JPH01151557A - Hypotensor - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula 1 [R<1>, R<2> and R<4> are lower alkyl; R<3> are nitro or lower alkyl which may contain 1-3 halogens as substituent groups; R<5> is phenyl which may contain 1-3 lower alkoxy groups, halogens, lower alkylthio groups, etc. as substituent groups; A is unsaturated chain hydrocarbon residue] and a salt thereof. EXAMPLE:Methyl 3-(4-tetrahydropyranyloxyphenyl)-2(E)-propenyl 1,4-dihydro-2,6- dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate. USE:A hypotensor having calcium antagonism, hypotensive action and safety free from side effects. PREPARATION:1-5mol. compound shown by formula 2 is reacted with 1mol. compound shown by formula 3 (X is OH or halogen) in the presence of a catalyst (e.g. hydrochloric acid gas or conc. sulfuric acid) according to an ordinary esterification reaction to give a compound shown by formula 1.

Description

[Detailed description of the invention] TECHNICAL FIELD The present invention relates to antihypertensive agents.

The antihypertensive agent of the present invention contains as an active ingredient a dihydropyridine represented by the following general formula (1), which has not been described in any literature.

[In the formula, R1, R2 and R4 each represent a lower alkyl group. R4 represents a nitro group or a lower alkyl group which may have 1 to 3 10 atoms (as a substituent). R5 is a lower alkoxy group, a 10gen atom, a lower alkyl+ruthio group, a hydroxyl group, a lower alkanoyloxy group, a tetrahedral O
It represents a phenyl group which may have 1 to 3 substituents selected from the group consisting of a pyranyl group and a lower alkoxy group. A represents an unsaturated chain hydrocarbon residue. ] The dihydropyridine derivative represented by the above general formula (1) of the present invention has an excellent calcium antagonistic effect (Ca
-Antagonist), has antihypertensive action, platelet aggregation inhibiting action, and phosphogesterase inhibitory action, such as coronary circulation improving agents such as coronary vasodilators, antihypertensive agents, thrombosis preventive or therapeutic agents, phosphogesterase inhibitors, etc. It is useful as

Examples of compounds related to the compounds of the present invention include the compounds described in JP-A-56-36455,
The publication describes that the compound is useful as an antihypertensive agent, a peripheral and cerebral vasodilator, and a therapeutic agent for coronary arteries. However, in the compound of the present invention, in the substituent R5-A-CH2-CO2- at the 3-position of the pyridine skeleton, A is an unsaturated chain hydrocarbon residue, whereas the compound is specifically disclosed in the above publication. These compounds are clearly different in that the group corresponding to A above is a saturated chain hydrocarbon residue. Moreover, the compound of the present invention has fewer side effects and has a longer duration of the medicinal effect than the compounds described in the above-mentioned publication.

Furthermore, the compound of the present invention also has lipid peroxide-lowering activity and calptichurin-inhibiting activity, and is useful as a lipid peroxide-lowering agent, an antiinflammatory agent, and an anticancer agent.

As used herein, lower alkyl groups include, for example, methyl, ethyl, d-D, iso-d, d-, and fer.
Examples include alkyl groups having 1 to 6 carbon atoms such as t-butyl, pentyl, and hesyl groups.

Examples of lower alkyl groups that may have a halogen atom as a substituent include trifluoromethyl, 2,2-lifluoroethyl SI, I-, in addition to the above alkyl groups having 1 to 6 carbon atoms. dichloroethyl, triclomethyl,
DikuOO methyl triz〇7methyl 2.2.2-t-
Lifluoroethyl-2,2,2-tric00ethyl12
-Rioethyl S 1.2-dicooethyl, 3.3.
3-) Ref00p0pill S3-Fluo0p0pill S4
As a substituent for the -chlorobutylS3-ri0O-2-methylethyl group, an alkyl group having 1 to 6 carbon atoms may have 1 to 3 halogen atoms. Examples of lower alkyl groups include methoxy, eth+, p0bo+, isopropyl, z+, ttrt-z, pentyl+, and hexyl+ etc. carbon number 1
-6 alk+shi groups may be mentioned. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

Examples of the lower alcohol group include, for example, meth + meth, 2-meth, s, l- meth, 3- meth, 4-meth, and 4-meth. Shizutoshishi, 1,1-dimethyl-2-Methogyu Shedoshishi, 5-Methophyshipe Methyloshishi, 6-Metho+Shihe+Shiroogyushishi,
2-Methyl-3-metoshizuO+shi, Etho+Simeto+
shi, 3-eto 10shi'''jOpo+shi, 6-etho+shihe+shiruojushi, 2-zuropo+shedoushishi, 4-zuropo+cipt+shi, 5-zuto 10sipe methyloshishi , peshitiruo 10simeto+shi, 1-beshichiruogyushedo+shi, 1.1-gomethyl-2-beshishiruobeshido+shi, 3-to+shiruojushizuOpo+shi, etc. each alco group +5 part has 1 or more carbon atoms
6 alko+sialko+shi groups can be mentioned.

As the unsaturated chain hydrocarbon residue, vinylezi, 1-50
Benirezi, I-methyl-1-propenylene, 2-methyl-1-propenylene, 2-10'-dipropenylene, 2-dipropenylene, 1-distillate, 3-dipropylene, 2-propenylene, 1 -Pesticide, 3-<Pentadiene, 4-Pentane, 1.3-Butadiene, 1,3-Pentadiene, 2-Pesite, 4-Pest, 2- + Senior, I- + Cattle, 5- + Seni, 3 -to±senileshi, 4-to+senileshi, 3.3-,; methyl-1-dichlorobenzene, 2-ethyl-1-zuobenileshi,
Ethinyl resin, 2-50 vinylene, l-duropylene resin,
I! Cytinylene, 3-pentynylene, 4-vestynylene, 2-
Shinireshi, l- to beef Shinireshi, 3- to + Shinireshi, 4-
Double bonds and/or triple bonds such as 1, 5-, 5-, 1, 3-, 1, 4-, 1, 3, 5-, etc. 1
Examples include linear or branched unsaturated hydrocarbon residues having 2 to 6 carbon atoms.

Examples of the lower alkylthio group include alkylthio groups having 1 to 6 carbon atoms, such as methylthio, ethylthio, duropylthio, isoduropylthio, butylthio, 1erf-butylthio, peshylthio, and hexylthio groups. .

Examples of the lower alkanoyl group include formyl group, acetyl group, zlopionyl group, tthyl group, iso tyl group, pentanoyl group, s tert- tyl group. and an alkanoyl group having 1 to 6 carbon atoms, such as a he+sanoyl group and a he+sanoyl group.

A substituent selected from the group consisting of a lower alkoxy group, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkanoyl group, a tetrahydropyranyl group, and a lower alkyl group; Examples of the phenyl group which may have 1 to 3 groups include phenyl, 2-13- or 4-OO phenyl, 2-. 3- or 4-fluorophenyl, 2-13- or 4-7phenyl, 2
-13- or 4-iodophenyl, 3.5-dichlorophenyl, 2.6-dichlorophenyl, 3.4-dichlorophenyl, 3.4-difluorophenyl, 3.5-didocephenyl, 2-13- or Imaichi-methylthiophenyl, 2-13- or 4-ethylthiophenyl, 4-
Pyrthiophenyl, 3-isopyruthiophenyl, 2-dimethylthiophenyl, 4-h+silthiophenyl, 3-pesitylthiophenyl, 4-1ert-dimethylthiophenyl, 3,4-dimethylthio phenyl, 2.5-
Dimethylthiophenyl, 2-. 3- or 4-methodeca diphenyl, 2-. 3- or 4-etho + diphenyl, 3
-diphenyl, 4-isodiphenyl,
3-diphenyl, 2-diphenyl,
4-tert-diphenyl, 4-tert-diphenyl, 3,4-dichlorophenyl, 3,4-sheddiphenyl, 2.5-umethodiphenyl, 2-
13- or 4-(2-tetrahydropyranyl)
Phenyl, 2,4-(2-tetrahydropyranyl-ocy)phenyl, 3-methylthio-4-ri00phenyl, 2
-riO-ro-6-methylthiophenyl, 2-metho-C3
-hydro+diphenyl, 3,4.5-trimethodiphenyl, 3,4.5-trimethylthiophenyl, 3,
4°5-trichlorophenyl, 2-13- or 4-human 0+ diphenyl, 3.4-. 1; diphenyl in sushi doro, 2,6-dihydro bovine diphenyl, 3,4.5-) diphenyl in sushi doro, 2-13- or 4-acetylo+diphenyl, 4-dihydro bovine diphenyl, 3-
IsozuO pionylo+diphenyl, 2-butylthiophenyl, 4-h+sanoylodedecophenyl, 3-pecitanoylodiphenyl, 4-terl-dutylthiophenyl, 3,4-diacetylodedecophenyl, 2,5-diacetylodiphenyl Decadiphenyl, 3,4.5-tridiacetylodecodiphenyl, 2-meth+cymetoxal diphenyl, 3-
(2-Metho+Shed beef) phenyl, 4-(1-Metho+
Phenyl, 2-(3-Metho+Si)Phenyl, 3-(4-Metho+Si)Phenyl, 4-(1,1-dimethyl-2- Met + Shed + Shi)
Phenyl, 2-(5-meth+silo-diphenyl), 3-(6-metho+silo-diphenyl), 4
-(2-methyl-3-meth+cyzuropocy)phenyl,
2-(etho+shimeth+shi)phenyl, 3-(3-ethogyushizuropo+shi)phenyl, 4-(61eth+shihe+shiruoshishishi)phenyl, 2-(2-propogyushido+shi) shi) phenyl, 3-(4-zu0pogyushizutoshishishi) phenyl, 4
-(5-buto+cypemethyl-10-cy)phenyl, 2-(peshyl-1-dimethyl-10-phenyl), 3-(1-dimethyl-2-phenyl), 4-(1,1-dimethyl-2-+silo) Cowshed+shi)phenyl, 2-(3-
As a substituent for the phenyl group, an alkoxy group having 1 to 6 carbon atoms, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a hydroxyl group, and a ruthio group having 1 to 6 carbon atoms. Mention may be made of an alkanoyloxy group, a tetrahydropyranyloxy group, or a phenyl group in which each alkoxy+9 moiety may have 1 to 3 alkoxy+sialkoxy groups having 1 to 6 carbon atoms.

