CA1255316A - 3-arylcarbonyl-1h-indoles useful as anti-rheumatic agents as well as intermediates and their production process - Google Patents

Abstract

D.N. 7356B DIV III

ABSTRACT OF THE DISCLOSURE

Disclosed are novel 3-arylcarbonyl-lH-indoles of the formula:

(II') (wherein R2' is hydrogen, alkyl or phenyl;
R3' is phenyl substituted by fluoro, lower-alkoxy, methylenedioxy, amino, cyano or phenyl or is naph-thyl optionally substituted by alkoxy;
R4' is hydrogen or fluoro) , which themselves have anti-rheumatic activities and also are useful as intermediates for producing analgesic, anti-rheumatic or anti-inflammatory substances of the formula:

(I') (wherein Alk is optionally alkyl substituted alkylene;
N=B is azido, optionally substituted amino or optio-nally substituted cyclic amino such as morpholi-nyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl, hexahydrodiazepinyl or the N=B N-oxide thereof, and the other symbols are as defined above).

Description

S 3 ~ 6 D.N. 7356B DIV III
This is a divisional application of Application Ser.
No. 488,073 filed August 2, 1985.
The parent application relates to novel compounds of the formula (I) described hereinafter having analgesic, anti-rheumatic and anti-inflammatory activities.
This divisional application relates to novel compounds of the formula (II') described hereinunder, which are included among those of the formula (II) described hereinafter and are useful as anti-rheumatic agen-ts as well as intermediates for producing the compounds of the formula (1).

Thus, an aspect of this divisional application pxovides a compound of the formula:

4 ~ l~ CO-R3' (II') (wherein:
R2' is hydrogen, lower-alkyl or phenyl;
R3' is fluorophenyl, difluorophenyl, lower-alkoxyphenyl, di-lower-alkoxyphenyl, lower-alkoxy fluorophenyl, methylenedioxyphenyl, aminophenyl, cyanophenyl, 2- or 4-biphenyl, 1- or 2-naphthyl or ~ower-alkoxy-substituted-l- or

2-naphthyl; and R4' is hydrogen or fluoro).
Another aspect of this application provides a process for preparing the compound of the formula (II'). This process comprises:

. . .

~53~6 - la - 22749-319F

reacting a 2-R2-indole of the formula R4' ~ l N ~ R ' (IV') H

(wherein the symbols having the meanings given above) with a lower-alkyl magnesium halide and reacting the resulting Grignard with the required R3'-carboxylic acid halide.
A still further aspect of this application provides a pharmaceutical composition comprising an anti-rheumatic effec-tive amount of a compound of the formula (II') as defined above in admixture with a pharmaceutically acceptable carrier or diluent.

In the Eollowing description, it should be understood that the expression "this invention" includes the subject matters of this divisional application, of the parent applica-tion and of other divisional applications filed from the same parent application.

- lb - 22749-319F

BACKGROUND_VF T~E INVENTION
(a~ Fleld of the Invention:
:
This invention relates to 3-arylcarbonyl- and 3-cycloalkylcarbonyl-l-aminoalkyl-lH-indoles which are use-fulasanalgesic,anti-rheumaticandanti-inflammatoryagents.
~b) Information ~isclosure Statement:
Deschamps et al. U.S. Patent 3,946,029 discloses compounds having the formula:

[~ ~R;

where, inter alia, A is alkylene, R2 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).
Specifically disclosed in both these references is the species, 2-isopropyl-3-(3-pyridylcarbonyl)-1-~2-(4-morpho-linyl~ethyl~1ndole~

ù~l` i.i ``~
~ ~5;~

Herbst U.S. Patent 3,489,770 generically discloses compounds having the formula:

1~

where, inter a_ , 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 variety of species where R2 is an arylcarbonyl group.
Specifically disclosed, for example, is the spe~ie6 "l-p-(chlorobenzoyl~-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, 27S (20), 123g 1242 (1974) discloses compounds of the formula:

lS ~n~ ~
CH2) n~N ~O

~here n is ~ or 3. No utility for the compounds is given.

SUMMARY

In a composition of matter aspect, the invention relates 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.

3~

--3~
In a second composition oE matter aspect, the inven-tion relates to 2-R2-3-R3-carbonylindoles useful as inter-mediates ~or the preparation oE said 2-~2-3~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 m~tter aspect, the invention relates to 2-R2-1-aminoalkyl-lH-indole~ 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 ~seful as analgesics.
In a process aspect, the invention relates to a process for preparing 2-R2-3-R3-carbonyl-1-aminoalkyl-lH-indoles which comprises reacting a 2-R2-3-R3-carbonyl-indole with an aminoalkyl halide in the presence o an acid-acceptor.
In a second process aspect, the invention relates to a process for preparing 2-R2-3-R3-carbonyl-l-amino-alkyl-lH-indoles which comprises reacting a 2-R2-1-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 for preparing said 2-R2-3-R3-carbonyl-1-aminoalkyl-lH-indoles which comprises reacting a 2-R2-3-2~ R3-carbonyl-1-tosyloxyalkyl- or 1-haloalkyl-1~-indole with an amine~
In a method aspect, the invention relates to a method of use of the said 2-R2-3-R3-carbonyl-1-aminoalkyl-lH-indoles for the relief of pain or of rheumatic or inflammatory conditions.

. , .

53~6 In a second method aspect, the invention relates to a method of use of the said 2-R2-3-R3-carbonylindoles ~or the relie~ of rheumatic conditions.
In a third method aspect, the invention relates to a method of use of the said 2-R2-1-aminoalkyl-lH-indoles for the relief of pain.
DETAILED DESCRIPTION OP THE PEIE~FERREO EMBODIMENTS
More specifically, the invention relates to 2-R2-3-R3-carbonyl-1-aminoalkyl-lH-indoles, which are useful as analgesic, anti-rheumatic and anti-inflammatory agents, having the formula:
z R4 ~ C-R3 N ~ ~2 Alk-N=B
I

where:
R~ is hydrogen, lower-alkyl, chloro, phenyl or lS benzyl (or phenyl or benzyl substituted by from one to two substituents selected from halo, lower-alkyl, lowex-alkoxy, hydroxy, amino, lower-alkyl-mercapto, lower-alkylsulfinyl or lower-alkyl-sulfonyl);
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-alkanoylaminOr benzoylamino, trifluoroacetylamino, lower-alkyl-l~S~16 ~ jos sulonylamino, carbamylamino, lower-alkylmercapto, lower-alkylsulf;nyl, low~r-alkylsulfonyl, cyano, formyl or hy~roxyiminomethyl~,methylenedioxyphenyl, 3- or 4-hydroxy-1-piperidinylphenyl, l-piperazinyl-phenyl, (].rl-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 sub~tituted by from one to two sub~tituents selected from lower-alkyl, lower-alkoxy, hydroxy, bromo, chloro, fluoro, lower-alkoxycarbonyl, carbamyl, cyano, lower-alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl or trifluoromethyl), thienyl, furyl, benzolb]furyl, benzolb]thienyl, quinolyl or (N lower-alkyl)pyrrolyl;
R4 is hydrogen or from one to two substituents selected ~rom 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 alw-lower-alkylene having the formula (CH2)n, where n is an integer ~rom 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, N,N-; 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)amino~ 4-morpholinyl, 2-lower-alkyl-4-morpholinyl, 2,6-di-lower-alkyl-4-i3~ 6 - 6 - 227~9-319 morpholinyl, 4-thiomorpholinyl, 4-~hiomorpi-olinyl-S-oxide,

4-thlomorpholinyl-s,S-dioxide, l-piperidinyl, 3- or 4-hydroxy-l-piperidinyl, 3- or 4-lower-alkanoyloxy-l-piperidinyl, 3- or 4-amino-l-piperidinyl, 3- or 4-(N-lower-alkanoylamino)-l-piperidinyl, 2-cyclohexylmethyl-l-piperidinyl, l-pyrrolidinyl, 3-hydroxy-l-pyrrolidinyl, l-azetidinyl, l-piperazinyl, 4-lower-alkyl-l.-piperazinyl, 4-lower-alkanoyl-1-piperazinyl, 4-carbo-lower-alkoxy-l-piperazinyl, hexallydro-91l-1,4-diazepin-4-yl or the N-B N-oxides thereof, with tile proviso that N=B is not amino, when R2 is methyl, R3 is phenyl, R~ is hydxogen and Alk is (CH2)3.
Preferred compounds of formula I above are those where:
R2 is hydrogen or lower-alkyl;
R3 is phenyl, chlorophenyl, Eluorophenyl, dichloro-phenyl, difluorophenyl, lower-alkoxyphenyl, di-lower-alkoxy-phenyl, hydroxyphenyl, lower-alkylphenyl, aminophenyl, lower-alkylaminophenyl, lower-alkanoylaminophenyl, ~enzoylaminopllenyl, trifluoroacetylaminophenyl~ lower-alkylmercaptophenyl, lower-alkylsulfinylphenyl, lower-alkylsulfonylphenyl, cyanophenyl, aminomethylpllenyl, styryl, 2- or 4-bipllenyl, l- or 2-naphthyl ~or l- or 2-naph-thyl substituted by lower-alkyl, lower-alkoxy, llydroxy, bromo, chloro or Eluoro), 2-thienyl, 2-, 3-, 4- or

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

D,N 35 ~553~6 C=Z is C=O;
Alk is 1,2-ethylene (-CH2CH2~ lower-alkyl-l, 2-ethylene (-CHRCH2-), 2-lower-alkyl-1,2-ethylene (-CH2CH~-), where ~ i5 lower-alkyl, 1,3-propylene (-Cll2CH2CH2-) or 1,4-butylene; and N=B is 4-morpholinyl, 3- or 4-hydroxy-1-piperi-dinyl, l-pyrrolidinyl~ 3-hydroxy-1-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-piper~zinyl.
PartiOularly preferred compounds of formula within the ambit oE the invention as defined above are those where: .
lS R~ is hydrogen or lower-alkyl:
R3 is phenyl, chlorophenyl, f-luorophenyl, 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-benzolb]thienyl;
R~ is hydrogen, lower alkoxy, fluoro or chloro in the 4-, 5-, 6- or 7-posit;on~;
C=Z 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~i3~6 -B-N=H is 4-morpholinyl, 3- or 4-hydroxy-1-piperidinyl, 1-pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl, NrN-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 where: -R2 is hydrogen or lower-alkyl;
R3 is phenyl, fluorophenyl, chlorophenyl, di-chlorophenyl, lower-alkoxyphenyl, di-lower-alkoxy-phenyl, hydroxyphenyl, 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 is C=O;
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, benzyloxyphenyl, methylene-dioxyphenylr lower-alkylphenyll di-lower-alkyl-phenyl, lower-alkylsulonylaminophenyl, carbamyl-.

- I '?'~5~jA
3:~6 _g_ aminophenyl, cyanophenyl, formylphenyl, oximino-methylenephenyl, (l-pyrrolyl~phenyl, guanidinyl-methylphenyl, N-cyanoguanidinylmethylphenyl, 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;
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-morpholinyl, 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 Alk-N=B
Ia 4 ~ C-R3 CH2CHCH2-N=B
OH
Ib where R2, R3, ~4, Alk, Z and N=B have the meanings ~iven above.
As used herein, unless specifically defined other-wise~ the terms lower-alkyl, lower-alkoxy and lower-alkanoyl mean monovalent, aliphatic radicals, including 3~
- 10 - 2~7~9-319 branched chain radicals, of from one to about four carbon atoms, for exaMple, methyl, ethyl, propyl, isopropyl, butyl, sec.-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec.-butoxy, formyl, acetyl, propionyl, butyryl and isobutyryl.
As used herein, the term cycloalkyl means saturated alicyclic groups having from three to seven ring carbon atoms, including cyclopropyl, cyclobutylr cyclopentyl, cyclohexyl and cycloheptyl.
As used herein, the -term halo means fluoro, chloro or bromo.
In one method, the compounds of formula I where C=Z
is C=0 are prepared by reacting a 2-~2-3-R3-carbonyl-1ll-indole oE formula II with an amino-lower-alkyl halide amino-lower-alkyl to~late in the presence oE an acid-acceptor:

4 ~ R + X-Allc-N-B ~ C2 ¦ Al~-N=B
l-l I
II ~C=Z is C=0) where R2, R3, R~, Alk and N=B have the meanings given above and X represents haloyen or -tosyloxyO The reaction is preferably carried out in an organic solventiner-t under -the conditions of the reaction such as dimethylformamide (hereinafter DMF), dimetllylsulfoxide (hereinafter DMS0) r a lower-alkanol or acetonitrile. Suitable acid-acceptors are an alkali metal carbonate, such as sodium carbonate or potassium carbonate, or an alkali metal hydride, such as L . 7 ~;i)/~
3~ ~

~odium hydride, an alkali metal amide, such as sodamide, or an alkali m~tal hydroxide, such as potassium hydroxide.
Preferred solvents are DMF and DMSOy and preferred acid-acceptors are sodium hydride, potassium carbonate and 5 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-R2-3-R3-carbonyl-lH-indoles of formula II
are in turn prepared by reacting a 2-R2-indole with a lower-alkyl magnesium halide and reacting the resulting Grignard with an appropriate R3-caeboxylic acid halide.
The reaction is carried out in an organic solvent inert under the conditions of the reaction, such as dimethyl ether, dioxane or tetrahydrofuran (hereinafter THF), at a temperature in the range from -5~C. to the boiling point of the solvent used.
Certain compounds within the ~mbit of formula II, namely those of formula II':

R4~CQ2_E~3 H
II' where R2 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 R4 is hydrogen or fluoro are novel species and comprise a further composition aspect of ~his inven-tion.

