JPH04257582A - Quinolidinone compound and its salt - Google Patents

Abstract

PURPOSE:To obtain a new quinoline compound having inhibitory action on allergy and ulcer. CONSTITUTION:A compound shown by the formula (R<1> is hydroxyaryl; R<2> is amidated carboxy) and a salt thereof such as N-(1H-tetrazol-5-yl)-1-(4- methoxyphenoxy)-4H-quinolizin-4-one-3-carboxamide. The compound shown by formula is obtained by reacting 2-chloromethylpyrimidine hydrochloride with 4-methoxyphenol and potassium carbonate in a solvent under heating to give 2-(4-methoxyphenoxymethyl) pyridin, then obtaining a yellow solid substance of 1-(4-methoxyphenoxy)-4H-quinolizin-4-one-3-carboxylic acid from 2-(4- methoxyphenoxymethyl)pyridine, suspending the yellow solid substance in a solvent, adding 1,1'-carbonyldiimidazole and further 5-amino-1H-tetrazole to the suspension to give the objective compound.

Description

[Detailed description of the invention]

0001

FIELD OF INDUSTRIAL APPLICATION This invention relates to quinolidinone compounds or salts thereof, and more particularly, this invention relates to novel quinolidinone compounds or salts thereof having inhibitory activity against allergies and ulcers.

0002

[Structure of the Invention] The quinolidinone compound of this invention has the following formula (
It can be shown as I). (In the formula, R1 means a hydroxyaryl group, and R2 means an amidated carboxy group.) The target compound (I) can be produced by a conventional method, for example, by subjecting the alkoxyaryl group in R1 to a deetherification reaction. Ru.

For conditions such as reagents, solvents, and reaction temperatures to be used in the production of the target compound (I), reference may be made to, for example, the production examples and examples described later. Suitable salts of the object compound (I) include pharmaceutically acceptable salts, especially the commonly used non-toxic salts, such as alkali metal salts such as sodium salts, potassium salts, and alkali metal salts such as calcium salts, magnesium salts, etc. Metal salts such as earth metal salts, ammonium salts, such as triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, organic base salts such as N,N'-dibenzylethylenediamine salts, such as hydrochlorides, hydrobromic acid Inorganic acid salts such as salts, sulfates, phosphates, such as formates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, P
-Organic acid salts such as toluene sulfonate, arginine salts,
Examples include salts with amino acids such as aspartate and glutamate.

Suitable "hydroxyaryl groups" include hydroxyphenyl, hydroxytolyl, hydroxyxylyl, hydroxycumenyl, hydroxynaphthyl,
Examples include hydroxybiphenyl.

[0005] A suitable "amidated carboxy group" includes an amide (-CONH2) which may have a suitable substituent on the nitrogen atom, and suitable substituents include the following suitable substituents. Examples include a heterocyclic group which may have a substituent. More specifically, the term "heterocyclic group" refers to a saturated or unsaturated heterocyclic group or a heteropolycyclic group containing at least one heteroatom such as an oxygen atom, a sulfur atom, a nitrogen atom, or the like. Particularly preferred heterocyclic groups include unsaturated 3 to 8 heterocyclic groups containing 1 to 4 nitrogen atoms.
more preferably 5- or 6-membered heteromonocyclic groups, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxides, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, e.g.
Triazolyl such as H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, tetrazolyl such as 1H-tetrazolyl, 2H-tetrazolyl, e.g. 1,2, Triazinyl, such as 3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, etc.: saturated 3- to 8-membered, more preferably 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms , such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;

Unsaturated fused heterocyclic groups containing 1 to 4 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,
Indazolyl, benzotriazolyl, etc.: unsaturated 3- to 8-membered, containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms;
More preferably 5- or 6-membered heteromonocyclic groups, such as oxazolyl, isoxazolyl, such as 1,2,
Oxadiazolyl, such as 4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.: saturated 3- to 8-membered, more preferably containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; 5- or 6-membered heteromonocyclic groups, such as morpholinyl, sydononyl, etc.: unsaturated fused heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as benzoxazolyl, benzoxadiazolyl, etc. : unsaturated 3- to 8-membered, more preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, examples of which include thiazolyl, isothiazolyl, e.g. 1,2,3 -thiadiazolyl, 1,2,4
-thiadiazolyl, 1,3,4-thiadiazolyl, 1,
Thiadiazolyl such as 2,5-thiadiazolyl, dihydrothiazinyl, etc.:

