CA1083570A - Pyrazolo [4',3':5,6] pyride [3,4-e] [1,2,4] triazolo- [1,5-a] pyrimidines derivatives - Google Patents

Pyrazolo [4',3':5,6] pyride [3,4-e] [1,2,4] triazolo- [1,5-a] pyrimidines derivatives

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CA1083570A
CA1083570A CA276,889A CA276889A CA1083570A CA 1083570 A CA1083570 A CA 1083570A CA 276889 A CA276889 A CA 276889A CA 1083570 A CA1083570 A CA 1083570A
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hydrogen
lower alkyl
compound
phenyl
ethyl
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Theodor Denzel
Hans Hoehn
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ER Squibb and Sons LLC
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ER Squibb and Sons LLC
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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Abstract

Abstract This invention describes new derivatives of pyrazolo-[4',3':5,6]pyrido[3:4-?][1,2,4]triazolo[1,5-a]pyrimidine deri-vative? having the general formula wherein Z is or ; R1 is hydroqen, lower alkyl, phenyl, phenyl-lower alkylene, benzoyl or substituted benzoyl wherein the benzoyl substitutent is one or two halogens, lower alkyl or trifluoromethyl groups; 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 alkoxy-lower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl, or lower alkylene, morpholine, thiamorpholine or piperazine, the substituents on said substituted phenyl and substituted benzoyl being halogen, lower alkoxy or lower alkyl. R4' is halo, , -S-R8, phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, lower alkyl or tri-fluoromethyl groups; lower alkoxy or substituted lower alkoxy wherein the lower alkoxy substituent is ; R5 is hydrogen or lower alkyl; R6 is hydrogen, lower alkyl, sub-stituted lower alkyl wherein the lower alkyl substituent is

Description

1~35qO

This invention relates to new derivatives of pyrazolo-[~',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine which are useful as antiinflammatory agents and central nervous system depressants.
The present invention provides a compound of the formula N

R~ _ ` N~ N R5 Rl .
wherein Z is ~N-R4 or \N ; Rl is hydrogen, lower ,l=o ~l1_R4' ~
alkyl, phenyl, phenyl-lower alkylene, benzoyl or substituted ~, benzoyl wherein the benzoyl substitutent is one or two halogens, lower alkyl or trifluoromethyl groups; 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 alkoxy-lower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl, or 7,, N-lower alkylene, morpholine, thiamorpholine or piperazine, the substituents on said substituted phenyl and substituted benzoyl being halogen, lower alkoxy or lower alkyl. R4 is halo, -N 7 , -S-R8, phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, Lower alkyl or tri-~` ~luoromethyl groups; lower alkoxy or ~ubstituted lower ~lkoxy wherein the lower alkoxy sub~titu~nt is -N ~ 1O ; R5 i~

;- ~

' - ' : "

lVI!33S70 hydrogen or lower alkyl; R6 is hydrogen, lower alkyl, sub-stituted lower alkyl wherein the lower alkyl substitu~nt is -N 1O , phenyl or substituted phenyl wherein the phenyl substituent is halogen, lower alkyl or trifluoromethyl, R7 is hydrogen or lower alkyl, or R6 and R7 together with the nitro-gen form one of the unsubstituted or substituted heterocyclics pyrrolidino, morpholino, thiamorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl wherein the heterocycle sub-stituent is lower alkyl or hydroxy-lower alkylene; R8, R9 and R10 each is hydrogen or lower alkyl; and acid addition salts thereof.
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 Cl-C4 and especially the Cl-C2 lower alkyl and lower alkylene groups are preferred.
The lower alkoxy groups are of the same type. The Cl-C4 and Cl-C2 groups are similarly preferred and especially preferred groups, respectively.
The substituted phenyl, substituted phenyloxy and sub-stituted benzoyl groups are simply substituted groups bearing on the phenyl ring one or two halogen ~preferably one), lower alkyl, lower alkoxy or trifluoromothyl groups, for example, p-chlorophenyl, o-chlorophenyl, p-bromophenyl, m-chlorophenyl, m-bromophenyl, p-tolyl, o-tolyl, o-ethylphenyl, p-methoxyphenyl, p-chlorophenyloxy, o-chlorophenyloxy, p-bromophenyloxy, m-chloro-: ~ . ., . -- . . . : - .

~ 7~ 9~A106/107 - phenyloxy, m-bromophenyloxy, p-tolyloxy, o-tolyloxy, o-ethyl-phenyloxy, p-trifluoromethylphenyloxy, 3,4-dichlorophenylo~y, 3,5-dimethylphenyloxy, p-bromobenzoyl, m-bromobenzoyl, 3,5-dichlorobenzoyl, p-methylbenzoyl, 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 (C2-C7) 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, methylthio-methylene, methylthioethylene, ethylthiomethylene and ethyl-thioethylene.
The amino-lower alkylene groups are of the same type, e.g., aminomethyl, aminoethyl, etc. The di-lower alkylamino-lower alkylene 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 l or 2 carbons. Thus, groups like dimethyl-` ~miY~hyl,~ diethylaminomethyl, dimethylaminoethyl, diethyl-aminoethyl, dimethylaminopropyl, piperidinomethyl, piperidino-ethyl, morpholinomethyl, morpholinoethyl, thiamorpholinomethyl, . ~
_3_ .
~, - : ~ . : , , ., 1083~i7~) ~Al o 6 /10 7 thiamorpholinoethyl, piperazinomethyl, piperazinoethyl, piperazinopropyl are included.
The amino groups -N 7, wherein R6 and R7 each represents hydrogen or lower alkyl include the amino group, lower alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino and butylamino and di-lower alkyl-amino groups such as dimethylamino, diethylamino, methylethyl-amino, dipropylamino and dibutylamino lpreferably, 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, thia-morpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl. These heterocyclic radicals may be unsubstituted or substituted with a lower alkyl or hydroxy-lower alkyl c3roup.
The preferred heterocyclics are piperidino, morpholino and 4-methylpiperazino.
The substituted lower alkoxy groups representcd by R4 and the substituted lower alkylamino groups represented by R6 may bear an amino group ~N as described above resulting in R4 substituents which are amino-lower alkoxy groups (-0-r lkylene N R10 ) and amino-lower alkyleneamino ~roup~ -(-NH-lower alkylene-N ), respectively, including, for example, aminomethoxy, aminoethoxy, aminopropoxy, methylamino-ethoxy, ethylaminoethoxy, ethylaminopropoxy, dimethylamino-methoxy, dimethylaminoethoxy, dimethylaminopropoxy, di~thyl-aminoethoxy, dimethylaminobutoxy, diethylaminopropoxy, amino-ethylamino, aminopropylamino, methylaminopropylamino, e-thyl-aminoethylamino, dimethylaminomethylamino, diethylaminom~thyl-amino, dimethylaminoethylamino, diethylaminoethylamino and ;30 dimethylaminopropylamlno. Preerred are those cJrou~)~ wherein :` :
, .: , , ., ;' ` ' ' -- ` ~. ~ ' ' ' ' ' ' ' 108;3~570 QAl06/la7 the lower alkyl and lower alkylene yroups have up -to 4 car-bons, especially 1 to 2 carbons. Especially preferred groups of this type are di-lower alkylamino-lower alkoxy, especially dimethylaminopropoxy and di-lower alkylamino-lower alkylene-amino, especially dimethylaminopropylamino.
In compounds of the formula -~1 N ~ ~ -R4 ~ Nl N R5 Rl 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 alkylthio, especially methylthio, or lower alkylsul-finyl, especially methylsulfinyl, with especial preference for hydrogen or lower alkyl; R4 is hydrogen, lower alkyl, 20 cspecially methyl, ethyl and isopentyl, or di-lower alkyl- .~
amino-lower aIkylene, especially dimethylaminopropyl and - :
dimethyIaminoethyl; RS is lower alkyl or hydrogen, especially hydrogen.
In compounds of the formula . . R3 ll N
: ~N ~
Ib : R2 ~----R4 ' : N ~ R5 ~1 .

. . , , ' ; , . . :, ~, . - :. , : .

~083$~0 QA10~/107 the preferred groups are those wherein Rl is hydrogen or lower alkyl, especially the latter and most especially ethyl;
R2 is hydrogen or lower alkyl, especially hydrogen; R3 is hydrogen, lower alkyl or lower alkylthio, especially hydrogen or methyl; R4 is amino, mercapto, lower alkylthio, especially methylthio, lower alkylamino, especially Cl-C4-lower alkyl-amino, lower alkoxy, especially Cl-C5-lower alkoxy, di(lower alkyl)amino, especially Cl-C4-di(lower alkyl)amino or di(lower alkyl)amino(lower alkoxy~ or di(lower alkyl)amino-lower alkyl-amino. R5 is hydrogen or lower alkyl, especially hydrogen.

