JPS6045575A - 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 An object of the present invention is to provide a novel 1,4-dihydropyridine compound. That is, according to the present invention, the following formula (1) [wherein R4 represents a cyan group or a substituted carbonyl group represented by -Co-R,', where R4' represents methoxymethyloxy, 1- 1 of the dish-transformed ogish group consisting of methyl-2-methoxyethyloxy and 2-cyanoethyloxy
), R2 is a cyan group or a substituted group represented by -CO-R2' is a nyl group (herein, R2' is a methyl group, or methoxy, methoxyethyloxy, 2-methoxyethyloxy, 1- A novel 1,4-dihydropyridine compound is provided, which is represented by one of the substituted oxy groups consisting of methyl-2-methoxyethyloxy and 2-cyanoethyloxy)].

All of the 1,4-dihydropyridine compounds represented by the above formula (1) are novel compounds that have not been described in literature. As described below, these compounds have a remarkable liver preserving 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.

The 1,4-dihydropyridine compound represented by the above formula (1) can be produced by the method described below.

That is, in the case of a compound in which R1 and R2 are both cyano groups in formula (1), 2-formyl-
By reacting p-dioxene and β-aminocrotononitrile in acetic acid (method 1)! l11! can be built. In addition, in the case of a compound in which R1 is a cyano group and the substituted carbonyl group of R2 is an acetyl group in formula (1), 2-formyl-p-dioxene, β-
Produced by heating aminocrotononitrile and hyacetylacetone in the presence or absence of an organic solvent such as ethanol, n-gropanol, isoproieol, pyridine, etc., preferably by heating and refluxing to cause a reaction 2). be able to.

Further, in formula (I), R1 is a cyano group and tq of R2
In the case of a compound in which the m carbonyl group is a substituted oxycar group, 2-formyl-p-dioxene, β
It can be produced by reacting -aminocrotononitrile and acetoacetate by heating or heating to reflux in the presence or absence of an organic solvent (method 3) in the same manner as method 2 above.

Furthermore, in formula (1), R, is a substituted carbonyl group and R
Substitution Cal yJ of 2? In the case of a compound in which the nyl group is an acetyl group, 2-formyl-p-dioxene, acetoacetate and 4-amino-3-penten-2-one are added in the same manner as above in the presence or absence of an organic solvent. It can be produced by heating or heating to reflux to react (Method 4). Also, in the formula (D, R1
In the case of a compound in which the substituted calyt = "nyl group and the fff of R2, the substituted calhonyl group is a substituted oxycar as a nyl group, 2-formyl-p-dioxene, acetoacetate, and β-aminocrotonic acid The ester is reacted by heating or heating under reflux in the presence or absence of an organic solvent in the same manner as above (Method 5), or 2-formyl-
Heating p-dioxene, acetoacetate and aqueous ammonia in the presence or absence of an organic solvent in the same manner as above,
Alternatively, it can be produced by heating under reflux (Method 6). However, in formula (1), R1 and/or R2
In the case of a compound in which methoxyethyloxycar is a nyl group, use methods 3 to 6 above to obtain a compound in which R1 and/or R2 is a nyl group in 2-cyanoethyloxycarboxylate, which is the object compound of the present invention. (method 3' to method 6). ') can be produced in particular.

These manufacturing methods (methods 1 to 6 and method 6/) are shown in the following reaction formula.

Method 1 Method 2 Method 3 Method 4 CHO Method 5 CHO Method 6 ■ ■ (These production methods are essentially known reaction methods conventionally used for the production of 1,4-dihydrogiridine compounds, such as special Publication No. 46-40625, Publication No. 56-3
It is the same as the method described in JP-A No. 7225, JP-A No. 51-108075, JP-A No. 53-92784, JP-A No. 54-103876, JP-A No. 55-64570, JP-A No. 55-89281, etc. Therefore, the compound of the present invention can be produced by appropriately applying other methods described in these known documents in addition to the above-mentioned method.

