CZ418791A3 - 2-oxo-indole-1-carboxamides substituted in position 3 as analgesic and antiphlogistic agents - Google Patents

Description

Technical field j f · 8 6 T 0

The invention relates to new chemical compounds which are valuable as pharmaceutical compositions useful _ ^f * in healthcare. In particular, the novel compounds of the present invention are 2-oxindole-1-carboxamide derivatives which are further substituted at the 3-position with an acyl group. These novel compounds are inhibitors of both the cyclooxygenase enzyme (CO) and the lipoxygenase enzyme (LO).

The compounds of the present invention are useful as analgesic agents in mammals, especially humans, and can be used to alleviate pain or to completely eliminate pain, such as pain conditions following surgery or trauma.

In addition to the use of the compounds of the invention in acute cases for the treatment of pain conditions, the compounds of the invention may be used in chronic diseases in mammals, particularly humans, to alleviate the symptoms of chronic diseases such as inflammatory diseases and pain associated with rheumatoid arthritis and osteoarthritis.

SUMMARY OF THE INVENTION

The present invention provides novel 2-oxindole-1-carboxamide compounds of formula (I)

and pharmaceutically acceptable salt salts thereof, wherein:

X is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio carbon atoms, C 1 -C 4 alkylsulfonyl, nitro, phenyl, C 2 -C 4 alkanoyl, benzoyl, thenoyl, C 2 -C 4 alkanamide, benzamide and Ν, Ν-dialkylsulfamoyl having 1 to 3 carbon atoms in each of said alkyl portions, and

Y is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, C 1 alkylthio up to 4 carbon atoms and a trifluoroethyl group, or X and Y, when combined, are 4,5-methylenedioxy, 5,6-methylenedioxy or

6,7-methylenedioxy or 4,5-ethylenedioxy,

5,6-ethylenedioxy or 6,7-ethylenedioxy, or X and Y when attached and attached to adjacent carbon atoms form a bivalent Z moiety, wherein Z moiety is selected from the group consisting of Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵

in which W represents an oxygen or sulfur atom,

R ¹ is a substituent selected from the group consisting of alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkenyl of 4 to 7 carbon atoms, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbon atoms said alkyl moiety, (substituted phenyl) alkyl having 1 to 3 carbon atoms in said alkyl moiety, phenoxyalkyl having 1 to 3 carbon atoms in said alkyl moiety, (substituted phenoxy) alkyl having 1 to 3 carbon atoms in the alkyl moiety said alkyl moiety, (thiophenoxy) alkyl having 1 to 3 carbon atoms in said alkyl moiety, naphthyl, bicyclo [2.2.1] theptan-2-yl, bicyclo [2.2.1] hept-5-en-2-yl and - ( CH _O) -qr in which is a substituent on said substituted phenyl, said (substituted phenyl) alkyl and V indicate n (substituted phenoxy) alkyl is a radical selected from the group consisting of fluorine, chlorine, bromine, C1-C4alkyl, C1-C4alkoxy and trifluoromethyl, and is zero, 1 or 2,

Q is a divalent 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, benz (b) furan and benzo (b) thiophene, and

R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

The compounds of formula I are effective as analgesic agents as well as agents useful in the treatment of inflammatory diseases such as arthritis. Accordingly, the present invention also provides a method of inducing an analgesic response in a mammal, particularly a human, a method of treating inflammatory diseases in a mammal, particularly a human, and pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.

A first group of preferred compounds of the present invention includes those compounds of formula (I) wherein Y is hydrogen and X is selected from the group consisting of 5-chloro, 6-chloro,

5-fluoro, 6-fluoro, 5-trifluoromethyl and the like

Within the scope of this first group of preferred compounds of the present invention, particularly preferred are compounds of the above formula (I), wherein R is benzyl, 2-furyl,

2-thienyl, (2-furyl) methyl or (2-thienyl) methyl.

However, a second group of preferred compounds of the present invention includes those compounds of formula I wherein X is selected from 5-chloro and 5-fluoro and Y is selected from 6-chloro and 6-fluoro. Within the aforementioned second group of preferred compounds of the present invention are compounds of formula I wherein R 1 is benzyl, 2-furyl, 2-thienyl, (2-furyl) methyl or (2-thienyl) methyl group.

With respect to the individual compounds, the following compounds are particularly preferred according to the invention:

5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide, i.e. a compound of formula I wherein X is 5-chloro,

Y is hydrogen and R is 2-thienyl,

5-Trifluoromethyl-3- (2- (2-thienyl) acetyl) -2-oxindole-1-carboxaid, i.e. a compound of formula I wherein X is 5-trifluoromethyl, Y is hydrogen, and R 6 is 2- (2-thienyl) acetyl,

6-fluoro-3- (2-phenylacetyl) -2-oxindole-1-carboxamide, i.e. a compound of formula I wherein X is 6-fluoro,

- 6 Y is a hydrogen atom and R ¹ is a benzyl group,

6-chloro-5-fluoro-3- (2-phenylacetyl) -2-oxindole-1-carboxamide, i.

5-fluoro, Y is 6-chloro and R 6 is benzyl,

5,6-difluoro-3- (2-furoyl) -2-oxindole-1-carboxamide, i.e. a compound of formula I wherein X is 5-fluoro,

Y is β-fluoro and R ¹ is a 2-furyl group, and

5,6-difluoro-3- (2-thenoyl) -2-oxindole-1-carboxamide, i.e. a compound of formula I wherein X is 5-fluoro,

Y is β-fluoro and R ¹ is a 2-thienyl group.

In addition, the present invention also relates to novel compounds of formula II

wherein X and Y are the same as defined above.

These compounds of formula (II) are intermediates in the preparation of compounds of formula (I) and are therefore useful as compounds for the preparation of compounds of formula (I).

The analgesic and anti-inflammatory compounds of the present invention are, as mentioned above, compounds of formula (I) in which the substituents X, Y and R 6 have been previously defined. That is, these compounds

7 of the present invention are 2-oxindole derivatives, which is a bicyclic amide of formula III

(III)

In particular, the analgesic and anti-inflammatory compounds of the present invention have a carboxaaid substituent group -C (= O) -NH _o at the 1-position and an acyloC η substituent group -G (= O) -R at the 3-position These substituents X and Y may be monovalent substituents as previously defined, or if they are on the adjacent carbon atom of the benzo ring, the substituents X and Y may be monovalent substituents as previously defined. ring to form aethylendioxyskupinu -OCHgO- or ethylenedioxy group, -OCH ₂ CH ₂ may further Moreover the substituents X and Y when they are attached to adjacent carbon atoms of the benzo ring of the 2-oxindole, form a divalent radical Z, so that the divalent Z together with the carbon atoms to which this divalent radical is attached form a linked carbocyclic or heterocyclic ring. Specific divalent groups for the substituent Z (i.e., the radicals Z ¹ to Z 2) have already been mentioned above. Thus, if Z represents Z ^1, X and Y together with the carbon atoms to which they are attached represent a linked cyclopentene ring, and if Z represents Z, then X and Y together with the carbon atoms to which they are attached represent a linked furan a ring or a thiophene ring. In addition, it should be noted that where:

- 7 4 5

Z represents a group Z or a group Z, and this group Z can be attached in any two ways and in any other manner. Thus, for example, when X and Y are attached to the 5th carbon atoa and the 6th carbon atoBU while forming a Z group, the formula I includes both of the above formulas:

In addition, this is very advantageous as can be appreciated by those skilled in the art that the analgesic and anti-inflammatory compounds of formula (I) wherein X, Y and R ¹ are the same as above. capable of enolization and therefore may exist in one or more tautomeric forms (enol forms). All such tautomeric (enol) forms of the compounds of formula (Ϊ) are within the scope of the present invention.

The compounds of formula (I) according to the invention are prepared by starting from the appropriate

2-oxindole-1-carboxaid compounds of formula II

(II) in which X and Y have the same meaning as above.

This process of the invention involves the attachment of the -C (= O) -r 1 substituent to the third position of the 2-oxindole core.

The -O (= O) - substituent is attached by reacting a compound of formula ( ¹¹⁾ with an activated carboxylic acid derivative of formula (-O) (= O) OH wherein P a is as defined above. This reaction is carried out by treatment of the above compound of formula II in an inert solvent with one alar equivalent, or an amount in an excess of an activated derivative of the compound of formula -0-O (= O) OH wherein R ^ is as defined above, in the presence one to four equivalents of the basic agent. The inert solvent used is a solvent in which:

At least one of the reactants used dissolves and the solvent does not react adversely with either the reactants or the product being prepared. However, polar aprotic solvents such as N, N-diaethyl formamide, Ν, dim-dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide are generally used in the practice of this invention. To activate the acid of formula

R ¹ -C (= O) OH is used by conventional methods. For example, acid halides such as acid chlorides, symmetrical acid anhydrides of the general formula ^-O (= O) -O-O (= O) ^{1 1,} and mixed acid anhydrides derived from blocked low molecular weight carboxylic acids of the general formula

Wherein R is a spatially bulky lower alkyl group, such as a t-butyl group that causes spatial blocking, and mixed carboxy-carbon anhydrides of the formula

R ¹ -C (= O) -OC (= O) -OR ⁴ wherein R is a low molecular weight alkyl group.

In addition, N -hydroxyimide esters (such as N-hydroxysucciniaid and N-hydroxyphthalide ester) are also used for these purposes;

11-4-nitrophenyl esters, thiel esters (such as thiolfenyl esters) and 2,4,5-trichlorophenyl esters, and silica of other similar compounds. In addition, when R 1 is a heteroaryl group (such as a furyl group), it is sometimes possible to use simple alkyl esters of formula

R ¹ -C (= O) -OR ⁴ wherein R is a low molecular weight alkyl group (such as an ethyl group) as activated acid derivatives of formula

R ¹ -C (= O) -OH used to attach a substituent

-0 (= 0) ^ ¹ where r! is as defined above, at the third position

2-Oxindole compounds of formula II.

To carry out the above reaction of a compound of formula II with an activated acid derivative of formula

A variety of basic agents can be used with R ¹ -C (= O) OH. However, tertiary amines such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine and 4- (N, N-dimethylamino) pyridine are preferred as basic agents.

The above reaction between a compound of formula (I ⁾ and an activated acid derivative of formula (I ⁾

R ¹ -G (= O) -OH, wherein R 1 is as defined above, is usually carried out at a temperature ranging from -10 ° C to 25 ° C. Typically, the reaction time ranges from 30 minutes to several hours. At the end of the reaction, the reaction medium is usually diluted with water and acidified, whereupon the reaction product thus obtained is separated by filtration. The reaction product thus obtained can be subjected to purification by any standard method, such as recrystallization.

The above 2-oxindole-1-carboxamide compounds of formula II can be prepared by two methods. Using the first procedure, 2- (2-ureidophenyl) acetic acid, a compound of formula IV, is cyclized by treatment with trifluoroacetic acid and trifluoroacetic acid anhydride according to the reaction:

CH ₂ -COOH nH-CO-NH ₂ wherein X and Y have the same meanings as described above In general, in this embodiment, the solution is

13 containing the compound of formula IV in trifluoroacetic acid treats trifluoroacetic anhydrides in an amount of 2 to 5 alar equivalents, and preferably about 3 alar equivalents, and the resulting solution is heated to the reflux temperature of the solvent used and refluxed. for a period of from 0.5 to 3 hours, usually about 1 hour. After removal of the solvents used, the compound of formula II is obtained. This compound of formula (II) can be purified using standard aetodes, such as recrystallization, and these methods can be employed if desired. Alternatively, the product may be used directly to prepare a compound of Formula I.

These compounds of formula IV may be prepared by basic hydrolysis of compounds of formula V

(IV) wherein X and Y are as defined above,

R is a lower alkyl group or a lower cyclic alkyl group. Particularly preferred groups for R 2 are isobutyl and cyclohexyl.

This basic hydrolysis of compounds of formula 2

Wherein R is isobutyl or

- a cyclohexyl group, is conveniently carried out by treating a compound of formula V with a dilute aqueous solution of sodium hydroxide used in large excess (such as 0.5 N to 3.0 N solution, usually 1.0 N solution is used), which is carried out at about room temperature or at a slightly higher temperature.

This reaction usually proceeds relatively quickly and, most commonly, is completed in about 1 to 2 hours. The reaction mixture is then acidified (with hydrochloric acid) and the product is collected by filtration or solvent extraction using a volatile, a water-immiscible solvent (organic solvent). The compound of formula (IV) may then be purified, for example, by recrystallization, if necessary, or may be used directly for cyclization to the 2-oxindole-1-carboxamide of formula (II).

The above compounds of formula V may be prepared by reacting a suitable 2-oxindole of formula VI with an acyl isocyanate of formula

R ² -C (= O) -N = C = O

(VI)

Conversion of a compound of Formula VI to a compound

The compounds of formula (V) may be prepared by heating the two reactants in substantially equimolar portions at the reflux temperature of the solvent used, toluene, for several hours, such as 2 hours.

According to a second embodiment of the process for preparing said 2-oxindole-1-carboxamide compound of formula (II), the 2-oxindole compound of formula (VI) is reacted with chlorosulfonylisocyanate to give N-chlorosulfonyl-2-oxindole-1-carboxamide compound of formula (VII) as an intermediate of this reaction, followed by removal of said chlorosulfonyl group by hydrolysis. The entire reaction process can be illustrated as follows:

X

(VI) v

X y j

O = C-NH-SO ₂ -C ₁ (VII)

(II)

In the first step of the reaction process, a suitable 2-oxindole compound of formula VI with chlorosulfonyl isocyanate is reacted in a reaction medium inert to the reaction, i.e. a solvent which is unreactive is used. with the chlorosulfonyl isocyanate, nor with the N-chlorosulfonyl-2-oxindole-1-carboxamide product of formula (VII). The above solvent is not necessarily the solvent by which the reagents used are completely dissolved. Representative solvents include dialkyl ethers such as diethyl ether, cyclic ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, xylene and toluene, chlorinated hydrocarbons such as methylene chloride and chloroform, acetonitrile; and mixtures of the above solvents.

This reaction is generally carried out at a temperature in the range of about ambient temperature (about 20 ° C) to the reflux temperature of the solvent used. Typically, temperatures in the range of about 25 ° C to about 110 ° G are used at this stage,

17 represents a preferred range of temperatures used. However, temperatures below 20 ° C, such as temperatures up to -70 ° C, can be used if desired. However, in practice, temperatures below 0 ° C are not used and should be avoided because of the yield of the desired product and hence for economic reasons.

The aforementioned 2-oxindole compound of formula (VI) and chlorosulfonyl isocyanate are typically reacted in an aolar ratio ranging from equimolar to 30% excess chlorosulfonyl isocyanate, i.e., from 1: 1 to 1: 1. It has been shown that a larger excess of chlorosulfonyl isocyanate does not provide any advantages and therefore does not use a larger ratio for economic reasons.

The chlorosulfonyl derivatives of formula (VII) thus obtained can be isolated, if necessary, or can be converted without isolation directly in the same reaction vessel as they were produced to the compound of formula (II). The isolation of this intermediate, i.e. the chlorosulfonyl compounds of formula VII, can be carried out according to methods well known in the art for those skilled in the art, for example by separating the compounds by filtration or by evaporation of the solvent.

