IE51694B1 - 3,8-optionally substituted-6,7-substituted-s-triazolo(4,3-b)pyridazines and compositions comprising them - Google Patents

Description

‘ATENT APPLICATION BY (71) THE DOW CHEMICAL COMPANY, A JORPORATION ORGANIZED AND EXISTING UNDER THE LAWS OF THE ΐΤΑΤΕ OF DELAWARE, UNITED STATES OF AMERICA, OF MIDLAND, 1OUNTY OF MIDLAND, STATE OF MICHIGAN, UNITED STATES OF AMERICA.

Price 90p The present invention relates to new pharmacologically active heterocyclic compounds. More particularly, the invention relates to 3,8-opti onal ly substi tuted-6,7-substi tuted-£-tri azol op, 3-bj pyri dazines corresponding to the formula wherein R3 represents hydrogen or loweralkyl; Rg represents amino, loweralkylamino, diloweralkylamino, or lower alkyl substituted heterocyclic amino, wherein the heterocyclic moiety forms a 5 or 7 membered ring, or Rg represents heterocyclic amino wherein the heterocyclic moiety forms a 5, 6 or 7 membered ring or lower alkyl substituted heterocyclic Ot? amino wherein the heterocyclic amino moiety forms aS^membered ring, the 5, 6 or 7 membered rings having one or two ring nitrogen atoms and optionally one ring sulfur or oxygen atom; Ry represents loweralkyl; Rg represents hydrogen or loweralkyl; or Ry and Rg taken together represent polymethylene or substituted polymethylene of 3 or 4 methylene units, e.g., -CH2-(CH2)n- wherein n is 2 or 3 substituted by loweralkyl, or methano or ethano bridges; and to pharmacologically acceptable salts of said compounds.

The compounds wherein R7 and Rg are polymethylene or substituted polymethylene having four methylene units can be named either as s-triazolo[4,3-b]pyridazines or as 7,8,9,10-tetrahydro(1,2,4)triazolo[3,4-a]phthalazines. When so named, the 7,8,9 and 10 positions refer to the carbons of the tetramethylene group attached to the pyridazine residue. A preferred group of such compounds are those corresponding to Formula I in which R? and Rg, taken together are polymethylene or bridged polymethylene, said bridged polymethylene compounds corresponding to the formula wherein Rg and Rg have the above significance, and B represents methylene or ethylene. Compounds of Formula II can be named as substituted triazolopyridazines or as tetrahydrotriazolophthalazines.

In the present specification and claims the terms loweralkyl and lower alkoxy refer to compounds containing one, two, three or four carbon atoms; and halo refers to fluoro, chloro or bromo. 51684 The invention is inclusive of subgroups of compounds of the above formula, for example, those wherein R3 is hydrogen; those wherein R3 and Rg are both hydrogen; those wherein R3 represents hydrogen, methyl, ethyl or propyl; those wherein Rg is pyrrolidino, those wherein Ry and Rg are substituted polymethylene substituted by loweralkyl, methano or ethano, those wherein Rg is piperidino; those wherein Rg is morpholino or thiamorpholino; those wherein Rg is amino; those wherein Rg is azepinyl or diazepinyl; or those wherein Rg is N-methyl piperazino; those wherein R_, and Rg are polymethylene; those wherein R_ and R. are substituted polymethylene, substituted with methano, etc. Such subgroups are apparent from the above description and the following specification; and further listing is omitted for the sake of brevity. Preferred groups of compounds comprise those wherein the loweralkyl is methyl; those wherein Rg is hydrogen; those wherein Rg is pyrrolidino, piperidino; 2-methylpyrrolidino, hexahydro-ΙΗ-azepin-l-yl, or 4-methyl-hexahydro-lH-l,4-diazepin-l-yl those wherein Rg is hydrogen or methyl; and those wherein R_ and Ro are polymethylene, with or without a methano or ethano bridge.

The compounds of the invention may be prepared by the reaction of a 3-halo-6-hydrazinopyridazine of formula III with a substituted carboxyl compound of formula IV HO-C-R3 IV wherein R3, R7 and Rg have the above significance and wherein X is halo, generally at a temperature of 40° to 150°C, preferably 100° to 130°C, in an excess of acid optionally diluted with an inert solvent, having a boiling point of 40° to 200°C, preferably 75° to 175°C, followed by reacting the resulting 6-halo-triazolopyridazine with the corresponding Rg amine, at a temperature of 75° to 160°C, preferably 100° to 140°C, in the same solvent employed for the reaction of compounds III and IV.

Useful solvents include either an inert organic solvent or a hydroxylic solvent such as, for example, water, C1-C4 alkanols and their admixtures with water, C^-C^ alkoxy alkanols, glycol ethers, dioxane, aliphatic and cycloaliphatic hydrocarbons, aromatic hydrocarbons, chlorobenzene and chlorinated aliphatic hydrocarbons such as methylene chloride. The reactions are preferably carried out at atmospheric pressure, although higher pressures may be employed if desired.

Thus, the compounds of the invention can be prepared by first reacting a 3-chloro-6-hydrazinopyridazine with an appropriate acid of formula XV. This reaction proceeds when the reactants are contacted and mixed, preferably at the boiling temperature of the reaction mixture. The first step of the reaction is preferably carried out in an excess of the reacting acid, the excess acid serving as reaction medium or component thereof.

The 6-halo-triazolopyridazine product can be recovered from the reaction mixture by evaporation to remove the excess acid reaction medium and can be purified by conventional procedures such as recrystallization and washing.

The substituted 6-halo-triazolopyridazine, in an appropriate solvent, is then reacted with excess Rg amine (e.g. at least two fold on a molar basis) or the Rg amine in the presence of an inorganic base such as, for example, sodium carbonate or a non-nucleophilic amine, as hydrogen halide acceptor. The reaction is preferably carried out at the boiling temperature, using excess Rg base. The product is recovered by conventional procedures such as concentration under reduced pressure.

The starting materials for the above method can be prepared by procedures which are known. The necessary pyridazines for the method above are obtained by reacting the appropriate 3,6-dihalo-4,5-substituted pyridazine with hydrazine hydrate.

In an alternative procedure for preparing substituted triazolopyridazines of Formulae I and II, a 3,6-dihalo-4,5-substituted pyridazine of Formula V The reaction is conveniently carried out in an inert solvent, as hereinbefore described, at a temperature of 25° to 150°C, preferably 50° to 140°C, in the presence of an inorganic base, such as, for example, sodium carbonate, a non-nucleophilic amine, or an excess of the Rg amine, as a hydrogen halide acceptor.

The resulting 3-halopyridazine is then reacted with a loweralkanoyl hydrazine of Formula VII R3C-NH-NH2 VII preferably in the presence of an acid catalyst, in an inert liquid medium, preferably an oxygenated solvent such as, for example, an alkylene glycol alkyl ether, at a temperature of from 50° to 200°C, preferably 100° to 175°C. The generation of hydrogen halide during the reaction accelerates the reaction rate. The product is recovered and purified by conventional procedures. These reactions are preferably carried out at atmospheric pressure although higher pressures may be employed if desired. In the above formulae, Rg, Rg, R? and Rg have the significance set out above with respect to Formulae I-IV.

The hydrazino pyridazine starting materials can be prepared by known procedures. For example, 3,6-dichloro-4-methylpyridazine heated at reflux with excess hydrazine hydrate (50 percent in water) for 0.3 to 1 hour produces 3-chloro-4-methyl-6-hydrazinopyridazine and 3-chloro-5methyl-6-hydrazinopyridazine. The isomers can be separated by fractional crystallization using ethanol as a solvent. See, Takahayashi, Pharm. Bull., 5, 229 (1957); Chem. Abstr. 52:6359, Linholter et al., Acta Chem. Scand. 16, 2389 (1962); Chem. Abstr. 59:1632g, Steck et al., J.

Amer. Chem. Soc., 76, 4454 (1954) and Homing et al., J.

Org. Chem., 20, 707 (1955).

