JPS60214786A - 1,4-dihydropyridine compound - 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 Technical Field The present invention relates to novel 1,4-dihydropyridine compounds.

Object and Structure of the Invention The object of the present invention is to provide a novel 1,4-dihydropyridine compound. That is, according to the present invention, formula (1
) [wherein R is 2-(5,6-dihydro-p-dioxynyl), 2-(3,5-dimethyl-5,6-dihydro-p
-Dioxynylin, 2-(3-methyl-5,6-dihydro-p-dioxinyl), 2-(3-methoxymethyl-
5,6--jhydro-p-dioxynyl), 5-(3,
4-dihydro-2H-pyranyl) and 2-(5,6-cyhydro-1,4-dithinyl), R1 is methyl, methoxy, ethoxy, methoxymethyloxy, 2-methoxyethyloxy R2 represents hydrogen or methoxymethyl (provided that when R is 2-(5,6-dihydro-p-dioxinyl), R2 represents methoxymethyl; 2-(3,5-dimethyl-5,6-dihydro-p-dioxynyl), 2-(3-methyl-5,6-dihydro-p-dioxinyl), 2-(3-methoxymethyl-5,6- cyhydro p-nooxynyl), 5-(3
, 4-dihydro-2H-pyranyl) and 2-(5,6-
A novel 1,4-dihydropyridine compound is provided, wherein R2 represents hydrogen.

Detailed Description of the Structure and Effects of the Invention The 1,4-dihydropyridine compound represented by the above formula (1) is a novel compound that has not been described in any literature. As described below, these compounds have a remarkable hepatoprotective effect and are also low in toxicity, so they are useful compounds that are expected to be used as therapeutic agents for liver diseases in the future.

According to the present invention, among the compounds represented by the above formula (1), those having a particularly remarkable hepatoprotective effect have R of 2-(5
, 6-dihydro-p-dioxynyl), 2-(3,5-
dimethyl-5,6-sihydro-p-zooxynyl), 2
-(3-methyl-5,6-dihydro-p-dioxynyl), 2-, (3-methoxymethyl-5,6-dihydro-
p-dioxynyl) and 5-(3,4-dihydro-2H
-granyl), especially 1,2-(5,6-
dihydro-p-dioxynyl), 2-(3,5-dimethyl-5,6-dihydro-p-dioxinyl) and 2-(
3-Methyl-5,6-dihydro-p-dioxynyl, and R1 is either methyl or methoxymethyloxy. Compounds having these specific substituents have a more pronounced hepatoprotective effect than other compounds, as will be described in detail in the Examples below, and are particularly promising compounds as pharmaceuticals.

Any of the compounds represented by the above formula (1) can be produced using a well-known reaction that has been conventionally used in the production of 1,4-dihydropyridine.

For example, a compound in which R4 is a methyl group in formula (1) is an aldehyde represented by formula (It) R-CHO(II) [wherein R represents the same meaning as above]. Produced by heating or heating to reflux to react with penten-2-one and acetylacetone in the presence or absence of an organic solvent such as ethanol, n-prono, nor, isozolo/f-nor, or pyridine. (Method-A). In formula (1), R
Compounds in which 1 is a group such as methoxy, ethoxy, 2-methoxyethyloxy, etc. are prepared by treating the aldehyde represented by the above formula (n) with β-aminocrotonic acid ester and acetoacetate in the presence or absence of an organic solvent. The reaction is carried out by heating or heating under reflux (Method-B), or by the formula (
It is produced by reacting the aldehyde represented by If) with acetoacetate and aqueous ammonia by heating, preferably under reflux, in the presence or absence of an organic solvent (Method-C). In addition, the compound in which R1 is a methoxymethyloxy group in formula (1) can be prepared by the above method - BJ
Alternatively, in the same manner as Method-C, a 1,4-dihydropyridinated metal compound having 2-cyanoethyloxycarbonyl groups at the 3 and 5 positions is produced, and then this compound is hydrolyzed with sodium hydroxide etc. It is produced by reacting the resulting hydrolyzate with chloromethyl methyl ether in an organic solvent such as dimethylformamide (Method-D).

Furthermore, compounds in which R2 is a methoxymethyl group in formula (1) can be prepared by adding each target compound obtained by the above-mentioned method A to method in the presence of sodium hydride in an organic solvent. It can be produced by reacting the following with chloromethyl methyl ether (Method-E). These manufacturing methods (Methods A to E) are shown in the following reaction formula.

Method-A Method-B These production methods are essentially known reaction methods conventionally used for the production of 1,4-dihydropyridine compounds (for example, Japanese Patent Publication No. 46-40625, Japanese Patent Publication No. 56-37).
No. 225, JP-A-51-108075, JP-A No. 51-108075
Publication No. 3-92784, Publication No. 54-103876,
The method described in Japanese Patent No. 55-64570, Japanese Publication No. 55-89281, Japanese Publication No. 58-159490, etc.) is the same as the method described in Japanese Publication No. 55-64570, Japanese Publication No. 55-89281, Japanese Publication No. 58-159490, etc. Therefore, the compound of the present invention can be used in addition to the above-mentioned methods described in these known documents. It can also be manufactured by appropriately applying other methods described above.

