This disclosure describes novel substituted 6-phenyl-1,2,4-triazolo[4,3-b]pyridazines useful as hypotensive agents.

BRIEF SUMMARY OF THE INVENTION 
This invention relates to new organic compounds and, more particularly, is 
concerned with novel substituted 6-phenyl-1,2,4-triazolo[4,3-b]pyridazines 
which may be represented by the following structural formula: 
##STR1## 
wherein R.sub.1, R.sub.2, and R.sub.3 are each individually selected from 
the group consisting of hydrogen and alkyl having up to 3 carbon atoms; 
and R.sub.4 is chloro, bromo, fluoro, cyano, trifluoromethyl, nitro, 
amino, acetamido, carbamoyl, thiocarbamoyl or alkyl having up to 4 carbon 
atoms with the proviso that at least one of R.sub.1 and R.sub.2 is 
hydrogen. The invention also includes novel compositions of matter 
containing the above-defined compounds useful as hypotensive agents and 
the method of meliorating hypertension in mammals therewith. 
DETAILED DESCRIPTION OF THE INVENTION 
The novel compounds of the present invention are generally obtainable as 
white to pale yellow crystalline materials having characteristic melting 
points and absorption spectra and which may be purified by 
recrystallization from common organic solvents such as methanol, ethanol, 
dimethylformamide, acetone, chloroform, ethyl acetate, and the like. They 
are appreciably soluble in non-polar organic solvents such as toluene, 
carbon tetrachloride, and the like but are relatively insoluble in water. 
The organic bases of this invention from non-toxid acid-addition salts 
with a variety of pharmacologically acceptable organic and inorganic 
salt-forming reagents. Thus, acid-addition salts, formed by admixture of 
the organic free base with one or two equivalents of an acid, suitably in 
a neutral solvent, are formed with such acids as sulfuric, phosphoric, 
hydrochloric, hydrobromic, sulfamic, citric, lactic, malic, succinic, 
tartaric, acetic, benzoic, gluconic, ascorbic, and the like. The 
acid-addition salts are relatively insoluble in non-polar organic solvents 
such as diethyl ether, benzene, toluene, and the like but are appreciably 
soluble in water. For purposes of this invention, the free bases are 
equivalent to their non-toxic and acid-addition salts. 
The novel compounds of the present invention may be readily prepared in 
accordance with the following reaction scheme: 
##STR2## 
wherein R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are as hereinabove defined. 
In accordance with the above reaction scheme, an appropriately substituted 
3-benzoylpropionic acid (I) is reacted with hydrazine hydrate at the 
reflux temperature in a lower alkanol solvent for a period of 12-24 hours 
to provide the corresponding, 4,5-dihydro-6-phenyl-3(2H)-pyridazinone 
(II). Treatment of the 4,5-dihydro-6-phenyl-3(2H)-pyridazinone (II) with 
bromine in glacial acetic acid solvent at steam bath temperature for a 
period of 2-4 hours provides the corresponding 6-phenyl-3(2H)-pyridazinone 
(III). Conversion of the 6-phenyl-3(2H)-pyridazinone (III) to the 
corresponding 3-chloro-6-phenylpyridazine (IV) is achieved by treatment 
with excess phosphorus oxychloride at steam bath temperature for a period 
of 4-8 hours. Interaction of the 3-chloro-6-phenylpyridazine (IV) with an 
acylhydrazine (V) at the reflux temperature in a lower alkanol solvent for 
a period of 24-48 hours provides the corresponding 
6-phenyl-1,2,4-triazolo[4,3-b]pyridazines (VI) of the present invention. 
The novel compounds of the present invention may also be readily prepared 
in accordance with the following reaction scheme: 
##STR3## 
wherein R.sub.1, R.sub.2, and R.sub.4 are as hereinabovve defined. In 
accordance with the above reaction scheme, an appropriately substituted 
3-chloro-6-phenylpyridzine (IV) is reacted with hydrazine hydrate at the 
reflux temperature in a lower alkanol solvent for a period 12-24 hours to 
provide the corresponding 3-hydrazino-6-phenylpyridazine (VII). Ring 
closure of the 3-hydrazino derivatives (VII) with lower alkyl 
orthoformates provides compounds of formula (VIII) wherein R.sub.3 is 
hydrogen. Ring closure of the 3-hydrazino derivatives (VII) with lower 
alkanoic acid anhydrides, lower alkanoic acid chlorides, or orthoesters of 
lower alkanoic acids provides compounds of formula (IX) wherein R.sub.3 is 
lower alkyl. The ring closures may be carried out with or without 
catalysis by bases such as pyridine or tri(lower alkyl) amines. Ring 
closures with lower alkyl orthoformates and orthoesters of lower alkanoic 
acids are preferably carried out without catalysis and without solvent, 
although an inert solvent may be used. The ring closures are usually 
accomplished by heating with or without a solvent at 50.degree. to 
175.degree. C. 
The novel compounds of the present invention possess anti-hypertensive 
activity at non-toxic doses and as such are useful as hypotensive agents. 
The compounds have been tested pharmacologically and found to have such 
properties with a desirable wide spread between doses producing lowered 
blood pressure and toxid symptoms. The hypotensive properties of the 
compounds of the present invention have been shown when orally 
administered to mammals, specifically warm-blooded animals, as follows* 
Conscious, normotensive male albino Wistar strain rats averaging 
approximately 250 grams were fastened to rat boards in a supine position 
by means of canvas and limb ties. The femoral areas were anesthetized 
(subcutaneous infiltration of lidocain), and the left or right common 
iliac arteries were exposed and clamped off proximally by an artery clamp 
and distally with thread. Incisions were made near the tie and short nylon 
catheters were inserted and tied in place. The other end of the catheters 
were fitted with 24 gauge hubless needles attached to thick-walled 
polyethylene tubes. The test compounds were administered to the animals 
orally, by gavage (stomach tube). The compounds were tested at 100 mg./kg. 
and were suspended or dissolved in 2% aqueous starch solution, 0.2 ml. of 
which gave, per 100 grams of body weight, the desired dose. Mean arterial 
blood pressure was measured 4 hours and 24 hours after administration of 
the compounds. Comparisons were then made to the means control pressure of 
122 mm. of mercury, which is the average of a number of controls recorded 
over months of testing. Blood pressure measurements were made with eight 
Statham P23 Db strain gauges (Statham Instruments, Inc., Los Angeles, 
California), attached to a Beckman Dynograph Recorder equipped with eight 
strain gauge preamplifiers with averaging circuits for measuring mean 
arterial blood pressure. The results with representative compounds of the 
present invention appear in Table I below. 
The novel compounds of the present invention were also tested for 
antihypertensive activity in a procedure using spontaneously hypertensive 
rats (SHR) as follows: One male adult (16-20 weeks old) about 300 grams 
SHR (Taconic Farms, Germantown, N.Y.) is dosed by gavage with the test 
compound at 100 mg/kg. with or without 0.9% sodium chloride loading at 25 
ml/kg. at 0-hour. A second identical dose is given at 24 hours and the 
mean arterial blood pressure (MABP) of conscious rats is measured directly 
by femoral artery puncture at 28 hours. The results of this test with 
representative compounds of the present invention also appear in Table I 
below. 
TABLE I 
__________________________________________________________________________ 
Hypotensive Activity In Rats 
##STR4## 
Spontaneous 
Normotensive Rats 
Hypertensive Rats 
Mean Arterial Blood 
Mean Arterial blood 
Compound Dose Pressure (mm. Hg) 
Pressure (mm. Hg) 
R.sub.1 
R.sub.2 
R.sub.3 
R.sub.4 
mg./kg. 
4 HR 24 HR 28 HR 
__________________________________________________________________________ 
CH.sub.3 
H H 4-cyano 
100 95 110 130 
103 113 
CH.sub.3 
H H 3-nitro 
100 102 93 
CH.sub.3 
H H 3-amino 
100 93 115 130 
H H H 4-bromo 
100 85 93 115 
H H H 4-fluoro 
100 88 
H H H 4-cyano 
100 108 
CH.sub.3 
H H 3-cyano 
100 88 
H H n-C.sub.3 H.sub.7 
3-trifluoro- 
100 112 
methyl 
CH.sub.3 
H H 4-bromo 
100 107 95 
CH.sub.3 
H H 4-thiocarba- 
100 101 106 
moyl 
H H H 4-chloro 
100 110 
H H H 3-trifluoro- 
100 90 
methyl 
H H CH.sub.3 
3-trifluoro- 
100 133 
methyl 
H CH.sub.3 
H 4-chloro 
100 138 
H H CH.sub.3 
4-chloro 
100 150 
H H CH.sub.3 
4-fluoro 
100 150 
H H H 3-amino 
100 164 
H CH.sub.3 
CH.sub.3 
4-chloro 
100 148 
Mean Control Pressure 
122 118 166 
__________________________________________________________________________ 
The novel compounds of the present invention have thus been found to be 
highly useful for lowering elevated blood pressure in mammals when 
administered in amounts ranging from about 1.0 milligram to about 25. 0 
mg. per kilogram of body weight per day. A preferred dosage regimen for 
optimum results would be from about 5.0 mg. to about 15.0 mg. per kilogram 
of body weight per day, and such dosage units are employed that a total of 
from about 0.35 gram to about 1.0 gram of active compound for a subject of 
about 70 kg. of body weight are administered in a 24 hour period. The 
dosage regimen may be adjusted to provide the optimum therapeutic 
response. For example, several divided doses may be administered daily or 
the dose may be proportionally reduced as indicated by the exigencies of 
the therapeutic situation. A decided practical advantage of this invention 
is that the active compounds may be administered in any conventient manner 
such as by the oral, intravenous, intramuscular, or subcutaneous routes. 
Compositions according to the present invention having the desired clarity, 
stability and adaptability for parenteral use are obtained by dissolving 
from 0.10 to 10.0% by weight of active compound in a vehicle consisting of 
a polyhydric aliphatic alcohol or mixtures thereof. Especially 
satisfactory are glycerin, propylene glycol, and polyethylene glycols. The 
polyethylene glycols consist of a mixture of non-volatile, normally 
liquid, polyethylene glycols which are soluble in both water and organic 
liquids and which have molecular weights of from about 200 to 1500 . 
Although the amount of acitve compound dissolved in the above vehicle may 
vary from 0.10 to 10.0% by weight, it is preferred that the amount of 
acitve compound employed be from about 3.0 to about 9.0% by weight. 
Although various mixtures of the aforementioned non-volatile polyethylene 
glycols may be employed, it is preferred to use a mixture having an 
average molecular weight of from about 200 to about 400. 
In addition to the active compound, the parenteral solutions may also 
contain various preservatives which may be used to prevent bacterial and 
fungal contamination. The preservatives which may be iused for these 
purposes are, for example, muristly-gamma-picolinium chloride, 
benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-.alpha.-glycerol 
ether, methyl and propyl parabens, and thimerosal. As a practical matter, 
it is also convenient to employ antioxidants. Suitable antioxidants 
include, for example, sodium bisulfite, sodium metabisulfite, and sodium 
formaldehyde sulfoxylate. Generally, form about 0.05 to about 0.2% 
concentrations of antioxidant are employed. 
For intramuscular injection, the preferred concentration of active compound 
is 0.25 to 0.50 mg./ml. of the finished composition. The novel compounds 
of the present invention are equally adapted to intravenous administration 
when diluted with water or diluents employed in intravenous therapy such 
as isotonic glucose in appropriate quantities. For intravenous use, 
initial concentrations down to about 0.05 to 0.25 mg./ml. of active 
ingredient are satisfactory. 
The active compounds of the present invention may be orally administered, 
for example, with an inert diluent or with an assimilable edible carrier, 
or they may be enclosed in hard or soft shell gelatin capsules, or they 
may be compressed into tablets, or they may be incorporated directly with 
the food of the diet. For oral therapeutic administration, the active 
compounds may be incorporated with excipients and used in the form of 
tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the 
like. Such compositions and preparations should contain at least 0.1% of 
active compound. The percentage of the compositions and preparations may, 
of course, be varied and may conventiently be between about 2 to about 60% 
of the weight of the unit. The amount of active compound in such 
therapeutically useful compositions is such that a suitable dosage will be 
obtained. Preferred compositions or preparations according to the present 
invention are prepared so that an oral dosage unit form contains between 
about 0.1 and 5.0 milligrams of active compound. 
