JP2625294B2 - Piperidine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel piperidine derivative useful as an antihistamine.

[0002]

2. Description of the Related Art To date, many piperidine derivatives useful as pharmacologically active ingredients have been found. Among these compounds, compounds having a part of the skeleton similar to the compound of the present invention include compounds disclosed in JP-A-60-94962 and JP-A-61-194068.

[0003]

While many of the conventional antihistamines act on the central nervous system to cause sedation (sleepiness), the present inventors have developed novel piperidine derivatives having effective pharmacological activity. As a result of intensive studies for synthesis, the novel piperidine derivative of the present invention, a pharmaceutically acceptable acid addition salt thereof, has useful pharmacological properties, particularly strong antihistamine activity and antiallergic activity, and The present inventors have found that thiopental, which is a central nervous system depressant, has little effect on enhancing sleepiness, and has completed the present invention.

[0004]

The novel piperidine derivative of the present invention has the general formula [I]

[0005]

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[Wherein, Ar ¹ and Ar ² each independently represent a phenyl group or a phenyl group having a halogen atom, a nitro group, a lower alkoxy group, a lower alkyl group or a halo-lower alkyl group as a substituent; A represents a linear alkylene group or an alkenylene group having at least 2 carbon atoms in a linear or main chain having 2 to 6 carbon atoms; B represents a lower alkyl group, a hydroxy group, a lower alkoxy group, a phenoxy group , An amino group, a lower alkylamino group or an anilino group] and a pharmaceutically acceptable acid addition salt thereof. In this specification, “lower” means having 1 to 4 carbon atoms unless otherwise specified.

[0007]

[0008]

In the above general formula [I], the substituted phenyl group represented by Ar ¹ or Ar ² is, for example, 4
-Fluoro, 2-chloro, 3-chloro, 4-chloro, 2
Phenyl group substituted with a halogen atom such as -bromo, 4-bromo, 2-iodo, 4-iodo;
A phenyl group substituted by a lower alkyl group such as -methyl, 4-methyl, 2,4-dimethyl, 3,4-dimethyl, 4-ethyl, 4-isopropyl, 4-n-propyl, 4-n-butyl; Phenyl group substituted with halo-lower alkyl group such as trifluoromethyl; 4-methoxy, 2,4
-A phenyl group substituted with an alkoxy group such as dimethoxy, 3,4-dimethoxy, 4-ethoxy;
Examples thereof include a phenyl group substituted with a nitro group such as 3-nitro and 4-nitro.

The linear or branched alkylene group having at least 2 carbon atoms in the main chain portion of A includes
Examples include ethylene, propylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene. Examples of the alkenylene group include vinylene, propenylene, 2-butenylene, 2-pentenylene,
Pentenylene is mentioned, and a linear alkylene group having 2 to 3 carbon atoms is preferable.

B is, for example, methyl, ethyl, propyl,
Lower alkyl groups such as isopropyl, butyl, isobutyl and t-butyl; hydroxy groups; methoxy, ethoxy,
lower alkoxy groups such as n-propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy; phenoxy groups; amino groups; methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, isopropylamino, n-butylamino; Lower alkylamino groups such as isobutylamino, sec-butylamino and t-butylamino; and anilino groups. Preferred B is a hydroxy group, a lower alkoxy group, an amino group, and a lower alkylamino group.

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

4- [4- (diphenylmethoxy) -1
Ethyl-piperidyl] butanoate and its fumarate salt; ethyl 4- [4-[(4-chlorophenyl) (phenyl) methoxy] -1-piperidyl] butanoate and its p
-Toluenesulfonate, ethyl 4- [4- [bis (4-methoxyphenyl) methoxy] -1-piperidyl] butanoate and its p-toluenesulfonate, 4- [4- [bis (4- Ethyl fluorophenyl) methoxy] -1-piperidyl] butanoate and its p-toluenesulfonate; ethyl 4- [4-[(4-methylphenyl) (phenyl) methoxy] -1-piperidyl] butanoate;

In the compound [I] of the present invention, when Ar ¹ and Ar ² are different, the carbon to which Ar ¹ and Ar ² are bonded is an asymmetric carbon and stereoisomers exist. Any of the mixtures are encompassed by the present invention. The compound represented by the formula [I] of the present invention is represented by the following reaction formula 1
3 can be produced.

