JPS6121626B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel tryptophan derivative and a method for producing the same, more specifically, the present invention relates to a novel tryptophan derivative and a method for producing the same, and more specifically, (However, R ¹ represents a hydroxyl group or a lower alkoxy group, and R ² represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, or a nitro group.) Concerning compounds and their production methods. The compound [ ] of the present invention has excellent blood lipid-lowering effects and lipid peroxide formation inhibiting effects, has few side effects such as liver dysfunction, and is a useful pharmaceutical compound as a blood lipid-lowering agent and an anti-arteriosclerotic agent. It is what it is. As a specific example of the compound of the present invention [], in the general formula [], R ¹ is a hydroxyl group; or a lower alkoxy group such as a methoxy group or an ethoxy group, and R ² is a hydrogen atom; a lower alkyl group such as a methyl group or an ethyl group. Examples include compounds such as a group; a lower alkoxy group such as a methoxy group or an ethoxy group; a halogen atom such as a chlorine atom; or a nitro group. Among these compounds, preferred are compounds in which R ¹ is a hydroxyl group or an ethoxy group and R ² is a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, or a tro group in the general formula []. According to the present invention, the target compound [] has the general formula (However, R ¹ has the same meaning as above.) A tryptophan compound represented by carbon disulfide (CS ₂ ) and the general formula (However, X represents a halogen atom, and R ² has the same meaning as above.) It can be produced by reacting with a benzyl halide represented by the following. In addition, among the target compounds [ ], compounds in which R ¹ is a lower alkoxy group have the general formula obtained from the above reaction. (However, R ² has the same meaning as above.) By esterifying the compound represented by the general formula (However, R ³ represents a lower alkyl group.) It can be produced by preparing the compound shown below. The reaction of the present invention will be specifically explained below. The reaction between the compound [], carbon disulfide (CS ₂ ), and the compound [] can be carried out in an appropriate solvent in the presence of a deoxidizing agent. Examples of deoxidizers include inorganic bases such as sodium hydroxide, sodium carbonate, sodium bicarbonate, and ammonia, or triethylamine, N-methylmorpholine, N.N-
Examples include organic bases such as dimethylaniline, pyridine, and basic ion exchange resins. Examples of the solvent include water or a mixed solvent of water and an organic solvent (eg, ethanol, tetrahydrofuran, dioxane, diglyme, monoglyme, etc.). This reaction is preferably carried out at -20°C to 50°C, particularly at 0°C to 30°C. The esterification reaction of compound [-a] is carried out using compound [-a], an alcohol represented by R ³ OH (where R ³ has the same meaning as above), and thionyl chloride or an appropriate acid catalyst (for example, chloride (hydrogen, sulfuric acid, toluenesulfonic acid, acidic ion exchange resin, etc.). formula
Preferred examples of alcohols represented by R ³ OH include methanol, ethanol, propanol, and the like. This reaction is preferably carried out at -40°C to 100°C, particularly at -20°C to 70°C. Of the compounds of the present invention thus obtained,
When a compound in which R ¹ is a hydroxyl group is used as a medicine, it can be used in the form of a free carboxylic acid, but it can also be used in the form of a pharmacologically acceptable salt thereof. Examples of such salts include alkali metal salts such as sodium salts, potassium salts, and lithium salts, alkaline earth metal salts such as calcium and magnesium salts, methylamine, ethylamine, diethylamine, triethylamine, benzylamine, pyrrolidine, piperidine, Cyclohexylamine, dicyclohexylamine, ethanolamine, diethanolamine, ornithine, lysine,
Salts with non-toxic amines or basic amino acids such as arginine or salts with carnitine are suitable. When the compound of the present invention [ ] is used as a medicine, it may be administered orally or parenterally. When administering the compound of the present invention [ ] orally,
For example, they may be tablets, capsules, granules, etc., containing customary excipients such as calcium carbonate, calcium phosphate, corn starch, potato starch, sugar, lactose, talc, magnesium stearate, etc. Good too. It may also be a liquid preparation such as an aqueous or oily suspension, solution, syrup, elixir, or the like. Furthermore, when administering parenterally, it is given in the form of an injection preparation, suppository, etc., and when it is an injection preparation, it is given in the form of a solution or suspension. For example, peanut oil, corn oil) or non-aqueous solutions (e.g.
polyethylene glycol, polypropylene glycol, lanolin, coconut oil, etc.). The compound [] of the present invention is DL form, D form, L form.
Although it is effective in conjunction with the body, it is more preferable to use the L form in view of the strength of its main action and toxicity. Experimental example 1 (lipid-lowering effect) The sample was mixed with powdered rat feed at a ratio of 0.1%, and the mixture was fed to SD male rats (body weight: 120~
140g, 6 animals per group) were allowed to take it ad libitum for one week.
Blood was collected from the tail under ether anesthesia, and the liver was immediately removed and the liver weight was measured. On the other hand, the amount of serum cholesterol was measured using the ZaK method (Amer.J.Clin.Pathol., Vol.24, PP1307
(1954)), serum triglyceride levels were determined by Van Handel−
Zilversmit method (J.Lab. & Clin.Med., Vol50;
PP152 (1957)). From these results, serum cholesterol and triglyceride reduction rates and relative liver weight increase rates were determined using the following formulas.
The results are shown in Table 1 below.

