CS269656B1 - New pharmacollogically active derivatives of 1,4-dihydropyridines and method of their preparation - Google Patents

Abstract

The subject of the solution are 1,4- -dihydropyridine of general formula I, in which R is phenyl substituted 2-, 3- or 4-nitro, or 2-, 3- or 4-pyridyl radical and n is all positive numbers from 1 to 9. These compounds are shown calclunantagonic activity. sposob preparation of 1,4-dihydropyridine derivatives of formula (I) lies in the condensation poly (ethylene glycol) bls (acetoacetate) of Formula II CH3COCH2CO2CH2 (CH20CH2) nCH2O2CCH2COCH3 wherein n is 7y53 with the aldehyde of formula III R - CH - O (III) wherein R is as defined above, in the presence of an ammonia donor. Reaction is carried out under high dilution conditions and utilizes the ammonium cation template effect and alkali metal and alkaline metal cations soil, most often at temperature confusion and in the environment of water and / or alcohol, or eter with carbon numbers 1 to 4.

Description

The invention relates to novel, pharmacologically active 1,4-dihydropyridine derivatives of the general formula I,

wherein R represents a phenyl radical substituted by a 2-, 3- or 4-nitro group, or a 2-, 3- or 4-pyridyl radical and n is a positive integer from 1 to 9 and a process for their preparation. Said compounds have an anticalcium effect and are potentially useful in the treatment of ischemic heart disease or hypertension. 4-Aryl-1,4-dihydro-3,5-dicarboxylates (e.g. nifedipine, nimodipine, nitrendipine) are highly potent calcium antagonists and are widely used in clinical practice in the treatment of hypertension, angina pectoris, peripheral, cerebral and vascular diseases.

The clinical effect of these substances has led to the synthesis of a number of analogous compounds. Compounds of this type are generally prepared by Hantzsch condensation or Hantzsch condensation. some of its modifications, as mentioned in the professional and patent literature, e.g. Justus Liebigs Ann. Chem. 215.1 (1882); J.Chem.Rev. 72.1 (1972); Chem.Rev. 82, 223 (1982); Arzneim.Fcrsch. 33, 1 (1983); U.S. pat. 3,485,847 and 3,644,627; Brit.pat. 1,173,862; U.S. Pat. 3,799,934 and 3,932,645; Ger.Offen. 1,670,824; Brit.pat. 1,516,793; Can.pat. 934,758 et seq.

A number of structure-activity studies on 1,4-dihydropyridines have been described in the literature, on the basis of which general structural requirements for the pharmacological activity of these compounds have been raised. In this connection, the activity of dialkyl 1,4-dihydro-2,6-dimethyl-4- (pyridyl) -3,5-dicarboxylate [J.Med.Chem.

29, 2524 (1986). In connection with the imitation of the reduction of the carbonyl group by the natural coenzyme NADH, the synthesis of several dihydropyridines with an incorporated pole (ethylene glycol) chain /J.Chem.Soc.Chem.Commun has recently been carried out. 1976, 964; J.Org.Chem. 45, 2854 (1980); J.Amer.Chem.Soc. 99, 3882 (1977).

The novel 1,4-dihydropyridine derivatives of the formula I differ from the known compounds by the ester moiety in the 3- and 5-positions and / or by substitution in the 4-position of the dihydropyridine ring. The present invention relates to pharmacologically active 1,4-dihydropyridine derivatives of the general formula I,

wherein R represents a phenyl radical substituted by a 2-, 3- or 4-nitro group, or a 2-, 3- or 4-pyridyl radical and n is a positive integer from 1 to 9;

The invention further relates to a process for the preparation of novel 1,4-dihydropyridine derivatives of the general formula I, which uses the high dilution method and the template effect of alkali metal and alkaline earth metal cations and ammonium cation in the synthesis of ionophores, which

CS 269656 B1 consists in that 1 to 2 equivalents of poly (ethylene glycol) bis (acetacetate) of the general formula II *

CH ₃ COCH ₂ CO ₂ CH ₂ (CH ₂ OCH ₂ ) _n CH ₂ O ₂ C CH ₂ COCH ₃ (II) where n is as defined above, react at 0 ° C to 100 ° C for up to 72 hours in a medium of water and / or an organic solvent miscible with water from the group of alcohol or ether, with an aldehyde of general formula III

R - CH = 0. (III) wherein R is as defined above, in the presence of an ammonia donor in the form of a free or salt, the ammonium salt anions being formed by acids with an acidity in the range of pK 4.5 to 8.0 and / or up to .5 equivalents of a salt containing an alkali metal or metal cation alkaline earth or ammonium cation.

