JPH0368876B2 - - Google Patents

Description

[Detailed Description of the Invention] This invention provides novel indole derivatives and FR
-900220 Concerning a new manufacturing method for substances.

Substance FR-900220 is a novel pharmacologically active substance isolated from the culture of Amauroascus sp. No. 6237 strain, which has antihypertensive effects, anti-infection effects, and suppressive effects on gastric juice secretion. A patent application (Japanese Patent Application No. 57-35692) has been filed.
Thereafter, as a result of structural research on the FR-900220 material, the present inventors estimated the structure of the FR-900220 material as follows.

((5aS, 7aS, 8aR, 13aS, 15aS, 16aR) −
8a,16a-bis(1,1-dimethyl-2-propenyl)-5,5a,8,8a,13,13a,16,16a-octahydropyrazino [1″,2″-1,5:4″ ,5″−
1′,5′]dipyrrolo[2,3-b:2′,3′-b′]diindole 7,15(7aH,15aH)-dione) Next, a method for producing FR-900220 substance by chemical synthesis was described. In addition to establishing this for the first time, we also established a new indole derivative represented by the following general formula () and a method for producing it.

The novel indole derivative of this invention is represented by the following general formula.

(In the formula, A is a 2-butenediylidene group or a tetramethylene group, R ¹ is hydrogen, a lower alkyl group, or a lower alkenyl group, R ² is hydrogen, a lower alkyl group, a lower alkenyl group, or an acyl group,
R ³ and R ⁴ each represent hydrogen or R ³ and R ⁴ together represent an oxo group) FR-900220 Substances and Indole Derivatives ()
and their salts are produced by the method shown below.

(In the formula, R ¹ , R ³ , R ⁴ and A have the same meanings as before.
R ¹ _a and R ² _a are each a lower alkenyl group, R ¹ _b and R ² _b are each a lower alkyl group, R ² _c and R ^e
are each a lower alkyl group or a lower alkenyl group, R ² _d is an acyl group, R ² _e is hydrogen or a lower alkenyl group, R ² _f is hydrogen or a lower alkyl group, R ^b is a lower alkyl group, an al(lower) alkyl group or an aryl group, R ^d is an amino-protecting group ^, and X ⁴ and It can be manufactured by

(In the formula, R ¹ _a , R ¹ _b , R ^b and R ^d have the same meanings as before, R ^a is an alkyl group, R ^c is an esterified carboxy group, X ¹ is an amino protecting group, X ² and ⁽³ means halogen) Various definitions in this specification will be explained in detail below.

Suitable examples of salts of the indole derivative () and various raw material compounds include salt addition salts such as hydrochloride and sulfate.

"Lower" means carbon number from 1 to 1 unless otherwise specified.
It means a group having 6 members.

Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, 1,1-dimethylpropyl,
Examples include 3-methylbutyl, pentyl, hexyl, and the like.

Examples of the lower alkenyl group include alkenyl groups having 2 to 6 carbon atoms, such as vinyl, allyl, isopropenyl, 3-methyl-2-butenyl, 1,1-dimethyl-2-propenyl, and 2-hexenyl.

Acyl group means a residue of an organic acid, preferably a residue of an organic carboxylic acid, and suitable examples include lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, pentanoyl, and hexanoyl. It will be done.

Examples of the al(lower) alkyl group include benzyl.

Examples of the aryl group include phenyl and tolyl.

Examples of the esterified carboxyl group include lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl.

As the amino protecting group, generally used protecting groups for amino groups can be mentioned as they are, and examples of such groups include al(lower) alkoxycarbonyl groups such as benzyloxycarbonyl.

Examples of the halogen include fluorine, chlorine, bromine, and iodine.

Next, the above manufacturing methods 1 to 8 will be explained in detail below.

Production method 1: Compound (a) or its salt is compound ()
Alternatively, a salt thereof can be produced by subjecting it to a desulfurization ring closure reaction.

This reaction is preferably carried out in the presence of a catalyst, such as Raney-nickel, a combination of titanium tetrachloride and an alkali metal aluminum hydride (such as lithium aluminum hydride), or a combination of an alkali metal and liquid ammonia. .

This reaction is typically carried out using e.g. tetrahydrofuran,
The reaction is carried out in a solvent that does not adversely affect the reaction, such as ether, benzene, toluene, methanol, ethanol, acetone, etc., under cooling or heating.

The reaction conditions for the above-mentioned catalyst, solvent, etc. may be appropriately selected and applied depending on the type of the raw material compound ().

Production method 2: Compound (b) can be produced by subjecting compound () to catalytic reduction. Suitable catalysts for catalytic reduction include platinum plates, platinum sponges,
Platinum catalysts such as platinum black, colloidal platinum, platinum oxide, platinum wire; palladium catalysts such as palladium sponge, palladium black, palladium oxide, palladium-carbon, or colloidal palladium; iridium, colloidal iridium, ruthenium oxide, colloidal rhodium, Platinum metal catalysts such as rhodium-alumina; nickel catalysts such as reduced nickel, nickel oxide or Raney-nickel; cobalt catalysts such as reduced cobalt, Raney-cobalt; iron catalysts such as reduced iron, Raney-iron; or Copper catalysts such as reduced copper, Raney copper or Ullmann copper are mentioned, and this catalytic reduction can usually be carried out in a hydrogen atmosphere at atmospheric pressure or under pressure at room temperature.

This reaction is usually carried out in a solvent that does not adversely affect the reaction, such as methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran, and the like.

Production method 3: Compound (c) or a salt thereof is a compound (c) or a salt thereof.
It can be produced by reacting a) or a salt thereof with aluminum hydride.

This reaction is usually carried out in a solvent that does not adversely affect the reaction, such as ether, tetrahydrofuran, benzene, toluene, etc., at temperatures ranging from cooling to room temperature.

Production method 4: Compound (e) can be produced by reacting compound (XI) with compound (d) or a salt thereof.

This reaction is preferably carried out in the presence of a base such as potassium carbonate.

This reaction is usually carried out at room temperature or under heating in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, dimethyl sulfoxide, dioxane, etc.

Production method 5: Compound (f) can be produced by reacting compound (d) or a salt thereof with compound () or a reactive derivative thereof.

Examples of reactive derivatives of compound () include acid anhydrides, acid halides, acid azides, active amides, and active esters.

This reaction is preferably carried out in the presence of an organic or inorganic base such as sodium hydride, potassium hydroxide, triethylamine, pyridine and the like.

Examples of the reaction solvent include those that do not adversely affect this reaction, such as N,N-dimethylformamide, dioxane, and dimethyl sulfoxide.

Although the reaction temperature is not particularly limited, it is usually carried out under cooling or heating.

Production method 6: Compound (h) can be produced by subjecting compound (g) to catalytic reduction.

Since the reaction conditions for this reaction and the catalytic reduction are substantially similar to those of Production Method 2, Production Method 2
Please refer to the explanation.

In general formula (g), when both the compound in which A is a 2-butene diylidene group and the catalyst for catalytic reduction are in high concentration and the hydrogen pressure is high, the 2-butene diylidene group is also reduced at the same time, and A is reduced. Compound (g) having a tetramethylene group may be obtained, and such cases are also included within the scope of this production method.

Production method 7: Compound (j) can be produced by subjecting compound (i) to catalytic reduction.

The conditions for catalytic reduction in this reaction are also substantially the same as the reaction conditions for catalytic reduction in Production Method 2, so please refer to the explanation of Production Method 2.

Production method 8: Compound (k) can be produced by reacting compound (XII) with compound (XI) or a salt thereof.

The starting compound (XI) is, for example, a known substance described in Tetrahedron Letters, pages 509-512 (1974).

This reaction is preferably carried out in the presence of a base such as sodium hydrogen carbonate.