~2s~

In another method, the compounds of Eormula I where C=z is C=o are prepared by reacting a 2-R2-1-aminoalkyl-1H~
indole of formula III with an appropriate R3-carboxylic acid halide (R3-CO-X) iJl the presence of 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 (hereina~ter EDC~. The reaction is carried out at a temperature from 0C, to the boiling point of the solvent used. The method is illustrated by the reactian:

4 ~ ~ R3 ~ 4 ~ ~ ~

Alk-N=B Alk-N=B

III I
(C=z is C=O) wh~re R2, R3, R4, Alk, N=B and X have the meanings given above.
The intermediate 2-R2-1-aminoalkyl-lH-indoles of formula III wherein R2~ R~, Alk and N=A have the previously given meanings comprise yet a Eurther composition aspect of 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 o an acid-acceptor, in an organic solvent inert under the conditions oE the reaction using the same conditions de-scribed above for the preparation of the compounds of ~or mula I by alkylation of the compounds of formula II.
In a second method, a 2-R2-indole of ormula IV is reacted with a halo-lower-alkanamide in the presence of a 3~l6 .

strong base, and the resulting 2-R2-lH-indole-l-alkanamide oE formula V is then reduced with lithium aluminum hydride.
The reaction of the 2-R2-indole of formula IV with the halo-lower-alkanamide is carried out in an appropriate organic solvent, such as DMF, at a temperature from -5C.
to about 50C. The reduction of the amides of formula V
with lithium aluminum hydride is carried out in an i.nert 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:

IV

4~R2 Alk-N=B
III

4~R2 Alk'-CO-N=B
V

where R2, R4, Alk and N=B have the meanings given above, and Alk' is lower-alkylene having the formula (CH2)nl, where n' i~ an integer ~rom 1 to 5 or such lower-alkylene ; group substituted on the ~-carbon atom by a lower-alkyl group.
In another method for preparing the compounds of formula I where C=Z is C=G, a 2-~2-3-R3-carbsnyl-1-~2-tosyloxy-lower-alkyl)- or (2-halo-lower-alkyl)-lH-indole of form~la 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 illustrated by the reaction:

-R3 ~;~ CO-R3 Alk--X ' Alk-l!l=B
VI

where R2, R3, R4 and N=B have the meanings given above, and X' represents a toluenesulfony.loxy or halo group.
The 2-~2-3-R3-carbonyl-1-(2-tosyloxy-lower-alkyl)-or 1-(2-halo-lower-alkyl)-1~-indoles of formula VI, where Alk is 1,2-ethylene, are in turn prepared by reaotion of a ~-R2-3-R3-carbonyl-indole of formula II with a lower-alkyl lithium, for example n-butyl lithium, in an inert organic solvent, such as TH~, dioxane or diethyl ether, ollowed by reaction of the resulting lithium salt with ethylene oxide.
~eaction oE the resulting 2-R2-3-~3-carbonyl-1-(2-hydroxy-ethyl)-lH-indole with toluenesulfonyl chloride in the p~esence of an acid-acceptor affords the 1-(2-tosyloxy-ethyl)-lH-indoles, while reaction of the product with a phosphorus trihalide affords the corresponding l-(2-halo-ethyl)-lH-indoles.
The 2-R~-3-R3-carbonyl-1-(2-halo-lower-alkyl)-lH-indoles of formula VI, where Alk has the other possible meanings, are prepared by reaction oE a 2-R2-3-R3-carbonyl ,, , !, .`:

~a~45~

-15~
indole of formula II with an a,~-dihalo-lower-alkane in the presence of a ~trong base, such as sodium hydride in an inert organic solvent, such as DMF. The reaction generally occurs at ambient temperature.
The compounds of ormula Ia are prepared by reaction ofa2-R2-3-formyl-1-aminoalkyl-lH-indolewithanappropriate methyl R3 ketone according to the reaction:
O
,~ CH0 ,~ CH=CHC-R3 R ~ ~ ~ + CH -C0-R3 R~

Alk-N=B Alk-N=B
Ia where R2, R3, R~, Alk and N=B have the meanings g~ven above. The reaction is c~rried out in the presence of a minelal acid and in an organic solvent inert under the conditions of the reaction. Preferred solvents are lower alkanols, such as methanol or ethanol.
The compounds of Eormula Ib, where Z is C=0, 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 DMS0, and reaction oftheresulting2-R2-3-R3-ca~bonyl-1-~1-(2,3-epoxy)propyl]-lH-indole with an appropriate amine, H-N=B, according to the reactions:

- Gl~

;53~6 -lG-O O
~ ~-R3 ~ C-R3 4 ~ ~ + XCH2CH-CH2 R4 ~ ~ ~ R2 H CH2C~ H2 II / o o ~

~1;~ ~;
CH~IHCH2-M=B
Ib OH
where R2, R3, R~, Alk and N=B have the meanings given above.
Another method for preparing the compounds of formula I where R~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 formula VII in an inert, 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, R~COCH2COR3, with an appropriate aminoalkylaminef B=N-Alk-NH2 under dehydrating conditions. The reaction is preferably carried out by heatin~ a solution o the reactants in an inert, water immiscible solvent under a Dean-Stark trap. The method is represented by the reaction sequence-O~R + H2N-Alk-N=B ~- C

Alk-N=~
VII
' ' ~. ~

.

~ 553~
o ¢~3 HO~ ~ ,CO R3 il , o Alk-N=B
~y 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 the 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 be carried out either catalytically with hydrogen, for example over a platinum oxide catalyst at ambient temperature and in an appropriate organic solvent, such as a lower-alkanol, ethyl acetate or acetic acid or mixtures thereof, at hydrogen pressures from around 30 to 60 p.s.i.g., or alternatively ~he reduction can be carried out chemically, for example with iron in the presence of hydrochloric acid in an appropriate organic solvent, for example a lower-alkanol. The reaction is carried out at temperatures from ambient to the boiling point of the solvent used for the reaction~
The aminophenyl compounds thus prepared can then be acylated or sulfonylated to prepare cornpounds where R3 is lower-alkanoylaminophenyl, henzoylaminophenyl, trifluoro-acetylaminophenyl or lower-alkylsulfonylaminophenyl by reaction of an appropriate acid anhydride or acid halide ~5 with the corresponding species where R3 is aminophenyl. It is advantageous, although not essential, to carry out the r . ~ ~ 56~
~;~S53~6 reaction in the presence of an acid acceptor, such as an alkali metal carbonate, for example potassium carbonate, or a tri-lower-alkylamine, such as trimethylamine or tri-ethylamine 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 chemistry and which can be used for effecting changes in functional groups attached to the R3-carbonyl group, (C=O)R3, involve cleavage of aryl ether functions, for example with aqueous alkali or a pyridine hydrohalide salt to produce thecorresponding phenoliccompoùnd (R3 ishydroxy-phenyl): preparation of compounds where R3 is phenyl sub-stituted by a variety of amine functions ~y reaction of the corresponding halophenyl species with an appropriate amine; catalytic debenzylation of benzyloxy-substituted species to prepare the corresponding phenolic compound (~3 is hydroxyphenyl); catalytic reduction of a nitrile function to produce the corresponding aminomethyl-substi-tuted species tR3 is aminomethylphenyl); saponification o~
amide groups to produce the corresponding amino compounds;
acylation of hydroxy-substituted species to produce the ~ 25 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 ~..

55~ 227,19-319 ~

species to prepare the corresponding mono- or di-:Lower-alkyl-arnino substituted species; reaction oE amino-substituted species with an alkali metal isocyanate to prepare the corres-ponding carbamylamino-substituted species (R3 is carbamyl-aminopllenyl); reaction oE an aminomethyl-substituted species with a di-lower-alkylcyanocarbonimidodithioate and reaction of the resulting product with ammonia to prepare the corresponding N-cyanoguanidinylme-thyl-substituted species (R3 is cyanoguani-dinylmet11ylphenyl); reduction oE a cyano-substituted species with sodium hypophosphite to prepare a corresponding formyl-substituted compound (~3 is formylphenyl); reaction of a formyl-phenyl species or a R3-carbonyl species with hydroxylamine to prepare the corresponding hydroxyiminomethylphenyl-substituted species (R3 is hydroxyiminomethylp11enyl) or the R3-carbonyl oximes (C=Z is C=NO11); reaction oE an aminophenyl species with a 2,5-di-lower-alkoxytetrahydrofuran to prepare a (l-pyrrolyl)-phenyl-substituted species (R3 is l-pyrrolylphenyl); oxidation of the N=B function, for example by fermentative procedures, or by oxidation with an organic peracid, such as perchloro-~20 benzoic acid, to prepare the corresponding N-oxides; or reaction of a l-aminoalkyl-l11-indole of formula III where R2 is hydrogen with hexamethylenephosphoramide 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 regenerated from the acid-addition salt form in conventional manner, -that is by treating -the salts 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 different acid to give back the same or a diEferent acid-addition salt. Thus the novel bases and all of their acid-addition salts are readily interconvertible.
It will thus be appreciated that formulas I, Ia, Ib and III not only represent the structural configuration of the bases of formulas I, Ia, Ib and III but are also representative of the structural entities which are common to all of the compounds of formulas I, Ia, Ib and ~II, whether in the form of the free base or in the form of the acid-addition salts of the hase. It has been found that, by virtue of these common structural entities the bases of 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 herein~elow. 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 do~es of 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 inventiont it is pre~erred, of course, to use pharmaceutically accepta~le salts. Although water insolu~ility, high toxicity or lack of crystalline 3~ ~

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, Eor 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 lS 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 procedures.
The novel feature of the compounds of the invention, then, resides in the ccncept of the bases and cationic forms of the new 2-R2-3-R3-carbonyl-1-aminoalkyl-lH-indoles of formulas I, Ia and Ib and the 2-R2-1-aminoalkyl-lH-indoles of formula III and not in any particular acid moiety or acid anion associated with the salt forms of the compounds; rather, the acid moieties or anions which can be associated with the salt forms are in themselves neither novel nor critical and therefore can be any acid anion or acid-like substance capable of salt formation with the bases.

~53~$

Thus appropriate acid-addition salts are those derived from such diverse acids as formic 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 acld, 2-Eurancarboxylic acid, cholic acid, pyrenecarboxylic acid, 2-pyridine-carboxylic acid, 3-indoleacetic acidr quinic acid, sul~amic acid, methanesulfonic 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, hydro~luoric 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 orqanic solvent and 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,2.5~i3~

and anti-inflammatory agents. Certain of the compounds of ormula II have been fo~nd t~ p~ssess anti-rheumatic activity, and certain of the compounds of formula III have been found to possess analgesic activity, thus indicating usefulness of those species as anti-rheumatic and analgesic agents, respectively.
The test procedures used to determine the analgesic activities oE 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 o~ the anti-bradykinin test, which is also a primary analgesic screening procedure, described by Berkowitz et al., J. Pharmacol. Exptl. Therap. 177, 500~508 (1971), Blane et al., J. PharmO PharmacolO 19, 367-373 (1967), Botha et al., Eur. J. Pharmacol. 6r ~12-321 (1969) and Deffenu et al., J. Pharm. Pharmacol. 18, 135 (1966); and the rat pa~ 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).
~5 Anti-rheumatic and anti-inf'ammatory 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 oE com-`--~
~ 3 ~6 -2~-pounds for potential use as disease modifying anti-rheumatic drugs. The procedure used to induce arthritis in rats is a modiEication of the methods published by Pearson, J. Chron. Dis. 16, 863-874 (1973) and by Glenn et al., 5 Amer. J. Vet. Res. 1180-1133 (1965). The adjuvant induced arthritis bears many oE the traits of rheumatoid arthritis.
It is 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 is 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 significant systemic arthritic disease which can be measured by swelling of the non-in~ected rear paw ~NIP~ 15 to 20 days following an initial in~ection on day 1 of com-plete Freund's ad~uvant into the right hindEoot 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. Nonsteroidal, anti-inflammatory drugs have no influence on the enhanced fibronectin levels seen in arthritic rats, while disease modifying anti-rheumatic drugs cause a significant decrease in plasma fibronectin.

