Note: Descriptions are shown in the official language in which they were submitted.
~5gj~
-1 ~680-307
1,3-DISUBSTITUTED 2-OXINDOLES AS ANALGESIC
AND ANTI-INFLAMMATORY AGENTS
_. _
This application relates to new chemical compounds
which are of value as new medicinal agents. More
particularly the new chemical compounds are derivatives
of 2-oxindole-1-carboxamide~ and they are further
substitllted at the 3-position and on the carboxamide
nitrogen by an acyl groupD These new chemical compounds
are inhibitors of both the cyclooxygenase (CO) and
lipoxygenase (LO) en~ymes~
The compounds of this invention possess analgesic
activity in mammals, particularly man, and they are
useful therefore for acute administration for ameliorating
or eliminating pain, such as the pain experienced by
patients recovering from surgery or trauma.
In addition to their usefulness for acute admini-
stration to combat pain, the compounds of this invention
are useful for chronic administration to mammals,
particularly man, to alleviate the symptoms of chronic
diseases, ~uch as the inflammation and pain associated
with rheumatoid arthritis and osteoarthritis.
~3
~s~s~
This invention provides novel 2-oxindole compounds
of the formula
X ~ R
y~l10 (:r
o=C~ C~ 2
o
and the pharmaceutically-accepta~le base salts thereof;
wherein
X is selected from the group consisting of hydrogen,
fluoro, chloro, bromo, alkyl having 1 to 4 carbons,
cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4
carbons, alkylthio having 1 to 4 carbons, trifluoro-
methyl, alkylsulfinyl having 1 to 4 carbons, alkyl-
sulfonyl having 1 to 4 carbon~, nitro, phenyl, alkanoyl
having 2 to 4 carbons, benzoyl, thenoyl, alkanamido
having 2 to 4 carbons, benzamido and N,N-dialkylsulfamoyl
having 1 to 3 carbons in each of ~aid alkyls; and Y is
- 15 selected from the group consisting of hydrogen, fluoro~
chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl
having 3 to 7 carbons, alkoxy having 1 to 4 carbons,
alkylthio having 1 to 4 carbons and trifluoromethyl;
or X and Y when taken together are a 4~5-, 5,6-
or 6,7 me~hyl~nedioxy group or a 4,5-, 5~6 or 6,7-
ethylenedioxy group;
or % and Y when taken together and when attached
to adjacent carbon atoms, form a divalent radical Z,
wherein Z is selected from the group consisting of
S56S~
-3-
/-` I~ ~
zl z2 z3
W
and
z4 z5
wherein W i5 oxygen or sulfur;
Rl is selected from the group consisting of alkyl
having l to 6 carbons, cycloalkyl having 3 to 7 carbons,
phenyl, substituted phenyl, phenylalkyl having l to 3
caxbons in said alkyl, (substituted phenyl)alkyl
h~ving l to 3 carbons in said alkyl, phenoxyalkyl
having l to 3 carbons in said alkyl, (sub~tituted
phenoxy)alkyl having l to 3 carbons in said alkyl,
naphthyl and -(CH2)n-Q-R ;
wherein the substituen~ on said substituked
phenyl, said (substituted phenyl)alkyl and said
(substituted phenoxy)alkyl is selected from the group
consisting of fluoro, chloro, alkyl having l to 3
carbons, alkoxy having 1 to 3 carbons and trifluoro-
methylg n is zero~ l or 2; Q is a divalent radical
derived from a compound selected from the group
consisting of furant thiophene, pyrrole, thiazole,
isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole,
1,2~5-thiadiazole, tetrahydrofuran, tetrahydrothiophene,
pyridine, pyrimidine, pyrazine, benzo[b]furan and
benzo[b]thiophene7 and R is hydrogen or alkyl having
1 to 3 carbons;
5~
-4-
and R2 is selected from the group consisting of
alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7
carbons, phenoxymethyl, furyl, thienyl, pyridyl and
R3
~4
wherein R3 and R4 are each selected from the group
consisting of hydrogen, fluoro, chloro, alkyl having 1
to 4 carbons, alkox~ having 1 to 4 carbons and tri-
fluoromethyl~
Said compounds of formula I are active as analyesic
agents r and as agents for treating inflammatory diseases,
such as the arthritides. Accordingly thi8 invention
also provides a method of elicî~ing an analgesic response
in a mammalian subject, especially man; a method of
treating an inflammatory di~ease in a mammalia.n subject,
especially man; and pharmaceutical compositions comprising
a compound of formula I and a pharmaceutically-acceptable
carrier.
A f irst preferred group of compounds of this
invention conslsts of the compounds of formula I,
wherein X and Y are each hydrogen and Rl ic selected
from the group consisting of 2-furyl, 2-thienyl and (2-
thienyl)methyl. Among this first preferred group,
particularly preferred compounds are those wherein R2
is phenylO
A second preferred group of compounds of this
invention consists Of the compounds of formula I J
wherein X is 5-chloro, Y is hydrogen and Rl is selected
from the group consisting of 2-furyl, 2-thienyl and
~2556S~
l2-thienyl)methyl. Among this second preferred group,
particularly preferred compounds are those wherein R2
is cyclohexyl~
Especially preferred individual compounds of the
invention are:
N-benzoyl-3-(2-furoyl~-2-oxindole-1-carboxamide
(I:X is hydrogen; Y is hydrogen; Rl is 2-furyl, R2 is
phenyl) and
N-cyclohexylcarbonyl-5-chloro-3 (2-thenoyl)-2-
oxindole-l-carboxamide (I:X is 5-chloro; Y i5 hydrogen;
Rl is 2-thienyl~ R2 is cyclohexyl).
Yet further this invention provides novel com-
pounds of the formula
X ~
y ~ N ~ O
O=C-NH-C-R2
o
wherein X, Y and R are as defined previously. The
compounds of formula II are useful as intermediates to
the compounds of formula I.
Also useful as intermediates to the compounds of
the formula I are the compounds of the formula
X ~ -Rl ---(IV)
57
-5a-
and the base salts thereof, wherein X, Y and Rl are
as defined previously. A preferred sub-group of
compounds of the formula IV consists of those compounds
in which X is hydrogen, 5~fluoro or 5-chloro; Y is
hydrogen, 6-fluoro or 6-chloro; and Rl is benzyl,
furyl, thienyl or thienylmethyl; provided that when X
and Y are both hydrogen, Rl is not benzyl. The
compounds of formula IV in said latter preferred sub-
group are novel, and as such they form part of this
invention.
The analgesic and antiinflammatory compounds of
this invention are the compounds of formula I, wherein
X, Y, Rl and R2 are as defined previously. Thus, the
compounds of this invention are derivatives of 2-
oxindole, the bicyclic amide of the formula
6~o
~5i657
~6-
More particularly, the analgesic and antiinflammatory
agents of this invention have an N acylcarboxamido
substituent, -C(-O)-NH-C(=O)-R2, at the l-position and
an acyl substituent, -C(-O)-Rl, at the 3-position of
2-oxindole, and the benzo ring can be further substi-
tuted by X and Y groups. X and ~ can be certain
monovalent substi~uents as defined previously, or X
and Y when on adjacent carbon atoms on the benzo ring
can represent a methylenedioxy group, -OCH2O-, or
ethylenedioxy gxoup, ~OCH2CH2O~. Yet further, X and
Y, when hey are attached to adjacent carbon atoms of
the benzo ring of khe 2-oxindole, can form a divalent
unit, æ, such that when Z is taken with the carbon
atoms ~o which it is attached it forms a ~used carbo-
cyclic or heterocyclic ring. Certain divalent groupsfor Z ~i e. zl_Z5) have been listed earlier. ~hus,
when Z is æl, X and Y when taken with the carbons to
which they are attached represent a fused cyclopentene
ring; and when Z is Z5, X and Y when taken with the
carbons to which they are attached represent a fused
furan or thiophene ring. Moreover, it is to be
understood that when Z is Z4 or ZS, the Z group can be
attached in either of two possible ways. Thus, for
example, when X and Y are at C-5 and C-6 and they are
Z5, the formula I embraces both o~ tha following
formulae:
~C-Rl
O=C--NH--I--R
~t5~657
I l--Rl
OE~n~o
, O=C-NH~ R
Additionally, as will be appreciated by one
skilled in ~he art, the analgesic and an~i-inflammatory
compounds of this invention o~ formula I, wherein X, Y,
Rl and R2 are defined previously, are capable of
enolization; and therefore they can exist in one or
more tautomeric (enolicl forms. All such tautomeric
(enolic~ forms of the compounds of formula I are
considered to be within the scope of this invention.
The compounds o~ formula I are prepared from the
appropriate 2-oxindole compound of the formula
" 11
wherein X and Y are as defined previously. This is
accomplished by attaching the substituent -C(=O)-
NH-C(=O)-R2 to the 1DPOSitiOn and the substituent
-C(=O)-Rl to the 3-positionO These su~stituents can be
attached in either order, and this leads to two vari-
ations in the method for making the compounds of
formula I, as sho~n in the Scheme.
