JPS6158473B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the formula (): (In the formula, R ¹ is a linear unsubstituted alkyl group having 1 to 5 carbon atoms; R ² is an unsubstituted phenyl group or a phenyl group substituted with a nitro group; R ³ is a hydrogen atom, and It is a straight-chain alkyl group, and the alkyl group is unsubstituted or one or more hydrogen atoms are substituted with an alkoxy group; R ⁴ is a hydrogen atom, and has 1 carbon number.
-4 linear or branched alkyl group, which is unsubstituted or has one of the hydrogen atoms alkoxy, carbalkoxy, dialkylamino, aryl or at least one N or O atom. ~6-membered heterocyclic ring, e.g. 1-piperidinyl,
4-morpholinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, imidazolyl, imidazolinyl, thienyl, thiazolyl, 1,2,3- or 1,2,4-triazolyl, etc., and these heterocyclic rings include alkyl, alkoxy, halogen, amino , acylamino, alkylamino, dialkylamino, carbalkoxy, hydroxy, nitrile, nitro, SOn-alkyl (n is 0 or 1-
2) Hydroxyimino and alkoxyimino 1,4-dihydropyridines optionally mono- or di-substituted with trifluoromethyl, or R ⁴ is alkenyl or cycloalkyl having 3 to 6 carbon atoms It relates to derivatives, their enantiomers, racemates, diastereoisomers, (E) and (Z)-isomers, and their salts with pharmacologically acceptable acids. The present invention also provides a method for reacting 3-acyl-1,4-dihydropyridine with hydroxylamine represented by the formula: H ₂ N-O-R ⁴ (wherein R ⁴ is the same as above), and in the resulting mixture. Hydroxyimino and alkoxy of formula (I) consisting of identifying the (E) and (Z)-stereoisomers and isolating at least one of the two (E) and (Z) in a pure state. This invention relates to a method for producing imino derivatives. The O-substituted hydroxylamine of the formula H ₂ N-O-R ⁴ used as starting material can be prepared by known methods, in particular by treating the corresponding R ⁴ -O-N-phthalimide with acid under mild conditions. It may be produced by hydrazinolysis. Incidentally, this reaction proceeds according to the reaction formula shown below. (In the formula, R ⁴ is the same as above, and X is halogen.) In addition, the hydroxylamine compound used to form the compound of the present invention, especially when R ⁴ has a basic group, is prepared according to the reaction formula shown below. It may also be produced from acetone oxime. Specific examples of the compound represented by formula () of the present invention include the following. Methyl 2,6-dimethyl-3-(1-hydroxyimino)-ethyl-4-(3-nitrophenyl)
-1,4-dihydropyridine-5-carboxylate, methyl 2,6-dimethyl-3-(1-methoxyimino)ethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate, methyl 2・6-dimethyl-3-(1-
ethoxyimino)ethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate, methyl 2,6-dimethyl-3-(1
-isopropoxyimino)-ethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5
-Carboxylate, methyl 2,6-dimethyl-
3-(1-n-butyroxyimino)ethyl-4-
(3-Nitrophenyl)-1,4-dihydropyridine-5-carboxylate, methyl 2,6-dimethyl-3-[1-(2-ethoxy)-ethoxyimino]]-ethyl-4-(3-nitrophenyl)- 1・
4-dihydropyridine-5-carboxylate,
Methyl 2,6-dimethyl-3-(1-allyloxyimino)ethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-5-carboxylate, methyl 2,6-dimethyl-3-(1-benzyloxyimino)ethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate, methyl 2・6-dimethyl-3-(1
-cyclopentyloxyimino)-ethyl-4-
(3-Nitrophenyl)-1,4-dihydropyridine-5-carboxylate, methyl 2,6-dimethyl-3-(1-ethoxycarbonyl)methoxyimino-ethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-5-carboxylate, methyl 2,6-dimethyl-3-[1-(2-N
-benzyl-N-methylamino)ethoxyimino]ethyl-4-(3-nitrophenyl)-1.4
-dihydropyridine-5-carboxylate, methyl 2,6-dimethyl-3-(2-N·N-dimethylamino)-ethoxyimino]ethyl-4-(3
-nitrophenyl)-1,4-dihydropyridine-5-carboxylate, methyl 2,6-dimethyl-3-[1-(2-piperidino)ethoxyimino]ethyl-4-(3-nitrophenyl)-1,4
-dihydropyridine-5-carboxylate, methyl 2,6-dimethyl-3-[1-(2-ethoxy)ethoxyimino-2-methoxy]ethyl-4
-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate, 2,6-dimethyl-3-{1-[2-(4-morpholinyl)ethoximino]ethyl}-4-(3-nitrophenyl)- 5
-Methoxycarbonyl-1,4-dihydropyridine. Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples. In addition, in the examples, melting points (mp) were measured using a Buchi apparatus in a capillary tube, and the values remain uncorrected. Ultraviolet absorption (UV) spectra were measured using a Varian CARY210 instrument.
