CS252847B2 - Process for the preparation of N, 3-disubstituted 2-oxindole-1-carboxamides - Google Patents

Abstract

A process for the preparation of N,3-disubstituted 2-oxindole-1-carboxamides of the general formula I in which the individual general symbols have the meaning given in the subject of the invention, and their pharmaceutically acceptable salts with bases, characterized in that a compound of the general formula IV R3, X and Y have the meaning given above, is reacted with an isocyanate of the general formula R2-N=C=O2 In which R has the meaning given above, in an inert solvent, and the resulting product is optionally converted into its pharmaceutically acceptable salt. The compounds produced are useful as analgesic agents and as agents for the treatment of inflammatory diseases such as arthritis.

Description

The invention describes novel chemical compounds. Specifically, these novel compounds are derivatives of 2-oxindole-1-carboxamide, which are further substituted at the 3-position with an acyl group and on the nitrogen of the carboxamide group with an alkyl, cycloalkyl, phenyl or substituted phenyl group. These novel compounds are inhibitors of the enzymes cyclooxygenase and lipoxygenase.

The compounds of the invention exhibit analgesic activity in mammals, particularly humans, and are therefore useful for acute administration to alleviate pain, such as that experienced by patients following surgery or trauma.

In addition to their utility for acute administration to alleviate or eliminate pain, the compounds of the invention can be used for chronic administration to mammals, particularly humans, to alleviate symptoms of chronic diseases such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis.

The invention relates to new derivatives of 2-oxindole-1-carboxamide of the general formula I

in which

X represents a hydrogen, fluorine or chlorine atom, a trifluoromethyl group, a nitro group, an alkanoyl group with 2 to 4 carbon atoms or a benzoyl group and

Y represents a hydrogen, fluorine or chlorine atom or

If X and Y are bonded to adjacent carbon atoms, they together form a divalent radical 1 5

Z selected from the group consisting of residues of formulae Z to Z

in which

W represents an oxygen or sulfur atom,

R ¹ represents an alkyl group with 1 to 6 carbon atoms, a trifluoromethyl group, a cycloalkyl group with 3 to 7 carbon atoms, a phenyl group optionally substituted by a fluorine or chlorine atom, a phenylalkyl group with 1 to 3 carbon atoms in the alkyl part optionally substituted on the phenyl nucleus by a chlorine or fluorine atom, a phenoxyalkyl group with 1 to 3 carbon atoms in the alkyl part, a bicyclo[2.2.1]heptan-2-yl group, a furyl radical optionally substituted by an alkyl group with 1 to 3 carbon atoms, a thienyl radical, a thienylmethyl radical, a tetrahydrofuranyl radical or a pyridyl radical and in

R represents an alkyl group with 1 to 6 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, a benzyl group or a residue of the general formula where

4 .

R and R are independently selected from the group consisting of hydrogen, fluorine and chlorine atoms, alkyl groups with 1 to 4 carbon atoms, alkoxy groups with 1 to 4 carbon atoms and trifluoromethyl group, and their pharmaceutically acceptable salts with bases.

The above-mentioned compounds of formula I are effective as analgesic agents and as agents for the treatment of inflammatory diseases such as arthritis. Accordingly, the invention also provides a method for inducing analgesia in mammals, especially humans, a method for treating inflammatory diseases in mammals, especially humans, and pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier.

A preferred group of substances according to the invention consists of compounds of general formula I, in which the individual symbols X and Y are independently selected from the group comprising a hydrogen atom,

2

5-fluoro, 6-fluoro, 5-chloro, 6-chloro-5-trifluoromethyl and 6-trifluoromethyl, and R and R are as defined above. Of this preferred group, those compounds in which R ³ represents a benzyl group, a 2-furyl group, a 2-thienyl group or a (2-thienyl)methyl group are particularly preferred.

Particularly preferred individual compounds according to the invention are:

N-tert.butyl-5-chloro-3-(2-furoyl)-2-oxindole-1-carboxamide {I: X = 5-chloro, Y = hydrogen,

R ³ = 2-furyl, R ² - tert.butyl);

N-tert.butyl-5-fluoro-3-(2-furoyl)-2-oxindole-1-carboxamide (X: X = 5-fluoro, Y = hydrogen,

R ³ = 2-furyl, R ² = tert.butyl);

N-tert.butyl-6-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide (I: X « 6-chloro, Y -hydrogen,

R ³ = 2-thienyl, R ² = tert-butyl);

N-(4-Methoxyphenyl)-3-(2-thenoyl)-2-oxindole-1-carboxamide U: X = hydrogen, Y = hydrogen, R ³ = = 2-thienyl, R = 4-methoxyphenyl) and

N-(2,4-difluorophenyl)-3-(2-furoyl)-2-oxindole-1-carboxamide (I: X = hydrogen, Y = hydrogen, R ³ = 2-furyl, R ² = 2,4-difluorophenyl).

Compounds of general formula I are named as derivatives of 2-oxindole, which is the compound corresponding to general formula II

(II)

Analgesic and anti-inflammatory agents of general formula I bear a carboxamide substituent

1 of the formula -C(=O)-NH-R at position 1 and an acyl substituent of the formula -C(=O)-R at position 3 of the 2-oxindole, wherein the fused benzene ring may be further substituted with substituents X and Y. The radicals X and Y may be certain monovalent substituents as defined above, or the symbols X and Y, bonded to adjacent carbon atoms of the benzene ring of the 2-oxindole nucleus, may form a divalent radical Z such that the radical Z together with the carbon atoms to which it is bonded forms a fused carbocyclic or heterocyclic ring. Specific divalent radicals in the meaning of the symbol Z (i.e., radicals Z to Z^) have been previously mentioned. Thus, if Z represents a residue of the formula Z, the symbols X and Y together with the carbon atoms to which they are attached form a fused cyclopentene ring, and if Z represents a residue of the formula, the symbols X and Y together with the carbon atoms to which they are attached form a fused furan or thiophene ring.

It should further be emphasized that if Z represents a residue of the formula Z$ or z\, this group in the meaning of the symbol Z can be attached in either of two possible ways. For example, if X and Y are located on carbon atoms in positions 5 and 6, and represent a residue of the formula Z , the general formula I includes both of the following formulas.

It is further apparent that the analgesic and anti-inflammatory compounds of the formula I according to the invention, where X, Y, R and R have the meanings given above, are capable of enolization and can therefore exist in one or more tautomeric (enol) forms. All such tautomeric (enol) forms of the compounds of the formula I are within the scope of the invention.

Compounds of general formula I are prepared from the corresponding 2-oxindole of general formula III

X

in which

X and Y have the meanings given above.

This preparation is carried out by introducing the substituent -C(=O)-NK-R into position 1 and the substituent -C(=O)-R ¹ into position 3. The said substituents can be introduced in any order, so that the method of producing compounds of general formula I can be carried out in two variants, as follows from the following reaction scheme:

The subject of the present invention is a process for the production of compounds of the above-mentioned general formula I and their pharmaceutically acceptable salts, characterized in that the compound of the general formula IV

O

in which

X and Y have the meanings given above, is reacted with an isocyanate of the general formula

R -N=C=O in which 2

R has the above meaning, in an inert solvent, and the resulting product is optionally converted into its pharmaceutically acceptable salt.

The second variant resulting from the above reaction scheme, consisting in introducing the substituent -C(=O)-R^* into position 3 of the compound of general formula V, is the subject of our related Czechoslovak patent specification No. 252,828.

