JPH05170736A - Diphenylmethoxypiperidine derivative and medicine containing the same - Google Patents

Abstract

PURPOSE:To provide a new diphenylmethoxypiperidine derivative or its salt simultaneously having more excellent antiallergic activity and more excellent antihistaminic activity than conventional compounds, having high safety and useful as an antiallergic agent, an antihistaminic agent and an antiasthmatic agent. CONSTITUTION:A diphenylmethoxypiperidine derivative of formula I (m is 2-5; R is H, halogen; B is OH, lower alkoxy, group of formula II) or its salt, e.g. 2-[2-(4-diphenylmethoxy)-1-piperidinyl] ethoxybenzoic acid methyl ester. The compound of formula I wherein B is OB' (B' is alkyl) is obtained e.g. by reacting a piperidine derivative of formula III with a salicylic acid derivative of formula IV in the presence of a base.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the following general formula (I)

[0002]

[Chemical 3]

(In the formula, m represents an integer of 2 to 5, R represents a hydrogen atom or a halogen atom, B represents a hydroxyl group, a lower alkoxy group or

[0004]

[Chemical 4]

Is shown. The present invention relates to a diphenylmethoxypiperidine derivative represented by the formula (1), an antiallergic agent, an antihistamine, and an antiasthma drug containing the same.

[0006]

2. Description of the Related Art Heretofore, many diphenylmethoxypiperidine derivatives have been found and their useful actions such as antiallergic action and antihistamine action have been known, but sufficient effects have been obtained. Compounds that have and are highly safe are not known. Has a pharmacological action such as an anti-allergic action and an antihistamine action,
As compounds having a skeleton partly similar to those of the compound (I) of the present invention, there are compounds disclosed in JP-A-2-25465 and JP-A-3-264562. Invention compound (I) is not described at all.

[0007]

[Means for Solving the Problems] The present inventors have conducted intensive studies to create a compound having both superior antiallergic action and antihistamine action and high safety, and to complete the present invention. I arrived. Examples of the lower alkoxy group in the present invention include linear or branched alkyl groups having 1 to 4 carbon atoms, and methoxy, ethoxy, propoxy, butoxy groups and isomers thereof are preferable. Examples of the halogen atom include chlorine, bromine, fluorine or iodine atom. The compound of the present invention can be used as a pharmaceutically acceptable salt, hydrochloric acid, nitric acid, sulfuric acid, acetic acid, maleic acid, fumaric acid, oxalic acid, citric acid, hydrobromic acid,
Acid addition salts such as succinic acid, sulfamic acid, mandelic acid, malonic acid, phosphoric acid, etc., or sodium salt, potassium salt,
Examples thereof include basic salts such as lithium salt and calcium salt. In addition, since the compound (I) of the present invention may have an asymmetric carbon atom, optical isomers may exist, but the present invention also includes these isomers. The compound (I) of the present invention can be produced, for example, as follows.

[0008]

[Chemical 5]

(In the formula, R and m have the same meanings as described above, B ¹ represents a lower alkyl group, and Z represents a halogen atom.) That is, the piperidine derivative represented by the general formula (II) and the general formula (II) By reacting the salicylic acid derivative represented by III) in the presence of a base, an ester derivative (Ia) which is a part of the compound of the present invention is produced.

The above reaction is preferably carried out in a solvent that does not affect the reaction. Examples of the solvent include esters such as methyl acetate and ethyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; acetonitrile, dimethyl sulfoxide, dimethylformamide and the like, Halogenated hydrocarbons such as dichloromethane and chloroform; aromatic hydrocarbons such as benzene, toluene and xylene can be used alone or in combination.
The reaction temperature may be changed according to the starting compound used, and it is usually advantageous to select it under atmospheric pressure in the range of 0 ° C. to the reflux temperature. Examples of the base include carbonates such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, triethylamine, diisopropylamine, DBU (1,8-diazabicyclo [5,4,0] -7-
Undecene) and other organic bases.

