JPS6117826B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel 5-(1-hydroxy-2-substituted amino)-alkyl-8-substituted carbostyryl or -3,4-dihydrocarbostyryl compounds. More specifically, the present invention relates to the general formula (In the formula, R ¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ² and R ³
together with the nitrogen atom to which they are bonded represents a piperidino group or a morpholino group, and R ⁴ and
R ⁵ represents a hydrogen atom, and the formula The carbostyril skeleton represented by the formula

【formula】 or

A novel 5-(1-hydroxy-2-
Substituted amino)-alkyl-8-substituted albostyryl or -3,4-dihydrocarbostyryl compounds. It is well known that certain carbostyril derivatives exhibit potent pharmacological activity. Representative compounds of this type are disclosed in Journal of Medical Chemistry, Vol. 15, pp. 260-266 (1972), Japanese Patent Publication No. 46-38789, and Chemical Abstracts, Vol. 62, pp. 16212e (1965), etc. There is. However, these prior art references indicate that compounds having a (1-hydroxy-2-substituted amino) alkyl group at the 5-position of the carbostyril structure or 3,4-dihydrocarbostyryl structure have excellent β-adrenergic receptor stimulating activity. does not indicate that it has. We have a 5-(1-hydroxy-2-substituted amino)-alkyl group at the 5th position of the carbostyryl structure or 3,4-dihydrocarbostyryl structure, and a substituent at the 1st and/or 8th position. Carbostyril derivatives or 3,4-dihydrocarbostyryl derivatives and their pharmacologically acceptable acid addition salts have β-adrenergic receptor stimulating activity and are therefore used as bronchodilators and peripheral vasodilators. ,
It has been found to be effective as a therapeutic agent such as antihypertensive agents and similar agents, particularly as a drug for the treatment of bronchial asthma. The object of the present invention is to satisfy the following general formula (a) A novel 5-(1-hydroxy-2-substituted amino)alkyl-8-substituted carbostyryl compound represented by and the following general formula (b) Novel 5-(1-hydroxy-2-substituted amino)alkyl-8-substituted-3,4 represented by
An object of the present invention is to provide a dihydrocarbostyryl compound. (In the formula, R ¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ² and R ³
together with the nitrogen atom to which they are bonded represents a piperidino group or a morpholino group, and R ⁴ and
R ⁵ represents a hydrogen atom). The 5-(1-hydroxy-2-substituted amino)alkyl-8-substituted carbostyril derivatives and 3,4-dihydrocarbostyryl derivatives of formula (a) and formula (b) and their acid addition salts are β-adreno It exhibits receptor stimulatory activity and is therefore effective as a bronchodilator, peripheral vasodilator or antihypertensive agent. The term "alkyl" as used herein with respect to R ¹ , R ² and R ³ means a straight or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, Contains propyl group, isopropyl group, butyl group, sec-butyl group, tertiary-butyl group, etc. The term "halogen" as used herein refers to fluoride, chlorine, bromine and iodine, preferably chlorine and bromine. The compounds of the present invention represented by formulas (a) and (b) can be produced from the starting carbostyryl compound of general formula () according to the following reaction schemes. Here, (A) represents a catalytic reaction and (B) represents a reduction using a reducing agent. In the diagram, R ⁴ and R ⁵ each represent a hydrogen atom or an alkyl group, and Y represents a hydrogen atom or

[Formula] Group or

[Formula] represents a group, and X' has the same meaning as X and may be the same as or different from X. In the chemical structure shown in the above diagram and throughout this specification and claims,
The dotted lines at the 3- and 6-positions of the carbostyryl moiety represent an additional single bond between the 3- and 4-positions or two hydrogen atoms bonded to the 3- and 4-positions. i.e. chemical structure is the chemical structure

[Formula] or

It represents a carbostyryl moiety or a 3,4-dihydrocarbostyryl moiety having the formula: As shown in the reaction scheme above, it is one intermediate in the method of the present invention. 1-substituted-5-haloacetyl-8-substituted-carbostyryl or 3,4-dihydrocarbostyryl represented by formula () is the corresponding 1-substituted-8-substituted-carbostyryl or -3,4-dihydrocarbostyryl. Styril ()
can be prepared in one step by reaction with haloacetyl halides in the presence of solvents or without solvents in the presence of well-known Lewis acid catalysts (route A). The compound of formula () in which R ₄ is a hydrogen atom, R ⁴
Alternative route (B)+ starting from 8-hydroxycarbostyryl or 8-hydroxy-3,4-dihydrocarbostyryl of formula () where is a hydrogen atom
It can be similarly produced using either (B)' or (C)+(C)'. In route (B)+(B)', 8-hydroxycarbostyryl or 8-hydroxy-3,
The reaction between 4-dihydrocarbostyryl () and an α-haloalkanoic acid halide of formula () is expressed by formula (a) This results in a novel 8-haloalkanoylcarbostyryl or -3,4-dihydrocarbostyryl in which X is a halogen atom, which is then subjected to rearrangement of the haloacetyl group to form the intermediate (). In route (C)+(C)', the reaction between the starting material () and the α-haloalkanoic acid halide is expressed by the formula (b) A new 5− where X is the same as defined above
This results in a haloalkanoyl-8-haloalkanoyloxycarbostyryl or -3,4-dihydrocarbostyryl product, which the 8-haloalkanoyl group is then hydrolyzed to form intermediate (). In fact, the reaction between 8-hydroxy-3,4-dihydrocarbostyryl and α-haloalkanoic acid halide can be carried out through the three reaction routes mentioned above, namely:
Proceed with the combinations of (A), (B) + (B)' and (C) + (C)'.
