JPH0977754A - New phenylpentadienoic acid compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having strong action to suppress the isolation of leucotrienoic acid, causing little central side actions such as drowsiness, having a broad safety range and useful as an antihistaminic agent, an anti-allergic agent and a treating agent for asthma. SOLUTION: The objective compound (salt) is expressed by formula I (X and Y are each a halogen or H; (m) and (n) are each 0-4; (p) is 2 or 3; A is O, an alkenylene, an alkynylene or single bond; Z is H or methoxy; R is H or an ester residue), e.g. 5- 4-[3-(4-benzhydrylpiperazin-1-yl)propoxy]-3- methoxyphenyl}penta-2,4-dienoic acid ethyl ester. The compound can be produced by condensing by benzhydryl derivative of formula II with a reactive aldehyde compound of formula III (L is a halogen, mesyloxy, etc.) to obtain a condensed aldehyde compound of formula IV, reacting the product with a dialkyl 4- phosphonocrotonic acid ester in the presence of a base and, as necessary, hydrolyzing the produced compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel phenylpentadienoic acid compound having excellent antihistamine and antiallergic activity, and the advantage of having few central side effects and containing a piperazine or diazepane skeleton in a side chain, Alternatively, it relates to a salt thereof and a pharmaceutical composition 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 has a benzhydryl piperazinyl group or a benzhydryl group [1,
4] having a diazepan-1-yl group and phenyl-2,
It is a novel compound having a 4-pentadienoic acid structure. These compounds were found out of a large number of piperazine or diazepane derivatives synthesized by the present inventors and do not have a phenolic hydroxyl group, which is a structural feature of conventional leukotriene production inhibitors, together with an antihistamine action. Nevertheless, surprisingly, it has a strong inhibitory action on leukotriene release, and it has the advantage of sufficiently suppressing delayed-onset asthma reaction in an in vivo test using an animal model of asthma as well as a steroid drug. is there. In addition, the central side effects such as drowsiness, which is 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 compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:

[Chemical 7] [Wherein X and Y are halogen atoms or hydrogen atoms, m and n are integers from 0 to 4, p is an integer from 2 or 3, A is an oxygen atom, an alkenylene group or an alkynylene group, or a single bond, 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 compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, such as an antihistamine or an antiallergic agent. And an asthma therapeutic agent.

A preferred group of compounds of the present invention is represented by the formula (I), wherein X is a fluorine, chlorine or hydrogen atom, Y is a fluorine or hydrogen atom, and a compound of the formula-(CH ₂ ) n is used.
-A- (CH ₂₎ a group represented by m-, total carbon number of 2 to 8 polymethylene group, alkenylene group or alkynylene group or polymethylene group having an oxygen atom interposed on the chain,,, Z is It is a phenyl-2,4-pentadienoic acid derivative which is hydrogen or a methoxy group, 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-benzhydryl-
[1,4] Diazepan-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 2) 5- {4- [3- (4-benzhydryl-
[1,4] Diazepan-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid (Compound 3) 5- {4- [3- (4-benzhydrylpiperazin-1-yl) ) Propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 4) 5- {4- [3- (4-benzhydrylpiperazin-1-yl) propoxy] -3-methoxyphenyl } Penta-2,4-dienoic acid (Compound 5) 5- {4- [4- (4-Benzhydrylpiperazin-1-yl) -2-butenyloxy] -3-methoxyphenyl} penta-2,4- Dienoic acid ethyl ester (Compound 6) 5- {4- [4- (4-Benzhydrylpiperazin-1-yl) -2-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid (Compound 7 ) 5- {4- [5- (4-benzhydryl pipera Down-1-yl) pentyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester

(Compound 8) 5- {4- [5- (4-benzhydrylpiperazin-1-yl) pentyloxy] -3-
Methoxyphenyl} penta-2,4-dienoic acid (Compound 9) 5- {4- [3- (4-benzhydrylpiperazin-1-yl) propoxy] -3,5-dimethoxyphenyl} penta-2,4 -Dienoic acid ethyl ester (Compound 10) 5- {4- [3- (4-Benzhydrylpiperazin-1-yl) propoxy] -3,5-dimethoxyphenyl} penta-2,4-dienoic acid (Compound 11 ) 5- {4- [2- (4-Benzhydrylpiperazin-1-yl) ethoxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 12) 5- {4- [2 -(4-Benzhydrylpiperazin-1-yl) ethoxy] -3-methoxyphenyl} penta-2,4-dienoic acid (Compound 13) 5- {4- [4- (4-Benzhydrylpiperazin-1) -Yl) butoxy] -3-methoxyphenyl} pe Data-2,4-diene acid ethyl ester

(Compound 14) 5- {4- [4- (4-benzhydrylpiperazin-1-yl) butoxy] -3-methoxyphenyl} penta-2,4-dienoic acid (Compound 15) 5- { 4- [6- (4-benzhydrylpiperazin-1-yl) hexyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 16) 5- {4- [6- (4 -Benzhydrylpiperazin-1-yl) hexyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid (Compound 17) 5- [4- (3- {4- [bis (4-fluorophenyl) Methylpiperazin-1-yl} propoxy)
-3-Methoxyphenyl] penta-2,4-dienoic acid ethyl ester (Compound 18) 5- [4- (3- {4- [bis (4-fluorophenyl) methylpiperazin-1-yl} propoxy)
-3-Methoxyphenyl] penta-2,4-dienoic acid (Compound 19) 5- [4- (4- {4-[(4-chlorophenyl) phenylmethyl] piperazin-1-yl} 2-butenyloxy) -3 -Methoxyphenyl] penta-2,4-
Dienoic acid ethyl ester

