JPH08151366A - 1-hydroxyindole derivative - Google Patents

Abstract

PURPOSE: To obtain a new compound having platelet aggregation-suppressing action, bronchodilatation or vasodepressor activity and useful as an antiplatelet agent, a bronchodilator or an antihypertensive agent. CONSTITUTION: This compound is expressed by formula I (A is a lower alkylene; R is a lower alkoxycarbonylamino, an alkanoylamino, etc.,; Y is H, nitro, etc., with the proviso that when R is acetylamino and Y is H, A is not ethylene and R is methoxycarbonyl and when Y is H, A is not methylene) or its salt, e.g. methyl 1-hydroxyindole-3-propionate. The compound is obtained by oxidizing 2,3-dihydroindole compound of formula II with an oxidizing agent (preferably combination, etc., of sodium tungstate and hydrogen peroxide). Furthermore, the compound of formula II is obtained by treating, e.g. an indole compound of formula III with sodium cyanoborohydride in acetic acid.

Description

Detailed Description of the Invention

[0001]

INDUSTRIAL APPLICABILITY The present invention is useful as a medicine.
It relates to a hydroxyindole derivative.

More specifically, the present invention has a general formula useful as an antiplatelet agent, a bronchodilator or a therapeutic agent for hypertension, which has a platelet aggregation inhibitory action, a bronchodilator action or a blood pressure lowering action.

[0003]

Embedded image

(A in the formula is a lower alkylene group, and R is
Has a lower alkoxycarbonylamino group, an alkanoylamino group, a halo lower alkanoylamino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkanoyloxy group, a lower alkoxycarbonyl group, and a lower alkyl group as a substituent. Good arylsulfonylamino group or general formula

[0005]

[Chemical 6]

A group represented by the formula (Z is a lower alkyl group which may be substituted with an aryl group), and Y
Is a hydrogen atom, a nitro group or a lower alkoxy group)
The present invention relates to a 1-hydroxyindole derivative represented by

[0007]

2. Description of the Related Art Some indole derivatives having a hydroxyl group at the 1-position of the indole skeleton have been known so far, but 1 having an alkyl group substituted with a certain substituent as in the present invention at the 3-position. Little is known about -hydroxyindole derivatives, and much less is known about the 1-hydroxyindole derivatives of the present invention exhibiting platelet aggregation-inhibiting action, bronchodilating action or hypotensive action.

[0008]

An object of the present invention is to provide a novel 1-hydroxyindole derivative useful as an antiplatelet agent, a bronchodilator or a therapeutic agent for hypertension.

[0009]

Means for Solving the Problems As a result of intensive studies on the 1-hydroxyindole derivative, the present inventors have found that the 1-hydroxyindole derivative of the present invention exhibits an excellent platelet aggregation inhibitory action, bronchodilator action or hypotensive action. Therefore, the present invention has been completed based on the finding that it has usefulness as an antiplatelet agent, a bronchodilator or a therapeutic agent for hypertension.

In the compound represented by the general formula (I) of the present invention, the lower alkyl group is a methyl group, an ethyl group or n.
-Propyl group, isopropyl group, n-butyl group, isobutyl group, tert-butyl group, sec-butyl group, n-
A linear or branched alkyl group having 1 to 6 carbon atoms such as a pentyl group and an n-hexyl group. A lower alkylene group means a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, Hexamethylene group, ethylmethylene group, propylene group, etc., having 1 to 6 carbon atoms
Is an alkylene group, and the lower alkoxy group is a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group,
Isobutoxy group, tert-butoxy group, butoxy group,
1 to 6 carbon atoms such as pentyloxy group and hexyloxy group
Refers to a linear or branched alkoxy group. The alkanoyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, hexanoyl group,
An alkylcarbonyl group having a linear or branched alkyl group such as an octanoyl group, a lauroyl group, a palmitoyl group, and a stearoyl group. A lower alkanoyl group means an alkanoyl group having 2 to 7 carbon atoms, and a halo lower alkanoyl group. The term "lower alkanoyl group" is substituted with a fluorine atom such as trifluoroacetyl group or a halogen atom such as chlorine atom, bromine atom or iodine atom. Further, the aryl group refers to an aromatic hydrocarbon group such as a phenyl group and a naphthyl group.

The 1-hydroxyindole derivative represented by the general formula (I) of the present invention is a novel compound except for a part thereof and can be produced as follows. That is, the compound of the present invention has the general formula

[0012]

[Chemical 7]

The 2,3-dihydroindole compound represented by the formula (A, R and Y have the same meanings as described above) can be easily produced by oxidizing with an oxidizing agent.

