JPS597707B2 - Carbo Stiril Yudou Taino Seizouhou - Google Patents

Description

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

The carbostyryl derivative of the present invention has the general formula [wherein R1 and R2 are the same or different and represent a hydrogen atom or a lower alkyl group, R3 represents a hydrogen atom, a lower alkyl group, or a lower alkanoyl group, and R4 and R5 are the same] Alternatively, it represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an aralkyl group, or a cycloalkyl group.

Further, R4 and R5 may be bonded to each other with or without an oxygen atom in addition to the nitrogen atom bonded together to form a morpholine ring group or a piperidine ring group. Note that the carbon bond between the 3rd and 4th positions represents a single or double bond. ] 5-(α-aminoalkanoyl)-8-hydroxycarpostyryl derivatives, all of which belong to new compounds, have β-adrenergic agonist action, intestinal tract and uterine muscle relaxing action, antihypertensive action, and decholesterol action. , anti-spasmodic action, anti-inflammatory action, coronary dilation action, immunosuppressive action, anti-allergic action, anti-Parkinson's disease action, diuretic action, anti-obesity action, β-adrenergic blocking action, anti-cancer action, weight gain action, anti-inflammatory action. It has viral effects and histamine H2 receptor inhibitory effects, and is important as a pharmaceutical. The carbostyryl derivative represented by general formula (1) of the present invention is produced by the following method.

That is, the bonds between general formulas are the same as above.

5-(α-haloalkanoyl)-8-hydroxycarbostyryl derivatives represented by the general formula [wherein R4 and R5 are the same as above]. ] The amine derivative represented by the formula (1) is reacted to obtain the carbostyril derivative represented by the general formula (1). The compound of general formula (), which is the starting material of the present invention, is also a new compound and can be produced, for example, by the following method.

That is, the known 8-hydroxycarbostyryl or 8
-Hydroxy-3,4-dihydrocarbostyryl or by alkylating their 1-position hydrogen by a conventional method, or 8
Using a carbostyril derivative represented by the general formula [in the formula, R1 and R3 are the same as above] obtained by alkylating or acylating the hydroxyl group at the position, for example, chloroacetyl chloride, α-chloropropionyl iodide, α - 2 or more carbon atoms such as promobutyrylfuromide
An α-haloalkanoyl halide in which a halogen atom such as chlorine, bromine or iodine is bonded to the α-position carbon and carbonyl group of four fatty acid residues is mixed with carbon disulfide, nitrobenzene, nitrobenzene, etc. in the presence of a known Lewis acid such as aluminum chloride. It is obtained by reacting in a solvent such as ethyl ether or dioxane at a temperature ranging from -10°C to the boiling point of the solvent.

Specific examples of compounds of general formula () include 1-methyl-5-chloroacetyl-8-hydroxycarbostyryl, 5-(
α-promobutyryl)-8-methoxycarbostyryl,
5-Chloroacetyl-8-acetoxy-3,4-dihydrocarbostyryl, 5-(α-bromopropionyl)-
Examples include 8-methoxy-3,4-dihydrocarbostyryl. The amines of the general formula () which are the other raw materials in the present invention include ammonia, methylethylamine, ethylamine, dimethylamine, isopropylamine, tert-butylamine, Sec-butylamine, benzylamine, α-methylbenzylamine, α・α -Dimethylphenethylamine, phenethylamine, morpholine, piperidine, cyclohexylamine and the like.
The reaction between the compound of general formula () and the compound of general formula () in the present invention may be carried out without a solvent, but is generally carried out in a solvent under 1 to 10 atmospheres.

Examples of the solvent used in this reaction include methanol, ethanol, isopropanol, dioxane, diethyl ether, ethyl acetate, acetonitrile, and benzene. This reaction is performed for a compound of general formula (H) with general formula ()
The compound may be used in an equimolar to large excess amount, but it is generally best to use a 3 to 10 times molar amount.
The reaction temperature is preferably from room temperature to 100°C or about the boiling point of the solvent. A compound in which the 8-position in the carbostyryl derivative represented by the general formula (1) of the present invention is an alkoxy group or an acyloxy group can be converted into an 8-hydroxy compound by a conventional hydrolysis reaction; Compounds of general formula (1) having a hydroxyl group can be prepared by alkylating or acylating the corresponding 8-
It can be an alkoxy or 8-acyloxy derivative.

The above hydrolysis reaction is carried out in a suitable solvent such as water, methanol or ethanol in the presence of an acidic catalyst such as hydrochloric acid or hydrobromic acid or an alkaline catalyst such as sodium hydroxide or potassium hydroxide at room temperature to the boiling point range of the solvent.

