JPH0559904B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel dihydropyridine derivatives with excellent pharmacological activity. More specifically, the present invention provides a general formula that has a strong and sustained blood pressure lowering effect, a peripheral vasodilation effect, a coronary artery dilation effect, a cerebral vasodilation effect, etc., and is useful as a medicine. [In the formula, R ¹ is a phenyl group which may be substituted with hydrogen or a halogen or a lower alkyl group, R ² is a phenyl group which may be substituted with a halogen or a lower alkyl group, R ³ is a halogen,
a phenyl group which may be substituted with a nitro or trifluoromethyl group, R ⁴ and R ⁵ are the same or different and are lower alkyl groups, A is an alkylene group, X is N or CH, m and n are 0 or 1 respectively] is provided. In the general formula (), each of the phenyl groups represented by R ¹ , R ² , and R ³ may have a substituent, and any number of these substituents may be substituted at any position on the benzene ring. In the case of R ³ ,
Particularly preferred are the ortho and/or meta positions. The halogen of the substituent includes fluorine, chlorine,
Examples include bromine and iodine, with fluorine or chlorine being particularly preferred; lower alkyl groups preferably have 1 to 6 carbon atoms; they may be linear or branched; for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples include sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.
Particularly preferred are those having 1 to 4 carbon atoms. As the lower alkyl group represented by R ⁴ and R ⁵ ,
Examples include those having 1 to 6 carbon atoms as described above, and those having 1 to 4 carbon atoms are particularly preferred. The alkylene group represented by A has 2 carbon atoms.
4 is preferred, and may be either linear or branched, and examples include ethylene, trimethylene, propylene, tetramethylene, and 1,2-dimethylethylene. When X is N, it means that the ring containing X is a piperazine ring, and when X is CH, it means that the ring is a piperidine ring. Further, when m and n are each 0, it indicates that R ² is directly bonded to piperazine or piperidine ring. The compound of the present invention represented by the general formula () has the general formula [In the formula, all symbols have the same meanings as above] Arylidene β-ketocarboxylic acid derivative () and the general formula It can be easily produced by reacting with an amidinoacetic acid ester derivative () represented by [wherein R ⁴ has the same meaning as above]. This reaction is carried out by reacting compound () and compound () in an organic solvent. Any solvent may be used as long as it is inert to the reaction, such as alcohols such as methanol, ethanol, propanol, 2-propanol, butanol, ethers such as dioxane, tetrahydrofuran, dimethoxyethane, diethyl ether, etc. , acetonitrile,
Pyridine, dimethylformamide, dimethyl sulfoxide and the like are preferably used. The reaction temperature is usually selected in the range of 20-200°C, but it is preferably carried out at the boiling point of the solvent used. Amidinoacetic acid ester () can be used in either the free form or in the form of hydrochloric acid, and when an acid salt is used, the reaction can be progressed by adding a base (for example, an alkali metal alcoholate) to the reaction system. Also, () is represented by the formula ('), which is an alternating isomer structure. This is also included in the present invention. ()
When and () are reacted, the reaction is carried out by using equimolar amounts of each or a slight excess of one of them. Arylidene β-ketocarboxylic acid ester () used as a raw material can be produced from an aldehyde () and β-ketocarboxylic acid ester () according to a known method as shown in the following formula [for example, Organic Reactions Vol. 15] , pp. 204-599 (1967)]. [In the formula, all symbols have the same meanings as above]. Therefore, in the method of the present invention, in some cases, instead of using (), () and () may be simultaneously reacted with (). In this case, () generated in the reaction system then reacts with () to produce the target product (). Moreover, () can be synthesized by the following method. [In the formula, R ₆ represents lower alkyl, Y represents halogen, and all other symbols have the same meanings as above] First, in parentheses, an epoxy compound (e.g., ethylene oxide, propylene oxide, etc.) having an alkylene corresponding to the A moiety; () is synthesized by reacting with a halohydrin represented by the formula (). The reaction between () and an epoxy compound is usually carried out in an appropriate solvent (e.g., water, methanol, ethanol, dioxane, tetrahydrofuran, etc.) at 20-100%