The raw material compounds used in the above production method, except for some aldehydes, are all known compounds, and can be easily obtained or produced by painters as needed. Namely, acetoacetate, β-aminocrotonate, acetylacetone and 4-
All amino-3-4-ten-2-ones are compounds commonly used as raw materials for producing 1,4-dihydropyridine compounds, and can be obtained commercially or easily synthesized as needed. Furthermore, among the aldehydes represented by formula (II), 2-formyl-p-dioxycene is M, S, 5haatakovskii''.

Izvsat, Akad, Nauk, S, 8. S
,R,0tde1. Khim.

Nauk,, 1685. (1961) etc., from p-dioxycene to 2-ethoxy-3
-Jethoxymethyl-p-dioxane can be easily synthesized, and 5-formyl-3,4-dihydro-2H-1rane is synthesized by L, 5katteboel; J, Org.

Chem, 35. (9), 3200~1- (1
It can be synthesized by the method described in 970).

Furthermore, 2-formyl-3,5-dimethyl-p-dioxene is made from 2゜6-dimethyl-p-dioxene,
It can be produced by reacting this with dimethylformamide and phosphorus oxychloride and then hydrolyzing the resulting product. In addition, 2-formyl-3-methyl-p-dioxene is made from 2-methyl-p-dioxene, and 2-formyl-1,4-dichene is made from 1
, 4-dichene as a raw material by the same operation.

2-formyl-3-methoxymethyl-p-dioxene is converted from 2-formyl-p-zoxene through 2-hydroxymethyl-p-dioxene to 2-methoxymethyl-p-dioxene.
It can be synthesized by synthesizing dioxene and then treating this compound in the same manner as above.

According to the present invention, the reaction product produced above, that is, the compound of formula (1), can be separated from the reaction mixture and purified by conventional methods such as extraction with a solvent, chromatography, crystallization, etc. I can do it.

EXAMPLES Next, reference examples and examples will be shown, and synthesis examples of the compounds according to the present invention and the results of pharmacological tests conducted to confirm their usefulness will be explained, but the scope of the present invention is not limited to these. Needless to say.

Reference Example 1 35.9 g (0,234 mol) of phosphorus oxychloride was added dropwise to 62 g of 2-formyl-3,5-dimethyl-p-dioxylformamide under ice cooling, and then 2 ，
25.4 g of 6-dimethyl-p-dioxene (0,223
mol) was added dropwise at a temperature below 10°C, and the mixture was stirred at 30°C for 1 hour. Pour the obtained reaction solution into ice water 120.9 g,
The mixture was neutralized with a suspension of 110 g of sodium hydrogen carbonate and IQQ ml of water, extracted with chloroform, dried with Glauber's salt, and then the chloroform was distilled off to obtain 23.5 g of the target substance as an oil (yield: 74.21). . The analytical values for this substance were as follows.

NMR (CDCl2, TMS) δ: 1.33 (3H
, d, dioxene-5-CH,), 2.20 (3H, s
, Dioxycene 2 Synthesis of 2-formyl-3-methyl-p-dioxene Dimethylformamide 50ml 1S Phosphorus oxychloride 16.
51 nl (1,80 mol), and 2-methy/l/-p
-Dioxene 16.5. ji' (0,165 mol) and reacted in the same manner as in Reference Example 1 to obtain 18.2 g (yield: 86.21) of the target substance in the form of an oil.The analytical value of this substance was as follows. there were.

NMR (CDC1, TMS) δ: 2.20 (3H,
s, dioxetyl-3-CH3), 4.00-4.50
(4H, m.

017E! L-0), 9.47 (IH, s, CHO) Reference Example 3 Synthesis of 2-formyl-3-methoxymethyl-p-dioxene 2-formyl-p-dioxene 28.809 (0,25
mol) was dissolved in 250 ml of water, 2.50 g (0,066 mol) of sodium borohydride was added to this solution while stirring under water cooling, and the mixture was further stirred at room temperature for 10 minutes. After stirring,
Salt was added to this solution to make a saturated solution, and the mixture was extracted with chloroform. After drying the chloroform phase with Glauber's salt, the solvent was distilled off to obtain 29.16 g (yield: 99.5%) of oily 2-hydroxymethyl-p-dioxene. The analytical values of this substance were as follows.

Boiling point: 66°C (0.1 mmHg) NMR (CDCt, , TMS) δ: 2.30 (IH
, a, OH), CH2-0), 6.06 (IH111%
vinyl H) then 10% oily sodium hydride 10.0
g (0.25 mol) in dimethoxyethane 250-, 2-hydroxymethyl-p-dioxene 29.16
g (0.25 mol) was added dropwise at room temperature with stirring. After dripping,
This mixed solution was cooled, and 38.3.9 (0.25 mol) of methyl iodide with a purity of 93% was added dropwise to it while stirring under water cooling.
After the reaction was heated and stirred at 40°C for 16 hours, dimethoxyethane was concentrated, the concentrate was poured into water, and extracted with chloroform. The chloroform phase was dried over t-mirabilite, the solvent was distilled off, the residue was dissolved in acetonitrile, washed with n-hexane, and the acetonitrile was distilled off to give 28.70 g of oily 2-methoxymethyl-p-dioxene (yield: 87
．． 8%) was obtained. The analysis value of this substance was 9 as shown below.

