JPH0699390B2 - Substituted vinyl derivative and pharmaceutical composition thereof - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel substituted vinyl derivative having an action of specifically inhibiting thromboxane A ₂ (TXA ₂ ) synthase.

TXA ₂ is one of the metabolites of arachidonic acid, and has platelet aggregation activity and vascular smooth muscle contraction activity. Therefore, it is known that when it is excessively produced in the body, it causes platelet aggregation, vascular occlusion, vasospasm and causes various diseases such as ischemic heart, kidney and brain. The present inventors have synthesized substances having TXA ₂ synthetase inhibitory action, results having conducted a search research, I found a group of novel compounds having excellent TXA ₂ synthetase inhibitory activity.

That is, the present invention has the general formula [In the formula, R ¹ represents an aromatic group which may have a substituent, a thienyl group, a furyl group, a pyridyl group or a benzothienyl group, and R ² represents a lower alkyl group, a hydroxymethyl group, a nitroxymethyl group, Formyl group, nitrogen-containing 5-membered ring-methyl group,
Acetal-methyl group, trialkylsilyloxymethyl group, alkyl or aryl-sulfonyloxymethyl group, alkyl or arylsulfonylaminocarbonyloxymethyl group, acyloxymethyl group, alkoxycarbonyloxymethyl group, halogenomethyl group, alkoxymethyl group, An aryloxymethyl group, a cyano group, an optionally substituted carbamoyl group, an optionally substituted carbamoyloxymethyl group, an optionally substituted thiocarbamoyloxymethyl group, a carboxyl group or an alkoxycarbonyl group, Indicates. n is And R ² is a carboxyl group or an alkoxycarbonyl group, 1 or an integer of 9 to 20, and otherwise an integer of 1 to 20. ] A substituted vinyl derivative represented by the following formula or a pharmacologically acceptable salt thereof, and a thromboxane containing a substituted vinyl derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient. A ₂ synthase inhibitor.

In the general formula, the aromatic group represented by R ¹ is an aryl group such as phenyl, naphthyl, α-naphthyl, β-naphthyl, the thienyl group is thienyl and 3-thienyl, and the furyl group is 2 -Furyl and 3-furyl, 2-pyridyl as the pyridyl group, 3-pyridyl and 4-pyridyl, 2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl as the benzothienyl group, 6-benzothienyl and 7
-Benzothienyl. These aromatic group, thienyl group, furyl group, pyridyl group and benzothienyl group may have a substituent at any position on the ring. Examples of the substituent include lower alkoxy (eg, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-
Butoxy, t-butoxy and the like having 1 to 4 carbon atoms, lower alkyl (eg methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl Such as those having 1 to 5 carbon atoms), trifluoromethyl, lower alkenyl (eg vinyl, allyl,
Pentenyl and the like having 2 to 5 carbon atoms), halogen (fluorine, chlorine, bromine, iodine), methylenedioxy and the like. With respect to R ² , examples of the lower alkyl group include those having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and the like. Examples of the methyl group include imidazolylmethyl (1-imidazolylmethyl, 2-imidazolylmethyl), triazolylmethyl (1-triazolylmethyl, 3
-Triazolylmethyl, 5-triazolylmethyl), tetrazolylmethyl (1-tetrazolylmethyl, 5-tetrazolylmethyl), etc. The hydrogen of the methyl group has 2 to 4 nitrogen atoms on the ring. Those substituted with a 5-membered ring group contained therein include acetal-methyl groups such as 2-tetrahydropyranyloxymethyl and 2-tetrahydrofuryloxymethyl, and trialkylsilyloxymethyl groups such as dimethyl tertiary. Examples of the alkyl- or aryl-sulfonyloxymethyl group include secondary butylsilyloxymethyl and the like.
-Toluenesulfonyloxymethyl is alkyl-
Or as the aryl-sulfonylaminocarbonyloxymethyl group, for example, methanesulfonylaminocarbonyloxymethyl, p-toluenesulfonylaminocarbonyloxymethyl and the like, the acyloxymethyl group is represented by the formula R ⁴ COOCH _2- [wherein, R ⁴ is hydrogen, C1-C6 alkyl (methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, n-pentyl, i-pentyl, n-hexyl etc.) or pyridyl (2-pyridyl, 3- Pyridyl, 4
-Pyridyl). The group represented by] is, for example, an alkoxycarbonyloxymethyl group such as methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, n-propoxycarbonyloxymethyl, i-propoxycarbonyloxymethyl, n-butoxycarbonyloxymethyl, i-butoxycarbonyl. Oxymethyl, n-pentyloxycarbonyloxymethyl, n-hexyloxycarbonyloxymethyl and the like having 3 to 8 carbon atoms, the halogenomethyl group is fluoromethyl, chloromethyl, bromomethyl and iodomethyl, and the alkoxymethyl group is, for example. A lower alkoxymethyl having 2 to 5 carbon atoms such as methoxymethyl, ethoxymethyl, n-propoxymethyl, i-propoxymethyl, n-butoxymethyl and i-butoxymethyl is aryloxymethyl. Examples thereof include phenyloxymethyl, 2-methylphenyloxymethyl, 3-methylphenyloxymethyl, 4-methylphenyloxymethyl, 2,4-dimethylphenyloxymethyl, 3,4-dimethylphenyloxy. A carbamoyl group which has 7 to 9 carbon atoms, such as methyl, may be substituted and is represented by the formula [In the formula, R ⁵ and R ⁶ are the same or different and each is hydrogen, carbon number 1 to 6
Alkyl (eg methyl, ethyl, n-propyl, i-
Propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, i-hexyl, etc.) or C _6-8 allyl (phenyl, 2-methylphenyl, 3-methylphenyl, 4 -Methylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl and the like). And a carbamoyloxymethyl group which may be substituted is represented by the formula: [In the formula, R ⁵ and R ⁶ are as defined above. ] The thiocarbamoyloxymethyl group which may be substituted is represented by the formula: [In the formula, R ⁵ and R ⁶ have the same meanings as described above. And an alkoxycarbonyl group having 2 to 2 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, and t-butoxycarbonyl. Five items are given respectively.

Examples of the pharmacologically acceptable salt of the compound represented by formula (I) include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, succinic acid, maleic acid, fumaric acid, oxalic acid, methane. An addition salt of an organic acid or an inorganic acid such as sulfonic acid or benzenesulfonic acid, or when R ² of the compound (I) is a carboxyl group, an alkali metal salt such as sodium salt or potassium salt, or an alkaline earth salt such as calcium salt. Examples thereof include metal salts.

The compound represented by the general formula (I) has the general formula And the general formula [Wherein each symbol has the same meaning as defined above] 2
There are various kinds of geometrical isomers, and the compound represented by the general formula (I-1) has a stronger thromboxane synthase inhibitory action than the compound represented by the general formula (I-2). I'm winning

Hereinafter, like the compound represented by the general formula (I-1),
A compound in which a pyridine ring having one carbon substituted with a double bond in a vinyl group and a hydrogen atom having another carbon substituted in the same direction are E isomers, and a compound represented by the general formula (I-2) As described above, a compound in which a pyridine ring substituted on one carbon and a hydrogen atom substituted on the other carbon sandwiching a double bond in a vinyl group are in opposite directions to each other is referred to as a Z isomer. .