When and Rg are cyclopentylene or cyclohexylene, the dichloro intermediate is conveniently prepared from a 4,5,6,7-tetrahydro-4,7-(methano or ethano)isobenzofuran-1,3-dione., Diels and Alder, Ann., 478, 149 (1930); Ann., 490, 236 (1931). The dione compound is reacted with excess hydrazine hydrate in an exothermic reaction to produce the corresponding hexahydro-5,8-(methano or ethano)phthalazine-l,4-dione. Additional heating at 100°-170°C for 10-30 minutes may be useful to complete the reaction. The phthalazine-1,4-dione is then reacted with excess phosphorus oxychloride heated at reflux for about 2-4 hours, cooled and the product hydrolyzed by careful addition of ice and water to produce the dichloro intermediate.

The 3,6,7,8-substituted-s-triazolo[4,3-b]pyridazine compounds corresponding to the above formulae and their pharmacologically acceptable salts have useful biological activity as bronchodilators and also have a desirably low toxicity and freedom from undesirable side effects at dosages consistent with good bronchodilator activity.

Some triazolopyridazines are known to have different properties. For example, 6-methyl-3-(4-morpholiny1)-8-phenyl-s-triazolo[4,3-b]pyridazine, rather than blocking histamine-induced bronchoconstriction, has been found to potentiate bronchoconstriction. The compound 6-morpholino-3-phenyl-s-triazolo[4,3-b]pyridazine, although a potent bronchodilator with a high LD5Q (low toxicity), has been found to produce audiogenic convulsions in laboratory animals at relatively low dosages. See, U.S. Patent 4,136,182.

The triazolopyridazine compounds are crystalline solids which can be readily formulated in aqueous or alcoholic liquids. In general, the free base compounds are readily soluble in aqueous liquids, and the triazolopyridazine compounds are conveniently employed in either free base or salt form.

In practicing the method an effective bronchodilating amount of one or more substituted triazolopyridazine is administered internally to a mammal in need thereof by a route effective to bring the compound into contact with the bronchial and tracheal tissues of the mammal. Administration can be carried out either by a parenteral route, such as by intravenous, intraperitoneal, or intramuscular injection, or by introduction into the gastrointestinal tract via oral or rectal administration, for example, in order to bring about such contact via the blood stream, or by intratracheal administration, by inhalation of a solution in the form of a spray, for example.

The effective bronchodilating amount of the compound, that is, the amount of the substituted triazolopyridazine sufficient to inhibit or alleviate bronchial spasm depends on various factors such as the size, type and age of the animal to be treated, the particular triazolopyridazine or pharmacologically-acceptable salt employed, the route and frequency of administration, the severity of spasm (if any) and the causative agent involved, and the time of administration. In particular cases, the dosage to be administered can be ascertained by conventional range finding techniques, for example, by observing the bronchodilator activity produced at different dosage rates. Good results can be obtained when the compound is administered at dosage rates from 1 to 3, to 10 to 50 milligrams of substituted triazolopyridazine compound per kilogram of animal body weight. It is generally desirable to administer individual dosages at the lowest amount which provides the desired protection from bronchial spasm consonant with a convenient dosing schedule. Dosage units adaptable to oral administration such as tablets, capsules, lozenges, elixirs, syrups and the like are preferred and the active triazolopyridazine compound can be formulated in conventional timed release capsule or tablet formulations.

Some of the compounds can produce audiogenic convulsant side effects at dosages which, though much higher than the effective dose for bronchodilation, are still below a toxic dosage. Bronchodilator activity can be obtained at high, but non-toxic dosages at which additional factors could promote undesirable convulsant side effects, by eliminating other factors contributing to audiogenic convulsions. However, it is preferable to employ the compounds at effective dosages substantially below the audiogenic convulsant dosage, e.g. at one third, to one fifth, one-tenth or less of the audiogenic convulsant dosage. The audiogenic convulsant dosage, (dosage producing audiogenic convulsions) can be determined in known procedures, as described for example in U.S. Patent 4,136,182.

In practising tbe method of the invention, the active ingredient is preferably incorporated in a composition comprising a pharmaceutical carrier and from about 5 to about 90 percent by weight of the substituted triazolopyridazine compound or a pharmacologically-acceptable salt thereof. The term pharmaceutical carrier refers to known pharmaceutical excipients useful in formulating pharmacologically-active compounds for internal administration to animals, and which are substantially non-toxic and non-sensitizing under conditions of use. The compositions can be prepared by known techniques for the preparation of tablets, capsules, lozenges, troches, suppositories, elixirs, syrups, emulsions, dispersions, wettable and effervescent powders, sterile injectable compositions, and can contain suitable excipients known to be useful in the preparation of the particular type of composition desired. Suitable pharmaceutical carriers and formulation techniques are found in standard texts, such as Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania.

As employed herein, the phrase pharmacologically acceptable salt refers to salts of the substituted triazolopyridazines, the anions of which are relatively nontoxic and innocuous to mammals at dosages consistent with good biological activity so that side effects ascribable to the anions do not vitiate the beneficial effects of the triazolopyridazine compounds. Suitable pharma15 cologically acceptable salts can be prepared by conventional procedures such as dissolving the free base compound in an inert organic solvent such as ether and treating the resulting solution with an excess ether solution of a suitable pharmacologically acceptable acid such as hydro20 chloric acid, or hydrobromic acid.

For the sake of brevity, such compounds will be hereinafter referred to simply as triazolopyridazines.

The following examples illustrate the invention.

Example 1 13.4 Grams (0.0845 mole) of 3-chloro-4-methyl-6-hydrazinopyridazine are dissolved in 100 milliliters of agueous 88 percent formic acid.

The mixture is heated at the boiling temperature under reflux for 2 hours. The mixture is evaporated under reduced pressure and the 7-methyl-6-chloro-s-triazolo[4,3-b]pyridazine intermediate product is obtained as a residue. The.residue is triturated with diethyl ether, and found to melt at a temperature of 157.5-158 °C. 7.8 Grams (0.0462 mole) of the 6-chloro-7-methyl-s-triazolo[4,3-b]pyridazine is mixed with 7.86 grams (0.0924 mole) of piperidine in 50 ml of ethanol. The mixture is heated at reflux temperature for 4 hours. The mixture is concentrated by evaporation and the residue of the reaction mixture is partitioned between agueous sodium bicarbonate solution and methylene chloride. The methylene chloride layer is separated, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The 7-methyl-6-piperidino-s-triazolo[4,3-b]pyridazine product is obtained as a residue from the evaporation. The product is recrystallized from hexane and found to melt at 78°-79°C. The structure of the product is confirmed by infrared spectroscopy, by nuclear magnetic resonance analysis, and by elemental analysis. (Calculated for cnH].5N5: C' H, 6.96; N, 32.24. Found: C, 60.40; H, 6.98; N, 32.17.) Example 2 6-Chloro-3,7-dimethyl-s-triazolo[4,3-b]pyridazine (4.56 grams; 0.025 mol) and 4.36 grams (0.05 mol) of morpholine are mixed together in 20 ml ethanol and heated at the boiling temperature under reflux for 4 hours. After cooling, crystals are observed in the reaction vessel.

The reaction mixture and crystals are partitioned between methylene chloride (50 ml) and water.

The agueous layer is extracted twice with methylene chloride and the combined methylene chloride layers are dried over anhydrous sodium sulfate. The dried methylene chloride solution is then evaporated to dryness under reduced pressure, and 5.68 grams of the 3,7-dimethyl-6-morpholino-s-triazolo[4,3-b]pyridazine product are obtained. The product is recrystallized twice from a benzene-hexane mixture. The product is found to melt at a temperature of 160e-174°C. Structure of the product is confirmed by infrared spectroscopy and by elemental analysis, and nuclear magnetic resonance analysis shows the presence of about 71 percent of the 3,7-dimethyl product with about 29 percent of the 3,8-dimethyl isomer.

