BG60375B2 - 3-substituted 2-oxindol-1-carboxamides and their application as analgetic and antiinflamation agents - Google Patents

Abstract

2-Oxindole-1-carboxamide compounds with a tertiary alkyl substituent are inhibitors of cyclooxygenase (c0) and lipoxygenase (l0) enzymes and are used as analgesic and anti-inflammatory agents in mammals. In particular, the compounds are used to relieve or eliminate pain in humans recovering from surgery or trauma, and in chronic diseases such as rheumatoid arthritis and osteomyelitis in humans. 65 claims nz

Description

The invention relates to novel compounds that are important as new medical substances. In particular, the novel compounds are derivatives of 2oxyindole-1-carboxamide, substituted at the 3-position by an acyl group, and are inhibitors of cyclooxygenase (CO) and lipoxygenase (LO) enzymes.

The compounds of the invention are used as analgesics in mammals, in particular in humans, and to alleviate or eliminate pain experienced by patients recovering from surgery or trauma.

In addition to their use in the treatment of acute pain, the compounds of the invention are used in chronic mammalian diseases, especially in humans, to relieve inflammation and pain associated with rheumatoid arthritis and osteoarthritis.

SUMMARY OF THE INVENTION

The new 2-oxindole-1-carboxamide compounds and the pharmaceutically acceptable basic salts thereof of the general formula:

o = c-NH ₂ in which X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, an alkyl radical having from 1 to 4 carbons, a cycloalkyl radical having from 3 to 7 carbons, an alkoxyl having from 1 to 4 carbon, trifluoromethyl, alkylthionyl, 1 to 4 carbons, alkylsulfonyl, 1 to 4 carbons, nitro, phenyl, alkanoyl, 2 to 4 carbons, benzoyl, tenoyl, alkanamido of 2 to 4 carbons, benzamido and Ν, ди-alkyl with 1 to 3 carbons in each of the foregoing alkyls; and Y is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl having from 1 to 4 carbons, alkylthio having from 1 to 4 carbons and trifluoromethyl; or X and Y taken together are a 4,5-, 5,6- or 6,7-methylenedioxy group; or X and Y, taken together and attached to adjacent carbon atoms, form a divalent radical Z in which Z is selected from the group consisting of:

wherein 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 said alkyl (substituted phenyl) alkyl of 1 to 15 carbon at said alkyl, (substituted phenoxy) alkyl of 1 to 3 carbon at specified alkyl, (thiophenoxy) alkyl of 1 to 3 carbon at specified alkyl, naphthyl, bicyclo [2.2.1] 1. heptane 2 - yl, bicyclo [2.] 2.1] hept-5-en-2-yl and - / CH _2/20 η-QR ^0; wherein the substituted phenyl, (substituted phenyl) alkyl and (substituted phenoxy) alkyl substituent is selected from the group consisting of fluorine, chlorine, bromine, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons 25 trifluoromethyl; η has a value of 0, 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, oxazole, isoxazole, 1,2,3-thiadiazole, 30 1,3,4-thiadiazole , 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo [b] furan and benzo [b] thiophene; and R ⁰ is hydrogen or alkyl having 1 to 3 carbons.

Said compounds of general formula I are active analgesics and agents for the treatment of inflammatory diseases, such as arthritis. According to the invention there is provided a method of producing a good analgesic response in mammals, in particular in humans, a method of treating inflammatory diseases in mammals, in particular in humans; and pharmaceutical compositions comprising a compound of formula I and pharmaceutically acceptable carriers45.

The first preferred group of compounds according to the invention consists of compounds of general formula I in which it is hydrogen and X is selected from the group consisting of 5-chloro, 650-chloro, 5-fluoro, 6-fluoro, 5-trifluoromethyl and 6-trifluoromethyl . In this first group, particularly preferred compounds are those wherein R ¹ is benzyl, 2-furyl, 2-thienyl, (2-furyl) methyl or (2-thienyl) methyl.

The second preferred group of compounds according to the invention consists of compounds of general formula I, in which 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- fluorine. In this second group, particularly preferred compounds are those wherein R 'is benzyl, 2-furyl, 2-thienyl, (2-furyl) -methyl or (2-thienyl) methyl.

Particularly preferred individual compounds of the invention are:

5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide (1: X is 5-chloro; Y is hydrogen; and R 'is 2-thienyl); 5-trifluoromethyl-3- (2- [2-thienyl] acetyl) 2-oxindole-1-carboxamide) 1: X is 5-trifluoromethyl; Y is hydrogen; and ^{R r} e 2- [2-thienyl] 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- (2furoyl) -2-oxindole-1-carboxamide (I :) X is 5fluoro; Y is 6-fluoro; and R 'is 2-furyl); and 5,6difluoro-3 (2-tenoyl) -2-oxindole-1-carboxamide (I :) X is 5-fluoro; Y is 6-fluoro; R 'is 2-thienyl).

The following are novel compounds of the invention of the general formula

In particular, the analgesic and anti-inflammatory substances of the invention have a carboxamide substituent, -C (= O) -NH ₂ , at the 1-position, and an acyl substituent, -C (= O) -R ',

3-position of 2-oxindole, and the benzo ring can be replaced by X and Y groups. X and Y may be known monovalent substituents such as the predetermined or X and Y, when adjacent to the benzo ring hydrocarbon atoms, may represent a methylenedioxy group, -OCH ₂ O-, or an ethylenedioxy group, -OCH ₂ CH ₂ O-. Further, X and Y, when attached to adjacent carbon atoms of a 2-oxindole benzo ring, may form a bivalent unit Z. When Z is taken with the carbon atoms to which it is attached, it forms a fused carbocyclic or heterocyclic ring. Known bivalent groups for Ζ (τ.ε.Ζ'-Ζ ⁵ ) are mentioned. When Z is Z ', X and Y together with the carbons to which they are attached represent a fused furan or thiophene ring. When Z is Z ⁴ or Z ^J , the Z group can be attached in both possible ways. For example, when X and Y are 5- ™ and

6- ™ position and are Z ⁵ , formula I includes the following two formulas:

Oh

II

o = c - nh ₂

in which X and Y are predetermined. The compounds of general formula II are used as intermediates for the compounds of general formula I.

Detailed description of the invention.

The analgesic and anti-inflammatory compounds of the invention are the compounds of general formula I in which X, Y and R 'are predetermined. The compounds are derivatives of 2-oxindole, the bicyclic amide of formula

II

o - c - nh ₂

The analgesic and anti-inflammatory compounds of this invention of general formula I, in which X, Y and R 'are predetermined, are potent enolizers and therefore may exist in one or more tautomeric / enol / form. All tautomeric (enal) forms of the compounds of general formula I are described in the invention.

The compounds of general formula I are

is prepared from a suitable 2-oxindole-1-carboxamide compound of the formula:

o = c — nh ₂ ¹¹ in which X and Y are predetermined. This is accompanied by the attachment of the substituent -C (= O) -R 'at the 3-position of the 2-oxindole nucleus.

The -C (= O) -R 'substituent is attached by reaction of a compound of formula II and an activated carboxylic acid derivative of formula R'-C (= O) OH. The reaction is carried out by treating said compound of formula II in an inert solvent of one molar equivalent or a weak residue of an activated derivative of a compound of formula R 1 C (= O) OH, in the presence of 1 to 4 equivalents of the parent substance. An inert solvent is one that dissolves at least one of the reagents and does not adversely interact with any of the reagents or product. In practice, a polar aprotic solvent such as N, N-diethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide is often used. Common methods for the activation of the acid of formula R'-C (= O) OH are used. For example, acidic X palides may be used, i. E. acidic chlorides, symmetric acidic anhydrides, R'-C (= O) -O-C (= O) -R ', low molecular weight carboxylic acidic anhydrides, R'-C (= 0) -C ( = O) -R ³ , where R ³ is a large low alkyl group, such as t-butyl, and mixed carbon-carbon anhydrides, R 1 C (= O) -O-C (= O) -O-R ⁴ , wherein R ⁴ is a low molecular weight alkyl group. Additionally, N-hydroximide esters (such as N-hydroxysuccinimide and N-hydroxyphthalimide esters), 4-nitrophenyl esters, thiol esters (such as thiophenyl esters) and 2,4,5-trichlorophenyl esters and the like can be used. Moreover, in those cases in which R'is a heteroaryl group (i.e. furyl), simple alkyl esters of the formula R'-C (= O) -O-R ⁴ in which R ⁴ is an alkyl group low molecular weight (namely ethyl) can sometimes be used as activated acid derivatives of formula R'-C (= O) -OH when attached to the -C (= O) -R 'substituent of 3- and the position of a 2-oxindole compound of formula II.

Various basic substances may be used in the reaction between a compound of formula II and an activated acid derivative of formula R'-C (= O) OH. Preferred basic substances are tertiary amines, such as trimethylamines, triethylamines, tributylamines, N-methylmorpholine, Nmethylpiperidine, and 4- (N, N-dimethylamino) pyridine.

The reaction between a compound of formula II and an activated acid derivative of formula R'-C (= O) -OH is generally carried out at temperature ranges from -10 ° to 25 °. The reaction time is usually from 30 minutes to several hours. At the end of the reaction, the reaction medium is usually diluted with water and acidified and the product can then be recovered by filtration. It can be purified by standard methods, for example recrystallization.

The 2-oxindole-1-carboxamide compounds of general formula II are prepared in two ways. In the first method, a compound of 2- (2-ureidophenyl) acetic acid of formula IV is cycled by treatment with trifluoroacetic acid and trifluoroacetic anhydride,

X _h ^ USN ₂ COOH and ^Y '^ / ⁴ NH - CO-NH ₂

IV where X and Y are predetermined. A solution of a compound of formula IV in trifluoroacetic acid is treated with 2 to 5 molar equivalents, and preferably with about 3 molar equivalents, of trifluoroacetic anhydride and the resulting solution is heated at reflux for 0.5 to 3 hours, typically for 1 hour. Upon removal of the solvents, the compound of formula II is formed which can be purified by standard technique, for example recrystallization. Alternatively, it may be used directly to form a compound of formula I.

The compounds of general formula IV can be obtained from basic hydrolysis of a compound of formula V:

Oct - '

I 2

O = c — NH — co — R

V where X and Y are predetermined and R ² is a lower alkyl group or a lower cycloalkyl group. Particularly used groups for R ² are isobutyl and cyclohexyl groups.

The basic hydrolysis of a compound of formula V in which R ² 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 / i.e. 0.5 N to 3.0 N, usually 1.0 N / at room temperature or slightly higher. The reaction usually proceeds relatively quickly and ends in 1 to 2 hours. The reaction mixture is then acidified (HCl) and the product is isolated by filtration or by solvent extraction using a volatile, water-insoluble, organic solvent. The compound of formula IV can be purified, for example by recrystallization, or it can cyclize directly to 2-oxindole-1-carboxamide of formula II.

The compounds of formula V are prepared by the reaction of a suitable 2-oxindole of formula VI and acylisocyanate of formula -C = O = C = 10:

N.

The conversion of VI to V can be accomplished by heating equivalent amounts of two reactants in reflux for several hours, for example, 2 hours.

In the second way, the preparation of the 2-oxindole-1-carboxamide compounds of formula 11,2-oxindole of formula VI is reacted with chlorosulfonyl-2-oxindole-1-carboxamide of formula VII, followed by removal of the chlorosulfonyl group by hydrolysis.

N.

VI

O = c — NH— SO ₂ - Cl

I o = c - nh ₂

II

The first part of the sequential reactions, the reaction between the appropriate 2-oxindole mixture of formula VI and chlorosulfonyl isocyanate, takes place in a neutral solvent medium, i. a solvent which does not react with chlorosulfonyl cyanate or N-chlorosulfonyl2-oxindole-1-carboxamide product of formula VII. Said solvent may cause complete dissolution of the reactants. Typical solvents are dialkyl ethers, for example 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 mixtures thereof.

The reaction is usually carried out at temperature ranges from room temperature (about 20 ° C) to reflux temperature for the solvent used. A temperature of 25 ° C to 110 ° C is preferred. Temperatures below 20 ° C, for example to -70 ° C, can be used if desired. Avoid temperatures below 0 ° C for economy.

The compound 2-oxindole of formula VI hydrosulfonyl isocyanate, followed by hydrolysis:

and chlorosulfonylisocyanate typically react in molar proportions ranging from equimolar to 30% excess chlorosulfonyl isocyanate, i.e. 1: 1 to 1: 1.3. Larger excess chlorosulfonyl isocyanate is not used for 5 economy reasons.

The chlorosulfonyl derivatives of general Formula VII, obtained in this way, if desired, can be recovered or directly converted into a compound of formula 10 II without being recovered in the same reaction vessel. Chlorosulfonyl intermediates of the general Formula VII are recovered by known procedures, for example, filtration or evaporation of the solvent. 15

The hydrolysis of the chlorosulfonyl derivatives of the general formula 'VII is accomplished by treating the compounds of the formula VII, with or without extraction thereof, with water, an acid or an aqueous base. Water or aquatic acid is preferred for the hydrolysis agent, even in cases where hydrolysis is a two-phase system. The rate of hydrolysis is fast enough to overcome any problems related to solubility of the reactants. 25 Using only water is more economical than other hydrolysis methods.

