WO1995015326A1

WO1995015326A1 - Novel indole or salt thereof

Info

Publication number: WO1995015326A1
Application number: PCT/JP1994/002024
Authority: WO
Inventors: Hideyoshi Nagaki; Minoru Neki; Hiroshi Sadaki; Takako Hori; Hirokazu Narita; Kimiyasu Shiraki
Original assignee: Toyama Chemical Co., Ltd.
Priority date: 1993-12-03
Filing date: 1994-12-01
Publication date: 1995-06-08
Also published as: JP3354258B2; AU1120595A; JPH07157482A

Abstract

A novel indole represented by general formula (1) or a salt thereof, having an antiviral activity against RNA viruses, especially, picornavirus, and thus being useful as a medicine for treating viral infections, wherein R1 represents at least one group selected from among hydrogen, halogen, nitro, cyano, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, optionally substituted lower alkylcarbonyl or optionally substituted lower alkoxycarbonyl; R2 represents hydrogen, halogen, optionally substituted lower alkyl or optionally substituted lower alkoxy; R3 represents any of groups (a) or (b), wherein R4 represents at least one hydrogen atom or optionally substituted lower alkyl; and A represents oxygen, sulfur or NR5 wherein R5 represents hydrogen or lower alkyl.

Description

Specification

New indoles or their salts

Technical field

The present invention relates to an antiviral agent that is also effective against an RNA virus, especially a picornavirus.

Background art

Currently, very few drugs are effective against viral infections. To date, chemically synthesized antiviral agents are effective against DNA viruses, for example, herpes virus, and are effective against RNA viruses, especially those that cause colds No drug has been found that is effective against the virus, Picornavirus.

Therefore, there is a strong ability to develop antiviral agents that are also effective against RNA viruses, especially picornaviruses.

Disclosure of the invention

Under such circumstances, the inventors of the present application have conducted intensive studies and as a result, have found that the novel indoles represented by the general formula [1] are effective compounds for RNA viruses, particularly picornavirus. We have completed this invention.

Hereinafter, this application description will be described in detail.

The present invention is based on the general formula

Wherein R ¹ is a hydrogen atom, a halogen atom, a nitro group, a cyano group, or a lower alkyl which may be substituted, At least one group selected from lower alkoxy, optionally substituted lower alkylthio, optionally substituted lower alkylcarbonyl and optionally substituted lower alkoxycarbonyl; R ² is a hydrogen atom, a halogen atom or an optionally substituted lower alk kills or optionally substituted lower alkoxy group; R ³ has the general formula

(Wherein, R ⁴ represents one or more hydrogen atoms or an optionally substituted lower alkyl group); A is an oxygen atom, a sulfur atom or

NR ⁵ (R ⁵ represents a hydrogen atom or a lower alkyl group). And a salt thereof.

In this specification, unless otherwise specified, each term has the following meaning.

Halogen atoms include fluorine, chlorine, bromine and iodine atoms; lower alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and pentyl the lower alkoxy group, for example, main butoxy, ethoxy, n- propoxy, C i _ ₅ alkoxy group such as n- butoxy and Penchiruokishi;; C preparative ₅ alkyl group and a lower Al Kiruchio groups include methylthio, lower alkyl force carbonyl group, for example, methylation carbonyl, a C Bok ₅ alkyl carbonylation Le groups such as E chill carbonyl and flop port pills carbonyl; Echiruchio, a C Bok ₅ alkylthio group such as propylthio and blanking Chiruchio.; Lower alkoxycarbonyl groups include, for example, methoxycarbonyl, Ibis Ci ₅ alkoxycarbonyl groups such as silylcarbonyl and propoxycarbonyl; aryl groups refer to groups such as phenyl and naphthyl.

And optionally substituted lower alkyl, lower substituted alkoxy, optionally substituted lower alkylthio, and optionally substituted lower alkylcarbonyl of RR ² and R ^4. Examples of the substituent of the lower alkoxycarbonyl group include a halogen atom, an optionally protected hydroxy group, a lower alkoxy group, a lower alkoxycarbonyl group, an aryl group, and a cyano group. force, such as an amino group which may be based and ^protected? like et be. Each group of RR ² and R ⁴ may be substituted with one or more of the above-mentioned substituents.

Examples of the protecting group for an optionally protected hydroxyl group and the protecting group for an optionally protected hydroxyl group in the substituents of R ¹ , R ² and R ⁴ include Protective Groups in Organic. Synthesis [Protective Groups in Organic Synthesis, written by Theodora. Greene, (1989) John Wiley & Sons, In] Each protecting group.

The salt of the indole derivative represented by the general formula [1] may be a pharmaceutically acceptable salt, for example, a salt with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; formic acid, acetic acid, and sulfuric acid Salts with carboxylic acids such as acids, fumaric acid, maleic acid, malic acid and tartaric acid; salts with acidic amino acids such as aspartic acid and glutamic acid; and methyl sulfonic acid, toluene sulfonic acid, hydroxy acid Benzene sulfone Salts with inorganic acids and organic acids such as salts with acids and sulfonic acids such as naphthalenesulfonic acid.

