JPS6028963A - Substituted vinyl derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R<1> is unsubstituted or substituted aromatic radical, heterocyclic radical; R<2> is H, hydroxyl, nitroxy, formyl, N-containing 5-membered ring, acetal, trialkylsilyloxy, alkyl- or arylsulfonyloxy, cyano, unsubstituted or substituted carbamoyl; n is 2-16; where n is 15, when R<2> is formyl or cyano]. EXAMPLE:(E)-1-Phenyl-1-(3-pyridyl)-heptene. USE:Since it is effective with low dose and causes little side-effects by long-term administration, the compound is used for prevention or treatment for thrombosis by blood platelet coagulation caused by thromboxan A2 and ischemic diseases caused by vascular twitch in heart, brain and peripheral circulation system. PREPARATION:The reaction of a compound of formula II with another compound of formula III (R<6> is methyl, COOR<7> where R<7> is H, lower alkyl; X<-> is halogen ion; m is 2-16) is conducted in the presence of a base in an organic solvent to give a compound of formula I where n is m-1 and R<2> is R<6>.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel substituted vinylμ derivatives that have the effect of specifically inhibiting thromboxane A2 (TXA2) synthesis.

TxA2 is one of the metabolites of afchidonic acid and has platelet aggregating and vascular smooth muscle contracting effects. Therefore, when it is produced in excess in the body, it is known to cause platelet aggregation, vascular occlusion, and vasospasm, leading to the development of various diseases such as ischemic heart, vision, and brain diseases. The present inventors conducted synthetic and exploratory research on substances that have a TXA2 synthetase inhibitory effect, and as a result, discovered a group of new compounds that have an excellent TXA2 synthetase inhibitory effect.

That is, the present invention is based on the general formula [where El is an aromatic group which may have a substituent,
A heterocyclic group, R2 is a hydrogen atom, a hydroxyl group, a nitrooxy group, a homiμ group, a nitrogen-containing five-membered ring group, an aceterμ group, a triaμkiμsilyloxy group, an aμkiμ- or an aryμm
sulfonyp oxy group, aμμm or ary μmsuμ
Honi μ Amitsuka μ Boni μ Oxy group, Ashy μ Oxy group,
Alkoxy carbon μ oxy group, halogen atom, alkoxy group, ary μ oxy group, cyano group, optionally substituted pamoy μ group, optionally substituted μ bamoyloxy group, even if substituted Good Chioka ~ Pamoiμ
Oxy group, force μ boxy μ group or μ oxygen group
group, and n represents an integer of 2 to 16. However, R2 is
When it is a mip group, a cyano group, or an optionally substituted p-p group, n is an integer of 1 to 15, and R2 is a poxy-poxy group or an ap-poxy-poxy group. In this case, n is an integer from 9 to 15. ] is a substituted vinyl μ derivative represented by

In the general formula (I), the aromatic group represented by R1 is, for example, an aryμ group such as Fe2μ, naphthyl, α-naphthylp, β-naphthylμ, and the heterocyclic group is, for example, Cheni/ L'(2-cheni p.

3-Cheni/l/), Furi μ(2-Frill, 3-Fri/
I/), pyridi Iv (2-pyridiμ, 3-pyridiμ.

4-Hylydi/L'), penzocheni* group (2-penzocheni μ, 3-penzocheni μ, 4-penzocheni μ,
5-pensothienyl μ, 6-pensothienyl.

7-Penzothiene iv > h can be given. These aromatic groups and heterocyclic groups may have a substituent at any position on the ring. The substituent includes lower alkoxy (eg, methoxy, ethoxy, n-propoxy, 1-propoxy, n-ethoxy).

i-gutoxy, t-butoxy, etc. prime numbers 1 to 4)
, lower alkyl /L/ (for example, methiμ, ethi /I/.

n-propyμ, i-propyμ, n-guchi/l', i-guchi Ivlt-guchi~, n-bench I' I 1-bench ρ, etc.), trifluoromethyl, lower γμkenji~ (e.g. vinyl, ant/X/.

Prime numbers 2 to 5, such as Benteniμ), halogens (7i, chlorine, bromine, iodine), methylenedioxy, etc. Examples of the nitrogen-containing 5-membered ring group represented by R2 include imidazoly/l'(1-imidazolyμ, 2-imidazoly/l'), )riasilyμ(1-triacyly~, 3-triacylyμ, 5-triacyly/ V), tetrasily/l/(1-tetrasily/L/, 5-tetofuzoli~
) having 2 to 4 nitrogen atoms on the ring. Examples of the acetal group represented by R2 include 2-tetrahydrofuryloxy and 2-tetrahydrofuryloxy, and examples of the tri-μ-μ-siliμ-oxy group include, for example, dimethyl tertiary-buty-μ-silip-oxy. . Examples of the aμm or aryμ-sulfoniumoxypoxy group represented by R2 include methane μhonipoxy, p-)/l/
Examples of the alkyl- or aryl-sulfonyloxy group include methanesulfonyloxy and p-toluenesulfonyloxy. The acyloxy group represented by R2 is represented by the formula R3COO-C, where W is a 9-order hydrogen prime number 1 to 6, aμ/L/(methyμ, ethyl.

n-propy μ, 1-propyl, n-guchi ρ, 1-petit μ
, n-bench μ, 1-plier μ, n-hexy μ, etc.) or pyridi/I/(2-pyridi~, 3-pyridi μ・4-
pyridi/L/). ] Examples include groups represented by the following.

Examples of the oxy group represented by R2 include methoxycarbonyoxy, ethoxycarbonyoxy, n-proboxycarbonyloxy, and n-proboxycarbonyloxy.7.1
- Glopoxycarbony-μoxy, n-1-toxycarbony-oxy-1-gutoxycarbony-oxy, n-pentyoxycarbony-oxy, n-hexyoxycarbony-oxy, etc. Prime numbers 2 to 7 Examples of halogen atoms include fluorine, chlorine, bromine, and iodine, and alkoxy groups include methoxy, ethoxy, n-propoxy,
Lower alkoxy having a prime number of 1 to 4 such as 1-propoxy, n-gutoxy, 1-gutoxy, etc., and aryloxy groups such as phenyloxy, 2-methypoxy, 3-methypoxy, 4-Methi/L/Fe2μ
oxy, 2.4-3'methy~pheniμoxy, 3.4-
Things with order prime numbers 6 to 8 such as Dimechi/L/Fueniμoki V [
In the formula, R4 and R5 are the same or different hydrogen primary prime number 1~
6's μ/L/ (for example, methi/l', ethyl.

n-propyl, 1-propy/' + n-guchi/l',
, i-Guchi lv, t-Guchi μ, n-pentyl, 1
-pentyl, n-hexy μ, 1-hexy μ, etc.) or 06-8 ali/l/(phenyv, 2-methy/I/pheny/1/13-methyA/phenyl, 4-methylphenyμ, 2゜4-dimethy lv7 2μ, 3.4-dimethyμ phe2μ, etc.). ] are listed.

R4 and R5 have the same meanings as above. ] Shown in 2R
4 and R5 have the same meanings as above. ] are listed respectively.

The compound represented by general formula (1) may be an addition salt of a pharmacologically acceptable organic or inorganic acid, and examples of such addition salts include hydrochloric acid, hydrobromic acid, phosphoric acid, Sulfuric acid, citric acid, succinic acid, maleic acid, zuma-μ
Examples include sea lion salts such as oxalic acid, methanesulfonic acid, and benzenesulfonic acid. When R2 in compound (1) is a ρboxyμ group, it may be an alkali metal salt such as a sodium salt or a potassium salt, or an alkaline earth metal salt such as a ρsium salt.