It is carried out at ℃. When synthesizing () by reacting () with (), it is preferable to carry out the reaction in the presence of a base such as sodium carbonate or potassium carbonate. In addition to the above solvents, acetone, methyl ethyl ketone, N, N- It can be carried out at 20-100°C using dimethylformamide or the like as appropriate. In the formula (), the halogen represented by Y is chlorine, bromine, or iodine, and when Y is chlorine or bromine, sodium iodide, potassium iodide, etc. are added to about 0.1-1 mole of () to promote the reaction. It may be carried out in the presence of about 1 mol. () is then reacted with diketene or a β-ketocarboxylic acid ester represented by () to synthesize (). The reaction between () and diketene is
The reaction is usually carried out by heating the mixture to about 40 DEG - about 130 DEG C., and a solvent inert to the reaction may be added as appropriate. In this reaction, a compound () in which R ⁵ is methyl is produced.
Separately, () can also be produced by reacting () with (). in the presence of a suitable inert solvent or in the absence of a solvent from about 20°C to about
It can be done at 100℃. (2) A compound () in which X is N and m and n are not 0 at the same time, ie, the following formula ('), can be produced as follows. [In the formula, Z is a leaving group, m' and n' are each 0 or 1, except when m' and n' are 0 at the same time] The leaving group represented by Z is the leaving group shown by Y above. In addition to the same halogens, methanesulfonyloxy,
Examples include sulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy groups. The reaction between () and (XI) is described in 1 above.
The reaction between () and () and the reaction between (') and diketene or () can be carried out under the same conditions as the reaction between () and diketene or (). The dihydropyridine derivative () produced by the above method is a new compound, and can be made to any purity by appropriately using known separation and purification means such as concentration, extraction, chromatography, reprecipitation, recrystallization, etc. Can be collected. Also()
Since it has a basic group, it can also be made into an acid addition salt by known means. Such salts include, for example, salts with inorganic acids (hydrochlorides, hydrobromides, phosphates, sulfates, etc.), salts with organic acids (acetates, oxalates, malonates, succinates, etc.). , maleate, fumarate, malate, tartrate, methanesulfonate, etc.). The compound () of the present invention and its salts have low toxicity and are suitable for mammals (e.g., mice, rats, rabbits,
It has strong and sustained blood pressure-lowering effects, peripheral vasodilation effects, coronary artery dilation effects, and cerebral vasodilation effects in humans (dogs, cats, monkeys, humans). , myocardial infarction, etc.), cerebral circulation disorders (cerebral infarction, transient ischemic attack, etc.) and other circulatory system diseases. When compound () and its salts are used as the above-mentioned pharmaceuticals, they are mixed with appropriate pharmaceutically acceptable carriers, excipients and diluents, and administered orally in the form of powder, granules, tablets, capsules, injections, etc. or can be projected parenterally. The amount of injection varies depending on the injection route, symptoms, and patient's weight or age, but for example, when orally administering to an adult hypertensive patient, it is 0.05-20 mg/Kg body weight/day, preferably 0.1-4 mg/Kg. It is desirable to project the weight/day in one to several times a day. The results of pharmacological tests showing the effectiveness of the compound () of the present invention are shown below. Blood pressure lowering effect Male spontaneously hypertensive rats (3-6 rats per group) aged 10-11 weeks were used. Blood pressure was measured using an automatic blood pressure measuring device (USM-105R) manufactured by Ueda Medical Co., Ltd., and the systolic blood pressure of the rat caudal artery was measured. The test compound was orally administered as a 5% gum arabic suspension (projected amount: 10 mg/Kg), and blood pressure was measured 1, 5, and 8 hours after application. The average values (mmHg) for each are shown in the table below.

