JPS5913510B2 - Calbostyril Yudou Tainoseizohou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (1) The present invention relates to a novel method for producing carbostyril derivatives.

The carbostyryl derivative obtained in the present invention has the following general formula:
2 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, A is an alkylene group having 1 to 4 carbon atoms with or without an alkyl group having 1 to 3 carbon atoms in the side chain, and an oxygen atom directly connected to the benzene ring. and an alkyleneoxy group having 1 to 4 carbon atoms and having or not having an alkyl group having 1 to 3 carbon atoms in the side chain.

B represents a phenyl group, p-methylphenyl group or p-methoxyphenyl group, and the dotted lines at the 3rd and 4th positions represent saturated or double bonds, respectively. ] is a 5-[(2-monosubstituted amino-1hydroxy)alkyl]carbostyryl derivative. The compounds obtained in the present invention are all new compounds, and have β-adrenergic nerve stimulating action, antispasmodic action, antihypertensive action, decholesterol action, antiinflammatory action, coronary dilation action, antiallergic action, and antiparkinsonian action. action,
It is important as a medicine because it has diuretic, antiviral, and β-adrenergic nerve blocking effects.

Representative compounds of formula [I] are shown in Table 1.

The 5-[(2-monosubstituted amino-1-hydroxy)alkyl]carbostyryl derivative represented by the formula [] has the general formula [where R1, R2, A. The dotted lines for B and 3rd and 4th place are the same as above.

It is produced by reducing a 5-(α-monosubstituted aminoalkanoyl)carbostyryl derivative represented by ].

As the reduction method, a wide range of known methods can be used, and specific examples thereof include methods using hydrogenating agents such as sodium boron hydride and lithium aluminum hydride;
Examples include a method of catalytic reduction in the presence of a metal catalyst such as palladium, palladium black, platinum, or Raney nickel.

When using a hydrogenating agent, it is usually about 0.5 to 5 times the mole of the compound of formula [], and when using a metal catalyst, it is usually about 0.5 to 5 times the mole of the compound of formula [].
] is usually used in an amount of about 0.1 to 0.5 weight per weight of the compound.

When a metal catalyst is used, the reduction is preferably carried out under hydrogen pressure of about 1 to 10 atmospheres. The above reduction reaction is carried out in an appropriate solvent such as water, methanol, ethanol, acetic acid, or tetrahydrofuran when using a hydrogenating agent, or in a solvent such as water, methanol, or ethanol when using a metal catalyst, usually under cooling with ice water. ~ It progresses easily in about 0.5 to 13 hours in the temperature range of the boiling point of the solvent, and 5-[(2
A monosubstituted amino-1-hydroxy)alkyl]carbostyryl derivative is produced.

The 5-(α-monosubstituted aminoalkanoyl)carbostyryl derivative represented by the general formula [ ] used as a starting material in the above is a new compound,
The dotted lines at the 2nd, 3rd and 4th positions are the same as above, and X represents a halogen atom.

5-(α-haloalkanoyl)carbostyryl derivative represented by ] and an amine represented by the general formula H2N-A-B [ ] [where A and B are the same as above] are subjected to a dehydrohalogenation condensation reaction Manufactured by

The compound of the formula [], which is one of the starting materials for the production of the compound of the general formula [] above, is also a new compound. Known carbostyril derivatives represented by the general formula [wherein R2
and X are the same as above, and X'' is the same or different from X and represents a halogen atom.

] in the presence of a Friedel-Crafts catalyst such as aluminum chloride,
It is produced by reacting in a solvent such as carbon disulfide or nitrobenzene at a temperature ranging from -10°C to the boiling point of the solvent. Further, as the compound of formula [] which is another starting material for the production of the compound of the above general formula [], a wide range of known compounds can be used, such as aniline, p-methoxyaniline, amphetamine, p-methoxyaniline, etc. Fetamine, 1-
Methyl-2-phenoxyethylamine, 3',4'-methylenedioxyamphetamine, p-methoxyphenethylamine, 1-methyl-3-phenylpropylamine,
Examples include p-methylamphetamine.

The condensation reaction for producing the compound of the above general formula [] is generally carried out using an excess of the amine of the formula [] in the absence of a solvent or in water,
It is carried out in a suitable solvent such as methanol, ethanol, isopropanol, acetonitrile, etc.

The reaction temperature of the condensation reaction is usually in the range of room temperature to the boiling point of the solvent, and the reaction usually proceeds easily in 0.5 to 10 hours, and the reaction temperature is usually within the range of room temperature to the boiling point of the solvent. A styryl derivative is produced. Compound of formula [] obtained as described above and formula [1] according to the present invention
The compound can be separated and purified by known means such as filtration, washing, and recrystallization.

All of the compounds of the present invention are amine derivatives and are often insoluble in water, but they can be used as pharmaceutically acceptable acid addition salts such as physiologically acceptable hydrochlorides, sulfates, maleates, and citrates. It can be made water soluble. The present invention will be described below with reference to reference examples and examples.