In accordance with the invention, the -C(=O) radical is attached by reacting a compound of general formula IV with an isocyanate of general formula r ² -n=c=o

Most commonly, this reaction is carried out by contacting substantially equimolar amounts of the reactants in an inert solvent at a temperature of from 50°C to 150°C, preferably from 100°C to 130°C. In this case, an inert solvent is understood to mean a solvent that dissolves at least one reactant and that does not react undesirably with either the reactants or the product. Typical solvents that can be used include aliphatic hydrocarbons such as octane, nonane, decyl and decalin, aromatic hydrocarbons such as benzene, chlorobenzene, toluene, xylene and tetralin, chlorinated hydrocarbons such as 1,2-dichloroethane, ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane and di(2-methoxyethyl)ether, and polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide. Reaction time dependent on reaction temperature. At temperatures of 100 to 130°C, reaction times of the order of a few hours, for example 5 to 10 hours, are usually used.

If the reaction of a compound of general formula IV with an isocyanate of general formula

R -N=C=O a relatively non-polar reaction solvent is used, the resulting product of general formula I is usually precipitated from the solution after the reaction is completed and the reaction mixture is cooled to room temperature. Under these conditions, the product is generally isolated by filtration. However, if relatively polar solvents are used and the product is still in solution after the reaction is completed, it can be isolated by evaporation of the solvent. Alternatively, when using water-miscible solvents, the product precipitates upon dilution of the reaction medium with water and can again be isolated by filtration. The reaction product of general formula I can be purified by standard procedures, for example by recrystallization.

The reaction between the compound of formula IV and the isocyanate of formula R -N=C=O can be accelerated by the addition of a base, such as a tertiary amine, for example trimethylamine, triethylamine, tributylamine, N-methylpiperidine, N-methylmorpholine or N,N-dimethylaniline. Usually about 1 to 4 equivalents of the basic agent are added, which allows the use of a reaction temperature in the range of 20 to 50 ° C. After the reaction is complete, the reaction medium must be neutralized (or acidified), after which the product is then isolated as described above.

Isocyanates of the general formula R -N=C=O can be prepared by standard procedures - see further Organic Functional Group Preparations”, Sandler and Káro, Part I, second edition, Academie

Press, Inc., New York, N.Y., 1983, Chapter 12, pp. 364-369. A particularly suitable method 2 consists in the reaction of the appropriate amine of the general formula R "Nt^ with phosgene, proceeding according to the following reaction scheme:

R ² -NH ₂ + COC1 ₂ -*· r ² -n=c=o + 2 HC1

Numerous isocyanates of the general formula R -N=C=O are known from the prior art.

The starting materials of general formula IV are prepared by introducing a side chain of the formula

-C(=O)-R^ to a compound of formula III by reaction with a derivative of the corresponding acid of formula 1 R -C(=O)-rOH in a lower alkanol solvent (e.g. ethanol) in the presence of an alkali metal salt of the lower alkanol solvent (e.g. sodium ethoxide) using standard procedures. Typical useful derivatives of the acid of formula R^-C(=O)CH include acid chlorides, acid anhydrides of the formula.

R ¹ -C(=0)-OC(=0)-R ¹ , k ¹ -C(=0)-OC(=0)-R ⁵ and R ² -C(=0)-0-C(=0)-OR ⁶ and simple alkyl esters of the general formula

R ¹ -C(=0)-OR ⁶ in 5 in which general formulae R represents a bulky lower alkyl group, such as a tert-butyl group and R^ represents a lower alkyl group. Usually a small excess of the acid derivative of the general formula R^-C(=0)-OH is used and the alkoxide is usually present in an amount ranging from one to two molar equivalents, based on the above-mentioned acid derivative of the general formula R^-C(=0)-OH. The reaction between the acid derivative of the general formula R^-C(=0)-OH and the compound of the general formula III is usually initiated at a temperature of 0 to 25 °C, but then the reaction mixture is generally heated to a temperature of 50 to 130 °C, preferably to a temperature of about 80 °C, to complete the reaction. Under these conditions, reaction times ranging from several hours, for example from two hours, to several days, for example up to two days, are usually used. The reaction mixture is then cooled, diluted with excess water and acidified, after which the product of general formula IV is isolated by filtration or standard solvent extraction.

The 2-oxindole compounds of formula III are prepared by known methods or by methods analogous to those known in the art (see Rodd's Chemistry of Carbon Compounds, 2nd ed., ed. 3. Coffey, vol. VI part A, Elsevier Scientific Publishing Company, 1973, pp. 448-450; Gassman et al., Journal of Organic Chemistry, 42, 1340 (1977); Wright et al., Journal of the American Chemical Society, 78, 221 (1956); Beckett et al., Tetrahedron, 24, 6093 (1968); U.S. Pat. Nos. 4,1 3,882,236, 4,006,161 and 4,160,032; Walker, Journal of the American Chemical Society, 77, 3844 (1955); Protiva et al., Collection of Czechoslovak Chemical Communications, 44, 2 108 (1979); McEvoy et al., Journal of Organic Chemistry,

38, 3350 (1973); Simet, Journal of Organic Chemistry, 28, 3580 (1963); Wieland et al., Chemische Berichte, £6, 253 (1963) and references cited therein].

The compounds of formula I are acidic and form salts with bases, all of which salts with bases which can be prepared by conventional methods are within the scope of the invention. For example, these salts can be prepared simply by bringing the acidic and basic components, usually in stoichiometric ratios, into contact either in a non-aqueous or in an aqueous or partially aqueous medium, as appropriate. The resulting salts are isolated either by filtration, precipitation with a non-solvent followed by filtration, or evaporation of the solvent, or in the case of aqueous solutions, by lyophilization. Typical salts of the compounds of formula I which can be prepared are salts with primary, secondary or tertiary amines, alkali metal salts and alkaline earth metal salts. The salts with ethanolamine, diethanolamine and triethanolamine are particularly valuable.

Both organic and inorganic basic agents can be used effectively to produce salts, including organic amines, alkali metal hydroxides, alkali metal carbonates, etc.

alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides and alkaline earth metal alkoxides. Representative examples of these bases include primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucamine, secondary amines such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine, tertiary amines such as triethylamine, triethanolamine, N,N-dimethylaniline, N-ethylpiperidine and N-methylmorpholine, hydroxides such as sodium hydroxide, alkoxides such as sodium ethoxide and potassium methoxide, hydrides such as calcium hydride and sodium hydride, and carbonates such as potassium carbonate and sodium carbonate.

The compounds of general formula I exhibit analgesic activity. This activity can be demonstrated in mice by blocking abdominal spasms induced by the application of 2-phenyl-1,4-benzoquinone.

This test is carried out using a method based on the procedure described by Siegmund et al., Proc. Soc. Exp. Biol. Med., 95, 729-731 (1957), adapted for a large number of experiments [see further Milne and Twomey, Agents and Actions, 10, 31-37 (1980)]. These experiments are carried out on male Carworth white mice (strain CF-1) weighing 18-20 g. All mice are fasted overnight before administration of the active substance and the start of the test.

Compounds of general formula I are dissolved or suspended in a vehicle consisting of 5% ethanol, 5% surfactant emulphor 620 (a mixture of oxyethylated fatty acid esters) and 90% saline. This vehicle also serves as a control. Logarithmically graded doses are used (i.e. ... 0.32, 1.0, 3.2, 10, 32 ... mg/kg). The test substances are administered orally at various concentrations to maintain a constant volume of administration - 10 ml/kg body weight. The above-mentioned method described by Milné and Twomey is used to determine the efficacy and potency of the effect.

Mice are given the test substance orally and 2 mg/kg of 2-phenyl-1,4-benzoquinone intraperitoneally one hour later. Immediately thereafter, the mice are individually placed in heated chambers made of transparent plastic and the number of abdominal contractions is recorded 5 minutes after the application of 2-phenyl-1,4-benzoquinone. This recording is carried out for 5 minutes. The degree of analgesia (% MPE) is then calculated based on the suppression of the number of abdominal contractions compared with control animals tested on the same day. The MPE value, which represents the best estimate of the dose that reduces abdominal contractions to 50% of the control value, is used to calculate the data found in determining the response to the applied dose in at least four such tests (N^5).

