NL8301289A - 2-SUBSTITUTED-3-INDOOLAMINS, METHODS FOR THEIR PREPARATION, PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND THEIR USE AS A MEDICINAL PRODUCT. - Google Patents

Description

2- Substituted-3-indole amines, methods of their preparation, pharmaceutical preparations containing them and their use as medicaments.

The invention relates to substituted xndoolamines, methods of their preparation, pharmaceutical compositions containing them and their use as a medicament, in particular as anti-diabetics.

The invention particularly relates to compounds of formula 1, wherein R 1 is a hydrogen, fluorine or chlorine atom, an alkyl group with 1 to 4 carbon atoms or an alkoxy group with 1 to 4 carbon atoms and and Rg, independently of each other, an alkyl group having 1-4 carbon atoms, or wherein R 1 and R 2 together with the adjacent nitrogen atom form a pyrrolidino, piperidino, hexamethyleneimino or morpholino ring and a) R represents a group of formula 20, X represents a hydrogen atom and m * is 2, 3 or 4, or b) R is a biphenyl, naphthyl, benzylphenyl, indanyl or fluorenyl group or a group of formula 20a, X is a hydrogen atom or a hydroxyl group and m * 1, 2 , 3 or 4, wherein in formulas 20 and 20a R 1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms and R 1. a hydrogen atom, an alkyl group of 1-4 carbon atoms, a phenyl group or a phenyl group substituted by halo, alkyl of 1-4 carbon atoms and / or alkoxy of 1-4 carbon atoms, in free base form or in the form of an acid addition salt.

The group of formula 20a may exist in an alternative, tautomeric form of formula 8 and in the form of cis-trans isomers at the C = C double bond.

All tautomeric shapes and geometric isomers are within the scope of the invention.

It will also be appreciated that compounds of formula 1 in which X has a meaning other than hydrogen can exist in the form of optically active isomers which can be separated in a conventional manner. These isomeric forms are also within the scope of the invention, generally referring to the racemic form unless otherwise indicated.

The compounds of the invention can be prepared a) when R is a group of formula 20a, by reduction of a compound of formula lp, wherein R., R_, type b * ^

RyR ^, R ^, X and m have the meanings defined in formula 1 /, with hydrogen in the presence of a catalyst, or b) when R is a biphenyl, naphthyl, benzylphenyl, indanyl or fluorenyl group or a group of formula 20 represents reduction of a compound of formula 2, wherein R 1, R 1, and R 2 have the meanings defined above, R 1 represents a biphenyl, naphthyl, benzylphenyl, indanyl, or fluorenyl group, or a group of formula 20 and and. Zj is a group of formula 16 or a (CE ^ ^ group and Z ^ is a direct bond, or Zj is a direct bond and Z 'represents a (CEL) group, where m has a defined meaning above has.

The reduction according to a) can suitably be carried out at a temperature between 20 and 60 ° C, in particular between 25 and 35 ° C and in an inert solvent * such as a low alcohol, for example methanol, or ethanol (preferably at room temperature) or, for example, dimethylformamide (preferably at higher temperatures).

The reduction is carried out in a hydrogen atmosphere using a suitable catalyst, such as, for example, platinum oxide, Raney nickel, palladium on carbon, etc., with 10% palladium pp carbon being preferred, and at 2 pressures of, for example, 1.05-7, at preferably 2.8-4.2 kg / cm. The reduction according to b) is carried out under conditions customary for reducing carbonyl groups.

Suitable solvents include hydrocarbons, for example hexane or benzene, and ethers, such as diethyl ether, dioxane or preferably tetrahydrofuran.

Examples of reducing agents are aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, diborane and preferably lithium aluminum hydride. If necessary, the reaction is carried out in an inert atmosphere, for example of helium, argon and in particular nitrogen. It will be clear that in all cases where the position in the -Zj-CO-Z2 ~ (N (R.2) (R3) group adjacent to the indole ring is occupied by carbonyl, the reduction is partial (yielding end products in which X represents a hydroxyl group) or complete (whereby end products can be obtained in which X represents a hydrogen atom) and that the degree of reduction will be influenced by the reaction conditions used, therefore partial temperatures are preferred for partial reduction, such as between - 30 and 40 ° C, for example between -5 and 10 ° C if R 'has a different meaning than a group of formula 20 and between 20 and 35 ° C if R' represents a group of formula 20.

If a complete reduction is desired, temperatures of, for example, 40 ° C to 150 ° C, preferably the reflux temperature of the reaction mixture, are used, wherein, if Zj = also lower temperatures, for instance between 0 and 60 ° C, are sufficient. The partial reduction can, of course, also be effected by choosing an appropriate, weak reducing agent.

The different starting materials can be prepared in a usual manner.

For example, the starting materials for process a) which partly fall under formula 1 can be analogous to process b) or, for example, in the manner as described for example

35 in EP Application No. 81810131 (Publn. No. 38298 A) or in USP

8301289 4 ► »4,336,391 are obtained.

The starting materials for method b) and their precursors are known or can be prepared analogously to known methods.

\ 5 Examples of such methods are illustrated by the reaction schemes A-K shown on the formula sheet.

In these reaction schemes, Y represents a chlorine or bromine atom and Y 'represents a hydroxyl group, chlorine or bromine atom.

Each Rg substituent independently represents an alkyl group of 1-4 carbon atoms and the remaining substituents have the meanings defined in Formula 1.

The reaction conditions are common for the particular reaction type and are generally not critical, examples are * (A) solvents (a) RT has a different meaning than the group of formula 20.

hydrocarbons, for example hexane or benzene, halogenated hydrocarbons, for example methylene chloride or chloroform, ethers, for example diethyl ether, dioxane and preferably tetrahydrofuran.

