JPH0977745A - Novel phenylpentadienoic acid derivative - Google Patents

Abstract

(57) 【Abstract】 PROBLEM TO BE SOLVED: An antihistamine having a strong leukotrienoic acid release-suppressing effect, suppressing a late-onset reaction of asthma, and having less central side effects such as drowsiness in conventional antihistamines and having a wide safety margin. To provide an antiallergic agent and a therapeutic agent for asthma. SOLUTION: General formula (I) [Wherein, X and Y are halogen, or a hydrogen atom, m
And n is an integer of 0 to 4, A is an oxygen atom, an alkynylene group or an alkynylene group, or has a single bond, and Z
Represents a hydrogen atom or a methoxy group, and R represents a hydrogen atom or an ester residue] or a phenylpentadienoic acid derivative or a pharmaceutically acceptable salt thereof,
And pharmaceutical compositions containing them and methods for producing them.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel phenylpentadienoic acid derivative having excellent antihistamine and antiallergic effects, and the advantage of having few central side effects and containing a piperidine skeleton in the side chain, or a derivative thereof. It relates to salts and pharmaceutical compositions containing them.

[0002]

BACKGROUND OF THE INVENTION A series of bioactive lipids known as leukotrienes exert their pharmacological effects on the respiratory system, cardiovascular system and gastrointestinal system. Leukotrienes are a group of eicosanoids that arise from the metabolism of arachidonic acid via the lipoxygenase pathway. These lipid derivatives are derived from LTA4 and are known to have the following two types. (1) Those containing a sulfide-peptide side chain (LT
C4, LTD4, LTE4). (2) Non-peptidic (LTB4). These leukotrienes are considered to be an important contributor to the pathogenesis of various inflammatory and ischemic disorders, and their pathophysiological roles have been vigorously studied in recent years.

(1) Peptide leukotriene (LTC
4, LTD. 4) Rafer, A. Lefer, AM, Biochemical, Pharmacolog
y), Vol. 35, No. 2, 123-127 (1986), the peptide leukotriene (LTC).
4, LTD4) has an action of stimulating various kinds of muscles, and has a strong tracheal contraction action as well as a vascular smooth muscle stimulating action. This vasoconstrictor action
It has been reported to occur in the cerebral, renal, and mesenteric vasculature.

The peptide leukotrienes are associated with many lung diseases and are known to be potent bronchoconstrictor agents in humans. The actions of LTC4 and LTD4 are more potent than histamine and have been shown to be selective peripheral airway agonists. [Drachen, Jay. M (Drazen, J.
M.), Proceedings of National Academy of Sciences USA (Proc.
Natural. Acad. Sci. USA), 77, 4354 (19)
80 years). ] Also, like LTB4, it has an action of enhancing the leakage of liquid through the capillary membrane in the vascular bed (an action of enhancing the permeability of blood vessels), and can increase the release of mucus from the human respiratory tract in vitro. It is shown.
[Marom, Z., et al. American Review of Respiratory Diseases (Am. Rev. Res.
Dis.) 126, 449-451 (1982). ]

(2) Non-peptide leukotriene (LT
About B4) LTB4 was first reported by Borgheat and Samuelsson in 1979, and later by Corey, EJ and coworkers 5 (S), 12 (R)-. Dihydroxy- (Z, E, E, Z) -6,
It was found to be 8,10,14-eicosatetraenoic acid and was found to be produced by mast cells, polynuclear leukocytes, monocytes and macrophages.

[0006] LTB4 is a powerful stimulator of PMN leukocytes in vivo, and has chemotaxis, adhesion, aggregation, degranulation,
It has become clear that LTB4 is an inflammatory messenger in vivo, leading to increased superoxide production and increased cytotoxicity. It is known that white blood cells have an action of promoting infiltration into the inner membrane and an action of enhancing leakage of liquid through the capillary membrane (permeability of blood vessels) like histamine. Experiments with dogs have revealed that it is associated with increased airway hyperreactivity in dogs. High levels of LTB4 have also been found in humans after lung lavage in patients with severe lung dysfunction. In addition, like other leukotrienes, LTB4 has been shown to be associated with inflammatory diseases, rheumatoid arthritis, gout and psoriasis. In addition, some of the cardiovascular, lung, skin, liver,
It has also been reported to be involved in allergic and inflammatory diseases such as asthma and inflammatory bowel disease. On the other hand, as is well known, histamine is released from mast cells similarly to LTs, and has the action of bronchoconstriction and the action of enhancing leakage of liquid through the reticulovascular membrane (permeability of blood vessels).

[0007]

The effects of these leukotrienes and histamines are involved in the pathological conditions of allergic asthma and atopic dermatitis in a complicated manner. The disease condition cannot be improved sufficiently. For example, a histamine H1 antagonist has been developed to stop the action of histamine and has been clinically applied, but it has side effects such as drowsiness, and has an anticholinergic action, so that it may be used in asthma due to a decrease in mucus secretion. On the contrary, it is not used for asthma patients because it has the drawback that it may worsen. If the side effect dose and the effective dose can be sufficiently separated, it can be a useful anti-asthma drug.

[0008] In addition, leukotriene D4 antagonist, leukotriene B, is used to stop the action of leukotrienes.
4 antagonists have also been studied, and there is a patent application for certain carboxylic acid derivatives that have both antihistamine action and leukotriene D4 antagonist action (EP0485).
984A2, JP-A-4-182467). However, even these compounds cannot stop the action of released LTB4, and thus have a drawback that the allergic action derived from LTB4 cannot be suppressed.

Studies have also been conducted on drugs that stop the production of leukotrienes themselves, rather than antagonize the action of leukotrienes. Inhibitors of 5-lipoxygenase, an enzyme that acts on arachidonic acid to biosynthesize leukotrienes, imidazole derivatives, and caffeic acid derivatives are disclosed in JP-A-5-331147 and 1-101822. Japanese Unexamined Patent Publication (Kokai) No. 61-122270 discloses an amide compound having a certain type of phenolic hydroxyl group in the molecule, which has a histamine antagonistic activity and an activity to stop the biosynthesis of leukotrienes. Although the inhibitory action of lipoxygenase in vitro is very strong, there is a drawback that it does not show a sufficient action in histamine-based reactions.

[0010]

The compound of the present invention is a novel compound having a benzhydryloxypiperidinyl group and a phenyl-2,4-pentadienoic acid structure. These compounds were found out of many novel piperidine derivatives synthesized by the present inventors, and they have an antihistamine action and a phenolic hydroxyl group which is a structural feature of conventional leukotriene production inhibitors. Nevertheless, surprisingly, it has a strong leukotriene release inhibitory effect, and has the advantage of suppressing the delayed-onset reaction of asthma in an in vivo test using an animal model of asthma as well as a steroid drug. Further, the central side effects such as drowsiness, which has been a problem with conventional antihistamines, are very few, and the compound has a wider safety margin than conventional antihistamines.

The compound of the present invention having such excellent advantages is a novel phenylpentadienoic acid derivative represented by the following general formula (I), or a pharmaceutically acceptable salt thereof:

[Chemical 7] [Wherein, X and Y are halogen, or a hydrogen atom, m
And n are integers from 0 to 4, A represents an oxygen atom, an alkenylene group or an alkynylene group, Z represents a hydrogen atom or a methoxy group, and R represents a hydrogen atom or an ester residue].

The present invention also provides a pharmaceutical composition containing, as an active ingredient, a phenylpentadienoic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, such as an antihistamine and an antiallergic agent. And an asthma therapeutic agent.

A preferred compound group of the present invention is the compound of the formula (I), wherein X is a fluorine, chlorine or hydrogen atom, Y is a fluorine or hydrogen atom, and the formula-(CH ₂ ) _n-
A- (CH _{2) m} - group represented by the total carbon number of 3 to 5 amino polymethylene group, alkenylene group, alkynylene group,
Or a polymethylene group in which an oxygen atom is present on the chain, and Z is hydrogen or a methoxy group, phenyl-
It is a 2,4-pentadienoic acid derivative, or an ester thereof, or a pharmaceutically acceptable salt thereof. As the ester residue, for example, a lower alkyl group such as methyl, ethyl and propyl ester is preferable, but other ester residue which can be easily converted into a free carboxylic acid when administered in vivo can be used.