PMR spectrum was obtained using VARIAN60MHz equipment.
Measurements were made in the indicator solvent using TMS as an internal standard. Example 1 [Production of methyl 2,6-dimethyl-3-(1-hydroxyimino)ethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate (hereinafter referred to as 0227A)] H. Meyer et al. (Arzneim.
20 g of methyl 2,6-dimethyl-3-acetyl-4-(3-nitrophenyl-1,4-dihydropyridine-5-carboxylate) prepared according to the method of Forsch., 31 (), 407 (1981)).
(0.0605 mol), 10 g (0.126 mol) of pyridine, and 8.82 g of hydroxylamine hydrochloride in 200 ml of dimethyl sulfoxide (DMSO) was left at room temperature for about 18 days. The solution was then poured into water and extracted with methylene chloride.
The organic layer was washed with water, dried and concentrated to a small volume to yield 3 g of a nearly pure hydroxyimino derivative precipitate. The pure target product was obtained by recrystallization from dichloroethane (mp 194-195°C). UV: λmax337nm (ε=7.380) PMR (DMSO-d ₆ ): δ1.83 (s, 3H, =C-
CH ₃ ), 2.00 (s, 3H, =C-CH ₃ ), 2.30
(s, 3H, = C-CH ₃ ), 3.57 (s, 3H,
OCH ₃ ), 4.83 (s, 1H, C ₄ H), 7.43−7.73
(m, 2H, = CH ar), 7.83−8.13 (m, 2H, =
CH ar), 8.53 (s, 1H, NH), 10.62 (s,
1H, OH) Elemental analysis value: C ₁₇ H ₁₉ N ₃ O ₅ (as 345.32) Theoretical value (%): C59.12 H5.55 N12.16 Actual value (%): C58.92 H5.64 N12.03 Example 2 [Methyl 2,6-dimethyl-3-(1-methoxyimino)ethyl-4-(3-nitrophenyl)-
Production of 1,4-dihydropyridine-5-carboxylate (hereinafter referred to as 0221A)] Methyl 2,6-dimethyl-3-acetyl-4-
(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate 22.8 g (0.069 mol),
A mixture of 11.91 g of pyridine and 8.08 g (0.097 mol) of O-methyl-hydroxylamine hydrochloride was refluxed in 280 ml of methanol for 15 hours. The reaction mixture was evaporated to dryness and the oily residue was dissolved in isopropanol 30
ml and left at -5°C for 1 hour. A small amount of unreacted 3-acetyl derivative was removed and the reaction mixture was evaporated to dryness and then dissolved in methylene chloride. After washing with water, it was dried, concentrated, and purified by column chromatography on silica gel (eluting with methylene chloride). Fractions containing the two stereoisomers were collected separately. The stereoisomer that formed more during the reaction was recrystallized from cyclohexane (mp 128-130°C). UV: λmax339nm (ε=6.880) PMR (DMSO-d ₆ ): δ1.83 (s, 3H, =C-
CH ₃ ), 2.00 (s, 3H, =C-CH ₃ ), 2.33
(s, 3H, = C-CH ₃ ), 3.57 (s, 3H,
OCH ₃ ), 3.73 (s, 3H, N-OCH ₃ ), 4.83
(s, 1H, C ₄ H), 7.40−7.77 (m, 2H, = CH
ar), 7.80−8.17 (m, 2H, = CH ar), 8.63
(s, 1H, NH) Elemental analysis value: C ₁₈ H ₂₁ N ₃ O ₅ (as 359.38) Theoretical value (%): C60.16 H5.89 N11.69 Actual value (%): C60.01 H5.98 N11.56 The other stereoisomers were not isolated in pure form, but were found in mixtures with the first isomer. In the PMR spectrum, both the proton of the methyl group next to the double bond and the other values shown below shifted upward. PMR (DMSO- _d6 ): δ1.70(s, 3H, =C-
CH ₃ ), 4.70 (s, 1H, C ₄ H), 8.50 (s, 1H,
NH) Elemental analysis value: C ₁₈ H ₂₁ N ₃ O ₅ (as 359.38) Theoretical value (%): C60.16 H5.89 N11.69 Actual value (%): C60.22 H6.01 N11.50 Example 3 (a) [Production of N-ethoxy-phthalimide] 24 g (0.147 mol) of N-hydroxyphthalimide was added to 120 ml of DMSO and heated at 40°C until completely dissolved. Then, 23.9 g (0.176 mol) of sodium acetate trihydrate and 15.92 ml (0.21 mol) of ethyl bromide were added while heating at 80°C.
