DE2741763A1 - SUBSTITUTED 6-PHENYL-1,2,4-TRIAZOLO SQUARE BRACKET TO 4.3 SQUARE BRACKET FOR PYRIDAZINE, METHOD OF MANUFACTURING IT AND MEDICINAL PRODUCTS CONTAINING IT - Google Patents

Description

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Case: 2638O yifZ 27 U 1763

AMERICAN CYANAMID COMPANY Wayne, New Jersey / USA

Substituted 6-phenyl-1 , 2, 4-triazolo / * 4, 3-bJ pyridazines, process for their preparation and pharmaceuticals containing them

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American Cyanamid Comp. Case: 263 80

The invention relates to substituted 6-phenyl-1,2,4-triazolo- ^ 4,3-b / pyridazine, process for the preparation of these compounds as well as medicinal products containing these compounds as active ingredients or their use.

The invention particularly relates to substituted 6-phenyl-1,2,4-triazolo ^ 4,3-b / pyridazines the general formula

in the

R ₁ , R ₂ and R_ independently of one another are hydrogen atoms or alkyl groups with up to 3 carbon atoms and

R. a hydrogen atom, a chlorine atom, a bromine atom, a fluorine atom, a cyano group, a trifluoromethyl group, a nitro group, an amino group, an acetamido group, a carbamoyl group, a thiocarbareoyl group or an alkyl group with up to to 4 carbon atoms with

the first proviso that at least one of the groups R ₁ and R- represents a hydrogen atom,

the second requirement that when the groups R ₁ , R- and R. each represent hydrogen atoms, R ₃ does not represent a methyl group, and the third requirement that when R ~ and R_ each represent methyl groups, R ₁ and F .. no hydrogen atoms represent, mean, and the pharmacologically acceptable acid addition salts of these compounds. The invention also relates to medicaments which contain these compounds as anti-anxiety agents and the use of these compounds for relieving anxiety in mammals.

The compounds of the invention are generally available in the form of light yellow crystalline materials, the characteristic Have melting points and absorption spectra and

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recrystallized from common organic solvents, such as methanol, ethanol, dimethylformamide, acetone, chloroform, ethyl acetate and the like, can be purified. They are readily soluble in non-polar organic solvents such as toluene, carbon tetrachloride and the like, and they dissolve but hardly in water. The organic bases of the invention form a wide variety of non-toxic acid addition salts of pharmacologically acceptable organic and inorganic salt-forming agents. Thus, the invention relates to also the acid addition salts of these compounds, which can be obtained by mixing the free base with one or two equivalents of one Acid, such as sulfuric acid, phosphoric acid, hydrochloric acid, Hydrochloric acid, sulfamic acid, citric acid, lactic acid, Malic acid, succinic acid, V7eic acid, acetic acid, benzoic acid, gluconic acid, ascorbic acid and the like, preferably in a neutral solvent. The acid addition salts are in non-polar organic solvents such as diethyl ether, Benzene, toluene and the like, relatively sparingly soluble, however, dissolve well in water. According to the invention are free bases are equivalent to their nontoxic acid addition salts.

The compounds according to the invention can be according to the create the following reaction scheme:

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OR ₁ R2

"II (hydrazine) -CH-CH-CO ₂ H.

(D

(IV)

(BronO

R ₂

R <

(H ₂ N-NH-CR ₃ )

N Ί R.

(VI)

in which R .., R, R and R _{4 have} the obpn nnqoqcbenen meanings. According to the above reaction scheme, a suitable substituted 3-benzoylpropionic acid of the general formula I with hydrazine hydrate is added to the corresponding 4,5-dihydro-6-phenyl-3 (2H) pyridazinone at the reflux temperature in a low molecular weight alkanol as solvent for 12 to 24 hours of the general formula II. By treating 4,5-dihydro-6-phenyl-3 (2H) -pyridazinone of the general formula II with bromine in glacial acetic acid as solvent, the corresponding 6-phenyl-3 (2H ) -pyridazinone of the general formula III, The conversion of the 6-phenyl-3 (2Π) -pyridazinone of the general formula III in the corresponding) J-Clilor-6-phenyl-pyridazine the

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general formula IV, egg trelohl: mm by treating this compound for a period of 4 to 8 hours at the temperature of a steam bath with excess phosphorus oxychloride. By reacting the 3-chloro-6-phenylpyridazine of the general formula IV with an acylhydrazine of the general formula V at the reflux temperature in a low molecular weight alkanol used as a solvent for 2-4 to 48 hours is obtained the corresponding 6-phenyl-1,2,4-triazolo / 4,3-b / -pyridazine according to the invention of the general formula VI.

The compounds of the invention can also be readily prepared according to the following reaction scheme:

NH-MH

(VII)

(IV)

(VIII)

alkyl

(IX)

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- JiT-

wherein R-, R "and R _{4 have} the meanings given above. According to the above reaction scheme, a suitably substituted 3-chloro-6-phenylpyridazine of the general formula IV with hydrazine hydrate in a low molecular weight alkanol used as solvent is used at the reflux temperature for 12 to 24 hours to give the corresponding 3-hydrazine-6-phenylpyridazine general formula VII around. The ring closure of the 3-hydrazino derivatives of the general formula VII with an orthoaseic acid alkyl ester with a lower molecular weight

IQ alkyl group gives the compounds of the general formula VIII, in which R _{3 stands} for a hydrogen atom. By ring closure of the 3-hydrazino derivatives of the general formula VII with a low molecular weight alkanecarboxylic acid anhydride, a low molecular weight alkanecarboxylic acid chloride or an orthoester of a low molecular weight alkanecarboxylic acid, the compounds of the general formula IX are obtained in which R ^ is a low molecular weight alkyl group. The ring closure can optionally be achieved in the presence of catalysts with the aid of bases such as pyridine or trialkylamines with low molecular weight alkyl groups. The ring closure with the orthoformic acid alkyl esters with low molecular weight alkyl groups and the orthoesters of low molecular weight alkanecarboxylic acids is preferably achieved without catalysts and without solvents, although an inert solvent can be used. The ring closure is generally achieved by heating the reactants to a temperature of 50 to 175 ° C., optionally working in the presence of a solvent.

The compounds of the invention have nontoxic Dosages have an ant! Hypertensive effect and can therefore be used as hypotensive agents are used. The pharmacological examination these compounds have shown that they have properties in which a sufficiently large safety margin between the doses at which a decrease in blood pressure is achieved and at which toxic

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Symptoms appear. The hypotensive properties of the compounds according to the invention were examined when administered orally to mammals, in particular warm-blooded animals, as follows: non-anesthetized, male albino rats of the Wistar tribe with normal blood pressure and an average weight of about 250 g are attached in the supine position with the help of canvas and articulated ligaments Rat mounting boards. Then the thigh areas are anesthetized (by subcutaneous infiltration of lidocaine) and the left or right common iliac arteries are exposed and clamped proximally with an arterial clamp and distally with a thread. Then incisions are made near the ligated site and short nylon catheters are inserted and tied in place. The other ends of the catheters are fitted with needles (24 gauge) that are free of needles and are attached to thick-walled polyethylene tubing. The compounds to be tested are administered orally via a nasogastric tube. The compounds are tested in a dose of 100 mg / kg body weight and used in the form of a 2% strength aqueous starch solution or suspension, which gives the desired dosage in an amount of 0.2 ml / 100 g body weight. Then, 4 hours and 24 hours after the administration of the compounds, the mean arterial blood pressures are measured. A comparison is made against the mean control blood pressure of 122 mmHg, which is the mean value of a number of control animals examined over several months. Blood pressure measurements are made with eight strain gauges (Statham P23 Db, Statham Instruments, Inc. Los Angeles, California / USA), _w ith a recorder (Beckman Dynograph recorder) are connected, which is equipped with eight strain gauge preamplifiers that to determine the have mean arterial blood pressure averaging circuits. The results obtained with representative compounds of the invention are shown in Table I below.

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The compounds according to the invention were also with regard to investigated their antihypertensive effects using the following procedure in spontaneously hypertensive rats (SHR) were used: a male, adult (aged 16 to 20 weeks) was administered spontaneously hypertensive rat weighing approximately 300 g (Taconic Farms, Germantown, N.Y./USA) via a 100 mg gavage of the compound to be investigated per kg, optionally in a 0.9% sodium chloride solution in a load of 25 mg / kg, this administration taking place at time O. A second identical dose is given 24 hours later, followed by the mean arterial blood pressure (MABP) of the non-anesthetized rat measured directly via a puncture of the femoral artery after 28 hours. The results this investigation of representative compounds according to the invention are also compiled in Table I below.

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TABLE I Hypotensive Effects in Rats

^R 2

R, - ^ X = L

link ^R 3 ^R 4 dose
(me / ke) Rats with normal blood pressure
mean arterial blood pressure
(ram Kg) 24 hours Spontaneously hypertensive rats
mean arterial blood pressure
(mm Hg) ^R i R, H 4-cyano 4 hours 110 28 hours CH ₃ H 100 95 113 130 H 3-nitro 103 93 CH ₃ H H 3-Araino 100 102 115 CH ₃ H H 4-bromine 100 93 93 130 H H H 4-fluoro 100 85 115 H H H 4-cyano 100 88 H H H 3-cyano 100 108 CH ₃ H 1-C ₃ H ₇ 3-tri-
fluorine-
methyl 100 88 H H 100 112

KJ

ro cn

TABLE I (continued)

^R l 1098 Ver
^R 2 jindunj
^R 3 ■
^R 4 dose
(mg / kg) Rats with normal blood pressure
mean arterial blood pressure
(mm Hg) 24 hours Spontaneously hypertensive rats
mean arterial blood pressure
(mm Hg) ro H
O 4 hours 95 28 hours CH ₃ 00 ϊϊ H H 4-bromine 100 107 106 CH ₃ ° * H H H 4-thiocarb-
amoyl 100 101 H H H H 4-chlorine 100 110 H H H 3-trifluoro
methyl 100 90 H H CH ₃ 3-trifluoro
methyl 100 133 CH ₃ H 4-chlorine 100 138 H CH ₃ 4-chlorine 100 150 H CH ₃ 4-fluoro 100 150 H H 3-amino 100 164 CH ₃ CH ₃ 4-chlorine 100 118 148 Mean control blood pressure 122 166

It can thus be seen that the compounds according to the invention are extremely effective for lowering the elevated blood pressure of mammals when used in amounts from about 1.0 mg to about 25.0 mg / kg body weight / day can be administered. A preferred dosage for best results is stretching from about 5.0 mg to about 15.0 mg / kg body weight / day, these dosage units being used in such a way that a patient weighing about 70 kg / 24 hours is given about 0.35 to about 1.0 g of the active ingredient.

The dosage can be adjusted in such a way that an optimal therapeutic effect is obtained. For example you can give several single doses a day or you can reduce the dose proportionally, depending on how it is the therapeutic situation requires. An essential practical one Advantage of the present invention is to be seen in that the active compounds in any suitable way administered, for example, by the oral, intravenous, intramuscular or subcutaneous route.

The compounds of the invention have also been found to be extreme Proven effective for anxiety relief in mammals when taken in dosages from about 0.03 mg to about 10.0 mg / kg body weight / day are given. A preferred dose for best results is from about 0.1 mg to about 5.0 mg / kg body weight / day, these dosage units being used in such a way that a patient with a body weight from about 70 kg about 7.0 mg to about 0.35 g of the active ingredient are given in the course of 24 hours. This dosage however, it can be adjusted in such a way that an optimal therapeutic effect is achieved. For example, you can give several single doses daily or you can adjust the dose proportionally depending on the therapeutic situation Reduce.

The compounds according to the invention thus have an effect on the central nervous system at non-toxic dosages

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and can therefore be used as anti-anxiety agents. this means that they cause certain reactions in certain standard tests on laboratory animals, of which it is known that they are in good correlation with an anxiety solution in humans. The compounds became pharmacological investigated, and it has been shown that they have this behavior with a desired wide interval between the dosages, that have an anxiolytic effect and the doses that cause toxic symptoms.

The anti-anxiety properties of the compounds according to the invention were determined in a study in which the anti-anxiety action is measured via the protection against convulsions caused by the administration of pentylenetetrazole. The compounds according to the invention are administered orally in specific doses in a 2% strength carrier material to groups of at least five rats. At the estimated time of greatest effect, the rats are treated intravenously with pentylenetetrazole at a dose of 21 to 23 mg / kg body weight. This dose is believed to induce clonic convulsions in 99% of the unprotected rats. The effective dose of the compound tested, which protects 50% of the animals (ED _1. ), is calculated according to the method of DH Finney (Statistical Methods in Biological Assay, Second Edition, Hafner Publishing Co., New York 0.964) 456 to 457). Representative results of this study are given in Table II below in comparison to the effect of chlordiazepoxide or meprobamate, which comparative compounds were tested in the same way. By RT Hill and DH Tedeschi ("Animal

ίΟ Testing and Screening Procedures in Evaluating Psychotropic Drugs "in" An Introduction to Psychopharmacology "edited by R. R. Rech and K.E. Moore, Raven Press, New York (1971) 237 to 288) it has been stated that a high degree of correlation between the control of pentylenetetrazole in rats caused cramps and anti-anxiety effects

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exists in higher warm-blooded animals.

TABLE II

Protection of rats against clonic convulsions caused by pentylenetetrazole

verb
^R l Landing
^R 2 ^R 3 ^R 4 Medium effective dose at
oral administration (ED ₅₀ )
(mg / kg) H H H 3-chlorine 8.2 H H CH ₃ 3-trifluoromethyl] 1.7 H H CH ₃ 4-fluoro 3.4 H H H 3-amino 15th CH ₃ H H 3-cyano 34 H H H 4-fluoro 5 H H H 4-chlorine 9.8 H H H 3-trifluoromethyl 3 2.5 3-methyl'-6-phenyl-
/ 4 ", 3-b7pyridazine 1,2,4-triazolo- 3 6-phenyl-l ,;
pyridazine >, 4-triazolo / 4, 3-t> 7- 9.5 Chlordiazepoxide 2.5 Meprobamate 22nd

The anti-anxiety effect was determined using the method of J.R. Vogel, B. Beer and D.E. Clody ("A Simple and Reliable Conflict Procedure for Testing Anti-Anxiety Agents", Psychopharmacologia, Vol. 21 (1971) 1 to 7), in which a passive avoidance behavior is used without getting used to it. By a change this method will highlight a conflict situation in rats.

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called. On groups of six naive rats (Sprague-Dawley weighing 200 to 220 g) that had been previously done for 48 hours without water and for 24 hours without Has kept feed, certain doses of the compounds to be examined are administered orally in the form of Suspensions in a 2% starch carrier material, each containing two drops of polyethylene glycol and polysorbate 80, or just the carrier material (for the controls). At the time of greatest effect, each rat is transferred to a plexiglass cage equipped with a soaking circuit is the floor consisting of a stainless steel net with a stainless steel drinking tube Joins steel, which is placed in a hole in one of the walls of the cage. The drinking circuit includes a stimulator, which emits single-phase square-wave pulses with a frequency of 60 Hz and a peak intensity of 0.2 mA, eLne time switch device, which switches alternating periods of 5 seconds each during the 5-minute examination period who are not shocked or given a shock

2C, an electromagnetic counting device for counting the Number of shocks the rat received during the shock delivery period and a delay device 1/2 second between successive shocks. After the rat is placed in the cage you let them explore the area and drink a 10% dextrose solution through the water tube is fed. After letting the rat drink for 20 seconds without penalty, the timer will be activated and the drinking switching device is started,

3O to alternating periods of 5 seconds each

who are not in shock or who are in shock. At the same time, the The number of shocks to which the rat was exposed during the study period of 5 minutes was determined. The percentage of rats receiving nine or more shocks in 4 to 5 minutes at each dose is considered a positive response

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used in calculating the mean effective dose (ED ^ _n ). The results of this investigation of representative compounds according to the invention are shown in Table III below in comparison with known substances of the prior art.