The tablets, troches, pills, capsules and the like may also contain the 
following: a binder such as gum tragcanth, acacia, corn starch or gelatin; 
excipients such as dicalcium phosphate; a disintegrating agent such as 
corn starch, potato starch, alginic acid and the like; a lubricant such as 
magnesium stearate; and a sweetening agent such as sucrose, lactose or 
saccharin may be added or a flavoring agent such as peppermint, oil of 
wintergreen, or cheery flavoring. When the dosage unit form is a capsule, 
it may contain, in addition to materials of the above type, a liquid 
carrier such as a fatty oil. Various other materials may be present as 
coatings or to otherwise modify the physical form of the dosage unit. For 
instance, tablets, pills, 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 propylparabens as preservatives, a dye and 
flavoring such as cherry or orange flavor. Of course, any material used in 
preparing any dosage unit form should be pharmaceutically pure and 
substnatially non-toxic in the amounts employed. 
This invention also relates to novel substituted 
6-phenyl-1,2,4-triazolo[4,3-b]pyridazines useful as hypotensive agents 
which may be represented by the following structural formula: 
##STR5## 
wherein R.sub.1, R.sub.2 and R.sub.3 are each individually selected from 
the group consisting of hydrogen and alkyl having up to 3 carbon atoms 
with the proviso that at least one of R.sub.1 and R.sub.2 is hydrogen; and 
two of the substituents R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are hydrogen 
and the remaining two are fluoro, chloro, bromo, methyl, methoxy, nitro, 
amino or trifluoromethyl. These novel compounds may be readily prepared in 
accordance with the reaction schemes hereinabove except that the moiety 
##STR6## 
as therein defined is replaced by the moiety 
##STR7## 
as defined immediately above. For purposes of this invention, these free 
bases are equivalent to their non-toxic acid-addition salts.

The invention will be described in greater detail in conjunction with the 
following specific examples. 
EXAMPLE 1 
Preparation of p(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)benzonitrile 
200 g. portion of 
p-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile [Journal 
of Medicinal Chemistry 17,281 (1974)] is suspended in 500 ml. of glacial 
acetic acid with overhead stirring at stream bath temperature, then 56 ml. 
of liquid bromine is dissolved in an additional 500 ml. of acetic acid and 
this solution is added to the stirring mixture all at once. After 
approximatley half an hour of heating, a vigorous exothermic reaction 
occurs with the expulsion of the excess bromine and hydrogen bromide. The 
reaction mixture is the diluted with 4 liters of distilled water and the 
resulting solid is filtered and the filter cake is copiously washed with 
water and is air dried. This material is recrystallized from a large 
amount of ethyl alcohol to afford the product 
p-(1,6-dihydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile as a white solid. 
A 45.9 g. portion of the above material and 250 ml. of phosphorous 
oxychloride is heated at steam bath temperature for 3 hours. The excess 
phosphorus oxychloride is decomposed by the slow addition of the reaction 
mixture to crushed ice with stirring. The resulting solid is filtered, 
washed with water and dried in vacuo. the material is then recrystallized 
from methyl alcohol to give 
p-(6-chloro-4-methyl-3-pyridazinyl)benzonitrile. 
A mixture of 14.6 g. of the above compound, 9.4 g. of formylhydrazine and 
175 ml. of butyl alcohol is stirred at reflux for 18 hours. The reaction 
mixture is concentrated free of solvent and the concentrate is triturated 
with petroleum ether and is filtered. The filter cake is air dried and the 
yellow solid is recrystallized twice from methyl alcohol, the resulting 
light yellow crystals are again recrystallized from methanol to afford the 
product of the example, m.p. 204.degree.-243.degree. C. 
EXAMPLE 2 
Preparation of 
p(3,7-dimethyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)-benzonitrile 
A 1.48 g. portion of acetic acid hydrazide is dissolved in 50 ml. of buyl 
alcohol with heating, then 4.58 g. of 
p-(6-chloro-4-methyl-3-pyridazinyl)benzonitrile (prepared as in Example 1) 
is added and complete solution occurs after heating for an additional 10 
minutes The solution is then heated at reflux for 18 hours. The reaction 
mixture is concentrated to afford 5.8 g. of orange solid which is washed 
with petroleum ether. This product is dissolved in 1:1 ethyl 
alcohol/acetone and is filtered through a pad of silica gel. The filter is 
washed copiously with acetone and the combined filtrates are concentrated 
to a yellow solid. The solid is dissolved in 100 ml. of acetone and the 
solution is cooled in dry ice-acetone to afford a tan solid which is 
collected by filtration, washed copiously with petroleum ether and air 
dried. This product is dissolved in methyl alcohol, is treated with 
activated charcoal and is filtered. The filtrate is used to recrystallize 
1.06 g. of yellowish crystals. A 500 mg. portion of the above is 
recrystallized twice from methanol and the resultant product is dried in 
vacuo to give the product of the example, m.p. 242.degree.-244.degree. C. 
EXAMPLE 3 
Preparation of 
p-(3-ethyl-7-methyl-1,2,4-triazole[4,3-b]pyridazin-6-yl)benzonitrile 
A mixture of 102.13 g. of ethyl propionate, 50 g. of hydrazine hydrate and 
150 ml. of ethyl alcohol is stirred at reflux for 24 hours. The rection 
mixture is concentrated free of solvent, then is cooled in ice and stirred 
with petroleum ether. A white solid results which is filtered, washed with 
petroleum ether and is dried in vacuo to afford propionic acid hydrazide 
as a white crystalline solid. 
A 30.8 g. portion of the above compound is dissolved in one liter of butyl 
alcohol (dried over 3-A molecular sieves), then 40.0 g. of 
p(6-chloro-4-methyl-3-pyridazinyl)benzonitrile (prepared as in Example 1) 
is added and the reaction mixture is allowed to heat at reflux for 18 
hours. The reaction mixture is concentrated free of solvent and the 
concentrate is triturated with petroleum ether, then is filtered. The 
filter cake is vacuum dried to afford a yellow solid which is then 
recrystallized from methyl alcohol to give the product of the example, 
m.p. 192.degree.-195.degree. C. 
EXAMPLE 4 
Preparation of 
p-(3-ethyl-7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)benzamide 
A 4.5 g. portion of 
p-(3-ethyl-7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)benzonitrile 
(prepared as described in Example 3) is dissolved in 50 ml. of ethyl 
alcohol with warming, then 50 ml. of 30% hydrogen peroxide is added with 
swirling and finally 50 ml. of 2N sodium hydroxide is added with swirling. 
The reaction is allowed to stand at room temperature for 3 hours, then is 
concentrated almost to dryness using as little heat as possible. The 
concentrate is diluted with water, filtered and the filter cake is then 
washed with water and air dried. The product is dissolved in acetone and 
filtered to remove insolubles then is recrystallized to afford a yellow 
solid as the product of the example, m.p. 210.degree.-213.degree. C. 
EXAMPLE 5 
Preparation of 7-methyl-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine 
A 28 g. portion of 3-(m-nitrobenzyoly)butyronitrile [prepared as described 
in J. Org. Chem., Vol. 38, No. 23, 4044-4048 (1973)] is added to one liter 
of 6N hydrochloric acid and is stirred at reflux for one hour using a 
magnetic stirrer and a heating mantle. The reaction mixture is cooled and 
extracted with methylene chloride. The organic layer is separated and 
extracted with saturated sodium bicarbonate. The bicarbonate layer is 
added dropwise to a stirred cold hydrochloric acid solution and the 
resulting solid is kept cold in ice then is filtered and air dried to 
afford 27.24 g. of 3-m-nitrobenzoyl butyric acid as a white solid. The 
entire amount of the preceding compound is mixed with 12.8 ml of 99% 
hydrazine hydrate in 140 ml. of ethyl alcohol and is stirred at reflux for 
3 hours. A solid beings to appear after about half an hour. The reaction 
mixture is cooled in an ice bath and the resulting solid is filtered and 
air dried to afford the compound 
4,5-dihydro-5-methyl-6-(m-nitrophenyl)-3-(2H)-pyridazinone as white to 
light yellow crystals. 
A 24.9 g. portion of the above material is dissolved in 200 ml. of warm 
stirred glacial acetic acid, then 6.2 ml. of bromine dissolved in 50 ml. 
of glacial acetic acid is added to this dropwise over a 15 minute period 
with the evolution of hydrogen bromide gas. The reaction mixture is warmed 
for an additional 20 minutes to expel the hydrogen bromide, then the 
mixture is poured into crushed ice. The resulting solid is filtered and 
washed with large amounts of water then is dried in vacuo to afford 24.2 
g. of 5-methyl-6-(m-nitrophenyl)-3-(2H)-pryidazinone as a cream colored 
solid. 
A 22.7 g portion of the preceding compouding is combined with 230 ml. of 
phosphorus oxychloride and heated on a steam bath for 3 hours. The 
reaction mixture is poured portionwise into crushed ice with stirring. The 
resulting solid is filtered, copiously washed with water and air dried to 
yield 15.6 g. of 3-chloro-5-methyl-6-(m-nitrogphenyl)pyridazine as a tan 
solid. 
A mixture of 14.97 g. of the compound above, 7.2 g. of formylhydrazine and 
200 ml. of butyl alcohol is stirred at reflux for 18 hours. The reaction 
mixture is decanted free of insolubles and the liquid portion is cooled in 
an ice bath to afford 13.28 g. of brown crystalline solid. This material 
is dissolved in 300 ml. of boiling methyl alcohol then is filtered to 
remove insolubles. The filtrate is clarified by treatment with activated 
charcoal and filtering. This filtrate is concentrated to a small volume 
and cooled to yield a tan-brown solid as the product of the example, m.p. 
213.degree.-218.degree. C. 
EXAMPLE 6 
Preparation of 6-(m-aminophenyl)-7-methyl-1,2,4-triazolo[4,3-b]pyridazine 
A mixture comprising 2.28 g of 
7-methyl-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine (prepared as 
described in Example 5), 100 ml. of ethyl alcohol and a catalytic amount 
of platinum oxide is shaken in a Parr shaker under 40 pounds of hydrogen 
pressure for 11/2 hours. The reaction mixture is filtered free of catalyst 
and the filtrate is concentrated to afford the product of the example as a 
yellow solid, m.p. 182.degree.-186.degree. C. 
EXAMPLE 7 
Preparation of 6-(p-bromophenyl)-1,2,4-triazolo[4,3-b]pyridazine 
A mixture of 3.76 g. of 3-(p-bromophenyl)-6-chloropyridazine, 1.80 g of 
formylhydrazine and 50 ml. of butyl alcohol is heated to reflux and 
allowed to reflux overnight. The reaction mixture is allowed to cool and 
the precipitated product is washed with water, air dried and 
recrystallized from methyl alcohol, m.p. 209.degree.-211.degree. C. 
EXAMPLE 8 
Preparation of 6-(p-fluorophenyl)-1,2,4-triazolo[4,3-b)pyridazine 
An 87 g sample of 6-(p-fluorophenyl)-4,5-dihydro-3(2H)-pyridazine (prepared 
as in U.S. Pat. No. 3,689,652, Example 6) is stirred in 800 ml. of glacial 
acetic acid in a 2 liter 3 necked flask on a steam bath. A solution of 
24.1 ml. of bromine liquid in 100 ml. of glacial acetic acid is prepared 
in a dropping funnel. A 15 ml. portion of this bromine solution is added 
dropwise to the reaction mixture which is heated with stirring until the 
mixture becomes ligher in color. The remainder of the bromine solution is 
then added with heating and stirring over about 30 minutes. The reaction 
mixture is then heated for one hour longer then is poured onto crushed 
ice. The solid formed is collected by filtration, washed with water and 
air dried overnight. The material is then dried at 65.degree. C. to afford 
82.0 g. of 6-(p-fluorophenyl)-3(2H)-pyridazinone as crystals, m.p. 
265.degree.-268.degree. C. 
The entire amount of the above compound is combined with 500 ml. of 
phosphorus oxychloride and is heated on a steam bath for 5 hours. The 
reaction mixture is cooled and the excess phosphorus oxychloride is 
removed using a rotary evaporator, then one liter of ice-water is added 
with stirring. The resulting solid is filtered, washed with water and air 
dried overnight. The solid is taken up in 2 liters of chloroform, treated 
with activated charcoal and filtered through diatomaceous earth. The 
chloroform filtrate is concentrated to a low volume, the precipitate 
formed is collected by filtration and washed with chloroform, then air 
dried to afford 3-chloro-6-(p-fluorophenyl)pyridazine as pinkish crystals. 
A 2.5 g portion of the above compound is mixed with 1.46 g of 
formylhydrazine and 40 ml. of butyl alcohol. The mixture is heated to 
reflux and is relfuxed overnight. The mixture is cooled in an ice bath and 
the precipitated product is collected by filtration, is washed with butyl 
alcohol and is dried overnight. The dried material is recrystallized from 
methyl alcohol to give the product of the example as crystals, m.p. 