Saturated 3- to 8-membered, more preferably 5- or 6-membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolidinyl: containing 3 to 8 unsaturated members, more preferably 5
or a 6-membered heteromonocyclic group, such as thienyl, dihydrodithienyl, dihydrodithionyl, etc.: an unsaturated fused heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms,
For example, benzothiazolyl, benzothiadiazolyl, etc.: unsaturated 3- to 8-membered, more preferably 5- or 6-membered heteromonocyclic group containing one oxygen atom, such as furyl, etc.: one oxygen atom and 1 to 2 Unsaturated 3-8 containing sulfur atoms
members, more preferably 5- or 6-membered heteromonocyclic groups, such as dihydroxathinyl: unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms, such as benzothienyl, benzodithiinyl, etc.: 1 oxygen atom and Examples include unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms, such as benzoxathinyl, and these "heterocyclic groups" include halogens such as chlorine, bromine, iodine or fluorine, For example, it may have one or more suitable substituents such as lower alkyl groups such as methyl, ethyl, propyl and the like.

In order to demonstrate the pharmacological usefulness of the quinolidinone compound (1), the results of pharmacological tests will be explained below. (1) Test compound N-(1H-tetrazol-5-yl)-1-(4-hydroxyphenoxy)-4H-quinolizin-4-one-3-carboxamide sodium salt (2) Test passive cutaneous anaphylaxis (PCA) effect on

0
[1] Test method PCA reaction Test subjects: 8 weeks old, weight 286-3
15 g male Sprague-Dury rats (manufactured by Japan SLC) were used. Five animals were observed for each experiment. 5
Double-crystallized ovalbumin (Seikagaku Corporation Lot P89301) was used as the antigen. Ovalbumin saline solution at 1.25 mg/ml/mouse was subcutaneously administered to 8-week-old male Sprague-Dury rats, and at the same time, killed bacteria pertussis adjuvant (manufactured by Kaken Pharmaceutical Co., Ltd.) (3.2 x 10
10 cells/1.6 μl/mouse) was administered intraperitoneally for sensitization. Blood was collected after 8 days, and the serum containing 60 times the PCA titer was used as an antiserum and stored at -80°C. The hair of the animals was shaved in advance with an electric razor, and 0.1 ml of rat antiserum dilution (1/32) was intradermally injected into each side of the back skin for passive sensitization. These were then treated with 0.5% Evans blue (1 ml) containing ovalbumin (5 ml) after 48 hours.
was injected intravenously to induce a passive cutaneous anaphylactic reaction. After 60 minutes, they were sacrificed and the pigment of the lesion was extracted. The activity of the drug was evaluated using the following formula. The drug was dissolved in physiological saline and administered intravenously along with the antigen.

[2] Test results

[0011] The present invention will be explained below according to production examples and examples. Production example 1 2-chloromethylpyridine hydrochloride (3.39g), 4-
Methoxyphenol (2.56 g) and potassium carbonate (8.56 g) were dissolved in N,N-dimethylformamide (25 g).
ml) and heat at 80°C for 4 hours. The mixture is cooled to room temperature, water is added and then extracted with methylene chloride. The extract was washed with saturated brine, dried, and the solvent was distilled off.
The residue was subjected to column chromatography on silica gel using a mixture of n-hexane and ethyl acetate (1:
Elution with 1) gives 2-(4-methoxyphenoxymethyl)pyridine (3.89 g) as an oil. mp: 35-37.5°C NMR (CDCl3, δ): 3.77 (3H, s), 5
．． 19 (2H, s), 6.78-7.0 (4H, m),
7.24 (1H, m), 7.53 (1H, d, J = 8H
z), 7.74 (1H, dt, J=2Hz and 8Hz
), 8.58 (1H, m)