The compound of the present invention can be produced by various methods, and an example thereof is the method shown in Reaction Scheme 1 below.

[Reaction Scheme-1] [In the formula, X represents a hydroxyl group or a halogen atom. R1, R2
, R3, R4, R5 and A are the same as above. ] Compound (2
) and compound (3), when X is a hydroxyl group, conditions for ordinary esterification reactions can be employed. This reaction is usually carried out in the presence of a catalyst, and as the catalyst used in this case, a wide variety of catalysts that are used in ordinary esterification reactions can be used. Typical examples include hydrochloric acid gas, concentrated sulfuric acid, ricic acid, polyricic acid, boron trifluoride, inorganic acids such as perchloric acid, trifluoroacetic acid, trifluorometadisulfonic acid, naphthalenesulfosic acid, p
-Organic acids such as tosylic acid, becisesulfonic acid, ethanesulfosic acid, trifoo metacissulfosic acid anhydride, thionyl chloride, tetramethyl chloride,
Examples include dehydrating agents such as acetocydimethyl acetal, dicyclohexylcarbodiimide (DCC), l-alkyl-2-halogenopyridinium halide or tosylate, and N,N-carbonyltritazyl. Roughly acidic iosi exchange resins can also be used as the catalyst.

The amount of these catalysts used is not particularly limited, and is used within the range used in normal esterification reactions. The above reaction proceeds either without a solvent or in a solvent. As the solvent used at this time, solvents used in ordinary esterification reactions can be effectively used. Aromatic hydrocarbons such as Tornizi, Jusashi, etc., halogenated hydrocarbons such as Diku Oo metashi, Diku Oo etash, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofurazine, dioxicol, etylecylicol 7-methyl ether Examples include ethers such as pyridine, etc. In the above reaction, compound (2) and compound (3)
The ratio of the former to the latter may be appropriately selected over a wide range, but it is preferable to use the former in an amount of from 7 to 5 times the amount of the latter, particularly preferably from an equimolar amount to 2 times the amount. In addition, when carrying out the above reaction, it is also possible to further increase the production rate by removing the produced water from the reaction system using a desiccant such as anhydrous calcium chloride, anhydrous sulfuric acid steel, anhydrous calcium sulfate, or ricinus pentoxide. be. The reaction temperature in this reaction may be appropriately selected and is not particularly limited, but is usually -20
It is best to carry out at a temperature of about 0 to 200℃, especially about 0 to 1
It is preferable to carry out the process at about 50°C. Although the reaction time depends on the type of raw materials and reaction conditions, the reaction is generally completed in about 10 minutes to 20 hours.

When X is a halogen atom, the compound of the present invention can be obtained by reacting under dehydrohalogenation reaction conditions. This dehydrohalogenation reaction is carried out using a basic compound as a dehydrohalogenating agent. A wide variety of known basic compounds can be used, including inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, silver carbonate, sodium methylate, sodium ethyl Examples include alcoholades such as lat, organic bases such as triethylamici, pyridine, #, #-dimethylanilisi, and the like. The reaction can be advantageously carried out in the presence of a solvent, and all inert solvents that do not adversely affect the reaction can be used, such as methanol, ethanol, dipanol, dibutanol, ethylene glycol, etc. alcohols, dimethyl ether, ethers such as tetrashidroflage, geojusashi, nanoglyme, diclyme,
Ketones such as acetol and methyl ethyl ketone, aromatic hydrocarbons such as beshizeshi, tornidi, +shireshi, esters such as methyl acetate and ethyl acetate, N,N-dimethylformamide, dimethylsulfo+side, he+samethyllisic acid triamide, etc. Examples include non-erotogenic polar solvents.

The reaction can also be carried out in the presence of metal iodides such as sodium iodide and potassium iodide. The ratio of compound (3) to compound (2) in the above method is not particularly limited, and can be selected from a wide range as appropriate;
It is usually desirable to use the latter in an amount equal to 5 times as much as the former, preferably in an amount of equal to 7 times to 2 times as much. Further, the reaction temperature is not particularly limited, but is usually room temperature to 200°C.
C, preferably room temperature to 160C. The reaction time is usually preferably 1 to 30 hours. Thus the general formula (+)
It is possible to obtain a compound of the present invention represented by

[Reaction scheme-2] (3a) +51 (1a) [In the formula, R1, R3, R'', R5 and A are the same as above.]
Compound (3a) and compound (
The reaction with 4) is carried out in a suitable solvent in the presence of a catalyst. As a catalyst, for example, a basic compound such as an organic base such as triethyl amici, pyridine, #, N-dimethylanili, an inorganic base such as sodium acetate or potassium carbonate, p
- Sulfosic acids such as toluenesulfosic acid, acidic compounds such as Lewis acids such as boron trifluoride, and the like. In addition, examples of solvents include aromatic hydrocarbons such as methane, toluene, and ethyl acetate, esters such as methyl acetate and ethyl acetate, methyl chloride, chloroform, and 1,2-dioxycarbonate.
80) f Silicated hydrocarbons such as O-ethyl, tetrahydroflage, ethers such as dioxyl, nitrate, diglyme, ketones such as acetol, methyl ethyl ketone, N, N-dimethylformamide, Examples of the solvent include non-disotropic polar solvents such as methyl sulfonate, hexamethyl lysic acid triamide, and N-methyl pyrrolido. The ratio of compound (3a) and compound (4) to be used is usually at least an equimolar amount of the latter to the former, preferably about 1 to 2 times the molar amount. The amount of the catalyst to be used is not particularly limited, but it is usually about 1/100 to 10 times the mole of compound (3a). Preferably, it may be used in an amount of about 1/10 to 5 times the mole. The reaction is usually carried out at -20-200°C, preferably at -20-1°C.

The process is generally completed in about 10 minutes to 20 hours at about ℃.

The reaction between compound (5) and compound (6) thus obtained is also carried out in a suitable solvent in the presence or absence of a catalyst. Examples of the solvents include alcohols such as methanol, ethanol, propatool, isopropanol, ditanol, and ethylene glycol; ethers; Aromatic hydrocarbons such as methylene chloride, ri00form, 1
．． 2-Halogenated hydrocarbons such as Jig 00 Etashi,
Examples include non-polypolar solvents such as 7V, #-dimethylformamide, dimethylsulfo+cyto, and hexamethyllysic acid triamide, carposi acids such as acetic acid and dilopiosic acid, and pyridine. For example, organic bases such as pyridine, hyperdihydride, triethylamide, diethylamide, DBU, metal alcoholides such as sodium ethylate, sodium methylate, and inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, potassium acetate, etc. Bases, mineral acids such as hydrochloric acid and sulfuric acid,
Examples include carboxylic acids such as acetic acid and piosic acid, and Lewis acids such as boron trifluoride. The ratio of compound (5) and compound (6) to be used is usually at least an equimolar amount of the latter to that of the former, preferably about 7 equimolar to 2 times the latter. The amount of catalyst used may be the same as the amount of catalyst used in the reaction between compound (3a) and compound (4). These 6 reactions are generally carried out at -20 to 200°C, preferably about -20 to 150°C, for 10 to 5 minutes.
It will finish in about 0 hours.

The reaction between compound (7) and compound (8) can be advantageously carried out in the presence of a solvent. All inert solvents that do not adversely affect the reaction can be used as solvents, such as ketones such as Attoshi, halogenated hydrocarbons such as chloroform, etc.
Alcohols such as methanol, ethanol, dilobanol, isodurobanol, and ethylene glycol, ethers such as diethyl ether, tetrahydrofuran, dioxic acid, awnoglyme, and diglyme, and aromatic hydrocarbons such as beshizene, tornidi, and silecium. methyl acetate,
Esters such as ethyl acetate, acetic acid, carposi acids such as diuropiosic acid, organic bases such as pyridine, non-JO tocy polar solvents such as N,N-dimethylformamide, dimethylsulfo+cyto, and hexamethyllysic acid triamide, etc. The ratio of compound (7) and compound ω) to be used is usually about 1 to 10 times the former, preferably about 1 to 2 times the former. The reaction is generally completed at about -20 to 200°C, preferably about 50 to 150°C, in about 10 minutes to 20 hours.

In this way, a compound represented by general formula (1a) can be obtained.

In addition, in reacting the compound (5) and the compound (6) and further reacting the compound (8), the compound (7) is not isolated as an intermediate, and the compound (
5), compound (6) and compound (8) can be present in the same reaction system to carry out simultaneous reaction (-step).

Compounds in which R5 in the compound represented by the general formula (1) represents a phenyl group having at least one hydroxyl group as a substituent include compounds in which R5 in the compound represented by the general formula +11 as a substituent is a lower alkoxy group, K can be obtained by hydrolyzing a compound having a phenyl group having at least one of a 10-cy group, a lower alkanoyl group, or a lower alkanoyl group.