Representative examples of compound (I) include (E)-7-
Feni/L/-7-(3-pyridiμ)-6-hepte-1
-oh μ, (E)-7-(3-pyridi/1/)-7-(
2-ch/L')-6-hebt 1-ohμ, (E)
-1-forceppamoiμoxy-7-pheni/L'-7-(
3-pyridi/L')-6-heptene.

(1)-1-forceμbamoiμoxy-7-(3-pyridi/
L')-7-(2-cheni/l/)-6-heptene.

(E)-1-acetoxy-7-phenylene/L/-7-(3
-pyridi/l')-6-heptene, (E)-1-fujini/l/-1-(3-pyridi/L')-1-heptene.

(1)-7-7E"/1'-7-(3-pyridi/V)-
6-Hegte 1-r ohμ nitric acid ester ~, (E)-1-
(2-chenyl)-1-(3-pyridi1v)-1-heptene, (E)-1-nicotinoyμoxy-7-phediμm7-(3-pyridi/L')-6-heptene, ( 1)
-12-pheny/L/-12-, (3-pyridiμ)-1
1-dodecaenoic acid, (E)-1'3-phediμm13-
(3-pyridi/v)-12-)lidecaenoic acid and salts thereof are obtained.

The substituted vinyl/l' derivatives represented by the general formula (1) and their salts have an inhibitory effect on thromboxane synthase, which has been solubilized and fractionated in platelet microsomes of humans, horses, etc., and is effective in mammals including humans. , exhibits a strong and long-lasting inhibitory effect on the biosynthesis of thromboxane A2 (TXA2).

In addition, the compound (1) of the present invention has an arterial smooth muscle relaxing effect,
It has the effect of increasing the production efficiency of prostaglandin (PGI), which inhibits platelet aggregation or re-dissociates aggregated platelets. That is, grosstaglandin G2 (PCO2) or grosstaglandin H2 (PCO2)
GH2) is thromboxane A2 l prostaglandin in vivo.

The compound (1) of the present invention is an important precursor for synthesizing PGH or other grosstaglandins. 1~10M
g/#), but on the other hand, the physiologically extremely useful prostaglandin 2 (PGI2) and other converting enzymes to prostaglandin, such as PGI 3 synthase and prostaglandin synthase. It shows almost no inhibitory effect on PGH2 or PGH2.
Increasing the utilization efficiency of CO2 in vivo, for example, increasing PGD2 in platelets and PGD2 in the presence of vascular endothelial cells.
It shows the effect of enhancing the production of G. Among them, compounds in which R2 in the general formula (I) is a force to boxy μ group have the above-mentioned strong effects. Compounds in which R2 in the general formula (1) is other than a force μ boxy μ group have the above-mentioned effects themselves, but in vivo it is thought that R2 is converted to a force μ boxy μ group, and 1 in vivo. In experiments, it exhibits the above-mentioned effect almost equivalent to that of a compound in which R2 is a force μ boxy μ group.

In this way, the substituted vinyl μs conductor represented by the general formula (1), -7' rostaglandin enzyme, (PG Engineering) synthase, grosstaglandin synthase (cyclooxygenase), and the synthesis of various prostaglandins. Thromboxane A2 (TXA2) has no inhibitory effect on enzymes.
Selectively, strongly and persistently inhibits synthetic enzymes.

Further, a compound in which R2 is 0NO2 in general formula (I) has a smooth muscle relaxing effect in addition to the above-mentioned action.

Furthermore, the compound of the present invention is characterized in that it has extremely low toxic effects on rats, dogs, etc., and has a wide range of toxicity and medicinally effective doses. Furthermore, the compound of the present invention is expected to have long-lasting efficacy in vivo and stable TXA2 synthase inhibitory action over a long period of time. The compounds according to the invention therefore:
The dosage used is small and there are fewer side effects from long-term use.
Thrombosis due to platelet aggregation based on 'll'XA2, or ischemic disease due to vascular contraction in the heart, brain, periphery, and circulatory system (e.g., myocardial infarction, stroke, vascular infarction in the kidneys, lungs, etc.) gastrointestinal system ulcers, etc.) and TXA2/PG engineering.

It is used in mammals including humans for the prevention or treatment of diseases based on imbalance (eg arteriosclerosis, hypertension, etc.). For example, the drug can be administered orally in the form of tablets, turnip tablets, powders, granules, etc., or parenterally in the form of injections or pellets.

The dosage for each adult is usually 20 to 20011 I per day orally and 10 to 100 I parenterally in 1 to 3 divided doses.

Compound (I) of the present invention can be produced, for example, by any of the methods described below.

[Production method 1] A compound represented by the general formula (wherein R has the same meaning as above) and the general formula % formula % () [wherein R6 is a methyl group or 2〇〇R? (In the formula,
R7B hydrogen atom or methiμ, ethyl~, n-globiμ,
1-propyl, n-crop μ, 1-crop/L/.

Indicates lower alkyl μ such as t-buty/L'. ), X- represents a halogen ion, and m represents an integer of 2 to 16. ], a compound represented by the general formula (wherein R1*R' and m have the same meanings as above) can be obtained.

In the general formula (m), the halogen ion represented by X- is, for example, a chlorine ion or a bromine ion.

Examples include diurium ion.

This reaction is usually carried out in an organic solvent in the presence of a base.

Examples of the base include n-butyllithium, lithium diisopropylamide, sodium hydride, potassium hydride, potassium tertiary butoxy, and sodium amide. Among them, lithium diisopropylamide, sodium hydride, and sodium amide are preferably used.

Examples of the solvent include ether p, tetrahydrofuran, dimethyl sp oxide, dimethyformamide, or a mixed solvent of two or more selected from these solvents. This reaction is preferably carried out under a dry inert gas atmosphere (for example, nitrogen gas, argon gas, helium gas, etc.). The reaction temperature varies 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. The progress of this reaction can be determined by observing the disappearance of the characteristic color of phosphorane, and the reaction is usually completed in about 1 to 6 hours.

[Manufacturing method 2] General formula (wherein R and m have the same meanings as above, , 7/ is a hydrogen atom, a lower 7μ kill group, a lower aμ coquinka to a boniμ
The compound represented by the general formula (wherein, Bl and m have the same meanings as above) can be produced by reducing the compound represented by the general formula (wherein Bl and m have the same meanings as above). .

In the general formula (E'-a''), examples of the lower a[mu] group represented by 7' include methi, ethyl A/, n-propy/l', i-propy/l/, fi-butyl, μ, 1
-guchiru, t-guchi~, etc. those with the next cumulative number 1-~4 are,
Examples of the lower alkoxycarbonyl group include those having an order prime number of 2 to 5, such as methoxycarbonyl, ethoxycarbonyl/l/, H-propoxycarbonyl, and 1-propoxycarbonyl.

In the general formula (A'-a'), the acid or ester compound in which B11 is a hydrogen atom or a lower atom group is usually diethyl ether, tetrahydro-7, 1.2
- The corresponding alcohol μ form (
knee b). This reduction reaction is B7
The process is easy when ' is a lower alkyl μ group. The reaction temperature is carried out in the range of -10°C to 70°C, and usually 1 to 70°C at room temperature.
The reaction was completed in 10 hours. The reducing agent is used in an amount of 1 to 2 moles. After the reaction, the excess reducing agent is decomposed and the desired product is extracted and separated using a conventional method.

