GB1563367A

GB1563367A - Pyrazolo pyridine derivatives

Info

Publication number: GB1563367A
Application number: GB17846/77A
Authority: GB
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1976-07-13
Filing date: 1977-04-28
Publication date: 1980-03-26
Also published as: DE2731649A1; JPS539797A; CA1083570A; FR2358405A1; FR2358405B1

Description

(54) PYRAZOLO PYRIDINE DERIVATIVES (71) We, E. R. SQUIBB & SONS INC., a corporation organised and existing under the laws of the State of Delaware, United States of America, of Lawrenceville-Princeton Road, Princeton, New Jersey, 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 invention provides compounds of the formula

wherein Z is N-R4 N C=O or C--R4' R' is hydrogen, lower alkyl, phenyl, phenyllower alkylene, benzoyl or substituted benzoyl wherein the benzoyl substituent is one or two halogen, lower alkyl or trifluoromethyl radicals; R2 is hydrogen, lower alkyl or phenyl; R3is hydrogen, lower alkyl, phenvl, lower alkylthio or lower alkylsulfinyl; R4 is hydrogen, lower alkyl, phenyl-lower alkylene, benzoyl substituted benzoyl, lower alkanoyl, lower alkoxy-lower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl, or

Rd N-lower alkylene, R7 morpholino, thiomorpholino or piperizino, the substituents on said substituted phenyl and substituted benzoyl being halogen, lower alkoxy or lower alkyl. R4' is halo.

phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, lower alkyl or trifluoromethyl radicals; lower alkoxy or substituted lower alkoxy wherein the lower alkoxy substituent is

Rs is hydrogen or lower alkyl; Rs is hydrogen, lower alkyl, substituted lower alkyl wherein the lower alkyl substittuent is

phenyl or substituted phenyl wherein the phenyl substituent is halogen, lower alkyl or trifluoromethyl, R7 is hydrogen or lower alkyl, or R8 and R? together with the nitrogen form one of the unsubstituted or substituted heterocyclics pyrrolidino, morpholino, thiomorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl wherein the heterocycle substituent is lower alkyl or hydroxy-lower alkylene; R8, R9 and Rl each is hydrogen or lower alkyl; and acid addition salts thereof. Other aspects of the invention are hereinafter defined in the claims.

The various groups represented by the symbols are of the following types and have the same meanings throughout this specification: The lower alkyl groups are straight or branched chain hydrocarbon groups having up to seven carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and pentyl. The lower alkylene groups are divalent radicals of the same kind. Examples of the phenyl-lower alkylene groups are benzyl, phenethyl and phenylisopropyl. The C14 and especially the C12 lower alkyl and lower alkylene groups are preferred. The lower alkoxy groups are of the same type.

The C1C and C12 groups are similarly preferred and especially preferred groups, respectively.

The substituted phenyl, substituted phenyloxy and substituted berizoyl groups are simply substituted groups bearing on the phenyl ring one or two halogen (preferably one), lower alkyl, lower alkoxy or trifluoromethyl groups, for example, p-chlorophenyl, o-chlorophenyl, p-bromophenyl, m-chlorophenyl, m-bromophenyl, ptolyl, o-tolyl, o-ethylphenyl, p-methoxyphenyl, p-chlorophenyloxy, o-chlorophenyloxy, pbromophenyloxy, m-chlorophenyloxy, m-bromophenyloxy, p-tolyloxy, o-tolyloxy, oethylphenyloxy, p-trifluoromethylphenyloxy, 3,4-dichlorophenyloxy, 3,5-dimethylphenyl- oxy, p-bromobenzoyl, m-bromobenzoyg, - 3,5dichlorobenzoyl, pmethylbenzoyl, ' o-ethylbenzoyl and p-trifluoromethylbenzoyl. Chlorine, bromine and methyl are the preferred substituents (only one) in both instances.

The halogens in each instance are the four common halogens but chlorine and bromine, especially chlorine, are preferred.

The lower alkanoyl groups are the acyl groups of the lower (C27) fatty acids, e.g., acetyl, propionyl, butyryl and isobutyryl.

Those with up to four carbons in the chain are preferred, especially acetyl.

The lower alkoxy-lower alkylene and lower alkylthio-lower alkylene groups represented by R5 have radicals like those described above including such groups as methoxy-methylene, ethoxymethylene, methoxyethylene, methylthiomethylene, methylthioethylene, ethylthiomethylene and ethylthioethylene.

The amino-lower alkylene groups are of the same type, e.g., aminomethyl, aminoethyl, etc.

The di-lower alkylamino-lower alkyene groups are also of the same type wherein the nitrogen is substituted with two lower alkyl groups.

In addition, the two lower alkyl groups may join in forming a heterocycle which may include an additional hetero atom. Preferably the lower alkyl and lower alkylene groups have up to 4 and especially 1 or 2 carbons. Thus, such groups as dimethylaminomethyl, diethylaminomethyl, dimethylaminoethyl, diethylaminoethyl, dimethylaminopropyl, piperidinomethyl, piperidinoethyl, morpholinomethyl, morpholinoethyl, thiomorpholinomethyl, thiamorpholinoethyl, piperazinomethyl, piperazinoethyl, piperazinopropyl are included.

The amino groups

wherein R6 and R? each represents hydrogen or lower alkyl include the amino group, lower alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino and butylamino and di-lower alkylamino groups such as dimethylarnino, diethylamino, methylethylamino, dipropylamino and dibutylamino (preferably, but not necessarily, both lower alkyl groups are the same in a given compound). R6 and R7 can also join with the nitrogen to form one of the heterocyclic radicals pyrrolidino, morpholino, thiamorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl. These heterocyclic radicals may be unsubstituted or substituted with a lower alkyl or hydroxy-lower alkyl group. The preferred heterocyclics are piperidino, morpholino and 4-methylpiperazino.

The substituted lower alkoxy groups represented by R4, and the substituted lower alkyl groups represented by R6 may bear an amino group

as described above resulting in R4, substituents which are amino-lower alkoxy groups

R9 (-lower alkylene--N Rl and amino-lower alkyleneamino groups

RD (-NH- lower aikylene-N ) R'" respectively, including, for example, aminomethoxy, aminoethoxy, aminopropoxy, methylaminoethoxy, ethylaminoethoxy, ethylaminopropoxy, dimethylaminomethoxy, dimethylaminoethoxy, dimethylaminopropoxy, diethylaminoethoxy, dimethylaminobutoxy, diethylaminopropoxy, ammoethylamino, aminopropylamino, methylaminopropylamino, ethylaminoethylamino, dimethylaminomethylamino, diethylaminomethylamino, dimethylaminoethylamino, diethylaminoethylamino and dimethylaminopropylamino. Preferred are those groups wherein the lower alkyl and lower alkylene groups have up to 40 carbons, especially 1 to 2 carbons. Especially preferred groups of this type are di-lower alkylamino-lower alkoxy, especially dimethylaminopropoxy and di-lower aLkylamino-lower alkyleneamino, especially dimethylarninopropylamino.

In compounds of the formula

the preferred groups are those wherein Rl is lower alkyl, especially ethyl; R2 is hydrogen or lower alkyl, especially hydrogen; R3 is hydrogen, lower alkyl, especially methyl, lower akylthio, especially methylthio, or lower alkyl sullinyl, especially methylsufinyl, with especial preference for hydrogen or lower alkyl; R4is hydrogen, lower alkyl, especially methyl, ethyl and isopentyl, or di-lower alkylamino-lower alkylene, especially dimethylaminopropyl and dimethylaminoethyl; R5 is lower alkyl or hydrogen, especially hydrogen.

In compounds of the formula

the preferred groups are those wherein Tri is hydrogen or lower alkyl, especially the latter and most especially ethyl; R2 is hydrogen or lower alkyl, especially hydrogen; R3 is hydro gen, lower alkyl or lower alkylthio, especially hydrogen or methyl; R4' is amino, mercapto, lower alkylthio, especiallv methvlthio, lower alkylamino, especially C1C4-lower alkylamino, lower alkoxy, especially C,--C,-lower alkoxv, di(lower alkyl)amino, especially C,- C4-di(lower alkyl)amino or di(lower alkvl)amino(lower alkoxy) or di(lower alkyl)aminolower alkylamino. R5 is hydrogen or lower alkvl, especially hydrogen.

The new compounds of Formula I are formed by the following series of reactions.

The symbols in the structural formulas have the same meaning as previously described.

A pyrazolo[3,4 - blpyridine of the formula

(produced according to the procedure given in U.S. Patent No. 3,761,487) is made to react with a lower alkoxymethylene cyanamide of the formula

or a lower alkylthiomethylene cyanamide of the formula

wherein R in both formulas is lower alkvl in an organic solvent such as alcohol.

Bv this reaction is obtained a compound of the formula

Compounds of Formula Ia, wherein R4 is other than hydrogen, are obtained bv treatment of the compound of Formula V wherein R4 is hydrogen, obtained as just described, with the halide R4-hal, wherein hal is a halos gen, preferably chlorine or bromine, and R4 has the meaning defined above, in the presence of a base, preferably a base of an alkali metal such as sodium hydride, sodium or potassium alcoholate, such as sodium or potassium methoxide or ethoxide or sodium or potassium hvdroxide in a solvent like diethyleneglycol dimethyl ether.

