JPS5810565A - Tryptophan derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:An N -benzylthio-thiocarbonyl-tryptophan compound of formulaI(R<1> is hydroxyl group or lower alkoxyl; R<2> is H, lower alkyl, lower alkoxyl, halogen or nitro) or a salt thereof. EXAMPLE:N -Benzylthio-thiocarbonyl-L-tryptophan. USE:Useful as an antilipemic agent and antiarteriosclerotic agents having improved antilipemic and inhibitory action on the formation of lipid peroxides without side effects, e.g. hepatic functional disorder. PROCESS:A tryptophan compound of formula II is reacted with carbon disulfide and a benzyl halide of formula III (X is halogen) preferably in the presence of a deacidifying agent at -20-+50 deg.C, particularly 0-30 deg.C, to give the compound of formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel tryptophan derivative and a method for producing the same, and more specifically, the present invention relates to a novel tryptophan derivative and a method for producing the same, and more specifically, it has the general formula (wherein R1 represents a hydroxyl group or a lower alkoxy group,
B! is a hydrogen atom, a lower alkyl group, a lower alkoxy group,
Represents a halogen atom or a nitro group. ) denoted by N″
- Benzylthio-thiocarbonyl-tryptophan compounds and their production method.

Compound (I) of the present invention has excellent blood lipid-lowering effects and lipid peroxide production 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. This is the result.

Specific examples of the compound (I) of the present invention include, in the general formula [I], R1 is a hydroxyl group; or a lower alkoxy group such as a methoxy group or an ethoxy group, and t is a hydrogen atom; a methyl group,
Examples include compounds such as a lower alkyl group such as an ethyl 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 V is a hydroxyl group or an ethoxy group, and V is a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, or a nitro group in the general formula [■].

According to the present invention, a tryptophan compound represented by the target compound CI) 11 general formula (where il has the same meaning as above) is combined with carbon disulfide (C8I) and the general formula (where X is) represents an atom, and V has the same meaning as above. ) can be produced by reacting with benzyl/1rides shown in (k). In addition, among the target compounds (I), compounds in which ILl is a lower alkoxy group can be obtained by esterifying the compound represented by the general formula (wherein V has the same meaning as above) obtained from the above reaction to obtain the general formula (However, R" represents a lower alkyl group.)

The reaction of the present invention will be specifically explained below.

Compound (II), carbon disulfide (CSs) and compound (
The reaction IN) can be carried out in a suitable solvent in the presence of a deoxidizing agent. Examples of deoxidizers include sodium hydroxide, sodium carbonate, and sodium hydrogen carbonate.

an inorganic base such as ammonia, or triethylamine,
Examples include organic bases such as N-methylmorpholine, N,N-dimethylaniline, pyridine, and basic ion exchange resins. As a solvent, water or water and an organic solvent (for example,
(ethanol, tetrahydrofuran, dioxane, guiglyme, monoglyme, etc.).

This reaction is preferably carried out at -20°C to 50°C, particularly at θ°C to 80°C.

The esterification reaction of compound [4] involves compound Cl-1) and RIOH (wherein, R'' has the same meaning as above.)
Alcohols represented by thionyl chloride or a suitable acid catalyst (for example, hydrogen chloride, sulfuric acid).

toluenesulfonic acid, acidic ion exchange resin, etc.). Examples of alcohols represented by the formula vOH include methanol.

Preferred examples include ethanol and glopanol. This reaction $1-4 (preferably carried out at 1-100°C, particularly -200 to 70°C).

Among the compounds CI) of the present invention obtained in this way, the compounds in which V is a hydroxyl group are used as whole medicines.

It can be used in the free carbo/acid form, but also in the form of its pharmacologically acceptable salts.

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, 7e') ethylamine, benzylamine, and pyrrolidine. , piperidine, cyclohexylamine, cyclohexylamine, ethanolamine, jetanolamine, ornithine, lysine,
Salts with non-toxic amines or basic amino acids such as arginine or salts with carnitine are suitable.

Compounds of the present invention CI)'t- When used as medicines.

It may be administered orally or parenterally. When the compound (I) of the present invention is administered orally, it can be administered in the form of tablets, capsules, granules, etc., for example.

They include conventional excipients such as calcium carbonate.

It may contain calcium phosphate, corn starch, potato starch, sugar, lactose, talc, magnesium stearate, etc.

It may also be in the form of liquid preparations such as aqueous or oily suspensions, solutions, syrups, elixirs, and the like.

Furthermore, when administering parenterally, it is given as an injection preparation, suppository, etc., and when it is an injection preparation, it is given in the form of a solution or suspension, and these are given in the form of distilled water for injection,
Essential oils (e.g. peanut oil, corn oil) or linear non-aqueous solvents (e.g.

polyethylene glycol, polypropylene glycol,
lanolin, coconut oil, etc.).

