US3696120A

US3696120A - 4-(2-hydroxy-3-amino propoxy)-indole derivatives

Info

Publication number: US3696120A
Application number: US58985A
Authority: US
Inventors: Franz Troxler
Original assignee: Individual
Current assignee: Individual
Priority date: 1969-08-05
Filing date: 1970-07-28
Publication date: 1972-10-03
Anticipated expiration: 1989-10-03
Also published as: GB1318050A; SE369522B; JPS5022555B1; PL81365B1; FR2068461B1; DE2038482A1; BE754360A; FR2068461A1

Abstract

The present invention concerns new indole derivatives of the formula:

WHEREIN R1 is lower alkyl of one to six carbon atoms, preferably of three to five carbon atoms, cycloalkyl of three or four carbon atoms or 3-phenylpropyl, R2 is methyl, hydroxymethyl, methoxymethyl, alkoxycarbonyl wherein the alkoxy group is of one to four carbon atoms or carboxyl. The compounds are useful in the treatment of angina pectoris and heart rhythm disorders.

Description

United States Patent Troxler [54] 4-(2-HYDROXY-3-AMINO PROPOXY)- INDOLE DERIVATIVES [72] Inventor: Franz Troxler, 39 Drosselstrasse,

4103 Bottmingen, Basel-Land, Switzerland 221 Filed: July 28,1970

21 App1.No.: 58,985

[30] Foreign Application Priority Data Aug. 5, 1969 Switzerland ..1 1918/69 Oct. 24, 1968 Switzerland ..l5866/69 June 24, 1970 Switzerland ..9536/70 Oct. 24, 1969 Switzerland ..15865/69 March 24, 1970 Switzerland ..4383/70 [52] US. Cl. 260/326. R, 260/326.13 R, 260/326.l5,

260/326.l6, 424/274 [51] Int. Cl. ..C07d 27/56 [58] Field of Search ..260/326.15, 326.14 R

[56] References Cited UNITED STATES PATENTS 3,471,515 10/1969 Troxleretal. ..260/326.15

[ 51 Oct. 3, 1972 Primary Examiner-Alex Mazel Assistant Examiner-Joseph A. Narcavage Attorney-Gerald D. Sharkin, Robert S. Honor, Frederick H. Weinfeldt, Richard E. Vila and Walter F. Jewell ABSTRACT The present invention concerns new indole derivatives of the formula:

CH: I

The compounds are useful in the treatment of angina pectoris and heart rhythm disorders.

8 Claims, No Drawings 4-(2-IIYDROXY-3-AMINO PROPOXYHNDOLE DERIVATIVES The present invention relates to new indole derivatives of formula I,

ii 'I wherein R, is lower alkyl of one to six carbon atoms,

preferably of three to five carbon atoms, cycloalkyl of three or four carbon atoms or 3-phenylp py R is methyl, hydroxymethyl, methoxymethyl, alkoxycarbonyl wherein the alkoxy group is of one to four carbon atoms or carboxyl,

as well as to processes for the production thereof.

The preferred compounds of formula I, wherein R, is lower alkyl, are those wherein the alkyl radical is branched or compact, especially those which are branched on the a carbon atom, e.g. the isopropyl, sec.butyl, tert.butyl, or 3-pentyl radical.

In accordance with the invention an indole derivative of formula I is obtained by a. reacting a compound of formula Ila,

wherein R is methyl, hydroxymethyl, methoxymethyl or alkoxycarbonyl wherein the alkoxy group is of one to four carbon atoms, or a compound of formula IIb,

OH (Ii-CHr-H-CHnY :CH3

H NR, m wherein R, is as defined above, to obtain a compound of formula la,

C H; 5 u

wherein R, and R are as defined above, or 10 b. debenzylating a compound of formula IV,

OH B,

wherein R is as defined above,

R, is lower alkyl of one to six carbon atoms,

preferably of three to five carbon atoms, cycloalkyl of three or four carbon atoms, or 3-phenylpropyl when R is methyl, hydroxymethyl or methoxymethyl, and

R, is methyl, ethyl, propyl, isopropyl or cyclopropyl when R, is alkoxycarbonyl, and

R and R are lower alkyl,

in an inert organic solvent, to obtain a compound of formula lb,

R is methyl or ethyl, and R and R are as defined above,

R a CH;

o-0 HrCII-CH NIIR K C 3 wherein R, is as defined above, and either each of I i R and R is lower alkyl of one to three carbon atoms, Q COOAlk or i H 10 R and R together are trrmethylene, or