Hydrolysis of the chlorosulfonyl derivatives of formula (VII) may be accomplished by treating compounds of formula (VII) either with or without separation of the reaction mixture from the reaction mixture with water, an aqueous acid solution or an aqueous solution of the base. Preferably

Water or an aqueous acid solution is used alone as the hydrolytic agent, which is the most common embodiment and can be carried out even when the hydrolysis process is carried out in a two-phase system. The rate of hydrolysis should be maintained at a sufficiently high level to overcome the solubility problem of the individual reactants. However, from a large industrial scale, the use of water alone is far more economical than other hydrolytic methods.

By using an aqueous solution of an organic acid as the hydrolytic agent, the problem associated with the formation of a two-phase reaction system can in some cases be overcome. This effect is often achieved when an aqueous acetic acid solution is used. The amount of acid used is not important and essential in carrying out this hydrolysis step. This amount may range from an amount less than an equimolar amount to an amount greater than an equimolar amount. Nor is the concentration of the acid used significant. In general, when an aqueous acid solution is used to carry out the hydrolysis step, about 0.1 moles of acid per mole of compound of formula (VII) to about 3 moles of acid per mole of compound of formula (VII) is used. For ease of handling, the concentration of acid used is generally from about 1 molar to about 6 molar.

An aqueous acid solution is often used when an intermediate of formula (VII) is isolated and a single-phase hydrolysis mixture is desired. Representative acids used for the hydrolysis include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, citric acid, and benzoic acid.

Alternatively, compounds of Formula I may also be prepared by reacting a compound of Formula VIII with chlorosulfonyl isocyanate, followed by hydrolysis, as outlined in the following scheme:

(VIII)

1. ci-s ₂ -n = c = o

2. H 0

In (I), in this scheme X, Ϊ and R ¹ have the same meaning as above. The reaction of a compound of formula VIII with a chlorosulfonylisocyanate and a subsequent hydrolysis step can be carried out as described above to convert the 2-oxindole compound of formula VI to a chlorosulfonyl compound of formula VII, followed by hydrolysis of the compound to give the final compound of formula

- 20 of formula II.

Compounds of formula (VIII) used in the above process are prepared by attaching the -C (= O) -R 6 substituent to the third position of the desired 2-oxindole compound of formula (VI). The acylation reaction may be carried out by reacting a compound of formula VI with a derivative of a suitable acid of formula

Where R · ¹ · is as defined above, which is carried out in a lower alkanol solvent (such as ethanol) and in the presence of an alkali metal salt and a lower alkanol solvent (such as sodium ethoxide) using standard procedures. Typical acid derivatives of the general formula

R ¹ -C (= O) -0H where r ^{1 is} R ¹ ; as defined above, which can be used for the above reaction include acid chlorides, acid anhydrides of the general formula

= -C (= O) -O-O (= O) -1} ^{1 of the} general formula

R ¹ -C (= O) -OC (= O) -R ³ and of the general formula

R @ 1 --G (.dbd.O) - O - C (.dbd.O) --R @ ⁴ and the simple alkyl esters of the formula

-21 1 ^ -0 (= 0) -01 ^

Wherein R, R and R have the same meaning as previously described.

Usually, a small excess of the acid derivative of the general formula is used for the above reaction

R ¹ -C (= O) -OH wherein R ¹ is as defined above, and said alkoxide salt is typically present in an amount ranging from one molar equivalent to two molar equivalents based on the amount of the above acid derivative of the general formula

R ¹ -C (= O) -OH wherein R ¹ is as previously defined. The above reaction between a derivative of said acid of general formula

R ¹ -C (= O) -OH where R 1 is as defined above, and a compound of formula (VI) and usually with initial heating to a temperature in the range of 0 ° C to 25 ° C, but then usually said mixture to a temperature in the range of about 50 ° C to about 130 ° C, preferably about 80 ° C to complete the reaction. Under these conditions, the reaction time ranges from a few hours, such as two hours, to about a few days, such as two days, which is the most common practice. The reaction mixture is cooled, diluted with excess water and then acidified. The product, i.e., the compound of formula (VIII), can then be collected by filtration or isolated by standard solvent extraction.

Some of the above 2-oxindole-1-carboxamide compounds of formula (II) may be prepared in conventional manner from other compounds of formula (II) by converting a compound of formula (II) with one particular substituent X or one particular substituent Y to a compound of formula II with another substituent X or Y. For example, a compound of formula II wherein X is alkylsulfinyl or alkylsulfonyl may be prepared from a suitable compound of formula II wherein X is alkylthio by oxidation.

This oxidation can be carried out by standard methods, such as a process using a peroxycarboxylic acid, such as 3-chloroperbenzoic acid.

1.0 to 1.2 molar equivalents of the oxidizing agent are used to convert the alkylthio group to the alkylsulfinyl group, and 2.0 to 2.4 molar equivalents of the oxidizing agent are used to convert the alkylthio group to the alkylsulfonyl group. In addition, compounds of formula (II) wherein X is an alkanamide compound or a benzamide group may be prepared by acylating the corresponding compound wherein X is an amino group.

This can be accomplished by acylation with alkanoyl chloride or benzoyl chloride using standard methods.

The above 2-oxindole compounds of formula (VI) are prepared by methods known in the art or by methods analogous to these known methods. In this regard, reference may be made, for example, to: Rodd's Chemistry of Carbon Compounds, Second Edition, S. Coffey, Volume TV, Part A, Slsevier Scientific Publishing Company, 1973, pp. 448-450 J Gassman et al., Journal of Organic Chemistry, 42, 1340 (1977) by J Wright et al.

- 23 Journal of the American Chemical Society, 78, 221 (1956) \

Beckett et al., Tetrahedron, 24, 6093 (1968) and U.S. Patent Nos. 3,882,236, 4,006,161 and 4,160,032 J Walker, Journal of the American Chemical Sodium, 77, 3844 (1955). et al., Collection of Czechoslovakian Chemical Communications, 44, 2108 (1979). McEvoy et al., Journal of Organic Chemistry,

38, 3350 (1973), Simet, Journal of Organic Chemistry, 28, 35SO (1963), * Wieland et al., Chemische Berichte,

96, 253 (1963) J and references cited therein.

The compounds of the formula I according to the invention are acidic compounds and can therefore form basic salts. All of these basic salts are within the scope of the present invention, and these basic salts may be prepared by conventional methods known in the art. For example, the basic salts can be prepared in a simple manner by contacting the acidic compound with the basic compound, usually in a stoichiometric ratio, and either in aqueous medium, non-aqueous medium or partially aqueous medium. The base salts may be prepared by converting one salt into another salt together. The salts thus prepared may be separated either by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, as appropriate, or, in the case of aqueous solutions, by lyophilization. Typical salts of the compound of formula (1) which may be prepared are primary amine salts, secondary amine salts and tertiary amine salts, as well as alkali metal and alkaline earth metal salts. Of particular interest are sodium salts, potassium salts, ammonium salts, ethanolamine salts,

- 24 diethanolamine salts and triethanolamine salts.

Bases useful in the preparation of these compounds may be of both organic and inorganic type, and suitably used bases include ammonia, organic amine compounds, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, hydrides alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides and alkaline earth metal alkoxides. Representative examples of these bases include ammonia, primary amines such as n-propylamine, m-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucamine, and secondary amines such as diethylamine, diethanolamine. , N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine J further include tertiary amines such as triethylamine, triethanolamine, Ν, Ν-dimethylaniline, N-ethylpiperidine and N-methylmorpholine J further hydroxides such as sodium hydroxide alkoxides, such as sodium ethoxide and potassium methoxide; hydrides such as calcium hydride and sodium hydride; and carbonates such as potassium carbonate and sodium carbonate.

Also included are solvates such as hydrates such as hemihydrate and monohydrate derived from the analgesic and anti-inflammatory compounds of Formula I of the present invention.

The compounds of the formula I according to the invention exhibit analgesic activity. This analgesic activity can be demonstrated in mice by demonstrating the blockade of abdominal tension induced by the administration of 2-phenyl-1,4.

- 25 benzoquinone (PBQ). This method is based on the method of Siegmund et al., Proc. Soc. Exp. Biol. Med., 95, 729-731, (1957), and has been adjusted to high capacity (see Milné and Iwomey, Agents and Actions, 10, 31-37, 1980). The mice used in these tests were male Carworth, albinos CF-1, weighing from 18 to 20 grams. These mice were fasted overnight before drug administration and prior to testing.

In the above test, compounds of formula I were dissolved or suspended in a vehicle containing ethanol (5%), emulsion 620 (a mixture of fatty acid derived polyoxyethylene esters and used at 5%), and further saline (90%). This vehicle also served as a control. The doses administered corresponded to the logarithmic series (i.e. ... 0.32 milligrams / kilogram, 1.0 mg / kg,

3.2 mgAg, 10 mg / kg, 32 mg / kg ...) and these amounts were based on the weight of the salt of the compound of formula I when applicable for this purpose and not the acid. The route of administration was oral and the concentrations used were varied to achieve a constant dose of 10 milliliters / kilogram of body weight of the mouse. The above Milny and Towney method was used to determine efficacy. The test mice were treated with the compounds by oral administration of the compounds and administered PBQ (i.e., 2-phenyl-1,4-benzoquinone) in an amount of 2 µl of gram A 1 gram after one hour. was administered intraperitoneally. Individually, the mice were then immediately placed in a heated illuminated chamber, and five minutes after PBQ administration, the number of abdominal constrictions was recorded over the next five minutes. Rate

The analgesic protection or effect (% MPE) was evaluated by suppressing abdominal constriction relative to the number of constrictions in a concomitant control animal test run on the same day. For at least four of these assays (N - 5), a value corresponding to ΜΡΕ ^ θ was achieved in response to the drug dose, which represents the best dose assessment reducing abdominal constriction to 50% compared to control results.

The compounds of formula I also exhibit anti-inflammatory activity. The anti-inflammatory activity of this invention has been demonstrated in rat assays using a standard assay in which carrageenin was used to induce edema in the paws of rats (see Winter et al., Proc. _, Soc. E. P. Eiol. Med. 111, 544 (1963).

In this test, male albino rats weighing from 150 grams to 190 grams were numbered and weighed, and labeled on the right lateral maleol with an ink mark.

Each paw was then immersed in mercury at exactly the ink mark level. This mercury was in a glass cylinder and connected to a Statham pressure transducer. The output of this transducer was routed through a control unit to a microvolt meter. The volume of mercury that was displaced by the submerged paw was recorded. The active substances were administered by gavage. One hour after drug administration, edema formation was induced by injecting 0.05 ml of a 1% carrageenin solution into the planar tissue of the marked paw. Immediately thereafter the paw volume was measured after injection. The increase in paw volume 3 hours after injection of carrageenin was a response to inflammation in each individual case.

The analgesic activity of the compounds of the present invention allows the compounds to be used for acute administration when needed in all mammals, in such acute cases to relieve pain in such cases as postoperative and traumatic conditions. . In addition, the compounds of formula (I) may be used in chronic cases in mammals to alleviate the symptoms of chronic diseases such as inflammatory rheumatoid arthritis and to alleviate the pain conditions associated with osteoarthritis and other musculoskeletal disorders.

Where the compounds of formula (4) or pharmaceutically acceptable salts thereof are intended for use as either analgesic or anti-inflammatory agents, the compounds may be administered to mammals either alone or in combination with pharmaceutically acceptable carriers. or pharmaceutical compositions are prepared by known methods in the art. The compounds may be administered orally or parenterally. Parenteral administration includes intravenous administration, intramuscular administration, subcutaneous administration, and topical administration.

In the case of pharmaceutical compositions comprising as active compounds compounds of formula I according to the invention or pharmaceutically acceptable salts thereof, the weight ratio of carrier to active compound is usually in the range from 1: 4 to 4: 1, preferably According to the invention, this ratio ranges from 1: 2 to 2: 1. However, in each particular case, this ratio

The choice chosen for a particular purpose depends on such factors as the solubility of the active agent, the intended dose and the precise mode of administration.

For oral use, the compounds of formula (I) may be administered, for example, in the form of tablets or capsules, or may be administered in the form of an aqueous solution or suspension. In the case of tablets for oral use, carriers which can be used are those commonly used for similar purposes, such as lactose or corn starch, and lubricating agents such as magnesium stearate. For oral administration, when the compounds of the invention are formulated as tablets or capsules, suitable diluents are lactose and dried corn starch. Where aqueous suspensions are required for oral administration, the active compounds of the present invention may be combined with emulsifying or suspending agents. If desired, certain sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, sterile solutions containing the active compound of the present invention are usually prepared, the pH of the solution being adjusted appropriately and the solution combined with a buffer. In the case of intravenous administration, the total concentration of solutes is controlled to prepare an isotonic agent.

When a compound of formula (I) or a salt thereof is used for the treatment of humans, the daily dose will usually be within the limits specified by the attending physician. In addition, the dose is adjusted according to the age of the patient, the patient's body weight and the response of each individual patient to the compound being administered, as well as taking into account the intensity of the patient's symptoms and the efficacy of the individual compound being administered to the patient. However, in general, for acute pain-relieving administration, the effective dose in most cases ranges from about 0.01 to 0.5 grams as needed (such as every four to six hours) . For chronic administration, in most cases the effective dose is from 0.01 to about 1.0 grams per day, and preferably from 20 to 250 milligrams per day as a single dose or in the form of divided doses. On the other hand, it should be noted that there may be instances where doses outside the limits mentioned are to be used.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula (I) according to the invention and the processes for their preparation will now be illustrated by means of specific examples, which are not to be construed as limiting the scope of the invention. In addition to these examples, some of the processes for the preparation of the starting materials for the process of the invention, which are referred to as the preparation, will be described below.

Example 1

Preparation of 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamino.

When performing the procedure of this example was

- 30 stirred suspension containing 21.1 grams (corresponding to 0.1 mol) of 5-chloro-2-oxindole-1-carboxamide and 26.9 grams (corresponding to 0.22 mol) of 4- (N, N-dimethylamino) of pyridine in 200 ml of Ν, Ν-dimethylformamide cooled to an ice bath temperature, to which was added a solution containing 16.1 g (0.11 mol) of 2-thenoyl chloride in 50 ml of N, N-dimethylformamide, this addition was performed dropwise. The reaction mixture was further stirred for about 30 minutes and then poured into a mixture containing one liter of water and 75 ml of 3 N hydrochloric acid. The resulting reaction mixture was cooled in an ice bath while the resulting solid was collected by filtration. The solid was washed with water and recrystallized from 1800 ml of acetic acid to give 26.6 g of the title compound as crumbly yellow crystals.

230 ° C (dec.).

Analysis of a sample of the above title compound, which was obtained in a similar manner, showed the following elemental analysis results:

Analysis calculated for C ^ GHgClN ^O ^S: C = 52.42 Found: C = 52.22

H = 2.83 N - 8.74% H = 2.81 N = 8.53%.

