JPH0446952B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the following general formula [] The present invention relates to a 4-quinolone derivative represented by, salts thereof, and pharmaceuticals. In the formula, R ¹ and R ² are the same or different and represent hydrogen, lower alkyl having 1 to 8 carbon atoms, or lower alkenyl having 2 to 4 carbon atoms,
^R3 is hydrogen, lower alkyl having 1 to 8 carbon atoms, lower alkenyl having 2 to 4 carbon atoms, aralkyl having 7 to 9 carbon atoms, lower alkyl having a chain length of 1 to 8 having 1 to 2 hydroxyl groups, and 1 ether bond. ~2 lower alkyl having 10 carbon atoms and optionally substituted with a hydroxyl group,
or -( _CH2 )nA (n=1-3, A is an acetyl group,
It represents an acetyloxy group, an alkoxycarbonyl group having 2 to 4 carbon atoms, an alkoxycarbonylacetyl group having 4 to 7 carbon atoms, a cyano group, or a phenoxy group. ) represents. Z is a phenyl group with or without one or more substituents (herein, the substituents are hydrogen, halogen, lower alkyl having 1 to 8 carbon atoms, halogenated lower alkyl having 1 to 3 carbon atoms, 1 to 3 carbon atoms, ~4 lower alkoxy, or
COOR ⁴ (R ⁴ represents hydrogen or lower alkyl having 1 to 4 carbon atoms). ), pyridyl, furyl or thienyl. The compound of the present invention has antiallergic action, expectorant action, platelet aggregation inhibitory action, etc., and is an antiallergic agent, antitussive expectorant, antithrombotic agent, etc. for animals including humans.
It is useful as a medicine such as an asthma treatment. This compound has superior characteristics compared to similar compounds to date, such as being able to be administered orally and having a long duration of efficacy. Sodium cromoglycate, which has been developed in recent years, is
Kotkus et al. reported that it is effective for allergic asthma (Adv. in Drug Res., 5 , 115
(1970)). This compound is thought to inhibit the release of chemical mediators from mast cells.
However, this compound did not exhibit any medicinal efficacy when administered orally, and had the disadvantage of having a short duration of medicinal action. However, in recent years, it has become one of the chemical mediators. slow reacting substance of
As it became clear that anaphylaxis (SRS-A) plays a major role during asthma attacks, SRS
It has been desired to develop a specific drug that antagonizes the action of -A and has biosynthesis inhibiting action. In view of the above, the inventors of the present invention have finally arrived at the present invention as a result of intensive research to find a drug that has an SRS-A antagonistic effect and a synthesis inhibitory effect. In this specification, examples of lower alkyl include methyl, ethyl, propyl, isopropyl,
Examples include butyl, pentyl, hexyl, heptyl, octyl, and the like, and examples of lower alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy. Examples of alkenyl include vinyl, allyl, etc., and examples of aralkyl include,
Contains benzyl, phenethyl, etc. Halogen represents fluorine, chlorine, bromine, and iodine. Examples of the substituent represented by Z include, in addition to phenyl, 2-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 2-iodophenyl, 2,4-dichlorophenyl, 3, 4-dichlorophenyl, 2,5-dichlorophenyl, o-tolyl, p-tolyl, 2-ethylphenyl, 4-isopropylphenyl, 4-n-pentylphenyl, 2,4-dimethylphenyl, 3-trifluoromethylphenyl enyl, 2-methoxyphenyl, 4-
Methoxyphenyl, 2-ethoxyphenyl, 2-
Examples include isopropoxyphenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 4-carboxyphenyl, 4-methoxycarbonylphenyl, and further examples include pyrrolyl, pyrrolinyl, pyridyl, furyl, Examples include thienyl. Compound [] is expressed as a 4-quinolone for convenience, but when R ¹ is hydrogen, it includes the following tautomers. The 4-quinolone derivative of the present invention has the general formula [] [In the formula, R ² , R ³ , and Z are the same as above. R ⁵ is lower alkyl (e.g. methyl, ethyl, propyl, etc.)
shows. ] or its tautomer by subjecting it to a ring-closing reaction. The reaction is carried out in a suitable solvent (high boiling point solvent such as dichlorobenzene, tetralin, diphenyl ether, diethylene glycol methyl ether) by heating for 30 minutes to 10 hours. In the compound of general formula [], R ¹ is lower alkyl,
In the case of alkenyl, the 4-
Lower alkyl halides, dialkyl sulfates,
Alternatively, it can be obtained by reacting with alkenyl halide. Examples of the alkyl halide used in this alkylation include methyl iodide, ethyl iodide, methyl bromide, ethyl bromide, propyl bromide, and butyl bromide. Further, examples of the dialkyl sulfuric acid used include dimethyl sulfuric acid, diethyl sulfuric acid, and the like. Furthermore, examples of the alkenyl halide used for alkenylation include vinyl bromide and allyl bromide. Examples of the base or deoxidizing agent used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium alkoxide, and sodium hydride. The reaction is carried out in a suitable solvent (tetrahydrofuran, dioxane, toluene, xylene, dimethylformamide, dimethyl sulfoxide, etc.) at 50 to 120 °C.