Therefore, the reaction product is obtained as a mixture of compounds (), (a) and (b). Generally, if the reaction is carried out at a relatively low temperature, the resulting product will be a mixture of compounds () and (a) and a small amount of compound (b), whereas if the reaction is carried out at a relatively high temperature, The resulting product contains compounds () and (b) and a small amount of compound (a)
It would be a mixture of. Separation of compound (), (a) or (b) from the reaction product can advantageously be carried out by well-known procedures, such as fractional crystallization. In one preferred embodiment for the separation, the solvent used is removed by distillation to obtain a residue or the reaction mixture is poured onto crushed ice blocks to precipitate the crystals. The residue or the crystals are washed with hot water or cold methanol. Reconsolidation of the insoluble material from methanol yields 5-haloalkanoyl-8-substituted-
Carbostyryl or -3,4-dihydrocarbostyryl () is obtained. The remaining methanolic mother liquor is concentrated to dryness under reduced pressure and the residue is recrystallized from acetone to obtain 8-haloalkanoyl-carbostyryl or -3,4-dihydrocarbostyryl (a). The resulting acetone mother liquor is then concentrated to dryness under reduced pressure and the residue is recrystallized from acetone or acetic acid ethyl ester to give 5-haloalkanoyl-8-haloalkanoyloxycarbostyryl or -3,4-
Dihydrocarbostyril (b) is obtained. The compounds of the present invention having formulas (a) and (b) are the 5-
(α-haloalkanoyl)-8-hydroxycarbostyryl or -3,4-dihydrocarbostyryl derivative with the formula () (wherein R ² and R ³ are the same as defined above) and reacted with an amine of formula () as shown in the reaction scheme. (wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined above) haloalkanoyl-8-substituted-carbostyryl or -
It can be produced from 3,4-dihydrocarbostyryl (). The method of the invention will be explained in more detail below. The 1- or 8-substituted-3,4-dihydrocarbostyryl () used as a starting material in the present invention is a known compound, and is also known, for example, by George R.Rettit
It can be easily produced by the method described in J.Org.Chem., Vol. 33, p. 1089 (1968). The α-haloalkanoic acid halides () that can be used in the present invention include α-chloropropionic acid chloride, α-bromopropionic acid chloride, α-chlorobutylic acid chloride, α-bromobutylic acid chloride, α-bromobutylic acid brolide,
Includes α-chlorovaleric acid chloride and the like. In reaction route (A), catalysts that can be used are conventional Lewis acids, such as aluminum bromide, aluminum chloride, subchloride, ferric chloride, iron stannate, boron trifluoride, etc., preferably chloride. It is aluminum. These catalysts are used in amounts of about 2 to 10 moles, preferably about 3 to 6 moles, per mole of starting carbostyryl compound (). This reaction can be carried out without a solvent, but the reaction runs more smoothly and directly in an inert organic solvent. Suitable examples of solvents that can be used in this reaction include carbon disulfide,
Examples include nitrobenzene, ether, dioxane, and carbon disulfide is preferred. These reaction solvents are generally used in an amount of 0.5 to 20 times, preferably 2 to 10 times, the volume of the reaction reagent. Reaction (A) comprises an equimolar amount to a large excess of α-haloalnoic acid halide, preferably about 2 to 20 moles, most preferably about 2 to 10 moles of α-haloalkanone per mole of starting carbostyryl compound (). It is carried out using acid halides. The reaction takes place at room temperature to approx.
Proceed at 150°C, preferably from room temperature to about 80°C. Reaction times vary depending on the reaction temperature used, but are generally about 1 to 20 hours, preferably about 1 to 20 hours.
It is 10 hours. Reaction (B) can be carried out using the same amount of the same catalyst used in reaction (A) in the same solvent used in reaction (A) or without a solvent. The reaction is carried out using an equimolar amount to a large excess of α-haloalkanoic acid halide, preferably about 2 to 20 moles, preferably about 2 to 10 moles of α-haloalkanoic acid halide per mole of starting carbostyryl compound. , for about 1 to 20 hours, preferably for about 1 to 10 hours, at a temperature of from about room temperature to about 150°C, preferably from about room temperature to about 80°C. 8-haloalkanoyloxy (-3,4-dihydro.carbostyryl to 5-haloalkanoyl-8-substituted-
Reaction (B)′ to obtain (3,4-dihydro)carbostyryl is commonly known as Fries rearrangement, and the reaction can be carried out in the same solvent as in reaction (A) or without using a solvent. It can be accomplished using the same catalyst as in (A). The temperature ranges from room temperature to about 150°C, preferably from room temperature to about 80°C, and the reaction time ranges from about 1 to 20 hours, preferably about 1 to 10 hours. This reaction is based on the previous reaction system
This reaction can be carried out in the presence of α-haloalkanoic acid halide remaining unreacted in (B). In such cases, the presence of the α-haloalkanoic acid halide increases the product, 5-haloalkanoyl-8-substituted-
It has been found that the yield of (3,4-hydro)carbostyryl () is improved. Reaction (C) can be carried out using the same amount of the same catalyst as used in reaction (A), in the same solvent as used in reaction (A) or without a solvent. The α-haloalkanoic acid halide is present in an equimolar amount to a large excess, but preferably in an 8-substituted-
(3,4-dihydro)carbostyryl () 1
from about 2 to about 20 moles per mole, most preferably from about 3 to about 20 moles per mole.
6 moles are used. Reaction temperature ranges from room temperature to approx.