Example 2

Reaction of the appropriate acid chloride

2-oxindole-1-carboxamide of the general formula

31 -CO-Cl, which was carried out essentially in the same manner as in Example 1, gave the following compounds, which are summarized in the form of the following table:

O

- 32 o β

φ

N

Φ i — t

What with

!with

what φ N p '>> XJ r — 4 O (0 O. β «: > o

Ή β

OJ CM

P ~ r — I

WHAT

P z-in O r-4 O

0.0

Φ

Eh

CO ú

CM C- <n r-1 what O 00 rd CM at\ ΡΊ CM ό n C- CM what r- r — f · » · * «* • fc · * «* «* σ \ 00 σ> 00 what Ολ C' 00 o> σ '

σ ' r-1 O ip> O 00 M " rd O ΓΊ cr \ O • M- rd O xt O σ ' · * «« · * * ► ·> «* «* • · * m CM m m m m CM

what O CT> Ό O σ> σ ' Ό m Xf- O what oo C- σ ' C- C- rd 1P> m Th rd m C- ip O P- IP LT \ IPi LP * tr \ ip ip ip ip

O P- σ ' Μ · Ρ- CM r — 1 O ip rd CM n Ρ- cq t- CM 00 C- CM «T Λ «* · » «* «Κ σ ' 00 σ ' 00 00 σ ' σ \ 00 cr> σ \

00 r-l what rd bunch what 00 <n Ό θ ' m σ ' 00 m rd σ ' '• φ rd σ ' · * · * · * * » «W * CM <n CM CM m m CM m m CM

OO r-1 σ ' m M · ip θ ' m what rd 00 rd M · 00 m CM ip rn CM lp cn ip CM m what LP VO 00 LP ip IP IP ip ip tP IP IP IP IP

IP ip • t # * σ ' CM O m O i-4 O CM m CM CM CM CM CM i — I 1 1 ό | 1 1 Ό Ό β IP LP Ό · * • M- O 00 r — 4 σ ' CM r-4 cp O O M · r-4 O (-1 m m xr m rd CM CM CM CM CM CM CM CM CM rd

rd jC -P Φ and rd C? Φ • id rd £ P Φ and x->. rd r — 4> s β P § rd & Φ • I — 1 rd > 5 » (—4 > ř £ Φ • rd H b t — 4 β rd β β r — 4 β β rd β >> p >> Φ P Φ P h Φ β 1 β • H 1 β • r4 1 β • rt 3 CM 3 β CM 3 β CM 3 β <p <W P X <P P X — z «Μ P »» 1 4 1 1 1 4 1 4 4 CM CM CM CM CM CM CM CM CM CM

β co

H

rd rd (-) r-4 rd O O O O O řq Pm lp Pn Λ 4 1 4 1 4 1 1 4 1 IP tr \ Ό Ό Ό IPs ir\ LP \ Ό Ό

6-F 2- (2-thienyl) methyl 214.4-217 56.61 3.48 8.80 55.97 3.52 8.65

Table 1 (continued)

8.17 O OS ir\ «3- · » C- O- Ol · * 00 SO OS · * t- Sat Ol [> X bunch Sí what C- X O C- · * · * · » «* · * Λ W 04 / OJ X X Ol IN G Φ N M- X Ol 0- OS Φ 00 C- oo SO X «* M · » (0 From O X Ol O and O ITS it it bunch bunch WHAT X X what X OJ what Sat Ol Os «H · » · * £ 5 what E- ο- 00 O- IR V_X 00 Sat χ 00 SO SO bunch O SO bunch · » · * ** «1 O r · W Ol OJ X Ol Ol Λ φ N P '>> S0 bunch ο- SO SO X O Ol WHAT χ Ol 00 CO O, · * Λ · » Λ 5 >> X O Ol X O O what LO bunch bunch bunch X G XOOI P - 00 O X O WHAT (0 P x-s Ό Ό Ό Ol X O LO LTS bunch l 1 X o * fc «* · * (XO bunch Ol X SO C- Φ X X From O P- EH Ol Ol Ol Ol X X of P Φ and r — 1 of X Φ X cb X > » X G Λ X G > 5 Φ P > » Φ G X »» G X 3 -G Ol 3 X! Al P P X 1 « 1 1 « Ol Ol Ol Ol OJ X X X X X fa fa fa fa fa O O O O O 1 1 1 1 X! bunch bunch bunch SO SO

X

G s

Ό

Td

O

CL,

XV>

O p

o o

>>

c <v

CG £

'CO >

WHAT

P (£ 0

Id

Φ

Whose

Ή

G

Ό5

P

XV

P o

X £ X (V

P

X> Ci

O.

G φ

XJ

O

X

WHAT

Φ

XS1

-WHAT

Φ

O

CU

O

X

W

O

Bye

O

P

N, N-dimethylformyl du

X 3 tsa G > Ό Φ · » OS Φ > o Ad X O 3 WHAT with AND) WHAT O G Ό N CD X X with O X what •O Whose •and >> O O Ad P G G G WHAT Λ Φ Φ O > p O Ό and X G Φ Φ what xo AND) > C0 > Ή O Φ 5> 3 Λ Ct

Ol x

- 34 Example 3

Preparation of 5-chloro-3-acetyl-2-oxindole-1-carboxamide

A stirred suspension containing 842 mg (equivalent to 4.0 mmol) of 5-chloro-2-oxindole-1-carboxamide and 1.08 g (equivalent to 8.8 mmol) of 4- (N, N) was stirred. -dimethylamino) pyridine in 15 ml of N, N-dimethylformamide was cooled to an ice bath temperature in an ice bath, followed by the addition of a solution containing 449 mg (equivalent to 4.4 mmol) of acetic anhydride in 5 ml Ν, Ν dimethylformamide is added dropwise. The reaction mixture was stirred for about 30 minutes and then poured into a mixture containing 75 ml of water and 3 ml of a 3 N hydrochloric acid solution. The resulting reaction mixture was cooled in an ice bath to give a solid which was collected by filtration. The solid was recrystallized from acetic acid to give 600 mg of friable crystals of light pink color.

Melting point : 237.5 ° C (dec.), Analysis for O ^ H ^ dN ^ O ^: calculated: found: C = 52.29 H = 3.59 N = 11.09% C = 52.08 H = 3.63 N = 11.04%. Example 4 Reactions of a suitable 2-oxindole-1-carboxamide with acti

a derivative of the corresponding carboxylic acid of the general formula

Where R ¹ is as defined above, using the same procedure as in Example 1 or Example 3, the following compounds were prepared:

- 36 CM

H

Ή

C

Ό5 • H

-P

O Ό Ό Ό Ό rM (X ΡΊ O <* -> Φ CM rM r-1 EM CM CM CM CM

bunch

KO O CM WHAT O CM 1 13 bunch * i — 1 O CM »» bunch in Ό 1 Ό «» 4 * !> C- O O O O O 00 pers O rH CM CM | —1 rH CM CM

> · «—4 fr — 4

MM> Χ «t-M

O

I mxXKXXXXXin

5-F H phenoxymethyl 201-202

- 37 r-4 <- * »o

O

M β

Ό5

-P

-P O n — 1 a

φ

6-i

Ό H rH 1 Ό Ο- ΚΟ H Ό bunch 00 H liA H OJ σ » 0J OJ 1 O rn 0J r- WHAT H KO OJ OJ IT Ό Ό Ό the IT \ 1 1 1 IO \ | 1 1 Ό the Ό · * «* · * O OJ cr> m r-4 the he O KO KO if\ the rn oo CF \ m 04 / OJ Xf r-4 KO 00 H OJ OJ σ> 0J O OJ OJ OJ OJ OJ OJ r-4 H H OJ OJ OJ H OJ OJ OJ OJ

AND

OJ

I §

-Bye

φ £

HI

OJ

r-4 H >> • OJ r * 4 rd H > » H and L H H > p H and X O \ l >> X > 5 O and Φ and and O C rM r-4 C Φ and C O X O and H Φ > p r4 r-4 Φ x O and and O C O El • rl C >> > 5 • rl O C O and H and H > 5 X O 3 X X X H and H O EC O EC O -P «Ρ WHOSE P • P -P EC O El what >> η > 5 • rl 1 1 1 Φ Φ 1 >> 0 > p • rl O H O X> OJ OJ OJ and and OJ O • rl O

4-chlorophenyl

Table 2 (continued) m m

33 X O O O O 1 1 1 KO X KO KO

X X rn m

1 H O 1 H O 1 (* · 1 rM rd IN m X ? Pm 1 X O O 1 X O ? H O 1 he fáj O 1 Et 1 the the ia the KO the O the the KO the the

- 38 i - I

Z — x

O o

M

G '£ 0 + ->

<0

-P o

rH

CU

Φ

E-t

LP IP

rd LO WHAT CM O 00 O\ tP rH CM O i-1 OL CM Ό Ό 1 rd Ό CM »—1 CM CM r — l 1

IP T r-1 LP LO CM LP WHAT WHAT Ό LP LO 1 LP 00 Ό IP CM IP r * d CM T3 LP CM Ό M- CM 1 O\ O 1 CM σ \ 1 M · r — l »» O O 1 what what LO ω I ^- 1 CM CM i — 1 CM rH CM CM CM CM i — 1 r — l CM CM r4 CM

rd rd rd > 5 > p • CM: CM ⁵ CM CM 1 1 1 C CJ C eo Cu WHAT -P -P -P cx cu cu ω H Φ Φ

ŘS Ž ι-S ŘS

H £ 2 rd rd > » r — II CM * • p Φ and r — II • CM r-tl CM * i — 1 -P r — 1 £ C2 • x-x • • & Φ Φ > p rd Φ CM i — 1 CM CM Z — S rd CU O £ φ <μ <P H i-1> to, £ \ l r — l >> kl >> ti Φ Ct > p CU O Φ O CU O i — 1 C? cu £ 2 rd O £ 2 O r-l • H r — l O I “1 > 5 > p Φ O O > » rd H P C4 41 £ 2 42 Cl 42 £ 2 N <P rM H £ 2 £> £ 2 Φ cu >> P ^ 5 Cu >> -P C2 Λ4 4- » C O and O O 1 O O O Φ Φ 1 >> >> Φ Φ 1 WHAT • p CM • rl OJ • rd and £ 3 rd O O and <μ • H £ 3 ’- £ 3 • rl £ 3

Table 2 (continued)

m m m m m m m m X X X Pq f-M fx < Pm Pm Pm t-M Pu O O Pu O O 1 O O O O o O O cn cn cn 1 1 1 1 1 1 1 AND 1 1 1 LP iP LP IP IP LP LO LO LO p- LO LO

Ό

LA

what Ό O CM O O O no 00 what 1 Ό Ό CCI i-1 r ~ t

Ό Ό IA Ό Ό Ό ia τ> Ό Lf \ 1 t ~ - 00 the O r4 C- the H CM CM rH oc rH O O CM σ \ σ \ O ro ro M · no CM CM CM CM CM H r-H CM CM CM CM CM CM CM

Table 2 (continued)

EG

ro rO Π0 ro bH Mm EC EC EC EC O O O O O 1 1 1 1 »» WHAT IA what ICO WHAT

EC EC EC

no nO no no no no no pM Em Em EC EC W EC O O O O O O O 1 1 1 1 1 1 1 the LA IA IA LA M ·

no

EC r-H r * 4 rH rH H O O 1 LA O | O 1 O | O 1 what IA 1 ď \ 1

4-Cl H cyclohexyl 188

Ό

T3 tfk Ό Ό Ό Ό kO lfk M CM kO O O O Lfk CM - «t- O m CM rH -st i — 1 CM Okay CM CM CM CM CM CM CM CM CM CM i — 1 CM CM 1 1 »» 1 1 1 1 1 Ό 1 1 1 m CM WHAT O lfk WHAT Okay Okay -st- r-l m O m 4- CM r-l O i — 1 00 Okay CM CM CM CM <M CM CM CM CM CM r * H i — 1 CM CM

r — I> 5

AND

CM »

§

4->

cu

Φ r-H r ~ I P3 i — I x:

+ ->

Φ CM J3 r-l r-t • CM | —1 £ r-l rH X.I £ Φ <1-1 Φ <H £ r-t > 5 5? r4 O ω Sm Φ CU φ > p r — 1 • H O O XS r-l O X3 rH X3 r * t rH r-l rH O > 5 ř-l O > 5 .3 >> + -> x: > p X3 >? r-l X3 ft r-l x: O 1 O C O C -P O -P »» • H CM 1 Φ 1 Φ Φ what >> φ CM X> -M- 4-1 4 * O 9 • rt O and

Table 2 (continued)

33 33

33

33

<O m 33 n r-> 33 33 33 <n O 33 r — 1 33 O O 33 i — 1 O O 33 oo oq O O O O O O O O O O 1 1 »» 1 1 1 1 1 1 1 1 -M- kO Lfk kO lfk lfk tfk lfk • sr lfk lfk lfk

5-Cl H cyclopentyl 215-214 d

- 41 r-1

O o

H c

MJ

-P what + ->

O

H eu φ

E-t

Ό

bunch I.E ur \ I.E I.E CM * » cr> bunch O- m CM <O m CJx C- QO CM m CM cn O 00 cn H CM CM CM 1 CM CM H CM t I.E 1 I.E I.E i.e I.E 1 1 m 1 1 1 1 00 C- VO 00 M3 CM M · CM O CM st- 00 VO 00 CM CM O H H H cn CM CM m O what m H CM CM CM CM CM CM CM CM CM CM CM H CM

Ό

H r-t and* CM CM 1 1 C C WHAT WHAT • P -P Cu CU Φ Φ

rH H HI • CM HI • CM rH >> 23 H of r — 1> » H r-1 rn £ • CM • CM -P <D • P 0) +> > 5 -P • P -P l L x — p rd x— \ H C -P C Φ Φ \ | rH rH B? Φ eu 3 φ CU rH and > p O H O H H & C Φ H £ C Φ O O O tí X 24 24 e < Φ H řn Φ • rl H H H H Φ O Pn >> η <n 23 N 23 B? 24 24 24 <P C O O ¢ 1 - * -P 53 -P 53 > p > p 1 Φ H H AND 1 1 Φ 1 1 Φ O O O rď 23 23 CM H CM 23 rM CM

Table 2 (continued) rc w 33 rn m

ί'η cn CM CM 33 33 Pm H H H H P »u H O O O O rd O O O O O frl O CQ O WITH & O O O 1 1 1 AND AND 1 1 1 1 1 1 1 1 LC \ MD VO tr \ if\ m LC \ <o M0 ir\ LTS LC \ M3

5-CH 2 H 4-chlorophenyl 247-248

'P c

Ό3

P (0 + ->)

O ip fa

Φ

EH

TO TO in OG rp rP

OJ OJ IT IT IT IT IT IT IT | 1 LO IT it lo it T3 LO IT LO LT \ IT IT it •to •to •to •to •to "to M Γ- lo 00 what rd m * 4 " WHAT Γ- O O r- m CD r — t Η rn rn OJ m From r-d m ΓΟ CD r — J OJ n- i — t 04 / 04 / From OJ OJ CM OJ CM OJ OJ CD OJ OJ CD CD

rH rd rd rP rd > 1 > » í> p > S > p x: X X X A * < -P • P -P -P -P Φ Φ Φ Φ and and and and and χ — X x — p. x — p X— \ x— \ rP rd rd rd rd rd rd r-J >> (-1 i — 1 iP >> & £? £ Š> rd > » ? rd >? O O C C rP H r-i f — j Φ φ Φ Φ C Φ YEAH AND-, Φ Φ > p > » >> • P • P • P • P Φ • P Φ Cm ÍH • P * P P ř < ÍH X X 40 x • P 40 • rd > p > 5 X3 Xí 3 3 3 3 • P -P -P -P 40 -P x fa and • P -P «Μ <P «Η 1 1 1 1 P J • P 1 1 1 1 AND 1 m m <n <n 1 OJ 1 CD CD m m m m m m - ' CD OJ

