US3489755A

US3489755A - Imidazo (1,2-b) pyridazines

Info

Publication number: US3489755A
Application number: US569845A
Authority: US
Inventors: Joseph G Lombardino
Original assignee: Pfizer Inc
Current assignee: Pfizer Inc
Priority date: 1966-08-03
Filing date: 1966-08-03
Publication date: 1970-01-13
Anticipated expiration: 1987-01-13
Also published as: GB1135893A

Description

United States Patent 3,489,755 IMIDAZO [1,2-b] PYRIDAZINES Joseph G. Lombardino, Niantic, C0nn., assignor to Chas. Pfizer & Co., Inc., New York, 'N.Y., a corporation of Delaware N0 Drawing. Filed Aug. 3, 1966, Ser. No. 569,845 Int. Cl. C07d 57/22 US. Cl. 260-2475 Claims ABSTRACT OF THE DISCLOSURE Imidazo[l,2-b]pyridazines and pharmaceutically acceptable acid addition salts thereof useful in the treatment of hypertension and for their potent anti-inflammatory effects.

This invention relates to new and useful organic nitrogen compounds in the field of heterocyclic chemistry. More particularly, it is concerned with certain novel imidazo[1,2-b]pyridazines and their acid addition salts.

The free base compounds of the present invention are of the following formulae:

wherein X is selected from the group consisting of hydrogen, chlorine, bromine, and alkyl and alkoxy containing from one to four carbon atoms; R is selected from the group consisting of hydrogen and alkyl containing from one to four carbon atoms; R and R" are each selected from the group consisting of alkyl and hydroxyalkyl containing from one to four carbon atoms, and phenylalkyl containing up to three carbon atoms in the alkyl moiety; and Z represent the atoms which together with N complete a member of the group consisting of pyrrolidino, piperidino, morpholino, thiamorpholino, N- alkylpiperazino and N-hydroxyalkylpiperazino containing up to four carbon atoms in the alkyl moiety, N- phenylalkylpiperazino containing up to three carbon atoms in the alkyl moiety, N-phenylpiperazino and homopiperidino. These compounds and their pharmaceutically acceptable acid addition salts are useful in the treatment of hypertension. In addition, they are also useful for their potent anti-inflammatory effects.

Typical compounds of the present invention include 3 dimethylaminomethyl 6 methoxyimidazo[l,2-b] pyridazine, 2-methyl-3-dimethylaminomethyl-6-methoxyimidazo[l,2-b]pyridazine, its dihydrochloride, 3-di(nbutyl)aminomethyl 6 methoxyimidazo[l,2-b]pyridazine dihydrochloride, its Z-methyl derivative, 2-methyl-3- (N-methyl-N-benzyl)aminomethyl 6 methoxyimidazo 1,2-b pyridazine dihydrochloride, 3 -di (fi-hydroxyethyl) aminomethyl 6 methoxyimidazoll,2-b]-pyridazine dihydrochloride, 2 methyl-3-di(fi-hydroxymethyl)aminomethyl 6 methoxyimidazo[1,2-blpyridazine, 3-piperidinomethyl 6 methoxyimidazo[l,2-b]pyridazine dihydrochloride, its Z-methyl derivative, 3-morpholinomethyl- 6-methoxyimidazo 1,2-b]pyridazine dihydrochloride, 2- methyl 3 morpholinomethyl-6-methoxyimidazo[1,2-b] pyridazine, 3 (4 methyl 1 piperazinylmethyl)-6- methoxyimidazo l,2-b]pyridazine trihydrochloride, 2- methyl-3-(4-phenyl-l-piperazinylmethyl) 6 methoxyimidazo[l,2-b]pyridazine and its trihydrochloride.