General formula [In the formula, R ¹ and n have the same meanings as described above, and R ^2e represents a lower alkyl group or a carboxyl group. ] The E isomer represented by [In the formula, R ¹ and n have the same meanings as described above, and R ^2f represents a lower alkyl, a cyano group, an optionally substituted carbamoyl group, a carboxyl group or an alkoxycarbonyl group. ] It can manufacture by heating the compound represented by these in the presence of a mineral acid.

The individual substituents represented by R ^2e and R ^2f are the same as defined for the corresponding substituent represented by R ² .

This reaction is usually carried out in water or a water-containing organic solvent,
The water-containing organic solvent may basically be one that is not decomposed by a mineral acid, and specific examples thereof include a mixed solvent of acetic acid, formic acid and the like and water. Examples of the mineral acid include hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, perchloric acid, methanesulfonic acid, etc.
Hydrobromic acid and phosphoric acid are preferably used. These catalysts are usually used in an amount of about 6 to 15 mol per 1 mol of the raw material compound (Iw). The reaction temperature is usually about 50 to 140 ° C, preferably 100 to 130 ° C. If the reaction temperature is too low, the reaction becomes slow, which is not preferable. The reaction time depends on the type and amount of catalyst,
Depending on the heating temperature, it is usually carried out by selecting conditions under which the acidic isomerization equilibrium is completed within 10 to 40 hours.

This reaction is an equilibrium reaction between the E isomer (Iv) and the Z isomer (Iw), and by subjecting either the E or Z isomer alone or any mixture thereof to the isomerization reaction, E
Isomer (Iv) (about 60-70%) and Z-isomer (Iw) (about 30-)
40%) mixture. As mentioned above,
In general, the E isomer is pharmacologically superior to the Z isomer, so it is desirable to apply this reaction to a mixture containing 40% or more of the Z isomer.

In this reaction, as a starting material, the compound of the general formula (Iw)
When a reaction is carried out using a compound in which R ^2f is a cyano group, an optionally substituted carbamoyl group or an alkoxycarbonyl group, hydrolysis proceeds in parallel and a carboxyl compound is obtained.

The target compound (Iv) (E isomer) obtained by this reaction is obtained by adjusting the pH of the reaction mixture solution with, for example, aqueous ammonia, sodium hydroxide, potassium hydroxide or the like.
After adjusting the pH to 5.0 to 6.0, the product is extracted with an organic solvent such as ethyl acetate, chloroform, or dichloromethane, and separated and purified by a means known per se, such as crystallization method or chromatography. You can The isomerization reaction is repeated for a mixture rich in the remaining Z isomer, which is obtained by separating the E isomer (Iv) by separation or fractional crystallization. The rate can be improved.

The substituted vinyl derivative represented by the general formula (I) and a pharmacologically acceptable salt thereof (hereinafter sometimes simply referred to as compound (I)) are thromboxane solubilized and fractionated from platelet microsomes of humans, horses and the like. It has a synthase-inhibiting action and exhibits a potent and long-lasting biosynthesis-inhibiting action of thromboxane A ₂ (TXA ₂ ) in mammals including humans.

Further, the compound (I) of the present invention has an arterial smooth muscle relaxing action,
It shows an effect of increasing the production efficiency of prostaglandin I ₂ (PGI ₂ ) which has an inhibitory effect on platelet aggregation or a re-dissociation effect on aggregated platelets. Ie prostaglandins
G ₂ (PGG ₂ ) or prostaglandin H ₂ (PGH ₂ ) is thromboxane A ₂ and prostaglandin in vivo.
Is an important precursor for the synthesis of I ₂ and other prostaglandins, the present invention compound (I) converting enzyme from PGH ₂ or PGG ₂ into thromboxane A ₂ (thromboxane A ₂ synthetase) Shows an inhibitory action at extremely low doses (1 to 10 mg / kg), while physiologically extremely useful prostaglandin I ₂ (PGI ₂ ) and other prostaglandin converting enzymes such as PGI ₂ It has almost no inhibitory effect on synthases and various prostaglandin synthases, but rather enhances the utilization efficiency of PGH ₂ or PGG ₂ in vivo, such as PGD ₂ in platelets and vascular endothelium. In the presence of cells, it shows a PGI ₂ production enhancing action. Among them, the compound in which R ^{2 in the} general formula (I) is a carboxyl group has a strong above-mentioned action. A compound of the general formula (I) in which R ² is other than a carboxyl group has the above-mentioned action by itself, but it is considered that R ² is converted to a carboxyl group in vivo, and in vivo experiments, The above-mentioned effects are almost the same as those of the compound in which R ² is a carboxyl group.

Thus, the compound (I) of the present invention has no inhibitory effect on prostaglandin I ₂ (PGI ₂ ) synthase, prostaglandin synthase (cyclooxygenase) and various prostaglandin synthases. , Thromboxane A ₂ (TXA ₂ ) synthase is selectively and potently and persistently inhibited.

Further, the compound of the general formula (I) in which R ² is ONO ₂ has a smooth muscle relaxing action in addition to the above actions.

Further, the compound of the present invention has a very low toxic effect on rats and dogs, and is characterized by a wide range of toxicity and therapeutically effective dose. In addition, the compound (I) of the present invention is expected to have a long-term stable TXA ₂ synthase inhibitory action without long-lasting drug effect in vivo. Therefore, the compound according to the present invention is used in a small dose and has few side effects due to long-term continuous use, and is caused by thrombosis due to platelet aggregation based on TXA ₂ or vasospasm in the heart, brain and periphery, and circulatory system. Prevention or treatment of ischemic diseases (eg myocardial infarction, stroke, vascular infarction such as kidneys and lungs, gastrointestinal ulcers etc.) and various diseases based on TXA ₂ / PGI ₂ imbalance (eg arteriosclerosis, hypertension etc.) For use in mammals, including humans.
As the administration method, for example, tablets, capsules, powders, granules and the like can be used orally, and injections and pellets can be administered parenterally. The daily dose for an adult is usually 20 to 200 mg orally and 10 to 100 mg parenterally in 1 to 3 divided doses per day.

The substituted vinyl derivative represented by the general formula (I) can be produced by any of the methods described below.

[Production method 1] General formula Wherein each symbol is as defined above] and a compound represented by the general formula _{(C 6 H 5) 3 P} + -CH 2 - (CH 2) n -R 2a · X - (III) [ In the formula, R ^2a is a lower alkyl group, a hydroxymethyl group,
Nitroxymethyl group, nitrogen-containing 5-membered ring-methyl group, acetal-methyl group, trialkylsilyloxymethyl group,
An alkyl or aryl-sulfonyloxymethyl group,
Alkyl or aryl sulfonylaminocarbonyloxymethyl group, acyloxymethyl group, alkoxycarbonyloxymethyl group, halogenomethyl group, alkoxymethyl group, aryloxymethyl group, cyano group, optionally substituted carbamoyl group, substituted A carbamoyloxymethyl group, an optionally substituted thiocarbamoyloxymethyl group, a carboxyl group or an alkoxycarbonyl group, X ⁻ represents a halogen ion, and n has the same meaning as described above. ] By reacting with a compound represented by the general formula [Wherein R ^2b is a lower alkyl group, a hydroxymethyl group,
Nitroxymethyl group, nitrogen-containing 5-membered ring-methyl group, acetal-methyl group, trialkylsilyloxymethyl group,
A compound represented by a halogenomethyl group, an alkoxymethyl group, an aryloxymethyl group, a cyano group, an optionally substituted carbamoyl group, a carboxyl group or an alkoxycarbonyl group, and other symbols having the same meanings as the above] Can be obtained.