R is hydrogen and R is phenethyl, 1 5 to obtain a compound of formula If,

in the presence of a catalyst and a lower alkanol of the formula AlkOH, wherein Alk is lower alkyl of one to four carbon atoms, to obtain a compound of formula lc,

wherein R," and Alk are as defined above, or

e. reducing a compound of formula Vll, on

where a free carboxyl group is required in the 2 position of the indole structure, the corresponding 2-alkoxycarbonyl compound is hydrolyzed, and where a hydroxymethyl group is required in the 2-position of the indole structure, the corresponding Z-carboxyl or wherein R, R and R are as defined above, and R,

is isopropyl, cyclopropyl, tert.butyl or tert.pentyl, in an inert organic solvent, to obtain a compound of formula Id,

an inert organic solvent, e.g. an aromatic hydrocarbon such as benzene or toluene, or in a wherein R," and R are as defined above, or cyclic ether such as dioxane, and has a duration of f. reducingacompound of formula Vlll, about 2 to 24 hours. The reaction temperature may range between 20 and 15C; the reaction is 0H preferably effected at the boiling temperature of the reaction mixture under reflux. In the compounds of formula llb, Y preferably signifies CHQNRRI chlorine or bromine.

b. The debenzylation of the compounds of formula 000R VH1 1V is conveniently effected by hydrogenation in H A. the presence of a catalyst, preferably a palladium catalyst, in an inert organic solvent, e.g. ethyl wherein R,"', R R and R are as defined above, in acetate, a cyclic or open chain ether such as the presence of a catalyst and a lower alkanol of the tetrahydrofuran, or a lower alkanol such as formula AlkOH, wherein Alk is as defined above, to

obtain a compound of formula le,

wherein R,"' and Alk are as defined above, or g. reducing an imine of formula lX,

2-alkoxycarbonyl compound is reduced.

Acid addition salts or salts of resulting free bases may be produced in conventional manner by reaction with an acid, and free bases may be liberated from salts by 35 treatment with a base.

The production of the new compounds may, for example, be efiected as follows:

a. The reaction of a compound of formula ll with a compound of formula lll is preferably effected in methanol or ethanol. Hydrogenation if preferably effected at room temperature and normal pressure. After hydrogenation is complete, the catalyst is filtered off.

c. The reduction of compounds of formula V may be effected as described in embodiment b) above. It should, however, be pointed out that an interchange of ester radicals my occur in the case of hydrogenation of a compound of formula Vl, (which is a special case of a compound of formula V), when a lower alkanol is used as solvent. This interchange of ester radicals can be avoided when reduction is effected in an alkanol R OH, wherein R is identical to the significance of R in formula VI.

The reduction of a compound of formula VI to a compound of formula Ic is likewise preferably effected in the presence of a palladium catalyst, conveniently at room temperature and normal pressure.

e. The reduction of a compound of fonnula VII can likewise be effected in a manner analogous to embodiment b) above. In this case an interchange of ester radicals, as indicated in section c), may likewise take place when a lower alkanol is used as solvent, it being possible to avoid this interchange in the same way as indicated in section c) above.

f. The reaction of a compound of formula VIII to obtain a compound of formula Ie may be effected as described in embodiment d).

The reduction of an imine of formula IX may, for

example, be effected by hydrogenation in the presence of a suitable metal catalyst, preferably a palladium catalyst, in an inert organic solvent, e.g.

ethyl acetate, or a lower alkanol such as methanol.

Hydrogenation is preferably effected at normal pressure and room temperature. After hydrogenation is complete, the catalyst is filtered off. In accordance with an alternative method of embodi-= ment g), reduction is effected with a complex.

borohydride. For example, an imine of formula IX is taken up in an inert organic solvent, e.g. a lower alkanol such as methanol, and solid sodium borohydride is added portionwise.

Hydrolysis of a 2-alkoxycarbonyl compound of formula I to the corresponding 2-carboxyl compound of formula I may, for example, be effected with aqueous alcoholic solutions of an excess of an alkali metal or alkaline earth metal hydroxide, e.g. sodium, potassium or barium hydroxide. Lower alkanols such as methanol or ethanol are preferably used as alcohols.

Hydrolysis may, for example, likewise be effected with an alkaline ion exchange resin.

Reduction of a 2-alkoxycarbonyl compound of formula I to the corresponding Z-hydroxymethyl compound may, for example, be effected with a complex aluminum hydride such as lithium aluminum hydride or sodium dihydro-bis-(2-methoxyethoxy)aluminate, in an inert organic solvent,.e.g. a cyclic or open chain ether such as tetrahydrofuran, preferably at the boiling temperature of the reaction mixture, and has a duration of one-half to several hours. The reaction mixture may be worked up by adding, e.g. water or a lower alkanol, removing the resulting precipitate by filtration and separating the organic phase. The precipitate is subsequently washed out with an inert organic solvent, and the combined organic phases are dried, e.g. over sodium sulphate. Upon concentrating the organic phase by evaporation, the Z-hydroxymethyl compound of formula 1 is obtained as residue.

The reduction may, for example, likewise be effected in accordance with the procedure of Bouveault-Blanc with sodium in alcohol.

