JPS5916876A - Basic ester antagonistic against calcium, manufacture and medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention [In the formula, R] is a linear or branched alkyl group having 1 to 5 carbon atoms, and one hydrogen atom may be substituted with an alkoxy group; x-nyl or nitrophenyl group: R3LL alkyl group having 1 to 4 carbon atoms,
Alkoxy group having 1 to 4 carbon atoms, FsOl, Brz
NO2, ONz alkoxy group having 1 to 4 carbon atoms, OF3,
A group consisting of OH, Nl2, mono- or dialkylamino group, mono- or diacylamino group, SH, S (0) n alkyl group (n is 1 or 2), acyl group having 1 to 5 carbon atoms, carbamoyl group, ureido group 1 to 6 selected from
or a 5- or 6-membered heteroaryl monocycle containing one or more N, O1S atoms, such as pyridyl,
Pyrazinyl, pyrimidyl, furyl, imidazolyl, chenyl, thiazolyl, 1.2.3-triazolyl, 1.2
．． 4-triazolyl, optionally mono-, di- or tri-substituted, such as by alkyl, alkoxy, halogen or trifluoromethyl; X has 2 carbon atoms
~5 linear or branched alkylene groups, one hydrogen atom of which may be substituted with an alkoxy group); racemic compounds, enantiomers and diastereoisomers thereof; and drugs thereof; It relates to addition salts with physically acceptable acids.

The invention also relates to a process for the preparation of esters of formula (I) by reacting novel intermediates as shown below under known reaction conditions, in particular in the Michael addition and development reaction 15. The intermediates are: A formula (■): acetoacetate represented by OH3-00-OH2-oooy (u), 3-aminocrotonate represented by formula 3 (11): % formula % (), 0 formula (IV): 2-aralkylidene-3-ketobutano represented by OH3-ao-o-oooy Qv)1HR2 and X are the same as above). The reaction in the production method of the present invention proceeds according to the reaction formula shown below.

υn3 υ mt2 un3Nl(3 (M 2 (H) However, R1, R2 and Y are the same as above.

The new basic acetoacetates of formula (Il) are prepared by known methods from the corresponding basic alcohols and diketenes. 3-aminocrotonates of formula (III) may be prepared by reacting intermediates of formula (If) with gaseous ammonia at about 0°0 in alcoholic solution.

Basic ylidene acetoacetate of formula CF/) may be prepared from intermediates of formula (II) by Nebenagel condensation.

Furthermore, the compound of formula (1) may be produced by reacting the piperazine of formula (1) with the p-roalkyl ester of formula (1). The chloroargyl ester (formula) can be obtained by condensation and cyclization as shown in the reaction formula summarized below.

R except that R1, R2, R3 and X in the formula are the same as above.

Regarding the reaction formulas (1) to (g) above, the reaction conditions are 1,4
-The same conditions commonly used for the synthesis of dihydropyridines. Therefore, the condensation between the acetoacetate of formula (II) of reaction scheme (a), the aldehyde of R2-OHO and the alkyl 3-amino-crotonate is usually carried out in a lower alcohol such as ethanol, propatool, isopropanol, etc. The mixing is carried out at the boiling point of ψI over a period of 2 to 20 hours.

Reactions of reaction formulas (b) to (f) may be carried out in the same manner. On the other hand, in reaction scheme (g), the reaction between the compounds of formulas (V) and (M) is preferably carried out in the presence of an acid acceptor, such as triethylamine, pyridine or a similar compound.

Specific examples of the compound of formula (1) of the present invention include the following.

