JPS6064962A - 2-(beta-aryl-beta-hydroxyethyl)dihydropyridine derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [X is CH=CH, CH=N, or O; R1 is H, lower alkyl, alkoxy, hydroxy, nitro, trifluoromethyl, or halogen; R2 is lower alkyl, N,N-dialkylaminoalkyl, or N-alkyl-N-(arylalkyl)aminoalkyl; R3 is lower alkyl; R4 is H, alkoxy, or halogen] and its salt. EXAMPLE:2-( beta-Phenyl-beta-hydroxyethyl )-4-phenyl-6-methyl-1,4-dihydropyridine-3,5- dicarboxylic acid dimethyl ester. USE:Showing antagonism on calcium and hypotensive action, useful for remedying disorder of cardiovascular system. PREPARATION:A compound shown by the formula II is reacted with a compound shown by the formula III and ammonia to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of the general formula (I) 1 [wherein, nitro group, trifluoromethyl group, or /) rogene atom such as fluorine, chlorine, bromine or iodine, R2 is a lower alkyl group, N,N-dialkylaminoalkyl group or N-alkyl-N-(orirualkyl)amino an alkyl group, R3 is a lower alkyl group, R4 is a hydrogen atom,
It means an alkoxy group or a halogen atom such as fluorine, chlorine, bromine or iodine. ] A new 2-(
The present invention relates to β-allyl-β-hydroxyethyl) dihydropyridine derivatives, pharmaceutically acceptable salts thereof, and methods for producing the same.

Further, the compound (I) of the present invention has two asymmetric carbon atoms, and there are four types of optical isomers corresponding to the two asymmetric carbon atoms. The present invention also includes these optical isomers and their salts.

The compounds of the present invention exhibit calcium antagonistic and antihypertensive effects and are therefore useful for the treatment of cardiovascular disorders.

The compound of the present invention represented by general formula (I) has the following (i)
, (ii) and (iii).

(i) General formula (n) It has the same meaning as clear. ] and the general formula (1) [wherein, X % R1 and R2 are the above general formula (1)]
It has the same meaning as the explanation. ] and ammonia may be dissolved in an inert organic solvent (water is used), a mixture of water and the inert organic solvent may be used.

), the reaction is carried out at room temperature to 200°C, preferably 60 to 140°C. In addition, the raw material compounds (11) and (■) can be prepared by known methods [Reference: For example, I → Ma Ryo et al., Chemistry
Letters (Chemistry Letters, 16
1-164 (1975) (ii) Ij, Meyer et al.
m,-Forsch,/Drug Res,)33,1
06-112 (1983)).

(ii) General formula (IV) [In the formula, R3 and R4 have the same meaning as explained in the above general formula (1). ] and the compound represented by the general formula (V) [wherein X and R have the same meaning as in the above description of the general formula (1). ] and general formula (Vl) In the formula C, R2 has the same meaning as described in the above general formula (1). ] in an inert organic solvent (when water is dissolved in the inert organic solvent used, a mixture of water and the inert organic solvent may be used), A method of reacting at room temperature to 200°C, preferably 60 to 140°C.

The raw material compound represented by the general formula (IV) can be easily obtained by reacting the compound represented by the above general formula (n) with ammonia, and can be isolated once or as it is without isolation. It may be used for reaction with a compound represented by general formula (V) and a compound represented by (Vl).

In addition, compounds represented by the above general formula (V) and (V
The compounds represented by I) may be reacted with each other to obtain a compound represented by the above general formula (III), and then reacted with a compound represented by the above general formula (IV).

(iii) General formula (■) [In the formula, R2 has the same meaning as described in the above general formula (1). ], the compound represented by the above general formula (■), and the compound represented by the above general formula (II) are dissolved in an inert organic solvent (water is used) (A mixture of water and an inert organic solvent may be used.) A method of reacting at room temperature to 200°C, preferably 60 to 140°C.

In dihydropyridines that exhibit myocardial contractility suppressing action and blood pressure lowering action, generally when a bulky substituent is introduced at the 2-position of the dihydropyridine nucleus, the ability to express these actions is reduced [Reference: F., Bosser 1- et al., Angebund Hiemi, International Edition;
English version (F.

