NO773245L - PROCEDURE FOR PREPARING NEW TRIAZOLOPYRIDAZINES - Google Patents

Description

Procedure for manufacturing new ones

triazolopyridazines

This invention relates to the production of new organics

compounds, and more particularly new substituted 6-phenyl1-1,2,4-triazolo[4,3-b]pyridazines which can be represented by the following structural formula

where R^, Rj and are each individually selected from the group consisting of hydrogen and alkyl of up to 3 carbon atoms, and R^ is hydrogen, chlorine, bromine, fluorine, cyano, trifluoromethyl, nitro, amino, acetamido,

carbamoyl, thiocarbamoyl or alkyl of up to 4 carbon atoms, with the first condition that at least one of oh R2 is hydrogen,

with the second condition that when R^, R2 and R^ are all hydrogen, then Rj cannot be methyl, and with the third condition that when R^

and R^ are both methyl, then Rj can. and R^not be hydrogen. The invention also includes new preparations containing the compounds defined above, which are useful as anti-anxiety agents, and a method for alleviating anxieties in mammals with these.

The new. compounds according to the invention are usually obtained as white to light yellow crystalline materials with characteristic/melting points and absorption spectra, and they can be purified by recrystallization from common organic solvents, such as methanol, ethanol, dimethylformamide, acetone, chloroform, ethyl acetate and the like. They are noticeably soluble in non-polar

organic solvents, such as toluene, carbon tetrachloride and the like, but they are relatively insoluble in water. The organic bases produced according to the invention form non-toxic acid addition salts with a range of pharmacologically acceptable organic

and inorganic salt-forming reagents. Acid addition salts formed by mixing the organic free base with one or two equivalents of an acid, suitably in a neutral solvent, are thus formed with such acids as sulfuric acid, phosphoric acid, 8altic acid, hydrobromic acid, sulfamic acid, citric acid, lactic acid, maleic acid, succinic acid , tartaric acid, acetic acid, benzoic acid, gluconic acid, ascorbic acid 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 the purposes of this invention, the free bases are equivalent to their non-toxic acid addition salts.

The new compounds can easily be prepared accordingly

with the following reaction core:

where R^, Rj# Rg and R^ are as previously indicated. In accordance with the reaction scheme above, a suitably substituted 3-benzoyl-propionic acid (I) is reacted with hydrazine hydrate at 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 affords 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 an excess of phosphorus oxychloride at steam bath temperature for a period of 4-8 hours. Interaction between 3-chloro-6-phenylpyridazine (IV) and an acylhydrazine (V) at the reflux temperature in a lower alkanol solvent over a period of 24-48 hours affords the corresponding 6-phenyl-1-1,2,4-triazolo[ 4, 3-b]pyridazines (VT) according to the present invention.

The new compounds can also be easily prepared in accordance with the following reaction scheme

where R 1 , R 2 and R 4 are as previously indicated. In accordance with the reaction scheme above, an appropriately substituted 3-chloro-6-phenyl-

pyrida2ine (IV) reacted with hydrazine hydrate at the reflux temperature in a lower alkanol solvent for a period of 12-24 hours to provide the corresponding 3-hydrazino-6-phenylpyradazine (VII). Cyclization of the 3-hydrazino derivatives (VII) with lower alkyl orthoformates affords the compounds of the formula (VTII) where R^ is hydrogen. Cyclization of the 3-hydrazino derivatives (VII) with lower alkanoic acid anhydrides, - lower alkanoic acid chlorides or orthoesters of lower alkanoic acids provides compounds of the formula (IX) where Rj is lower alkyl. The cyclization can be carried out with or without catalysis with bases such as pyridine or tri(lower alkyl)amines. Cyclization with lower alkyl orthoformates and orthoesters of lower alkanoic acids is preferably carried out without catalysis and without solvent,

although an inert solvent may be used. The cyclizations are usually carried out by heating with or without solvent at 50 to 175°C.

The new compounds prepared in accordance with the present invention have antihypertensive activity at non-toxic doses and as such are useful as hypotensive agents. The compounds have been pharmacologically tested and have been found to have such properties with a desirable wide spread between doses which produce lowered blood pressure and which produce toxic symptoms. The hypotensive properties of the new compounds have been demonstrated by oral administration to mammals, especially warm-blooded animals, in the following manner Conscious, normotensive male albino rats of the Wistar breed with an average weight of approximately 250 g were attached to a rat table in the back -recumbent position with the help of bands of soft sailcloth. The femoral parts were anesthetized (subcutaneous infiltration of lidocaine) and the right or left main artery was exposed and separated from the innermost parts with an artery clamp and removed from the center with thread. An incision was made near the underligature and short nylon catheters were inserted and tied appropriately. The other ends of the catheters were fitted with 24 aligned centerless needles attached to thick-walled polyethylene tubing. The test compounds were administered orally to the animals, by gavage (stomach tube). The compounds were tested at 100 mg/kg and were suspended or dissolved in a 2% aqueous StiveIse solution, and 0.2 ml of this gave, per 100 g of body weight, the desired dose. The mean arterial blood pressure was measured 4 hours and 24 hours after administration of the compounds. Comparisons were then made with the average pressure for comparison tests, of 122 mm of mercury, which is the average of a number of comparison tests obtained by testing over several months. Blood pressure measurements were made with eight Statham P23 Db voltage measuring instruments (Statham Instruments, Inc., Los Angeles, California), attached to a Beckman Dynograph Recorder equipped with eight voltage measuring instruments with preamplifiers with averaging circuits for measuring mean arterial blood pressure. The results with the representative compounds prepared according to the present invention are shown in Table I below.

The new compounds produced according to the present invention were also tested with regard to antihypertensive activity by a method using spontaneously hypertensive rats (SHP) in the following way: An adult male (SHR) with a weight of approx. 300 g (16-20 weeks old) (Taconic Farms, Germantown, N.Y.) were fed the test compound by gavage with 100 mgAg with or without 0.9% sodium chloride supplement at 25 ml/kg at 0-hour. Another identical dose was given at 24 hours and the mean arterial blood pressure (MABP) of conscious rats was measured directly by femoral artery puncture at 28 hours. The results of this test with representative compounds produced according to the present invention are also shown in Table I below. The new compounds produced according to the present invention have thus been found to be very useful in reducing high blood pressure in mammals when administered in amounts ranging from approx. 1.0 mg to approx. 25.0 mg per kg body weight per

day. A preferred regimen to achieve optimal results will be from approx. 5.0 mg to approx. 15.0 mg per kg body weight per day,

and such dose units are used that a total of approx. 0.35 g to approx. 1.0 g of active compound for an individual of approx. 70 kg of body weight in a period of 24 hours. The regimen can be adjusted to provide the optimal therapeutic response.

For example, several divided doses can be administered daily or the dose can be reduced in accordance with imperative needs of the therapeutic situation. A definite practical advantage of the invention is that the active compounds can be administered in any convenient manner, such as by oral, intravenous, intramuscular or subcutaneous administration.

The new compounds have been found to be very useful in alleviating agitation in mammals when administered in amounts ranging from about 0.03 mg to approx. 10.0 mg per kg body weight per day. A preferred regimen to achieve optimal results will be from approx. 0.1 mg to approx. 5.0 mg per kg body weight per day, and such dosage units are used that a total of approx. 7.0 mg to approx. 0.35 g of active compound for an individual of approx. 70 kg of body weight in a period of 24 hours. This regimen can be adjusted to provide the optimal therapeutic response. For example, several divided doses can be administered daily or the dose can be reduced in accordance with imperative needs of the therapeutic situation. A decided practical advantage of the invention is that the active compounds can be administered in any convenient way,

such as by oral, intravenous, intramuscular or subcutaneous administration.

The new compounds prepared in accordance with the present invention possess central nervous system activity at non-toxic doses and as such are useful as anxiolytic agents. That is, they produce certain responses in standard tests with laboratory animals, which are known to correspond well with the relief of anxiety in humans. The compounds have been tested pharmacologically and have been found to have such properties with a desirable wide spread between doses that produce anxiolytic activity and doses that produce toxic symptoms.

The anti-anxiety properties of the new compounds have been established by one test showing anti-anxiety activity by measuring protection against convulsions resulting from the administration of pentylenetetrazole. Graded dosage amounts of the compounds of this invention were administered orally, in a 2% starch adjuvant, to groups of at least 5 rats. At the assessed time for peak effect, the rats were treated intravenously with pentylenetetrazole at a dose of 21 to 23 mg/kg body weight. This dose is estimated to cause clonic seizures in 99% of untreated rats. The effective dose (ED,.q) of the test compound for protection of 50% of the animals is calculated by the method of D. H. Finney in "Statistical Methods in Biological Assay", Second Edition, Hafner Publishing Co., New York, 1964, pp. 456-457. Representative results are set forth in Table I below, in comparison with chlordiazepoxide or meptrobamate, which were tested in exactly the same manner. It has been stated (R. T. Hill and D. H. Tedeschi, "Animal Testing and Screening Procedures in Evaluating Psychotropic Drugs" in "An Introduction to Psychopharmacology", Eds. R. R. Rech and K. E» Moore, Raven Press, New York, p. 237 -288 (1971) that there is a high degree of agreement between antagonism of pentylenetetrazole seizures in rats and anti-anxiety effects in higher warm-blooded animals.

Another test that has been used to assess antianxiety effects is an unconditioned passive withdrawal procedure described by J. R. Vogel, B. Beer, and D. E. Clody, "A Simple and Reliable Conflict Procedure for Testing Anti-Anxiety Agents", Psychbpharmacologia, Vol. 21, pp. 1-7 (1971). A conflict situation is induced in rats by a modification of this method. To groups of six naïve Sprague-Dawley rats (200-220 g), which have previously been without water for 48 hours and without food for 24 hours, are administered graded oral doses of the test compound suspended in 2% starch adjuvant which also contains 2 drops of polyethylene glycol and polysorbate 80, or adjuvant alone (comparisons). At the time of peak effect, each rat is placed in a Plexiglas box fitted with a drinking meter circuit connected between a stainless steel grid floor and a stainless steel drinking tube inserted into a hole in one of the walls of the box. A stimulator delivers monophasic, 60-period square-wave pulses of 0.2 raililliampere in peak intensity, a timer provides alternating periods of 5 seconds of "shock-free" and 5 seconds of "shock available" during a 5-minute test period , and an electromagnetic counter to count the number of shocks received by the rat during the shock-available period and a dwell time of half a second between the successive shocks, is incorporated into the drinking meter circuit. After the rat is placed in the box, it is explored and given the opportunity to drink 10% dextrose solution supplied through the tap. After 20 seconds of continuous unpunished drinking, the timer and drink meter circuitry is activated and alternates between 5-second shock-free and 5-second shock-available periods. The number of shocks received by the rat during a 5 minute test period is recorded. The percentage of rats receiving 9 or more shocks within 4 to 5 minutes at each dose rate is designated as a positive response when calculating the mean effective dose (EDgQ). The results of this test for representative compounds according to the invention appear in table II below.

Preparations that have the desired clarity, stability and applicability for parenteral use are obtained by dissolving from 0.10 to 10.0% by weight of the active compound in an excipient consisting of a polyhydric aliphatic alcohol or mixtures thereof. Particularly satisfactory are glycerol, propylene glycol and polyethylene glycols. The polyethylene glycols consist of a mixture of non-volatile, usually liquid polyethylene glycols which are soluble in both water and organic liquids and which have molecular weights of from approx. 200 to 1500. Although the amount of active compound dissolved in the above-mentioned aid may vary from 0.10 to 10.0% by weight, it is preferred that the amount of active compound used is from approx. 3.0 to approx. 9.0% by weight. Although different mixtures of the aforementioned non-volatile polyethylene glycols can be used, it is preferred to use a mixture with an average molecular weight of from approx. 200 to approx. 400.