Specific examples of preferred compounds of the present invention include the following. (Compound 1) 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid (Compound 3) 5- {4- [4- (4-Benzhydryloxypiperidin-1-yl) butoxy] -3-methoxyphenyl} penta-2,4-dienoic acid (Compound 4) 5- {4- [3- (4-benzhydryl Oxypiperidin-1-yl) propoxy] -3,5-dimethoxymethoxyphenyl} penta-2,4-dienoic acid (Compound 5) 5- [4- (4- {4- [bis (4-fluorophenyl) methoxy] Piperidin-1-yl} -2-butenyloxy) -3-methoxyphenyl] penta-2,4-dienoic acid (Compound 6) 5- [4- (3- {4- [bis (4-fluorophenyl) methoxypiperidine -1-yl} propoxy)
-3-Methoxyphenyl] penta-2,4-dienoic acid (Compound 7) 5- [4- (3- {4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl} propoxy) -3-methoxy Phenyl] penta-2,4-dienoic acid

(Compound 8) 5- [4- (4- {4-[(4-
Chlorophenyl) phenylmethoxy] piperidin-1-yl-2-butenyloxy) -3-methoxyphenyl] penta-2,4-dienoic acid (Compound 9) 5- {4- [4- (4-benzhydryloxypiperidine- 1-yl) -2-butenyloxy] -3-
Methoxyphenyl} penta-2,4-dienoic acid (Compound 11) 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) -2-butynyloxy] -3
-Methoxyphenyl} penta-2,4-dienoic acid (Compound 12) 5- (4- {2- [2- (4-benzhydryloxypiperidin-1-yl) ethoxy] ethoxy}-
3-Methoxyphenyl) penta-2,4-dienoic acid (Compound 13) 5- {4- [3- (4-Benzhydryloxypiperidin-1-yl) propoxy] -3-methoxyphenyl} penta-2, 4-Dienoic acid ethyl ester (Compound 15) 5- {4- [5- (4-Benzhydryloxypiperidin-1-yl) pentyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 16) 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) propoxy] -3,5-dimethoxymethoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 17) 5- [4- (4- {4- [bis (4-fluorophenyl) methoxy] piperidin-1-yl} -2-butenyloxy) -3-methoxyphenyl] penta-2,4
-Dienoic acid ethyl ester

(Compound 18) 5- [4- (3- {4- [bis
(4-Fluorophenyl) methoxypiperidin-1-yl} propoxy) -3-methoxyphenyl] penta-2,4
-Dienoic acid ethyl ester (Compound 19) 5- [4- (3- {4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl} propoxy) -3-methoxyphenyl] penta-2,4-diene Acid ethyl ester (Compound 20) 5- [4- (4- {4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl-2-butenyloxy) -3-methoxyphenyl] penta-2,4
-Dienoic acid ethyl ester (Compound 21) 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) -2-butenyloxy]-
3-Methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 23) 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) -2-butynyloxy] -3
-Methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 24) 5- (4- {2- [2- (4-benzhydryloxypiperidin-1-yl) ethoxy] ethoxy}-
3-Methoxyphenyl) penta-2,4-dienoic acid ethyl ester

Particularly preferred compounds are acid salts of the above compound 1, for example, hydrochlorides, compounds 9, 17, 20, 2
2-trans-butenyloxy compounds such as 1, compounds 9 and 2
It is a cis isomer such as 1.

The compound (I) of the present invention can be produced, for example, by the reaction described below. Reaction formula 1)

Embedded image [Wherein, X, Y, m, n, A, Z and R represent the same meaning as described above, L represents a halogen atom, a mesyloxy group,
Alternatively, it represents a toluenesulfonyloxy group. ]

That is, a benzhydryl derivative represented by the general formula (II) and a reactive aldehyde compound represented by the general formula (III) are subjected to a condensation reaction, preferably in the presence of a suitable base to give a general compound. A condensed aldehyde compound represented by the formula (IV) is produced. This reaction is preferably carried out in a suitable solvent that does not affect the reaction. Examples of such a solvent include water, esters such as methyl acetate and ethyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, ketones such as acetone and methyl ethyl ketone; halogenated hydrocarbons such as dichloromethane and chloroform. Aromatic hydrocarbons such as benzene, toluene and xylene; other acetonitrile, dimethylsulfoxide, dimethylformamide and the like can be used alone or in combination of two or more. The reaction temperature varies depending on the raw materials used, but is preferably 0 ° C. to the boiling point of the solvent.
Further, coexistence of a base catalyst is generally effective for the progress of the reaction, but it is not essential. When coexisting with a base, potassium hydroxide, caustic soda, potassium carbonate, sodium carbonate, triethylamine, pyridine, tributylammonium hydroxide and the like are preferable.

In the intermediate compound represented by the general formula (IV),
The dialkyl 4-phosphonocrotonate ester is reacted in the presence of a base to produce the target compound represented by the general formula (V). As a solvent for this reaction, a solvent inert to this reaction, such as dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, dioxane, or toluene, can be used. The reaction temperature is preferably between -20 ° C and the boiling point of the solvent. As the base, potassium carbonate, sodium hydride, lithium diisopropylamide and the like are preferable. In the general formula (V), in the case where R is an ester residue, the ester compound of (V) may be further added, if necessary, by a conventional method of ester hydrolysis, for example, potassium hydroxide, sodium hydroxide, By treating with potassium carbonate, lithium hydroxide or the like, the target compound in the form of the free acid represented by the general formula (VI) can be obtained. As the reaction solvent in that case, it is preferable to use, for example, ethanol, methanol, isopropanol, acetone or the like. The reaction temperature is preferably 0 ° C to the boiling point of the solvent.

The reactive aldehyde compound of the general formula (III) can be synthesized by the reaction shown in the following reaction formula 2). Reaction formula 2)

Embedded image [Wherein, m, n, A and Z have the same meanings as described above, and L
And W represent a halogen atom, a mesyloxy group or a toluenesulfonyloxy group. That is, the compound represented by the general formula (VII) and the compound represented by the general formula (V
The reactive aldehyde compound (III) is obtained by reacting the benzaldehyde derivative represented by III) in the presence of a suitable base. As the reaction solvent, it is preferable to use a solvent such as acetonitrile, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, dioxane or acetone. As the base, it is preferable to use potassium carbonate, sodium hydride, lithium diisopropylamide, sodium methoxide, potassium butoxide and the like.

The compound of the present invention can also be produced by the reaction represented by the following reaction formula 3). Reaction formula 3)

Embedded image

Embedded image [Wherein the symbols have the same meanings as described above] That is, the compound represented by the general formula (VII) is added to the hydroxyphenylpentadienoic acid compound represented by the general formula (IX) synthesized by a known method. Compound (III)
To obtain a reactive pentadienoic acid compound represented by the general formula (X), which is reacted with a benzhydryl derivative represented by the general formula (II),
By reacting the compounds (II) and (III) in the reaction formula 1) under the same conditions as described above,
The target compound represented by the general formula (V) can be obtained and further hydrolyzed as necessary to synthesize the free type target compound represented by the general formula (VI).

Some of the target compounds of the present invention have stereoisomers and optical isomers, but the present invention also includes all of these isomers. The salts of the compound of the present invention include pharmaceutically acceptable salts, for example, hydrochloric acid, nitric acid, sulfuric acid, maleic acid, naphthalenedisulfonic acid, benzenesulfonic acid, fumaric acid, hydrobromic acid, citric acid, hydrobromic acid. , Tartaric acid, succinic acid, sulfamic acid, mandelic acid,
Acid addition salts such as malonic acid and phosphoric acid, and basic salts such as sodium salts, potassium salts, lithium salts, calcium salts, zinc salts and the like are preferable, but not limited thereto.

The compound (I) of the present invention can be formulated into a preparation for oral administration or parenteral administration by a conventional method by mixing a pharmaceutically acceptable carrier or auxiliary agent known per se. it can. As a solid preparation for oral administration,
Tablets, powders, granules, capsules and the like can be used. For example, the compound (I) of the present invention may be mixed with a suitable additive,
Excipients such as lactose, mannitol, corn starch, crystalline cellulose, etc .; cellulose derivatives, gum arabic,
It is produced by appropriately combining with a binder such as gelatin; a disintegrating agent such as carboxymethyl cellulose calcium; a lubricant such as talc and magnesium stearate. Further, these solid preparations can be used as a coating agent, for example, an enteric agent, by using a coating base such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylate copolymer.

The liquid preparation for oral administration may be an emulsion, a solution, a suspension, a syrup, an elixir and the like. For example, the compound (I) of the present invention is combined with a generally used inert diluent, for example, purified water, ethanol, etc., a wetting agent, an auxiliary agent such as a suspending agent, a sweetener, etc.
It can be produced by containing a flavoring agent, an aromatic agent, an antiseptic agent and the like. In addition, an aerosol can be prepared by a known method. Formulations for parenteral administration include injectable solutions, inhalants, external preparations, eye drops, and
It is also possible to use a nasal drop, an application agent such as an ointment, or the like. The dose of the compound (I) of the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration route and administration method, administration period, etc.
It is preferred that the administration range from 0.1 to 500 mg, particularly from 5 to 50 mg, is orally administered once to several times a day, or that the range from 0.1 to 500 mg is parenterally administered once to several times a day.