The use of aqueous organic acid as a hydrolyzing agent sometimes prevents the development of two-phase 30 reaction systems, for example when using aqueous acetic acid. The amount of acid is not critical to the hydrolysis step. It may range from less than an equimolar amount to greater than an equivalent amount. 35 The concentration of acid used is also not critical. When an acid is used for the hydrolysis step, it is applied from about 0.1 mole acid per mole of compound VII to 3 mole acid per mole 40 compound of formula VII. Commonly used acid concentrations of about 1 molar to 6 molar are for ease of treatment. The use of an acid is often delayed until the intermediate 45 of Formula VII is isolated, preferably a single-phase hydrolysis mixture. Acids such as hydrochloric, sulfuric, nitric, phosphoric, acetic, formic, citric and benzoic are preferred.

In the other method, compounds of general 50 of formula I may also be prepared by reaction of a compound of formula VIII and

VIII where Χ, Υ and R ′ are as defined above. The reaction of a compound of formula VIII with chlorosulfonyl isocyanate and the subsequent hydrolysis step are carried out in the same manner as described above for the conversion of a 2-oxindole compound of formula VI into a chlorosulfonyl compound of formula VII and its subsequent hydrolysis to give a compound with formula 11.

The compounds of general formula VIII are prepared by attaching the -C (= O) -R 'substituent at the 3-position to the corresponding 2-oxindole compound of formula IV. This acylation is carried out by reacting a compound of formula VI and a derivative of a suitable acid of formula R'-C (= O) -OH in a low alkaline solvent (eg sodium ethylate) according to standard procedures. Typical acid derivatives of formula R'-C (= O) OH that can be used include acid chlorides, acid anhydrides of formula R'-C (= O) -O-C (= K)) - R ' , R'C (= O) -O-C (= O) -R ³ and R'-C (= O) -O-C (= O) -OR 'and simple alkyl esters of the formula R'-C ( = 0) OR ⁴ in which R ³ and R ⁴ are predetermined. Generally, a small residue of an acid derivative of formula R'-C (= O) OH is used, and the alcohol salt is usually present in an amount of I to 2 molar equivalents based on known acid derivatives of formula R'-C (= O) 0H. The reaction between an acid derivative of formula R'-C (= O) OH and a compound of formula VI usually begins at 0 ° to 25 ° C, but then the reaction mixture is warmed to temperatures ranging from 50 ° to 130 ° C. and most commonly about 80 ° C for full response. Under these conditions, the reaction time is from several hours, for example 2 hours, to several days, for example 2 days. The reaction mixture was then cooled, diluted with water and acidified. The product of formula VIII can be recovered by filtration or by a standard solvent extraction procedure.

Some of the 2-oxindole-1-carboxamide compounds of formula II can be prepared from other compounds of general formula II by converting one X or Y substituent to another X or Y substituent. For example, compounds of formula II wherein X is alkylthionyl may be prepared from a suitable compound of formula II wherein X is alkylthio by oxidation. This oxidation can be accomplished by standard methods, for example, using peroxycarboxylic acid such as 3-chloroperbenzoic acid. 1.0 to 1.2 molar equivalents of oxidant are used to convert alkylthio to alkylthionyl, 2.0 to 2.4 molar equivalents of oxidant are used to convert alkylthio to alkylsulfonyl. In addition, compounds of formula II wherein X is alkanamido or benzoamido can be prepared by acylation of the corresponding compound wherein X is amino. This can be done by acylation with alkanoyl chloride or benzoyl chloride according to standard procedures.

The 2-oxindole compounds of formula VI are prepared by known methods or analogous to known methods. Reference: 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, 42, 1340 (1977); Wright et al., Journal of the American Chemical Society, 78,221 / 1956 /; Beckett et al., Tetraherdon, 24.6093 / 1968 /; US 3 882 236, US 4 006 161 and US 4 160 032; Walker, Journal of the American Chemical Society, 77, 3844 (1955); Against et al., Collection of Czechoslowakian Chemical Communications, 44, 2108/1979 /; McEvoy et al., Journal of Organic Chemistry, 38,3580 / 1963 / Wieland et al., Chemische Berichte, 96,253 / 1963 / and the references cited therein.

The compounds of general formula V are acids form the basic salts. All such basic salts are encompassed by this invention and can be prepared by conventional methods. For example, they can be prepared simply by contacting actually existing acidic and basic acids, usually in stoichiometric terms, in a suitable aqueous, non-aqueous or partially aqueous medium, or by converting one salt to another. The salts are extracted accordingly either by filtration or by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization. Typical salts of compounds of general formula I that can be prepared are primary, secondary and tertiary amino salts, alkali metal salts and alkaline earth metal salts. Sodium, potassium, ammonium, ethanolamino, diethanolamino and triethanolamino salts are particularly valuable.

The main substances used for the formation of salt belong to both organic and inorganic species and include ammonia, organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal oxides, alkaline earth metal carbonates, alkaline earth metal hydrides and alkaline earth metal alkoxides. Examples of such bases are: ammonia, primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucoamine; secondary amines such as diethylamine, diethanalamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, triethanalamine, N, N-dimethylaniline, N-ethylpiperidine and N-methyl-morpholine; hydroxides such as sodium hydroxide; alkoxides such as sodium ethoxide and potassium methoxy hydrides such as calcium hydride and sodium hydride and carbonates such as potassium carbonate and sodium carbonate.

This invention also describes solvates, for example hydrates, such as hemihydrates and monohydrates of analgesic and anti-inflammatory compounds of general formula I.

The compounds of general formula I exhibit analgesic activity. This activity was tested in mice by demonstrating abdominal stretch blockade induced by the introduction of 2-phenyl-1,4-benzoquinone (PBQ). The method used is based on that of Siegmund et al., Proc.Soc.Exp.Biol.Med., 95,729731 / 1957, adapting for higher throughput (see further Milne and Twomey, Agents and Actions , 10, 31-37, (1980) The mice used in this experiment were female Carworth, an albino CF-1 species, weighing 18-20 g. All mice were fasted overnight overnight before drug administration and study.

The compounds of general formula I are dissolved or precipitated in a solvent consisting of ethanol 5%, emulphor 620 (mixture of polyoxyethylene fatty acid esters) 5% and saline 90%. This solvent also serves as a control. The doses are logarithmically graded / ie ... 0.32, 1.0 10, 32 ... mg / kg and are calculated from the weight of the salt when added rather than the acid. The route of administration is oral, at various concentrations to allow a constant dosage of 10 ml / kg of mouse weight. The Milne and Twoney method mentioned above is used to determine efficiency and power. Mice are given the oral compounds, and 1 hour thereafter receive a PBQ, 2 mg / kg body weight, intraperitoneally. Individual mice were then placed in a warm light room and 5 min after PBQ insertion, the amount of abdominal tightness was recorded for 5 min. The degree of analgesic protection (% MPE) is calculated based on the suppression of abdominal tightness, with regard to those counted in competing control animals from the same day. At least four such determinations (N <5) provide data on responses to generate MPE _J0 doses, the best established dose that reduces abdominal tightness to 50% of control levels.

The compounds of general formula I also have an anti-inflammatory effect. This action was tested in rats by a method based on the standard test for induced swelling of the rat leg by carrageenin / Winter et al., Proc, Soc.Exp.Biol. Med., Ill, 544, / 1963 /.

Non-anesthetized adult female albino rats up to 150 to 190 g in weight were numbered, weighed, and marked with ink placed on the right lateral maleolus. Each paw is immersed in mercury, next to the ink mark. The mercury is stored in a glass cylinder connected to a Statham - pressure transducer. The output from the converter goes through the control unit to the microvoltmeter. The volume of mercury displaced by the dipping of the paw is recorded. Medicines are given by injection. One hour after administration of the drug, swelling is induced by injecting 0.05 ml of a 1% solution of carrageenin into the thin foot of the labeled paws. Immediately afterwards, the volume of the injected foot is measured. An increase in leg volume 3 hours after carrageenan injection appears as an individual inflammatory response.

The analgesic action of the compounds of the general Formula I makes them useful for rapid administration to mammals in order to control pain, for example, postoperative pain and trauma pain. In addition, the compounds of general formula I are used for the chronic administration of mammals to relieve symptoms of chronic diseases such as inflammation in rheumatoid arthritis and pain associated with osteoarthritis and other musculoskeletal disorders.

When a compound of formula I or a pharmaceutically acceptable salt thereof is used either as an analgesic or as an anti-inflammatory substance, it may be administered to the mammal or alone or, preferably, in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to the pharmaceutical composition practice. The compound may be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and superficial.

For a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, the weight ratio of the carrier to the active ingredient should be in the range of 1: 4 to 4: 1, and preferably 1: 2 to 2: 1. In each case, the ratio chosen depends on factors such as the solubility of the active ingredient, the dose selected and the exact route of administration.

For oral administration of a compound of formula I according to the invention, tablets, capsules, aqueous solution or suspension are suitable. In case oral tablets are administered, the carriers commonly used include lactose and dried cereal starch. When aqueous suspensions are preferred, the active ingredient is combined with emulsifying or suspending agents. If desired, known sweetening or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are prepared and the pH of the solutions must be suitably adjusted and buffered. For intravenous use, the total concentration of solutes is necessary to ensure its isotonic preparation.

When a compound of formula I or a salt thereof is used by humans, the daily dosage is usually prescribed by a physician and depends on the age, weight and individual response of the patient, as well as the severity of the symptoms and the potency of the individual compound selected. To relieve acute pain, the effective dose is in most cases 0.01 to 0.5 g, dosed as necessary (eg every 4 to 6 hours). In most cases, to relieve chronic pain, the effective dose is from 0.01 to 1.0 g / day, preferably from 20 to 250 mg per day, once or twice. In some cases, dosing beyond these limits may be necessary.

The following examples illustrate the invention.

Example 1. 5-Chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide.

Stirred sludge of 21.1 g (0.1 mol) of 5-chloro-2-oxindole-1-carboxamide and 26.9 g (0.22 mol) of 4- (N, N-dimethylamino) pyridine in 200 ml of N, N- The dimethylformamide was cooled to ice bath temperature and then a solution of 16.1 g / 0.11 mol / 2-thenoyl chloride and 50 ml of N, N-dimethylformamide was added dropwise. Stirring was continued for 30 minutes and then the reaction mixture was poured into a mixture of 1 liter of water and 75 ml of 3-hydrochloric acid. The resulting mixture was cooled in an ice bath and the solids were then collected by filtration.

The solids were washed with water and then recrystallized from 1800 ml of acetic acid to give 26.6 g of the title compound as a yellow powder, mp 230 ° C (decomposition).

A sample of the compound indicated in the title of a similar experiment gave the same results in elemental analysis.

Analysis: Calculated for C _n H ₉ Cl _{2 2} O ₃ 8: C, 52.42; H, 2.83; N, 8.74%. Found: C, 52.22; H, 2.81; N, 8.53%.

Example 2. The reaction of a suitable 2-oxindole-1-carboxamide with the required anhydride of the formula R'-CO-CI, essentially according to the preparation of example 1, gave the following compounds:

Oh

II x

γ

o = c - nh ₂

Table 1

Melting Point Calculated /% / Found /% /

X R ' / ° C / ¹ · ² C H N C H N 5-CI 2-furyl 234d 55.18 2.98 9.20 55.06 3.09 9.32 5-CI 2- (2-thienyl) methyl 240d ³ 53.81 3.31 8.37 53.40 3.31 8.37 6-CI 2-furyl 218-219 55.19 2.98 9.19 54.89 2.90 9.23 6-CI 2-thienyl 201-202 52.44 2.83 8.74 51.86 3.03 8.61 6-CI 2- (2-thienyl) methyl 219-220 53.83 3.31 8.37 53.70 3.45 8.38 5-F 2-furyl 232d 58.34 3.15 9.72 57.99 3.13 9.70 5-F 2-thienyl 213d 55.25 2.98 9.21 55.49 3.00 9.28

5-F 2- (2-thienyl)

methyl 243d 56.59 3.48 8.80 56.76 3.48 8.81 6-F 2-furyl 230.5-233.5 58.33 3.13 9.75 57.73 3.04 9.72 6-F 2-thienyl 117.5-120.5 55.26 2.96 9.21 55.14 2.91 9.15 6-F 2- (2-thienyl) methyl 214.5-217 56.61 3.48 8.80 55.97 3.52 8.65 5-CF ₃ 2-furyl 235.5d 53.26 2.68 8.28 52.84 2.97 8.17 5-CF, 2-thienyl 212.5d 50.85 2.56 7.91 50.43 2.72 7.90 5-CF ₃ 2- (2-thienyl) methyl 223.5d 52.17 3.01 7.61 51.72 3.37 7.45 6-CF ₃ 2-furyl 206-208 53.26 2.68 8.28 52.87 3.03 8.27 6-CF ₃ 2-thienyl 117-180 50.86 2.56 7.91 50.69 2.75 7.96

1. All compounds are recrystallized from acetic acid unless otherwise indicated.

2. The letter "d" means that said compound melts with decomposition.

3. Recrystallized from N, N-dimethylformamide.

Example 3 5-Chloro-3-acetyl-2-oxindole-20 1 -carboxamide.