A compound of general formula (1) in which R5 is a phoenic group having at least one lower alkoxy group, a tetrahydropyranyl group, or a lower alkoxy group as a substituent [hereinafter, this compound will be referred to as The hydrolysis reaction of "compound (Ib) j" is carried out without a solvent or by reacting with an acid in an appropriate solvent.

As a solvent, for example, water, nitrobeshizeshi, torunidi,
Aromatic hydrocarbons such as beshizeshi, saturated hydrocarbons such as octane, lower alcohols such as methanol, ethanol, and isozobanol, ethers such as geobeshisashi, tetrahydroflag, acetone, etc. ketosis,
Examples include acetic acid, acetonitrile, and mixed solvents thereof. Examples of acids include mineral acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid; carboxylic acids such as p-toluethyl sulfosic acid, pyridyl p-, toluethyl sulfosic acid, acetic acid, and dioxypiosic acid; aluminum chloride, tin chloride, and fluoride. Examples include boron and zinc chloride. The amount of such acid to be used is preferably at least equal to or more than 7,000 mol per pound of compound (lb), usually in a large amount. The reaction temperature is usually -30~
The temperature is preferably 200°C, preferably about -30 to 100°C, and the reaction is generally completed in about 0.5 to 8 hours.

The hydrolysis reaction of the compound of the general formula (11), in which R5 is a phenyl group having at least one lower alkanoyl group as a substituent, can be carried out in the same manner as the widely used hydrolysis reaction of esters. 0 to 100 in an inert solvent in the presence of an acid or alkali, catalyst, etc.
The process is carried out at a temperature of 1 to 5 hours. Examples of catalysts include inorganic acids such as hydrochloric acid, sulfuric acid, and aluminum chloride; organic acids such as acetic acid and formic acid; sodium hydroxide;
Examples include inorganic bases such as sodium carbonate and potassium hydroxide, and organic bases such as acitania, trie, and tylamici. Examples of the inert solvent include water, alcohols such as methyl alcohol and ethyl alcohol, carposi acids such as acetic acid and pionic acid, ethers such as ethyl ether, and amides such as dimethylformamide and acetamide.

In the compound represented by the general formula f+l, R5 represents a phenyl group having at least one lower alkoxy group, a tetra-dropyranyl group, or a lower alkoxy-lower alkoxy group as a substituent, the compound represented by the general formula A compound represented by (1) in which R5 represents a phenyl group having at least one hydroxyl group as a substituent [hereinafter, this compound will be referred to as "compound (lc) J]" can also be obtained by alkylation. The alkylation reaction is carried out under normal alkylation reaction conditions, for example, using an alkylating agent in the presence of a basic compound. Compounds include, for example, metals, alkali metals such as sodium and potassium metal, hydrides, hydroxides, carbonates, bicarbonates or alcoholades of these alkali metals, aromatic amici compounds such as pyridyl and piperidine, triethyl Examples include organic bases such as amici, N,N-diethylanilisi, l,8-diazapisic-O, and oxidecy-7.

Examples of the alkylation agent include lower alkyl halide,
Examples include tetrahydrogenyl halide, dihydropyran, lower alkyl halide, sialic sulfuric acid, sialic oak, and the like.

When a lower alkyl halide, a tetrahydro-pyranyl halide, or a lower alkoxybalide is used as the alkyl-forming agent, the acylation reaction proceeds advantageously in a suitable solvent, and the solvent used in this case is ,water,
Lower alcohols such as methanol, ethanol, isodurobanol, n-dutanol, ethers such as diethyl ether, gosaisan, tetrahydroflazi, etc., ketones such as acetone, methyl ethyl ketone, carbonized halides such as chloroform, dichlorothane, etc. Hydrogens, nitrobenzene, chloride t! Examples of the solvent include aromatic hydrocarbons such as dichloromethane, benzene, tornidi, and dimethylformamide, and non-dimethylformamide polar solvents such as N,N-dimethylformamide and dimethylformamide. The amount of alkalinizing agent used is usually the compound (
It is preferable to use at least about 7 moles or more, preferably about 1 to 5 moles, relative to IC). The reaction temperature is generally -20 to 200°C, preferably 0 to 100°C.
It is generally completed in about 10 minutes to 24 hours.

When sialyl sulfuric acid is used as the alkylating agent, the alkylating reaction is carried out in an inert solvent at room temperature to 150°C. Here, examples of the sialyl sulfuric acid include dimethyl sulfuric acid, diethyl sulfuric acid, and the like. As an inert solvent, Beshit! Examples include aromatic hydrocarbons such as carbon dioxide, carbon dioxide, etc., and ethers such as dioxic acid, tetrahydrofuryl ether, and diethyl ether.

When using dihydrohydride as the alkylating agent, the alkylating reaction is carried out in the presence of an acid, usually at 0 to 150°C in a solvent.
Preferably, the process is completed at around 0 to 100°C in about 0.5 to IO hours. As acids, for example, mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, p-'r-lecisulfosic acid, pyridi'J
Examples include p-tornidisulfonic acid. Examples of solvents include lower alcohols such as methanol, ethanol, and isopropanol, diethyl ether,
Ethers such as diodorofuran and tetrahydrofuran, aromatic hydrocarbons such as benzene and tornidi, saturated hydrocarbons such as trichloride and octase, ketones such as acetol, acetic acid, acetonitrile, and the like. Examples include mixed solvents of .

The amount of dihydropyran used is the usual compound.

(1c) is usually at least equal to 7, preferably 1
It is preferable to use up to 5 times the molar amount.

A compound represented by the general formula (!) in which R5 represents a phenyl group having at least one lower alkanoyloxy group as a substituent can also be obtained by acylating compound (IC). The acylation reaction is carried out according to a conventional method using, for example, an acid halide such as a lower alkashi acid halide, or an acid anhydride such as an alkashi acid anhydride as an acylating agent. The reaction using acid parite is carried out in an inert solvent using a dehydrogenating agent such as triethyl amici, diisopropylethyl amici, pyridyl, N,N-diethyl ether, etc. if necessary. It is carried out within a temperature range of 50 to 150°C for 1 to 24 hours. Further, the reaction using an acid anhydride is carried out in an inert solvent at a temperature ranging from room temperature to 200° C. for about 1 to 10 hours. Examples of inert solvents used in each of the above reactions include aromatic hydrocarbons such as nitrobenzene and benzene chloride; amici compounds such as pyridyl and N,N-dimethylanili; ethers such as methyl ether and ethyl ether; dichloromethane and dichloromethane. , halogenated hydrocarbons such as chloroform, etc. can be used. The amount of the above-mentioned acylating agent to be used is generally l'f nyl or more, preferably 1 to 5'f nyl, based on compound (Ic) Itl.

The compound of general formula (3) used as a starting material in the above reaction scheme-1 and the compound of general formula (3a) used as a starting material in the above reaction scheme-2 include new compounds. Compound [General formula (3b)
, (3C), (3d) and (3/)) are produced according to the following reaction schemes-3 to 5.

[Reaction Scheme-3] (3b) (3c) [In the formula, R5 is the same as above. R6 represents a hydrogen atom or a lower alkyl group. R7 represents a lower alkyl group.

R8 represents a carboxyl group or a group -P(OR9)2 (R9 is a lower alkyl group). B and D represent unsaturated alkylene groups. m and 0 represent 0 or 1. X represents a hydrogen atom. ] The reaction between the compound of general formula (9) and the compound of general formula (101) can be carried out by reacting in a solvent in the presence of a basic compound.The basic compound used here includes: Inorganic bases such as sodium metal, potassium metal, sodium hydride, sodium amide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, metal alcoholades such as sodium methylate, sodium ethylate, lysine , piperidine, tenorishi, triethylamine, N, N-
Examples include organic bases such as dimethylanilisi. As a solvent, any solvent can be used as long as it does not affect the reaction, but examples include ethers such as diethyl ether, dioxane, tetrahydrofradi, nantsuclimes, and diglyme, and aromatic solvents such as benzene, toluene, and silane. Hydrocarbons, aliphatic hydrocarbons such as n-hechusashi, hezutane, Schiff Ohe beef san, etc., amines such as pyridyl, #, #-dimethylanilis, N,N-dimethylformamide (DM
F), dimethylsulfoside (DMSO), hexamethyllisic acid triamide (CHMPA), and other non-protocytic polar solvents. The reaction temperature is usually 0 to 150°C
The temperature is preferably room temperature to around 120°C, and the reaction is generally completed in about 0.5 to 15 hours. General formula (9
) The amount of the compound of general formula (10) to be used is usually at least an equimolar amount of the latter to the former,
Preferably, the molar amount is from 7 to 2 times the molar amount.

The reduction reaction of the compound of general formula (ll) is usually carried out using a hydrogenation reducing agent. As the hydrogenation reducing agent, for example, sodium borohydride, aluminum hydride, mulithium hydride, diisobutylaluminum hydride (DIBAL), etc.
), sialaluminum hydride, diporasi, etc., and the amount used is usually 0.1 to 3 times the molar amount of the compound of general formula (11), preferably 0.5 to 2 times.
It is better to double the molar amount. This reduction reaction is usually carried out using an appropriate solvent, such as water, lower alcohols such as methanol, ethanol, and isopropanol, ethers such as tetrahydroflazide, diethyl ether, and diglyme, and aromatic carbonization such as beshizene, tornidi, and +sireshi. The reaction is carried out using hydrogen or the like, usually at about -60 to 50°C, preferably from 0°C to room temperature, for about 10 minutes to about 5 hours.

In addition, when using lithium aluminum hydride, sialaluminum hydride, or diboracy as a reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofurage, diglyme, beshizene, torunidi, and diborane.

