SE451722B - 1-PYRIDINYL-2- (DIALKYLAMINO) -ETENYL-ALKYLKETONS USED AS INTERMEDIATES IN THE PREPARATION OF PYRIDINONES WITH CARDIOTONIC PROPERTIES - Google Patents

Description

451 722 2 of formula I, wherein Q is hydrogen, amino or cyano, PY is 4-pyridinyl or 3-pyridinyl, R 1 is hydrogen and R is methyl or ethyl.

Particularly preferred compounds are 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinonitrile (formula I, wherein Q is CN, R 1 is H, PY is 4-pyridinyl and R is methyl) , 3-amino-6-ethyl-5- (4-pyridinyl) -6-methyl-2 (1H) -pyridinone (formula I, wherein Q is NH 2, R 1 is H, PY is 4-pyridinyl and R is methyl), 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone (formula I, wherein R 1 is H, PY is 4-pyridinyl and R is methyl) and 6-ethyl-5- (4- pyridinyl) -2 (1H) -pyridinone (formula I, wherein R 1 is H, PY is 4-pyridinyl and R is ethyl), or pharmaceutically acceptable acid addition salts thereof.

These particularly preferred embodiments have been found to have significantly higher cardiotonic activity than the corresponding desalkyl compounds, 3-amino-5- (4-pyridinyl) -2 (1H) -pyridinone, known as amrinone, 1,2-dihydro-2-oxo -5- (4-pyridinyl) -nicotinonitrile and 5- (4-pyridinyl) -2 (1H) -pyridinone.

A compound of formula I as defined above can be prepared by a process which comprises a) reacting a compound having the formula R 3 R 4 NCH = CC (= O) -R III in PY wherein R 3 and R 4 each represent lower alkyl, with malonamide to form a compound of formula I, wherein Q is carbamyl, or b) reacting a compound of formula III above with N-R 1 -p (- cyanoacetamide to form a compound of formula I, wherein Q is cyano.

The present invention relates to the compounds of formula III.

Said compounds are prepared by reacting a PY-methyl- (lower alkyl) -ketone of the formula PY-CH 2 -C (= O) -R (II) with di (lower alkyl) -formamide-di- (lower alkyl) -acetal to form 1-PY-2- [di- (lower alkyl) -aminqf-ethenyl- (lower alkyl) ketone of formula III 'R¿R4Ncr1 = cc (= o) -R (III) PY 451 722 wherein R 3 and R 4 are each lower alkyl and one is preferably methyl, and PY, R, R and R * have the meaning given above. The term "lower alkyl" in the present context as meaning R 1, R 3 and R 4 as meaning "lower alkyl" in lower alkylamino or di- (lower alkyl) amino, as meaning Q or as a substituent in PY in formula I, refers to alkyl groups having 1-6 carbon atoms which may form straight or branched chains, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-amyl, n- hexyl and the like.

Examples of PY, when PY is 4-, 3- or 2-pyridinyl having one or two lower alkyl substituents, are the following groups: 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4 pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively referred to as 2-methyl-5-pyridinyl, 4-methyl-2-pyridinyl, 6-methyl-2-pyridinyl, 2,3 -dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 4,6-dimethyl-2-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4 -pyridinyl, 2-n-hexyl-4-pyridinyl, 2,6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl, 2,6-diisopropyl-α-pyridinyl, 2,6-di-n -hexyl-4-pyridinyl and the like.

The compounds of formula III are useful both in the free base form and in the form of the acid addition salts, and both forms are within the scope of the invention. The acid addition salts are simply a more convenient form of use; and in practice the use of the salt form is inherent use of the base form. The acids which can be used to prepare the acid addition salts preferably include those which in combination with the free base form pharmaceutically acceptable salts, i.e. salts whose anions are relatively harmless to the animal organism in pharmaceutical doses of the salts, whereby the beneficial cardiotonic properties of the free base (I) are not disturbed by side effects attributed to the anions. In practicing the invention, it is convenient to use the free base form; However, suitable pharmaceutically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid as well as organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonicuronic acid, p-sulfonic acid , quinic acid and the like, which give hydrochloride, sulphate, phosphate, sulphamate, acetate, citrate, lactate, tartrate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate, cyclohexylsulphamate resp. kinat.