13ossert et al., Angew, Chem, Int.
Ed, Engl.) 20, 762 (1981)].
The present inventors have surprisingly discovered that the compound of the present invention, in which an aralkyl group, which is a type of bulky substituent, is introduced into the 2-position of the dihydropyridine nucleus, and a hydroxyl group is further introduced into the alkylene group of this aralkyl group, causes myocardial contraction. The present invention was completed based on the discovery that the duration of the inhibitory action and blood pressure lowering action was not decreased without decreasing the activity.

As mentioned above, the compounds of the present invention suppress the contraction of smooth muscle and cardiac muscle through calcium antagonism, and are therefore useful for the treatment of coronary diseases, brain diseases, and hypertension in mammals.

When the compound of the present invention is used for the above-mentioned therapeutic purposes, the compound of the present invention is formed into a pharmaceutical or veterinary composition comprising a pharmaceutically or veterinarily acceptable diluent or carrier.

These compositions may be in forms suitable for oral administration, such as tablets or capsules, in forms suitable for inhalation, e.g. aerosols or solutions suitable for spraying, in forms suitable for intrauterine injection or parenteral administration, e.g. for use as injections. or in the form of suppositories suitable for anal or intravaginal use, or in forms suitable for transdermal use, such as liniments, ointments, plasters or poultices. It can be used in any shape.

The composition containing the compound of the present invention preferably contains about 0.1 to 99.0% of the compound of the present invention, based on the weight of the total composition.
5%, more preferably about 0. Contains 5-9'5%.

In addition to the compounds of the invention or compositions containing the compounds of the invention, other pharmaceutically or veterinary active compounds can be included. Additionally, these compositions can contain more than one compound of the invention.

1 for intravenous administration of a drug containing the compound of the present invention 9
The daily dosage varies depending on the type and severity of the symptoms being treated and individual differences (age, gender, sensitivity, etc.).
Active ingredient 0゜0001-10+ng per kg of body weight
, preferably 0.0005 to 1. For oral administration, a suitable daily dosage is 0.005 to 100, preferably 0.005, of active ingredient per k+r body weight.
~50■.

A suitable daily dosage for transdermal administration is 0.005 to 100, preferably 0.005 to 50, of the active ingredient per kg of body weight. These daily dosages can be administered in two or more divided doses per day, if necessary.

The above-mentioned composition containing the compound of the present invention can be produced by a conventional method, and can contain conventional excipients.

[Reference example ■] Calcium antagonism in the isolated left atrium of a guinea pig After killing a male guinea pig, a specimen of the isolated left atrium was prepared.
It was suspended in a nutrient solution in a Magnus tank, and its contractile response was recorded via an isometric transducer. A calcium chloride solution was cumulatively added to the isolated left atrial muscle driven by electrical stimulation, and a dose-contraction curve was determined to serve as a control group. Separately, in the presence of the test compound, a calcium ion dose-contraction curve was determined in the same manner to determine the treatment group.

The I)A2 value, which represents the calcium antagonistic effect of the test compound, was calculated from the difference in response between the control group and the treated group, and Table 1 shows the p'A2 values of the test compound and known calcium antagonists. .

Table 1 Strength of antagonistic effect on calcium contraction Next, the results of a durability test of the antihypertensive effect of the compound of the present invention are shown.

[Reference Example 2] Durability test of blood pressure lowering effect The blood pressure lowering effect of the compound of the present invention and the duration of this effect were determined by
- Tested using SHR anesthetized with chloralose. In this test, a group of 3 to 5 SHR rats was used, and blood pressure in the femoral artery of each rat was invasively measured. To administer each compound, each compound was dissolved in 3% Tween 80-normal saline and injected into the femoral vein, and from the correlation between the drug dose and the maximum blood pressure reduction rate, the drug amount required for 30% blood pressure reduction E D3. (■/kg) was plotted as a graph. The duration is 1/1 from the point of maximum blood pressure drop.
2, and the duration of 30% blood pressure reduction (min) was plotted as a graph based on the correlation between drug dose and duration. These results are shown in Table 2. The blood pressure lowering effect of nifedipine determined by this test method is also included in the same table for comparison. Table 2 Sustainability test of blood pressure lowering effect The present invention will be described in more detail below with reference to Examples.