The corresponding 6-piperidino compound is similarly obtained with about 30 percent of the 3,8-dimethyl isomer. The product melts at 102°-114°C.

Example 3 6-Chloro-7-methyl-s-triazolo[4,3-b]pyridazine (2.4 grams; 0.014 mol) and excess pyrrolidine (about 0.028 mol) are mixed together in ethanol and heated under reflux overnight (about 18 hours). The reaction mixture is then evaporated and the residue is partitioned between methylene chloride and saturated agueous sodium bicarbonate solution. The methylene chloride layer is separated, washed with water, dried with anhydrous sodium sulfate, and evaporated to dryness. The 7-methyl-6-pyrrolidino-s-triazolo[4,3-b]pyridazine product is crystallized from ethanol and observed to melt at 186°-187°C. Molecular weight calculated: 203.24, mass spectroscopy (70 eV) m/e 203. 7-Methyl-6-morpholino-s-triazolo[4,3-b]pyridazine is similarly prepared and found to melt at 172°-173°C. Calculated C, Η, N: 54.78, 5.98, 31.95; Found C, Η, N: 54.90, 5.76, 31.84.

Example 4 7-Methyl-6-N-methylpiperazino-s-triazolo[4,3-b]pyridazine is similarly prepared. This product is found to melt at 169°-170°C. The product is found by elemental analysis to have carbon, hydrogen, and nitrogen contents of 56.8, 6.7 and 36.2 percent, respectively, as compared with the theoretical contents of 56.9, 6.9 and 36.2 percent, respectively, calculated for the named structure. Molecular weight, calculated: 232.2, by mass spectroscopy (70 eV) m/e 232.

Example 5 l-Chloro-4-hydrazino-5,6,7,8-tetrahydro-5,8-methanophthalazine (25 grams; 0.12 mol) was mixed with 150 milliliters of formic acid and heated at the boiling temperature under reflux for 2 hours. The reaction mixture was concentrated by evaporation under reduced pressure and taken up in agueous sodium bicarbonate. The resulting precipitate was collected by filtration, washed with water and dried in air. The 6-chloro-7,8,9,10-tetrahydro-7,10-methano[1,2,4]triazolo-[3,4-a]phthalazine product (21.6 grams, 82.5% yield) was found to melt at 155°-156°C, and at 157°-158eC after recrystallization from a benzene-hexane mixture.

The structure was confirmed by infrared spectroscopy, nuclear magnetic resonance analysis and elemental analysis. (Calculated for C10H9C1N4: C, 54.42; H, 4.11; N, 25.39. Found: C, 54.40; H, 4.12; N, 25.20). This 6-chloro compound (6.5 grams, 0.029 mol) was mixed with 25 milliliters of N-methylpiperazine, and the mixture heated at boiling under reflux for 6 hours. The mixture was concentrated by evaporation under reduced pressure, then partitioned between methylene chloride and water. The organic layer was separated, dried over sodium sulfate and concentrated to obtain the 7,8,9,10-tetrahydro-6-[4-methyl-l-piperazinyl]15 -7,10-methano(l,2,4)triazolo[3,4-a]phthalazine product. After recrystallization from benzene/hexane, 6.6 grams (79 percent yield) of the product were obtained, with a melting point of 172°-173°C. Structure was confirmed by infrared and nuclear magnetic resonance analysis, and by elemental analysis. (Calculated for ci5H20N6: C, 63.35; H, 7.09; N, 29.56. Found: C, 63.30; H, 7.05; N, 29.33.) Example 6 In a procedure similar to that of Example , l-chloro-4-hydrazino-5,6,7,8-tetrahydro-5,8-methanophthalazine (25.0 grams, 0.119 mol) was mixed with 150 milliliters of acetic acid, and the mixture was heated at the boiling temperature under reflux for two hours. The reaction mixture was concentrated and the residue taken up in aqueous sodium bicarbonate. The resulting precipitate was collected, washed with water and air-dried to yield 23.4 grams (84 percent yield) of 6-chloro-7,8,9,10-tetrahydro-3-methyl-7,10-methano(1,2,4)triazolo[3,4-a]phthalazine. After reerystallization from benzene-hexane this product melted at 137°-138°C. Infrared spectroscopy and elemental analysis were consistent with the named structure.

The 6-chloro-7,8,9,10-tetrahydro-3-methyl7,10-methano(1,2,4)triazolo[3,4-a]phthalazine (4.5 grams, 0.019 mol) was mixed with 25 milliliters of morpholine and the mixture heated at boiling under reflux for eight hours. The reaction mixture was concentrated and partitioned between methylene chloride and water. The organic layer was collected, dried over sodium sulfate and evaporated to dryness to yield 4.4 grams (80.6% yield) of 7,8,9,10-tetrahydro-3-methyl-6-(4-morpholinyl)-7,10-methano(1,2,4)triazolo[3,4-a]phthalazine. After reerystallization from benzene-hexane the product was found to melt at 166°-168°c. Infrared analysis and nuclear magnetic resonance analysis confirmed the assigned structure, as did elemental analysis. Calculated for C15H19N5O: C, 63.14; H, 6.71; N, 24.55. Found: C, 63.20; H, 6.71; N, 24.32.

Examples 7-14 In a procedure similar to those of the preceding examples, the following compounds are prepared. In each case the R? and Rg substituents of Formula I, taken together are 1,3-cyclopentylene, and the compounds thus correspond to the general formula wherein R- and R, are as defined above with respect □ o to Formula I. μ Τ3 β «Η Φ Φ υ •Η μ >4 Φ Λ CM ιΛ t*· CO CO φ CO Φ Φ μ C β β β β Φ φ Φ Φ Φ Φ Ν μ X X X X X •η ¢4 φ Φ Φ Φ Φ rH φ Χ2 XJ Λ Λ Λ rH > 1 1 Φ rH φ φ Φ Φ φ μ 0 β β β β β ω ω φ φ Φ Φ φ >1 Ν Ν Ν Ν Ν μ β β β β β ο Φ Φ Φ Φ Φ φ Λ Λ Λ Λ XI & rH β Φ Λ μ Φ U mo Sp Ρ β rH ·Η Φ o vO & cn od Ό β β Ο O' ο u m t% rH CM cn CO rH O σ» CM o Φ | CO γΗ rH CM rH if> CM 1 σ» 1 CM rH «η CO co CM O «η CM f- rH rH CM rH rH CM >1 rH rH >1 rH •Η >( β >1 >1 C >1 0.43 •rl ¢4 β •rH β I ·Η — Ό •H •μ •μ rlfl 41 •μ Ό rH Ή •ΰ < —Ό rH •H 0 rH •μ ιΗ -Η 0 μ XJ 0 μ >ίΗ Μ μ Φ a μ φ 43 >ιθ μ Λ μ μ α Ρ CH >t •Η 0 >1 •μ di • ε Ph ίΧι I ENU I 1 rH 1 rH i-H rH rn as *e r- co σ» cn K υ cn υ κ CM rH Ρ Ό £ r-i ¢) φ ο ♦rt Ρ >-» β) £ ο -rt ρ Π3 Ν >Ρ •rt C ι—I φ Η > Φ γ-η Ρ Ο (0 ω >1 Ρ υ φ ο Ο>ο ΰ •Η Ρ Ρ £ rrt ·η Φ Ο ε ε Ό £ £ Ο α ε ο υ φ £ Φ X Φ £ I φ £ Φ Ν £ Ρ φ £ Ρ Φ I Γ-Ι ο £ Φ £ Ο •rt Ρ £ r—I Ο (Q Φ £ Φ Ν £ Φ £ Φ £ Ρ cn £ •rt Ρ φ Ρ £ Ρ £ Φ Φ · (0 (Q Ρ Ί3 Η £ Φ Φ (Ο Φ Φ Ο cn £ Ό cn Φ-rt Η (Ν Ν Ρ 1 1 £ 0 σ» Ρ φ Η CN > ££ ι-Ι CN ϋ £ 0 •rt Ρ Ό Φ >ι ϋ] £ Φ ·Η φ £ Ό Ό •rl Φ Φ γ-1 rrt Ρ Φ £ >1 >1 0 Ρ Ρ 1 £ 1 £ (rt Ρ rrt -rt frt-rt£ Φ 1 Ν 1 Μ □ Φ Ρ rrt Φ rrt Φ 0 £ Φ >ι Μ >ι Ρ Ρ Ρ Ρ £ Φ £ Φ Ό -rt Ρ Οι Ρ Οι >1 σ* Οι φ «rt Φ -rt £ £ -η ε Οι S Oi-rt •rt ϋ 1 t Ό > Φ — rrt Ρ cn Ε U Ο Λ ω φ ο •rt Ρ Ό (0 >t Φ £ σ» Ί? «rt φ Ο υ ε -σ £ ο Ρ Ρ 'rt Ε £ Examples 15-23 l-Chloro-4-hydrazino-5,6,7,8-tetrahydro-5,8-ethanophthalazine (2.5 grams, 0.111 mol) was mixed with 150 milliliters of formic acid. The mixture was heated at the boiling temperature under reflux for 2 hours, then evaporated to dryness.

