JPH0559109B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel dihydropyridine derivatives having excellent pharmacological activity. More specifically, the present invention provides a strong and sustained blood pressure lowering effect, a peripheral vasodilator effect, a coronary artery dilator effect,
General formula () that has cerebral vasodilatory effects and is useful as a medicine, etc. [In the formula, R ¹ is hydrogen or a phenyl group, R ² is a phenyl group, R ³ is a phenyl group which may be substituted with a halogen or a nitro group, R ⁴ , R ⁵ ,
R ⁶ is the same or different and represents a lower alkyl group, A
represents an alkylene group, and m and n represent 0 or 1, respectively. In the general formula (), among the phenyl groups represented by R ¹ , R ² , and R ³ , the phenyl group represented by R ³ may be substituted with a halogen or a nitro group. Any number of these substituents may be substituted at any position on the benzene ring, and the ortho and/or meta positions are particularly preferred. The halogen of the substituent includes fluorine, chlorine,
Examples include bromine and moron, with fluorine or chlorine being particularly preferred. The lower alkyl group represented by R ⁴ , R ⁵ , R ⁶ may be linear or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl-t Examples include those having 1 to 6 carbon atoms such as butyl, pentyl, isopentyl, neopentyl, and hexyl, 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 linear or branched, and may be ethylene, trimethylene, propylene,
Examples include tetramethylene and 1,2-dimethylethylene. When m and n are each 0, it indicates that R ² is directly bonded to the 4-position of the piperidine ring. The compound of the present invention represented by the general formula () is It can be produced by subjecting any component constituting the above dihydropyridine derivative () and the remaining component to a dehydration ring-closing reaction by means known per se. Next, specific examples of manufacturing the compounds of the present invention will be shown. Manufacturing method A Manufacturing method B Manufacturing method C Manufacturing method D () + NH ₃ + () → () Manufacturing method E Production method F ()+NH ₃ +()→() Each production method will be explained in detail below. Production method A In this method, compounds (), () and () are reacted in an appropriate solvent to produce (). This reaction is generally carried out at a temperature of about 20°C to about 160°C, preferably about 50°C to about 130°C, and particularly conveniently carried out at the boiling point of the solvent used. Any solvent may be used as long as it is inert to the reaction, such as methanol, ethanol,
propanol, isopropanol, butanol,
Alkanols such as sec-butanol, ethers such as ethyl ether, dioxane, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether,
Examples include acetic acid, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile. The reaction time is usually 0.5 to 15 hours until the reaction is completed. The usage amount of (), () and () is 1 to 1 mol of each of the other two compounds for 1 mol of one of the three compounds.
This is done by using 1.5 mol. The starting compound () is known or can be produced according to a known method [for example, J.Am.Chem.
See Soc., 67 , 1017 (1945)]. Compound () can be produced, for example, as follows. [In the formula, R ⁷ represents a lower alkyl group, Y represents a halogen, and all other symbols have the same meanings as above] First, in parentheses, an epoxy compound having an alkylene corresponding to the A portion (e.g., ethylene oxide, propylene oxide) or (XI) is synthesized by reacting with a halohydrin represented by formula (). The reaction between () and an epoxy compound is usually carried out at 20℃-100℃ in an appropriate solvent (e.g., water, methanol, ethanol, dioxane, tetrahydrofuran, etc.).
It is carried out at ℃. In addition, when synthesizing (XI) 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°C to 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. (XI) is then reacted with diketene or a β-ketoester represented by (XII) to synthesize (). The reaction between (XI) and diketene is usually carried out by heating the mixture to about 40°C to about 130°C, and an inert solvent may be appropriately added to the reaction. In this reaction, a compound () in which R ⁶ is methyl is produced. Separately, () can be produced by reacting β-ketoesters represented by (XI) and (XII), and this reaction can be carried out using, for example, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, sodium amide. , in the presence of a base such as sodium metal, in a suitable inert solvent or without a solvent at about 20°C to about 100°C. Production method B It can be carried out under substantially the same conditions as production method A. The raw material compound ( ) used in this method can be synthesized by reacting the raw material compound ( ) used in production method A with ammonia. i.e. ()
is dissolved in an appropriate solvent (e.g., methanol, ethanol, ethyl ether, dioxane, tetrahydrofuran) and excess ammonia gas is removed from about 0°C to about
() can be easily synthesized by conducting the reaction at 60°C or by adding a solution of ammonia in the above solvent and reacting in a closed container at about 0°C to about 60°C. Production method C In this method, benzylidene β-ketoester () and compound () are reacted to obtain the target compound (). The reaction conditions for this reaction are also substantially the same as those in Production Method A, and the reaction is carried out by reacting 0.8 to 1.5 moles of compound () with respect to 1 mole of compound (). Benzylidene β used as raw material
-Ketoesters () are known or can be prepared from aldehydes () and β-ketoesters () according to known methods [e.g.