This reaction is usually carried out at about room temperature in a solvent that does not adversely affect the reaction, such as N,N-dimethylformamide, dimethyl sulfoxide, dioxane, etc.

The target compounds of the above production methods 1 to 8 can be isolated and purified by conventional methods to lead to desired salts.

Next, the manufacturing route (A route,
Route B) will be explained in detail.

Method 1 Compound () or a salt thereof can be produced by reacting compound () or a salt thereof with an oxidizing agent.

As the oxidizing agent for this reaction, a combination of dimethyl sulfoxide and concentrated hydrochloric acid is often used.

This reaction is usually carried out at room temperature or under elevated temperature in or without a solvent that does not adversely affect the reaction.

Method 2 Compound () or a salt thereof can be produced by reacting Compound () or a salt thereof with an alkyl esterifying agent or with an acid catalyst in the presence of a large amount of alkanol.

Alkanols and derivatives thereof are exemplified as alkyl esterification agents for this reaction. Examples of alkanol derivatives include alkyl halides such as methyl iodide.

This reaction is often carried out in a solvent that does not adversely affect the reaction, such as dimethylformamide, dioxane, acetone, etc., at a temperature around room temperature.

Method 3 Compound () or a salt thereof can be produced by reacting compound () or a salt thereof with a sulfurizing agent.

Phosphorus pentasulfide is often used as a sulfiding agent in this reaction.

This reaction is preferably carried out in the presence of an organic base such as pyridine or triethylamine.

This reaction is typically carried out using e.g. benzene, toluene,
The reaction is carried out in or without a solvent that does not adversely affect the reaction, such as methylene chloride, at room temperature or under heating to reflux.

Method 4 Compound () or a salt thereof can be produced by reacting compound () with compound () or a salt thereof.

This reaction is usually carried out in a solvent that does not adversely affect the reaction, such as acetone, and is often carried out at a temperature around room temperature.

Method 5 Compound () or its salt is prepared by hydrolyzing compound () or its salt in the presence of a base.

As the base, alkali metal hydroxides such as sodium hydroxide are often used.

This reaction is usually carried out at room temperature or under heating in a solvent that does not adversely affect the reaction, such as water, methanol, ethanol, tetrahydrofuran, or the like.

Method 6 Compound () or a salt thereof can be produced by hydrolyzing compound () or a salt thereof in the presence of an acid or subjecting it to catalytic reduction.

The acid used in this reaction is often a mixture of hydrobromic acid and acetic acid.

Further, the catalytic reduction is carried out using a commonly used catalyst for catalytic reduction such as platinum black under pressure of about normal pressure to about 3 atmospheres.

This reaction is usually carried out without a solvent or in a solvent that does not adversely affect the reaction, such as methanol, ethanol, dioxane, ethyl acetate, etc., at a temperature around room temperature.

Method 7 Compound (XI) or a salt thereof can be produced by subjecting compound () or a salt thereof to a peptide bond-forming reaction.

All general peptide bond forming reactions can be applied to this reaction, but it is usually carried out in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide, and in a solvent that does not adversely affect this reaction, such as ethyl acetate or dioxane. , carried out under cooling or heating.

In order to prevent racemization during the reaction, it is preferable to use a racemization inhibitor such as N-hydroxysuccinimide.

Method 8 Compound (XII) or a salt thereof is prepared by hydrolyzing or catalytically reducing compound (XI) or a salt thereof in the presence of an acid.

This reaction is substantially the same as that of Method 6 above, so please refer to the description of Method 6 above for reaction conditions.

Method 9 Compound () or its salt is compound (XII)
Alternatively, it can be produced by subjecting a salt thereof to a ring-closing reaction.

A preferable example of this ring-closing reaction is a ring-closing reaction carried out in the presence of an ammoniacal alcohol such as ammonia-saturated methanol.

This reaction is usually carried out without a solvent or in a solvent that does not adversely affect the reaction, such as methanol, ethanol, or tetrahydrofuran, under cooling or at a temperature of about room temperature.

Method 10 Compound (a) or a salt thereof is a compound (
) or a salt thereof with compound (XI).

This reaction is usually carried out in a solvent that does not adversely affect the reaction, such as dioxane, dimethylformamide, acetone, etc., under cooling or at a temperature around room temperature.

Method 11 Compound (b) or a salt thereof is a compound (
It is produced by subjecting a) or a salt thereof to catalytic reduction.

The catalyst for catalytic reduction in this reaction includes, for example, a commonly used catalyst for catalytic reduction such as platinum dioxide.

This reaction is usually carried out in a solvent that does not adversely affect the reaction, such as methanol, ethanol, ethyl acetate, dioxane, tetrahydrofuran, etc., at a temperature ranging from cooling to room temperature.

Method 12 Compound () is produced by reacting Compound () with Compound () or its salt.

Among the raw material compounds (), N ^a -benzyloxycarbonyl-L-tryptophan methyl ester was produced by the method described in Chemical and Pharmaceutical Bulletin Vol. 23, pp. 3106-3113 (1975). Other compounds can also be produced in a similar manner.

The conditions for this reaction are substantially the same as in Production Method 4, so please refer to the description of Production Method 4.

Method 13 Compound () or its salt is
) is produced by subjecting it to a deesterification reaction.

This deesterification reaction is usually carried out by hydrolyzing the compound (2) or a salt thereof in the presence of a base such as sodium hydroxide.

This reaction is usually carried out at about room temperature in a solvent that does not adversely affect the reaction, such as water, methanol, or ethanol.

Method 14 Compound () is produced by reacting Compound () or a salt thereof with N-hydroxysuccinimide.

This reaction is typically carried out using e.g. dioxane, N,N
-N,N'- in a solvent such as dimethylformamide
This is often carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, under cooling or at a temperature around room temperature.

As mentioned above, the indole derivative () of the present invention has a blood pressure lowering effect and is useful as a blood pressure lowering agent, and also has an infection prevention effect against pathogenic bacteria and is useful as an agent for preventing and treating infectious diseases. Although indole derivatives () and their pharmaceutically acceptable salts can be administered to mammals including humans as they are, they are generally administered as a preparation in combination with various pharmaceutically acceptable carriers. Examples of such formulations include capsules, tablets, granules, powders, solutions, and the like.
Further, examples of pharmaceutically acceptable salts include acid addition salts such as hydrochloride and sulfate. Further pharmaceutically acceptable carriers include, for example, sucrose, starch, mannitrate, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, methylcellulose, hydroxypropylcellulose, gelatin, gum arabic, carboxymetal cellulose, magnesium stearate. , surfactants, water, and other carriers commonly used in the above formulations.

The dosage of indole derivatives () and their pharmaceutically acceptable salts varies depending on the type of disease, patient's weight, age, and administration method, but usually
The optimal dosage is often selected from within the range of 10 μg to 100 mg/Kg/day.

Next, a specific example of the method for producing the raw materials shown in Route A and Route B will be explained using production examples.

Production example 1 (1) 50 g of N ^a -(benzyloxycarbonyl)-L-tryptophan dimethyl sulfoxide
Add 250 ml of concentrated hydrochloric acid all at once to 105 ml of the solution while stirring. Accompanied by intense heat generation and gas production. After stirring the reaction solution for another 30 minutes, add 1 part of water.
Extract three times with 300 ml of ethyl acetate. The combined organic layers were washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure to give 2-benzyloxycarbonylamino-3-(2-oxo-3-
29 g of isodolinyl)propionic acid are obtained.

