DE2065321A1 - INDOL DERIVATIVES - Google Patents

Description

Indole derivatives The invention relates to new indole derivatives and their Salts with physiologically compatible acids. The invention also relates to methods to create these new connections. The invention also relates to pharmaceutical preparations containing the new indole derivatives as the active ingredient and their salts with physiologically acceptable acids.

The new indole derivatives according to the present invention are characterized by the general formula: in which X and Y are a hydrogen atom, a halogen atom, a lower Al, myl or alkoxy radical, R1 is a hydrogen atom or a lower alkyl radical which is optionally substituted by an aryl radical, R2 is a hydrogen atom or a lower alkyl, aryl , or is a lower aralkyl radical, R3 is a lower alkyl radical or the two R3 groups together with the nitrogen atom attached to them form a heterocyclic ring and A is an alkylene chain with 2-3 carbon atoms and salts of the compounds according to formula (I) with physiologically compatible acids.

The indole derivatives according to the invention and their addition salts can be obtained by one of the following processes: 1. For compounds of the general formula (1) in which X, Y, R22, R3 and A are those given above in connection with the formula (1) Can have meaning and R1 is a hydrogen atom and in the case of the addition salts of these compounds, an indole derivative of the general formula is first used: in which XY and R2 can have the meaning given above in connection with der-BorMel (I), with a compound of the general formula: or an addition salt thereof, in which X1 denotes a halogen atom or a group functionally equivalent to this and R3 and A have the meaning given above for the formula (I), so that a compound of the general formula: arises, in which X, Y, R2, R3 and A have the meaning given in connection with the formula (I).

The reaction is carried out in a suitable solvent such as Ethyl acetate, acetone, dimethylformamide, dimethyl sulfoxide or mixtures of these solvents in the presence of an acid-binding agent, for example aluminum carbonate or sodium hydride, executed.

The compounds corresponding to the above formula (IV) are then in a suitable solvent such as methanol or ethanol, under Use of a basic agent, preferably ammonia or an alkali metal alkoxide subjected to a deacetylation, after which compounds of the general formula (I) are present in which R1 is a hydrogen atom.

2. For compounds of the general formula (I) in which X, Y, R2, R3 and A have the meaning given above in connection with the formula (I) and R represents a lower alkyl group substituted by an aryl group can be, compounds falling under the formula (I) in which R1 is still for represents a hydrogen atom with an alkylating agent of the general formula: X'2 - R4 (V) in which x2 is a halogen atom and R4 stands for a lower alkyl group, which may be substituted by an aryl group. The response is in a suitable solvent such as dimethylformamide or toluene carried out in the presence of an acid-binding agent, for example sodium hydride, after which, if appropriate, the indole derivatives obtained in this way are converted into the corresponding Salts are converted with physiologically compatible acids. The acid addition salts are made by reacting the basic form of the indole derivatives with no less than one equivalent of the corresponding acid in an organic Solvent, such as ethanol or isopropanol obtained.

The salts are conveniently used for isolation and / or purification of the compounds according to the invention are used. They can be known in and of themselves Way into the corresponding salts with other physiologically acceptable acids being transformed.

The new indole derivatives of the general formula (I) as well as theirs Salts with physiologically compatible acids have valuable pharmacological properties Properties and are therefore in the.

treatment of considerable benefit, particularly as an anti-inflammatory Agent, the anti-inflammatory effect was, for example, after oral administration found in rats as a relative inhibition of foot inflammation, which by Carrageenin according to the method of C. A. Winter et al. (Proc. Soc. Exp.

Diol. Med. 111 (1962) p. 544).

Examples of indole derivatives that have anti-inflammatory effects at an oral dose of 100 mg / kg are shown in Table I below given together with benzydamine as a comparative substance belonging to the prior art. The values for LD50 (rat) p.o. of the indole derivatives given in Table I. are significantly higher than 100 mg / kg.