~'~

i) . , ~ A

-25_ The pleurisy macrophage assay is designed to define anti~arthritic drugs which 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 drugs are not. The activity o species in the pleurisy macrophage model thus indicates disease modifying anti-rheuma~ic drug activity. The macrophage is the characteristic cell type in chronic inflammatory responses in the rheumatoid synovium as well as other sites When activated, macrophages produce a large variety oE secretory products, including neutral proteases which play a destructive role in arthritis lAckerman et al., J.
Pharmacol. Exp. Thera. 215, 588 (1980)3. The in vivo model of inflammatory cell accumulation in the rat pleural cavity permits quantitation and differentiation of the accumulated cells. The cellular components are similar to those seen in the inflamed synoviumO It has been hypo-thes;zed 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 compounds of formulas I, Ia, Ib, II and III of the invention can be prepared for pharmaceutical use by incorporating them in unit dosage form as tablets or capsules for oral or parenteral administration either alone or in combination with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum D N
~ 5 acacia and the like. Still further, the compounds can be formulated for oral or parenteral 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 so 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 physlcal condition of the patient, the potency of the active component and the patient's res-ponse thereto. ~n efective 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 oE study of their inErared, ultraviolet and NMR spectra. The structures were con~irmed by the correspondence between calculated and ~ found values Eor elementary analyses for the elements.
; The following examples will further lllustrate the invention without, however, limiting it thereto.
2S All melting points are uncorrected.

J ~

~5~:~6 EXEMPLARY_DIS_OSURE
Preparation of Intermediates A. The Co ~ a II:
Preparation lA
To a solutlon 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 6nO g~ (0 04 mole) of 2,7-dimethylindo~e in 30 ml. oE anhydrous ether. When addition was complete, the reaction mixture was stirred at room temperature Eor one hour, 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 anhydro-ls ether. The mixture was stirred at room temperature Eor approximately twelve hours, then on a steam bath for two hours and then treated with ice water. Excess ammonium chloride was added~ and the ether layer was separated, dried and evaporated to dry-ness to sive a solid which was collected by filtration and washed thoroughly with water and ether to give ~.5 g. (76%) of 2,7-dimethyl-3-~4-methoxybenzoyljindole, m.p. 182-184C.
Preparations lB - lAU
Following a procedure similar to that described above in Preparation lA, substituting Eor the 2,7-dimethyl-indole and the 4-methoxybenzoyl chloride used therein an ~5 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 purification, were used directly in the next step of the synthesis of the final products of .

i` 1 35,jA
~53~;

-~8-Eormula I, and no melting points were taken. In a few cases, the weight of the products was not obtained, and so calculation oE yields oE products in those instances are not possible. Here and elsewhere in the tables included 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, oE
product is given in ,-olumns headed "Yield"~

: .

-2~

Tahle A
Prepn. R2 R3 R4 - m.p./~c~v~ Yiel~3 lE~ C H 3 4-C H 3 C 6 H 4 - 215-217/D M F-H 2 85 lC C ~3 2-fury1 - 9 lD CH3 4-CH35C6H4 lE CH3 4-NO2C6H4 - 23 1E CH3 4-CH30C6H4 ~F 199-202/i-PrOH
lG ~H3 4-CH3OC6H4 7-F 204-205/H20 42 lH CH3 4-CH3OC6H4 7-CH30 68 1-I CH3 3 6 4 ~/7-F(a) 55 lJ CH3 4-FC~ - 19~201,~EtOH 38 lK C~3 3'4 CH2 6H3 210-213/i-PrOH 60 lL CH3 3~enzolb]thieny1 - 181-183 64 lM CH3 2~enzo[b]hlry1 - 218-220/i-PrOH 62 lN CH3 2-CH30C~H4 - 203-206/i-PrO~ 75 1-O CH3 3-F-4-CH3OC6H3 - 160-165/EtOH 39 lP CH3 2~aphthyl - 208 213/i-PrOH 57 lQ 4 3C6H4 5-CH3 139-1g2/EtOH 42 lR CH3 3~ C6 4 64 1~; C~13 6 4 21~218/iPrOH 44 lT CH3 4-CNC6~14 - 211-213/EtOAc 7 lU CH3 C6H5 4-CH3 176-179/EtOAc 65 1V c~3 4 2 5 6 4 19~201~EtOAc 7û
lW CH3 3 2 6 4 218-221/DMF-H20 20 lX CH3 4-CH3C6H4 - 207-209/Et3H 60 lY CH3 3-CH30C~jH4 - 163-164/EtOAc: 63 lZ H 4-C~l3Oc6H9 - 80(b) lAA C6H5 4-CH3OC6H4 - 25 lA13 H C6~15 5-CH30 46 lAC . CH3 4-CH3OC6H4 6-CH3O 53 lAD CH3 4 2 6 4 6-CH30 - 73 1AE CH3 C6H5 - 185-186/MeOH 64 lAF 6 5 241-242/MeOH 38 1AG CH3 4-C1C6H4 - 183-185/MeOH 34 1AH CH3 4-CH3OC6H4 6-C1 5a lAI C H3 ~ 3 6 ,4 6-C6H 5C H20 51 lAJ CH3 2,3-~CH2OC6H3 ~ 239.~240/CH3CN 98 lAK CH3 2 6 5 6 4 238-240/MeOH 39 1AI~ ~3 4 6H5C6H4 225-228 56 3~ -~3~

Ta~le A contd.

Prepn. R2 R3 R4 m.p./Sc~v~ Yield lAM CH3 l-naphthyl - 223-224/i-PrOH 69 lAN CH3 ~ ( 3 )2 6 3 185-187 87 lAO CH3 3,~(CH3O)2C6H3 - 182-184 85 lAP CH(CH3)2 4-CH3Oc6H4 176-178/EtOA~ 44 lAQ CH(CH3)2 4-CH3C)C6H4 173-175 11 lA R C H 3 2-F C 6 H 4 5-F 247-249/i-PrO H 10 lAS CH3 4-CH3O-l-naphthyl - 286-289/i-PrOH 24 lAT C H3 4-C6H5C6H4 ~F 234-235.5/EtOH 36 lAU c~3 4CH3OC~H4 - 200-203 97 (a3 Product corx~isted of a mixture of the ~fluoro and the 7-flLIorv isomersO
(b) Two mcdar equivalents of ~e Gr~nard reagent used, th~s resiL~ing in acylat on at both the 1- ar d 3-p~si :ions of ~nd~e denvative. The de~ired product was obtained by heat~ng a m~xture ~f the crude product in methaslcil and sodium hydrox~de.
'~

:`:

.: . , -~. 7~,~A
~2S~3:~

Pre~ration lAV

A mixture of 50 g. (0.03 mole) of phenylmercapto-acetone and 76.8 9. tO.3 mole) of 3-benzyloxyphenylhydra~
zine in 750 ml. of ethanol was heated on a steam bath for six hours and then stirred at room temperature Eor 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 of crude product 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 w;th methylene dichloride, and the organic layer was washed with water, then with dilute hydrochloric acid, dried over magnesium sulfate, iltered and concentrated to dryness to give 40 9. of additional product which was recrystallized from diethyl ether/methylene dichloride to give 29.7 9. of product (com-bined yield 71.7 9., 69%) of 2-methyl-3-phenylmerca~to-6-benzylox~_ndole, 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 l liter of ethanol was heated under reflux for three hours, stirred at ambient temperature for about twelve hours, then refluxed for an additional three hours and the catalyst ~ ": , ' , removed by filtration. The filtrate was taken to dryness in vacuo to give an oil which was passed through a pad of Florisil and eluted with ethyl acetate. Evaporation of the solution to dryness afforded 5.2 9. (26~ of 2-methylindole .

A mixture of 5 9. (0.034 mole) of the latter, 5.9 ml (0.051 mole) of benzyl chloride and 13.8 g. (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 for 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-me~yl-ndole, m~p. 90-93C., used as the starting material for the preparation of the compound of Preparation lAI in Table 1 above.
Preparation 2 To a solution of 20 9. (0.071 mole) of 2-methyl-3-(4-methylmercaptobenæoyl)indole (Preparation lU) in 400 ml. of chloroform was added, dropwise with stirring, a solution of 16.7 g.10.081 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 twelve hours and then washed three times with saturated sodium bicarbonate solution and dried over magnesium sulfate. The mixture was filtered, the filtrate was :

. ~
,::

l l 7356A
53:~

concentrated to near dryness, and the solid which separated was collected and recrystallized from ethyl acetate to give 1~.5 g. (69%) of 2-me h~l-3~(4-methy~ ulfinylbenzoyl) indole.
Prepara_ on 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 hours, the catalyst was removed by filtration and the solvent taken off 1n vacuo to leave 11.4 9. of crude product, which was recrystallized from ethanol to give 4.5 g. (45%) of 2-methyl~3-(4-aminubenzoyl)-indole, m.p. 220-223 C
B. The Compounds of Formula III
(2) By Alkylation of the Compounds of Formula IV
Preparation 4A
To a stirred suspension of 229.5 g. ~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 stirred 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 : 25 the reaction mixture gradually rose during the addition of the 2-methylindole as well as on stirring after addition ~ ~ ;oA
S3~i6 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 l 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 g. (92%) of 2-methyl-1-l2-(4-morpholinyllethyl]-lH-indole, m.p. 63-65C.
Preparation 4B
Following a procedure similar to that described above in Preparation 4A, 20.09. (0.134 mole~ of 5-fluoro-2-methylindole were reacted with 24.1 g. (0.147 mole) of 4-(3-chloropropyl)morpholine in 46 ml. of dry DMF in the presence of 8.0 9. (0.201 mole) of a 60% mineral oil dis-persion oE 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~ 165-167C.
Preparation 4C
Following a procedure similar to that described in Preparation 4Ar 50 g. (0.43 mole) of indole were reacted with 159 9. ~0.85 mole) o 4-(2-chloroethyl)morpholine 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 pxoduct was isolated in the form of the free base to give 45.6 9. ~46~1 f 1-[2~(4-morpholinyl)ethyl]-lH-lndole.

~L2~3~

-35~
Preparation 4D
To a stirred suspension of 322 g. (0.81 mole) of a 60~ mineral oil dispersion of sodium hydride in 250 ml. of dry DMF was added dropwise a solution of 100 g. (0.67 mole) of 5-fluoro-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 9. (0.67 mole) of ethyl a-bromopropionate. Workup of the reaction mixture, after quenching with water and extraction of the product with ethyl acetate, afforded ethyl a -~S-fluoro-2-methyl-1-indolyl)-propionate.
The latter was reduced with 525 ml. of a lM solution of diisobutyl aluminum in 1150 ml. of toluene to give 130 g. (94%) of 5 luoro-2-methyl-l-(l-methyl-2~hydroxyethyl) lH-indole.
The latter, on reaction with 144 g. (0.76 mole) of p-toluenesulfonyl chloride in 350 ml. oE pyridine using the procedure described in Preparation 7A afforded 65 9. (20~) of 5-fluoro-2-methyl-1-[1-methyl-2-(p-toluene-sulfonyloxy~ethyl]-lH-indole, m.p. 136-140C.
(b) Via the Amides of Formula V
Preparation 5A
Following a procedure similar ~o that described in Preparation 4 above, 32.8 9. ~0.25 mole) of 2-methylindole ;~ 25 in 160 ml. o dry DMF was reacted with 13.4 y. (0.28 mole~
; of a 50~ mineral oil dispersion of sodium hydride in 200 ml. of dry DMF, and the resulting sodium salt was then reacted with 62 g. tO.28 mole) of 4-(a-bromopropionyl)-morpholine in 160 ml. of DM~ to give 55.3 g. (59~) of 4-[-(2-n!ethxl-lH-lndol-l yl)~ropiony ]morpholine.

~S~

The latter (130 g., 0.48 rnole), dissolved in 900 ml. of THF, was added to 80 ml~ (0.80 mole) of a solution of boron methyl sulfide c~mplex in THF under nitrogen while cooling in an ice bath. When addition was complete, the mixture was stirred for eighteen hours at room temperature, heated under reflux for four hours, quenched by addition of about 1 liter of methanol, boiled for about fifteen min-utes, concentrated essentially to dryness and then diluted with aqueous 6N hydrochloric acid. The mixture was ex-tracted with methylene dichloride, ~nd the raffinate was basified with 35~ sodium hydroxide and 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-methyl-l-[l-methyl-2-t4-morpholinyllethyl]-lH-indole as an oil. A portion of the latter was reacted with .
methanesulEonic acid to give the monomethanesulEonate as the 4:1 hydrate, m,p. 154-157C.