IR ν ^Nujo1 _MAX cm ^-1 ; 3250, 1720〜1680, 1620, 1520,
1230, 1050 (2) 2-benzyloxycarbonylamino-3-
Add 100 ml of anhydrous 10% hydrochloric acid-methanol solution to a solution of 18 g of (2-oxo-3-indolinyl)propionic acid dissolved in 100 ml of dry methanol.
Add. The reaction solution is left at room temperature overnight.
The solvent was distilled off under reduced pressure and dried to give 2-benzyloxycarbonylamino-3-(2-oxo-
18 g of 3-indolinyl)propionic acid methyl ester are obtained as an oil.

IR ν ^Nujo1 _MAX cm ^-1 ; 3250, 1730〜1680, 1620, 1520,
1220, 1180, 1050 NMR (CDCl ₃ , ppm); 9.2-9.1 (1H, broad),
7.4-6.8 (9H, m), 6.37 (0.5H, d, J=9
Hz), 6.15 (0.5H, d, J=8Hz), 5.12 (1H,
s), 5.03 (1H, s), 4.8-4.5 (1H, m), 3.7
(1.5H, s), 3.67 (1.5H, s), 3.6~3.4 (1H,
m), 2.5-2.2 (2H, m) MS; 368 (M ⁺ ) (3) 2-benzyloxycarbonylamino-3-
Dissolve 18 g of (2-oxo-3-indolinyl) propionic acid methyl ester in 116 ml of pyridine and add 5.8 g of phosphorus pentasulfide. The mixture is stirred and refluxed for 3 hours under argon. After cooling the reaction solution, 1 part of cold water was added to the resulting residue and the pH was adjusted to 2 with concentrated hydrochloric acid.
Extract with 300 ml of ethyl acetate four times, wash the combined organic layers four times with water, and then dry. When the solvent was distilled off, 2-benzyloxycarbonylamino-3
-(2-thioxo-3-indolinyl)propionic acid methyl ester is obtained. This compound is subjected to the next reaction without purification.

Dissolved in 100ml of acetone, anhydrous potassium carbonate 13
2.2 ml of methyl iodide was added dropwise while stirring. After continuing stirring at room temperature for an additional 5 minutes, the solvent is distilled off. Add 500ml of water to the resulting residue,
Extract twice with 200 ml of chloroform and dry the combined organic layers. When the solvent was distilled off, 18g of crude product was obtained.
get. The 2-benzyloxycarbonylamino-3-
6.2 g of (2-methylthio-3-indolyl)propionic acid methyl ester are obtained.

IR ν ^CHCl3 _MAX cm ^-1 ; 3480, 3450, 3350, 3030, 2970,
2940, 1720, 1510, 1450, 1440, 1350, 1220,
1060, 700 NMR ( _CDCl3 , ppm); 8.33 (1H, s), 7.5-7.0
(9H, m), 5.43 (1H, d, J=8Hz), 5.05
(2H, s), 4.87-4.50 (1H, m), 3.63 (3H,
s), 3.33 (2H, d, J = 6Hz), 2.3 (3H, s) (4) 2-benzyloxycarbonylamino-3-
To a solution of 4 g of (2-methylthio-3-indolyl) propionic acid methyl ester dissolved in a mixture of 10 ml of methanol and 10 ml of tetrahydrofuran, 11 ml of a 1N aqueous sodium hydroxide solution and 6 ml of water were added, and the mixture was stirred overnight at room temperature in an argon stream. do.

Water was added to the residue obtained by distilling off the organic solvent under reduced pressure, acidified with citric acid, and extracted with ethyl acetate. After washing the organic layer with saturated brine and drying over anhydrous magnesium sulfate, the solvent was distilled off to give 2-benzyloxycarbonylamino-
3.8 g of 3-(2-methylthio-3-indolyl)propionic acid are obtained as an oil.

IR ν ^CHCl3 _MAX cm ^-1 ; 3640, 3000, 2920, 1720~1710,
1500, 1450, 1340, 1220, 1060 NMR (CDCl ₃ , ppm); 8.3-8.0 (2H, broad),
7.5-6.8 (9H, m), 5.56-5.37 (1H, m), 4.97
(2H, s), 4.73-4.57 (1H, m), 3.33 (2H,
d, J=6Hz), 2.2(3H,s) (5) 2-benzyloxycarbonylamino-3-
Dissolve 6 g of (2-methylthio-3-indolyl) propionic acid methyl ester in 10 ml of acetic acid,
While cooling and stirring, add 23 ml of anhydrous hydrobromic acid (30% acetic acid solution). After continuing stirring at room temperature for another 60 minutes, the reaction solution was poured into 500 ml of n-hexane and allowed to stand for a while. A cooled saturated aqueous sodium carbonate solution is added to the residue obtained by discarding the supernatant, and the mixture is extracted twice with ethyl acetate. The extracted layer was washed with saturated brine, dried over anhydrous potassium carbonate, the solvent was distilled off, and 2-
3.9 g of amino-3-(2-methylthio-3-indolyl)propionic acid methyl ester are obtained.

IR ν ^CHCl3 _MAX cm ^-1 ; 3470, 3370, 3000, 2960, 1730,
1450, 1440, 1340, 1280, 1220 NMR (CDCl ₃ , ppm); 8.86 (1H, Broad S),
7.56-7.44 (1H, m), 7.2-7.0 (3H, m), 3.96
~3.82 (1H, m), 3.68 (3H, s), 3.4~3.0
(2H, m), 2.32 (3H, s), 1.72 (2H, broad s) (6) 2-benzyloxycarbonylamino-3-
(2-methylthio-3-indolyl)propionic acid 5.3 and 2-amino-3-(2-methylthio-
3-indolyl)propionic acid methyl ester
3.9g and N-hydroxysuccinimide 1.75g
was dissolved in a mixture of 100 ml of ethyl acetate and 100 ml of dioxane, and N,
20 ml of an ethyl acetate solution containing 2.85 g of N'-dicyclohexylcarbodiimide is added dropwise.

After stirring overnight at room temperature, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the resulting residue and filtered.

The solution is washed successively with a 1N aqueous hydrochloric acid solution, a 5% aqueous sodium bicarbonate solution, and a saturated saline solution, and then dried. 11 g of the oil obtained by distilling off the solvent was subjected to silica gel column chromatography and eluted with benzene:ethyl acetate (5:1) to obtain 2-
[2-benzyloxycarbonylamino-3-
4.5 g of (2-methylthio-3-indolyl)propionamide]-3-(2-methylthio-3-indolyl)propionic acid methyl ester are obtained.

IR ν ^CHCl3 _MAX cm ^-1 ; 3460, 3410, 3000, 1720, 1670,
1500, 1450, 1440, 1340, 1220, 690 NMR ( _CDCl3 , ppm); 8.13 (2H, s), 7.3-7.0
(13H, m), 6.3 (1H, d, J=8Hz), 5.4
(1H, d, J=8Hz), 4.97 (2H, s), 4.8~
4.4 (2H, m), 3.5 (3H, s), 3.3~3.17 (4H,
m), 2.2(6H,s) (7) 2-[2-benzyloxycarbonylamino-3-(2-methylthio-3-indolyl)propionamide]-3-(2-methylthio-3-
Indolyl) propionic acid methyl ester 4.5
Dissolve g in 9 ml of acetic acid, and add 11 ml of hydrobromic anhydride (30% acetic acid solution) while stirring on ice. After continuing stirring at room temperature for another 50 minutes, the mixture was poured into 500 ml of n-hexane and allowed to stand for a while.

The gummy residue obtained by discarding the supernatant,
Add chilled saturated aqueous sodium carbonate solution and extract twice with ethyl acetate. After washing the extracted layer with saturated brine and drying over anhydrous potassium carbonate, the solvent was distilled off to give 2-[2-amino-3-
3.3 g of (2-methylthio-3-indolyl)propionamide]-3-(2-methylthio-3-indolyl)propionic acid methyl ester are obtained.

