CA1255312A - 3-arylcarbonyl- and 3-cycloalkylcarbonyl-1- substituted alkyl-1h-indoles useful as intermediates for producing analgesic anti-rheumatic and anti- inflammatory agents - Google Patents

Abstract

D.N. 7356B DIV V

ABSTRACT OF THE DISCLOSURE
Indole compounds of the formula:

VI

[wherein R2 is hydrogen, alkyl, optionally substituted phenyl or optionally substituted benzyl;
R3 is optionally alkoxy-substituted cyclohexyl, option-ally substituted phenyl, optionally substituted styryl biphenyl, optionally substituted naphthyl, thienyl, furyl, benzofuryl, benzothienyl, quinolyl or pyrrolyl;
R4 is hydrogen or a substituent;
Alk is optionally alkyl-substituted alkylene; and X is toluenesulfonyl or halo], are useful as intermediates for producing analgesic, anti-rheumatic and anti-inflammatory compounds such as those of the formula:

I

wherein Z is O or NOH, N=B is azido, optionally substituted amino, optionally substituted morpholinyl, optionally substituted thiomorpholinyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, azetidinyl, optionally substituted piperazinyl or hexahydrodiazepinyl, and the other symbols are as defined above].

Description

~ 1 D~No 7356s DIV V

This is a divisional application of Serial No.
488,073 filed August 2, 1985.
The parent application relates to 2-R2~3-R3-carbonyl-l-aminoalkyl-lH-indoles of formula I described hereinafter which have analgesic, anti-rheumatic and anti-inflammatory activities.
This divisional application relates to novel com-pounds oE the Eormula VI described below useful for the produc-tion of the compounds of formula I of the parent application.

Thus, an aspect of this application provides a compound of the formula 4 ~ CO-R3 Alk-X' [wherein:
R2 is hydrogen, lower-alkyl, chloro, phenyl or benzyl (or phenyl or benzyl substitut~d by from one to two sub-stituents selected from halo, lower-alkyl, lowe.r-alkoxy, hydroxy, amino~ lower-alkylmercapto, lower-alkylsulfinyl or lower-alkylsulfonyl);
R3 is cyclohexyl, lower-alkoxycyclohexyl, phenyl (or phenyl substituted by from one to kwo substituents selected from halo, lower-alkoxy, hydroxy, benzyloxy, lower alkyl, nitro, amino, lower-alkylamino, di-lower-alkylamino, lower-alkoxy-lowex-alkylamino, lower alkanoylamino, benzoylamino, trifluoro-acetylamino, lower alkylsulfonylamino, carbamylamino, lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, cyano, formyl or hydroxyiminomethylj, methylenedioxyphenyl, 3- or 4-hydroxy-l-piperidinylphenyl~ l-piperazinylphenyl/ (lH-imidazol-

2 2 2 7 4 9 - 3 1 9 11 D.N . 7356B DIV V
- la -l-yl)phenyl, (l-pyrrolyl)phenyl, aminomethylphenyl, guanidinyl-methylphenyl, N-cyanoguanidinylMethylphenyl, styryl, lower-alkyl-substituted-styryl, fluoro-substituted-s~yryl, 2-4-biphenyl, 1 or 2-naphthyl (or 1- or 2-naphthyl substituted by from one to two substituents selected from lower-alkyl, lower-alkoxy, hydroxy, bromo, chloro, fluoro, lower~alkoxycarbonyl, carbamyl, cyano, lower-alkylmercap~o, lower-alkysulfinyl, lower-alkylsulfonyl or trifluoromethyl), thienyl, Euryl, benæo[b]furyl, benzo[b]thienyl, quinolyl or (N-lower-alkyl)pyrrolyl;
R4 is hydrogen or from one to two substituents selected from lower-alkyl, hydroxy, lower-alkoxy or halo in the 4-, 5-, 6- or 7-positions;
Alk is ~ lower-alkylene having the formula (CH2)n where n is an integer from 2 to 6, or such lower-alkylene substituted on the ~- or the ~-carbon atom by a lower-alkyl group; and X' is toluenesulfonyloxy or halo].
Another aspect of this application provides a process for producing the compound o~ the ~ormula VI. This process comprises~
~a) in the case where Alk is 1,2-ethylene, reacting a 2-R2-3-R3-carbonyl-indole of the formula II:

R4 ~ ~ -CO-R II

with a lower-alkyl lithium, reacting the resulting lithium salt with ethylene oxide, and t;~

- lb - 22749~319H

react.i~g the so-formed 2-R2-3-R3-carbonyl-1-(2-hydroxyethyl)-lH-indole wi-th toluenesulfonyl chloride in the presence of an acid-acceptor to form a compound of the formula VI where X' is a toluenesulEonyloxy yroup, or with a phosphorus trihalide to form a compound o~ the formula VI where X' is a halo group; or (b) in ~he case where X' is halo and Alk is other than 1,2-ethylene, reacting a 2-R2-3-R3-carbonyl-indole of the formula II with an a,~-di.halo-lower-alkane in the presence of a strong base.
In the following description, it should be under-stood that the -term "this invention" includes the subject matters of this divisional application, of the parent applica-tion and of other divisional application filed from the same parent applica-tion.

S3~ _ -lc -BACKGROUND OF THE INVENTION
S(a) Field of the Invention:
This invention relates to 3-arylcarbonyl- and 3-cycloalkylcarbonyl-l-aminoalk~1-lH-indoles which are use-fulasanalgesic,anti-rheumaticandanti-inflammatoryagents.
~b) Information Disclosure Statement:
10Deschamps et al. U~S~ Patent 3,946,029 discloses compounds having the formula:

¢ ~R3 A-N ~~4 ~R5 wh~re, inter alia, A is alkylene; R is one to four carbon alkyl; R3 is a 2-, 3- or 4-pyridyl group; and R4 and R5 are joined together to form, with the nitrogen atom, a piperidino, pyrrolidino or morpholino group. The compounds are said to possess fibrinolytic and anti-inflammatory activities.
Essentially the same disclosure is found in Inion et al., Eur. J. of Med. Chem., 10 (3), 276-285 (1975).
~ SpeciEically disclosed in both these reerences is the : species, 2-isopropyl-3-(3-pyridylcarbonyl)-1-[2-14-mcrpho-linyl)ethyl]indole.

.
~ . . .

~5,~ 2 Herbst U.S. Patent 3,489,770 generically dlscloses compounds having the formula:

f ~

where, inter alia, Rl is "diloweralkylamino, pyrrolidinyl, piperidino and morpholino and R2 is ~ .. cyclo~lower)alkanoyl and adamantanylcarbonyl". Although not within the ambit of the above-defined genus, the Herbst patent also discloses a var;ety of species where R2 is an arylcarbonyl group.
Spe~ifically disclosed, for example, is the species "l-p-(chiorobenzoyl)-3-~2-morpholinoethyl)indole". The compounds are said to possess anti-inflammatory, hypo-tensive, hypoglycemic and CNS activities.
Tambute, Acad. Sci. Comp. Rend., Ser. C; 278 (20~, 1239-1242 (1974) discloses compounds of the formula:

[~.C6H5 ~ 2)n ~

where n is 2 or 3. No utility for the compounds i~ given.

SUMMARY
In a composition of matter aspect, the invention relate~ to 2~R2-3-R3-carbonyl-1 aminoalkyl-lH-indoles and their acid-addition salts which are useful as analgesic, anti-rheumatic and anti-inflammatory agents.

53~ 2 In a second composition of matter aspect, the inven-tion relates to 2-R2-3-R3-carbonylindoles useful as inter-mediates for the preparation of said 2-R2-3-R3-carbonyl-1-aminoalkyl-lH-indoles. Certain of the 2-R2-3-R3-carbonyl-indoles are also useful as anti-rheumatic agents.
In a third composition of matter aspect, the invention relates to 2-R2-1-amlnoalkyl-lH-indoles also useful as intermediates for the preparation of said 2-R2-3-R3-carbonyl-l-aminoalkyl-lH-indoles. Certain of the 2-R2-1-aminoalkyl-lH-indoles are also useful as analgesics.
In a process aspect, the invention relates to a process for preparing 2-R2-3-R3-carbonyl-1-aminoalkyl-lH-indoles which comprise~ reaçting a 2-R2-3-R3-carbonyl-indole with an aminoalkyl halide in the presence of an acid-acceptos.
In a second process aspect, the invention relates to a process for preparing 2-R~-3-R3-ca~bonyl-1-amino-alkyl-l~-indoles which comprises reacting a 2-R~ amino-alkyl-lH-indole with an arylcarboxylic acid halide or a cycloalkanecarboxylic acid halide in the presence of a Lewis acid.
In a third process aspect, the invention relates to a process Eor preparing said 2-R2-3-R3-carbonyl-1-aminoalkyl-lH-indoles which comprises reacting a 2-R2-3-~S R3-carbonyl-1-tosyloxyalkyl- or l-haloalkyl-lH-indole with an amine.
In a method aspect, the invention relates to a method of use of the said 2-R2-3-R3-carbonyl l-aminoalkyl-lH-indoles for the relief of pain or of rheumatic or inflammatory conditions.

In a second method aspect, the invention relates to a method of us~ of the said 2-R2-3-R3-carbonylindoles for the relief of rheumatic conditlons.
In a thi~d method aspect, the inv~ntion relates to a method of use of the said 2-R2-1-aminoalkyl-lH-indoles Eor the relief of pain.
DETAILE:D DESCRIPTION OF THE PREFERRED EMBODIMENTS
More specifically, the invention relates to 2-R2-3-R3-carbonyl-1-aminoalkyl-lH-indoles, which are useful a~
analgesic, anti-rheumatic and anti-inflammatory agents, having the formula:
R4 ~ R2~3 Alk-N=B
I
where:
R2 is hydrogen, lower-alkyl, ohloro, phenyl or benzyl (or phenyl or benzyl substituted by from one to two substituents selected from halo, lower-alkyl, lower-alkoxy, hydroxy, amino~ lower-alkyl-mercapto, lower-alkylsulfinyl or lower-alkyl-sulfonyl);
~o R3 is cyclohexyl, lower-alkoxycyclohexyl, phenyl (or phenyl substituted by from one to two substituents selected from halo, lower-alkoxy, hydroxy, benzyloxy, lower-alkyl, nitro, amino, lower-alkylamino, di-lower-alkylamino, lower-alkoxy-lower-alkylamino, lower-alkanoylam1no, benzoylamino, . tri~luoroacetylamino, lower-alkyl-~: .
' `
: :.

'~S 3~ ~
~. Ij . ; J j~B

sulfonylamino, carbamylamino, lower-alkylmercapto, lower-alkylsulf3n-yl, lower alkylsulfonyl, cyano, formyl or hy~roxyiminomethYl)~methylenedioxyphenyl~

3- or 4-hydroxy-1-piperidinylphenyl, 1-piperazinyl-S phenyl, (].~-imidazol-l-yl)phenyl,(l-pyrrolyl)-phenyl, aminomethylphenyl, guanidinylmethylphenyl, N-cyanoguanidinylmethylphenyl, styryl, lower-alkyl-substituted-styryl, fluoro-substituted-styryl, 2-or 4-biphenyl, 1- or 2-naphthyl (or 1- or 2-naphthyl substituted by from one to two substituen~s selected from lower-alkyl, lo~er-alkoxy, hydroxy, bromo, chloro, Eluoro, lower-alkoxycarbonyl, carbamyl, cyano, lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl or triEluoromethyl), thienyl, furyl, benzo[b]furyl, benzo[b]thienyl, quinolyl or (N-lower-alkyl)pyrrolyl;
~ is hydrogen or from one to two substit~ents selected from lower-alkyl, hydroxy, lower-alkoxy or halo in the 4-, 5-, 6- or 7- positions;
C=Z is C=O or C=NOH;
Alk is ~,~-lower-alkylene having the ormula (CH2)n, where n i5 an integer from 2 to 6, or such lower-alkylene substituted on the ~- or the ~-carbon atom by a lower-alkyl group; and N=B is azido, amino, N-lower-alkylamino, NrN-di-lower alkylamino, N-(hydroxy-lower-alkyl)amino, N,N-di-(hydroxy-lower-alkyl)amino, N-lower-alkyl-N-(hydroxy-lower-alkyl)amino, N-(lower-alkoxy-loWer-alkyl)amino, N-(halo~n-propyl)aminor ~-morpholinyl, 2-lower-alkyl~4-morpholinyl, 2rG-di-lower-al~yl-4 ' ~fl2~
- 6 - 227~9-319 morpholinyl, 4-thiomorpholinyl, 4-thi.omorpholinyl S-oxide,

4-thiomorpllolin~l-S,S-dioxide, l-piperidinyl, 3- or 4-hydroxy-l-piperidin~], 3- or 4-lower-alkanoyloxy-1-piperidinyl, 3- or 4-amino-1-piperidinyl, 3- or 4-(N-lower-alkanoylamino)-l-piperidinyl, 2-cyclohexylmethyl-1-piperidinyl, l-pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl, l-azetidinyl, l-p.iperazinyl, 4-lower-alkyl-l-piperazinyl, 4-lower-alkanoyl-1-piperazinyl, 4-carbo-l`.Jw~r-alkoxy-1-piperazinyl, he~ahydro-4}l-1,4-diazepin-4-yl or the N=B N~oxides thereof, with the proviso that N=B is not amino, when R2 is methyl, R3 is phenyl, R~ is hydrogen and Alk is (Cll2)3.
PreEerred compounds of formula I above are those where:
R2 is hydrogen or lower-alkyl;
R3 is phenyl, chlorophenyl, fluorophenyl, dichloro-phenyl, difluorophenyl, lower-alkoxyphenyl~ di-lower-alkoxy-phenyl, hydroxyphenyl, lower-alkylphenyl, aminophenyl, lower-alkylaminophenyl, lower-alkanoylaminophenyl, ~enzoylaminopl-enyl, trifluoroacetylaminophenyl, lower-alkylmercaptophenyl, lower-alkylsulfinylphenyl, lower-alkylsulfonylphenyl, cyanophenyl, aminometllylpllenyl, s-tyryl, 2- or 4-biphenyl, 1- or 2-naphthyl (or 1- or 2-napll-thyl substituted by lower-alkyl, lower-al~oxy, llydroxy, bromo, chloro or fluoro), 2-thienyl~ 2-, 3-, 4- or

5-benzo[b3furylr 2-, 3-, 4- or 5-benzo~b]thienyl or 2- or 3-(N-lower-alkyl)pyrrolyl;
R4 is hydrogen or lower-alkyl, lower-alkoxy, fluoro or chloro in the 4-, 5-, 6- or 7-positions;

D.N 356A

;a.~S~3 C=Z is C=O;
Alk is 1,2-ethylene ~-CH2CH~-), l-lower-alkyl-l, 2-ethylene l-CH~CH2-), 2-lower-alkyl-1,2-ethylene (-CH2CHR-), where R is lower-alkyl, 1,3-propyle~e ~-CH2CH2C~-) or 1,4-butylene: and N=B i~ 4-morpholinyl, 3 or 4-hydroxy-1-piperi-dinyl, l-pyrrolidinyl, 3-hydro~y-l~pyrrolidinyl, N-lower-alkylamino, N,N-di-lower-alkylamino, N,N-di-(hydroxy lower-alkyl)amino, l-piperazinyl, 4-lower-alkyl-l-piperazinyl or 4-lower-alkanoyl-1 piperazinyl.
Particularly preferred compounds oE formula within the ambit of the invention as defined above are those where: .
R2 is hydxogen or lower-alkyl:
R3 is phenyl, chlorophenyl, fluorophenyl, difluorophenyl, lower-alkoxyphenyl, lower-alkyl-phenyl, aminophenyl, lower-alkylaminophenyl, lower alkanoylaminophenyl, trifluoroacetylaminophenyl, lower-alkylmercaptophenyl, lower alkylsulfinyl~
phenyl, aminomethylphenyl~ 1 or 2-naphthyl (or 1-or 2-naphthyl substituted by lower-alkyl, lower-alkoxy, hydroxy, bromo, chloro or fluoro), 2-thienyl, 2-, 3-, 4- or 5-benzo~b]Euryl or 2 , 3-, 4-or 5-benzo[b]thienyl;
R4 is hydrogen, lower alkoxy, fluoro or chloro in the 4-, 5-, 6- or 7-positions1 C=~ is C=O;
Alk is 1,2-ethylene, 2-lower-alkyl-1,2-ethylene, 1-lower-alkyl-1,2-ethylene, 1,3~propylene or 1,4-butylene; and 5;.3~.~

