JPH0225465A - Piperidine derivative, production thereof and pharmaceutical composition containing the same derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (Ar<1> and Ar<2> are phenyl or phenyl or pyridyl having alkyl substituted by halogen, etc.; A is alkylene or alkenylene; B is alkyl, hydroxy, alkoxy, phenoxy, alkylamino, anilino, phenyl, etc., provided that at least either of Ar<1> and Ar<2> is pyridyl when B is phenyl or alkyl-substituted phenyl) and salts thereof. EXAMPLE:3-[4-[(4-Chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]propionic acid. USE:An antihistaminic and antiallergic medicine. PREPARATION:For example, a compound expressed by formula II is reacted with a compound expressed by formula III (W is eliminative group) to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a novel piperidine derivative, a method for producing the same, and an antihistamine and antiallergic pharmaceutical composition containing the same.

(Prior Art) To date, many piperidine derivatives useful as pharmacologically active ingredients have been discovered. Among these compounds, there is a compound disclosed in JP-A-60-94962 that has the same pharmacological action as the compound of the present invention and has a partially similar skeleton. In this publication, the pyridyl group of the aryl moiety in the present invention is not described at all.

Additionally, JP-A-61-194068 discloses a building derivative and a 5-lipoxygenase action inhibitor containing the same, which has a structure that is partially similar to the compound of the present invention. The compounds have different structures in the portion adjacent to the carbonyl group, and also have different pharmacological actions.

(Problem to be Solved by the Invention) Most conventional antihistamines act on the central nervous system and cause sedation (drowsiness), but the inventors have developed a new piperidine derivative that has effective pharmacological activity. As a result of intensive research aimed at synthesizing the novel piperidine derivatives of the present invention, the pharmaceutically acceptable anti-salting thereof has useful pharmacological properties, particularly strong antihistamine and antiallergic properties. Moreover, they discovered that the effect of thiopencur, a central depressant, on enhancing sleepiness was small, leading to the completion of the present invention.

[Structure of the Invention] (Means for Solving the Problems) The novel piperidine derivative of the present invention has the general formula []: [where Ar' and Ar2 are each independently a phenyl group, a halogen atom, a nitro group, A is a group selected from the group consisting of a lower alkoxy group, a lower alkyl group, or a phenyl group having a lower alkyl group substituted with a halogen atom, and a pyridyl group; A is a linear group having 2 to 6 carbon atoms; Or, it represents a branched alkylene group or alkenylene group having at least 2 carbon atoms in the main chain; B is a lower alkyl group, hydroxy group, lower alkoxy group, phenoxy group, amine group, lower alkylamino group, aryno group; represents a group selected from the group consisting of a phenyl group, a phenyl group substituted with a lower alkyl group, and a phenyl group substituted with a lower alkyl group. However, if B is a phenyl group or a phenyl group substituted with a lower alkyl group, the above Ar' or Ar
At least one of 2 is a pyridyl group. ] and pharmaceutically acceptable acid addition salts thereof.

In this specification, "lower" means having 1 to 4 carbon atoms, unless otherwise specified.

In the above general formula [I], examples of the substituted phenyl group represented by Ar'' or Ar2 include 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl,
Phenyl groups substituted with halogen atoms, such as 4-chlorophenyl, 2-bromophenyl, 4-bromophenyl, 2-iodophenyl, 4-iodophenyl, 2-methyl, 3-methyl, 4-methyl, 2,4-dimethyl , 34-
Phenyl group substituted with an alkyl group such as dimethyl, 4-ethyl, 4-isopropyl, 4-n-propyl, 4-n-butyl, phenyl group substituted with trifluoromethyl group, 4-methoxy, 2.4- A phenyl group substituted with an alkoxy group such as dimethoxy, 3,4-dimethoxy, 4-ethoxy, a phenyl group substituted with a nitro group such as 2-2I, 3-21, or 4-nitro, Alternatively, it represents a pyridyl group such as 2-pyridyl, 3-pyridyl, 4-pyridyl, etc., and it is preferable that at least one of Ar" and Ar2 is a pyridyl group.

A is a linear or branched alkylene group having at least two carbon atoms in the connecting chain portion, such as ethylene group, propylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, etc. Alternatively, it represents an alkenylene group, such as a vinylene group, a propenylene group, a 2-butenylene group, a 2-pentenylene group, a 3-pentenylene group, and a linear alkylene group or alkenylene group having 2 to 5 carbon atoms is preferable.

B is, for example, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, inbutyl, t-butyl,
Lower alkyl groups such as cyclobutyl: Hydroxyl groups:
Methoxy, polyoxy, propoxy, impropoxy,
Lower alkoxy groups such as butoxy, imbutoxy, t-butoxy; Amino groups: methylamino, dimethylamino,
ethylamino, diethylamino, propylamine, isopropylamine, butylamino, inbutylamino, t
- Lower alkylamino groups such as butylamino: anilino group; phenyl group, and phenyl substituted with lower alkyl groups such as methylphenyl, ethylphenyl, propylphenyl, isopropylphenyl, butylphenyl, imbutylphenyl, t-butylphenyl It represents a group, and is preferably a hydroxy group, an ester thereof, an amide thereof, or the like.