The reaction mixture obtained in accordance with the above embodiments of the process may, for example, be worked up by concentrating it by evaporation, shaking out the residue between an aqueous acid, e.g. l N tartaric acid or 1 N hydrochloric acid, and a inert organic solvent which is not miscible with the acid, such as ethyl acetate, making the acid aqueous phase neutral, e.g. with an aqueous sodium carbonate solution,taking up the liberated basic product in an inert organic solvent such as methylene chloride, separating and drying the organic phase and finally concentrating the same by evaporation, preferably at reduced pressure.

The compounds of formula II are new. A compound of formula II may, for example, be produced by reacting a compound of formula X,

wherein R is as defined above, with an epihalohydrin, preferably epichlorhydrin or epibromhydrin. The compound of formula X is preferably employed in the reaction inthe form of its ammonium or alkali metal salt, e. g. as sodium salt, with the epihalohydrin, conveniently in the absence of oxygen or alternatively in the presence of a base such as piperidine.

After removing the excess epihalohydrin by distillation or completely concentrating the reaction mixture by evaporation, optionally in a vacuum, the residue .(mixture of the compounds of formulas Ila and IIb) can R1 7 l C ACE-CH2- OH2CnHs Xla wherein R is as defined above, or a compound of formula XIb,

(l)H YCHPCH-CI2TNTE2CQHB wherein R and Y are as defined above, or a mixture of the compounds of formulas Xla and XIb, hereinafter referred to as compounds of formula Xl, with a compound of formula X.

This reaction may, for example, be effected as follows:

One to three equivalents of a compound of formula XI are added to a solution or a suspension of a compound of formula X or its alkali metal or ammonium salt, e.g. the sodium salt of a compound of formula X. The reaction may, for example, be effected by stirring the mixture for an extended period, e.g. about 1 to 24 hours, while heating to 20 to l20C, preferably in the absence of oxygen.

XII)

The compounds of formula Xla may be produced in accordance with known processes, e.g. by treatment of a compound of formula Xlb with an alkali. The compounds of formula Xlb may, for example, be obtained by reacting an amine of formula Xlll,

Xlll

XII

wherein R is as defined above, with a compound of formula Xl, and aminomethylating the resulting reaction product, e.g. under the conditions of a Mannich reaction.

The reaction of a compound of formula Xll with a compound of formula X] may be effected in a manner analogous to that described for the production of compounds of formula IV.

The compounds of formula Vll (including the compounds of formula Vlll) are likewise new. A compound Vll may be obtained in a manner analogous to the method for obtaining a compound of formula V, by aminomethylation of a compound of formula XlV,

H XIV wherein R and R are as defined above. A compound of formula XIV, used as starting material for this reaction, may be produced from a compound of formula Xll by reaction with an epihalohydrin (in a manner analogous to the production of a compound of formulas lla and llb) and treatment of the resulting reaction product with the corresponding amine (in a manner analogous to embodiment a) above).

The compounds of formula [X are likewise new. A compound [X may, for example, be produced by debenzylating a compound of formula XV,

wherein R is as defined above, and

H XVI wherein R is as defined above, with the corresponding ketone or the corresponding aldehyde. After removing the excess aldehyde or the excess ketone by distillation, the resulting imine of formula lX is used as such for the next reaction without further purification.

The removal of the benzyl radical( s) may, for example, be effected in a manner analogous to process b). A compound of formula XV may be produced from a compound of formula X as described in process a).

The compounds of formula X are new, and such compound may, for example, be produced by aminomethylation of a compound of formula XVll,

g XVII wherein R is as defined above,

and subsequent hydrogenation of the resulting Mannich base of formula XVIII,

H XVIII wherein R, R and R are as defined above.

Aminomethylation may be effected under the conditions of a Mannich reaction. Hydrogenation of a compound of formula XVlll may, for example, be effected as described in process b).

A compound of formula Xll may, for example, be obtained by hydrogenolytic debenzylation of a compound of formula XVII.

The compounds of formula XVll are new with the exception of 4-benzyloxy-2-methyl indole.

4-Benzyloxy-Z-hydroxymethyl indole may be produced by reduction of 4-benzyloxyindole-2-carboxylic acid, e.g. with lithium aluminum hydride or sodium dihydro-bis-( 2-methoxyethoxy) aluminate, in an inert organic solvent such as dioxane or benzene.

4-Benzyloxy-2-methoxymethyl indole may, for example, be obtained by etherifying 4-benzyloxy-2- hydroxymethyl indole with diazomethane in the presence of boron trifluoride in an inert organic solvent, eg a cyclic or open chain ether such as diethyl ether.

The corresponding esters may be obtained by esterification of 4-benzyloxyindole-2-carboxylic acid, in accordance with conventional processes.

Insofar as the production of the starting materials is not described, these are known or may be produced in accordance with known processes or in a manner analogous to the processes described herein or to known processes.