Organic Reactions Vol. 15, pp. 204-599 (1967)
reference〕. Production method D In this method, ammonia and compound () are reacted simultaneously in place of () in production method C. At this time, it is thought that ammonia and () first react to produce (), and () reacts with (), so this reaction can be carried out under substantially the same reaction conditions as Production Method C. . ()
The amount of () used per 1 mole is usually 0.8
-1.5 mol, the amount of ammonia used is 1-5 mol. Production Method E This method can be carried out by reacting () and () under substantially the same reaction conditions as Production Method C. Benzylidene β-ketoester () used as a raw material can be synthesized similarly to () by reacting aldehyde () and β-ketoester () according to a known method [for example, Organic Reactions Vol. 15, 204-
(See page 599 (1967)). The reaction is usually carried out using 0.8-1.5 moles of () per 1 mole of (). Production method F In this method, instead of () in production method E, ammonia and () are reacted simultaneously. At this time, it is thought that ammonia and () first react to produce (), and () reacts with (), so this reaction can be carried out under substantially the same reaction conditions as in Production Method E. The amount of () used per 1 mol of () is usually 0.8-1.5 mol, and the amount of ammonia used is 1-5 mol. The novel dihydropyridine derivative () produced by the above method can be obtained by separation and purification methods known per se, such as concentration, extraction, chromatography,
By appropriately using reprecipitation, recrystallization, etc., it can be collected with any purity. Moreover, since () has a basic group, it can also be made into an acid addition salt by known means. Such salts are preferably pharmaceutically acceptable non-toxic salts, such as salts with inorganic acids (hydrochlorides, hydrobromides, phosphates, sulfates, etc.) and salts with organic acids (acetate, etc.). , succinate,
maleate, fumarate, malate, tartrate, methanesulfonate, etc.). The compound () of the present invention and its salts have low toxicity and have strong and sustained blood pressure-lowering effects, peripheral vasodilatory effects, coronary artery dilator effects, and cerebral vasodilatory effects in mammals (e.g., mice, rats, rabbits, dogs, cats, and humans). It has vasodilatory effects, such as hypertension in humans, ischemic heart disease (angina pectoris, myocardial infarction, etc.),
It is useful as a prophylactic and therapeutic agent for circulatory system diseases such as cerebral and peripheral circulatory disorders (cerebral infarction, transient ischemic attack, etc.). In particular, compared to conventional dihydropyridine derivatives (e.g., nifedipine, nicardipine), it is superior in both strength and duration of action.
~2 times) to achieve stable hypotensive effect. When compound () and its salts are used as the above 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 it can be administered parenterally. The dosage varies depending on the administration route, symptoms, patient's weight or age, but for example, when orally administered to adult hypertensive patients, it is 0.05-20 mg/Kg body weight/day, preferably 0.1-4 mg/Kg. It is desirable to divide the dose per day into one to several doses per 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 to 6 rats per group) aged 10 to 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 (dose: 10 mg/Kg), and blood pressure was measured 1, 5, and 8 hours after administration. 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 below. All melting points were measured using the hot plate method and are uncorrected. Example 1 m-nitrobenzaldehyde (0.63 g), acetoacetic acid 2-(4-diphenylmethylpiperidino)
A mixture of ethyl (1.55 g), methyl 3-aminocrotonate (0.48 g) and 32-propanol (10 ml) was heated under reflux for 8 hours with stirring. The solvent was distilled off, the residue was chromatographed using silica gel (80 g), and dichloromethane-methanol (40:
1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-(4-diphenylmethylpiperidino) Ethyl methyl was obtained as an oil. This was treated with a small amount of isopropyl ether and hexane under cooling to give a yellow powder, which was dried under reduced pressure over phosphorus pentoxide.
