JPS6326751B2 - - Google Patents

Description

[Detailed description of the invention]

The object of the present invention is to This is a new method for producing carbostyril derivatives. In the general formula, W represents a vinylene group, ethylene group or 2-methyl-vinylene group, and D
represents a linear or branched alkylene group having 2 to 6 carbon atoms, m represents 1,
R ₁ represents a hydrogen atom, and R ₂ represents a cycloalkyl group, phenyl group, naphthyl group, phenylalkyl group, pyridyl group, or quinolyl group having 3 to 6 carbon atoms (however, the above aromatic nucleus alkyl, hydroxy, methoxy, amino, cyclohexyl, phenyl or halogen atom), and R ₃ and R ₄ may be the same or different and may be substituted by a hydrogen atom or a halogen atom or an alkyl group. represent Compounds of the general formula have useful pharmacological properties. They not only have a positive inotropic effect but also particularly antithrombotic activity. Pharmacological tests were conducted on the following compounds for this antithrombotic effect: (Compound according to the method of the present invention) A=6-(4-phenylsulfinylbutoxy)-
3,4-dihydrocarbostyryl B=6-[4-(2-pyridylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl C=6-(2-phenylsulfinyl-ethoxy)
-3,4-dihydrocarbostyryl D=6-(4-benzylsulfinyl-butoxy)
-3,4-dihydrocarbostyryl E=6-[4-(4-chlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl F=6-(4-cyclohexylsulfinyl-butoxy)- 3,4-dihydrocarbostyryl G=6-[4-(2-naphthylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl H=6-[4-(2-methoxyphenylsulfinyl)- butoxy]-3,4-dihydrocarbostyryl I = 6-(4-phenylsulfinyl-butoxy)
-Carbostyryl K=6-[4-(4-hydroxy-3,5-di-
tert-butyl-phenylsulfinyl)-butoxy]carbostyryl L = 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]carbostyryl M = 4-methyl-6-(4-phenylsulfinyl) rufinyl-butoxy)-carbostyryl N=6-[4-(2,5-dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl O=6-[4-(3,4-dichloro phenylsulfinyl)-butoxy]-3,4-dihydro-carbostyryl P=6-[4-(3,4-dichloro-phenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl Q=6 -[4-(2-pyridylsulfinyl)-butoxy]carbostyryl R=4-methyl-6-[4-(2-pyridylsulfinyl)-butoxy]carbostyryl S=6-[4-(4 -cyclohexyl-phenylsulfinyl)-butoxy]carbostyryl T=6-[4-(4-biphenylylsulfinyl)
-butoxy]carbostyryl U=6-[4-(2-quinolylsulfinyl)-butoxy]carbostyryl V=6-[4-(4-tert, butyl-phenylsulfinyl)-butoxy]-3 ,4-dihydrocarbostyryl W=6-[4-(4-biphenylylsulfinyl)
-butoxy]-3,4-dihydrocarbostyryl X=6-[2-(phenylsulfinylmethyl)-
benzyloxy]-3,4-dihydrocarbostyryl Y = 5-nitro-6-(4-phenylsulfinyl-butoxy)-carbostyryl Z = 6-(6-phenylsulfinyl-hexoxy)-3,4 -dihydrocarbostyryl (control compound) AA=6-(3-ethylthio-propoxy)-3,
4-dihydrocarbostyryl BB=6-(3-ethylsulfonyl-propoxy)
-3,4-dihydrocarbostyryl CC=6-(3-ethylthio-propoxy)-carbostyryl DD=6-(3-ethylsulfonylpropoxy)-
Calbostyril. Test method: Determination of platelet aggregation according to the method of Born and Cross (J. Physiol. Vol. 170, p. 397 (1964)) Platelet aggregation was determined in platelet-rich blood glands of healthy individuals. The decrease in optical density was measured and recorded spectrophotometrically after addition of adenosine-diphosphate or collagen. The aggregation rate was calculated from the slope angle of this concentration curve (Vmax). Optical density is indicated as the point on the curve where the maximum amount of light is transmitted (OD). The EC ₅₀ column in the table indicates optical density. Select a small but sufficient amount of collagen to cause irreversible aggregation. Approximately 0.01 ml of collagen solution was added to 1 ml of platelet-rich blood to induce maximum aggregation (commercially available collagen from Hormonchemie, Myuncheng). The amount of adenosine-diphosphate (ADP) was selected to produce only the first phase of the BORN curve. The required amount of ADP was approximately 1.10 ^-6 mol/. Boehringer