The process employed for preparing the novel compounds of this invention is a Mannich reaction and it involves treating a S-unsubstituted imidaZo[ 1,2-b]pyridazine with formaldehyde and a secondary amine to form 3,489,755 Patented Jan. 13, 1970 the corresponding 3-aminomethylimidazo[1,2-b]pyridazine base compound. The secondary amine employed is of the formula R'R"NH or where R, R and Z are each as previously defined. A convenient source of formaldehyde such as Formalin, i.e., 37% aqueous formaldehyde, or paraformaldehyde may be used. In general, the reaction is most desirably carried out in the presence of a reaction-inert aqueous polar organic solvent medium at a temperature that is in the range of from about 20 C. up to about C. for a period of about one to fifty hours. Suitable reaction-inert polar organic solvents include water-miscible lower alkanols such as methanol, ethanol and isopropanol, as well as N,N-di(lower alkyl) lower alkanoic acid amides such as N,N-dimethylformamide, N,N-diethylformamide and N,N-dimethylacetamide. However, the preferred organic solvent for this reaction is a lower al'kane hydrocarbon carboxylic acid such as acetic acid, propionic acid, isobutyric acid, and so on.

The amount of each reagent employed in the reaction may vary to some extent, but it is preferable to employ at least an equimolar amount of both the secondary amine and the formaldehyde reagent With respect to the imidazo[1,2-b]pyridazine base. A particularly preferred reactant molar ratio is tWo molar equivalents each of the secondary amine and formaldehyde per mOlar equivalent of the 3-unsubstituted imidazo[1,2-b]pyridazine base compound. The formaldehyde reagent employed may be Formalin or it may be formed in situ by depolymerizing paraformaldehyde with an acid such as concentrated hydrochloric acid.

Upon completion of the reaction, the product may be treated with dilute aqueous alkali, e.g., 10% aqueous sodium hydroxide solution and then extracted with a water-immiscible organic solvent of low volatility, such as a halogenated hydrocarbon solvent, e.g., methylene chloride or a lower dialkyl ether such as diethyl ether. In those cases Where the organic base compound does not crystallize readily after removal of the volatile organic solvent, the hydrochloride or another acid addition salt can be prepared therefrom in an aqueous or lower alkanol solvent system, using an excess of the chosen acid. The crystalline salt compound is then easily precipitated therefrom by concentration of the latter solution to a small volume followed by the addition of an anti-solvent, such as diethyl ether, to the mixture.

The 3-unsubstituted imidazo[1,2-b]pyridazines used in the above reaction process are easily obtained from the corresponding 3-aminopyridazine and the appropriate halocarbonyl compound in the presence of a mild base in accordance with the procedure of W. L. Mosby, Heterocyclic Systems With Bridgehead Nitrogen Atoms, A. Weissberger, Ed., Interscience Publishers, Inc., New York, NY. (1961), p. 460 ff. This entails heating the 3- aminopyridazine base with a slight excess of the aforementioned halocarbonyl compound, which is preferably, a chloroor bromoacetaldehyde or a corresponding halo substituted ketone, in the presence of a mild base, such as sodium bicarbonate and in an aqueous alcoholic sol vent medium, with the preferred alcohol being a lower alkanol such as methanol or ethanol. The 3-aminopyridazine base and the halocarbonyl compound are all commercially available reagents or are easily prepared by those skilled in the art from readily available starting materials.

Inasmuch as the 3-aminomethylimidazo [1,2-b]pyridazine compounds of this invention are basic compounds, they are capable of forming a wide variety of salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable to first isolate the 3-aminomethylimidazo[1,2-1pyridazine base compound from the reaction mixture as a pharmaceutically unacceptable salt, then convert the latter back to the free base compound by treatment with an alkaline reagent and thereafter convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the 3-aminomethylimidazo[l,2-b]pyridazine base compounds of this invention are readily prepared by treating the base compound With an equivalent amount of the chosen acid in an aqueous solution or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained.