Boiling point: 62.5°C (9mm Hg) NMR (CDC/!, 3, TMS) δ: 3.31
(3HXs, 0-CH5), 3-76 (2H-,
8% CH2-0-CH3), 4.07 (4H%
ms o-CH2-CH2-0), 6.08 (IH,!
+, vinyl H) Next, 37.19.9 (0.24 mol) of phosphorus oxychloride was added dropwise to 70-dimethylformamide while stirring under water cooling, and then 28.70 g (0.24 mol) of 2-methoxymethyl-p-dioxene was added dropwise to 70-dimethylformamide. , 22 mol) was added dropwise. The mixture was stirred for 1 hour while cooling with water, for 1 hour at room temperature, and then heated and stirred at 50° C. for 1 hour. After stirring, the reaction solution was cooled, poured into ice water, neutralized with sodium bicarbonate, and extracted with chloroform. After drying the chloroform phase with Glauber's salt, the solvent was concentrated to dryness and the residue was distilled under reduced pressure to obtain the target substance in the form of an oil (15.6
79 (yield 44.9%) was obtained. The analytical values of this substance were as follows.

Boiling point 288℃ (0.3mmHg) NMR (CDC/!, 3, TMS) δ' 3.42
(3H% s 10-CHs), 4, 22 (4H
, m, 0-CH2-CH2-0), 4.33 (2H
Xs, CH2-0-CH,), 9.61 (IH, s, C
HO) Reference Example 4 Synthesis of 2-formyl-1,4-dichene To 31.0Ji+ (0.42 mol) of dimethylformamide was added phosphorus oxychloride 2 while keeping the temperature of the solution at 0 to 5°C under water cooling and stirring.
2.2 g (0.14 mol) was added dropwise. Next, 1,4-dichene 16.6. ! ii! (0
, 14 mol) was added dropwise while keeping the temperature of the solution below 10° C., the temperature of the solution was gradually returned to room temperature, and the reaction was further stirred for 30 minutes on a 60° C. water bath to complete the reaction. After the reaction, the resulting reaction solution was poured into ice water, hydrolyzed with sodium bicarbonate, saturated with sodium chloride, and extracted four times with chloroform. After drying the chloroform phase with magnesium sulfate, the solvent was distilled off.
The obtained oily substance is distilled under reduced pressure to obtain an oily target substance 10.
8J9 (yield 52.6%) was obtained. The analytical values for this substance were as follows.

Boiling point: 123.5°C (0.7 Hg) IR&#KBrcm-': 1650 (C=0), 11
50 (co)ax NMR (CD, OD, TMS) δ: 3.25
(4H, m5ll-CH2-CH2-8), 7, 47 (IH, a, vinyl H), 9.20 (IHX
slCHO) Example 1 (synthesis example) a) 3,5-diacetyl-4-(2-(5,6-dihydro-p-dioxynyl)]-]2,6-dimethyl-1,
Synthesis of 4-dihydropyridi 2-formyl-p-nooxene 2.85N (0,025 mol), acetylacetone 2
．． 50 g (0,025 mol) and 2.489 (0,025 mol) of 4-amino-3-penten-2-one were mixed, and the mixture was heated and stirred at 110° C. for 24 hours. After cooling, the reaction mixture was chromatographed on a 15 g column of 7 liters (developing, eluent: chloroform:ethyl acetate = 5:1).
After purification using a mixed solvent of V/V), recrystallization from inzorotsuknol yielded 0.97 g (yield 14.0%) of the target substance in the form of pale yellow crystals. The analytical values of this substance were as follows.

Melting point: 186.0-187.0°C IR Si KB'cm-': 3260 (NH), 16
60 (C=C), ax 1230 (C-0), NMR (CDC1,, TMS) δ: 2. '30 (
6H,s, 2.6-CH5), 2.34(6H,II,
2 x C0CH,), 3.93 (4H.

s, O-C CH, -0), 4.50 (I H, 8
, 4-H), 5.75 (IHXs, vinyl H), 7.3
5 (lH%br, NH) Elemental analysis value (as C45■I1.NO4) Calculated value:
C, 64,97; H, 6,91: Nv5. o5(%
) Experimental value: C, 65,09: H, 6,80; N, 4.
90(9)) b) 3,5-noacetyl-4-[2-(5
, 6-dihydro-p-dioxynyl): ]-] Synthesis of 1-methoxymethyl-2,6-nomethyl-14-dihydropyridine Suspension of 25 rILl of dimethoxyethane and 0.40 g (0.01 mol) of 60% oily sodium hydride 3,5-Diacetyl-4-[2-(5
,6-dihydro-p-dioxynyl)-2゜6-dimethyl-1,4-dihydrogiridine 1,0g (0,003
After stirring for 30 minutes under water cooling, 0.81 g (0.01 mol) of chloromethyl methyl ether was added dropwise little by little, and the mixture was further stirred at room temperature for 2 hours. After the reaction, dimethoxyethane was distilled off under reduced pressure, and the obtained crystals were washed with ether and recrystallized from a mixed solvent of n-hexane and methylene chloride, yielding 0.50 g of the target substance as yellow crystals (
A yield of 43.1%) was obtained. The analytical values for this substance were as follows.