When the isomer of the indole derivative represented by the general formula [1] is an isomer (for example, an optical isomer, a geometric isomer and a tautomer), the compound of the present invention includes those isomers. And hydrates, solvates and various crystal forms.

Representative compounds in the compounds of the present invention include the following compounds.

• 1-Methyl-1- (4-, 5-dihydro-2-oxazolyl) indole

• 1-Methyl-1- (4,5-dihydro-1-methyl-2-oxazolyl) indole

• 1-Methyl-1- (4,5-dihydro-5-methyl-1-oxazolyl) indole

· 5-Fluoro-1-methyl-2- (4,5-dihydro-1-oxosazolyl) indole

• 1,3-Dimethyl-2- (4,5-dihydro-1-oxazolyl) indole ■

-1-Methyl-1- (4,5-dihydro-4,4-dimethyl-1-oxazolyl) indole

• 4-methyl-1- 1-methyl-2- (4,5-dihydro-2-oxazolyl) indole

-5-Methyl-1- 1-methyl-2- (4,5-dihydro-2-oxoxazolyl) indole

· 6-chloro-1-methyl-2- (4,5-dihydro-2-oxa Zoril) Indore

7-Chloro-1-methyl-1- (4,5-dihydro-2-oxazolyl) indole

• 1-methyl-5-nitro-2- (4,5-dihydro-2-oxazolyl) indole

• 5,7-difluoro-1-methyl-1- (4,5-dihydro-1 2

—Oxazolyl) indole

• 5-Fluoro-1-methyl-2- (4,5-dihydro-4-methyl-12-xazolyl) indole

· 5-Fluoro-1,3-dimethyl-1- (4-, 5-dihydro-2-oxazolyl) indole

• 5-Acetyl-1-methyl-1- (4,5-dihydro-1-oxosazolyl) indole

• 1-Methyl-5-methylthio-12- (4,5-dihydro-12-oxazolyl) indole

• 1,5-Dimethyl-1- (4,5-dihydro-2-oxazolyl) indole

-3-Bromo-2- (4,5-dihydro-1-oxazolyl) benzothiophene

· 1-Ethyl-1-5-fluoro-3-methyl-2- (4,5-dihydro-2-oxazolyl) indole

• 1,3-Dimethyl-6-fluoro-2- (4,5-dihydro-2-oxazolyl) indole

• 3-Ethyl-1-5-fluoro-1-methyl-1- (4,5-dihydrido-2-oxazolyl) indole • 1,3-Dimethyl-5-fluoro-7-methoxy-1- (4-, 5-dihydro-1-oxazolyl) indole

• 5-cyano-1,3-dimethyl-2- (4,5-dihydro-1-oxazolyl) indole

· 5-fluoro-3-methyl-1- (4,5-dihydro-1-oxosazolyl) -1H-indole

• 2— (4,5-dihydro-2-oxazolyl) 1-1H—indole

• 3-Ethyl-1-fluoro-2- (4,5-dihydro-2-oxazolyl) -1H-indole

• 5-Fluoro-7-Methoxy-3-Methyl-1- (4,5-dihydro-2-oxazolyl) 1-1H-indole

• 5-Methoxy-1-methyl-2- (4,5-dihydro-1-oxosazolyl) indole

'5-Fluoro-1-methyl-1- (3-methyl-1,2,4-oxoxazol-1-yl) indole

• 1-Methyl-1- (3-methyl-1,2,4-oxaziazol-15-yl) indole

• 1-Methyl-1- (5-methyl-1,2,4-oxaziazol—3-yl) indole

• 3-Methyl-1- (4-, 5-dihydro-2-oxazolyl) benzofuran

-3-Methyl-2- '(4,5-dihydro-1-4-methyl-2-oxazolyl) benzofuran

· 5-Methyl-1- (4,5-dihidro''2-xazolyl) ben Zofran

• 3,5-Dimethyl-2- (4,5-dihydro-12-year-old xazolyl) benzofuran

• 3,5-Dimethyl-2- (4,5-dihydro-4-methyl-2-oxazolyl) benzofuran

• 5-chloro-2- (4,5-dihydro-2-oxazolyl) benzofuran

.5—Chloro-3-methyl-1- (4,5-dihydro-2-oxazolyl) benzofuran

· 5-Chloro-3-methyl-1- (4,5-dihydro-1-methyl 4--2-xazolyl) benzofuran

• 2- (4,5-dihydro-2-xoxazolyl) benzothiophene '3-methyl-2- (4,5-dihydro-2-xoxazolyl) benzozothiophene