Further, for alkylation or acylation of a compound having an 8-hydroxyl group in the compound of general formula (1), a compound of the general formula ' [wherein R3 represents a lower alkyl group or a lower alkanoyl group, and X represents a halogen atom] is used.

Alternatively, an alkylating agent or acylating agent represented by the general formula [wherein R3'' represents a methyl group or an ethyl group] is used.

] Alkylation or acylation is carried out using an alkylating agent represented by the following formula. Examples of alkylating agents of general formula () include methyl iodide, ethyl chloride, Tert
Examples of alkylating agents of general formula (V) include dimethyl sulfate, . Examples include diethyl sulfate. Other alkylating agents such as diazomethane can also be used. Examples of the acylating agent include acetyl chloride and acetyl iodide. The alkylation or acylation reaction of the 8-hydroxyl group is carried out using the above alkylating agent in an appropriate solvent such as water, methanol, ethanol, isopropanol, acetone, benzene, toluene, pyridine, etc. under ice cooling or basicity within the boiling point range of the solvent. Alternatively, the reaction may be carried out by reacting an acylating agent in an amount equal to or three times the amount of the carbostyryl derivative.

A part of the carbostyril derivative represented by the general formula (1) obtained by the present invention forms a hydrogen halide salt due to the hydrogen halide generated during the reaction.

Therefore, the reaction product is prepared by adding the same or different type of hydrogen halide to the mono-hydrogen halide and isolating the entire amount as a single or mixed hydrogen halide salt, followed by dilution with an appropriate solution such as water, methanol, ethanol, etc. Sodium hydroxide in solvent,
After the compound of general formula (1) is isolated as a free base using potassium hydroxide, sodium carbonate, potassium carbonate, etc., it may be converted into a pharmaceutically acceptable acid addition salt if necessary. Reference examples showing production examples of starting material compounds of the present invention and examples of the present invention are shown below.

Reference example 1 8-methoxy-3,4-dihydrocarbostyryl 17t
chloroacetyl chloride 66y1 nitrobenzene 3
Add 0 ml of aluminum chloride, gradually add 100 f of aluminum chloride under ice cooling, stir at room temperature for 30 minutes, and leave to stand for another 30 minutes.

Next, this reaction solution was poured into 700 ml of ice water, and the resulting precipitate was collected, washed with ethanol, and recrystallized from methanol to give a needle-shaped 5-
20 tons of chloroacetyl-8-methoxy-3,4-dihydrocarbostyryl are obtained. Reference Example 2 1-Methyl-8-methoxycarbostyryl 407 and nitrobenzene 30ml11chloroacetyl chloride 70ml
1 was added thereto, and while the entire solution was cooled with ice water, aluminum chloride 2307 was gradually added thereto, and the mixture was stirred and reacted at 60° C. for 4 hours.

After the reaction, the entire reaction solution was poured into 1e of ice water, the resulting precipitate was collected, washed with ether, and then diluted with chloroform-
Recrystallized from ethanol (2:5) to obtain Mp2O4~20
1-Methyl-5-chloroacetyl 8-methoxycarbostyryl 327 is obtained at 5.5°C. Reference Example 3 50 t of α-promobutyryl bromide, 507 ml of anhydrous aluminum chloride, and 400 ml of carbon disulfide are added to 20 f of 8-hydroxycarbostyryl, and the mixture is heated and reacted at 50° C. for 13 hours.

After the reaction, the carbon disulfide layer is removed by tilting and crushed ice is added to the residue to crystallize it. Next, this was washed with water and then recrystallized from methanol to give Mp2l8~219°C (colored decomposition).
Colorless amorphous 5-(α-promobutyryl)-8-hydroxycarbostyryl 27f is obtained. Example 1 4 t of 5-chloroacetyl-8-methoxy-3.4 dihydrocarbostyryl is dissolved in 60 ml of isopropanol, and tert-butylamine 207 is added dropwise over 20 minutes while stirring at 60°C.

After further heating and stirring for 40 minutes, the solvent was distilled off and the mixture was concentrated to 10 volumes, and concentrated hydrochloric acid was added to give a pH of ~2. The precipitate deposited here was collected and recrystallized from ethanol-acetone to obtain Mp2O8~210°C, colorless amorphous 5-Ter.
2.0f of t-butylaminoacetyl-8methoxy-3,4-dihydrocarbostyryl hydrochloride is obtained. Example 2 5-chloroacetyl-8-methoxy-3,4 dihydrocarbostyryl 3f7 was dissolved in 40 ml of isopropanol, heated to 60°C with stirring, and 10 t of Sec-butylamine was added.
was added dropwise, heated and stirred for 2.5 hours, the solvent was distilled off and concentrated to ten volumes, and the precipitate was collected by saturation with dry hydrochloric acid gas.
Recrystallization from ethanol gave 5-See-butylaminoacetyl-8-methoxy-3,4-dihydrocarbostyryl hydrochloride 1.8 as colorless needles, Mp2l2-214°C.
get f.