The definition of the individual substituent, the group represented by R ^2a and R ^2b, R ²
Is the same as the definition of the corresponding substituent represented by. Examples of the halogen ion represented by X ⁻ include chlorine ion, bromine ion, and iodine ion.

This reaction is usually performed in an organic solvent in the presence of a base.
Examples of the base include n-butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride, tertiary butoxypotassium, sodium amide and the like. Among them, lithium diisopropylamide, sodium hydride and sodium amide are preferably used. Examples of the solvent include ether, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, or a mixed solvent of two or more selected from these solvents. This reaction is preferably carried out in a dry inert gas (eg, nitrogen gas, argon gas, helium gas, etc.) atmosphere. The reaction temperature will differ depending on the type of reaction solvent and the type of basic compound used, but is usually in the range of -70 ° C to 30 ° C. In this reaction, the progress of the reaction can be known by observing the disappearance of the characteristic color of phosphorane, and the reaction is usually completed in about 1 to 6 hours.

In this reaction, the compound of general formula (I
In II) R ^2a is an alkylsulfonyloxymethyl group, an arylsulfonyloxymethyl group, an alkylsulfonylaminocarbonyloxymethyl group, an arylsulfonylaminocarbonyloxymethyl group, an asyloxymethyl group, an alkoxycarbonyloxymethyl group, even if substituted When a compound having a good carbamoyloxymethyl group or an optionally substituted thiocarbamoyloxymethyl group is used, a compound (Ia) in which R ^2b is hydroxymethyl may be obtained.

[Production Example 2] General formula [In the formula, R ¹ and n have the same meanings as described above, and R ³ represents a hydrogen atom, a lower alkyl group, a lower alkoxycarbonyl group or an N-succinimide group. ] By reducing the compound represented by the general formula A substituted vinyl derivative represented by the formula [wherein R ¹ and n have the same meanings as described above] can be produced.

The lower alkyl represented by R ³ includes, for example, methyl,
Those having 1 to 4 carbon atoms such as ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl, and lower alkoxycarbonyl groups include, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl. , i
-Propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, t-butoxycarbonyl, etc., with 2 carbon atoms
~ 5 can be mentioned.

In the general formula (Ib), a carboxylic acid or ester compound in which R ³ is a hydrogen atom or a lower alkyl group is usually reacted with lithium aluminum hydride in a solvent such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane. This can lead to the corresponding alcohol (Ic). This reduction reaction easily proceeds when R ³ is a lower alkyl group. The reaction temperature is -10 ° C to 70 ° C, and the reaction is usually completed at room temperature for 1 to 10 hours. The reducing agent is used in a molar amount of 1 to 2 times. After the reaction, the excess reducing agent is decomposed, and the target product is extracted and separated by a method known in the art.

Further, in the general formula (Ib), a compound in which R ³ is a lower alkoxycarbonyl group or a succinimide group is methanol,
Ethanol, diethyl ether, tetrahydrofuran,
The corresponding alcohol compound (Ic) can be obtained by reduction with sodium borohydride or potassium borohydride in 1,2-dimethoxyethane or a water-containing solvent thereof.

[Production method 3] General formula [Wherein each symbol has the same meaning as defined above] by oxidizing the compound represented by the general formula A substituted vinyl derivative represented by the formula [wherein each symbol has the same meaning as described above] can be produced.

This reaction is carried out by reacting the compound represented by the general formula (Id) with an oxidizing agent in a suitable solvent. Examples of the oxidizing agent include hydrogen peroxide, peracetic acid, perbenzoic acid and m-chloro. Peroxides such as perbenzoic acid are preferably used, and examples of the solvent include water or organic solvents such as chloroform, methylene chloride, acetic acid, ethyl acetate and the like. The reaction temperature is generally -30 ° -50 ° C, preferably -10 ° -30 ° C.

[Production method 4] General formula [Each symbol in the formula has the same meaning as described above. ] By acylating, carbamoylating, thiocarbamoylating or alkyl-, arylsulfonylaminocarbonylating or alkoxycarbonylating the compound represented by [Wherein R ¹ , n and Is as defined above, R ^2d is an acyloxymethyl group,
An optionally substituted carbamoyloxymethyl group, an optionally substituted thiocarbamoyloxymethyl group,
An alkyl- or arylsulfonylaminocarbonyloxymethyl group or an alkoxycarbonyloxymethyl group is shown. ) The compound represented by this formula can be produced.

In the general formula (Ig), an acyloxymethyl group represented by R ^2d , an optionally substituted carbamoyloxymethyl group, an optionally substituted thiocarbamoyloxymethyl group, or an alkyl- or arylsulfonylaminocarbonyloxymethyl group Are the same as their definitions for R ² .

In the acylation or alkoxycarbonyloxylation reaction, the corresponding acid chloride, acid anhydride, chlorocarbonic acid ester or the like is reacted with a compound represented by the general formula (Ic) in the presence of a basic substance (eg, triethylamine, pyridine). It is done by things. This reaction is usually carried out in dimethylformamide, pyridine or chloroform at -10 ° to 30 ° C.
Done in. Acetic anhydride, propionic anhydride, and benzoic anhydride are used as acid anhydrides, and acetyl chloride, butyric acid chloride, isobutyric acid chloride, nicotinic acid chloride, and benzoyl chloride are used as acid chlorides.
Examples of the chlorocarbonic acid ester include methyl chlorocarbonate, ethyl chlorocarbonate, benzyl chlorocarbonate, tert-butyl chlorocarbonate and the like.

Reactions such as (substituted) -carbamoylation, (substituted) -thiocarbamoylation or alkyl- or aryl-sulfonylaminocarbonylation may be carried out with organic or inorganic acids (eg,
Cyanate or thiocyanate in the presence of trifluoroacetic acid, methanesulfonic acid, hydrochloric acid) or alkyl or aryl cyanic acid, alkyl or aryl thiocyanic acid in the presence of triethylamine or pyridine, or alkyl or aryl sulfonyl cyanic acid Can be carried out by using

Examples of cyanates or thiocyanates include sodium cyanate, potassium cyanate, sodium thiocyanate,
Potassium thiocyanate and the like can also be used as the alkyl or aryl group of alkyl or aryl cyanic acid, alkyl or aryl thiocyanic acid, alkyl or aryl sulfonyl cyanate, for example, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, phenyl, 3 -Pyridyl and the like.

The reaction temperature is 0 ° C to 50 ° C, and the reaction is completed in 1 to 10 hours. The reaction is carried out without solvent or in an anhydrous solvent (eg chloroform, methylene chloride).