Examples of the oxidizing agent used in the above manufacturing method include organic peroxides, metal peroxides and persulfuric acid. The metal peroxide is used by being generated in the reaction system with a salt of metal oxide and a peroxide, and examples of such a salt include salts of tungstic acid, molybdic acid, vanadate, and the like. Hydrogen peroxide water can be used as the oxide. Among these combinations of metal oxide salts and peroxides, the combination of sodium tungstate and hydrogen peroxide solution is most preferable. Examples of the organic peroxide include m-chloroperbenzoic acid and the like.

For example, the metal peroxide is represented by the general formula (I
0.0) for 2,3-dihydroindole compound of I)
It is used in a combination of 5 to 1.0 times mole of metal oxide and 1 to 10 times mole of peroxide, and the ratio of 0.2 times mole of metal oxide salt and 10 times mole of peroxide is most preferable. preferable.

In order to suitably carry out the above-mentioned production method, the 2,3-dihydroindole compound represented by the general formula (II) is dissolved in an inert organic solvent, for example, methanol, and the mixture is added with an oxidizer under stirring with ice cooling. For example, a 0.2-fold molar aqueous solution of sodium tungstate dihydrate and a 10-fold molar aqueous solution of hydrogen peroxide are added as they are, or a methanol solution thereof is added and the mixture is stirred at room temperature. The compound of the general formula (I) of the present invention is obtained by treatment and purification.

The 2,3-dihydroindole compound of the general formula (II) used as a starting material in the above production method is

[0018]

Embedded image

The indole compound of formula (A, R and Y have the same meanings as defined above) is treated with sodium borohydride in acetic acid or with triethylsilane in trifluoroacetic acid. It can be obtained by

Further, the indole compound represented by the general formula (III) used as a starting material in the above-mentioned production method also includes a known compound, and it can be obtained as a commercial product, or can be obtained by a method described in the literature or similar thereto. Can be obtained by various methods.

Among the compounds represented by the general formula (I) of the present invention, the compound having a nitro group as a substituent is
Chemiche Ber., 95.
Volume, 2205-2221, 1962; Journal of the American Chemical Society (JACS), 80, 4621-4622, 1958; The Journal of Organic Chemistry (JOC. ), 22 volumes, 84-8
5 pages, 1957; The Chemistry of Indore's (THE CHEMISTRY OF INDO
LES), Richard. J. By Sundberg,
ACADEMIC PRESS INC. Publishing, 197
After introducing a nitro group in the middle of the production process or forming a corresponding intermediate nitro compound by the method described in literatures such as Year 0 and books, or a method similar thereto,
It can also be produced by carrying out a reaction according to a conventional method using the compound, or finally introducing a nitro group.

The compound represented by the general formula (I) of the present invention is approximately 0.3 to 4 in the in vitro platelet aggregation inhibitory action measurement test induced by arachidonic acid using rabbit platelet-rich plasma. It exhibited an activity of inhibiting platelet aggregation by 50% at a concentration of 0 μM. For example, cilostazol inhibited platelet aggregation by 50% at a concentration of about 3.10 μM, while 1-hydroxy-Nb-methoxycarbonyltryptamine and methyl 1-hydroxyindole-3-propionate were about 0.32 μM.
The concentration of platelets inhibited platelet aggregation by 50%. Similarly, 1-hydroxy-Nb, Nb-dimethyltryptamine has a concentration of about 2.90 μM, and 1-hydroxy-6-nitro-Nb-trifluoroacetyltryptamine has a concentration of about 3.31 μM. -Nb-acetyltryptamine inhibited platelet aggregation by 50% at a concentration of about 3.40 μM. Thus, the compound of the present invention has an excellent inhibitory effect on platelet aggregation and is a useful compound as an antiplatelet agent.

Nutrient water (physiological) at 37 ° C.
Using an isolated guinea pig trachea suspended in al salt solution, 1 g resting tension
The relaxation action of tracheal smooth muscle of the compound represented by the general formula (I) of the present invention was measured under gtension). As a result, for example, 1-hydroxy-Nb-acetyltryptamine was 90% at 10 μg / ml, 3 μl against the maximum relaxation induced by 0.3 μg / ml epinephrine.
In g / ml, 50% showed an action of relaxing tracheal smooth muscle. Thus, the compound of the present invention has an excellent bronchodilator effect and is a useful compound as a bronchodilator.

The antihypertensive effect of the compound represented by the general formula (I) of the present invention is that the systolic blood pressure is 180 to 220 mmH.
g of non-anesthetized spontaneously hypertensive rats (SHR). As a result, for example, 1-hydroxy-Nb
-Acetyltryptamine lowered blood pressure by 25%, 26%, and 22% of the blood pressure before the administration under the temperature control of 32 ± 1 ° C. at 1, 2, and 4 hours after 100 mg / kg oral administration, respectively. Thus, the compound of the present invention has an excellent antihypertensive effect and is a useful compound as a therapeutic agent for hypertension.