[0011]

[Chemical 6]

(In the formula, R and m have the same meanings as described above.) Next, the ester derivative (I
The corresponding carboxylic acid derivative (Ib) is obtained by subjecting a) to a commonly used hydrolysis reaction, and further the carboxylic acid derivative (Ib) is condensed with 5-amino-1H-tetrazole to give the compound of the present invention. It can be led to the compound (Ic) which is a part of the compound. This condensation reaction is preferably carried out according to a known method in a solvent that does not influence the reaction, and examples thereof include esters such as methyl acetate and ethyl acetate; amides such as dimethylformamide and diethylformamide; diethyl ether and diisopropyl. Ethers such as ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as acetonitrile and dimethylsulfoxide; dichloromethane and chloroform; aromatic hydrocarbons such as benzene, toluene and xylene can be used alone or in combination. As the condensing agent, N, N'-dicyclohexylcarbodiimide, 1,1 '
And carbodiimide derivatives such as carbonyldiimidazole. The reaction temperature may be changed according to the starting compound used, and it is usually advantageous to select it under atmospheric pressure in the range of 0 ° C. to the reflux temperature.

The compound (I) of the present invention thus obtained is
As described below, it has excellent antihistamine action, antiallergic action, and high safety, so it is a therapeutic agent for various allergic diseases, for example, an anti-inflammatory agent, a therapeutic agent for nephritis, hepatitis and pancreatitis, and prevention of respiratory diseases. And / or is effective as a therapeutic and anti-asthma drug.

The compound (I) of the present invention can be used as a preparation for oral administration or parenteral administration by incorporating a pharmaceutically acceptable auxiliary agent. As a preparation for oral administration, the above compound is used as a suitable additive such as lactose, mannitol, corn starch, excipients such as crystalline cellulose, cellulose derivative, gum arabic, binder such as gelatin, carboxymethyl cellulose calcium and the like. Tablets, powders, granules and capsules can be prepared by appropriately combining with disintegrants, talc, lubricants such as magnesium stearate and the like. Further, these solid preparations can be made into enteric preparations by using a coating base such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylate copolymer. Liquid preparations for oral administration include emulsions, solutions, suspensions, syrups, elixirs and the like, and may include generally used inert diluents such as purified water and ethanol. The composition may contain, in addition to the inert diluent, auxiliary agents such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative. In addition, an aerosol formulation formulated by a known method can also be used. As a preparation for parenteral administration, a liquid for injection can be prepared by combining, for example, water, ethanol, glycerin, a conventional surfactant and the like. Furthermore, an inhalant, a liquid for external use, an eye drop, a nasal drop, and a coating agent such as an ointment can be prepared by a known method. The dose of the compound (I) of the present invention is
Depending on symptoms, therapeutic effect, administration method, administration period,
Usually, it is orally administered in the range of 1 to 500 mg / day, preferably 5 to 50 mg / day, 1 to 3 times a day, or 0.1
It is parenterally administered once to several times a day in the range of up to 500 mg.

[0015]

[Action]

<Antihistamine action> Male Hartley guinea pig (body weight
The ileum was excised from 300 to 600 g) and suspended in a Magnus tank (30 ° C., under aeration) filled with 10 ml of Tyrode solution with an initial load of 0.5 g. The contractile response of the isolated ileum to histamine (3 × 10 ^-7 mol) was measured by isotonic tension change. The test compound was treated for 3 minutes before the addition of histamine to examine its action, and the antihistamine action (50% inhibitory concentration: IC ₅₀ value) was determined. As a result, the IC ₅₀ of each Example compound was 0.02 to 0.06.
The value in μM is shown.

<Anti-allergic action> Male SD rats (body weight: 150 to 250 g) were shaved in advance on their backs and physiological saline and anti-DNP-As (Dini-Dini) diluted to an appropriate concentration with physiological saline were used.
trophenyl conjugated Ascaris) IgE serum (0.1 ml) was injected intradermally in the dorsal skin and passively sensitized. 2.5 mg / ml after 48 hours
DNP-BSA (Dinitrophenyl conjugated Bovine Seru
1 ml of 0.5% Evans Blue physiological saline containing m Albumin) was intravenously administered. Thirty minutes later, exsanguination was performed, and the blue spots on the dorsal skin were punched out using a leather punch, and the amount of leaked pigment was measured according to the method of Harada et al. (Allergy, 15, 1-7, (1966)). Leakage pigment amount by passive sensitization skin anaphylaxis (PCA) was determined by subtracting the leakage pigment amount at the physiological saline administration site from the leakage dye amount at the PCA site. 5 test compounds
Suspended in% gum arabic or 0.5% methylcellulose
10 mg / 4 ml / kg was orally administered 1 hour before the antigen administration. The efficacy of the test compound was judged by the suppression rate of the leaked pigment amount (antiallergic effect). The results are shown in Table 1.