2-(4-phenyl)piperazino-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate, 2-[4-(2-thiazolyl) ]] Piperazinoethyl 26-cymethyl-4-(5-nitrophenyl)-
5-methoxycarbonyl-1,4-dihydropyridine-
3-carboxylate, 2-(4-(2-pyrimidyl)
]] Piperazinoethyl 2,6-dimethyl-4(5-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carpoxyle), 2-(4-
(2-methoxyphenyl)]]piperazinony f'V
2.6-dimethyl-4-(3-nitrophenyl)-5-
Me1xycarbonyl-1,4-dihydropyridine-3-
2-(4-(2-tolyl))piperazino-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate, 2-( 4-(2-ritetraphenyl)]]piperazinoethyl 26-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate,
2-(4-(3-chlorophenyl)]]piperazinoethyl 2.6-cymethyl-4(3-nitrophenyl)-5
-methoxycarbonyl-1,4-dihydropyridine-3
-carboxylene), 2-(4-(4-chlorophenyl)]]piperazinoethyl 26-cymethyl-4- (3
-nitrophenyl)-5-methoxy ybonyl 1,
4-dihydropyridine-3-carboxylate, 2-(
4-(4-fluorophenyl)]]piperazinoethyl 2,6-dimethy/I/4-(3-nitrophenyl)-5
-methoxycarbonyl-1,4-dihydropyridine-3
-carboxylate, 2-(s-monotrifluoromethyl-phenyl)]pipera"sinoethyl 2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate, 2-(4-(4-methoxyphenyl)]]piperazinoethyl 2,6-dimedy-4(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate, 2-(4 2-(4- (3,4-dimethylphenyl)]]piberazinoedyl 2,6-dimethyl-4(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxyl 2-Viridy] Piperazino'-ethyl 2,6-dimethy/L/-4
-(3-nitrophenyl)-5-methoxycarbonyl-
1,4-dihydropyridine-3-carboxylene), 2
(4-(4-fluorophenyl)]]piperazinoethyl 26-cymethyl-4-(3-nitrophenyl)-5-
)]] Piperazinoethyl 2,6-cymethyl-4(3
-nitrophenyl)-5-(2-methoxy)ethoxycarbonyl-1,4-dihydropyridine-3-carboxylate, 2-(4-(4-fluorophenyl)]]piperazinoethyl 2,6-dimethyl-4( 3-nitrophenyl)-5-isobutoxycarbonyl-1,4-dihydropyridine-3-carboxylate.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 (2-(4-phenyl)piperazino-ethyl 2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate (hereinafter referred to as 0219A) Manufacturing] (a) 1-
20.65 g (0.1 mol) of phenyl-4-(2-hydroxyethyl)-piperazine was dissolved in toluene.
8. Add the diketene to the solution heated to 5-80°C with stirring. a
3p (o, 105 mol) was added dropwise over about 1 hour. The reaction progress was monitored by high performance liquid chromatography (hereinafter referred to as II
(called PLO). After stirring for 2.5 hours at 75-800C, the reaction was complete. Solvent t [removed under vacuum, 2-
The residue consisting of (4-phenyl)piperazino-ethyl 3-oxobutanoate was sufficiently purified to the extent that it could be used without purification.

PMR spectrum analysis value (δ value: ppm): (O
DO13) 2, 23 ([1,3)k 0H300), 2
．． 67 (m, /+H), 3.17 (m, 4H
), 3, 47 (s, 2H, 0OOH200), 4.
23 (t, 2H,0OH2) (b) 32.699 (0,1126 mol) of the ketoester obtained in (a), 3-ditho-benzaldehyde 20. s8g(0,
135 mol) and methyl 3-aminocrotone) 1
A mixture of 4.29 (0,123 mol) was heated to reflux in a 5 ml Impropat Tool 9'. The mixture completely dissolved within a few minutes and the solution was refluxed for about 4 hours. The progress of the reaction is
Tracked with PLO. Traces of insoluble material were filtered off and the solution was evaporated under vacuum. The oily residue was dissolved in ethyl acetate and purified by adsorption onto a silica gel column (eluted with ethyl acetate). Fractions containing the target substance were evaporated to dryness under vacuum. The residue was crystallized from a small amount of diethyl ether to give pale yellow crystals (mp12B~130°0, yield 48%).

Uv: λ238nm (ε=36.338), λmax
352nm (ε=7.012) PMR (δ value: ppm) ' (ODO/3)2,
38 (8, (SH, = O-0H3), 2.66 (
m, 6)r), 3.18 (m.

4H), 3.67 (s, 3H,0OH3), 4.
27 (t, 2H, OOHha, 5, 20 (s, 1H
,04 groan, 6.47 (s, 1)1SNH) ,6.6
7-8.27 (m19H% 0Har) Elemental analysis value: 028H32N406 (MW520.
59) Theoretical value (2)): 064.60 H6
, 18N10.76 Actual value (%): 064.4B
H6,28N10.92 Example 2 (2-(4-(2-thiazolyl))]piperazinoethyl 2,6-dimedyru-4(3-nitrophenyl)-5-
Methoxycarbonyl-1,4-dihydropyridine-3-
Production of carboxylate (hereinafter referred to as 0240A) Example 1 except that 2-(4-(2-thiazolyl)-1-piperazinyl]ethyl 3-oxobutanoate was used)
The pale yellow target substance was obtained by crystallization from diethyl ether in the same manner as above (mp155-157°0
).