[Production method 5] General formula [In the formula, R ¹ and n have the same meanings as described above, and R ⁷ represents an alkyl or aryl group. ] By reducing the compound represented by the general formula [In the formula, R ¹ and n have the same meanings as described above. ] The compound represented by these can be manufactured.

In the general formula (Ih), examples of the alkyl or aryl group represented by R ⁷ include methyl and p-tolyl, and —CH ₂ OSO
₂ R ⁷ is the same as the alkyl- or aryl-sulfonyloxymethyl group represented by R ² .

This reaction is usually carried out in an atmosphere of argon, helium or nitrogen gas, in an ether solvent such as dimethyl ether, tetrahydrofuran, 1,2-dimethoxyethane or in hexamethylphosphoramide, a reducing agent such as lithium aluminum hydride or sodium cyanoborohydride. Is carried out by reducing with. The amount of the reducing agent used is the compound (I
h) 0.5 to 2 mol is preferable to 1 mol, and the reaction temperature is usually 10 to 80 ° C.

[Production method 6] General formula [Each symbol in the formula has the same meaning as described above. ] By reacting a compound represented by [Wherein R ¹ , n and Has the same meaning as above, and X represents a halogen atom. ] The halogen compound represented by these can be obtained.

In the general formula (Ik), the halogen atom represented by X includes fluorine, chlorine, bromine and iodine, and —CH ₂ X is the same as the halogenomethyl group represented by R ² . In this reaction, exchange reaction with sodium bromide, potassium bromide, sodium iodide, potassium iodide, triethylamine, hydrochloride, etc. in a solvent such as methylene chloride, chloroform, acetone, methanol, hydrous acetone, hydrous methanol. It is carried out by. The reaction is usually completed in 1 to 20 hours at 0 to 50 ° C.

[Production Method 7] By reacting the compound represented by the general formula (Ij) or (Ik) with silver nitrate, [Wherein R ¹ , n and Is as defined above. ] The compound represented by these can be manufactured.

This reaction is usually carried out, for example, with acetonitrile, dioxane,
It is carried out in a solvent such as 1,2-dimethoxyethane or acetone. The amount of silver nitrate used is compound (Ij) or (Ik) 1
The amount is preferably 1 to 1.2 mol per mol. The reaction is usually carried out at room temperature, and the reaction time is usually 2 to 5 hours.

[Production method 8] General formula [Each symbol in the formula has the same meaning as described above. ] The compound of the general formula [Wherein R ¹ , n and Is as defined above. ] The compound represented by these can be manufactured.

This reaction generally proceeds easily by using a known means for conducting an alcohol to an aldehyde. For example, the compound (Im) can be oxidized by using a chromic acid-pyridine complex or a dimethyl sulfoxide-oxalic acid chloride-triethylamine mixed solution.

[Production Method 9] A compound represented by the general formula (Ij) or (Ik) is reacted with an alkali metal alkoxide or an aryl oxide to give a compound represented by the general formula [Wherein R ¹ , n and Has the same meaning as defined above, and R ⁸ represents an alkyl group or an aryl group. ] The compound represented by these can be manufactured.

In the general formula (Io), examples of the alkyl group and aryl group represented by R ⁸ include methyl and p-tolyl.
—CH ₂ OR ⁸ has the same definition as each of the alkoxymethyl group and aryloxymethyl represented by R ² .

This reaction is carried out in the alcohol or phenol corresponding to the sodium or potassium alkoxide or sodium or potassium phenoxide corresponding to the alkoxy group or aryloxy group to be introduced.
Examples of alkoxides include methoxide, ethoxide, and propoxide. Examples of alcohols include methanol, ethanol and propanol.

[Production Method 10] By reacting a compound represented by the general formula (Im) with dihydropyran or dihydrofuran in the presence of an acid catalyst, the general formula [Wherein R ¹ , n and Has the same meaning as above, and R ⁹ represents an acetal group. ] The compound represented by these can be manufactured.

In the general formula (Ip), the acetal group represented by R ⁹ is
Examples thereof include 2-tetrahydropyranyloxy, 2-tetrahydrofuryloxy and the like, and —CH ₂ R ⁹ is the same as acetal-methyl in the definition of R ² .

This reaction is usually performed in the presence of an acid catalyst. Examples of the acid catalyst include p-toluenesulfonic acid and camphorsulfonic acid. As a reaction solvent, anhydrous chloroform, methylene chloride, etc. are often used. The reaction is usually completed at 0 ° to 30 ° C for 1 to 3 hours.

[Production Method 11] Compound represented by general formula (Ik) and general formula R ¹⁰ —H (IV) [In the formula, R ¹⁰ represents a nitrogen-containing 5-membered ring group. ] By reacting with a compound represented by the general formula [In the formula, each symbol has the same meaning as described above. ] The compound represented by these can be manufactured.

In formula (Iq), the nitrogen-containing 5-membered ring group represented by R ¹⁰ is —CH ₂
This is the same as the definition of the nitrogen-containing 5-membered ring-methyl group represented by R ² as R ¹⁰ .

This reaction is usually carried out in the presence of a base such as sodium hydride or potassium tertiary butoxy. The reaction solvent is dimethylformamide, dimethylsulfoxide,
1,2-dimethoxyethane tertiary butanol is used,
The reaction is usually performed at 0 to 50 ° C.

[Production method 12] General formula [In the formula, Y represents a chlorine atom or a lower alkoxy group, and R ¹ and n have the same meanings as described above. ] And a compound represented by the general formula [In the formula, R ⁵ and R ⁶ have the same meanings as described above. ] By reacting with the general formula [In the formula, each symbol has the same meaning as described above. ] Can be manufactured.

This amidation reaction is a generally known method, for example, in the general formula (Ir), when Y is alkoxy, the compound is a solvent-free solvent such as methanol, ethanol, dioxane, or toluene and the amine compound in a temperature range of 0 ° to 100 ° Can be done at. Further, in the general formula (Ir), when Y is a chlorine atom, it can be carried out in the presence of pyridine, triethylamine, sodium carbonate, potassium carbonate or the like in methylene chloride, chloroform, acetone, a water-containing solvent or the like.

[Production Method 13] By reacting the compound represented by the general formula (Ij) or (Ik) with sodium cyanide or potassium cyanide, [In the formula, each symbol has the same meaning as described above. ] The compound represented by these can be manufactured.

This reaction can be carried out according to a known nitration reaction. For example, dimethyl sulfoxide or dimethylformamide is used as the reaction solvent, and the reaction is completed at 0 ° to 30 ° C in 5 to 20 hours.

[Production Method 14] The compound represented by the general formula (Ic) and the general formula R ⁷ —SO ₂ —Cl (VI) [wherein, R ₇ has the same meaning as described above. ] By reacting with a compound represented by the general formula [In the formula, each symbol has the same meaning as described above. ] The compound represented by these can be manufactured.

This reaction can be carried out in the presence of pyridine or triethylamine in a dimethylformamide, methylene chloride or chloroform solvent in the temperature range of 0 ° to 30 ° C.

