JPH0219117B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel 3-vinylindolizine derivative represented by the following general formula (1). (In the formula, R is a hydrogen atom, a lower alkyl group, or a phenyl group, R ¹ is a hydrogen atom or a lower alkyl group,
R ² is a hydrogen atom or a lower alkylthio group, R ³ and R ⁴ are a cyano group, lower alkanoyl group or lower alkoxycarbonyl group, R ⁵ is a lower alkyl group having a lower alkoxycarbonyl group or phenyl group as a substituent, lower The lower alkyl group defined in the present invention is an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl group, and the lower alkylthio group is methylthio, ethylthio, propylthio. , an alkylthio group having 1 to 4 carbon atoms such as butylthio group, an alkoxycarbonyl group having 2 to 5 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl group as a lower alkanoyl group, Examples include alkanoyl groups having 2 to 5 carbon atoms such as acetyl, propanoyl, butanoyl, and pentanoyl groups. The compound of the present invention represented by the above general formula (1) has platelet aggregation inhibiting action, anti-inflammatory action, anti-allergic action,
It has antibacterial effects and is useful as a medicine. The method for producing the compound of the present invention will be explained below.
The compound of the present invention can be prepared by, for example, reacting a base with a pyridinium compound represented by the general formula (2), and then forming the pyridinium compound represented by the general formula (4).
It is produced by reacting an olefin compound represented by formula (5) with a halide represented by general formula (5). <Reaction process formula> (In each formula, R and R ¹ to ^{R 5} are the same as above,
(R ⁶ is a lower alkyl group, R ⁷ is a lower alkoxy group or a lower alkylthio group, and X and Y are halogen atoms.) The viridinium compound 2 used as a raw material in the above formula is a known compound, such as a journal.・Of Organic Chemistry (J.
Org. Chem) 36 , 2451 (1971) or a similar method. Examples of bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide, alkali metal hydrogencarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and sodium carbonate. , alkali metal carbonates such as potassium carbonate, alkaline earth metal carbonates such as calcium carbonate and magnesium carbonate, inorganic bases such as metal alkoxides such as sodium methoxide, sodium ethoxide and potassium butoxide, pyridine, picoline, triethylamine, N-methyl Examples include organic bases such as piperidine. Although the amount of the base to be used can be selected as appropriate, it is generally advantageous to use the base in an amount of about 1 to 2 times the amount of the pyridinium compound 2. The reaction between the viridinium compound 2 and the base is usually carried out in a solvent. The solvent is not particularly limited as long as it is inert to the reaction, but examples include methanol,
Lower alcohols such as ethanol and propanol, ethers such as ether, tetrahydrofuran, and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, and dimethyl sulfoxide. , aprotic polar solvents such as dimethylformamide, etc., depending on the type of the viridinium compound 2 and the base used. The reaction temperature is not particularly limited, but
The reaction usually proceeds advantageously when carried out at around -20 to 150°C. The above reaction produces a dihydroindolizin-2-one compound represented by general formula (3). This can be isolated from the reaction system by a conventional method, but in the present invention, this dihydroindolizine-
Without isolating the 2-one compound 3, the olefin compound represented by the general formula (4) and the halide represented by the general formula (5) can be subsequently introduced into the reaction system and reacted. The amounts of the olefin compound 4 and the halide 5 to be used can be selected as appropriate, but it is usually advantageous to use about 1 to 5 times the molar amount of each of the viridinium compounds 2.
The reaction temperature is not particularly limited, but is generally room temperature to 150℃.
It is advantageous to carry out the reaction at a temperature of about 0.degree. The 3-vinylindolizine derivative 1 produced in this reaction can be easily isolated by conventional separation means such as recrystallization, column chromatography, etc. In the 3-vinylindolizine derivatives represented by the general formula (1) of the present invention, for compounds in which R ⁵ is a lower alkyl group, the compound represented by the general formula (6) is substituted for the halide 5 as shown below. It can also be produced by reacting. (In the formula, R, R ¹ to ^{R 4} , R ⁶ to ^{R 7} and X are the same as above, and R ⁵ ' means a lower alkyl group) In addition, -Vinyl indolizine derivatives can also be produced by reacting a compound represented by general formula (7) in place of halide 5, as shown below. (In the formula, R, R ¹ to R ⁴ , R ⁶ to ^{R 7} and X are the same as above, and R ⁵ ″ means a lower alkanoyl group or a benzoyl group) Representative examples of 3-vinyl indolizine derivatives are listed below, and then production examples of each compound are listed as examples.

【table】

【table】

【table】

【table】

[Table] C H N C H
N
23 71.12 5.19 7.21 71.23 5.14
7.16
24 74.30 4.62 6.42 74.39 4.63
6.32
25 68.89 5.30 6.69 68.90 5.31
6.67
26 67.54 4.05 11.25 67.55 4.16 1
1.28
Example 1 2-benzyl-1-(ethoxycarbonylmethyl)pyridinium bromide 1.008 g (3 mmol)
60 ml of sodium ethoxide ethanol solution (containing 6 mmol of sodium ethoxide) was added to 60 ml of ethanol solution containing sodium ethoxide, and after reacting at 60 to 80°C for 3 minutes, 0.507 g of ethyl α-cyano-β-ethoxy-acrylate (3 mmol) is added. After reacting for 1 minute, add 2 ml of acetic anhydride and react for 5 minutes. The reaction mixture was concentrated under reduced pressure, the residue was separated on an alumina column using ether-chloroform, and then recrystallized from ethanol to give 2-
Acetoxy-3-(2-cyano-2-ethoxycarbonylvinyl)-1-phenylindolizine (Compound No. 19) was obtained. Other compounds were synthesized in the same manner as in Example 1.

Claims (1)

[Claims] 1. General formula (In the formula, R is a hydrogen atom, a lower alkyl group, or a phenyl group, R ¹ is a hydrogen atom or a lower alkyl group,
R ² is a hydrogen atom or a lower alkylthio group, R ³ and R ⁴ are a cyano group, lower alkanoyl group or lower alkoxycarbonyl group, R ⁵ is a lower alkyl group having a lower alkoxycarbonyl group or phenyl group as a substituent, lower A 3-vinylindolizine derivative represented by an alkanoyl group or a benzoyl group.