Compounds of Formula Ia, wherein R3 is lower alkvlsulfinyl are obtained from the corresponding compound of Formula Ia wherein R3 is lower alkvlthio by oxidizing the latter, e.g., with an alkali metal periodate like sodium metaperiodate.

Reaction of the compound of Formula V with a chlorinating agent such as phosphorus oxychloride or phosphorus pentachloride, results in the formation of a compound of the formula

Compounds of Formula Ib wherein R4' is lower alkoxy or amino-lower alkoxy are now produced by reaction of the compound of Formula VI with an alcoholate of the formula lower alkyl-OMe or

R9 Me-O-lower alkylene-N VII Rl wherein Me is an alkali metal such as sodium or potassium.

When R3 is lower alkylsulfinyl, the compound of Formula V wherein R3 is lower alkylthio is first formed, e.g., by reaction of the compound of Formula II with the compound of Formula IV wherein R3 is lower alkylthio.

This product is oxidized, e.g., with an alkali metal periodate like sodium metaperiodate and then further processed as described above.

Compounds of Formula Ib wherein R4' is lower alkylthio are obtained by reaction of a compound of Formula VI with an alkali metal mercaptide of the formula R-S-Me VIII wherein Me is again an alkali metal such as sodium or potassium and R8 is lower alkyl.

Compounds of Formula Ib wherein R4' is mercapto are obtained by reaction of a compound of Formula VI with an alkali metal sulfide such as sodium sulfide. Compounds of Formula Ib wherein R4, is an amino group or amino-lower alkylene group are produced by reaction of a compound of Formula- VII with an amine of the formula

R9 H2N-lower alkylene-N X RI0 at elevated temperatures.

The compounds of Formula I form salts which are also part of this invention. The salts include acid addition salts, particularly the non-toxic, physiologically acceptable members. These salts are formed by reaction with one or more equivalents of a variety of inorganic and organic acids providing acid addition salts, including, for example, hydrohalides (especially hydrochloride and hydrobromide), sulfate, nitrate, borate, phosphate, oxalate, tartrate, maleate, citrate, acetate, ascorbate, succinate, aryl- and alkanesulfonates like benzene-sulfonate, methanesulfonate, cyclohexanesulfamate and toluene-sulfonate, etc. The acid addition salts frequently provide a convenient means for isolating the product, e.g., by forming and precipitating a salt (which is not necessarily non-toxic) in an appropriate medium in which the salt is insoluble, then after separation of the salt, neutralizing with a base such as barium hydroxide or sodium hydroxide, to obtain the free base of Formula I. Other salts can then be formed from the free base by reaction with an equivalent or more of acid containing the desired anion.

The compounds of this invention have antiinflammatory properties and may be used as antiinflammatory agents, for example, to reduce local inflammatory conditions such as those of an edematous nature or resulting from proliferation of connective tissue in various mammalian species such as rats, dogs and the like when given orally in dosages of 1 to 50 mg/kg/day, preferably 2 to 15 mg/kg/ day, in single or 2 to 4 divided doses, as indicated by the carageenan edema or delayed hypersensitivity skin reaction tests in rats.

They can also be used topically. The new compounds of this inventon also have central nervous system depressant activity and can be used as psychotropic agents, e.g., as ataractic agents for the relief of anxiety and tension states, for example, in mice, cats, rats, dogs and other mammalian species. For this purpose a compound or mixture of compounds of Formula I, or non-toxic, physiologically acceptable acid addition salt thereof, is preferably administered orally, but parenteral routes such as subcutaneously, intramuscularly, intravenously or intraperitoneally in the described dosages, can also be employed. A single dose, or preferably 2 to 4 divided daily doses, provided on a basis of 5 to 50 mg/kg/day, preferably 10 to 25 mg/kg/day, is appropriate.

The compounds of the invention can be utilized by formulation in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for parenteral administration. 10 to 300 mg of a compound or mixture of compounds of Formula I or physiologically acceptable acid addition salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.

Illustrative of the adjuvants which may be incorporated in tablets, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate, a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; a flavoring agent such as peppermint, oil or wintergreen or cherry. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit.

For instance, tablets or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives a dye and a flavoring such as cherry or orange flavor.

For topical administration as an antiinflammatory agent, a conventional lotion, ointment or cream containing 0.1 to 3 percent by weight of a compound of Formula I or its salt is formulated.

The following examples illustrate the present invention. All temperatures are in degrees celsius.

Example 1 8 - Ethyl - 4H - pyrazolo [4',3' :5,6] pyrido- [3,4 - e] [1,2,4]triazolo - [1,5 - a]pyrimi din - 5(8H)one 249 g of 1 - ethyl - 4 - hydrazino - lH- pyrazolo[3,4 - b]pyridine - 5 - carboxylic acid, ethyl ester (1 mol) are refluxed in 1.5 liters of dry dioxane together with 98 g of ethoxymethylene cyanamide for 12 hours. After cooling to room temperature, the precipitated 8ethyl - 4H - pyrazolo [4',3': 5,6] pyrido [3,4 e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H)one is filtered off and recrystallized from dimethylformamide, yield 135 g. (53%); m.p.

355356 .

Example 2 4 - [3 - (Dimethylamino)propyl] - 8 - ethyl 4H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5 (8H) - one 5.1 g. of 8 - ethyl - 4H - pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5'8H) - one (0.02 mol.) obtained in Example 1 are treated with 0.6 g. of sodium hydride in 50 ml. of diethylene glycol dimethyl ether at 1500 for 1 hour. After this time, the temperature is lowered to about 90 and 3.6 g. of 3 - (dimethylamino)propyl chloride are added and heating is continued for 12 hours with stirring. The precipitated inorganic salt is filtered off and the filtrate evaporated to dryness. The remaining 4 - [3 - (dimethylamino)propyl] - 8 - ethyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) - one is recrystallized from butanol, yield 4.5 g. (66%); m.p.

175177 .

Example 3 8 - Ethyl - 4 - (3 - methylbutyl) - 4H - pyra zolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]- triazolo [1,5 - a] pyrimidin - 5(8H) - one 2.6 g. of 8 - ethyl - 4H - pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H)- one obtained as in Example 1 (0.01 mol.) are treated with 1 g. of sodium ethoxide in 50 ml. of diethyleneglycoldimethyl ether at 1200 for 2 hours.

After this time, 2 g. of 3 - methyl - 1 - bromobutane are added and heating is continued for 12 hours at the same temperature with continuous stirring. The inorganic precipitate is filtered off and the mother liquor evaporated to dryness. The remaining 8 - ethyl - 4 (3 - methylbutyl) - 4H - pyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one is recrystallized from alcohol, yield 2.1 g. (64%); m.p. 175-177 .

Example 4 8 - Ethyl - 4 - methyl - 4H - pyrazolo[4',3': 5,6]pyrido[3,4 e][1,2,4]triazolo[1,5 a]pyrimidin - 5(8H)- one 2.6 g. of 8 - ethyl - 4H - pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one (0.01 mol.) are treated with 0.3 g. of sodium in 50 ml. of di ethyleneglycol dimethyl ether at reflux temperature with stirring for 30 minutes.

After this time, the temperature is lowered to 60 and 3 g. of methyl iodide are added.

Stirring and heating is continued for 12 hours.

The precipitate of sodium iodide is filtered off and the solvent distilled from the mother liquor. The remaining 8 - ethyl - 4 - methyl 4H - pyrazolo[4',3' : 5,6]pyrido[3,4 [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one is recrystallized from butanol, yield 2 g.

(74%); m.p. 208-210 .

Example 5 8 - Ethyl - 2 - methylthio - 4H - pyrazolo- [4',3': 5,6] pyrido [3,4 e] [1,2,4]tri azolo[l,5 - a]pyrimidin - 5(8H)- one 249 g. of 1 - ethyl - 4 - hydrazino - lH- pyrazolo[3,4 - b]pyridine - 5 - carboxylic acid, ethyl ester (1 mol.) are refluxed in 2 liters of butyl alcohol with 114 g. of dimer captomethylmethylene cyanamide for 10 hours.

The solution is cooled to room temperature and the precipitated 8 - ethyl - 2 - methylthio4H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one is filtered off, yield 140 g. (34%); m.p. > 300 (DMF).

Example 6 8 - Ethyl - 2 - methylsulfinyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) - one 3.01 g. of 8 - ethyl - 2 - methylthio - 4H pyrazolo [4',3': 5,6] pyrido [3,4 - e] [1,2,4] tri- azolo [1,5 - a]pyrimidin - 5)8H) - one obtained in Example 5 are oxidized with 2.2 g. of sodium metaperiodate in aqueous alcohol for 7 days at room temperature. The precipitate of 8 - ethyl - 2 - methylsulfinyl - 4H - pyra zolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) one is filtered off, washed with water and recrystallized from dimethylformamide, yield 2.8 g. (88%); m.p.

> 300 .

Example 7 4,8 - Diethyl - 4H - pyrazolo[4',3':5,6] pyrido[3,4 - e][1,2,4]triazolo[1,5 - a] pyrimidin - 5(8H) - one By substituting ethyl iodide for the methyl iodide in the procedure of Example 4, 4,8 dimethyl - 4H - pyrazolo[4',3':5,6]pyrido [3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin 5(8H) - one is obtained.