(B) R 'represents a group of formula 20, additionally water or an excess of a compound of formula 11, preferably a mixture of water, diethyl ether and an excess of a compound of formula 11.

Temperatures, for example between -20 ° C and 50 ° C, in particular between -5 ° C and 10 ° C. (R 'does not represent a group of formula 20) and between 20 and 30 ° C (R' represents a group of formula 20 for).

(B) solvents as for (A) (a).

Temperatures, For example, between -20 ° C and 50 ° C, in particular between 20 ° C and 30 ° C. It is also recommended that 8301289 * 4 5 have a compound of formula 12 at a temperature between about -5 ° C and 5 ° C is added.

(C) solvents, for example low alkanols, such as methanol, and preferably ethanol.

Temperatures, for example between 60 ° C and 150 ° C, preferably under reflux of the reaction mixture.

(D) 10 (a) (Yf = OH) reaction of a compound of formula 4 in acetonitrile with acetic acid, in the presence of phosphoric acid and trifluoroacetic anhydride.

(b) (Y = chlorine or bromine) reaction of a compound of formula 4 with silver trifluoromethanesulfonate 15 and then with the desired acetyl halide.

Solvents b), for example halogenated hydrocarbons, such as chloroform and preferably methylene chloride.

Temperatures, for example 20 a) between 10 and 80 ° C, preferably between 20 and 40 ° C, b) between 20 and 45 ° C, preferably between 25 and 35 ° C.

(E) reaction of a compound of formula 25 with a halogenating agent such as thionyl bromide, phosphorus oxychloride and preferably thionyl chloride.

Solvents, for example aromatic hydrocarbons, such as benzene or toluene, ethers, such as diethyl ether, dioxane and in particular tetrahydrofuran.

Temperatures, for example between 0 and 60 ° C, preferably between 20 and 30 ° C.

(F) reaction of a compound of formula 6 with hydrogen bromide or preferably with hydrogen chloride in water.

Temperatures, for example between 90 and 150 ° C, 8301289 V 5a preferably under reflux.

(G) reaction of a compound of formula 7 with a compound of formula 14 in the presence of lithium, potassium or preferably sodium metal in excess (14).

Temperature, for example 100-200 ° C, preferably 120-150 ° C.

(H) reaction of a compound of formula 4 with a compound of formula 11 in an aqueous formaldehyde solution and in the presence of acetic acid and an organic co-solvent.

15 830 1 28 9 * · * 6

Co-solvent 3, for example ether, such as diethyl ether, tetrahydrofuran and in particular dioxane.

Temperatures, for example between -10 and 30 ° C, in particular between 0 and 10 ° C.

5) a compound of formula 9 is first reacted with N-hydroxysuceinimide and dicyclohexyl-carbodiimide and then with a compound of formula 11.

Solvents such as (a) (a) chlorinated hydrocarbons, such as methylene chloride, are recommended and for the second step additionally water.

Temperatures, for example between 10 and 50 ° C, preferably between 20 and 30 ° C.

(j) conventional hydrolysis using, for example, NaOH, KOH, HCl.

Solvents, for example, aqueous alcohols.

Temperatures, for example between 15 and 80 ° C, preferably between 25 and 45 ° C.

(K) analogous to (D) (a),

The final and intermediate products obtained according to the above-described processes can be separated and purified in a usual manner.

If necessary, the intermediates can be reacted further without separation.

Insofar as the preparation of other starting materials has not been described above, they are known or may be prepared from known materials in a conventional manner. In this connection reference is made in particular to EP Appln. No. 81810131 (Publn. No. 38298 A) and US 4,336,391, which discloses various methods, for example, for preparing compounds of formula 4, wherein R 1 represents a group of formula 20.

The compounds of formula I can be obtained both in free hash form and, if desired, in the form of an acid addition salt. The acid addition salt forms of the compounds of formula 1 are also part of the invention.

The free base forms of the compounds of formula 1 can be converted into the acid addition salt forms in a conventional manner and vice versa.

Examples of suitable salt-forming acids are hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, acetic acid, maleic acid, fumaric acid, etc.

The compounds of formula 1 have a pharmacological action. In particular, they inhibit or counteract postprandial hyperglycemia, as shown by a decrease in blood sugar levels in male Wistar rats following oral starch feeding. In this experiment, Wistar male rats in groups of 5, which had been fasted for 16 hours *, were given an initial dose of 50-200 mg / kg p.o. of the test compound. One hour later, the rats were fed 1.0 g per kg body weight of cooked starch food. 30 minutes after the starch was administered, the rats were anesthetized with 120 mg per kg body weight sodium-20 hexobarbital and the blood was collected by cardiac puncture. The blood samples were placed in an autoanalysis vessel containing 0.1 ml heparin (1000 units per ml).

The heparinized blood was used to determine the blood sugar level with an auto-analyzer. The blood sugar level was compared to that of the control group, which received 0.5% carboxymethyl cellulose and an oral starch food and were treated simultaneously.

Thus, the compounds are indicated for use in treating diabetes by inhibiting or counteracting postprandial hyperglycemia.

An indicated suitable daily dose is between about 50 and 2000mg, for example between 75 and 2000 (type a) or between 50 and 1000 (type b), preferably e.g.

8301289 * φ 8 administered 2-4 times daily in separate doses of approximately 12.5-100 mg. Administration is preferably with meals, for example three times a day in dosages of about 20-700 mg, especially for a meal containing many carbohydrates.