However, if B is a phenyl group or a phenyl group substituted with a lower alkyl group, the Ar' or Ar
At least one of 2 is a pyridyl group.

Next, examples of representative compounds of the present invention will be listed, but it goes without saying that the present invention is not limited to these compounds.

・3-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]propionic acid-3-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl] Ethyl propionate, ・4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]butanoic acid, ・4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1 -piperidyl]ethyl butanoate and its para-toluenesulfonate, -4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl 7-butanamide and its maleate, -4-(4 ethyl -diphenylmethoxy-nipiperidyl)butanoate and its fumarate, ・Ethyl 4-[4-(phenyl-2-pyridylme]xy)-1-piperidylcobutanoate and its para-toluenesulfonate, ・4- [4-(phenyl-3-biυdylmethoxy)-
Ethyl 1-piperidylcobutanoate and its para-toluenesulfonate, 4-[4-[(4-chlorophenyl)-phenylmethoxy]-1-piperidyl]butanoate and its para-toluenesulfonate, 4 -C1-(4,4'-
ethyl dimethoxyphenylmethoxy)-1-piperidylcobutanoate and its para-toluenesulfonate, φ4-[4-(4,4'-difluorophenylmethoxy)-1-piperidylcobutanoate and its para-
Toluenesulfonate, -4-[4-[(4-methylphenyl]-phenylmethoxyco-1-piperidylcobutanoic acid ethyl ester, E2 ・l-[4-[(4-chlorophenyl)-2-pyridyl) Propyl methoxy]-1-piperidyl]butanoate and its para-toluenesulfonate salt, ethyl 4-[4-((4-chlorophenyl)-2-pyridylmethoxy]-1-piperidylco-2-butenoate, 5- [4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]-2-pentanone and its fumarate salt, 4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-(3 According to the invention, the formula [II The compound represented by can be produced by methods 1 to 3 shown in the following reaction formulas 1 to 3.

Method" Reaction formula (1) [In the formula, W is a group that can be eliminated, for example, a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom, or a reaction group such as a methanesulfonyloxy group or a para-toluenesulfonyloxy group. Ar5. Ar
2. A and B have the same meanings as above. ] Compound [II] and its salt can be easily produced by reacting compound [II] with a compound represented by formula [ml] as shown in reaction formula (1).

Compound [111] is used in an amount of 1 to 3 per mole of compound [II].
Add moles.

The above reaction is carried out in a suitable organic solvent that is inert to the reaction. Examples of suitable organic solvents include lower alcohols such as methanol, ethanol, probanol and butanol, aromatic hydrocarbons such as benzene, toluene and xylene, 1,4-dioxane, T
Examples include ethers such as HF, ketones such as acetone, ethyl methyl ketone, and methyl isobutyl ketone, amides such as N,N dimethylformamide, and mixed solvents of two or more of these. Additionally, this reaction is preferably carried out in the presence of a base, and examples of such bases include alkali metal hydroxides such as sodium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, potassium carbonate, etc. Alkali metal carbonates, alkaline earth metal carbonates such as calcium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate, alkali metal hydrides such as sodium hydride, alkaline earth metal hydrides such as calcium hydride, sodium methoxide, etc. Examples include alkoxides of alkali metals, trialkylamines such as triethylamine, and pyridine compounds. These bases are added in an amount of 1 to 3 mol per 1 mol of compound [II].

Small amounts of suitable metal iodides, such as sodium or potassium iodide, may also be added as reaction promoters. In order to increase the reaction rate, it is preferable to carry out the reaction at a slightly elevated temperature, and in some cases, the reaction can also be carried out at the reflux temperature of the reaction mixture. Reaction time is 2-24 hours.

The reaction products are separated from the reaction mixture and, if necessary, further purified by generally known methods.

Furthermore, in the above formula [I], when B represents a lower alkoxy group, phenoxy group, amino group, lower alkylamino group or anilino group, the compound of the present invention can be produced by the following method.

Ar2 [IV] [V] Reaction formula (2) [In the formula, W' is a group that can be eliminated, for example, a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, or a hydroxy group, and B' is a lower alkoxy A group selected from the group consisting of a phenoxy group, an amino group, a lower alkylamino group, and an anilino group;
has the same meaning as above. ] Compound [I] and its salt can be easily produced by reacting compound [IV] with a compound represented by formula [V], as shown in reaction formula (2). Compound [V] is added in an amount of 1 to 3 mol per 1 mol of compound [IV].