The residue was triturated with saturated agueous sodium bicarbonate. The resulting white solid was collected, washed with water and air dried to yield 23.0 grams (88% yield) of 6-chloro-7,8,9,10-tetrahydro-7,10-ethano(1,2,4)triazolo[3,4-a ]phthalazine, melting at 137°-140°c. After recrystallization from a mixture of benzene and hexane the purified product melted at 140.5°-141°c. Infrared spectroscopy and elemental analysis confirmed the designated structure.

In substantially the same procedure, using acetic acid instead of formic acid, 23.8 grams of 6-chloro-7,8,9,10-tetrahydro-3-methyl-7,10-ethano(l,2,4)triazolo[3,4-a]phthalazine was produced (86 percent yield). Melting point 178°-179°C after recrystallization from benzene-hexane.

Using 5 to 10 grams of one of the two above substituted 6-chloro-triazolopyridazines and 50 milliliters of the appropriate amine Rg reactant, the following compounds were prepared. Reaction mixtures were heated at reflux for about 2 hours. Reaction mixtures were then concentrated and partitioned between water and methylene chloride.

The organic layers were dried and concentrated.

In each case, the Ry and Rg substituent is 1,4-cyclohexylene, so the compounds are nameable as 51094 7,8,9,10-tetrahydro-3,6-substituted-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines, corresponding to the general formula wherein R_ and R, are as defined above with respect J D to Formula I. fi ο •rl Ρ to Ν -Ρ •H fi Η 0) d <0 rH 4J 0 ω ω >1 li υ φ os o Oto •5+j ρ β rH ·Η tt 0 ε a > ιΛ η r* Φ ω Ν CO if) cn co cn © cn cn rH CO cn CO in co CM o o rH rH rH rH CM I CM CM CM CM ι I rH 1 rH 1 O © >· > co 5j< CM © © rH r—i rH rH CM CM CM CM CM to li tt rH rH rH a >, rH >1 rH rH •H fi fi >1 fi >1 >1 a •rf •H a •rl β fi 1 Ό Ό •rH Ό •rH •ri rH •ri •ri rH •ri r-i 1 rH o rH •H 0 rH 0 tt 43 0 li Jfi tHrH li •rt a li tt a 42 >1 li a u li a n •P fi >1 •ri 0 >1 •ri 0 tt-H a a ε a a ε I ε n rH 1 rH «*· rH 1 rH os cn S3 cn X □ cn X o X u Ό fi fi O a in mo f* co r—4 rH rH rH Φ O rH •H CM CM 61694 73 Ρ β Ρ Φ φ ϋ •rt rt >1 φ ft c ο •rt Ρ β Ν Ρ •rt β Ρ 0) Ρ > (Ο Ρ Ρ ο ω ω >1 rt ϋ φ Οί υ φΐο β •rt Ρ Ρ β Ρ *rt Φ Ο ε ft Ό β β Ο α ε ο ο Ul Θ Ρ φ ι Ρ Ο β β Ρ Φ Ο Π rt Φ > Ο I (ΰ rt φ ftp •rt α CUE ι cq Ρ I = Ρ >»P A >i Ρ β Φ -rt 2 N I si* Φ β β X Φ I φ β φ Ν β Φ Λ ο <Ν cq ι ω ι Φ β ω rt β Φ Ρ ft -η φ cu Φ ι rt Η Ρ 1 — rrt >,Ρ 43 th Ρ β φ -rt 2 Ν I Μ* Ό β Φ β Φ (UPH Ο 43 43 β β ·Η Ρ Η 0 ρ ρ ρ >rt β-rt β 3 5 Ό Φ ft Φ Η · Φ Μ -rt S Ο Ό Ό rt β ϋ φ 10 Φ·Η β φ φ Ρ Ρ rrt rt 43 rt Φ Φ U Ο Ρ ft 43 ' Ρ Ό Ρ Ο θ' β β β Ό 10 -rt β rt Ρ 73 β φ ρ Φ Ρ β rt rt •rt ίθ β Φ ρ Φ rt Ρ .Η rt Ρ β Φ υ *Η ρ β ? rt Ρ Ρ ρ φ-rt β β C •rt 43 β Ρ rt Ο ε η >ι·η « ο ο 43 -Η (0 ο Ό ε ω ιη · Ό Φ Ό β ω Φ > Φ β 5 β β S ρ 43 β •rt O' rt ο Η η ρ ιο *0 cq ρ φ ρ ω cq Ό β -rt •ri ο β Φ nJ Ό rt ϋ Ρ rt β Ο (fl β Ρ β ρ Φ β β β Ο 43 rt £ Ο Φ ftO β Λ ϋ S ρ cq rt β ο β ϋ cq β Ο U Φ β U Ο Φ O' rt Ρ *rt (fl Ρ Ο Ρ Ρ 43 Ρ β Ο rt W β U 43 Ό ω S β ω 5η φ β rt Φ ε 43 43 Φ -rt Ρ Φ β Ρ Ό Ό Μ rt rt 43 -rt Ο Φ Ρ Θ'Ρ Ό rt ω •Η β Ο Φ θ' cq 5 β ρ Ό Λ β 43 Φ Ρ·Η θ' β Ό UP Ρ β ο Φ Ο β Ό Ρ •rt -rt -rt rt rt β β > ρ rt Ό β β w Ρ β Ό >ιΡ Φ Ο Ρ I 43 β Φ rt ω ο rt -rt ιη Ό ω ω ρ Ό ρ φ -η β 43 rt 43 73 Φ Φ Ρ Ο Ρ 73 43 -rt Ρ >,ρ β Eri >43Ρ 43 β Ο Ο cn ϋ 73 β Ό · -rt Φ Φ Φ p φ ω ω β rt β (Q β rt ·π Ρ β * >ι Φ Ο 43 Ρ Μ Ό β 73 Φ 5 φ ε 43 φ • Ρ 73 β β Ο ft ε ο ο ϋ Ρ Ρ •rt β φ β •rt β β υ ω 43 ρ Ρ (Q 73 rt Φ >1 >1 ϋ >1 Ο β Ρ Ρ Φ 43 β Ρ rt Ρ Ρ β Ό Ρ rt β ft β 0 C β Φ Ρ β κ (0 υ β ε ε ω β Example 24 l-Chloro-4-hydrazino-5,6,7,8-tetrahydrophthalazine, also nameable as 3-chloro-4,5-tetramethylene-6-hydrazino pyridazine, (50 grams, 0.25 mol) was mixed with 250 milliliters of formic acid. The mixture was heated at the boiling temperature under reflux for 2 hours. The mixture was concentrated by evaporation under reduced pressure, and the oily residue mixed with saturated agueous sodium bicarbonate solution. The resulting white solid was separated by filtration, washed with water and dried in air. The 6-chloro-7,8,9,10-tetrahydro(l,2,4)triazolo[3,4-a]phthalazine product was recrystallized from alcohol-hexane and found to melt at 124°-125°C. (Yield 42.4 grams, 81 percent). Elemental analysis confirmed the structure. .4 Grams (0.05 mol) of the 6-chloro-7,8,9.10- tetrahydro(1,2,4,triazolo[3,4-a]phthalazine were mixed with 8.53 grams (0.12 mol) pyrrolidine in 100 milliliters of ethanol. The mixture was heated at the boiling temperature under reflux for 10 hours, then concentrated by evaporation under reduced pressure until a solid residue was obtained. The solid was partitioned between methylene chloride and water; the organic layer was collected and the water layer extracted twice with methylene chloride. The methylene chloride layer and extracts were combined, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure.