°C, preferably from room temperature to about 80 °C, and the reaction time is about 1 hour to 20 hours, preferably about 1 hour to
Approximately 10 hours. Reaction for obtaining compound () from the obtained 5-(α-haloalkanoyl)-8-haloalkanoyloxy-(3,4-dihydro)carbostyryl
(C)' in the presence of a solvent such as water, a lower alkanol such as methanol, ethanol or isopropanol, a catalyst such as a basic substance such as an alkali metal hydroxide or carbonate, such as sodium hydroxide, potassium hydroxide; This can be carried out using sodium carbonate, potassium carbonate, etc., or inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. The amount of catalyst will vary depending on the type of catalyst used. For example, hydrochloric acid or sodium hydroxide is used in an amount of 1 to 5 moles per mole of 5-(α-haloalkanoyl)-8-haloalkanoyloxy-(3,4-hydro)carbostyryl. The reaction is generally about 0.5~
5 hours at a temperature of about 0° C. to 150° C., but at temperatures of 0° C. to 40° C. if basic substances are used as catalysts and from 70° C. to 70° C. if inorganic acids are used as catalysts. It is carried out at a temperature of 100°C. 5-(α-haloalkanoyl)-1 obtained above
- and/or -8-substituted-(3,4-dihydro)
Amines that can be used in the reaction with carbostyryl () include cycloalkylamines such as cyclobutylamine, cyclopentylamine, cyclohexylamine, and substituted or unsubstituted heterocyclic amines such as piperidine, morpholine, 2
-Methyl-piperidine, 3-methylpiperidine, and the like. Amine () and 5-(α-haloalkanoyl)-
This reaction between 1- and -8-substituted-(3,4-dihydro)carbostyryl () is carried out at about atmospheric pressure to about 10 atmospheres in a suitable solvent or from room temperature using the amine itself as a solvent. The 5-
(α-substituted-aminoalkanoyl)-8-substituted-
(3,4-dihydro)carbostyryl (), 5-
(α-Substituted-aminoalkanoyl)-8-alkoxy)-(3,4-dihydro)carbostyryl (
a) or 5-(α-substituted-aminoalkanoyl)-
8-hydroxy(3,4-dihydro)carbostyryl (b) can be obtained. Alternatively, carbostyryl compounds or 3,4-dihydrocarbostyryl compounds (a) in which R ⁴ represents an alkyl group are dealkylated with hydrogen halide prior to reduction to obtain compounds of formula (b);
Alternatively, carbostyryl compounds or 3,4-dihydrocarbostyryl compounds in which R ⁴ represents a hydroxy group can be alkylated prior to reduction to obtain formula (a) as shown in the reaction scheme. The hydrogen halide used in the dealkylation includes hydrogen bromide, hydrogen chloride, hydrogen iodide, and preferably hydrogen bromide. These hydrogen halides are advantageously prepared in a solvent such as methanol, ethanol, isopropanol, preferably water, at about
10-50% solution, preferably 47% of hydrogen halide
Can be used in aqueous solution. This dealkylation reaction generally involves heating the hydrogen halide to compound (a) for about 2 to 20 hours, preferably for about 5 to 10 hours, at a temperature of about 100 to 150°C, preferably at reflux temperature. This can be carried out using a large excess amount, preferably a large excess amount, from an equimolar amount. Alkylation of compounds of formula (b) can be accomplished by reaction with alkylating agents well known in the art in the presence of basic compounds. Suitable examples of alkylating agents include alkyl halides such as alkyl iodides, alkyl chlorides, alkyl bromides, dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, and the like. Suitable examples of basic substances include alkali metals such as sodium metal, potassium metal and their hydroxides, carbonates, bicarbonates and alkotees, and aromatic amines such as pyridine, piperidine, and the like. The alkylation is advantageously carried out using an equimolar amount to a large excess of alkylating agent, preferably 5 to 10 moles of alkylating agent per mole of compound of formula (b).
The process proceeds in a solvent such as water, a lower alkanol such as methanol, ethanol, isopropanol or n-butanol, or a ketone such as acetone or methyl ethyl ketone. The alkylation generally proceeds at room temperature. The reduction of 5-(α-substituted-aminoalkanoyl)carbostyryl of formula (), (a) or (b) to a compound of the invention of formula (), (a) or (b), respectively, is carried out using lithium aluminum hydride. , conventional reduction using reducing agents such as sodium borohydride, etc., or palladium black,
This can be carried out by conventional catalytic reduction in the presence of hydrogen and a catalyst such as palladium on carbon, Raney-nickel, platinum black, acidic platinum or the like. The reducing agent is added in a solvent at a temperature of about 0° C. to 100° C., preferably about 20° C. to 50° C., at atmospheric pressure, per mole of carbostyril compound of formula (a). Amounts of molar, preferably about 2 to 5 molar may be used. When sodium borohydride is used as the reducing agent, the solvent is preferably water or an alkanol such as methanol or ethanol. When lithium aluminum hydride is used as the reducing agent, the solvent is anhydrous diethyl ether, ethyl acetate, Non-aqueous solvents such as tetrahydrofuran and the like are preferred. Catalytic reduction is carried out at a temperature from room temperature to about 150°C, preferably from room temperature to about 120°C, at atmospheric pressure to about 100 atmospheres,
A solvent such as water, or methanol, under an atmosphere of hydrogen, preferably at a pressure of from atmospheric pressure to about 50 atmospheres.
from about 0.05 to about 1 mole per mole of carbostyryl compound of formula (a) in an alkanol such as ethanol or isopropanol, preferably about
The reduction system can advantageously be carried out with stirring of the abovementioned catalysts in amounts of 0.1 mol to 0.5 mol. Advantageously, the catalytic reduction is carried out at atmospheric pressure and at a temperature above about 50°C, or under pressure at a temperature above about room temperature. Catalytic reduction and reduction with reducing agents that can be used in the method of the invention are shown in more detail in the reaction scheme. These reactions can be carried out in the same manner as described above for the reduction of compounds of formulas (), (a) and (b). 3-
A formula () having a double bond between the 4-position and the 4-position,
Catalytic reduction of a compound of (a) or (b) generally produces the corresponding 3,4-dihydrocarbostyryl of formula (), (a) or (b), respectively, saturated in the 3,4-position. However, catalytic reduction can reduce only the 5-position of carbostyryl compounds of formula (), (a) or (b) and reduce the 3- and 4-positions if the conditions of reduction are carefully controlled.