TABLE III

link

Medium effective dose

(ED ₅₀ , mg / kg)

3-methyl-6-phenyl-1,2,4-triazolo / 4,3-b7pyridazine Chlordiazepoxide meprobamate

100

9.6

51.9

The medicaments according to the invention, which have the desired clarity, Stability and suitability for parenteral administration are obtained by dissolving from 0.10 to 10.0% by weight of the active ingredient in a carrier material that contains a polyhydric aliphatic alcohol or a mixture of several such alcohols includes. Glycerine, propylene glycol and polyethylene glycols are particularly suitable. The polyethylene glycols comprise a mixture from non-volatile, normally liquid, polyethylene glycols, which exist in both water and organic Liquids are soluble and have molecular weights from about 200 to about 1500. Although the amount in which the active ingredient is dissolved in the said carrier material, can vary from 0.10 to 10.0 wt .- X, it is preferred that the used The amount of active ingredient is about 3.0 to about 9.0% by weight. Although various mixtures of the above-mentioned non-volatile polyethylene glycols can be used, one uses preferably a mixture of polyethylene glycols having an average molecular weight of from about 200 to about 400.

In addition to the active ingredient, those to be administered parenterally can be used

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Solutions contain various preservatives that prevent bacterial or fungal contamination. The preservatives used for this purpose are, for example, myristyl-V-picolinium chloride, benzalkonium chloride, phenethyl alcohol, chlorophenyl-o-gly.-erine ether, methyl paraben, propyl paraben and thimerosal. For practical reasons it is also suitable to use antioxidants. Suitable antioxidants are, for example, sodium bisulfite, sodium metabisulfite and sodium formaldehyde sulfoxylate. Generally, the antioxidant will be used in concentrations of from about 0.05 to about 0.2 percent.

For the purpose of intramuscular injection, the active ingredient is used in a concentration of preferably 0.25 to 0.50 mg / ml of the finished preparation. The compounds according to the invention can also be used after dilution with water or diluents commonly used for intravenous administration of active ingredients are used, such as isotonic glucose solutions, used in appropriate amounts will. For intravenous use are initial concentrations of the active ingredient up to about 0.05 to 0.25 mg / ml is satisfactory.

The active compounds of the invention can also administered orally, for example together with an inert diluent or with an assimilable one edible carrier material or they can be placed in hard or soft gelatin capsules and compressed into tablets or add directly to the food or feed. The active ingredients can be used for oral therapeutic administration incorporate into appropriate binders or carrier materials and in the form of tablets, pastilles, capsules, elixirs, Use suspensions, syrups, wafers, and the like. These preparations and preparations should contain at least 0.1% of the active ingredient. The percentage concentration of the active ingredients in the preparations and preparations can of course

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vary and can usually be between about 2 and about 60 % by weight of the dosage form. The amount of active ingredient in these therapeutically useful preparations is such that a suitable dosage will ultimately be achieved. The preparations or preparations according to the invention are preferably manufactured in such a way that a dose unit to be administered orally contains between about 0.1 and 5.0 mg of the active ingredient.

The tablets, troches, pills, capsules and the like can further contain: a binding agent, such as gum tragacanth, acacia gum, corn starch or gelatin; Carrier materials such as dicalcium phosphate; a tablet disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose or saccharin and a flavor such as peppermint oil, wintergreen oil or cherry flavor. When the dosage unit form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier material such as a fatty oil. Various other materials may be present as coating materials or otherwise modify the physical form of the unit dose. For example, the tablets, pills, or capsules can be coated with shellac, sugar, or both. The syrups or elixirs can contain the active ingredient, sucrose as a sweetener, methyl-paraben and propyl-paraben as a preservative, a color and a flavor such as a cherry or orange flavor. Of course , the material for the manufacture of any unit dosage forms should be pharmaceutically pure and substantially in the quantities used.

30 genes are not toxic.

The invention also relates to substituted 6-phenyl-l, 2,4-triazolo / 3,3-b7pyridazines, which are effective as hypotensive and anxiolytic agents and the following in general formula

J * 32,

correspond in the

R ₁ , R_ and R_ independently of one another hydrogen atoms or alkyl groups with up to 3 carbon atoms with the proviso that at least one of the groups R. and R_ represents a hydrogen atom and two of the substituents R ^, R_, R, and R_ represent hydrogen atoms and the the remaining two substituents represent fluorine atoms, chlorine atoms, bromine atoms, methyl groups, methoxy groups, nitro groups, amino groups or trifluoromethyl groups.

These compounds according to the invention can be obtained with the aid of Prepare the reaction schemes given above, with the difference that the radical defined above of the following formula

by a residue of the following general formula

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as defined in the previous section. According to the invention are those corresponding to this general formula free bases are equivalent to their nontoxic acid addition salts.

The following examples serve to further illustrate the invention.

example 1

p- (7-methyl-1,2,4-triazolo / 4,3-b7-pyridazin-6-yl) -benzonitrile.

200 g of p- (1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) benzonitrile are suspended (Journal of Medicinal Chemistry 17 (1974) 281) in 5OO ml of glacial acetic acid with stirring from above at the Steam bath temperature, whereupon 56 ml of liquid bromine are dissolved in a further 500 ml of acetic acid and this solution is poured into one serving added to the mixture. After heating for about 1/2 hour there is a violent exothermic reaction, in which excess bromine and hydrogen bromide are expelled. The reaction mixture is then diluted with 4 liters of distilled water. V7asser, filter off the solid that has formed, wash the filter cake well with water and dry it in the air. That The material is recrystallized from a large amount of ethyl alcohol and the product is obtained, p- (1,6-dihydro-4-methyl-6-oxo-3-pyridazinyl) benzonitrile, in the form of a white solid.

45.9 g of the above material and 250 ml of phosphorus oxychloride are heated for 3 hours to the temperature of a steam bath. Then decompose the excess phosphorus oxychloride, by slowly adding the reaction mixture to crushed ice with stirring. The solid formed is filtered off, washes it with water and dries it in a vacuum. The material is then recrystallized from methyl alcohol to give p- (6-

3O chloro-4-methyl-3-pyridazinyl) benzonitrile.

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A mixture of 14.6 g of the above compound is stirred, 9.4 g formylhydrazine and 175 ml butyl alcohol for 18 hours at the reflux temperature. The mixture is then concentrated to remove the solvent and the concentrate is triturated with petroleum ether and filtered. The filter cake is air dried, after which the yellow solid is made up twice Recrystallized methyl alcohol and the pale yellow crystals obtained are recrystallized again from methanol and one the title compound is obtained, which melts at 240 to 243 ° C.

IO example 2

p- (3,7-Dimethyl-1,2,4-triazolo / 3,3-b7-pyridazin-6-yl) -benzonitrile.

1.48 g of acetic acid hydrazide are dissolved in 50 ml with warming Butyl alcohol. 4.58 g of p- (6-chloro-4-methyl-3-pyridazinyl) benzonitrile are then added (which has been prepared according to the procedure of Example 1), whereby the material sinks through further heating for 10 minutes completely dissolves. The solution is then refluxed for 18 hours. The solution is concentrated and 5.8 g of an orange solid is obtained, which is washed with petroleum ether. The product is dissolved in an ethyl alcohol / acetone mixture (1/1) and filtered through a layer of silica gel. The filter is washed well with acetone and concentrate the combined filtrates to a yellow solid. The solid is dissolved in 100 ml of acetone, the solution cools in a dry ice / acetone mixture and a yellow-brown colored solid is obtained, which is filtered off, Washes well with petroleum ether and air dry. The product is dissolved in methyl alcohol and treated with activated charcoal and filtered. 1.06 g of yellowish crystals are crystallized from the filtrate. 500 mg of these crystals crystallized twice from methanol, whereupon the product obtained is dried in vacuo. F 242 to 244 ° C.

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Example 3

ρ-O-ethyl-T-methyl-l, 2,4-triazolo / 4,3-b7pyridazin-6-yl) benzonitrile

A mixture of 102.13 g of ethyl propionate is heated, 50 g of hydrazine hydrate and 150 ml of ethyl alcohol for 24 hours with stirring to reflux. The reaction mixture is freed remove the solvent, cool it in ice and stir it with petroleum ether. A white solid is obtained which filtered off, washed with petroleum ether and dried in vacuo, whereby propionic acid hydrazide is in the form of a white crystalline solid is obtained.

Dissolve 3O.8 g of the compound obtained in this way in 1 1 of butyl alcohol (which has been dried over molecular sieves 3-A) then gives 40.0 g (of the one prepared according to Example 1) P- (6-chloro-4 -.-ethyl-3-pyridazinyl) benzonitrile and the reaction mixture is heated to reflux for 18 hours. The reaction mixture is then freed from the solvent by concentration, the concentrate is triturated with petroleum, ether and filtered. The filter cake is dried in a vacuum,

a yellow solid obtained from methyl alcohol recrystallized, whereby the title compound is obtained. F 192 to 195 ° C.

Example 4

p- (3-Ethyl-7-methyl-1,2,4-triazolo / 4,3-b7-pyridazin-6-yl) -benzamide.

4.5 g of p- (3-ethyl-7-methyl-1,2,4-triazolo / 4,3-b7pyridazin-6-yl) benzonitrile are dissolved (which has been prepared according to the procedure of Example 3) in 50 ml of ethyl alcohol with heating, then add 50 ml of 30% hydrogen peroxide while swirling the reaction mixture and finally 50 ml of 2N sodium

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hydroxide solution while swirling the reaction mixture. The reaction mixture is left to stand at room temperature for 3 hours and then concentrated at as low a level as possible Temperature practically dry. The concentrate is diluted with water and filtered, whereupon the filter cake with Washed with water and allowed to air dry. The product is dissolved in acetone and filtered to remove the insoluble ones Proportions, whereupon the material is recrystallized and the title compound in the form of a yellow solid

10, which melts at 210 to 213 ° C.

Example 5

7-methyl-6- (m-nitrophenyl) -1,2,4-triazolo / 4,3-b7pyridazine

28 g of 3- (m-nitrobenzoyl) -butyronitrile (which one after the procedure described in J. Org. Chem.

Vol. 38, No. 23 (1973) 4044-4048) to 1 1 6N hydrochloric acid solution and stir for 1 hour using a magnetic stirrer and heating mantle to reflux. The reaction mixture is then cooled and extracted with methylene chloride. The organic layer is separated and extracted with saturated sodium bicarbonate solution. The sodium bicarbonate layer is added dropwise a stirred cold hydrochloric acid solution and cool the solid formed with ice, filtered, dried on the Air and receives 27.24 g of 3-m-nitrobenzoyl-butyric acid in the form of a white solid. The entire amount of the compound is mixed one with 12.8 ml of 99% hydrazine hydrate in 140 ml of ethyl alcohol and stirred for 3 hours at the reflux temperature. A solid begins to appear after about 1/2 hour. The reaction mixture is cooled in an ice bath, filtered the solid formed is dried in the air and receives 4,5-dihydro-5-methyl-6- (m-nitrophenyl) -3 (2H) -pyridazinone in the form of white to light yellow crystals.

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Dissolve 24.9 g of the above material in 2OO ml of warm glacial acetic acid with stirring and then added dropwise in the course of 15 minutes, 6.2 ml of bromine in the form of a solution in 5O ml of glacial acetic acid, with hydrogen bromide gas is released. The reaction mixture is heated for a further 20 minutes to remove the hydrogen bromide and the mixture is poured onto crushed ice. The solid formed is filtered off, washed with large amounts of water and dried in vacuo, 24.2 g of 5-methyl-6- (m-nitrophenyl) -3 (2H) pyridazinone being obtained in the form of a cream-colored solid.

22.7 g of the compound obtained are combined with 230 ml of phosphorus oxychloride and heated on a steam bath for 3 hours. The reaction mixture is then poured into crushed ice in portions with stirring. The solid formed is filtered off, washed well with water and dried in air, giving 15.6 g of S-chloro-S-methyl-o- (m-nitrophenyl) pyridazine in the form of a yellow-brown solid .

A mixture of 14.97 g of the compound obtained in the above manner, 7.2 g of formylhydrazine and 200 ml of butyl alcohol is heated to reflux with stirring for 18 hours. The reaction mixture is then decanted from the insoluble materials, the liquid phase is cooled in an ice bath and 13.28 g of a brown, crystalline solid are obtained. This material is dissolved in 300 ml of boiling methyl alcohol and filtered to remove the insoluble components. The filtrate is clarified by treating with activated charcoal and filtering. This filtrate is concentrated to a small volume and cooled to give the title compound in the form of a yellow-brown colored solid. F 213 to 218 ° C.

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Example6

6- (m-Aminophenyl) -7-methyl-1,2,4-triazolo / 4,3-b7pyridazine

A mixture of 2.28 g of 7-methyl-6- (m-nitrophenyl) -1,2,4-triazolo / 3,3-b7pyridazine is shaken (which has been prepared according to the procedure of Example 5), 100 ml of ethyl alcohol and a catalytic amount of platinum oxide in a Parr shaker for 1 1/2 hours under one

Hydrogen pressure of 2.81 kg / cm (40 psi). The catalyst was then filtered off from the reaction mixture and the filtrate was concentrated to give the title compound which was obtained as a yellow solid. F 182-186 ° C.

Example 7

6- (p-Bromophenyl) -1,2,4-triazolo / 4,3-b7pyridazine

A mixture of 3.76 g of 3- (p-bromophenyl) -6-chloropyridazine is heated, 180 g of formylhydrazine and 50 ml of butyl alcohol to reflux, heated to reflux overnight, Allow the reaction mixture to cool, wash the precipitated product with water, air-dry it and crystallize it from methyl alcohol. The title compound is obtained, melting at 2O9 at 211.degree.

Example 8

6- (p-Fluorophenyl) -1,2, 4-triazolo / 4 ~, 3-b7pyridazine

In a 2 liter three-necked flask, stir one on a steam bath Mixture of 87 g of 6- (p-fluorophenyl) -4,5-dihydro-3 (2H) -pyridazinone (prepared according to the procedure of US Pat. No. 3,689,652, Example 6) and 800 ml of glacial acetic acid. One prepares then a solution of 24.1 ml of bromine in 100 ml of glacial acetic acid in a dropping funnel. Then 15 ml of this bromine

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solution to the reaction mixture, which is heated with stirring until the mixture turns lighter in color. Then you give the rest the bromine solution with stirring and heating in the course of about 30 minutes. Then the reaction mixture is heated during one more hour and then pour it onto crushed ice. The solid formed is filtered off and washed with water and air dried overnight. The material is then dried at 65 ° C. and yields 6- (p-fluorophenyl) -3 (2H) -pyridazinone in the form of crystals that melt at 265 to 268 ° C.

The total amount of the above compound is made with 500 ml of phosphorus oxychloride combined and heated on a steam bath for 5 hours. Then the reaction mixture is cooled, removed the excess phosphorus oxychloride using a rotary evaporator and then added 1 l of ice water with stirring. The solid obtained is filtered off, washed with water and air-dried overnight. The solid is taken up in 2 l of chloroform, treated with activated charcoal and filtered through diatomaceous earth. The chloroform filtrate is concentrated to a small volume, after which the precipitate formed is filtered off and washed with chloroform and air dried and 3-chloro-6- (p-fluorophenyl) -pyridazine in the form of pink crystals.

2.5 g of this compound are mixed with 1.46 g of formylhydrazine and 40 ml of butyl alcohol. The mixture is heated to reflux and then kept at the reflux temperature overnight. The mixture is then cooled on an ice bath, the precipitated product is filtered off, washed with butyl alcohol and dry it overnight. The dried material is recrystallized from methyl alcohol to give the title compound

3O in the form of crystals. F 197 to 198 ° C.

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Example 9

ρ- (1,2,4-triazolo / 3,3-b7-pyridazin-6-yl) -benzonitrile

86.3 g of 6- (p-bromophenyl) -4,5-dihydro-3 (2H) -pyridazinone (which has been prepared according to US Pat. No. 3,689,652, Example 5) are dissolved in 500 ml of glacial acetic acid by heating continuous stirring at 80 ⁰ C. Then was added dropwise over a period of 1 hour at a temperature of 75 to 80 ⁰ C a solution of 60 g bromine in 80 ml of acetic acid. A solid is separated off towards the end of the addition. The reaction mixture is then heated on a steam bath for 1/2 hour and finally poured into 3 l of an ice / water mixture. The white solid formed is filtered off 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 product formed in the above manner and 9.1O g of copper (I) cyanide in 70 ml of dimethylformamide is heated with stirring for 5 1/2 hours to reflux. A solid falls during this time the end. The hot mixture is poured into a solution of 46 ml of ethylenediamine in 23Ο ml of water. The mixture is stirred during 30 minutes at the ice bath temperature, filtered the formed Precipitate is washed off with water until the washing liquids are colorless and p- (1,6-dihydro-6-oxo-3-pyridazinyl) -benzonitrile is obtained as a yellow solid.

