JPS6054959B2 - carbostyril derivatives - Google Patents

Description

[Detailed description of the invention] The present invention relates to novel rubostyril derivatives.

The compound of the present invention is a novel compound, which has the general formula [wherein R is a lower alkyl group, OHOHC2H5 1 or 1:], and the bonds at the 3rd and 4th positions of the bostyryl skeleton are Indicates a single bond or a double bond, respectively.

] and its acid addition salts. The compound of the present invention has excellent β-adrenergic nerve stimulating action and gastric acid secretion suppressing action, and is an anti-asthmatic drug.
It is useful as an anti-ulcer drug. In the above general formula [1], the lower alkyl group represented by R may include a straight chain or branched alkyl group having 1 to 4 carbon atoms,
Specifically, methyl, ethyl, propyl, isopropyl,
Examples include butyl and tert-butyl groups.

Representative compounds of the present invention are listed below. 05
-(2-Hydroxy-3-Tert-butylaminopropoxy)-8-(β-D-glucuronic acid-1-yl)-
3,4-dihydrocarbostyryl 05-(2-hydroxy-3-isopropylaminopropoxy)-8-(β-
D-glucuronic acid-1-yl) carbostyril 05-(
2-Hydroxy-3-ethylaminopropoxy)-8-
(β-D-glucuronic acid-1-yl)-3,4-dihydrocarbostyryl 05-(1-hydroxy-2-isopropylaminobutyl)-8-(β-D-glucuronic acid-1-yl)carbostyryl 05- (1-hydroxy-2
The compound of the present invention can be synthesized by various methods, including
A preferable example thereof is produced as shown in the following formula.

Basic Compound "゛゜"゛[4゛] Hydrolyzed 5-Tomi] [In the above formula, R1 is a lower alkanoyl group, R2 is a lower alkyl group, and X is a halogen atom.

The bonds at the R, A and 3rd and 4th positions are the same as above. ] That is, in the presence of a basic compound, a known 8-hydroxycarbostyryl derivative represented by the general formula [formula] and a known glucuronic acid derivative represented by the general formula [■] are reacted to form the general formula [■].
], and then isolate and purify the compound of the general formula [■], or without isolating and purifying it, from the compound of the general formula [■] represented by R1 and R2. The compound of the present invention is produced by removing the protecting group.

The reaction between the compound of general formula [■] and the compound of general formula [■] is preferably carried out in a conventional inert solvent.

Such solvents include water, lower alcohols such as methanol, ethanol and propanol, ethers such as dioxane and tetrahydrofuran, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene and toluene, ethyl acetate and methyl acetate. Examples include esters such as, dimethyl sulfoxide, dimethyl formamide, and mixed solvents thereof. General formula [Old compound and general formula]
] The ratio of the compound to be used is not particularly limited and is appropriately selected from a wide range, but usually the latter is used in an equimolar to 5 molar ratio to the former.
It is preferable to use twice the molar amount, preferably equimolar to twice the molar amount. The reaction is carried out in the presence of a basic compound. The basic compounds used include alkali metals such as sodium and potassium, alkali metal alcoholates such as sodium methylate, sodium ethylate, and potassium ethylate, and alkali metals or alkalis such as sodium hydroxide, potassium hydroxide, and potassium hydroxide. Examples include earth metal hydroxides. The amount of the basic compound to be used is not particularly limited and may be appropriately selected from a wide range.
Usually equimolar to 5 times the molar amount of the compound of general formula [■],
It is preferable to use equimolar to twice the molar amount. The reaction temperature is usually 0 to 50°C, preferably 0 to 30°C, and the reaction is usually completed in 1 hour to 3 days. The compound of the general formula [■] obtained in this way is used as it is or after being isolated and purified, R1 and R are obtained from the compound of the general formula [■].
2 is treated to remove the protecting group shown in 2. As a method for removing the protecting group, for example, a method using a hydrolysis reaction using a conventional acid or basic compound as a catalyst can be mentioned. Such acid or basic compounds include alkali metal alcoholates such as sodium methylate, sodium ethylate, and potassium ethylate, and alkali metal or alkaline earth metal hydroxides such as potassium hydroxide, sodium hydroxide, and calcium hydroxide. , alkali metal carbonates such as sodium carbonate, potassium carbonate, and potassium hydrogen carbonate, inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, organic acids such as p-toluenesulfonic acid and acetic acid, acidic or basic ion exchange resins, etc. I can give an example. The reaction is preferably carried out in a solvent such as water, a lower alcohol such as methanol, ethanol or propanol, dioxane or tetrahydrofuran. The reaction temperature is usually 0 to 50°C, preferably 0 to 30°C, and the reaction is usually completed in 3 to 2 days. After completion of the reaction, the compound of general formula [1] thus obtained is isolated from the reaction mixture according to a conventional method.