After 2 hours and 15 minutes, the reaction mixture was dissolved in chloroform 600
ml, washed with 10% potassium bicarbonate, and dried. After removing the solvent, 19.3 g (yield 68.7%) of N-ethoxy-phthalimide was obtained (mp95~
97°C) (A. Rougny et al., Bull. Soc. Chim. Fr. 833 (1976)). (b) [Preparation of O-ethylhydroxylamine hydrochloride 13.7 g (71.7 mmol) of the product obtained in (a)
3.59 g (71.7 mmol) of hydrazine hydrate was added to a warm solution of hydrazine hydrate in 65 ml of ethanol. The reaction mixture was heated for 20 minutes, then 37% hydrochloric acid 8.87
ml and heated for an additional 20 minutes. 25.3 ml of water was added and the reaction mixture was heated for a further 20 min to 0°C.
The mixture was cooled to 100%, filtered, and washed with absolute alcohol. Dry the mother liquor and immerse the residue in ethanol 100%.
ml, the insoluble material was filtered off, and the mother liquor was dried. The solid thus obtained was washed with boiling ethyl acetate and filtered to give 6 g of O-ethylhydroxylamine hydrochloride (86% yield, mp 120-125
°C) (BJRNicolaus et al., Ann. Chim.
53 , 281 (1963) mp125-127°C). (c) [Production of methyl 2,6-dimethyl-3-(1-ethoxyimino)ethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate (hereinafter referred to as 0235A)] Starting material The reaction was carried out in the same manner as in Example 2, except that O-ethyl-hydroxylamine hydrochloride was used as the solvent, and the desired product was obtained by recrystallization from cyclohexane (mp 123-125°C). This product was analyzed by high performance liquid chromatography (hereinafter referred to as HPLC) and PMR. The majority (over 95%) of the compounds obtained were one of two stereoisomers. UV: λmax339nm (ε=7.377) PMR (DMSO-d ₆ ): δ1.10 (t, 3H, =C-
CH ₃ ), 1.85 (s, 3H, =C-CH ₃ ), 2.00
(s, 3H, =C- _CH3 ), 2.33(s, 3H, =C
−CH ₃ ), 3.57 (s, 3H, OCH ₃ ), 3.97
(q, 2H, OCH ₂ ), 4.80 (s, 1H, C ₄ H),
7.43−7.73 (m, 2H, = CH ar), 7.83−8.17
(m, 2H, = CH ar), 8.57 (s, 1H, NH) Elemental analysis value: C ₁₉ H ₂₃ N ₃ O ₅ (as 373.36) Theoretical value (%): C61.12 H6.21 N11.25 Actual measurement Value (%): C60.94 H6.34 N10.90 Other stereo isomers are shown below.
It was identified by the signal of PMR spectrum. δ1.70 (s, 3H, = C-CH ₃ ), 3.43 (s,
3H, OCH ₃ ), 4.70 (s, 1H, C ₄ H), 8.43
(s, 1H, NH) Example 4 [Methyl 2,6-dimethyl-3-[1-(ethoxycarbonyl)methoxyimino]ethyl-4-
Production of (3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate (hereinafter referred to as 0234A)] A pale yellow oil was obtained in the same manner as in Example 2, except that ethylaminooxyacetate was used.