The halogenation reaction of the obtained compound of general formula (3b) is as follows:
Ethers such as Geo Gyusan and Tetrahydrofradi, Ri0
Compound (3b) in a solvent such as 0 form, methylene chloride, halogenated hydrocarbons such as carbon tetrachloride, or without a solvent.
For example, hydrochloric acid, hydrochloric acid such as hydrobromic acid, N,
A halogenating agent such as N-diethyl 1L/゛1.2゜2-trichlorovinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus chloride, thionyl chloride, etc. is usually heated at room temperature to about 150°C, preferably at room temperature. The reaction is carried out at ~80°C for ~6 hours. The amount of the halogenating agent used may be at least equimolar to the compound of general formula (3b), and usually an excess amount.

[Reaction Scheme-4] (12) (1) (3d) [In the formula, R5,8%m and Xl are the same as above. t is 3 to 6
indicates an integer. ] The reaction that leads a compound with a general 2 odor to a compound with a rumored general formula θ is carried out in the presence of a basic compound and in a neutral solvent.

Inert solvents that can be used include, for example, ethers such as Dio-sashimi, tetrahedral, ethyl, and 7 glycol dimethyl ether, aromatic hydrocarbons such as beshizen, tornidi, and silene, methanol, ethanol, and isozylene. Lower alcohols such as acetonitrile,
Examples include polar solvents such as #, #-dimethylformamide, and dimethylsulfo+cyto. Examples of basic compounds include calcium carbonate, sodium carbonate, potassium carbonate,
Abasic bases such as sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium amide, sodium hydride, potassium hydride, sodium methylate, sodium ethylate, triethylamine, pyridine, beef laver,
・1.5-diazabicyclo[4゜3.0]nonene-5(
DBN'), 1.5-diazabiscif D C5,4,0)
bovine dececy 5CDBU), 1,4-diazabicycloC
2,2,2) Organic bases such as octasi (DABCO) can be mentioned. The above reaction is usually carried out at room temperature to 200°C, preferably 60 to 120°C, and generally 1 to 24°C.
The reaction completes in about an hour.

The reduction of the compound of the general formula (1) can be carried out under the same conditions as the reduction reaction of the compound of the general formula (Kawa) of the reaction scheme-3.

The reaction between the compound of general formula θ4) and the compound of general formula θ5) is carried out in a suitable solvent. Examples of the solvent that can be used here include ethers such as diosaccharide, tetrahydrofradiate, and diethyl ether, and halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride. The reaction temperature is usually about 0 to 150°C, preferably about 0 to 100°C, and generally takes about 10 minutes to 60°C.
The reaction completes in about an hour. The amount of the compound of general formula 205) to be used is usually at least an equimolar amount, preferably an excess amount, relative to the compound of general formula 04).

[Reaction Scheme-5] (3e) R5-CB>CmiC-CD). -CH20H (3f
) [In the formula, R5, R7, Bs Os m, 0 and Xl are the same as above. M represents a metal such as copper, sodium, lithium, potassium or the like. ] The reaction between the compound of general formula (3e) and the compound of general formula (16) is carried out in a suitable solvent. Examples of solvents that can be used include ethers such as diethyl ether, dioxane, tetrahydrofuran, nantsuklyme, and diglyme, aromatic hydrocarbons such as beshizene, toluene, and beef sardine, n-he+sashi, and hezu. aliphatic hydrocarbons such as sulfur, sulfate, etc., pyridine, /'/, #-dimethylanilis, etc., N,N-dimethylformamide (DM
Examples include non-toxic polar solvents such as F), dimethyl sulfoside (DMSO), helimethyl lysic acid triamide C, HMPA'), and the like. The reaction temperature is usually 0 to 200
℃, preferably around room temperature to 1.50℃,
Generally, the reaction is completed in about 5 to 10 hours.

The amount of the compound of general formula (3e) to be used is
The amount should be at least equal to 7 moles, preferably equal to 1.5 times the mole of the compound.

The reduction reaction of the compound of the general formula Oη is carried out by the reaction scheme-3
It can be carried out under the same conditions as the reduction reaction of the compound of general formula (11).

Compounds of general formulas (3b), (3c), (3d) and (3f) can be prepared by oxidizing the compounds in the presence of a suitable oxidizing agent, where % and t are the same as above. ] can be converted into a compound. A part of this compound is the starting material (compound of general formula (9)) in the reaction scheme-3, and therefore the reactions of reaction schemes-3 to 5.9 and the above oxidation reaction are carried out sequentially. Therefore, various desired compounds of general formula (3) can be obtained. Examples of the oxidizing agent used in the above oxidation reaction include potassium D-mate, sodium dichromate, chromium dioxide, pyridinyl oxide, chromium compounds such as anhydrous chromium dioxide-dipyridine complex, manganese dioxide, and potassium permanganate. Manganese compounds such as lead tetraacetate, periodic acid, dimethylsulfo+cyto, dimethylamidiodeocyto such as dimethylamidiodeocyto, pyridine-p-nide O such as pyridine-p-nide O, N-dimethylanilisi, etc. Examples include compounds such as Examples of solvents used include aromatic hydrocarbons such as benzene, torunidi, and +tare 9, halogenated hydrocarbons such as methylene chloride, RI00 form, and carbon tetrachloride, diethyl ether, dioxane, and tetrahydrofradiate. ethers, aliphatic hydrocarbons such as hetosan, pecitane, and Schiff Ohetosashi, ketones such as acetone and methyl ethyl ketosis, lower alcohols such as methanol, ethanol, and isobasanol, water,
Examples include acetic acid, dimethylsulfo+cyto, and the like. In this reaction, acids such as sulfuric acid and perchloric acid may be used as a catalyst.

The reaction temperature is usually 0 to 200°C, preferably 0 to 150°C.
[Reaction equation-7] 0 (+21 [R5 in the formula,
Bs ms and Xl are the same as above. ] General 2 (11
The reaction between the compound of formula (a) and the compound of general formula (a) is carried out in a suitable solvent. Solvents used include diethyl ether, dioxane, tetrahydrofuran, 1.2-
, :; Aromatic hydrocarbons such as meth + siethane, aromatic hydrocarbons such as beshizeshi, beef shireshi, torunidi, aliphatic hydrocarbons such as he + san, hezutashi, beshitashi, etc., or mixed solvents thereof. etc. can be exemplified.

The reaction temperature is usually -70 to 50°C, preferably ~
The temperature is preferably 65°C to around room temperature, and the reaction is generally carried out at 3 to 30°C.
It will be completed in about 30 hours. The amount of general formula (19) to be used is usually at least 2 moles, preferably about 2 to 3 times the mole of the compound of formula @0).

The compound of general formula (12) in which m is 0 [ie, the compound of general formula (12a)] can also be produced by the method of reaction scheme-8.

[Reaction scheme-8] (21)(Xl(CH2)tCO)20(23)(12
a) [In the formula, R5 and Xl are the same as above. X2 represents a halogen atom. ] The reaction between the compound of general formula (21) and the compound of general formula Kan or the compound within the general formula is generally called the Friedel-Crach reaction, and this reaction is carried out in the presence of a Lewis acid in an appropriate solvent. It is done. As the solvent used in this case, those commonly used in this type of reaction are advantageously used, such as carbon disulfide, NidoObeshizeshi, Chlorbeshizetsu! Examples include dichloroethane, dichloroethane, dichloroethane, trichloroethane, and tetrachloroethane. Furthermore, conventionally used Lewis acids are preferably used, such as aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, and the like. The amount of Lewis acid to be used may be determined appropriately, but it is usually expressed by the general formula (2
2 to 6 times the amount of the compound in 1), preferably 3
About 4 times the molar amount is used. The amount of the compound of the general formula Kan or the compound of the general formula (23) to be used is usually at least an equimolar amount, preferably an equimolar amount to 3 times the amount of the compound of the general formula (2D).Reaction temperature is appropriately selected within a wide range, but is usually about 0 to 120°C, preferably about 0 to 70°C.
．． It will be completed in about 5 to 6 hours.

[Reaction scheme-9] (37) (3h) [In the formula, R5,
E, D, m and O are the same as above. R9 represents a hydroxyl group or a lower alkanoyl group. ] The reduction reaction of general formula (39) can be performed according to various known reduction reactions. For example, a catalytic reduction method using a catalyst such as palladium black, palladium carbon, platinum oxide, platinum black, Raney nickel, or residlar catalyst, or a reduction method using sodium borohydride, lithium aluminum hydride, etc. can be applied.

In the case of reduction by catalytic reduction method, a commonly used solvent such as water, methanol, ethanol, isodulobanol, acetic acid, diodecane, tetrahydroflazi, etc. is used, and in the presence of the above-mentioned catalyst, the temperature is usually normal pressure to 20 atmospheres, preferably 20 atmospheres. It is preferable to carry out the reaction in a hydrogen atmosphere at normal pressure to 1O atm, usually at a temperature of -30°C to 100°C, preferably 0 to 50°C. The amount of catalyst used is usually 0.1 to 40% relative to the compound of general formula [39].
% by weight, preferably from 1 to 20% by weight. The reaction time is usually 1 to 12 hours.

When reduction is carried out using a reducing agent such as lithium aluminum hydride, the amount of the reducing agent is preferably 1.5 to 3.5 times, preferably 1.5 to 3.5 times, based on the compound of general formula (3g). The amount of
The reaction may be carried out at ~100°C, preferably from 0°C to 70°C, for about 30 minutes to 12 hours. The compound represented by the general formula (3h) can be easily obtained by these reduction reactions.