[0015]

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In the formula, W is a group capable of leaving, for example, a halogen atom such as a chlorine atom, a bromine atom and an iodine atom, or a reactive ester group such as a methanesulfonyloxy group and a p-toluenesulfonyloxy group; Ar ¹ ,
Ar ² , A and B are as defined above. ]

Compound [I] can be easily produced by reacting compound [III] with compound [IV] as shown in reaction formula (1). Compound (IV) is
1 to 3 mol is added per 1 mol of compound [III].

The above reaction is carried out in water or an inert solvent. Suitable organic solvents include, for example, lower alcohols such as methanol, ethanol, propanol and butanol; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as 1,4-dioxane and tetrahydrofuran; acetone, ethylmethyl Ketones such as ketone and methyl isobutyl ketone; amides such as N, N-dimethylformamide; or a mixed solvent of two or more of these.

The reaction is preferably carried out in the presence of a base. Examples of such a base include an alkali metal hydroxide such as sodium hydroxide; an alkaline earth metal hydroxide such as calcium hydroxide. Alkali metal carbonates such as potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; alkali metal acid carbonates such as sodium bicarbonate; alkali metal hydrides such as sodium hydride; calcium hydride etc. Alkaline earth metal hydrides; alkali metal alkoxides such as sodium methoxide; trialkylamines such as triethylamine and pyridine compounds. These bases are added in an amount of 1 to 3 mol per 1 mol of the compound [III].

A small amount of metal iodide such as sodium or potassium iodide may be added as a reaction accelerator. In order to increase the reaction rate, the reaction is preferably carried out at a slightly elevated temperature. In some cases, the reaction may be carried out at the reflux temperature of the reaction mixture. The reaction time is 2 to 24 hours. The reaction product is separated from the reaction mixture and, if necessary, further purified by generally known methods.

In the above formula [I], the compound in which B represents a lower alkoxy group, a phenoxy group, an amino group, a lower alkylamino group or an anilino group can also be produced by the following method.

[0022]

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Wherein W 'is a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, or a hydroxy group; B' is a lower alkoxy group, a phenoxy group, an amino group or a lower alkylamino group. Or an anilino group;
r ¹ , Ar ² and A are as defined above. ]

Compound [I] can be easily produced by reacting compound [V] with compound [VI] as shown in reaction formula (2). Compound [VI] is added in an amount of 1 to 3 mol per 1 mol of compound [V].

The compound [V] in which W 'represents a halogen atom can be obtained by converting the corresponding carboxylic acid into a halide by a known method. The above reaction is carried out in an inert solvent at -5 to 30C, and the reaction time is 1 to 10 hours.

When W 'represents a hydroxy group, the above reaction is carried out in an inert solvent, for example, in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, trifluoroacetic anhydride or N-acylimidazole. The dehydrating agent is used in an amount of 1 to 2 mol per 1 mol of the compound [V], the reaction temperature is -5 to 30 ° C, and the reaction time is 1 to 24 hours.

In the above formula [I], the compound of the present invention can be produced by the following method from the compound wherein B represents a hydroxy group.

[0028]

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Wherein R is a lower alkyl group such as methyl and ethyl, and Ar ¹ , Ar ² and A are as defined above. ]

Compound [I] can be easily produced by hydrolyzing compound [VII] under basic conditions. This hydrolysis is carried out in aqueous methanol, aqueous alcohol such as ethanol, for example, sodium hydroxide,
It is preferable to use 1 to 5 mol of an inorganic base such as potassium hydroxide per 1 mol of the compound [VII], and to increase the reaction temperature at room temperature or at a slightly elevated temperature. The reaction can also be carried out at the reflux temperature of the mixture. The reaction time is 1 to 10 hours.

Piperidine derivative used as raw material
[III] can be produced, for example, according to the following standard method.

