FI77851C - 1-PYRIDINYL-2- (DIALKYLAMINO) ETHENYLALKYLKETONER. - Google Patents

Description

The invention relates to 1-pyridinyl-2- (dialkylamino) ethenylalkyl ketones, which are intermediates useful in the preparation of cardiac drugs for the preparation of 5- (pyridinyl) -2-1H-pyridinyl-2-1H-pyridine.

The preparation of said 5- (pyridinyl) -2 (1H) -pyridinone derivatives is described in Finnish patent application 803652 and has the formula I:

PY Q

"O"

R 1 wherein Q is hydrogen, amino, cyano, carbamyl, halo, lower -20 alkylamino, di- (lower alkyl) amino, lower acylamino, carboxy or lower carbalkoxy, is hydrogen, lower alkyl or lower hydroxyalkyl, R is lower alkyl and PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower alkyl substituents, or a pharmaceutically acceptable acid addition or cationic salts. The compounds of formula I are useful cardiac drugs as determined by standard pharmacological evaluation methods. Compounds of formula I wherein Q is carbamyl or cyano or Q is hydrogen are also useful intermediates for the preparation of the corresponding compounds wherein Q is amino and halo, respectively. Compounds of formula I wherein Q is halo are also useful intermediates for the preparation of the corresponding 3- (pio- or di- (lower alkyl) amino) compounds. In preferred embodiments of formula I, Q is hydrogen, amino or cyano, PY is 277785 4-pyridinyl or 3-pyridinyl, is hydrogen and R is methyl or ethyl. Particularly preferred embodiments 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-pyrid-5-dinyl and R is methyl), 3-amino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridone (Formula I wherein Q is NH 2, R 1 is H, PY is 4-pyridinyl and R is ethyl), 3-amino-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-5-10 (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 were found to have significantly greater cardiac activity than the corresponding known compounds 3-amino-5- (4-pyridinyl) -2 (1H) -pyridinone, known as amrinone, 1,2-dihydro-2-oxo-5 - (4-pyridinyl) -nicotinonitrile 2Q and 5- (4-pyridinyl) -2 (1H) -pyridinone.

The compounds of formula I as defined above may be prepared by a method known from a) administering a compound of formula R3R4NCH = C-C (= O) -R (III)

PY

wherein R 3 and R 2 are each lower alkyl, react with Malonamide to give a compound of formula I wherein Q is carbamyl, or b) reacting a compound of formula III above with NR 4 -C 6 -cyanoacetamide to give a compound of formula I , where Q is cyano.

This invention relates to compounds of formula III as defined above. These compounds are prepared by reacting 35- to 85-P-methyl-lower alkyl ketone of the formula PY-CH2-C (= O) -R (II) with di- (lower alkyl) formamide-di- (lower alkyl) - with acetal to 1-PY-2- [di- (lower alkyl) amino] ethenyl-lower alkyl ketone of formula III R3R4NCH = CC (= O) -R (III)

PY

wherein R 1 and R 2 are each lower alkyl and the other is preferably methyl and PY, R, R 1 and R 'are as defined in formula I.

As used herein, the term "lower alkyl", e.g., as meaning R, R 2 and R 4, or in a lower alkylamino or di- (lower alkyl) amino when Q or a substituent on PY, means 1-6 carbon atoms. straight-chain or branched alkyl radicals containing, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-amyl, n-hexyl, etc.

When the group PY is 4-, 3- or 2-pyridinyl having one or two lower alkyl-2Q substituents, examples thereof are 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4- pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternative name 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-30-4-pyridinyl , 2,6-di-n-hexyl-4-pyridinyl, etc.