When W' represents a halogen atom, compound [IV] can be obtained by converting the corresponding carboxylic acid into a halide by a known method. In this case, the above reaction (reaction formula (2)) is carried out in an inert solvent at -5 to 30°C, and the reaction time is 1 to 10 hours.

In addition, when W' is a hydroxy group, the above reaction (reaction formula (2)) can be carried out in an inert solvent by dehydration of dicyclohexylcarbodiimide, trifluoroacetic anhydride, N-acylimidazole, etc. carried out in the presence of a drug. The dehydrating agent is used in an amount of 1 to 2 mol per 1 mol of the compound [■], the reaction temperature is -5 to 30°C, and the reaction time is 1 to 24 hours.

Next, when B represents a hydroxy group in the above formula [1], the compound of the present invention can be produced by the following method.

Ar2 [■] Reaction formula (3) [In the formula, R is a lower alkyl group such as methyl or ethyl, and Ar', Ar2 and A have the same meanings as above. ] Compound [I] can be easily produced by hydrolyzing compound [VI] under basic conditions, as shown in reaction formula (3). This hydrolysis is carried out at room temperature or by increasing the reaction rate using 1 to 5 mol of an inorganic base such as sodium hydroxide or potassium hydroxide per 1 mol of compound [VI] in an Ar2 aqueous alcohol such as aqueous methanol or ethanol. In order to achieve this, it is preferable to carry out the reaction a little below A, and in some cases, the reaction can also be carried out at the reflux temperature of the reaction mixture.

Reaction time is 1-10 hours.

In addition, as a raw material, the piperidine derivative [II
] can be produced according to standard methods such as the following.

[■] [■] (''In the reaction formula 1, X represents a halogen atom or a reactive ester group such as para-toluenesulfonyloxy group, and Q represents a formyl group, ethoxycarbonyl group, t-butoxycarbonyl group, etc. represents a protecting group for the amine group of Ar
” and Ar2 have the same meanings as above) First, the reactive ester [■] and the compound [■] are reacted to O-alkylate, and then the protecting group Q of the amine group of the obtained compound [IX] is The desired intermediate product [11] can be produced by removal using conventional methods.

Furthermore, by reacting the compound [I] of the present invention with an appropriate acid, it can be made into a non-toxic, pharmacologically effective acid addition salt. In this case, examples of suitable acids include 1 hydrohalic acids such as hydrochloric acid and hydrobromic acid;
Inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, hydroxyacetic acid, 2-hydroxypropionic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, dihydroxyfumaric acid, oxalic acid, benzoic acid Examples include organic acids such as cinnamic acid, salicylic acid, methanesulfonic acid, X))sulfonic acid, benzenesulfonic acid, 4-methyl-benzenesulfonic acid, cyclohexylsulfamic acid, and 4-aminesalicylic acid.

The compound of the present invention represented by formula [I] and its pharmaceutically acceptable acid addition salts have useful pharmacological properties, particularly strong antihistamine and antiallergic properties. Furthermore, it has the characteristic that secondary effects such as stimulation or depression on the central nervous system, which are often seen with conventional antihistamines, are minimized, and it can be used alone or in combination with an appropriate carrier to It can be used as an effective drug for the treatment of animals. in particular,
It can be applied to the treatment of allergic skin diseases such as armpits, eczema, and dermatitis, and sneezing, nasal discharge, cough sputum, and bronchial asthma caused by respiratory tract inflammation such as allergic rhinitis and common cold.

When the compound of the present invention is used as an antihistamine, it is mainly administered orally or by application. The dosage may be adjusted appropriately depending on the disease, severity of symptoms, age, etc., and is usually about 2 to 50 II 1 g, preferably about 5 to 25 mg per day for adults.

In order to formulate a compound of the present invention, it is prepared into a dosage form such as a tablet, a capsule powder, a syrup, an ointment, etc. by a conventional method in the technical field of pharmaceutical preparation.

In general, the compound of the present invention relaxes the smooth muscles of the trachea and blood vessels both in vitro and in vivo, and is effective at a dose of 1 mg per kg of animal body weight.
In guinea pigs administered orally at a dose of 1, it significantly suppresses histamine hydrochloride-induced shock death.

Furthermore, when thiobental was used as a central depressant and the effect of these compounds on the duration of the induced anesthetic effect was investigated, almost no significant enhancing effect was observed. The pharmacological test results for the following representative compounds belonging to the present invention are shown below.