The remaining formula (), (a) of the double bond between
It should be noted that it can also be used to form the corresponding carbostyril compound of (b). However, the 5-
For reduction of only the position, it is preferable to use the above-mentioned reducing agent. The conversion or inverse conversion of a compound of formula (a) to a compound of formula (b), i.e. alkylation or dealkylation, is as described for the alkylation or dealkylation of a compound of formula (a) or (b). It can be carried out by the same method as the above method. As shown in the reaction scheme, a 3,4-dihydrocarbostyryl compound can be converted to the corresponding carbostyryl compound at any stage of the process of the invention. The conversion or dehydrogenation of the compound of formula (b) to the compound of formula (a) involves the 3-
This can be carried out by any known method capable of forming a double bond between the 3-position and the 4-position by releasing hydrogen atoms from each of the 3- and 4-positions.
This dehydrogenation can be carried out by (1) using a dehydrogenating agent such as chloranil (tetrachloro-1,4-benzoquinone) or dichlorodicyano-1,4-benzoquinone, or (2) dehydrating sulfur, selenium dioxide, etc. This can be achieved by a method using a plating agent, preferably by using the above method (1) or (2).
Both dehydrogenations are carried out in solvents such as aromatic hydrocarbons such as benzene, toluene, xylene, phenetol, and chlorobenzene, lower alkanols such as methanol, ethanol, isopropanol, and tert-butanol, ethers such as dioxane, ketones such as acetone, and water. , in a solvent such as acetic acid. The dehydrogenation can advantageously be carried out from room temperature to the reflux temperature of the dehydrogenation system, preferably at or near the reflux temperature. Both the compound of formula () and the compound of formula () obtained as described above are basic substances and can form acid addition salts with various organic or inorganic acids. Particularly useful such salts are inorganic acids such as hydrochloric, sulfuric, phosphoric, hydrobromic, etc., or organic acids such as oxalic, maleic, fumaric, malic, citric, tartaric, ascorbic, etc. It is a pharmacologically acceptable acid addition salt formed with an acid. These acid addition salts are easily prepared by well-known methods, such as by adding an equivalent to an excess of the acid to a solution of the compound dissolved in a suitable organic solvent such as methanol, ethanol, isopropanol, acetic acid, etc. can be manufactured. Both the free base of the compound of formula () and its acid addition salt exhibit stimulatory activity on β-adrenergic receptors and are therefore very effective as drugs for the treatment of diseases such as bronchial asthma. be. As will be apparent to those skilled in the art, the compounds of the present invention contain two asymmetric centers and may therefore provide four optically active forms. The invention will be illustrated in further detail by reference to the following references and examples, which are given for illustrative purposes only and do not limit the scope of the invention. It should not be construed that it does. Unless otherwise noted, all parts, percentages, proportions, etc. are by weight. Reference example 1 After dissolving 27 g of 8-hydroxycarbostyril and 37 ml of chloroacetyl chloride in 250 ml of nitrobenzene, gradually adding 85 g of aluminum chloride.
Stirred at 70°C for 20 hours. After adding 500 ml of 10% hydrochloric acid, nitrobenzene was 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 g of 5-chloroacetyl-8-hydroxycarbostyryl as pale yellow crystals with a melting point of 285-287°C (decomposition). Reference Example 2 After adding 20 g of aluminum chloride to 5.0 g of 8-hydroxycarbostyril and mixing well, 10 g of chloroacetyl chloride was gradually added while cooling with ice water. A heating reaction was carried out at 40 to 45°C for 2 hours to produce 8-chloroacetoxycarbostyryl. then
After stirring at 70℃ for 3 hours and cooling, remove the precipitated crystals and add water.
2.6 g of 5-chloroacetyl-8-hydroxycarbostyryl as pale yellow crystals with a melting point of 285-287°C (decomposed) after washing with 300 ml and recrystallizing from methanol.
I got it. A portion of the 8-chloroacetoxycarbostyryl produced in the intermediate was taken out and recrystallized from acetone to obtain pale yellow crystals, whose melting point was confirmed to be 248-250°C (decomposed). Reference Example 3 To 0.5 g of 8-hydroxycarbostyril were added 1.5 g of chloroacetyl chloride and 20 ml of carbon disulfide, and 2 g of aluminum chloride was gradually added under cooling with ice water. After thoroughly mixing, the mixture was gradually heated and refluxed for 30 minutes. After cooling, excess chloroacetyl chloride and carbon disulfide were removed, and crushed ice was added to the residue for crystallization. After washing with water, recrystallize from acetone to melting point.
0.45 g of 8-chloroacetoxycarbostyryl was obtained as pale yellow crystals at 248-251°C (decomposition). Reference Example 4 20 g of aluminum chloride and 10 g of chloroacetyl chloride were added to 1.0 g of 8-chloroacetoxycarbostyryl obtained in Reference Example 3, and the mixture was heated at 75 to 85°C for 1 hour. Pour into crushed ice while hot to collect precipitated crystals, wash with water and recrystallize from methanol to obtain a melting point of 285-287°C.
(decomposition) of pale yellow crystals of 5-chloroacetyl-8
-3.7 g of hydroxycarbostyril were obtained. Reference Example 5 7.3 g of 8-hydroxycarbostyryl and 12.5 g of chloroacetyl chloride were mixed with 70 g of nitrobenzene.
ml, and gradually add 30 g of aluminum chloride while stirring on ice. After stirring at 50-55°C for 6 hours, the mixture was placed in ice water. The precipitated crystals were taken, washed with methanol, and then recrystallized from acetone to obtain a melting point of 239-241.
