Note: Descriptions are shown in the official language in which they were submitted.
22749-319H
~ 1 D~No 7356s DIV V
This is a divisional application of Serial No.
488,073 filed August 2, 1985.
The parent application relates to 2-R2~3-R3-carbonyl-
l-aminoalkyl-lH-indoles of formula I described hereinafter
which have analgesic, anti-rheumatic and anti-inflammatory
activities.
This divisional application relates to novel com-
pounds oE the Eormula VI described below useful for the produc-
tion of the compounds of formula I of the parent application.
Thus, an aspect of this application provides a
compound of the formula
4 ~ CO-R3
N R2 VI
Alk-X'
[wherein:
R2 is hydrogen, lower-alkyl, chloro, phenyl or
benzyl (or phenyl or benzyl substitut~d by from one to two sub-
stituents selected from halo, lower-alkyl, lowe.r-alkoxy, hydroxy,
amino~ lower-alkylmercapto, lower-alkylsulfinyl or lower-
alkylsulfonyl);
R3 is cyclohexyl, lower-alkoxycyclohexyl, phenyl (or
phenyl substituted by from one to kwo substituents selected from
halo, lower-alkoxy, hydroxy, benzyloxy, lower alkyl, nitro,
amino, lower-alkylamino, di-lower-alkylamino, lower-alkoxy-
lowex-alkylamino, lower alkanoylamino, benzoylamino, trifluoro-
acetylamino, lower alkylsulfonylamino, carbamylamino, lower-
alkylmercapto, lower-alkylsulfinyl, lower-alkylsulfonyl, cyano,
formyl or hydroxyiminomethylj, methylenedioxyphenyl, 3- or 4-
hydroxy-l-piperidinylphenyl~ l-piperazinylphenyl/ (lH-imidazol-
2 2 2 7 4 9 - 3 1 9 11
D.N . 7356B DIV V
- la -
l-yl)phenyl, (l-pyrrolyl)phenyl, aminomethylphenyl, guanidinyl-
methylphenyl, N-cyanoguanidinylMethylphenyl, styryl, lower-alkyl-
substituted-styryl, fluoro-substituted-s~yryl, 2-4-biphenyl, 1
or 2-naphthyl (or 1- or 2-naphthyl substituted by from one to
two substituents selected from lower-alkyl, lower-alkoxy, hydroxy,
bromo, chloro, fluoro, lower~alkoxycarbonyl, carbamyl, cyano,
lower-alkylmercap~o, lower-alkysulfinyl, lower-alkylsulfonyl or
trifluoromethyl), thienyl, Euryl, benæo[b]furyl, benzo[b]thienyl,
quinolyl or (N-lower-alkyl)pyrrolyl;
R4 is hydrogen or from one to two substituents
selected from lower-alkyl, hydroxy, lower-alkoxy or halo in the
4-, 5-, 6- or 7-positions;
Alk is ~ lower-alkylene having the formula (CH2)n
where n is an integer from 2 to 6, or such lower-alkylene
substituted on the ~- or the ~-carbon atom by a lower-alkyl
group; and
X' is toluenesulfonyloxy or halo].
Another aspect of this application provides a process
for producing the compound o~ the ~ormula VI. This process
comprises~
~a) in the case where Alk is 1,2-ethylene,
reacting a 2-R2-3-R3-carbonyl-indole of the formula
II:
R4 ~ ~ -CO-R II
with a lower-alkyl lithium,
reacting the resulting lithium salt with ethylene
oxide, and
t;~
- lb - 22749~319H
react.i~g the so-formed 2-R2-3-R3-carbonyl-1-(2-
hydroxyethyl)-lH-indole wi-th toluenesulfonyl chloride in the
presence of an acid-acceptor to form a compound of the formula
VI where X' is a toluenesulEonyloxy yroup, or with a phosphorus
trihalide to form a compound o~ the formula VI where X' is a
halo group; or
(b) in ~he case where X' is halo and Alk is other than
1,2-ethylene,
reacting a 2-R2-3-R3-carbonyl-indole of the formula
II with an a,~-di.halo-lower-alkane in the presence of a strong
base.
In the following description, it should be under-
stood that the -term "this invention" includes the subject
matters of this divisional application, of the parent applica-
tion and of other divisional application filed from the same
parent applica-tion.
S3~ _
-lc -
BACKGROUND OF THE INVENTION
S(a) Field of the Invention:
This invention relates to 3-arylcarbonyl- and 3-
cycloalkylcarbonyl-l-aminoalk~1-lH-indoles which are use-
fulasanalgesic,anti-rheumaticandanti-inflammatoryagents.
~b) Information Disclosure Statement:
10Deschamps et al. U~S~ Patent 3,946,029 discloses
compounds having the formula:
¢ ~R3
A-N ~~4
~R5
wh~re, inter alia, A is alkylene; R is one to four carbon
-- 2
alkyl; R3 is a 2-, 3- or 4-pyridyl group; and R4 and R5 are
joined together to form, with the nitrogen atom, a
piperidino, pyrrolidino or morpholino group. The compounds
are said to possess fibrinolytic and anti-inflammatory
activities.
Essentially the same disclosure is found in Inion
et al., Eur. J. of Med. Chem., 10 (3), 276-285 (1975).
~ SpeciEically disclosed in both these reerences is the
: species, 2-isopropyl-3-(3-pyridylcarbonyl)-1-[2-14-mcrpho-
linyl)ethyl]indole.
.
~ . . .
~5,~ 2
--2--
Herbst U.S. Patent 3,489,770 generically dlscloses
compounds having the formula:
f ~
where, inter alia, Rl is "diloweralkylamino, pyrrolidinyl,
piperidino and morpholino and R2 is ~ .. cyclo~lower)alkanoyl
and adamantanylcarbonyl". Although not within the ambit
of the above-defined genus, the Herbst patent also discloses
a var;ety of species where R2 is an arylcarbonyl group.
Spe~ifically disclosed, for example, is the species "l-p-
(chiorobenzoyl)-3-~2-morpholinoethyl)indole". The
compounds are said to possess anti-inflammatory, hypo-
tensive, hypoglycemic and CNS activities.
Tambute, Acad. Sci. Comp. Rend., Ser. C; 278 (20~,
1239-1242 (1974) discloses compounds of the formula:
[~.C6H5
~ 2)n ~
where n is 2 or 3. No utility for the compounds i~ given.
SUMMARY
In a composition of matter aspect, the invention
relate~ to 2~R2-3-R3-carbonyl-1 aminoalkyl-lH-indoles and
their acid-addition salts which are useful as analgesic,
anti-rheumatic and anti-inflammatory agents.
53~ 2
In a second composition of matter aspect, the inven-
tion relates to 2-R2-3-R3-carbonylindoles useful as inter-
mediates for the preparation of said 2-R2-3-R3-carbonyl-1-
aminoalkyl-lH-indoles. Certain of the 2-R2-3-R3-carbonyl-
indoles are also useful as anti-rheumatic agents.
In a third composition of matter aspect, the invention
relates to 2-R2-1-amlnoalkyl-lH-indoles also useful as
intermediates for the preparation of said 2-R2-3-R3-
carbonyl-l-aminoalkyl-lH-indoles. Certain of the 2-R2-1-
aminoalkyl-lH-indoles are also useful as analgesics.
In a process aspect, the invention relates to a
process for preparing 2-R2-3-R3-carbonyl-1-aminoalkyl-lH-
indoles which comprise~ reaçting a 2-R2-3-R3-carbonyl-
indole with an aminoalkyl halide in the presence of an
acid-acceptos.
In a second process aspect, the invention relates
to a process for preparing 2-R~-3-R3-ca~bonyl-1-amino-
alkyl-l~-indoles which comprises reacting a 2-R~ amino-
alkyl-lH-indole with an arylcarboxylic acid halide or a
cycloalkanecarboxylic acid halide in the presence of a
Lewis acid.
In a third process aspect, the invention relates
to a process Eor preparing said 2-R2-3-R3-carbonyl-1-
aminoalkyl-lH-indoles which comprises reacting a 2-R2-3-
~S R3-carbonyl-1-tosyloxyalkyl- or l-haloalkyl-lH-indole with
an amine.
In a method aspect, the invention relates to a
method of use of the said 2-R2-3-R3-carbonyl l-aminoalkyl-
lH-indoles for the relief of pain or of rheumatic or
inflammatory conditions.
In a second method aspect, the invention relates to
a method of us~ of the said 2-R2-3-R3-carbonylindoles for
the relief of rheumatic conditlons.
In a thi~d method aspect, the inv~ntion relates to a
method of use of the said 2-R2-1-aminoalkyl-lH-indoles Eor
the relief of pain.
DETAILE:D DESCRIPTION OF THE PREFERRED EMBODIMENTS
More specifically, the invention relates to 2-R2-3-
R3-carbonyl-1-aminoalkyl-lH-indoles, which are useful a~
analgesic, anti-rheumatic and anti-inflammatory agents,
having the formula:
R4 ~ R2~3
Alk-N=B
I
where:
R2 is hydrogen, lower-alkyl, ohloro, phenyl or
benzyl (or phenyl or benzyl substituted by from one
to two substituents selected from halo, lower-
alkyl, lower-alkoxy, hydroxy, amino~ lower-alkyl-
mercapto, lower-alkylsulfinyl or lower-alkyl-
sulfonyl);
~o R3 is cyclohexyl, lower-alkoxycyclohexyl,
phenyl (or phenyl substituted by from one to two
substituents selected from halo, lower-alkoxy,
hydroxy, benzyloxy, lower-alkyl, nitro, amino,
lower-alkylamino, di-lower-alkylamino, lower-
alkoxy-lower-alkylamino, lower-alkanoylam1no,
benzoylamino, . tri~luoroacetylamino, lower-alkyl-
~: .
'
`
: :.
'~S 3~ ~
~. Ij . ; J j~B
sulfonylamino, carbamylamino, lower-alkylmercapto,
lower-alkylsulf3n-yl, lower alkylsulfonyl, cyano,
formyl or hy~roxyiminomethYl)~methylenedioxyphenyl~
3- or 4-hydroxy-1-piperidinylphenyl, 1-piperazinyl-
S phenyl, (].~-imidazol-l-yl)phenyl,(l-pyrrolyl)-
phenyl, aminomethylphenyl, guanidinylmethylphenyl,
N-cyanoguanidinylmethylphenyl, styryl, lower-alkyl-
substituted-styryl, fluoro-substituted-styryl, 2-
or 4-biphenyl, 1- or 2-naphthyl (or 1- or 2-naphthyl
substituted by from one to two substituen~s selected
from lower-alkyl, lo~er-alkoxy, hydroxy, bromo,
chloro, Eluoro, lower-alkoxycarbonyl, carbamyl,
cyano, lower-alkylmercapto, lower-alkylsulfinyl,
lower-alkylsulfonyl or triEluoromethyl), thienyl,
furyl, benzo[b]furyl, benzo[b]thienyl, quinolyl or
(N-lower-alkyl)pyrrolyl;
~ is hydrogen or from one to two substit~ents
selected from lower-alkyl, hydroxy, lower-alkoxy or
halo in the 4-, 5-, 6- or 7- positions;
C=Z is C=O or C=NOH;
Alk is ~,~-lower-alkylene having the ormula
(CH2)n, where n i5 an integer from 2 to 6, or such
lower-alkylene substituted on the ~- or the ~-carbon
atom by a lower-alkyl group; and
N=B is azido, amino, N-lower-alkylamino, NrN-
di-lower alkylamino, N-(hydroxy-lower-alkyl)amino,
N,N-di-(hydroxy-lower-alkyl)amino, N-lower-alkyl-N-
(hydroxy-lower-alkyl)amino, N-(lower-alkoxy-loWer-
alkyl)amino, N-(halo~n-propyl)aminor ~-morpholinyl,
2-lower-alkyl~4-morpholinyl, 2rG-di-lower-al~yl-4
'
~fl2~
- 6 - 227~9-319
morpholinyl, 4-thiomorpholinyl, 4-thi.omorpholinyl S-oxide,
4-thiomorpllolin~l-S,S-dioxide, l-piperidinyl, 3- or 4-hydroxy-
l-piperidin~], 3- or 4-lower-alkanoyloxy-1-piperidinyl, 3- or
4-amino-1-piperidinyl, 3- or 4-(N-lower-alkanoylamino)-l-
piperidinyl, 2-cyclohexylmethyl-1-piperidinyl, l-pyrrolidinyl,
3-hydroxy-1-pyrrolidinyl, l-azetidinyl, l-p.iperazinyl, 4-lower-
alkyl-l-piperazinyl, 4-lower-alkanoyl-1-piperazinyl, 4-carbo-
l`.Jw~r-alkoxy-1-piperazinyl, he~ahydro-4}l-1,4-diazepin-4-yl or
the N=B N~oxides thereof, with the proviso that N=B is not
amino, when R2 is methyl, R3 is phenyl, R~ is hydrogen and Alk
is (Cll2)3.
PreEerred compounds of formula I above are those
where:
R2 is hydrogen or lower-alkyl;
R3 is phenyl, chlorophenyl, fluorophenyl, dichloro-
phenyl, difluorophenyl, lower-alkoxyphenyl~ di-lower-alkoxy-
phenyl, hydroxyphenyl, lower-alkylphenyl, aminophenyl, lower-
alkylaminophenyl, lower-alkanoylaminophenyl, ~enzoylaminopl-enyl,
trifluoroacetylaminophenyl, lower-alkylmercaptophenyl, lower-
alkylsulfinylphenyl, lower-alkylsulfonylphenyl, cyanophenyl,
aminometllylpllenyl, s-tyryl, 2- or 4-biphenyl, 1- or 2-naphthyl
(or 1- or 2-napll-thyl substituted by lower-alkyl, lower-al~oxy,
llydroxy, bromo, chloro or fluoro), 2-thienyl~ 2-, 3-, 4- or
5-benzo[b3furylr 2-, 3-, 4- or 5-benzo~b]thienyl or 2- or 3-
(N-lower-alkyl)pyrrolyl;
R4 is hydrogen or lower-alkyl, lower-alkoxy, fluoro
or chloro in the 4-, 5-, 6- or 7-positions;
D.N 356A
;a.~S~3
--7--
C=Z is C=O;
Alk is 1,2-ethylene ~-CH2CH~-), l-lower-alkyl-l,
2-ethylene l-CH~CH2-), 2-lower-alkyl-1,2-ethylene
(-CH2CHR-), where R is lower-alkyl, 1,3-
propyle~e ~-CH2CH2C~-) or 1,4-butylene: and
N=B i~ 4-morpholinyl, 3 or 4-hydroxy-1-piperi-
dinyl, l-pyrrolidinyl, 3-hydro~y-l~pyrrolidinyl,
N-lower-alkylamino, N,N-di-lower-alkylamino, N,N-
di-(hydroxy lower-alkyl)amino, l-piperazinyl, 4-
lower-alkyl-l-piperazinyl or 4-lower-alkanoyl-1
piperazinyl.
Particularly preferred compounds oE formula
within the ambit of the invention as defined above are
those where: .
R2 is hydxogen or lower-alkyl:
R3 is phenyl, chlorophenyl, fluorophenyl,
difluorophenyl, lower-alkoxyphenyl, lower-alkyl-
phenyl, aminophenyl, lower-alkylaminophenyl, lower
alkanoylaminophenyl, trifluoroacetylaminophenyl,
lower-alkylmercaptophenyl, lower alkylsulfinyl~
phenyl, aminomethylphenyl~ 1 or 2-naphthyl (or 1-
or 2-naphthyl substituted by lower-alkyl, lower-
alkoxy, hydroxy, bromo, chloro or fluoro), 2-
thienyl, 2-, 3-, 4- or 5-benzo~b]Euryl or 2 , 3-, 4-
or 5-benzo[b]thienyl;
R4 is hydrogen, lower alkoxy, fluoro or chloro
in the 4-, 5-, 6- or 7-positions1
C=~ is C=O;
Alk is 1,2-ethylene, 2-lower-alkyl-1,2-ethylene,
1-lower-alkyl-1,2-ethylene, 1,3~propylene or 1,4-
butylene; and
5;.3~.~
N=B is 4-morpholinyl, 3- or 4 hydroxy-l-
piperidinyl, l-pyrrolidinyl, 3-hydroxy-1-
pyrrolidinyl, N,N-di-lower-alkylamino, N,N-di-
(hydroxy-lower-alkyl)amino, l-piperazinyl or 4-
lower-alkyl-l-piperazinyl.
Other preferred compounds of formula I within
the ambit of the invention as defined above are those
wheres
R2 is hydrogen or lower-alkyl;
R3 is phenyl, fluorophenyl, chlorophenyl, di-
chlorophenyl, lower-alkoxyphenyl, di-lower-alkoxy-
phenyl, hydroxyph~nyl, lower-alkanoylaminophenyl,
benzoylaminophenyl, lower-alkylsulfonylphenyl,
cyanophenyl, styryl, l-naphthyl, lower-alkoxy-
substituted-l- or 2-naphthyl, 3-benzo[b~thienyl or
2- or 3-(N-lower-alkyl)pyrrolyl;
' R4 is hydrogen or lower-alkyl, lower-alkoxy,
fluoro or chloro in the 4-, 5-, 6~ or 7-positions;
C=Z i~ C=~;
Alk is 1,2-ethylene, 1-lower-alkyl~1,2-
ethylene, 2-lower-alkyl-1,2-ethylene, 1,3-propyl-
lene or 1,4-butylene; and
N=B is 4-morpholinyl or l-pyrrolidinyl.