The resulting colorless solid 6-(l-pyrrolidinyl)7.8.9.10- tetrahydro(1,2,4)triazolo[3,4-a]phthalazine product was crystallized from ethanol and found to melt at 194-195.5°C. 9 Grams of product were obtained, a 74 percent yield from this step. 51894 Elemental analysis confirmed the structure (Calculated for C13H17N5: C, 64.17; H, 7.04; N, 28,79 Found: C, 64.4; H, 7.01; N, 28.83.) The product is also named as 6-pyrrolidino-7,8-tetramethylene5 -s-triazolo[4,3-b]pyridazine.

Example 25 In a similar procedure, 6-piperidino-7,8-tetramethylene-s-triazolo[4,3-b]pyridazine, also named as 6-piperidino-7,8,9,10-tetrahydro10 (l,2,4)triazolo[3,4-a]phthalazine, melting at 134.5-135.5°C was prepared.

Example 26 In a procedure similar to those of the preceding examples, 40 grams of 3-chloro-4,515 -dimethyl-6-hydrazinopyridazine and 200 milliliters of aqueous 80 percent formic acid were heated at reflux for 90 minutes to obtain 6-chloro -7,8-dimethyl-s-triazolo[4,3-b]pyridazine. This triazolopyridazine (9.18 grams, 0.05 mole) was mixed with 12.25 grams N-methylpiperazine in 80 milliliters of ethanol, and the mixture was heated at reflux for 3 hours. The product was recovered by evaporation, partitioning the oily residue between methylene chloride and water and evaporation of the organic layer. The resulting 6-(N-methylpiperazino)-7,8-dimethyl-s-triazolo[4,3-b]pyridazine was obtained as colorless crystals. Thin layer chromotography on silica gel developed with 90 percent chloroform: 10 percent methanol indicated the presence of triazolopyridazine intermediate in the product.

The product was taken up in excess N-methylpiperazine and heated at reflux for 12 hours, 61694 followed by 2 hours of reflux in 20 milliliters of N-methylpiperazine. The resulting 6-(N-methylpiperazino)-7,8-dimethyl-s-triazolo[4,3-b]pyridazine was obtained as colorless crystals.

Thin layer chromotography on silica gel developed with 90 percent chloroform: 10 percent methanol indicated the presence of triazolopyridazine intermediate in the product. The product was taken up in excess N-methylpiperazine and heated at reflux for 12 hours, followed by 2 hours of reflux in 20 milliliters of N-methylpipera2ine.

The resulting 6-(N-methylpiperazino)-7,8-dimethyl-s-triazolo[4,3-b]pyridazine was separated as before, crystallized from benzene-hexane and found to melt at 170°-172°C. (Calculated: C, 58.51; H, 7.37; N, 34.12. Found: C, 58.70; H, 7.27; N, 34.18.) Example 27 In a procedure similar to Example 25, 5-chloro-7,8,9,10-tetrahydro(1,2,4)triazolo[3,4-a]phthalazine (prepared as in Example 24) (10 grams, 0.048 mol) and 12.2 grams (0.122 mol) of N-methylpiperazine in 100 milliliters of ethanol were heated at reflux for 20 hours. Thin layer chromatography (TLC) showed the presence of unreacted phthalazine. The ethanol was evaporated, 50 milliliters of N-methylpiperazine were added and the mixture heated at reflux for 2 hours, after which TLC indicated the reaction to be complete. The mixture was concentrated, and partitioned between methylene chloride and water, and the residue from evaporation of the methylene chloride was recrystallized twice from a mixture of benzene and hexane, then once from hexane. 516 9 4 The 6-(4-methyl-l-piperazinyl)-7,8-tetramethylene(l,2,4)triazolo[4,3-b]pyridazine product was found to melt at 160-162°C. 12.45 Grams of the product were obtained (95 percent yield). The structure was confirmed by nuclear magnetic resonance analysis and infrared spectroscopy. (Calculated: C, 61.74; H, 7.40; N, 30.86. Found: C, 61.90; H, 7.35; N, 30.59). Nuclear magnetic resonance (CDClg); δ 9.84 (s, 1, CH); 3.4-3.0 (m,6); 2.8-2.5 (m,6); 2.38 (s, 3, CH3); 2.1-1.7 (m, 4, CHg CHg CHg CHg).

Melting point of monohydrochloride salt 265°-266°C.

In similar procedures, the following are prepared: 7,8-Dimethyl-6-pyrrolidino-s-triazolo15 [4,3-b]pyridazine, melting at 143°-144°C; 6-Morpholino-7,8-tetramethylene-s-triazolo[4,3-b]pyridazine, also named as 6-morpholino-7,8,9,10-tetrahydro(1,2,4)triazolo[3,4-a]phthalazine, melting at 194°-196°C; 6-Morpholino-7,8-dimethyl-s-triazolo[4,3-bJpyridazine, molecular weight 233.27, melting at 143°145 °C; 6-(2-Methylpiperidino)-7,8-tetramethylene-s-triazolo-[4,3-b]pyridazine, melting at 84°-86e, molecular weight 299.41. 6-Piperidino-3-methyl-7,8-tetramethylene-s-triazolo[4,3-b]pyridazine, melting at 144-144.5°C; 6-Piperidino-3,7,8-trimethyl-s-triazolo[4,3-b]pyridazine, melting at 138-139°C; 6-Morpholino-3,7,8-trimethyl-s-triazolo[4,3-b]pyridazine, melting at 123-124°C; 6-Piperidino-7,8-dimethyl-s-triazolo[4,3-b]pyridazine, melting at 127-128°C; 6-Morpholino-3-methyl-7,8-tetramethylene-s-triazolo[4,3-b]pyridazine, melting at 189-190°C; Example 28 6-Chloro-7,8,9,10-tetrahydro(1,2,4)triazolo[3,4-a]phthalazine (7.2 grams; 0.0345 mole) was mixed with 20 milliliters of hexamethyleneimine and 100 milliliters of methanol. The mixture was heated at the boiling temperature under reflux for 30 hours, cooled and partitioned between methylene chloride and water.

The methylene chloride layer was dried and evaporated to dryness. The residue was recrystallized from benzene-hexane to give the 6-(hexahydro-lH-azepin-1-yl)-7,8-tetramethylene(1,2,4)triazolo[4,3-b)pyridazine as colorless crystals, melting at 109°C. Elemental analysis: C, Η, N calculated: 66.39; 7.80; 25.81; C, Η, N found: 66.04; 7.42; 25.76, The above reaction was carried out without the methanol reaction medium, and the product was found to melt at 108°-109°C.

Example 29 .65 Grams of 6-chloro-7,8-tetramethylene(1,2,4)triazolo[4,3-b]pyridazine and 35 milliliters of 2-methylpyrrolidine were mixed and heated under 516 9 4 reflux for two hours. The reaction mixture was evaporated to dryness, and partitioned between methylene chloride and water. The methylene chloride layer was dried and evaporated to leave 12.5 grams (64.8% yield) of 6-(2-methylpyrrolidinyl) 7,8-tetramethylene(1,2,4)triazolo[4,3-b]pyridazine. The product was recrystallized from benzene-hexane and found to melt at 146°-147°C. C, Η, N calculated 65.34; 7.44; 27.22. C, Η, N found: 65.5; 7.51; 27.36.