[Table] The present invention will be explained in more detail with reference to Examples and Reference Examples below. All melting points shown in the examples below were measured by the hot plate method and are uncorrected. Example 1 (1) m-nitrobenzaldehyde (1.67g), 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate (4.20g), bendene (40ml)
A mixture of Dean- and piperidine (0.05 g)
The mixture was heated under reflux for 4 hours while removing moisture using a Stark apparatus. After washing with water and drying (MgSO ₄ ), the solvent was distilled off, and the residue was purified using a column of silica gel (100 g) [ethyl ale-ethyl acetate (10:
1, v/v)], 2-
(3-Nitropenzylidene)acetoacetic acid 2-(4
-benzhydryl-1-piperazinyl)ethyl was obtained as an oil. Yield: 4.37g. NMR
( _CDCl3 )δ: 2.38 (3H, s, _COCH3 ), 4.14~
4.53 (3H, m, −COOCH ₂ CH ₂ −,

[Formula]), 7.10-8.75 (14H, m) (2) 2-(3-nitrobenzylidene)acetoacetic acid 2-(4-benzhydryl-1-piperazinyl)
In an absolute ethanol (10 ml) solution of ethyl (4.37 g) and ethyl hydrochloride amidinoacetate (1.42 g),
Sodium (0.20g) was dissolved in absolute ethanol (10g).
ml) was added dropwise under reflux with stirring. about
Added in 15 minutes and heated under reflux for an additional 5 minutes.
NaCl was filtered off and the liquid was concentrated under reduced pressure. The residue was purified with a column of silica gel (120 g),
Ethyl ether-ethyl acetate (10:1, v/
2-amino-1,4-
Dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridicarboxylic acid 5-[2-
(4-Benzhydryl-1-piperazinyl)ethyl]3-ethyl was obtained as a yellow powder. yield
3.22g. Oxalate was obtained as crystals by adding an ethanol solution of oxalic acid to an ethanol solution of 2.48 g of this product. Yield: 2.52g. Recrystallization from ethanol-ethyl ether gave yellow crystals (1.83 g). Melting point 152-153℃ Elemental analysis value C ₃₅ H ₃₉ N ₅ O ₆・C ₂ H ₂ O ₄ Calculated value C, 62.09; H, 5.77; N, 9.78 Experimental value C, 62.47; H, 6.09; N, 9.57 Thereafter, the following compounds were obtained in the same manner as in Example 1. Example 2 2-amino-1,4-dihydro-6-methyl-
4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 5-{2-[4-(4,4'-dimethylbenzhydryl)-1-piperazinyl]ethyl}3
-Ethyl oxalate: Melting point 180-182℃ Elemental analysis value C ₃₇ H ₄₃ N ₅ O ₆・C ₂ H ₂ O ₄・1/2H ₂ O Calculated value C, 62.22; H, 6.16; N, 9.30 Experiment Value C, 62.43; H, 6.03; N, 9.18 Example 3 2-Amino-1,4-dihydro-6-methyl-
4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 5-{2-[4-(4,4'-difluoropenzhydryl)-1-piperazinyl]ethyl}