Compound A 4-(4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]ethyl butanoate (prepared in Example 3-a) Compound B 4-[4-[(4-chlorophenyl)- 2-pyridylmethoxy]-1-piperidyl]butanoic acid ethyl para-toluenesulfone acetate salt (prepared in Example 3-b) Compound C 4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl ]butanoic acid (prepared in Example 4) Compound D 4- [4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]butanamide maleate (prepared in Example 5) Compound E 4- (4-diphenylmethoxy-1-piperidyl)butanoate ethyl fumarate (prepared in Example 8) Compound F 4- [4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]-2-butene Ethyl acid (
Prepared in Example 14) Compound G 5- [4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]-2-pentanone fumarate (Prepared in Example 15) Compound H 1-[ (4-chlorophenyl)-2-pyridylmethoxy]-1-(3-benzoylpropyl)piperidine (prepared in Example 16) Hartlay male guinea pigs weighing 200-250 g were used. After feeding the experimental animals for 5 hours, the test substance was orally administered at a dose of 1 mg/Kg. Test substance administration 2
After an hour, histamine hydrochloride 1.25 mg/Kg was intravenously administered to induce histamine shock. The potency of the test substance was determined by the inhibition rate of histamine-induced shock death. The test results are shown in Table 1.

A 5-week-old male ddY mouse produced by Openkur was used. Sodium thiobental is dissolved in physiological saline, test substance is 0.5%
A suspending agent containing Tween 80 and 1% tragacanth gum was prepared in a ratio of 1:25. After feeding the real animals for 4 hours, 60 mg/10+a//Kg of the test substance was administered intraperitoneally (or orally), and 20 minutes later (1 hour after oral administration), 30 ml 1 g/kg of sodium thiobental was administered. 1
0ml/Kg was administered intravenously. The time from immediately after intravenous administration to the onset of the righting reflex was measured, and this was defined as the anesthesia time. The formula for calculating the anesthesia extension rate is shown below.

The test results are shown in Table 1.

Allergy treatments primarily involve either inhibiting the release of chemical mediators or inhibiting their interaction with specific receptors.
Antihistamines, known as H1 polymer antagonists, play a major role. However, H1 polymers exist not only in the peripheral system but also in the central nervous system, and when antihistamines block central system receptors, they bring about the undesirable side effect of sedation (drowsiness). Therefore, in order to reduce this side effect, it is desirable to prevent the drug from entering the central system. That is, drugs that do not easily pass through the blood-brain barrier leading to the central nervous system and that act only on peripheral H1 polymers are preferred. Tilfenazine and astemizole as control drugs are said to have almost no sedative side effects.

From the test results summarized in Table 1, it was confirmed that among the six compounds used as control drugs, all except tilphenazine significantly increased the sleep time induced by thiopencour. The novel piperidine salt conductor, which is a compound of the present invention, generally has less potentiating effect on thiobental, therefore no significant prolongation of sleep time is observed, and moreover, it has stronger antihistamine activity than tilphenazine. Furthermore, it was confirmed that the compound of the present invention is extremely safe, can be used continuously as a medicine for a long period of time, and has good tolerability in a mouse toxicity test conducted by oral administration.

For example, for compound B, the LD50 for male mice
is 2200mg/Kg.

(Example) The present invention will be explained in more detail by the following examples. However, the compounds listed as examples are for explaining the present invention in more detail, and do not exceed the scope of the present invention in any way. It is not limited.

4-[(4-chlorophenyl)-2-pyridylmethoxycopiperidine2. OOg (6,61 mmol), and 3
- After dissolving 1.43 g (7.90 mmol) of ethyl bromopropionate in dioxane 10+, 1.09 g (7.89 mmol) of potassium carbonate was added to this mixed solution, and the oil bath temperature was 80°C. The mixture was heated and stirred for 8 hours back and forth. After the reaction was completed, the insoluble matter was separated from the furnace, and the furnace liquid was concentrated under reduced pressure. The residual liquid was mixed with a volume ratio of chloroform and methanol of 19.
: Separation was performed by silica gel column chromatography using a mixed solvent of 1 as a developing solvent. Both parts of the isolated target compound were concentrated under reduced pressure to give 3-[4[(4-chlorophenyl)
1.78 g (67%) of ethyl-2-pyridylmethoxy]-1-piperidyl]propionate was obtained. Melting point 1551
56 degree mass spectrometry value: EI-MSN+No peak.

CI-MS m/e=403(M”+1)” HNM
R (CDC13): δ (ppm) = 1.25 (3H, t), 2.02
(2H, b).

2.28 (28, b), 2.85-3.17 (88,
m).

3.74 (IH, m), 4.1.6 (2H, q).

5.58 (IH, s), 7.17~? , 73 (7H,
m).

8.52 (IH, m) Ethyl 3-[4-((4-chlorophenyl)-2-pyridylmethoxy]-1piperidyl]propionate obtained in Example 1 1,0 Og(2, 48 mmol) was dissolved in a mixed solution of 50% by weight aqueous hydroxide solution 1- and 8 d of ethanol, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure, neutralized with diluted hydrochloric acid, and then extracted with trichloroform. The chloroform layer was dried over anhydrous sodium sulfate and then concentrated to obtain 0.86 g (92%) of 3[4-[(4-chlorophenyl)-2-pyridylmethoxy3-i-piperidylcopropionic acid].

Mass spectrometry value: EI-MS No N+ peak.