(Compound 20) 5- [4- (4- {4-[(4
-Chlorophenyl) phenylmethyl] piperazin-1-yl} 2-butenyloxy) -3-methoxyphenyl] penta-2,4-dienoic acid (compound 21) 5- (4- {2- [2- (4-benzhi) Drylpiperazin-1-yl) ethoxy] ethoxy} -3-methoxyphenyl) penta-2,4-dienoic acid ethyl ester (Compound 22) 5- (4- {2- [2- (4-benzhydrylpiperazine- 1-yl) ethoxy] ethoxy} -3-methoxyphenyl) penta-2,4-dienoic acid (Compound 23) 5- {4- [7- (4-benzhydrylpiperazin-1-yl) heptyloxy]- 3-Methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 24) 5- {4- [7- (4-benzhydrylpiperazin-1-yl) heptyloxy] -3-methoxyphenyl} penta- 2,4-die Acid (Compound 25) 5- {4- [8- (4-Benzhydrylpiperazin-1-yl) octyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 26) 5- {4- [8- (4-Benzhydrylpiperazin-1-yl) octyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid

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

Embedded image [In the formula, X, Y, m, n, p, A, Z and R represent the same meaning as described above, and L represents a halogen atom, a mesyloxy group or 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. A condensed aldehyde compound represented by the general 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, dimethyl sulfoxide, 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, it is generally effective to allow a base catalyst to coexist for the progress of the reaction, but it is not essential. When coexisting with a base, caustic potash, caustic soda, potassium carbonate, sodium carbonate, triethylamine, pyridine, tributylammonium hydroxide and the like are preferable.

A dialkyl 4-phosphonocrotonic acid ester is added to the intermediate compound represented by the general formula (IV).
The reaction is performed 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) is further optionally subjected to a conventional method of ester hydrolysis, for example,
By treating with potassium hydroxide, sodium hydroxide, 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. At that time, it is preferable to use ethanol, methanol, isopropanol, acetone or the like as a reaction solvent. Reaction temperature is 0 ° C
~ Between boiling points of solvents.

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 reactive aldehyde compound (III) is obtained by reacting the compound represented by the general formula (VII) with the benzaldehyde derivative represented by the general formula VIII 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, 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 hydroxyphenylpentadienoic acid compound represented by the general formula (IX) synthesized by a known method is replaced with the compound represented by the general formula (VII) in the same manner as in the above-mentioned compound (III) synthesis. The reaction is carried out under reaction conditions to obtain a reactive pentadienoic acid compound represented by the general formula (X), which is reacted with the benzhydryl derivative represented by the general formula (II) in the reaction formula 1) to obtain the compound (II).
And (III) are reacted under the same conditions to obtain the target compound represented by the general formula (V), and if necessary, further hydrolyzed to give the general formula (VI).
The target compound in the free form represented by can be synthesized.

Some of the target compounds of the present invention have stereoisomers and optical isomers, but the present invention includes all isomers. The salt of the compound of the present invention, a pharmaceutically acceptable salt, 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, malonic acid, phosphoric acid and other acid addition salts, or sodium salt, potassium salt, lithium salt, calcium salt, zinc Basic salts such as salts 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,
It can be a tablet, powder, granule, or capsule.
For example, the compound (I) of the present invention may be added to a suitable additive, for example, an excipient such as lactose, mannitol, corn starch, crystalline cellulose or the like; a binder such as a cellulose derivative, gum arabic or gelatin; carboxymethylcellulose calcium or the like. A disintegrating agent of talc, a talc, a lubricant such as magnesium stearate, etc., and the like. 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 drug for oral administration may be an emulsion, a solution, a suspension, a syrup or an elixir. For example, the compound (I) of the present invention is combined with a generally used inert diluent, for example, purified water, ethanol and the like, an auxiliary agent such as a lubricant and a suspension agent, a sweetener and the like,
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.

The preparations for parenteral administration include injectable solutions, inhalants, external solutions, eye drops,
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]

Experimental Example 2: Inhibition of leukocyte infiltration in guinea pig alveoli Tested according to the method described in "American Revue of Respiratory Diseases", 1990, Vol. 142, pp. 680-1685, as follows. 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 Leukocyte infiltration inhibiting compound Eosinophil suppression% Neutrophil suppression% Mononuclear cell suppression% Compound 8 of the present invention 100% 80% 100% JP-A-4-182467 20% 30% 10% Implementation Compound of Example 15 (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 on 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 action on anaphylactic airway contraction reaction 10 mg / kg Administration inhibitory rate Compound of the present invention 8 72% Compound of the present invention 12 85%

Experimental Example 4: Anaphylactic Leukotriene (LT) B4 / C from Actively Sensitized Guinea Pig Lung Sections
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 the start of 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 Anaphylaxis leukotriene release inhibitory effect LTB4 LTC4 (IC ₅₀ ) Compound 8 of the present invention 15 μM 10 μM Compound 12 of the present invention 12 30 μM 20 μM JP 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 anti-allergic 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.

Example 1 5- {4- [3- (4-benzhydrylpiperazine-1-
Il) propoxy] -3-methoxyphenyl} penta-2,
Preparation of 4-dienoic acid ethyl ester (Compound 3) 4-Benzhydrylpiperazine (0.81 g, 3.08 mmo)
l), 4-chloropropoxy-3-methoxyphenylpentadienoic acid ethyl ester (1 g), and sodium bicarbonate (0.518 g) were dissolved in acetonitrile (20 ml) and heated at 60 ° C. for 4 hours. Pour the reaction solution into water,
It was 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 -CD ₃ OD) δ ppm: 1.31
(3H, t, J = 6.9), 2.01 (2H, m), 2.
40-2.6 (10H, m), 3.89 (3H, s),
4.08 (2H, t, J = 6.9), 4.20 to 4.3 (3
H, m), 5.95 (1H, d, J = 15.2), 6.7
~ 7.5 (16H, m)