The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned 3-aminomethylimidazo[1,2-b1pyridazine base compounds of this invention are those which form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydriodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, oxalate, succinate, maleate, gluconate, saccharate, methanesulfonate, ethanesulfonate, benezenesulfonate and p-toluenesulfonate salts.

As previously indicated, the 3-aminomethylimidazo [l,2-b]pyridazine compounds of this invention are all therapeutically useful for the treatment of hypertension. This is due to their ability to lower the blood pressure of correspondingly hypertensive subjects a statistically significant degree. For instance, 2-methyl-3-(4-phenyl-lpiperazinylmethyl) 6 methoxyimidazo[1,2-] pyridazine trihydrochloride, a typical agent of the present invention, has been found to lower the blood pressure of renal hypertensive rats to a significant degree (e.g., up to 25 mm. Hg) when orally administered to them at 20 mg./ kg. for a period of three days. It was also found to lower the blood pressure of renal hypertensive dogs at 10 mg./kg., orally, with the eifect reaching a maximum of 30 mm. Hg after two hours subsequent to the drug administration. The compounds of this invention may be administered to a hypertensive subject as antihypertensive agents by either the oral or parenteral routes of administration and in either case, without causing any unwanted side effects to occur in the subject so being treated. In general, these compounds are ordinarily administered in dosages ranging from between about 0.15 mg. to about 4.8 mg. per kg. of body weight per day, depending upon the weight and condition of the subject being treated and the particular route of administration chosen.

The 3-aminomethylimidazo[l,2-b]pyridazine compounds of this invention may be administered either alone or in combination with pharmaceutically acceptable inert carriers and in both single and multiple dosages. More particularly, the novel compounds of this invention can be administered in a wide variety of diiferent dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical compositions can be suitably sweetened and/ or flavored by means of various agents of the type commonly employed for just such purposes. In general, the therapeutically-effective compounds of this invention are pres ent in such dosage forms at concentration levels ranging from between about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufiicient to provide the desired unit dosage previously indicated.

For purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelating capsules; preferred materials in this connection would also include lactose or milk sugar as well as high molecular Weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/ or suspending agents as Well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

For purposes of parenteral administration, solutions of these particular 3-arninomethylimidazo 1,2-b] pyridazines in sesame or peanut oil or in aqueous-propylene glycol or N,N-dimethylformamide may be employed, as Well as sterile aqueous solutions of the corresponding watersoluble, non-toxic mineral and organic acid addition salts previously enumerated. Such aqueous solutions should be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufi'icient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection routes.

EXAMPLE I In a 3-liter, three-necked round-bottomed flask equipped with mechanical stirrer and having a nitrogen-inlet tube and reflux condenser attached thereto, there were placed 120 g. (0.6 mole) of chloroacetaldehyde (40% solution in water), 400 ml. of ethanol and ml. of water while under a nitrogen atmosphere. Stirring was commenced and a solution consisting of 62.6 g. (0.5 mole) of S-amino- -methoxypyridazine dissolved in 100 ml. of warm ethanol was added thereto. To the resulting clear red solution, there were then added slowly 50.4 g. (0.6 mole) of powdered sodium bicarbonate followed by a two-hour reflux period which produced a rapid gas evolution. At the end of the two hours, no further gas evolved and the dark solution was concentrated under vacuum to a volume of 250 ml. and then treated with 200 ml. of water. The resulting aqueous solution was then exhaustively extracted with three-successive 200 ml. portions of diethyl ether, and the combined ether extracts were dried over anhydrous sodium sulfate and subsequently filtered. Following removal of the drying agent, the ethereal solvent was evaporated under reduced pressure over a water-bath to obtain a residual semi-solid which was then dissolved in a minimum amount (ca. 50 ml.) of hot ethanol to give a clear solution. This solution was then filtered while hot in the presence of charcoal and on subsequent cooling, deposited a pale tan crystalline solid, which was later collected by means of suction filtration and dried in a vacuum desiccator. In this manner, there was obtained 26.9 g. (36%) of 6-methoxyimidazo[1,2-b1pyridazine, M.P. 100-103 C.;

EtOH max.

