JPH05148234A - Alkanoic acid derivative - Google Patents

Abstract

PURPOSE:To provide the subject new compound having antihistaminic activity, thus useful as a therapeutic agent for bronchial asthma, allergic rhinitis, dermatosis, or urticaria. CONSTITUTION:A compound of formula I [X is H, halogen or lower alkoxy; Y and A are each CH or N; B is (lower alkyl-substituted)amino or formula II; Z is O or single bond; R is H or lower alkyl; (k) is 0-1; (m) is 0-2; (n) is 1-3; (p) is 0-3], e.g. 3-{4-[N-benzyl-N-phenyl)amino]piperidino}propionic acid. The compound of the formula I is obtained by reacting a compound of formula III with a compound of formula IV (W is halogen; R<1> is lower alkyl) in a solvent (e.g. THF) in the presence of a base such as triethylamine.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel alkanoic acid derivative having antihistamine and antiallergic effects and useful as a therapeutic agent for bronchial asthma, allergic rhinitis, skin diseases, urticaria, etc. The present invention relates to a pharmacologically acceptable salt.

[0002]

2. Description of the Related Art Conventionally, as an antihistamine according to the present invention, chlorpheniramine represented by the following formula [The Merck Index, 11th Edition, 2180]

[Chemical 3] And pyrilamine [Merck index,
(The MerckIndex), 11th edition, 7996]

[Chemical 4] Is commercially available and is used for the treatment of allergic rhinitis, skin diseases and the like.

[0003]

A number of antihistamines have been developed so far and are used for the treatment of allergic skin diseases and rhinitis, but they have a central inhibitory effect on sleepiness and sedation as a side effect. Is a big drawback,
Another drawback is that it has an anticholinergic effect that contributes to side effects such as dry mouth and mydriasis. Various studies have been made so far in order to eliminate these drawbacks, but the present situation is still not sufficient.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in view of the above circumstances, and as a result, found a compound having a strong antihistamine action and an antiallergic action, and having less side effects such as central inhibitory action, The present invention has been completed.

That is, the present invention has the following general formula (I):

[Chemical 5] (In the formula, X is a hydrogen atom, a halogen atom or a lower alkoxy group, Y is CH or N, A is CH or N, and B is an amino group which may be substituted with a lower alkyl group or the following formula:

[Chemical 6] , Z is an oxygen atom or a single bond, R is a hydrogen atom or a lower alkyl group, k is 0 to 1, and m is 0 to
2, n is an integer of 1 to 3, and p is an integer of 0 to 3. ), A novel alkanoic acid derivative represented by the formula (1) and a pharmacologically acceptable salt thereof.

In the general formula (I) of the present invention, the halogen atom represented by X is, for example, a fluorine, chlorine or bromine atom, and the lower alkoxy group is, for example, methoxy, ethoxy or n-propoxy. , Isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy groups and the like, examples of the amino group which may be substituted with a lower alkyl group represented by B include amino, methylamino and ethylamino. , N-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino and the like are lower alkyl groups represented by R, for example, methyl, ethyl, n-propyl. , Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl groups and the like.

The compound represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt, or a base or an acid can be liberated from the produced salt, if desired. ..

As the pharmacologically acceptable salt of the compound represented by the above general formula (I) of the present invention, an acid addition salt or an alkali addition salt is provided. Examples of the acid addition salt include hydrochloric acid and odor. Hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and other mineral salts,
Organic acid salts such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, oxalic acid, lactic acid, tartaric acid and the like, and examples of the alkali addition salt include metal salts such as sodium, potassium and calcium, ammonium salts. , Methylamine,
Examples thereof include salts of organic bases such as ethylamine, dimethylamine, triethylamine, ethanolamine, piperidine and piperazine.

The compound represented by the above general formula (I) of the present invention has one asymmetric carbon atom in some cases, and an optically active substance may exist, but the present invention also includes these compounds. It

The novel alkanoic acid derivative represented by the general formula (I) of the present invention can be produced as follows. That is, the following general formula (II)

[Chemical 7] (In the formula, X, Y, A, B, k and m have the same meanings as described above.), And a compound represented by the following general formula (III) W- (CH ₂ ) _n- Z- (CH ₂ ) _p -COOR 'or _{CH 2 = CHCOOR' (III)} ( wherein, the R 'is a lower alkyl group, W is a halogen atom, Z, n and p are represented by representative.) the same meaning as above It can be produced by reacting a compound with or without a solvent in the presence or absence of a base and, if necessary, hydrolyzing with an acid or a base in the solvent.

The solvent used in the alkylation reaction in the present production method may be any solvent as long as it does not inhibit the reaction, for example, benzene, toluene, tetrahydrofuran, dioxane, acetone, acetonitrile, methanol, ethanol, isopropanol, n-. Butanol, dimethyl sulfoxide, N, N-dimethylformamide and the like can be mentioned.

