CS252847B2 - Method of n,3-disubstituted 2-oxindole-1-carboxyamides production - Google Patents

Abstract

Process for preparing N, 3-disubstituted 2-oxindole-1-carboxamides of formula I where the general symbols have as defined in the subject matter of the invention and their pharmaceutically acceptable salts with bases characterized in that it is a compound of formula IV R 3, X and Y are as defined above, leaving react with an isocyanate of the formula R 2 -N = C = O 2 Wherein R is as defined above, in an inert solvent, and the resulting product it is optionally converted to its pharmaceutically usable salt. Produced the compounds are useful as analgesic agents and as agents for treating inflammatory agents diseases such as arthritis.

Description

The present invention provides novel chemical compounds. In particular, the novel compounds are 2-oxindole-1-carboxamide derivatives which are further substituted at the 3-position by an acyl group and at the nitrogen of the carboxamide moiety with an alkyl, cycloalkyl, phenyl or substituted phenyl group. These novel compounds are inhibitors of cyclooxygenase and lipoxygenase enzymes.

The compounds of the invention exhibit analgesic activity in mammals, particularly humans, and are therefore useful for acute administration to alleviate pain relief, such as those occurring in patients after surgery or trauma.

In addition to its 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 present invention relates to novel 2-oxindole-1-carboxamide derivatives of formula (I)

in which

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 radicals of formulas Z to Z

in which

W represents an oxygen or sulfur atom,

R ¹ is C 1 -C 6 alkyl, trifluoromethyl, C 3 -C 7 cycloalkyl, phenyl optionally substituted by fluorine or chlorine, C 1 -C 3 phenylalkyl optionally substituted on the phenyl core with a chlorine or fluorine atom, a C 1 -C 3 phenoxyalkyl group, a bicyclo [2.2.1] heptan-2-yl group, a furyl residue optionally substituted with a C 1 -C 3 alkyl group, a thienyl group a residue, a thienylmethyl residue, a tetrahydrofuranyl residue or a pyridyl residue; and v

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:

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.

The above 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 of inducing analgesia 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 preferred group of compounds of the invention are those compounds of formula I wherein X and Y are independently selected from the group consisting of hydrogen,

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 are zvlášř preferred are those compounds wherein R ³ is benzyl, 2-furyl, 2-thienyl or (2-thienyl) methyl.

Particularly preferred individual compounds of 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-l-carboxamide (I: X = H, Y = H, R ³ = 2-furyl, R ² = 2,4- difluorophenyl).

The compounds of formula I are named as 2-oxindole derivatives, which is a compound corresponding to formula II

(II)

The analgesic and anti-inflammatory agents of formula I carry a carboxamide substituent

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

It should further be pointed out that when Z represents a radical of the formula Z $ or z ', this Z group can be attached in any of two possible ways. For example, when X and Y are on the 5 and 6 carbon atoms and represent a radical of formula Z, formula I includes both of the following formulas.

Further, it will be appreciated that the analgesic and anti-inflammatory active compounds of formula (I) according to the invention wherein X, Y, R and R are as defined above are capable of enolization and therefore may exist in one or more tautomeric (enol) forms. All such tautomeric (enol) forms of the compounds of formula I are within the scope of the invention.

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

X

in which

X and Y are as defined above.

This preparation is accomplished by introducing the -C (= O) -NK-R substituent at the 1-position and the -C (= O) -R ¹ substituent at the 3-position. two variants, as follows from the following reaction scheme:

The present invention provides a process for the preparation of the compounds of formula (I) and pharmaceutically acceptable salts thereof, which comprises:

O

in which

X and Y are as defined above, reacted with an isocyanate of the formula

R = C = O wherein 2

R is as defined above, in an inert solvent, and the resulting product is optionally converted to its pharmaceutically acceptable salt.

The second variant resulting from the above reaction scheme, consisting in introducing the -C (= O) -R 4 'substituent into the 3-position of the compound of formula (V), is the subject of our co-pending Czechoslovak patent specification 252,828.

In accordance with the invention, the radical -C (= O) is linked by reacting a compound of formula IV with an isocyanate of 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 to 130 ° C. By an inert solvent is meant a solvent which dissolves at least one reactant and which does not react undesirably with either the reactants or the product. Typical useful solvents include aliphatic hydrocarbons such as octane, nonane, deca and decalin, aromatic hydrocarbons such as benzene, chlorobenzene, toluene, xylene and tetralin, chlorinated hydrocarbons such as 1,2-dichloroethane, ethers such as tetrahydrofuran, dioxane, 2-dimethoxyethane and di (2-methoxyethyl) ether, and polar aprotic solvents such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and dimethylsulfoxide. The reaction time depends on the reaction temperature. At temperatures of from 100 to 130 ° C, reaction times of about several hours, for example 5 to 10 hours, are usually employed.