3-isopropyl oxalate: Melting point 143-144℃ Elemental analysis C ₃₆ H ₃₉ F ₂ N ₅ O ₆・C ₂ H ₂ O ₄・1/2H ₂ O
Calculated value C, 58.91; H, 5.46; N, 9.04 Experimental value C, 59.14; H, 5.32; N, 8.92 Example 4 2-Amino-1,4-dihydro-6-methyl-
4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 5-{2-[4-(2,2-diphenylethyl)-1-piperazinyl]ethyl}3-ethyl oxalate: Melting point 206-208℃ Element Analytical value C ₃₆ H ₄₁ N ₅ O ₆・C ₂ H ₂ O ₄ Calculated value C, 62.54; H, 5.94; N, 9.60 Experimental value C, 62.90; H, 5.91; N, 9.28 Example 5 2-Amino -1,4-dihydro-6-methyl-
4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 5-[2-(4-benzhydrylpiperidino)ethyl]3-ethyl oxalate: Melting point
153-155℃ Elemental analysis value C ₃₆ H ₄₀ N ₄ O ₆・C ₂ H ₂ O ₄ Calculated value C, 63.86; H, 5.92; N, 7.84 Experimental value C, 63.87; H, 5.89; N, 7.73 Implementation Example 6 2-amino-1,4-dihydro-6-methyl-
4-(3-trifluoromethylphenyl)-3,5
-5-[2-(4-benzhydryl-1-piperazinyl)ethyl 3-ethyl pyridinedicarboxylate:
Pale yellow powder IR (Nujol) cm ^-1 : 3450, 3325,
1700, 1685, 1670. NMR ( _CDCl3 )δ: 1.16
(3H, t, J=7.2Hz), 2.24 (3H, s), 2.39 (8H,
broad), 2.52 (2H, t, J=6.6Hz), 3.87−4.23
(5H, m), 4.89 (1H, s), 6.14 (2H, s,
NH ₂ ), 6.67 (1H, s, NH), 7.08−7.53 (14H,
m) Elemental analysis value C ₃₆ H ₃₉ F ₃ N ₄ O ₄ Calculated value C, 66.65; H, 6.06; N, 8.64 Experimental value C, 66.81; H, 6.16; N, 8.60 Example 7 2-Amino-1 ,4-dihydro-6-methyl-
4-(3-trifluoromethylphenyl)-3,5
-pyridinedicarboxylic acid 5-[2-(4-benzhydryl-1-piperazinyl)ethyl 3-ethyl 3
-Isopropyl: pale yellow powder IR (Nujol) cm
^-1 : 3440, 3315, 1700, 1670NMR ( _CDCl3 ) δ:
1.00 (3H, d, J = 6Hz), 1.20 (3H, d, J = 6
Hz), 2.22 (3H, s,), 2.40 (8H, broad), 2.52
(2H, t, J=6Hz), 4.40 (2H, t, J=6Hz)
4.17 (1H, s), 4.87 (1H, s), 4.88 (1H, m),
6.17 (2H, broad s, NH ₂ ), 6.75 (1H, s,
NH), 7.0-7.55 (14H, m) Elemental analysis value C ₃₇ H ₄₁ F ₃ N ₄ O ₄ Calculated value C, 67.05; H, 6.24; N, 8.45 Experimental value C, 67.06; H, 6.27; N, 8.47 Example 8 2-amino-1,4-dihydro-6-methyl-
4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 5-{2-[4-(4,4'-dichlorobenzhydryl)-1-piperazinyl]ethyl}3
-Ethyl dihydrochloride: Melting point 174-175℃ Elemental analysis value C ₃₅ H ₃₇ Cl ₂ N ₅ O ₆・2HCl・H ₂ O Calculated value C, 53.51; H, 5.26; N, 8.92 Experimental value C, 53.58; H, 5.21; N, 8.85 Example 9 2-amino-4-(2,3-dichlorophenyl)
-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 5-{2-[4-(4,4'-dichlorobenzhydryl)-1-piperazinyl]ethyl}3-ethyl trihydrochloride Salt: Melting point 187-188℃ Elemental analysis value C ₃₅ H ₃₆ Cl ₄ N ₄ O As ₄・3HCl Calculated value C, 50.78; H, 4.75; N, 6.77 Experimental value C, 50.69; H, 4.78; N, 6.70 Implemented Example 10 2-amino-1,4-dihydro-6-methyl-