Examples 30-36 In procedures similar to those of Examples 28 and 29, the following 6-substituted-7,8-tetramethylene-s-triazolo[4,3-b]pyridazines were pre15 pared. The compounds are identified below by the Rg substituents; Ry and Rg being tetramethylene and Rg being hydrogen.

Example -Be Yield (Percent) Melting Point °C 30 Methylamino 86 155-156 31 Dimethylamino 71.7 153-154 32 3-Methylpiperidino 100 99-102 33 4-Methylpiperidino 100 152.5-154 34 Hexahydro-4-methyl1H-1,4-diazepin-l-yl 63.3 135-136 35 dihydrochloride salt of 34- 249-251 36 Ethylamino - 250-251 |Ρ· Examples 37-43 In a similar procedure, the following compounds were prepared, in which R3 is methyl, R7 and Rg are tetramethylene, and Rg is identified below. Example - Yield (Percent) Melting Point °C 37 Methylamino 78.1 279-280 38 Dimethylamino 72.6 128-129 39 2-Methyl-1-pyrrolidinyl 50 142 40 3-Methylpiperidino 61 152-153 41 4-Methylpiperidino 81.7 143-144 42 4-methyl-l-piperazinyl 66.8 183 43 Hexahydro-4-methy1-1H-1,4-diazepin-l-yl 56.6 114-115 dihydrochloride 56.9 240-241 Examples 44-52 A. A solution of 98.5 grams (0.496 mole) of l-chloro-4-hydrazino-5,6,7,8-tetrahydrophthalazine in 300 milliliters of propionic acid was heated at reflux for 18 hours, then concentrated by evaporation to half the original volume. The solution was diluted with aqueous sodium carbonate until neutral (pH 7). The resulting precipitate was collected, air-dried at ambient temperature, then dried in a drying over to produce 105 grams (0.444 mol) of 6-chloro-3-ethyl-7,8,9,10-tetrahydro-l,2,4-triazolo[3,4-a]phthalazine, melting at 93 °-94°C (89.6% yield). Calculated for C,55.81; H, 5.53; N, 23.67. Found: C, 56.00; H, 5.63; N, 23.87.

B. In a procedure similar to the foregoing examples, the 6-chlorotetramethylenetriazolopyridazine intermediate product was reacted with excess Rg amine (more than two equivalents) at reflux. Reaction progress was monitored by thin layer chromatography on silica gel, developed with 9:l-chloroform:methanol, where the 65 -chloro intermediate appeared as a fluorescent spot and the product was nonfluorescent. After reaction was complete, the reaction mixtures were concentrated, and the residue partitioned between water and methylene chloride. The organic layer was dried with sodium sulfate, concentrated and the residue recrystallized from benzene-hexane. Salts were formed by dissolving the base in acetone and adding ethereal acid (hydrogen chloride). Using the above 6-chloro intermediate, the following were prepared, in which R3 is ethyl, R? and Rg are tetramethylene, and Rg is identified below.

Example -Be Yield (Percent) Melting Point °C 44 Hexahydro-4-Methy1-1H-1,4-diazepin-l-yl 44 95-96 45 Dihydrochloride of 44 * 53 225-228 46 Hexahydroazepin-l-yl 28.2 104 47 Morpholino 62.0 170-171 48 Piperidino 57.8 135-136 49 2-Methylpyrro1idino 55.2 152-153 50 Pyrrolidino 59.8 118-119 51 4-Methyl-l-piperazinyl 67.8 172-173 52 Dihydrochloride 51 ft-k 86.7 250-252 * Recrystallized from methanol-acetone ** Recrystallized from isopropanol Examples 53-55 A. In a procedure similar to that of Example 44A, 98.5 grams of l-chloro-4-hydrazino-5,6,7,8-tetrahydrophthalazine were heated at reflux in 300 milliliters of isobutyric acid. After 18 hours, excess isobutyric acid was distilled off and the residue neutralized with aqueous sodium bicarbonate. The resulting solid 6-chloro-7,8,9,10-tetrahydro-3-(1-methylethyl)-1,2,4-triazolo[3,4-a]-phthalazine was collected and air-dried to yield 100 grams (80.4 percent yield). After reerystallization from isopropanol the yield was 56.2 grams, melting at 67-68°C.

B. Using the above 6-chloro intermediate product, and the procedure described in Example 44B and the preceding Examples, the following compounds were prepared, in which Rg is isopropyl, R? and Rg are tetramethylene, and Rg is identified below: Yield Melting Example _Rg _ (Percent) Point °C 53 Hexahydro-4-methyl-lH-1,4-diazepin-l-yl 55.9 62-63 54 2-Methyl-pyrrolidino 44.5 129-130 55 Pyrrolidino 32.6 119-121 Example 56 One gram (0.49 mole) of 3,6-dichloro-4,5tetramethylenepyridazine, 78.3 grams (0.738 mole) sodium carbonate, and 500 milliliters of diglyme (diethylene glycol dimethyl ether) were mixed. 46.1 Grams (0.54 mole) of 2-methylpyrrolidine was added slowly with stirring, and the mixture was heated at reflux (134.5°C) for hours, then cooled to 95°C. 400 Milliliters deionized water was added, and the mixture was cooled to about 25°C. The resulting crystals were separated by filtration, washed with water and dried under reduced pressure to yield 104.0 grams of 3-chloro-6-(2-methyl-l-pyrrolidinyl)-4,5-tetramethylenepyridazine, melting at 134-136°C. 210 Grams (0.834 mole) of 3-chloro-6-(2-methyl1-pyrrolidinyl)-4,5-tetramethylenepyridazine, 216 grams (2.92 moles) ethyl formate and 1260 milliliters of ethylene glycol ethyl ether were mixed. Over a 10 minute period, 146.2 grams (2.92 moles) of hydrazine hydrate was added, to form formyl hydrazine in situ. During the addition, the temperature increased from 25°C to 35°C. The mixture was heated at 100°C for about 30 minutes, during which time 100 milliliters of ethanol, water and the reaction medium were collected in a Dean Stark trap. The mixture was then heated to reflux at 120°C for 24 hours, cooled to 95°C, and diluted slowly with about 5 liters of deionized water. The solution was cooled and seeded with product crystals at 60°C, then cooled to 25°C. The crystalline product was collected by filtration, washed with four 500 milliliter portions of deionized water and dried under reduced pressure for about 18 hours at 95°C. 144.3 Grams (67.2% yield) of 6-(2-methyl-l-pyrrolidinyl)25 -7,8-tetramethylene-l,2,4-triazolo[4,3-b]pyridazine were obtained as a crystalline solid, melting at 144-145°C.

Example 57 Bronchodilator activity of representative triazolopyridazine compounds of the invention is examined in the Konzett-Rossler guinea pig preparation according to accepted procedures. See Konzett and Rossler; Arch. f.

Exp. Path. u. Pharmakol. 195: 71-74 (1940); Rosenthale and Dervinis, Arch. Int. Pharmacodyn. 172: 9194 (1968).

In this procedure an anesthetized guinea pig is artificially respired with a fixed volume of air. The volume of air is selected to slightly exceed the capacity of the guinea pig's lungs, and the excess air or overflow is measured. Test compounds are evaluated by administering a test compound intravenously 2 minutes prior to administration of an agonist compound (histamine, serotonin or acetylcholine) following 3 previous agonist doses resulting in relatively uniform (± 10 percent) bronchoconstriction. When the bronchospasm resulting from administration of the agonist compound occurs, the animal's lungs can receive less air, and hence the overflow” is measurably increased. When a test compound blocks the bronchoconstriction induced by administration of the agonist compound, the results can be expressed quantitatively as a percent blockade. This is calculated by dividing the overflow agonist response measured after administration of the test compound by the average of the 3 preceding agonist responses, multiplying by 100 and subtracting this value from 100 percent. The results can also be expressed in comparison to a known bronchodilator, such as aminophylline. In such procedure, comparative results are expressed as percent aminophylline, calculated by expressing the percentage blockade produced by a test compound as a percentage of the average percent blockade produced by dosages of aminophylline administered to the same test animal employed for the test compound with the aminophylline observations preceding and following the evaluation of the test compound in that animal.