Melting point: 126.0-127.5°C IRj/KBri': 1660 (C=C), 1
645 (C=C), ax 1220 (C-Q)' NMR (CDC13, TMS) δ: 2.35 (
6H% m, 2.6-CH5), 2.37 (6H,s,
2 X C0CH5), 3.33 (3n% 8-,
cH2-o-C5), 3.90 (4H% 11.0-
CH-CH2-0'), 4.43 (I H,!1.4
-H), 4.73 (2HXa 1N-CH2-0),
5.67 (IH, s, vinyl H) Elemental analysis value (as C17■23N05) Calculated value: C,
63,54;H, 7,21:N, 4.3 Experimental value: C
,63,61SR,7,23:N,4.53(Working margin Example 2 (Synthesis example) a) 4-[:2-(5,6-dihydro-p-dioxynyl)]-]2.6 -Nomethyl-1,4-dihydropyridine 3,5-dical? Synthesis of bis(2-cyanethyl)ester 2-formyl-p-zoxene 2.309 (0,02
mol), acetoacetic acid 2-cyanoethyl ester 5.80
．． @ (0,037 mol), and 28 thiammonia water 3.
It was dissolved in 5dt-inzolopanol 30- and heated under reflux for 24 hours. After cooling, the reaction solution was concentrated, and the precipitated crystals were collected by filtration. When these crystals were recrystallized from ethanol, 2.76 g of the target substance was obtained as pale yellow crystals (yield: 35.3%).
)was gotten. The analytical values of this substance were as follows.

Melting point: 135.5-137.0°C 1695 (C=0), 120-0 (C-0), 1120
(C-O) NMR (CD, OD, TMS) δ: 2.31
(61(+me2+6-CHs)+2,
75 (4H, t, 2XCOO-C1(woo-CH,
-CN).

3-93 (4H, s, O-CH2-CH2-0)
, 4.34 (4H.

t, 2XCOO-CH, -CH2-CN), 4
．． 45 (IH, 8, 4-H).

5.91 (IH, s, vinyl H), 6.32 (IH, b
r, NH) elemental analysis value (as C1, H21N3o6)
Calculated values: C, 58,91; H, 5,46; N, 10.
85 (%) Experimental value: C, 58,67; H, 5,55;
N, 10.85@) b) Synthesis of 4-(2-(5,6-dihydro-p-diodimethyl)ester 4-[:2-(5,6-dihydro-p-dioxynyl)
)-2,6-dimethyl-1,4-dihydropyridine-3
, 3.30 g (8.52 mmol) of 5-dicarboxylic acid bis(2-cyanethyl) ester in dimethoxyethane 1
5 of water and 17.1 N of aqueous 1N sodium hydroxide solution were added, and after stirring at room temperature for 1 hour, 30
The solvent was distilled off under reduced pressure on a water bath at .degree. Next, anhydrous dimethylformamide was added to the obtained residue, and the suspension was stirred.
5 mmol) was added thereto, and the mixture was stirred at room temperature overnight. Then,
The solvent was concentrated, ethyl acetate was added to dissolve, washed with water, dried over Glauber's salt, and then the solvent was distilled off. 50 silica dal for the residue
Chromatography using a column of g [Development, eluent; n
- mixed solvent of hexane:ethyl acetate = 1:1 (V/V)] to obtain crystals. When this crystal was recrystallized from ethanol, the desired substance was found as a white crystal with a concentration of 0.81%.
9 (yield 25.7%) was obtained. The analytical values of this substance were as follows.

Melting point: 105.5-106.5°C 1660 (C=C), 1200 (C-0), 10710
75(C-0)N CDC15, TMS) δ:2.3
3(6H,s,2,6-CH5)13.48(6H11
1,2×0-CH6), 3.93 (4H, s.

0-CH2-CH2-0), 4.53 (IH, 8
, 4-H), 5.23.

5, 39 (4H, AB q , J = 6.6 Hz
, 2XO-CH2+CHs).

5.93 (IH, s, vinyl H), 6.15 (IH, b
r, NH) Elemental analysis value (as C17H23NO8) Calculated value: C, 55,38: H, 6,28; N, 3.7
9) Experimental values: C, 55, 44: H, 6, 24: N,
3.90(1)c) 4-(2-(5,6-dihydro-p-dioxynyl)]-]1-methoxymethyl-2,
Synthesis of 6-nomethyl-14-dihydropyridine-3,5-dicarboxylic acid bis(methoxymethyl) ester (4-C2-C5,6-sihydro-P-dioxynyl)
)-2,6-dimethyl-1,4-dihydropyridi7-3
95-dicarboxylic acid bis(methoxymethyl)ester 2
．． 6.9 (7.04 mmol) in dimethoxyethane 30
0.48 g (12 mmol) of 60% sodium hydride was added to this solution under ice-cooling and stirring, and the mixture was further stirred at room temperature for 20 minutes. Next, this solution was stirred again under water cooling, and 1.0% of chloromethyl methyl ether was added into the solution.
A solution of 0p (12.4 mmol) dissolved in 10 m of dimethoxyethane was added dropwise, and the mixture was further stirred under water cooling for 30 minutes. After the reaction, dimethoxyethane was distilled off under reduced pressure, and ethyl acetate was added to the residue, which was washed with water, dried over sodium sulfate, and then the solvent was distilled off. The residue was developed by chromatography on a 7 liter 100 g column.