[Table] Relative liver weight of control group

[Table] Experimental example 2 (inhibitory effect on lipid peroxide production) 2.4 ml of phosphate buffer (0.067M, PH7.4), 0.5 ml of 10% rat brain homogenate, and an ethanol solution in which the specimen was dissolved (analyte concentration: 10 ^-3 M) ) were mixed, placed at 37°C, and after 30 minutes, 1 ml of 20% trichloroacetic acid solution was added. The amount of lipid peroxide was determined by a colorimetric method using thiobarbituric acid (J. Robak et al., Biochem.
Pharmacol., Vol. 25, PP2237 (1976)). The lipid peroxide production inhibition rate was calculated using the following formula. The results are shown in Table 2 below.

[Table] Absorbance of control group

【table】

[Table] Example 1 L-tryptophan 12.3g 50% ethanol
Add 60 ml of 2N sodium hydroxide and 3.6 ml of carbon disulfide to the 150 ml solution, and stir at room temperature for 2 hours. 10.2 g of benzyl bromide was added dropwise to the mixture over 1.5 hours, and the mixture was stirred at room temperature for 3 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to remove the solvent.
Add water and ether to the residue and shake well.
Separate the aqueous layer, make the liquid acidic with 10% hydrochloric acid, and extract with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off under reduced pressure. The oily residue was dissolved in ether, 4.2 g of cyclohexylamine was added dropwise, and the precipitated crystals were collected by filtration and recrystallized from methanol. Add 10% citric acid solution and ether to the crystals and shake well. The ether layer was separated, washed with water, dried, and the ether was distilled off under reduced pressure to obtain N-benzylthio-thiocarbonyl-
8.2 g of L-tryptophan are obtained as a pale yellow resinous substance. Yield: 37% IRν ^Nuj _nax cm ^-1 : 3350, 1720, 1600, 1550 [α] ²⁰ _D +41・8° (C=1.0, methanol) Example 2 50% ethanol of 12.3 g of L-tryptophan
Add 60 ml of 2N sodium hydroxide and 3.6 ml of carbon disulfide to the 150 ml solution, and stir at room temperature for 2 hours. 9.7 g of 4-chlorobenzyl chloride was added to the mixture.
The mixture was added dropwise over a period of time and stirred at room temperature for 2 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to remove the solvent. Add water and ether to the residue and shake well. Separate the aqueous layer, make the liquid acidic with 10% hydrochloric acid,
Extract with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off under reduced pressure. The oily residue is dissolved in ether and 4.5 g of cyclohexylamine are added dropwise. The precipitated crystals are collected by filtration and recrystallized from a mixture of ethyl acetate and n-hexane. Add 10% citric acid solution and ether to the crystals and shake well. Separate the ether layer, wash it with water, dry it,
By distilling off the ether under reduced pressure, N
(4chlorobenzylthio-thiocarbonyl)-L-
0.1 g of tryptophan I is obtained as a pale yellow powder. Yield: 42% MP 48°C to 52°C IRν ^Nuj _nax cm ^-1 : 3320, 1710, 1490 [α] ²⁰ _D +36.2° (C=1.0, methanol) Example 3 50% of 12.3 g of L-tryptophan ethanol
Add 60 ml of 2N sodium hydroxide and 3.6 ml of carbon disulfide to the 150 ml solution, and stir at room temperature for 2 hours.
8.4 g of 4-methylbenzyl chloride was added to the mixture.
Add dropwise over 1.5 hours and stir at room temperature for 3.5 hours.
After the reaction is completed, the reaction solution is concentrated under reduced pressure to remove the solvent. Add water and ether to the residue and shake well. Separate the aqueous layer, make the liquid acidic with 10% hydrochloric acid, and extract with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off under reduced pressure. Dissolve the oily residue in ether and cyclohexylamine 4.0
g was added dropwise, the precipitated crystals were collected by filtration, and recrystallized from isopropyl alcohol. Add 10% citric acid solution and ether to the crystals and shake well.
The ether layer was separated, washed with water and dried, and the ether was distilled off under reduced pressure to obtain N〓-(4-
8.4 g of methylbenzylthio-thiocarbonyl)-L-tryptophan are obtained as a pale yellow powder. Yield: 36% MP 55℃～57℃ IRν ^Nuj _nax cm ^-1 : 3430, 3350, 1720, 1620, 1550
,
1510 [α] ²⁰ _D +39.2° (C = 1.0, methanol) Example 4 12.3 g of L-tryptophan and potassium carbonate
8.3g of carbon disulfide in 260ml of 50% ethanol solution
Add 7.9 ml dropwise over 10 minutes at 14°C to 17°C.
Stir for 1 hour at ~21°C. Add 19.4 g of 4-nitrobenzyl bromide to the mixture and stir at room temperature for 18 hours. After the reaction is completed, the reaction solution is concentrated under reduced pressure to remove the solvent. Add water and ether to the residue and shake well. Separate the aqueous layer, make the liquid acidic with 10% hydrochloric acid, and extract with ethyl acetate. The extract is washed with water, dried, and the solvent is distilled off under reduced pressure. The oily residue was purified by silica gel chromatography (solvent: chloroform:methanol = 50:1) to obtain N-(4-nitrobenzylthio-thiocarbonyl)-L-tryptophan.
10.3 g are obtained as a yellow powder. Yield: 41% MP 74°C to 79°C IRν ^Nuj _nax cm ^-1 : 3400, 3320, 1710, 1510 [α] ¹⁸ _D +62.2° (C=1.1, ethanol) Example 5 10.2 g of L-tryptophan 50% ethanol
Add 50 ml of 2N sodium hydroxide to 125 ml, add 3.0 ml of carbon disulfide dropwise to this solution over 6 minutes at 10°C to 14°C, and stir at room temperature for 2 hours. 7.8 g of 4-methoxybenzyl chloride was added to the mixture at 13°C to 18°C.
Add dropwise at ℃ for 50 minutes and stir at room temperature for 2.5 hours. Add 10% hydrochloric acid to the reaction solution to make it neutral,
The solution is concentrated under reduced pressure. 10 to the resulting concentrate
% hydrochloric acid to make the liquid acidic, and extracted with ethyl acetate. The extract is washed with water, dried and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel chromatography (solvent: chloroform: methanol = 50:
By purifying in step 1), 9.6 g of N-(4-methoxybenzylthio-thiocarbonyl)-L-tryptophan is obtained as a yellow powder. Yield: 48% MP 63.5°C to 67.5°C IRν ^Nuj _nax cm ^-1 : 3410, 3325, 1715, 1510 [α] ²¹ _D +80.2° (C = 1.0, chloroform) Example 6 Obtained in Example 1 7.1 g of the cyclohexylammonium salt of N-benzylthio-thiocarbonyl-L-tryptophan is suspended in ethyl acetate, and a 0.5M citric acid solution is added to the suspension, followed by vigorous stirring. After separating the ethyl acetate solution, wash it with water,
After drying, the solvent is distilled off under reduced pressure. To a solution of the obtained residue in 50 ml of ethanol was added dropwise 2.1 g of thionyl chloride at -23°C, followed by stirring at room temperature for 18 hours while gradually raising the temperature. Further, stir at 70°C for 90 minutes. After the reaction is completed, the reaction solution is concentrated under reduced pressure to remove the solvent. Dissolve the residue in ether,
The mixture was washed successively with water, IN potassium carbonate, and water, and after drying, the solvent was distilled off under reduced pressure to obtain 5.7 g of N-benzylthio-thiocarbonyl-L-tryptophan ethyl ester as a pale yellow oil. Yield: 95% IRν ^liq _nax cm ^-1 : 3410, 3330, 1725, 1490 Mass m/e: 398, 275, 216, 128, 123, 91 [α] ¹⁸ _D +7.6° (C = 1.0, ethanol )