· 3-methyl-1- (4,5-dihydro-4-methyl-2-oxazolyl) benzo-1,000-phen

• 5-Methyl-1- (4,5-dihydro-12-oxazolyl) benzozofen

'3,5-Dimethyl-2- (4,5-dihydro ^ "2-oxazolyl) benzothiophene

• 3,5-Dimethyl-2- (4,5-dihydro-4-methyl-2-oxazolyl) benzothiophene

• 5-Fluoro-2 (4,5-dihydro-1-oxazolyl) benzothiophene

· 5-Fluoro-3-methyl-1- (4,5-dihydro-1-2-oxo Sazolyl) benzothiophene

5-Fluoro-3-methyl-1- (4,5-dihydro-4-methyl-2-oxazolyl) benzothiophene

• 5-Methoxycarbonyl-1-1-methyl-2- (4,5-dihydro-2-oxazolyl) indole

Next, a method for producing the indole derivative represented by the general formula [1] or a salt thereof will be described.

—The indole derivative of the general formula [1] or a salt thereof can be produced, for example, by the following production methods 1 to 3.

[Formulation 1]

Or its salt

[Formulation 3]

[6]

[5] [1c]

Or its salt

"Wherein, R ¹ R ² , R ⁴ and A each have the same meaning as described above.” The compounds of the general formulas [la], [lb], [1c] and [4] and the salts of hydroxylamine may be pharmaceutically acceptable salts, such as hydrochloric acid, hydrobromic acid and the like. Salts with mineral acids such as, sulfuric and phosphoric acids; salts with carboxylic acids such as formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, malic acid and tartaric acid; salts with acidic amino acids such as aspartic acid and glutamic acid And salts with inorganic and organic acids such as salts with sulfonic acids such as methanesulfonic acid, toluenesulfonic acid, hydroxybenzenesulfonic acid and naphthalenesulfonic acid.

Next, the method for producing the indole derivative represented by the general formula [1] or a salt thereof will be described in more detail according to the above-mentioned production methods 1 to 3.

[Formulation 1]

The compound of the general formula [la] or a salt thereof can be obtained by an intramolecular dehydration reaction of the compound of the general formula [2]. The dehydrating agent used is not particularly limited, but preferably includes thionyl chloride or Mitsunobu (Mitsunobu) reagents (getyl azodicarboxylate and triphenylphosphine).

Further, in the case of the compound represented by the general formula [2], wherein A is NH, the target compound can be obtained by reacting the compound with thionyl chloride in the presence of an organic base such as triethylamine or pyridine. When using thionyl chloride, the amount of the organic compound used may be 1 to 5 times the molar amount of the compound of the general formula [2], and the amount of the organic base used may be about equimolar to that of the thioerk-based compound. is there. This reaction is carried out usually at 0 to 50: preferably 10 to 25 * for 0.1 to 5 hours. The solvent used in this reaction has a negative effect on the reaction. It does not need to be affected, and examples thereof include ethers such as tetrahydrofuran and 1,4-dioxane; halogenated hydrocarbons such as methylene chloride and chloroform; and esters such as ethyl acetate and isopropyl acetate. These solvents may be used alone or in combination of two or more.

Further, the amount of the Mitsunobu reagent to be used may be 1 to 3 times the mol of the compound of the general formula [2], respectively. This reaction is carried out usually for 1 to 50, preferably for 10 to 25, for 15 minutes to 5 hours. The solvent used in this reaction may be any solvent that does not adversely affect the reaction, for example, ethers such as tetrahydrofuran and 1,4-dioxane; and aromatic hydrocarbons such as benzene and toluene. These solvents may be used alone or in combination of two or more.

[Method 2]

The compound of the general formula [lb] or a salt thereof is obtained by reacting the compound of the general formula [3] and the compound of the general formula [4] or a salt thereof in the presence of a base. The compound can be obtained by isolating the product and subjecting it to azeotropic dehydration for 1 to 3 hours using an aromatic hydrocarbon such as toluene or xylene as a solvent. The base used in this reaction, for example, organic bases force such Toryechiruamin and ^pyridine? These may if 1-2 mols per mol of the compound of the amount of the organic base of the general formula [3]. The compound of the general formula [4] or a salt thereof may be used in an amount of 1 to 2 moles per mol of the compound of the general formula [3]. This reaction is usually carried out at 10 to 50 t, preferably 0 to 25, for 15 minutes to 10 hours. The solvent used in this reaction Anything that does not have an effect can be used, for example, halogenated hydrocarbons such as methylene chloride and black form.

[Formulation 3]

Reacting the compound of the general formula [5] with hydroxylamine or a salt thereof in the presence or absence of a solvent, and then reacting the obtained product with the acid anhydride of the general formula [6] Thus, a compound of the general formula [1c] or a salt thereof can be obtained. The solvent used in this reaction may be any solvent that does not adversely affect the reaction, for example, ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxetane; alcohols such as methanol and ethanol; Amides such as N, N-dimethylformamide; and dimethylsulfoxide. These solvents may be used alone or in combination of two or more. Further, preferred solvents include alcohols such as methanol and ethanol. The amount of hydroxylamine or a salt thereof may be 1 to 2 times the mol of the compound of the general formula [5], and the reaction is 50 to 100, and is carried out for 0.5 to 10 hours. I just need. The compound of the general formula [6] may be used in an amount of 10 to 30-fold the amount of the obtained product, and the reaction is carried out at 100 to 160 ° C for 0.5 to 10 hours. do it.