Example 8 8 - Ethyl - 4 - (2 - morpholino)ethyl - 4H pyrazolo [4',3': 5,6]pyrido [3,4 [1,2,4]triazolo[1,5 - a]pyrimidin - 5'8H)- one 2.7 g. of 8 - ethyl - 4H - pyrazolo[4',3': 5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a] pyrimidin - 5(8H) - one (0.01 mol.) and 0.3 g. of sodium are refluxed for one hour in 30 ml. of diethyleneglykol dimethylether with stirring. The temperature is lowered to 90 and 2 g. of 1 - chloro - 2 - morpholinoethane are added and stirring is continued for 24 hours. The inorganic precipitate is filtered off, the solvent removed in vacuo to obtain the product, 8 - ethyl - 4 - (2 - morpholino) ethyl - 4H - pyrazolo[4',3':5,6]pyrido[3,4 e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one.

Example 9 8 - Ethyl - 4 - (2 - piperidino)ethyl - 4H pyrazolo[4',3'.5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one By substituting for the dimethylaminopropyl chloride in Example 2 the equivalent amount of I - chloro - 2 - piperidino - ethane, 8 - ethyl 4 - (2 - piperidino) - ethyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 a]pyrimidin - 5(8H) - one is obtained.

Example 10 4 - [2 - (Diethylamino)ethyl] - 8 - ethyl - 4H pyrazolo[4',3': 5,6]pyrido[3,4 [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one By substituting for the (3 - dimethylamino)propyl chloride in Example 2 the equivalent amount of 1 - chloro - 2 - diethylaminoethane, 4- [2 - (diethylamino)ethyl] - 8 - ethyl - 4H pyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4] triazolo[l,5 - a]pyrimidin - 5(8H) - one is obtained.

Example 11 4- Methyl - 4H - pyrazolo[4',3':5,6]pyrido [3,4 - e][1,2,4]triazolo[1.5 - a]pyrimi din - 5(8H) - one By substituting an equivalent amount of 4 hydrazino - 111 - pyrazolo [3,4 - b]pyridine- 5 - carboxylic acid, ethyl ester for the 1 ethyl - 4 - hydrazino - iH - pyrazolo [3,4- b]pyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example 1 then continuing as in Example 4, 4H - pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one and 4 - methyl - 4Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4] triazolo[l,5 - a]pyrimidin - 5(8H) - one, respectively, are obtained.

Example 12 4 - Butyl - 8 - ethyl - 4H - pyrazolo-4',3': 5,6] pyrido [3,4 e] [1,2,4] triazolo [1,5- a]pyrimidin - 5'8H) - one By substituting butyl iodide for the methyl iodide in the procedure of Example 4, 4butyl - 8 - ethyl - 4H - pyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one is obtained.

Example 13 4 - Phenylmethyl - 4H - pyrazolo[4',3':5,6] pyrido[3,4 - e][1,2,4]triazolo[1,5 - a] pyrimidin - 5(8H) - one By substituting the 4H - pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimido - 5(8H) - one of Example 11 for the 8 - ethyl - 4H - pyrazolo[4',3':5,6]pyrido [3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin5(8H) - one one benzyl iodide for the methyl iodide in the procedure of Example 4, 4phenylmethyl - 4H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one is obtained.

Example 14 8 - Ethyl - 4 - phenylethyl - 4H - pyrazolo- [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) - one By substituting phenylethyl bromide for the methyl iodide in the procedure of Example 4 8 - ethyl - 4 - phenylethyl - 4H - pyrazolo- [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) - one is obtained.

Example 15 4,8,10 - Trimethyl - 4H - pyrazolo[4',3':5,6] pyrido[3,4 - e][1,2,4]triazolo[1,5 - a] pyrimidin-5(8H) - one By substituting 1,3 - dimethyl - 4 - hydrazino - 1H - pyrazolo[3,4 - b]pyridine - 5carboxylic acid, ethy ester for the 1 - ethyl4 hydrazino - 1H - pyrazolo [3,4 - b]pyridine- 5 - carboxylic acid, ethyl ester in the procedure of Example 1 and proceeding as in Example 4, 8, 10 - dimethyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5a]pyrimidin - 5(8H) - one and 4,8,10 - trimethyl - 4H - pyrazolo[4',3':5,6]pyrido [3,4 - e][1,2,4)triazolo[1,5 - a]pyrimidin5(8H) - one are obtained.

Example 16 2 - Ethyl - 8 - isopropyl - 4 - propionyl - 4H pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1.5 - a]pyrimidin - 5(8H) one By substituting 1 - isopropyl - 4 - hydrazino - 111 - pyrazolo [3,4 - b]pyridine - 5 carboxylic acid, ethyl ester for the 1 - ethyl4 - hydrazino - 1H - pyrazolo[3,4 - b]pyridine5 - carboxylic acid, ethyl ester and 1 - ethoxypropylidene cyanamide for the ethoxymethylene cryanamide in the procedure of Example 1, and then proceeding as in Example 4 but substituting propionyl bromide for the methyl iodide, 2 - ethyl - 8 - isopropyl - 4H - pyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) - one and 2 - ethyl8 - isopropyl - 4 - propionyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5a]pyrimidin - 5(8H) - one, respectively, are obtained.

Example 17 4 - (4 - Chlorobenzoyl) - 10 - ethyl - 4H pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one By substituting 4 - hydrazino - 3 - ethyl 1H - pyrazolo[3,4 - b]pyridine - 5 - carboxy lic acid propyl ester for the 1 - ethyl - 4 hydrazino - 1H - pyrazolo[3,4 - b]pyridine 5 - carboxylic acid, ethyl ester in the pro cedure of Example 1, and then substituting 4 - chlorobenzoyl bromide for the methyl iodide in the procedure of Example 4, 10 ethyl - 4H - pyrazolo[4',3':5,6] - pyrido [3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin5(8H) - one and 4 - (4 - chlorobenzoyl) -10 ethyl - 4H - pyrazolo[4',3':5,6]pyrido[3,4e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H)one, respectively are obtained.

Example 18 4 - Benzoyl - 8 - phenyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) - one By substituting 4 - hydrazino - 1 phenyl1H - pyrazolo[3,4 - b]pyridine - 5 - carboxylic acid, ethyl ester for the 1 - ethyl - 4hydrazino - 1H- pyrazolo[3,4 - b]pyridine5 - carboxylic acid, ethyl ester in the procedure of Example 1, then proceeding as in Example 4 but substituting benzoyl iodide for the methyl iodide, 8 - phenyl - 4Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one and 4 - benzoyl - 8 - phenyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]thiazolo [1,5 - a]pyrimidin - 5(8H) - one, respectively, are obtained.

Example 19 4,6 - Dimethyl - 8 - ethyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) a]pyrimidin - 5(8H) - one, respectively, are obtained.

Example 22 4,8 - Diethyl - 2 - phenyl - 411 pyrazolo [4',3':5,6]pyrido[3,4 - e] [1,2,4]tri azolo[1,5 - a]pyrimidin - 5(8H) - one By substituting α - ethoxybenzylidene cyanamide for the ethoxymethylene cyanamide in the procedure of Example 1, then proceeding as in Example 4 but substituting ethyl iodide for the methyl iodide, 8 - ethyl - 2 - phenyl4H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one and 4,8 - diethyl - 2 - phenyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) - one, respectively, are obtained.

Example 23 4 - Phenyl - 4H - pyrazolo[4',3':5,6]pyrido [3,4 - e][1,2,4]triazolo[1,5 - a]pyrimi din - 5(8H) - one a) 8 - Furfuryl - 4 - phenyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) - one By substituting 4 - hydrazino - 1 - furfurylpyrazolo[3,4 - b]pyridine - 5 - carboxylic acid, ethyl ester for the 1 - ethyl - 4 - hydrazino1H - pyrazolo[3,4 - b]pyridine - 5 - carboxylic acid, ethyl ester in Example 1, 8 - fur furyl - 4H - pyrazolo[4',3': 5,6]pyrido(3,4e][1,2,4]triazolo[1,5 - a]pyrimidin- 5(8H)one is obtained. This compound is now processed as in Example 4, substituting bromobenzene for the methyl iodide. A small amount of copper catalyst is added to obtain 8 - fur furyl - 4 - phenyl - 4H - pyrazolo[4',3':5,6]- pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one. b) 4 - Phenyl - 4H - pyrazolo[4',3':5,6]- pyrido[3,4 - e](1,2,4]triazolo[1,5 - a] pyrimidin -5(811) - one 0.01 mol. of 8 - furfuryl - 4 - phenyl - 4Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one is heated in 50 ml. of diethyleneglycol dimethylether containing 0.01 mol. of selenium dioxide at reflux temperature with stirring for two hours. The mixture is filtered hot and evaporated to dryness. 4 - Phenyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5a]pyrimidin - 5(8H) - one remains.

Example 24 8 - Benzoyl - 4 - phenyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 a]pyrimidin - 5(8H) - one 0.01 mol. of 4 - phenyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5a]pyrimidin - 5(8H) - one and 0.02 mol. of benzoyl chloride are stirred overnight in 50 ml. of dry pyridine at room temperature.

On addition of 50 ml. of water, 8 - benzoyl4 - phenyl - 4H - pyrazolo [4',3' :5,6] pyrido- [3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin 5(8H) - one is filtered off.

