Note: Descriptions are shown in the official language in which they were submitted.
~z~
The present invention relates to novel N-~2-
(5-methoxy-6-haloindol-3-yl)ethyl]amides which are valuable,
orally active, ovulation inhibitors.
Melatonin (N-acetyl-5-methoxytryptamine) is a
natural product isolated from the pineal glands of beef
cattle. It is reported by Ying and Greep, Endocrinolog~l 92
(1), 333-5 (1973), that melatonin has an inhibitory e~fect
on ovulation in cyclic rodents. This inhibitory efect is
realized when melatonin is administered intracardially in
relativèly large doses during the critical period of pro-
estrus. However, when melatonin is administered orally, its
inhibitory effect on ovulation is substantially diminished
over that available by intracardial administration. It now
has been discovered that a particular class of tryptamines,
N-acyl-5-methoxy-6-halotryptamines, exhibit a high level of
activity as ovulation inhibitor even when administered
orally.
~he present invention provides novel compounds of
the formula
H
T~ R 3~ CH0 2
X ~ R
~ I
,, R2 .'
in which
R is hydrogen, Cl-C4 alkyl, phenyl, or phenyl
substituted with halo, Cl-C4 alkyl or Cl-C4
alkoxy;
Rl is hydrogen or Cl-C4 alkyl;
X-3964~ -2-
_ . .. . _ . . . ... . ... _ .. .
, . .. . . . . .. . . .. . .. . .
~L~7;~7
R2 is hydrogen or R3, and R3 is haloacetyl, Cl-C5 : : .
,: -
alkanoyl, benzoyl, or benzoyl substituted withhalo or methyl; and
X is halogen. :
The present invention also provides a process for .~ :
preparing novel 5-methoxy-6-halotryptamine compounds of
formula I wherein R, Rl, R2, R3 and X are as defined above,
which comprises reacting a 5-methoxy-6-halotryptamine com-
pound of the formula
~ o-CH -CH -NH II
., I .
H ~ :
; wherein R and X are as defined above,
with an active derivative of a carboxylic acid of the formula
: O
-C-OH III
:: wherein Rl is as defined above; and if desired reacting
the compound so obtained wherein R2 is hydrogen with an
acylating agent of the formula
R3-Cl IIIa ~;
wherein R3 is as defined above, in the presence of a strong
base.
Compounds of formula I are orally active as
inhibitors of ovulation in mammals.
Preferred compounds of formula I are those in
which R2 is hydrogen.
X-3964A -3-
~L072~ 7
Another preferred class of compounds of formula I
are those in which R~ is haloacetyl, Cl-C5 alkanoyl, benzoyl,
or benzoyl substituted with halo or methyl.
In the definition of the compounds of this in- ~ -
vention, the term "Cl-C4 alkyl" is employed. By this term ~ -
is meant any of the following groups: methyl, ethyl,
isopropyl, n-propyl, n-butyl, isobutyl, sec-butyl, and
t-butyl.
~he term "Cl-C4 alkoxy" also is employed herein ~ ;~
and includes methoxy, ethoxy, n-propoxy, isopropoxy, n
butoxy, isobutoxy, sec-butoxy, and t-butoxy.
The terms "halo" and "halogen" where used herein
include chlorot bromo, iodo, and fluoro, and, preferably,
chloro.
When, in the above definition, the term R repre-
sents a substituted phenyl group, examples of such a group
include 4-chlorophenyl, 2-fluorophenyl, 3-iodophenyl, 4-
bromophenyl, 3,4-dibromophenyl, 4-methylphenyl, 2~ethylphenyl,
3-n-propylphenyl, 4-isopropylphenyl, 4-n-butylphenyl, 3-
2Q t-butylphenyl, 4-sec-butylphenyl, 3,4-dimethylphenyl, 4-
methoxyphenyl, 3-ethoxyphenyl, 2-n-propylphenyl, 4-iso-
propoxyphenyl, 3-isobutoxyphenyl, 4-t-bu~oxyphenyl or
3-ethoxy~4-methoxyphenyl.
The term "haloacetyl" as used herein in definition
of the group R2 refers to chloroacetyl, bromoacetyl, fluoro-
acetyl, and iodoacetyl~
The term "Cl-C5 alkanoyl" as used herein with
reference to the group R2 includes formyl, acetyl, propionyl,
butyryl, a-methylpropionyl, valeryl, a-methylbutyryl,
X-3964A -4-
1~7Z0~37
.
~-methylbutyryl, and pivaloyl. Preferred Cl-C5 alkanoyl~ ~
groups are acetyl and pivaloyl, and, most preferably,;:
acetyl.
The term "benzoyl substituted with halo" used in :~ :
definition of the group R2 defines mono- and dihalobenzoyl
groupsO Specific monohalobenzoyl groups are chlorobenzoyl,
bromoben~oyl, fluorobenzoyl, and iodobenæoyl. Preferably,
. the monohalobenzoyl group is a 4-halobenzoyl, and the ;:
`: preferred halo substituent is chloro.
The dihalobenzoyl groups defined by R2 generally
are those in which both of the halo substituents are the ~:
same, and, preferably, are those in which the halo substituents
are located in the 2- and 4-positions. Typical dihalo-
benzoyl groups include 2,4-dichlorobenzoyl, 2,4-dibromo-
; benzoyl, 2,4-difluorobenzoyl, and 2,4-diiodobenzoyl. The
preferred group is 2,4-dichlorobenzoyl.
The term "benzoyl substituted with methyl" con-
templates "methylbenzoyl", "dimethylbenzoyl", and "tri-
methylbenzoyl'l. Preferred groups include 2-methylbenzoyl,
2,6-dimethylbenzoyl, or 2,4,6-trimethylbenzoyl.