The obtained compound of the general formula [1] or a salt thereof can be isolated and purified by a conventional method such as extraction, crystallization, distillation and column chromatography. In addition, the compound represented by the general formula [1] or a salt thereof is known per se such as an alkylation reaction, an acylation reaction, a cyclization reaction, a substitution reaction, a hydrolysis reaction, an oxidation reaction, a reduction reaction, and deprotection. By appropriately combining the above methods, the desired general formula [1] can be converted to Or a salt thereof. Furthermore, in the above-mentioned process for producing the compound of the present invention, in the compounds of the general formulas [2] to [6] or salts thereof, isomers such as optical isomers, geometric isomers and tautomers, etc. ₀ case, the Ru with isomers thereof but present

The compounds of the general formulas [2], [3] and [5] used in the present invention can be produced by the following production method A.

[Production method A]

H

"Wherein, R ⁶ is a lower alkyl group; RR ² , R ⁴ and A each have the same meaning as described above.”

Hereinafter, the production methods of the compounds of the general formulas [2], [3] and [5] will be described in more detail according to the production method A. The compound of the general formula [2] can be obtained by reacting the compound of the general formula [7] with the compound of the general formula [8] in the presence or absence of a solvent. The solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as xylene. The amount of the compound represented by the general formula [8] may be 3 to 10 times the molar amount of the compound represented by the general formula [7]. The reaction may be carried out at 0 to 180 for 0.5 to 10 hours. The compound of the general formula [2] can also be obtained by reacting the compound of the general formula [3] with the compound of the general formula [8] in the presence of a base. The solvent used in this reaction may be any solvent that does not adversely affect the reaction, and includes, for example, halogenated hydrocarbons such as methylene chloride. The compound of the general formula [8] may be used in an amount of 1 to 2 moles per mole of the compound of the general formula [3]. Examples of the base include organic bases such as triethylamine and pyridine. The amount of the organic base used may be 1 to 2 moles per mole of the compound of the general formula [3]. This reaction may be carried out at −30 to 30 for 0.5 to 2 hours.

-The compound of the general formula [3] is obtained by halogenating the compound of the general formula [9], for example, in the presence of a catalytic amount of N, N-dimethylformamide, such as thionyl chloride and oxalyl chloride. Can be obtained by reacting with a halogenating agent. The amount of the halogenating agent to be used may be 1 to 3 moles relative to the compound of the general formula [9]. This reaction is usually carried out for 10 to 502, preferably for 0 to 30, for 20 minutes to 5 hours. The solvent used in this reaction may be any solvent that does not adversely affect the reaction, such as methylene chloride and Examples thereof include halogenated hydrocarbons such as loroform; and aromatic hydrocarbons such as benzene and toluene. These solvents may be used alone or in combination of two or more.

The compound of the general formula [10] can be obtained by amination of the compound of the general formula [9], for example, by reacting the compound of the general formula [9] according to a conventional method described in Shin-Jikken Kagaku Koza Vol. 14, No. 1147-1150. be able to.

The compound of the general formula [10] can be obtained by aminating the compound of the general formula [7], for example, by reacting the compound of the general formula [7] by a conventional method described in New Experimental Chemistry Lecture, Vol. 14, pp. 1136-1147. You can also get it.

The compound of the general formula [9] can be obtained by usual hydrolysis of the compound of the general formula [7], for example, in the presence of an acid or an alkali.

The compound of the general formula [5] can be obtained by subjecting the compound of the general formula [10] to a dehydration reaction, for example, by a conventional method described in New Experimental Chemistry Lecture Vol. 14, pp. 1470-1474, that is, phosphoryl trichloride, It can be obtained by reacting with a dehydrating agent such as nyl chloride, phosphorus pentachloride and diphosphorus pentoxide in the presence or absence of a solvent. The solvent used in this reaction may be any solvent which does not adversely affect the reaction. Examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform, and aromatic hydrocarbons such as benzene and toluene. Hydrogens, etc., and these solvents may be used alone or in combination of two or more. For example, when phosphoryl trichloride is used, the amount used is 3 to 20 times, preferably 5 to; This reaction may be carried out usually at 80 to reflux temperature for 20 minutes to 5 hours.

The compound of the general formula [10] is obtained by aminating the compound of the general formula [3], For example, it can be obtained by reacting concentrated aqueous ammonia. In this reaction, the amount of concentrated aqueous ammonia used may be a large excess with respect to the one compound [3]. Examples of solvents used in this reaction include halogenated hydrocarbons such as methylene chloride and chloroform; and aromatic hydrocarbons such as benzene and toluene. These solvents may be used alone or in combination of two or more. It may be used by mixing. This reaction is carried out usually at a temperature of 30 to 50, preferably at a temperature of -20 to 30 for 20 minutes to 5 hours.