Example 25 4 - Methyl - 8 - (2 - methylbenzoyl) - 4H pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin 5(8H) - one By substituting 1 - (4 - methylbenzoyl) - 4hydryzino - 1H - pyrazolo[3,4 - b]pyridine5 - carboxylic acid, ethyl ester for the 1 - ethyl 4 - hydrazino - 1H - pyrazolo[3,4 - b]pyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example 1, then proceeding as in Example 4, 8 - (4 - methylbenzoyl) - 4Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one and 4 - methyl - 8 - (4 - methylbenzoyl) - 4Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[l,5 - a] - pyrimidin - 5(8H) - one, respectively, are obtained.

Example 26 4 - (2 Aminoethyl) - 6 - methyl - 8 - ethyl 4H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one By substituting the 8 - ethyl - 6 - methyl 4H - pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) - one obtained in Example 19 in the procedure of Example 2 but substituting 2 - chloroethyl amine for the dimethylaminopropyl chloride, 4 - (2 - aminoethyl) - 6 - methyl - 8 - ethyl 4H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one is obtained.

Example 27 4 - (3 - Ethoxypropyl) - 8 - ethyl - 4H- pyrazolo [4',3': 5,6] pyrido [3,4 - e] - [1,2,4] triazolo[1,5 - a]pyrimidin - 5(8H)- one By substituting 3 - ethoxypropyl chloride for the dimethylaminopropyl chloride in the procedure of Example 2, 4 - (3 - ethoxypro pyl) - 8 - ethyl - 4H - pyrazolo[4',3':5,6] pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimi din - 5(8H) - one is obtained.

Exammple 28 4 - Methylthiomethyl - 4H - pyrazolo[4',3': 5,6] pyrido [3,4 - e] [1,2,4]triazolo[1,5- a]pyrimidin -5(811) - one By substituting methylthiomethyl chloride for the dimethylaminopropyl chloride in the procedure of Example 2 and substituting the 4H - pyrazolo[1,5 - a]pyrazolo[4',3':5,6] pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimi din - 5(8H) - one obtained in Example 11 for the 8 - ethyl - 4H - pyrazolo[4',3':5,6]- pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimi din - 5(8H) - one, 4 - methylthiomethyl - 4H pyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4] triazolo[1,5 - a]pyrimidin - 5(8H) - one is obtained.

Example 29 8 - Benzoyl - 4 - (p - methylphenyl) - 4H pyrazolo[4',3': 5,6]pyrido[3,4 - el - [1,2,4]triazolo[1,5 - a]pyrimidin - 5(811)- one By substituting p-methylphenyl bromide for the bromobenzene in the procedure of Example 23a, then proceeding as in part b and Example 24, 4 - (p - methyiphenyl) - 4Hpyrazolo[4',3':5,6]pyrido - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) - one and 8benzoyl - 4 - (p - methylphenyl) - 4H pyrazolo[4',3' : 5,6]pyrido[3,4 - e] [1,2,4]tri- azolo[1,5 - a]pyrimidin - 5(8H) - one, respectively, are obtained.

Example 30 4 - [2 - Diethylamino)ethyl] - 8,10 - di methyl - 4H - pyrazolo[4',3':5,6]pyrido [3,4 - e][1,2,4]triazolo[1,5 - a]pyrimi din - 5(8H) - one By substituting diethylaminoethyl chloride for the dimethylaminopropyl chloride and utilizing the 8,10 - dimethyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5a]pyrimidin - 5(8H) - one product of Example 15 instead of 8 - ethyl - 4H - pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a] pyrimidin - 5(8H) - one in the procedure of Example 2, 4 - [2 - (diethylamino)ethyl] 8,10 - dimethyl - 4H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimi din - 5(8H) - one is obtained.

Example 31 4 - Dimethylaminomethyl - 8 - phenyl - 4H- pyrazolo [4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one By substituting dimethylaminomethyl chloride for the dimethylaminopropyl chloride in the procedure of Example 2 and utilizing 8phenyl - 4H - pyrazolo[4',3':5,6]pyrido[3,4e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one product of Example 18 instead of 8ethyl - 4H - pyrazolo[4',3': 5,6]pyrido[3,4 e] [1,2,4]triazolo[1,5 - alpyrimidin - 5(811)- one, 4 - dimethyl - aminomethyl - 8 - phenyl4H - pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H)one is obtained.

Example 32 8 - Ethyl - 4 - (2 - thiamorpholino)ethyl - 4H pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one By substituting 1 - chloro - 2 - thiamorpholinoethane for the 1 - chloro - 2 - morpholinoethane in the procedure of Example 8, 8-ethyl4 - (2 - thiamorpholino)ethyl - 4H - pyrazolo- [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5a]pyrimidin - 5(8H) - one is obtained.

Example 33 4 - (3 - Piperazino)propyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]tri azolo[l,5 - a]pyrimidin - 5(8H) - one By substituting 3 - piperazinopropyl chloride for the 1 - chloro - 2 - morpholinoethane in the procedure of Example 8 and utilizing the 4H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one product of Example 11, 4 - (3 - piperazino)propyl - 4H - pyrazolo [4',3': 5,6] pyrido [3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin 5(8H) - one is obtained.

Example 34 The following ingredients are used to make 1,000 200 mg. tablets each containing 100 mg. of active ingredient: 8 - ethyl - 4H - pyrazolo[4',3': 5,6]pyrido[3,4 - e][1,2,4] triazolo [1,5 - a]pyrimidine- 5(8H) - one 100 gm.

Polyvinyl pyrrolidone 7.5 gm.

Lactose 20 gm.

Magnesium stearate 3.5 gm.

Corn starch 17.5 gm.

Avicel - Trade Mark (micro crystalline cellulose) 51.5 gm.

The medicament and lactose are thoroughly admixed. The polyvinyl pyrrolidone is dissolved in ethanol USP to make a 30% solution. This solution is used to granulate the mixture of medicament and lactose. The granulation is passed through a No. 16 screen and air dried. The dried granulation is then passed through a No. 20 screen. To the screened granulate are added the magnesium stearate, Avicel and the corn starch and the mixture is blended. The blend is then compressed into 200 mg tablets on a standard concave punch. The tablets are then veneer coated with methyl cellulose in a spray pan.

Example 35 N - [3 - (Dimethylamino)propyl] - 8 - ethyl 811 - pyrazolo[4',3':5,6]pyrido[3,4 [1,2,4]triazolo[1,5 - a]pyrimidin - 5 amine a) 8 - Ethyl - 4H - pyrazolo[4',3':5,6]- pyrido[3,4 - e][1,2,4]triazolo[1,5 - a] pyrimidin - 5(8H) - one 249 g of 1 ethyl - 4 - hydrazino - 1H pyrazolo [3,4 - b]pyridine - 5 - carboxylic acid, ethyl ester (1 mol.) are refluxed in 1.5 liters of dry dioxane together with 98 g of ethoxvmethylene cyanamide for 12 hours.

After cooling to room temperature, the precipitated 8 - ethyl - 4H - pyrazolo[4',3':5,6]- pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one is filtered off and recrystal lized from dimethylformamide, yield 135 g.

(53%); m.p. 355-356 . b) 5 Chloro - 8 - ethyl - 8H - pyrazolo [4',3' : 5,6]pyrido[3,4 - e] [1,2,4]triazolo- [1,5 - a]pyrimidine 25.5 g. of 8 - ethyl - 4H - pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one (0.1 mol.) are refluxed in 100 ml. of phosphorus oxychloride for 12 tours. After this time, the excess of phosphorus oxychloride is distilled off in vacuo, the residue is treated with dry acetone and filtered off. 25 g. of 5 - chloro - 8 - ethyl8H - pyrazolo [4',3' : 5,6]pyrido [3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine are obtained yield 92%; m.p. 196-1970. c) N - [3 - (Dimethylamino)propyl] - 8 ethyl - 8H - pyrazolo [4',3' : 5,6]pyrido- (3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimi din - 5 - amine 2.7 g. of 5 - chloro - 8 - ethyl - 8H pyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidine are treated with 5 g. of 3 - dimethylaminopropylamine with stirring at 80 for 1 hour. The excess amine is removed in vacuo and the residue dissolved in hot ethyl acetate. The solution is filtered and the N - [3 - (dimethylamino)propyl] - 8ethyl - 8H - pyrazolo]4',3': 5,6]pyrido [3,4- e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5 - amine precipitates on cooling, yield 2.8 g. (83%); m.p. 190-192 . Treating the product with ethanolic HCI yields the hydrochloride salt.

Example 36 8 - Ethyl - N - (1 - methylpropyl) - 8H pyrazolo [4',3': 5,6]pyrido[3,4 - e] - [1,2,4]triazolo[1,5 - a]pyrimidin - 5 amine By substituting 1 - methylpropylamine for the 3 - dimethylaminopropylamine in the procedure of Example 35c, 8 - ethyl - N - (1methvlpropyl) - 8H - pyrazolo[4',3':5,6]- pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5 - amine is obtained, yield 78%; m.p.

228230' (methanol).

Example 37 N,N - 8 - Triethyl - 8H - pyrazolo[4',3': 5,6]pyridot3,4 - e] [1,2,4]triazolo[1,5 a]pyrimidin - 5 - amine By substituting diethylamine for the 3dimethylaminopropylamine in the procedure of Example 35c, N,N - 8 - triethyl - 8Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4] triazolo[1,5 - alpyrimidin - 5 - amine is formed, yield 71 %; m.p. 215-217 (ethyl acetate).