EXAMPLE H In a suitable round-bottomed flask equipped with heating mantle, stirrer and reflux condenser and having a nitrogen-inlet tube, there were placed 38 g. (0.30 mole) of 3-amino-6-methoxypyridazine dissolved in 180 m1. of ethanol. The mixture was stirred at room temperature for approximately 15 minutes until a clear yellow solution was obtained, at which point there were then added 30.7 g. (0.33 mole) of freshly distilled chloro-2-propanone followed by a two-hour reflux period with continued stirring. Upon cooling the reaction mixture to room temperature for ten minutes, there were then added 27.7 g. (0.33 mole) of powdered sodium bicarbonate dissolved in 120 ml. of warm water, and this, in turn, led to an extremely vigorous reaction with much gas evolution. The resulting reaction mixture was then next refluxed for 25 hours. At the end of this time, the mixture was cooled to room temperature and treated with 200 ml. of water, followed by extraction with five-100 ml. portions of chloroform. The combined chloroform extracts were then dried over anhydrous sodium sulfate and filtered, and the resulting filtrate subsequently treated with charcoal and again filtered. Evaporation of the latter filtrate to near dryness while under reduced pressure then gave a semi-solid residual material, which was subsequently triturated with ca. 100 ml. of water at room temperature and filtered. The filtered material was dried in a vacuum desiccator to constant weight and amounted to 30.5 g. (62%) of 2-methyl-6-methoxyimidazo[1,2-b]pyridazine, M.P. 87-89 C. after one recrystallization from hot water.

Analysis.--Calcd. for C H N O: C, 58.88; H, 5.56; N, 25.75. Found: C, 58.63; H, 5.38;N, 25.74.

EXAMPLE III The procedure of Example I is employed to prepare the following compounds from the appropriate 3-amino-6- methoxypyridazine and chloroacetaldehyde or u-chloroketone:

EXAMPLE IV In a round-bottomed flask equipped with mechanical stirrer and reflux condenser and having a nitrogen-inlet tube attached thereto, there were placed 1.5 g. (0.01 mole) of 6-methoxyimidazo[1,2-b]pyridazine and 2.4 g. (0.04 mole) of glacial acetic acid while under a nitrogen atmosphere. Stirring was commenced and the clear yellow solution was cooled to 0 C. by means of an ice bath, at which point there were then added to the mixture 0.90 g. (0.01 mole) of 50% dimethylamine in water. After allowing the mixture to cool once again to 0 C., 0.82 g. (0.01 mole) of 37% aqueous formaldehyde (Formalin) were slowly added thereto followed by continued stirring at room temperature for 70 hours. To this mixture, there were then added 0.90 g. (0.01 mole) of 50% dimethylamine in water and 0.82 g. (0.01 mole) of 37% aqueous formaldehyde, and stirring was continued for an additional hours thereafterwards also at room temperature. The resultant reaction mixture was then warmed for one hour at 70 C. by means of a hot Water bath and cooled to 0 C. afterwards, before being basified with 10% aqueous sodium hydroxide solution. This was followed by extraction with threeml. portions of diethyl ether, and the latter ethereal extracts were subsequently combined and dried over anhydrous sodium sulfate. After removing the drying agent by means of filtration and the ether solvent by means of evaporation under reduced pressure, there was obtained a pale brown residual oil which slowly crystallized to a soft yellow solid. In this manner, there were obtained 1.8 g. (86%) of 3-dimethylaminomethyl-6- methoxyimidazo[1,2-b]-pyridazine, M.P. 9395 C. after recrystallization from warm n-hexane. An analytical sample was prepared therefrom by drying for 4 hours at 25 C. in a drying piston under reduced pressure.

Analysis.-Calcd. for C H N O: C, 58.20; H, 6.84; N, 27.15. Found: C, 58.16; H, 6.77; N, 27.44.