197.degree.-198.degree. C. 
EXAMPLE 9 
Preparation of p-(1,2,4-triazolo[4,3-b]pyridazine-6-yl)benzonitrile 
An 86.3 g sample of 6-(p-bromophenyl)-4,5-dihydro-3-(2H)-pyridazinone 
(prepared as in U.S. Pat. No. 3,689,652 Example 5) is dissolved in 500 ml. 
of glacial acetic acid by heating to 80.degree. C. with continuous 
stirring. A solution of 60 g. of bromine in 80 ml. of acetic acid is added 
dropwise at 75.degree.-80.degree. C over a 1 hour period. A solid is 
separated near the end of the addition. The reaction mixture is heated 
with stirring on the steam bath for half an hour mote, then is poured into 
3 liters of cracked ice-water. The white solid formed is collected by 
filtration and is air dried. The product is then recrystallized from ethyl 
alcohol to afford 6-(p-bromophenyl)-3(2H)-pyridazinone. 
A mixture of 19.20 g. of the product above and 9.10 g of cuprous cyanide in 
70 ml. of dimethylformamide is stirred at reflux temperature for 51/2 
hours. A solid is precipitated during this time. The hot mixture is poured 
into a solution of 46 ml. of ethylenediamine in 230 ml. of water. The 
mixture is stirred at ice-bath temperature for 30 minutes, the precipitate 
is collected by filtration and washed with water until the washings are 
colorless to afford p-(1,6-dihydro-6-oxo-3-pyridazinyl)benzonitrile as a 
yellow solid. 
A stirred solution of 3.42 g. of the preceding material in 25 ml. of 
phosphorus oxychloride is heated at reflux temperature for 3 hours, Most 
of the excess phosphorus oxychloride is removed under reduced pressure 
then cracked ice-water is added to the concentrate which is stirred. The 
solid is collected by filtration and after air-drying is recrystallized 
from dimethylformamide-water to give 
p-(6-chloro-3-pyridazinyl)benzonitrile as crystals, m.p. 
236.degree.-238.degree. C. 
A mixture of 1.00 g of the above product. 0.84 g. of formylhydrazine and 25 
ml. of n-butyl alcohol is stirred at reflux temperature for 17 hours and 
45 minutes. The solvent is removed under reduced pressure and the residue 
is triturated with ethyl alcohol. The mixture is filtered and the solid is 
recrystallized from dimethylformamide-water to afford 
p-(1,2,4-triazolo[4,3-b]pyridazine-6-yl)benzonitrile as an orange solid, 
m.p. 272.degree.-274.degree. C. 
EXAMPLE 10 
Preparation of 
m-(7-methyl-1,2,4-triazolo[4,3-b]pyridazine-6-yl)benzonitrile 
A 15 g. portion of 
m-(1,4,5,6,-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile [Journal 
of Medicinal Chemistry 17, 281 (1974)]is suspended in 75 ml. of glacial 
acetic acid with stirring at steam bath temperature. Then 3.75 ml. of 
bromine in 25 ml. of acetic acid is added dropwise over a 15 minute 
period. The reaction mixture is heated on a steam bath for an additional 
a30 minutes then is poured onto crushed ice. The resulting solid is 
collected by filtration, copiously washed with water and dried to afford 
m-(1,6-dihydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile as a cream 
colored solid. 
A 10.0 g. portion of the above material and 100 ml. of phosphorus 
oxychloride is heated on a steam bath for 3 hours. The excess phosphorus 
oxychloride is decomposed by the slow addition of the reaction mixture to 
cold water with stirring. The resulting solid is filtered and the filter 
cake is copiously washed with water. The product is air dried to afford 
m-(6-chloro-4-methyl-3-pyridazinyl)benzonitrile as a cream colored solid. 
A mixture of 3.0 g of the above compound 1.57 g of formylhydrazine and 100 
ml. of butyl alcohol is stirred at reflux for 18 hours. The reaction 
mixture is cooled in an ice bath filtered to collect the solid formed. The 
product of the example is then recrystallized from methyl alcohol to 
afford a cream colored solid, m.p. 214.degree.-216.degree. C. 
EXAMPLE 11 
Preparation of 
3-propyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-1,2,4-triazolo[4,3- 
b]pyridazine 
A 112 g. portion of p-toluenesulfonic acid is dissolved in 500 ml. of 
tetrahydrofuran with stirring. Then 106 g. of morpholine is added 
portionwise with stirring. A 95.63 g portion of 
m-trifluoromethylbenzaldehyde is added and the reaction mixture is stirred 
at reflux for 2 hours. The reaction mixture is cooled and a solution of 
42.2 g of potassium cyanide in 75 ml. of water is added. The mixture is 
then allowed to stir at reflux overnight. The reaction mixture is 
concentrated free of solvent and the concentrate is partitioned between 
water and chloroform. the organic layer is washed with saturated sodium 
bisulfite, dried over magnesium sulfate, treated with activated charcoal 
and filtered. The filtrate is concentrated in vacuo to afford 
.alpha.-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-4-morpholineaceonitril 
e as a dark yellow oil. A 67.0 g. portion of the oil above is dissolved in 
two liters of tetrahydrofuran with stirring at room temperature. Stirring 
is continued while eight 10 ml. portions of ethyl acrylate and nine 5 ml. 
portions of a 30% solution of potassium hydroxide in ethyl alcohol are 
added to the reaction mixture over a 5 hour period. This reaction is 
slightly exothermic. The reaction mixture is allowed to stir at room 
temperature overnight. The mixture is treated with activated charcoal and 
filtered. The filtrate is concentrated free of solvent then is stripped 
several times with toluene. The concentrate is stirred with diethyl ether 
and filtered to remove insolubles. The filtrate is concentrated to a 
yellow oil then is chromatographed on a 75 cm. .times. 8 cm. glass column 
containing silica gel with chloroform as the solvent. The chromotographed 
material is stripped of chloroform to afford 47.0 g. of ethyl 
.gamma.-cyano-.gamma.-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-4-morpho 
linebutyrate as a yellow oil. The entire amount of the preceding product is 
combined with 2 liters of ethyl alcohol and 7.3 ml. of hydrazine hydrate. 
The mixture is stirred at reflux for 18 hours, then is concentrated free 
of solvent to afford a yellow oil which is stirred with petroleum ether to 
yield 14.55 g. of 
4,5-dihydro-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-3(2H)-pyridazino 
ne as a white solid. The total amount of the product above is dissolved in 
225 ml. of glacial acetic acid at ambient temperature, then 3.33 ml. of 
bromine is dissolved in 25 ml. of acetic acid and 2.5 ml. of this solution 
is added to the starting material above at room temperature. The reaction 
mixture is warmed on a steam bath for half an hour while the remaining 
bromine-acetic acid solution is added dropwise. Following complete 
dicoloration, the reaction mixture is heated on a steam bath for half an 
hour, and is concentrated free of solvent. The solid concentrate is washed 
with water, filtered and air dried to afford 
6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-3(2H)-pyridazinone as a 
cream colored solid. 
A 12.55 g portion of the above product and 200 ml. of phsophorus 
oxychloride is heated on a steam bath for 18 hours. The reaction mixture 
is concentrated free of excess phosphorus oxychloride and the concentrate 
is triturated with cold water. The resulting solid is filtered and the 
filter cake is washed with water. The material is air dried to afford 
3-chloro-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)pyridazine as a 
cream colored solid. 
A mixture of 6.0 g. of the preceding product, 4.74 g. of butyric acid 
hydrazide and 75 ml. of butyl alcohol is allowed to stir at reflux for 48 
hours. The reaction mixture is concentrated free of solvent and the 
concentrate is taken up in ethyl alcohol, treated with activated charcoal 
and filtered. The filtrate is concentrated to a small residue, cooled in 
an ice bath and the resulting solid is filtered to afford the product of 
the example as a cream colored solid. This material is recrystallized from 
ethyl alcohol and dried in vacuo to afford crystals, m.p. 
118.degree.-120.degree. C. 
EXAMPLE 12 
Preparation of 3'-(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)acetanilide 
A 1.5 g. portion of 
6-(m-aminophenyl)-7-methyl-1,2,4-triazolo[4,3-b]pyridazine (prepared as in 
Example 6) is dissolved in 30 ml. of pyridine at room temperature. To the 
solution is added 6.0 ml. of acetic anhydride and the reaction mixture is 
heated on a steam bath for 1 hour. The reaction mixture is cooled in an 
ice bath and is filtered. The filter cake is washed with petroleum ether 
and is dried to afford the product of the example as cream colored 
crystals, m.p. 298.degree.-301.degree. C. 
EXAMPLE 13 
Preparation of 6-(p-bromophenyl)-7-methyl-1,2,4-triazolo[4,3-b]pyridazine 
A 10.0 g. portion of 6-(p-bromophenyl)-5-methyl -3-(2H)-puyridazinone 
]Journal of Medicinal Chemistry 17, 281 (1974)] and 100 ml. of phosphorus 
oxychloride is heated at steam bath temperature for 3 hours. The mixture 
is added dropwise to cold water while stirring. The resulting solid is 
filtered and washed with water to afford 
3-(p-bromophenyl)-6-chloro-4-methylpyridazine as a grey solid. 
A mixture of 1.5 g of the above compound, 0.64 g. of formylhydrazine and 25 
ml. of butyl alcohol is stirred at reflux for 18 hours. The reaction 
mixture is cooled in an ice bath, filtered and the solid is recrystallized 
from methyl alcohol to afford the product of the example as a yellow 
solid, m.p. 219.degree.-222.degree. C. 
EXAMPLE 14 
Preparation of 
p-(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)thiobenzamide 
A 2.1 g. portion of 
p-(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)benzonitrile (prepared as 
in Example 1) is partially dissolved in a solvent mixture of 50 ml. of 
pyridine plus 5.0 ml. of triethylamine. Hydrogen sulfide gas is bubbled 
into the reaction mixture over a 3 hour period during which time the color 
of the reaction mixture changes from yellow to green. A solid begins to 
form in the reaction mixture approximately 15 minutes after the addition 
of the hydrogen sulfide gas is begun. The mixture is then filtered and the 
yellow solid is washed with petroleum ether to afford the product of the 
example as a bright yellow solid, m.p. 268.degree.-272.degree. C. 
EXAMPLE 15 
Preparation of 6-(3-bromo-p-methoxyphenyl)-1,2,4-triazolo[4,3-b]pyridazine 
A suspension of 100 g. of 6-(3-bromo-4-methoxyphenyl)-3(2H)-pyridazinone 
[J. Heterocyclic Chem. 11, 775 (1974) ]in 150 ml. of phosphorus 
oxychloride is refluxed until a clear solution is obtained (approximately 
5 hours). The solution is cooled and excess phosphorus oxychloride is 
removed under vacuum to give a brown solid which is triturated with ice 
water. The solid is collected by filtration and is recrystallized to 
afford 3-(3-bromo-4-methoxyphenyl)-6-chloropyridazine. 
A mixture of 5.28 g. of the preceding compound, 75 ml. of butyl alcohol and 
2.88 g. of formylhydrazine is heated to reflux and is refluxed overnight. 
The reaction mixture is cooled to room temperature and the product is 
collected by filtration. This material is then recrystallized from methyl 
alcohol to give the product of the example as crystals, m.p. 
226.degree.-228.degree. C. 
Example 16 
Preparation of 6-(p-chlorophenyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine 
A 47.5 g. portion of 6-(p-chlorophenyl)-4,5-dihydro-3(2H)-pyridazinone 
(prepared as in Example 1 of U.S. Pat. No. 3,689,652) is dissolved in 250 
ml. of glacial acetic acid at 65.degree.-70.degree. C with stirring. Then 
a solution of 14 ml. (42 g.) of bromine liquid in 50 ml. of acetic acid is 
added portionwise during a 20 minute period. The reaction mixture is 
stirred at 65.degree. C. for 3 hours and is cooled to 4.degree. C. The 
precipitate is collected and washed with 100 ml. of ethyl acetate. The 
solid is suspended in 500 ml. of water, 25 ml. of concentrated ammonium 
hydroxide is added and the mixture is stirred at room temperature 
overnight. the precipitate is collected, washed with 500 ml. of water and 
dried at 60.degree. C. to afford 6-(p-chlorophenyl)-3(2H)-pyridazinone. 