Eluent; n-hexane: ethyl acetate = 1:1 (V/V
)] to obtain crystals. When this crystal was recrystallized from ether, the desired substance 1.1 was found as a white crystal.
9g (yield 4o, 9%) was obtained. The analytical values of this substance were as follows.

Melting point near 8.5-80.0℃ IRvK"m-': 1705 (C=0), 1680m
&X (C=C), 1635 (C=C), 1140 (C-O
) NMR (CDCt, , TMS) δ: 2.49
(6H,s,2-6-CHs).

3.34 (3H-s, N-CH2-0-CHs)
, 3.48 (6H, s.

2 X Coo-CH2-0-CH,), 3.90
(4H, 8.

0-CH-CH-0), 4.63 (IH, 8, 4-H)
, 4.74 (2H, tr, N-CH2-0) -5,
25, 5, 38 (4H, ABq −J = 6.04H
z , 2 X coo -CH2-0-CH3) , 5
-83 (I H-S# Vinyl H) Elemental analysis value (c, as 9H27NO9) Calculated value:
C,55,20:H,6,58;N,3.39 (1) Experimental value: C,55,28:H,6,57:N,3.48
(a) Example 3 (synthesis example) 3,5-diacetyl-2,6-nomethyl-4-(2-(
Synthesis of 3,5-trimethyl-5,6-dihydro-p-dioxynyl)-1,4-dihydropyridine 2-formyl-3,5-dimethyl-p-zoxene2.
841 (0.02 mol), acetylacetone 2.009
(0.02 mol), and 4-amino-3-pentene-
3.0 g (0.03 mol) of 2-one was dissolved in Ingrocnol 20d, and a sealed tube reaction was performed at 165° C. for 72 hours. After cooling, the reaction solution was concentrated to dryness, the residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate, and then the solvent was distilled off to crystallize. The obtained crystals were washed with cold diethyl ether and recrystallized with ethyl acetate to obtain 0.74.9 of the target substance as pale yellow crystals. The analytical values of this substance were as follows.

Melting point: 177.5-182.5°C 1590 (C=C), 1220 (C-0) NhlB-(
CDCt3-TMS) a: 1.13 (3H
, d , ); k Kisey-5-CH3) 11.90
(3H18j Zooxe/-3-CH3).

2.27 (6H,s, 2XCOCH,), 2.30 (6
H, s, 2.6-4.63 (IH,!1.4-H), 6
．． 50 (IH, br, NH) elemental analysis value (C47H2,
(as NO4) Calculated value: C, 66, 86: H, 7, 5
9: N, 4.59 (g) Experimental value: C', 66.92:
H, 7,44; N, 4.70 (a) Practical row 4 (synthetic row) 2.6-trimethyl-4- (2-(3,5-trimethyl-
5,6-dihydro-p-dioxynyl)]-1,4-dihydropyrinone-3,5--/Synthesis of cargenic acid dimethyl ester 2-formyl-3,5-tmethyl-p-dioxene2.
84 g (0.02 mol), acetoacetic acid methyl ester 4
．． 64 g (0.04%), and β-aminocrotym
Mix 2.30 g (0.02 mol) of methyl ester,
The mixture was heated and stirred at 120°C for 6 hours and then at 140°C for an additional 2 hours. After cooling, the reaction mixture was purified using Chromadog, 7F [developing, eluent; mixed solvent of benzene:ethyl acetate = 4:i (V/V)] using a 200 g column of silica gel, and then crystals were extracted with diethyl ether. Upon heating, 1.28p of the target substance in the form of pale yellow crystals was obtained. The analytical values for this substance were as follows.

Melting point: 153.5-157.5°C =C), 1640 (C=C), 1210 (C-0)NM
R(CDC/=, , TMS)δ: 1.17(3
H, d, nooxene-5-Ci (3), 1.90 (3
H,it, dioxene-3-C)I, ).

4.67 (IH, s, 4-H), 6.00 (if (, b
r, NH) Elemental analysis value (as C17H23N06) Calculated value: C+60.52; Ht6.87; Nt4.15
(a) Experimental value: C, 60, 24; H, 6° 78: N,
4.33 J) Practical row 5 (synthetic row) a) 2,6-nomethyl-4-(2-(3,5-trimethyl-5,6-dihydro-p-dioxynyl)]-]1.4
--/hydropyridine-35-dicargenic acid bis(2-
Synthesis of cyanoethyl) ester 2-formyl-3,5-
Dimethyl-p-dioxene 1.42. @ (10.0 mmol), acetoacetic acid 2-cyanoethyl ester 1.6
0 g (10.3 mmol) and 1.60 J7 (10.4 mmol) of β-aminocrotonic acid 2-cyanoethyl ester were heated and stirred at 100° C. for 16 hours. After cooling, the reaction mixture was chromatographed on a 200 g silica column (developing, eluent: n-hexane:ethyl acetate=
1:1 (V/V) mixed solvent] to obtain an oily target substance 2.02.9 (yield: 48.6 cm). The analytical values of this substance were as follows.