Next, the pharmacological action of the compounds of the present invention will be explained with reference to examples of representative compounds and salts thereof. Experimental Example 1: Anti-allergic action An anti-DNP-As (dinitrophenyl conjugate) was prepared by cutting the back part of a male SD rat (body weight: 150 to 250 g) in advance and diluting it to an appropriate concentration with a living saline solution and a physiological saline solution. Ascaris (Dinitrophenyl conjuugated Ascari)
s)) 0.1 ml of IgE serum was injected intradermally on the back to passively sensitize. 48 hours later 2.5 ml DNP-As 300 μM
1 ml of a physiological saline solution containing 0.5% Evans Blue was intravenously administered. After 30 minutes, exsanguinated and lethal under anesthesia, the blue spot on the back skin was punched out using a leather punch, and the method of Harada et al.
-7 (1966)), the amount of leaked dye was measured. The amount of leaking dye by passive sensitization anaphylaxis [PCA] is
It was determined by subtracting the amount of leakage dye at the physiological saline administration site from the amount of leakage dye at the PCA site. The test compound was suspended in 0.5% methylcellulose, and 10 mg / 4 ml / kg was administered as the antigen 1.
Oral administration was performed before the time. The efficacy of the test compound was judged by the rate of suppression of the amount of leaked pigment (antiallergic effect). First result
It is shown in the table.

Table 1 Inhibition of anti-allergic effect % Hydrochloride of compound 1 of the present invention 93% 2-trans-butenyloxy form of compound 9 of the present invention 50%

Experimental Example 2: Inhibitory action on leukocyte infiltration in guinea pig alveoli According to the method described in "American Revue of Respiratory Diseases", 1990, Vol. 142, pp. 680-685, the following test was conducted. did. Hartley guinea pigs (5 weeks old) were passively sensitized for 48 hours by intravenously injecting rabbit anti-ovalbumin (hereinafter abbreviated as OA) serum (0.25 ml / animal). An antihistamine (mepyramine, 10 mg) was intraperitoneally administered to prevent asthma death due to an immediate asthmatic reaction (IAR), and 0.25% OA antigen was exposed for 10 minutes using an ultrasonic nebulizer. After 24 hours, bronchoalveolar (BAL) lavage was performed under pentobarbital anesthesia, and the total number of white blood cells infiltrating the respiratory tract was measured with a call counter. In addition, a preparation sample was prepared, the ratio of mononuclear cells, eosinophils, and neutrophils in the bronchoalveolar lavage fluid (BALF) was examined, and each number was calculated from total white blood cells.
30 mg of each compound was suspended in 0.5% methylcellulose containing the surfactant Tween 80, exposed to OA antigen, and
Oral administration was performed before and 6 hours later. The inhibitory rate of leukocyte infiltration into the bronchoalveolar lavage fluid of the compound-administered group was calculated by the following formula assuming that the number of leukocytes in the group not administered with the compound after OA exposure was 0 and the number of infiltrated leukocytes in the group not administered with OA antigen was 100. Was calculated.

[Equation 1]

The results obtained in the above test are shown in Table 2.

Table 2 Compounds Eosinophil Inhibition% Neutrophil Inhibition% Mononuclear Cell Inhibition% Hydrochloride of Compound 1 of the Invention 60% 47% 55% JP-A-4-182467 20% 30% 10% Examples 15 compounds (control)

This test showed that the compounds of the present invention are also effective for allergic late-onset asthma symptoms.
Drugs such as oxatomide, ketotifen, and diphenhydramine were ineffective in this study. Cetirizine used as a control compound was not found to have a clear effect as compared with the compound of the present invention.

Experimental Example 3: Inhibitory action of anaphylactic airway contraction reaction The following test was conducted according to the overflow method of Konzet and Roessler. Hartley guinea pigs (5 weeks old) were treated with OA serum (0.1 ml / ani).
(mal) was intravenously injected and passively sensitized for 48 hours. Urethane (1.
(5 mg / kg) Anesthesia, tracheal cannula insertion, artificial ventilation with a respirator (10 ml / kg / stroke, 60 stroke / min.), And Galamine triethiodide (5 mg / kg)
Immobilize with kg; ip). About 1 hour later, 1 mg / kg of the drug was intravenously injected, and 15 minutes later, the antigen was administered (ovalbumin,
An anaphylactic airway constriction reaction is induced by 0.10 mg / kg (intravenous injection). Anaphylactic airway constriction occurs, increasing airway resistance and spilling air from the ventilator. The amount of air that overflows at this time (Ventilation Over F
(low volume) (hereinafter abbreviated as VOFV)) over time, and the peak value of VOFV is 0% in the group without OA administration and drug administration, 100% before administration of OA is 100%, and the anaphylactic airway of the drug administration group It was calculated as the shrinkage inhibition rate.
That is, the suppression rate of the peak was calculated by the following formula and expressed in% in Table 3.

Calculation was made by the following formula, and the value was expressed in%.

[Equation 2]

Table 3 Table 3 Inhibitory effect on anaphylactic air-constriction reaction 10 mg Administration rate 1 mg Administration rate Hydrochloride of Compound 1 of the present invention 85% 80% Compound 9 of the present invention 85% 85% 2-trans-butenyloxy body

Experimental Example 4: Anaphylactic leukotriene (LT) B4 / C from actively sensitized guinea pig lung slices
4 Release-inhibitory effect Watanabe-Kohno an
The experiment was performed according to the method described in "D Parker" (J.Immuno 1.125.946-) 1. Active sensitization of guinea pigs Male guinea pigs (4 weeks old, purchased from Japan SLC). ) Is preliminarily bred for 2 weeks, and then the back is shaved under an anesthesia of Ketararu,
Active immunization was carried out by intradermal administration of 1 ml of the antigen solution (containing 1 mg of ovalbumin, which is an antigen) prepared as described below, at 5 sites on the back. The antigen solution used was prepared by dissolving 20 mg of the antigen (ovalbumin) in 10 ml of physiological saline and adding it to an equal volume of Freund's complete adjuvant and mixing the mixture vigorously.

2. Preparation of Lung Section Two to three weeks after the sensitization, the actively sensitized guinea pigs were exsanguinated and killed, the lungs were washed with Tyrode's solution (not containing Ca), and then the lungs were excised. The isolated lung was sliced into 3 mm square pieces in ice-cold Tyrode's solution to prepare lung sections. 2 ml of the thus-prepared lung slice 200 mg in a test tube
It was suspended in the water-cooled Tyrode's solution.

3. Leukotriene release inhibitory activity from lung slices Leukotriene release reaction from lung slices was carried out in a constant temperature bath at 37 ° C. Five minutes after starting the heating, calcium chloride CaCl ₂ was added to the lung section suspension to a concentration of 1.8 mM, and 10 minutes later, the test compound was added. Dimethyl sulfoxide (DMS) was prepared so that the test compound was 10 mM.
O) and dissolved in the lung suspension to 10 μM to 100 μM
M was added. An equal volume of DMSO was added to the control group to which no test compound was added. After 10 minutes of pre-incubation, the antigen ovalbumin 2
The suspension was added to the suspension to give mg / ml, and the anaphylactic reaction was started. After reacting for 15 minutes, the supernatant of the suspension was filtered with a nylon mesh. LTB4 and LTC in the supernatant of the suspension
4 was quantified by the EIA method (using a Cayman kit), and the amount released from the lung section was determined.

The inhibition rate was calculated by comparing the free amounts of the control group and the test drug-added group. The results are shown in Table 4, showing that the compound of the present invention was 8 to 10% higher than the comparative control compound.
Has about twice as powerful action.

Table 4 Table 4 Anaphylactic leukotriene release inhibitory effect LTB4 LTC4 (IC ₅₀ ) Hydrochloride of Compound 1 of the present invention 15 μM 10 μM Compound 9 of the present invention 15 μM 10 μM 2-trans-butenyloxy compound JP-A-4-182467 100 μM or more 100 μM or more Compound of Example 15 (control) Ketotifen (control) 100 μM or more 100 μM or more

Experimental Example 5: Toxicity test Four to five week-old ICR mice were used as one group consisting of five mice.
The compound of each experimental example was suspended in an aqueous solution of 0.5% methylcellulose in physiological saline, and 300 mg / day and 6 mg / day, respectively.
It was administered at a dose of 00 mg / kg for 1 week, weight gain, organ weight, blood biochemical value, etc. were measured and compared with that of terfenadine, which is known to be relatively less toxic. As a result, terfenadine was found to lose body weight and abnormal liver function at a dose of 300 mg / kg, but no abnormalities were observed in the compound of the present invention.

From the results of Experimental Examples 1 to 5 described above, it became clear that the compound of the present invention exhibits excellent antiallergic action and leukocyte infiltration inhibiting action, and its toxicity is extremely low even after continuous administration. From such experimental results, the compound of the present invention is particularly useful as a therapeutic agent for rhinitis, a therapeutic agent for atopic dermatitis, and a therapeutic agent for psoriasis.