Production Example 2 2-(4-methoxyphenoxymethyl)pyridine (28
．． A solution of 9 g) in dry tetrahydrofuran (400 ml) is cooled to -60°C and a 1.6 molar solution of n-butyllithium in n-hexane (92.5 ml) is added. The reaction solution is gradually raised to -20°C. After cooling to -60°C, a complex of cuprous bromide and dimethyl sulfide (31
．． 7g). The reaction solution was heated to -20°C, and dimethyl ethoxymethylene malonate (29.8 ml) was added dropwise. After the dropwise addition, the temperature is gradually raised to 0°C, an aqueous ammonium chloride solution is added, insoluble matter is filtered off, the solvent of the filtrate is distilled off, diluted aqueous ammonia is added to the residue, and the mixture is extracted with chloroform. The extract is washed with water, dried and the solvent is evaporated. The residue was subjected to column chromatography using silica gel, and a mixture of n-hexane and ethyl acetate (
1:1) to give 3-ethoxy-2-ethoxycarbonyl-4-(4-methoxyphenoxy)-4-(2-
Ethyl pyridylbutyrate (56.2 g) is obtained as an oil.

Production Example 3 Ethyl 3-ethoxy-2-ethoxycarbonyl-4-(4-methoxyphenoxy)-4-(2-pyridyl)butyrate (56.2 g) and 1,8-diazabicyclo[5.4.0
] Unde-7-ene (22.4 ml) was dissolved in toluene (30 ml).
0 ml) and reflux for 4.5 hours. After cooling, the mixture is diluted with ethyl acetate, washed successively with water, diluted hydrochloric acid, water and an aqueous sodium bicarbonate solution, dried, and the solvent is distilled off. The oily residue was dissolved and treated with activated charcoal to give 3-ethoxycarbonyl-1-(4-methoxyphenoxy)-4H-quinolidin-4-one (53 g) as a crude oil. NMR (CDCl3, δ): 1.41 (3H, t, J=
7Ht), 3.79 (3H, s), 4.40 (2H, q
, J=7Hz), 6.8-6.95 (4H, m), 7.
25 (1H, m), 7.54 (1H, m), 7.92 (
1H, m), 8.23 (1H, s), 9.48 (1H,
m)

Production Example 4 Crude 3-ethoxycarbonyl-1-(4-methoxyphenoxy)-4H-quinolidin-4-one (53 g) was dissolved in methanol, an aqueous solution (220 ml) of sodium hydroxide (21 g) was added, Reflux for 1.5 hours. After cooling,
Diluted with water, adjusted to pH 1-2 with concentrated hydrochloric acid, stirred the formed solid, collected by filtration, washed with water and methanol,
1-(4-methoxyphenoxy)-4H-quinolidine-
4-one-3-carboxylic acid (29.7 g) is obtained as a yellow solid. mp 175-178°C NMR (DMSO-d6, δ): 3.76 (3H, s)
, 6.94 (2H, m), 7.08 (2H, m), 7.
76 (1H, dt, J=2Hz and 7Hz), 7.9
6 (1H, s), 8.05-8.25 (2H, m), 9
．． 39 (1H, d, J=7Hz)

Example 1 1-(4-methoxyphenoxy)-4H-quinolidine-
4-one-3-carboxylic acid (13.4 g) was suspended in N,N-dimethylformamide (110 ml) with stirring, and 1,1'-carbonyldiimidazole (8.56 g) was added.
and heated at room temperature for 20 minutes and then at 100°C for 30 minutes. 5-Amino-1H-tetrazole (4.02 g) is added in one portion to the solution containing the active ester at 100°C. Solids formed so additional N,N-dimethylformamide (30 ml) was added and stirred for an additional 40 minutes. The pH was adjusted to 2 with concentrated hydrochloric acid while cooling on ice, and the precipitate formed was collected by filtration and washed successively with water and ethanol. N-(
1H-tetrazol-5-yl)-1-(4-methoxyphenoxy)-4H-quinolidin-4-one-3-carboxamide (15.0 g) is obtained. mp>250°C NMR (DMSO-d6, δ): 3.75 (3H, s)
, 6.96 (2H, m), 7.09 (2H, m), 7.
85 (1H, m) 8.0-8.1 (3H, m), 9
．． 51 (1H, d, J = 7Hz), 13.3 (1H, s
)