Claims (1)

[Claims] 1. General formula (However, R ¹ represents a hydroxyl group or a lower alkoxy group, and R ² represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, or a nitro group.) A compound or a pharmaceutically acceptable salt thereof. 2 In the general formula [), R ¹ is a hydroxyl group,
The compound according to claim 1, wherein R ² is a chlorine atom. 3. The compound according to claim 1, wherein in the general formula [], R ¹ is an ethoxy group and R ² is a hydrogen atom. 4 In the general formula [], R ¹ is a hydroxyl group,
The compound according to claim 1, wherein R ² is a methoxy group. 5 General formula (However, R ¹ represents a hydroxyl group or a lower alkoxy group.) A tryptophan compound represented by carbon disulfide (CS ₂ ) and the general formula (However, X represents a halogen atom, and ^R2 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, or a nitro group.) General formula characterized by its pharmacologically acceptable salts (However, R ¹ and R ² have the same meanings as above.) A method for producing a N-benzylthio-thiocarbonyl-tryptophan compound or a pharmacologically acceptable salt thereof. 6 General formula (However, ^R2 represents a hydrogen atom, a lower alkyl group, a lower alkoxy, a halogen atom, or a nitro group.) A general formula characterized by esterifying the N-benzylthio-thiocarbonyl-tryptophan compound represented by (However, R ³ represents a lower alkyl group, and R ² has the same meaning as above.) A method for producing an N-benzylthio thiocarbonyl tryptophan ester compound.