The compounds of formula I and pharmaceutically acceptable acid addition salts thereof are useful because they possess pharmacological activity in animals. More particularly, the compounds are useful in the treatment of angina pectoris and heart rhythm disorders, including tachycardia, as indicated by their B-blocking activity (blocking effect on the vascular, adrenergic B-receptors). The activity is illustrated by an inhibition of the positive inotropic adrenalin effect on the spontaneously beating guinea pig atrium and also by an inhibition of the hypotension caused by isoproterenol l-( 3 ,4-dihydrxyphenyl )-2- isopropylamine-ethanol] in the narcotized cat.

For the abovementioned use, the dosage administered will naturally vary depending on the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained at doses between about 0.004 and 0.6 mg/kg animal body weight. For the larger mammals, the total daily dose is in the range of from about to about 100 milligrams of the compound. The daily dose may be given in divided doses two to three times a day, or in sustained release form. Dosage forms suitable for oral administration comprise from about L5 to about 50 milligrams of the compound admixed with a solid or liquid pharmaceutical carrier or diluent.

In the following examples which illustrate the invention without in any way limiting its scope, all temperatures are indicated in degrees Centigrade and are uncorrected.

EXAMPLE 1 2,3-Dimethyl-4-( 2-hydroxy-3-isopropylaminopropoxy)indole indole [process a)] A solution of 8.1 g of 2,3-dimethyl-4-hydroxyindole in 35 cc of dioxane is added to a solution of 2.01 g of sodium hydroxide in 35 cc of water, in an atmosphere of nitrogen and while stirring, and subsequently 9.3 g of epichlorhydrin diluted with 25 cc of dioxane/water lzl are added. The reaction mixture is stirred at room temperature for a further 24 hours, is extracted four times with methylene chloride, and the combined organic layers which have been dried over magnesium sulphate are concentrated by evaporation at reduced pressure. The resulting oily residue of 2,3-dimethyl-4- 2,3-epoxypropoxy)indole, without characterization, is heated to the boil for hours with 30 cc of isopropylamine in 70 cc of absolute dioxane. The reaction mixture is subsequently evaporated to dryness at reduced pressure, the residue is shaken out thrice between ethyl acetate and a l N tartaric acid solution, and 5 N sodium hydroxide solution is added to the combined tartaric acid phases until an alkaline reaction is obtained. Extraction is subsequently effected 4 times with methylene chloride, and the combined organic layers which have been dried over magnesium sulphate are concentrated by evaporation at reduced pressure. The title compound crystallizes as maleate from ethanol/ethyl acetate and has a MP. of 15 l-l53.

The 2,3-dimethyl-4-hydroxyindole, required as starting material, is obtained as follows:

4-Benzyloxy-2-methyl gramine is quaternized with methyl iodide (M.P. 203205) and subsequently reduced with lithium aluminum hydride in dioxane at 90 to give 2,3-dimethyl-4-benzyloxyindole (prisms from ethyl acetate with a M.P. of l25-l27). Debenzylation of 2,3-dimethyl-4-benzyloxyindole with hydrogen in the presence of a 5 percent palladium catalyst on aluminum oxide yields 2,3-dimethyl-4- hydroxyindole which crystallizes from benzene in prisms having a MP. of l00-l04.

The 4-benzyloxy-2-methyl gramine, required as starting material, is obtained as follows:

4-Benzyloxyindole-2-carboxylic acid dimethyl amide is reduced in boiling tetrahydrofuran with lithium aluminum hydride to 4-benzyloxy-Z-dimethylaminomethyl indole (M.P. ll6-l 18). Quaternization of this compound with methyl iodide and subsequent deamination with lithium aluminum hydride in boiling dioxane yields 4-benzyloxy-2-methyl indole (prisms from ether/petroleum ether with a MP. of 88-90), which is converted with formaldehyde solution and dimethyl amine in alcohol/glacial acetic acid into 4-benzyloxy-2- methyl gramine, the hydrochloride of this compound having a MP. of l85l87 after crystallization from ethanol.

EXAMPLE 2 2,3-Dimethyl-4-(2-hydroxy-3-isopropylaminopropoxy)indole [process a)] 10 g of 2,3-dimethyl-4-hydroxyindole and cc of epichlorhydrin are heated to the boil for 5 hours after the addition of 2 drops of piperidine. The excess epichlorhydrin is removed by distillation at reduced pressure and the resulting residue is reacted with isopropylamine as described in Example 1.

EXAMPLE 3 4-[ 2-l-lydroxy-3-( 3-pentylamino)propoxy1-3-methylindole-2-carboxylic acid ethyl ester [process a)] The title compound is obtained as a viscous oil in a manner analogous to that described in Example l or 2, from 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester, using 3-pentylamine in place of isopropylamine; the hydrogen maleate of the title compound crystallizes from ethanol/ether in cubes having a MP. of 153-l 55 The 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester, used as starting material, is produced as follows:

Esterification of 4-benzyloxyindole-2-carboxylic acid with ethanol yields the corresponding ethyl ester (M.P. l68-l70). 4-Benzyloxyindole-2-carboxylic acid ethyl ester is converted with formaldehyde, dimethyl amine and glacial acetic acid in ethanolic solution into 4-benzyloxy-3-dimethylaminomethylindole-2-carboxylic acid ethyl ester (M.P.l l5l 17 from benzene/petroleum ether, MP. of the hydrochloride 205207 from ethanol), and 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester is either produced directly with hydrogen in the presence of a palladium catalyst (5 percent Pd on charcoal), or the methiodide of the above Mannich base is reduced in ethanolic solution with sodium borohydride to give 4- benzyloxy-3-methylindole-2-carboxylic acid ethyl ester (M.P. l49150 from benzene in cubes), and this is subsequently debenzylated with hydrogen in the presence of a palladium catalyst (5 percent Pd on charcoal), to give 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester M.P. l60-l 62 from ethanol).