When reacting a compound of formula IV with an isocyanate of formula

R = N = C = O uses a relatively non-polar reaction solvent, the resulting product of formula (I) is usually excluded from the solution upon completion of the reaction and after cooling the reaction mixture 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 completion of the reaction, it can be isolated by evaporation of the solvent. Alternatively, using water-miscible solvents, by diluting the reaction medium with water, the product precipitates and can be recovered by filtration. The reaction product of formula (I) may be purified by standard procedures, for example by recrystallization.

The reaction between a compound of formula IV and an 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 Ν, dim-dimethylaniline . Typically, about 1 to 4 equivalents of the basic agent is added to allow the reaction temperature to be used in the range of 20 to 50 ° C. After completion of the reaction, the reaction medium must be neutralized (or acidified) and the product isolated as described above.

Isocyanates of the formula R -N = C = O can be prepared by standard procedures - see below Organic Functional Group Preparations ”, Sandler and Kara, Part I, Second Edition, Academia

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

R ² -NH ₂ + COCl ₂ - (R ² -n = c = o + 2 HCl)

Numerous of the isocyanates of the formula R -N = C = O are known in the art.

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

-C (= O) -R 6 to a compound of formula III by reaction with a corresponding acid derivative of general 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 1 -C (= O) CH include acid chloride, acid anhydrides of formula.

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

R ¹ -C (= O) -OR ⁶ in 5 in which the general formulas represent a bulky lower alkyl group such as a tert-butyl group and R 6 represents a lower alkyl group. Usually a small excess of the acid derivative of the formula R 1 -C (= O) -OH is used and the alkoxide is usually present in an amount ranging from one to two mol equivalents based on the above-mentioned acid derivative of the formula R 1 -C (= O) -OH. The reaction between an acid derivative of the formula R 1 -C (= O) -OH and a compound of the formula III is usually started at 0 to 25 ° C, but the reaction mixture is generally heated to 50 to 130 ° C to complete the reaction, preferably to a temperature of about 80 ° C. Under these conditions reaction times ranging from several hours, for example two hours, to several days, for example two days, are usually used. The reaction mixture is then cooled, diluted with excess water and acidified, and the product of 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 Rods Chemistry of Carbon Compounds, second edition, 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, 6,093 (1968); U.S. Pat. 3,882,236, 4,006,161 and 4,160,032; Walker, Journal of the American Chemical Society, 77, 3,844 (1955); Protiva et al., Collection of Czechoslovak Chemical Communications, 44, 2,108 (1979); McEvoy et al., Journal of Organic Chemistry,

38, 3,350 (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 a salt with a base, all of which with a base which can be prepared by conventional methods are within the scope of the invention. For example, these salts can be prepared simply by contacting the acid and base components, usually in a stoichiometric ratio, either in a non-aqueous or aqueous or partially aqueous medium, as appropriate in each case. The resulting salts are isolated either by filtration, by precipitation with a non-solvent followed by filtration, or by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization. Typical salts of the compounds of formula I that can be prepared are salts with primary, secondary or tertiary amines, alkali metal salts and alkaline earth metal salts. Of particular interest are the salts with ethanolamine, diethanolamine and triethanolamine.

Suitably, both organic and inorganic basic agents, such as organic amines, alkali metal hydroxides, alkali metal carbonates, can be used to produce salts.

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 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, Ν, Ν-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 formula I exhibit analgesic activity. This activity can be demonstrated in mice by blocking abdomen convulsions induced by the application of 2-phenyl-1,4-benzoquinone.

This assay is performed 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 Milne and Twomey, Agents and Actions, 10, 31-37 (1980)]. These experiments were performed on male Carworth white mice (CF-1 strain) weighing 18-20 g. All mice were fasted overnight before administration of the drug and starting the test.

The compounds of formula I are dissolved or suspended in a vehicle comprising 5% ethanol, 5% surfactant emulsion 620 (a mixture of oxethylated fatty acid esters) and 90% saline. This vehicle also serves as a control. Logarithmically scaled doses (i.e. ... 0.32, 1.0, 3.2, 10, 32 ... mg / kg) are used. Test substances are administered orally at various concentrations to maintain a constant volume of 10 ml / kg body weight. The method described above by Milné and Twomey is used to determine potency and potency.