Following a procedure similar to that described in Preparation 5A above, 29.29 g. (0.25 mole) of indole in 200 ml. of dry DMF was reacted with 13.4 g. (0.28 mole) of a 50~ mineral oil dispersion of sodium hydride in 200 ml. of dry DMF and the resulting sodium salt reacted with 62.0 g.
(0.28 mole~ of 4-(a-bromopropionyl)morpholine in 200 ml. of dry DMF and the product recrystallized from isopropanol to give 13.7 9. (21%) of 4-[~-(lH-indol-l-yl)proplonyl]-morpholine, m.p. 92-94C. The latter (20 g., 0.078 mole~
in 300 ml~ of 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. t90~) of 1~ methyl-2-[4-morpho-~ , m.p. 35 37C.

I~ ., I . ~ "-~.Z$~ 6 Preparation 5C
Following a procedure similar to that described in Preparation 5B, 83 9. (0063 mole) of 2-methylindole was reacted with 30 g. (0.75 ~ole) of a 60~ mineral oil dis-persion of sodium hydride, and the resulting sodium salt was 5 reacted with a molar equivalent amount of 4-(a-bromo-butyryl)morpholine in 100 ml. of DMF. The crude product thus obtained was reduced ~ith 25 g. (0.66 mole) of lithium aluminum hydride in 500 ml. of THF. The product was isolated in the form of the hydrochloride to give 53.4 g.
(27%) of 2-methyl-1-11-ethyl-2-(4-morpholinyl~ethyl]-lH
indole hydrochloridet m.p. 159-162C. (from ethyl acetate-ether).
Preparation 6 To a solution of 23 g. (0.1 mole) of 1-~2-(4-morpho-linyl)ethyl]-lH-indole (Preparation 4C) in 120 ml. of THF
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. o~ hexa~ethylphosphoramide followed by 10 ml.
of ethyl iodide while maintaining the temperature at 0C.
The mixture was then guenched with ice, extracted with ether, and the combined organic extracts were washed first with water, then with brine, dried over magnesi~m sulEate, taken to dryness and chromatographed on silica gel, eluting 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 gO
and 4.2 9. of solid material in the next three fractions.
These fractions were recrystalli2ed from hexane to give 8.3 g. (32%) of 2-ethyl-1-[2-(4-morpholinyl indole, m p. 59-60.5C

C The ~
Prepara ion 7A
To a suspension of 50 g. (0.19 mole) of 2-methyl-3-t4-methoxybenzoyl)indole lpreparation lAU) in 400 ml. of THF was added, over a one and a half 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 forty-five minutes, recooled to 0C. and treated dropwise, over a thirty minute period, with a solution of 93.7 ml. ~0.19 mole) oE a 2.06 M
solution of ethylene oxide in THF. The reaction mixture was gradually allow~d to warm to room temperature and then treated with 200 ml. of a saturaked ammonium chloride solution. The solvent was removed in vacuo, the residual solid was filteredr washed with water and extracted with boiling ether, and the ether extracts were taken to dryness to give 23 g. (39~) of 2-methyl-3-(4-methoxybenzoyl)-1-~2-hydroxyethyl~ indole, m~p. 75-78C.
A solution of 10 9. (0.032 mole) oE the latter and 6.48 9. (0.034 mole) of p-toluenesulEonyl chloride in 100 ml. of pyridine was stirred at room temperature for about twelve hours and the reaction mixture diluted with ethyl acetate and washed with water. The organic layer was separated, drled 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 9.
(52~) of 2-methyl-3-(4-methoxybenzoyl~-1-t2-~-toluene~
sulfonyloxyethyl)~lH-indole, m.p. 62-65C.

*Trademark D . t`l, 7 ' - ~

~9 Preparation 7B
Following a procedure similar to that described in Preparation 7A above, 9.75 g. (0.0375 mole) of 2-~ethyl-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.SM solution of ethylene oxide in T13F to give 2-methyl-3-(4-cyanobenzoyl)-1-(2-hydroxyethyl)-lH-indole. Reaction of 30.4 g. (0.1 mole) oE the latter with 21.0 g. (0.11 mole) of p-toluenesulfonyl chloride in 50 ml. of methylene dichloride in the presence of 50 ml. of 35% sodium hydroxide and 0.91 9. (0.004 mole) of benzyl trimethyl-ammonium chloride afforded 38.3 9. (84%) of 2-me~y~-3-(4-~y~ æoy~ (2-p-toluenesulfonyloxyethyl~ -indole m.p. 165-167C.
Preparation 7C
; 15 Following a procedure similar to that described in Preparation 7A above, 20 g. (0.1 mole) of 2-methyl-3-(4~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 g. (0.13 mole) of ethylene oxide to give 18 g. (73%) of 2-methyl-3-(4-ethylbenzoyl?-1-~2-hydroxyethyll-lH-indole. Reaction of the latter (0.058 mole) with 14.32 9. (0.075 mole) of p-toluenesulfonyl chloride in 400 ml. of methylene dichloride in the presence of 50 ml. of 35% sodium hydroxide and 1.6 g. (0.007~ mole) of benzyl trimethylammonium chloride af~orded 27 g. (95~) of 2-methyl-3-(4-ethylbenzoyl)-1-(2-p-toluenesulEonyloxyethxl)-lH-indole as a red oil.

D.N. 7~.
3~

Preparation 7D
A solution of 5.0 9. (0.068 mole) o~ 2-methyl-5~fluoro-3-(4-methoxybenzoyl)indole (Preparation lF) in 100 ml. of dry DMF wa5 cooled in an ice bath at 0C and then treated with 18.17 9. (0.09 mole) o~ -dibromopropane.
The solution was stirred for a few minutes at 0C, then treated portionwise with 1.08 g. ~0.027 mole) oE a 60%
mineral oil dispersion of sodium hydride, stirred for about fifteen minutes in an ice bath, then Eor 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 with water, then with brine and then dried and taken to dryness. Crystal-lization of the residue from ethanol afforded 4 g. (55~) of 1~(3-bromopropyl)-5-fluoro-2-methyl~3-(4-methoxybenzoyl)-lH-indole, m.p. 133-135C.
Preparation 7E
Following a proceaure similar 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 g. ~0.34 mole) of a 60~
mineral oil dispersion oE sodium hydride, and the product ; recrystalli~ed from ethyl aceta~e/hexane to give 5.0 g. of 1-~4-bromobutyl)-2-methyl-3-~4 methoxybenzoyl~ l-indole, m.p. 83-863C.

ai~iJ316 Preparation 7F
Following a procedure similar to that described in Preparation 7D above, 35 g. (0.122 mole) of 2-methyl-3-(1-naphthylcarbonyl)indole (Preparation lAM) was reacted with 124 g. (0.614 mole) of 1,3-dibromopropane in 700 ml of DMF
in the presence of 7.5 g. (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 18.38 9. (37%3 of 1-(3-bromo-proeylL~-meth~l-3--Ll-naphthylca-rbonyl)-lH-indole~ m.p.
115-116C.
Preparation 7G
Following a procedure similar to that described in Preparation 7D above, 73.86 g~ (0.3 mole) of 2-methyl-3-(4-methoxybenzoyl)indole ~Preparation lA~) was reacted with 302.33 g. ~1.5 moles) of 1,3-dibromopropane in 250 ml. of DMF in the presence of 17.37 gO (0.45 mole~ of a 60%
mineral oil dispersion of sodium hydride. There was thus obtained 1-~3-brcmopropyl)-2-methyl-3-~4-methoxybenzoyl)-lH-indole.
Preparation 7H
Following a procedure similar to that described in Preparation 7D above, 15.0 9. (0.053 mole) of 5-fluoro-2-methyl-3-(4-methoxybenzoyl)indole (Preparation lF~ was reacted with 9.18 g. (0.058 mole) of 1-bromo-3-chloro-propane in 232 ml. of DMF in the presence of 3.2 g. (0.0795 mole~ of a 60% mineral oil dispersion of sodium hydride.
Ther2 was thus obtained 15~3 9. (80%) of 1-(3-chloro-prop~ 5-fluoro-2-methyl-3-t4-methoxybenzoyl)-lH-indole.

*Trademark .

D . l~
~S53~~

Preparation 7I
.

Following a procedure similar to that descfibed in Prepar~tion 7A above, 24.8 9. ~0 087 mole~ of 2-methyl-3-(l-naphthylcarbonyl)indole IPreparation lAM) in 300 ml. of 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 9. (74%) of 2-met_yl-3-(1-naphth~carbon~1)-1-(2-hydroxyeth~ 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 10 dichloride in the presence of 340 ml. of 35~ sodium hydroxide and 006 g. (0.0026) mole of benzyl trimethyl-; ammonium chloride afforded 20.1 g. (64~) of 2-methyl-3-(1-naphthylcarbonyl)-1-(2-p-toluenesulfonyloxyethyl)-lH-indole as a viscous oil.
Preparatlon 8 A solution of 42 g. (0.116 mole) of 5-~luoro-2-methyl-l-[l-methyl-2-(p-tolu2nesulEonyloxy)ethyl~-lH-indole (Preparation 4D) and 50 ml. of morpholine in 400 ml. of DMF
was heated on a steam bath for seventy-two hours, poured 20 into water and the mixture extracted with ethyl acetate.
The combined organic extracts were dried and taken to dry-ness to give 20 g. 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~) of 5-fluoro-2-methyl-25 1~ methyl-2-~-morpholinyl)ethyl]-lH-indole as the first, third and fourth through the seventh fractions.
The second Eraction, on conversion to the hydro-chloride salt and recrystallization from methanol-ether, .

- . .

. Ii, 7 ~,~
~2 ~ 3 afforded 1.0 g. of S-fluoro-2-methyl-1-[1-methyl-2-(di-methylaminolethyl]-lH-indole hydrochloride, m.p. 208.5-211.5~C, 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 major product.
Preparation 9A
Following a procedure similar to that described in Preparation 5A above, 24.0 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 9. (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 lS DMF. The product was recrystallized from ethyl acetate-hexane to give 10.6 g. t44%) of 5-fluoro-2-methyl-3-(4-methox~benzo~ 2,3-epoxy)~ropyl]-lH-indole as a yellow solid.
Preparation gB
Following a procedure similar to that described in Preparation 9~ above, 100 9. (0.377 mole) of 2-methyl-3-(4-methoxybenzoyl)indole ~Preparation lAU) in 1500 ml. of D~F
was reacted with 174.6 g. (1.89 moles) of epichlorohydrin in the presence of 19.92 y. (0.42 mole) of a 50% mineral oil dispersion of sodium hydride in 500 ml. of DMF. There was thus obtained 2-methyl-3-~-methoxybenzoyl)-1-[1-(2,3-epoxylpropyl]-lH-indole.
.

., ~ ~53~ ~ D. 1`1. 7356A

Preparation 9C
Following a procedure similar to that described in Preparation 9A above, 28~7 g. (0.1 mole) of 2-methyl-3-11-naphthylcarbonyl)indole IPreparation lAM) in 165 ml. of DMSO was reacted with 27.39 g. (0.2 mole) of epibromohydrin in the presence of 6.6 g. (0.1 mole) oE powdered potassium hydroxide and the product pùriied by chromatography on silica gel, eluting with ethyl acetate~hexane. There was thus obtained 32.3 g. (95~) of 2-methyl-3-~-naphthyl-carbonyl)~ (2,3-epoxy~propyl]-lH-indole.