The reaction temperature and pressure are not critical and may be varied depending on the medium and reactants used. The reaction is preferably carried out at a temperature from 0 ° C to the boiling point of the reaction mixture, more preferably at room temperature and at normal atmospheric pressure, in water, and / or ethanol, using 1 equivalent of compound of formula II, 20 to 40 equivalents of ammonia donors. and 1 equivalent of an alkali metal cation or an alkaline earth metal cation or an ammonium cation. The product of formula I isolated from the reaction mixture is purified by column chromatography, crystallization and is obtained in a yield of 20-30%.

The prepared 1,4-dihydropyridine derivatives of the general formula I are new compounds not yet described in the literature which show typical effects of calcium entry blockers (calcium antagonists or slow or voltage-dependent calcium channel blockers) similar to those of nifedipine.

These substances were evaluated for their toxic effects as well as their pharmacodynamic efficacy on isolated depolarized smooth muscle and the spontaneously beating right atrium of guinea pigs. The toxicity and pharmacodynamic effects of the studied substances were compared with the effects of nifedipine and verapamil, substances with anticalcal action, which are widely used in clinical practice.

Table 1

Identification of the substance of general formula I n R la 3 o-N0 ₀ C _and H. 2 o 4 Ib 3 m-NO ₂ C ₆ H ₄ Ic 3 pn ° ₂ c ₆ h ₄ Id 3 2-pyridyl Ie 3 3-pyridyl If 3 4-pyridyl Ig 2 2-pyridyl Ih 2 3-pyridyl I 2 4-pyridyl li 1 3-pyridyl Ij 7-8 3-pyridyl

The new 1,4-dihydropyridine derivatives (Table 1) are characterized by several times lower toxicity than nifedipine:

The LD50 (median lethal dose) of nifedipine is present in male mice at

after. application of 345 mg / kg i.v. application of 4.2 mg / kg, while in the analyzed representatives of individual groups. in no case did it reach the value of LD ^ q. In terms of solvent, the substance could only be applied up to a dose of 7.5 mg / kg i.v. in terms of solvent and solubility, which did not even reach the LD50 values and at p.o. no animals died after administration of 10,000 mg / kg (i.e. LD50 is higher).

In le it was possible to reach the values of LD ^ g, which holi at

after. application of 7586.9 mg / kg i.v. application of 103.05 mg / kg and for Ih no animal died at

iv when administered up to a dose of 30 mgAg after administration up to a dose of 10,000 mgAg, which means that the i.l LD50 values are higher than could be administered to the animals ¹ .

When evaluating the ability of the prepared 1,4-dihydropyridine derivatives to affect calcium-induced contractions on guinea pig ileum smooth muscle with a depolarized high KCl solution, the new derivatives were shown to be up to two orders of magnitude less effective than nifedipine, but their efficacy was that of verapamil. Derivatives with a nitrophenyl skeleton were more effective than derivatives with a pyridine nucleus in the molecule. In addition, o- and m-derivatives have been shown to be more effective than β-derivatives. (Tab.2).

Table 2

Substance pA ₂ values against CaCl _{2 -induced contractions}

la ·· 7.09 Ib 7.08 Ic 6.47 Id 6.15 le 6.22 If ' 6.19 Ig 6.74 Ih 6.72 I 6.55 Nifedipine 9.06 Verapamil 7.0

When evaluating the negative chronotropic and inotropic effects of 1,4-dihydropyridine derivatives, their effect on isolated spontaneously beating right atria of guinea pigs was shown to be due to both verapamil and nifedipine. The order of their effectiveness was similar to that of smooth muscle exposure. Even in this case, no difference was found between the o- and m-derivative for Id and Ig vs. Ie and Ih. However, for substances with a nitrophenyl residue in the molecule, meta-derivative Ib shows a higher activity! as an ortho-derivative, (Tab. 3).