Stirred sludge of 842 mg (4.0 mmol) 5chloro-2-oxindole-1-carboxamide and 1.08 g (8.8 mmol)

4- (N, N-dimethylamino) pyridine and 15 ml Ν, N-dimethylformamide was cooled to a temperature of 25 in an ice bath and then a solution of 449 mg / 4.4 mmol / acetic anhydride and 5 ml of N, N-dimethylformamide was added dropwise. . Stirring was continued for 30 min and then the reaction mixture was poured into a mixture of 75 ml of water and 3 ml of 3N 30 hydrochloric acid. The resulting mixture was cooled in an ice bath and the solid was removed by filtration. The solid was recrystallized from acetic acid to give 600 ml of powdered pale pink crystals, mp 237.5 ° C (decomposition).

Analysis: Calculated for C _h H ₉ CIN ₂ O ₃ : C, 52.29; H, 3.59; N, 11.09%. Found: C, 52.08; H, 3.63; N, 11.04%.

Example 4. Reaction of a suitable 2-oxindole-1-carboxamide with an activated carboxylic acid derivative of the formula R'-CO-OH, essentially according to the procedure of Examples 1 or 3, gave the following compounds:

Oh

II x

Y

o = c — νη ₂

Table 2

X Υ R ' Melting point / ° C. / ^{1 2 3} Η Η 2-furyl 223d Η Η 2-thienyl 210d Η Η 2- (2-thienyl) methyl 233d Η Η cyclohexyl 213d

Η H isopropyl 205-206 Η H cyclopropyl 207.5-208.5 Η H phenoxymethyl 187.5d Η H (4-chlorophenoxy) methyl 190d Η H methyl 200-201.5 5-C1 H cyclohexyl 210d 5-F H phenoxymethyl 201-202d 5-F H isopropyl 230d 5-F H cyclohexyl 222d 5-C1 H isopropyl 229d 5-C1 H cyclopropyl 243.5d 6-F H Bicyclo (2.2.1) Hyptan-2-yl 115.5-114 4-C1 H 2-thienyl 165-167d 4-C1 H 2-furyl 183-185d 5-CH ₃ 6-F 2-furyl 210-215 6-F H methyl 226.5-229 5-OCH ₃ '6-OCH ₃ methyl 226-230 5-OCH, 6-OCH ₃ 2-thienyl 195-197 6-CI H cyclohexyl 225-226 5-CF ₃ H isopropyl 203d 5-F H cyclopropyl 228.5d H H 4-chlorophenyl 229d H H 4-methylphenyl 214.5d H H benzyl 226.5d H H 1- (phenyl) ethyl 188.5-189.5d 5-CF ₃ H cyclopropyl 265d 5-CF ₃ H cyclohexyl 185-186 5-CF ₃ H methyl 225d 5-CF ₃ H phenyl 221.5d 5-CF ₃ H 4-chlorophenyl 225d 5-CF ₃ H 4-methylphenyl 224d 6-CF ₃ H isopropyl 199-202 6-CF ₃ H bicyclo (2.2.1) heptan-2-yl 192-198 6-SCH ₃ H (2-thienyl) methyl 214-215 4-SCH H bicyclo (2.2.1) heptan-2-yl 200-202 6-F H isopropyl 188-191 6-SCH, H bicyclo (2.2.1) heptan-2-yl 218.5-220.5 5-CF ₃ H benzyl 217d 5-CF ₃ H 1- (phenyl) ethyl 208d 5-CF ₃ H phenoxymethyl 205.5-206.5d 5-CH, 6-CH ₃ 2-furyl 220d 4-CH ₃ 5-CH ₃ 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 231d 5-CI H phenyl 232.5d 5-CI H 4-chlorophenyl 242d 5-CI H 4-methylphenyl 231d 5-CI H benzyl 244.5d 6-CI H benzyl 229-230d 4-CI H cyclohexyl 188-189

4-CI H isopropyl 158-160 4-SCH ₃ H 2-furyl 203-206 6-No H bicyclo (2.2.1) heptan-2-yl 232-235 5-CH ₃ H (2-thienyl) methyl 243-244d 6-CI H 4-chlorophenyl 220-222 5-CH ₃ H phenyl 215-216.5d 5-OCH ₃ H 4-chlorophenyl 238-240d 5-OCH ₃ H phenyl 209-210d 5-CH ₃ H cyclohexyl 219-220d 4-CI 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-CI H cyclopentyl 214-215d 5-CI H cyclobutyl 214-215d 5-CF ₃ H cyclopentyl 188-189 6-CI - H cyclobutyl 227d 6-CI H cyclopentyl 224-225.5d 5-CI H 1-Phenylethyl 206d 5-CI H phenoxymethyl 218d 5-F H bicyclo (2.2.1) heptan-2-yl 216d 5-CF ₃ H bicyclo (2.2.1) heptan-2-yl 212d 6-No H 2-Furil 234-237 6-CI H 1- (phenyl) ethyl 222-223d 5-NO ₂ H 2-thienyl 220.5-225 5-NO ₂ H benzyl 232-236 5-OCH ₃ H 1- (phenyl) ethyl 204-205.5 5-OCH ₃ H 2-thienyl 188-189d 6-CI H phenyl 236-237d 5-CH ₃ H 4-chlorophenyl 247-248d H H 2-pyrrolyl 214-215d 5-CI H 2-pyrrolyl 217-218d 5-F H 3-thienyl 236.5d 5-CI H 3-thienyl 238d 5-F H 3-furyl 229.5d 5-CI H 3-furyl 231.5d 6-CI H 3-furyl 223.5d 5-CF ₃ H 3-furyl 214d 5-F H (3-thienyl) methyl 239.5d 5-CI H (3-thienyl) methyl 237d 6-CI H (3-thienyl) methyl 220.5d 5-CF ₃ H (3-thienyl) methyl 210.5d 5-CI 6-CI 2-thienyl 227d 5-CI 6-CI (2-thienyl) methyl 243d b-c ₆ and ₅ H 2-thienyl 212d 6-C ₆ H ₃ H (2-thienyl) methyl 215d Η H 2,4-dichlorophenyl 221d 5-CI H trifluoromethyl 224-225d 5-CH ₃ H 2-furyl 214-215d 5-CH ₃ H benzyl 249-250d 5-CH ₃ H 2-thienyl 221-222d

5-OCH ₃ H (2-thienyl) methyl 239-242d 5-CI H bicyclo (2.2.1) heptan-2-yl 219-221d 5-CF ₃ H trifluoromethyl 217-219d 5-OCH ₃ H benzyl 240-24id 5-OCH ₃ H methyl 233-234d 5-CFj H 3-thienyl 225d 6-CI H (3-thienyl) methyl 220.5d H H 5-pyrimidinyl 238-240d 5-CI H bicyclo [2.2.1] hept-2-en-5-yl 211.5d H H bicyclo [2.2.1] hept-2-en-5-yl 210.5d 6-CI H bicyclo [2.2.1] hept-2-en-5-yl 219d 5-CI H 1-Phenylethyl 192-193 ² 5-CF ₃ H 1-Phenylethyl 169.5-170.5 ³ 5-CI H 1-Phenylethyl 193-194 ⁴ 5-CF ₃ H 1-Phenylethyl 172-173 ⁵ 5-CF ₃ H 3-Trifluoromethyl benzyl 153-155d 6-CI H 3-Trifluoromethyl benzyl 200-202d H H 2-chlorobenzyl 236d 5-CI H 2-chlorobenzyl 237.5d 5-F H 2-chlorobenzyl 231 d 5-CF ₃ H 2-chlorobenzyl 198.5-199.5 5-F H 3-Trifluoromethylbenzyl 214-215d 6-CI H 3-thienyl 210-212d 6-CI H 3-chlorobenzyl 231d 5-CI H 4-chlorobenzyl 242-243d 6-CI H 4-chlorobenzyl 195-198d 5-F H 4-chlorobenzyl 232-234d 5-CI H 3-chlorobenzyl 222-225d 5-F H 3-chlorobenzyl 219-220d H H 3-Trifluoromethylbenzyl 235-236d 5-C ₆ H _$ CO H benzyl 231d 5-C ₆ H ₃ CO H (2-thienyl) methyl 236-238 5-C ₆ H ₃ CO H 2-thienyl 185-187 5-CH ₃ CO H benzyl 239-241 5-C H SCO * H (2-thienyl) methyl 230-232 6-F H 5-Methyl-3-isoxazole yl 224-226 5-CI H 5-methyl-3-isoxazolyl 252-254 5-CH ₃ CO H (2-thienyl) methyl 226-227 5-C ₄ H ₃ SCO ⁶ H benzyl 243-245 5-F H 5-methyl-3-isoxazolyl 225-226 5-F 6-CI (2-thienyl) methyl 228-230 5-F 6-CI 2-furyl 250-251 5-F 6-CI 2-thienyl 220-221 5-CI H 1,2,3-Thiadiazol-4-yl 234-238 6-F H 1,2,3-Thiadiazol-4-yl 225-227 5-F 6-CI benzyl 243-245 6-CF ₃ H 1-phenylethyl 228-231 ' 6-F H 1-Phenylethyl 192-194 * 5-CI H 1-phenoxyethyl 220-222 6-F H 1-phenoxyethyl 200-202 6-F H 2-phenolethyl 149-150.5

5-CI H 2-phenylethyl 199-201 5-F 6-F 2-furyl 240-241.5 5-F 6-F benzyl 234-237 5-F 6-F (2-thienyl) methyl 236-238 5-NOJ H 2-furyl 157-160 5-NO ₂ H (2-thienyl) methyl 209-212 5-CI H 3-fluoromethylbenzyl 218-219 5-NO ₂ H 1-Phenylethyl 208.5-211 5-CI H (2-furyl) methyl 233-236 6-F H (2-furyl) methyl 212-214 6-F H 1,2,5-Thiadiazol-3-yl 237.5-241 5-CI H 1,2,5-Thiadiazol-3-yl 240.5-243 6-CF ₃ H 1-phenylethyl 235-237 ' 6-F H 1-phenylethyl 194-196 ¹⁰ 6-F H 1-phenylethyl 166-170 6-CF, H 1-Phenylethyl 205-207 6-CFj H (2-thienyl) methyl 217-218 5-F 6-CI 2-tetrahydrofuryl 213.5-215 5-NO ₂ H 2-tetrahydrofuryl 216-219 5-CI H 4-isothiazolyl 255 5-CI H 2-thiazolyl 227 5-CI H 1-methyl-5-pyrazolyl 254

The 'd' in this column indicates that the compound is melting with decomposition.

² / a / D ²³ = -300.3 ° ³ / a / D ²³ = -174.3 °

7a / D ²³ ^ 303.8 ° ⁵ / a / D ²³ = + - 169.7 ° ⁶ 5- (2-Tenoyl)

7 (70 ^ = - 154.9 ⁰

7a / D ²³ = H-184.9 °

Example 5. Reaction of 2-tenoyl chloride 35 and 2-furoyl chloride with 5,6-methylenedioxy-2-oxindole-1-carboxamide using the procedure of Example 1 gave the following compounds:

5,6-methylenedioxy-3- (2-tenoyl) -2-oxindole-1-carboxamide, melting point 215 ° C-40 217 ° C (decomposition) and

5,6-methylenedioxy-3- (2-furoyl) -2-oxindole-1-carboxamide, mp 234 ° -235 ° C (decomposition), respectively.