Table 2 (continued) i — I i — 1 o t t ockooooooococookoooclolooo to <n m K

rP rd rp (P fa rd rp fa rP rd LO O fa O fa O O O fa O O O O O O 1 1 1 1 1 1 »» 1 1 1 1 1 1 1 LO LO LO LO LO LO LO it it LO LO LO Lf \ LO

M c

HIM

-p

CO + -> O i — I 3. Φ EH

Ό lp> CM CM Ό lp, | —1 CM O LP, CM Ό CM CM CM Ό CM CM Ό i — 1 CM CM Ό σ * r-1 CM Ό i — 1 Φ CM Ό • Φ CM Ό Ό • 1 1 1 »» 1 1 1 1 Ό in r-l Ht- φ · CJ \ i — 1 σ \ σ ' C- O m lp, r-l CM CM r-l • Φ CM m r-1 r—) • Φ m CM CM CM CM CM CM CM CM CM CM CM CM CM

r-l

AND

CM

AND

P

rH (H Φ £ r — 1 £ £ -p C r4 P Η » rM § Φ «Η £ Φ and • CM > p x X ~ X Sh -P OF-, • -P r-l O Φ r-l CM φ r-1 and pH \ l O and i — 1 ï φ X3 O O rH § tí Φ ÍH O r-l C? • rl • rl 3 > » r4 Φ • rl r-l 3 r-l > » Φ X3 Ό r-l >> • rl X Λί r-l > » X • rl -P 1 3 N -P > p 1-1 N -P x 1 M · • rl 4-1 C • p 1 O • rl C Φ X » CM 1 Φ 1 CM -r-l 3. Φ CM -P CM YEAH CM '-p Yeah -P X m

Table 2 (continued) x X 32

X X

X 32 x

LP, 32 O r * i 32 m 32 33 p Ό r — 1 32 32 32 O i — 1 Pm O O Pm O O O O O O O O O O O 1 1 1 1 1 1 1 1 1 »» 1 Ό X LP, in lp, lp, lp, LP, IP, tP, IP, LP,

6-C 1 H (3-thienyl) methyl 220.5 d

Η H 5-pyrimidinyl 238-240 d

5-Cl H-bicyclo [2.2.1] hept-2-en-5-yl 211.5 d

- 44 r ~ I

Ή c

OJ

P as + ->

O

H

CL

Φ fH po

Ό CM after cn f — 1 bunch E* O Γ- Η 1 xt M · σ \ rH bunch after Γ— i — 1 Ό bunch LfS H Ό CM O CM Ό ITS cn cn H 1 Ό bunch H CM Ό CM H CM bunch Ό 1 ITS 1 1 | 1 Ό bunch Ό 1X0 1 1 · » «* «* O cn CM cn m CM after O Sat γ- H what O r-4 i — 1 I ^- 1 cn S0 σ \ Γ- bunch O after ρο AFTER cn H H ΡΠ CM CM H H γΗ Η H CM CM CM CM H CM CM

trs l

and φ

t

CM

AND

-P

O.

<L <

Hl bunch

AND

G

Φ

AND

CM

I p

CL

Φ iX i — II r — I> 9 N G Φ X3 H ^ 9 XJ i — I> 9 N G Φ X) t— (> 9

H

N

C

Φ x>

H £

• • P P rH H H f — 1 P H CM CM H H r4 rH Φ cg > 9 > 9 > 9 > 9 2 > 9 • • > 9 > 9 > 9 > 9 and and N N N N and N CM CM Yippee x: x: x: G G G G C G G G 1 in P P P P O O Φ Φ Φ Φ O rH Φ Xl XI Φ φ φ φ 3 3 X> X> X> X3 3 Xi O O H H H H H H G G G G H C G H H > p > 9 > 9 <P O O O O «Ρ Φ O 14 C C G G • rt • rl H H H H • H • rt H > 9 > 9 Φ Φ Φ Φ G G x: x: x: X3 G x: x: O O «Η «Η Cp <P P P O O O O P P O • H • H 1 1 1 1 1 1 1 1 1 1 1 1 1 X) X) H H H H after after CM CM CM CM AFTER AFTER CM

Table 2 (continued) t — H * _ <Hr- »μγ ** HH pi-i h-m mm Um um lH r-H

AFTER what AFTER H H Pq H CP H H & M H H O O O O O O O O CP O O O 1 1 1 1 AND 1 1 1 1 1 1 1 1 SO ITS bunch (TS bunch Lf \ X » X tT \ tTS tro bunch X) SO

- 45 o

M C Ό Ό Ό Ό T3 Ό 'B X n 00 ^ í · LO O X 00 Γ- X CM WHAT M · C- it p- Ch m OJ OJ m m ΟΟ st- m CM IO CM M- WHAT OJ X CM CM CM OJ CM X CM CM CM CM OJ CM X O __ | t 1 1 1 1 t Ό ¹ J 1 1 1 ¹ 1 1 r — 1 Q. OJ 10 CM CM σ \ IO X X IO Ch O st CM WHAT m ω sj · σ> m CM r-1 m m m 00 m m CM it CM M · E- < OJ χ CM CM CM CM CM CM X CM CM CM CM CM CM

rH> tsi c

Φ

X r4 f — i >>

rH x

* o

N

0)

X ι — I

O

X> p

X

X X X O O X r — 1 rH X X X X Φ Φ (0 Φ >> > » >> Φ and and X X and tSJ CJ N IS) and x — p x — x 1 < x> (3 C (3 (3 α r — 4 r4 m m X Φ Φ 0> Φ φ O X >? »» »» > a X X X X X 3 and $ 3 X X (3 P Im to P X Φ £ 3 Φ b 5> Φ O O O O O ¢ -1 X X Φ X • H X X X i — 1 i — t X X X X • rl > » X X X X X X > í X X X X X fd tSJ X X CJ X Φ Φ X (4 O O O O O X C AND X C 1 and and J £ 3 1 1 1 1 1 1 Φ CM 1 Φ CM 1 1 CM Φ M · τΓ m m X CM X it IO X

Table 2 (continued)

XXX x

X

O O O O O O O O O O O AT) O ω IO it it O he O O 33 X X m X X » X X X X X X X x · X X T O 1 O 1 Bye 1 O 1 Bye 1 O 1 <? Ϊ O 1 Bye 1 O 1 O 1 O 1 IO WHAT IO IO IO 33 to it it it IO X it it it

Melting point (° G)

C - ir \ m oo -

WHAT O rH rH WHAT t- IP » rH CM CM O rH iH tř- CM m tr \ CM WHAT CM H ^- ΓΟ H · CM O ΙΡ » O H * en CM CM CM CM CM CM CM CM σ » rH CM CM r-1 CM CM CM 1 1 1 t 1 1 1 1 1 1 1 1 1 5 1 ir" 00 O O H · IP> Í ~ O WHAT CM O O <J \ σ \ O H- CM CM tr » CM m CM • M- CM cr> CM O <4 · σ » H- m CM CM CM CM OJ CM CM CM rH CM CM rH rH CM CM

iH rH rH >> > 5 rH 1 1 O H- H- N rH 1 1 WHAT X £ rH O rH O O P N N 03 / OJ Φ <0 (H rH • H € • H • H rH rH >> > p rH iH »» tí tí > p > p tí tí řň řn m rH WHAT (0 tí tí P P tí tí 1 rH • H ‘R ~ t P P Φ Φ P P rH tí >> x: Λ Φ Φ > p > p Φ Φ Φ rH tí P P rH rH X X rH rH rH X! • H > p Φ »» | rH >> O O £ >> h rH P SW AND-, • H cn m > p tí C and C tí > p Φ P 3 x: • t tSJ Φ Φ φ Φ Φ Φ □ N t fo 1 P CM CM C fo fo fo fo fo fo fo C T CM t «« •with Φ 1 1 1 1 »» 1 1 Φ LC \ v_t CM CM rH rH tí rH rH rH rH CM CM CM tí

C '05>

O

KJ ffl o

and

rH rH rH rH O O O O 1 t t t tí WHAT WHAT X X co

t-H M h * 4 * PyH hH P-t t-fo fo

I fo fo

AND

MO

CM 5 5 rH

C8

EH m

iH fo rH rH fo 1 fo fo O fo fo O fo O fo fo O fo fo 1 AND 1 t t 1 1 1 1 1 AND 1 1 rubs tr \ li> tr \ ir\ what LTC WHAT Ό LP » WHAT vQ rubs tPe ir\

- 47

X 'CO

P

CO p

O

(”((X φ

Η

O P P

what n O SO CM p pers p P P CM SO n «« P P 'Φ CM n CM OS Γ- η rd σ \ rd O t— P Γ— O WHAT P CM t — 1 CM CM 1 CM CM 1 1 CM rd P CM CM 1 and 1 1 bunch 1 1 bunch bunch | 1 1 1 t "to •to ** SO Γ- OS 00 00 n CM Γ- O bunch M · SO bunch C- n ιο O P O n P η St n σ> Sat O P CM p CM CM CM CM CM CM CM CM rd P CM CM

P

X

N x

Φ

X

xf xf £ rd rd O O X P P > p X ts) N P φ Φ P X X (0 WHAT Φ G G Φ rd P p P p rd rd P P and p χ — s. P WITH > p X j3 with Ό (O Ό WHAT of of Bye X Bye X P > » > p O P xs p P P P P P p? X X 3 Φ P rd X X Φ Φ Φ φ x ω rd Φ P P X > p P P P P P P Φ • H > » • H ^ -t > » X X t 1 >? b E? ř? P X X ♦ H X 3 3 bunch bunch X X x Φ X p 3 P X Φ <P <P · » "to Φ Φ Φ P 1 1 p 1 1 CSJ CM «Η <H «X 1 CM 1 CM 1 »» CM CM •to •to 1 | 1 1 CM CM n P V-x rd rd P rd P P —- ’

Table 2 (continued)

Pq

AND

SO

CM CM CM n n n O O P O P rd Pq Pq 1 Pq Pq Pq 1 2 1 2 1 O J 2 1 O 1 Pq 1 Pq »» O 1 O Pq IN O 1 bunch bunch bunch bunch tes bunch SO sO bunch Sat SO sO Sat Sat

5-F 6-C 12 -tetrahydrofuryl 213.5-215

Ή

C '03 • P

-W O r — I O. Φ E-t θ '(—4

OJ

AND

SQ it C- Φ r — 4 IO Ol LO OJ Ol Ol OJ

i — 4

rM £ 3 rH O N 03 / 3 <P O with and 3 O H »» Ό bl >> it >> 03 / i — 4 1 x: • H O r — 1 03 / XI bl >> 3 • P φ x: 4- » O • H P Φ cn Λ φ P • H P and 1 1 1 Ol 'J' Ol t — 1

£

Φ

TO)

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Ή> <D -P + o

i — I tl ^Λ Λ.

Φ IX X 1 1 • H TjJ> P l / a Xl co

Si xsi

OJ c

Φ a

&

Ό • H 3 O r-I • C O r-I ž

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by $ 4 a

O O i — 4 AFTER ró σ ' what • t 3 Λ what Φ I.e- O pers 4-t 00 O r — I 1 i — l f — i 1 Ol

and

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O • g r — I r — I

Table 2 (continued)> 4k -, M ►— «l-M P * -4 I - **»

OJ

O r-1 r — 1 rH with AND O 1 it O | O | lf \ ir\

O a

O

Γ4

O

+ -> O O O O O and O AFTER AFTER 00 t— pers -P · * O M AFTER what M · > O O it it AFTER i — 1 AFTER r — 1 (—4 1 AND ♦ + of-* + with r — l Ό II II II II í >> II O after AFTER AFTER AFTER 3 AFTER Ol Ol OJ OJ Φ Ol O ^ fl fl fl , fl JC fl 3 IX IX X l \ -p Φ 1 1 1 1 1 1 ca m ý | and Ol ( t Ή and to, AND XI 1 xi 1 it Xi r — 4 OJ after LO it X

- 49 Example

The following compounds were prepared by reacting 2-thenoyl chloride and 2-furoyl chloride with 5,6-methylenedioxy-2-oxindole-1-carboxaaid using the same procedure as in Example 1:

5.6-methylenedioxy-3- (2-thenoyl) -2-oxindole-1-carboxamide J, m.p .: 215-217 ° C (dec.), And

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

Example 6

In this example, the appropriate acid chloride was formed by reaction of a suitable acid chloride

with the required 2-oxindole-1-carboxamide using the same procedure as in Example 1, the following compounds listed in Table 3 were prepared.

R '

O = C-NH 1

- 50 Table 3

X Y R ¹ 5-n-OC ₄ H _g H 2-fůry1 5-OC ₂ H ₅ H 2-thienyl 7-C1 H (2-thienyl) methyl 6-F H n-hexyl 5-F H cycloheptyl 5-C1 H 2-fluorophenyl 5-n-C1-4 H 2-furyl _5-CH3 H 4-bromophenyl δ-SCH ₃ H 3-n-butylphenyl 5-CF ₃ H 3-methoxyphenyl 5-n-SC ₄ H ₉ H 4-isobutoxyphenyl _5-CH3 6-CH " j 3- (phenyl) propyl δ-OCH ₃ H 3- (phenoxy) propyl 6-SCH. H 2-thienyl 5-NC ₂ H (3-fluorophenoxy) methyl H H cyclobut-1-en-1-yl 5-C1 H cyclohep-1-en-1-yl 6-F H (thiophenoxy) methyl 5-CF ₃ H 3- (thiophenoxy) propyl H H 1-imidazolyl 5-C1 6-C1 2-tetrahydropyranyl 6-N-SC ₄ H ₉ H (4-chlorophenoxy) methyl 5-OCH ₃ 6-OCH ₃ (2-thienyl) methyl

Table 3 (continuation) X Y R ¹ 5-C1 H (2-furyl) methyl 5-F 6-C1 (4-bromophenoxy) methyl 5-F 6-C1 2-thrahydro-thiopyranes1 6-C1 H (2-methylthiophenoxy) methyl 6-Br H (4-thienylphenoxy) methyl 6-N-SC ₄ H ₉ H 2-thienyl 7-C1 H (3-methylphenoxy) methyl 4-SCH ₃ H (4-butoxyphenoxy) methyl 5-NO ₂ H 3-furyl _{4-CH3 5-CH3} 3-thienyl 6-SCH ₃ H 3-methyl-2-furyl 7-Cl H 5-propyl-2-furyl 5-CH _{(CH3) 2} H 3-methyl-2-thienyl 5-F 6-C1 5-propyl-2-thienyl 5-NO ₂ H 3- (3-thienyl) propyl 5-OC ₂ H ₅ H 1- (2-Furyl) ethyl 7-C1 H 3- (2-furyl) propyl 6-CH ₃ SO H 2-thienyl 6-n-C ^H ^SO SO H 2-furyl 4-CH ₃ SO ₂ H 3-fluorophenyl 6-nC ₄ H _g SO ₂ H 2-thiazolyl 5-NO ₂ H 2- (3-thienyl) ethyl --C H H _K 6 5 H 4-chlorophenyl

- 52 Table 3 (continued)

X Y R ¹ H 5-Br 2- (2-tolyl) ethyl 5-CH 2 CO H 4-trifluoromethylphenyl 6-n-Cy 4 CO H 4-isothiazolyl 5-Cl H 1-Naphthyl 5-C ₆ H ₅ CO H 1,2,3-thi adiazol-4-yl 5-CH-3 SCO ¹ 4 H 3- (3-chlorophenyl) propyl 6-CF ₃ H (4-thiazolyl) methyl 6-F H 1,2,5-thiadiazol-3-yl 5-CH-CONH H 1-methyl-1-phenylethyl 5-Cl 6-Cl 5-methyl-4-isoxazolyl 5- (CH ₃ ) ₂ CH-CONH H 2- (4-isopropylphenyl) ethyl 5 C ₆ H ₅ CONH H 2-thienyl 5-CH. 6-OH 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-C1 4-pyridyl 6-C1 H 3-tetrahydrothienyl H H 5-pyrimidyl 5-CH-, 6-F 2-pyrazinyl H H 2-n-propyl-4-thiazolyl 5-Br H 2-oxazolyl H H 3-isoxazolyl H at if 1,3,4-thiadiazol-2-yl

5- (2-thenoyl)

EXAMPLE 7 In carrying out the process of this example, the appropriate acid chloride was reacted with the desired acid chloride

The following compounds listed in Table 4 were prepared by 2-oxindole-1-carboxamide using the procedure of Example 1.