In addition, in the general formula (E + a#), compounds in which R7' is a lower acetoxycarbonyl μ group or a succinimide group include methano-/I/, ethano-μ, diethyl μ ether lv
Reduction with sodium borohydride, potassium borohydride, etc. in 1,2-dimethoxyethane, 1,2-dimethoxyethane, or a water-containing solvent thereof leads to the corresponding alcohol form (I-b). be able to.

[Production method 3] Av/v conversion of the compound represented by general formula (I-b),
Carbamoi μ-ization, thioka μ-pamoi μ-ization or a~ki~-
, by converting it into an aryl group or an alkoxycarbonyl group (wherein R1 and m have the same meanings as above, and R8 is an acyloxy group, even if substituted) (represents a bamoyloxy group, an optionally substituted thiocapamoyloxy group, a 7μ- or an aryl oxy-oxy group, or an ap-oxycarbonyloxy group). The represented compounds can be prepared.

In the general formula CI-c), an acyloxy group represented by R8 and an optionally substituted pamoyl group.

An optionally substituted thiocarbamoyloxy group.

Or Aki p- or Allie μ Shoni μ Amitsuka μ
Both ponyμoxy groups have the same definition as those shown by R2.

Acylation or aμoxycarponyloxylation reaction is carried out by reacting the corresponding acid chlorphyte, acid anhydride, chlorosubacid ester μ, etc. with the general formula It is carried out by reacting with a compound represented by b). This reaction uses dimethylformamide.

The reaction is carried out in pyridine or chloroform, usually at -10' to 30''C. As the acid anhydride, acetic anhydride, propionic anhydride, benzoic anhydride is used, and as the acid chlorophyte, acetyl chloride, butyric acid chloride.

Chlophyte isobutyrate, nicotinic acid chloride, and bency μ chloride are also used as chloro/L/restored acid esters such as chloroμ methyl carbonate, chlorolv ethyl chloride, chloro/I/benzi chloride/L', and chlorolv subacid. Examples include tertiary croaker μ.

Reactions such as (substituted)-carbamoylation, (substituted)-thiocarpamoylation, or (substituted)-sulfonyl puminocarbonylation are carried out using organic or inorganic acids (e.g. trifluoroacetic acid,
cyanate or thiocyanate in the presence of methane sulfonic acid, hydrochloric acid), alkyl μ or ary/l/V anoic acid, alkyl p or ary thiocyanic acid in the presence of amine or pyridine, Alternatively, it can be carried out by using alky-p or alino-V sulfonic acid.

As cyanate or thiocyanate, sodium cyanate, potassium cyanate, sodium thiocyanate,
Potassium thiophanate and the like may also be used as 1μ Kiμ or Allyμ cyanic acid, Alkiμ or Allyμ thiocyanic acid, Alkiμ or Allyμ IV7. lVhoniμ cyanic acid alkyμ
Or as an ary μ group, for example, methi μ, ethyl, isopropy μ, propy μ, guchi μ, isoguti μ, fe2 μ,
Examples include 3-pyridi μ.

The reaction is completed in 1 to 10 hours at a reaction temperature line of 0° to 50°C. The reaction may be carried out in a solvent-free or anhydrous solvent (e.g. chloroform,
methylene chloride).

[Production method 4] By reducing the compound represented by the general formula (wherein Bl and m have the same meanings as above and IC1R9 represents an alkyl~- or aryμm sulfoniμ group), a compound represented by the general formula (formula (wherein, R and m have the same meanings as above) can be produced.

In the general formula (I-d), the alkyl p-monen represented by R9 is methanesulfony/v, p
-) μ Enthus μ Honi μ etc. is off.

This reaction is usually carried out in an atmosphere of argon, helium, or nitrogen gas, using dimethyl ether/V, tetrahydrofuran, 1.2-
It is carried out by reduction using a reducing agent such as lithium aluminum hydride or sodium cyanoborohydride in an ether μ-based solution such as dimethoxyethane or hexamethylene μphosphoμ amide. The amount of the reducing agent used is preferably 0.5 to 2 moμ per 1 moμ of compound CI-d), and the reaction temperature is usually 10 to 80°C.

[Production method 5] By reacting the compound g represented by the general formula (d) with a halogen compound, shows. ] can be obtained.

In the general formula (nee e), the halogen atom represented by X is R2
It is the same as the halogen atom shown in .

This reaction uses methylene crophyte and chloroform.

Acetone, methanol μ, hydrated acetone, hydrated methanol/
This is carried out by carrying out an exchange reaction with sodium bromide, potassium bromide, sodium iodide, potassium iodide, triethylamine-hydrochloride, etc. in a solvent such as L'. Usually 0
The reaction is completed in 1 to 20 hours at ~50°C.

[Production method 6] By reacting a compound represented by the general formula CI-d) or (nee e) with silver nitrate, a compound represented by the general formula (wherein 1 and m have the same meanings as above) is produced. compounds can be manufactured.

This reaction is usually carried out using, for example, acetonitrile p, dioxane,
It is carried out in a solvent such as 1,2-dimethoxyethane or acetone. The amount of silver nitrate to be used is preferably 1 to 1.2 mol per 17 μ of the compound CI-d) or (nee e).

The reaction is usually carried out at room temperature, and the reaction time is usually 2 to 5 hours.

[Production Method 7] A compound represented by the general formula (wherein El and m have the same meanings as above) can be produced by oxidizing the compound represented by the general formula CI-b).

This reaction generally proceeds easily by using known means for converting alcohol into aldehyde. For example, compound CI-g) can be oxidized using a chromic acid-pyridine complex or a mixed solution of chromic acid-pyridine complex or dimethysium oxalate-triethylamine.

[Production method 8] By reacting the compound represented by the general formula (I-d) or (I-e) with an alkali metal alkoxide or an aryl oxide (wherein R1 and m have the same meanings as above). (Ap, RNO represents an alkoxy group or an aryμoxy group) can be produced.

In the general formula (nee h), an a μ koxy group represented by R10,
The ary μoxy groups are the same as their definition in R2.

This reaction is carried out using a sodium or potassium alkoxide or a sodium or potassium phenoxide corresponding to the alkoxy group or L aryloxy group to be introduced in a corresponding A-μ or pheno-μ.

Examples of the alkoxide include methoxide, ethoxide, and propoxide. Examples of alcohol-μ include methano-μ, ethanol-μ, and propano-p.

[Production method 9] A compound represented by the general formula CI-b) and dihydropyran or dihydrofuran are reacted in the presence of an acid catalyst to produce a compound represented by the general formula (wherein R1 and R2 have the same meanings as above, R11
indicates an aceter μ group. ) can be produced.

In the general formula (I-1), the aceter μ group represented by R11 is the same as the aceter group in the definition of R2.

This reaction is usually carried out in the presence of an acid catalyst.

Examples of the acid catalyst include p-)μ-enesμ-phonic acid, camphors-μ-phonic acid, and the like. As the reaction solvent, natural water roloform, methane chloride, etc. are often used. The reaction is usually completed in 1 to 3 hours at θ° to 30°C.