The compounds of formula III are useful both in their free base form and in the form of their acid addition salts, and both forms are a subject of the invention. Acid addition salts are merely a more convenient form of use and thus it is natural that in practice more, 77851 4 salt forms are used than the base form. Acids useful in the preparation of acid addition salts are preferably those which together with the free base form pharmaceutically acceptable salts, i.e. salts whose anions are relatively harmless to the animal when the salts are administered at pharmaceutical doses, i.e. the side effects of the anions must not interfere with the free base. When utilizing the invention, it is convenient to use the free base form. Also included within the scope of the invention are suitable pharmaceutically acceptable acid addition salts formed with mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid, and organic acids such as acetic acid, citric acid, citric acid, lactic acid, tartaric acid, tartaric acid, methane -toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, etc., to give hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, sulfonate sulfonate, benzene sulfonate, pentene sulfonate, respectively, .

Acid addition salts of said basic compound (I or III) are prepared either by dissolving the free base in an aqueous or aqueous-alcoholic solution containing the appropriate acid or other suitable solvent and isolating the salt by evaporating the solution or reacting the free base and acid in an organic solvent to separate the salt. directly or by concentrating the solution.

Although pharmaceutically acceptable salts of said basic compound (I or III) are preferred, all acid addition salts are within the scope of the invention. All acid addition salts are useful as a source of the free base form even if the salt 35 is desired to be prepared only as an intermediate, e.g. for purification or identification purposes, or when used as an intermediate for the preparation of a pharmaceutically acceptable salt by ion exchange.

The molecular structures of the compounds of formulas I and III were determined on the basis of the data provided by the infrared, nuclear magnetic resonance and mass spectra and the correspondence between the calculated and obtained values obtained in the elemental analysis.

In the following, the practice and use of the present invention will be generally described as being capable of being practiced and used by one skilled in the art of pharmaceutical chemistry.

The preparation of 1-PY-2- (dimethylamino) ethenyl-lower alkyl ketone (III) by reacting PY-methyl-lower alkyl-ketone (II) with dimethylformamide di- (lower alkyl) acetal is carried out by stirring the reaction. in the presence or absence of a suitable solvent. The reaction is conveniently carried out at room temperature, i.e. at about 20-25 ° C, or by heating the reactants to about 100 ° C, preferably in an aprotic solvent and suitably hexamethylphosphoramide due to the process used to prepare PY-methyl-lower alkyl ketone as in Example A1 below. mentioned. Other suitable solvents include tetrahydrofuran, dimethylformamide, aceto-nitrile, ether, benzene, dioxane, etc. The reaction can also be carried out without a solvent, preferably using an excess of dimethylformamide-di- (lower alkyl) acetal. This method is further described in Examples A-1 to A-17 below.

The PY-methyl-lower alkyl ketones (II) used as intermediates are generally known compounds which can be prepared by known methods / as starting materials, e.g. Rec. trav. chim. 72, 522 (1953), U.S. Patent 3,133,077 (5-12-64), Bull. Soc. Chim. 1968, 4132, Chem.

35 Abstrs. 79, 8539h (1973), Chem. Abstrs. 81, 120 401a 6 77851 (1974), J. Org. Chem. 39, 3834 (1974), Chem. Abstrs. 87, 6594q (1977), J. Org. Chem. 43, 2286 (1978) J.

The use of compounds of formula III as intermediates in the preparation of compounds of formula I is described in detail in Finnish patent application 803652.

A. 1-PY-2- (dimethylamino) ethenyl-lower alkyl ketones A-1. 1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone

A mixture of 20 g of (4-pyridinyl) methyl methyl ketone (alternative name 1- (4-pyridinyl) -2-propanone) and 30 cm of hexamethylphosphoramide was diluted with 65 cm of dimethylformamide dimethyl acetal and the resulting mixture was heated. with vertical cooling for 30 minutes. TLC analysis showed one spot indicating the completion of the reaction (in the second run, the reaction appeared to be complete after 30 minutes at room temperature). The reaction mixture was evaporated on a rotary evaporator under vacuum at about 20 mm to give 24 g of a crystalline residue. This was purified by continuous chromatography extraction through alumina (ca. 15 ° g) eluting with refluxing chloroform. After 1.5 hours, the extract was heated in vacuo to remove chloroform to give 23.2 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone, alternatively 4-dimethylamino-2- (4-pyridinyl) -3 as a pale yellow crystalline solid. buten-2-one.