Note that the present invention is not limited to these Examples.

Example 1 1.06 g of henzaldehyde, 1.15 g of methyl 2-aminocrotonate, and 2.22' g of methyl 5-phenyl-5-hydroxypentanoate-3-one were dissolved in 10 m of ethanol for 4 hours. It refluxed. The reaction solution was concentrated, and the concentrated solution was subjected to alumina column chromatography (f
4 medium; benzene: ethyl acetate = 4: 1 (v/v)
) to obtain the desired product. This was recrystallized from a mixed solvent of ethyl acetate and hexane to form colorless needle-like crystals of 2-(
β-phenyl-β-hydroxyethyl)-4-phenyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester 0.97 g (yield 24%)
was gotten. Melting point: 175-178°C.

Note that this compound is a mixture of diastereoisomers.

NMR (CDC13): δ7.44-7.0 (Lo
ll, m), 6.40.6.32 (1■, s)
, 5.17 ~ 4.83 (III, m) , 4.96
(111, s), 3.90 ~ 2;60 (211
, m), 3.61 (6H, s), 2°10.2.
08 (311,s).

Ms, m/e (intensity ratio > 73 (1B), 22
4 (30).

280 (17), 298 (20), 312 (
100), 313 (18), 329 (13)
, 331 (24), 373 (12).

Hereinafter, the compounds shown in Table 3 were obtained in the same manner as in Example 1, and the synthesis examples and spectral data (NMR (CDC13
) δ: and MS, m/e (intensity ratio)] Example R Yield Melting point 1 number-" 911, m), 5.
68 (01,s), 5.20~4.70 (Il
l, m), 3.52, 3.48 (611,s),
3°71~2.65 (2H, m), 2.34. r
28 (311, s).

MS: 312 (50), 417. (100),
435 (60452'IOM.

3 m-No2 30 53-57 (spectrum data) NMR: 8.12-7.20 (911, m), 5
．． 16 (II(,s), 5.22-5.07 (l
tl,m), 3.6Ci, 3.64 (611,s
), 3.0'0~2.48 (211, m), 2
．． 22, 2.16 (311, s).

MS=224 (20) 280 (15) 298
(20) 312 (104o-CF3 28 207
~20B (spectrum data) NMIl: 7.60~7.18 (911, m)
, 6.13-5.90 (III, broad s)
, 5.60-5.45 (Ill, broad s)
, 5.28~5.17 (11Lm), 3.57 (
311,s), 3.55 (311,s), 3.7
2-2.25 (211, m), 2.08 (3H,
s).

MS: 224 (20) 280 (16), 3
12 (100), 313 (2033023398
205784751M5 m-CF3 26 149~
151 (spectral data) NMR: 1.10-6.78 (911, m), 6.
05 (III, broads), 5.55 (II
I, broad s), 5.28-4.80 (iH
, m), 3.60 (3H,s), 3.57 (31
Ls), 4.16 ~ 2.27 (211, m),
2.17, 2.12 (311, s).

MS: 224 (10), 280 (25), 29
8' (16), 312 (10 (spectral data) NMR: 7.65-6.90 (9H, m), 6.
13-5.8 (i (Ill, broad s), 5
．． 38 (HLbroad s), 5.24-4.8
3 (111, m), 3.61, 3.60.3.57
,3.55 (6H,s) ,4.13~2゜30 (
21Lm), 2.16, 2.08 (3H,s).

MS: 224 (28), 280 (12),
312 (100), 313 () 330'13
423 (14441 (2M.

7 m-Cl27 163-164 (spectral data) NMR: 1.52-6.97 (9H, m), 6.1
7, 6.08 (Ill, broad s), 5.2
6-4.88 (18, broad s), 4.97
(Ill, m), 3.66.3.66.3.64
(611,s) ,3',86~2.60 (211,
m), 2.08, 2.06 (3Ls).

MS: 78 (100), 224 (20), 2
80 (16), 298 (16), 312 (90
), 313 (18), 330 (23), 42
3 (6), 43 o-0C11323173-17
4 (spectral data) NMR near, 47-(i, 72 (911, m), 6.1
0-5.88 (II, broads), 5.23
(11Lbroad s), 5.14~4.93 (
111, m), 3.62, 3.58 (611, s)
, 3.42-2.50 (211, m), 2.17
(31Ls).

MS: 224 (72), 28o (36), 2
98 (17), 312 (100), 313
(21), 330 (46), 360 (18)
, 406 (23419(18) 437 (11M
.

9 m-01122 oil (spectral data) MS: (measured value after TMS conversion) 179 (23), 312 (100'), 313
(22) ,402 (47567(2M” +-T
M.S.

10 m-cl+36 yellow solid (spectral data) NMR: 7.80-6.60 (911, m), 6
．． 27, 6.18 (III, broad s), 5
．． 34-4.80 (III, m), 4.96 (I
ll, s), 4.26-2.36 (2+1.m)
, 3.63, 3. ．． 62 (61Ls), 2.30
(311,s), 2.28 (311,s).

MS: 134 (1B), 224 (15),
280 (25), 298 (20”), 312
(100), 313 (18), 330 (52)
, 421 (5,M"), - 11p-Cl135 yellow solid (spectral data) NMR near, 94-6.72 (911,m), 6.
36, 6.24 (III, broads), 5.
22-4.74 (ill, m), 4.92 (II
Ls), 4.14-2.56 (21Lm), 3.
60 (611,s), 2.24 (61Ls).

MS: 224 (40), 280 (17),
312 (100), 313 (24), 326 (
18), 330 (42), 344 (20),
421 (5,M).

Example 12 In Example 1, 5-methyl-2-furfural 1. was used instead of benzaldehyde. When a similar operation is performed using Log, 2-(β-phenyl-β-hydroxyethyl)
-4-(5-methylfuryl-2-yl)-6-methyl-
0.91 g (yield 22%) of 1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester was obtained.

NMR (CDCI!); δ7.48~, 7.10
(511, m), 6.1B, 6.02 (IH, br
oad s) , 5.81 (ill, s) , 5.7
'3 (LH, s), 5.11 (III, broa
ds), 4.16-2.56 (211, m),
3.70 (611,s), 2.20 (311,s
), 2.17 (311,s).

MS+m/e (intensity ratio): 82 (20), 19
1 (37) , 246 (27) , 296 (27
), 302 (34), 334 (100), 35
2(23), 411 (M”, 23).

Example 13 When the same operation as in Example 1 was performed using 1 g of β-naphthylaldehyde instead of benzaldehyde, 2-
(β-phenyl-β-hydroxyethyl)-4-(β-
naphthyl)-6-methyl-1,4-dihydropyridine-
0.90 g of 3,5-dicarboxylic acid dimethyl ester was obtained. Yield 31%, melting point 199-202℃ NMR (CD(:13): δ7.90-7.06(
, 1211, m).

6.12, 6.03 (III, b'roads)
, 5.24-4.94 (III, m) , 5.16
(11Lbroad s), 4.15~2.28
(211, m), 3.62 (611, s), 2.
18, 2.11 (311, s).

MS, m/e (intensity ratio): 224 (15), 2
80 (12), 312 (100), 313 (2
0), 330 (27), 439 (17), 4
57 (6, M”).

Example 14 1.06 g of benzaldehyde, 2-aminochlorine [2
2.48 g of -(N-methyl-N-hensylamino)ethyl ester and 2.22 g of methyl 5-phenyl-5-hydroxy-pentanoate-3-one were dissolved in 20 ml of ethanol and refluxed for 6 hours. After concentrating the reaction solution, silica gel column chromatography (solvent:
After separating the fraction containing the target product using Hensen: ethyl acetate-3: 1 (V/V)), basic alumina column chromatography (vehicle: Hensen: Nishi), ethyl acetate-3: 2 (v/v) ) ) to obtain the target product 2-(β-phenyl-β-hydroxyethyl)-3-methoxycarbonyl-4-phenyl-6-methyl-1,4
-dihydropyridine-5-carboxylic acid 2-(N-methyl-N-hensylamino)ethyl ester 0.76 g (yield 14%, yellow oil) was obtained.