Among the compounds of the general formula (I) of the present invention, for the compound having an asymmetric carbon atom, any of the R configuration compound, the S configuration compound or a mixture thereof may be used.

In the compound of the general formula (I) of the present invention, the substituent R is a lower alkoxycarbonylamino group, a lower alkoxycarbonyl group, a lower alkanoyloxy group or an arylsulfonyl which may be substituted with a lower alkyl group. Amino group and the like are preferable, and specifically, 1
-Hydroxy-Nb-methoxycarbonyltryptamine, methyl 1-hydroxyindole-3-propionate, methyl 1-hydroxyindole-3-butyrate, 1-hydroxy-Nb- (4-methylbenzenesulfonyl) indole-3-methanamine, 4- (1
-Hydroxyindol-3-yl) butyl acetate and the like can be mentioned.

The compound represented by the general formula (I) of the present invention can be converted into its pharmaceutically acceptable salt according to a conventional method. Examples of these salts include salts with inorganic bases such as sodium salts, potassium salts, calcium salts and the like. These pharmacologically acceptable salts also exhibit the same platelet aggregation inhibitory action, bronchodilator action or blood pressure lowering action as the free form, and are useful as antiplatelet agents, bronchodilator agents or therapeutic agents for hypertension.

1-represented by the general formula (I) of the present invention
When the hydroxyindole derivative and its salt are used for actual therapy, they are orally or parenterally administered as a suitable pharmaceutical composition such as tablets, powders, granules, capsules, injections and the like.

These pharmaceutical compositions are appropriately mixed with pharmaceutical additives such as suitable excipients, disintegrants, binders, lubricants and the like by a method used in pharmacy depending on the dosage form,
It can be produced by preparing in a conventional manner.

For example, tablets are prepared by adding a suitable excipient, a disintegrating agent, a binder, a lubricant, etc. to the compound of the present invention or a salt thereof, and compressing them according to a conventional method. If necessary, the tablets may be coated to give film-coated tablets, sugar-coated tablets, enteric-coated tablets and the like.

The compound represented by the above general formula (I) of the present invention has a very high level of safety. For example, 1-hydroxy-Nb-acetyltryptamine is added to a mouse in an amount of 300.
In the acute toxicity test of oral administration of mg / kg or intraperitoneal administration of 100 mg / kg, no death was observed after 72 hours.

The dose is appropriately determined according to the sex, age, body weight, degree of symptoms of the subject patient, but in the case of oral administration, it is generally 0.1 to 10 per adult day.
In the case of parenteral administration of 00 mg, the daily dose for adults is approximately 0.
It is administered within the range of 01 to 100 mg.

[0033]

EXAMPLES The contents of the present invention will be described in more detail with reference to the following reference examples and examples. All melting points of the compounds of Reference Examples and Examples are uncorrected.

General Synthesis Method of 2,3-Dihydroindole Derivative Method A: Triethylsilane was added to a solution prepared by previously dissolving the indole derivative in trifluoroacetic acid,
The stirring was continued at room temperature or under heating for the time described in Reference Example. After distilling off the solvent under reduced pressure, sodium hydroxide aqueous solution or sodium hydrogen carbonate aqueous solution was added to the obtained residue, or water was added, and then sodium hydroxide or sodium hydrogen carbonate was added under ice cooling to make the mixture alkaline. , Methylene chloride-methanol (95: 5, v / v). The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the crude product obtained by evaporating the filtrate under reduced pressure was subjected to column chromatography using silica gel as a carrier, using the elution solvent described in Reference Example.

Method B: Sodium borohydride was added to a solution prepared by previously dissolving an indole derivative in acetic acid, and stirring was continued at room temperature for the time described in Reference Example. Water was added to the reaction solution, and sodium hydroxide was added under ice-cooling to neutralize it, and then methylene chloride-methanol (9
5: 5, v / v). The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the crude product obtained by evaporating the filtrate under reduced pressure was subjected to column chromatography using silica gel as a carrier, using the elution solvent described in Reference Example.

Reference Example 1.2 Synthesis of 2,3-dihydro-Nb-methoxycarbonyltryptamine In method A of the general synthesis method, 0.22 ml of triethylsilane, 250.3 mg of Nb-methoxycarbonyltryptamine, 10 ml of triethylsilane were used. 55 with fluoroacetic acid
The mixture was heated and stirred at 0 ° C for 2 hours. The solvent was distilled off under reduced pressure, 2N aqueous sodium hydroxide solution was added to the obtained residue to make it alkaline, and after the post-treatment, the obtained crude product was treated with methylene chloride-methanol (97: 3, v / v). Was purified by column chromatography using silica gel as the eluent and 236.9 mg (94%) of 2,3.
-Dihydro-Nb-methoxycarbonyltryptamine was obtained.

