,6 - dimethyl - 1,2,4 - triazine, 3 - hydrazino - 5 - (3' trifluoromethyl - phenyl) - 1,2,4 - triazine, 3 - methoxy - 5 - (3' - chlorophenyl) 1,2,4 - triazine and 3 - methoxy - 5 - (4' - morpholino - phenyl) - 1,2,4 - triazine.

18. A method as claimed in claim 16 or 17, wherein the therapeutically sufficient amount ranges from I to 300 mg/kg/day.

19. A method as claimed in claim 18, wherein the therapeutically - sufficient amount ranges from 25 to 200 mg/kg/day.