NMR (CDC,!3): δ7.48~6.97 (
1511,m), 6.03' (11Lbroa
ds), 5.20-4.92 (III, m),
5.0 (Ill, broads), 4.24-4
．． 00 (211,m), 3.61 (311,s)
, 3.50 (21Ls) , 3.78-2.33
(211, m), 2.63 (211, t, J-81
1z), 2.19 (31Ls), 2.16,2
．． 10 (311, s).

MS, m/e (intensity ratio): 99 (57), 1
34 (100), 167 (72), 298 (
27) , 445 (10) , 540 (8 Ura.

Hereinafter, the compounds shown in Table 4 were obtained in the same manner as in Example 14. Synthesis examples and spectral data (NMR (CDCl2
) δ: and MS, m/e (intensity ratio)] Example R
Yield number one (%) 15 o-NO28,1 (spectral data) NMR: 7.72-6.85 (1411, m)
, 5.76 (III, br.

ad s), 5.13-4.80 (III, m)
, 4.37-3.92 (211, m) , 3.57,
3.53 (:3tl,s), 3.43 (21Ls
), 2. t30~2.42 (211, m), 2.
22 (31Ls), 2.20, 2.13 (311
,s).

-Nezumi 2"■μμ"B" 1J O-Door Worker 11--16 m
-N0z 13.8 (spectrum data) NMII: 8.17 to 7.68 (1411, m-)
, 7.68 (III, br.

ad's), 5.22-4.91 (ill, m)
, 5.12 (11Lbroad s) , 4.27~
3.96 (211, m), 3.60 (311, s
), 3.50 (2+1.s), 3.67~2.3
1 (211, m), 2.63 (2H, t, J=7
11z), 2.18 (611,s),.

MS: 134, (90), 147 (100)
, 148 (33), 298 (170-CF3
18 (spectral data) NMR near, 72-6.90 (1411, m),
6.41, 6.37 (III, broads),
5.55 (III, broad s) +5.17~
4.86 (111, m), 4.34-3.96 (
211,m), 3.58 (311,s), 3.4
6 (211,s), 3.37~2.28 (2,1
+, m), 2.58 (2H, t, J=811z)
,2.25 (311,s> ,2.16 (3H,
s).

MS: 90 (47), 134 (100), 1
47 (98), 148 (No. 66y "Fumin L" moonshi Ω aim-, 590 (5) Part 6 (4, M > -18m-
CF34 (spectral data) NMR near, 58-6.91 (1411, m),
6.43 (I'll, br.

ad s), 5.15 to 4.82 (ill, m)
, 5', 02 (Ill, broad s), 4.
22-3.95 (211, m), 3.76-2.
23 (211, m), 3,. 58 (311,s)
, 3.46. (211,s), 2.69 ~2.
40 (211, m), 2.14 (211, s)
, 2.11 (311,s).

MS: 99 (32), 134 (100,), 1
67 (88), 298 (919o -C132 (spectral data) NMR near, 46-6.83 (148, m), 6
．． 65 (III, br.

ad s), 5.38 (LH, broad s)
, 5.07~4.86 (ill, m), 4.23~
3.95' (2tlm), 3.57, 3.56 (
3H,s), 3.43 (211,s), 3.77
~2.24 (211, m), 2.71~2.45
(2H, m) , 2.22, 2.20 (311, s)
, 2.11 (311,s).

MS: 91 (30), 134 (94), 1
47 (100), 148 (7B), 29B (
39), 408 (13), 556 (10)'
, 574 (7,M”+1.

20 m-C140 (spectral data) NMR: 7.66-6.85 (14H, m),
6.35, 6.27 (Ill, broads),
5.17-4.82 (LH, m), 4.97 (I
H, br.

ad s), 4.15 (21Lt,'J=611z
) , 4.61, 4.60 (3fl, s) , 3.
48 (211,s), 3.84~2.35 (21
1, m) , 2.62 (211, t, J=711z
), 2.17 (311,s), 2.14,2. L
O(311,s).