N=B is 4-morpholinyl, 3- or 4 hydroxy-l-piperidinyl, l-pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl, N,N-di-lower-alkylamino, N,N-di-(hydroxy-lower-alkyl)amino, l-piperazinyl or 4-lower-alkyl-l-piperazinyl.
Other preferred compounds of formula I within the ambit of the invention as defined above are those wheres R2 is hydrogen or lower-alkyl;
R3 is phenyl, fluorophenyl, chlorophenyl, di-chlorophenyl, lower-alkoxyphenyl, di-lower-alkoxy-phenyl, hydroxyph~nyl, lower-alkanoylaminophenyl, benzoylaminophenyl, lower-alkylsulfonylphenyl, cyanophenyl, styryl, l-naphthyl, lower-alkoxy-substituted-l- or 2-naphthyl, 3-benzo[b~thienyl or 2- or 3-(N-lower-alkyl)pyrrolyl;
' R4 is hydrogen or lower-alkyl, lower-alkoxy, fluoro or chloro in the 4-, 5-, 6~ or 7-positions;
C=Z i~ C=~;
Alk is 1,2-ethylene, 1-lower-alkyl~1,2-ethylene, 2-lower-alkyl-1,2-ethylene, 1,3-propyl-lene or 1,4-butylene; and N=B is 4-morpholinyl or l-pyrrolidinyl.
Still other preferred compounds of formula I within the ambit of the .invention as defined above are those where:
R2 is hydrogen, lower-alkyl or phenyl:
R3 is cyclohexyl, lower-alkoxycyclohexyl, phenyl, fluorophenyl, lower-alkoxyphenyl, lower alkoxy-fluorophenyl f benzyloxyphenyl, methylene-dioxyphenyl, lower-alkylphenyl, di-lower-alkyl-phenyl, lower-alkylsulfonylaminophenyl, carbamyl-I '. 735~A
3~
g aminophenyl~ cyanophenyl, formylphenyl, oximino-methylenephenyl, (l-pyrrolyl1phenyl, guanidinyl-methylphenyl, N-cyanoguanidinylmethylphenyl, 2-naphthyl, 2-furyl or 2-benso[b]thienyl;
R~ is hydrogen or lower-alkyll hydroxy or lower-alkoxy in the 4-, 5-~ 6- or 7~positions;
C=Z is C=O or C-NOH
Alk is 1,2-ethylene or 1-lower-alkyl-1,2-ethyl-ene; and N~B is 4-morpholinylJ l-piperidinyl or 1-pyrrolidinyl or the N-oxides thereof.
Also considered to be within the ambit of the invention are species having the formulas Ia and Ib:
o 4 ~ 3 Alk-N-B
Ia Z
~ 3~3: A
CHz IC~ICH2-N=B
OH
Ib where R2, R3, R4, Alk, 2 and N=B have the meanings given above.
As used hereinJ unless specifically defined other~
~ wise, the terms lower-alkyl, lower alkoxy and lower-:~ 20 alkanoyl mean monovalent, aliphatic radicals, including ,~

- 10 - 227~9-319 branched chain radicals, of from one to about four carbon atoms, Eor example, methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, me~hoxy, e-thoxy, propoxy, isopropoxy, butoxy, sec.-butoxy, Eormyl, acetyl, propionyl, butyryl and isobutyryl.
~ s used herein, the term cycloalkyl means saturated alicyclic groups haviny from three to seven ring carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheY~yl and cycloheptyl.
As used herein, the term halo means fluoro, chloro or bromo.
In one me~hod, the compounds oE formula I where C=Z
is C-O are prepared by reacting a 2-~2-3-R3-carbonyl-11l-indole of Eormula II with an amino-lower-alkyl halide amino-lower-alkyl tosylate in the presence of an acid-acceptor:

R -~ X-Alk-N~

¦ Alk-N=B
II (C=Z is C=O) whe~e R2, ~3, R4, Alk and N=B have the meanings given above and X represents halogen or tosyloxy. The reaction is preferably carried out in an organic solventinert under the conditions of the reaction such as dimethylEormaMide (hereina~ter DMF), dimethylsulfoxide (hereinafter DMSO), a lower-alkanol or acetonitrile. Suitable acid-acceptors are an alkali metal carbonate, such as sodium carbona-te or potassium carbonate, or an alkali metal hydride/ such as ~25S~

sodium hydrider an alkali metal amide, such as soda~ide, or an alkali metal hydroxide, such as potassium hyd~oxide.
Preferred solvents are DMF and DMS0, and preferred acid-acoeptors are sodium hydride, potassium carbonate and potassium hydroxide~ The reaction is carried out at a temperature in the range from around 0C. to the boiling point of the solvent used.
The 2-~2-3-R3-carbonyl-1~-indoles of formula II
are in turn prepared by reacting a 2-iR2-indole with a lower-alkyl magnesium hal;de and reacting the resulting Grignard with an appropriate R3-carboxylic acid halide.
The reaction is carried out in an organic solvent inert under the conditions o~ the reaction, such as dimethyl ether, dioxane or tetrahydrofuran (hereinafter THF), at a temperature in the range from -SC. to the boiling point of the solvent used.
Certain compounds withih the ambit oE formula II, namely those o~ formula II':

4 ~ ~ C0-R3' II' where ~2 is hydrogen, lower-alkyl or phenyl; ~3' is fluoro-phenyl, difluorophenyl, lower-alkoxyphenyl, di-lower-alkoxyphenyl, lower-alkoxy-fluorophenyl, methylene-dioxyphenyl, aminophenyl, cyanophenyl, 2- or 4-biphenyl, 1- or 2- naphthyl or lower-alkoxy substituted-l~ or 2-naphthyl and iR4 is hydrogen or fluoro are novel species and comprise a further composition aspect of this inven-tion.

j.

L

- t t~

In another method, the compounds of formula I where C=Z is C~O are prepared by reacting a 2-~2-1-aminoalkyl-lH-indole of formula III with an ~ppropriate R3-carbo~ylic acid halide (R3-CO-X) in the presence o a Lewis acid, such as aluminum chloride, and in an organic solvent inert under the conditions of the reaction. Suitable solvents are chlorinated hydrocarbons such as methylene dichloride (hereinafter MDC) or ethylene dichloride (hereinafter BDC). The reaction is carried out at a temperature from 0C. to the boiling point oE the sol~ent used. The method is illustrated by thP reaction-4~7J--R 3 ~ 4 f~

Alk-N=B Alk-N=B
III I
(C=z is C=O) where R2, R3, R4, Alk, N=B and X have the meaninys given above.
The intermediate 2-R2-1-aminoalkyl-lH-indoles of Eormula III wherein R2, R4, Alk and N=B have the previously given meanings comprise yet a further composition aspect oE
the present invention. These compounds are prepared by one of two methods. In one method, a 2-R2~indole of formula IV
is reacted with an amino-lower-alkyl halide in the presence of an acid-acceptor, in an organic solvent inert under the conditions of the reaction using the same conditions de-scribed above for the preparation of the compounds of for-mula I by alkylation o the compounds oE formula II.
In a second method, a 2-R2-indole of formula IV is reacted with a halo-lo~er-alkanamide in the presence of a ~2~

strong base, and the resulting 2-R2-lH-indole-l-alkanamide of formula V is then reduced with lithium aluminu~ hydride.
The reaction of the 2-R2-indole of formula IV with the halo-lower-alkanamide is carried out in an appropriate S organic solvent, such as DMF, at a temperature f~om -5~C.
to about 50C. The reduction of the amides of formula V
with lithium aluminum hydride is carried out ;n an inert organic solvent, such as diethyl ether, THF or dioxane, at a temperature from -5C. to about 50C. The two methods are illustrated by the following reaction sequence:

Il \
IV

¦ 4 ~

Alk-N=B
III

~ _ /

~1;,3--R2 il~lk ' -CO-N=B
~I
where R2, R~, Alk and N=B have the meanings given above, and Alk' is lower-alkylene having the formula (CH2)n,, where n1 is an integer from 1 to 5 or 5UCIl lower-alkylene group substituted on the ~-carbon atom by a lower-alkyl group.
In another method for preparing the compounds oE
formula I where C=Z i~ C=O, a 2-R2-3-R3-carbonyl-1-(2-3 ~'~
~2749-3]9H
-14- D.N. 7356B DIV V
tosyloxy~lower-alkyl~- or (2-halo-lower-alkyl)-lli-indole of ormula VI is reacted with a molar equivalent amount of an amine, H-N=B, in an organic solvent inert under the con-ditions of the reaction, such as acetonitrile, a lower-alkanol or DMF. The reaction is preferably carried out by heating a solution of the reactants at the boiling point of the mixture The method is ill~strated by the reaction:

4 ~ ~ HN~ 4 t ~ C2_R3 Alk-X' Alk-N=B
VI

where R2t R3, R4 and N=B have the meanings given above, and X' represents a toluenesulfonyloxy or halo group.
The 2-R2-3-R3~carbonyl-1-(2-tosyloxy-lower-alkyl)-or 1-(2-halo-lower-alkyl)-lH-indoles of formula VI, whe~e Alk is 1,2-ethylene, are in turn prepared by reaction o a 2-R2-3-R3-carbonyl-indole o fo~mula II with a lower-alkyl lithium, for example n-butyl lithium, in an inert organic solvent, such as THF, dioxane or diethyl ether, ollowed by reaction of the resulting lithium salt with ethylene oxide.
Reaction of the resulting 2-~2-3-R3-carbonyl-1-(2-hydroxy-ethyl)-lH-indole with toluenesulfonyl chloride in the presence of an acid-acceptor affords the 1-(2-tosyloxy-ethyl)-lH-in~oles, while reaction of the product with a phosphorus trihalide affords the corresponding l-(2-halo-ethyl)-lH-indoles.
The 2-R2-3-R3-carbonyl-1-(2-halo-lower-al~yl)-lH-indoles of formula VI, where Alk has the other possible meanings, are prepared by reaction of a 2-R~-3-R3-carbonyl indole of Eormula II with an a,0-dihalo lower-alkane in the presence of a strong base, such as sodium hydride in an inert organic solvent, such as D~. The reaction generally occurs at ambient te~perature.
The compounds of formula Ia are prepared by reaction ofa2-R2-3-formyl-l~aminoalkyl-lH-indole with anappropriate methyl R3 ketone according to the reaction:

~ CHO ,~"~ ~CH=CHC-R3 R4- ~ + c~3-co R ~4- ¦r ¦~
N ~ R2 ~~ ~ N ~ R2 Alk-N=B Alk-N=B
Ia where R2, R3, R4, Alk and N=B have the meanings given above. The reaction is carried out in the presence of a mineral acid and in an organic solvent inert under the conditions of the reactlon. Preferred solvents are lower alkanol~, such as methanol or ethanol.
The compounds of formula Ib, where Z is C=O, are prepared by reaction of a 2-R2-3-R3-carbonylindole of formula II with an epihalohydrin in the presence of a strong base, such as an alkali metal hydride, in an inert solvent, such as DMF or DMSO, and reaction oEtheresulting2-R2-3-R3-carbonyl-1-[1-(2,3-epoxy)propyl]-lH-indole with an appropriate amine, H-N=B, according to the reactions:

GI~
3~

--~ 6--~4~ ~ r ~ XC~CII-Cl~2 R4~ R2 II /
~

~\~ C-R3 CH2ICHCH2-N=B
Ib where R2, R3, R4, Alk and N=B have the meanings given above.
Another method for preparing the compounds o~
formula I where R4 is 5-hydroxyand C=Z is C=O comprises reacting benzoquinone with an appropriate N~ lk-N=B)-N-(l-R2-3-oxo~3 R3-propenyl)amine of ~ormula VII in an inertr wa~er immiscible organic solvent, such as nitro-methane. The N-(N=B-alkyl)-N-(l-R2-3-oxo-3-R3-propenyl)-amine in turn is prepared by reaction of a 1,3-diketone, R2COCH2COR3, with an appropriate aminoalkylamine, B=N-Al};-NH2 under dehydrating conditions. The reaction is preferably carried out by heating a solution of the reactants in ~n inert, water immiscible solvent under a Dean-Stark trap. The method is repre~ented by the reaction ~equenceo "C~ ~ H2N-A~ =g ~ N/ \ R
Alk-N=B
VII

~ -~ r 3 ~
o VI~ ~ CO-R3 ~1 , o Alk-N=s By further chemical manipulations of various functional groups in the-compounds of formulas I, Ia and Ib prepared by one or more of the above-described methods, other compounds within the ambit of the invention can be prepared. For example ~he compounds where R3 is amino-phenyl are advantageously prepared from the corresponding species where R3 is nitrophenyl by reduction of the latter.
The reduction can he carried out either catalytically with hydrogen, for example over a platinum oxide catalyst at ambient temperature and 'n an appropriate organic solvent, such as a lower-alkanol, ethyl acetate or acetic acid or mixtures thereo, at hydrogen pressures from around 30 to 60 p.sOi.g., or alterpatively the reduction can be carried out chemically~ fo~ example with l~on in the presence of hydrochloric acid in an appropriate organic ~olventr for example a lower-alkanol. The reaction is carried out at temperatures from ambient to the bolling point of the solvent used for the reaction.
The aminophenyl compounds thus prepared can then be acylated or sulfonylated to pr'epare compounds where R3 is lower-alkanoylaminophenyl, benzoylaminophenyl, trifluoro-acetylaminophenyl or lower-alkylsulfonylaminophenyl by reaction of an appropriate acid anhydride or acid halide with the corresponding species where R3 is aminophenyl. It i~ advantageous, although not essential, to carry out the .. . :.

1 . 7356A

-~8-reaction in the presence of an acid acceptor, such as an alkali metal carbonate, or example potassium carbonate, or a tri~lower-alkylamine, such as trimethylamine or tri-etllylamine The reaction is carried out in an inert organic solvent at a temperature in the range from -5C. to around 80C. Suitable solvents are acetic acid, MDC, EDC
or toluene.
Other simple chemical transformations which are entirely conventional and well known to those skilled in the art of chemistey and which can be used for effecting changes in functional groups attached to the R3-carbonyl group, (C=O)R3, involve eleavage of aryl ether functions, for example with aqueous alkali or a pyridine hydrohalide salt to produce the corresponding phenolic compound (R3 is hydroxy-phenyl); preparation of compounds where R3 is phenyl sub-stituted by a variety of amine functions by reaction oE the corresponc7ing halophenyl species with an appropriate amine; catalytic debenzylation oE benzyloxy-substituted species to prepare the corresponding phenolic compo~nd (R3 is hydroxyphenyl); catalytic reduction of a nitrile function to produce the corresponding aminomethyl-substi-tuted species tR3 is aminomethylphenyl); saponifieation of amide groups to produce the corresponding amino compounds;
aeylation of hydroxy-substituted species to produce the corresponding esters; acylation of amino-substituted species to prepare the corresponding amides; oxidation of ; sulfides to prepare either the corresponding S-oxides or S,S-dioxides; reductive alkylation of amino substituted - 19 - 22749--319 ~-species to prepare the corresponding mono- or di-lower-alkyl-amino substituted species; reaction of amino-substituted s~ecies with an alk~li n~e~al isocyanate to prepare the corres-ponding carbamylamino-s~stituted species ~R3 is carbamyl-aminophenyl); reaction of an aminomethyl-substituted species with a di-lower-alkylcyanocarbonimidodithioate and reaction oE
the resulting product with ammonia to prepare the corresponding N-cyanoguanidinylmethyl-substituted species (R3 is cyanoguani-dinyl.methylphenyl); reduction oE a cyano-substituted species with sodium hypophosphite to prepare a corresponding formyl-substituted compound (R3 is Eormylphenyl); reaction of a Eormyl-phenyl species or a R3-carbonyl species with hydroxylamine to prepare the corresponding hydroxyiminometllylphenyl-substituted species (~3 is hydroxyiminomethylphenyl) or the R3-carbonyl oximes (C=Z is C-NOII); reaction of an aminophenyl species with a 2,5-di-lower-alkoxytetrahydroEuran to prepare a (l-pyrrolyl)-phenyl-substituted species (R3 is l-pyrrolylpllenyl); oxidation of tlle N=B function, for example by fermen-tative procedures, or by oxidation with an organic peracid, such as perchloro-benzoic acid, to prepare the corresponding N-oxides; or reaction oE a l-aminoalkyl-lll-indole of formula III where 1l2 is hydrogen with hexamethylenepllosphoramide followed by a lower-alkyl halide to prepare the corresponding compounds of formula III where R2 is lower-alkyl..
The compounds of formulas I, Ia, Ib and III in free base form are converted to the acid-addition salt form by interaction of the base with an acid. In like manner, the free base can be reyenerated from the acid-addition salt Eorm in conventional manner, that is by -treating the salts ~ 53~2 with cold, weak aqueous bases, for example alkali metal carbonates and alkali metal bicarbonates. The bases thus regenerated can be interacted with the same or a di~ferent acid to give back the same or a different acid-addition s~lt. Thus the novel bases and all of their acid-additio~
salts are readily interconvertible.
It will thus be appreciated that formulas I, Ia, Ib and III not only represent the structural configuration of the baces of formulas I, Ia, Ib and III but are also repeesentative of the structural entities which are common to all of the compounds of formulas I, Ia, Ib and III, whether in the form of the free base or in the form of the acid-addition salts of the base. It has been found that, by virtue of these common structural entities the bases of ; 15 formulas I, Ia and Ib, and certain of the bases of formula III, and their acid~addition salts have inherent pharma-cological activity of a type to be more fully described hereinbelow. This inherent pharmacological activity can be enjoyed in useful form for pharmaceutical purposes by employing the free bases themselves or the acid-addition salts formed from pharmaceutically acceptable acids, that is acids whose anions are innocuous to the animal organism in effective doses oE the salts so that beneficial properties inherent in the common structural entity represented by the free bases are not vitiated by side effects ascribable to the anions.
In utilizing this pharmacological activity of the salts of the invention, it is preerred, of course, to use pharmaceutically acceptable salts, Although water insolubility, high tox~city or lack o crystalline 3~
-21~
character may make some particular salt species unsuitable or less desirable for use as such in a given pharmaceutical application, the water-insoluble or toxic salts can be con-verted to the corresponding pharmaceutically acceptable bases by decomposition of the salts with aqueous base as explained above, or alternatively they can be converted to any desired pharmaceutically acceptable acid-addition salt by double decomposition reactions involving the anion, for example by ion-exchange procedures.
Moreover, apart from their usefulness in pharma-ceutical applications, the salts are useful as characteriz-ing or identifying derivatives of the free bases or in isolation or purification procedures. Like all of the acid-addition salts, such characterizing or purification salt derivatives can, if desired, be used to regenerate the pharmaceutically acceptable free bases by reaction of the salts with aqueous base, or alternatively they can be con-verted to a pharmaceutically acceptable acid-addition salt by, for example, ion-exhange proced~res.
The novel feature of the compounds of the invention, then, resides in the concept of the bases and cationic Eorms of the new 2-R2-3-R3-carbonyl-1-aminoalkyl-lH-indoles of formulas I, Ia and Ib and the 2-R~ aminoalkyl-lH-indoles of formula III and not in any particular acid moiety or acid anion associated with the salt forms oE the compounds; rather, the acid moieties or anions which can be associated with the salt orms are in themselves neither novel nor critical and therefore can be any acid anion or acid--like substance capable of ~alt Eormation with the bases ~z~