Preparation Example of Target Compound [Example 1] 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-diene Preparation of acid ethyl ester (Compound 13) 4-Benzhydryloxypiperidine (0.81 g, 3.
08 mmol), 4-bromopropoxy-3-methoxyphenylpentadienoic acid ethyl ester (1 g, 3.08 mmo
l) and sodium bicarbonate (0.518g, 6.16mm)
ol) was dissolved in acetonitrile (20 ml) and the solution was mixed at 60 ° C for 4
Heated for hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1: 1). The eluate was concentrated under reduced pressure to obtain the target compound (1 g). ¹ H-NMR (CDCl ₃ ) δppm 1.34 (3H, t, J
= 6.9), 1.6 to 2.1 (4H, m), 2.1 to 2.3
(2H, m), 2.5 (2H, m), 2.78 (2H, m
m), 3.44 (1H, m), 3.89 (3H, s),
4.09 (2H, t, J = 5.9), 4.22 (2H,
q, J = 6.9), 5.51 (1H, s), 5.94 (2
H, d, J = 15.9), 6.00 (1H, d, J = 1
4.1), 6.6 to 7.7 (16H, m) IR (KBr): 1700, 1623, 1595, 15
12, 1265, 1139 EI-MS: (m / z): 555 (M +, 30%), 3
08 (70%), 167 (100%)

Example 2 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester maleate (Production of Maleic Acid Salt of Compound 13) The target compound was obtained by dissolving the produced compound of Example 1 in ethanol, adding an equivalent amount of maleic acid, heating and cooling. ¹ H-NMR (CDCl ₃ ) δppm 1.23 (3H, t, J
= 6.9), 1.6 to 2.5 (6H, m), 2.5 (2H,
m), 2.8 to 3.4 (4H, m), 3.80 (3H,
s), 4.14 (2H, t, J = 5.9), 4.22 (2
H, q, J = 6.9), 5.51 (1H, s), 5.94
(2H, d, J = 15.9), 6.00 (2H, s, male
ic acid), 6.00 (1H, d, J = 14.1), 6.6
~ 7.7 (16H, m) IR (KBr): 1699, 1623, 1595, 15
142, 1265, 1139 EI-MS: (m / z) :, 555 (M +, 30%),
308 (70%), 167 (100%)

Example 3 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester maleate Preparation of (Compound 13 Maleate) Under nitrogen atmosphere, 60% sodium hydride (4.53 g, 1
(13.3 mmol) was washed with hexane, suspended in dimethylformamide (hereinafter abbreviated as DMF) (150 ml), cooled to 0 ° C., and diethyl 4-phosphonocrotonic acid ethyl ester (26.2 g, 104.5 mmol) was added dropwise. And stir for about 1 hour. 4- [3- (4-Benzhydryloxypiperidin-1-yl) -2-propoxy] -3-methoxybenzaldehyde (40 g, 87.15 mmol) was added as powder and stirred for 4 hours. The reaction solution was mixed with ethyl acetate (700 ml) -water (1
Partition with L), take the ethyl acetate layer and wash 3 times with water (1 L). The ethyl acetate layer was placed on silica gel (150 g) and eluted with ethyl acetate (1.5 L). Maleic acid (8.5 g) was added to the concentrated residue of the eluate under reduced pressure. The precipitated crystals were collected by filtration to obtain the desired compound (45 g). The results of the analysis were in agreement with those of Example 2.

Example 4 of 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid (Compound 1) Preparation 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (19 g) dissolved in methanol (300 ml) Then, 2N sodium hydroxide (40 ml) was added, and the mixture was heated under reflux for 3 hours. The reaction solution was cooled to room temperature, and methanol was distilled off under reduced pressure. About 1000 ml of water was added to the residue, and 2N hydrochloric acid aqueous solution (40
ml) was added and stirred overnight. The precipitated solid was collected by filtration and washed with water. The solid obtained was dried under reduced pressure to obtain 18 g of the desired compound. ¹ H-NMR (CDCl ₃ ) δppm 1.8-2.1 (2H,
m), 2.1 to 2.3 (4H, m), 2.8 to 3.3 (6
H, m), 3.74 (1H, m), 3.87 (3H,
s), 4.15 (2H, t, J = 5.9Hz), 5.45
(1H, s), 5.80 (1H, d, J = 15.2),
6.6 to 7.7 (16H, m) IR (KBr): 1690, 1623, 1595, 15
12, 1263, 1139 EI-MS: (m / z): 527 (M +, 10%), 3
60 (6%), 167 (100%)

[Table 5]

Example 5 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid hydrochloride (Compound 1 Preparation of 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid (10 g) in acetone (200 ml) )
Suspended in 4N hydrogen chloride in ethyl acetate (4.61 ml)
Was added, isopropyl ether (100 ml) was added, and the mixture was stirred at room temperature. The precipitated powder was collected by filtration to obtain 10 g of the target compound. ¹ H-NMR (CDCl ₃ ) δppm 1.8-2.1 (2H,
m), 2.1 to 2.3 (4H, m), 3.0 to 3.6 (6
H, m), 3.87 (3H, s), 4.15 (2H, t,
J = 5.9), 5.45 (1H, s), 5.93 (1H,
d, J = 15.2), 6.6 to 7.7 (16H, m) R (KBr): 3028, 1699, 1623, 159
5,1512,1265,1137

[Table 6] Elemental analysis value (as C ₃₃ H ₃₇ O ₅ N ₁ · HCl · 0.5H ₂ O) C (%) H (%) N (%) Theoretical value 69.16 6.68 2.44 experiment Value 69.43 6.92 2.50

Example 6 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) -2-trans-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid Production of ethyl ester maleate (2-trans-butenyloxy form of compound 21) 60% sodium hydride (2.80 g, 1 under nitrogen atmosphere)
(17 mmol) was washed with hexane, suspended in DMF (250 ml), cooled to 0 ° C., and diethyl 4-phosphonocrotonic acid ethyl ester (34.5 g, 138 mmol) was added dropwise.
Stir for about 1 hour. 4- [4- (4-benzhydryloxypiperidin-1-yl) -2-butenyloxy] -3-
Methoxybenzaldehyde (50 g, 106 mmol) is added to the powder and stirred for 4 hours. The reaction solution was mixed with ethyl acetate (70
(0 ml) -water (1 L) and the ethyl acetate layer is taken and washed 3 times with water (1 L). Ethanol (600 ml) was added to the concentrated residue of the organic layer to dissolve it, and maleic acid (1
2.3g) and stir overnight at room temperature. The precipitated crystals are collected by filtration and recrystallized from ethanol to obtain the target compound (57.9 g). ¹ H-NMR (CDCl ₃ ) δppm 1.32 (3H, t, J
= 6.9), 1.9 to 2.2 (4H, m), 2.95 to 3.
13 (2H, m), 3.27 to 3.42 (2H, m),
3.61 (2H, d, J = 6.9), 3.84 (1H,
m), 3.90 (3H, s), 4.23 (2H, q, J =
6.9), 4.66 (2H, d, J = 5.0), 5.42
(2H, m), 5.88-6.21 (3H, m), 6.2
6 (2H, s), 6.96 to 7.02 (2H, m), 7.
23 to 7.68 (11H, m) IR (KBr): 3557, 2958, 2474, 17
07, 1624, 1595, 1512, 1263, 11
36 EI-MS: (m / z): 567 (M +, 4%), 32
0 (100%), 167 (90%)

[Table 7]

Example 7 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) -2-trans-butenyloxy] -3-
Methoxyphenyl} penta-2,4-dienoic acid (compound 9
2-trans-butenyloxy derivative of 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) -2-trans-butenyloxy] -3-methoxyphenyl} obtained in Example 6. Penta-2,4-dienoic acid ethyl ester was hydrolyzed and synthesized in the same manner as in Example 4. ¹ H-NMR (CDCl ₃ ) δppm 1.8 to 2.3 (4H,
m), 2.8 to 3.3 (4H, m), 3.60 (2H,
m), 3.88 (3H, s), 4.15 (2H, t, J =
5.9), 4.67 (2H, m), 5.45 (1H,
s), 5.95 (2H, m), 5.98 (1H, d, J =
15.2), 6.6 to 7.7 (16H, m) IR (KBr): 1693, 1625, 1595, 15
12, 1263, 1139 EI-MS: (m / z): 539 (M +, 2%), 49
5 (3%), 167 (100%)

Table 8 Elemental analysis _{(C 34 H 37 O 5 N} · 0.9H 2 O as a) C (%) H (% ) N (%) Theoretical values 73.47 7.03 2.52 Found 73. 45 6.97 2.42

Example 8 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) butoxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 15 ) The compound of Example 37 was reacted with 4-benzhydryloxypiperidine in the same manner as in Example 1 to obtain the target product. ¹ H-NMR (CDCl ₃ ) δppm 1.34 (3H, t, J
= 6.9), 1.6 to 2.1 (6H, m), 2.1 to 2.3
(2H, m), 2.5 (2H, m), 2.78 (2H, m
m), 3.44 (1H, m), 3.89 (3H, s),
4.09 (2H, t, J = 5.9), 4.22 (2H,
q, J = 6.9), 5.51 (1H, s), 5.94 (2
H, d, J = 15.9), 6.00 (1H, d, J = 1
4.1), 6.6 to 7.7 (16H, m) IR (KBr): 1700, 1623, 1595, 15
12, 1265, 1139 EI-MS: (m / z) :, 569 (M +, 20%),
167 (100%)