Yield 0.76g (29.9%). Melting point 82-85℃ (sinter) IR (CHCl ₃ ) cm ^-1 : 3340 (NH), 1700, 1690 (C
=O). NMR (CDCl ₃ ) δ: 0.9-2.2 (7H, m, piperidine), 2.32 (6H, s, 2- and 6-position CH ₃ ),
2.54 (2H, t, J = 6Hz, [formula]), 2.81 (2H, m, piperidine), 3.43 (2H, d, J =
10.8Hz, [formula]), 3.59 (3H, s, COO CH ₃ ), 4.14 (2H, t, J=6Hz), -O CH O ₂ CH ₂
-), 5.09 (1H, s, H at 4th position), 5.92 (1H, s,
NH), 7.0−8.1 (14H, m, aryl H). Elemental analysis value C ₃₆ H ₃₉ N ₃ O ₆ Calculated value C, 70.92; H, 6.45; N, 6.89 Experimental value C, 70.56; H, 6.35; N, 6.86 Example 2 2,3-dichlorobenzaldehyde (0.615
g), 2-(4-diphenylmethylpiperidino)ethyl acetoacetate (1.30g), ethyl 3-aminocrotonate (0.450g), 2-propanol (10ml)
By treating the mixture in the same manner as in Example 1, 4-(2,3-dichlorophenyl)-
1,4-dihydro-2,6-dimethyl-3,5-
2-(4-diphenylmethylpiperidino)ethyl pyridinedicarboxylate Ethyl pyridinedicarboxylate was obtained as a pale yellow powder. Yield 0.272g (11.9%). Melting point 81-85℃
(sinter) IR (CHCl ₃ ) cm ⁻¹ : 3350 (NH), 1690 (C=0). NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.5Hz,
-CH ₂ CH ₃ ), 0.8-2.2 (7H, m, piperidine),
2.25 (6H, s, 2- and 6th position CH ₃ ), 2.52 (2H,
t, J = 6 Hz, [formula]), 2.77 (2H, m, piperidine), 3.45 (2H, d, J = 10, 8 Hz,
[Formula]), 3.9-4.24 (4H, m, -O CH ₂ CH ₂ - and - CH ₂ CH ₃ ), 5.41 (1H, s, H at 4th position), 5.73 (1H, s, NH), 6.9- 7.3 (13H, m,
Aryl H). Elemental analysis value C ₃₇ H ₄₁ Cl ₂ N ₂ O ₄ Calculated value C, 68.51; H, 6.37; N, 4.32 Experimental value C, 68.73; H, 6.32; N, 3.93 Example 3 2-(3-nitrobenzylidene ) acetoacetic acid 2
-(4-phenylpiperidino)ethyl (500 mg),
A mixture of methyl 2-aminocrotonate (170 mg) and 2-propanol (8 ml) was heated under reflux for 6 hours. The solvent was distilled off and the residue was dissolved in silica gel (30g).
1,4-dihydro-2,6-dimethyl-4-
Methyl 2-(4-phenylpiperidino)ethyl (3-nitrophenyl)-3,5-pyridinedicarboxylate was obtained as crystals. This was recrystallized from 2-propanol to obtain pale yellow crystals. Yield 87mg. melting point
159−160℃. IR (Nujol) cm ^-1 : 3375 (NH),
1710, 1660 (C=O). NMR ( _CDCl3 ) δ: 1.6-2.2 (7H, m, piperidine), 2.36 and 2.38 (3H, s, 2- and 6-positions, respectively)
CH ₃ ), 2.62 (2H, t, J = 6Hz,
[Formula]), 2.98 (2H, m, piperidine), 3.63 (3H, s, -OCH ₃ ), 4.20 (2H, t, J
=6Hz, -O CH ₂ CH ₂ -), 5.13 (1H, s, 4th position H), 5.81 (1H, s, NH), 7.1-8.2 (9H, m, aryl H). Elemental analysis value C ₂₉ H ₃₃ N ₃ O ₆ Calculated value C, 67.04; H, 6.40; N, 8.09 Experimental value C, 67.04; H, 6.36; N, 8.09 Reference example 1 (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 ( _CDCl3 )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 = 6 Hz), 6.9-7.5 (10 H, m) (2) Diketene (0.33 ml) was added to a solution of 4-diphenylmethyl-1-piperidine ethanol (1.04 g) in toluene (2 ml) at 70°C, and then 70℃
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 acetone acetate 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) Reference Example 2 (1) 4-Phenylpiperidine and ethylene bromohydrin were reacted in the same manner as in Reference Example 1, and the resulting oily 4-phenyl-1-piperidineethanol was then reacted. Acetoacetic acid 2-(4-phenylpiperidino) by reacting with diketene
Ethyl was obtained as an oil. IR (Neat) cm ^-1 :
1745, 1720. NMR (CDCl ₃ ) δ: 1.7−2.1 (7H,
m), 2.28 (3H, s), 2.67 (2H, t, J=6
Hz), 3.01 (2H, m), 3.46 (2H, s), 4.30 (2H,
t, J = 6 Hz), 7.22 (5H, s) (2) m-nitrobenzaldehyde (0.66 g), 2-(4-phenylpiperidino)ethyl acetoacetate (1.2 g), piperidine (0.1 ml) and A mixture of benzene (20 ml) was heated under reflux overnight while removing water azeotropically and the solvent was distilled off. The residue was purified on silica gel (50 g) [ethyl acetate-hexane (1:1, v/v)] to give 2-(3-
2-(4-phenylpiperidino)ethyl nitrobenzylidene)acetoacetate was obtained as an oil. Yield 0.80g (45.7%). IR (Neat) cm ^-1 :
1730, 1700, 1670.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is hydrogen or a phenyl group, R ² is a phenyl group, R ³ is a phenyl group which may be substituted with a halogen or a nitro group, R ⁴ , R ⁵ ,
R ⁶ is the same or different and represents a lower alkyl group, A
represents an alkylene group, and m and n represent 0 or 1, respectively].