Table I. Compound LD50 (mouse)% inhibition mg / kg ip 100 mg / kg po 3- (2-Diethylaminoethoxy) indole hydrochloride 150 47 1-n-Butyl-3- (2-diethylaminoethoxy) indolebioxalate 125 32 1-Benzyl-3- (2-diethylaminoethoxy) indole hvdrochlorid 100 50 1-benzyl-3- (2-diethylaminoethoxy) -5-methoxy- indole hydrochloride 150 58 1-Benzyl-3- (3-dimethylaminopropoxy) indolebioxalate 150 59 3- (2- (1-piperidyl) ethoxy) indole hydrochloride 150 41 5-chloro-3- (2-diethylaminoethoxy) indolebioxalate 300 70 1-Benzyl-5-chloro-3- (2-diethylaminoethoxy) - indole hydrochloride 100 34 5-methyl-3- (2- (1-piperidyl) ethoxy) indole hydrochloride 150 28 1-benzyl-3- (2-diethylaminoethoxy) -2-phenyl- indole dioxalate 200 22 2-benzyl-3- (2-diethylaminoethoxy) indole hydrochloride 75 85 Benzydamine 200 23 When using the compounds according to the invention as therapeutically active agents, they can be used either alone or in combination with pharmaceutically acceptable carrier substances, the proportion of which depends on the solubility and chemical nature of the compound, the type of administration and current pharmaceutical practice. For example, they can be administered orally in the form of tablets or capsules containing starch, hilly sugar, certain types of clay, etc. as carriers. They can also be applied sublingually in the form of lozenges or candies, in which the active ingredient is mixed with sugar and corn syrups, flavorings and colorings. The water is removed from the mixture to the extent necessary for pressing it into a solid form. The compounds can also be used orally in the form of solutions which may contain colorants and flavorings. But they can also be administered parenterally, i.e. intramuscularly, intravenously or subcutaneously. For parenteral administration, the compounds can be used in the form of sterile solutions which also contain other dissolved substances, such as, for example, sufficient amounts of salts and glucose to make the solution isotonic. The dose used by the substances according to the invention varies with the mode of administration and also depends on the particular compound used. It still depends on the person to be treated. The compounds according to the invention can in principle be administered in doses such that on the one hand good therapeutic effects are achieved, but on the other hand disadvantageous or harmful side effects are excluded.

The used den are in the range of 5 mg to about 2000 mg per day, although in individual cases a decrease or increase in the in Doses lying in this area may be necessary.

The following examples illustrate the preparation of the new indole derivatives described in detail, Examples 1-15 initially showing the preparation of the Indicate intermediate products from which the final products can be made.

Example 1 1-Acetyl-3- (2-diethylaminoethoxy) indole hydrochloride.

1-Acetylindoxyl (17.5 g) and potassium carbonate (28 g) are mixed with tetrahydrofuran (100 ml) and water (1 ml) mixed. It is 2-diethylaminoethyl chloride (80 ml a 1.24 molar solution in toluene) added; the mixture is taking 3 hours Boiled under reflux. Then again 2-diethylaminoethyl chloride (80 ml of above-mentioned solution) and then a further 3 hours under reflux heated. The reaction mixture is filtered off and the filtrate is concentrated in vacuo a. The residue is dissolved in diethyl ether (150 ml) and extracted with acetic acid (2 x 100 ml of a 2N aqueous solution). The acetic acid extract is made with sodium hydroxide solution (6n) at 0-10 ° C alkaline and extracted the obtained mixture with ether (2 x 100 ml). The ether extract is dried and concentrated by evaporation; the remaining residue is dissolved in isopropanol (50 ml). The addition of a Solution of hydrochloric acid in isopropanol gives 1-acetyl-3- (2-diethylaminoethoxy) indole hydrochloride (23.5 g) with a melting point of 158-160 ° C. Recrystallization from isopropanol results 22 g (71% yield) of the pure compound with a melting point of 165-166 ° C.

Analysis for C16H23O2N2Cl: Calc .: a 61.8; H: 7.5; 0: 10.3; N: 9.0; Cl: 11.4; Found: C, 61.5; H: 7.5; 0: 10.3; N: 8.8; Cl: 11.6.

Example 2 1-Acetyl-5-methoxy-3- (2- (1-piperidyl) ethoxy) indole hydrochloride.

To a mixture of 1-acetyl-5-methoxyindoxyl (21 g) and potassium carbonate (27.6 g) in tetrahydrofuran (100 ml) are added 2- (1-piperidyl) ethyl chloride (53 ml a 1.24 molar solution in toluene) and the reaction mixture is heated for 3 hours under reflux. One more sets 2- (1-piperidyl) ethyl chloride (53 ml of the above mentioned solution) and then refluxed for a further 3 hours. The reaction mixture is worked up as described in Example 1 and gives so 1-acetyl5-methoxy-3- (2- (1-piperidyl) ethoxy) indole hydrochloride (26.5 g, 75% yield) with a melting point of 218-220 ° C.

Analysis for C18H25O3N2Cl: Calculated: C: 61.3; H: 7.1; a: 13.6; N: 7.9; Cl: 10.1; Found: C, 61.3; H: 7.1; 0: 13.5; N: 7.9; al: 10.0.