Example 9 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) butoxy] -3-methoxyphenyl} penta-2,4-dienoic acid (Compound 3) Implementation The corresponding ethyl ester obtained in Example 8 was synthesized by hydrolysis in the same manner as in Example 4. ¹ H-NMR (CDCl ₃ ) δppm 1.7 to 2.3 (8H,
m), 2.8 to 3.3 (6H, m), 3.70 (1H,
m), 3.83 (3H, s), 4.01 (2H, t, J =
5.9), 5.45 (1H, s), 5.82 (1H, d,
J = 15.2), 6.6 to 7.7 (16H, m) IR (KBr): 1691, 1625, 1595, 15
12, 1263, 1139 EI-MS: (m / z): 541 (M +, 20%), 2
80 (20%), 220 (30%), 167 (100
%)

Example 10 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) propoxy] -3,5-dimethoxymethoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 16) As a raw material, 4-benzhydryloxypiperidine and the aldehyde of Example 35 were reacted in the same manner as in Example 27,
4- [3- (4-benzhydryloxypiperidine-1-
Yield) propoxy] -3,5-dimethoxybenzaldehyde is obtained. Then, diethyl 4-phosphonocrotonic acid ethyl ester was reacted in the same manner as in Example 14, and the reaction product was treated in the same manner to obtain the target compound. ¹ H-NMR (CDCl ₃ ) δppm 1.37 (3H, t, J
= 6.3), 1.78 (2H, m), 1.91 (2H,
m), 2.15 (2H, m) 2.52 (2H, m), 2.
78 (2H, m) 3.45 (1H, m), 3.87 (6
H, s), 4.06 (2H, t, J = 6.3), 4.25
(2H, t, J = 7.2), 5.42 (1H, s), 6.
03 (1H, d, J = 15.2), 6.6 to 7.7 (15
H, m) EI-MS: (m / z), 585 (M +, 20%), 1
67 (100%)

Example 11 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) propoxy] -3,5-dimethoxymethoxyphenyl} penta-2,4-dienoic acid (compound 4) The corresponding ethyl ester obtained in Example 10 was hydrolyzed and synthesized in the same manner as in Example 4. ¹ H-NMR (CDCl ₃ ) δppm 1.8-2.1 (2H,
m), 2.1 to 2.3 (4H, m), 2.8 to 3.3 (6
H, m), 3.74 (1H, m), 3.87 (6H,
s), 4.15 (2H, t, J = 5.9), 5.45 (1
H, s), 6.03 (1H, d, J = 15.2), 6.6
~ 7.7 (15H, m) IR (KBr): 1699,1622,1579,15
04,1242,1126 EI-MS: (m / z): 557 (M +, 10%), 3
08 (60%), 167 (100%)

Example 12 5- [4- (3- {4- [bis (4-fluorophenyl) methoxypiperidin-1-yl} propoxy) -3-methoxyphenyl] penta-2,4-dienoic acid Ethyl Ester (Compound 18) Using bis (4-fluorophenyl) methoxypiperidine as the raw material and the ester of Example 36, the reaction was performed in the same manner as in Example 1 for synthesis. ¹ H-NMR (CDCl ₃ ) δppm 1.32 (3H, t, J
= 6.3), 1.7 to 2.3 (6H, m), 2.45 (2
H, m), 2.71 (2H, m), 3.41 (1H,
m), 3.89 (3H, s), 4.09 (2H, t, J =
6.9), 4.20 (2H, q, J = 5.9), 5.48
(1H, s), 5.94 (1H, d, J = 15.2),
6.6 to 7.7 (14H, m) IR (KBr): 1700, 1623, 1595, 15
12, 1265, 1139 EI-MS: (m / z): 591 (M +, 30%).

Example 13 5- [4- (3- {4- [bis (4-fluorophenyl) methoxypiperidin-1-yl} propoxy) -3-methoxyphenyl] penta-2,4-dienoic acid (Compound 6) The corresponding ethyl ester obtained in Example 12 was hydrolyzed and synthesized in the same manner as in Example 4. ¹ H-NMR (CDCl ₃ ) δppm 1.8-2.1 (2H,
m), 2.1 to 2.3 (4H, m), 2.8 to 3.3 (6
H, m), 3.74 (1H, m), 3.87 (3H,
s), 4.15 (2H, t, J = 5.9), 5.45 (1
H, s), 5.80 (1H, d, J = 15.2), 6.6
~ 7.7 (14H, m) IR (KBr): 1690, 1623, 1595, 15
12,1263,1139 EI-MS: (m / z): 563 (M +).

[Table 9]

Example 14 5- [4- (4- {4- [bis (4-fluorophenyl) methoxy] piperidin-1-yl} -2-trans-butenyloxy) -3-methoxyphenyl] penta- 2,4-dienoic acid ethyl ester (2-trans-butenyl compound 17) Sodium hydride (0.31 g) was washed with hexane, and then D
After suspending in MF (30 ml), diethyl 4-phosphonocrotonic acid ethyl ester (1.63 g) was added dropwise under ice cooling.
After stirring for 1 hour, the aldehyde of Example 30 (3.0 g) was added to D
Add dissolved in MF (10 ml) and stir overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate and applied to a silica gel column to obtain 3.55 g of the desired product. ¹ H-NMR (CDCl ₃ ) δppm 1.37 (3H, t, J
= 6.3), 1.8 to 2.1 (2H, m), 2.1 to 2.3
(4H, m), 2.8 to 3.3 (6H, m), 3.74
(1H, m), 3.87 (3H, s), 4.15 (2H,
m), 5.45 (1H, s), 5.80 (1H, d, J =
15.2), 6.6 to 7.7 (14H, m) IR (KBr): 1699, 1623, 1595, 15
12, 1265, 1139 EI-MS: (m / z): 603 (M +, 10%).

Example 15 5- [4- (4- {4- [bis (4-fluorophenyl) methoxy] piperidin-1-yl} -2-trans-butenyloxy) -3-methoxyphenyl] penta- 2,4-dienoic acid (2-transbutenyl compound 5) The corresponding ethyl ester obtained in Example 14 was hydrolyzed in the same manner as in Example 4 to synthesize. ¹ H-NMR (CDCl ₃ ) δppm 1.8-2.1 (2H,
m), 2.1 to 2.3 (2H, m), 2.8 to 3.3 (4
H, m), 3.50 (2H, m), 3.74 (1H,
m), 3.87 (3H, s), 4.04 (2H, m),
5.39 (1H, s), 5.94 (1H, d, J = 15.
2), 6.11 (2H, m), 6.6 to 7.7 (16H,
m) IR (KBr): 1695, 1623, 1600, 15
08, 1265, 1139 EI-MS: (m / z): 575 (M +, 0.1%),
531 (2%), 203 (100%)

[Table 10]

Example 16 5- [4- (3- {4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl} propoxy) -3-methoxyphenyl] penta-2,4-dienoic acid Ethyl ester (Compound 19) The ester of Example 36 and 4-[(4-chlorophenyl)
Phenylmethoxy] piperidine was synthesized in the same manner as in Example 1. ¹ H-NMR (CDCl ₃ ) δppm 1.32 (3H, t, J
= 6.3), 1.7 to 2.3 (6H, m), 2.45 (2
H, m), 2.71 (2H, m), 3.41 (1H,
m), 3.89 (3H, s), 4.09 (2H, t, J =
6.9), 4.20 (2H, q, J = 5.9), 5.48
(1H, s), 5.94 (1H, d, J = 15.2),
6.6 to 7.7 (15H, m) IR (KBr): 1690, 1623, 1595, 15
12,1263,1139

Example 17 5- [4- (3- {4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl} propoxy) -3-methoxyphenyl] penta-2,4-dienoic acid (Compound 7) The corresponding ethyl ester obtained in Example 16 was hydrolyzed and synthesized in the same manner as in Example 4. ¹ H-NMR (CDCl ₃ ) δppm 1.9 to 2.2 (2H,
m), 2.1 to 2.3 (4H, m), 2.8 to 3.3 (6
H, m), 3.74 (1H, m), 3.87 (3H,
s), 4.14 (2H, t, J = 5.9), 5.45 (1
H, s), 5.92 (1H, d, J = 15.2), 6.6
~ 7.7 (15H, m) IR (KBr): 1697, 1623, 1595, 15
12, 1263, 1139 EI-MS: (m / z): 561 (M +, 1%), 34
2 (35%), 201 (100%)

[Table 10]

Example 18 5- [4- (4- {4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl-2-trans-butenyloxy) -3-methoxyphenyl] penta-2, 4-Dienoic acid ethyl ester Using the compound of Example 31 as a raw material, diethyl 4-phosphonocrotonic acid ethyl ester was reacted in the same manner as in Example 14 to synthesize. ¹ H-NMR (CDCl ₃ ) δppm 1.30 (3H, t, J
= 6.9), 1.8 to 2.4 (4H, m), 2.69 (2
H, m), 2.95 (2H, m), 3.40 (1H,
m), 3.90 (3H, s), 4.13 (2H, q, J =
6.9), 5.47 (1H, s), 5.78 (2H, m)
5.95 (1H, d, J = 15.2), 6.6 to 7.7 (1
5H, m)