In addition to the active compound, the parenteral solutions can also contain various preservatives that can be used to prevent bacterial and fungal contamination.

The preservatives that can be used for these purposes are, for example, myristyl-picolinium chloride, benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-α-glycerol ether, methyl and propyl parabens and thimerosal. For practical reasons, it is also convenient to use antioxidants. Suitable antioxidants include, for example, sodium bisulphite, sodium reta bisulphite and sodium forraaldehyde sulphoxylate. Generally, concentrations of antioxidants of from approx. 0.05 to approx. 0.2%.

For intramuscular injection, the preferred concentration of active compound is 0.25 to 0.50 mg/ml of the finished product. preparation. The new compounds are equally suitable for intravenous administration when diluted with water as when diluents for intravenous therapy, such as isotonic glucose, are used in appropriate amounts. For intravenous use, it is satisfactory with initial concentrations down to c. 0.05 to 0.25 mg/ml of active ingredient.

The active compounds produced according to the present invention can be administered orally, for example with an inert diluent or with an assimilable edible carrier,

or they may be enclosed in hard or soft gelatin shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food. For oral therapeutic administration, the active compounds may be incorporated

with inert shaping agents and used in the form of tablets,

troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such mixtures and preparations should contain at least 0.1% of active compound. The percentage content in the mixtures and preparations can of course be varied and it can conveniently be between approx. 2 and approx. 60% by weight based on the weight of the unit. The quantity with

active compound in such therapeutically useful mixtures is such that an appropriate dosage will be obtained. Preferred mixtures or preparations are prepared so that an oral dosage unit form contains between approx. 0.1 and 5.0 mg of active compound.

The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gourami tragacanth, acacia, corn starch or gelatin, inert shaping agents such as dicalcium phosphate, a weathering agent such as corn starch, potato starch, alginic acid and like, a lubricant such as magnesium stearate, a sweetener such as sucrose, lactose or saccharin or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring. When the dosage unit form is a capsule, it may, in addition to materials of the above type, contain a liquid carrier such as a fatty oil. Various other materials may be present as coating agents or to otherwise modify the physical form of the dosage unit. For example, tablets, pills or capsules can be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetener1, methyl and propyl parabens as preservatives, a coloring agent and flavoring agent such as cherry or orange flavoring. Of course, any material used in the manufacture of any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used.

The invention also relates to the production of new substituted 6-phenyl-1,2,4-triazolo[4,3-blpyridazines which are useful as hypotensive and neurodepressant agents, which can be represented by the following structural formula:

where R 1 , R 2 and R 2 are each individually selected from the group consisting of hydrogen and alkyl of up to 3 carbon atoms with the proviso that at least one of R 2 and R 2 is hydrogen; and two of the substituents R 1 , R 1 , R 8 and R 7 are hydrogen and the remaining two are fluorine, chlorine, bromine, methyl, methoxy, nitro, amino or trifluoromethyl. These new compounds can be easily prepared in accordance with the reaction schemes above, except that the proportion indicated there is replaced by the proportion

as defined immediately above. For the purposes of this invention, these free bases are equivalent to their non-toxic acid addition salts.

The invention will be described in more detail in connection with the following specific examples.

Example 1

Preparation of p(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)-benzonitrile

A 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 glacial acetic acid with overhead stirring at steam bath temperature, then 56 ml of liquid bromine is dissolved in a further 500 ml of acetic acid, and this solution is added in one portion to the stirred mixture. After heating for approximately 1/2 hour, a strong exothermic reaction takes place during the expulsion of the excess bromine and hydrogen bromide. The reaction mixture is then diluted with 4 liters of distilled water and the resulting solid is filtered and the filter cake is abundantly washed with water and air-dried. This material is recrystallized from a large amount of ethyl alcohol to give the product p-(1,6-dihydro-4-methyl-6-oxo-3-pyridazinyl)benzonitrile as a white solid.

A portion of 45.9 g of the above material and 250 ml of phosphorus oxychloride is heated at steam bath temperature for 3 hours. The excess phosphorus oxychloride is decomposed by slowly adding the reaction mixture to crushed ice while 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 finely divided with petroleum ether and filtered. The filter cake is air-dried and the yellow solid is recrystallized twice from methyl alcohol,

and the resulting pale yellow crystals are again recrystallized from methanol to give the example product, sra.p. 240-243°C.

Example 2 Preparation of p-(3,7-dimethyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)-bezonitrile A portion of 1.48 g of acetic acid hydrazide is dissolved in 50 ral of butyl alcohol under heating, then 4.58 g of p-(6-chloro-4-methyl-3-pyridazinyl)-benzonitrile (prepared as in example 1) becomes

added and complete solution is obtained after heating for a further 10 minutes. The solution is then heated at reflux for 18 hours. The reaction mixture is concentrated to give 5.8 g of orange solid which is washed with petroleum ether. This product is dissolved in 1l ethyl alcohol/acetone and is filtered through a pad of silica gel. The filter is washed with copious acetone and the combined filtrates are concentrated to give a yellow solid. The solid is dissolved in 100 ral of acetone and the solution is cooled in dry ice-acetone to give a light brown solid which is collected by filtration,

washed with plenty of petroleum ether. and air dried. This product is dissolved in methyl alcohol, treated with activated charcoal and filtered. The filtrate is used to recrystallize 1.06 g of yellowish crystals. A 500 vpg portion of the above is recrystallized twice, from methanol and the resulting product is dried in vacuo to give the example product, m.p. 242-244°C.

Example 3 Preparation of p-(3-ethyl-7-methyl-1-1,2,4-triazolo [4,3-b Ipyridazin-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 under reflux for 24 hours. The reaction mixture is concentrated until free of solvent, then cooled in ice and stirred with petroleum ether. This results in a white solid which is filtered, washed with petroleum ether and stirred in vacuo to give propionic hydrazide as a white crystalline solid.

A portion of 30.8 g of the above-mentioned compound is dissolved in one liter of butyl alcohol (dried over 3-A molecular sieves), then 40.0 g of p-(6-chloro-4-ethyl-3 -pyridazinyl)-benzonitrile (prepared as in example 1) and the reaction mixture is allowed to heat at reflux for 18 hours. The reaction mixture is concentrated until free of solvent and the concentrate is finely divided with petroleum ether and then filtered. The filter cake is vacuum dried to give a yellow solid which is then recrystallized from methyl alcohol to give the example product, syrup. 192-195°C.

Example 4

Preparation of p-(3-ethyl-7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)-benzamide

A portion of 4.5 g 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 while heating, then 50 ml of 30% hydrogen peroxide is added while stirring and finally 50 ml of 2N sodium hydroxide is added while stirring. The reaction mixture is allowed to stand at room temperature for three hours and is then 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, and then recrystallized to give a yellow solid like the example product, m.p. 210-213°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-nitrobenzoyl)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 yarme jacket. 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 and then filtered and air-dried to give 27.24 g of 3-m-nitrobenzoyl-butyric acid as a white solid fabric. 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 substance begins to appear after approx. 1/2 hour. The reaction mixture is cooled in an ice bath and the resulting solid becomes . filtered and air-dried to give the compound 4,5-dihydro-5-methyl-6-(m-nitrophenyl)-3(2H)-pyridazinone as white to pale yellow crystals.

A portion of 24.9 g of the above-mentioned material is dissolved in 200 ral of warm stirred glacial acetic acid, and then 6.2 ral of bromine dissolved in 50 ml of glacial acetic acid is added dropwise over a period of 15 minutes during the evolution of hydrogen bromide. gas. The reaction mixture is heated for an additional 20 minutes to drive off the hydrogen bromide and then the mixture is poured into crushed ice. The resulting solid is filtered and washed with copious amounts of water and then dried in vacuo to give 24.2 g of 5-ethyl-6-(m-nitrophenyl)-3(2H)-pyridazinone as a cream colored solid . One portion of 22.7 g of the preceding compound is combined with 230 ral of phosphorus oxychloride and heated on a steam bath for 3 hours. The reaction mixture is poured portionwise into crushed ice while stirring. The resulting solid is filtered, washed with plenty of water and air dried to give 15.6 g of 3-chloro-5-methyl-6-(m-nitrophenyl)pyridazine as a light brown solid.

A mixture of 14.97 g of the above compound, 7.2 g, formylhydrazine and 200 ml of butyl alcohol is stirred at reflux for 18 hours. The reaction mixture is decanted until it is

free of insoluble matter and the liquid portion is cooled in an ice bath to give 13.28 g of brown crystalline solid* This material is dissolved in 300 ml of boiling methyl alcohol and then filtered to remove insoluble matter. The filtrate is made clear by treatment with activated charcoal and filtration. This filtrate is concentrated to a small volume and is cooled to give a light brown solid as the example product, m.p. 213-218°C..'

Example 6

Preparation of 6-(m-aminophenyl)-7-methyl-rl,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 are shaken in a Parr shaker under a hydrogen pressure of 18.4 kg - for 1 1/2 hours. The reaction mixture is filtered free of catalyst and the filtrate is concentrated to give the sample product as a yellow solid, sra.p. 182-186<0>C.

Example 7

Preparation of 6-(p-bromophenyl)-1,2,4-tria2olo[4,3-b]pyridazine

A mixture of 3.76 g of 3-(p-bromophenyl)-6-chloro-pyridazine,

1.80 g of formylhydrazine and 50 ml of butyl alcohol are heated to reflux and treated under 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. 209-211°C.^

Example 8

Preparation of 6-(p-fluorophenyl)-1,2/4-triazolo[4,3-b]pyridazine

A sample of 87 g of 6-(p-fluorophenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as in U.S. Patent No. 3,689,652, Example 6)[is stirred in 800 ml of glacial acetic acid in a 2-liter 3-neck

flask on a steam bath. A solution of 24.1 ml bromine liquid in 100 ml glacial acetic acid is formed in a dropping funnel. A portion of 15 ml of this bromine solution is added dropwise to the reaction mixture, which

is heated with stirring until the mixture acquires a lighter,

color. The rest of the bromine solution is then added while heating and stirring during approx. 30 minutes. The reaction mixture is then heated for a further 1 hour and then poured onto crushed ice. The precipitate formed is collected by filtration, washed with water and air-dried overnight. The material is then dried at 65°C to give 82.0 g of 6-(p-fluorophenyl)-3(2H)-pyridazinone

as crystal, m.p. 265-268°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 excess phosphorus oxychloride is removed using a rotary evaporator, and 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 small volume, the resulting precipitate is collected by filtration and washed with chloroform, and then air-dried to give 3-chloro-6-(p-fluorophenyl)-pyridazine as bright red crystals.

A portion of 2.5 g 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 refluxed overnight. The mixture is cooled in an ice bath and the precipitated product is collected by filtration, washed with butyl alcohol and dried overnight. The dried material remains

recrystallized from methyl alcohol to give the example product as crystals, m.p. 197-198°C.

Example 9

Preparation of p-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)benzonitrile

A sample of 86.3 g of 6-(p-bromophenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as in U.S. Patent No. 3,689,652, Example 5) is dissolved in 500 ml of glacial acetic acid at heating to 80°C with continuous stirring. A solution of 60 g of bromine in 80 ml of acetic acid is added dropwise at 75-80°C over a period of one hour. A solid is separated near the end of the addition. The reaction mixture is heated with stirring on a steam bath for half an hour more, and is then poured into 3 liters of crushed ice water. The white solid formed is collected by filtration and air-dried. The product is then recrystallized from ethyl alcohol to give 6-(p-bromophenyl)-3(2H)-pyridazinone.