Example 3 2.77 ml of 1-methyl-5-chloroacetyl-8-methoxycarbostyryl was dissolved in 40 ml of isopropanol, and 9 y of isopropylamine was heated to 55-60°C with stirring.
is added dropwise over a period of 1.5 hours.

After the dropwise addition, stirring was continued at the same temperature for an additional hour. After the solvent is concentrated by distillation under reduced pressure, 40 d of isopropanol is added to remove insoluble materials, and concentrated hydrochloric acid is added to the resulting solution to adjust the pH to 2-3. After cooling, the precipitate was collected and recrystallized from ethanol to give Mp of 272-275°C (decomposition). 0.4f of white amorphous 1-methyl-5-isopropylaminoacetyl-8-methoxycarbostyryl hydrochloride is obtained. Example
4 2.5y of 5-chloroacetyl-8-methoxy-3,4 dihydrocarbostyryl is dissolved in 50a of isopropanol, and 4.97% of cyclohexylamine is gradually added dropwise.

Note that stirring was continued for 2.5 hours at 60°C. Next, the solvent was concentrated by distillation, and the concentrated residue was washed three times with 20 ml of petroleum ether, and then the residue was washed with 25 to 30 ml of isopropanol.
The precipitate was recrystallized from ethanol to give colorless needle-shaped crystals of 5-cyclohexylaminoacetyl-8methoxy-3,4-dihydrocarbostyryl. 1.4y of hydrochloride is obtained. Example 5 10f of 5-chloroacetyl-8-hydroxycarbostyryl was suspended in 60ml of benzene, and 9m2 of morpholine was suspended in 60ml of benzene.
After stirring under heating and refluxing for 4 hours, the precipitate formed was collected.

Dissolve in 60ml of isopropanol and add concentrated hydrochloric acid to adjust the pH to 2-3. After cooling, the precipitate was collected ▲, recrystallized from ethanol, then dissolved in 20 ml of water, and sodium bicarbonate was added thereto to adjust the pH to 7.5-8.0. After cooling, the precipitate was collected ▲ and dissolved in ethanol. Recrystallized from Mp238
˜239.5° C. (decomposition), yielding 4.27 g of amorphous 5-morpholinoacetyl-8-hydroxycarbostyryl.
Example 6 5-chloroacetyl-8-hydroxycarbostyryl 5
After adding 40 ml of α·α-dimethylphenethylamine to Y and stirring at room temperature for 5 hours in the dark, excess amine was extracted and removed with petroleum ether, and the precipitate was washed with ether.

Next, methanol containing hydrochloric acid is added to remove insoluble matter, and the methanol solution is concentrated to dryness. The residue was recrystallized from methanol to give 5-(α・α
Dimethylphenethylamino)acetyl-8-hydroxycarbostyryl hydrochloride + hydrate 6.1f is obtained. Example 7 5-isopropylaminoacetyl-8-methoxy-3.
4-dihydrocarbostyryl hydrochloride 17 was dissolved in 10 ml of 47% hydrobromic acid, and 2.5
Heat and stir for an hour.

Next, 10 ml of ethanol and 5 ml of water are added to this reaction solution and concentrated, further 20 ml of water is added, and the pH is adjusted to 6.5 to 7.5 with sodium hydrogen carbonate. A lot of the precipitate is collected, washed with water and dried, then dissolved in isopropanol and saturated with dry hydrochloric acid gas. The precipitate obtained here was collected and recrystallized from ethanol to give Mp274-27.
5°C, colorless amorphous 5-isopropylaminoacetyl-
0.5y of 8-hydroxy-3.4 dihydrocarbostyryl hydrochloride is obtained. Example 88-Methoxy-5-(α-
1.57 ml of tert-butylaminobutyryl-3,4-dihydrocarbostyryl was dissolved in 15 ml of 47% hydrobromic acid and heated under reflux at 140 to 150°C for 19 hours.

After the reaction is completed, the reaction solution is concentrated, and then acetone is added to crystallize it. The crystals were recrystallized from ethanol-acetone, Mpl44-146℃ (decomposition), colorless amorphous 8.
-Hydroxy-5-(α-Tert-butylaminoptyryl)-3,4-dihydrocarpostyryl hydrobromide dihydrate 1.17 is obtained. Example 9 5-isopropylaminoacetyl-8-hydroxy-3,4-dihydrocarbostyryl 3f, sodium hydroxide 0.5y, water 20
ml, and 1.37 g of dimethyl sulfate was added dropwise over 1 hour while stirring under ice cooling, and the mixture was further reacted at 40 to 50°C for 2 hours.