Example 6. By reaction of a suitable chloranhydride of formula R'-CO-CI with the required 2-oxindole-1-carboxamide, the following compounds can be prepared using the procedure of Example 1:

Table 3

X In R ¹ 5-p-OS _h N, H 2-furyl 5-OS ₂ H ₅ H 2-thienyl 7-CI H (2-thienyl) methyl 6-F H p-hexyl 5-F H cycloheptyl 5-CI H 2-fluorophenyl 5-n-C ₄ H, H 2-furyl 5-CH ₃ H 4-bromophenyl 6-SCH ₃ H 3-p-butyl phenyl 5-CF ₃ H 3-methoxyphenyl 5-n-SC ₄ H, H 4-isobutoxyphenyl 5-CH ₃ 6-CH ₃ 3- (phenyl) propyl 6-OCH ₃ H 3- (phenoxy) prop 6-SCH ₃ H 2-thienyl 5-NO ₂ H (3-fluorophenoxy) methyl Η H cyclobutyl-1-en-1-yl 5-CI H cyclohept-1-en-1-yl 6-F H (thiophenoxy) methyl 5-CF ₃ H 3- (thiophenoxypropyl) H H 1-imidazolyl 5-CI 6-CI 2-tetrahydropyranyl 6-n-SC ₄ H, H (4-chlorophenoxy) methyl 5-OCH ₃ 6-OCH ₃ (2-thienyl) methyl 5-CI H (2-furyl) methyl 5-F 6-CI (4-bromophenoxy) methyl 5-F 6-CI 2-tetrahydrothiopyranyl 6-CI H (2-methylphenoxy) methyl 6-No H (4-Isobutylphenoxy) methyl 6-n-SCH H 2-thienyl 7-CI H (3-methoxyphenoxy) methyl 4-SCH ₃ H (4-butoxyphenoxy) methyl 5-NO ₂ H 3-furyl 4-CH ₃ 5-CH ₃ 3-thienyl 6-CH ₃ H 3-methyl-2-furyl 7-CI H 6-propyl-2-furyl 5-CH / CH _3/2 H 3-methyl-2-thienyl 5-F 6-CI 5-propyl-2-thienyl

5-NO ₂ H 3- (3-thienyl) propyl 5-OS ₂ H ₅ H 1- (2-furyl) ethyl 7-CI H 3- (2-furyl) propyl 6-CH ₃ SO H 3-thienyl 6-nC ₄ H, SO H 2-furyl 4-CH ₃ SO ₂ H 3-fluorophenyl 6-nC ₄ H ₉ SO ₂ H 2-thiazolyl 5-NO ₂ H 2- (3-thienyl) ethyl 6-C ₆ H ₅ H 4-chlorophenyl Η 5-No 2- (2-tolyl) ethyl 5-CH ₃ CO H 4-Trifluoromethyl phenyl 6-n-C ₃ H ₇ CO H 4-isothiazolyl 5-CI H 1-naphthyl 5-CH CO., LTD 0 J H 1,2,3-Thiadiazol-4-yl 5-C ₄ H ₃ SCO ' H 3- (3-chlorophenyl) propyl 6-CF ₃ H (4-thiazolyl) methyl 6-F H 1,2,5-Thiadiazol-3-yl 5-CH ₃ CONH H 1-methyl-1-phenylethyl 5-CI 6-CI 5-methyl-4-isoxazolyl 5- / CH _3/2 CH-CONH H 2- (4-isopropylphenyl) ethyl 5-C.H, COH H 2-thienyl 5-CH ₃ 6-CH ₃ 4-isopropoxyphenyl 5-SO ₂ N / CH _3/2 H benzyl 5-F 6-F 4-chlorophenoxy 5-SO ₂ N / nC ₃ H _7/2 H 2-tetrahydrofuryl H 4-CI 4-Pyridyl 6-CI H 3-tetrahydrothienyl H H 5-pyrimidyl 5-CH ₃ 6-F 2-Pyrazinyl H H 2-n-propyl-4-thiazolyl 5-No H 2-oxazolyl H H 3-isoxazolyl H H 1,3,4-Thiadiazol-2-yl

5- (2-Tenoyl)

Example 7. By reaction of the appropriate chloranhydride with the required 2-oxindole-1carboxamide, the following compounds can be prepared using the procedure of Example 1:

Table 4

X and Y ⁺ R ¹ 4-CH ₂ -CH ₂ -CH ₂ -5 2-furyl 5-CH ₂ -CH ₂ -CH ₂ -6 2-thienyl 6-CH ₂ -CH ₂ -CH ₂ -CH ₂ -7 2-furyl 5-CH = CH-CH = CH-6 (2-thienyl) methyl 5-O-CH ₂ -CH ₂ -6 2-thienyl 5-CH ₂ -CH ₂ -O-6 2-furyl 5-S-CH ₂ -CH ₂ -6 2-thienyl 5-O-CH = CH-6 2-furyl 5-S-CH = CH-6 (2-thienyl) methyl 5-CH “CH-S-6 2-furyl

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

Example 8 5-Chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide. To a stirred solution of

429.9 g (2.0.04 mol) of 5-chloro-2-oxindole-1-carboxamide in 4 l of N, N-dimethylformamide was added

547.9 g (4.48 mole) of 4- (N, N-dimethylamino) pyridine and the mixture was then cooled to 8 ° C. A solution of 328 g (2.23 mol / tenoyl fluoride in 800 ml of N, N-dimethylformamide) was added to this mixture with continuous stirring for more than 30 minutes while maintaining the temperature between 8 ° and 15 ° C. Stirring was continued for 30 minutes and then the reaction mixture was poured into a mixture of 510 ml of concentrated hydrochloric acid and 12 l of water, while stirring. Stirring is continued for another 2 hours, then the solids are collected by filtration and washed with water and then with methanol. The solids were dried to give 675.6 g of the title compound.

Part of the title compound (673.5 g, 2.1 mol) was added to 13 l of methanol and the mixture was heated to reflux. To this mixture was added 136 g (2.22 mol / ethanolamine). The resulting solution was cooled to 50 ° C, 65 g of decolorized carbon was added, and then the solution was warmed to reflux and maintained for 1 hour. The warm solution was filtered through a superfilter (infuser soil) and the filtrate cooled to 40 ° C. 392 ml of concentrated hydrochloric acid were added to the filtrate, slowly for 30 min. The mixture was cooled to 20-23 ° C, stirred for 30 min and then the solids were collected by filtration and washed with methanol. The solids were dried to give 589 g of the title compound, melting point 22917

231.5 ° C (dec.).

Example 9. Ethanolamine salt of 5-chloro-

3- (2-Tenoyl) -2-oxindole-1-carboxamide. Sludge of 321 mg (1.0 mmol) of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide in 25-30 ml of diisopropyl alcohol was warmed to boiling and then a solution of 67 mg of ethanolamine in 1 ml was added. diisopropyl alcohol. A yellow solution is obtained for 2-3 minutes. The solution is boiled to 12-13 ml and then allowed to cool. The solids that appear are collected by filtration. 255 mg of the title salt are obtained as yellow crystals, mp 165.5 ° -167 ° C (gentle decomposition).

Analysis: Calculated for C ₁₆ H ₁₆ CIN ₃ O ₄ : C, 15 50.32; H, 4.22; N, 11.00%. Found: C, 50.52; H, 4.44; N, 10.88%

Example 10. The 5-chloro-3 (2-tenoyl) -2-oxindole-1-carboxamide sodium salt.

Part A. To a stirred sludge of 20 g (62.4 mmol) of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide in 400 ml of methanol was added 4.14 ml (68.6 mmol) of ethanolamine dropwise at room temperature. To this pure solution was added a solution of 6.74 g (124.7 mmol / sodium methoxide in methanol). The resulting mixture was warmed to 90 ° C and then allowed to cool, stirring overnight. The solids obtained were collected by filtration and dried at room temperature under high vacuum overnight to give 18.12 g of crude product. The crude product was recrystallized from methanol-isoprotanol to give 1.73 g of crystallization and 10.36 g of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide sodium monohydrate. Both crystals formed melt at 236 ° -238 ° C.

Calculated for C ₁₄ H, CIN ₂ O ₃ SNa.H ₂ O Analysis: Found for I croup Found for II croup C, 46.48 46.99 46.71 H 3.06 2.68 2.70 N, 7.74 7.98 7.79

The remainder of the first cropping is dried again. Anhydrous sodium 35 is obtained 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide salt, mp 237 ° -238 ° C. Analysis: Calculated for Set to re-dry C ₁₄ H _g CIN ₂ O ₃ SNa n substance from the first lap- dive C, 48.92 48.23 H, 2.64 2.81 N, 8.15 7.89

Part B. To a stirred slurry of 20 g (62.4 mmol) of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide in 400 ml of methanol was added 4.14 ml (68.6 mmol) of ethanolamine dropwise at room temperature. 6.74 g of sodium methoxide powder was added to the thus obtained pure solution 5 and the mixture was stirred overnight. The solids formed were collected by filtration and dried under high vacuum overnight. A 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide hemihydrate was obtained, mp 238 ° -239 ° C.

Analysis: Calculated for C _{| 4} H _g CIN ₂ O ₃ SNa.0.5H ₂ O Established C, 47.67 47.72 H, 2.85 2.73 N, 7.94 7.70

Example 11 Potassium salt of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide. The procedure of Example 10, Part B, was repeated, replacing the sodium powder with a solution of 7.00 g of potassium hydroxide in methanol. The potassium salt of 5chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide was obtained in the potassium salt, mp 214 ° -216 ° C.

Analysis: Calculated for c ₁₄ h, cin ₂ o ₃ sk.h ₂ o Established With 44.30 44.29 H, 2.93 2.67 N, 7.41 7.22

Example 12 The ammonium salt of 5-chloro-3 - / in methanol instead of sodium methoxide powder.

2-Tenoyl / -2-oxindole-1-carboxamide. The salt of the title compound The anhydrous salt indicated in the title was prepared, analogously to Example 40, with a melting point of 203 ° -204 ° C.

10, Part B, using ammonium solution

Calculated for C ₁₄ H _g CIN ₂ SO ₃ .NH ₄ Analysis: Established C, 49.64 49.75 H, 3.86 3.53 N, 12.41 12.20

Example 13 2-Oxindole-1-carboxamide. 194 mg (10 mmol) of 2- (2-ureidophenyl) acetic acid was dissolved in 4 ml of trifluoroacetic anhydride and the mixture was heated at reflux for 1 hour. The reaction mixture was cooled and the solvent removed by evaporation in vacuo. The precipitate was turned to powder by the action of 5-8 ml of saturated atrium bicarbonate solution, and the material remaining outside the solution was collected by filtration. The solids thus obtained were recrystallized from ethanol to give 61 mg of the title compound as colorless needles, mp 179 ° -180 ° C (gentle decomposition).

Analysis: Calculated for C ₉ H _lg N ₂ O _2: C, 61.36; H, 4.58; N, 15.91%. Found: C, 61.40; H, 4.80; N, 15.77%.

Example 14 5-Chloro-2-oxindole-1-carboxamide. Cyclization of 4.78 g / 0.021 mol / 2/5-chloro-2-ureidophenyl / acetic acid and 8.0 g / 0.065 mol / trifluoroacetic anhydride in 75 ml of trifluoroacetic acid according to the method of Example 13, followed by recrystallization of the crude product of acetone from acetone , gives 80 mg of the title compound, mp 211 ° C (decomposition).

Analysis: Calculated for C ₉ H, CIN ₂ O ₂ : C, 51.32; H, 3.35; N, 13.30%. Found: C, 51.37; H1 3.37; N, 13.53%.

Example 15. By cyclization of 2- (2-urea-ureophenyl / acetic acid) compounds of Preparation 3 with trifluoroacetic anhydride in trifluoroacetic acid according to the procedure of Example 13, the following compounds can be prepared: 6-chloro-2-oxindole-1-carboxamide; 5-fluoro-2-oxindole-1-carboxamide;

6-fluoro-2-oxindole-1-carboxamide; 5-Trifluoromethyl-2-oxindole-1-carboxamide and 6-trifluoromethyl-2-oxindole-1-carboxamide.

Example 16 2-Oxindole-1-carboxamide. Chlorosulfonyl isocyanate (1.20 g, 8.4 mmol) was added to a mixture of 2-oxindole (0.94 g, 7.1 mmol) and ether (30 ml) and the reaction was stirred continuously for 20 hours at room temperature. The ether was removed in vacuo and the residue treated with water (10 ml) and 1NHCI (10 ml). Ethyl acetate (125 mL) was added and the mixture was stirred for 1 hour. The ethyl acetate phase was separated, washed with 1 NHCI (1x50 ml), brine (2x100 ml) and dried (MgSO 4). The crude product concentration obtained was 0.97 g (77%). Recrystallization from ethanol yielded 0.18 g of the title product, mp 177 ° -179 ^< 'C.

Example 17. 2-Oxindole-1-carboxamide. To the stirred mixture of 2-oxindole (5.86 g, 44.0 mol) and dry toluene (160 ml) was added chlorosulfonyl isocyanate (7.47 g, 52.8 mmol). Hydrochloric acid is released immediately. The mixture was stirred at reflux for 15 min and then cooled to room temperature. Water (50 ml) was added to the cooled mixture (part of the HCl was initially removed) and the mixture was then stirred for 1.5 hours. The solids formed were collected by filtration and dried (4.10 g). The filtrate was extracted with ethyl acetate (100 ml) and the resulting extract washed with brine (2x100 ml) and dried (MgSO ₄ ). Evaporation of the extract under reduced pressure gave 4.16 g of a solid. The collected solids were recrystallized by dissolving in acetonitrile (200 ml), followed by concentration of the solution under reduced pressure to about 75 ml. The small amount of amorphous material which is separated is filtered off, the filtrate is discolored and concentrated under reduced pressure to about 50 ml volume, then crystals are charged. The title compound was obtained on dark red crystals, which were filtered off and dried (3.0 g); 38% /.