[Production Method 15] By reacting a compound represented by the general formula (Ic) with a trialkylsilyl chloride in the presence of pyridiline or triethylamine, a compound of the general formula [In the formula, R ¹ and n have the same meanings as described above, and R ¹¹ represents a trialkylsilyloxy group. ] The compound represented by these can be manufactured.

In the general formula (Iu), trialkyl silyl group represented by R ¹¹ are as defined trialkylsilyl oxymethyl group in R ² a -CH ₂ R ^11.

The reaction is usually carried out in methylene chloride or chloroform and can be carried out in the range of 0 ° to 30 ° C.

The substituted vinyl derivative (I) thus produced is
For example, it can be separated and purified by usual means such as extraction, concentration, crystallization method and liquid chromatography.
Compound (I) belongs to the tri-substituted olefin compound,
Geometrical isomers of species may exist, and the isomers can be separated by a fractional crystallization method, chromatography or the like, if necessary.

The compound of the general formula (II) is obtained by reacting an organolithium compound with an aldehyde compound to obtain a compound (VII), and then adding manganese dioxide or dimethyl sulfoxide-oxalic acid to the compound (VII). It can be produced by reacting chloride.

[In the formula, each symbol has the same meaning as described above. Hereinafter, the present invention will be described more specifically with reference to Examples, Experimental Examples and Reference Examples.

Example 1 (Compound Id-1) Sodium amide (3.12 g, 80 mmole) was added to dimethyl sulfoxide (35 ml) under a nitrogen stream, and the mixture was stirred at room temperature for 10 minutes. Hexyltriphenylphosphonium bromide (33.7g, 79mmole) keeping the reaction temperature below 40 ℃
After stirring for 1 hour, add dimethyl sulfoxide (30m) containing 3-benzoylpyridine (14.5g, 79mmole).
l) The solution was added at room temperature. After dropping, add another 3 at room temperature.
After reacting for 0 minutes, 2N hydrochloric acid (500 ml) was added, and the neutral component was removed with toluene. The aqueous layer was made alkaline with sodium carbonate and the oily product was extracted twice with ether. The ether layers were combined, washed with water, dried (magnesium sulfate), and the organic solvent was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and developed with isopropyl ether: ethyl acetate (4: 1) to give 1-phenyl-1- (3-pyridyl) -1-heptene (18.2 g, 92%) as an isomer. Obtained as a mixture (E: Z = 1: 1).

The compounds Id-1 to Id-7 produced according to this example are shown in the table.
Shown in 1.

Example 2 (Compounds Id-8 and Id-9) Sodium hydride (60% oily dispersion, 2.7 g, 68 mmole) was washed with hexane, hexane was removed under reduced pressure, and then dimethyl sulfoxide (40 ml) was added. The mixture was heated and stirred at 85 ° C for 1 hour. After cooling, a dimethyl sulfoxide solution (20 ml) containing 10-carboxydecanyltriphenylphosphonium bromide (18.0 g, 34 mmole) was added dropwise. 10 minutes later,
3-Benzoylpyridine (6.2g, 33.8mmole) was dissolved in dimethylsulfoxide (10ml) and added. After reacting for 1 hour, water (200 ml) was added and the reaction product was washed with toluene. The aqueous layer was neutralized with 2N hydrochloric acid to pH 5.2, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and developed with ethyl acetate. The product was fractionally recrystallized from isopropyl ether to give (Z) -12-phenyl-12-
(3-pyridyl) -11-dodecaenoic acid (3.2 g) (compound
Id-8) was obtained.

The crystal mother liquor was dissolved in ethanol (20 ml), thionyl chloride (3 ml) was added thereto, and the mixture was allowed to stand at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, 5% aqueous sodium carbonate (50 ml) was added, the product was extracted with methylene chloride, the organic layer was washed with water, dried and concentrated. The residue was subjected to silica gel chromatography, developed with isopropyl ether, and the resulting ethyl ester was hydrolyzed to give (E) -12-phenyl-12- (3
-Pyridyl) -11-dodecaenoic acid (2.3 g) (Compound Id-
9) was obtained.

Tables of compounds Id-10 to Id-13 produced according to this example
Shown in 2.

Example 3 (E) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid ethyl ester (1.5 g, 4.8 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml) and cooled with ice. Lithium aluminum hydride (0.5 g) was gradually added thereto. After stirring the mixture at 0 ° C. for 30 minutes, saturated Rochelle salt water was added to precipitate inorganic substances. The organic layer was separated, the precipitate was washed with tetrahydrofuran (30 ml), combined with a tetrahydrofuran solution, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethyl acetate to obtain (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol (1.
2 g, 94%) (Compound Id-14) was obtained as an oil.

Compounds Id-15 to Id-18 produced according to this example are shown in Table-
Shown in 3.

Example 4 (Id-17) (E) -7- (3-pyridyl) -7- (2-thienyl)
-6-Heptenoic acid (0.4g, 1.4mmole) was dissolved in anhydrous tetrahydrofuran (20ml), lithium aluminum hydride (0.1g, 2.6mmole) was added thereto, and the mixture was stirred at 50 ° C for 1 hour. To the reaction solution was added saturated Rochelle salt water (10 ml),
The organic layer is separated and the precipitate is tetrahydrofuran (20 ml)
The extract was washed with, combined with a tetrahydrofuran solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel chromatography and eluted with ethyl acetate (E)-
7- (3-Pyridyl) -7- (2-thienyl) -6-hept-1-ol (0.21 g, 52%) (Compound Id-17) was obtained.

Compounds Id-14, Id-15, Id-1 produced according to this example
7, Id-18 is shown in Table-3.

Example 5 (Compound Id-19) (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol (0.4 g, 1.5 mmole) was added to methylene chloride (1).
Dissolve in 0 ml), pyridine (0.4 ml) and acetic anhydride (0.2 m
l) was added and left at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and developed with ethyl acetate to give (E) -7-phenyl-7- (3-
Pyridyl) -6-hept-1-ol acetic acid ester (0.4 g, 86%) (Compound (Id-19) was obtained as an oily substance.

Compound Id-22 was similarly prepared.

Example 6 (Compound Id-20) (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol (1.2 g, 4.5 mmole) was added to formic acid (10 ml) and heated for 7 hours. Refluxed. After cooling and concentration under reduced pressure, the obtained oily substance was subjected to silica gel chromatography and eluted with isopropyl ether-ethyl acetate (1: 1) to obtain (E) -7-phenyl-7- (3-pyridyl) -6. -Hept-1-ol formic acid ester (1.2g, 91%) (Compound Id-20) was obtained as an oil.

Example 7 (Compound Id-21) (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol (0.8g, 3mmole) was added to methylene chloride (10m).
l), pyridine (2 ml) and nicotinic acid chloride hydrochloride (0.55 g, 3 mmole) were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, the residue was chromatographed on silica gel and developed with isopropyl ether-ethyl acetate (1: 1) to give (E) -7-phenyl-7-.
(3-Pyridyl) -6-hept-1-ol nicotinic acid ester (1.0 g, 89.6%) (Compound Id-21) was obtained as an oily substance.