Table 3

Fabric PD ₂ values in spontaneous decrease frequency contraction forces la 6.36 6.04 Ib 6.87 6.91 Id 4.99 4.80 Ie 4.89 5.09 ig, 5.51 5.31 Ih 5.20 5.15 Nifedipine 7.00 7.15 Verapamil 6.58 6.76

Due to the action of new 1,4-dihydropyridine derivatives, substance Ib is equally effective on myocardium and smooth eval, substance 1a is mild and substances Ie, Id, Ig and Ih are significantly more effective on smooth muscle than on myocardium.

The details of the process for the preparation of the 1,4-dihydropyridine derivative of the general formula I are given in the following examples, which, however, do not limit the scope of the invention in any way.

The starting compounds of formula II mentioned in the examples below were prepared according to the procedure described in J.Org.Chem. 45., 2854 (1980)], by transesterification of ethyl acetoacetate with the appropriate poly (ethylene glycol).

Example 1

18.20 Dimethyl-21- (3-nitrophenyl) -3,6,9,12,15-pentaoxa-19-azabicyclo [15.3.1] henicosa-1 (20), 17-diene-2,16-dione ( Ib).

To a solution of 22.0 g (0.061 mol) of tetraethylene glycol bis (acetoacetate) (II, n = 3) in 3000 ml of water containing 180 g (1.88 mol) of ammonium carbonate is added dropwise over 8 hours with vigorous stirring. solution of 9.0 g (0.060 mol) of 3-nitrobenzaldehyde in 160 ml of ethanol. The rye-colored reaction mixture was further stirred at room temperature for 48 hours, then extracted several times with chloroform, and the combined extract was washed with water, brine and dried (MgSO 4). Distilling off the solvent gave 25.8 g of a honey-like substance, from which the product was isolated by flash chromatography on a silica gel column (250 g, 16 .mu.m, eluent 10% acetone in CHCl3). 6.9 g (24 g) of product Ib were obtained, m.p. 106-107 ° C (isopropyl alcohol). (CDCl 3, δ ppm): dihydropyridine nucleus (alk

DHP): 2.36 (s, 6H, 18.2O-CH ₃ ); 5.23 (s, 1H, 21-CH); 6.64 (s, IB, NH); polyethylene glycol chain (PEG alkali): 3.39 (ddd, J = 8.0, J = 2.0, J ^gem = -11.0, 2H, OCH 2); 3.56-3.87 (m, 10H, OCH 2); 4.10 (ddd, J = 8.0, J = 2.0, J ^Eem = -12.4, 2H, COOCa2); 4.28 (ddd, J = 4.4, J = 2.2, J ^Ee ® = -12.1., 2H, COOCH 2); R: 8.17 (t, J 26 = 2.4, J 24 = 1.7, 1H, H-2); 7.98 (ddd, J4 5 = 8.1, J4 6 = 1.2, 1H, H-4); 7.41 (t, J 56 = 7.9, 1H, H-5); 7.99 (ddd, 1H, H-6). For ^C 23 H 28 N 2 O 9 (476.50) calculated: 57.98% c '5.92% H, 5.88% N; Found: 57.87% C, 6.13% H, 5.67% N.

Example 2

The procedure of Example 1, except that an equivalent amount of 2-nitrobenzaldehyde was used instead of 3-nitrobenzaldehyde, was prepared: 18,20-Dimethyl-21- (2-nitrophenyl) -3,6,9,12,15-penteoxa -19-azabicyclo /15.3.1./henicosa-1(20),17-diene-2,16-dione (la) in a yield of 21%, m.p. 196-197 ° C (ethyl acetate-petroleum ether).

CS 269656 B1 1 H-NMR (CDCl 3 / δ ppm): DHP: 2.29 (s, 6H, 18.20 CH ₃ ); 5.73 (s, IB, 21-CH); 6.31 (s, 1 H, NH); PEG: 3.53-3.84 (m, 12H, OCH 2); 3.99 (ddd, J = 4.8, J = 2.0, J ^ge “^ -12.3. ,, 28,

COOCH ₂ ); 4.33 (ddd, J = 7.6, J = 2.2, J ^sem = -12.1, 2H, COOCH ₂ ); R; 7.41-7.50 (m, 2H, 8-3.4).

7.24 (ddd, J _{5 6} = 7.9, J _{5 4} = 7.3, ₃ = 1.5, IB, H-5); 7.68 (dd, J _{6 4} = 1.4, 8-6).