EXAMPLE 4 2,3-Dimethyl-4-(2-hydroxy-3-isopropylaminopropoxy)indole [process b)] r 4.8 g of l-( N-benzylisopropylamino)-3-chloro-2- propanol are added to a solution of 1.61 g of 2,3- dimethyl-4-hydroxyindole and 0.4 g of sodium hydroxide in 150 cc of methanol, and the mixture is heated to the coil for 20 hours. The solvent is evaporated at reduced pressure, the residue is triturated several times with petroleum ether and shaking out is finally effected between water and ethyl acetate. The combined ethyl acetate phases which have been dried over magnesium sulphate are concentrated by evaporation at reduced pressure.

The resulting amorphous 4-[ 3-( N- benzylisopropylamino)-2-hydroxypropoxy]-2,3- dimethyl indole is taken up in 100 cc of methanol and after the addition of l g of a palladium catalyst (5 percent Pd on aluminum oxide), shaking is effected with hydrogen until the taking up of hydrogen is complete.

The catalyst is filtered off, the filtrate is evaporated to dryness at reduced pressure and worked up as described in Example 1 to obtain the compound of the heading.

l-( N-Benzylisopropylamino )-3-chloro-2-propanol may, for example, be produced as follows:

A mixture of 18.4 g of epichlorhydrin and 29.8 g of N-benzylisopropylamine in 100 cc of benzene is heated to the boil at reflux for 24 hours, the solvent is removed by evaporation and the residue is distilled in a high vacuum. l-( N-Benzylisopropylamino)-3-chloro-2- propanol, having a B.P. of l l1 Il0.2 mm of Hg, is obtained.

EXAMPLE 5 2,3Dimethyl-4-(2-hydroxy-3-isopropylaminopropoxy)indole [process g)] 4-( 3-Dibenzylamino-Z-hydroxypropoxy)-2,3- dimethyl indole is obtained as viscous oil in a manner analogous to that described in Example 1, using dibenzylamine in place ofisopropylamine.

5 g of a palladium catalyst (5 percent Pd on charcoal) in 75 cc of methanol are added to 5 g of this crude product without further purification, and shaking is effected with hydrogen until the taking up of hydrogen is complete. The catalyst is filtered off and the solvend is evaporated at reduced pressure. The resulting amorphous 4-(3-amino-2-hydroxypropoxy)- 2,3-dimethyl indole is taken up in 50 cc of acetone and is allowed to stand at room temperature for 24 hours. The solution is subsequently evaporated to dryness at reduced pressure and the title compound is isolated as described in Example 1. The residue is again dissolved in 50 *cc of methanol, and after the addition of 5 g ofa palladium catalyst (5 percent Pd on aluminum oxide), shaking is effected with hydrogen until the taking up of hydrogen is complete. The catalyst is filtered off, the solution evaporated to dryness at reduced pressure and working up as described in Example 1 is effected to obtain the compound of the heading.

EXAMPLE 6 4-[2-Hydroxy-3-( 3-pentylamino)propoxy]-3-methylindole-2-carboxylic acid ethyl ester [process g)] The title compound (M.P. 153-l 55) is produced in a manner analogous to the process described in Example 5, from 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester M.P. l60-162).

EXAMPLE 7 4-( 2-Hydroxy-3-isopropylaminopropoxy-2-hydroxymethyl-3-methyl indole [process 0)] 55.5 g of 4-( 2-hydroxy-3-isopropylaminopropoxy)- 2-hydroxymethyl indole are heated to the boil for 8 hours with 38 g of benzyl bromide and 22.3g of triethylamine in 1.3 liters of tetrahydrofuran. The reaction mixture is evaporated to dryness and the residue is shaken out between methylene chloride and a l N tartaric acid solution. The pH of the combined tartaric acid phases is adjusted to 8 to 9 with a 10 percent soda solution, while cooling with ice, and are extracted 4 times with 200 cc amounts of methylene chloride. After drying the methylene chloride phases over magnesium sulphate, these are concentrated by evaporation at reduced pressure. The crude product is subsequently crystallized with ethanol and yields 4-(3- benzylisopropylamino-Z-hydroxypropoxy)-2-hydroxymethyl indole having a MP. of 133-l 36.