Example 18 6-Fluoro-5-methyl-2-oxindole-1-carboxamide. Following the procedure of Example 17, the title compound was prepared from 6-fluoro-5-methyl-2-oxindole (1.0 g, 6.0 mmol) and chlorosulfonyl isocyanate (1.0 g, 7.3 mmol) in toluene (30 ml). Water (5 ml) was used for the hydrolysis step. The yield was 0.58 g, 46% with a melting point of 200 ° -203 ° C.

Analysis: Calculated for C ₁₀ H ₉ N ₂ O ₂ F: C, 57.69; H, 4.36; N, 13.46. Found: C, 57.02; H, 4.41; N, 12.85%.

A sample of chlorosulfonyl prior to hydrolysis was immediately removed and subjected to mass spectral analysis for accurate mass determination: C ₁₀ H, N ₂ 0 ₂ SCI: 307.9848.

Example 19. 2-Oxindole-1-carboxamide. To the 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 was heated in a steam bath for 10 min. The pure solution formed for about 3 minutes followed by the almost immediate formation of a precipitate. The reaction mixture was cooled in an ice bath for 30 min and then the solid was filtered off and dried in the open air.

The chlorosulfonyl intermediate thus obtained is added to a 2: 1 mixture of acetic acid and water (240 ml) and the slurry formed is heated in a steam bath for 10 minutes. It is cooled in ice 10 in a bath and an off-white solid, which is formed, filtered and dried in the open from the concentration of the mother liquor to a viscous mass, and its filtration gives 1.2 g of additional product. The combined solids were recrystallized from about 250 ml of ethanol; the yield was 11.48 g (65%).

Example 20. Substituted-2-oxindole-1carboxamide.

The following compounds are prepared by reaction of a suitable 2-oxindole with chlorosulfonyl isocyanate, followed by hydrolysis using the procedure of Example 19.

o = c - nh ₂

Table 5

X In mp / ° C. / Calculated Analysis N Installed C Η P N. N 5-CH ₃ N. 215-216d 5-OCH ₃ N. 191-192 4-CI N. 201-202 ¹ 51.32 3.35 13.30 51.04 3.26 13.24 5-CI N. 211d 51.32 3.35 13.30 51.14 3.48 13.21 6-C1 N. 221-222d 51.32 3.35 13.30 51.07 3.30 13.31 5-F N. 198 ² 55.67 3.64 14.43 56.25 3.79 14.53 5-CF ₃ N. 214.5 ² 49.19 2.89 11.48 48.90 3.05 11.50 4-CH ₃ 5-CH ₃ 222d 64.69 5.92 13.72 64.57 5.94 13.64 5-CH ₃ 6-CH ₃ 214.5 ' 64.69 5.92 13.72 64.52 6.67 13.68 5-CI 6-CI 245d 44.11 2.47 11.43 43.98 2.55 11.58

'Recrystallized from ethanol;

² Recrystallized from acetonitrile; 'Recrystallized from acetic acid.

Example 21. 5,6-methylenedioxo-2-oxindole-1-carboxamide. 5,6-methylenedioxy-2-oxindole-1-carboxamide was prepared by reaction of 5,6-methylenedioxy-2-oxindole with chlorosulfonyl, isocyanate, followed by hydrolysis using the procedure of Example 19. The product was melted at 237 ° -238 ° C. (decomposition) / after recrystallization from acetic acid.

Example 22. By reaction of a suitable 2-oxindole with chlorosulfonyl isocyanate followed by hydrolysis using the procedure of Example 19, compounds can be obtained.

o = c — nh ₂

Table 6

X In 5-p-OS ₄ N, H 5-OC ₂ H _s H 7-CI H 5-n-C ₄ H, H 5-n-SC ₄ Hj H 6-OCH ₃ H 6-n-SC ₄ H, H 5-CH / CH _3/2 H 6-nC ₄ H, SO H 6-nC ₄ H, SO ₂ H Η 5-No 6-n-C ₃ H ₇ CO H 5- / CH _3/2 CHCONH H 5-SO ₂ N / CH _3/2 H 5-SO ₂ N / nC ₃ H, / ₂ H

Example 23. By reaction of a suitable 2-oxindole with chlorosulfonyl isocyanate, followed by hydrolysis using the procedure of Example 19, the following tricyclic compounds can be obtained:

o = c - nh ₂

Table 7

X and Y ⁺

4- CH ₂ -CH ₂ -CH ₂ -5

5- CH ₂ -CH ₂ -CH ₂ -6

6- CH ₂ -CH ₂ -CH ₂ -CH ₂ -7

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 ₂ -6

5-S-CH = CH-6

5-CH = CH-S-6 ⁺ B this column the number to the left of the formula shows the point of attachment of this end of the formula to the 2-oxindole nucleus, and the number to the right the point of attachment of that end of the formula to the 2-oxindole core.

Example 24 6-Methylthio-2-oxindole-1carboxamide. 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 ° to 10 ° C. The reaction mixture was stirred for 1 hour. Then water (100 ml) was added and stirring was continued for 10 minutes. The aqueous solution was extracted with ethyl acetate (600 ml), which was then successively washed with water and brine, dried (MgSO ₄ ) and evaporated under reduced pressure. to give a gray solid which is recrystallized from acetonitrile. The yield is 3.0 g. An additional 0.71 g of the product is obtained from the mother liquor. Total yield is 3.71 g / 50.6%/; mp 176-179 ° C.

Example 25. 5,6-Dimethoxy-2-oxindole-carboxamide. Following the procedure of Example 24, the title compound was obtained 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 by evaporation of the ethyl acetate extract was recrystallized from acetonitrile / acetic acid (1: 1). Yield = 6.02 g (60%), mp 206.5 ° -209 ° C.

Example 26 6-Trifluoromethyl-2-oxin15 dol-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 was stirred for 45 min. 2Q water / 100 was added. ml / and the aqueous solution was stirred for 1 hour. The precipitate which formed was filtered and recrystallized from acetonitrile to give 0.92 g of the title product. Extraction of fil25 tert of the aqueous reaction mixture with ethyl acetate (300 mL), followed by drying the extract over MgSO ₄ and evaporating it under reduced pressure, yielded an additional product 2.2. d.

A further product (1.85 g) was recovered from the pooling of mother liquors from acetonitrile recrystallizations and concentration under reduced pressure. Total yield was 4.97 g, (51%); with melting point 207.5 ° 35 ²¹⁰ ° ^C ·

Example 27. The procedure of Example 26 was repeated using the appropriate substituted 2-oxindole. The following compounds are obtained.

I o = c - nh ₂

Table 8

Melting point /°C./

4-SCH ₃ H

181-184

6-F N. 191.5-194 6-Br N. 205-208 5-NO N. 201-205 5-F 6-CI 229-23I ¹ 5-F 6-F 198-201

'The reaction takes place in toluene as a solvent. The starting material and product are contaminated with any of the corresponding 4-chloro-5-fluoro-isomers.

Example 28 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, with stirring, at 5 ° C. 2.2. ml / 25.8 mmol / chlorosulfonyl isocyanate. Stirring was continued for 1 hour at 0 ° -5 ° C and then 100 ml of water were added. The solid was recovered by filtration and added to a mixture of 40 ml methacetic acid and 80 ml water. The resulting mixture was warmed to 100 ° C for 1 h, cooled and filtered. Dry the residue to give 3.1. g of the title compound, mp 188 ° -189 ° C.

Example 29. 5-Benzoyl-2-oxindole-1-carboxamide. Mixture of 10.1 g / 42 mmol / 5-benzoyl-2-oxindole, 4.4. ml / 51 mmol / chlorosulfonyl isocyanate and 300 ml of tetrahydrofuran was stirred at room temperature for 6 hours, then the solution was removed by evaporation in vacuo. The residue was added to methacetic acid (150 ml) and 300 ml of water and the resulting mixture was heated in reflux for 2 hours. The reaction mixture was cooled and the liquid was removed by decantation. The adhesive residue is converted to powder under the action of acetonitrile to give a solid which is recovered by filtration and then recrystallized from a mixture of propanol and acetonitrile in a 1: 1 ratio. 4.1 g of the title compound are obtained as a solid with a melting point of 210 ° -211 ° C.

Example 30. Reaction of 5-acetyl-2-oxindole and 5- (2-thenoyl) -2-oxindole with chlorosulfonyl isocyanate followed by hydrolysis with aqueous acetic acid according to the procedure of Example 29 gave the following compounds:

5-acetyl-2-oxindole-1-carboxamide, 34%, melting point 225 ° C (decomposition) from CH ₃ CN and 5- (2-theonyl) -2-oxindole-1-carboxamide, 51% yield melting point 200 ° C (decomposition) from CH ₃ OH / CH ₃ CN, respectively.

Example 31 5. Acetamido-2-oxindole-1carboxamide. A slurry of 0.5 g (2.6 mmol) of 5amino-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. . Stirring was continued at about -10 ° C for 20 min at room temperature for 15 min, then 20 ml of 1N hydrochloric acid were added. The solid was recovered by filtration and dried to give 0.20 g of the title compound as a creamy solid.

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

Example 32 5-Benzamido-2-oxindole-1carboxamide. Otacylation of 5-amino-2-oxindole-1-carboxamide with benzoyl chloride according to the procedure of Example 31 gave 90% yield of the title compound as a cream solid, mp 223 ° -226 ° C.

Example 33 4-Methylsulfonyl-2-oxindole-1-carboxamide. The title compound is obtained by oxidizing 2.5 g of 4methylthio-2-oxindole-1-carboxamide with 2.4 molar equivalents of 3-chloroperbenzoic acid in THF at room temperature according to standard procedures. The product was isolated as a solid (0.81 g, 28% yield).

Example 34. 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-chlorobenzoic acid in THF at room temperature according to standard procedures yields 1.13 g of the title compound contaminated with the corresponding sulfoxide.

Example 35 4-Methylthionyl-2-oxindole-1-carboxamide. Oxidation of 1.0 g of 4-methylthio-2-oxindole-2-carboxamide with 1.1 molar equivalents of 3-chloroperbenzoic acid in tetrahydrofuran at a temperature of about 0 ° C gives 0.9 g of the title compound is melting point 198.5 ° -200 ° C.

Similarly, oxidation of 6methylthio-2-oxindole-N-carboxamide with 3-chloroperbenzoic acid gives 6-methylthionyl 2-oxindole-1-carboxamide.

Example 36 3/2-Furoyl] -6-fluoro-2-oxindole-1-carboxamide. Following the procedure of Example 24, the title compound was prepared in 17% yield of 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 /. The yield is “60 mg with a melting point of 231 ° -235 ° C.

Example 37 3- (2- (Tenoyl) -5-chloro-2-oxindole-1-carboxamide. 0.52 ml (5.9 mmol) of chlorosulfonyl isocyanate was added to a stirred slurry of 1.5 g (5.4.4 mmol) of 3- (2-thenoyl) -5-chloro-2-oxindole in 15 ml of dry acetonitrile and the reaction mixture was stirred at room temperature for 2 hours. o'clock. A small sample was separated, filtered and evaporated in vacuo to give a small sample of N-chlorosulfonyl-3- (2-thenoyl) -5-chloro-2-oxindole-1-carboxamide, melting point 166 ° - 169 ° C. 30 ml of water were added slowly to the remainder of the reaction mixture, stirring continuously for 1 hour. The reaction mixture was then poured into 50 ml of 1N hydrochloric acid containing ice pieces and the resulting mixture was stirred for 20 min. The yellow solid was recovered by filtration, washed with water and diisopropyl ether and recrystallized from methacetic acid to give 200 mg of the first croup of the title compound, melting point 213 ° 215 ° C. The mother liquors from which the first cropping was derived precipitated a yellow yellow solid later. The last solid was recovered by filtration to give 470 mg of a second crop of the title compounds. The second crouponization is recrystallized from methacetic acid and combined with the first crouponization recrystallized from methacetic acid. This gave 280 mg of the title compound, mp 232 ° -234 ° C.

Getting 1.

2- (2-ureidophenyl) acetic acid. The sludge of 2.9 g (0.01 g mol) of N-cyclohexylcarbonyl-2-oxindole-1-carboxamide in 50 ml of 1N calcium hydroxide solution was stirred at room temperature for about 30 min, during which time the solid dissolved. At this point, the reaction mixture was acidified with concentrated hydrochloric acid, ice-cold, and then extracted with ethyl acetate. The extracts were washed with saturated sodium chloride solution, dried (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, melting point 174.5 ° C. (decomposition).

Analysis: Calculated for C 24 H 25 N 4 O: C, 55.66; H, 5.19; N, 14.43%.

Found: C, 55.37; H, 5.33; N, 14.38%.

Receipt 2.