The new compounds of Formula I are formed by the follow-ing series of reactions. The symbols in the structural for-mulas have the same meaning as previously described.
A pyrazolo[3,4-b]pyridine of the formula ~ / COO-lower alkyl R _ , ~ , II
\ N ~ ~ 5 (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 RO C= N- C =N III

or a lower alkylthiomethylene cyanamide of the formula ; / C ~ M~ C - N IV
R-S

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

, ,. . . . . . ..
,, . . ,, . - ,~ .

~ 357~ Q~lU6/107 By this reaction is obtained a compound of the formula ~ N~J /

R O

Compounds of Formula Ia, wherein R4 is other than hydrogen, are obtained by treatment of the compound of For-mula V wherein R4 is hydrogen, obtained as just described, - with the halide R4-hal, wherein hal is a halogen, 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 hydroxide in a solvent like diethyleneglycol dimethyl ather.
Compounds o Formula Ia, wherein R3 is lower alkylsul-finyl are obtained from the corresponding compound of Formula Ia wherein R3 is lower alkylthio by oxidizing the latter, e.g., with an alkali metal periodate like sodium metaperiodate.
Reaction of the compound of ~ormula V with a chlorinating agent such as phosphorus oxychloride or phosphorus pentachloride, ~; results in the Eormation of a compound of the formula : ' ' ..: ' - - ' , ~ , .

1~83S7~ QA106/107 N ~ N

R~ Cl VI

Compounds of Formula Ib wherein R4 is lower alkoxy or amino-lower alkoxy are now produced by xeaction of the compound of Formula VI with an alcoholate o~ the formula lower alkyl-0-Me or Me-0-lower alkylene -N VII
Rl O

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 ' R8 S - Me VIII
~ . .
` wherein Me is ayain an alkali metal such as sodium or potassium ; and R8 i5 lower alkyl. Compounds oE Formula Ib wherein ~ is ~ 30 mercapto are obtained by xeaction of a compound of Formula VI

.. ` ' ~ 3S~0 QA106/107 with an alkali metal sulfide such as sodium sulfide. Com-pounds of Formula Ib wherein R4 is an amino group or amino-lower alkylene group are produced by reaction of a compound of Formula ~II with an amine of the formula ~R6 R9 HN or H2~ -lower alkylene -N X
R7 ~10 at elevated temperatures.
The new 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 pro-viding acid a~dition salts 9 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 sal~, 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 new compounds of this invention have antiinflammatory -~- properties and are useful as antiinflammatory ayents, for - 30 example, to reduce local inflammatory condikions such as those ~10~/107 1~83570 of an edematous nature or resulting from proliferation o~
connective tissue in various mammalian species such as rats, dogs and the like when given orally in dosages of about 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 invention 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 xoutes such as subcutaneously, intramuscularly, intravenously or intraperitoneally in the described dosages, can also be employed. A single dose, or preferably 2 to 4 divlded daily doses, provided on a basis of about 5 to 50 mg/kg/day, pre-ferably about 10 to 25 mg/kg/day, is appropriate.
The compounds of the invention can be ukilized by formu-latlon in compositions such as tablets, capsules or elixirs for oral administration or in sterile solutions or suspensions for ; parenteral administration. About 10 to 300 mg o a compound or mixture of compounds of Formula I or physiologically acceptable acid addition salt is compounded with a physiologically accep-table vehicle, carrier, excipient, binder, preservative, stabi- ~ -lizer, flavor, etc.' in a unit dosage form as called for by accepted pharmaceutical practice. The amount o active substance in these compositions or preparation~ is ~uch that a su:itable dosage in the range indicated is obtained.

:

',,; . ' . ~ ' , ; , . ~

~357~ ~A106/107 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 dosaye 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 about 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]p~rimidin-5(8H)one 249 g o~ l-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (l mol) are refluxed in 1.5 liters of dry dioxane together with 98 g of ethoxymethylene - 30 cyanamide for 12 hours. After cooling to room temperature, the ~8~7~ QA106/107 precipitated 8-ethyl-4H~pyrazolo[4',3':5,6]pyrido[3,~-e]-[l~2~4]triazolo[l~5-aIpyrimidin-5(~H)-one is filtered off and recrystallized from dimethylformamide, yield 135 g. (53~);
m.p. 355-356.
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 ; 10 in Example 1 are treated with 0.6 g. of sodium hydride in 50 ml of diethylene glycol dimethyl ether at 150 for 1 hour. Ater 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. 175-177.
Example 3 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
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 trea~ed with 1 g. of sodium ethoxide in 50 ml. of diethyleneglycoldimethyl ether at 120 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 li~uor evaporated to dryness. The . . .
i . .

~ Vf~357(J

remaining 8-ethyl-4-(3-methylbutyl)-4H-pyrazolo[4',3':5,6]-pyrido[3,4-~ [1,2,4]triazolo[l,s_~pyrimidin-5(8H)-one is recrystallized from alcohol, yield 2.1 g. (64%)i m.p.
175-177 .
Example 4 8-Ethyl-4-methyl-4H-pyrazolo[4'~3l:5,6]pyrido[3,4-e][1,2,41-triazolo[l~s_~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.) 1~ are treated with 0.3 g. of sodium in 50 ml. of diethylene-glycol 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-e][1,2,4]triazolo[l,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]PYrid[3 4-e]-~1,2,4]triazolo[l s-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 dimercaptomethylmethylene cyanamide for 10 hours. The solution is cooled to room temperature and the precipitated 8-ethyl-2-methylthio-4H-pyrazoIo[4'~3':5~6]pyrido[3~4-e~[1~2~4]triazolo~1~5-a]-,; j pyrimidin-5(8}1)-one is filtercd o~f, yield 140 y. (46~);

m-p- > 300 (DMF).
'~;

; ' .

$70 Q~106/107 Example 6 E h 1 2-meth lsulfin 1-4H- razolo[~',3' 5,6]P rido[~
8- t Y - Y Y PY y ~ f [1,2,4]triazolo[1,5-a]pyrimidin-5(8~l)-one
3.01 g. of 8-ethyl-2-methylthio-4H-pyrazolo[4',3':5,6]-pyrido[3,4-e]l1,2,4]triazolo[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-pyrazolo[4',3':5,6]-pyrido[3,4-e][1,2,4]triazolo[1,5-ajpyrimidin-5(8~l)-onc 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[l 5-a]pvrimidin-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]triazololl,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-e][1,2,4]tr~azolo[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]txiazolo[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 diethyleneglycol 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 solvont removed in vacuo -to obtain the product, 8-ethyl-4-(2-morphoLino)-ethyl-4H-pyra7010[4',3':5,61py~ido[3,4-eJIl,2,4Jtri~olo-. . . - , . -: .
. . ~

lVi 33571~) ~Al o 6/10 7 [1,5-a]pyrimidin-5(8H)-one.
Example 9 8-Ethyl-4-(2-piperidino)ethyl-4H-pyrazolo[4',3': 5, 6] p~rido-[3~4-e][l~2l4]triazolo[l~5-a]pyrimidin-5(8H)-one By substituting for the dimethylaminopropyl chloride in Example 2 the equivalent amount of 1-chloro-2-piperidino-ethane, 8-ethyl-4-(2-piperidino)-ethyl-4H-pyrazolo[4',3':5,6]-pyrido[3,4-e]l1,2,4]triazolol1,5-alpyrimidin-5(8H)-one is obtained.

Example 10 4-[2-(Diethylamino)ethylJ-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 for the (3-dimethylamino)propyl chloride in Example 2 the equivalent amount of l-chloro-2-~iethylaminoethane, 4-[2-(diethylamino)ethyl]-8-ethyl-4H-pyrazolo[4',3':5,6]pyrido~,4-e ][1,2,4]triazolo[1,5-a]pyrimidin-
5(8H)-one is obtained.
Example 11 4-Methyl-4H-pyrazolo[4',3':5,6]pyrido[3,4 e][l,2,4]triazolo-[1,5-a]pyrimidin-5(8H)~one By substituting an equivalent amount of 4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the l-ethyl-4-hydrazino-lH-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-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]-pyrimidin-5~8H)-one, respectively, are obtained.