Example 38 5 - Ethoxy - 8 - ethyl - 8H - pyrazolo[4',3': 5,6]pyridof3,4 - e][1,2,4]triazolo[1,5 a] pyrimidine 2.7 g. of 5 - chloro - 8 - ethvl - 8Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4] triazolo[1,5 - a]pvrimidine of Example 35b (0.01 mol.) are added with stirring to a solution of 2.3 g. of sodium in 50 ml. of dry ethanol. The mixture is stirred at room temperature for 6 hours. The precipitate is filtered off, washed with water and recrystallized from ethanol to obtain 5 - ethoxy - 8ethyl - 8H - pyrazolo[4',3':5,6]pyrido - [3,4e][1,2,4]triazolo[1,5 - a]pyrimidine, yield 2.1 g. (74%); m.p. 196-197 .

Example 39 8 - Ethyl - 5 - methoxy - 8H - pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 a]pyrimidine 5 - Cholro - 8 - ethyl - 8H - pyrazolo[4',3': 5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a] pyrimidine of Example 35b is treated with sodium methoxide in methanol as described in Example 38 to obtain 8 - ethyl - 5 - meth oxy - 8H - pyrazolo[4',3':5,6]pyrido[3,4 e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5 - amine yield 68%; m.p. 215-216 (alcohol).

Example 40 5 - Butoxy - 8 - ethyl - 8H - pyrazolo[4',3'.

5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine By substituting butyl alcohol for ethanol in Example 38 5 - butoxy - 8 - ethyl - 8H pyrazolo [4',3': 5,6]pyrido[3,4 - e][1,2,4] - triazolo[1,5 - a]pyrimidine is obtained, yield 81%; m.p. 140-142 (butanol).

Example 41 5 - [2 - (Dimethylamino)ethoxy] - 8 - ethyl 8H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine 8.9 g. of 2 - dimethylaminoethanol are dissolved in 200 ml. of anhydrous benzene.

To this solution a corresponding amount of butyl-lithium in hexane is added with stir ring: After 1 hour, 5.5 g. of 5 - chloro - 8ethyl - 8H - pyrazolo[4',3': 5,6]pyrido[3,4- e][1,2,4]triazolo[1,5 -a]pyrimidine of Example 35b are added and the mixture is refluxed with stirring for 12 hours. The solvent is distilled off in vacuo and the residue is treated with 5 ml. of water and filtered off.

Recrystallisation from ethyl acetate yields 4.5 g. of 5 - [2 - (dimethylamino)ethoxy]8 - ethyl - 8H - pyrazolo[4',3':5,6]pyrido [3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine; m.p. 149-150 .

Example 42 8 - Ethyl - 5 - (3 - methylbutoxy) - 8H pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine By substituting 3 - methylbutanol for the 2 - dimethylaminoethanol in the procedure of Example 41, 8 - ethyl - 5 - (3 - methylbutoxy) 8H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine is obtained, yield 68%; m.p. 140-142 : Example 43 8 - Ethyl -5 - methylthio - 8H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidine 2.7 g. of 5 - chloro - 8 - ethyl - 8Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4] triazolo[1,5 - a]pyrimidine are treated with 1,5 g. of sodium methylmercaptide in 30 ml. of dimethylformamide with stirring at 80 for 5 hours. After this time, 10 ml. of water are added and the precipitate, 8 - ethyl - 5methyltio - 8H - pyrazolo[4',3':5,6]pyrido [3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidine, is filtered off, yield 2.2 g. (77%); m.p. 198200 (butanol).

Example 44 8 - Ethyl - 5 - ethoxy - 2 - methylthio - SH- pyrazolo[4',3' : 5,6]pyrido[3,4 - e] - [1,2,4]triazolo[1,5 - a]pyrimidine a) 8 - Ethyl - 2 - methylthio - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5(8H) - one 24.9 g. of 1 - ethyl - 4 - hydrazino - lH- pyrazolo[3,4 - b]pyridine - 5 - carboxylic acid, ethyl ester (0.1 mol.) are heated in 200 ml. of butyl alcohol with 11.5 g. of di(methylmercapto)methyl - methylene cyanamide for 10 hours. The solution is cooled to room temperature and the precipitated 8 - ethyl - 2methylthio - 4H - pyrazolo[4',3':5,6]pyrido [3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin 5(8H) - one is filtered off, yield 14.0 g. (46%); m.p. > 300 (DMF). b) 8 - Ethyl - 5 - ethoxy - 2 - methylthio 8H - pyrazolo[4',3':5,6]pyrido(3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine 14 g. of 8 - ethyl - 2 - methyltio - 4H pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]tri- azolo[l,5 - a]pyrimidin - 5(8H) - one are treated with 50 ml of phosphorus oxychloride at 80 for 24 hours. The excess phosphorus oxychloride is distilled off and the residue carefully treated with 100 ml. of alcohol.

After evaporation of the alcohol the remaining 8 - ethyl - 5 - ethoxy - 2 - methylthio - 8Hpyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]tri- azolo [1,5 - a]pyrimidine is recrystallized from dimethylformamide, yield 53%; m.p. 209211 .

Example 45 8 - Ethyl - 5 - ethoxy - 2 - methylsulfinvl 8H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine a) 8 - Ethyl - 2 - methylsulfinyl - 4H pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one 3.01 g. of 8 - ethyl - 2 - methylthio - 4Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one obtained in Example 44a are oxidized with 2.2 g. of sodium metaperiodate in aqueous alcohol for 7 days at room temperature. The precipitate of 8 - ethyl - 2 - methylsulfinyl4H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one is filtered off, washed with water and recrvstallized from dimethylformamide, yield 2.8 g. (88%); m.p. > 300 . b) 8 - Ethyl - 5 - ethoxy - 2 - methylsulfinyl 8H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine By substituting the product of part a in the procedure of Example 44b, 8 - ethyl - 5ethoxy - 2 - methylsulfinyl - 811 pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5a]pyrimidine is obtained.

Example 46 8 - Ethyl - N - methyl - 8H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]tri azolo[1,5 - a]pyrimidin - 5 - amine By substituting methylamine for the 3 - dimethylaminopropylamine in the procedure of Example 35c, 8 - ethyl - N - methyl - 8Hpyrazolo [4',3': 5,6] pyrido [3,4 - e] [1,2,4] triazolo[1,5 - a]pyrimidin - 5 - amine is obtained m.p. > 300 .

Example 47 8 - Ethyl - 5 - (1 - piperidinyl) - 8H pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine By substituting piperidine for the 3 - dimethylaminopropylamine in Example 35c, 8 - ethyl - 5 - (1 - piperidinyl) - 8H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5a]pyrimidine is obtained.

Example 48 N - [2 - (Diethylamino)ethyl] - 8 - ethyl 8H - pyrazolo[4',3': 5,6]pyrido[3,4 [1,2,4]triazolo[1,5 - a]pyrimidin - 5 amine By substituting for the (3-dimethylamino)propylamine in Example 35c the equivalent amount of 2 - (diethylamino)ethylamine, N [2 - (diethylamino)ethyl] - 8 - ethyl - 8Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin - 5 - amine is obtained.

Example 49 5 - Methoxy - 8H -pyrazolo[4',3':5,6]pyrido [3,4 - e][1,2,4]triazolo[1,5 - a]pyrimi dine By substituting an equivalent amount of 4hydrazino - 111 - pyrazolo [3,4 - b]pyridine5 - carboxylic acid, ethyl ester for the 1 - ethyl4 - hydrazino - 1H - pyrazolo[3,4 - b]pyridine5 - carboxylic acid, ethyl ester in the procedure of Example 35a, b, then continuing as in Example 38 but substituting methanol for ethanol, 411 - pyrazolo [4',3': 5,6]pyrido[3,4- e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one, 5 - chloro - 8H - pyrazolo[4',3':5,6] pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimi dine and 5 - methoxy - 8H - pyrazolo[4',3': 5,6]pyrido[3,4 - e][1,2,4triazolo[1,5 - a]pyrimidine, respectively, are obtained.

Example 50 5 - Phenylmethoxy - 8H - pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 aj pyrimidine By substituting the 5 - chloro - 8H - pyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidine of Example 49 for the 5chloro - 8 - ethyl - 8H - pyrazolo[4',3':5,6] pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidine and benzyl alcohol for the ethanol in the procedure of Example 38, 5 - phenylmethoxy - 8H - pyrazolo[4',3':5,6]pyrido [3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine is obtained.

Example 51 8 - Ethyl -5 - (2 - phenylethoxy) - 8H pyrazolo [4',3 :5,6]pyrido[3,4 - e] - [1,2,4]triazolo[1,5 - a]pyrimidine By substituting phenylethyl alcohol for the ethanol in the procedure of Example 38, 8ethyl - 5 - (2 - phenylethoxy) - 8H - pyrazolo- [4',3' : 5,6]pyrido [3,4 - e] [1,2,4] triazolo [1,5a]pyrimidine is obtained.