O r~
S3~

Preparation of the_Final ProduL:~
A, From the Co Example lA
Following a procedure similar to that described in Preparation 4 above, 25 9. (0.10 mole) of 3-(4-methoxy-benzoyl)indole (Preparation lZ) in 100 ml. of DMF was reacted with 5.76 9. (3.12 mole) of a 50% dispersion of sodium hydride in mineral oil in 120 ml. of DMF, and the resulting sodium salt was reacted with 0.1~ mole of 4-(2-chloroethyl)morpholine (freed from 26.05 g. of the corres-ponding hydrochloride) in 120 ml. of DMF to give 42 9, of 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 g. (20%) of 3-(4-methoxyben~oyl)-1-[2-(4-mo~pholinyl)ethyl]-lE~-indole methanesulfonate monohydrate, m.p. llO-112C.
Examples lB-lCR
Following a procedure similar to that described in Example lA above, the following species of formula I
in Table 1 were prepared by reaction of a 2-R2-3-R3-carbonyl-lH-indole oE ~ormula II with an appropriate halo alkyl-amine or tosyloxyalkylamine. The acid-acceptor and reaction solvent used in the reactions are given in the column headed "Cat./Solv.". ~ere and elsewhere in the tables, the form in which the product was isolated, either ~ as the ree base or as an acid-addition salt, is given in ':~

r , -15 ~ A
~53~ -columns headed "sase/salt"~ and the abbreviations 1'Morph.", "Pip." and "Pyr." in the columns headed N=B
represent the 4 morpholinyl, l-piperidinyl and l-pyrro-lidinyl groups, respectively. In Table l, unless noted otherwise, an appropriate chloroalkylamine was used as the alkylating agent. Here and elsewhere in the speciEication and the claims, the alkylene groups, Alk, are depicted as they would appear with the l-indolyl moiety attached to the carbon atom at the leEt.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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B From the Compounds of Formula III
xample 2A
To a stirred, refluxing solution of 13.2 g. (0.054 mole) of l-[l-methyl-2-(4-morpholinyl)ethyl~-lH-indole (Preparation 5B) in 150 ml. vf ethylene dichloride was added, over a period of about one hour, a mixture of 17.35 9. (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 reflu~ 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 hydroxide. The mixture was transferred to a separatory funnel, the organic 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 magnesium sulfate, filtered again and evaporated to dryness to give a viscous oil (22.55 g.) which solidified on cooling. The latter was recrystallized, after charcoaling, from isopropanol to give 15.78 g. (81%) of 3-(4-methylbenzoyl)-1-[1 methyl-~-(4-mor~holinyl?ethyl]-lH-indole, m.p. 116.5-118C.

D. 7 ,~
~2SS3~

Examples 2B-2BI
Following a procedure similar to that described in Example 2A above, the following species of formula I
in Table 2 below were prepared by reaction of a 2-R2-l-aminoalkyl-lH-indole of formula III with an appropriate acid chloride (R3CO-Cl) in the presence of aluminum chloride.
The solvent used to carry out the reaction, methylene dichloride (MDC) or ethylene dichloride (EDC), is given in the column headed "Solv."

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~S~6 5~-C From the Compounds of Formula VI
.

Example 3A
A solution of ]0 g. ~0.022 mole) of 2-methyl-3-(4-methoxybenzoyl)-1-[2-(p-toluenesulfonyloxy)ethyl]-lH-indole 5 (Preparation 7A) and 8.74 g. (0.086 mole) of 4-hydroxy-piperidine in 50 ml. of dry acetonitrile was heated under reflux for about forty eight hours, and the mixture was then diluted with ethyl acetate and washed with water. The organic 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 to give the product, in the form of the free base, as a brown oil. The latter was converted to the hydro-chloride salt in ethyl acetate and ethereal hydrogen chloride to give 2.6 9. (27~) of 2-methyl-3-(4-methoxy-benzoyl)-1~[2-(4-hydroxy-1-Eiperidinyl)ethyl]-lH-indole hydrochloride hemihydrate, m.p. 226-229C.
Examples 3B - 3AM
Following a procedure similar to that described in Example 3A above, the ~ollowing species of ~ormula I in Table 3 below were prepared by reaction oE a 2-methyl-3-R3-carbonyl-1-(2-tosyloxyethyl)-lH-indole or a 2-methyl-3-R3-carbonyl-l-(halo-lower-alk~l)-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 o Examples 3X-3AJ and 3AL
the corresponding l-(bromo-lower-alkyl~-lH-indole.

D . ~ 5 6 A
31~

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s~

D. Miscellaneous Processes Example 4A
Following a procedure similar to that described in Preparation3above,8.0g. (O.Q2mole) of2-methyl-3-t3-nitro-benzoyl)-1-[2-~4-morpholinyl~ethyl3 lH-indole ~ExamplelAD) in 175 ml. of ethyl acetate and 75 ml. of acetic acid ~as reduced with hydrogen in a Parr shaker over 0.~ 9. of platinum oxide. The product was isolated in the form of the free base and recrystallized from ethyl acetate to give

6.0 g. (83%) o 2-methyl-3-53-aminobenzoyl)-1-[2-l4-morpho-linyl)ethyl]-lH-indole, m.p. 167-169C.

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)ethyl]-lH-indole ~Example lCQ) in 100 ml. of glacial acetic acid and 100 ml. of ethyl acetate was reduced with hydrogen over platinum oxide and the produc~, in the form of the free base, was recrystal-lized from ethyl acetate to give 19.05 9. (75%) oE 2 methyl-3-(4-aminobenzoyl~-1-[~4-morpholinyl~eth~l]-lH-lndole, .p. 154-1~6~C.
A small amount of the free base was reacted with methanesulfonic acid and the product recrystallized from eth~nol to give the corresponding methanesulfonate as an orange powder, m.p. 221-223~C.

. . .

D.N. 7~6A
~5~

E mple 4C
To a stirred suspension of 2.5 g. (0.0059 mole) of 2-methyl-3-(4-nitrobenzoyl)-6-rnethoxy-1-[2-(4-morpholinyl)-ethyl~-lH-indole (~xample lANj and 2 g. (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 Eor two and a half hours, then cooled and made basic with 15% alcoholic potassium hydroxide solution. The mixture was Eiltered, the filtrate was taken to dryness in 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%~ of 2-meth~1-3-(4-aminobenzoyl)-6-methoxy-1-[2-~4-morpholin~l)ethyl]-lH-indole, m.p. 126-128C.

~ . 7~,6A

~Z~

Example 4D
Following a procedure similar to that described in Example 4C above, 7.3 9. (0.018 mole) of 2-methyl-3-(4-nitrobenzoyl)-1-[1-methyl-2-(4-~orpholinyl)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 mlO 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 of the free base to give 3.7 9. ~54~) of -methyl-3-~4-aminobenzo~L~1-[1-methy~-2-(4-morpho-li~yl?ethyl]-lH-indole, m.p. 192-195C
.

Example 5A
To a solution of 4.0 9. (0.01 mole) of 2-methyl-; 3-~4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole - lS (Example 4~) in 20 ml. of glacial acetic acid was added 2.~

ml. (0.023 mole) of acetic anhydride and 2 drops o~ 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 decan~ation, triturated with water to produce a solid material which was collected and recrystal-lized from ethyl acetate to give 2.3 9. ~56~) of 2-methyl-3-~4-acetylaminobenz_ylL~[2-~4-morpholinyl)ethyl]-lH~
indole, m.p. 173.5-174.5C.

L_~. ;6A
3~j -63~

Examples_5s-5F
Following a procedure similar to that described in Example 5A above, the following compounds of formula I in Table 5 below were prepared by acylation of an appropriate 2-methyl-3-(aminobenzoyl)-1-aminoalkyl-lH-indole. In each instance, ~2 is CH3; R4 is hydrogen; Alk is (CH2)2; and N=B
is 4-morpholinyl. ~11 compounds were isolated and charac-terized as the free basesO The acylating agent and the reaction solvent are given in the column headed "AcX/Solv."

3~6 ~4-;, ~ ~ ,~ ~

,~ O ~ O ~ ~
,~ ,¢ U ~ ~ U
~ ~ , r~ D
U
o Z 0~ '~
~ E~ U
~ ~ ~ Y ~

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D.. ~, 73~., -~5-Exam~le 6 Following a procedure similar to that described in Preparation 3 above, 14.0 g. (0.03 mole) of 2-methyl-3-(4-benzyloxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole (Example lAG) in 250 ml. of ethanol was red~ced with hydrogen in a Parr shaker over 1.0 g. of 5% palladium-on-charcoal. The product was converted to the hydro-chloride salt which was recrystallized from water to give 11.1 g. (92~) of 2-methyl-3~ d~o~ben~yl)-1-[2-(4~
morpholinyllethyl]-lH-indole hydrochloride, m.p. 286-28~C.
:~; Example 7 ~; A mixture of 7.5 9. (0.02 mole) of 2-methyl-3-14-cyanobenzoyl)-1 [2-(4-morpholinyl)ethyl]-lH-indole ~:~ 15 ~Example lAF), 100 ml of ethanol, 15 ml. of liquid ammonia 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 mixture was then cooled, the catalyst was removed by filtration, and the solution was taken to dryness in vacuo to give 7.2 9. of : product as a green foamy material which was converted to the hydrochloride salt to give 1.7 g. (19%) of 2-methyl-3-: (4-aminomethylbenzoyl~ 2-l4-morpholinyl?ethyl~-lH-indole ~ dihydrochloride, m.p. 196-208C.

:

L) . ; j ~

2~53~
-66~
Examele 8A
A mixture of 10.4 g. (00023 mole) of 2-methyl-3-[4~
(N-triEluoroacetylaminolbenzoyl]-1-[2-(4-morpholinyl)ethyl]-lH-indole (Example 5C), 20 g. (0.20 mole) of potassium S carbonate and 5 ml. (11.4 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 foa~, which was partitioned between water and chloroform and extracted twice with chloroform. The 1~ combined extracts were washed with brine, fîltered and taken to dryness to give a yellow oil which was dissolved 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 g. of 2-~ethyl-3-[9-~N-meth~1-N-trifluoroacetylaminoLbenzoyl]~ 2-(4-morpholinyl)-ethyl~-lH-i _ole 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 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 g. (37%) of 2-methyl-3-(4-methylaminobenæoyll-1-[2-(4-morpholinyl)-ethyl]-lH-indole dihy~chloride hemihydrate, mOp 190-lg2C.

D., 7~J~
~ 5~ 6 Following a procedure similar to that described in Example 8A, 22 9. (0.049 mole) of 2-methyl-3~[4-(N-trifluoroacetylamino)benzoyl]-1-[2-(4-morpholinyl)ethyl]-lH-indole (Example 5C) was reacted with 35.9 g. (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]-1-[2-(4-morpholinyl)ethyl]-lH-indole (24 g., 98%) hydrolyzed by refluxing in a solution o~ 500 ml. of 10~ sodium hydroxide and 100 ml. of ethanol.
The resulting crude product was chromatographed on silica gel, eluting with 25% acetone-hexane. The higher RE
material was collected and dried to give 2.6 g. of 2-ethyl-3-(4-butylaminobenzoyl~-1-[2-(4-mor~holinyl~ethyl]-lH-indole, m.p. 129.0~130.0C.

D. N . j6A
3~

-6~-Exarnple 9 To a stirred suspension oE 12.0 9. ~0.03 mole) of 2-methyl-3-(4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyll-lH-indole (Example 4B) in 15 ml. of glaci~l acetic acid and 30 ml. of water was added a solution of 4.5 9. (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-indole, m.pO 192-202C
Example 10 To a stirred su~pension sf 3.77 g. (0.01 mole) of 2-methyl-3-l4 aminomethylbenzoyl)-1-[2-(4-morpholinyl)-ethyll-l~l-indole ~Example 7) in 30 ml. of toluene was added a solution oE dimethyl cyanocarbonimidodithioate in 20 ml. of toluene. The l~ixture was stirred for an hour and a half, and the solid which separated was col-lected and dried to give 4.75 9. of the correspon~ing 3-(4-aminomethylbenzoyl)~N-(methyl cyanocarbonimido~hioate).
The latter (4.0 g., 0.008 mole), in 75 ml oE
isopropanol and 25 ml of liquid ammonia, was heated in an autoclave for one hour at 100C. The reaction mixture was then filtered, allowed ~o evaporate to dryness, and the resulting pale yellow foam was recrystallized from acetonitrile to give 2.3 g. (65%) of 2-methyl-3-(4-cyano-~uanidinylm~ylbenzoy~ 2-~4-mor~holinyl)ethy~ H
indole, m.p. 191.5-195C.

: :.

3~2~

Example_ll A mixture of 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, S 50 ml. of 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 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 sulfate, filtered and concen-trated to dryness to give an oil which was recrystallized ~rom ethyl acetate to afford 1.5 g. (15%) of 2-methyl-3-~4-formylbenzoyl)-1-~2-(4-morpholinyl)ethyl]-lH-indole m.p. 149 lSO~C.
Example 12 A mixture of 2.5 g. (0.006 mole~ of 2-methyl-3-~4-formylbenzoyl)-1-[2-(4-morpholinyl)ethyl~-lH-indole (Example 11~, 0.55 g. (0.0067 mole) of sodium acetate and 0.51 g. (0.0073 mole) of hydroxylamine hydrochloride in 24 ml. of ethanol, 5 ml. of methanol and 6 ml. of water was heated under reElux for one hour and then concentrated to drynes in vacuo. The residual solid was collected, washed with water and diethyl ether to give 2.5 g. ~95%~ of 2-_3-~-hydroxYiminomethv1benzoy ~ 2-(4-morpholinyl)-ethyl]-lH-indole, m.p~ 184-186~C
:~

G. 1~ . ,j,~

~255i3~

Exam~le 13A
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 9. (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, dried 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 acetate~diethyl ether afEorded crystals which were collected to give 9.5 9. (46~1 of 2-methyl- -~4-et.hoxybenzo~l)-1-[2-(4-morpholinyl)ethylJ-lH-indole oximel m.p. 166-169~C.