4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 5-{2-[4-(3-chlorophenyl)
-1-Piperazinyl]ethyl}3-ethyl: Yellow powder IR (Nujol) cm ^-1 : 3450, 3315, 1670
NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 6.9Hz),
2.30 (3H, s), 2.47-2.74 (6H, m), 2.99-3.23
(4H, m), 4.06 (2H, q, J = 6.9Hz), 4.18 (2H,
t, J=6Hz), 5.00 (1H, s), 6.32 (2H, broad
s, NH ₂ ), 6.65−8.18 (8H, m), 6.97 (1H, s,
NH) Elemental analysis value C ₂₈ H ₃₂ ClN ₅ O ₆ Calculated value C, 59.00; H, 5.66; N, 12.29 Experimental value C, 58.69; H, 5.30; N, 11.98 Example 11 2-amino-1,4 -dihydro-6-methyl-
3-isopropyl 4-(3-nitrophenyl)-3,5-pyridinedicarboxylate 5-{2-[4-(2
-methylphenyl)-1-piperazinyl]ethyl}
Oxalate: Melting point 157-160℃ Elemental analysis value C ₃₀ H ₃₇ N ₅ O ₆ .C ₂ H ₂ O ₄ Calculated value C, 58.80; H, 6.01; N, 10.71 Experimental value C, 58.56; H, 6.00 ;N, 10.59 Reference Example 1 (1) Benzhydryl bromide (21.7 g) was added dropwise to a mixture of piperazine ethanol (11.4 g), powdered potassium carbonate (24.3 g), and N,N-dimethylformamide (100 ml) while stirring. . After stirring at room temperature for 2 hours, the mixture was diluted with water and extracted with ethyl ether. The ethyl ether layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography (eluting with hexane-ethyl acetate (2:1)) to obtain 21.9 g (84.2%) of 4-benzhydryl-1-pyrazineethanol oil. IR
(Neat): 3380 cm ^-1 NMR (CDCl ₃ ) δ: 2.46
(10H, broad s), 3.57 (2H, t, J=6.5),
4.20 (1H, s), 7.03-7.45 (12H, m) The following compounds were obtained in the same manner. 4-(4,4'difluorobenzhydryl)-1
- Piperazine ethanol: Oil IR
(Neat): 3380 cm ^-1 NMR (CDCl ₃ ) δ: 2.2−
2.7 (10H, m), 3.54 (2H, t, J=6), 4.18
(1H, s), 6.8−7.4 (8H, m) 4-(4,4'dichlorobenzhydryl)-1-
Piperazine ethanol: Oil IR (Neat):
3400cm ^-1 NMR ( _CDCl3 ) δ: 2.2−2.6 (10H,
m), 2.82 (1H, s, OH), 3.53 (2H, t, J=
6), 4.14 (1H, s), 7.23 (8H, s) 4-(4,4'-dimethylbenzhydryl)-1
- Piperazine ethanol: Oil IR
(Neat): 3400cm ^-1 NMR (CDCl ₃ ) δ: 2.24
(6H, s), 2.2−2.7 (10H, m), 3.54 (2H, t,
J = 6), 4.21 (1H, s), 6.9-7.3 (8H, m) (2) Add diketene (5.1g) to 4-benzhydryl-1-piperazine ethanol (18.1g),
After heating at 70-80℃ for 1.5 hours with stirring,
Purified by silica gel chromatography (eluted with hexane-ethyl acetate (3:2)) and purified with acetoacetic acid 2-
(4-Benzhydryl-1-piperazinyl)ethyl was obtained as an oil. Yield 17.1g (73.6
%) IR (Neat): 1730, 1715cm ^-1 NMR
(CDCl ₃ ) δ: 2.22 (3H, s), 2.43 (10H,
broad), 3.39 (2H, s), 4.18 (1H, s), 4.20