A stirred solution of 3.42 g of the material prepared in the above manner in 45 ml of phosphorus oxychloride is heated to the reflux temperature over 3 hours. Most of the excess phosphorus oxychloride is drawn off under reduced pressure Pressure is released, after which an ice / water mixture is added to the stirred concentrate. The solid is filtered off and recrystallizes it after drying in the air from a dimethylformamide / water mixture, whereby one kriötalli-

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nes p- (o-chloro-S-pyridazinyl) benzonitrile is obtained. F 236 to 238 ° C.

A mixture of 1.00 g of the above product, 0.84 g, is stirred Formylhydrazine and 25 ml of n-butyl alcohol for 17 hours and 45 minutes at reflux temperature. Then you pull the solvent under reduced pressure and the residue is triturated with ethyl alcohol. The mixture is filtered and crystallized the solid from a dimethylformamide / water mixture, where p- (1,2,4-triazolo / 3,3-b7pyridazin-6-yl) benzonitrile is obtained in the form of an orange solid. M.p. 272 to 274 ° C.

Example 10

_m _ (7-methyl-1,2,4-triazolo / 4 ", 3-b7-pyridazin-6-yl) -benzonitrile

15 g of m- (1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl) benzonitrile are suspended (Journal of Medicinal Chemistry 17, (1974) 281) in 75 ml of glacial acetic acid, which is done at the steam bath temperature stirs. A solution of 3.75 ml of bromine in 25 ml of acetic acid is then added dropwise over 15 minutes. The reaction mixture is heated on a steam bath for an additional 30 minutes and then poured onto crushed ice. Of the The solid formed is filtered off, washed well with water and dried, and this gives m- (1,6-dihydro-4-methyl-6-oxo-3-pyridazinyl) -benzonitrile in the form of an off-white solid.

10.0 g of the above material and 100 ml of phosphorus oxychloride are heated for 3 hours on a steam bath. Then decompose the excess phosphorus oxychloride by slow Add the reaction mixture to cold water with stirring. The solid formed is filtered off, after which the filter cake is obtained washes well with water. The product is air-dried and m- (6-chloro-4-methyl-3-pyridazinyl) benzonitrile is obtained in the form of an off-white solid.

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A mixture of 3.0 g of the above compound is stirred, 1.57 g formylhydrazine and 100 ml butyl alcohol during 18 Hours at reflux temperature. The reaction mixture is then cooled in an ice bath and filtered off the solid formed. The title compound is then made from methyl alcohol recrystallizes and gives a cream-colored solid which melts at 214-216 ° C.

Example 11

3-propyl-6- ", <*, <* -tr if luoro-m-tolyl) -1, 2, 4-triazolo / 4", 3-b7pyridazine

112 g of p-toluenesulfonic acid are dissolved in 500 ml with stirring Tetrahydrofuran. Then 106 g are added in portions with stirring Morpholine too. 95.63 g of m-trifluoromethylbenzaldehyde are added and stir the reaction mixture for 2 hours at the reflux temperature. The reaction mixture is then cooled and add a solution of 42.2 g of potassium cyanide in 75 ml of water. The reaction mixture is then mixed overnight at Reflux temperature, draws the solvent by concentration the reaction mixture and distribute the concentrate between water and chloroform. The organic layer is washed with saturated sodium bisulfite solution, dried over magnesium sulfate, treated with activated charcoal and filtered. The filtrate is concentrated in vacuo and gives <- (e (, e <, «(- Trifluoro-m-tolyl ) -4-morpholine acetonitrile in the form of a dark yellow oil.

67.0 g of this oil are dissolved in 2 l of tetrahydrofuran with stirring at room temperature. Eight 10 ml portions of ethyl acrylate are then added and nine 5 ml servings of 30 fc potassium hydroxide solution in ethyl alcohol over the course of 5 hours Stir to the reaction mixture. The reaction is slightly exothermic. The reaction mixture is stirred at room temperature overnight. Then the mixture is treated with activated charcoal and filtered. The filtrate is freed from the solvent and stripped several times with toluene. Then stir the con-

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concentrate with diethyl ether and filtered to remove the insoluble components. The filtrate is concentrated to a yellow oil, which is then chromatographed on a glass column (75 cm × 8 cm) charged with silica gel, chloroform being used as the solvent. The chromatographed material is freed from chloroform and gives 47.0g Y-cyano-V- (c ^ ei.d-trifluoro-m-tolyl) -4-morpholine butyric acid ethyl ester in the form of a yellow oil. The total amount of this product is combined with 2 liters of ethyl alcohol and 7.3 ml of hydrazine hydrate. The mixture is stirred at reflux for 18 hours, then the solvent is stripped off and a yellow oil is obtained, which is stirred with petroleum ether, 14.55 g of 4,5-dihydro-6- (<*, «<, <*, - trif luoro-m-tolyl) -3 (2H) -pyridazinone is obtained in the form of a white solid. The entire amount of the above product is dissolved in 225 ml of glacial acetic acid at room 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 was heated for 1/2 hour on a steam bath, and adding the remaining _t bromine solution in acetic acid dropwise. After complete decolorization, the reaction mixture is heated on a steam bath for 1/2 hour and the solvent is then stripped off with concentration. The solid concentrate is washed with water, filtered and air-dried to give 6- (*, «( M trifluoro-m-tolyl) -3 (2H) -pyridazinone in the form of a cream-colored solid.

12.55 g of the above product and 200 ml of phosphorus oxychloride are heated for 18 hours on a steam bath. The reaction mixture is then concentrated to remove the excess Phosphorus oxide chloride and rub the concentrate with cold water. The solid formed is filtered off, whereupon the filter cake is washed with water and the material is air-dried, 3-chloro-6- (° i, δ <, "C-trifluoromolyl) pyridazine in the form of a cream-colored solid

35 holds.

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A mixture of 6.0 g of the above product, 4.74 g, is stirred Butyric hydrazide and 75 ml of butyl alcohol for 48 hours at the reflux temperature. Then the solvent is withdrawn from the reaction mixture, the concentrate with ethyl alcohol decreases on, treated with activated charcoal and filtered. The FiI-entered is concentrated to a small residue and in a Chilled ice bath. The remaining solid is filtered off and gives the oil compound in the form of an off-white Solids. The material is recrystallized from ethyl alcohol and dried in vacuo to obtain crystals with a Melting point from HR to 12O ° r.

Example 12

3 '- (7-methyl-1,2,4-triazolo / 4,3-b / pytidazin-6-yl) acetanilide

Dissolve 1.5 g of 6- (in-allynophotivl) 7-mini hyl-1, 2, 4-triazolo / 4 ", 3-b7-. Pyridazine (prepared according to Heinpiol. 6) in 30 ml of pyridine at room temperature. 7 , u dor Lösuncj GIBL mn η 6.0 ml of acetic anhydride, followed by heating the Rcaktionsminchuiig for 1 hour on a steam bath. Then the mixture is cooled, the reaction mixture in an ice bath and filtered. the filter cake is washed with petroleum ether and dried to yield the title compound in the form of cream-colored crystals. F 298 to 30l ° C.

Example 13

6- (p-Bromophenyl) -7-methyl-1,2,4-triazolo / 3,3-b7pyridazine

10.0 g of 6- (p-bromophenyl) -5-methyl-3 (2H) -pyridazinone (Journal of Medicinal Chemistry 17 (1974) 281) and 100 ml of phosphorus oxychloride are heated to the temperature of a steam bath for 3 hours. The mixture is then added dropwise to cold water while stirring. The pounded fuel is filtered off, washed with water and gives 3- (p- -hromophenyl) -6-chloro-4-

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methylpyridazine in the form of a gray solid.

A mixture of 1.5 g of the above compound, 0.64 g, is stirred Formylhydrazine and 25 ml of butyl alcohol for 18 hours the reflux temperature. The reaction mixture is then cooled in an ice bath, filtered and the solid is crystallized from methyl alcohol and gives the title compound in the form of a yellow solid. F 219 to 222 ° C.

Example 14

p_ (7-methyl-1,2,4-triazolo / 3,3-b7pyridazin-6-yl) thiobenzamide

2.1 gp ~ (7-Mothy] 1 ₍ 2, Ί triazolo / 3,3-b7pyridazin-6-yl) -benzonitrile (Hergonte] II 5.0 ml of triethylamine Then, in the course of 3 hours, hydrogen sulfide gas is passed into the reaction mixture, the color of the reaction mixture changing from yellow to green . the mixture is filtered and washed the yellow solid with petroleum ether, to give the title compound as a light-

2o yellow solid is obtained. F 268 to 272 ° C.

Example 15

6- (3-bromo p-mel · hoxypheny 1) 1,2,4 triazolo / 3,3-b7pyridazine

It is heated in suspension with 100 g of 6- (3-bromo-4-methoxyphenyl) . 3 (2H) -pyrida / Irion (J. Holnrooyolic Chem. 11 (1974) 775) in ml of phosphorus oxychloride to reflux until one has obtained a clear solution (this is the case after about 5 hours is). Then one cools the lmnui, / lnht of excess phosphorus oxychloride in a vacuum a brown solid

8UUti12 / 0896

COPV

that you rub in with ice water. The solid is filtered off and recrystallized and gives 3- (3-bromo-4-methoxyphenyl) -6-chloropyridazine.

A mixture of 5.28 g of the obicen compound is heated, Reflux 75 ml of butyl alcohol and 2.88 g of formylhydrazine overnight. The reaction mixture is then cooled Room temperature and the product is filtered off. The material is recrystallized from methyl alcohol to give the title compound in the form of crystals that melt at 226 to 228 C.

IO example 16

6- (p-Chlorophenyl) -3-methyl-1,2,4-triazolo / ?, 3-b7pyridazine

47.5 g of 6- (p-chlorophenyl) -4,5-dihydro-3 (2H) -pyridazinone (prepared according to Example 1 of US Pat. No. 3,689,652) are dissolved in 250 ml of glacial acetic acid with stirring at a temperature of 65 up to 70 ⁰ C.

A solution of 14 ml (42 g) of liquid bromine in 50 ml of acetic acid is then added in portions over the course of 20 minutes. The reaction mixture is stirred for 3 hours at 65 ° C., then cooled to 4 ° C., the precipitate is recovered and washed with 100 ml of ethyl acetate. The solid is suspended in 500 ml of water, 25 ml of concentrated ammonium hydroxide solution are added and the mixture is stirred overnight at room temperature. The precipitate is separated, washed with 500 ml of water and dried at 60 ⁰ C and yields 6- (p-chlorophenyl) -3 (2H) -pyridazinone.

A mixture of 34.5 g of the above material and 150 ml of phosphorus oxychloride is heated to the boil for 4 hours Reflux. The reaction mixture is then cooled and poured onto 2 kg of ice. After standing for 2 hours occasional stirring, the precipitate is separated off and washed with water. The solid is boiling in 500 ml Benzene dissolved, clarified with activated charcoal and filtered. The FiI

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entered, the mixture is cooled to room temperature, whereupon the solid is separated off, washed with a small amount of benzene and turned on the air is dried. The material is recrystallized with ethyl alcohol after treatment with activated charcoal The product is separated off, washed with ethyl alcohol and then with ether, yielding 3-chloro-6- (p-chlorophenyl) pyridazine. F 209 to 211 ° C.

A mixture of 10.0 g of the above product, 6.6 g, is heated Hydrazine hydrate and 150 ml of butyl alcohol to reflux overnight. The reaction mixture is then cooled and filtered and washes the solid with butyl alcohol and with water. The butyl alcohol filtrate obtained is on a rotary evaporator concentrated to give further crystalline product which is washed with butyl alcohol and water. The united material yields 6- (p-chlorophenyl) -3 ~ hydrazinopyridazine, which in Melts from 156 to 160 ° C.

6.6 g of that prepared in the manner described above are heated Materials, 140 ml of p-dioxane and 4.64 g of diisopropylethylamine until the material has dissolved. Then you cool down the solution to about room temperature and gives 2.66 g of acetyl chloride to. The reaction mixture is then cooled on an ice bath and stirred overnight. Then you pull the solvent in vacuo and the residue is treated with ethyl alcohol. The flask is heated, a solid precipitating out. This material is filtered off, whereupon the ethanol is concentrated further and the title compound is obtained in the form of crystals. F 208 up to 210 ° C.

Example 17

6- (p-Chlorophenyl) -8-methyl-1,2,4-triazolo / 4 ~, 3-b7pyridazine

270 g of aluminum chloride are carefully added to a solution of 114 g of methylsuccinic anhydride in 400 ml of chlorobenzene. then

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The mixture is heated to 65 ° C. for 11/2 hours, cooled, quenched with ice and concentrated hydrochloric acid and extracted with benzene. The benzene layer is extracted with an aqueous sodium bicarbonate solution. After adjusting the pH of the sodium bicarbonate solution to 6.3, concentrated hydrochloric acid is slowly added over a few hours with stirring. At a pH of 5.7, 78 g of white crystals are filtered off. Recrystallization of this material from an ethanol / water mixture gives 3- (p-chlorobenzoyl) -2-methy! Propionic acid in the form of white crystals. A mixture of 35.5O g of the above compound, 85 ml of hydrazine hydrate and 400 ml of ethyl alcohol is stirred for 18 hours at the reflux temperature. The reaction mixture is then concentrated to about 75 % of the original volume, cooled on an ice bath and filtered, and 26.62 g of 6- (p-chlorophenyl) -4,5-dihydro-4-methyl-3 (2H) -pyridazinone are obtained in the form of a yellow solid. A further 4.7 g of the product are obtained from the above filtrate.

31.32 g of the above combined product are dissolved in 250 ml of glacial acetic acid at room temperature with stirring. 8.2 ml of liquid bromine are then 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 then increased until the bromine color has disappeared. The remaining bromine solution is then added over the course of 20 minutes with heating. The reaction mixture is heated on the steam bath for a further half an hour and then diluted with ice water. The solid formed is filtered off, washed with water and air-dried and gives 6- (p-chlorophenyl) -4-methy.l- 3 (2H) -pyridazinone in the form of a cream-colored solid.

15.0 g of the above compound and 200 ml of phosphorus oxychloride are heated for 18 hours on a steam bath. The solvent is then drawn off by concentrating the reaction mixture

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and stir the concentrate with cold water. The precipitate is filtered off and washed with water to give 3-chloro-6- (p-chlorophenyl) -4-methylpyridazine in the form of a pink solid.

2.0 g of the above compound are mixed with 1.08 g of formylhydrazine and 60 ml of butyl alcohol. The mixture is then refluxed for 48 hours. The reaction mixture is cooled on an ice bath, the solid formed is filtered off, washed with petroleum ether and air-dried

and receives a yellow-brown colored solid. The title compound is recrystallized from methyl alcohol after treatment with activated charcoal and gives white crystals which at Melting at 230 to 233 ° C.

Example 18

3-methyl-6- («,« (A-trifluoro-m-tolyl) -1, 2, 4-triazolo / 4, 3-b7-pyridazine.

A mixture of 6.0 g of 3-chloro-6- (*, «<,« (- trifluorom-tolyl) is heated pyridazine (prepared according to Example 11), 3.44 g of acetylhydrazine and 75 ml of n-butyl alcohol for 48 hours to reflux. The solvent is then drawn off in vacuo, the residue is dissolved in ethyl alcohol and treated with activated carbon. The filtrate is concentrated, cooled and filtered to give an orange solid. The recrystallization this material from methyl alcohol gives the Ti

tel compound in the form of crystals that melt at 193 to 194 ° C.

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Example 19 6- (p-Chlorophenyl) -1,2,4-triazolo / 4 ", 3-b7pyridazine

A mixture of 9.0 g of 3-chloro-6- (p-chlorophenyl) pyridazine (prepared according to Example 16), 5.1 g of formylhydrazine and 60 ml of butyl alcohol is heated to the reflux temperature for 40 hours. The reaction mixture is then cooled, filtered and the solid is washed with petroleum ether and with water. Then the material is heated with 125 ml of ethanol and
filters off the insoluble material. The filtrate is cooled, the precipitate separated and combined with the insoluble material separated in the above manner. The combined solids are recrystallized from 130 ml of ethyl alcohol and give the title compound in the form of crystals
a melting point of 216 to 218 ° C.