The compounds of formula 1 also exhibit fasting hypoglycaemic activity, as evidenced by a decrease in serum glycose levels in 4 Cebus male rats weighing 2-4 kg, which had been fasted for 16-18 hours before the test. An interval of at least 3 days was made between the days on which the test was conducted. The test compound was suspended for oral dose in 0.5% carboxy methyl cellulose (CMC). 2 Blood samples for the basal serum glycose level were taken at minus 30 minutes and for the administration of the placebo (0.5% CMC) or the compound in an amount of 5-40 mg / kg body weight of the animals. Blood samples were then taken every hour and for 6 hours. Serum glycosis levels were determined by the technicon auto-analyzer 2-glucose oxidase method and then compared with the control glycose levels receiving 0.5% CMC orally and treated concomitantly.

The compounds are additionally indicated for the treatment of diabetes as hypoglycemic agents. An indicated daily dose for this indication is between about 25 and about 400 mg, preferably, for example, administered 2-4 times a day in a unit dosage form containing about 6 to about 200 mg, or in a slow-release form.

Thus, the invention also relates to a method of treating diabetes by inhibiting or counteracting postprandial hyperglycaemia by administering one or more compounds of the formula (I) and / or its acid addition salts and also to compounds 8301289 8a Formula 1 and / or its acid addition salts for use as a medicament, for example, as an agent for inhibiting or inhibiting postprandial hyperglycemia.

The compounds of formula 1 can be administered both in free base form and in the form of pharmaceutically acceptable acid addition salts, for example as mentioned above, the salts having a similar degree of activity as the free forms.

The compounds of formula 1 and / or their pharmaceutically acceptable acid addition salts can be administered both alone and in admixture with a pharmaceutically acceptable diluent or carrier and, if desired, other excipients and orally in forms such as tablets, elixirs, capsules or suspensions or parenterally in forms such as injectable solutions or suspensions are given.

The recommended pharmaceutical preparations from the viewpoint of ease of preparation and administration are solid preparations, in particular tablets of hard or liquid-filled capsules. A particular group of compounds includes those of formula 1, wherein R represents a group of formula 20, wherein R ^ represents a hydrogen atom or an alkyl group of 1-4 carbon atoms and R ^ represents a hydrogen atom, an alkyl group of 1-4 carbon atoms or a phenyl group, X represents a hydrogen atom and m = 2, in free base form or in 30 830 1 28 9 «9 in the form of an acid addition salt.

Another group of compounds of formula 1 includes those compounds wherein R represents a biphenyl, naphthyl, benzylphenyl, indanyl or fluorenyl group 5 or a group of formula 20a, as defined in formula 1, X is a hydrogen atom or a hydroxyl group and m * 1 or 2, in free base form or in the form of an acid addition salt.

Examples of alkyl groups are the methyl, ethyl and isopropyl group and of alkoxy groups the methoxy and ethoxy group.

Particularly important meanings of the substituents are: R = a) a group of formula b) biphenyl, naphthyl, benzylphenyl, indanyl or fluorenyl, in particular naphthyl or biphenyl, such as 2-naphthyl, o-biphenyl and p-biphenyl, in particular naphthyl, such as 2-naphthyl 20 c) a group of formula 20a

Rj - a) H

b) fluorine or chlorine c) an alkyl group with 1-4 carbon atoms d) an alkoxy group with 1-4 carbon atoms e) H, F, CH 2 or OC 4, in particular hydrogen R 2, R 2 = a) independently from each other, an alkyl group of 1 to 4 carbon atoms b) the same alkyl group of 1 to 4 carbon atoms c) each a methyl group d) pyrrolidino, piperidino, hexamethyleneimino or morpholino, in particular pyrrolidino 35 8301289 «* * 10 R ^, = a) independently of one another, an alkyl group of 1-4 carbon atoms h) independently of one another a phenyl group c) an independently substituted phenyl group, as defined d) R1 = an alkyl group of 1-4 carbon atoms, in particular the methyl - or ethyl group R 1 = an alkyl group with 1 to 4 carbon atoms, in particular the methyl or ethyl group.

E) R4 = CH3 r5 = c2h5 f) R4 = CH3 R ^ = phenyl X = a) hydrogen b) the hydroxyl group m = a) 1, 2 or 3 b) 1 or 2.

20

Combinations of the aforementioned groups are particularly recommended.

Particularly recommended individual compounds are 2- (3-ethyl-5-methyl-isoxazoly 1) -3- (3-dimethylaminopropyl) -25 indole, 2- (2-naphthyl) -3-Cl- (Ν, Ν-dimethylamino) ethyl i-indole and 4-amino-3- £ 3- (3-dimethylaminopropyl) indol-2-yl7-3-hexene-2-one and in particular 4-amino-3- £ 3- (2-dimethylamino- 1-hydroxyethyl) -indol-2-yl7-3-hexen-2-one, in free base form or in the form of an acid addition salt.

30

Example A

2- (5-methyl-3-pheny1-4-oxazolyl) -3- (dimethylaminomethyl) -Indole (the compound of formtile 7).

A mixture of 20.6 ml (0.24 mol) 37% aqueous 8301289 φ 11 formaldehyde, 18 ml (0.12 mol) 40 X aqueous dimethylamine and 80 ml acetic acid was cooled to 0 ° C and a solution of Drop 25.5 g (0.113 mol) of 2- (5-methyl-3-phenyl-4-isoxazolyl) -indole in 45 ml of acetic acid and 125 ml of dioxane. After dripping, the mixture was stirred at room temperature for 1 hour and poured into 500 ml of ice water. The resulting solution was made alkaline by adding a 20% solution of potassium hydroxide and then extracted with methylene chloride. The methylene chloride was washed with water, a sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated to give the title compound, mp: 88-90 ° C.

The preparation of the precursors of this compound and analogs thereof is described in European patent application 81810131 (publ. 38298A).