Thus appropriate acid-addition salts are those derived from such diverse acids as ~ormic acid, acetic acid, isobutyric acid, alpha-mercaptopropionic acid, malic acid, fumaric acid, succinic acid, succinamic acid, tar-taric acid, citric acid, lactic acid, benzoic acid, 4-methoxybenzoic acid, phthalic acid, anthranilic acid, 1-naphthalenecarboxylic acid, cinnamic acid, cyclohexane-carboxylic acid, mandelic acid, tropic acid, crotonic acid, acetylenedicarboxylic acid, sorbic acid, 2-furancarboxylic acid, cholic acid, pyrenecarboxylic acid, 2-pyridine-carboxylic acid, 3-indoleacetic acid, quinic acid, sulfamic acid, methanesulEonic acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzene-sulfinic acid, butylarsonic acid, diethylphosphonic acid, p-aminophenylarsinic acid, phenylstibnic acid, phenyl-pho.sphinous acid, methylphosphinic acid, phenylphosphinic acid, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydriodic acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrocyanic acid, phospho-tungstic acid, molybdic acid, phosphomolybdic acid, pyro-phosphoric acid, arsenic acid, picric acid, picrolonic acid, barbituric acid, boron trifluoride and the like.
The acid-addition salts are prepared by reacting the free base and the acid in an organic solvent and 2S isolating the salt directly or by concentration of the solution.
In standard pharmacological test procedures, the compounds of formulas I, Ia and Ib have been found to pos-sess analgesic, anti~rheumatic and anti-inflammatory activities and are thus useful as analgesic, anti-rheumatic L , 7 ~ A
53~2 and anti-inflammatory agents. Certain of the compounds of formula II have been Eound to possess anti-rheumatic activity, and certain of the compounds of formula III have been found to possess analgesic activity, thus indicating S usefulness of those species as anti-rheumatic and analgesic agents, respectively.
The test procedures used to determine the analgesic activities of the compounds have been described in detail in the prior art and are as follows: The acetylcholine-induced abdominal constriction test, which is a primary analgesic screening test designed to measure the ability of a test agent to suppress acetylcholine-induced abdominal constriction in mice, described by Collier et al., Brit.
J. Pharmacol. Chemotherap. 32, 295 (1968), a modification of the anti-bradykinin test, which is also a primary analgesic screening procedure, described by Berkowitz et al., J. Pharmacol. Exptl. Therap. 177, 500-50a (1971), Blane et al., JO Pharm. Pharmacol. 19, 367-373 (1967), Botha et al., Eur. J. Pharmacol. 6, 312-321 (1969~ and Deffenu et al., J. Pharm. Pharmacol. 18, 135 (1966)s and the rat paw flexion test, described by Kuzuna et al., Chem.
Pharm. Bull., 23, 1184-1191 (1975), Winter et al., J.
Pharm. Exptl. Therap., 211, 678-685 (1979~ and Capetola et al., J. Pharm. Exptl. Therap. 214, 16-23 (1980).
An~i-rheumatic and ant;-inflammato~y;activities of the compounds of the invention were determined using the developing adjuvant arthritis ASSay in rats, the plasma fibronectin assay in arthritic rats and the pleurisy macro-phage assay in rats. The developing adjuvant arthritis as-say was used in conjunction with the plasma fibronectin as-say as a primary screening method in the evaluation of com-3~;~

pounds for potential use as disease modifying anti-rheumatic drugs. The procedure used to induce arthritis in rats is a modification of the methods published by Pearson, J. ChronO Dis. 16, 863-874 (1973) and by Glenn et al., j Amer. J. Vet. Res. 1180~1193 (1965). ~rhe adjuvant induced arthritiq bears many o the traits of rheumatoid artllritis.
It i~ a chronic, progressive, deforming arthritis of the peripheral joints, with a primary mononuclear cell response consisting of bone and joint space invasion by pannus. In order to detect disease modifying anti-rheumatic drug activity, drug treatment i5 started before the disease has become irrevocably established. Since such drugs are not designed to be administered prophylactically, drug treat-ment of adjuvant arthritis is initiated at a time when the disease is developing but is not yet irreversible. Animals develop signi~icant systemic arthritic disease which can be measured by swelling of the non~injected rear paw (NIP) lS
to 20 days following an initial injection on day 1 of com-plete Freund's adjuvant into the right hindfoot paw.
The important role played by fibronectin in arthritis has been evidenced by clinical [Scott et al., Ann. Rheum Dis. 40, 142 (1981)] as well as experimental [Weissmann, J. Lab. Clin~ Med. 100, 322 (1982)] studies.
Plasma fibronectin measurements are made using the tech-nique of rocket immuno-electrophoresis. Fibronectin levels in the arthritic rat are significantly higher than in normal animals. Nonsteroldal, anti-inflammatory drugs have no influence on the enhanced ibronectin levels seen in arthritic rats, while disease modifying anti-rheumatic drugs cause a significant decrease in plasma fibronectin.

V 7~A

-25_ The pleurisy macrophage assay is designed to define anti-arthritic drugs ~hich inhibit macrophage accumulation in the pleural cavity following injection of an inflam-matory stimulus. Standard disease modifying anti-rheumatic drugs are active in this assay while nonsteroidal anti~inflammatory druys are not. The activity of species in the pleurisy macrophage model thus indicates disease modifying anti-rheumatic drug activity. The macrophage i5 the characteristic cell type in chronic inflammatory responses in the rheumatoid synovium as well as other si~es. When activated, macrophages produce a large variety of secretory products, including neutral proteases which play a destructive role in arthritis [Ackerman et al., J.
Pharmacol. Exp. Thera. 215, 588 (19B0)]. The in vivo model of inflammatory cell accumulation in the rat pleural cavity permits quantitation and di~ferentiation of the ; accumulated cells. The cellular components are similar to those seen in the inflamed synovium. It has been hypo-thesized that drugs which are effective inhibitors of pleurisy macrophage activity may also be effective in slow-ing or reversing progression of arthritic disease (Ackerman ), and the procedure used is a modification of the method published by Ackerman et al.
The co~pounds of formulas I, Ia, Ib, II and III of the invention can be prepared for pharmaceutical use by -~ incorporating them in unit dosa~e form as tablets or capsules or oral or parenteral administration either alone or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearateJ gum D.N 35GA

acacia and the like. Still further, the compounds can be formulated for oral ~r parenter~l administration either in aqueous solutions of the water soluble salts or in aqueous alcohol! glycol or oil solutions or oil-water emulsions in the same manner as conventional medicinal substances are prepared.
The percentages of active component in such com-positions may be varied 60 that a suitable dosage is obtained. The dosage administered to a particular patient is variable, depending upon the clinician's judgment using as criteria: the route of administration, the duration of treatment, the size and physical condition of the patient, the potency of the active co~ponent and the patient's res-ponse thereto. An efEective dosage amount of the active component can thus only be determined by the clinician after a consideration of all criteria and using his best judgment on the patient's behalf.
The molecular structures of the compounds of the invention were assigned on the basis of study of their 2~ infrared, ultraviolet and NMR spectra. The structures were confirmed by the correspondence between calculated and found values for elementary analyses for the elements.
The following examplas will further illustrate the invention without, however, limiting it thereto.
All melting points are uncorrected.

~5~3~

~XEMPLARY DISCLOSURE
Preparati~n of Intermediates A. The_Com~ounds of Formula II:
Preparation lA
To a solution of 0.05 mole of methyl magnesium bromide in about 45 ml. of anhydrous diethyl ether at 0C.
under a nitrogen atmosphere was added, dropwise, a solution containing 6.0 g. (0.04 mole) of 2,7-dimethylindole in 30 ml. of anhydrous ether. When addition was complete r the reaction mixture was stirred at room temperature for one hour r then cooled in an ice bath and treated dropwise with a solution of 8.53 g. (0.05 mole) of 4-methoxybenzoyl chloride in 20 ml. of anhydrous ether. The mixture was stirred at room temperature for approximately twelve hours, the~ on a steam bath for two hours and then treated with ice water. Excess ammonium chlsride was added, and the ether layer was separated, dried and evaporated to dry-ness to give a solid which was collected by filtration and washed thoroughly witll water and ether to give 8.5 9. (76~) of 2L7-dimethyl-3-(4-methoxybenzoyl)indole, m.p, 132-184C.
Preparations lB - lAU
Following a procedure similar to that described above in Preparation 1~, substituting for the 2,7-dimethyl-indole and the 4-methoxybenzoyl chloride used therein an appropriate 2-R2-R4-indole and an appropriate aroyl-chloride (R3CO-Cl), the following species of formula II
listed in Table A were prepared. In some instances the products, without further purificationr were used directly in the next step of the synthesis of the final products of . , .

i ~. /3~
3:~

--2~-formula I, and no ~elting points were taken. In a few cases, the weight of the products was not obtained, and so calculation of yields of products in those instances are not possible. Here and elsewhere in the tables included S with this specification, the melting point of the product (in ~C.) and the recrystallization solvent are given in columns headed "m.p./Solv.", and the yield, in percent, of product is given in columns headed "Yield".

~5~
-2~

Tahle A
Preprl. R2 R3 R4 m.p.~Sclv~ Yi~l~
lB CH3 3 6 4 215-217/DMF-H20 85 lC CH3 2~fury1 - 98 lD CH3 4-CH3SC6H4 lE CH3 4 2 6 4 23 lF CH3 4-c~l3ocfiH4 S-F 199-202/i-PrOH
lG CH3 4-CE13OC6H4 7-F 204-205/H20 42 lH C ~3 4 C 3 ~6 4 7-C H30 68 1-I ~ H 3 4-C H 3 O c 6 }~ F ~a) 5S
lJ CH3 4-FC,~ - 19~201~EtOH 3a lR CH3 3'4-~CH2OC6H3 - 21~213/i-PrOH 60 lL CH3 3~enzo[b]thienyl - 181 183 64 lM CH3 2~enzo[b]h~ 218-220/i-PrOH 62 lN CH3 2-CH3OC6H4 - 203-206/i-PrOH 75 1-0 CH3 3-F-4-CH30C6H3 - 16~165/EtOH 39 lP c~3 2~aphthyl - 208-213/i-PrOH 57 lQ R 4-CH3Oc6H4 ~CH3 189-192/EtOE1 42 lR C~3 3-FC6H4 - 64 lS CH3 6 4 216-21B/iPrOH 44 lT CH3 4-CNC6~14 - 211~213/EtOAc 7 lU CH3 C6H5 4-CH3 176-179/EtOAc 65 lV CH3 2 5 6 4 199-20VEtOA-~ 7Q
lW CH3 3-N2C6H4 - 218-221/DMF-H20 20 lX CH3 4 3 6 4 207-209/EtoH 60 lY CH3 3-CH30C6H4 - 163-164~EtOAc 63 lZ H 4 CH30C6H,~ 80(b) lAA C6H5 4-CH30(: 6H4 25 lAB H C6E~5 5-CH30 46 lAC CH3 4 3 6 4 6 CH3 5 lAD CH3 4-N2C6H4 6 CH3O 73 lAE CH3 C~jH5 ~ 18~186/MeOB 64 lAF 6 5 241-24VMeOf~ 38 lAG CH3 4-ClC6H4 - 183-185/MeOH 34 lP~H CH3 4-CH3OC6H4 6-C1 58 3.AI CH3 4-CH3OC6H4 6-C6H5CH2O Sl lAJ CH3 2'3-OC~l2OC6H3 ~ 239.~240/CH3CN 9 lAK CH3 6 5 6 4 238-240/MeOH 3g lAL C~8 4 6H~C6H4 225-228 56 3~

Table A conbd~

Prepn. R2 R3 R4 m.p./Sclv. Yield __ _ _ _ lA M c~l3 l-naph~lyl - 223-224/i-PrOH 69 lA N c~3 2,3-~CH3O)2C6~3 185-187 87 lA O C H3 3~S~(CH30)2C6H3 ~ 182-184 85 lAP CH (CH3)2 4-CH30C6H4 176-178/EtOA~ 44 lA Q C H(C H3)2 4-CH3OC6H4 5-F 173-175 11 lAR CH3 2-FC6H~ ~F 247 249/i-PrOH 10 lAS C H 3 4-C H 3 O-l~naphthyl - 286-289/i-PrO H 24 lAT C H3 4-C5H5C6H4 5-F 234-235.5/EtOH 36 lA U C H3 4-CH3OC6H4 - 200-203 97 (a~ Product cons~sted of a mixture oE the ~fluoro and the 7-~Luoro isomers (b) T wo m(ilar equivalenb; of the Grignard reagent used, thus res~ting in acylati~n at both the 1- and 3 posi~ions of indc~ derivative. The de~red product was obtained by heat:ing a mixture of the crude product in methan~
and sodium hydroxide.

...
.

~. 735 Preparation lAV

A mixture of 50 g. ~0.03 mole) oE phenylmercapto-acetone and 76.8 9. (0.3 mole) of 3-benzyloxyphellylhydra-zine in 750 ml of ethanol was heated on a steam bath for six hours and then stirred at room temperature for about twelve hours. The solid which separated was collected, washed with water and the filtrate set aside. The solid was dissolved in methylene dichloride, the organic solution was washed with water, then with dilute hydrochloric acid, dried over magnesium sulfate, filtered and taken to dryness to yield a first crop oE ceude produc~ which was stirred with ether for about forty-eight hours and then filtered and dried to give 56 g. of product. The original filtrate, previously set aside, was mixed with methylene d.ichloride, and the organic layer was washed with water, then with dilute hydrochloric acid, dried over magnesium sulfate, filtered and concentrated to dryness to give 40 g. of additional product which wa~ recrystalli~ed from diethyl ether/methyl~ne dichloride to give 29.7 9. of product (com-bined yield 71.7 9., 69%) of 2-methyl-3-phenylmercapto-6-benz~loxyindole~ m.p. 146-148C.
A mixture of 25 9. (0.072 mole) of the latter with 50 teaspoons of a Raney nickel/ethanol suspension in 1 lit2r of ethanol was heated under reflux for three hours, : ~tirred at ambient temperature for about twelve hours, then ~ 25 refluxed for an additivnal three hours and the catalyst 3;~

removed by filtration The filtrate was taken to dryness ln vacuo to give an oil which was passed through a pad of Florisil and eluted with ethyl acetate. Evaporation of the solution to dryness aEforded 5.2 g. (26~) of 6-hydroxy-2-methylindole A mixture of 5 9. t0.03~ mole) of the latter, 5.9 ml (0.051 mole~ of benzyl chloride and 13.8 9. (0.1 mole) of potassium carbonate in 200 ml of DMF was stirred at room temperature for two hours, then heated on a steam bath Eor two hours and the mixture poured into ice/water.
The solid which separated was collected, dissolved in ethyl acetate, and the organic solution was washed with water, then with brine, dried over magnesium sulfate, filtered and taken to dryness to give 2.5 9. of 6-benzyloxy-2-methyl-indole, m p. 90-93C., used as the starting material ~or the preparation of the compound o Pr~paration lAI in Table 1 aboveO
Preparation 2 To a solution of 20 g. (0.071 mole) o 2-methyl-~0 3-(4-methylmercaptobenzoyl)indole (Preparation lD) in 400 ml. of chloroform was added, dropwise with stirring, a solution of 16.7 g~(O.Q81 mole) of 3-chloroperbenzoic acid (80~) in 170 ml. of chloroform while cooling the mixture in an ice~methanol bath. When addition was complete, the solution was stirred at room temperature for approximately twalve hours and then washed three times with saturated sodium bicarbonate solution and dried over magnesium sulfate T~ mixture was iltered, ~he filtrate was ~ 7356A

;3~

concentrated to near dryness~; and the solid which separated was collected and recrystallized Erom ethyl acetate to give 14.5 9. (69%) of 2-meth~1-3-(4-methylsulfinylben indole.
Preparation 3 2-Methyl-3-(4-nitrobenzoyl)indole (Preparation lE) (11.2 9., 0.04 mole) dissolved in a solution of 100 ml. of glacial acetic acid and 200 ml. of ethyl acetate was reduced with hydrogen over 0.6 g. of platinum oxide catalyst in a Parr shaker, and when reduction was complete, in about two and a half hour~, the catalyst was removed by filtration and the solvent taken off in vacuo to leave 11.4 g. of crude product, whlch wa~ recrystallized from ethanol to give 4.5 q. (45~) of 2-methyl-3-(4-aminobenzoyl~-indole, m.p. 220-223 C.
B. The~ ounds of Formula_III
(a~ B~_Alkylation o the Compounds of Formula IV
Preparation 4A
~o a stirred suspension of 229.5 9. (1.22 moles~ of N-(2-chloroethyl)morpholine hydrochloride in 300 ml. of DMSO at ambient temperature was added 200 9. ~3.03 moles) of 85~ potassium hydroxide pellets, and the suspension was stirxed for five minutes and then treated dropwise at ambient temperature with a solution of 133.7 9. (1.0 mole) of 2-methylindole in 140 ml. of DMSO. The temperature of the reaction mixture gradually rose during the addition of the 2-methylindole as well as on stirring after addition . .
., .

r . 7 ~A

was complete. When the temperature reached 78C., the mix-ture was cooled in a water bath until the temperature sub-sided to 75C., and the mixture was stirred for a total of three and a half hours while the temperature subsided to ambient. The mixture was then diluted with 1 liter of water and extracted with toluene. The extracts were washed with water, dried over magnesium sulfate and taken to dry-ness in vacuo, and the residual dark oil was crystallized from heptane to give 224 9. (92%) oE 2-methyl-1~2-(4-morpholinyl)ethyl]-lH-indole, m p 6~-65C
.
Preparation 4B
Following a procedure similar to that described above in Preparation 4A, 20.09. I0.134 moleJ of 5-1uoro-2-methylindole were reacted with 24.1 g. (0.147 mole~ of 4-(3-chloropropyl)morpholine in 46 ml. o dry DMF in the pre~ence of ~.0 g. ~0.201 mole) of a 60% mineral oil dis-persion of sodium hydride. The product was isolated in the form of its maleate salt to give 30.0 9. ~81~) of 5-fluoro-2-methyl-1-[3-(4-morpholinyl~propyl]-lH-indole maleate, m.p. 165-167~C~
Preparation 4C
Following a procedure similar to that described in Preparation 4A, 50 g. (0.43 mole~ of indole were reacted with 159 9. (0.85 mole) of 4-(2-chloroethyl1morpholine in 850 ml. of dry DMF in the presence of 209 g. ~0.50 mole) of a 60% mineral oil dispersion of sodium hydride. The product was isolated in the form oF the free base to give 45.6 g. (46~) of 1~[2-~4~ pholin~1)ethyl]-lH-indole.