A mixture of 19.20 g of the above product and 9.10 g of copper (I) cyanide in 70 ml of dimethylformamide is stirred at reflux temperature for 5 1/2 hours. During this time, a solid is precipitated. 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 give 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 and then water with crushed ice 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)benzo-

nitrile as crystals, m.p. 236-238°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 give p-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)benzonitrile as an orange solid, m.p. 272-274°Ci

Example 10

Preparation of m-(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-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 glacial acetic acid while stirring at steam bath temperature. Then 3.75 ml of bromine in 25 ml of acetic acid is added dropwise over a period of 15 minutes. The reaction mixture is heated on a steam bath for an additional 30 minutes and then poured onto crushed ice. The resulting solid is collected by filtration, washed with plenty of water and dried to give ra-(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 are heated on a steam bath for 3 hours. The excess phosphorus oxychloride is decomposed by slowly adding the reaction mixture to cold water while stirring. The resulting solid is filtered and the filter cake is washed with plenty of water. The product is air-dried to give m-(6-chloro-4-ethyl-3-pyridazinyl)benzonitrile as a cream 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 and filtered to collect the solid formed. The Example product is then recrystallized from methyl alcohol to give a cream colored solid, m.p. 214-216°C.

Example 11

Preparation of 3-propyl-6-(a,a,ot-trifluoro-m-tolyl)-1,2,4-triazolo-[4,3-b]pyridazine

A portion of 112 g of p-toluenesulfonic acid is dissolved

in 500 ml of tetrahydrofuran with stirring. Then 106 g becomes morphorin,

added in portions while stirring. A portion of 95.63 g of ra-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 set aside.to.be touched to? backtracking overnight. The reaction mixture is then concentrated until it is 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 give α-(α,α,α-trifluoro-m-tolyl)-4-morpholine acetonitrile as a dark yellow oil. A portion of 67.0 g of this oil 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 over a period of 5 hours. This reaction is slightly exothermic. The reaction mixture is left to stir at room temperature overnight. The mixture is treated with activated charcoal and filtered. The filtrate is concentrated until it is free of solvent and is stripped several times with toluene. The concentrate is stirred with diethyl ether and filtered to remove insoluble substances. The filtrate is concentrated to a yellow oil which is then chromatographed on a glass column of 75 cm x 8 cm containing silica gel with chloroform as solvent. The chromatographed material is stripped of chloroform to give 47.0 g of ethyl γ-cyano-γ-(α,α,α-trifluoro-m-tolyl)-4-morphorline butyrate as a yellow oil. The entire amount of the preceding product is combined with two liters of ethyl alcohol and 7.3 ml of hydrazide hydrate. The mixture is stirred at reflux for 18 hours, then concentrated until free of solvent to give a yellow oil which is triturated with petroleum ether to give 14.55 g of 4,5-dihydro-6-(a,a, ot-trifluoro-m-tolyl)-3(2H)-pyridazinone as a white solid. The total amount of the above product 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 above starting material at room temperature. The reaction mixture is heated on a steam bath for half an hour while the remainder of the bromo-acetic acid solution is added dropwise. After complete decolorization, the reaction mixture is heated

on a steam bath for half an hour, and it is concentrated until

it is solvent free. The solid concentrate is washed with water, filtered and air-dried to give 6-(α,α,α-trifluoro-m-tolyl)-3(2H)-pyridazinone as a cream solid.

A portion of 12.55 g of. the product, dvenfor and 200 ml of phosphorus oxychloride are heated on a steam bath for 18 hours. The reaction mixture is concentrated until it is free of the excess phosphorus oxychloride and the concentrate becomes. finely divided with cold water. The resulting solid is filtered and the filter cake is washed with water. The material is air-dried to give 3-chloro-6-(α,α,Gf-trifluoro-m-tolyl)pyridazine as a cream solid.

A mixture of 6.0 g of the preceding product, 4.74 g of citric acid hydrazide and 75 ml of butyl alcohol is left to stir at room temperature for 48 hours. The reaction mixture is concentrated until it is 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 give the sample product as a cream colored solid. This material is recrystallized from ethyl alcohol and dried in vacuo to give crystals, m.p. 118-120 C.

Example 12

Preparation of 3'-(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)-acetanilide

A portion of 1.5 g 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. 6.0 ml of acetic anhydride is added to the solution and the reaction mixture is heated in a steam bath for one hour. The reaction mixture is cooled in an ice bath and is filtered. The filter cake is washed with petroleum ether and dried to give the sample product as cream-colored crystals, m.p. 298-301°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)-pyridazinone [Journal of Medicinal Chemistry, 17, 281 (1974)] and 100 ml of phosphorus oxychloride is heated at room temperature in 3 hours. The mixture is added drop by drop to cold water while stirring. The resulting solid is filtered and washed with water to give 3-(p-bromophenyl)-6-chloro-4-methylpyridazine as a gray solid.

A mixture of 1.5 g of the above compound, 0.64 g of formylhydrazine and 25 ml of butyl alcohol is obtained. stirred at reflux for 18 hours. The reaction mixture is cooled in an ice bath, filtered and the solid recrystallized from methyl alcohol to give the sample product as a yellow solid, m.p. 219-222°C. ,

Example 14

Preparation of p-(7-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)-thiobenzamide

A portion of 2.1 g of p-(7-methyl-1,2,4-triazolo[4,3-b]-pyridazih-6-yl)benzonitrile (prepared as in Example 1) is partially dissolved in a solvent1 -mixture of 50 ml pyridine and 5.0

ml of triethylamine. Hydrogen sulphide gas is bubbled into the reaction mixture over a period of 3 hours during which the color of the reaction mixture changes from yellow to green. A solid starts to form in the reaction mixture approximately 15 minutes after the addition of hydrogen sulfide gas begins. The mixture is then filtered and the yellow solid is washed with petroleum ether to give the sample product as a pale yellow solid, m.p. 268-272°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. Heterocyphelic Chem. ^11; 775 (1974)] in 150 ral 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 give 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 sample product as crystals, m.p. 226-228°C.

Example 16 Preparation of 6-(p-chlorophenyl)-3-methyl-1,2,4-triazolo[4,3-b]-pyridazine A portion of 47.5 g with 6-(p-chlorophenyl)-4, 5-Dihydro-3(2H)-pyridazinone (prepared as in Example 1 U.S. Patent No. 3,689,652) is dissolved in 250 ml of glacial acetic acid at 65-70°C with stirring. Then a solution of 14 ral (42 g) of liquid bromine in 50 ral of acetic acid is added portionwise over a period of 20 minutes. The reaction mixture is stirred at 65°C for 3 hours and is cooled to

4°C. The skimming is collected and washed with 100 ml of ethyl acetate.

The solid is suspended in 500 ml of water, 25 ral of concentrated aramonium hydroxide is added and the mixture is stirred at room temperature overnight. The precipitate is collected, washed with 500 ral water and dried at 60°C to give 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 kg of ice. After

stand for 2 hours with stirring. occasionally, the precipitate is collected and washed with water. The solid is dissolved in 500 ml of boiling benzene, then clarified with activated charcoal and filtered. The filtrate is cooled to room temperature and that

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 give 3-chloro-6-(p-chlorophenyl)pyridazine, mp: 209-211°C.

A mixture of 10.0 g of the above product, 6.6 g of hydrazine hydrate and 150 ml of butyl alcohol is refluxed overnight. The reaction mixture is cooled, filtered and the solid is washed with butyl alcohol and with water. The butyl alcohol filtrate is concentrated on a rotary evaporator and further crystalline product is obtained, which is washed with butyl alcohol and with water. The combined materials give 6-(p-chlorophenyl)-3-hydrazinopyridazine, m.p. 156-160°C.

A mixture of 6.6 g of the above material (prepared in the manner described), 140 ral of p-dioxane and 4.64 g of diisopropylethylaraine is heated until a solution is obtained. 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 left to stir overnight. The solvent is then removed under vacuum and ethyl alcohol is added to the residue. The flask is heated and a solid is precipitated. This material is removed by filtration and the ethanol is further concentrated to give the sample product as crystals, m.p. 208-210°C.

Example 17

Preparation of 6-(p-chlorophenyl)-8-methyl-1,2,4-triazolo[4,3-bl-pvridazine To a solution of 114 g of methylsuccinic anhydride in 400 ml of chlorobenzene, 270 g of aluminum chloride are carefully added. The mixture is heated to 65°C for 1 1/2 hours, 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, it is concentrated

hydrochloric acid slowly added 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 gives 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 left to stir for 18 hours. The reaction mixture is concentrated to approx. 75% of the original volume, is cooled in an ice bath and filtered to give 26.62 g of 6-(p-chlorophenyl)-4,5-dihydro-4-methyl-3(2H)-pyridazinone as a yellow solid fabric. A further 4.7 g of the product is obtained from the above-mentioned filtrate.

The combined product above (31.32 g) is dissolved in 250 ral of glacial acetic acid at room temperature with stirring. A portion of 8.2 ml of pure 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 raised until the color due to bromine has disappeared. The remaining bromine solution is added during heating during 20 minutes. The reaction mixture is heated on the steam bath for a further 1/2 hour and is diluted with ice water. The resulting solid is filtered, washed with water and air-dried to give 6-(p-chlorophenyl)-4-methyl-3(2H)-pyridazinone as a cream solid.

A portion of 15.0 g of the above compound and 200 ml of phosphorus oxychloride is heated on a steam bath for 18 hours. The reaction mixture is concentrated until it is free of solvent and the concentrate is stirred with cold water. The precipitate is filtered and the solid is washed with water to give 3-chloro-6-(p-chlorophenyl)-4-methylpyridazine as a pink solid.

A 2.0 g portion of the above compound 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 give a light brown solid,

i The Example product is recrystallized from methyl alcohol, after treatment with activated charcoal, for . to give white crystals, , m.p. 230-233°C.

Example 18

Preparation of 3-methyl-6-(a,a,o-trifluoro-m-tolyl)-1,2,4-triazolo-(4,3-b]pyridazine A portion of 6.0 g and 3-chloro- 6-(α,α,α-trifluoro-m-tolyl)-pyridazine (prepared as in Example 11), 3.44 g of acetylhydrazine and 75 ml of n-butyl alcohol are refluxed for 48 hours. The solvent is removed under vacuum and the residue is dissolved in ethyl alcohol and treated with activated charcoal. The filtrate is concentrated, quenched and filtered to give an orange solid. Recrystallization from methyl alcohol gives the sample product as crystals, mp 193-194°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 ral of butyl alcohol is heated at reflux temperature for 40 hours. The reaction mixture is cooled, filtered and the solid is 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 raw material collected above, the combined solids are recrystallized from 130 ml of ethyl alcohol to provide the sample product as crystals, m.p. 216-218°C.

Example 20

Preparation of 6-(α,α,tt-trifluoro-m-tolyl)-1,2,4-triazolo[4,3-blpyridazine

A mixture of 6.0 g of 3-chloro-6-(α,α,ot-trifluoro-m-tolyl)-pyridazine (prepared as in Example 11), 2.78 g of formylhydrazine and 75 ml of butyl alcohol is set aside to stir at reflux temperature for 48 hours. The reaction mixture is concentrated until it is 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 give the sample product as cream-colored crystals, m.p. 140-143°C.

Example 21

Preparation of 6-(p-chlorophenyl)-3-ethyl1-1,2,4-triazolo4,3-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 hydrazide and 60 ral of butyl alcohol is stirred at reflux temperature for 48 hours. The mixture is cooled, filtered and the solid is washed with petroleum ether and with water. The material is recrystallized from 50 ml of ethyl alcohol to give the sample product as crystals, m.p. 197-199°C.

Example 22

Preparation of 6-(p-fluorophenyl)-3-methyl-1,2,4-triazolo[4,3-blpyridazine 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 are refluxed until a clear solution is obtained. The reaction mixture is cooled, filtered and the solid precipitate is washed with hexane and with water. The solid is recrystallized from 50 ml of ethyl alcohol to give the sample product as crystals, m.p. 227-229°C.

