IE850288L - Analgesic oxindoles. - Google Patents

Description

7 6 8 9 This application relates to new chemical compounds which are of value as new medicinal agents. More 5 particularly the new chemical compounds are derivatives of 2-oxindole«l-carboKamidet» and they are further substituted at the 3-position. and on the carboxamide nitrogen by an acyl group. These new chemical compounds are inhibitors of both the eyelooxygenase |CO| and 10 lipoxygenase (LOp ensymes* 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 15 patients recovering from surgery or trauma.

In addition to their usefulness for acute administration to combat painf the compounds of this invention are useful for chronic administration to mammals * particularly man., to alleviate the symptoms of chronic 20 diseases,, such as the inflammation and pain associated v/ith rheumatoid arthritis and osteoarthritis.

U.S.P. 3,634f453 describes certain 2-oxindole-3~ carboxamide antiinflammatory agents which can also be substituted in the 1-position by 2,2, 2-trifluoroethyl, 25 alkyl, alkenyl of up to 4 carbon atoms or phenylalkvl having up to 3 carbon atoms in the alkyl moiety.

This invention provides novel 2-oxindole compounds of the formula (T) 0=C—NH-C-R" II 0 and the pharmaceutically-acceptable base salts thereof; wherein X and Y are each independently hydrogen, fluoro, chloro, bromo, methyl or trifluoromethyl; R 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, or -(CI^)n~Q~R°; wherein n is zero, 1 or 2; Q is a divalent radical derived from furan or thiophene; and R° is hydrogen or alkyl having 1 to 3 carbons; and R is alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenoxymethyl, or 3 4 wherein R and R are each hydrogen, fluoro, chloro, methyl, methoxy, or trifluoromethyl.

Said compounds of formula I are active as analgesic agents, and as agents for treating inflammatory diseases such as the arthritides. Accordingly this invention also provides pharmaceutical compositions comprising a compound of formula I and a pharmaceuticalIv-acceptabl carrier.

A first preferred group of compounds of this invention consists of the compounds of formula I, wherein X and Y are each hydrogen and is selected from the group consisting of 2~furvl? 2-thienyl and (2-thienyl J methyl „ Among this first preferred group,,, particularly preferred compounds are those wherein is phenyl.

A second preferred group of compounds of this invention consists of the compounds of formula I, wherein X is 5-chloro^ Y is hydrogen and is selected from the group consisting of 2-furvl, 2-thienyl and 4 (2-thienyl)methyl. Among this second preferred groupe 2 particularly preferred compounds are those wherein R is cyclohexyl* Especially preferred individual compounds of the invention are: N-benzoyi-3-(2-furoyl)-2-oxindole-l-carboxamide (I:X 1 2 is hydrogen; Y is hydrogen; R is 2-furyl; R is phenyl) and N-cyclohexylcarbony1-5-chloro-3-(2-thenoyl)-2- oxindole-l-carboxamide (I:X is 5-chloro; Y is hydrogen; 1 2 R is 2-thienyl; R is cyclohexyl).

Yet further this invention provides novel compounds of the formula 0 2 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 ® p< n—rc~R~ — H and the base salts thereof, wherein X, Y and R^" 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 R"*" is benzyl, furyl, thienyl or thienylmethyl; provided that when X and Y are both 5 hydrogen,, is not benzyl. The compounds of formula (IV) in said "preferred sub-group" are novel, and they form the subject of our European divisional patent application no. 5 The analgesic and antiinflammatory compounds of this invention are the compounds of formula I, wherein X, Y, 1 2 R and R are as defined previously. Thus f the compounds of this invention are derivatives of 2-oxindole, the bicyclic amide of the formula 4 More particularly, the analgesic and antiinflammatory agents of this invention have an IV-acylcarboxamido 2 substituent, -C(=0)-NH-C(=0)-R , at the 1-position and an acyl substituent, -C(=0)-R"'"/ at the 3-position of 15 2-oxindole, and the benzo ring can be further substituted by said X and Y groups.

As will be appreciated by one skilled in the art, the analgesic and anti-inflammatory compounds 1 2 of this invention of formula I, wherein X, Y, R and R 20 are defined previously, are capable of enolization, and therefore they can exist in one or more tautomeric (cnolic) forms. All such tautomeric (enolic) forms of the compounds of formula I are considered to be within the scope of this invention. 8 The compounds of formula I are prepared from the appropriate 2-oxindole compound of the formula wherein X and Y are as defined previously. This is accomplished by attaching the substituent ~C{=0)~ MH-C(=0]-R^ to the 1-position and the substituent ~C{=0)-R~ to the 3-position. These substituents can be attached in either order, and this leads to two variations in the method for making the compounds of formula I, as shown in the Scheme. 7 SCHEME fill! (IV) 0=C-NH~C~R-O 0-C~NH~jy-R 0 However, if relatively polar solvents are used and the product is not out of solution at the end of the reaction, the product can be recovered by solvent evaporation orin the case or water-miscibie solvents, 9 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 11} can be purified by standard methods£, e.-g., 5 recrvstallication.

The reaction between a compound of formula. IV and an acyl isocyanate of formula R2-C(=0)-N=C=Q can be speeded up by the addition of a base, such as a tertiary- amine, e.g.,, trimethylamine, triethylamine, 10 tributylamineM-methylpiperidine t, H-methyImorpholine or N?imethy1aniline* From about one to about four equivalents of the basic agent is usually added,, and this permits the use of reaction temperature from 20 to 50°C. At the end of the reaction, the reaction. 15 medium must be neutralised (or made acidic) and then the product is isolated as described earlier* The ~C(=0)-R^ 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 R~~ 20 C(=0)0H. The reaction is carried out by treating said compound of formula II in an inert solvent with one snolar equivalent, or a slight excess,, of an activated derivative of a compound of formula R*-C(-0)0H, in the presence of from one to four equivalents of a basic 25 agent. An inert solvent is one which will dissolve at least one of the reactants., and will not adversely interact with either of the reactants or the product. However,, in practice, a polar, aprotic solvent, such as N,N~dimethylformamide, N,N~dimethylacetamide, N-30 raethylpyrrolidone or dimethyl sulfoxide, is commonly used- Conventional methods for activating the acid of formula R*-C(=0)0H are used. For example, acid haliclese.g., acid chlorides; symmetrical acid •til iT® jl u i i anhydrides, R —C(=0)-0-C(=0)—R ; mixed acid anhydrides with a hindered low-molecular weight carboxylic acid, 1 s *5 R -C(=0)-0-C(=0)-R , where R is a bulky lower-alky1 group such as t-butyl; and mixed carboxylic-carbonic 5 anhydridest R1-C(=0)-0~C(=0)-0R°, wherein R6 is a lower-alky 1 group, can all be used. In addition, N-hydroxyimide esters (such as N-hydroxvsuccinimide and N-hydroxyphthalimide esters) f 4-nitrophenyl esters,, thiol esters (such as thiol phenyl esters) and 2,4^5-10 trichloropheny1 esters,, and the 1 ike, can be used. ft wide variety of basic agents can be used in the reaction between, a compound of formula II and the activated derivative of the acid of the formula R*-C(=0)OH. However, preferred basic agents are tertiary 15 amines, such as trimethyIamine, triethylamine , tributylamine ,, N-methy Imorphol ine , N-methyIpiperidine and 4-(N-dimethy1amino)pyridine.