15 Example 20 6- (tf, «, et-Trifluoro-m-tolyl) -1, 2, 4-triazolo / 4", 3-b7pyridazine

A mixture of 6.0 g of 3-chloro-6 - (^, ^ (, ^ - trifluorom-tolyl) -pyridazine (prepared according to Example 11), 2.78 g, is stirred
Formylhydrazine and 75 ml of butyl alcohol for 48 hours at the reflux temperature. Then mar. the solvent is removed from the reaction mixture, the residue is dissolved in ethyl alcohol, treated with activated charcoal and filtered. The filtrate is cooled in an ice bath and an off-white solid is separated. The solid is heated with diethyl ether and the mixture is filtered. The solid becomes from ethyl acetate
recrystallizes and gives the title compound in the form of cream-colored crystals. F 140 to 143 ° C.

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Example 21

6- (p-Chlorophenyr-3-ethyl-1,2,4-triazolo / 4,3-b7pyridazine

A mixture of 9, Og 3-chloro-6- (p-chlorophenyl) pyridazine is stirred (prepared according to Example 6), 7.4 g of propionic acid hydrazide and 60 ml of butyl alcohol for 48 hours at the Reflux temperature. The mixture is then cooled, filtered, and the solid is washed with petroleum ether and with water. That Material is recrystallized from 50 ml of ethyl alcohol and gives the title compound in the form of crystals with a

IO melting point from 197 to 199 ° C.

Example 22

6- (p-Fluorophenyl) -3-methyl -1, 2, 4-triazolo / 4 ", 3-b7pyridazine

A mixture of 6.25 g of 3-chloro-6- (p-fluorophenyl) pyridazine is heated (prepared according to Example 8), 4.65 g of acetylhydrazine and 50 ml of butyl alcohol to reflux until one

receives clear solution. Then the reaction mixture is cooled, filtered, the solid precipitate was washed with hexane and with water. The solid is crystallized from 50 ml of ethyl alcohol and receives the title compound at 227 to 229 ° C

2O melts.

Example 23

3-methyl-6- (m-nitrophenyl) -1,2,4-triazolo / 3,3-b7pyridazine

(Chem J. Med., 17 (1974) 273) A mixture of 9.9 g of 6- (m-nitrophenyl) -4,5-dihydro-3-pyridazone and 8O mL of ^ice-1 2 S acetate with stirring on a steam bath and then a solution of 2.41 ml of bromine in 10 ml of glacial acetic acid is added dropwise over 30 minutes. The mixture is heated for a further 45 minutes

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with stirring and then pour the reaction mixture onto crushed ice. The crystalline product is filtered and with Water washed. 6- (in-nitrophenyl) -3-pyridazone is obtained in practically quantitative yield. F 275 ° C.

A mixture of 6 g of the above product is heated 35 ml of phosphorus oxychloride for 4 hours on a steam bath and then concentrated to remove (ion excess phosphorus oxychloride oin. The residue is quenched in ice water and filtered remove the insoluble solid, wash with water and air dry. The product is dissolved in chloroform, with activated charcoal bnhandel I iiiui ynkiHrt. The chloroform solution one concentrates and receives 4.0 g of 3-chloro-6- (m-nitrpphenyl) pyridazine. F 206 to 208 ° C.

A mixture of 3.0 g of the above compound is heated, 2, Og acetylhydrazine and 3O ml butanol for 72 hours 'to reflux and then cool. The precipitate is filtered off, washed with hexane and with water and turned on air dried. The product is brought to the boil with 100 ml of 95% ethyl alcohol and filtered. The unsolvable Material (F 241 to 243 ° C) consists of 3-methyl-6- (m-nitrophenyl) -1,2, 4-triazolo / 4 ~, 3-b7pyridazine.

Example 24

6- (m-nitrophenyl) -1, 2,4-triazolo / 4,3-b7pyridazine

The above title compound is obtained at 231 to 233 ° C . melts if, in the procedure of the example, formylhydrazine is replaced by acetylhydrazine.

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- 3-β- -

Example 25

6- (m-aminophenyl) -3-mot hyl-l, 2, 4-triazolo / 4 ", 3-b7pyridazin

Nine mixture is shaken with 5.1 g of 3-methyl-6- (m-nitrophenyl) -1, 2,4-triazolo / 4 \ λ b / pyrldazine (prepared according to Example 23), 60 ml of trifluorosetic acid and 0.9 g of a catalyst (10 % palladium-on-carbon) in a Parr hydrogenation device under a water pressure of about 2.46 kg /

2
cm (35 psi) when water intake has ended. Then filtered catalyst don t \ h and concentrated the reaction mixture. The residue dissolves in 1⁄2 ti Wnaser and adjusts it to a pH value of 5 by adding 5N sodium hydroxide]. The insoluble material is filtered off, washed with water and 6- (m-aminophenyl) -3-methyl-1,2,4-triazolo / 3,3-b7pyridazine is obtained. 193 ° C.

Example 26

6- (m-Aminophenyl) -1, 2,4-triazolo / 3,3-b7pyridazine

This gives the title compound, melting at 225 ° C, by reduction of (according to Example 24 produced) 6- (m-nitro-phenyl]) - l, 2,4 riazolo A / 4.1 B / pyrldazin according to the procedure of Example 25.

B ei a P i_e_ 1 2_7

6- (m-Acetamidophenyl) -1,2,4 -tri n7.olo / 3, 3-b7pyridazine

A mixture is now 1.0 g 6- (m-aminophenyl) -1,2,4-triazolo / 4 \ 3-b7pyrida7.in (henjoMlnlH according to Example 26) and 4 ml Acetic anhydride stand for 2 hours at room temperature, then rubbed with ether and filtered. The insoluble material is recrystallized from ethyl alcohol and 6- (m-acetamido-

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phenyl) -1, 2, 4-triazolo / 4 ", 3-b7pyridazine in the form of yellow Crystals that melt at 248-25O ° C.

Example 28

6- (m-Acetamidophenyl) -3-methyl-1,2,4-triazolo / 4 ", 3-b7pyridazine

The title compound is obtained by reacting 6- (m-aminophenyl) -3-methyl-1,2,4-triazolo / 3, 3-b7pyridazine (prepared according to Example 25) and acetic anhydride according to the procedure of example 27.

Example 29
3-methyl-6- (p-tert-butylphenyl) -I ₁ 2, 4-triazolo / 4,3-b7pyridazine

A mixture of 16.5 g of 3-p-tert-butylbenzoylpropionic acid (Journal Organic Chem. Soc. 19 (1954) 802) and 8.25 ml of hydrazine hydrate is dissolved in 140 ml of absolute ethyl alcohol. The clear solution is then stirred for 4 hours at the RUckfluitem temperature and cooled overnight. The product is separated off, washed with ethyl alcohol and dried in vacuo and gives 13.1 g of 6- (p-tert-butylphenyl) -4,5-dihydro-3 (2H) -pyridazinone in the form of a white solid.

8.0 g of the above material is stirred in 80 ml of glacial acetic acid and a solution of 5.82 g of bromine in 20 ml of glacial acetic acid is added dropwise. The reaction mixture is then heated to about 100 ^° C., with discoloration taking place. The bromine / acetic acid solution is added as quickly as the discoloration disappears, which takes about 15 minutes. The mixture is then stirred for 1 hour at 100 ° C. and poured onto 150 ml of ice. The white solid formed is filtered off and then dissolved in 400 ml of acetone. The acetone solution is dried over magnesium sulfate and concentrated while diluting with hexane.

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By crystallizing from about 100 ml of an acetone / hexane mixture 4.82 g of 6- (p-tert-butylphenyl) -3 (2H) -pyridazinone are obtained in the form of a light yellow solid.

A mixture of 22.8 g of the compound prepared in the above manner and 115 ml of phosphorus oxychloride is heated

a steam bath until a clear solution is obtained. This solution is heated for 5 hours and then concentrated in vacuo. The The residue is treated with ice water, the solid obtained is separated off and dried in vacuo, giving 22.0g of 3- (ptert-butylphenyl) -6-chloropyridazine in the form of an off-white solid.

A mixture of 5.0 g of 3- (p-tert-butylphenyl) -6-chloropyridazine, 3.13 g of acetylhydrazide and 50 ml of n-butanol is heated
reflux for 48 hours. The mixture is then concentrated in vacuo and the residue is stirred with 100 ml of water and 100 ml of ether. The mixture is filtered and 3.0 g of a yellow-brown colored solid are obtained, which at
144 to 146 C melts. Recrystallization from an acetone / hexane mixture gives the product in the form of light yellow

2O crystals that melt at 142 to 145 ° C.

Example 30

6- (p-tert-butylphenyl) -1,2,4-triazolo / 4,3, -b7pyridazine

A mixture of 5.0 g of 3- (p-tert-butylphenyl) -6-chloropyridazine is heated, 2.54 g of formyl hydrazide and 50 ml of n-butyl alcohol with stirring for 48 hours at reflux.

The mixture is then cooled and filtered. The solid is washed with petroleum ether and with water and dried in vacuo and gives 0.80 g of product. The filtrate is concentrated in vacuo below 80 C and gives further product, which is stirred with 150 ml of water and 150 m diethyl ether,

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whereupon it is filtered off and dried in vacuo and 3.0 g of one orange solid is obtained. Recrystallization from ethyl alcohol gives the title compound in the form of off-white Crystals with a melting point of 270 to 275 ° C.

Example 31 Manufacture of 50 mg tablets

For the production of tablets containing 50 mg of the active ingredient the following components are used:

Per tablet

0.050 g of 3-methyl-6- (m-acetamidophenyl) -1,2,4-triazolo- / 3,3-b7pyridazine

0.08O g of lactose

0.010 g corn starch (for the mixture) 0.08 g corn starch (for the paste)

0.148 g

O, OO2 g magnesium stearate (1 %)

Pro IO OOO Tablets 5OO G 8OO G ) 1OO G 75 G 1475 G 15th G

0.150 g i 149Ο g

Mix 3-methyl-6- (m-acetamidophenyl) -1,2,4-triazolo- / 3,3-b7pyridazine, Lactose and corn starch (for the mixture). The corn starch (for the paste) is suspended in 600 ml of water and heated with stirring until a paste is obtained.

This paste is then used to granulate the mixed powders. If necessary, you can use more Water. The wet granulate is then rubbed through a No. 8 hand screen and dried at a temperature of 48.9 ° C (120 ° F). The dry granules are then passed through a No. 16 sieve. The mixture is made with 1% magnesium stearate as a lubricant added and compressed into tablets in a suitable tabletting device.

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Mem ever 500 mg 40 ml 15O mg 10 mg IO mg 50 mg ad 100 ml

Example 32

Preparation of an oral suspension

The orally administered suspension is made up of the following components:

5 component

3-ethyl-6- (p-carbamoylphenyl) -1,2,4-triazolo / 4,3-b7pyridazine

Sorbitol solution (70% N.F.) sodium benzoate

10 saccharin

Red dye
Cherry flavor
least. water

The sorbitol solution is added to 40 ml of distilled water and suspended therein 3-ethyl-6- (p-carbamoylphenyl) -1, 2, 4-triazolo / 4 ", 3-b7-pyridazine. Then you add saccharin, sodium benzoate, the flavor and the color and dissolve the materials. The volume is adjusted to 100 ml with distilled water. Each ml of the syrup formed contains 5 mg of 3-ethyl-6- (p-carbamoylphenyl) -1, 2, 4-triazolo / 4 ", 3-b7pyridazine.

Example 33

Preparation of a solution to be administered parenterally.

In a solution of 700 ml of propylene glycol and 200 ml of water for injections, 20.0 g are suspended with stirring 3, 7-Dimethyl-6- (p-aminophenyl) -1, 2, 4-triazolo / 4 ", 3-t> 7pyridazine monohydrochloride. After the material is suspended, adjust the pH to 5.5 with hydrochloric acid and bring!

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the volume with water for injections to 100 ml. The The formulation is sterilized and filled into 5.0 ml ampoules, each containing 2.0 ml of the material (which is 40 mg of the active ingredient), whereupon the ampoules are melted under nitrogen.

Example 34

6- (p-Chlorophenyl) -3, 8-dimethyl-1,2,4-triazolo / 4 ", 3-b7pyridazine

A mixture of 1.0 g of 3-chloro-6- (p-chlorophenyl) -4-methylpyridazine is heated, 0.62 g of acetic acid hydrazide and 10 ml of n-butanol reflux for 48 hours. The solvent is then drawn off and the residue is dissolved in dichloromethane and filtered through magnesol. The solid obtained from the filtrate is recrystallized from a dichloromethane / hexane mixture and yields 0.6 g of a solid melting at 209-212 ° C. Recrystallization from a dichloromethane / hexane mixture gives the title compound in the form of light pink crystals. M.p. 215 to 217 ° C.

Example 35

6 - («(, *, <* - trifluoro-p-tolyl) -1, 2, 4-triazolo / 4", 3-b7pyridazine.

A solution of 76.0 g of p-toluenesulfonic acid in 400 ml is cooled Tetrahydrofuran in an ice bath while adding 69.5 g of morpholine. Then remove the cooling bath and give it when it is reached the room temperature 65, Og p-trifluoromethylbenzaldehyde to, after which it is heated to reflux temperature for 2 hours. The reaction mixture is cooled in an ice bath, whereupon a solution of 32.6 potassium cyanide in 55 ml of water is added and the mixture on the Heated to reflux temperature. The solvent is then drawn off and the residue is partitioned between chloroform and water.

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The organic layer is washed with water, saturated sodium bisulfite solution and saturated sodium chloride solution, dried and evaporated to give OC- (OC, oC, ° C-trifluoroptolyl) -4-morpholine acetonitrile in the form of a yellow-brown solid. F 80 to 90 ⁰ C.

A solution of 52.3 g of C- (^, ^ (, o ^ -trifluoro-p-tolyl) 4-morpholine acetonitrile is stirred in 5OO ml of dry tetrahydrofuran at room temperature, during which 1 ml portions every half hour 30% potassium hydroxide solution in ethanol and 25 ml portions Acrylic acid ethyl ester is added until a total of 5 ml of the base and 150 ml of acrylic acid ethyl ester have been added. After completion After the addition, the mixture is stirred for 48 hours at room temperature. After filtering off the filtrate is concentrated, dissolved in methylene chloride, passed over magnesol and recrystallized from a methylene chloride / hexane mixture, whereby the ^ f-Cyano-V- (oC, oc, oc.-trif luor-p-tolyl) -4-morpholine-butyric acid ethyl ester in the form of cream-colored crystals. Mp 96 to 97 ° C.

A solution of 38.0 g of the above compound and is heated 9, Og hydrazine hydrate in 6OO ml of ethanol for 24 hours for Reflux. Then the solution is treated with activated charcoal, filtered and concentrated the filtrate. The residue is recrystallized from a methylene chloride / hexane mixture and gives 6- («C, e <, <X-Trifluoro-p-tolyl) -4,5-dihydro-3 (2H) -pyridazinoi in the form of cream-colored crystals. F 177 to 178 ° C.

A solution of 14.5 g of the above compound is heated Carefully place 1O.4 g of bromine in 150 ml of acetic acid on a steam bath until the material is completely discolored. Then heated one for another 30 minutes, after which it is poured onto crushed ice. The solid formed is filtered off with water washed and gives 6- (o (, oC, ot-trifluoro-p-tolyl) -3 (3H) -pyridazinone in the form of dirty white crystals. F 191 to

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193 ° C.

A mixture now 11 O g of oblynri compound and 150 ml Phosphoroxidclilorid is heated währoiid ^r> fllinulnn on a steam bath. The solution is then concentrated while stripping off the solvent, the residue is washed with cold water and 3-chloro-6 - («, o (,« <- trif lm »r ρ I dl yi) pyridazine is obtained in the form of a white solid . F 186 bin IRn ⁰ C.

A mixture of 4.5O g of 3-chloro-6- («<, o (, <K-trifluoro-p-tolyl) -pyridazine, 2.09 g of formylhydrazine and 100 ml of n-butanol with stirring for 3 days to reflux. The solvent is then drawn off, the residue is dissolved in methylene chloride, passed over magnesol and the crystallized solid obtained from the filtrate from a methylene chloride / hexane mixture to give the product in the form of white Receives crystals. F 16Ö to 161 ° C.

Example 36

3-methyl-6- (OC, (X, o (-trifluor-p-tol γΐ) -1, 2, 4-triazolo / ?, 3-b7pyridazine.