Example B

The diethyl ester of β-2- (5-methyl-3-phenyl-4-isoxazolyl) indol-3-ylinetin: hydropropanedioic acid (compound of formula 6).

A mixture of 19.8 g (0.06 mol) 2- (5-methyl-3-phenyl-4-isoxazolyl) -3- (dimethylaminomethyl) indole and 30 g (0.185 mol) diethyl malonate was heated to 120 ° C and to this was added 100 mg of sodium metal. The mixture was then heated at 120 ° C for 5 hours and an additional 100 mg of sodium metal was added. The temperature was raised to 140 ° C and the reaction mixture was kept at this temperature for 18 hours. The mixture was then cooled and poured onto 150 ml of 10% hydrochloric acid and extracted with ether.

The ether extracts were washed with a saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated to remove the ether and excess diethyl malonate to give the title compound as an oil.

8301289

»V

12

Example C

2- (5-methyl-3-phenyl-4-isoxazolyl) -3-indole propionic acid (compound of formula 5).

. A mixture of 22.8 g (0.05 mol) of the diethyl ester of / - (S-methyl-S-phenyl---isoxazolyl) -indol-3-ylmethyl-propanedioic acid and 150 ml of 12 N hydrochloric acid was heated for 65 hours under reflux. The mixture was then cooled and extracted with ether. The ether was washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated. Then the solid residue was decolorized with charcoal and recrystallized from a mixture of ether and hexane to give the title compound, mp 170-172 ° C.

Example D

2- (5-methyl-3-phenyl-4-isoxazolyl) -3-indole-propionyl chloride (compound of formula 3a).

A mixture of 5.1 g (0.0147 mol) of 2- (5-methyl-3-phenyl-4-isoxazolyl) -3-indole propionic acid and 7.0 g (0.059 mol) of thionyl chloride in 200 ml of tetrahydrofuran 18 was stirred hours at room temperature. The solvent was then removed under reduced pressure to obtain the title compound.

25

Example E

N, N-dimethyl-2- (5-methyl-3-phenyl-4-isoxazolyl) -3-indole-propion amide (compound of formula 2).

A suspension of 5.35 g (0.0147 mole) of 2- (5-methyl-3-phenyl-4-isoxazolyl) -3-indole-propionyl chloride in 100 ml of methylene chloride was added to 150 ml of a 40% solution of dimethylamine in water, keeping the temperature between 0 and 10 ° C. The mixture was then stirred at room temperature for 2 hours and then extracted with methylene chloride. The combined organic layers 8301289 13 were washed with water, dried over magnesium sulfate, filtered and evaporated. The solid residue was recrystallized from ethanol to give the title compound, mp: 174-177 ° C.

The following compounds were prepared in an analogous manner or in another manner described above 10 8301289 14 ö CS ö

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Example F

2- (3-ethyl-5-methyl-4-isoxazolyl) -3-acetylindole (compound of formula 3b)

To a mixture of 0.77 ml (13.45 mmol) acetic acid and 0.17 g (1.47 mmol) 85% phosphoric acid in 10 ml acetonitrile at room temperature 1.9 ml (13.45 mmol) trifluoroacetic anhydride was added . The mixture was stirred for 15 minutes and then 1.0 g (4.42 mol) of 2- (3-ethyl-5-methyl-nsoxazolyl) -indole in 10 ml of aceto-10 nitrile were added dropwise thereto. The mixture was stirred at room temperature for 3.5 hours, then poured into water and extracted with ether.

The ether extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting oil was filtered through silica gel using a mixture of 10% methanol and methylene chloride. The solvent was evaporated and the resulting oil was dissolved in ether. The solution was washed with a 10% sodium bicarbonate water solution, decolorized with charcoal, dried over magnesium sulfate and evaporated under reduced pressure. The resulting oil crystallizes by treatment with ether to give the title compound, mp: 170-171 ° C.

In another method, 41.8 g (0.0163 mol) of silver trifluoromethanesulfonate were added in portions to a solution of 33.5 g (0.148 mol) of 2- (3-ethyl-5-methyl-4-isoxazolyl) indole in 450 ml of methylene chloride. 12.8 g (0.163 mol) of acetyl chloride in 50 ml of methylene chloride were then added dropwise to the resulting suspension. During the addition, the temperature rose to 35 ° C. After the addition, the mixture was stirred at room temperature for 4 hours and then filtered. The filtrate was washed with 150 ml of a 2 N aqueous sodium hydroxide solution, water and a 2 N aqueous sodium hydroxide solution, then dried over anhydrous magnesium sulfate and finally evaporated under reduced pressure to give an oil.

8301289 16

The oil was crystallized from ether to give the title compound, mp 170-173 ° C.

Example G

3-dimethylamino-1-Q- (3-ethyl-5-methyl-4-isoxazolyl) -indole-3-yl-7-propanone (compound of formula 2).

A mixture of 12 g (0.045 mol) 2- (3-ethyl-5-methyl-4-isoxazolyl) -3-acetylindole, 4 g (0.049 mol) dimethylamine hydrochloride and 0.5 ml concentrated hydrochloric acid in 70 ml was heated ethanol under reflux and then added 14 g (0.470 mol) of paraformaldehyde in portions over 5 hours. The resulting mixture was refluxed for an additional 24 hours, cooled and evaporated under reduced pressure. Then the obtained residue was dissolved in 300 ml of methylene chloride and washed with 200 ml of 2N hydrochloric acid. The aqueous acid was cooled and made alkaline with a 2N sodium hydroxide solution and extracted with methylene chloride.

The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was crystallized from ether to give the title compound, mp: 146-148 ° C.