MS: 91 (24), 434 (96), 1
47 (toO), 14B (15210-OC11
338 (spectral data) NMR near, 46-6.52 (1411, m),
6.13 (1)1. br.

ad s), 5.27, 5.31 (ill, s)
, 5.06-4.8 (IH, m), 4.30-3.9
6 (211, m), 3.69 (311, s),
3.56 (311,s), 3.49 (211,s
), 3.83-2.28 (211, m), 2.7
6-2.45 (211, m), 2.23, 2.21
(311,s), 2.17 (311,s).

MS: 91 (30), 134 (100), 1
47 (7B), 148 (72), 298 (1
9), 404 (24), 552 (20,M −
11,0), 5697 to1+.

22 0-C11312 (spectrum data) NMR near, 56-6.85 (1411, m),
5.23-4.88 (Ill, m), 5.13 (
LH,s), 4.31-3.91 (211,m)
, '3.51 (311, s) , 3.41 (2H,
s), 2.99-2.52 (2tlm), 2.7
5-2゜38 (211, m), 3.22 (611
,s), 3.21 (311,s).

MS: 91 (45), 134 (100),
147 (81), 1411 (88), 298
(33), 445 (19), 536 (7; M
-H, LO), 554 (10 m M), '-----□-- 23 m-C11336 (spectrum data) NMR: 7.67-6.50 (1411, m)
, 6.52, 6.46 (III, broad s)
,,5.15~4.88 (1tlm),4.98
(1! I, s), 4.25-4.04 (2tl, m)
, 3.80-2.34 (211, m) , 3.59
(3H,s), 3.48 (211,s), 2.
62 (211,t, J=711z), 2.23
(611,s), 2.18 (311,s).

MS: 91 (40), 134 (100), 1
47 (E12), 148 (73”), 298
(25), 406 (14), 536 (7,M
-II□O), 554 (+5, Ll24p-Cll334 (spectral data) NMR: 7.60-6.78 (1411, m)
, 6.27, 6.19 (Ill, broad s5.
5.17-4.99 (IH, m), 4.96 (H
l, s), 4.22-4.04 (21!, m), 3
．． 62.3.60 (311,s), 3.49 (21
1,s), 3.81 ~ 2.36 (211,m)
, 2.63 (211,s, J-711z), 2.
23 (6H,s), 2.19 (311,s).

MS: 91 (32'), 134 (100)
, 147 (87) , 146 (79') , 298
(35), 388 (27), 536 (11,
M-14UO), 55 Example 25 When the same operation as in Example 14 was performed using 0.77 g of 2-furfural instead of benzaldehyde, 2
-(β-phenyl-β-hydroxyethyl)-3-methoxycarbonyl-4-(2-furyl)-6-methyl-1
,4-dihydropyridine-5-carboxylic acid 2-(N-methyl-N-hensylamino)ethyl ester 1.81
g (34% yield, brown oil) was obtained.

NMR (CDC13): δ7.43~1.01 (
fill, m), G, 76.6.57 (11Lb
road s), 6.24-6.10 (III, m
), 5.96, 5.85 (LH, d, J=411z
), 5.20 (III, s), 5.14-4
．． 88 (LH, m), 4.33-3.97 (21
1,m), 3.63 (311,s), 3.52
(21(,s), 3.75~2.40 (211,m
), 3.68 (21Lt, J=711z), 2.
20 (311,s), 2.15,2.11 (31
1, S).

M S + m / e (intensity ratio): 207 (1
3), 279 (10), 356 (10), 4
25 (52), 426 (11), 488 (1
2), 531 (100, M++1).

Example 26 Perform the same operation as in Example 14 using 0.86 g of pyridine-2-aldehyde instead of benzaldehyde. 7,2-(β-phenyl-β-hydroxyethyl)
-3-methoxycarbonyl-4-(2-pyridyl)-6
2.58 g of -methyl-1,4-dihydropyridine-5-carboxylic acid 2-(N-methyl-N-benzylamino)ethyl ester (yield 48%, yellow curved material) was obtained.

NMR (CDCl2): δ8.38 (IH, d,
J=511z), 1. '69~6.80 (131
1,m), 5.2B, 5.24 (111,s)
, 5.20-4.98 (III, m) , 4.32~
3.94 (211, m), 3.91-2.40 (2
11,m)', 3.61.3.57 (311,s)
, 3.52 (211,s) , 2.68 (211,s)
,t, J=711z) ,2.21,2.23 (3
11,s), 2.15,2゜17 (311,s)
.