Commercially available ADP from Mannheim was used. The amount of compound that causes 50% inhibition of platelet aggregation was determined from the graph (EC ₅₀ )

【table】

[Table] It has been recognized that carbostyril of the general formula can also be prepared according to the following method. General formula appropriately formed in the reaction mixture (In the formula, D, W, R ₁ to R ₄ and m are the same as defined above, and Z represents a nucleophilically convertible group such as a hydroxy group, a halogen atom, alkoxy, aryloxy or aralkoxy group) Cyclization of the compound. The cyclization is carried out in the presence of a condensing agent such as sulfuric acid, concentrated hydrochloric acid, phosphoric acid or thionyl chloride as appropriate, in a solvent such as glacial acetic acid, tetrahydrofuran, dioxane, chloroform, triene, ethanol or in an excess of condensing agent used. at elevated temperatures, for example between 50 and 200°C, but preferably
Preferably it is carried out at a temperature between 80 and 150°C.
However, the reaction can also be carried out without solvent and/or condensing agent. It is not necessary to isolate the compound of the general formula and use it as is as a starting material. This compound can be prepared in situ from the corresponding nitro compound by, for example, reducing the nitro group with hydrogen in the presence of a hydrogenation catalyst such as palladium-charcoal, palladium-calcium carbonate or palladium-calcium carbonate plus lead acetate (Rindler's catalyst). Thus, by reduction with metals such as iron, tin or zinc in the presence of acids, salts such as iron()-sulfate, zinc()-chloride, chromium()-chloride or dithionite can be prepared. by reduction with sodium hydrazine or by reduction with hydrazine in the presence of Raney-nickel. When m represents 1 in the corresponding nitro compound, the reduction of the nitro group is carried out with an equivalent amount of the necessary reducing agent.
For example with metal salts such as iron-()-sulfate, tin-()-chloride, chromium-()-chloride or sodium dithionite or in the presence of a hydrogenation catalyst deactivated with hydrogen, e.g. palladium
It is appropriate to conduct this in the presence of calcium carbonate + lead acetate. If, for example, this reduction is carried out in the presence of palladium-charcoal, the sulfoxide groups will also be partially reduced. Furthermore, if W in the corresponding nitro compound represents a vinylene group, this group can be converted into the corresponding ethylene group by hydrogenation, in particular the reduction catalytically with activated hydrogen, for example palladium- This is the case when carried out with hydrogen in the presence of charcoal. The compounds of the general formula used as starting materials are partly known from the literature and they can be obtained by known methods. That is, compounds of the general formula are obtained by reducing the corresponding nitro compounds, which in turn are obtained by alkylating the corresponding 2-nitro-5-hydroxy compounds with the corresponding α,ω dihalogen alkanes, and then by reducing the corresponding nitro compounds. by reaction with a mercapto compound and optionally subsequent oxidation with hydrogen peroxide. The following examples illustrate the invention. Example 1 (Reference example) 6-[4-(2-pyridylsulfonyl)-butoxy]-3,4-dihydro-carbostyryl (a) 2-nitro-5-hydroxy-cinnamic acid methyl ester 21.0 g of 2- Nitro-5-hydroxy-cinnamic acid [S. N. Chakravertei (SN
Chakravarti) and PLNRao, Chem. Sasa. (Chem.Soc.)
1938, 172] in 200 ml of methanol.
Add 86 ml of thionyl chloride to this solution while stirring.
Add dropwise within 45 minutes, at a temperature of 36°C.