Example 8 (Compound Id-23) (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol (2.0 g, 7.4 mmole) was added to methylene chloride (2
0 ml) and add sodium cyanate (0.50 g, 7.7
mmole) and trifluoroacetic acid (5 ml) were added, and the mixture was stirred at room temperature for 20 hr. The reaction product was concentrated under reduced pressure, potassium carbonate (1 g), water (20 ml) and methylene chloride (50 ml) were added thereto, and the mixture was shaken and then the organic layer was separated, washed with water, dried and concentrated. The residue was recrystallized from isopropyl ether to give (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol carbamate (1.82 g, 79).
%) (Compound Id-23) was obtained.

Example 9 (Compound Id-27) (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol (4g, 15mmole) and phenyl isocyanate (1.6ml, 15mmole) were added to methylene chloride. Dissolve in (20 ml), add triethylamine (0.5 ml) to this, and mix at room temperature for 3
Stir the time. The reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel chromatography, and isopropyl ether-
It was developed with ethyl acetate (2: 1) and the product was recrystallized from a mixed solution of ethyl acetate and isopropyl ether (E).
-7-phenyl-7- (3-pyridyl) -6-hepte-
1-ol phenylcarbamic acid ester (3.2g, 55
%)was gotten.

Example 10 (Compound Id-24) According to Example 9, (E) -7-phenyl-7- (3-
Pyridyl) -6-hept-1-ol (2.0 g, 7.4 mmol
e) and methyl isocyanate (500 mg.8.8 mmole) were reacted in the presence of triethylamine to give (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol.
Methylcarbamic acid ester (2.2g) (Compound Id-24)
Was obtained as an oily substance. The compound forms a crystalline salt with oxalic acid.

Example 11 (Compound Id-25) According to Example 9, (E) -7-phenyl-7- (3-
Pyridyl) -6-hept-1-ol (2.0 g, 7.4 mmol
When e) is reacted with n-butyl isocyanate (0.8 g) in the presence of triethylamine, (E) -7-phenyl-
7- (3-pyridyl) -6-hept-1-ol n-
Butylcarbamic acid ester (2.3g) (Compound Id-25)
Was obtained as an oil.

This product forms a crystalline salt with oxalic acid.

Example 12 (Compound Id-28) According to Example 9, (E) -7-phenyl-7- (3-
Pyridyl) -6-hept-1-ol (2.0 g, 7.4 mmol
When e) and phenyl isothiocyanate (1.0 g, 7.5 mmole) are reacted in the presence of triethylamine, (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-olphenylthiocarbamic acid The ester (2.2g) (Compound Id-28) was obtained as crystals.

Example 13 (Compound Id-29) (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol (2.0 g, 7.4 mmole) was added to methylene chloride (2
0 ml), p-toluenesulfonyl isocyanate (1.5 g, 7.6 mmole) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel chromatography, developed with isopropyl ether-ethyl acetate (1: 1), and the product was recrystallized from ethyl acetate to give (E) -7-phenyl-7-. (3-Pyridyl) -6-hept-1-ol p-toluenesulfonylcarbamic acid ester (2.1 g, 60%) (Compound Id-29) was obtained.

Example 14 (Compound Id-5) (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol P-toluenesulfonic acid ester (0.45 g, 1.07 mmole) was added to hexamethylphosphole. Amide (2
ml) and add sodium iodide (0.2g, 1.3mmol
e) was added and stirred for 10 minutes. Then, sodium cyanoborohydride (0.1 g, 16 mmole) was added, and the mixture was stirred at 100 ° C for 1 hr. After cooling the reaction, water (10 ml) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with isopropyl ether-ethyl acetate (4: 1) to give (E) -1-phenyl-1- (3-pyridyl)-.
1-Heptene (0.2g, 75%) was obtained as an oil.

(E) -1-phenyl-1- (3-pyridyl) -1-heptene was also obtained by reducing the above p-toluenesulfonic acid ester with lithium aluminum hydride in tetrahydrofuran.

Compounds Id-1 to Id-7 were produced in the same manner.

Example 15 (Compound Id-30) (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol p-toluenesulfonic acid ester (15 g, 36 mmole) and sodium iodide (18 g, 120mmole)
And sodium iodide (18g, 120mmole9 acetone (100m
l) and stirred at room temperature for 3 hours. Water (2
00 ml) was added and the product was extracted twice with ethyl ether. The organic layer was washed with water, dried (magnesium sulfate) and concentrated under reduced pressure to give (E) -1-iodo-7-phenyl-7-.
(3-Pyridyl) -6-heptene (13 g, 96%) was obtained as an oily substance.

Compound Id-31 was produced according to this example.

Example 16 (Compound Id-32) (E) -1-Iodo-7-phenyl-7- (3-pyridyl) -6-heptene (3.7 g, 10 mmole) was dissolved in acetonitrile (100 ml), and silver nitrate (5 g, 30 mmole) was added and the mixture was stirred at room temperature. After 3 hours, water (100 ml) and ethyl acetate (100 ml) were added, and the insoluble material was passed through. The liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, the organic layer was washed with water, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with isopropyl ether-ethyl acetate (1: 1) to give (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol.
The nitrate ester (2.5 g, 80%) (Compound Id-32) was obtained as an oil. The oxalate salt of this product was recrystallized from acetone.

Compounds Id-33 to Id-34 produced in the same manner are shown in Table-5.

Example 17 (Compound Id-35) Oxazolyl chloride (0.3 ml) was mixed with methylene chloride (10 m).
l), cooled to −60 ° C., and a methylene chloride (10 ml) solution containing dimethyl sulfoxide (0.6 ml) was added dropwise thereto. After stirring at the same temperature for 10 minutes, (E + Z)-
6-phenyl-6- (3-pyridyl) -5-hexe-1
-A solution of all (0.7g, 2.7mmole) in methylene chloride (5ml) was added and stirred for 10 minutes. Then triethylamine (3m
l) was added and the temperature was gradually raised to room temperature. Water (50 ml) was added to the reaction solution, and the product was extracted with ether. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with isopropyl ether-ethyl acetate (1: 1) to give (E + Z) -1-formyl-5.
-Phenyl-5- (3-pyridyl-4-pentene (0.5
g, 70%) (Compound Id-35) was obtained as an oil.

Compound Id-363 was similarly prepared.

Example 18 (Id-37) (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol p-toluenesulfonic acid ester (0.2g, 0.5mmole) was added to 28% sodium methylate. In methanol solution (1 ml) and left at room temperature for 3 days.
After the reaction, water (10 ml) was added, the product was extracted twice with ethyl acetate, the organic layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on silica gel and developed with isopropyl ether-ethyl acetate (1: 1) to give (E) -1-
Methoxy-7-phenyl-7- (3-pyridyl) -6-
Heptene (0.1 g, 75%) (Compound Id-37) was obtained as an oil.

Example 19 (Compound Id-38) (E) -1-iodo-7-phenyl-7- (3-pyridyl) -6-heptene (0.6g, 1.6mmole), phenol (0.2g, 2.1mmole) were added to tetrahydrofuran. It was dissolved in a mixed solvent of (10 ml) and dimethylformamide (2 ml), sodium hydride (60% oily, 0.1 g, 2.5 mmole) was added thereto, and the mixture was stirred at room temperature for 1.5 hours. After the reaction, add water (20 ml),
The product was extracted with ether, the organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography and developed with isopropyl ether-ethyl acetate (2: 1) to give (E) -1-phenoxy-7-phenyl-7-.
(3-Pyridyl) -6-heptene (0.5 g, 73%) (Compound Id-38) was obtained as an oil.

Example 20 (E) -7-phenyl-7- (3-pyridyl) -6-hexen-1-ol (1.0 g, 3.7 mmole) was dissolved in methylene chloride, and 3,4-dihydro-α-pyran was dissolved therein. (0.6 ml) was added. Subsequently, D-camphorsulfonic acid (1.4 g, 6 mmole) was added to this, and the mixture was stirred at room temperature.
After 1 hour, saturated aqueous sodium hydrogen carbonate solution was added, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure to obtain (E) -7-phenyl-1- (2-pyranyloxy) -7- (3-pyridyl) -6-hexene (1.28 g, 90
%) (Compound Id-39) was obtained as an oil.

Example 21 (Compound Id-40) (E + Z) -1-iodo-6-phenyl-6- (3-pyridyl) -5-hexene (0.38,0.83mmole) and imidazole (0.2g, 3mmole) were added to dimethylformamide ( 10 ml)
Sodium hydride (60% oily, 0.2g, 5m
mole) and stirred for 1 hour at room temperature. After the reaction, water (10 ml) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography and eluted with ethanol-ethyl acetate-triethylamine (1: 20-: 0.1) to give (E + Z) -1-
(1-Imidazolyl) -6-phenyl-6- (3-pyridyl) -5-hexene (0.25 g, 95%) was obtained as an oil.

Compounds Id-41 to Id-42 produced in the same manner are shown in Table-6.

Example 22 (Compound Id-43) (E) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid (0.56g, 2mmole) was added to oxalyl chloride (5m).
l) and heated at 50% for 1 hour. The reaction solution was concentrated under reduced pressure, a 5% ammonia methanol solution (5 ml) was added thereto, and the mixture was left at room temperature for 1 hour. After the reaction, methanol was removed under reduced pressure, and the residue was recrystallized from isopropyl ether to give (E) -7-phenyl-7- (3-pyridyl) -6-
Heptenoic acid amide (0.48 g) was obtained.

Example 23 (Compound Id-44) (E) -7-phenyl-7- prepared according to Example 22.
A methylene chloride solution (20 ml) containing aniline (200 mg) and potassium carbonate (300 mg) were added to (3-pyridyl) -6-heptenoyl chloride / hydrochloride (0.67 g, 2 mmole), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, washed with water, the methylene chloride solution was dried and concentrated, and the residue was recrystallized from ethyl acetate to give (E) -7-phenyl-7-
(3-Pyridyl) -6-heptenoic acid N-phenylamide (620 mg) (Compound Id-44) was obtained.

Example 24 (Compound Id-45) (E) -7-phenyl-7- (3-pyridyl) -6-hepten-1-ol p-toluenesulfonic acid ester (1.0 g, 2.4 mmole) was added to dimethyl sulfoxide. (10 ml)
Dissolve in, add sodium cyanide (0.3g, 6mmole) 1
Stir for 8 hours. Water (100 ml) was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography,
Development with ethyl acetate-isopropyl ether (1: 1) gave (E) -1-cyano-7-phenyl-7- (3-pyridyl) -6-heptene (0.5 g, 76%).

Example 25 (Compound Id-46) (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol (2.3 g, 8.6 mmole) was added to methylene chloride (2
Pyridine (1 ml) and p-toluenesulfonyl chloride (1.8 g, 9.4 mmole) were added. After reacting overnight at room temperature, water (30 ml) was added to the reaction product, and the product was extracted with ethyl acetate. The organic layer was washed with water and dried, and then the solvent was distilled off. The obtained oily substance was subjected to silica gel chromatography, and isopropyl ether-ethyl acetate (1:
Elution with 1) gave (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol p-toluenesulfonyl ester (3.15 g, 88%) as an oil.

Compound Id-47 was produced in the same manner.

Example 26 (Compound Id-48) (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol (1.0 g, 3.7 mmole) and imidazole (0.25 g, 3.7 mmole) in dimethyl. It was dissolved in formamide (10 ml), dimethyl t-butylsilyl chloride (0.55 g, 3.7 mmole) was added thereto, and the mixture was stirred for 1 hr. Water (20 ml) was added to the reaction product, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried, and the solvent was concentrated under reduced pressure. The residue was chromatographed on silica gel and developed with isopropyl ether-ethyl acetate (1: 1) to give (E) -7-
Phenyl-7- (3-pyridyl) -6-hept-1-ol dimethyl t-butylsilyl ester (1.1 g, 84
%) Was obtained as an oil.

Example 27 (Compound Ie-2) (E) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid (1.5 g, 5.3 mmole) was dissolved in chloroform (50 ml) and stirred at room temperature. -Chloroperbenzoic acid 1.
3g (purity 70%, 5.3mmole) was added. After 2 hours, the reaction solution was concentrated under reduced pressure. Ethyl acetate (30 ml) was added to the residue to give (E) -7-phenyl-7- (1-oxide-3-pyridyl) -6-heptenoic acid (1.5 g) as crystals.

Example 28 (Compound Ie-7) (E) -7-phenyl-7- (3-pyridyl) -6-hept-1-ol (4 g, 15 mmole) was added to chloroform (20 ml).
And m-chloroperbenzoic acid (3.7 g,
Purity 70%, 15mmole) was added, and the temperature was raised to room temperature, followed by stirring for 1.5 hours. After the reaction solution was concentrated under reduced pressure, the residue was subjected to silica gel chromatography,
After eluting with ethyl acetate and developing with ethanol-ethyl acetate (1: 4), (E) -7-phenyl-7- (1
-Oxide-3-pyridyl) -6-hept-1-ol (3.2g) was obtained.

Compounds (Ie-1 to Ie produced according to Examples 27 and 28 above)
-9) is shown in Table-10. The melting point is uncorrected.

Example 36 A. Capsule (1) Compound Id-17 50 mg (2) Cellulose fine powder 30 mg (3) Lactose 37 mg (4) Magnesium stearate 3 mg Total 120 mg The above ingredients were mixed and filled in a gelatin capsule.

B. Soft Capsule (1) Compound Id-19 50 mg (2) Corn oil 100 mg Total 150 mg A mixed solution of the above components (1) and (2) was prepared and filled in a soft capsule by a conventional method.

C. Tablets (1) Compound Id-17 50 mg (2) Lactose 34 mg (3) Corn starch 10.6 mg (4) Corn starch (paste-like) 5 mg (5) Magnesium stearate 0.4 mg (6) Carboxymethylcellulose calcium 20 mg Total 120 mg All of the above components were mixed by a conventional method and pressure-molded with a tableting machine to give tablets.