Examples of the compounds of formula I include the
following:
N-[2-(5-methoxy-6-chloroindol-3-yl)ethyl]acetamide;
N-~2-(5-rnethoxy-6-fluoroindol-3-yl)ethyl]acetamide;
~ N-[2-(5-methoxy-6-brornoindol-3-yl)ethyl]formamide;. ~-; N-[2-(5-methoxy-6-iodoindol-3-yl)ethyl]propi-
onamide;
N-[2-(5-methoxy 6-chloroindol-3-yl)ethyl]-n-
butyrarnide;
X-3964A -5-
~72~\87 : `
N [2-(2-methyl-5-methoxy-6-bromo.indol-3-yl)ethyl]-
acetamide;
N-[2-(2-ethyl-5-methoxy 6-chloroindol 3-yl)ethyl~
: acetamide;
.,: N-[2-(2-n-propyl-5-methoxy 6-chloroindol-3-yl)-
ethyl]formamide; . .
``~ N-[2-(2-n-butyl-5 methoxy-6-chloroindol-3-yl)-
~, e~hyl]formamide;
N-[2-~2 ethyl-5-methoxy-6-iodoindol 3-yl)ethyl]-
. 10 propionamide;
: N-[2-(2-isopropyl-5-methoxy-6-fluoroindol-3-yl)- ~1.. :
." ~ ~
:l ethyl]-a-methylpropionamide; .~
1 N-[2-(2-phenyl-5-methoxy-6-chloroindol-3-yl)ethyl]- :.;
¦ formamide; ;.
:~l N [2-(2-phenyl-5-methoxy-6-bromoindol-3-yl)ethyl]-
acetamide;
N-[2-(2-phenyl-5-methoxy-6-iodoindol-3-yl)ethyl]- '~
propionamide; ~ .
N-12-((2-(4-chlorophenyl)-5-methoxy-6-chloroindol -
20 3-yl)~ethyl]formamide; ~;:
` N-[2-((2-(3-~luorophenyl)-5-methoxy-6-bromoindol-
3-yl))ethyl]acetamide; -
N-[2-((2-(2-fluorophenyl)-5-methoxy-6 chloroindo].-
3-yl))ethyl]propionamide;
N-[2-((2-~4-methylphenyl)-5-methoxy-6-bromoindol-
3-yl))ethyl]formamide; ~
N-[2-((2-(3-ethylphenyl)-5-methoxy-6-fluoroindol- :
3-yl))ethyl]butyramide;
; N-[2-((2-(4-n-propylphenyl)-5-methoxy-6-chloro-
indol-3-yl))ethyl]formamide;
: X-3964A -6-
' ~'
~L~7Z~87
N-[2-((2-(3-isopropylphenyl)-5-methoxy-6-fluoro-
indol-3-yl))ethyl3acetamide;
N-[2-((2-(4 methoxyphenyl)-5-methoxy-6 chloroindol- :
3-yl))ethyl]propionamide;
N-[2-((2-(3-ethoxyphenyl)-5-methoxy-6-bromoindol- :
3-yl))ethyl]acetamide;
N-E2-((2-(3-n-propoxyphenyl)-5-methoxy-6-fluor
indol-3-yl))ethyl]acetamide;
N-[2-((2-(4-t-butoxyphenyl)-5-methoxy-6-chloro-
indol-3-yl))ethyl]formamide;
.. . .
N-[2-((2-(3-n-butoxyphenyl)-5-methoxy-6-chloro-
; indol-3-yl))ethyl]acetamide;
N-[2 (1-acetyl-5-methoxy-6-chloroindol-3-yl)-
ethyl]acetamide;
: N-[2~ propionyl-5-methoxy-6-fluoroindol-3-
yl)ethyl]acetamide;
N-[2-(1-pivaloyl-5-methoxy-6-bromoindol-3-yl)-
; ethyl]formamide;
N-[2-(1-chloroacetyl-5-methoxy-6-iodoindol-3- :
yl)ethyl]propionamide;
N-[2-(1-bromoacetyl-5-methoxy-6-chloroindol-3-
yl)ethyl]-n-butyramide: :
N-[2-(1-valeryl-2-methyl-5-methoxy-6-bromoindol-
3-yl)ethyl]acetamide;
N-[2-(1-butyryl-2-ethyl 5-methoxy-6-chloroindol- i
3-yl)ethyl]acetamide;
N-[2-~1-benzoyl-2-n-propyl-5 methoxy-6-chloroindol-
3-yl)ethyl]formamide;
~ N-[[2-[1~(4-chlorobenzoyl)-2-n-butyl-5-methoxy-6-
: 30 chloroindol-3-yl]ethyl]]formamide;
X-3964A -7-
Z~8'7
. ~
N-[ L2- [1- (4-bromobenzoyl)-2-ethyl-5~methoxy-6- -
iodoindol-3-yl]ethyl]]propionamide; ~: ~
N-~[2-[1-(2,4-dichlorobenzoyl)-2-isopropyl-5- . ~ -
; methoxy-6-fluoroindol-3-yl]ethyl]]-a-m~thylpropionamide; ~ .
N-[[2-[1-(2,4-di1uorobenzoyl)-2-phenyl-5-methoxy-
6-chloroindol-3-yllethyl]]formamide; : :
N-[[2-[1 (4-iodobenæoyl)-2-phenyl-5-methoxy-6-
bromoindol-3-yl]ethyl]]acetamide; ~ ~-
N-[[2-[1-(2-methylbenzoyl)-2-phenyl-S-methoxy-6- -~
iodoindol-3-yl]ethyl]]propionamide;
N-[[2-[1-(2,6-dimethylbenzoyl)-2-(4-chlorophenyl)- .~ .
5-methoxy-6-chloroindol-3-yl]ethyl]]formamide;
i N-[[2-[1-(2,4,6-trimethylbenzoyl)-2-(3-fluoro
phenyl)-5-methoxy-6-bromoindol-3-yl]ethyl]]acetamide;
N-[2-(1-pivaloyl-5~methoxy-6-chloroindol-3-yl)-
ethyl]acetamide; .