[0037]

Reference Example 2. Synthesis of 2,3-dihydro-Nb-trifluoroacetyltryptamine In method A of the general synthetic method, 4.10 ml of triethylsilane, 5.4570 g of Nb-trifluoroacetyltryptamine, 200 ml. Of trifluoroacetic acid,
The mixture was heated and stirred at 55 ° C for 1 hour. The solvent was distilled off under reduced pressure,
Aqueous sodium hydrogen carbonate solution was added to the obtained residue to make it alkaline (pH 8.0), and after the post-treatment, the obtained crude product was treated with methylene chloride-methanol (99: 1, v / v).
Purified by column chromatography using silica gel as a carrier with v) as an elution solvent.
(96%) of 2,3-dihydro-Nb-trifluoroacetyltryptamine was obtained.

[0039]

Reference Example 3. Synthesis of 2,3-dihydro-Nb-propyltryptamine In the general synthesis method A, 0.57 ml of triethylsilane, 238.7 mg of Nb-propyltryptamine,
Using 30 ml of trifluoroacetic acid, the mixture was heated with stirring at 55 to 60 ° C. for 4 hours. The solvent was distilled off under reduced pressure, sodium hydroxide aqueous solution was added to the obtained residue to make it alkaline, and after the post-treatment, the obtained crude product was treated with methylene chloride-methanol-29% aqueous ammonia (46: 5: 0.
5, v / v) as an elution solvent and purified by column chromatography using silica gel as a carrier.
Obtained mg (93%) of 2,3-dihydro-Nb-propyltryptamine.

[0041]

Reference Example 4.2 Synthesis of 2,3-dihydro-Nb-palmitoyltryptamine In method A of the general synthesis method, 234.3 mg of triethylsilane, 402.3 mg of Nb-palmitoyltryptamine, 33 ml of trifluoroacetic acid. Using 60 to 6
The mixture was heated and stirred at 5 ° C for 3 hours. The solvent was distilled off under reduced pressure, 2N aqueous sodium hydroxide solution was added to the obtained residue to make it alkaline, and after post-treatment, the obtained crude product was treated with methylene chloride-methanol (99: 1, v / v). Purification was carried out by column chromatography using silica gel as a carrier, using 395.9 mg (98%) of 2,
3-Dihydro-Nb-palmitoyltryptamine was obtained.

[0043]

Reference Example 5. Synthesis of 4- (2,3-dihydroindol-3-yl) butyl acetate In method B of the general synthetic method, 2.2765 g of sodium borohydride, 1.6361 g of 4- Using (indol-3-yl) butyl acetate, 50 ml of acetic acid, stirring was continued for 4 hours at room temperature. After the post-treatment, the obtained crude product was purified by column chromatography using ethyl acetate-hexane (1: 5, v / v) as an elution solvent and silica gel as a carrier.
Obtained 1.4153 g (86%) of 4- (2,3-dihydroindol-3-yl) butyl acetate.

[0045]

Reference Example 6. (3S, 6S) -3-Benzyl-6-((3RS) -2,3-dihydroindole-3
Synthesis of -ylmethyl) -2,5-piperazinedione In method A of the general synthetic method, 0.097 ml of triethylsilane, 101.5 mg of (3S, 6S) -3-benzyl-6- (indole-3-) Ilmethyl) -2,5-piperazinedione, using 3 ml of trifluoroacetic acid,
The mixture was heated and stirred at 65 ° C for 3 hours. The solvent was distilled off under reduced pressure,
Aqueous sodium hydrogen carbonate solution is added to the obtained residue to make it alkaline, and after the post-treatment, the obtained crude product is subjected to methylene chloride-methanol (95: 5, v / v) as an elution solvent and silica gel as a carrier. After purification by column chromatography, 96.7 mg (95%) of (3
S, 6S) -3-Benzyl-6-((3RS) -2,3
-Dihydroindol-3-ylmethyl) -2,5-piperazinedione was obtained as a 1: 1 mixture of stereoisomers for the indole 3-position.

The respective stereoisomers (stereoisomer a and stereoisomer b) were chloroform-methanol-29.
It was possible to separate by repeating column chromatography using silica gel as a carrier with% ammonia water (46: 2: 0.2, v / v) as an elution solvent.
-Oxidation to hydroxyindole used this 1: 1 mixture as is.