(2H, t, J=6), 6.64-7.73 (10H, m) The following compound was obtained in the same manner. Acetoacetic acid 2-[4-(4,4'-difluorobenzhydryl)-1-piperazinyl]ethyl: Oil IR (Neat): 1740, 1715 cm ^-1
NMR ( _CDCl3 ) δ: 2.25 (3H, s), 2.2−2.7
(10H, m), 3.40 (2H, s), 4.18 (1H, s),
4.25 (2H, t, J = 6), 6.8-7.5 (8H, m), 2-[4-(4,4'-dichlorobenzhydryl)-1-piperazinyl]ethyl acetoacetate: Oil IR ( Neat): 1740, 1715cm ^-1 NMR
(CDCl ₃ ) δ: 2.23 (3H, s), 2.3−2.8 (10H,
m), 3.42 (2H, s), 4.17 (1H, s), 4.23 (2H,
t, J=6), 7.28 (8H, s) Acetoacetic acid 2-[4-(4,4'-dimethylbenzhydryl)-1-piperazinyl]ethyl:
Oil IR (Neat): 1740, 1715cm ^-1 NMR
(CDCl ₃ ) δ: 2.23 (3H, s), 2.25 (6H, s),
2.3−2.8 (10H, m), 3.40 (2H, s), 4.12 (1H,
s), 4.23 (2H, t, J=6), 7.03 (4H, d,
J=9), 7.27 (4H, d, J=9) Reference example 2 (1) 1-(3-chlorophenyl)piperazine hydrochloride (5g), powdered potassium carbonate (12g), N,N
- Ethylene promhydrin (5.4 g) was added dropwise into a mixture of dimethylformamide (35 ml) with stirring. After further stirring overnight at room temperature, the mixture was diluted with 100 ml of water and extracted with ethyl ether. The ethyl ether layer was washed with saturated brine, dried over Na ₂ SO ₄ and the solvent was distilled off. The residue was purified by silica gel chromatography (eluted with ethyl acetate-methanol (4:1)) to obtain 4.06 g (78.6%) of 4-(3-chlorophenyl-1-piperazine ethanol) as an oil. IR (Neat) :3380
cm ^-1 NMR (CDCl ₃ ) δ: 2.47−2.79 (6H, m),
3.06−3.35 (5H, m), 3.68 (2H, t, J=5.5
Hz), 6.65−−. 48 (4H, m) The following compound was obtained in the same manner. 4-(2-Methylphenyl)-1-piperazine ethanol: Oil (2) By reacting the 4-phenyl-1-piperazine ethanol obtained in (1) with diketene in the same manner as in Reference Example 1-2, the following The compound was obtained. Ethyl acetoacetate 2-[4-(3-chlorophenyl)-1-piperazinyl]: Oil IR
(Neat): 1740, 1715 cm ^-1 NMR (CDCl ₃ ) δ:
2.24 (3H, s), 2.50−2.82 (7H, m), 3.06−
3.13 (4H, m), 3.44 (2H, s), 4.28 (2H, t),
6.60−7.36 (4H, m) Acetoacetic acid 2-[4-(2-methylphenyl)
-1-Piperazinyl]ethyl: Oil Reference Example 3 (1) In a mixture of 1-(2,2-diphenylethyl)piperazine (4.30 g), potassium carbonate (6.7 g), and N,N-dimethylformamide (20 ml). , while stirring ethylene promhydrin (4.03
g) was added dropwise. The mixture was stirred at room temperature overnight, then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with Na ₂ SO ₄ ,
The solvent was distilled off. The residue was chromatographed on silica gel and eluted with ethyl ether ethyl acetate-methanol (10:2:1, v/v) to give 4-(2,2-diphenylethyl)-1-piperazineethanol as an oil. Ta. Yield: 4.24g. NMR ( _CDCl3 ) δ: 2.45 (11H, broad
s,