;
N-[2-(1-chloroacetyl-5-methoxy-6-chloroindol-3-
yl)ethyl]acetamide; -
N-[[2 ~1-(4-chlorobenzoyl)-5-methoxy-6-chloro-~ :
. .
indol-3-yl]ethyl~]acetamid~;
~ -[[2-[1-(2,4-dichlorobenzoyl~-5-methoxy-6-
chloroindol-3-yl]ethyl]]acetamide;
N-[[2-[1-(2-methylbenzoyl)-S-methoxy-6-chloro-
indol-3-yl]ethyl~l-acetamide; ;,
N-[[2-[1-(2,6-dimethylbenzoyl)-5-methoxy-6-
~: chloroindol-3-yl]ethyl]]acetamide;
N-[~2-[1-(2,4,6-trimethylbenzoyl)-5-methoxy-6-
chloroindol-3-yl~ethyl]]acetamide;
.:. and the like.
..
X-3964A -8-
, :.
'',
~'` ' .
~7~87
The compounds of formula I are prepared by
acylating a substituted tryptamine of the formula
2 2 2 II
R
H
in which X and R are as aforedescribed. The acylation is
accomplished by employment of conventional procedures. For
` example, the substituted tryptamine can be reacted with an
- 10 activated form of a carboxylic acid of the formula
O ~
" III
in which Rl is as defined hereinabove. Suitable such ac-
tivated forms include, Eor example, the anhydride or mixed
anhydride of the carboxylic acid. Acylation also can be
carried out by reacting the carboxylic acid in the form of
; its acid halide with the tryptamine in the presence of a ~-
hydrogen halide acceptor. Hydrogen halide acceptors which
; can be used include a tertiary amine, such as pyridine,
or triethylamine; alkylene oxides, such as propylene oxide;
urea and substituted ureas, such as N-methylurea; and inorganic
bases, such as sodium bicarbonate, potassium bicarbonate,
sodium carbonate, or sodium bisulfite.
The substituted tryptamines used as starting ma-
terials in the aforedescribed acylation are prepared by a
variety of known procedures. A preparation of 5-methoxy-
6-halotryptamines is illustrated by the following generalized
reaction scheme:
X-3964A -9-
~ i
CH O ~ \ CHGH30~ ~ \ /C~13 `-
NH ~ O ~ ----~------- 3
(IV) (V)
pyridine HCI
~ /
HO\ ~ \ /CH HO~ ~ \ /CH3
T O ~ HONO ~ ~
X/~ ~ \NO ~ HOAc~b~ /o :
~¦~ 3 M S
h K2C3H30~T~ \ ~/CH3 ::
X ~o/ NO2 DMMe IX ~,,/ NOæ
(VIII) (IX)
(MeO)2CHNMe2
~ / DMF
CHDO~ HCHoO~ ~ \ ~ I = CHN(CH )
X~ ~ ~ / \N / Ra Ni / ~2
(XI) H (X) .
CH O
Et2NH ~'
: HOAc
: H O
~ /Z
: NaCN
DMF
MeOH
: H O ~
: Mel `:
~. / ` ! ~
~ ~ \ o-----o--C~ CN CHD ~ --C~I -C~l~-
X ~ / \N / AIH3 ~ X~
3 0(XII ) H LHAFIH~ (XIII )
X-3964A -10-
: .
! . : . . ~ : ' . . ~ ` " ' : ., ' . ~ ' ' ; '
` ~L07~2~87
- :,
As shown in the above generalized reaction scheme,
the 5-methoxy-6-halotryptamines are prepared by first halo-
genating 3-methoxy-4-aminotoluene (IV) to give 3-methoxy-4-
halotoluene (V). The halogenated compound then is reacted
with pyridine hydrochloride at an elevated temperature in
the range of from about 180C. to about 240C. to provide a
2-halo-5-methylphenol (VI). The phenol is reacted with
sodium nitrite in acid solution at a temperature from about ;
0C. to about 20C. to give an intermediate nitroso compound
~VII). Reaction of the nitroso compound with aqueous nitric
acid at a temperature in the ranye of from about 30C. to
about 60C. provides a 2-halo-4-nitro-5-methylphenol (VIII).
In those cases in which X is chloro, the 2-chlorophenol
intermediate compound is commercially available and thus may
itself be used as the initial starting material.
The halonitrophenol then is alkylated, for example,
by refluxing it with dimethyl sulfate and potassium car-
bonate in methanol or ethanol, or by heating it with methyl
iodide and potassium carbonate in N,N-dimethylformamide, to
provide 2~nitro-4-halo-5-mPthoxytoluene (IX). The nitro-
toluene compound is reacted with N,N-dimethylformamide di-
methylacetal in N,N-dimethylformamide at a temperature of
from about 100C. to about 130C. to give an N,N-dimethyl-2-
(2'-nitro-4'-halo-5'-methoxyphenyl)ethyleneamine intermediate
(X), which, upon hydrogenation over Raney nickel, cyclizes
to give a 5-methoxy-6-haloindole (XI).
The haloindole then is treated with diethylamine
and formalin in aqueous acetic acid solution. The resulting
mixture is added to aqueous base, and the total is extracted.
X-3964A -11-
' -
l~Z~t~7
The solvents are evaporated, and the recovered intermediate ;~
product is dissolved in a mixture of water, methanol and
N,N-dimethylformamide and is reacted with sodium cyanide.
Methyl iodide then is added dropwise to the solution to give
a 3-cyanomethyl-5-methoxy-6-haloindole (XII). The cyano
compound is reduced with a metal hydride, for example,
lithium aluminum hydride, to provide the desired 5-methoxy-
6-halotryptamine (XIII).
Tryptamines having a substituent at the 2-position
of the indole moiety are prepared by a modification of the
aforedescribed sequence. Compound (X), prepared as described
above, is treated with a compound of the formula
O . .
R'-C-Y
in which Y is halo and R' is Cl-C4 alkyl, phenyl or sub-
stituted phenyl as aforedescribed. This reaction is carried
out in the presence of triethylamine or pyridine and at room
temperature to produce the corresponding 2-acyl substituted
ethyleneamine (XIV). The ethyleneamine then is treated with
hydrochloric acid in aqueous dioxane at a temperature of
about 100C. to produce the corresponding 2-nitro-4-halo-
5-methoxybenzyl ketone (XV). The latter is ring-closed by
treatment with hydrogen over Raney nickel at a temperature
of about 25C. to about 40C. to the desired 2-substituted
indole (XVI~. This sequence is illustrated by the following
generalized reaction scheme:
X~3964A -12
. ~ ~
~ 7z~
o
H3C0~ ~ \ /CH = CHN(CH~)2 R'-C-Y
R pyr i d ï ne
(X) or
triethylamine
R'
C = O
I HCI
H C0 ~ ~ CHN(CH ) H 0
t R dioxane
~N02 reflux
1 0 (XIV)
Il H2
H C0 ~ \ ~CH -C-R' Raney
3 ~ ~ 2 _Nlckel___~
Benzene
X ~ a ~ NO2
(~7)
H~CO~
: X ~ ~ N R'
(~VI) H
Compound (XVI) then is treated in the manner
aforedescribed with reference to compound (XI) to produce
the desired tryptamine. ~.
Alternatively, the indole, whether unsubstituted
at the 2-position (compound XI) or substituted at the
2-position (compound XVI), can be treated by the following
. generalized scheme to produce the desired tryptamine inter-
mediate:
' . .
X-3964A -13-
~:,
~;
7 - ~
: ~.
o .:
~ ~ DMF 3 ~
X~ ~ N20H X ~/ \N/ R
. .
H (XVII) H
(XI or XVI)
H CN0
NH40Ac
H C0 ~ \ H CO~ CH=CHNO
3 t j~ --b--CH -CH -NH 3
X ~ R ~ LIAIH4 X ~/ \N/ \R ~ `
(XIX) H AIH3 ~XV~II) H ~ -
As shown by the above generalized scheme, the
indole is treated with phosphorus oxychloride and DMF to
produce the corresponding 3-formyl indole (XVII). The
latter is treated with nitromethane and ammonium acetate to
obtain the corresponding 3-(2'-nitroethenyl)indole (XVIII),
which then is reduced to the desired tryptamine (XIX)~
Compounds of formula I in which R2 is other than
hydrogen are prepared from the N-unacylated compounds.
They are prepared by treating the latter with an appropriate
acylating agent. Typically, the N-unacylated compound is
reacted with at least an equimolar amount of an acyl halide
of the formula R3Cl in which R3 represents any of the groups
defined above. The reaction is carried out in the presence
of a moderate molar excess (about 10%) of a strong base such
as sodium hydride at room temperature in an inert solvent
and for a time sufficient to accomplish conversion.
~, .
X-3964A -14-
, `` :
~7;~37
The compounds of formula I exhibit an inhibitory
effect on ovulation when administered orally. This inhibitory
effect is markedly superior to the effect achieved by oral
administration of melatonin. Thus, the compounds of formula
I are especially useful as orally active inhibitors of
o~ulation in birds and mammals. As a result, therefore, the
compounds of formula I are useful in controlling the animal ; `~
population and as contraceptives in living beings. The
compounds of formula I also are valuable for animal pest
control. For example, the compounds of formula I can be
formulated in combination with baits and/or attractants and
placed in feeding stations accessible to undesirable rodents
and other small animals including Canidae such as coyotes,
foxes, wo~ves, jackals, and wild do~s; and birds, such as
starlings, gul]s, redwing blackbirds, or pigeons, to greatly
reduce the population thereof. By reason of the activity of
the compounds of formula I, they can be used to reduce
hazards to aviation by lessening the presence of birds and
animals on runways and in the vicinity of air fields. The `~
compounds also can be used to reduce the population of
undesirable birds and animals so as to aid in the prevention
and the spread of disease, and to reduce the destruction of
property in both rural and urban areas.
The compounds of formula I can be administered as
such, or they can be compounded and formulated into phar-
maceutical preparations in unit dosage form for oral or
parenteral administration. In the compounding or formulation,
organic or inorganic solids and/or liquids which are pharma-
seutically acceptable carriers can be employed. Suitable
X-3964A -15-
_. . . .. , __ ..
~ 7;~q~87
such carriers will be well recognized by those of ordinary
skill in the art. The compositions may take the form of
tablets, powder granules, capsules, suspensions, or solution.
The compounds of formula I when administered in an
effective amount, will produce the inhibition of pregnancy
in birds and mammals. The usual daily dose is ~rom about
0.02 milligrams to about 20 milligrams per kilogram body
weight of the recipient. The preferred daily dose is from
about 1 milligram to about 8 milligrams per kilogram body
weight of the recipient.
The following examples are provided to fuxther
illustrate this invention. They are not intended to be
limiting upon the scope thereof.
Example 1
N-[2-(5 ~5ethoxy-6-chloroindol-3-yl)ethyl]acetamide ,
A mixture of 142 g. `~1.10 mole) of 2-chloro-5-
methylphenol in 300 ml. of acetic acid and 40 ml. of
; sulfuric acid was preparedO The mixture was stirred, and a
solution of 70 g. of sodium nitrite in 200 ml. of water was
added dropwise over a period of about 100 minutes. During
the sodium nitrite addition the temperature of the mixture
was maintained at 8-12C. with an ice-salt bath. After the
addition was completed, the mixture was stirred for another
30 minutes and then was poured into a large volume of ice
water. The crude 2-chloro-4-nitroso-5 methylphenol was
collected by filtration and used without further purification.
The crude nitroso compound was added in portions
to a stirred solution of 100 ml. of 70~ nitric acid and 300
ml. of water maintained at a temperature of about 40-50C.
X-3964A -16-
~L~7ZC~g~7
..
Heating and stirring were continued until the evolution of
brown fumes ceased. The mixture was then poured into water,
and the product was collected by filtration. The product
was recrystalliæed from ethanol-water. After collecting the
first crop, the mother liquor was concentrated and chilled
to yield a second crop of product. Total yield was 155 g.
(83~) of 2-chloro-4-nitro-5-methylphenol, m.p. 142-4C.
A mixture of 25 g. ~0.133 mole) of the 2-chloro-4-
nitro-5-methylphenol, 20 g. (0.145 mole) of potassium car-
bonate, and 14 ml. (18.6 g.; 0.148 mole) of dimethyl sulfate
in 500 ml. of absolute ethanol was refluxed for two hours.