Example 19 5- [4- (4- {4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl} -2-trans-butenyloxy) -3-methoxyphenyl] penta-2 , 4-dienoic acid The corresponding ethyl ester obtained in Example 18 was converted into Example 14
It was hydrolyzed and synthesized in the same manner as. ¹ H-NMR (CDCl ₃ ) δppm 1.8-2.1 (2H,
m), 2.1 to 2.3 (4H, m), 2.8 to 3.3 (6
H, m), 3.74 (1H, m), 3.87 (3H,
s), 4.15 (2H, t, J = 5.9), 5.45 (1
H, s), 5.80 (1H, d, J = 15.2), 6.6
~ 7.7 (15H, m) IR (KBr): 1690, 1623, 1595, 15
12, 1263, 1139 EI-MS: (m / z): 573

[Table 11]

Example 20 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) -2-cis-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid Ethyl ester
Naphthalene-1,5-disulfonate (Compound 21-2
-Naphthalene-1,5-disulfonate of cis-butenyloxy form) Under the same reaction conditions as in Example 1, 4-benzhydryloxypiperidine (2.67 g) and 5- [4- of Example 40 were used.
(4-chloro-2-cisbutenyloxy) -3-methoxyphenyl] penta-2,4-dienoic acid ethyl ester (3.36 g) was reacted, and the reaction solution was treated in the same manner as in Example 1. , Silica gel column chromatography, and eluted with ethyl acetate. The eluate was dissolved in ethanol (30 ml), 1,5-naphthalenedisulfonic acid (1.8 g) was added, and the precipitated crystals were collected by filtration to obtain the desired product. ¹ H-NMR (CDCl ₃ ) δppm 1.32 (3H, t, J
= 6.9), 1.8 to 2.1 (4H, m), 2.1 to 2.3
(4H, m), 3.04 (2H, m), 3.35 (2H,
m), 3.60 (3H, s), 3.75 (1H, m),
3.96 (2H, m), 4.22 (2H, q, J = 6.
9), 4.62 (2H, m), 5.37 (1H, s),
5.82 (1H, m), 5.98 (1H, d, J = 15.
2), 6.00 (1H, m), 6.6 to 7.7 (17H,
m), 8.20 (1H, d, J = 7.0), 8.20 (1
H, d, J = 7.0), 9.05 (1H, d) IR (KBr): 1701, 1622, 1595, 15
12, 1319, 1132 FAB-MS: (m / z): 568 (M +, 2%), 3
20 (10%), 167 (100%)

[Table 12]

Example 21 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) -2-cis-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid (2- of compound 9
Cis-butenyloxy derivative) The corresponding ethyl ester obtained in Example 20 was hydrolyzed in the same manner as in Example 4 to synthesize. ¹ H-NMR (CDCl ₃ ) δppm 1.8 to 2.2 (4H,
m), 2.8 to 3.3 (4H, m), 3.40 (2H,
m), 3.74 (1H, m), 3.83 (3H, s),
4.70 (2H, m, J = 5.9), 5.47 (1H,
s), 5.80 (1H, m), 5.96 (1H, d, J =
15.2), 6.01 (1H, m), 6.6 to 7.7 (16
H, m) IR (KBr): 1690, 1625, 1595, 15
12, 1263, 1139 EI-MS: (m / z): 539 (M +, 12%), 3
20 (10%), 167 (100%)

[Table 13]

Example 22 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) -2-butynyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester 1/2
Naphthalene sulfonate (1/2 naphthalene sulfonate of compound 23) The compound of Example 38 was used as a raw material, and the same reaction as in Example 1 was carried out to synthesize. ¹ H-NMR (CDCl ₃ ) δppm 1.32 (3H, t, J
= 6.9), 1.8 to 2.1 (2H, m), 2.1 to 2.3
(4H, m), 3.0-3.6 (8H, m), 3.74
(1H, m), 3.74 (3H, s), 3.86 (3H,
s), 4.23 (2H, t, J = 5.9), 4.68 (2
H, s), 5.39 (1H, s), 5.94 (1H, d,
J = 15.2), 6.6 to 7.7 (16H, m), 8.20
(1H, d, J = 8), 9.01 (1H, d) EI-MS (m / z): 565 (M +)

Example 23 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) -2-butynyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid (compound 11) The corresponding ethyl ester obtained in Example 22 was hydrolyzed and synthesized in the same manner as in Example 4. ¹ H-NMR (CDCl ₃ ) δppm 1.8 to 2.3 (4H,
m), 2.8 to 3.3 (4H, m), 3.70 (2H,
m), 3.74 (1H, m), 3.89 (3H, s),
4.79 (2H, s), 5.45 (1H, s), 5.96
(1H, d, J = 15.2), 6.6 to 7.7 (16H,
m) IR (KBr): 1695, 1623, 1595, 15
10, 1265, 1137 EI-MS: (m / z): 537 (M +, 3%), 16
7 (100%)

[Table 14]

Example 24 5- (4- {2- [2- (4-benzhydryloxypiperidin-1-yl) ethoxy] ethoxy} -3-methoxyphenyl) penta-2,4-dienoic acid Ethyl ester (Compound 24) Example 14 using the aldehyde of Example 29 as a raw material
It was synthesized by reacting diethyl 4-phosphonocrotonic acid ethyl ester in the same manner as in. ¹ H-NMR (CDCl ₃ ) δppm 1.30 (3H, t, J
= 6.9), 1.6 to 2.3 (6H, m), 2.58 (2
H, t, J = 5.9), 2.79 (2H, m), 3.68
(2H, t, J = 5.9), 3.87 (2H, t, J =
4.9), 3.89 (3H, s), 4.25 (2H, t,
J = 4.9), 5.45 (1H, s), 5.80 (1H,
d, J = 15.2), 6.6 to 7.7 (16H, m) EI-MS: (m / z) 585 (M +).

Example 25 5- (4- {2- [2- (4-benzhydryloxypiperidin-1-yl) ethoxy] ethoxy} -3-methoxyphenyl) penta-2,4-dienoic acid Hydrochloride (Compound 12
Hydrochloric acid salt of) The corresponding ethyl ester obtained in Example 24 was synthesized in the same manner as in Example 4 by hydrolysis. ¹ H-NMR (CDCl ₃ ) δppm 1.6-2.1 (2H,
m), 2.2-2.4 (2H, m), 3.0-3.5 (6
H, m), 3.74 (1H, m), 3.85 (2H, t,
J = 5.9), 3.87 (3H, s), 4.09 (2H,
t, J = 4.9), 4.18 (2H, t, J = 4.9),
5.40 (1H, s), 5.80 (1H, d, J = 15.
2), 6.6 to 7.7 (16H, m) IR (KBr): 1695, 1623, 1595, 15
12, 1265, 1139 EI-MS: (m / z): 557 (M +, 2%), 28
0 (50%), 167 (100%)

[Table 15] Elemental analysis value (as C ₃₄ H ₃₉ O ₆ N ₁ · HCl · 2.5H ₂ O) C (%) H (%) N (%) Theoretical value 63.89 7.09 2.19 Experiment Value 63.70 7.36 2.25

Example 26 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) pentyloxy] -3-methoxyphenyl}
Penta-2,4-dienoic acid ethyl ester (Compound 1
5) DMF with 4- (5-chloropentyloxy) methoxybenzaldehyde (2.56 g), 4-benzhydryloxypiperidine (2.67 g) and sodium hydrogen carbonate (2 g)
Suspend in (30 ml) and heat at 100 ° C. for 8 hours. The reaction mixture was eluted with ethyl acetate and concentrated under reduced pressure to give an aldehyde derivative (4.87 g). Sodium hydride (0.63 g) was washed with hexane, suspended in DMF (30 ml), and triethylphosphonocrotonic acid ester (3.36 g) was added dropwise under ice cooling. After stirring for 1 hour, the aldehyde obtained above (4.
5 g) is dissolved in DMF (10 ml) and added, and the mixture is stirred overnight at room temperature. The reaction solution was poured into water, extracted with ethyl acetate,
It was subjected to silica gel column chromatography to obtain 4.3 g of the desired product as an oil. ¹ H-NMR (CDCl ₃ ) δppm 1.34 (3H, t, J
= 6.9), 1.5-2.1 (6H, m), 2.0-2.3
(4H, m), 2.50 (2H, m), 2.78 (2H,
m), 3.45 (1H, m), 3.89 (3H, s),
4.09 (2H, t, J = 5.9), 4.22 (2H,
q, J = 6.9), 5.51 (1H, s), 5.94 (2
H, d, J = 15.9), 6.00 (1H, d, J = 1
4.1), 6.6 to 7.7 (16H, m) IR (KBr): 1700, 1623, 1595, 15
12, 1265, 1139 EI-MS: (m / z): 583 (M +, 30%), 3
08 (70%), 167 (100%)