Example 2 5- {4- [3- (4-benzhydrylpiperazine-1-
Il) propoxy] -3-methoxyphenyl} penta-2,
Preparation of 4-dienoic acid dihydrochloride (hydrochloride of compound 4) 5- {4- [3- (4-benzhydrylpiperazin-1-yl) propoxy] -3-methoxyphenyl} obtained in Example 1. Penta-2,4-dienoic acid ethyl ester (19 g)
Was dissolved in methanol (300 ml), 2N aqueous sodium hydroxide solution (40 ml) was added, and the mixture was heated under reflux for 3 hr. 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, 2N aqueous hydrochloric acid solution (40 ml) was added with stirring, and the mixture was stirred overnight. The precipitated solid was collected by filtration and washed with water. The obtained solid was dried under reduced pressure, dissolved in acetone, and added with 4N hydrogen chloride-ethyl acetate solution to obtain the target compound (18 g) as a hydrochloride salt. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δppm: 2.30
(2H, m), 3.40-4.24 (15H, m), 5.
32 (1H, s), 5.93 (1H, d, J = 15.
2), 6.69 to 6.86 (3H, m), 6.97 to 7.0
1 (2H, m), 7.35 to 7.50 (7H, m), 7.
83 to 7.92 (4H, m) FAB-MS (m / z): 513 (MH +), 16
7,157 IR λcm ⁻¹ : 3433, 3003, 2555, 170
3,1620,1593,1512,1456

Table 5 Elemental analysis _{(C 32 H 36 N 2 O} 4 · 2HCl · H 2 O as) C (%) H (% ) N (%) Theoretical values 63.68 6.34 4.52 Found 63 .62 6.57 4.52

Example 3 5- {4- [4- (4-benzhydrylpiperazine-1-
Il) -2-trans-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 5) 60% sodium hydride (2.80 g, 1 under nitrogen atmosphere)
(17 mmol) was washed with hexane, suspended in dimethylformamide (hereinafter abbreviated as DMF) (250 ml), cooled to 0 ° C., and diethyl 4-phosphonocrotonic acid ethyl ester (34.5 g, 138 mmol) was added dropwise to about 1 Stir for hours. A powder of 4- [4- (4-benzhydrylpiperazin-1-yl) -2-butenyloxy] -3-methoxybenzaldehyde (50 g) was added and the mixture was stirred for 4 hours. The reaction mixture was partitioned with ethyl acetate (700 ml) -water (1 L), the ethyl acetate layer was taken, and washed with water (1 L) three times. The residue obtained by concentrating the organic layer was subjected to silica gel chromatography (56 g)
To obtain the target compound of. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.31
(3H, t, J = 6.9), 2.3 to 2.5 (8H,
m), 3.02 (2H, m), 3.90 (3H, s),
4.2-4.3 (3H, m), 4.6 (2H, m), 5.8
6 (2H, brs), 5.94 (1H, d, J = 15.
2), 6.7-7.4 (16H, m)

Example 4 5- {4- [4- (4-benzhydrylpiperazine-1-
Preparation of (yl) -2-trans-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid (Compound 6) The corresponding ethyl ester obtained in Example 3 was hydrolyzed in the same manner as in Example 2. I did it. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δppm: 1.8-
2.1 (8H, m), 2.6-2.8 (2H, m), 3.3
6 (2H, m), 3.90 (3H, s), 4.30 (1
H, s), 4.65 (2H, m), 5.94 (1H, d,
J = 15.2), 6.04 (2H, s), 6.7-7.4.
(16H, m) EI-MS (m / z): 524 (M +, 5%), 167
(100%), 305 (80%) IR λcm ⁻¹ : 3479, 2956, 2538, 169
5,1623,1595,1510,1452,162
3,1139

[Table 6]

Example 5 5- {4- [5- (4-benzhydrylpiperazine-1-
Il) pentyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 7) In the same manner as in Example 3, the above target compound was obtained. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.31
(3H, t, J = 6.9), 1.53 (4H, m), 1.
85 (2H, m), 2.2-2.6 (4H, m), 3.8
9 (3H, s), 4.01 (2H, t, J = 6.9),
4.22 (2H, q, J = 6.9), 5.95 (1H,
d, J = 15.2), 5.94 (1H, d, J = 15.
2) IR λcm ⁻¹ : 1695, 1623, 1595, 151
2,1274,1139

Example 6 5- {4- [5- (4-benzhydrylpiperazine-1-
Il) pentyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid hydrochloride The corresponding ethyl ester obtained in Example 5 was synthesized in the same manner as in Example 2 by hydrolysis. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.70
(2H, m), 1.9 (4H, m), 3.19 (2H,
m), 3.40-3.8 (10H, m), 3.89 (3
H, s), 4.05 (2H, t, J = 6.9), 5.32
(1H, s), 5.93 (1H, d, J = 15.2),
6.69 to 6.86 (3H, m), 6.97 to 7.01 (2
H, m), 7.35 to 7.50 (7H, m), 7.83 to
7.92 (4H, m) EI-MS (m / z): 540 (M +, 40%), 16
7 (100%) IR λcm ⁻¹ : 3438, 3043, 2621, 168
9,1622,1593,1512,1263

Table 7 Elemental analysis (C ₃₄ H ₄₀ N as _{2 O 4 · 2HCl · 2.5H 2} O) C (%) H (%) N (%) Theoretical values 62.00 6.88 4.25 Experimental Value 61.88 7.05 4.36

Example 7 5- {4- [3- (4-benzhydrylpiperazine-1-
Il) propoxy] -3,5-dimethoxyphenyl} penta-2,4-dienoic acid ethyl ester 1,5-naphthalenedisulfonate (1,5-naphthalenedisulfonate of compound 9) In the same manner as in Example 3. The above target compound was obtained. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.33
(3H, t, J = 6.9), 2.17 (2H, m), 3.
78 (3H, s), 4.0-4.2 (5H, m), 5.9
8 (1H, d, J = 15.2), 6.6 to 7.6 (15
H, m), 8.29 (2H, d, J = 6.9), 9.15
(2H, d, J = 9.6)

[Table 8] Elemental analysis value (as C ₄₅ H ₅₀ N ₂ O ₁₁ S ₂ · 2.2H ₂ O) C (%) H (%) N (%) Theoretical value 60.15 6.09 3.12 Experiment Value 60.12 6.00 3.12

