# Patent

## Title
Triazoles, and their use against insect pests

## Abstract

This is a division of application Ser. No. 351,185, filed Feb. 22, 1982 now U.S. Pat. No. 4,419,353 which in turn is a division of application Ser. No. 245,188, filed Mar. 18, 1981, now U.S. Pat. No. 4,336,379, which in turn is continuation-in-part of application Ser. No. 196,785, filed Oct. 14, 1980, now abandoned, which in turn is a continuation-in-part of application Ser. No. 138,872, filed Apr. 10, 1980, now abandoned.

## Background
This invention relates to substituted indolamines which exhibit anti-diabetic activity. In particular, it relates to substituted isoxazolyl indolamines and pharmaceutically acceptable acid addition salts.

The compounds of this invention may be represented by the following structural formula: ##STR3## wherein R.sub.1 represents hydrogen, fluoro, chloro, lower alkyl, i.e., alkyl having 1 to 4 carbon atoms, e.g., methyl, ethyl, isopropyl and the like, or lower alkoxy, i.e., alkoxy having 1 to 4 carbon atoms, e.g., methoxy, ethoxy, and the like, and above, or ##STR4## wherein n is 1, 2 or 3, and defined above.

The compounds of formula (I), are prepared according to the following reaction scheme: ##STR5##

R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined above.

The compounds of formula (I) are prepared by reducing a compound of the formula (II) in the presence of an inert atmosphere, e.g., nitrogen, helium or argon, preferably nitrogen, with a reducing agent such as lithium aluminum hydride, or diborane, preferably lithium aluminum hydride. The reaction is carried out in the presence of an inert organic solvent, and although the particular solvent employed is not critical, the preferred solvents include an ether such as diethylether, dioxane or tetrahydrofuran, the latter being especially preferred. The temperature of the reaction may vbe critical, and it is preferred that the reaction be run at a temperature of from about 10.degree. to 30.degree. C., preferably 20.degree. to 25.degree. C. The reaction is run from about 1 to 12 hours, preferably from about 2 to 5 hours. The product is recovered using conventional techniques, e.g., crystallization.

The compounds of formula (II) are prepared according to the following reaction scheme: ##STR6## where X represents chloro or bromo, and R.sub.1, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined above.

The compounds of formula (II) are prepared by treating a compound of the formula (III) with a compound of the formula (IV) in the presence of a solvent. Although the particular solvent employed is not critical, the preferred solvents include water, an excess of a compound of the formula (IV) or an ether such as diethylether dioxane or tetrahydrofuran, or an aromatic hydrocarbon such as benzene, toluene and the like, preferably the combination of water, diethylether and excess compound of formula (IV). The temperature of the reaction is not critical, but it is preferred that the reaction be run from about -10.degree. to 50.degree. C., preferably from about 20.degree. to 30.degree. C. The reaction is run from about 30 minutes to 4 hours, preferably from about 1 to 2 hours. The product is recovered using conventional techniques e.g., filtration.

The compounds of formula (III) are prepared in accordance with the following reaction scheme: ##STR7## where X, R.sub.1, R.sub.5 and R.sub.6 are as defined above.

The compounds of formula (III) are prepared by treating a compound of the formula (V) with a compound of the formula (VI), namely oxalyl chloride or oxalyl bromide, in the presence of an inert organic solvent. Although the particular solvent employed is not critical, the preferred solvents include an ether such as diethylether, dioxane or tetrahydrofuran, or an aromatic hydrocarbon such as benzene, toluene and the like, preferably diethylether. The temperature of the reaction is not critical, but it is preferred that the reaction be run at a temperature of from about -10.degree. to 50.degree. C., preferably from about 20.degree. to 30.degree. C. The reaction is run from about 1 to 12 hours, preferably from about 3 to 6 hours. The product may be recovered by conventional techniques, however, in this case, it is not isolated instead the compounds of formula (III) are employed in situ as a starting materials in the preparation of compounds (II).

The compounds of formula (V) are prepared in accordance with the following reaction scheme: ##STR8## where R.sub.1, R.sub.5 and R.sub.6 are as defined above.