The method described in Example 2 above is used for production of the following compounds according to the above formula (IV) an, in'der R2 and Y stands for a hydrogen atom and A is an ethylene chain: Example X N (R3) 2 Yield Melting point no.

3 - N (CH3) 2nd HCl 39% 215-216 ° C 4 - N (CH2) 5th HCl 47% 202-203 ° C 5 5-Cl N (C2H5) 2.HCla) 73% 191-192 ° C 6 5-Cl N (CH2) 5.HCl 69% 259-260 ° C 7 5-CH3 N (CH3) 2.HCl 40% 236-237 ° C 8 5-CH3 N (CH2) 5.HCl 50% 219-220 ° C 9 5-CH3O N (CH3) 2.HCl 69% 214-215 ° C 10 5-CH3O N (C2H5) 2.HCl 25% 133-135 ° C a) contains 2 mol of water of hydration example 11 1-Acotyl-3- (2-diethylaminoethoxy) indole hydrochloride.

A mixture of 1-acetylindoxyl is heated under reflux for 7 hours (3.5 g), 2-diethylaminoethyl chloride hydrochloride (6.9 g) and potassium carbonate (11 g) in ethyl acetate (100 ml) to which water (1 ml) was added. The mixture will cooled and water (100 ml) is added. The organic phase is separated Washed with sodium hydroxide solution (2 x 25 ml in solution) and then with acetic acid (2 x 50 ml of a 1N solution) extracted. The acetic acid extract is added at ~ 0-10 ° C Sodium hydroxide solution (6N) added in excess; the mixture becomes with ether (2 x 50 ml) extracted. The ether extract is dried and concentrated by evaporation; the remaining residue is dissolved in isopropanol (10 ml). Addition of a solution of hydrochloric acid in isopropanol gives 1-acetyl-3- (2-diethylaminoethoxy) indole hydrochloride (4.0 g), melting point 155-157 ° C. Recrystallization from isopropanol gives 3.7 g (600 yield) of pure compound with a melting point of 165-166 ° C.

Example 12 1-Acetyl-3- (3-dimethylaminopropoxy) indole bioxalate.

A mixture of 1-acetylindoxyl (8.8 g), 3-dimethylaninopropyl chloride hydrochloride (15.8 g) and potassium carbonate (27 g) in dimethyl sulfoxide, DXS0 (100 ml) at 40 ° C Vigorously stirred for 24 hours. @ Water (500 ml) is added and the The suspension obtained is extracted with chloroform (3 × 100 ml). The chloroform extract - is dried and concentrated; the remaining residue is dissolved in isopropanol (100 ml) dissolved. Addition of a solution of oxalic acid (8 g) in isopropanol (100 ml) and subsequent cooling gives 1-acetyl-3- (3-dimethylaminopropoxy) indole oxalate (9.2 g) with a melting point of 167-168 ° C. Recrystallization from methanol (total yield: 26%) increases the melting point to 1761770C.

Analysis for C17H22, O6N2: Calculated: C: 58.3; H: 6.3; 0: 27.4; N: 8.0; Found: C: 58.3; H: 6.6; 0: 27.8; N: 8.0.

Example 13 1-Acetyl-3- (2-diethylaminoethoxy) -4-methoxyindole hydrochloride.

A mixture of 1-acetyl-4-methoxyindoxyl (24.7 g), 1-diethylaminoethyl chloride hydrochloride (41.6 g) and potassium carbonate (66.3 g) in DXSO (300 ml) and ethyl acetate (300 ml) kept at 50 ° C. for 6 hours with stirring. The reaction mixture was poured into ice water (1.5 l) and the resulting ethyl acetate layer was separated off. The aqueous phase was extracted twice with ethyl acetate (2 x 400 ml) and the The combined ethyl acetate deposits were dried and in vacuo concentrated. The residue was dissolved in isopropanol. By adding hydrogen chloride in isopropanol at 0-5 ° C. was 1-acetyl-3- (2-diethylaminoethoxy) -4-methoxyindole hydrochloride (22 g, 51) with a melting point from 146-14700 '.

In a manner analogous to that described in Example 13, the following were carried out Compounds Prepared: Example 14 1-S, cetyl-5-chloro-5- (2-diethylaminodiathoxy) indole hydrochloride.

Melting point 188-190 ° C, yield 49%. (The response time was 3 Hours).

Example 15 1-Acetyl-3- (2-diethylaminoathoxy) -2-phenylindole.