Example 8 5- {4- [3- (4-benzhydrylpiperazine-1-
Il) propoxy] -3,5-dimethoxyphenyl} penta-2,4-dienoic acid 1,5-naphthalenedisulfonate (1,5-naphthalenedisulfonate of compound 10) Corresponding ethyl obtained in Example 7 The ester was hydrolyzed and synthesized in the same manner as in Example 2. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δppm: 2.1 (2
H, m), 3.4 to 3.7 (10H, m), 3.83 (3
H, s), 4.00 (2H, t, J = 6.9), 5.98.
(1H, d, J = 15.2), 6.66 (2H, s),
6.8 (2H, m), 7.26 to 7.55 (11H,
m), 8.22 (2H, d, J = 6.9), 9.07 (2
H, d, J = 9.6) EI-MS (m / z): 543 (M +, 10%), 1
67 (100%), 185 (20%) IR λcm ⁻¹ : 3448, 3026, 1699, 162
3,1579,1502,1242,1126,611

TABLE 9 Elemental analysis (C ₃₈ H ₄₂ N ₂ as _{O 8 S 1 · 2.3H 2 O} ) C (%) H (%) N (%) Theoretical values 62.67 6.45 3.85 Experimental Value 62.83 6.30 3.85

Example 9 5- {4- [2- (4-benzhydrylpiperazine-1-
Iyl) ethoxy] -3-methoxyphenyl} penta-2,4
-Dienoic acid ethyl ester (Compound 11) In the same manner as in Example 3, the above target compound was obtained. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.31
(3H, t, J = 6.9), 2.4 to 2.7 (8H,
m), 2.86 (2H, d, J = 6.3), 3.87 (3
H, s), 4.1 to 4.3 (5H, m), 5.95 (1
H, d, J = 15.2), 6.7 to 7.4 (16H, m)

Example 10 5- {4- [2- (4-benzhydrylpiperazine-1-
Iyl) ethoxy] -3-methoxyphenyl} penta-2,4
-Dienoic acid hydrochloride (hydrochloride of compound 12) The corresponding ethyl ester obtained in Example 9 was synthesized by hydrolysis in the same manner as in Example 2. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δppm: 2.8-
2.9 (4H, m), 3.46 (2H, brs), 3.87
(3H, s), 4.38 (1H, s), 4.57 (2H,
m), 5.98 (1H, d, J = 15.2), 6.7 to 7.
4 (16H, m) EI-MS (m / z): 498 (M +, 95%), 16
7 (100%) IR λcm ^-1 : 3057, 1697, 1623, 159
5,1512,1265,1139

TABLE 10 Elemental analysis _{(C 31 H 34 N 2 O} 4 · 1HCl · 1. 3H as _{2 O) C (%) H} (%) N (%) Theoretical values 66.67 6.78 5.02 Experimental Value 66.83 6.70 5.02

Example 11 5- {4- [4- (4-benzhydrylpiperazine-1-
Ile) butoxy] -3-methoxyphenyl} penta-2,4
-Dienoic acid ethyl ester (Compound 13) In the same manner as in Example 3, the above-mentioned target compound was obtained. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.31
(3H, t, J = 6.9), 1.6 to 1.8 (4H,
m), 2.3 to 2.6 (10H, m), 3.89 (3H,
s), 4.0-4.3 (5H, m), 5.95 (1H,
d, J = 15.2), 6.8 to 7.5 (16H, m)

Example 12 5- {4- [4- (4-benzhydrylpiperazine-1-
Ile) butoxy] -3-methoxyphenyl} penta-2,4
-Dienoic acid hydrochloride (hydrochloride of compound 14) The corresponding ethyl ester obtained in Example 11 was synthesized by hydrolysis in the same manner as in Example 2. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δppm: 1.8-
2.2 (4H, m), 3.19 (2H, m), 3.40-
3.8 (10H, m), 3.89 (3H, s), 5.32
(1H, s), 5.93 (1H, d, J = 15.2),
6.69 to 6.86 (3H, m), 6.97 to 7.01 (2
H, m), 7.35 to 7.50 (7H, m), 7.83 to
7.92 (4H, m) EI-MS (m / z): 526 (M +, 40%), 16
7 (100%) IR λcm ⁻¹ : 3433, 3003, 2555, 169
3,1622,1593,1512,1456

TABLE 11 Elemental analysis _{(C 33 H 38 N 2 O} 4 · 2HCl · 2H 2 O as a) C (%) H (% ) N (%) Theoretical values 62.36 6.65 4.41 Found 62 .76 6.93 4.42

Example 13 5- {4- [6- (4-benzhydrylpiperazine-1-
Il) hexyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester maleate salt (maleate salt of compound 15) In the same manner as in Example 3, the above-mentioned target compound was obtained. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.31
(3H, t, J = 6.9), 1.3 to 1.4 (8H,
m), 2.3 to 2.6 (8H, m), 3.89 (3H,
s), 4.0-4.3 (5H, m), 5.94 (1H,
d, J = 15.2), 6.7 to 7.5 (18H, m)

Example 14 5- {4- [6- (4-benzhydrylpiperazine-1-
Il) hexyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid (Compound 16) The corresponding ethyl ester obtained in Example 13 was synthesized by hydrolysis in the same manner as in Example 2. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δppm: 1.4-
1.9 (4H, m), 2.3-2.8 (10H, m), 2.
9 (2H, m), 3.84 (3H, s), 3.96 (2
H, t, J = 6.9), 4.28 (1H, s), 5.96
(1H, d, J = 15.2), 6.6 to 7.4 (16H,
m) EI-MS (m / z): 554 (M +, 30%), 16
7 (100%), 195 (30%) IR λcm ⁻¹ : 3523, 2937, 1693, 162
3,1595,1512,1465,1263,113
7,1001,707

Table 12 Elemental analysis values (as C ₃₅ H ₄₂ N ₂ O ₄ .1.5H ₂ O) C (%) H (%) N (%) Theoretical value 72.27 7.79 4.82 Experimental value 72 .23 7.50 4.23

Example 15 5- [4- (3- {4- [bis (4-fluorophenyl) methylpiperazin-1-yl} propoxy) -3-methoxyphenyl] penta-2,4-dienoic acid Ethyl ester (Compound 17) In the same manner as in Example 3, the above-mentioned target compound was obtained. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.34
(3H, t, J = 6.9), 1.9 to 2.0 (2H,
m), 2.3 to 2.6 (8H, m), 3.5 (2H,
m), 3.89 (3H, s), 4.0-4.2 (5H,
m), 5.95 (1H, d, J = 15.2), 6.7 to 7.
5 (14H, m)