CI-MS m/e=375(M++1)11(-NM
R(CDCl2): δ(pPffl) = 1.82(4)1. b),
2.51 (2H, t).

2.58 (2H, b), 2.27 (2H, t).

2.90(2)1. b), 3.85 (IH, m15
．． 58(It(,s), 7.15-7.74(7H,
m).

8.52 (IH, m) 4[(4-chlorophecol)-2 pyridylmethoxy] 4.98 g (16,4
5 mmol) and ethyl 4-bromobutanoate 3.8.5
g (19,74 mmol) in acetone, and then 2.73 g (19,74 mmol) of potassium carbonate was added to this mixture.
75 mmol) was added thereto, and the mixture was heated and stirred under reflux for 4 hours. After the reaction was completed, the insoluble matter was separated from the furnace, and the furnace liquid was concentrated under reduced pressure.

The residue was separated by silica gel column chromatography using a mixed solvent of chloroform and methanol in a volume ratio of 30:1 as a developing solvent. Both parts of the isolated target compound were concentrated under reduced pressure to obtain an oily product of 4-[4[(4-chlorophenyl)].
6.26 g (91%) of ethyl-2-pyridylmethoxy]-1-piperidylcobutanoate was obtained.

Mass spectrometry value: EI-111sM+no peak.

CI-MS m/e=417(N”+1)L H-N
MR (CDCl2): δ (ppm) -1,13 (3H, t), 1.1
0 to 1.98 (BH, b, m).

2.12(2)1. b), 2.33(4H,t
).

2.70 (2H, b), 3.45 (IH, m).

4.11 (2H, q), 5.59 (1) 1. s).

7.12-7.72 (7H, m), 8.50 (IH, m
) b) 5.33 g of ethyl ester obtained in a) above
(12,78 mmol) and 2.43 g (12,78 mmol) of rose-toluenesulfonic acid were added to 70 g of ethanol.
After dissolving the mixture into a homogeneous solution, the mixed solution was concentrated under reduced pressure. The residue was crystallized from isopropyl ether. The separated product was recrystallized from ethyl acetate,
4-[1[(4-chlorophecol)-2-pyridylmethoxyco-1-piperidylcobutaneethyl-p-toluenesulfonebutanefp6.88g (91%), melting point 130
-132°C was obtained.

Elemental analysis value: Calculated value as 023829CIN203/C7H803S: Cel, +6 HEl, 33 N 4.7
8 real ll 1 l I value: Cfil, I4 HEl, 2
Using ethyl 4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]butanoate obtained in Example 3, the procedure described in Example 2 was carried out. 4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]butanoic acid was obtained in the same manner as described above.

Mass spectrometry value: EI-MS No N” peak.

CI-MS m/e=389(M"+1)' H-N
MR (CDCl2): δ (ppm) = 1.84-1.98 (ftH, b,
m), 2.58 (2H, t).

2.73 (48, b, m), 2.92 (2H, b)
.

3.88 (lH, m), 7.17-7.22 (7) 1
．． m).

8.51 (IH, m), 11.31 (IH, b) real]
a) 0.50 g (1,29 mmol) of 4-[4-[(4-chlorophenyl)-2-pyridylmethoxy 1-ipiperidyl]butanoic acid obtained in Example 4 was dissolved in dichloromethane 5d. After that, 0.32 g (1.55 mmol) of dicyclohexylcarposiimide was added in an ice bath. To this reaction mixture was added a dichloromethane solution containing ammonia gas dissolved therein, and the mixture was stirred at room temperature for 10 hours. After the reaction was completed, the insoluble matter was separated from the furnace, and the furnace liquid was concentrated under reduced pressure. The residual liquid was separated by silica gel column chromatography using a mixture of chloroform, methanol, and concentrated ammonia water (Ca content: 25% by weight) in a volume ratio of 90:9:1 as a developing solvent. Both parts of the isolated target compound were concentrated under reduced pressure to give an oily product of 1-[4-[(4-chlorophenyl)].
0.38 g (76%) of -2-pyridylmethoxy]-1-piperidyl]butanamide was obtained.

Mass spectrometry value: El-MS No N+ peak.

CI-MS m/e=388(llI”+1)L H
-NMR (CDCl2): δ (ppm) = 1.58-1. ! 117 (BH,b
, m), 2.10 (2H, b).

2.23 (2H, t), 2.31 (2H, t).

2.72(2)1. b), 3.45 (IH, m).

5, Eil (IH, s), 8.30 (IH, b, s)
.

6.82 (IH, b, s), 7.11-7.70 (
7H, m).

8.51 (IH, m) b) 0.38 g (0,98
mmol) in ethanol, maleic acid 0
．． 11 g (0.98 mmol) were added. The precipitated white crystals were recrystallized from ethyl acetate to give 4-[4-[(4-
chlorophenyl) 2-biridylmethoxyco-1-piperidyl] butanamide maleate 0.35 g (71%
), melting point 123.5-124.5°C.