The compounds of formula I also exhibit anti-inflammatory activity. This activity is demonstrated by tests on rats using a method based on the standard rat carrageenan-induced limb edema test (Winter et al., Proc. Soc. Exp. Biol. Med., 111,

544, 1962).

Unanesthetized adult male white rats weighing 150 to 190 g are numbered, weighed, and an ink mark is made on their hind limb in the area of the lateral ankle. The marked limb of the animal is then immersed in mercury so that the mercury level reaches exactly to the mark. The mercury is contained in a glass cylinder connected to a pressure transducer (Statham).

The output from the transducer is routed through a control unit to a microvoltmeter. The volume of mercury displaced by the immersed limb is recorded. The test substances are administered by gavage. One hour after the application of the test substance, edema is induced by injection of 0.05 ml of a 1% carrageenan solution into the plantar tissue of the marked limb. The volume of this limb is measured immediately afterwards.

The increase in limb volume 3 hours after carrageenan injection compared to control animals that were given vehicle without active substance only represents an individual inflammatory response.

The results achieved in the test just described are summarized in the following table, where they are presented in percentage values of inhibition of edema formation upon application of the test substances, compared to the condition in control animals.

X R ¹ R ² dose (mg/kg) inhibition (%) H methyl phenyl 33 40 H methyl phenyl 10 20 H methyl 4-chlorophenyl 33 4 H methyl 3-(trifluoromethyl)phenyl 33 24 H methyl 2,4-difluorophenyl 33 19 H methyl 4-fluorophenyl 33 20 H phenyl phenyl 33 8 H phenyl 4-chlorophenyl 33 6 H 3-pyridyl phenyl 33 39 H 3-pyridyl 4-chlorophenyl 33 10 H phenyl 2,4-difluorophenyl 33 22 H benzyl phenyl 33 17 H benzyl 2,4-difluorophenyl 33 23 H benzyl 4-chlorophenyl 33 14 H 2-thienyi 4-fluorophenyl 33 17

Continuation table

X R ¹ R ² (mg/kg) inhi^ H 2-furyl 4-fluorophenyl ^: <3 34 H 2-furyl 4-fluorophenanthrene !<·, 7 H cyclohexyl 4-fluorophenyl 3 3 13 H 2-thenyl 2,4-difluorophenyl 33 2 3 H 2-thenyl phenyl 33 40 H isopropyl 4-fluorophenyl 33 2 6 H cyclopropyl 4-fluorophenyl 26 H 2-furyl phenyl 3 3 4 8 H 2-furyl phenyl 10 1 6 H 2-furyl 2,4-difluorophenyl 33 5 3 H 2-furyl 2,4-difluorophenyl 10 2 3 H 2-thienyl phenyl 3 3 3 6 H 2-thienyl 2, 4-difluorophenyl 3 3 37 H 2r-thienyl 2,4-difluorophenyl 18 13 H 2-thienyl 2,4-difluorophenyl 1.8 10 H trifluoromethyl 4-fluorophenyl 33 12 H 2-furyl 4-chlorophenyl 32 12 H 2-furyl 2-(trifluoromethyl)phenyl 32 30 ru phenoxymethyl phenyl 32 20 H trifluoromethyl phenyl 32 24 H trifluoromethyl 2, 4-difluorophenyl 33 about B phenoxymethyl 4-chlorophenyl 32 35 H phenoxymethyl 4-chlorophenyl 10 6 I phenoxymethy1 2,4-difluorophenyl 3 2 25 H 2-thenyl 4-chlorophenylJ 3 2 26

Continuation table

X R ¹ R ² dose (mg/kg) inhibit: <%) H 2-thenyl 4-fluorophenyl 32 8 H 2-thenyl 3-tolyl 32 7 H 2-thenyl 3-fluorophenyl 32 9 H 2-thenyl 3-trifluoromethylphenyl 32 3 H 1-phenylethyl 2,4-difluorophenyl 32 17 H 2-thienyl 2-trifluoromethylphenyl 32 25 H 1-phenylethyl 4-fluorophenyl 32 25 H 2-furyl 2,4-dichlorophenyl 32 10 H 2-furyl 3-anisyl 32 12 H 2-thienyl 2,4-dichlorophenyl 32 7 H 2-thienyl 3-anisyl 32 8 H 2-furyl cyclohexyl 32 18 H 2-thienyl cyclohexyl 32 14 H phenoxymethyl cyclohexyl 32 23 H benzyl cyclohexyl 32 11 H 2-furyl 4-anisyl 32 36 H 2-thienyl 4-anisyl 32 40 H 2-furyl 2,4-dimethylphenyl 32 34 H 2-thienyl 2,4-dimethylphenyl 32 28 H 2-furyl 4-ethylphenyl 32 19 H 2-thienyl 4-ethylphenyl 32 26 H 4-chlorobenzyl phenyl 32 15 H 4-chlorobenzyl 2, 4-difluorophenyl 32 10 H 4-chlorobenzyl 4-chlorophenyl 32 16 H 4 - c h 1 o r be s i ·/. and 1 4-fluorophenyl 32 10

25284

Continuation table

X R ¹ R ² < ^: vk --, Ufig/xgí inhib bi í β Ϊ H 4-fluorobenzyl phenyl L: 23 H 4-fluorobenzyl phenyl 3 2 21 H 4-fluorobenzyl 4-chlorophenyl 3 2 17 H 4-fluorobenzyl 4-fluorophenyl 12 11 H 3-thenyl phenyl 32 3C H 3-thenyl 2,4-difluorophenylX 32 14 H 3-thenyl 4-chlorophenyl 32 11 fi 3-thenyl 4-fluorophenyl 3 2 25 H 3-furyl phenyl 32 26 H 3-furyl 2, 4-difluorophenyl 3 2 39 H 3-furyl 4-chlorophenyl 3? 3 H 3-furyl 4-fluorophenyl 3 3 29 H 3-thienyl phenyl 32 19 H 3-thienyl 2,4-difluorophenyl 9 13 H 3-thienyl 4-chlorophenyl 32 23 H 3-thienyl 4-fluorophenyl 32 16 H 4-chlorophenyl 4-fluoro-Oi;y i 32 12 He knows methyl benzyl 32 ' 19 í-i 2-furyl benzyl 32 20 H 2-thienyl benzyl 32 26 He knows phenyl bitches 1. 32 23 H 4-pyridyl 4-chlorophenyl 32 3 H 5-methyl-2-furyl phenyl 32 3 H 5-raethy1-2-fury1 2,4-difluorophenyl 32 23 He knows ?-pyridesX 4-chlorophenyl 32 4

Continuation table

X R ¹ R ² dose (mg/kg) inhibition (%) H 2-furyl ethyl 32 30 H 2-thienyl ethyl 32 22 H 2-thenyl ethyl 32 15 H methyl ethyl 32 5 5-Cl 2-furyl ethyl 32 27 5-Cl 2-thienyl ethyl 32 38 5-Cl methyl ethyl 32 3 5-Cl 2-thenyl ethyl 32 16 5-Cl 2-thienyl isopropyl 32 32 5-Cl 2-thenyl isoprr -pyl 32 25 5-Cl methyl isopropyl 32 16 5-Cl 2-furyl n-butyl 3 2 42 5-Cl 2-furyl n-butyl 10 3 3 5-Cl 2-furyl n-butyl 3.2 16 5-Cl 2-thenyl n-butyl 32 3 5-Cl 2-furyl tert.butyl 32 54 5-Cl 2-furyl tert.butyl 10 · 35 5-<.' 2-furyl tert.butyl 3.2 31 H 2-furyl isopropyl 32 42 H 2-furyl isopropyl 10 29 H 2-furyl isopropyl 3.2 17 H 2-thienyl isopropyl 32 46 H 2-thienyl isopropyl 10 3f(. H 2-thienyl isopropyl 3.2 24 5-Cl ic.-.. hyl tert.butyl 32 4 3