The following compounds were prepared similarly or otherwise as described above.

8301289 17

Table B

(* as prepared in the examples F + G) compound I 2 stuff R * Rj R4 R5 3b R2 R3 Z2 = (CH2) 2 5 --------- i) * 20 H CH CH melt-CH CH melting point: P ^ t: 146-148 ° 173 ° j) H ch3 phenyl CH3 CH3 10 k) H CH3 CH3 CH3 CH3 l) H CH3 C ^^ pyrrolidino m) F CH3 phenyl CH3 CH3 n) 2-naphthyl H - - CH3 CH3 o) o-bifeyl H - - CH3 CH3 15

Example H

H, N-dimethy 1-2- (2-naphthy 1-3-indoo-1) glyoxamide (compound of formula 2).

A solution of 11.0 ml (0.123 mol) oxalyl chloride in 150 ml tetrahydrofuran was cooled to 5 ° C and then 27.0 g (0.111 mol) 2- (2-naphthyl) indole in 150 ml tetrahydrofuran was added dropwise to this solution. while keeping the temperature between 0 and 10 ° C. The mixture was allowed to stir at room temperature for 2 hours, then cooled to 10 ° C and 100 ml of a 40% aqueous solution of dimethylamine was quickly added thereto. The mixture was then stirred at room temperature for 1 hour and the phases were separated.

The tetrahydrofuran layer was washed with a solution of sodium chloride and the water layer with methylene chloride. After that, the organic layers were combined and dried over magnesium sulfate, filtered and evaporated. The solid product obtained was treated with ether to give the compound mentioned in title 8301289 18, m.p .: 208-210 ° C,

The following compounds were prepared analogously or in another manner described above.

5

Table C

0 * as prepared in H) 10 krerbin- R [ΊΓ ill Γ R. "| ÏT rI Ö 1 2 3 4 5 iing (Zt = -G-) p) * 2-naphthyl H CH CH. - - melting point: • ^ -3 wyj »''» «» n 208-210

Q) o-biphenyl H

r) p-biphenyl H

s) o-benzyl-

phenyl H

t) 2-fluorine

Nyl H

u) 5-indanyl H

v) naphthyl F

w) „CH3 x)„ ch3c 25 y) the group with form- v γ mule 20 H. CH_phenyl z) naphthyl H pyrrolidino - aa) „H piperidino - - ab)„ R morpholino - - 30

Example I

The methyl ester of 2- (3-ethyl-5-methyl-4-isoxazolyl-X-oxoindole-3-butane acid (compound of formula 10).

35

To a solution of 59.4 g of 8301289 * 19 (0.45 mol) mono-methyl succinate in 300 ml of acetonitrile, 5.5 g of 85% phosphoric acid were added dropwise and then 63.5 ml (0.45 mol) of trifluoroacetic anhydride to. The mixture was stirred at room temperature for 15 minutes and then added 33.9 g (0.15 mol) of 2- (3-ethyl-5-methyl-4-isoxazolyl) indole in 300 acetonitrile. The mixture was then stirred overnight at room temperature, after which 1.5 L of water and 1 L of ether were added. The layers were separated and the ether washed with water and made alkaline by adding solid sodium carbonate and water. The mixture was stirred at room temperature for 1 hour and the layers were separated, the ether washed with water, dried over magnesium sulfate, filtered and evaporated to give the title compound.

15

Example J

2- (3-ethyl-5-methyl-4-isoxazo] yl)% oxo-indole-3-butanoic acid (compound of formula 9).

20 A solution of the methyl ester of 2- (3-ethyl-5-methyl-4-isoxazolyl) -1-oxo-indole-3-butanoic acid in 250 ml of methanol was added to 250 ml of a 2N sodium hydroxide solution the mixture was heated at a temperature between 40 and 45 ° C for 15 minutes and then stirred at room temperature for 1 hour. Ether and water were then added to the mixture and the layers separated, the ether layer washed with water and the combined water layers washed with ether, charcoal treated and filtered through Celite. The aqueous basic solution was made acidic by careful addition of concentrated hydrochloric acid. The aqueous acidic solution was washed with water, a sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The resulting foam was crystallized to give the title compound, melting point: 98-110 ° C.

8301289 20

Example K, 2- (3-ethyl-5-methyl-4-isoxazolyl) -N, N-dimethyl-Q-oxo-indole-3-butanamide (compound of formula 2).

A solution of 978 mg (0.003 mol) of 2- (3-ethyl-5-methyl-4-isoxazolyl) -1-oxo-indole-3-butanoic acid in 15 ml of methylene chloride was treated with 345 mg (0.003 mol) of N- hydroxy succinimide and added dropwise 615 mg (0.003 mol) of dicyclohexylcarbodiimide in 10 ml of CH 2 Cl 2. The mixture was then stirred at room temperature for 5 hours. Then, the mixture was filtered, the filter cake washed with CH 2 Cl 2 and the combined CK 2 Cl 4 la and added dropwise to 20 ml of a 40% aqueous solution of dimethylamine and 20 ml CH 2 Cl. The mixture was stirred overnight, added water, separated the layers, washed the C 1 -C 6 with water, a sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. Crystallization of the residue gave the title compound, mp: 144.5-148 ° C.

20

Example I

4-amino-3- 3- (2-dimethylamino-1-hydroxyethyl-1) -indol-2-yl-3-hexene-2-one (compound No. 1).