A mixture of 34.5 g. of the preceding material and 150 ml. of phosphorus 
oxychloride is refluxed for 4 hours. The reaction mixture is cooled and 
poured into 2 k. of ice. After standing for 2 hours with occasional 
stirring, the precipitate is collected and washed with water. The solid is 
dissolved in 500 ml. of boiling benzene, clarified with activated charcoal 
and filtered. The filtrate is cooled to room temperature and the solid is 
collected, washed with a small amount of benzene and air dried. This 
material is recrystallized from ethyl alcohol after treatment with 
activated charcoal. The product is collected, washed with ethyl alcohol 
followed by ether to afford 3-chloro-6-(p-chlorophenyl)pyridazine, m.p. 
209.degree. -211.degree. C. 
A mixture of 10.0 g. of the product above, 6.6 g. of hydrazine hydrate and 
150 ml. of butyl alcohol is refluxed overnight. The reaction mixture is 
cooled, filtered and the solid washed with butyl alcohol and with water. 
The butyl alcohol filtrate above is concentrated on a rotating evaporator 
and additional crystalline product is obtained which is washed with butyl 
alcohol and with water. The combined material affords 
6-(p-chlorophenyl)-3-hydrazinopyridazine, m.p. 156.degree. -160.degree. C. 
A mixture of 6.6 g. of the above material (prepared in the manner 
described), 140 ml. of p-dioxane and 4.64 g. of diisopropylethylamine is 
warmed until solution occurs. The solution is then cooled to near room 
temperature and 2.66 g. of acetyl chloride is added. The reaction mixture 
is then cooled in an ice bath and allowed to stir overnight. The solvent 
is then removed under vacuum and ethyl alcohol is added to the residue. 
The flask is warmed and a solid is precipitated. This material is removed 
by filtration and the ethanol is further concentrated to afford the 
product of the example as crystals, m.p. 208.degree.-210.degree. C. 
EXAMPLE 17 
Preparation of 6-(p-chlorophenyl)-8-methyl-1,2,4-triazolo[4,3-b]pyridazine 
To a solution of 114 g. of methylsuccinic anhydride in 400 ml. of 
chlorobenzene is added carefully 270 g. of aluminum chloride. The mixture 
is heated to 65.degree. C. for 11/2 hours, is cooled, quenched with ice 
and concentrated hydrochloric acid and extracted with benzene. The benzene 
layer is extracted with aqueous sodium bicarbonate. After adjusting the pH 
of the bicarbonate solution to 6.3, concentrated hydrochloric acid is 
added slowly over a period of several hours with stirring. At pH 5.7, 78 
g. of white crystals are filtered off. Recrystallization of this material 
from ethanol-water affords 3-(p-chlorobenzoyl)-2-methylpropionic acid as 
white crystals. A mixture of 35.50 g. of the preceding compound, 85 ml. of 
hydrazine hydrate and 400 ml. of ethyl alcohol is allowed to stir at 
reflux for 18 hours. The reaction mixture is concentrated to about 75% of 
the original volume, cooled in an ice bath and filtered to yield 26.62 g. 
of 6-(p-chlorophenyl)-4,5-dihydro-4-methyl-3(2H)-pyridazinone as a yellow 
solid. An additional 4.7 g. of product is obtained from the filtrate 
above. 
The combined product above (31.32 g.) is dissolved in 250 ml. of glacial 
acetic acid at room temperature with stirring. An 8.2 ml. portion of 
liquid bromine is dissolved in 50 ml. of glacial acetic acid and 25% of 
this solution is added to the reaction mixture. The temperature of the 
reaction mixture is increased until all the coloration due to bromine is 
gone. The remaining bromine solution is added with warming over a 20 
minute period. The reaction mixture is warmed on the steam bath for an 
additional 1/2 hour and is diluted with ice water. The resulting solid is 
filtered, washed with water and air dried to afford 
6-(p-chlorophenyl)-4-methyl-3-(2H)-pyridazinone as a cream colored solid. 
A 15.0 g. portion of the preceding compound and 200 ml. of phosphorus 
oxychloride is heated on a steam bath for 18 hours. The reaction mixture 
is concentrated free of solvent and the concentrate is stirred with cold 
water. The precipitate is filtered and the solid is washed with water to 
afford 3-chloro-6-(p-chlorophenyl)-4-methylpyridazine as a pink solid. 
A 2.0 g. portion of the compound above is mixed with 1.08 g. of 
formylhydrazine and 60 ml. of butyl alcohol. The mixture is refluxed for 
48 hours. The reaction mixture is cooled in an ice bath and the resulting 
solid is filtered, washed with petroleum ether and air dried to afford a 
tan solid. The product of the example is recrystallized from methyl 
alcohol after treatment with activated charcoal to afford white crystals, 
m.p. 230.degree.-233.degree. C. 
EXAMPLE 18 
Preparation of 3-methyl-6-(.alpha., .alpha.,.alpha. 
-trifluoro-m-tolyl)-1,2,4-triazolo[4,3-b]pyridazine 
A 6.0 g. portion of 3-chloro-6-(.alpha. ,.alpha. 
,.alpha.-trifluoro-m-tolyl)pyridazine (prepared as in Example 11), 3.44 g. 
of acetylhydrazine and 75 ml. of n-butyl alcohol is refluxed for 48 hours. 
The solvent is removed under vacuum and the residue dissolved in ethyl 
alcohol and treated with activated carbon. The filtrate is concentrated, 
chilled and filtered to give an orange solid. Recrystallization from 
methyl alcohol affords the product of the example as crystals, m.p. 
193.degree.-194.degree. C. 
EXAMPLE 19 
Preparation of 6-(p-chlorophenyl)-1,2,4-triazolo[4,3-b]pyridazine 
A mixture of 9.0 g. of 3-chloro-6-(p-chlorophenyl)pyridazine (prepared as 
in Example 16), 5.1 g. of formylhydrazine and 60 ml. of butyl alcohol is 
heated at reflux temperature for 40 hours. The reaction mixture is cooled, 
filtered and the solid washed with petroleum ether and with water. The 
material is then heated with 125 ml. of ethanol and the insoluble material 
is collected by filtration. The filtrate is cooled and the precipitate is 
collected and combined with the insoluble material collected above. The 
combined solids are recrystallized from 130 ml. of ethyl alcohol to 
provide the product of the example as crystals, m.p. 
216.degree.-218.degree. C. 
EXAMPLE 20 
Preparation of 6-(.alpha. ,.alpha. 
,.alpha.-trifluoro-m-tolyl)-1,2,4-triazolo[4,3-b]pyridazine 
A mixture of 6.0 g. of 3-chloro-6-(.alpha. ,.alpha. 
,.alpha.-trifluoro-m-tolyl)pyridazine (prepared as in Example 11), 2.78 g. 
of formylhydrazine and 75 ml. of butyl alcohol is allowed to stir at 
reflux tremperature for 48 hours. The reaction mixture is concentrated 
free of solvent and the residue is dissolved in ethyl alcohol, treated 
with activated charcoal and filtered. The filtrate is cooled in an ice 
bath and the cream colored solid is collected. The solid is heated with 
diethyl ether and the mixture is filtered. The solid is recrystallized 
from ethyl acetate to afford the product of the example as cream colored 
crystals, m.p. 140.degree.-143.degree. C. 
EXAMPLE 21 
Preparation of 6-(p-chlorophenyl)-3-ethyl-1,2,4-triazolo[4,3-b]pyridazine 
A mixture of 9.0 g. of 3-chloro-6-(p-chlorophenyl)pyridazine (prepared as 
in Example 16), 7.4 g. of propionic acid hydrazide and 60 ml. of butyl 
alcohol is stirred at reflux temperature for 48 hours. The mixture is 
chilled, filtered and the solid is washed with petroleum ether and with 
water. The material is recrystallized from 50 ml. of ethyl alcohol to 
afford the product of the example as crystals, m.p. 
197.degree.-199.degree. C. 
EXAMPLE 22 
Preparation of 6-(p-fluorophenyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine 
A mixture of 6.25 g. of 3-chloro-6-(p-fluorophenyl)pyridazine (prepared as 
in Example 8), 4.65 g. of acetylhydrazine and 50 ml. of butyl alcohol is 
refluxed until a clear solution results. The reaction mixture is cooled, 
filtered, and the solid precipitate washed with hexane and with water. The 
solid is recrystallized from 50 ml. of ethyl alcohol to give the product 
of the example as crystals, m.p. 227.degree.-229.degree. C. 
EXAMPLE 23 
Preparation of 3-methyl-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine 
A mixture of 9.9 g. of 6-(m-nitrophenyl)-4,5-dihydro-3-pyridazone [J. Med. 
Chem. 17, 273 (1974)] and 80 ml. of glacial acetic acid is stirred and 
heated on the steam bath and a solution of 2.41 ml. of bromine in 10 ml. 
of glacial acetic acid is added dropwise over a period of 30 minutes. 
Heating and stirring is continued for 45 minutes longer and the reaction 
mixture is poured onto crushed ice. The crystalline product is filtered 
and washed with water. The yield of 6-(m-nitrophenyl)-3-pyridazone, m.p. 
275.degree. C., is nearly quantitative. 
A mixture of 6 g. of the above product and 35 ml. of phosphorus oxychloride 
is heated on a steam bath for 4 hours and concentrated to remove the 
excess POCl.sub.3. The residue is poured into ice water and the insoluble 
solid is filtered, washed with water and air dried. The product is 
dissolved in chloroform, treated with activated carbon and clarified. The 
chloroform solution is concentrated to obtain 4.0 g. of 
3-chloro-6-(m-nitrophenyl)pyridazine, m.p. 206.degree.-208.degree. C. 
A mixture of 3.0 g. of the preceding compound, 2.0 g. of acetylhydrazine 
and 30 ml. of butanol is heated at reflux temperature for 72 hours and 
cooled. The precipitate is filtered, washed with hexane, with water, and 
air dried. The product is boiled with 100 ml. of 95% ethyl alcohol and 
filtered. The insoluble material, m.p. 241.degree.-243.degree. C, is 
3-methyl-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine. 
EXAMPLE 24 
Preparation of 6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine 
The above compound, m.p. 231.degree.-233.degree. C., is obtained when 
formylhydrazine is substituted for acetylhydrazine in the procedure of 
Example 23. 
EXAMPLE 25 
Preparation of 6-(m-aminophenyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine 
A mixture of 5.1 g. of 
3-methyl-6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine (prepared as in 
Example 23), 60 ml. of trifluoroacetic acid and 0.9 g. of 10% palladium 
catalyst on carbon is shaken in a Parr hydrogenator under about 35 pounds 
of hydrogen pressure until hydrogen uptake is complete. The catalyst is 
filtered off and the reaction mixture is concentrated. The residue is 
dissolved in water and adjusted to pH 5 by addition of 5N NaOH. The 
insoluble material is filtered off and washed with water to obtain 
6-(m-aminophenyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine, m.p. 
193.degree. C. 
EXAMPLE 26 
Preparation of 6-(m-aminophenyl)-1,2,4-triazolo[4,3-b]pyridazine 
The compound of the example, m.p. 225.degree. C., is obtained when 
6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine (prepared as in Example 
24) is reduced by the procedure of Example 25. 
EXAMPLE 27 
Preparation of 6-(m-acetamidophenyl)-1,2,4-triazolo[4,3-b]pyridazine 
A mixture of 1.0 g. of g. of 
6-(m-aminophenyl)-1,2,4-triazolo[4,3-b]pyridazine (prepared as in Example 
26) and 4 ml. of acetic anhydride is left at room temperature for 2 hours 
and then is triturated with ether and filtered. The insoluble material is 
recrystallized from ethyl alcohol to afford yellow crystals of 
6-(m-acetamidophenyl)-1,2,4-triazolo[4,3-b]pyridazine, m.p. 
248.degree.-250.degree. C. 
EXAMPLE 28 
Preparation of 
6-(m-acetamidophenyl)-3-methyl-1,2,4-triazolo-[4,3-b]pyridazine 
The compound above is obtained when 
6-(m-aminophenyl)-3-methyl-1,2,4-triazolo[4,3-b]pyridazine (prepared as in 
Example 25) and acetic anhydride are reacted as described in Example 27. 
EXAMPLE 29 
Preparation of 
3-methyl-6-(p-tert-butylphenyl)-1,2,4-triazolo[4,3-b]pyridazine 
A mixture of 16.5 g. of 3-p-tert-butylbenzoyl propionic acid [Journal 
Organic Chem. Soc. 19, 802 (1954)] and 8.25 ml. of hydrazine hydrate is 
dissolved in 140 ml. of absolute ethyl alcohol. The clear solution is 
stirred under reflux for 4 hours and chilled overnight. The product is 
collected, washed with ethyl alcohol and dried in vacuo to yield 13.1 g. 
of 6-(p-tert-butylphenyl)-4,5-dihydro-3(2H)-pyridazinone as a white solid. 