For C ₂₃ H ₂₀ N ₂ O 2 (476.50) calculated: 57.98% C, 5.92% H, 5.88% * N; Found: 57.65 * C, 5.80% 8, 5.92% N.

Example 3 ·

Following the procedure of Example 1, except that an equivalent amount of 4-nitrobenzaldehyde was used instead of 2-nitrobenzaldehyde, the following was prepared:

18,2O-Dimethyl-21- (4-nitrophenyl) -3,6,9,12,15-pentaoxa-19-azabicyclo [15.3.1] henicosa-1 (20), 17-diene-2,16- dione (Ic) in yield 23 mp 226-227 ° C (ethyl acetate-petroleum ether). ¹ H-NMR (CDCl 3, iT, ppm); DHP: 2.35 (s, 6H, 18.2O-CH 3); 5.18 (s, 1 H, 21-CH); 6.24 (s, 18, NH); PEG: 3.30 (ddd, J = 8.5, J = 2.1, J ^gem = -11.2, 2H, OCH 3); 3.55-3.86 (m, 10H, OCH 2);

4.03 (ddd, J = 8.5, J = 1.8, J ^gem = -12.3, 2H, COOCH 3); 4.26 (ddd, J = 4.4, J = 1.8, J ^gea = -12.3, 2H, COOCH ₂ ); R: 8.10 (dt, J _{2 3} = J ₅ ¢ = 8.9, 2H, H-2,6); 7.69 (dt, 2H, H-3.5).

For C ₂₃ H ₂₈ N ₂ O _g (476.50) calculated: 57-98% C, 5.92% H; 5.88% N; Found: 58.20% C, 6.11% H, 6.09% N.

Example 4

15,17-Dimethyl-18- (3-pyridyl) -3,6,9,12-tetraoxa-16-azabicyclo [12.3. l./hexadeca-1 (17), 14-diene-2,13-dione (Ih).

To a stirred solution of 14.3 g (0.045 mol) of triethylene glycol bis (acetoacetate) (II, n = 2) in 2350 cl of water containing 135.0 g (1.40 mol) of ammonium carbonate was added dropwise with stirring. 6 hours solution of 4.82 g (0.045 mol) of 3-pyridinecarbaldehyde in water (150 mol). The mixture was further stirred at room temperature for 48 hours, extracted several times with dichloromethane, the combined extract washed with water, brine, dried (MgSO ₄ ), the solvent distilled off and the product isolated from the obtained substance (15.7 g) isolated by flash chromatography on a silica gel column. (200g, 15 / um, eluent 2% MeOH in CHC1 _3). 4.5 g (26%) of product Ih, m.p. 307-308 [deg.] C. (ethanol), were obtained.

¹ H-NMR (CDCl ₃ , (δ, ppm): DHP: 2.37 (s, 6H, 15.17-CH ₃ ); 5.47 (α, 1H, 18-CH): 6.07 (s, 18, NH); PEG; 3.62-3.78 (m, 8HOCH ₂ ); 3.87-3.97 (m, 2H, COOCH ₂ ); 4.36-4.47 (m, 2H, COOCH ₂ ); R: 8.62 (dd, J _{2 4} = 2.4, J _{2 5} = 0.9, 1H, H-2); 7.65 (mt, J ₄ ¢ = 1.7, J _{4 5} = 7.'8, 1H, H-4), 7.16 (ddd, J _{5> 6} = 4.8, 1H, H-5); 8.38 (dd, 1H, H-6).

For C _{2 O} H ₂₄ N ₂ O £ (388.4) “calculated: 61.85% C, 6.23% H, 7.21% N, found: 61.64% C, 6.59% H, 6.97% N.

Example 5

Following the procedure of Example 4, except that an equivalent amount of 2-pyridinecarbaldehyde was used instead of 3-pyridinecarbaldehyde, the following was prepared:

15,17-Dimethyl-18- (2-pyridyl) -3,6,9,12-tetraoxa-16-azabicyclo [12.3.1] hexadeca-1 (17), 14-diene-2,13-dione ( Ig) in a yield of 20%, m.p. 289.5-292 ° C (ethanol).