A mixture of 3.1 g of 25 (0.01 mol) of dimethyl thylaminomethyl-2- (3-ethyl-5-methyl-4-isoxazolyl) -indole-3-methanol and 0.31 g of 5 was hydrogenated % palladium on charcoal in 70 ml ethanol at 3.5 kg / cm 2 and 25 ° C until no starting material was present according to thin layer chromatography (3 days). The mixture was then filtered through Celite 30 and the Celite was washed with ethanol. Then, the combined ethanol filtrates were evaporated under reduced pressure and the resulting oil crystallized from ether to give the title compound, mp 90-104 ° C.

Likewise, the following 8301289 β 21 compounds can be obtained (R = the group of formula 20a).

5 Ibinbin XR, BL rI ΪΓ rI p ——— 1 2 3 4 5 iing 1 (ii) 1 OH H CH3 CH3 CH3 phenyl 1 (iii) 1 OH F CH3 CH3 GH3 Cfo J0 1 (iv) 1 OH CH3 CH3 CH3 CH3 ji (v) i oh ch3o ch3 ch3 ch3! c 2 h 5 1 (vi) 1 OH H morpholino CH C Η, | J ém 3 1 (vii) 1 OH H pyrrolidino CH3 melting point: 177-179 ° 1 (viii) 1 OH H piperidino CH3 C ^ H ^ 1 (ix) 1 OH H CH3 CH3 C2H5 CH3 melting point: 184-185 ° 20

Example II

4-amino-3-Z3- (3-dimethylaminopropyl) indol-2-ylL7-4-methyl-3-buten-2-one (compound no. 2 (i)).

A mixture of 3.6 g (0.01 mol) of 2- (5-methyl-3-phenyl-4-isoxazolyl) -3- (dimethylamphnopropyl) -1H-indole and 0.75 g of Raney nickel was hydrogenated in 75 ml of methanol at 3.5 kg / cm and at 25 ° C until no starting material was present according to thin layer chromatography (18 hours). The mixture was then filtered through Celite and the Celite 30 was washed with methanol. The combined methanol filtrates were evaporated under reduced pressure and the resulting oil was crystallized from ethanol to give the title compound, mp: 268-269 ° C.

Likewise, the following 8301289 22 compounds were prepared, wherein R represents a group of formula 20a.

5 compound XR, R „R„ R. Rc J 1 2 3 4 5 thing 2 (ii) 1 Η H CH3 CH3 CH3 2 (iiii 1 Η H C & 3 CH3 CH3 phenyl melting point: 10 222-224 ° 2 (iv ) 1 HF CH3 CH3 CH3 phenyl 2 (v) 1 H CH3 Ci3 CH3 CH3 phenyl 2 (vil 1 H CH30 CH3 CH3 CH3 phenyl 2 (vii) 1 iïïï morpholino CH3 phenyl ^ 2 (viii) 1 iïïï piperidino Cï3 phenyl 2 (ix) 2 ïï ïï Cïï, CH »Cï_ C_ïc melt-

3 3 3 SU

point: 158-159.5 ° _________1 20

Example III

2- (5-methyl-3-phenyl-4-isoxazolyl) -3- (3-dimethylaminopropyl) indole.

A solution of 2.0 g (0.0054 mol) of N, N-dimethyl-2- (5-methyl-3-phenyl-4-isoxazolyl) -3-indole propion amide in 80 ml of tetrahydrofuran was added dropwise to a suspension of 0.82 g (0.0216 mol) of lithium aluminum hydride in 40 ml of tetrahydrofuran, keeping the temperature between 20 and 25 ° C. After the addition, the reaction mixture was stirred at room temperature for 2 hours, cooled and the reaction mixture was quenched by adding 2 ml of water in 20 ml of tetrahydrofuran. The resulting mixture was dried over magnesium sulfate, filtered and evaporated. The solid residue was recrystallized from ethanol to give 2- (5-methyl-3-8301289-phenyl-4-isoxazolyl) -3- (3-dimethylaminopropyl) -indole, mp: 156-157 ° C.

Example IV

2- (3-ethyl-5-methyl-4-isoxazolyl) -3- (3-dimethylamino-propyl 1) -indole.

A mixture of 5.0 g (0.015 mol) of 3-dimethyl-amino-1- 2- (3-ethyl-5-methyl-4-isoxazolyl) -indole-10 3-yl / -1-propanone was instilled Add 120 ml of tetrahydrofuran to a refluxed mixture of 2.0 g of lithium aluminum hydride (0.053 mol) and 200 ml of tetrahydrofuran. The mixture obtained by combining was refluxed for 1 hour, cooled in an ice bath and quenched by carefully adding 7 ml of water. The mixture was then filtered through Celite and the solvent was distilled off under reduced pressure to give an oil which slowly crystallized out. The crystals were treated with ether to give 2- (3-ethyl-5-methyl-4-isoxazolyl) -20 3- (3-dimethylaminopropyl) indole, mp: 131-133 ° C.

Example V

3-dimethylamino-1-Z2- (3-ethyl-5-methyl-4-isoxazolyl) -indole-3-yl-7-propanol.

A suspension of 816 mg (0.022 mol) of lithium aluminum hydride in 125 ml of tetrahydrofuran was cooled to 5 ° C in a nitrogen atmosphere and 3.5 g (0.011 mol) of 3-dimethylamino-1- / 2- (3-ethyl-) were added thereto. 5-Methyl-4-isoxazolyl) -indol-3-y-7-1-propanone in 125 ml of tetrahydrofuran, keeping the temperature between 5 and 8 ° C. The resulting mixture was then stirred at a temperature between 0 and 5 ° C for 4 hours, then cooled to -50 ° C and quenched by adding 10 ml of a saturated 8301289 24 magnesium sulfate solution. The mixture was then warmed to room temperature, filtered and the filtrate evaporated under the pressure of dryness. The resulting residue was dissolved in methylene chloride, washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was crystallized from ether to give 3-dimethylamino- 1- [2- (3-eth.y 1 -5-methyl-4-isoxazoly 1) -indol-3-yl7-1-propanol, melting point: 166-169 ° C was obtained.