All of the raw material compounds used in the above production method are known compounds, and can be easily obtained or produced by those skilled in the art as needed. That is, β−
Aminocrotononitrile, ace)acetic acid 9 ester, β-aminocrotonic acid ester, acetylacetone, and 4-amino-3-penten-2-one are all compounds commonly used as raw materials for the production of 1,4-dihydropyridine compounds. It can be obtained as a commercially available product or easily synthesized as needed.

Moreover, 2-formyl-p-dioxene is M, S.

5hosLalcovalcii, Izveat, A.
kad, Nauk, S, S, S, R-OLdel, Kb
It can be synthesized from p-dioxene via 2-ethoxy-3-jethoxymethyl-p-dioxane by the method described in J.I.M., Nauk, 1685, (1961).

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

EXAMPLES Next, Examples will be given to explain synthesis examples of compounds according to the present invention and the results of pharmacological tests conducted to confirm their usefulness.

Example 1 (synthesis example) 3.5-dicyano-4-1:2-(5,6-cyhydro-p-diogycinyl)-2,6-dimethyl-1.4-
Synthesis of dihydropyridine 7.72 g of β-aminocrotononitrile with a purity of 85φ (
0.08 mol) is added to 20 ml of acetic acid to form a solution.

Separately, 2-formyl-p-dioxene 4.569 (0,0
A solution of 4 mol) dissolved in 8 tall acetic acid was prepared,
This was added dropwise to the above solution while stirring and keeping the temperature below 20°C. After the dropwise addition, the temperature of the reaction solution was raised to 60° C., stirred for 5 minutes, and after cooling, the reaction solution was condensed to dryness. 7 left
U was dissolved in ethyl acetate, washed with deuterated water and water, dried over Glauber's salt, and then the solvent was distilled off.

The residue was chromatographed on a 160 g column of silica gel [Development, eluent: chloroform:ethyl acetate-3:
1 (v/v) of a mixed solvent] and then recrystallized twice from ethanol to obtain 2.06 N (yield: 21.2 qb) of the desired substance as white crystals. The analytical values for this substance were as follows.

Melting point: 212.0-213.5°C IRν”Brc+++-’: 3400 (NH),
3260 (NH).

2210 (CN) +' 1660 (C=C) NMR (
DMSO-d6. DSS) δ: 2.01 (6H,s
, 2.6-CI(3), 3.70(IH,s,4-H
), 4.01 (4H, s.

0-CH,,-C) 1 person-〇), 6.09(IH,a
, vinyl H).

9.30 (IH, br, NH) Elemental analysis value (as C14H13N302) Calculation part: C
,64,19:H,5,39;N,17.27(%)Experimental value:C,63,92;H,5,46:N,17.01
(%) Example 2 (synthesis example) 3-acetyl-5-cyano-4-(2-(5,6-dihydro-p-dioxynyl)')-2,6-dimethyl-1
, 4-dihydropyridine 1939 (0.02 mol) of β-aminocrotononitrile with a purity of 85%, 1.93 g (0.02 mol) of acetylacetone, and 2.289 g (0.02 mol) of 2-formyl-p-dioxene. mol) was dissolved in isopropanol 1QmJ and heated under reflux for 3 hours. After cooling, the reaction solution was concentrated to dryness, and the residue was purified with silica gel 3.
After purification by chromatography [development, eluent; mixed solvent of chloroform:ethyl acetate-3:1 (v/v)] using a 00 g column, crystallization was performed using a mixed solvent of diethyl ether and diisozorobyl ether. did. When this crystal was recrystallized from ethanol, 0.82 g of the target substance in the form of pale yellow crystals was obtained. The analytical values for this substance were as follows.

Melting point: 172.0-174.0°C I RJ'''cm-': 3280 (NH),
2200(CN), 1(i80(C=C) tJr+iR(DMS O-d 6.D S S ) δ
: , 2.06 (311, s I6-CI(3).