Continuation table

X R ¹ R ² dose inhibit. (mg/kg) (%) 5-Cl methyl tert.butyl 10 39 5-Cl methyl tert.butyl 3.2 24 H 2-furyl tert.butyl 32 31 5-Cl 2-thienyl tert.butyl 32 41 5-Cl 2-thienyl tert.butyl 10 34 5-Cl 2-thienyl tert.butyl 3.2 13 5-Cl 2-furyl. cyclohexyl 32 18 5-Cl methyl cyclohexyl 32 4 5-Cl 2-thenyl cyclohexyl 32 17 H 2-thenyl .tert.butyl 32 14 H 2-thienyl tert.butyl 32 51 H 2-thienyl tert.butyl 10 31 H 2-thienyl tert.butyl 3.2 18 H methyl tert.butyl 32 27 5-Cl 2-thenyl tert.butyl 32 35 H methyl isopropyl 32 17 H 2-furyl n-butyl 32 20 5-Cl 2-thienyl n-butyl 32 10 5-Cl methyl n-butyl 32 10 5-Cl 2-thienyl cyclohexyl 32 40 5-Cl 2-thienyl cyclohexyl 10 25 5-Cl 2-thienyl cyclohexyl 3.2 17 H 2-thienyl n-butyl 32 33 5-Cl cyclohexyl tert.butyl 32 8 5-Cl • cyclopentyl tert.butyl 32 26

Table of continuations

X R ¹ R ^from dose (mg/kg) inhibition <%) 5-C1 cyclobutyl tert.butyl 32 43 5-Cl cyclobutyl tert.butyl 10 20 5-CF ₃ 2-thienyl tert.butyl 32 14 5-CF ₃ 2-furyl tert.butyl 32 30 5-CF ₃ 2-thenyl tert.butyl 32 5 5-CF ₃ bicycle |~2,2, ]] heptan-2-yl tert.butyl 32 15 6-Cl 2-thienyl tert.butyl 32 63 6-Cl 2-thienyl tert.butyl 10 29 6-Cl 2-thienyl tert.butyl 3.2 27 6-Cl 2-furyl tert.butyl 32 68 6-Cl 2-furyl tert.butyl 10 27 6-Cl 2-furyl tert.butyl 3.2 15 5-Cl bicyclo[2,2,1]heptan-2-yl tert.butyl 32 3 6-Cl 2-thenyl tert.butyl 32 17 6-Cl bicyclo[2,2,1]heptan-2-yl tert.butyl 32 7 5-F 2-furyl tert.butyl 32 67 5-F 2-furyl tert.butyl 10 51 5-F 2-furyl tert.butyl 3.2 40 5-F 2-thienyl tert.butyl 32 51 5-F 2-thenyl target .'butyl 32 32 6-Cl 2-furyl isopropyl 32 66 6-Cl 2-furyl cyclohexyl 32 38 5-Cl 2-furyl phenyl 32 55 5-Cl 2-furyl 2,4-difluorophenyl 32 36

Continuation table

X R ¹ R ² dose (mg/kg) inhibition (%) ' 5-Cl 2-thienyl phenyl 32 26 5-Cl 2-thenyl phenyl 32 56 5-Cl 2-thenyl 2,4-difluorophenyl 32 28 6-Cl 2-thienyl isopropyl 32 14 6-Cl 2-thienyl cyclohexyl 32 22 6-Cl 3-thenyl tert.butyl 32 22 6-Cl 3-furyl tert.butyl 32 54 6-Cl 3-thienyl tert.butyl 32 32 6-Cl 2-furyl ethyl 32 36 6-Cl 2-thienyl ethyl 32 29 5-Cl 2-chlorobenzyl phenyl 32 4 5-Cl 2-thienyl 2,4-difluorophenyl 32 11 5-Cl 4-chlorobenzyl tert.butyl 32 22 5-F 2-furyl isopropyl 32 50 5-F 2-thienyl isopropyl 32 37 5-F 2-thenyl isopropyl 32 38 5-F 3-furyl isopropyl 32 45 5-F 3-thienyl isopropyl 32 22 5-F 3-thenyl isopropyl 32 40 6-CF ₃ benzyl phenyl 32 8 6-F 2-thienyl phenyl 32 19

Due to their analgesic activity, the compounds of formula I are useful for acute administration to mammals for the relief of pain, for example post-operative pain or post-traumatic pain. Furthermore, the compounds of formula I are useful for chronic administration to mammals for the relief of symptoms of chronic diseases, such as inflammation in rheumatoid arthritis, and for the relief of pain in osteoarthritis and other musculoskeletal disorders.

When using a compound of formula I or a pharmaceutically acceptable salt thereof as either an analgesic agent or an anti-inflammatory agent, the compound may be administered to a mammal either alone or, preferably, in combination with pharmaceutically acceptable diluents or carriers in the form of pharmaceutical compositions, in accordance with standard pharmaceutical practice. The active compound may be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration.

In a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof, the weight ratio of carrier to active ingredient will normally be in the range of 1:4 to 4:1, preferably 1:2 to 2:1. In any particular case, however, the exact ratio will depend on such factors as the solubility of the active ingredient, the dosage contemplated and the intended route of administration.

The compound of formula I according to the invention can be administered orally, for example, in the form of tablets or capsules, or in the form of an aqueous solution or suspension. Tablets intended for oral administration usually contain carriers commonly used for this purpose, including lactose and corn starch, and in their manufacture, lubricants such as magnesium stearate are generally used. Suitable diluents for the preparation of capsules for oral administration are lactose and dried corn starch. To prepare aqueous suspensions for oral administration, the active ingredient is combined with emulsifiers and suspending agents. If desired, certain sweeteners and/or flavorings can be added. For intramuscular, intraperitoneal, subcutaneous and intravenous applications, sterile solutions of the active ingredients are usually prepared, the pH of these solutions being suitably adjusted and buffered. When manufacturing preparations for intravenous administration, it is necessary to control the total concentration of soluble components so that the resulting preparation is always isotonic.

The daily dose of a compound of the general formula I or its salt in human medicine is usually determined by the attending physician. This dose will also vary depending on the age, weight and response of the patient, as well as on the severity of the symptoms in the patient and the efficacy of the compound applied. For acute application for pain relief, the dose that produces an effective analgesic response will in most cases range from 0.02 to *0.5 g as needed (for example, for application every 4 hours to 24 hours). In the case of chronic applications for the relief (treatment) of inflammation and pain, the daily dose will in most cases range from 0.02 to 1.0 g, preferably from 0.05 to 0.5 g, which total daily dose can be administered once or in several partial doses. In individual cases, however, it may be necessary to apply doses outside these limits.

The invention is illustrated by the following translations of embodiments and preparations, which, however, do not limit the scope of the invention in any way.

Example 1

N-phenyl-3-acetyl-2-oxindole-1-carboxamide

To a suspension of 526 mg (3.0 mmol) of 3-acetyl-2-oxindole in 6 ml of toluene was added 393 mg (3.3 mmol) of phenyl isocyanate with stirring and the mixture was heated to reflux for 7 hours. The reaction mixture was cooled to room temperature and the precipitate was filtered off. The solid material thus obtained gave, after recrystallization from about 20 ml of acetonitrile, 229 mg of the title compound as off-white needle-like crystals, melting at 171-173 °C.

Analysis: calculated for 69.38% C, 4.79% H, 9.52% N;

found 69.31% C, 4.97% H, 9.59% N.

Example 2

N-(2,4-difluorophenyl)-3-(2-furoyl)-2-oxindole-1-carboxamide

To a solution of 682 mg (3.0 mmol) of 3-(2-furoyl)-2-oxindole in 8 ml of dimethyl sulfoxide, 668 mg (6.6 mmol) of triethylamine and then 512 mg (3.3 mmol) of 2,4-difluorophenyl isocyanate are added with stirring. Stirring is continued for 1 hour, after which the reaction mixture is poured into 60 ml of water. The resulting mixture is acidified with 3N hydrochloric acid and then cooled in ice. The precipitated solid material is filtered off and recrystallized from about 35 ml of acetic acid.