Mice are dosed orally with test compound and after 1 hour intraperitoneally with 2 mg / kg 2-phenyl-1,4-benzoquinone. Immediately thereafter, mice were individually housed in heated plastic chambers and abdominal constrictions were counted 5 minutes after application of 2-phenyl-1,4-benzoquinone. This recording is performed for 5 minutes · The degree of analgesia (% MPE) is then calculated based on suppression of the number of ebdominal constrictions as compared to control animals tested on the same day. For the calculation of the MPE value, which is the best estimate of the dose reducing abdominal constriction to 50% of the control value, the data found in the dose response determination in at least four such assays (N ^ 5) are used.

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

544 (1962).

Non-anesthetized adult male white rats weighing 150-190 g are numbered, weighed and inked on their hind limb in the ankle region. The labeled limb of the animal is then immersed in mercury so that the level of mercury reaches exactly the mark. Mercury is found in a glass cylinder connected to a pressure transducer (Statham).

The output of the converter is led through the control unit to the microvolt meter. The volume of mercury displaced by the immersed limb is recorded. Test substances are administered by gavage. One hour after administration of the test substance, injection of 0.05 ml of a 1% carrageenin solution into the plantar tissue of the labeled limb induced edema. Immediately thereafter, the volume of this limb is measured.

The increase in limb volume at 3 hours post-carrageenin injection compared to that in control animals receiving only the vehicle without active agent represents an individual inflammatory response.

The results obtained with the test just described are summarized in the following table, where they are given as percent inhibition of edema formation with the test substances compared to the control animals.

X R ¹ R ² dose (mg / kg) inhibition (%) H methyl phenyl 33 40 H methyl phenyl 10 20 May H methyl 4-chlorophenyl 33 4 H methyl 3- (trifluoromethyl) phenyl 33 24 H methyl 2,4-difluorophenyl 33 19 Dec H methyl 4-fluorophenyl 33 20 May 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 22nd H benzyl phenyl 33 17 H benzyl 2,4-difluorophenyl 33 23 H benzyl 4-chlorophenyl 33 14 H 2-thienyl 4-fluorophenyl 33 17

Continuation table

X R ¹ R ² ř.zvka (mg / kg) ínhi ^ H 2-furyl 4-fluoropheny ^: <3 34 H 2-furyl 4-f luorfenv '· ! <·, 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-Fluorenyl 33 2 6 H eyclopropyl 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-chloro 32 12 H 2-furyl 2- (trifluoromethyl) phenyl 32 30 r phenoxymethyl phenyl 32 20 May H trifluoromethyl phenyl 32 24 H trifluoromethyl 2,4-difluorophenyl 33 O (B) phenoxymethyl 4-chlorophenyl  32 35 H phenoxymethyl 4-chlorophenyl 10 6 Ή f e n oxyme t h y1 2,4-difluorophenyl 3 2 25 H 2-thenyl 4-chlorophenyl 3 2 26

Continuation table

X R ¹ R ² dose (mg / kg) inhib: <%) 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 Dec H 2-thienyl 4-ethylphenyl 32 26 H 4-chlorobenzyl phenyl 32 15 Dec 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 · /. y 1 4-fluorophenyl 32 10

25284

Continuation table

X R ¹ R ² < ^: vk -, Ufig / xgi inhi 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 fí 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 Dec 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-fluorophenyl; 32 12 She knows methyl benzyl 32 ' 19 Dec i-i 2-furyl benzyl 32 20 May H 2-thienyl benzyl 32 2ó She knows phenyl females 1. 32 23 H 4-pyridyl 4-chlorophenyl 32 3 H 5-methyl-2-furyl phenyl 32 3 H 5-methyl-2-furyl 2,4-difluorophenyl 32 23 She knows ? -pyridyX 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 22nd H 2-thenyl ethyl 32 15 Dec H methyl ethyl 32 5 5-Cl 2-furyl ethyl 32 27 Mar: 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 isopropyl 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 hc tert.butyl 32 4 3

Continuation table

X R ¹ R ² dose inhibi. (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 .terc.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 Mar: 5-Cl 2-thenyl tert-butyl 32 35 H methyl isopropyl 32 17 H 2-furyl n-butyl 32 20 May 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