A mixture of 4, Bn y! V chlorine-6 - (^, O (, e (_trif luorp-tolyl) -pyridazine, Bring 2.58 g of acethydrazide and 100 ml of n-butanol to the reflux temperature for 3 days. Then you pull that The solvent is removed and the residue is dissolved in methylene chloride, the solution is crystallized through the Magnesol unit and from the Filtrate recovered solid nus ninor methylene chloride / hexane mixture around and receives the title template in the form of yellow-brown Crystals. M.p. 199 to 20 ° C.

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Example 37 Ot- (m-Chlorophenyl) -4-morpholine nontonitrile

To a cold Lösuncj of '/ (> y p-toluenesulfonic acid in 5OO ml Tetrahydrofurnti are iiirin 87 g morpholine and 50.6 g of m-chlorobenzaldehyde. Man (> thlt / (the mixture for 2 1/2 hours at reflux, 100 ml of tetrahydrofuran distilled off from the mixture, cooled and a solution of 28.6 g of potassium cyanide in 100 ml of water was added.The mixture was refluxed for 5 hours and evaporated to dryness in vacuo in methylene chloride, whereupon the solution is washed with water, with a sodium bisulfite solution and with a saturated sodium chloride solution and dried over sodium chloride. The solution is passed over a short column filled with hydrous magnesium silicate. The eluent is added with hexane evaporated, with crystals aunnchoidon. By cooling and filtering orh.Mlt now 78.0 g dm Ki In! all that melt at 72 to 73 ° C.

B e 1 s ρ t ο 1 38

20 3- (m-chlorobenzoyl) prop '"ill tr I I

120 drops of a 30% solution of potassium hydroxide in methanol are added to a solution of 2'λ, βq o <- (iii-chlorophenyl) -4-morpholine acetonitrile in 100 ml of tetrahydrofuran. 4.1 ml of acrylonitrile are added to the mixture, the temperature rising

45 ° C increases. After stirring for 1 hour, the mixture is concentrated to dryness in vacuo. The residue is dissolved in Methylene chloride and leads in through a short column filled with hydrous magnesium silicate. The eluate will concentrated in vacuo and gives 36.6 g of a yellow oil. The oil is on a steam bath with a mixture of 15Ο ml Acetic acid and 10 ml of water heated for 1 hour. Then pulls

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the solvent is removed in vacuo and the residue is treated with water. The mixture is filtered and 18.8 g of crystals are obtained. M.p. 49 to 51 ° C.

Example 39
\ 3- (m-chlorobenzoyl) -2-methylpropionitrile.

To a solution of 11.8 g of fc (- (m-chlorophenyl) -4-morpholine acetonitrile 60 drops of a 30% strength solution of potassium hydroxide in methanol are added to 5O ml of tetrahydrofuran. The solution is added then with 4.62 ml of methacrylonitrile, the tempe-

.0 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 over a short column, which is charged with hydrous magnesium silicate and the eluate is concentrated, whereby 15.5 g of a yellow oil are obtained.

.5 The oil is heated for 1 hour on a steam bath with a mixture of 75 ml of acetic acid and 5 ml of water, then the solvent is removed in vacuo. The addition of water to the residue gives 11.2 g of crystals, which at 72 to Melting at 75 ° C. The recrystallization of the crystals from a

»O methylene chloride / hexane mixture gives 8.95 g of crystals, the melt at 79.5 to 80.5 ° C.

Example 4P

3- (m-chlorobenzoyl) -2-methylpropionic acid.

A mixture of 7.90 g of 3- (m-chlorobenzoyl) -2-Ϊ5 methylpropionnitrile and 75 ml of concentrated hydrochloric acid is heated to reflux for 1 hour. 8/5 g of crystals which ^{melt at 102 to 105 °} C. are obtained by cooling. The crystals are dissolved in 50 ml In sodium hydroxide solution, the mixture is filtered and the filtrate is acidified with In chlorine (O hydrochloric acid solution. 8.15 g are obtained by filtration

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Crystals that melt at 103 to 105 ° C.

Example 41

6- (m-Chlorophenyl) -4,5-dihydro-4-methyl-3 (2H) -pyridazinone

A mixture of 7.11 g of 3- (m-chlorobenzoyl) -2-methylpropionic acid is heated, 50 ml of ethanol and 3.0 ml of hydrazine hydrate for 2 hours to reflux. By cooling and Filtration gives crystals (F 150 to 151 ° C.) which are recrystallized from ethanol and give 5.72 g of crystals. F 152 to 153 ° C.

10 Example 42 3- (m-Chlorobenzoyl) propionic acid.

Mar. heated a mixture of 8.1 g of 3- (m-chlorobenzoyl) propionitrile and refluxing 80 ml of concentrated hydrochloric acid for 7 hours. Separates as it cools an oil from which crystallizes and gives 8.8 g of crystals (F 1O5 to 107 ° C). The crystals are in sodium hydroxide solution dissolved, whereupon the mixture is filtered off, the filtrate is acidified with 1N hydrochloric acid and 8.7 g of crystals results. F 103 to 105 ° C.

2O Example 43 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 6O ml of glacial acetic acid is heated on a steam bath and then 25 % of a solution of 4, Ol g of bromine in 5 ml of acetic acid are added. After the bromine color has disappeared, the rest of the bromine solution is gradually added. One heats up

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the mixture for 0.5 hours on a steam bath and pour then on ice. The filtration gives crystals (F 243.5 to 245 C), which are recrystallized from ethanol and 4.0 g Gives crystals with a melting point of 244 to 245 ° C.

Example 44

6- (m-Chlorophenyl) -4,5-dihydro-3 (2H> -pyridazinone

A mixture of 7.7Og 3- (m-chlorobenzoyl) propionic acid is heated, 50 ml of ethanol and 3.0 ml of hydrazine hydrate for 2 hours to reflux. Then you cool the mixture .O off, filtered and the crystals crystallized (6.3O g, F to 147 C) from ethanol, 5.50 g of crystals with a melting point of 150 to 151 ° C being obtained.

Example 45

6- (m-Chlorophenyl) -3 (2H) -pyridazinone

L5 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 on a steam bath. 25 % of a solution of 4.01 g of bromine in 15 ml of glacial acetic acid are then added. After the bromine color has disappeared, the remaining bromine solution is added. The mixture is heated on a steam bath for an additional 0.5 hour and then the mixture is poured onto ice. The mixture is filtered and 3.30 g of crystals which melt at 214 to 216 ° C. are obtained.

Example 46

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 heated during

6 hours to reflux. The mixture is then concentrated to dryness in vacuo, and water is added to the residue. By filtering off, 3.28 g of crystals which melt at 138 to 140 ° C. are obtained. Recrystallization from ethanol gives 2.80 g of crystals with a melting point of 138 to

Example 47 3-Chloro-6- (m-chlorophenyl) pyridazine

A mixture of 25 ml of phosphorus oxychloride and 3.0g 6- (m-chlorophenyl) -3 (2H) -pyridazinone is heated for 6 hours to reflux. The mixture is concentrated in vacuo, and water is added to the residue. Obtained by filtration 3.30 g of crystals which melt at 155 to 157 ° C are added. Recrystallization from ethanol gives 2.75 g of crystals a melting point of 157 to 158 ° C.

Example 48

6- (m-ChlorophenyD-8-methyl-1,2,4-triazolo / 4,3-b7pyridazine

A mixture of 2.0 g of 3-chloro-6- (m-chlorophenyl) -4-methylpyridazine is heated, 50 ml of n-butanol and 1.08 g of formylhydrazine reflux for 18 hours. The mixture is then concentrated to dryness in vacuo and the residue is dissolved in Methylene chloride. The solution is passed over a short column filled with hydrous magnesium silicate. That eluted Material is heated to reflux while gradually adding hexane until crystals separate out. By cooling down and filtration gives 1.20 g of crystals. F 173 to 176 C. The crystals are dissolved in methylene chloride and passed through a short column filled with hydrous magnesium silicate, whereupon the eluent with the addition of Hexane is concentrated and 0.83 g of crystals results in

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Melting up to 182 ° C.

Example 49

6- (m-Chlorophenyl) -3-methyl-1,2,4-triazolo / 4 ", 3-b7pyridazine

A mixture of 2.0 g of 3-chloro-6- (m-chlorophenyl) pyridazine, 50 ml of n-butanol and 1.32 g of acetylhydrazine is heated to reflux for 18 hours. The mixture is then concentrated to dryness in vacuo, whereupon the residue is dissolved in methylene chloride. The solution is passed through a short column filled with hydrous magnesium silicate, after which the eluted material is heated to reflux, with hexane being added gradually until crystals separate out. Cooling and filtering give 1.50 g of crystals. F 171 to 172.5 ⁰ C.

15 Example 50

6- (m-Chlorophenyl) -3,8-dimethyl-1,2,4-triazolo / 4,3-b7pyridazine

A mixture of 7.17 g of 3-chloro-6- (m-chlorophenyl) -4-methylpyridazine is heated, 100 ml of n-butanol and 6.96 g of acetylhydrazine to reflux overnight. Then you cool the mixture off, filtered and obtained a solid. The solid is dissolved in methylene chloride, whereupon the solution over a short column filled with hydrous magnesium silicate leads. The eluate is heated to reflux, with hexane is gradually added until crystals form

divorce. Cooling and filtering give 3.30 g Crystals with a melting point of 193.5 to 195.5 ° C.

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Example 51

3- (m-Chlorophenyl) -6-hydrazinopyridazine

A mixture of 6.85 g of 3-chloro-6- (m-chlorophenyl) pyridazine is heated, 100 ml of n-butanol and 3.05 g of hydrazine hydrate to reflux overnight. One pulls the solvent in The vacuum is released and a semi-solid solid is obtained, which is dissolved in the minimum amount of hot nitromethane. By cooling down 3.5 g of an amorphous solid are obtained.

Example 52
6- (o-fluorophenyl) -1, 2, 4-triazolo / 4 ~, 3-b7pyridazine

The following reactions are carried out according to the procedure of Example 35: O-fluorobenzaldehyde is reacted with p-toluenesulfonic acid, morpholine and potassium cyanide to give <X- (o-fluorophenyl) -4-morpholine acetonitrile, which is obtained in the form of a yellow oil. The Y- (o-fluorophenyl) -4-morpholine acetonitrile obtained as product is reacted with ethyl acrylate to give Y-cyano-Y "- (of luophenyl) -4-morpholine-butyric acid ethyl ester in the form of an oil. A solution of the resulting Combination with hydrazine hydrate in ethanol at reflux and this gives crystalline 6- (o-fluorophenyl) -4,5-dihydro-3 (2H) -pyridazinone (melting point 119 ° to 121 ° C.) The compound obtained is heated with bromine in acetic acid and receives 6- (o-fluorophenyl) -3 (2H) -pyridazinone in the form of crystals (which are recrystallized from a methylene chloride / hexane mixture),

25 that melt at 173 to 175 ° C.

Then heating a mixture of the obtained compound and phosphorous oxychloride on the steam bath with the formation of crystalline 3-chloro-6- (o-fluorophenyl) pyridazine, F 95 to 96 ° C.

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-t- (o-fluorine Then heat a mixture of 5.0 g of 3-chloro-t- ( phenyl) pyridazine and 2.88 g of formylhydrazine in 75 ml of n-butanol to reflux for 48 hours and reworks the procedure described in Example 35, giving 1.1 g of the product in the form of cream-colored crystals receives. F 161 to 163 ° C.

Example 53

3-methyl-6- (o-fluorophenyl) -1,2,4-triazolo / 3,3-b7pyridazine

Following the procedure of Example 36, a mixture is heated from 2.5 g of 3-chloro-6- (o-fluorophenyl) pyridazine and 1.76 g of acetylhydrazine in 50 ml of n-butanol to boiling for 48 hours at reflux to give 2 g of the product as off-white crystals. F 147 to 149 ° C.

Example 54 15 6- (m-Fluorophenyl) -1,2,4-triazolo / 3,3-b7pyridazine

Following the procedure of Example 35, the following are carried out Reactions by:

It reacts m-fluorobenzaldehyde with p-toluenesulfonic acid, morpholine and potassium cyanide to give ck- (m-fluorophenyl) -4-morpholine acetonitrile, which after recrystallization from a methylene chloride / hexane mixture in the form of crystals with a melting point of 74 to 75 ° C is present.

The above compound is combined with ethyl acrylate to give crystalline Y-cyano-V- (m-fluorophenyl) -4-morpholine butyric acid ethyl ester um, which melts at 88 to 90 ° C. after recrystallization from a methylene chloride / hexane mixture.

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A solution of the above compound with hydrazine hydrate in ethanol is heated to reflux and crystalline products are obtained 6- (m-Fluorophenyl) -4,5-dihydro-3 (2H) -pyridazinone (das after recrystallization from a methylene chloride / hexane mixture melts at 132 to 134 ° C.

The above compound is heated with bromine in acetic acid and crystalline 6- (m-fluorophenyl) -3 (2H) -pyridaz-ynone is obtained after recrystallization from a methylene / hexane mixture melts at 207 to 209 ° C.

A mixture of the above compound and phosphorus oxychloride is heated to reflux and gives crystalline 3-chloro-6- (m-fluorophenyl) pyridazine, F 133 to 135 ° C.

Then a mixture of 3.6 g of 3-chloro-6- (m-fluorophenyl) is heated pyridazine and 2.06 g of formylhydrazine in 50 ml of n-butanol for 48 hours to reflux and that works Material according to the procedure of Example 35, wherein the product is obtained in the form of crystals with a melting point of 159 to 161 ° C.

Example 55
3-methyl-6- (m-fluorophenyl) -1,2,4-triazolo / 4,3-b7pyridazine

According to the procedure of 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 heated to reflux for 48 hours, whereby 2 , 0 g of the product is obtained in the form of crystals with a melting point of 184 to 186 ° C.

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for

Example 56

6- (o-chloropheny.l) -1,2, 4-trJn '/ ol η £ λ, 1- b7pyi'idazine

Following the IJoinpinls 35 procedure, the following are carried out Reactions by:

One sets o-chlorobenzaldehyde with p-toluenesulfonic acid, morpholine and potassium cyanide to <* - (o-chlorophenyl) -4-morpholine acetonitrile to, which is obtained in crystalline form and after recrystallization from a methylene chloride / hexane mixture melts at 40 to 42 ° C.

^T he above compound is reacted with ethyl acrylate to V ^ cyano-X- (o-chlorophenyl) -4-morpholinbuttersäureäthylester which is obtained in the form of oils.

A solution of the above compound and hydrazine hydrate is then heated in ethanol to the fH orinn mn reflux, being crystalline 6- (o-chlorophenyl) -4,5-dihyrtrr »1 (2Π) -pyridazinone is obtained, 114 to 116 ° C.

The compound obtained is heated in contact with bromine in acetic acid with the formation of crystalline II (o ( ¹ III orphenyl) -3 (2H) -pyridazinone, melting point 214 to 216 ° C.

M ^to A mixture of the compound nbUjtin with phosphorus oxychloride is brought to reflux and receives crystalline 3-chloro-6- (o-chlorophenyl) -pyridazine, F 145 to 147 ° C.

A mixture of 5.67 g of 3-chloro-6- (o-chlorophenyl) pyridazine is heated and 3.03 g of formylhydrazine in 50 ml of butanol for 48 hours to reflux and obtain 2.3 g of the product in the form of light yellow crystals. F 156 to 158 ° C.

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Example 57

3-methyl-6- (o-chlorophenyl) -1,2,4-triazolo / 3,3-b7pyridazine

Following the procedure of Example 36, a mixture of 5.5 g of 3-chloro-6- (o-chlorophenyl) pyridazine, 3.6 g, is heated Acetylhydrazine and 75 ml of n-butanol for 72 hours at reflux and obtained 2.2 g of the product in the form of dirty white crystals, F 146 to 148 ° C.

