JPS6036425B2 - Method for producing carbostyril derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Technical Field The present invention relates to a method for producing novel carbostyryl derivatives.

Structure of the Invention The carbostyril derivative obtained in the present invention has the general formula: Indicates the group.

Also, A is also teeth shows.

].

The above-mentioned compounds and acid addition salts thereof are new compounds and are useful as pharmaceuticals having bronchodilatory effects and the like. The method of the present invention is carried out using the general formula [where R, , R2 and A represent the same meanings as above.

] A compound represented by the general formula (R3CO)nX (0) [in the formula R
3 represents the same meaning as above, and x represents a halogen atom or an oxygen atom.

Further, n represents 1 when X is a halogen atom or 2 when X is an oxygen atom. ] This is carried out by acylation with a compound represented by

The compound of general formula (1) used as a raw material in the above-mentioned methods of the present invention is a new compound.

The compound can be obtained, for example, through the following reaction. That is, 8-hydroxycarbostyryl represented by the known formula and general formula
L. [In the formula, X' and X are the same or different and represent a halogen atom, and R represents the same meaning as above.

] is reacted with a Q-halo fatty acid halide represented by the following in the presence of a Lewis acid to obtain a novel general formula [wherein R and X have the same meanings as above.

] is obtained.

Then, the compound is expressed by the general formula R2N ratio [In the formula, R2 represents the same meaning as above.

] By reacting with an amine represented by the general formula [
In the formula, R and R2 have the same meanings as above.

] is obtained.

Furthermore, the keto group at the 5-position was reduced by reducing the compound (la) in the presence of a hydrogenating agent such as sodium boron hydride or lithium aluminum hydride or a catalytic reduction catalyst such as palladium carbon, palladium black, or platinum oxide. General Formula [In the formula, R and R2 represent the same meanings as above.

] can be obtained.

The compound of general formula (1) used as a raw material in the present invention includes each compound represented by the above general formulas (la) and (lb). Examples of the lower alkyl group having 1 to 4 carbon atoms represented by R and R2 in the compound of the one-stage formula (1) include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and rt-butyl groups. Can be mentioned.

In the present invention, the general formula (0
) are commonly known acylating agents, and typical examples include acetyl chloride, propionyl chloride, butyryl chloride, etc., as well as corresponding acid halides such as bromide and iodide, or acetic anhydride; Examples include acid anhydrides such as propionic anhydride.
The acylation reaction between the compound of general formula (1) and the compound of general formula (0) of the present invention may be carried out without a solvent since the acylating agent itself acts as a solvent, but it is usually carried out in the presence of a solvent. It will be done. The solvent used at this time is not particularly limited, but typical examples include dichloromethane, dichloroethane, benzene, pyridine, ethyl ether, etc. These solvents may be used alone or in a mixture. May be used. In this reaction, the ratio of the compound of general formula (1) and the compound of general formula (b) to be used may be appropriately selected and is not particularly limited, but it is generally sufficient to use an equivalent amount to a large excess of the latter relative to the former.

In addition, the reaction temperature in this reaction may be selected appropriately, but
The reaction proceeds easily in the temperature range of 0 to 70 oo. This reaction produces a target compound in which the 2-position oxo group (which exists as a hydroxyl group due to tautomerism) and the 8-position hydroxyl group of the compound of general formula (1) are acylated.

The target compound thus obtained can be isolated and purified by conventional separation means. As the separation means, for example, solvent extraction method, dilution method, recrystallization method, column chromatography, preparative thin layer chromatography, etc. can be employed.
The carbostyryl derivative obtained by the present invention can be reacted with an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as maleic acid or fumaric acid to form a physiologically acceptable acid addition salt according to a conventional method, if necessary. can.

Examples A suitable method for obtaining the compound of general formula (1) used as a raw material in the method of the present invention is shown in the following Reference Examples, followed by Examples.

Reference Example 8 - Hydroxycarbostyril (27%) and chloroacetyl chloride (37%) were dissolved in nitrobenzene (250%), ammonium chloride (85%) was gradually added, and the mixture was heated at 70°C for 2 hours.

After addition of 10% hydrochloric acid 500ml, nitrobenzene is removed by steam distillation.

After cooling, the precipitated crystals were collected in a furnace, washed with 300 ml of hot water, and then recrystallized from methanol to give 5-chloroacetyl-8-hydroxycarbostyryl as pale yellow crystals with an mp of 285-2870 (decomposition point) of 14.0 ml. get. Next, 12.6 μl of the above chloroacetyl-8-hydroxy-carbostyril was suspended in 130 μl of isopropanol, and 25.5 μl of isopropylamine was added dropwise to the suspension. 55-6000
So I prayed for three hours.

After cooling, add concentrated hydrochloric acid to adjust the pH to 2-3. The precipitated crystals were collected in a furnace, washed with acetone, and then recrystallized from tanol-dimethylformamide to obtain mp. 286
~2 spots. 0 (decomposition point) pale yellow crystal 5-isoph.