HPLC analysis showed a single peak in 97.3% area. PMR (DMSO-d ₆ ): δ1.20 (t, 3H, CH ₃ ),
1.93 (s, 3H, = C-CH ₃ ), 2.00 (s, 3H, =
C- _CH3 ), 2.30 (s, 3H, =C- _CH3 ), 3.56
(s, 3H, OCH ₃ ), 4.10 (q, 2H, OCH ₂ ),
4.53 (s, 2H, OCH ₂ CO), 4.77 (s, 1H,
C ₄ H), 7.37−7.77 (m, 2H, = CH ar), 7.80
−8.17 (m, 2H, = CH ar), 8.63 (s, 1H,
NH) Elemental analysis value: C ₂₁ H ₂₅ N ₃ O ₇ (as 431.43) Theoretical value (%): C58.46 H5.85 N9.73 Actual value (%): C58.64 H5.96 N9.52 In HPLC Other stereoisomers that could not be separated, but only traces of octopus, were detected based on the PMR spectrum signals shown below. δ1.80 (s, 3H, = C-CH ₃ ), 3.43 (s, 3H,
OCH ₃ ), 4.40 (s, 2H, OCH ₂ CO), 4.87 (s,
1H, C ₄ H), 8.43 (s, 1H, NH) Example 5 (a) Production of [2-[2-(N-benzyl-N-methyl-amino)ethoxy]-1,3-isoindolinedione ] 2-Hydroxy-1,3-isoindolinedione (N-hydroxy-phthalimide) 6.54g
(0.04 mol) of triethylamine in 100 ml of acetonitrile and 1-chloro-2-[N-benzyl-
0.0425 mol of N-methylamino]-ethane (KOH
(obtained from the hydrochloride salt) was added. The resulting solution was refluxed with the disappearance of hydroxy-isoindolinedione being controlled by HPLC. After 3 hours, the reaction mixture was filtered, concentrated to 1/3 of its starting volume, diluted with 200 ml of methylene chloride and washed with aqueous potassium bicarbonate solution. The organic layer was concentrated and the resulting oily residue (8.91 g) was dissolved in boiling cyclohexane.
The solution was filtered and evaporated to dryness to give 8.6 g of an oil. This product was found to be pure by HPLC analysis. PMR (CDCl ₃ ): δ2.30 (s, 3H, NCH ₃ ),
2.90 (t, 2H, CH ₂ N), 3.63 (s, 2H,
ar, CH ₂ N), 4.37 (t, 2H, OCH ₂ ), 7.30
(s, 5H, = CH ar), 7.65−7.95 (m, 4H,
= CH ar) Elemental analysis value: C ₁₈ H ₁₈ N ₂ O ₃ (as 310.36) Theoretical value (%): C69.66 H5.85 N9.02 Actual value (%): C69.48 H5.95 N8.90 (b) [Production of 2-(aminoxy)-N-benzyl-N-methyl-ethylamine hydrochloride] 8.76 g of the compound obtained in Example 5-(a) above
(0.0282 mol) was dissolved in 25 ml of absolute ethanol. Heat the solution to reflux and stir thoroughly.
When 1.35 g (0.027 mol) of 100% hydrazine hydrate was added, a precipitate was immediately deposited. After boiling for 6 minutes, 4.1 ml of concentrated hydrochloric acid was added and refluxed for an additional 10 minutes. During this time the reaction mixture became substantially more fluid. Then 10 ml of water was added and the reaction mixture was cooled in an ice-water bath. The phthalic hydrazide was removed by filtration, and the solution was concentrated to dryness. The solid thus obtained was washed several times with boiling ethyl acetate and the supernatant liquid was decanted. The 6.6 g of product obtained was tested by both perchloric acid titration and iodometric titration. Next, the results of PMR analysis conducted in DMSO- _d6 are shown. δ2.73(s, 3H, 〓CH ₃ ), 3.48(t, 2H,
CH ₂ 〓), 4.47 (s, 2H, ar CH ₂ 〓), 4.67
(t, 2H, OCH ₂ ), 7.33−7.83 (m, 5H, =CH
ar) Elemental analysis value: C ₁₀ H ₁₆ N ₂ O・2HCl (as 253.17) Theoretical value (%):
C47.44 H7.16 N11.06 Cl 28.00 Actual value (%):
C47.24 H7.42 N10.89 Cl 27.81 The corresponding base was a pale yellow oil. PMR (CDCl ₃ ): δ2.27 (s, 3H, NCH ₃ ),
2.61 (t, 2H, CH ₂ N), 3.53 (s, 2H, ar
CH ₂ N), 3.80 (t, 2H, OCH ₂ ), 7.33
(s, 5H, aromatics) (c) [Methyl 2,6-dimethyl-3-[1-(2-
Production of N-benzyl-N-methyl-amino)ethoxy-iminoethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate (hereinafter referred to as 0224A)] Methyl 2,6-dimethyl- 3-(acetyl-