Y

- 54 Table 4

and X and Y R 4-CH ₂ -GH ₂ -CH ₂ -5 2-furyl 5-GH 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 on the left side of the formula represents the point of attachment of this end of the formula to the 2-oxindole core and the number on the right side of the formula indicates the point of attachment of this end of the formula to the 2-oxindole core.

- 55 Example 8

5-Chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide.

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

Then, a portion (673.5 g, 2.1 mol) of the title compound was added to 13 liters of methanol, and the mixture was heated to reflux. 136 g (2.22 mol) of ethanolamine were then added to the refluxing mixture. The resulting solution was then

After cooling to 50 ° C, 65 grams of carbon was added to decolorize the solution, and the solution was again heated to reflux and maintained at this temperature for 1 hour. The hot solution was filtered through supercelite (a type of diatomaceous earth) and the filtrate was cooled to 40 ° C. To the filtrate was added 392 mL of concentrated hydrochloric acid slowly over 30 minutes. The mixture was cooled to 20-23 ° C and stirred for 30 minutes to give a solid which was collected by filtration and washed with methanol. The solid was dried to give 589 grams of the title compound.

Melting point: 229-231.5 ° C (dec.).

Example 9

5-Chloro-3- (2-thenoyl) 2-oxindole-1-carboxamide ethanolamine salt.

In this example, the suspension was 321 mg (1.0 mmol).

5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide in 25-30 ml of diisopropyl alcohol was heated until boiling, and then a solution containing 67 mg of ethanolamine in 1 ml of diisopropyl alcohol was added. The mixture was heated to boiling to reduce the volume of the solution to 12-13 milliliters and then allowed to cool. The solid was collected and collected by filtration to give 255

57 mg of the desired salt as yellow crystals of the title compound of this example.

Melting point: 165.5 - 167 ° C (slight decomposition).

Analysis for C- ^H ^ClNjO ^S:

calculated: C = 50.32 H = 4.22 N = 11.00% found: C = 50.52 H = 4.44 N = 10.88%,

Example

Preparation of 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide sodium salt.

part

To a stirred suspension of 20 grams (62.4 mmol) of 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide in 400 mL of methanol was added 4.14 mL (corresponding to 68.6 mmol) of ethanolamine was added dropwise at room temperature. A clear solution was obtained, and a solution containing 6.74 g (124.7 mmol) of sodium methoxide in methanol was added. The resulting mixture was heated to about 90 ° C and then cooled and stirred overnight. The solid was collected by filtration and dried at room temperature and high vacuum overnight to give 18.12 g of crude product. The crude product was recrystallized from methanol-isopropanol to give 1.73 g of the first crop and 10.36 g of the second crop of 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide sodium monohydrate. Both fractions had a melting point ranging from

- 58 236 ° C to 238 ° C.

Analysis Calculated for . H., 0 Found (first share) Found (second part) 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 crop was then dried again. There was thus obtained 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide anhydrous sodium salt.

M.p .: 237-238 ° C.

Analysis Calcd. For C- ^HgClN ^O ^Sa Found for re-dried first: fraction C 48.92 48.23 H 2.64 2.81 N 8.15 7.89

- 59 Part B.

In the process of this embodiment, a stirred suspension containing 20 grams (corresponding to &lt; / RTI &gt;

62.4 mmol of 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide in 400 ml of methanol was added dropwise 4.14 ml (corresponding to 68.6 mmol) of ethanolamine dropwise. at room temperature.

A clear solution was obtained, and 6.74 g of sodium methoxide powder was added thereto, and the mixture was stirred overnight. The solid was collected by filtration and dried under high vacuum for overnight.

How was he? prepared:; 5-Chloro-3- (2-thenoyl) 2-oxindole-1-carboxamide hemihydrate.

Mp .: 238-239 ° C.

Analysis Calculated for C ₁₄ H ₈ ClN ₂ O ₃ SNa. O, 5H ₂ O Found C 47.67 47.72 H 2.85 2.73 N 7.94 7.70

Example 11

Preparation of 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide potassium salt.

Example 10, Part B was repeated except that a solution containing 7.00 grams of potassium hydroxide in methanol was used instead of powdered sodium methoxide. The potassium salt monohydrate was prepared by 5-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide.

Melting point: 214-216 ° C.

Analysis Calculated for ^C 14 ^H 8 ^ClN 2 ^O 3 ^SK · ^K 2 ° Found C 44.30 44.29 H 2.93 2.67 N 7.41 7.22

Example 12

Preparation of 5-chloro-3- (2-thenoyl) -2-oxindole 1-carboxamide ammonium salt.

The above salt was prepared essentially as described in Example 10, Part 3 using a solution of ammonia in methanol instead of powdered sodium methoxide. In this way, the anhydrous salt mentioned in the title of this example was prepared.

Melting point: 203-204 ° C.

-61Analysis

Calcd. For ^C 14 ^H 8 ^O 1 ^N 2 ^SO 3 · ^NH 4

Found

C 49.64 49.75 H 3.86 3.53 N 12.41 12.20

Example 13

Preparation of 2-oxindole-1-carboxamide.

To a solution containing 194 mg (1.0 mmol) of 2- (2-ureidophenyl) acetic acid in 4 mL of trifluoroacetic acid was added 630 mg (3.0 mmol) of acid anhydride. trifluoroacetic acid and the mixture was heated to reflux for about 1 hour. The reaction mixture was cooled and the solvent was removed by evaporation under vacuum. The residue was triturated with 5-8 mL of saturated sodium bicarbonate solution and the solid remaining in the solution was collected by filtration. The solid was recrystallized from ethanol to give 61 mg of the title compound as colorless needles.

Melting point: 179 - 180 ° G, slight decomposition I

- 62 Analysis calculated for: ^C 9 ^H 18 ^N 2 ° 2

C = 61.36 C = 61.40

H = 4.53 N = 15.91%

H = 4.80 N = 15.77%.

Example

Preparation of 5-chloro-2-oxindole-1-carboxamide.

The title compound was prepared by cyclization of 4.78 g (0.021 mol) of 2- (5-chloro-2-ureidophenyl) acetic acid using 8.0 g (0.063 mol) of trifluoroacetic anhydride in 75 g. ml of trifluoroacetic acid using the method described in Example 13 above, followed by recrystallization of the crude product from acetonitrile. 80 mg of the title compound are obtained.

Melting point : 211 ° C (with decomposition). Analysis for c ₉ h ₇ c ₂ d ₂ • calculated: C = 51.32 H = 3.35 N = 13.30 % found: C = 51.37 H = 3.37 N = 13.53 %. Example 15 Dec

The compounds were obtained by cyclization of 2- (2-ureidophenyl) acetic acid, prepared according to Preparation 3 below, with trifluoroacetic anhydride in the presence of trifluoroacetic acid, using the same procedure as described above. Procedure in Example 13:

6-chloro-2-oxindole-1-carboxamide,

5-fluoro-2-oxindole-1-carboxamide,

6-fluoro-2-oxindole-1-carboxamide,

5-Trifluoromethyl-2-oxindole-1-carboxamide a

6-Trifluoromethyl-2-oxindole-1-carboxamide.

Example 16

Preparation of 2-oxindole-1-carboxamide.

In this example, chlorosulfonyl isocyanate (1.20 g, corresponding to 8.4 mmol) was added to a mixture of 2-oxindole (0.94 g, corresponding to 7.1 mmol) in ether (30 ml). ml) and the reaction mixture was stirred at room temperature for 20 hours. The ether was removed under vacuum and the residue was treated with water (10 ml) and 1N hydrochloric acid solution (10 ml). Ethyl acetate (125 mL) was added to the reaction mixture, and the mixture was stirred for one hour. The ethyl acetate phase was separated, washed with 1 N hydrochloric acid solution (50 ml each), brine (2 x 100 ml) and dried (MgSO4). After concentration, 0.97 g (77% yield) of crude product was obtained. Recrystallization from ethanol gave 0.18 g of the title compound.

Melting point: 177-179 ° C.

Example

64 Process for preparing 2-oxindole-1-carboxamide.

To the stirred mixture containing 2-oxindole (5.86 g, 44.0 mmol) in dry toluene (160 mL) was added chlorosulfonyl isocyanate (7.47 g, 52.8 mmol). After the addition, hydrogen chloride evolution began immediately, the mixture was stirred under reflux at the reflux temperature of the solvent for 15 minutes and then cooled to room temperature. Water (50 ml) was added to the reaction mixture, which immediately liberated some hydrogen chloride, and stirred for 1.5 hours.

A solid was formed, which was collected by filtration and then dried (4.10 g solids). The filtrate was extracted with ethyl acetate (100 mL) and the extract was washed with brine (2 x 100 mL) and dried (MgSO4). Evaporation of the extract under reduced pressure gave 4.16 g of a solid. The solids were combined and recrystallized by dissolution in acetonitrile (200 mL) followed by concentration of the solution under reduced pressure to about 75 mL. A small amount of amorphous material was separated by filtration and the filtrate was decolorized and concentrated under reduced pressure to a volume of about 50 ml, and the filtrate was seeded. The title compound is obtained in the dark form

65 red crystals which were then filtered off and dried (yield 3.0 g, corresponding to 38%).

Example 18

Preparation of 6-fluoro-5-methyl-2-oxindole-1-carboxamide.

The title compound was prepared in the same manner as in Example 17, starting from 6-fluoro-5-methyl-2-oxindole (1.0 g, 6.0 mmol) and chlorosulfonyl isocyanate ( 1.03 g (7.3 mmol) which was dissolved in toluene (30 ml). To carry out the hydrolysis was

water used (5 ml). Yield: 0.58 grams (46%) Melting point : 200-203 ° C, Analysis for ^C 1O ^H 9 ^N 2 ° 2 ^F: calculated: C = 57.69 H = 4.36 N = 13.46 *, found: C = 57.02 H = 4.41 N = 12.85 %.

A sample of the chlorosulfonyl intermediate was taken prior to hydrolysis for mass spectral analysis to accurately determine:

^C 10 ^H 8 ^N 2 ° 4 ^SC1: 307.9848.

Example 19

Preparation process

Of 2-oxindole-1-carboxamide.

To a suspension of 2-oxindole (13.3 g, equivalent to 0.10 mol) in toluene (150 mL) was added chlorosulfonyl isocyanate (15.6 g, equivalent

66 (0.11 mol), the reaction mixture was heated on a steam bath for 10 minutes. After about three minutes a clear solution was formed, whereupon a precipitate immediately formed. The reaction mixture was cooled in an ice bath and kept on the ice bath for 30 minutes to give a solid which was then filtered and air dried.

The chlorosulfonyl intermediate was added to a 2: 1 mixture of acetic acid and water (240 mL) and the suspension was heated on a steam bath for 10 minutes. The reaction mixture was then cooled in an ice bath to give an off-white solid, which was filtered off and air dried. The mother liquor was concentrated to a slurry which was then filtered to give an additional 1.2 g of product. The solids were combined and recrystallized from about 250 mL of ethanol.

Yield: 11.48 g (65%).

Example 20

Preparation of substituted 2-oxindole-1-carboxamides.

The compounds in the following table were prepared by reacting the appropriate 2-oxindole with chlorosulfonyl isocyanate followed by hydrolysis and using the procedure described in Example 19.

LO co 44 r — 13 X CO o

C

Φ nj

Φ rP

WHAT

p · rd rd rn CD CM m tr \ "to · * · » "to m m m M rd rd rd rd

LO what O cl CD P m t- »» •to •to •to m m <n m

C*- it O rd O CD "to "to •to •to H rd rd LO LO ir\ Lf \ LO

O O O rn m m m •to "to "to "to m m m rd rd rd rd

LO LO IO XT <n <n m •to •to •to "to m <n m m

X

O 3 what Φ the -P '> p XJ r — 1 O WHAT and C > o

M tí

HIM

-P

WHAT

-P z->

o fp O and φ A

CD CD CM C- m m m LO •to •to •to <k rd rd rd LO bunch ITS bunch LO

Ό rd Ό LO CM CD CD rP CL O CD CD (P CD CD J r 1 *O 1 CM LO (P rP rd rP what rP CL O rd CD CL CD iP CM CM CM rP

m

X O Ip rp rd O O O O O fa 1 1 • t AND 1 LO LO p · IIL %O LO

Φ

N φ

Η

Λ

what O G Φ tSJ p '>> XJ rP O WHAT CX G > p <1 > O

Ή c

'WHAT

O M · what what Lf \ LO LO ITL · * λ • t "with rH m m r — l r — l H r4 r — l

ITL C- ΙΓ, O σ> LO IfL · » · * m ur \ LO CM

O P- CM what OL m ICL Ol • t «* what p- m p- LO \O

00 CM CM Ε- C- r — 1 ΠΊ n? r-T r4 rP rP H

OL CM CM P— 00 OL OL p- · * «* · * · » CM bunch ITL CM

σ \ & OL r — I r4 M " LO r — 1 • h · « · » '· * σ \ P M " xj- LO <O

Table 5 (continued) co

P χ-χ O rP o tx o Φ

H -

ITL Ό at\ Ό Tf CM ITL r — 1 CM r — l P CM CM C \ J CM

m ΠΊ X X H O O O 1 1 1 X ITL LO LO

m ΠΊ P> 4 X X r — l O O O O 1 1 1 1 ITL P ICL ITL

XU>

O

3 1—1 o X 3 i — 1 • H G P ♦ rl C O -P Φ -P O O £ • H r — l G> CG -P Φ O what 5 N M N Φ Φ Φ O O O WHAT WHAT WHAT tS) IS) N • rl Ή • rl i — 1 <—1 r — 1 WHAT WHAT 3 -P -P P ω WHAT 03 / ? » 4} > 5 G G 4! 42 42 Φ CU Φ G G G i — 1 CM m

- 69 Example 21

Preparation of 5,6-methylenedioxy-2-oxindole-1-carboxamide.

5,6-methylenedioxy-2-oxindole-1-carboxamide was prepared by reacting 5,6-methylenedioxy-2-oxindole with chlorosulfonyl isocyanate, followed by hydrolysis of the product, and the procedure was as in Example 19. Melting point The product obtained after recrystallization from acetic acid ranged from 237 to 238 ° C (with decomposition).

Example 22

The compounds in the following table were prepared by reacting the appropriate 2-oxindole with chlorosulfonyl isocyanate followed by hydrolysis of the product using the same procedure as in Example 19.