~5~57
., -B-
SCHEME
N ~ O
IIIl
'/
x~b~Rl y~O
O=C-NH~c-R2
(IV) (II)
U~O
O=C-NH-~-R
o
(I)
Thus the first variation involves the sequence:
compound III to compound IV to compound I, while the
second variation involves the sequence: compound III
to compound II to compound I.
g_
The -C(=o~-NH-C(=0)-R2 group is attached by
reacting a compou~d of the formula III or a compound
o~ the formula IV with an acyl isocyanate of the
formula R2-C(=O)-N-C=Oo Most commonly, ~he reaction
5 i5 carried out by contacting substantially equimolar
quantities of the xeactants in an inert solvent at a
temperature in the range ~rom 50 to 150Co ~ and
preferably ~rom 100 ~o 130~C. In this context an
inert solven~ is one which will dissolve at least one
of the reac~ants, and which does not adversely interact
with either of the xeactants or the product. Typical
solvents which can be used include aliphatio hydro-
carbons, su~h as octane, nonane, decane and decalin;
aromatic hydrocarbons, such as benzene, chlorobenzene,
toluene, xylenes and tetralin; chlorinated hydrocarbons,
such as 1~2-dichloroethane; e~hers, such as ~etra-
hydrofuran, dioxane, l,2-dimethoxyethane and di(2-
methoxyethyl)ether; and polar, aprotic solvents such
as N,N-dimethylformamide, N,N-dimethylacetamide, N
methylpyrrolidone and dimethyl sulfoxide. The reaction
time varies according to the reaction temperature, but
at a temperature from 100 to 130~., reaction times of
- a few hours, e.g , 5 to 10 hours are commonly used.
When a relatively ~on-polar reaction solvent is
used for the reaction of a compound of formula III or
IV with an acyl isocyanate of formula R2-C(=0)-N=C-0,
the product (I or II) is usually out of solution at
the end of the reaction when the reaction mixture is
cooled to room temperture. ~nder these circumstances
the product is usually recovered by filtration.
However, if relatively polar solvents are used and ~he
product is not out of solution at the end of the
reaction, the product can be recovered by solvent
evaporation or, in ~he case of water-miscible solvants,
,: .. .;,~, . . ., ;~,
~5~65~
., --10--
by dilution of the reaction medium with water. This
causes the product to precipitate and again it can
be recovered by filtration~ The reaction product (I
or II) can be purified by standard mathods, e.g.,
recrystallization.
The reaction between a compound of formula IV
and an acyl isocyanate of formula R2 C(=O)-N=C=O can
b~ ~peeded up by the addition of a base, such as a
tertiary ami~e, e~g., trimethylamine, triethylamine,
~ributylamine, N-methylpiperidine, N-methylmorpholine
or N,N dimethylaniline. From about one to about four
equivalents o the basic agent is usually added, and
this p~rmits the use of reaction temperature from 20
to 50C. At ~he end of the reaction, the reaction
lS medium must be neutralized (or made acidic) and then
the product is isolated as described earlier.
The -C(=O)-Rl side-chain can be attached to a
compound of the formula II by reaction with an activated
derivative of a carboxylic acid of the formula Rl-
C~-O)OH. The reaction is carried out by treating said
compound of formula II in an inert solvent with one
molar equivalent, or a 51 ight excess, o~ an activated
~ derivative of a compound of formula Rl-C(=O)O~, in the
presence o~ from one to four equivalents o a basic
agent. An inert solvent is one which will dissolve at
least one of the reactants, and will not adversely
interact wi~h either of the reactants or the product.
However, in practice, a polar, aprotic solvent, such
as-N,N-dimethylformamide, N,N-dimethylacetamide, N-
methylpyrrolidone or dimethyl sulfoxide, is commonlyused~ Conventional methods for activating the acid of
formula R1-C(=O)O~ are used. For example, acid
halides, e.g., acid chlorides; symmetrical acid
- - - x ;i,~ ~,. ..
. . j , . ~ .. . .
~2~S~57
., --11--
anhydrides, Rl-C(=0)-0-C(=0)-Rl; mixed acid anhydrides
with a hindered low-molecular weight carboxylic acid,
Rl-c~=o)-o-c(=o)-R5~ where R5 is a bulXy lower-alkyl
group such as t-~utyl; and mixed carboxylic-carbonic
anhydrides, Rl-C(=0) 0-C(=0)-OR6, wherein R6 is a
lower-alkyl group! can all be used. In addition, N-
hydroxyimide esters (such as N-hydroxysuccinimide and
N-hydroxyphthalimide esters)~ 4-nitrophenyl esters,
thiol esters (such as thiol phenyl esters) and Z,4,5-
trichlorophenyl esters, and the like, can be ~sed.
A wide variety of basic agents can be used in thereac~ion between a compound of formula II and the
activated derivative of the acid of the formula Rl-
C(=0)0~. However, preferred basic agents are tertiary
amines, such as trimethylamine, triethylamine, tri-
bu~ylamine, N-methylmorpholine, N-methylpiperidine and
4-(N,N-dimethylamino)pyridine.
The reaction between a compound of the formula II
and the activated derivative of the acid of formula
Rl-C(=0)-0~ is usually carried out in the temperature
range from ~10 to 25C. Reaction times of from 30
minutes to a Eew hours are common. At the end of the
~ reaction, the reaction medi~ is usually diluted with
water and acidiied, and then the product can be
recovered by filtration. It can be purified by
~tandard methods, such as recrystallization.
The -C(=0)-Rl side-chain can be attached to a
compound of the ~ormula III by reaction with a derivative
o the appropriate acid of the formula Rl-C(=0)-OH,
in a lower-alkanol solvent (e.g. ethanol), in the
presence of an alkali metal salt o~ the lower-alkanol
solvent (e.g. sodium ethoxide), according to s~andard
procedures. ~ypical derivatives of the acid of the
~255~S'7
-12~
formula Rl-C(=O)O~ which can be used include acid
chlorides, acid anhydrides of the formula Rl-C(=O)-O-
Ct=O)-Rl, Rl-C(=o)-o-c(=o~-R5 and Rl-C(=O)-O-C(=O~-OR6,
and simple alkyl esters of ~he formula Rl C(=O) OR6,
wherein R5 and R6 are as defined previously. Usually,
a small excess of the derivative of the acid of
formula Rl-C(=O)-OH is used, and the alkoxide salt is
usually present in an amount from one to two molar
equivalentsy based on said derivative of the acid of
formula Rl-C~=O~OH. The reaction between the dPrivative
of the acid of the formula Rl-C(=O)OH and the compound
of formula III is usually started at 0 to 25C., but
it is then usual to heat the reaction mixture at a
temperature in the range from 50 to 130C., and
preferably at about 80C., to complete the reaction.
Vnder these circumstances, reaction times of a few
hours, e.g~ two hours, up to a few days, e.g., two
days, are commonly used. The reaction mix~ure is then
cooled, diluted with an excess of water, and acidified.
The product of formula IV can then be recovered by
filtration or by the standard procedure of solvent
extraction.
Th~ acyl isocyanates of the formula R2-C(=O)-
N=C=O which are known can be prepared by the published
procedures. Those which are analogs of known compounds
can be prepared by analogous procedures. In general,
the corresponding amide of the formula R~-C(=O)-NH2
reacts with oxalyl chloride, or the acid chloride of
formula R2~C(=O)-Cl reacts with silver cyanateO
Consult: Speziale et al., Journal of Or~anic chemistry,
28, 1805 (1963) and 30, 4306 (1965~; Ramirez et al.,
Journal of Organic Chemist~, 34, 376 (1969); and
~556~7
~. -13-
Naito et al., Journal of Antibiotics (Japan), 18, 145
(~965~.
The 2-oxindole compounds of formula III are
prepared ~y known methods, or methods analogous to
known methods. Con~ult: "Rodd's Chemistry of Carbon
Compounds,~ Second Edition, S. Coffey editor, Volume
IV Part A, Elsevier Scientific Publishing Company,
1973, pp. 448-450; Gassman et al., Journal of Organic
Chemi~tr~, 42, 1340 (19~7~; Wright et al., Journal of
the American Chemi~al ~ , 78, 221 ~1956); Beckett
et al.~ Tetra edron, 24, 6093 (1968); United States
Patents Nos. 3,882,236, 4,006,161 and 4,160,032;
Walker, Journal of the American Chemical Societ~, 77,
3844 (1955); Protiva et al., Collection of Czechoslovakian
Chemical Communications, 44, 2108 (1979); ~cE~oy et al.,
Journal o Or~ic Chemistry, 38, 3350 (1973); Simet,
Journal _ Organic Chemistry, 28, 3580 (1963);
- Wieland et al., Chemische Berichte, 96, 253 51963);
and reEerences cited therein.