Production Example of Intermediate Compound [Example 27] 4- [4- (4-benzhydryloxypiperidine-1-
Il) -2-butenyloxy] -3-methoxybenzaldehyde 4-benzhydryloxypiperidine hydrochloride (63.2
g, 0.208 mol), 4- (4-chloro-2-butenyloxy) -3-methoxybenzaldehyde (50.1 g, 0.20 g).
208 mol) and sodium hydrogen carbonate (35.0 g, 0.
416 mol) was dissolved in DMF (500 ml) and stirred at 90 ° C. for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was put on silica gel (200 g) and eluted with 4 L of ethyl acetate. The eluate was concentrated, and the precipitated solid was stirred with isopropyl ether and collected by filtration to give the title compound (76.8 g). ¹ H-NMR (CDCl ₃ ) δppm 1.64-1.93 (4
H, m), 2.07 to 2.20 (2H, m), 2.65
2.76 (2H, m), 3.00 (2H, d, J = 5.
0), 3.38 to 3.49 (1H, m), 3.93 (3
H, s), 4.69 (2H, d, J = 4.3), 5.51
(1H, s), 5.82-5.98 (2H, m), 6.9
6 (1H, d, J = 8.6), 7.20 to 7.43 (12
H, m), 9.84 (1H, s) EI-MS: (m / z): 471 (M +), 320,3.
04,167 (base), 138

[Table 16]

Similar to Example 27, the following Examples 28 to
31 compounds were synthesized. [Example 28] 4- [3- (4-benzhydryloxypiperidine-1-
¹ -NMR (CDCl ₃ ) δppm 1.64-2.20 (6)
H, m), 2.50 (2H, m), 2.75 (2H,
m), 3.00 (2H, d, J = 5.0), 3.45 (1
H, m), 3.93 (3H, s), 5.51 (1H,
s), 6.96 (1H, d, J = 8.6), 7.20 to 7.
43 (12H, m), 9.84 (1H, s) EI-MS: (m / z): 459 (M +).

Example 29 4- {2- [2- (4-benzhydryloxypiperidin-1-yl) ethoxy] ethoxy} -3-methoxybenzaldehyde ¹ H-NMR (CDCl ₃ ) δppm 1.6 ~ 2.1 (4H,
m), 2.1 to 2.3 (2H, m), 2.57 (2H,
m), 2.75 (2H, m), 3.42 (1H, m),
3.68 (2H, t, J = 5.9), 3.87 (2H,
t, J = 4.9), 3.89 (3H, s), 4.25 (2
H, t, J = 4.9), 5.50 (1H, s), 6.98
(1H, d, J = 7.9), 6.6 to 7.7 (12H,
m), 9.84 (1H, s) IR (KBr): 1690, 1623, 1595, 15
12, 1263, 1139 EI-MS: (m / z): 489 (M +).

Example 30 4- (4- {4- [bis (4-fluorophenyl) methoxy]]
Piperidin-1-yl} 2-trans-butenyloxy) -3-methoxybenzaldehyde ¹ H-NMR (CDCl ₃ ) δppm 1.64 to 1.99 (4
H, m), 2.07 to 2.20 (2H, m), 2.65
2.76 (2H, m), 3.00 (2H, d, J = 5.
0), 3.89 (1H, m), 3.93 (3H, s),
4.69 (2H, m), 5.46 (1H, s), 5.90
(2H, m), 6.9 to 7.5 (11H, m), 9.84
(1H, s) EI-MS: (m / z): 507 (M +)

Example 31 4- (4- {4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl-2-trans-butenyloxy) -3-methoxybenzaldehyde ¹ H-NMR (CDCl ₃ ) δppm 1.64 to 1.93 (4
H, m), 2.07 to 2.20 (2H, m), 2.65
2.76 (2H, m), 3.00 (2H, d, J = 5.
0), 3.38 to 3.49 (1H, m), 3.93 (3
H, s), 4.68 (2H, d, J = 4.3), 5.51
(1H, s), 5.82-5.98 (2H, m), 6.9
6 (1H, d, J = 8.6), 7.20 to 7.43 (11
H, m), 9.84 (1H, s) EI-MS: (m / z): 506 (M +).

Example 32 Preparation of 4- (5-chloropentyloxy) -3-methoxybenzaldehyde Vanillin (82.02 g, 0.54 mol) and potassium carbonate (81.8 g, 0.593 mol) were added to DMF ( 500 m
l), stirred at 90 ° C. for about 1 hour, cooled to room temperature, and 1-bromo-4-chloropentane (100 g,
0.54 mol) was added and the mixture was stirred for 24 hours. The reaction solution is poured into water, extracted with ethyl acetate, dried, and concentrated under reduced pressure. Isopropyl ether was added to the concentrated residue, and the mixture was stirred, and the solidified product was collected by filtration and dried to give the title compound (100 g). Yield 72%. ¹ H-NMR (CDCl ₃ ) δppm 1.67 (2H, m),
1.8-2.1 (4H, m), 3.58 (2H, t, J =
6.6), 3.93 (3H, s), 4.12 (2H, t,
J = 6.9), 6.97 (1H, d, J = 7.9), 7.3
5-7.5 (2H, m), 9.85 (1H, s) EI-MS: (m / z): 256 (M +)

Example 33 4- (4-chloro-2-trans-butenyloxy) -3
-Methoxybenzaldehyde Vanillin (50 g, 0.328 mol) and potassium carbonate (54.3 g, 0.39 mol) were suspended in DMF (500 ml), stirred at 90 ° C for about 1 hour, then cooled to room temperature,
1,4-trans-dichlorobutene (191g, 1.52m
ol) was added and the mixture was stirred for 24 hours. The reaction solution is poured into water, extracted with ethyl acetate, dried, and concentrated under reduced pressure. Isopropyl ether was added to the concentrated residue and the mixture was stirred, and the solidified product was collected by filtration and dried to give the title compound (50 g). Yield 6
3%. ¹ H-NMR (CDCl ₃ ) δppm 3.95 (3H, s),
4.10 (2H, m), 4.72 (2H, m), 6.05
(2H, m), 7.02 (1H, d, J = 7.9), 7.
35-7.5 (2H, m), 9.86 (1H, s) EI-MS: (m / z): 240 (M +)

Example 34 4- [2- (2-chloroethoxy) ethoxy] -3-methoxybenzaldehyde 2-chloroethoxyethanol (8.20 g, 65.83 m)
mol), vanillin (10.0 g, 65.8 mmol) and triphenylphosphine (18.9 g, 72.4 mmol) were dissolved in tetrahydrofuran (hereinafter abbreviated as THF) (300 ml), and diethyl azodiene was added at -10 ° C. Carboxylate (12.6 g, 72.4 mmol) was added dropwise over 30 minutes.
The reaction mixture was stirred overnight. THF is distilled off under reduced pressure, isopropyl ether is added, and the mixture is stirred. The precipitated crystals were filtered off and the filtrate was concentrated. The concentrate was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2: 8). The title compound was crystallized when the eluate was concentrated and left to stand. Yield 12g. Yield 70%. ¹ H-NMR (CDCl ₃ ) δppm 3.66 (2H, t, J
= 6.9), 3.85 (2H, t, J = 6.9), 3.93
(3H, s), 3.96 (2H, t, J = 6.9), 4.
30 (2H, t, J = 6.9), 7.02 (1H, d, J
= 9.6), 7.35-7.5 (2H, m), 9.86
(1H, s) MS (m / z): 258 (M +), 152, 107

Example 35 4- (3-chloropropoxy) -3,5-dimethoxybenzaldehyde 4-hydroxy-3,5-dimethoxybenzaldehyde (10 g, 0.055 mol), 28% sodium methoxide (81.8 g) , 0.593 mol) was dissolved in DMF (500 ml) and 1-bromo-3-chloropropane (8.64) was added.
g, 0.055 mol) and stir overnight. 50 ° C
Heat to stir overnight. The reaction solution is poured into water, extracted with toluene, dried, and concentrated under reduced pressure. The concentrated residue was subjected to column chromatography and eluted with ethyl acetate-hexane (2: 8) to give 9.33 g (66%) of the title compound. ¹ H-NMR (CDCl ₃ ) δppm 2.19 (2H, quinte
t, J = 6.6), 3.86 (2H, t, J = 6.9),
3.91 (6H, s), 3.96 (2H, t, J = 6.
9), 4.10 (2H, t, J = 6.9), 7.12 (1
H, d, J = 9.6), 9.86 (1H, s) EI-MS: (m / z): 258 (M +).

Example 36 5- [4- (3-chloropropoxy) -3-methoxyphenyl] pentadienoic acid ethyl ester 1-bromo-3-chloropropane (1.53 g), potassium carbonate (1.34 g), 5- (4-hydroxy-3-methoxyphenyl) pentadienoic acid ethyl ester (3.11
g) is stirred in DMF (30 ml) at room temperature for 3 hours. The reaction solution is poured into water and extracted with ethyl acetate. After the extract was dried and concentrated, it was subjected to silica gel column chromatography, and hexane-
Elute with ethyl acetate. The eluate was concentrated to obtain the target compound (3.2 g). ¹ H-NMR (CDCl ₃ ) δppm 1.32 (3H, t, J
= 6.9), 2.31 (2H, m), 3.78 (2H,
t, J = 6.6), 3.91 (3H, s), 4.22 (4
H, m), 6.7 to 7.4 (6H, m) EI-MS: (m / z): 324 (M +).