[0048]

[0049]

Reference Example 7. (3S, 6S) -6-((3R
S) -2,3-Dihydroindol-3-ylmethyl)
Synthesis of -3-isobutyl-2,5-piperazinedione In method A of the general synthetic method, 0.11 ml of triethylsilane and 99.4 mg of (3S, 6S) -6- (indol-3-ylmethyl)- 3-isobutyl-2,5-piperazinedione, with 3 ml trifluoroacetic acid, 6
The mixture was heated and stirred at 0 ° C for 15 hours. Further, 0.22 ml of triethylsilane was added, and the mixture was heated with stirring at 60 ° C. for 2 hours.
The solvent was evaporated under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the obtained residue to make it alkaline, and after the post-treatment, the obtained crude product was treated with chloroform-methanol-29% aqueous ammonia (46: 2: 0). .2, v / v) as an elution solvent and purified by column chromatography using silica gel as a carrier to obtain 82.6 g (83%) of (3S, 6).
S) -6-((3RS) -2,3-Dihydroindol-3-ylmethyl) -3-isobutyl-2,5-piperazinedione was obtained as a 1: 1 mixture of stereoisomers at the indole 3-position. Subsequent oxidation to 1-hydroxyindole used this 1: 1 mixture as is.

[0051]

Reference Example 8. Synthesis of 2,3-dihydro-6-nitro-Nb-trifluoroacetyltryptamine 200.2 mg of 2,3-dihydro-Nb-trifluoroacetyltryptamine was dissolved in a solution of concentrated sulfuric acid 9 ml. , 74.1 mg of sodium nitrate was added under ice cooling, and the temperature was 0 ° C.
And stirred for 30 minutes. The reaction mixture was poured into ice water, adjusted to pH 7.0 with 2N aqueous sodium hydroxide solution, and extracted with methylene chloride. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was filtered off and the filtrate was evaporated under reduced pressure to give a crude product, which was treated with methylene chloride-methanol (98: 2, v /
Purification by column chromatography using v) as an elution solvent and silica gel as a carrier was carried out to 232.7 mg.
(99%) of 2,3-dihydro-6-nitro-Nb-trifluoroacetyltryptamine was obtained.

[0053]

Reference Example 9.2,3-Dihydro-Nb- (4
-Methylbenzenesulfonyl) indole-3-methanamine In the general synthesis method B, 247.7 mg of sodium borohydride, Nb- (4-
Methylbenzenesulfonyl) indole-3-methanamine, 10 ml of acetic acid was used and stirring was continued for 5 hours at room temperature. After the post-treatment, the obtained crude product was purified by column chromatography using acetic acid ethyl ester-hexane (1: 1, v / v) as an elution solvent and silica gel as a carrier to obtain 144.3 mg (71 %) 2,3-
Dihydro-Nb- (4-methylbenzenesulfonyl) indole-3-methanamine was obtained.

[0055]

General Synthesis Method of 1-Hydroxyindole Derivative A solution prepared by previously dissolving 2,3-dihydroindole derivative in methanol to prepare an aqueous solution of sodium tungstate dihydrate (0.2 times mol) dissolved in water. Added to. Hydrogen peroxide solution (10 times mol) was added to the obtained mixed solution as it was or after being dissolved in methanol under ice-cooling stirring. Furthermore, stirring was continued at room temperature for the time described in the example. Water was added to the reaction solution, and the mixture was extracted with methylene chloride-methanol (95: 5, v / v). The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the crude product obtained by distilling the filtrate under reduced pressure was subjected to column chromatography using silica gel or alumina as a carrier, using the elution solvent or the developing solvent described in Example, or Preparative thin layer chromatography was performed.

Example 1. Synthesis of 1-Hydroxy-Nb-trifluoroacetylindole-3-methanamine In the general method of synthesis, 83.5 mg sodium tungstate dihydrate, 3.0 ml water, 309.0 mg 2,3-dihydro. -Nb-trifluoroacetylindole-3-methanamine, 30.0 ml of methanol,
Using 1.10 ml of 35% hydrogen peroxide solution as it was, stirring was continued for 30 minutes at room temperature (22 ° C.). The crude product obtained after the post-treatment was treated with ether-hexane (1: 1, v
/ V) was used as an elution solvent and column chromatography was carried out using silica gel as a carrier. As a result, 213.6 mg of 1-hydroxy-Nb-trifluoroacetylindole-3-methanamine was obtained from the less polar fraction.
(65%), the recovered raw material is 5 from the highly polar fraction.
Obtained 4.3 mg (18%).