An 8.00 g. portion of the preceding material in 80 ml. of glacial acetic 
acid is stirred while the dropwise addition of a solution of 5.82 g. of 
bromine in 20 ml. of glacial acetic acid is begun. The reaction mixture is 
heated to about 100.degree. C. and decolorization occurs. The 
bromine/acetic acid solution is added as rapidly as decolorization occurs 
and is completed in about 15 minutes. The mixture is stirred for 1 hour at 
100.degree. C., then is poured into 150 ml. of ice. The white solid formed 
is collected by filtration, then is dissolved in 400 ml. of acetone. The 
acetone solution is dried over magnesium sulfate and is concentrated while 
diluting with hexane. Crystallization from about 100 ml. of acetone/hexane 
affords 4.82 g. of 6-(p-tert-butylphenyl)-3(2H)-pyridazinone as a light 
yellow solid. 
A mixture of 22.8 g. of the above compound (prepared in the manner 
described) and 115 ml. of phosphorus oxychloride is warmed on a steam bath 
until a clear solution results. This solution is heated for 5 hours, then 
is concentrated in vacuo. The residue is treated with ice water and the 
resulting solid is collected and dried in vacuo to yield 22.0 g. of 
3-(p-tert-butylphenyl)-6-chloropyridazine as an off-white solid. 
A mixture of 5.0 of 3-(p-tert-butylphenyl)-6-chloropyridazine, 3.13 g. of 
acetylhydrazide and 50 ml. of n-butanol is refluxed for 48 hours. The 
mixture is concentrated under vacuum and the residue stirred with 100 ml. 
of water and 100 ml. of ether. The mixture is filtered to give 3.0 g. of 
tan solid, m.p. 144.degree.-146.degree. C. Recrystallization from 
acetone/hexane gives the product as pale yellow crystals, m.p. 
142.degree.-145.degree. C. 
EXAMPLE 30 
Preparation of 6-(p-tert-butylphenyl)-1,2,4-triazolo[4,3-b]-pyridazine 
A mixture of 5.0 g. of 3-(p-tert-butylphenyl)-6-chloropyridazine, 2.54 g. 
of formylhydrazide and 50 ml. of n-butyl alcohol is stirred under reflux 
for 48 hours. The mixture is chilled and filtered. The solid is washed 
with petroleum ether and water and dried in vacuo to yield 0.80 g. of 
product. The filtrate is concentrated in vacuo below 80.degree. C. to 
afford additional product which is stirred with 150 ml. of water and 150 
ml. of diethyl ether, collected by filtration and dried in vacuo to yield 
3.0 g. of an orange solid. Recrystallization from ethyl alcohol gives the 
product of the example as off-white crystals, m.p. 270.degree.-275.degree. 
C. 
EXAMPLE 31 
Preparation of 50 mg. Tablets 
______________________________________ 
Per Tablet Per 10,000 Tablets 
______________________________________ 
0.050 gm. 
3-methyl-6-(m-acet- 
amidophenyl)-1,2,4- 
triazolo[4,3-b]- 
pyridazine 500 gm. 
0.080 gm. 
Lactose 800 gm. 
0.010 gm. 
Corn Starch (for mix) 
100 gm. 
0.008 gm. 
Corn Starch (for paste) 
75 gm. 
0.148 gm. 1475 gm. 
0.002 gm. 
Magnesium Stearate (1%) 
15 gm. 
0.150 gm. 1490 gm. 
______________________________________ 
The 3-methyl-6-(m-acetamidophenyl)-1,2,4-triazolo[4,3-b-]pyridazine, 
lactose and corn starch (for mix) are blended together. The corn starch 
(for paste) is suspended in 600 ml. of water and heated with stirring to 
form a paste. This paste is then used to granulate the mixed powders. 
Additional water is used if necessary. The wet granules are passed through 
a No. 8 hand screen and dried at 120.degree. F. The dry granules are then 
passed through a No. 16 screen. The mixture is lubricated with 1% 
magnesium stearate and compressed into tablets in a suitable tableting 
machine. 
EXAMPLE 32 
Preparation of Oral Suspension 
______________________________________ 
Ingredient Amount 
______________________________________ 
3-ethyl-6-(p-carbamoylphenyl)- 
1,2,4-triazolo[4,3-b]pyrida- 
zine 500 mg. 
Sorbitol solution (70% N.F.) 
40 ml. 
Sodium benzoate 150 mg. 
Saccharin 10 mg. 
Red dye 10 mg. 
Cherry flavor 50 mg. 
Distilled water qs to 100 ml. 
______________________________________ 
The sorbitol solution is added to 40 ml. of distilled water and the 
3-ethyl-6-(p-carbamoylphenyl)-1,2,4-triazolo[4,3-b]pyridazine is suspended 
therein. The saccharin, sodium benzoate, flavor and dye are added and 
dissolved. The volume is adjusted to 100 ml. with distilled water. Each 
ml. of syrup contains 5 mg. 
3-ethyl-6-(p-carbamoylphenyl)-1,2,4-triazolo[4,3-b]pyridazine. 
EXAMPLE 33 
Preparation of Parenteral Solution 
In a solution of 700 ml. of propylene glycol and 200 ml. of water for 
injection is suspended 20.0 grams of 
3,7-dimethyl-6-(p-aminophenyl)-1,2,4-triazolo[4,3-b]pyridazine 
monohydrochloride with stirring. After suspension is complete, the pH is 
adjusted to 5.5 with hydrochloric acid and the volume is made up to 1000 
ml. with water for injection. The formulation is sterilized, filled into 
5.0 ml. ampoules each containing 2.0 ml. (representing 40 mg. of drug) and 
sealed under nitrogen. 
EXAMPLE 34 
Preparation of 
6-(p-chlorophenyl)-3,8-dimethyl-1,2,4-triazolo-[4,3-b]pyridazine 
A mixture of 1.0 g. of 3-chloro-6-(p-chlorophenyl)-4-methylpyridazine, 0.62 
g. of acetic acid hydrazide and 10 ml. of n-butanol is refluxed for 48 
hours. The solvent is removed and the residue dissolved in dichloromethane 
and filtered through magnesol. The solid from the filtrate is 
recrystallized from dichloromethane-hexane to give 0.6 g. of solid, m.p. 
209.degree.-212.degree. C. Recrystallization from dichloromethane-hexane 
gives the product of the example as light pink colored crystals, m.p. 
215.degree.-217.degree. C. 
EXAMPLE 35 
Preparation of 
6-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-1,2,4-triazolo[4,3-b]pyridaz 
ine 
A solution of 76.0 g. of p-toluenesulfonic acid in 400 ml. of 
tetrahydrofuran is cooled in an ice bath while 69.5 g. of morpholine is 
added. The cooling bath is removed and upon reaching ambient temperature 
65.0 g. p-trifluoromethyl benzaldehyde is added followed by heating at 
reflux temperature for 2 hours. The reaction mixture is cooled in ice bath 
and a solution of 32.6 g. of potassium cyanide in 55 ml. of water added 
followed by heating at reflux temperature for 18 hours. The solvent is 
removed and the residue is partitioned between chloroform and water. The 
organic layer is washed with water, saturated sodium bisulfite and 
saturated sodium chloride solution, dried and evaported to yield 
.alpha.-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-4-morpholineacetonitri 
le as a tan solid, m.p. 89.degree.-90.degree. C. 
A solution of 52.3 g. of 
.alpha.-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-4-morpholineacetonitri 
le in 500 ml. of dry tetrahydrofuran is stirred at ambient temperature 
while 1 ml. portions of 30% potassium hydroxide in ethanol and 25 ml. 
portions of ethyl acrylate is added every half hour until a total of 5 ml. 
of the base and 150 ml. of ethyl acrylate is added. After the addition, 
the mixture is stirred at ambient temperature for 48 hours. Following 
filtration, the filtrate is concentrated, dissolved in methylene chloride, 
passed through magnesol and recrystallized from methylene chloride/hexane 
to afford ethyl 
.gamma.-cyano-.gamma.(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-4-morphol 
inebutyrate as cream colored crystals, m.p. 96.degree. -97.degree. C. 
A solution of 38.0 g. of the preceding compound, 9.0 g. of hydrazine 
hydrate and 600 ml. of ethanol is refluxed for 24 hours. The solution is 
treated with activated charcoal, filtered and the filtrate concentrated. 
The residue is crystallized from methylene chloride/hexane to give 
6-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-4,5-dihydro-3(2H)-pyridazino 
ne as cream colored crystals, m.p. 177.degree.-178.degree. C. 
A solution of 14.5 g. of the preceding compound and 10.4 g. of bromine in 
150 ml. of acetic acid is heated slowly on a steam bath until complete 
discoloration occurs. Heating is continued for an additional 30 minutes 
followed by pouring onto crushed ice. The resulting solid is filtered, 
washed with water to give 
6-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-3(2H)-pyridazinone as 
off-white crystals, m.p. 191.degree.-193.degree. C. 
A mixture of 11.0 g. of the preceding compound and 150 ml. of phosphorus 
oxychloride is heated on a steam bath for 5 hours. The solution is 
concentrated free of solvent and the residue is washed with cold water to 
yield 3-chloro-6-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)pyridazine as 
a white solid, m.p. 186.degree.-188.degree. C. 
A mixture of 4.50 g. of 
3-chloro-6-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)pyridazine, 2.09 g. 
of formylhydrazine and 100 ml. of n-butanol is stirred and refluxed for 3 
days. The solvent is removed and the residue dissolved in methylene 
chloride, passed through magnesol and the solid from the filtrate 
recrystallized from methylene chloride/hexane to afford the product as 
white crystals, m.p. 160.degree.-161.degree. C. 
EXAMPLE 36 
Preparation of 
3-methyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-1,2,4-triazolo[4,3- 
b]-pyridazine 
A mixture of 4.50 g. of 
3-chloro-6-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)pyridazine, 2.58 g. 
of acethydrazide and 100 ml. of n-butanol is heated at reflux temperature 
for 3 days. The solvent is removed and the resin dissolved in methylene 
chloride, passed through magnesol and the solid from the filtrate 
recrystallized from methylene chloride/hexane to afford the product as tan 
crystals, m.p. 199.degree.-201.degree. C. 
EXAMPLE 37 
Preparation of .alpha.-(m-chlorophenyl)-4-morpholineacetonitrile 
To a cold solution of 76 g. of p-toluenesulfonic acid in 500 ml. of 
tetrachydrofuran is added 87 g. of morpholine and 50.6 g. of 
m-chlorobenzaldehyde. The mixture is refluxed for 2.5 hrs. and 100 ml. of 
tetrahydrofuran distilled off the mixture is cooled, and a solution of 
28.6 g. of KCN in 100 ml. of water is added. The mixture is refluxed for 5 
hrs. and concentrated to dryness under vacuum. The residue is dissolved in 
methylene chloride and the solution washed with water, sodium bisulfite 
solution, saturated NaCL solution and dried (Na.sub.2 SO.sub.4). The 
solution is passed through a short column of hydrous magnesium silicate. 
The eluent is refluxed while hexane is added until crystals separated. 
Cooling and filtering gives 78.0 g. of crystals, m.p. 
72.degree.-73.degree. C. 
EXAMPLE 38 
Preparation of 3-(m-chlorobenzoyl)propionitrile 
To a solution of 23.6 g. of 
.alpha.-(m-chlorophenyl)-4-morpholineacetonitrile in 100 ml. of 
tetrahydrofuran is added 120 drops of a 30% solution of KOH in methanol. 
To the mixture is added 4.1 ml. of acrylonitrile (temperature rose to 
45.degree. C.). After stirring 1 hr., the mixture is concentrated to 
dryness under vacuum. The residue is dissolved in methylene chloride and 
passed through a short column of hydrous magnesium silicate. The eluent is 
concentrated under vacuum to give 36.6 g. of a yellow oil. The oil is 
heated (steam bath) with a mixture of 150 ml. of acetic acid and 10 ml. of 
water for 1 hr. The solvent is removed under vacuum and the residue 
treated with water. The mixture is filtered to give 18.8 g. of crystals, 
m.p. 49.degree.-51.degree. C. 