EXAMPLE V The procedure described in the previous example was initially followed except that 1.6 g. (0.01 mole) of 2- methyl-6-methoxyimidazo[1,2b]pyridazine was employed as the pyridazine reactant. In this particular case, it was also necessary to employ an additional 2.4 g. (0.04 mole) of glacial acetic acid in order to achieve a clear solution. The reaction mixture was next stirred for approximately 21 hours (overnight) at room temperature and then stirred in a water-bath at 50 C. for twenty-two hours. After further stirring at room temperature for 47 hours, an additional 0.90 g. (0.01 mole) of 50% dimethylamine in water and 0.82 g. (0.01 mole) of 37% aqueous formaldehyde were added, and stirring was continued for another 50.5 hours at room temperature. The resultant reaction mixture was then warmed in a waterbath at 50 C. for one hour and allowed to stir overnight for approximately 16 hours at room temperature before basification was effected in the manner described in Example IV. Isolation of the desired material was next carried out in exactly the same manner as that described in the previous example and there was finally obtained a 1.5 g. (71%) yield of 2-methyl-3-dimethylaminomethyl-6-methoxyimidazo[1,2-b]pyridazine as final product, M.P. 69-71 C. after drying in a vacuum desiccator for approximately two days.

The hydrochloride salt of 2-methyl-3-dimethylaminomethyl-6-methoxyimidazo[1,2-b]pyridazine was prepared by dissolving ca. 200 mg. of the base compound in approximately 5 ml. of water and acidifying the resulting aqueous mixture with an excess of 6 N hydrochloric acid. The resultant solution was then evaporated to dryness under reduced pressure to obtain a clear oil as residual material, which was subsequently dissolved in ethanol. Precipitation of the desired salt from this solution was then effected by adding diethyl ether to the mixture to give 2-methyl-3-dimethylaminomethyl 6 methoxyimidazo[1,2-b]pyridazine dihydrochloride, M.P. 200-204 C. (decomp.).

Analysis.Calcd. for C H N 02HCl: C, 45.06; H, 6.19; N, 19.11. Found: C, 44.73; H, 5.98; N, 19.09.

EXAMPLE VI The procedure described in Example V was initially followed except that N-phenylpiperazine was employed as starting material in place of dimethylamine. In this particular case, the amounts and ingredients of reagents combined together were specifically as follows: 4.8 g. (0.03 mole) of 2-methyl-6-methoxyimidazo[1,2-b]pyridazine, 10 g. (0.16 mole) of glacial acetic acid, 2.4 g.

(0.03 mole) of 37% aqueous formaldehyde (Formalin) and 4.8 g. (0.03 mole) of N-phenylpiperazine. After stirring the reaction mixture for approximately 21 hours (overnight) at room temperature, it was then heated for two hours on a steam bath and subsequently allowed to cool down to room temperature, once again, before being basified in the usual manner. Isolation of the desired material was next accomplished in almost exactly the same manner as before (see Example IV), except that four-100 ml. portions of diethyl ether were employed and the basified mixture was first diluted with a further 100 ml. portion of water before the extraction step was carried out. In this way, there was obtained a yield of 2-methyl-3-(4-phenyl-l-piperazinylmethyl) 6 methoxyimidazo[1,2-b]pyridazine in the form of a pale yellow oil, which slowly crystallized on standing and on subsequent trituration with diethyl ether gave a crystalline product melting at l36-140 C.