Example 23

Preparation of 3-methyl-6-(m-nitrophenyl)-1,2,4-triazolof4,3-b]-pyridazine

A mixture of 9.9 g of 6-(m-nitrophenyl)-4,5-dihydro-3-pyridazone [J. With. Chera. 17, 273 (1974)] and 80 ral glacial acetic acid are stirred and up-

heated on a steam bath and a solution of 2.41 ml of bromine in 10 ml of ice-

vinegar is added drop by drop over the course of 30 minutes. Heating and stirring are continued for a further 45 minutes and the reaction mixture is poured onto crushed ice. The crystal

The resulting product is filtered and washed with water. The yield of 6-(m-nitrophenyl)-3-pyridazone, m.p. 275°C, is almost 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 excess POCl₂. 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, bé-

acted with activated carbon and prepared. The chloroform solution is concentrated to give 4.0 g of 3-chloro-6-(m-nitrophenyl)-pyridazine, m.p. 206-208°C.

A mixture of 3.0 g of the preceding compound,

2.0 g of acetylhydrazine and 30 ml of butanol are heated at reflux for 72 hours and cooled. The precipitate is filtered, washed with hexane, with water and is air-dried. The product is boiled with 100 ml of 95% ethyl alcohol and filtered. The insoluble material, m.p. 241-243°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. 231-233°C, is obtained when formylhydrazine is inserted instead of acetylhydrazine in the method in 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 approx. 15.9 kg of hydrogen pressure until the 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 adding 5N NaOH. The insoluble material is filtered off and washed with water to obtain 6-(m-aminophenyl)-3-ethyl-1,2,4-triazolo[4,3-b]-pyridazine, m.p. 193°C.

Example 26

Preparation of 6-(m-aminophenyl)-1,2,4-triazolo[4,3-b1pyridazine

Example compoundIsen, sm.p. 225°C, is obtained when 6-(m-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine (prepared as in example 24) is reduced by the method in example 25.

Example 27 Preparation of 6-(m-acetaaridophenyl)-1,2,4-triazolo[4,3-b]-pyridazine

A mixture of 1.0 g of 6-(m-aminophenyl)-1,2,4-triazolo-[4,3-bIpyridazine (prepared as in Example 26) and 4 ral of acetic anhydride is left at room temperature for 2 hours and then triturated with ether and filtered. The insoluble material is recrystallized from ethyl alcohol to give yellow crystals of 6-(m-acetamidophenyl)-1,2,4-triazolo[4,3^b]pyridazine, m.p. 248-250°C.

Example 28

Preparation of 6-(m-acetamidophenyl)-3-ethyl-1,2,4-triazolo[4,3-b]-pyridazine

The above compound 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-raethyl-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 ral of hydrazine hydrate are dissolved in 140 ml of absolute ethyl alcohol. The clear solution is stirred under reflux for 4 hours and cooled overnight. The product is collected, washed with ethyl alcohol and dried in vacuo to give 13.1 g of 6-(p-tert-butylphenyl)-4,5-dihydro-3(2H)pyridazinone as a white solid.

A portion of 8.00 g of the preceding material in 80 ml of glacial acetic acid is stirred while initiating the dropwise addition of 5.82 g of bromine in 20 ml of glacial acetic acid. The reaction mixture is heated to approx. 100°C and decolorization takes place. Brora/acetic acid solution is added as quickly as decolorization takes place and is complete after approx. 15 minutes. The mixture is stirred for one hour at 100°C and is then poured onto 150 ml of ice. The white solid formed is collected by filtration and then dissolved in 400 ml of acetone. The acetone solution is dried over magnesium sulfate and concentrated while diluting with hexane. Crystallization from approx. 100 ml of acetone/hexane gives 4.82 g of 6-(p-tert-butyl-phenyl)-3(2H)pyridazinone as a pale yellow solid.

A mixture of 22.8 g of the above compound (prepared as described) and 115 ml of phosphorus oxychloride is heated on a steam bath until a clear solution is formed. This solution is heated for 5 hours and then concentrated in vacuo. The residue is treated with ice water and the resulting solid is collected and dried in vacuo to give 22.0 g of 3-(p-tert-butylphenyl)-6-chloropyridazine as an off-white solid.

A mixture of 5.0 g of 3-(p-tert-butylphenyl)-6-chloro-pyridazine, 3.13 g of acetylhydrazine and 50 ml of n-butanol is refluxed for 48 hours. The mixture is concentrated under vacuum and the residue is stirred with 100 ml of water and 100 ral of ether. The mixture is filtered to give 3.0 g of light brown solid, m.p. 144-146°C. Recrystallization from acetone/hexane gives the product as pale yellow crystals, m.p. 142-145°C.

Example 30

Preparation of 6-(p-tert-butylphenyl)-1,2,4-triazolo[4,3-bl-pvridazine

A mixture of 5.0 g of 3-(p-tert-butylphenyl)-6-chloro-pyridazine, 2.54 g of formylhydrazine and 50 ml of n-butyl alcohol is stirred under reflux for 48 hours. The mixture is cooled and filtered. The solid is washed with petroleum ether and water and dried in vacuo to give 0.80 g of the product. The filtrate is concentrated in vacuo below 80°C to give further product, which is stirred with 150 mL of water and 150 mL of diethyl ether, collected by filtration and dried in vacuo to give 3.0 g of an orange colored substance. Recrystallization from ethyl alcohol gives the example product as crystals with second-class white color, m.p. 270r275°C.

Example 31

Production of 50 mg tablets

The 3-methyl-6-(m-acetaraidophenyl)-1,2,4-triazolo[4,3-b]pyridazine, the lactose and the corn starch (for mixing) are mixed together. The cornstarch (for paste) is suspended in 600 ml of water°9 heated with stirring to form a paste. This paste is then used to granulate the mixed powders. If necessary, additional water is used. The wet granules are passed through a hand sieve No. 8 and dried at 49°C. The dry granules are then passed through a sifter. 16. The mixture is smeared with 1% magnesium stearate and compressed into tablets in a suitable

tablet forming machine.

Example 32

Preparation of oral suspension

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, flavoring and coloring are added and dissolved. The volume is adjusted to 100 ml with distilled water. Each ml of syrup contains 5 mg of 3-ethyl-6-(p-carbamoylphenyl)-1,2,4-triazolo(4,3-b]pyridazine.

Example 33

Preparation of parenteral solution

In a solution containing 700 ral of propylene glycol and 200 ral of water for injection, 20.0 g of 3,7-diraethyl-6-(p-amino-phenyl)-1,2,4-triazolo[4,3-b ]pyridazine monohydrochloride with stirring. After the 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 composition is sterilized, refilled

5.0 ml ampoules each containing 2.0 ml (representing 40 mg, with drug) and sealed under nitrogen.

Example 34

Preparation of 6-(p-chlorophenyl)-3,8-dimethyl-1,2,4-triazolo[413-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 is dissolved in d&chloromethane and filtered through magnesol. The solid from the filtrate is recrystallized from dichloromethane-hexane to give 0.6 g of solid, m.p. 209-212°C. Recrystallization from dichloroethane-hexane gives the example product as pink crystals, m.p. 215-217°C.

Example 35

First Ilation of 6- ( a , a, a-trifluoro-p-tolyl) - 1, 2 , 4- triazolo [ 4, 3»- b ] -

pyridazine

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 after the surrounding . temperature is reached, 65.0 g of p-trifluoromethylbenzaldehyde are added, followed by heating at reflux temperature for 2 hours. The reaction mixture is cooled in an ice bath and a solution of 32.6 g of potassium cyanide in 55 ml of water is 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 solutions, dried and evaporated to

give of-(α,α,α-trifluoro-p-tolyl)-4-morpholine acetonitrile as a light brown solid, m.p. 89-90°C.

A solution of 52.3 g of ot-(α,α,α-trifluoro-p-tolyl)-4-morpholineacetonitrile 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 are added every half hour until a total of 5 ml of the base and 150 ml of ethyl acrylate have been added. After the addition, the mixture is stirred at ambient temperature for 48 hours. After filtration, the filtrate is concentrated, dissolved in methylene chloride, passed through magnesol and recrystallized from ethylene chloride/hexane to give ethyl γ-cyano-γ(α,α,α-trifluoro-p-tolyl)-4-morpholine-butyrate as cream colored krsytåiler, sm.p. 96-97°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 is concentrated. The residue is crystallized from methylene chloride/hexane to give 6-(α,α>of-trifluoro-p-tolyl)-4,5-dihydro-3(2H)pyridazinone as cream crystals, m.p.

177-178°C. ,

A solution of 14.5 g of the preceding compound and 10.4 g of bromine in 150 ml of acetic acid is slowly heated on a steam bath until complete decolorization takes place. Heating continues for a further 30 minutes, followed by pouring onto crushed ice. The resulting solid is filtered and washed with v-Ar:water to give 6-(c^a.o^trifluoro-p-tolyl)-3(2H)pyridazinone as off-white crystals, m.p. 191-193°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 until free of solvent and the residue is washed with cold water to give 3-chloro-6-(a.a.a-trifluoro-p-tolylDpyridazine) as a white solid, mp 186-188°C.

A mixture of 4.50 g of 3-chloro-6-(α,α,α-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 is dissolved in methylene chloride, passed through magnesol

and the solid from the filtrate is recrystallized from methylene/clofide/hexane to give the product as white crystals, m.p. 160-161°C.

Example 36 -. Preparation of 3- metvl-. 6-(a,a,oi-trifluoro-p-tolvl)-l,2,4-tfiazolo-[4,3-b]pyridazine

A mixture of 4.50 g of 3-chloro-6-(of,α,Qf-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 residue is dissolved in methylene chloride, passed through magnesol and the solid from the filtrate is recrystallized from methylene chloride/hexane to give the product as light brown crystals, m.p. 199-201°C.

Example 37

Preparation of ot-(m-chlorophenyl)-4-morpholine acetonitrile

To a cold solution of 76 g with p-toluenesulfonic acid i.

87 g of morpholine and 50.6 g of ra-chlorobenzaldehyde are added to 500 ml of tetrahydrofuran. The mixture is refluxed for 2 1/2 hours and 100 ml of tetrahydrofuran is distilled off and 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 hours and concentrated to dryness under vacuum. The residue is dissolved in methylene chloride and the solution is washed with water, sodium bisulphite solution, saturated NaCl solution and is dried (Na 2 SO 4 ). The solution is passed through a short column of hydrous magnesium silicate. The eluent is refluxed while hexane is added until crystals separate. Cooling and filtration gives 78.0 g of crystals, m.p. 72-73°C.

Example 38

Preparation of 3-(m-chlorobenzoyl)propionitrile

120 drops of a 30% solution of KOH in methanol are added to a solution of 23.6 g of o-(m-chlorophenyl)-4-morpholineacetofcinitrile in 100 ml of tetrahydrofuran. 4.1 ml of acrylonitrile is added to the mixture (the temperature rises to 45°C). After stirring for 1 hour, 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 hour. The solvent is removed under vacuum and the residue is treated with water. The mixture is filtered to give 18.8 g of crystals, m.p. 49-51°C.

Example 39

3-(m-Chlorobenzoyl)-2-methylpropionitrile

60 drops of a 30% solution of KOH in methanol are added to a solution of 11.8 g of α-(m-chlorophenyl)-4-morpholine acetonitrile in 50 nil of tetrahydrofuran. For the solution it is set

4.62 ml of methacrylonitrile (temperature rises to 42°C). After stirring for 1 hour, the mixture is concentrated to dryness and the residue is dissolved in methylene chloride. The solution is passed through a short column of hydrous magnesium silicate and the eluent is concentrated to give 15.5 g of a yellow oil. The oil is heated (steam bath) with a mixture of 75 ral of acetic acid and 5 ml of water for 1 hour, and the solvent is removed under vacuum. To-

addition of water to the residue gives 11.2 g of crystals, m.p. 72-75°C. Recrystallization from ethylene chloride-hexane gives 8.95 g of crystals, m.p. 79.5-80.5°C.

