US3860609A - 3-aminoalkyloxyindoles - Google Patents

Abstract

This invention is concerned with novel and pharmaceutically active indole derivatives having the structure:

AND THE SALTS THEREOF WITH PHYSIOLOGICALLY ACCEPTABLE ACIDS, IN WHICH EACH OF X and Y is selected from the group consisting of hydrogen, hydroxy, lower alkyl having 1-3 carbon atoms and lower alkoxy having 1-3 carbon atoms, R1 is selected from the group consisting of hydrogen, lower alkyl having 1-4 carbon atoms and benzyl, R2 is selected from the group consisting of hydrogen, lower alkyl having 1-4 carbon atoms, benzyl and phenyl, R3 is selected from the group consisting of hydrogen, lower alkyl having 1-8 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, benzyl and 2-phenylethyl, and A is a straight or branched alkylene chain containing from 2 to 4 carbon atoms.

Description

United States Patent [191 Lundt 51 Jan. 14,1975

[ 3-AMINOALKYLOXYINDOLES [75] Inventor: Behrend Friedrich Lundt, Lyngby,

Denmark.

[73] Assignee: Novo Terapeutisk Laboratorium A/S, Bagsvaerd, Denmark [22] Filed: Nov. 10, 1972 [21] Appl. No.: 305,239

Related U.S. Application Data [63] Continuation-in-part of Ser. Nos. 39,863, May 22, 1970, abandoned, and Ser. No. 201,550, May 20, 1970, and Ser. No. 287,311, Sept. 8, 1972.

[30] Foreign Application Priority Data May 27, 1970 Great Britain 26683/70 [52] U.S. Cl..... 260/326.l5, 260/326.11 R, 424/274 [51] Int. Cl C07d 27/56 [58] Field of Search 260/326.15

[56] References Cited UNITED STATES PATENTS 3,703,524 11/1972 Braendstroem et al 260/293.6l

Primary Examiner-Joseph A. Narcavage Attorney, Agent, or FirmSynnestvedt & Lechner 57 7 ABSTRACT This invention is concerned with novel and pharmaceutically active indole derivatives having the structure:

R is selected from the .group consisting of hydrogen, lower alkyl having l-8 carbon atoms, cycloalkyl having 5 or 6 carbon atoms, benzyl and 2-phenylethyl, and A is a straight or branched alkylene chain containing from 2 to 4 carbon atoms.

10 Claims, No Drawings 1 g-AMINQALKYLOXYINDOLES in which:

each of X and Y is selected from the group consisting of hydrogen; hydroxy; lower alkyl having 13 carbon atoms and lower alkoxy having l-3 carbon atoms,

R is selected from the group consisting of hydrogen;

lower alkyl having 1-4 carbon atoms and benzyl,

R is selected from the group consisting of hydrogen; lower alkyl having l-4 carbon atoms; benzyl and phenyl,

R is selected from the group consisting of hydrogen; lower alkyl having 1-8 carbon atoms; cycloalkyl having 5 or 6 carbon atoms; benzyl and 2-phenylethyl, and

A is a straight or branched alkylene chain containing from 2 to 4 carbon atoms,

and salts of the said compounds of formula I with physiologically acceptable acids.

Examples of acids which are able to form physiologically tolerable salts with indole derivatives of the above formula are inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, as well as organic acids such as acetic acid, tartaric acid,-citric acid, oxalic acid, fumaric acid and maleic acid.

The novel indole derivatives of the above formula (1) and their acid addition salts may according to the invention be prepared in one or more of the following manners:

a. Compounds of the general formula (I) in which X, Y, A, R, R and R are as defined in connection with formula (I) may be prepared by hydrogenolysis of the corresponding compounds of the general formula:

in which: each of the substituents X and Y is selected from the group consisting of hydrogen; benzyloxy; lower alkyl having 1-3 carbon atoms and'lower alkoxy having l-3 carbon atoms, A, R, R and R are as defined above, and R represents benzyl.

The particular compounds of the general formula (I) in which R represents benzyl may be prepared by partially hydrogenolysing the corresponding compounds of the general formula (11) in which R and R are benzyl. 5 The said hydrogenolysis is performed in a solvent, such as ethanol, in the presence of a suitable catalyst, e.g,, palladium on carbon, or

b, Compounds of the general formula (1) in which X, Y, A, R, R and R are as indicated in connection with formula (I), excluding, however, compounds in which R represents hydrogen, may be prepared by converting under suitable hydrogenolytic conditions indole derivatives of the general formula 11, in which,

X, Y, R, R and A are as defined in connection with formula (11), and each of R and R" is selected from the group consisting of hydrogen and benzyl,

in the presence of the particular aldehyde or ketone selected as a precursor, in a reductive alkylation process, of the substitutent R The reaction is performed in a solvent such as ethanol in the presence of hydrogen and a suitable catalyst such as palladium on carbon, or 1 c. Compounds of the general formula (1) in which X, Y and A, R, R and R are as defined in connection with formula (1), excluding, however, compounds in which R represents hydrogen, may be prepared by reacting in a suitable solvent, e.g., methanol or tetrahydrofuran, indole derivatives of the general formula:

in which X, Y, R, R and A-are as defined above with. the particular aldehyde or. ketone selected as a precursor, in a reductive alkylation process, of the substituent R followed by treatment of the reaction mixture with a suitable reductive agent, e.g., sodium borohydride, whereafter, if desired, the indole derivatives thus prepared may be converted into salts with physiologically acceptable acids. The acid additionsalts are prepared by reacting the base form of the indole derivatives with no less than one equivalent of the appropriate acid in an organic solvent such as ethanol or isopropanol. Such salts may advantageously be used for the purpose of isolating and/or purifying the compounds of this invention, and may be transformed in a manner known, per se, into the corresponding salts with other physiologically acceptable acids.

The present invention also provides processes analogous to those described and claimed in the said U.S.

pat. application Sen No. 39,863 for preparing the novel intermediary indole derivatives of the general formula (11) in which X, Y, A, R, R R and R are as defined in connection with formula (11) excluding, however, compounds in which R represents hydrogen.

The first step comprises condensing indoxyl derivatives of the general formula:

COCH

in which X, Y and R are as defined above, with compounds of the general formula:

acids exhibit valuable pharmacological properties and are thus of potential utility in human therapy, particularly as analgetic and antiinflammatory agents.

Thus, formula I indole derivatives have been found to hydrochloride 2 R 5 exhibit, in varying degrees, anti-inflammatory activity X A N 3 (V) when evaluated by various standard pharmacological 8 tests involving both oral and parenteral administration to animals. For example, in one such test pedal inflamin which A, R and R are as defined above, and X repmation was induced in rats by Carrageenin according resents a halogen atom or agroup functionally equiva- 10 to thfi {method of wlmher (it ill, lent therewith, thus producing a compound of the gen- E P 1 (1962) P- 544); and the era] formula: inflammatoryactivity was expressed in terms of per cent inhibition of pedal inflammation. Antl- L inflammatory values for a number of formula I indole O A I l5 derivatives administered orally are presented in Table 3 l. R Furthermore, indole derivatives of the present inven- 1 2 (VI) tion exhibit, in varying degrees, an additional analgetie Y N B effect. Many of the formula I indole compounds exhibit I both anti-inflammatory and analgetic activity and (,OCH3 therefore may be particularly suited for the treatment of inflammatory conditions accompanied by pain. in which X', Y, A, R R and R are as defined above. g i i i gs f g g g g i The reaction is performed in a suitable solvent, such as p 1 y e bmqns m i pharmacological tests performed in a variety of animal dimethylformamide or dimethylsulfoxlde 1n the presspecies. For example, the analgetlc activity was exam enee of an acid-binding agent such as potassium earmed after subcutaneous administration to mice in the bonate or sodium hydride. I