Example 2 N-(1H-tetrazol-5-yl)-1-(4-methoxyphenoxy)-4H-quinolidin-4-one-3
- Carboxamide (15.0 g) was suspended in N,N-dimethylformamide (120 ml), triethylamine (7.2 ml) and trityl chloride (12.2 g)
were added sequentially and stirred at 50°C for 1.5 hours. After cooling, an aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the precipitate is collected by filtration. This precipitate is dissolved in chloroform, washed with an aqueous sodium hydrogen carbonate solution, dried, and then the solvent is distilled off. The residue was subjected to column chromatography using alumina and a mixture of methylene chloride and ethyl acetate (9:
1), N-(1-trityl-1H-tetrazol-5-yl)-1-(4-methoxyphenoxy)-
4H-quinolidin-4-one-3-carboxamide (2
4.0 g) is obtained. mp: 175-178°C NMR (CDCl3, δ): 3.79 (3H, s), 6
．． 8-7.0 (4H, m), 7.1-7.45 (16H
, m), 7.72 (1H, m), 8.12 (1H, d,
J = 9Hz), 8.53 (1H, s), 9.43 (1H
, d, J=7Hz)

Example 3 Aluminum chloride (16.5 g) and ethanethiol (1
N-(1-trityl-1H-tetrazol-5-yl)-1-(4-methoxyphenoxy)-4H-quinolidin-4-one-3- was added to a solution of methylene chloride (200 ml) of 8 ml) under ice cooling. A solution of carboxamide (15 g) in methylene chloride is added dropwise over 10 minutes. After dropping, 1.
Stir vigorously for 5 hours. The mixture was then treated with 3N hydrochloric acid under ice-cooling, heated and stirred in a 50°C water bath, and methylene chloride and ethanethiol were distilled off. The solid matter produced was collected by filtration, and water,
Washed with ethanol and diethyl ether, N-(1
H-tetrazol-5-yl)-1-(4-hydroxyphenoxy)-4H-quinolidin-4-one-3-carboxamide (7.82 g) is obtained. mp>250°C NMR (DMSO-d6, δ): 6.77 (2H, s)
, 6.97 (2H, m), 7.75 (1H, m), 80
5-8.2 (3H, m) 9.35 (1H, s), 9.4
8 (1H, d, J=7Hz)

Example 4 N-(1H-tetrazol-5-yl)-1-(4-hydroxyphenoxy-4H-quinolidin-4-one-
3-carboxamide (3.81 g) was suspended in water (80 ml), and 1N aqueous sodium hydroxide solution (10.4 ml) was added.
Add and dissolve by heating at 80°C. Insoluble materials are removed by filtration, the filtrate is allowed to stand under ice cooling, and the precipitate formed is collected by filtration. After washing with cold water and drying, the sodium salt of N-(1H-tetrazol-5-yl)-1-(4-hydroxyphenoxy)-4H-quinolidin-4-one-3-carboxamide (2.21 g) is obtained. . mp>250°C NMR (DMSO-d6, δ): 6.76 (2H, m)
, 6.95 (2H, m), 7.64 (1H, dt, J=
2Hz and 7Hz), 8.00 (1H, m), 8
．． 13 (1H, d, J = 7Hz), 8.21 (1H, s
), 9.38-9.45 (2H, m), 12.21 (1
H,s)

Claims (1)

[Claims] 1. A quinolidinone compound or a salt thereof represented by the general formula: (wherein R1 means a hydroxyaryl group and R2 means an amidated carboxy group, respectively).