1725 (C=C), 1120 (C-0) NMR (CD
Ct, TMS) δ: 1.13 (3H, d, dioxene-5-CH3), 1.93 (3H-s-dioxene-3-CH3).

2.30(6H,5e2e6-cH3)t2.73(4
H, t, 2XCOO-CH2-CH-CN), 3.
20-4.10 (3H, m.

4.61 (LH, 8, 4-H), 6.33 (LH, br
, NH) b) 2,6-nomethyl-4-(2-(3,5-
dimethyl-5,6-dihydro-p-dioxynyl)]-
] Synthesis of 1,4-dihydropyridine-3,5-nocaldic acid 2,6-nomethyl-4-(2-(3,5-dimethyl-5
,6-dihuman90-p~dioxynyl)]-]1,4-
Dihyropyridine-3.5dicardoic acid bis(2-cyanethyl) ester 2.02. Li+ was dissolved in 1 liter of dimethoxyethane (N++ liter), 25 liters of water and 9.6 liters of a 1N aqueous sodium hydroxide solution were added, and after stirring at room temperature for 5 hours, the reaction solution was washed 5 times with nochloromethane. Add 1N hydrochloric acid to the reaction solution, filter out the precipitated crystals, wash with water, and dry to give 0.51.9 (yield 33.9%).
) was obtained. The analytical values of this substance were as follows.

=C), 1210(C-0) c) 2*6-nomethyl-4-[2-(3,5-dimethyl-5,6-dihydro-p-dioxynyl)]-]1,4
-dihydropyridine-3.5 radical? Synthesis of 2.6-dimethyl-4-(2
-(3,5-dimethyl-5,6-dihydro-p-dioxynyl)]-]1,4-dihydropyridine-3.5nocargenic acid 1.16p (3,75 mmol) ozomethoxyethane 15+/ and dimethylformamide 0.9 (1 (8.91 mmol) of triethylamine and 0.7018.70 mmol of chloromethyl methyl ether) were added dropwise to this suspension under stirring while cooling with water, and Stirring was performed for hours. After the reaction, the solvent was distilled off under reduced pressure on a water bath at 30°C, and the resulting residue was dissolved in ethyl acetate, washed with ice water, dried over Glauber's salt, and then the solvent was distilled off. The obtained residue was subjected to chromatography on a Silica Dull 709 column [development, eluent; mixed solvent of n-hex/:ethyl acetate = 1:1 (V/V)] to obtain crystals. When these crystals were recrystallized from diethyl ether, 0.43 g of the target substance was obtained as white crystals (yield: 28.8 To
)was gotten. The analytical values of this substance were as follows.

Melting point near 9.5-81.5℃ =0), 1650 (C=C), 1200 (C-0)=
NMR (CDC43, TMS) δ: 1.13 (3H
,d, dioxene-5-aH3), 1.95 (3
Hes-dioxene-3-CH,).

4.70 (IH, s, 4-H), 5.27 (4H2s,
2XCOO-CH2-0), 5.90 (I H, b
r, NH) Implementation row 6 (synthesis row) 3.5-diacetyl-2,6-nomethyl-4-(2-(
3-Methyl-5,6-dihydro-p-dioxynyl))
-1,4--,'Synthesis of hydropyridine 2-formyl-3-methyl-p-nooxene 12.89
(0,1%), 17tyl acetylO,Og(o,
i mol), and 4-amino-3-penten-2-one 1
0.0 g (0.1 mol) of isoderonol()-30t
/ and subjected to a sealed tube reaction at 160°C for 15 hours.

After cooling, the reaction solution was concentrated to dryness and crystallized. The obtained crystals were washed with diethyl ether and then recrystallized with ethanol to obtain 2.62p of the target substance as pale yellow crystals. The analytical values of this substance were as follows.

Melting point: 201.5-203.0°C 1590 (C=C), 1220 (C-0) NMR (DM
SO-d6, DSS) a: 1.83 (3H, s
,) O#7-3-CHs) ,2.20 (12H
1s, 2.6-CI (3゜2 x C0CH5)
, 3.80 (4H,3,0-CH,-CH,-0)
.

4.53(IH=s-4-H)-8,53(IH,br
, NH) Example 7 (Synthesis Example) 3.5-cyacetyl-4-(2-(3-methoxymethyl-5,6-dihydro-p-dioxynyl)]-]2,6
Synthesis of -nomethyl-1,4-dihydropyridi 3.55 g of 4-amino-3-penten-2-one (0,
034 mol), acetylacetone 3.38. p(0,0
34 mol), and 2-pormyl-3-methoxymethyl-
3.56 Ji' (0,023 mol) of p-dioxene was dissolved in 10 tnl of isopro/4'/- and heated in a sealed tube at 120°C for 16 hours. After cooling, the reaction solution was concentrated to dryness, and the residue was chromatographed (developed, eluent: ethyl acetate) on a 30 og column of silica dal.
After the preparation, recrystallization with a mixed solvent of ethanol and diisopropyl ether yielded the desired substance as yellow crystals with a concentration of 0.70
1 was obtained. The analytical values of this substance were as follows.