13.2 g of glacial acetic acid are added to a solution of 27 g of 4-( 3-benzylisopropylamino-2-hydroxypropoxy)-2-hydroxymethyl indole in 600 cc of methanol, 1 1.9 g of a 33 percent solution of dimethylamine in ethanol are first added dropwise at +2", and subsequently 7.35 g of a 36 percent aqueous formaldehyde solution are added dropwise at the same temperature, and the reaction mixture is allowed to stand at room temperature for 16 hours. The reaction mixture is evaporated to dryness at reduced pressure and the residue is shaken out between ethyl acetate and a l N tartaric acid solution. The combined tartaric acid extracts are made alkaline with a 5 N sodium hydroxide solution, while cooling with ice, and are extracted with methylene chloride. The evaporation residue of the methylene chloride extracts is crystallized with ethanol/petroleum ether, whereby 3-dimethylaminomethyl-4-( 3- benzylisopropylamino-Z-hydroxypropoxy)-2-hydroxymethyl indole is obtained in the form of crystals having a MP. of l39-l40.

10 g of 3-dimethylaminomethyl-4-( 3- benzylisopropylamino-Z-hydroxypropoxy)-2-hydroxymethyl indole in 350 cc of methanol are shaken with hydrogen in the presence of 10 g of a palladium catalyst (5 percent Pd on charcoal) until the taking up of hydrogen is complete. The catalyst is filtered off, the filtrate is washed well with hot methanol and concentration is effected until crystallization of the title compound commences. M.P. l 52, needles.

The 2-hydroxymethyl-4-( 2-hydroxy-3- isopropylaminopropoxy)indole, used as starting material (M.P. l45l48), may, for example, be produced as described in Example 1, from 4-hydroxy- 2-hydroxymethy1 indole by reaction with epichlorhydrin and subsequent reaction of the reaction product with isopropylamine.

4-Hydroxy-2-hydroxymethyl indole (MP 1 12-1 14 from benzene/ethyl acetate) is obtained by debenzyla- EXAMPLE 8 4-( 3-Cyclopropylamino-2-hydroxypropoxy )-3- methylindole-2-carboxylic acid ethyl ester [process c)] 4-( 3-Benzylocyclopropylamino-2-hydroxypropoxy)- 3-dimethylaminomethylindole-Lcarboxylic acid ethyl ester is obtained in a manner analogous to that described in Example 7 by aminomethylation from 4- 3-benzylcylopropylamino-2-hydroxypropoxy)indole- 2-carboxylic acid ethyl ester (M.P. l25-l27 from benzene), the compound is isolated by chromatography (silica gel with methylene chloride and 2 percent of methanol) and is taken up in 70 cc of ethanol without further purification and is shaken with hydrogen in the presence of 2 g of a palladium catalyst (5 percent Pd on charcoal) until the taking up of hydrogen is complete. The catalyst is filtered off, the filtrate is acidified with an excess of a 2 N solution of hydrochloric acid in ethanol and is concentrated by evaporation at reduced pressure until crystallization commences. The hydrochloride of the title compound crystallizes in fine needles having a M.P. of 228-231.

4-( 3-Benzylcyclopropylamino-2-hydroxypropoxy)indole-2-carboxylic acid ethyl ester (M.P. 125127 from benzene) is obtained in accordance with Example 3, by using 4-hydroxyindole-2-carboxylic acid ethyl ester in place of 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester and benzylcyclopropylamine in place of 3-pentylamine.

4-Hydroxyindole-2-carboxylic acid ethyl ester (M.P. l59l60) is obtained by catalytic debenzylation with palladium/hydrogen of 4-benzyloxyindole-2-carboxylic acid ethyl ester.

EXAMPLE 9 4-( 2-Hydroxy-3-isopropylaminopropoxy)-3-methylindole-2-carboxylic acid methyl ester [process d)] 14.9 g of 4-( 3-benzylisopropylamino-2-hydroxypropoxy)-indole-2-carboxylic acid ethyl ester are dissolved in methanol, an excess of a 2 N solution of hydrochloric acid in methanol is added and the solution is concentrated by evaporation. The resulting hydrochloride is heated to the boil while stirring for 4 hours with 2 g of paraformaldehyde, 3 g of dimethylamine hydrochloride and 3 drops of concentrated hydrochloric acid in 25 cc of isopropanol. The reaction mixture is subsequently evaporated to dryness at reduced pressure and the evaporation residue is recrystallized from ethanol. 4-( 3- Benzylisopropylamino-2-hydroxypropoxy)-3- dimethylaminomethylindole-2-carboxylic acid ethyl ester hydrochloride has a M.P. of 168-l72 with foam- The base is liberated in the usual manner from 8 g of this Mannich base, is taken up in 200 cc of methanol and shaken with hydrogen in the presence of 5 g of a palladium catalyst (5 percent Pd on charcoal) until the taking up of hydrogen is complete. The catalyst is removed by filtration, the solvent, is evaporated at reduced pressure and the crude title compound is crystallized from ether. M.P. 122-124, needles from ether.