IR ν ^CHCl3 _MAX cm ^-1 ; 3470, 3350, 3000, 2930, 1730,
1660, 1510, 1450, 1440, 1340, 1230 NMR (CDCl ₃ , ppm); 8.47 (2H, broad), 7.8
~7.0 (9H, m), 4.93 (1H, d, J=8Hz),
3.7~3.3 (8H, m), 2.37 (3H, s), 2.30 (3H,
s), 1.83 (2H, broad) (8) 2-[2-amino-3-(2-methylthio-3
-indolyl)propionamide]-3-(2-
3.3 g of methylthio-3-indolyl)propionic acid methyl ester is dissolved in 100 ml of anhydrous methanol, and the solution is saturated with ammonia gas by passing dry ammonia gas under ice-cooling and stirring.

After standing at room temperature for 4 hours, the residue obtained by drying under reduced pressure was subjected to silica gel column chromatography and eluted with chloroform containing 5% methanol to obtain 3,6-bis[(2-methylthio-3 -indolyl)methyl]-2,5
- 2.2 g of piperazinedione are obtained.

IR ν ^Nujo1 _MAX cm ^-1 ; 3410, 3390, 3200, 3050, 1670,
1330, 750, 740 NMR (CD ₃ OD, ppm); 7.3-6.8 (8H, m), 4.2
~4.0 (2H, m), 3.33 ~ 3.17 (4H, m), 2.33
(6H, s) NMR (pyridine-d ₅ , ppm); 11.7 (2H, broad), 8.02-7.8 (2H, m), 4.67-4.43 (2H,
m), 3.57 (2H, dd, J = 4.5Hz and 18Hz),
2.88 (2H, dd, J = 10Hz and 18Hz) (9) 3,6-bis[(2-methylthio-3-indolyl)methyl]-2,5-piperazinedione
Dissolve 0.4g in 1.6ml of dioxane, add 1g of potassium carbonate and 1-bromo-3-methyl-2-butene.
Add 1.6 ml and stir at room temperature for 48 hours under an argon atmosphere.

Add 100ml of ethyl acetate to the reaction mixture, add water,
After sequentially washing with saturated saline, drying with anhydrous magnesium sulfate.

The oil obtained by distilling off the solvent was purified by silica gel thin layer chromatography (developed with chloroform containing 3% methanol),
(3S, 6S)-3,6-bis[[(RS)-3-(1,
1-dimethyl-2-propenyl)-2-methylthio-3H-indol-3-yl]methyl]-
300 mg of 2,5-piperazinedione is obtained.

IR ν ^CHCl3 _MAX cm ^-1 ; 3380, 2970, 2920, 1680, 1500,
1460, 1450, 1380, 1370, 1330, 920 (10) 3,6-bis[(3-(1,1-dimethyl-2
220 mg of -propenyl)-2-methylthio-3H-indol-3-yl]methyl]-2,5-piperazinedione is dissolved in 5 ml of ethyl acetate, 40 mg of platinum dioxide is added, and catalytic reduction is carried out at room temperature and 1 atm for 5 hours. The liquid from which the platinum catalyst was removed was dried under reduced pressure, and the resulting oil was purified by silica gel thin layer chromatography (developed with chloroform containing 3% methanol) to obtain (3S, 6S).
20.0 mg of -3,6-bis[[(RS)-3-(1,1-dimethylpropyl)-2-methylthio-3H-indol-3-yl]methyl]-2,5-piperazinedione is obtained.

IR ν ^CHCl3 _MAX cm ^-1 ; 3360, 2970, 2920, 2870, 1680,
1500, 1460, 1450, 1390, 1370, 1330, 1260,
1160, 1130 Production example 2 (1) Dissolve (3S,6S)-3,6.-bis[(2-methylthio-3-indolyl)methyl]-2,5-piperazinedione (500 mg) in dioxane (2 ml). , potassium carbonate (1200 mg) and 1-bromo-3-methyl-2-butene (2.1 ml) were added,
Stir at room temperature for 7 days under an argon stream.

After the reaction, water is added, extracted with ethyl acetate, and the extracted layer is washed with water and dried. The oil obtained by distilling off the solvent was subjected to silica gel column chromatography and eluted with chloroform containing 3% methanol. Fractions containing the target product were collected and dried under reduced pressure, and the resulting residue was purified by thin layer chromatography (developing agent: ethyl acetate) to obtain (3S,
6S)-3,6-bis[[R]-3-(1,1-dimethyl-2-propenyl)-2-methylthio-
3H-indol-3-yl]methyl]-2,5
- Obtain piperazinedione (113 mg).

[α] _D ; −198.3° (C = 0.64, CHCl ₃ ) uV λ ^EtOH _MAX nm; 285, 293, 300 IR ν ^CHCl3 _MAX cm ^-1 ; 3380, 2960, 1675, 1500, 1380,
1360, 920 NMR ( _CDCl3 , ppm); 7.56-7.0 (8H, m), 6.06
(2H, dd, J = 10.5Hz and 17Hz), 5.2 (2H,
dd, J=10.5Hz and 1Hz), 5.08(2H, dd,
J = 17Hz and 1Hz), 4.88 (2H, d, J = 3
Hz), 3.24-3.0 (2H, m), 2.72 (6H, s), 2.8
~2.7 (4H), 1.08 (6H, s), 1.04 (6H, s) MS m/z; 600 (M ⁺ ) (2) (3S, 6S)-3,6-bis[(R)-3- (1,
1-dimethyl-2-propenyl)-2-methylthio-3H-indol-3-yl]methyl]-
Dissolve 2,5-piperazinedione (30 mg) in 7 ml of ethyl acetate, add platinum dioxide (20 mg),
Catalytic reduction is performed at room temperature and pressure for 5 hours.

The catalyst was removed, the liquid was dried under reduced pressure, and the resulting residue was purified by thin layer chromatography to obtain (3S,6S)-3,6-bis[[(R)-3-
(1,1-dimethylpropyl)-2-methylthio-3H-indol-3-yl]methyl]-2,
Obtain 5-piperazinedione (20 ml).

IR ν ^CHCl3 _MAX cm ^-1 ; 3380, 2960, 1680, 1500, 1450 NMR (CDCl ₃ , ppm); 7.6~7.0 (8H, m), 5.0~
4.9 (2H, broad), 2.73 (6H, s), 3.3-2.7
(6H), 1.3-0.6 (22H, m) MS m/z; 604 (M ⁺ ) Production example 3 (1) N〓-(benzyloxycarbonyl)-L-tryptophan methyl ester (15 g) was dissolved in acetone ( 10 ml) and sodium carbonate (18.7
g) and 1-bromo-3-methyl-2-butene (26 ml) were added, and the mixture was stirred overnight at room temperature under a stream of argon. Water is added to the reaction solution, extracted with ethyl acetate, and the extracted layer is washed with water and dried. Next, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, eluted with a mixture of benzene and ethyl acetate (20:1), and (2S, 3aS,
8aS)-1-benzyloxycarbonyl-2-
Methoxycarbonyl-3a,8-bis(3-methyl-2-butenyl)-1,2,3,3a,8,
8a-hexahydropyrrolo[2,3-b]indole (6.0 g), IR ν ^CHCl3 _MAX cm ^-1 ; 2920, 1740, 1700, 1600, 1410 NMR (CDCl ₃ , ppm); 7.32 (5H, s), 7.3~6.4
(4H, m), 5.5-4.9 (5H, m), 4.36-4.1 (2H,
m), 3.84-3.72 (1H, m), 3.46 (3H, s), 2.6
~2.1 (4H, m), 1.76 (3H, s), 1.66 (6H,
s), 1.56 (3H, s) and (2S, 3aR, 8aR)-1-benzyloxycarbonyl-2-methoxycarbonyl-3a,
8-bis(3-methyl-2-butenyl)-1,2,
3,3a,8,8a-hexahydropyrrolo[2,3
-b] Obtain indole (4.4 g).