In the compound of general formula (3h), when R9 is a lower alkanoyl group, the above R5 is a phenyl group having at least one substituted lower alkanoyl group, hydrolysis reaction of a compound of general formula +1+ It is also possible to lead to a compound in which R9 is a hydroxyl group by hydrolysis under the same conditions as above.

A part of the compound of general formula (3g) is shown in the following reaction scheme-I
It can be manufactured according to the method of O.

[Reaction scheme-101 (3e) R5-CB) C=C-CD)-R10m
0 (3i) [In the formula, R5, 13, m, Xl, M, D and 0 are the same as above. R10 represents a lower alkanoyl group. ] General formula (
The reaction between the compound of formula (3e) and the compound of general formula (24) can be carried out under the same conditions as the reaction of the compound of general formula (3e) and the compound of general formula (+6i) in the reaction scheme-5.

Among the compounds represented by the general formula (1) thus obtained, those having a basic group can form salts with pharmacologically acceptable acids. Specifically, such acids include sulfuric acid, nitric acid,
Inorganic acids such as hydrochloric acid and hydrobromic acid, oxalic acid, maleic acid,
Examples include organic acids such as fumaric acid, riff-5 acid, citric acid, and benzoic acid.

The compound of the present invention thus obtained can be easily isolated and purified by commonly used separation means.

Examples of such separation methods include precipitation methods, extraction methods, recrystallization methods, column chromatography, and thin-layer chromatography.

The compounds of the present invention naturally include optical isomers.

The compounds of the present invention can be administered to animals and humans as such or together with conventional pharmaceutical carriers.

The dosage unit form is not particularly limited and can be appropriately selected and used as required. Such dosage unit forms include tablets,
Examples include oral preparations such as granules and oral solutions, and parenteral preparations such as injections. The amount of the active ingredient to be administered is not particularly limited and is appropriately selected from a wide range, but in order to achieve the desired effect, the amount of the active ingredient to be administered should be 0.06 per body weight IKf per day.
It is preferable to set it to ~l0Tnv. It is also preferred that the dosage unit form contains 1 to 500 ml of the active ingredient.

In the present invention, oral preparations such as tablets, forceps, and oral solutions are manufactured according to conventional methods. That is, tablets are prepared by mixing the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearicate, talcum, and gum arabic. Capsules are prepared by mixing the compound of the present invention with an inert pharmaceutical filler or diluent, and filling the mixture into hard gelatin capsules, soft forceps, and the like. Shea powder or shea powder is produced by mixing the compound of the present invention with sweeteners such as sucrose, preservatives such as methyl and propylparabens, coloring agents, seasonings, and the like. Moreover, parenteral preparations are manufactured according to conventional methods. That is, a drug for parenteral administration is prepared by dissolving the compound of the present invention in a sterile liquid carrier. The preferred carrier is water or saline.

A solution having the desired clarity, stability and suitability for parenteral use is prepared by dissolving about 1 to 500 μl of the active ingredient in polyethylene cyclolicol having a molecular weight of 200 to 5000, dissolved in water and an organic solvent. be done. Such liquid preparations include sodium carboxyl dimethylcellulose, methylcellulose
It is preferable that a lubricant such as polyvinylvinyl alcohol, polyvinylvinylic acid, or polyvinyl alcohol be contained. Furthermore, the above liquid preparation contains bactericides and fungicides such as benzyl alcohol, phenol, and thimerosal, as well as isotonic agents such as sucrose and sodium chloride, local anesthetics, stabilizers, buffers, etc. as necessary. Good too. To further increase stability, parenterally administered drugs may be frozen after filling and water removed by freeze drying techniques known in the art. The lyophilized powder can then be reconstituted immediately before use.

Examples of formulations of the present invention using active ingredient compounds are listed below.

Preparation of tablets 5 μm each methyl, 3-(4-human O+diphenyl)-2-benyl 1,4-dimethyl-4-(3-nitrophenyl)pyridicy 3,5-
100 for oral use containing dicarpoxylate
0 tablets are prepared according to the following recipe.

- Dicarbo + Sylate Lactose (Japanese Pharmacopoeia) 50 Causi Starch (Japanese Pharmacopoeia) 25 Crystal Cell O-'s (Japanese Pharmacopoeia) 25 Methylcellulose (Japanese Pharmacopoeia) 1.5 Magnesium Stearicate (Japanese Pharmacopoeia) Fang Jing)! Methyl, 3
-(diphenyl in 4-hydro)-2-benyl 1.
Thoroughly mix 4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridy-3,5-dicarpoxysilate, lactose, causi starch and crystalline cellulose, and granulate with a 5% aqueous solution of methyl cellulose. Then pass through a 200 mesh sieve and carefully dry. 200 dried granules
It is passed through a mesh sieve and mixed with magnesium stearate and pressed into tablets.

Preparation of force cell formulation: 10 Wq each of methyl, 3-(4-diphenyl)-2-diphenyl, 1,4-diphenyl 2.6
-cymethyl-4-(3-nitrophenyl)pyridy3
, 5-dicarpo+sylate for oral use are prepared according to the following formulation.

Shido-2,6-cymethyl-4-(3-nitrophenyl)tl? Rigisy 3.5-dicarbobovine sylate lactose (Japanese Pharmacopoeia) 80 Starch (Japanese Pharmacopoeia) 30 Talc (Japanese Pharmacopoeia) 5 Magnesium stearicate (Japanese Pharmacopoeia) The mixture is thoroughly stirred and then filled into gelatinous capsules of desired size for oral administration.

Preparation of Injection A sterilized aqueous solution suitable for parenteral administration is prepared according to the following recipe: Monodicarboxylate polyethylene cylicol (Japanese Pharmacopoeia crystal) 0.9 Molecular weight: 4000 Sodium chloride (Japanese Pharmacopoeia crystal) 0.9 Polio Shisie Resi Sorbitan Seven Oleate
0.4 (Japanese Pharmacopoeia) Sodium metabisulfite 0.1
Methyl-paraben (Japanese Pharmacopoeia)
O,+SzuO pill-paraben (Japanese Pharmacopoeia)
0.02 Distilled water for injection
+00 (m/) The above-mentioned rosefish, sodium metabisulfite and sodium chloride were dissolved in about half the amount of distilled water at 80° C. with stirring. The resulting solution was cooled to 40°C, and methyl, 3-(4-diphenyl)-2
-dibenyl 1,4-dihydro-2,6-dimethyl-4-(3-nido-phenyl)pyridy 3,5-dicarboxylate and polio+thiolenate were dissolved in the solution. . The solution was then adjusted to the final volume by adding distilled water for injection and sterilized by sterile filtration using a suitable filter paper.

Reference examples and working examples are listed below.

Reference example l p-human 0+cybesizaldehyde 2CM' and tnoethylmaOnate 32.5fKe lysine 6m7! and 0.2 ml of piperidi'J were added and heated at 100 to 110°C for 10 minutes.
After heating and stirring for an hour, the mixture was cooled, chloroform was added thereto, washed successively with saturated potassium bisulfite water and water, dried over magnesium sulfate, and the solvent was concentrated. Ethyl at ゜22
Get 4-shido 0 + shishishinamate.

mp 70-71°C, pale yellow amorphous crystal Reference Example 2 25.5y of ethyl 3-Hydroxycinnamate is obtained.

mp65-68℃ (Recrystallized from iso-jO pyl ether) Reference example 3 Imakaichi Hyde 0 + Sea 3-ri O besizaldehyde 25.8
Reference example 1 using 9 and 7 noethylma 0 nate 32.5F
Similarly, ethyl 4-humanO+cy3- of 462
Get 00 Cinnamate.

mpH 8 to 119°C (recrystallized from methylene chloride) Colorless prismatic crystal reference example 4 To 30 ml of an anhydrous ether solution of ethyl 4-hydro + shishishinamate 51, dihydropiracif, 1 m/and p-
After adding 50 my of toluethyl sulfosic acid and stirring at room temperature for 2 hours, the reaction solution was neutralized with 1% NaOH, washed with water and dried (mirabilite), and the solvent was distilled off to give 6.8 f of ethyl 4-(2-tetrahydro diranyl) (10) Obtain Cinnamate.

m952 to 53°C Colorless amorphous product reference example 5 50 ml of an anhydrous ether solution containing 6.82 ethyl 4-(2-tetrahydropyranyl)cycinnamate,
It is added dropwise to an anhydrous ether solution containing 0.47 F of lithium aluminum hydride cooled to -30°C. After the dropwise addition was completed, the mixture was stirred at the same temperature for 1 hour, and the temperature was gradually raised to -10°C. Saturated sodium sulfate solution was gradually added thereto to remove the precipitate. After drying the furnace solution with Glauber's salt, it was concentrated to dryness, and the residue was purified by silica gel chromatography (eluent: chloroform).
3.22 of 4-(2-tetrahydropyranyl)cinnamyl alcohol is obtained as a colorless oil.

ηD1.5520 Reference Example 6 Pyridium chlorochromate 182 was added once under water cooling to an anhydrous methylene chloride solution containing 15511 Imaichi (2-tetrahydrohyranyl-o-jushi)shicinamyl alcohol 15511 and 5.22 kg of sodium acetate. After stirring at the same temperature for 1 hour, the mixture was returned to room temperature and further stirred for 1 hour. Ether l OOml
After adding , the reaction solution was filtered through Celite, the eluate was concentrated,
The residue was chromatographed on silica gel and then recrystallized from ether to obtain 3.52 g of 4-(2-tetrahydropyranyl-ox-)cinnamyl alcohol in the form of colorless needles.

mp65-67°C Reference Example 7 5.62% of triethylphosphonoacetate was added dropwise to a tetrahydrofuran solution of 1.06F of 60tin sodium hydride, stirred at room temperature, and then stirred at 40'C for 1 hour.