Oka 9 Compound 1111j (I) of the present invention is DL form, D form,
Although it is effective together with the L-form, 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 specimen was mixed with powdered rat feed KO at a ratio of 1%, and the skeleton mixture was mixed with t-5D male rats (body weight: 120-1401
, 6 animals per group) were given free access for one week, then blood was collected from the tail under ether anesthesia, and the liver was immediately removed and weighed. on the other hand.

Calculate the amount of serum cholesterol by 1alL using the collected blood.
(Amer, J, CI in - Psithol,
, Vol 24. PP1807 (1954))
, serum triglyceride level was determined by Van Handel-Zi
l versmit method (J, Lab, & C1inl
Med, Vol 5Q; DeP15g (1957)
) Measured from K. 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.

Experimental Example 2 (Lipid peroxide production inhibiting effect) Phosphate buffer (0,067M, PH7,4) 2.4
m/, 10% rat brain homogenate 0.5 g/and an ethanol solution in which the specimen was dissolved (sample concentration 1 (r”M)
0. Mix IIIt, place 37trE, and after 80 minutes E
Go % trichloroacetic acid solution lII/l- was added. The amount of lipid peroxide was determined by the colorimetric method using thiobarbic acid (J,
RobaK, et al.

Biochem, Pharmacol, Vol.
g5. I"p2287 (1976)) was measured. The inhibition rate of lipid peroxide production was determined by the following formula. The results are shown in Table 2 below.

Table 2 Example 1 L-) 1 g of lipdoan, 150 g of 8 f 50% ethanol/solution, 60 g of 2N hydroxide) and 3.6 g of carbon disulfide are added and stirred at room temperature. 10.2 f of benzyl bromide was added dropwise to the mixture over a period of 1.5 hours, and the mixture was stirred at room temperature for 3 hours. After the reaction is complete.

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 and
Make the liquid acidic with 0% 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 add cyclohexylamine 4
．． Drop 2f.

The precipitated crystals are collected by filtration and recrystallized from methanol.

Add IOX 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 fiN''-benzylthio-thiocarbonyl-L-tributophane 8.2
1 is obtained as a pale yellow resinous material.

Yield: 87! X IRy'4% am":ss 5 o, 172
0. ta゛oo, 1550 [α]^+41.
8° (C=1.0. Methanol) Example 2 L-tributophane 12.89 50% ethanol 15
0g1/solution r2N hydroxide) 60m/IJum/and 8.6++g/carbon disulfide are added and stirred at room temperature for 2 hours. 4-chloropenzyl chloride in the mixture, do 9.7
f was added dropwise over a period of 1 hour, and the mixture was stirred at room temperature for 2 hours.

After the reaction is completed, one 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, add cyclohexylamine 4.5 citric acid solution and ether,
Shake well. Separate the ether layer, wash with water, and dry.

By distilling off the ether under reduced pressure, N''-(4chlorobenzylthio-thiocarbonyl)-L-)riptolaane 10.11t- is obtained as a pale yellow powder.

Yield: 42% M, P, 413t:: ~52℃ ■Death count ts-”: 88g0.1710.1490
[α9%0+86.2° (C=1.0.methanol) Example 8 L-) 60 m of 2N sodium hydroxide and 8.6 d of carbon disulfide were added to the Lipton Anne 1L8fo50 1 5 0 IIl solution, and the mixture was heated at room temperature for 2 hours. Stir. 8.4f of 4-methylbenzyl chloride was added dropwise to the mixture over a period of 1.5 hours! Stir at warm temperature for 8.5 hours.

After the reaction is completed, one reaction solution is concentrated under reduced pressure to remove the solvent. Add water and ether to the residue and shake well. The aqueous layer is separated, made acidic with 10% hydrochloric acid, and extracted 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 add cyclohexylamine4. Of is added dropwise, and the precipitated crystals are collected by filtration and recrystallized (from isopropyl alcohol). 10 in this crystal
% citric acid solution and ether and shake well.

Separate the ether layer, wash with water, and dry.

By distilling off the ether under reduced pressure, p, N'-(4-
methylbenzylthio-thiocarbonyl)-L-tryptophan 8.4I is obtained as a pale yellow powder.

Yield: 86X M, P, 55℃~57℃ 1'lLy Niichiban 3-'': 8480.8850.1
120.1610° 1550, 1510 [α3 +89.2° (C=1,0. Methanol) Example 4 L-tryptophan 1g, sf and potassium carbonate 8.8
Carbon disulfide in 260s/solution of 50X ethanol 7.
It was added dropwise over 10 minutes at 9 sl/1l - 14°C to 17t, and stirred for 1 hour at 17°C to 211°C. 4 to the mixture
-Add 19.49 liters of nitrobenzyl bromide.

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. The aqueous layer is separated, made acidic with 10% hydrochloric acid, and extracted 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:l) to obtain N''-(
10.81 of 4-nitropendylthio-thiocarbonyl)-L-)ligtophan is obtained as a yellow powder.