Example 40

Preparation of 3-(r-chlorobenzoyl)-2-rethylpropionic acid A mixture of 7.90 g of 3-(m-chlorobenzoyl)-2-methyl-propionitrile and 75 ml of concentrated hydrochloric acid is refluxed for 1 hour. Cooling gives 8.5 g of crystals, m.p. 102-105°C. The crystals are dissolved in 50 ml of 1N NaOH, the mixture is filtered and the filtrate is acidified with 1N HCl. Filtration yields 8.15 g of crystals, m.p. 103-105°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-ethylpropionic acid, 50 ml of ethanol and 3.0 ml of hydrazine hydrate is refluxed for 2 hours. Cooling and filtration give crystals (m.p. 150-151<W>C) which are recrystallized from ethanol to give 5.72 g of crystals, m.p. 152-153°C.

Example 42

Preparation of 3-(m-chlorobenzoyl)propionic acid

A mixture of 8.1 g with 3-(m-chlorobenzoyl)propionitrile

and 80 ml conc. HCl is refluxed for 7 hours. Cooling gives an oil which crystallizes to give 8.8 g of crystals, m.p. 105-107°C. The crystals are dissolved in UH NaOH and the mixture is filtered. The filtrate is acidified with IN HCl to

give 8.7 g of crystals, m.p. 103-105°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 quarter portion of a solution of 4.01 g of bromine in 5 ral of acetic acid is added. After the bromine color has disappeared, the rest of the bromine solution is gradually added. The mixture is heated (steam bath) for 1/2 hour and poured onto ice. Filtering

<s?.ir crystals (m.p. 243.5-245°C) which are recrystallized from ethanol to give 4.0 g of crystals, m.p. 244-245°C.

Example 44 Preparation of 6-(m-chlorophenyl)f4,5-dihydro-2(2H)pyridazinone A mixture of 7.70 g with 3-(m-chlorobenzoyl)-propionic acid, 50 ml of ethanol and 3.0 ml of hydrazine hydrate is reflux treated

for 2 hours. The mixture is cooled, filtered, and the crystals (6.2 g, m.p. 146-147°C) are recrystallized from ethanol to

give 5.50 g of crystals, m.p. 150-151°C.

v Example 45

Preparation of 6-(m-chlorophenyl)-3(2H)pyridazinone A mixture of 4.45 g of 6-(m-chlorophenyl)-4,5-dihydro-3-(2H)-pyridazinone and 50 ml of glacial acetic acid is heated in a steam bath. A quarter portion of a solution of 4.01 g of bromine in 15 ml of glacial acetic acid is added. When the bromine color has disappeared, the remainder of the bromine solution is added. The mixture is heated on a steam bath for another 1/2 hour and the mixture is poured onto ice. The mixture is filtered to give 3.30 g of crystals, m.p. 214-216°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 hours. The mixture is concentrated to dryness under vacuum and water is added to the residue. Filtration yields 3.28 g of crystals, m.p. 138-140°C. Recrystallization from ethanol yields 2.80 g of crystals, m.p. 138-141°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)pyridazinone is refluxed for 6 hours. The mixture is concentrated under vacuum and water is added to the residue. Filtration yields 3.30 g of crystals, m.p. 155-157°C. Recrystallization from ethanol gives 2.75 g of crystals, mp 157-158°C.

Example 48 Preparation of 6-(m-chlorophenyl)-8-methyl-1,2,4-triazolo[4,3-b]-pyridazine A mixture of 2.0 g with 3-chloro-6-(m-chlorophenyl) )-4-methyl-pyridazine, 50 ml of n-butanol and 1.08 g of formylhydrazine are refluxed for 18 hours. The mixture is concentrated to dryness under vacuum and the residue is 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 separate. Cooling and filtration gives 1.20 g of crystals, m.p. 173-176°C. The crystals in methylene chloride are passed through a short column of hydrous magnesium silicate and the eluent is concentrated with the addition of hexane to give 0.83 g of crystals, m.p. 181-182°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 ral of n-butanol and 1.32 g of acetylhydrazine is refluxed for 18 hours. The mixture is concentrated to dryness under vacuum and the residue is dissolved in methylene chloride. The solution is passed through a short column of hydrous magnesium silicate. The eluent is refluxed while gradually adding hexane until crystals separate. Cooling and filtration give 1.50 g of crystals, m.p. 171-172.5°C.

Example 50

Preparation of 6-(ra-chlorophenyl)-3,8-diiraethyl-1,2,4-triazolo[4,3-b]-pyridazine A mixture of 7.17 g of 3-chloro-6-(m-chlorophenyl) )-4-ethylpyridazine, 100 ml of n-butanol and 6.96 g of acetylhydrazine are refluxed overnight. The mixture is cooled and filtered to give a solid. The solid is dissolved in methylene chloride and the solution is passed through a short column of hydrous igneous silicate. The eluent is refluxed while gradually adding hexane until crystals separate. Cooling and filtration gives 3.30 g of crystals, m.p. 193.5-195.<5>°C.

Example 51 Preparation of 3-(m-chlorophenyl)-6-hydrazinopyridine

A mixture of 6.85 g of 3-chloro-6-(m-chlorophenyl)-pyridazine, 100 ral 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 minimal amount of hot nitromethane. Cooling gives 3.5 g of an amorphous £'« solid.

Example 52

Preparation of 6-(o-fluorophenyl)-1,2,4-triazolb[4,3-b]pyridazine

As in Example 35, the following reactions are carried out, o-fluorobenzaldehyde is reacted with p-toluenesulfonic acid, morpholine and KCN to give o-(o-fluorophenyl)-4-morpholine acetonitrile as a yellow oil. The product γ-(o-fluorophenyl)-4-morpholine acetonitrile is reacted with ethyl acrylate to give ethyl γ-cyano-γ-(o-fluorophenyl)-4-morpholine butyrate as an oil. A solution of the pre-

title compound and hydrazine hydrate in ethanol are refluxed to give 6-(o-fluorophenyl)-4,5-dihydro-3(2H)-pyridazinone as crystals, m.p. 119-121°C. The preceding compound is heated with bromine in acetic acid to give 6-(o-fluorophenyl)-3(2H)pyridazinone as crystals (from CH 2 Cl 2 -hexane), m.p. 173-175°C.

A mixture of the preceding compound and phosphorus oxychloride is refluxed on a steam bath to give 3-chloro-6-(o-fluorophenyl)pyridazine as crystals, m.p. 95-96°C.

A mixture of 5.0 g with 3-chloro-6-(o-fluorophenyl)pyridazine

and 2.88 g of formylhydrazine in 75 ml of n-butanol are refluxed

traded for 48 hours and is processed as in example 35 in order to

give 1.1 g of the product as cream-colored crystals, m.p. 161-163°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 hours to give 2.0 g of product as crystals of second-class white color, m.p. 147-149°C.

Example 54

Preparation of 6-(m-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine

As in example 35, the following turnovers are carried out. m-Fluorobenzaldehyde is reacted with p-toluenesulfonic acid, morpholine and KCN to give a-(ra-fluorophenyl)-4-morpholineacetonitrile as crystals (from<CH>jClj-hexane), m.p. 74-75°C.

The preceding compound is reacted with ethyl acrylate

to give ethyl γ-cyano-γ-(m-fluorophenyl)-4-morpholinebutyrate as crystals (from CH2Cl2-hexane), m.p. 88-90°C.

A solution of the preceding compound and hydrazine hydrate in ethanol is refluxed to give 6-(m-fluorophenyl)-4,5-dihydro-3-(2H)pyridazinone as crystals (from CH 2 Cl 1 -hexane), m.p. 132-134°C.

The preceding compound is heated with bromine in acetic acid to give 6-(m-fluorophenyl)-3(2H)pyridazinone as crystals (from C<H>2Cl2-hexane), m.p. 207-209°C.

A mixture of the preceding compound and phosphorus oxychloride is refluxed to give 3-chloro-6-(ra-fluorophenyl)-pyridazine as crystals, m.p. 133-135°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 hours and worked up as in Example 35 to give the product as crystals, m.p. 159-161°C.

Example 55

Preparation of 3-methyl-6-(m-fluorophenyl)-1,2,4-triazolo[4,3-blpyridazine

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 for 48 hours to give 2.0 g of the product as crystals, m.p. 184-186°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 α-(p-chlorophenyl)-4-morpholineacetonitrile as crystals (from CH2Cl2-hexane), m.p. . 40-42°C.

The preceding compound is reacted with ethyl acrylate

to give ethyl γ-cyano-Y-(o-chlorophenyl)-4-morpholine butyrate 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. 114-116°C.

The preceding compound is heated with bromine in acetic acid to give 6-(o-chlorophenyl)-3(2H)-pyridazinone as crystals, m.p. 214-216°C.

A mixture of the preceding compound and phosphorus oxychloride is refluxed to give 3-chloro-6-(o-chlorophenyl)-pyridazine as crystals, m.p. 145-147°C.

A mixture of 5.67 g of 3-chloro-6-(o-chlorophenyl)-pyridazine and 3.03 g of formylhydrazine in 50 ml of butanol is refluxed for 48 hours to give 2.3 g of product as pale yellow crystals , sm.p. 156-158°C.

Example 57

Preparation of 3T-methyl-6-(o-chlorophenyl)-1,2,4-triazolo[4,3-bl-pvridazine

As in Example 36, a mixture of 5.5 g of 3-chloro-6-(o-chlorophenyl)pyridazine and 3.6 g of acetylhydrazine in 75 ml of n-butanol is refluxed for 72 hours to give 2.2 g of product as crystals of second-class white color, m.p. 146-148°C.

Example 58 Preparation of 4-methyl-6-(a,Qt,at-trifluoro-ratoyl)-4>5-dihydro-3(2H)pyridazinone

5 ml of a solution of 30% potassium hydroxide in methanol. 22.0 ml of methacrylonitrile is added to the mixture and the mixture is stirred overnight. 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 a yellow oil which is crystallized

from ether-hexane to give 47 g of cream-colored crystals, m.p. 88-90°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 hours. The solvent is removed to give an oil. A mixture of the oil in 500 ml of 6N HCl is refluxed for 24 hours. The mixture is cooled and extracted with chloroform. The chloroform layer is washed with water and saturated NaCl solution

and is passed through a column of hydrous magnesium silicate. The solvent is removed from the eluent and the residue is crystallized from ether-hexane to give 29.4 g of 2-methyl-3-(m-trifluoromethylbenzoyl)propionic acid as pink crystals, m.p. 90-93°C.

A mixture of the preceding compound (25.4 g) and

5.0 ml of hydrazine hydrate in 200 ral of ethanol is refluxed for 18 hours. The mixture is cooled and filtered to give 21.8 g of product as cream-colored crystals, m.p. 188-190°C. A sample is recrystallized from CHClj-hexane to give off-white crystals, m.p. 191-193°C.

Example 59

Preparation of 8-methyl-6-(a,g,a-trifluoro-m-tolyl)-1,2,4-triazolo-[4,3-b]pyridazine

To a solution of 4-methyl-6-(α,α,Qf-trifluoro-m-tolyi)-4,5-dihydro-3(2H)pyridazinone (20.5 g) in 200 ml of acetic acid, por 8 ions vi 8 put 14.4 bromine in 25 ml of acetic acid.. The mixture is heated for 1/2 hour and the solvent is removed under vacuum. To the residue is added ice and water and the mixture is filtered to give 20.4 g of 8-raet<y>1 -6-(α,α,α-trifluoro-m-tol<y>1)-3( 2H)-pyridazinone as cream-colored crystals, m.p. 234-237°C.