The compounds of formula (V) are prepared by cyclizing a compound of the formula (VII) with an acid, such as acetic acid, p-toluenesulfonic acid or polyphosphoric acid, the latter being especially preferred in the presence of an inert solvent. Although the particular solvent employed is not critical, the preferred solvents include the aromatic hydrocarbons such as benzene, toluene and the like, or an excess of the acid utilized above, the latter being especially preferred. The temperature of the reaction is not critical, but it is preferred that the reaction be run from about 70.degree. to 150.degree. C., preferably from about 105.degree. to 120.degree. C. The reaction is run from about 1 to 12 hours, preferably from about 3 to 6 hours. The product is recovered using conventional techniques, e.g., filtration.

The compounds of formula (VII) are prepared according to the following reaction scheme: ##STR9## where R.sub.1, R.sub.5 R.sub.6 are as defined above.

The compounds of formula (VII) are prepared by treating a compound of the formula (VIII) with a compound of the formula (IX) in the presence of an inert organic solvent and an acid catalyst such as p-toluensulfonic acid, polyphosphoric acid or sulfuric acid, preferably p-toluensulfonic acid. The particular solvent employed is not critical, but it is preferred that the reaction be run in the presence of the lower alkanols, e.g., methanol, ethanol and the like, or the aromatic hydrocarbons such as benzene, toluene and the like, preferably, however, ethanol. The temperature of the reaction is not critical, but it is preferred that the reaction be run from about 0.degree. to 100.degree. C., preferably from about 20.degree. to 35.degree. C. The reaction is run from about 12 to 72 hours, preferably from about 36 to 52 hours. The product is recovered using conventional techniques, e.g., filtration.

Another aspect of this invention and the preferred method of preparing the compounds of formula (V) in which R.sub.5 represents ethyl may be illustrated by the following reaction scheme. ##STR10## where RLi represents an alkyl lithium,

The compounds of formula (Vb) are prepared by first reacting a compound of the formula (Va) with two equivalents of an alkyl lithium in the presence of an organic co-solvent. Although the particular alkyl lithium employed is not critical, it is preferred that the reaction be run in t-butyl lithium or n-butyl lithium the latter being especially preferred. The reaction is preferably carried out in the presence of an ether such as diethylether, tetrahydrofuran or dioxane in combination with an aliphatic hydrocarbon such as pentane, hexane and the like, especially tetrahydrofuran and hexane. The temperature of this reaction is not critical, but it is preferred that the reaction be run at a temperature of from about -75.degree. to -40.degree. C. preferably from about -60.degree. to -50.degree. C. The reaction is run from about 10 minutes to 60 minutes preferably from about 25 to 40 minutes.

The resulting product is not isolated but instead is then reacted with an alkyl halide such as methylbromide, methyliodide and the like preferably methyliodide in the presence of an inert organic solvent to form compounds (Vb). The preferred ineert organic solvent includes the ethers such as diethylether, tetrahydrofuran or dioxane or the aromatic hydrocarbons such as benzene, toluene and the like, preferably tetrahydrofuran. The temperature of the reaction is not critical but it is preferred that the reaction be run at a temperature of from about -75.degree. to -40.degree. C., preferably from about -60.degree. to -50.degree. C. The reaction is run from about 1 to 8 hours preferably from about 3 to 6 hours. The resulting product may be recovered by conventional techniques e.g. filtration followed by evaporation. It should be noted that the compounds of the formula (Vb) are precursors and may be employed in accordance with the reaction scheme set out on page 4 of the Specification to obtain the compounds of formula (III) wherein R.sub.5 represents ethyl.

Many of the compounds of formulae (IV), (VI), (VIII), and (IX) are known and may be prepared by methods described in the literature. The compounds of formulae (IV), (VI), (VIII), and (IX) not specifically described may be prepared by analogous methods from known starting materials.

It will be understood that the compounds of formula (I) may exist in the form of optically active isomers and can be separated and recovered by conventional techniques, and that such isomeric forms are included within the scope of the invention.

The compounds of formula (I), and their pharmaceutically acceptable salts, are useful because they exhibit pharmacological activity in animals. In particular, the compounds of formula (I) are useful in the treatment of diabetes as hypoglycemic agents and inhibiting or impeding post-prandial hyperglycemia.