Example 58

4-methyl-6- «, d, δ (-trif 1 nor tn VnI yl) -4, 5-dihydro-3 (2H) -pyridazinone

To a lorning of 60, ο q Q ((<X, <¥, <* _ Tr if luor-m-tolyl) -4-morpholinacotonl I rti in 2on ml of TpIrnhydrofuran is added 5 ml of a 30% solution of Ka Liquid oxide in methanol. 22.0 ml of methacrylonitrile are then added to the mixture and the mixture is stirred overnight. In order to dry the reaction mixture in vacuo and the residue in chloroform. The solution is carried along with it water-containing magnesium silicate, onyl (Ina eluted material to a yellow oil, which is crystallized from an ether / hexane mixture to give 47 g of cream-colored crystals, temperature 88 to 90 ° C. 107 g of the above compound are heated with 600 ml of acetic acid and 75 ml of water on a steam bath for 18 hours, the solvent is then stripped off to give an oil, a mixture of the oil and 500 ml of 6N hydrochloric acid is refluxed for 24 hours and the mixture is cooled off and extracted with chloroform . The chloroform layer is washed with water and saturated sodium chloride solution and passed over a layer of magnon I containing water! 1 ikat filled column. Then the solvent is drawn off with inl from the eluted material and the residue is crystallized from an ether / hexane mixture,

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29.4 g of 2-methyl-3- (m-trifluoromethylbenzoyl) propionic acid Preserves in the form of light pink crystals, F 90 to 93 ° C.

A mixture of 25.4 g of the above compound and is heated 5.0 ml of hydrazine hydrate in 2OO ml of ethanol for 18 hours Reflux. The mixture is then cooled and filtered to obtain 21.8 g of the product in the form of cream Crystals, mp 188-19O ° C. A sample is recrystallized from a chloroform / hexane mixture and off-white is obtained Crystals with a melting point of 191 to 193 ° C.

Example. 59

8-methyl-6- (0 (, 0 <, CUtrifluoro-m-tolyl) -1, 2, 4-triazolo / 4, 3-t> 7-pyridazine.

To a solution of 20.5 g of 4-methyl-6- (^, ct ^ 4,5-dihydro-3 (2H) -pyridazinone in 2OO ml of acetic acid is added 14.4 g of bromine in 25 ml of acetic acid in portions. The mixture is heated for 0.5 hour and then the solvent is drawn off in a vacuum. Ice and water are added to the residue and the mixture is filtered, 20.4 g of 8-methyl-6 - («(, ci ^ - trifluoro-m-tolyl) -3 (2H) -pyridazinone in the form of cream-colored Crystals obtained, m.p. 234 to 237 ° C.

19.4 g of the above compound and 200 ml of phosphorus oxychloride are heated for 18 hours on a steam bath. The mixture is then concentrated to dryness in vacuo and the Residue with ice and water. The mixture is filtered and the solid is crystallized from a chloroform / hexane mixture to, 18.0 g of 3-chloro-4-methyl-6- (ol, O (, tf-trifluorom-tolyl) -pyridazine obtained in the form of cream-colored crystals, mp 123 to 126 ° C.

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A mixture of 8.0 g of the above compound is heated, 3.52 g of formylhydrazine and 125 ml of n-butanol are refluxed for 48 hours and then evaporated to dryness in vacuo a. The residue is dissolved in chloroform and passed through a column filled with hydrous magnesium silicate, whereupon the eluate is concentrated and the residue is recrystallized from a methylene chloride / hexane mixture, the product is obtained in the form of crystals with a melting point of 181 to 183 °.

10 Example 60

3, 8-Dimethyl-6 ~ (<*, *> (, << - trifluoro-m-tolyl) -1, 2, 4-triazolo / 4 \ 3-t> 7-pyridazine.

Following the procedure of Example 36, a mixture is heated from 8, Og 3-chloro-4-methyl-6- («<, o (, o (-trifluoro-m-tolyl) pyridazine, 4.34 g of acetylhydrazine and 125 ml of n-butanol are refluxed for 48 hours, 3.9 g of the product obtained in the form of crystals with a melting point of 196 to 198 ° C.

Example 61

7-methyl-6- (<*, <* - trifluoro-m-tolyl) -1, 2, 4-triazolo / 4 *, 3-b7pyridazine

To a solution of 0 (- (<X, O (, 0 (-Trifluoro-m-tolyl) -4-morpholine acetonitrile 1.0 ml of a 3O% solution of potassium hydroxide in ethanol is added to 100 ml of tetrahydrofuran. To the mix 2.56 g of crotononitrile are added and the mixture is stirred for 18 hours at room temperature. Then you narrow the mixture in a vacuum to dryness and dissolve the residue in chloroform. The solution is passed over a water-containing one Magnesium silicate filled column. The eluate is concentrated and

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gives 17.3 g of an oil which is crystallized from hexane and recrystallized from a chloroform / hexane mixture, whereby crystalline 3-methyl-2-morpholino-2- («(, * C << - trifluoro-mtolyl) -glutaronitrile obtained, F 115 to 118 ° C.

A mixture of 39 g of the above compound and 500 ml of 75% acetic acid is heated to reflux for 48 hours and the solvent is then removed in vacuo. The residue is dissolved in methylone chloride and the solution is washed with water, with a saturated sodium bicarbonate solution ^and a saturated sodium chloride solution. The organic layer of ammonium sulfate is then dried and passed over a column filled with water-containing magnesium sulfate. The eluate is concentrated and gives 27.4 g of 3- (m-trifluoromethylbenzoyl) butyronitrile in the form of a quarter of oil.

A mixture is then heated to reflux for 18 hours at 26.4 q dm: the above compound and 500 ml of 6N Chlorwnr.nerstol fsiiui t>w'llirond. You cool down and extract with dichloromethane. The organic * flchidite is extracted with a saturated sodium bicarbonate solution. The aqueous basic extract is acidified with 6N hydrochloric acid and extracted with. Ether. The ether layer is washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated, and 24.3 g of 3- (m-trifluoromethylbenzoyl) butyric acid are obtained in the form of a colorless oil.

A mixture of 24.3 g of the above compound, 5.0 ml of hydrazine hydrate and 200 ml of ethanol is heated to reflux for 18 hours and the solvent is then removed in vacuo. Don IUIcUnI and lönl niuii in Dl dilomethane, whereupon the solution is poured over a column I filled with insignificant magnesium silicate. One entjl dttri Khinl. and receives 20.7 g of 5-methyl-e-K, ^, c (I r I fluorine-tu I c> l yl) 4, Π dihydro-3 (2H) -pyridazinone in the form of white crystals with a melting point from 132 to 134 ° C. The recrystalline I r,: \\ lon now a methylene chloride / -

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Hexane mixture gives white crystals with a melting point

from 142 to 144 ° C.

The above compound orhlLzLman in acetic acid with bromine and receives 5-methyl-6- ("(, ^, rj ^ -trifluoro-m-tolyl) -3 (2H) -pyridazinone in the form of white crystals with a melting point of 224 to 227 ° C.

B ei a ρ i. Q "1 62.

3,7-Diniethyl-6 - (<*., <* AJL-t-iJi: iuur-in-tolyl) -1, 2, 4-triazolo / 4 ", 3-b7-pyridazine.

According to the procedure in Example 36, a mixture of 8.0 g of 3-ChI nr- »~ niothyl-6- (V _- Ql, (X-trifluoro-m-tolyl) -pyridazine is heated and 4.34 g of acnliylhydrazine in 125 ml of n-butanol for 48 hours at the slodon under reflux and receives 6.2 g of cream-colored crystals, mp 185 to 187 ° C.

15 Example 63

6- (m-Tolyl) -1, 2, 4-triazolo / 4 ", 3-b7pyridazine

Following the procedure of Example 35, the following reactions are carried out:

One sets m-tolualdehyde with p-toluenesulfonic acid, morpholine and potassium cyanide to << - (in-tolyl) -4-morpholine-acetonitrile, which falls in the form of crystalline and at 59 to 60 ° C melts.

The above compound is reacted with ethyl acrylate to give Y-cyano- X- (m-tolyl) -4-morplioi i η butyric acid ethyl ester, which is obtained in the form of an oil.

A solution of this compound with hydrazine hydrate is heated

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in ethanol to reflux and receives 6- (m-ToIyI) -4,5-dihydro-3 (2H) -pyridazinone in the form of white crystals, F 130 to 132 ° C.

The above compound is heated with bromine in acetic acid and 6- (m-tolyl) -3 (2H) -pyridazinone is obtained in the form of white crystals, F 202 to 2O5 ° C.

A mixture of the above compound and phosphorus oxychloride is then heated to reflux and 3-chloro-6- (m-tolyl) pyridazine is obtained in the form of dirty white crystals, F 112 to 113 ° C.

A mixture of 6.0 g of 3-chloro-6- (m-tolyl) pyridazine and 3.52 g of formylhydrazine in 100 ml of n-butanol is heated during 48 hours to reflux and the material is worked up according to the procedure of Example 35, using 2, Og white crystals (after recrystallization from a chloroform / hexane mixture) which melt at 164 to 166 ° C.

Example 64

3-methyl-6- (m-tolyl) -1,2,4-triazolo / S, 3-b? Pyridazine

Following the procedure of Example 36, a mixture of 6.0 g of 3-chloro-6- (m-tolyl) pyridazine and 4.34 g is heated Acetylhydrazine in 100 ml of n-butanol for 48 hours at reflux and receives 2.0 g of cream-colored crystals, F 160 to 162 ° C.

Example 65

3-propyl-6 - (*, *, * - trifluoro-p-tolyl) -1, 2,4-triazolo / 4 \ 3-b7-pyridazine

A mixture of 5.0 g of 3-chloro-6- (rt, oc, o <-trif luor-

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p-tolyl) pyridazine, 3.94 g of butyric acid hydrazide and 100 ml reflux n-butanol for 48 hours. The solvent is then drawn off in vacuo and the residue is dissolved in chloroform. The solution is passed through a column filled with hydrous magnesium silicate and concentrated Eluate, 3.2 g of product being obtained after recrystallization from a chloroform / hexane mixture gives crystals with a melting point of 173 to 175 ° C.

Example 66

3-ethyl-6- (<<, o (, o (-trifluoro-m-tolyl) -1, 2, 4-triazolo / ?, 3-t> 7-pyridazine.

A mixture of 5.0 g of 3-chloro-6- (o ("Q (, Q (_trifluorom-tolyl) pyridazine, 3.40 g of propionic acid hydrazide and 100 ml of n-butanol for 48 hours at reflux. then If the solvent is removed in vacuo, the residue is dissolved in chloroform, the solution is passed over a water-containing solution Magnesium silicate-filled column and the eluate is concentrated, 3.0 g of crystals being obtained after recrystallization melt from a chloroform / hexane mixture at 183 to 185 ° C.

20 Example 67

3-ethyl-6- («, egg, rt-trifluoro-p-tolyl) -1,2, 4-triazolo / 4", 3-b7-pyridazine.

Following the procedure of Example 65, 5.0 g of 3-chloro-6- (* C, QC, ct-trifluoro-p-tolyl) pyridazine and 3.4O g of propionic hydrazide are heated in 1OO ml of butanol to reflux for 48 hours and 3.1 g of dirty-white crystals are obtained melt after recrystallization from a chloroform / hexane mixture at 194 to 196 ° C.

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Example 68

6- (4-chloro - <*, «, <* _ trifluoro-m-tolyl) -1, 2, 4-triazolo / 3, 3-b7-pyridazine.

Using the method described in "Organic Syntheses" converts 5-amino-2-chlorobenzotrifluoride into 4-chloro-3- (trifluoromethyl) -benzaldehyde. Following the demonstration of the example 35 one then carries out the following reactions:

13.9 g of 4-chloro-3- (trif luotinol hyl) -benzaldehyde, 14.27 g of p-toluenesulfonic acid, 13.0 g of MorphuMii and 4.88 g of potassium cyanide are added to <(- / 3-chloro-3- . (trifluoromethyl) phony17-4-morpholineacetonitrile to that accumulates all having a melting point of 73 ° to 74 ° C in the form of white Krini Mnη nolzt then 14.0 g of this compound with ethyl acrylate to \ T-cyano-V "- / 3 -chlor-3- (trifluoromethyl) -phenyl7-4-morpholine butyric acid ethyl ester to,

[5 which is obtained in the form of a yellow oil in a yield of 16.5 g. 16.5 g of this compound are then reacted with 2.11 of hydrazine in 100 ml of ethanol and 4.2 g of 6- / 4 "-chloro-3- (trifluoromethyl) -phenyl7-4,5-dihydro-3 (2H ) -pyridazinone, which is obtained in the form of white crystals that grow at 195 to 198 ° C

O melt. This intermediate product is dissolved with bromine in

Acetic acid and receives 6- / 3-chloro-3- (trifluoromethyl) -phenyl7-3 (2H) -pyridazinone in the form of white crystals that melted at 249-251 ° C. Mnn get zl- nlno muscle from 5 g of this Compound and 60 ml of phosphorus oxychloride for 18 hours to boiling on the circulatory flow and erliM 11 1 rhi f) r-6- / 3-chloro-3- (trifluoromethyl) -phenyl / pyridazine In the shape of cream-colored crystals that melt at 145 to 147 ° C. Then you heat it up a mixture of 2.2 g of the obiqon prebond, 0.9 g of formylhydrazine and ΓιΟ ml n-Mnlnnol wMhiniul 4M mouths to simmer on Reflux and receives 2.1 g of the module, dns at 211 to 214.degree melts. The recrystallization of n-l'ropanol now gives cream-colored Crystals, F 217 to 218 ° (!.

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Yf Example 69

3-Metliyl-6 "(4-chloro-O *, ** / *. -Tr \ riuor-m-tolyl) -1, 2, 4-triazolo / 3,3-b7pyridazin

After the introduction, one heats one up Mixture of 2.2 g of S-chloro-ö-z ^ -chlor-S- (trifluoromethyl) -phenyl7 pyridazine and 1.11 g of Amt yi hydrazine in 50 ml of butanol during 48 SI unilon for boiling mn click flow and receives the product in Form of crystals, l · '2f »7 am 269 ° C.

Example 70
6- (3,4-dichlorophenyl) -1, 2,4-triazolo / 3,3-b7pyridazine

Following the procedure of Example 35, the following reactions are carried out:

106.3 g of 3,4-dichlorobenzaldehyde are reacted with 124 g of p-toluenesulfonic acid, 122 g of morpholine and 45 g of potassium cyanide in 500 ml of tetrahydrofuran and 136.9 g of C- (3,4-dichlorophenyl) -4-morpholine are obtained -ncetonitrile in the form of cream-colored crystals with a Schiuolzpunkl from fi ¹ ) to 71 ° C. Then 136.9 g of this compound are reacted with 50 ml of ethyl acrylate in 600 ml of tetrahydrofuran and nrliHH · 132.6 g of a yellow-brown oil.

These 132.6 g of the oil π and Tfi ml of hydrazine hydrate are heated in 5OO ml of ethanol to the boil with reflux, 63.5 g of 6- (3,4-dichlorophenyl) -4, 5-dihydro-3 (211) -pyridazinone is obtained in the form of yellow crystals, F 16H am 182 ° C. Then you heat it up 63.45 g of this intermediate option or M with 67.5 g of sodium m-nitrobenzenesulfonate and 52.0 g of nutritive hydroxide in 2 liters of water Night on a steam bath and add 26.4 g of 6- (3,4-dichlorophenyl) -3 (2H) -pyridazinone in the form of yellow-brown crystals with a melting point of 215 to 218 ° C. Then you heat it up 10 g of the above compound with 100 ml of phosphorus oxychloride on a steam bath to obtain 8.9 g of 3-chloro-6- (3,4-dichlorophenyl) -

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pyridazine. Obtained by column chromatography on silica gel using a chloroform / methanol mixture (95/5) 5.5 g of the product in the form of crystals, F 188 to 189 ° C.

Example 71

3-methyl-6- (3,4-dichlorophenyl) -1,2,4-triazolo / 4 ", 3-b7pyridazine

A mixture of 2.6 g of 3-chloro-o- (3,4-dichlorophenyl) is heated pyridazine and 1.8 g of acetic acid hydrazide in 50 ml of n-butanol for 24 hours to reflux and obtain the title compound, which melts at 267 to 269 ° C.

Example 72

For the production of tablets containing 50 mg of the active ingredient, the following components are used:

Per tablet Per 3,7,8-triethyl-6-phenyl-
1,2,4-triazolo / 3,3-b7-
pyridazine 10,000 Tablets 0.050 g Lactose 5OO G 0.080 g Corn starch (for the mixture) 8OO G 0.010 g Corn starch (for pasta) 1OO G 0.008 g 75 G 0.148 g Magnesium stearate (1 X) 1475 G O, OO2 g 15th G

0.150 g 1490 g

Mix 3, 7, 8-triethyl-6-phenyl-l, 2, 4-triazolo / 4 ~, 3-b7-pyridazine, Lactose and corn starch (for the mixture). The corn starch for the paste is then suspended in 600 ml of water and heated while stirring until a paste forms. This paste is then used to granulate the powder mixture. If necessary you add more water. The wet granules

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is passed through a No. 8 hand screen and dried at a temperature of 48.9 ° C (120 ° F). The dry granules are then passed through a No. 16 sieve. The mixture is mixed with 1 % magnesium stearate as a lubricant and pressed into tablets using a suitable tablet machine.