Example 16 5- [4- (3- {4- [bis (4-fluorophenyl) methylpiperazin-1-yl} propoxy) -3-methoxyphenyl] penta-2,4-dienoic acid (Compound 18) The corresponding ethyl ester obtained in Example 15 was synthesized by hydrolysis in the same manner as in Example 2. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 2.3 (2
H, m), 2.6-2.8 (4H, m), 2.9-3.1
(6H, m), 3.87 (3H, s), 4.15 (2H,
t, J = 5.9), 4.3 (1H, s), 5.78 (1
H, d, J = 15.2), 6.7 to 7.4 (14H, m) EI-MS (m / z): 548 (M +, 70%), 20.
3 (100%), 290 (70%) IR λcm ⁻¹ : 3444, 3003, 1695, 162
3,1505,1265,1222,1139,100
1,827

Table 13 Elemental analysis value (as C ₃₂ H ₃₄ N ₂ O ₄ F ₂ .2H ₂ O) C (%) H (%) N (%) Theoretical value 65.74 6.54 4.79 Experimental value 65 .71 6.24 4.63

Example 17 5- [4- (4- {4-[(4-chlorophenyl) phenylmethyl] piperazin-1-yl} 2-butenyloxy) -3
-Methoxyphenyl] penta-2,4-dienoic acid ethyl ester (Compound 19) In the same manner as in Example 3, the above-mentioned target compound was obtained. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.31
(3H, t, J = 6.9), 2.3 to 2.5 (8H,
m), 3.02 (2H, m), 3.90 (3H, s),
4.2 (3H, m), 4.6 (2H, m), 5.87 (2
H, m), 5.94 (1H, d, J = 15.2), 6.7
~ 7.5 (15H, m)

Example 18 5- [4- (4- {4-[(4-chlorophenyl) phenylmethyl] piperazin-1-yl} 2-butenyloxy) -3
-Methoxyphenyl] penta-2,4-dienoic acid (Compound 20) The corresponding ethyl ester obtained in Example 17 was synthesized by hydrolysis in the same manner as in Example 2. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δppm: 2.4-
2.8 (8H, m), 3.2 (2H, m), 3.89 (3
H, s), 4.22 (1H, s), 4.6 (2H, m),
5.90-5.96 (3H, m), 6.7-7.4 (15
H, m) EI-MS (m / z): 558 (M +, 5%), 201
(100%), 299 (3%) IR λcm ⁻¹ : 3423, 2812, 1689, 162
3,1595,1510,1488,1263,113
9,1001,757

TABLE 14 Elemental analysis value _{(C 33 H 35 N 2 O} 4 as _{Cl · 0.4H 2 O) C (} %) H (%) N (%) Theoretical values 69.99 6.37 4.95 Found 69.86 6.31 5.07

Example 19 5- (4- {2- [2- (4-benzhydrylpiperazine-
1-yl) ethoxy] ethoxy} -3-methoxyphenyl)
Penta-2,4-dienoic acid ethyl ester (Compound 2
1) In the same manner as in Example 3, the above target compound was obtained. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.31
(3H, t, J = 6.9), 2.3 to 2.6 (8H,
m), 2.6 (2H, t, J = 5.94), 3.67 (2
H, t, J = 5.9), 3.80 to 3.84 (5H,
m), 4.1-4.3 (5H, m), 5.96 (1H,
d, J = 15.2), 6.7 to 7.5 (16H, m)

Example 20 5- (4- {2- [2- (4-benzhydrylpiperazine-
1-yl) ethoxy] ethoxy} -3-methoxyphenyl)
Penta-2,4-dienoic acid hydrochloride (Compound 22) The corresponding ethyl ester obtained in Example 19 was synthesized by hydrolysis in the same manner as in Example 2. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δppm: 3.45
(2H, m), 3.67 (3H, s), 3.80 to 4.2
(8H, m), 5.96 (1H, d, J = 15.2),
6.8-7.5 (16H, m) EI-MS (m / z): 542 (M +, 50%), 16
7 (100%) IR λcm ⁻¹ : 3004, 2683, 1697, 162
2,1595,1512,1454,1265,113
9,1004,707

[Table 15] Elemental analysis value (as C ₃₃ H ₃₈ N ₂ O ₅ , .2HCl.0.7H ₂ O) C (%) H (%) N (%) Theoretical value 63.10 6.64 4.76 Experimental value 63.22 6.74 4.72

Example 21 5- {4- [7- (4-benzhydrylpiperazine-1-
Il) heptyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 23) In the same manner as in Example 3, the above target compound was obtained. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.31
(3H, t, J = 6.9), 1.3 to 1.6 (8H,
m), 1.7 to 1.8 (2H, m), 2.3 to 2.6 (10
H, m), 3.89 (3H, s), 4.0 to 4.2 (5
H, m), 5.94 (1H, d, J = 15.2), 6.7
~ 7.5 (16H, m)

Example 22 5- {4- [7- (4-benzhydrylpiperazine-1-
Il) heptyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid (Compound 24) The corresponding ethyl ester obtained in Example 21 was synthesized by hydrolysis in the same manner as in Example 2. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δppm: 1.3-
1.5 (6H, m), 1.6 to 1.9 (4H, m), 2.5
~ 3.0 (10H, m), 3.86 (3H, s), 3.9
4 (2H, t, J = 6.9), 4.27 (1H, s),
6.0 (1H, d, J = 15.2), 6.7 to 7.4 (16
H, m) EI-MS (m / z): 568 (M +, 27%), 16
7 (100%), 401 (38%) IR λcm ⁻¹ : 3479, 2937, 2810, 162
3,1595,1512,1465,1263,113
9,1001,707

Table 16 Elemental analysis values (as C ₃₆ H ₄₄ N ₂ O ₄ , .2.3H ₂ O) C (%) H (%) N (%) Theoretical value 70.87 8.02 4.59 Experimental value 70.95 7.82 4.27