4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate (0.0125 mol), 2-(aminoxy)-N-phenyl-methyl-N-methyl-ethylamine hydrochloride (0.0125
A light yellow oil was obtained in the same manner as in Example 2, except that pyridine (0.375 mol) and pyridine (0.375 mol) were used. This was dissolved in isopropyl ether, and after a while, crystals with a mp of 127-129°C were separated. The obtained product was analyzed by HPLC and PMR. The product consisted of over 90% of one of two stereoisomers. UV: λ246nm (ε=16.255), λ341nm (ε=
7.155) PMR (DMSO−d ₆ ): δ1.85(s, 3H, =C−
CH ₃ ), 1.97 (s, 3H, =C-CH ₃ ), 2.13
(s, 3H, NCH ₃ ), 2.30 (s, 3H, =C-
CH ₃ ), 2.50 (t, 2H, CH ₂ N), 3.45 (s,
2H, NCH ₂ ar), 3.55 (s, 3H, OCH ₃ ),
4.07 (t, 2H, OCH ₂ ), 4.80 (s, 1H,
C ₄ H), 7.30 (s, 5H, = CH ar), 7.40−
7.73 (m, 2H, = CH ar), 7.80−8.13 (m,
2H, = CH ar), 8.60 (s, 1H, NH) Other isomers were identified by the PMR signals shown below. δ1.68 (s, 3H, = C-CH ₃ ), 4.70 (s,
1H, C ₄ H), 8.47 (s, 1H, NH) Elemental analysis value: C ₂₇ H ₃₂ N ₄ O ₅ (as 492.58) Theoretical value (%): C65.84 H6.55 N11.37 Actual value (%) ): C65.88 H6.48 N11.14 The O-substituted hydroxylamines shown in Table 1 were prepared in substantially the same manner as in the examples above.

[Table] Furthermore, such a hydroxylamine compound may be produced by a method similar to the method for producing O-(2-N·N-dimethylamino)-ethylhydroxylamine shown below. Acetone oxime 7.31g (0.1 mol), 2-N.
N-dimethylaminoethyl chloride hydrochloride 15.844
g (0.11 mol), potassium carbonate 41.46 g (0.3 mol)
A mixture of 150 ml of toluene and 150 ml of toluene was heated under reflux for 20 hours. After cooling, the solid product was filtered and the mother liquor was concentrated to yield 10.77 g of 2-N.N-dimethylaminoethyl acetone oxime as an oil. The obtained oil
The mixture was reacted with 85 ml of 10% hydrochloric acid and heated under reflux for 22 hours. The resulting reaction mixture was concentrated, the residue was dissolved in warm ethanol, and diethyl ether was added until cloudiness occurred. The mixture was cooled and filtered to give 4 g (31% yield) of 2-(N·N-dimethyl)-ethoxyamine dihydrochloride (mp 178-182°C) (RC Peterson).
Journ.Pharm.Sci., 58, 141 (1969) mp180
~182℃). Other compounds of formula () of the present invention were prepared using methods similar to those used in the above examples. These are summarized in Table 2.

【table】

〔Method〕

(Toxicity upon intravenous administration in mice) A detached CD1 mouse obtained from Charles River, weighing 25 g, was used. The test compound was dissolved in dimethyl sulfoxide, and 0.01 ml per 10 g of body weight was administered intravenously. The LD ₅₀ value 7 days after administration was calculated using Litchfield-Wilcoxon (Litchfield-Wilcoxon).
Wilcoxon (Experimental Therapeutics, 96, 99
(1949)). (Antagonistic effect on calcium in the colon cord of guinea pigs) Hartley albino guinea pigs with an average weight of 450 g were used. Naunyn pre-depolarized colonic cord (taenia coli)
Calcium antagonism was determined by stimulation every 20 minutes with a single submaximal concentration of _CaCl2 , 10 ^-3 M, according to the method of Schmied.Arch.Pharmacol.318, 235 (1982). . The test compound was contacted with the above preparation for 10 minutes. Percentage of maximum inhibition (%) to ED ₅₀
The value was calculated. [Results] The results are summarized in Table 3.