925 mg of the title compound are obtained in the form of yellow crystals with a melting point of 191-192°C.

Analysis: calculated for 62.83% C, 3.16% H, 7.33% N;

found 62.70% C, 3.07 i H, 7.26% N.

Example 3

The following compounds were prepared by a procedure analogous to that in Examples 1 and 2:

X R ¹ R ² Melting point H 2-furyl ethyl 201 to 201.5 H 2-thienyl ethyl 128 to 129.5 H (2-thienyl)methyl ethyl 130 to 131 H methyl ethyl 157 to 158 5-Cl 2-furyl ethyl 134 to 135 5-Cl 2-thienyl ethyl 154 to 155 5-Cl methyl ethyl 173 to 174 5-Cl (2-thienyl)methyl ethyl 154 to 155 5-Cl 2-thienyl isopropyl 129 to 130 5-Cl (2-thienyl)methyl isopropyl 155 to 156 5-Cl methyl isopropyl 186 to 187 5-Cl 2-furyl n-butyl 100 to 101 5-Cl 2-thienyl n-butyl 152 to 153

Table X continued • R ¹ R ² Melting point (°C) 5-Cl 2-furyl tert.butyl 171 to 171.5 H 2-furyl isopropyl 114 to 115 H 2-thienyl isopropyl 177 to 178.5 5-Cl methyl tert.butyl 219 to 220 H 2-furyl tert.butyl 160 to 161 5-Cl 2-thienyl tert.butyl 178 to 179.5 H (2-thienyl)methyl tert.butyl 141 to 142 (decomposition) H 2-thienyl tert.butyl 163 to 164 H methyl tert.butyl • 163 to 164 5-Cl (2-thienyl)methyl tert.butyl 218 to 219 (decomposition) H methyl isopropyl 162.5 to 163.5 H 2-furyl n-butyl 87 to 88 5-Cl 2-thienyl n-butyl 123 to 124 5-Cl methyl n-butyl 167 to 169 H 2-thienyl n-butyl 137 to 138 5-Cl cyclohexyl tert.butyl 239 to 240 (decomposition) 5-Cl cyclopentyl tert.butyl 229 to 230 (decomposition) 5-Cl cyclobutyl tert.butyl 226 to 227 (decomposition) 5-CF ₃ 2-thienyl tert.butyl 162 to 163 5-CF ₃ 2-furyl tert.butyl 171.5 to 172.5 5-CF ₃ (2-thienyl)methyl tert.butyl 133 to 134 6-C1 2-furyl tert.butyl 168.5 to 169.5 6-Cl (2-thienyl)methyl tert.butyl 151 to 152 5-Cl 2-furyl cyclohexyl 138 to 139 5-Cl methyl cyclohexyl 226 to 227 5-Cl (2-thienyl)methyl cyclohexyl 153 to 154

Continuation table

X R ¹ R ² Melting point <°C) 5-C1 2-thienyl cyclohexyl 158 to 159 H methyl 3-(trifluoromethyl)phenyl 186 to 188 H methyl 2,4-difluorophenyl 161 to 162 H methyl 4-fluorophenyl 181 to 183 H benzyl phenyl 145 to 147 H (2-thienyl)methyl 2,4-difluorophenyl 165 to 167 H (2-thienyl)methyl phenyl 165 to 167 H isopropyl 4-fluorophenyl 176 to 177 H cyclopropyl 4-fluorophenyl 202 to 203 H 2-thienyl phenyl 152 to 153 H 2-thienyl 2,4-difluorophenyl 164 to 165 H 2-furyl 4-chlorophenyl 200.5 to 201.5 (decomposition) H 2-furyl 2-(trifluoromethyl)phenyl 202 to 203 (decomposition) H trifluoromethyl 4-chlorophenyl 202 to 230 H trifluoromethyl 2,4-difluorophenyl 133.5 to 134.5 H 2-thienyl 2-(trifluoromethyl)phenyl 166.5 to 167.5 (decomposition) H 2-furyl 2,4-dichlorophenyl 235.5 (decomposition) H 2-furyl 3-methoxyphenyl 137 to 138 H 2-thienyl 2,4-dichlorophenyl 221.5 to 222.5 (decomposition) H 2-furyl 4-methoxyphenyl 168 to 169.5 H 2-thienyl 4-methoxyphenyl 178.5 to 179.5 H 2-furyl 2, 4-dimethylphenyl 176 to 177 H 2-thienyl 2,4-dimethylphenyl 171 to 172 H 2-furyl 4-ethylphenyl 154.5 to 155.5 H 2-thienyl 4-ethylphenyl 131 to 132 H methyl 4-chlorophenyl 225 to 227

Continuation table

XR ¹

Melting point (°C)

H phenyl phenyl 176 until 177 H phenyl 4-chlorophenyl 215 until 217 H 3-pyridyl phenyl 193 until ¹⁹⁵ H 4-fluorophenyl 4-chlorophenyl 212 until 213 H 3-pyridylL 4-chlorophenyl 220 until 221 H 4-fluorophenyl phenyl 189 until 191 H phenyl 2,4-difluorophenyl 204 until 206 H benzyl 2,4-difluorophenyl 151 until 152 H benzyl 4-chlorophenyl 178 until 179 H 2-thienyl 4-fluorophenyl 175 until 176.5 H 2-furyl 4-fluorophenyl 166.5 until 167.5 (decomposition) H cyclohexyl 4-fluorophenyl 180 until 181 H 2-furyl phenyl 162 until 163 H 3-pyridyl 2,4-difluorophenyl 254 (decomposition) H trifluoromethyl 4-fluorophenyl 203 until 204 H trifluoromethyl phenyl .139.5 until 140.5 H phenoxymethyl phenyl 158 until 159 H phenoxymethyl 4-chlorophenyl 137.5 until 138.5 H phenoxymethyl 2,4-difluorophenyl 137.5 until 138.5 H (2-thienyl)methyl 4-chlorophenyl 165 until 166 H (2-thienyl)methyl 4-fluorophenyl 161 until 163 H (2-thienyl)methyl 3-tolyl 147 until 149 H {2-thienyl)methyl 3-fluorophenyl 152 until 154 H (2-thienyl)methyl 3-trifluoromethylphenyl 139 until 140 H 1-phenylethyl 2,4-difluorophenyl 152.5 until 154 H 2-thienyl 4-chlorophenyl 196.5 until 197.5

Continuation table

XR ¹ R ² Melting point (°C)

H 1-phenylethyl 4-fluorophenyl 166 until 167 H 2-thienyl 3-methoxyphenyl 148.5 until 149.5 H 2-furyl cyclohexyl 104 until 105 H 2-thienyl cyclohexyl 116 until 117 H phenoxymethyl cyclohexyl 159 until 160 H benzyl cyclohexyl 122 until 123 H 4-chlorobenzyl phenyl 180 until 181 H 4-chlorobenzyl 2,4-difluorophenyl 182 until 183 H 4-chlorobenzyl 4-chlorophenyl 184 until .186 H 4-chlorobenzyl 4-fluorophenyl 165 until 166 H 4-fluorobenzyl phenyl 179 until 181 H 4-fluorobenzyl 2,4-difluorophenyl 189 until 191 H 4-fluorobenzyl 4-chlorophenyl 205 until 207 H 4-fluorobenzyl 4-fluorophenyl 198 until 199 H (3-thienyl)methyl phenyl 133 until 134 H (3-thienyl)methyl 2,4-difluorophenyl 162 until 163 (3-thienyl)methyl 4-chlorophenyl 182 until 184 ri (3-thienyl)methyl 4-fluorophenyl 145 until 147 3-furyl phenyl 145 until 146 H 3-furyl 2,4-difluorophenyl 178 until 179 H 3-furyl 4-chlorophenyl 190 until 191 H 3-furyl 4-fluorophenyl 189 until 190 H 3-thienyl phenyl 166 until 168 H 3-thienyl 2,4-difluorophenyl 188 until 190 H 3-thienyl 4-chlorophenyl 216 until 218 H 3-'thienyl 4-fluorophenyl 209.5 until 210.5