Uv:λ237nm (ε=29.536),'A
263nm (ε=19.562), λmax352
nm (ε= 7.131) P'MR (δ value: ppm
): (ODO/3)2,37 (a,6H,=
O-0H3), 2.65 (m, 6H), 5.43
(t, 4H), 5, 67 (s, 3H, 0OH3),
4.23 (t, 2H,0OH2), 5.13 (s
, I.H.

04 →, 6.55 (e, IHXNH), 6.58 (
d, 11 (, j = 0H-3), 7.17 (d, IH1
= OH-N), 7.27~8.23 (m, 4H
1=OHar) Elemental analysis value' 025H29N506S
Theoretical value ((6): 05/), 91 H5, 54N
13.27 Actual value (%): 056.77 H5,6
4N 13.18 Example 3 [2-(4-(2-pyrimidinolitupiperazino-ethyl 2,6-dimethy/L/-4-(3-nitrophenyl)
-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate (hereinafter referred to as 0241A)
Production of 3-nitrobenzaldehyde, methyl 6-aminocrotonate and ethyl 2-(4-(2-pyrimidyl)-1
-Piperazinyl-3-oxobutanoate was refluxed in isopropanol, purified with hydrochloric acid, and a pale yellow solid was obtained by regenerating the base. The target compound was obtained by recrystallization from ethyl ether (mp145-147°0)
.

Uv:λ240mm (ε=48.086),)m
ax348nm (ε=Otsu135) PMR (δ value: p
pm): (ODO/3)2,37 (g,6H
, = O-0H3), 2.60 (m, 6H), 3.
67 (s, 5H.

00H3), 3.80 (t, 4 groan, 4.23 (
t, 2H,0OH2), 5.1! l (e, I
H, 04H), 6.23 (s, 1HSu)o, 6
．． 47 (t, IH,=OHpyri→, 7, 17~
8.20 (m, 4H, = 0Har), 8.5
0 (d, 2H,=OHpyrim), elemental analysis value:
026H3ON606 (as MW522.56)
Theoretical value (%'): 059.715 H5,79N
16. o7 actual value (%): C359, 62H5,
es N 1. ls, 28 Example 4 (2-(4-(2-methoxyphenyl))]-]piperazinoethyl 2,6-dimethyl-4(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3 -Carboxylate (hereinafter referred to as 0242A)
Production of 2-(4-(2-methoxyphenyl)-piperazinyl)
Example 1 except that ethyl 3-ogisobutanoate was used
After recrystallizing from diethyl ether in the same manner as above, the desired product (
mp157-158°O) was obtained.

Uv: λ237nm (ε=34.261), Sma
x352nm (ε==S, 91S) PMR: (δ1i
-7: ppm): (ODO/3)2, 57
(s, 6H, = O-OH3), 2.67 (m,
6H), 3.03 (m, 4)I), 3,67 (s
, 3H,0O00H3) ,3.87 ,(s,3H
,=O−00H3) ,4.23(t, 2H,0OH
2), 5.13 (s, IH, 04H), 6.0
7 (8, IH, N1(), 6, 9S (s, 4H, =
0Har), Otsu17~B, 20 (m, 4H,
==OHar) Elemental analysis value: 02gH34N407
(As MW550.62) Theoretical value (%): 06
3.26 H6,22N 10.17 Actual value ((6)
: 063.09 H6,27N 9.95 Example 5 (2-(4-(2-)lyl)]]piperazinoethyl 2
6-dimethy/1/-4-(3-nitrophenyl)-5-
Carbonyl-1,4-dihydropyridine-3-
Production of carboxylate (hereinafter referred to as 0245A)] The crude product was produced in the same manner as in Example 1, except that 2-(4-(2-tolyl)-1-piperazinyl)ethyl 6-ocyptanoate was used. This product was purified through hydrochloride to regenerate the base. Recrystallization from diethyl ether gave the desired substance (mp 155-157°0).

Uv: λ237nm (ε=34.78[1), λ
max352nm (ε=7.268) PMR (δ value:
ppm)! CODO/3) 2, 27-2.38
(3s, 9H, =O-OH3), 2.43-3.0
7 (2m.