[0032]

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(In the above reaction formula, X represents a halogen atom or a reactive ester group such as p-toluenesulfonyloxy group, and Q represents protection of an amino group such as formyl group, ethoxycarbonyl group or t-butoxycarbonyl group. Represents a group, and Ar ¹ and Ar ² are as defined above.

First, the compound [VIII] and the compound [IX] are reacted and O-alkylated, and then the obtained compound [X]
The desired intermediate product [III] can be prepared by removing the protecting group Q of the amino group of the above by using a general method.

The compound [I] of the present invention can be converted into a non-toxic, pharmacologically effective acid addition salt by reacting a suitable acid with the compound [I]. In this case, examples of suitable acids include, for example, hydrohalic acids such as hydrochloric acid and hydrobromic acid; inorganic acids such as sulfuric acid, nitric acid and phosphoric acid; acetic acid, propionic acid, hydroxyacetic acid and 2-hydroxypropion Acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, dihydroxyfumaric acid, oxalic acid, benzoic acid, cinnamic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, Organic acids such as cyclohexylsulfamic acid and 4-aminosalicylic acid are exemplified.

The compound of the present invention represented by the formula [I] and a pharmaceutically acceptable acid addition salt thereof have useful pharmacological properties,
It has particularly strong antihistamine activity and antiallergic activity. Furthermore, it has the feature that secondary effects such as stimulation or suppression on the central nervous system often seen in the case of conventional antihistamines are minimized,
As such or in combination with a suitable carrier, they can be used as effective medicaments for the treatment of humans and animals.
Specifically, the present invention can be applied to treatment or treatment of allergic skin diseases such as urticaria, eczema and dermatitis, sneezing due to upper respiratory inflammation such as allergic rhinitis cold, nasal discharge, cough, and bronchial asthma.

When the compound of the present invention is used as an antihistamine, it is administered mainly by oral administration or parenteral administration such as injection or application. The dosage is appropriately adjusted depending on the difference in disease, the degree of symptoms, age, etc., and is usually about 2 to 50 mg, preferably about 5 to 25 mg per adult day.

To formulate the compound of the present invention, tablets, capsules,
Powders, syrups, intravenous injections, intramuscular injections, ointments, etc.

In general, the compounds of the present invention relax tracheal and vascular smooth muscles, and guinea pigs orally administered at a dose of 1 mg / kg body weight of animal significantly suppresses histamine hydrochloride-induced shock death. . In addition, when thiopental was used as a central nervous system depressant and the effect on the duration of induced anesthetic action was examined for these compounds, a remarkable potentiating effect was hardly observed. Pharmacological test results for the following representative compounds belonging to the present invention are shown below.

Compound A 4- [4- (diphenylmethoxy) -1-piperidyl]
Ethyl butanoate fumarate (prepared in Example 1-b) Compound B Ethyl 4- [4-[(4-chlorophenyl) (phenyl) methoxy] -1-piperidyl] butanoate p-toluenesulfonate (Example 2) Prepared in -b)

Pharmacological test Histamine shock death protective effect Male Hartley guinea pigs weighing 200 to 250 g were used. After fasting the experimental animal for 5 hours, 1 mg of the test substance
/ Kg orally. Two hours after administration of the test substance, histamine hydrochloride was intravenously administered at 1.25 mg / Kg to induce histamine shock. The titer of the test substance was determined by the rate of inhibition of histamine-induced shock death. Table 1 shows the test results.

Anesthesia time prolongation effect by thiopental A ddY male mouse 5 weeks old was used. Thiopental sodium is dissolved in physiological saline, and the test substance is 0.5%
Tween 80 and 1% tragacanth were prepared in a 1: 2.5 ratio suspension. After fasting the experimental animals for 4 hours, the test substance 60 mg / 10 ml / Kg was intraperitoneally administered (or orally administered), and 20 minutes later (1 hour after oral administration), 30 mg / 10 ml / Kg sodium thiopental was administered. It was administered intravenously. The time from immediately after intravenous administration to the onset of the righting reflex was measured and defined as the anesthesia time. The formula for calculating the anesthesia extension rate is shown below. Table 1 shows the test results.