Elemental analysis value: Calculated value as C21H2BN302C1/C4H404: C59,58He,oo N 8.34 Actual value:
C58,68H5,85N 8.3 In a similar way,
N-dimethyl-4[4-[(4-chlorophenyl)-2
-pyridylme).xy]-1-piperidyl]butanamide was obtained.

Mass spectrometry value/El-MS: No N+ peak.

CI-MS m/e=41ft(M"+l)' H-
NMR (CDC13) δ (ppm) = 1.82 ~ 2.00 (f (H, b, m
), 2.1B (2H, b).

2.33 (28, t), 2.38 (2H, t).

2.75 (2H, b), 2.92 (3H, s).

3.00 (3H, s), 3.48 (IH, m).

5.80(IH,s), 7.12~7.71(?H,
m).

8.50 (IH, m) Example 11 a) Using 4-[(4-chlorophenyl)-2-pyridylmethoxycopiperidine and propyl 4-chlorobutanoate, as described in Example 3-a) In a similar manner, 4-
[1[(4-chloro7xnyl)-2-pyridylmethoxy]-1-piperidyl]butane butypropyl was obtained.

Mass spectrometry value/EI-MS No N+ peak.

CI-MS m/e=431(M++1)' H-NM
R (CDCl2): δ (ppm) = 0.92 (3H, t), 1.
55-1.96 (8H, m) 2.10 (2H, b), 2
．． 32 (4H, t) 2.71 (2Hb), 3.45
(IH, m) 4.01 (2H, t), 5. eO(I
H,s)? , 12-7.71 (7H, m), 8.50 (
IH, m) b) Using the propyl ester obtained in a) above and para-toluenesulfonic acid, Example 3-b
) was used to obtain 4-[4-[(4chlorophenyl)-2-pyridylmethoxy]1-piperidylcobutanoic acid propyl para-toluenesulfonate, melting point 122-123°C.

Elemental analysis value: Calculated value as C24H34CIN203/c7HBo3s: Cfil,? 3 Hfi, 52 N 4.
84 actual value: C[il, el HB, 57 N
4.84 Diphenyl chloride a) 4-(4-diphenylmethoxy-1-
Ethyl piperidyl)butanoate was obtained.

Mass spectrometry value: El-MS No N+ peak.

CI-MS m/e=382(M++1)' H-NM
R(CDCl2): δ(ppm) = 1.24(38,t), 1.17
~198 (8H, b, m).

2.15 (2H, b), 2.吋(2H,t).

2.36(2H,t), 2.75(21(,b)3
．． 44 (IH, m), 4.12 (2H, q).

5.51 (IH, s), 7.20 ~ 7.40 (I
4-(4-diphenylmethoxy-1=piperidyl) was prepared in a similar manner as described in Example 3-b) using the ethyl ester obtained in a) of OH, m) b) ) Ethyl butanoate fumarate, melting point LO6-10
7°C was obtained.

Elemental analysis value: 2483103N・C4H4O4 y2H20 calculation value・C1111(,39H7,16N 2.78
Actual value: Cf3Et, 44 H7,01N 2.
4-[4=(phenyl-2-
Ethyl pyridylmethoxy-1-piperidylcobutanoate was obtained.

Mass spectrometry value/ET-MS No N+ peak.

CI-MS m/e=383(M"+1)' H-N
MR (CDC13): δ (ppm) = 1.24 (3H, t), 1.65
~2.00 (6H, b, m).

2.11 (2H, b), 2.31 (4) 1. m).

2.72 (2H, b), 3.47 (IH, m).

4.11 (2H, q), 5.64 (IH, s).

7.10-7.70 (8H, m), 8.50 (IH,
m) b) The ethyl ester obtained in a) above and para-
4-[4-(phenyl-2-pyridylmeI.xy)-1-piperidylcobutaneethyl p-toluenesulfonate, in a similar manner as described in Example 3-b) using toluenesulfonic acid. A melting point of 84-85°C was obtained.

Elemental analysis value: C23H3ON203-11aO3S ・Calculated value as 34H20: C63,92H8,97N 4.97
Actual value: CEI3.79 1 (8,83N 4.9
7 fruit is t1 tongue a) 4-[(4-chlorophenyl)phenylmethoxy)
4-[4-[
Ethyl (4-chlorophenyl)phenylmethoxy]-1-piperidyl]butanoate was obtained.

Mass spectrometry value El-MS No N+ peak.

CI-MS m/e=418(M++1)' H-N
MR (CDCl2): δ (ppm) = 1.24 (3H, t), 1.
133-1.93 (EIH, b, m).

2.10(2)1. b), 2.32 (4H, t
).

2.70 (2H, b), 3.40 (IH, m).

4.11 (2H, q), 5.47 (I) l, s).