10

Example VI

2- (3-ethyl-5-methyl-4-isoxazolyl) -3- (4-dimethylaminobutyl) indole.

A solution of 5.3 g (0.015 mole) of 2- (3-ethyl-1-5-methyl-4-isoxazolyl) -N, N-dimethyl-1-oxo-indole-3-butanamide was dripped in 25 ml of dry tetrahydrofuran to a refluxed suspension of 1.71 g (0.045 mol) of lithium aluminum hydroxide in 50 ml of tetrahydrofuran.

After the addition, the mixture was heated to reflux for 2 hours, then cooled and quenched by adding ethyl acetate, a 2N solution of sodium hydroxide and water. The mixture was filtered and the tetrahydrofuran was evaporated. The resulting residue was dissolved in CH2 Cl2, washed with water, dried over magnesium sulfate, filtered and evaporated. The resulting residue was dissolved in ether and converted into the hydrochloride with gaseous HCl to give the title compound as hydrochloride, mp: 155.5-157.5 ° C.

30

Example VII

2- (2-naphthyl) -3- / S- (N, N-dimethylamino) ethyl-Indole.

A suspension of 4.5 g (0.0119 mol), lithium aluminum hydride and 800 ml of tetrahydrofuran was heated in a nitrogen atmosphere at 55 ° C and added 10.0 g (0.029 mol) N, N in portions 8301289 25 over 10 minutes. dimethyl-2- (2-naphthyl) -3-indole glyoxamide. The mixture was then heated under reflux for 2 hours, cooled to -60 ° C and quenched by carefully adding 150 ml of a saturated magnesium sulfate solution. The mixture was warmed to room temperature and filtered through Celite and the Celite was washed with methylene chloride. The layers in the filtrate were separated and the water layer was washed with methylene chloride. Then the organic layers were combined, dried over magnesium sulfate, filtered and evaporated. The residue was treated with ether and the resulting solid product was recrystallized from ethanol to give the title compound, mp 185-186 ° C.

15

Example VIII

2- (2-naphthyl) -3- / 1-hydroxy-2- (Ν, Ν-dimethylamino) ethyl-indole.

A suspension of 4.5 g (0.19 mole) of lithium aluminum hydride in 800 ml of tetrahydrofuran was cooled to 4 ° C in a nitrogen atmosphere and 10.0 g (0.029 mole) of N, N-dimethyl was added in portions over 5 minutes. -2- (2-naphthyl) -3-indole glyoxamide, keeping the temperature below 10 ° C. The reaction mixture was then stirred at 5 ° C for 2 hours, then cooled to -60 ° C and quenched by adding 150 ml of a saturated magnesium sulfate solution. The mixture was then warmed to room temperature, filtered through Celite and the Celite was washed with methylene chloride. The layers in the filtrate were separated and the water layer was washed with methylene chloride. The organic layers were then combined, dried over magnesium sulfate, filtered and evaporated.

The residue was treated with ether and the resulting solid product was chromatographed on silica gel to give 2- (2-naphthyl) -3- / 1-hydroxy-2- (N, N-dimethylamino) ethyl 7 -indole, 8301289 26 melting point 172-174 ° C was obtained.

The following compounds were obtained analogously to the above-given Examples III-VI.

5 _ __________________ compound 10 R Rj ^ 3 ^ 4 ^ 5 thing 9 2 H 20 H CR3 CR3 CH3 CH3 10 10 2 HF CH3 Cï3 Cï3 phenyl 11 2 HH morph olino CH3 phenyl 12 2 Η H pyrrolidino CR ^ phenyl 13 2 Pip H piperidino CH3 phenyl 14 2 RH pyrrolidino CH3 15 15 2 OH H CH3 CHg CH3 phenyl 16 2 OR 'F CH3 CH3 C & 3 17 2 H 2-naphthyl H CH3 CH3 18 2 R o-biphenyl H CH3 CH3 - - 20_ 19 2 OH 2-naphthyl H CH3 CH3 20 2 OH o-biphenyl H CH3 CH3 - - 21 1 H „H CH- CH“ - - - melting point: 3 3 159-161 25 22 1 H p -biphenyl H CH „CH, - - melting point: 3 3 166-167 23 1 R o -benzylphenyl H CH3 CH3 30 24 IR 2-fluorenyl H CH3 CH3 - - 25 1 R 5- indyl dan H CH3 CH3 - - 26 1 H 2-naphthyl F CH3 CH3 35 27 1 H „CH3 CH3 CH3 - - 8301289 -. * 27 (continued) table 128 1 H 2-naphth-CH30 CH3 CH3 5 f 29 1 H ty ^ H pyrrolidino 30 IH · H piperidino 31 1 H ,, H morpholino 32 1 OH o-biphenyl H CH. CH, - - melting point: 3 3 166-168 10 33 1 OH p-biphenyl H CH3 CH3 - “34 1 OH o-benzylphenyl H CH3 CH3 - - 35 1 OH 2-fluoc · 15 fe- nyl H CH3 CH3 36 1 OH 5-phenyl H CH3 CH3 - ~ 37 1 OH 2-naphthyl F CH3 CH3 20 38 1 OH 2-naphthyl CH3 CH3 CH3 - - 39 1 OH „CH30 CH3 CH3 40 I OH „H pyrrolidino 41 1 OH„ H piperidino 42 1 OH „H morpholino - - _ 30 8301289

Claims (7)