The reaction between a compound of the formula II and the activated derivative of the acid of formula 20 R~-C(=0)-OH is usually carried out in the temperature range from -10 to 25°C. Reaction times of from 30 minutes to a few hours are common. At the end of the reaction, the reaction medium is usually diluted with water and acidified, and then the product can be 25 recovered by filtration. It can be purified by standard methods, such as recrystal1ization.

The -C(=0)-R side-chain can be attached to a compound of the formula III by reaction with a derivative of the appropriate acid of the formula R1-C(=0)™0H, 30 in a lower-alkanol solvent (e.g. ethanol), in the presence of an alkali metal salt of the lower-alkanol solvent (e.g. sodium ethoxide), according to standard procedures. Typical derivatives of the acid of the i i 1 formula R -C(^0)0H which can be used include acid chlorides,, acid anhydrides of the formula R^-C(=0)-0~ C(=0)—R1, Rx-C(=0)-0~C(=0)-R5 and R^-C(=0)-0-C (=O)~0R6, and simple alkyl esters of the formula R'"-C( =0)-OR^e C r 5 wherein R and R are as defined previously. Usually, a small excess of the derivative of the acid of formula R~*-C(=0)~0H is used,, and the alkoxide salt is usually present in an amount from one to two molar equivalents., based on said derivative of the acid of 10 formula R~-C(=0)0H. The reaction between the derivative X of the acid of the formula R -C(=0)0H and the compound of formula III is usually started at 0 to 25°C., but it is then usual to heat the reaction mixture at a temperature in the range from 50 to 130°C«, and 15 preferably at about 80°C.? to complete the reaction. Under these circumstances t. reaction times of a few hourst e.g - two hours,, up to a few days, e.g., two days, are commonly used- The reaction mixture is then cooled? diluted with an excess of water, and acidified. 20 The product of formula IV can then be recovered by filtration or by the standard procedure of solvent extraction.

The acyl isocyanates of the formula R -C(=0)— N=C=0 which are known can be prepared by the published 25 procedures - Those which are analogs of known compounds can be prepared by analogous procedures. In general, the corresponding amide of the formula R"-C(=0)~NH, reacts with oxalyl chloride, or the acid chloride of *7 formula R -C(-0)—Cl reacts with silver cyanate. 30 Consult: Spesiale et sJ., Journal of Organic Chemistry, 23 , 1805 (1S 6 3 / and 3 Q f 4306 (1965),- Ramirez efc a!., Journal of Organic Chemistry, 34, 376 (1969); and i 2 Naito et a_l. , Journal of Antibiotics (Japan) , 18, 145 (1965).

The 2-oxindole compounds of formula III are prepared by known methods, or methods analogous to 5 known methods. Consult: "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 Chemistry, 4 2, 1340 (1977); Wright et al., Journal of 10 the American Chemical Society,, 78, 221 (1956); Beckett et al_» , Tetrahedron, 24,, 6093 (1958); United States Patents Nos. 3 ,882 , 236 , 4 ,, 0 0 6 161 and 4,160,032; Walker, Journal of the American Chemical Society, 11, 3844 (1955); Protiva et a_l. , Col lection of Czechoslovakian 15 Chemical Communications, 44, 2108 (1979); McEvoy et al., Journal of Organic Chemistry, 38, 3350 (1973); Simet, Journal of Organic Chemistry, 28, 3580 (1963); Wieland et al_. , Cheniische Berichte, 96, 253 (1963); and references cited therein, 20 The compounds of the formula I are acidic and they form base salts. All such base salts are within the scope of this invention and they can be prepared by conventional methods™ For example, they can be prepared simply by contacting the acidic and basic 25 entities,, 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,, 30 as appropriate, or, in the case of aqueous solutions, by lyophilisation. Typical salts of the compounds of formula I which can be prepared are primary, secondary and tertiary amine salts, alkali metal salts and alkaline earth metal salts. Especially valuable are the ethanolamine, diethanolamine and triethanolamine salts.

Basic agents suitably employed in salt formation belong to both the organic and inorganic types,, and they include organic amines, alkali metal hydroxides, alkali metal carbonates,, alkali metal bicarbonates,, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides and alkaline earth metal alkoxides. Representative examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, £-toluidine, ethanolamine and glucamine; secondary amines, such as diethylamine, diethanolamine, N-methylglucamine, N-methy). anil ine , morphol ine, pyrrolidine and piperidine; tertiary amines, such as trie thy1am ine, triethanolamine, H^N-dimethylaniline, N-ethylpiperidine and N« methylmorpholine; hydroxides, such as sodium hydroxide? alkoxides, such as sodium ethoxide and potassium methoxidey hydrides, such as calcium hydride and sodium hydride; and carbonates, such as potassium 1 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-l,4-benzoquinone (P3Q)- The method used was based on that of Siegmund et al.f Proc. Soc. Exp. Biol. Med., 9 5: 729-731, 1957, as adapted for high throughput (see further Milne and Twomey, Agents and Actions, 10; 31-37, i 4 1980). The mice used in those experiments were Carworth males, albino CF-1 strain, weighing 18-20 g. All mice were fasted overnight prior to drug administration and testing. 5 The compounds of formula I were dissolved or suspended in a vehicle consisting of ethanol (5%), emulphor 620 (a mixture of polyoxyethylene fatty acid esters, 5%) and saline (90%). This vehicle also served as control. Doses were on a logarithmic scale 10 (i.e.,, ... 0.32, 1.0, 3.2, 10, 32... mg/kg) e and were calculated from 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/kg of body weight. The afore-15 said method of Milne and Twomey was used to determine efficacy and potency. Mice were treated with compounds orally, and one hour later received PBQ, 2 mg/kg, intraperitoneally. Individual mice were then immediately placed in a warmed Lucite (transparent 20 plastic) chamber, andf starting five minutes after PBQ administrationa the number of abdominal constrictions during the subsequent 5 minutes was recorded. The degree of analgesic protection (% MPE) was calculated on the basis of suppression of abdominal constriction 25 relative to counts from concurrent control animals run on the same day. At least four such determinations (M > 5) provided dose-response data for generation of an MPE^q ,, the best estimate of the dose that reduces abdominal constriction to 50% of control levels. 30 The compounds of formula I also possess anti inflammatory activity. This activity has been demonstrated in rats by a method based on the standard carrageenin-induced rat-foot edema test. (Winter ejt al. # E>roc., Soc. Exp. Biol. Med., 111: 544, 1963). i s Qnanesthetized,, adult,, nialet, albino rats of 150 g to 190 g body weight were numbered, weighed, and an ink mark placed on the right lateral malleolus. Each paw was immersad in mercury exactly to the ink mark. The mercury was contained in a glass cylinder, connected to a Statham Pressure Transducer. The output from the transducer was fed through a control unit to a micro-vol tameter. The volume of mercury displaced by the immersed paw was read. Drugs were given by gavage. One hour after drug administration, edema was induced by injection of 0.0.5 ml of 1% solution of carrageenin into the plantar tissue of the marked paws- Immediately thereafter, the volume of the injected foot was measured. The increase in foot volume 3 hours after the injection of carrageenin constitutes the individual inflammatory response.