L . 7 :¦~bt~

Pre~aration 4D
To a ~tirred suspension of 322 9. (0.81 mole) of a 60% mineral oil dispersion oE sodium hydride in 250 ml. of dry DMF was added dropwise a sol~tion of 100 9. (0.67 mole) of 5-Eluoro-2-methylindole in 300 ml.
of dry DMF. The mixture WAS stirred at ambient temperature for thirty minutes and then treated dropwise with cooling with a solution of 121.5 g. (0.67 mole~ of ethyl ~- ~
bromopropionate. Workup of the reaction mixture, after quenching with water and extraction of the product with ethyl acetate, afforded ~yl ~. -(5-fluoro-2-methyl-l~indolyl)-E~ ionate.
The latter was reduced with 525 ml. of a l.M solution of diisobutyl aluminum in llS0 ml. of toluene to give 130 g. ~94~) of 5-fluoro-2-methx~-1-51-methyl-2-hydroxyethyl)-lH-indole.
_ The latter, on reaction with 144 9. (0.76 mole) of p-toluenesulEonyl chloride in 350 ml. of pyridine using the procedure described in Preparation 7A afforded 65 9. (20~) of S-fluoro-2-methyl-1-[1-methyl-2-(p-toluene-sulonyloxx~ethyl]-lH-indole, m.p. 136-140C.
~b) Via the Amides_of Formula V
Preparation 5A
Following a procedure similar to that described in Preparation 4 above, 32.8 g. (0.25 mole3 of 2-methylindole in 160 ml. of dry DMF was reacted with 13.4 9. (0.~8 mole) of a 50% mineral oil dispersion of sodium hydride in 200 ml. of dry D~F, and the resulting sodium salt was then reacted with 62 g. ~0.28 mole) of 4~ bromopropionyl)-morpholine in 160 ml. of DMF to give $5.3 g. (59%) of 4-[~-~ .

5~

The latter (130 g., 0.48 mole), dissolved in 900 ml. oE THF, was added to 80 ml. 10.80 mole) of a solution of boron methyl sulfide complex in THF under nitrogen while cooling in an ice bath. When additi~n was complete, the mixture was stirred for eighteen hours at room temperature, heated under reflux for four hours, quenched by addition o~
about 1 liter of methanol, ~oiled for about fiEteen min-utes, concentrated essentially to dryness and then diluted with aqueous 6N hydrochloric acid. The mixture was ex-tracted with methylene dichloride, and the raEfinate was basified with 35% sodium hydroxide an~ extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and concentrated to dryness to give 42.6 g.
~34~) of 2-rnethyl-1-[1-methyl-2-(4-morpholinyl)ethyl]-lH-indole as an oil~ A portion of the latter was reacted with methanesulfonic acid to give the monomethanesulonate as the ~:1 hydrate, m.p. 154-157C.
PreFaration 5B
Following a procedure similar to that described in Prepara~ion 5~ above, 29.29 9. (0.25 mole) of indole in 200 ml. of dry DMF was reacted with 13.4 g. (~.28 mole) of a 50~ mineral oil dispersion of sodium hydride in 200 ml. of dry DMF and the resultiny sodium salt reacted with 62.0 9.
~0~28 mole) of 4-(a-bromopropionyl)morpholine in 200 ml. of 2S dry DMF and the product recrystallized from isopropanol to give 13.7 g. (21%) oE 4-[a (lH-indol-l-~l)pr~piorlyl]-mor~hQline, ~.p. 92-94C. The latter (20 g., 0.078 mole~
~; in 300 ml. oE diethyl ether was reduced with 3.12 g.
(0.078) mole of lithium aluminum hydride in 100 ml. of di-ethyl ether to give 17 g. (90%) of 1-[l~met~yl-2-~4-morpho~
linyl)eth~l]-lH-indole, m.p. 35-37C.
, ~. . .

1).11, ' ' ~

Following a procedure similar to that described in Preparation 5B, 83 gO (0.53 mole) of 2-methylindole was reacted with 30 90 (0.7S mole) oE a 60% mlneral oil dis-persion of sodium hydride, and the resulting sodium salt was reacted with a molar equivalent amount of 4-(a-bromo-butyryl)morpholine in 100 ml. of DMF. The crude product thus obtained was reduced with 25 g. (0.66 mole3 of lithium aluminum hydride in 500 ml. of THF. The product was isolated in the form of the hydrochloride to give 53.4 g.
10 (27%) of 2-meth~l-1-[1-ethyl-2-(4-m_ ~holinyl?ethyl]-lH-indole hydrochlorlde, m.p. 159-162C. (from ethyl acetate-ether).
Pre~aration 6 To a solution of 23 g. (0.1 mole) of 1-~2-~4-morpho-15 linyl)ethyl]-lH-indole (Preparation 4C) in 120 ml. of T~IF
was added 60 ml. of 2.1M butyl lithium in hexane while maintaining the temperature at 0C. The mixture was allowed to warm up to room temperature and was then treated with 18 ml. of hexamethylphosphoramide ~ollowed by 10 ml.
20 of ethyl iodide while maintaining the temperature at 0C.
The mixture was then quenched with ice, extracted with etherv and the combined organic extracts were washed first with water, then with brine, dried over magnesium sulfate, taken to dryness and chromatographed on silica gel, eluting 25 with 40:50 ethyl acetate:hexane. Four fractions were obtained which, on evaporation to dryness, afforded 4.0 g.
of a yellow oil from the first fraction and 9.6 g., 3.6 g.
and 4.2 g. of 5Olid material in the next three fractions.
These fractions were recrystallized from hexane to 30 give B.3 g. (32~) of 2-eth~ [2-(4-morpholinyl)ethyl]-lH-indole, m.p. 59-60.5C.

53:~

38- D.N. 7356B DIV V
C. The_Com~ounds of Formula V-I
Preparation 7A
To a suspension of 50 9. tO.l9 mole) of 2-methyl-3-(4-methoxybenzoyl)indole ~Preparation lAU) in 400 ml. of THF was added, over a one and a hal~ hour period, 74.25 ml.
(0.19 mole~ of a 2.6M solution of n-butyl lithium in hexane. The reaction mixture was stirred for one hour at 0C., at room temperature for orty-Eive minutes, recooled to O~C. and treated dropwise, over a thirty minute period, with a solution of g307 ml. (0.19 mole) o~ a 2.06 M
solution of ethylene oxide in THF. The reaction mixture was gradually allowed to warm to room temperature and then treated with 200 ml. of a saturated ammonium chloride solution. The solvent was removed in vacuo, the residual solid was filtered, washed with water and extracted with boiling ether, and the ether extracts were taken to dryness to give 23 g. (39~) of 2-metl-yl-3-(4-methoxyben20Yl)-1~(2-hydroxyethyl)-lH-indole, m.p. 75-78C.
A solution of 10 9. ~0.032 mole) oE the latter and 6.48 g. (0.034 mole) of p-toluenesulfonyl chloride in 100 ml. of pyridine was stirred at room temperature for about twelve houes and the reaction mixture diluted with ethyl acetate and washed with water. The organic layer was separated, dried over magnesium sulfate, filtered and con-centrated to dryness to give a brown gum. The latter was dissolved in methylene dichloride and the solution chroma-;~ tographed on a short column of Florisil to give 7.8 g.
(52~) o~ 2-methyl-3-(4-methoxybenzoyl)-1-~2-p toluene-sulfonyloxyethyl)-lH-indole, m.p. 62-65C.

* Tr~demark D. I`J o 7 ~ A

Preparation 7B
F~llowing a procedure similar to that described ~n Preparation 7A above, 9.75 9O (0.0375 mole) of 2-methyl-3-(4-cyanobenzoyl)indole (Preparation lT) in 125 ml. of THF
was treated with 16.65 ml. (0.04 mole~ of a 2.4M solution of n-butyl lithium in hexane followed by 11.4 ml. of a 3.5M solution of ethylene oxide in THF to give 2-methyl-3-~4-cy~nobenzo~yl?-1-(2-hydroxyethxlL-lH-indole Reaction .

of 30.4 g. (0.1 mole~ of the latter with 21.0 9. (0.11 mole) o~ p-toluenesulfonyl chloride in 50 ml. of methylene dichloride in the presence of 50 ml. of 35~ sodium hydroxide and 0,9l g. (0.004 mole) of benzyl trimethyl-ammonium chloride afforded 38.3 9. (84%) of 2-methyl-3-(4-cyanobenzoyl~-1-(2-p-toluenesulfonyloxyethyl)-lH-indole, m.p. 165-167C.
Preparation 7C
Following a procedure similar to that described in Preparation 7A above, 20 9. (0.1 mole~ of 2-methyl-3-t4-ethylbenzoyl~indole (Preparation lV) in 200 ml. of THF
was treated with 51 ml. (0.11 mole) of a 2.15 M solution of n-butyl lithium in hexane followed by 6.16 9. (0013 mole) of ethylene oxide to give 18 g. (73~) of 2-methyl-3-(4-ethylbenzoyl)-1-(2-hydroxyethyl~-lH-indole. Reaction of the latter (0,058 mole) with 14.32 g. (0.075 m~le) of p-toluenesulfonyl chloride in 400 ml. of methylene dichloride in the presence of 50 ml. of 35~ sodium hydroxide and 1.6 g. (0.0076 mole) of benzyl trimethylammonium chloride af~orded 27 9. (95~) of 2-methyl~3-(4-ethylbenzoylj~ 2-p-toluenesulfonyloxyethyl)-lH-lndole as a red oil.

.
.

D.N. 7_~A

Preparation_7D
A solution oE ~.0 g. (0.068 mole) of 2-methyl-5 fluoro-3-~4-methoxybenzoyl~indole ~Prepa~ation lF~ in 100 ml of dry DMF was cooled in an ice bath at 0C and then treated with 18.17 g. t0.09 mole) of 1,3-dibromopropane.
The solution was stirred for a few minutes at 0C, then treated portionwise with 1.08 g. (0.027 mole) of a 60~
mineral oil dispersion of sodium hydride, stireed for about fifteen minutes in an ice bath, then for an additional twelve hours at ambient temperature, treated with a small amount of water and taken to dryness in vacuo. The residue was partitioned between water and methylene dichloride, the organic layer was separated, washed first wi th water, then with brine and then dried and taken to dryness. Crystal-lization of the residue from ethanol aEEorded 4 9. ~55%) of 1~3-bromopropyl)-5-fluoro-2-methyl-3-(4-methoxybenzoyl~-lH-indole, m.p. 133-135C.
Preparation 7E
Following a procedure simllar to that described in Preparation 7D above, 60 9. (0.23 mole) of 2-methyl-3-(4-methoxybenzoyl)indole (Preparation lAU) was reacted with 244.1 g. (1.13 mole) of 1,4-dibromobutane in 200 ml of DMF in the presence of 13.8 9. (0.34 mole) of a 60~
mineral oil dispersion of sodium hydride~ and ~he peoduct recrystallized Erom ethyl acetate/hexane to give 5.0 gO of ~14-bromobutyl)~2-methyl-3-~4-methox~benzoyl)-lH-lndole, m.p~ 83-86C.

22749-319E~
-41- D.N. 7356s DIV V

Preparation 7F
Following a procedure similar to that descrihed in Preparation 7D above, 35 9. (0.122 mole) of 2-methyl-3~
naphthylcarbonyl)indole (Preparation lAM) was reacted with 12~ 9. (0.614 mole) of 1,3-dibromopropane in 700 ml of D-MF
in the presence of 7.5 9. (0.188 mole) of a 60% mineral oil dispersion of sodium hydride, and the product purified by chromatography on Kieselgel 60 in 50~ ethyl acetate/hexane.
There was thus obtained 1~.38 g. (37~) of 1-(3-bromo-propyl)-2-meth~l-3-(1-naphthylcarbonyl~-lH-indole, m p 115-~16C.
Preparation 7G
Following a procedure similar to that describ~d in Preparation 7D above, 73.86 9~ (0.3 mole) of 2-methyl-3-(4-methoxybenzoyl)indole (Preparation lAU) was reacted with 302.33 g. (1.5 moles) of 1,3-dibromopropane in 250 ml. of DMF in the presence of 17.97 9. ~0.45 mole) of a 60%
mineral oil dispersion o sodium hydride. There was thus obtained 1-(3~b_omopropYl)-2-methyl-3-(4-methoxybenzoyl)-lH indole.
Preparatlon 7H
Following a procedure similar to that described in Preparation 7D above, 15.0 9. (0.053 mo].e) of S-fluoro 2-methyl-3-(4-methoxybenzoyl~indole (Preparation lF) was reacted with 9.18 9. (0.058 mole) of 1-bromo-3-chloro-propane in 232 ml. of DMF in the presence of 3.2 9. (0.0795 mole~ of a 60~ mineral oil dispersion oE sodium hydride.
! There was thus obtained 15.3 9. (80%) of 1-3-chloro-propyl~-5-Eluoro-2-methyl-3~(4-methoxybenzoyl)-lH-indole.

* Trademark D.l~.7 ~,~
3 1 ~2 Pee ~ratlon 7I
Following a procedure similar to that described in Preparation 7A above, 24.a g. (0.087 mole) of 2-methyl-3-(l-naphthylcarbonyl)indole (Preparation lAM~ in 300 ml. oE
THF was treated with 35 ml. (0.09 mole) of a 2.6M solution of n-butyl lithium in hexane followed by 56 ml. of a 2.6M
solution of ethylene oxide in THF to give 21.3 g. (74~) of 2-methy:L-3-(1-naphthylcarbonyl)-1-(2-nydroxyethyl)-lH-indole.
Reaction of the latter (0.065 mole) with 18.5 g. (0.097 mole) of p-toluenesulfonyl chloride in 400 ml, of methylene dichloride in the presence of 340 ml. of 35% sodium hydroxide and 0.6 9. (0.0026) mole of benzyl trimethyl-ammonium chloride afforded 20.1 9. (64%) of 2-methyl-3-(1-na~hthy~carbony~ (2-p-toluenesulfonyloxyethy~ H-indole as a viscous oil.
Preparation 8 A solution of 42 9. (0.116 mole) of 5-fluoro-2-methyl~ l-methyl-2-(p-toluenesulfonyloxy)ethyl~-lH-indole (Prepar~tion 4D) and 50 ml. of morpholine in 400 ml. of DMF
was heated on a steam bath for seventy-two hours, poured into water and the mixture extracted with ethyl acetate.
The combined ~rganic extracts were dried and taken to dry-ness to give 20 9O of crude product which was purified by HPLC, eluting the product with 2:1 hexane:ethyl acetate.
There was thus obtained 10.4 9~ (32~) f 3cl3~955=3Cl-~3Yl=
2 1-[l-methyl-2-~4-morpholinyllethy~ H-indole as the S

~irst, third and fourth through the seventh Eractions.
The second fraction, on conversion to the hydro-chloride salt and recrystallization from methanol-ether, ~ . 7 ~5~3 3L~

afforded 1.0 g. of 5-fluoro-2-methyl-1-[1-methyl-2-(di-methylaminolethyl]-lH-indole hydrochloride, m.p. 208.5-211.5C, produced by amination of the tosylate by the DMF used as a solvent.
It is contemplated that, by replacing the morpholine in the above-described procedure with dimethylamine, the dimethylamino species can be obtained as the maj~r productO
Preparation 9A
Following a procedure similar to that described in Preparation S~ above, 2400 9. (0.071 mole) of 5-fluoro-2-methyl-3-(4-methoxybenzoyl)indole (Preparation lF) in 200 ml. of dry DMF was reacted with 35.2 g. (0.35 mole) oE
epichlorohydrin in the presence of 3.1 g. (0.078 mole) of a 60% mineral oil dispersion of sodium hydride in 100 ml. of DMF. The product was recrystallized from ethyl acetate-hexane to give 10.6 9. (44%) of 5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1-[1-(2,3-epoxy)~ropyl] lH-indole as a yellow solid.
Preparation 9B
Following a procedure similar to that described in Preparation 9A above, 100 g. (0 377 moleJ of 2-methyl-3-(4-methoxybenzoyl~indole ~Preparation lAU) in 1500 ml. of DMF
was reacted with 174.6 g. (1.~9 moles) of epichlorohydrin in the presence of 19~92 g. (0~42 mole) of a 50% mineral oil disper~ion of sodium hydride in 500 ml. of DMF. There was thus obtained 2-methyl-3-(4-m thoxybenzoyl~-1-l1-(2,3-epoxy)propyl]-lH ndole.