5-chloroacetyl in light yellow crystals at °C (decomposition)
3.5 g of 8-chloroacetoxycarbostyryl is obtained. Reference Example 6 1.7 g of 5-chloroacetyl-8-chloroacetoxycarbostyril obtained in Reference Example 5 was added to 50 ml of 10% hydrochloric acid.
and stir at 95-100°C for 2 hours. After cooling, the precipitated crystals were collected, washed with water, and then recrystallized from methanol to give pale yellow crystals with a melting point of 285-286°C (decomposed).
Chloracetyl-8-hydroxycarbostyryl
Get 1.1g. Reference Example 7 2.5 g of 5-chloroacetyl-8-chloroacetoxycarbostyryl obtained in Reference Example 5 is added to 30 ml of a 5% aqueous potassium hydroxide solution, and the mixture is stirred at 20 to 25°C for 30 minutes. While cooling, add dilute hydrochloric acid to adjust the pH to 2 to 3.
The precipitated crystals were collected, washed with water, and then recrystallized from methanol to obtain 1.7 g of 5-chloroacetyl-8-hydroxycarbostyryl as pale yellow crystals with a melting point of 285-287°C (decomposed). Reference Example 8 20 g of aluminum chloride is gradually added to 4.5 g of 8-hydroxycarbostyryl and 10 g of chloroacetyl chloride while stirring under ice cooling. Then 55-60℃
5-chloroacetyl-8-
Produces chloracetoxycarbostyryl,
Then, add 40 ml of 5% potassium hydroxide and stir at room temperature for 30 minutes. Next, add 10% hydrochloric acid to make an acidic solution and collect the precipitated crystals. After washing with water, recrystallize from methanol to obtain light yellow crystals with a melting point of 285-286℃ (decomposition).
2.3 g of -chloroacetyl-8-hydroxy-carbostyril are obtained. Before adding 5% aqueous potassium hydroxide to the above, a portion of it was taken out from the reaction system and poured into ice water, the precipitated crystals were collected, washed with methanol, and then recrystallized from ethyl acetate to obtain a solution with a melting point of 238. Pale yellow crystals of 5-chloroacetyl-8-chloroacetoxycarbostyryl were obtained at ~241°C (decomposition). Reference Example 9 10 g of 5-chloroacetyl-8-hydroxycarbostyryl produced in Reference Example 4 or 8 was added to benzene.
Pyridine to this suspension suspended in 50 ml
10 ml were added and the mixture was then allowed to react for 6 hours with heating under reflux stirring. The reaction mixture was filtered to obtain the reaction product, which was then washed with benzene and then with 50 ml of isopropanol. The resulting insoluble material was dissolved in 150 ml of 2% hydrochloric acid. The solution was concentrated to dryness under reduced pressure, and the resulting residue was recrystallized from ethanol to give white amorphous 5-piperidinoacetyl-8-hydroxycarbostyryl hydrochloride 1/2 with a melting point of 239-241°C (decomposition). 7.5 g of dihydrate was obtained. Reference Example 10 10 g of 5-chloroacetyl-8-hydroxycarbostyryl produced in Reference Example 4 or 8 was added to benzene.
9 ml of morpholine were added to this suspension and the mixture was then allowed to react for 4 hours under reflux and stirring. The reaction mixture was cooled and the resulting precipitate was collected. This precipitate was dissolved in 60 ml of isopropanol, and the solution was adjusted to pH 2-3 with concentrated hydrochloric acid. The resulting acidic solution was cooled with ice and the precipitate formed was removed and then recrystallized from ethanol. Dissolve this precipitate in 20 ml of water and dilute the solution with sodium bicarbonate to pH 7.5.
The temperature was adjusted to ~8.0 and cooled in an ice bath. The precipitate formed on cooling is removed and recrystallized from ethanol to obtain a melting point of 238.
4.2 g of white amorphous 5-morpholinoacetyl-8-hydroxycarbostyryl with a temperature of ~239.5°C (decomposed) was obtained. The product thus obtained is
Confirmed by IR spectrum analysis, NMR spectrum analysis, and elemental analysis. Reference example 11 24.3 g of 8-hydroxy-3,4-dihydrocarbostyryl and 68 g of chloroacetyl chloride
is added to 130 ml of carbon disulfide, and 200 g of aluminum chloride is gradually added while stirring while cooling with ice water. After stirring at 60-70°C for 6 hours, carbon disulfide is distilled off. Pour the residue into 500 ml of ice water. Take the precipitated crystals,
After washing with water, the crystals were recrystallized twice from methanol to obtain 8.0 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyryl as pale yellow crystals with a melting point of 189-191°C. Reference example 12 Dissolve 13 g of 8-hydroxy-3,4-dihydrocarbostyryl and 20 g of chloroacetyl chloride in 100 ml of nitrobenzene, and dissolve aluminum chloride.
After gradually adding 40 g, stir at 70-75°C for 15 hours. Nitrobenzene is removed by steam distillation. After cooling, the precipitated crystals were collected, washed with hot water, and then recrystallized from methanol to give pale yellow crystals of 5-chloroacetyl-8-hydroxy- with a melting point of 189-190°C.
7.2 g of 3,4-dihydrocarbostyryl are obtained. Reference Example 13 To 17 g of 8-methoxy-3,4-dihydrocarbostyryl were added 66 g of chloroacetyl chloride and 30 ml of nitrobenzene. Aluminum chloride under ice cooling
100 g was gradually added and stirred at room temperature for 30 minutes. 30
After standing for a minute, it was poured into 700 ml of ice water. The precipitate was collected, then washed with ethanol, and recrystallized from methanol to obtain a white needle-like substance with a melting point of 187-188°C.