This is done by heating at ℃ for 30 minutes to 10 hours. A compound represented by the general formula [] is a compound represented by the general formula [] [In the formula, Z, R ₂ and R ⁵ are the same as above. ] and the general formula [] [In the formula, R ³ is the same as above. It can be obtained by condensing aminobenzoic esters represented by The reaction is carried out in a suitable solvent (benzene, toluene, chloroform, etc.) in the presence of a catalytic amount of acid (p-toluenesulfonic acid, benzenesulfonic acid, sulfuric acid, hydrochloric acid, etc.) for 1 to 3 days, followed by Dean Stark reaction. It can be obtained by dehydration using a device described above, or by heating under reflux in ethanol for 1 to 3 days in the presence of active anhydrous calcium sulfate. In the general formula [], when R ² is lower alkyl or alkenyl, the general formula [] ZCOCH ₂ COOR ⁵ [] [in the formula, Z and R ⁵ are the same as above. ] with an alkyl halide or an alkenyl halide in the presence of a base. The reaction was carried out using an appropriate solvent (benzene, toluene, tetrahydrofuran, methanol, ethanol, dimethylformamide,
acetonitrile, etc.), using sodium hydride, sodium alkoxide, etc. as a base to prepare an alkyl halide (e.g., methyl iodide, ethyl iodide, methyl bromide, ethyl bromide,
Propyl bromide, butyl bromide, etc.) or alkenyl halides (e.g. vinyl bromide, allyl bromide, etc.) are reacted with the reaction mixture, and the mixture is stirred at -5 to 80°C for 30 minutes to 5 hours. The benzoyl (heterocyclic carbonyl) acetate derivative used as a starting material in the above reaction is partly a known compound and partly a new compound. The compound represented by the general formula [] is the general formula [] ZCOCH ₃ [] [wherein Z is the same as above. ) is synthesized by reacting a dialkyl carbonate, such as dimethyl carbonate, diethyl carbonate, etc., with an acetyl compound represented by ] in the presence of a base, such as sodium hydride, sodium amide, etc., in a suitable solvent, such as ether, tetrahydrofuran, etc. , or
The acetic acid ester is reacted with n-butyllithium in the presence of cyclohexylisopropylamine, and then the general formula [] ZCOCl [] [In the formula, Z is the same as above. It can also be synthesized by reacting the acid chloride represented by ] in a suitable solvent such as ether or tetrahydrofuran. Other methods include reacting acetoacetate with an acid chloride represented by the general formula [ ] in the presence of a base in a suitable solvent, such as water or tetrahydrofuran, and deacetylating it with ammonium chloride, or adding benzoic acid to an alkali metal salt of acetoacetate. It can also be synthesized by a method in which esters are reacted and then deacetylated. The 4-quinolone derivative obtained as described above can be easily isolated and purified by conventional methods such as recrystallization and chromatography. Of the compounds of the present invention thus produced, R ³
Compounds in which is hydrogen can readily form salts with common pharmaceutically acceptable basic compounds. Examples of the basic compound include inorganic basic compounds such as sodium hydroxide, potassium hydroxide, potassium aluminum hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate, morpholine, and piperazine. , thiomorpholine, triethylamine, and other organic base compounds. On the other hand, when possible, salts with mineral acids and organic acids are included (e.g. 2-(2-chlorophenyl)-4
-hydroxyquinoline-8-carboxylic acid ethyl hydrochloride). [In the formula, R ¹ , R ² , R ³ , R ⁵ and Z are the same as above. X
indicates halogen. ] In addition, the compound represented by the general formula [ ] can also be synthesized by the following method. The compound according to the present invention has an anti-allergic effect, so it can be used for bronchial asthma, hay fever (nasal allergy), etc.
It may be possible to administer it to urticaria and atopic dermatitis. Furthermore, since it has anti-inflammatory effects, it can be administered to patients suffering from chronic rheumatoid arthritis, postoperative pain, osteoarthritis, low back pain, shoulder periarthritis, cervicobrachial syndrome, acute upper respiratory tract inflammation, toothache, and menstrual pain. Furthermore, since it has a platelet aggregation inhibiting effect, it is considered to be effective for various diseases caused by platelet hyperaggregation. The efficacy of the compound of the present invention as an antiallergic agent was determined by a passive skin hypersensitivity test (PCA) in rats.