After cooling to room temperature, a THE solution containing 5.62% of 4-(2-tetrahydrogoranilo+shi)cinnamyl alcohol was added, and after stirring at room temperature for 2 hours, it was poured into 100 m/ml of water. After adding ether and extracting with ether, the mixture was washed successively with water and saturated brine, and then dried with Glauber's salt. Ethyl 5-(4-(2-tetrahydrobyranyloxy)phenyl:)-2(E) was recrystallized from isodyl ether to give colorless needle-like crystals.

3.82 of 4(E)-pecitadienoate are obtained.

mp66-67.5℃ Reference Example 8 Ethyl 5-(4-(2-tetradropyranyloxy)phenyl]-2(E), 4CE)-pecitadienoate 3.62% of anhydrous solution of 3Qml of becised acid was cooled with water. Diisobutylaluminum hydride 15ml (25%W/
V) was added dropwise and stirred at room temperature for 2 hours, then poured into saturated aqueous asimonia chloride and stirred at room temperature for 2 hours.

Insoluble matter is filtered through Celite, and the insoluble matter is washed with ether. The organic layer was washed with water and dried with sodium sulfate. After concentration, the residue is recrystallized into Oloform-n- + sashimi to form colorless needle-like crystals of 5-
(4-(2-tetradropyranyl)phenyl) -2
, (E) , 4 (E)-Pecitadienol 2.82
get.

mp54-58℃ Reference example 9 p-human O + diacetophenone 25? , 5 Q ml of dihydropiracy and 0.252 mL of p-toluenesulfosic acid were stirred in anhydrous ether at room temperature for 2 hours, neutralized with IN sodium hydroxide, washed successively with water and saturated brine, and dried with sodium sulfate. Concentration yields 342 4-(2-tetrahydropyranyl)acetophenols.

mp79-83℃ Colorless rhythmic crystal reference example lO Triethylphosphonoacetate 45.8? and 60
A solution of anhydrous tetrahydrofurage containing 8.72% sodium hydride was stirred at 40° C. for 1 hour, cooled, and 307% of 4-(2-tetrahydrohydride)acetophenol was added thereto. After heating under reflux for 4 hours, the solvent was distilled off, and the residue was extracted with ether, washed with water, and dried. After further concentration, the residue is purified using a silica gel column and a 27.5F ethyl 3-methyl-p-(2-tetrahydropyranyl-ocy)cinnamate.

Pale yellow oil “H-NMR (90MHz, CDC43) δ:1
．． 29 (3H, t, J=6Hz), 1.4~
2. I (6H, m), 2.49C3H, d, J-
IHz), 3.3 to 3-9 (2H, m>, 4.10
(2H, q, J=61-h), 5.3-5.45
(IH, m), 6-03 (IH, d, J= IH
z), 6-9 to 7.4 (4H, m) Reference Example 11 Ethyl 3-methyl-p-C2-tetrahydropyranyl) Cinnamate 27.5F tetrahydroflazide solution was added with diisobutylaluminum hydride ( 25%W/V
)J18ml was added dropwise at room temperature.

After 2 hours, pour into ice-cold aqueous ammonium chloride and remove insoluble matter. The tear fluid was washed with water, dried with Glauber's salt, and then condensed, and the residue was purified using silica gel column chromatography to obtain 12.7
A colorless oily 3-methyl-p-(2-tetrahydropyranyloxy)shicinnatriyl alcohol of f is obtained.

"H-NMR (90MHz %CDCt3) δ: 1.5
~2.0 (6H, m>, 2.0 (3H, S ), 3
．． 3-4-0 (2H, m), 4. I~4.3 (3H
, m), 5-26-5-4 (I H, m), 5.81
(IH, t, J=6Hz), 6.8-7.
5 (4H, m) Reference example 12 Aluminum chloride 532 and thioanisole 26.29
24.0 ml of γ-chlorodityryl chloride was added dropwise to the carbon disulfide solution under water cooling. After 1 hour and 30 minutes, the mixture was poured into ice water to remove insoluble matter, dissolved in chloroform, washed with water, dried with Glauber's salt, and concentrated. Dry.

Recrystallization from methanol gives pale yellow prismatic crystals of 36.22 gamma-di-Do-4-methylthiothiophenes.

mp75-76°C Reference example 13 γ-ri00-4-methylthiodthyrophenoxy35ri, 1
．． 8-Diazapicyl 0 (: 5.4.O), pale yellow prismatic crystal cyclodilopyl (4-methylthiophenyl) ketone 24.6? get.

mp76-76.5°C Reference example 14 Cyclodopyl (4-methylthiophenyl)ketone 24
To 200 mJ of methanol solution of
Add an appropriate amount of acetate and concentrate under reduced pressure. Chloroform was added to the residue, washed with water, dried over Glauber's salt, and the solvent was distilled off to obtain 1-(cyclodiOvir,hydro+dimethyl)-4-methylthiophenyl 182 as a colorless oil.

NMR (90MHz %CDC63) δ: 0.2'-0
, 7 (4H, 771), 0.9-1.4 (IH, m'
), 1.4-2.0 (6H, m), 3.2-3-7 (
2H, 772), 5, 17-5.3 (IH, yy+)
, 6.8 to 7.3 (8H, 771) Reference Example 15 1-(Shifuroduropyru, Shidoroshidimethyl)-4-methylthiophenyl 5 to a dioxic acid solution (+01/),
While cooling with water, 6 ml of 47-thihydrobromic acid was added dropwise, and after stirring for 30 minutes, the mixture was concentrated under reduced pressure. Water was added to the residue, extracted with ether, washed with water, dried over Glauber's salt, and concentrated to dryness. The residue was recrystallized from methanol to obtain 4- (4'-
Methylthiophenyl")-3CE)-dthenyl bromide is obtained.

mp54-56℃ Reference example 16 p-iodophenol 101, dihydrohirashi 8ml!
and p-toluethysulfosic acid catalyst amount in anhydrous ether 30
ml and stirred at room temperature for 2 hours.

After washing the reaction solution with water and drying, the solvent was distilled off to obtain a yellow oily 4-
12.4 grams of (2-tetrahydrohyranyl)-1-iotobenzei were obtained.

bp84-87℃ (25ruHf) Reference Example 17 Triethylphosphonocrotonate 6.25f at 60
% sodium hydride 1.06F in tetrahydrofuran solution at room temperature and stirred for 1 hour at 40°C. After cooling to room temperature, p-(2-tetra-drovilanilo+
C) Add a tetrahydrofuran solution containing 5.01 ml of besizaldehyde, stir at room temperature for 2 hours, and then pour into 100 ml of water. After extraction with ether, the extract was washed successively with water and saturated brine, and then dried with Glauber's salt. The solvent was distilled off, and the residue was subjected to silica gel chromatography (eluent: saline chloroform).
and then recrystallized from isoduroyl ether to give 4.0 IP of ethyl 5-[4-(2-tetrahydropyranyl diphenyl)]-2CE), 4CE).
- Obtain Pecitadienoate.

Colorless needle-like crystals, mp 66-67.5°C Reference example 18 p-tetrahytone
and 1-ide copper (
I) A solution of 7 QmJ of anhydrous lysine with a concentration of +1.32 is heated under reflux for 6 hours under an alkoxy atmosphere.

After the reaction is completed, the reaction solution is poured into water and extracted with RI00 form.

Wash with water, dry and remove the solvent. The residue was purified by silica gel column chromatography (eluent: chloroform:n- to beef san = I:I) to obtain 82 4-C4-C2-
Tetra-dropyranyl-3-phenyl-3-thenyl acetate is obtained.

Colorless oil "H-NMR (601'vfHz, CZ) CZ3) δ
:6-98 (2H, d, J=8Hz), 6.
63 (2H, d, J=8Hz), 6.15
(lH, m), 4.05 (2H, / , J='6H
z), 3.3-3-7 (2H, m), 2.58 (
2H, / , J = 6Hz), 1.97 (3H,
s), 1.5 to 1.9 (6H, m) Reference Example 19 Hydrogenation of 4-C4-<2-tetrahydropyranyloxy)phenyl-3-butynyl acetate 2.4f to anhydrous tetrahydrofuran solution Add aluminum lithium I2 and heat under reflux for 12 hours. After the reaction is completed, saturated sodium sulfate solution is gradually added to remove the precipitate, and the solution F is dried over sodium sulfate and concentrated to dryness. The resulting residue was purified by silica gel column chromatography to obtain 2 g of 4-((2-tetrahydropyranyloxy)phenyl)-3CE)-dthenyl alcohol as a colorless oil.

"H-NMR (90MHz %CDC25) δ: 1,'
l+-2-I (6H, m), 2.43 (2H, q
, J=6Hz), 3.4~4.0 (5H, 7M
), 5-37 (IH, m), 6.03 (IH.

d, t, J=I6Hz, 6Hz”), 6.40CIH
, d, J=16Hz), 6.97 (2H, d, J
=9Hz), 7.25 (2H,d.

J=9Hz) Example 1 4-(2-tetrahydropyranylo+shi)cinnamonomed alcohol 5.42.1,4-dihydro-2,6-dimethyl-5-methoxy,carbonyl-4-(3 -nitrophenyl)pyridicy 3-carpodialate 11.5F and DCC7,1f are dissolved in 3Qml of pyridine and stirred at room temperature overnight. Add 200 grams of water to the reaction solution, and extract with ethyl acetate. After washing with water, saturated potassium hydrogen sulfate, water, and saturated brine in this order, drying and distilling off the solvent. The obtained residue was filtered with Silikage J Rekalamuku 0 Mud Tarafie (eluent: RiO
3.4t of methyl 3-(4-
Tetra-dropyranyl+diphenyl) -2CE>-
Zropenyl 1,4-dihydro0-2,6-dimethyl-4
-(3-nitrophenyl)pyridy-3,5-''; obtains the carbodiic acid rate.