Example 73

Used to make a suspension to be administered orally the following components:

Component quantity

3,8-di-n-butyl-6-phenyl-1,2,4-triazolo-500 mg
/ 4 ", 3-b7pyridazine

Sorbitol solution (7O% N .F.) Sodium benzoate
Saccharin
Red dye 15 cherry flavor
Distilled water

The sorbitol solution is added to 40 ml of distilled water and
3.8-di-n-butyl-6-phenyl-1,2,4-triazolo / 4 ", 3-b7pyridazine is suspended in this mixture. Saccharin, sodium benzoate, the flavoring and the color are then added and the materials are dissolved The volume is then adjusted to 100 ml with distilled water. Each ml of the syrup contains 5 mg of 3,8-di-nbutyl-6-phenyl-1,2,4-triazolo / 4 ~, 3-b7pyridazine.

Example 74
Preparation of a solution to be administered parenterally.

In a solution of 700 ml of propylene glycol and 200 ml of water
for injection purposes one suspends 20.0 g of 7,8-di-n-propyl-6-phenyl-l, 2,4-triazolo / 4, Sb ^ pyridazine monohydrochloride, what

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40 ml 150 mg IO mg 10 mg 5O mg ad 1OO ml

takes place with stirring. After the suspension is obtained, the pH is adjusted to 5.5 with hydrochloric acid and the Volume with water for injections to 100 ml. Sterilize the formulation and fills each 2.0 ml of the formulation into 5.0 ml ampoules (each containing 40 mg of the active ingredient) and melts them under nitrogen.

Example 75

3,7,8-Trimethyl-6-phenyl-1,2,4-triazolo / 4 \ 3-t> 7pyridazine

1 l of ethyl alcohol is added to 200 g of 3-benzoyl-2,3-dimethylpropionic acid and 6O g of hydrazine hydrate and the mixture is stirred at the reflux temperature for 18 hours. The reaction mixture is then cooled in an ice bath and the 4,5-dihydro-4,5-dimethyl-6-phenyl-3 (2H) -pyridazinone obtained in the form of a cream-colored solid is obtained in the customary manner. This product is partially dissolved in 600 ml of glacial acetic acid. To this partial solution, a solution of 50 ml of bromine in 100 ml of glacial acetic acid is added in portions, heating on a steam bath (and about 15 % of the bromine solution being added to the reaction mixture before heating begins and about 1 hour is required for the Complete addition, during which time hydrogen bromide gas is released). When the addition is complete, the reaction mixture is heated on the steam bath for 1 hour and then the mixture is poured onto crushed ice. The solid obtained is filtered off in vacuo, washed well with water and air-dried and gives 4,5-dimethyl-6-phenyl-3 (2H) -pyridazinone in the form of a cream-colored solid. This material is added to 800 ml of phosphorus oxychloride and heated on a steam bath for 5 hours. The reaction mixture is concentrated to remove the excess phosphorus oxychloride and then diluted with cold water. The solid obtained is filtered off in vacuo, washed well with water and air-dried and gives 3-chloro-4,5-dimethyl-6-phenyl-pyridazine in the form of a pink solid

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Fabric. 10 g of this product are heated with 8 g of N-acetylhydrazine and 100 ml of n-butyl alcohol for 48 hours Stir to reflux. The reaction mixture is then cooled in an ice bath and the solid obtained is filtered in a vacuum, washes it first with petroleum ether, then with water and dries it in the air. The solid is after the treatment with activated charcoal is recrystallized from ethyl alcohol and dried in vacuo and gives 3,7,8-trimethyl-6-phenyl-1,2,4-triazolo / 4,3-b7pyridazine in the form of a white

10 solids.

Example 76

7-methyl-6-phenyl-1,2,4-triazolo / 4,3-fc> 7pyridazine

10 g of 6- (p-bromophenyl) -5-methyl-3 (2H) -pyridazinone are heated (J. Medicinal Chem. 17 (1974) 281) and 100 ml of phosphorus oxychloride for 3 hours on the steam bath. Then you give the mixture dropwise with stirring to cold water. The solid formed is filtered off and washed with water and gives 3- (p-bromophenyl) -6-chloro-4-methyl-pyridazine in the form of a gray solid. A mixture is then heated from 1.5 g of this compound, 0.64 g of formylhydrazine and 25 ml n-butyl alcohol for 18 hours with stirring to reflux. The reaction mixture is cooled in an ice bath, filtered and the solid crystallized from methyl alcohol, 6- (p-bromophenyl) -7-methyl-l, 2,4-triazolo / 3,3-b7-

25 receives pyridazine.

A mixture of 10 g of the above material, 30 ml of ammonium hydroxide, 250 ml of ethyl alcohol and a catalytic one is shaken Amount of 10% palladium on charcoal in a Parr shaker during 18 hours. The inclusion of the water

hydrogen, which is carried out under a pressure of 2.46 kg / cm (35 psi), finished in 2 hours. The reaction mixture is then filtered to remove the catalyst, whereupon the

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The filtrate is concentrated to a white solid which is triturated with petroleum ether. The solid is filtered off, on the
Air dried and from a methanol / ethyl acetate mixture
recrystallized, with 7-methyl-6-phenyl-l, 2,4-triazolo / 4,3-b7-j pyridazine obtained in the form of white crystals, F. 188 bis
19O ° C.

Example 77

3-methyl-6-phenyl-1,2,4-triazolo / 4,3-b7pyridazine

The title compound is prepared according to the procedure of LO Duffin et al described in GB-PS 839 02O dated June 29, 1960 is.

Example 78

3,8-dimethyl-6-phenyl-1,2,4-triazolo / 3,3-b7pyridazine

The title compound is prepared according to the method of Leclerc L5 and Wermuth (Bull. Soc. Chim. France, No. 5 (1971) 1752).

Example 79

3-isopropyl-6-phenyl-1,2,4-triazolo / 3,3-b7pyridazine

The procedure of Example 4 is repeated except that instead of the 3-benzoyl-2,3-dimethyl-propionic acid used there and N-acetylhydrazine equimolar amounts of 3-benzoyl-3-isopropyl-propionic acid and N-formylhydrazine is used. The title compound is obtained in a similarly good yield.

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Example 80

8-Isobutyl-6-phenyl-1,2,4-triazolo / 4,3-b7pyridazine

Following the procedure of Example 4, 3-benzoyl-2-isobutyl-propionic acid is converted in 3-chloro-4-isobutylpyridazine, which is used to form the title compound with N-formylhydrazine implements.

Example 81

3-ethyl-7-methyl-6-phenyl-1,2,4-triazolo / 4,3-b7pyridazine

The general procedure of Example 4 is repeated, but replacing the 3-benzoyl-2,3-dimethylpropionic acid used there and the N-acetylhydrazine used there by 3-benzoyl-3-methyl-propionic acid or N-propionylhydrazine.

Example 82

6-phenyl-1,2,4-triazolo / 4 ", 3-b / pyridazine

10 g of 3-chloro-6-phenyl-pyridazine (Chemical Abstract 44, 5616i), 6.6 g of formylhydrazine and 100 ml of n-butanol are heated during 48 hours to reflux. The reaction mixture is then cooled in an ice bath. The solid obtained is filtered off, washed with petroleum ether and with water and dried in the air and gives 6-phenyl-1,2,4-triazolo / 4 ~, 3-b7-pyridazine in the form of yellow-brown crystals, F 138 to 139 ° C.

Example 83

8-methyl-6-phenyl-1,2,4-triazolo / 4 ~, 3-b7pyridazine

A mixture of 13.2 g of 4-methyl-6-phenyl-3 (2H) -pyridazinone is heated and 2OO ml of phosphorus oxychloride for 18 hours

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on a steam room. The reaction / mixture is filtered off, whereupon the filtrate to remove the excess phosphorus oxychloride is narrowed. Mnn ι o'clock I the residue with ice water and filtered. The residue was washed wildly with water and dried in the air and gave 3-chloro-4-methyl-6-phenyl-pyridazine in the form of an off-white solid.

A mixture is heated aun ^ .05 i | the above product, 1.2 g formylhydrazine and 50 ml η-hat »um I while stirring 48 hours to reflux. Pnriri, the reaction mixture is concentrated to remove the solvent, and the mixture is stirred Residue with diethyl ether, the mixture is filtered and a creamy solid is obtained. This solid becomes Recrystallized from methanol after treatment with activated charcoal. The methanol filtrate is left slowly at room temperature Evaporate, white needles forming next to a dark yellow oil. The oil is removed and the needles are washed with it a small Meriqo Di Ml hylät Jut, don mnn decanted. the Needles are then made from a methanol / diethyl ether / petroleum ether mixture recrystallized and give fl-Mothyl-6-phenyl-l, 2,4-triezolo / 4 ", 3-t> 7pyrida?: In the form of white crystals, F 15Ο up to 151 ° C.

Example H 4

3-n-propyl-6-phenyl-l, 2, 4-triazol ο / Ά, 3-b7pyridazin

One heats a Ml nehtiiKi from Io <| I ⁽¹ Ii I or -6-phenylpyridazine, 11.2 g butyric Hydra / Id and I no ml ti lliilanol, omhiicj during 4O hours at reflux. Hie! Is then cooled, whereupon ABFI the precipitate I IrLert and with petroleum ether and washed with water. This oil is concentrated to an oil from which a precipitate forms after the addition of petroleum ether. The precipitate is separated off and washed with petroleum ether and with water. The solids are combined and extracted from 30 ml Recrystallized ethanol, whereby one

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stallincM 3 ti- propyl-6 plmiiy 1 1,2, 4-triazolo / 4 ~, 3-b7pyridazine receives, F 123 to 125 ^f V.

At s_ρ J. _e .1 85

3-ethyl-6-phenyl-1,2,4 tr inzoin / i, 3-b> 7pyridazine

A mixture of 7.6 g of ^ -chloro-o-phenylpyridazine is stirred, 7.4 g of propionic acid hydrazide and 60 ml of n-butanol for 48 hours on reflux. Then the solution is cooled in a cooled room, concentrated to remove the solvent and triturated with water to form crystals. The mixture is filtered, washed with petroleum ether and water and dried. The product is made from 20 ml of ethanol recrystallized and gives 3-ethyl-6-phenyl-l, 2,4-triazolo- / 4 ", 3-b7pyridazine, F 133 to 135 ° C.

A mixture of the above compound and formylhydrazine is then heated in n-butanol w.'iluond to reflux for 24 hours and receives 6- (3, 4-lHchlorophenyl) -1, 2, 4-triazolo / 4 ", 3-b7-pyridazine.

Example 86

3-methyl-6- (3, 4 diclil orphony I) I, 2, 4-triazolo / 4 ", 3-b7pyridazine

A mixture is now heated to 2.6 g of 3-chloro-6- (3,4-dichlorophenyl) pyridazine and 1.8 g of F, nnig! iiiurr <hydrazide in 50 ml of n-butanol during Boil for 24 hours on the waste stream and the title compound is obtained.

Example 87

6- / 2-ChIOr-S- (trifluoromethyl) -pheny ^ -triazolo / ?, 3-b7pyridazine According to the previous phrase from HnI spiel 68, 3-amino

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4-chlorobenzotrifluoride in 2-chloro-5- (fluoromethyl) -benzaldehyde, which is converted into 3-chloro-6- / 2-chloro 1- (trifluoromethyl) phenyl7-pyridazine, (Inn is obtained in the form of cream-colored crystals A mixture of 2.2 g of this compound with 0.9 g of forinyl hydrazine and 50 ml of n-butanol is then heated to reflux for 48 hours, and the title compound is obtained.

Example 88

-S- (trifluoromethyl) -pheny.17-1 / 2, 4-triazolo-

/ 3,3-b7pyridazine

Following the procedure of Example 36, a mixture is heated from 2.2 g of S-chloro-o-Zz-chloro-S- (trifluoromethyl) -phenyl-7-pyridazine and 1.11 q acetylhyrn7! i η in 50 ml of n-butanol during 48 hours to boil at the Rücki I Uli and receive the title compound.

Example 89

6- / 3-Nitro-3- (trifluorinothyl) pimiiy / 1 (2H) -pyridazinone

A mixture of 2.0 g of 6- / 3- (trifluoromethyl) phenyl7-3 is heated (2H) -pyridazinone and 10 ml of lactic nitric acid for 30 minutes on a steam engine. The mixture is poured then place on crushed ice, filter, and wash the solid with water. 2.2 g of the yellow solid are then dissolved in 20 ml 5N sodium hydroxide solution, cool the mixture with an ice bath and filter. The solid is dissolved in water, the The solution is acidic with hydrochloric acid, the solid is filtered off, washed with water and 1.0 g of cream-colored crystals are obtained. F 235 to 238 ° C. Recrystallization from a dimethylformamide / water mixture gives the product in the form of crystals which melt at 238 to 241 ° C.

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Bot π ρ i ο J. 9O

6- / 4 ~ -nitro-3- (trifluoromml hy I) phenyl7-l, 2, 4-triazolo / 3, 3-b7-pyridazine.

A mixture of 7.0 g of 6- / 4-nitro-3- (trifluoromethyl) -phenyl7-3 (2H) -pyridazinone is heated and 80 ml of phosphorus oxychloride for 18 hours on a steam bath. Then you pull the solvent and the residue is treated with ice water. Filtration gives 7.2 g of 3-chloro-6- / 3-nitro-3- (trifluoromethyl) -phenyl7-pyrirla7.in in the form of yellow-brown crystals, F 129 to 135 ° C. Recrystallization from a dichloromethane / hexane mixture gives cream-colored crystals, mp 151 to 155 ° C. The compound obtained is separated with formylhydrazine in am Reflux of the collected η lliilnnol for 24 hours and is maintained the title compound.

15 Example 91

3-methyl-6- / 4 "-nitro-3- (trifluoromethyl) -phenyl7-l, 2,4-triazolo / 4", 3-b7pyridazine

Heat a Minrhuncj min Ί, Ο g of 3-chloro-6- / 3-nitro-3- (trifluoromethyl) -phonyl7 pyi I <1π7 · .1η and 1.95 g acetylhydrazine i ⁿ ° 4 ^m l of n-butanol reflux for 1Π hours and the title compound is obtained in the form of crystals, melting point 293 ° to 295 ° C.

Example 92

6- / 4 "-Fluoro-3- (trifluoromethyl) -phenyl7-1, 2, 4-triazolo / 4", 3-b7-pyridazine

Do you just reduce a mixture? 10 g 6- / 4 * -nitro-3- (trifluoromethyl) -phenyl7-3 (2H) -pyridazinone in 50 ml trifluoroacetic acid

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with hydrogen using palladium on carbon as a catalyst and receives 6- / 3-AmInO-S- (trifluoromethyl) -phenyl73 (2H) -pyridazinone. The compound obtained is converted by the method described in J. Org. Chem. 26 (1961) 468 into 6- / 4 ~ -fluoro-3- (trifluoromethyl) -phenyl7-3 (2H) -pyridazinone. The compound formed is according to the procedure of Example 47 reacted with phosphorus oxychloride and leads to 3-chloro-6- / 4-fluoro-3- (trifluoromethyl) -phenyl7-pyridazine, the is reacted by the method of Example 48 with formylhydrazine to give the title compound.

Example 93

3-methyl- / 4 "-f luoro-3- (trifluoromethyl) -pheny17-1, 2, 4-triazolo- / 4", 3-b7pyridazine

Following the procedure of Example 36, 3-chloro-6- / 3-fluoro-3- (trifluoromethyl) phenyl7-pyridazine is used with acetic hydrazide in n-butanol and the title compound is obtained.

Example 94

3-methyl- / 4-chloro-3- (trifluoromethyl) -phenyl7-l, 2,4-triazolo- / 4 ", 3-b7pyridazine

The procedure described in J. Org. Chem. 25 (1961) 468 converts 6- / 3-amino-3- (trifluoromethyl) -phenyl7-3 (2H) -pyridazine in 6- / 3-chloro-5- (trifluoromethyl) -phenyl7-3 (2H) -pyridazinone around. The compound obtained is converted into 3-chloro-6- / 4 "-chloro-3- (trifluoromethyl) using phosphorus oxychloride -phenyl7-pyridazine that with acetic acid hydrazide following the procedure of Example 36 gives the title compound, mp 267 to 269 ° C.