6.5 hours of ropylaminoacetyl-8-hydroxycarbostyril hydrochloride [compound (la)] was obtained.
．． Further, 1.0 m of the above 5-isopropyl acetyl-8-hydroxycarbostyryl hydrochloride was dissolved in 40 M of water, 0.5 m of palladium carbon was added as a catalyst, heated to 35-4000 ℃, and hydrogen was absorbed under the sea bream azusa. let When the reduction is completed, the catalyst is separated into furnaces,
The furnace liquid is concentrated and dried under reduced pressure. Further, ether/ethanol is added and the mixture is repeatedly concentrated to dryness to completely remove water, and then acetone is added to the residue for crystallization. Recrystallized from ethanol-acetone to obtain mp. 210-2120 (
0.4 ml of pale yellow amorphous 5-(2-isopropylamino-1-hydroxy)ethyl-8-hydroxycarbostyryl hydrochloride [compound (lb)] having a decomposition point) was obtained. Example 1 8-Hydroxy-5-(Q-isopropylaminobutyryl) Rubostyril 1 20 pyridine was added on a table, 2 parts of imbutyryl chloride was added dropwise under ice-water condensation, 3
After the hour is done, it is heated for another 2 hours at 35-40℃.

Add about 200 grams of ethyl ether, add a small amount of cold water to the formed precipitate, and stir. The precipitate is washed with acetone and then with ethyl ether. The obtained crystals are recrystallized from acetone to give a melting point of 214 to 21,500 (color decomposition point).
0.6 of 2,8-bis(isobutyryloxy)-51(Q-isopropylaminobutyryl)quinoline hydrochloride was obtained. Example 2 2,8-diisobutyryloxy-5-(1
-Hydroxy-2-isopropylamino)butylquinoline hydrochloride is obtained.

Melting point: 201 to 203 qo (decomposition point) Example 3 5-(1-hydroxy-2-isopropylamino)butyl-8-hydroxycarpostyril 3 is dissolved in 200 ml of anhydrous chloroform, and isobutyric anhydride 3' is dissolved. drip.

The reaction mixture is stirred at room temperature for 5 hours. The solvent is distilled off under reduced pressure, petroleum ether is added to the residue, and the precipitate is filtered out.

The precipitate was washed with ice-cold saturated bicarbonate over 50 ml of water. Neutralize with thorium aqueous solution, take out the lower solution and wash with water. This insoluble substance was a mixture of about 7 compounds by thin layer chromatography, and was analyzed by silica gel column chromatography [silica gel: grade C-200 (manufactured by Wako Pure Chemical Industries, Ltd.)].
Eluent: chloroform:methanol=20:1]
Fractionate each fraction into a thin layer of silica gel.
The mixture is checked using matoography, and the fractions containing the same components are combined, and the solvent is then removed from each of them to separate five compounds. Also, 5 parts of ethanol saturated with hydrogen chloride gas was added to each residue, and then petroleum ether was added. The precipitated crystals are collected in a furnace and recrystallized from acetone to obtain the following compounds. 0 5-(1-isobutyryloxy-2-isopropylamino)butyl-8-isobutyryloxycarbostyryl hydrochloride yield 1.5 minutes, mpl 98-19 movements 0 0 2,8-diisobutyryloxy-5 -(1-Hydroxy-2-isopropylamino)butylquinoline hydrochloride Yield: 0.1 night, mp201-20: 0 (decomposition point): 0
5-(1-Hydroxy-2-isopropylamino)butyl-8-isobutyryloxycarbostyryl hydrochloride Yield: 0.4 evening, mp228-229°C (color decomposition point)○
2-isobutyryloxy-5-(1-hydroxy-2-isopropylamide/)butyl-8-hydroxyquinoline hydrochloride Yield: 0.1 night, mp 225-226.5°C (color decomposition point) 0 2,8- Diisobutyryloxy-5-(
1-isobutyryloxy-2-isopropylamide/)butylquinoline hydrochloride Yield 0.1 evening, mp187-18
8° C. (Pharmacological test method) Yudai (weight 10-15k9) is given 30 doses of pentobalpital sodium salt/k9 intravenously for anesthesia and fixed in the dorsal position.

Insert the cannula into the trachea, and
Konzett-Ro″ssler) method
t day. & Ro″ssler R.,
''Ve u Ch San. rdnug Z. Unte
Mother uChungen and Bronchial
"Moskolatm", Arch. Exp. Path
．． , Pharmack, 195, P71-74, 27-
40, (1940)], artificial respiration was performed, and the amount of air that overflowed during inhalation was measured using a pneumotachmeter to measure bronchial resistance and recorded on a polygraph. Recorded. Histamine 10 kg/kg was used as the bronchoconstrictor, and the test compound was administered through the femoral vein 1 minute before histamine administration. In order to suppress spontaneous breathing and maintain constant anesthesia, administer pentobarbital sodium salt with an automatic injector.
kg/hr. ED5. Values were calculated using a Dose-Response curve. At the same time, a transducer
The heart rate was measured via r), the measured value was recorded on a polygraph, and the ED25 was calculated from the polygraph.

The results are shown in Table 1. The following compounds were used as test compounds. Test compound A 2,8-diisobutyryloxy-5-(1-hydroxy-2-isopropylamino)butylquinoline hydrochloride (Example 2) Table 1 In Table 1, ED spots a) and ED25b) are The results are expressed as relative values when the same test results using proterenol are set as 1.00.

From Table 1 above, it can be seen that the compounds of the present invention have a bronchodilating effect.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 and R_2 are hydrogen atoms or carbon atoms 1 to 4]
A indicates ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or ▲There are mathematical formulas, chemical formulas, tables, etc.▼. ] A compound represented by the general formula (R_3CO)nX [wherein R_3 represents a lower alkyl group having 1 to 4 carbon atoms, and X represents a halogen atom or an oxygen atom. Further, n represents 1 when X is a halogen atom or 2 when X is an oxygen atom. [In the formula, R_1, R_2, R_3 and A have the same meanings as above. ] A method for producing a carbostiri derivative, which is characterized by obtaining a compound represented by the following.