Continuation table

X R ¹ 0 R~ Temperature . melting point (°C) H 4-chlorophenyl 4-fluorophenyl 219 until 220 H methyl benzyl 162 until 16 4 H 2-thienyl benzyl 117 until 118 H 2-furyl benzyl 124 until 126 H 4-pyridyl phenyl 212.5 until 213.5 (decomposition) H 4-pyridyl 2,4-difluorophenyl 229 until 230 H 4-pyridyl 4-chlorophenyl 211 until 213 (decomposition) H 2-pyridyl phenyl 208 until 209 H 5-methyl-2-furyl phenyl 156 until 157 H 5-methyl-2-furyl 2,4-difluorophenyl 189 until 191 H 2-pyridyl 2,4-difluorophenyl 230 until 232 H 2-pyridyl 4-chlorophenyl 207 until 208 (decomposition) 5-CF ₃ bicyclo £2,2,1]heptan-2-yl tert.butyl 212.5 (decomposition) 5-C1 bicyclo[2,2, heptan-2-yl , butyl 23 5 236 (decomposition) 6-C1 bicyclo £2,2,1]heptan-2-yl tert.butyl 225 (decomposition) 5-F 2-furyl target < butyl 184 _f 5 nl 1 5.5 5-F 2-thienyl tore«. butyl 183.5 (decomposition) 5-F (2-thienyl)methyl tert.butyl 192.5 until 199, 5 G-Cl 2-furyl isopropyl j 5 5 - 5 until 1'6.5 6-C1 2-furyl cyclohexyl 1. !i 4 until i ' 5 5-C1 2-furyl phenyl 191 .5 and 192.5 5-Cl 2-furyl 2,4-Diphenyl 4 until 21 5 5-Cl 2-thienyl phenyl 1 9 4 and J 9 5 5-Cl (2-thienyl)methyl phenyl 167.5 ,TŽ 1 - 9

Table X continuation of R ¹ R ² Melting point (°C) 5-Cl (2-thienyl)methyl 2,4-difluorophenyl 211.5 to 212.5 6-Cl 2-thienyl isopropyl 118 to 119 6-Cl 2-thienyl cyclohexyl 145 to 146 5-Cl (3-thienyl)methyl tert.butyl 222 to 224 5-Cl 3-furyl tert.butyl 181 to 182 (decomposition) 5-Cl 3-thienyl tert.butyl 209 to 211 (decomposition) 6-Cl 2-furyl ethyl 157.5 to 158.5 6-Cl 2-thienyl ethyl 138 to 139 5-Cl 2-chlorobenzyl phenyl 218 to 219 (decomposition) 5-Cl 2-chlorobenzyl 2, 4-difluorophenyl 216 (decomposition) 5-Cl 2-thienyl 2,4-difluorophenyl 200.5 to 201.5 5-Cl 4-chlorobenzyl tert.butyl 214 to 216 (decomposition) 5-F 2-furyl isopropyl 141 to 142 5-F 2-thienyl isopropyl 185 to 187 5-F (2-thienyl)methyl isopropyl 143 to 144 5-F 3-furyl isopropyl 163 to 164 5-F 3-thienyl isopropyl 179 to 180.5 5-F (3-thienyl) ntethyl isopropyl 156 to 157 6-CF ₃ 2-thienyl phenyl 187 to 189 6-CF3 benzyl phenyl 169 to 170 6-F 2-thienyl phenyl 174 to 175 6-F 2-thienyl 4-methoxyphenyl 175 to 176 5-CH _r C0 6 5 benzyl phenyl 167 to 170 5~CH ₃ CO (2-thienyl)methyl phenyl 194 to 196 5-Cl benzyl 4-methoxyphenyl 198 to 200 5-Cl (2-thienyl)methyl 4-methoxyphenyl 195 to 197

The table continues

XR ¹ R" Melting point (°C)

5-F 2-thienyl phenyl 164 until 1.6 6 5-F 2-thienyl 4-methoxyphenyl 177 until 179 5-NO ₂ phenoxymethyl phenyl 224 until 225 5-C _r H_CO 6 5 2-thienyl phenyl 160 until 163 5-CH _c CO 6 5 (2-thienyl)methyl phenyl 171 until 173 5-CH^CO 2-thienyl phenyl 193 until 195 5- _CH3CO benzyl phenyl 195 until 198 5-C1 2-thienyl 4-methoxyphenyl 185 until 187 5-C1 benzyl phenyl 156 until 158 5-F benzyl phenyl 175 until 177 5-C1 4-chlorophenyl phenyl 239 until 240 6-F 2-tetrahydrofuranyl 4-methoxyphenyl 170 until 172

Example 4

N-tert-butyl-6-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide, ethanolamine salt

To a suspension of 3.77 g of N-tert-butyl-6-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide in 60 ml of methanol was added 610 mg of ethanolamine. The resulting mixture was heated to reflux for 5 minutes and then allowed to cool. The title compound was obtained by filtering off the precipitate that separated.

Prepared

3-(2-furoyl)-2-oxindole

To a solution of 5.5 g (0.24 mol) of sodium in 150 ml of ethanol at room temperature, 13.3 g (0.10 mol) of 2-oxindole were added with stirring. The resulting suspension was cooled in ice and 15.7 g (0.12 mol) of 2-furoyl chloride was added dropwise over 10 to 15 minutes. The cooling bath was removed, 100 ml of ethanol was added, the reaction mixture was heated to reflux for 7 hours and then left to stand overnight. The solid material was filtered off, taken up in 400 ml of water and the resulting mixture was acidified with concentrated hydrochloric acid. After cooling in ice, the solid product was filtered off and recrystallized from 150 ml of acetic acid. 8.3 g of yellow crystalline material melting with decomposition at 209 to 210 °C were obtained.

Analysis: calculated for C 12 H 12 O 12 N 68.72% C, 3.99% H, 6.17% N;

found 68.25% C, 4.05% H, 6.20% N.

Preparation 2

By a procedure analogous to that in preparation 1, the following additional products are obtained by reacting 2-oxindole with the chloride of the respective acid:

3-(2-thenoyl)-2-oxindole, melting point 189-190°C (yield 17%).

3-[2-(2-thienyl)acetyl]-2-oxindole, melting point 191-192.5 °C (yield 38%).

3-(2-phenoxyacetyl)-2-oxindole with a melting point of 135 to 136 °C (yield 42%) and

5-chloro-3-[2-(2-thienyl)acetyl]-2-oxindole, melting point 228-230 °C (yield 22%).

Preparation 3

3-(3-furoyl)-2-oxindole

To a solution of 2.8 g (0.12 mol) of sodium in 200 ml of ethanol, 13.3 g (0.10 mol) of 2-oxindole and then 16.8 g of ethyl 3-furoate were added with stirring. The mixture was heated to reflux for 47 hours, then cooled and the solvent was evaporated in vacuo. The residue was triturated with 200 ml of ether, the solid material was filtered off and discarded. The filtrate was evaporated in vacuo, the residue was triturated with diisopropyl ether and the mixture was filtered. The solid was suspended in 250 ml of water, the suspension was acidified with concentrated hydrochloric acid and the resulting mixture was stirred, during which a solid product precipitated from it, which was isolated by filtration and recrystallized first from acetic acid and then from acetonitrile. 705 mg of the title compound are obtained, melting point 185-186°C.

Analysis: calculated for C 25 H 20 O 2 N 68.72% C, 3.99% H, 6.17% N;

found 68.72% C, 4.14% H, 6.14% N.