Continuation table

X R ¹ R ^z dose (mg / kg) inhibition <%) 5-C1 cyclobutyl tert-butyl 32 43 5-Cl cyclobutyl tert.butyl 10 20 May 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 bicyclo [2.2.1] heptan-2-yl tert.butyl 32 15 Dec 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 Mar: 6-Cl 2-furyl tert.butyl 32 68 6-Cl 2-furyl tert-butyl 10 27 Mar: 6-Cl 2-furyl tert-butyl 3.2 15 Dec 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 tert 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 22nd 6-Cl 3-thenyl tert.butyl 32 22nd 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 22nd 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 22nd 5-F 3-thenyl isopropyl 32 40 6-CF ₃ benzyl phenyl 32 8 6-F 2-thienyl phenyl 32 19 Dec

Because of their analgesic activity, the compounds of formula I are useful for acute administration to mammals for the purpose of suppressing pain, such as post-operative pain or post-traumatic pain. Further, the compounds of Formula I are useful for chronic administration to mammals for the alleviation of symptoms of chronic diseases such as inflammation in rheumatoid arthritis, and for the relief of pain in osteroarthritis and other musculoskeletal disorders.

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

In a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, the weight ratio of carrier to active agent normally ranges from 1: 4 to 4: 1, preferably from 1: 2 to 2: 1. In any particular case, however, the exact ratio depends on such factors as the solubility of the active agent, the intended dosage and the intended route of administration.

Orally, the compound of formula (I) of the invention may be administered, for example, in the form of tablets or capsules, or in the form of an aqueous solution or suspension. Tablets for oral administration usually contain carriers commonly used for these purposes, including lactose and corn starch, and glidants such as magnesium stearate are generally used in their manufacture. Suitable diluents for preparing 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 sweetening and / or flavoring agents may be added. For instramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile active compound solutions are usually prepared, the pH of which should be suitably adjusted and buffered. In the preparation of preparations for intravenous administration, the total concentration of the soluble components should be controlled so that the resulting preparation is still isotonic.

The daily dose of a compound of formula I or a salt thereof in human medicine is usually determined by the attending physician. In addition, this dose will vary depending on the age, weight and response of the patient, as well as the severity of the patient's symptoms and the efficacy of the compound administered. For acute pain relief, the dose eliciting an effective analgesic response will in most cases range from 0.02 to * 0.5 g as needed (for example, every 4 hours to 24 hours). In the case of chronic applications for the treatment of inflammation and pain, the daily dose will generally be from 0.02 to 1.0 g, preferably from 0.05 to 0.5 g, which may be administered as a single daily dose. or in several sub-doses. However, in individual cases, doses outside these limits may need to be administered.

The invention is illustrated by the following translations and embodiments, which are not to be construed as limiting 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, 393 mg (3> 3 mmol) of phenyl isocyanate was added with stirring and the mixture was heated under reflux for 7 hours. The reaction mixture was cooled to room temperature and the precipitate formed was filtered off. The solid thus obtained, after recrystallization from about 20 ml of acetonitrile, yields 229 mg of the title compound as off-white needles having a melting point of 171-173 ° C.

Analysis: Calculated: C, 69.38; H, 4.79; N, 9.52.

Found: C, 69.31; H, 4.97; N, 9.59.

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 dimethylsulfoxide was added with stirring 668 mg (6.6 mmol) of triethylamine and then 512 mg (3.3 mmol) of 2. Of 4-difluorophenyl isocyanate. Stirring is continued for 1 hour and the reaction mixture is poured into 60 ml of water. The resulting mixture was 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 is obtained as yellow crystals, m.p. 191-192 ° C.

Analysis: Calculated: C, 62.83; H, 3.16; N, 7.33.

Found: C, 62.70; H, 3.07; N, 7.26.