Compounds of the general formula [7] or [9] are described, for example, in Organic Syntheses, Vol. 5, pp. 567-571 (197), Chemical 'and' Pharmaceutical 'Bretin (Chem. Pharm. Bultin). l.) Vol. 24 (5), pp. 1076-1082 (1976), Organic Syntheses, Vol. 4, 590-593 (1963), Chemische Berichte ) It can be obtained by the method described in Vol. 88, pp. 34-38 (1955) or a method analogous thereto. The compound obtained as a carboxylic acid derivative is derived into a compound of the general formula [7] by a usual esterification method. Further, the compound in which A is N-alkyl can be obtained by reacting the compound in which A is NH by a conventional method.

When the compound of the present invention is used as a medicine, pharmaceutically usable additives such as excipients, carriers and diluents may be appropriately mixed, and these may be injected, tablets, capsules, nasal drops It can be administered orally or parenterally in the form of a preparation, suppository or powder. Dose, orally or parenterally administered, typically, adult about 1 day 1-LOOOmg, the force to be administered in single or divided ^doses?, Age of the patient, depending on body weight and symptoms It can be selected as appropriate.

Next, the pharmacological action of the representative compound of the present invention will be described. The test compound numbers in Table 1 correspond to the numbers in the examples described later.

[Measurement of antiviral activity]

The antiviral activity of the compound of the present invention is described in Archives 'Ob' Virology (Arch. Virol) Vol. 117, pp. 165-171 (1991) [K. Shiraki et al.]. This was performed according to the in vitro plaque reduction method. Using poliovirus (Polio-I), the measurement was carried out by the following method. That is, Vero cells (derived from African green monkey kidney cells) were converted to 100 pfuZ200-1 poliovirus-I

(Sabin strain), add 10, "g / ml or 1 g / ml test compound, and incubate on a Petri dish for 3 days at 37. The effect is to count the number of plaques formed, Table 1 shows the test results of the compound of the present invention.

Suruga, compound antiviral activity

No. T / C (%)

1 0.0

4 13.8

11 0.0

13 18.9

14 4.2

15 40.2 22 0. 0

27 0.0 **

28 0. 0 **

* Means 1 / g / inl dose

Is the value at lO g / ml administration

BEST MODE FOR CARRYING OUT THE INVENTION Next, the present invention will be described with reference to examples and examples. However, the present invention is not limited to these. The mixing ratios of the mixed solvent and the eluent are all volume ratios. In addition, silica gel 60 (manufactured by Merck) was used as the carrier in column chromatography. Reference example 1

5.0 g of 1-methylindole-2-methyl carboxylate is suspended in 3.6 ml of ethanolamine and reacted at 160 for 1 hour. After cooling, 50 ml of ethyl acetate and 50 ml of water are added to the obtained suspension, and the organic layer is separated. The separated organic layer is washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is washed with diisopropyl ether and collected by filtration to give N- (2-hydroxyethyl) -11-methyl-indole-2- having a melting point of 137.0-139.0 ° C. Obtain 3.8 g of carboxamide.

Reference example 2

Dissolve 3.0 g of 1-methylindole-12-methylcarboxylate in 15 ml of methanol and 30 ml of 1N aqueous sodium hydroxide solution and reflux for 30 minutes. After cooling, adjust the pH to 2 by adding 1 N hydrochloric acid to the resulting solution. The precipitated crystals are collected by filtration and dried to give 1.8 g of 1-methylindole-12-carboxylic acid having a melting point of 212.0-213.0 ° C. Reference example 3

Suspend 1.8 g of 1-methylindole-12-carboxylic acid in 18 ml of methylene chloride, add 0.1 ml of N, N-dimethylformamide, and cool to 5. 1.6 g of oxalyl chloride is added dropwise to the obtained suspension over a period of 5 minutes. After the dropwise addition, the mixture is stirred at room temperature for 1 hour, and then the solvent is distilled off under reduced pressure to obtain 1.9 g of solid 1-methyl-1-indole-1-carboxylic acid chloride.

Reference example 4

Suspension of 2.0 g of 1-methylindole-12-carboxylic acid chloride in 20 ml of methylene chloride and cooling to 130. To the obtained suspension, 1.25 g of triethylamine and 0.76 g of ethanolamine are added, the temperature is raised to 25 ° C over 30 minutes, and the mixture is stirred at the same temperature for 1 hour. 20 ml of water is added to the reaction mixture, and the organic layer is separated. The separated organic layer is washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was washed with diisopropyl ether and collected by filtration to give N- (2-hydroxyethyl) -11-methyl-indole-12-carboxamide having a melting point of 137.0—139.0 1.8 g. Get. Reference example 5

1.9 g of 1-methyl-1-chloro-2-carboxylic acid chloride is gradually added to a mixture of 19 ml of methylene chloride and 19 ml of concentrated aqueous ammonia cooled to 110 ° C. The reaction mixture is allowed to warm to room temperature over 30 minutes and stirred at the same temperature for 30 minutes. The precipitated crystals are collected by filtration to give 1.6 g of 1-dimethyl-indole-2-carboxamide having a melting point of 166.0 to 168.0 ° C.