Example 13B
Following a procedure similar to that described in Example 13A above, 44 g. (OolO1 mole) of 5-Eluoro-3-[2-fluorobenzoyl)-2-methyl~ 3-~4-morpholinyl~propyl]-lH-indole 2n (Example 2BB) was reacted with 70.3 9. (1.01 moles) of hydroxylamine hydrochloride in S00 ml of pyridine and the product recrystallized from acetonitrile to give 15.5 9.
(37~) of 5-fluoro-3-(2-fluorobenzoyl)~2-methyl-1-[3-~4-morpholiny~ pyl]-lH-indole o ime, m.p. 150-162C.

D, N . ~jt ;i3~ .

~71-Example 13C
Following a procedure similar to that described in Example 13A above, in two runs a total of 28.3 9. (0.77 mole) oE3-(Z-fluoroben~oyl)-2-methyl-1-[2-(4-morpholinyl)-ethyl]-lH-indole (Example lZ) was reacted with a total of 53.7 9. (0.77 mole) of hydroxylamine hydrochloride in a total of 575 ml. of pyridine to give a total of 24.4 9. of crude product. The latter was dissolved in a solution of 54.1 g. of sodium methoxide in 500 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 8.0 g. (33%) of ~E)-3-~2-fluorobenzoyl)-2-methyl-1-[2-l4-mor~holinyl)ethyl~-lH-indole oxim_, m~p.
160-167C.
Example 14 A mixture of 8 g. (0.022 mole) of 2-methyl-3-(4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyll lH-indole (Example 4B~ and 4.28 ml. (0.033 mole) of 2,5-dimethoxy-tetrahydrofuran in 40 ml. of glacial acetic acid was heated ùnder reflux for one hour and then poured into an ice/water mixture, The mixture was rendered alkaline by addition of ~- 10~ sodium bicarbonate solution, and ~he solid which separated was collec~ed and dissolved in methylene dichloride. The or~anic solution was dried over magnesium . .

3~;

sulfate, Eiltered and the filtrate concentrated to dryness in vacuo and then chromatogeaphed through a pad of Florisil, eluting with methylene dichloride~ There was thus o~tained 4.5 g. of an ~il which, on trituration with diethyl ether, afforded a light yellow powder which was collected to give 3.5 g. (38%) of 2-methyl-3-[4-~lE3-pyrr l-yl)b_nzox1~-1-[2-(4-moræholinyl~ethyl]-lH-indole~ m.p.
125-127C.
Example 15 To each of three 14 liter fermentors containing lO
liters of soybean meal/dextrose medium (containing 5 g./
liter of soybean meal, 5 g./liter of brewer's yeast, 5 g./
liter of dipotassium hydrogen phosphate and 20 g./liter o~
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]-1ll-indole (Example lB), and the mixtures were cultured for five days in the presence of Fusarium solani (Mart.) with stirring at 400 rpm at a temperature of 26-27C. while sparging with air at 5 liters per minute. The mixtures were then separately extracted with 20 liters of methylene dichloride using 20 liters per fermentor, and the combined extracts were concentrated to 20 liters. The concentrate was washed first with 2 liters of 0.05N sodium hydroxide, then two times with 2 liters of water, and the organic layer was concentrated to about l liter, dried over sodium sulfate, charcoaled, filtered and further evaporated to dryness to give an oily residue which solidified on cool-ing. The latter was recrystallized from acetone/diethyl ether to give 2.7 g. (43%j of 2-methyl-3-(4-methoxy-benzoyl)~ 2-(4-morpholinyl)ethyll-lH-indole/N~MOR)-oxide, ~.p. 14~-144C.

.. :.

D.N. ; ~A

Example 16A
A mixture of 38.3 g. (0.10 mole) oE 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 210C. for Eour hours and the mixture allowed to cool. The solidified reaction mixture was partitioned between ethyl acetate and aqueous sodium carbonate by warming on a steam bath, and the organic layer was separated, taken to dryness and subjected to high performance li~uid 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 g. ~23%) of 2-methyl-3-(2-hydroxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole~ m.p.
115-116C.
Example 16B
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 9. (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 9. (67~) of 5-fluoro-2-methyl-3-(4-hydroxybenzoyl)-1-[3-(4-morpholi~yl)propyl~-lH-indole hydrochlorlde, m.p. 290-292C. ~from DMF-ether).

' D.. 73~ , _, ~5~

Example 17 A mixture of 1.9 g. (0.005 mole) of 2-methyl-3-(4-aminomethylbenzoyl~ [2-~4-morpholinyl~ethyl]-lH-indole IExample 7), 0.7 g. (0.0025 mole) of 2-methyl-2-thiopseudourea sulfate and 10 ml of water was heated on asteam bath for two hours and then filtered. The filtrate was taken to dryness, and the residue was recrystallized from methanol to give 1.0 9. (85%) of 2-methyl-3-(4-sulfate (2:1), m.p. 170-180C.
Example 18 Following a procedure similar to that described in Preparation 3 above, a solution of 0.9 g. (0.0019 mole) of 6-~enzyloxy-2-methyl-3-(4-methoxybenæoyl)-1-[2-(4-morpho linyl)ethyl]-lH-indole (Example lBK) in 200 ml. of methanol was reduced wi~h hydrogen over three spatulas ~approxi-mately 1.5 g.) oE 10~ palladium-on-chaecoal 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-dlethyl ether to give 0.35 g. of 6-hydroxy-2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-morpholinyl~thyl]-lH~indole hydro--~hl ~ide hv~lr~~o (3:4)~ m.p. 135-187C.

D.l 7~ A
~Si3~

Example_l9 To 70 ml. of dry DMF was added, dropwise with stir-ring, 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) oE 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 g. 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 gO (86~) of 3-formyl-2-methyl-1-[2-~4-morpholinyl) ethyl~-lH-lndole, m.p. 115-116C.
A solution containing 13.6 g. (0.05 mole) of the latter and 9.0 g. (0.06 mole) of 4-methoxyacetophenone in 50 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 ~or twenty-four hours. The solid which separated was collected by filtration, washed with absolute ethanol and then recrystallized first from methanol and then from 50~
ethanol to give 5.3 g. (24~1 of 1-~2-methyl-1-[2-~4-mor~ho-linyl?ethyl]-lH-indol-3-yl}-3-~4-methoxyphenyl)propen-3-one ~!b29~ e, m.p. 259-262C.

~. 7~
5 ~

Example 20A
Following a procedure similar to that described inExamplel9 above~3-acetyl-2-methy~ 2-(4-morpholinyl) e~t~y~l _ was prepared by reaction of 12 9. (0.05 mole) of 2-methyl-1-[2-(4-morpholinyl)ethyl~ indole (Preparation 4A) with 10 ml. (0.11 mole) of phosphorus oxychloride in 25 ml. oÇ dimethylacetamide. The product was dissolved in isopropanol and the solution treated with ethereal hydrogen chloride to give 6 9. (37%) of the 1~ product as the hydrochloride saltt m.p. 249-253 C.
To a solution of 6 gO (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. (0.14 mole) of 2-methylbenzaldehyde. The mixture was heated under reflux for one and a half hours, concentrated to ~ryness and the product, in the form of the free base, recrystalli~ed once from ethyl acetate and once from isopropanol to give 7.9 g.
(41~) of 3-(2-methylcinnamoyl)-2-methyl-1-~2-(4-morpho-linyl)ethyl]-l~-indoler m.p. 131-135C.
Example 20B
Following a procedure similar to that des~ribed in Example 20A above, 14.75 g. (0.0516 mole) of 3-acetyl-2-methyl~ 2-(4-morpholinyl)ethyl]-lH-indole (Example 20A) was reacted with 2-fluorobenzaldehyde in 260 ml oÇ ethanol in the presence of 3.44 g. (0 061 mole) of potassium hydroxide pellets and the product, in the form of the Çree base~ recrystallized from ethyl acetate to give 10.0 g.
(54%) of 3-(?-Eluorocinnamoyl)-2-methyl-1-~2-(4-morpho_ lin~l)ethyl]-lH-indole, m.p. 113-116C.
~: ~

~z~

Example 21 A solution of 11 9. (0.025 mole) of 1-[2-~3-hydroxy-l-piperidinyl)ethyl]-2-~ethyl-3-(4-methoxybenzoyl)-lH-indole (Example 3B) in 50 ml. of pyridine and 25 ml. of acetic anhydride was allowed to stand at ambie~t 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 g. (59%) of 1-[2-~3 acetoxy-1-piperidinyl)ethyl]-2-methyl-3-(4 methoxybenzoy~ H-indole maleate (1:1), m.p. 161-161.5C.
Example 22 To a stirred solution of 12.5 g. (0.03 mole) of 2-methyl-3-(4-methoxybenzoyl)-1-[2-(1-piperazinyl)ethyl]-1~1-indole (Example lL)in 150 ml. of pyridine was added, with stirring while cooling in an ice bath, 7.1 9. (0.066 mole) of ethyl chloroformate. When addition was complete, the solution was stirred in an ice bath ~or 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. t41~) of 1-[2-(4-~ .

D.N._~35~
~z~
-78~

carbethoxy-l-pi~erazinyl)ethyl~-2-meth~1-3-(4-methoxy-benzoyl)-lH-indole maleate (1:1), m.p. 155-156C.
xample 23A
A solution of 12.5 g. (0.033 mole) of 2-methyl-3~(4-methoxybenzoyl)-1-[2-(1-piperazinyl)ethyl]-lH-indole (Example lL) in 150 ml. of 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 10 water and ~he mixture extracted with ethyl acetate. The organic solution, on 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 4D2 g~ of maleic acid. The solid which separated was collected and recrystallized from ethanol to give 7.36 g. (42%) of 1-[2-(4-acetyl-]-piperazinyl)-ethYl] 2-methvl-3-(4-methoxybenzoYl)-lH-indole maleate 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]-lH-indole (Example lBN) was reacted with 50 ml. of acetic anhydride in 150 ml. o~ pyridine and the product isolated in the form of the methanesulfonate salt to give 6.6 9.
(41~) of 5-~luoro-2-methyl-3-(4-methoxybenzoyl)-1-[3-(4-acetyl-l-piperazinyl)propyl~-lH-indole methanesul~onate, m.p. 170-171C.

;

. .

D.~ 6A
~5~3~6 Example 24 A solution of 15 9. (0.04 mole) oE 2-methyl-3-(4-aminobenzoyl)-l-[2-(4-morpholinyl)ethyl]-lH-indole (Example 4B), 12 g. (0.4 mole) of formaldehyde and 7.5 9.
(0.119 mole) of sodium cyanoborohydride in 250 ml. of 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 mixture 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.
(43%) of 3-t4-dimethylaminobenzoyl~-2-methyl~ 2-(4 morpholinyl)eth~1]-lH-indole, m.p. 152~154C.
xample 25A
A solution of 19.1 9. (0.047 mole) oE 1-(3-bromo-propyl)-5-fluoro~2-methyl~3-(4-methoxybenzoyl)-lH-indole ~Preparation 7D) in 500 ml. of acetone and 50 ml. of water was treated with 3.05 g. ~0.047 mole) of sodium azide and the mixture heated under reflux for about eighteen hours and then taken to dryness in vacuo. The residue was partitioned 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~) of 1~53-azidopropyl)-5-fluoro-2-methyl-3-(4-methoxybenzoyl)-lH-indole, m.p. 69-73.

.