It can be raised to After stirring for a further 25 minutes, the reaction mixture is cooled on an ice bath to obtain 18.6 g of 2-nitro-5-hydroxy-cinnamate methyl-ester. Melting point: 201-203℃. (b) 2-Nitro-5-bromobutoxy-cinnamic acid methyl ester 22.3 g 2-nitro-5-hydroxy-cinnamic acid methyl ester, 59.7 ml 1,4-dibromobutane and 13.8 g in 200 ml dimethyl sulfoxide. A mixture of 15 g of potassium carbonate at room temperature
Stir for an hour. After adding 800 ml of water, the reaction mixture is extracted with chloroform and, after evaporation of the solvent, 31.7 g of 2-nitro-5-brombutoxy-cinnamate methyl ester are isolated. Melting point: 60.5-63℃. (c) 2-Nitro-5-[4-(2-pyridylmercapto)-butoxy]-cinnamic acid methyl ester A mixture of 5 g potassium carbonate and 4.0 g 2-mercaptopyridine in 100 ml dimethyl sulfoxide for 60 minutes. After stirring, add 10.75g of 2
-Nitro-5-bromo-butoxy-cinnamic acid methyl ester is added and the mixture is stirred at room temperature for 18
Stir for an hour. 400 ml of water are added and the oily reaction product is isolated by ether extraction. Yield: 11.0g (94.2% of theory). (d) 2-nitro-5-[4-(2-pyridylsulfonyl)-butoxy]-cinnamate methyl ester 7.0 g of 2-nitro-5-[4-(2-pyridylmercapto)-butoxy]-cinnamate methyl ester Dissolve the acid methyl ester in 70 ml of acetic acid. 35% of 5.0ml
Hydrogen peroxide is added and the mixture is kept at room temperature for 3 days. After distilling off the glacial acetic acid, the reaction product is recrystallized from chloroform/methanol. Yield: 3.5g (46.2% of theory). Melting point: 118-121℃. (e) 6-[4-(2-pyridylsulfonyl)-butoxy]-3,4-dihydrocarbostyryl 2.1 g of 2-nitro-5-[4-(2-pyridylsulfonyl)-butoxy]-cinnamic acid Dissolve methyl ester in 20ml of glacial acetic acid and add 0.5g of this
hydrogenation using 10% palladium on charcoal at 3 bar hydrogen pressure at room temperature. After distilling off the glacial acetic acid,
The residue is refluxed with 20 ml of concentrated hydrochloric acid for 4 hours. The reaction product was neutralized with 2N sodium hydroxide solution,
and extract with chloroform. The evaporation residue is recrystallized from xylene. Yield: 1.06g (55.6% of theory). Melting point: 121-123℃. Example 2 (Reference example) 6-[4-(2-pyridylsulfonyl)-butoxy]-carbostyryl 2.0 g of 2-nitro-5-[4-(2-pyridylsulfonyl)-butoxy]-cinnamate methyl ester and 3.0 g of sodium dithionite.
Reflux in 20 ml water and 10 ml ethanol for 4 hours to obtain a clear solution. The reaction mixture is evaporated and refluxed for 3 hours with 20 ml of concentrated hydrochloric acid. 2n
After neutralization with sodium hydroxide solution, the reaction product is extracted with ether and recrystallized from xylene by addition of a small amount of dimethylformamide. Yield: 0.5g (29% of theory) Melting point: 176-179°C. This material can be obtained in a similar manner using a Lindlar catalyst (palladium partially inactivated by lead) instead of sodium dithionite as reducing agent. Thereby, only the nitro group is reduced, and 6-[4-(2-pyridylsulfonyl)
-butoxy]-carbostyril is obtained after treatment with concentrated hydrochloric acid. Example 3 (Reference example) 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-carbostyryl 4.5 g of 2-nitro-5-[4-(3,4-dichlorophenylmercapto)- butoxy]-cinnamic acid methyl ester (melting point: 91-92℃, 2-nitro-
5-Hydroxy-cinnamate methyl-ester and 4
-(3,4-dichlorophenylmercapto)-butyl-bromide) is refluxed for 4 hours in a mixture of 50 ml of ethanol and 50 ml of water. After removing the solvent, the residue is refluxed for 4 hours with 100 ml of concentrated hydrochloric acid. The crystalline material obtained is filtered by absorption and recrystallized from xylene. Yield: 1.2g (31% of theory). Melting point: 144℃. Example 4 6-[4-(3,4-dichlorophenyl-sulfinyl)-butoxy]-carbostyryl(a) 2-nitro-5-[4-(3,4-dichlorophenyl-sulfinyl)-butoxy]- Cinnamic acid methyl ester 11.2 g of 2-nitro-5-hydroxy-cinnamic acid methyl ester are dissolved in 150 ml of dimethyl sulfoxide. This solution is mixed with 9.2 g of anhydrous potassium carbonate and stirred for 15 minutes.