The compounds of formula (I) are useful in the treatment of diabetes as hypoglycemic agents as indicated by the lowering of blood glucose in 6 to 8 week old male Royal Hart mice weighing 30 to 35 grams which are fasted in groups of 5 for 16 hours and then are given an initial dose of 50 to 200 milligrams per kilogram of animal body weight of the compound orally. Two hours after the test compound is administered the mice are anesthetized with 85 milligrams per kilogram of animal body weight of sodium hexobarbital and five minutes later blood is collected via cardiac puncture. The blood samples are placed in an autoanalyzer cup containing 0.025 milliliters of heparin (1,000 units per milliliter); and the samples are capped, shaken and stored in ice. The glucose level is determined by the autoanalyzer potassium ferric cyanide N-2b method and these glucose levels are then compared with the glucose levels of the control group which receives orally 0.5% carboxymethyl cellulose and is run concurrently. To validate this experiment, a known hypoglycemic standard is included each time the test is run.

The compounds of formula (I) are also useful in treatment of diabetes by inhibiting or impeding post-prandial hyperglycemia as indicated by a lowering of the blood sugar levels in male Wistar rats after an oral starch load. In this test male Wistar rats in groups of 5 which are fasted for 16 hours are given an initial dose of from 25 to 200 mg/kg p.o. of the test compound. Once hour later the rats are given 1.0 grams per kilogram of animal body weight of cooked starch load. Thirty minutes after administration of the starch, the rats are anesthetized with 120 milligrams per kilogram of animal body weight of sodium hexobarbital after which blood is collected via cardiac puncture. The blood samples are placed in an autoanalyzer cup containing 0.1 milliliters of heparin (1,000 units per milliliters). The heparinized blood is used to determine the blood sugar level with an autoanalyzer. The blood sugar content is compared to the control group which receives 0.5% carboxymethyl cellulose and an oral starch load and are run concurrently.

For both the hypoglycemic and inhibiting post-prandial hyperglycemia use, the compounds of formula (I) and their non-toxic, pharmaceutically acceptable salts may be administered orally or parenterally as such or admixed with conventional pharmaceutical carriers. They may be administered orally in such forms as tablets, dispersible powders, granules, capsules, syrups and elixirs, and parenterally as solutions, e.g., a sterile injectable aqueous solution. The compositions for oral use may contain one or more conventional adjuvants, such as sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutically acceptable excipients, e.g., inert diluents, such as calcium carbonate, sodium carbonate, lactose, and talc, granulating and disintegrating agents, e.g., starch and alginic acid, binding agents, e.g., magnesium stearate, stearic acid and talc. The tablets may be uncoated by known techniques to delay disintegration and absorption in the gastro-intestinal tract and thereby provide a sustained action over a longer period. Similarly, suspensions, syrups and elixirs mau contain the active ingredient in admixture with any of the conventional excipients utilized in the preparation of such compositions, e.g., suspending agents such as methylcellulose, tragacanth and sodium alginate; wetting agents such as lecithin, polyoxyethylene stearate and polyoxyethylene sorbitan monooleate; and preservatives such as ethyl p-hydroxybenzoate. Capsules may contain the active ingredient alone or admixed with an inert solid diluent, e.g., calcium carbonate, calcium phosphate and kaolin. The injectable compositions are formulated as known in the art. These pharmaceutical preparations may contain up to about 90% of the active ingredient in combination with the carrier or adjuvant.

The hypoglycemic effective amount of active ingredient employed in the treatment of diabetes may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general satisfactory results in the treatment of diabetes are obtained when a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at a daily dosage of from about 5 milligrams to about 800 milligrams per kilogram of animal body weight, preferably given orally and in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 50 milligrams to about 2000 milligrams. Unit dosage forms suitable for internal use comprise from about 12.5 milligrams to about 2000 milligrams, more usually 12.5 to 1000 milligrams, of the active compound in intimate admixture with a solid or liquid, pharmaceutically acceptable carrier.

The effective amount of active ingredient for inhibiting post-prandial hyperglycemia employed in the treatment of diabetes may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. However, in general satisfactory results in the treatment of diabetes are obtained when a compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered at a daily dosage of from about 5 milligrams to about 80 milligrams per kilogram of animal body weight, preferably given orally and in divided doses two to four times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 25 milligrams to about 1000 milligrams, preferably given at mealtime as conventional in treatments with substances having such activity, e.g., three times a day, particularly before a carbohydrate-rich meal.

The compounds of formula (I) may be similarly administered in the form of their non-toxic pharmaceutically acceptable acid addition salts. Such salts possess the same order of activity as the free base and are readily prepated by reacting the compound with a pharmaceutically acceptable acid by conventional techniques, and accordingly are included within the scope of this invention. Representative of the inorganic salts are the hydrochloride, hydrobromide, hydroiodide, phosphate (including hydrogen phosphate), metaphosphate, and sulfate (including hydrogen sulfate). Representative examples of the organic salts are the acetate, maleate, fumarate and the like.