[0058]

Example 2. Synthesis of Nb-acetyl-1-hydroxyindole-3-methanamine In the general synthetic method, 149.8 mg sodium tungstate dihydrate, 4.5 ml water, 428.8 mg Nb-acetyl-2,3. -Dihydroindole-3-methanamine, 40.0 ml of methanol, 2.574 g
30% hydrogen peroxide solution was dissolved in 5.0 ml of methanol and used, and stirring was continued at room temperature (23 ° C.) for 25 minutes.
After the post-treatment, the obtained crude product was subjected to column chromatography using silica gel as a carrier and using acetic acid ethyl ester-hexane (2: 1, v / v) as an eluent.
Obtained 2.5 mg (66%) of Nb-acetyl-1-hydroxyindole-3-methanamine.

[0060]

Example 3. 1-hydroxy-Nb, Nb
-Synthesis of dimethyltryptamine In the general synthetic method, 132.5 mg of sodium tungstate dihydrate 4.0 ml of water, 378.9 mg of 2,3-dihydro-Nb, Nb-dimethyltryptamine, 40.0 ml Using methanol and 2.0 ml of 35% hydrogen peroxide as it is, at room temperature (22 ° C.), 20
Stirring was continued for a minute. The crude product obtained after the post-treatment was recrystallized from methanol-water to obtain 153.0 mg of 1-hydroxy-Nb, Nb-dimethyltryptamine as colorless needle crystals. The mother liquor was chloroform-methanol-2.
Column chromatography was performed using silica gel as a carrier using 9% aqueous ammonia (46: 5: 0.5, v / v) as an elution solvent. As a result, 19.1 mg (5%) of raw material was recovered from the less polar fraction. However, from the more polar fraction, an additional 70.5 mg of 1-hydroxy-
Nb, Nb-dimethyltryptamine was obtained.

[0062]

Example 4. Synthesis of 1-hydroxy-Nb-methoxycarbonyltryptamine In the general synthetic method, 56.1 mg sodium tungstate dihydrate, 1.8 ml water, 185.9 mg 2,3-dihydro-Nb-methoxycarbonyl were prepared. Tryptamine, 18.0 ml methanol, 0.86 ml 35
% Hydrogen peroxide solution is used as is, at room temperature (22 ° C)
Stirring was continued for 60 minutes. The crude product obtained after the post-treatment,
Methylene chloride-methanol (97: 3, v / v) and acetic acid ethyl ester-hexane (2: 1, v / v)
Column chromatography using silica gel as a carrier with the eluent as an eluent for purification to obtain 131.5 m
g (67%) of 1-hydroxy-Nb-methoxycarbonyltryptamine was obtained.

[0064]

Example 5. Synthesis of 1-Hydroxy-Nb-trifluoroacetyltryptamine In a general synthetic method, 57.8 mg sodium tungstate dihydrate, 2.2 ml water, 218.6 mg 2,3-dihydro-Nb-tri were prepared. Fluoroacetyltryptamine, 20.0 m methanol, 984.0 mg 3
5% hydrogen peroxide solution was dissolved in 2.0 ml of methanol and used, and stirring was continued at room temperature (22 ° C.) for 45 minutes. After workup, the crude product obtained was treated with methylene chloride-methanol (99: 1, v / v) and ethyl acetate-
Purification was carried out by repeating column chromatography using silica gel as a carrier with hexane (1: 3, v / v) as an elution solvent to obtain 165.3 mg (72%) of 1-hydroxy-Nb-trifluoroacetyltryptamine. It was

[0066]

Example 6. Synthesis of 1-Hydroxy-Nb-propyltryptamine In the general synthetic method, 101.0 mg sodium tungstate dihydrate, 3.0 ml water, 310.5 mg 2,3-dihydro-Nb-propyltryptamine, Three
Using 0.0 ml of methanol and 1.3 ml of 35% hydrogen peroxide solution as they were, stirring was continued at room temperature (19 ° C.) for 15 minutes. After the post-treatment, the crude product obtained was subjected to a mixing ratio of 46: 5: 0.5 (v / v) to 10 with chloroform-methanol-29% aqueous ammonia as an elution solvent.
It was changed to 0: 20: 2, gradually increased in polarity, and purified by performing column chromatography using silica gel as a carrier to obtain 190.0 mg (57%) of 1-hydroxy-.
Nb-propyltryptamine was obtained.

[0068]

Example 7. Synthesis of Nb-palmitoyl-1-hydroxytryptamine In the general synthetic method, using 8.8 mg of sodium tungstate dihydrate, 1.0 ml of water, 50.1 mg of 2,3-dihydro-Nb-palmitoyl was used. Tryptamine was dissolved in a mixed solvent of 7.0 ml of methanol and 2.0 ml of methylene chloride, and 134.9 mg of 35% hydrogen peroxide solution was dissolved in 1.0 ml of methanol for use at room temperature (25 ° C). The resulting crude product was treated with chloroform-methanol-29% after continuous stirring for an hour.
25.7 mg (50%) was obtained by repeating column chromatography using silica gel as a carrier with aqueous ammonia (46: 3: 0.3, v / v) as an elution solvent.
Nb-palmitoyl-1-hydroxytryptamine was obtained.