[Production method 10] A compound represented by general formula (I-e) and general formula R12-
H(P!) (in the formula, B12 represents a nitrogen-containing 5-membered ring group) is reacted with a compound represented by the general formula (in the formula, R
1, R12 and m have the same meanings as above. ) can be produced.

In the general formula (I-j), the nitrogen-containing 5-membered ring group represented by R12 can be regarded as the same as that in the definition of R.

This reaction is usually carried out in the presence of a base such as sodium hydride or potassium tertiary butoxy. The reaction solvents used are dimethic acid μformamide, dimethoxyphoxylate, and 1,2-dimethoxyethane tertiary getano μ, and the reaction is usually carried out at 0 to 50°C.

[Manufacturing method 11] General formula [In the formula, Y is a chloro atom and OR? (Bl, R7
and m have the same meanings as above). ] by reacting the compound represented by the general formula (wherein R4 and R5 have the same meanings as above), the compound represented by the general formula (wherein R1 + R' + R5 and m have the same meanings as above) is reacted. ) can be manufactured.

This amidation reaction can be carried out using generally known methods, such as the general formula (
-■-k) When Y is OR7, no solvent or methanol, ethanol, dioxane.

It can be carried out with an amine compound in a solvent such as toluene at a temperature range of 0° to 100°C. Also, the general formula (knee k)
In, when Y is a chlorine μ atom, pyridine, triethyl μamine, sodium rehydrate.

It can be carried out in the presence of potassium subacid, etc., in methylene chlorophyte, chloroform, acetone, a water-containing solvent, etc.

[Production method 12] By reacting the compound represented by the general formula (I-d) or CI-e) with sodium cyanide or potassium cyanide, the compound represented by the general formula (wherein R1 and m have the same meanings as above). A compound represented by can be produced.

This reaction can be carried out using a commonly known Nitriμ compound. For example, dimethyμ sp oxide or dimethyμ formamide is used as the reaction solvent, and the reaction is completed in 5 to 20 hours at 0 to 30°C.

[Production method 13] Compound represented by general formula (I-b) and general formula R9-C
1(Vl) (wherein R9 has the same meaning as above) to form a compound represented by the general formula (wherein R",
R9 and m have the same meanings as above. ) can be produced.

This reaction can be carried out in the presence of pyridine or triethyl amine in a solvent such as rainbow methamide, methylene chloride or chloroform at a temperature range of 0° to 30°C.

[Production method 14] By reacting the compound represented by the general formula (nee b) with tria μ-kylsiliμ chloride in the presence of pyridine or triethylamine, the compound represented by the general formula (in the formula, R1 and m
has the same meaning as above, and R13 represents a trialkypsilylμoxy group. ) can be produced.

In the general formula (I-n), the trialkyμsiliμoxy group represented by R13 has the same definition as that in B.

The reaction is usually carried out in methylene chloride or chloroform, and can be carried out at a temperature in the range of 06 to 30°C.

The substituted vinyl derivative (1) produced in this way is:
For example, separation by conventional means such as extraction, concentration, crystallization, liquid chromatography, etc.

Can be purified. In addition, compound (1) belongs to trisubstituted olefin compounds, and there may be two types of geometric isomers. Separation of isomers may be carried out by fractional crystallization or chromatography, if necessary. be able to.

EXAMPLES The present invention will be explained in more detail by describing Examples and Experimental Examples below.

Production method 1 Example 1 (Compound 1) Sodium amide (3,12 f/, 80 mmole) was added to dimethyl sulfoxide (35 g/) under a nitrogen stream, and the mixture was stirred at room temperature for 10 minutes. While keeping the reaction temperature below 40°C, add hexyμtriphenyμphosphonium bromide (33,7f + 79 mmole) and add 1
After stirring for an hour, 3-bency μpyridine (14,
A solution of dimethysium oxide (30ge) containing 5f 179 mmole was added at room temperature.

After the dropwise addition was completed, the reaction was continued for another 30 minutes at room temperature, and then
Normal hydrochloric acid (5001M/) was added, and neutral components were removed with toene. The aqueous layer was made alkaline with sodium acetate and the oily product was extracted twice with ether. The ether layers were combined, washed with water, dried (magnesium sulfate), and then the organic solvent was concentrated under reduced pressure. The residue was subjected to silica gel chromatography using isopropyl ether/v:ethylacetate/l/(4:
1), 1-pheny/l'-1-(3-viridi/I')-1-heftene (18,2N, 92%) is converted into a mixture of its isomers (E: Z=l:l). Obtained.

Table 1 shows compounds I-1 to Ni-7 produced according to this example.
It was shown to.

(Left below) Production method 2 Example 2 (Compound I-8 and Ni-9) Sodium hydride (60% oil dispersion, 2.79°59
mmole) was washed with hexane, the hexane was removed under reduced pressure, and dimethic acid μoxide (40jlt) was washed with hexane.
was added, and the mixture was heated and stirred at 85°C for 1 hour. After cooling, dimethyl μ containing 10-force μ poxydecani μ tripheny μ phosphonium bromide (1B, Of, 34 mmole)
A sulfoxide solution (20 g/) was added dropwise. After 10 minutes, 3-bency μpyridine (6,2f.

33,8 mmole) was mixed with dimethysium phosphate (10
+++l) and added. After reacting for 1 hour, add water (20
0gt) was added and the reaction 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 then evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and developed with ethyl acetate. When the product is fractionally recrystallized with inpropylene ether, <z> -12-7μm12-
(3-pyridi/l')-11-dodecaenoic acid (3,2F
) (Compound 8) was obtained.

The crystal mother liquor was dissolved in ethanol/I/(20-2), and this renitio dip chloride (3 gt) was added and left at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and diluted with 5% aqueous sodium hydroxide (
50+/) was added, the product was extracted with methylene chloride, and the organic layer was washed with water, dried, and concentrated.

The residue was subjected to silica gel μ chromatography and developed with isoglopyte μ, and the resulting Ethi A/, Z step μ was hydrolyzed to yield (E)-12-phenyv-12-(3-viridiμ). -11-dodecaenoic acid (2,31)C compound 9) was obtained.

Compounds Ni 10 to Ni 13 produced according to this example are shown in Table 2.

(Left below) Example 3 (E) T-phenyl-7(3-pyridi/l/)-6-
Ethyl heptenoate yvxy, rtv<1.5N, 4
．． 8m mole) in anhydrous tetrahydrofuran (30g
? ) and cooled on ice. Lithium aluminum hydride (0.5F) was gradually added to this. The mixture was heated at 0°C for 30
After stirring for a minute, saturated Rochelle brine was added to precipitate the inorganic substances. The organic layer was separated, the precipitate was washed with tetrahydrofuran (30 g/), the tetrahydrofuran solution was combined, and after drying over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure. The residue was subjected to silicage μ chroma F-graphy,
When eluted with ethyl acetate μ, (E)-7-phenylene/L'-7
-(3-viridi/I/)-6-hebte 1-oh/L/
(1st, 2nd floor.

94%) (compound 14) was obtained as an oil.

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

Example 4 (I-17) (E)-7-(3-viridi/1')-7-(2-chix
= A/) -6-hey'? 7 acid (0,41F
, 1.4 mmole) in anhydrous tetrahydrofuran (2
(1++/) and lithium aluminum hydride (0.1jl.

2.6 mmole) and stirred at 50°C for 1 hour.