Reference example 6 1.6 g of 1-methyl-indole-1-carboxamide is suspended in 4.8 ml of phosphoryl trichloride and stirred at 100 for 30 minutes. After cooling, pour the resulting suspension into ice water. After adding 50 ml of ethyl acetate and adjusting the pH to 7 with a saturated aqueous solution of sodium hydrogen carbonate, the organic layer is separated. The separated organic layer is washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue was purified by column chromatography [eluent; hexane: ethyl acetate = 10: 1] to obtain 1.2 g of 2-cyano-1-methylindole having a melting point of 70.0-71.0. obtain.

Example 1

N- (2-Hydroxitytyl) 1 1-Methyl-indole 2 -Carboxamide 0.5 g is suspended in 8 ml of isopropyl acetate, and 0.54 g of thionyl chloride is added dropwise in 201: over 10 minutes. I do. The reaction mixture is stirred at the same temperature for 30 minutes. The precipitated crystals are collected by filtration and gradually added to a mixture of 10 ml of ethyl acetate and 10 ml of a saturated aqueous solution of sodium hydrogen carbonate. The organic layer is separated, washed with ice and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from disopropyl ether to give 1-methyl-1- (4,5-dihydro-1-2-oxazolyl) indole having a melting point of 101.5—102.5. Get 2g.

IR (KBr) cm " ¹ : 1651, 1472, 1224, 1058 Examples 2 to 23

In the same manner as in Example 1, the compounds in Table 2 are obtained. RR ² , R ⁴ and A in Table 2 are expressed by the following equations, respectively.

Represents a substituent of the compound represented by

In addition, the numbers attached to the groups R ¹ and R ^{4 in} the table indicate the substitution positions.

No. R ^l R ^k R ⁴ A

4 5-FHH N-CH ₃

5 H CH ₃ H N-CH ₃

6 HH 4,4-di -CH ₃ N-CH ₃

7 4-C1 HH N-CH ₃

8 5-C1 HH N-CH ₃

9 6-C1 H H. N-CH ₃

10 7-C1 HH N-CH ₃

13 5-FH 4-CH _{; i} N-CH ₃

14 5-F CH ₃ H N-CH ₃

16 5-CH3S HH N-CH ₃ 17 5-CH ₃ HH N-CH ₃

18 H Br H S

19 5-F CH ₃ H NC ₂ H ₅

20 6-F CH 3 H N-CH ₃

21 5-F 2 ^ 5 H N-CH ₃

22 5 -F, 7-0CH ₃ CH ₃ H N-CH ₃

23-1-CN CH H N- CH 3

The following shows the physical properties of Compound Nos. 2 to 2.3 shown in Table 2 _c No. 2: IR (KBr) cm " ¹ : 1650, 1471, 1282, 1223

Melting point: 69.0-70.0

No. 3: IR (KBr) cm " ¹ : 1654, 1220, 1052, 732

Melting point: 46. 5—47. Ot:

No. 4: IR (KBr) cm " ¹ : 1654, 1475, 1220, 1189

Melting point: 133.5—135.5

No. 5: IR (KBr) cm— ¹ : 1640, 1471, 1357, 1304, 1082

Melting point: 145.0-145.5

No. 6: IR (KBr) cm— ¹ : 1654, 1472, 1268, 1053

Melting point: 79.0-.800.5

No. 7: IR (KBr) cm " ¹ : 1652, 1611

Melting point: 92.0-94.0

No. 8: IR (KBr) cm— ¹ : 1649, 1540, 1470, 1218

Melting point: 99.0-102.5 ° C

No. 9: IR (KBr) cm— ¹ : 1653, 1611, 1542, 1218

Melting point: 100. 5— 102.5

No. 10: IR (KBr) cm— ¹ : 1656, 1461, 1402, 1229 Melting point: 124.5-127.0

No. 11: IR (KBr) cm- ¹ : 1655, 1508, 1330, 1311 Melting point: 220.5-224.0

No. 12: IR (KBr) cm— ¹ : 1654, 1581, 1474, 1222 melting point; 140.5—142.5

No. 13: IR (KBr) cm- ¹ : 1655, 1516, 1475, 1412 Melting point: 104.0-0-104.5

No. 14: IR (KBr) cm- ¹ : 1641, 1487, 1245, 1180 melting point; 142.5—143. 01:

No. 15: IR (KBr) cm- ¹ : 1668, 1654, 1606, 1359 Melting point: 143.0-144.