EXAMPLE 39 
3-(m-chlorobenzoyl)-2-methylpropionitrile 
To a solution of 11.8 g. of 
.alpha.-(m-chlorophenyl)-4-morpholineacetonitrile in 50 ml. of 
tetrahydrofuran is added 60 drops of a 30% solution of KOH in methanol. To 
the solution is added 4.62 ml. of methacrylonitrile (temperature rose to 
42.degree. C.). After stirring for 1 hr., the mixture is concentrated to 
dryness and the residue dissolved in methylene chloride. The solution is 
passed through a short column of hydrous magnesium silicate and the eluent 
concentrated to give 15.5 g. of a yellow oil. The oil is heated (steam 
bath) with a mixture of 75 ml. of acetic acid and 5 ml. of water for 1 hr. 
and the solvent removed under vacuum. Addition of water to the residue 
gives 11.2 g. of crystals, m.p. 72.degree.-75.degree. C. Recrystallization 
from methylene chloride-hexane gives 8.95 g. of crystals, m.p. 
79.5.degree.-80.5.degree. C. 
EXAMPLE 40 
Preparation of 3-(m-chlorobenzoyl)-2-methylpropionic 
A mixture of 7.90 g. of 3-(m-chlorobenzoyl)-2-methylpropionitrile and 75 
ml. of concentrated hydrochloric acid is refluxed for 1 hr. Cooling gives 
8.5 g. of crystals, m.p. 102.degree.-105.degree. C. The crystals are 
dissolved in 50 ml. of 1N NaOH, the mixture is filtered and the filtrate 
acidified with 1N Hcl. Filtration gives 8.15 g. of crystals, m.p. 
103.degree.-105.degree. C. 
EXAMPLE 41 
Preparation of 6-(m-chlorophenyl)4,5-dihydro-4-methyl-3(2H)-pyridazinone 
A mixture of 7.11 g. of 3-(m-chlorobenzoyl)-2-methylpropionic acid, 50 ml. 
of ethanol and 3.0 ml. of hydrazine hydrate is refluxed for 2 hrs. Cooling 
and filtering gives crystals, (m.p. 150.degree.-151.degree. C.) which are 
recrystallized from ethanol to give 5.72 g. of crystals, m.p. 
152.degree.-153.degree.. 
EXAMPLE 42 
Preparation of 3-(m-chlorobenzoyl)propionic Acid 
A mixture of 8.1 g. of 3-(m-chlorobenzoyl)propionitrile and 80 ml. of cone 
Hcl is refluxed for 7 hrs. Cooling gives an oil which crystallized to give 
8.8 g. of crystals, m.p. 105.degree.-107.degree. C. The crystals are 
dissolved in 1N NaOH and the mixture filtered. The filtrate is audified 
with 1N HCl to give 8.7 g. of crystals m.p. 103.degree.-105.degree. C. 
EXAMPLE 43 
Preparation of 6-(m-chlorophenyl-4-methyl-3-(2H)pyridazinone 
A solution of 4.66 g. of 
6(m-chlorophenyl)-4,5-dihydro-4-methyl)-3(2H)pyridazinone in 60 ml of 
glacial acetic acid is heated on a steam bath and a one-quarter portion of 
a solution of 4.01 g. of bromine in 5 ml. of acetic acid added. After the 
bromine color disappeared, the remainder of the bromine solution is added 
gradually. The mixture is heated (steam bath) for 0.5 hr. and poured onto 
ice. Filtration gives crystals (m.p. 243.5.degree.-245.degree. C.) which 
are recrystallized from ethanol to give 4.0 g of crystals, 
244.degree.-245.degree. C. 
EXAMPLE 44 
Preparation of 6-(m-chlorophenyl)-4,5-dihydro-2(2H)pyridazinone 
A mixture of 7.70 g. of 3(m-chlorobenzoyl)-propionic acid, 50 ml. of 
ethanol and 3.0 ml. of hydrazine hydrate is refluxed for 2 hrs. The 
mixture is cooled, filtered and the crystals (6.30 g. m.p. 
146.degree.-147.degree. C.) recrystallized from ethanol to give 5.50 g. of 
crystals, m.p. 150.degree.-151.degree. C. 
EXAMPLE 45 
Preparation of 6-(m-chlorophenyl)-3(2H)-pyridazinone 
A mixture of 4.45 g. of 6-(m-chlorophenyl)-4,5-dehydro-3(2H)-pyridazinone 
and 50 ml. of glacial acetic is heated on a steam bath. A one-quarter 
portion of a solution of 4.01 g. of bromine in 15 ml. of glacial acetic 
acid is added. When the bromine color disappeared, the remainder of the 
bromine solution is added. The mixture is heated on a steam bath for an 
additional 0.5 hr. and the mixture poured onto ice. The mixture is 
filtered to give 3.30 g. of crystals. m.p. 214.degree.-216.degree. C. 
EXAMPLE 46 
Preparation of 3-chloro-6-(m-chlorophenyl)-4-methylpyridazine 
A mixture of 25 ml. of phosphorus oxychloride and 3.0 g. of 
6-(m-chlorophenyl)-4-methyl-3(2H)-pyridazinone is refluxed for 6 hrs. The 
mixture is concentrated to dryness under vacuum and water added to the 
residue. Filtration gives 3.28 g. of crystals, m.p. 
138.degree.-140.degree. C. Recrystallized from ethanol gives 2.80 g. of 
crystals, m.p. 138.degree.-141.degree. C. 
EXAMPLE 47 
Preparation of 3-chloro-6-(m-chlorophenyl)pyridazine 
A mixture of 25 ml. of phosphorus oxychloride and 3.0 g. of 
6-(m-chlorophenyl)-3(2H)-pyridazinoic is refluxed for 6 hr. The mixture is 
concentrated under vacuum and water added to the residue. Filtration gives 
3.30 g. of crystals, m.p. 155.degree.-157.degree. C. Recrystallization 
from ethanol gives 2.75 g. of crystals, m.p. 157.degree.-158.degree. C. 
EXAMPLE 48 
Preparation of 6-(m-chlorophenyl)-8-methyl-1,2,4-triazolo-[4,3-b]pyridazine 
A mixture of 2.0 g. of 3-chloro-6-(m-chlorophenyl)-4-methylpyridazine, 50 
ml. of n-butanol and 1.08 g. of formylhydrazine is refluxed for 18 hrs. 
The mixture is concentrated to dryness under vacuum and the residue 
dissolved in methylene chloride. The solution is passed through a short 
column of hydrous magnesium silicate. The eluent is refluxed while hexane 
is added gradually until crystals separated. Cooling and filtering gives 
1.20 g. of crystals, m.p. 173.degree.-176.degree. C. The crystals in 
methylene chloride are passed through a short column of hydrous magnesium 
silicate and the eluent concentrated with the addition of hexane to give 
0.83 g. of crystals, m.p. 181.degree.-182.degree. C. 
EXAMPLE 49 
Preparation of 6-(m-chlorophenyl)-3-methyl-1,2,4-triazolo-[4,3-b]pyridazine 
A mixture of 2.0 g. of 3-chloro-6-(m-chlorophenyl)pyridazine, 50 ml. of 
n-butanol and 1.32 g. of acetylhydrazine is refluxed for 18 hrs. The 
mixture is concentrated to dryness under vacuum and the residue dissolved 
in methylene chloride. The solution is passed through a short column of 
hydrous magnesium silicate. The eluent is refluxed while hexane is 
gradually added until crystals separated. Cooling and filtering gives 1.50 
g. of crystals, m.p. 171.degree.-172.5.degree. C. 
EXAMPLE 50 
Preparation of 
6-(m-chlorophenyl)-3,8-dimethyl-1,2,4-triazolo-[4,3-b]pyridazine 
A mixture of 7.17 g. of 3-chloro-6-(m-chlorophenyl)-4-methylpyridazine, 100 
ml. of n-butanol and 6.96 g. of acetylhydrazine is refluxed overnight. The 
mixture is coated and filtered to give solid. The solid is dissolved in 
methylene chloride and the solution passed through a short column of 
hydrous magnesium silicate. The eluent is refluxed while hexane is 
gradually added until crystals separated. Cooling and filtering gives 3.30 
g. of crystals, m.p. 193.5.degree.-195.5.degree. C. 
EXAMPLE 51 
Preparation of 3-(m-chlorophenyl)-6-hydrazinopyridazine 
A mixture of 6.85 g of 3-chloro-6-(m-chlorophenyl)pyridazine, 100 ml. of 
n-butanol and 3.05 g. of hydrazine hydrate is refluxed overnight. The 
solvent is removed under vacuum to give a semi-solid. The solid is 
dissolved in a minimum of hot nitromethane. Cooling gives 3.5 g. of 
amorphous solid. 
EXAMPLE 52 
Preparation of 6-(o-fluorophenyl)-1,2,4- triazolo-[4,3-b]pyridazine 
As in Example 35, the following reactions are carried out. 
o-Fluorobenzaldehyde is reacted with p-toluenesulfonic acid, morphaline 
and KCN to give .alpha.-(o-fluorophenyl)-4-morpholineacetonitrile as a 
yellow oil. The product .gamma.-(o-fluorophenyl)-4-morpholineacetonitrile 
is reacted with ethyl acrylate to give ethyl 
.gamma.-cyano-.gamma.-(o-fluorophenyl)-4-morpholenebutyrate as an oil. A 
solution of the preceding compound and hydrazine hydrate in ethanol is 
refluxed to give 6-(o-fluorophenyl)-4,5-dihydro-3(2H)-pyridazinone as 
crystals, m.p. 119.degree.-121.degree. C. The preceding compound is heated 
with bromine in acetic acid to give 6-(o-fluorophenyl)-3(2H)pyridazinone 
as crystals (from CH.sub.2 Cl.sub.2 -hexane), m.p. 173.degree.-175.degree. 
C. 
A mixture of the preceding compoound and phosphorus oxychloride is refluxed 
on a steam bath to give 3-chloro-6-(o-fluorophenyl)pyridazine as crystals, 
m.p. 95.degree.-96.degree. C. 
A mixture of 5.0 g. of 3-chloro-6-(o-fluorophenyl)pyridazine and 2.88 g. of 
formylhydrazine in 75 ml. n-butanol is refluxed for 48 hrs. and worked up 
as in Example 35 to give 1.1 g. of product as cream colored crystals, m.p. 
161.degree.-163.degree. C. 
EXAMPLE 53 
Preparation of 3-methyl-6-(o-fluorophenyl)-1,2,4-triazolo-[4,3-b]pyridazine 
As in Example 36, a mixture of 2.5 g. of 
3-chloro-6-(o-fluorophenyl)-pyridazine and 1.76 g. of acetylhydrazine in 
50 ml. of n-butanol is refluxed for 48 hrs. to give 2.0 g. of product as 
off-white crystals, m.p. 147.degree.-149.degree. C. 
EXAMPLE 54 
Preparation of 6-(m-fluorophenyl)-1,2,4-triazolo-[4,3-b]pyridazine 
As in Example 35, the following reactions are carried out. 
m-Fluorobenzaldehyde is reacted with p-toluenesulfonic acid, morpholine 
and KCN to give .alpha.-(m-fluorophenyl)-4-morpholineacetonitrile as 
crystals (from CH.sub.2 Cl.sub.2 -hexane) m.p. 74.degree.-75.degree. C. 
The preceding compound is reacted with ethyl acrylate to give ethyl 
.gamma.-cyano-.gamma.-(m-fluorophenyl)-4-morpholinebutyrate as crystals 
(from CH.sub.2 Cl.sub.2 -hexane), m.p. 88.degree.-90.degree. C. 
A solution of the preceding compound and hydrazine hydrate in ethanol is 
refluxed to give 6-(m-fluorophenyl)-4,5-dehydro-3-(2H)pyridazinone as 
crystals (from CH.sub.2 Cl.sub.2 -hexane), m.p. 132.degree.-134.degree. C. 
The preceding compound is heated with bromine in acetic acid to give 
6-(m-fluorophenyl)-3(2H)pyridazinone as crystals (from CH.sub.2 Cl.sub.2 
-hexane), m.p. 207.degree.-209.degree. C. 
A mixture of the preceding compound and phosphorus oxychloride is refluxed 
to give 3-chloro-6-(m-fluorophenyl)pyridazine as crystals, m.p. 
133.degree.-135.degree. C. 
A mixture of 3.6 g. of 3-chloro-6-(m-fluorophenyl)pyridazine and 2.06 g. of 
formylhydrazine in 50 ml. of n-butanol is refluxed for 48 hr. and worked 
up as in Example 35 to give the product as crystals, m.p. 
159.degree.-161.degree. C. 