1. Compounds of formula 1, wherein R 1 is a hydrogen, fluorine or chlorine atom, an alkyl group of 1 to 4 carbon atoms or an alkoxy group of 1 to 4 carbon atoms and R 2 and R 2, independently, an alkyl group of 1 to 4 carbon atoms, or wherein R 2 and R 2 together with the adjacent nitrogen atom form a pyrrolidino, piperidino, hexamethyleneimino or morpholino group and a) R represent a group of formula 20 and X a hydrogen atom and m = 2, 3 or 4 or 10 b) R represents a biphenyl, naphthyl, benzylphenyl, indanyl or fluorenyl group or a group of formula 20a and X represent a hydrogen atom or a hydroxyl group and m = 1, 2, 3 or 4, wherein in formulas 20 and 20a R 1 a hydrogen atom or an alkyl group with 1-4 carbon atoms and R 1 represents a hydrogen atom, an alkyl group of 1-4 carbon atoms, a phenyl group or a phenyl group which is substituted by halogen, alkyl of 1-4 carbon atoms and / or alkoxy with 1-4 carbon atoms, in free base form or in the form of an acid addition salt. 20 Compounds according to claim 1, wherein R represents a group of formula 20a, in free base form or in the form of an acid addition salt. Compounds according to claim 2, wherein R 1 is a methyl group and R 1. represent an ethyl or phenyl group, in free base form or in the form of an acid addition salt. Compounds according to claim 1, wherein R represents a naphthyl group, in free base form or in the form of an acid addition salt. Compounds according to claims 2-4, wherein m - 1, in free base form or in the form of an acid addition salt. 8301289 '29 - Compounds according to any one of claims 1-5, wherein Rj is a hydrogen atom. 7. 2- (3-Ethyl-5-methyl-1-isoxazolyl) -3- (3-dimethylamino-propyl) -indole, 2- (2-naphthyl) -3- / 2N, N-dimethyl-5 amino) -ethyl] -indole, 4-amino-3- / 3- (3-dime thy1aminopropy1) -indole-2-yl7-3-hexen-2-one and 4-amino-3- / 3- (2-dimethylamino-1h-hydroxyethyl) indol-2-yl7-3-hexen-2-one, in the form of a free base or acid addition salt. 8. Process for preparing an aromatic compound, characterized in that a compound according to claim 1 is prepared in free base form or in the form of an acid addition salt by a) if R represents a group of formula 20a, a compound of formula lp, where R ^, R ^, R ^, R ^, R ^, X and m have the meanings defined in formula III, in the presence of a catalyst to be reduced with hydrogen, or b) if R is a biphenyl, naphthyl, benzyl-phenyl, indanyl or fluorenyl group or a group of formula 20 represents a compound of formula 2, wherein R 1, R 2 and R g have the meanings defined above, R 'represents a biphenyl, naphthyl, benzylphenyl, indanyl or fluorenyl group or a group of formula 20 and either Zj represents a group of formula 16 or and a direct bond is 25, or Zj represents a direct bond and Z ^ represents a (C ^ m group, in which m has a previously defined meaning, to reduce the compound thus obtained in free base form or in in the form of an acid addition salt. Pharmaceutical composition containing one or more compounds according to any one of claims 1-7 in free base form and / or in the form of a pharmaceutically acceptable acid addition salt thereof, optionally together with a pharmaceutically acceptable diluent and / or carrier. 10. A method of treating diabetes by inhibiting or counteracting post-prandial hyper-8301289 * 30 glycemia by administering one or more compounds of the formula 1 in free base form and / or in the form of a pharmaceutically acceptable acid addition salt thereof. Compounds according to any one of claims 5 to 7 in free base form or in the form of a pharmaceutically acceptable acid addition salt thereof for use as a medicament. 12. Compounds according to any one of claims 1-7 in free base form or in the form of a pharmaceutically acceptable acid addition salt for use as anti-diabetic. 13. Methods as described in the description and / or examples. 15/8301289 ft ί Ra X Rg. yCH- (CH ^ -N · ^ * R, CH-iCH ^ -w / 'LII Xr> ro — if \ r. ^' V'r 1 Wk / '* o' H s ° 1p _ n / R * J - = - tr Vw ^ ^ ΛνΛ „, 2 -C = C (OH) R ^ 0 H 2 C ^ NH 8 -C- (CH ^. (^ YHh —C —CO —Ri Ri 16 XX? <» ,, * * 20 '20a H n \ / 3a - B -, "fjT_L + fc0Y ^ - *" 3 a. R' 12 -C- 4 * 1. ^ cochs ΧΪΧ, t NH (R ^) N excess ( CHOlp 7 fe | 3 (an μ “(or as salt) '—D— 3b 11 R, Όζχ, + ch» cov' - ^ 3b 4 H 13 R1 - (CHi) CO OH YVl, "- ^ 38 (2, - ^) 830 1 28 9 k5 ^ N ^ R 'H 5 Sandoz A.G. in Basel, Switzerland _______________ V η- * -F— COORt R, Λ CHj-CH JnmerasUS (m = 2) XXX, ^ _r - H 6 ü / CHi ^ coor4 x'CHzN-v + CHj -— *. 6 \ || \ XCHi ^ CO0Rt R "14 7 - H - Riv ^ n XXl * “*» 4 - 7 -I- "4 x 0 0 r, Y ^^ _ J- (ch,) w— cooh * hn (r ^ 3) _ ^ 2 (2i = - c- (ch ^ „) W \ '9" H 3 —J- 0 R1 _ I' - | T- C- (CH2) - COOR, - ^ 9 -K-, ^ COOH ΧΧλ, * lC ^ "- *" Ο H ^ COORi 4 15 830 1 28 9 Sandoz AG in Basel, Switzerland