D, i`l . 7 3 5 ~A
3~

Preparation 9C
Following a procedure similar to that described in Preparation 9A above~ 23.7 g. (0.1 mole) of 2-methyl-3-(1-naphthylcarbonyl)indole (Preparation lAM) in 165 ml~ oE
DMSO was reacted with 27.39 9. (0.2 mole) oE epibromohydrin in the presence of 6.6 g. (0.1 mole) oE powdered potassium hydroxide and the product purified by chromatography on sillca gel, eluting with ethyl acetate-hexane. There was thus obtained 32.3 g. (95~ of 2-methyl-3-(1-naphthyl-carbonyl)-1-[1-(2,3-epoxy)propyl~-lH-indole.

/ ~) j O r~

-4~~

Preparation ~. h~ Yi~l E~d~ct~ of Formula I
A. From the Compounds of Formula II
Example lA
Following a procedure similar to that described 5 in Preparation 4 above, 25 g. ~0.10 mole) of 3-~4-methoxy-benzoyl)indole (Preparation lZ) in 100 ml. of DMF was reacted with 5.76 g. (0.12 mole) of a 50~ dispersion of sodium hydride in mineral oil in 120 ~1. of DMF, and the resulting sodium salt was reacted with 0.14 mole of 4-(2-chloroethyl)morpholine (freed from 26.06 9. of the corres-pondinq hydrochloride) in 120 ml. of DMF to give 42 9. o the crude product as an oil which, on trituration with ethyl acetate/diethyl ether/hexane, gave a yellow crystal-line solid which was converted to the methanesulfonate salt to afford 9.5 9. ~20~) of 3-(4-methoxybenzoyl1-1-[2-(4-morpholin~l~ethyl]-lH-indole methanesulfonate ~onohydrate, m.p. 110-112C.

Following a procedure similar to that described in Example lA above, the following species oE Eormula I
in Table 1 were prepared by reaction of a 2-R2-3-R3-carbonyl-lH-indole of formula II with an appr~priate halo alkyl-amine or tosyloxyalkylamineO The acid-acceptor and reaction solvent used in the reactions are given in the column headed "Cat.~Solv.". Here and elsewhere in the tables, the form in which the product was isolated, either as the free base or as an acid-addition salt, is given in . 7350A

3;~

columns headed "Base/Salt" ! and the abbreviations "Morph.", "Pip. " and "Pyr." in the columns headed N=B
represent the 4-morpholinyl, l-piperidinyl and l-pyrro-lidinyl groups, respectively. In Table 1, unless noted otherwise, an appropriate chloroalkylamine was used as the alkylating agent. Here and elsewhere in the speci~ication and the claims, the alkylene groups, Alk, are depicted 3S
they would appear with the l-indolyl moiety attached to the carbon atom at the left.end of the alkylene chain and with the amine group, N-B, attached to the carbon at the right end of the chain.

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D , 135~A

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B. From the Compounds of Formula III
Exam~le 2A
To a stirred, refluxing solution of 13.2 9. (0.054 mole) of 1 [1-methyl-2-(4-morpholinyl)ethyl]-lH-indole (Prepasation 5B) in 150 ml. of ethylene dichloride was addedr over a period of about one hour, a mixture of 17.35 g. (0.13 mole) of aluminum chloride and 10.08 9. (0.065 mole) of 4-methylbenzoyl chloride in 200 ml. of ethylene dichloride. When addition was complete, the mixture was heated under re~lux under a nitrogen atmosphere for three and a half hours and then poured, with stirring, into 1 liter of ice and water containing 300 ml. of 5N sodium hydsoxide. The mixture was transferred to a separatory funnel, the organi~ layer was separated, and the aqueous layer was washed with an additional 300 ml. of ethylene dichloride. The combined organic extracts were then washed with brine, filtered, dried over maynesium sulfate, filtered again and evaporated to dryness to give a viscous oil (22.55 g.) which solidified on cooling~ The latter was recrystallized, after charcoal;ng, from isopropanol to give 15~78 9. (81~) of 3-(4~methylbenzoyl)-1-[1-methyl-2-~4-morpholinyl~ethyl]~lH-indole, m.p. 116.5-118~C.

::
. . ;.

D . 1 ~ j .) .\
S~

Examples 2B-2~I
Following a procedure similar to that described in ~xample 2A above, the following species o formula I
in Table 2 below were prepared by reaction of a 2-R2-l-aminoalkyl~1~1-indole of formula III with an appropriate acid chloride (R3Co-Cl) in the presence of aluminum chlorideO
The solvent used to carry out the reaction, methylene dichloride (MDC) or ethylene dichloride ~EDC), is given in the column headed "Solv."

D . ~ 7 3 5 ~; ~

~1 1 e ~ ~ ~ 9 e u~ B
m m ;a m m ~ m m m ~ m ~ m ~ m ~ 1~ m m m m m ~o ~ ¦ V ~ U ~ U ~ ~ W ~ U U

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D.r~. 7356A
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CO r~L~ 3L~ a VI
-~ E_e 3A
A solution o 10 9. (0.022 mole~ of 2-methyl-3-t4-methoxyben~oyl)-1-[2-(p-toluenesulfonyloxy)ethyl]-lH-indole S (Preparation 7A) and 8.74 g. (0.086 mole) of 4-hydroxy-pipeeidine in 50 ml. of dry acetonitrile was heated under reflux for about Eorty eight hours, and the mixture was then diluted with ethyl acetate and washed with water. The org~nic layer was extracted with 2N hydrochloric acid, then with water, and the combined aqueous washings were com-bined, basified with 10~ sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to dryness ko give the product, in the form of the Eree base, as a brown oil. The latter was converted to the hydro-chloride salt in ethyl acetate and ethereal hydrogen chloride to give 2.5 9O (27%) of 2-methyl-3-(4-methoxy-benzoyl)-1-[2-(4-hydroxy-1-piperidinyl)ethyl]-lH-indole hydrochloride hemihydrate, mOp. 226-229C.
Exameles 3B - 3AM
~ ollowing a procedure ~imilar to that described in Example 3A above, the following species of formula I in Table 3 below were prepared by reaction of a 2-methyl-3-R3-carbonyl-1-~2-tosyloxyethyl)-lH-indole or a 2-methyl-3-R3-carbonyl-l-(halo-lower-alkyl)-lH-indole of formula VI with an appropriate amine, HN=B, where R2, in each instance, is CH3. The starting material in each of Examples 3B-3V, 3AK
and 3AM was the corresponding 1-~2-tosyloxyethyl)-lH-indole, in Example 3W the corresponding 1-(3-chloro-propyl)-lH-indole; and in each of Examples 3X-3AJ and 3AL
the corresponding l-tbromo-lower-alkyl)-lH-indole.

- D.~. 7356A

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Z ;Z; Z
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.~J. 1~A

D. Miscellaneous Processes .
Example 4A
Following a procedure similar to that described in Preparation3above,800g. (0.02mole) of2-methyl-3-(3-nitro-benzoyl)-1-[2-(4-morphol}nyl)ethyl]-lH-indole (Example lAD) in 175 ml. of ethyl acetate and 75 ml. of acetic acid was reduced with hydrogen in a Parr shaker over 0.3 g. of platin~m oxide. The product wa~ isolated in the form oE
the Eree base and recrystallized from ethyl acetate to give

6.0 g. (83%) of 2-methyl-3-(3-aminobenzo~ [2-(4~morpho-linyl)eth~l]-lH-indole, m.p. 167-169C.
xample 4B
Following a procedure similar to that described in Example 4A above, 28 g. (0.07 mole) of 2-methyl-3-(4-nitro-benzoyl)-1-[2-(4-morpholinyl)et.hyl3~1H~indole (Example lCQ) in lO0 ml. of glaclal acetic acid and 100 ml. o~ ethyl acetate was reduced with hydrogen over platinum oxide and the product, in the form of the free base, was recrystal-lized from ethyl acetate to give 19.05 9. (75%) of 2-methyl-3-(4-aminobenzoyl)-1-l2-(Q-morpholinyl)ethy~l-lH-indole, m~p. 154-156C.
A small amount of the free base was reacted with methanesulfonic acid and the product recrystallized from ethanol to give the corresponding methanesulonate as an orange powder, m.p. 221-223C.

D,N. 7 ~ol~

Example 4C
To a stirred suspension of 2.5 g. tO.0059 mole) of 2-methyl~ 9-nitrobenzoyl)-6-methoxy-1-[2~(4-morpholinyl)-ethyll-lH-indole (Example lAN) and 2 9. (0.036 mole) of iron filings in 25 ml. of 50% aqueous ethanol in a three-necked flask equipped with a reflux condenser and a stirrer was added, over a five minute period with stirring, 0.93 ml. of a solution containing 5 ml. of concentrated hydro-chloric acid in 25 ml. of 50~ aqueous ethanol. When addition was complete, the reaction mixture was heated under reflux for two and a half hours, then cooled and made basic with 15% alcoholic potassium hydroxide solution. The mixture was filtered, the filtrate was taken to dryness ln vacuo, and the oily product was dissolved in methylene dichloride and the organic solution washed first with alkali, then with water and then with brine and dried over magnesium sulfate. Filtration of the solution and concen-tration to dryness afforded an oil which, on trituration with ethyl acetate/diethyl ether, crystallized to give 1.4 9. (71~) o~ 2-methyl-3-1 -aminobenzoyl)-6-methoxy-1-[2-(4-morpholinyl)ethyl]-lH-lndole, m.p. 126~128DC.

.. '_i. 7356A

-6~-xample 4D
Following a procedure similar to that described in Example 4C above, 7.3 9~ (0.018 mole) of ~-methyl-3-(4-nitrobenzoyl)-1-[l-methyl-2-t4-morpholinyl)ethyl]-lH-indole (Example 2K), dissolved in 75 ml. of 50% ethanol, was reduced with 6 g. (0.11 mole) of iron filings and 2.8 ml. of a solution containing 5.2 ml. of concentrated hydro-chloric acid in 25 ml. of 50~ ethanol. The product was isolated in the form o the free base to give 3.7 9. (54~) of 2-methyl-3-54-aminoben2Oyl)-l-[l-methyl-2 (4-morDho-linyl)ethyl~-lH-in~ole, m p. 192-195C
Example 5A
To a sol~tion of 4.0 g. (0.01 mole) of 2-methyl-3-(4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole (Example 4B) in 20 ml. of glacial acetic acid was added 2.3 ml. 10.023 mole) of acetic anhydride and 2 dxops of con~
centrated sulfuric acid. The mixture was warmed slightly, then poured into water and the aqueous mixture basiEied by addition of 10% sodium hydroxide. The gum which separated was isolated by decantation, triturated with water to produce a solid material which was collected and recrystal-lized from ethyl acetate to give 2.3 g. (56%) of 2-methyl-3-(4-acetylaminobenzoyl)~ 2 (4~ pholinyl)ethyl]-lH-indole, m.p. 173.5-174.5C.

L-l- 7356A

~63-Exam~les 5B-5F
Following a procedure similar to that described in Example 5A above, the following compounds oE formula I in Table 5 below ~ere prepared ~y acylation of an appropriate 2-methyl-3-(aminobenzoyl)-1-aminoalkyl-lH-indole. In each instance, R2 is CH3; R4 is hydrogen; Alk is (CH2)2; and N=~
is 4~morpholinyl. All compounds were isolated and charac-terized as the free bases. The acylating agent and the reaction solvent are given in the column headed "AcX/Solv."

. 7 3 ~)~, '\

~4-~ _ ~ ~ ~ o o, . ~Dr~
,~

au ~

t~ U ,, ~D ~ ~ rn ~ ~
~ ~C ~

~ D
m ~: z C~ n", mu, .~ ~
~ , m ;~ u ~ ~ ~ Y ~

~ p~ C~ a ~ ~
U~
~ .

D..~ 7356A

~65-Following a procedure similar to that described in Preparation 3 above, 14.0 9. (0.03 mole) of 2-methyl-3-(4-benzyloxybenzoyl)-1-12-(4-morpholinyl)ethyl~-lH-indole (Example lAG) in 250 ml. of ethanol was reduced with hydrogen in a Parr shaker over 1.0 g. of 5% palladium-on-chaecoal. The product was converted to the hydro-chloride salt whlch was recrystallized from water to give 11.1 g. (923) of 2-methyl-3-t4-hydroxybenzoyl)-1-[2-(4-morpholinyljethyl]-lH-indole hydrochloride, m.p. 2~6-288C.
Example 7 A mixture oE 7.5 g. (0.02 mole) of 2-methyl-3-(4-cyanobenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole (Example lAF), 100 ml. o~ ethanol, 15 ml. of liquid am~lonia and 2 tablespoons of a Raney nickel in ethanol suspension was heated in an autoclave at 50C. under an initial hydrogen pressure of 320 p.s.i~g~ The m-ixture was then cooled, the catalyst was removed by filtration, and the solution was taken to dryness in vacuo to give 7.2 g. of .product as a green foamy material which was converted to the hydrochlo~ide salt ~o give 1.7 9. (19~) of 2-methyl-3-(4-aminomethylbenzovl)~ 2-(4-morpholinyl)ethyl]-lH indole dihydrochloride, m.p. 196-208C.

.. .

. .

Example 8A
A mixture of 10.4 g. (0.023 mole) of 2-methyl-3-[4-~N-triEluoroacetylamino)benzoyl~1-[2-(4-morpholinyl)ethyl]-l~-indole (Example 5C), 20 g. (0.20 mole) of potassium S carbonate and 5 ml. ~]1.4 g., 0.08 mole) of methyl iodide in 100 ml. of acetone was heated under reflux with stir-ring for two hours and then taken to dryness to yield a yellow ~oam, which was partitioned between water and chloroform and extracted twice with chloroform. The combined extracts were washed with brine, filtered and taken to dryness to give a yellow oil which was dissol~ed in isopropanol and treated with excess hydrogen chloride followed by additional isopropanol. The solution was diLuted with ether, and the solid which separated was collected and dried to give 4.6 9. of 2-methyl-3-[4-(N-methyl-N-triEluoroacetylamino)benzoyl~ [2-(4-morpholinyl)-ethyl]-lH-indole hydrochloride, m.p. 224-226C.
The latter (3.7 9., 0.007 mole) was mixed with 25 ml. of 10% sodium hydroxide, and the mixture was heated ; 20 under reflux for one hour. On cooling, a solid separated from the mixture which was collected, dissolved in isopropanol and treated with excess hydrogen chloride and isopropanol.
The solid which separated was collected and recrystallized from methanol/diethyl ether to give 1.2 9. (37~) of 2-methyl-3-~4-methylaminobenzoyl~ [2-~4-morpholinyl)-ethyl~-lH-indole_dihydrochloride hemihydrate, m.p. 190-192C.

D., 735~A

_ a~e~
Following a procedure similar to that described in Example 8A, 22 9. (0.049 mole) of 2-methyl-3-[4-(N-trifluoroacetylamino)ben~oyl]-l-[2-(4-morpholinyl)ethyl]~
lH-indole (Example 5C~ was reacted with 35.9 9. (0.129 mole) of butyl iodide in 250 ml. of acetone in the pres-ence of 48 g. (0.343 mole) of potassium carbonate and the resulting 2-methyl-3-[4-(N-butyl-N-trifluoroacetyl-amino)benzoyl]-l-[2-(4-morpholinyl)ethyl]-lH-indole (24 g., 98%) hydrolyzed by refluxing in a solution of 500 ml. of 10% sodium hydroxide and 100 ml. of ethanol.
The resulting crude product was chromatographed on silica gel, elutin~ with 25% acetone-hexane. The higher Rf material was collected and dried to give 2.6 9. of 2-methyl-3-(4-butylaminobenzoyl~ 2-(4-morpholinyl1ethyl~-lH-indole, m.p. 129.0-130.0C.

D. N . j6A
:~Z~ 2 6~~
Example 9 To a stirred suspension of 12.0 9. (0.03 mole) of 2-methyl-3-(4-aminobenzoyl3-1-[2-(4-morpholinyl)ethyl]-lH-indole (Example 4~) in 15 ml. of glacial acetic acid and 30 ml. of water was added a solution of 4.5 g. ~0.06 mole) of sodium isocyanate in 30 ml. of water. The mix-ture was stirred at room temperature for two hours, then diluted with water and made alkaline with 10% sodium hydroxide. The solid which separated was collected and recrystallized from DMF to give 5.9 g. (48~) of 2-methyl-3-(4-carbamylaminobenzoy~ 2-(4-m_rpholinyl~ethyl]-lH-lndole, m.p 192-202C.
~e~
o a stirred suspension of 3.77 g. (0.01 mole) of 2-methyl-3-(4-aminomethylbenzoyl)-1-[2-(4-morpholinyl)-ethyl]-l~-indole (Example 7) in 30 ml. of toluene was added a solution of dimethyl cyanoc~rbonimidodithioate in 20 ml. of toluene. The mixture was stirred for an hour and a half, and the solid which separated was col-lected and dried to give 4.75 g. of the corresponding 3-(4~aminomethylbenzoyl)-N~(methyl cyanocarbonimidothioate~.
The latter (4.0 g., O.OOB mole), in 75 ml of i~opropa~ol and 25 ml oE liquid ammonia, was heated in an autoclave for one hour at 100C. The reaction mixture was then filtered, allowed to evaporate to dryness, and the resulting pale yellow foam was recrystalllzed from acetonitrile to give 2.3 9. (65g) of 2-methyl-3-(4-cyano-guanidinylmethylbenzoyl~ [~-(4-morpholinyl)ethyl~-lH-indole, m.p. 191.5-195C.

D . i ~ . '- ,13 -69~
~ le 11 A mixture o 10 g. (0.027 mole) of 2-methyl-3-(4-cyanobenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole ~Example lAF), 20 g. (0.19 mole) of sodium hypophosphite, 50 ml. oE water, 50 ml. of glacial acetic acid, 100 ml. of pyridine and two spatulas of Raney nickel was heated to about 40C. for two and a half hours and then filtered.
The Filtrate was taken to dryness in vacuo, and the result-ing oil was washed with toluene and again concentrated to 10 dryness to remove residual pyridine. The residual oil was suspended in aqueous alkali and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulEate, filtered and concen-trated to dryness to give an oil which was recrystallized 15 from ethyl acetate to aEord 1.5 9. (15~) of 2 _ ~y~
(4-ormylbenzoyl)-1-[2-L4-mor~holinyl)ethyl]-lH-indole, m.p. 149-150C.
Exam~le 12 ~ mixture of 2.5 g. (0.0~6 mole) of 2-methyl-3-~4-formylbenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole (Example 11), 0.55 g. (~.0067 mole) of sodium acetate and O.Sl 9. (0.0073 mole~ of hydroxylamine hydrochlori~e in 24 ml. of ethanol, 5 ml. of methanol and 6 ml. of water was heated under reflux for one hour and then concentrated to dryness in vacuo. The residual solid was collected, washed with water and diethyl e~her t~ give 2.5 9. (95%) of 2-methyl-3-(~-hydroxyi~ __thylben~o~~-1-[2-(4-morpholinyl)-ethyl~ indole, m,p. 184-186C.

:~2~

A mixture oE 20 g. (0.053 mole) of 2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole ~Example lB) and 20 g. (0.29 mole) of hydroxylamine hydro-chloride in 100 ml. of pyridine was heated under reflux for about twelve hours and then diluted with methylene dichloride. The organic mixture was washed five times with water, then with brine, dxied over magnesium sulfate, fil~
tered and taken to dryness in vacuo to give a dark green oil which was washed three times with toluene and again concentrated to dryness in vacuo. Trituration of the residue with ethyl ~cetate/diethyl ether afforded crystals which were collected to giYe 9.5 g. (46%~ of 2-methyl-3-(4-oxime, m.p. 166-169C.
_xam~ple 13B
Following a procedure sim-lar to that described in Example 13A above, 44 9~ (0.101 mole~ of 5-fluoro~3-(2-fluorobenzoyl)-2-methyl-1-13-(4-morpholinyl~propyl]-lH-indole (Example 2BB) was reacted with 70.3 9. (1.01 moles) of hydroxylamine hydrochloride in 500 ml of pyridine and the product recrystallized from acetonit~ile to give 15.5 9.
(37%) of 5-fluoro-3-(2--Eluorobenzoyll-2-methyl-1~[3-(4-morpholinyl)propyl3-lH-indole oxime, m.p. 150-162C.

D. N . ~ 6A
~2~

Exa~
.
Following a procedure similar to that described in Example 13A above, in two runs a total of 28.3 g. (0.77 mole) of 3~(2-fluorobenzoyl)-2-methyl-1-[2-(4-morpholinyl)-ethyl]-lH-indole (Bxample lZ) was reacted with a total of 53.7 g. (0.77 mole~ of hydroxylamine hydrochloride in a total of 575 ml~ of pyridine to give a total of 24.4 g. of crude product. The latter was dissolved in a solution of 54.1 g. of sodium methoxide in S00 ml. of methanol, and the solution was heated under reflux for forty-eight hours and then taken to dryness in vacuo. The residue was par-titioned between chloroform and water, and the chloroform-soluble material was flash chromatographed on silica gel eluting with 98:2 chloroform:isopropanol. The slower mov-ing material was isolated and recrystallized from toluene-hexane to give ~.0 g. (33~) of ~~L~3-(2-Eluorobenzoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl?-lH-indole oxime, m.p.
160-167~C.
Example 14 A mixture of 8 g. (0.022 mole) of 2-methyl-3-(4-aminoben~oyl)-1-[2-~4-morpholinyl)ethyl]-lH-indole (Example 4~) and 4.28 ml. ~0.0~3 mole3 of 2,5-dimethoxy-tetrahydrofuran in 40 ml. o~ glacial acetic acid was heated under reflux for one hour and then poured into an iceJwater mixture. The mixture was rendered alkaline by addition of 10% sodium bicarbonate solution, and the solid which separated was collected and dissolved in methylene dichloride, The organic solution was dried over magnesiu~

5~3~2 sulfate, filtered and the filtrate concentrated to dryness ln vacuo and then chromatographed through a pad of Florisil, eluting with methylene dichloride. There was thus obtained 4.5 9~ o~ an oil which, on trituration with S diethyl ether, afforded a light yellow powder which was collected to give 3.5 g. ~38%) oE 2-methyl-3-[4~~1H-yy~rol-l~yl)benzoyl3~ 2-(4-morpholinyl~ethyl]-1~-indole, m.p.
125-127C.
Example 15 To each of three 14 liter fermentors containing 10 liters of soybean meal/dextrose medium (containing 5 g./
liter of soybean meal, 5 g./liter of brewer's yeast, 5 9./
liter of dipo~assium hydrogen phosphate and ~0 g./liter of dextrose) at pH 6.4, was added 2.0 g. ~0.016 mole total) of 2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-indole (Example lB), and the mixtures were cultured for five days in the presence of FusarLum solani (Mart.) with stirring at 400 rpm at a temperature of 26-27~C~ while sparging with air at 5 liters per minute. The mixtures were then separately extracted with 20 liters o methylene dichloride using 20 liters per fermentor, and the combined extracts were concentrated to 20 liters~ The concentrate was washed first with 2 llters of 0.05N sodium hydroxide, then two times with 2 liters of water, and the organic layer was concentrated to about 1 liter, dried over sodium sulfate, charcoaled, Eiltered and further evaporated to dryness to give an oily residue which solidiEied on cool-ing. The latter was recrystallized from acetone/diethyl ether to give 2.7 g. (43%) of 2-methyl-3-(4-methoxy-benzoyl~ 2-l4-morpholinyl)ethyl]-lH-indole/N(MoR)-oxide m.p. 142-144C.

... ~

D. N .

Example 16A
A mixture o 38.3 g. (0.10 mole) of 2-methyl-3-(2-methoxybenzoyl) 1-[2-~4-morpholinyl)ethyl] lH-indole (Example lU) and 35 2 9. (0.31 mole) of pyridine hydro-chloride was heated in an oil bath at 210~C. for four hours and the mixture allowed to cool. The solidified reaction mixtùre was partitioned between ethyl acetate and aqueo~s sodium carbonate by warming on a steam bath, and the organic layer was separated, taken to dryness and subjected to high performance liquid chromatography on a silica gel column in 1:1 hexane:ethyl acetate. The first 7 liters of eluate were discarded, and the next 8 liters were col-lected, taken to dryness and the residue recrystallized from isopropanol to give 8.33 9. ~23%~ of 2-methyl-3-~2-hydroxybenzoyl)-1-[2-(4-m~ holinyl)eth~l]-lH-indole, m.p.
. 115-116C.

Following a procedure similar to that described in Example 16A, 15.8 g. ~0.035 mole) of 5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1-[3-(4-morpholinyl)propyl]-lH-indole hydrochloride (Example lI) was heated with 20.4 g. (0.176 mole~ of pyridine hydrochloride at 210C. in an oil bath ~or two hours, and the product isolated as the hydro-chloride salt to give 9.2 g. (67%) of 5-fluoro-2-methyl-3-(4-hydroxybenzoyl)-1-[3-(4-morpholinyl)eropyl~-lH-indole h~rochloride, m.p. 290-292~C. (from DMF-ether).

, ~

.

D.. 7356A
:~2~

~ 17 A mixture of 1.9 g. (0.005 mole) of 2-methyl-3-~4-aminomethylbenzoyl)-1-[2-(4~morpholinyl)ethyl]-lH-indole ~Example 7), 0.7 9. (0.0025 mole) of 2-methyl-2-thiopseudourea sulfate and 10 ml oE water was heated on asteam bath for two hours and then filtered. The Eiltrate was taken to dryness, and the residue was recrystallized from methanol to give 1.0 g. (85~) of 2-methyl-3-t4-guanidinylmethylbenzoyl)-1-[2-(4-morpholinyl)ethyl~-lH-indole sulfate (2:1), m.p. 170-180~C
-Example 18 Following a procedure similar to that described in Preparation 3 above, a solution of 0.9 g. (0~0019 mole) of 6-benzyloxy-2-methyl-3-(4-methoxybenzoyl)-1-l2-(4-morpho-linyl~ethyl~-lH-indole (Example lBK) in 200 ml. of methanol was reduced with hydrogen over three spatulas (app~oxi-mately 1.5 9.) of 10% palladium-on-charcoal under a hydrogen pressure of 50 p.s.i.g. at ambient temperature in a Parr shaker. The product was isolated in the form of the hydrochloride which was recrystallized from ethyl acetate-; diethyl ether to give 0.35 9. of 6-hydroxy-2-methyl-3-~4-methoxybenzoyl)-1-[2-(4-morpholinyl~ ethyl~-lH-indole hydro-chloride hydrate (3:4) t m.p. 185-187C.

D.l 73S6~
3~

Example_l9 To 70 ml of dry DMF was added, dropwise with stir-rin~, 15 ml. of phosphorus oxychloride while cooling in an ice bath. The mixture was then treated with a solution of 24.4 9~ ~0.10 mole) of 2-methyl-1-[2-(4-morpholinyl)-ethyl~-lH-indole (Preparation 4A) in 50 ml. of DMF while continuing to cool in an ice bath. When addition was com-plete, the mixture was stirred for about one hour and then poured into 50 9. of ice to give a clear solution which was chilled to about 20C. and basified by the addition of 150 ml. of 35% potassium hydroxide. The mixture was warmed to about 70, then chilled in an ice bath, and the solid which separated was collected, dried and recrystallized from ethyl acetate to give 23.3 9. ~86%) of 3-formyl-2-methyl-1-12-(4-moryholinYl) ethyl]-l~-indole, m.p. 115-116C.
A solution conta~ning 13~6 g. (0O05 mole) of the latter and 9.0 g. (0~06 mole) of 4-methoxyacetophenone in S0 ml. of absolute ethanol was treated with 500 ml. of 3.7N ethanolic hydrogen chloride in a thin stream, while stirring, and the resulting red solution was stirred for twenty-four hours. The solid which separated was collected by filtration, wa~hed with absolute ethanol and then recrystallized first from methanol and then from 50~
ethanol to give 5.3 9. (24%) of 1-~2-methyl-1-[2-(4-morpho-lin l~eth 1]-lH-indol-3- 1~-3-(4-methox heny1)propen-3-one Y, Y - Y ! YP
monoh~drochloride, m.p. 259-2S2C.

V. 7356A
3~ ~

Example_20A
Following a procedure similar to that described inExamplel9 above, 3-acetyl-2-methyl-1-~2-(4-m_ pholinyl)-ethyl]-lH-indole was prepared by reaction of 12 9. (0.05 mole) of 2-methyl-1-l2-~4-morpholinyl)ethyl]-lH-indole ~Preparation 4A) with 10 ml. (0.11 mole~ of phosphorus oxychloride in 25 ml. of dimethylacetamide. The product was dissolved in isopropanol and the solution treated with ethereal hydrogen chloride to give 6 g. (373) of the product as the hydrochloride salt, m.p. 249-253 C.
To a solution of 6 9. (0.107 mole) of potassium hydroxide pellets in 350 ml. of absolute ethanol was added 15 9. (0.047 mole) of the latter and 19 g. tO.14 mole) of 2-methylbenzaldehyde. The mixture was heated under reflux for one and a half hours, concentrated to dryness and the product, in the orm of the free base~ recrystallized oncerom ethyl acetate and once from isopropanol to give 7.9 g.
(41~) of 3~(2-methylcinnamoyl)-2-methyl-1-[2-(4-morpho-linylJethyl~-lH-indole, m.p. 131-135C.
Example 20B
Following a procedure similar to that described in Example 20A above, 14.75 g. (Q.0516 mole) of 3-acetyl-2-methyl-1-[2-(4-morpholinyl)ethyl]-lH-indole (Example 20A) was reacted with 2-fluorobenzaldehyde in 260 ml. o ethanol in the presence of 3.44 g. (Q.061 mole) of potassium hydroxide pellets and the product, in the form of the free base, recrystallized from ethyl acetate to give 10.0 g.
l~4%) of 3-(2-fluorocinnamoyl)-2-methyl-1-~2-14-morpho-liny~ethyl]-lH-indole, m.p. 113-116C.

~ e~_21 A solution of 11 g. (0.025 mole~ of 1-l2-(3-hydroxy-l-piperidinyl)ethyl)-2-methyl-3-l4-methoxybenzoyl)-]H-indole (Example 3B) in 50 ml. of pyridine and 25 ml. of acetic anhydride was allowed to stand at ambient temperature for about forty-eight hours and the mixture then poured into ice water. The oily solid which separated was collected, dissolved in ethyl acetate and the solution washed first with dilute sodium hydroxide, then with brine, dried and taken to dryness. The residue was dissolved in ethyl acetate, the solution treated with 3.67 g. of maleic acid, the mixture heated to boiling to dissolve all solid, then cooled, and the solid which separated was collected and recrystallized once again from ethyl acetate to give 8.12 9O ~59%) of 1_[2_(3_acetoxy-1-piperidinyl)ethx~]-2-methyl-3-(4-methoxybenzoyl)-lH-indole maleate (1:1), m.p. I61-:. ' 161.5C.
Example 2Z
To a stirred solution of 12.5 g~ (0.03 mole) of 2-methyl-3-(4-methoxybenzoyl)-1-[2-tl-piperazinyl)ethyl]-lH-indole (Example lL)in 150 ml. of pyridine was added, with stirring while cooling in an ice bath, 7.1 g. ~0.066 mole3 of ethyl chloroformate. When addition was complete, the solution was stirred in an ice bath for thirty minutes, then allowed to stand at ambient temperature for about eighteen hours and then poured into ice water. Extraction of the mixture with ethyl acetate afforded the crude product in the form of the free base which was dissolved in ethyl acetate and converted to the maleate salt by addition of 2.6 g. of maleic acid. The latter was recrystallized from ethyl acetate-ether to give 7.6 g. (41%) of 1-12-(4-D. N . 356A

carbethoxy-l-piperaz_nyl)eth~1]-2-methyl-3-t4-methox~-benz~yl)-lH-indole_maleate (1:1), m.p. 155-156C.
Exam~le 23A
A ~olution of 12.5 9. (0.033 mole) of 2-methyl-3-(4-methoxyben~oyl)-1-[2-(1 piperazinyl)ethyl~ indole (Example lL) in 150 ml, oE pyridine was cooled in an ice bath and treated with 50 ml. of acetic anhydride and the solution allowed to stand at ambient temperature for about eighteen hours. The solution was then poured into ice water and the mixture extracted with ethyl acetate. The organic solution, Oll washing with brine, drying over sodium sulfate and evaporation to dryness, afforded the crude product which was taken into ethyl acetate and the solution treated with 4.2 g. of maleic acid. The solid which separated was collected and recrystallized from ethanol to give 7.36 g. (42~1 of 1-[2~(4~acetyl-l-pi~eraziny~)-ethyl]-2-methyl-3-_~4-methoxy~enzoyl)-1~-indole maleate (1:1), m.p. 147.5-152C.
Example 23B
Following a procedure similar to that described above in Example 23A, 11.9 g. (0.029 mole~ of 5-fluoro-2 methyl-3-(4-methoxybenzoyl~-1-[3-(1-piperazinyl)propyl]-l~-indole (Example lBN) was reacted with 50 ml. of acetic anhydride in 150 ml. of pyridine and the product isolated in the form o the methanesulfonate salt to give 6.6 g.
141~) of 5-1uoro-2-methyl-3-~4 methoxybenzoyl)-l-[3-~4 acety~l-l-~iperaz ~ propyl]-lH-indole_ methanesulfonate, m.p. 170 171C.

~r~ D.~735~A

Example 24 A solution of 15 9. t0.04 mole) of 2-methyl-3-(4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole (Example 4s)~ 12 9. (0.4 mole) oE formaldehyde and 7.5 g.
I0.119 mole) cf sodium cyanoborohydride in 250 ml. o acetonitrile was stirred for thirty minutes and then treated dropwise with acetic acid until acidic. The mix-ture was stirred for about eighteen hours, then poured into aqueous potassium hydroxide and the ~ixture extracted with ether. The organic extracts, on drying over magnesium sul-fate and concentration to dryness, afforded a yellow solid which was recrystallized from isopropanol to give 7.5 9.
~48~3 of 3-(4-dimethylamlnobenzoyl)-2-methyl-1-[2-(4-morpholinyl~ethyll-lH-indole, m.p. 152-154C.
Example 25A
A solution of 19.1 g. ~0.047 mole) of 1-(3-bromo-propyl)-5-fluoro-2-methyl-3-(4-methoxybenzoyl)-lH-indole (Preparation 7D) in 500 ml. o acetone and 50 ml. of water was treated with 3.05 9. (0.047 mole) of sodium azide and the mixture heated under reflux for about eigh~een hours and then taken to dryness in vacuo. The residue was part~tioned between ethyl acetate and water, and the organic layer separated, washed with brine, taken to dry-ness and the residue recrystallized from isopropanol to give 10.3 9. (60%) oE 1-(3-azidopropyl~-5-fluoro-2-methyl-3-(4-methoxybenzoylL=~indole, m.p. 69-73.