[0070]

Example 8 Synthesis of 4- (1-hydroxyindol-3-yl) butyl acetate In the general method of synthesis, 33.7 mg sodium tungstate dihydrate, 1.0 ml water, 113. 8 mg of 4
-(2,3, dihydroindol-3-yl) butyl
Acetate, 8.0 ml methanol, 559.6 mg
30% hydrogen peroxide solution of was dissolved in 1.0 ml of methanol and used, and stirring was continued at room temperature (26 ° C.) for 20 minutes.
After the post-treatment, the obtained crude product was treated with ethyl acetate-
Column chromatography was performed using hexane (1: 3, v / v) as an elution solvent and silica gel as a carrier.
Obtained 8.8 mg (57%) of 4- (1-hydroxyindol-3-yl) butyl acetate.

[0072]

Example 9. Synthesis of methyl 1-hydroxyindole-3-propionate In a general synthetic method, 154.6 mg sodium tungstate dihydrate, 5.0 ml water, 456.9 mg methyl-2,3-dihydroindole-3. -Propionate, 50.0 ml of methanol, 2.55 ml of 35
% Hydrogen peroxide solution is used as it is at room temperature (26 ° C)
Stirring was continued for 1 hour. After work-up, the resulting crude product is
Purification was carried out by column chromatography using silica gel and alumina as a carrier, respectively, using ethyl acetate-hexane (1: 3, v / v) as an elution solvent.
Obtained 08.8 mg (22%) of methyl 1-hydroxyindole-3-propionate.

[0074]

Example 10. Synthesis of methyl 1-hydroxyindole-3-butyrate In the general method of synthesis, 199.8 mg sodium tungstate dihydrate, 6.0 ml water, 672.2 mg methyl 2,3-dihydroindole-3- Butyrate, 60.0 ml of methanol, and 3.0 ml of 35% aqueous hydrogen peroxide were used as they were, and stirring was continued at room temperature (15 ° C.) for 1 hour. After the post-treatment, the obtained crude product was purified by column chromatography using silica gel and alumina as a carrier, respectively, using ethyl acetate-hexane (2: 5, v / v) as an elution solvent to purify 37
Obtained 0.7 mg (52%) of methyl 1-hydroxyindole-3-butyrate.

[0076]

Example 11. Synthesis of (3S, 6S) -3-benzyl-6- (1-hydroxyindol-3-ylmethyl) -2,5-piperazinedione In the general synthetic method, 6.0 mg of sodium tungstate dihydrate, 0.6 ml of water, 30.0 mg of (3
S, 6S) -3-Benzyl-6-((3-R, S)-
2,3-dihydroindol-3-ylmethyl) -2,
5-piperazinedione, 4.0 ml of methanol-methylene chloride (1: 1, v / v), 105.3 mg of 30% hydrogen peroxide solution was dissolved in 2.0 ml of methanol, and the mixture was stirred at room temperature for 1 hour. Continued. After the post-treatment, the obtained crude product was subjected to column chromatography using chloroform-methanol-29% aqueous ammonia (46: 2: 0.2, v / v) as an elution solvent and silica gel as a carrier, and 20 0.7 mg (66.2%) of (3S, 6
S) -3-Benzyl-6- (1-hydroxyindol-3-ylmethyl) -2,5-piperazinedione was obtained.

[0078]

Example 12 (3S, 6S) -6- (1
Synthesis of -Hydroxyindol-3-ylmethyl) -3-isobutyl-2,5-piperazinedione In the general synthetic method, 10.7 mg sodium tungstate dihydrate, 0.9 ml water, 48.7 mg (3
S, 6S) -6-((3-R, S) -2,3-Dihydroindol-3-ylmethyl) -3-isobutyl-2,
5-piperazinedione, 8.0 ml of methanol-methylene chloride (5: 3, v / v), 184.6 mg of 3
0% hydrogen peroxide solution was dissolved in 1.0 ml of methanol and used, and stirring was continued at room temperature for 1 hour. After the post-treatment, the obtained crude product was subjected to column chromatography using chloroform-methanol-29% aqueous ammonia (46: 5: 0.5, v / v) as an elution solvent and silica gel as a carrier to give 32. 0.3 mg (63.4%) of (3S, 6S)
-6- (1-hydroxyindol-3-ylmethyl)
-3-Isobutyl-2,5-piperazinedione was obtained.