,- :. . ' - ' IL083S7al Example 12 4-Butyl-8-ethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[l~5-a]pyrimidin-5(8H?-one By substituting butyl iodide for the methyl iodide in the procedure of Example 4, 4-bu-tyl-8-ethyl-4H-pyrazolo-.. [4',3':5,6]pyrido~,4-e ][1,2,4]triazolo[l,s_~pyrimidin-5(8H)-one is obtained.
Example 13 4-Phenylmethyl-4H-pyrazolo[4',3':5,6]pyrido[3 4-e][1,2,4]-tr~azolo[l,5-~pyrimidin-5(8H)-one By substituting the 4H-pyrazolo[4',3':5,6]pyrido-[3,4-~ [1,2,4]triazolo~,5-a ]pyrimidin-5(8H)-one of Example 11 for the 8-ethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4_el[1,2,4]-triazolo~1,5-~pyrimidin-5(8H)-one and benzyl iodide for the -methyl iodide in the procedure of Example 4, 4-phenylmethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]-pyrimidin-5(8Hj-one is obtained.
Example 14 8-Ethyl-4-~:henylethyl-4H-pyrazolo[4',3':5,6]pyrido~4-e ]-[1,2,4]triazolo[1,5-~pyrlmidin-5(8H)-one ~
By substituting phenylethyl bromide for the ~e-thyl iodide in the procedure of Example 4 8-ethyl-4~phenylethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-~ [1,2,4]triazolo[1,5-a]-pyrimidin-5(8H)-one is obtained.
~ Example 15 4~8~lo-Trimethvl-4H-~yrazolo[4~3~:5~6]pyrido~4-e] [1,2,4]-; triazolo[1,5-~pyrimidin-5(8H)-one By substituting 1,3-dimethyl-4-hydrazi.no~lll-pyrazolo~3,4-b]pyridine-5-carboxylic acid, o~hyl e~t~
- 30 for the 1-ethyl-4-hydrazino~ pyrazolo[3,4-bJpy~ c~-5-, .. .

.

, ~ .. : .: . . .
' `:; " ' , ' ' , ~3$'^~0 ~:L06/1~7 carboxylic acid, ethyl es-ter in the procedure oE Example 1 and proceeding as in Example 4, 8,10-dimethyl-4H-pyrazolo-[4',3':5,6jpyrido[3,4-e]~1,2,4]triazolo ~,5-a]pyri~idin-5(8H)-one and 4,8,10-trimethyl-4H-pyrazolo[4',3':5,6]pyrido-[3~9-e][l~2~4]triazolo[l~5-a]pyrimidin-5(8H)-one are obtained.
Example 16 2-Ethyl-8-isopropyl-4-propionyl-4H-pyrazolo[4',3':5,6]pyrid [3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8TI)-one By substituting l-isopropyl-4-hydrazino-lH-pyrazolo-~3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic aciid, ethyl ester and l-ethoxypropylidene cyanamide for the ethoxymethylene cyanamide in the procedure of Example 1, and then proceeding as in Example 4 but substituting propionyl bromide fox the methyl iodide, 2-ethyl-8-isopropyl-4H-pyrazolo[4l~3l:5~6]pyrido~4-e][l~2~4]triazolo[l~s-a]-pyrimidin-5(8H)-one and 2-ethyl-8-isopropyl-4-propionyl-4H-pyrazolol4',3':5,6]pyrido[3,4-e][1,2,4]triazolol1,5-~- -: 20 pyrimidin-5(8H)-one, respectively, are obtained.
Example 17 .
4-(4-Chlorobenzoyl)-1 ethyl-4H-pyrazolo[4'~3':5,6]pyrid [3,4-~ [1,2,4]triazolo[1,5-aJ~yrimidin-5(8H)-one By substituting 4-hydrazino-3-ethyl-lH-pyrazolo-[3,4-b]pyridine-5-carboxylic acid propyl ester for thc l-ethyll4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in the procedure 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-~ [1,2,4]triazolo[1,5-~pyrim.i.din-5(8~l)-one and . , , ~.. , . , -:~ ~. . .. . . . .

~013357~) QAlo6/lo7 4-(4-chlorobenzoyl)-10-ethyl-4H-pyrazolo[4',3':5,6]pyrido-[3~4~e][l~2~4]triazolo[l~5-a]pyrimidin-s(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[l s-a]pyrimidin-5(8H)-one By substituting 4-hydrazino-1-phenyl-lH-pyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-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-4H-pyrazolo[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[l,5-a]pyrimidin-5(8H)-one, respectively, are obtained.
.
~ Example 19 4~6-Dimethyl-8-ethyl-4H-pyrazolo[4ll3l:5/6]pyrido[3~4-e]
~1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one By substituting l-ethyl-4-hydrazino-6-methyl-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl es~er for the l-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in the procedure of Example 1, then proceeding as in Example 4, 8-ethyl-6-methyl-4H-pyrazolo-[4'j3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8ll)-. ~ .
one and 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)-one, respectively, are obtained.
. , ~ ,.'' ' . , .

~3S7~ Q~106/~07 Example 20 8-Benzyl-4-(3-methylbutyl)-4H-pyrazolo[4',3':5,6]pyrido~,4-e]-[1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one By substituting l-benzyl-4-hydrazino-11-1-pyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in the procedure of Example 1 then proceeding as in Example 3, 8-benzyl-4H-pyrazolo~4',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one and 8-benzyl-4-(3-methylbutyl)-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo-[ 1,5-~pyrimidin-5(8H)-one, respectively, are obtained.
Example 21 4-Methy.L-8-phenylethyl-2-propyl-4H-pyrazolo[4l~3l:5~6]
pyrido[3,4-e][1,2,4]triazolo[1 5 a]pyrimidin-5(8H)-one By substituting l-phenylethyl-4-hydrazino-lH-pyrazolo-[3,4-b]pyridine-5-carboxylic acid, methyl ester for the 1-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester and l-ethoxybutylidene cyanamide for the ethoxymethylene cyanamide in the procedure of Example 1, then proceeding as in Example 4, 2-propyl-8-phenylethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[l,5-a]-pyrimidin-5(8H)-one and 4-methyl-8-phenylethyl-2-propyl-4H- -: :
pyrazolol4',3':5,63pyrido[3,4-e]~1,2,4]triazolo[1,s-alpyrimidin- :- -5(i8H)-one, respectively, are obtained.
~- : Example 22 .8-Diethyl-2-phenyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-el-.
1,2,4]triazolo[1,5-a~pyrimidin-5(8H)-one By ~ubstituting a-ethoxybenzylidene cyanaml.de ~or the ethoxymethylene cyanamide in the procedure o~ Example 1, then proceeding as in Example 4 but substitutin~ ethyl iodide ~or the .

3S~O

methyl iodide, 8-ethyl-2-phenyl-4H-pyrazolo[4'~3':5~6]pyrido~
[3,4-q [1,2,4]triazolo~,5-a]pyrimidin-5(8H)~one and 4,8-diethyl-2-phenyl-4H-pyrazolo[4',3l:5,6]pyrido~,4-e][1,2,4]triazolo~,s_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]~yrimidin-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]pyrlmidin~5(8H)~one By substituting 4-hydrazino-1-furfurylpyrazolo~
[3,4-b]pyridine-5~carboxylic acid, ethyl ester for the 1~
ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5~carboxylic acid, ethyl ester in Example 1, 8-furfuryl-4H-pyrazolo-[4',3':5,6]pyrido[3,4_e][1,2,4]triazolo[l 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~furfuryl-4-phenyl-4H-pyrazolo[4',3':5,6]pyrido~3,4_e][1,2,4]triazolo~
[l~5-a]pyrimidin-5(8H)-one.
b) 4-Phenyl-4H-pyrazolo[4',3':5,6~Pyrido[3 4-e][1,2,4]-triazolo[l~5-a]pyrimidin-5(8H)-one -0.01 mol. of 1-furfuryl-4-phenyl-4H-pyrazolo-[4',3':5,6]pyrido[3,4_e][1,2,4]triazolo[l,s_a]pyrimidin-5(8H)-one is heated in 50 ml. of diethyleneglycol dimethyl-ether 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[1,5~al~
pyrimidin-5(8H)-one remains.

83S~O

Example 24 8-Benzoyl-4-Phenyl-4H-p~razolo[4ll3l: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][l~2~4]triazolo[l~5-a]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-benzoyl-4-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-(4-methylbenzoyl)-4H-pyrazolo[4',3':5,6]pyrido-~,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one ~y substituting 1-(4-methylbenzoyl)-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the l-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-S-carboxylic acid, ethyl ester in the procedure of Example 1, then proceeding as in Example 4, 8-(4-methylbenzoyl)-4H-pyrazolo[4',3':5,6]pyrido~,4-e][1,2,4]triazolol1,5-~-pyrimidin-5(8H)-one and 4-methyl-8-(4-methylbenzoyl)-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo ~,5-a]-pyrimidin-5(8H3-one, respectively, are obtained.
Example 26 4-~2-AmlnoethYl)-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 substitukin~ 2-chloroethylamine for the dimethylaminopropyl chloride, 4-(2-alllinoetllyl)-6-methyl--' ' ~ ~; "