[0017]

[Table 1]

<Toxicity test> ICR mice aged 4 to 5 weeks were used as one group consisting of 10 mice. The compound of each Example was suspended in 5% gum arabic and orally administered at a dose of 1000 mg / kg, respectively, and observed for 7 days. As a result, no deaths due to the toxicity of the compound of the present invention were observed.

[0019]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. Example 1 2- [2- [4- (Diphenylmethoxy) -1-piperidinyl] ethoxy] benzoic acid methyl ester

[0020]

[Chemical 7]

4-diphenylmethoxypiperidine 9.6 g
(36 mmol) was dissolved in 100 ml of acetone, and 2- (2-
Bromoethoxy) benzoic acid methyl ester
11.1 g (43 mmol) and 7.5 g (54 mmol) of potassium carbonate were added, and the mixture was heated with stirring for 3 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 10.6 g of the title compound. Yield 66
%. Oil MS (m / z): 445 (M ⁺ ) IR (nujol) cm ^-1 : 3027, 1730, 1610 NMR (CDCl ₃ ) δ: 1.73 to 1.82 (2H, m), 1.90 (2
H, t), 2.33 (2H, dt), 2.85 (2H, t), 2.93 (2
H, t), 3.44 to 3.50 (1H, m), 3.87 (3H, s), 4.1
7 (2H, t), 5.54 (1H, s), 6.96 to 7.80 (14H,
m)

Example 2 2- [2- [4- (diphenylmethoxy) -1-piperidinyl] ethoxy] benzoic acid

[0023]

[Chemical 8]

10 g (22 mmol) of 2- [2- [4- (diphenylmethoxy) -1-piperidinyl] ethoxy] benzoic acid methyl ester obtained in Example 1.
Is dissolved in 100 ml of ethanol and 20 ml of 10% potassium hydroxide is added.
Was added and stirred at 50 ° C. for 30 minutes. After cooling, water was added and acetic acid was further added to adjust the pH to 6. The solvent was concentrated under reduced pressure and the precipitated crystal was collected by filtration to obtain 6.9 g of the title compound. Yield 73
%. Melting point: 194 ° C. MS (m / z): 431 (M ⁺ ) IR (nujol) cm ⁻¹ : 1539 NMR (DMSO-d ₆ ) δ: 1.69 to 1.75 (2H, m), 1.89
(2H, m), 2.51 (2H, m), 2.83 (2H, t), 2.92
(2H, m), 3.47 (1H, m), 4.13 (1H, brs), 4.33
(2H, t), 5.63 (1H, s), 6.98 to 7.56 (14H, m)

Example 3 2- [2- [4- (diphenylmethoxy) -1-piperidinyl] ethoxy] -N-1H-tetrazol-5-yl-benzamide

[0026]

[Chemical 9]

0.5 g (1.2 mmol) of 2- [2- [4- (diphenylmethoxy) -1-piperidinyl] ethoxy] benzoic acid obtained in Example 2 was dissolved in 5 ml of anhydrous dimethylformamide to prepare 1,1 ′. -0.18 g (1.7 mmol) of carbodiimidazole was added and stirred at 70 ° C for 20 minutes. After cooling, 0.38 g (2.3 mmol) of 5-aminotetrazole was added, and the mixture was stirred at 70 ° C for 2 hours. After cooling, water was added to the reaction solution and the precipitated crystals were collected by filtration to give 0.4 g of the title compound.
Got Yield 69%. Melting point (decomposition point): 168 to 170 ° C. MS (m / z): 499 (M ⁺ +1) IR (nujol) cm ⁻¹ : 3370, 1674 NMR (CDCl ₃ ) δ: 1.74 (2H, m), 1.89 ( 2H,
m), 2.51 (2H, t), 2.78 (2H, m), 2.93 (2H,
t), 3.48 (1H, m), 4.37 (2H, t), 5.47 (1H,
s), 7.02 to 8.16 (14H, m), 10.58 (1H, brs)