The acid addition salts of the basic compound (I or III) are prepared either by dissolving the free base in an aqueous solution or an aqueous / alcoholic solution or other suitable solvent containing the acid and isolating the salt by evaporation of the solution or by reacting it. the free base and the acid in an organic solvent, whereby the salt separates directly or can be obtained by concentrating the solution. Although pharmaceutically acceptable salts of the basic compounds (III) are preferred, all acid addition salts are within the scope of the invention. All acid addition salts are useful as sources of the free base form, although the particular salt itself is desirable only as an intermediate product, such as, for example, when the salt is formed for purification or identification purposes only or when used as an intermediate for the preparation of a pharmaceutically acceptable. salt by ion exchange processes.

The molecular structures of the compounds of formula III were determined on the basis of evidence obtained by IR, NMR and mass spectra and on the basis of agreement between calculated and found values in elemental analyzes.

The method of use and application of the invention is described below in general terms, whereby a person skilled in the art can utilize it. The preparation of 1-PY-2- (dimethylamino) -ethenyl- (lower alkyl) ketone (III) by reaction of PY-methyl- (lower alkyl) ketone (II) with dimethylformamide di- ( lower alkyl) acetal is carried out by mixing the reactants in the presence or absence of a suitable solvent. The reaction is conveniently carried out at room temperature; i.e. about 20-25 ° C, or by heating the reactants up to about 100 ° C, preferably in an aprotic solvent, preferably hexamethylphosphoramide due to the method of preparing PY-methyl (lower alkyl) ketone as set forth below in Example A1 Other suitable solvents include tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, dioxane and the like. Likewise, the reaction can be carried out without any solvent, preferably using an excess of dimethylformamide di- (lower alkyl) acetal. This procedure is further illustrated below in Examples A-1 to A-17.

The intermediate PY-methyl (lower alkyl) ketones (II) are generally known compounds which are prepared according to known methods [1.ex. as stated in Reo. trotting. chim 12, 522 (l953); U.S. Patent No. 3.1.33.'777 (s-iz-szn; Bun. soc. chim 1_9s_§, 4132; Chem. Abstrs. 12, 8539h (l973); Chem. Abstrs. §l, l20.40la (l974) ; .J. Org. Chem. Åg, 3834 (1974); Chem. Abstrs. Ål, 6594q (1977): J. Org. Chem. Åg, 2286 (1978L7. 451 722 6 The following examples further illustrate the invention without limiting the same .

Example A. 1-PY-2- (dimethylamino) ethenyl (lower alkyl) ketones A-1. 1- (4-Pyridinyl) -2- (dimethylamino) -ethyl ethyl ketone A mixture containing 20 g of (4-pyridinyl) -methyl methyl ketone [alternatively called 1- (4-pyridinyl) -2-propanone] and 30 ml of hexamethylphosphoramide was diluted with 65 g ml of dimethylformamide dimethyl acetal and the resulting mixture was refluxed for 30 minutes. TLC analysis showed a single spot, which showed the completion of the reaction (in another experiment, the reaction was found to be complete after 30 minutes at room temperature). The reaction mixture was evaporated under reduced pressure using a rotary evaporator and a pressure of about 15 mm to give a crystalline residue weighing 24 g. The residue was purified by continuous chromatographic extraction on alumina (about 150 g) using of refluxing chloroform as eluent. After 1.5 hours, the extract was heated in vacuo to remove chloroform to give a light yellow crystalline material, 23.2 g of 1- (4-pyridinyl) -2- - (dimethylamino) ethenylmethyl ketone, alternatively designated 4-dimethylamino-2 - (4-pyridinyl) -3-buten-2-one.