Example 52 5 - Phenyloxy - 8,10 - dimethyl - 811 - pyra- zolo[4',3':5,6]pyrido[3,4 - e][1,2,4]tri azolo[l,5 - a]pyrimidine By substituting 1,3 - dimethyl - 4 hydrazino - 1H - pyrazolo[3,4 - b]pyridine 5 - carboxalic acid, ethyl ester for the 1 ethyl - 4 - hydrazino - 1H - pyrazolo[3,4 - b]pyridine - 5 - carboxylic acid, ethyl ester in the procedure of Example 35 and proceeding as in Example 38, but substituting phenol for the ethanol, 8,10 - dimethyl - 4H - pyrazolo [4',3': 5,6] - pyrido[3,4 - e][1,2,4]triazolo- [1,5 - a]pyrimidin - 5(8H) - one, 5 - chloro8,10 - dimethyl - 8H - pyrazolo[4',3':5,6]- pyrido[3,4 - ej [1,2,4]triazolo[1,5 - a]pyrimidine and 5 - phenyloxy - 8,10 - dimethyl8H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine, respectively, are obtained.

Example 53 2 - Ethyl - 8 - isopropyl - 5 - morpholino 8H - pyrazolo[4',3':5,6]pyrido[3,4 [1,2,4] triazolo [1,5 - a] pyrimidine By substituting 1 - isopropyl - 4 hydrazino - 1H - pyrazolo[3,4 - b]pyridine 5 - carboxylic acid, ethyl ester for the 1 ethyl - 4 - hydrazino - 1H - pyrazolo[3,4 b]pyridine - 5 - carboxylic acid, ethyl ester and 1 - ethoxypropylidene cyanamide for the ethoxy methylene cyanamide in part a and morpholine for the 3 - dimethylaminopropylamine in part c of the procedure of Example 35, 2ethyl 8 - isopropyl - 4H - pyrazolo[4',3': 5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a1- pyrimidin - 5(8H) - one, 5 - chloro - 2ethyl - 8 - isopropyl - 8H - pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine and 2 - ethyl - 8 - isopropyl - 5 morpholino - 8H- - pyrazolo [4',3': 5,6] pyrido- [3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine, respectively, are obtained.

Example 54 5 - (4 - Chlorophenyloxy) - 10 - ethyl - 8H pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4] triazolo [1,5 - al pyrimidine By substituting 3 - ethyl - 4 - hydrazino1H - pyrazolo[3,4 - b]pyridine - 5 - carboxylic acid propyl ester for the 1 - ethyl - 4 hydrazino - 111 - pyrazolo [3,4 - b]pyridine 5 - carboxylic acid, ethyl ester in the procedure of Example 35a, b and then following the procedure of Example 38 but substituting 4chlorophenol for the ethanol, 10 - ethyl - 4H pyrazolo [4',3': 5,6]pyrido[3,4 - e] [1,2,4] triazolo[1,5 - a]pyrimidin - 5(8H) - one, 5 chloro 10 - ethyl - 8H- - pyrazolo[4',3':5,6]- pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine and 5 - (4 - chlorophenyloxy) - 10 - ethyl8H - pyrazolo [4',3' :5,6] pyrido [3,4 - e] - [1,2,4] triazolo [1,5 - a] pyrimidine, respectively, are obtained.

Example 55 5 - (3 - methylphenyloxy) - 8 - phenyl - 8H pyrazolo[4',3':5,6]pyrido[3,4 - a] - [1,2,4]triazolo[1,5 - a]pyrimidine By substituting 4 - hydrazino - 1 - phenyl1H - pyrazolo[3,4 - b]pyridine - 5 - carboxylic acid, ethyl ester for the 1 - ethyl - 4 - hydrazino - 1H - pyrazolo[3,4 - b]pyridine - 5carboxylic acid, ethyl ester in the procedure of Example 35a, b, then proceeding as in Example 38 but substituting 3 - methylphenol for the ethanol 8 - phenyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 e][1,2,4]triazolo[1,5a]pyrimidin - 5(8H) - one, 5 - chloro - 8phenyl - 811 - pyrazolo [4',3': 5,6] pyrido [3,4- e][1,2,4]triazolo[1,5 - a]pyrimidine and 5 (3 - methylphenyloxy) - 8 - phenyl - 8H pyrazolo[4',3': 5,6]pyrido [3,4 - e] [1,2,4]tri- azolo [1,5 - a]pyrimidine, respectively, are obtained.

Example 56 N - [2 - (Diethylamino)ethyl] - 8 - ethyl 6 - methyl - 8H - pyrazolo[4',3':5,6] pyrido[3,4 - e][1,2,4]triazolo[1,5 - a] pyrimidin -5 - amine By substituting 1 - ethyl - 4 - hydrazino 6 - methyl - 111 - pyrazolo[3,4 - b]pyridine5 - carboxylic acid, ethyl ester for the 1ethyl - 4 - hydrazino - 1H - pyrazolo[3,4 pyridine - 5 - carboxylic acid, ethyl ester in part a and 2 - diethylaminoethylamine for the 3-dimethylaminopropylamine in part c of the procedure of Example 35a, b, 8 - ethyl - 6methyl - 4H - pyrazolo[4',3':5,6]pyrido[3,4e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H)one , 5 - chloro - 8 - ethyl - 6 - methyl - 8Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidine and N - [2 - (diethylamino)ethyl] - 8 - ethyl - 6 - methyl8H - pyrazolo[4',3': 5,6]pyrido[3,4 [1,2,4]triazolo[1,5 - a]pyrimidin - 5 - amine, respectively, are obtained.

Example 57 8 - Benzyl - N - (1 - methylpropyl) - 8H pyrazolo[4',3': 5,6]pyrido[3,4 - eJ - (1,2,4]triazolo[1,5 - a]pyrimidin - 5 amine By substituting 1 - benzyl - 4 - hyrazino1H - pyrazolo[3,4 - b]pyridine - 5 - carboxylic acid, ethyl ester for the 1 - ethyl - 4hydrazino - 1H - pyrazolo[3,4 - b]pyridine5 - carboxilic acid, ethyl ester in the procedure of Example 35a, b, then proceeding as in Example 36, 8 - benzyl - 4H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5a]pyrimidin - 5(8H) - one and 8 - benzyl - 5chloro - 8H - pyrozolo[4',3':5,6]pyrido[3,4e][1,2,4]triazolo[1,5 - a]pyrimidine and 8benzyl - N - (1 - methyl - propyl) - 8Hpyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]tri- azolo[l,5 - a]pyrimidin - 5 - amine, respectively, are obtained.

Example 58 5 - Methoxy - 8 - phenylethyl - 2 - propyl 811 - pyrazolo[4',3': 5,6]pyrido [3,4 [1,2,4] tri the procedure of Example 35, 8 - (4 - methylbenzoyl) - 4H - pyrazolo[4',3':5,6]pyrido [3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin5(8H) - one, 5 - chloro - 8 - (4 - methylbenzoyl) - 8H - pyrazolo[4',3':5,6]pyrido [3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidine and N - [3 - (dimethylamino) - propyl] - 8 (4 - methylbenzoyl) - 8H - pyrazolo[4',3': 5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin - 5 - amine, respectively, are obtained.

Example 62 5 - (2 - Aminoethoxy) - 6 - methyl - 8 - ethyl- 8H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine By substituting the 8 - ethyl - 6 - methyl4H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H)one obtained in Exaple 56 in the procedure of Example 41 but substituting 2 - hydroxyethylamine for the 2 - dimethylaminoethanol, 5 - (2 - aminoethoxy) - 6 - methyl - 8 - ethyl4H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine is obtained.

Example 63 N - Phenyl - 8 - ethyl - 8H - pyrazolo[4',3': 5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 a]pyrimidin - 5 - amine By substituting anilinie for the 3 - dimethylaminopropyl amine in the procedure of Example 35c, N - phenyl - 8 - ethyl - 8Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin - 5 - amine is obtained.

Example 64 8 - Ethyl -N - (2 - methylphenyl) - 8H pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5 amine By substituting o-toluidine for the 3 - di methylaminopropylamine in the procedure of Example 35c, 8 - ethyl - N - (2 - methyl phenyl) - 8H - pyrazolo[4',3':5,6]pyrido[3,4- e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5 - amine is obtained.

Example 65 N - '2 - Dimethylaminoethyl - 8,10 - di methyl - 8H - pyrazolo[4',3':5,6] pyrido[3,4 - e][1,2,4]triazolo[1,5 - a] pyrimidin - 5 - amine By substituting 2 - dimethylaminoethylamine for the 3 - dimethylaminopropyl - 1 - amine in part c and utilizing the 8,10 - dimethyl 8H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) one of Example 52 instead of 8 - ethyl - 4H pyrazolo [4',3': 5,6]pyrido[3,4 - e] [1,2,4]tri- azolo[l,5 - a]pyrimidin - 5(8H) - one in part b of the procedure of Example 35, N - (2 dimethylaminoethyl) - 8,10 - dimethyl - 8H pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]tri- azolo[l,5 - a]pyrimidin - 5 - amine is obtained.

Example 66 N - (3 - (Diethylaminopropyl) - 8 - phenyl 8H - pyrazolo [4',3' :5,6] pyrido [3,4 - e]- [1,2,4] triazolo[1,5 - a]pyrimidin - 5 amine By substituting 3-diethylaminopropylamine for the 3-dimethylaminopropyl - 1 - amine in part c of the procedure of Example 35 and utilizing 8 - phenyl - 4H - pyrazolo[4',3': 5,6]pyrido[4,3 - d][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one product of Example 55 instead of 8 - ethyl - 4H - pyrazolo[4',3'; 5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin - 5(8H) - one in part b, N - 3 - (diethylaminopropyl) - 8 - phenyl - 8H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidin - 5 - amine is obtained.