An additional 19 g. of potassium carbonate and 5 ml. of
dimethyl sulfate were added to the mixture, and refluxing
was continued for two hours. After cooling, the mixture was
poured into one liter of cold water and extracted with
several portions of ether. The ether extracts were combined,
mixed with methylene chloride, and washed with water. The
extracts then were dried over sodium sulfate, and the
soIvents were removed in vacuo. The residue was washed with
petroleum ether and dried to yield 26.4 g. (94 percent) of
2-nitro-4-chloro-5-methoxytoluene.
A solution of 15.1 g. (0.075 mole) of the 2-nitro-
4-chloro-5-methoxytoluene, 10.7 g. (0.09 mole) of N,N-di-
methylformamide-dimethylacetal, and 1.0 g. of triethylenedi-
amine in 100 ml. of N,N-dimethylformamide was heated over-
night at about 120C. in a distillation apparatus under a
gentle nitrogen sweep to yield N,N-dimethyl-2-(2'-nitro-
4'-chloro-5'-methoxyphenyl)ethyleneamine. The intermediate
was not isolated. Instead, it was hydrogenated in situ over
X-3964A -17-
~.~72~7
0.4 g. of Raney nickel at 15 psi during which time the
temperature rose to 40-50C. The hydrogenated solu~ion was
filtered, and the filtrate was poured into 500 ml. of ice
water containing 10 ml. of acetic acid. The resulting
mixture was extracted with several portions of methylene -
chloride. The co~bined organic extracts were washed with
sodium chloride solution and dried over sodium sulfate. The
solvent was removed, and the crude product was sublimed at 4
mm. pressure and 130~C. The colorless sublimate was
recrystallized from methanol-water to yield 6.1 g. (45
percent) of 5-methoxy-6~chloroindole, m.p. 126-28C~ ~
A solution of 14 ml. of 60 percent acetic acid and ! ~;
4.8 g. of diethylamine was prepared and cooled to about 5C.
To this solution were added 5.1 ml. of formalin. After
stirring for ten minutes, the cold solution was added to a
cold solution of 10 g. (55 mmole) of 5~methoxy-6-chloro- -
indole in 20 ml. of absolute ethanol. The solution was
allowed to warm to room temperature and was stirred for one
hour. The solution then was poured into 200 ml. of cold lN
sodium hydroxide, and the mixture was extracted several
,~
times with ether. The combined ether extracts were washed
with sodium chloride solution, dried over sodium sulate,
and the solvent removed in vacuo.
The residue was ta]cen up in a solution of 200 ml.
of methanoll 10 ml. of N,N-dimethylformamide, 10 ml. of
water and 13.3 g. (0.27 mole) of sodium cyanide. To this
solution were added dropwise over a period of about one hour
~; 21 ml. (48 g., 0.34 mole) of methyl iodide. After the addi- ;
tion of methyl iodide was complete) the solution was stirred
X-3964A -18-
:'
` ~7;~87
for about one hour and then was poured into ice water. The
aqueous mixture then was extracted with methylene chloride.
The extract was dried over sodium sulfate, and the solvent
was removed in vacuo. The residue was recrystallized from
an ether-pentane mixture to yield 6.1 g. (50 percent) of 3-
cyanomethyl~5-methoxy-6-chloroindole, m.p. 133-137C.
A solution 7.6 g. (0.2 mole) of lithium aluminum
hydride in 200 ml. of tetrahydrofuran was stirred under
nitrogen while a solution o 5.2 ml. (9.8 g.~ 0.1 mole) of
100 percent sulfuric acid in 40 ml. of tetrahydrouran was
added. A solution of 6.0 g. (27 mmoles) of 3~cyanomethyl-
5-methoxy-6-chloroindole in 40 ml. of tetrahydrofuran then
was added over a 30-minute period. The reaction was allowed
to proceed for another hour with stirring. The mixture then
was poured into ice followed by 20 percent sodium hydroxide
solution. The resulting mixture was extracted with several
portions of chlorofo~m. The extracts were washed with
sodium chloride solution, dried over sodium sulfate, and the
solvent was removed in vacuo. The residue was boiled in
ether, and a small amount of pentane was added. The mixture
was cooled, and the crystalline product collected by fil-
tration. Ater drying, 5.04 g. (83 percent) of 5-methoxy-
6-chlorotryptamine were obtained.
To a solution of 0.5 g. (2.23 ~oles) of the
tryptamine in 5 ml. of pyridine was added 0.5 ml. of acetic
anhydride. The mixture was allowed to stand overnight. The
solvent was removed ln vacuo, and the residue was taken up
in a mixture o chloroform and ethyl acetate. The solution
was washed with sodium bicarbonate solution and dried over
X-3964A -19-
.. . . . .. .. . .. .
~ 72~8~ ~
sodium sulfate. The solvent was removed ln vacuo. Theresidue was boiled in benzene. After cooling the product
was collected and the benzene treatment was repeated. The
product then was dried to yield 0.52 g. (87 percent) of
N-[2-(5-methoxy-6-chloroindol-3-yl)ethyl]acetamide, m.p.
149 d 5 150 C~
Example 2
N-[2-(5-Methoxy-6-chloroindol~3-yl)ethyl3propionamide
A solution of 0.5 g. (2.23 mmole) of 5-methoxy- `
6-chlorotryptamine, prepared as described in Example 1, in 4
ml. of benzene and 1 ml. of pyridine was acylated with
propionic anhydride following the procedure described in
Example 1. N-[2-(5-Methoxy-6-chloroindol-3-yl)ethyl]propi-
onamide, 0.56 g., m.p. 100-101C~, was obtained.
Example 3
; N-[2-(5-Methoxy-6-chloroindol-3-yl)ethyl]butyramide
A solution of 0O5 g. (2.23 mmole) of 5-methoxy-6-
chlorotryptamine, prepared as described in Example 1, in 5
ml. of pyridine was acylated with butyryl chloride following
the procedure described in Example 1. N-[2-(5-Methoxy-6-
chloroindol-3-yl)ethyl]butyramide, 0.41 g. (62 percent),
m.p. 98-98.5C., was obtained.
ExamPle 4
N-[2-(5-Methoxy-6-fluoroindol-3-yl)ethyl~acetamide
To 68.5 grams (0.5 mole) of 2-methoxy-4-methyl-
aniline in a 2 liter flask was added a solution of 136 ml.
of concentrated hydrochloric acid in 930 ml. of water. The
solution was cooled and stirred at about -5~C., and a solu-
tion of 42 grams (0.61 mole) of sodium nitrite in 110 ml. of
X-3964A -20-
.
.
~07Z01~7
water was slowly added. The mixture was maintained atabout -5C. for about 2~ minutes after which 75 ml. (0.60
mole) of 65 percent aqueous hexafluorophosphoric acid were
rapidly added. ~he resulting mixture was stirred and
maintained cold for about 30 minutes, and the resulting
product then was collected by filtration. The product was
washed with 400 ml. of cold water followed by a solution of
120 ml. of methanol and 460 ml. of ether. The resulting
diazonium hexafluorophosphate salt was collected on a filter
and dried ln vacuo overnightO The resulting dried salt
; weighed 1S5 grams (96 percent).
A 1 liter flask containing 500 ml. of mineral oil
was fitted with a reflux condenser, a magnetic stirrer, a
thermometer, and a connecting tube leading to a 300 ml.
Erlenmeyer flask. To the Erlenmeyer flask was added the
entire quantity of the diazonium salt. The oil was heated
to 165C. by means of an oil bath. The diazonium salt then
was added in portions over a 45 minute period. There was a
slightly exothermic reaction. Upon complet.ion of the re-
20 action, the flask was rapidly cooled and 400 ml. of 10
percent aqueous sodium carbonate solution were ¢autiously
added. The mixture was subjected to steam distillation.
The resulting oily layer was collected. The aqueous layer
was extracted with 350 ml. portions of methylene chloride. ;
The methylene chloride extracts were added to the oil, and
the entire mixture was dried over sodium sulfate. The
solvent was removed in vacuo, and the product was distilled
to obtain 34.2 grams of 3-methoxy-4-fluorotoluene, b.p. 30 mm
93_95C.
X-3964A -21-
. . . ~ .:. . : : ,, ,
72~137
To a 500 ml. ~lask were added 200 grams of pyridine
hydrochloride. The flask was fitted with a magnetic stirrer,
a reflux condenser, and a nitrogen bubbler. The pyridine
salt was heated to about 180C. to remove any moisture. The
salt then was allowed to cool somewhat, and 34 grams (0O243
mole) of the fluorotoluene compound were added. The mixture
; was heated to 220C. and maintained there for about three
hours. The mixture then was cooled, and a large volume of
water was added. The reaction mixture then was extracted
with several portions of methylene chloride. The methylene
chloride extracts were combined, and the solvent was removed
n vacuo to obtain a pale yellow product which by nmr
analysis indicated the presence of about 5 percent of
starting material. The product then was taken up in an
excess of lM sodium hydroxide. The solution was extracted
with methylene chloride, and the aqueous layer then was
acidified with hydrochloric acid. The acidified portion was
extracted with methylene chloride. Evaporation of the
methylene chloride extract and distillation of the residue
gave 26.6 yrams of 2-fluoro-5-methylphenol, b.p.30 86-93C.
A solution of 26.6 grams (0.21 mole) of the
fluorophenol in 63 ml. of acetic acid and 8.5 ml. of
sulfuric acid was stirred at 8-12C. While the mixture was
cooled and stirred, a solution of 15 grams oE sodium nitrite
in 42 ml. of water was added dropwise over a period of about
l hour. Stirring was continued for an additional 30
minutes. The mixture then was poured into a large volume of
ice water. The resulting crude product was collected by
filtration, thoroughly washed with water, and air dried
X-3964A -22-
while on the filter. The resulting crude nitroso compound
then was added in portions to a stirred solution of 20 ml.
of 70 percent nitric acid and 60 ml. of water maintained a~
40-50C. Heating and stirring were continued until the
evolution of brown fumes became negligible. The mixture
then was poured into ice water, and the crude product was
collected. The crude product then was recrystallized from
ethanol-water to obtain a irst and a second crop. A total
of 25.4 grams (70 percent) of 2-fluoro-4-nitro~5-methyl-
phenol was obtained; m.p. 110-111.5C.
A mixture of 25 grams (0.15 mole) of the fluoro-
nitrophenol, 22 grams of potassium carbonate, 15.4 ml. of
dimethyl sulfate, and 550 ml. of ethanol was refluxed over-
night. Analysis of the reaction mixture indicated that no
alkylation had taken place. The mixture then was diluted
with 300 ml. of N,N-dimethylformamide and about 50 ml. of
water. Two equivalents of methyl iodide then were added.
The mixture was heated at 100C. overnight. The mixture
then was cooled and added to a large volume of ice water.
The product separated, was collected by filtration, and
dried. The collected product was recrystalli2ed from
methanol-water to obtain 22.2 grams of 2-nitro-4-fluoro-
5-methoxytoluene, m.p. 95-95.5C.
A mixture of 10 grams (0.054 mole) of the fluoro-
nitrotoluene, 7.7 grams (0.065 mole) of N,N-dimethylformamide
dimethylacetal, and 1.0 grams of triethylenediamine in
75 ml. of N,N-dimethylormamide was heated at 125C. under a
gentle nitrogen sweep overnight. The solvent then was
removed in vacuo with gentle application of heat. The
~ X-3964A -23
':'
. ~
~L~72~37
resulting residue was taken up in methanol and filtered to
give a deep red-green iridescent product, m.p. 116-117C.
A total of 8.35 grams (64 percent) oE N,N-dlmethyl-2-(2'-
nitro-4'-fluoro-5'-methoxyphenyl)ethyleneamine was obtained.
The ethyleneamine was hydrogenated in benzene over -~
Raney nickel. The resulting reaction mixture was washed
with 500 ml. of water containing 4 ml. of phosphoric acid.
The resulting aqueous phase then was extracted with methylene
chloride, and all the organic portions were combined. The
combined organic solutions then were washed with aqueous
sodium chloride solution and dried over sodium sulfate. The
solvent then was removed in vacuo, and the resulting crude
product was sublimed from a fused state at 0.2 mm. pressure.
The resulting sublimate was recrystallized from methanol-
water to obtain a first and second crop totalling 3.02 grams
(54 percent) of 5-methoxy-6-fluoroindole, m.p. 73-74C.
To a mixture o 2.8 ml. of 60 percent acetic acid -~
and 0.96 grams of diethylamine maintained at about 5C. was
, .................... .
added 1.0 ml. of formalin. The resulting solution was added
to a mixture of 2.0 grams (12.1 mmole) of the fluoroindole
in 4 ml. of absolute ethanol. The solution was allowed to
; warm to room temperature and was stirred for about one hour.
The solution then was poured into 40 ml. of lN sodium
hydroxide. The resulting mixture was extracted several
times with ether. The ether extracts were combined and
washed with aqueous sodium chloride solution, dried over
sodium sulfate, and evaporated. The resulting residue was
added to a solution of 40 ml. of methanol, 2 ml. of N,N-
; dimethylformamide, 2 ml. of water, and 20 66 grams of sodium
~-~ X-3g64A -24-
'`` .
cyanide. To tha resulting mixture then were added dropwise
4.2 ml. (9.6 grams; 0.068 mole) of methyl iodide over a
period of about one hour. The resulting mixture was main-
tained for about another hour. The mixture then was poured
into ice water, and the aqueous mixture was extracted with
methylene chloride. The extract was dried over sodium
sulfate, and the solvent was removed ln vacuo. The residual
product then was washed with a cold mixture of ether and
petroleum ether. The product was recrystallized from
benzene-hexane to obtain l.ll grams (45 percent) of 3-
eyanomethyl-5-methoxy-6~fluoroindole, m.p. 97-98C.
A solution of l.9 grams (0.05 mole) of lithium
aluminum hydride in 50 ml. of tetrahydrofuran was prepared
and stirred under nitrogen. A solution of 1.3 ml. (2~45
grams; 0.025 mole) of lO0 percent sulfuric acid in 10 ml. of
tetrahydrofuran was prepared and then was added to the
lithium aluminum hydride solution~ The resulting mixture
contained lithium sulfate as a suspension. A solution of
l.0 grams (4.9 mmole) of the cyanomethylindole in lO ml. of
tetrahydrofuran then was added to the mixture over a period
of about 15 minutes. Stirring was continued for an addi-
tional one hour. The reaction mixture then was poured into
ice followed by 20 percent sodium hydroxide solution. The
resulting mixture was extracted with severaL portions of
chloroform. The extracts were washed with sodium chloride
solution, dried over sodium sulfate, and the solvent was
removed ln vacuo. The resulting residual oil crystallized
;~; upon addition of ether. The tan product was washed three
times with small amounts of a 1:1 mixture of ether and
X-3964A -25-
''' ,
,'''
~LO~ 7
petroleum ether. Upon drying, 0.83 grams (81 percent) of
5-methoxy-6-fluorotryptamine was obtained. m.p. 114~117C.
Recrystallized from benzene-hexane, m.p. 120-121C.
A mixture of 0.75 grams (3.6 mmole) of the trypt-
amine, 2.0 ml. of pyridine, and 8.0 ml. of benzene was pre-
pared. Acetic anhydride ~1.0 ml.) was slowly added. The
mixture was stirred at room temperature for four hours, and
the solvents then were removed in vacuo with moderate
heating. The resulting crystalline residue was dissolved in
; 10 a 1:1 mixture of warm ethyl acetate and chloroform. The
solution was washed with water, then with sodium chloride
solution, and then dried over sodium sulfate. The solvents
were removed ln vacuo. The crystalline residue was boiled
in ben7ene for a few minutes. The mixture was allowed to
stand at room temperature for several hours, and the re-
sulting product was collected by filtration and dried to
obtain 0.81 grams (90 percent) of N-[2-(5-methoxy-6-fluoro-
indol-3-yl)ethyl]acetamide, m.p. 158-159C.
Example 5
.
N-[2-(6-Chloro-5-methoxy-2-methylindol-3-yl)ethyl]acetamide
To a solution of 20 g. (0.078 mole) of N,N-di-
methyl-2-(2'-nitro-4'--chloro-5'-methoxyphenyl)ethyleneamine
and 19.8 ml. (19.4 g., 0.25 mole) of pyridine in 200 ml. of
methylene chloride was added dropwise a solution of 11 ml.
(12.2 g., 0.156 mole) of acetyl chloride in 200 ml. of
methylene chloride. The addition was carried out over a
period of about three hours. The mixture was stirred over-
night and then was poured into a large volume of cold NaHCQ3
; solution. The aqueous phase was extracted with fresh
X-3964A -26
~`
methylene chloride. The combined organic solutions were
washed with water and dried over sodium sulfate. Removal of
the solvent ln vacuo gave a residue which was dissolved in
450 ml. of dioxane. To the resulting solution were added
150 ml. of lM HCl solution. After stirring overnight at
room temperature, the solution was refluxed for thre~ days.
After cooling, 80 ml. of lM NaOH were added, and the bulk of
the dioxane was removed under reduced pressure. The product
was then extracted into chloroform. The extract was
evaporatedl and the residue was chromatographed over 200 g.
of florosil, eluting with benzene. Crystallization from
benzene-hexane gave 6.49 g. (34% yield) of 4-chloro-
5-methoxy-2-nitrophenylacetone, m.p. 114~115C.
Using 2 g. of Raney nickel, 6.49 g. (0.026 mole)
of the arylacetone in 90 ml. of benzene were hydrogenated
under 50 psi of hydrogen for 1 hour. The exothermic re
duction caused the temperature to rise to 40C. After
removal of the benzene, the residue was crystallized from
methanol-water affording 1.5 g. of 6-chloro-5-methoxy-
2-methylindole, m.p. 115-116C. Evapoxation of the mother
liquor followed by sublimation and recrystallization from
methanol-water provided another 0~62 g. of product, m.p.
114-115C. Total yield: 2.12 g., 41%.
A mixture oE 3.6 ml. (3.42 g. 0.047 mole) of DMF
and 1.04 ml. (1.74 g., 0.0114 mole) of phosphorus oxychloride
was prepared at 10-20C. After 15 minutes, 2.05 g. (0.0105
mole) of the indole in 1 ml. of DMF was added, and the
~; temperature was raised to 35C. After one hour the mixture
was poured onto crushed ice. This mixture was treated
X-3964A -27-
_ , . .
gradually with 2 g. of NaOH in 10 ml. of water~ maintainingan acidic pH through the first three-fourths of the addition.
Following acldition of the base, the mixture was boiled for
one hour~ Aft~r the mixture was cooled and allowed to stand
-overnight, the product was collected. Boiling the product
in methanol afforded 2.13 g. (91% yield) of pure 6-chloro-
5-methoxy~2-methylindole-3-carboxaldehyde, m.p~ 256 dec.
A mixture of 0.5 g. (0.002 mole) of the indole-
carboxaldehyde, 40 ml. of nitromethane, 10 drops of acetic
acid, and 0.4 g. of ammonium acetate was re1uxed overnight.
Another 0.4 g. of ammonium acetate was added, and the
mixture was refluxed for an additional day. The ni~ro-
methane was removed ln vacuo, and the xesidue was washed
with water. Recrystalli2ation from ethanol gave 0.35 g.
(59% yield~ of pure 1-(6'-chloro~5'-methoxy-2' methylindol-
3'-yl)-2-nitroethene, m.p. 238dec.
A solution of 1.47 g. (0.039 mole) of lithium
aluminum hydride in 90 ml. of THF was stirred under nitrogen.
A solution of 1.02 mlu of sulfuric acid (100%) in 15 ml. of
THF was added to the mixture followed by addition over a one
hour period of a solution of 0.35 g. (0.0013 mole) of the
nitrovinylindole in 15 ml. of THF. The mixture was stirred
overnight, and the excess hydride then was destroyed by
addition of ice chips. The mixture then was poured into a
20~ NaOH solution, and the total was extracted with several
portions of chloroform. After drying over sodium sulfate,
the solvent was removed rom the extracts, and the residue
- was recrystallized from benzene-hexane. The yield of 6-
chloro-5-methoxy-2-methyltryptamine, m.p. 152 153; was
3~ 0.50 g. (79%).
X-3964A -28-
-
A solution of 0.11 g. of the tryptamine in 5 ml.
of benzene and 0.37 ml. of pyridine was stirred in an ice
bath. To the stirred mixture was added 0.05 ml of acetic
anhydride. After stirring for one hour at room temperature,
the mixture was poured into ice water and extracted with
benzene. The benzene extract was dried over sodium sulfate
and evaporated ln vacuo. The residue was chromatographed
over 10 g. of silica gel eluting with ethyl acetate. The
pure N-~2-(6-chloro-5-methoxy-2-methylindol-3-yl)ethyl]-
acetamide, m.p. 119-121; weighing 0.11 g. (85~ yield) was
recovered.
Example 6
N-[2-(1-Acetyl-5-methoxy-6-chloroindol-3-yl)ethyl]-
acetamide.
To 30 ml. of N,N-dimethylformamide were added
210.7 mg. (0.79 mmole) of N-[2-(5-methoxy-6-chloroindol-3-
yl)ethyl]acetamide (prepared as in Example 1) followed by
20.8 mg. of sodium hydride. The resulting mixture was
stirred at room temperature for about one hour, and 68.2 mg.
(0.06 ml.) of acetyl chloride were added. The mixture wàs
stirred for an additional hour and then was poured into ice
., .
water containing a small amount of acetic acid. The
resulting mixture was extracted with chloroform, and the
extract was washed twice with saturated aqueous sodium
`~ chloride solution. The chloroform extract was dried over
sodium sulfate and was concentrated in a rotary evaporator.
The residue was recrystallized from benzene-ether and was
vacuum-dried to obtain 108 mg. (40.8~) of the title com-
pound, m.p. 178-181C. ``~
X-3964A -29-
: .
~ ":
``` 1IDf720~7
Analysis, Calc'd for C15H17N~O3Cl: C, 58.35; H, 5.55;
N, 9.07.
Found : C, 58.02*; H, 5.82*;
N, 9.07.*
*Result is an average of two analyses.
IR (KBr) 1646 (C=O~, 1703 cm 1 (C=O).
UV ~max ~MeOH) 256 (~ 17,200), 274 sh nm (~ 10,300).
NMR ~DMSO-d6) ~ 1.81 (g, 3H, amide Ac); 2.29 ~t, J--7
Hz., 2H, a-CH2); 2.58 (s, 3H, 1-Ac); 3.37 (q, J-7 Hz, 2H,
~-CH2); 3.90 (s, 3H, OCH3); 7.33 (s, lH, 4-H); 7.67 (s, lH,
2-H); 7.99 (broad t, lH, N-H); and 8.31 (s, lH, 7-H)~ `
The following Table is provided to show ovulation
inhibitory activity of the compounds of formula I. Adult
female rats with regular estrus cycles of four days each are
employed. The estrus cycle consists of two days of diestrus
followed by a day of proestrus and then a day of estrus. On
the afternoon of proestrus, luteiniæing hormone (LH) is
; released into the blood by the pituitary gland. The LH
~ travels to the ovary where it induces ovulation, resulting
`~20 in the presence of eggs in the oviduct on the day of estrus.
The test compound is administered orally at noon
on the day of proestrus. The rat is sacrificed on the fol-
`lowing day ~estrus), and the oviduct is removed and examined
imicroscopically for the presence of ova. rrhe absence of ova
-~indicates that the compound is active in blocking ovulation.
~...
`:;.
:
~' :
X-3964A -30-
. ,
....
Table
Inhibiti n of Ovulation
H3CQ~ --o--CH2-CHz-NH C R
~I~ ,D\ /~
: Inhibition
R Rl XMin. Eff. Dose, mg.
H CH3 Ha 8
H CH3 Cl
H C2H5 Cl
H C3H7 Cl
H CH3 F
CH3 CH3 Cl 1 ~.
:.
'`:
.",
' :'';' .
. '
, . :
.,', ,~
;:
:' .;
. '~
:
i
`~ X-3964A -31-