- 70 Table 6

X IN X 5-n-CC ₄ H ₅ H 5-oc ₂ h ₅ H 7-01 H 5-nC ₄ H _g H 5-n-SC ₄ H ₉ H 6-OCHj H 6-n-SC ₄ H _g H 5-CH (CH3) ₂ H 6-nC ₄ H _g SO H 6-n-C ^SO SO, H H 5-Br onC, H ₇ C0 f H 5- (CH ₃ ) ₂ CHCO ₃ NH H 5-Sat ₂ n (ch ₃ ) ₂ H 5-SO-N (n-C, H) 2 u 7 2 H

71 Example 23

The following table shows the tricyclic compounds which may be prepared by reacting in a suitable 2-oxindole with chlorosulfonyl isocyanate followed by hydrolysis of the product so obtained as in Example 19.

- 72 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 -

5-CH ₂ -CH ₂ -O-6 5-S-CH ₂ -CH ₂ -6 5-O 'CH = CH-6 5-S-CH = CH-6 · 5-CH = CH-S-6 <

in this column, the number on the left side of the formula represents the point of attachment of this end of the formula to the 2-oxindole core and the number on the right side of the formula indicates the point of attachment of this end of the formula to the 2-oxindole core.

73 Example 24

Preparation of 6-methylthio-2-oxindole-1-carboxamide.

In this example, chlorosulfonyl isocyanate (5.66 g, equivalent to 0.04 mol) was added to a suspension containing 6-methylthio-2-oxindole (6.0 g, equivalent to 0.033 mol) in acetonitrile (in 60 ml) was carried out at a temperature ranging from 5 to 10 ° C. The reaction mixture was stirred for a barley hour. Water (100 mL) was added to the reaction mixture, and the mixture was stirred for ten minutes. The aqueous solution was extracted with ethyl acetate (600 mL), washed with water and brine, dried (MgSO4) and concentrated in vacuo to give a gray solid. which was recrystallized from acetonitrile by sweat. The yield was 3.0 grams.

An additional 0.71 g of product was obtained from the mother liquor. The total yield was 3.71 g (corresponding to 50.6%).

Melting point: 176-179 ° C.

Example 25

Preparation process

5,6-dimethoxy-2-oxindole-1-carboxamide.

In the same manner as in Example 24, the title compound was prepared from 5,6-dimethoxy-2-oxindole (8.0 g, 0.042 mol), chlorosulfonyl isocyanate ( in an amount of 7.08 grams, corresponding to 0.05 mol);

74 acetonitrile (75 ml). The crude product obtained after evaporation of ethyl acetate was recrystallized from acetonitrile / acetic acid (1: 1).

Yield: 6.02 g (60%);

Melting point: 206.5 * 209 ⁰ ° C.

Example 26

Preparation process

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

To a suspension containing 6-trifluoromethyl-2-oxindole (8.0 grams, equivalent to 0.04 mol) in acetonitrile (80 mL), chlorosulfonyl isocyanate (6.65 grams) was added. (0.047 mol) and the reaction mixture was stirred for 45 minutes. Water (100 mL) was added to the reaction mixture, and the aqueous mixture was stirred for one hour. The precipitate was filtered and recrystallized from acetonitrile to give 0.92 g of the title product. Extract the filtrate from the above aqueous reaction mixture with ethyl acetate (300 mL) followed by drying the extract with MgSO4 and evaporating the extract under reduced pressure to give an additional portion of the product. of this example. Recrystallization from acetonitrile gave an additional 2.2 g of product.

Additional product (1.85 g) was obtained by combining the mother liquors from acetonitrile recrystallization and concentrating the combined portions under reduced pressure.

- 75 Total yield: 4.97 g (51%) J mp 207.5 ^{0 to} 210 ° C.

Example 27

The compounds listed in Table 8 below were prepared in the same manner as in Example 26 starting from the appropriate substituted 2-oxindole.

Table ϊ O = C-NH ₂ 8 X Y Melting point (° C) 4-SCH ₃ H 181-184 6-F H 191.5 - 194 6-Br H 205-203 5-NO ₂ H 201-205 5-F 6-C1 229-231 ¹ 5-F 6-F 198 - 201

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

Example

Preparation of 6-phenyl-2-oxindole-1-carboxamide.

6-phenyl-2-oxindole in a mixture of 100 ml of toluene and 25 ml of tetrahydrofuran was added to the mixture containing 4.5 g (corresponding to 21.5 mmol) of 6-phenyl-2-oxindole, with stirring at 5 ° C.

2.2 ml (25.8 mmol) of chlorosulfonyl isocyanate. Stirring was continued for 1 hour at 0-5 ° C and 100 ml water was added. The solid was separated and collected by filtration and then added to a mixture of 40 ml of glacial acetic acid and 80 ml of water.

The resulting reaction mixture was heated at 100 ° C for 1 hour, cooled and filtered. The residue was dried to give 3.1 g of the desired end product.

Melting point: 188-189 ° C.

Example 29

Preparation process

5-Benzoyl-2-oxindole-1-carboxamide.

A mixture of 10.1 g (42 mmol) of 5-benzoyl-2-oxindole, 4.4 ml (51 mmol of chlorosulfonylisocyanate) and 300 ml of tetrahydrofuran was stirred at room temperature for one hour. 6 hours and then the solvent was removed by evaporation under vacuum. The residue was added to 150 ml of glacial acetic acid a

77,300 ml of water and the resulting reaction mixture was then heated at reflux for 2 hours. The reaction mixture was cooled and the supernatant was separated by decantation. The remaining gum was triturated with acetonitrile to give a solid which was collected by filtration and recrystallized from n-propanol / acetonitrile 1: 1. 4.1 g of the title compound are obtained in the form of a solid.

Melting point: 210-211 ° C.

Example 30

The compounds were prepared by reacting 5-acetyl-2-oxindole and 5- (2-thenoyl) 2-oxindole with chlorosulfonyl isocyanate followed by hydrolysis of the obtained product with an aqueous acetic acid solution, essentially the same as the procedure. according to example 29:

5-acetyl-2-oxindole-1-carboxamide:

yield 34%, melting point: 225 ° C (dec.) (from CH 3 CN), a

5- (2-thenoyl) -2-oxindole-1-carboxamide:

yield 51%, melting point: 200 ° C (starting), (from CH 3 OH / CH 3 CN).

Example 31

Preparation of 5-acetamido-2-oxindole-1-carboxamide.

In this example, a suspension containing 0.5 grams (equivalent to 2.6 mmol) was used.

78 5-amino-2-oxindole-1-carboxamide and 0.35 grams of 4- (N, N-dimethylamino) pyridine, stirred at 10 ° C, and then 0.20 ml (corresponding to 2.8 mmol) of acetyl chloride. The reaction mixture was further stirred at about -10 ° C for 20 minutes and at room temperature for an additional 15 minutes, then 20 ml of 1 N hydrochloric acid solution was added to the reaction mixture.

The solid was collected by filtration and dried to give 0.20 g of the title compound as an cream solid.

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

Example 32

Preparation process

5-Benzamido-2-oxindole-1-carboxamide.

Prepared by acylating 5-amino-2-oxindole-1-carboxamide with benzoyl chloride essentially following the same procedure as in Example 31 to give the title compound in 90% yield. and the product was in the form of a cream colored solid.

Melting point: 223 - 226 ° C.

Example 33

Preparation process

4-methylsulfonyl-2-oxindole-1-carboxamide.

The title compound was prepared by oxidizing 2.5 grams of 4-methylthio-2-oxindole-1-carboxamide with 2.4 molar equivalents of 3-chloroperbenzoic acid in tetrahydrofuran at room temperature using standard methods. This product was isolated as a solid (0.1g, 28% yield).

Example 34

Preparation of 6-methylsulfonyl-2-oxindole-1-carboxamide.

The title compound was prepared by oxidation of 1.25 g

6-methylthio-2-oxindole-1-carboxamide with 2.1 molar equivalents of 3-chloroperbenzoic acid in tetrahydrofuran was carried out at room temperature using standard methods. 1.13 g of the title compound is contaminated with the corresponding sulfoxide.

Example 35

Preparation of 4-methylsulfinyl-2-oxindole-1-carboxamide.

The title compound was prepared by oxidizing 1.0 grams of 4-methylthio-2-oxindole-1-carboxamide with 1.1 molar equivalents.

3-chloroperbenzoic acid in tetrahydrofuran at 0 ° C to give 0.9 g of the title compound.

Melting point: 198.5 - 200 ° G.

In analogy to the oxidation of 6-methylthio-2-oxindole-1-carboxamide with 3-chloroperbenzoic acid, 6-methylsulfinyl-2-oxindole-1-carboxamide was prepared.

- 80 Example 36

Preparation of 3- (2-furoyl) -6-fluoro-2-oxindole-1-carboxamide.

The title compound was prepared in the same manner as in Example 24, starting from 3- (2-furoyl) -6-fluoro-2-oxindole (0.30 g, corresponding to 1.2 mmol), chlorosulfonyl isocyanate (0.20 g, corresponding to 1.4 mmol), acetonitrile (15 mL) and water (10 mL). This product was obtained in 17% yield. The amount of product obtained was 60 milligrams. Melting point: 231-235 ° C.

Example 37

Preparation of 3- (2-thenoyl) -5-chloro-2-oxindole-1-carboxamide.

To this stirred suspension containing 1.5 g (5.4 mmol) of 3- (2-thenoyl) -5-chloro-2-oxindole in 15 mL of dry acetonitrile was added 0.52 mL ( (5.9 mmol) of chlorosulfonyl isocyanate and the reaction mixture was stirred at room temperature for 2 hours. The small sample was separated from the reaction mixture, filtered and evaporated under vacuum to give a small amount of N-chlorosulfonyl-3- (2-thenoyl) 5-chloro-2-oxindole-1-carboxamide at a temperature of melting in the range of 166 ° C to 169 ° C. To the remaining portion of the above reaction mixture was added 30 mL of water by slow stirring with stirring and stirring was continued for 1 hour. The reaction mixture was poured into 50 ml of 1 N hydrochloric acid solution containing ice pieces, and the resulting mixture was stirred for 20 minutes. A yellow solid was obtained,

Which was collected by filtration, washed with water and diisopropyl ether and recrystallized from glacial acetic acid to give 200 mg of the first crop of the title compound, m.p. 213-215 Deň: 32 ° C. From the mother liquor from which the first crop was obtained, a further crop of yellow solid was then collected by settling. The solid was collected by filtration to give 470 mg of a second crop of the title compound. The second crop was recrystallized from glacial acetic acid and combined with the first crop and recrystallized from glacial acetic acid. 280 mg of the title compound are obtained.

M.p .: 232-234 ° C.

Preparation 1

Preparation of 2- (2-ureidophenyl) acetic acid.

In this procedure, a suspension containing 2.9 grams (equivalent to 0.01 mole) of N-cyclohexylcarbonyl-2-oxindole-1-carboxamide in 50 ml of 1 N potassium hydroxide solution was stirred at room temperature for about 30 minutes, during this time the solid gradually dissolved into solution. At this point, the reaction mixture was acidified with a concentrated hydrochloric acid solution while cooling in an ice bath, after which the reaction mixture was extracted with ethyl acetate. The extracts were washed with saturated sodium chloride solution, and thereafter was dried over sodium sulphate Na ₂ S0 ^ and then

82 evaporated in vacuo to give an oily solid residue. The oily solid residue was washed with diisopropyl ether and recrystallized from ethanol to give 70 mg of the title compound.

in the header of this example. Melting point: 174.5 ° C (with decomposition). Analysis for C ^ HH ^N ^O: calculated: C = 55.66 found: C = 55.37 H = 5.19 N = H = 5.33 N = 14.43 14.38 % %. Preparation 2

Preparation of 2- (5-chloro-2-ureidophenyl) acetic acid.

The title compound was prepared in 43% yield by hydrolyzing N-isobutyryl-5-chloro-2-oxindole-1-carboxamide with 1 N potassium hydroxide solution essentially as described in Preparation 1. Upon completion of the hydrolysis, the reaction mixture was acidified and the desired product precipitated. The product was collected by filtration and recrystallized from ethanol to give the title compound as colorless crystals.

187.5 ° C (dec.).

For C C CH ^CIN CO ^ requires C ~ 47.28 found: C = 47.11

H = 3.98 N = 12.26%

H = 3.98 N = 12.20%.

Preparation 3

The hydrolysis of N-isobutyryl-2-oxindole-1-carboxamides obtained

The following compounds were prepared according to Preparation 6 using potassium hydroxide using the procedure of Preparation 1:

2- (4-chloro-2-ureidophenyl) acetic acid,

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

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

2- (5-trifluoromethyl-2-ureidophenyl) acetic acid and 2- (4-trifluoromethyl-2-ureidophenyl) acetic acid.

Preparation 4

Preparation of N-cyclohexylcarbonyl-2-oxindole-1-carboxamide.

To the stirred suspension containing 20.0 g (0.15 mol) of 2-oxindole in 150 ml of toluene was added 29.6 g (0.19 mol) of cyclohexylcarbonyl isocyanate. The reaction mixture was heated to reflux for about 30 minutes and then cooled to room temperature. The solid was collected by filtration and recrystallized from ethanol. 26.5 g of the title compound are obtained as friable colorless crystals.

Melting point Analysis calculated for:

: 144.5 ⁰ - 145.5 ° C;

^C 16 ^H 18 ^N 2 ° 3 ^:

C = 67.11 H = 6.34 N = 9.79% C = 67.00 H = 6.36 N - 9.77%

Preparation

84 Preparation of N-isobutyryl-5-chloro-2-oxindole-1-carboxamide.

To a stirred suspension of 8.38 g (0.05 mol) of 5-chloro-2-oxindole in 250 ml of toluene was added 6.79 g (0.06 mol) of isobutyryl isocyanate and the reaction mixture was heated at reflux for 5.5 hours. The reaction mixture was cooled to room temperature, separating a small amount of insoluble material which was collected by filtration, and then the solvent was removed by evaporation under vacuum. The residue was recrystallized from acetonitrile (using decolorizing carbon) followed by recrystallization from ethanol to give 3.23 g of the title compound as pink crystals.

Melting point : 139-141 ° C. Analysis for C _iA3 C1N ₂ 0 ₃ : calculated • • C = 55.62 H = 4.67 N = 9.98% found • • C = 55.53 H = 4.48 N = 9.97%. Ex and v and 6 At carrying out the procedure of of this embodiment were

the following compounds were prepared by reacting a suitable substituted 2-oxindole with isobutyryl isocyanate and following the same procedure as in Preparation 5 above:

N-isobutyryl-6-chloro-2-oxindole-1-carboxamide,

N-isobutyryl-5-fluoro-2-oxidine-1-carboxamides,

- 85 N-isobutyryl-6-fluoro-2-oxindole-1-carboxamide,

N-18-butyryl-5-trifluoromethyl-2-oxindole-1-carboxamide; and N-isobutyryl-6-trifluoromethyl-2-oxindole-1-carboxamide.

Preparation 7

Preparation of 5-chloro-2-oxindole.

To the stirred suspension containing 100 grams (0.55 mol) of 5-chloroisatin in 930 ml of ethanol was added 40 ml (0.826 mol) of hydrazine hydrate to give a red solution. The solution was refluxed for 3.5 hours, during which time a precipitate formed. The reaction mixture was stirred overnight to form another portion of the precipitate, and then all of the precipitate was filtered off to give 5-chloro-3-hydrazono-2-oxindole as a yellow solid.

This material was dried under vacuum in a vacuum oven. The weight of the dried solid was 105.4 grams.