IR ν ^CHCl3 _MAX cm ^-1 ; 2920, 1720, 1700, 1600, 1410 NMR (CDCl ₃ , ppm); 7.32 (5H, s), 7.3 to 6.3
(4H, m), 5.4~5.0 (5H, m), 4.76~4.52
(1H, m), 4.24~, 3.88 (2H, m), 3.24 (3H,
s), 2.5-2.3 (4H, m), 1.68 (9H, s), 1.54
(3H,s) (2) (2S,3aS,8aS-1-benzyloxycarbonyl-2-methoxycarbonyl-3a,8-
Bis(3-methyl-2-butenyl)-1,2,
3,3a,8,8a-hexahydropyrrolo[2,
3-b] Dissolve indole (240 mg) in methanol (3 ml), add 1N sodium hydroxide solution (0.6 ml), and stir overnight at room temperature under an argon atmosphere. After adjusting the reaction solution to be acidic, it was extracted with diethyl ether, and the extracted layer was dried and concentrated under reduced pressure to give (2S, 3aS, 8aS)-1-benzyloxycarbonyl-3a,8-bis(3-methyl-
2-butenyl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-
2-carboxylic acid (228 mg) is obtained.

IR ν ^CHCl3 _MAX cm ^-1 ; 2920, 1710, 1700, 1600, 1410 (3) (2S, 3aS, 8aS)-1-benzyloxycarbonyl-3a,8-bis(3-methyl-2-butenyl)-1 , 2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid (225 mg) and N-hydroxysuccinimide (55 mg) were dissolved in dioxane (20 ml), N,N'-
After adding 98 mg of dicyclohexylcarbodiimide under ice-cooling and stirring, the mixture was stirred overnight at room temperature. After filtering the reaction solution, ethyl acetate was added to the solution, washed with water, dried, and concentrated under reduced pressure to give (2S, 3aS, 8aS)-1-benzyloxycarbonyl-3a,8-bis(3
-methyl-2-butenyl)-2-succinimidoxycarbonyl-1,2,3,3a,8,
228 mg of 8a-hexahydropyrrolo[2,3-b]indole are obtained.

IR ν ^CHCl3 _nax cm ^-1 ; 2930, 1820, 1780, 1740, 1710 Production example 4 Dissolve 1 g of N-t-butoxycarbonyl-L-tryptophan methyl ester in 2 ml of acetone, and dissolve 2.6 g of sodium hydrogen carbonate and 1 -Bromo-3
Add 4 ml of -methyl-2-butene and stir overnight at room temperature under an argon atmosphere. Add water to the reaction solution,
Extract with ethyl acetate, wash the extracted layer with water, and dry.
The residue obtained by evaporating the solvent was subjected to silica gel column chromatography, eluted with a mixture of benzene and ethyl acetate (20:1), and from each fraction,
(2S,3aS,8aS)-1-t-butyloxycarbonyl-2-methoxycarbonyl-3a,8-bis(3-methyl-2-butenyl)-1,2,3,3a,
8,8a-hexahydropyrrolo[2,3-b]indole 415 mg, IR ν ^CHCl3 _nax cm ^-1 ; 2980, 1740, 1690, 1600, 1490 NMR (CDCl ₃ , ppm); 7.2-6.3 (4H, m) ,5.47
(1H, broad), 5.3~4.8 (2H, m), 4.3~4.0
(3H, m), 3.77 (3H, s), 2.6~2.2 (4H, m),
1.8-1.6 (12H, m), 143 (9H, s) and (2S, 3aR, 8aR)-1-t-butoxycarbonyl-2-methoxycarbonyl-3a,8
-bis(3-methyl-2-butenyl)-1,2,
3,3a,8,8a-hexahydropyrrolo[2,3
-b] Obtain 65 mg of indole.

IR ν ^CHCl3 _nax cm ^-1 ; 2990, 1730, 1690, 1610, NMR (CDCl ₃ , ppm); 7.2~6.3 (4H, m), 5.5~
5.0 (3H, m), 4.6 (1H, m), 4.2~4.0 (2H,
m), 3.37 (3H, s), 2.6~2.4 (4H, m), 1.8~
1.6 (12H, m), 1.5 (9H, s) Next, the present invention will be explained using examples.

Example 1 0.08 ml of titanium tetrachloride was added to 20 ml of anhydrous tetrahydrofuran containing 51 mg of lithium aluminum hydride, and the mixture was stirred and refluxed for 1 hour at room temperature under an argon atmosphere. Add (3S,6S)-3,6-bis[[(RS)-3-(1,1-dimethyl-2-propenyl)-2-methylthio-3H-indol-3-yl]methyl]-2 to this mixture. , 5-piperazinedione dissolved in 5 ml of anhydrous tetrahydrofuran was added dropwise to the mixture under stirring and refluxing, and refluxing was continued for an additional 3 hours.

After cooling the reaction mixture, diethyl ether saturated with water is added dropwise to the mixture under ice-cooling and stirring to remove the formed precipitate.

Add 100 ml of ethyl acetate to the solution, wash sequentially with water and saturated saline, and then dry. The oil obtained by distilling off the solvent was purified by thin layer chromatography (developed with benzene:ethyl acetate 10:1) to obtain (5aS, 7aS, 8aR, 13aS, 15aS, 16aR)-
8a,16a-bis(1,1-dimethyl-2-propenyl)-5,5a,8,8a,13,13a,16,16a-octahydropyrazino [1″,2″-1,5:4″ ,5″−
3 mg of 1',5']dipyrrolo[2,3-b:2',3'-b']diindole-7,15(7aH,15aH)-dione is obtained.

UV λ ^EtOH _MAX ; 245, 300nm MS; 508 (M ⁺ ) Other various instrumental analysis values for this product [IR, NMR]
The results also matched those of the standard FR-900220 substance.

Example 2 Raney nickel dispersed in ethanol
W2 is (3S, 6S)-3,6-bis [[(RS)-3-
(1,1-dimethylpropyl)-2-methylthio-
3H-indol-3-yl]methyl]-2,5-
Add to 5 ml of acetone solution containing 90 mg of piperazinedione, and stir and reflux for 2 hours. After cooling, the Raney-nickel was removed, the solvent was distilled off, and the resulting residue was purified by thin layer chromatography (developed with benzene:ethyl acetate 10:1).
(5aS, 7aS, 8aR, 13aS, 15aS, 16aR) −8a,
16a-bis(1,1-dimethylpropyl)-5,
5a,8,8a,13,13a,16,16a-octahydropyrdino(1″,2″-1,5:4″,5″-1′,5′]dipyrrolo[2,3-b:2 9 mg of diindole-7,15(7aH,15aH)-dione is obtained.

IR ν ^CHCl3 _MAX cm ^-1 ; 3410, 2960, 2870, 1660, 1610,
1480, 1465, 1420, 1390, 1370, 1340, 1300,
1290, 1240, 1150, 1080, 1060 NMR ( _CDCl3 , ppm); 7.12-6.94 (4H, m),
6.76-6.44 (4H, m), 5.46 (2H, s), 4.9 (2H,
Broad s) 3.86 (2H, t, J=8Hz), 2.48
(4H, d, J=8Hz), 1.6~1.2 (4H, m),
0.92 (12H, s), 0.8 (6H, t, J = 8Hz) [α] _D ; -619° (C = 1.0, CHCl ₃ ) Example 3 (3S,6S)-3,6-bis[[(R)-3(1,1
20 mg of -dimethylpropyl)-2-methylthio-3H-indol-3-yl]methyl]-2,5-piperazinedione was dissolved in 5 ml of acetone, and Raney-nickel W2 dispersed in ethanol was added.
Heat to reflux while stirring for 70 minutes.