Tablets and capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in treating diabetes, at a dose of one tablet or capsule, 2 to 4 times a day. Weight (mg.) Ingredients            tablet  capsule ______________________________________ .alpha.-(dimethylaminoethyl)-2-(3-ethyl- 200     200 5-methyl-4-isoxazolyl)-1H--indole- 3-methanol tragacanth             10      -- lactose                247.5   300 corn starch            25      -- talcum                 15      -- magnesium stearate     2.5     -- Total                  500     500 ______________________________________

A mixture of 61.1 g. (0.4 mole) of 4-acetyl-3-ethyl-5-methyl-isoxazole, 39.4 ml. (0.4 mole) of phenyl hydrazine and 500 mg. toluenesulfonic acid in 400 ml. ethanol is stirred at room temperature for 48 hours. The resulting solid is filtered and washed with cold ether to give 1-(3-ethyl-5-methyl-4-isoxazolyl)-1-ethanone phenyl hydrazone; m.p. 72.degree. to 75.degree. C.

Following the above procedure and using in place of 4-acetyl-3-ethyl-5-methyl isoxazole an equivalent amount of respectively.

Again, following the above procedure and using in place of phenyl hydrazine an equivalent amount of respectively.

Again following the procedure set out in Example 1 and using in place of 4-acetyl-3-ethyl-5-methyl-isoxazole an equivalent amount of hydrazine an equivalent amount of p-fluorphenyl hydrazine there is obtained:

To 1350 grams of polyphosphoric acid at 100.degree. to 110.degree. C. there is added portionwise 74.5 g. (0.307 mole) of 1-(3-ethyl-5-methyl-4-isoxazolyl)-1-ethanone phenyl hydrazone while maintaining the temperature between 105.degree. C. and 115.degree. C. After addition is complete, the mixture is stirred at 100.degree. to 110.degree. C. for 3 hours. The mixture is then poured onto ice and water and the resulting gum extracted into methylene chloride. The methylene chloride is decolorized, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 2-(3-ethyl-5-methyl-4-isoxazolyl)-indole.

Following the above procedure and using in place of 1-(3-ethyl-5-methyl-4-isoxazolyl)-1-ethanone phenyl hydrazone an equivalent amount of

there is obtained

Again, following the procedure set out in Example 2 and using in place of 1-(3-ethyl-5-methyl-4-isoxazolyl)-1-ethanone phenyl hydrazone an equivalent amount of there is obtained

A mixture of 163 g. (0.72 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-indole and 3 liters of ether are cooled to 0.degree. to 10.degree. C. and 61.6 ml. (0.72 mole) of oxyalyl chloride in 450 ml. of ether is added dropwise, maintaining the temperature at 0.degree. to 10.degree. C. during the addition. The cooling bath is removed and the mixture allowed to warm to room temperature. After 11/2 hours, some starting material is still present and 3.1 ml. (0.0362 mole) of oxalyl chloride is added and the mixture stirred for additional 11/2 hours longer. Total stirring at room temperature is 3 hours. The solvent is evaporated in vacuo to give a solid residue. The residue is suspended in ether and evaporated twice more to give 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxyl chloride.

Following the above procedure and using in place of 2-(3-ethyl-5-methyl-4-isoxazolyl)-indole an equivalent amount of

there is obtained respectively.

Again, following the procedure set out in Example 3, and using in place of 2-(3-ethyl-5-methyl-4-isoxazolyl)-indole an eqivalent amount of

79.0 g. (0.250 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxyl chloride is added portionwise to a 0.degree. to 10.degree. C. cooled mixture of 1200 ml. of 40% aqueous dimethylamine and 1000 ml. of ether. The resulting mixture is stirred for 1 hour without an ice bath and then filtered. The solid is then washed well with water and with three portions of cold ether to give N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylamide; m.p. 212.degree. to 215.degree. C.

Following the above procedure and using in place of 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxyl chloride an equivalent amount of

there is obtained 5-fluoro-N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylami de, 5-methyl-N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylami de, or 5-methoxy-N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylam ide, respectively.

Also following the above procedure and using in place of dimethylamine an equivalent amount of respectively.