EXAMPLE 55 
Preparation of 3-methyl-6-(m-fluorophenyl)-1,2,4-triazolo-[4,3-b]pyridazine 
As in Example 36, a mixture of 3.0 g. of 
3-chloro-6-(m-fluorophenyl)pyridazine, 2.14 g. of acetylhydrazine and 50 
ml. of n-butanol is refluxed 48 hrs. to give 2.0 g. of the product as 
crystals, m.p. 184.degree.-186.degree. C. 
EXAMPLE 56 
Preparation of 6-(o-chlorophenyl)-1,2,4-triazolo-[4,3-b]pyridazine 
As in Example 35, the following reactions are carried out. 
o-Chlorobenzaldehyde is reacted with p-toluenesulfonic acid, morpholine 
and KCN to give .alpha.-(o-chlorophenyl)-4-morpholineacetonitrile as 
crystals (from CH.sub.2 Cl.sub.2 -hexane), m.p. 40.degree.-42.degree. C. 
The preceding compound is reacted with ethyl acrylate to give ethyl 
.gamma.-cyano-.gamma.-(o-chlorophenyl)-4-morpholinebutyrate as an oil. 
A solution of the preceding compound and hydrazine hydrate in ethanol is 
refluxed to give 6-(o-chlorophenyl)-4,5-dihydro-3(2H)pyridazinone as 
crystals, m.p. 114.degree.-116.degree. C. 
The preceding compound is heated with bromine in acetic acid to give 
6-(o-chlorophenyl)-3(2H)-pyridazinone as crystals, m.p. 
214.degree.-216.degree. C. 
A mixture of the preceding compound and phosphorus oxychloride is refluxed 
to give 3-chloro-6-(o-chlorophenyl)pyridazine as crystals, m.p. 
145.degree.-147.degree. C. 
A mixture of 5.67 g. of 3-chloro-6-(o-chlorophenyl)pyridazine, 3.03 g. of 
formylhydrazine in 50 ml. of butanol is refluxed 48 hrs. to give 2.3 g. of 
product as pale yellow crystals, m.p. 156.degree.-158.degree. C. 
EXAMPLE 57 
Preparation of 3-methyl-6-(o-chlorophenyl)-1,2,4-triazolo-[4,3-b]pyridazine 
As in Example 36, a mixture of 5.5 g. of 3-chloro-6-(o-chlorophenyl) 
pyridazine, 3.6 g. of acetylhydrazine in 75 ml. of n-butanol is refluxed 
for 72 hrs. to give 2.2 g. or product as off-white crystals, m.p. 
146.degree.-148.degree. C. 
EXAMPLE 58 
Preparation of 
4-methyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-4,5-dihydro-3(2H)-p 
yridazinone 
To a solution of 60.0 g. of 
.alpha.-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-4-morpholineacetonitri 
le in 200 ml. of tetrahydrofuran is added 5 ml. of a solution of 30% 
potassium hydroxide in methanol. To the mixture is added 22.0 ml. of 
methacrylonitrile and the mixture is stirred overnight. The mixture is 
concentrated to dryness under vacuum and the residue dissolved in 
chloroform. The solution is passed through a column of hydrous magnesium 
silicate. The eluent is concentrated to a yellow oil which is crystallized 
from etherhexane to give 47 g. of cream colored crystals, m.p. 
88.degree.-90.degree. C. The preceding compound (107 g.) is heated on a 
steam bath with a mixture of 600 ml. of acetic acid and 75 ml. of water 
for 18 hrs. The solvent is removed to give an oil. A mixture of the oil in 
500 ml. of 6N Hcl is refluxed for 24 hrs. The mixture is cooled and 
extracted with chlorofrom. The chloroform layer is washed with water and 
saturated NaCl solution and passed through a column of hydrous magnesium 
silicate. The solvent is removed from the eluent and the residue 
crystallized from ether-hexane to give 29.4 g. 
2-methyl-3-(m-trifluoromethylbenzoyl)propionic acid as light pink 
crystals, m.p. 90.degree.-93.degree. C. 
A mixture of the preceding compound (25.4 g.) and 5.0 ml. of hydrazine 
hydrate in 200 ml. of ethanol is refluxed for 18 hr. The mixture is cooled 
and filtered to give 21.8 g. of product as cream colored crystals, m.p. 
188.degree.-190.degree. C. A sample is recrystallized from CHC13-hexane to 
give off white crystals, m.p. 191.degree.-193.degree. C. 
EXAMPLE 59 
Preparation of 
8-methyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-1,2,4-triazolo-[4,3 
-b]pyridazine 
To a solution of 
4-methyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-4,5-dihydro-3(2H)py 
ridazinone (20.5 g.) in 200 ml. of acetic acid is added portionwise 14.4 g. 
of bromine in 25 ml. of acetic acid. The mixture is heated for 0.5 hr. and 
the solvent removed under vacuum. To the residue is added ice and water 
and the mixture is filtered to give 20.4 g. of 
8-methyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-3(2H)pyridazinone 
as cream colored crystals, m.p. 234.degree.-237.degree. C. 
The preceding compound (19.4 g.) and 200 ml. of phosphorus oxychloride is 
heated on a steam bath for 18 hrs. The mixture is concentrated to dryness 
under vacuum and to the residue is added ice and water. The mixture is 
filtered and the solid recrystallized from CHCl.sub.3 -hexane to give 18.0 
g. of 
3-chloro-4-methyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)pyridazine 
as cream colored crystals, m.p. 123.degree.-126.degree. C. 
A mixture of 8.0 g. of the preceding compound, 3.52 g. of formylhydrazine 
and 125 ml. of n-butanol is refluxed for 48 hrs. and concentrated to 
dryness under vacuum. The residue in CHCl.sub.3 is passed through a column 
of hydrous magnesium silicate, the eluent is concentrated and the residue 
crystallized from CH.sub.2 Cl.sub.2 -hexane to give the product as 
crystals, m.p. 181.degree.-183.degree. C. 
EXAMPLE 60 
Preparation of 
3,8-dimethyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-1,2,4-triazolo[ 
4,3-b]pyridazine 
As in Example 36, a mixture of 8.0 g. of 
3-chloro-4-methyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)pyridazine, 
4.34 g. of acetylhydrazine in 125 ml. of n-butanol is refluxed for 48 hrs. 
to give 3.9 g. of product as crystals, m.p. 196.degree.-198.degree. C. 
EXAMPLE 61 
Preparation of 
7-methyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-1,2,4-triazolo[4,3- 
b]pyridazine 
To a solution of 
.alpha.-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-4-morpholineacetonitri 
le in 100 ml. of tetrahydrofuran is added 1.0 ml. of 30% KOH-ethanol 
solution. To the mixture is added 2.56 g. of crotononitrile and the 
mixture is stirred at room temperature for 18 hrs. The mixture is 
concentrated to dryness under vacuum and the residue is dissolved in 
chloroform. The solution is passed through a column of hydrous magnesium 
silicate. The eluent is concentrated to an oil (17.3 g) which is 
crystallized from hexane and recrystallized from CHCL.sub.3 -hexane to 
give 3-methyl-2-morpholino-2-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)gl 
utaronitrile as crystals, m.p. 115.degree.-118.degree. C. 
A mixture of the preceding compound (39 g) in 500 ml. of 75% acetic acid is 
refluxed for 48 hr. and the solvent removed under vacuum. The residue is 
dissolved in CH.sub.2 Cl.sub.2 and the solution washed with water, 
saturated sodium bicarbonate and saturated NaCl solution. The organic 
layer dried (MgSO.sub.4) and passed through a column of hydrous magnesium 
silicate. The eluent is concentrated to give 27.4 g. of 
3-(m-trifluoromethylbenzoyl)butyronitrile as a yellow oil. 
A mixture of the preceding compound (26.4 g) and 500 ml. of 6N HCl is 
refluxed for 18 hr. The mixture is cooled and extracted with 
dichloromethane. The organic layer is extracted with saturated NaHCO.sub.3 
solution. The basic aqueous extract is acidified with 6N HCl and extracted 
with ether. The ether layer is washed with saturated NaCl solution, dried 
(MgSO.sub.4) and concentrated to give 24.3 g of 
3-(m-trifluoromethylbenzoyl)-butyric acid as a colorless oil. 
A mixture of the preceding compound (24.3 g.), 5.0 ml. of hydrazine hydrate 
and 200 ml. of ethanol is refluxed for 18 hr. and the solvent removed 
under vacuum. The residue is dissolved in dichloromethane and the solution 
passed through a column of hydrous magnesium silicate. The eluent is 
concentrated to give 20.7 g of 
5-methyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-4,5-dihydro-3(2H)py 
ridazinone as white crystals, m.p. 132.degree.-134.degree. C. 
Recrystallization from CH.sub.2 Cl.sub.2 -hexane gives white crystals, 
m.p. 142.degree.-144.degree. C. 
The preceding compound is heated with bromine in acetic acid to give 
5-methyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-3-(2H)pyridazinone 
as white crystals, m.p. 224.degree.-227.degree. C. 
EXAMPLE 62 
Preparation of 
3,7-dimethyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-1,2,4-triazolo[ 
4,3-b]pyridazine 
As in Example 36, a mixture of 8.0 g of 
3-chloro-5-methyl-6-(.alpha.,.alpha.,.alpha.trifluoro-m-tolyl)pyridazine 
and 4.34 g. of acetylhydrazine in 125 ml. of n-butanol is refluxed for 48 
hr. to give 6.2 g. of cream colored crystals, m.p. 185.degree.-187.degree. 
C. 
EXAMPLE 63 
Preparation of 6-(m-tolyl)-1,2,4-triazolo [4,3-b]pyridazine 
As in Example 35, the following reactions are carried out. m-Tolualdehyde 
is reacted with p-toluenesulfonic acid, morpholine and KCN to give 
.alpha.-(m-tolyl)-4-morpholineacetonitrile as crystals, m.p. 
59.degree.-60.degree. C. 
The preceding compound is reacted with ethyl acrylate to give ethyl 
.gamma.-cyano-.gamma.-(m-tolyl)-4-morpholinebutyrate as an oil. 
A solution of the preceding compound and hydrazine hydrate in ethanol is 
refluxed to give 6-(m-tolyl)-4,5-dihydro-3(2H)pyridazinone as white 
crystals, 130.degree.-132.degree. C. 
The preceding compound is heated with bromine in acetic acid to give 
6-(m-tolyl)-3(2 H)pyridazinone as white crystals, m.p. 
202.degree.-205.degree. C. 
A mixture of the preceding compound and phosphorus oxychloride is refluxed 
to give 3-chloro-6-(m-tolyl)-pyridazine as off-white crystals, m.p. 
112.degree.-113.degree. C. 
A mixture of 6.0 g of 3-chloro-6-(m-tolyl)pyridazine and 3.52 g of 
formylhydrazine in 100 ml. of n-butanol is refluxed for 48 hrs. and worked 
up as in Example 35 to give 2.0 g. of white crystals (from CHCl.sub.3 
-hexane), m.p. 164.degree.-166.degree. C. 
EXAMPLE 64 
Preparation of 3-methyl-6-(m-tolyl)-1,2,4,-triazolo [4,3-b]pyridazine 
As in Example 36, a mixture of 6.0 g. of 3-chloro-6-(m-tolyl)pyridazine and 
4.34 g of acetylhydrazine in 100 ml. of n-butanol is refluxed for 48 hr. 
to give 2.0 g. of cream colored crystals, m.p. 160.degree.-162.degree. C. 
EXAMPLE 65 
Preparation of 
3-propyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-1,2,4-triazolo-[4,3 
-b]pyridazine 
A mixture of 5.0 g of 3-chloro-6-(.alpha.,.alpha., 
.alpha.-trifluoro-p-tolyl)pyridazine, 3.94 g. of butyric acid hydrazide 
and 100 ml. of n-butanol is refluxed for 48 hr. The solvent is removed 
under vacuum and the residue dissolved in chloroform. The solution is 
passed through a column of hydrous magnesium silicate and the eluent 
concentrated to give 3.2 g. of product Recrystallization from CHCl.sub.3 
-hexane gives crystals, m.p. 173.degree.-175.degree. C. 
EXAMPLE 66 
Preparation of 3ethyl-6-(.alpha. ,.alpha. 
,.alpha.-trifluoro-m-tolyl)-1,2,4-triazolo[4,3-b]pyridazine 
A mixture of 5.0 g. of 
3-chloro-6-(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)pyridazine, 3.40 g. 
of propionic acid hydrazide and 100 ml. of n-butanol is refluxed for 48 
hr. The solvent is removed under vacuum and the residue dissolved in 
chloroform. The solution is passed through a column of hydrous magnesium 
silicate and the eluent concentrated to give 3.0 g. of crystals (from 
CHCl.sub.3 -hexane), m.p. 183.degree.-185.degree. C. 