The reaction solution was filtered, the solution was dried under reduced pressure, and the resulting residue was purified by thin layer chromatography (developing agent: benzene: ethyl acetate 10:1).
(5aS, 7aS, 8aR, 13aS, 15aS, 16aR) 8a, 16a
-bis(1,1-dimethylpropyl)-5,5a,
8,8a-13,13a,16,16a-octahydropyrazino[1″,2″-1,5:4″,5″-1′,5′]dipyrrolo[2,3-b:2′, 3′-b′] diindole-7,
7 mg of 15(7aH, 15aH)-dione is obtained.

The instrumental analysis values of this product were consistent with those of the target substance of Example 2.

Example 4 (5aS, 7aS, 8aR, 13aS, 15aS, 16aR) −8a,
16a-bis(1,1-dimethyl-2-propenyl)-5,5a,8,8a-13,13a,16,16a-octahydropyrazino [1″,2″-1,5:4″,5 ″−1′
，
Dissolve 500 mg of 5′]dipyrrolo[2,3-b:2′,3′-b′]diindole-7,15(7aH,15aH)-dione in 50 ml of ethanol, add 140 mg of platinum dioxide,
Catalytic reduction is carried out at room temperature and normal pressure for 4 hours. Then, the catalyst was removed from the reaction solution, the solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel chromatography and eluted with chloroform. The eluate is concentrated under reduced pressure to obtain crystals of the target product. This was recrystallized from ethanol and (5aS, 7aS, 8aR, 13aS, 15aS, 16aR) −
8a,16a-bis(1,1-dimethylpropyl)-
5,5a,8,8a,13,13a,16,16a-octahydropyrazino [1″,2″-1,5:4″,5″-1′,5′
]
400 mg of dipyrrolo[2,3-b:2',3'-b']diindole-7,15(7aH,15aH)-dione are obtained.

The instrumental analysis values of this product were consistent with those of the target substance of Example 2.

Example 5 (5aS, 7aS, 8aR, 13aS, 15aS, 16aR) −8a,
16a-bis(1,1-dimethylpropyl)-5,
5a,8,8a,13,13a,16,16a-octahydropyrazino[1″,2″-1,5:4″,5″-1′,5′]dipyrrolo[2,3-b:2 ′,3′-b′]Diindole-7,15(7aH,15aH)-dione (50 mg) was dissolved in 1 ml of pyridine, 0.9 ml of acetic anhydride was added, and the mixture was heated at 100°C for 5
Time reacts. After cooling, add methanol to decompose acetic anhydride, add 1N hydrochloric acid to the reaction mixture, and extract with chloroform. The extracted layer is washed successively with 1N hydrochloric acid, 5% aqueous sodium bicarbonate solution and water, and then dried over magnesium sulfate. Next, the residue obtained by concentration under reduced pressure was subjected to silica gel thin layer chromatography [developing solvent: benzene: ethyl acetate (10:1)].
5,13-diacetyl-8a,16a-bis(1,1-dimethylpropyl)-5,5a,8,8a,
13, 13a, 16, 16a-octahydropyrazino [1″,
2″-1, 5: 4″, 5″-1′, 5′] Dipyrrolo [2, 3
-b:2′,3′-b′]diindole-7,15(7aH,
15aH)-dione 30mg (diacetyl form) and 5-acetyl-8a,16a-bis(1,1-dimethylpropyl)-5,5a,8,8a,13,13a,16,16a-octahydropyrazino [1 ″, 2″-1, 5: 4″, 5″-1′
，
7 mg (monoacetyl form) of 5']dipyrrolo[2,3-b:2',3'-b']diindole-7,15(7aH,15aH)-dione is obtained.

(a) Physical properties of diacetyl compound: [α] _D −165° (C = 2.0, CHCl ₃ ) CD [θ];, 105000 (249 nm), −9000 (280 nm) IR ν ^CHCl3 _MAX cm ^-1 ; 2960, 1660 , 1590, 1380 NMR (CDCl ₃ , ppm); 7.96-7.8 (2H, m), 7.4
~7.0 (6H, m), 6.07 (2H, s), 3.84 (2H,
dd, J=7.0 and 105Hz), 2.60 (6H, s), 2.7
~2.4 (4H, m), 1.32 (4H, q, J = 7.5Hz),
0.95 (12H, s), 0.83 (6H, t, J = 7.5Hz) (b) Physical properties of monoacetyl body: NMR (CDCl ₃ ppm); 7.84 (1H, m), 7.4-7.0
(5H, m), 6.70 (1H, d), 6.46 (1H, d),
6.07 (1H, s), 5.46 (1H, s), 4.9 (1H, s),
3.84 (2H, m), 2.60 (3H, s), 2.5 (4H, m),
1.3 (4H, m), 0.96 (12H, s), 0.82 (6H, t,
J=7Hz) Example 6 In anhydrous diethyl ether (20 ml) containing 40 mg of aluminum chloride under ice-cooling and stirring in a nitrogen stream,
Add 34 mg of lithium aluminum hydride little by little. After addition, stir for an additional 40 minutes at room temperature. To this, (5aS, 7aS, 8aR, 13aS, 15aS, 16aR) −
8a,16a-bis(1,1-dimethylpropyl)-
5,5a,8,8a,13,13a,16,16a-octahydropyrazino [1″,2″-1,5:4″,5″-1′,5′
]
A solution of 150 mg of dipyrrolo[2,3-b:2′,3′-b′]diindole-7,15(7aH,15aH)-dione dissolved in 5 ml of anhydrous diethyl ether was added dropwise under ice-cooling and stirring. Keep on ice for an additional 30 minutes. The reaction solution was then concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography (developed with chloroform containing 3% methanol) to give 8a,16a-bis(1,1-dimethylpropyl)-5, 5a, 7,
7a, 8, 8a, 13, 13a, 15, 15a, 16, 16a-dodecahydropyrazino [1″, 2″-1, 5: 4″, 5″-1′
，
72 mg of 5']dipyrrolo[2,3-b:2',3'-b']diindole is obtained.

[α] _D −207.1゜ (C=1.28, CHCl ₃ ) CD [θ]; −87100 [247nm), −11600 (296nm) UV λ ^MeOH _MAX ; 245301nm IR ν ^CHCl3 _MAX cm ^-1 ; 3420, 2950, 1600 , 1480, 1460 ¹ H-NMR (CDCl ₃ , ppm); 7.2-6.4 (8H, m),
4.63 (2H, s), 4.08 (2H, s), 3.0~1.2 (14H,
m), 1.0 to 0.7 (18H, m) MS m/z; 484 (M ⁺ ) Example 7 (5aS, 7aS, 8aR, 13aS, 15aS, 16aR) −8a,
16a-bis(1,1-dimethyl-2-propenyl)-5,5a,8,8a,13,13a,16,16a-octahydropyrazino[1″,2″-1,5:4″,5 ″−1′
，
Dissolve 70 mg of 5′]dipyrrolo[2,3-b:2′,3′-b′]diindole-7,15(7aH,15aH)-dione in 0.7 ml of acetic acid, add 160 mg of platinum dioxide, and stir at room temperature. Catalytic reduction is carried out at 4 atm. Next, the catalyst was removed and the residue obtained by drying under reduced pressure was subjected to silica gel thin layer chromatography (developed with chloroform containing 5% methanol) to give 8a,16a-bis(1,1-dimethylpropyl)- 1, 2, 3, 4,
4a, 5, 5a, 8, 8a, 8b, 9, 10, 11, 12,
12a, 13, 13a, 16, 16a, 16b-eicosahydropyrazino [1″, 2″-1, 5: 4″, 5″-1′, 5′] dipyrrolo [2, 3-b: 2′ ,3'-b']diindole-7,15(7aH,15aH)-dione (33.5 mg) is obtained.