[0043]

[Table 1]

[0044] Allergy treatment is a one of either primarily or inhibiting the release of chemical mediators (chemical mediator), or to suppress their interaction with specific receptors, known as the H ₁ receptor antagonist Selected antihistamines play a major role. However, H ₁ receptor is not only the peripheral system, also present in the central nervous and antihistamines to block the central system receptors, resulting in an undesirable side effect of sedation (sleepiness). Therefore, in order to reduce this side effect, it is desirable to prevent the drug from flowing into the central system. In other words, hardly cross the blood brain barrier, leading to the central nervous system, drugs acting only on H ₁ receptors in peripheral are preferred. Terfenadine and astemizole as control drugs are said to have few sedative side effects.

From the test results summarized in Table 1, it was confirmed that, among the above-mentioned six compounds used as control drugs, all except terfenadine significantly increased the sleep time induced by tympental. The novel piperidine derivative which is the compound of the present invention generally has a small potentiating effect on thiopental, and therefore does not show a remarkable prolongation of sleep time, and has a stronger antihistamine activity than terfenadine. Further, it was confirmed that the compound of the present invention has extremely high safety, can be used for a long term as a medicament, and has good tolerability in a mouse toxicity test by oral administration.

[0046]

The present invention will be described in more detail with reference to the following examples. The compounds given as examples are for illustrating the present invention in more detail and do not limit the scope of the present invention. Not something.

Example 1 a) 4.40 g of 4- (diphenylmethoxy) piperidine
(16.45 mmol) and 3.85 g (19.74 mmol) of ethyl 4-bromobutanoate were dissolved in 35 ml of acetone, and 2.73 g of potassium carbonate was added to the mixture.
(19.75 mmol), and the mixture was stirred under reflux for 4 hours. After completion of the reaction, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. Residue is chloroform / methanol volume ratio 3
Separation was performed by silica gel column chromatography using a 0: 1 mixed solvent as a developing solvent. The isolated fraction of the target compound was concentrated under reduced pressure, and the oily ethyl 4- [4- (diphenyl) methoxy-1-piperidyl] butanoate 5.6 was obtained.
5 g (90%) were obtained.

Mass spectrum: EI-MS M ⁺ no peak, CI-MS
m / e = 382 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.24 (3H, t), 1.17 to 1.98 (6H, b, m), 2.15 (2
H, b), 2.31 (2H, t), 2.36 (2H, t), 2.75 (2H, b), 3.44 (1
H, m), 4.12 (2H, q), 5.51 (1H, s), 7.20 to 7.40 (10H,
m)

B) 5.33 g (12.78 mmol) of the ethyl ester obtained in a) above and 1.48 of fumaric acid
g (12.78 mmol) was dissolved in 70 ml of ethanol to make a homogeneous solution, and the mixed solution was concentrated under reduced pressure. The residue was crystallized from isopropyl ether. The filtered product was recrystallized from ethyl acetate to give 4- [4-
6.20 g (91%) of (diphenyl) methoxy-1-piperidyl] butanoic acid ethyl fumarate were obtained.

Melting point: 106-107 ° C. Elemental analysis value (%): C ₂₄ H ₃₁ O ₃ N ₄ C ₄ H ₄ O ₄ 1/2 H ₂ O Calculated value: C 66.39 H 7.16 N 2.76 Actual value: C 66.44 H 7.01 N 2.71

Example 2 a) Using 4-[(4-chlorophenyl) (phenyl) methoxy] piperidine and ethyl 4-bromobutanoate
In the same manner as in Example 1-a), ethyl 4- [4-[(4-chlorophenyl) (phenyl) methoxy] -1-piperidyl] butanoate was obtained.

Mass spectrum: EI-MS M ⁺ no peak, CI-MS
m / e = 416 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.24 (3H, t), 1.63 to 1.93 (6H, b, m), 2.10 (2
H, b), 2.32 (4H, t), 2.70 (2H, b), 3.40 (1H, m), 4.11 (2
H, q), 5.47 (1H, s), 7.28 (9H, m)

B) Using the ethyl ester obtained in the above a) and p-toluenesulfonic acid, 4- [4-[(4-chlorophenyl)] was obtained in the same manner as in Example 1-b).
(Phenyl) methoxy] -1-piperidyl] butanoic acid ethyl p-toluenesulfonate was obtained.