Saturated Rossier μ brine (10g?) was added to the reaction solution, the organic layer was separated, and the precipitate was dissolved in tetrahydrofuran (20gj).
The mixture was washed with water, combined with a tetrahydrofuran solution, dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was subjected to silica gel μ chromatography and eluted with ethyl acetate to give (E)-7-(3-pyridi/L/)-7.
-(2-cheni/l/)-6-hebte 1-ohμ(0
, 21N, 52%) (compound 1-17) was obtained.

Compounds l-14, l-15, produced according to this example
Table 3 shows l-17 and l-18.

Inasa Production Method 3 Example 5 (Compound 19) (E)-7-Fx2/L/-7,-(3-pyridi/v)
-6-Hebte 1-oh/l/ (0,4f, 1.
5 mmole) in methylene chloride (10 g/),
Pyridine (0.4g/),! : Acetic anhydride (0.2g/)
was added and left at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and developed with ethyl acetate to give (Fi)-7-fe2μm7-(3-
Pyridi/L')-6-hebutate 1-ohμ acetate ester/l/(0,4F, 86%) (compound 1-19) was obtained as an oil.

Compound Ni 22 was produced in the same manner.

Example 6 (Compound l-20) (E)-7-yeniμm7-(3-pyridi/shi)-6-
Hebuti-1-oh/' (1,2f, 4.5 mm
ole) was added to formic acid (10 ml) and heated under reflux for 7 hours.

After cooling, it was concentrated under reduced pressure, and the obtained oil was subjected to silica gel chromatography and eluted with isopropylene ether-ethyl acetate/l/(1:l) to give (E)-7-yeneμm7-(3- pyridi μ)-6-hedete 1-o〃
Formic acid aesthetic μ (1,2F, 91%) (compound knee 20)
was obtained as an oil.

Example 7 (Compound 21) CB)-7-phenylene/L'-7-(3-pyridi/L/)
-6-hedete 1-oh A/ (0,81+ 3mmo
le) in methylene chloride (10 g/), pyridine (2111) and nicotinic acid clophyte hydrochloride (0,55
1+3 mmole) and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and developed with isoglopiether-ethyl acetate μ(Ill) to give (E)-1-phenylene.
-7-(,3-pyridiμ)-6-hebuty1-ohμ
Nicotinic acid ester/'(1, Of.

89.6%) (compound 1-21) was obtained as an oily substance.

Example 8 (Compound l-23) (E)-7-pheny/L'-7-(3-pyridi/L/)
-6-hebuty-1-oh/' (2,Of, 7.4
m mole) in methylene chloride (20M/),
To this was added sodium cyanate (0.5Of, 7.7 m
Add 1 mole) and trifluoroacetic acid (5 moles) and stir at room temperature for 2
Stirred for 0 hours. The reaction product was concentrated under reduced pressure, and potassium subacid (lIi), water (20 gt), and methylene chloride (50 gt) were added thereto, and after shaking and mixing, the organic layer was separated, washed with water, dried, and concentrated. Isopropylene ether residue
When recrystallized, (E)-7-7E2/l'-7-(3
-pyridiμ)-6-hebutate 1-ohμ force μpamic acid ester μ(1,82F, 79%) (compound 23) was obtained.

Example 9 (Compound 27) (E)-7-phenylated-7-(3-pyridi/L/)-6
- Heguthe 1-oh/' (41,15 mmole) and pheniN isocyanate (1,6d + 15 mmol
e) was dissolved in methylene chloride (20 g/), triethylamine (0.5 g?) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography.
When the product is recrystallized from a mixed solution of ethyl acetate μ and isopropyl ether ρ, (E)-7 is obtained.
-Fe2μm7-(3-pyridiIv)-6-Hebute1
-au μ phenyl force μ bamic acid ester/I/(3,2
F, 55%) I was very satisfied.

Example 10 (Compound l-24) According to Example 9, (E)-7-phenyA/-7-(3
-pyridiA/)-6-hebute1-ohμ(2,Of
, 7.4 mmole) and IA J1J acid) flV (50
When 0~+8.8 mmole) is reacted in the presence of triethylamine, (E)-7-pheny/L'-7-(
3-pyridyl)-6-hebutate 1-ohμmethyμcarbamate N (2,2f) (compound 24)
was obtained as an oil. This compound forms crystalline salts with oxalic acid.

Example 11 (Compound 25) According to Example 9, (E)-7-pheni1v-7-(3
-Pyridil/)-6-Hebute1-O〃(2,Of
When isocyanic acid n-guti/'(0,8F) is reacted with (E)-7-pheniμm7-(3-pyridi/l) in the presence of triethylamine,
/)-6-hebuty-1-oh/I'n-butymucarbamic acid ester/l/(2,:1M) (compound 25) was obtained as an oil.

Weight forms crystalline salts with oxalic acid.

Example 12 (Compound l-28) According to Example 9, (E)-7-phenylv-T-(3
-pyridyl)-6-hebuter-1-ol (2,Of,
7.4 mmole) and phenyl isothiocyanate/L/
(1, Q t , 7.5 m mole) was reacted in the presence of triethylamine to form (E)-7-phenymu-
7-(3-pyridi/V)-6-hebutate-1-ol phenyl-thiocapamic acid ester/'(2,2F) (compound 1-28) was obtained as crystals.

Example 13 (Compound l-29) (E)-7-phenyl-7-(3-pyridi/L/)-6
-Hebte 1-O/I' (2,Of, 7.4mm
Dissolve ole) in methylene chloride (20sr/) and add isocyanic acid p-)μ ence μhoni/L/(1,5
F.

7.6 mmole) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to obtain inpropyl p-ether μ-acetic acid
The product was recrystallized from ethyl acetate to give (E)-7-phediμm7-(3-pyridi/L').
-6-hebte 1-ohlv p-) Luens phoniμ
Force μ Bamate Ester (2,1F.

60%) (compound l-29) was obtained.

(Leaving space below) Production method 4 Example 14 (Compound 5) (E)-7-phediμm7-(3-pyridiμ)-6-hebuty1-oh/L/I)-)μenesulfonic acid ester /v (0.45f, 1.07 mmole) was dissolved in hexamethymuphosphomuamide (2 g/), and sodium iodide (0.2f, 1.3 mmole) was added thereto and stirred for 10 minutes. Then, sodium cyanoborohydride (0.1f, 16 mmole) was added to 100
Stir at ℃ for 1 hour. After cooling the reactant, add water (10+w
t) was added and the product was extracted with ethyl acetate. The nucleated layer was washed with water, dried, and concentrated under reduced pressure. The residue is chromatographed on silica gel, eluting with isopropyl p-ether μ-ethylacetate/I/(4:l). ! =(E)-1-y-1v-1-(3-pyridine-1-heptene (0,2F,
75%) was obtained as an oil.

(E)-1-pheny/L'-1-(3-pyridine-1
- Hair "Tenha E p -) / l / N μ fonic acid ester in tetrahydrofuran, lithium hydride ap
It was also obtained by reduction with miniram.

Compounds I-1 to 71 were prepared in the same manner.

mli production method 5 Example 15 (compound l-30) (E)-7-pheniμm1-(3-pyridi/L/)-6
-Hebute 1-ol lv p-)
gg? ) and stirred at room temperature for 3 hours.

Water (200g?) was added to the reaction and the product was extracted twice with ethyphenate. The organic layer was washed with water, dried (magnesium sulfate), and concentrated under reduced pressure to give (E)-1-iodo-7-
Phenyl A/-7-(3-pyridi/L')-6-heptene (13F, 96%) was obtained as an oil.