16.5 g of 4-(3,4-dichlorophenylsulfinyl)-butyl bromide are added and the mixture is stirred for 40 hours at room temperature. reaction mixture
Dilute with 1000 ml of water and extract with a mixture of 200 ml of chloroform and 100 ml of methanol.
Evaporation of the organic solvent yields an oily residue,
On treatment with ether it is obtained in crystalline form. Yield: 13g (57% of theory). Melting point: 78-81°C (b) 2-Amino-5-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-cinnamate methyl ester 4.2 g of 2-nitro-5-[4 -(3,4-dichlorophenylsulfinyl)-butoxy]-cinnamate methyl ester was prepared in 100 ml of methanol with 0.5 g of Lindlar's catalyst (palladium partially deactivated by lead acetate). Hydrogenate with calcium carbonate) at a hydrogen pressure of 3 bar for 12 hours at room temperature. After removing the catalyst, the solvent is evaporated and the resinous dark residue is used directly in the next reaction. (c) 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-carbostyryl The above-mentioned 2-amino-5-[4-(3,4-dichlorophenylsulfinyl)- [butoxy]-cinnamic acid methyl ester is heated to boiling for 3 hours with 80 ml of 5N hydrochloric acid and filtered hot. After cooling the filtrate, colorless crystals are obtained. Yield: 2.1 g (56% of theory). Melting point: 191-192℃. In the above reaction method, if iron powder and 80% acetic acid are used as the ring group of 2-nitro-5-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-cinnamate methyl ester, too,
Furthermore, 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-carbostyryl is obtained as a reaction product. Example 5 2.3 g of 2-nitro-5-(3,4-dichlorophenylsulfinyl)-butoxy-cinnamic acid methyl ester are dissolved in 20 ml of glacial acetic acid as in Example 5b.
Hydrogenation is carried out using 0.2 g of palladium on charcoal at a hydrogen pressure of 3 bar for 7 hours at room temperature. After removing the catalyst, the glacial acetic acid was distilled off and the residue was poured into 40 ml of
Heat with 5N hydrochloric acid until boiling for 1 hour.
The reaction mixture is extracted with a small amount of chloroform and chromatographed on thin layer plates (Merck silica gel 60F ₂₅₄ ) with ethylene chloride/methanol 9:1. The obtained compound
Confirm by spraying with UV-light and iodine spray. Rf value: 0.30: 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-carbostyryl. Blue-violet color with iodine spray. Rf value: 0.42: 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-carbostyryl.