No. 16: IR (KBr) cm- ¹ : 1652, 1509, 1471, 1212 melting point; 103.0-0-104.0

No. 17: IR (KBr) cm— ¹ : 1651, 1522, 1475, 1409 Melting point: 121.0-122.5

No. 18: IR (KBr) cm— ¹ : 1634, 1518, 1357, 1263 melting point; 105. 0—106. 0

No. 19: IR (KBr) cm— ¹ : 1651, 1487, 1356, 1307 Melting point: 80.0—81.0

No. 20: IR (KBr) cm— ¹ : 1642, 1474, 1230, 1191 melting point; 128.0—129.0

No. 21: IR (KBr) cm— ¹ : 1645, 1488, 1243, 1177 Melting point: 71.0—73.0

No. 22: IR (KBr) cm- ¹ : 1646, 1581, 1457, 1315 melting point; 128.0-129.0 No. 23: IR (KBr) cm— ¹ : 2215, 1646, 1485, 1380

Melting point: 215.0-218.

Example 24

5-Fluoro-N- (2-hydroxyethyl) -13-methyl-1H-indole-12-carboxamide 3.8 g was suspended in 70 ml of methylene chloride, and 1.7 g of triethylamine was added. I do. To the resulting suspension, 2. lg of thionyl chloride is added dropwise over 10 minutes. After dropping, stir at 25 for 30 minutes. The reaction mixture is poured into a mixture of 70 ml of porphyrin form and 70 ml of 1 N aqueous sodium hydroxide solution, and stirred for 10 minutes. The organic layer is separated, washed with water and saturated aqueous solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give a compound having a melting point of 185.5—186.0, showing 5-fluoro-3-methyl-2- (4,5-dihydro1-2-oxazo-11-). Indore 3.3 g.

IR (KBr) cm- ¹ : 1645, 1483, 1458, 1293

Examples 25 to 27

The following compounds were obtained in the same manner as in Example 24.

2- (4,5 dihydro-1-oxazolyl) -1H-indole

IR (KBr) cm " ¹ : 1654, 1343, 1317, 1188

Melting point: 183.0-185.5

3-Ethyl-5-Fluoro-2- (4,5-Dihidro 2-Oxazolyl) 1H-Indole

IR (KBr) cm- ¹ : 1639, 1458, 1250, 1166

Melting point: 157.0-158.

5-fluoro-7-methoxy-3-methyl-2- (4,5-dihydrogen Low 2—xazolyl) 1 H—indole

IR (KBr) cm " ¹ : 1649, 1585, 1409, 1318

Melting point: 155.0-157.0

Example 28

A suspension of 0.41 g of N- (2-hydroxyethyl) -1-5-methyl-1-methylindole 2-carboxamide in 4.0 ml of tetrahydrofuran was added, and 0.52 g of triphenylphosphine was added at 25. Cooling. To the obtained suspension, 2.0 ml of a tetrahydrofuran solution of 0.35 g of getyl azodicarboxylate is added dropwise at 5 over 10 minutes, followed by stirring at the same temperature for 30 minutes. The reaction mixture is heated to 20 and stirred at the same temperature for 4 hours. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 5: 1] to give a 5-medium compound having a melting point of 109.0—111.5. 0.24 g of toxic 1-methyl-21- (4,5-dihydro-12-xazolyl) indole is obtained. IR (KBr) cm— ¹ : 1651, 1518, 1473, 1214

Example 29

Suspension of 5-fluoro-1-methyl-indole-12-potassium chlorobutanoate l.Og in 10 ml of methylene chloride, then add 0.42 g of acetoamidoxime and cool to 5. To the resulting suspension, 0.8 ml of triethylamine is added dropwise over a period of 5 minutes. After the dropwise addition, the mixture is stirred at room temperature for 30 minutes, 20 ml of water is added, and the crystals are collected by filtration. The obtained crystals are suspended in 30 ml of xylene, azeotropically dehydrated for 1 hour, and then the solvent is distilled off under reduced pressure. The residue obtained was recrystallized from diisopropyl ether to give 5-fluoro-1-methyl-2— (3-methyl-1,2,4-oxoxazidolu-5 with a melting point of 141.0—142.0. —Ill) Indore 0.35g is obtained.

IR (KBr) cm— ¹ : 1615, 1578, 1472, 1326

Example 30

In the same manner as in Example 29, 1-methyl-2- (3-methyl-1,2,4-oxoxadiazole-15-yl) indole having a melting point of 120-121 is obtained.

IR (KBr) cm— ¹ : 1608, 1475, 1430, 1328

Example 31

0.8 g of 2-cyano-1-methyl-indole, 0.4 g of hydroxylamine hydrochloride and 0.8 g of sodium acetate trihydrate are added to 8 ml of edanol, and the mixture is heated under reflux for 7 hours. After cooling, insoluble materials are removed by filtration, and the solvent is distilled off under reduced pressure. The obtained residue is heated under reflux for 1 hour with 8 ml of acetic anhydride. After cooling, the reaction mixture is poured into saturated aqueous sodium hydrogen carbonate solution (30 ml) and ethyl acetate (30 ml) and stirred for 10 minutes. 'The organic layer is separated, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was purified by column chromatography [eluent; hexane: ethyl acetate = 10: 1], and recrystallized from a mixture of ethyl acetate and diisopropyl ether to obtain a melting point.