Melting point 92-94 ° C. Elemental analysis (%): C ₂₄ H ₃₀ ClNO ₃ · C ₇ H ₈ O ₃ S · 1/4 H ₂ O Calculated: C 62.82 H 6.55 N 2.36 Found: C 62.85 H 6.53 N 2.33

Example 3 a) Example 1 using 4- [bis (4-methoxyphenyl) methoxy] piperidine and ethyl 4-bromobutanoate
In the same manner as in -a), ethyl 4- [4- [bis (4-methoxyphenyl) methoxy] -1-piperidyl] butanoate was obtained.

Mass spectrum: EI-MS M ⁺ no peak, CI-MS
m / e = 442 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.23 (3H, t), 1.62 to 1.93 (6H, b, m), 2.09 (2
H, b), 2.30 (4H, m), 2.72 (2H, b), 3.39 (1H, m), 3.76 (6
H, s), 4.11 (2H, q), 5.43 (1H, m), 6.83 (4H, m), 7.22 (4
H, m)

B) Using the ethyl ester obtained in the above a) and p-toluenesulfonic acid, 4- [4- [bis (4-methoxyphenyl)] was obtained in the same manner as in Example 1-b). [Methoxy] -1-piperidyl] ethyl butanoate p-
The toluene sulfonate was obtained.

Melting point: 93-95.5 ° C. Elemental analysis (%): C ₂₆ H ₃₅ O ₅ N · C ₇ H ₈ O ₃ S Calculated: C 64.58 H 7.06 N 2.28 Actual: C 64.37 H 7.31 N 2.64

Example 4 a) Using 4- [bis (4-fluorophenyl) methoxy] piperidine and ethyl 4-bromobutanoate, in the same manner as in Example 1-a), 4- [4- [bis Ethyl (4-fluorophenyl) methoxy] -1-piperidyl] butanoate was obtained.

Mass spectrometry value: EI-MS M ⁺ no peak, CI-MS
m / e = 418 (M ⁺ +1) ¹ H-NMR (CDCl ₃ ): δ (ppm) = 1.24 (3H, t), 1.63 to 1.92 (6H, b, m), 2.13 (2
H, b), 2.33 (4H, m), 2.74 (2H, b), 3.38 (1H, m), 4.12 (2
H, q), 5.46 (1H, s), 7.00 (4H, m), 7.28 (4H, m)

B) Using the ethyl ester obtained in the above a) and p-toluenesulfonic acid, 4- [4- [bis (4-fluorophenyl)] was obtained in the same manner as in Example 1-b). [Methoxy] -1-piperidyl] ethyl butanoate p-
The toluene sulfonate was obtained.

Melting point: 122-123 ° C. Elemental analysis (%): C ₂₄ H ₂₉ F ₂ NO ₃ · C ₇ H ₈ O ₃ S · 1/2 H ₂ O Calculated: C 62.19 H 6.40 N 2.34 : C 62.29 H 6.49 N 2.37

[0063]

The novel compounds according to the present invention are pharmaceutically or pharmacologically useful, especially antihistamines which do not cause drowsiness and have antihistamine or antiallergic activity.

 ──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Hiroshi Fujiwara 5 Ube Kosan Co., Ltd., Ube Research Laboratory, 1978 Kogushi, Ube City, Yamaguchi Prefecture

Claims (1)

(57) [Claims] 1. A compound of the general formula [I] [In the formula, Ar ¹ and Ar ² each independently represent a phenyl group or a phenyl group having a halogen atom, a nitro group, a lower alkoxy group, a lower alkyl group or a halo-lower alkyl group as a substituent; B represents a linear or branched alkylene group or alkenylene group having at least 2 carbon atoms in the main chain, and B represents a lower alkyl group, a hydroxy group, a lower alkoxy group, a phenoxy group, an amino group. , A lower alkylamino group or an anilino group] and pharmaceutically acceptable acid addition salts thereof.