The compounds of the ormula I are acidic an~
they form base salts. All such base salts are within
the scope of this invention and they can ~e prepared
~ by conventional methods. For example, they can be
prepaxed simply by contacting the acidic and basic
en~ities, usually in a stoichiometric ratio, in either
an aqueous, non-aqueous or partially aqueous medium,
as appropriate. The salts are recovered either by
filtration, by precipitation with a non-solvent
followed by filtration, by evaporation of the solvent,
as appropriate, or, in the case of aqueous ~olution~,
by lyophilization. Typical salts of the compounds of
formula I which can be prepared re primary, secondary
., . , - ~
.,. . ~rr _ ' ~ ' . . ` ~ .
~2~ 7
and tertiary amine salts, alkali metal salts and
alkaline earth metal salts. Especially valuable are
the ethanolamine, diethanolamine and triethanolamine
sal~s.
Basic agents suitably employed in salt formation
be7Ong to both the organic and inorganic types, and
they include organic amines, alkali metal hydroxides,
alkali metal car~onates 9 alkali metal bicarbonates,
alkali metal hydrides, alkali metal alkoxides, alkaline
earth metal hydroxides, alkaline earth ~etal carbonates,
alkaline earth metal hydrides and alkaline earth metal
alkoxides. Representatlve examples of such bases ar~
primary amines, such as n-propylamine, n-butylamine,
aniline, cyclohexylamine, benzylamine, ~-toluidine,
ethanolamine and glucamine; secondary amines, ~uch as
diethylamine, diethanolamine, N-methylglucamine, N-
methylaniline, morpholine, pyrrolidine and piperidine;
tertiary amines, such as triethylamine, triethanol-
amine, N,N dimethylaniline, N-ethylpiperidine and l~_
methylmorpholine; hydroxides, such as sodium hydroxide;
alkoxides, such as sodium ethoxide and potassium
methoxide; hydrides, such as calcium hydride and
sodium hydride; and carbonates, such as potassium
carbonate and sodium carbonate.
The compounds of formula I possess analgesic
activity. This activity has been demonstrated in mice
by showing blockade of the abdominal stretching
induced by administration of 2-phenyl 1,4-benzoquinone
~P~Q). The method used was based on that of Siegmund
et al., Proc. So _xp. ~iol. M~d., 95: 729-731,
1957, as adapted for high throughput (see further
Milne and Twomey, ~2~ and Actions, 10: 31-37,
, . . , ,: .
S7
-15~
1980)~ The mice used in these experiments were
Carworth males, albino CF 1 strain, weighing 18-20 g.
All mice were fasted overnight prior to drug adminis-
tration and testing.
The compounds of formula I were dissolved or
suspended in a vehicle consisting of ethanol (5%),
emulphor 620 (a mixture of polyoxyethylene fatty acid
es~ers, 5%) and saline (90%)O This vehicle also
served as control. Doses were on a logarithmic scale
~i.e., ... 0.32, 1l0, 3.2, 10, 32.. ~ mg/kg), and were
calculated ~rom weights of the salt when applicable,
and not of the acid. The route of administration was
oral, with concentrations varied to allow a constant
dosage volume of 10 ml/k~ of body weight. The afore-
lS said ~ethod o~ Milne and Twomey was used to determine
efficacy and potency. ~ice were treated with com-
pounds orally, and one hour later received PBQ, 2
mg/kg, intrapexitoneally. Individual mice were then
immediately pl~ced in a warmed Lucite (transparent
plastic~ chamber, and, starting five minutes after
PBQ administration t the number of abdominal constrictions
during the sub-qequent 5 minutes was recorded. The
-- degree of analgesic protection (% MPE) was calculated
on the basis o~ suppression of abdominal constriction
relative to counts from concurrent control animals
run on the same day. At least four such determinations
(N ~ S) provided dose-response data for generation of
an MPE50~ the be t estimate of ~he dose that reduces
abdominal constriction to 50% of control levels.
The compounds of formula I also possess anti-
infla~matory activity. This activity has been demonstrated
in rats by a method based on the standard carra~eenin-
induced rat foot edema test. (Winter et al., Proc.
S . Exp. Biol. Med., 111: 544, 1963~
;
--.
~;25~
Unanesthetized, adult, male, albino rats of 150 g
to 190 g body weight were numbered, weighed, and an
i~k mark placed on the right lateral malleolus. Each
paw was immersed in mercury exactly to the ink marX.
The mexcury was contained in a glass cylinder, connected
to a Sta~ham Pressure Transducer. The output from ~he
transducer was fed through a control unit to a micro-
voltameter. The volume o~ mercury displaced by the
immer~ed paw was r~ad~ ~rugs were given by gavage.
One hour after drug administration, edema was induced
by injection of 0.05 ml of 1~ solution of carrageenin
into the plantar tissue of ~he marked paws. Immediately
thereafter, the volume of the injected foot was
measured. The increase in ~oot volume 3 hours after
the injection of carrageenin constitutes the indi~idual
infla~matory response.
The analgesic activity of the compounds of
formula I makes them useful for acute administration
to mammals or the control of pain, e.g., post-operative
pain and the pain of trauma. Additionally the compounds
o~ formula I are use~ul for chronic administration to
mammals for the alleviation of the symptoms of chronic
diseases, such as the inflammation of rheumatoid
arthritis, and the pain associated with osteoarthritis
and other musculoskeletal disorders.
When a ¢ompound of the formula I or a pharma-
ceu~ically acceptable salt thereof is to be used as
either an analgesic agent or an anti-inflammatory
agent, it can be administered to a mammalian subject
either alone, orr preferably0 in combina~ion with
pharmaceutically-acceptable carriers or diluents in a
pharmaceutical composition, according to standard
pharmaceutical practice. A compound can ~e administered
- .
~ . . ~ .
~S56~i~
-17-
orally or parenterallyO Parenteral administration
includPs intravenous, intramuscular, intraperitoneal,
subcu~aneous and topical administration.
In a pharmaceutical composition comprising a
compound of ormula I, or a pharmaceutically-acceptable
salt thereof, the weight ratio of carrier to active
ingredient will normally be in the range from 1:4 to
4:1, and preferably 1:2 to 2:1. However, in any given
case, the.ra~io chosen will depend on such factors as
~he solubility of the active component, the dosage
contempl~ted and the precise route of administration.
For oxal use of a compound of formula I of this
invention, ~he compound can be administered, for
example, in the ~orm of tablets or capsules, or as an
aqueous solution or suspension. In the case of
tablets for oral use, carxiers which are commonly used
include lactose and corn starch, and lubricating
agents, such as magnesium stearate, are commonly
added. For oral administration in capsule form,
useful diluents are lactose and dried corn starch.
When aqueous suspensions are required for oral use,
the active ingredient is combined with emulsifiying
and suspending agents. I~ desired, certain sweetening
and/or flavoring agents can be added. For intramuscular,
intraperitoneal, subcutaneous and intravenous use,
sterile solutions of the active ingredient are u~ually
prepared, and the pH of the solutions should be
suitably adjusted and buffered. For intravenous use,
the total concentration of solutes should be controlled
to render the preparation isotonic.
When a compound of formula I or salt thereof is
used in a human subject, the daily dosage will normally
be determined by the prescribing physician. Moreover,
,
~5657
-18-
the dosage will vary according to the age, weight and
response o~ the individual patient, as well as the
severity of the patient's symptoms and the potency of
the particular compound being administered. However,
for acute administration to relieve pain, an effective
analgesic response eliciting dose in most instances
will be 0.1 to 1.0 g as needed (e.g., every four to
six hours3. For chronio administration to alleviate
~trea~) inflammation and pain, in most instances an
effective dose will be from 0.S to 3.0 g per day, and
preferably 0.5 to 1.5 g per day, in single or divided
doses. On the other hand, it may be necessary to use
dosages outside these limits in some cases.
The following examples and preparations are being
15 provided solely for the purpose of further illustration.
12~jS~57
--19--
EXAMPLE 1
N-Benzoyl-3-(2-furoyl)-2-oxindol~
A mixture of 909 mg (4.0 mmole~ of 3-(2-furoyl)-
2woxindole and 706 mg (408 mmole) of bPnzoyl iso-
! cyanate in 25 ml of toluene was heated to reflux and
then it was heated a~ reflux tempexature for 7 hours.
The mixture was allowed to stand at room temperature
overnight and then the precipitate which had formed
~as removed by filtration, g~ving 1.3 g of crude
product. Th~ crude product was recrystallized from ca
30 ml of acetic acid, giving 920 mg of the title
compound, mp 184C (dec).
AnalYsis: Calcd. ~or C21H1405N2: C, 67.37; H, 3.77;
N, 7.49~. Found- C, 66.90; H~ 4.02; N, 7.38~.
.,:; . ........... . .