The preceding compound (19.4 g) and 200 ml of phosphorus oxychloride are heated on a steam bath for 18 hours. The mixture is concentrated to dryness under vacuum and ice and water are added to the residue. The mixture is filtered and the solid is recrystallized from CHClj-hexane to give 18.0 g of 3-chloro-4-methyl-6-(α,α,α-trifluoro-m-tolyl)pyridazine as cream-colored crystals, m.p. .p. 123-126°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 hours and concentrated to dryness under vacuum. The residue in CHCl3 is passed through a column of hydrous magnesium silicate, the eluent is concentrated and the residue is crystallized from CH2Cl3-hexane to give the product as crystals, m.p. 181-183C.

Example 60 Preparation of 3,8-dimethyl-6-(a,at,a-trifluoro-m-tolyl)-!,2,4-triazolo[4,3-b]pyridazine As in example 36, a mixture of 8 .0 g of 3-chloro-4-methyl-6-(α,o?,Q!-trifluoro-m-tolyl)pyridazine and .4.34 g of acetylhydrazine in 125 ml of n-butanol refluxed for 48 hours to give 3.9 g of product as crystals, m.p. 196-198°C.

Example 61 Preparation of 7-methyl 1-6- (a . a; ot-trifluoro-m-tolyl)-1, 2 , 4- triazolo-[ 4, 3- b] pyridazine To a solution of ot^ (a ,a,o-trifluoro-rar-tolyl)-4-morpholineacetonitrile in 100 ml of tetrahydrofuran, 1.0 ml of a 30% KOH-ethanol solution is added. 2.56 g of crotononitrile are added to the mixture and the mixture is stirred at room temperature for 18 hours. 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 CHCl₂-hexane to give 3-α-ethyl-2-arorfolino-2-(α,α,α-trifluoro-ra-tolyl) glutaronitrile as crystals, m.p. 115-118°C.

A mixture of the preceding compound (39 g) in 500 ml of 75% acetic acid is refluxed for 48 hours and the solvent is removed under vacuum. The residue is dissolved in CHjClj and the solution is washed with water, saturated sodium bicarbonate and saturated NaCl solution. The organic layer is dried (MgSO 4 ) and passed through a column of hydrous magnesium silicate. The eluent is concentrated to give 27.4 g of 3-(m-trifluoroethylbenzoyDbutyronitrile) as a yellow oil.

A mixture of the preceding compound (26.4 g) and

500 ml of 6N HCl is refluxed for 18 hours. The mixture is cooled and extracted with dichloromethane. The organic layer is extracted with saturated NaHCO 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 4 ) and concentrated to give 24.2 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 hours and the solvent is removed under vacuum. The residue is dissolved in dichloromethane and the solution is passed through a column of hydrous magnesium silicate. The eluent is concentrated to give 20.7 g of 5-methyl-6-(α,α,α-trifluoro-m-tolyl)-4,5-dihydro-3(2H)pyridazinone as white crystals, m.p. 132-134°C. Recrystallization from CH2Cl2-hexane gives white crystals, m.p. 142-144°C.

The preceding compound is heated with bromine in acetic acid to give 5-methyl-6-(α,α,α-trifluoro-m-tolyl)-3(2H)pyridazinone as white crystals, m.p. 224-227°C.

Example 62

Preparation of 3,7-dimethyl-6-(a,a,a-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-(α,α,α-trifluoro-m-tolyl)pyridazine and 4.34 g of acetylhydrazine in 125 ml of n-butanol is refluxed for 48 hours to give 6.2 g of cream-colored crystals, m.p. 185-187°C.

Example 63

Preparation of 6-(m-tolyl)-1,2,4-triazolo[4,3-b]pyridazine

As in example 35, the following turnovers are carried out. m-tolualdehyde is reacted with p-toluenesulfonic acid, morpholine and KCN to give of-(m-tolyl)-4-morpholine-acetonitrile as crystals, m.p. 59-60°C.

The preceding compound is reacted with ethyl acrylate to give ethyl-γ-cyanor-γ-(m-tolyl)-4-morpholine butyrate 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, m.p. 130-132°C.

The preceding compound is heated with bromine in acetic acid to give 6-(m-tolyl)-3(2H)pyridazinone as white crystals, m.p. 202-205°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. 112-113°C.

A mixture of 6.0 g of 3-chloro-6-j(m-tolyl)pyridazine and 3.52 g of formylhydrazine in 100 ml of n-butanol is refluxed for 48 hours and worked up as in Example 35 to give 2.0 g with white crystals (from CHClj-hexane), m.p. 164-166°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 ral of n-butanol is refluxed for 48 hours to give 2.0 g of cream colored

crystals, m.p. 160-162°C.

Example 65

Preparation of 3-propyl-6-(a,a,atrifluoro-p-tolyl)-1,2,4-triazolo-[4,3-b]pyridazine

A mixture of 5.0 g of 3-chloro-6-(α,α,α-trifluoro-p-tolylf-pyridazine, 3.94 g of butyric hydrazide and 100 ml of n-butanol is refluxed for 48 hours. The solvent becomes removed under vacuum and the residue dissolved in chloroform..The solution is passed through a column of hydrous magnesium silicate and the eluent is concentrated to give 3.2 g of product.Recrystallization from CHClg-hexane gives crystals, mp 173-175° C.

Example 66

Preparation of 3-ethyl-6-(a,a,a-trifluoro-m-tolyl)-1,2,4-triazolo-[4,3-b]pyridazine A mixture of 5.0 g with 3-chloro- 6-(α,α,α-trifluoro-m-tolyl)pyridazine, 3.40 g of propionic hydrazide and 100 ml of n-butanol are refluxed for 48 hours. The solvent is removed under vacuum and the residue is dissolved in chloroform. The solution is passed through a column of hydrous magnesium silicate and the eluent is concentrated to give 3.0 g of crystals (from CHCl 2 -hexane), mp 183-185°C.

Example 67

Preparation of 3-ethyl1-6-(a,q,a-trifluoro-p-tolyl)-1,2,4-triazolo-[4,3-b]pyridazine

As in Example 65, 5.0 g of 3-chloro-6-(α,α,α-trifluoro-p-tolyl)pyridazine and 3.40 g of propionic hydrazide in 100 mL of butanol are refluxed for 48 h to give 3 .1 g of white crystals (from CHClj-hexane), m.p. 194-196°C.

Example 68

Preparation of 6-(4-chloro-a,a,a-trifluoro-m-tolyl)-1,2,4-triazolo-[4,3-b]pyridazine

According to the method in "Organic Synthesés", 5-amino-2-chlorobenzotrifluridide is converted into 4-chloro-3-(trifluoromethyl)benzaldehyde. As in example 35, the following turnovers 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 were reacted

to give α-[4-chloro-3-(trifluoromethyl)phenyl]-4-morpholine acetonitrile as white crystals, m.p. 73-74°C This compound (14.0 g) is reacted with ethyl acrylate to give ethyl γ-cyano-γ-[4-chloro-3-(trifluoromethyl)phenyl]-4-morpholine butyrate as a yellow oil (16, 5 g). This compound (16.5 g) is reacted with 2.11 g of hydrazine in 100

ral ethanol to give 6-[4-chloro-3-(trifluoromethyl)phenyl]-4,5-dihydro-3(2H)-pyridazinone (4.2 g) as white crystals, m.p. 195-198°C. This intermediate is heated with bromine in acetic acid to give 6-[4-chloro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone as white crystals, m.p. 249-251°C. A mixture of this compound (5 g) and 60 ml of phosphorus oxychloride is refluxed for 18 hours to give 3-chloro-6-[4-chloro-3-(trifluoromethyl)phenylpyridazine as cream crystals, m.p. 145-147°C. A mixture of

2.2 g of the preceding compound, 0>9 g of formylhydrazine and 50 ml of n-butanol are refluxed for 48 hours to give 2.1 g of

product, sm.p. 211-214°C. Recrystallization from n-propanol gives cream-coloured crystals, m.p. 217-218°C.

Example 69

Preparation of 3-methyl-6-(4-chloro-a,a,a-trifluoro-m-tolyl)-1,2,4-triazolo[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 refluxed for 48 hours to give the product as crystals, m.p. 267-269°C.

Example 70 Preparation of 6-(3,4-dichlorophenyl)-1,2,4-triazolo[4,3-b]pyridazine

As in example 35, the following turnovers are carried out. 3,4-Dichlorobenzaldehyde (106.3 g) is reacted with 124 g of p-toluenesulfonic acid, 122 g of morpholine and 45 g of potassium cyanide in 500 ml of tetrahydrofuran to give 136.9 g of α-(3,4-dichlorophenyl) -4-morpholine acetonitrile as cream-coloured crystals, m.p. 69-71°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 light brown oil. This oil (132.6 g) and 36 ml of hydrazine hydrate in 500 ml of ethanol are refluxed to give 63.5 g of 6-(3,4-dichlorophenyl)-4,5-dihydro-3(2H)-pyridazinone as yellow crystals, m.p. 168-182°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 are heated on a steam bath overnight to give 26.4 g of 6-(3,4- dichlorophenyl)-3(2H)-pyridazinone as light brown crystals, m.p. 215-218°C. The preceding compound (10 g) and 100 ml of phosphorus oxychloride are 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. 188-189°C.

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 hours to give the example product, sm .p. 267-269°C.

Example 72

Preparation of 50 rag'a tablets

The 3,7,8-triethyl-6-phenyl 1-1,2,4-:triazolo[4,3-b]pyridazine, the lactose and the corn starch (for mixing) are mixed together. The cornstarch (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 moist granules are passed through a No. 8 hand sieve and dried at 49°C. The dry granules are then passed through a No. 16 sieve. The mixture is smeared with 1% magnesium stearate and compressed into tablets in a suitable tablet forming machine.

Example 73

Preparation of oral suspension

The sorbitol solution is added to 40 ml of distilled water and the 3,8-di-n-butyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine is suspended therein. The saccharin, sodium benzoate, flavoring and coloring are added and dissolved. The volume is adjusted to 100 ml with distilled water. Each ml of syrup contains 5 mg of 3,8-di-n-buty1-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine.

Example 74

Preparation of parenteral solution

In a solution of 700 ml of propylene glycol and 200 ml of water for injection, 20.0 g of 7,8-di-n-propyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine monohydrochloride are suspended while stirring. After the 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 composition is sterilized, filled into 5.0 ml ampoules each containing 2.0 ral (representing 40 mg of drug) and sealed under nitrogen.

Example 75

Preparation of 3, 7, 8-triraethyl-6-phenyl-1,2,4-triazolo[4,3-b1-pyridazine A portion of 200 g with 3-benzoyl-2,3-dimethyl-propionic acid and 60 g of hydrazine hydrate is added to one liter of ethyl alcohol and stirred at reflux for 18 hours. as a cream-colored solid. This product is partially dissolved in 600 ml of glacial acetic acid. In addition, a solution of 50 ral of bromine in 100 ral of glacial acetic acid is added portionwise while heating on a steam bath (approximately 15% of bromine solution is added to the reaction mixture before heating begins and approximately 1 hour is required to complete the addition, and during this time hydrogen bromide gas is released). After the addition is complete, the reaction mixture is heated on a steam bath for one hour and then the mixture is poured onto crushed ice. The resulting solid is filtered in vacuo, washed with plenty of water and air-dried to give 4,5-diraethyl-6-phenyl-3(2H)pyridazinone as a cream solid. This material is added to 800 ml

phosphorus oxychloride and is heated on a steam bath for 5 hours.