Got 20g. This product was confirmed to be 5-chloroacetyl-8-methoxy-3,4-dihydrocarbostyryl from the results of NMR, IR, and elemental analysis. Reference Example 14 To 8.5 g of 8-methoxy-3,4-dihydrocarbostyryl were added 33 g of chloroacetyl chloride and 30 ml of carbon disulfide. 50g of aluminum chloride under ice cooling
was gradually added and stirred at room temperature for 2 hours. After the carbon disulfide layer was removed by tilting, crushed ice was added to allow crystallization. The resulting precipitated crystals were then washed with ethanol and recrystallized from methanol to a melting point of 187.
11 g of white needle-like material was obtained, ~188°C. This product was confirmed to be 5-chloroacetyl-8-methoxy-3,4-dihydrocarbostyryl from the results of NMR, IR, and elemental analysis. Reference Example 15 24.3 g of 8-hydroxy-3,4-dihydrocarbostyryl and 68 g of chloroacetyl chloride are added to 130 ml of carbon disulfide, and 200 g of aluminum chloride is gradually added while stirring under ice-water cooling. The reaction is carried out for 4 hours under ice cooling to produce 8-chloroacetoxy-3,4-dihydrocarbostyryl. Then 60~
After stirring at 70°C for 2 hours, carbon disulfide was distilled off. The residue was poured into 500 ml of ice water, the precipitated crystals were separated, washed with water, and then recrystallized twice from methanol to give pale yellow crystals of 5-chloroacetyl-8-hydroxy-3,4 with a melting point of 189-191°C. - Obtain 8.0 g of dihydrocarbostyril. Furthermore, 8- generated in the middle
A portion of the reaction product was taken out and the melting point of chloroacetoxy-3,4-dihydrocarbostyryl was confirmed by recrystallization, and it was found to be 183-186°C. Reference example 16 Add 40 g of aluminum chloride to 11.5 g of 8-hydroxy-3,4-dihydrocarbostyryl, mix well, and add chloroacetyl chloride under ice water cooling.
Gradually add 21g. After heating and stirring at 35-40°C for 2 hours, excess chloroacetyl chloride is distilled off. Pour the residue into crushed ice water, collect the precipitated crystals, wash with water, and recrystallize from acetone to obtain mp.182-184.
8-Chloroacetoxy-3,4 in pale yellow crystals at °C
- 5.6 g of dihydrocarbostyril are obtained. Reference example 17 Dissolve 13 g of 8-hydroxy-3,4-dihydrocarbostyryl and 20 g of chloroacetyl chloride in 100 ml of nitrobenzene, and dissolve aluminum chloride.
After gradually adding 40 g and stirring at 70-75 °C for 15 h, nitrobenzene is removed by steam distillation. After cooling, the precipitated crystals were collected, washed with hot water, and then recrystallized from methanol to give 5-chloroacetyl-8-hydroxy- as pale yellow crystals with a mp of 189 to 190°C.
7.2 g of 3,4-dihydrocarbostyryl are obtained. Reference example 18 6.0 g of 8-hydroxy-3,4-dihydrocarbostyryl and 15.0 g of chloroacetyl chloride
30 g of aluminum chloride is gradually added to the solution while stirring on ice. Next, stir at 55 to 60°C for 6 hours.
-chloroacetyl-8-chloroacetoxy-3,
After 4-dihydrocarbostyryl is produced, 50 ml of 10% aqueous hydrochloric acid solution is added and stirred at 95-100°C for 3 hours. After cooling, the precipitated crystals were collected, washed with water, and then recrystallized from methanol to obtain a melting point of 189.
5-Chloroacetyl-8 as pale yellow crystals at ~190℃
-Hydroxy-3,4-dihydrocarbostyryl
Get 2.7g. Before hydrolysis, a portion of the reaction system was taken out and poured into ice water to collect the precipitated crystals, washed with hot methanol and recrystallized from dimethylformamide-methanol (volume ratio 1:1). 5-chloroacetyl-8-chloroacetoxy-3,4-dihydrocarbostyryl was obtained as pale yellow crystals with a melting point of 206-207°C. Reference example 19 8-hydroxycarbostyril 20g, α-bromobutyric acid bromide 50g, anhydrous aluminum chloride
Add 50 g of carbon disulfide and 400 ml of carbon disulfide, heat at 50°C for 13 hours, remove the carbon disulfide layer at an angle, add crushed ice to the residue to crystallize it, and then collect and wash with water. Furthermore, it was recrystallized from methanol and 5-(α
27 g of -bromobutyryl)-8-hydroxycarbostyryl are obtained. Melting point 218-219℃ (color decomposition). Reference example 20 10g of 8-hydroxycarbostyril, 25g of α-bromobutyric acid chloride, anhydrous aluminum chloride
Add 25g, heat at 70°C for 4 hours while mixing thoroughly, add crushed ice to crystallize, remove and wash with water. Further recrystallization from methanol yields 12.6 g of 5-(α-bromobutyryl)-8-hydroxycarbostyryl. Melting point 218-219℃ (color decomposition). Reference Example 21 Add 25 g of α-bromobutyric acid bromide and 100 ml of nitrobenzene to 10 g of 8-hydroxycarbostyril, and add 25 g of anhydrous aluminum chloride while cooling. After heating at 70°C for 10 hours, the precipitated crystals were poured into crushed ice, washed with water, and recrystallized from methanol to give 5-(α-bromobutyryl)-8-.
Obtain 11.2 g of hydroxycarbostyril. melting point 217
~218.5℃ (color decomposition). Reference Example 22 5 ml of morpholine was prepared in Examples 19 to 21.
It was added to 5 g of (α-bromobutyryl)-8-hydroxycarbostyryl, and the mixture was reacted for 4 hours at a temperature of 40° C. with stirring. Next, the reaction mixture was concentrated under reduced pressure, and 100 ml of water was added to the resulting residue. The mixture was stirred and filtered, then the mother liquor was concentrated under reduced pressure. The residue was dissolved in acetone and the solution was filtered to remove insoluble material. Next, the liquid was concentrated under reduced pressure, the pH was adjusted to 2 to 3 with concentrated hydrochloric acid, and the precipitate formed by cooling in an ice bath was recrystallized from ethanol to determine the melting point.