7a~

8-ethyl-4H-pyrazolo[4', 3': 5,6]pyrido[ 3,4-e] [1,2,4]triazolo-[lr5-a]pyrimidin-5(8H)-one is obtained.
Example 27 4-(3-Ethoxypropyl)-8-ethyl-4H-pyrazolo[4',3':5,6]pyrido-[3,4-e][l,2,4]~riazolO[ll5-a]pyrimidin-5~8H)-one By substituting 3-ethoxypropyl chloride for the dimethyl-aminopropyl chloride in the procedure of Example 2, 4-(3-ethoxypropyl)-8-ethyl-4H-pyrazolo[4',3':5,6]pyrido~3,4-el-[1,2,4]triazolo[1,5-a]pyrimidin-5(8H) one is obtained.
Example 28 4-Methylthiomethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[l,s-a~pyrimidin-5(8H)-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[l,s-~pyrimidin-5(8H)-one obtained in Example 11 for the 8-ethyl-4H-pyrazolo[4',3':5,6]pyridoB,4-e ][1,2,4]-triazolo[l,5-a]pyrimidin-5(8H)-one, 4-methylthiomethyl-4H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[l,5-a]-pyrimidin-5(8H)-one is obtained.
Example 29 ~ -; 8-Benzoy~ (p-methylphen~l)-4H-pyrazolo[4',3':5,6]pyrido-4-e][1,2,4]triazolo[1,5-~pyrimidin-5(8H)-one By substituting p-methylphenyl bromide for the bromo-benzene in the procedure of Example 23a, then proceeding as in part b and Example 24, 4-(p-methylphenyl)-4H-pyrazolo-[4',3':5,6]pyrido[3,4~~ [1,2,4]triazolo~,5-a]pyrimidin-5(8H)-one and 8-benzoyl-4-(p-methylphenyl)-4H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo~,5-alpyrimidin-5(8H)-one, respectively, are obtained.

, ~L083S~0 ~A106/101 Example 30 -[2-Diethylamino)ethyl]-8,10-dimethyl-4H-pyrazolo-[4',3':5,6]pyrido[3,4-e~[1,2,4]triazolo rl, s-a]pyrimidin-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,s_a~-pyrimidin-5(8H)-one product of Example 15 instead of 8-ethyl-4H-pyrazolo[4l,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[l,s-a]pyrimidin-5(8H)-one is obtained.
Example 31 4-Dimethylaminomethyl-8-phenyl-4H-pyrazolo[4l,3':5,6]pyrido-[3,4-e3[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 8-phenyl-4H-pyrazolo[4',3l:5,6]pyrido[3,4-e.i-[1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one product of Example 18 instead o~ 8-ethyl-4H-pyrazolo[4l,3l:5,6]pyrido-- [3,4-e.][1,2,4]triazolo~,5-a]pyrimidin-5(8H)-one, 4-dimethyl-aminomethyl-8-phenyl-4H-pyrazolo[4l,3l:5,6]pyrido~,4-e]-[1,2,4]triazolo[l,5-~pyrimidin-5(8H)-one is obtained.
Example 32 8-EthYl-4-(2-thiamorpholino)ethyl-4H-pYrazolo[4',3':5,6]-pyrido~,4-e][1,2,4]triaxolo~,s_a]pyrimidin-5~8~ one B~ substituting l-chloro-2-thiamorpholinoethane for the l-chloro-2-morpholinoethane in the procedure of Example 8, 8-ethyl~4-(2-thiamorpholino)ethyl-41l-pyrazolo-~V1~3S7V
~A106/107 r ~

~41 ~31 :5,6]pyrido[3,4-e][1,2,4]triazolo[l,5-a~pyrirnidin- -5(8H)-one is obtained.

Example 33 4-(3-Piperazino)propyl-~H-pyrazolo[4~3':5~6]pYrido[3~4-e]-[1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one By substituting 3-piperazinopropyl chloride for the ~ l-chloro-2-morpholinoethane in the procedure of Example 8 ; and utilizing the 4H-pyrazolo[4',3':5,6]pyrido~,4-e][1,2,4]-triazolo[l,S-alpyrimidin-s(8H)-one product of Example ll, 4-(3-piperazino)propyl-4H-pyrazolo[~',3':5,6]pyrido-[3~4-e][l~2~4]triazolo[l~s-a]pyrimidin-5(8H)-one is obtained.
Example 34 - The following ingredients are used to ma~e 1,000 200 mg. tablets each containing 100 mg. of active ingredient~
8-ethyl-4H-pyrazolo[4',3':5,6]pyrido- ~
[3,4-e][1,2,41triazolo[1,5-a]pyrimidine- ~ ;
5(8H)-one lO0 gm.
Polyvinyl pyrrolidone 7.5 gm.
Lactose 20 gm. - -Magnesium stearate 3.5 gm.
Corn starch 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 granula~e 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 rnagnesium stearate, Avicel - 30 and the corn starch and the mixture is blended. The blend .. ~ ~ ' t * Trade Mark -24- ~ I

1~3S7~ Q~106/107 is then compressed into 200 mg tablets on a standard con-cave punch. The tablets are then veneer coated with methyl cellulose in a spray pan.

Example 35 N-[3-(Dimethylamino)propyl]-8-ethyl-8H-pyrazolo[4',3':5,6]-pyrido[3,4-e][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[l,5-a]pyrimidin-5(8H)-one .
249 g of l-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]-pyridine-5-carboxylic acid, ethyl ester (l mol) are refluxed in 1.5 liters of dry dioxane together with 98 g of ethoxymethylene cyanamide for 12 hours. After cool-ing to room temperature, the precipitated 8-ethyl-4H-' '' ~

' ~ .

- , ,, - : . .
: .. . ~ . : .... . .
. . :. : . . ; . : .
. .

~0~35~0 ' Q~106~107 .
pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo~1,5-a]-pyrimidin-5(8H)-one is filtered o~f and recrystallized from dimethylformanide, yield 135 g. (53%); m.p. 355-356 .
b) 5-Chloro-8-eth-yl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[l,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 ox~chloride for 12 hours.
After this time, the excess of phospllorus oxychloride is distLlled off in vacuo, the residue is treated with dry acetone and filtered off. 25 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 obtained, yield 92%; m.p. 196-197.
c) N~ (Dimethylamino)propY1]-8-ethYl-8H-pyrazolo=
[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-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 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]-8-ethyl-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 HCl yields the hydrochloride salt.
Example 36 8-Ethyl-N-(l-methylpropyl)-8H-pyrazolo[4l~3l:s~6]pyrid [3,4-e][1 2,4]triazolo[1,5-a] rimidin-5-amine .,'` -- -- ' PY

By substituting 1-methylpropylamine for thc 3-dimethyl-, :

:
. , ~ 35~
~A106/107 ~minopropylamine in the procedure of Example3~ c, 8 ethyl-N-(l-methylpropyl)-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. 228-230 (methanol).
Example 37 N,N-8-Triethyl-8H-pyrazol-o[-4l~3l:5!6]pyrido[3~4-e][l~2~4]
triazolo[l,5-a]~yrimldln-5-amine By substituting diethylamine ~or the 3-dimethylamino-propylamine in the procedure o Example35 c, N,N-8-triethyl-8H-pyrazolo~4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]-pyrimidin-5-amine is formed, yield 71~; m.p. 215-217 (ethyl acetate~.
Example 38 5-Ethoxy-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[l,5-a]pyrimidine 2.7 g. of 5-chloro-8-ethyl-8H-pyrazolo[4',3':5,6]-- pyxido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine of Example35 b (0.01 mol.) are added with stirring to a solution o~ 2.3 g.
of sodium in 50 ml. of dry ethanol. The mixture is stirred at room tPmperature for 6 hours. The precipitate is filtered off, washed with water and recrystallized from ethanol to obtain 5-ethoxy-8-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,S-a]pyrimidine, yield 2.1 g. (74 m.p. I96-197.
Example 39 B-Ethyl-5-methoxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[l,5-a]pyrimidine 5-Chloro-8-ethyl-8H-pyrazolo[4',3':5,61pyrido-[3j4-e][1,2,4]triazolo[1,5-a]pyrimidine oE Example 35 b is - 30 treated with sodium methoxide in methanol as described in ~, , .

- . . . .. , :~ : ~
.

~ )83S~O
~A106/107 Example 38 to obtain 8-ethyl~5-methoxy-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-sutoxy-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[l,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 stirring.
After 1 hour, 5.5 g. o~ 5-chloro-8-ethyl-8H-pyrazolo-[4',3':5,6]pyridol3,4-e] [1,2,4]triazolo[1,5-a]pyrimidine of Example 35 b are added and the mixture is refluxed with stirring or 12 hours. The solvent is distilled off in -vacuo and the residue is treated with 5 ml. of water and filtered off. Recrystallization ~rom ethyl acetate yields 4.5 g. of 5-[2-(dimethylamino)ethoxy]-8-ethyl-8~-pyrazolo-.. . .
[4',3':5,6]pyrido13,4-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-13,4-e] [1,2,4]triaæolo[1,5-a]pyrimidine By substituting 3-methylbutanol for the 2-dimethyl-- 30aminoethanol in the procedure of Example 41, 8-ethyl-5-. .
: . .