MS, m/e (intensity ratio) (FD mass spe
ctrum): 542 (100, Mll”),
543 (34).

Example 27 Henzaldehyde 1.06g, 2-aminocrotonic acid 2
- (N,N-dimethylamino)ethyl ester 1.7
2 g and 2.22 g of methyl 5-phenyl-5-hydroxypentanoate-3-one in 20 ml of ethanol.
and refluxed for 4 hours. After concentrating the reaction solution, it was purified by silica gel column chromatography (solvent: ethyl acetate:methanol = 2:3 (V/V)) to obtain the target product 2-(β-phenyl-β-hydroxyethyl)-3. -Methoxycarbonyl-4-phenyl-6-methyl-1,4-dihydropyridine-5-carboxylic acid 2-
(N,N-dimethylamino)ethyl nisder 0.6g
(13% yield, yellow oil) was obtained.

NMR (CDC13): δ7.51-6.96 (t
oll, m), 6.08-5.94 (III, b
road s), 5.12-4.97 (III, m
), 4.91 (IH,s), 4.20-3.94
(21Lm), 3. ! j8, 3.59 (3) 1. s)
, 2.62-2.31 (2)1. m), 2.18
(611, s).

MS, m/e (intensity ratio) (FD mass spec
trum): 467 (26), 465 (100
, M −+1 ).

Hereinafter, the compounds shown in Table 5 were obtained in the same manner as in Example 27.

Table 5 Synthesis Examples and Spectral Data (NMR (CDC13
) δ: and MS, m/e (intensity ratio)] Example R yield "IL, -1X door 28 m-CF310 (spectral data) NMR: 7.65-6.89 (141 Lm),
6.26, 6.20 (LH, broads), 5
．． 20-4.91 (III, m), 5.00 (I
II, s), 4.28-3.90 (211, m),
3.64 (31Ls), 3.48~2゜64 (2
11,m) ,2.32 (211,L,J=811z
), 2.22 (61Ls gate S: 58 (100)
, 71 (79), 72 (48), 298 (154
42 (21,514 (5M -18.

29 o-CF3 8 (spectral data) Ml (measured value after TMS conversion) 71 (65), 72 (100), 179 (5
7), 280 (73), 298 (8s), 369
(92), 388 (70), 442 (44)
, 532 (Continued from page 1 of 43 Patent Applicant Nissan Chemical Industries, Ltd.

Claims (1)

[Claims] (1) General formula (1) [wherein, X is CH-'CH, CH=N or 0, R1
is a hydrogen atom, lower alkyl group, alkoxy group, hydroxy group, nitro group, trifluoromethyl group or fluorine,
A halogen atom such as chlorine, bromine or iodine, R2 is a lower alkyl group, N,N-dialkylaminoalkyl group or N-alkyl-N-(allylalkyl)aminoalkyl group, R3 is a lower alkyl group, R4 is a lower alkyl group, hydrogen atom,
It means an alkoxy group or a halogen atom such as fluorine, chlorine, bromine or iodine. ] 2-(β-allyl-β-hydroxyethyl) dihydropyridine derivative and its pharmaceutically acceptable salt (2) In the method for producing a compound represented by general formula (1), general formula (II) [formula Among them, R3 and R4 have the same meaning as explained in the above general formula (1). ] β-keto acid derivative represented by the general formula (II) [wherein, X, R+ and R2 have the same meanings as in the above general formula (■). ] A method of reacting a compound shown in ] with ammonia. '(3) In the method for producing a compound represented by general formula (1), general formula (IV) [wherein + R'3 and R4 have the same meaning as in the above description of general formula (1). ] and the general formula (
V) [In the formula, X and R1 have the same meanings as described in the above general formula (1). A method of reacting a compound represented by the formula (Vl) with a compound represented by the general formula (Vl) (wherein R2 has the same meaning as described for the general formula (I) above). (4) General formula (I) In the method for producing the compound shown in
General Formula (■) [In the formula, R2 has the same meaning as explained in the above general formula (I). ] A method of reacting a compound represented by the above general formula (■) and a compound represented by the above general formula (II).