EXAMPLE 67 
Preparation of 
3-ethyl-6-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)-1,2,4-triazolo[4,3-b 
]pyridazine 
As in Example 65, 5.0 g. of 
3-chloro-6-(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)pyridazine and 3.40 
g. of propionic acid hydrazide in 100 ml. of butanol is refluxed for 48 
hr. to give 3.1 g of white crystals (from CHCl.sub.3 -hexane), m.p. 
194.degree.-196.degree. C. 
EXAMPLE 68 
Preparation of 
6-(4-chloro-.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-1,2,4-triazolo[4,3- 
b]pyridazine 
According to the method in "Organic Syntheses", 
5-amino-2-chlorobenzotrifluoride is converted to 
4-chloro-3-(trifluoromethyl)benzaldehyde. As in Example 35, the following 
reactions are carried out. 4-Chloro-3-(trifluoromethyl)benzaldehyde (13.9 
g.), 14.27 g. of p-toluenesulfonic acid, 13.01 g. of morpholine and 4.88 
g. of potassium cyanide is reacted to give 
.alpha.-[4-chloro-3-(trifluoromethyl)phenyl]-4-morpholineacetonitrile as 
white crystals, m.p. 73.degree.-74.degree. C. This compound (14.0g.) is 
reacted with ethyl acrylate to give ethyl 
.gamma.-cyano-.gamma.-[4-chloro-3-(trifluoromethyl)phenyl]-4-morpholinebut 
yrate as a yellow oil (16.5 g.). This compound (16.5 g.) is reacted with 
2.11 g. of hydrazine in 100 ml. of ethanol to give 
6-[4-chloro-3-(trifluoromethyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone (4.2 
g.) as white crystals, m.p. 195.degree.-198.degree. C. This intermediate 
is heated with bromine in acetic acid to give 
6-[4-chloro-3-(trifluoromethyl)phenyl]-3-(2 H)-pyridazinone as white 
crystlas, m.p. 249.degree.-251.degree. C. A mixture of this compound (5 
g.) and 60 ml. of phosphoric oxychloride is refluxed 18 hours to give 
3-chloro-6-[4-chloro--3-(trifluoromethyl)phenyl]pyridazine as cream 
colored crystals, m.p. 145.degree.-147.degree. C. A mixture of 2.2 g. of 
the preceding compound, 0.9 g. of formylhydrazine, and 50 ml. of n-butanol 
is refluxed for 48 hours to give 2.1 g. of product, m.p. 
211.degree.-214.degree. C. Recrystallization from n-propanol gives cream 
colored crystals, m.p. 217.degree.-218.degree. C. 
EXAMPLE 69 
Preparation of 
3-methyl-6-(4-chloro-.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)-1,2,4-tria 
zolo[4,3-b]pyridazine 
As in Example 36, a mixture of 2,2 g. of 
3-chloro-6-[4-chloro-3-(trifluoromethyl)phenyl]pyridazine and 1.11 g. of 
acetylhydrazine in 50 ml. of butanol is refluxed for 48 hours to give the 
product as crystals, m.p. 267.degree.-269.degree. C. 
EXAMPLE 70 
Preparation of 6-(3,4-dichlorophenyl)-1,2,4-triazolo[4,3-b]pyridazine 
As in Example 35, the following reactions were carried out. 
3,4-Dichlorobenzaldehyde (106.3 g.) is reacted with 124 g. 
p-toluenesulfonic acid. 122 g. of morpholine, and 45 g. of potassium 
cyanide in 500 ml. of tetrahydrofuran to give 136.9 g. of 
.alpha.-(3,4-dichlorophenyl)-4-morpholineacetonitrile as cream colored 
crystals, m.p. 69.degree.-71.degree. C. This compound (136.9 g.) is 
reacted with 50 ml. of ethyl acrylate in 600 ml. of tetrahydrofuran to 
give 132.6 g. of a tan oil. This oil (132.6 g.) and 36 ml. of hydrazine 
hydrate in 500 ml. of ethanol is refluxed to give 63.5 g. of 
6-(3,4-dichlorophenyl)-4,5-dihydro-3(2H)-pyridazinone as yellow crystals, 
m.p. 168.degree.-182.degree. C. This intermediate (63.45 g). and 67.5 g. 
of sodium m-nitrobenzenesulfonate and 52.0 g. of sodium hydroxide in 2 
liters of water is heated on a steam bath overnight to give 26.4 g. of 
6-(3,4-dichlorophenyl)-3(2H)-pyridazinone as tan crystals, m.p. 
215.degree.-218.degree. C. The preceding compound (10 g.) and 100 ml. of 
phosphorus oxychloride is heated on a steam bath to give 8.9 g. of 
3-chloro-6-(3,4-dichlorophenyl)pyridazine. Column chromatography on silica 
gel with chloroform-methanol (95.5) gives 5.5 g. of product as crystals, 
m.p. 188.degree.-189.degree. C. 
A mixture of the preceding compound and formylhydrazine in n-butanol is 
refluxed for 24 hrs. to give 
6-(3,4-dichlorophenyl)-1,2,4-triazolo[4,3-b]pyridazine. 
EXAMPLE 71 
Preparation of 
3-methyl-6-(3,4-dichlorophenyl)-1,2,4-triazolo[4,3-b]pyridazine 
A mixture of 2.6 g. of 3-chloro-6-(3,4-dichlorophenyl)pyridazine and 1.8 g. 
of acetic acid hydrazide is heated in 50 ml. of n-butanol for 24 hrs. to 
give the product of the example. 
EXAMPLE 72 
Preparation of 
6-[2-chloro-5-(trifluoromethyl)phenyl]triazolo[4,3-b]pyridazine 
As in Example 68, 3-amino-4-chlorobenzotrifluoride is converted to 
2-chloro-5-(trifluoromethyl)benzaldehyde, which is converted to 
3-chloro-6-[2-chloro-5-(trifluoromethyl)phenyl]pyridazine as cream colored 
crystals. A mixture of 2.2 g. of this compound, 0.9 g. of formylhydrazine 
and 50 ml. of n-butanol is refluxed for 48 hours to give the product of 
the example. 
EXAMPLE 73 
Preparation of 
3-methyl-6-[2-chloro-5-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyrid 
azine 
As in Example 36, a mixture of 2.2 g. of 
3-chloro-6-[2-chloro-5-(trifluoromethyl)phenyl]pyridazine and 1.11 g. of 
acetylhydrazine in 50 ml. of n-butanol is refluxed for 48 hours to give 
the product of the example. 
EXAMPLE 74 
Preparation of 6-[4-nitro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone 
A mixture of 2.0 g. of 6-[3-trifluoromethyl)phenyl]-3(2H)-pyridazinone and 
10 ml. of fuming nitric acid is heated on a steam bath for 30 min. The 
mixture is poured onto crushed ice, filtered and the solid washed with 
water. The yellow solid (2.2 g.) is dissolved in 20 ml. of 5N NaOH. The 
mixture is chilled (ice bath) and filtered. The solid is dissolved in 
water the solution acidified with hydrochloric acid. The solid is filtered 
and washed with water to give 1.0 g. of cream colored crystals m.p. 
235.degree.-238.degree. C. Recrystallization from dimethylformamide-water 
gave product as crystals, m.p. 238.degree.-241.degree. C. 
EXAMPLE 75 
Preparation of 
6-[4-nitro-3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine 
A mixture of 7.0 g. of 
6-[4-nitro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone and 80 ml. of 
phosphorus oxychloride is heated on a steam bath for 18 hours. The solvent 
is removed and ice water added to the residue. Filtration gives 7.2 g. of 
3-chloro-6-[4-nitro-3-(trifluoromethyl)phenyl]pyridazine as tan crystals, 
m.p. 129.degree.-135.degree. C. Recrystallization from 
dichloromethane-hexane gives cream colored crystals, m.p. 
151.degree.-155.degree. C. The preceding compound is reacted with 
formylhydrazine in refluxing n-butanol for 24 hours to give the product of 
the example. 
EXAMPLE 76 
Preparation of 
3-methyl-6-[4-nitro-3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyrida 
zine 
A mixture of 4.0 g. of 
3-chloro-6-[4-nitro-3-(trifluoromethyl)phenyl]pyridazine and 1.95 g. of 
acetylhydrazine in 40 ml. of n-butanol is refluxed for 18 hours to give 
the product as crystals m.p. 293.degree.-295.degree. C. 
EXAMALE 77 
Preparation of 
6-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine 
A mixture 10 g. of 6-[4-nitro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone 
in 50 ml. of trifluoroacetic acid is reduced with hydrogen and palladium 
on carbon to give 
6-[4-amino-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone. The preceding 
compound is converted to 
6-[4-fluoro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone by the procedure 
described in J. Org. Chem., 26, 468 (1961). The preceding compound is 
reacted with phosphorus oxychloride as described in Example 47 to give 
3-chloro-6-[4-fluoro-3-(trifluoromethyl)phenyl]pyridazine., which is 
reacted with formylhydrazine as described in Example 48 to give the 
product of the example. 
EXAMPLE 78 
Preparation of 
3-methyl-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridaz 
ine 
As described in Example 36, 
3-chloro-6-[4-fluoro-3-(trifluoromethyl)phenyl]pyridazine is reacted with 
acetic acid hydrazide in n-butanol to give the product of the example. 
EXAMPLE 79 
Preparation of 
3-methyl-[4-chloro-3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]-pyrida 
zine 
According to procedure in J. Org. Chem., 25, 468 (1961), 
6-[4-amino-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone is converted to 
6-[3-chloro-5-(trifluoromethyl)phenyl]-3(2H)-pyridazinone. The preceding 
compound is reacted with phosphorus oxychloride to give 
3-chloro-6-[4-chloro-3-trifluoromethyl)phenyl]pyridazine which is reacted 
with acetic acid hydrazide, as in Example 36, to give the product m.p. 
267.degree.-269.degree. C. 
EXAMPLE 80 
Preparation of 
3-methyl-6-[4amino-3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridaz 
ine 
A mixture of 5 g. of 
3-methyl-6-[3-nitro-5-trifluormethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazi 
ne in 75 ml. of trifluoroacetic acid is reduced with hydrogen and palladium 
on carbon catalyst to give the product of the example. Recrystallization 
from methanol gives cream colored crystals, m.p. 240.degree.-242.degree. 
C. 
EXAMPLE 81 
Preparation of 
3-methyl-6-(2-chloro-5-methylphenyl)-1,2,4-triazolo[4,3-b]pyridazine 
As described in Example 35, 2-chloro-5-methylbenzaldehyde is reacted with 
morpholine and potassium cyanide to give 
.gamma.-(2-chloro-5-methylphenyl)-4-morpholineacetonitrile. In a similar 
manner as described in Example 35, the preceding compound is converted to 
3-chloro-6-(2-chloro-5-methylphenyl)pyridazine which is reacted with 
acetic acid hydrazide in refluxing n-butanol for 24 hours to give the 
product of the example. 
EXAMPLE 82 
Preparation of 
3-methyl-6-(2,3-dichlorophenyl)-1,2,4-triazolo[4,3-b]pyridazine 
As described in Example 35, 2,3-dichlorobenzaldehyde is converted to 
3-chloro-6-(2,3-dichlorophenyl)pyridazine. A mixture of this compound and 
acetic acid hydrazide in n-butanol is refluxed for 24 hours to give the 
product of the example. 
EXAMPLE 83 
Preparation of 6-(2-methyl-5-chlorophenyl)-1,2,4-triazolo[4,3-b]pyridazine 
As described in Example 35, 2-methyl-5-chlorobenzaldehyde is converted to 
3-chloro-6-(2-methyl-5-chlorophenyl)pyridazine. A mixture of the preceding 
compound and formylhydrazine in n-butanol is refluxed for 24 hours to give 
the product of the example. 
EXAMPLE 84 
Preparation of 
6-[3-chloro-5-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine 
As described in Example 35, 3-chloro-5-(trifluoromethyl)benzaldehyde is 
converted to 3-chloro-6-[3-chloro-5-(trifluoromethyl)phenyl]pyridazine. 
This compound is reacted with formylhydrazine in refluxing n-butanol for 
24 hours to give the product of the example. 
EXAMPLE 85 
Preparation of 
3-methyl-6-[3-chloro-5-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyrid 
azine 
A mixture of 3-chloro-6-[3-chloro-5-(trifluoromethyl)phenyl]pyridazine and 
acetic acid hydrazide in n-butanol is refluxed for 24 hours to give the 
product of the example.