【table】

[Table] As is clear from Table 3, the compounds of the present invention exhibit excellent calcium antagonism and are therefore useful for the treatment of hypertension, various types of angina, ischemia, other cardiovascular diseases, etc. and useful for prevention. Among the test compounds, 0265B, 0246B, 0247B,
0270B and 0224A are contractions due to CaCl ₂ that increase even if the tissue is repeatedly washed.
was suppressed. Since this suppression phenomenon is observed even after tissue washing, the ED ₅₀ value of calcium antagonism is
It was calculated by considering the maximum inhibition that can be obtained independently from the time of onset of inhibition. Furthermore, the compounds of the present invention exhibit a more favorable therapeutic effect than the comparative examples because they have lower toxicity on average and extremely high calcium antagonistic effects than the comparative examples. I found out. The present invention also encompasses all industrial objects related to the therapeutic use of esters of formula (). 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 present invention may be administered orally or parenterally, for example in the form of tablets, capsules, sachets including hydrogenated dispersible powders, vials for injection, and the like. The compounds of the invention may be administered to adults 1 to 3 times a day for 10 to 30 minutes.
100 mg can be administered.

Claims (1)

[Claims] 1 Formula (): (In the formula, R ¹ is a linear unsubstituted alkyl group having 1 to 5 carbon atoms; R ² is an unsubstituted phenyl group or a phenyl group substituted with a nitro group; R ³ is a hydrogen atom, and A straight-chain alkyl group, which is unsubstituted or substituted with at least one alkoxy group; R ⁴ is a hydrogen atom, and has 1 carbon number.
~4 linear or branched alkyl groups, which are unsubstituted or substituted with alkoxy, carbalkoxy, dialkylamino, aryl or a 5- to 6-membered heterocyclic ring having at least one N or O atom has been or
R ⁴ is alkenyl or a cycloalkyl group having 3 to 6 carbon atoms) and their enantiomers, racemates, diastereoisomers, (E) and (Z)-isomers, or their pharmacologically acceptable Salt with uric acid. 2. The compound according to claim 1, wherein R ⁴ is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with aryl or a monocyclic heterocyclic ring, and its enantiomer, racemate, dia Stereoisomers and (E) and (Z)-isomers or their salts with pharmacologically acceptable acids. 3 The monocyclic heterocyclic ring is 1-piperidinyl or 4
-morpholinyl and its enantiomers, racemates, diastereoisomers and (E) and (Z)-isomers or their salts with pharmacologically acceptable acids. 4 3-acyl-1,4-dihydropyridine with the formula: H ₂ N-O-R ⁴ (wherein R ⁴ is a linear or branched alkyl group having 1 to 4 carbon atoms, and the alkyl group is unsubstituted or substituted with alkoxy, carbalkoxy, dialkylamino, aryl or a 5- to 6-membered heterocyclic ring having at least one N or O atom, or R ⁴ is an alkenyl or a cycloalkyl group having 3 to 6 carbon atoms Formula () obtained by reacting with hydroxylamine represented by ) and isolating the (E) and (Z)-diastereoisomers: (In the formula, R ¹ is a linear unsubstituted alkyl group having 1 to 5 carbon atoms; R ² is an unsubstituted phenyl group or a phenyl group substituted with a nitro group; R ³ is a hydrogen atom, and A linear alkyl group, which is unsubstituted or substituted with at least one alkoxy group; R ⁴ is the same as above) and its enantiomers, racemic compounds, diastereoisomers and ( E) and (Z)-isomers or their salts with pharmacologically acceptable acids. 5 Formula (): (In the formula, R ¹ is a linear unsubstituted alkyl group having 1 to 5 carbon atoms; R ² is an unsubstituted phenyl group or a phenyl group substituted with a nitro group; R ³ is a hydrogen atom, and A straight-chain alkyl group, which is unsubstituted or substituted with at least one alkoxy group; R ⁴ is a hydrogen atom, and has 1 carbon number.
~4 linear or branched alkyl groups, which are unsubstituted or substituted with alkoxy, carbalkoxy, dialkylamino, aryl or a 5- to 6-membered heterocyclic ring having at least one N or O atom has been or
R ⁴ is alkenyl or a cycloalkyl group having 3 to 6 carbon atoms) and their enantiomers, racemates, diastereoisomers, (E) and (Z)-isomers, or their pharmacologically acceptable A calcium antagonist whose active ingredient is a salt with uric acid. 6. Claim 5, wherein the dosage form is a tablet, capsule, sachet, powder, or vial.
Calcium antagonists as described in section.