SU1303025A3 - Method for producing derivatives of 1,4-dihydropyridine - Google Patents

Abstract

- The invention relates to derivatives of heterocyclic compounds, in particular, dihydropyridine of the general formula IR O- (O) CC-CHR, jgC (O) -OKz N CR4-N-R5 HjC-C-NH-C-CH2-0-CH -C CH — C 0, where R and R 3 are each independently C — —C — alkyl; R, j is phenyl, 2-chloro- or 2,3-dichlorophenip; R - C, -C-alkyl, morpholimyl, piperidinyl, group N (R) 2; Rj and R are H or C, -C-alkyl, which have an antihypertensive effect and can be used in medicine. To detect activity among compounds of the indicated class, new (I) were obtained. Their synthesis is carried out from -alkilo- vogue ketoester of the corresponding dihydropyridine and guanidine hydrochloride R, -C (NH) NH, j-HCl, where R is indicated above, when boiling in an alcohol medium in the presence of an organic base. The resulting compound I, if necessary, is alkylated with a C -C-alkyl halide. Tests I show that they are non-toxic and exhibit an effective coronary expanding activity. 2 tab. i CO so oo so oo SP see

Description

This invention relates to a process for the preparation of novel 1,4-dihydropyridine derivatives of general formula (I)

HRt RjOOCs ivxCOORj

Hjc

w

H

CH,

f5

with -C-alkyl.

20

where R, is phenyl, 2-chlorofensh1, 2,3-fO-dichlorophenyl; each independently C, alkyl; R - -alkyl, morpholinyl,

piperid, inyl, group NCR), where R is hydrogen, C-C-alkyl;

Rg is hydrogen,

have antihypertensive effects.

The purpose of the invention is the development, on the basis of a well-known method, of a method for the preparation of new derivatives of 1,4-dihydropyridines with valuable pharmacological properties.

Example 1. 2-Amino-6- {4- (2- -chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl methoxymethyl} -4-pyrimidone .

A solution of guanidine hydrochloride (0.20 g), ethyl 4- {4- (2-chlorophenyl) -3-ethoxycarboxy-1-5-methoxycarbonyl-6-meTyl-1,4-dihydropyridin-2-yl methcarbonyl-6-methyl- 1, 4-dihydropyridine-2-yl methoxy | adeo-a11. Tetata (0.74 g); 1, 5-diazabiticalo (4, 3.0) -non-5-ene (0.25 g) and guanidine hydrochloride (0, 14 g) in ethanol (30 ml) is heated at reflux for 5.5 h and then evaporated. The residue was dissolved in chloroform, the solution was washed successively with water, with a 10% aqueous solution of sodium carbonate and water, dried over magnesium sulfate and evaporated. The residue is triturated with ethyl acetate, and the resultant precipitate is collected, washed thoroughly with diethyl ether, recrystallized from a mixture of ethyl acetate and ethanol, and the mixture is prepared to give the title compound (0.7.0 g), mp. 222-225 ° C.

Found,%: C 52.10; H 4.56; N 10.54.

Wh ..

-z-f af i 4 f

Incl.%: C 52.78; H 4.62;

N 10.70.

25

Examples 3-9. The following compounds are prepared analogously to examples 1 or 2 using the reaction of the corresponding; its 4- (1,4-dihydropyridin-2-yl-methoxy) acetocetate with 30 amide guanidine and described in Table. one.

EXAMPLE 10 2-Amino-6- {C4- (2,3-dichlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-di-L-meTyl-1, 4-dihydropyridine-l-hcm.1hydropyridin-2-yl methoxymethyl-3oxy acetoacetate (0.99 g) and 1 5-di-: 3 „ethyl-4-pyrimidone.

Azabicyclo (4,3,0) -non-5-ene (0.30 g) 2-amino-6- {4- (2,3-dichloro-in ethanol (50 ml) is stirred at

phenyl) -3-ztoxycarbonyl-5-methoxy-carbonyl-6-methyl-1,4-dihydropyridine -2-yl methoxymethyl} -4-pyrimidone (0.52 g), iodomethane (0.14 g) and potassium carbonate ( 0.14 g) in dimethyl form amide (20 ml) is stirred at room temperature for 4 days and then evaporated. The residue was partitioned between chloroform and water, and the organic layer was washed twice with water, dried under anhydrous magnesium sulfate, and evaporated. The residue is recrystallized from ethyl acetate, to obtain the target compound (0.23 g, mp. 202-205 ° C.

room temperature for 5 days, and then evaporated. The residue is dissolved in chloroform and washed with 2 M hydrochloric acid, 10% aqueous sodium carbonate and water, the sugate is MgSO4 and evaporated. The residual solid is recrystallized from ethyl acetate, to obtain the target compound (0.23 g), so pl. 185-187 p.

Found,%: C 56.08; H 5.14; N11.33

SiV lN.f

Calculated,%: C 56.50; H 5.15;

N 11.46.

Example 2. 2-Amino-6- {4- - (2,3-dichlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl methoxymethyl -4- pyrimidone.

A solution of ethyl (2,3-dichlorophenp) -3 ethoxycarbonyl-5-methoxy

carbonyl-6-methyl-1,4-dihydropyridin--2-yl methoxy | adeo-11 tetra (0.74 g); 1, 5-diazabiticlo (4, 3.0) -non-5-ene (0.25 g ) and guanidine hydrochloride (0.14 g) in ethanol (30 ml) is heated at reflux for 5.5 h and then evaporated. The residue was dissolved in chloroform, the solution was washed successively with water, with a 10% aqueous solution of sodium carbonate and water, dried over magnesium sulfate and evaporated. The residue is triturated with ethyl acetate, and the powder of the precipitate is collected, washed thoroughly with diethyl ether, recrystallized from a mixture of ethyl acetate and ethanol and suction, to give the title compound (0.7.0 g), mp. 222-225 ° C.