2.20 (6H, s 12-CHs , CO-CH5
), 3.97 (511, s.

4, -H,0-CI-I2-CH2-0), 5.9
4 (I H, [1, Vinyl H).

9.20 (IH, br, NI () Elemental analysis value (as C14H16N203) Calculated value: C
,64,60;I(,6,20:N,10.76(chi)
Experimental value: C, 64, 44, H, 6, 19:N, 10.8
2(H) Example 3 (Synthesis Example) 5-cyano-4-(2-(5,6-cyhydro-p-diogycinyl))-2,6-dimethyl-1,4-dihydropyridine-3-calanoic acid methyl ester Synthesis of 579 g of β-aminocrotononitrile with a purity of 85 tons (0
, 06 mol), acetoacetic acid methyl ester 696 g (0
,06 mol) and 2-formyl-p-dioxene 6.8
49 (0.06 mol) in Impropatool 30ml
The mixture was dissolved in water and heated under reflux for 16 hours. After cooling, the reaction solution was dried to 8M, and the residue was purified by chromatography using a column of 280 g of silica gel (developing, eluent: chloroform:methanol = 80:1 (mixed solvent of v7')), and then purified with acetic acid. Recrystallization from ethyl yielded 1.04 g of the target substance as pale yellow crystals.The analytical values of this substance were as follows:0 Melting point: 185.5-187.0°C IRvKBrcm-1: 3300 (NH), 2200 (
CN), 1700ax (C=C), 1250(C-0) NMR (DMSO-d6.DSS) δ: 2.06 (
3H, s, 6-CII5).

2.23 (3H, a, 2-CH5), 3.63 (3
H,s,0-CH5).

3.87 (IH18, 4-H) I3.96 (4H1sl
O-CH2-CH2-0).

5.88 (IH, s, vinyl H), 9.25 (IH, b
r, NH) elemental analysis value (as C14H16N204)
Calculated value: C, 6086; H, 5, 84: N, 10.14
(Related) Experimental value: C, 60, 65; H, 5, 82; N, 1
0.11 (H) Example 4 (Synthesis Example) 4- [=-2-(5,6-sihydro p-diogycinyl) )-2,6-dimethyl-1,4-dihydropyridine-3,S-dicarpazoic acid Synthesis of bis(1-methyl-2-methoxyethyl) esterAcetoacetic acid 1-methyl-2-methoxyethyl ester 4
．． 70g (0,027 mol), β-aminocrotonic acid 1
-Methyl-2-methoxyethyl Nisdel 4.68 g (
0,027 mol) and 3.08 g (0,027 mol) of 2-formyl-p-dioxene were mixed and heated and stirred at 150° C. for 16 hours. After cooling, the reaction mixture was chromatographed on a 320 g column of silica gel.
Eluent; mixed solvent of benzene:acetone-5:1 (v/v)] was prepared to prepare V#, and then crystallized with a mixed solvent of diethyl ether and diisopropyl ether. When these crystals were recrystallized from a mixed solvent of diethyl ether, diisopropyl ether and ethanol, 056 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 120.0-1220°C I RνKBrcm-1: 3250(NH), 1
700 (C=O), 1270aX (C-O) NMR (CDCl2.TMS) b: 1.25 (
6H, d, 2XCH-CH3).

2.27 (6TI, s, 2.6-CH5), 3.
36 (6H, a, 2XO-CH6), 3.45 (4H,
d, 2XCH-CH2-0), 3.91(4H-
9O-CH2-CH2-0), 4.44 (I H, a
, 4-H).