【formula】

[Formula] and OH), 2.96 (2H, d, J = 7.5Hz,

[Formula]), 3.55 (2H, t, J=5.7Hz,

【formula】) , 4.18 (1H, t, J=7.5Hz,

[Formula], 7.24 (10H, s, aryl H) (2) 4-(2,2-diphenylethyl)- obtained in (1)
60 in 1-piperazine ethanol (4.23 g)
Diketene (1.26 g) was added dropwise with stirring at °C. Thereafter, the mixture was further heated and stirred at 80°C for 1 hour. The reaction mixture was subjected to silica gel chromatography using ethyl ether-ethyl acetate (5:1,
acetoacetic acid 2 by elution with v/v)
-[4-(2,2'-diphenylethyl)-1-piperazinyl]ethyl was obtained as an oil. Yield 4.52g. IR (Neat): cm ^-1 : 1740, 1710. NMR
(CDCl ₃ ) δ: 2.24 (3H, s, CH ₃ ), 2.44 (8H,
broad s,

[Formula]), 2.57 (2H, t, J=6Hz,

[Formula]), 2.95 (2H, d, J = 7.5 Hz,

[Formula]), 3.42 (2H, s, - COCH ₂ CO-), 4.17 (1H, t, J = 7.5Hz,

[Formula]), 4.22 (2H, t, J=6Hz,

[Formula]), 7.20 (10H, s, aryl H). Elemental analysis value C ₂₄ H ₃₀ N ₂ O ₃ Calculated value C73.07, H7.66, N7.10 Experimental value C73.08, H7.58, N7.10 Reference example 4 (1) 4-diphenylmethylpiperidine (1g),
Ethylene bromohydrin (0.37 ml) was added to a mixture of powdered potassium carbonate (1.1 g) and N,N-dimethylformamide (10 ml) with stirring.
was added dropwise and stirred for an additional 4 hours at room temperature. The precipitate was filtered off, the filtrate was concentrated under reduced pressure, water was added, and the mixture was extracted with dichloromethane. The dichloromethane layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off.
The residue was purified by silica gel chromatography [CH ₂ Cl ₂
-MeOH (25:1, v/v)] to give 4-diphenylmethyl-1-piperidineethanol as an oil. Yield 1.08g
(91.9%) IR (Neat) cm ^-1 : 3380. NMR
(CDCl ₃ ) δ: 1.0−2.2 (7H, m), 2.49 (2H,
t, J=6Hz), 2.70−3.0 (2H, m), 3.04
(1H, broad s, OH), 3.48 (2H, d, J=
11.4Hz), 3.56 (2H, t, J=6Hz), 6.9-7.5
(10H, m) (2) Diketene (0.33 ml) was added to 4-diphenylmethyl-1-piperidine ethanol (1.04 g) in toluene (2 ml) at 70°C, and further heated at 70°C.
Stir for 1 hour. The solvent was distilled off under reduced pressure,
The residue was purified by silica gel chromatography [hexane-ethyl acetate (2:3, v/v) to obtain 2-(4-diphenylmethylpiperidino)ethyl acetoacetate as an oil. Yield: 1.23g (92.1%). IR (Neat) cm ^-1 : 1740,
1720. NMR ( _CDCl3 ) δ: 1.1−2.1 (7H, m),
2.23 (3H, s), 2.58 (2H, t, J=6Hz),
2.85 (2H, m), 3.48 (2H, d, J = 10.8Hz),
3.40 (2H, s), 4.22 (2H, t, J=6Hz), 6.9
-7.3 (10H, m).

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a phenyl group which may be substituted with hydrogen or a halogen or a lower alkyl group, R ² is a phenyl group which may be substituted with a halogen or a lower alkyl group, R ₃ is a halogen,
a phenyl group which may be substituted with a nitro or trifluoromethyl group, R ⁴ and R ⁵ are the same or different and are lower alkyl groups, A is an alkylene group, X is N or CH, m and n are 0 or 1 respectively]. 2 General formula [In the formula, R ¹ is a phenyl group which may be substituted with hydrogen or a halogen or a lower alkyl group, R ² is a phenyl group which may be substituted with a halogen or a lower alkyl group, R ³ is a halogen,
a phenyl group which may be substituted with a nitro or trifluoromethyl group, R ⁵ is a lower alkyl group, A is an alkylene group, X is N or CH,
arylidene β-ketocarboxylic acid ester represented by m and n each represent 0 or 1] and the general formula A general formula characterized by reacting with an amidinoacetic acid ester represented by [wherein R ⁴ represents a lower alkyl group] A method for producing a dihydropyridine derivative represented by the formula [wherein all symbols have the same meanings as above].