Example 3

The following compounds were prepared in an analogous manner to 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 171-171.5 H 2-furyl isopropyl 114 to 115 H 2-thienyl isopropyl 177-178.5 5-Cl methyl tert.butyl 219 to 220 H 2-furyl tert-butyl 160 to 161 5-Cl 2-thienyl tert.butyl 178-179.5 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 168-169.5 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 to 177 H phenyl 4-chlorophenyl 215 to 217 H 3-pyridyl phenyl 193 to ¹⁹⁵ H 4-fluorophenyl 4-chlorophenyl 212 to 213 H 3-Pyridyl 4-chlorophenyl 220 to 221 H 4-fluorophenyl phenyl 189 to 191 H phenyl 2,4-difluorophenyl 204 to 206 H benzyl 2,4-difluorophenyl 151 to 152 H benzyl 4-chlorophenyl 178 to 179 H 2-thienyl 4-fluorophenyl 175 to 176.5 H 2-furyl 4-fluorophenyl 166.5 to 167.5 (decomposition) H cyclohexyl 4-fluorophenyl 180 to 181 H 2-furyl phenyl 162 to 163 H 3-pyridyl 2,4-difluorophenyl 254 (decomposition) H trifluoromethyl 4-fluorophenyl 203 to 204 H trifluoromethyl phenyl .139.5 to 140.5 H phenoxymethyl phenyl 158 to 159 H phenoxymethyl 4-chlorophenyl 137.5 to 138.5 H phenoxymethyl 2,4-difluorophenyl 137.5 to 138.5 H (2-thienyl) methyl 4-chlorophenyl 165 to 166 H (2-thienyl) methyl 4-fluorophenyl 161 to 163 H (2-thienyl) methyl 3-tolyl 147 to 149 H (2-thienyl) methyl 3-fluorophenyl 152 to 154 H (2-thienyl) methyl 3-trifluoromethylphenyl 139 to 140 H 1-phenylethyl 2,4-difluorophenyl 152.5 to 154 H 2-thienyl 4-chlorophenyl 196.5 to 197.5

Continuation table

XR ¹ R ² Melting point (° C)

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

Continuation table

X R ¹ 0 R ~ Temperature . melting point (° C) H 4-chlorophenyl 4-fluorophenyl 219 to 220 H methyl benzyl 162 to 16 4 H 2-thienyl benzyl 117 to 118 H 2-furyl benzyl 124 to 126 H 4-pyridyl phenyl 212.5 to 213.5 (decomposition) H 4-pyridyl 2,4-difluorophenyl 229 to 230 H 4-pyridyl 4-chlorophenyl 211 to 213 (decomposition) H 2-pyridyl phenyl 208 to 209 H 5-methyl-2-furyl phenyl 156 to 157 H 5-methyl-2-furyl 2,4-difluorophenyl 189 to 191 H 2-pyridyl 2,4-difluorophenyl 230 to 232 H 2-pyridyl 4-chlorophenyl 207 to 208 (decomposition) 5-CF ₃ bicyclo [2.2.1] heptan-2-yl tert.butyl 212.5 (dec 5-C1 bicyclo [2.2.1] 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 tert-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 to 199, 5 G-Cl 2-furyl isopropyl j 5 5 - 5 to 1'6,5 6-C1 2-furyl cyclohexyl 1.! I 4 to i '5 5-C1 2-furyl phenyl 191, 5 and ž 192.5 5-Cl 2-furyl 2,4-difluorophenyl 4 to 21 5 5-Cl 2-thienyl phenyl 1 9 4 and ž J 9 5 5-Cl (2-thienyl) methyl phenyl 167.5 , TŽ 1 - 9

Table X continued 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) methyl 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 CO 6 5 benzyl phenyl 167 to 170 _5-CH3 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 to 1.6 6 5-F 2-thienyl 4-methoxyphenyl 177 to 179 5-NO ₂ phenoxymethyl phenyl 224 to 225 5 -C 5 _R 6 H_CO 2-thienyl phenyl 160 to 163 5-CH _c CO 6 5 (2-thienyl) methyl phenyl 171 to 173 5-CH 2 CO 2-thienyl phenyl 193 to 195 5-CH ₃ CO benzyl phenyl 195 to 198 5-C1 2-thienyl 4-methoxyphenyl 185 to 187 5-C1 benzyl phenyl 156 to 158 5-F benzyl phenyl 175 to 177 5-C1 4-chlorophenyl phenyl 239 to 240 6-F 2-tetrahydrofuranyl 4-methoxyphenyl 170 to 172

Example 4

Ethanolamine salt of N-tert-butyl-6-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide

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, then allowed to cool. The title salt is obtained by filtering off the precipitate formed.

Prepared

3- (2-furoyl) -2-oxindole

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

For C 6 HH ^O ^N: C, 68.72; H, 3.99; N, 6.17.

Found: C, 68.25; H, 4.05; N, 6.20.

Preparation 2

By following an analogous procedure to that of Preparation 1, the following additional products are obtained by reacting 2-oxindole with the appropriate acid chloride:

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

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

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

5-chloro-3- [2- (2-thienyl) acetyl] -2-oxindole, m.p. 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 was added with stirring first 13.3 g (0.10 mol) of 2-oxindole and then 16.8 g of ethyl 3-furoate. The mixture was refluxed for 47 hours, cooled, and the solvent 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 triturated with diisopropyl ether and filtered. The solid is suspended in 250 ml of water, acidified with concentrated hydrochloric acid, and the resulting mixture is stirred, precipitating a solid which is isolated by filtration and recrystallized first from acetic acid and then from acetonitrile. 705 mg of the title compound are obtained, m.p. 185-186 ° C.