5.08 (2T(, m, 2XCOO-CH), 5.8
5 (IH, a, vinyl H) 16.16 (IH, br
, NTI) elemental analysis values (as C2, H3, NO8)
Calculated value: C, 59, 28: H, 7, 3CN, 3.29 (
Fishing fruit IJli: C, 59, 26: H, 7, 1G; N,
3.37 (%) Example 5 (Synthesis example) 4-[2-(5,6-dihydro-p-dioxynyl)
)-2,6-dimethyl-1,4-dihydropyridine-3
, 5-dicarboxylic acid bis(2-cyanoethyl) ester 2-formyl-p-dioxene 2.309 (0,02
mol), acetoacetic acid 2-cyanoethyl ester 5809
CO0,037 mol), and 3.5 mol of anthonia water
ml was dissolved in 30ml of isozolo-gunol and heated under reflux for 24 hours. After cooling, the reaction solution was concentrated and the precipitated crystals were filtered. When this crystal was recrystallized from ethanol, 276 g of the target substance (yield: 35 g) was obtained as pale yellow crystals.
．． 3%) was obtained. The analytical values of this substance were as follows.

Melting point: 135.5-137.0°C ■R, KBr atl-': 3345 (NH), 2
325 (CiE:N), 1695naX (C=0), 1200 (C-0), 1120 (
C-0) NMR (CD30D, TMS) δ: 2.31 (
6H1s, 216-CII3).

2.75 (4H, t, 2XCOO-CH2-CH
2-CN), 3.93(4T(,a, OCI(2
-CHz-0), 4.34 (4H, t.

2XC00-CH2-CH2-CN), 4.4
5 (I H, @, 4-H).

5.91 (IH, s, vinyl H), 6.32 (IH
, br, NH) Elemental analysis value (as C1, H2, N306) Calculated value: C, 58, 91: H, 5, 46: N, 10
．． 85 (fishing experiment value: C, 58, 67: H, 5, 55: N
, 1058(H) Example 6 (Synthesis Example) 4-C2-(5,6-dihydro-p-dioxinyl)
)-2,6-dimethyl-1,4-dihydrodiy-3
．． 5-Dical? Synthesis of acid bis(methoxymethyl) ester 4-C2-(5,6-dihydro-p-dioxynyl)
)-2,6-dimethyl-1.4--, Z hydropyridine-3,S-dicarboxylic acid bis(2-cyanoethyl) ester 3.30,! 7 (8.52 mmol) was dissolved in 10 rnl of dimethoxyethane, 5 Qml of water and 17.1 ml of 1N aqueous sodium hydroxide solution were added, and after stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure on a water bath at 30°C. I left.

Next, anhydrous dimethylformamide was added to the obtained residue, and the mixture was stirred and suspended. 2.0 g (25 mmol) of chloromethyl methyl ether was added thereto, and the mixture was stirred overnight at room temperature. Next, the solvent was concentrated, ethyl acetate was added to dissolve it, washed with water, dried over Glauber's salt, and then the solvent was distilled off. The residue was chromatographed on a 50 g column of silica gel [
Development, eluent; n-hexane:ethyl acetate-1:1
(v/v) mixed solvent] to form crystals. When the crystals were recrystallized from ethanol, 0.81 g (yield 25.7%) of the target substance as white crystals was obtained. The analytical values for this substance were as follows.

Melting point: 105.5-106.5°C IRVl ("cm': 3345 (NU), 1
695 (C=O), 1660ax (cmc), xzoo (c-o), 1o7s (c-o)
NMR (CDC73, Tl1(S)δ: 233 (6
11, s, 2, 6-CII3).

3.48 (6H, s, 2×0-CH5), 393
(4H, s.

0-CH2-CH2-0), 4.53(IH, 8,4-
H), 5.23°5.39 (4H, ALI q
1. r=66Hz, 2XO-CH2-0-CHs
) 15.93 (IH, s, vinyl H), 6.15 (
IH, br, NH) elemental analysis value (C17H23NO8
) n-1 calculation i: c, 55.28: H, 6, 28
:N, 3.79 (Uri 5) Experimental value: C, 55, 44:H
, 6, 24:N, 3.90 (testing the effect of the compound of the present invention on liver damage induced by carbon tetrachloride) , 9. However, for GOT 2, 100-week-old animals weighing 230 to 2,601 kg were used in each group, and carbon tetrachloride and the drug were administered in the manner described below, and blood was collected to determine the index of liver damage. , GPT, ALP and bilirubin were determined.