The above preparation can be carried out using other solvents instead of hexamethylphosphoramide, e.g. dimethylformamide, acetonitrile or other above solvents or also in the absence of a solvent; however, hexamethylphosphoramide is preferably used because (4-pyridinyl) -methylmethyl ketone is conveniently prepared as a mixture together with hexamethylphosphoramide, as shown in the following preparation: To a stirred solution containing 70 ml of freshly distilled diisopropylamine and 200 ml of tetrahydrofuran was added under dropwise over 20 minutes 210 ml of 2.4M n-butyllithium in n-hexane and the reaction mixture was stirred for about 35 minutes at about 0-5 ° C. To the cold solution was added dropwise over a period of 10 minutes 90 ml of dry hexamethylphosphoramide (no temperature change) and the resulting light yellow solution was stirred for 15 minutes. To the cold solution at 0 ° C was added a solution of the now 4-picoline in 150 ml of dry tetrahydrofuran over a 15-minute period and stirring was continued for 30 minutes at 0 ° C. Then a mixture containing 50 ml of dry ethyl acetate and 150 ml of tetrahydrofuran was added over a 15-minute period (the temperature rose from 00 to about 600) and the resulting mixture was stirred for 20 minutes at 0 ° C.

The ice bath was then removed and stirring was continued for another 90 minutes, after which the temperature of the reaction mixture rose to about 25 ° C. The reaction mixture was then cooled in an ice bath and added with 60 ml of acetic acid for a period of about 30 minutes. The tetrahydrofuran was distilled off using a rotary evaporator in vacuo. The remaining mixture was diluted with 400 ml of water and the aqueous mixture was extracted successively with two 250 ml portions of isopropyl acetate and three portions of 80 ml of chloroform. The solvents were distilled off under reduced pressure to obtain about 137 g of a mixture consisting primarily of the desired product and hexamethylphosphoramide. A second experiment using the same amounts was performed as above, except that after adding 60 ml of glacial acetic acid, the mixture was diluted with only 200 ml of water, after which the phases were separated and the aqueous phase was extracted with five 100 ml portions of chloroform. The chloroform extract was washed with brine and the chloroform was distilled off in vacuo. The residual mixture of the desired ketone and hexamethylphosphoramide was combined with the above 137 g of the same mixture, and the combined mixture was distilled under reduced pressure to obtain the following fractions: I. 63 g, b.p. 120-112 ° C at 4 mm; II. 59 g of a pale yellow oil, b.p. 13-315 ° C at 3 mm; and III. 69 g of a pale yellow oil, b.p. Investigation of fraction III by NMR showed that it consisted of a 2: 3 mixture, by weight, of (4-pyridinyl) -methyl methyl ketone and hexamethylphosphoramide. The acid addition salts of the 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone were conveniently prepared by the addition of the acid in question, e.g. methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid to a mixture of 5 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone in about 100 ml of aqueous methanol, to a pH of about 2-3, cooling of the mixture after partial evaporation and recovery of the precipitated salt, e.g. the dimethanesulfonate, the sulfate resp. the phosphate.

Likewise, the acid addition salt could conveniently be prepared in aqueous solution by addition to water and with stirring molar equivalent amounts of 1- (14-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone and the acid in question, e.g. lactic acid or hydrochloric acid for the production of the monolactate resp. the monohydrochloride in aqueous solution.

A-2. 1- (4-Pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone A mixture containing 87.5 g (4-nyridinyl) -methyl ethyl ketone [alternatively called 1- (4-pyridinyl) -2-butanone] and 160 ml of hexamethylphosphoramide was diluted with 100 g of dimethylformamide dimethylacetal and the resulting mixture was stirred under nitrogen at room temperature for 45 minutes. The methanol formed in the reaction was distilled off in vacuo using a rotary evaporator and residual material was distilled under reduced pressure to obtain two functions, one of which was boiled via 45 ° C at 0.5 mm and but others at 9o-9s ° c via 0.5 mm.

After TLC analysis, predominantly only a single spot was obtained for each fraction; the two fractions were combined (135 g) and taken up in 600 ml of chloroform. The resulting solution was washed with two 300 ml portions of water and the water was re-extracted with three 100 ml portions of chloroform. The combined chloroform solutions were dried over anhydrous sodium sulfate and purified by continuous extraction chromatography on 300 ml of alumina using refluxing chloroform as eluent. The chloroform was distilled off in vacuo to give a red oil which crystallized on storage in an ice bath overnight. The crystalline material was dissolved in carbon tetrachloride, cyclohexane was added and the mixture was cooled to give 64 g of the resulting crystalline crystalline product, (451,722) 1- (4-pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone. An additional 11 g of crystalline product was obtained from the mother liquor by continuous extraction chromatography on alumina using refluxing chloroform as eluent.