[0080]

Example 13 Synthesis of 1-Hydroxy-Nb-Acetyltryptamine In the general synthetic method, 66.4 mg sodium tungstate dihydrate, 2.0 ml water, 205.2 mg N were added.
b-acetyl-2,3-dihydrotryptamine, 20.
Using 0 ml of methanol and 1.03 ml of 30% aqueous hydrogen peroxide as they were, stirring was continued at room temperature (22 ° C.) for 60 minutes. The crude product obtained after the post-treatment was purified by repeatedly performing column chromatography using methylene chloride-methanol (95: 5, v / v) as an elution solvent and silica gel as a carrier to obtain 121.5 mg (55%). 1) -Hydroxy-Nb-acetyltryptamine was obtained.

[0082]

Example 14 Synthesis of 1-hydroxy-6-nitro-Nb-trifluoroacetyltryptamine In the general method of synthesis, 12.9 mg sodium tungstate dihydrate, 0.5 ml water, 51.8 mg 2,
3-dihydro-6-nitro-Nb-trifluoroacetyltryptamine, 4.0 ml methanol, 193.8
Using 30 mg of 30% hydrogen peroxide solution dissolved in 1.0 ml of methanol, stirring was continued at room temperature (22 ° C.) for 7 hours. The crude product obtained after the post-treatment after extraction with acetic acid ethyl ester was treated with methylene chloride-methanol (98: 2,
v / v) and acetic acid ethyl ester-hexane (1:
(3, v / v) as an elution solvent and repeatedly purified by column chromatography using silica gel as a carrier,
Obtained 42.1 mg (78%) of 1-hydroxy-6-nitro-Nb-trifluoroacetyltryptamine.

[0084]

Example 15. Synthesis of Nb-acetyl-1-hydroxy-5-methoxytryptamine In the general synthetic method, 48.9 mg sodium tungstate dihydrate, 1.8 ml water, 173.4 mg N were used.
b-Acetyl-2,3-dihydro-5-methoxytryptamine, 18.0 ml methanol, 1.84 ml 3
Using 0% hydrogen peroxide as it is, at room temperature (22 ° C)
Stirring was continued for 10 minutes. The crude product obtained after the post-treatment,
Chloroform-methanol-29% ammonia water (4
6: 2: 0.2, v / v) was used as an elution solvent and column chromatography was carried out using silica gel as a carrier.
0.2 mg (22%) of Nb-acetyl-1-hydroxy-5-methoxytryptamine was obtained.

[0086]

Example 16. 1-Hydroxy-Nb- (4
Synthesis of -Methylbenzenesulfonyl) indole-3-methanamine In the general synthetic method, 57.4 mg sodium tungstate dihydrate, 1.7 ml water, 265.0 mg 2,3-dihydro-Nb- ( 4-methylbenzenesulfonyl) indole-3-methanamine, 13.0 ml of methanol, 957.9 mg of 30% aqueous hydrogen peroxide dissolved in 3.0 ml of methanol were used at room temperature (2
The stirring was continued for 30 minutes. The crude product obtained after the post-treatment was treated with methylene chloride-methanol (99: 1, v /
Column chromatography was carried out using v) as an elution solvent and silica gel as a carrier to yield 186.9 mg (67%).
1-hydroxy-Nb- (4-methylbenzenesulfonyl) indole-3-methanamine was obtained.

[0088]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location C07D 209/16 8217-4C 209/18 8217-4C 403/06 209

Claims (2)

[Claims] 1. A general formula: (A in the formula is a lower alkylene group, R is a lower alkoxycarbonylamino group, an alkanoylamino group, a halo lower alkanoylamino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkanoyloxy group, a lower alkoxycarbonyl group. Group, an arylsulfonylamino group which may have a lower alkyl group as a substituent, or a general formula: (Wherein Z is a lower alkyl group which may be substituted with an aryl group), Y is a hydrogen atom,
A nitro group or a lower alkoxy group, provided that R is an acetylamino group and Y is a hydrogen atom, A is not an ethylene group, R is a methoxycarbonyl group, and Y is a hydrogen atom. , A is not a methylene group), and a 1-hydroxyindole derivative and a pharmaceutically acceptable salt thereof. 2. A general formula: (A in the formula is a lower alkylene group, R is a lower alkoxycarbonylamino group, an alkanoylamino group, a halo lower alkanoylamino group, a mono-lower alkylamino group, a di-lower alkylamino group, a lower alkanoyloxy group, a lower alkoxycarbonyl group. Group, an arylsulfonylamino group which may have a lower alkyl group as a substituent, or a general formula: (Wherein Z is a lower alkyl group which may be substituted with an aryl group), Y is a hydrogen atom,
A nitro group or a lower alkoxy group) 1
-An antiplatelet agent comprising a hydroxyindole derivative and a pharmacologically acceptable salt thereof as an active ingredient.