Example 23 5- {4- [8- (4-benzhydrylpiperazine-1-
Il) octyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 25) In the same manner as in Example 3, the above target compound was obtained. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.31
(3H, t, J = 6.9), 1.3 to 1.6 (10H,
m), 1.7 to 1.8 (2H, m), 2.3 to 2.6 (10
H, m), 3.89 (3H, s), 4.0 to 4.2 (5
H, m), 5.94 (1H, d, J = 15.2), 6.7
~ 7.5 (16H, m)

Example 24 5- {4- [8- (4-benzhydrylpiperazine-1-
Il) octyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid hydrochloride (hydrochloride of compound 26) Synthesized by hydrolyzing the corresponding ethyl ester obtained in Example 23 in the same manner as in Example 2. did. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δppm: 1.3-
1.5 (6H, m), 1.8 to 1.9 (6H, m), 2.8
~ 3.0 (8H, m), 3.4-3.5 (2H, m), 3.
90 (3H, s), 4.01 (2H, t, J = 6.9),
5.95 (1H, d, J = 15.2), 6.8 to 7.5 (1
6H, m) EI-MS (m / z): 582 (M +, 45%), 16
7 (100%), 415 (80%) IR λcm ⁻¹ : 3415, 2993, 1622, 159
3,1512,1265,1137,1001,707

TABLE 17 Elemental analysis value _{(C 37 H 46 N 2 O} 4, · 1HCl · 1.7H as _{2 O) C (%) H} (%) N (%) Theoretical values 68.39 7.81 4.31 Experimental value 68.12 7.72 4.08

Example 25 5- {4- [3- (4-benzhydryl- [1,4] diazepan-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester (Compound 1) In the same manner as in Example 3, the above-mentioned target compound was obtained. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 1.31
(3H, t, J = 6.9), 2.0-2.1 (2H,
m), 2.6-2.9 (12H, m), 3.89 (3H,
s), 4.12 (2H, t, J = 6.9), 4.3 (2
H, q, J = 6.9), 4.6 (1H, s), 5.95
(1H, d, J = 15.2), 6.7 to 7.5 (16H,
m)

Example 26 5- {4- [3- (4-benzhydryl- [1,4] diazepan-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid (compound 2) The corresponding ethyl ester obtained in Example 25 was hydrolyzed and synthesized in the same manner as in Example 2. ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ ppm: 2.2 (2
H, m), 2.4 (2H, m), 2.7 (2H, m),
3.0 (2H, m), 3.2-3.5 (6H, m), 3.8
6 (3H, s), 4.1 (2H, t), 4.63 (1H,
s), 5.92 (1H, d, J = 15.2), 6.7 to 7.
5 (16H, m) EI-MS (m / z): 526 (M +, 20%), 16
7 (60%), 359 (100%) IR λcm ^-1 : 3406, 1695, 1623, 159
5,1512,1465,1265,1137,100
2,709

Production Example of Intermediate Compound [Example 27] 4- [5- (4-benzhydrylpiperazin-1-yl)
Preparation of pentyloxy] -3-methoxybenzaldehyde Benzhydrylpiperazine (54.4 g, 216 mmol),
4-chloropentyloxy-3-methoxybenzaldehyde (50 g, 196 mmol) and sodium hydrogen carbonate (33 g, 393 mmol) were suspended in DMF (500 ml),
Stir at 70 ° 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 1 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 (74 g, 80%). ¹ H-NMR (CDCl ₃ ) δppm: 1.4 to 1.7 (4H,
m), 1.91 (2H, m), 2.20 to 2.7 (10
H, m), 3.90 (3H, s), 4.08 (2H, t,
J = 4.9), 4.21 (1H, s), 6.95 (1H,
d, J = 8.9), 7.1-7.5 (12H, m), 9.9
5 (1H, s) IR λcm ⁻¹ : 1683, 1585, 1520, 126
5,1134 MS (m / z): 472 (M +, 2%), 280 (35
%), 203,167 (100%)

The following Example 28 was carried out in the same manner as Example 27.
~ 33 compounds were synthesized. Example 28 4- [4- (4-benzhydrylpiperazin-1-yl)
2-Butenyloxy] -3-methoxybenzaldehyde fumarate ¹ H-NMR (CDCl ₃ ) δppm: 2.20 to 3.3 (10
H, m), 3.70 (2H, m), 3.92 (3H,
s), 4.08 (2H, t, J = 4.9), 4.21 (1
H, s), 4.42 (1H, s), 4.73 (2H,
m), 5.9 to 6.2 (2H, m), 6.38 (2H,
s), 6.95 (1H, d, J = 8.9), 7.1 to 7.5
(12H, m), 9.95 (1H, s)

Example 29 4- [3- (4-benzhydrylpiperazin-1-yl)
Propoxy] -3-methoxybenzaldehyde ¹ H-NMR (CDCl ₃ ) δppm: 2.04 (2H, quint
et, J = 6.9), 2.30 to 2.57 (10H, m),
3.91 (3H, s), 4.16 (2H, d, J = 4.
3), 4.22 (1H, s), 6.99 (1H, d, J =
8.6), 7.20-7.43 (12H, m), 9.84
(1H, s)

Example 30 4- {2- [2- (4-benzhydrylpiperazine-1-
Iyl) ethoxy] ethoxy} -3-methoxybenzaldehyde ¹ H-NMR (CDCl ₃ ) δppm: 2.4 to 2.7 (8H,
m), 2.60 (2H, t, J = 5.8), 3.68 (2
H, t, J = 5.6), 3.82 (3H, s), 3.87
(2H, t, J = 4.9), 4.19 (1H, s), 4.
24 (2H, t, J = 4.9), 6.97 (1H, d, J
= 7.9), 7.1-7.5 (12H, m), 9.84 (1
H, s)