The trihydrochloride salt of 2-methyl-3-(4-phenyl-lpiperazinylmethyl)-6 methoxyimidazo[l,2-b]pyridazine was prepared by dissolving the base compound in 50 mlof methanol, adding excess methanolic hydrochloric acid thereto and then evaporating the resulting methanolic solution to dryness While under reduced pressure to afford a yellow viscous oil. On trituration of the latter material with ethanol, followed by cooling, there was obtained a crystalline solid material, which amounted to a 5.8 g. (68%) yield of 2-methyl-3-(4-phenyl-1-piperazinylmethyl -6-methoxyimidazo 1,2-b] pyridazine trihydrochloride after treatment of the resulting filtrate with diethyl ether to precipitate further solid. The analytical sample was prepared by dissolving ca. 100 mg. of the product in hot ethanol and filtering, followed by concentration of the resulting filtrate to one-half of its original volume in vacuo and slow cooling to room temperature. Upon the addition of diethyl ether to the cooled concentrate, there was obtained a white crystalline solid product, M.P. 2ll-212 C. after drying for 4 hours at 57 C. while in a drying piston under reduced pressure. Analysis.Calcd. for C H N 03HCl: C, 51.07; H, 5.87; N, 15.68. Found: C, 51.27; H, 6.15; N, 15.94.

EXAMPLE VII 157 C. (decomp.).

Z-methyl 3 di(n-butyl)aminomethyl-6-n1ethoxyimidazo 1,2-b] pyridazine dihydrochloride (semi-hydrate M.P. 1675-1685 C.

3-di(B-hydroxyethyl)aminomethyl 6 methoxyimidazo[1,2-b]pyridazine dihydrochloride, M.P. 209-2l1 C.

(decomp.).

2 -methyl 3 di(,B-hydroxyethyl)aminomethyl-G-methoxyimidazo[1,2-b]pyridazine, M.P. 129-l30 C.

2-methyl 3 (N- methyl-N-benzyl)aminomethyl-6- metho'xyimidazo[1,2-b]pyridazine dihydrochloride (semihydrate), M.P. 204-205 C. (decomp.).

3 piperidinomethyl 6 methoxyimidazo[1,2-b1pyridazine dihydrochloride (semi-hydrate), M.P. 191-193 C. (decomp.)

2 methyl 3 piperidinornethyl 6 methoxyimidazo [1,2-b1pyridazine dihydrochloride (semi-hydrate), M.P. 209-2105 C.

3 morpholinomethyl 6 methoxyimidazo[l,2-b]pyridazine dihydrochloride (semi-hydrate), M.P. 211-213 C. (decomp.)

2 methyl 3 morpholinomethyl 6 methoxyimidazo [1,2-b1pyridazine, M.P. 76-78 C.

3 (4 methyl 1 piperazinylmethyl) 6 methoxyimidazo[l,2 b]pyridazine trihydrochloride (monohydrate), M.P. 202-204" C. (decomp.)

2 methyl 3 (4 methyl 1 piperazinylmethyl) 6- methoxyimidazo[l,2 'blpyridazine trihydrochloride (monohydrate), M.P. 207-208 C. (decomp.)

Subsequent conversion of each of the above hydrochlorides to the free base compound in each instance via 5 N NaOH then affords the corresponding 3-aminomethyl-6- methoxyimidazo l ,2-b pyridazine.

EXAMPLE VIII The procedure of Examples IV-VI is again employed to prepare the following compounds listed in the table below, starting from the appropriate imidazo[l,2-b]pyridazine base (reported in Examples I-III) and the proper secondary amine starting material in each instance:

The procedure of Examples IV-VI is again repeated to prepare the following compounds listed in the table below, starting from the appropriate imidazo[1,2-b]pyridazine base (reported in Examples I-III) and the proper secondary amine starting material in each individual instance:

9 EXAMPLE X The non-toxic hydrohalide acid addition salts of each of the 3-aminomethylimidazo[1,2-b]pyridazine bases reported previously in Examples IV-IX, such as the hydrochloride, hydrobromide and hydriodide salts thereof, are each individually prepared by first dissolving the respective organic base compound in absolute ether followed by introduction of the appropriate hydrogen halide gas into the reaction solution until saturation of same is complete with respect to said gas, whereupon the desired salt precipitates from said solution as a crystalline product. For instance, when 3-dimethylaminomethyl-6- methoxyirnidazo[1,2-b]pyridazine is dissolved in anhydrous diethyl ether and dry hydrogen chloride gas is sub sequently passed into the resulting solution until saturation of same is complete with respect to said gas, there is obtained a crystalline precipitate of 3-dimethylaminomethyl-6-methoxyimidazo[ l ,2-b] pyridazine dihydrochloride.

