JPS5936619B2 - 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 carbostyryl derivative obtained in the present invention has the general formula [wherein R1 and R2 are a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, R3 is a lower alkyl group having 1 to 4 carbon atoms,
A represents -C1 or -CH-.

Furthermore, the bonds at the 3rd and 4th positions represent a single bond or a double bond. ]
It is expressed as

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 [wherein R1, R2, A and the bonds at the 3rd and 4th positions have the same meanings as above.

] The compound represented by the general formula [wherein R3 represents the same meaning as above, and X represents...a rogen atom or an oxygen atom.

Further, n represents 1 when X is a halogen atom or 2 when X is an oxygen atom. ] is applied to the compound represented by . The compound of general formula () used as a raw material in the above method of the present invention is a new compound.

The compound can be obtained, for example, through the following reaction. That is, the known general formula [wherein the bonds at the 3rd and 4th positions represent the same meanings as above].

] and the general formula [where X' and x are the same or different and represent a halogen atom, and R1 represents the same meaning as above.

] in the presence of a Lewis acid to form a new general formula [wherein R1, X and 3
, the bond at the 4th position has the same meaning as above.

] is obtained.

Then, the compound is expressed by the general formula: [In the formula, Rl, R2 and the bonds at the 3rd and 4th positions have the same meanings as above.

] is obtained.

Furthermore, the keto group at the 5-position was reduced by reducing the compound (1a) 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, Rl, R2 and the bonds at the 3rd and 4th positions have the same meanings as above.

] can be obtained.

The compound of general formula (I) used as a raw material in the present invention includes each compound represented by the above general formulas (1a) and (Ib). Examples of the lower alkyl group having 1 to 4 carbon atoms represented by R1 and R2 in the compound of the above general formula (I) include methyl, ethyl, propyl, isopropyl, butyl, Sec-butyl, and tert-butyl groups. .

General formula () used as the other raw material in the present invention
Compounds are commonly known acylating agents, and representative compounds include acetyl chloride, propionyl chloride, butyryl chloride, etc., as well as corresponding acid halides such as bromide and iodide, acetic anhydride, and anhydride. Examples include acid anhydrides such as propionic acid.

The acylation reaction between the compound of general formula (I) and the compound of general formula () 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 (I) and the compound of general formula () 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 a temperature range of 0 to 70°C. The target compound is obtained by this reaction.

The target compound thus obtained can be isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography,
Preparative thin layer chromatography etc. can be used. The carbostyril derivative obtained according to 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. I can do it.

Examples An appropriate method for obtaining the compound of general formula (I) 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-Hydroxycarbostyryl 27y) 37ml of chloroacetyl chloride is dissolved in 250ml of nitrobenzene, 85y of aluminum chloride is gradually added, and the mixture is stirred at 70°C for 20 hours.

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

After cooling, the precipitated crystals were collected, washed with 300 ml of hot water, and then recrystallized from methanol to obtain 14.0 f of 5-chloroacetyl "8-hydroxycarbostyryl" in the form of light yellow crystals with an Mp of 285-287°C (decomposition point). Next, the above 5-chloroacetyl-8-hydroxycarbostyryl 1.2.6
1 is isopropanol 1301! t, and 25.5 t of isopropylamine is added dropwise while stirring.

Stir at 55-60°C for 3 hours.

After cooling, add concentrated hydrochloric acid to adjust the pH to 2-3. F the precipitated crystals
After washing with acetone and recrystallizing from methanol-dimethylformamide, Mp. 286
5-isopropylaminoacetyl-8-hydroxycarbostyryl hydrochloride [compound (a)] 6.5y is obtained as pale yellow crystals with a temperature of ~288°C (decomposition point). Furthermore, 1.0 f of the above 5-isopropylaminoacetyl-8-hydroxycarbostyryl hydrochloride is dissolved in 40 a11 C of water, 0.5 f of palladium on carbon is added as a catalyst, heated to 35 to 40°C, and hydrogen is absorbed while stirring.

When the reduction is completed, the catalyst is separated from the P solution, and the P solution is concentrated to dryness under reduced pressure. Further, ethanol is added and concentration to dryness is repeated to completely remove water, and then acetone is added to the residue for crystallization. Recrystallized from ethanol-acetone to obtain Mp. Pale yellow amorphous 5-(2-isopropylamino-1-hydroxy)ethyl-8-hydroxycarbostyryl hydrochloride with a temperature of 210°C to 212°C (decomposition point) [
Compound (Ib)]0.47 was obtained. Example 1 Pyridine 12a was added to 0.4f of 5-(1-hydroxy-2-isopropylamino)butyl-8-hydroxycarbostyryl, and 0.4f of isobutyryl chloride was added under stirring under ice-water cooling.
．． 6d was gradually added dropwise, and the mixture was further stirred for 3 hours.

Approximately 200 ml of ethyl ether is added, and the precipitate is thoroughly washed with ethyl ether and then dissolved in 50,111 ml of water. After washing with dichloroethane five times, the aqueous layer is concentrated to dryness and crystallized by adding acetone. Recrystallization from acetone yields 0.337 g of 5-(1-hydroxy-2-isopropylamino)butyl-8-isobutyryloxycarbostyryl hydrochloride having a melting point of 228-229°C (color decomposition point). Example 2 50 ml of pyridine is added to 8-hydroxy-5-(α-isopropylaminobutyryl) carbostyryl 2.5f, and 5 ml of isobutyryl chloride is gradually added dropwise with stirring while cooling with ice water, followed by further stirring for 2 hours.