The reaction mixture is concentrated to remove excess phosphorus oxychloride and is then diluted with cold water. The resulting solid is filtered in vacuo, washed abundantly

with water and air-dried to give 3-chloro-4,5-dimethyl-6-phenyl-pyridazine as a pale pink solid. A portion of 10 g of this product plus 8 g of N-acetylhydrazine and 100 ml of n-butyl alcohol is set aside to stir under reflux for 48 hours. The reaction mixture is cooled in an ice bath and the resulting solid is filtered in vacuo, washed first with petroleum ether and then with

water and is air-dried. The solid is recrystallized from ethyl alcohol after treatment with activated charcoal and is dried in vacuo to give 3,7,8-trimethyl-6-phenyl-1,2,4-triazolo-(4,3-b1pyridazine) as a white solid.

Example 76 Preparation of 7-methyl-6-phenyl-1,2,4-triazol6[4,3-b]pyridazine Eh portion of 10 g with 6-(p-bromophenyl)-5-raethyl-3(2H)- pyridazinone (J. Medicinal Chem., 17, 281 (1974)] and 100 ml of phosphorus oxychloride are heated at steam bath temperature for 3 hours. The mixture is added dropwise to cold water with stirring. The resulting solid is filtered and washed with water to give 3-(p-bromophenyl)-6-chloro-4-methyl-pyridazine as a gray

solid. A mixture of 1.5 g of this compound, 0.64 g of formylhydrazine and 25 ml of n-butyl alcohol is stirred under reflux for 18 hours. The reaction mixture is cooled in an ice bath, filtered, and the solid recrystallized from methyl alcohol to give 6-(p-bromophenyl)-7-methyl-1,2,4-triazolo[4,3-b]-pyridazine .

A mixture of 10 g of the above material, 30 ml of araranium hydroxide', 250 ml of ethyl alcohol and a catalytic amount

with 10% palladium on charcoal is shaken in a Parr shaker for 18 hours. The absorption of 15.9 kg of hydrogen is completed within 2 hours. The reaction mixture is then filtered to remove the catalyst and the filtrate is concentrated to a white solid which is triturated with petroleum ether. The solid is collected by filtration, air-dried and recrystallized

from methanol-ethyl acetate to give 7-methyl-6-phenyl-1,2,4-triazolo-[4,3-b]pyridazine as white crystals, m.p. 188-190°C.

Example 77

Preparation of 3-methyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine The title compound is prepared by the method of Duffin et al, as set forth in British Patent No. 839,020, issued June 29, 1960.

Example 78 Preparation of 3,8-dimethyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine The title compound is prepared by the method of Leelerc&Wermuth as stated in Bull. Soc. Chim. France, No. 5, 1752 (1971).

Example 79 Preparation of 7-isopropyl-6-phenyl-1,2,4-triazolo[4,3-b]pyridazine

The procedure from Example 4 is repeated using equimolar amounts of 3-benzoyl-3-isopropylpropionic acid and N-formylhydrazine instead of the 3-benzoyl-2,3-dimethylpropionic acid and N-acetylnydrazine used in that example. In this way

is obtained title-connectIsen with equally good yield.

Example 80 Preparation of 8-isobutyl-6-phenyl-1,2,4-triazolo{4,3-b]pyridazine

By following the general procedure in Example 4, 3-benzoyl-2-isobutyl-propionic acid is converted to 3-chloro-4-isobutylpyridazine which is treated with N-formylhydrazine to give the title compound.

Example 81

Preparation of 3-ethyl1-7-methyl1-6-phenyl1-1,2,4-triazolo[4,3-b]-pyridazine

The general procedure from Example 4 is repeated, but the 3-benzoyl-2,3-diethylpropionic acid and N-acetylhydrazine used in that example are replaced with 3-benzoyl-3-raethylpropionic acid and N-propionylhydrazine.

Example 82

Preparation of 6-pheny1-1,2,4-triazolo[4,3-b]pyridazine

A portion of 10 g of 3-chloro-6-phenylpyridazine (Chem. Abs., 44, 56161), 6.6 g of formylhydrazine and 100 ml of n-butanol is refluxed for 48 hours. The reaction mixture is cooled in an ice bath. The resulting solid is filtered, washed with petroleum ether and water and is air dried to give 6-phenyl-1-1,2,4-triazolo[4,3-b]pyridazine as light brown crystals, m.p. 138-139°C.

Example 83

Preparation of 8-methyl-6-phenyl-1,2,4-triazolo[4,3-bIpyridazine

A mixture of 13.2 g of 4-methyl-6-phenyl-3(2H)pyridazinone and 200 ral of phosphorus oxychloride is heated on a steam bath for 18 hours. The reaction mixture is filtered. The filtrate is concentrated until it is free of excess phosphorus oxychloride. The residue is stirred with ice water and filtered. The solid is washed with water and air-dried to give 3-chloro-4-methyl-6-phenyl-pyridazine as a cream colored solid.

A mixture of 2.05 g of the above product, 1.2 g of formylhydrazine and 50 ml of n-butanol is stirred and refluxed for 48 hours. The reaction mixture is concentrated until it is free

for solvent and the residue is stirred with diethyl ether. The mixture is filtered to give a cream colored solid. This

solid is recrystallized from methanol after treatment with activated charcoal. The methanol filtrate is allowed to evaporate slowly at room temperature, and this results in the formation of white

needles together with a dark yellow oil. The oil is removed and the needles are washed with a small amount of diethyl ether which is decanted. The needles are then recrystallized from methanol-diethyl ether-petroleum ether. to give 8-raethyl-6-phenyl-1,2,4-triazolo(4,3-b]pyridazine as white crystals, m.p. 150-151°C.

Example 84

Preparation of 3-n-propy1-6-pheny1-1,2,4-triazolo[4,3-b]pyridazine

A mixture of 10 g of 3-chloro-6-phenylpyridazine, 11.2 g of butyric hydrazide and 100 ml of n-butanol is heated under reflux for 40 hours. The solution is cooled and the precipitate is filtered and washed with petroleum ether and water. The filtrate is concentrated to an oil in which a precipitate is formed by the addition of petroleum ether. The precipitate is collected and washed with petroleum ether and water. The solids are combined and recrystallized from 30 mL of ethanol to give 3-n-propyl-6-phenyl-1,2,4-triazolo[4,3-b]-pyridazine as crystals, m.p. 123-125°C.

Example 85

Preparation of 3-ethyl1-6-phenyl-1,2,4-triazolo[4,3-blpyridazine A mixture of 7.6 g of 3-chloro-6-phenylpyridazine, 7.4 g of propionic acid hydrazide and 60 ml of n- butanol is stirred at reflux temperature for 48 hours. The solution is cooled in a cold room, concentrated to remove the solvent and triturated with water to give crystals. The mixture is filtered, washed with petroleum ether and water and dried. The product is recrystallized from 20 ml of ethanol to give 3-ethyl-6-phenyl-1,2,4-triazol-14,3-b]pyridazine, m.p. 133-135°C.

A mixture of the preceding compound and formylhydrazine in n-butanol is refluxed for 24 hours to give 6-(3,4-dichlorophenyl)-1,2,4-triazolo[4,3-b]pyridazine.

Example 86

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 hydrazide is heated in 50 ml of n-butanol for 24 hours to give the example product.

Example 87

Preparation of 6-[2-chloro-5-(trifluoromethyl)phenyl]triazolo[4,3-b]-pyridazine 3

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 example product.

Example 88 Preparation of 3-methyl-[2-chloro-5-(trifluoromethyl)phenyl]1,2,4-triazolo(4,3-b]pyridazine

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 sample product.

Example 89

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 minutes. The mixture is poured onto crushed ice, filtered and the solid is washed with water. The yellow solid (2.2 g) is dissolved in 20 ml of 5N NaOH. The mixture is quenched (ice bath) and filtered. The solid is dissolved in water and the solution is acidified with hydrochloric acid. The solid is filtered and washed with water to give 1.0 g of cream-colored crystals, m.p. 235-238°C. Recrystallization from dimethylformamide-water gives the product as crystals, m.p. 238-241°c.

Example 90

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 is added to the residue* Filtration gives 7.2 g of 3-chloro-6-[4-nitro-3-(trifluoromethyl)phenyl]pyridazine as light brown crystals, snwp. 129-135°C. Recrystallization from dichloromethane-hexane gives cream-coloured crystals, m.p. 151-155°C. The preceding compound is reacted with formylhydrazine in n-butanol under reflux for 24 hours to give the example product.

Example 91 Preparation of 3-methyl-6-[4-nitro-3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine

A mixture of 4.0 g of 3-chloro-6-[4-nitro-3-(trifluoromethyl)-in one 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. 293-295°C.

Example 92

Preparation of 6-[4-fluoro-3-(trifluoromethyl),phenyl1-1,2,4-triazolo-[4,3-b]pyridazine A mixture of 10 g of 6-[4-nitro-3-(trifluoromethyl) phenyl]-3(2H)pyridazinone in 50 ral trifluoroacetic acid is reduced by

hydrogen and palladium on carbon to give 6-{4-amino-3-(trifluoromethyl)phenyl]1-3(2H)pyridazinone. The preceding compound is converted to 6-[4-fluoro-3-(trifluoromethyl)phenyl]-3(2H)pyridazinone by the method 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 sample product.

Example 93 Preparation of 3-raethyl-[4-fluoro-3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine

As described in Example 36, 3-chloro-6-[4-fluoro-3-(trifluoromethyl)phenyl]pyridazine is reacted with acetic hydrazide in n-butanol to give the example product.

Example 94 Preparation of 3-methyl-[4-chloro-3-(trifluoromethyl)phenyl]-1.2,4-triazolo[4,3-b]pyridazine

In accordance with the procedure in J. Org. Chem., 25, 468

(1961) becomes 6-[4-amino-3-(trifluoromethyl)phenyl]-3(2H)pyridazinone

converted to 6-[3-chloro-5-(trifluoromethyl)phenyl]-3(2H)pyridazinone. The preceding compound is reacted with phosphorus oxychloride for

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. 267-269°C. - Example 95 Preparation of 3-methyl-6-[4-amino-3-(trifluoromethyl)phenyl]-1,2,4- •

triazolo[4,3-b]pyridazine A mixture of 5 g of 3-methyl-6-[3-trifluoro-5-trifluoromethyl)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 75 ml of trifluoroacetic acid is reduced with hydrogen and palladium-on-carbon catalyst to form the example product. Recrystallization from methanol

gives cream-colored crystals, m.p. 240-242°C.

Example 96

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-methyl-benz- aldehyde reacted with morpholine and potassium cyanide to give γ-(2-chloro-5-methylphenyl)-4-morpholine acetonitrile. In a similar way 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 n-butanol under reflux for 24 hours to give Example - the product.

Example 97 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 hydrazide in n-butanol is refluxed for 24 hours to give the example product.-Example 98 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 x 24 hours to give the example product.

Example 99

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-6-13-chloro-5-(trifluoromethyl)phenyl]-pyridazine. This compound is reacted with formylhydrazine in n-butanol under reflux for 24 hours to give the example product.

Example 100

Preparation of 3-methyl-6-[3-chloro-5-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine A mixture of 3-chloro-6-[3-chloro- 5-(trifluoromethyl)phenyl]-pyridazine and acetic hydrazide in n-butanol are refluxed for 24 hours to give the example product.