NMRδ (CDCt3): 1.4 to 2.0 (6H, m>, 2.26 (6H, m)
, 3.53 (3H.

S), 3.4-4.0 (2H, 2F+), 4.58
(2H, d, /= 6Hz), 5.03 (IH
,s), 5-30 (IH,t, J=3Hz
), 5.97 (IH, dt, Ja=6Hz,
Jb=16Hz), 6.30CIH, bs), 6.3
7 (lH, d, J = 16Hz), 6.88 (
2H,d, J-9Hz), 7.14 (2H,d
, J=9Hz), 7.20 (IH,t,
J = 6Hz), 7.50 (IH, dt, Ja
=2Hz, Jb-61-h), 7.82 (IH
,dt, Ja=2Hz.

Jb=6Hz), 8-00(IH,t, J=2Hz
>Example 2 Methyl 3-(4-tetrahydropyranyl-diphenyl)-2-dibenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5
-Dissolve 3.42 y of dicarboxylate in 5 Q ml of methanol, add 0.2 y of p-tolnidisulfonic acid, and stir at room temperature for 4 hours. After neutralization by adding sodium hydrogen carbonate, methanol was distilled off, and the residue was purified using silica gel.
After purification with madosilaffy (eluent: chloroform), recrystallization from becise cether yields methyl as a yellow powder.
3-(4-human 0 bovine diphenyl) -2(E) 10 benyl 1,4-dihydro-2,6-cymethyl-4-(3
2f of -nitrophenyl)pyridine-3,5-dicarpo bovine sylate is obtained.

yy+p137.5-139℃ Example 3 Anhydrous methylene chloride solution 2 of 1.61 tetramethylurea
Add 1.99% of oxalyl chloride to 9m/ at room temperature,
After heating under reflux for an hour, 4.3 t of dicarbonyl-4-(3-nitrophenyl)pyridine-3-carpodiaic acid in 1,4-dihydro-2,6-dimethyl-5-meth was added to the suspension. 1.7% of 3-p-(2-tetra-dropyranyl+thi)phenyl-di-Opal alcohol under water-cooling and stirring.
? and pyridine 3.5'ml anhydrous methylene chloride IQ
ml solution dropwise and stirred at room temperature for 3 hours. While cooling with water, the reaction solution was poured into 1N hydrochloric acid, washed with water and dried with 3-caliber sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: RI00-form) to give methyl 3-C4-C2-tetrahydropynyl 1,4-dihydro-2,
2.82 of 6-dimethyl-imaichi (3-nitrophenyl)pyridy 3,5-dicarpo+sylate is obtained.

Light yellow amorphous product Example 4 Methyl 3-[4-(2-tetrahydropyranyl diphenyl)]-2-vinyl 1,4-dihydro-2
,6,; 2.72 methyl-4-(3-di-O)pyridy-3,5-dicarboxylate in methanol 3
Dissolve in 0ml and add 10μ of p-toluene sulfosic acid to it.
Add and stir for 1 hour. After neutralizing the reaction solution by adding saturated aqueous sodium hydrogen carbonate solution, 10 Qml of water was added and extracted with chloroform. After washing with water three times, drying with Glauber's salt and distilling off the solvent. The residue was subjected to silica gel column chromatography (
Eluate: Purified with ethyl acetate:n- (4:I), then recrystallized with tetrahydrofluoride-n- (1:1) to give yellow prismatic crystals of methyl 3-(4-1:t).
"o+diphenyl)-2-'l robinyl 1,4-dihydro[]-]2,6-dimethyl-4-3-nitrophenyl)pyridine-3,5-dicarboxylate 1.2F is obtained.

mp173-176°C Example 5 Dicarbonyl-4-(3-nitrophenyl)pyridy-3- in 1,4-dihydro-2,6-dimethyl-5-meth
Carboxylic acid 1.9f, 30% sodium hydroxide aqueous solution 0
．． 78ml and HMP AI 5ml! 4-(4-Methylthiophenyl)-3(E)-thenyl bromide! is added to the mixed solution under ice-cooling. , 52 is added dropwise.

After stirring at room temperature for 8 hours and then at 40-45°C for 5 hours, the reaction solution was poured into ice water and extracted with chloroform. After washing with water, drying with sodium sulfate, and then distilling off the solvent. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate:
After purification with ethyl acetate-n-+salt = 12), it was recrystallized with beef maroon into ethyl acetate-n- to give methyl 4-(4-
Methylthiophenyl)-3(E)-dthenyl 1.4-
Dihydro-2,6-dimethyl-4-(3-:l-lophenyl)pyridy 3.5-dicarbo+sylate 1.0?
get.

mp165-170°C Example 6 1- (2(E)-acetoacetyl dimethylvinyl)-
4-(2-tetrahydroviranyl)benzecy3.
36F, 2-methylmerca-tobenzaldide 1.5
f and 1.22 ml of methyl 3-amic 0 tonate were added to 2 Q ml of isodurobanol, and the mixture was heated under reflux for 8 hours. After concentration, the residue was purified by silica gel column chromatography (eluent: RIOO form) to obtain 1.29 methyl
3-(4-tetrahydropyranyl diphenyl) -
2(E)-DuObenyl 1,4-dihydro-2,6-dimethyl-4-(3-nido-0-phenyl)pyridine-3,5
- Obtain dicarpo bovine sylate.

NMRδ (CDC13): 1.4-2.0C6H,m>, 2.26 (6H,m)
, 3.53C3H.

S), 3.4-4.0 (2H, m), 4.58 (2
H, d, /= 6H2), 5.03 (IH, s
), 5.30 (IH, t, J= 3Hz), 5
-97 (IH, di, Ja= 6Hz%lb=
16Hz), 6.30CIH, bs), 6.37 (
IH, d, J= I 6Hz), 6.88 (2
H, d, J=9Hz), 7. l4C2H,d,
J=9Hz), 7.20(IH,t, J=6Hz)
, 7.50 (IH, dt.

Ja = 2Hz%lb = 61h), 7.82 (I
H, di, Ja = 2Hz, Jb = 6Hz
), 8.00 (IH, t, J=2Hz) Examples 7 to 30 Each compound listed in Table 1 was obtained in the same manner as in Examples 1 and 6 using appropriate starting materials.

Examples 33-58 Each compound listed in Table 2 is obtained in the same manner as in Example 3 using appropriate starting materials.

Examples 59 to 84 Using appropriate starting materials, each compound listed in Table 3 was obtained in the same manner as in Example 5.0 NMR1) (90MHz 1CDC23): 2.28
(3H,s), 2.35 (6H,s), ・3.
6C3H,s), 4.67 (2H,d, J=
7Hz), 5.12 (lH,s), 6.06 (
IH, broad, s), 6. l5CIH,d
, t, Ja=7Hz.

Jb=I6Hz), 6.50(IH,d, J=
16Hz), 7.03 (2H,d, J=8Hz
), 7.30 (2H, d, J=BHz),
7-32 (IH, t, J=BHz), 7.63 (IH
vdt, Ja=2Hz, Jb=8Hz),
7.97CIH, d, t, Ja=2Hz, Jb=8Hz
), 8.12 (IH,t, J=2Hz)NM
R2) (90MHz-CDC43): 1.45-2
．． 10 (6H, m), 2.30 (6H, t ), 3.
40-4.00 (2H, m), 3-56 (3H, s
), 4-63 (2H, d, J=6Hz), 5-1
0 (IH,s), 5.37 (IH,t, J=
3Hz), 6.17 (IH, d, t, Ja-6
Hz, Jb=I6Hz), 6.45CIH,
d.

J=I 6Hz), 6.65-7.20 (4H, m
), 7.30 (IH,t.

J-7Hz), 7.62 (IH, d, l, Ja=2Hz
, Jb=7Hz), 7.95CIH,d,t, Ja=
2Hz, Jb=7Hz>, 8.13 (IH.

/ , J = 2Hz) NMR3) (90MHz, CDC43): 2.30
(3H,s), 2.32 (3H,s), 3.3
8 (3H,s), 3.53 (3H,s), 4.
65 (2H,d, J=7Hz), 5.10(
IH,s), 5.13 (2H,s), 6-20 (
IH, dt, Ja=6Hz, Jb-16Hz
), 6.47 (IH,s), 6.87 (IH,d
.

J=16Hz), 6-87 to 7-48 (5H, m)
, 7.62 (IH,di.

Ja-2Hz, jb=7Hz), 7.93 (
IH, di, Ja7-2Hz.

Jb=7Hz), 8.12 (IH,t, J=2
Hz)NMR''') (90MHz 1CDC4y)
:1.5C)-1,95(6H,m), l-97C3
H,s), 2.32 (6H.

S), 3.34-3.90 (IH, m), 3.53
(3H,s), 4,65 (2H,d, J=7Hz),
5.03 (IH, s), 5.33 (IH, t.

, J-3Jh), 5.70 (IH,/, J=7
Hz), 5.95 (IH.

broad + s), 6.97 (2H, d,
J = 9Hz), 7.23 (2H.

d, J=9Hz), 7.28(IH,/, J=
7Hz>, 7.58 (IH.

d, t, Ja=2Hz, Jb=7Hz
), 7.93 (IH, dt, Ja=2Hz,
Jb=7Hz), 8.08 (lH,t, J
= 2Hz) NMR5) (90MHz - CDC23
) '1.30~2-0 (6H, m), 2.32 (6
H,s), 3.53C3H.