Reference example 1 8-methoxycarbostyryl 10y1 nitrobenzene 1
5ml and α-promobutyryl bromide 30f7 were mixed, and anhydrous aluminum chloride 32V was gradually added under ice cooling, followed by stirring at 55 to 60°C for 4 hours.

The reaction solution was poured into 200 ml of ice water, the precipitate formed was collected, washed with ethanol, and recrystallized from methanol to give 5-(α-promobutyryl)-8 with a melting point of 169-170°C.
-Methoxycarbostyril 11.5y is obtained. Reference example
2. Mix 8-methoxycarbostyryl JMoV, chloroacetyl chloride 9y, and 10 ml of nitrobenzene, and slowly add 217 ml of anhydrous aluminum chloride under ice-cooling.
Stir at 65°C for 4 hours.

The reaction solution was poured into 500 ml of ice water, the precipitate formed was collected, washed with ethanol, and then recrystallized from methanol to obtain 5-chloroacetyl-8-methoxycarbostyryl 8.5f7 having a melting point of 243-244°C. Reference example 35-
(α-bromopropionyl)-8-methoxy-3,4-
After adding 20y of (2p-methoxyphenylethyl)amine to 5y of dihydrocarbostyryl and stirring at room temperature for 6 hours,
Excess amine was extracted and removed with petroleum ether, the precipitate was washed with ether, and methanol was added to dissolve it.

47% hydrochloric acid was added to the methanol layer to adjust the pH to +1 to remove insoluble materials, and the mixture was concentrated and dried. The residue was recrystallized from methanol ether to give white crystals of 5-[α(2-p-methoxyphenylethyl)aminopropionyl]-8-methoxy-3,4-dihydrocarbostyryl hydrobromide.3.
I got 6y. M. p. 198-20 "C (Decomposition) Reference Examples 4 and 5 The following compound was obtained by operating in the same manner as in Reference Example 3.

Reference Example 45-[(1-Methyl-2-p-methoxyphenylethyl)aminobutyryl]-8-hydroxycarbostyryl hydrobromide monohydrate M. p. 28l~283℃
(decomposition), white crystal reference example 58-benzyloxy-5
-[(1-Methyl-2phenoxyethyl)aminoacetyl]carbostyril hydrochloride M. p. 2l7~220℃,
White crystal Example 1 8-benzyloxy-5-[(1-methyl-2phenoxyethyl)aminoacetyl]carbostyril hydrochloride 2V
Add 50 ml of methanol to the solution and add caustic potash under stirring under ice water cooling.
A methanol solution was added to make the mixture slightly alkaline, and 1.27 g of sodium boron hydride was added little by little, followed by further stirring at room temperature for 1 hour.

Concentrated hydrochloric acid was added to the reaction solution to make the pH level 1, and the precipitate was removed.The solution was then concentrated to dryness, and methanol was added thereto and concentrated to dryness. The residue was crystallized by adding acetone, collected, washed with a small amount of concentrated hydrochloric acid, and recrystallized from ethanol-ether to give white crystals of 8-benzyloxy-5-[(1
-Hydroxy-2-(1-methyl-2-phenoxyethyl)amino)ethyl]carbostyril hydrochloride monohydrate 1
．． I got 47. M. p. 192-19 "C (decomposition) Example 2 5-[α-(2-p-methoxyphenylethyl)aminopropionyl]-8-methoxy-3,4 dihydrocarbostyryl hydrobromide 1.5f7 with palladium black 0.47
After adding 100 ml of water and carrying out catalytic reduction under a hydrogen pressure of 5 atm at 60° C. for 12 hours, the catalyst was removed and the solution was concentrated and dried.

The residue was recrystallized from water to give white crystals of 5-[(1-hydroxy-2(2-p-methoxyphenylethyl)amino)propyl]-8-methoxy-3,4-dihydrocarbostyryl hydrogen bromide. A salt % hydrate of 1.27 was obtained. M. p.
173-175% C (decomposition) Examples 3 and 4 The following compound was obtained by operating in the same manner as in Example 1.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. an alkyl group, R^2 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, A is an alkylene group having 1 to 4 carbon atoms with or without an alkyl group having 1 to 3 carbon atoms in the side chain, benzene Each represents an alkyleneoxy group having 1 to 4 carbon atoms which has an oxygen atom directly connected to the ring and has or does not have an alkyl group having 1 to 3 carbon atoms in the side chain. B represents a phenyl group, p-methylphenyl group or p-methoxyphenyl group, and the dotted lines at the 3rd and 4th positions represent saturated or double bonds, respectively. ] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, A, The dotted lines for B and 3rd and 4th place are the same as above. ] A method for producing a 5-[(2-substituted amino-1-hydroxy)alkyl]carbostyryl derivative.