The analgesic activity of the compounds of formula I makes them useful for acute administration to mammals for the control of pain, e.g., post-operative pain and the pain of trauma- Additionally the compounds of formula I are useful Cor chronic administration to mammals for the alleviation of the symptoms of chronic diseases,, such as the inflamination of rheumatoid arthritis, and the pain associated with osteoarthritis and other musculoskeletal disorders.

When a compound of the formula I or a pharmaceutical ly 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, or, preferably in combination with pharmaceutically-acceptable carriers or diluents in a pharmaceutical composition,, according to standard pharmaceutical practice, h compound can be administered 1r< Q orally or parenterally. Parenteral administration includes intravenous,, intramuscular., intraperitoneal, subcutaneous and topical administration.

In a pharmaceutical composition comprising a compound of formula 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,ratio chosen will depend on such factors as the solubility of the active component., the dosage contemplated and the precise route of administration.

For oral use of a compound of formula I of this invention.# the compound can be administered,, for example t. in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use,, carriers which are commonly used include lactose and corn starch, and lubricating agents£, such as magnesium stearatee, 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. If desired, certain sweetening and/or flavoring sigents can be added. For intramuscular# intraperitoneal# subcutaneous and intravenous use, sterile solutions of the active ingredient are usually 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, the dosage will vary according to the age, weight and response of 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 painP 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 hours)- For chronic administration to alleviate I treat) inflammation and pain, in most instances an effective dose will be from 0.5 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 provided solely for the purpose of further illustration. 1 8 EXAMPLE 1 N-Benzoyl~3-(2-furoyl)-2-oxindole-1- carboxamide A mixture of 909 mg (4.0 mmole) of 3-(2-furoyl)-5 2-oxindole and 706 mg (4.8 mmole) of benzoyl iso- cvanate in 25 ml of toluene was heated to reflux and then it was heated at reflux temperature for 7 hours. The mixture was allowed to stand at room temperature overnight and then the precipitate which had formed 10 was removed by filtration,, giving 1.3 g of crude product. The crude product was recrystal1ized from ca 30 ml of acetic acid, giving 920 mg of the title compound, rnp 184°C (dec).

Analysis; Calcd. for H-, 4°5N2: C, 67.37; H, 3.77; 15 N, 7.49%. Found: C, 66.90; H, 4.02; N, 7.38%. 0 1 The ultraviolet spectrum of the title compound showed absorptions as follows: Solvent CH30H CB,0H + 1 Analysis Calcd. for C-, gH-i 4°4N2 : Found: C, 67.07; C, 66.78; H t H e 4.38; N, 8.69%. 4.65; N, 8.62%. 2 I EXAMPLE 4 N-BenzoyI-3- ( 2~thenoyl) - 2-oxindole-1- carboxamide To a stirred solution of 48 6 mg (2.0 mmole) of 5 3-(2-thenoylJ-2-oxindole and 445 mg (4,4 mmole) of triefchylamine in 5 ral of dimethyl sulfoxide was added 324 sag (2.2 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 10 3N hydrochloric acid. The resulting mixture was cooled in an ice-bath and the solid was removed by filtration. The solid was recrystalIised from ca. 30 ml of 2:1 ethanol;water to give 190 mg of the title compound as fluffy, yellow crystals, mp 165-166°C. 15 (dec).

Analysis: Calcd. for C21H14°4N2S: C' 64 - 60 ? H, 3.61; N, 7.18%. Found: C, 64.53; H, 3.75; N, 7.10%.

EXAMPLE 5 Reaction of the appropriate H-substituted-2-20 oxindole-l-carboxamide with the requisite acid chloride of the formula R^~C0-Clt» substantially according to the procedure of Example 2, afforded the following compounds: Halting Point r2 (®C)^ 5 H 2-thienyl phenyl 165=1SS H {2-thienyl)-methyl phenyl 108-190 5-Cl 2-fury1 phenyl 206-208 5-C1 2-thienyl phenyl 190-192 10 5-Cl {2-thienyl}- methyl phenyl 213-214 H 2-furyl cyclo-hexyl 178.5 15 H 2-thienyl cyclo-hexyl 14 3.5" 14 4.5 H (2-thienyl)» methyl cyclo-hexyl 175.5- 176-5 5-CI 2-furyl cyclo™ hexyl 185*=186 20 5-C1 2-thienyl cyclo-hexyl 167 5-Cl {2-thienyl3 - methyl cyclo-hexyl 181-133 Analysis Calculated Found C H N C u n N 64,60 3,61 7.18 64.53 3.75 7,10 65,33 3,99 6,93 65.39 3.93 6,96 61,70 3 ,20 6,85 61.54 3.21 6,71 59 , 37 3.08 6,59 59.12 3,32 6,59 60,21 3,44 6,38 60.35 3.62 6,37 66,30 5.30 7,37 66,09 5, 24 7,22 63.62 5.09 7,07 63,45 5,27 7-11 64 . 37 5,40 6,83 64 , 60 5,49 6.74 60, 30 4 , 62 6,75 60,59 4 . 88 6,77 58,54 4,44 6,50 58,41 4,60 6,52 59,39 4 ,76 6.30 58.97 5.03 6, 23 X R1 R2 Melting Point CC)1 5 H 2-fury1 t"butyl 201.5 H 2-thienyl t-butyl 177,5 H {2-thienyl)-methyl t-butyl 1922 5-Cl 2-=fury 1 t-butyl 191 10 5-Cl 2-thienyl t-butyl 200.S 5-Cl {2-thienyl)-methyl t-butyl 155 H 2-fury1 isopropyl 191.5 H 2-thienyl isopropyl 153.5-154,5 15 H (2-thienyl)« methyl isopropyl 15 6-157 3 5-Cl 2-furyl isopropyl 176-177 5-Cl 2-thienyl isopropyl 16 5 = 16 6 2 #3 20 5-Cl (2-thienyl)-methyl isopropyl 160-1693 All compounds were recrystal!ized from acetic noted otherwise, 7 Recrystal1ized from acetonitrile « ^Melted without decomposition.

Analysis Calculated Found C H N C K N 64 ,40 5,12 7,91 64.24 5.11 7.97 61, 60 4.90 7.56 61.72 4,95 7,60 62,48 5,24 7,29 62,59 5,29 7.48 58.69 4,41 7.21 58,S 6 4.45 7.05 56.36 4.23 6.92 56.55 4 119 7,05 57.34 4,57 6, 69 57,28 4.58 6. 55 63.52 4.74 8.23 63.30 4.73 8,23 60,66 4,53 7,86 60,91 4,75 7.98 61.60 4.90 7,56 61.59 5,01 7,56 57,69 4,03 7.47 57.68 4,08 7.37 55, 32 3.87 7.17 55.19 •3.89 7.14 56,37 4 .23 6.92 56.17 4,41 6.97 acid and melted with decomposition unless 2 4 EXAMPLE 6 M~Benzoyi«3~(2-thenoyl)-2-oxindole~l-carboxamide was also prepared by reaction of 3-(2-thenoyli-2-oxindole with benzoyl isocyanate using the method of 5 Example 1.

N-Bensovl-3-(2-[2-thienylJ acetyl)-2-oxindole-l-carboxamide was prepared by reaction of 3-(2-[2-thienyl]acetyl)-2-oxindole with benzoyl isocyanate using the method of Example 1. 10 EXAMPLE 7 Following the method of Example 1 (Method A), Example 2 or 3 (Method B), or Example 4 (Method C), the following compounds were made: X R1 R2 Method of Prep^ aration Mel ting Point ( °C)l H methyl phenyl A,B 19 8~200d H isopropyl phenyl B 165d H cyclohexvl phenyl B 18ld 5 5-Cl methyl phenyl B 215-2l7d 5-Cl isopropyl phenyl B 185.5-187»5d 5-Cl cyclohexyl phenyl B 192-194d E phenoxymethyl phenyl A 202d H 3-furvl phenyl C 187d 10 5-Cl cyclopropyl phenyl B 213~215d H cyclopropyl phenyl B 173d H isopropyl phenyl B 165d H 1-phenylethyl phenyl B 173d 5-Cl benzyl phenyl B 239-240d 15 5-CH.j 2-furyl phenyl B 204-205d H (3-thienyl)- methyl phenyl B 195-197d 6-C1 2-thienyl phenyl B 192-193d 6-F 2-furyl phenyl B 189-190 6~F 2-thienvl phenyl , B 190-194 20 5-Cl 5-ethyl-2~ furyl phenyl B 202-203.5d H 5-ethyl-2~ furyl phenyl 3 174-175 5-F 2-furyl phenyl B 172d 5-F (2-thienyl)-methyl phenyl B 189d 25 6-Cl 2-furyl phenyl B 199-200 5-F (2-thienyl)~ methyl phenyl B 167d 5-Cl (2-thienyl)-methyl phenyl B 199-200d Method Melting of PreoT Point R' R* aracion (°C) H 2-thienyl H 2-furyl E methyl H benzyl H cyclopropyl H (2-thienyl) methyl 5-CH^ 2-thienyl 5-Cl 2-furvl S-CH^ 2-furyl 5-Cl 2-thienyl H H H H H H H (2-thienyl) methyl 2—thienvl 2-furyl cyclopropyl isopropyl 2-furvl 2-thienyl isopropyl propyl 2-thienyl 4-fluoro-phenyl 4-fluoro-phenvl 4-fluoro-phenyl 4-fluoro-phenvl 4-fluoro-phenyl 4-fluoro- phenyl 4-fluoro-phenyl 4-fiuoro-phenyl 4-fluoro-phenyl 4-fluoro-phenyl 4-methoxy- pher^yl 4-methoxv-phenyl 4-methoxv-phenyl 4-methoxy-phenyl 4-methoxy-phenvl 4—chloro— phenyl 4-chloro- phenvl 4-chloro- phenvl 4-chloro-phenyl 2-methyl-phenyl A A B B B B A B B B B B B B B B 163.5-164.5d 164 »5d 205-207d 20 7-2 0 9d 167.5d 216~217d 178-179d 197-199d 179-181d 191.5-192.5d 197-198d 173d 14 6d 193d 125d 180-181d 170-17Id 164-165d 184~185d 173.5d 2 7 X R1 R2 Method of Prepj aration Mel ting Point ( °C) Z H 2-furyl 2-methy1-phenyl B 167-168d H (2-thienyl)-methyl 2-methyl-phenyl B 179.5d H cyclopropyl cyclohexyl B 153-154d 5 H methyl cyclohexyl B 167~168d H 1-pheny1ethy1 cyclohexyl B 19 Id H 5-methyl-2-furyl cyclohexyl B 163-165d 5-Cl 5-methyl-2-furyl cyclohexyl B 197.5d 5-Cl methyl cyclohexyl B 214.5d 10 5-Cl propyl cyclohexyl B 162-163d 5-Cl isopropyl cyclohexyl B 205-206d 5-CH3 2-furyl cyclohexyl B 170-171 5-CH3 2-thienyl cyclohexyl B 153-154.5d H 5-ethvl-2-furyl cyclohexyl B 146-147 15 5™CH3 5-ethyl-2-furyl cyclohexyl B 190-191 5-CH3 (2-thienyl)-methyl cyclohexyl B 158-159 5-Cl 5-ethyl-2- furvl cyclohexyl B 210-211d 6~C1 2-furyl' cyclohexyl 3 183-184 5-F 2-furyl cyclohexyl B 186.5- 187.5d 20 5-F 2-thienyl cyclohexyl B 145.5- 146.5d 5-F (2-thienylJ -methyl cyclohexyl B 164-165 2 8 X R1 R2 Method of Prepy aration Mel ting Point ( °C)jL S-Cl 2-thienyl cyclohexyl B 172-173 S-Cl (2-thienyl)-methyl cyclohexyl B 173-l75d 4-CI 2-thienyl cyclohexyl B 189-190 5 4-CI {2-thienyl5 -methyl cyclohexyl B 172-173 4-CI rnethvl cyclohexyl B 131-132 5~CF3 2-furyl cyclohexyl B 194-195d 5"CF3 2-thienyl cyclohexyl B 171-172d 6-F 2-furyl cyclohexyl B 164-166 10 6-F 2-thienyl cyclohexyl B 5-CH j 2-thienyl t-butyl B 189-5d 5-CH3 methyl t-butyl B 194d 5-Cl methyl t-butyl B 211.5d 5—CH^ 5-ethyl-2- furyl t-butyl 8 214-215 15 5-Cl 5~ethyl-2-furyl t-butyl B 224-225 5-F 2-furyl t-butyl B 212.5d 5-F 2-thienyl t-butyl B 183.5d 5-F (2-thienyl)-methyl t-butyl B 161d 6-C1 2-thienyl t-butyl B 191-192 20 5-CH3 2-thie.nvl isopropyl B 146-147d S-C:^ 2-furyl. isopropyl B 166-167d 5-CH3 phenoxymethyl isopropyl B 184-18 6 5-Cl phenoxymethyl isopropyl B 186-188d 5-Cl bensvl isopropyl B 184-185 25 5-Cl cyclohexyl isopropyl B 206~208d 5~CH3 5-methyl~2" furyl isopropyl B 194d 5-CH3 methyl isopropyl B 158-159 Z 9 X R1 R2 Method of Preparation Mel ting Point ( °C) 5-Cl 5~methyl-2- furyl isopropyl B 19 8,5-199*5 5-Cl methyl isopropyl B 215-216 H methyl isopropyl B 170-172 5 K cyclohexyl isopropyl B 188-189 H benzyl isopropyl B 145-146 B phenoxymethyl isopropyl B 157-158 5-Cl 5-ethyl-2-furyl isopropyl B 209-211d 5-Cl isopropyl isopropyl B 142-143 10 6-C1 2-furyl isopropyl B 18 4 -18 5 d S-Cl 2-thienyl isopropyl B 174 . 5-17! 6-C1 (2-thienyl)-methyl isopropyl B 157-158d H 2-thienyl phenoxymethyl B 161-162 5-Cl 2-thienyl phenoxymethyl B 182-183 15 H 2-furyl phenoxymethyl B 173-175d E (2-thienyl)~ methyl phenoxymethyl B 193-194 5-Cl 2-furyl phenoxymethyl B 194-195.

^The letter h in this column indicates that the compound was prepared substantially according to Example 1; the 20 letter B indicates that the compound was prepared substantially according to Example 2 or 3,- and the letter C indicates that the compound was prepared substantially according to Example 4.

"The letter "dB indicates that the compound melted 25 with decomposition- 3 0 EXAMPLE 8 Ethanolamine Salt of N-Benzovl-3-(2-furoyl)- 2~oxindole-l-carboxamide To a slurry of 56 2 mg (1.5 mmole) of N-benzoyl-3~(2-furoyl)-2-oxindoXs-l-carboxamide in 10 ml of methanol was added 101 mg (X.S5 mmole) of ethanolamine. The resulting mixture was heated to boiling for a few minutes and then it was allowed to cool. The solid which precipitated was recovered by filtration to give 524 mg of the title salt,, mp 165-166°C. Yield; 80%.

Analysis; Calcd. for c?3H2l°6N3: 4.86; N, 9,65%. Found: C, 6 3.27; H( 4.95; N, 9.58%.

EXAMPLE 9 The diethanolamine salt of N-benzoyl-3-(2-furovl)-2-oxindole-l-carboxamide was prepared by substituting diethanolamine for ethanolamine in the procedure of Example 8 - The product melted at 157" 158 °C. Yield: 74%.

Analysis: Calcd. for C25n">501^3Cf 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-l-carboxamide was prepared by substituting triethanolamine for ethanolamine in the procedure of Example 8 . The product melted at 154-155°C. Yield: 60%.

Analvsis; Calcd. for C^HjcjOg^: C» 61.94; H, 5.58; N, 8-03%. Found: Cf 61.84; Ht 5.61; N, 7-99%.

EXAMPLE 11 N-Benzoyl-2-oxindole-1-carboxamide To a stirred slurry of 399 mg (3.0 mmole) of 2-oxindolo in 7 ml of toluene was added 485 mg (3.3 mmole) of benzoyl isocyanate. The mixture was heated under reflux for 2-2 hours and then it was cooled to room temperature. The solid was recovered by filtration and it 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-lization of the precipitate from acetonitrile gave 131 mg of the title compound, mp 183,5-18 4.5°C.

Analysis; Calcd. for C1 gH-, : C, 68 .56; H, 4.32; N, 9.99%. Found; C, 68.37; H, 4.58; N, 10.16%.

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: 0=C-&H-C-R" 11 o X R Melting 1 Point(0°C)~ Yield(%) 5-Cl phenyl 193-195 43 5-CH3 phenyl 202-203 68 S-Cl phenyl 206-207 59 6~F phenyl 174-175.5 5-F phenyl 18 7d 37 H 4-fluorophenvl 17 7 -17 8 d 21 S-CH^ 4-fluorophenyl 209-211d 78 5-Cl 4-fluorophenvl 19 8 ~ 19 9 d 59 H 4-me thoxvpheny1 180d 72 H 4-chlorophenvl 186.5-187 - 5d 53 H 2-methylphenyl 166.5-167 . 5 59 H cyclohexyl 144.5=145 .5 6 2 5-Cl cyclohexyl 172-174 63 5-CH3 cyclohexyl 140-141.5 68 6-Cl cyclohexyl 181-182 56 5-F cyclohexyl 163.5-164 .5 63 4-CI cyclohexyl 5~CF3 cyclohexyl 6-F cyclohexyl B t-butyl 5~CH3 t-butyl 5-Cl t-butyl 5-F t-butyl S-Cl t-butyl K isopropyl 5~CH3 isopropyl 5-Cl isopropyl 6-Cl isopropyl H phenoxymethyl 5-Cl phenoxymethyl Melting ^ Point(0°C)~ Yield(%) 173-174 69 177.5-178 . 5d 40 203-206 43 151—152 35 202.5d 34 176.5-177 . 5d 43 161.5-162 . 5d 31 146-147 42 114-115 23 169-171 38 164-165 77 128-129 69 187-188 78 218-219 51 *The letter "d" in this column indicates that the material melted with decomposition. 34 PREPARATION 1 3-(2-Furoyl)-2-oxindole To a stirred solution of 5.5 g (0.24 mole) of sodium in 150 ml of ethanol wss added 13.3 g (0,10 5 mole! of 2-oxindole at room temperature. The resulting slurry was cooled to ice-bath temperature, and then 15.7 g 10.12 mole) of 2-furoyl chloride was added, dropwise, during 10-15 minutes. The ice-bath was removed, and additional 100 ml of ethanol was added 10 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 filtered off. The solid was added to 400 ml of water and the resulting mixture was acidified using concentrated 15 hydrochloric acid. The mixture was cooled with ice and the solid was collected by filtration. The solid residue was recrystal1ised from 150 ml of acetic acid, affording 8-3 g of yellow crystals,, sap 209-210 (dec). 20 Analysis; Calcd. for cl3H003N: C, 68,72? H, 3.99; N, 6.17%. Pound: 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 le gave the 25 following additional products: 3-(2-thenoyl|-2-oxindole„ mp 189-190°Cti> 17% yield? 3-(2-12-thienyl]acetyl J-2-oxindole, mp 191-192-5°C, 38% yield; 30 3~(2-phenoxyacetylJ-2-oxindole, mp 135-136°C, 42% yield; and 5-chloro-3-(2-[2-thienyl]acetyl)-2-oxindole^ mp 2 2 8-2 30°C., 22% yield.

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 5 mole) of 2-oxindolefollowed 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 10 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 15 was stirred to give a solidf which was recovered by filtration. This latter solid was recrystal1ized from acetic acid followed by acetonitrile to give 705 mg of the title compound, mp 185-186°C.

Analysis; Calcd. for 3H9O3N: C, 68.72; H, 3.99; 20 N, 6.17%. Found; C, 68.72; H, 4.14; N, 6.14%. 3 8 PREPARATION 3A React: ion of the appropriate 2-oxindole with the ethyl ester of the requisite carboxylic acid, substantially according to the procedure of Preparation 5 3, gave the following compounds: 5-chloro-3-(2-thenoyl)-2-oxindolee mp 190.5-192°C., 36% yield; 5-chloro-3-(2-furoyl)-2-oxindole, mp 234-235°C. 54% yield; 10 5-chloro-3-(2-phenylacetyl)-2-oxindole, mo 241- 2 4 3 °C,, 61% yield; 5-fluoro-3-(2-furoyl)-2-oxindole, mp 222-224°C. 51V, yield; 5-fl.uoro-3-(2-thenoyl)-2-oxindolo, mp 200-203°C 15 26% yield; 6-fluoro-3-(2-furoyl)-2-oxindole, mp 239-242°C. 26% yield; and 6-chloro-5-fluoro-3-(2-thenoyl)-2-oxindole, mp 212-215°C., 20% yield. 20 PREPARATION 4 5—Chloro-2-oxindole To a stirred slurry of 100 g (0.55 mol) of 5-chloroisatin in 930 ml of ethanol was added 40 ml (0.826 mol) of hydrazine hydrate, resulting in a red 25 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-chloro-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 portionwisef during 10 minutes, to a solution of 125.1 g of sodium methoxide in 900 ml of absolute ethanol. The resultan solution was heated under reflux for 10 minutes and then it was concentrated iri vacuo to a gummy solid. The gummy solid was dissolved in 400 ml of water and the aqueous solution thus obtained was decolorized with activated carbon and then poured into a mixture of 1 liter of water and 180 ml of concentrated hydrochloric 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 was recrystal1ized from ethanol to give 4 8.9 g of the title compound# mp 193~195°C. (dec).

In an analogous fashion,, 5-methvlisatin was converted into 5-methy1-2-oxindole by treatment with hydrazine hydrate followed sodium ethoxide in ethanol™ The product melted at 173-174°C, PREPARATION 5 4 ,5-Dimethyl~2~oxindole and 5,6-dimethyl--2-oxindole 3e4"Dimethylaniline was converted into 3,4-di-methvl-isonitrosoacetanilide by reaction with chloral hydrate and hydroxvlamine, using the method described in "Organic Syntheses/" Collective Volume I, page 327. The 3,4-dimethyl-isonitrosoacetanilide was cyclized with sulfuric acidt, according to the method of Baker et al. , Journal of Organic Chemistry,, 17, 149 (1952), to give 4,5-dimethylisatin (m.p. 225-226° C.) and 5,6-dimethvlisatin {m.p. 217-218° C.). 38 PREPARATION 5 (Cont„) 4 e 5-Dimethyl isatin was converted into 4,15-dimethyl-2-oxindole, m.p. 245.5-247. 5° C., by treatment with hydrazine hydrate,, followed by sodium ethoxide in 5 ethanol t, substantially according to the procedure of Preparation 4.

In like manner, 5 , S~dimethylisatin was converted into 5y6-dimethyl-2-oxindole, m.p. 196-5-198° C., by treatment with hydrazine hydrate,, followed by sodium 10 ethoxide in ethanol, substantially according to the procedure of Preparation 4.

PREPARATION 6 4-Chloro-2-oxindole and 6-chloro-2-oxindole A. 3-Chloro-lsonitrosoacetan.il iae 15 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 20 water. A thick precipitate formed * To the reaction mixture was then added, with stirring,, a solution of 155 c (2.23 moll of hydroxy1amine in 500 ml of water® Stirring was continued and the reaction mixture was warmed slowly and it was maintained between 60 and 25 75°C. for approximately 6 hours, during which time an additional 1 liter of water had been added to facilitate stirring. The reaction mixture was then cooled and the precipitate was recovered by filtration. The wet solid was dried to give 136.1 g of 3-chloro-30 isonitrosoacetanilide.

PREPARATION 6 (Cont.) B» 4-Chloroisatin and S-chloroisafcin To 775 ml of concentrated sulfuric acid? preheated to 70°C. e, was added, with stirring, 136 g of 3-chloro-isonitrosoacetaniliae at such a rate as to maintain the reaction medium at a temperature between 75 and 85®C» When all the solid had been "added,, the reaction mixture was heated at 90°C. for an additional 30 minutes. The reaction mixture was then cooled? and poured slowly onto ca 2 liters of icewith 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 solution by the addition of £a 700 ml of 3N sodium hydroxide. The solution was filtered*, and then pH was adjusted to 8 with concentrated hydrochloric acid* At this point, 120 ml of a mixture of 80 parts water and 20 parts concentrated hydrochloric acid was added- The solid which precipitated was recovered by filtration, washed with water and dried to give 50 g of crude 4-chloroisatin. The filtrate from which the 4-chloroisatirx 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,, to give 4 3 g of crude 6-chloroisatin.

The crude 4-chloroisatin was recrystal1ized from acetic acid to give 43-3 g of material melting at 258-259°C.

The crude 6-chloroisatin was recrystallised from acetic acid to give 36.2 g of material melting at 261- PREPARATION 6 (Cont.) C. 4-Chloro-2-oxindole To a stirred slurry of 4 3.3 g of 4-chloroisatin in 350 ml of ethanol was added 17-3 ml of hydrazine 5 hydrate, and then the reaction mixture was heated under reflux for 2 hours. The reaction mixture was cooled, and the precipitate was recovered by filtration to give 4 3»5 g of 4-chloro-3-hydr a%ono~ 2-ox indol emp 235-236°C« 10 To a stirred solution of 22 g of sodium in 4 50 ml of anhydrous ethanol was added,, portionwise, 43.5 g of 4-chloro-3-hydrazono-2-oxindo 1 eand the resulting solution was heated under reflux for 30 minutes. The cooled solution was then concentrated to a gum1? 15 which was dissolved in 400 ml of water and decolorised 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-20 lized from ethanol, giving 22-4 g of 4-chloro-2™oxindolee, mp 216-218"C {dec)- D„ 6-Chloro~2-oxindole Reaction of 36-2 g of S-chloroisatin with hydrazine hydrate followed by sodium ethoxide in ethanol, sub-25 stantially according to C above, afforded 14-2 g of 6-chloro-2-oxiitdole, mp 196-198°C- 4 i PREPARATION 7 5,6-Difluoro-2-oxindole Reaction of 3,4-difluoroaniline i#ith chloral hydrate and hydroxy1amine followed cyclisation with 5 sulfuric acidf in a manner analogous to Parts A and B of Preparation gave 5 f 6~difluoroisatin, which was reacted with hydrazine hydrate followed by sodium methoxide in ethanol, in a manner analogous to Preparation 4, to give the title compound,,, m.p- 187-10 190°C.

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 15 ~ 6 5 ° C 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 -65°C, and then was added, dropwise, a solution of 13.4 g (0-1 mol) of ethyl 2-(methylthio)acetate in 20 25 ml of dichloromethane. Stirring was continued at -60*0. for 1 hour and then was added, dropwise, at -60 to -65°C# a solution of 11.1 g CO.11 moll of triethylamine in 25 ml of dichloromethane. The cooling bath was removed, and when the reaction mixture 25 had warmed to room temperaturet 100 ml of water was added. The phases were separated, and the organic phase was washed with saturated sodium chloride solution, dried (Na2S04) and evaporated in vacuo- The residue was dissolved in 350 ml of diethyl ether, to 30 which was added 40 ml of 2N hydrochloric acid- This mixture was stirred at room temperature overnight. The phases were separated and the ether phase was washed 4 2 PREPARATION 8 fCont.) with water, followed saturated sodium chloride® The dried {NajSO^J ether phase was evaporated in vacuo to give 17 g of an orange-brown solid which was triturated 5 under isopropyl ether. The solid was then recrystal-lised form ethanol [? to give 5,58 g of 5-f luoro-3-raethylthio~2~oxindole, mp 151.5-152.5°C.

Analysis; Calcd for C^HgOMFS: C, 54.80;- H,. 4 ,,091 N, 7.10%. Found; C, 54,74; H, 4.11; N, 7.11%. 10 A sample of the above 5-fluoro-3-methylthio~2- oxindola (986 mg, 5.0 mmol) 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 15 was washed with absolute ethanol. The combined ethanol solutions were evaporated in vacuo and the residue was dissolved in dichloromethane. The dichloromethane solution was dried ijNfijSO^) and evaporated in vacuo to give 475 mg of 5-fluoro~2~oxindole# mp 121-20 134°C.

In analogous fashion, 4-trifluoromethylaniline was reacted with t-butyl hypochlorite, ethyl 2-(methyl-thiol acetate and trxethylamine followed by reduction of the 3-thioraethyl-5-tri£luoromethyl~2~oxindoIe thus 25 obtained with Raney nickel,, to give 5-fcrifluoromethyl-2-oxindole, mp 189.5-190.5°C.

PREPARATION 9 5-Methoxy-2-oxindole 5-Methoxy-2-oxindole was prepared from 4-methoxy-30 aniline in a manner similar to the procedure of Preparation 8, except that the initial chlorination step was carried out using a solution of chlorine gas in dichloromethane in place of Jt-butyl hypochlorite. The title product melted at 150.5-151.5° C.

PREPARATION 10 6"Chloro~5~-fluoro~2--oxindole To 130 ml of toluene was added,, with stirring, 24.G g ,0.165 mole) of 3~chloro~4~fluoroaniline and 13.5 ml (0.166 mole) of pyridine- The resulting solution was cooled to ca 0CC. and 13.2 ml CO-166 mole) of 2-chloroacetyl chloride was added. The reaction mixture was stirred at room temperature for 5 hours and then it was extracted twice with 100 ml of IN hydrochloric acid,, followed by 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried using magnesium sulfate? and then it was concentrated jLn vacuo to give 32,6 g (88% yield) of M~{2-chloroacetyl)~3-chloro-4-fluoroaniline.

A 26.63-g sample of the N—C2-chloroacetyl)-3-chloro-4-fluoroaniline was thoroughly mixed with 64 g of anhydrous aluminum chloride, and the mixture was heated at 210~230CC. for 8.5 hours. The reaction mixture was then poured onto a mixture of ice and IN hydrochloric acid, with stirring. 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-tog raphed on 800 g of silica gel. Elution of the column, followed by evaporation of the fractions, produced 11.7 g of the N-f 2-chloroacetyl)-3-chloro-4-fluoroaniline, followed by 3-0 g of S-chloro-S-fluoro-2—oxinaole. The latter material was recrystal1ized from toluene to give 1-70 g {7% yield) of the title compound, mp 196-206°C. Analysis 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- PREPARATION 11 5-Fluoro-5~methyl-2-oxindole to intimate mixture of 11.62 g (57,6 mmol) of N— {2-chloroacetyl)-3-fluoro-4~methylaniline and 30.6 g (229.5 mmol) of anhydrous aluminum chloride was heated to 210-220°C. After 4 hours,, the reaction mixture was cooled and then added to 100 ml of IN hydrochloric acid ana 50 ml of ice. A tan solid formed, which was collected by filtration and recrystal1ized from aqueous ethanol. Three crops were obtained, weighing 4.49 g, 2.28 g and 1.0 ge respectively. The crop weighing 1.0 g was further recrystallised from water to give 280 mg of the title compound, mp 168.5-171°C.

PREPARATION 12 S-Bromo-2-oxindole To 9.4 g of sodium hydride was added 195 ml of dimethyl sulfoxide,, followed by the dropwise addition of 22.37 ml of dimethyl malonate. At the end of the additione the mixture was heated to 100° C. and maintained at that temperature for 4 0 minutes. At this point, 25 g of 1 „4*-dibromo"2-n,itroben2ene was added all at once. The reaction mixture was maintained at 100° C- for 4 hours and then it was added to 1.0 liter of saturated 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 (MgSO^) solution was evaporatedand the residue was recrystal-lized from ethyl acetate-hexane to give 22.45 g of dimethyl 2-(4-bromo-2-nitrophenvl}malonate.

A solution of 17.4 g of dimethyl 2-(4~bromo-2-nitrophenyl)malonate and 4.6 g of lithium chloride in 150 ml of dimethyl sulfoxide was placed in an oil bath at 100° C. After 3 hours,, the reaction mixture was 45 PREPARATION 12 (Contd) cooled to room temperature and then it was poured into a mixture of 500 ml of ethyl acetate and 500 ml of saturated sodium chloride solution. The layers were separated and the aqueous layer aas extracted with further ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution? dried using sodium sulfate,, and then evaporated in vacuo. The residue was chromatographed using silica gel as adsorbant and ethyl acetate-hexane mixture as eluant.

This afforded 9.4 g of methyl 2~(4-bromo~2-nitrophenyl)-acetate.

To a solution of 7.4 g of methyl 2-(4~>bromo-2-nitrophenvl)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 filtered, washed with saturated sodium chloride 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 * m.p. 213-214° C.

In like manner, starting with 1f 4 , 5-tnchloro-2~* nitrobenzene, 5,S-dichloro-2-oxindole was prepared, m.p. 209-210° C.

PREPARATION 13 6-Phenyl-2-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„ of dimethyl sulfoxidet, 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 100°C. for 1 hour, cooled, and poured onto a mixture of ice-water containing 5 g. of ammonium chloride. The mixture thus obtained was extracted with ethyl acetate, and the extracts were washed with sodium chloride solution and dried using magnesium sulfate. Evaporation in vacuo to give an oil, which was chromatographed using silica gel and then recrystal1ized from methanol to afford 6 g. of dimethyl 2~(3-nitro-4-diphenylyl)- malonate# m.p, 82~83°C» h portion (S g«) of the above nitro compound was reduced with hydrogen over a platinum catalyst„ in a mixture of 50 ml. of tetrahvdrofuran and 10 ml. of 2 methanol,, at a pressure of ca 5 kg/cm # 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 recrystallised from methanol to give 1.1 g. of ethyl 6~phenvl-2-oxindole-l-carboxylate# m.p. 115-117°C.

The above ethyl ester (1.0 g.) and 100 ml. of 6N hydrochloric acid was heated under reflux for 3 hours and then allowed to stand at room temperature for 3 4 7 PREPARATION 13 (Cont.) days. The solid was collected by filtration and dried ? to give 700 mg. of 6-phenyl-2-oxindolei, m.p. 175-176°C„ PREPARATION 14 5-Acetyl-2-oxindole To 95 ml. of carbon disulfide was added 27 g. (0,202 mole) of aluminum chloride,, followed by the dropwise addition of a solution of 3 ml. (0.04 2 mole) 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 residue was triturated under water and recovered by filtration. After drying,, 3,2 g. of the title compound was obtained,, -nup. 225-227°C„ Reaction of 2-oxindole with benzoyl chloride and with 2-thenoyl chloride in the presence of aluminum chloride,, substantially according to the above proceduret afforded the following compounds? 5~benzoyl-2-oxindole? m.p. 203-205°C. (from CH30H) and 5-(2-thenoyl)-2-oxindole, m.p„ 2ll-213°C. (from CH3CN).

PREPARATION 15 5-Bromo-2-oxindole, 5-nitro-2-oxindole and 5-amino-2-oxindole can be prepared as described in Beckett et al. f Tetrahedron,, 24 , 6093 (19 68) » 5-Amino-2-ox indo1e can be acylated to give 5-alkanamido- 2-oxindole and 5-henzaraido-2-ox indolee using standard procedures. 5-n-Butyl~2-oxindole can be prepared by reaction of 5-n-butylisatin with hydrazine hydrate 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 hydroxy 1 aminefollowed by cyclization with sulfuric acid£, according to the procedure of Parts A and B of Preparation 6. 5-Ethoxy-2-oxindole can be prepared by conversion of 3-hydroxy-S-nitro-toluene into 3-ethoxv-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-oxindoie by the method described by Beckett et al», (Tetrahedron, 24, 6093 [19681 ) g, for the conversion of 3~methoxy~6~nitro-toluene into 5-methoxy~2~-oxindole„ 5~n~Butoxy~2-oxindole can be prepared in like manner„ but substitutii n-hutyl iodide for ethyl iodide. 5„6-Dimethoxy-2-oxindole can be prepared by the method of Walker., Journal of the American Chemical Society, 77, 3844 (1955). 7-Chloro~2™oxindole can be prepared by the method described in United States Patent No. 3,882,? 236- 4-Th iomethvl-2-ox indole and 6~thiomethyl-2-*oxindol can be prepared by the method described in United States Patent Mo, 4,006,161. 5-n-Butylthio-2-oxindole can be prepared in like manner2, but substituting 4-butylthioaniline for the 3-methylthioaniline. 4 9 PREPARATION 15 (Cont.) 5,6-Methylenedioxv-2-oxindole can be prepared by the method of McEvoy et al - , Journal of Organic Chemistry, 38 , 3350 (1973). 5s6-Ethylenedioxy-2~ 5 oxindole can be prepared in analogous fashion. 5-Fluoro-2-oxindole can be prepared according to Protiva et al., Collection of Czechoslovakian Chemical Communications, 44, 2108 (1979) and United States Patent No. 4,160,032. 10 S-Trifluoromethyl-2-oxindole can be prepared according to Simet,, Journal of Organic Chemistry,, 28, 3580 (1963). 6-Methoxy-2-oxindole can be prepared according to Wieland et al., Chemische Berichte, 96, 253 (1963). 15 5-Cyclopropyl-2-oxindole and 5-cycloheptyl-2- oxindole can be prepared by reaction of 5--cyclopropyl isatin and 5-cycloheptyl isatin,. respectively, with hydrazine hydrate followed by sodium methoxide in ethanol,, according to the procedure of Preparation 20 4. 5-Cyclopropylisatin and 5-cycloheptylisatin can be prepared from 4-cyclopropylaniline and 4-cyclo-heptylaniline, respectivelyt„ by treatment with chloral hydrate and hydroxy1amine, followed by cyclIzation with sulfuric acid,, according to Parts A 25 and B of Preparation 6. 5 0

Claims (18)

1. A 2-oxindole compound of the formula II 0 or a pharmaceutically-acceptable base salt thereof, wherein X and Y are each independently hydrogen, fluoro, chloro, bromo, methyl or trifluoromethyl; R"*" 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 alky]., or - (CI^) _Q-R°; wherein n is zero, 1 or 2; Q is a divalent radical derived from furan or thiophene; and R° is hydrogen or alkyl having 1 to 3 carbons; 2 and R is alkyl having 1 to 6 carbons, cycloalkyl having 3 to 7 carbons, phenoxymethyl, or 3 4 wherein R and R are each hydrogen, fluoro, chloro, methyl, methoxy, or trifluoromethyl.

2. A compound according to claim 1, wherein R 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, 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 or thienylalky1 having 1 to 3 carbons in said alkyl.

3. A compound according to claim 2, wherein Y is hydrogen.

4. A compound according to claim 3, wherein X is hydrogen.

5. A compound according to claim 4, wherein is 2-furyl, 2-thienyl or (2-thienyl)methyl.

6. A compound according to claim 5? wherein R1 2 is 2-furyl and R is phenyl.

7. A compound according to claim 3, wherein X is 5-chloro and R is 2-furyl, 2-thienyl or (2-thienyl)-methyl.

8. A compound according to claim 7, wherein 2 is 2-thienyl and R is cyclohexyl.

9. A pharmaceutical composition, which connrises a pharmaceutically-acceptable diluent or carrier and a 2-oxindole compound or pharmaceutically-acceotable base salt thereof as claimed in any one of the preceding claims.

10. A compound of the formula (I) as claimed in any one of claims 1 to 8, or a pharmaceutically-acceptable base salt thereof, for use as a medicament.

11. The use of a compound of the formula (I) as claimed in any one of claims 1 to 8, or of a pharmaceutically acceptable base salt thereof, for the manufacture of a medicament for use as an analgesic or antiinflammatory agent, S 2

12. A compound of the formula II 0 2 or a base salt thereof, wherein X, Y and R are as defined in claim 1.

13. A 2-oxindole compound of the formula I given and defined in Claim 1 or a pharmaceutically-acceptable base salt thereof, substantially as hereinbefore described and exemplified.

14. A process for preparing a 2-oxindole compound of the formula I given and defined in Claim 1 or a pharmaceutically-acceptable base salt thereof, substantially as hereinbefore described and exemplified,

15. A 2-oxindole compound of the formula I given and defined in Claim 1 or a pharmaceutically-acceptable base salt thereof, whenever prepared by a process claim in Claim 14.

16. A pharmaceutical composition according to Claim 9, substantially as hereinbefore described-

17. Use according to Claim 11, substantially as hereinbefore described.

18. A compound of the formula II given and defined in Claim 12 or a base salt thereof, substantially as hereinbefore described and exemplified. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.