¹ H-NMR (CDCl ₃ , <ppm): DHP: 2.25 (s, 6H, 15.17-CH ₃ ); 5.63 (a, 1H, 18-CH); 9.38 (s, 1 H, NH); PEG: 3.62-3.91 (m, 8H OCH ₂ and 2H COOCH ₂ ); 4.40-4.51 (m, COOCH 3); P: 7.63 (ddd, J. = 7.8, J = -1.3, J, _Λ = 1.0, 1 H, H-3); 7.60 (ddd, J. == 7.3, J, ¢ = 1.6, 1H, H-4) J 7.16 (m? 'J = 4.8 ^' 1H, H-5), 8.48 (dt, 1H, H-6) . '

For C _{2 O} H ₂₄ N ₂ O ₆ (388.4) calculated: 61.85% C, 6.23% H, 7.21% N; Found: 61.99% C, 6.38% H, 7.02% N.

CS 269656 Bl

Example 6

Following the procedure of Example 4, except that an equivalent amount of 4-pyridinecarbaldehyde was used instead of 3-pyridinecarbaldehyde, the following was prepared:

15,17-Dimethyl-18- (4-pyridyl) -3,6,9,12-tetraoxa-16-azabicyclo [12.3.1] hexadeca-1 (17),

14-diene-2,13-dione (Ich) in a yield of 26 m.p. 255-256 ° C (isopropyl alcohol).

^X H-NMR (CDClpX, ppm): EPA: 2.37 (s, 6H, CH-15,17), 5:50 (β, 1 H, 18-CH); 6.39 (s, III, NH); PEG; 3.63-3.76 (m, 8H, OCH ₂ ); 3.89-4.09 (m, 2H, COOCH ₂ ); 4.38-4.49 (m, 2H, CCOCn ₂ ); R: 8.44 (dd, J _{2 3} = J $ ₆ = 4.5, J _{2 5} = J _{3 6} = 1.6, 2K, H-2.6); 7.28 (dd, 2H, H-3.5).

For C ₂ O ^H 24 ^N 2 ° 6 ⁽ ' ³⁸⁸ · ⁴⁾ calculated: 61.85% C, 6.23% H, 7.21% N; Found: 61.74% C, 6.49% H, 7.10% N.

Example 7

Following the procedure of Example 4, except that instead of triethylene glycol bis (acetoacetate) and 3-pyridinecarbaldehyde, an equivalent amount of tetraethyl glycol bis (acetoacetate and 2-pyridinecarbaldehyde) was used:

18,20-Dimethyl-21- (2-pyridyl) -3,6,9,12,15-pentaoxa-19-azabicyclo [15.3.1./henicosa-1 (20), 17-diene-2,16- dione (Id) in 23% yield, m.p. 257-258 ° C (ethanol).

^X H-NMR (CDCl-PJ · ppm): EPA: 2.25 (s, 6H, CH3-18.2); 5.26 (s, 1H, 21-CH); 9.39 (s, 1 H, NH); PEG; 3.34 (ddd, J-8.2, J = 2.2, J ^gem = -10.8, 2H, OCH 2); 3.54-3.90 (m, 10H, OCH ₂ );

4.06 (ddd, J = 8.2, J = 1.8, J ^is ® = -12.5, 2H, COOCH2); 4.21 (ddd, J = 4.6, J = 2.2, J ^sem = -12.5, 2H, COOCH 2); R: 7.83 (dt, J _{3> 4} = 7.8, J ₃ $ = 1.3, J _{3 6} = 0.8, LH, H-3); 7.64 (ddd, J ₄ $ = 7.3, J _{4 6} = 1.9, 1H, H-4); 7.13 (ddd, J _{5 β} = 4.9, 1H, H-5); 8.47 (ddd, LH, H-6). '

For C ₂₂ H ₂ R ₂ O ₇ (432.5) calculated: 61.10% C,% H, 6:53, 6:48% N; Found: 60.90% C, 6.64% H, 6.37% N.,

Example 8

Following the procedure of Example 4, except that an equivalent amount of tetraethylene glycol bie (acetoacetate) was used instead of triethylene glycol bis (acetoacetate), 18,2O-Dimethyl-21 (3-pyridyl) -3,6,9,12 was prepared. 15-pentaoxa-19-azabicyclo [15.3.1] henicosa-1 (20), 17-diene-2,16-dione (Ie) in a yield of 30%, m.p. 258-259 ° C (isopropyl alcohol).