The dried solid was added portionwise over 10 minutes to a solution containing 125.1 grams of sodium methoxide in 900 mL of absolute ethanol. The resulting solution was heated at reflux for 10 minutes and then concentrated in vacuo to a gummy solid. The gummy solid was dissolved in 400 ml of water and the aqueous solution was decolourised with charcoal and poured into a mixture of 1 liter of water and 180 ml of concentrated hydrochloric acid containing ice. A reddish-brown solid precipitated, which was collected by filtration and washed well with water.

The solid was dried and washed with diethyl ether. Finally, it was recrystallized from ethanol to give 48.9 g of the title compound. Mp 193-195 ° C (dec.).

In an analogous manner to that described above, 5-methylisatin was converted to 5-methyl-2-oxindole, which was treated with hydrazine hydrate followed by treatment with sodium ethoxide in ethanol. The product had a melting range of 173 ° C to 174 ° C.

Preparation 8

Preparation of 4,5-dimethyl-2-oxindole and 5,10-dimethyl-2-oxindole.

In carrying out the process of this embodiment was

The 3,4-dimethylaniline was converted to 3,4-dimethylisonitrosoacetanilide by reaction with chloral hydrate and hydroxylamine using the procedure described in Organic Syntheses, Collective Volume I, p. 327. This 3,4-dimethylisonitrosoacetanilide was then cyclized by treatment with sulfuric acid. using the method of Baker et al., Journal of Organic Chemistry, 17, 149 (1952), to give 4,5-dimethylisatin (m.p. 225 DEG-226 DEG C.) and 5.5. -dimethylisatin (m.p. 217-218 ° C).

The 4,5-dimethylisatin thus obtained was converted to

4,5-dimethyl-2-oxindole (m.p. 245.5 ° C to 247.5 ° C) by treatment with hydrazine hydrate, wherein:

87 followed by treatment with sodium ethoxide in ethanol. This procedure was essentially the same as in Preparation 7.

In a similar manner, 5,6-dimethylisatin was converted to 5,6-dimethyl-2-oxindole (m.p.

196.5 ° C to 198 ° C) by processing

5,6-dimethylisatin hydrazine hydrate followed by treatment with sodium ethoxide in ethanol, in the same manner as in Preparation 7.

Preparation 9

Preparation of 4-chloro-2-oxindole and 6-chloro-2-oxindole.

A. Preparation of 3-Chloroisonitrosoacetanilide.

To the stirred solution containing 113.23 grams (0.686 moles) of chloral hydrate in 2 liters of water was added 419 grams (corresponding to 2.95 moles) of sodium sulfate, followed by the addition of a solution prepared from 89.25 grams (equivalent to 0.70 mol)

3-chloroaniline, 62 ml concentrated hydrochloric acid and 500 ml water. In this way a thick precipitate was formed. A solution containing 155 grams (2.23 mol) of hydroxylamine in 500 ml of water was added to the reaction mixture with stirring. The reaction mixture was stirred and slowly warmed to a temperature in the range of 60-75 ° C and held at this temperature for about an hour, and more was added during this time. 1 liter of water to facilitate mixing. The reaction mixture was cooled to form a precipitate and the precipitate was collected by filtration. The wet solid so obtained was dried,

88 to give 136.1 g of the desired 3-chloroisonitrosoacetanilide.

3. Preparation of 4-chloroisatin and 6-chloroisatin.

To this 775 ml of concentrated sulfuric acid, which had been preheated to 70 ° C, was added 136 grams of 3-chlorisonitrosoacetanilide while stirring at such a rate that the temperature of the reaction medium was maintained at 75 ° C. C to 85 ° C. After all solids had been added, the reaction mixture was heated to 90 ° C and maintained at this temperature for an additional 30 minutes. The reaction mixture was cooled and poured onto approximately 2 liters of ice with stirring. Additional ice was then added as necessary to maintain the temperature below ambient temperature. A red-orange precipitate was obtained, which was collected by filtration, washed with water and dried. The solid was suspended in 2 L of water and dissolved by the addition of about 700 mL of 3 N sodium hydroxide solution. The solution was filtered and the pH was adjusted to 8 by addition of concentrated hydrochloric acid. At this point, 120 ml of a mixture containing 80 parts of water and 20 parts of concentrated hydrochloric acid was added. A solid precipitated, which was collected by filtration, washed with water and dried to give 50 grams of crude 4-chloroisatin. The filtrate obtained by filtering out 4-chloroisatin was then further acidified to pH 0 using concentrated hydrochloric acid to give an additional precipitate.

The precipitate was collected by filtration, then

The solid was washed with water and dried to give 43 grams of crude 6-chloroisatin.

The crude 4-chloroisatin was recrystallized from acetic acid to give 43.3 g of material, mp 258-259 ° C.

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

C. Preparation of 4-chloro-2-oxindole.

To a stirred slurry containing 43.3 grams of 4-chloroisatin in 350 mL of ethanol was added 17.3 mL of hydrazine hydrate, and the reaction mixture was then heated at reflux for 2 hours. The reaction mixture was cooled to give a precipitate which was collected by filtration to give 43.5 g of 4-chloro-3-hydrazono-2-oxindole, mp 235-236 ° C.

To a stirred solution of 22 grams of sodium in 450 ml of anhydrous ethanol was added portionwise 43.5 grams of 4-chloro-3-hydrazono-2-oxindole, and the resulting solution was heated to reflux for 30 minutes.

The solution was cooled and concentrated to a gummy material which was dissolved in 400 ml of water and decolorized with activated carbon. The resulting solution thus obtained

90 was then poured into a mixture of 1 liter of water and 45 ml of concentrated hydrochloric acid. The precipitate was collected by filtration, dried and recrystallized from ethanol to give 22.4 g of 4-chloro-2-oxindole.

M.p .: 216-218 ° C (dec.).

D. Process for preparing 6-chloro-2-oxindole.

This was obtained by reacting 36.2 grams of 6-chloroisatin with hydrazine hydrate followed by treatment with sodium ethoxide in ethanol in essentially the same manner as in Procedure C (see above). 14.2 g of 6-chloro-2-oxindole were obtained.

Melting point: 196-198 ° C.

Preparation 10

Preparation of 5,6-difluoro-2-oxindole.

The compound was obtained by reacting 3,4-difluoroaniline with chloral hydrate and hydroxylamine, followed by cyclization using sulfuric acid and following the same procedure as described in Parts A and B of Preparation 9, and procedure was obtained

5,6-difluoroisatin, which was then reacted with hydrazine hydrate followed by treatment with sodium methoxide in ethanol, following the same procedure as in Preparation 7. The title compound was obtained. .

M.p .: 187-190 ° C.

- 91 Preparation 11

Preparation of 5-fluoro-2-oxindole.

To the stirred solution containing 11.1 grams (equivalent to 0.1 mole) of 4-fluoroaniline in 200 mL of dichloromethane was added dropwise at a temperature ranging from -60 to -65 ° C. a solution containing 10.8 g (0.1 mol) of t-butyl hypochlorite in 25 ml of dichloromethane. The reaction mixture was further stirred for 10 minutes at a temperature maintained between -60 ° C and -65 ° C and a solution containing 13.4 g (0.1 mol) was added dropwise to the reaction solution.

2- (methylthio) ethyl acetate in 25 mL of dichloromethane. The reaction solution was further stirred at -60 ° C for 1 hour and then slowly added dropwise to the reaction solution at a temperature ranging from -60 to -65 ° C with a solution containing 11.1 grams (corresponding to 0.11 mol) of triethylamine in 25 ml of dichloromethane. The cooling bath was removed and the temperature of the reaction solution was allowed to rise to room temperature at which time 100 ml of water were added. The phases were separated, the organic phase was washed with saturated sodium chloride solution, dried (Na ₂ SO 4) and evaporated under vacuum. The residue was dissolved in 350 ml of diethyl ether and 40 ml of a 2 N hydrochloric acid solution were added. The mixture was stirred at room temperature overnight. In this way, the phases that

The ether phase was then washed with water, followed by washing with saturated sodium chloride solution. The ether phase was dried over Na 2 SO 4 and evaporated in vacuo to give 17 grams of an orange-brown solid. which was then triturated with isopropyl ether. The solid was recrystallized from ethanol to give 5.58 g of 5-fluoro-1-methylthio-2-oxindole. 151.5 ° C - 152.5 ° C.

Analysis for C ^ HHgONFS:

calculated: C = 54.80 H = 4.09 N = 7.10% found: C = 54.74 H = 4.11 N = 7.11%.

Then, a sample of 5-fluoro-3-methylthio-2-oxindole (986 mg, 5.0 mmol) was added to 2 tablespoons of Raney nickel in 50 mL of absolute ethanol, followed by heating the reaction mixture at a temperature of reflux the solvent for 2 hours. Then, the catalyst used was removed by decantation and washed with absolute ethanol. The ethanol solutions were combined and evaporated under vacuum and the residue was dissolved in dichloromethane. The dichloromethane solution was dried (Na2SO4) and evaporated in vacuo to give 5-fluoro-2-oxindole (475 mg).

Melting point: 121-134 ° C.

In an analogous manner to that described above, it was

4-Trifluoromethylaniline reacted with t-butyl hypochlorite, 2- (methylthio) ethyl acetate and triethyl amine, followed by reduction of the thus obtained 3-thiomethyl-5-trifluoromethyl-2-oxindole using Raney nickel, and

93 method gave 5-trifluoromethyl-2-oxindole. Melting point: 189.5-190.5 ° C.

Preparation 12

Preparation process

Of 5-methoxy-2-oxindole.

In carrying out the process according to this embodiment, it was

5-Methoxy-2-oxindole prepared from 4-methoxyaniline by a procedure similar to that of Preparation 11 except that the initial chlorination was performed using a solution of chlorine gas in dichloromethane instead of t-butyl hypochlorite. The melting point of the product thus obtained was between 150.5 and 151.5 ° C.

Preparation 13

Preparation of 6-chloro-5-fluoro-2-oxindole.

To 130 ml of toluene, 24.0 g (0.165 mol) of 3-chloro-4-fluoroaniline was added with stirring, and

13.5 ml (corresponding to 0.166 mol) of pyridine.

The resulting solution was cooled to 0 ° C and 2-chloroacetyl chloride (13.2 mL, 0.166 mol) was added. The reaction mixture was stirred at room temperature for 5 hours and then extracted twice with 100 ml of 1 N hydrochloric acid solution, followed by extraction with 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried over magnesium sulphate and concentrated in vacuo to give 32.6 g (88% yield).

- 94 N- (2-chloroethyl) -3-chloro-4-fluoroaniline.

A 26.63 gram sample of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline was thoroughly mixed with 64 grams of anhydrous aluminum chloride, and the mixture was heated at a temperature of 210 to 230 ° C. for 8.5 hours. The reaction mixture was poured into a mixture of ice and 1 N hydrochloric acid with stirring. Stirring was continued for an additional 30 minutes while the solid was collected by filtration (22.0 g). The solid was dissolved in a 1: 1 mixture of ethyl acetate and hexane and chromatographed on 800 g of silica gel. The silica gel column was eluted followed by evaporation of the fractions to give 11.7 grams of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline, followed by 3.0 grams of 6. -chloro-5-fluoro-2-oxindole. The latter was recrystallized from toluene to give 1.70 g (7% yield) of the title compound.

Melting point: 196 - 206 ° C;

NMR spectroscopy showed that this product was contaminated with some 4-chloro-5-fluoro-2-oxinol.

Preparation 14

Preparation of 6-fluoro-5-methyl-2-oxindole.

In the process of this embodiment, the initial mixture containing 11.62 grams (corresponding to

57.6 mmol) of N- (2-chloroacetyl) -3-fluoro-4-methylaniline and 30.6 g (corresponding to 229.5 mmol) of anhydrous aluminum chloride are heated to a temperature ranging from 210 to 220 ° C. After heating for 4 hours, the reaction mixture was cooled and 100 ml of 1 N hydrochloric acid solution and 50 ml of ice were added. A reddish-brown solid was formed, which was collected by filtration and recrystallized from aqueous ethanol. Three fractions of 4.49 grams, 2.28 grams and 1.0 grams were obtained from this mother liquor. A 1.0 gram portion was recrystallized from water to give 280 mg of the title compound.

Melting point: 168.5-171 ° C.

Preparation 15

Preparation process

6-bromo-2-oxindole.

To 9.4 grams of sodium hydride, 195 milliliters of dimethylsulfoxide was added, followed by the addition of

22.37 grams of malonic acid dimethyl ester. At the end of the addition, the mixture was heated to 100 ° C and held at this temperature for 40 minutes. At this point, 25 grams of 1,4-dibromo-2-nitrobenzene was added to the reaction mixture as a single addition. The reaction mixture was held at 100 ° C for 4 hours and then added to 1.0 L of saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate and recovered

The 96 extracts were then washed with ammonium chloride solution, then with water and then with sodium chloride (saturated solution).

It was dried (magnesium sulfate) and the solvent was evaporated to give a residue which was recrystallized from ethyl acetate / hexane to give 22.45 g of 2- (4- (4-) dimethyl ester). bromo-24-nitrophenyl) malic acid.

Then, a solution containing 17.4 grams of 2- (4-bromo-2-nitrophenyl) malonic acid dimethyl ester and 4.6 grams of lithium chloride in 150 ml of dimethyl sulfoxide was placed in an oil bath which was heated to 100 ° C. After heating for 3 hours, the reaction mixture was cooled to room temperature and then poured into a mixture containing 500 ml of ethyl acetate and 500 ml of saturated sodium chloride solution. The layers were separated and the aqueous layer was extracted with an additional portion of ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate, and evaporated under vacuum. The residue was chromatographed on silica gel with ethyl acetate / hexane as the eluent. 9.4 g of 2- (4-bromo-2-nitrophenyl) acetic acid methyl ester was obtained.

Then, to a solution containing 7.4 grams of 2- (4-bromo-2-nitrophenyl) acetic acid methyl ester in 75 ml of acetic acid was added 6.1 grams of iron powder. The traction mixture thus obtained was then placed in an oil bath heated to 10 ° C.

After heating the reaction mixture in an oil bath for 1 hour, the solvent was removed by evaporation under vacuum, and the residue was dissolved in 250 ml of ethyl acetate. The solution was filtered, washed with saturated sodium chloride solution, dried over sodium sulfate, evaporated with activated carbon and evaporated under vacuum. 5.3 g of 6-bromo-2-oxindole were obtained as a white crystalline solid.

Melting point: 213-214 ° C.

In a similar manner, starting from 1,4,5-trichloro-2-nitrobenzene, 5,6-dichloro-2-oxindole was prepared.

Melting point: 209-210 ° C.

Preparation 16

Preparation process

6-phenyl-2-oxindole.

50 ml of dimethylsulfoxide was added to 3.46 g (0.072 mole) of sodium hydride, followed by addition of a solution containing 8.2 ml (0.072 mole) of dimethyl malonic acid in 10 ml of dimethylsulfoxide, this addition was made slowly dropwise with stirring. After the addition was complete, the reaction mixture was stirred for an additional hour and then a solution containing 10 g (0.036 mol) of 4-bromo-3-nitrodiphenyl in 50 ml of dimethylsulfoxide was added. The reaction mixture was heated to 100 ° C for 1 hour and cooled and poured onto ice / water,

- 98 containing 5 grams of ammonium chloride. The reaction mixture was extracted with ethyl acetate, and the extracts were washed with sodium chloride and dried over magnesium sulfate. Evaporate in vacuo to give an oily material which is chromatographed on silica gel and recrystallized from methanol to give 6 grams of 2- (3-dimethyl-3-dimethyl ester). (nitro-4-diphenylyl) malonic acid.