D. '.; 735~A
~25S;~

The latter (0.028 mole) was dissolved in 265 ml. of etha~ol and 35 ml. of T~F and reduced witIl hydrogen over 1.0 g. of 10% palladium-on-charcoal in a PaLr shaker. When reduction was complete, in about four hours, the mixture was filtered, the filt~ate taken to dryness and the residue dissolved in ethyl acetate and treated with 3.13 9. oE
maleic acid and heated to dissolve all the material. The solid which separated was collected and recrystallized from isopropanol to give 9.7 g. (76~) of 1-(3-amino~ropyl~-5-fluoro-2-methyl-3-~4-methox~benzoyl)-lH-indole maleate (1:1), m.p. 169-171C.
Example 25B
Following a procedure similar to that described in Example 25A above, 13.98 g. I~OO3 mole) of 2-methyl-3-~4-methoxybenzoyl)-1-(2-tosyloxyethyl)-lH-indole (Preparation 7A~ in 325 ml. oE acetone and 32.5 ml. of water was reacted with 1.96 9. (0.03 mole) of sodium azide and the product recrystallized from isopropanol to give 6.1 9. t61%) of 1-m.p. 91-93C.
The latter (0.024 mole), dissolved in 250 ml. of ethanol and 50 ml. of T~IF, was reduced with hydrogen over 0.8 g. of 10% palladium~on-charcoal at 47 p,s.i.g. and the product i~olated in the form oE the maleate salt to give

7 6 g (753) of ]-(2-aminoethyl)-2-me~yl-3-(4-methoxy--benzuyl)-lH-indole maleate, m.p. 165-166C.
Example 26A
A mixture of 10 9. (0.027 mole) of 3-(4-Eluoro-benzoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-lH-indole, ~ 7 ~Example lQ) 2.5 g. (0.033 mole) oE 2-methoxyethylamine and 7.6 g. ~Q.054 mole) of potassium carbonate in 15 ml.
of DMSO was heated at 95C under nitrogen and the mixture then poured into ice water. The solid which separated was collected, dissolved in methylene dichloride and the solution washed with brine, dried over magnesium sulfate, filtered and taken to dryness in vac~o. Recrystallization of the residue from ethyl acetate-ether afforded 4.2 g.
(37~ of 2-methyl-3-[4- (2-methoxyethylamino3 benzoyl]-l- [2-(4-morpholinyl)e ~ , m.p. 121-123C.
Examples 26B-26I
Following a procedure similar to that described in Example 26A above, reaction of a 3-(4-halobenzoyl)-2-methyl-1-~2-(4-morpho1inyl)ethyl]-lH-indole with an . appropriate amine in the presence of potassium carbonate afforded the species of formula I in Table 26 where, in each instance, R2 is CH3; and N-B is 4-morpholinyl. The species of Examples 26B-26D, 26G and 26H were obtained from the corresponding 4-fluorobenzoyl starting material, and the species of Examples 26E, 26F and 26I were obtained from the corresponding bromobenzoyl (or bromonaphthyl) starting materials.

D._~: 7356A

- 8 ~ -Y

~ r` ~ u~ ~ o O o ,~
~ ~ 1`1 m ~ rl ~ m m ~ m ,~ I O o u, a a c~ ~ o ~ ~ o ~, ~ ~ ~ ~ ~ ~ . ~ ~
~ ~ ts ec ~ c . ~ ~ o C~ C~ U U ~ y, y E~

,~ N N ~, ~ ~ tJ
';~ o ~

,1, ~, ~,. ~ ~ U-~ 1 ~ m u Q ,~

.

:~lZ5~3 A mixture oE ~.2 g. (O.G2 mole) of 1-[2-t4-formyl-1-pipera~inyl)ethyl]-2-methyl-3-(4-methoxybenzoyl)-lH-indole (Example 3S) and 2.06 g. (0.05~ mole~ o sodium hyd~oxide in 100 ml. o~ ethanol and 80 ml, of water was heated under reflux f8r four hours, then poured into ice water and extracted with ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate, taken to dry-ness and the residue dissolved in ethyl acetate. The solution was treated with an excess of a lN solution of methanesulfonic acid, and the solid which separated was collected and recrystallized frcm ethanol to give 9.0 9.
(79~) of 2-methyl-3-(4-methoxybenzoyl)-l- E2-~æipera-zinyl)ethyl]-lH-indole dimethanesulfonate, m.pO 240C.
Examples 27B-27D
Following a procedure similar to th~t described in Example 26A above, the ~ollowing specie~ of formula I were similarly prepared:
Example 27B - 1-[2-l2-hydroxyethylamino)ethyl]-2-methyl-3-(4-methoxybenzoyl)-lH-indole, m.p. 99-lOO.SC. l14.29., 50~), prepared by saponification of 30.8 g. (O.U8 mole) of 1-[2-~N-formyl-2-hydroxyethylamino)ethyl]-2-methyl-3-(4-methoxybenzoyl)-lH-indole (Example 3AK) ~ith 9.7 9. (0.243 mole) of sodlum hydroxide in 160 ml. of water and 200 ml.
of ethanol;
Example 27 - 1-[2-(3-amino-1-piperidinyl~ethyl]-2-methyl-3-~4-methoxybenzoyl)-lH-indole maleate ~1:2), ~.p. 142.5-144C, (1.5 9., 49~), prepared by saponificati~n of 1.6 9.
(0.0026 mole~ oE 1-[2-(3-acetylamino~l-piperidinyl)ethyl]-~51:j3~

-8~-2-methyl-3-(4-methoxybenæoyl)-lil-indole ~Example 3N) with 1.6 g. (0.04 mole) of sodium hydroxide in 2 ml. of water and 6 ml. of ethylene glycol; and Example 27D - 5-fluo~o-2-methyl-3-(4-methoxybenzoyl)-1-[3-(l-piperaæinyl)pro~yl]-lH-indole dimethanesulfonate, m.p.
114-115UC (8~7 g., 27%), prepared by saponification of 23 9.
~0.053 mole) of 5-fluoro-1-13-(4-formyl-1-piperazinyl)-propyll-2-methyl-3-(4-methoxybenzoyl)-lH-indole (Example 3AL) with 5.6 g. (0.014 mole) of sodium hydroxide in 265 ml. of ethanol and 210 ml. of water.
Example 23 ~o a solution containing 16.9 9. (0.044 mole~ of 1-(3-bromopropyl)-2-methyl-3-~4-methoxybenzoyl)-lH-indole (Preparation 7G) in 200 ml. of DMF was added 5 g. (0.088 mole) o~ azetidine. The mixture was stirred or about 24 hours at ambient temperature, thea diluted with water and extracted with ethyl acetate. The organic extracts were washed with water, then with brine, dried over magnesium sulfate, filtered and taken to dryness. The residue was taken into ethyl acetate, the solution diluted with ethereal hydrogen chloride, and the solid which separated was collected and recrystallized repeatedly from isopro-panol to give 2.0 9. (10%~ of 1-[3-(3-chloroPro~ylamino)-p~opYl~-2-methyl-3-~4-methoxybenzoyl ~lH-indole hydro-chloride, m.p. 140-142C.
Example 29A
To a solution of 15.0 g. 10.032 mole) of 5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1-[3-(4-thiomorpholinyl)propyl]-lH-indole hydrochloride (Example 3AF) in 195 ml~ of glacial -as-acetic acid was added 8.12 g. (0.038 mole) of an 80~
solution of m-chloroperbenzoic acid, and the solution was stirred at ambient temperature fo~ ~bout forty-eight hours and then poured into 300 ml. of ice water. The mixture was treated with l 9. of sodium bisulphite, basiEied with 35~
sodium hydroxide and then extracted with chloroform. The oeganic extracts, on washing with water, then with brine, drying over sodium sulfate and evaporation to dryness afforded 1.9 9. of the product as the free base which was converted to the maleate salt by solution of the base in ethyl acetate and addition of one equivalent of maleic acid. The salt was recrystallized from ethanol to give 12.85 9. (72%) of 5-fluoro-2-meth~l-3-t4-methoxybenzoyl)-l-[3-(4-thiomorpholinyl)propyl]-lH-indole S-oxide maleate, m.p. l60-l6lC.
Examples_29~ and 29C
Following a procedure similar to that described in Example 29A abovef the following species of formula I were similarly prepared:
~xample 29B - 2-methyl-3-(4-methoxybenzoyl)~l-[2-~4-thio-morpholinyl)ethyl]-lH-indole S-oxide maleate, m.p. 179-180C. (7.2 g., 82%), prepared by oxidatio~ of llp g. (0.028 mole) of 2-methyl-3-~4-methoxybenzoyl)-l-12-~4-thiomorpho-linyl)ethyll-lH_indole ~Example 3U) with 6.7 g. ~0.03 mole) of m-chloroperben~oic acid in llO ml. of glacial acetic acid; and Example 29C - 2-methyl-3-(4-methoxybenzoyl)-1-[2-~4-thio-morpholinyl)ethyl]-lH-indole S,N-dioxid~ dihydrate, m.p.
l43-l45C. ~3.9 9., 27%), prepared by oxidation of 12.0 9.
.

~5~

(0.030 mole) of 2-methyl-3-(4-methoxybenzoyl)~ 2-(4-thiomorpholinyl)ethylJ-lH-~ndole (Example 3U) with 6.6 g.
~0.030 mole) of m-chloroperbenzoic acid in 120 ml. of chloroform.

A solution of 28.7 9. (0.177 mole) of benzoyl-acetone and 23.2 ml. (0.177 mole) of 2-(4-morpholinyl)-ethylamine in 600 ml. of toluene was heated under reflux Eor ten and a half hours under a Dean-Stark trap and the solution then cooled and taken to dryness to give N-[2-(4-morpholinyl)ethyl]-M-~l-methyl-3-oxo-3-phenylpropenyl)amine as a yellow solid.
The latter (11.3 g., 0.41 mole~ and 8.9 9. t0.082 mole) of benzoquinone in 40 ml. of nitromethane was stirred under nitrogen for forty-eight hours at room temperature and the mixture then filtered through silica gel and the filtrate adsorbed onto silica gel and flash chromatographed using S~ acetone in ethyl acetate. The product was taken off in the early and middle fractions which were taken to dryness. The product was recrystallized first from ethyl acetate and then rom methanol to give 1.0 9. (7~) of 3-benzoyl-S-hydroxy-2-methyl-1-[2-~9-morpholinyl)ethyll-lH~
indole t m. p. 215-217C.
Example 31~

A solution of 13.4 9. (0.0395 mole) of 5-fluoro-2-methyl-3-(4-methoxybenzoyl)-1-[1-(2,3-epoxy)propyl]-lH-indole ~Preparation 9A) and 4.79 g. (0.055 mole) oE morpholine in 60 ml. of chloroform was heated under reElux for about forty-eight hours and then taken to dryness in vacuo. The crude product was dissolved in methylene dichloride, and ;3~

the solution was ~reated with an excess of ethereal hydrogen chloride and then diluted with ether. The solid which separated was collected and recrystallized from methanol-ether to give 13.3 g. (61%) of morphollnyl~er-E~l]-5-fluoro- -meth~l 3-(4-methoxybenzoyl) lH-indole hydrochloride hydrate, (lHCl.l 1/4H20), m.p.
143-145C.
Examples 31B-31-0 Following a procedure similar to that described in Example 31A above, reaction of a 1-11-(2,3-epoxy)propyl]-3-R3-carbonyl-lH-indole with an amine, HN=B, afforded the following compounds of formula Ib listed ln Table 31, where R2 in each instance is CH3.

.. .. ..

L . 7~ A

-~18~

r ~ ~ r cn m ,~

~ ~ ~
, O ~ g .~ ~ ~ U
~3 ~ U
,, 8 ,, 53 R. ~ ~ ~ b ~ b ~ ~ '' T '' T ~
o CO ~ ~ ~ ,, U m a~ ~ m ~ ~
~ 9~ 0 ~
~1 ~ , h 1~ S4 h I ~
r m m ~ E5 8 E~ u~~ u n ~ a u u u ~ a n Q .~ ;~
r~ $

~_, ~ z ~ ,, ~ ,, ,1 ~ z z SZ Z 3: Ei ~ u u v ~ u ~. ~) o u u tJ v u ", $ ~
O O O O O O O O O O O O O ,~ ,a ~ C~ ~ y U f: y 5~ Y '' 6 ~ U a Ci~ 1~ V ~ æ z 5 ~2~3~

--8g--~e~
Following a procedure similar to that described above in Example 25A, 60 g. (0.165 mole~ oE 1-(3-azido-2-hydroxy-l~propyl)-2-methyl-3-(4-methoxybenzoyl)-lH-indole tExamPle 31J) in 500 ml. of ethanol was reduced with hydrogen over 35 g. of palladium-on-barium sulfate catalyst. The product was isolated in the form oF the free base and recrystallized from ethyl acetate to give 10.2 g.
~18~) of 1-(3-amino-2-hydroxy-l-propyl)-2-methvl-3-~4 methoxybenzoyl~-lH-indole, m.p. 152-153~C.
~xample 33 The hydrobromide salt of 2-methyl-3-(4-methoxy-benzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole (Example lB) (10.0 9., 0.026 mole) ~as prepared by passing hydrogen bcomide gas into a solution of the former in 2~0 ml. of MDC. The hydrobromide was isolated, redissolved in 300 ml.
of MDC and the solution treated with 6.94 g. (0.039 mole) of N-bromosuccinimide. The solution was heated under reflux and irradiated with light for twenty minutes, and the solid which had separated was taken into chloroform-ethyl acetate and the solution extracted with aqueous potassium carbonate, dried over magnesium sulfate and taken to dryness. The residue was chromatographed on silica gel, the product being eluted with 25% acetone in toluene, which was isolated and recrystallized from toluene to give 3.7 9.
(31~) of S-bromo-2-methyl-3-(4-methylbenzo~1)-1-~2-(4-orpholinyl)ethyl~-lH-indole, m.p. 134.5-136C.

D _. 73SG~
5S3~

--so--Examples 34A--34H
Following a procedure si~.ilar to that described in Example 2A above, it is contemplated that other species of formula I as follows can be prepared by reaction oE a 2-R2-1-[2-(4-morpholinyl)ethyl~-lH-indole with an ap-propr;.ate aroyl chloride (R3COCl) in the presence of al~mi-num chloride in methylene dichloride:
Example 34A - 2-methyl-1-[2-t4-morpholinyl)ethyl]-3-~2-quinolinecarbonylL-lH-indole, by reaction of 2-methyl-1-12-(4-morpholinyl)ethyl]-lH~indole with 2-quinoline carboxylic acid chloride;
Example 34B - 2-methyl-1-[2-~4-morpholinyl)ethyl]-3-(3-quinolinecarbonyl~-lH~indole, by reaction of 2-methyl-1-12-(4-morpholinyl)ethyl]-lH-indole with 3-quinoline carboxylic lS acid chloride;
Exame~e 34C - 2-methyl-1-[2-(4-morpholinyl)ethyll-3-~4-quinolinecarbonYl)-l~-indole, by re~ction of 2-methyl-1-~ 12-~4-morpholinyl)ethyll-1~-indole with 4-quinoline carboxylic : acid chloride, Example_ 34D - 2-meth.yl-1-12-~4-morpholinyl~ethyll-3-(5 quinolinecarbonyl)-lll-indole, by reaction of 2-methyl-1-12-(4-morpholinyl)ethyl]-1~-indole with 5-q~inoline car-boxylic acid chloride;
xample 34E - 2-methyl-1-[2-(4-morPholinyl)ethyl]-3-(6-q~inolinecarbonyl)-lH-indole, by reaction of 2-methyl-1-12-~4-morpholinyl~ethyl]-lH-indole with 6-quinoline carboxylic acid chloride:
.

D._~ 7356A
~Z~ 2 2-methyl-1-[2-(4-morpholinyl)ethyl]-3-(7-quinolinecarbonyl)-lH-indole, prepared by reaction of 2-methyl-1-[2-(4 morpholinyl)ethyl]-lH-indole with 7-quinoline carboxylic acid chloride;
~ y~ - 2-methyl-1-[2-(4 quinolinecarbonyl)-lH-indole~ by reaction of 2-methyl-1-[2-(4-morpholinyl)ethyl]-lH indole with 8-quinoline car-boxylic acid chloride; and Exam~le 34H - 2-benzyl-1-[2-~4-morpholinyl~ethyl]-3-~4-methoxybenzoyl)-lH-indole, by reaction of 2-benzyl-1-[2-(4-morpholinyl)ethyl]-lH-indole with 4-methoxybenzoyl chloride.

_ D.~ 7356A
lL~5~3~ ~

BIOLOGICAL TEST RESULTS
The 3-R3-carbonyl-1-aminoalkyl-1ll-indoles of formulas I, Ia and Ib of the invention were tested in the a~etylcholine-induced abdo~inal constriction test ~Ach), the anti-bradykinin test (~RDK) and the rat paw flexion test (P,F.~, all ln vivo tests, and were found to have analgesic activity. Data so-obtained are given in Table B
below. Unless noted otherwise, all data were obtained on oral administration and are expressed either as the ED50 or as the percent inhibition at a given dose level ~thus 30~100 or 30% inhibition at 100 mg.~kg.) In some instances, the compounds were retested two or more times, and ED50 values were calculated for each series of repeat tests. In such instances, each of the ED50 values so-obtained is given in a series of values, thus 6, 23, 30, 43 in the case of the species of Example lAW
in the acetylcholine-induced abdominal constriction test.