White amorphous 5- with a temperature of 179-182℃ (decomposition)
2.1 g of (α-morpholinobutyryl)-8-hydroxycarbostyryl hydrochloride monohydrate was obtained. The product thus obtained was confirmed by NMR spectroscopy, IR spectroscopy and elemental analysis. Reference Example 23 17.1 g of α-bromopropionyl chloride, 27 g of anhydrous aluminum chloride and 8 ml of nitrobenzene were mixed with 8-methoxy-3,4-dihydrocarbostyryl.
8g and heat the mixture at 50°C for 1 hour while stirring.
Heated to a temperature of 60°C. The reaction mixture was then poured into ice-water
The mixture was poured onto 200ml, and the precipitate formed was collected and washed with water. This precipitate was then recrystallized from ethanol to yield 11.5 g of material with a melting point of 154°C to 155°C.
The product thus obtained was confirmed to be 5-(α-bromopropionyl)-8-methoxy-3,4-dihydrocarbostyryl by NMR spectroscopy, IR spectroscopy, and elemental analysis. Reference example 24 26.4 g of α-bromobutyl bromide, 17.5 g of anhydrous aluminum chloride and 5 ml of nitrobenzene
-methoxy-3,4-dihydrocarbostyryl
Add 5g to 50-60 g for 1 hour while stirring the mixture.
heated to a temperature of °C. Next, mix the reaction mixture with ice-water.
The mixture was poured into 100 ml, and the precipitate formed was collected and washed with water. The precipitate was then recrystallized from ethanol to yield 5 g of material with a melting point of 151-152°C. The product thus obtained was confirmed to be 5-(α-bromobutyryl)-8-methoxy-3,4-dihydrocarbostyryl by NMR spectroscopy, IR spectroscopy, and elemental analysis. Example 1 5 g of 5-(α-bromoprobionyl)-8-hydroxy-3,4-dihydrocarbostyryl are suspended in 30 ml of benzene, 4.2 ml of morpholine are added to this suspension, and the mixture is then brought under reflux. The reaction was allowed to proceed for 4 hours while heating. The reaction mixture was filtered, and the liquid was washed with water and concentrated under reduced pressure to remove remaining water. Pour the resulting residue into 50 ml of isopropanol.
The solution was adjusted to pH 2-3 with concentrated hydrochloric acid. A viscous precipitate formed by cooling in an ice bath was separated and dissolved by heating in acetone. After cooling the solution, the precipitate formed was dissolved in 30 ml of water and the pH was adjusted to 7.5-8 with sodium bicarbonate. Collect the precipitate formed by cooling in an ice bath and add 10 ml of 47% hydrogen bromide aqueous solution.
and then concentrated under reduced pressure. The residue thus obtained was washed with 10 ml of ethanol and recrystallized from ethanol to give a white amorphous 5-(α-morpholino)-propionyl-8-hydroxy-3 having a melting point of 235-236°C (decomposed). , 2.6 g of 4-dihydrocarbostyryl hydrobromide monohydrate was obtained. Reference example 25 30ml of nitrobenzene and chloroacetyl chloride
70ml of 1-methyl-8-methoxycarbostyryl
130 g of aluminum chloride was gradually added thereto while cooling the mixture in an ice bath, and the mixture was reacted at a temperature of 60° C. for 4 hours with stirring.
The reaction mixture was then poured into 1 portion of ice water to precipitate the product. The precipitate was collected, washed with diethyl ether, and recrystallized from a mixture of chloroform and ethanol (2:5 volume ratio) to give a melting point of 204-205.5°C.
32 g of white amorphous 1-methyl-5-chloroacetyl-8-methoxycarbostyryl having the following properties were obtained. The product thus obtained was subjected to elemental analysis.
Confirmed by IR spectrum analysis and NMR spectrum analysis. Reference example 26 Add 7.4 g of 1-methyl-8-hydroxycarbostyryl to 40 ml of nitrobenzene and 12 ml of monochloroacetyl chloride, gradually add 20 g of aluminum chloride to the mixture while cooling it with ice water, and then add 18 g of aluminum chloride while stirring the mixture. The reaction was carried out at a temperature of 60°C for an hour. The reaction mixture was then poured into 500 ml of ice water to precipitate the product. The precipitate was collected, washed with diethyl ether and recrystallized from a mixture of ethanol and dimethylformamide (1:1 by volume) to give a white amorphous 1-
2.8 g of methyl-5-chloroacetyl-8-hydroxycarbostyryl was obtained. The product thus obtained was subjected to elemental analysis and IR spectroscopy.
Confirmed by NMR spectrum analysis. Example 2 5-piperidinoacetyl produced in Reference Example 2
2.0 g of 8-hydroxycarbostyryl hydrochloride was dissolved in 200 ml of methanol, 2.0 g of sodium borohydride was added while cooling the solution in an ice bath, and the mixture was stirred for 2 hours. The mixture was adjusted to pH 2-3 with concentrated hydrochloric acid.
The mixture was allowed to stand at room temperature for 1 hour and then filtered. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 30 ml of ethanol. The solution was filtered to remove insoluble materials, and the solution was concentrated under reduced pressure. These operations (dissolution in ethanol, filtration and concentration) were performed in 3 steps.