The above intermediate (4-pyridinyl) -methyl ethyl ketone was obtained in admixture with hexamethylphosphoramide as follows: To a mixture containing 200 ml of tetrahydrofuran and 70 ml of diisopropylamine under nitrogen at 0-500 was added 210 ml of 2,4N n-butyllithium in n-hexane and the resulting mixture was stirred for 30 minutes. Then, over a 10-minute period, 90 ml of hexamethylphosphoramide was added, followed by stirring the mixture for 15 minutes. Then, over a 15-minute period, a solution of 4 ml of 4-picoline in isomethyl of tetrahyarofuran was added; of stirring for 30 minutes at about 0 ° C. The cooling of the reaction mixture on an ice / acetone bath was replaced by cooling on a dry ice / acetone bath and to the reaction mixture was added over a 20 minute period a mixture of 75 ml of ethyl propionate in an equal volume of tetrahydrofuran. The reaction mixture was then allowed to warm to room temperature over a period of about 90 minutes and then heated at about 3500 for 30 minutes. The mixture was then cooled on an ice / acetone bath and to this was added 60 ml of glacial acetic acid for 30 minutes. The resulting pale yellow suspension was diluted with 200 ml of water. The mixture was extracted with three 150 ml portions of ethyl acetate and the ethyl acetate extract was washed again with brine. The extract was heated in vacuo to remove ethyl acetate and the residue was taken up in ethyl acetate again.

The solution was washed with water and then heated in vacuo to remove ethyl acetate followed by heating the residue in vacuo at 50 ° C for about 30 minutes to give 10 g of a pale yellow oil. The pale yellow oil was combined with the corresponding samples obtained from two further experiments and then distilled in vacuo to give 256 g of a fraction with a boiling point of 85 Å105 ° C at 0.5-1.0 mm. NMR analysis of this fraction showed that it was a mixture of (4-pyridinyl) -methyl ethyl ketone and hexamethylphosphoramide in the molar ratio 1: 1.55, i.e. 35% or 0.35 x 256 = 90ßg of the ketone. 451 722 10 A-3. 1- (4-Pyridinyl) -2- (dimethylamino) -ethenyl-n-propyl ketone A mixture containing 80 g (4-pyridinyl) -methyl-n-propyl ketone [alternatively called 1- (4-pyridinyl) -2- pentanone and 46 ml of hexamethylphosphoramide were diluted with 250 ml of acetonitrile. To the mixture was added 90 ml of dimethylformamide dimethyl acetal, and the resulting reaction mixture was heated on a steam bath for 90 minutes and then distilled under vacuum at about 2 mm to remove volatiles including methanol, acetonitrile and hexamethylphosphoramide. The residue was diluted with ethyl acetate and washed with water. The combined water washes were extracted with five 150 ml portions of ethyl acetate.

The combined ethyl acetate solutions were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue crystallized on storage in a freezer. The crystalline product was slurried in cyclohexane, filtered and dried overnight at 30 ° C to give a yellow crystalline product, 97 g of 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl-n -propyl ketone, m.p. 48-5000.