Melting point: I 59.0-160. OC IRp””z-1: 3370 (NH), 166
5 (Cax ==Q) * 1210 (C-0) NMR (CDC13, TMS) δ: 2.27 (6
H, sa2-6-CH5).

2.32 (6H,s, 2XCOCH3), 3.35 (3
H,g.

0-CF(,), 3.89 (4H,8,0-CH
, -CH, -0), 4.17(2H,8,CH2-
0-CH3) t4.80 (IH, s, 4-H).

6.74 (IH, br, NH) Elemental analysis value (as C17H2, No5) Calculated value: C
,63,54:H,? , 21; N, 4.36 (4) Experimental value: C, 63, 26;) I, ? , 30; N, 4.58
Example 8 (synthesis example) 3.5-diacetyl-4-(5-(3,4-dihydro-
Synthesis of 2H-pyranyl)-2,6-dimethyl-1,4-dihydropyrinone 5-formyl-3,4-dihydro-2H-pyran8.8
9p (79.3 mmol), acetylacetone 8.3
5.9 (83.4 mmol), and 4-amino-3-
8.20 g (82.7 mmol) of penten-2-one was dissolved in pyridine 100- and heated under reflux for one week. After cooling, the reaction solution was concentrated, and the residue was chromatographed on a 500 g column of silica dal (developing, eluent: n-hexane:ethyl acetate = 1 (V/V) mixed solvent) to obtain crystals. When this crystal was recrystallized from ethanol, 0.89 g of the target substance in the form of pale yellow crystals was obtained. The analytical values of this substance were as follows.

Melting point: 192.0-192.5°C Br IRν cm-': 3280 (NH), 164
0 (C=0).

ax 1220 (C-0) NMR (CDC43, TMS) δ: 1.70-1.9
0 (4H, m, dihydrobilane-al 4-CH2)
+ 2-27 (6H, s 1216-CH3) 1
2.30 (6H,s, 2XCOCH3), 3.
70-3.95 (2H, m.

dihydrobilane-2-CH2), 4.35 (IH2
g, 4-H).

6.34 (IH, s, vinyl H), 6.57 (IH, b
r, NH) Elemental analysis value (as C46H21N03) Calculated value: C, 69,79; ) I, 7.69: N
, 5.09 (capital) experimental value: C, 69, 77; H,
7°62; N, 5.20) Example 9 (Synthesis Example) 3,5-Cyacetyl-4(2-(5,6-cyhydro-1,4-dithinyl)]-]2,6-cymethyl-1 ．．
Synthesis of 4-dihydropyridi 2.97 g (20.3 mmol) of 2-formyl-1,4-dichene, 2.25 g (22.5 mmol) of acetylacetone, and 4-amino-
2.20.9 (22.2 mmol) of 3-penten-2-one was dissolved in birinone 40- and heated under reflux for 48 hours.

After cooling, the reaction solution was concentrated to dryness, and the residue was crystallized from ethyl acetate to obtain yellow crystals. This crystal is converted into ethyl chloride. ? r Shito, the target substance of Fukaredan in the past 0.
96II was obtained. The analytical values for this substance were as follows.

Melting point: 206.5-208.0°C Br IRν cm-': 3280 (NH), 166
0 (C=0).

aX 1640 (C=C), 1220 (C-0) NMR (CD
Cl2. TMS) δ: 2.33 (6H,s, 2.6-
CHρ.

2.36 (6H, s -2-X C0CH5) , 3
．． 06 (4H, s, 5-C)12-CH2-8)
, 4.70 (IH, 8, 4-H) , 5.93 (I
H.

B, vinyl H), 6.97 (IH, br, NH) elemental analysis value (as C15H1, N02S2) calculated value: C,
5B, 22; H, 6, 19; N, 4.53; S,
20.72 (%) Experimental value: C, 5B, 19; H, 6, 1
9; N, 4.67: S, 20.50 (%) Example 10 (
Test Example) Test of the effect of the compound of the present invention on liver damage caused by carbon tetrachloride 5 LC-Wistar male rats (9 weeks old, body weight 22
Carbon tetrachloride and the test drug were administered to each group of 5 animals (0 to 240 g) in the manner described below, and the effects were determined by collecting blood and measuring GOT, GPT, AtP, and bilirubin, which are indicators of liver damage. did.

The test drug was suspended in 0.1% Tween-80 at a ratio of 404 N and orally administered at a ratio of 200 N at 25 and 1 hour before administration of carbon tetrachloride. However, 0.1% Tween-80 was orally administered in the same manner at a rate of 5 doses to the group administered with 4-carbon alone.

Carbon tetrachloride was administered intraperitoneally as a 1o% (v/v) olive oil solution at a rate of 5 ml (0.5 ln as carbon tetrachloride, 17 kg) 1 hour after the final administration of the drug.

In addition, the control group (normal) received 5 rrd17 olive oil.
Similarly, the drug was administered intraperitoneally at a ratio of 9 to 9.

Blood was collected from the carotid artery under bentoharbital anesthesia 24 hours after the administration of carbonate (however, the animals were fasted for 18 to 22 hours before blood collection).

Next, the collected blood was allowed to stand at room temperature, and then the serum was separated.