The intermediates of the general formula (II) in tail-clip test according to F. Haftner (Dcutsche Mcd. h R1 t h d d Wochenschrift, 55 (1929), p. 731). The analgctrc acrhepresen.s roggtn prepare g i g tivity, in terms of ED -values, of a number of formula S 6p T J .eace conipoun S 6 l indole derivatives, is presented in Table ll. genira I g m a g 9 vent Sue f as An overall evaluation of the data from the various :3 am) ano a; l lg agent pre standard animal tests using these novel indole derivaa y ammoma or l a a meta OX1 f; h I tives reflects a wide spectrum of anti-inflammatory ac For the preiparatlon mte rmedlates O t e genera tivity and/or analgetic activity and indicates that the fofmula p In whlch, R ls dlfffirem m hydrogen a compounds of this invention may have valuable and adthird step is added which comprises reacting the deacevantageous therapeutic properties as Compared m thc tylated Compou nds Produced the Second Step above anti-inflammatory agents and analgetic agents that are with an alkylatmg agent of the general formula: Widely used at he present mm X3 R5 40 However, for reasons of safety of administration, the preferred formula I indole derivatives are those which (Vll) exhibit anti-inflammatory activity and/or analgetic ac- I tivity when administered to mammals at a dosage level Whlch X3 15 halogen atom and l Selected from below that of the LD -value of that particular comthe group consisting of lower alkyl having 1-4 C-atoms pound. and y t All of the compounds in Table l exhibit very pro- The T636110" Performed a sultable Solvent Such nounced anti-inflammatory activity at dosage levels sigas dimethylformamide or toluene, in the presence of an ifi tl b l their LDwvaiuex acid binding agent, Such as Sodium y All of the compounds in Table ll exhibit very pro- The novel indole denvatlves of the gene1'al formula pounced analgetic activity at dosage levels significantly (l) as well as their salts with physiologically acceptable below h i LD 1 Table l Anti-inflammatory effect: Compound inhibition I00 mg/kg orally 3-(3-aminopropoxy)indole hydrochloride 48 3 (2-isopropylamin0ethoxy)indole hydrochloride 66 3-(2-n-propylaminoethoxy)indole hydrochloride 62 3-(2-aminoethoxy)-2-methylindole hydrochloride 39 3-(Z-aminoethoxy)-2-phenylindole 77 3-(2-isopropylaminoethoxy)-4-methoxyindole hydrochloride 34 3-(2-isopropylaminoethoxy)-2-phenylindole hydrochloride 79 l-benzyl-3-(2-isopropylaminoethoxyl-2-phenylindole hydrochloride 67 l-benzyl-3-(2-isopropylaminoethoxy)4-methoxy|ndole l hydrochloride 67 1-benzyl-3-(2-isopropylaminoethoxy)indole n Table l-Continued Anti-inflammatory effect:

Compound inhibition 100 mg/kg orally 3-(Z-aminoethoxy)-5-methylindole hydrogen oxalate l-n-butyl-3-(Z-isopropylaminoethoxy)indole hydrochloride 2-benzyl-3-(2-isopropylaminoethoxy)indole hydrochloride 3-(Z-cyelohexylaminoethoxy)-5-methoxyindole hydrochloride 52 3-(Z-ethylaminoethoxy)indole hydrochloride 3-(Z-isopropylaminoethoxy)-5-methoxyindole hydrochloride 50 mg/kg orally Table II Analgetic effect:

Haffners test mg/kg s.c.

Compound All formula I compounds exhibiting significant antiinflammatory activity also possess a measurable, but varying analgetic activity, whereas some formula 1 compounds possess analgetic activity, only.

The group of indole derivatives within the general formula I that exhibit only analgetic effects are those having the structure and the acid addition salts thereof with physiologically acceptable acids, in which R is lower alkyl having 4-7 carbon atoms, benzyl and 2-phenylethyl, and A is ethylene.

In addition, many of the compounds in Tables I and II exhibit high degrees of activity as to both effects.

When the compounds of the present invention are employed as therapeutic agents they may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar, certain types of clay and so forth. They may be administered sublingually in the form of troches or lozenges in which (VIlI) the active ingredient is mixed with sugar and corn syrups, flavoring agents and dyes; and then dehydrated sufficiently to be pressed into a solid form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents, or they may be injected parenterally,'that is intramuscularly, intravenously or subcutaneously. For parenteral administration, they may be used in the form of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the route of administration and the particular compound chosen. Furthermore, it will vary with the subject under treatment. In general, the compounds of this invention are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects and preferably at a dose level that is in the range of from 5 mg to about 2,000 mg per day, although, in individual cases, division as well as multiplication of doses may be necessary.

The preparation of the novel indole derivatives of the present invention is illustrated in detail in the following examples.

EXAMPLE I 3-(2-aminoethoxy)indole hydrogen oxalate 3-(2-dibenzylaminoethoxy)indole (35.7 g), dissolved in ethanol (400 ml of 99%) was hydrogenolyzed in the presence of palladium/carbon (10 g of l()%) at 5060 psi and 25C in the course of about l8 hours. The catalyst was filtered off and the filtrate was concentrated in vacuum. The residue, dissolved in ethanol (30 ml) was cautiously added to a solution of oxalic acid (27 g) in ethanol (125 ml). The resulting precipitate was recrystallized from aqueous ethanol (75%), yielding 3-(2-aminoethoxy)indole hydrogen oxalate (13.6 g, 51% yield)) with mp. 134136C. Anal. calcd. for C H O N C, 54.1%; H, 5.3%; N, 10.6%. Found:

C, 54.0%; H, 5.3%; N, 10.6%.

The intermediate, 3-(Z-dibenzylaminoethoxy)indole, was prepared in the following manner:

A mixture of l-acetylindoxyl (17.5 g), 2- dibenzylaminoethyl chloride hydrochloride (44.5 g) and potassium carbonate (62 g) in dimethylsulfoxide (DMSO, 200 ml) was left with stirring at 40C for 12 hours. The precipitate which formed after the addition of ice-water (1 L) was filtered off and recrystallized from ethanol. Alternatively, the precipitate was extracted with ethyl acetate (2 X 600 ml) followed by concentration of the ethyl acetate extract. The residue so obtained yielded after recrystallization from ethanol 1-acetyl-3-(2-dibenzy1aminoethoxy)indole (34 g, 85% yield) with mp. 105107C.

l-aeetyl-3-(2-dibenzylaminoethyoxy)indole (100 g) was treated for min. with a refluxing solution of sodium ethoxide, prepared from sodium (29 g), in ethanol (700 ml of 99%). The reaction mixture was cooled to 10-20C and water (1400 ml) was slowly added. The solid material so obtained was recrystallized from a mixture of benzene 100 ml) and isooctane (200 ml), yielding 3-(2-dibenzylaminoethoxy)indole (58 g, 65% yield) with mp. 7576C.

EXAMPLE 2 3-(2-aminoethoxy)-5-methoxyindole 3-(2 dibenzylaminoethoxy-S-methoxyindo1e (108 g) was hydrogenolyzed by a procedure analogous to that described in Example 1. The reaction mixture, freed from the catalyst, was concentrated in vacuum and the crude 3-(2-aminoethoxy)-5-methoxyindole was recrystallized from toluene (150 ml). The pure compound (40.6 g, 72% yield) had the mp. 103-104C. Anal. calcd. for C H O N C, 64.1%; H, 6.8%; O, 15.5%; N, 13.6%. Found:

C, 63.8%; H, 6.9%; O, 15.7%; N, 13.8%.

The starting material, 3-(Z-dibenzylaminoethoxy)-5- methoxyindole was prepared in the following manner:

A mixture of 1-aeetyl-5-methoxyindoxyl (75 g), 2- dibenzylaminoethyl chloride hydrochloride (163 g) and potassium carbonate (228 g) in DMSO (730 ml) was kept with stirring for 6 hours at 40C. The reaction mixture was treated with icewater (4 L) and the resulting suspension was extracted with ethyl acetate (3 X 400 ml). The ethyl acetate extract was dried and concentrated in vacuum. Recrystallization of the residue from ethanol gave 1-acetyl-3-(2-dibenzylaminoethoxy)-5-methoxyindole (122 g, 78% yield) with mp. 8283C. This compound was deacetylated in the manner described in Example 1. The product, 3-(2- dibenzylaminoethoxy)-5-methoxyindole, was isolated as an oil.

EXAMPLE 3 3-(2-aminoethoxy)-5-hydroxyindole hydrogen oxalate.

starting 5-benzyloxy-3-(2-dibenzylaminoethoxy)indolc was subjected to hydrogenolysis and worked up in the manner described in Example 1, thus affording 3-(2- aminoethoxy)-5-hydroxyindole hydrogen oxalate with mp. l65-166C in 50% yield.

The starting material, 5-benzyloxy-3-( 2- dibenzylaminoethoxy)indole, was synthesized by aminoalkylation of 1-acetyl-5-benzyl-oxyindoxyl in a procedure analogous to that described in Example 1 and deacetylation of the product was effected as indicated in the same example. 5-benzyloxy-3-(2-dibenzylaminoethoxy)indole with mp. 8788C crystallized direct from the reaction mixture without addition of water. The overall yield, based on 1-acctyl-5-bcnzyloxyindoxyl, was 68.5%.

EXAMPLE 4 3-(2-aminoethoxy)-5-methy1indole hydrogen oxalate In a procedure analogous to that of Example 1, but

from 3-(Z-dibenzylaminoethoxy)-5- methylindole, 3-(2-aminoethoxy)-5-methylindole hydrogen oxalate with mp. 139140C was obtained in 35% yield. The crystalline salt contains water of hydration which is retained tenaciously, even after drying in vacuum.

The intermediate, 3-(2dibenzylaminoethoxy)-5- methylindole was prepared in the following manner:

l-acetyl-S-methylindoxyl was aminoalkylated by the procedure described in Example 2, yielding 1-acetyl-3- (2-dibenzylaminoethoxy)-5-methylindole with mp. 104-105C in 68% yield.

1-acetyl-3-(2-dibenzylaminoe'thoxy))-5- methylindole (32 g), dissolved in methanol (350 ml) saturated with ammonia was heated in an autoclave to 60C for 6 hours. The reaction mixture was cooled and concentrated in vacuum, leaving a residue which after recrystallization from a mixture of benzene (60 ml) and isooctane (250 ml) afforded 3-(2-dibenzylaminocthoxy)-5-methylindole with mp. 57-58C. The yield was 50%.

EXAMPLE 5 3-(3-aminopropoxy)indole hydrochloride A solution of 3-(3-dibenzylaminopropoxy)indole hydrochloride in ethanol was subjected to hydrogenolysis in a manner similar to that of Example 1. The product, 3-(3-aminopropoxy)indole hydrochloride, with mp. 176-l78C was obtained in 41% yield.

3-(3-dibenzylaminopropoxy)indole hydrochloride was synthesized by the following procedure:

A mixture of l-acetylindoxyl (35 g), 3- dibenzylaminopropyl chloride hydrochloride (68.2 g) and potassium carbonate (91 g) in DMSO (400 ml) was left with stirring at 60C for 24 hours. The reaction mixture was treated with ice-water (1.5 L) and the aqueous suspension was extracted with ethyl acetate (3 X 500 ml). The ethyl acetate extract was dried and freed of solvent. Recrystallization from ethanol yielded 1-acetyl-3-(3-dibenzy1aminopropoxy)indole (34.5 g, 42% yield).with mp. 99l00C.

Sodium (12.8 g) was dissolved in ethanol (290 ml of 99%) and 1-acetyl-3-(3-dibenzylaminopropoxy)indolc (46 g) was added. The mixture was refluxed for 30 minutes, cooled to about 25C and subsequently treated with ice-water (1.7 L). The resulting emulsion was extracted with ethyl acetate (3 X 200 ml). Addition of a solution of hydrogen chloride in ethanol to the dried ethyl acetate phase afforded a crystalline precipitate of 3-(3-dibenzylaminopropoxy)indole hydrochloride (42.5 g, 93.5% yield) with mp. 180-181C.

EXAMPLE 6 3(2-methylaminoethoxy)indole hydrochloride 3-(2-(N-benzyl-N-methylamino)ethoxy)indole (10 g), dissolved in ethanol (150 ml of 99%) was hydrogenated in the presence of palladium/carbon (2 g of 10%) at 50-60 psi and 25C for 10-18 hours. After removal of the catalyst, the solution was concentrated in vacuum and the residue was dissolved in isopropanol (30 ml). Addition of a solution of hydrogen chloride in isopropanol at O5C converted the base into a crystalline hydrochloride. Recrystallization from isopropanol afforded 3-(Z-methylaminoethoxy)indole hydrochloride (4.7 g, 70% yield) with mp. 140141C.

Anal. calcd. for C H ON Clz C, 58.3%; H, 6.7%; O, 7.1%; N, 12.4%; C1, 15.6% Found:

C, 58.0%; H, 7.0%; O, 7.3%; N, 12.4%; C1, 15.5%;

3-(2-(N-benzyl-N-methylamino)ethoxy)indole is prepared by the method described below:

A mixture of l-acetylindoxyl (17.5 g), Z-(N-benzyl- N-methylamino)ethyl chloride hydrochloride (33 g) and potassium carbonate (62 g) was refluxed for 48 hours in ethyl acetate (500 ml) containing water (5 ml). After chilling, the reaction mixture was filtered and the filtrate was concentrated. The residue so obtained was recrystallized from isopropanol, affording 1-acetyl-3-(2-(N-benzyl-N- methylamino)ethoxy)indole (22 g, 68% yield) with mp. 7274C.

l-acetyl-3-(Z-(N-benzyl-N- methylamino)ethoxy)indole was deacetylated according to the procedure described in Example 4. The product, 3-(2-(N-benzyl-N-methylamino)ethoxy)indole, was isolated as an oil.

EXAMPLE 7 3-(2-benzylaminoethoxy)indole hydrochloride 3-(2-dibenzylaminoethoxy)indole (7.1 g, 20 mmol) EXAMPLE 8 3-(2-isopropylaminoethoxy)indole hydrochloride 3-(Z-dibenzylaminoethoxy)indole (7.1 g), dissolved in a mixture of ethanol (75 ml of 99%) and acetone (25 ml) was hydrogenated in the presence of palladium/- carbon (2 g of 10%) at -60 psi and 25C for 18 hours. The catalyst was filtered off and the filtrate was concentrated in vacuum. The resulting residue was dissolved in isopropanol (30 ml) and converted at 0-5C into the crystalline 3-(2-isopropylaminoethoxy)indole hydrochloride (3.45 g) with mp. 160-163C. Recrystallization from ethanol (yield: 2.1 g, 45%) raised the mp. to l83-185C. Anal. calcd. for C 3H 9ON2C]:

C, 61.3%; H, 7.5%; N, 11.0%; C1, 13.9% Found:

C, 61.3%; H, 7.8%; N, 11.0%; C], 13.9%

EXAMPLE 9 3-(2-cyclohexylaminoethoxy)indole hydrochloride By the same procedure as that of Example 8, but substituting cyclohexanone for acetone, 3-( 2 cyclohexylaminoethoxy)indole hydrochloride with mp. 225227C was obtained in 42% yield.

EXAMPLE l0 EXAMPLE ll 3-(2-n-butylaminoethoxy)-5-methoxyindole chloride 3-(2-aminoethoxy)-5-methoxyindole (5.15g) was dissolved in dry methanol (50 ml), a solution of n butyraldehyde (2.1 g) in dry methanol (10 ml) was added at 05C and the mixture was left at that temperature for 30 minutes. Reductive alkylation was performed in the presence of palladium/carbon (l of 10%) and hydrogen (50-60 psi) at 25C for 2 hours. The reaction mixture was worked up described in previous examples and yielded 3-(2-n-butylaminoethoxy)indole hydrochloride (3.8 g) with mp. 18919 OC. Recrystallization from ethanol (yield: 2.9 g, 39%) raised the mp. to l93l94C. Anal. calcd. for C, H O N Cl:

C, 60.3%; H, 7.8%; N, 9.4%;-Cl, 11.9% Found:

C, 60.3%; H, 8.0%; N, 9.5%; Cl, 11.7%

EXAMPLE l2 3-(2-isopropylaminoethoxy)indole hydrochloride In a manner similar to that described in Example 10, 3-(2-isopropylaminoethoxy)indole hydrochloride with mp. 174l75C was obtained in 43% yield.

EXAMPLE 13 3-(2-cyclohexylaminoethoxy)-5-methoxyindole hydrochloride By an analogous procedure 3-(2- cyclohexylaminoethoxy)-5-methoxyindole hydrochlo ride with mp. l92-193C was obtained in 65% yield.

EXAMPLE 14 3-( 2-aminopropoxy )indole hydrochloride hydro- To a solution of sodium (11 g) in ethanol (260 ml of 99%) was added 1-acetyl-3-(2-dibenzylaminopropoxy)indole (39 g). The mixture was refluxed for 30 minutes, cooled to about 25C and subsequently treated 5C into the crystalline 3-(2-( l-methylbutyl)aminoethoxy) indole hydrochloride (3.5 g) with mp. 189l92C. Recrystallization from isopropanol (yield: 2.9 g, 51%) raised the mp. to 197l98C.

with ice-water (2.0 L). The resulting emulsion was ex- An l, l d f C H ON Cl; tracted with ethyl acetate (3 X 330 ml) and the dried C, 63.7%; H, 8.2%; O, 5.7%; N, 9.9%; Cl, 12.5% ethyl acetate extract was concentrated in vacuum. The Found: residue, 3-(2-dibenzylaminopropoxy)indole, dissolved C, 63.6%; H, 8.3%; O, 5.8%; N, 9.9%; Cl, 12.6% in ethanol (350 ml of 99%) was h dro enated in the presence of palladium/carbon (6 g of 1 O%) at 50-60 EXAMPLE 16 psi and 25C for 18 hours. After removal of the cata- 3-(2-n-butylaminoethoxy)indole hydrochloride. lyst, the solution was concentrated in vacuum and the In an analogous procedure, 3-(2-n-butylaminoethoxresidue was dissolved in isopropanol (120 ml). Addiy)in hy r h ri wi h mp. l7 l7 was pr tion of a solution of hydrogen chloride in isopropanol pared in 10% yield. at 05C converted the base into a crystalline hydrol5 chloride. Recrystallization from isopropanol afforded EXAMPLE l7 3-(2-aminopropoxy)indole hydrochloride. The overall -p y y )ifldolc hydrochlorideyield of 3-(2-aminopropoxy)indole hydrochloride with 3-(2-aminoerhoxyfindole yd o oxaliltC was mp 95 96(j was 6()% dissolved in methanol (200 ml) at 60C and a solution l 1 fo CHHISONzC]; 20 of sodium hydroxide (2.64 g) in methanol (50 ml) was C 583 7 61%; O 7 1%; N, 12 4%; 1 155% added.The mixture was allowed to stand at 25C for Found minutes and the precipitated sodium oxalate was fil- C, 5 0%; H, 9%; O, 72%; N Cl 151% tered off. To the filtrate was added n-valcraldehyde To prepare the starting material, a mixture of 1-acet- (258 in methanol l at 004C in course ylindoxyl 49 g), 1 dibenzylamino 2 oh1oroprooano of 15 mlnutes. The reaction mixture was kept at 0-5C d hl id (130 g) and potassium Carbonate 74 g) for minutes and then subjected to hydrogenation in in dimethylsulfoxide (DMSO) (560 ml) was left with the Presence Of Palladium/Carbon g of at stirring at C for 12 hours. The reaction mixture was -60 P and for The fy W118 treated with ioowator (2,500 m]) and the resulting tered off and the filtrate concentrated ln vacuum. The omu|sion extracted with chloroform (3 X 250 The 30 resulting crystalline residue was partitioned between dried chloroform extract was concentrated in vacuum, ethyl acetate (400 ml) and will (2 X and h i a residue which at room temperature was ethyl acetate phase was dried and concentrated in vacl d i a mixture of ethanol 4 parts) and isopropa; uum. The residue was dissolved in isopropanol 160 t 1 part) From this Solution Chilled to 0 5 ml), and addition of a solution of hydrogen chloride in acetyl-3-(2-dibenzylaminopropoxy)indole (39 g, 34%) 35 lsopropanol at i followed y cofflmg with mp. l1l-ll2C, crystallized, forded 3-(2-n-pentylammoethoxy) lndole hydrochloride (4.9 g) with mp. l-l6lC.

Recrystallization from ethanol (recovery: 4.1 g, 48% EXAMPLE 5 yield) raised the mp. to l166C. 3-(2-(1-methylbutyl)aminoethoxy)indole hydrochlo- 40 Anal- Caicdfor 15 23 2 i C, 63.7%; H, 8.2%; O, 5.9%; N, 9.9%; Cl, 12.5%

3-(Z-dibenzylaminoethoxy)indole (7.1 g), dissolved FOlmdl in a mixture of ethanol ml of 99%) and methyl n- 36%; H, N, propy] ketone (8 6 was h d d i h pres- In a similar manner, by substituting the appropriate ence f ll di b (2 g f 10%) t 50-60 i 45 aldehyde for n-valeraldehyde, the following comand 25C for 18 hours. The catalyst was filtered off and p nd of the gen r l f rm la 1. in which X. Y. R and the filtrate was concentrated in vacuum. The residue, R2 are hydrogen, and A is an ethylene group. were pre dissolved in isopropanol (20 ml), was converted at pared:

Example 5 Melting Time for No. R Salt; Yield Point hydroge:

' c nation (hours) 18 CH (CH HCl 40% -171 2 CH 19 clicli HCl 45% 189-190 2 l 2o C H CH CH H01 51% 162-163 2 21 CH CH CH llCl 22% 198-4 99 2 22 CH (CH l-lCl 50% 162-163 2 Continued Example 5 Melting Time for No, R Salt Yield Point hydroge:

nation (hours) ea" 3\ 23 CHCH CH HCl 55% 181-182 2 CH CH 3 2 2 1 CHCH HCl 45% 1611 .1 65 8 CH CH 25 CH CH Cl-l C IHCH (COOii) 5 1% 180-181 l CH 26 (CH CCH (00010 19% 177-178 6 27 CH (C1-1 HCl 154-155 2 2 CH CH HCl 38% 174-175 I 2 a) This compound was purified by recrystallization from iso:

propanol before converting it to the hydrochloride.

EXAMPLE 29 solution, chilled to 05C, crystallized 5,6-dimethoxy-3-(2-isopropylaminoethoxy)indole hydrochloride 1-acetyl-3-(2-dibenzylaminoethoxy)-5,6- v dimethoxyindole was deacetylated by a procedure analogous to that of Example 1. 3-(2- dibenzy1aminoethoxy)-5,6-dimethoxyindole, isolated as an oil was converted to 5,6-dimethoxy-3-(2- isopropylaminoethoxy) indole hydrochloride with. mp. 197-198C by the method described in Example 15. Hydrogenation was complete in 7 hours and the overall yield was 15%.

The starting material, 1-acetyl-3-( 2- dibenzylaminoethoxy)-5,6-dimethoxyindo1e, was prepared in the following manner:

6-bromoveratric acid (127 g), prepared by treated veratic acid with bromine in acetic acid, and glycine (71 g) was dissolved in water (725 m1) at 40C and pH 10. The reaction was initiated by addition of copper powder (3.5 g). The pH was maintained at 10 by addition of a sodium hydroxide solution (6N) and the reaction temperature was kept at 40C by cooling. After 30 minutes the reaction ceased. The reaction mixture, freed of copper powder, was added to chilled hydrochloric acid (1,000 ml of 2 N), yielding N (carboxymethyl)-4,S-dimethoxy-anthranilic acid (114.6 g, 86%) with mp. l81182C.

To a mixture of N-(carboxymethyl)-4,5-dimethoxyanthranilic acid (49 g)) in acetic anhydride (300 ml) was added tri-ethylamine (84 ml) with cooling The solution so obtained was kept at C for 1 hour and then refluxed for minutes. The reaction mixture was cooled and concentrated in vacuum, leaving a residue which on treatment with ice-water (900 ml) afforded 1,3-diacetyl-5,6-dimethoxyindoxyl. This compound was dissolved in a refluxing solution of sodium sulfite (60 g) in water (1,000 mi) and ethanol (500 m1), and the solution was kept at reflux for 1 /2 hours. The ethanol was distilled off and from the remaining aqueous l-acetyl-5,6-dimethoxyindoxyl (26.4 g. 59% yield) with mp. 238242C. Y v

To a solution ofl-acetyl-S,o-dimethoxyindoxyl (44.7 g) and Z-dibenzylamihoethyl. chloride hydrochloride (84.3 g) in DMSO (1000 'ml) was cautiously added potassium carbonate (117 g). The mixture was left with stirring for 9 hours at 60C and for another 9 hours at room temperature, followed by treatment with icewater (5,000 ml). The resulting suspension was extracted with chlorform (2 X 1000 ml) and the chl0roform extract was dried and concentrated in vacuum, leaving a residue which upon recrystallization from ethanol (275 ml) yielded 1-acety|3-( 2- dibenzylaminoethoxy)5,6-dimethoxyindole (45.5 g, 52.3%) with mp. 113115C.

EXAMPLE 30 minutes with a refluxing solution of sodium (6.) g) inethanol (325 ml of 99%). The reaction mixture was chilled and added to ice-water (1,500 ml). The resulting suspension was extracted with ethyl acetate (3 X 500. ml) and the extract was dried and concentrated in vacuum. The residue, containing 3-(2-(N-bcnzyl-N-nbutylaminoethoxy)indole was dissolved in ethanol (300 ml of 99%), treated with charcoal (5 g) and subjected to hydrogenolysis in the presence of palladium/carbon (2 g of 10%) for 2 hours at 25C and 50-60 psi. The catalyst was filtered off and the filtrate concentrated in vacuum. To the residue, dissolved in isopropanol 175 ml) was added hydrogen chloride in isopropanol at 35C. After chilling to 05C, 3-(2n-butylamin.oethoxy)indole hydrochloride (12.4 g, 20?! overall yield) with mp. -171C was obtained.

The intermediate, 1-acetyl-3-(2(N-bcnzyl-N-nbutylamino-ethoxy)indole (mp. 44-45C) was prepared in 36% yield by a procedure analogous to that described in Example 2.

EXAMPLE 31 3-(2-isopropylaminoethoxy)indole hydrochloride A procedure analogous to that of the previous example was used for the preparation of 3-(2- isopropylaminoethoxy)-indole hydrochloride with mp. 188189C. The overall yield was 71%. The starting material, 1-acetyl-3-( 2-(N-benzyl-N-isopropylamino)ethoxy)indole, was synthesized in the following manner:

l-acetylindoxyl (40.3 g), Z-(N-benzyl-N- isopropylamino)-ethyl chloride hydrochloride (63.0 g) and potassium carbonate (95.3 g) was mixed with DMSO (350 ml). The reaction mixture was kept with stirring at 40C for 18 hours and slowly added to icewater (1.4 L), thus affording the crystalline l-acetyl-3- (2-(N-benzyl-N-isopropylamino)ethoxy)indole (64.7 g) with mp. 5972C. Recrystallization from isopropanol (yield: 49.6 g, 62 raised the mp. to 8385C.

EXAMPLE 32 3-(2-isopropylaminopropoxy)indole hydrochloride In a manner analogous to that described in Example 17, 3-(2-isopropylaminopropoxy)indole hydrochloride with mp. 225226C was prepared in 47% yield.

EXAMPLE 33 3-(2-aminoethoxy)-2-methylindole hydrochloride 1-acetyl-3-(Z-dibenzylaminoethoxy)-2- methy1indole( 10.6 g) was treated with a refluxing solution of sodium ethoxide, prepared from metallic sodium (2.9 g), inethanol 150 ml of 99%). After cooling to room temperature and addition of ice-water (750 ml) the reaction mixture was extracted with ethyl acetate (2 X 250 ml); extract was dried and concentrated in vacuum.

The residue, consisting of 3-(2-dibenzylaminoethoxy)-2-methylindole, was dissolved in ethanol (100 ml of 99%) and subjected to hydrogenolysis in the presence of palladium/carbon (2 g of 10% at 25C and 50-60 psi for 24 hours. The product, freed of catalyst and solvent, was dissolved in isopropanol (40 ml). Addition at O-5C of a solution of hydrogen chloride in isopropanol, followed by ether (200 ml) afforded the crystalline 3-(2-aminoethoxy)-2-methylindole hydrochloride (3.5 g) with mp. 170-175C. Recrystallization from isopropanol gave the pure compound (2 g, 35% yield) with mp. 183184C.

Anal. calcd. for C H ON CI:

C, 58,3%; H, 6.7%; N, 12.4%; C1, 15.6%

Found:

C, 58.2%; H, 6.9%; N, 12.2%; C1, 15.6%

The intermediate, 1-acetyl-3-(2- dibenzylaminoethoxy)-2-methylindole was prepared in the following manner:

A mixture of 1-acetyl-2-methylindoxyl (37.6 g), 2- (dibenzylamino)ethyl chloride hydrochloride (88.2 g) and finely ground potassium carbonate (124.4 g) in DMSO (400 ml) was kept with stirring at 45C for 24 hours. The reaction mixture was added to ice-water (2 L) and extracted with ethyl acetate (3 X 500 ml). The extract was dried and concentrated in vacuum. When a solution of the residue in isopropanol (150 ml) was chilled slowly to 5C, a crystalline precipitate of 1- acetyl-3-(Z-dibenzylaminoethoxy)-2-methylindole (24 g, 29% yield) with mp. 7880C was obtained. Recrystallization from isopropanol raised the mp. to 8283C.

EXAMPLE 34 3-(2-isobutylaminoethoxy)-2-methylindole hydrochloride To a solution in methanol ml) of crude 3-(2- aminoethoxy)-2-methyl indole, prepared from l-acetyl- 3-(Z-dibenzylaminoethoxy)-2-methylindole (12.3 g) as described in Example 33, was added a solution of isobutyraldehyde (2.16 g) in methanol (20 ml) and the mixture was kept at 05C for 30 minutes. Palladium/- carbon (1 g of 10%) was added and the reaction mixture was hydrogenated at 25C and 50-60 psi for 2 hours. Filtration from the catalyst, followed by evaporation in vacuum of the solvent left a residue which was dissolved in isopropanol (80 ml). Addition at 05C of a solution of hydrogen chloride in isopropanol gave the crystalline 3-(2-isobutylaminoethoxy)-2-methylindolc hydrochloride (4.1 g) with mp. 165C. The pure compound with mp. 1681'69C (3.5 g, 40% yield) was obtained by recrystallization from isopropanolv Anal. calcd. for C H ON Cl:

C, 63.7%; H, 8.2%; N, 9.9%; Cl, 12.5% Found:

C, 63.0%; H, 8.2%; N, 9.8%;C1, 13.0%

EXAM PLE 35 3-( 2-aminoethoxy)-2phenylindole 3-(2-dibenzylaminoethoxy)-2-pheny1indole (10 g),

dissolved in a mixture of ethanol (200 ml) and toluene (200 ml) was subjected to hydrogenolysis in'the presence of palladium/carbon (3 g of 10%)at 25C and 'in vacuum of the solvent left a residue of 3-(2- aminoethoxy)-2-phenylindole which was purified by recrystallization from toluene. The recrystallized product (2.8 g, 48% yield) had mp. 114-115C. Anal. calcd. for C, H, ON

C, 76.2%; H, 6.4%; N, 11.1%

C, 75.8% H, 6.7%; N, 10.9%

The intermediate. 3-(2-dibenzylaminoethoxy)-2- phenylindole, was prepared in the following manner:

A mixture of l-acetyl-Z-phenylindoxyl (50 g), 2- dibenzylaminoethyl chloride hydrochloride (88.5 g) and finely ground potassium carbonate (124.4 g) in DMSO (400 ml) was left with vigorous stirring at 60C for 5 hours. The reaction mixture was added to icewater (2L) and extracted with ethyl acetate (3 X 500 ml). The extract was dried and concentrated in vacuum. The residue so obtained, consisting of 1-acetyl-3- (2-dibenzylaminoethoxy)-2-phenylindole, was treated for 15 minutes with a refluxing solution of sodium ethoxide, prepared from metallic sodium (23 g), in ethanol (1 L of 99%).

When the reaction mixture was left at 05C the crystalline 3-(2-dibenzylaminoethoxy)-2-phenylindole (57 g, 71% yield) with mp. 147I49C was obtained.

EXAMPLE 36 3-(2-isobutylaminoethoxy)-2-phenylindole hydrochloride To a solution of crude 3-'(2-aminoethoxy)-2- phenylindole, prepared from 3-( 2- dibenzylaminoethoxy)-2-phenylindole (10 g) as described in Example 35, in anhydrous. methanol (150 ml) was added in the course of 15 minutes at 0-5C a solution of isobutyraldehyde (1.66 g) in methanol (20 ml) and the mixture was kept at -5C for 30 minutes. The reaction mixture was then hydrogenated for 2 hours at room temperature and 5060 psi in the presence of palladium/carbon (l g of 10%). Filtration from the catalyst, followed by evaporation in vacuum of the solvent left a residue which was dissolved in isopropanol (140 ml). Addition at 05C ofa solution of hydrogen chloride in isopropanol yielded 3-(2- isobutylaminoethoxy)-2-phenylindole hydrochloride (3.7 g) with mp. 233-235C. Recrystallization from ethanol (yield: 3.1 g, 44%) raised the mp. to 236238C. Anal. calcd. for C H ON Cl:

C, 69.6%; H, 7.3%; N, 8.1%; Cl, 10.3% Found:

C, 69.2% H, 7.5%; N, 8.1%; Cl, 10.6%

EXAMPLE 37 3-(2-aminoethoxy)-6-methoxyindole 3-(2-dibenzylaminoethoxy)-6-methoxyindole'(15 g), dissolved in ethanol (350 ml of 99%),was subjected to hydrogenolysis in the presence of palladium/carbon (5g of at 25C and 50-60 psi for 7 hours.

Filtration from the catalyst, followed by evaporation in vacuum of the solvent left a crystalline residue (7g) containing 3-(Z-aminoethoxy)-6-methoxyindole. A fraction (2 g) of this residue, recrystallized from isopropanol, yielded the pure compound (0.6 g, 26%) with mp. 129132C. The remainder (5 g) was used in the following Example 38. Anal. Calcd. for C111! u Qg Ngi C, 64.1%; H, 6.7%; N, 13.6% Found:

The starting material, 3-(Z-dibenzylaminoethoxy)-6- methoxyindole, was prepared in the following manner:

A mixture of l-acetyl-6-methoxyindoxyl (28.7 g), 2- dibenzylaminoethyl chloride hydrochloride (62.0 g) and finely ground potassium carbonate (87.0 'g) in DMSO (275 ml) was stirred vigorously at 40C for 18 hours. The reaction mixture was added to ice-water (1,250 ml) and extracted with ethyl acetate (4 X 300 ml). The extract was dried and the solvent was evaporated in vacuum, leaving a residue which was recrystallized from a mixture of ethanol (150 ml) and ethyl acetate (50 ml). The compound 1-acetyl-3-(2- dibenzylaminoethoxy)6-methoxyindole with mp. 9697C (21 g, 35% yield) so obtained was dissolved in ethanol (275 ml of 99%) containing sodium ethoxide prepared in situ from metallic sodium (5.5 g). Refluxing the solution for minutes followed by chilling to 05C yielded the crystalline 3-(2- dibenzylaminoethyl)-6-methoxyindole (16.5 g, 87%) with mp. 83-84C.

EXAMPLE 38 3-(2-isobutylaminoethoxy)-6-methoxyindole hydrogen oxalate The crude 3-(2-aminoethoxy)-6-methoxyindole (5 g), prepared in Example 37 above, was subjected to a reductive alkylation with isobutyraldehyde in a manner analogous to that described in Example 36, followed by filtration and evaporation of the solvent. A chilled solution of the residue in ethanol (90 ml of 99%) was added at 05C in the course of minutes to a solution of oxalic acid (6.3 g) in ethanol (50 ml) and the mixture was left for 30 minutes at the same temperature. The crystalline 3-(2-isobutylaminoethoxy)-6- methoxyindole hydrogen oxalate was isolated and recrystallized from aqueous ethanol The pure' compound (2.7 g, 32%) has mp. -161C. Anal. calcd. for C H O N C, 57.9%; H, 6.9%; N, 10.0% Found:

C, 56.9%; H, 6.7%; N, 7.8%

EXAMPLE 39 3-(2-aminoethoxy)-4-methoxyindole 3-(2-dibenzylaminoethoxy)-4-methoxyindole (17 g), dissolved in ethanol (550 ml of 99%) was hydrogenolysed in the presence of palladium/carbon (5 g of 10%) at 25C and 50-60 psi in the course of 26 hours. Filtration from the catalyst, followed by evaporation in vacuum of the solvent left a residue (9.2 g). One half of this residue was recrystallized from isopropanol. yielding 3-(2-aminoethoxy)-4-methoxyindole (275g, 55% yield) with mp. 146l 50C. The other half of the residue was used in the following Example 40. Anal. calcd. for C H N O C, 64.1%; H, 6.9%; N, 13.6% Found:

C, 64.3%; H, 7.0%; N, 13.5%

The intermediate, methoxyindole, was prepared-in the following manner:

To a solution of 6-methoxyanthranilic acid (46.5 g) and sodium hydroxide (23.6 g) in water (100 ml) was added a solution of chloracetic acid (26.5 g) and sodium carbonate (18 g) in water (50 ml). After heating to 50C for 6 hours, a solution ofchloracetic acid (13.2 g), sodium hydroxide (6 g) and sodium carbonate (8.5

g) in water (25 ml) was added and heating was continued. The same addition was repeated after 12 hours, the reaction mixture was left at 50C for further 10 hours, cooled and added slowly and with vigorous stirring to hydrochloric acid (275 ml of 4 N). N- carboxymethyl-6methoxyanthranilic acid (36.1 g, 57%) with mp. -186C was isolated.-

Triethylamine (52.5 ml) was added at room temperature to a solution of Ncarboxymethyl-6- methoxyanthranilic acid (31.5 g) in acetic anhydride ml). The reaction mixture was kept at 25C for 1 hour and then heated to reflux temperature for an additional period of 30 minutes, followed by evaporation of the solvent. After treatment of the residue with icewater (750 ml), the crystalline 1,3-diacetyl-4- methoxyindoxyl (31.1 g) with mp. l45148C was obtained.

A solution of 1,3-diacetyl-4-methoxyindoxyl (31.1 g) in ethanol (800 ml of 96%) was added to a solution of sodium sulfite (44 g) in water (800 ml) at 50C and the reaction mixture was kept at that temperature for 2 hours. Ethanol was stripped off and, after cooling, l-acetyl-4-methoxyindoxyl with mp. 145l46C 18.5 g, 65% yield) was obtained from the remaining aqueous solution.

A mixture of l acetyl-4-methoxyindoxyl (13.1 g), 2- dibenzyl aminoethyl chloride hydrochloride (26.6 g) and potassium carbonate (33.2 g) in DMSO (125 ml) was stirred vigorously at 40C for 18 hours. lee-water (800 ml) was added and the mixture was extracted with ethyl acetate (3 X 200 ml). The reaction product was worked up in the usual manner and recrystallized from isopropanol, yielding 1 -acetyl-3-( 2- 3-( 2-dibenzylaminoeth0Xy)-4- dibenzylaminoethoxy)-4-methoxyindole (15 g, 58%

' yield) with mp. 125126C.

EXAMPLE 40 3-(2-isobutylaminoethoxy)-4-methoxyindole hydrogen oxalate To a solution in methanol (100 ml) of the crude 3-(2 aminoethoxy)-4-methoxyindole (4.6 g), prepared in Example 39 above, was added isobutyraldehyde (3.2 g) and a molecular sieve g of type 3A) and the reaction mixture was left at 25C with stirring for 2 hours.

Sodium borohydride (1.7 g) was added portionwise in the course of 10 minutes and after additional 1 hour at 25C the molecular sieve was filtered off, and the solvent evaporated in vacuum. The residue was partitioned between water (2 X 150 ml) and ethyl acetate (200 ml), the ethyl acetate phase was dried and concentrated in vacuum.

A solution of the residue in ethanol (25 ml of 99%) was added at 25C to a solution of oxalic acid (6.0 g) in ethanol (50 ml of 99%). Chilling of the suspension to 05 C yielded the crystalline 3-( 2- isobutylaminoethoxy)-4-methoxyindole hydrogen oxalate (3.9 g). Recrystallization from aqueous ethanol (80%) yielded the pure compound (2.9 g, 51% yield) with mp. ll52C.

Anal. calcd. for C17H24N2O6, H20:

C, 55.1%; H, 7.1%; N, 7.6% Found:

C, 55.4%; H, 7.2%; N, 7.8%

EXAMPLE 41 3-(2-isopropylaminoethoxy)-4-methoxyindole chloride In a manner analogous to that described in Example 8, 3-(2-isopropylaminoethoxy)-4-methoxyindole hydrochloride with mp. 216-218C was obtained in 477 yield.

hydro- EXAMPLE 42 EXAMPLE 43 3-(2-ethylaminoethoxy)-2-pheny1indole hydrochloride Starting from l-acetyl-2-pheny1indole, 3-(2- ethylaminoethoxy)-2-phenylindo1e hydrochloride with mp. 257-259C was prepared using procedures analogous to those described in example 31. In this example debenzylation was complete after 24 hours and the catalyst had to be exchanged after 8 hours. The overall yeild was 35%.

EXAMPLE 44 3-(2-isopropylaminoethoxy)-2-pheny1indole chloride 3-(2-dibenzylaminoethoxy)-2-phcnylindole was converted to 3-(2-isopropylaminoethoxy)-2-phenylindole hydrochloride with mp. 207-208C by the method described in Example 8. The reaction was performed in toluene instead of ethanol. The yield was 45%.

EXAMPLE 45 3-(2-aminoethoxy)-2-benzylindole 2-benzyl-3-(Z-dibenzylaminoethoxy)indole (4.66 g), dissolvedin a mixture of toluene (50 ml) and ethanol (50 ml) was hydrogenolyzed in the presence of palladium/carbon (3 g of 10%) at 50-60 psi and 25C in the course of about 60 hours. The. catalyst was filtered off and the filtrate concentrated in vacuum. The residue was recrystallized from a 1:1 mixture of isooctane and ethyl acetate, affording 3-(2-aminoethoxy)-2- benzylindole (0.80 g, 29% yield) with mp. 1l31 14C. Anal. calcd. for C H N O:

C, 76.7%; H, 6.8%; N, 10.5%

Found:

C, 76.3%; H, 6.6%; N, 10.4% The starting material, 2-benzyl-3-(2- dibenzylaminoethoxy) indole, was prepared in the following manner:

o-chlorobenzoic acid (156.6 g) and phenylalanine (289 g) were heated to reflux in water 1.5 L) at pH 9. Cuprous oxide (4 g) was added, and the pH was maintained at pH 9 by addition of a sodium hydroxide solution (6 N) while the reaction mixture was kept under reflux for 8 hours. After 3 hours a further portion of cuprous oxide (4 g) was added. The reaction mixture, freed ofinsoluble salts, was added to chilled hydrochlo ric acid (800 m1 of 6 N), yielding N-(1-carboxy-2- phenylethy1)anthranilic acid (204 g, 72%) with mp. 140C.

To a mixture of N-( 1-carboxy-2-phenylethyl)anthranilic acid (173 g) and acetic anhydride (900 ml) was added triethylamine ml) with cooling. The solution so obtained was kept at 25C for 2 hours and refluxed for 30 minutes. The reaction mixture was cooled andconcentrated in vacuum, leaving a residue which on treatment with ice-water (3 L) afforded 2-benzyl-1,3-diacetylindoxyl. A solution of this compound in ethanol (1.8 L) was added to a refluxing solution of sodium sulfite (184 g) in water (2.8 L). and reflux was continued for a further 1 /2 hours. From the re action mixture, cooled to 20C, l-acetyl-Z-henzylindoxyl (71 g, 45% yield) with mp. l15-117C crystallized.

To a mixture of 1-acetyl-2-benzylindoxyl (71 g), 2- (dibenzylamino)ethyl chloride hydrochloride (118 g) in DMSO (670 ml) was cautiously added potassium carbonate (147 g). The reaction mixture was left with stirring for 18 hours at 50C, and then treated with icewater (3.5 L). The resulting emulsion was extracted with ethyl acetate (3 X 750 ml), and the ethyl acetate extract was dried and concentrated in vacuum. leaving 1-acetyl-2-benzyl-3-(ZdibenZyIaminoethoXy)indolc as an oil. This compound was treated for 30 minutes with a refluxing solution of sodium ethoxidc, prepared from sodium (18.5 g) in ethanol (1.4 L, 99%). The reaction hydro mixture was cooled to l20C and added to water (6.5 L). The resulting emulsion was extracted with ethyl acetate (3 X 1 L) and the ethyl acetate was dried and concentrated in vacuum, leaving a residue, which after recrystallization from a mixture of isooctane (1.8 L) and benzene (0.6 L) yielded 2benzyl-3-(2- dibenzylaminoethoxy)indole (43 g) with mp. 9698C. The over-all yield was 36%.

EXAMPLE 46 hydroisopropylaminoethoxy)indole hydrochloride (9.9 g)v with mp. 204205C. Recrystallization from ethanol raised the mp. to 211C. The yield was 5.8g(40%). Anal. calcd. for C H C1 N 0:

C, 69.6%; H, 7.3%; CI, 10.3%; N, 8.1% Found:

C, 69.6%; H, 7.3%; Cl, 10.5%; N, 8.1%

EXAMPLE 47 l-ben2yl-3-( 2-isopropylaminoethoxy)indole chloride l-acetyl-3-( 2-( N-benzyl-N-isopropylamino )ethoxy)indole (59.5 g) was deacetylated by the procedure described in Example 30.

The crude 3-(2-(N-benzyl-N-isopropylamino)ethoxy)indole was dissolved in dimethylformamide, DMF, (500 ml) and the solution was concentrated in vacuum.

hydro- The residue dissolved in DMF (500 ml) was added in the course of 15 minutes at 25C to a stirred suspension of sodium hydride (8.6 g of a 50% suspension in mineral oil) in DMF (250 ml). The reaction mixture was left with stirring at 25C for 2 hours and benzyl chloride (22.8 g) dissolved in DMF (30 ml) was added in the course of 15 minutes. The reaction mixture was kept at 25C for another hour and then poured into iee-water (5 L). The resulting emulsion was extracted with ethyl acetate (3 X 750 ml) and the ethyl acetate extract was concentrated in vacuum. The residue containing 1- benzyl-3-(2-(N-benzyl-N-isopropylamino)ethoxy)indole was dissolved in ethanol (400 ml of 99%), treated with charcoal (7 g) and then subjected to hydrogenolysis in the presence of palladium/carbon (10 g of 10%) at 50-60 psi and 25C for 10 hours. The catalyst was filtered off and to the filtrate, concentrated in vacuum to about 200 ml, was added a solution of hydrogen.

chloride at 60C. After chilling to 0-5C, 1-benzyl-3- (2-isopropylaminoethoxy)indole hydrochloride (36 g, 61% over-all yield) with mp. 19920()C was obtained. Anal. calcd. for C H Cl N 0:

C, 69.6%; H, 7.3%;C1, 10.3%; N, 8.1% Found:

C, 69.8%; H, 7.2%; Cl, 10.4%; N, 8.3%

EXAMPLE 48 1-benzyl-3-( 2-isopropylaminoethoxy )-2-phenylindole hydrochloride 3-( 2-(N-benzyl-N-isopropylamino)ethoxy-2- 3-(Z-isopropylaminoethoxy)-4-methoxyindole hydrophenylindole (28.3 g) was converted to 1-benzyl-3-(2- (N-benzyl-N-isopropylamino)ethoxy)-2-phenylindolc by a procedure analogous to that of the previous example. The latter compound, recrystallized from ethanol, was dissolved in toluene ml) and ethanol (240 ml) and hydrogenolyzed in the presence of palladium/carbon (4 g of 10%) at 25C and 50-60 psi for 5 hours. The catalyst was filtered off and the filtrate concentrated in vacuum. To the residue, dissolved in isopropanol, was added a solution of hydrogen chloride in isopropanol at 05C, and 1-bcnzyl-3-(2- isopropylaminoethoxy)-2-phenylindole hydrochloride (26.8 g) with mp. l88-l 89C was obtained. Recrystallization from ethanol raised the mp. to 193C The over-all yield was 22.7 g (73%). Anal. calcd. for C H- CI N 0:

C, 74.2%; H, 7.0%; Cl, 8.4%; N, 6.7%

Found:

C, 74.0%; H, 7.0 CI, 8.4%; N, 6.7% The starting material, B-(Z-(N-benZyI-N- isopropylamino) ethoxy)-2-phenylindole with mp. l l2l 14C, was prepared in the manner described in Example 31. The yield was 79% starting from l-acetyl- Z-phenylindole.

EXAMPLE49 chloride In a manner similar to that described in Example 30, 3-(2-isopropylaminoethoxy)-4-methoxyindole' hydrochloride with mp. 218C was prepared in 69% yield.

The starting material, 1-acetyl-3-(Z-(N-benzyl-N- isopropylamino)eth0xy)-4-m ethoxyindole, was prepared in the following manner:

To a mixture of 1-acetyl-4-methoxyindoxyl (15.3 g) and 2-(N-benzyl-N-isopropylamino)ethyl chloride hydrochloride (27.9g) in DMSO ml) was cautiously added potassium carbonate (41.5 g). The reaction mixture was left with stirring for 18 hours at'50C and then poured into ice-water (600 ml). The resulting emulsion was extracted with ethyl acetate (3 X 200 ml), and the extract was dried and concentrated in vacuum. The residue so obtained yielded, after trituration with isopropanol, l-acetyl-3-(2'(N-benzyl-N- isopropylamino)ethoxy)-4-methoxyindole (24 g, 74%) with mp. 104-105C.

EXAMPLE50 in isopropanol at 2()30C. After chilling to 0-5C,

l-benzyl-3-(2-isopropylaminoethoxy)-4- methoxyindole hydrochloride (15.4 'g) with mp. l8l-183C was obtained. The over-all yield was 80%.

Anal. calcd. for C H Cl N C, 67.3%; H, 7.3%; Cl, 9.5%; N, 7.5%

I Found:

i 1-benzyl-3-(2-isopropylaminoethoxy)-2-methylindole hydrochloride A mixture of 1-acetyl-2-methylindoxyl (25.5 g), 2- (N-benzyl-N-isopropylamino)ethyl chloride hydrochloride (50.5 g) and potassium carbonate (74.5 g) in DMSO (250 ml) was kept with stirring at 50C for 10 hours. The reaction mixture was worked up as described in Example 45, affording 1-acetyl-3-(2-(N- benzyl-N-isopropylamino)ethoxy)-2-methylindole, which was converted to 1-benzyl-3-(2(N-benzyl-N- isopropylamino)ethoxy)-2-methylindole by procedure analogous to those described in Example 47. The latter compound, isolated as an oil, was dissolved in ethanol (250 ml of 99%), treated with charcoal (5 g) and bydrogenolyzed in the presence of palladium/carbon (5 g of at 50-60 psi and 25C for 24 hours. The catalyst was replaced by a fresh portion (3 g) and hydrogenolysis was continued for an addition period of 6 hours. The reaction mixture was worked up as described in the previous example and yielded, after recrystallization from isopropanol, 1-benzyl-3 -(2- isopropylaminoethoxy)-2-methylindole hydrochloride (9.6 g, 40% over-all yield) with mp. 169*170C. Anal. calcd. for C H Cl N 0:

C, 70.3%; H, 7.6%; C1, 9.9%; N, 7.8% Found:

C, 70.2%; H, 7.5%; Cl, 10.1%;N, 7.7%

EXAMPLE 52 1--q-butyl-3-(2-isopropylaminoethoxy)indole chloride 3-( 2-( N-benzyl-N-isopropylamino )ethoxy )indole g) was alkylated with n-butyl bromide by the procedure described in Example 47. The product, 3-(2- (N-benzyl-N-isopropylamino)ethoxy)-l-n-butylindole, isolated as an oil, was dissolved in a mixture of toluene (100 ml) and ethanol (100 ml of 99%), treated with charcoal (3 g) and hydrogenolyzed in the presence of palladium/carbon (3 g of 10%) at 50-60 psi and C for 13 hours. The catalyst was filtered off and the filtrate concentrated in vacuum. The residue was dissolved in isopropanol, and to the solution was added a solution of hydrogen chloride in isopropanol at 20-30C. After chilling to 0-5C, 1-n-butyl-3-(2- isopropylaminoethoxy)indole hydrochloride (11.9 g) with mp. 143144C was obtained. Recrystallization from isopropanol afforded 10.3 g of the compound with mp. 143-144C. The over-all yield was 50%. Anal. calcd. for C H Cl N 0:

C, 65.7%; H, 8.8%; Cl, 11.4%; N, 9.0% Found:

C, 65.8%; H, 8.5%; C1, 11.5%; N, 9.0%

hydro- EXAMPLE 53 1-benzyl-3-(2-isopropylaminoethoxy)-5- methoxyindole hydrochloride l-acetyl-3-(2-(N-benzyl-N-isopropylamino)ethoxy)- S-methoxyindole (50.5 g) was converted to 1-benzyl-3- (2-(N-benzyl-N-isopropylamino)ethoxy)-5- methoxyindole as described in Example 47. The latter compound was subjected to hydrogenolysis for 3 hours by the procedure described in the previous example, yielding 1-benzyl-3-( 2-isopropylaminoethoxy)-5- methoxyindole hydrochloride (33.4 g, over-all yield with mp. 144-l45C. Anal. calcd. for C H Cl N 0:

C, 67.3%; H, 7.3%; Cl, 9.5%; N, 7.5% Found:

C, 67.6 H, 7.3%; Cl, 9.6%; N, 7.5%

The starting material, l-acetyl-3-(2-(N-benzyl-N- isopropylamino)ethoxy)-5-methoxyind0le with mp. 108110C was prepared in yield in a manner analogous to that described in Example 49. The reaction time was 10 hours.

EXAMPLE 54 methylindole hydrochloride (10g) was treated with asolution of sodium hydroxide (50 ml of l N) and the resulting emulsion was extracted with chloroform (2 X 50 ml). The chloroform extract was dried and concentrated in vacuum. The residue dissolved in ethanol (200 ml of 99%) was hydrogenolized in the presence of palladium/carbon (3 g of 10%) at 5060 psi and 25C for 1018 hours. The reaction mixture worked up as described in Example 52, yielded 3-(2-aminoethoxy)- 5-methoxy-l-methylindole hydrochloride (3.5 g, 59%) with mp. l57158C. Anal. calcd. for C H Cl N 0 C, 56.2%; H, 6.7%; CI, 13.8%; N, 10.9%; 0, 12.5%

Found:

C, 56.1%; H, 6.7%; Cl, 13.7%; N,-l0.8%; O, 12.7%

3-(2-dibenzylaminoethoxy)-5-methoxy-1- methylindole hydrochloride with mp. 177-l78C was prepared as described in Example 47. The yield was 65%.

EXAMPLE 55 and the salts thereof with physiologically acceptable acids, in which each ofX and Y is selected from the group consisting of hydrogen, hydroxy, lower alkyl having l3 carbon atoms and lower alkoxy having l-3 carbon atoms,

R is selected from the group consisting of hydrogen; lower alkyl having l4 carbon atoms and henzyl,

25 I 26 R is selected from the group consisting of hydrogen, 6, A compound according to claim 1, namely, 1-

lower alkyl having l4 carbon atoms, benzyl and benZyl-3-(Z-isoprgpylaminoethoxy) ind phenyl, hydrochloride, R selected from the group consistlng of hydrogen, 5 7. A Compound according to claim 1, namely,

lower alkyl having 1-8 carbon atoms, cycloalkyl benzyl 3 (zisopropylaminoethoxy) indo1c having 5 or 6 carbon atoms, benzyl and 2- hydrochloride 1 phenylethyl, and

Aisastraight or branched alkylene chain containing A compound according to claim namely L benzyl-3-(2-isopropylaminoethoxy)Z-phenyI-indolc from 2 to 4 carbon atoms. 10 h drochloride 2. The hydrochloride of a compound according to y claim 1 9. A compound according to claim 1, namely, 1-

benzyl-3-( 2isopropylaminoeth0xy )-4-methoxy- 3. The oxalate of a derivative according to claim 1.

indolehydrochloride.

4. A compound according to claim 1, namely, 3-(2- isopropylaminoethoxy)-indole-hydrochloride. 10. A compound according to claim 1, namely, 1-

5. A compound according to claim 1, namely, 3-(2- benzyl-3-(2-isopropylaminoethoxy)-5-mcthoxyisopropylaminoethoxy)-4-methoxy-indoleindolehydrochloride. hydrochloride.

UNITED STATE PATENT OFFICE CERTIFICATE OF CCRRECTTCN PATENT NO. 1 3,860,609 DATED J u ry 1 1975 INVENTOR(S) Behrend Friedrich Lundt It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below;

On the caption page, at [75], "Lyngby" should read --Srz$borg 3n the caption page, at [63], "May 20, 1970." should read November 23, l97l-- 4 On the caption page at [30], "May 27, 1970" should read -May 27, 1969-- In the specification: Jolum'n 1, lines .5-6, "May 20, 1970" should read --November 23, l97l- Column 1, line 6 "R should read --R Column l, line 30, "ED should read -LD Column l, lines 50-51, "propounced" should read --pronounced-- Jolumn l, Table I, third line from bottom of page "l hydrochloride" should read -hydrochloride- Column 5, Table I, fourth line from end of Table "hydrochloride 52" should read -hydrochloride-. The number "52" should appear in the "Anti-inflammatory. column. Column 5, Table II, sixth line of table, "-isopropylaminoethoxy)5" should read -iso',..-ropylaminoethoxy)-5- Column 7, Example 2, second line, "-5-" should read )-5 Column 8 Example line 32, )-5" sho ld d 5 Column 12, Example 17, line ll, O, 5 9%" should read -O, 5 7%- Column 13, Example 29, line 45, "treated" should read treating- Column 13, Example 29, line U6, "veratic" should read --veratrio-- Jolumn. 15, Example 33, line 12 "10%" should read lO%)- Column 15, "Example 33, line 52, "58,3%" should read 58 .3%--

Column 16, Example 35, lines il- 42, "C, 75. 8% H," should read ---Found: C, 75.8%; H, Column 17, Example 37, line 5, "dibenzylaminoethyl" should read -dibenzylaminoethoxy- Column 18, Example 39, line 21, "1 16-150" should read l 47-l50- Column 2 1, line 17, "We claim" should read -I claim Column 25, Claim 3, "derivative" should read --compound Signed and Sealed this fourteenth Day Of October 1975 [SEAL] A ttest:

RUTH C. MASON C. MARSHALL DANN Arresting ()ffrcer Commissioner ofPaIents and Trademarks

Claims (9)

1. 2. The hydrochloride of a compound according to claim 1.
2. 3. The oxalate of a derivative according to claim 1.
3. 4. A compound according to claim 1, namely, 3-(2-isopropylaminoethoxy)-indole-hydrochloride.
4. 5. A compound according to claim 1, namely, 3-(2-isopropylaminoethoxy)-4-methoxy-indole-hydrochloride.
5. 6. A compound according to claim 1, namely, 1-benzyl-3-(2-isopropylaminoethoxy)-indole-hydrochloride.
6. 7. A compound according to claim 1, namely, 1-benzyl-3-(2-isopropylaminoethoxy)-indole-hydrochloride.
7. 8. A compound according to claim 1, namely, 1-benzyl-3-(2-isopropylaminoethoxy)-2-phenyl-indole hydrochloride.
8. 9. A compound according to claim 1, namely, 1-benzyl-3-(2-isopropylaminoethoxy)-4-methoxy-indolehydrochloride.
9. 10. A compound according to claim 1, namely, 1-benzyl-3-(2-isopropylaminoethoxy)-5-methoxy-indolehydrochloride.