Examples of the base used include potassium carbonate, sodium carbonate, pyridine, triethylamine and the like, and the reaction is carried out in the range of 0 ° C to 200 ° C.

The acid used in the hydrolysis reaction is, for example, hydrochloric acid, sulfuric acid or the like, and the base is, for example,
For example, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate and the like can be used as the reaction solvent, for example, water, methanol, ethanol,
Acetone, tetrahydrofuran, etc. are mentioned, and the reaction is 0
It is carried out in the range of 100 ° C to 100 ° C.

The above general formula used as the starting material
Most of the compounds represented by (II) are the European Journal of Medicinal Chemistry (Eur.JM
ed. Chem), Vol. 22, p. 91 (1987) and the like, and the production methods thereof are described in Reference Examples.

The above-mentioned general formula (I) produced in this manner
The antiallergic agent containing the novel alkanoic acid derivative represented by and the pharmacologically acceptable salt thereof as an active ingredient can be administered orally or parenterally. Examples of the dosage form of the oral administration agent include tablets, capsules, powders, fine granules, granules, solutions and syrups, and the dosage form of the parenteral administration agent includes, for example, injections and suppositories. Agents, inhalants, eye drops, nasal drops, ointments and patches. For the preparation of these preparations, pharmacologically and pharmaceutically acceptable additives can be added, and excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, diluents Agents, bases, solubilizers or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants, adhesives, etc. are used.

In the oral preparation, transdermal preparation, and transmucosal preparation, as excipients, glucose, lactose, D-mannitol,
Starch, crystalline cellulose, etc., as disintegrants, disintegration aids, carboxymethyl cellulose, starch, carboxymethyl cellulose calcium, etc. as binders,
Hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, etc., lubricants such as magnesium stearate, talc, etc., coating agents such as hydroxypropylmethylcellulose, sucrose, titanium oxide, etc. as bases, vaseline, liquid Paraffin, polyethylene glycol, hard fat, etc., propellant, CFC, diethyl ether, compressed gas, etc., adhesive, sodium polyacrylate, polyvinyl alcohol, methyl cellulose, polyisobutylene, polybutene, etc. as base cloth,
Ingredients such as cotton cloth or plastic sheet are used as a dissolving agent or a solubilizing agent that can form an aqueous or injectable solution type injection agent in distilled water for injection, physiological saline, propylene glycol, etc. However, glucose, sodium chloride, D-mannitol, glycerin, etc. are used as isotonic agents, and pharmaceutical ingredients such as inorganic acids, organic acids or inorganic bases, organic bases, etc. are used as pH adjusters.

The dose of the compound of the present invention to a treated patient is 1 to 500 mg per day for oral administration, usually in adults.
The dose can be increased or decreased depending on the age, symptoms, etc.

[0018]

The present invention will be described below with reference to reference examples and examples, but the present invention is not limited to the specific details of these examples.

Reference Example 1 4-[(N-benzyl-N-phenyl) amino] -1-
Ethyl piperidinecarboxylate 4-[(N-benzyl-N-phenyl) amino] -1-
Methylpiperidine 13.8 g, ethyl chlorocarbonate 23.
A mixture of 4 ml and 110 ml of toluene was heated to reflux for 2 hours. A 20% aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with methylene chloride. The extract was washed with water and dehydrated, and the solvent was distilled off. The residue is recrystallized from acetone, mp 120-1
10.8 g of colorless crystals at 21 ° C. were obtained. Elemental analysis value C ₂₁ H ₂₆ N ₂ O ₂ theoretical value C, 74.53; H, 7.74; N, 8.28 experimental value C, 74.55; H, 7.78; N, 8.37

According to the method of Reference Example 1, Reference Examples 2 to 4
Was obtained.

Reference Example 2 [3- (4-chlorophenyl) -3- (2-pyridyl)]
Propyl] methyl ethyl carbamate Properties Light yellow liquid IR spectrum ν (liq) cm ^-1 : 1698 MS spectrum m / z: 332, 334 (3: 1, M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm 1.25 (3H, t, J = 7H
z), 2.16-2.34 (1H, m), 2.43-2.61 (1H, m), 2.90 (3H, s), 3.08
-3.31 (2H, m), 4.05 (1H, t, J = 7Hz), 4.12 (2H, t, J = 7Hz), 7.02
-7.19 (2H, m), 7.20-7.35 (4H, m), 7.52-7.63 (1H, m), 8.51-
8.61 (1H, m)