Still other preferred compounds of formula I within
the ambit of the .invention as defined above are those where:
R2 is hydrogen, lower-alkyl or phenyl:
R3 is cyclohexyl, lower-alkoxycyclohexyl,
phenyl, fluorophenyl, lower-alkoxyphenyl, lower
alkoxy-fluorophenyl f benzyloxyphenyl, methylene-
dioxyphenyl, lower-alkylphenyl, di-lower-alkyl-
phenyl, lower-alkylsulfonylaminophenyl, carbamyl-
I '. 735~A
3~
g
aminophenyl~ cyanophenyl, formylphenyl, oximino-
methylenephenyl, (l-pyrrolyl1phenyl, guanidinyl-
methylphenyl, N-cyanoguanidinylmethylphenyl, 2-
naphthyl, 2-furyl or 2-benso[b]thienyl;
R~ is hydrogen or lower-alkyll hydroxy or
lower-alkoxy in the 4-, 5-~ 6- or 7~positions;
C=Z is C=O or C-NOH
Alk is 1,2-ethylene or 1-lower-alkyl-1,2-ethyl-
ene; and
N~B is 4-morpholinylJ l-piperidinyl or 1-
pyrrolidinyl or the N-oxides thereof.
Also considered to be within the ambit of the
invention are species having the formulas Ia and Ib:
o
4 ~ 3
Alk-N-B
Ia
Z
~ 3~3: A
CHz IC~ICH2-N=B
OH
Ib
where R2, R3, R4, Alk, 2 and N=B have the meanings given
above.
As used hereinJ unless specifically defined other~
~ wise, the terms lower-alkyl, lower alkoxy and lower-
:~ 20 alkanoyl mean monovalent, aliphatic radicals, including
,~
- 10 - 227~9-319
branched chain radicals, of from one to about four carbon atoms,
Eor example, methyl, ethyl, propyl, isopropyl, butyl, sec.-
butyl, me~hoxy, e-thoxy, propoxy, isopropoxy, butoxy, sec.-
butoxy, Eormyl, acetyl, propionyl, butyryl and isobutyryl.
~ s used herein, the term cycloalkyl means saturated
alicyclic groups haviny from three to seven ring carbon atoms,
including cyclopropyl, cyclobutyl, cyclopentyl, cycloheY~yl and
cycloheptyl.
As used herein, the term halo means fluoro, chloro or
bromo.
In one me~hod, the compounds oE formula I where C=Z
is C-O are prepared by reacting a 2-~2-3-R3-carbonyl-11l-indole
of Eormula II with an amino-lower-alkyl halide amino-lower-alkyl
tosylate in the presence of an acid-acceptor:
R -~ X-Alk-N~
¦ Alk-N=B
II (C=Z is C=O)
whe~e R2, ~3, R4, Alk and N=B have the meanings given above and
X represents halogen or tosyloxy. The reaction is preferably
carried out in an organic solventinert under the conditions of
the reaction such as dimethylEormaMide (hereina~ter DMF),
dimethylsulfoxide (hereinafter DMSO), a lower-alkanol or
acetonitrile. Suitable acid-acceptors are an alkali metal
carbonate, such as sodium carbona-te or potassium carbonate, or
an alkali metal hydride/ such as
~25S~
sodium hydrider an alkali metal amide, such as soda~ide, or
an alkali metal hydroxide, such as potassium hyd~oxide.
Preferred solvents are DMF and DMS0, and preferred acid-
acoeptors are sodium hydride, potassium carbonate and
potassium hydroxide~ The reaction is carried out at a
temperature in the range from around 0C. to the boiling
point of the solvent used.
The 2-~2-3-R3-carbonyl-1~-indoles of formula II
are in turn prepared by reacting a 2-iR2-indole with a
lower-alkyl magnesium hal;de and reacting the resulting
Grignard with an appropriate R3-carboxylic acid halide.
The reaction is carried out in an organic solvent inert
under the conditions o~ the reaction, such as dimethyl
ether, dioxane or tetrahydrofuran (hereinafter THF), at a
temperature in the range from -SC. to the boiling point of
the solvent used.
Certain compounds withih the ambit oE formula
II, namely those o~ formula II':
4 ~ ~ C0-R3'
II'
where ~2 is hydrogen, lower-alkyl or phenyl; ~3' is fluoro-
phenyl, difluorophenyl, lower-alkoxyphenyl, di-lower-
alkoxyphenyl, lower-alkoxy-fluorophenyl, methylene-
dioxyphenyl, aminophenyl, cyanophenyl, 2- or 4-biphenyl,
1- or 2- naphthyl or lower-alkoxy substituted-l~ or 2-
naphthyl and iR4 is hydrogen or fluoro are novel species
and comprise a further composition aspect of this inven-
tion.
j.
L
- t t~
-12-
In another method, the compounds of formula I where
C=Z is C~O are prepared by reacting a 2-~2-1-aminoalkyl-lH-
indole of formula III with an ~ppropriate R3-carbo~ylic
acid halide (R3-CO-X) in the presence o a Lewis acid, such
as aluminum chloride, and in an organic solvent inert under
the conditions of the reaction. Suitable solvents are
chlorinated hydrocarbons such as methylene dichloride
(hereinafter MDC) or ethylene dichloride (hereinafter
BDC). The reaction is carried out at a temperature from
0C. to the boiling point oE the sol~ent used. The method
is illustrated by thP reaction-
4~7J--R 3 ~ 4 f~
Alk-N=B Alk-N=B
III I
(C=z is C=O)
where R2, R3, R4, Alk, N=B and X have the meaninys given above.
The intermediate 2-R2-1-aminoalkyl-lH-indoles of
Eormula III wherein R2, R4, Alk and N=B have the previously
given meanings comprise yet a further composition aspect oE
the present invention. These compounds are prepared by one
of two methods. In one method, a 2-R2~indole of formula IV
is reacted with an amino-lower-alkyl halide in the presence
of an acid-acceptor, in an organic solvent inert under the
conditions of the reaction using the same conditions de-
scribed above for the preparation of the compounds of for-
mula I by alkylation o the compounds oE formula II.
In a second method, a 2-R2-indole of formula IV is
reacted with a halo-lo~er-alkanamide in the presence of a
~2~
-13-
strong base, and the resulting 2-R2-lH-indole-l-alkanamide
of formula V is then reduced with lithium aluminu~ hydride.
The reaction of the 2-R2-indole of formula IV with the
halo-lower-alkanamide is carried out in an appropriate
S organic solvent, such as DMF, at a temperature f~om -5~C.
to about 50C. The reduction of the amides of formula V
with lithium aluminum hydride is carried out ;n an inert
organic solvent, such as diethyl ether, THF or dioxane, at
a temperature from -5C. to about 50C. The two methods
are illustrated by the following reaction sequence:
R2
Il \
IV
¦ 4 ~
Alk-N=B
III
~ _ /
~1;,3--R2
il~lk ' -CO-N=B
~I
where R2, R~, Alk and N=B have the meanings given above,
and Alk' is lower-alkylene having the formula (CH2)n,,
where n1 is an integer from 1 to 5 or 5UCIl lower-alkylene
group substituted on the ~-carbon atom by a lower-alkyl
group.
In another method for preparing the compounds oE
formula I where C=Z i~ C=O, a 2-R2-3-R3-carbonyl-1-(2-
3 ~'~
~2749-3]9H
-14- D.N. 7356B DIV V
tosyloxy~lower-alkyl~- or (2-halo-lower-alkyl)-lli-indole of
ormula VI is reacted with a molar equivalent amount of an
amine, H-N=B, in an organic solvent inert under the con-
ditions of the reaction, such as acetonitrile, a lower-
alkanol or DMF. The reaction is preferably carried out by
heating a solution of the reactants at the boiling point of
the mixture The method is ill~strated by the reaction:
4 ~ ~ HN~ 4 t ~ C2_R3
Alk-X' Alk-N=B
VI
where R2t R3, R4 and N=B have the meanings given above,
and X' represents a toluenesulfonyloxy or halo group.
The 2-R2-3-R3~carbonyl-1-(2-tosyloxy-lower-alkyl)-
or 1-(2-halo-lower-alkyl)-lH-indoles of formula VI, whe~e
Alk is 1,2-ethylene, are in turn prepared by reaction o a
2-R2-3-R3-carbonyl-indole o fo~mula II with a lower-alkyl
lithium, for example n-butyl lithium, in an inert organic
solvent, such as THF, dioxane or diethyl ether, ollowed by
reaction of the resulting lithium salt with ethylene oxide.
Reaction of the resulting 2-~2-3-R3-carbonyl-1-(2-hydroxy-
ethyl)-lH-indole with toluenesulfonyl chloride in the
presence of an acid-acceptor affords the 1-(2-tosyloxy-
ethyl)-lH-in~oles, while reaction of the product with a
phosphorus trihalide affords the corresponding l-(2-halo-
ethyl)-lH-indoles.
The 2-R2-3-R3-carbonyl-1-(2-halo-lower-al~yl)-lH-
indoles of formula VI, where Alk has the other possible
meanings, are prepared by reaction of a 2-R~-3-R3-carbonyl
-15-
indole of Eormula II with an a,0-dihalo lower-alkane in the
presence of a strong base, such as sodium hydride in an
inert organic solvent, such as D~. The reaction generally
occurs at ambient te~perature.
The compounds of formula Ia are prepared by reaction
ofa2-R2-3-formyl-l~aminoalkyl-lH-indole with anappropriate
methyl R3 ketone according to the reaction:
~ CHO ,~"~ ~CH=CHC-R3
R4- ~ + c~3-co R ~4- ¦r ¦~
N ~ R2 ~~ ~ N ~ R2
Alk-N=B Alk-N=B
Ia
where R2, R3, R4, Alk and N=B have the meanings
given above. The reaction is carried out in the presence
of a mineral acid and in an organic solvent inert under
the conditions of the reactlon. Preferred solvents are
lower alkanol~, such as methanol or ethanol.
The compounds of formula Ib, where Z is C=O,
are prepared by reaction of a 2-R2-3-R3-carbonylindole
of formula II with an epihalohydrin in the presence of
a strong base, such as an alkali metal hydride, in
an inert solvent, such as DMF or DMSO, and reaction
oEtheresulting2-R2-3-R3-carbonyl-1-[1-(2,3-epoxy)propyl]-
lH-indole with an appropriate amine, H-N=B, according
to the reactions:
GI~
3~
--~ 6--
~4~ ~ r ~ XC~CII-Cl~2 R4~ R2
H CH2CH-5H2
II /
~
~\~ C-R3
CH2ICHCH2-N=B
Ib
where R2, R3, R4, Alk and N=B have the meanings given above.
Another method for preparing the compounds o~
formula I where R4 is 5-hydroxyand C=Z is C=O comprises
reacting benzoquinone with an appropriate N~ lk-N=B)-N-
(l-R2-3-oxo~3 R3-propenyl)amine of ~ormula VII in an
inertr wa~er immiscible organic solvent, such as nitro-
methane. The N-(N=B-alkyl)-N-(l-R2-3-oxo-3-R3-propenyl)-
amine in turn is prepared by reaction of a 1,3-diketone,
R2COCH2COR3, with an appropriate aminoalkylamine, B=N-Al};-
NH2 under dehydrating conditions. The reaction is
preferably carried out by heating a solution of the
reactants in ~n inert, water immiscible solvent under a
Dean-Stark trap. The method is repre~ented by the reaction
~equenceo
CH2COR3 CHCOR3
"C~ ~ H2N-A~ =g ~ N/ \ R
Alk-N=B
VII
~ -~ r
3 ~
o
VI~ ~ CO-R3
~1 ,
o Alk-N=s
By further chemical manipulations of various
functional groups in the-compounds of formulas I, Ia and Ib
prepared by one or more of the above-described methods,
other compounds within the ambit of the invention can be
prepared. For example ~he compounds where R3 is amino-
phenyl are advantageously prepared from the corresponding
species where R3 is nitrophenyl by reduction of the latter.
The reduction can he carried out either catalytically
with hydrogen, for example over a platinum oxide catalyst
at ambient temperature and 'n an appropriate organic
solvent, such as a lower-alkanol, ethyl acetate or acetic
acid or mixtures thereo, at hydrogen pressures from around
30 to 60 p.sOi.g., or alterpatively the reduction can
be carried out chemically~ fo~ example with l~on in the
presence of hydrochloric acid in an appropriate organic
~olventr for example a lower-alkanol. The reaction is
carried out at temperatures from ambient to the bolling
point of the solvent used for the reaction.
The aminophenyl compounds thus prepared can then be
acylated or sulfonylated to pr'epare compounds where R3 is
lower-alkanoylaminophenyl, benzoylaminophenyl, trifluoro-
acetylaminophenyl or lower-alkylsulfonylaminophenyl by
reaction of an appropriate acid anhydride or acid halide
with the corresponding species where R3 is aminophenyl. It
i~ advantageous, although not essential, to carry out the
.. . :.
1 . 7356A
-~8-
reaction in the presence of an acid acceptor, such as an
alkali metal carbonate, or example potassium carbonate, or
a tri~lower-alkylamine, such as trimethylamine or tri-
etllylamine The reaction is carried out in an inert
organic solvent at a temperature in the range from -5C. to
around 80C. Suitable solvents are acetic acid, MDC, EDC
or toluene.
Other simple chemical transformations which are
entirely conventional and well known to those skilled in
the art of chemistey and which can be used for effecting
changes in functional groups attached to the R3-carbonyl
group, (C=O)R3, involve eleavage of aryl ether functions, for
example with aqueous alkali or a pyridine hydrohalide salt
to produce the corresponding phenolic compound (R3 is hydroxy-
phenyl); preparation of compounds where R3 is phenyl sub-
stituted by a variety of amine functions by reaction oE the
corresponc7ing halophenyl species with an appropriate
amine; catalytic debenzylation oE benzyloxy-substituted
species to prepare the corresponding phenolic compo~nd
(R3 is hydroxyphenyl); catalytic reduction of a nitrile
function to produce the corresponding aminomethyl-substi-
tuted species tR3 is aminomethylphenyl); saponifieation of
amide groups to produce the corresponding amino compounds;
aeylation of hydroxy-substituted species to produce the
corresponding esters; acylation of amino-substituted
species to prepare the corresponding amides; oxidation of
; sulfides to prepare either the corresponding S-oxides or
S,S-dioxides; reductive alkylation of amino substituted
- 19 - 22749--319 ~-
species to prepare the corresponding mono- or di-lower-alkyl-
amino substituted species; reaction of amino-substituted
s~ecies with an alk~li n~e~al isocyanate to prepare the corres-
ponding carbamylamino-s~stituted species ~R3 is carbamyl-
aminophenyl); reaction of an aminomethyl-substituted species
with a di-lower-alkylcyanocarbonimidodithioate and reaction oE
the resulting product with ammonia to prepare the corresponding
N-cyanoguanidinylmethyl-substituted species (R3 is cyanoguani-
dinyl.methylphenyl); reduction oE a cyano-substituted species
with sodium hypophosphite to prepare a corresponding formyl-
substituted compound (R3 is Eormylphenyl); reaction of a Eormyl-
phenyl species or a R3-carbonyl species with hydroxylamine to
prepare the corresponding hydroxyiminometllylphenyl-substituted
species (~3 is hydroxyiminomethylphenyl) or the R3-carbonyl
oximes (C=Z is C-NOII); reaction of an aminophenyl species with
a 2,5-di-lower-alkoxytetrahydroEuran to prepare a (l-pyrrolyl)-
phenyl-substituted species (R3 is l-pyrrolylpllenyl); oxidation
of tlle N=B function, for example by fermen-tative procedures,
or by oxidation with an organic peracid, such as perchloro-
benzoic acid, to prepare the corresponding N-oxides; or reaction
oE a l-aminoalkyl-lll-indole of formula III where 1l2 is hydrogen
with hexamethylenepllosphoramide followed by a lower-alkyl halide
to prepare the corresponding compounds of formula III where R2
is lower-alkyl..
The compounds of formulas I, Ia, Ib and III in free
base form are converted to the acid-addition salt form by
interaction of the base with an acid. In like manner, the
free base can be reyenerated from the acid-addition salt Eorm
in conventional manner, that is by -treating the salts
~ 53~2
-20-
with cold, weak aqueous bases, for example alkali metal
carbonates and alkali metal bicarbonates. The bases thus
regenerated can be interacted with the same or a di~ferent
acid to give back the same or a different acid-addition
s~lt. Thus the novel bases and all of their acid-additio~
salts are readily interconvertible.
It will thus be appreciated that formulas I, Ia, Ib
and III not only represent the structural configuration of
the baces of formulas I, Ia, Ib and III but are also
repeesentative of the structural entities which are common
to all of the compounds of formulas I, Ia, Ib and III,
whether in the form of the free base or in the form of the
acid-addition salts of the base. It has been found that,
by virtue of these common structural entities the bases of
; 15 formulas I, Ia and Ib, and certain of the bases of formula
III, and their acid~addition salts have inherent pharma-
cological activity of a type to be more fully described
hereinbelow. This inherent pharmacological activity can be
enjoyed in useful form for pharmaceutical purposes by
employing the free bases themselves or the acid-addition
salts formed from pharmaceutically acceptable acids, that
is acids whose anions are innocuous to the animal organism
in effective doses oE the salts so that beneficial
properties inherent in the common structural entity
represented by the free bases are not vitiated by side
effects ascribable to the anions.