Repeated times. The resulting residue was heated and dissolved in acetone, and the precipitate formed by cooling was collected and recrystallized from isopropanol, with a melting point of 146-148°C (decomposition).
white amorphous 5-(1-hydroxy-2
-piperidino)ethyl-8-hydroxycarbostyryl hydrochloride 11/2 hydrate was obtained. The product thus obtained was confirmed by IR spectral analysis, NMR spectral analysis and elemental analysis. Example 3 5-morpholinoacetyl produced in Reference Example 10
1.0g of 8-hydroxycarbostyril in methanol
1.2 g of sodium borohydride was added to this solution and the mixture was reacted for 2 hours with stirring. The reaction mixture was adjusted to pH2~ with concentrated hydrochloric acid.
3 and the mixture was left at room temperature for 1 hour. The reaction mixture was then filtered and the liquid was concentrated under reduced pressure. The residue was dissolved in 20 ml of ethanol, the solution was filtered to remove insoluble materials, and the solution was concentrated under reduced pressure. This operation (dissolving in ethanol, filtration and concentration) was repeated three times, and the residue thus obtained was recrystallized from acetone. The precipitated crystals are collected, strained with 20 ml of an aqueous sodium bicarbonate solution, crushed to remove soluble substances, washed with water, and dissolved in ethanol by heating. The resulting solution was adjusted to pH 2-3 with concentrated hydrochloric acid, and the precipitate formed by cooling was removed to give a melting point of 157-158.5°C.
A white amorphous 5-(1-hydroxy-2-morpholino)ethyl-8-hydroxycarbostyryl hydrochloride 11/2 hydrate having (decomposition) was obtained. The product thus obtained was confirmed by IR spectral analysis, NMR spectral analysis and elemental analysis. Example 4 1.5 g of 5-piperidinoacetyl-8-hydroxycarbostyryl hydrochloride was dissolved in 100 ml of water, 0.5 g of palladium carbon and 0.2 g of palladium black were added to the solution, and the resulting mixture was then shaken. 70℃ while
Catalytic reduction was carried out under atmospheric pressure in a hydrogen atmosphere for 4 days at a temperature of . After completion of the reduction, the reaction mixture was filtered to separately remove the catalyst, and the liquid was concentrated and dried under reduced pressure. The resulting residue was heated and dissolved in acetone, and the solution was then cooled. The precipitate formed upon cooling is recrystallized from isopropanol to a melting point of 136-139°C.
White amorphous 5-(2-pipetodino-1-hydroxy)ethyl-8-hydroxy- with (decomposition)
0.8 g of 3,4-dihydrocarbostyryl hydrochloride 1/2 hydrate was obtained. The product thus obtained is
It was confirmed by IR spectrum analysis, NMR spectrum analysis and elemental analysis. Example 5 15 ml of 47% hydrobromic acid was added to 1.5 g of 5-(1-hydroxy-2-tert-butylamino)propyl-8-methoxy-3,4-dihydrocarbostyryl, heated under reflux for 15 hours, and then concentrated. Dry and add acetone to crystallize. The crystals were recrystallized from ethanol-acetone to obtain 1.4 g of a substance with a melting point of 198-199°C (decomposed). Based on the analysis results of NMR, IR and elemental analysis, this product is 5-(1-hydroxy-2
-tert-butylamino)propyl-8-hydroxy-3,4-dihydrocarbostyryl hydrobromide monohydrate. The target compound of the present invention obtained in the same manner as in Example 5 is shown below. 5-1-hydroxy-2-morpholinobutyl-8-hydroxy-3, melting point 127-129°C (decomposition)
4-dihydrocarbostyril hydrochloride. 5-1-hydroxy-2-morpholinobutyl-8-hydroxy-3, melting point 183-185°C (decomposition)
4-dihydrocarbostyryl hydrobromide. Example 6 1.0 g of 5-(2-morpholinobutyryl)-8-hydroxy-3,4-dihydrocarbostyryl hydrobromide was dissolved in 70 ml of water, and 0.2 g of palladium carbon and 0.3 g of palladium black were added to this solution. g was added and the mixture was then catalytically reduced at atmospheric pressure under a hydrogen atmosphere at a temperature of 70° C. for 10 days with shaking. After completion of the reduction, the catalyst is separately removed by filtering the reaction mixture.
The liquid was concentrated and dried under reduced pressure. The resulting residue was heated and dissolved in acetone, then the solution was cooled. The precipitate formed by cooling is recrystallized from ethanol to determine the melting point.
White amorphous 5- with a temperature of 183-185℃ (decomposition)
(1-hydroxy-2-morpholino)butyl-8
-Hydroxy-3,4-dihydrocarbostyryl hydrobromide 1/2 hydrate (0.7 g) was obtained. The product thus obtained was analyzed by NMR spectroscopy and IR.
Confirmed by spectral analysis and elemental analysis. The compounds of the present invention can be prepared in tablets, powders, granules, capsules, syrups, solutions, preferably in combination with pharmacologically acceptable carriers or excipients well known in the art, at dosage levels of 100 g to 50 mg/Kg/day. It can be administered by oral, intravenous, intramuscular or inhalation routes in pharmaceutically customary dosage forms such as , suspensions, inhalants and the like. Compounds of the invention and dosage forms containing at least one of the compounds of the invention can be administered in single or multiple doses. Formulation Example Prescription of Pharmaceutical Composition Lactose 55g Corn starch 22g Crystalline cellulose 22g Methylcellulose 0.8g Active ingredient 0.1g The above ingredients were mixed in a conventional manner and press-molded into tablets to make 1000 tablets. Although the present invention has been described in detail with reference examples, examples, and formulation examples thereof, it will be obvious to those skilled in the art that the present invention can be changed or modified in various ways without departing from the spirit and scope of the present invention. .

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and R ² and R ³
together with the nitrogen atom to which they are bonded represents a piperidino group or a morpholino group, and R ⁴ and
R ⁵ represents a hydrogen atom, and the formula The carbostyryl skeleton represented by the formula [Formula] or [Formula] Styryl derivatives or pharmaceutically usable acid addition salts thereof.