: . :
: . i ~ 357V

(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-~yrazolo[4'~3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidine 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 1.5 g. of sodium methylmercaptide in 30 ml. of dimethylformamide with stirring at 80 for 5 hours. After th~s time, 10 ml. of water are added and the precipitate, 8-ethyl-5-methylthio-8H-pyrazolo[4l~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. 198-200 (butanol).
Example 44 8-Eth ;-5-ethoxy-2-methylthio-8H-pyrazolo[4',3':5,6]pyrido-[3,4-e][1,2,4]triazo1o[1,5-a]pyrimidine a) 8-Ethyl-2-methylthio-4H-pyrazolo[4',3':5!6]pyrido-[3,4-e][1,2,4]tr~azolo[1,5-a]py~imidin-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 .
precLpitated 8-ethyl-2-methylthio-4H-pyrazolo[4',3':5,6]-pyrido[3,4-e][1,2,4]triaæolo[1,5-a]pyrimidin-5(BH)-one is flltered off, yield 14.0 g, (~6~); m.p.~ 300 (DMF).
b) 8-Ethyl-S-ethoxy-2-methylthio-3ll-pyr~zol ~ 5,6 pyrido~3,4-e][1,2,4]triazolo[1,5-a]pyrimidine lq g. of 8-ethyl-2-methylthio-4H-pyr~zolo[~',3':5,6]-83S7~
Q~106/107 pyrido[3,4-e][1,2,4]triazolo[1,5-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 ahd the residue carefully treated with 100 ml. of alcohol. After evaporation of the alcohol the remaining 8-ethyl-5-ethoxy-2-methylthio-8H-pyrazolo[4',3':5,6]-pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is recrystallized from dimethylformamide, yield 53~; m.p. 209-211.
Example 45 8 Eth 1-5-ethox -2-meth lsulfinyl-8H- yrazolo[4',3,:5,6]-_, y _y Y P
~yridol3,4-e][1,2,4]triazolo[1,5-a]pyrimidine ) 8 Eth 1-2-meth lsulfin 1-4H- razolo[4',3':5,6]pyrido-a - y y Y PY
[3,4-e][1,2,4]triazolo[1,5-a]pyrimldin-5(8H)-one 3.01 g. of 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 obtained in Example 44 a are oxidized with 2.2 g. of sodium meta-periodate in aqueous alcohol for 7 days at room temperature.
The precipitate of 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 is filtered off, washed with water and recrystallized 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 o~ Example 44 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 is obtained.

`:

` -30-`

~0~3570 Example 4 6 8-Ethyl-N-methyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidin-S-amine By substituting methylamine for the 3-dimethylamino-propylamine in the procedure of Example 35 c,8-ethyl-N-methyl-8H-pyrazolo[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-p~razolo[4',3':5,6]Pyrido-[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine By substituting piperidine for the 3-dimethylamino-propylamine in Example 35 c,8-ethyl-5-(1-piperidinyl)-8H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is obtained.
Example 48 N-[2-(Diethylamino)ethyl]-8-ethyl-8H-pyrazolo[4',3':5,6]-~yrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5-amine ~ -By susbtituting for the (3-dimethylamino~propylamine in Example 35 cthe equivalent amount of 2~diethylamino)ethyl- ;
amine, N-[2-~diethylamino)ethyl]-8-ethyl-8H-pyrazolo~4',3':5,6]-pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5-amune is obtained.
Example 49 5-Methoxy-8H-pyrazolol4',3':5,6]pyrido[3,4-e][1,2,4]triazolo-[l,S-a]pyrimidine By substituting an equivalent amount of 4-hydrazino-.
lH-pyrazolo[3,4-b]pyridine-5-carboxy1ic acid, ethyl ester `~ for the 1-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in the procedure of ~xample 35 a, b then continuing as in Exarnple38 but substituting methanol for ethanol, 4H-pyraxolo[~',3':5,6]pyrido[3,4-e][1,2,4]-.

.
, .
` . . ' ' ' ' ` ' 835~

triazolo[l~s-a]pyrimidin-s (8H) -one, 5-chloro-8H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine and 5-methoxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[l,5-a]pyrimidine, reSpectively/ are obtained.
Example 50 5-Phenylmethoxy-8H-pyrazolo[4',3':5,6]pyri~o[3,4-e][1,2,4]-triazolo[l,5-a]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 5-chloro-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-phenyl-: methoxy-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo-[1,5-a]pyrimidine is obtained.
Example 51 8-EthY1-5-(2-phenylethoxy)-8H-pyrazolo[4',3':5,6]pyrido-[3,4-e]l1,2,4]triazolo~1,5-a~pyrimidine By substituting.phenylethyl alcohol for the ethanol in the procedure of Example38,8-ethyl-5-(2-phenylethoxy)-8H-pyrazolo[4l,3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]-pyrimidine is obtained.
Example 52 S-Phenyloxy-8,10~dimethyl-8H-Pyrazolo[4',3':5,6]pyrido-~3.,4-e][1,2,4]triazolo[1,5-a]pyrimidine .
By substituting 1,3-dimethyl-4-hydrazino-lH-pyraeolo[3,4-blpyridine-5-carboxylic acid, ethyl est~r for~the l-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl este~ in the procedure o~ l.xample 35 ~ and proceeding as in Example38, but substitut:ing phenol ``~ 30 for the ethanol, 8,10-dimethyl-4H-pyrazolo[~',3':5,6]-8;~
~A106/].07 pyrido[3,4-e][1,2,4]triazolo[1,5-a~pyrimidin-5(8H)-one, 5-chloro-8,10-dimethyl-8H~pyrazolo[4',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidine and 5-phenyloxy-8,10-dimethyl-8H-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-e][1,2,4]triazolo[1,5-a]pyrimidine By substituting l-isopropyl-4-hydrazino-lH-pyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester and l-ethoxypropylidene cyanamide for the ethoxymethylene cyanamide in part a and morpholine for the 3-dimethylaminopropylamine in part c of the procedure o~ Example 35, 2-ethyl-8-isopropyl-4H-pyrazolo-[41,3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin- -5(8H)-one, 5-chloro-2-ethyl-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]-` 20 [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]11,2,4]triazolo[1,5-a]pyrimidine By substituting 3-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]-pyridine-5-carboxylic acid propyl ester for the 1-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, . ethyl ester in the procedure of Example35a, b and then following the procedure of Example 38but subst:ituting 4-30 - chlorophenol for the ethanol, 10-ethyl-41l-pyra~olo[4',3':5,6]-. ~33-.. . . . , , . . ,. :
- .
. . . . . .

,A106/107 pyrido[3,4-e][1,2,4]triazolo[l,5-a]pyrimidin-5(g}l)-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-ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,~-e][1,2,4]-triazolo[l,5-a]pyrimidine, respectively, are obtained.
EXample 55 5-(3-methylphenyloxy)-8-phenyl-8H-pyrazolo[4',3':5,6]pyrido-[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine By substituting 4-hydrazino-1-phenyl-lH-pyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester ~or the 1-ethyI-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in the procedure of Example 35 a, b, then proceeding as in Example38 but substituting 3-methylphenol for the ethanol, 8-phenyl-4H-pyrazolo[4',3':5,6]pyrido~
[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one, 5-chloro-8-phenyl-8H-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]triazolo[1,5-a]-pyrimidine, respectlvely, are obtained.
Example 56 N-t2-(Diethylamino)ethyl]-8-ethYl-6-methyl-8H-Pyrazolo-:5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5-amine .
By substituting l-ethyl-4-hydrazino-6-methyl-lH- --pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester ~or the l-ethyl-4-hydrazino-lH-pyràzolo[3,4-b~pyridine-S-carboxylic acid, ethyl ester in part a and 2-diethyl-amino~ethylamine or the 3-dimethylaminopropylamine in part c o the procedure of Example 35a, b, 8-ethyl-6-methyl-4H-pyrazolol4',3':5,6]pyrido[3,q-e][1,2,4]triazolo-.