Example 31 4- [6- (4-benzhydrylpiperazin-1-yl)
Hexyloxy] -3-methoxybenzaldehyde ¹ H-NMR (CDCl ₃ ) δppm: 1.3 to 1.6 (6H,
m), 1.88 (2H, m), 2.20 to 2.7 (10
H, m), 3.90 (3H, s), 4.08 (2H, t,
J = 4.9), 4.19 (1H, s), 6.95 (1H,
d, J = 8.9), 7.1-7.5 (12H, m), 9.8
4 (1H, s)

Example 32 4- [7- (4-benzhydrylpiperazin-1-yl)
Heptyloxy] -3-methoxybenzaldehyde ¹ H-NMR (CDCl ₃ ) δppm: 1.2 to 1.6 (8H,
m), 1.79 (2H, m), 2.20 to 2.7 (10
H, m), 3.90 (3H, s), 4.08 (2H, t,
J = 4.9), 4.19 (1H, s), 6.95 (1H,
d, J = 8.9), 7.1-7.5 (12H, m), 9.9
5 (1H, s)

Example 33 4- [8- (4-benzhydrylpiperazin-1-yl)
Octyloxy] -3-methoxybenzaldehyde ¹ H-NMR (CDCl ₃ ) δ ppm: 1.2 to 1.6 (10
H, m), 1.77 (2H, m), 2.20 to 2.7 (1
0H, m), 3.90 (3H, s), 4.08 (2H,
t, J = 4.9), 4.19 (1H, s), 6.95 (1
H, d, J = 8.9), 7.1-7.5 (12H, m),
9.95 (1H, s)

Example 34 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 ml). ), Stirred at 90 ° C. for about 1 hour, then cooled to room temperature and 1-bromo-4-chloropentane (100 g, 0.5
(4 mol) and 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, 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 to 2.1 (4H, m), 3.58 (2H,
t, J = 6.6), 3.93 (3H, s), 4.12 (2
H, t, J = 6.9), 6.97 (1H, d, J = 7.
9), 7.35-7.5 (2H, m), 9.85 (1H,
s)

The following Example 35 was carried out in the same manner as Example 34.
~ 37 compounds were synthesized. Example 35 4- (6-Bromohexyloxy) -3-methoxybenzaldehyde ¹ H-NMR (CDCl ₃ ) δppm: 1.4 to 1.7 (4H,
m), 1.90 (4H, m), 3.43 (2H, t, J =
6.6), 3.93 (3H, s), 4.11 (2H, t,
J = 6.9), 6.97 (1H, d, J = 7.9), 7.3
5 to 7.5 (2H, m), 9.85 (1H, s) EI-MS: (m / z): 256 (M ⁺ ).

Example 36 4- (7-Bromoheptyloxy) -3-methoxybenzaldehyde ¹ H-NMR (CDCl ₃ ) δppm: 1.27 to 1.7 (6
H, m), 1.8 to 2.1 (4H, m), 3.58 (2
H, t, J = 6.6), 3.93 (3H, s), 4.13
(2H, t, J = 6.9), 6.97 (1H, d, J =
7.9), 7.35-7.5 (2H, m), 9.85 (1
H, s)

Example 37 4- (8-Bromooctyloxy) -3-methoxybenzaldehyde ¹ H-NMR (CDCl ₃ ) δppm: 1.27 to 1.7 (8
H, m), 1.8 to 2.1 (4H, m), 3.58 (2
H, t, J = 6.6), 3.93 (3H, s), 4.13
(2H, t, J = 6.9), 6.97 (1H, d, J =
7.9), 7.35-7.5 (2H, m), 9.85 (1
H, s)

Example 38 4- (4-chloro-2-trans-butenyloxy) -3
-Preparation of 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) is added and 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, the mixture was stirred, and the solidified product was collected by filtration and dried to obtain 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 39 Preparation of 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) are dissolved in tetrahydrofuran (hereinafter abbreviated as THF) (300 ml),
-10 ° C, diethyl azodicarboxylate (12.6
g, 72.4 mmol) is added dropwise over 30 minutes. The reaction mixture is stirred overnight. THF is distilled off under reduced pressure, isopropyl ether is added, and the mixture is stirred. The precipitated crystals are filtered off and the filtrate is 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 1
2 g, yield 70%. ¹ H-NMR (CDCl ₃ ) δppm: 13.66 (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 (1
H, d, J = 9.6), 7.35-7.5 (2H, m),
9.86 (1H, s) MS (m / z): 258 (M +), 152, 107

Example 40 Preparation of 4- (3-chloropropoxy) -3,5-dimethoxybenzaldehyde 4-hydroxy-3,5-dimethoxybenzaldehyde (10 g, 0.055 mol) and 28% sodium methoxide (81 0.8g, 0.593mol) to DMF (500m
l) and dissolved in 1-bromo-3-chloropropane (8.6
4 g, 0.055 mol) is added and stirred overnight. 50 more
Heat to ° C and 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, quint
et, 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)

Example 41 Preparation of 5- [4- (3-chloropropoxy) -3-methoxyphenyl] penta-2,4-dienoic 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), 6.7-7.4 (6H, m)

Thereafter, the ester compounds of Examples 42 and 43 were obtained in the same manner as in the previous example. [Example 42] 5- [4- (4-chlorobutoxy) -3-methoxyphenyl] penta-2,4-dienoic 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 to 7.4 (6H, m)

Example 43 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), 3.9
1 (3H, s), 4.1 to 4.4 (4H, m), 5.96
(1H, d, J = 15.9), 7.5-7.4 (6H,
m)

The objective compounds of the present invention obtained in Examples 1 to 26 are shown in Table 5 according to the general formula (I).

[Table 18]

[Table 19]

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display location C07D 243/08 505 C07D 243/08 505 (72) Inventor Mari Iwata 4 Kitahama, Chuo-ku, Osaka City, Osaka Prefecture 5-33, Sumitomo Metal Industries, Ltd.