The compound was isolated as an oil (the reaction time was 10 Hours).

Example 16 3- (2-Diethylaminoethoxy) indole hydrochloride.

1-Acetyl-3- (2-diethylaminoathoxy) indole hydrochloride (15.6 g) is in methanol (200 ml) saturated with ammonia at 60 ° C. for 7 hours in an autoclave heated. The reaction mixture is cooled and freed from the solvent in vacuo and the residue dissolved in isopropanol (50 ml). Addition of a solution of hydrogen chloride in isopropanol at 0-5 ° C. gives 3- (2-diethylaminoethoxy) indole hydrochloride (12.6 g) with a Melting point between 156-157 ° C. The pure connection (11.2 g, 84% yield) with a melting point of 157-158 ° C. are obtained after recrystallization from isopropanol.

Analysis for C14H21 ° N2Cl: Calc .: C: 62.6; H: 7.9; N: 10.4; Cl: 13.2; Found: C, 62.5; H: 7.9; N: 10.1; Cl: 13.2.

Following the same procedure as described in Example 16 the following compounds according to the general formula (I) (R1 = R2 = Y = H) prepared: Example X A N (R3) 2 Yield Melting Point 17 - (CH2) 2 N (CH3) 2.HCl 83% 180-181 ° C 18 - (CH2) 2 N (CH2) 5.HCl 78% 191-192 ° C 19 - (CH2) 3 N (CH3) 2. (COOH) 2 74% 125-126 ° C 20 5-Cl (CH2) 2 N (CH2) 5.HCl 90% 195-196 ° C 21 5-Cl (CH2) 2 N (C2H5) 2. (COOH) 2 60% 124-126 ° C 22 5-CH3 (CH2) 2 N (CH3) 2. (COOH) 2 10% 139-140 ° C 23 5-CH3 (CH2) 2 N (CH2) 5.HCl 59% 182-183 ° C 24 5-CH3O (CH2) 2 N (CH3) 2 82% 99-100 ° C 25 5-CH3O (CH2) 2 N (CH2) 5.HCl 74% 164-165 ° C example 26 5-chloro-3- (2-diethylaminoethoxy) indole.

1-acetyl-5-chloro-3- (2-diethylaminoethoxy) indole hydrochloride (34 g) were for 30 minutes under the reflux condenser with a solution of sodium ethoxide cooked, which has been prepared from sodium (9.2 g) and ethanol (500 ml, 99%) was.

Ice water was slowly added to the reaction mixture, which had been cooled to 200.degree added, with 5-chloro-3- (2-diethylaminoethoxy) indole (24 g) having a melting point of 28 ° C was obtained.

Recrystallization from isopropanol raised the melting point to 99 ° C on (yield: 19.6 g, 74%).

Analysis for C14H19ClN2O: Calculated: C: 63.1; H: 7.2; Cl: 13.3; N: 10.5; Found: C, 62.8; H: 7.2; Cl: 13.3; N: 10.5.

In a manner analogous to that described in Example 26, the following were prepared obtained under the general formula (I) compounds in which R1 and Y stand for a hydrogen atom and A means an ethylene chain: example X R2 N (R3) 2 Yield Melting Point No.

27 H h N (C2H5) 2 72% 87-88 ° C 28 5-CH3O- H N (C2H5) 2 75% 76-77 ° C 29a) H Ph N (C2H5) 2 30 4-CH3O- H N (C2H5) 2 70% 70-71 ° C a) the compound was isolated as an oil Example 31 1-Benzyl-5-chloro-3- (2-diethylaminoethoxy) indole hydrochloride.

A solution of 5-chloro-3- (2-diethylaminoethoxy) indole (15 g) in dimethylformamide, DMF, (100 ml) was concentrated in vacuo.

The residue dissolved in DMF (120 ml) became at 25 ° C in the course of 15 minutes of an agitated suspension of sodium hydride (2.9 g of a 500% Suspension in mineral oil) in XDMF (60 ml) was added. The reaction mixture was kept at 25 ° C. for 2 hours with stirring and then benzyl chloride (7.6 g) dissolved in DMF (20 ml) was added over 15 minutes at 25 ° C. The reaction mixture was left to stand for a further hour at 25 ° C and then poured into ice water (1.2 l). The emulsion obtained was made with ethyl acetate (3 x 400 ml) extracted; the ethyl acetate extract was dried and concentrated in vacuo. The residue 4 was dissolved in isopropanol. By adding a solution of hydrogen chloride in isopropanol 20-30 0 with subsequent cooling to 0-5 ° C was 1-benzyl-5-chloro-3- (2-diethylaminoethoxy) indole hydrochloride (20.5 g) with a Melting point of 162-163 ° C obtained.