After the reaction is completed, the reaction solution is extracted with chloroform, washed with water and dried, then hydrochloric acid gas is introduced to separate the precipitated crystals, which are recrystallized from ethanol to obtain colorless and amorphous 5-
Isopropylaminoacetyl-8-methoxy-3,4-
2.17 of dihydrocarbostyril hydrochloride monohydrate is obtained. Example 10 50 ml of pyridine was added to 2.57 ml of 8-hydroxy-5-(α-isopropylaminobutyryl) carbostyril, and 5 ml of isobutyryl chloride was gradually added dropwise while stirring under ice cooling. Continue stirring for an additional 2 hours.

Next, about 500 ml of ethyl ether was added to the reaction solution, the precipitated crystals were collected, washed with ether, stirred in a small amount of cold water, and the crystals were collected again. After washing with a small amount of cold water, wash with acetone and A-Y-tel. The obtained crystals were recrystallized from acetone to give colorless and amorphous 8-isobutyryloxy-5-(α
Isopropylaminobutyryl) carbostyril hydrochloride 2
．． Obtain 1f. General formula (1
) Compounds are illustrated in Table-1.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 and R^2 are the same or different and represent a hydrogen atom or a lower alkyl group, R^3 is a hydrogen atom, Indicates a lower alkyl group or a lower alkanoyl group. In addition, X represents a halogen atom, and the carbon bond at the 3rd and 4th positions is 1
Indicates a double or double bond. ] 5-(α-haloalkanoyl)-8-hydroxycarbostyryl derivatives represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc.
^4 and R^5 are the same or different and represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an aralkyl group, or a cycloalkyl group. Further, R^4 and R^5 may be bonded to each other with or without an oxygen atom in addition to the nitrogen atom bonded together to form a morpholine ring group or a piperidine ring group.
] There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ that are characterized by reacting with amine derivatives represented by The carbon bond between the 3rd and 4th positions is the same as above. ] A method for producing a carbostyryl derivative represented by 2 General formula ▲ Numerical formula, chemical formula, table, etc. produced by the method set forth in claim 1 ▼ [In the formula, R^1 and R^2 are the same or different and represent a hydrogen atom or a lower alkyl group. , R^3 represents a lower alkyl group or lower alkanoyl group, R^4 and R^
5 is the same or different and represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an aralkyl group, or a cycloalkyl group. Note that R^4 and R^5 may be bonded to each other with or without an oxygen atom in addition to the nitrogen atom bonded together to form a morpholine ring group or a piperidine ring group.
Further, the carbon bond at the 3rd and 4th positions represents a single or double bond.
] General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^4, R^5 and 3.4 A method for producing a carbostyryl derivative represented by the above carbon-carbon bond. 3 General formula ▲ Numerical formula, chemical formula, table, etc. manufactured by the method described in claim 1 ▼ [In the formula, R^1 and R^2 are the same or different and are a hydrogen atom or a lower alkyl group] and R^4 and R^5 are the same or different and represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an aralkyl group, or a cycloalkyl group. Note that R^4 and R^5 may be bonded to each other with or without an oxygen atom in addition to the nitrogen atom bonded together to form a morpholine ring group or a piperidine ring group.
Further, the carbon bond at the 3rd and 4th positions represents a single or double bond.
] to the carbostyril derivative represented by the general formula R^3'
X [In the formula, R^3' represents a lower alkyl group or a lower alkanoyl group, and X represents a halogen atom. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^3, R^4, A method for producing a carbostyryl derivative represented by R^5 and the carbon-carbon bond at the 3rd and 4th positions are the same as above. 4 General formula ▲ Numerical formula, chemical formula, table, etc. manufactured by the method described in claim 1 ▼ [In the formula, R^1 and R^2 are the same or different and are a hydrogen atom or a lower alkyl group] and R^4 and R^5 are the same or different and represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an aralkyl group, or a cycloalkyl group. Note that R^4 and R^5 may be bonded to each other with or without an oxygen atom in addition to the nitrogen atom bonded together to form a morpholine ring group or a piperidine ring group.
Further, the carbon bond at the 3rd and 4th positions represents a single or double bond.
] to the carbostyryl derivative represented by the general formula (R^3
A general formula characterized by reacting an alkylating agent represented by ``O)_2SO_2 [in the formula, R^3'' represents a methyl group or an ethyl group] ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R ^1, R^2, R^3, R^4, R^5, and the carbon-carbon bonds at the 3rd and 4th positions are the same as above] A method for producing a carbostyril derivative.