': ' ' .' . ., ' ` :` ' ..',. ", , . '' ~ ' ' ' , ' , ' .
- ` . :.. : ,, , , ~ : :

1~33~
::aAl 0 6 /1 t~ 7 [1,5-a]pyrimidin-~(8H)-one, 5-chloro-8-ethyl-6-methy1-8H-pyrazolo[4',3':5,6]pyrido~3,~-e][1,2,4]triazolo[1,5-a]-pyrimidine and N-[2-tdiethylamino)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, respectively, are obtained.
Example 57 8-Benzyl-N-(l-methylpropyl~-8H-pyrazolo[4',3':5,6]pyrido-[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5-amine By substituting l-benzyl-4-hydrazino-lH-pyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in the procedure of Example35a, b then proceeding as in Example 36, 8-benzyl-4H-pyrazolo[4',3':5,6]
pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one and 8-benzyl-5-chloro-8H-pyrazolo[4',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidine and 8-benzyl-N-(l-methyl-propyl)-8H-pyrazolo[4',3':5,6]pyrldo[3,4-e][1,2,4]triazolo-[1,5-a]pyrimidin-5-amine, respectively, are obtained. .
; Example 58 S-Methoxy-8-phenylethyl-2-propyl-8H-pyrazolo[4',3':5,6]-pyrido[3 ! 4-e][1,2,4]triazolo[1,5-a]pyrimidine By substituting l-phenylethyl-4-hydrazino-lH-pyrazolo-[3,4-b]pyridine-5-carboxylic acid, methyl ester for the 1-~ ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic ; acid, e~hyl ester and l-ethoxybutylidene cyanamide for the ethoxymethylene cyanamide in part a of the procedure of . Example 35a, b then proceeding as in Example 39, 2-propyl-8-phenylethyl-4H-pyra~olo[4',3':5,6]pyrido[3,4-e][1,2,~]-triazolo[3,2-b]:pyrimidin-5(8H)~orle, 5~chloro-8~phenyle~hyl-2-propyl-8H-pyrazolo[~',3':5,~]pyrido[3,4-e][1,2,~]~riazo:lo-.
..

. . ' . . . . . . . . . .
,: . ... .. :
. . .. . .. .~ . .

~8;~
~A106/107 [1,5-a]pyrimidine and 5-methoxy-8-phenylethyl~2-propyl-8H-pyrazolo[4',3':5,6~pyrido[3,4-e][1,2,4]triazolo[1,5-a]-pyrimidine, respectively, are obtained.
Exam~le 59 N,N,8-Triethyl-2-phenyl-8H-pyrazolo[4~3~:5~6]pyrido[3~4-e]
: [1,2,4]triazolo[1,5-a]pyrimidin-5-amine By substituting -ethoxybenzylidene cyanamide for the ethoxymethylene cyanamide in the procedure of Example 35 a, b then proceeding as in Example 37,8-ethyl-2-phenyl-4H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one, 5-chloro-8-ethyl-2-phenyl-8H-pyrazolo[4',3':5,6]-pyrido[3,4-e][1,2,4]triazolo[1,~-a]pyrimidine and N,N,8-trie.thy.l-2-phenyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[l,5-z]pyrimidin-S-amine, respectively, are obtained.
Example 60 8-BenzoyL-5-phenyloxy-8H-pyr-azolo[4'~3l:s~6]pyrido[3~4-e]
[1,2,4]triazolo[1,5-a]pyrimidine i , ,, a) 8-Furfuryl-5-Phenyloxy-8H-Eyrazolo[4l~3l:5~6]pyrido [3,4-e][1,2,4]triazolo[1,5-a]pyrimidine By substituting 4-hydrazino-1-furfurylpyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in Example35a, 8-furfuryl-4H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4~triazolo[1,5-a]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 35 b and then as in Example38, substitutin~
phenol for the ethanol to obtain 8-furfuryl-5-phenyloxy-~ ' 8H-pyrazolo[4',3':5,6~pyrido[3,4-e][1,2,4]triazolo-[l,S-a]pyrimidine .
.~ , .

: -36-:

- . ., . ;:, ., . :
.. .. , ~.. ... .

3S~
~A106/107 b) 5-Phenyloxy-8H-pyraæolo[4',3':5,6]pyrido[3,4-e]~ ,4]_ triazolo~l,5-a]pyrimidine 0.01 mol. o~ 8-furfuryl-5-phenyloxy-8H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is heated in 50 ml. of diethyleneglycol dimethyl ether containing 0.01 mol. of s~lenium dioxide at reflux te~pera-; ture with stirring for two hours. The mixture is filtered hot and evaporated to dryness. 5-Phenyloxy-8H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine remains.
c) 8-Benzoyl-5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido-[3,4-e]tl,2,4]triazolo[1,5-a]pyrimidine 0.01 mol. of 5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido-~3,4-e][1,2,4]triazolo[1,5-a]pyrimidine 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-benzoyl-5-phenyloxy-8H-pyrazolo[4',3':5,6]pyrido-[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine is filtered off.
Example 61 N-[3-(Dimethylamino)propyl]-8-(4-methylbenzoyl)-8H-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]p~rimidin-5-amine By substituting 1-(4-methylbenzoyl)-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the l-ethyl-4-hydrazino-lH-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in 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]pyrimidin-5(8H)-one, 5-chloro-8-(4-methylbenzoyl)-8H-pyrazolo[~',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidine and N-[3-(dim~thylamino)-propyl]-8-~4-methylbenzoyl)-8H-pyrazolo[4',3':$,6]pyrido-, :, . - . . . . : , ~, , ~, . . .

3S~

~106/107 [3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-S-arnine, respectively, are obtained.
Example 62 5-(2-Aminoethoxy)-6-methyl-8-eth~1-8H-pyrazolo~4',3':5,6]-~yrido[3,4-e][1,2,4]triazolo[1,5-a]p~rimicline By substituting the 8-ethyl-6-methyl-4~-pyrazolo-[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidin-5(8H)-one obtained in Example 56 in the procedure of Example41 but substituting 2-hydroxyethylamine for the 2-dimethylaminoethanol, 5-(2-aminoethoxy)-6-methyl-8-ethyl-4H-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-amlne By substituting aniline for the 3-dimethylaminopropyl amine in the procedure o~ Example35 c, N-phenyl-8-ethyl-8H-pyrazolo[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-dimethylamino-propyIamine in the procedure of Example35c, 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 is obtained.

Example 65 ' N-(2-~imethylaminoethyl-8,10 ~ ethyl-8H-pyrazolo~4'~3':5~6]-pyrido~3,4-e][1,2,4]triaæolo[1,5-alpyrimidin-S-arnine By substitutincJ 2-dimethylaminoctllylamina for the . . . .

33S~7l) 3-dimethylaminopropyl-1-amine in part c and utilizirl~ the 8,10-dimethyl-3H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[l,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]triazolo-[1,5-a]pyrimidin-5(8H)-one in part b of -the procedure of Example35, N- (2-dimethylaminoethyl)-8,10-dimethyl-8H-pyrazolo[4',3,:5,6]pyrido[3,4-e][1,2,4]triazolol1,5-a]-pyrimidin-5-amine is obtained.
Example 66 .-N-(3~Diethylaminopropyl) 8-phenyl-8H-pyrazolo[4',3':5,6]-pyrldo[3,4-e][1,2,4]tr azolo[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]pyrldo[3,4-e][1,2,4]triazolo[1,5-a]-20 pyrimidin-5-amine is obtained.
Example 67 8-EthYl-5-thiamorpholino-8H-pyrazolo[4',3':5,6]pyr~do- :
[3 ! 4-e][1,2,4]triazolo[1,5-a]pyrimidine `
By substituting thiamorpholine for the 3-dimethyl-aminopropyl-l-amine in the procedure of Example 35, 8-ethyl-5-thiamorpholino-8H-pyrazolo[4',3':5,6]pyri.do-[3,4-e][1,2,4]triazolo[1,5-alpyrimidine is obtained.

-:
~ .

.

`: .

~' ~ ' ~'' ' 'i ' 83S~O

Example 68 8-Ethyl-5- (~æerazino) -8H-pyrazolo [4',3':5,6]pyrido[~,4-e]-[1,2,4]triazolo[1,5-a]pyrimidine By substituting piperazine for the 3-dimethylamino-propylamine in the procedure of Example 35, 8-ethyl-5-(piperazino)-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[l,5-aJpyrimidine 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 or the 3-(dimethylamino)propylamine in the procedure of Example 35 c, 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 is formed.
Examp]e 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 pyrrolidine for 3-(dimethylamino)propyl-amine in the procedure of Example 35c, 8-ethyl-5-(1-pyrrolidinyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2/4]-triazolo[l,5-a]pyximidine is obtained.
Example 71 8-Ethyl-N-I3-(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-pyrazolo[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-tri1uoromethylaniline are refluxed in butyl alcohol for 24 hour~ with stirring.
The solvent is removed in vacuo and the residue treated with 20 ml. of water and filtered off. Recrystallization --~.......................... . .

` 1~8~5~ 106/107 from alcohol yields 8-ethyl~N-[3-(trifluorornethyl)phenyl]-8H-pyrazolo[4',3,:5,6]pyrido[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]pyrimidin-5-amine By substituting aqueous ammonia (30%) for -the diethyl-amine 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]pyrimidin-5-amine is obtained.
Example 73 8-Ethyl-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-teiazolo[l,5-a]pyrimidine-5-thiol 5.6 g. of 5-chloro-8-ethyl-8H-pyrazolo[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-e][1,2,4]triazolo[1,5-a]-pyrimidine-5-thiol precipitates and is filtered off.
Example 74 8-Ethyl-S-~l-pyrazolyl)-8~-pyrazolo[4',3':5,6]pYrido-[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine - By substituting pyrazole for the 3-(dlmethylamino)-propylamine in the procedure of Example 35c, 8-ethyl 5-(l-pyrazolyl)-8H-pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]-triazolo[l,S-~]pyrimidine i5 obtained.