S), 3-3-3-95 (2H, mr), 4-79
(2H,s), 5.07(IH,s), 5-33 (
IH,/, J=3Hz), 6.02 (IH.

S), 6.93C2H,d, J=IOHz), 7.28
(2H, tt, 1=10Hz), 7.27 (l
H,t, J=BHz), 7.66 (IH,
d.

J-8Hz), 7.93 (IH,d, J=8
Hz), 8-10 (IH,s) NMR6) (90
MH2%CDCt3): 1.40-2.10 (6H,
m>, 2.32 (6H, s), 3.43 (3H.

S), 3.20-3.85 (2H, m), 4.43
(2H, d, J = 7Hz), 4-95 (IH,
s), 5.23 (IH, t, J= 3Hz)
, 5.40-5.80 (IH, m), 5.93-6-5
3 (3H, m), 6.60 (IH.

S), 6.87 (2H, d, J-10Hz),
7.20C2H,d, J=10Hz), 7.23 (I
H,t, J=8Hz), 7.53CIH,d.

/ , Ja-2Hz, Jb=8Hz), 7.
88 (IH, d, t, Ja=2Hz, Jb-8H
z) NMR7) (60MHz 1CDC23) '1.40
~2.0 (6H, m), 2.30 (3H, s),
2.33C3H.

S), 3.20-3.90 (2H, m), 3.60
(3H,s), 4-63 (2H,d, J=6
Hz), 5.37 (IH, t, J= 3Hz)
, 5.80 (IH,s), 6.03 (IH,d,
t, Ja=6Hz, Jb=16Hz), 6
．． 80 (IH, s), 6.38 (IH, d, J=
16Hz), 6.90 (2H, d, J= 9Hz
), 7.20 (2H, d, J=9Hz),
6.75-7.80 (4#, m) NMR8) (90MHz-cDcz3): 1.43
~2.15 (6H, m), 2.30 (6H, s), 3
．． 38 (3H.

S), 3. -20~3.80 (2H, m), 4.47
(2H, dd, Ja=3Hz, Jb-7Hz
), 5.23 (IH,t, J=3Hz),
5.43 (IH, s), 6.83 (IH, broad
s), 5.94 CIH, dt.

Ja=6Hz, Jb=I6Hz), 6.2
3CIH, d, J=16Hz), 6.87 (2H, d
, J-9Hz), 7-13C2H,d, J=9H
z), 6.75-7.60 (4H, m) NMR9) (90MHz1CDCt3) '1.5-2
．． I (6H, m), 2.28 (3H, s ), 3.
53 (3H.

S), 3-76 (3H,s), 3.4-4.1 (I
H, m), 4.57C2H, d, J=6), 5-27
(IH, / , J = 3Hz), 5.99 (IH,
di, Ja-6Hz, Jb=16Hz), 6.07(1
7'/, s), 6.36 CIH, d, J=I6"), 6
．． 73 (IH, d, J=7Hz), 6.78
(IH, s), 6-93 (IH, d, J= 7H
z), 7.18 (IH, /, J=7Hz), 7.50
(IH, di, Ja=2Hz.

Jb=7Hz), 7.83 (IH, di, Ja=
2Hz, Jb=7Hz), 7.99CIH,
t, J=2Hz) NMR") (60MHz %CDC43) '1.24
(3H,t, J=7Hz), 2.37 (3
H,s) 1.3.66C3H,s), 3-79 (2
H, q, J" 7Hz), 4.70 (2H.

d, J-6Hz), 5.16 (IH, s), 5.
30 (2H,s), 5.91 (IH, broad
s), 6-10CIH, dt, Ja=6Hz.

Jb=I6Hz), 6.40CIH,d,/=I
6Hz), 7.00-7.47 (4H, m), 7.64
(IH, dt, Ja=2Hz, Jb=7H
z), 7.97 ('I H,di, Ja= 2H
z, Jb=7Hz), 8.14(lH,/, J
= 2Hz) NMR11) (90MHz% CDC13)".

1.40-2. IQ (6H, m), 2.26 (6H,
mr), 3.53 (3H.

S), 3.40-4. σ(2H,m), 4.58C2H
, d, J=6), 5.03 (IH,s), 5.30
(IH, / , J = 3Hz), 5.97 (IH
,di, Ja=6Hz, Jb=16Hz')
, 6.30 (IH.

broad s ), 6.37 (IH, d, J=
I 61h), 6.88 (2H.

d, J-9Hz),? , 14 (2H,d,
J=9Hz), 7.20(IH,/, J=6Hz
), 7.50 (IH,di, Ja=2Hz.

Jb=6Hz>, 7.82 (IH, di, Ja=2
Hz, Jb=6Hz), 8.00(IH, t, J=
2Hz>8MR12) (90MH2%CDC23): 1.522
．． 1 (6H, m), 2.33 (6H, s), 2.4
8 (2H.

q, J-6Hz), 3.58 (3H, s),
3.5-4.0 (2H, m), 4.15C2H,t, J
=6Hz), 5.09 (IH,s), 5.40 (
IH, m), 5.93 (IH, d, t, J=I5Hz
, 6Hz>, 6.30 (IH,s), 6-32 (I
H, d, 1=I5Hz), 6.96<2H, d, 1=
9Hz>, 7.19 (2H, d, 1=9Hz), 7.1
~7.3 (IH, m), 7-5-7-7 (IH, d, m
, J=6Hz), 7.8~B, 0(IH, d, m, J
=61h), 8.10(IH,m) Example 85 Methyl 3-(4-diphenyl)-2(E) monolopenyl 1,4-dihydro-2,6-dimethyl-4
-(3-nitrophenyl)pyridicy 3.5-dicarbo+sylate 0.59 is dissolved in pyridicy 5 ml, and 0.5 ml of acetic anhydride is added under water cooling. - After leaving overnight, pour into ice water and extract with ether. Dilute the ether layer with dilute hydrochloric acid to 10%
Wash sequentially with heavy sodium chloride water and water. After drying with Glauber's salt and concentrating, the residue was purified with silica gel chromatography (methanol:chloroform=I:100) to obtain methyl 3-(4-attylodecadiphenyl)-2(E
) -propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridy 3,5-dicarbo+sylate 0.42 was obtained.

2.28 (3H, s), 2-35 (6H, s)
, 3.64 (3H,s), 4.67 (2H,d
, J-7H2), 5.12 (IH, s), 6.06 (
IH, broad s), 6.15 (IH, d, t
, Ja=7Hz, Jb=16Hz), 6
．． 50 (IH, d, J= 16Hz), 7.03C2
H.

d, J=8Hz), 7.30 (2H,d,
J=8Hz), 7.32 (IH.

t, J=8Hz), 7.63 (IH,di,
Ja=2Hz, Jb=8Hz), 7.97 (
IH, d, t, Ja= 2Hx, Jb= 8H
z), 8, 12 (IH, t, J= 2Hz)
Pharmacological Test Methods Tile cuff method for systolic blood pressure and heart rate
cuff method). That is,
Thermostatic box (FR-12R5, l5UZU) for 4 experimental animals
Incubate at 0°C for 15 minutes to dilate the caudal artery and ELEC.
TROSPHYGMOMANOMETER (PE-30
0, Narco-biosystems) and Ishikuki Record-')-(RECTI-HORIZ 8
s%5AN-E1') was used to measure systolic blood pressure.

The experiment was conducted without anesthesia and under semi-restraint. The test drug was suspended in 0.15% arabic powder solution at the time of use so that the administration volume was 2.5 ml/Ky, and the drug was forcibly administered orally using an oral administration tube. The experimental animals were not fasted, and systolic blood pressure was measured before administration of the test drug (PRE) and at 8.24.30.48.54.72 hours after administration. In the experimental results, PRE is an absolute value, and after drug administration, PR is
It is shown as a change from E.

Test compound A! Methyl 3-(4-hydrobofiphenyl)-2(E
)-propenyl 1,4-dihydro-2,6-dimethyl-4-(3-nido-0-phenyl)pyridy3.5-,
;carboxylate 2 methyl 3-phenyl-2 (E
) --j Lopenyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridi, 7-3.5-
dicarbo+sylate 3 methyl 5-(4-hydrodiphenyl)-2(E
), 4 (E)-hecitagenyl l, Imaichi dihydro-2,6-: methyl-4-(3-nitrophenyl)pyridy 3,5-dicarpoxysylate methyl 3-methyl-3-(4-hydro bovine diphenyl') -2(E)-zuObenyl 1,4-dihytoO-
2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarpoxylate 5 methyl 3-phenyl-2-vinyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) phenyl) pyridicy 3.5-,;
-2,6-dimethyl-4-(3-dito-0)-pyridine-3,5-dicarpoxysilate (comparative compound, compound disclosed in JP-A-56-36455) The compound is disclosed in JP-A-56-3645.
It is clear that the drug's efficacy lasts longer than the compound described in Publication No. 5.

(that's all)

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1, R^2 and R^4 each represent a lower alkyl group. R^3 represents a nitro group or a lower alkyl group that may have 1 to 3 halogen atoms as a substituent. R^5 has 1 to 3 substituents selected from the group consisting of a lower alkoxy group, a halogen atom, a lower alkylthio group, a hydroxyl group, a lower alkanoyloxy group, a tetrahydropyranyloxy group, and a lower alkoxy lower alkoxy group. Indicates a certain phenyl group. A represents an unsaturated chain hydrocarbon residue. ] An antihypertensive agent containing a dihydropyridine derivative or a salt thereof as an active ingredient.