D.l.. 7 ~A
~2S~3~6 --~o--The latter (0.028 mole) was dissolved in 265 ml. of ethanol and 35 ml. of THF and reduced with hydrogen over 1.0 g. of 10% palladium-on-charcoal in a Parr shaker. When reduction was complete, in about four hours, the mixture was fil~ered, the filtrate taken to dryness and the residue dissolved in ethyl acetate and treated with 3.13 g. of maleic acid and heated to dissolve all the material. The solid which separated was collected and recrystallized from isopropanol to give 9.7 9. (76%~ of 1-(3-aminopropyl)-5 fluoro-2-methyl-3-(4-methoxybenzoyl)-1~-indole maleate m.p. 169-171~C.
Example 25B
Following a procedure similar to that described in Example 25A above, 13.9B g~ (0.03 mole) of 2-methyl-3-(4-methoxybenzoyl)-1-(2-tosyloxyethyl)-lH-indole (Preparation 7A) in 325 mlO oE acetone and 32~ 5 ml~ of water was reacted with 1.96 g. (0.03 mole) of sodium azide and the product recrystallized from isopropanol to give 6.1 9. (61%) of 1-(2-a3idoethyl~-2-methyl-3-~4-methoxybenzoyl) lH-indole, m.p. 91-~3C
~ The latter (0.024 mole), dissolved in 250 ml. of -~ ethanol and 50 ml of THF, was reduced with hydrogen over 0.8 9. of 10% palladium-on-charcoal at 47 p.s.i.g. and the ~; product isolated in the form of the maleate salt to give

7.6 9. ~75%j of 1-(2-aminoethyl)-2~methyl-3-(4-methoxy-benzoyl)-lH-indole maleate, m.p. 165-166C
:~:
~ Example 26A
:, A mixture of 10 g. (0.027 mole) of 3-(4-fluoro-benzoyl)-2-methyl-1-[2-14-morpholinyl)ethyl~-lH-indole, 1). ;bA
~Z~53~6 -Bl-(Example lQ) 2.5 9. (0.033 mole) o 2 methoxyethylamine and 7.6 9. (0.054 mole) of potassium carbonate in 15 ml.
of DMSO was heated at g50C 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 vacuo. Recrystallization of the residue from ethyl acetate-ether aEforded 4.~ g.
(37%) of 2-methyl-3-~4-(2-methoxyethylamino?benzoyl]-1-[2-(4-mor~holinyl~ethyl]-1~-indole, m.p. 121-123C.
Examples 26B-26I
~ollowing a procedure similar to that described in Example 26~ above, reaction oE a 3-(4-halobenzoyl)-2-methyl-1-[2-(4-morpholinyl)ethylJ-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 ~6E, 26F and 26I were obtained from the corresponding bromobenzoyl (or bromonaphthyl) starting materials.

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:, .. ..
- ; ' ~ ~3~ S 3 _a~
A mixture of 8.2 g ~0.02 mole) of 1-[2-(4-formyl-1-piperazinyl)ethyl~-2-methyl-3-(4-methoxybenzoyl)-lH~indole (Example 3S) and 2.06 9. (0.052 mole) of sodium hydroxide S in 100 ml. of ethanol and 80 ml. of water was heated under reflux for 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 from ethanol to give 9.0 g.
(79~) of 2-methyl-3-(4-methoxybenzoyl)-1-[2-(1-pipera-zinyl)ethyl]-lH-indole dimethanesulfonate, m.p. Z~0C.
Examples 27B-27D
Following a procedure similar to that described in Example 26A above, the following species of formula I were similarly prepared.
Exam~le 27B - 1-[2-t2-hydroxyethylamino)ethyl~-2-methyl-3-~4-methoxybenzoyl)-lH-indole, m.p. 99-100.5C. (14.2g., 50%), prepared by saponification of 30.8 g. ~0.08 mole) of 1-[2-(N-formyl~2-hydroxyethylamino)ethyl]-2-methyl-3-(4-methoxybenzoyl)-lH-indole ~Example 3AK) with 9 7 9 (0.243 mole) of sodium hydroxide in 160 ml. of water and 200 ml.
of ethanol;
Example 27C - 1-12-(3-amino-1-piperidinyl)ethyl3-2-methyl~
3-(4-methoxybenzoylL-lH-indole maleate (1:2), m.p. 142.5-144C. ~1.5 g~, 49%), prepared by saponification of 1.6 9.
(0.0026 mole) of 1-[2-(3-acetylamino-l-piperidinyl)ethyl3 3~

2-methyl-3-(4-methoxybenzoyl)-lH-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-fluoro-2-met~ 3-~4-methoxybenzo~ [3-(l-piperazinyl)propyl]-lEI-indole dimethanesulEonate, m.p.
114-115C (8.7 9., 27%), prepared by saponification of 23 g.
~0.053 mole) of 5-fluoro-1-[3-(4-formyl-1-piperazinyl)-propyl~-2-methyl-3-(4-methoxybenzoyl)-lH-indole (Example 3~L) with 5.6 g. (0.014 mole) of sodium hydroxide in 265 ml. of ethanol and 210 ml. of water.
Example 28 To 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) of azetidine. The mixture was stirred for about 24 hours at ambient temperature, theQ diluted with water and extracted with ethyl acetate. The organic extract~ were washed with water, then with brine, dried over magnesium sulfate, filtered and taken to dryness. The re~idue ~7as 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 g. (10~) of 1-[3-(3-chloro~opylamino)-propyl]-2-methyl-3-(4-methox~enzo~L~lH-indole hydro-chloride, m.p. 140-142C.
Example 29A
To a solution of 15.0 9. (0.032 mole) o 5-fluoro-2-methyl-3-t4-methoxybenzoyl)-1-[3-(4-thiomorpholinyl)propyl~-lH-indole hydrochloride (Example 3AF) in 195 ml. of glacial c, ,~

-~5-acetic acid was added 8.12 ~. (0.038 mole) of an 80~
solution of m-chloroperben~oic acid, and the solution was ~tirred at ambient temperature for about forty-eight hours and then poured into 300 ml. of ice water. The mixture was 5 treated with 1 g. of sodium bisulphite, basified with 35%
sodium hydroxide and then extracted with chloroform. The organic 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 g. (72~) of 5-fluoro-2-methyl 3-(4-methoxybenzoyl)-1-13-(4-thiomorpholinyl)pro~yl]-lH-indole S-oxide maleate, m.p. 160-161C.
Examples 29B and 29C
Following a procedure similar to that described in Example 29A above, the following species of formula I were imilarly prepared:
Example 29B - 2-methyl-3- ~-met oxybenzoyl)-1-[2-(4~thio-morpholiny~Lethyl]-lH-indole S xide maleate, m.p. 179-1~0C. (7.2 g., 82%)~ prepared by oxidation of llP gO (0.028 mole) of 2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-thiomorpho-linyl)ethyl~ indole (Example 3V) with 6.7 g. (0.03 mole) ~ 25 of m-chloroperbenzoic acid in 110 ml. of glacial acetic i~ acid and Exam~le 29C - 2-methyl 3-(4-methoxybenzoyl)-1-[2-~thio-morpholinyl~e-thy~ H-indole-s~ ioxide dihydrate, m.p. ~
143-145C. (3.9 g., 27%), prepared by oxidation of 12.0 9.

. .

~5~

-~6-(0.030 mole) of 2-methyl-3~(4-methoxybenzoyl)-1-[2-(4-thiomorpholinyl)ethyl]-lH-indole (Exampl2 3u) with 6.6 9.
~0.030 mole) of m-chloroperbenzoic acid in 120 ml. o~
chloroform.
Example 30 A solution of 28.7 g. (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 for ten and a half hours under a 3ean-Stark trap and the solution then cooled and taken to dryness to give N-[2-(4-morpholinyl3ethyl]-N-(l-methyl-3-oxo-3-phenylpropenyl)amine as a yellow solid.
The latter (11.3 g., 0.41 mole) and B.9 g. (0.082 -~ mole) o~ 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 5% 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 from methanol to give 1.0 g. t7~) of 3-benzoyl-5-hydroxy-2-methyl-1-[2-~4-morpholinyl)ethyl~-lH-indole, m.p. 215-217C.
Example 31A
A solution oE 13.4 g. (0.0395 mole) of 5-fluoro-2-methyl-3-(4-methoxybenzoy~ 1-(2,3-epoxy)propyl~-lH-indole (Preparation 9A) and 4.79 g. (0.055 mole3 of morpholine in 60 ml. ~ chloroform was heated under reflux for about forty-eight hours and then taken to dryness in vacuo. The crude product was dissolved in methylene dichloride, and ~2~S~

-~7-the solution was treated with an excess oE ethereal hydrogen chloride and then diluted with ether. The solid which separated was collected and recrystallized from methanol-ether to give 13.3 9. (61~) of 1-[2-hydroxy-3-(4-morpholinylL ~o~ hyl-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,~-epoxy)propyl]-3-R3-carbonyl~lH-indole with an amine, HN=B, afforded the following compounds of formula Ib listed in Table 31, where R2 in each instance is CH3.

L . ~ > A
~ 2~S~:~6 ¦ r ~ 0 a~ ~ r ~ co " ~ n~

~5 V ~ ~ ~
x x ,_ o ~ c~ ~ x o ~c o x 1~ z ~
~ , o .~ Z ~
~ ~ U v E~ ~ C~ U ~ ~ U ~ E~ a a Q C~

S~I Z Z ~ ~ I Z Z Z ~S 3 ~

m ~ D j~3 ~ ~ ~) ~ ~ ~ ~- ~ r~ ~ ~ ~ ~ 0 y V C~ K ~ æ z;
.

~ . ~ . . . .

Example 32 Following a procedure similar to that described above in Example 25A, 60 9. (0.165 mole~ of 1-(3-azido-2-hydroxy-l-propyl)-2-methyl-3-~4-methoxybenxoyl)-lEI-indole (Example 31J) in 500 ml. of ethanol was reduced with hydrogen over 35 9. 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-1-proE~1)-2-methyl-3-(4-methoxybenzoyl)-lH-indole, m.p 152-153C
Example 33 The hydrobromide salt of 2-methyl-3~(4-methoxy-benzoyl)-1-[2-(4~morpholinyl)ethyl~-lH-indole (Example lB) (10.0 g., 0.026 mole) was prepared by passing hydrogen bromide gas into a solution of the former in 200 ml. of MDC. The hydrobromide was isolated, redissolved in 300 ml.
of MDC and the solution treated with 6.g4 9. (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 re~rystallized from toluene to give 3.7 g.
(31%) of 5-bromo-2-methyl-3-~4-methxlbenzoyl)-1-[2-~4-, m.p. 134.5-136C.

D~_. 56A

Examples 34A-34H
Following a procedure similar to that described : in Example 2A above, it is contemplated that other species of formula I as follows can be prepared by reaction of a 2-~2-1-[2-(4-morpholinyl)ethyl~-lH-indole with an ap-~: propriate aroyl chloride (R3COCl) in the presence of alumi-num chloride in methylene dichloride:
Example 34A - 2-methyl-1-[2-(4-morpholinyl~et~1]-3-~2-quinolinecarbonyl)-lH-indole, by reaction of 2-methyl-1-t2-(4-morpholinyl)ethyl~-lH-indole with 2-quinoline carboxylic acid chloride;
Examp].e 34B - 2-methyl-1-[2-(4-morpholinyl)ethyl]-3-(3-quinolinecarbonyl)-lH-indole, by reaction of 2-methyl-1-[2-(4-morpholinyl)ethyl]-lH-indole with 3-quinoline carboxylic acid chloride;
Example 3~C - 2-methyl-1-[2-(4-morpholinyl)ethyl]-3-(4-qulnolinecarbonylJ-lH-indole, by reaction of 2-methyl-1-[2-(4-morpholinyl~ethyl]-lH-indole with 4-quinoline carboxylic acid chloride;
Examp~e 34D - 2-methyl-1-[2-(4-morPholinylJethyl]-3-(5-quinolinecarbonyl)-lH-indole, by reaction of 2-methyl-1-12-(4-morpholinyl)ethyll-1~-indole with 5-quinoline car-boxylic acid chloride;
Example 34E - 2-methyl-1-[2~ morpholinyl)ethyl]-3-(6-quinolinecarbonylJ-l~-indole~ by reaction of 2-methyl-1-~2 ~4-morpholinyl)ethyl]-lH-indole with 6-quinoline carboxylic acid chloride;
.
~` .

D..~. 56A

Example 34F - 2-methyl-1-[2~L4-morpholinyl)ethx1]-3-(7-~uinolinecarbonyll-lH-1ndole, prepared by reaction of 2-methyl-1-~2-(4-morpholinyl~ethyl]-lH-indole with 7-quinoline carboxylic acid chloride;
5 Example 34G - 2-methyl-1--e2-(4-morpholinyl)ethyl]-3-(8-quinolinecarbonyll-lH-indole, by reaction of 2-methyl-1-[2-(4-morpholinyl)ethyl]-1~-indole with 8-quinoline car-boxylic acid chloride; and Example 34H - 2-benzyl-1-[2-(4-morpholinyl)ethyl]-3-(4-methoxybenzoyl3-lH-indole, by reaction of 2-benzyl-1-[2-14-morpholinyl)ethyl]-lH-indole with 4-methoxybenzoyl chloride.

D . j~; 7 3 r ~2~

BIOLOGICAL TEST RESULT
The 3-R3-carbonyl-1 aminoalkyl-lH-indoles of formulas I, Ia and Ib of the invention were tested in the acetylcholine-induced abdominal constriction te~t (Ach), the anti-bradykinin test (BRDK) and the rat paw flexion test (P.F.), all in vivo testsl a~d 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 ED5~ 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 ED5~ 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, 28, 30, 43 in ~he ca5e of the species of Example lAW
in the acetylcholine-induced abdominal constriction test.