4-(3-Benzylisopropylamino-2-hydroxypropyl)indole12-carobxylic acid ethyl ester (M.P. l03-l05) is obtained as indicated in Example 8 for the production of 4-( 3-benzylcyclopropylamino-2-hydroxypropoxy)indole-2-carboxy1ic acid ethyl ester, except that benzylisopropylamine is used in place of benzylcyclopropylamine.

EXAMPLE 10 4-(3-tert.butylamino-2-hydroxypropoxy)-3-methylin dole-2-carboxylic acid ethyl ester [process e)] 5.7 g of glacial acetic acid are added to a solution of 10.8 g of 4-( 3-tert.butylamino-2-hydroxypropoxy)indole-2-carboxy1ic acid ethyl ester in 500 cc of ethanol, while stirring and cooling with ice, 8.8 g of a 33 percent solution of dimethylamine in ethanol are then added and 4.0 g of a 36 percent aqueous solution of formaldehyde are finally added. The reaction mixture is allowed to react at room temperature for 4 days, is then concentrated by evaporation at reduced pressure, and the basic components are isolated in the usual manner by extraction between ether/1 N tartaric acid. Chromatography on 50 parts of water-saturated silica gel with methylene chloride and 0.5 percent of methanol yields 4-(3tert.butylamino-Z-hydroxypropoxy)-3- dimethylaminomethylindole-2-carboxylic acid ethyl ester M.P. 139-l 40 from ethyl acetate.

3.0 g of the above compound are taken up in 150 cc of ethanol and shaking is effected with hydrogen in the presence of 5 g of a palladium catalyst 5 percent Pd on charcoal) until the taking up of hydrogen is complete. The catalyst is removed by filtration, the filtrate is evaporated to dryness at reduced pressure, and the title compound is crystallized as hydrogen maleate from ethanol/ethyl acetate. M.P. 96-l 00.

4-( 3-tert.butylamino-Z-hydroxypropoxy )indole-2- carboxylic acid ethyl ester (the N-cyclohexyl sulphate has a M.P. of l69171) is obtained as indicated in Example 8 for the production of 4-( 3-benzylcyclopropylamino-2-hydroxypropoxy)indole-Z-carboxylic acid ethyl ester, except that tert.butylamine is used in place of benzylcyclopropylamine.

EXAMPLE 1 l 4-(3-Cyclopropylamino-2-hydroxypropoxy)-3- methylindole-Z-carboxylic acid ethyl ester [process e)] The title compound is obtained in a manner analogous to that indicated in Example 10 by hydrogenation of 4-(3-cyclopropylamino-2-hydroxypropoxy)-3-dimethylaminomethylindole-2-carboxylic acid ethyl ester (the bishydrogen maleate thereof crystallizes from ethanol in needle druses having a M.P. of 148); the hydrochloride of the title compound crystallizes in needles having a M.P. of 22823 1.

The ester used as starting material is obtained by reacting 4-hydroxyindole-2-carboxylic acid ethyl ester as indicated in Example 1 or 2with epichlorhydrin, reacting the reaction product with cyclopropylamine and aminomethylating the resulting 4-( 3- cyclopropylamino-2-hydroxypropoxy)indo1e-2-carboxylic acid ethyl ester M.P. l47).

EXAMPLE 12 4-(2-l-lydroxy-3-isopropylaminopropoxy)-3-methylindole-2carboxylic acid (Hydrolysis of compound of Example 9) 4.6 g of 4-( 2-hydroxy-3-isopropylaminopropoxy)-3- methylindole-2-carboxylic acid methyl ester are heated to the boil while stirring for 2 hours with 4.55 g of crystalline barium hydroxide in 60 cc of methanol and 185 cc of water. l4.2 cc of 2 N sulphuric acid are subsequently added, the reaction mixture is filtered through talc until clear and is washed well with boiling water. After concentrating the filtrate, the title compound crystallizes in white crystals having a MP. of 27 l-273 (decomp.).

EXAMPLE l3 4-( 2-Hydroxy3-isopropylaminopropoxy)-2-hydroxymethyl-3-methyl indole [process a)] The title compound, having a MP. of 150l52, is produced in a manner analogous to that described in Example 1 from 4-hydroxy-2-hydroxymethyl-3-methyl indole.

The 4-hydroxy-2-hydroxymethyl-3-methyl indole, used as starting material, may, for example, be produced as follows:

4-Benzyloxy-2-hydroxymethyl indole is converted with formaldehyde, dimethylamine and glacial acetic acid in ethanolic solution into 4-benzyloxy-2-hydroxymethyl gramine (M.P. l27l29, crystallization from ethanol), and reduction is subsequently effected with hydrogen in the presence of a palladium catalyst percent Pd on charcoal), to give 4-hydroxy-2-hydroxymethyl-3-methyl indole. M.P. l35l36 from ethyl acetate.