Compound Ni 31 was produced according to this example.

Production method 6 Example 16 (compound l-32) (E)-1-iodo-7-7enymu-T-(3-pyridyl)-6-heptene (3,7f, IOmmolle)
was dissolved in 100 μl/l/l, silver nitrate (5 g + 30 mmole) was added, and the mixture was stirred at room temperature.

After 3 hours, water (100sr/) and ethyl acetate yv (10
0 gyl) was added, and insoluble matter was filtered. The filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, the organic layer was washed with water, and dried (
magnesium sulfate), and then concentrated under reduced pressure. The residue was subjected to silica gluchromatography, and isopropyl ether μ-
Elution with ethyl acetate/l/(1:l) yields (E)-7-phenylene/'-7-(3-hyperzylene-6-heptene-1-
Oμ nitrate/l' (2.5f, 80%) (compound l-32) was obtained as an oil. Ice crystal oxalate was recrystallized from acetone.

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

Production method T Example 17 (Compound l-35) Oxacylyl chloride (0.3 ml) was added to methylene chloride (10 g?), cooled to -60°C, and chloride containing dimethyl sulfoxide (0.6 gt) was added. A methylene (IQgt) solution was added dropwise. After stirring at the same temperature for 10 minutes, (E+z)-6-phenylene/v-6-CB-pyridiμ)-5-hex-1-ohμ(0,7f, 2
．． A solution of 7 mmole) of methylene chloride (5 g+/) was added and stirred for 10 minutes. Then triethylamine C3m
1) was added and the temperature was gradually raised to room temperature. Water (50d) was added to this reaction solution, and the product was extracted with etherμ. After washing the organic layer with water and drying, the residue was subjected to silica gel p chromatography and eluted with isopropyl ether-ethyl acetate/l/(1:1) to give (E+Z)-1-.
hoμmi/I/-5-yeniρ-5-(3-pyridi7LL
/-4-bentene (0,5Ii, 70%) (compound l-
35) was obtained as an oily substance.

Compound Ni 36 was produced in the same manner.

Production method 8 Example 18 (compound l-37) (E)-7-phenylene/l/-7-(3-pyridi/L/)
-6-hebutate 1-oh A/p-)μenesulfonic acid ester/1' (0.2f, 0.5 mmole) was added to a 28% sodium methimethite methanol-μ solution (1m/p-).
) K was dissolved and left at room temperature for 3 days. After the reaction, water (10
ml) was added, and the product was extracted twice with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure. The residue was subjected to μ chromatography on silicage gel and developed with isoglobyl ether μ-ethyl acetate/l/(1:I) to give (E)-1-methoxy-7-phenyA/-7-(3-pyridi/ L')-6-
Heptene (0, If.

15%) (Compound I-37) was obtained as an oil.

Example 19 (Compound l-38) CE)-1-iodo-7-pheny/L/-7-(3-pyridi/l/)-6-heptene (0,6f, 1.6mmo
le) + 7 x no/I/(0,2f, 2.1
mmole ) in a mixed solvent of tetrahydrofuran (10 m) and dimethyl μformamide (21), and add sodium hydride (60% oily + 0.1 f,
2.5 mmole) and stirred at room temperature for 1.5 hours! I stirred it. Reaction water (20 g/) was added, and the product was extracted with ether μ. The organic layer was washed with water, dried, and concentrated under reduced pressure.

The residue was subjected to silica g μ chromatography and developed with L1 isopropyl μether-ethyl acetate/l/(2:l) to give (E)-1-phenoxy-7-phenylene μ-I-(3-pyridi/L'). -6-hebutene <0.51.73%) (compound l-38) was obtained as an oil.

Production method 9 Example 20 (E)-7-phenyl-7-(3-pyridi/I/)-6
-hexene-1-oh A/ (1,01, 3,7 mmo
Dissolve le) in methylene chloride and add 3.4-
Dihydro-a-bilane (0.6 g/) was added. Next, D-can 77-sulfonic acid (1.4 g) was added to this.

5 mmole) and stirred at room temperature. 1 hour later
Add saturated sodium hydrogen oxide solution and dissolve the product in ethyl acetate μ
Extracted with. The organic layer was washed with water, dried and concentrated under reduced pressure.
) 7-7, =Iv-1-(2-pyranyloxy)-
7-(3-pyridi/l/)-6-hexene (1,28j
F, 90%) (compound 39) was obtained as an oil.

Production method 10 Example 21 (compound 1-40) (E+Z)-1-iodo-5-7,=Iv-5-(3-
pyridi/l')-5-hexene (0,3B.

0.83 mmole) and imidazo-IV (0.2f
, 3 mmole) and dimethymu-formamide (1011
/) and add sodium hydride (60% oily,
0.2f, 5mmole) was added and stirred at room temperature for 1 hour. After the reaction, water (10 g/) was added and the product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography to obtain ethanol/I
-=-Ethyl acetate μ-triethyl μamine (1:20:0.
1) When "C' elutes (E+Z)-1-(1-imidazoly IV)-6-phenyA/-6-(3-pyridi p)
-5-hexene (o, 25F, 95%) was obtained as an oil.

Table 6 shows Compounds Ni 41 and Ni 42 produced in the same manner.

(Left below) Production method 11 Example 22 (Compound 43) (E)-7-y/L'-7-(3-pyridi/I/)
-6-hegetenoic acid (0,56f, 2.mmole
) was dissolved in oxalyl chloride (5 liters), and 50'
The mixture was heated at C for 1 hour. The reaction solution was subjected to 7M MR treatment, and then 5
% ammonia methanol solution (5 zl) was added and left at room temperature for 1 hour. After the reaction, methanol-μ is removed under reduced pressure and the residue is recrystallized from isopropylene ether (E).
-7-phenyl-7-(3-pyridi/I/)-6-1
Thenic acid amide (0.48F) was obtained.

Example 23 (Compound l-44) Example 22≠(E)-7-phenylene μm7
- (,3-pyridip)-6-hegetenoic acid clophyto
7=phosphorus (2
Methylene chloride solution containing σ(1') (2 ml
) and potassium subacid (3009) were added and stirred at room temperature for 4 minutes. Water was added to the reaction solution, and after washing with water, the methylene crophyte solution was dried and concentrated, and the residue was recrystallized from ethyl acetate to obtain (E)-7-phenyl-7-(3-pyridi/l/).
-6-heptenoic acid N-phenymuamide (620#) (compound 44) was obtained.

Production method 12 Example 24 (compound l-45) (E)-7-pheny/7-7-(3-pyridi/I/]-
6-hebuten-1-ol p-)luene pphonic acid ester/l/ (1,Of!, 2.4 mmole)
was dissolved in dimethyl sulfoxide (,log/), and sodium cyanide (0.39.6 mmole) was added to 1
I stirred it for 8 hours. Add water (100Ml) to the reaction solution,
Convert the product into ethyl acetate! Extracted with. Wash the organic layer with water, dry it,
It was concentrated under reduced pressure. The residue was subjected to silica gluchromatography and developed with ethyl acetate ρ-isoglobyl ether (III) to give (E)-1-cyano-1-7E/l/-
7-(3-pyridiμ)-6-heptene C0,51,76
%)was gotten.

Production method 13 Example 25 (compound 46) (E)-7-7e=*-7-(3-pyridi/v)-6-
Hegte 1-O IV (2,3f, 8.6 mm
ole) was dissolved in methylene chloride (20 to 1), and to this were added pyridine (Igt) and p-)ρene-μ fonyl chloride (18f, 9.4 mmole). After reacting overnight at room temperature, water (3(1+l)) was added to the reaction mixture, and the product was extracted with ethyl acetate.The organic layer was washed with water, dried, and the solvent was distilled off.The obtained oil was chromatographed on silica gel. Isoglopylete μm ethyl acetate/L
'(1:l) elutes with (E)-7-phenylene/L'-
7-(3-pyridi/L')-6-hebute 1-4-μ
p-)μenesulfonyρ ester C3,159,88%
) was obtained as an oil.

Compound Ni 47 was produced in the same manner.

Production method 14 Example 26 (compound 1-48') (E)-7-pheniμmI-(3-pyridi/L/)-
6-hebta 1-oμ (1,Of, 3.7mmo
le) and imidazo-/I/(0,251,3,7mmo
le) in dimethyμhopamide (10 ml),
To this, dimethy/L/l-guchi/VVsp chloride (0
,55jF.

3.7 mmole) was added and stirred for 1 hour. Water (2 (Ig/)) was added to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was washed with water, dried, and the solvent was concentrated under reduced pressure. When developed with μ-ethylacetate/l/(1:1), (E)-7-phenyleneμm7-(3-pyridi/L')-
6-hebte 1-oh μ dimethi/Mt-guchi μ Syria tzcs? A/(1,1F, 84%) is obtained as an oil.

(Margin below) Experimental Example 1 Suppressing effect on blood thromboxane A2 (TXA2) production in rats Eight male Prague-Dawley rats F, 7 to 8 weeks old, were used in a group of 5 rats. To rats in the compound administration group, the compound was suspended in water using a small amount of gum arabic per 10q/# body weight and orally administered at a volume of 2 Wtl/kg.

On the other hand, rats in the control group received only the gum arabic suspension. Two hours after administration, rats were treated with pendopa μ bitter μ.
Sodium (50#/#.

The animals were anesthetized by intraperitoneal injection, and ls+l blood was collected from the abdominal aorta. After leaving the blood at 25℃ for 90 minutes, 15.00o
Serum was separated by centrifugation at r\In for 2 minutes.

Radioimmunoassay of thromboxane B2 ('IXB2), a stable substitute of TXA2, produced in blood during standing [Shibouta et al.
Biachemical Pharmacol, 28
3601 1979). The TXA2 synthesis inhibition rate (%) was determined based on the difference in TXB2 production ability between the control group and the compound-administered group.

The results for typical compounds are shown in Table 8. Table 8 Reference Example 1 Dimethyl sulfoxide (350 ml) under nitrogen stream
Sodium amide (31f, 0.79 molv) was added to the solution and stirred at room temperature for 10 minutes. The reaction temperature was kept below 40°C.

After adding 0.306 mo/L/) and stirring for 1 hour,
-Pency μpyridine (55F, 0.301 mo/L/)
A solution of dimethysium oxide (50 g/) containing the following was added at room temperature with stirring. After the dropwise addition was completed, the reaction was allowed to continue for another 30 minutes at room temperature, then water (700 ml) was added and neutral substances were extracted twice with toluene. pH the aqueous layer with 6N hydrochloric acid.
was adjusted to 5.5 and the product was extracted twice with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure to yield (E)-7-phenyl-7-(3-pyridi/L/)-6-heptenoic acid and (Z)-7-pheni-7-(3-pyridi/L/)-6-heptenoic acid. /1/)-
An isotropic compound of 6-heptenoic acid (71, Of) was obtained. Add this mixture to 47% hydrobromic acid (3001!/)
and water (300ml), +10'c? '18
heated for an hour. - After cooling, the pH was adjusted to 5.5 with 50% aqueous sodium hydroxide and the product was extracted twice with ethyl acetate.

The organic layer was washed with water, dried, and concentrated under reduced pressure. The resulting oil was dissolved in ethyl acetate (100 g/μ) and left at room temperature for 1 day to obtain a crystal. When this was separated in a furnace, (x)-7-pheny/L/-7-(3-pyridi/L/)-6-heptenoic acid (28,6N, 33.8%) was obtained.

When this furnace liquid was concentrated, a mixture (40,4F) of (E)- and (Z)-7-7ethyl-7-(3-pyridi/l')-6-hebutyenoic acids (3 bodies: 2 body=11=23) was obtained. When this mixture was repeatedly subjected to the same acid isomerization reaction as above, (E)-7-phenylene/I/-7-(3-pyridi/l')-6-heptenoic acid (16,79,19, 7%
) were further obtained. Furthermore, when the same acid isomerization reaction is repeated twice, (E)-7-7,4-7-<3-pyridi/
I')-6-heptenoic acid (12,3f, 14.5%
)was gotten.

The crystalline material obtained by the above acid isomerization reaction and crystallization operation (
57,69) was crystallized twice from ethyl acetate (120 liters) to obtain more than 99% of (E)-7-pheniμm7-(3
-pyridi/L')-6-hebutyenoic acid <52.3F, 6
1.7%) was obtained. Melting point 114-115°C.

Elemental analysis theoretical value (for C engineering, H□9N02) c, 76.84
; L6.81; N, 4.98 Actual value c, 76.76; H, 6,69; li+4.68 nuclear magnetic resonance spectrum/I/(δ value, p, p, m, TM
8 internal standard, same below): 11.8 (IH, cooH
).

8.55 (2H, m), 7.46 (IH, a, 711
1z), 7.31 (3H, m), 7.16 (3H, m)
, 6.13 (1H1t.

7Hz), 2.29 (2H, t, 7Hz) Reference Example 2 Sodium hydride (IF, 60% oil) was added to dimethypsμ oxide (25g?) under a nitrogen stream, and heated at 85°C for 1 hour while stirring. After heating, the reaction solution was cooled to room temperature, and 5-carboxypentyltriphenylphosphonium bromide (5,2f, 11 mm/I/) was gradually added thereto and stirred for 10 minutes. Add to this 3-(3,4-
methylenedioxybency/I/)pyridine (2,5F
, 0.11 mo/I/) of tetrahydrofuran (1(
1g/) solution was added dropwise.

After the addition, the mixture was further stirred at room temperature for 30 minutes. After the reaction was completed, water (100gl) was added, and neutral substances were extracted twice with toluene (50wl).The pH of the aqueous layer was adjusted to 5.5 with 2N hydrochloric acid, and the product was extracted with ethyl acetate. This organic layer was washed with water, dried (magnesium sulfate), concentrated under reduced pressure, and the residue was subjected to silica gel μ chromatography and eluted with ethyl acetate. When crystallized from μ (Z)
-7-(3,4-methyV-dioxyphenylene/')-7-
(3-pyridi Iv)-6-heptenoic acid (0,4f,
24.6%) was obtained. Melting point 90-91°C.

Nuclear magnetic resonance spectrum/l': 9.20 (C00H
), 8.46 (2H, m), 7.50 (IH, m),
7.30 (IH, m).

6.68 (IH, d , 2H2), 6.68 (IH, d
, 8Hz).

6.53 (IH, dd, 8Hz, 2Hz), 6.05 (
IH,t.

7Hz), 5.92 (2H, e), 2.28 (2H, m
).

2.03 (2H, m), 1.57 (4H, m).