5~
-20-
EXAMPLE 2
N-Benzoyl-3-(2-furoyl)-2-oxindole-1
To 30 ml of N,N~dimethylformamide was add~d,
with stirring, 2.8 g (10 mmole) o~ N-benzoyl-2-
oxindole-l~carboxamide, followed by 2.9 g (24 mmole)
of 4-~ ,N-dimethylamino~pyridine. The mixture was
cooled in an ice-bath and then to it was added,
dropwise, with stirring, during 10 minutes, a solution
o~ 1.6 g (12 mmole) of 2-furoyl chloride in 10 ml of
N,N dimethylformamide. Stirring was continued for 30
minutes and then the reaction mixtuxe was poured into
a mixture prepared from 250 ml of water and 8.5 ml of
3N hydrochloric acid. The resulting mixture was
cooled in an ice-bath and ~le solid was removed by
filtration. The solid was recrystallized from ca. 75
ml of acetic acid to give 2.94 g of the title compound
a~ yellow-brown crystals, mp 190C.
The ultraviolet spectrum of the title compound
showed absorptions as follows:
SolventWavelength E~silon
(nanometers)
CH30H 245 6,920
375 2,530
CH OH ~ 1 drop 249 7,200
O.~N NaO~ 372 2,710
CH OH + 1 drop 241 9,070
O.~N HC1
~5~65~7
-21-
EXAMPLE 3
N-Ben~oyl~3-acetyl-2-oxindole-
l-carboxamide
To a stirred slurry of 841 mg ~3.0 mmole) of N-
benzoyl-2-ox.indole-l-carboxamide in 5 ml of N,N-
dimethylformamide was added 806 mg (6.6 mmole) of 4-
(N,N-dimethylamino)pyridine. S~irring was continued
for a few minutes, and then the slurry was cooled in
an ice-bath and a solution of 337 mg (3~3 mmole) of
acetic anhydride in 2 ml of N,N-dimethylformamide was
added dropwise. 5~irring was continued for l hour,
and then the reaction mixture was poured onto a
mixture of 65-70 ml. of ice~water and 2.2 ml of 3N
hydrochloric acid. The solid which precipitated was
recovered by filtration. It was recrystallized from
ethanol to give 385 m~ of the title compound as tan
crystals, mp 198C.'
Analysis Calcd. for C18Hl4O4N2:
C, 67.07; H, 4.38; N, 8.69%.
- 20 Found: C, 66.78; H, 4.65; N, 8.62%.
.
.
~5~57
!
-22-
EXAMPLE 4
N-Benzoyl-3-l2-thenoyl)-2-oxindole-1-
carboxamide
To a stirred solution of 486 mg (2.0 mmole) of
3-(2-thenoyl)-2-oxindole and 445 mg t4.4 mmole) of
triethylamine in 5 ml of dimethyl sulfoxide was added
324 mg ~202 mmole~ of benzoyl isocyanate. Stirring
was continued for 1 hour, and then the mixture was
poured into a mixture of 50 ml of water and 1.7 ml of
3N hydrochloric acid. The resulting mixture wa~
cooled in an ice-bath and the solid was removed by
filtration. The solid was recrystallized from ca. 30
ml of 2-1 ethanol:water to give 190 mg of the title
compound as fluffy~ yellow crystals, mp 165-166C.
(dec).
~ y~ C . C21H144N S: C, 64.60; H,
3.61; N, 7.18~. Fou~d: C, 64.53; H, 3.75; N, 7.10%.
XAMPLE 5
Reaction of the appropriate N-substituted-2-
oxindole-l-carboxamide with the requisite acid
chloride of the formula Rl-C0-Cl, substantially
according to the procedure of Example 2, afforded the
following compounds 5
X ~-Rl
O=C--NH C-R2
o
. . - . . , , -- :
~5~;57
--23--
_ __
O ~ ~1 O~ 1` ~ ~1 ~ r~ ~ r~
Z ~ o~
_ r~
q~
~; Ir) ~`J N ~ I` 01 ~0 0 r~l
C ~ 9 0
._
~ cr~ In O a~
U I~ '1 0 ~ U~ il~ ~ cn
~ ~ ~ ~ o w ~ ~r o ~o co
~1 . U~
~ ._ _
~ GO ~ Ul a~ o o
æ
._ _
,~ ~ o c~ ~ o a~ o ~ ~ ~D
o~r ~ o ~ ~o ~ I`
3 ~ ~ r~
O
~ o ~ o r~ o ~ ~ o
U C) ~o ~ r~ ~ ~ ~ ~ ~ c~ u~
~ o ~ r o c~
. . _
~:: ~ O a:J N ~r
a~ o ~ _I I I c~ oo
~ s -- ~l ~ ~ ~ ~ u~ u~ u~
~1 0 0 In ~ O O ~ ~ '7 ~ Ul ~ID U~ r~ ~1
5 P~ _ ~ o a~
o ,~ o _~ o _I o _I o _I o ,,
' C.~ O X t~ X U X O X ~ X ~) X
.c .c s .c s ~ a~
Q. Cl. Q ~ ~ U ~ ~- S t~
I I ~ ~ .
~1
~r1 S ~ )~ rl .C ~ h rl .C
N _ ~ ~ F t~l C`J w
X
~ I æ
. ~,~ .
,
~S~i7
--2 4--
_ _
r o co u~ In u~ ~ co~ r~ ~ ~ u~
~D ~r o o u~
Z
~ r~ I~ r r ~ r
~ _
u~
:~ ~ o o co
O X O . ~ . O . . . . . . ~ O
U~ ~U~ ~ ep ~r ~P ~ul ~ ~ ~P .rl
_ V
~ ~ O~CO O ~
N r ~N ~ 0~ I O
C.)
CO U:~ ~` ~ O _I 1` U
_ _
~C Z o~
r~ r r~ D 0 r~
~ - ~
o ~ ~ P ~ o ~ I` ~1
a~ _I crt~ .~r ~I It7 1~ Ul al ~ co
~1 ~ . . ~ o
3 ~ e
~ o o co a~r ~ ~ o a~ ~ I`
U ~ ID ~ U~
u .. ... ... ...
~ ~ o ,~
, .~
rl
~ u~ ~ ~ ~ u
~ e ^ u~ n u~
~ o
o o O ,~ r ~ ~1 0 u~
O 1~ ~ D~ O In a~
Q~
'1 0 0 0 0 0 0
~ ~ ~ ~ ~~ ~ o
3 ~Q~ Qo~o~ ~ ~o a~
. ~ OI I I I h E
Cl O U
~ . h h a)
S~ ~ S ~ ~ rl S ~ S~ rl S ~ S~ rl S ~ U~
J~ S ~ ,C~ S ~ S~ 3 N O
I ~ ~ ~ I ~ C S~ ~1 S
I I N ~ J I I N C) I I N a)
-- ~ t~l --E N ~I ~l N --E O S ,~ 3
~cq y u ~ ~ ~ o u c~ ~~
. _I O ~ ~
~: C ~
S65~
-25-
EXAUPLE 6
N-Benzoyl-3-(2-thenoyl)-2-oxindole-1-carboxamide
was also prepared by reaction of 3-(2-thenoyl)-2-
oxindole with benzoyl isocyanate using the method of
S Example 1,
N-~enzoyl 3 (2~[2-thienyl]acetyl)-2-oxindole-1-
carboxamide was prepared by reaction of 3-(2~[2-
~hienyl]acetyl)-2-oxindole with benzoyl isocyanate
u~ing the method of Example 1.
la EXaMPLE 7
Following ~he method of Example 1 (Method A),
Example 2 or 3 ~ethod B), or Example 4 (Method C),
the following compounds were made:
X ~-R
N ~ O
O=C-NH-ll-R2
-26-
Method Melting
1 2 0~ Prepl Poin~
X R R aration (C)
,,
H me~hyl phenyl A,B 198-200d
H isopropylphenyl B 165d
- H cyclohexylphenyl B 181d
5~5-Cl methyl phenyl B 215-217d
~5-Cl isc,propyl phenyl B 185 5_
~5-Cl cyclohexylphenyl B 192-194d
phenoxyme~hyl phenyl A 202d
~ 3-furyl phenyl C 187d
~ 5-Cl cyclopropyl phenyl B 213-215d
H cyclopropyl phenyl B 173d
H isopropyl phenyl B 155d
~ l-phenylethyl phenyl B 173d
5-Cl benzyl phenyl B 239-240d
S-C~3 2-furyl phenyl B 204-205d
H (3-thienyl)~
me~hyl phenyl ~ l9S-197d
6-C1 2-thienylphenyl B 192-193d
6-F 2-furyl phenyl B 189-190
6-F 2-thienylphenyl B 190-194
20 ~ S~Cl 5-ethyl-2-
furyl phenyl B 202-203.5d
H 5-ethyl-2-
furyl phenyl B 174-175
`~ S F 2 furyl phenyl B 172d
5-F (2-thienyl)-
methyl phenyl B 189d
'6-Cl 2-furyl phenyl B 199-200
5-F (2~thienyl)-
methyl phenyl B 167d
~Cl l2-thienyl)-
methyl phenyl B 199-20Od
~27-
Method Melting
1 of Prep~ Poin~
X R . - R2 arationl (C)
2~thienyl 4-fluoro- C 163.5-
phenyl 164.5d
2 furyl 4-fluoro- C 164.5d
phenyl
. methyl 4-1uoro- A 205-207d
phenyl
~ benzyl 4-fluoro- ~ 207-209d
phlenyl
cyclopropyl 4-fluoro- B 167.5d
. phenyl
8 ~2-thienyl)- 4-fluoro-
methyl phenyl A 216-217d
5-CH3 2-thienyl 4-fluoro- B 178-179d
phenyl
5-C1 2-furyl 4-fluoro- B 197-199d
phenyl
5-C~3 2-~uryl 4-~luoro~ B 179-181d
phenyl
5-C1 2-thienyl 4-fluoro- B 19105-
phenyl 192.5d
EI l~thienYl)- 4-methoxy-
methyl phe~yl A 197-198d
- ~ 2-thienyl 4-methoxy~ B 173d
phenyl
H 2-furyl 4-methoxy- B 146d
phenyl
~ cyclopropyl 4-methoxy- B 193d
phenyl
H isopropyl 4-methoxy- B 125d
phenyl
H 2-furyl 4~chloro- B 180-18~d
phenyl
2-thienyl 4~chloro- B 170-171d
phenyl
isopropyl 4-chloro- B 164-16~d
phenyl
~ propyl phenyl B 184-185d
H 2-thienyl 2 methyl- B - 173.5d
phenyl
565~7
-28~
Method Melting
of Prep- Poin~
X Rl ' R2 arationl ( C)
2 furyl 2-methyl- B 167-168d
phenyl
H (2-thienyl)- 2-methyl-
methyl phenyl B 179.5d
~ cyclopropyl cyclohexyl B 153-154d
5 ~ me~hyl cyclohexyl B 167-168d
l-phenylethyl cyclohexyl B l91d
H 5-methyl-2-
fu~yl cyclohexyl ~ 163-165d
S-Cl 5-methyl-2-
furyl cyclohexyl B 197.5d
5 Cl methyl cyclohexyl B 214.5d
10 5-Cl propyl cyclohexyl B 162-163d
S Cl isopropyl cyclohexyl B 205-206d
5-CH3 2-furyl cyclohexyl B 170-171
S-C~3 2-thienyl cyclohexyl B 153-154.5d
H S-ethyl-2-
fu~yl cyclohexyl B 146-147
15 5-CH 5-ethyl-2-
3 furyl cyclohexyl B 190-191
5~CH (2-thienyl)-
- 3 methyl cyclohexyl B 158-159
S-Cl 5-ethyl-2-
furyl cyclohexyl B 210-211d
6-C1 2-furyl cyclohexyl B 1~3-184
S-F 2-furyl cyclohexyl B 186.5-
, 18?.5d
5-F 2-~hienyl cyclohexyl B 145 5-
5-F ~2-thienyl)- .
methyl cyclohexyl B 164-165
;' ~ ~-- ^ ''^ ~; ~ ~ - : , 7~; S, t,,~
~5S~S~
.
' -29
Method Melting
1 2 of Prepl Poin~
X R R aration t C~
6-C1 2-thie~yl cyclohexyl ~ 172-173
6-C1 ~2-~hienyl)-
methyl oyclohexyl B 173-175d
4--Cl 2-~hienyl cyclohexyl B 189-190
4-C1 ~2 thienyl)-
methyl cyclohexyl B 172-173
~-Cl methyl oyclohexyl B 131-132
5-CF3 2-furyl cyclohexyl B 194-195d
S~CF3 2-thienyl cyclohexyl B 171-172d
6-F 2-furyl cyclohexyl B 164-166
6-F 2-thienyl cyclohexyl
5-C~3 2-thienyl t-butyl B 189.5d
5-CH3 methyl t-butyl B 194d
5-Cl methyl t-butyl B 211.5d
5-C~ 5-ethyl-2-
3 furyl t-butyl B 214-215
5-C1 5-ethyl-2-
~uryl t-butyl B 224-225
5-F 2-furyl t-butyl ~ 212 . Sd
5-F 2-thienyl t-butyl B 183.5d
- 5-F (~-thienyl)-
methyl t-butyl B 161d
6-C1 2-thienyl t-butyl B 191-192
~o 5-C~3 2-thienyl isopropyl B 146-147d
~-CN3 2-furyl isopropyl B 166-167d
5-C~3 phenoxymethyl isopropyl B 184-186
5-Cl phenoxymethyl isoprop~l B 186-188d
5~Cl b~nzyl isopropyl 8 184-185
S-C1 eyclohexyl isopropyl B 206 208d
S~CH 5 methyl-2-
3 furyl isopro~yl B 194d
5-C~3 methyl isopropyl B 158-159
65~
-30-
Method Melting
1 2 of Prepl Poin~
X R R aration (C)
5-Cl S methyl-2- isopropyl B 198.5-
furyl 199.5
5-Cl methyl isopropyl B 215-216
~ methyl isopropyl B 170-172
~ cyclohexyl isopropyl B 188-189
benzyl isopropyl R 145-146
~ phenoxyme~hyl isopropyl ~ 157-158
5 C1 5-ethyl-2-
furyl isopropyl 8 209-211d
5-Cl isopropyl isopropyl B 142-143
6~C1 2-furyl isopropyl B 184-185d
6-Cl. 2-thienyl isopropyl B 174.5-175
6-Cl (2-thiei~yl)-
methyl isopropyl B 157-15~d
H 2-thienyl phenoxy- B 161-162
methyl
5~C1 2-thienyl phenoxy- B 182-183
mekhyl
~ 2-furyl phenoxy- ~ 173-175d
methyl
H (2-thienyl)~ phenoxy-
-- methyl methyl B 193-194
5-C1 2-furyl phenoxy- B 194-195.5
methyl
l~he letter A ln this column indicates that the compound
was p~epared substantially according to Example l; the
letter B indicates that the compound was prepared
~ubstantially according to Example 2 or 3; and the
letter C indicates that the compound was prepared
~ubstantially according to Example 4.
~The letter "d" indicateis that the compound melted
with decomposition.
~S56~
-31-
EXAMPLE 8
Eth~nolamine Salt of N-Benzoyl-3-(2-furoyl)-
2-oxindole l-carboxamide
To a slurry of 562 mg (1.5 mmole) of N-benzoyl-
3-(2-furoyl)-2-oxindole-1-carboxamide in 10 ml of
methanol was added 101 my (1.65 mmole) of e~hanolamine.
The resul~ing mixture was heated to boiling for a few
minutes and then it was allowed ~o coolO The solid
which precipitated was recovered by filtratlon to
~ive 524 mg of the title salt, mp 165-166C. Yield:
80%.
Y~ 23H2106N3: C~ 63.44; H, 4.86;
N, 9.65%. Found: C, 63.27; H, 4.95; N, 9.58%.
EXAMPLE 9
The diethanolamine salt of N-~enzoyl-3-(2-
furoyl)-2-oxindole-1-carboxamide was prepared by
substituting diethanolamine for ethanolamine in the
procedure of Example 8 . The product melted at 157-
158C. Yield: 74%.
Analysis: Calcd. for C25H25O7N3: C, 62.62; H, 5.26;
N, 8.76~. Found: C, 62.53; H, 5.31; N, 8.74~.
EXAMPLE 10
The triethanolamine salt of N-benzoyl-3-(2-
furoyl)-2-oxindole-1-carboxamide was prepared by
substituting triethanolamine for ethanolamine in the
procedure of Example 8 . The product melted at 154-
155C. Yield: 60~.
y~ Calcd- for C27H2so8N3 C, 61.94; H7 5.58;
N, 8.03%. Found: C, 61.84; H, 5.61; N, 7.99%.
~5~i~S~7
; -32-
EXAMPLE 11
N-Be~zoyl-2-oxindole-1-carboxamide
To a stirred slurry of 399 mg (3.0 mmole) of 2-
oxindole in 7 ml of toluene was added 485 mg (3.3
mmole) of benzoyl isocyanate. The mixture wa~ heated
llnder re~lux for 2.2 hours and th~n it was cooled to
room temperature. The solid was recovered by ~
txation and i~ was then dissolved in ca. 10 ml of hot
acetonitrile. The acetonitrile solution was decolorized
using activated carbon and then allowed to cool and
the precipitate was recovered by filtration. Recrystal-
li~ation of the precipitate from acetonitrile gave 131
mg of the ti~le compound, mp 183.5-184.5~C.
Analysis: Calcd- for C16H12O3N2 C,
15 N, 9O99%~ Found: C, 68.37; H, 4.58; N, 10.16%.
XS~57
,. -33-
EXAMPLE 12
Reaction of the appropriate 2-oxindole with the
requisite acyl isocyanate, substantially according to
the procedure of Example 11, afforded the following
compounds:
X~
~0
O=C--NII--c-R2
O
Melting
X R2 Point(0C)l Yield(~)
, . . . . _ _
5-Cl phenyl 193-195 43
S-C~3 phenyl 202-203 58
6-Cl phenyl 206-207 59
6-F phenyl 174-175.5
5-F phenyl 187d 37
H 4-fluorophenyl 177-178d 21
__ 5-C~3 4-fluorophenyl 209-211d 78
5-C1 4-fluorophenyl 198-199d 59
H 4-methoxyphenyl 180d 72
H 4-chlorophenyl 18~.5-187.5d 53
2-methylphenyl 166.5-167.5 59
~ cyclohexyl 144>5-145~5 62
20 S Cl cyclohexyl 172-174 63
5-C~3 cyclohexyl 140~141.5 68
6-Cl cyclohexyl 181-182 56
5-F cyclohexyl 163.5-164.5 63
-34-
Melting
X R2 Point(0C)1 Yield(%)
4 Cl cyclohexyl 173~174 69
5-CF3 cyclohexyl 177.5-178.5d 40
6-F cyclohexyl 203-206 43
~ t-~utyl 151-152 35
5-CH3 t-butyl 202.5d 34
5-Cl t-butyl 176.5-177.5d 43
5-F t-butyl 161.5-162.5d 31
6 Cl t-butyl 1~6-147 42
H isopropyl 114-115 23
5-C~3 isopropyl 169-171 38
5-Cl isopropyl 164-165 77
6-Cl i~opropyl 128-129 69
phenoxymethyl 187 188 78
S-Cl phenoxymethyl 218-219 51
. ..
lThe letter "d~ in this column indicates that the
material meltecl with decomposition.
~;Z5~
-35-
PREPARATION 1
3-(2-Furoy~)-2-oxlndole
To a stirred solution of 5.5 g (0.24 mole) of
sodium in 150 ml of ethanol was added 13.3 g (0.10
mole) of 2-oxindole at room temperature. The resulting
slurry was cooled to ice bath temperature, and then
15.7 g ~0.12 mole) of 2 furoyl chloride was added,
dropwi~e, during 10-15 minutes. The ice-bath was
removed, and additional 100 ml of ethanol was added
and then the reaction mixture was heated under reflux
for 7 hours. The reaction mixture was allowed to
stand overnight and then the solid was Eiltered off.
The solid was added to 400 ml of water and the
resulting mixture was acidified using concentrated
hydrochloric acid. The mixture was cooled with ice
and the solid was collected by filtration. The solid
residue was recrystallized from 150 ml of acetic
acid, affording 8.3 g of yellow crystals, mp 209-210C.
(dec).
Analysls: Calcd. for C13HgO3N: C, 68.72; H, 3.99;
N, 6.17~. Found: C, 68.25; H, 4.05; N, 6.20~.
PREPARATION 2
Reaction of 2-oxindole with the appropriate acid
chloride, using the method of Preparation 1, gave the
following additional products:
3-(2-thenoyl)-2 oxindole, mp 189-190C, 17
yield;
3 (2~[2-thienyl]acetyl3-2-oxindole, mp 191-
192.5C, 38% yield;
3-(2-phenoxyacetyl~-2-oxindole, mp 135-136C~
42% yield; and
5-chloro-3-(2-[2-thienyl]acetyl)-2~oxindole,
mp 228-230Co, 22~ yield.
~;Z5~
-36-
PREPARATION 3
3-(3-Furoyl~-2-oxindole
To a stirred solution of 2.8 g (0.12 mole) of
sodium in 200 ml of ethanol was added 13.3 g (0.10
mole) of 2-oxindole, followed by 16.8 g of ethyl 3-
furoate. The mixture was heated under reflux for 47
hours, cooled and then the solvent was removed by
evaporation in vacuo. The residue was triturated
.
under 200 ml of ether, and the solid was collected by
filtration and discarded. The filtrate was evaporated
in vacuo, and the residue triturated under diisopropyl
ether and recovered by filtration. The solid was
suspended in 250 ml of water, which was then acidified
with concentrated hydrochloric acid. This mixture
was stirred to give a solid, which was recovered by
filtration. This latter solid was recrystallized
from acetic acid followed by acetonitrile to give 705
mg of the title compound, mp 185-186C~
Analysis: Calcd. for C13HgO3N: C, 68.72; H, 3.99;
N, 6.17%. Found: C, 68.72; H, 4.14; N, 6.14~.
PREPARATION 3A
Reaction of the appropriate 2-oxindole with the
ethyl ester of the requisite carboxylic acid, sub-
stantially according to the procedure of Preparation
3, gave the following compounds:
5-chloro-3-(2-thenoyl)-2-oxindole, mp 190.5-
192C., 36~ yield;
5-chloro-3-~2-furoyl)-2-oxindole, mp 234-235C.,
54~ yield;
5-chloro-3-(2-phenylacetyl)-2-oxindole, mp 241-
243C., 61% yield;
~SS6~7
-36a~
PREPARATION 3A (Cont.)
5 fluoro-3~2-furoyl)-2-oxindole, mp 222-224C.,
51% yield;
5-fluoro-3-(2-thenoyl3-2-oxindole, mp 200-203C.,
26% yield;
6~fluoro-3-(2-furoyl)-2-oxindole, mp 239-242C.,
26% yield; and
6-chloro-5-fluoro-3-~2-thenoyl)-2-oxindole, mp
212-215~C~, 20% yield.
PREPAPATION 4
5-Chloro-2~oxindole
_ _ , .. _ . .. .
To a stirred slurry of 100 g (0.55 mol3 of 5-
chloroisatin in 930 ml of ethanol was added 40 ml
(0.826 mol) of hydrazine hydrate, resulting in a red
solution. The solution was heated under reflux for
3.5 hours, during which time a precipitate appeared.
The reaction mixture was stirred overnight, and then
the precipitate was recovered by filtration to give
5-chloxo-3-hydrazono-2-oxindole as a yellow solid,
--37--
PREPARATION 4 ( Cont
which was dried in a vacuum oven. The dried solid
weighed 105.4 g
The dried solid was then added portionwise,
during 10 minutes, to a solution of 125.1 g of sodium
methoxide in 900 ml of absolute e~hanol. The resultant
solution was heated under reflux for 10 minutes and
then it was concentrated in vacuo to a gummy solid.
The gummy solid was dissolved in 400 ml of wat2r and
the aqueous solution thus ob~ained was decolorized
with activated carbon and then poured into a mix~ure
of 1 liter of water and 180 ml of concentrated hydro
chloric acid containing ice chips. A tan solid
precipitated and it was collected by filtration and
washed thoroughly with water. The solid was dried
and then it was washed with diethyl ether. Finally
it wa~ recrystallized from ethanol to give 48.9 g of
the title compound, mp 193-195C. (dec).
In an analogous fashion, 5-methylisatin was
converted into 5-methyl-2-oxindole by treatment with
hydrazine. hydrate followed sodium ethoxide in ethanol.
The product melted at 173-174C.
PREPARATION 5
4,5-Dimethyl-2-oxindole and
5,6-dimethYl-2-oxindole
3,4-Dimethylaniline was converted into 3,4-di-
methyl-isonitrosoacetanilide by reaction with chloral
hydrate and hydroxylamine, using the method des~ribed
in-~Organic Syntheses," Collective Volume I, page
327. The 3,4-dimethyl-isonitrosoacetanilide was
cyclize~ with sulfuric acid, according to the method
of Baker et al., Journal of ~ ~ , 17r
149 (1952)~ to give 4,5-dimethylisatin (m.p. 225-226
C~) and 5,6-dimethylisatin tm.p~ 217-218 C.).
~5~S~7
-38-
PREPARATION 5 (Cont.~
4,5-Dimethylisatin was converted into 4,5-dimethyl-
2-oxindole, m.p~ 245.5-247.5 C., by treatment with
hydrazine hydrate, followed by sodium ethoxide in
ethanol, ~ubs~antially according to the procedure of
Preparation 4
In like manner, 5,6-dimethylisatin was converted
into 5,6~dimethyl-2=~oxindole, m.p. 196.5-198 C., by
treatment with hydrazine hydrate, followed by sodium
ethoxide in e~hanol, substan~ially according to the
procedure of Preparation 4.
PREP~RATION 6
4-Chloro~2-oxindole and 6-chloro-2-oxindole
Ao 3-Chloro-is~itrns~ ~e~ilid~
To a stirred solution of 113.23 g (0.686 mol) of
chloral hydrate in 2 liters of water was added 419 g
(2.95 mol) of sodium sulfate, followed by a solution
prepared from 89.25 g ~0.70 mol) of 3-chloroaniline,
62 ml of concentrated hydrochloric acid and 500 ml of
water. A thick precipitate formed. To the reaction
mixture was then added, with stirring, a solution of
155 g (2.23 mol) of hydroxylamine in 500 ml of water.
Stirring was continued and the reaction mixture was
warmed slowly and it was maintained between 60 and
75C. for approximately 6 hours, during which time an
additional 1 liter of water had been added to facili-
tate stirring. The reaction mixture was then cooled
and the precipitate was recovered by filtration. The
wet solid was dried to give 13601 g of 3-chloro-
isonitrosoacatanilide.
~S ~3~
-39-
PREPARATION 6 (Cont.)
B. 4-Ch10roisatin and 6-chloroisatin
To 775 ml of concentrated sulfuric acid, preheated
to 70C., was added, with stirring, 136 g of 3-chloro-
i~onitrosoacetanilide at such a rate as to maintain
the reaction medium at a temperature between 75 and
85C. When all the solid had been added, the reaction
mixture was hea~ed at 90C. for an additional 30
minutes. -The reaction mixture was then cooled, and
poured slowly onto ca 2 liters of ice, with stirring.
Additional ice was added as necessary to maintain the
temperature below room temperature. A red-orange
precipitate formed which was recovered by filtration,
washed with water and dried. The resultant solid was
slurried in 2 liters of water, and then it was brought
into so1ution by the addition of ca 700 ml of 3N
sodium hydroxide. The ~olu~ion was filtered, and then
pH was adjusted to 8 with concentrated hydrochloric
acid. At this point, 120 ml of a mixture of 8~ parts
water and 20 parts concentrated hydrochloric acid was
added. The solid which precipitated was recovered by
~iltration, washed with water and dried to give 50 g
of crude 4-chloroisatin~ The filtrate from which the
4-chloroisatin had been recovered was further acidified
to pH 0 using concentrated hydrochloric acid, whereupon
a further precipitate formed. It was recovered by
filtration, washed with water and dried t to give 43 g
of crude 6-chloroisatin.
The crude 4-chloroisatin was recrystallized from
acetic acid to give 43~3 g of material melting at 258-
259C.
The crude 6-chloroisatin was recrystallized from
acetic acid to give 36.2 g of ma~erial melting at 261-
262C.
~2SSq~57
-40-
PREPARATIOW 6 ~Cont.)
.. .. . . , _ ,
C. 4 Chloro-2-oxindole
To a stirred slurry of 43.3 g of 4-chloroisatin in
350 ml of ethanol was added 17.3 ml of hydrazine
hydrate, and ~hen the reaction mixture was heated under
reflux for 2 hours The reaction mixture was cooled,
and the precipi~ate was recovered by filtration to give
43.5 g of 4-chloro-3-hydrazono-2-oxindole, ~p 235-
236C.
To a stirred solution of 22 g of sodium in 450 ml
of anhydrous ethanol was added, portionwise, 43.5 g of
4~chloro~3-hydrazono-2-oxindole, and the resulting
solution was heated under reflux for 30 minutes.
The cooled solution was then concentrated to a gum,
which was di~solved in 400 ml of water and decolorized
using activated carbon. The resulting solution was
poured onto a mixture of 1 liter of water and 45 ml of
concentrated hydrochloric acid. The precipitate which
formed was recovered by filtration, dried and recrystal-
lized from ethanol, giving 22.4 g of 4-chloro-2-oxindole,
mp 216-218C (dec).
D. 6-Chloro-2 oxindole
Reaction of 36.2 g of 6-chloroisatin with hydrazine
hydrate followed by sodium ethoxide in ethanol, sub-
~5 stantially according to C abovet afforded 14.2 g of 6
chloro-2-oxindole, mp 196~198C.
~IJ,S~S7
PREPARATION 7
~ ,...................................... .
Reaction of 3,4-difluoroaniline with chloral
hydrate and hydroxylamine followed cyclization with
sulfuric acid, in a manner analogous to Parts A and
o~ Preparation 6, ~ave 5,6~difluoroisatin, which wa~
xeacted with hydrazine hydrate followed by sodium
methoxide in ethanol~ in a manner analogous to
Preparation 4, to give the title compound~ m~pO 187-
190C.
PREPARATION 8
5-Fluoro-2-oxindole
To a stirred solution of 11.1 g (0.1 mol) of 4-
fluoroaniline in 200 ml of dichloromethane, at 60 to
-65C, was added, dropwise, a solution of 10.8 g (0.1
mol) of t butyl hypochlorite in 25 ml of dichloro-
methane. Stirring was continued for 10 minutes at
-60 to -65C, and then was added, dropwise, a solution
of 13.4 g (0.1 mol) of ethyl 2-(methylthio)acetate in
2S ml of dichloromethane. Stirring was continued at
-60C. for 1 hour and then was added, dropwise, at
- 60 to -65C, a solution of 11.1 g ~0.11 mol~ of
triethylamine in 25 ml of dichloromethane. The
cooling bath was removed, and when the reaction mixture
had warmed to room tempexature, 100 ml of water was
added. The phases were separated, and the organi~
phase was washed with saturated sodium chloride
solution, dried (Na2SO4) and evaporated in vacuo. The
residue was dissolved in 350 ml of diethyl ether, to
which was added 40 ml of 2N hydrochloric acid. This
mixture was stirred at room temperature overnight. The
phases werP separated and the ether phase was washed
.
~Z5~ 7
--42--
PREPARATION 8 tCont. )
__ _ .
with water, followed saturated sodium chloride. The
dried (Na2So~) ether phase was evaporated in vacuo to
give 17 g of an orange-brown solid which was triturated
under isopropyl ethera The solid was then recrystal-
lized form ethanol, to give 5.58 g of 5-fluoro-3-
methylthio-2-oxindole, mp 151.5-152.5C.
y~. Calcd for CgH80NFS C, 54.80; ~, 4~09; N,
7~10%o Found: C, 54.74; H, 4.11; N, 7.11~.
A sample of the above 5-fluoro 3-methylthio-2-
oxindole (986 mg, 5.0 mmol3 was added to 2 teaspoonsful
of Raney nickel under 50 ml of absolute ethanol, and
then the reaction mixture was heated under reflux for
2 hours. The catalyst was removed by decantation and
was washed with absolute ethanol. The combined
ethanol solutions were evaporated in vacuo and the
residue was dissolved in dichloromethane. The dichloro-
methane solution was dried (Na2so4) and evaporated in
vacuo to give 475 mg of 5-fluoro-2-oxindole, mp 121-
134C.
In analogous fashion, 4-trifluoromethylaniline
- was reacted with t-~utyl hypochlorite, ethyl 2-(methyl-
thio)acetate and triethylamine followed by reduction
of ~he 3-thiomethyl-5-~rifluoromethyl-2-oxindole ~hus
obtained with Raney nickel, to give 5-trifluoromethyl-
2 oxindole, mp 189.5-190.5C.
PREPAPcATION 9
~h~
5-Methoxy-2-oxindole was prepared from 4-methoxy-
aniline in a manner similar to the procedure of
Preparation 8, except tha~ the initial chlorination
step was carried out using a solution of chlorine gas
in dichloromethane in place of t-butyl hypochlorite.
The title product melted at 150~5 151.5 C.
556~t~
-43-
PREPARATION lO
6-Chloro-S-fluoro-2-oxindole
To 130 ml of toluene was added, with stirring,
24.0 g (0~165 mole) of 3-chloro-4-fluoroaniline and
13.5 ml ~0.166 mole) of pyridine. The resulting
solution was cooled ~o ca 0C. and 13.2 ml ~0.166
mole) of 2-chloroacetyl chloride was added. The
reaction mixture wa~ stirred at room temperature for
5 hours and ~hen it was extractea twice with 100 ml of
lM hydrochloric acid, followed by 100 ml of satura~ed
sodium chloride solution. The resulting toluen2
solution was dried using magnesium sulfate, and then
it was concentrated in vacuo to give 32.6 g (88%
yield) of N-(2-chloroacetyl)-3-chloro~-4-fluoroaniline.
lS A 26.63-g sample of the N-(2-chloroacetyl)-3-
chloro-4-~luoroaniline was thoroughly mixed with 64 g
of anhydrous aluminum chloride, and the mixture was
heated at 210-230C~ for 8.5 hours. The reaction
mixture was then poured onto a mix~ure of ice and lN
hydrochloric acid, with stirxing. Stirring was
continued for 30 minutes, and then the solid was
collected by filtration ~22.0 g). The solid was
dissolved in 1:1 ethyl acetate-hexane and chroma~
tographed on 800 g of silica gel. Elution of ~he
column, followed by evapsration o~ the fxactions,
produced 11.7 g of the N~(2-chloroacetyl)-3-chloro-4-
fluoroaniline, followed by 3.0 g of 6-chloro-5-fluoro-
2-oxindole. The la~ter material was recrystallized
~rom toluene to give 1.70 g (7~ yield) of ~he titl~
compound~ mp 196-206C. ~nalysis by NMR spectroscopy
indicated that the product was contaminated by some 4-
chloro-5-fluoro-2-oxindole. A second crop weighing
0.8 g was obtained.
~s~
PREPARATION 11
6-Fluoro-5-methyl-2~oxindole
An intimate mixture of 11.62 g (57.6 m~ol) of N-
(2-chloroacetyl)-3-fluoro-4~methylaniline and 30.6 g
(229.5 mmol~ of anhydrous aluminum chloride was heated
to 210-220C. Af~er 4 hours, the reac~ion mixture was
cooled and then added to 100 ml of lN hydrochloric acid
and 50 ml of ice. A tan solid ormed, which was
collected by filtration and recrystallized from aqueous
etha~ol. Three crops were obtained, weighing ~.49 g,
2.28 g and 1~0 g, respectively The crop weighing 1.0
g was further recrystallized from water to give 280 mg
of the title compound, mp 168.S-171C.
PREPARATION 1 2
lS 6-Bromo 2~oxindole
To 9.4 g of sodium hydride was added l9S ml of
dimethyl sul~oxide, followed b~ the dropwîse addition
of 22.37 ml of dimethyl malonate. At the end o the
addition, the mixture was heated to 100 C. and main-
tained at that temperature for 40 minutes. At thispoint, 25 9 of 1,4~dibromo~2-nitrobenzene was added
all at once. The reaction mixtuxe was maintained at
100 C. ~or 4 hours and then it was added to 1.O liter
of qaturated ammonium chloride solution. The resulting
mixture was extracted with ethyl acetate and the
extracts were washed with ammonium chloride solution,
water and saturated sodium chloride. The dried (MgSO4)
solutio~ was evapora~ed, and the residue was recrystal-
lized from ethyl acetate-hexane to give 22.45 g of
dimethyl 2-(4-bromo~2-nitrophenyl)malonate.
A solution of 17.4 g of dimethyl 2-(4-bromo-2-
nitrophenyl)malonate and 416 g of lithium chloride in
150 ml o dimethyl suloxide was placed in a~ oil bath
at lOOQ C. After 3 hours, the reaction mixture was
~'~5565~;~
--45--
PREPARATION 12 (Contd)
cool~d to room temperature and then it was poured into
a mixture of S00 ml of ethyl acetate and 500 ml of
saturated sodium chloride solution. The layers were
separated and the aqueous layer was extracted with
further ethyl acetate. The combined organic layers
were washed with saturated sodium chloride solution,
dried using sodium sula e, and then evaporated in acuo.
The residue was chromatographed using silica gel as
adsorbant and ethyl acetate-hexane mixture as eluant.
This afforded 9.4 g of me~hyl 2-(4-bromo-2~nitrophenyl3-
acetate.
To a solution of 7.4 g of methyl 2-(4-bromo-2
nitrophenyl)acetate in 75 ml of acetic acid was added
6.1 g of iron powder. The reaction mixture was placed
in an oil bath at 100 C. After 1 hour, the solvent was
removed by evaporation in vacuo, and the residue was
dissolved in 250 ml of ethyl acetate. The solution was
~iltered, washed with saturated sodium chlDride solution,
dried using sodium sulfate, decolorized using activated
carbon, and evaporated in vacuo. This afforded 5.3 g
of 6-bromo-2-oxindole as a white crystalline solid,
mOp. 213-214 C.
In like manner, starting with 1,4,5-trichloro-2-
nitrobenzene, 5,6-dichloro-2-oxindole was prepared,
m.p. 209~210 C.
~51~7
-46-
PREPARATION 13
6-Phenyl~~-oxindole
To 3~46 g. (0.072 mole) of sodium hydride was
added 50 ml. of dimethyl sulfoxide followed by the
dropwise addition of a solution of 8.2 ml. (0.072
mole) of dimethyl malonate in 10 ml. o~ dimethyl
sulfoxide, with stirring. After completion of the
addition, stirring was continued for 1 hour, and then
a solution of 10 g. (0.036 mole) of 4-bromo-3-nitro-
diphenyl in 50 ml. of dimethyl sulfoxide was added~
The reaction mixture was heated to 100C. for 1 hour,
cooled, and poured onto a mixture of ice-water
containing 5 g. o ammo~ium chloride. The mixture
thus obtained was extracted with ethyl acetate, and
the extracts were washed with sodium chloride solu~ion
and dried using magnesium sulfate. Evaporation in
vacuo to give an oil, which was chromatographed using
silica g~l and then recrystallized from methanol to
afford 6 g. of dimethyl 2~(3-nitro-4-diphenylyl)-
malonate, m.p. 82-83C.
A portion (5 g.) of the above nitro compound was
- reduced with hydrogen over a platinum catalyst, in a
mixture of 50 ml. of tetxahydrofuran and 10 ml. of
methanol, at a pres~ure of ca 5 kg/cm2, to give the
corresponding amine. The latter compound was refluxed
in ethanol for 16 hours, and then the product was
recovered by solvent evaporation and recrystallized
from methanol to give 1.1 g. of ethyl 6-phen~1-2-
oxindole-l-carboxylate, m.p. 115-117C.
The above ethyl ester (1.0 g.) and 100 ml. o~ 6N
hydrachloric acid was heated under reflux or 3 hours
and then allowed to stand at room temperature for 3
~S~657
47-
PREPARATION 13 (Cont.)
days. The solid was collected by filtration and
dried, to give 700 mg. of 6-phenyl-2-oxindole, m.p.
175-176C.
PREPARATION 14
5-Acetyl-2-oxindole
To 95 ml. of carbon disulfide was added 27 g.
(00202 mole) of aluminum chloride, followed ~y the
dropwise addition of a solution of 3 ml. (0.042 mole)
lG of acetyl chloride in 5 ml. of carbon disulfide, with
stirring. Stirring was continued for 5 minutes and
then 4.4 g. (0.033 mole) of 2-oxindole was added. The
resulting mixture was heated under reflux for 4 hours
and cooled. The carbon disulfide was removed by
decantation and the xesidue was triturated under
water and recovered by filtration. After drying, 3.2
g. of the title compound was obtaine~, m.pO 225-
227C
Reaction of 2-oxindole with ben~oyl chloride and
with 2-thenoyl chloride in the presence of aluminum
chloride, substantially according to the above
~ procedure, afforded the following compounds:
5-benzoyl-2-oxindole, m.p. 203-205C. (from
CH30H) and
5~(2-thenoyl)-2-oxindole, m.p. 211-213C. (from
C~3CN).
~LZ556~
--48--
PREPARATION 1 5
5~Bromo-2 oxindole, 5~nitro-2-oxindole and 5-
amino-2~oxindole can be prepared as described in
Beckett et al., Tetrahedron, 24, 6093 (1968). 5-
Amino-2~oxindole can be acylated to give 5-alkanamido-
2-oxindole and 5~benzamido-2~oxindole, using standard
procedt-:re t.
5-n-Butyl-2 oxindole can be prepared by reaction
of 5-n-butylisatin wi~h hydrazine hydra~e followed by
sodium methoxide in ethanol, according to the procedure
of Preparation 4. 5-n~Butylisatin can be prepared
from 4-n butylaniline by treatment with chloral
hydrate and hydroxylamine, followed by cyclization
with sul~uxic acid, according to the procedure of
Parts A and B of Preparation 6.
5-Ethoxy-2 oxindole can be prepared by conversion
o~ 3-hydroxy-6-nitro-toluene into 3-ethoxy 6-nitro-
toluene by standard methods (potassium carbonate and
ethyl iodide in acetone), followed by conversion of the
3-ethoxy-6-nitrotoluene into 5-ethoxy-2~oxindole by the
method described by Beckett et alO, (Tetrahedron, 24,
6093 [1968]), for the conversion of 3-mekhoxy 6-nitro-
toluene into 5-methoxy-2-oxindole. 5-n-Butoxy 2-
oxindole can be prepared in like manner, but substituting
n-butyl iodide for ethyl iodide.
5,6-Dimethoxy-2-oxindole can be prepared by ~he
method of Walker, Journal of the American Chemica1
, 77, 3844 (1955~.
7-Chloro-2-oxindole can be prepared by the method
described in ~nited States Patent No. 3,8827236.
4-Thiomethyl-Z-oxindole and 6 thiomethyl-2-oxindole
can be prepared b~ the method described in ~nited
S~ates Patent No. 4,006,161~ 5-n-Butylthio 2-oxindole
can be prepared in like manner, but substituting 4-
butylthioaniline for the 3-methylthioaniline.
3LZS~;57
--49--
PREPARATION 15 (Cont.)
5,6-Methylenedioxy-2-oxindole can be prepared by
the method of McEvoy et al., Journal of Organic
~ y, 38, 3350 11973). 5,6-Ethylenedioxy-2-
oxindole can be prepared in analogous fashion.
6-Fluoro-2-oxindole can be prepared according to
Protiva et al., Collection of Czechoslovakian Chemical
CommunicatLon~, 44, 2108 ~1979~ and United St~tes
Patent No. 4,160,032.
6-Trifluoromethyl 2-oxindole can be prepared
according to Sim~tS Journal of ~ , 28,
358~ 63).
6-Methoxy-2-oxindole can be prepar4d according
to Wieland et al., Chemische Berichte, 96, 253 (1963)o
_ _ __
5 Cyclopropyl-2 oxindole and 5~cycloheptyl-2-
oxindole can be prepared by reaction of 5 cyclo-
propylisatin and S-cycloheptylisatin, respectively,
with hydxazine hydrate followed by sodium ~ethoxide
in ethanol, according ~o the procedure of Preparation
4. 5-Cyclopropylisatin and 5 cycloheptylisatin can
bP prepared from 4-cyclopropylaniline and 4-cyclo
heptylaniline, respectively, by treatment with
- chloral hydrate and hydroxylamine, followed by
cyclization with sulfuric acid, according to Parts A
and B of Preparation 6.