^X H-NMR (CDClpcf, ppm): EPA: 2.33 (s, 6H, 18,20-CH 3); 5.03 (s, 1 H, 21-CH); 6.98 (s, 1 H, NH); PEG: 3.39 (ddd, J = 7.9, J = 2.3, J ^gem = -11.0, 2H, OCH 2); 3.56-3.86 (m, 10H, OCH 2;

4.09 (ddd, J = 7.9, J = 2.0, J ^Bem = -12.2: 2H, COOCH2); 4.21 (ddd, J = 4.6, J = 2.3, J ^Bem = -12.2, 2H, COOCH 2); R: 8.63 (dd, J _{2 4} = 2.3, J _{2 5} = 0.9, 1H, H-2); 7.88 (ddd, J ₄ $ = 7.8, J _{4> 6} = 1.7, 1H, H-4); 7.19 (ddd, J $ ₆ = 4.8, ¹² >H-5I; 8.36 (dd, 1H, H-6).

Pre ^c ₂₂ H ₂₈ N ₂ O ₇ (432.5) calculated: 61.10% C, 6.53 «H, 6.48% N; Found: 61.29% C, 6.76% H, 6.35% N.

Example 9

Following the procedure of Example 4, except that instead of triethylene glycol bis (acetoacetate) and 3-pyridinecarbaldehyde, an equivalent amount of tetraethylene glycol bis (acetoacetate) and 4-pyridinecarbaldehyde was used:

18,20-Dimethyl-21- (4-pyridyl) -3,6,9,12,15-pentaoxa-19-azabicyclo [15.3.1-] henicosa-K 2 O), 17-diene-2,16-dione (If) in a yield of 27%, m.p. 209-210 ° C (ethanol).

^X H-NMR (EMSO-G.c, ppm): EPA: 2.27 (s, 6H, 18,20-CH 3); 4.84 (s, 1H, 21-CH); 8.88 (s, 1 H, NH); PEG: 3.25 (ddd, J = 7.8, J = 2.0, J ^gem = -11.0, 2H, OCH 2); 3-5Ο-3.66 (m, 10H, OCH ₂ );

3.93 (ddd, J = 7.8, J = 1.8, J ^Bem = -12.3, 2H, COOCH ₂ ); 4.11 (ddd, J = 5.1, J = 2.0, J ^gein = -12.3,

2H, COOCH ₂ ); R; 8.38 (dd, J _{2 3} = J $ ₆ = 4.4, ^J 2 5 ^{= J} 3 6 ^{= X} · ⁷ ' ^2H > 7 · ³⁴ (dd, ^2H >

H-3.5). ’’ ’’

For Ο ₂₂ Η _{2 &} Ν ₂ Ο ₇ (432.5) calculated: 61.10% C, 6.53% H, 6.48% N; Found: 60.89% C, 6.39% H, 6.51% N..

CS 269656 Bl

Example 10

Following the procedure of Example 4, except that an equivalent amount of diethylene glycol bis (acetoacetate) (II, n = L) was used instead of triethyl glycol bis (acetoacetate), the following was prepared: 12,14-Dimethyl-15- (3-pyridyl) ) -3,6,9-trioxa-13-azabicyclo [9.3.1] trideca-1 (14), 11-diene-2,10-dione (II) in 20% yield, mp 184-185 ° C (ethyl acetate-n-hexane). 1 H-NMR (CDCl 3, ppm): DHP: 2.43 (s, 6H, 12.14-CH 2); 6.08 (s, 1 H, 15-CH); 7.76 (s, 1 H, NH); PEG: 3.60-3.77 (m, 4H, OCH 3); 3.97-4.07 (m, 2H, COOCH 3); 4.53-4.63 (m, 2H, COGCH 3); R: 7.15 (ddd, J. = 7.7, J- = 4.7, Jr ₂ = 0.9, 1H, H-5); 7.52 (dddd, J-, = 2.3, J-, = 1.7, Jg, CH (15) = 0.9, 1H, H-6); 8:34 (ddd, J = 0.7 _{4 2,} 1 H, H-4); 8.36 (m, 1 H, H-2).

For θΐ8 ^Η 2Ο ^Ν 2 ° 5 (344.4) calculated: 62.78% C, 5.85% H, 8.13% N; Found: 62.93% C, 6.00% H, 8.22% N.