2- (5-Chloro-2-urleidophenyl) acetic acid. The title compound is obtained in 43% yield by hydrolysis of -N-isobutyl-5-chloro-2-oxindole-1-carboxamide with 1N potassium hydroxide according to procedure 1. After the hydrolysis is complete and the reaction mixture is acidified, the product precipitates. It was recovered by filtration and recrystallized from ethanol to give the title compound as colorless crystals, mp 187.5 ° C (decomposition).

Analysis: Calculated for C ₉ H, CIN ₂ O ₃ : C, 47.28; H, 3.97;

N, 12.26%. Found: C, 47.11; H, 3.98; N, 12.20%.

Receipt 3.

By hydrolysis of N-isobutyryl-2-oxindole-1-carboxamides from Preparation 6 with potassium hydroxide using the procedure from Preparation 1, the following compounds can be obtained:

2- (4-chloro-2-y reidophenyl) acetic acid,

2- (5-fluoro-2-uridophenyl) acetic acid,

2- (4-fluoro-2-uridophenyl) acetic acid,

2- (5-Trifluoromethyl-2-ureidophenyl) acetic acid and

2/4-Trifluoromethyl-2-ureidophenyl / acetic acid.

Receipt 4.

M-Cyclohexylcarbonyl-2-oxindole-1carboxamide To a stirred sludge of 20.0 g /0.15 mol / 2-oxindole in 150 ml toluene was added 29.6 g /0.19 mol / cyclohexylcarbonyl isocyanate. The mixture was heated at reflux for about 30 min and then cooled to room temperature. The solid was recovered by filtration and then recrystallized from ethanol. It turns out

26.5 of the title compound as powderless colorless crystals, mp 144.5 ° -145 ° C.

Analysis: Calculated for C _{16 H] g} N ₂ O _3: S.67.11; H, 6.34; N, 9.79%.

Found: C, 67.00; H, 6.36; N, 9.77%.

Receipt 5.

N - Isobutyryl-5-chloro-2-oxindole-1-carboxamide To a stirred sludge of 8.38 g / 0.05 mol / 5-chloro-2-oxindole in 250 ml toluene was added 6.79 g / 0.06 mol / isobutyryl isocyanate, and the reaction the mixture is heated at reflux for

5.5 hours. The reaction mixture was cooled to room temperature. A small amount of the insoluble substance is recovered by filtration and the solvent is recovered by evaporation in vacuo. The residue was recrystallized from acetonitrile using colorless carbon, followed by recrystallization from ethanol to give 3.23 g of the title compound as pink crystals, mp 139 ° -141 ° C.

Analysis: Calculated for _{C] 3} H ₁₃ CIN ₂ 0 _3: C, 55.62; H, 4.67; N, 9.98%.

Found: C, 55.53; H, 4.48; N, 9.97%.

Preparation 6. By reaction of a suitably substituted 2-oxindole with isobutyryl isocyanate using the procedure of Preparation 5, the following compounds can be obtained:

N-isobutyryl-6-chloro-2-oxindole-1-carboxamide, N-isobutyryl-5-fluoro-2-oxindole-1-carboxamide, N-isobutyryl-6-fluoro-2-oxindole-1-carboxamide;

N-isobutyl-5-trifluoromethyl-2-oxindole-1-carboxamide and

N-isobutyl-6-trifluoromethyl-2-oxindole-1-carboxamide.

Receipt 7.

5-Chloro-2-oxindole. To a stirred sludge of 100 g (0.55 moles) of 5-chloroisatin in 930 ml of ethanol was added 40 ml (0.885 moles) of hydrazine hydrate to form a red solution. The solution was heated at reflux for 3.5 hours, during which time a precipitate appeared. The reaction mixture was stirred overnight, and the precipitate was then removed by filtration to give 5-chloro-3-hydrazono-2-oxydol as a yellow solid, which was dried in a vacuum oven. The dried solid weighed 105.4 g and was added portionwise over 10 minutes to a solution of 125.1 g of sodium methoxide in 900 ml of pure ethanol. The resulting solution was heated at reflux for 10 min and concentrated in vacuo to a sticky solid. The adhesive solid was dissolved in 400 ml of water and the aqueous solution thus obtained was decolourised with activated carbon and then poured into a mixture of 1 l of water and 180 ml of concentrated hydrochloric acid containing ice pieces. The reddish solid precipitated, collected by filtration and washed with plenty of 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 (decomposition).

Similarly, 5-methylisatin is converted to 5-methyl-2-oxindole by treatment with hydrazine hydrate and then with sodium ethylate in ethanol. The product melts at 173 ° -174 ° C.

Receipt 8.

4,5-Dimethyl-2-oxindole and 5,6-dimethyl2-oxindole. 3,4-Dimethylaniline is converted to 3,4-dimethylisonitroacetanilide by reaction with chloral hydrate and hydroxylamine using the method described in "Organic Synthe ses", Collective Volume I, page 327. 3,4-Dimethylisonitrosoacetanilide is cyclized with sulfuric acid , according to the method of Baker et al., Journal of Organic Chemistry, 17, 149 (1952) to obtain 4,5-dimethylisatin (melting point 217 ° -218 ° C).

4,5-Dimethylisatin is converted to 4,5-dimethyl-2-oxindole, melting point 245 ° 247,5 ° C by treatment with hydrazine hydrate and then with sodium ethyl acetate in ethanol according to the procedure of Preparation 7.

Similarly, 5,6-dimethylisatin is converted to 5,6-dimethyl-2-oxindole, melting point 196.5 ° -198 ° C by treatment with hydrazine hydrate and then with sodium ethylate in ethanol, according to the preparation procedure 7.

Receipt 9.

4-Chloro-2-oxindole and 6-chloro-2-oxindole.

A.Z. Chloro-isonitrosoacetanilide. To a stirred solution of 113.23 g / 0.686 mol / chloral hydrate in 2 l of water was added 419 g / 2.95 mol / sodium sulfate, then a solution obtained from 89.25 g / 0.70 mol / 3 chloroaniline, 62 ml of concentrated hydrochloric acid and 500 ml of water. A thick precipitate forms. A stirring solution of 165 g (2.23 mol / hydroxylamine) in 500 ml of water was added to the reaction mixture. Stirring was continued and the reaction was slowly warmed and maintained at 60 and 75 ° C for about 6 hours, during which time an additional 1 liter of water was added to facilitate stirring. The reaction mixture was cooled and the precipitate was removed by filtration. The wet solid was dried to give 136.1 g

3-chloro-isonitrosoacetanilide.

B. 4-Chlorisatin and 6-Chlorisatin. To 775 ml of concentrated sulfuric acid, pre-warmed to 70 ° C, 136 g of 3-chloroisonitrosoacetanilide was stirred at such a speed that the reaction medium was maintained at a temperature between 75 ° -85 ° C. When all the solid was added, the reaction mixture was warmed to 90 ° C for another 30 minutes. The reaction mixture was cooled and poured slowly over about 2 liters of ice with stirring. If necessary, additional ice is added to keep the temperature below room temperature. An orange-red precipitate formed, which was collected by filtration, washed with water and dried. The resulting solid was slurried with 2 l of water and converted into solution by the addition of about 700 ml of sodium hydroxide. The solution was filtered and the 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 it was extracted

The 4-chloroisatin is then acidified to pH 0 using concentrated hydrochloric acid to form an additional precipitate. It was recovered by filtration 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 a substance melting at 258 ° -259 ° C.

The crude 6-chloroisatin was recrystallized from acetic acid to give a substance melting at 261 ° -262 ° C.

B. 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 was filtered off to give 43.5 g

4-chloro-3-hydrazono-2-oxindole, mp 235 ° -236 ° C.

To a stirred solution of 22 g of sodium in 450 ml of anhydrous ethanol was added in portions

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 concentrated to a resin, which was dissolved in 400 ml of water and decolorized with activated carbon. The resulting solution was poured onto a mixture of 1 liter of water and 45 ml of concentrated hydrochloric acid. The precipitate formed was collected by filtration, dried and recrystallized from ethanol to give 22.4 g of 4-chloro-2-oxindole, melting point 216 ^at -218 * C (decomposition).

G. 6-Chloro-2-oxindole. Reaction of 36.2 g of 6-chloroisatin with hydrazine hydrate followed by sodium ethylate in ethanol according to point B yields 14.2 g of 6-chloro-2-oxindole with a melting point of 196 ° -198 ° C.

Receipt 10.

5,6-Difluoro-2-oxindole. From the reaction of

3,4-difluoroaniline with chloral hydrate and hydroxylamine, followed by cyclization with sulfuric acid as described in Parts A and B of Preparation 9, yields 5,6-difluoroisatin which is reacted with hydrazine hydrate, then with sodium methylate in ethanol, in the manner described in Preparation 7. The title compound is formed, melting point 187 ° Ί90 ^ο Ο.

Receipt 11.

5-Fluoro-2-oxindole. To a stirred solution of 11.1 g (0.1 mol) of 4-fluoroaniline in 200 ml of dichloromethane, a solution of 10.8 g (0.1 mol) of t-butyl hypochlorite in 25 ml of dichloromethane was added dropwise at -60 ° to -65 ° C. Stirring was continued for a further 10 min at -60 ° C to -65 ° C and then a solution of 13.4 g (0.1 mol / ethyl-2- (methylthio) acetate in 25 ml of dichloromethane was added dropwise. Stirring was continued at -60 ° C for another hour and then a solution of 11.1 g (0.11 mol / triethylamine in 25 ml of dichloromethane) was added dropwise at 60 ° to -65 ° C. The cooling bath was removed and 100 ml of water was added when the reaction mixture was warmed to room temperature. The phases were separated and the organic phase was washed with saturated sodium chloride solution, dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was dissolved in 350 ml of diethyl ether to which 40 ml of 2 hydrochloric acid was added. This mixture was stirred at room temperature overnight. The phases were separated and the ether phase was washed first with water and then with saturated sodium chloride. The dried (Na ₂ SO ₄ ) ether phase was evaporated in vacuo to give 17 g of an orange-brown solid, which was converted to powder by isopropyl ether. The solid was recrystallized from ethanol to give 5.58 g of 5-fluoro-

3-methylthio-2-oxindole, melting point 151.5 ° -152.5 ° C.

Analysis: Calculated for C ₉ H ₄ ONFS: 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-Methylthio-2-oxindole (986 mg, 5.0 mmol) was added to 2 teaspoons of rhenium-nickel in 50 ml of pure ethanol and then the reaction mixture was heated by reflux. at 2 o'clock. The catalysis of the fertilizer was removed by decantation and washed with pure ethanol. The combined ethanol solutions were evaporated in vacuo and the residue was dissolved in dichloromethane. The dichloromethane solution was dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 475 mg of 5-fluoro-2-oxindole with a melting point of 121 ° -134 ° C.

In a similar fashion, 4-trifluoromethylaniline was reacted with t-butyl hypochloride, ethyl (2-methylthio) acetate and triethylamine, followed by reduction of rhenium-nickel-derived 3-thiomethyl-5-trifluoromethyl-2oxindole to give 5-trifluoromethyl -Oxindole, mp 189.5 ° -190.5 ° C.

Receipt 12.

5-Methoxy-2-oxindole.

5- Methoxy-2-oxindole is prepared from 4methoxyaniline in a manner similar to the procedure from Preparation 11, except for the initial chlorination, which is carried out using chlorine gas in dichloromethane in place of t-butyl hypochlorite. The title product melts at 150.5 ° -151.5 ° C.

Receipt 13.

6- Chloro-5-fluoro-2-oxindole. 24.0 g (0.165 mol) were added to the stirring mixture of 130 ml of toluene.

3-chloro-4-fluoroaniline and 13.5 ml (0.166 mol) of pyridine. The resulting solution was cooled to about 0 &lt; 0 &gt; C and then 13.2 ml (0.166 mol) of 2-chloroacetyl chloride was added. The reaction mixture was stirred at room temperature for 5 hours and then extracted twice with 100 ml of 1N hydrochloric acid followed by 100 ml of saturated sodium chloride solution. The toluene solution formed was dried using magnesium sulfate and then concentrated in vacuo to afford

32.6 g (88% yield) of b1- (2-chloro-acetyl) -3-chloro-

4-fluoroaniline.

26.63 g of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline sample are mixed with 64 g of anhydrous aluminum chloride and the mixture is warmed to 210 ° 230 ° 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 min 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. Washing the column followed by evaporation of the fractions gave 11.7 g of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline and 3.0 g

6-chloro-5-fluoro-2-oxindole. The latter was recrystallized from toluene to give 1.70 g (7% yield) of the title compound, mp 196 ° -206 ° C. Analysis by NMR spectroscopy showed that the product was contaminated with 4-chloro-5-fluoro-2-oxindole.

Receipt 14.