Claims (20)

1. Compound selected from the group consisting of compounds of the formula: where each of RjV and R^ is individually selected from the group consisting of hydrogen and alkyl with up to 3 carbon atoms and R^ is hydrogen, fluorine; chlorine, bromine, cyano, trifluoromethyl, nitro, amino, acetamido, carbamoyl, thibcarbamoyl or alkyl with up to 4 carbon atoms, with the first condition that at least one of R^ pggR2 is hydrogen, with the second condition that when R^ , R 2 and R^ are all hydrogen, then Rg cannot be methyl, and with the third condition that when R2 and Rg are both methyl, then R^ and R^ cannot be hydrogen? and pharmacologically acceptable acid addition salts thereof. 2. A compound according to claim 1, wherein R 1 and R 2 are both hydrogen, R 1 is methyl and is meta-trifluoromethyl. 3. Procedure for the preparation of compounds of the formula: where each of R^, R2 and R^ is individually selected from the group consisting of hydrogen and alkyl with up to 3 carbon atoms and R4 is hydrogen, fluorine in chlorine, bromine, cyano, trifluoromethyl, nitro, amino, acetamido, carbamoyl, thiocarbamoyl or alkyl with up to 4 carbon atoms, with the first condition that at least one of R 1 and R 2 is hydrogen, the second condition that when R 1 , R 2 and R 4 are all hydrogen, then R 2 cannot be methyl, and the third condition that when R 2 and R 8 are both methyl, then R 2 and R 4 cannot be hydrogen, which includes bringing a connection with the formula? where R1, R2, and R4 are as indicated above, in contact with a compound of the formula: 0 H2 N-NH-c!-R3 where R is as indicated above, in a lower-alkanol solvent at the reflux temperature thereof for a period of time sufficient for a significant degree of ring closure to take place, with the condition that at least one of R 1 and R 2 is hydrogen. 4. Procedure for the preparation of compounds of the formula: where each of R^, R2 and R3 is individually selected from the group consisting of hydrogen < and alkyl with up to 3 carbon atoms and R^ is hydrogen, fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, acetamido, carbamoyl, thiocarbamoyl or alkyl with up to 4 carbon atoms, with the first condition that at least one of R^ and R2 is hydrogen, the second condition that when R^ and R2 are both hydrogen, then R^ cannot be methyl, and the third condition that when R2 and R^ both is methyl, then R^ cannot be hydrogen, characterized by bringing a compound with the formula: where R^, R2 °S R4 is as above, in contact with a lower-alkyl orthoformate at 50 to 175°C for 1-24 hours, or with an alkanoic acid anhydride, an alkanoic acid chloride or an orthoether of an alkanoic acid in which the alkanoic acids have from 2-4 carbon atoms At 50 to 175°C in an inert solvent for 1-50 hours. 5. A method of reducing high blood pressure in a mammal, which comprises administering internally to a mammal of an effective amount of a compound selected from the group consisting of compounds of the formula: where each of R^ , R2 and R^ is individually selected from the group consisting of hydrogen and alkyl with up to 3 carbon atoms and R^ is hydrogen, fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, acetamido, carbamoyl, thiocarbamoyl or alkyl with up to 4 carbon atoms, with the first condition that at least one of R^ and R2 is hydrogen, the second condition that when R^ and R2 are both .hydrogen, then R^ cannot be methyl, and the third condition that when R2 and R^ are both methyl, then R^ cannot be hydrogen} and pharmacologically acceptable acid addition salts hence. 6. Therapeutic preparation in dosage unit form useful for lowering high blood pressure in mammals, comprising, together with a pharmaceutical carrier, from about 1.0 to approx. 25.0 mg per kg body weight per daily dosage unit of a compound selected from the group consisting of compounds of the formula: where each of R^, <R>2 and R^ is individually selected from the group consisting of. hydrogen and alkyl with up to 3 carbon atoms and R4 is hydrogen, fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, acetamido, carbamoyl, thiocarbamoyl or alkyl with up to 4 carbon atoms, with the first condition that at least one of and &2 is hydrogen, the second condition that when R 2 and R 2 are both hydrogen, then R 2 cannot be methyl, and the third condition that when R 2 and R 2 are both methyl, then R 2 cannot be hydrogen; and the pharmacologically acceptable acid addition salts thereof. 7. A method of alleviating agitation in a mammal, comprising administering internally to a mammal an effective amount of 3-methyl-6-phenyl-1,2,4-triazolo[4,3-blpyridazine or a pharmacologically acceptable acid addition salt thereof . 8. Therapeutic preparation in dosage unit form which is useful for alleviating restlessness in mammals, which includes from approx. 0.03 to approx. 10.0 mg per kg body weight per daily dosage unit of 3-methyl-6-phenyl-1,2,4-triazolo[4,3-blpyridazine or a pharmacologically acceptable acid addition salt thereof together with a pharmaceutical carrier. 9. Compound selected from the group consisting of compounds of the formula: where each of R^ , <R>2 and <R>^ is individually selected from the group consisting of hydrogen and alkyl with up to 3 carbon atoms and each of R4 , <R>5 , <R>g and R7 is individually selected from the group consisting of hydrogen, chlorine, bromine, fluorine, methyl, trifluoromethyl, nitro, methoxy, amino, with the first condition that at least one of R^ and R2 is hydrogen, and the second condition that two of R^ , R,., R^ and R^ are hydrogen and the remaining two are individually selected from the group consisting of chlorine, bromine, fluorine, methyl, trifluoromethyl, nitro, methoxy and amino, and the pharmaceutically acceptable salts thereof. 10. Procedure for the preparation of compounds of the formula: where each of R2 and R3 is individually selected from the group consisting of hydrogen and alkyl with up to 3 carbon atoms and R^ , R5#-Rg and R7 are individually selected from the group consisting of hydrogen, chlorine, bromine, fluorine, methyl» trifluoromethyl, nitro, methoxy, amino, with the first condition that at least one of R^ and R2 is hydrogen and the second condition that two of R^ , R,. , Rg and R? is hydrogen and the remaining two are individually selected from the group consisting of chlorine, bromine, fluorine, methyl, trifluoromethyl, nitro, methoxy and amino, and the pharmaceutically acceptable salts thereof, characterized in that a compound of the formula where R^, R2 , R4 , Rg, Rg and R? is as above, indicated, brought into contact with a compound of the formula: where R is as above, in a lower alkanol solvent at 50 to 206°C for 1-48 hours, and said product is recovered therefrom. 11. Procedure for preparing a compound of the formula: where each of R 1 , R 2 and R 8 is individually selected from the group consisting of hydrogen and alkyl with up to 3 carbon atoms and R 1 , R 1 , R 2 and R y are individually selected from the group consisting of hydrogen; . chlorine, bromine, fluorine, methyl, trifluoromethyl, nitro, methoxy, amino, with the first condition that at least one of R^ and R2 is hydrogen, and with the second condition that two of R^ , R1-, Rg and R7 are hydrogen and the remaining two are individually selected from the group consisting of chlorine, bromine, fluorine, methyl, trifluoromethyl, nitro, methoxy and amino, and the pharmaceutically acceptable salts thereof, * characterized in that a compound with the formula wherein Ry, R2, R4, Rg, <Rg> and R7 are as indicated above, is contacted with a lower alkyl orthoformate at 50 to 175°C for 1-48 hours or with a compound selected from the group consisting of, alkanoic anhydrides, alkanoic acid chlorides and orthoesters of alkanoic acids where the alkanoic acids have from 2 to 4 carbon atoms at 50 to 175°C in an inert solvent for a period of 1-48 hours, and recovery of said product therefrom. 12. Compound selected from the group consisting of compounds of the formula: where each of R^ and R2 is individually selected from the group consisting of hydrogen and alkyl with up to 3 carbon atoms, Rg is chlorine, fluorine, methyl, methoxy or trifluoromethyl and R^ is chlorine, fluorine, methyl, bromine or trifluoromethyl, and the pharmacologically acceptable acid addition salts thereof. 13. Compound according to claim 12, wherein R 1 is hydrogen, R 2 is methyl/ R 8 is chlorine and R 1 is trifluoromethyl. 14. A method of reducing high blood pressure in a mammal, which comprises intranasally administering to the mammal an effective amount of a compound selected from the group consisting of compounds of the formula: where R^ and R2 are each individually selected from the group consisting of hydrogen and alkyl with up to 3 carbon atoms, R3 is chlorine, fluorine, methyl, methoxy or trifluoromethyl and R4 is chlorine, fluorine, methyl, bromine or trifluoromethyl, and the pharmacologically acceptable acid-addis ion salts thereof. 15. Therapeutic preparation in dosage unit form useful for lowering high blood pressure in mammals, which, together with a pharmaceutical carrier, comprises from approx. 1.0 to approx. 25.0 mk per kg body weight per daily dosage unit of a compound selected from the group consisting of compounds of the formula: where R^ and Rj are each individually selected from the group consisting of hydrogen and alkyl with up to 3 carbon atoms, R^ is chlorine, fluorine, methyl, methoxy or trifluoromethyl and R4 is chlorine, fluorine, methyl, bromine or trifluoromethyl, and they pharmacologically acceptable acid addition ion salts thereof. 16. Procedure for the preparation of compounds of the formula: where each of R^ and R2 is individually selected from the group consisting of hydrogen and alkyl with up to 3 carbon atoms and R4 is hydrogen, fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, acetamido, carbamoyl, thiocarbamoyl or alkyl with up to to 4 carbon atoms, which involves bringing a compound of the formula: where R^ , R2 and R^ are as indicated above, in contact with a lower alkyl orthoformate at 50 to 175°C for a period sufficient for a significant degree of ring closure to take place, with the condition that at least one of R 1 and R 2 is hydrogen. 17. Procedure for the preparation of compounds of the formula: where each of R^ and R2 is individually selected from the group consisting of hydrogen and alkyl with up to 3 carbon atoms and R^ is hydrogen, fluorine, chlorine, bromine, cyano, trifluoromethyl, nitro, amino, acetamido, carbamoyl, thiocarbamoyl or alkyl of up to 4 carbon atoms, which includes bringing a compound of the formula: where R 1 , R 2 and R 2 are as indicated above, in conjunction with a compound selected from the group consisting of alkanoic anhydrides, alkanoic acid chlorides and orthoesters of alkanoic acids where the alkanoic acids have from 2 to 4 carbon atoms at 50 to 175°C in an inert solvent for a period of time which is sufficient for a significant degree of ring closure to take place, with the condition that at least one of R 1 and R 2 is hydrogen. 18. Procedure for the preparation of compounds of the formula: where each of R^ and R2 is individually selected from the group consisting of hydrogen and alkyl with up to 3 carbon atoms, Rg is chlorine, fluorine, methyl, methoxy or trifluoromethyl and R^ is chlorine, fluorine, methyl, bromine or trifluoromethyl, which includes to bring a connection with the formula: where R^, Rg and R^ are 3 as above, in contact with a compound of the formula where R 2 is as indicated above, in a lower alkanol solvent at the reflux temperature for this for a period of time which is sufficient for a significant degree of ring closure to take place. 19. Procedure for the preparation of compounds of the formula: where R^ is selected from the group consisting of hydrogen and alkyl of up to 3 carbon atoms, Rg is chlorine, fluorine, methyl, methoxy or trifluoromethyl and R^ is chlorine, fluorine, methyl, bromine or trifluoromethyl, which includes bringing a compound with the formula: where R^ , Rg and R^ are as indicated above, in contact with a lower alkyl orthoformate at 50 to 175°C for a period of time which is sufficient for a significant degree of ring closure to take place. 20. Procedure for preparing compounds of the formula: where Ry is selected from the group consisting of hydrogen and alkyl of up to 3 carbon atoms, Rg is chlorine, fluorine, methyl, methoxy or trifluoromethyl and R^ is chlorine, fluorine, methyl, bromine or trifluoromethyl, which comprises bringing a compound of the formula : where R^ , Rg and R^ are as indicated above, in contact with a compound selected from the group consisting of alkanoic anhydrides, alkanoic acid chlorides and orthoesters of alkanoic acids where the alkanoic acids have from 2 to 4 carbon atoms at 50 to 135°C in an inert solvent for a period of time that is sufficient for a significant degree of circularity to take place.