.~ , ~ ~ ~ 3 ~ 70 Q~10~/107 E~ample 75 8-Ethyl-5-(dihydropyrid~zin-1-yl)-8H-p~razolo~4',3':5,6]~
pyrido~3, 4-e ] [ 1 ! 2, 4 ] triazolo[l,5-a]pyrimidine By substi-tuting dihydropyridazine for the 3-(dimethyl-amino)propylamine in the procedure o~ Example 35c, 8-ethyl-5-(dihydropyridazin-l-yl)-8H-pyrazolo~4',3':5,6]pyrido[3,4-e]-[ 1, 2, 4 ] triazolo[l,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)propyl]-8-e-thyl-8H-pyrazolo[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.
Corn starch 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.
'' * Trade Mark .. , . ,, ~, . ~ , . . . .

Claims (76)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. Process for preparing a compound of the formula wherein Z is or ; R1 is hydrogen, lower alkyl, phenyl, phenyl-lower alkylene, benzoyl or substituted benzoyl wherein the benzoyl substituent is one or two halogens, lower alkyl or trifluoromethyl groups; 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 alkoxy-lower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl, or alkylene, morpholine, thiamorpholine or piperazine, the substituents on said substituted phenyl and substituted benzoyl being halogen, lower alkoxy or lower alkyl. R4' is halo, , -S-R8, phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, lower alkyl or tri-fluoromethyl groups; lower alkoxy or substituted lower alkoxy wherein the lower alkoxy substituent is ; R5 is hydrogen or lower alkyl; R6 is hydrogen, lower alkyl, sub-stituted 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 R6 and R7 together with the nitro-gen form one of the unsubstituted or substituted heterocyclics pyrrolidino, morpholino, thiamorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl wherein the heterocycle sub-stituent 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 II

wherein R1, R2 and R5 are defined as above with a compound of the formula III

or IV

wherein R is lower alkyl and R3 is defined as above to form a compound of the formula V

wherein R1, R2, R3 and R5 are defined as above and, if desired, treating a compound of Formula V with a compound of the formula R4-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 VI

wherein R1, R2, R3 and R5 are defined as above and, if desired, reacting the compound of Formula VI with a compound of the formula lower alkyl-O-Me or Me-O-lower alkylene- wherein Me is an alkali metal and R9 and R10 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 wherain R6, R7, R9 and R10 are defined as above.
2. The process of Claim 1 for preparing a compound of the formula wherein R1, R2, R3, R4 and R5 are defined as in Claim 1 which comprises reacting a compound of the formula II

wherein R1, R2 and R5 are defined as in Claim 1 with a compound of the formula III

or IV

wherein R and R3 are defined as in Claim 1 to form a com-pound of the formula V

wherein R1, R2, R3 and R5 are defined as in Claim 1 and, if desired, treating a compound of Formula V with a compound of the formula R4-hal wherein hal is defined as in Claim 1 and R4 is defined as in Claim 1 other then hydrogen in the presence of a base.
3. The process of Claim 1 for preparing a compound of the formula wherein R1, R2, R3, R4 and R5 are defined as in Claim 1 which comprises reacting a compound of the formula wherein R1, R2, R3 and R5 are defined as in Claim 1 with a chlorinating agent to form a compound of the formula VI

wherein R1, R2, R3 and R5 are defined as in Claim 1 and, if desired, reacting the compound of Formula VI with a com-pound of the formula lower alkyl-O-me or Me-O-lower alkylene- VII