Preparation4

By a procedure analogous to that in Preparation 3, the following compounds are obtained by reacting the appropriate 2-oxindole with the ethyl ester of the corresponding carboxylic acid:

5-chloro-3-(2-thenoyl)-2-oxindole with a melting point of 190.5 to 192 °C (yield 36 Ž),

5-chloro-3-(2-furoyl)-2-oxindole, melting point 234 to 235 °C (yield 54%),

5-chloro-3-(2-phenylacetyl)-2-oxindole with a melting point of 241 to 243 °C (yield 61%),

5-fluoro-3-(2-furoyl)-2-oxindole, melting point 222 to 224 °C (yield 51%),

5-fluoro-3-(2-thenoyl)-2-oxindole with a melting point of 200 to 203 °C (yield 26%),

6-fluoro-3-(2-furoyl)-2-oxindole with a melting point of 239 to 242 °C (yield 26%) and

6-chloro-5-fluoro-3-(2-thenoyl)-2-oxindole with a melting point of 212 to 2Γ5 °C (yield %).

In an analogous manner, using the respective 2-oxindole and ethyl ester according to Preparation 3, the following compounds are obtained:

5-trifluoromethyl-3-(2-furoyl)-2-oxindole a

6-trifluoromethyl-3-(2-thenoyl)-2-oxindole.

Preparation 5

3-trifluoroacetyl-2-oxindole

3.0 g (0.13 mol) of sodium are dissolved in 150 ml of ethanol and 13.3 g (0.10 mol) of 2-oxindole are added to the solution at room temperature with stirring. The resulting mixture is cooled in ice and 18.5 g (0.13 mol) of ethyl 2,2,2-trifluoroacetate is added rapidly with stirring. The cooling bath is removed, the reaction mixture is heated to the boiling point of the solvent under reflux, boiled for 1 hour, then cooled and most of the solvent is evaporated in vacuo. The residue is taken up in 300 ml of water, 100 ml of concentrated hydrochloric acid are added, the resulting mixture is cooled in ice and the solid material that has separated is filtered off. This solid product is dissolved in ethyl acetate, the ethyl acetate solution is washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. After recrystallization of the residue from toluene, 13.2 g of the title compound are obtained in the form of yellow crystals with a melting point of 183.5-184.5°C.

Analysis: calculated for 52.41% C, 2.64% H, 6.11% N;

found 52.52% C, 2.75% H, 6.04% N.

Preparation 6

5-chloro-2-oxindole

To a suspension of 100 g (0.55 mol) of 5-chloroisatin in 930 ml of ethanol, 40 ml (0.826 mol) of hydrazine hydrate was added with stirring to form a red solution. This solution was heated to reflux for 3.5 hours, during which time a precipitate separated. The reaction mixture was stirred overnight and the precipitate was then filtered off. 5-chloro-3-hydrazono-2-oxindole was obtained as a yellow solid.

This substance, which weighed 105.4 g after drying in a vacuum oven, was added portionwise over 10 minutes to a solution of 125.1 g of sodium methoxide in 900 ml of absolute ethanol. The resulting solution was heated to reflux for 10 minutes and then concentrated in vacuo. The resinous solid residue was dissolved in 400 ml of water, the aqueous solution was decolorized with activated charcoal and poured into a mixture of 1 liter of water and 180 ml of concentrated hydrochloric acid containing ice cubes. The precipitated reddish-yellow solid was filtered off, washed thoroughly with water, dried, washed with diethyl ether and finally recrystallized from ethanol. 38.9 g of the title compound were obtained, melting at 193-195 °C with decomposition.

In an analogous manner, 5-methylisatin is converted to 5-methyl-2-oxindole by treatment first with hydrazine hydrate and then with sodium ethoxide in ethanol. The product melts at 173-174 °C.

Preparation 7

4-chloro-2-oxindole and 6-chloro-2-oxindole

A. 3-Chloro-isonitrosoacetanilide

To a solution of 113.23 g (0.686 mol) of chloral hydrate in 2 liters of water, 419 g (2.95 mol) of sodium sulfate are added with stirring, followed by a solution prepared from 89.25 g (0.70 mol) of 3-chloroaniline, 62 ml of concentrated hydrochloric acid and 500 ml of water, a thick precipitate separating out. A solution of 155 g (2.23 mol) of hydroxylamine in 500 ml of water is added with stirring, the reaction mixture is slowly heated with constant stirring and maintained at a temperature between 60 and 75 °C for about 6 hours, during which time another 1 liter of water is added to it to facilitate stirring. The resulting mixture is cooled, the precipitate separated is filtered off and dried. 136.1 g of 3-chloroisonitrosoacetanilide is obtained.

B. 4-chlorisatin and 6-chlorisatin

To 775 ml of concentrated sulfuric acid, preheated to 70 °C, 136 g of 3-chloro-isonitrosoacetanilide are added with stirring at such a rate that the temperature of the reaction medium is maintained between 75 and 85 °C. After addition of all the solid material, the reaction mixture is heated to 90 °C for a further 30 minutes, then cooled and slowly poured onto approximately 2 liters of ice with stirring. Additional ice is added as necessary to maintain the temperature below room temperature. The red-orange precipitate that separates is filtered off and, after washing with water, dried. The solid material is suspended in 2 liters of water and brought into solution by adding approximately 700 ml of 3N sodium hydroxide. The solution is filtered and its pH is adjusted to 8 with concentrated hydrochloric acid. 120 ml of a mixture of 80 parts of water and 20 parts of concentrated hydrochloric acid are added, the precipitated solid product is filtered off and, after washing with water, dried. 50 g of crude 4-chloroisatin is obtained. The filtrate after isolation of 4-chloroisatin is acidified with concentrated hydrochloric acid to pH 0, whereby another precipitate is separated, which, after filtering off, washing with water and drying, gives 43 g of crude 6-chloroisatin.

The crude 4-chloroisatin was recrystallized from acetic acid to give 43.3 g of a substance melting at 258-259°C.

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

C. 4-chloro-2-oxindole

To a suspension of 43.3 g of 4-chloroisatin in 350 ml of ethanol is added 17.3 ml of hydrazine hydrate, the reaction mixture is heated to reflux for 2 hours, then cooled and the precipitate is filtered off. 43.5 g of 4-chloro-3-hydrazono-2-oxindole with a melting point of 235-236 °C is obtained.

To a solution of 22 g of sodium in 450 ml of anhydrous ethanol is added in portions with stirring

43.5 g of 4-chloro-3-hydrazono-2-oxindole, the resulting solution is heated to reflux for 30 minutes, then cooled and concentrated to a resinous residue, which is dissolved in 400 ml of water. The solution is decolorized with activated carbon and poured into a mixture of 1 liter of water and 45 ml of concentrated hydrochloric acid. The precipitate that separates is filtered off and, after drying, recrystallized from ethanol. 22.4 g of 4-chloro-2-oxindole melting with decomposition at 216-218 °C is obtained.

D. 6-chloro-2-oxindole

By a procedure analogous to that in Preparation 2C, 14.2 g of 6-chloro-2-oxindole with a melting point of 196-198 °C is obtained by reacting 6-chloroisatin with hydrazine hydrate.

Preparation 8

5,6-difluoro-2-oxindole

By a procedure analogous to that in paragraphs A and B of the previous preparation, the reaction of 3,4-difluoroaniline with chloral hydrate and hydroxylamine, followed by cyclization with sulfuric acid, yields 5,6-difluoroisatin, which is treated with hydrazine hydrate and then with sodium methoxide in ethanol by a procedure analogous to that in preparation 6. The title compound is obtained, with a melting point of 187-190 °C.