The anti-SRS-A effect was evaluated using the ileum of guinea pigs. Test method 1 (PCA) () Antiserum rich in homocytotropic antibodies was prepared in a manner similar to that performed by Tada and Okumura [J. Immunol. Vol. 106 (1971), 1002
See page]. Specifically, Wistar rats weighing 180-200 g were tested by Strejan and Campbell [J.
Immunol. vol. 98 (1967), p. 893] and
Eisen [J.Am.Chem.Soc. vol. 75 (1953), 4593
DNP-As (2,
4-dinitrophenyl-coupledascaris extract)
1 mg (as protein) and 1x pertussis vaccine
10 ¹⁰ pieces were administered into the footpad in 4 minutes. again in 5 days
0.5 mg of DNP-As was administered alone into the back muscle. On the 8th day after the first immunization, blood was collected from the descending aorta under ether anesthesia, and the obtained serum was stored at -80°C and liquefied before use. () The effects of the test compounds were investigated as follows. The antiserum obtained by the method in () was diluted several times with physiological saline, and 0.05 ml of each dilution was added to the body weight.
It was administered to the dorsal cortex of 140-160 g Wistar rats. 2 mg DNP-As as protein amount after 72 hours
and Evans blue (2.5 mg) dissolved in 1 ml of physiological saline was administered intravenously at a rate of 5 ml/Kg. The animals were sacrificed 30 minutes after the administration of the antigen solution, and the diameter of the blue spot that appeared at the site where the antiserum was administered was measured. Follow the same method as above using a diluted antiserum that always shows spots of 10 mm or more.
A PCA test was conducted to determine the effectiveness of the test compound. That is, a diluted antiserum solution was administered to two locations on the back. The test compound was administered at 10 mg/hour for each hour of antigen solution administration.
Kg was administered orally. The method of Beack and Steinetz [J.Pharmacol.
exp Ther, Vol. 131 (1961, p. 400)], the leaked pigment was extracted and the amount of pigment was measured. Inhibition rate = (1-A'/A) x 100 where A' represents the amount of dye in the test compound treated group, and A represents the amount of dye in the control group. Test method 2 Anti-SRS-A (Slow Reacting Substance of
Immediately after slaughtering male Hartley guinea pigs weighing 300 to 350 g, the ileum of 1.0 cm to 1.5 cm was removed from the ileocecal region and treated with atropine 10 ^-7 g/ml and pyrilamine.
¹⁰ ml Tyrode's solution (95% O ₂ ,
5% _CO2 saturation). SRS-A (histamine) 5n produced using sensitized guinea pig lungs
The antagonistic effect of the test compound treated 5 minutes before the contraction induced by applying 20 units of SRS-A (1 unit is the amount of SRS-A that exhibits contraction equal to g) was measured using an isotonic transducer. Recorded and measured. Inhibition rate (%) of test compound = (1-A'/A) x 100, where A' is the contraction height of test compound + SRS-A,
A was calculated based on the contraction height of SRS-A.

【table】

[Table] R ¹ R ² R ³
Suppression rate% Suppression rate%

Claims (1)

[Claims] First-order general formula [] [In the formula, R ¹ and R ² are the same or different, hydrogen,
Lower alkyl having 1 to 8 carbon atoms, or 2 to 4 carbon atoms
represents lower alkenyl, R ³ is lower alkyl having 5 to 8 carbon atoms, lower alkenyl having 2 to 4 carbon atoms,
Lower alkyl having 1 to 8 carbon atoms and having 1 to 2 hydroxyl groups, lower alkyl having 3 to 10 carbon atoms having 1 to 2 ether bonds and optionally substituted with a hydroxyl group, or -(CH ₂ ) nA (n=1 to 3, A represents an acetyl group, an acetyloxy group, an alkoxycarbonyl group having 2 to 4 carbon atoms, an alkoxycarbonylacetyl group having 4 to 7 carbon atoms, a cyano group, or a phenoxy group). Z is a phenyl group with or without one or more substituents (herein, the substituents are hydrogen, halogen, lower alkyl having 1 to 8 carbon atoms, halogenated lower alkyl having 1 to 3 carbon atoms, 1 to 3 carbon atoms, ~4 lower alkoxy, or
COOR ⁴ (R ⁴ represents hydrogen or lower alkyl having 1 to 4 carbon atoms). ), pyridyl, furyl or thienyl. ] and its salt.