10H), 5.67 (e, 3) (XOOH3), 4
．． 23 (t, 2H, OOH, 5.15 (s, I
H104H), 6.27 (s, I H, NH)
, 6.7”r~8.23 (m, 88, = OHar) Elemental analysis value: 02gH34N406 (MW534.
62 binding) Theoretical value (%): O65,15H6,41
N 10.47 Actual value (%): 065.02 H6
,51N10.05Example 6 (2-(4-phthynyl)piperazino-ethyl 2,6-dimethyl-4-,(3-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylate ( (hereinafter referred to as 0219A)] (Ft.
) 2-Chloroethyl acetoacetate 18.55
9 (112 mmol), 3-2l robenzaldehye)
A mixture of 20.389 (134 mmol) and 14.29 (123 mmol) of methyl 3-aminocrotonate was dissolved in 93 m/m of isopropanol and heated to reflux for 4 hours. The reaction mixture was evaporated to dryness and the residue It was dissolved in a small amount of methylene chloride and chromatographed on a silica gel column (eluted with methylene chloride).

Collect the fractions containing the target substance, evaporate the solvent,
Dilute the residue with diethyl ether and isopropyl ether 1
:1 to give 2-chloroethyl 5-carbomethoxy-1,4-dihydro-2,6-dimethyl-4-(3-
Nitrophenyl)-3-pyridinecarboxylate 16
g (yield 36%) (mp1go~132°0) (
Literature direct: 130-131°0 (M rumor Iwanami et al. Oh
em,, Fharm; Bull, 27.142
6 (1979)).

Subsequent elution with ethyl acetate isolates a more polar substance from the chromatographic column, which is 2-
It was found to be hydroxyethyl 2°6-dimethyl-4-(3-nitrophenyl)-5-medoxycarbonyl-1,4-dihydropyridine-3-carboxylate (
German Offenlegungeschri
ft 2.629.892).

The following intermediates were produced in the same manner as above.

2-Chloroethyl 2,6-dimethyl-4-(3-nitrophenyl)-5-ethoxy-carbonyl-1,4-dihydropyridine-3-carboxylate, yield 79%, m
p15o~153°O (Ohem, Fharm.

BuLl, 27.1426 (1979)); 2-chloroethyl 2,6-dimethyl-4-(3-nitrophenyl)
-5-(2-methoxy)ethoxy-carbonyl-1,4
-dihydropyridine-3-carboxylate, yield 61
%, mp 136-13900; 2-chloroethyl 2,6-dimethyl-4-(3-nitrophenyl)-5-isobutoxycarbonyl-1,4-dihydropyridine-3-carboxylate, JIy rate 26%, mp 150-153° O.

Analytical and spectroscopic data for these compounds were consistent with their structures.

(b) 2-chloroethyl-5-carbomethoxy-1
゜4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate 3.95g
(10 mmol), 1-phenylpiperazine 1,629
(10 mmol), triethylamine 1.45 m/
(10 mmol) and sodium iodide 1.59 (1
A mixture of 0 mmol) was heated under reflux for 4 hours in an Improper Tool 40ml. - After standing overnight, the reaction mixture was evaporated to dryness and the residue was dissolved in 100 mA of methylene chloride, washed with water and dried over N2SO4.

After evaporation of the solvent, 8 g of the oil obtained was purified by silica gel column tetrachromatography (elution using a mixture of ethyl acetate and methylene chloride with increasing amounts of ethyl acetate).

The fraction containing the target substance was concentrated, and the residue was crystallized from diethylnithyl to give the target substance 2.359% (yield: 4
5.2%, m9128-130°C). This was identical to the product of Example 1.

Various compounds of the invention were prepared in substantially the same manner as in the Examples above using the appropriate intermediates as starting materials. These compounds and the compounds obtained in the above examples are collectively shown in Table 1.

Compounds of the invention were subjected to a series of pharmacological tests.

Next, the method and results will be summarized.

[Toxicity after intravenous administration in mice] Male ODI mice, weighing 259, obtained from Charles Riper (Italy) were used. The test compound was dissolved in dimethyl sulfoxide, and 0.01 ml per 102 body weight was administered intravenously. The LD50 value 7 days after administration was determined by Litchfield-Wilcoxon (Litchfield-Wi), c
oxon) (Experimental Therapeutics (FXperl, menta), Therape
utics, 96%99 (1949)).

[Antagonistic effect on calcium in guinea pig colon cord]

Hartley Alpino (Hartl) with an average weight of 4509
eyalbino) guinea pig) fr. Pre-depolarized colonic cord (taenia coli) was
nyn Schmied, Aroh.