6-Fluoro-5-methyl-2-oxindole. A mixture of 11.62 g (57.6 mmol) of N- (2-chloroacetyl) -3-fluoro-44-methylaniline and 30.6 g (229.5 mmol) of anhydrous aluminum chloride was warmed to 210 ° 220 ° C. After 4 hours, the reaction mixture was cooled and then added to 1N hydrochloric acid and 50 ml of ice. A reddish-brown solid is formed which is collected by filtration and recrystallized from aqueous ethanol. Three crystals weighing 4.49, 2.28 and 1.0 were obtained, respectively. The crystal weighing 1.0 g was subsequently recrystallized from water to give 280 mg of the title compound, mp 168.5 ° -171 ° C.

Receipt 15.

6-Bromo-2-oxindole. To 9.4 g of sodium hydride was added 195 ml of dimethyl sulfoxide, and then 22.37 ml of dimethyl malonate was added dropwise. At the end of the addition, the mixture was warmed to 100 ° C and maintained at this temperature for 40 minutes. In this step, 25 g of 1,4-dibromo-2-nitrobenzene were added in one step. The reaction mixture was maintained at 100 ° C for 4 hours 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 a solution of ammonium chloride, water and saturated sodium chloride. The dried (MgSO ₄ ) solution 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 17.4 g of dimethyl 2- (4-bromo-2nitrophenyl) 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 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 was extracted with additional 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 on silica gel as an adsorbent and ethyl acetate-hexane as the eluent. It turns out

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

To a solution of 7.4 g of methyl 2- (4-bromo-nitrophenyl) acetate in 75 ml of acetic acid was added 6.1 g of iron powder. The reaction mixture was placed in an oil bath at 100 ° C. After 1 hour, the solvent was removed by evaporation in vacuo and the residue was dissolved in 250 ml of ethyl acetate. The solution was filtered, washed with saturated sodium chloride solution, dried with sodium sulfate, decolorized with activated charcoal and evaporated in vacuo. 5.3 g of 6-bromo-2-oxindole are obtained as a white crystalline solid, mp 213 ° -214 ° C.

Similarly, from starting material

1,4,5-trichloro-2-nitrobenzene, 5.6 dichloro-2-oxindole is obtained, with a melting point of 209 ° 210 ° C.

Receipt 16.

6-Phenyl-2-oxindole. To 3.46 g (0.072 mol) of sodium hydride was added 50 ml of dimethyl sulfoxide, then a solution of 8.2 ml (0.072 mol) of dimethyl malonate in 10 ml of dimethyl sulfoxide was added dropwise with stirring. Stirring was continued for 1 hour and then a solution of 10 g (0.036 mol) of 4-bromo-3-nitrodiphenyl in 50 ml of dimethylsulfoxide was added. The reaction mixture was warmed to 100 ° C for 1 hour, cooled and poured onto an ice water mixture containing 5 g of ammonium chloride. The mixture thus obtained is extracted with ethyl acetate and the extracts are washed with sodium chloride solution and dried using magnesium sulfate. It is evaporated in vacuo to yield an oil which is chromatographed using silica gel and then recrystallized from methanol to give 6 g of dimethyl 2- (3-nitro-4-diphenyl) malonate, melting point 82 ° -83 ° C.

Part (5 g) of the nitro compound obtained above 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 kg / cm ² to give the corresponding amine. The latter compound was refluxed for 16 hours and then the product was recovered by evaporation of the solvent and recrystallization from methanol to give 1.1 ethyl 6-phenyl-2-oxindole-1-carboxylate, melting point 115 ° -117 ° C.

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

Receipt 17.

5-Acetyl-2-oxindole. To 95 ml of sulfur carbon was added 27 g (0.202 mol) of aluminum chloride and, with stirring, a solution of 3 ml (0.042 mol / acetyl chloride) in 5 ml of sulfur carbon was added dropwise. Stirring was continued for 5 min and then 4.4 g (0.033 mol / 2-oxindole) was added. The resulting mixture was heated at reflux for 4 hours and cooled. The carbon sulphide is recovered by decantation, and the residue is turned to dust under water and recovered by filtration. Drying gave 3.2 g of the title compound, mp 225 ° 227 ° C.

Reaction of 2-oxindole with benzoyl chloride and 2-tenoyl chloride in the presence of aluminum chloride according to the procedure described above yields the following compounds:

5-benzoyl-2-oxindole, melting point 203 ° -205 ° C (from CH3OH) and 5- (2-tenoyl) -2-oxindole, melting point 211 ° -213 ⁰ C (from CH ₃ C).

Receipt 18.

5-Bromo-2-oxindole can be obtained from bromination of 2-oxindole; see. Beckett et al., Tetrahedron, 24, 6093 (1968) and Sumpter et al., Journal of the American Chemical Society, 67, 1656 (1945).

5-n-Butyl-2-oxindole can be obtained from the reaction of 5-n-butyl isatin with hydrazine hydrate followed by sodium methoxide in ethanol according to the procedure of Preparation 7. 5-nB-Butylamine can be obtained from 4-butylaniline by treatment with chloral hydrate and hydroxylamine, followed by cyclization with sulfuric acid according to the procedure of parts A and B of preparation 9.

5-Ethoxy-2-oxindole can be obtained by converting 3-hydroxy-6-nitrotoluene to 3-ethoxy-6-nitro-toluene by standard methods (potassium carbonate and ethyl iodide in acetone). The following is the conversion of 3-ethoxy-6-nitrotoluene to 5-ethoxy-2-oxindole in the manner described by

Beckett et al., Tetrahedron, 24, 6093 (1968), for the conversion of 3-methoxy-6-nitrotoluene to

5-methoxy-2-oxindole. 5-n-Butoxy-2-oxindole can be similarly prepared, but replacing with n-butyl iodide by ethyl iodide.

5.6- Dimethoxy-2-oxindole can be obtained 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 US 3 882 236.

4- Thiomethyl-2-oxindole and 6-thiomethyl2-oxindole can be prepared by the method described in US 4 006 161. 5-n-Butylthio-2-oxindole can be prepared in a similar manner by 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, 38, 3350 (1973). 5,6Ethylenedioxy-2-oxindole can be prepared in an analogous manner.

6-Fluoro-2-oxindole can be prepared according to Provita et al., Collection of Czechoslovakian Chemical Communications, 44, 2108 (1979) and US 4 160 032.

6-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).

5- Nitro-2-oxindole can be prepared by the method of Sumpter et al., Journal of the American Chemical Society, 67, 499 (1945).

5-Cyclopropyl-2-oxindole and 5-cycloheptyl-2-oxindole can be prepared by reaction of 5-cyclopropylisatin and 5-cyclohyptilizatin, respectively, with hydrazine chlorate followed by sodium methoxide in ethanol according to the procedure of Preparation 7. -Lysatin can be obtained from, respectively, 4-cyclopropylaniline and 4-cyclohyptylaniline by treatment with hydrochloride and hydroxylamine, followed by cyclization with sulfuric acid according to parts A and B of Preparation 9.

Receipt 19.

3- (2-furyl) -2-oxindole. To a stirred solution of 5.5 g (0.24 mol / 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 15.7 g /0.12 mol / 2-furoyl chloride was added dropwise over 10-15 minutes. The ice bath was removed and 100 ml of ethanol was added and then the reaction mixture was added. is heated at reflux for 7 hours. The reaction mixture was kept overnight and then the solid was filtered off. The solid was added to 400 ml of water and the resulting mixture was acidified with concentrated hydrochloric acid. The mixture was cooled with ice and the solid was collected by filtration. The solid residue was recrystallized from 150 ml of acetic acid to give 8.3 g of yellow crystals, mp 209 ° -210 ° C (decomposition).

Analysis: Calculated for C ₁₃ H, O ₃ N: C, 68.72; H, 3.99; N, 6.17%. Found: C, 68.25; H, 4.05; N, 6.20%.

Receipt 20.

The reaction of 2-oxindole with the appropriate acid chloride by the method of Preparation 19 yields the following additional products: 3- (2-tenoyl) -2-oxindole, melting point 189 "-190 ° C, 17% yield; 3- (2- [2-thenoyl] acetyl) -2-oxindole, mp 191 ° -192.5 ° C, 38% yield; and 3- (2-phenoxyacetyl) -2-oxindole, mp 135 ° -136 ° C, 42% yield.

Receipt 21.

3- (3-Furoyl) -2-oxindole. To a stirred solution of 2.8 g (0.12 mol) in sodium in 200 ml of ethanol was added 13.3 g (0.10 mol) of 2-oxindole and 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 turned to a powder under 200 ml of ether and the solid was collected by filtration and discarded. The filtrate was evaporated in vacuo and the residue was taken up in isopropyl alcohol and extracted by filtration. The solid was suspended in 250 ml of water, then acidified with concentrated hydrochloric acid. This mixture was stirred to give a solid which was recovered by filtration. This last solid was recrystallized from acetic acid followed by acetonitrile to afford 705 mg of the title compound, mp 185 ° -186 ° C.

Analysis: Calculated for C _{t 3} H ₉ O ₃ N: C, 68.72; H, 3.99; N, 6.17%. Found: C, 68.72;

H, 4.14; N, 6.14%.

Receipt 22.

5-Amino-2-oxindole-1-carboxamide.

To a solution of 5.0 g of 5-nitro-2-oxindole-15 carboxamide in 110 ml of N, N-dimethylformamide was added 0.5 g of 10% palladium-carbon and the resulting mixture was shaken under a carbon atmosphere of an initial pressure of 5 kg / l. cm2 until carbon is no longer absorbed.

The catalyst was removed by filtration and then the filtrate was diluted with brine and extracted with ethyl acetate. The extracts were dried (MgSO ₄ ) and evaporated in vacuo to give a dark colored oil, 15 which solidified after being turned to powder under water. 3.0 g of the title compound are obtained as a yellow solid, mp 189 ° -191 ° C.

Claims (15)