The above intermediate (4-pyridinyl) -methyl-n-propyl ketone was obtained in admixture with hexamethylphosphoramide as follows: To a stirred solution of 70 ml of diisopropylamine in 200 ml of tetrahydrofuran under nitrogen at about 0 ° C (using an ice bath) was added 210 ml 2.4N n-butyllithium for 20 minutes and the resulting mixture was stirred for 30 minutes at about 0 ° C; To the mixture was added with stirring for 10 minutes 90 ml of hexamethylphosphoramide and the resulting mixture was stirred for another 10 minutes. Then 45 ml of 4-picoline in 140 ml of tetrahydrofuran were added dropwise over 15-20 minutes. The resulting dark orange-brown solution was stirred at 0 ° C for 30 minutes and then treated dropwise over a period of 18 minutes with a solution consisting of 68 ml of ethyl butyrate. in 68 ml of tetrahydrofuran, the temperature rising from -8 ° C to + 8-10 ° C. The reaction mixture was removed from the ice bath and allowed to warm to room temperature over a period of 75 minutes. The reaction mixture was cooled again and to this was added dropwise over 15 minutes 60 ml of glacial acetic acid. A pale yellow solid separated and a suspension formed. The suspension was diluted with water and extracted with two 200 ml portions of ethyl acetate. The ethyl acetate p. Sr »451 722 μl extract was washed with three 100 ml northionic brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give 107 g of a mixture consisting primarily of (4-pyridinyl) methyl-n-propyl ketone and hexamethylphosphoramide. . The mixture obtained in this experiment was combined with the corresponding mixtures obtained in two other experiments and the combined mixtures were distilled under vacuum to obtain as the essential fraction with the boiling point 80-90 ° C at 0.2 mm a mixture consisting of 80 g (4- pyridinyl) -methyl-n-propyl ketone and 46 g of hexamethylphosphoramide. In the manner described in Example A-2 but using a molar equivalent amount of the corresponding P1-methyl- (lower alkyl) -ketone (II) instead of (4-pyridinyl) -methylethyl ketone, the corresponding 1-PY 2- (Dimethylamino) ethenyl (lower alkyl) ketones according to Examples A-4 to A-1v are obtained.

A-4. 1- (3-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone using (3-pyridinyl) -methyl methyl ketone.

A ~ 5. 1- (2-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone using (2-pyridinyl) methylmethyl ketone.

A-6. 1- (4-pyridinyl) -2- (dimethylamino) ethenyl isopropyl ketone using (4-pyridinyl) methyl isopropyl ketone.

A-7. 1- (4-pyridinyl) -2- (dimethylamino) ethenyl n-butyl ketone using (4-pyridinyl) methyl n-butyl ketone.

A-8. 1- (4-pyridinyl) -2- (dimethylamino) ethenyl isobutyl ketone using (4-pyridinyl) methyl isobutyl ketone.

A-9. 1- (4-Pyridinyl) -2- (dimethylamino) ethenyl tert-butyl ketone using (4-pyridinyl) methyl tert-butyl ketone.

A-10. 1- (4-pyridinyl) -2- (dimethylamino) ethenyl-n-pentyl ketone using (4-pyridinyl) methyl-n-pentyl ketone. 451 722 12 A-ll. 1- (2-methyl-4-pyridinyl) -2- (dimethylamino) -ethyl ethyl ketone using (2-methyl-4-pyridinyl) methyl ethyl ketone.

A-12. 1- (5-Methyl-2-pyridinyl) -2- (dimethylamino) -ethenylmethyl ketone using (5-methyl-2-pyridinyl) methyl methyl ketone.

A-13. 1- (5-ethyl-2-pyridinyl) -2- (dimethylamino) -ethyl ethyl ketone using (5-ethyl-42-pyridinyl) methyl ethyl ketone.

A-14. 1- (3-pyridinyl) -2- (dimethylamino) ethenylethyl ketone using (B-pyridinyl) methyl ethyl ketone. 'A-15. 1- (4,6-dimethyl-2-pyridinyl) -2- (dinethylaminolethenylmethyl ketone using (4,6-dimethyl-2-pyridinyl) methylmethyl ketone.

A-16. 1- (6-methyl-2-pyridinyl) -2- (dimethylamino) -ethenylisopropyl ketone using (6-methyl-2-pyridinyl) methyl isopropyl ketone.

A-17 1- (2-pyridinyl) -2- (dimethylamino) ethenyl n-hexyl ketone using (2-pyridinyl) methyl n-hexyl ketone. O!

Claims (1)

A PATENTIC REQUIREMENT As a chemically intermediate compound having the formula R3R4NCH =? - C (= O) -R PY wherein R is lower alkyl, R3 and R4 are each lower alkyl and PY is 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl having one or two lower alkyl groups as substituents.