Pharmacol, 31 B, 235 (198
2) at a single submaximal concentration of OaO/2 of 10-3M.
Calcium antagonism was measured by stimulation every 20 minutes. The test compound was brought into contact with the inclined pre-vagation for 1°. ED5Q from the percentage of maximum inhibition (%)
The value was calculated.

[Hypotensive effect in spontaneously hypertensive rats] 70~
100-day-old male spontaneously hypertensive rats (5 pt.
aneous bypertensive rat %
(hereinafter referred to as SHR) was used. A blood pressure recorder (BP-Reao) with a sleeve (5 leaves) attached to the tail of the test animal was used.
Systolic arterial blood pressure (5ystol) was measured by inducing pressure with a rcler
ic arterial blood pre88ur
e) 5ABP (hereinafter referred to as 5ABP) was measured. The test animals were prewarmed at 39°O for 15-20 minutes in a ventilated chamber.

The test animals were also pretrained for the test 1-2 days prior to the test, which consisted of basic recordings, pharmacological administration, and subsequent recordings 1 and 3 hours after administration.

All test compounds were suspended in 0.4% carboxymethylcellulose (Methoel) and administered orally.

In addition, 2 ml of the carrier was administered per kilogram of body weight.

Compound (1) was tested at three different doses and the mD25% was determined.

[Itoyoshi Ka]

The results are summarized in Table 2.

Table 2 As shown in Table 2, the compound of the present invention exhibits a calcium antagonistic effect, and therefore is effective against hypertension, various types of angina, ischemia, and N6. It is useful in the treatment and prevention of blood war diseases.

Excluding only compound 0241A), the compound of the present invention continues to increase even if the tissue is repeatedly washed.
The contraction (contraction B) due to aO12 is n
III] Compound 0241A and nifedipine (
The effect of N1fedipine on contraction was easily reversed when contact of the test compound with the tissue was interrupted. Since this suppression phenomenon is observed even after tissue washing, zD5
0 (1α was calculated by taking into account the maximum inhibition obtained independently of the time of onset of inhibition. Hypotensive activity)
0264B, 0250B.

Except for 0249B) which showed excellent hypotensive activity, the ratio was similar to that of nifedipine (Example 7).

0264B among compounds substituted with halogen.

For 0250B and 0249B, administration after 5
Even at 0.5 min, the hypotensive activity was 5, which was about twice the activity of nifedipine.

Regarding toxicity, compound (1) of the invention was generally less toxic than nifedipine. In addition, compared with Nicardipine (N1carlipins), which is another comparative example, the compound (1) of the present invention had almost the same strength of calcium antagonistic action;
In the ro test, the duration of action was long.

The present invention also encompasses all industrial objects relating to the therapeutic use of esters of formula (I). The invention therefore relates to a pharmaceutical formulation containing a predetermined amount of an ester of the invention or a salt thereof. The compounds of the invention may be administered orally or parenterally,
Examples include tablets, capsules, small sachets containing water≠bovine dispersible powder, and vials for injection.
The compounds of the invention may be administered to adults 5 to 50 doses 1 to 3 times per day.

211100 7138-41239
100 ) 6970-41 213100 ) 7138-4・(
C07D 417/12 211100 7138-4-277
100) 7330-4 priority claim ■May 11, 1983 Q) Ita IJA (IT) ■2
1043A/83 [Phase] Inventor: Cesare Casacram, Republic of Italy, Milan, Republic of Italy, Arece Via Campogallo 2167 @H Author: Fratsuf de Marchi, Republic of Italy, Milan, City of Via Francesco d'Asocisi 17 o Inventor: Matsimo Nikoff 81 Matteochi, Via, Pavia, Italian Republic

Claims (1)