Recrystallization from isopropanol resulted in a compound (19.7 g, 91%) with a melting point of 16400.

Analysis for C21H26Cl2N2O: Der .: C: 64.1; H: 6.7; Cl: 18.0; N: 7.1; Found: C: 64.0; H: 6.7; Cl: 18.1; N: 7.1.

Example 32 1-Benzyl-3- (2-diethylaminouthoxy) -2-phenylindole oxalate.

3- (2-Diethylaminoäthoxy) -2-phenylindole, according to the example 29 obtained as an oil was benzylated as described in the previous example. The residue obtained after the concentration of the ethyl acetate extract was in Dissolved ethanol and added to a solution of oxalic acid in ethanol at 20-30 ° C. After cooling to 0-5 ° C., 1-benzyl-3- (2-diethylaminoethoxy) -2-phenylindolbioxalate was obtained obtained with a melting point of 125-127 ° C. Recrystallization from ethanol raised the melting point to 129-130 ° C. The total yield over three stages was 53%.

Analysis for C29H32N205: Calculated: C, 71.3; H: 6.6; N: 5.7; Found: C: 71.5; H: 6.6; N: 5.6.

The following compounds falling under the general formula (I), in which Y - R2: H, were carried out according to procedures similar to those in the examples 31 and 32, obtained: Example X A R1 N (R3) 2 yield melting point no.

33 H (CH2) 2 PhCH2 N (C2H5) 2HCl 63% 144-146 ° C 34 H (CH2) 2 CH3 (CH2) 3 N (C2H5) 2 (COOH) 2 35% 110-112 ° C 35 5-CH3O (CH2) 2 PhCH2 N (C2H5) 2HCl 88% 172-173 ° C 36 H (CH2) 3 PhCH2 N (CH3) 2 (COOH) 2 53% 144-145 ° C 37 4-CH3O (CH2) 2 PhCH2 N (C2H5) 2HCl 65% 136-138 ° C Example 38 2-Benzyl-3- (2-diethylaminoethoxy) indole hydrochloride.

Line mixture of 1-acetyl-2-benzylindoxyl (13.2 g), 2- (diethylamino) ethyl chloride hydrochloride (17.2 g) and potassium carbonate (27.6 g) were added for 7 hours with vigorous stirring in ethyl acetate (200 ml) which still contained water (5 ml) under the reflux condenser cooked. The reaction mixture was poured into ice water (300 ml) and the resulting Ethyl acetate layer separated. The aqueous phase was washed with ethyl acetate (100 ml) extracted and the combined ethyl acetate deposits were dried and concentrated in vacuo.

The residue was refluxed for 15 minutes a solution of sodium methoxide (8.1 g) in ethanol (200 ml, 99% strength). the The reaction mixture was cooled and added to ice water (11). The received Emulsion was extracted with ethyl acetate (3 x 150 ml) and the ethyl acetate extract was dried and concentrated in vacuo. To the residue that is in isopropanol (50 ml) was dissolved, hydrogen chloride in isopropanol was added at 0-5 ° C.

2-Benzyl-3- (2-diethylaminoethoxy) indole hydrochloride (13.5 g) with a Melting point of 168-170 ° C obtained in this way became from ethanol recrystallized. The recrystallized product had a melting point of 173-174OC. The total yield was 62%.

Analysis for C21H27N20O1: Calc .: a: 70.3; H: 7.6; N: 7.8; Cl: 9.9; Found: C: 70.1; H: 7.8; N: 7.9; Cl: 10.1.

Example 39 3- (2- (1-Pyrrolidinyl) ethoxy) indole hydrochloride.

In a corresponding way as described in the previous example was 3- (2- (1-pyrrolidinyl) ethoxy) indole hydrochloride with a melting point of 170-172 ° C produced in a yield of 44%.

Claims (1)

Claim Indole derivatives of the general formula in which X and Y represent a hydrogen atom. Halogen atom, a lower alkyl or alkoxy radical, R1 denotes a hydrogen atom or a lower alkyl radical which is optionally substituted by an aryl radical, R2 denotes a hydrogen atom or a lower alkyl, aryl or lower aralkyl radical, R3 stands for a lower alkyl radical or the two R3 groups together with the nitrogen atom attached to them form a heterocyclic ring and A denotes an alkylene chain with 2-3 carbon atoms and salts of the compounds according to formula (I) with physiologically acceptable acids.