I'able B

Exampl~ Ach BRDK P.F.
lA 73 56 IB 24,50,30,37 8.1 (~v.) 41,26,3~,58 6.7 (LV.) 21, 4B (s.c.) .lC 1~6 .
lD 34,10,54,22 0/100 64 5.1 (Lv.) 4g ~s.c.
lE ~/100 lF 20 0/200 88/100 13 (iv.) lG 84 0/3 ~v.) 50/10 (LY-) 100/30 (iVq) lH 33/100 71~300 0/3 ~V.) 30/10 (Lv.) 100/30 (i~.) 2/30 (s.c.) 8.5 (iv.) lJ 86 6~7 (iv.) lE~ 255 1--0/1 (LV.) 30/3 (LV.) 25/5.5 (LV.) 44/1~ liv.) lN 35.8 l-O 91.6 lP ~0/100 4.5 (iv.
lQ 7/24 27~79 60/23~3 60~793 D .-'~, 7 ~
3~

T~le B (co~
Exa m~le Ach s R D K P .F.
lR 198 lS ~o 162 10/1 (iv.) 20~3 (1~V.3 100/10 (iv.) lT 106 3.8 (Lv.) lV 155 lV 20/300 1 W 0~30 ~0/3qO

10/1 (iv~) 0/1.73 (LV.) 86/3 (iv.) lAA 10~100 lAB 47/300 lAC 30 - û/200 43/30 10/1.77 (iv.) 57/50 10/2.~ (iv.) 75/100 80/3 (iv.) 100/10 (iv~) lAE 29 20/300 66.2 lAF 200 0/3 (iV.) 0/10 (iv.) 30/30 (LV.) lAG 40/100 47f300 10/10 (iv.) 56/3V (iv.) ~0~30 ~s.c.) lAH 85 l~I 74 lAJ 13/100 lAK 40/300 lAL 113 lA M 32 5 (LV-) 3L;25~5;~ 2 D~_; 7356A

Exa m p~e Ach B R D K P.F.
lA0 2a 1ll 75/100 lAP 42 ~/S0 lAQ S3/300 0~10 17 (iv.) 12/30 lA R 27/150 13/25 (~c.) lAS 33/300 lAT 30 0/50,200 lAU 42 0/S0 lAV 38 0/50 lAW 6,28,30,43 229 26 lA X 45 û/212 lA Y 11,37,49 141 0/30,100 8.5 (LV.) 20/300 : lAZ 10,27/50 : 73/100 lB A 197 lBB 97 le c 40/100 1~ D 65 .l~E 50.9 lBF 0/30 lB G 33/300 1~ 0/30 5~550 7/30 (6c.) 50~10 (iv.J
lBI 13/300 0/6 27/100 (~c.) 0.69 (iv.) l~J 0/100 l~L 0/100 lB M 0~100 - 1~ N 36 ~ lBP 28 ;~

12~53~2 D, . 7356A

Table B (cont'~

xa mp7~_ Ach B R D K P .F .
1~ R 123 ~3T 90/100 ~ W 10/100 lBZ 0/100 lC~ 20/100 lCB 60/100 lCC 10/100 lCD 79 lCE 0/100 lCF 24 lCG 46.3 lC H 105 lCI 70/100 lCJ 56 lC K30/100 l C L30/100 2~ ~7/30~

2C 19,33 0/30 3.3 (LV.) 60/300 2D 20~100 ~0/300 2H ~9 2.6 (Lv.) 18 (~c.) o D , 7 356A
~fl f p 1~
-~7 -Table ~

Ach BRDK P.F.

2P ~0/100 2Q 20~100 2t~ 88 2A}~ 20/100 2A K 30/0.3 (iv.) 2AL 20/O~lliv.) 2P~0 40/100 3P~ 681 3E~ 26.5 50/30 10 ~SC.) 8~/100 3 ~v-) ~6/300 -sa-~a!:~e B ~con~'~
Examp~e Ach BRDK P.F.
3~ 9.7 (iv.

3J 30/10 (iv.) 3 R 45.7 3V 253.8 3AF 138.6 4A 16 53 0,12/100 4B 24,25,21,15 3~,28,19 27.6 6 (iv.) 20/1 (Lv.) 29/3 (iv.) 30/10 (i.'~.) 5E~ 25 61 0/10 57/3 (iv.) ~9/1 tiv.~

~. . .

99 ~5~

Table B~ ont'd.) Ach BRDR P.F.

0/10 (iv.) 0/300 0/30 (iv.) 13/30 (s.c.) 7 ~0 0/300

9 27/300 20/30 (s.c:.) 7~30 (Sc.) 13/3U (&c.) 1613 20/10~
17 7/30 33,/100 ~c.) 6.6 (ac lg 40/100 22 ~6.8 25A (r) 82.5 26A 40~100 2~C 30/100 26E 73.1 u / ~ ju~
~L2~3~~

-10 0 -Tahle B (con~'d.l Exa m~e Ach B R D K P .F .

27A 20.7 27B 59.8 27C 29.4 27 D ~0 29~ 60,80/100 29~ 60,70/100 29C 0~100 31F 0/3 tiV~) 30/100(Lc.v.) 80/10 (Lv.) 31-I 31,40,88/100 31N 90,100/100 32 8~

(r) N =B is a m~no The 3-R3-carbonyl-1-am~noa1cyl-lH-~dc~es o~ formul~s I, Ia and ~b of the invention were also test~3 in the develop~ng adjuvant arthrit~c assay, the plasma fibronectin a~ay and the pleurisy macr~phage a~say in rats. Data ~obtained, expre~ied as ~vall;es as a measure of the statistical ~nilïcance of the results for each of ~e parameters measured, ie. inhibition of inl~ammation of non-~r~ected paw (NIP) and ir~ected paw (right paw vc~me or RPV), lower~ng of ~asma fibronectin levels (FN) and is)hibit.~on of macrophage accumulation in theEileural cavity ~MAC), are given in Ta~Le C. Compounds were consi3ered active at p ~ 0.05 ~vels. Non statistically s~gnificant xesulb; are recorded as l~_tl~

~25~3:~

Table C
ExamF~e N:rP RPV FN MAC
lB (~ 0.01 0.01 lF 0.01 0.01 lI 0.01 0.01 0.01 0.01 lU -- _ _ lAC
lAO - _ _ lRP
lA~
lB A - - O .01 lBB
lBD
lBE _ 0 05 lBL 0.01 0.05 0.01 113 M 0.01 0.01 0.01 0.01 lBN
lEI O - Q.O1 0.05 lBP 0.01 0.01 lBQ(~ 0.01 0.01 0.01 OoOl lBR 0.01 0.01 0.01 lB Z 0.05 0.01 0.01 lCC _ _ lCE
lCF 0.01 0.01 lC G 0.01 0.01 0.01 lCH
lCJ 0.01 0.01 - -lCL
lC M - 0.01 lC O 0.01 0.01 lCP 0.01 O.~ï 0.01 0.01 2C 0.01 0.01 0.01 0.01 2E 0.01 0.01 2U - - 0.01 Y 0,05 ~ .

55~

T~le C (c~n~.) Exampl~ NIP RPV FN MAC

2AC o.os - -2AE 0.01 0.01 2AF 0.01 0.01 2AG 0.01 - 0.01 2AI 0.01 0.01 0.01 2AK _ _ _ 2A O 0.01 0.01 0.01 0.05 2AW - _ _ 0 05 2~X -- _ .
2A Y 0cOl 0.05 2B~ - 0.01 0.05 2BF - 0.01 0.01 3D - _ _ 3E 0.01 3F 0.05 0.01 3K - 0.01 0.05 3T - 0.01 3 W 0.01 0.01 0.05 3AF - OoOl 3AG 0,01 0.01 0.01 3AH OoOl ~ OvOl 3Al O~Ol O~Ol ~ 0~05 `
3AJ OvOl O~Ol 0005 6 ~ 0~05 13U - - OoOl 12S53~ ;~ D I ~ ~ o l~

:
ExampLe NIP RPV FN MAC
16A 0.05 - -19 -- _ _ 20A - - 0.05 22 0.01 0.01 - O.OS
23A 0.01 0.01 0.01 23B 0.01 0.01 0.01 24 0.05 0.01 26F 0.05 0.01 -26 G - - 0.01 27A 0.05 0.01 27E~ 0.05 0.01 27 D 0.01 0.01 29A 0.05 0.01 31A 0.01 0.1~1 -31B 0.01 31~ 0.01 31J 0.05 31L 0.05 0.01 - -31M 0.01 - 0.01 31N 0.01 0.01 31-0 0.01 0.01 - -32 OoOl O~Ol 0~05 (s) The maleate salt ~ The lower mel~ing p~lymorph Certain speciPs of the intermediate 2-R2-3-(R3 carbon~4-indc~es oE
form~a II were also tested arld found active in one or more of the acetylchc~ine-induced abdominal constriction test (Ach), the developing adjuvant arthri~c assay ~NIP and RPY), the Bbronectin a~;ay (FNl and th2 ~deunsy macrophage a~y (MP.C). Data ~ob~ained, e~preæd as de~cribed above, are given ~n Ta~le D.

-104~

Table D

PreE?n. Ach NIP RPV FN MAC
lF 0/100 - - -lAJ
lA K 20/lO0 - - - 0.05 lAL 20/lO0 0.01 - 0.01 0.01 lA M - - 0.01 1~N n.o~ o.ol - -lAO 40/lO0 lA Q 0.01 0.01 U.01 Certain spec~es of the mtermediate 2-R2-1-aminoalkyl-lH-indciLes of formula m were tested and found ac~ive ~n the acetylchQline-induced abdominal cor~striction test. Thus 2-methyl-1-[1-methyl-2-(4-morpho-linyl~ethyl]-lH ind~le methaneslllfonate hydrate ~Preparat~on SA) pro-duced 40 9~ inhibit~on at 300 mg./kg. (p.o.), and the ED50 of 5-fhloro-2-methyl-l-(l-methyl-2 dimethy~aminoefflyl~-lH-indo~ ~Preparati~n 8) was found to be 25 mg./lcg. ~? -)~

Claims (8)

D.N. 7356B DIV V
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound of the formula VI
[wherein:
R2 is hydrogen, lower-alkyl, chloro, phenyl or benzyl (or phenyl or benzyl substituted by from one to two sub-stituents selected from halo, lower-alkyl, lower-alkoxy, hydroxy, amino, lower-alkylmercapto, lower-alkylsulfinyl or lower-alkylsulfonyl);
R3 is cyclohexyl, lower-alkoxycyclohexyl, phenyl (or phenyl substituted by from one to two substituents selected from halo, lower-alkoxy, hydroxy, benzyloxy, lower-alkyl, nitro, amino, lower-alkylamino, di-lower-alkylamino, lower-alkoxy-lower-alkylamino, lower alkanoylamino, benzoylamino, trifluoroacetyl-amino, lower-alkylsulfonylamino, carbamylamino, lower-alkyl-mercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, cyano, formyl or hydroxyiminomethyl), methylenedioxyphenyl, 3- or 4-hydroxyl-1-piperidinylphenyl, 1-piperazinylphenyl, (1H-imidazol-1-yl) phenyl, (1-pyrrolyl)phenyl, aminomethylphenyl, guanidinylmethyl-phenyl, N-cyanoguanidinylmethylphenyl, styryl, lower-alkyl-substituted-styryl, fluoro-substituted-styryl, 2-4 biphenyl, 1-or 2-naphthyl (or 1- or 2-naphthyl substituted by from one to two substituents selected from lower-alkyl, lower-alkoxy, hydroxy, bromo, chloro, fluoro, lower-alkoxycarbonyl, carbamyl, cyano, lower-alkylmercapto, lower-alkylsulfinyl, lower-alkyl-sulfonyl or trifluoromethyl), thienyl, furyl, benzo[b]furyl, benzo[b]thienyl, quinolyl or (N-lower-alkyl)pyrrolyl;
R4 is hydrogen or from one to two substituents selected from lower-alkyll hydroxy, lower-alkoxy or halo in the 4-, 5-, 6- or 7-positions;
Alk is .alpha.,.omega.-lower-alkylene having the formula (CH2)n where n is an integer from 2 to 6, or such lower-alkylene substituted on the .alpha.- or the .omega.-carbon atom by a lower-alkyl group; and X' is toluenesulfonyloxy or halo].

2. A process for producing a compound of the formula VI as defined in claim 1 which comprises:
(a) in the case where Alk is 1,2-ethylene reacting a 2-R2-3-R3-carbonyl-indole of the formula II:

II

with a lower-alkyl lithium, reacting the resulting lithium salt with ethylene oxide, and reacting the so-formed 2-R2-3-R3-carbonyl-1-(2-hydroxyethyl)-1H-indole with toluenesulfonyl chloride in the presence of an acid-acceptor to form a compound of the formula VI where X' is a toluenesulfonyloxy group, or with a phosphorus trihalide to form a compound of the formula VI where X' is a halo group; or (b) in the case where X' is halo and Alk is other than 1,2-ethylene, reacting a 2-R2-3-R3-carbonyl-indole of the formula II with an .alpha.,.omega.-dihalo-lower-alkane in the presence of a strony base.

3. A compound according to claim 1, wherein:

R2 is hydrogen or lower-alkyl;
R3 is phenyl, chlorophenyl, fluorophenyl, dichloro-phenyl, difluorophenyl, lower-alkoxyphenyl, di-lower-alkoxy-phenyl, hydroxyphenyl, lower-alkylphenyl, aminophenyl, lower-alkylaminophenyl, lower-alkanoylaminophenyl, benzoylaminophenyl, trifluoroacetylaminophenyl, lower-alkylmercaptophenyl, lower-alkylsulfinylphenyl, lower-alkylsulfonylphenyl, cyanophenyl, aminomethylphenyl, styryl, 2- or 4-biphenyl, 1- or 2-naphthyl (or 1- or 2-naphthyl substituted by lower-alkyl, lower-alkoxy, hydroxy, bromo, chloro or fluoro), 2-thienyl, 2-, 3-, 4- or 5-benzo[b]furyl, 2-, 3-, 4- or 5-benzo[b]thienyl or 2- or 3-(N-lower-alkyl)pyrrolyl;
R4 is hydrogen or lower-alkyl, lower-alkoxy, fluoro or chloro in the 4-, 5-, 6- or 7-positions;
Alk is 1,2-ethylene (-CH2CH2-), 1-lower-alkyl-1, 2-ethylene (-CHRCH2-), 2-lower-alkyl-1,2-ethylene (-CH2CHR-), where R is lower-alkyl, 1,3-propylene (-CH2CH2CH2-) or 1,4-butylene.

4. A compound according to claim 1, wherein:
R2 is hydrogen or lower-alkyl;
R3 is phenyl, chlorophenyl, fluorophenyl, difluoro-phenyl, lower-alkoxyphenyl, lower-alkylphenyl, aminophenyl, lower-alkylaminophenyl, lower alkanoylaminophenyl, trifluoro-acetylaminophenyl, lower-alkylmercaptophenyl, lower-alkyl-sulfinylphenyl, aminomethylphenyl, 1- or 2-naphthyl (or 1- or 2-naphthyl substituted by lower-alkyl, lower-alkoxy, hydroxy, bromo, chloro or fluoro), 2-thienyl, 2-, 3-, 4- or 5-benzo[b]
furyl or 2-, 3-, 4- or 5-benzo[b]thienyl;

R4 is hydrogen, lower alkoxy, fluoro or chloro in the 4-, 5-, 6- or 7-positions;

Alk is 1,2-ethylene, 2-lower-alkyl 1,2-ethylene, 1-lower-alkyl-1,2 ethylene, 1,3-propylene or 1,4-butylene.

5. A compound according to claim 1, wherein:
R2 is hydrogen or lower-alkyl;
R3 is phenyl, fluorophenyl, chlorophenyl, dichloro-phenyl, lower-alkoxyphenyl, di-lower-alkoxyphenyl, hydroxyphenyl, lower-alkanoylaminophenyl, benzoylaminophenyl, lower-alkylsul-fonylphenyl, cyanophenyl, styryl, 1-naphthyl, lower alkoxy-substituted-1- or 2-naphthyl, 3-benzo[b]thienyl or 2- or 3-(N-lower-alkyl)pyrrolyl;
R4 is hydrogen or lower-alkyl, lower-alkoxy, fluoro or chloro in the 4-, 5-, 6- or 7-positions;
Alk is 1,2-ethylene, 1-lower-alkyl-1,2-ethylene, 2-lower-alkyl-1,2-ethylene, 1,3-propylene or 1,4-butylene.

6. A compound according to claim 1, wherein:
R2 is hydrogen, lower-alkyl or phenyl;
R3 is cyclohexyl, lower-alkoxycyclohexyl, phenyl, fluorophenyl, lower-alkoxyphenyl, lower-alkoxy-fluorophenyl, benzyloxyphenyl, methylenedioxyphenyl, lower-alkylphenyl, di-lower-alkylphenyl, lower-alkylsulfonylaminophenyl, carbamyl-aminophenyl, cyanophenyl, formylphenyl, oximinomethylenephenyl, (1-pyrrolyl)phenyl, guanidinylmethylphenyl, N-cyanoguanidinyl-methylphenyl, 2-naphthyl, 2-furyl or 2-benzo[b]thienyl;
R4 is hydrogen or lower-alkyl, hydroxy or lower-alkoxy in the 4-, 5-, 6- or 7-positions;
Alk is 1,2-ethylene or 1-lower-alkyl-1,2-ethylene.

7. A compound according to claim 1, 3 or 4, wherein X' is toluenesulfonyloxy, bromo or chloro.

8. A compound according to claim 5 or 6, wherein X' is toluenesulfonyloxy, bromo or chloro.