The above preparation can be carried out using other solvents instead of hexamethylphosphoramide, e.g. dimethylformamide, acetonitrile or other solvents mentioned above or without a solvent. But it was convenient to use hexamethylphosphoramide because (4-pyridinyl) methylmethyl ketone was conveniently prepared as a mixture with hexamethylphosphoramide, as evidenced by the following preparation: To a stirred solution of 70 cin of freshly distilled diisopropylamine and 200 c At C and under nitrogen, 3 was added dropwise over 20 minutes 210 cm2 of 2,4-m 5 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 90 cm -1 of dry hexamethylphosphoramide (no change in temperature) over 10 minutes, and the resulting pale yellow solution was stirred for 15 minutes. To a cold solution at 0 ° C was added over 15 minutes a solution of 3 cm 3 of 50-picoline in 150 cm of dry tetrahydrofuran and stirring was continued for 30 minutes at 0 ° C. A mixture of 50 cm of dry ethyl acetate and 150 cm of tetrahydrofuran (temperature rose from 0 ° C to about 6 ° C) was then added over 15 minutes and the resulting mixture was stirred for 20 minutes at 0 ° C. The ice bath was then removed and stirring was continued for an additional 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 60 cm of acetic acid was added over a period of about 30 minutes. Tetrahydrofuran was removed by distillation in vacuo on a rotary evaporator. The remaining mixture was diluted with 3 x 40 cm of water and the aqueous mixture was extracted successively with two 250 cm portions of isopropyl acetate and three 80 cm 2 portions of chloroform. The solvents were removed by distillation in vacuo to give about 137 g of a mixture of 77851 consisting essentially of the desired product and hexamethylphosphoramide. A second run was performed in the same amounts as above, except that after 3 cm of 60 cm glacial acetic acid was added, the mixture was diluted with only 200 cm 5 of water, 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 removed by distillation in vacuo. The remaining mixture of the desired ketone and hexamethylphosphoramide was combined with 137 g of the same mixture obtained above, the combined mixture was distilled in vacuo to give the following fractions: I. 63 g, b.p. 110-112 ° C / 4 mm, II. 59 g of pale yellow oil, b.p. 113-115 ° C / 3 mm and III. 69 g of pale yellow oil, b.p. 115-118 ° C / 2.5 mm. NMR analysis of fraction III showed that it was formed from a 2: 3 mixture by weight of (4-pyridinyl) methyl methyl ketone and hexamethylphosphoramide.

The acid addition salts of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone are conveniently prepared by adding 20 g of a mixture of 5 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone in about 100 ml of aqueous methanol. an appropriate acid, e.g. methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid, to a pH of about 2-3, cooling the mixture after partial evaporation and isolating the precipitated salt, e.g. dimethanesulfonate, sulphate or phosphate, respectively. The acid addition salt can also be conveniently prepared in aqueous solution by adding with stirring to the water a molar equivalent of both 1- (4-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone and the appropriate acid, e.g.