Experimental Example 1 Blood thromboxane A ₂ (TXA ₂ ) production inhibitory action in rats Male Sprague-Dawley rats aged 7 to 8 weeks were used as a group of 5 rats. 10 mg of compound in the rat of compound administration group
Suspended in water with a small amount of gum arabic for 2 kg
Orally administered in a dose of / kg. On the other hand, only the gum arabic suspension was administered to the rats of the control group. Two hours after the administration, the rat was anesthetized with pentobarbital sodium (50 mg / kg, intraperitoneal injection), and 1 ml of blood was collected from the abdominal aorta. The blood was allowed to stand at 25 ° C for 90 minutes and then centrifuged at 15,000 rpm for 2 minutes to separate serum. Radioimmunoassay of thromboxane B ₂ (TXB ₂ ) which is a stable metabolite of TXA ₂ produced in blood during standing [Shibouta et.al Biochemical
Pharmacol, 28 3601 1979]. The TXA ₂ synthesis inhibition rate (%) was calculated from the difference in TXB ₂ production ability between the control group and the compound-administered group.

The results of the representative compounds are shown in Table-11 below.

Reference Example 1 Method A 3-Brompyridine (10.0 g, 63 mmol) under an argon stream.
e) was dissolved in ether (200 ml) and cooled to -30 ° C.
An n-butyllithium hexane solution (1.62 molar concentration, 40 ml) was added dropwise to this solution over 10 minutes, and the mixture was stirred for 5 minutes under the same reaction conditions. To this reaction solution, a solution of p-isopropylbenzaldehyde (10.0 g, 67 mmole) in ether (20 ml) was added 5 times.
Dropped in minutes. The reaction temperature was gradually raised to room temperature, water (300 ml) was then added to the reaction product, and the product was extracted with ethyl acetate (300 ml). The organic layer was washed with water, dried (magnesium sulfate), concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and developed with ethyl acetate to develop the desired secondary alcohol (VIIa-2 in Table-14) (9 g, 76%).

Secondary alcohols produced according to the above method (Table 14
VIIa-1 to VIIa-22) are summarized in Table-14.

Method B Benzothiophene (2.0 g, 14.9 mmole) was dissolved in tetrahydrofuran (6 ml) and ether (12 ml) and the temperature was -20 to 0 ° C.
N-butyllithium hexane solution (1.62 molar concentration, 12.
5 ml) was added dropwise to give a blue solution. After 15 minutes, a solution of nicotinaldehyde (1.6 g) in tetrahydrofuran (5 ml) was added dropwise at 0 to 25 ° C. After stirring for 1 hour, water (50 ml) was added to the reaction solution, and the product was extracted with ethyl acetate. After separation and purification according to a conventional method, secondary alcohols (Table 14
VIIa-23) (2.1 g) was obtained. Physical properties and others are shown in Table-14.

Reference Example 2 The alcohol derivative (VIIa) produced in Reference Example 1 was produced according to either method A or method B shown below to obtain a carbonyl derivative [compound (IIa)]. . Oxidation with manganese dioxide was applicable to the oxidation of all secondary alcohols (VIIa), and oxidation with dimethylsulfoxide-oxalic chloride was applicable to all but the compound containing the thiophene nucleus.

Method A Alcohol derivative (VIIa-11) (4.0g, 21mmole) was dissolved in methylene chloride (70ml) and manganese dioxide (13g) was added.
Was added and the mixture was heated and stirred for 10 hours. After the reaction, the manganese dioxide was separated, the manganese dioxide was thoroughly washed with ethyl acetate and acetone, the solution was concentrated, and the product was recrystallized from an isopropyl ether-ethyl acetate mixed solution to give a carbonyl compound (IIa-12 in Table-15). (3 g, 75%) was obtained.

Method B Add oxalic acid chloride (2.2 ml) to methylene chloride (50 m
It was dissolved in l) and cooled to -60 ° C. Methylene chloride (5m) containing dimethyl sulfoxide (4ml) was added to this solution.
l) The solution was added dropwise within the temperature range of -60 ° C to -50 ° C. Then, a solution of alcohol compound (VIIa-2, 4.5g, 20mmole) in methylene chloride (50ml) was added dropwise under the same temperature conditions over 10 minutes, and after 15 minutes, triethylamine (15ml) was gradually added, and then for about 1 hour. In short, the reaction temperature was raised to room temperature. After the reaction, water (20 ml) was added, the solvent was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried, concentrated under reduced pressure, and the product was purified by silica gel chromatography according to a conventional method to give a carbonyl compound (II in Table 15).
a-3, 4.3 g, 98%) was obtained.

The reaction was carried out according to the above two methods to produce carbonyl compounds shown in Table-15 (IIa-1 to IIa-25 in Table-15).

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification number Internal reference number for FI Technical indication C07D 213/48 213/55 213/56 213/57 213/80 213/89 401/06 233 7602− 4C 249 7602-4C 257 7602-4C 405/06 213 7602-4C 405/12 213 7602-4C 409/06 213 7602-4C // C07F 7/18 A C12N 9/99 9359-4B

Claims (2)

[Claims] 1. A general formula [In the formula, R ¹ represents an aromatic group which may have a substituent, a thienyl group, a furyl group, a pyridyl group or a benzothienyl group, and R ² represents a lower alkyl group, a hydroxymethyl group, a nitroxymethyl group, Formyl group, nitrogen-containing 5-membered ring-methyl group,
Acetal-methyl group, trialkylsilyloxymethyl group, alkyl or aryl-sulfonyloxymethyl group, alkyl or arylsulfonylaminocarbonyloxymethyl group, acyloxymethyl group, alkoxycarbonyloxymethyl group, halogenomethyl group, alkoxymethyl group, An aryloxymethyl group, a cyano group, an optionally substituted carbamoyl group, an optionally substituted carbamoyloxymethyl group, an optionally substituted thiocarbamoyloxymethyl group, a carboxyl group or an alkoxycarbonyl group, Indicates. n is And R ² is a carboxyl group or an alkoxycarbonyl group, 1 or an integer of 9 to 20, and otherwise an integer of 1 to 20. ] The substituted vinyl derivative represented by these, or its pharmacologically acceptable salt. 2. General formula [In the formula, R ¹ represents an aromatic group which may have a substituent, a thienyl group, a furyl group, a pyridyl group or a benzothienyl group, and R ² represents a lower alkyl group, a hydroxymethyl group, a nitroxymethyl group, Formyl group, nitrogen-containing 5-membered ring-methyl group,
Acetal-methyl group, trialkylsilyloxymethyl group, alkyl or aryl-sulfonyloxymethyl group, alkyl or arylsulfonylaminocarbonyloxymethyl group, acyloxymethyl group, alkoxycarbonyloxymethyl group, halogenomethyl group, alkoxymethyl group, An aryloxymethyl group, a cyano group, an optionally substituted carbamoyl group, an optionally substituted carbamoyloxymethyl group, an optionally substituted thiocarbamoyloxymethyl group, a carboxyl group or an alkoxycarbonyl group, Indicates. n is And R ² is a carboxyl group or an alkoxycarbonyl group, 1 or an integer of 9 to 20, and otherwise an integer of 1 to 20. ] A thromboxane A ₂ synthase inhibitor containing as an active ingredient a substituted vinyl derivative represented by the following or a pharmacologically acceptable salt thereof.