In representative operations with triazolopyridazine compounds of the invention, administered intravenously at a dosage rate of 3 milligrams of test compound per kilogram of animal body weight (except as otherwise indicated) and using aminophylline at a dosage rate of 10 milligrams per kilogram for comparison and histamine as the agonist, representative compounds gave excellent results in terms of percent blockade of histamine and percent of aminophylline. 7,8-Dimethyl-6-pyrrolidino-s-triazolo[4,3-b]-pyridazine, administered as an agueous solution was found to give a 65 percent blockade of histamine, amount ing to 67 percent of aminophylline activity.

In similar operations, the compound 6-pyrrolidino-7,8-tetramethylene-s-triazolo[4,3-b]pyridazine and the compound 6-morpholino-7,8-tetramethylene-s-triazolo [4, 3-b Jpyridazine gave 100 and 75 percent blockade of histamine, respectively, amounting to 105 and 113 percent of aminophylline activity. 3,7-Dimethyl-6-morpholino-s-triazolo[4,3-b]pyridazine, 6-(N-methylpiperazino)-7-methyl-s-triazolo[4,3-b]pyridazine, and 3,7-dimethyl-6-piperidino-s-triazolo[4,3-b]pyridazine gave average percent blockades of 61, 39 and 48 percent, respectively.

Example 58 - Audiogenic Convulsive Side Effects Certain xanthine compounds, such as the known bronchodilator aminophylline, have central nervous sys25 tem stimulant side effects which are difficult to detect in animal models which are satisfactory for evaluating other compounds. The interaction of sound with the convulsive threshold of drugs is a known phenomenon which can be used to evaluate such side effects. See, for . example, Schlesinger et al., Life Science 4, 2345-2351 (1965), 7, 437-447 (1968) and 9 (I) 721-729 (1970); Buckholtz, Pharmacol. Biochem. and Behavior 3, 65-68 (1975); and U.S. Patent 4,136,182. In a procedure for pharmacological evaluation, the lowering of the convulsive threshold, or the lowering of the LD50, hy sound can be studied in mice.

In the test operations, mice are administered a test compound by intraperitoneal injection at various dosages, and the number of mice showing tonic convulsions and the number of fatalities occurring within 30 minutes is recorded. The ED5Q for tonic convulsions, and the 30 minute LD50 are then determined. These operations are carried out in standard laboratory cages with mice that have become acclimated to the laboratory.

The surviving mice are then also exposed to sound about 30 minutes after dosing. The sound exposure is carried out by placing the mice in a sound insulated cage with a bell which emits 120 decibels of sound, and activating the bell for two minutes. The number of tonic convulsions and fatalities are then recorded to determine the ED5Q and ld5Q in the presence of the sound challenge.

In a series of similar experiments, the ratio of the 30 minute without sound to the sound-induced LD5Q for aminophylline, theophylline and caffeine has been found to be greater than 3 for all three compounds, while strychnine exhibited no significant change in toxicity with sound. U.S. Patent 4,136,182.

Various triazolopyridazine compounds have been found to exhibit increased toxicity and lowered convulsive thresholds in such procedures, similar to aminophylline. Other triazolopyridazines which have bronchodilator activity exhibit much less toxic potential for audiogenic seizures. For example, the ratio of LD50 without sound to LDjq with sound for 6-morpholino-7,8-tetramethylene-s-triazolo[4,3-b]pyridazine was found to be 3.8 while the ratio for 6-morpholino-3-methyl-7,8-tetramethylene-s-triazolo[4,3-b]pyridazine was found to be about 1.18. Surprisingly, some triazolopyridazines have been found to exhibit a significant lowering of audiogenic convulsive threshold without an associated increase in sound-induced deaths, as indicated by a low for audiogenic tonic convulsions in comparison to the LD5q with sound. The compound 6-morpholino15 -7-methyl-s-triazolo[4,3-b]pyridazine exhibits desirable bronchodilator activity; and its sound-induced LD,-o of 280 mg/kg is not greatly below its 30 minute LD50 of 327 mg/kg. However, its EDgQ for audiogenic tonic convulsions is only 45 mg/kg. 6-Morpholino-3,7-dimethyl-s-triazolo[4,3-bJpyridazine in contrast has been found to exhibit much less reduction in convulsive threshold, with an LDcn of 228, LD-„ with sound of 148, and an audio□ U OU genic convulsion of 135 mg/kg.