A-2. 1- (4-Pyridinyl) -2- (dimethylamino) ethenyl ethyl ketone 35 Mixture of 87.5 g of (4-pyridinyl) methylethyl 9,778,81 ketone (alternative name 1- (4-pyridinyl) -2-butanone ) and 160 cm -1 of hexamethylphosphoramide, diluted with 100 g of dimethylformamide dimethyl acetal and the resulting mixture was stirred for 45 minutes under a nitrogen blanket and at room temperature. The methanol formed in the reaction was removed by distillation in vacuo on a rotary evaporator, and the remaining material was distilled in vacuo to give two fractions, one of which b.p. was 45-80 ° C / 0.5 mm and the second b.p. 90-95 ° C / 0.5 mm. When it was found by TLC that each fraction formed essentially only a single spot, the two fractions were combined (= 135 g) and dissolved in 600 cm -1 of chloroform. The resulting solution was washed with two 3,300 cm portions of water and the aqueous solution was extracted 3 with three 100 cm portions of chloroform. The combined chloroform solution was dried over anhydrous sodium sulfate and purified by continuous chromatographic extraction with 300 mothers of alumina eluting with refluxing chloroform. The chloroform was removed by distillation in vacuo to give a red oil which crystallized on standing overnight in an ice bath. The crystalline material was dissolved in carbon tetrachloride, cyclohexane was added, the mixture was cooled to give 64 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenylethyl ketone as a yellow crystalline product. An additional 11 g of crystalline product was obtained from the mother liquor by continuous chromatography extraction through alumina eluting with refluxing chloroform.

The above intermediate (4-pyridinyl) methyl ethyl ketone was obtained as a mixture with hexamethylphosphoramide as follows: To a mixture of 200 cm of tetrahydrofuran 30 and 70 cm 3 of diisopropylamine under nitrogen and at 0-5 ° C was added 210 cm -1 2,4-n-n-butyllithium in n-hexane and the resulting mixture were stirred for 30 minutes, then 90 cm 3 of hexamethylphosphoramide was added over 10 minutes and the mixture was stirred for 15 minutes, after which a solution of 48 cm 4 was added over 15 minutes. -pico- 3 10 77851 lines in 150 cm tetrahydrofuran and then stirred for 30 minutes at about 0. The ice-acetone bath used to cool the reaction mixture was replaced with a dry ice-acetone bath, and a mixture of 75 cm-1 ethyl propionate was added to the reaction mixture over 20 minutes. The reaction mixture was then allowed to warm to room temperature over about 90 minutes and then warmed to about 35 ° C over about 30 minutes. During the. The mixture was then cooled in an ice-acetone bath and 60 cm of glacial acetic acid was added over 30 minutes.

3

The resulting pale yellow suspension was diluted with 200 cm of water. The mixture was extracted with three 150 cm portions of ethyl acetate and the ethyl acetate extract was backwashed with brine. The extract was heated in vacuo to remove ethyl acetate and the residue was redissolved in ethyl acetate. The solution was washed with water, then heated in vacuo to remove ethyl acetate, the residue heated in vacuo at 50 ° C for about 30 minutes to give 100 g of a pale yellow oil. This oil and the corresponding samples from two additional runs were combined, distilled in vacuo to give 256 g of a fraction having a b.p. was 85-105 ° C / 0.5-1.0 mm. According to NMR, this fraction was a 1: 1.55 molar mixture of (4-pyridinyl) methyl ethyl ketone and hexamethylphosphoramide, i.e. the yield of said ketone 25 was 35%, i.e. 0.35 x 256 = 90 g.

A-3. 1- (4-pyridinyl) -2- (dimethylamino) ethenyl n-propyl ketone

A mixture of 80 g of (4-pyridinyl) methyl-n-propyl ketone (alternative name 1- (4-pyridinyl) -2-pentanone) and 46 cm -1 of hexamethylphosphoramide was diluted to 250 cm 3. acetonitrile. To the mixture was added 90 cm of dimethylformamide dimethyl acetal, the resulting reaction mixture was heated on a water bath for 90 minutes and then distilled in vacuo at a pressure of about 2 mm of volatiles, e.g.

35 to remove methanol, acetonitrile and hexamethylphosphoramide. The residue was diluted with ethyl acetate and the mixture was washed with water. The combined water washes were extracted with five 150 cm 2 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 standing in a freezer. The crystalline product was slurried in cyclohexane, filtered, dried overnight at 30 ° C to give 97 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl-n-propyl ketone as a yellow crystalline product, m.p. 48-50 ° C.