For example, it can be isolated and purified by conventional methods such as extraction with a solvent, recrystallization, and column chromatography. The compound of general formula [1] can easily form an acid addition salt with a pharmaceutically acceptable acid.

Examples of such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, p-toluenesulfonic acid, and acetic acid. Can be done. Furthermore, the present invention also includes optical isomers. Examples are given below to clearly explain the present invention.

Example 1 5.3y of potassium hydroxide was added to 300ml of methanol.
Dissolve in 1.

Add 1 % of 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril hydrochloride to this solution.
Add 3y, dissolve and concentrate to dryness. Add methyl (Try 0-
Acetyl-α-D-glucopyranosylbromide) uronate 19y is dissolved in 100 ml of acetone, and the methanol solution of the potassium salt prepared above is added dropwise while stirring under water cooling. The reaction solution changes from brown to blackish brown as it is added dropwise.
After stirring the reaction at room temperature for 3 days, the reaction solution is concentrated at a low temperature.

Dissolve this residue in a small amount of water and prepare Amperlite XAD-2.
- (280ml) and wash the column with 1.5 times the amount of water. Next, 600 r of 5.0% ethanol! Elute with Ll and concentrate.

After dissolving the residue in a small amount of water again, Sephadex LH-2
Separate using 0. This fraction is concentrated and the residue is CH3O.
Nα-methanol solution (0.5y-50ml) 50ml
Add and leave at room temperature for about 5 hours to hydrolyze. After hydrolysis, it is neutralized with acetic acid and separated again using Sephadex LH-20. This fraction was converted into QAE-Secardex A-
25 (CH3COO type 1) (solvent: water) to give white amorphous crystals of 5-(1-hydroxy-2-isopropylaminobutyl)-8-(β-D-glucuronic acid-
1-yl) Carbostyril 31 potacylate 7.6y is obtained.
Melting point: 204°C (decomposed) Example 2 5-(2-hydroxy-3-Tert-butylaminopropoxy)-8-hydroxy-3,4-dihydrocarbostyryl was added to a solution of 1.3 q of potassium hydroxide dissolved in 40 mt of methanol. Add and dissolve hydrochloride 3,4y.

After concentration under reduced pressure, the residue was dissolved in 30 ml of methanol, and the p solution was added dropwise to 4.2 y of methyl (tri-0-acetyl-α-D-glucopyranosyl L-rubu7amide) uronate, which had been previously dissolved in 40 ml of acetone, under water cooling and stirring. After stirring the reaction solution at room temperature for 3 days, the reaction solution was concentrated, adsorbed onto Sephadex LLI-20, and eluted with 30% ethanol. After concentrating the eluate, CH3ONα-methanol (a).
5y-50 mL), warmed slightly, and then left at room temperature overnight. After concentrating the reaction solution again, it was dissolved in a small amount of water, adsorbed on Sephadex LH-20, and eluted with 30% tar. Furthermore, QAE-Security Index A-25
After purification using (CH3COO type 1), it was adsorbed on Sephadex LH-20 and eluted with 30% ethanol. This eluate was crystallized using methanol-ethyl ether to give pale yellow amorphous crystals of 5-(2-hydroxy-3-Tert-butylaminopropoxy)-8-(
1.63y of β-D-glucuronic acid-1-yl)-3,4-dihydrocarbostyryl is obtained. Melting point 21rc (decomposition)

Claims (1)

[Claims] 1 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R is a lower alkyl group, A is ▲ There are ▲ mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ Numerical formulas, chemical formulas, tables, etc. There is ▼, and the bonds at the 3rd and 4th positions of the carbostyril skeleton represent a single bond or a double bond, respectively. ] Carbostyryl derivatives and acid addition salts thereof.