Reference Example 3 Dimethyp sulfoxide (250 g
) in sodium hydride (60% oily).

10g, 0.25mol) and heated at 85℃ for 1 hour2
5) Then, cool to room temperature, and while keeping it at 40°C, gradually add 5-boxybentyl triphenyl phosphonium bromide (52f, 0.11 mo/L') and stir for 10 minutes. Thereafter, a tetrahydrofuran (60+/) solution containing 2-nicotinoylthiophene (20F, 0.117μ) was added dropwise thereto. After the dropwise addition was completed, the mixture was stirred at room temperature for 30 minutes, then water (300 g/) was added to the reaction solution, and the aqueous solution was extracted twice with toene (300 g/).
Neutral substances were removed. The pH of the aqueous layer was adjusted to 5.5 with 2N hydrochloric acid.
The product was extracted with ethyl acetate. Ethyl acetate/I/
The layer was washed with water, dried (magnesium sulfate), and then concentrated under reduced pressure.

The residue was subjected to silica gel column chromatography, eluted with ethyl acetate, and after concentration, the resulting oil was dissolved in ethyl acetate and left overnight to form (Z)-7-(3-pyridiy).
v>-7-<2-che=Az)-6-heptenoic acid (9
g, 29%) was obtained. Melting point 93-94°C.

Nuclear magnetic resonance spectrum /I/: l 1.90 (II
, cooH).

8.53 (2H, m), 7.62 (IH, m), 7.
20 (IH, m), 7.15 (IH, m), 6.85 (
IHlm), 6.48 (IH, m), 6.22 (IH
,t,,7Hz).

2.35 (+H9m), 1.63 (4H, m).

The 2-isomer (1,Of) obtained in the above reaction was dissolved in a 50% aqueous phosphoric acid solution (10 g?) and heated at 100°C for 16 hours. After the reaction, the pH was adjusted to 5.5 with aqueous ammonia, and the product was extracted and separated according to a conventional method. When this crude product was measured by high performance liquid chromatography, the ratio of E-isomer to Z-isomer was 76:14. When this crude product (0.92 g) was recrystallized from ethyl acetate (E)
-7-(3-pyridi/L')-7-(2-ch2μ)-
6-heptenoic acid (0.65 g) was obtained. Melting point 84
-85℃.

Nuclear magnetic resonance spectrum: 10. Furnace 0 (IH, C00)
-1) 8.59 (IH1d+2Hz), 8.48 (IH
,d,d.

2'f12.4H2)1 7.58CII(,d+t,
7Hz, 2Hz) +7.29(+H,m), 7.24(
IH, d, a, 4Hz.

7Hz), γ', 04 (lH, m), 6.85 (lH+
m).

6.04 (IH, t, 8Hz), 2.34 (4H, m)
.

1.64 (4n, m).

Reference Example 4 According to Reference Example 1, (R:+Z)-6-pheny/l/-6-(3
-pyridi/L/)-5-hexenoic acid was produced.

δ11.1(II(,C00H), 8.53(I
H, m), 8.45 (IH, m), 7.20 (I
Hlm), 6. l7(Z).

6.12 (En (IH, t, 7Hz), 2.32 (2H
, m).

2.17 (2H+m) + 1.79 (2H9m) Reference Example 5 (E)-7-pheni/L'-7-(3-pyridiρ)-6
-Heptenoic acid (10F)/-1v (100111
), and thiodiμ chloride (20f) was gradually added thereto. The reaction solution was left overnight.

The reaction solution was concentrated under reduced pressure, neutralized by adding 5% aqueous potassium hydroxide solution, and the product was extracted with methylene chloride. The organic layer is washed with water, dried, and concentrated to give (E)-7-yeni, /'-
7-(3-pyridi/l/)-6-heptenoic acid ethylephteμ (11,2N) was obtained.

δ8.49 (IH, d, 2Hz), 8.41 (IH, d
d.

2Hz, 711z), 7.3 (7H1m), 6.08 (
IH+t, 8Hz), 4.09 (2H1q, 6Hz),
2.19 (4H, m), 1.56 (2H, m), 1.2
2 (3H, t.

5Hz) In the same reaction as above, (E)-7-phediμ-T-(2
-Cheni/L/)-6-heptenoic acid ethyleph fl,
(E+Z)-6-7E"IV 6-(3-pyridyl)
-5-hexenoic acid ethyl p-ester μ and (Z)-7-(3
, 4-methylenedioxyphenylene/l')-7-(3-pyridiIV)-6-hair"te:/acid ethimuentemu was prepared.

Reference Example 6 From the isomer mixture (1:1 in E/Z) of (E)- and (Z)-7-pheni/L/-7-(3-pyridi/V)-6-heptenoic acid ethyl ester ( Separation and purification of E)- and (Z)-isomers were performed as follows.
-Ethyl heptenoate N: r-ste/L' (l, Of
) in acetonitrile lv (2 g?) and injected into Rover Column np-6 (manufactured by Muri Co., Ltd., C type), and mixed bath K.
(acetonitrile/L//methanol/I//water/acetic acid/aqueous ammonia - 3400: 1000: 2000:6
: 3)-? 'Expanded. (Z)-isomer (0,4
1F) elutes first, followed by (E)-isomer C0,42
f) was eluted. Repeat the same operation and 8.51 (E
+2)-Mixture purer (Z)-7-pheniμm7-
(3-pyridiIv)-6-heptenoic acid ester (
3, Of) was obtained as an oil.

The above (Z)-isomer ethyl ester/'(2,Of) was dissolved in a mixed solvent of 20 g of methanol/ethyl ester (1) and water (15 ml), sodium hydroxide (1f) was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted with 2N hydrochloric acid.
was adjusted to 5.5 and the product was extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off under reduced pressure. Dilute the residue with ethyl acetate
Yosu recrystallization results in (Z-)-? -Fe2μm7-(3-
Pyridi/l/)-6-hegthenic acid (1,5F), mp
, 93-94°C were obtained.

Reference Example 7 According to Example 2, 3-force μ boxypropyl μ triphenyl μ
From phosphonium bromide and 3-bency μpyridine (E1Z)-5-yx=N-5-(3-pyridi/l/)
-4-pentaenoic acid was obtained. This (E+Z) isomer mixture was fractionally recrystallized from isoglopiate μ-ethyl acetate μ to yield (E)-5-pheny1v-5-(3-pyridi/I
/)-4-pentaenoic acid was obtained. mp, 10911
0℃.

Claims (1)

[Claims] In the general formula C, Bl is an aromatic group which may have a substituent,
The heterocyclic group is a B2ti hydrogen atom, hydroxyl group, nitrooxy group, formi μ group, nitrogen-containing 5-membered ring group, aceter μ group, tria μkiμ silly μoxy group, apkiμm or aryμsulfoniμoxy group, alkyl .mu.m or ary-2-s.mu.amino group, acy .mu.oxy group, 7poxycarponyloxy group, halogen atom, alkoxy group. Aryloxy group, cyano group, optionally substituted thiocabamoy group, optionally substituted carbamoy/leooxy group, optionally substituted thiocabamoy poxy group
n represents an integer of 2 to 16; Tatata, B2 is homumimu
group, cyano group or optionally substituted force μ bamoi p
When it is a group, n is an integer from 1 to 15, and R2 is a force μ
When it is a poxy μ group or an alkoxycarbonyl group, n is an integer τ of 9 to 15. ] A substituted vinyl derivative represented by