In utilizing this pharmacological activity of
the salts of the invention, it is preerred, of course, to
use pharmaceutically acceptable salts, Although water
insolubility, high tox~city or lack o crystalline
3~
-21~
character may make some particular salt species unsuitable
or less desirable for use as such in a given pharmaceutical
application, the water-insoluble or toxic salts can be con-
verted to the corresponding pharmaceutically acceptable
bases by decomposition of the salts with aqueous base as
explained above, or alternatively they can be converted to
any desired pharmaceutically acceptable acid-addition salt
by double decomposition reactions involving the anion, for
example by ion-exchange procedures.
Moreover, apart from their usefulness in pharma-
ceutical applications, the salts are useful as characteriz-
ing or identifying derivatives of the free bases or in
isolation or purification procedures. Like all of the
acid-addition salts, such characterizing or purification
salt derivatives can, if desired, be used to regenerate the
pharmaceutically acceptable free bases by reaction of the
salts with aqueous base, or alternatively they can be con-
verted to a pharmaceutically acceptable acid-addition salt
by, for example, ion-exhange proced~res.
The novel feature of the compounds of the invention,
then, resides in the concept of the bases and cationic
Eorms of the new 2-R2-3-R3-carbonyl-1-aminoalkyl-lH-
indoles of formulas I, Ia and Ib and the 2-R~ aminoalkyl-
lH-indoles of formula III and not in any particular acid
moiety or acid anion associated with the salt forms oE the
compounds; rather, the acid moieties or anions which can be
associated with the salt orms are in themselves neither
novel nor critical and therefore can be any acid anion or
acid--like substance capable of ~alt Eormation with the
bases
~z~
--22--
Thus appropriate acid-addition salts are those
derived from such diverse acids as ~ormic acid, acetic
acid, isobutyric acid, alpha-mercaptopropionic acid, malic
acid, fumaric acid, succinic acid, succinamic acid, tar-
taric acid, citric acid, lactic acid, benzoic acid, 4-
methoxybenzoic acid, phthalic acid, anthranilic acid, 1-
naphthalenecarboxylic acid, cinnamic acid, cyclohexane-
carboxylic acid, mandelic acid, tropic acid, crotonic acid,
acetylenedicarboxylic acid, sorbic acid, 2-furancarboxylic
acid, cholic acid, pyrenecarboxylic acid, 2-pyridine-
carboxylic acid, 3-indoleacetic acid, quinic acid,
sulfamic acid, methanesulEonic acid, isethionic acid,
benzenesulfonic acid, p-toluenesulfonic acid, benzene-
sulfinic acid, butylarsonic acid, diethylphosphonic acid,
p-aminophenylarsinic acid, phenylstibnic acid, phenyl-
pho.sphinous acid, methylphosphinic acid, phenylphosphinic
acid, hydrofluoric acid, hydrochloric acid, hydrobromic
acid, hydriodic acid, perchloric acid, nitric acid,
sulfuric acid, phosphoric acid, hydrocyanic acid, phospho-
tungstic acid, molybdic acid, phosphomolybdic acid, pyro-
phosphoric acid, arsenic acid, picric acid, picrolonic
acid, barbituric acid, boron trifluoride and the like.
The acid-addition salts are prepared by reacting
the free base and the acid in an organic solvent and
2S isolating the salt directly or by concentration of the
solution.
In standard pharmacological test procedures, the
compounds of formulas I, Ia and Ib have been found to pos-
sess analgesic, anti~rheumatic and anti-inflammatory
activities and are thus useful as analgesic, anti-rheumatic
L , 7 ~ A
53~2
23-
and anti-inflammatory agents. Certain of the compounds of
formula II have been Eound to possess anti-rheumatic
activity, and certain of the compounds of formula III have
been found to possess analgesic activity, thus indicating
S usefulness of those species as anti-rheumatic and analgesic
agents, respectively.
The test procedures used to determine the analgesic
activities of the compounds have been described in detail
in the prior art and are as follows: The acetylcholine-
induced abdominal constriction test, which is a primary
analgesic screening test designed to measure the ability of
a test agent to suppress acetylcholine-induced abdominal
constriction in mice, described by Collier et al., Brit.
J. Pharmacol. Chemotherap. 32, 295 (1968), a modification
of the anti-bradykinin test, which is also a primary
analgesic screening procedure, described by Berkowitz et
al., J. Pharmacol. Exptl. Therap. 177, 500-50a (1971),
Blane et al., JO Pharm. Pharmacol. 19, 367-373 (1967),
Botha et al., Eur. J. Pharmacol. 6, 312-321 (1969~ and
Deffenu et al., J. Pharm. Pharmacol. 18, 135 (1966)s and
the rat paw flexion test, described by Kuzuna et al., Chem.
Pharm. Bull., 23, 1184-1191 (1975), Winter et al., J.
Pharm. Exptl. Therap., 211, 678-685 (1979~ and Capetola et
al., J. Pharm. Exptl. Therap. 214, 16-23 (1980).
An~i-rheumatic and ant;-inflammato~y;activities of
the compounds of the invention were determined using the
developing adjuvant arthritis ASSay in rats, the plasma
fibronectin assay in arthritic rats and the pleurisy macro-
phage assay in rats. The developing adjuvant arthritis as-
say was used in conjunction with the plasma fibronectin as-
say as a primary screening method in the evaluation of com-
3~;~
-24-
pounds for potential use as disease modifying anti-
rheumatic drugs. The procedure used to induce arthritis in
rats is a modification of the methods published by Pearson,
J. ChronO Dis. 16, 863-874 (1973) and by Glenn et al.,
j Amer. J. Vet. Res. 1180~1193 (1965). ~rhe adjuvant induced
arthritiq bears many o the traits of rheumatoid artllritis.
It i~ a chronic, progressive, deforming arthritis of the
peripheral joints, with a primary mononuclear cell response
consisting of bone and joint space invasion by pannus. In
order to detect disease modifying anti-rheumatic drug
activity, drug treatment i5 started before the disease has
become irrevocably established. Since such drugs are not
designed to be administered prophylactically, drug treat-
ment of adjuvant arthritis is initiated at a time when the
disease is developing but is not yet irreversible. Animals
develop signi~icant systemic arthritic disease which can be
measured by swelling of the non~injected rear paw (NIP) lS
to 20 days following an initial injection on day 1 of com-
plete Freund's adjuvant into the right hindfoot paw.
The important role played by fibronectin in
arthritis has been evidenced by clinical [Scott et al.,
Ann. Rheum Dis. 40, 142 (1981)] as well as experimental
[Weissmann, J. Lab. Clin~ Med. 100, 322 (1982)] studies.
Plasma fibronectin measurements are made using the tech-
nique of rocket immuno-electrophoresis. Fibronectin
levels in the arthritic rat are significantly higher than
in normal animals. Nonsteroldal, anti-inflammatory drugs
have no influence on the enhanced ibronectin levels seen
in arthritic rats, while disease modifying anti-rheumatic
drugs cause a significant decrease in plasma fibronectin.
V 7~A
-25_
The pleurisy macrophage assay is designed to define
anti-arthritic drugs ~hich inhibit macrophage accumulation
in the pleural cavity following injection of an inflam-
matory stimulus. Standard disease modifying anti-
rheumatic drugs are active in this assay while nonsteroidal
anti~inflammatory druys are not. The activity of species
in the pleurisy macrophage model thus indicates disease
modifying anti-rheumatic drug activity. The macrophage i5
the characteristic cell type in chronic inflammatory
responses in the rheumatoid synovium as well as other
si~es. When activated, macrophages produce a large variety
of secretory products, including neutral proteases which
play a destructive role in arthritis [Ackerman et al., J.
Pharmacol. Exp. Thera. 215, 588 (19B0)]. The in vivo
model of inflammatory cell accumulation in the rat pleural
cavity permits quantitation and di~ferentiation of the
; accumulated cells. The cellular components are similar to
those seen in the inflamed synovium. It has been hypo-
thesized that drugs which are effective inhibitors of
pleurisy macrophage activity may also be effective in slow-
ing or reversing progression of arthritic disease (Ackerman
), and the procedure used is a modification of the
method published by Ackerman et al.
The co~pounds of formulas I, Ia, Ib, II and III of
the invention can be prepared for pharmaceutical use by
-~ incorporating them in unit dosa~e form as tablets or
capsules or oral or parenteral administration either alone
or in combination with suitable adjuvants such as calcium
carbonate, starch, lactose, talc, magnesium stearateJ gum
D.N 35GA
-26-
acacia and the like. Still further, the compounds can be
formulated for oral ~r parenter~l administration either in
aqueous solutions of the water soluble salts or in aqueous
alcohol! glycol or oil solutions or oil-water emulsions in
the same manner as conventional medicinal substances are
prepared.
The percentages of active component in such com-
positions may be varied 60 that a suitable dosage is
obtained. The dosage administered to a particular patient
is variable, depending upon the clinician's judgment using
as criteria: the route of administration, the duration of
treatment, the size and physical condition of the patient,
the potency of the active co~ponent and the patient's res-
ponse thereto. An efEective dosage amount of the active
component can thus only be determined by the clinician
after a consideration of all criteria and using his best
judgment on the patient's behalf.
The molecular structures of the compounds of the
invention were assigned on the basis of study of their
2~ infrared, ultraviolet and NMR spectra. The structures were
confirmed by the correspondence between calculated and
found values for elementary analyses for the elements.
The following examplas will further illustrate
the invention without, however, limiting it thereto.
All melting points are uncorrected.
~5~3~
~XEMPLARY DISCLOSURE
Preparati~n of Intermediates
A. The_Com~ounds of Formula II:
Preparation lA
To a solution of 0.05 mole of methyl magnesium
bromide in about 45 ml. of anhydrous diethyl ether at 0C.
under a nitrogen atmosphere was added, dropwise, a solution
containing 6.0 g. (0.04 mole) of 2,7-dimethylindole in 30
ml. of anhydrous ether. When addition was complete r the
reaction mixture was stirred at room temperature for one
hour r then cooled in an ice bath and treated dropwise with
a solution of 8.53 g. (0.05 mole) of 4-methoxybenzoyl
chloride in 20 ml. of anhydrous ether. The mixture
was stirred at room temperature for approximately twelve
hours, the~ on a steam bath for two hours and then treated
with ice water. Excess ammonium chlsride was added, and
the ether layer was separated, dried and evaporated to dry-
ness to give a solid which was collected by filtration and
washed thoroughly witll water and ether to give 8.5 9. (76~)
of 2L7-dimethyl-3-(4-methoxybenzoyl)indole, m.p, 132-184C.
Preparations lB - lAU
Following a procedure similar to that described
above in Preparation 1~, substituting for the 2,7-dimethyl-
indole and the 4-methoxybenzoyl chloride used therein an
appropriate 2-R2-R4-indole and an appropriate aroyl-
chloride (R3CO-Cl), the following species of formula II
listed in Table A were prepared. In some instances the
products, without further purificationr were used directly
in the next step of the synthesis of the final products of
. , .
i ~. /3~
3:~
--2~-
formula I, and no ~elting points were taken. In a few
cases, the weight of the products was not obtained, and so
calculation of yields of products in those instances are
not possible. Here and elsewhere in the tables included
S with this specification, the melting point of the product
(in ~C.) and the recrystallization solvent are given in
columns headed "m.p./Solv.", and the yield, in percent, of
product is given in columns headed "Yield".
~5~
-2~
Tahle A
Preprl. R2 R3 R4 m.p.~Sclv~ Yi~l~
lB CH3 3 6 4 215-217/DMF-H20 85
lC CH3 2~fury1 - 98
lD CH3 4-CH3SC6H4
lE CH3 4 2 6 4 23
lF CH3 4-c~l3ocfiH4 S-F 199-202/i-PrOH
lG CH3 4-CE13OC6H4 7-F 204-205/H20 42
lH C ~3 4 C 3 ~6 4 7-C H30 68
1-I ~ H 3 4-C H 3 O c 6 }~ F ~a) 5S
lJ CH3 4-FC,~ - 19~201~EtOH 3a
lR CH3 3'4-~CH2OC6H3 - 21~213/i-PrOH 60
lL CH3 3~enzo[b]thienyl - 181 183 64
lM CH3 2~enzo[b]h~ 218-220/i-PrOH 62
lN CH3 2-CH3OC6H4 - 203-206/i-PrOH 75
1-0 CH3 3-F-4-CH30C6H3 - 16~165/EtOH 39
lP c~3 2~aphthyl - 208-213/i-PrOH 57
lQ R 4-CH3Oc6H4 ~CH3 189-192/EtOE1 42
lR C~3 3-FC6H4 - 64
lS CH3 6 4 216-21B/iPrOH 44
lT CH3 4-CNC6~14 - 211~213/EtOAc 7
lU CH3 C6H5 4-CH3 176-179/EtOAc 65
lV CH3 2 5 6 4 199-20VEtOA-~ 7Q
lW CH3 3-N2C6H4 - 218-221/DMF-H20 20
lX CH3 4 3 6 4 207-209/EtoH 60
lY CH3 3-CH30C6H4 - 163-164~EtOAc 63
lZ H 4 CH30C6H,~ 80(b)
lAA C6H5 4-CH30(: 6H4 25
lAB H C6E~5 5-CH30 46
lAC CH3 4 3 6 4 6 CH3 5
lAD CH3 4-N2C6H4 6 CH3O 73
lAE CH3 C~jH5 ~ 18~186/MeOB 64
lAF 6 5 241-24VMeOf~ 38
lAG CH3 4-ClC6H4 - 183-185/MeOH 34
lP~H CH3 4-CH3OC6H4 6-C1 58
3.AI CH3 4-CH3OC6H4 6-C6H5CH2O Sl
lAJ CH3 2'3-OC~l2OC6H3 ~ 239.~240/CH3CN 9
lAK CH3 6 5 6 4 238-240/MeOH 3g
lAL C~8 4 6H~C6H4 225-228 56
3~
-30-
Table A conbd~
Prepn. R2 R3 R4 m.p./Sclv. Yield
__ _ _ _
lA M c~l3 l-naph~lyl - 223-224/i-PrOH 69
lA N c~3 2,3-~CH3O)2C6~3 185-187 87
lA O C H3 3~S~(CH30)2C6H3 ~ 182-184 85
lAP CH (CH3)2 4-CH30C6H4 176-178/EtOA~ 44
lA Q C H(C H3)2 4-CH3OC6H4 5-F 173-175 11
lAR CH3 2-FC6H~ ~F 247 249/i-PrOH 10
lAS C H 3 4-C H 3 O-l~naphthyl - 286-289/i-PrO H 24
lAT C H3 4-C5H5C6H4 5-F 234-235.5/EtOH 36
lA U C H3 4-CH3OC6H4 - 200-203 97
(a~ Product cons~sted of a mixture oE the ~fluoro and the 7-~Luoro isomers
(b) T wo m(ilar equivalenb; of the Grignard reagent used, thus res~ting in
acylati~n at both the 1- and 3 posi~ions of indc~ derivative. The de~red
product was obtained by heat:ing a mixture of the crude product in methan~
and sodium hydroxide.
...
.
~. 735
Preparation lAV
A mixture of 50 g. ~0.03 mole) oE phenylmercapto-
acetone and 76.8 9. (0.3 mole) of 3-benzyloxyphellylhydra-
zine in 750 ml of ethanol was heated on a steam bath for
six hours and then stirred at room temperature for about
twelve hours. The solid which separated was collected,
washed with water and the filtrate set aside. The solid
was dissolved in methylene dichloride, the organic solution
was washed with water, then with dilute hydrochloric acid,
dried over magnesium sulfate, filtered and taken to dryness
to yield a first crop oE ceude produc~ which was stirred
with ether for about forty-eight hours and then filtered
and dried to give 56 g. of product. The original filtrate,
previously set aside, was mixed with methylene d.ichloride,
and the organic layer was washed with water, then with
dilute hydrochloric acid, dried over magnesium sulfate,
filtered and concentrated to dryness to give 40 g. of
additional product which wa~ recrystalli~ed from diethyl
ether/methyl~ne dichloride to give 29.7 9. of product (com-
bined yield 71.7 9., 69%) of 2-methyl-3-phenylmercapto-6-
benz~loxyindole~ m.p. 146-148C.
A mixture of 25 9. (0.072 mole) of the latter with
50 teaspoons of a Raney nickel/ethanol suspension in 1
lit2r of ethanol was heated under reflux for three hours,
: ~tirred at ambient temperature for about twelve hours, then
~ 25 refluxed for an additivnal three hours and the catalyst
3;~
-32-
removed by filtration The filtrate was taken to dryness
ln vacuo to give an oil which was passed through a pad of
Florisil and eluted with ethyl acetate. Evaporation of the
solution to dryness aEforded 5.2 g. (26~) of 6-hydroxy-
2-methylindole
A mixture of 5 9. t0.03~ mole) of the latter,
5.9 ml (0.051 mole~ of benzyl chloride and 13.8 9. (0.1
mole) of potassium carbonate in 200 ml of DMF was stirred
at room temperature for two hours, then heated on a steam
bath Eor two hours and the mixture poured into ice/water.
The solid which separated was collected, dissolved in ethyl
acetate, and the organic solution was washed with water,
then with brine, dried over magnesium sulfate, filtered and
taken to dryness to give 2.5 9. of 6-benzyloxy-2-methyl-
indole, m p. 90-93C., used as the starting material ~or
the preparation of the compound o Pr~paration lAI in Table
1 aboveO
Preparation 2
To a solution of 20 g. (0.071 mole) o 2-methyl-
~0 3-(4-methylmercaptobenzoyl)indole (Preparation lD) in 400
ml. of chloroform was added, dropwise with stirring, a
solution of 16.7 g~(O.Q81 mole) of 3-chloroperbenzoic acid
(80~) in 170 ml. of chloroform while cooling the mixture
in an ice~methanol bath. When addition was complete, the
solution was stirred at room temperature for approximately
twalve hours and then washed three times with saturated
sodium bicarbonate solution and dried over magnesium
sulfate T~ mixture was iltered, ~he filtrate was
~ 7356A
;3~
33-
concentrated to near dryness~; and the solid which separated
was collected and recrystallized Erom ethyl acetate to give
14.5 9. (69%) of 2-meth~1-3-(4-methylsulfinylben
indole.