Reference Example 3 [2- [N- (4-Methoxybenzyl) -N- (2-pyridyl) amino] ethyl] methyl carbamate Properties colorless liquid IR spectrum ν (liq) cm ^-1 : 1698 MS spectrum m / z: 343 (M ⁺ ) NMR spectrum δ (DMSO-d ₆ ) ppm: 1.11 (3H, t, J =
7Hz), 2.80 (3H, s), 3.36 (2H, t, J = 6.5Hz), 3.61 (2H, t, J = 6.5
Hz), 3.71 (3H, s), 3.97 (2H, q, J = 7Hz), 4.64 (2H, s), 6.50-6.
66 (2H, m), 6.85 (2H, d, J = 8.5Hz), 7.14 (2H, d, J = 8.5Hz), 7.3
9-7.48 (1H, m), 8.03-8.10 (1H, m)

Reference Example 4 4-[[N- (4-chlorobenzyl) -N-phenyl]
Amino] -1-piperidinecarboxylic acid ethyl hydrochloride hydrochloride Properties colorless prism crystals (acetone) Melting point 136-138 ° C Elemental analysis C ₂₁ H ₂₅ ClN ₂ O ₂ · HCl Theoretical C, 61.62; H, 6.40; N, 6.84 Experimental value C, 61.56; H, 6.36; N, 6.72

Reference Example 5 4-[(N-benzyl-N-phenyl) amino] piperidine 4-[(N-benzyl-N-phenyl) amino] -1-
A mixture of 9.50 g of ethyl piperidinecarboxylate, 6.62 g of potassium hydroxide and 40 ml of n-butanol was added to 1.
The mixture was heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, acidified with 10% hydrochloric acid, and then washed with isopropyl ether. The aqueous layer was made alkaline with potassium carbonate and then extracted with methylene chloride. After dehydrating the extract, the solvent was distilled off. The residue is recrystallized from ethyl acetate, melting point 11
2.09 g of pale brown prism crystals at 9 to 120 ° C. were obtained. Elemental analysis value C ₁₈ H ₂₂ N ₂ theoretical value C, 81.16; H, 8.32; N, 10.52 experimental value C, 81.30; H, 8.48; N, 10.52

According to the method of Reference Example 5, Reference Examples 6 to 8
Was obtained.

Reference Example 6 2- [4-chloro-α- [2- (methylamino) ethyl] benzyl] pyridine Properties Light yellow liquid IR spectrum ν (liq) cm ^-1 : 1592 MS spectrum m / z: 260, 262 (3: 1, M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 2.23-2.70 (4H,
m), 2.45 (3H, s), 3.79 (1H, s), 4.20 (1H, t, J = 7.5Hz), 7.03-
7.17 (2H, m), 7.25 (4H, s), 7.50-7.62 (1H, m), 8.51-8.60 (1
H, m)

Reference Example 7 2- [N-[(2-methylamino) ethyl] -N- (4
-Methoxybenzyl) amino] pyridine Properties colorless liquid IR spectrum ν (liq) cm ^-1 : 3320 MS spectrum m / z: 271 (M ⁺ ) NMR spectrum δ (CDCl ₃ ) ppm: 1.88 (1H, s), 2.4
3 (3H, s), 2.82 (2H, t, J = 6.5Hz), 3.68 (2H, t, J = 6.5Hz), 3.77
(3H, s), 4.70 (2H, s), 6.46-6.59 (2H, m), 6.83 (2H, d, J = 9H
z), 7.14 (2H, d, J = 9Hz), 7.34-7.44 (1H, m), 8.12-8.18 (1H,
m)

Reference Example 8 4-[[N- (4-chlorobenzyl) -N-phenyl]
Amino] piperidine Properties Light yellow prismatic crystal (AcOEt) Melting point 147-149 ° C Elemental analysis value C ₁₈ H ₂₁ ClN ₂ theoretical value C, 71.87; H, 7.04; N, 9.31 experimental value C, 71.56; H, 7.11; N, 9.13

Example 1 3- [4-[(N-benzyl-N-phenyl) amino]
A mixture of 4-[(N-benzyl-N-phenyl) amino] piperidine piperidino] propionic acid 1.49 g, ethyl acrylate 0.8 ml and ethanol 4.7 ml was heated under reflux for 30 minutes. To the reaction solution was added 6.4 ml of 2N sodium hydroxide aqueous solution, and the mixture was heated under reflux for 1 hour. The solvent was distilled off under reduced pressure and the pH was adjusted to 10% with hydrochloric acid.
After adjusting to about 7, precipitated crystals were collected by filtration. The crystals were washed with water and recrystallized from a mixed solution of ethanol and isopropyl ether to give 1.80 g of slightly orange crystals having a melting point of 110 to 113 ° C. Elemental analysis value C ₂₁ H ₂₆ N ₂ O ₂ · 2H ₂ O theoretical value C, 67.35; H, 8.07; N, 7.48 experimental value C, 67.46; H, 7.70; N, 7.51

In accordance with the method of Example 1, Examples 2 to 4
Was obtained.