Example 67 8 - Ethyl - 5 - thiamorpholino - 8H - pyrazolo [4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidine By substituting thiamorpholine for the 3dimethylaminopropyl - 1 - amine in the procedure of Example 35, 8 - ethyl - 5 - thiamorpholino - 8H - pyrazolo [4',3': 5,6] pyrido [3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine is obtained.

Example 68 8 - Ethyl - 5 - [piperazino) - 8H - pyrazolo [4',3': 5,6]pyrido[3,4 - e] [1,2,4]triazolo- [1,5 - a]pyrimidine By substituting piperazine for the 3- methylamino propylamine in the procedure of Example 35, 8 - ethyl - 5 - (piperazino) - 8H pyrazolo[4',3': 5,6]pyrido[3,4 - e] [1,2,4]tri- azolo[l,5 - a]pyrimidine is obtained.

Example 69 8 - Ethyl - 5 - (4 - methyl - 1 - piperazinyl) 8H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine By substituting 4 - methylpiperazine for the 3 - (dimethylamino)propylamine in the procedure of Example 35c, 8 - ethyl - 5 - (4methyl - 1 - piperazinyl) - 8H - pyrazolo [4',3': 5,6]pyrido[3,4 e] [1,2,4]triazolo[1,5- a]pyrimidine is formed.

Example 70 8 - Ethyl - 5 - (1 - pyrrolidinyl) - 8H pyrazolo[4',3':5,6]pyrido[3,4 - e] (1,2,4]triazolo[1,5 - a]pyrimidine By substituting pyrolidine for 3 - (di methylamino)propylamine in the procedure of Example 35c, 8 - ethyl - 5 - (1 - pyrrolidinyl8H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine is obtainend.

Example 71 8 - Ethyl - N - [3 - [trifluoromethyl)phenyl] 8H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5 amine 5.8 g. of 5 - chloro - 8 - ethyl - 8H - pyra zolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo [1,5 - a]pyrimidine (0.02 mol.), 3 g. of triethylamine and 3.3 g. of 3 - trifluoromethylaniline are refluxed in butyl alcohol for 24 hours with stirring. The solvent is removed in vacuo and the residue treated with 20 ml. of water and filtered off. Recrystallization from alcohol yields 8 - ethyl - N - [3 - (trifluoromethyl]phenyl] - 8H - pyrazolo[4',3':5,6] pvrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidin - 5 - amine.

Example 72 8 - Ethyl - 8H - pyrazolo[4',3':5,6]pyrido [3,4 - e][1,2,4]triazolo[1,5 - a]pyrimi din - 5 - amine By substituting aqueous ammonia (30%) for the diethylamine in the procedure of Example 37, 8 - ethyl - 8H - pyrazolo[4',3':5,6]pyrido [3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidin5 - amine is obtained.

Example 73 8 - Ethyl - 8H - pyrazolo[4',3':5,6]pyrido [3,4 - e] [I,2,4]triazolo[1,5 - a]pyrimi dine - 5 - thiol 5.6 g. of 5 - chloro - 8 - ethyl - 8Hpyrazolo[4',3':5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidine (0.02 mol.) are dissolved in 100 ml. of dimethylformamide. 2 g. of powdered sodium sulfide are added and the mixture is stirred for 1 hour. After this time, the solution is carefully acidified with acetic acid. 8 - Ethyl - 8H - pyrazolo[3',4': 5,6]pyrido[3,4 - ej [1,2,4]triazolo[1,5 - a]pyrimidine - 5 - thiol precipitates and is filtered off.

Example 74 8 - Ethyl - 5 - (1 - pyrazolyl) - 8H - pyrazolo [4',3' : 5,6]pyrido[3,4 - e] [1,2,4]triazolo- [1,5 - a]pyrimidine By substituting pyrazole for the 3 - (dimethylamino) - propylamine in the procedure of Example 35c, 8 - ethyl - 5 - (1 - pyrazolyl)8H - pyrazolo[4',3':5,6]pyrido[3,4 - e] [1,2,4]triazolo[1,5 - a]pyrimidine is obtained.

Example 75 8 - Ethyl - 5 - (dihydropyridazin - 1 - yl) 8H - pyrazolo[4',3':5,6]pyrido[3,4 [1,2,4] triazolo [1,5 - a] pyrimidine By substituting dihydropyridazine for the 3 - (dimethylamino)propylamine in the procedure of Example 35c, 8 - ethyl - 5 - (dihydropyridazin - 1 - yl) - 8H - pyrazolo[4',3': 5,6]pyrido[3,4 - e][1,2,4]triazolo[1,5 - a]pyrimidine is obtained.

Example 76 The following ingredients are used to make 1,000 200 mg. tablets each containing 100 mg. of active ingredient: N - - [3 - (Dimethylamino]pro- pyl] - 8 - ethyl - 8H - pyra zolo [4',3' :5,6] pyrido(3,4 e] [1,2,4]triazolo[1,5 - a] - pyrimidine - 5 - amine 100 gm.

Polyvinyl pyrrolidone 7.5 gm.

Lactose 20 gm.

Magnesium stearate 3.5 gm.

Cornstarch 17.5 gm.

Avicel (microcrystalline cellulose) 51.5 gm.

The medicament and lactose are thoroughly admixed. The polyvinyl pyrrolidone is dissolved in ethanol USP to make a 30% solution. This solution is used to granulate the mixture of medicament and lactose. The granulation is passed through a No. 16 screen and air dried. The dried granulation is then passed through a No. 20 screen. To the screened granulate are added the magnesium stearate, Avicel and the corn starch and the mixture is blended. The blend is then compressed into 200 mg. tablets on a standard concave punch. The tablets are then veneer coated with methyl cellulose in a spray pan.

Claims

WHAT WE CLAIM IS: -

1. A compound of the formula

wherein Z is

R1 is hydrogen, lower alkyl, phenyl, phenyllower alkylene, benzoyl or substituted benzoyl wherein the benzoyl substituent is one or two halogen, lower alkyl or trifluoromethyl radicals; R2 is hydrogen, lower alkyl or phenyl; R3 is hydrogen, lower alkyl, phenyl, lower alkylthio or lower alkylsulfinyl; R4 is hydrogen, lower alkyl, phenyl-lower alkylene, benzoyl, substituted benzoyl, lower alkanoyl, lower alkoxylower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl, or

R6 N-lower alkylene, morpholino, thiamorpholino, or piperazino, the substituents on said substituted phenyl and substituted benzoyl being halogen, lower alkoxy or lower alkyl. R41 is halo,

phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, lower alkyl or trifluoromethyl radicals; lower alkoxy or substituted lower alkoxy wherein the lower alkoxy substituent

R5 is hydrogen or lower alkyl; R6 is hydrogen, lower alkyl, substituted lower alkyl wherein the lower alkyl substituent is

phenyl or substituted phenyl wherein the phenyl substituent is halogen, lower alkyl or trifluoromethyl, R7 is hydrogen or lower alkyl, or R8 and R7 together with the nitrogen form one of the unsubstituted or substituted heterocyclics pyrrolidino, morpholinq thiamorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl wherein the heterocycle substituent is lower alkyl or hydroxy-lower alkylene; R8, R9 and R10 each is hydrogen or lower alkyl; or such a compound in acid addition salt form.

2. A compound of the formula

wherein R1 is hydrogen, lower alkyl, phenyl, phenyl-lower alkylene, benzoyl or substituted benzoyl; R and R5 each is hydrogen or lower alkyl; R is hydrogen, lower alkyl, phenyl, lower alkylthio or lower alkylsulfinyl; R4 is hydrogen, lower alkyl, phenyl lower alkylene, benzoyl5 substituted benzoyl, lower alkanoyl, lower alkoxy-lower alkylene, lower alkylthiolower alkylene, phenyl, substituted phenyl, amino-layer alkylene or

R N-lower alkylene, w wherein R6 and RI each is lower alkyl or together join to complete the heterocycle piperidene, morpholine, thiomorpholine or piperazine, the substituents on said substituted phenyl and substituted benzoyl being halogen, lower alkoxy or lower alkyl; or such a com- pound in acid addition salt form.

3. A compound as in Claim 2 wherein Rl is lower alkyl; R2 and R5 each is hydrogen or lower alkyl; R is hydrogen, lower alkyl, lower alkylthio or lower alkylsulfinyl; and R4 is hydrogen, lower alkyl or di-lower alkylamino-lower alkylene.

4. A compound as in Claim 2 wherein R is lower alkyl, R, R and R5 each is hydrogen or lower alkyl; and R4 is hydrogen, lower alkyl or di-lower alkylamino-lower alkylene.

5. A compound as in Claim 4 wherein the lower alkyl and lower alkylene groups have up to 4 carbon atoms.

6. A compound as in Claim 2 wherein R4 is lower alkyl.

7. A compound as in Claim 2 wherein R4 is di-lower alkylamino-lower alkylene.

8. A compound as in claim 2 wherein R3 is lower alkylthio.

9. A compound as in Claim 2 wherein R3 is lower alkylsulfinyl.

10. A compound as in Claim 2 wherein R1 and R4 each is lower alkyl and R2, R3 and R5 each is hydrogen.

11. A compound as in Claim 2 wherein R, R3 and R5 each is hydrogen.

12. A compound as in claim 11 wherein R' is ethyl and Tri is hydrogen.

13. A compound as in Claim 11 wherein RI is ethyl and Tri is isopentyl.

14. A compound as in Claim 11 wherein R is ethyl and R4 is 3-dimethylaminopropyl.

15. A compound as in Claim 11 wherein R is ethyl and R4 is methyl.

16. A compound as in Claim 2 wherein R is ethyl, R2, R4 and R5 each is hydrogen and Tri is methylthio.

17. A compound as in Claim 2 wherein R is ethyl, R2, R4 and RI each is hydrogen and R3 is methylsulfinyl.

18. A compound of the formula

wherein R is hydrogen, lower alkyl, phenyl, phenyl-lower alkylene, benzoyl or substituted benzoyl wherein the benzoyl substituent is one or two halogen, lower alkyl or trifluoromethyl radicals; R2 is hydrogen, lower alkyl or phenyl; R3 is hydrogen, lower alkyl, phenyl, lower alkylthio or lower alkylsulfinyl; R4' is halo,

phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, lower alkyl or trifluoromethyl radicals; lower alkoxy or substituted lower alkoxy wherein the lower alkoxy substituent is

R5 is hydrogen or lower alkyl; R6 is hydrogen, lower alkyl, substituted lower alkyl wherein the lower alkyl substituent is

phenyl, substituted phenyl wherein the phenyl substituent is halogen, lower alkyl or trifluoro- methyl, RI is hydrogen or lower alkyl, or R6 and R7 together with the nitrogen form one of the unsubstituted or substituted heterocyclics pyrrolidino, morpholino, thiamorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl wherein the heterocycle substituent is lower alkyl or hydroxy-lower alkylene; R8, R9 and R10 each is hydrogen or lower alkyl; and acid addition salts thereof.

19. A compound as in Claim 18 wherein R, R and R5 each is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl or lower alkylthio; R is amino, mercapto, lower alkylthio, lower alkylamino, lower alkoxy, di(lower alkyl)amino, di(lower alkyl)amino-lower alkylamino or di(lower alkyl)amino-lower alkoxy.

20. A compound as in Claim 18 wherein R, R and R5 each is hydrogen.

21. A compound as in claim 18 wherein R4, is di(lower alkyl)amino.

22. A compound as in Claim 18 wherein R4' is lower alkoxy.

23. A compound as in Claim 18 wherein R4' is di(lower alkyl)amino-lower alkylamino.

24. A compound as in Claim 18 wherein R4' is di(lower alkyl)amino-lower alkoxy.

25. A compound as in Claim 18 wherein R4' is halogen.

26. A compound as in Claim 18 wherein R4' is lower alkylthio.

27. A compound as in Claim 18 wherein R4' is lower alkylamino.

28. A compound as in Claim 20 wherein Rl is lower alkyl and R5 is lower alkylamino.

29. A compound as in Claim 20 wherein Rl is lower alkyl and R5 is lower alkoxy.

30. A compound as in Claim 20 wherein Rl is ethyl and R4' is chloro.

31. A compound as in Claim 20 wherein R1 is ethyl and R4' is butylamino.

32. A compound as in Claim 20 wherein Rl is ethyl and R4' is ethoxy.

33. A compound as in Claim 20 wherein RI is ethyl and R4' is 3-(dimethylamino)propylamino.

34. A compound as in Claim 20 wherein R is ethyl and R5 is diethylamino.

34. A compound as in Claim 20 wherein R is ethyl and R4' is 3-methylbutoxy.

34. A compound as in Claim 20 wherein R1 is ethyl and R4' is methoxy.

37. A compound as in Claim 20 wherein Rl is ethyl and Ra is 1-methylpropylamino.

38. A compound as in Claim 20 wherein RI is ethyl and R4' is dimethylaminoethoxy.

39. Process for preparing a compound of the formula

wherein Z is N-R4 N or C=O C-R4 RI is hydrogen, lower alkyl, phenyl, phenyllower alkylene, benzoyl or substituted benzoyl wherein the benzoyl substituent is one or two halogen, lower alkyl or trifluoromethyl radicals; Ra is hydrogen, lower alkyl or phenyl; R3 is hydrogen, lower alkyl, phenyl, lower alkylthio or lower alkylsulfinyl; R4 is hydrogen, lower alkyl, phenyl-lower alkylene, benzoyl, substituted benzoyl, lower alkanoyl, lower alkoxy-lower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl, or

RB N-lower alkylene, R7/ morpholino, thiomorpholino, or piperazino, the substituents on said substituted phenyl and substituted benzoyl being halogen, lower alkoxy or lower alkyl, R4' is halo,

phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, lower alkyl or trifluoromethyl groups; lower alkoxy or substituted lower alkoxy wherein the lower alkoxy substituent is

R5 is hydrogen or lower alkyl; R6 is hydrogen, lower alkyl, substituted lower alkyl wherein the lower alkyl substituent is

phenyl or substituted phenyl wherein the phenyl substituent is halogen, lower alkyl or trifluoromethyl, R7 is hydrogen or lower alkyl, or Ra and R7 together with the nitrogen form one of the unsubstituted or substituted heterocyclics pyrrolidino, morpholino, thiomorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl wherein the heterocycle substituent is lower alkyl or hydroxy-lower alkylene; R8, R9 and R10 each is hydrogen or lower alkyl; and acid addition salts thereof which comprises reacting a compound of the formula

wherein R, R and R5 are defined as above with a compound of the formula

wherein R is lower alkyl and R is defined as above to form a compound of the formula

wherein R, R2, R3 and R5 are defined as above and, if desired, treating a compound of Formula V with a compound of the formula RI-hal wherein hal is halogen and R4 is defined as above other than hydrogen in the presence of a base or, if desired, reacting a compound of formula V with a chlorinating agent to form a compound of the formula

wherein R, R2, RI and R5 are defined as above and, if desired, reacting the compound of Formula VI with a compound of the formula lower all:yl-0-Me or Me-O-lower

R" alkylene-N RI0 wherein Me is an alkali metal and R9 and Rl are defined as above or with a compound of the formula R8-S-Me wherein R8 is lower alkyl and Me is defined as above or with an alkali metal sulfide or with an amine of the formula

or H2N-lower

Ra alkylene-N RI0 wherein Ra, RI, R9 and Rl are defined as above.

40. The process of Claim 39 for preparing a compound of the formula

wherein Rl, R2, RI, R4 and R5 are defined as in Claim 39 which comprises reacting a compound of the formula

wherein R, R and R5 are defined as in Claim 39 with a compound of the formula

wherein R and R are defined as in Claim 39 to form a compound of the formula

wherein Rl, RI, R3 and R5 are defined as in Claim 39 and, if desired, treating a compound of Formula V with a compound of the formula RI-hal wherein hal is defined as in Claim 39 and R4 is defined as in Claim 39 other than hydrogen in the presence of a base.

41. The process of Claim 39 for preparing a compound of the formula

wherein R, R, R , R4' and R5 are defined as in Claim 39 which comprises reacting a compound of the formula

wherein R, RI, R3 and R5 are defined as in Claim 39 with a chlorinating agent to form a compound of the formula

wherein Rl, RI, R3 and R5 are defined as in Claim 39 and, if desired, reacting the compound of Formula VI with a compound of the formula lower alkyl-O-Me or Me-O-lower

R9 alkylene-N VII RI' Rl wherein Me, R9 and Rl are defined as in Claim 39 or with a compound of the formula R8-S-Me wherein R8 and Me are defined as in Claim 39 or with an alkali metal sulfide or with an amine of the formula

H2N-lower

RI alkylene-N \Rt wherein Ra, RI, Ra and R10 are defined as in Claim 39.

42. The compound of claim 1 when prepared the process of Claim 39.

43. The compound of Claim 2 when prepared the process of Claim 40.

44. The compound of Claim 18 when prepared the process of Claim 41.

45. The compound of Claim 2 as named in any of Examples 1-33.

46. A pharmaceutical composition comprising a compound as claimed in any one of Claims 2-17, 43 and 45 and a pharmaceutical carrier.

47. A composition as claimed in Claim 46 in the form of a tablet, capsule, elixir, sterile injectable preparation, lotion, ointment or cream.

48. A composition as claimed in Claim 46 or 47, which includes a binder, preservative, stabilizer, flavour, sweetener, lubricant or disintegrating agent.

49. A composition as claimed in Claim 46, substantially as described in Example 34.

50. The compound of Claim 18 as named in any of Examples 35-75.

51. A pharmaceutical composition comprising a compound as claimed in any one of claims 18-38, 44 and 50 and a pharmaceutical carrier.

52. A composition as claimed in Claim 51 in the form of a tablet, capsule, elixir, sterile injectable preparation, lotion, ointment or cream. ~~~~~~~~~~~~~~~~~~~~~~

53. A composition as claimed in Claim 51 or 52, which includes a binder, preservative, stabilizer, flavour, sweetener, lubricant or disintegrating agent.

54. A composition as claimed in Claim 51, substantially as described in Example 76.