Found,%: C 52.10; H 4.56; N 10.54.

Wh ..

-z-f af i 4 f

Incl.%: C 52.78; H 4.62;

N 10.70.

Examples 3-9. The following compounds are prepared analogously to examples 1 or 2 using the reaction of the corresponding; its 4- (1,4-dihydropyridin-2-yl-methoxy) acetocetate with amidine guanidine and are characterized in Table. one.

EXAMPLE 10 2-Amino-6- {C4- (2,3-dichlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl methoxymethyl - 3 2-amino-6- {4- (2,3-dichloro-

phenyl) -3-ztoxycarbonyl-5-methoxy-carbonyl-6-methyl-1,4-dihydropyridin--2-yl methoxymethyl} -4-pyrimidone (0.52 g), iodomethane (0.14 g) and potassium carbonate (0.14 g) in dimethylformamide (20 ml) is stirred at room temperature for 4 days and then evaporated. The residue was partitioned between chloroform and water, and the organic layer was washed twice with water, dried under anhydrous magnesium sulfate, and evaporated. The residue is recrystallized from ethyl acetate, to obtain the target compound (0.23 g), so pl. 202-205 ° C.

Found,%: C 53.42; H 4.87; N 10.49.

Calculated,%: C 53.64; H 4.88;

N 10.43.

PRI me R 11. (., 3-Dichlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1, 4-dihydropyridin--2-yl-1-methoxymethyl -2, 3-dimethyl-4-pyrimidone is obtained using 6-4- (2,3-Dichlorophenyl) -3-ethoxycarbonyl-5-methox. Dicarbonyl-6-methyl--1,4-dihydropyridin-2-yl methoxymethyl -2-methyl-4-pyrimido on c. as the original substance. The product has t, pl. 153-158 ° C.

Found,%: C 55.66; H 5.09; N 7.97.

L,

Calculated,%: C 55.98; H 5.07; N 7.83.

The ability of compounds to inhibit the advancement of calcium cells is demonstrated by their effectiveness in reducing the response of an isolated cardiac cord to an increase in calcium ion concentration in vitro. The test is conducted using spirally cut out rat aorta strips with one end fixed and the other connected to a force transducer. The tissue is immersed in a bath of physiological saline solution containing potassium ions at a concentration of 45 mmol and not containing calcium. Calcium chloride is added to the bath with a pipette, giving a final calcium ion concentration of 2 mm. There is a change in tension or tension caused by the resulting contraction of the tissue. The bath is dried and replaced with fresh brine, after 45 minutes the procedure is repeated with the particular compound tested. The concentration of compound required to reduce the response by 50% is recorded.

The results of pharmacological tests are shown in Table. 2

The resulting compounds are not toxic to rats and dogs at the dosage levels used.

To assess the duration of the effect of the selected compounds, a dose is administered intravenously (adjusted to provide approximately 60% of the maximum coronary expansion) and the time required

mine in order to cause a 50% reduction in maximum resistance of the coronary vessel. The following results were obtained: nifedipine has a half-life of 5-10 minutes, the substance according to example 2 is 8.5 hours and the substance according to example 4-55 minutes.

Claims (1)

Invention Formula The method of obtaining 1,4-dihydropyridine derivatives of general formula (T.) HRi 15 R200Cs OCOOR3 R HjC N CH -O-CH AxSo n where R is phenyl, 2-chlorophenyl, 2,3-dichlorophene; each / c-yy is independently C -C-alkyl; C, -C-apkil, morpholinyl, piperidinyl, group N (Rp, j, where k is hydrogen, C-C. kil; hydrogen, C, -C-alkyl, I differ by the fact that the dihydropyridine ketoester of the general formula (II) H R, RjOOCvX-COOBs H, C Lng-O-SNg-CO-SNg-COg-Nb R ". R. where R, R, R. x, vg are as defined,  -alkyl, is reacted with a compound of formula (III) and 45 R.-cf NH. HC1 where R has the indicated meaning, when boiling in alcohol in the presence of an organic base, and the resulting compound of formula (I), where R is hydrogen, is optionally alkylated with C, -C-alkyl halide. Table 1 D  0-CH2-W O n CH C.HS CH 230-235 (raelozh.) Poluguid-58.31 5.41 8.32 army (58.00) (5.48) (8.45) CH. C. “5 C1 CH, C.HS SI, C1 Nf CH, C. “5 H five C, HS C1 N (CK) 219-222 Same 32 CH, five CH, f.Hs C1 The calculated values are given in parentheses. Tabliya2 Example 225-230 Hydrate 53.64 4.70 7.91 (53.34) (5.03) (7.77) 220 51.02 4.67 10.53 (51.02) (4.47) (10.35) 196-198 Free 62.71 5.18 7.50 base (63,32) (5,13) (7,64) Also 54,135.18 9.90 (54.45) (5.12) (10.16) 57.025.56 10.08 (58.01) (5.59) (10.02) 147-150 56.85 5.65 9.34 (56.85) (5.45) (9.47) Molar coni, concentration of compound 1C, threo buoy to reduce the response of isolated rat aorta strips to an increase in calcium ions by 50%, M 3, 1.5P-10 1.73-10 -e -e -eight 4 5 6 7 8 9 10 I 1 12 13 Editor M.Blanar Compiled by M. Borin Tehred I. Popovich. Order 1227/57 Circulation 372Subscription VNIIPI USSR State Committee for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5 Production and printing company, Uzhgorod, st. Design, And 2.51 10 1.15 10. 5.01- 10 2.00-10 1.00-10 5.01-10 3.9f; -io 2.51 - 10 1.25-10 1.58-10 Proofreader M. Demchik