4-Hydroxy-2-hydroxymethyl-3-methyl indole may likewise be obtained by converting 4-benzyloxyindole- 2-carboxylic acid ethyl ester in accordance with the above Mannich process into 4-benzyloxy-3- dimethylaminomethylindole-2-carboxylic acid ester (M.P. of the hydrochloride 205207, crystallization from ethanol), quaternizing the resulting ester with methyl iodide to the methiodide, reducing this with lithium aluminum hydride in tetrahydrofuran to 4- benzyloxy-2-hydroxymethyl-3-methyl indole (M.P. l29-l3l from methylene chloride), and finally debenzylating with hydrogen in the presence of a palladium catalyst 5 percent Pd on aluminum oxide).

EXAMPLE l4 4-( 2-Hydroxy-3-isopropylaminopropoxy)-2-hydroxymcthyl-3-mcthyl indole.

A solution of 32 g of 4-( 2-hydroxy-3- isopropylaminopropoxy)-3-mcthylindolc-2-carboxylic acid methyl ester in 250 cc of absolute tetrahydrofuran is added dropwise while stirring and in an atmosphere of nitrogen within minutes to a boiling suspension of 7.6 g of lithium aluminum hydride in 200 cc of absolute tetrahydrofuran and stirring is continued for a further 2 hours. The reaction mixture is then cooled to 40 and 20 cc of water are added dropwise. The resulting precipitate is filtered ofi, washed well with tetrahydrofuran, and the organic solution is dried over sodium sulphate. The evaporation residue is recrystallized from ethanol, whereby the title compound, having a MP. of l50-l 52, is obtained.

The 4-(2-hydroxy-3-rsopropylammopropoxy)-3- methylindole-2-carboxylic acid methyl ester, required as starting material, is produced as described in Example 9.

EXAMPLE 15 4-( 2-Hydroxy-3-isopropylaminopropoxy)-2-hydroxymethyl-3-methyl indole.

The title compound which is identical with the compound produced in Example 14, is obtained in a manner analogous to that described in Example 14, except that 4-(2-hydroxy-3-isopropylaminopropoxy)-3- methylindole-2-carboxylic acid is used in place of 4-(2- hydroxy-3-isopropylaminopropoxy)-3-methylindole-2- carboxylic acid methyl ester.

The 4-( 2-hydroxy-3-isopropylaminopropoxy)-3- methylindole-2-carboxylic acid, required as starting material, is, for example, produced as described in Example 12.

What is claimed is:

l. A compound of the formula: v, wherein R is lower alkyl of one to six carbon atoms, cycloalkyl of three to four carbon atoms or 3-phenyl- P PYL R is methyl, hydroxymethyl, methoxymethyl, alkoxycarbonyl wherein the alkoxy group is of one to four carbon atoms or carboxyl, or a pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1, which is 2,3-dimethyl- 4-(2hydroxy-3-isopropylaminopropoxy)indole.

3. The compound of claim 1, which is 4-[2-hydroxy- 3-( 3-pentylamino)propoxy]-3-methylindole-2-carboxylic acid ethyl ester.

4. The compound of claim 1, which is 4-(2-hydroxy- 3-isopropylaminopropoxy)-2-hydroxymethyl-3-methyl indole.

5. The compound of claim 1, which is 4-( 3- cyclopropylamino-2-hydroxypropoxy)-3-methylinole- 2-carboxylic acid ethyl ester.

6. The compound of claim 1, which is 4-(2-hydroxy- 3-isopropylaminopropoxy)-3methylindole-2-carboxylic acid methyl ester.

7. The compound of claim 1, which is 4-( 3-tert.butylamino-2-hydroxypropoxy)-3-methylindole-2-carboxylic acid ethyl ester.

8. The compound of claim 1, which is 4-(2-hydroxy- 3-isopropylaminopropoxy)-3-methylindole-2-carboxylic acid.

Claims

2. The compound of claim 1, which is 2,3-dimethyl-4-(2hydroxy-3-isopropylaminopropoxy)indole.
3. The compound of claim 1, which is 4-(2-hydroxy-3-(3-pentylamino)propoxy)-3-methylindole-2-carboxylic acid ethyl ester.
4. The compound of claim 1, which is 4-(2-hydroxy-3-isopropylaminopropoxy)-2-hydroxymethyl-3-methyl indole.
5. The compound of claim 1, which is 4-(3-cyclopropylamino-2-hydroxypropoxy)-3-methylinole-2-carboxylic acid ethyl ester.
6. The compound of claim 1, which is 4-(2-HYDROXY-3-isopropylaminopropoxy)-3-methylindole-2-carboxylic acid methyl ester.
7. The compound of claim 1, which is 4-(3-tert.butylamino-2-hydroxypropoxy)-3-methylindole-2-carboxylic acid ethyl ester.
8. The compound of claim 1, which is 4-(2-hydroxy-3-isopropylaminopropoxy)-3-methylindole-2-carboxylic acid.