~ra~ B

Exam~ Ach BRDK P~F.
lA 73 56 ~B 24,50,30,37 8.1 (LV.) '11,26,34,58 6.7 tl.~l.) 21, 'l8 (SC.) lC 126 .
lD 34,10,54,22 0/100 64 5.1 (iV.) 49 (S~C.) lE 0/100 lF 20 0~200 8B/100 13 (i v.) lG 84 0/3 (iv.) 50/10 (iv.) 100/30 (iv.
lH 33/100 0/3 ~iv.) 30/10 (iv.~
~: 100/30 (i.v.) ~ V30 (~c.) :~ ~ 75

8~5 (iv.) : : lJ 86 : 6.7 (iv.) 1~/1 (iv.) 30/3 ~v.) 25/~.5 (iv.
~4/10 (iv.) lM 5~/100 lN 35.8 l-O 91.6 lP 40/100 4.5 ~iv.

27~79 ~: 60/238 67~435 ., ~

D.~
~2~5;~6 --94 ~

Tahle B ~cont'd~
BRI:)K P!F.
lR 198 lS 40 162 .l~/l (iv.) 20/3 (iV.) 100/10 (LV.) lT 106 3.8 liv.) lU 155 lV 20/300 10/1 ~iv.) 0/1.73 (iv.) ~6/3 (iv.) lZ 68 lAA 10/100 lAB 47/300 lAC 30 - 0/200 43/30 0/1.77 (iV.) 57/50 0/2.2 (iV.) 75/100 ao/3 (~V.) 100/10 ~ivo) lAE 29 20/300 66.2 lAE' 200 0/3 (iv.) : 0/10 (iv.) 30/30 (iv.) lAG 40/100 10/10 (ivo) 5~/3~ (iv.) 20/30 (s.c.) lP~H 85 ~AI 74 lAJ 13/100 lA K 40/300 lAL 113 lA M 32 5 ~v.) ~ ~S~ D~_ . 7~ A

Table B (cont'~
Exam~ Ach BRDK P,F.
lA O 28 111 75/100 lAP 42 0/50 lA Q 53/300 0/10 17 (L~J.) 12/30 lA R 27/150 13/25 (~c.) lAS 33~300 lAT 30 0/50,200 lA U 42 0/50 lAV 38 0/50 lA W 6,28,30,43 229 26 lA X 45 0/212 lAY 11,37,49 141 0/30,100 8.5 (~v.) 20/300 .: lAZ 10, 27/50 20/'75 53~50 lBA 197 lBB 9~
lB C 40/100 lBD 65 : LBE So.g l~F 0/30 lBG 33/300 lB H 0/30 27~00 53/3~)0 : 58/550 7/30 (Sc.) so/la (iv.) lBI 13/300 0/6 27~100 (~c.) 0.69 (LV.) lBJ 0/100 lBL 0~00 lBM ~/100 lBN 36 lBO 173 lBP 28 . .
. ,, :

D . ~ 6A

Table B (cont~

Ach BRDK P.F

lBT90/100 lB W10/100 lBZ 0/100 lCA20/100 lCB60/130 lCC10/100 lC D 79 lCE 0/100 lCF 24 lC G46.3 lC H 105 lCI70/100 lCJ 56 lC K30/100 lCL30/100 : 33/550 ~C 19,33 0/30 3.3 (Lv.) 6~/300 ~0/300 2~ 42 .6 (~v.) 18 (~c.

~ .

~z~ D . 5 6 A

^-97 -Ta~ B~~dL

Exa mp~e Ach B R D K _.F.

2~ 30/100 2P~E 20/100 2A(3 143 2A K 30/0O3 (iv.~
2AL 20/O.l(iv.) 2~U 30/100 2BC j :L0/100 3B 26.5 10 (ac.) a6/100 3 ~v.) 86/300 98 ~ D5 Ta~Le B (cont'~
Examp~ Ach BRDK P.F.
3 H 9 .7 (iv.) 3 I 30/lO0 3J 30~10 (iv.) 3 R 45.7 3M 10/lO0 3R 40/lO0 3S ~0/100 3V 253.8 3~ 69 3AF 138.6 3A(; 42 4A 16 53 0,12/lO0 4B 24,25,21,15 38,28,19 27.6 6 ~iv.) 4 ~) 24 5A 31 0~3G0 20~1 (LV.) 29/3 ILV.) 30/10 (iv.) 5C l9 ~0/30 57/3 (LV.) 29/1 (~.V.) ... ~ .

~S53~

Table B (con~d.~

Exam ~ Ach BRD K P.F.

~0/300 0/10 liv.) 0/300 0/30 (Lv.3 13/30 (ac.) 7 ~0 0/300

9 27/300 20/30 (~c.) 7/30 (~c.) 13/30 (ac.) ~: 0/30 : 13C 20/100 16~ 20/100 17 7/30 33/100 (ac.) 6.6 (ac.) 22 66.8 23~ 39 25A (r) 32.5 25~ 42 2~C 30/100 26E 73.1 .

~ ~s~
--10 0-- .

Ta e s-(cont~d.~

Exam~ Ach sRDK P,F.

27~ 20.7 27B 59.8 27C 29.4 2gA 60,80/100 29B 60,70/100

10/100 31F 0/3 (LV.) 30/100(ic.v.) 80/10 (LV.~
.~ 31-I 31,40,88~100 31N 90~100/100 (r) N=B is a mino The 3-R3~arbony1-.l-aminoalky1-lH-ind~iles of formulas I, Ia and :Ib of the invention were also tested in the deveLcJping adjuvant arthritic assay, the pdasma fibronec*in a~ay and the p~euri~ macrcphage assay in rats. Data s~obtained, - expre~;ed as p~alues as a measure of the sta~stical si~ lcance of the resul~s for each of the parameters measured, ie. inhibition of ini~mmation of non-i~ected.paw (NIP) and ir~ected paw (right paw vc~me or RPV), I:wering of ~sma hbronec~ .levels (FN) and inhibit~on of macrophage accumulation in ~e ~- p~eural cavity (MAC), are given in Ta~Le C. Compounds were cons~dered active atp< 0.05leve~ Non statisticallysignificantresiL~are recorded as"-".

-101- ~ 3~

Tal~le C

xam~e NIP RPV FN MAC
lB (~ 0.01 0.01 lF 0.01. 0.01 ~I 0.01 0.01 0.01 0.01 lU -- _ _ lAC
1~0 _ _ _ l~P
lAW
lBA - - 0.01 lBB
lBD
lBE - O.û5 -lBL 0.01 0.05 0.01 lB M OoOl O~Ol O~Ol O~Ol lBN
lB O - 0.01 0.05 lBP 0.01 0.01 lB Q (~ 0.01 0.01 0.01 0.01 lB R 0.01 0.01 0.01 lBZ 0.05 0.01 0.01 lCC -- _ _ lC~
lCF 0.01 0.01 lC G 0.01 0.01 0.01 lCH - _ _ ~CJ 0.01 0.01 lCL - - 0.01 lC M - 0.01 lC O 0.01 0.01 lCP 0.01 0.~1 0.01 0.01 2C 0.01 0.01 ~.01 0.01 ~E 0.01 0.01 ~U - - 0.01 ~Y 0.05 ~ - .
"'', ' :

i:), 7 ~ A

Table C (contd.) ~_ N~ RPV FN MAC

2AC 0.05 - -2AE 0.01 0.01 2AF 0.01 0.01 2AG 0.01 - 0.01 2AI 0.01 0.01 0.01 2A O 0.01 0.01 0.01 0.05 2AU - _ 0 05 2A Y 0.01 0.05 2BB - 0.01 0.05 2BF - 0.01 0.01 3D - _ _ 3E: 0.01 3F 0.05 0.01 3G - _ _ 3 K - 0.01 0.05 3T - 0.01 3U -- _ _ 3 W 0.01 0.01 0O05 3AF - 0~01 3AG 0.01 0.01 0.01 3AH 0.01 - 0.01 3AI 0.01 0.01 . 0.05 3AJ 0.01 0.01 0.05 - -6 _ -- 0.05 13B - - 0~01 --1.0 3--Tal~C (COn~.) EXamF~ P RPV FN MAC
16A 0.05 - - .
19 -- _ .
20A - 0.05 20B - _ 22 0.01 0.~1 - 0.05 23A 0.01 OoOl O~Ol 23B 0.01 0.01 0.01 24 0.05 0.01 25~ _ ~6F 0.05 0.01 26 G - - 0.01 27A 0.05 0.01 27B 0.05 0.01 27D 0.01 0.01 29A 0.05 0DO1 31~ 0.01 0.01 31B 0.01 311~ 0.01 31J 0.05 31L 0.05 0.01 31M 0.01 - 0.01 31N 0.01 0.01 - -31-O 0.01 0.01 - -32 0.01 0.01 0.05 (s) The m~Leai:e salt The lower me~ting pciLymorph Certain spec~es oE the intermediate 2-R2-3-(R3 carbony:l~-indc~es oE
formula Ir were als~ tested and found active in one or more oE the acetvlch~line-induced abdom~nal consb~t~on test (Ach), the develop~ng adduvant arthriti~ a~ay (NIP and E~PV), the ~bronectin a~;ay (FN) and the ~ur~y macro~?hage a~3ay (MAC), Data s~obtained, expre~;ed as described abwe, are given in Tahle D.

., :

-10 4 ~

Ta~e D

Prepn. Ach N:~? RPV FN MAC
lF 0/100 - -lAJ
lA K 20/100 - - - 0.05 lAI, 20/100 0.01 - 0.01 0.01 lA M - - 0.01 lA N 0.01 0.01 -lA O 40~100 lA Q 0.01 0.01 0.01 Certain ~pecies of the intermediate 2-R2-1-aminoaL~cyl-lH-ird~es of formul~ m were tested and found active in the acetylch~lin~duced abdominal constriction test. Thus 2-meth~l-1-[1-methyl-2-(4-morpho-linyVethyl]-lH-indcle methanes~fonate hydrate (Preparati~n 5A) pr~
duced 40% islhibition at 300 mg./lcg. (p.o.), and the ED50 of 5-Luoro-2-methyl-l-(1-methyl-2~methylaminoethyl~-lH indcile (Preparation 8) was fa~nd to be 25 mg./kg. (p.o.l.

Claims (15)

D.N. 7356B DIV III

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A compound of the formula:

(II') (wherein:
R2' is hydrogen, lower-alkyl or phenyl;
R3' is fluorophenyl, 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-1- or 2- naphthyl; and R4' is hydrogen or fluoro).

2. A process for preparing a compound of the formula (II') as defined in claim 1, which comprises reacting a 2-R2-indole of the formula (IV') (wherein the symbols having the meanings given in claim 1) with a lower-alkyl magnesium halide and reacting the result-ing Grignard with the required R3'-carboxylic acid halide.

3. The compound according to claim 1 wherein R2' is lower-alkyl, R3' is 4-biphenylyl or 4-methoxyphenyl, and R4' is hydrogen or 5-fluoro.

4. The compound according to claim 1, wherein R2' is methyl, R3' is 4-biphenylyl and R4' is hydrogen.

5. A process for the preparation of 3-(4-biphenylyl-carbonyl)-2-methylindole which comprises reacting 2-methyl-indole with methyl magnesium bromide under Grignard reaction conditions, and reacting the resulting Grignard with 4-biphenylylcarbonyl choride.

6. 3-(4-Biphenylylcarbonyl)-2-methylindole.

7. A pharmaceutical composition comprising an anti-rheu-matic effective amount of a compound of the formula (II') as defined in claim 1 in admixture with a pharmaceutically accep-table carrier or diluent.

8. The compound according to claim 1, wherein R2' is lower-alkyl.

9. The compound according to claim 8, wherein R4' is hydrogen.

10. The compound according to claim 8, wherein R4' is fluoro.

11. The compound according to claim 9 or 10, wherein R2' is methyl or isopropyl.

12. The compound according to claim 8, 9 or 10, wherein R3 is 2-,3- or 4-fluorophenyl, 2-,3- or 4-methoxyphenyl, 3-fluoro-4,methoxyphenyl, 2,3-, 3,4-methylenedioxyphenyl, 2,3- or 3,5-dimethoxyphenyl, 4-aminophenyl, 4-cyanophenyl, 2- or 4-biphenyl, 1- or 2-naphthyl or 4-methoxy-1-naphthyl.

13. The compound according claim 1, wherein:
R2' is methyl, isopropyl or phenyl:
R4' is hydrogen or 5-fluoro; and R3' is 2-,3-or 4-fluorophenyl, 2-,3- or 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, 2,3-, 3,4-methylenedioxyphenyl, 2,3-or 3,5-dimethoxyphenyl, 4-aminophenyl, 4-cyanophenyl, 2- or 4-biphenyl, 1- or 2-naphthyl or 4-methoxy-1-naphthyl.

14. The composition of claim 7, wherein such compound is as defined in claim 3 or 6.

15. The composition of claim 7, wherein such compound is as defined in claim 8 or 13.