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Example 95

-S- (trifluoromethyl) -phenyl7-l, 2,4-triazolo-

/ 4,3-b7-pyridazine

A mixture of 5 g of S-methyl-o-VÜ-nitro-S- (trifluoromethyl) -phenyl7-1,2,4-triazolo / ?, 3-b7pyridazine is reduced in 75 ml of trifluoroacetic acid with hydrogen and palladium-on-carbon as a catalyst and receives the title compound which, after recrystallization from methanol, turns cream-colored crystals supplies, F 240 to 242 ° C.

10 Example 96

3-methyl-6- (2-chloro-5-methylphenyl) -1, 2, 4-triazolo / 4 ", 3-b7-pyridazine.

Following the procedure of Example 35, 2-chloro-5-methyl-benzaldehyde is reacted with morpholine and potassium cyanide to give Y- (2-chloro-5-methylphenyl) -4-morpholine-acetonitrile. In a manner similar to that described in Example 35, the above compound is converted into 3-chloro-6- (2-chloro-5-methylphenyl) pyridazine, which is refluxed with acetic hydrazide in n-butanol for 24 hours, whereby the

Forms 20 title compound.

Example 97

3-methyl-6- (2,3-dichlorophenyl) -1,2,4-triazolo / 4 \ 3-b7pyridazine

Following the procedure of Example 35, 2,3-dichlorobenzaldehyde is converted in 3-chloro-6- (2,3-dichlorophenyl) pyridazine. Then a mixture of this compound and is heated Acetic hydrazide in n-butanol is refluxed for 24 hours and the title compound is obtained.

809812/0896

Example 98 6- (2-methyl-5-chlorophenyl) -1,2,4-triazolo / 4 _/ 3-b7pyridazine

Following the procedure of Example 35, 2-methyl-5-chlorobenzaldehyde is converted into 3-chloro-6- (2-methyl-5-chlorophenyl) pyridazine. A mixture of the above compound is then heated and formylhydrazine in n-butanol to reflux for 24 hours and obtain the title compound.

Example 99

-S- (trifluoromethyl) -phenyl? -1, 2, 4-triazolo / 4 ", 3-b7-

.0 pyridazine

Following the procedure of Example 35, 3-chloro-5- (trifluoromethyl) benzaldehyde is converted in S-chloro-ö-ZS-chloro-ö- (trifluoromethyl) -phenyl7-pyridazine The compound obtained is treated with formylhydrazine in n-butanol for 24 hours Heated to reflux and gives the title compound.

Example lOO

-S- (trifluoromethyl) -phenyl7-l, 2,4-triazolo-

/ 4 ", 3-b7pyridazine

A mixture of ^ -Chlor-e-ZZ-chlorS- (trif luor-

! 0 methyl) -phenyl7-pyridazine and acetic acid hydrazide in n-butanol

reflux for 24 hours and the title compound is obtained .

8Ubö12 / 0896

Claims (1)

Claims 1. Substituted 6-phenyl-1,2,4-triazolo / 4,3-b7pyridazine the general formula in the R ₁ , R_ and R ^ independently of one another are hydrogen atoms or alkyl groups with up to 3 carbon atoms and R. is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a trifluoromethyl group, a nitro group, an amino group, an acetamido group, a carbamoyl group, mean a thiocarbamoyl group or an alkyl group of up to 4 carbon atoms with first condition that at least one of the groups R. and R _{2 represents} a hydrogen atom, the second proviso that when R, R and R are all hydrogen atoms represent, R-, no methyl group and the third proviso that when R ₉ and R. each denote methyl groups, R and R do not represent hydrogen atoms and the pharmacologically acceptable acid addition salts of these compounds. 2. Compounds according to claim 1, characterized in that R ₁ and R "are hydrogen atoms, R- is a methyl group and R- is an m-trifluoromethyl group. 8U9Ö12 / 08Ö6 27A1763 3. Substituted 6-phenyl-1,2,4-triazolo / 3,3-b7pyridazine the general formula in the R., R- and R- independently of one another hydrogen atoms or alkyl groups with up to 3 carbon atoms, R., R_, R- and R_ independently of one another are hydrogen atoms, 4 i> ο / Chlorine atoms, bromine atoms, fluorine atoms, methyl groups, trifluoromethyl groups, Mean nitro groups, methoxy groups or amino groups, with the first condition that at least one of the groups R- and R_ represents a hydrogen atom and the second condition that two of the groups R., R _1. , R _fi and R_ are hydrogen atoms and the remaining two groups are independently chlorine atoms, bromine atoms, fluorine atoms , Methyl groups, trifluoromethyl groups, nitro groups, methoxy groups and amino groups, and the pharmaceutically acceptable salts of these compounds. Substituted 6-phenyl-1,2,4-triazolo / 3, 3-t> 7pyridazine der general formula 809812/0896 in the R. and R "independently of one another are hydrogen atoms or Alkyl groups with up to 3 carbon atoms, R represents a chlorine atom, a fluorine atom, a methyl group, a methoxy group or a trifluoromethyl group and R. mean a chlorine atom, a fluorine atom, a methyl group, a bromine atom or a trifluoromethyl group, and the pharmacologically acceptable acid addition salts of these compounds. 5. A compound according to claim 4, characterized in that R _{1 is} a hydrogen atom, R _{2 is} a methyl group, R ^ is a chlorine atom and R. is a trifluoromethyl group. 6. A method for preparing substituted 6-phenyl-l, 2, 4-triazolo / 4,3-b7pyridazinen of the general formula in the R ₁ , R "and R- independently of one another are hydrogen atoms or alkyl groups with up to 3 carbon atoms and R. A hydrogen atom, a fluorine atom, a chlorine atom Bromine atom, a cyano group, a trifluoromethyl group, a Nitro group, an amino group, an acetamido group, a carbamoyl group, a thiocarbamoyl group or an alkyl group with up to 4 carbon atoms mean, with the first proviso that at least one of the groups 25 R ₁ and R represents a hydrogen atom, the second proviso that when R, R "and R. all represent hydrogen atoms, R- is not a methyl group and
the third requirement that if R "and R are each methyl 809812/0896 represent groups, R ₁ and R do not represent hydrogen atoms, characterized in that a compound of the general formula with a compound of the general formula H ₃ N-NH-CR ₃ in which formulas the substituents R ₁ , R ₀ , R_ and R. 12 3 4 have the meanings given above, in a low molecular weight alkanol as a solvent the reflux temperature of the solvent during a Time that is sufficient for a substantial ring closure. 7. Process for the preparation of substituted 6-phenyl-1,2,4-triazolo / 3,3-b7pyridazines the general formula ^R 2 in which R, R ₃ and R ₃ independently of one another are hydrogen atoms or alkyl groups with up to 3 carbon atoms and R. a hydrogen atom, a fluorine atom, a chlorine atom 4th Bromine atom, a cyano group, a trifluoromethyl group, a Nitro group, an amino group, an acetamido group, a Carbamoyl group, a thiocarbamoyl group or an alkyl 809812/089 * -JtS - mean a group with up to 4 carbon atoms, with the first proviso that at least one of the groups R ₁ and R represents a hydrogen atom, the second proviso that when R ₁ , R_ and R. are all hydrogen atoms, R ^ is not a methyl group and the third proviso that when R "and R ^ are each methyl groups mean, R and R. do not represent hydrogen atoms, characterized in that one connects IO of the general formula NH-NH ₂ in which R ₁ , R 1 and R have the meanings given above, with an orthoformic acid alkyl ester with a low molecular weight alkyl group at a temperature of 50 to 175 ° C. for 1 to 24 hours or with an alkanecarboxylic anhydride, an alkanecarboxylic acid chloride and / or an orthoester of an alkanecarboxylic acid , which alkanecarboxylic acids have 2 to 4 carbon atoms, for 1 to 50 hours in an inert solvent at a temperature of 20 5O to 175 ° C converts. 8. Process for the preparation of substituted 6-phenyl-l, 2,4-triazolo / 4 *, 3-b7pyridazines of the general formula R- 609812/0896 - Yes - wherein R., R and R independently of one another are hydrogen atoms or alkyl groups with up to 3 carbon atoms and R-, R_, R, and R_ independently of one another are hydrogen atoms, Chlorine atoms, bromine atoms, fluorine atoms, methyl groups, trifluoromethyl groups, Mean nitro groups, methoxy groups or amino groups, with the first proviso that at least one of the groups R- and R "represents a hydrogen atom and the second condition that two of the groups R., R-, R, and R_ Mean hydrogen atoms and the remaining two groups independently of one another chlorine atoms, bromine atoms, fluorine atoms, methyl groups, trifluoromethyl groups, nitro groups, methoxy groups or represent amino groups, as well as the pharmaceutically acceptable acid addition salts of these compounds, characterized in that a compound of the general formula with a compound of the general formula H ₂ NNHCR ₃ in which formulas R., R_, R_, R., R _c , R _c and R "the above DO 7 have given meanings in a low molecular weight alkanol as a solvent for 1 to Reacts 48 hours at a temperature of 50 to 2OO ° C and the product wins. 809812/0896 Process for the preparation of substituted 6-phenyl-1,2,4-triazolo / ?, 3-b7pyridazines the general formula wherein R-, R "and R- independently of one another are hydrogen atoms or alkyl groups with up to 3 carbon atoms and R, Rr, R, and R independently of one another are hydrogen atoms, 4 ^ ο / Chlorine atoms, bromine atoms, fluorine atoms, methyl groups, trifluoromethyl groups, Mean nitro groups, methoxy groups or amino groups, with the first proviso that at least one of the groups R ₁ and R_ represents a hydrogen atom and the second proviso that two of the groups R., R, R and R represent hydrogen atoms and the remaining two groups independently of one another are chlorine atoms, bromine atoms, Represent fluorine atoms, methyl groups, trifluoromethyl groups, nitro groups, methoxy groups or amino groups, and the pharmaceutically acceptable salts of these compounds, characterized in that a compound of the general formula NHNH ₂ 809812/0896 in which R-, R_, R., R, R and R_ have the meanings given above have 1 to 48 hours at a temperature of 50 to 175 ° C with an orthoformic acid alkyl ester with a low molecular weight alkyl group or for 1 to 48 hours in an inert solvent at 50 to 175 C with an alkanecarboxylic acid anhydride, an alkanecarboxylic acid chloride and / or an orthoester of an alkanecarboxylic acid, which alkanecarboxylic acids have 2 to 4 carbon atoms, converts and isolates the product formed. .0 10. Process for the preparation of substituted 6-phenyl-l, 2,4-triazolo / 4 ", 3-b7pyridazines of the general formula in which R ₁ and R "are independently hydrogen atoms or alkyl groups with 1 to 3 carbon atoms and R. a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, a nitro group, an amino group, an acetamido group, a carbamoyl group, a thiocarbamoyl group or an alkyl group with up to 4 carbon atoms with the proviso that at least one of the groups R ₁ and R "represents a hydrogen atom, characterized in that a compound of the general formula NH-NH ₂ 809812/0896 in which R ₁ , R ~ and R have the meanings given above, is reacted with an orthoformic acid alkyl ester with a low molecular weight alkyl group at 50 to 175 ° C. for a period of time which is sufficient to bring about a sufficient degree of ring closure. 11. Process for the preparation of substituted 6-phenyl-1,2,4-triazolo / 3,3-b7pyridazines the general formula wherein R and R ~ independently of one another are hydrogen atoms or alkyl groups with up to 3 carbon atoms and R is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a trifluoromethyl group, a nitro group, an amino group, an acetamido group, a carbamoyl group, a thiocarbamoyl group or denote an alkyl group with up to 4 carbon atoms with the proviso that at least one of the groups R ₁ and R "represents a hydrogen atom, characterized in that a compound of the general formula NH-NH ₂ 20 "" _N wherein R, R "and R. have the meanings given above, 809812/0896 with an alkanecarboxylic acid anhydride, an alkanecarboxylic acid chloride and / or an orthoester of an alkanecarboxylic acid, which alkanecarboxylic acids have 2 to 4 carbon atoms, in an inert solvent at 50 to 175 C for a period of time which is sufficient for a substantial degree of ring closure. 12. Process for the preparation of substituted 6-phenyl-1,2,4-triazolo / 3,3-b7pyridazines the general formula IO what R. and R "independently of one another are hydrogen atoms or Alkyl groups with up to 3 carbon atoms, R- a chlorine atom, a fluorine atom, a methyl group, a Methoxy group or a trifluoromethyl group and R. mean a chlorine atom, a fluorine atom, a bromine atom, a methyl group or a trifluoromethyl group, thereby characterized in that a compound of the general formula ^C 3 - 20 with a compound of the general formula 809812/0896 in which formulas R-, R ", R- and R, those given above Have meanings in a low molecular weight alkanol as a solvent at the reflux temperature of the solvent during a Time that is sufficient for a sufficient degree of ring closure. 13. Process for the preparation of substituted 6-phenyl-1, 2,4-triazolo / 4,3-b7pyridazines of the general formula IO in the R _{1 is} a hydrogen atom or an alkyl group with up to 3 carbon atoms, R., a chlorine atom, a fluorine atom, a methyl group, a Methoxy group or a trifluoromethyl group and R. mean a chlorine atom, a fluorine atom, a methyl group, a bromine atom or a trifluoromethyl group, thereby characterized in that a compound of the general formula NH-NH ₂ 2O 809812/0896 in which R ₁ , R and R have the meanings given above, is reacted with an orthoformic acid alkyl ester with a low molecular weight alkyl group at a temperature of 50 to 175 ° C. for a period of time which is sufficient for a noticeable degree of ring closure. 14. Process for the preparation of substituted 6-phenyl-1,2,4-triazolo / 3,3-b7pyridazines the general formula \ alkyl in the R is a hydrogen atom or an alkyl group with up to 3 carbon atoms, R- is a chlorine atom, a fluorine atom, a methyl group, a methoxy group or a trifluoromethyl group and
R. mean a chlorine atom, a fluorine atom, a bromine atom, a methyl group or a trifluoromethyl group, characterized in that a compound of the general formula MH-NH ₂ in the R ₁ , R- and R. have the meanings given above, with an alkanecarboxylic acid anhydride, an alkanecarboxylic acid chloride and / or an orthoester of an alkanecarboxylic acid, which alkanecarboxylic acids have 2 to 4 carbon atoms, 809812/0896 in an inert solvent at a temperature of 5O to 175 ° C for a period of time which is sufficient for a sufficient degree of ring closure. 15. Medicinal products with an anxiety-inducing effect, thereby indicates that there is at least one compound according to claim 1 and customary, pharmacologically acceptable binders, Contains carrier materials and / or auxiliaries. 16. Medicines in dosage unit form for reducing the elevated blood pressure in mammals, characterized in that that it is per dose unit to be administered daily and per kilogram of the body weight of the patient to be treated about 1.0 to about 25.0 mg of a compound according to Contains claim 1 in combination with a pharmaceutical carrier material. 17. Medicines in unit dose form for the relief of anxiety in mammals, characterized in that it is per daily dose unit to be administered and per kilogram of the to treating patients about 0.03 mg to about 10.0 mg 3-methyl-6-phenyl-1, 2, 4-triazolo / 4 ~, 3-fc> 7pyridazine or a pharmacologically acceptable acid addition salt thereof in Contains combination with a pharmaceutical carrier material. 18. Medicines in unit dose form to reduce the increased Blood pressure in mammals, characterized in that it is per dose unit to be administered daily and per Kilograms of the body weight of the patient to be treated about 1.0 mg to about 25.0 mg of a compound according to claim 4 in combination with a pharmaceutical carrier material. 19. Use of the compounds according to claim 1 for reduction 809812/0898 27A1763 the increased blood pressure in mammals by internal administration an effective dose of these compounds. 20. Use of 3-methyl-6-phenyl-1,2,4-triazolo / 4,3-b7pyridazine or a pharmacologically acceptable acid addition salt thereof for the relief of anxiety in mammals by administering an effective amount internally thereof Link. 21. Use of the compounds according to claim 4 for reducing the elevated blood pressure of mammals by internal administration an effective amount of this compound. 809812/0896