Similar to Example 36, the following Examples 37-
40 compounds were synthesized. Example 37 5- [4- (4-chlorobutoxy) -3-methoxyphenyl] pentadienoic acid ethyl ester ¹ H-NMR (CDCl ₃ ) δppm 1.32 (3H, t, J
= 6.9), 2.00 (4H, m), 3.63 (2H,
t, J = 6.6), 3.91 (3H, s), 4.08 (2
H, t, J = 6.6), 4.23 (2H, t, J = 6.6.
9), 6.7-7.4 (6H, m) EI-MS: (m / z): 338 (M +).

Example 38 5- [4- (4-chloro-2-butynyloxy) -3-methoxyphenyl] penta-2,4-dienoic acid ethyl ester ¹ H-NMR δppm 1.32 (3H, t , J = 6.9),
3.93 (3H, s), 4.17 (2H, s), 4.25
(2H, q, J = 6.9), 4.83 (2H, s), 5.
98 (1H, d, J = 15.9), 6.7 to 7.5 (6
H, m) EI-MS (m / z): 334 (M +).

Example 39 5- [4- (2-chloroethoxy) -3-methoxyphenyl] penta-2,4-dienoic acid ethyl ester ¹ H-NMR (CDCl ₃ ) δppm 1.32 (3H, t, J
= 6.6), 3.83 (2H, t, J = 6.9), 3.91
(3H, s), 4.1-4.4 (4H, m), 5.96
(1H, d, J = 15.9), 7.5-7.4 (6H,
m) EI-MS, (m / z), 310 (M +)

Example 40 5- [4- (4-chloro-2-cis-butenyloxy)-
3-Methoxyphenyl] penta-2,4-dienoic acid ethyl ester ¹ H-NMR (CDCl ₃ ) δppm 1.32 (3H, t, J
= 6.9), 3.93 (3H, s), 4.08 (2H,
m), 4.25 (2H, q, J = 6.9), 4.65 (2
H, m), 5.98 (1H, d, J = 15.9), 5.9
-6.1 (2H, m), 6.7-7.5 (6H, m) EI-MS (m / z): 336 (M +).

The target compounds of the present invention obtained in Examples 1 to 26 above are represented by the general formula (I).
It is as shown in the table.

[Table 17]

[Table 18]

Front page continuation (72) Inventor Mari Iwata 4-53-3 Kitahama, Chuo-ku, Osaka City, Osaka Prefecture Sumitomo Metal Industries, Ltd.

Claims (13)

[Claims] 1. General formula (1): [Wherein, X and Y are halogen, or a hydrogen atom, m
And n is an integer of 0 to 4, A is an oxygen atom, an alkenylene group or an alkynylene group, or a single bond, and Z is
Represents a hydrogen atom or a methoxy group, and R represents a hydrogen atom or an ester residue], or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein m and n are 0, and A is an alkenylene group having 3 to 5 carbon atoms or an alkynylene group. 3. m and n are each 1 to 3;
The compound of claim 1, wherein A is a single bond. 4. m and n are each 1 to 3, and
The compound according to claim 1, wherein A is an oxygen atom. 5. The compound according to claim 1, wherein X and Y are the same or different and each is a fluorine, chlorine or hydrogen atom. 6. The compound according to claim 1, wherein Z is a hydrogen atom. 7. The method according to claim 1, wherein Z is a methoxy group.
A compound as described. 8. The compound according to claim 1, wherein R is a hydrogen atom. 9. The compound according to claim 1, wherein R is a lower alkyl group. 10. 5- {4- [3- (4-Benzhydryloxypiperidin-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid; 5- {4- [4 −
(4-Benzhydryloxypiperidin-1-yl) butoxy] -3-methoxyphenyl} penta-2,4-dienoic acid; 5- {4- [3- (4-benzhydryloxypiperidin-1-yl) ) Propoxy] -3,5-dimethoxymethoxyphenyl} penta-2,4-dienoic acid; 5- [4- (4
-{4- [bis (4-fluorophenyl) methoxypiperidin-1-yl} -2-butenyloxy) -3-methoxyphenyl] penta-2,4-dienoic acid; 5- [4- (3- {4
-[Bis (4-fluorophenyl) methoxypiperidine-
1-yl} propoxy) -3-methoxyphenyl] penta-2,4-dienoic acid; 5- [4- (3- {4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl} propoxy)- 3-Methoxyphenyl] penta-2,4-dienoic acid; 5- [4- (4- {4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl-2-butenyloxy) -3-methoxyphenyl] Penta-2,4-dienoic acid; 5- {4- [4- (4-benzhydryloxypiperidin-1-yl) -2-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid; 5- {4- [4-
(4-benzhydryloxypiperidin-1-yl) -2
-Butynyloxy] -3-methoxyphenyl} penta-2,
4-dienoic acid; 5- (4- {2- [2- (4-benzhydryloxypiperidin-1-yl) ethoxy] ethoxy}-
3-Methoxyphenyl) penta-2,4-dienoic acid; 5-
{4- [3- (4-benzhydryloxypiperidine-1
-Yl) propoxy] -3-methoxyphenyl} penta-
2,4-dienoic acid ethyl ester; 5- {4- [5- (4
-Benzhydryloxypiperidin-1-yl) pentyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester; 5- {4- [3- (4-benzhydryloxypiperidine-1- Il) propoxy] -3,
5-dimethoxymethoxyphenyl} penta-2,4-dienoic acid ethyl ester; 5- [4- (3- {4- [bis (4-
Fluorophenyl) methoxypiperidin-1-yl} propoxy) -3-methoxyphenyl] penta-2,4-dienoic acid ethyl ester; 5- [4- (3- {4-[(4-chlorophenyl) phenylmethoxy] piperidine -1-yl}
Propoxy) -3-methoxyphenyl] penta-2,4-
Dienoic acid ethyl ester; 5- [4- (4- {4- [bis
(4-Fluorophenyl) methoxy] piperidin-1-yl} -2-butenyloxy) -3-methoxyphenyl] penta-2,4-dienoic acid ethyl ester; 5- [4- (4
-{4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl-2-butenyloxy) -3-methoxyphenyl] penta-2,4-dienoic acid ethyl ester; 5- {4- [4- (4 -Benzhydryloxypiperidin-1-yl) -2-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester;
5- {4- [4- (4-benzhydryloxypiperidin-1-yl) -2-butynyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester; and 5- (4- { 2- [2- (4-Benzhydryloxypiperidin-1-yl) ethoxy] ethoxy} -3-methoxyphenyl) penta-2,4-dienoic acid Ethyl ester selected from the phenylpentadienoic acids of claim 1. Derivatives, or pharmaceutically acceptable salts thereof. 11. 5- {4- [4- (4-Benzhydryloxypiperidin-1-yl) -2-trans-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid; 5- {4- [4- (4-Benzhydryloxypiperidin-1-yl) -2-cis-butenyloxy] -3
-Methoxyphenyl} penta-2,4-dienoic acid; 5-
[4- (4- {4- [bis (4-fluorophenyl) methoxy] piperidin-1-yl} -2-trans-butenyloxy) -3-methoxyphenyl] penta-2,4-dienoic acid ethyl ester; 5 -[4- (4- {4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl-2
-Trans-butenyloxy) -3-methoxyphenyl]
Penta-2,4-dienoic acid ethyl ester; 5- {4-
[4- (4-Benzhydryloxypiperidin-1-yl) -2-trans-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester; and 5- {4- [4- ( 4. A novel phenylpentadienoic acid derivative according to claim 1, selected from 4-benzhydryloxypiperidin-1-yl) -2-cis-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester. A pharmaceutically acceptable salt thereof. 12. A compound represented by the general formula (I): [Wherein, X and Y are halogen, or a hydrogen atom, m
And n is an integer of 0 to 4, A represents an oxygen atom, an alkenylene group or an alkynylene group, Z represents a hydrogen atom or a methoxy group, and R represents a hydrogen atom or an ester residue]. A method for producing an acid derivative or a pharmaceutically acceptable salt thereof, which comprises a compound represented by the general formula (II): The benzhydryl derivative represented by [the symbols in the formula have the same meanings as above] is represented by the general formula (III): [Wherein, L represents a halogen atom, a mesyloxy group or a toluenesulfonyloxy group, and the other have the same meanings as described above], and a condensation reaction is performed with a reactive aldehyde compound represented by the general formula (IV) ] [Wherein the symbols in the formula have the same meanings as described above], the condensed aldehyde compound is reacted with a dialkyl 4-phosphonocrotonic acid ester in the presence of a base, and, if necessary, the resulting compound. A method of hydrolyzing. 13. A compound represented by the general formula (I): [Wherein, X and Y are halogen or hydrogen, m and n are integers from 0 to 4, A is an oxygen atom, an alkenylene group or an alkynylene group, or a single bond, and Z is a hydrogen atom or a methoxy group. , R represents a hydrogen atom or an ester residue. ] The pharmaceutical composition which uses the phenyl pentadienoic acid derivative represented by these, or its pharmaceutically acceptable salt as an active ingredient.