Melting point: 82 - 83 ° C.

A portion (5 grams) of the above nitro compound was reduced with hydrogen using a platinum catalyst in a mixture containing 50 ml of tetrahydrofuran and 10 ml of methanol at a pressure of about 5 kg / cm to give the corresponding amine. The mixture was refluxed with a solvent (ethanol) for 16 hours, the product was evaporated and the solid was recrystallized from methanol to give a solid. 1 g of 6-phenyl-2-oxindole-1-carboxylate ethyl ester.

Melting point: 115 - 117 ° C.

The ethyl ester (1.0 g) and 100 ml of a 6 N hydrochloric acid solution were refluxed for 3 hours and then allowed to stand at room temperature for 3 days. The solid was collected by filtration and dried to give 70C milligrams of 6-phenyl-2-oxindole. Melting point: 175-176 ° C.

- 99 Preparation 17

Preparation of 5-acetyl-2-oxindole.

To 95 milliliters of carbon disulfide, 27 grams (equivalent to 0.202 moles) of aluminum chloride was added, followed by the addition of a solution containing 3 milliliters (equivalent to 0.042 moles) of acetyl chloride in 5 milliliters of carbon disulfide. dropwise and with stirring. Stirring was continued for 5 minutes and 4.4 g (0.033 mol) of 2-oxindole was added to the reaction mixture. The resulting reaction mixture was heated at reflux temperature for 4 hours and then cooled. The carbon disulfide was removed by decantation and the residue was triturated under water and the product collected by filtration. After drying, the product weighed 3.2 grams. The melting point of the title product was 225-227 ° C.

Reaction of 2-oxindole with benzoyl chloride and 2-thenoyl chloride in the presence of aluminum chloride following essentially the same procedure as described above gave the following compounds:

5-benzoyl-2-oxindole, m.p. 203-205 ° C (from CH 3 OH), a

5- (2-thenoyl) -2-oxindole, m.p. 211-213 ° C (from CH 2 GN).

- 100 Preparation 18

5-3romo-2-oxindole was prepared by bromination of 2-oxindole see further details: Beckett et al. Tetrahedron, 24 years old,

6093 (1968) and Sumpter et al., Journal of the American Chemical Society, 67, 1656 (1954).

5-n-Butyl-2-oxindole may be prepared by reacting 5-n-butylisatin with hydrazine hydrate followed by treatment with sodium methoxide in ethanol using the procedure of Preparation 7. Further, 5-n-butylisatin can be prepared from 4-n-butylaniline by treatment with chloral hydrate and hydroxylamine followed by cyclization using sulfuric acid using the procedure of Parts A and B of Preparation 9 above.

5-Ethoxy-2-oxindole can be prepared by conversion

3-hydroxy-6-nitro-toluene to 3-ethoxy-6-nitro-toluene using standard methods (using potassium carbonate and ethyl iodide in acetone) followed by conversion of 3-ethoxy-6-nitrotoluene to 5-ethoxy- 2-oxindole using the method described by Beckett et al. in Tetrahedron,

24, 6093 (1968) for the conversion of 3-methoxy-o-nitrotoluene to 5-methoxy-2-oxindole. The 5-n-butoxy-2-oxindole may be prepared in the same manner, but replacing n-butyl iodide with ethyl iodide.

5,6-Dimethoxy-2-oxindole can be prepared by the method of Walker, see Journal of the American Chemical Society, 77, 3344 (1955).

7-Chloro-2-oxindole can be prepared as described in U.S. Pat.

382 236.

4-Thiomethyl-2-oxindole and 6-thiomethyl-2-oxindole may be prepared by the method described in U.S. Patent No. 4 OC6,161. Furthermore, 5-n-butylthio-2-oxindole can be prepared in the same manner, but substituting 4-butylthioaniline for 3-methylthioaniline.

5,6-Methylenedioxy-2-oxindole can be prepared according to the method of McSvoy et al., See Journal of Organic Chemistry, 38, 3350 (1973). Further, 5,6-ethylenedioxy-2-oxindole can be prepared in an analogous manner.

6-Fluoro-2-oxindole can be prepared according to the procedure of Protiva et al. 4,106,032.

6-Trifluoromethyl-2-oxindole can be prepared by the method of Simet, see Journal of Organic Chemistry, 28, 3530 (1963).

6-Methoxy-2-oxindole can be prepared by the method of tfieland et al., Chemische 3erichte, 96, 253 (1963).

5-Nitro-2-oxindole can be prepared according to 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 reacting 5-cyclopropylisatin and 5-cycloheptylisatin with hydrazine hydrate, followed by treatment with sodium methoxide in ethanol and the same procedure as that described in Preparation 7. 5 -cyclopropylisatin and 5-cycloheptylisatin can be prepared from 4-cyclopropylaniline and 4-cycloheptylaniline by treatment with chloral hydrate and hydroxylamine, wherein:

102 is then followed by cyclization using sulfuric acid, the procedure being the same as in Parts A and 3 of Preparation 9.

Preparation 19

Preparation of 3- (2-furoyl) -2-oxindole.

When done.! To a stirred solution containing 5.5 grams (0.24 mol) of sodium in 150 ml ethanol was added 13.3 grams (0.10 mol) of 2-oxindole at room temperature. The slurry was cooled to an ice bath temperature in an ice bath, and 15.7 g (0.12 mol) of 2-furoyl chloride was added dropwise over a period of 10 to 10 hours. Fifteen minutes. The ice bath was removed, an additional 100 mL of ethanol was added to the reaction mixture, and the mixture was heated to reflux and maintained at this temperature for 7 hours. The reaction mixture was allowed to stand overnight and the solid collected by filtration. The solid was added to 400 mL of water, and the resulting mixture was acidified with concentrated hydrochloric acid. The mixture was ice-cooled and the solid collected by filtration.

The solid was recrystallized from 150 ml of acetic acid to give 8.3 g of yellow crystals as above.

Mp 209-210 ° C (dec.).

Analysis for C ^ jH ^O ON:

- 103 calculated

C = 68.72 C = 68.25

N = 6.17 N = 6.20

H = 3.99% H = 4.05%

Preparation

The following compounds were prepared by reaction of 2-oxindole with the appropriate acid chloride using the same procedure as in Preparation 19:

3- (2-thenoyl) -2-oxindole, m.p. 189-190 ° C,% yield,

3- (2- / -2-thienyl7-acetyl) -2-oxindole, m.p. 191 DEG C., yield 38%, and

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

192.5

Preparation 21

Preparation of 3- (3-furoyl) -2-oxindole.

To a stirred solution containing 2.8 grams (0.12 mol) of sodium in 200 milliliters of ethanol was added 13.3 grams (0.10 mol) of 2-oxindole, followed by the addition of 16 , 8 grams of ethyl 3-furoate. The mixture was heated at reflux for 47 hours, cooled, and the solvent removed by evaporation under vacuum. The residue was triturated in 2C milliliters of ether and the solid was collected by filtration and set aside. The filtrate was evaporated to a residue

The residue was then triturated using isopropyl alcohol and the product collected by filtration.

The solid was suspended in 250 ml of water and acidified with concentrated hydrochloric acid. The mixture was stirred to give a solid which was collected by filtration. The solid was recrystallized from acetic acid followed by recrystallization from acetonitrile and the above-mentioned.

A blunt of 705 mg of the title compound was prepared. Melting point : 185-186 ° C. Analysis for ^C 13 ^H 9 ° 3 ^N calculated: C = 68.72 H = 3.99 N = 6.17% found: C = 68.72 H = 4.14 N = 6.14%.

Preparation 22

Preparation of 5-amino-2-oxindole-1-carboxamide.

To a solution containing 5.0 grams of 5-nitro-2-oxindole-1-carboxamide in 110 mL of Ν, dimethyl-dimethylformamide was added 0.5 grams of 10-nitric acid. The resulting mixture was then shaken under a hydrogen atmosphere using a hydrogen pressure of 5 kg / cm at the beginning of the process until hydrogen absorption ceased. The catalyst was removed from the reaction mixture by filtration and the filtrate was diluted with brine and extracted with ethyl acetate. In this way they were obtained

The extracts were dried over MgSO4 and evaporated in vacuo to give a dark colored oil which solidified after trituration with water. 3.0 g of the title compound are obtained in the form of a yellow solid.

Melting point: 189-191 ° C

Claims (29)

Patent claims 1. The 2-oxindole-1-carboxamides substituted in the 3-position of formula I - R (I) wherein: X a substituent selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio carbon, trifluoromethyl, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, nitro, phenyl, C 2 -C 4 alkanoyl, benzoyl, thenoyl, C 2 -C 4 alkanamide carbon, a benzamide group and a Ν, Ν-dialkylsulfamoyl group having 1 to 3 carbon atoms in each of said alkyl groups, and Y is a substituent selected from the group consisting of an atom 106 hydrogen, fluorine, chlorine, bromine, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and trifluoromethyl, or X and Y together are 4,5-methylenedioxy, 5,6-methylenedioxy or 6,7-methylenedioxy or 4,5-ethylenedioxy, 5,6-ethylenedioxy or 6,7-ethylenedioxy, or X and Y together when attached to adjacent adjacent carbon atoms, is a divalent radical Z, which radical is selected from the group consisting of w- wherein W represents oxygen or sulfur, R ¹ is a substituent selected from the group consisting of alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, cycloalkenyl of 4 to 7 carbon atoms, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbon atoms in said alkyl moiety, (substituted phenyl) alkyl 107 a group having 1 to 3 carbon atoms in said alkyl moiety, a phenoxyalkyl group having 1 to 3 carbon atoms in said alkyl moiety, a (substituted phenoxy) alkyl group having 1 to 3 carbon atoms in the alkyl moiety, a (thiophenoxy) alkyl group having 1 to 3 3 carbon atoms in the alkyl moiety, naphthyl, bicyclo [2.2.1] heptan-2-yl, bicyclo [2.2.1] hept-5-en-2-yl, and - (CH ₂ ) _n -QR, wherein said substituent is in said substituted phenyl group, in said (substituted phenyl) alkyl group and in said (substituted phenoxy) alkyl group selected from the group consisting of fluorine atom, chlorine atom, bromine atom, C 1 -C 4 alkyl group, C 1 -C 4 alkoxy group 4 carbon atoms and a trifluoromethyl group, n is zero, 1 or 2, Q is a divalent 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 [b] furan and benzo [b] thiophene, and R is hydrogen or (C 1 -C 3) -alkyl, and pharmaceutically acceptable base salts thereof. A compound according to claim 1 wherein X and Y are each selected from the group consisting of hydrogen, fluorine, chlorine, bromine, C 1 -C 4 alkyl, alkoxy C 1 -C 4 -alkyl, C 1 -C 4 -alkylthio, nitro and trifluoromethyl, or X and Y taken together are 4,5-methylenedioxy, 5,6-methylenedioxy or 6,7-methylenedioxy, and R ¹ is a substituent selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, phenyl, substituted phenyl, C 1 -C 3 phenylalkyl, C 1 -C 3 phenoxyalkyl 3 carbon atoms in the alkyl moiety, (substituted phenoxy) alkyl having 1 to 3 carbon atoms in the alkyl moiety, furyl, thienyl, pyrrolyl, alkylfuryl having 1 to 3 carbon atoms in the alkyl moiety, alkylthienyl having 1 to 3 carbon atoms in the alkyl moiety, a furylalkyl group having 1 to 3 carbon atoms in the alkyl moiety, a thienylalkyl group having 1 to 3 carbon atoms in the alkyl moiety, and a bicyclo [2.2.1] heptan-2-yl group, wherein the substituent in said substituted phenoxy group; in said substituted phenyl the group is selected from the group consisting of fluorine, chlorine, bromine, C 1 -C 4 alkyl and C 1 -C 4 alkoxy. A compound according to claim 2, wherein Y is hydrogen. The compound of claim 3, wherein X is a residue selected from the group consisting of 5-chloro, 6-chloro, 109 5-fluoro, 6-fluoro, 5-trifluoromethyl and 6-trifluoromethyl. A compound according to claim 4, 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 5, wherein X is 5-chloro or 6-chloro. 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 ¹ is 2-thienyl. The compound of claim 6, wherein X is 6-chloro and R ¹ is 2-thienyl. The compound of claim 5, wherein X is 5-fluoro or 6-fluoro. The compound of claim 10, wherein X is 5-fluoro and R ¹ is (2-thienyl) methyl. 110 The compound of claim 10, wherein X is 6-fluoro and R ¹ 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 ¹ 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 a residue selected from the group consisting of 5-chloro and 5-fluoro and the substituent Y is selected from the group consisting of 6-chloro and 6-fluoro. The compound of claim 17, wherein R ¹ is a residue selected from the group consisting of benzyl, 2-furyl, 2-thienyl, (2-furyl) methyl, and (2-thienyl) methyl. 111 The compound of claim 18, wherein X is 5-fluoro, Y is 6-chloro, and R ¹ is benzyl. A compound of formula I according to claim 1 for use as a medicament for eliciting an analgesic response in a mammal. A compound of formula I according to claim 1 for use as a medicament for the treatment of inflammatory diseases in mammals. A pharmaceutical composition for use as an analgesic and anti-inflammatory agent in a mammal comprising a pharmaceutically acceptable carrier and a 2-oxindole-1-carboxamide compound of formula I according to claim 1 in an amount exhibiting an analgesic reaction or an amount for treating an inflammatory disease, wherein the weight ratio of the pharmaceutically acceptable carrier to the 2-oxindole-1-carboxamide compound ranges from 1: 4 to 4: 1. A compound of formula II AND 112 (II) in which: X is a substituent selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 atoms carbon, trifluoromethyl, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, nitro, phenyl, C 2 -C 4 alkanoyl, benzoyl, thenoyl, C 2 -C 4 alkanamide carbon, benzamide and N, N-dialkylsulfamoyl having 1 to 3 carbon atoms in each of said alkyl groups, and Y is a substituent selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or X and Y together represent 4,5-methylenedioxy, 13, 5,6-methylenedioxy or 6,7-methylenedioxy or 4,5-ethylenedioxy, 5,6-ethylenedioxy or 6,7-ethylenedioxy, or X and Y taken together when attached to adjacent adjacent carbon atoms represent a divalent radical Z, which radical is selected from the group consisting of wherein W is oxygen or sulfur as an intermediate for the preparation of a compound of formula I. The compound of claim 23, wherein X and Y are each selected from hydrogen, fluoro, chloro, bromo, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio. carbon atoms, nitro and trifluoromethyl, or X and Y together represent 4,5-methylenedioxy, 5,6-methylenedioxy or 6,7-methylenedioxy. 114 The compound of claim 24, wherein Y is hydrogen and X is selected from the group consisting of 5-chloro, 6-chloro, 5-fluoro, 6-fluoro, 5-trifluoromethyl and 6-trifluoromethyl. The compound of claim 25, wherein X is 5-chloro. The compound of claim 25, wherein X is 5-trifluoromethyl. The compound of claim 23, wherein X is a residue selected from the group consisting of 5-chloro and 5-fluoro, and Y is a residue selected from the group consisting of: 6-chloro and 6-fluoro. The compound of claim 28, wherein X is 5-fluoro and Y is 6-chloro.