GOT and GPT in serum are measured by UV method.
tP was measured by the Bessy-Lowry method, and bilirubin was measured by the diazo method. The results are shown in Table 1. The test drugs A to C are as follows.

A: Compound of Example 3 B: Compound of Example ρ18 C: Compound of Example 9 Space below Example 11 (Test Reli) Test of the effect of the compound of the present invention on liver damage induced by carbon tetrachloride 8LC-Wl The test was conducted in the same manner as in Experiment 9110, except that 8 male and female Star rats (1 weight: 170 to 210 g) were used. The results are shown in Tables 2 and 3. The test drug D-I is as follows.

D: Compound of Example ib) E: Compound of Example 2c) F: Compound G of Example 5c) Compound H: Compound of Example 17 I: Compound of Example 6 Reli 12 (test row) Acute toxicity test of compounds of the present invention Test drugs (test drugs A, D, and H used in Example 10 and Example Row 11) were administered to 5LC-Wistar male rats (
After oral administration to 5 withdrawals (1 weight 100-125 g),
After one week of follow-up, LD5. The values were calculated and the following results were obtained.

A: LD5o=2 U 9 or more D in 00hr9/
: LDso = 9 or more in 1500IQ/H: LDi
o=2000'? As is clear from the test examples of A9 and above, the compound of the present invention is effective in treating and preventing liver damage induced by carbon tetrachloride, etc., and has low toxicity, so it can be used to treat liver diseases caused by various causes. It is a useful compound that is expected to be used as a therapeutic drug.

1. Indication of the case 1982 Patent Application No. 66675 2. Name of the invention 1.4-dihydropyridine compound 3. Person making the amendment Case Relationship Patent applicant name Nikken Kagaku Co., Ltd. (1 other person) 4. Agent address Shizuko Toranomon Building, 8-10 Toranomon-chome, Minato-ku, Tokyo 105 Telephone (504) 0721 5. Specification subject to amendment Column 6 of "Detailed Description of the Invention", Contents of Amendment (1) Page 6 of the Specification, Lines 7-8 [(3-Methyl-5,6
-dihydro-p-dioxynyl" to r(3-methyl-5
, 6-dihydro-p-dioxynyl)J.

(2) Page 12, line 3 r 5hastakovski
Correct i J to ' 5hostakovskii J.

(3) On page 16, line 6, ``10%'' is corrected to ``60%J.''

(4) Correct page 17, line 2 rcH20-CH3J to "Inhong-0-CH3J.

(5) Same page 18, lines 19-20 rs-CL1-CH1
Correct 2SJ by 'S CH2C% SJ.

(6) On page 21, line 12, ro C112-C02-〇” is corrected to “0-Ckin-Cblood-O”.

(7) Same page 23 line 6 rlO, 85J '10.58
Correct to J.

(8) Page 24, line 12 rl 695 (C=O)
Correct J to '1695 (C=O)J.

(9) Same page 24 bottom line r55.38J '55.28
Correct to J.

(10) Page 26, line 16 r 2 X COOC11
2-〇-(JI3J' 2 XCOO-CLL OC
H3J d correction.

(11) Page 35, line 17 rc412 0 CH3J
Correct to "C抛-〇-CH5J.

that's all

Claims (1)

[Claims] 1. Formula (1) [wherein R is 2-(5,6-dihydro-p-dioxynyl), 2-(3,5-dimethyl-5,6-dihydro-p
-dioxynyl), 2-(3-methyl-5,6-dihydro-p-dioxynyl), 2-(3-methoxymethyl-
5,6-dihydro-p-dioxyel), 5-(3,4
-dihydro-2H-pyranyl) and 2-(5,6-sihydro-1,4-dithinyl), and R1 represents methyl, methoxy, ethoxy, methoxymethyloxy and 2-methoxyethyloxy. R2 represents hydrogen or methoxymethyl (provided that when R is 2-(5,6-dihydro-p-dioxynyl), R2 represents methoxymethyl; -(3,5-dimethyl-5,6-dihydro-p-dioxynyl), 2-(3-methyl-5,6-dihydro-p-zooxynyl), 2-(3-methoxymethyl-5,6-dihydro- p-dioxynyl), 5-(3
, 4-dihydro-2H-pyranyl) and 2-(5,6-
1,4-dihydropyridine compounds represented by the following formula: (1,4-dithinyl), R2 represents hydrogen. 2, R is 2-(5,6-dihydro-p-dioxynyl)
The 1,4-dihydropyridine compound according to claim 1, wherein R1 is a group selected from methyl and methoxymethyloxy, and R2 is methoxymethyl. 3, R is 2-(3,5-dimethyl-5,6-dihydro-
p-dioxynyl) or 2-(3-methyl-5,6-
The 1,4-dihydropyridine compound according to claim 1, wherein R is methyl or methoxymethyloxy (J), and R2 is hydrogen. 4, R is 2-(3,5-tumethyl-5,6-dihydro-
p-dioxynyl), 2-(3-methyl-5,6-dihydro-p-dioxynyl), 2-(3-methoxymethyl-5,6-dihydro-p-sooxynyl) and 5-(3
, 4-dihydro-2H-pyranyl), 9, R1 is methyl, and 9, R2 is hydrogen.