124-125 1-Methyl-1-2- (5-methyl-1,2,4-oxazadiazo-1-yl 3-yl) 0.33 g of indole is obtained.

IR (KBr) cm ^-1 : 1582, 1473, 1293

Industrial applicability

The compound of the present invention has antiviral activity against the RNA virus, especially Picornavirus, and is useful as a therapeutic agent for infection by the virus.

Claims

The scope of the claims

1. General formula

Wherein R ¹ is a hydrogen atom, a halogen atom, a nitro group, a cyano group or a lower alkyl which may be substituted, a lower alkoxy which may be substituted, a lower alkylthio which may be substituted, One or more groups selected from optionally substituted lower alkylcarbonyl or optionally substituted lower alkoxycarbonyl group; R ² is a hydrogen atom, a halogen atom or an optionally substituted lower alkyl; Or a lower alkoxy group which may be substituted; R ³ is a group represented by the general formula

y- _ _R 4.

, O no

(Wherein, R ⁴ represents one or more hydrogen atoms or a lower alkyl group which may be substituted); A is an oxygen atom, a sulfur atom or NR ⁵ (R ⁵ is a hydrogen atom or a lower alkyl group) Represents a group). And a salt thereof.

2. R ¹ is a hydrogen atom, a halogen atom or a lower alkyl group which may be substituted; R ² force A hydrogen atom, a halogen atom or a lower alkyl group which may be substituted; A force A sulfur atom or NR ⁵ 2. The indole or a salt thereof according to claim 1.

3. R ¹ is a hydrogen atom or a halogen atom; to claim 1, which is A force NR ^5; R ² force ^ hydrogen, halo gen atom or a methyl group The indole or the salt thereof according to the above.

4. The indole or a salt thereof according to claim 3, wherein R ⁵ is a hydrogen atom or a methyl group.

5. 1 ^ ³ ^? , general formula

(Wherein R ⁴ represents one or more hydrogen atoms or a lower alkyl group which may be substituted). The indole or a salt thereof according to claim 4, wherein

6. 5-Fluoro-1-methyl-12- (4,5-dihydro-12-oxazolyl) indole or a salt thereof.

7. 5-Fluoro-1-methyl-1- (4,5-dihydro-4-methyl-2-oxazolyl) indole or a salt thereof.

8. 5-fluoro-1,3-dimethyl-2- (4,5-dihydro-12-xazolyl) indole or a salt thereof.

9. General formula

Wherein R ¹ is a hydrogen atom, a halogen atom, a nitro group, a cyano group or a lower alkyl which may be substituted, a lower alkoxy which may be substituted, a lower alkylthio which may be substituted, R ² represents a hydrogen atom, a halogen atom or an optionally substituted lower alkylcarbonyl or one or more groups selected from an optionally substituted lower alkoxycarbonyl group; Kill also properly is an optionally substituted lower alkoxy group which may be substituted; R ³ is the formula humans. ,

(Wherein, R ⁴ represents one or more hydrogen atoms or a lower alkyl group which may be substituted); A is an oxygen atom, a sulfur atom or NR ⁵ (R ⁵ is a hydrogen atom or a lower alkyl group) Represents a group). An antiviral agent containing an indole represented by the formula or a salt thereof.

10. R ¹ is a hydrogen atom, a halogen atom or a lower alkyl group which may be substituted; R ² is a hydrogen atom, a halogen atom or a lower alkyl group which may be substituted; A is a sulfur atom or the antiviral agent according to claim 9 NR Ru ⁵ der.

1 1. R ¹ is a hydrogen atom or a halogen atom; R ² forces a hydrogen atom, C androgenic atom or a methyl group; A is an anti-virus agent according to claim 9 is NR ^5.

12. R ⁵ force? The antiviral agent according to claim 11, which is a hydrogen atom or a methyl group.

13. R ³ force general formula

(Wherein, R ⁴ represents one or more hydrogen atoms or a lower alkyl group which may be substituted).

1 4.5-Fluoro-1-methyl-1-2- (4,5-dihydro-2-oxazolyl) indole, 5-Fluoro-1-methyl-1- (4,5-dihydroxy 4-methyl-12-oxazolyl) indole or 5-fluoro-1,3-dimethyl-2- (4,5-dihydro-12-oxazolyl) indole or a salt thereof Item 10. The antiviral agent according to Item 9,

15. The antiviral agent according to any one of claims 9 to 14, wherein the virus is a picornavirus.

16. The antiviral agent according to any one of claims 9 to 14, wherein the virus is a poliovirus. '

17. Use of the indole described in claim 1 or a salt thereof as an antiviral agent.