Approximately 500 mt of ethyl ether is added, and the precipitate is washed with ethyl ether.Then, the precipitate is stirred in a small amount of cold water, collected, and washed with a small amount of cold water, acetone, and then ethyl ether. The resulting crystals are recrystallized from acetone to obtain 2.1f of 8-isobutyryloxy-15-(α-isopropylaminobutyryl) carbostyril hydrochloride having a melting point of 231 to 233°C (color decomposition point). Example 3 25 ml of pyridine was added to 5-(1-hydroxy-2-isopropylamino)butyl-8-hydroxy-3,4-dihydrocarpostyryl hydrochloride 1y, and the mixture was cooled with ice water and stirred.
Add 3 ml of isobutyryl chloride dropwise and stir for an additional 3 hours.

Approximately 200 ml of ethyl ether was added, and acetone was added to the precipitate to crystallize it, and then recrystallized from acetone to obtain 5-(1-hydroxy-2-isopropylamino) with a melting point of 239-240°C (colored decomposition point). Butyl-8-isobutyryloxy-3,4-dihydrocarbostyryl hydrochloride 0.
Get 87.

Examples 4 to 8 Typical target compounds of the present invention obtained by reacting in the same manner as in the above Examples using appropriate starting materials are shown in Table 1 below.

Note that Table 1 also lists the compounds of Examples 1 to 3 above. Example 9 5-(1-hydroxy-2-isopropylamino)butyl-8-hydroxycarbostyryl 3V at 200 mi
was dissolved in anhydrous chloroform, and 3 ml of isobutyric anhydride was added dropwise.

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 a lot of the precipitate is collected.

The precipitate is neutralized with 50 ml of ice-cold saturated aqueous sodium bicarbonate solution, and the insoluble material is collected and washed with water. This insoluble substance is a mixture of about 7 compounds in thin layer chromatography, and it is analyzed in silica gel column chromatography [
Silica gel: Grade C-200 (manufactured by Wako Pure Chemical Industries, Ltd.), eluent: chloroformrimethanol = 20:1] at 10
Fractionate by ml, check each fraction using silica gel thin layer chromatography, combine the fractions containing the same components, and then distill off the solvent from each to separate 5 compounds. do. Also, 5m for each residue.
Add ethanol saturated with hydrogen chloride gas, followed by petroleum ether. A lot of the precipitated crystals are collected and recrystallized from acetone to obtain the following compounds. . 5-(1-isobutyryloxy-2-isopropylamino)butyl-
8-isobutyryloxycarbostyryl hydrochloride yield 1
．． 5y, mp198-199°C.

2,8-Diisobutyryloxy-5-(1-hydroxy-2-isopropylamino)butylquinoline hydrochloride Yield: 0. IV, mp201-203°C (decomposition point). .

5-(1-Hydroxy-2-isopropylamino)butyl-8-isobutyryloxycarbostyryl hydrochloride yield 0.4V,. mp228-229°C (color decomposition point).

2-Isoptyryloxy-5-(1-hydroxy-2-
Isopropylamino)butyl-8-hydroxyquinoline hydrochloride yield: 0. IV. mp225-226.5℃(
color decomposition point) 402.8-diisobutyryloxy-5-
(1-isobutyryloxy-2-isopropylamino)
Butylquinoline hydrochloride yield 0.1f7, Mpl87-
188° C. <Drug implantation test method> A male dog (body weight 10-15 kg) is anesthetized by intravenously administering 30 mf7/K9 of pentobarbital sodium salt and fixed in a dorsal position.

Insert the cannula into the trachea, and
KOnzett-R6ssler) method [KOnzett
H. &R6sslerR. , “VersuchsanO
rdnmgzOUntersuchungenande
rBrOnchialMOskOlatur-Arch
．． Exp. Path. , Pharmack) 195, P
7l-74, 27-40, (1940)], and the amount of air overflowing during inhalation was measured using a pneumotachometer (PneumOtach).
Bronchial resistance was measured and recorded on a polygraph.

Histamine 10 pV/K9 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 4T of pentobarbital sodium salt using an automatic injector.
Injected with IVf7/Kfl/Hr. ED5O values were calculated using a dose-response (DOse-RespOnse) curve. At the same time, the transducer
The heart rate was measured via a transducer (nsducer), the measured value was recorded on a polygraph, and the ED25 was calculated from the polygraph. The results are shown in Table 2. The following compounds were used as test compounds. Test compound A. 8-isobutyryloxy-5-(1-hydroxy-
2-isopropylamino)butylcarbostyryl hydrochloride (Example 1)B. 8-isobutyryloxy-5-(1
-Hydroxy-2-Tert-butylamino)propylcarbostyryl hydrochloride (Example 6)C. 8-acetoxy-5-(1-hydroxy-2-ethylamino)butylcarbostyryl hydrochloride (Example 8) It is clear from Table 2 above that all of the compounds of the present invention have bronchodilatory effects.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 and R_2 represent a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms, and A is ▲ Numerical formula, chemical formula, table, etc. etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼. Furthermore, the bonds at the 3rd and 4th positions represent a single bond or a double bond. ]
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, A and the bonds at the 3rd and 4th positions have the same meanings as above. A method for producing a carbostyril derivative, which comprises obtaining a carbostyril derivative represented by the formula: