DD232039A5 - PROCESS FOR PREPARING A 2-OXINIDOL-1-CARBOXAMIDE COMPOUND - Google Patents

Abstract

Certain novel 2-oxindole-1-carboxamide compounds having an acyl substituent at the 3-position are inhibitors of the enzymes cyclooxygenase (CO) and lipoxygenase (LO) and are useful as analgesic and antiperspirant agents in mammals. In particular, the compounds of the present invention are useful for alleviating or eliminating pain in humans recovering from surgery or trauma, and in alleviating the symptoms of chronic diseases such as rheumatoid arthritis and osteoarthritis in humans.

Description

Process for the preparation of a 2-oxindole-1-carboxamide

connection

Field of application of the invention

This invention relates to novel chemical compounds of value as new drugs. In particular, the novel chemical compounds are derivatives of 2-oxindole-1-carboxamide, and are further substituted in the 3-position by an acyl group. These new chemical compounds are inhibitors of both the enzyme cyclooxygenase (CO) and lipoxygenasei (LO).

The compounds of this invention are useful as analgesic agents in mammals, particularly humans, and are experienced in relieving or eliminating pain, such as pain, from the patient recovering from surgery or trauma.

ifir / ^ v, /; K;) 54 ;,

In addition to their usefulness for acute administration for pain control, the compounds of this invention are useful for chronic administration to mammals, particularly humans, for alleviating the symptoms of chronic diseases such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis.

Aim and presentation of the essence of the invention

This invention provides novel 2-0xindole-1-carboxamide compounds of the formula

(D

and their pharmaceutically acceptable base salts, wherein X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbons, cycloalkyl with

3 to 7 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, trifluoromethyl, alkylsulfinyl of 1 to 4 carbons, alkylsulfonyl of 1 to 4 carbons

4 carbons, nitro, phenyl, alkanoyl of 2 to 4 carbons, benzoyl, thenoyl, alkanamido of 2 to 4 carbons, benzamido or N, N-dialkylsulfamoyl of 1 to 3 carbons in each of the alkyls; and Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxy of 1 to 4 carbons, alkylthio of 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, taken together and adjacent to each other

pendent to form a divalent radical Z, wherein Z is selected from

W-

and

z ⁴ z ⁵

where W is oxygen or sulfur;

R is selected from the group consisting of alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, cycloalkenyl of 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbons in the alkyl, (substituted phenyl ) alkyl having 1 to 3 carbons in the alkyl, phenoxyalkyl having 1 to 3 carbons in the alkyl, (substituted phenoxy) alkyl having 1 to 3 carbons in the alkyl, (thiophenoxy) alkyl having 1 to 3 carbons in the alkyl, naphthyl, bicyclo / 2, 2, 7-heptan-2-yl, bicyclo / 2, 2, 1-hept-5-en-2-yl and - (CH ₂ J _n -QR ⁰ ;

wherein the substituent on the substituted phenyl, the (substituted phenyl) alkyl and the (substituted phenoxy) alkyl is selected from the group consisting of fluoro, bromo, chloro, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 Carbons or trifluoromethyl,

η is zero, 1 or 2, Q is a bivalent radical derived from a compound selected from the group consisting of furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, cxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo / b / furan and benzo / b / -thiophene, and R ° is hydrogen or alkyl with 1 to 3 carbon atoms

is lenlen.

The compounds of formula I are active as analgesic agents and as agents for the treatment of inflammatory diseases such as arthritis. Thus, this invention provides a method for eliciting an allergic response in mammals, particularly humans, a method of treating an inflammatory disease in a mammal, particularly in humans, and pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.

A first preferred group of compounds of this invention consists of the compounds of formula I wherein Y. is hydrogen and X is selected from the group consisting of 5-chloro, 6-chloro, 5-fluoro, 6-fluoro, 5-trifluoromethyl and 6-trifluoromethyl. Within this first preferred group, particularly preferred compounds are those wherein R is benzyl, 2-furyl, 2-thienyl, (2-furyl) methyl or (2-thienyl) methyl.

A second preferred group of compounds of this invention consists of the compounds of formula I wherein X is selected from the group consisting of 5-chloro and 5-fluoro and Y is selected from the group consisting of 6-chloro and 6-fluoro. Within this second preferred group, particularly preferred compounds are those wherein R is benzyl, 2-furyl, 2-thienyl, (2-furyl) methyl or (2-thienyl) methyl.

Particularly preferred single compounds of the invention are:

5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide (I: X is 5-chloro; Y is hydrogen; and R is 2-thienyl); 5-trifluoromethyl-3- (2- / 2-thienyl-7-acetyl) -2-oxindole-1-carboxamide (I: X is 5-trifluoromethyl, Y is hydrogen, and R is 2- / thien-

yl / acetyl); 6-Fluoro-3- (2-phenylacetyl) -2-oxindole-1-carboxamide (I: X is 6-fluoro, Y is hydrogen and R is benzyl); 6-chloro-5-fluoro-3- (2-phenylacetyl) -2-oxindole-1-carboxamide (I: X is 5-fluoro, Y is 6-chloro and R is benzyl); 5,6-Difluoro-3- (2-furoyl) -2-oxindole-1-carboxamide (I: X is 5-fluoro, Y is 6-fluoro and R is 2-furyl); and 5,6-difluoro-3- (2-thenoyl) -2-oxindole-i-carboxamide (I: X is 5-fluoro; Y is 6-fluoro; R is 2-thienyl).

Further, this invention still provides novel compounds of the formula

(II)

YO = C-NH ₂

wherein X and Y are as previously defined. The compounds of formula II are useful as intermediates for the compounds of formula I.

The afialgetic and anti-inflammatory compounds of this invention are the compounds of formula I wherein X, Y and R are as previously defined. Thus, the compounds of this invention are derivatives of 2-oxindole, the bicyclic amide of the formula

(III)

More particularly, the analgesic and antiinflammatory agents of this invention have a carboxamide substituent, -Ct = O) -NH- in-1 position and an acyl substituent.

1-C (= O) -R / in 3-position of the 2-oxindole, and the benzo ring may be further substituted by X and Y groups.

X and Y may be certain monovalent substituents as previously defined, or X and Υψ when adjacent to carbon atoms on the benzo ring may represent a methylenedioxy group, -OCH 2 -O-, or an ethylenedioxy group, -OCH 2 Cl 2 O-. Still further, X and Y, when attached to adjacent carbon atoms, of the benzo ring of the 2-oxindole, can form a divalent unit Z such that when Z is taken together with the carbon atoms to which it is attached, a condensed carbocyclic or heterocyclic ring forms. Certain divalent groups for Z (ie Z-Z) have been listed earlier. So when ZZ is X and Y, when combined with the carbons to which they are attached mean

taken, a condensed cyclopentene ring, and

when Z is Z, X and Y, when taken together with the carbons to which they are attached, represent a fused furan or thiophene ring. It is further understood that

4 5

if Z is Z or Z, the group Z can be appended in one of two possible ways. Thus, for example, when X and Y are C-5 and C-6 and Z is Formula I both have the following formulas

'W

O = C-NH.

In addition, as will be appreciated by those skilled in the art, the analgesic and anti-inflammatory compounds of this invention of formula I, wherein X, Y and R are as previously defined, are enolisable, and therefore they can be used in one

or more tautomeric (enolic) forms exist. All such tautomeric (enolic) forms of the compounds of formula I are considered to be within the scope of the invention.

The compounds of formula I are prepared from the appropriate 2-oxindole-1-carboxamide compound of the formula

(ID

0-C-NH ₂

wherein X and Y are as previously defined. This is done by appending the substituent C (= O) -R to the 3-position of the 2-oxindole nucleus.

The -C (= O) -R substituent is appended by reacting a compound of formula II with an activated derivative of a carboxylic acid of the formula R -Ci = O) OH. The reaction is carried out by treating the compound of formula II in an inert solvent with one molar equivalent or a slight excess of an activated derivative of a compound of formula R -C (= O) OH in the presence of 1 to 4 equivalents of a basic agent. An inert solvent is one which dissolves at least one of the reactants and does not adversely interact with any of the reactants or the product. In practice, however, a polar, aprotic solvent such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide is usually used. Conventional methods for activating the acid of the formula R -C (= O) OH are used. For example, acid halides, e.g.

iae .1

Acid chlorides, symmetrical acid anhydrides, R -C (= O) -O-C (= O) mixed acid anhydrides with a hindered low molecular weight

1 3 3

gular carboxylic acid, R -C (= O) -O-C (= O) -R, where R is a

lower alkyl group such as t-butyl, and mixed

1 4

Carboxylic acid-carbonic anhydrides, R -Ci = O) -O-C (= O) -OR, where

Rin R is a low molecular weight alkyl group can be used. In addition, N-hydroxyimide esters (such as N-hydroxysuccinimide and N-hydroxyphthalimide ester), 4-nitrophenyl ester, thiolester (such as thiolphenyl ester) and 2,4,5-trichlorophenyl ester and the like can be used. Further, in those cases where R is a heteroaryl group (e.g., furyl),

1 4 4 simple alkyl esters of the formula R -C (= O) -OR, wherein R is a low molecular weight alkyl group (eg ethyl), sometimes used as the activated derivative of the acid of the formula R -C (= O) -OH, if the -C (= O) -R substituent in the 3-position of the 2-oxindole compound of formula II is attached.

A 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 formula R -C (= O) OH. However, preferred basic agents are tertiary amines such as trimethylamine, triethylamine, tributylamine, 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 the formula R -C (= O) -OH is carried out

comfortably in the temperature range of -.10 to 25 ° C carried out. Reaction times 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 recovered by filtration. It can be purified by standard methods, such as recrystallization.

The 2-oxindole-1-carboxamide compounds of the formula II can be prepared by two methods. In the first method, a 2- (2-ureidophenyl) acetic acid compound of the formula IV is cyclized by treatment with trifluoroacetic acid or trifluoroacetic anhydride:

CH ₂ -COOH

► (II)

NH-CO-NH ₂

(IV)

wherein X and Y are as previously defined. In general, a solution of a compound of formula IV in trifluoroacetic acid is treated with from 2 to 5 mol equivalent and preferably about 3 molar equivalents of trifluoroacetic anhydride, and the resulting solution is heated to reflux for 0.5 to 3 hours and usually for about 1 hour. Removal of the solvents then provides the compound of formula II. The compound of formula II may be purified by standard techniques, such as by recrystallization if desired. Alternatively, it may be used directly to form a compound of formula I.

The compounds of formula IV can be prepared by basic hydrolysis of a compound of formula V:

(V)

wherein X and Y are as previously defined and R is a lower alkyl group or a lower cycloalkyl group. Especially brai groups.

useful groups for R are isobutyl and cyclohexyl

The basic hydrolysis of a compound of formula V, wherein

2 'R is isobutyl or cyclohexyl, is usually carried out by treating a compound of formula V with a large excess of dilute aqueous potassium hydroxide solution (e.g.

0.5 η to 3.0 η, usually 1.0 η) at about room temperature or slightly above. The reaction usually takes place relatively quickly and is usually completed in 1 to 2 hours. The reaction mixture is then acidified (HCl) and the product is then isolated by filtration or by solvent extraction using a volatile, water immiscible organic solvent. The compound of formula IV may e.g. by recrystallization, if desired, or it can be cyclized directly to a 2-0xindole-1-carboxamide of formula II.

The compounds of formula V are prepared by reacting the appropriate 2-oxindole of formula VI with an acyl isocyanate of the formula R ² -C (= O) -N = C = O:

 > (V)

(VI)

The conversion of VI to V can be accomplished by heating substantially equimolar amounts of the two reaction components in refluxing toluene for a few hours, e.g. 2 h, done.

In the second process for preparing the 2-0-oxindole-1-carboxamide compounds of formula II, a 2-oxindole of formula VI is reacted with chlorosulfonyl isocyanate to give the N-chlorosulfonyl-2-oxindole-1-carboxamide intermediate of formula VII, followed by a Cleavage of the chlorosulfonyl by hydrolysis, namely

 ·> O in

VI

O = C-NH-SQ ₂ -Cl VII

O = C-NH,

II

The first step of the series, the reaction of the appropriate 2-oxindole compound of formula VI with chlorosulfonyl isocyanate, is carried out in a reaction-inert solvent medium, i. a solvent which does not react with the chlorosulfonyl onyl isocyanate or the N-chlorosulfonyl-2-oxindole-i-carboxamide product of formula VII. The solvent need not completely dissolve the reaction components. Representative solvents are dialkyl ethers such as diethyl ether; cyclic ethers, such as dioxane and

tetrahydrofuran; aromatic hydrocarbons, such as benzene, xylene and toluene; chlorinated hydrocarbons, such as methylene chloride and chloroform; acetonitrile; and their mixtures.

The reaction is generally carried out at temperatures ranging from room temperature (about 20 ° C) to the reflux temperature of the solvent used. In general, temperatures of 25 ° C to 110 ° C are favored. Temperatures below 20 ° C, eg down to -70 ° C, may be used if desired. However, temperatures below ⁰ C are avoided, if practical, from the standpoint of the yield of the desired product for reasons of economy.

The 2-oxindole compound of formula VI and chlorosulfonyl isocyanate are generally employed in molar ratios ranging from equimolar to 30% excess of chlorosulfonyl isocyanate, i. 1: 1 to 1: 1.3, implemented. Larger excesses of chlorosulfonyl isocyanate appear to provide no advantages and are not used for reasons of economy.

The chlorosulfonyl derivatives of the formula VII thus prepared can be isolated if desired, or they can be converted directly in the same reaction vessel without isolation into a compound of formula II. Isolation of the chlorosulfonyl intermediate compound of formula VII is carried out by procedures known to those skilled in the art, e.g. by filtration or by evaporation of the solvent.

The hydrolysis of the chlorosulfonyl derivatives of the formula VII is carried out by treating the compounds of the formula VII with or without their isolation with water, aqueous acid or aqueous base. Water alone or aqueous acid are generally preferred as the hydrolyzing agent, even in cases where the hydrolysis step comprises a two-phase system. The rate of hydrolysis is fast enough to avoid any

overcome solubility problems of the reaction components. However, from the viewpoint of large-scale conversions, the use of water alone is more economical than the other hydrolysis methods.

The use of an aqueous organic acid as a hydrolyzing agent sometimes overcomes the development of two-phase reaction systems. This is often the case when using aqueous acetic acid. The amount of acid is not critical for the hydrolysis step. It can range from less than equimolar amounts to more than equimolar amounts. Also not critical is the concentration of the acid used. In general, when aqueous acid is used for the hydrolysis step, about 0.1 mole of acid per mole of compound of formula VII will utilize up to 3 moles of acid per mole of compound of formula VII. Acid concentrations of about 1 molar to 6 molar are generally used for ease of handling. Often, the use of aqueous acid is chosen when the intermediate of formula VII is isolated and a single phase hydrolysis mixture is desired. Representative acids are hydrochloric, sulfuric, nitric, phosphoric, acetic, formic, citric and benzoic acids.

In an alternative method, the compounds of the formula I can also be prepared by reacting a compound of the formula VIII with chlorosulfonyl isocyanate and subsequent hydrolysis:

1. Cl-SO ₀ -N = C = O £ _► τ

2. H ₂ O

VIII

wherein X, Y and R are as previously defined. The reaction of the compound of formula VIII with chlorosulfonyl isocyanate and the subsequent hydrolysis step are also carried out as previously described for the conversion of the 2-oxindole compound of formula VI to the chlorosulfonyl compound of formula VII and the subsequent hydrolysis to the compound of formula II.

The compounds of formula VIII are prepared by appending the -Ci = O) -R substituent to the 3-position of the required 2-oxindole compound of formula VI. This acylation reaction is carried out by reacting a compound of formula VI with a derivative of the appropriate acid of the formula R -C (= O) -OH in a lower alkanol solvent (eg, ethanol) in the presence of an alkali metal salt of the lower alkanol solvent (eg, sodium ethylate) by standard -Arbeitsweisen. Typical derivatives of the acid of the formula R -C (= O) OH which may be used include acid chlorides, acid anhydrides of the formula R ¹ -C (= O) -O-C (= O) -R ¹ , R ¹ -C (= 0) -0-C (= 0) -R ³

1 4

and R is -C (= O) -O-C (= O) -OR, and simple alkyl esters of the formula

1 4 3 4

R is -C (= O) -OR, wherein R and R are as previously defined. Usually, a slight excess of the derivative of the acid of the formula R -C (= O) -OH is used, and the alcoholate is usually present in an amount of from 1 to 2 molar equivalents, based on the derivative of the acid of the formula R -C (= O) ) OH, available. The reaction between the derivative of the acid of formula RC (= O) OH and the compound of formula VI is usually begun at 0 to 25 ° C, but it is then usual, the reaction mixture to a temperature in the range of 50 to 130 ° C. and preferably to about 80 ° C to complete the reaction. Under these conditions, reaction times of a few hours, e.g. 2 hours, up to a few days, e.g. 2 days, applied. The reaction mixture is then cooled, diluted with an excess of water and acidified. The product of formula VIII may then be recovered by filtration or by the standard procedure of solvent extraction.

_ ι 5 -

Some of the 2-0xindole-1-carboxamide compounds of formula II can be conveniently prepared from other compounds of formula II by converting one X or Y substituent to another X or Y substituent. For example, compounds of formula II wherein X is alkylsulfinyl or alkylsulfonyl can be prepared from the appropriate compound of formula II wherein X is alkylthio by oxidation. This oxidation can be carried out by standard methods, e.g. using a peroxycarboxylic acid, such as 3-chloroperbenzoic acid. For the conversion of alkylthio into alkylsulfinyl 1.0 to 1.2 molar equivalents of oxidizing agent are used; For the conversion of alkylthio into alkylsulfonyl, 2.0 to 2.4 molar equivalents of oxidizing agent are used. In addition, compounds of formula II wherein X is alkanamido or benzamido can be prepared by acylating the corresponding compound wherein X is amino. This can be done by acylating with an alkanoyl chloride or benzoyl chloride according to standard procedures.

The 2-oxindole compounds of the formula VI are prepared by known methods or by methods analogous to known methods. See "Rodd's Chemistry of Carbon Compounds", 2nd Ed., S. Coffey, Vol. IV Part A, Elsevier Scientific Publishing Company, 1973, p. 448-450; Gassman et al., Journal of Organic Chemistry, 42, 1340 (1977); . Wright et al, Journal of the American Chemical Society, 7J5./ ²²¹ (1956); Beckett et al., Tetrahedron, 2 ±, 6093 (1968); U.S. Patents 3,882,236, 4,006 and 4,160,032; Walker, Journal of the American Chemical Society, TJ, 3844 (1955); Protiva et al., Collection of Czechoslovakian Chemical Communications, 4_4_, 2108 (1979); McEvoy et al., Journal of Organic Chemistry, 3%, 3350 (1973); Simet, Journal of Organic Chemistry, 28, 3580 (1963); Wieland et al., Chemische Berichte, yy., 253 (1963); and the citations mentioned therein.

The compounds of the formula I are acidic and form base salts. All such salts are within the scope of this invention, and

they can be made by conventional methods. For example, they can be prepared simply by contacting the acidic and basic components, usually in stoichiometric proportions, either in aqueous, nonaqueous or partially aqueous medium as appropriate, or by interconversion of one salt with another. 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 solutions by lyophilization. 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. Particularly valuable are the sodium, potassium, ammonium, ethanolamine, diethanolamine and triethanolamine salts.

Basic agents suitably used in salt formation include both organic and inorganic types and include ammonia, organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alcoholates, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides and alkaline earth metal alcoholates. Representative examples of such bases include ammonia, primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucamine; secondary amines such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, triethanolamine, Ν, Ν-dimethylaniline, N-ethylpiperidine and N-methylmorpholine; Hydroxides, such as, sodium hydroxide; Alcoholates, such as sodium ethylate and potassium methylate; Hydrides, such as calcium hydride and sodium hydride; and carbonates such as potassium carbonate and sodium carbonate.

Also included in the invention are solvates, e.g. Hydrates, such as hemihydrates and monohydrates, the analgesic and inflammatory

dungshemmenden compounds of formula I.

The compounds of the formula I have analgesic activity. This activity has been demonstrated in mice by demonstrating blocking of the abdominal lining induced by administration of 2-phenyl-i, 4-benzoquinone (PBQ). The method used was based on that of Siegmund et al., Proc. Soc. Exp. Biol. Med., 9J5 / 729-731 (1957), adapted for high throughput (see also Milne and Twomey, Agents and Actions JjO, 31-37 (198O)). The mice used in these experiments were Carworth males, albino CF-1 strain, weighing 18 to 20 g. All mice were fasted overnight prior to drug administration and testing.

The compounds of formula I were dissolved or suspended in a carrier consisting of ethanol (5%), Emulphor 620 (a mixture of polyoxyethylene fatty acid esters, 5%) and saline (90%). This carrier also served as a control. Doses were on a logarithmic scale (ie ... 0.32, 1.0, 3.2, 10, 32 ... mg / kg) and were calculated from the weights of the salt, if applicable, and not the acid. The route of administration was oral, with concentrations varied to allow a constant dosage of 10 ml / kg of mouse. The aforementioned method of Milne and Twomey was used to determine potency and potency. Mice were treated orally with compounds and received PBQ, 2 mg / kg intraperitoneally one hour later. Individual mice were then immediately placed in a heated lucite chamber and, starting 5 min after PBQ administration, the number of abdominal contractions was recorded during the following 5 min. The level of analgesic protection (% MPE) was calculated based on suppression of abdominal contraction relative to counts of concurrent daytime control animal passage. At least four such determinations (N ^ 5) provided dose-responsive data for the formation of an MPE _5Q value

best dose determination, which reduces abdominal contractions to 50% of control values.

The compounds of formula I also possess anti-inflammatory activity. This activity has been demonstrated in rats by a method based on the carrageenin-induced rat paw edema standard test (Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544 (1963)).

Non-anesthetized adult male albino rats of 150 to 19Og body weight were numbered, weighed and a color marker attached to the right lateral ankle. Each paw was dipped in mercury exactly to the color mark. The mercury was contained in a glass cylinder connected to a Statham pressure transducer. The output of the transducer was fed through a control unit to a microvoltameter. The volume of mercury displaced by the submerged paw was read. Drugs were given by force-feeding. One hour after drug administration, the edema was injected by injecting 0.05 ml of a 1% carrageenin solution into the plantar tissue of the labeled paw. Immediately thereafter, the volume of the injected paw was measured. The increase in foot volume 3 hours after injection of carrageenin represents the individual inflammatory response.

The analgesic activity of the compounds of formula I makes them suitable for acute administration to mammals for the control of pain, e.g. postoperative pain and traumatic pain, useful. In addition, the compounds of formula I are useful for chronic mammalian administration for relieving the symptoms of chronic diseases, such as rheumatoid arthritis, and the pain associated with osteoarthritis and other musculoskeletal disorders.

When a compound of formula I or a pharmaceutically acceptable salt thereof is to be used either as an analgesic or an anti-inflammatory agent, it may be administered to a nipple either alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice , A compound can be administered 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 of 1: 4 to 4: 1 and preferably 1: 2 to 2: 1. In any given case, however, the chosen ratio will depend on such factors as the solubility of the active ingredient, the dosage considered, and the exact route of administration.

For oral use of a compound of formula I of this invention, the compound may be e.g. in tablets or capsules or as an aqueous solution or as a suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricants such as magnesium stearate are usually 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 emulsifying and suspending agents. If desired, certain sweetening and / or flavoring agents may 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 solute concentration should be controlled so that the preparation becomes isotonic.

When a compound of formula I or its salt is applied in humans, the daily dosage will normally be determined by the prescribing physician. In addition, the dosage will vary with the age, weight and response of the individual patient as well as the severity of the patient's symptoms and the particular compound being administered. However, for acute administration for pain relief, an effective dose in most cases will be 0.01 to 0.5 g, as needed (eg, every 4 to 6 h). · For chronic administration, an effective dose will be 0.01 in most cases to 1.0 g per day and preferably 20 to 250 mg per day in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.

embodiments

The following examples and preparations are given solely for the purpose of further illustration.

example 1

5-chloro-3- (2-thenoyl) -2-oxindole-I-carboxamide

A stirred slurry of 21.1 g (0.1 mol) of 5-chloro-2-oxindole-ircarboxamide and 26.9 g (0.22 mol) of 4- (Ν, Ν-dimethylamino) pyridine in 200 ml of N, N Dimethylformamide was cooled to ice-bath temperature and then a solution of 16.1 g (0.11 mol) of 2-thenoyl chloride in 50 ml of N, N-dimethylformamide was added dropwise. Stirring was continued for about 30 minutes, and then the reaction mixture was poured into a mixture of 1 liter of water and 75 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice bath and then the solid was passed through

Filtration collected. The solid was washed with water and then recrystallized from 1800 ml of acetic acid to give 26.6 g of the title compound as a pale yellow crystals, m.p. 23O ° C (dec.).

A sample of the title compound from a similar experiment gave the following results in the elemental analysis.

Analysis for C ₁₄ H ₉ ClN ₃ O ₃ S,%

Calc .: C 52.42 H 2.83 N 8.74 Found: C 52.22 H 2.81 N 8.53

Example 2

Reacting the appropriate 2-oxindole-1-carboxamide with the required acid chloride of the formula R-CO-Cl, essentially according to the procedure of Example 1, afforded the following compounds:

O = C-NH.

analysis

ι 2-furyl M.p. ( ⁰ C.) ¹ ' ² C calculated (%) N gef. C (%) N X R ¹ 2- (2-thienyl) methyl 234d 55.18 H 9.20 55.06 H 9.32 5-Cl 2-furyl 24Od ³ 53.81 2.98 8.37 53.40 3.09 8.37 5-Cl 2-thienyl 218-219 55 _r 19 3 _t 3l " 9.19 54.89 3.31 9.23 6-Cl 2- (2-thienyl) methyl 201-202 52.44 2.98 8.74 51.86 2.90 8.61 6-Cl 219-220 53.83 2.83 8.37 53.70 3.03 8.38 6-Cl 3.31 3.45

Example 2 (continued)

ι 2-furyl Mp. calc. C (%) analysis Found C * U) N R ¹ , 2-thienyl CC.) ¹ ' ² 58.34 H 57.99 H 9.70 X 2- (2-thienyl) methyl 232d 55.25 3.15 N 55.49 3 13 9.28 5-P 2-furyl 231d 56.59 2.98 9.72 56.76 3 00 8.81 5-P 2-thienyl 243d 58.33 3.48 9.21 57.73 3 48 9.72 5-F 2- (2-ihienyl) methyl 230.5 to 233.5 55.26 3.13 8.80 55.14 3 , 04 9.15 6-F 2-Euryl 117.5 to 120.5 56.61 2.96 9.75 55.97 2 91 8.65 6-P 2-thienyl 214.5 to 217 53.26 3.48 9.21 52.84 3 , 52 8.17 6-F 2- (2-thienyl) methyl 235,5d 50.85 2.68 8.80 50.43 2 96 7.90 5-CF3 2-furyl 212,5d 52.17 2.56 8.28 51.72 2 .72 7.45 5-CP3 2-thienyl 223,5d 53.26 3.01 7.91 52.87 3 , 37 8.27 5-CF3 206-208 50.86 2.68 7.61 50.69 3 , 03 7.96 6-CP3 177-180 2.56 8.28 2 75 6-CF3 7.91

All compounds were recrystallized from acetic acid unless otherwise specified. The letter "d" in this column indicates that the compound melted under decomposition. Uncrystallised from Ν, Ν-dimethylformamide.

Example 3 5-Chloro-3-acetyl-2-oxindole-1-carboxamide

A stirred slurry of 842 mg (4.0 mmol) of 5-chloro-2-oxindole-1-carboxamide and 1.08 g (8.8 mmol) of 4- (N, N-dimethylamino) pyridine in 15 ml of N, N Dimethylformamide was cooled to ice-bath temperature, and then a solution of 44.9 mg (4.4 mmol) of acetic anhydride in 5 ml of Ν, Ν-dimethylformamide was added dropwise. It was further stirred for about 30 minutes, and then the reaction mixture was poured into a mixture of 75 ml of water and 3 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice bath and the solid recovered by filtration. The solid was recrystallized from acetic acid to give 600 mg of loose, pale pink crystals. M.p. 237.5 ° C (decomp.).

Analysis for

Calc .: C 52.29 H 3.59 N 11.09 Found: C 52, O 8 H 3.63 N 11.04

Example 4

Reacting the appropriate 2-oxindole-1-carboxamide with an activated derivative of the required carboxylic acid of the formula R-CO-OH, essentially according to the procedure of Example 1 or Example 3, afforded the following compounds:

ν 0

Y £ ΛΑ YO = C-NH ₂ 2-Riryl M.p. ( ⁰ C) ¹ X H R ¹ 2-thienyl 223d H H   2- (2-thienyl) methyl 21Od H H cyclohexyl 233d H H isopropyl 213d H H cyclopropyl 205-206 H H phenoxymethyl 207.5 to 208.5 H H (4 - <2-chloro-phenoxy) methyl 187,5d H H methyl 19Od H H cyclohexyl 200 to 201.5 H H phenoxymethyl 210d 5-Cl H isopropyl 201-202d 5-F H cyclohexyl 23Od 5-F H isopropyl 222d 5-F H cyclopropyl 229d 5-Cl H ' Bicyclo [2.2.1] heptan-2-yl 243,5d 5-Cl H 111.5 to 114 6-F

Example 4 (continued)

X B y R · * · m.p. 2-thienyl ( ⁰ C) ¹ 4-Cl H H 2-furyl 165-167d 4-Cl H B 2-furyl 183-185d 5-CH ₃ H 6-F methyl 210-215 6-F 5-CF ₃ H methyl 226.5 to 229 5-OCH ₃ 5-CF ₃ 6-OCH ₃ 2-thienyl 226-230 5-OCH ₃ 5-CF ₃ 6-OCB ₃ cyclohexyl 195-197 6-Cl 5-CF ₃ B isopropyl 225-226 5-CF ₃ 5-CF ₃ H cyclopropyl 203d 5-F 5-CF ₃ B 4-chloro-phenyl 228,5d 6-CF ₃ H 4-methylphenyl 229d 6-CF ₃ B benzyl 214,5d 6-SCH ₃ B 1- (phenyl) ethyl 226,5d 4-SCH B cyclopropyl 188.5 to 189.5 B cyclohexyl 265d B methyl 185-186 B Phenyl 225d B 4-chloro-phenyl 221 _f 5d H 4-methylphenyl 225d B isopropyl 224d B Bicyclol2.2.1] heptan-2-yl 199-202 B (2-T.-hienyl! Methyl 192-198 B Bicyclo [2.2.1] heptan-2-yl 214-215 B 200-202

example 4 (cont reduction; M.p. ( ⁰ C) ¹ R Xsopropyl 188-191 X Y BicycloI2.2.IJheptan-2-yl 218.5 to 220.5 6-F H benzyl 217d 6-SCH ₃ H 1- (phenyl! Ethyl 208d 5-CF ₃ H ' phenoxymethyl 205,5-206,5d 5-CF ₃ H 2-Fury1 22Od 5-CF ₃ H 2-furyl 191d 5-CH ₃ 6-CH ₃ 2-thienyl 197d 4-CH ₃ 5-CH ₃ 2-thienyl 205d 5-CH ₃ . 6-CH ₃ (2-thienyl) methyl 23 ld 4-CH ₃ 5-CH ₃ phenyl 232,5d 5-CH ₃ 6-CH ₃ 4-chloro-phenyl 242d 5-Cl H 4-Methylpheny1 231d 5-Cl H benzyl 244,5d 5-Cl H benzyl 229-23Od 5-Cl H cyclohexyl 188-189 6-Cl H isopropyl 158-160 4-Cl H 2-furyl 203-206 4-Cl H Bicyclo12.2.1] heptan-2-yl 232-235 4-SCH ₃ H (2-thienyl) methyl 243-244d 6-Br H 4-chloro-phenyl 220-222 5-CH ₃ H phenyl 215-216,5d 6-Cl H 5-CH H

Example 4 (continued)

X Y R Schmp. ( ⁰ C) ¹ 5-OCH ₃ H 4-chloro-phenyl 238-24Od 5-OCH ₃ H phenyl 2Q9-210d. 5-CH ₃ H cyclohexyl 219-22Qd 4-Cl H methyl 184d 5-OCH ₃ H isopropyl 194-195 5-OCH ₃ H cyclohexyl 221-222 5-CH ₃ H methyl 223-224d 5-Cl H cyclopentyl 214-215d 5-Cl H cyclobutyl 214-215d 5-CF ₃ H cyclopentyl 188-189 6-Cl H cyclobutyl 227d 6-Cl H cyclopentyl 224-225,5d 5-Cl H 1-phenylethyl 206d 5-Cl H phenoxymethyl 218d 5-F H Bicyclo [2.2.1] heptan-2-y 1 216d 5-CF ₃ H Bicyclo [2.2.1] heptan-2-yl 212d 6-Br H 2-furyl 234-237 6-Cl H l- (phenyl! ethyl 222-223d 5-NO ₂ H 2-thienyl 220.5 to 225 5-NO ₂ H benzyl 232-236 5-OCH ₃ H 1-CPhenyl1ethyl 204-205 j6 5-0CH- H 2-thienyl 188-189d

Example 4 (continued)

X Y R ¹ phenyl M.p. ( ⁰ C) ¹ 6-Cl H 4-chloro-phenyl 236-237d 5-CH ₃ H 2-pyrrolyl 247-248d H H 2-pyrrolyl 214-215d 5-Cl H 3 ^ thienyl 217-218d 5-F H 3-thienyl 236 _t 5d 5-Cl H 3-furyl 238d 5-F H 3-furyl 229,5d 5-Cl H 3-furyl 231,5d 6-Cl H 3-furyl 223 _t 5d 5-CF ₃ H (3-thienyl) methyl 214d 5-F H (3-thienyl) methyl 239,5d 5-Cl H (3-ThienylJmetfiyl 237d 6-Cl H (3 ^ thienyl) methyl 220,5d 5-CF ₃ H 2-thienyl 210,5d 5-Cl 6-Cl (2-thienyl) methyl 227d 5-Cl 6-Cl 2-TJiienyl 243d 6-C ₆ H ₅ H (2-thienyl) methyl 212d ⁶ - ^C 6Hc H 215d

Example 4 (continued)

X H Y R ¹ M.p. ( ⁰ C) ¹ 5-Cl H 2,4-dichloro-phenyl 221d 5-CH ₃ H Trifluoro-methyl 224-225d 5-CH3 H 2-furyl 214-215d 5-CH ₃ H benzyl 249-25Od 5-OCH ₃ H 2-thienyl 221-222d 5-Cl H (2-thienyl) methyl 239-242d 5-CF ₃ B Bicyclo [2.2.1] heptan-2-yl 219-221d 5-OCH ₃ H Trifluoro-methyl 217-219d 5-OCH ₃ H B enyl 240-241d 5-CF ₃ H M ethyl 233-234d 6-Cl H 3-thienyl 225d H H (3-thienyl) methyl 220,5d 5-Cl H 5-pyrimidinyl 238-24Od H H Bicyclo [2.2. 1] hept-2-en-5-yl 211 _t 5d 6-Cl H Bicyclo [2.2.1] hept-2-en-5-yl * 210,5d 5-Cl H Bicyclo [2.2.1] hept-2-en-5-yl 219d 5-CF ₃ e 1-phenylethyl 192-193 ² 5-Cl H 1-phenylethyl 169.5 to 170.5 ' H 1-P henylethyl 193-194 ⁴

Example 4 (continued) XY m.p. ( ⁰ C) ¹

5-CF ₃ H

5-CF ₃ H

6-Cl H

H H

5-Cl H

5-F H

5-CF ₃ . H

5-F H

6-Cl H

6-Cl H

5-Cl H

6-Cl H

5-F H

5-Cl H

5-F H

H H

SC ₆ H ₅ CQ H

5-C ₆ H ₅ CO H

5-C ₆ H ₅ CO H

5-CH ₃ CO H

5-C ₄ H ₃ SCO ⁶ H

1-phenylethyl

3-trifluoro-methylbenzyl

3-trifluoro-methylbenzyl

2-chloro-benzyl

2-chloro-benzyl

2-chloro-benzyl

2-chloro-benzyl

3-trifluoro-methylbenzyl

3-thienyl

2-C hlor-benzyl

4- £ hlor-benzyl

4-Chloro-benzyl

4-Chloro-benzyl

3-chloro-benzyl

3-chloro-benzyl

3-Trifluorvmethylbenzyl

3-benzyl (2-thienyl) methyl

2-thienyl

Benzyl (2-thienyl) methyl

172-173 °

153-155d

200-202d

236d

237,5d

231d

198.5 to 199.5

214-2l5d

210-212d

231d

242-243d

195-198d

232-234d

222-225d

219-22Od

235-236d

23ld

236-238

185-187

239-241

230-232

Example 4 (continued)

X 6-F Y R ¹ M.p. ( ⁰ C) 5-Cl H S-methyl-3-isoxazolyl 224-226 5-CH ₃ CO H S-methyl-3-isoxazolyl 252-254 5-C ₄ H ₃ SCO ⁶ H (2-thienyl) methyl 226-227 5-F H benzyl 243-245 5-F H S-methyl-3-isoxazolyl 225-226 5-F 6-Cl {2-thienyl) methyl 228-230 5-F 6-Cl 2-furyl 250-251 5-Cl 6-Cl 2-thienyl 220-221 6-F H 1,2,3 ^J thiadiazol-4-yl 234-238 5-F H 1,2, 3-thiadiazol-4-yl 225-227 6-CF ₃ 6-Cl benzyl 243-245 6-F H 1-phenylethyl 228-231 ^ 5-Cl H 1-phenylethyl 192-194 ⁸ 6-F H 1-phenoxyethyl 220-222 6-F H 1-phenoxyethyl 200-202 5-Cl H 2-phenylethyl 149 to 150.5 5-F H 2-Pheny1ethyl 199-201 5-F 6-F 2-furyl 240 to 241.5 5-F 6-F benzyl 234-237 5-NO ^ 6-F (2-thienyl) methyl 236-238 H 2-furyl 157-160

Example 4 (continued)

^R Schnp. ( ⁰ C)

5-NO ₂ H (2-thiethyl) methyl 209-212

5-Cl H 3 -trifluoromethylbenzyl 218-219

5-NO ₂ H 1-phenylethyl 208.5-211

5-Cl H (2-furyl) methyl 233-236

6-F H (2-furyl) methyl 212-214

6-F HI, 2,5-thiadiazol-3-yl 237.5-241

5-Cl H l, 2,5-thiadiazol-3-yl 240.5-243

6-CF ₃ H 1-phenylethyl 235-237 ⁹

6-FH 1-phenylethyl 194-196 ¹⁰

6-FH 1-phenylethyl 166-170 ¹¹

6-CF ₃ H 1-phenylethyl 205-207 ¹¹

6-CF ₃ H (2-thienyl) methyl 217-218 '

5-F 6-Cl 2-Tetrahydrofury 1 213.5-215

5-NO ₂ H 2 -tetrahydrofury 1 216-219

5-Cl H 4-isothiazolyl 255

5-Cl H 2-thiazolyl ^r '227

5-Cl H 1-methyl-5-pyrazolyl 254

Example 4 (continued)

The letter "d" in this column indicates that the compound melted under decomposition.

² [alpha] ^ ³ = -300.3 °

³ [alpha] ²³ = -174.3 °

⁴ [alpha] ²³ = + 303.8 °

⁵ [alpha] ²³ = + 169.7 ° ⁶ 5- (2-thenoyl)

⁷ [alpha] ²³ = + 154.9 °

⁸ [alpha] ²³ = + 184.9 °

D D D

⁹ [alpha] ²³ = -170.9 ° ¹⁰ [alpha] ²³ = -198.3 ° 11

The starting 2-phenylpropionyl chloride was

racemic.

Example 5

Reaction of 2-thenoyl chloride and 2-furoyl chloride with 5,6-methylenedioxy-2-oxindole-i-carboxamide using the procedure of Example 1 afforded the following compounds:

5,6-Methylenedioxy-3- (2-thenoyl) -2-oxindole-i-carboxamide, m.p. 215-217 ° C. (Zers.) Resp.

5,6-Methylenedioxy-3- (2-furoyl) -2-oxindole-1-carboxamide, m.p. 234-235 ° C. (Dec.).

Example 6

By reacting the appropriate acid chloride with the required 2-oxindole-1-carboxamide using the procedure of Example 1, the following compounds can be prepared:

X and Y *

4-CH ₂ -CH ₂ -CH ₂ -5

6-CH ₂ -CH ₂ -CH ₂ -CH ₂ -? 5-CH = CH-CH = CH-6

5-O-CH ₂ -CH ₂ -6 5-CH ₂ -CH ₂ -O-6 5-S-CH ₂ -CH ₂ -6 5-O-CH = CH-6 5-S-CH = CH- 6

5-CH = CH-S-6

2-Furyl2-Thienyl2-furyl

(2-thienyl) -methyl 2-thienyl 2-furyl 2-thienyl 2-furyl

(2-thienyl) .methyl

2-furyl

In this column, the number to the left in the formula indicates the point of attachment of the end of the formula to the 2-oxindole nucleus and the number to the right indicates the point of attachment of that end of the formula with the 2-oxindole nucleus.

Example 7

5-chloro-3- (2-thenoyl) -2-oxindole-I-carboxamide

To a stirred slurry of 429.9 g (2.04 mol) of 5-chloro-2-oxindole-1-carboxamide in 4 L of N, N-dimethylformamide was added 547.9 g (4.48 mol) of 4- (N, N). N-dimethylamino) pyridine, and then the mixture was cooled to 8 ° C. To this mixture was added, with stirring, a solution of 328 g (2.23 mol) of thenoyl chloride in 800 ml of N, N-dimethylformamide over 30 min, maintaining the temperature between 8 and 15 ° C. Stirring was continued for 30 minutes and then the reaction mixture was poured with stirring into a mixture of 510 ml of concentrated hydrochloric acid and 12 liters of water. Stirring was continued for 2 hours and then the solid was collected by filtration and washed with water, then with methanol. The solid was dried to give 675.6 g of the title compound.

A portion (67, 3.5 g, 2.1 mol) of the title compound above was added to 13 L of methanol, and the mixture was heated to reflux. To the refluxing mixture was added 136 g (2.22 mol) of ethanolamine. The resulting solution was cooled to 50 ° C, 65 g of decolorizing carbon was added and then the solution was again heated to reflux temperature and held for one hour. The hot solution was filtered through Supercel (a diatomaceous earth) and the filtrate was cooled to 40 ° C. To the filtrate, 392 ml of concentrated hydrochloric acid was added slowly over 30 minutes. The mixture was cooled to 2O-23 ° C, stirred for 30 min and then the solid was collected by filtration and washed with methanol. The festival- . The product was dried to give 589 g of the title compound, m.p. 229-231.5 ° C (dec.).

Example 8

Ethanolamine salt of 5-chloro-3- (2-thenoyl) -2-oxindole-1- carboxamide

A slurry of 321 mg of (1, OmMoI) 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide in 25-30 ml of diisopropyl alcohol was heated to boiling and then a solution of 67 mg of ethanolamine in 1 ml of diisopropyl alcohol added. This provided a yellow solution in 2 to 3 minutes. The solution was boiled to 12 to 13 ml and allowed to cool. The solid which appeared was recovered by filtration to give 255 mg of the title salt as yellow crystals, m.p. 165.5-167 ° C (slight decomposition).

Analysis for C ₁₆ H ₁₆ ClN ₃ O ₄ S,%

Calc .: C 50.32 H 4.22 N 11.00 Found: C 50.52 H 4.44 N 10.88

Example 9 Sodium salt of 5-chloro-3- (2-thenoyl) -2-oxindole-i-carboxamide

Part A

To a stirred slurry of 20 g (62.4 mmol) of 5-chloro-3- (2-thenoyl) -2-oxindole-i-carboxamide in 400 ml of methanol was added 4.14 ml (68.6 mmol) of ethanolamine at room temperature dripped. To the clear solution thus obtained was added a solution of 6.74 g (124.7 mmol) of sodium methylate in methanol. The resulting mixture was warmed to about 90 ° C and allowed to cool and was stirred overnight. The solid that formed was collected by filtration and dried at room temperature under high vacuum overnight to yield 18.12 g of crude product. The crude product

was recrystallized from methanol / isopropanol to give 1.73 g of a first crop and 10.36 g of a second crop of the monohydrate of the sodium salt of 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide. Both yields melted bei'236-238 ⁰ C.

Analysis: C calculated for found for the first yield found for the second crop C ₁ H 46.48 46,99 46.71 N 3.06 2.68 2.70 7.74 7.98 7.79

The remainder of the first crop was redried. This provided the anhydrous sodium salt of 5-chloro-3- (2-thenoyl) - ^ -oxindole-1-carboxamide, m.p. 237-238 ° C.

Analysis: calculated for C ₁₄ H ₈ ClN ₂ O ₃ SNa found for the re-dried first crop 48.92 48.23 C '2.64 2.81 H 8.15 7.89 N part B

To a stirred slurry of 20 g (62.4 mmol) of 5-chloro-3- (2-thenoyl) -2-oxindole-i-carboxamide in 400 ml of methanol was added 4.14 ml (68.6 mmol) of ethanolamine at room temperature dripped. To the clear solution thus obtained was added 6.74 g of powdered sodium methylate, and the mixture was stirred overnight. The solid that formed was collected by filtration and dried under high vacuum overnight. This provided the hemihydrate of 5-chloro-3- (2-

thenoyl) -2-oxindole-i-carboxamide, m.p. 238-239C.

Analysis:

calculated for found

C ₁₄ HgClN ₂ O ₃ SNa-O, 5H ₂ O

C 47 0 from , 67 - " 47 72 H 2 85 2 , 73 N 7 , 94 (2-thenoyl) 7 70 example 1 potassium salt 5-chloro-3- -2-oxindole-i-carboxamide

The procedure of Example 9, part B was repeated except that the powdered sodium methylate was replaced by a solution of 7.00 g of potassium hydroxide in methanol. This provided the monohydrate of the potassium salt of 5-chloro-3- (2-thenoyl) -2-oxindole-i-carboxamide, m.p. 214-216C.

Analysis:

calculated for found

C ₁₄ H ₈ ClN ₂ O ₃ SK-H ₂ O

C 44 11 ; 3o H 2 , 93 N 7 , 41 example

44 29 2, 67 7, 22

Ammonium salt of 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide

The title salt was prepared essentially according to the procedure of Example 9, Part B, using a solution of ammonia in methanol instead of the powdered sodium methylate. This provided anhydrous title salt, mp 2O3-2O4 ° C.

Analysis:

calculated for

C 49 12 , 64 H 3 , 86 N 12 , 41 example 2-oxine-1-d-carboxamide

found 75 49 , 53 3 20 12

To a solution of 194 mg (1.0 mmol) of 2- (2-ureidophenyl) acetic acid in 4 mL of trifluoroacetic acid was added 630 mg (3.0 mmol) of trifluoroacetic anhydride and the mixture was then heated at reflux for about 1 h. The reaction mixture was cooled and the solvent removed by evaporation in vacuo. The residue was triturated under 5-8 ml of saturated sodium bicarbonate solution and the material remaining outside the solution was collected by filtration. The solution thus obtained was crystallized from ethanol environmentally _J to 61 mg of the title compound as colorless needles, mp. (Slight decomposition) to give 179-18O ° C.

analysis For 13 About: C gef. : C example

61, 36 H 4.58 N 15.91 61.40 H 4.80 N 15.77

5-chloro-2-oxindole-1-carboxamide

Cyclization of 4.78 g (0.021 mol) of 2- (5-chloro-2-ureidophenyl) acetic acid with 8.0 g (0.063 mol) of trifluoroacetic anhydride in 75 ml of trifluoroacetic acid by the method of Example 1.

12, followed by recrystallization of the crude product from acetonitrile gave 80 mg of the title compound, mp. 211 ° C (dec.).

Analysis for C ₉ H ₇₂₂

Calc .: C 51.32 H 3.35 N 13.30 Found: C 51.37 H 3.37 N 13.53

Example 14

2-oxindole-1-carboxamide

Chlorosulfonyl isocyanate (1.20 g, 8.4 mmol) was added to a mixture of 2-0xindole (0.94 g, 7.1 mmol) in ether (30 mL) and the reaction stirred at room temperature for 20 h. The ether was removed in vacuo and the residue was treated with water (10 ml) and 1 N HCl (10 ml). Ethyl acetate (125 ml) was added and the mixture was stirred for 1 h. The ethyl acetate phase was separated, washed with 1 N HCl (1 × 50 ml), brine (2 × 100 ml) and dried (over MgSO ₄ ). Concentration provided 0.97 g (77%) of crude product. Recrystallization from ethanol gave 0.18 g of the title product, m.p. 177-179 ° C.

Example 15

2-oxindole-1-carboxamide

To a stirred mixture of 2-oxindole (5.86 g, 44.0 mmol) and dry toluene (160 mL) was added chlorosulfonyl isocyanate (7.47 g, 52.8 mmol). Hydrogen chloride evolved immediately. The mixture was stirred at reflux for 15 minutes and then cooled to room temperature. Water (50 ml) was added to the cooled mixture (some HCl was first developed) and then the mixture was stirred for 1.5 h. The solid which formed was collected by filtration and dried

(4.10 g). The filtrate was extracted with ethyl acetate (100 ml) and the resulting extract was washed with brine (2 × 100 ml) and dried (over MgSO ₄ ). Evaporation of the extract under reduced pressure gave 4.16 g of solid. The combined solids were recrystallized by dissolving in acetonitrile (200 ml) and then concentrating the solution under reduced pressure to about 75 ml. The small amount of amorphous material which separated out was filtered off, the filtrate was decolorized and concentrated under reduced pressure to about 50 ml volume, then seeded. This gave the title compound as dark red crystals which were filtered off and dried (3.0 g, 38%).

Example 16 6-Fluoro-5-methyl-2-oxindole-1-carboxamide

Following the procedure of Example 15, the title compound was prepared from 6-fluoro-5-methyl-2-oxindole (1.0 g, 6.0 mmol) and chlorosulfonyl isocyanate (1.03 g, 7.3 mmol) in toluene (30 mL). manufactured. Water (5 ml) was used for the hydrolysis step. Yield = 0.58 g, 46%, mp. 2OO-2O3 ° C.

Analysis for C ₁₀ H ₉ N ₂ O ₂ F,%

Calc .: C 57.69 H 4.36 N 13.46 Fug. C 57.02 H 4.41 N 12.85

A sample of the chlorosulfonyl intermediate was removed prior to hydrolysis and subjected to mass spectrum analysis for accurate mass determination: C ,. HgN ₂ O ₄ SCI: 307.9848.

Example 17 2-oxindole-1-carboxamide

To a slurry of 2-oxindole (13.3 g, 0.10 mol) in toluene (150 mL) was added chlorosulfonyl isocyanate (15.6 g, 0.11 mol) and the reaction mixture heated on a steam bath for 10 min (within about 3 min A clear solution formed, which almost immediately precipitate formed). The reaction mixture was cooled in an ice bath for 30 minutes and then the solid was filtered off and air dried.

The resulting chlorosulfonyl intermediate was added to a 2: 1 mixture of acetic acid / water (240 ml) and the resulting slurry was heated on a steam bath for 10 min. It was cooled in an ice bath and the near-white solid which was formed, was filtered off and air dried. Concentration of the mother liquor to a slurry and filtration yielded an additional 1.2 g of product. The combined solids were recrystallized from about 250 ml of ethanol; Yield = 11.48 g (65%).

Example 18 Substituted 2-0xindole-1-carboxamides

The following compounds were prepared by reacting the appropriate 2-oxindole with chlorosulfonyl isocyanate and subsequent hydrolysis using the procedure of Example 17.

X Y Mp. (° C) C berechiBt 13 N analysis - found • 3.26 13 N 5-CH ₃ H H 13 3.48 13 5-OCH ₃ H 215-216d 13 C 3.30 13 4-Cl H 191-192 51.32 30 24 5-Cl H 201-202 ¹ 51.32 3.35 30 , 21 6-Cl H 211d 51.32 3.35 30 , 04 , 31 221-222d 3.35 , 14 , 07 H 51 51 51

Example 18 (continued)

X Y M.p. ( ⁰ C) analysis calculated C H N found C H N 5-P 5-CP ₃ 4 -CH ₃ 5 -CH ₃ 5-Cl HH 5 -CH ₃ 6 -CH ₃ 6-Cl 198 ² 214.5 ² 222d 214.5 ³ 245d 55.67 49.19 64.69 64.69 44.11 3.64 2.89 5.92 5 _f 92 2.47 14,43 11,48 13,72 13,72 11,43 , 56.25 48.90 64.57 64.52 43.98 3.79 3.05 5.94 • 6.67 2.55 14.53 11.50 13.64 13.68 11.58

recrystallized from ethanol recrystallized from acetonitrile recrystallized from acetic acid

Example 19

5,6-methylenedioxy-2-oxindole-1-carboxamide

5,6-Methylenedioxy-2-oxindole-1-carboxamide was prepared by reacting 5,6-methylenedioxy-2-oxindole with chlorosulfonyl isocyanate followed by hydrolysis using the procedure of Example 17. The product melted at 237-238 ° C (dec.) After recrystallization from acetic acid,

Example 20

By reacting the appropriate 2-oxindole with chlorosulfonyl isocyanate followed by hydrolysis using the procedure of Example 17, the following tricyclic

made connections, are:

X. ^

X and Y *

5-CH ₂ -CH ₂ -CH ₂ -6

5-CH = CH-CH = CH-6

5-O-CH ₂ -CH ₂ -6

5-CH ₂ -CH ₂ -O-6

5-S-CH ₂ -CH ₂ -6

5-O-CH = CH-6

5-S-CH = CH-6

5-CH = CH-S-6

* In this column, the figure on the left of the formula indicates the point of attachment of this end of the formula with the 2-oxindole nucleus, and the number on the right indicates the point of attachment of that end of the formula with the 2-oxindole nucleus.

Example 21

6-methylthio-2-oxindole-1-carboxamide

Chlorosulfonyl isocyanate (5.66 g, 0.04 mol) was added to a slurry of 6-methylthio-2-oxindole (6.0 g, 0.033 mol) in acetonitrile (60 ml) at 5-10 ° C. The reaction mixture was stirred for one hour. Water (100 ml) was then added and stirring continued for 10 minutes. The aqueous solution was extracted with ethyl acetate (600 ml), which was then washed successively with water and brine, dried (over MgSO 4) and evaporated under reduced pressure to give a gray solid which was recrystallized from acetonitrile. Yield = 3.0 g. Another 0.71 g of product was obtained from the mother liquor. Total yield = 3.71 g (50.6%); M.p. 176-179 ° C.

Example 22

5,6-Dimethoxy-2-oxindole-1-carboxamide

Following the procedure of Example 21, the title compound was prepared from 5,6-dimethoxy-2-oxindole (8.0 g, 0.042 mol), chlorosulfonyl isocyanate (7.08 g, 0.05 mol) and acetonitrile (75 mL). The crude product obtained after evaporation of the ethyl acetate extract was recrystallized from acetonitrile / acetic acid (1: 1). Yield = 6.02 (60%); M.p. 206.5-209 ⁰ C.

Example 23

6-trifluoromethyl-2-oxindole-1-carboxamide

To a slurry of 6-trifluoromethyl-2-oxindole (8.0 g, 0.04 mol) in acetonitrile (80 ml) was added chlorosulfonyl isocyanate (6.65 g, 0.047 mol) and the mixture stirred for 45 min. Water (100 ml) was then added and the aqueous mixture was stirred for one hour. The precipitate which formed was filtered off and recrystallised from acetonitrile.

to give 0/92 g of the title product. Extraction of the filtrate from the aqueous reaction mixture with ethyl acetate (300 ml) followed by drying of the extract over MgSO ₄ and then evaporation under reduced pressure gave further product. Recrystallization from acetonitrile gave an additional 2.2 g of product.

Additional product (1.85 g) was recovered by combining the mother liquors from the acetonitrile recrystallizations and concentration under reduced pressure. Total yield = 4.97 g (51%); M.p. 207.5-21O ⁰ C.

Example 24

Repeating the procedure of Example 23 but using the appropriately substituted 2-oxindole afforded the following compounds.

Y X O = C-NH ₂ M.p. ( ⁰ C) 4-SCH ₃ Y 181-184 6-F H 191.5 to 194 6-Br H 205-208 5-NO ₂ H 201-205 5-F H 229-231 ¹ 5-F 6-Cl 198-201 6-F

Reaction procedure in toluene as solvent. Both the starting material and the product were contaminated with some of the corresponding 4-chloro-5-fluoro isomer.

Example 25 6-Phenyl-2-oxindole-1-carboxamide

To 4.5 g (21.5 mmol) of 6-phenyl-2-oxindole in a mixture of 100 ml of toluene and 25 ml of tetrahydrofuran was added 2.2 ml (25.8 mmol) of chlorosulfonyl isocyanate with stirring at 5 ° C. Stirring was continued for one hour at 0 to 5 ° C and then 100 ml of water was added. The solid was collected by filtration and added to a mixture of 40 ml of glacial acetic acid and 80 ml of water. The resulting mixture was heated to 100 ° C for 1 h, cooled and filtered. The residue was dried to give 3.1 g of the title compound, m.p. 188-189 ° C.

Example 26

5-Benzoy1-2-oxindole-1-carboxamide

A mixture of 10.1 g (42 mmol) of 5-benzoyl-2-oxindole, 4.4 ml (51 mmol) of chlorosulfonyl isocyanate and 300 ml of tetrahydrofuran was stirred at room temperature for 6 hours and then the solvent was removed in vacuo by evaporation. The residue was added to 150 ml of glacial acetic acid and 300 ml of water, and the resulting mixture was heated at reflux for 2 hours. The reaction mixture was cooled and the supernatant decanted. The residual resinous residue was triturated under acetonitrile to give a solid which was recovered by filtration and then recrystallized from a 1: 1 mixture of n-propanol and acetonitrile. This yielded 4.1 g of the title compound as a solid, mp. 210-211 ⁰ C.

Example 27

Reaction of 5-acetyl-2-oxindole and 5- (2-thenoyl) -2-oxindole with chlorosulfonyl isocyanate, followed by hydrolysis with aqueous acetic acid, essentially according to the procedure

from Example 26, provided the following compounds:

S-acetyl-2-oxindole-i-carboxamide, 34% yield, mp. 225 ⁰ C, (dec.) (From CH ₃ CN) or

5- (2-Thenoyl) -2-oxindole-i-carboxamide, 51% yield, mp. 200 ° C, (dec.) (From CH ₃ OHZCH ₃ CN).

Example 28 5-Acetamido-2-oxindole-1-carboxamide

A slurry of 0.5 g (2.6 mmol) of 5-amino-2-oxindole-1-carboxamide and 0.35 g of 4- (N, N-dimethylamino) -pyridine was stirred at 10 ^° C. and then 0.20 ml (2.8 mmol) of acetyl chloride was added. The stirring was at ca. -10 ° C for 20 min and at room temperature for 15 min, and then 20 ml of 1 η hydrochloric acid were added. The solid was collected by filtration and dried to give 0.20 g of the title compound as an off-white solid.

By replacing the acetyl chloride with butanoyl chloride in the above procedure, 5-butanamido-2-oxindole-1-carboxamide can be prepared.

Example 29 5-Benzamido-2-oxindole-1-carboxamide

Acylation of 5-amino-2-oxindole-1-carboxamide with benzoyl chloride, essentially according to the procedure of Example 28, afforded a 90% yield of the title compound as an off-white solid, m.p. 223-226 ° C.

Example 30

4-Methyl-sulfonyl-2-oxindole-1-carboxamide

The title compound was prepared by oxidation of 2.5 g of 4-methylthio-2-oxindole-1-carboxamide with 2/4 molar equivalents of 3-chloroperbenzoic acid in tetrahydrofuran at room temperature according to standard procedures. The product was isolated as a solid (0.81 g, 28% yield).

Example 31

6-methylsulfonyl-2-oxindole-1-carboxamide

Oxidation of 1.25 g of 6-methylthio-2-oxindole-1-carboxamide with 2.1 molar equivalents of 3-chloroperbenzoic acid in tetrahydrofuran at room temperature by standard procedures afforded 1.13 g of the title compound, contaminated with the corresponding sulfoxide.

Example 32

4-methylsulfinyl-2-oxindole-1-carboxamide

Oxidation of 1.0 g of 4-methylthio-2-oxindole-1-carboxamide with 1.1 molar equivalents of 3-chloroperbenzoic acid in tetrahydrofuran at about 0 ⁰ C afforded 0.9 g of the title compound, mp. 198,5-2OO ° C ,

Similarly, oxidation of 6-methylthio-2-oxindole-1-carboxamide with 3-chloroperbenzoic acid gave 6-methylsulfinyl-2-oxindole-1-carboxamide.

Example 33

3- (2-furoyl) -6-fluoro-2-oxindole-1-carboxamide

In substantial accordance with the procedure of Example 21, the title compound was prepared in 17% yield from 3- (2-furoyl) -6-fluoro-2-oxindole (0.30 g, 1.2 mmol), chlorosulfonyl isocyanate (0.20 g, 1.4 mmol), acetonitrile (15 ml) and water (10 ml). Yield = 60 mg, mp 231-235 ° C.

Example 34

3- (2-thenoyl) -5-chloro-2-oxindole-1-carboxamide

To a stirred slurry of 1.5 g (5.4 mmol) of 3- (2-thenoyl) -5-chloro-2-oxindole in 15 mL of dry acetonitrile was added 0.52 mL (5.9 mmol) of chlorosulfonyl isocyanate, and the reaction mixture was stirred at room temperature for 2 h. A small sample was taken, filtered and evaporated in vacuo to give a small sample of N-chlorosulfonyl-3- (2-thenoyl) -5-chloro-2-oxindole-1-carboxamide, mp. 166-169 ° C , To the rest of the reaction mixture, 30 ml of water was added slowly with stirring and stirring continued for 1 h. The reaction mixture was then poured into 50 ml of 1N hydrochloric acid containing ice chips, and the resulting mixture was stirred for 20 minutes. The yellow solid was collected by filtration, washed with water and diisopropyl ether, and recrystallized from glacial acetic acid to give 200 mg of a first crop of the title compound, mp 213-215 ° C. The mother liquors from which the first crop had been recovered deposited another yellow solid. The latter solid was recovered by filtration to give 470 mg of a second crop of the title compound. The second crop was recrystallized from glacial acetic acid and combined with the first crop and recrystallized from glacial acetic acid. This gave 280 mg of the title compound, mp 232-234 ° C.

Production 1

2- (2-ureidophenyl) acetic acid

A slurry of 2.9 g (0.01 mol) of N-cyclohexylcarbonyl-2-oxindole-1-carboxamide in 50 ml of 1 N potassium hydroxide solution was stirred at room temperature for about 30 minutes, during which the solid went into solution. Now, the reaction mixture was acidified with concentrated hydrochloric acid under ice-cooling and then extracted with ethyl acetate. The extracts were washed with saturated sodium chloride solution (dried over Na ₂ SO ₄₎ and evaporated in vacuo to give an oily solid The oily solid was washed with diisopropyl ether and then recrystallized from ethanol to give 70 mg of the title compound, mp 174.5 To give ° (Zers.).

Analysis for CqH. N ₃ O ₃ ,%

Calc .: C 55.66 H 5.19 N 14.43 Found: C 55.37 H 5.33 N 14.38

Production 2

2 (5-chloro-2-ureidophenyl) acetic acid

The title compound was prepared in 43% yield by hydrolysis of N-isobutyryl-5-chloro-2-oxindole-1-carboxamide with 1 η potassium hydroxide, essentially according to the procedure of Preparation 1. Upon complete hydrolysis and acidification of the reaction mixture, the product precipitated. It was collected by filtration and recrystallized from ethanol to give the title compound as colorless crystals, m.p. 187.5 ° C (dec.).

Analysis for C ₉ H ₉ ClN ₂ O ₃ ,%

Calc .: C 47.28 H 3.97 N 12.26 Found: C 47.11 H 3.98 N 12.20

Production 3 N-Cyclohexylcarbony1-2-oxindole-1-carboxamide

To a stirred slurry of 20.0 g (0.15 mol) of 2-oxindole in 150 mL of toluene was added 29.6 g (0.19 mol) of cyclohexylcarbonyl isocyanate. The mixture was heated at reflux for about 30 minutes and then cooled to room temperature. The solid was collected by filtration and then recrystallized from ethanol. This provided 26.5 g of the title compound as fluffy, colorless crystals, mp 144.5-145.5 ° C.

Analysis for ^c ig ^H -is ^N 2 ° 3 ' ^%

Calc .: C 67.11 H 6.34 N 9.79 Found: 'C 67.00 H 6.36 N 9.77

Production 4 N-isobutyryl-5-chloro-2-oxindole-1-carboxamide

To a stirred slurry of 8.38 g (0.05 mole) of 5-chloro-2-oxindole in 250 ml of toluene was added 6.79 g (0.06 mole) of isobutyryl isocyanate and the reaction mixture was refluxed for 5.5 hours heated. The reaction mixture was cooled to room temperature, a small amount of insoluble material was removed by filtration, and then the solvent was evaporated in vacuo. The residue was crystallized from acetonitrile (decolorizing with charcoal) to give, followed by recrystallization from ethanol to give 3.23 g of the title compound as pink crystals, mp. 139-141 ⁰ C, to yield.

analysis For ^C 13 ^H 1 H lN 2 ° 3 ' ^% 9 , 98 calc .: C 55 , 62 H 4 , 67 N 9 97 Found .: C 55 , 53 4 48 N

Preparation 5 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 solution. The solution was heated at reflux for 3.5 hours to give a precipitate. The reaction mixture was stirred overnight, and then the precipitate was collected by filtration to give 5-chloro-3-hydrazono-2-oxihdol as a yellow solid, which was dried in a vacuum oven. The dried solid weighed 105.4 g.

The dried solid was then added portionwise over 10 minutes to a solution of 125.1 g of sodium methylate in 900 ml of absolute methanol. The resulting solution was heated at reflux for 10 minutes and then concentrated in vacuo to a resinous solid. The resinous solid was dissolved in 400 ml of water and the resulting aqueous solution was decolorized with activated charcoal and then poured into a mixture of 1 liter of water and 180 ml of concentrated hydrochloric acid containing ice chips. A tan solid separated, was collected by filtration and washed well with water. The solid was dried and then washed with diethyl ether. Finally, it was recrystallized from ethanol to give 48.9 g of the title compound, mp 193-195 ° C (dec.) . ._

Analogously, 5-methylisatin in 5-methyl-2-oxindole was converted to ethanol by treatment with hydrazine hydrate, then with sodium ethylate. The product melted at 173-174 ° C.

Production 6

_{4/5-dimethyl-2-oxindole} and 5,6-dimethyl-2-oxindole

3,4-Dimethylaniline was converted to 3,4-dimethylisonitrosoacetanilide by reaction with chloralhydrate and hydroxylamine using the method described in "Organic Syntheses", Vol. I, p. 327. The 3,4-dimethyl-isonitrosoacetanilide was cyclized with sulfuric acid by the method of Baker et al./ Journal of Organic Chemistry V7, 149 (1952) to 4.5-dimethylisatin (mp. 225-226 ⁰ C) and 5, 6-dimethylisatin (mp 217-218 ° C).

4,5-dimethylisatin was converted to 4,5-dimethyl-2-oxindole, m.p. 245.5-247.5 ° C, by treatment with hydrazine hydrate, then sodium ethylate in ethanol, essentially according to the procedure of Preparation 5 ,

Similarly, 5,6-dimethylisatin in 5,6-dimethyl-2-oxindole, mp. .196,5-198 ⁰ C, by treatment with hydrazine hydrate, then sodium ethoxide in ethanol · transformed essentially according to the procedure of Preparation 5, ,

Production 7

4-Chloro-2-oxindole and 6-chloro-2-oxindole A. 3-Chloro-isonitrosoacetanilide

To a stirred solution of 113.23 g (0.686 mol) of chloral hydrate in 2 L of water was added 419 g (2.95 mol) of sodium sulfate, then 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 became slow

heated and maintained between 60 and 75 ° C for about 6 hours, with an additional one liter of water added to facilitate stirring. The reaction mixture was then cooled and the precipitate filtered off. The wet solid was dried / to give 136.1 g of S-chloro-isonitrosoacetanilide.

4-chloroisatin and 6-chloroisatin

To 775 ml of concentrated sulfuric acid preheated to 70 ° C,>. were added with stirring 136 g of 3-chloro-isonitrosoacetanilid at such a rate that the reaction medium was maintained at a temperature between 75 and 85 ° C. When all of 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 about 2 liters of ice with stirring. Additional ice was added, if necessary, to keep the temperature below room temperature. A red-orange precipitate formed which was filtered off, washed with water and dried. The resulting solid was slurried in 2 1 of water and then brought into solution by adding about 700 ml of 3 η sodium hydroxide. The solution was filtered, and then the pH was adjusted to 8 with con- j centered hydrochloric acid. Then, 120 ml of a mixture of 80 parts of water and 20 parts of concentrated hydrochloric acid were added. The solid which separated out was filtered off, washed with water and dried to give 50 g of crude 4-chloroisatin. The _# of which the 4-chloroisatin had been won FII appeared, was further acidified with concentrated hydrochloric acid to pH 0, whereupon a further precipitate formed. It was filtered off, washed with water and dried 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 to yield at 258-259 ⁰ C.

The crude 6-chloroisatin was recrystallized from acetic acid to give 36.2 g of material, melting at 261-262 ° C.

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 then the reaction mixture was heated at reflux for 2 hours. The reaction mixture was cooled and the precipitate filtered off to give 43.5 g of 4-chloro-3-hydrazone-2-oxindole, m.p. 235-236 ° C.

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-oxindole and the resulting solution was heated at reflux for 30 min.

The cooled solution was then concentrated to a resin which was dissolved in 400 ml of water and decolorized with charcoal. 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 collected by filtration, dried and recrystallized from ethanol to give 22.4 g of 4-chloro-2-oxindole, m.p. 216-218 ° C (dec.).

D. 6-chloro-2-oxindole

Reacting 36.2 g of 6-chloroisatin with hydrazine hydrate, then with sodium ethylate in ethanol, substantially from C above, yielded 14.2 g of 6-chloro-2-oxindole, mp 196-198 °.

Production 8

5,6-difluoro-2-oxindole

Reacting 3,4-difluoroaniline with chloral hydrate and hydroxylamine and then cyclising with sulfuric acid in a manner analogous to parts A and B of Preparation 7

to 187-190 ⁰ C to give gave 5,6-difluoroisatin, which was reacted with hydrazine hydrate and then with sodium methoxide in ethanol, in a manner analogous to Preparation 5, the title compound, mp..

Preparation 9 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 -65 ⁰ C was added a solution of 10.8 g (0.1 mol) of t-butyl hypochlorite in 25 ml of dichloromethane added dropwise. The mixture was stirred for a further 10 minutes at -60 to -6 ° C., then a solution of 13.4 g (0.1 mole) of ethyl 2- (methylthio) acetate in 25 ml of dichloromethane was added dropwise. The mixture was further stirred for 1 h at -60 ° C, and then at -60 to -65 ° C, a solution of 11.1 g (0.11 mol) of triethylamine in 25 ml of dichloromethane was added dropwise. The cooling bath was removed, and when the reaction had warmed to room temperature, 100 ml of water was added. The phases were separated and the organic phase was washed with saturated sodium chloride solution, dried over Na 2 SO 4 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 were separated and the ether phase was washed with water, then with saturated sodium chloride. The ether phase (dried over Na ₂ SO ₄ ) was evaporated in vacuo to give 17 g of an orange-brown solid which was triturated under isopropyl ether. The solid was then recrystallized from ethanol to give 5.58 g of 5-fluoro-3-methylthio-2-oxindole, mp. 151.5 to 152.5 ⁰ C.

Analysis for C ₉ HgONFS,% calc .: C 54.80 H 4.09 N 7.10 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 mmol) was added to 2 teaspoons full of Raney nickel under 50 mL absolute ethanol, and then the reaction mixture was heated at reflux for 2 h. The catalyst was removed by decantation and washed with absolute ethanol. The combined ethanol solutions were evaporated in vacuo and the residue dissolved in dichloromethane. The dichloromethane solution was dried over Na 2 SO 4 and evaporated in vacuo to give 475 mg of 5-fluoro-2-oxindole, m.p. 121-134 ° C.

Analogously, 4-trifluoromethylaniline was reacted with t-butyl hypochlorite, ethyl-2 (methylthio) acetate and triethylamine, followed by reduction of the thus obtained 3-thiomethyl-5-trifluoromethyl-2-oxindole with Raney nickel to give 5-trifluoromethyl- 2-oxindole, mp 189.5-190.5 ° C.

Preparation 10 5-Methoxy-2-oxindole

5-Methoxy-2-oxindole was prepared from 4-methoxyaniline similar to the procedure of Preparation 9 except that the initial chlorination step was carried out with a solution of chlorine gas in dichloromethane instead of t-butyl hypochlorite. The title product melted at 150.5 to 151.5 ⁰ C.

Preparation 11 6-Chloro-5-fluoro-2-oxindole

To 130 ml of toluene were added, with stirring, 24.0 g (0.165 mol) of 3-chloro-4-fluoroaniline and 13.5 ml (0.166 mol) of pyridine. The resulting solution was cooled to ca. ⁰ ° C and 13.2 ml (0.166 mol) of 2-chloroacetyl chloride were added. The reaction mixture was stirred at room temperature for 5 h and then

twice with 1OO ml of 1 η hydrochloric acid, then extracted 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried with magnesium sulfate and then concentrated in vacuo to give 32.6 g (88% yield) of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline.

A 26.63 g sample of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline was thoroughly mixed with 64 g of anhydrous aluminum chloride, and the mixture was heated to 21O-23O ° C for 8.5 hours. The reaction mixture was then poured onto a mixture of ice and 1N 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 chromatographed on 800 g of silica gel. Elution of the column, followed by concentration of the fractions yielded 11, J g of N- {2-chloroacetyl) -3-chloro-4-fluoroaniline, then 3.0 g of 6-chloro-5-fluoro-2-oxindole. The latter material was recrystallized from toluene to give 1.70 g (7% yield) of the title compound, mp. 196-206 ⁰ C to give. Analysis by NMR spectroscopy indicated that the product was contaminated with some 4-chloro-5-fluoro-2-oxindole.

Preparation 12 6-Fluoro-5-methyl-2-oxindole

An 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 to 22O ° C , After 4 hours, the reaction mixture was cooled and then added to 10.0 ml of 1N hydrochloric acid and 50 ml of ice. A tan solid formed, which was collected by filtration and recrystallized from aqueous ethanol. Three yields were obtained, weighing 4.49 g, 2.28 g and 1.0 g, respectively. The yield 1.0g vast was further recrystallized from water to give 280 mg of the title compound, mp. 168.5 to 171 ⁰ C to give.

Preparation 13 6-Bromo-2-oxindole

To 9.4 g of sodium hydride was added 195 ml of dimethylsulfoxide, followed by dropwise addition of 22.37 ml of dimethyl malonate. At the end of the addition, the mixture was heated to 100 ° C and held at this temperature for 40 minutes. Now 25 g of 1,4-dibromo-2-nitrobenzene were added in one go. The reaction mixture was kept at 100 ^° C. for 4 h and then added to 1.0 l 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 solvent (dried over MgSO 4) was evaporated and the residue was recrystallized from ethyl acetate / hexane to give 22.45 g of dimethyl 2- (4-bromo-2-nitrophenyl) malonate.

A solution of 1.7 g of dimethyl 2- (4-bromo-2-nitrophenyl) malonate and 4.6 g of lithium chloride in 150 ml of dimethylsulfoxide was placed in an oil bath at 100 ° C. After 3 h, the reaction mixture was cooled to room temperature and then 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 extracted with more ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried with sodium sulfate and then evaporated in vacuo. The residue was chromatographed with silica gel as the adsorbent and ethyl acetate / hexane mixture as the eluent. This provided 9.4 g of methyl 2- (4-bromo-2-nitrophenyl) 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 ⁰ C. After one hour, the solvent was removed in vacuo.

evaporated and the residue dissolved in 250 ml of ethyl acetate. The solution was filtered, washed with saturated sodium chloride solution, dried with sodium sulfate, decolorized with charcoal and evaporated in vacuo. This provided 5.3 g of 6-bromo-2-oxindole as a white crystalline solid, m.p. 213-214 ° C.

Was prepared similarly, starting from 1,4 _r 5-trichloro-2-nitrobenzene, 5,6-dichloro-2-oxindole, mp. 2O9-21O ° C prepared.

Production 14

6-Pheny1-2-oxindole

To 3.46 g (0.072 mol) of sodium hydride was added 50 ml of dime of 1-sulfoxide followed by the dropwise addition of a solution of 8.2 ml (0.072 mol). Dimethylmalonate in 10 ml of dimethyl sulfoxide with stirring. After completion of the addition, stirring was continued for one hour, and then a solution of 10 g (0.036 mol) of 4-bromo-3-nitro-diphenyl in 50 ml of dimethyl sulfoxide was added. The reaction mixture was heated at 100 ° C for one hour, cooled, poured onto a mixture of ice / water containing 5 g of ammonium chloride. The resulting mixture was extracted with ethyl acetate, and the extracts were washed with sodium chloride solution and dried with magnesium sulfate. Evaporation in vacuo gave an oil which was chromatographed with silica gel and then recrystallized from methanol to give 6 g of dimethyl 2- (3-nitro-4-diphenyl-yl) -malonate, m.p. 82-83 ° C, to deliver.

A portion (5 g) of the above nitro compound was reduced with hydrogen over a platinum catalyst in a mixture of 50 ml of tetrahydrofuran and 10 ml of methanol at a pressure of about 5 bar (5 kg / cm ² ) to the corresponding amine. The latter compound was refluxed in ethanol for 16 hours and then the product was recovered by evaporation of the solvent and recrystallized from methanol to give 1.1 g of ethyl 6-phenyl-2-oxindole-1-carboxylate.

M.p. 115-117 ° C, to give.

The above ethyl ester (1.0 g) and 100 ml of 6N hydrochloric acid were heated at reflux for 3 hours and allowed to stand at room temperature for 3 days. The solid was collected by filtration and dried to give 700 ml of 6-phenyl-2-oxindole, m.p. 175-176 ° C.

Production 15

5-Acety1-2-oxindole

To 95 ml of carbon disulfide was added 27 g (0.202 mol) of aluminum chloride, followed by dropwise addition of a solution of 3 ml (0.042 mol) 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 at reflux for 4 hours and cooled. The carbon disulfide was decanted and the residue triturated under water and recovered by filtration. After drying, 3.2 g of the title compound, mp 225-227 ° C were obtained.

Reacting the 2-oxindole with benzoyl chloride and with 2-thenoyl chloride in the presence of aluminum chloride, essentially as in the above procedure, afforded the following compounds:

5-Benzoyl-2-oxindole, m.p. 2O3-2O5 ° C (from CH ₃ OH) and 5- (2-thenoyl) -2-oxindole, m.p. 211-213 ° C (from CH ₃ CN).

Production 16

5-bromo-2-oxindole can be brominated by bromination. see Beckett et al., Tetrahedron, 24 , 6093 (1968) and Sumpter et al. Journal of the American Chemical Society, p. 7, 1656 (1945).

5-n-Butyl-2-oxindole can be prepared by reacting 5-n-butylisatin with hydrazine hydrate, then with sodium methylate in ethanol, following the procedure of Preparation 5. 5-n-butylisatin can be prepared from 4-n-butylaniline by treatment with chloral hydrate and hydroxylamine followed by cyclization with sulfuric acid following the procedure of Parts A and B of Preparation 7.

5-Ethoxy-2-oxindole can be prepared by converting 3-hydroxy-6-nitro-toluene into 3-ethoxy-6-nitrotoluene by standard methods (potassium carbonate and ethyl iodide in acetone), followed by conversion of 3-ethoxy-6-nitrotoluene in 5-ethoxy-2-oxindole according to the method described by Beckett et al., Tetrahedron 2A, 6093 (1968) for the conversion of 3-methoxy-6-nitro-toluene in 5-methoxy-2-oxindole. 5-n-butoxy-2-oxindole can be prepared similarly, but substituting n-butyl iodide for the ethyl iodide.

5,6-dimethoxy-2-oxindole can be prepared by the method of Walker, Journal of the American Chemical Society 22 '3844 (1955).

7-Chloro-2-oxindole can be prepared by the method described in U.S. Patent 3,882,236.

4-Thiomethyl-2-oxindole and 6-thiomethyl-2-oxindole can be prepared by the method described in U.S. Patent 4,006,161. 5-n-butylthio-2-oxindole can be prepared similarly but replacing 3-methylthioaniline with 4-butylthioaniline.

5,6-Methylenedioxy-2-oxindole can be prepared by the method of McEvoy et al., Journal of Organic Chemistry 3'3350 (1973). 5,6-ethylenedioxy-2-oxindole can be prepared analogously.

6-Fluoro-2-oxindole can be synthesized according to Protiva et al., Collection of Czechoslovakian Chemical Communications 4_4_, 2108 (1979).

and U.S. Patent 4,160,032.

6-Trifluoromethyl-2-oxindole can be prepared according to Simet, Journal of Organic Chemistry 2 pounds, 3580 (1963).

6-Methoxy-2-oxindole can be prepared according to Wieland et al., Chemische Berichte 96, 253 (1963).

5-nitro-2-oxindole can be prepared by the method of Sumpter et al., Journal of American Chemical Society SJ, 499 (1945).

5-Cyclopropyl-2-oxindole and 5-cycloheptyl-2-oxindole can be prepared by reacting 5-cyclopropyl isatin or 5-cycloheptylisatin with hydrazine hydrate, then sodium methylate in ethanol, following the procedure of Preparation 5. 5-Cyclopropylisatin and 5-cycloheptylisatin can be prepared from 4-cyclopropylaniline and 4-cycloheptylaniline, respectively, by treatment with chloral hydrate and hydroxylamine, then by cyclization with sulfuric acid after parts A and B of preparation.

Production 17

3- (2-furoyl) -2-oxindole

To a stirred solution of 5.5 g (0.24 mol) of sodium in 150 ml of ethanol was added 13.3 g (0.10 mol) of 2-oxindole at room temperature. The resulting slurry was cooled to ice-bath temperature, and then 1.5.7 g (0.12 mol) of 2-furoyl chloride was added dropwise over 10 to 15 minutes. The ice-bath was removed and an additional 100 ml of ethanol was added and then the reaction mixture was heated at 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 treated with con

acidified centered hydrochloric acid. The mixture was cooled with ice and the solid collected by filtration. The solid residue was recrystallized from 150 ml of acetic acid to give 8.3 g of yellow crystals afforded, mp. 209-21O ⁰ C (dec.).

Analysis for C ₁₃ H ₉ O ₃ N,%

Calc .: C 68.72 H 3.99 N 6.17 Found: C 68.25 H 4.05 N 6.20

Production 18

Reaction of 2-oxindole with the appropriate acid chloride using the method of Preparation 17 gave the following further products:

3- (2-thenoyl) -2-oxindole, mp 189-190 ° C, 17% yield;

3- (2- / 2-thienyl / acetyl) -2-oxindole, m.p. 191-192.5 °, 38% yield; and

3- (2-phenoxyacetyl) -2-oxindole, m.p. 135-136 ° C, 42% yield.

Production 19

3- (3-furoyl) -2-oxindole

To a stirred solution of 2.8 g (0.12 mol) of sodium in 200 ml of ethanol was added 13.3 g (0.10 mol) of 2-0xindole then 16.8 g of ethyl 3-furoate. The mixture was heated at reflux for 47 h, cooled and then the solvent was removed by evaporation in vacuo. The residue was triturated under 200 ml of ether and the solid collected by filtration and discarded. The filtrate was evaporated in vacuo and the residue triturated under isopropyl alcohol and recovered by filtration. The solid was suspended in 250 ml of water, which was then acidified with concentrated hydrochloric acid

has been. This mixture was stirred to give a solid which was collected by filtration. This latter solid was recrystallized from acetic acid then acetonitrile to give 705 mg of the title compound, m.p. 185-186 ° C.

Analysis for C ₁₃ H ₉ O ₃ N,%

calc .: C 68.72 H 3.99 N 6.17 f. C, 68.72, H, 4.14, N, 6.14. Preparation 20 5-Amino-2-oxindole-1-carboxamide

To a solution of 5.0 g of 5-nitro-2-oxindole-1-carboxamide in 110 ml of Ν, Ν-dimethylformamide was added 0.5 g of 10% Pd / C and the resulting mixture under a hydrogen atmosphere at an initial pressure shaken from 5 bar (5 kg / cm ² ) until hydrogen uptake ceased. The catalyst was filtered off and the filtrate was diluted with brine and extracted with ethyl acetate. The extracts were dried (over MgSO 4) and evaporated in vacuo to give a dark colored oil which solidified after trituration under water. This yielded 3.0 g of the title compound as a yellow solid, mp. 189-191 ⁰ C.

Claims (8)

invention claim A process for producing a 2-oxindole-1-carboxamide compound of the formula (D O = C-NH ₂ or a pharmaceutically acceptable base salt thereof, in X is hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, trifluoromethyl, alkylsulfinyl of 1 to 4 carbons, Alkylsulfonyl of 1 to 4 carbons, nitro, phenyl, alkanoyl of 2 to 4 carbons, benzoyl, thenoyl, alkanamido of 2 to 4 carbons, benzamido or N, N-dialkylsulfamoyl of 1 to 3 carbons in each of the alkyls; and Y is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxy of Ϊ to 4 carbons, alkylthio of 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 taken together and pendant from adjacent carbon atoms form a bivalent radical Z wherein Z is selected from and where W is oxygen or sulfur; R ^{1 is} alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, cycloalkenyl of 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbons in the alkyl, (substituted phenyl) alkyl of 1 to 3 carbons in the alkyl, phenoxyalkyl having 1 to 3 carbon atoms in the alkyl, (substituted phenoxy) alkyl having 1 to 3 carbon atoms in the alkyl, (thiophenoxy) alkyl having 1 to 3 carbon atoms in the alkyl, naphthyl, bicyclo / ^^. i7heptan-2-yl, bicyclo / 2.2. \ J- hept-5-en-2-yl or - (CH ₂ J _n -QR ⁰ ; wherein the substituent on the substituted phenyl, the (substituted phenyl) alkyl and the (substituted phenoxy) alkyl include fluoro, bromo, chloro, alkyl of 1 to 4 carbons, alkoxy with Is 1 to 4 carbons or trifluoromethyl, η is zero, 1 or 2, Q is a divalent radical derived from a compound selected from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3 / 4-thiadiazole, 1 , 2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo / b / furan and benzo / b / -thiophene, and R ° is hydrogen or alkyl of 1 to 3 carbons; characterized in that a compound of the formula (ID is reacted with an activated derivative of a carboxylic acid of the formula R -C (= O) -OH. 2. The method according to item 1, characterized in that X and Y are each hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, nitro or trifluoromethyl, or X and Y taken together are a 4,5-, 5,6- or 6,7-methylenedioxy group and R is alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbons in the alkyl., Phenoxyalkyl of 1 to 3 carbons in the alkyl, (substituted phenoxy) alkyl of T to 3 Carbons in the alkyl, furyl, thienyl, pyrrolyl, Alkylfuryl having 1 to 3 carbons in the alkyl, alkylthienyl having 1 to 3 carbons in the alkyl, furylalkyl having 1 to 3 carbons in the alkyl, thienylalkyl having 1 to 3 carbons in the alkyl or bicyclo / 2.2.1 / heptan-2-yl, wherein the substituent on the substituted phenyl group and on the substituted phenoxy group is fluoro, chloro, bromo, alkyl of 1 to 4 carbons or alkoxy of 1 to 4 carbons. 3. The method according to item 1 or item 2, characterized in that the reaction in an inert solvent using a molar equivalent or a slight excess of the activated derivative of the carboxylic acid of formula R -C (= 0) -OH in the presence of 1.bis 4 molar equivalents of a basic agent is carried out. 4. A process according to any one of items 1 to 3, characterized in that the activated derivative of the carboxylic acid of the formula R -C (= O) -OH is an acid halide, a symmetrical 1 1 acid anhydride of the formula R -C (= O) -O-C (= O> R, a 1 3 mixed anhydride of the formula R -C (= O) -O-C (= O) -R, a 1 4 mixed anhydride of the formula R -C (= O) -O-C (= O) -OR, an alkyl 1 4
ester of the formal R C (= O) -OR, an N-hydroxyimide ester, a 4- Nitrophenyl ester, a thiophenyl ester _: or a 2,4,5-trichloronyl ester, wherein R is a bulky Ni 'is a low molecular weight alkyl group. phenyl, wherein R is a bulky lower alkyl group and A process according to any one of items 1 to 4, characterized in that it is carried out in a polar aprotic solvent at a temperature in the range of -10 to 25 ° C, and that the basic agent is a tertiary amine. 6. A method according to any one of items 1 to 5, wherein X is hydrogen, 5-chloro, 5-fluoro or 5-trifluoromethyl, Y is hydrogen, 6-chloro, 6-fluoro or 6-yl. Trifluoromethyl and R ^{1 is} benzyl, 2-furyl, 2-thienyl, (2-furyl) methyl or (2-thienyl) methyl. 7. The method according to item 6, characterized in that X is 5-chloro, Y is hydrogen and R ^{1 is} 2-thienyl. 8. The method according to item 6, characterized in that X is 5-fluoro, Y is 6-chloro and R is benzyl.