Following the procedure of Example 4 and using in place of 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxyl chloride an equivalent amount of 5-fluoro-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylchloride and in place of dimethylamine an equivalent amount of pyrrolidine there is obtained.

Again, following the procedure of Example 4 and using in place of 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxyl chloride an equivalent amount of there is obtained. 5-fluoro-N,N-dimethyl-2-(3,5-dimethyl-4-isoxazolyl)-3-indoleglyoxylamide, or 5-fluoro-N,N-dimethyl-2-(5-ethyl-3-methyl-4-isoxazolyl)-3-indoleglyoxylami de.

Also following the procedure of Example 4 and using in place of 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxyl chloride an equivalent amount of starting materials (t) and (s) respectively and in place of dimethylamine an equivalent amount of pyrrolidine there is obtained or -methanol.

To a suspension of 9.9 g (0.26 mole) of lithium aluminum hydride and 950 ml. tetrahydrofuran under nitrogen there is added 21.0 g. (0.065 mole) of N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylamide in 735 ml. of tetrahydrofuran, while maintaining the temperature between 20.degree. to 25.degree. C. After addition is complete, the mixture is stirred at room temperature for 5 hours then cooled to 0.degree. and quenched by the addition dropwise of 20 ml. of water in 180 ml. of tetrahydrofuran. The resulting solids are filtered and the tetrahydrofuran dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is recrystallized from ethanol to give .alpha.-(dimethylaminomethyl)-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indole- 3-methanol; m.p. 178.degree. to 180.degree. C.

Following the above procedure and using in place of N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylamide an equivalent amount of N,N-dimethyl-2-(3-isopropyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylamide, 5-fluoro-N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylami de, 5-methyl-N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylami de, 5-methoxy-N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indoleglyoxylam ide, 5-fluoro-N,N-dimethyl-2-(3,5-dimethyl-4-isoxazolyl)-3-indoleglyoxylamide, 5-fluoro-N,N-dimethyl-2-(5-ethyl-3-methyl-4-isoxazolyl)-3-indoleglyoxylami de, or

there is obtained .alpha.-(dimethylaminomethyl)-2-(3-ethyl-4-isoxazolyl)-1H-indole-3-methano l, m.p. 148.degree. to 150.degree. C. .alpha.-(dimethylaminomethyl)-2-(3,5-diethyl-4-isoxazolyl)-1H-indole-3-met hanol, m.p. 148.degree. to 149.degree. C. .alpha.-(dimethylaminomethyl)-2-(3-ethyl-5-isopropyl-4-isoxazolyl)-1H-indo le-3-methanol, .alpha.-(dimethylaminomethyl)-2-(3-ethyl-5-t-butyl-4-isoxazolyl)-1H-indole -3-methanol, .alpha.-dimethylaminomethyl)-2-(3,5-dimethyl-4-isoxazolyl)-1H-indole-3-met hanol, m.p. 188.degree. to 189.degree. C. .alpha.-(dimethylaminomethyl)-2-(5-methyl-4-isoxazolyl)-1H-indole-3-methan ol, .alpha.-(dimethylaminomethyl)-2-(5-methyl-3-propyl-4-isoxazolyl)-1H-indole -3-methanol, m.p. 176.degree. to 178.degree. C. .alpha.-(dimethylaminomethyl)-2-(5-methyl-3-t-butyl-4-isoxazolyl)-1H-indol e-3-methanol, m.p. 205.degree. to 206.degree. C. .alpha.-(dimethylaminomethyl-2-(5-ethyl-3-methyl-4-isoxazolyl)-1H-indole-3 -methanol, m.p. 153.degree. to 155.degree. C. .alpha.-(dimethylaminomethyl)-2-(3-isopropyl-5-methyl-4-isoxazolyl)-1H-ind ole-3-methanol, m.p. 186.degree. to 188.degree. C. .alpha.-(dimethylaminomethyl)-5-fluoro-2-(3-ethyl-5-methyl-4-isoxazolyl)-1 H-indole-3-methanol, m.p. 125.degree. to 127.degree. C. .alpha.-(dimethylaminomethyl)-5-methyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-1 H-indole-3-methanol, .alpha.-(dimethylaminomethyl)-5-methoxy-2-(3-ethyl-5-methyl-4-isoxazolyl)- 1H-indole-3-methanol, .alpha.-(diethylaminomethyl)-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3 -methanol, m.p. 153.degree. to 154.degree. C. .alpha.-(morpholinomethyl)-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3-m ethanol, m.p. 169.degree. to 171.degree. C. .alpha.-(pyrrolidinomethyl)-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3- methanol, m.p. 166.degree. to 168.degree. C. .alpha.-(piperidinomethyl)-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3-m ethanol, m.p. 166.degree. to 167.degree. C. .alpha.-(pyrrolidinomethyl)-5-fluoro-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H- indole-3-methanol, m.p. 159.degree. to 160.degree. C. .alpha.-dimethylaminomethyl)-5-fluoro-2-(3,5-dimethyl-4-isoxazolyl)-1H-ind ole-3-methanol, m.p. 175.degree. to 178.degree. C. .alpha.-(dimethylaminomethyl)-5-fluoro-2-(3-methyl-5-ethyl-4-isoxazolyl)-1 H-indole-3-methanol, m.p. 79.degree. to 80.degree. C. .alpha.-(pyrrolidinomethyl)-5-fluoro-2-(5-ethyl-3-methyl-4-isoxazolyl)-1H- indole-3-methanol, m.p. 168.degree. to 169.degree. C., or .alpha.-(pyrrolidinomethyl)-5-fluoro-2-(3,5-dimethyl-4-isoxazolyl)-1H-indo le-3-methanol, respectively.