EXAMPLE XI The nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, oxalate, succinate, meleate, gluconate, saccharate, methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate salts of each of the aforementioned 3- aminomethylimidazo[1,2-b]pyridazine base compounds reported previously in Examples IV-IX are all prepared by separately dissolving in a suitable amount of ethanol the proper molar amounts of the respective acid and the appropriate organic base and then mixing the two solutions, followed by the addition of diethyl ether to the resulting reaction solution in order to effect precipitation of the desired acid addition salt therefrom. For instance, when equimolar amounts of 2-methyl-3-morpholinomethyl-6-methoxyimidazo[1,2-b]pyridazine and concentrated sulfuric acid react in accordance with the procedure, the corresponding product obtained is 2-methyl-3-morpholinomethyl-6-methoxyimidazo[1,2-b]pyridazine sulfate.

What is claimed is:

1. A compound selected from the group consisting of and the pharmaceutically acceptable acid addition salts thereof, wherein X is selected from the group consisting of hydrogen, chlorine, bromine, and alkyl and alkoxy containing from one to four carbon atoms; R is selected from the group consisting of hydrogen and alkyl containing from one to four carbon atoms; R and R" are each selected from the group consisting of alkyl and hydroxyalkyl containing from one to four carbon atoms, and phenylalkyl containing up to three carbon atoms in the alkyl moiety; and Z represents the atoms which together with N complete a member of the group consisting of pyrrolidino, piperidino, morpholino, thiamorpholino, N- alkylpiperazine and N-hydroxyalkylpiperazino containing up to four carbon atoms in the alkyl moiety, N-phenylalkylpiperazino containing up to three carbon atoms in the alkyl moiety, N-phenylpiperazino and homopiperidino.

2. A compound of claim 1 wherein X is alkoxy containing from one to four carbon atoms, R is hydrogen and R and R" are each alkyl containing from one to four carbon atoms.

3. A compound of claim 1 wherein X is alkoxy containing from one to four carbon atoms, R is alkyl containing from one to four carbon atoms and R and R" are each alkyl containing from one to four carbon atoms.

4. A compound of claim 1 wherein X is alkoxy containing from one to four carbon atoms, R is alkyl containing from one to four carbon atoms and R and R" are each hydroxyalkyl containing from one to four carbon atoms.

5. A compound of claim 1 wherein X is alkoxy containing from one to four carbon atoms, R is hydrogen and Z represents the atoms which together with N complete the piperidino radical.

6. A compound of claim 1 wherein X is alkoxy containing from one to four carbon atoms, R is alkyl containing from one to four carbon atoms and Z represents the atoms which together with N complete the piperidino radical.

7. A compound of claim 1 wherein X is alkoxy containing from one to four carbon atoms, R is alkyl containing from one to four carbon atoms and Z represents the atoms which together with N complete the morpholino radical.

8. A compound of claim 1 wherein X is alkoxy containing from one to four carbon atoms, R is alkyl containing from one to four carbon atoms and Z represents the atoms which together with N complete the N-alkylpiperazino radical.

9. A compound of claim 1 wherein X is alkoxy containing from one to four carbon atoms, R is alkyl containing from one to four carbon atoms and Z represents the atoms which together with N complete the N-phenylpiperazino radical.

10. The compound of claim 1 wherein X is methoxy, R is methyl and Z represents the atoms which together with N complete the N-phenylpiperazino radical.

References Cited C. A. 62, 5273hYoneda et a1.

ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner U.S. Cl. X.R.