7.28 (9H, m) b) 4-[1 -[(4chlorophenyl)phenylmethoxy]-1-piperidylcobutanoic acid ethyl para-toluenesulfonate, melting point 92-94°C was obtained.

Elemental analysis value: C24H3oCIN0311C7H803Say4H2
Calculated value as 0: CI32.82 8 Ei, 55
N 2.313 actual value: CB2.85 HE
Example 3-a using 4-(phenyl-3-pyridylmethoxy)piperidine and ethyl 4-bromobutanoate
), 4-[4-phenyl-
Ethyl 3-pyridylmethoxy] -piperidyl]butanoate was obtained.

Mass spectrometry value: EI-MSM+no peak.

CI-MS m/e=383(M"+1)'H
-NMR (CDC13): δ (ppm) = 1.24 (3H, t), 1.82
~1.96 (OH, b, m) 2.12 (2H, b),
2.32 (4H, m).

2.72 (2H, b), 3.44 (IH, m).

4.12 (2H, q), 5.53 (IH, s)7.
20-7.36 (eH, m), 7.63 (IH, m
).

8.49 (IH, m), 8. flO(IH,d)b)
4- (4-(phenyl-3-pyridylmethoxy)- Ethyl 1-piperidylcobutanoate, melting point 10
1.5-103°C was obtained.

Elemental analysis value: C23f (3ON203 ・C7HBO3S Φ34H
Calculated value as 20 + CB4.44 86.94
N 5.01 Actual value: C64, 29HB, 94
Example 3 using 4-[bis(4-methoxyphenyl)methoxycopiperidine and ethyl 4-bromobutanoate]
In a similar manner as described under -a), ethyl 4-[4-[bis(4-methoxyphenyl)methoxy]-1-piperidyl]butanoate was obtained.

Mass spectrometry value: EI-MSN + peakless CI-MS m
/e=442(M"+1)"H-+IMR(CDC
l2 ): δ(Ppl++) = 1.23(3)1. t),
1.82-1.93 ([f)I, b, m).

2.09 (2H, b), 2.30 (4H, m).

2.72 (2H, b), 3.39 (IH, m).

3.7Ei (6H, s), 4.11 (2H, q)5.
43 (IH, m), 6.83 (4H, m).

7.22(4H,m) b) 4-[4 -[Bis(4-methoxyphenyl)methoxy]-1-piperidylcobutanoic acid ethyl bara-toluenesulfonate, melting point 93-95.5°C
I got it.

Elemental analysis value: Calculated value as C2BH3505N-C7HBO3S:
C64,58H7,08N 2.28 Actual value: 0
64.37 H7,31N 2.84 a) As described in Example 3-a) using 4-(bis(4-fluorophenyl)methoxycopiperidine and ethyl 4-bromobutanoate) In a similar manner, 4-[1-[
Ethyl bis(4-fluorophenyl)methoxyco-1-piperidyl]butanoate was obtained.

Mass spectrometry value: EI-MS N” No peak CI-M
S m/e=418(M"+1)' H-NMR(C
DC13): δ (ppm) ” 1.24 (3H, t), 1.83
-1.92 (6H, b, m).

2.13 (2H, b), 2.33 (4H, m).

2.74 (2H, i]), 3.38 (IH, m).

4.12 (2H, q), 5.46 (IH, s).

7.00 (4H, m), 7.28 (4H, m) b)
J: Using the ethyl ester obtained in a) above and para-toluenesulfonic acid, 4-[4-[bis(4-fluorophenyl ) Methoxy]-1-piperidyl]butanoic acid ethyl para-toluenesulfonate, melting point 121-123°C was obtained.

Elemental analysis value: 024H29F2NO3・C7HBO3S ・Suka H20
Calculated value as: C82,19He,40N2
．． 34 actual value + CB2.29 H8,49N 2
．． A similar procedure as described in Example 3-a) was performed using 4-[(4-chlorophecol)-2-pyridylmethoxy]piperidine and ethyl 4-bromo-2-butenoate. in a way,
Ethyl 4-[4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]-2-butenoate was obtained.

Mass spectrometry value: El-MS No N+ peak.

CI-MS m/e=415CM"1)' H
-NMR (CDC13): δ (ppm) = 1.27 (2H, t), 1.78
(2H, b).

1.90 (2H, b), 2.24 (2H, b).

2.75 (2H, b), 3.13 (2H, dd).

3.49 (1) I, m), 4.18 (2H, q).

5.59 (IH, s), 5.91 ((IH, m).

Ei, 93 (IH, dt), 7.13~? , 72 (7
)1. m) 8.50 (IH, m) Actual speed 11 above j a) Using 4-[(4-chlorophenyl)-2-pyridylmethoxycopiperidine and 5-chloro-2-pentanone, Example 3-a) In a similar manner as described in 5-
(4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidyl]-2-pentanone was obtained.

Mass spectrometry value: EI-MSN+no peak.