Claims (15)

[Claims] 1. A compound represented by the general formula (1): [Wherein X and Y are halogen atoms or hydrogen atoms, m and n are integers from 0 to 4, p is an integer from 2 or 3, A is an oxygen atom, an alkenylene group or an alkynylene group, or a single bond, Z 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 p is 2. 3. The compound according to claim 1, wherein p is 3. 4. m and n are 0, A is an alkenylene group having 3 to 5 carbon atoms or an alkynylene group,
The compound according to claims 1 to 3. 5. The compound according to claim 1, wherein m and n are not 0 and are 2 to 8 in total, and A is a single bond. 6. m and n are each 1 to 3, and
The compound according to claim 1, wherein A is an oxygen atom. 7. The compound according to claim 1, wherein X and Y are the same or different and each is a fluorine, chlorine or hydrogen atom. 8. The compound according to claim 1, wherein Z is a hydrogen atom. 9. The method according to claim 1, wherein Z is a methoxy group.
A compound as described. 10. The compound according to claim 1, wherein R is hydrogen. 11. The method according to claim 1, wherein R is a lower alkyl group.
9. The compound according to 9 above. 12. 5- {4- [3- (4-Benzhydryl- [1,4] diazepan-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester; 5- {4- [3- (4-Benzhydryl- [1,4] diazepan-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid; 5- {4- [3- (4- Benzhydrylpiperazin-1-yl) propoxy] -3-
Methoxyphenyl} penta-2,4-dienoic acid ethyl ester; 5- {4- [3- (4-benzhydrylpiperazin-1-yl) propoxy] -3-methoxyphenyl} penta-2,4-dienoic acid 5- {4- [4- (4-benzhydrylpiperazin-1-yl) -2-butenyloxy]-
3-Methoxyphenyl} penta-2,4-dienoic acid ethyl ester; 5- {4- [4- (4-benzhydrylpiperazin-1-yl) -2-butenyloxy] -3-methoxyphenyl} penta-2 , 4-dienoic acid; 5- {4- [5-
(4-Benzhydrylpiperazin-1-yl) pentyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester; 5- {4- [5- (4-benzhydrylpiperazin-1- Il) pentyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid; 5- {4- [3-
(4-Benzhydrylpiperazin-1-yl) propoxy] -3,5-dimethoxyphenyl} penta-2,4-dienoic acid ethyl ester; 5- {4- [3- (4-benzhydrylpiperazin-1) -Yl) propoxy] -3,5-dimethoxyphenyl} penta-2,4-dienoic acid; 5- {4-
[2- (4-Benzhydrylpiperazin-1-yl) ethoxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester; 5- {4- [2- (4-benzhydrylpiperazine- 1-yl) ethoxy] -3-methoxyphenyl} penta-2,4-dienoic acid; 5- {4- [4- (4-
Benzhydrylpiperazin-1-yl) butoxy] -3-
Methoxyphenyl} penta-2,4-dienoic acid ethyl ester; 5- {4- [4- (4-benzhydrylpiperazin-1-yl) butoxy] -3-methoxyphenyl} penta-2,4-dienoic acid 5- {4- [6- (4-benzhydrylpiperazin-1-yl) hexyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid ethyl ester; 5- {4- [6- ( 4-Benzhydrylpiperazine-
1-yl) hexyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid; 5- [4- (3- {4- [bis (4
-Fluorophenyl) methylpiperazin-1-yl} propoxy) -3-methoxyphenyl] penta-2,4-dienoic acid ethyl ester; 5- [4- (3- {4- [bis (4-
Fluorophenyl) methylpiperazin-1-yl} propoxy) -3-methoxyphenyl] penta-2,4-dienoic acid; 5- [4- (4- {4-[(4-chlorophenyl) phenylmethyl] piperazine-1 -Yl} 2-butenyloxy)
-3-Methoxyphenyl] penta-2,4-dienoic acid ethyl ester; 5- [4- (4- {4-[(4-chlorophenyl) phenylmethyl] piperazin-1-yl} 2-butenyloxy) -3- Methoxyphenyl] penta-2,4-
5- (4- {2- [2- (4-benzhydrylpiperazin-1-yl) ethoxy] ethoxy} -3-methoxyphenyl) penta-2,4-dienoic acid ethyl ester; 5- ( 4- {2- [2- (4-benzhydrylpiperazin-1-yl) ethoxy] ethoxy} -3-methoxyphenyl) penta-2,4-dienoic acid; 5- {4- [7- (4-
Benzhydrylpiperazin-1-yl) heptyloxy]
-3-Methoxyphenyl} penta-2,4-dienoic acid ethyl ester; 5- {4- [7- (4-benzhydrylpiperazin-1-yl) heptyloxy] -3-methoxyphenyl} penta-2, 4-dienoic acid; 5- {4- [8- (4
-Benzhydrylpiperazin-1-yl) octyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid
Ethyl ester; and 5- {4- [8- (4-benzhydrylpiperazin-1-yl) octyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid. Phenylpentadienoic acid compounds or pharmaceutically acceptable salts thereof. 13. 5- {4- [4- (4-benzhydrylpiperazin-1-yl) -2-trans-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid
An ethyl ester; and 5- {4- [4- (4-benzhydrylpiperazin-1-yl) -2-trans-butenyloxy] -3-methoxyphenyl} penta-2,4-dienoic acid Item 1. A phenylpentadienoic acid compound or a pharmaceutically acceptable salt thereof according to Item 1. 14. A compound represented by the general formula (I): [Wherein X and Y are halogen atoms or hydrogen atoms, m and n are integers from 0 to 4, p is an integer from 2 or 3, A is an oxygen atom, an alkenylene group or an alkynylene group, or a single bond. , Z represents a hydrogen atom or a methoxy group, and R represents a hydrogen atom or an ester residue] and a pharmaceutically acceptable salt thereof, which is represented by the general formula ( I
I) [Chemical 3] 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. 15. A compound represented by the general formula (I): [Wherein X and Y are halogen atoms or hydrogen atoms, m and n are integers from 0 to 4, p is an integer from 2 or 3, A is an oxygen atom, an alkenylene group or an alkynylene group, or a single bond. , Z represents a hydrogen atom or a methoxy group, and R represents a hydrogen atom or an ester residue. ] The pharmaceutical composition which uses the phenyl pentadienoic acid compound represented by these, or its pharmaceutically acceptable salt as an active ingredient.