wherein Me, R9 and R10 are defined as in Claim 1 or with a compound of the formula R8-S-Me wherein R8 and Me are defined as in Claim 1 or with an alkali metal sulfide or with an amine of the formula or wherein R6, R7, R9 and R10 are defined as in Claim 1.
4. The process of Claim 2 wherein R1 is lower alkyl; R2 and R5 each is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl, lower alkylthio or lower alkylsulfinyl; and R4 is hydrogen, lower alkyl or di-lower alkylamino-lower alkylene.
5. The process of Claim 2 wherein R1 is lower alkyl, R2, R3 and R5 each is hydrogen or lower alkyl; and R4 is hydrogen, lower alkyl or di-lower alkylamino-lower alkylene.
6. The process of Claim 2 wherein the lower alkyl and lower alkylene groups have up to 4 carbon atoms.
7. The process of Claim 2 wherein R4 is lower alkyl.
8. The process of Claim 2 wherein R4 is di-lower alkylamino-lower alkylene.
9. The process of Claim 2 wherein R3 is lower alkylthio.
10. The process of Claim 2 wherein R3 is lower alkylsulfinyl.
11. The process of Claim 2 wherein R1 and R4 each is lower alkyl and R2, R3 and R5 each is hydrogen.
12. The process of Claim 2 wherein R2, R3 and R5 each is hydrogen.
13. The process of Claim 2 wherein R1 is ethyl and R4 is hydrogen; R2, R3 and R5 each is hydrogen.
14. The process of Claim 2 wherein R1 is ethyl and R4 is isopentyl; R2, R3 and R5 each is hydrogen.
15. The process of Claim 2 wherein R1 is ethyl and R4 is 3-dimethylaminopropyl; R2, R3 and R5 each is hydrogen.
16. The process of Claim 2 wherein R1 is ethyl and R4 is methyl; R2, R3 and R5 each is hydrogen.
17. The process of Claim 2 wherein R1 is ethyl, R2, R4 and R5 each is hydrogen and R3 is methylthio.
18. The process of Claim 2 wherein R1 is ethyl, R2, R4 and R5 each is hydrogen and R3 is methylsulfinyl.
19. The process of Claim 3 wherein R1, R2 and R5 each is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl or lower alkylthio; R4 is amino, mercapto, lower alkylthio, lower alkyl-amino, lower alkoxy, di(lower alkyl)amino, di(lower alkyl)amino-lower alkylamino or di(lower alkyl)amino-lower alkoxy.
20. The process of Claim 3 wherein R2, R3 and R5 each is hydrogen.
21. The process of Claim 3 wherein R4' is di(lower alkyl)-amino.
22. The process of Claim 3 wherein R4' is lower alkoxy.
23. The process of Claim 3 wherein R4' is di(lower alkyl)-amino-lower alkylamino.
24. The process of Claim 3 wherein R4' is di(lower alkyl)-amino-lower alkoxy.
25. The process of Claim 3 wherein R4' is halogen.
26. The process of Claim 3 wherein R4' is lower alkylthio.
27. The process of Claim 3 wherein R4' is lower alkylamino.
28. The process of Claim 3 wherein R1 is lower alkyl and R4' is lower alkylamino; R2, R3 and R5 each is hydrogen.
29. The process of Claim 3 wherein R1 is lower alkyl and R4' is lower alkoxy; R2, R3 and R5 each is hydrogen.
30. The process of Claim 3 wherein R1 is ethyl and R4' is chloro; R2, R3 and R5 each is hydrogen.
31. The process of Claim 3 wherein R1 is ethyl and R4' is butylamino; R2, R3 and R5 each is hydrogen.
32. The process of Claim 3 wherein R1 is ethyl and R4' is ethoxy; R2, R3 and R5 each is hydrogen.
33. The process of Claim 3 wherein R1 is ethyl and R4' is 3-(dimethylamino)propylamino; R2, R3 and R5 each is hydrogen.
34. The process of Claim 3 wherein R1 is ethyl and R5 is diethylamino; R2, R3 and R5 each is hydrogen.
35. The process of Claim 3 wherein R1 is ethyl and R4' is 3-methylbutoxy; R2, R3 and R5 each is hydrogen.
36. The process of Claim 3 wherein R1 is ethyl and R4' is methoxy; R2, R3 and R5 each is hydrogen.
37. The process of Claim 3 wherein R1 is ethyl and R5 is 1-methylpropylamino; R2, R3 and R5 each is hydrogen.
38. The process of Claim 3 wherein R1 is ethyl and R4' is dimethylaminoethoxy; R2, R3 and R5 each is hydrogen.
39. A compound of the formula wherein Z is or ; R1 is hydrogen, lower alkyl, phenyl, phenyl-lower alkylene, benzoyl or substituted benzoyl wherein the benzoyl substituent is one or two halogens, lower alkyl or trifluoromethyl groups; 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 alkoxy-lower alkylene, lower alkylthio-lower alkylene, phenyl, substituted phenyl, or alkylene, morpholine, thiamorpholine or piperazine, the substituents on said substituted phenyl and substituted benzoyl being halogen, lower alkoxy or lower alkyl. R4' is halo, , -S-R8, phenyl-lower alkoxy, phenyloxy, substituted phenyloxy wherein the phenyl ring bears one or two halogen, lower alkyl or tri-fluoromethyl groups; lower alkoxy or substituted lower alkoxy wherein the lower alkoxy substituent is ; R5 is hydrogen or lower alkyl; R6 is hydrogen, lower alkyl, sub-stituted 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 R6 and R7 together with the nitro-gen form one of the unsubstituted or substituted heterocyclics pyrrolidino, morpholino, thiamorpholino, piperidino, pyrazolyl, dihydropyridazinyl or piperazinyl wherein the heterocycle sub-stituent is lower alkyl or hydroxy-lower alkylene; R8, R9 and R10 each is hydrogen or lower alkyl; and acid addition salts thereof when prepared by the process of Claim 1.
40. A compound of the formula Ia wherein R1 is hydrogen; lower alkyl, phenyl, phenyl-lower alkylene, benzoyl or substituted benzoyl; R2 and R5 each is hydrogen or loweralkyl; 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, amino-lower alkyl-ene or alkylene wherein R6 and R7 each is lower alkyl or together join to complete the heterocycle piperidine, morpholine, thiamorpholine or piperazine, the substituents on said substituted phenyl and substituted benzoyl being halogen, lower alkoxy or lower alkyl whenever prepared by the process of Claim 2.
41. A compound as in Claim 40 wherein R1 is lower alkyl; R2 and R5 each is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl, lower alkylthio or lower alkylsulfinyl;
and R4 is hydrogen, lower alkyl or di-lower alkylamino-lower alkylene whenever prepared by the process of Claim 4.
42. A compound as in Claim 40 wherein R1 is lower alkyl, R2, R3 and R5 each is hydrogen or lower alkyl; and R4 is hydrogen, lower alkyl or di-lower alkylamino-lower alkylene whenever prepared by the process of Claim 5.
43. A compound as in Claim 40 wherein R1 is lower alkyl, R2, R3 and R5 each is hydrogen or lower alkyl; and R4 is hydrogen, lower alkyl or di-lower alkylamino-lower alkylene;
the lower alkyl and lower alkylene groups have up to 4 carbon atoms whenever prepared by the process of Claim 6.
44. A compound as in Claim 40 wherein R4 is lower alkyl whenever prepared by the process of Claim 7.
45. A compound as in Claim 40 wherein R4 is di-lower alkylamino-lower alkylene whenever prepared by the process of Claim 8.
46. A compound as in Claim 40 wherein R3 is lower alkyl-thio whenever prepared by the process of Claim 9.
47. A compound as in Claim 40 wherein R3 is lower alkyl-sulfinyl whenever prepared by the process of Claim 10.
48. A compound as in Claim 40 wherein R1 and R4 each is lower alkyl and R2, R3 and R5 each is hydrogen whenever prepared by the process of Claim 11.
49. A compound as in Claim 40 wherein R2, R3 and R5 each is hydrogen whenever prepared by the process of Claim 12.
50. A compound as in Claim 40 wherein R2, R3 and R5 each is hydrogen; R5 is ethyl and R4 is hydrogen whenever prepared by the process of Claim 13.
51. A compound as in Claim 40 wherein R2, R3 and R5 each is hydrogen; R1 is ethyl and R4 is isopentyl whenever prepared by the process of Claim 14.
52. A compound as in Claim 40 wherein R2, R3 and R5 each is hydrogen; R1 is ethyl and R4 is 3-dimethylaminopropyl whenever prepared by the process of Claim 15.
53. A compound as in Claim 40 wherein R2, R3 and R5 each is hydrogen; R1 is ethyl and R4 is methyl whenever prepared by the process of Claim 16.
54. A compound as in Claim 40 wherein R1 is ethyl, R2, R4 and R5 each is hydrogen and R3 is methylthio whenever prepared by the process of Claim 17.
55. A compound as in Claim 40 wherein R1 is ethyl, R2, R4 and R5 each is hydrogen and R3 is methylsulfinyl whenever prepared by the process of Claim 18.
56. A compound of the formula Ib wherein R1 is hydrogen, lower alkyl, phenyl, phenyl-lower alkylene, benzoyl or substituted benzoyl wherein the benzoyl substituent is one or two halogens, lower alkyl or trifluoro-methyl groups; R2 is hydrogen, lower alkyl or phenyl; R3 is hydrogen, lower alkyl, phenyl, lower alkylthio or lower alkyl-sulfinyl; R4' is halo, , -S-R8, 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, substituted phenyl wherein the phenyl substituent is halogen, lower alkyl or trifluoromethyl, R7 is hydrogen or lower alkyl, or R6 and R7 together with the nitrogen form one of the unsubstituted or substituted heterocyclics pyrrolidino, morpholino, thiamor-pholino, piperidino, pyrazolyl, dihydropyridazinyl or pipera-zinyl 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 whenever prepared by the process of Claim 3.
57. A compound as in Claim 56 wherein R1, R2 and R5 each is hydrogen or lower alkyl; R3 is hydrogen, lower alkyl or lower alkylthio; R4' 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 whenever prepared by the process of Claim 19.
58. A compound as in Claim 56 wherein R2, R3 and R5 each is hydrogen whenever prepared by the process of Claim 20.
59. A compound as in Claim 56 wherein R4' is di(lower alkyl)-amino whenever prepared by the process of Claim 21.
60. A compound as in Claim 56 wherein 4' is lower alkoxy whenever prepared by the process of Claim 22.
61. A compound as in Claim 56 wherein R4 is di-(lower alkyl)amino-lower alkylamino whenever prepared by the process of Claim 23.
62. A compound as in Claim 56 wherein R4' is di(lower alkyl)amino-lower alkoxy whenever prepared by the process of Claim 24.
63. A compound as in Claim 56 wherein R4 is halogen whenever prepared by the process of Claim 25.
64. A compound as in Claim 56 wherein R4 is lower alkylthio whenever prepared by the process of Claim 26.
65. A compound as in Claim 56 wherein R4 is lower alkylamino whenever prepared by the process of Claim 27.
66. A compound as in Claim 56 wherein R2, R3 and R5 each is hydrogen; R1 is lower alkyl and R4 is lower alkylamino whenever prepared by the process of Claim 28.
67. A compound as in Claim 56 wherein R2, R3 and R5 each is hydrogen; R1 is lower alkyl and R4 is lower alkoxy whenever prepared by the process of Claim 29.
68. A compound as in Claim 56 wherein R2, R3 and R5 each is hydrogen; R1 is ethyl and R4 is chloro whenever prepared by the process of Claim 30.
69. A compound as in Claim 56 wherein R2, R3 and R5 each is hydrogen; R1 is ethyl and R4' is butylamino whenever prepared by the process of Claim 31.
70. A compound as in Claim 56 wherein R2, R3 and R5 each is hydrogen; R1 is ethyl and R4' is ethoxy whenever prepared by the process of Claim 32.
71. A compound as in Claim 56 wherein R2, R3 and R5 each is hydrogen; R1 is ethyl and R4' is 3-(dimethylamino)propyl-amino whenever prepared by the process of Claim 33.
72. A compound as in Claim 56 wherein R2, R3 and R5 each is hydrogen; R1 is ethyl and R4' is diethylamino whenever prepared by the process of Claim 34.
73. A compound as in Claim 56 wherein R2, R3 and R5 each is hydrogen; R1 is ethyl and R4' is 3-methylbutoxy whenever prepared by the process of Claim 35.
74. A compound as in Claim 56 wherein R2, R3 and R5 each is hydrogen; R1 is ethyl and R4 is methoxy whenever prepared by the process of Claim 36.
75. A compound as in Claim 56 wherein R2, R3 and R5 each is hydrogen; R1 is ethyl and R4' is 1-methylpropylamino whenever prepared by the process of Claim 37.
76. A compound as in Claim 56 wherein R2, R3 and R5 each is hydrogen; R1 is ethyl and R4' is dimethylaminoethoxy whenever prepared by the process of Claim 38.
CA276,889A 1976-07-13 1977-04-25 Pyrazolo [4',3':5,6] pyride [3,4-e] [1,2,4] triazolo- [1,5-a] pyrimidines derivatives Expired CA1083570A (en)

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US05/704,855 US4269836A (en) 1976-07-13 1976-07-13 4H-Pyrazolo[4',3':5,6]pyrido[4,3-d][1,2,4]triazolo[3,2-b]-pyrimidin-5(8H)one and derivatives thereof
US704,855 1976-07-13
US715,599 1976-08-18
US05/715,599 US4078064A (en) 1976-08-18 1976-08-18 8H-Pyrazolo[4',3':5,6]pyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidines

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JPS57111309A (en) * 1980-12-29 1982-07-10 Achilles Corp Production of low-density rigid urethane foam
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JPS539797A (en) 1978-01-28
FR2358405B1 (en) 1980-01-18
FR2358405A1 (en) 1978-02-10
GB1563367A (en) 1980-03-26
DE2731649A1 (en) 1978-01-19

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