Examples 4 to 9 Example 4 shown in Tables 2 to 3 according to the method of Examples 1 to 3.
~ The compound of Example 9 was obtained. The name of each compound is as follows. In the table, R, m and B represent the compound (I) of the present invention.
Indicates the symbol inside. Example 4 2- [3- [4- (Diphenylmethoxy) -1-piperidinyl] propoxy] benzoic acid methyl ester Example 5 2- [3- [4- (Diphenylmethoxy) -1-piperidinyl] propoxy] ben Zoic Acid Example 6 2- [3- [4- (Diphenylmethoxy) -1-piperidinyl] propoxy] -N-1H-tetrazol-5-yl-benzamide Example 7 2- [2- [4-[(4 -Chlorophenyl) phenylmethoxy] -1-piperidinyl] ethoxy] benzoic acid methyl ester Example 8 2- [2- [4-[(4-chlorophenyl) phenylmethoxy] -1-piperidinyl] ethoxy] benzoic acid Example 9 2- [2- [4-[(4-chlorophenyl) phenylmethoxy] -1-piperidi Nyl] ethoxy] -N-1H-tetrazol-5-yl-benzamide

[0029]

[Table 2]

[0030]

[Table 3]

Formulation Example 1 Compound of Example 2 50 g Lactose 315 g Corn starch 125 g Crystalline cellulose 25 g The above ingredients were uniformly mixed, 200 ml of 7.5% hydroxypropylcellulose aqueous solution was added, and a 0.5 mm diameter screen was used by an extrusion granulator. To form granules, which were immediately rounded by a marumerizer and dried to give granules. 1.9 kg of a film coating solution having the following composition was coated on this dry granule using a fluidized bed granulator to give an enteric coated granule. Coating liquid composition: Hydroxypropyl methylcellulose phthalate 5.0 (w / w)% Stearic acid 0.25 (w / w)% Methylene chloride 50.0 (w / w)% Ethanol 44.75 (w / w)%

Formulation Example 2 Compound of Example 6 20 g Lactose 100 g Corn starch 36 g Crystalline cellulose 30 g Carboxymethyl cellulose calcium 10 g Magnesium stearate 4 g The ingredients of the above composition were uniformly mixed, and the diameter was measured with a single tableting machine.
A tablet of 200 mg was made with a 7.5 mm punch. Next, the tablets were spray-coated with a coating solution having the following composition, and each tablet was coated with 10 mg to give enteric film-coated tablets. Coating liquid composition: Hydroxypropylmethylcellulose tarate 8.0 (w / w)% Glycerin fatty acid ester 0.4 (w / w)% Methylene chloride 50.0 (w / w)% Salix beeswax 0.1 (w / w)% Isopropanol 41.5 (w / w) )%

Formulation Example 3 Compound of Example 9 0.1 (w / w)% Ethanol 20.0 (w / w)% Propellant 114 49.2 (w / w)% Propellant 12 30.7 (w / w)% It was made into an aerosol by the method.

[0034]

INDUSTRIAL APPLICABILITY As described above, the compound (I) of the present invention exhibits a strong antihistamine action and is highly safe. Therefore, excellent therapeutic agents for various allergic diseases such as anti-inflammatory agents, nephritis, hepatitis and It is useful as a therapeutic agent for pancreatitis, a preventive and / or therapeutic agent for respiratory diseases and an anti-asthma drug.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor, Akira Abe, Oshikiri, Konan-cho, Oza-gun, Saitama Prefecture 2512−1, Central Research Laboratory, Zeria Shinyaku Kogyo Co., Ltd. 2512-1 Zuma Shinyaku Kogyo Co., Ltd. Central Research Laboratory (72) Inventor Mihide Segawa Osamu Prefecture Konan-cho, Osato-gun Oshikiri Numazu 2512-1 Zeria Shinyaku Kogyo Co., Ltd. Central Research Center

Claims (4)

[Claims] 1. A compound represented by the general formula (I): (In the formula, m represents an integer of 2 to 5, R represents a hydrogen atom or a halogen atom, B represents a hydroxyl group, a lower alkoxy group, or Indicates. ) The diphenyl methoxy piperidine derivative and its salt represented by these. 2. An antihistamine agent containing the diphenylmethoxypiperidine derivative according to claim 1 as an active ingredient. 3. An anti-allergic agent comprising the diphenylmethoxypiperidine derivative according to claim 1 as an active ingredient. 4. The antiallergic agent according to claim 3, which is an antiasthma drug.