Example 11 By the procedure of Example 4, except that instead of triethylene glycol bis (acetoacetate) an equivalent amount of poly (ethylene glycol) bis (acetoacetate) was used, with an average molecular weight of 568, substance Ij with an average molecular weight of 626 was prepared in a yield of 35 as rye waxy substance. .

¹ H-NMR (CDCl ₃ , δ, ppm): 2.34-2.37 (s, CH ₃ ); 5.03-5.05 (s, CH); 6.87-6.93 (s, NH); PEG: 3.60-3.71 (m, OCH 3); 4.16-4.23 (m, COOCH 3); R: 7.14-7.23 (m, H-4.5); 7.67-7.74 (m, H-6); 8.35-8.39 (m, H-2). The signals occur in the indicated chemical shift interval due to the non-uniform length of poly (ethylene glycol) used.

Example 12

Following the procedure of Example 4, but substituting ammonium carbonate for an equivalent amount of ammonium acetate and exchanging triethylene glycol bis (acetoacetate) for an equivalent amount of tetraethyl glycol bis (acetoacetate), 18,20-dimethyl-21 (3-pyridyl) -3,6,9 was prepared. 12,15-pentaoxa-19-azabicyclo [15.3.1.] Henicosa-1 (20), 17-diene-2,16-dione) in 32% yield, identical by TLC and H.NMR spectroscopy with an authentic sample.

Example 13

To a stirred solution of 9.54 g (0.03 mol) of triethylene glycol bis (acetoacetate) in 1700 ml of water containing 24.0 ml of 26% aqueous ammonia (0.3 mol) and 6.40 g (0.06 mol) of sodium carbonate was added dropwise with stirring. a solution of 3.21 g (0.03 mol) of 2-pyridinecarbaldehyde in water (100 ml) over 6 hours. The mixture was stirred at room temperature for 48 hours, extracted several times with dichloromethane, and the combined extract was washed with water, brine and dried. The product obtained from the extract according to the procedure of Example 4 was identical by TLC and m.p. with an authentic Ig sample.

The 1,4-dihydropyridine derivatives of the present invention are effective calcium entry blockers and thus provide the possibility; use as a pharmaceutical in the pharmaceutical industry. Because the molecules of these substances also include a polyether chain (crown ethers), they have been complexed to verify alkali metal, alkaline earth metal and alkaline earth metal cations, respectively. other and can therefore be used! in these fields, which use this feature such as e.g. in the chemical industry (separation of metal ions, isotopes, ion selective electrodes, ion selective transport membranes).

Claims (6)

OBJECT OF THE INVENTION Novel, pharmacologically active 1,4-dihydropyridine derivatives of the general formula I wherein R represents a phenyl radical substituted by a 2-, 3- or 4-nitro group, or a 2-, 3- or 4-pyridyl radical and n is a positive integer from 1 to 9. * 2. A process for the preparation of novel 1,4-dihydropyridine derivatives of general formula I, according to item 1, characterized in that 1 to 2 equivalents of poly (ethylene glycol) bis (acetoacetate) of general formula II CH ₃ COCH ₂ CO ₂ CH ₂ (CH ₂ OCH ₂ ) _n CH ₂ O ₂ CCH ₂ COCH ₃ (II) where n is as defined in point 1, react at a temperature of 0 ° C to 100 ° C for up to 72 hours in the presence of water and / or alcohol or ether having 1 to 4 carbon atoms, with an aldehyde of formula III R - CH = O (III) where R has the meaning given in point 1, v. pří presence of ammonia donor from the group consisting of ammonia, in free form or ammonium salt of ^one of the acidity pK of about 4.5 to 8.0 such as carbonate or ammonium acetate, and aqueous ammonia being preferred and, together with up to 5 equivalents of alkali metal or alkaline earth metal above defined acids. 3. The method according to item 2, characterized in that an aqueous ammonia solution is used as the ammonia donor. 4. The process according to item 2, characterized in that the reaction is carried out in a medium of water and / or ethanol. 5. The process according to item 2, characterized in that the reaction is carried out at room temperature. 6. The process of claim 2, wherein the condensation uses 1 equivalent of the appropriate poly (ethylene glycol) bis (acetacetate) of formula II, 20 to 40 equivalents of ammonia donor and 1 equivalent of alkali metal or alkaline earth metal cation, or ammonium cation, per 1 mol of aldehyde of formula III. ·