Preparation 9

5-fluoro-2-oxindole

A solution of 10.8 g (0.1 mol) of tert-butyl hypochlorite in 25 ml of dichloromethane is added dropwise to a solution of 11.1 g (0.1 mol) of 4-fluoroaniline in 200 ml of dichloromethane at a temperature of -60 °C to -65 °C with stirring. Stirring is continued at a temperature of -60 to -65 °C for another 10 minutes, after which a solution of 13.4 g (0.1 mol) of ethyl-2-(methylthio)acetate in 25 ml of dichloromethane is added dropwise to the mixture. The mixture is stirred for another 1 hour at a temperature of -60 °C, after which a solution of 11.1 g (0.11 mol) of triethylamine in 25 ml of dichloromethane is added dropwise at a temperature of -60 to -65 °C. The cooling bath is removed and after warming the reaction mixture to room temperature, 100 ml of water is added to it. The phases are separated, the organic phase is washed with saturated sodium chloride solution and evaporated in vacuo. The residue is dissolved in 350 ml of diethyl ether to which 40 ml of 2N hydrochloric acid have been added. The mixture is stirred overnight at room temperature, then the phases are separated and the ether phase is washed first with water and then with saturated sodium chloride solution. After drying over sodium sulfate, the ether phase is evaporated in vacuo. 17 g of an orange-brown solid are obtained, which are triturated with isopropyl ether. The solid then gives, after recrystallization from ethanol, 5.58 g of 5-fluoro-3-methylthio-2-oxindole, melting point 151.5 to

152.5 °C.

Analysis: for CgHgONFS calculated 54.80% C, 4.09% H, 7.10% N;

found 54.74% C, 4.11% H, 7.11% N.

986 mg (5.0 mmol) of the 5-fluoro-3-methylthio-2-oxindole prepared above were added to a mixture of two teaspoons of Raney nickel and 50 ml of absolute ethanol, and the reaction mixture was heated to reflux for 2 hours. The catalyst was separated by decantation and washed with absolute ethanol. The combined ethanol solutions were evaporated in vacuo and the residue was dissolved in dichloromethane. The dichloromethane solution was dried over sodium sulfate and evaporated in vacuo to give 475 mg of 5-fluoro-2-oxindole, mp 121-134 °C.

In an analogous manner, 4-trifluoromethylaniline is reacted with tert-butyl hypochlorite, ethyl 2-(methylthio)acetate and triethylamine, and the resulting 3-thiomethyl-5-trifluoromethyl-2-oxindole is reduced with Raney nickel. 5-trifluoromethyl-2-oxindole with a melting point of 189.5-190.5 °C is obtained. _

Preparation 10

6-chloro-5-fluoro-2-oxindole

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

13.5 ml (0.166 mol) of pyridine. The resulting solution is cooled to about 0 °C and added to it

13.2 ml (0.166 mol) of 2-chloroacetyl chloride. The reaction mixture is stirred at room temperature for 5 hours and then extracted first twice with 100 ml of 1N hydrochloric acid and then with 100 ml of saturated sodium chloride solution. The resulting toluene solution is dried over magnesium sulfate and concentrated in vacuo. 32.6 g (88%) of N-(2-chloroacetyl)-3-chloro-4-fluoroaniline are obtained.

26.63 g of this N-(2-chloroacetyl)-3-chloro-4-fluoroaniline are thoroughly mixed with 64 g of anhydrous aluminum chloride and the mixture is heated at 210-230 °C for 8.5 hours. The reaction mixture is poured into a mixture of ice and 1N hydrochloric acid with stirring, the resulting mixture is stirred for another 30 minutes, after which the solid material is filtered off. 22.0 g of solid product are obtained, which are dissolved in a mixture of equal parts of ethyl acetate and hexane, and chromatographed on 800 g of silica gel. After evaporation of the respective eluates, first 11.7 g of N-(2-chloroacetyl)-3-chloro-4-fluoroaniline and then 3.0 g of 6-chloro-5-fluoro-2-oxindole are obtained. The latter product, after recrystallization from toluene, gave 1.70 g (7% yield) of the title compound, mp 196-206 °C. According to NMR spectroscopy, this product was contaminated with some 4-chloro-5-fluoro-2-oxindole. A second crop of 0.8 g of this product was obtained.

Preparation 11

5-acetyl-2-oxindole

To 95 ml of carbon disulfide, 27 g (0.202 mol) of aluminum chloride are first added, and then a solution of 3 ml (0.042 mol) of acetyl chloride in 5 ml of carbon disulfide is added dropwise with stirring. Stirring is continued for 5 minutes, then 4.4 g (0.033 mol) of 2-oxindole is added, the resulting mixture is heated to reflux for 4 hours and then cooled. The carbon disulfide is separated by decantation and the residue is triturated with water. After filtration and drying, 3.2 g of the title compound are obtained, melting at 225-227 °C.

By a procedure analogous to the above, the reaction of 2-oxindole with benzoyl chloride in the presence of aluminum chloride yields 5-benzoyl-2-oxindole, melting after crystallization from methanol at 203-205 °C.

Claims (7)

SUBJECT OF THE INVENTION A process for the preparation of N, 3-disubstituted 2-oxindole-1-carboxamides of formula I wherein: X represents a hydrogen, fluorine or chlorine atom, a trifluoromethyl group, a nitro group, a C2 -C4 alkanoyl group or a benzoyl group and Y represents a hydrogen, fluorine or chlorine atom; X and Y, when attached to adjacent carbon atoms, together form a bivalent radical 15 Z is selected from the group consisting of Z and Z (zO (Z ² ) (z ³ ) '(z ⁴ ) (z ⁵ ) in which W represents an oxygen or sulfur atom, R 1 represents an alkyl group having 1 to 6 carbon atoms, trifluoromethyl, C 3 -C 7 cycloalkyl, phenyl optionally substituted by fluorine or chlorine, phenylalkyl, C 1-3 alkyl, optionally substituted on the phenyl core with chlorine or fluorine, C 1 -C 3 phenoxyalkyl C 3 alkyls, bicyclo [2.2.1] heptan-2-yl, furyl optionally substituted with C 1 -C 3 alkyl, thienyl, thienylmethyl, tetrahydrofuranyl or pyridyl; and R represents a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, a benzyl group or a radical of formula wherein: 3 4 R and R are independently selected from the group consisting of hydrogen, fluorine and chlorine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and trifluoromethyl, and pharmaceutically acceptable base salts thereof; wherein the compound of formula IV C-R (IV) wherein R ³ , X and Y are as defined above, reacted with an isocyanate of the formula R ² -N = C = O wherein 2 R is as defined above, in an inert solvent, and the resulting product is optionally converted into its pharmaceutically acceptable salt. 2. A process according to claim 1, wherein the corresponding starting materials are used to form a compound of formula (I) in which: X is attached at the 5 or 6 position and represents a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl group and Y represents a hydrogen atom, R ³ represents an alkyl group having 1 to 6 carbon atoms; C 3 -C 7, furyl, thienyl, C 1 -C 3 phenylalkyl, thienylmethyl or trifluoromethyl; in R represents a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group or a radical of formula (R ³⁾ in which: R ³ and R ⁴ are each independently hydrogen, fluorine or chlorine, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or trifluoromethyl, and pharmaceutically acceptable salts thereof. 2. A process according to claim 1 or 2, wherein the compound of formula (IV): EMI3.0 wherein: X (IV) X, Y and R ¹ have the above meanings, is reacted with one molar equivalent of an isocyanate of formula -N = C = O in which R ² has the above meanings, in an inert solvent at a temperature from 50 to 150 ° C. 4. The process of claim 3 wherein the reaction is carried out in a solvent selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, ethers, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide. 5. A process according to any one of claims 1, 3 and 4, wherein the corresponding starting materials are used to form a compound of formula I wherein Y is hydrogen and X is hydrogen, 5-chloro, 6-chloro , 5-fluoro or 6-fluoro and the remaining general symbols are as defined above. 6. A process according to claim 5, wherein the corresponding starting materials are used to form a compound of formula (1) in which it is benzyl, 2-furyl, 2-thienyl or (2-thienyl) methyl and the remainder the general symbols have the meaning given in point 5. 7. A process according to claim 6, wherein the corresponding starting materials are used to form a compound of formula (I) wherein X is 5-chloro, R1 is 2-furyl 2, R is t-butyl and Y is as in point 6.