Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
QA106/107
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
R3 T N
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~
;- ~
' - ' : "
QA106/107
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-
R9
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
R3 N
-~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 .
--5--
. . , , ' ; ,
. . :, ~, . - :. , : .
~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
HN- NH 2
~ / 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
R3
RO C= N- C =N III
or a lower alkylthiomethylene cyanamide of the formula
R3
; / C ~ M~ C - N IV
R-S
wherein R in both formulas is lower alkyl in an organic
solvent such as alcohol.
,
--6--
,. . . . . . ..
,, . . ,, . - ,~ .
~ 357~ Q~lU6/107
By this reaction is obtained a compound of the formula
R3 I N
~ 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
: '
'
..: '
-7-
- - ' , ~ , .
1~83S7~ QA106/107
R3
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
R9
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
.. ` '
8-
~ 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
-11-
~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
-12- -
. . .
i . .
~ Vf~357(J
QA106/107
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).
'~;
-13-
; '
.
$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-
-14-
. . . - , . -: .
. . ~
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.
-15-
,- :. . ' - '
IL083S7al
QA106/107
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-
,
.. .
--16--
.
, ~ .. : .: . . .
' `:; " ' , ' ' ,
~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
-17-
. , , ~.. , . , -
:~ ~. . .. . . . .
~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.
. ,
~ ,.'' ' . ,
-18-
.
~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
-19-
.
3S~O
QA106/107
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.
-20-
83S~O
QA106/107
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-
-' '
-21-
~ ~; "
7a~
QA106/107
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.
-22-
,
~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-
--23--
~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-
' '' ~
' ~ .
-25-
- , ,, - : . .
: .. . ~ . : .... . .
. . :. : . . ; . : .
. .
~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-
, :
-26-
:
. ,
~ 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
~, , .
-27-
- . . . .. , :~ : ~
.
~ )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-
. .
: . .
-28-
: . :
: . i
~ 357V
QA106/107
(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]-
29
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
52A106/107
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]-
.
--31--
.
,
.
` . . ' ' ' ' ` '
835~
QA106/107
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]-
-32-
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-
.. . . . , , . . ,. :
- .
. . . . . .
57V
,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-
.
-34-
': ' ' .' . ., ' ` :` ' ..',. ", , . '' ~ ' ' ' , ' , ' .
- ` . :.. : ,, , , ~ : :
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-
.
..
-35-
. . '
. . . . . . . . . .
,: . ... .. :
. . .. . .. .~ . .
~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-
-37-
, :, . - . . . . : ,
~, , ~, . . .
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
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. . . .
33S~7l)
QA106/107
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.
-:
~ .
.
-39-
`: .
~' ~ ' ~'' ' 'i '
83S~O
QA106/101
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.
.~ ,
-41-
~ ~ ~ 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.
''
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* Trade Mark
.. , . ,, ~, . ~ , . . . .