20 Claims 1. A 2-Oxindole-1-carboxamide compound of the formula: X Y 30 o = c-nh ₂ and the pharmaceutically acceptable basic salts thereof, wherein X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxy of 1 to 4 carbons, 1 to 4 carbon alkylthio, trifluoromethyl, 1 to 4 carbon alkylthionyl, 1 to 4 carbon alkyl, nitro, phenyl, 2 to 4 40 carbon alkanoyl, benzoyl, tenoyl, 2 to 4 carbonamido, benzo and N, N-dialkylsulfamoyl having 1 to 3 carbons in each of the foregoing alkyls; and Y is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, 45 alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxyl of 1 to 4 carbons, alkoctio of 1 to 4 carbons and trifluoromethyl; or X and Y when taken together are 4,5-, 5,6- or 2-furyl, 2-thienyl, (2-furyl) methyl and (2-thienyl) methyl. The method of claim 56, wherein X is 5-fluoro, Y is 6-chloro and R ¹ is benzyl. 15 A pharmaceutical composition for use as an analgesic and anti-inflammatory substance in a mammal comprising a pharmaceutically acceptable carrier and a specified amount of a 2-oxindole-1-carboxamide 20 compound for the analgesic response or treatment of an inflammatory disease according to claim 1, wherein the ratio of the weight of the pharmaceutically acceptable carrier to that of the 2-oxindole-1-carboxamide compound is in the range of 1: 4 to 4: 1. 59. A compound of formula Oh II x γ o = c-nh ₂ in which X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl having from 1 to 4 carbons, cycloalkyl having from 3 to 7 carbons, alkoxy with 1 to 4 carbons , alkylthio having from 1 to 4 carbons, trifluoromethyl, alkylthionyl having from 1 to 4 carbons, alkylsulfonyl having from 1 to 4 carbons, nitro, phenyl, alkanoyl having from 2 to 4 carbons, benzoyl, tenoyl, alkanamido with 2 to 4 carbons, benzamido N, N-dialkylsulfamoyl having 1 to 3 carbons in each of the 45 alkyls mentioned; and Y is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl having from 1 to 4 carbons, cycloalkyl having from 3 to 7 carbons, alkoxy having from 1 to 4 carbons, alkylthio having from 1 to 4 carbons and trifluoromethyl; or X and Y, when taken together, are a 4,5-, 5,6- or 6,7-methylenedioxy group or a 4,5-, 5,6- or 6,7-ethylenedioxy group; or X and Y, when taken together and attached to adjacent carbon atoms, form a divalent radical Z in which Z is selected from the group consisting of: CC C in which W is oxygen or sulfur. The compound of claim 59, wherein X and Y are selected from the group consisting of hydrogen, fluorine, bromine, chlorine, alkyl having from 1 to 4 carbons, alkoxy having from 1 to 4 carbons, alkylthio having from 1 to 4 carbons, nitro and trifluoromethyl; or X and Y when taken together are The compound of claim 1, wherein X and Y are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, nitro and trifluoromethyl; or X and Y, when taken together, are 4,5-, 5,6- or 6,7-methylenedioxy group; and R ¹ is selected from the group consisting of alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbons in said alkyl, phenoxyalkyl of 1 to 3 carbons in said alkyl, / substituted phenoxy / alkyl of 1 to 3 carbons in said alkyl, furyl, thienyl, pyrrolyl, alkylfuryl of 1 to 3 carbons in said alkyl, alkylthienyl of 1 to 3 carbons in said alkyl, furylalkyl of 1 to 3 carbons in said alkyl, thienylalkyl having 1 to 3 carbons in said alkyl and bicyclo (2.2.1) heptan-2-yl; wherein the substituent of said substituted phenyl group and said substituted phenoxy group is selected from the group consisting of fluorine, chlorine, bromine, alkyl of 1 to 4 carbons and alkoxy of 1 to 4 carbons. The compound of claim 2, wherein Y is hydrogen. 3 carbons in the specified alkyl (substituted phenoxy) alkyl with 1 to 3 carbons in the specified alkyl, (thiophenoxy) -alkyl with 1 to 3 carbons in the said alkyl, naphthyl, bicyclo [2.2.1] heptan2-yl, bicyclo [2.2.1 ] hept.-5-en-2-yl and - (CH ₂ / nQR ¹ ; wherein the substituted phenyl, (substituted phenyl) alkyl and (substituted phenoxy) alkyl substituent is selected from the group consisting of fluorine, chlorine, bromine, alkyl with 1 to 4,5-, 5,6- or 6,7-methylenedioxy group. A compound according to claim 60, The compound of claim 3, wherein X is selected from the group consisting of 5-chloro, 6-chloro, 5-fluoro, 6-fluoro, 5-trifluoromethyl and 6-trifluoromethyl. 4 carbons, 1 to 4 carbon alkoxy and 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, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo [c] furan and benzo [c] thiophene; and R ⁰ is hydrogen or alkyl having 1 to 3 carbons. 5 where 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. The compound of claim 61, wherein X is 5-chloro. 63. Compound according to A 5,6- or 6,7-methylenedioxy group; R ¹ is selected from the group consisting of alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbons in said alkyl, phenoxyalkyl of 1 to 3 carbons in said alkyl / substituted phenoxy / alkyl of 1 to 3 carbons in said alkyl, furyl, thienyl, pyrrolyl, alkylfuryl of 1 to 3 carbons in said alkyl, alkylthienyl of 1 to 3 carbons in said alkyl, furylalkyl of 1 to 3 carbons in said alkyl, thienylalkyl 1 to 3 carbons in said alkyl and bicyclo [2.2.1] heptan-2yl; wherein the substituent of the substituted phenyl group and the phenoxy group is selected from the group consisting of fluorine, chlorine, bromine, alkyl of 1 to 4 carbons and alkoxy of 1 to 4 carbons. The method of claim 21, wherein Y is hydrogen. The method of claim 22, wherein X is selected from the group consisting of 5-fluorine, A 5,6- or 6,7-methylenedioxy group or a 4,5-, 5,6 or 6,7-ethylenedioxy group; or X and Y, when taken together and attached to adjacent carbon atoms, form a bivalent radical Z, where Z is selected from the group consisting of C wherein W is oxygen or sulfur; R ¹ 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 said alkyl, (substituted phenyl) alkyl of 1 to 3 carbons in said alkyl, phenoxyalkyl of 1 to 3 carbons in said alkyl (substituted phenoxy) alkyl of 1 to 3 carbons in said alkyl, (thiophenoxy) alkyl of 1 to 3 carbons in said alkyl, naphthyl, bicyclo [ 2.2.1] heptan-2-yl, bicyclo [2.2.1] hept.-5-en2-yl and - / CH 2 / nQR °; wherein said substituted phenyl, (substituted phenyl) alkyl and (substituted phenoxy) alkyl is selected from the group consisting of fluorine, chlorine, bromine, 1 to 4 carbon alkyl, 1 to 4 carbon alkoxy and trifluoromethyl; η has a value of 0, 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, oxazole, isoxazole, 1,2,3 thiadiazole, 1,3,4-thiadiazole, 1, 2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo [c] furan and benzo [c] thiophene; and R 'is hydrogen or alkyl having from 1 to 3 carbons. The method of claim 20, wherein X and Y are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 hydrogen, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, nitro and trifluoromethyl; or X and Y when taken together are 4.5-, The compound of claim 4, wherein R ¹ is selected from the group consisting of benzyl, 2-furyl, 2-thienyl, (2-furyl) methyl and (2-thienyl) methyl. A 6,7-methylenedioxy group or a 4,5-, 5,6- or 6,7-ethylenedioxy group; or X and Y, when taken together and attached to adjacent carbon atoms, form a divalent radical Z, Z being selected from the group, such that 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 said alkyl, (substituted phenyl) alkyl with 1 to 3 carbons in said alkyl, phenoxyalkyl with 1 to 3 carbons in said alkyl, (substituted phenoxy) alkyl with 1 to 3 carbons in said alkyl, (thiophenoxy) alkyl with 1 to 3 carbons in said alkyl, naphthyl, bicyclo [ 2.2.1] heptan-2-yl, bicyclo [2.2.1] hept.-5-en-2-yl and - / CH 2 / nQR °; wherein the substituted phenyl, (substituted phenyl) alkyl and said substituted phenoxy / alkyl is selected from the group consisting of fluorine, chlorine, bromine, 1 to 4 carbon alkyl, 1 to 4 carbon alkoxy and trifluoromethyl; n is 0, 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, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4 thiadiazole, 1, 2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo [c] furan and benzo [c] thiophene; and R <0> is hydrogen or alkyl of 1 to 3 carbons. The method of claim 39, wherein X and Y are selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl having from 1 to 4 carbons, alkoxy having from 1 to 4 5 carbons, alkylthio having from 1 to 4 carbons, nitro and trifluoromethyl; or X and Y taken together are a 4,5-, 5,6- or 6,7-methylenedioxy group; R ¹ is selected from the group consisting of alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbons in said alkyl, phenoxyalkyl of 1 to 3 carbons in said alkyl, ( substituted phenoxy) alkyl of 1 to 3 carbons in said alkyl, furyl, thienyl, pyrrolyl, alkylfuryl of 1 to 3 carbons in said alkyl, alkylthienyl of 1 to 3 carbons in said alkyl, furylalkyl of 1 to 3 carbons in said alkyl, thienyl with 1 to 3 carbons in alkyl and bicyclo [2.2.1] heptan-2-yl; wherein the substituent of said substituted phenyl group and the substituted phenoxy group is selected from the group consisting of fluorine, chlorine, bromine, alkyl of 1 to 4 carbons and alkoxy of 1 to 4 carbons. 25 The method of claim 40, wherein Y is hydrogen. The method of claim 41, wherein X is selected from the group consisting of 5-chloro, 6-chloro, 5-fluoro, 6-fluoro, 5-trifluoromethyl 30 and 6-trifluoromethyl. The method of claim 42, wherein R ¹ is selected from the group consisting of 2-furyl, 2-thienyl and (2-thienyl) methyl. The method of claim 43, wherein 35 X is 5-chloro or 6-chloro. The method of claim 44, wherein X is 5-chloro and R ¹ is 2-furyl. The method of claim 44, wherein X is 5-chloro and R ¹ is 2-thienyl. 40 The method of claim 44, wherein X is 6-chloro and R ¹ is 2-thienyl. The method of claim 43, wherein X is 5-fluorine or 6-fluorine. The method of claim 48, wherein X is 5-fluoro and R ¹ is (2-thienyl) methyl. The method of claim 48, wherein X is 6-fluorine and R ¹ is benzyl. The method of claim 48, wherein X is 6-fluoro and R ¹ is 2-thienyl. 50 The method of claim 43, wherein X is 5-trifluoromethyl or 6-trifluoromethyl. The method of claim 52, wherein X is 5-trifluoromethyl and R ¹ is (2-thienyl) methyl. The method of claim 52, wherein X is 6-trifluoromethyl and R ¹ is 2-furyl. The method of claim 40, wherein X is selected from the group consisting of 5-chloro, 5-fluoro and Y is selected from the group consisting of 6-chloro and 6-fluoro. The method of claim 55, wherein 10 R ¹ is selected from the group consisting of benzyl, 6-fluoro, 5-chloro, 6-chloro, 5-trifluoromethyl, 6 trifluoromethyl. The method of claim 23, wherein R ¹ is selected from the group consisting of 2 furyl, 2-thienyl and (2-thienyl) methyl. The method of claim 24, wherein 5 X is 5-chloro or 6-chloro. The method of claim 25, wherein X is 5-chloro and R ¹ is 2-furyl. The method of claim 25, wherein X is 5-chloro and R ¹ is 2-thienyl. 10 The method of claim 25, wherein X is 6-chloro and R ¹ is 2-thienyl. The method of claim 24, wherein X is 5-fluorine or 6-fluorine. The method of claim 29, wherein 15 X is 5-fluoro and R ¹ is (2-thienyl) methyl. The method of claim 29, wherein X is 6-fluorine and R ¹ is benzyl. The method of claim 29, wherein X is 6-fluoro and R ¹ is 2-thienyl. 20 The method of claim 24, wherein X is 5-trifluoromethyl or 6-trifluoromethyl. The method of claim 33, wherein X is 5-trifluoromethyl and R ¹ is (2-thienyl) methyl. The method of claim 33, wherein 25 X is 6-trifluoromethyl and R 'is 2-furyl. The method of claim 21, 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. 30 The method of claim 36, wherein R ¹ is selected from the group consisting of benzyl, 2-furyl, 2-thienyl, (2-furyl) methyl and (2-thienyl) methyl. The method of claim 37, wherein X is 5-fluorine, Y is 6-chloro and R ¹ is benzyl. 39. A method of treating mammalian inflammatory diseases comprising administering a specified amount of a 2-oxindole-1-carboxamide compound of formula o = c-nh ₂ or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl having from 1 to 4 carbons, cycloalkyl having from 3 to 7 carbons, alkoxy with 1 to 4 carbons, trifluoromethyl, alkylthionyl with 1 to 4 carbons, alkylsulfonyl with 1 to 4 carbons, nitro, phenyl , 2- to 4-carbon alkanoyl, benzoyl, tenoyl, 2 to 4-carbonamido, benzamido and N, N- ialkilsulfamoil having 1 to 3 carbons in each of said alkyls; and Y is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl having from 1 to 4 carbons, cycloalkyl having from 3 to 7 carbons, alkoxy having from 1 to 4 carbons, alkylthio having from 1 to 4 carbons and trifluoromethyl; or X and Y when taken together are 4,5-, 5,6- or The compound of claim 5, wherein X is 5-chloro or 6-chloro. A 6,7-methylenedioxy group or 4,5-, 5,6- or 6,750 ethylenedioxy group; or X and Y, when taken together and when attached to adjacent carbon atoms, form a bivalent radical31 Z, where Z is selected from the group consisting of where W is oxygen or sulfur; 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 said alkyl, (substituted phenyl) alkyl with 1 to 3 carbons in said alkyl, phenoxyalkyl having 1 to The compound of claim 6, wherein X is 5-chloro and R ¹ is 2-furyl. The compound of claim 6, wherein X is 5-chloro and R * is 2-thienyl. The compound of claim 6, wherein X is 6-chloro and R ¹ is 2-thienyl. 10 claim 61, wherein X is 5-trifluoromethyl. The compound of claim 59, 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. The compound of claim 5, wherein X is 5-fluorine or 6-fluorine. The compound of claim 10, wherein X is 5-fluoro and R ¹ is (2-thienyl) methyl. The compound of claim 10, wherein X is 6-fluoro and R 'is benzyl. The compound of claim 10, wherein X is 6-fluoro and R ¹ is 2-thienyl. The compound of claim 5, wherein X is 5-trifluoromethyl or 6-trifluoromethyl. The compound of claim 14, wherein X is 5-trifluoromethyl and R 'is (2-thienyl) methyl. The compound of claim 14, wherein X is 6-trifluoromethyl and R ¹ is 2-furyl. The compound of claim 2, 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. The compound of claim 17, wherein R ¹ is selected from the group consisting of benzyl, 2-furyl, 2-thienyl, (2-furyl) methyl and (2-thienyl) methyl. The compound of claim 18, wherein X is 5-fluoro, Y is 6-chloro and R ¹ is benzyl. 20. A method of extracting an analgesic response in a mammal comprising administering a specified amount of a 2-oxindole-1-carboxamide compound of formula Oh I o = c-nh ₂ for eliciting an analgesic response in said mammals or a pharmaceutically acceptable salt thereof; wherein X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl having from 1 to 4 carbons, cycloalkyl having from 3 to 7 carbons, alkoxy having from 1 to 4 carbons, alkylthio having from 1 to 4 carbons, trifluoromethyl, alkylthionyl of 1 to 4 carbons, alkylsulfonyl of 1 to 4 carbons, nitro, phenyl, alkanoyl of 2 to 4 carbons, benzoyl, tenoyl, alkanamido having 2 to 4 carbons, benzamido and N, dialkylsulfonyl 3 carbons in each of the foregoing alkyls; and Y is selected from the group consisting of 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 and trifluoromethyl; or X and Y when taken together are 4.5-, The compound of claim 64, wherein X is 5-fluoro and Y is 6-chloro.