CA1255657A - 1,3-disubstituted 2-oxindoles as analgesic and anti- inflammatory agents - Google Patents

Abstract

1,3-DISUBSTITUTED 2-OXINDOLES AS ANALGESIC
AND ANTI-INFLAMMATORY AGENTS
Abstract Certain 2-oxindole-1-carboxamide compounds having an acyl substituent at the 3-position, and also on the carboxamide nitrogen atom, are inhibitors of the cyclooxygenase (CO) and lipoxygenase (LO) enzymes, and are useful as analgesic agents and anti-inflammatory agents in mammalian subjects. These 2-oxindole-1-carboxamide compounds are of particular value for acute administration for ameliorating pain in human patients recovering from surgery or trauma, and also for chronic administration to human subjects for alleviating the symptoms of chronic diseases, such as rheumatoid arthritis and osteoarthritis.
Certain 2-oxindole-1-carboxamide compounds unsubstituted at C-3, but having an acyl substituent on the carbox-amide nitrogen atom, are useful as intermediates to the aforementioned analgesic and anti-inflammatory agents.

Description

~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~

/-` 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~

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 ~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) -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, , . . , ,: .

-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~

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 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 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~

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 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 !

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%.

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 _ __ 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
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S65~

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 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~

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~

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%.

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~.

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-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-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 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~

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~.

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~

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~.

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.

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, 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.

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 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~

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 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 ~ ,...................................... .
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.

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 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~

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~

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.

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~;~

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 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 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.

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-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~

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 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.

Claims (28)

1. A process for preparing 2-oxindole compound of the formula ---( I ) or a pharmaceutically-acceptable base salt thereof;
wherein X is 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, trifluoromethyl, alkylsulfinyl having 1 to 4 carbons, alkylsulfonyl having 1 to 4 carbons, nitro, phenyl, alkanoyl having 2 to 4 carbons, benzoyl, thenoyl, alkanamido having 2 to 4 carbons, benzamido or N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls; and Y is 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 or trifluoromethyl;
or X and Y when taken together are a 4,5-, 5,6-or 6,7-methylenedioxy group or a 4,5-, 5,6- or 6,7-ethylenedioxy group;
or X and Y when taken together and when attached to adjacent carbon atoms, form a divalent radical Z, wherein Z is selected from wherein W is oxygen or sulfur;
R1 is alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, (substituted phenyl)alkyl having 1 to 3 carbons in said alkyl, phenoxyalkyl having 1 to 3 carbons in said alkyl, (substituted phenoxy)alkyl having 1 to 3 carbons in said alkyl, naphthyl or -(CH2)n-Q-R°;
wherein the substituent on said substituted phenyl, said (substituted phenyl)alkyl and said (substituted phenoxy)alkyl is fluoro, chloro, alkyl having 1 to 3 carbons, alkoxy haviny 1 to 3 carbons or trifluoromethyl; n is zero, 1 or 2; Q is a divalent radical derived from a compound selected from furan, 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]-thiophene, and R° is hydrogen or alkyl having 1 to 3 carbons;

and R2 is alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenoxymethyl, furyl, thienyl, pyridyl or wherein R3 and R4 are each hydrogen, fluoro, chloro, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons or trifluoromethyl;
characterized by (A) reacting a compound of the formula ---( IV) with an acyl isocyanate of the formula R2-C(=O)-N=C=O
in an inert solvent; or (B) reacting a compound of the formula ---(II) with an activated derivative of a carboxylic acid of the formula R1-C(=O)-OH, in an inert solvent.

2. A process according to claim 1, characterized in that X and Y are each hydrogen, fluoro, chloro, bromo, alkyl having 1 to 4 carbons, cycloalkyl having 3 to 7 carbons, alkoxy having 1 to 4 carbons, alkyl-thio having 1 to 4 carbons or trifluoromethyl;
or X and Y when taken together are a 4,5-, 5,6-or 6,7-methylenedioxy group or a 4,5-, 5,6- or 6,7-ethylenedioxy group;
R1 is alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, phenoxyalkyl having 1 to 3 carbons in said alkyl, furyl, thienyl, pyrrolyl, alkylfuryl having 1 to 3 carbons in said alkyl, alkylthienyl having 1 to 3 carbons in said alkyl, furylalkyl having 1 to 3 carbons in said alkyl, thienylalkyl having 1 to 3 carbons in said alkyl, naphthyl, benzo[b]furyl or benzo[b]thienyl;
and R2 is alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenoxymethyl or wherein R3 and R4 are each hydrogen, fluoro, chloro, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 caxbons or trifluoromethyl.

3. A process according to claim 2, characterized by reacting a compound of the formula ---(IV) with substantially one molar equivalent of an acyl isocyanate of the formula R2-C(=O)-N=C=O, in an inert solvent, at a temperature in the range from 50 to 150°C.

4. A process according to claim 3, characterized in that the reaction is carried out in a solvent selected from aliphatic hydrocarbon, aromatic hydrocarbons, ethers, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide.

5. A process according to claim 2, characterized by reacting a compound of the formula ---(II) with one molar equivalent or a slight excess of an activated derivative of a carboxylic acid of the formula R1-C(=O)-OH, in an inert solvent, in the presence of from one to four molar equivalents of a basic agent, at a temperature in the range from -10 to 25°C.

6. A process according to claim 5, characterized in that said activated derivative is an acid chloride, and the reaction is carried out in a polar, aprotic solvent.

- 54a -

7. A process according to claim 2, characterized in that Y
is hydrogen and X is hydrogen or 5-chloro.

8. A process according to claim 7, characterized in that R1 is 2-furyl, 2-thienyl or (2-thienyl)methyl.

9. A process according to claim 8, characterized in that X
and Y are both hydrogen, R1 is 2-furyl and R2 is phenyl.

10. A process according to claim 3 or 4, characterized in that Y is hydrogen and X is hydrogen or 5-chloro.

11. A process according to claim 5 or 6, characterized in that Y is hydrogen and X is hydrogen or 5-chloro.

12. A 2-oxindole compound of formula I as defined in claim 1, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

13. A process for the preparation of N-benzoyl-3-(2-furoyl)-2-oxindole-1-carboxamide which comprises reacting 3-(2-furoyl)-2-oxindole with benzoyl-isocyanate in toluene.

14. A process for the preparation of N-benzoyl-3-(2-furoyl)-2-oxindole-1-carboxamide which comprises reacting N-benzoyl-2-oxindole-1-carboxamide with 2-furoyl chloride in the presence of N,N-dimethylformamide and 4-(N,N-dimethylamino)pyridine.

15. A process for the preparation of a 2-oxindole according to claim 1 wherein X is hydrogen, Y is hydrogen, R1 is 2-furyl and R2 is phenyl.

16. N-benzoyl-3-(2-furoyl)-2-oxindole-1-carboxamide whenever prepared by the process of claim 13, 14 or 15 or by an obvious chemical equivalent thereof.

]7. A process for the preparation of N-cyclohexylcarbonyl-5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide which comprises reacting N-cyclohexyl-carbonyl-5-chloro-2-oxindole-1-carboxamide with 2-thenoyl chloride.

18. A process for the preparation of a 2-oxindole according to claim 1 wherein X is 5-chloro, Y is hydrogen, R1 is 2-thienyl and R2 is cyclohexyl.

19. N-cyclohexylcarbonyl-5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide whenever prepared by the process of claim 17 or 18 or by an obvious chemical equivalent thereof.

20. A 2-oxindole compound of the formula ---( I ) and the pharmaceutically-acceptable base salts thereof;
wherein X is 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, trifluoromethyl, alkylsulfinyl having 1 to 4 carbons, alkylsulfonyl having 1 to 4 carbons, nitro, phenyl, alkanoyl having 2 to 4 carbons, benzoyl, thenoyl, alkanamido having 2 to 4 carbons, benzamido or N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls; and Y is 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 or trifluoromethyl;
or X and Y when taken together are a 4,5-, 5,6-or 6,7-methylenedioxy group or a 4,5-, 5,6- or 6,7-ethylenedioxy group;
or X and Y when taken together and when attached to adjacent carbon atoms, form a divalent radical Z, wherein Z is selected from wherein W is oxygen or sulfur;
R1 is alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, (substituted phenyl)alkyl having 1 to 3 carbons in said alkyl, phenoxyalkyl having 1 to 3 carbons in said alkyl, (substituted phenoxy)alkyl having 1 to 3 carbons in said alkyl, naphthyl or -(CH2)n-Q-R°;
wherein the substituent on said substituted phenyl, said (substituted phenyl)alkyl and said (substituted phenoxy)alkyl is fluoro, chloro, alkyl having 1 to 3 carbons, alkoxy having 1 to 3 carbons or trifluoromethyl; n is zero, 1 or 2; Q is a divalent radical derived from a compound selected from furan, thiophene, pyrrole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, pyrldine, pyrimidine, pyrazine, benzo[b]furan and benzo[b]-thiophene; and R° is hydrogen or alkyl having 1 to 3 carbons;

and R2 is alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenoxymethyl, furyl, thienyl, pyridyl or wherein R3 and R4 are each hydrogen, fluoro, chloro, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons or trifluoromethyl.

21. A compound according to claim 20, wherein X and Y are each 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 or trifluoromethyl;
or X and Y when taken together are a 4,5-, 5,6 or 6,7-methylenedioxy group or a 4,5-, 5,6- or 6,7 ethylenedioxy group;
R1 is alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, phenoxyalkyl having 1 to 3 carbons in said alkyl, furyl, thienyl, pyrrolyl, alkylfuryl having 1 to 3 carbons in said alkyl, alkylthienyl having 1 to 3 carbons in said alkyl, furylalkyl having 1 to 3 carbons in said alkyl, thienylalkyl having 1 to 3 carbons in said alkyl, naphthyl, benzo[b]furyl or benzo[b]thienyl;

and R2 is alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenoxymethyl or wherein R3 and R4 are each hydrogen, fluoro, chloro, aikyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons or trifluoromethyl.

22. A compound according to claim 21,wherein Y
is hydrogen.

23. A compound according to claim 22,wherein X
is hydrogen.

24. A compound according to claim 23,wherein R1 i5 2-furyl, 2-thienyl or (2-thienyl1methyl)methyl.

25. A compound according to claim23, wherein R1 is 2-furyl and R2 is phenyl.

26. A compound according to claim 22,wherein X
is 5-chloro and R1 is 2-furyl, 2-thienyl or (2-thienyl)-methyl.

27. A compound according to claim 26,wherein R1 is 2-thienyl and R2 is cyclohexyl.

28. A pharmaceutical composition, which comprises a pharmaceutically-acceptable carrier and a 2-oxindole compound according to claim 20.