C4-MS m/e=387(M"+1)' H-N
MR (CDC: I3): δ (ppm) = 1. flO~1.95(6H,b,
m), 2.08 (2H, b).

2.14 (3H, s), 2.27 (2H, t).

2.43 (2H, t), 2.70 (2) 1. b).

3.44 (IH, m), 5.59 (IH, s) 7.1
1 to 7.71 (7H, m), 8.50 (IH, m)b
) Using the ketone obtained in a) above and fumaric acid,
In a similar manner as described in Example 3-b), 5-[
4-[(4-chlorophenyl)-2-pyridylmethoxy]-1-piperidylco-2-pentanone fumarate, melting point 113-114.5°C? , 9Ei (2H, m),
8.51 (IH, m) was obtained.

Elemental analysis value: C22H27CIN202・C4)! 404・%H20
Calculated values as: Cel, 53 He, 25 N
5.52 actual value: CIil, 50 H8,15
4 by the method described in Example 3-a) using 4-[(4-chlorophenyl)-2-pyridylmethoxycopiperidine and 3-chloro-1-benzoylpropane. −[(
4-chlorophenyl)-2pyridylmethoxy]-1-(
3-benzoylpropyl)piperidine was obtained.

Mass spectrometry value: EI-MSN+no peak.

CI-MS m/e=448(M”+1)”H-N
MR (CDC: +3): δ (ppm) = 1.88 (2H, b), 2.11
(4H, b, m).

2.67 (4H, b), 2.94 (2H, b).

3.10 (2H, t), 3.83 (LH, m15.5
7(IH,s), 7.14-7.72(lot(,m
).

Fruit 1 is 1↓1 Using the method described in Example 1 using 4-[(4-chlorophenyl)-2-pyridylmethoxycopiperidine and 3-chloro-1-(4tert-butylbenzoyl)propane, 4-((4-chlorophenyl)-2-pyridylmethoxy]-1[3-(4-tert-butylbenzoyl)propylcopiperidine was obtained.

Mass spectrometry value: EI-MSN+no peak.

CI-MS m/e=505(M”+1)”H-N
MR (CDC: +3): δ (ppm) = 1.33 (9H, s), 1. Ei
8 (2H, b).

1.90 (4H, b, m), 2.14 (2H, b)
.

2.39 (2H, t), 2.73 (2H, b).

2.97 (2H, t), 3.45 (IH, m).

5.59 (IH, sC7, 12-7.71 (9H, m)
.

7.90 (2H, m), 8.50 (IH, m) (Effect of the invention) The novel compound according to the present invention has a pharmaceutical or medicinal effect,
In particular, it provides a pharmaceutical composition having antihistamine activity or antiallergic activity, and is of great industrial importance.

Claims (5)

[Claims] (1) General formula [I]: ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, Ar^1 and Ar^2 each independently represent a phenyl group; a halogen atom, a nitro group, a lower alkoxy A is a group selected from the group consisting of a phenyl group having a lower alkyl group, a lower alkyl group or a lower alkyl group substituted with a halogen atom; and a pyridyl group; B represents a branched alkylene or alkenylene group having at least 2 carbon atoms in the chain; B is a lower alkyl group, hydroxy group, lower alkoxy group, phenoxy group, amino group, lower alkylamino group, anilino group, phenyl represents a group selected from the group consisting of a phenyl group substituted with a lower alkyl group, and a phenyl group substituted with a lower alkyl group. However, when B is a phenyl group or a phenyl group substituted with a lower alkyl group, at least one of Ar^1 and Ar^2 is a pyridyl group. ] A compound represented by these, and a pharmaceutically acceptable acid addition salt thereof. (2) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, Ar^1 and Ar^2 are as defined in claim 1. ] and the general formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, W is a group that can be eliminated; A and B are claimed in claim 1
As defined in . ] A general formula characterized by reacting a compound represented by: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, Ar^1, Ar^2, A and B have the same meanings as above. ] A method for producing the compound according to claim 1 and a pharmaceutically acceptable acid addition salt thereof. (3) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, W' represents a group that can be eliminated, and Ar^1, Ar^
2 and A are as defined in claim 1. ] and the general formula: HB' [wherein B' represents a group selected from the group consisting of a lower alkoxy group, a phenoxy group, an amino group, a lower alkylamino group, and an anilino group. ] A general formula characterized by reacting a compound represented by: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, Ar^1, Ar^2, A and B have the same meanings as above. ] A method for producing the compound according to claim 1 and a pharmaceutically acceptable acid addition salt thereof. (4) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R represents a lower alkyl group, Ar^1, Ar^
2 and A are as defined in claim 1. ] General formula characterized by hydrolyzing the compound represented by: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, Ar^1, Ar^2 and A have the same meanings as above. ] A method for producing the compound according to claim 1 and a pharmaceutically acceptable acid addition salt thereof. (5) An antihistamine and antiallergic pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.