[Scope of Claims] (In the formula, R1 is a linear or branched alkyl group having 1 to 25 carbon atoms, substituted or unsubstituted by an alkoxy group; R2 is a phenyl or nitrophenyl group; R34m- 51 Alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, 01. Er, NO2
, ON, alkoxy group having 1 to 4 carbon atoms, OF3.0HX
NH2, mono- or diacylamino group, 5H1S(0)
a phenyl group substituted or unsubstituted with 1 to 2 groups selected from the group consisting of an alkyl group (- is 1 or 2), an acyl group having 1 to 5 carbon atoms, a carbamoyl group, and a ureido group; Or 1 or more N, O, S
1,4-dihydropyridine represented by a 5- or 6-membered heteroaryl monocyclic ring containing atoms; x is a linear or branched alkylene group having 2 to 5 carbon atoms substituted with an alkoxy group or not Basic esters of -3,5-dicarboxylic acids and their racemates, enantiomers and diastereoisomers or addition salts thereof with pharmacologically acceptable acids. R3 is unsubstituted pyridyl, pyrazinyl, pyrimidyl, furyl, imidazolyl, chenyl, thiazolyl, 1',
2.3-) The basic ester according to claim 1, which is a mono-, di- or tri-substituted group with a riazolyl, 1,2,4-triazolyl group or an alkyl, alkoxy, halogen or trifluoromethyl group; Racemates, enantiomers and diastereoisomers thereof or their addition salts with pharmacologically acceptable acids. 3 (a) React the acetoacetate represented by formula (II) with an aldehyde and an alkyl 3-aminocrotonate according to the reaction formula shown below; 2 (Il) (b) 3-aminocrotonate represented by the plaster is reacted with an alkyl acetoacetate and an aldehyde according to the reaction formula shown below; 2 (N') (d) 3-aminocronate represented by the formula (Jll) is reacted with alkyl 2-aralkylidene-3-ketobutanoate according to the reaction formula shown below; ) (e) 2-aralkylidene-3- represented by the formula (F/)
Ketobutanoate is reacted with alkyl acetoacetate and ammonia according to the following reaction formula; 2! (f) Acetoacetate represented by formula (II) is reacted with alkyl 2-aralkylidene 3-ketobutanoate and ammonia according to the reaction formula shown below; (V) is reacted with piperazine represented by (V) according to the reaction formula shown below. Branched alkyl group; R2 is phenyl or nitrophenyl group; R is an alkyl group having 1 to 4 carbon atoms, 1 to 4 carbon atoms
alkoxy group, F, O/, Br −, NO2, CJ
N-, W alkoxy group with prime number 1 to 4, OF3, OH,
NH2, mono- or dialkylamino group, mono- or diacylamino group, 5RXfll(0)n alkyl group (n
is 1 or 2), 1 to 6 carbon atoms selected from the group consisting of 1 to 5 acyl groups, carbamoyl groups, and ureido groups.
a phenyl group substituted or unsubstituted by a group of 5 or containing one or more N, O1S atoms
or a 6-membered heteroaryl monocyclic ring; A process for producing basic esters of 1,4-dihydropyridine-3,5-dicarboxylic acid and their racemic compounds, enantiomers and diastereoisomers or their pharmacologically acceptable addition salts with licoric acid. 4 Formula (1): (wherein, R1 is a linear or branched alkyl group having 1 to 5 carbon atoms, substituted or unsubstituted by an alkoxy group; R2 is phenyl or nitrophenyl%: R3 Alkyl group having 1 to 4 carbon atoms, 1 carbon number
~4 alkoxy groups, F, OlzEr%NO2
, ON, alkoxy group having 1 to 4 carbon atoms, OF3, OH
, Nl2, mono- or dialkylamino group, mono- or diacylamino group, SH, S (O alkyl group (n is 1
or 2), a phenyl group substituted or unsubstituted with one to three groups selected from the group consisting of carbon 5K acyl groups, carbamoyl groups, and ureido groups, or one or more NXO, 5- or 6-membered heteroaryl monocyclic ring containing an S atom; 1,4-
containing the active ingredient value of at least one of the basic esters of dihydropyridine-3,5-dicarboxylic acid and its compounds, enantiomers and diastereoisomers or their addition salts with pharmacologically acceptable acids; A medicine that antagonizes calcium. 5. The medicament according to claim 4, wherein the dosage form is a tablet, capsule, sachet, powder, or vial. 6 Formula: OH300-OH2-C100Y 2-5 carbon atoms substituted or unsubstituted with koxy group
Acetoacetate represented by a linear or branched alkylene group, R3 is the same residue as in claim 1). 7 Formula: 0H3-0(Nl2)=OH-C100Y
A linear or branched alkylene group having 2 to 5 carbon atoms substituted or unsubstituted with an xy group, R3
is the same as described in claim 1 above) 3-aminocrotonate represented by the formula: OH3-00-0-000Y1 HR2 (wherein R2 haphenylmata is substituted with nitrophenyl) or unsubstituted or unsubstituted linear or branched alkyl group having 2 to 5 carbon atoms, R3 is the same residue as in claim 1) 2-Aralkylidene-3-oxobutanoate as shown.