Example 2 3- [N- [3- (4-chlorophenyl) -3- (2-
Pyridyl) propyl] -N-methylamino] propionic acid Properties slightly yellow liquid IR spectrum ν (liq) cm ⁻¹ : 1594 NMR spectrum δ (CDCl ₃ ) ppm ： 2.22-2.70 (6H,
m), 2.47 (3H, s), 2.83 (2H, t, J = 6Hz), 4.06 (1H, t, J = 7Hz), 7.
09-7.18 (2H, m), 7.26 (4H, s), 7.55-7.64 (1H, m), 8.56-8.62
(1H, m), 8.70 (1H, br)

Example 3 3- [N- [2- [N '-(4-methoxybenzyl)-]
N '- (2-pyridyl) amino] ethyl] -N- methylamino] propionate properties colorless prisms (AcOEt) mp 105-106 ° C. Elemental analysis C ₁₉ H ₂₅ N ₃ O ₃ theory C, 66.45; H , 7.34; N, 12.24 Experimental value C, 66.47; H, 7.35; N, 12.16

Example 4 3- [4-[[N- (4-chlorobenzyl) -N-phenyl] amino] piperidino] propionic acid Properties Colorless crystals (AcOEt) Melting point 141-142 ° C. Elemental analysis C ₂₁ H ₂₅ ClN ₂ O ₂ · 3 / 4H ₂ O theoretical value C, 65.28; H, 6.91; N, 7.25 experimental value C, 65.37; H, 6.93; N, 7.22

Example 5 Methyl 2- [4-[[N- (4-chlorobenzyl) -N-phenyl] amino] piperidino] ethoxyacetate 4- [N- (4-chlorobenzyl) -N-phenyl] amino ] Piperidine 3.00 g, methyl 2-chloroethoxyacetate 3.04 g, potassium carbonate 1.38 g and N, N
A mixture of 20 ml of dimethylformamide was heated and stirred at 80 ° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with diisopropyl ether. The diisopropyl ether layer was extracted with hydrochloric acid, the aqueous layer was made alkaline with potassium carbonate, and extracted with methylene chloride. The extract was evaporated under reduced pressure, and the obtained residue was treated with column chromatography (silica gel, methylene chloride-methanol) to give pale brown crystals 2.6.
7 g was obtained. Recrystallization from a mixed solution of ethyl acetate and diisopropyl ether gave 2.05 g of pale yellow needle crystals having a melting point of 89.5 to 90.5 ° C. Elemental analysis value C ₂₃ H ₂₉ ClN ₂ O ₃ theoretical value C, 66.26; H, 7.01; N, 6.72 experimental value C, 66.23; H, 6.88; N, 6.72

Example 6 2- [4-[[N- (4-chlorobenzyl) -N-phenyl] amino] piperidino] ethoxyacetic acid 2- [4-[[N- (4-chlorobenzyl) -N-] Methyl phenyl] amino] piperidino] ethoxyacetate 1.9
A mixture of 0 g, 4.5 ml of 2N aqueous sodium hydroxide solution and 19 ml of methanol was refluxed for 1 hour. After distilling off the solvent under reduced pressure, 10% hydrochloric acid was added to the residue to adjust the liquidity to pH 7, the precipitated crystals were collected by filtration, and recrystallized from ethanol to give pale brown needles having a melting point of 115.5 to 117 ° C. 1.54 g of crystals were obtained. Elemental analysis _{C 22 H 27 ClN 2 O 3} · 2H 2 O Theoretical value C, 60.20; H, 7.12; N, 6.38 Found C, 60.09; H, 7.07; N, 6.44

[0036]

INDUSTRIAL APPLICABILITY The novel alkanoic acid derivative represented by the general formula (I) and the pharmacologically acceptable salt thereof of the present invention have excellent antihistamine activity and antiallergic activity and, in addition, have a central activity. Since it has no inhibitory effect, it is extremely useful as a therapeutic agent for various allergic diseases and bronchial asthma.

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Claims (1)

[Claims] 1. The following general formula: (In the formula, X is a hydrogen atom, a halogen atom or a lower alkoxy group, Y is CH or N, A is CH or N, and B is an amino group which may be substituted with a lower alkyl group or the following formula: 2] , Z is an oxygen atom or a single bond, R is a hydrogen atom or a lower alkyl group, k is 0 to 1, and m is 0 to
2, n is an integer of 1 to 3, and p is an integer of 0 to 3. ) An alkanoic acid derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof.