(54) INDOLE DERIVATIVES OF AMIDES AND AMINO ESTERSAND PROCESS FOR THEIR MANUFACTURE(71) We, HOECHST AKTIENGESELLSCHAFT, a body corporate organised according to the laws of the Federal Republic of Germany, of 6230Frankfurt (Main) 80, Postfach 80 03 20, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- The present invention relates to indole derivatives of amides and amino esters and to a process for the manufacture of these compounds.
This invention provides indole derivatives of the formula I
in which R1 stands for a chlorine or bromine atom, R2 stands for an amino group of the formula
wherein RS represents a hydrogen atom and R" an (amino)alkyl group of the formula
wherein A' is a single bond or stands for a straight-chain or branched alkylene group having up to 6 carbon atoms, which may be substituted by one or more substituents which may be the same or different, selected from hydroxy groups and alkoxy and acyloxy groups both having 1 to 4 carbon atoms, and whereinR7 and R8 may be identical or different and each stands for a hydrogen atom, a cycloalkyl group having 5 to 7 carbon atoms, a straight-chain or branched alkyl group having 1 to 6 carbon atoms, a phenyl group which may carry one or more substituents, which may be the same or different, selected from alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, methylenedioxy, hydroxy, nitro, and amino groups and halogen atoms, and ifR7 and R' stand for alkyl groups, these groups may form together with the nitrogen atom a 5-, 6- or 7-membered heterocyclic ring which may be substituted by one or more substituents, which may be the same or different, selected from alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 4 carbon atoms, hydroxy and carboxy groups, and alkoxycarbonyl groups having 1 to 4 carbon atoms in the alkyl moiety, and wherein one of the carbon atoms may be replaced by oxygen, sulphur or nitrogen atom, this latter being optionally substituted by a phenyl group which may be substituted by one or more substituents, which may be the same or different, selected from alkyl groups having 1 to 4 carbon atoms, alkoxy groups having I to 4 carbon atoms, methylenedioxy, hydroxy, nitro and amino groups, and halogen atoms, or the nitrogen atom may be substituted by an alkenyl group having 3 to 8 carbon atoms or an alkynyl group of 3 to 8 carbon atoms, by a formyl group or by an alkyl group having 1 to 4 carbon atoms which may be substituted by one or more substituents, which may be the same or different, selected from hydroxy groups, dialkylamino and alkoxy groups having 1 to 4 carbon atoms in the or each alkyl moiety; ethylenedioxy and trimethylenedioxy groups, dioxan and dioxolan groups, and phenyl groups having the optional substituents mentioned above, and aminocarbonyl groups of the formula
wherein Rs and R'O have the same meaning as R7 and R8 with the proviso that they may form together with the nitrogen atom a 5-, 6- or 7-membered ring which may be substituted as defined above and wherein one of the carbon atoms may be replaced by an oxygen, sulphur or nitrogen atom, this latter being, however, unsubstituted, or R5 represents a hydrogen atom and Rss represents an alkyl group having from 1 to 6 carbon atoms which may be substituted by one or more substituents, which may be the same or different, selected from alkoxy groups having from I to 4 carbon atoms, alkenyloxy groups having 3, 4 or 5 carbon atoms1 hydroxy and carboxy groups, alkoxy carbonyl groups having from 1 to 6 carbon atoms in the alkyl moiety, dialkylamino groups having from 1 to 4 carbon atoms in each alkyl moiety, cycloalkyl and cycloalkenyl radicals having from 5 to 7 carbon atoms, and chlorine and bromine atoms, pyridyl groups and phenyl groups which may be substituted as defined above, or R5 represents a hydrogen atom and R represents a cycloalkyl group having from 5 to 7 carbon atoms which may be substituted by one or more substituents, which may be the same or different, selected from alkyl, alkenyl and alkynyl groups having up to 4 carbon atoms and dialkylamino groups having from 1 to 4 carbon atoms in each alkyl moiety, or RD represents a hydrogen atom and R8 represents a 1- adamantyl or norbornyl group, or an alkenyl or alkynyl group having from 3 to 10 carbon atoms, or RB and R0 together with the nitrogen atom form a 5- or 6-membered saturatedheterocyclic ring in which one of the carbon atoms may be replaced by anitrogen atom which may be substituted as mentioned above for R7 and R8, orR2 stands for an aminoalkoxy group of the formula
wherein A2 stands for a straight-chain or branched alkylene group having 2 to 6carbon atoms which may be, halogenated and/or substituted by an alkyl grouphaving 1 to 4 carbon atoms and/or by a phenyl group optionally having thesubstituents mentioned above, and wherein R11 and R12 have the same meaningsas R7 and R8, orR2 stands for a basic radical of the formula O(CH2)nR13, wherein R'3 standsfor a 5- or 6-membered heterocyclic ring containing a nitrogen atom, and nstands for zero or 1,R3 stands for a hydrogen atom, a hydroxy group, an alkoxy group having 1 to 5carbon atoms, a fluorine, chlorine or bromine atom, or a nitro, amino orbenzyloxy group, m stands for the integer 1, 2 or 3,R4 stands for a hydrogen atom, a saturated or unsaturated, straight-chain orbranched aliphatic hydrocarbon radical having up to 5 carbon atoms, or abenzyl or phenyl group, the phenyl nucleus of which may be substituted asdefined above for R2.
The invention also provides the salts, especially, the physiologically tolerable salts, of the compounds of formula I.
R' preferably represents a chlorine atom, and R2 preferably represents the radical
wherein R7 and R8 together with the nitrogen atom form an optionally substituted 6- or 7-membered ring, for example, a 4-methyl-l-piperazinylamino or piperidinoamino radical. A further, preferred meaning for R2 is the radical
wherein A1 stands for a straight-chain or branched alkylene group having 2 or 3 carbon atoms, which may be substituted by a hydroxy group and wherein R7 and RB are different from each other and R7 represents a hydrogen atom and R8 a linear or branched alkyl group having 1 to 3 carbon atoms, or R7 and RB are identical, and they both stand for the same alkyl group having I to 4 carbon atoms, or together with the nitrogen atom they form a 5- or 6-membered ring which may contain another hetero atom, for example, a morpholino, piperidino, piperazino, 4-methylpiperazino or pyrrolidino group. Further preferred radicals R2 are the l-piperazinyl group
wherein Y represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a ss-hydroxyethyl, 2-(1,3-dioxolan-2-yl)-ethyl, 2-(1,3-dioxan-2-yl)-ethyl, 3,4methylenedioxybenzyl, or pyrrolidino-carbonylmethyl group, a phenyl group which is unsubstituted or is substituted by a chlorine atom or a methoxy or nitro group, or represents an allyl, 2-methylallyl or propargyl group.
R2 also preferably represents an aminoalkyloxy group
wherein A2 stands for a straight-chain or branched alkylene group having 2 or 3 carbon atoms, and R" and R12 are different from each other, R11 representing a hydrogen atom and R12 a linear or branched alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 5 to 7 carbon atoms, or R" and R12 are identical, and both stand for the same alkyl group having 1 to 4 carbon atoms, or together with the nitrogen atom they represent a 5- or 6-membered ring which may contain another hetero atom, for example, a morpholino, 4-methylpiperazino, piperidino or pyrrolidino group.
Also preferred as R is the radical -O-(CH2)n-R13, wherein n is 0 or 1, andR13 stands for a 6-membered, basic, nitrogen-containing heterocyclic radical, for example a l-methyl-4-piperidyloxy, l-methyl-3-piperidyloxy, l-methyl-3-piperidyl- methoxy, 2-pyridyloxy, or 4-pyridyloxy radical.
R3 preferably represents a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms, especially a methoxy group, preferably in the 4-, 5- and/or 6position.
R4 preferably stands for a hydrogen atom, a methyl, phenyl or benzyl group, or an o-, m- or p-(C1-C4)-alkoxyphenyl group, especially a methoxyphenyl group.
The invention also provides a process for the manufacture of a compound of formula I which comprises (a,) reacting a compound of the formula II
CHOR III (R )mR4 (az) oxidizing the aldehyde of formula III to yield the corresponding carboxylicacid of the formula IV
in which R3, R4, and m are defined as in formula I, and (a3) reacting the acid of formula IV with an amine of the formula
or with an alcohol of the formula
or HOACH2)nR'3, wherein A2, RB, RI, R", R12 and R'3 and n are defined as informula I, or (b) reacting a compound of the formula II as defined sub (a1) with phosphorusoxychloride and dimethylformamide to yield a 3-dimethylaminomethylenecompound of the formula V
and (b2) converting the compound of formula V by reaction with phosphorusoxychloride or oxybromide into a compound of the formula III
and converting this compound according to steps (a2) and (a3) into a compound of formula I, or (c) reacting a compound of the formula I, in which R1 and R4 and m are defined asabove with the proviso that R2 contains a secondary amino group, with analkylating agent of the formula R14X, wherein X stands for a chlorine orbromine atom and R14 has one of the meanings given for R7 and RB with theexception of a hydrogen atom, especially an alkenyl group having 3 to 8carbon atoms or for an alkynyl group having 3 to 8 carbon atoms or for analkyl group having I to 6 carbon atoms which may be substituted by one ormore of the same or different substituents selected from hydroxy groups,alkoxy groups having 1 to 4 carbon atoms, ethylenedioxy and trimethylenedioxy groups, and optionally substituted phenyl groups, or by the group
wherein Re and R'O are defined as above and, if desired, (d) converting a resulting compound of formula I into a salt, or a resulting salt intothe free compound.
The oxo-indole of formula II used as the starting material for variants (a) and (b) of the process of the invention is known in the art and may be prepared according to the method of K. E. Schulte, J. Reisch and U. Stoess (Arch. Pharm.
305, (1972), p. 523) and H. A. H. Beckett, R. W. Daisley, J. Walker (Tetrahedron 24 (1968), p. 6093).
According to method (a), the oxo-indole of formula II may be reacted in known manner according to Vilsmeier-Haack (O. Bayer in Houben-Weyl:Methoden der organischen Chemie, 4th edition, Y. Thieme, Stuttgart, 1954, Vol.
7/1 p. 29). The aldehyde of formula III may then be oxidized according to known methods, for example, using potassium permanganate, to yield the corresponding carboxylic acid of formula IV.
The compound of formula III in which R4 is CeH5 and R3 is H is disclosed in the art. Its preparation by the Vilsmeier formylation of N-phenyl-oxo-indole (K. E.
Schulte, J. Reisch and U. Stoess, Arch. Pharm. 305, p. 523 1972)), however, leads to a mixture of products, from which the pure compound of formula III can be obtained only after complicated purification operations (L. Marchetti and A.
Andreani, Annali di Chimica 63, p. 681 (1973)).
When, however, according to method (b), N-phenyl-oxo-indole is reacted with dimethylformamide and phosphorus oxychloride at a temperature of from 0 C to 30"C, the result is a pure product of formula V in a very good yield. A solvent is generally used, for example, an inert anhydrous organic solvent, for example, chloroform, carbon tetrachloride, dioxan, benzene, toluene, chlorobenzene, orN,N-dimethylformamide. The compound of formula V is then converted into the compound of formula III by reaction with POCK, or POUR,, preferably using the phosphorus oxychloride or oxybromide in an at least equivalent amount, advantageously in a 3- to 5-fold excess. A solvent is again generally used, for example, an inert aprotic solvent, for example, benzene, toluene, chlorobenzene, chloroform or carbon tetrachloride. The reaction is generally carried out at temperatures of from 30 to 1000C, preferably from 50 to 800C.
Under these conditions, any other compound of formula II may be reacted to yield the corresponding compound of formula III.
The compound of formula III obtained according to (b) is then converted according to methods (a2) and (a3) into a compound of formula I.
According to step (a3), the carboxylic acid of formula IV is converted, according to the usual methods of ester or amide formation for example via an acid chloride or mixed anhydride, into an ester or amide. For esterification with an alcohol still containing secondary amino groups, a salt of the amino alcohol is used.
According to method (c), a secondary amino group may be alkylated according to known methods using an alkylating agent of the defined formulaXR14.
The compounds of formula I and the salts are interconvertible in the usual manner.
Physiologically tolerable salts are especially those formed with the following acids: hydrochloric, hydrobromic or hydroiodic acid, phosphoric acid, sulphuric acid, methylsulphuric acid, amidosulphonic acid, nitric acid; formic acid, acetic acid, propionic acid, succinic acid, tartaric acid, lactic acid, malonic acid, fumaric acid, oxalic acid, citric acid, malic acid, mucic acid, benzoic acid, salicylic acid, aceturic acid, embonic acid, naphthalene-l,5-disulphonic acid, ascorbic acid, phenylacetic acid, p-amino-salicylic acid, hydroxyethane-sulphonic acid, benzenesulphonic acid, or synthetic resins containing acid groups, for example those having an ion exchanger effect.
The compounds of the invention have valuable pharmacological properties, for example, they have an effect on the coronary circulation, which aPpears as a hypotensive effect and especially as an antiarrhythmic activity. These compounds are therefore suitable for the treatment of disturbances in the cardiac rhythm. This antiarrhythmic activity was established on a dog that had been poisoned with strophanthin, on a cat exposed to hypothermia and by means of the digotoxinaconitin fibrillation test on the guinea pig-Landendorff heart. The pharmacological effects have also been tested on rats.
The invention also provides a pharmaceutical preparation which comprises a compound of formula I or a physiologically tolerable salt thereof as active ingredient in admixture or conjunction with a pharmaceutically suitable carrier.
The preparations are, for example, in a form suitable for oral administration, and are preferably in unit dosage form. The preparations are, for example, tablets, gelatine capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. The carrier is for example, magnesium carbonate, lactose or corn starch, or magnesium stearate. The preparation may be in the form of dry or moist granules, which may be administered per se or may be compressed or filled into capsules. As oily carrier material or solvents, there are especially used vegetable and animal oils, for example sunflower oil or castor.oil.
Especially advantageous are preparations suitable for parenteral for example. intravenous administration. Such preparations advantageously comprise a physiologically tolerable salt as the active substance.
Solvents suitable for preparations for intravenous administration are, for example, water, physiological sodium chloride solutions and alcohols, for example ethanol, propane-diol and glycerol; furthermore, sugar solutions, for example glucose and mannitol solutions, and mixtures of two or more of the various solvents mentioned.
For oral administration, a unit dose generally comprises from 501,000 mg, preferably from 100500 mg of the active substance, whereas the unit dose of the active substance for intravenous or intramuscular administration is generally from 20100 mg, preferably 50 mg.
The daily dose for oral administration is generally within the range of from 502,00Q mg, preferably 500 mg, and for the intravenous or intramuscular administration it is within the range of from 20--500 mg, preferably 100 mg.
The compounds of formula I may also be used as intermediate products for the manufacture of indole derivatives which carry basic substituents in the 2- and 3positions. The following Examples illustrate the invention.
Example 1.
2-Chloro-l-phenyl-indole 3-carboxylic acid (4-methyl) piperazide hydrochloride(a) 2-Chloro-l-phenyl-indole 3-carbaldehydeTo 130 ml of N,N-dimethylformamide, 130 ml of phosphorus oxychloride wereadded dropwise while cooling, so that the temperature did not exceed +25 C.
Stirring was continued for 30 minutes at room temperature, 400 ml of anhydrous toluene were added, and then 209 g ( I mol) of N-phenyl-oxo-indole were introduced portionwise while cooling to maintain the temperature between 30 and 35"C. Stirring was continued for 2 hours at room temperature, 1 1 of chloroform was added, and the mixture was washed several times with water, at last with an aqueous sodium bi-carbonate solution. The solvent was eliminated in vacuo. and the crystallized residue was washed with diisopropyl ether to yield 230 g of a browncolored 3-dimethylamino-methylene-l-phenyl-2-indolinone melting at 13W132 C (87% of the theoretical yield).
The product was heated to the boil for 6 hours in a mixture of 450 ml of chloroform and 225 ml of phosphorus oxychloride, the cooled solution was washed with water, and the solvent was eliminated in vacuo. The crystallized residue (192 g = 86 of the theoretical yield) melted upon washing with diisopropyl ether at 132--134"C.
(b) 2-Chloro-l-phenyl-indole 3-carboxylic acid256 g ( I mol) of 2-chloro- 1 -phenyl-indole 3-carboxaldehyde were suspended in a mixture of 3.5 1 of acetone, 2.5 1 of 1M phosphate buffer (pH 7) and 1.71 of water and 230 g of potassium permanganate were added portionwise while stirring at 40 C within 4 hours. Stirring was continued for 2 hours, and 20 g of sodium bisulfate were added. The precipitate was suction-filtered, washed twice with 300 ml of water each time, the faintly yellow filtrate was strongly acidified with concentrated hydrochloride acid. The precipitated acid was suction-filtered and washed with water until neutral.
Yield: 190 g (71% of the theoretical yield), m.p. 220--221"C.
(c) 2-Chloro- 1 -phenyl-indole 3-carboxylic acid (4-methyl)-piperazide hydrochloride135.5 g (0.5 mol) of 2-chloro-l-phenyl-indole 3-carboxylic acid and 110 ml (1.5 mols) of thionyl chloride were heated at the boil until the evolution of gas ceased: excess thionyl chloride was eliminated in vacuo, and the crude crystallized acid chloride was dissolved in 500 ml of chloroform. At -20"C, a mixture of 75 g (0.75 mol) of N-methyl-piperazine and 55 ml (0.7 mol) of pyridine in 100 ml of chloroform was added while cooling and stirring, so that the temperature did not exceed +10at. Stirring was continued for 3 hours at room temperature, the solution was washed three times with water, and the solvent was eliminated in vacuo. The residue was freed from pyridine still present by dissolving it twice in toluene and evaporating the toluene in vacuo. The crude resinous base was dissolved in 250 ml of acetone, and an excess of ethanolic hydrochloric acid was added. The crystal mass was suction-filtered and washed with acetone.
Yield: 168 g (86% of the theoretical yield), m.p. 248--2500C.
Example 2.
2-Chloro-l-phenyl-indole 3-carboxylic acid piperazide (a) 2-Chloro-l-phenyl-indole 3-carboxylic acid (4-formyl)-piperazideThis compound was prepared as in Example 1 (c) from 2-chloro-1-phenyl- indole 3-carboxylic acid chloride and N-formyl-piperazin. The reaction solution was washed successively with water, 2N hydrochloric acid and water. After the solvent had been eliminated an amorphous brown compound was obtained, which was uniform according to the thin layer chromatogram.
(b) 2-Chloro-l-phenyl-indole 3-carboxylic acid piperazide0.13 mol of the N-formyl compound obtained sub (a) was dissolved in 350 ml of ethanol and after addition of 100 ml of a 30% sodium hydroxide solution, the solution was stirred for 6 hours at room temperature. Then, 400 ml of water were added, and the mixture was extracted three times with methylene chloride. The resinous residue of the organic phase was dissolved in acetone, and a solution of an equivalent amount of maleic acid in acetone was added. The crystal mass was suction-filtered and washed with acetone.
Yield: 54 g (91% of the theoretical yield), m.p. 147"C (maleinate).
The substituted 2-chioro- 1 -phenyl-indole 3-carboxylic acid derivatives of theExamples listed in Table I and the pharmaceutically suitable salts were prepared from 2-chloro-1-phenyl-indole 3-carboxylic acid chloride and the corresponding bases according to Example 1 (c).
TABLE 1
o o c t o cz CI ru oc a oo $ d, E cc , ,E s XCno r, CI P, 1 S O "rq O s q Od~crar o o 21 6 o 4f= = = 7 -HNCH2Cfl(OH) CH2NHCH(CH 3)2 resin; hydwchloride (110 o n 1 "1 xx o o c -HN(cH2)3 NH amorphous; hydrochloride (decump. 240 9 E O t amorphous; hydrochloride (decomp. 250 E 10 -HNCH2 CH2-M Err Q C 1 N Q U ; l 11 -WN(CH2)3 N LL I I O s B b x H ~ x m
Example No. R2 m.p. 0C, salt (m.p. 0C) 12 -flN(CW2)3 N NCH2 cH2oH amorphous; dihydrochloride (decomp. > 2500) 13 D NC/I2 CH2 OH | oxalate (170 g 1720) 14 -N NC6Hs f hydrochloride 3 15 r 5 hydrochloride (amorphous) E E E cz O O E E OCH3 17 -N N NO2 amorphous; hydrochloride (decomp. > 3000) 'U 18 -N N NH2 amorphous; dihydrochloride (amorphous) 'U 19 m\ -N N-CH-C6H
Example No. R2 m.p. 0C, Salt (m.p. 0C) -HNN(c2H5)2 111 112; hydrochloride (225 - 226) vx N n o rm 21 -HN-N W W hydrochloride (2910) 'U E 145 s wo hydrochloride (decomp. > 2500) 6 o 23 N O s o s amorphous; hydrochloride (decomp. > 2300) E ~ x t E Y < 24 b amorphous; hydrochlonde (amorphous) CH 25 -HN-N' amorphous; hydrochloride (amorphous) CH3 C ?Ee z e N C > l n N N N Example 26.
2 - Chloro 5 - methoxy - I - methyl - indole 3 - carboxylic acid (4 - methyl)piperazidehydrochloride(a) 2-Chloro-5-methoxy- 1 -methyl-indole 3-carbaldehydeTo a mixture of 33 ml of N,N-dimethylformamide and 30 ml of chloroform, 22ml of phosphorus oxychloride were added dropwise, while cooling with ice. After20 minutes, a solution of 20 g of 5-methoxy-l-methyl-oxo-indole in 30 ml ofchloroform was added dropwise so as to maintain the temperature between 25 and 300 C. The mixture was allowed to stand for 3 hours at room temperature, and thena mixture of 400 ml of saturated aqueous sodium bicarbonate solution was addedwhile stirring. The organic phase was separated, washed with water and the solventwas eliminated in vacuo. The dark-red oily residue was chromatographed by meansof silica gel 60 (0.06-0.2 mm, deactivated by 10% of water, column size 3.5 x 80cm) and a toluene/ethyl acetate 8:1 (v/v) mixture. After athirst fraction of 200 ml, the above-specified compound was eluted.
Yield: 11 g of light yellow crystals, m.p. 1150C.
(b) 2-Chloro-5-methoxy- I -methyl-indole 3-carboxylic acid21 g of potassium permanganate were added portionwise at 350C within 4hours to a suspension of 16 g of 2-chloro-5-methoxy-1-methyl-indole-3-carb aldehyde in 280 ml of acetone, 210 ml of phosphate buffer (pH 7) and 140 ml of water. Stirring was continued for 2 hours until the violet color had disappeared, 3 g of sodium bisulfite were added, and after standing overnight, the precipitate was separated by suction-filtration. After acidification, 1 g of carboxylic acid was precipitated from the filtrate. The precipitate was digested twice with 100 ml ofN,N-dimethyl-formamide each time, undissolved substance was separated by filtration, and the filtrate was diluted with 400 ml of water. The separated crystal mass was suction-filtered and washed with water to yield 10 g.
The overall yield was 11 g (64% of the theoretical yield), m.p. 2422440 C.
Add chloride: from the acid and thionyl chloride. m.p. 132--134"C.
(c) 2-Chloro-5-methoxy- 1 -methyl-indole 3-carboxylic acid (4-methyl)piperazideThe above substance was prepared according to Example I (c) from 2-chloro5-methoxy-l-methyl-indole 3-carboxylic acid chloride and N-methyl-piperazine in chloroform, m.p. 124--1250C.
Example 27.
The substituted 2-chloro-5-methoxy- I-methyl-indole 3-carboxylic acid derivatives of formula I and the pharmacologically useful salts thereof were prepared from 2-chloro-5-methoxy- 1 -methyl-indole 3-carboxylic acid chloride and the corresponding bases according to the Examples 1(c), 2 (a) and 2 (b). The bases and the radicals R2 are listed in Table 1.
Example 28.
2-Chloro-13-methoxyphenyl)-indole 3-carboxylic acid (4-methyl)piperazide (a) 1 .(3-Hydroxyphenyl)-2-indolinone To a stirred mixture of 415 g (1.5 mols) of N-phenyl-N-(3-methoxy-phenyl)chloroacetic acid amide and 600 ml of o-dichlorobenzene, 300 g of AIC13 were added at ro
(b) l-(3-methoxyphenyl)-2-indolinone 23 ml (0.24 mol) of dimethylsulfate were added dropwise to a solution of 45 g (0.2 mol) of l-(3-hydroxyphenyl)-2-indolinone in 150 ml of 2N NaOH and 50 ml of water. Cooling kept the temperature between 25 and 30"C. Stirring was continued for 17 hours at room temperature, the precipitate was suction-filtered, washed with water until neutral and then washed twice with 20 ml of ethanal each time.
Yield: 32 g (68% of the theoretical yield), m.p. 104--106"C.
(c) 2-Chloro-1-(3-methoxyphenyl)-indole 3-carbaldehydeTo a reaction product according to Vilsmeier prepared according to ExampleI from 30 ml of N,N-dimethylformamide and 30 ml of phosphorus oxychloride, 80 ml of anhydrous toluene were added, and while stirring 48 g (0.2 mol) of 1-(3methoxyphenyl)-2-indolinone were introduced portionwise so as to maintain the temperature between 25 and 30"C, when cooling slightly. Stirring was continued for 30 minutes, the mixture was diluted with 500 ml of chloroform, and the solution was washed several times with water and aqueous sodium bicarbonate solution.
After the solvent had been evaporated in vacuo, 3-dimethylamino-methylene-1 (3methoxy-phenyl)-2-indolinone remained as a crystallized residue which melted at 98-990C- The crystallized product was dissolved in 200 ml of toluene, and after addition of 70 ml of phosphorus oxychloride, the solution was stirred for 45 minutes at 750 C.
After cooling, 500 g of ice and 300 ml of ice water were added in one portion to the solution, whereupon the temperature of the mixture reached 550C after 10 minutes when stirring. The crystal mass which had formed at the same tirne was suctionfiltered after addition of 100 ml of ether, washed with water until neutral and washed twice with ether.
Yield: 29 g, m.p. 1670 C. Concentration of the mother liquor yielded further 9 g, m.p. 166--167"C.
Overall yield: 38 g (70 /O of the theoretical yield).
(d) 2-Chloro-1-(3-methoxyphenyl)-indole 3-carboxylic acidThis compound was obtained as in Example 1 (b) from 27 g (0.1 mol) of 2chloro-1-(3-methoxyphenyl)-indole 3-carbaldehyde in 500 ml of acetone, 300 ml ofIM phosphate buffer (pH 7) and 100 ml of water by oxidation with 40 g of potassium permanganate.
Yield: 18 g (60% of the theoretical yield), m.p. 196-198 C.
Acid chloride: From the acid and thionyl chloride, m.p. 142-143 C.
(e) 2-Chloro-1-(3-methoxyphenyl)-indole 3-carboxylic acid (4.methyl)piperazide This compound was prepared as in Example I (c) from 2-chloro l-(3-methoxy phenyl)-indole-3-carboxylic acid chloride and N-methyl-piperazine.
Yield: resin, hydrochloride, decomposition above 2500 C, 85% of the theoretical yield.
Example 29.
The substituted 2-chloro-1-(3-methoxyphenyl)-indole 3-carboxylic acid derivates of formula I and the pharmacologically useful salts thereof were prepared from 2-chloro-1-(3-methoxyphenyl)-indole 3-carboxylic acid chloride and the corresponding bases according to Examples 1(c), 2 (a) and 2 (b). The bases and the radicals R2 are listed in Table 1.
Example 30.
The following 2-chloro-indole carboxylic acids of formula I listed in Table 2 were prepared according to Examples 1, 2, 27 and 29 from the corresponding carboxylic acid chlorides and the amines of the formula HR2.
TABLE 2
R3 | R4 R2 4-Cl H 4-methyl-1-piperazinyl 5-Br H 4-hydroxyethyl-1-piperazinyl 7-Cl H 1-piperazinyl 5-NO2 H 4-methyl-1-piperazinyl 5-NH2 H 4-methyl-1-piperazinyl 5,7-Di-Br H 4-methyl-1-piperazinylH C6H5CH2- 1-piperazinyl 5-F CH3 4-methyl-1-piperazinyl 5-F C2H5 1-piperazinyl 5-Cl n-C3H7 4-methyl-1-piperazinyl 5-Br n-C4Hg diethylaminoethylamino 5-NO2 CH3 4-methyl-1-piperazinyl 5-NH2 CH3 4-methyl-1-piperazinyl 4-CH3O CH3 1-piperazinyl 7-CH3O CH3 morpholinoethylamino 5-C2H5 0 CH3 4-hydroxyethyl-1-piperazinyl 5-C3H70 CH3 4-phenyl-1-piperazinyl 5-C4H9O C6H5 4-methyl-1-piperazinyl 5-C5H11O CH3 4-methyl-1-piperazinyl 6-C2H5O C6H5 1-piperazinyl 6-C3H7O C6H5 piperidinoamino 6-C4H9O CH3 4-methyl-1-piperazinyl 6-C6H5CH2O C6H5 4-methyl-1-piperazinyl-amino 5,6-Di-CH3O CH3 4-methyl-1-piperazinyl 5,6-Di-C2H5O C6H5 1-piperazinyl 5-C2H5O,6-CH3O CH3 4-methyl-1-piperazinyl 5,6-Di-C3H7O CH3 4-methyl-1-piperazinyl Example 31.
2 - Chloro - I - phenyl - indole 3 - carboxylic acid 2 - diethylamino ethyl ester hydrochloride27.1 g (0.1 mol) of 2-chloro-l-phenyl-indole 3-carboxylic acid were refluxed with 30 ml of thionyl chloride until the evolution of gas had ceased. Excess thionyl chloride was eliminated in vacuo, and the crude acid chloride was dissolved in 100 ml of anhydrous chloroform. After cooling to -200C, a mixture of 15.2 g (0.13 mol) of diethylamino-ethanol and 15 ml (0.19 mol) of pyridine in 50 ml of chloroform was added, and the mixture was stirred for 3 hours at room temperature. The solution was diluted with chloroform and washed three times with water. The solvent was eliminated in vacuo, the residue was dissolved in toluene and again concentrated in vacuo. The resinous crude base was dissolved in 100 ml of chloroform and ethanolic hydrochloric acid was added until a pH of I was reached.
The solvent was eliminated in vacuo, and the residue was digested three times with acetone and concentrated. The precipitate was then suction-filtered and washed with acetone.
Yield: 21 g (52% of the theoretical yield) of colorless crystals, m.p. 162--163"C.
The substituted 2-chloro-indole 3-carboxylic acid esters of the Examples listed in Table 3 and the pharmacologically useful salts thereof were prepared as inExample 31 from the indole carboxylic acid chloride and the corresponding basic alcohol.
TABLE 3:
Example No. R2 m.p. oC; salt (m.p. OC) 32 -OCH2CH2N(CH3)2 resin; hydrdchloride (171-1730) 33 -O(CH)3N(CH)2 127-1300; hydrochloride (228-2290) 34 -OCHZ Chit2 1NSo resin; hydrochloride (2480) 35 -OCH2 CHZ N3 resin; hydrochloride (250-2510) 36 -OCHZCH2 resin; hydrochloride (230-2320) 37 OtoNCH3 amorphous; hydrochloride decomp. > 2500 38 -O ) amorphous; hydrochloride decomp. > 2650 CH3 39 ~ < 4 amorphous; hydrochloride decomp. > 2300 Example 40.
2 - Chloro - I - phenyl - indole 3 - carboxylic acid 2 - cyclohexylamino - ethyl esterhydrochlorideGaseous hydrogen chloride was introduced into a solution of 30 g (0.21 mol) of 2-cyclohexylamino-ethanol in 300 ml of ethyl acetate until the solution reached a pH of 1. The so-obtained suspension of the amine hydrochloride was then added to 0.2 mol of 2-chloro-l-phenyl-indole 3-carboxylic acid chloride which had been prepared from 54.2 g of the corresponding acid according to Example 5, and the mixture was heated to the boil for 17 hours while stirring. After cooling. the precipitate was suction-filtered and washed with ethyl acetate.
Melting point: 212--215"C. After recrystallization from ethanol, the melting point was 215-217 C.
Yield: 69 g (80% of the theoretical yield).
Example 41.
The substituted 2-chloro-indole 3-carboxylic acid esters of formula I listed inTable 4 were prepared according to Example 40 from 2-chloro-indole 3-carboxylic acid chlorides and the hydrochlorides of the corresponding basic amino alcohols. TABLE 4:
R3 R4 R2 5-CH,O CH3 --0 CA?2 C/I2 NH 6-CH,O C6Hs -oCH2CH2NU OH2 CHZ NH 5,6-DiCH30 CH3 -ocH2 cH2 NH 6-C2Hs O C6H5 -ocA?2CH2NH H C6Hs C#2 CH2-N NH H C6H -OCH fr \ CHZ (C6#5) C N84 H C2H -OCH2CH2NHCH(CH3)2 H C6H5 0(7no H C6H -O-CH-CH2NH2 C Example 42.
2 - Chloro- 1 - phenyl - indole 3 - carboxylic acid [4 - (2 - (1,3 - dioxolan -2 - yl) - ethyl'piperazideA mixture of 13.6 (40 mmols) of 2-chloro-l-phenyl-indole 3-carboxylic acid piperazide (Example 2), 17 g (0.125 mol) of 2-(2-chloroethyl)- 1 ,3-dioxolane, 20 ml of triethylamine and 120 ml of toluene were kept boiling for 48 hours while stirring.
The cooled mixture was diluted with ethyl acetate, washed three times with water, and the resinous residue of the organic phase was chromatographed using silica gel (60 0.06--0.2 mm, deactivated by 10% of water; column size: 3.5 x 100 cm) and ethyl acetate. After a first fraction of 11, the above compound was eluted as a resin.
The hydrochloride melted at 23e2320C.
Yield: 9.5 g of hydrochloride (50 /O of the theoretical yield).
Example 43.
2 - Chloro - I -phenyl - indole 3 - carboxylic acid [4 - (3,4 - methylene - dioxy - benzyl)]piperazideA mixture of 12 g (35 mmols) of 2-chloro-l-phenyl-indole 3-carboxylic acid piperazide (Example 2), 17 g (0.1 mol) of piperonyl chloride, 17 ml of triethylamine and 100 ml of toluene were refluxed for 24 hours. The cooled solution was diluted with ethyl acetate, washed with water and the solvent was eliminated in vacuo. The resinous residue was dissolved in acetone, excess ethanolic hydrochloric acid (40 mmols) was added, and the precipitate formed was suction-filtered and washed with acetone.
The yield of colorless product was 15.2 g (85% of the theoretical yield) m.p.
241--243"C.
Example 44.
The compounds of Table 5 were prepared from the carboxylic acid piperazides and the corresponding alkyl halides according to Examples 42 and 43.
TABLE 5:
Rl R4 R H C6H, 0 -CA?2 CM2 C0 H C6Hs CH2C--CH H C6H -CH2-CH=CH2 6-CH;O C6HB CH2CO 5-CH,O CH3 -CHCO-N O 5,6-Di-CH;O CH3 -CH2C6H3 6-C2Hs O C6H -CH2CONHCH3 H C2HB -CH,-CrC-CH, H C6H5 -CH2CH2N(C2H5)2