Preparation 3
2-Methyl-3-(4-nitrobenzoyl)indole (Preparation lE)
(11.2 9., 0.04 mole) dissolved in a solution of 100 ml. of
glacial acetic acid and 200 ml. of ethyl acetate was
reduced with hydrogen over 0.6 g. of platinum oxide
catalyst in a Parr shaker, and when reduction was complete,
in about two and a half hour~, the catalyst was removed by
filtration and the solvent taken off in vacuo to leave 11.4
g. of crude product, whlch wa~ recrystallized from ethanol
to give 4.5 q. (45~) of 2-methyl-3-(4-aminobenzoyl~-
indole, m.p. 220-223 C.
B. The~ ounds of Formula_III
(a~ B~_Alkylation o the Compounds of Formula IV
Preparation 4A
~o a stirred suspension of 229.5 9. (1.22 moles~ of
N-(2-chloroethyl)morpholine hydrochloride in 300 ml. of
DMSO at ambient temperature was added 200 9. ~3.03 moles)
of 85~ potassium hydroxide pellets, and the suspension was
stirxed for five minutes and then treated dropwise at
ambient temperature with a solution of 133.7 9. (1.0 mole)
of 2-methylindole in 140 ml. of DMSO. The temperature of
the reaction mixture gradually rose during the addition of
the 2-methylindole as well as on stirring after addition
. .
., .
r . 7 ~A
-34-
was complete. When the temperature reached 78C., the mix-
ture was cooled in a water bath until the temperature sub-
sided to 75C., and the mixture was stirred for a total of
three and a half hours while the temperature subsided to
ambient. The mixture was then diluted with 1 liter of
water and extracted with toluene. The extracts were washed
with water, dried over magnesium sulfate and taken to dry-
ness in vacuo, and the residual dark oil was crystallized
from heptane to give 224 9. (92%) oE 2-methyl-1~2-(4-
morpholinyl)ethyl]-lH-indole, m p 6~-65C
.
Preparation 4B
Following a procedure similar to that described
above in Preparation 4A, 20.09. I0.134 moleJ of 5-1uoro-2-
methylindole were reacted with 24.1 g. (0.147 mole~ of 4-
(3-chloropropyl)morpholine in 46 ml. o dry DMF in the
pre~ence of ~.0 g. ~0.201 mole) of a 60% mineral oil dis-
persion of sodium hydride. The product was isolated in
the form of its maleate salt to give 30.0 9. ~81~) of 5-
fluoro-2-methyl-1-[3-(4-morpholinyl~propyl]-lH-indole
maleate, m.p. 165-167~C~
Preparation 4C
Following a procedure similar to that described in
Preparation 4A, 50 g. (0.43 mole~ of indole were reacted
with 159 9. (0.85 mole) of 4-(2-chloroethyl1morpholine in
850 ml. of dry DMF in the presence of 209 g. ~0.50 mole) of
a 60% mineral oil dispersion of sodium hydride. The
product was isolated in the form oF the free base to give
45.6 g. (46~) of 1~[2-~4~ pholin~1)ethyl]-lH-indole.
L . 7 :¦~bt~
Pre~aration 4D
To a ~tirred suspension of 322 9. (0.81 mole)
of a 60% mineral oil dispersion oE sodium hydride in
250 ml. of dry DMF was added dropwise a sol~tion of 100
9. (0.67 mole) of 5-Eluoro-2-methylindole in 300 ml.
of dry DMF. The mixture WAS stirred at ambient temperature
for thirty minutes and then treated dropwise with
cooling with a solution of 121.5 g. (0.67 mole~ of ethyl ~- ~
bromopropionate. Workup of the reaction mixture, after
quenching with water and extraction of the product with ethyl
acetate, afforded ~yl ~. -(5-fluoro-2-methyl-l~indolyl)-
E~ ionate.
The latter was reduced with 525 ml. of a l.M solution
of diisobutyl aluminum in llS0 ml. of toluene to give 130
g. ~94~) of 5-fluoro-2-methx~-1-51-methyl-2-hydroxyethyl)-
lH-indole.
_
The latter, on reaction with 144 9. (0.76 mole)
of p-toluenesulEonyl chloride in 350 ml. of pyridine
using the procedure described in Preparation 7A afforded
65 9. (20~) of S-fluoro-2-methyl-1-[1-methyl-2-(p-toluene-
sulonyloxx~ethyl]-lH-indole, m.p. 136-140C.
~b) Via the Amides_of Formula V
Preparation 5A
Following a procedure similar to that described in
Preparation 4 above, 32.8 g. (0.25 mole3 of 2-methylindole
in 160 ml. of dry DMF was reacted with 13.4 9. (0.~8 mole)
of a 50% mineral oil dispersion of sodium hydride in 200
ml. of dry D~F, and the resulting sodium salt was then
reacted with 62 g. ~0.28 mole) of 4~ bromopropionyl)-
morpholine in 160 ml. of DMF to give $5.3 g. (59%) of 4-[~-
~ .
5~
-36-
The latter (130 g., 0.48 mole), dissolved in 900
ml. oE THF, was added to 80 ml. 10.80 mole) of a solution of
boron methyl sulfide complex in THF under nitrogen while
cooling in an ice bath. When additi~n was complete, the
mixture was stirred for eighteen hours at room temperature,
heated under reflux for four hours, quenched by addition o~
about 1 liter of methanol, ~oiled for about fiEteen min-
utes, concentrated essentially to dryness and then diluted
with aqueous 6N hydrochloric acid. The mixture was ex-
tracted with methylene dichloride, and the raEfinate was
basified with 35% sodium hydroxide an~ extracted with ethyl
acetate. The combined organic extracts were washed with
brine, dried and concentrated to dryness to give 42.6 g.
~34~) of 2-rnethyl-1-[1-methyl-2-(4-morpholinyl)ethyl]-lH-
indole as an oil~ A portion of the latter was reacted with
methanesulfonic acid to give the monomethanesulonate as
the ~:1 hydrate, m.p. 154-157C.
PreFaration 5B
Following a procedure similar to that described
in Prepara~ion 5~ above, 29.29 9. (0.25 mole) of indole in
200 ml. of dry DMF was reacted with 13.4 g. (~.28 mole) of a
50~ mineral oil dispersion of sodium hydride in 200 ml. of
dry DMF and the resultiny sodium salt reacted with 62.0 9.
~0~28 mole) of 4-(a-bromopropionyl)morpholine in 200 ml. of
2S dry DMF and the product recrystallized from isopropanol to
give 13.7 g. (21%) oE 4-[a (lH-indol-l-~l)pr~piorlyl]-
mor~hQline, ~.p. 92-94C. The latter (20 g., 0.078 mole~
~; in 300 ml. oE diethyl ether was reduced with 3.12 g.
(0.078) mole of lithium aluminum hydride in 100 ml. of di-
ethyl ether to give 17 g. (90%) of 1-[l~met~yl-2-~4-morpho~
linyl)eth~l]-lH-indole, m.p. 35-37C.
,
~. . .
1).11, ' ' ~
Following a procedure similar to that described in
Preparation 5B, 83 gO (0.53 mole) of 2-methylindole was
reacted with 30 90 (0.7S mole) oE a 60% mlneral oil dis-
persion of sodium hydride, and the resulting sodium salt was
reacted with a molar equivalent amount of 4-(a-bromo-
butyryl)morpholine in 100 ml. of DMF. The crude product
thus obtained was reduced with 25 g. (0.66 mole3 of lithium
aluminum hydride in 500 ml. of THF. The product was
isolated in the form of the hydrochloride to give 53.4 g.
10 (27%) of 2-meth~l-1-[1-ethyl-2-(4-m_ ~holinyl?ethyl]-lH-
indole hydrochlorlde, m.p. 159-162C. (from ethyl acetate-
ether).
Pre~aration 6
To a solution of 23 g. (0.1 mole) of 1-~2-~4-morpho-
15 linyl)ethyl]-lH-indole (Preparation 4C) in 120 ml. of T~IF
was added 60 ml. of 2.1M butyl lithium in hexane while
maintaining the temperature at 0C. The mixture was
allowed to warm up to room temperature and was then treated
with 18 ml. of hexamethylphosphoramide ~ollowed by 10 ml.
20 of ethyl iodide while maintaining the temperature at 0C.
The mixture was then quenched with ice, extracted with
etherv and the combined organic extracts were washed first
with water, then with brine, dried over magnesium sulfate,
taken to dryness and chromatographed on silica gel, eluting
25 with 40:50 ethyl acetate:hexane. Four fractions were
obtained which, on evaporation to dryness, afforded 4.0 g.
of a yellow oil from the first fraction and 9.6 g., 3.6 g.
and 4.2 g. of 5Olid material in the next three fractions.
These fractions were recrystallized from hexane to
30 give B.3 g. (32~) of 2-eth~ [2-(4-morpholinyl)ethyl]-lH-
indole, m.p. 59-60.5C.
53:~
22749-319H
38- D.N. 7356B DIV V
C. The_Com~ounds of Formula V-I
Preparation 7A
To a suspension of 50 9. tO.l9 mole) of 2-methyl-3-
(4-methoxybenzoyl)indole ~Preparation lAU) in 400 ml. of
THF was added, over a one and a hal~ hour period, 74.25 ml.
(0.19 mole~ of a 2.6M solution of n-butyl lithium in
hexane. The reaction mixture was stirred for one hour at
0C., at room temperature for orty-Eive minutes, recooled
to O~C. and treated dropwise, over a thirty minute period,
with a solution of g307 ml. (0.19 mole) o~ a 2.06 M
solution of ethylene oxide in THF. The reaction mixture
was gradually allowed to warm to room temperature and then
treated with 200 ml. of a saturated ammonium chloride
solution. The solvent was removed in vacuo, the residual
solid was filtered, washed with water and extracted with
boiling ether, and the ether extracts were taken to dryness
to give 23 g. (39~) of 2-metl-yl-3-(4-methoxyben20Yl)-1~(2-
hydroxyethyl)-lH-indole, m.p. 75-78C.
A solution of 10 9. ~0.032 mole) oE the latter
and 6.48 g. (0.034 mole) of p-toluenesulfonyl chloride in
100 ml. of pyridine was stirred at room temperature for
about twelve houes and the reaction mixture diluted with
ethyl acetate and washed with water. The organic layer was
separated, dried over magnesium sulfate, filtered and con-
centrated to dryness to give a brown gum. The latter was
dissolved in methylene dichloride and the solution chroma-
;~ tographed on a short column of Florisil to give 7.8 g.
(52~) o~ 2-methyl-3-(4-methoxybenzoyl)-1-~2-p toluene-
sulfonyloxyethyl)-lH-indole, m.p. 62-65C.
* Tr~demark
D. I`J o 7 ~ A
-39-
Preparation 7B
F~llowing a procedure similar to that described
~n Preparation 7A above, 9.75 9O (0.0375 mole) of 2-methyl-
3-(4-cyanobenzoyl)indole (Preparation lT) in 125 ml. of THF
was treated with 16.65 ml. (0.04 mole~ of a 2.4M solution
of n-butyl lithium in hexane followed by 11.4 ml. of a
3.5M solution of ethylene oxide in THF to give 2-methyl-3-
~4-cy~nobenzo~yl?-1-(2-hydroxyethxlL-lH-indole Reaction
.
of 30.4 g. (0.1 mole~ of the latter with 21.0 9. (0.11
mole) o~ p-toluenesulfonyl chloride in 50 ml. of methylene
dichloride in the presence of 50 ml. of 35~ sodium
hydroxide and 0,9l g. (0.004 mole) of benzyl trimethyl-
ammonium chloride afforded 38.3 9. (84%) of 2-methyl-3-(4-
cyanobenzoyl~-1-(2-p-toluenesulfonyloxyethyl)-lH-indole,
m.p. 165-167C.
Preparation 7C
Following a procedure similar to that described
in Preparation 7A above, 20 9. (0.1 mole~ of 2-methyl-
3-t4-ethylbenzoyl~indole (Preparation lV) in 200 ml. of THF
was treated with 51 ml. (0.11 mole) of a 2.15 M solution of
n-butyl lithium in hexane followed by 6.16 9. (0013 mole)
of ethylene oxide to give 18 g. (73~) of 2-methyl-3-(4-
ethylbenzoyl)-1-(2-hydroxyethyl~-lH-indole. Reaction of
the latter (0,058 mole) with 14.32 g. (0.075 m~le) of p-
toluenesulfonyl chloride in 400 ml. of methylene dichloride
in the presence of 50 ml. of 35~ sodium hydroxide and 1.6
g. (0.0076 mole) of benzyl trimethylammonium chloride
af~orded 27 9. (95~) of 2-methyl~3-(4-ethylbenzoylj~ 2-
p-toluenesulfonyloxyethyl)-lH-lndole as a red oil.
.
.
D.N. 7_~A
-40-
Preparation_7D
A solution oE ~.0 g. (0.068 mole) of 2-methyl-
5 fluoro-3-~4-methoxybenzoyl~indole ~Prepa~ation lF~ in
100 ml of dry DMF was cooled in an ice bath at 0C and then
treated with 18.17 g. t0.09 mole) of 1,3-dibromopropane.
The solution was stirred for a few minutes at 0C, then
treated portionwise with 1.08 g. (0.027 mole) of a 60~
mineral oil dispersion of sodium hydride, stireed for about
fifteen minutes in an ice bath, then for an additional
twelve hours at ambient temperature, treated with a small
amount of water and taken to dryness in vacuo. The residue
was partitioned between water and methylene dichloride, the
organic layer was separated, washed first wi th water, then
with brine and then dried and taken to dryness. Crystal-
lization of the residue from ethanol aEEorded 4 9. ~55%) of
1~3-bromopropyl)-5-fluoro-2-methyl-3-(4-methoxybenzoyl~-
lH-indole, m.p. 133-135C.
Preparation 7E
Following a procedure simllar to that described
in Preparation 7D above, 60 9. (0.23 mole) of 2-methyl-3-
(4-methoxybenzoyl)indole (Preparation lAU) was reacted
with 244.1 g. (1.13 mole) of 1,4-dibromobutane in 200 ml
of DMF in the presence of 13.8 9. (0.34 mole) of a 60~
mineral oil dispersion of sodium hydride~ and ~he peoduct
recrystallized Erom ethyl acetate/hexane to give 5.0 gO of
~14-bromobutyl)~2-methyl-3-~4-methox~benzoyl)-lH-lndole,
m.p~ 83-86C.
22749-319E~
-41- D.N. 7356s DIV V
Preparation 7F
Following a procedure similar to that descrihed in
Preparation 7D above, 35 9. (0.122 mole) of 2-methyl-3~
naphthylcarbonyl)indole (Preparation lAM) was reacted with
12~ 9. (0.614 mole) of 1,3-dibromopropane in 700 ml of D-MF
in the presence of 7.5 9. (0.188 mole) of a 60% mineral oil
dispersion of sodium hydride, and the product purified by
chromatography on Kieselgel 60 in 50~ ethyl acetate/hexane.
There was thus obtained 1~.38 g. (37~) of 1-(3-bromo-
propyl)-2-meth~l-3-(1-naphthylcarbonyl~-lH-indole, m p
115-~16C.
Preparation 7G
Following a procedure similar to that describ~d in
Preparation 7D above, 73.86 9~ (0.3 mole) of 2-methyl-3-(4-
methoxybenzoyl)indole (Preparation lAU) was reacted with
302.33 g. (1.5 moles) of 1,3-dibromopropane in 250 ml. of
DMF in the presence of 17.97 9. ~0.45 mole) of a 60%
mineral oil dispersion o sodium hydride. There was thus
obtained 1-(3~b_omopropYl)-2-methyl-3-(4-methoxybenzoyl)-
lH indole.
Preparatlon 7H
Following a procedure similar to that described in
Preparation 7D above, 15.0 9. (0.053 mo].e) of S-fluoro 2-
methyl-3-(4-methoxybenzoyl~indole (Preparation lF) was
reacted with 9.18 9. (0.058 mole) of 1-bromo-3-chloro-
propane in 232 ml. of DMF in the presence of 3.2 9. (0.0795
mole~ of a 60~ mineral oil dispersion oE sodium hydride.
! There was thus obtained 15.3 9. (80%) of 1-3-chloro-
propyl~-5-Eluoro-2-methyl-3~(4-methoxybenzoyl)-lH-indole.
* Trademark
D.l~.7 ~,~
3 1 ~2
-42-
Pee ~ratlon 7I
Following a procedure similar to that described in
Preparation 7A above, 24.a g. (0.087 mole) of 2-methyl-3-
(l-naphthylcarbonyl)indole (Preparation lAM~ in 300 ml. oE
THF was treated with 35 ml. (0.09 mole) of a 2.6M solution
of n-butyl lithium in hexane followed by 56 ml. of a 2.6M
solution of ethylene oxide in THF to give 21.3 g. (74~) of
2-methy:L-3-(1-naphthylcarbonyl)-1-(2-nydroxyethyl)-lH-indole.
Reaction of the latter (0.065 mole) with 18.5 g. (0.097
mole) of p-toluenesulfonyl chloride in 400 ml, of methylene
dichloride in the presence of 340 ml. of 35% sodium
hydroxide and 0.6 9. (0.0026) mole of benzyl trimethyl-
ammonium chloride afforded 20.1 9. (64%) of 2-methyl-3-(1-
na~hthy~carbony~ (2-p-toluenesulfonyloxyethy~ H-indole
as a viscous oil.
Preparation 8
A solution of 42 9. (0.116 mole) of 5-fluoro-2-
methyl~ l-methyl-2-(p-toluenesulfonyloxy)ethyl~-lH-indole
(Prepar~tion 4D) and 50 ml. of morpholine in 400 ml. of DMF
was heated on a steam bath for seventy-two hours, poured
into water and the mixture extracted with ethyl acetate.
The combined ~rganic extracts were dried and taken to dry-
ness to give 20 9O of crude product which was purified by
HPLC, eluting the product with 2:1 hexane:ethyl acetate.
There was thus obtained 10.4 9~ (32~) f 3cl3~955=3Cl-~3Yl=
2 1-[l-methyl-2-~4-morpholinyllethy~ H-indole as the
S
~irst, third and fourth through the seventh Eractions.
The second fraction, on conversion to the hydro-
chloride salt and recrystallization from methanol-ether,
~ . 7
~5~3 3L~
afforded 1.0 g. of 5-fluoro-2-methyl-1-[1-methyl-2-(di-
methylaminolethyl]-lH-indole hydrochloride, m.p. 208.5-
211.5C, produced by amination of the tosylate by the DMF used
as a solvent.
It is contemplated that, by replacing the morpholine
in the above-described procedure with dimethylamine, the
dimethylamino species can be obtained as the maj~r productO
Preparation 9A
Following a procedure similar to that described in
Preparation S~ above, 2400 9. (0.071 mole) of 5-fluoro-2-
methyl-3-(4-methoxybenzoyl)indole (Preparation lF) in 200
ml. of dry DMF was reacted with 35.2 g. (0.35 mole) oE
epichlorohydrin in the presence of 3.1 g. (0.078 mole) of a
60% mineral oil dispersion of sodium hydride in 100 ml. of
DMF. The product was recrystallized from ethyl acetate-
hexane to give 10.6 9. (44%) of 5-fluoro-2-methyl-3-(4-
methoxybenzoyl)-1-[1-(2,3-epoxy)~ropyl] lH-indole as a
yellow solid.
Preparation 9B
Following a procedure similar to that described in
Preparation 9A above, 100 g. (0 377 moleJ of 2-methyl-3-(4-
methoxybenzoyl~indole ~Preparation lAU) in 1500 ml. of DMF
was reacted with 174.6 g. (1.~9 moles) of epichlorohydrin
in the presence of 19~92 g. (0~42 mole) of a 50% mineral
oil disper~ion of sodium hydride in 500 ml. of DMF. There
was thus obtained 2-methyl-3-(4-m thoxybenzoyl~-1-l1-(2,3-
epoxy)propyl]-lH ndole.
D, i`l . 7 3 5 ~A
3~
-44-
Preparation 9C
Following a procedure similar to that described in
Preparation 9A above~ 23.7 g. (0.1 mole) of 2-methyl-3-(1-
naphthylcarbonyl)indole (Preparation lAM) in 165 ml~ oE
DMSO was reacted with 27.39 9. (0.2 mole) oE epibromohydrin
in the presence of 6.6 g. (0.1 mole) oE powdered potassium
hydroxide and the product purified by chromatography on
sillca gel, eluting with ethyl acetate-hexane. There was
thus obtained 32.3 g. (95~ of 2-methyl-3-(1-naphthyl-
carbonyl)-1-[1-(2,3-epoxy)propyl~-lH-indole.
/ ~) j O r~
-4~~
Preparation ~. h~ Yi~l E~d~ct~ of Formula I
A. From the Compounds of Formula II
Example lA
Following a procedure similar to that described
5 in Preparation 4 above, 25 g. ~0.10 mole) of 3-~4-methoxy-
benzoyl)indole (Preparation lZ) in 100 ml. of DMF was
reacted with 5.76 g. (0.12 mole) of a 50~ dispersion of
sodium hydride in mineral oil in 120 ~1. of DMF, and the
resulting sodium salt was reacted with 0.14 mole of 4-(2-
chloroethyl)morpholine (freed from 26.06 9. of the corres-
pondinq hydrochloride) in 120 ml. of DMF to give 42 9. o
the crude product as an oil which, on trituration with
ethyl acetate/diethyl ether/hexane, gave a yellow crystal-
line solid which was converted to the methanesulfonate salt
to afford 9.5 9. ~20~) of 3-(4-methoxybenzoyl1-1-[2-(4-
morpholin~l~ethyl]-lH-indole methanesulfonate ~onohydrate,
m.p. 110-112C.
Following a procedure similar to that described
in Example lA above, the following species oE Eormula I
in Table 1 were prepared by reaction of a 2-R2-3-R3-carbonyl-
lH-indole of formula II with an appr~priate halo alkyl-
amine or tosyloxyalkylamineO The acid-acceptor and
reaction solvent used in the reactions are given in the
column headed "Cat.~Solv.". Here and elsewhere in the
tables, the form in which the product was isolated, either
as the free base or as an acid-addition salt, is given in
. 7350A
3;~
-46-
columns headed "Base/Salt" ! and the abbreviations
"Morph.", "Pip. " and "Pyr." in the columns headed N=B
represent the 4-morpholinyl, l-piperidinyl and l-pyrro-
lidinyl groups, respectively. In Table 1, unless noted
otherwise, an appropriate chloroalkylamine was used as the
alkylating agent. Here and elsewhere in the speci~ication
and the claims, the alkylene groups, Alk, are depicted 3S
they would appear with the l-indolyl moiety attached to the
carbon atom at the left.end of the alkylene chain and with
the amine group, N-B, attached to the carbon at the right
end of the chain.
:~2~5i3~2
--47--
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3:~ ~
-52-
B. From the Compounds of Formula III
Exam~le 2A
To a stirred, refluxing solution of 13.2 9. (0.054
mole) of 1 [1-methyl-2-(4-morpholinyl)ethyl]-lH-indole
(Prepasation 5B) in 150 ml. of ethylene dichloride was
addedr over a period of about one hour, a mixture of 17.35
g. (0.13 mole) of aluminum chloride and 10.08 9. (0.065
mole) of 4-methylbenzoyl chloride in 200 ml. of ethylene
dichloride. When addition was complete, the mixture was
heated under re~lux under a nitrogen atmosphere for three
and a half hours and then poured, with stirring, into 1
liter of ice and water containing 300 ml. of 5N sodium
hydsoxide. The mixture was transferred to a separatory
funnel, the organi~ layer was separated, and the aqueous
layer was washed with an additional 300 ml. of ethylene
dichloride. The combined organic extracts were then washed
with brine, filtered, dried over maynesium sulfate,
filtered again and evaporated to dryness to give a viscous
oil (22.55 g.) which solidified on cooling~ The latter was
recrystallized, after charcoal;ng, from isopropanol to
give 15~78 9. (81~) of 3-(4~methylbenzoyl)-1-[1-methyl-2-
~4-morpholinyl~ethyl]~lH-indole, m.p. 116.5-118~C.
::
. . ;.
D . 1 ~ j .) .\
S~
-53-
Examples 2B-2~I
Following a procedure similar to that described
in ~xample 2A above, the following species o formula I
in Table 2 below were prepared by reaction of a 2-R2-
l-aminoalkyl~1~1-indole of formula III with an appropriate
acid chloride (R3Co-Cl) in the presence of aluminum chlorideO
The solvent used to carry out the reaction, methylene
dichloride (MDC) or ethylene dichloride ~EDC), is given
in the column headed "Solv."
D . ~ 7 3 5 ~; ~
~1 1
e ~ ~ ~ 9 e
u~ B
m m ;a m m ~ m m m ~ m ~ m ~ m ~ 1~ m m m m m ~o
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r I r r r r r ~ r r r O
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D.r~. 7356A
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u U~ u' ~ ~ u~ ~ ~ ~ u= u' y y r u
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3~
-57-
CO r~L~ 3L~ a VI
-
~ E_e 3A
A solution o 10 9. (0.022 mole~ of 2-methyl-3-t4-
methoxyben~oyl)-1-[2-(p-toluenesulfonyloxy)ethyl]-lH-indole
S (Preparation 7A) and 8.74 g. (0.086 mole) of 4-hydroxy-
pipeeidine in 50 ml. of dry acetonitrile was heated under
reflux for about Eorty eight hours, and the mixture was
then diluted with ethyl acetate and washed with water. The
org~nic layer was extracted with 2N hydrochloric acid, then
with water, and the combined aqueous washings were com-
bined, basified with 10~ sodium hydroxide and extracted
with ethyl acetate. The combined organic extracts were
dried over magnesium sulfate, filtered and concentrated to
dryness ko give the product, in the form of the Eree base,
as a brown oil. The latter was converted to the hydro-
chloride salt in ethyl acetate and ethereal hydrogen
chloride to give 2.5 9O (27%) of 2-methyl-3-(4-methoxy-
benzoyl)-1-[2-(4-hydroxy-1-piperidinyl)ethyl]-lH-indole
hydrochloride hemihydrate, mOp. 226-229C.
Exameles 3B - 3AM
~ ollowing a procedure ~imilar to that described in
Example 3A above, the following species of formula I in
Table 3 below were prepared by reaction of a 2-methyl-3-R3-
carbonyl-1-~2-tosyloxyethyl)-lH-indole or a 2-methyl-3-R3-
carbonyl-l-(halo-lower-alkyl)-lH-indole of formula VI with
an appropriate amine, HN=B, where R2, in each instance, is
CH3. The starting material in each of Examples 3B-3V, 3AK
and 3AM was the corresponding 1-~2-tosyloxyethyl)-lH-
indole, in Example 3W the corresponding 1-(3-chloro-
propyl)-lH-indole; and in each of Examples 3X-3AJ and 3AL
the corresponding l-tbromo-lower-alkyl)-lH-indole.
- D.~. 7356A
--58--
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r O~ n O ~ ~ ~ o ~ ~ O
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D. Ii, 73-u~
3312
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o~ O to) ~ O O U ~ ~ O ~o~ ~ O t) ~o~ ~o~ 0~ 0 ~ 'Q ;~ C
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.~J. 1~A
-60-
D. Miscellaneous Processes
.
Example 4A
Following a procedure similar to that described in
Preparation3above,800g. (0.02mole) of2-methyl-3-(3-nitro-
benzoyl)-1-[2-(4-morphol}nyl)ethyl]-lH-indole (Example lAD)
in 175 ml. of ethyl acetate and 75 ml. of acetic acid was
reduced with hydrogen in a Parr shaker over 0.3 g. of
platin~m oxide. The product wa~ isolated in the form oE
the Eree base and recrystallized from ethyl acetate to give
6.0 g. (83%) of 2-methyl-3-(3-aminobenzo~ [2-(4~morpho-
linyl)eth~l]-lH-indole, m.p. 167-169C.
xample 4B
Following a procedure similar to that described in
Example 4A above, 28 g. (0.07 mole) of 2-methyl-3-(4-nitro-
benzoyl)-1-[2-(4-morpholinyl)et.hyl3~1H~indole (Example
lCQ) in lO0 ml. of glaclal acetic acid and 100 ml. o~ ethyl
acetate was reduced with hydrogen over platinum oxide and
the product, in the form of the free base, was recrystal-
lized from ethyl acetate to give 19.05 9. (75%) of 2-
methyl-3-(4-aminobenzoyl)-1-l2-(Q-morpholinyl)ethy~l-lH-indole,
m~p. 154-156C.
A small amount of the free base was reacted with
methanesulfonic acid and the product recrystallized from
ethanol to give the corresponding methanesulonate as
an orange powder, m.p. 221-223C.
D,N. 7 ~ol~
-61
Example 4C
To a stirred suspension of 2.5 g. tO.0059 mole)
of 2-methyl~ 9-nitrobenzoyl)-6-methoxy-1-[2~(4-morpholinyl)-
ethyll-lH-indole (Example lAN) and 2 9. (0.036 mole) of
iron filings in 25 ml. of 50% aqueous ethanol in a three-
necked flask equipped with a reflux condenser and a stirrer
was added, over a five minute period with stirring, 0.93
ml. of a solution containing 5 ml. of concentrated hydro-
chloric acid in 25 ml. of 50~ aqueous ethanol. When
addition was complete, the reaction mixture was heated
under reflux for two and a half hours, then cooled and made
basic with 15% alcoholic potassium hydroxide solution. The
mixture was filtered, the filtrate was taken to dryness ln
vacuo, and the oily product was dissolved in methylene
dichloride and the organic solution washed first with
alkali, then with water and then with brine and dried over
magnesium sulfate. Filtration of the solution and concen-
tration to dryness afforded an oil which, on trituration
with ethyl acetate/diethyl ether, crystallized to give 1.4
9. (71~) o~ 2-methyl-3-1 -aminobenzoyl)-6-methoxy-1-[2-(4-
morpholinyl)ethyl]-lH-lndole, m.p. 126~128DC.
.. '_i. 7356A
-6~-
xample 4D
Following a procedure similar to that described
in Example 4C above, 7.3 9~ (0.018 mole) of ~-methyl-
3-(4-nitrobenzoyl)-1-[l-methyl-2-t4-morpholinyl)ethyl]-lH-
indole (Example 2K), dissolved in 75 ml. of 50% ethanol,
was reduced with 6 g. (0.11 mole) of iron filings and 2.8
ml. of a solution containing 5.2 ml. of concentrated hydro-
chloric acid in 25 ml. of 50~ ethanol. The product was
isolated in the form o the free base to give 3.7 9. (54~)
of 2-methyl-3-54-aminoben2Oyl)-l-[l-methyl-2 (4-morDho-
linyl)ethyl~-lH-in~ole, m p. 192-195C
Example 5A
To a sol~tion of 4.0 g. (0.01 mole) of 2-methyl-
3-(4-aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole
(Example 4B) in 20 ml. of glacial acetic acid was added 2.3
ml. 10.023 mole) of acetic anhydride and 2 dxops of con~
centrated sulfuric acid. The mixture was warmed slightly,
then poured into water and the aqueous mixture basiEied by
addition of 10% sodium hydroxide. The gum which separated
was isolated by decantation, triturated with water to
produce a solid material which was collected and recrystal-
lized from ethyl acetate to give 2.3 g. (56%) of 2-methyl-
3-(4-acetylaminobenzoyl)~ 2 (4~ pholinyl)ethyl]-lH-
indole, m.p. 173.5-174.5C.
L-l- 7356A
~63-
Exam~les 5B-5F
Following a procedure similar to that described in
Example 5A above, the following compounds oE formula I in
Table 5 below ~ere prepared ~y acylation of an appropriate
2-methyl-3-(aminobenzoyl)-1-aminoalkyl-lH-indole. In each
instance, R2 is CH3; R4 is hydrogen; Alk is (CH2)2; and N=~
is 4~morpholinyl. All compounds were isolated and charac-
terized as the free bases. The acylating agent and the
reaction solvent are given in the column headed "AcX/Solv."
. 7 3 ~)~, '\
~4-
~ _
~ ~ ~ o o,
. ~Dr~
,~
au ~
t~ U ,, ~D ~ ~ rn ~ ~
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m ~: z
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U~
~ .
D..~ 7356A
~65-
Following a procedure similar to that described
in Preparation 3 above, 14.0 9. (0.03 mole) of 2-methyl-
3-(4-benzyloxybenzoyl)-1-12-(4-morpholinyl)ethyl~-lH-
indole (Example lAG) in 250 ml. of ethanol was reduced
with hydrogen in a Parr shaker over 1.0 g. of 5% palladium-
on-chaecoal. The product was converted to the hydro-
chloride salt whlch was recrystallized from water to give
11.1 g. (923) of 2-methyl-3-t4-hydroxybenzoyl)-1-[2-(4-
morpholinyljethyl]-lH-indole hydrochloride, m.p. 2~6-
288C.
Example 7
A mixture oE 7.5 g. (0.02 mole) of 2-methyl-3-
(4-cyanobenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole
(Example lAF), 100 ml. o~ ethanol, 15 ml. of liquid am~lonia
and 2 tablespoons of a Raney nickel in ethanol suspension
was heated in an autoclave at 50C. under an initial
hydrogen pressure of 320 p.s.i~g~ The m-ixture was then
cooled, the catalyst was removed by filtration, and the
solution was taken to dryness in vacuo to give 7.2 g. of
.product as a green foamy material which was converted to
the hydrochlo~ide salt ~o give 1.7 9. (19~) of 2-methyl-3-
(4-aminomethylbenzovl)~ 2-(4-morpholinyl)ethyl]-lH indole
dihydrochloride, m.p. 196-208C.
.. .
. .
-66-
Example 8A
A mixture of 10.4 g. (0.023 mole) of 2-methyl-3-[4-
~N-triEluoroacetylamino)benzoyl~1-[2-(4-morpholinyl)ethyl]-
l~-indole (Example 5C), 20 g. (0.20 mole) of potassium
S carbonate and 5 ml. ~]1.4 g., 0.08 mole) of methyl iodide
in 100 ml. of acetone was heated under reflux with stir-
ring for two hours and then taken to dryness to yield
a yellow ~oam, which was partitioned between water and
chloroform and extracted twice with chloroform. The
combined extracts were washed with brine, filtered and
taken to dryness to give a yellow oil which was dissol~ed
in isopropanol and treated with excess hydrogen chloride
followed by additional isopropanol. The solution was
diLuted with ether, and the solid which separated was
collected and dried to give 4.6 9. of 2-methyl-3-[4-(N-
methyl-N-triEluoroacetylamino)benzoyl~ [2-(4-morpholinyl)-
ethyl]-lH-indole hydrochloride, m.p. 224-226C.
The latter (3.7 9., 0.007 mole) was mixed with
25 ml. of 10% sodium hydroxide, and the mixture was heated
; 20 under reflux for one hour. On cooling, a solid separated
from the mixture which was collected, dissolved in isopropanol
and treated with excess hydrogen chloride and isopropanol.
The solid which separated was collected and recrystallized
from methanol/diethyl ether to give 1.2 9. (37~) of 2-
methyl-3-~4-methylaminobenzoyl~ [2-~4-morpholinyl)-
ethyl~-lH-indole_dihydrochloride hemihydrate, m.p. 190-
192C.
D., 735~A
-67-
_ a~e~
Following a procedure similar to that described
in Example 8A, 22 9. (0.049 mole) of 2-methyl-3-[4-(N-
trifluoroacetylamino)ben~oyl]-l-[2-(4-morpholinyl)ethyl]~
lH-indole (Example 5C~ was reacted with 35.9 9. (0.129
mole) of butyl iodide in 250 ml. of acetone in the pres-
ence of 48 g. (0.343 mole) of potassium carbonate and
the resulting 2-methyl-3-[4-(N-butyl-N-trifluoroacetyl-
amino)benzoyl]-l-[2-(4-morpholinyl)ethyl]-lH-indole (24
g., 98%) hydrolyzed by refluxing in a solution of 500
ml. of 10% sodium hydroxide and 100 ml. of ethanol.
The resulting crude product was chromatographed on silica
gel, elutin~ with 25% acetone-hexane. The higher Rf
material was collected and dried to give 2.6 9. of 2-
methyl-3-(4-butylaminobenzoyl~ 2-(4-morpholinyl1ethyl~-
lH-indole, m.p. 129.0-130.0C.
D. N . j6A
:~Z~ 2
6~~
Example 9
To a stirred suspension of 12.0 9. (0.03 mole)
of 2-methyl-3-(4-aminobenzoyl3-1-[2-(4-morpholinyl)ethyl]-
lH-indole (Example 4~) in 15 ml. of glacial acetic acid
and 30 ml. of water was added a solution of 4.5 g. ~0.06
mole) of sodium isocyanate in 30 ml. of water. The mix-
ture was stirred at room temperature for two hours, then
diluted with water and made alkaline with 10% sodium
hydroxide. The solid which separated was collected and
recrystallized from DMF to give 5.9 g. (48~) of 2-methyl-
3-(4-carbamylaminobenzoy~ 2-(4-m_rpholinyl~ethyl]-
lH-lndole, m.p 192-202C.
~e~
o a stirred suspension of 3.77 g. (0.01 mole)
of 2-methyl-3-(4-aminomethylbenzoyl)-1-[2-(4-morpholinyl)-
ethyl]-l~-indole (Example 7) in 30 ml. of toluene was
added a solution of dimethyl cyanoc~rbonimidodithioate
in 20 ml. of toluene. The mixture was stirred for an
hour and a half, and the solid which separated was col-
lected and dried to give 4.75 g. of the corresponding
3-(4~aminomethylbenzoyl)-N~(methyl cyanocarbonimidothioate~.
The latter (4.0 g., O.OOB mole), in 75 ml of
i~opropa~ol and 25 ml oE liquid ammonia, was heated in
an autoclave for one hour at 100C. The reaction mixture
was then filtered, allowed to evaporate to dryness, and
the resulting pale yellow foam was recrystalllzed from
acetonitrile to give 2.3 9. (65g) of 2-methyl-3-(4-cyano-
guanidinylmethylbenzoyl~ [~-(4-morpholinyl)ethyl~-lH-
indole, m.p. 191.5-195C.
D . i ~ . '- ,13
-69~
~ le 11
A mixture o 10 g. (0.027 mole) of 2-methyl-3-(4-
cyanobenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole
~Example lAF), 20 g. (0.19 mole) of sodium hypophosphite,
50 ml. oE water, 50 ml. of glacial acetic acid, 100 ml. of
pyridine and two spatulas of Raney nickel was heated to
about 40C. for two and a half hours and then filtered.
The Filtrate was taken to dryness in vacuo, and the result-
ing oil was washed with toluene and again concentrated to
10 dryness to remove residual pyridine. The residual oil was
suspended in aqueous alkali and extracted with ethyl
acetate. The combined organic extracts were washed with
brine, dried over magnesium sulEate, filtered and concen-
trated to dryness to give an oil which was recrystallized
15 from ethyl acetate to aEord 1.5 9. (15~) of 2 _ ~y~
(4-ormylbenzoyl)-1-[2-L4-mor~holinyl)ethyl]-lH-indole,
m.p. 149-150C.
Exam~le 12
~ mixture of 2.5 g. (0.0~6 mole) of 2-methyl-3-
~4-formylbenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole
(Example 11), 0.55 g. (~.0067 mole) of sodium acetate and
O.Sl 9. (0.0073 mole~ of hydroxylamine hydrochlori~e in 24
ml. of ethanol, 5 ml. of methanol and 6 ml. of water was
heated under reflux for one hour and then concentrated to
dryness in vacuo. The residual solid was collected, washed
with water and diethyl e~her t~ give 2.5 9. (95%) of 2-
methyl-3-(~-hydroxyi~ __thylben~o~~-1-[2-(4-morpholinyl)-
ethyl~ indole, m,p. 184-186C.
:~2~
-70-
A mixture oE 20 g. (0.053 mole) of 2-methyl-3-
(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole
~Example lB) and 20 g. (0.29 mole) of hydroxylamine hydro-
chloride in 100 ml. of pyridine was heated under reflux for
about twelve hours and then diluted with methylene
dichloride. The organic mixture was washed five times with
water, then with brine, dxied over magnesium sulfate, fil~
tered and taken to dryness in vacuo to give a dark green
oil which was washed three times with toluene and again
concentrated to dryness in vacuo. Trituration of the
residue with ethyl ~cetate/diethyl ether afforded crystals
which were collected to giYe 9.5 g. (46%~ of 2-methyl-3-(4-
oxime, m.p. 166-169C.
_xam~ple 13B
Following a procedure sim-lar to that described in
Example 13A above, 44 9~ (0.101 mole~ of 5-fluoro~3-(2-
fluorobenzoyl)-2-methyl-1-13-(4-morpholinyl~propyl]-lH-indole
(Example 2BB) was reacted with 70.3 9. (1.01 moles) of
hydroxylamine hydrochloride in 500 ml of pyridine and the
product recrystallized from acetonit~ile to give 15.5 9.
(37%) of 5-fluoro-3-(2--Eluorobenzoyll-2-methyl-1~[3-(4-
morpholinyl)propyl3-lH-indole oxime, m.p. 150-162C.
D. N . ~ 6A
~2~
-71-
Exa~
.
Following a procedure similar to that described in
Example 13A above, in two runs a total of 28.3 g. (0.77
mole) of 3~(2-fluorobenzoyl)-2-methyl-1-[2-(4-morpholinyl)-
ethyl]-lH-indole (Bxample lZ) was reacted with a total of
53.7 g. (0.77 mole~ of hydroxylamine hydrochloride in a
total of 575 ml~ of pyridine to give a total of 24.4 g. of
crude product. The latter was dissolved in a solution of
54.1 g. of sodium methoxide in S00 ml. of methanol, and
the solution was heated under reflux for forty-eight hours
and then taken to dryness in vacuo. The residue was par-
titioned between chloroform and water, and the chloroform-
soluble material was flash chromatographed on silica gel
eluting with 98:2 chloroform:isopropanol. The slower mov-
ing material was isolated and recrystallized from toluene-
hexane to give ~.0 g. (33~) of ~~L~3-(2-Eluorobenzoyl)-2-
methyl-1-[2-(4-morpholinyl)ethyl?-lH-indole oxime, m.p.
160-167~C.
Example 14
A mixture of 8 g. (0.022 mole) of 2-methyl-3-(4-
aminoben~oyl)-1-[2-~4-morpholinyl)ethyl]-lH-indole
(Example 4~) and 4.28 ml. ~0.0~3 mole3 of 2,5-dimethoxy-
tetrahydrofuran in 40 ml. o~ glacial acetic acid was heated
under reflux for one hour and then poured into an iceJwater
mixture. The mixture was rendered alkaline by addition of
10% sodium bicarbonate solution, and the solid which
separated was collected and dissolved in methylene
dichloride, The organic solution was dried over magnesiu~
5~3~2
-72-
sulfate, filtered and the filtrate concentrated to dryness
ln vacuo and then chromatographed through a pad of
Florisil, eluting with methylene dichloride. There was
thus obtained 4.5 9~ o~ an oil which, on trituration with
S diethyl ether, afforded a light yellow powder which was
collected to give 3.5 g. ~38%) oE 2-methyl-3-[4~~1H-yy~rol-
l~yl)benzoyl3~ 2-(4-morpholinyl~ethyl]-1~-indole, m.p.
125-127C.
Example 15
To each of three 14 liter fermentors containing 10
liters of soybean meal/dextrose medium (containing 5 g./
liter of soybean meal, 5 g./liter of brewer's yeast, 5 9./
liter of dipo~assium hydrogen phosphate and ~0 g./liter of
dextrose) at pH 6.4, was added 2.0 g. ~0.016 mole total) of
2-methyl-3-(4-methoxybenzoyl)-1-[2-(4-morpholinyl)ethyl]-1H-
indole (Example lB), and the mixtures were cultured for
five days in the presence of FusarLum solani (Mart.) with
stirring at 400 rpm at a temperature of 26-27~C~ while
sparging with air at 5 liters per minute. The mixtures
were then separately extracted with 20 liters o methylene
dichloride using 20 liters per fermentor, and the combined
extracts were concentrated to 20 liters~ The concentrate
was washed first with 2 llters of 0.05N sodium hydroxide,
then two times with 2 liters of water, and the organic
layer was concentrated to about 1 liter, dried over sodium
sulfate, charcoaled, Eiltered and further evaporated to
dryness to give an oily residue which solidiEied on cool-
ing. The latter was recrystallized from acetone/diethyl
ether to give 2.7 g. (43%) of 2-methyl-3-(4-methoxy-
benzoyl~ 2-l4-morpholinyl)ethyl]-lH-indole/N(MoR)-oxide
m.p. 142-144C.
... ~
D. N .
-73-
Example 16A
A mixture o 38.3 g. (0.10 mole) of 2-methyl-3-
(2-methoxybenzoyl) 1-[2-~4-morpholinyl)ethyl] lH-indole
(Example lU) and 35 2 9. (0.31 mole) of pyridine hydro-
chloride was heated in an oil bath at 210~C. for four hours
and the mixture allowed to cool. The solidified reaction
mixtùre was partitioned between ethyl acetate and aqueo~s
sodium carbonate by warming on a steam bath, and the
organic layer was separated, taken to dryness and subjected
to high performance liquid chromatography on a silica gel
column in 1:1 hexane:ethyl acetate. The first 7 liters of
eluate were discarded, and the next 8 liters were col-
lected, taken to dryness and the residue recrystallized
from isopropanol to give 8.33 9. ~23%~ of 2-methyl-3-~2-
hydroxybenzoyl)-1-[2-(4-m~ holinyl)eth~l]-lH-indole, m.p.
. 115-116C.
Following a procedure similar to that described in
Example 16A, 15.8 g. ~0.035 mole) of 5-fluoro-2-methyl-3-
(4-methoxybenzoyl)-1-[3-(4-morpholinyl)propyl]-lH-indole
hydrochloride (Example lI) was heated with 20.4 g. (0.176
mole~ of pyridine hydrochloride at 210C. in an oil bath
~or two hours, and the product isolated as the hydro-
chloride salt to give 9.2 g. (67%) of 5-fluoro-2-methyl-3-
(4-hydroxybenzoyl)-1-[3-(4-morpholinyl)eropyl~-lH-indole
h~rochloride, m.p. 290-292~C. (from DMF-ether).
, ~
.
D.. 7356A
:~2~
-74-
~ 17
A mixture of 1.9 g. (0.005 mole) of 2-methyl-3-
~4-aminomethylbenzoyl)-1-[2-(4~morpholinyl)ethyl]-lH-
indole ~Example 7), 0.7 9. (0.0025 mole) of 2-methyl-2-
thiopseudourea sulfate and 10 ml oE water was heated on asteam bath for two hours and then filtered. The Eiltrate
was taken to dryness, and the residue was recrystallized
from methanol to give 1.0 g. (85~) of 2-methyl-3-t4-
guanidinylmethylbenzoyl)-1-[2-(4-morpholinyl)ethyl~-lH-indole
sulfate (2:1), m.p. 170-180~C
-
Example 18
Following a procedure similar to that described
in Preparation 3 above, a solution of 0.9 g. (0~0019 mole)
of 6-benzyloxy-2-methyl-3-(4-methoxybenzoyl)-1-l2-(4-morpho-
linyl~ethyl~-lH-indole (Example lBK) in 200 ml. of methanol
was reduced with hydrogen over three spatulas (app~oxi-
mately 1.5 9.) of 10% palladium-on-charcoal under a
hydrogen pressure of 50 p.s.i.g. at ambient temperature in
a Parr shaker. The product was isolated in the form of the
hydrochloride which was recrystallized from ethyl acetate-
; diethyl ether to give 0.35 9. of 6-hydroxy-2-methyl-3-~4-
methoxybenzoyl)-1-[2-(4-morpholinyl~ ethyl~-lH-indole hydro-
chloride hydrate (3:4) t m.p. 185-187C.
D.l 73S6~
3~
-75-
Example_l9
To 70 ml of dry DMF was added, dropwise with stir-
rin~, 15 ml. of phosphorus oxychloride while cooling in an
ice bath. The mixture was then treated with a solution of
24.4 9~ ~0.10 mole) of 2-methyl-1-[2-(4-morpholinyl)-
ethyl~-lH-indole (Preparation 4A) in 50 ml. of DMF while
continuing to cool in an ice bath. When addition was com-
plete, the mixture was stirred for about one hour and then
poured into 50 9. of ice to give a clear solution which was
chilled to about 20C. and basified by the addition of 150
ml. of 35% potassium hydroxide. The mixture was warmed to
about 70, then chilled in an ice bath, and the solid which
separated was collected, dried and recrystallized from
ethyl acetate to give 23.3 9. ~86%) of 3-formyl-2-methyl-1-
12-(4-moryholinYl) ethyl]-l~-indole, m.p. 115-116C.
A solution conta~ning 13~6 g. (0O05 mole) of the
latter and 9.0 g. (0~06 mole) of 4-methoxyacetophenone in
S0 ml. of absolute ethanol was treated with 500 ml. of
3.7N ethanolic hydrogen chloride in a thin stream, while
stirring, and the resulting red solution was stirred for
twenty-four hours. The solid which separated was collected
by filtration, wa~hed with absolute ethanol and then
recrystallized first from methanol and then from 50~
ethanol to give 5.3 9. (24%) of 1-~2-methyl-1-[2-(4-morpho-
lin l~eth 1]-lH-indol-3- 1~-3-(4-methox heny1)propen-3-one
Y, Y - Y ! YP
monoh~drochloride, m.p. 259-2S2C.
V. 7356A
3~ ~
-76-
Example_20A
Following a procedure similar to that described
inExamplel9 above, 3-acetyl-2-methyl-1-~2-(4-m_ pholinyl)-
ethyl]-lH-indole was prepared by reaction of 12 9. (0.05
mole) of 2-methyl-1-l2-~4-morpholinyl)ethyl]-lH-indole
~Preparation 4A) with 10 ml. (0.11 mole~ of phosphorus
oxychloride in 25 ml. of dimethylacetamide. The product
was dissolved in isopropanol and the solution treated with
ethereal hydrogen chloride to give 6 g. (373) of the
product as the hydrochloride salt, m.p. 249-253 C.
To a solution of 6 9. (0.107 mole) of potassium
hydroxide pellets in 350 ml. of absolute ethanol was added
15 9. (0.047 mole) of the latter and 19 g. tO.14 mole) of 2-
methylbenzaldehyde. The mixture was heated under reflux
for one and a half hours, concentrated to dryness and the
product, in the orm of the free base~ recrystallized oncerom ethyl acetate and once from isopropanol to give 7.9 g.
(41~) of 3~(2-methylcinnamoyl)-2-methyl-1-[2-(4-morpho-
linylJethyl~-lH-indole, m.p. 131-135C.
Example 20B
Following a procedure similar to that described in
Example 20A above, 14.75 g. (Q.0516 mole) of 3-acetyl-2-
methyl-1-[2-(4-morpholinyl)ethyl]-lH-indole (Example 20A)
was reacted with 2-fluorobenzaldehyde in 260 ml. o ethanol
in the presence of 3.44 g. (Q.061 mole) of potassium
hydroxide pellets and the product, in the form of the free
base, recrystallized from ethyl acetate to give 10.0 g.
l~4%) of 3-(2-fluorocinnamoyl)-2-methyl-1-~2-14-morpho-
liny~ethyl]-lH-indole, m.p. 113-116C.
~ e~_21
A solution of 11 g. (0.025 mole~ of 1-l2-(3-hydroxy-
l-piperidinyl)ethyl)-2-methyl-3-l4-methoxybenzoyl)-]H-indole
(Example 3B) in 50 ml. of pyridine and 25 ml. of acetic
anhydride was allowed to stand at ambient temperature for
about forty-eight hours and the mixture then poured into
ice water. The oily solid which separated was collected,
dissolved in ethyl acetate and the solution washed first
with dilute sodium hydroxide, then with brine, dried and
taken to dryness. The residue was dissolved in ethyl
acetate, the solution treated with 3.67 g. of maleic acid,
the mixture heated to boiling to dissolve all solid, then
cooled, and the solid which separated was collected and
recrystallized once again from ethyl acetate to give 8.12
9O ~59%) of 1_[2_(3_acetoxy-1-piperidinyl)ethx~]-2-methyl-
3-(4-methoxybenzoyl)-lH-indole maleate (1:1), m.p. I61-
:. '
161.5C.