The following table illustrates the bronchodilator activity of representative compounds of the invention and their acute toxicity and audiogenic convulsive properties. υ μ •η d C (0 α> rn c σΐΗ u 0 3Q •μ > ra ό ΰ 0 o < υ •d d ω o d •rl 4) d 4> •Η Ό g ti ti * •μ υ ω ο Ή γΗ S3 CQ co rO -Φ o m o co rt O' N tn (S rl I-l H (0 ιί) φ O σ» ro ν cn ΟΝ i-l i-l Η H CQ t*· Φ O' H «Φ cn σ» CsJ Η H rK iH Ν Η Η CO ιθ cn ιζ> <η co Ό β Ο I υ ft Λ 4) □ β •Η 4) JS rj *2 d μ Ή 41 ω ti ό μ ΰ μ d «ο ο μ α ε φ ο μ ο ti >1 β •rl Ν ti 4) ft •Η ft I β ί β β •rl •Η r—1 •rl •Η Ό >1 ι—1 -ύ •rl •Η to 0 Ή pH μ μ Λ k« Ο 4) 4> ft 4) μ ft Σ μ ft μ •Η I 0 •Η >t ft Ζ ε ft ft cn CO S3 S3 SJ S3 υ υ S3 υ μ •η β β φ 0) ΙΟ ΟΉ •S? Ό β β Ο < Ο Ό Ο β m β Q Ο μ] W •Η ε ο ιη Ο Q (Ο J Φ β Φ *μ Ό S Φ Φ 44 μ υ ιο ο •Η γ-I X CO Ό β β Ο a ε ο ο C'·* f·* in co ω φ rH rH Ο 1-1 Φ ιθ h r» m ο co Μ1 Φ4 CO Ο Φ Ε** ι—Η ι—Ι rH r* ιη ιη ό co ό Μ1 Ρ* CO co Ο CO Η Η Η Η > cm in φ Φ Φ > Φ* ιθ CO co > >1 >1 co β β ffl •μ •μ Ν Ν - Φ Φ Φ Γ-β μ μ ffl Φ φ φ rH a a 43 >1 *μ •μ υ μ ιθ| a a •μ β ffl 1 | ι 43 Φ ι-ί Η I I r—I ι-1 >1 >ι & α a c <Η •Η ϋ > 01 U Ό I β (Ο β Ο «Η a ε φ ο μ ο Φ Φ Φ ε ε I 1 2 Ζ co ffl υ ε ο β •μ Ό •μ rH Ο μ μ >1 a 0 α 0 0 •μ β β Ό -μ •μ •μ Ό rH rH ♦μ 0 0 μ 43 μ Φ a μ a μ >1 •μ 0 a a ε co ffl υ s ffl co ffl u Ο £ •rl fi fi Φ OJ IQ 3* rrt •S£ Ό fi 3 O < □ O if) C O w o in fi •rt a o fO o 4) fi Φ •rt 3 g φ Φ £ 4J U ω o •rt irt Ε Λ CO E TJ oo E fi Φ £ rrt fi □ > 3 •rt >4 0 £ V fir S£ ε 0 0 fi rrt u •rt □ >· (Α ϋ I Η ο- o- m OJ xj< rrt c-l Φ Η rrt rH rH r-4 ο- r- n m «φ rrt 5$ CO rrt »—I rrt rrt frt 10 0· > CO rtf cn χί* γη rrt rrt frt rrt rrt in io O OJ oo in φ (fi co m fi S JD O irt U Φ >1 fi c •rt •rt M M Φ Φ Irt 4) 4) fir fir •rrt •rt ΦΙ E E Ε 1 0 0 1 1 fl fi frt rrt 0 •rt •rt 1 | C 3 3 trt rrt •rt •rt •rt >1 rrt rrt rrt £ £ 0 0 0 4J £ £ Irt irt 4) 4) fir Irt Irt ε ε Irt >1 >1 1 ( o E E Z z ε m m ml E E Ε 1 U E U E E υ +j Ή β β (0 υ ω φη o ? -rl > Ό C β Ο < Ο min Sound ο in ο in ο β 0) •Η Ό S Ό <α Ρ υ ω ο •Η »—i π λ Ό β β Ο α ε ο υ > X Λ ϋ Ή β (0 Ό > β 45 β Ρ ο α> as ε ο (0 υ ·Η col os I cn| X I Φ r- cm ο in ο > > φ m CM CM CM Η Μ1 r* cm co Ο Ρ* > CM CM cm cn Η sj* > CM > co O CM CM -41 CM CM cn CM in <Μ Φ C0 Η Φ νθ Φ Φ O 0 β O 0 ο β •r! β β β •rl Ό Η ·Η •rl T3 •rl Η *0 rU •H rH Ο ·Η Ο Ul 0 45 Μ 45 0) M α α> a a Ui μ a Ul •ri >1 ο ·Η ο CU CU ε cu ε cn cn cn S o § a a σι cn aj on a u S υ-Ρ fi § φ (fi ο ζΤΝί-ι ιη Ο fi Ω η > ω Ό fi fi Ο <□ Ό Ο fi ΙΛ §9 (0 fi •rt S ο ιϋ °9 Φ fi φ •rt Ό S fi Π3Α 4J ϋ (fi Ο •rt γ-Η X « Ό fi fi Ο i* ο υ rχ Λ υ •rt Λ fi •rt (fi ι-. Ό > cxr Ρ 0 Φ χε 6 ο ω U-rt η ro η in cn fi* η fi* co ID Ο rrt Ο CO ro fi* fi* cn co CM CM rH o CM ro r- fi* o ro CM CM rH fi* ro ro ro X I ro fi* O' ro o ro CM CM 0 rH >4 fi •rt N fi Jh Φ x rt X 1 •K fi ri 0 0 •rt 1 fi fi Ό rH •rt •rt •rt o ri rH Λ •rt 0 0 +J JC X Φ Φ x P ε X M >1 1 •rt o X X X ε ro tc X o ’ ro X I trt fi ro Φ ffl A CC Ο X >1 A X O fi fi to rt s I υ h o Uh Ό Φ Ό fi rH o a Example 59 - Histamine Aerosol Exposure In another procedure, test compounds were administered to guinea pigs by intraperitoneal injection and the guinea pigs were challenged two hours later by exposure to a histamine aerosol. Untreated animals collapse when exposed to the histamine aerosol. In these operations, the animals were observed, and an was calculated as the dosage at which fifty percent of the animals displayed a collapse time greater than the mean collapse time plus two standard deviation units observed with control animals treated with the injection vehicle alone. The ED5Q's of representative compounds are set out in the following table.

Compound of Example No. ED5Q (m?/kg i.p.) 28 5.0 29 1.6 30 4.0 31 2.5 32 1.8 20 33 1.3 37 2.1 38 2.2 43 (dihydroehloride) 23.8 44 5.0 25 45 <5 46 (estimated) 4.95 50 <2.5 52 36.4 54 (estimated) 7.9 30 55 (estimated) 5.1

Claims (18)

1. A compound having the general formula: wherein

2. A compound as claimed in claim 1 which has the formula: wherein B represents methylene or ethylene.

3. A compound as claimed in claim 1 wherein

4. A compound as claimed in claim 1 wherein Ry and Rg are 1,3cyclopentylene 5. 3,6-dihalo-4,5-substituted pyridazine of the general formula: with the corresponding Rg-amine in an inert solvent at a temperature in the range of from 25° to 150° in the presence of an inorganic base to prepare a 3-halopyridazine of the general formula: and then reacting the resultant 3-halopyridazine with a loweralkanoyl hydrazine of the formula: II RgC-NH -NH 2 in an inert liquid medium at a temperature in the range of from 50° 5 10. A compound as claimed in claim 1 or claim 5 which is as specifically exemplified in any one of Examples 1 to 56. 5,6 or 7 membered ring having one or two ring nitrogen atoms and optionally one ring sulfur or oxygen atom or lower alkyl substituted heterocyclic amino wherein the heterocyclic moiety forms a 6 membered ring having one or two ring nitrogen atoms and optionally one ring sulfur

5. A compound of formula given in claim 1 wherein Rg, Rg, Ry and R g are as defined before and wherein Rg additionally 10 represents heterocyclic amino wherein the heterocyclic moiety forms a 5 Ry and Rg together are tetramethylene, Rg is hydrogen an Rg is 2-methyl-1-pyrrolidinyl. 5 Rj represents hydrogen or loweralkyl; Rg represents amino, loweralkylamino, diloweralkylamino, or lower alkyl substituted heterocyclic amino, wherein the heterocyclic moiety forms a 5 or 7 membered ring, having one or two ring nitrogen atoms and optionally one ring sulfur or oxygen atom;

6. A compound as claimed in claim 5 wherein Ry and Rg are tetramethylene, Rg is hydrogen and R g is hexahydro-1H-azepin-l-yl.

7. A compound as claimed in claim 5 wherein Rg is N-methyl-l-piperazinyl, pyrrolidino, piperidino or morpholino.

8. A compound as claimed in claim 5 or claim 7 wherein R 3 is hydrogen.

9. A compound as claimed in any one of claims 5, 7 or wherein Ry and Rg are tetramethylene.

10. Claim 1 or claim 5 which process comprises reacting a 3-halo-6~hydrazinopyridazine of the general formula: wherein Ry and Rg are as defined in claim 1 and X is halo, with a compound of the formula: II 10 Ry represents loweralkyl; Rg represents hydrogen or loweralkyl; or Ry and Rg taken together represent polymethylene or substituted polymethylene of 3 or 4 methylene units substituted by loweralkyl, or by methano or ethano bridges thereof, and the pharmacologically

11. A pharmaceutically acceptable salt of a compound as claimed in any one of claims 1 to 9.

12. A process for the preparation of a compound as claimed in

13. A process for the preparation of a compound as claimed in claim 1 or claim 5 which process comprises reacting a

14. A process for the preparation of a compound as defined in Claim 1 substantially as described herein with reference to the Examples.

15. A compound as claimed in claim 1 or claim 6 whenever prepared 5 by a process as claimed in any one of claims 12 to 14. 15 to 200°C. 15 HO - C —Rg ^herein Rg is as defined in claim 1 at a temperature in the range of from 40° to 150°C in an excess of acid, followed by the reaction of the resulting 6-halo-triazolopyridazine with the corresponding Rg amine, where Rg is as defined in claim 1 or claim 5, at a temperature in the range of from 75° to 160°C in the same solvent as that employed in the production of the 6-halo-triazolopyridazine. 15 or oxygen atom. 15 acceptable salts of said compounds.

16. A brojhodilator composition which comprises an effective amount of a compound as claimed in any one of claims 1 to 10 or claim 15, or a salt as claimed in claim 11, in admixture with a pharmaceutically acceptable carrier. 10

17. 6-(hexahydro-4-methyl1H-l,4-diazepin-l-yl)-3-methyl-7,8 -tetramethylene-s-triazolo f4,3-bj pyridazine.

18. 6-(hexahydro-4-methyl4H-1,4-diazepin-1-yl)-3-methyl-7,8r- Ί tetramethylene-s-triazolo i_4,3-bi pyridazine dihydroehloride.