[α] _D −173.9° (C=1.4, CHCl ₃ ) IR ν ^CHCl3 _MAX cm ⁻¹ ; 3300, 2920, 1660, 1400 NMR (CDCl ₃ , ppm); 5.38 (2H, s), 4.33 (2H,
dd, J = 6Hz and 10Hz), 3.5~3.3 (2H,
m), 3.0 (2H, dd, J = 6Hz and 15Hz), 2.3
(2H, s), 2.2~1.1 (24H, m), 1.0~0.6
(18H, m) MS m/z; 427, 453, 495, 524 (M ⁺ ) NMR (Py−d ₅・ppm); 5.68 (2H, s), 4.54
(2H, dd, J = 6Hz and 10Hz), 4.2~4.0
(2H, m), 3.56-3.44 (2H, m), 3.2 (2H,
dd, J=6Hz and 15Hz), 2.06~1.16 (24H,
m), 0.96 to 0.64 (18H, m) Example 8 (5aS, 7aS, 8aR, 13aS, 15aS, 16aR) −8a,
16a-bis(1,1-dimethylpropyl)-5,
5a,8,8a,13,13a,16,16a-octahydropyrazino[1″,2″-1,5:4″,5″-1′,5′]dipyrrolo[2,3-b:2 ′,3′-b′]Diindole-7,15(7aH,15aH)-dione (130 mg) was added to N,N-
Dissolved in 5 ml of dimethylformamide, 180 mg of potassium carbonate and 1-bromo-3-methyl-2-butene.
Add 0.4ml. The reaction solution was then stirred at 70°C for 5 hours. After cooling the reaction solution, water was added and extracted with ethyl acetate. The extracted layer is washed with water and saturated brine, dried, and concentrated under reduced pressure to obtain a residue. This was dissolved in 10 ml of ethanol, 30 mg of platinum dioxide was added, and catalytic reduction was carried out at room temperature and normal pressure for 3 hours. The liquid obtained by removing the catalyst was concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography.
8a,16a-bis(1,1-dimethylpropyl)-
5,13-diisopentyl-5,5a,8,8a,13,
13a, 16, 16a-octahydropyrazino [1″, 2″-
1,5:4″,5″−1′,5′] Dipyrrolo [2,3−
b: 2′, 3′-b′] diindole-7, 15 (7aH,
110 mg of 15aH)-dione are obtained.

[α] _D −470.8° (C=0.8, CHCl ₃ ) CD [θ]; −125000 (255 nm), −36800 (311 nm) IR ν ^CHCl3 _MAX cm ^-1 ; 2960, 1655, 1600, 1430 ¹ H−NMR (CDCl ₃ , ppm); 7.12-7.0 (4H, m),
6.66-6.52 (2H, m), 6.32-6.24 (2H, m),
5.80 (2H, s), 4.06 (2H, dd, J=6 and 11
Hz), 3.46-3.20 (4H, m), 2.56 (2H, dd, J
= 6Hz and 11Hz), 2.28 (2H, dd, J = 11Hz
and 11Hz), 1.7~1.2 (10H, m), 1.0~0.8
(30H, m) Example 9 (3S,6S)-3,6-bis(indole-3-
ylmethyl)-2,5-piperazinedione was dissolved in 0.7 ml of N,N-dimethylformamide,
Add 680 mg of sodium hydrogen carbonate and 0.95 ml of 1-bromo-3-methyl-2-butene, and stir at room temperature in an argon stream for 8 hours. Water is added to the reaction solution, extracted with ethyl acetate, and the extracted layer is washed with water and dried. Next, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography and eluted with carbon tetrachloride containing 10% diethyl ether. 15aS, 16aS)
-5,8a,13,16a-tetrakis(3-methyl-
2-butenyl)-5,5a,8,8a,13,13a,16,
16a-octahydropyrazino [1″,2″-1,5:
4″, 5″-1′, 5′] Dipyrrolo [2, 3-b: 2′, 3′
−
b'] Diindole-7,15(7aH,15aH)-dione 53mg [a] _D -406.4゜(C=0.96, _CHCl3 ) IR ν ^CHCl3 _MAX cm ^-1 ; 3000, 1660, 1600, 1490, ^{1430 1} H-NMR (CDCl ₃ , ppm); 7.2-6.3 (8H, m),
5.50 (2H, s), 5.3~4.9 (4H, m), 4.3~3.9
(6H, m), 2.8~2.0 (8H, m), 1.8~1.6 (24H,
m) and (5aS, 7aS, 8aR, 13aR, 15aS,
16aS)-5,8a,13,16a-tetrakis(3-methyl-2-butenyl)-5,5a,8,8a,13,
13a, 16, 16a-octahydropyrazino [1″, 2″-
1,5:4″,5″−1′,5′] Dipyrrolo [2,3−
b: 2′, 3′-b′] diindole-7, 15 (7aH,
15aH)-dione 240 mg [α] _D −115.4° (C=1.06, CHCl ₃ ) IR ν ^CHCl3 _MAX cm ⁻¹ ; 3000, 1670, 1600, 1480 NMR (CDCl ₃ , ppm); 7.2–6.4 (8H, m ), 5.35
(1H, s) 5.32 (1H, s), 5.3~4.9 (4H, m),
4.5~4.0 (6H, m), 2.7~2,2 (8H, m), 1.9
~1.5 (24H, m) and (5aR, 7aS, 8aR, 13aR, 15aS,
16aR)-5,8a,13,16a-tetrakis(3-methyl-2-butenyl)-5,5a,8,8a,13,
13a, 16, 16a-octahydropyrazino [1″, 2″-
1,5:4″,5″−1′,5′] Dipyrrolo [2,3−
b: 2′, 3′-b′] diindole-7, 15 (7aH,
63 mg of 15aH)-dione are obtained.

[α] _D +136.2° (C=1.2, CHCl ₃ ) IR ν ^CHCl3 _MAX cm ^-1 ; 3000, 1675, 1600, 1480 ′H-NMR (CDCl ₃ , ppm); 7.3 to 6.8 (8H, m) ，
5.40 (2H, s), 5.3~4.9 (4H, m), 4.6~4.0
(6H, m), 2.6 to 2.3 (8H, m), 1.8 to 1.6 (24H) Example 10 (5aR, 7aS, 8aR, 13aR, 15aS, 16aR) −
5,8a,13,16a-tetrakis(3-methyl-2
-butenyl)-5, 5a, 8, 8a, 13, 13a, 16,
16a-octahydropyrazino [1″,2″-1,5:
4″, 5″-1′, 5′] Dipyrrolo [2, 3-b: 2′, 3′
−
b] Dissolve 35 mg of diindole-7,15(7aH,15aH)-dione in 5 ml of ethanol, and dissolve platinum dioxide 2
mg and catalytic reduction at room temperature and normal pressure for 45 minutes.
The catalyst was removed, the liquid was dried under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developing solution: chloroform) to obtain (5aR, 7aS,
8aR, 13aR, 15aS, 16aR) -5, 8a, 13, 16a-
Tetraisopentyl-5, 5a, 8, 8a, 13,
13a, 16, 16a-octahydropyrazino [1″, 2″-
1,5:4″,5″−1′,5′] Dipyrrolo [2,3−
b: 2′, 3′-b′] diindole-7, 15 (7aH,
17.5 mg of 15aH)-dione are obtained.