The above intermediate (4-pyridinyl) methyl-n-propyl ketone was obtained as a mixture with hexamethylphosphoramide 3 as follows: To a stirred solution of 70 cm 3 of diisopropylamine in 200 cm tetrahydrofuran under nitrogen and at about 0 ° C (ice bath used) , additional

O

210 cm -1 of 2,4-n n-butyllithium were added over 20 minutes, the resulting mixture was stirred for 30 minutes at about 0 ° C, 90 cm -1 of hexamethylphosphoramide was added to the mixture over 10 minutes with stirring, and the resulting mixture was stirred for a further 10 minutes. Then 45 cm 4-picoline in 140 cm tetrahydrofuran was added dropwise over 15-20 3 3 minutes. The resulting dark orange-brown solution was stirred for 30 minutes at 0 ° C and then treated with a solution of 68 cm 2 of ethyl butyrate in 68 cm 2 of tetrahydrofuran, dropping over 18 minutes at -8 ° C to + 8 °. .10 ° C. The reaction mixture was removed from the ice bath and allowed to warm to room temperature over 75 minutes. The reaction mixture was re-cooled and 60 cm @ 2 of glacial acetic acid were added dropwise over 15 minutes. A pale yellow solid separated and a suspension formed. This was diluted with water and extracted 3 with two 200 cm portions of ethyl acetate. The ethyl acetate extract was washed with three 100 cm3 portions of brine, dried over anhydrous sodium sulfate, evaporated in vacuo to give 107 g of a mixture consisting essentially of (4-pyridinyl) methyl-n-propyl ketone and hexamidomethylphosphorus. The mixture obtained in this run and the corresponding mixtures from the other two runs were combined, the combined mixtures were distilled in vacuo to give the main fraction, b.p. 80-90 ° C / 0.2 mm, a mixture of 80 g of (4-pyridinyl) methyl-n-propyl ketone and 46 g of hexamethylphosphoramide.

Following the procedure described in Example A-2, but using a molar equivalent of the appropriate PY-methyl-lower alkyl ketone (II) instead of (4-pyridinyl) methyl ethyl ketone, the corresponding 1-Examples of Examples A-4 to A-17 can be obtained. PY-2- (dimethylamino) ethenyl lower-alkyl ketones.

15 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) methyl methyl 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-boryl ketone using (4-pyridinyl) methyl-n-butyl ketone.

25 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.

A-II. 1- (2-methyl-4-pyridinyl) -2- (dimethylamino) -ethylethyl ketone using (2-methyl-4-pyridinyl) methyl ethyl ketone.

13 77851 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) ethynyl ethyl ketone.

A-14. 1- (3-pyridinyl) -2- (dimethylamino) ethenylethyl ketone using (3-pyridinyl) methyl ethyl ketone. A-15. 1- (4,6-Dimethyl-2-pyridinyl) -2- (dimethylamino) ethenylmethyl ketone using (4,6-dimethyl-2-pyridin-10-yl) methyl methyl ketone.

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

A-17. 1- (2-pyridinyl) -2- (dimethylamino) ethenyl-n-15 hexyl ketone using (2-pyridinyl) methyl-n-hexyl ketone.

When (3-methyl-4-pyridinyl) methyl methyl ketone is used, the method of Example A-2 gives 1- (3-methyl-4-pyridinyl) -2- (dimethylamino) -ethylmethyl ketone having a melting point of 124- 125 ° C.

Claims (4)

14 77851 A compound of formula III: R 3r 4nch = cc (= o) -r (III) PY wherein R is lower alkyl, R 1 and R 2 are each lower alkyl and PY is 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl having one or two lower alkyl substituents. Compound according to Claim 1, characterized in that PY is 4-pyridinyl and R is methyl or ethyl. Compound according to Claim 1 or 2, characterized in that R 1 and R 2 are each methyl. Process for the preparation of a compound according to claim 1, characterized in that a pyridinylmethyl (lower alkyl) ketone of the formula PY-CH 2 -C (= O) -R is reacted with di- (lower alkyl) formamide. - (lower alkyl) acetal.