The .alpha.-(dimethylaminomethyl)-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indole- 3-methanol of Example 5 is an effective anti-diabetic agent at a dosage of 200 mg two to four times a day.

The title compound of Example 5 has an ED.sub.25 of 75.0 mg/kg p.o. in mice as a hypoglycemic agent.

A preferred process for preparing the compounds of formula (V) wherein R.sub.5 represents ethyl in particular the 2-(5-ethyl-3-methyl-4-isoxazolyl)-indole [compound of formula Vb].

A solution of 5 g (0.024 mole) of 2-(3,5-dimethyl-4-isoxazolyl)-indole in 100 ml of dry tetrahydrofuran is cooled to -60.degree. and treated by dropwise addition with 32.4 ml of 1.6M n-butyllithium in hexane (0.052 mole) maintaining temperature at -60.degree. C. The resulting mixture is then stirred at -60.degree. C. for 30 min. and then treated by dropwise addition of 4.01 g (0.028 mole) of methyl iodide in 10 ml dry tetrahydrofuran. The resulting mixture is stirred at -60.degree. for 4 hours and quenched by the addition of 6 ml saturated ammonium chloride solution. The mixture is then warmed to room temperature and treated with 50 ml of water and extracted with methylene chloride. The organic layers are dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting oil is then purified by filtration through silica gel to give 2-(5-ethyl-3-methyl-4-isoxazolyl)-indole as a viscous oil.

## Claims

1. A compound of the formula ##STR11## wherein R.sub.1 represents hydrogen, fluoro, chloro, lower alkyl having 1 to 4 carbon atoms, or lower alkoxy having R.sub.3 and R.sub.4 each independently represent lower alkyl having R.sub.3 and R.sub.4 together with N represent ##STR12## wherein n is 1, 2 or 3, and R.sub.5 and R.sub.6 each independently represent hydrogen or lower

2. The compound of claim 1 which is N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole-glyoxylamide.

3. A compound of the formula ##STR13## where X represents chloro or bromo and wherein R.sub.1 represents hydrogen, fluoro, chloro, lower alkyl R.sub.5 and R.sub.6 each independently represent hydrogen or lower alkyl

4. The compound of claim 3 which is 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole-glyoxylchloride.

5. A compound of the formula ##STR14## wherein R.sub.1 represents hydrogen, fluoro, chloro, lower alkyl having 1 to 4 carbon atoms, or lower alkoxy having R.sub.5 and R.sub.6 each independently represent hydrogen or lower

6. The compound of claim 5 which is 2-(3-ethyl-5-methyl-4-isoxazolyl)-indole.

7. A compound of the formula ##STR15## wherein R.sub.1 represents hydrogen, fluoro, chloro, lower alkyl having 1 to 4 carbon atoms, or lower alkoxy having R.sub.5 and R.sub.6 each independently represent hydrogen or lower

8. The compound of claim 7 which is 1-(3-ethyl-5-methyl-4-isoxazolyl)-1-ethanone-phenylhydrazone.