Example 2Z
To a stirred solution of 12.5 g~ (0.03 mole) of 2-
methyl-3-(4-methoxybenzoyl)-1-[2-tl-piperazinyl)ethyl]-lH-
indole (Example lL)in 150 ml. of pyridine was added, with
stirring while cooling in an ice bath, 7.1 g. ~0.066 mole3
of ethyl chloroformate. When addition was complete, the
solution was stirred in an ice bath for thirty minutes,
then allowed to stand at ambient temperature for about
eighteen hours and then poured into ice water. Extraction
of the mixture with ethyl acetate afforded the crude
product in the form of the free base which was dissolved in
ethyl acetate and converted to the maleate salt by addition
of 2.6 g. of maleic acid. The latter was recrystallized
from ethyl acetate-ether to give 7.6 g. (41%) of 1-12-(4-
D. N . 356A
--78--
carbethoxy-l-piperaz_nyl)eth~1]-2-methyl-3-t4-methox~-
benz~yl)-lH-indole_maleate (1:1), m.p. 155-156C.
Exam~le 23A
A ~olution of 12.5 9. (0.033 mole) of 2-methyl-3-(4-
methoxyben~oyl)-1-[2-(1 piperazinyl)ethyl~ indole
(Example lL) in 150 ml, oE pyridine was cooled in an ice
bath and treated with 50 ml. of acetic anhydride and the
solution allowed to stand at ambient temperature for about
eighteen hours. The solution was then poured into ice
water and the mixture extracted with ethyl acetate. The
organic solution, Oll washing with brine, drying over sodium
sulfate and evaporation to dryness, afforded the crude
product which was taken into ethyl acetate and the solution
treated with 4.2 g. of maleic acid. The solid which
separated was collected and recrystallized from ethanol to
give 7.36 g. (42~1 of 1-[2~(4~acetyl-l-pi~eraziny~)-
ethyl]-2-methyl-3-_~4-methoxy~enzoyl)-1~-indole maleate
(1:1), m.p. 147.5-152C.
Example 23B
Following a procedure similar to that described
above in Example 23A, 11.9 g. (0.029 mole~ of 5-fluoro-2
methyl-3-(4-methoxybenzoyl~-1-[3-(1-piperazinyl)propyl]-
l~-indole (Example lBN) was reacted with 50 ml. of acetic
anhydride in 150 ml. of pyridine and the product isolated
in the form o the methanesulfonate salt to give 6.6 g.
141~) of 5-1uoro-2-methyl-3-~4 methoxybenzoyl)-l-[3-~4
acety~l-l-~iperaz ~ propyl]-lH-indole_ methanesulfonate,
m.p. 170 171C.
~r~ D.~735~A
-79-
Example 24
A solution of 15 9. t0.04 mole) of 2-methyl-3-(4-
aminobenzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole
(Example 4s)~ 12 9. (0.4 mole) oE formaldehyde and 7.5 g.
I0.119 mole) cf sodium cyanoborohydride in 250 ml. o
acetonitrile was stirred for thirty minutes and then
treated dropwise with acetic acid until acidic. The mix-
ture was stirred for about eighteen hours, then poured into
aqueous potassium hydroxide and the ~ixture extracted with
ether. The organic extracts, on drying over magnesium sul-
fate and concentration to dryness, afforded a yellow solid
which was recrystallized from isopropanol to give 7.5 9.
~48~3 of 3-(4-dimethylamlnobenzoyl)-2-methyl-1-[2-(4-
morpholinyl~ethyll-lH-indole, m.p. 152-154C.
Example 25A
A solution of 19.1 g. ~0.047 mole) of 1-(3-bromo-
propyl)-5-fluoro-2-methyl-3-(4-methoxybenzoyl)-lH-indole
(Preparation 7D) in 500 ml. o acetone and 50 ml. of water
was treated with 3.05 9. (0.047 mole) of sodium azide and
the mixture heated under reflux for about eigh~een hours
and then taken to dryness in vacuo. The residue was
part~tioned between ethyl acetate and water, and the
organic layer separated, washed with brine, taken to dry-
ness and the residue recrystallized from isopropanol to
give 10.3 9. (60%) oE 1-(3-azidopropyl~-5-fluoro-2-methyl-
3-(4-methoxybenzoylL=~indole, m.p. 69-73.
D. '.; 735~A
~25S;~
--80--
The latter (0.028 mole) was dissolved in 265 ml. of
etha~ol and 35 ml. of T~F and reduced witIl hydrogen over
1.0 g. of 10% palladium-on-charcoal in a PaLr shaker. When
reduction was complete, in about four hours, the mixture
was filtered, the filt~ate taken to dryness and the residue
dissolved in ethyl acetate and treated with 3.13 9. oE
maleic acid and heated to dissolve all the material. The
solid which separated was collected and recrystallized from
isopropanol to give 9.7 g. (76~) of 1-(3-amino~ropyl~-5-
fluoro-2-methyl-3-~4-methox~benzoyl)-lH-indole maleate (1:1),
m.p. 169-171C.
Example 25B
Following a procedure similar to that described in
Example 25A above, 13.98 g. I~OO3 mole) of 2-methyl-3-~4-
methoxybenzoyl)-1-(2-tosyloxyethyl)-lH-indole (Preparation
7A~ in 325 ml. oE acetone and 32.5 ml. of water was reacted
with 1.96 9. (0.03 mole) of sodium azide and the product
recrystallized from isopropanol to give 6.1 9. t61%) of 1-
m.p. 91-93C.
The latter (0.024 mole), dissolved in 250 ml. of
ethanol and 50 ml. of T~IF, was reduced with hydrogen over
0.8 g. of 10% palladium~on-charcoal at 47 p,s.i.g. and the
product i~olated in the form oE the maleate salt to give
7 6 g (753) of ]-(2-aminoethyl)-2-me~yl-3-(4-methoxy-
-
benzuyl)-lH-indole maleate, m.p. 165-166C.
Example 26A
A mixture of 10 9. (0.027 mole) of 3-(4-Eluoro-
benzoyl)-2-methyl-1-[2-(4-morpholinyl)ethyl]-lH-indole,
~ 7
-81-
~Example lQ) 2.5 g. (0.033 mole) oE 2-methoxyethylamine
and 7.6 g. ~Q.054 mole) of potassium carbonate in 15 ml.
of DMSO was heated at 95C under nitrogen and the mixture
then poured into ice water. The solid which separated was
collected, dissolved in methylene dichloride and the
solution washed with brine, dried over magnesium sulfate,
filtered and taken to dryness in vac~o. Recrystallization
of the residue from ethyl acetate-ether afforded 4.2 g.
(37~ of 2-methyl-3-[4- (2-methoxyethylamino3 benzoyl]-l- [2-
(4-morpholinyl)e ~ , m.p. 121-123C.
Examples 26B-26I
Following a procedure similar to that described in
Example 26A above, reaction of a 3-(4-halobenzoyl)-2-
methyl-1-~2-(4-morpho1inyl)ethyl]-lH-indole with an
. appropriate amine in the presence of potassium carbonate
afforded the species of formula I in Table 26 where, in
each instance, R2 is CH3; and N-B is 4-morpholinyl. The
species of Examples 26B-26D, 26G and 26H were obtained from
the corresponding 4-fluorobenzoyl starting material, and
the species of Examples 26E, 26F and 26I were obtained from
the corresponding bromobenzoyl (or bromonaphthyl) starting
materials.
D._~: 7356A
- 8 ~ -
Y
~ r` ~ u~ ~ o
O o ,~
~ ~ 1`1
m ~ rl ~ m m ~ m
,~ I O o
u, a a c~ ~ o ~ ~ o ~,
~ ~ ~ ~ ~ ~ . ~ ~
~ ~ ts ec ~ c
. ~ ~ o C~ C~ U U ~ y, y
E~
,~ N N ~, ~ ~ tJ
';~ o
~
,1, ~, ~,. ~ ~ U-
~ 1
~ m u Q ,~
.
:~lZ5~3
-83-
A mixture oE ~.2 g. (O.G2 mole) of 1-[2-t4-formyl-1-
pipera~inyl)ethyl]-2-methyl-3-(4-methoxybenzoyl)-lH-indole
(Example 3S) and 2.06 g. (0.05~ mole~ o sodium hyd~oxide
in 100 ml. o~ ethanol and 80 ml, of water was heated under
reflux f8r four hours, then poured into ice water and
extracted with ethyl acetate. The organic solution was
washed with brine, dried over sodium sulfate, taken to dry-
ness and the residue dissolved in ethyl acetate. The
solution was treated with an excess of a lN solution of
methanesulfonic acid, and the solid which separated was
collected and recrystallized frcm ethanol to give 9.0 9.
(79~) of 2-methyl-3-(4-methoxybenzoyl)-l- E2-~æipera-
zinyl)ethyl]-lH-indole dimethanesulfonate, m.pO 240C.
Examples 27B-27D
Following a procedure similar to th~t described in
Example 26A above, the ~ollowing specie~ of formula I were
similarly prepared:
Example 27B - 1-[2-l2-hydroxyethylamino)ethyl]-2-methyl-3-
(4-methoxybenzoyl)-lH-indole, m.p. 99-lOO.SC. l14.29.,
50~), prepared by saponification of 30.8 g. (O.U8 mole) of
1-[2-~N-formyl-2-hydroxyethylamino)ethyl]-2-methyl-3-(4-
methoxybenzoyl)-lH-indole (Example 3AK) ~ith 9.7 9. (0.243
mole) of sodlum hydroxide in 160 ml. of water and 200 ml.
of ethanol;
Example 27 - 1-[2-(3-amino-1-piperidinyl~ethyl]-2-methyl-
3-~4-methoxybenzoyl)-lH-indole maleate ~1:2), ~.p. 142.5-
144C, (1.5 9., 49~), prepared by saponificati~n of 1.6 9.
(0.0026 mole~ oE 1-[2-(3-acetylamino~l-piperidinyl)ethyl]-
~51:j3~
-8~-
2-methyl-3-(4-methoxybenæoyl)-lil-indole ~Example 3N) with
1.6 g. (0.04 mole) of sodium hydroxide in 2 ml. of water
and 6 ml. of ethylene glycol; and
Example 27D - 5-fluo~o-2-methyl-3-(4-methoxybenzoyl)-1-[3-
(l-piperaæinyl)pro~yl]-lH-indole dimethanesulfonate, m.p.
114-115UC (8~7 g., 27%), prepared by saponification of 23 9.
~0.053 mole) of 5-fluoro-1-13-(4-formyl-1-piperazinyl)-
propyll-2-methyl-3-(4-methoxybenzoyl)-lH-indole (Example
3AL) with 5.6 g. (0.014 mole) of sodium hydroxide in 265
ml. of ethanol and 210 ml. of water.
Example 23
~o a solution containing 16.9 9. (0.044 mole~ of 1-
(3-bromopropyl)-2-methyl-3-~4-methoxybenzoyl)-lH-indole
(Preparation 7G) in 200 ml. of DMF was added 5 g. (0.088
mole) o~ azetidine. The mixture was stirred or about 24
hours at ambient temperature, thea diluted with water and
extracted with ethyl acetate. The organic extracts were
washed with water, then with brine, dried over magnesium
sulfate, filtered and taken to dryness. The residue was
taken into ethyl acetate, the solution diluted with
ethereal hydrogen chloride, and the solid which separated
was collected and recrystallized repeatedly from isopro-
panol to give 2.0 9. (10%~ of 1-[3-(3-chloroPro~ylamino)-
p~opYl~-2-methyl-3-~4-methoxybenzoyl ~lH-indole hydro-
chloride, m.p. 140-142C.
Example 29A
To a solution of 15.0 g. 10.032 mole) of 5-fluoro-2-
methyl-3-(4-methoxybenzoyl)-1-[3-(4-thiomorpholinyl)propyl]-
lH-indole hydrochloride (Example 3AF) in 195 ml~ of glacial
/35
-as-
acetic acid was added 8.12 g. (0.038 mole) of an 80~
solution of m-chloroperbenzoic acid, and the solution was
stirred at ambient temperature fo~ ~bout forty-eight hours
and then poured into 300 ml. of ice water. The mixture was
treated with l 9. of sodium bisulphite, basiEied with 35~
sodium hydroxide and then extracted with chloroform. The
oeganic extracts, on washing with water, then with brine,
drying over sodium sulfate and evaporation to dryness
afforded 1.9 9. of the product as the free base which was
converted to the maleate salt by solution of the base in
ethyl acetate and addition of one equivalent of maleic
acid. The salt was recrystallized from ethanol to give
12.85 9. (72%) of 5-fluoro-2-meth~l-3-t4-methoxybenzoyl)-
l-[3-(4-thiomorpholinyl)propyl]-lH-indole S-oxide maleate,
m.p. l60-l6lC.
Examples_29~ and 29C
Following a procedure similar to that described
in Example 29A abovef the following species of formula
I were similarly prepared:
~xample 29B - 2-methyl-3-(4-methoxybenzoyl)~l-[2-~4-thio-
morpholinyl)ethyl]-lH-indole S-oxide maleate, m.p. 179-
180C. (7.2 g., 82%), prepared by oxidatio~ of llp g. (0.028
mole) of 2-methyl-3-~4-methoxybenzoyl)-l-12-~4-thiomorpho-
linyl)ethyll-lH_indole ~Example 3U) with 6.7 g. ~0.03 mole)
of m-chloroperben~oic acid in llO ml. of glacial acetic
acid; and
Example 29C - 2-methyl-3-(4-methoxybenzoyl)-1-[2-~4-thio-
morpholinyl)ethyl]-lH-indole S,N-dioxid~ dihydrate, m.p.
l43-l45C. ~3.9 9., 27%), prepared by oxidation of 12.0 9.
.
~5~
(0.030 mole) of 2-methyl-3-(4-methoxybenzoyl)~ 2-(4-
thiomorpholinyl)ethylJ-lH-~ndole (Example 3U) with 6.6 g.
~0.030 mole) of m-chloroperbenzoic acid in 120 ml. of
chloroform.
A solution of 28.7 9. (0.177 mole) of benzoyl-
acetone and 23.2 ml. (0.177 mole) of 2-(4-morpholinyl)-
ethylamine in 600 ml. of toluene was heated under reflux
Eor ten and a half hours under a Dean-Stark trap and the
solution then cooled and taken to dryness to give N-[2-(4-
morpholinyl)ethyl]-M-~l-methyl-3-oxo-3-phenylpropenyl)amine
as a yellow solid.
The latter (11.3 g., 0.41 mole~ and 8.9 9. t0.082
mole) of benzoquinone in 40 ml. of nitromethane was stirred
under nitrogen for forty-eight hours at room temperature
and the mixture then filtered through silica gel and the
filtrate adsorbed onto silica gel and flash chromatographed
using S~ acetone in ethyl acetate. The product was taken
off in the early and middle fractions which were taken to
dryness. The product was recrystallized first from ethyl
acetate and then rom methanol to give 1.0 9. (7~) of 3-
benzoyl-S-hydroxy-2-methyl-1-[2-~9-morpholinyl)ethyll-lH~
indole t m. p. 215-217C.
Example 31~
A solution of 13.4 9. (0.0395 mole) of 5-fluoro-2-
methyl-3-(4-methoxybenzoyl)-1-[1-(2,3-epoxy)propyl]-lH-indole
~Preparation 9A) and 4.79 g. (0.055 mole) oE morpholine in
60 ml. of chloroform was heated under reElux for about
forty-eight hours and then taken to dryness in vacuo. The
crude product was dissolved in methylene dichloride, and
;3~
-87-
the solution was ~reated with an excess of ethereal
hydrogen chloride and then diluted with ether. The solid
which separated was collected and recrystallized from
methanol-ether to give 13.3 g. (61%) of
morphollnyl~er-E~l]-5-fluoro- -meth~l 3-(4-methoxybenzoyl)
lH-indole hydrochloride hydrate, (lHCl.l 1/4H20), m.p.
143-145C.
Examples 31B-31-0
Following a procedure similar to that described in
Example 31A above, reaction of a 1-11-(2,3-epoxy)propyl]-
3-R3-carbonyl-lH-indole with an amine, HN=B, afforded the
following compounds of formula Ib listed ln Table 31,
where R2 in each instance is CH3.
.. .. ..
L . 7~ A
-~18~
r ~ ~ r cn m ,~
~ ~ ~
, O ~ g .~ ~ ~ U
~3 ~ U
,, 8 ,, 53
R. ~ ~ ~ b ~ b
~ ~ '' T '' T ~
o CO ~ ~ ~ ,,
U m a~ ~ m ~ ~
~ 9~ 0 ~
~1 ~ , h 1~ S4 h I ~
r m m ~ E5 8
E~ u~~ u n ~ a u u u ~ a n Q .~ ;~
r~ $
~_, ~ z ~ ,, ~ ,, ,1 ~ z z SZ Z 3: Ei
~ u u v ~ u ~. ~) o u u tJ v u ", $ ~
O O O O O O O O O O O O O ,~ ,a
~ C~ ~ y U f: y 5~ Y ''
6 ~ U a Ci~ 1~ V ~ æ z 5
~2~3~
--8g--
~e~
Following a procedure similar to that described
above in Example 25A, 60 g. (0.165 mole~ oE 1-(3-azido-2-
hydroxy-l~propyl)-2-methyl-3-(4-methoxybenzoyl)-lH-indole
tExamPle 31J) in 500 ml. of ethanol was reduced with
hydrogen over 35 g. of palladium-on-barium sulfate
catalyst. The product was isolated in the form oF the free
base and recrystallized from ethyl acetate to give 10.2 g.
~18~) of 1-(3-amino-2-hydroxy-l-propyl)-2-methvl-3-~4
methoxybenzoyl~-lH-indole, m.p. 152-153~C.
~xample 33
The hydrobromide salt of 2-methyl-3-(4-methoxy-
benzoyl)-1-[2-(4-morpholinyl)ethyl]-lH-indole (Example lB)
(10.0 9., 0.026 mole) ~as prepared by passing hydrogen
bcomide gas into a solution of the former in 2~0 ml. of
MDC. The hydrobromide was isolated, redissolved in 300 ml.
of MDC and the solution treated with 6.94 g. (0.039 mole)
of N-bromosuccinimide. The solution was heated under
reflux and irradiated with light for twenty minutes, and
the solid which had separated was taken into chloroform-
ethyl acetate and the solution extracted with aqueous
potassium carbonate, dried over magnesium sulfate and taken
to dryness. The residue was chromatographed on silica gel,
the product being eluted with 25% acetone in toluene, which
was isolated and recrystallized from toluene to give 3.7 9.
(31~) of S-bromo-2-methyl-3-(4-methylbenzo~1)-1-~2-(4-
orpholinyl)ethyl~-lH-indole, m.p. 134.5-136C.
D _. 73SG~
5S3~
--so--
Examples 34A--34H
Following a procedure si~.ilar to that described
in Example 2A above, it is contemplated that other species
of formula I as follows can be prepared by reaction oE a 2-
R2-1-[2-(4-morpholinyl)ethyl~-lH-indole with an ap-
propr;.ate aroyl chloride (R3COCl) in the presence of al~mi-
num chloride in methylene dichloride:
Example 34A - 2-methyl-1-[2-t4-morpholinyl)ethyl]-3-~2-
quinolinecarbonylL-lH-indole, by reaction of 2-methyl-
1-12-(4-morpholinyl)ethyl]-lH~indole with 2-quinoline
carboxylic acid chloride;
Example 34B - 2-methyl-1-[2-~4-morpholinyl)ethyl]-3-(3-
quinolinecarbonyl~-lH~indole, by reaction of 2-methyl-1-12-
(4-morpholinyl)ethyl]-lH-indole with 3-quinoline carboxylic
lS acid chloride;
Exame~e 34C - 2-methyl-1-[2-(4-morpholinyl)ethyll-3-~4-
quinolinecarbonYl)-l~-indole, by re~ction of 2-methyl-1-
~ 12-~4-morpholinyl)ethyll-1~-indole with 4-quinoline carboxylic
: acid chloride,
Example_ 34D - 2-meth.yl-1-12-~4-morpholinyl~ethyll-3-(5
quinolinecarbonyl)-lll-indole, by reaction of 2-methyl-
1-12-(4-morpholinyl)ethyl]-1~-indole with 5-q~inoline car-
boxylic acid chloride;
xample 34E - 2-methyl-1-[2-(4-morPholinyl)ethyl]-3-(6-
q~inolinecarbonyl)-lH-indole, by reaction of 2-methyl-
1-12-~4-morpholinyl~ethyl]-lH-indole with 6-quinoline
carboxylic acid chloride:
.
D._~ 7356A
~Z~ 2
2-methyl-1-[2-(4-morpholinyl)ethyl]-3-(7-
quinolinecarbonyl)-lH-indole, prepared by reaction of
2-methyl-1-[2-(4 morpholinyl)ethyl]-lH-indole with 7-
quinoline carboxylic acid chloride;
~ y~ - 2-methyl-1-[2-(4
quinolinecarbonyl)-lH-indole~ by reaction of 2-methyl-1-
[2-(4-morpholinyl)ethyl]-lH indole with 8-quinoline car-
boxylic acid chloride; and
Exam~le 34H - 2-benzyl-1-[2-~4-morpholinyl~ethyl]-3-~4-
methoxybenzoyl)-lH-indole, by reaction of 2-benzyl-1-[2-
(4-morpholinyl)ethyl]-lH-indole with 4-methoxybenzoyl
chloride.
_ D.~ 7356A
lL~5~3~ ~
-92-
BIOLOGICAL TEST RESULTS
The 3-R3-carbonyl-1-aminoalkyl-1ll-indoles of
formulas I, Ia and Ib of the invention were tested in the
a~etylcholine-induced abdo~inal constriction test ~Ach),
the anti-bradykinin test (~RDK) and the rat paw flexion
test (P,F.~, all ln vivo tests, and were found to have
analgesic activity. Data so-obtained are given in Table B
below. Unless noted otherwise, all data were obtained on
oral administration and are expressed either as the ED50 or
as the percent inhibition at a given dose level ~thus
30~100 or 30% inhibition at 100 mg.~kg.)
In some instances, the compounds were retested
two or more times, and ED50 values were calculated for each
series of repeat tests. In such instances, each of the
ED50 values so-obtained is given in a series of values,
thus 6, 23, 30, 43 in the case of the species of Example lAW
in the acetylcholine-induced abdominal constriction test.
-93
I'able B
Exampl~ Ach BRDK P.F.
lA 73 56
IB 24,50,30,37 8.1 (~v.)
41,26,3~,58
6.7 (LV.)
21, 4B (s.c.)
.lC 1~6 .
lD 34,10,54,22 0/100 64
5.1 (Lv.)
4g ~s.c.
lE ~/100
lF 20 0/200 88/100
13 (iv.)
lG 84
0/3 ~v.)
50/10 (LY-)
100/30 (iVq)
lH 33/100
71~300
0/3 ~V.)
30/10 (Lv.)
100/30 (i~.)
2/30 (s.c.)
8.5 (iv.)
lJ 86
6~7 (iv.)
lE~ 255
1--0/1 (LV.)
30/3 (LV.)
25/5.5 (LV.)
44/1~ liv.)
1 M 50/100
lN 35.8
l-O 91.6
lP ~0/100
4.5 (iv.
lQ 7/24
27~79
60/23~3
67/435
60~793
67/1000
D .-'~, 7 ~
3~
--94--
T~le B (co~
Exa m~le Ach s R D K P .F.
lR 198
lS ~o 162
10/1 (iv.)
20~3 (1~V.3
100/10 (iv.)
lT 106
3.8 (Lv.)
lV 155
lV 20/300
1 W 0~30
~0/3qO
47/550
10/1 (iv~)
0/1.73 (LV.)
86/3 (iv.)
X 7/300
30/100
68
lAA 10~100
lAB 47/300
lAC 30 - û/200 43/30
10/1.77 (iv.) 57/50
10/2.~ (iv.) 75/100
80/3 (iv.)
100/10 (iv~)
lAE 29 20/300 66.2
lAF 200
0/3 (iV.)
0/10 (iv.)
30/30 (LV.)
lAG 40/100
47f300
10/10 (iv.)
56/3V (iv.)
~0~30 ~s.c.)
lAH 85
l~I 74
lAJ 13/100
53/300
lAK 40/300
47/550
lAL 113
lA M 32
5 (LV-)
3L;25~5;~ 2 D~_; 7356A
--95--
Exa m p~e Ach B R D K P.F.
lA0 2a 1ll 75/100
lAP 42 ~/S0
33/Z00
60/400
lAQ S3/300 0~10
17 (iv.) 12/30
12/100
lA R 27/150
27/300
13/25 (~c.)
lAS 33/300
lAT 30 0/50,200
lAU 42 0/S0
lAV 38 0/50
lAW 6,28,30,43 229 26
lA X 45 û/212
lA Y 11,37,49 141 0/30,100
8.5 (LV.) 20/300
: lAZ 10,27/50
20/75
: 73/100
53/150
lB A 197
lBB 97
le c 40/100
1~ D 65
.l~E 50.9
lBF 0/30
lB G 33/300
1~ 0/30
27/100
53/300
5~550
7/30 (6c.)
50~10 (iv.J
lBI 13/300 0/6
27/100 (~c.)
0.69 (iv.)
l~J 0/100
l~L 0/100
lB M 0~100
- 1~ N 36
O 173
~ lBP 28
;~
12~53~2 D, . 7356A
- 96 -
Table B (cont'~
xa mp7~_ Ach B R D K P .F .
1~ R 123
~3T 90/100
~ W 10/100
lBZ 0/100
lC~ 20/100
lCB 60/100
lCC 10/100
lCD 79
lCE 0/100
lCF 24
lCG 46.3
lC H 105
lCI 70/100
lCJ 56
lC K30/100
l C L30/100
2A 7/30
60/300
73/550
67/1000
2~ ~7/30~
33/550
2C 19,33 0/30
3.3 (LV.) 60/300
2D 20~100
~0/300
67/1000
2E 33
2F 20/30
40/100
33/300
2G 42
2H ~9
28 132 62/100
2.6 (Lv.)
18 (~c.)
o
2L 10/100
2M 20/100
D , 7 356A
~fl f p 1~
-~7 -
Table ~
Ach BRDK P.F.
2N 20/100
2-O 20/100
2P ~0/100
2Q 20~100
2R 10/100
2S 0/100
2T 30/100
2t~ 88
2V 20/100
2W 72
2AB 91
2AC 30/100
2A D 10/100
2AE 20/100
2AF 30/100
2A G 143
2A}~ 20/100
2A K 30/0.3 (iv.)
2AL 20/O~lliv.)
2A M 80/100
2A N 90
2P~0 40/100
2AP 27
2A R 50/100
2AT 20/100
2A U 30/100
2AV 10/100
2A W 20/100
2A X 0/100
2A Z 26
2BB 40/100
2BC 10/100
2B D 15
2DE 30/100
2BF 30/100
3P~ 681
3E~ 26.5 50/30
10 ~SC.) 8~/100
3 ~v-) ~6/300
3C 53
-sa-
~a!:~e B ~con~'~
Examp~e Ach BRDK P.F.
3~ 9.7 (iv.
3-I 30/100
3J 30/10 (iv.)
3 R 45.7
3L 44
3M 10/100
3N 40/100
3-O 76
3P 71
3Q 40/100
3R 40/100
3S 40/100
3T 53
3U 30/100
3V 253.8
3W 49
3Y 69
3AA 22
3AB 25
3AC 21
3AD 100/100
3AF 138.6
3AG 42
3AH 30/100
3AJ 35
4A 16 53 0,12/100
4B 24,25,21,15 3~,28,19 27.6
6 (iv.)
4C 37
4D 24
5A 31 0/300
20/1 (Lv.)
29/3 (iv.)
30/10 (i.'~.)
5E~ 25 61 0/10
12/30
12/100
5C 19 20/30
60/100
60/300
5D 84 20/200
57/3 (iv.)
~9/1 tiv.~
~. . .
99 ~5~
Table B~ ont'd.)
Ach BRDR P.F.
5E 38/150
40/300
5F 76
6 83 0/100
0/10 (iv.) 0/300
0/30 (iv.)
13/30 (s.c.)
7 ~0 0/300
8A 32 62/30
8B 35/100
9 27/300
20/30 (s.c:.)
0/30
7~30 (Sc.)
11 20/30
13/3U (&c.)
12 13/30
0/30
13A 139
13B 0/100
13C 20/100
14 40/100
155
16A 10/100
1613 20/10~
17 7/30 33,/100 ~c.)
6.6 (ac
18 30/100
lg 40/100
20A 123
20B 40/100
21 31
22 ~6.8
23A 85
23B 39
25A (r) 82.5
25B 42
26A 40~100
26B 40/100
2~C 30/100
26D 30/100
26E 73.1
26F 61
u / ~ ju~
~L2~3~~
-10 0 -
Tahle B (con~'d.l
Exa m~e Ach B R D K P .F .
26G 20/100
27A 20.7
27B 59.8
27C 29.4
27 D ~0
28 90/100
29~ 60,80/100
29~ 60,70/100
29C 0~100
10/100
31A 58
31C 53
31F 0/3 tiV~)
31G 133
31H 56
30/100(Lc.v.)
80/10 (Lv.)
31-I 31,40,88/100
31J 10/100
31 K 28
31L 32
31M 26
31N 90,100/100
31-O 100/100
32 8~
33 20/100
(r) N =B is a m~no
The 3-R3-carbonyl-1-am~noa1cyl-lH-~dc~es o~ formul~s I, Ia and ~b of the
invention were also test~3 in the develop~ng adjuvant arthrit~c assay, the plasma
fibronectin a~ay and the pleurisy macr~phage a~say in rats. Data ~obtained,
expre~ied as ~vall;es as a measure of the statistical ~nilïcance of the results
for each of ~e parameters measured, ie. inhibition of inl~ammation of non-
~r~ected paw (NIP) and ir~ected paw (right paw vc~me or RPV), lower~ng of
~asma fibronectin levels (FN) and is)hibit.~on of macrophage accumulation in theEileural cavity ~MAC), are given in Ta~Le C. Compounds were consi3ered active
at p ~ 0.05 ~vels. Non statistically s~gnificant xesulb; are recorded as l~_tl~
~25~3:~
-10 1-
Table C
ExamF~e N:rP RPV FN MAC
lB (~ 0.01 0.01
lF 0.01 0.01
lI 0.01 0.01 0.01 0.01
lU -- _ _
lAC
lAO - _ _
lRP
lA~
lB A - - O .01
lBB
lBD
lBE _ 0 05
lBL 0.01 0.05 0.01
113 M 0.01 0.01 0.01 0.01
lBN
lEI O - Q.O1 0.05
lBP 0.01 0.01
lBQ(~ 0.01 0.01 0.01 OoOl
lBR 0.01 0.01 0.01
lB Z 0.05 0.01 0.01
lCC _ _
lCE
lCF 0.01 0.01
lC G 0.01 0.01 0.01
lCH
lCJ 0.01 0.01 - -
lCL
lC M - 0.01
lC O 0.01 0.01
lCP 0.01 O.~ï 0.01 0.01
2C 0.01 0.01 0.01 0.01
2E 0.01 0.01
2R
2S
2U - - 0.01
2V
Y 0,05
~ .
5 6 A
55~
-102-
T~le C (c~n~.)
Exampl~ NIP RPV FN MAC
2AA
2AB - - -
2AC o.os - -
2AD
2AE 0.01 0.01
2AF 0.01 0.01
2AG 0.01 - 0.01
2AI 0.01 0.01 0.01
2AK _ _ _
2AN - -
2A O 0.01 0.01 0.01 0.05
2AQ
2AS
2AT - - -
2A U
2AV
2AW - _ _ 0 05
2~X -- _ .
2A Y 0cOl 0.05
2B~ - 0.01 0.05
2BF - 0.01 0.01
3D - _ _
3E 0.01
3F 0.05 0.01
3G
3K - 0.01 0.05
3T - 0.01
3U
3 W 0.01 0.01 0.05
3AF - OoOl
3AG 0,01 0.01 0.01
3AH OoOl ~ OvOl
3Al O~Ol O~Ol ~ 0~05 `
3AJ OvOl O~Ol 0005
6 ~ 0~05
13U - - OoOl
13C
12S53~ ;~ D I ~ ~ o l~
--103--
:
ExampLe NIP RPV FN MAC
16A 0.05 - -
19 -- _ _
20A - - 0.05
20B - - - -
21 -- -- --
22 0.01 0.01 - O.OS
23A 0.01 0.01 0.01
23B 0.01 0.01 0.01
24 0.05 0.01
25A
25B
26E
26F 0.05 0.01 -
26 G - - 0.01
27A 0.05 0.01
27E~ 0.05 0.01
27 D 0.01 0.01
29A 0.05 0.01
29B
31A 0.01 0.1~1 -
31B 0.01
31~ 0.01
31J 0.05
31L 0.05 0.01 - -
31M 0.01 - 0.01
31N 0.01 0.01
31-0 0.01 0.01 - -
32 OoOl O~Ol 0~05
(s) The maleate salt
~ The lower mel~ing p~lymorph
Certain speciPs of the intermediate 2-R2-3-(R3 carbon~4-indc~es oE
form~a II were also tested arld found active in one or more of the
acetylchc~ine-induced abdominal constriction test (Ach), the developing
adjuvant arthri~c assay ~NIP and RPY), the Bbronectin a~;ay (FNl and
th2 ~deunsy macrophage a~y (MP.C). Data ~ob~ained, e~preæd as
de~cribed above, are given ~n Ta~le D.
-104~
Table D
PreE?n. Ach NIP RPV FN MAC
lF 0/100 - - -
lAJ
lA K 20/lO0 - - - 0.05
lAL 20/lO0 0.01 - 0.01 0.01
lA M - - 0.01
1~N n.o~ o.ol - -
lAO 40/lO0
lA Q 0.01 0.01 U.01
Certain spec~es of the mtermediate 2-R2-1-aminoalkyl-lH-indciLes of
formula m were tested and found ac~ive ~n the acetylchQline-induced
abdominal cor~striction test. Thus 2-methyl-1-[1-methyl-2-(4-morpho-
linyl~ethyl]-lH ind~le methaneslllfonate hydrate ~Preparat~on SA) pro-
duced 40 9~ inhibit~on at 300 mg./kg. (p.o.), and the ED50 of 5-fhloro-2-
methyl-l-(l-methyl-2 dimethy~aminoefflyl~-lH-indo~ ~Preparati~n 8)
was found to be 25 mg./lcg. ~? -)~