Iodine spray turns orange-yellow at first, then gradually gray-
Violet. Rf value: 0.45: 6-[4-(3,4-dichlorophenyl-sulfinyl)-butoxy]-3,4-dihydro-carbostyryl. Strong orange-yellow color with iodine spray. Rf value: 0.57: 6-[4-(3,4-dichlorophenyl-mercapto)-butoxy]-3,4-dihydro-carbostyryl. Pale egg yellow with iodine spray. The following compounds are prepared analogously to the above examples. 6-(4-phenylsulfinylbutoxy)-
3,4-dihydrocarbostyryl melting point: 144.5-145.5°C 6-[4-(2-pyridylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl melting point: 144.5-146°C. 6-(2-phenylsulfinyl-ethoxy)-
3,4-dihydro-carbostyryl Melting point: 171-172°C 6-(4-benzylsulfinyl-butoxy)-
3,4-dihydrocarbostyryl Melting point: 141.5-142℃ 6-[4-(4-chlorophenylsulfinyl)
-butoxy]-3,4-dihydrocarbostyril melting point: 148-149.5°C 6-(4-cyclohexylsulfinyl-butoxy)-3,4-dihydrocarbostyryl melting point: 153-155.5°C 6-[4-(2 -naphthylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl melting point: 147.5-148.5°C 6-[4-(2-methoxyphenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl melting point: 130.5-133℃ 6-(4-phenylsulfinyl-butoxy)-
Carbostyril melting point: 181-182.5℃ 6-[4-(4-hydroxy-3,5-di-tert
-butyl-phenylsulfinyl)-butoxy]-
Carbostyril melting point: 192-194℃ 6-[4-(3,4-dichlorophenylsulfinyl)-butoxy]-carbostyril melting point: 191-196℃ 4-methyl-6-(4-phenylsulfinyl -butoxy)-carbostyril melting point: 167-168℃ 6-[4-(2,5-dichlorophenylsulfinyl)-butoxy]-3,4-dihydrocarbostyril melting point: 185-186℃ 6-[4 -(2-naphthyl-sulfinyl)-butoxy]-3,4-dihydrocarbostyryl Melting point: 147.5-148.5°C 6-[4-(4-biphenylylsulfinyl)-
Butoxy]-carbostyril melting point: 196-197℃ 6-[4-(2-quinolylsulfinyl)-butoxy]-carbostyril melting point: 197-198℃ 6-[4-cyclohexylsulfinyl)-butoxy] -Carbostyril melting point: 169-170℃ 5-bromo-6-(4-phenylsulfinyl-butoxy)-carbostyril melting point: 190-191℃ 6-[4-(3,5-dibromo-4-aminophene) 6-[4-(3,5-dibromo-4-aminophenylsulfinyl)-butoxy]-carbostyryl Melting point: 205 -207℃ 6-[4-(4-cyclohexylphenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl Melting point: 155-157℃ 6-[4-(4-cyclohexylphenylsulfinyl)-butoxy ]-Carbostyril melting point: 188-190℃ 6-[4-(4-tert-butylphenylsulfinyl)-butoxy]-carbostyril melting point: 164-166℃ 6-[4-(3,4-dichlor Phenylsulfinyl)-butoxy]-3,4-dihydrocarbostyryl Melting point: 106.5-108°C Melting point: 148-149°C (recrystallized once from toluene and once from ethanol)

Claims (1)

[Claims] 1. General formula [In the formula, W represents a vinylene group, ethylene group or 2-methyl-vinylene group, D represents a linear or branched alkylene group having 2 to 6 carbon atoms, m represents 1, R ₁ represents a hydrogen atom, and R ₂ represents a cycloalkyl group, phenyl group, naphthyl group, phenylalkyl group, pyridyl group, or quinolyl group having 3 to 6 carbon atoms (however, the above aromatic nucleus is an alkyl group). , hydroxy, methoxy, amino, cyclohexyl, phenyl or halogen atoms), and R ₃ and R ₄ may be the same or different and represent a hydrogen atom, a halogen atom or an alkyl group ] A method for producing a carbostyryl derivative represented by the general formula (wherein D, W, R ₁ to R ₄ and m are the same as defined above, and Z represents a nucleophilically exchangeable group) is characterized by cyclizing the compound represented by Production method. 2. A process according to claim 1, wherein the reaction is carried out in the presence of a condensing agent such as sulfuric acid, concentrated hydrochloric acid, phosphoric acid or thionyl chloride. 3. The reaction is carried out at a temperature between 50 and 200°C, preferably
3. The method of any one of claims 1 and 2, carried out at a temperature between 80 and 150<0>C. 4 Claim 1 in which the reaction is carried out in a solvent
2. The method of any one of paragraphs 2 and 3.