Yield: 41% M,? , 74°C to 79°C IRν 3 , 8400.88g0.1710.15
10(α)”,” +62.2° (C=1.1.z/
/-k) Example 5 L-tryptophan 10.2 F 50% ethanol 1
Add 2N sodium hydroxide 50 resistant to 25Wt.

To this solution, 8.0 - of carbon disulfide was added dropwise at 10°C to 14°C over 6 minutes, and the mixture was stirred at room temperature for 2 hours.

7.8 ft- of 4-methoxybenzyl chloride was added to the mixture.
Add dropwise at 18°C to 18°C over 50 minutes and stir at room temperature for 2.5 hours. IOX hydrochloric acid was added to the reaction solution to make the liquid neutral, and the solution was subjected to EjlJ1 under reduced pressure.

Add 10% hydrochloric acid to the obtained concentrate to make the liquid acidic,
Extract 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 = 50:1)
By refining.

N'-(4-methoxybenzylthio thiocarbonyl)
-L-)Lyptophan 9.6f is obtained as a yellow powder. Yield: 48% M, P, 68.5°C to 67.5°C IILy,:':4m-" = 841L 8825m
1715.1510[α)%1+so,g0(C=1
．． 0. chloroform) Example 6 9N'-benzylthio thiocarbonyl- obtained in Example 1
L-)Liptophan cyclohexylammonium salt q
, ly@suspended in ethyl acetate, and added 0.5M to the suspension.
Add citric acid solution and stir vigorously. After separating the ethyl acetate solution, it is washed with water, dried once, and then the solvent is distilled off under reduced pressure. 2.1 f of thionyl chloride was added dropwise to a 50 m ethanol solution of the obtained residue at -28°C, and the mixture was stirred at room temperature for 18 hours while gradually raising the temperature. Furthermore, 70
Stir at r for 90 minutes. After the reaction is completed, one reaction solution is concentrated under reduced pressure to remove the solvent. Dissolve the residue in ether,
Wash sequentially with water, IN potassium carbonate, and water.

After drying, the solvent was distilled off under reduced pressure to obtain 5.7 g of N''-benzylthio-thiocarbonyl-L-trypto7ane ethyl ester as a pale yellow oil. Yield: 9
5% IRs';:cIr'': 8410.8880.1
725.1490Mass m/e: 898.27
5.216.128.128.91(α)',' +
7.6° (C=1,0.et/-r) Agent Patent Attorney Chubu Shoji Voluntary Procedure Amendment Showa! 2, 72f12r, Mr. Commissioner of the Japan Patent Office 1, Indication of the case Showa patent application No. 2, Name of the invention 3. Relationship with the case of the person making the amendment Patent applicant 3-21 Doshomachi, Higashi-ku, Osaka-shi, Osaka (541)
295) Tanabe Pharmaceutical Co., Ltd. Representative Matsuhara - Department 4, Agent 3-16-89 Kashima, Yodogawa-ku, Osaka-shi, Osaka (532
) Tanabe Pharmaceutical Co., Ltd. (6461) Patent Attorney Shoji Do Nakajima (06-301-1221 Patent Office) 5, Number of inventions increased by amendment 6, Detailed explanation of the invention in the specification subject to amendment 7, Contents of Amendment As shown in the attached sheet, Contents of Amendment 1, page 8 of the specification, line 1 from h to ``cyclohexylamine'' is corrected to [cyclohexylamine, 1.

2.Page 9 of the specification, 5th line from the bottom "Zil verRmit method" f: Corrected to "Zilv@rsIIIit method".

3. Specification page 12 2. 8th row from the bottom [Stir at room temperature. ] [Stir at room temperature for 2 hours. ]1 correction.

Agent: Patent Attorney Masaharu Naka

Claims (1)

[Scope of Claims] (However, *R"ti represents a hydroxyl group or a lower alkoxy group, and R3 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, or a nitro group.)
``-benzylthio-thiocarbonyl-tryptophan compound or a pharmacologically acceptable salt thereof. 2. In the general formula (I), V is a hydroxyl group and R'' is a chlorine atom, according to claim 1. Compound. 8. In general formula [I], R1 is an ethoxy group. The compound according to claim 1, wherein Bl is a hydrogen atom. - The compound according to claim S, item 1, wherein in the general formula [I], TLl is a hydroxyl group and R1 is an ethoxy group. 5. A tryptophan compound represented by the general formula (wherein R1 represents a hydroxyl group or a lower alkoxy group) is mixed with carbon disulfide (C8
m) and the general formula (wherein A product represented by the general formula (provided that the R1 and R1 lines have the same meanings as above) characterized by reacting with a dirnoride and then optionally converting the product into a pharmacologically acceptable salt thereof. A method for producing N'-benzylthio-thiocarponyl ligtophan compounds or pharmacologically acceptable salts thereof. 6. General formula (wherein R1 is a hydrogen atom, a lower alkyl group, a lower alkoxy, a halogen atom, or a nitro group) (wherein R1 represents a lower alkyl group and R3 has the same meaning as above) A method for producing f-benzylthio-thiocarbonyl-tryptophan ester compounds.