[α] _D +202.4゜ (C=0.875, CHCl ₃ ) UV λ ^EtOH _MAX nm (ε); 252 (23600), 303 (5900) IR ν ^CHCl3 _MAX cm ^-1 ; 2950, 1675, 1605, 1480, 1390 NMR ( _CDCl3 , ppm); 7.1-6.3 (8H, m), 5.55
(2H, s), 4.38 (2H, t, J=9Hz), 3.4~
3.3 (4H, m), 2.37 (4H, d, J=9Hz), 2.0
~1.1 (16H, m), 1.0 ~ 0.75 (24H, m) MS m/z; 581, 595, 652 (M ⁺ ) Example 11 (5aS, 7aS, 8aR, 13aR, 15aS, 16aS) -5,
8a,13,16a-tetrakis-(3-methyl-2-
butenyl) -5,5a,8,8a,13,13a,16,16a
-Octahydropyrazino [1″, 2″-1,5:4″,
5″-1′, 5′] Dipyrrolo [2, 3-b: 2′, 3′-b′
]
Diindole-7,15(7aH,15aH)-dione 40
mg was dissolved in 5 ml of ethanol, 20 mg of platinum dioxide was added, and catalytic reduction was carried out at room temperature and normal pressure for 60 minutes. The catalyst was removed, the liquid was dried under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (chloroform as a developing agent) to obtain (5aS, 7aS, 8aR,
13aR, 15aS, 16aS) -5,8a,13,16a-tetraisopentyl-5,5a,8,8a,13,13a,16,
16a-octahydropyrazino [1″,2″-1,5:
4″, 5″-1′, 5′] Dipyrrolo [2, 3-b: 2′, 3′
−
b'] 24.7 mg of diindole-7,15(7aH,15aH)-dione is obtained.

[α] _D −102.1゜(C=1.24, CHCl ₃ ) UV λ ^EtOH _MAX nm (ε); 253 (20600), 306 (5400) IR ν ^CHCl3 _MAX cm ^-1 ; 2950, 1670, 1600, 1480, 1400 NMR ( _CDCl3 , ppm); 7.2-6.3 (8H, m), 5.47
(2H, s), 4.47~4.0 (2H, m), 3.7~3.3 (4H,
m), 2.8-2.0 (4H, m), 1.9-1.07 (16H, m),
1.0-0.77 (2H, m) MS m/z; 652 (M ⁺ ) Example 12 (5aS, 7aS, 8aS, 13aS, 15aS, 16aS) -5,
8a,13,16a-tetrakis-(3-methyl-2-
butenyl) 5, 5a, 8, 8a, 13, 13a, 16, 16a
-Octahydropyrazino [1″, 2″-1,5:4″,
5″-1′, 5′] Dipyrrolo [2, 3-b: 2′, 3′-b′
]
Diindole-7,15(7aH,15aH)-dione 40
mg was dissolved in 5 ml of ethyl acetate, 50 mg of platinum dioxide was added, and catalytic reduction was carried out at room temperature and normal pressure for 60 minutes. The catalyst was removed, the liquid was dried under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (developer: chloroform) to obtain (5aS, 7aS, 8aS,
13aS, 15aS, 16aS) -5,8a,13,16a-tetraisopentyl-5,5a,8,8a,13,13a,16,
16a-octahydropyrazino [1″,2″-1,5:
4″, 5″-1′, 5′] Dipyrrolo [2, 3-b: 2′, 3′
−
b'] 28 mg of diindole-7,15(7aH,15aH)-dione is obtained.

[α] _D −433.3° (C=1.25, CHCl ₃ ) UV λ ^EtOH _MAX nm (ε); 254 (20400), 310 (5300) IR ν ^CHCl3 _MAX cm ^-1 ; 2950, 1655, 1600, 1490 NMR ( CDCl ₃ , ppm); 7.1-6.2 (8H, m), 5.57
(2H, s), 4.11 (2H, dd, J = 6Hz and 11
Hz), 3.5-3.3 (4H, m), 2.7 (2H, dd, J=6
Hz and 11Hz), 2.1 (2H, dd, J = 11Hz), 1.9
~1.07 (16H, m), 1.0 ~ 0.77 (24H, m) MS m/z; 652 (M ⁺ ) Example 13 (2S,3aS,8aS)-1-benzyloxycarbonyl-3a,8-bis(3-methyl-2-butenyl)-2-succinimidoxycarbonyl-1,
2,3,3a,8,8a-hexahydropyrrolo[2,
3-b] Dissolve 228 mg of indole in ethyl acetate,
Add 50 mg of palladium black and 50 mg of platinum dioxide, and catalytically reduce the mixture at room temperature and 4 atm for 4 hours. The catalyst was removed, the liquid was dried under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography.
(5aS, 7aS, 8aS, 13aS, 15aS, 16aS) -5,
8a, 13, 16a-tetraisopentyl-5, 5a,
8,8a,13,13a,16,16a-octahydropyrazino[1″,2″-1,5:4″,5″-1′,5′]dipyrrolo[2,3-b:2′, 3′-b′] diindole-7,
Obtain 51 mg of 15(7aH, 15aH)-dione.

The thin layer chromatogram and instrumental analysis values of this product were consistent with those of the target substance of Example 12.

Example 14 (2S,3aR,8aR)-1-benzyloxycarbonyl-2-methoxycarbonyl-3a,8-bis-(3-methyl-2-butenyl)-1,2,3,
3a,8,8a-hexahydropyrrolo[2,3-b]
Dissolve 250mg of indole in 5ml of methanol, 1N
Add 0.64 ml of sodium hydroxide and stir overnight at room temperature under a stream of argon. After making the reaction solution acidic,
Extract with diethyl ether, wash the extracted layer with water, and then dry. The reaction solution was concentrated under reduced pressure, and (2S, 3aR, 8aR) −
1-benzyloxycarbonyl-3a,8-bis-(3-methyl-2-butenyl)-1,2,3,
3a,8,8a-hexahydropyrrolo[2,3-b]
60 mg of indole-2-carboxylic acid are obtained. This and 40 mg of N-hydroxysuccinimide are dissolved in a mixed solution of 5 ml of dioxane and 5 ml of ethyl acetate, and 70 mg of N,N'-dicyclohexylcarbodiimide is added while cooling with ice and stirring. Then stir overnight at room temperature. The reaction solution was filtered, the solution was dried under reduced pressure, the resulting residue was dissolved in ethyl acetate, and 50 mg of palladium black was dissolved.
and 50 mg of platinum dioxide were added, and catalytic reduction was carried out at room temperature and 4 atm for 5 hours. The reaction solution was filtered, the solution was dried under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography to obtain (5aR, 7aS, 8aR,
13aR, 15aS, 16aR) -5,8a,13,16a-tetraisopentyl-5,5a,8,8a,13,13a,16,
16a-octahydropyrazino [1″,2″-1,5:
4″, 5″-1′, 5′] Dipyrrolo [2, 3-b: 2′, 3′
−
b'] Obtain 10 mg of diindole-7,15(7aH,15aH)-dione.

The thin layer chromatogram and instrumental analysis values of this product were consistent with those of the target substance of Example 10.

Claims (1)

[Claims] 1. General formula (In the formula, A is a 2-butenediylidene group or a tetramethylene group, R ¹ is hydrogen, a lower alkyl group, or a lower alkenyl group, R ² is hydrogen, a lower alkyl group, a lower alkenyl group, or an acyl group,
R ³ and R ⁴ each represent hydrogen or R ³ and R ⁴ taken together mean an oxo group, respectively) or a pharmaceutically acceptable salt thereof (provided that FR-900220 substances and (excluding its pharmaceutically acceptable salts). 2 General formula (In the formula, A is a 2-butenediylidene group or a tetramethylene group, R ¹ is hydrogen, a lower alkyl group,
(lower alkenyl group or acyl group, R ^b means lower alkyl group) or a salt thereof is subjected to a desulfurization ring closure reaction to form the general formula (wherein A and R ¹ have the same meanings as above) A method for producing a compound or a salt thereof.