The test materials were suspended in 01 Tween-80 at a ratio of 404 and orally administered at a ratio of 200 T('')A<9, respectively, 25 and 1 hour before administration of carbon tetrachloride; η.

However, 0.1% Tween-
80 to 5 ++I g/IC,! / was administered orally in the same manner.

Carbon tetrachloride was administered intraperitoneally as a 10% (v/v) olive oil solution at a rate of 51 nl/I<9 (0.5 ml/I<g as carbon tetrachloride) 1 hour after the final administration of the drug.

In addition, the control group (normal) was given 5 m67 kg of olive oil.
It was administered intraperitoneally in the same manner.

Blood should be collected for 24 hours after carbon tetrachloride administration (however, 1 hour before blood collection)
Fasted for 8 to 22 hours. ) was performed through the carotid artery under pendoparbital anesthesia.

Next, the collected blood was left at room temperature, and then the serum was separated.

GOT and GPT in serum are measured by UV method.
LP's 011] constant is AIP: Bessy-Lowr
The y method and the diazo method are used to measure bilirubin.

The results are shown in Tables 1 to 3. The test drugs A to G are as follows.

A: Compound 91 B: Compound 12 C: Compound D of Example 3: Compound E of Example 4: Compound i515 ■P: Compound of Example 6 Procedural amendment (voluntary) August-2, 1980 Patent Mr. Manabu Shiga, Commissioner of the Office■, Indication of the case 1982 Patent Application No. 15240.5 2, Name of the invention 1.4-dihydropyridine compound 3, Relationship with the person making the amendment Case Patent applicant name Nikken Chemical Co., Ltd. (1 other person) 4. Agent address: Shizuka Toranomon Building, 8-10 Toranomon-chome, Minato-ku, Tokyo 105 Phone: (504) 0721 Name: Patent attorney (6579) Akira Aoki (4 other people) 5. Amendment Column 6 of "Detailed Description of the Invention" of the subject specification, contents of amendment (1) Measurement of rAffP on page 20, line 8 of the specification is Aj!
P:J rAj! The measurement of P is corrected in 111.

(2) GOT (K, tJ,
') The second row from the bottom of the column is r1064±569.''
is corrected to 1604±569.

(3) Add the following sentence next to Table 3 on page 22 of the specification.

r Example 8 (Test Example) Acute testing of compounds of the present invention The test drugs (test drugs A and F used in Example 7) were
C-Wistar male rats (age 5a, weight 100~
After oral administration to 125 g), the progress was observed for one week and the LD5o value was calculated, and the following results were obtained.

A: L Dso = 1000 mg/kg or more - F: L Dso = 2000 mg/kg or more As is clear from the test examples, the compound of the present invention is effective in treating and preventing liver damage induced by carbon tetrachloride, etc. Because of its low toxicity, it is a useful compound that is expected to be used as a therapeutic agent for liver diseases caused by various causes. 1 or more

Claims (1)

[Claims] 1. Formula (1) represents a substituted carbonyl group, where R1' is one of the substituted oxy groups consisting of methoxymethyloxy, 1-methyl-2-methoxyethyloxy, and 2-cyanoethyloxy. ), R2 represents a cyano group or a substituted carbonyl group represented by -Co-R2' (here, R2' is a methyl group, or methoxy, methoxymethyloxy, 2-methoxyethyloxy, 1-methyl-2 - one of the substituted oxy groups from methoxyethyloxy and 2-cyanoethyloxy
1,4-dihydropyridine compound represented by