For C 6^H HOgN: C, 68.72; H, 3.99; N, 6.17.

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

Preparation4

In analogy to Preparation 3, the following compounds are obtained by reaction of the corresponding 2-oxindole with the ethyl ester of the corresponding carboxylic acid:

5-chloro-3- (2-thenoyl) -2-oxindole, m.p. 190.5-192 ° C (yield 36 °),

5-chloro-3- (2-furoyl) -2-oxindole, m.p. 234-235 ° C (yield 54%),

5-chloro-3- (2-phenylacetyl) -2-oxindole, m.p. 241-243 ° C (yield 61%),

5-fluoro-3- (2-furoyl) -2-oxindole, m.p. 222-224 ° C (yield 51%),

5-fluoro-3- (2-thenoyl) -2-oxindole, m.p. 200-203 ° C (26% yield),

6-fluoro-3- (2-furoyl) -2-oxindole, m.p. 239-242 ° C (26% yield); and

6-chloro-5-fluoro-3- (2-thenoyl) -2-oxindole, m.p. 212-2-5 ° C (yield%).

Using the corresponding 2-oxindole and ethyl ester in the same manner as in Preparation 3, the following compounds were obtained in an analogous manner:

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 at room temperature with stirring. The resulting mixture was cooled in ice and 18.5 g (0.13 mol) of ethyl 2,2,2-trifluoroacetate was added rapidly with stirring. Remove the cooling bath, heat the reaction mixture to reflux, boil for 1 hour, then cool and evaporate most of the solvent 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 precipitated solid material is filtered off. The solid product was dissolved in ethyl acetate, the ethyl acetate solution was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. Recrystallization of the residue from toluene gave the title compound (13.2 g) as yellow crystals, m.p. 183.5-184.5 ° C.

Analysis: Calculated: C 52.41, H 2.64, N 6.11.

Found: C, 52.52; H, 2.75; N, 6.04.

Preparation 6

5-chloro-2-oxindole

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

This material, which after drying in a vacuum oven weighs 105.4 g, is added portionwise over a period of 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 charcoal and poured into a mixture of 1 liter of water and 180 ml of concentrated hydrochloric acid containing chunks of ice. The precipitated red-yellow solid is filtered off, washed thoroughly with water, dried, washed with diethyl ether and finally recrystallized from ethanol. 38.9 g of the title compound, melting at 193-195 ° C, decomposes.

In an analogous manner, 5-methylisatin is first converted to 5-methyl-2-oxindole by treatment with hydrazine hydrate and then 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 is added with stirring first 419 g (2.95 mol) of sodium sulfate and then a solution prepared from 89.25 g (0.70 mol) of 3-chloroaniline, 62 ml of concentrated hydrochloric acid and 500 ml of water, whereupon a thick precipitate formed. A solution of 155 g (2.23 mol) of hydroxylamine in 500 ml of water is added with stirring, the reaction mixture is slowly warmed with stirring, and is maintained at a temperature between 60 and 75 ° C for about 6 hours, during which time add 1 liter of water to facilitate stirring. The resulting mixture was cooled, the precipitate formed was filtered off and dried. 136.1 g of 3-chlorisonitrosoacetanilide are obtained.

B. 4-Chloroisatin and 6-Chloroisatin

To 775 ml of concentrated sulfuric acid, preheated to 70 ° C, was added with stirring 136 g of 3-chloro-isonitrosoacetanilide at such a rate that the temperature of the reaction medium was maintained between 75 and 85 ° C. After all solid material has been added, the reaction mixture is heated at 90 ° C for a further 30 minutes, then cooled and poured slowly into about 2 liters of ice with stirring. Additional ice is added as necessary to keep the temperature below room temperature. The red-orange precipitate formed is filtered off and dried after washing with water. The solid material was suspended in 2 liters of water and dissolved in about 700 ml of 3N sodium hydroxide. The solution is filtered and adjusted to pH 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 is filtered off and washed with water and dried. 50 g of crude 4-chloroisatin are obtained. The filtrate was acidified with concentrated hydrochloric acid to pH 0 after isolation of 4-chloroisatin, whereupon a further precipitate was formed which, after filtration, washed with water and dried, yielded 43 g of crude 6-chloroisatin.

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

The crude 6-chloroisatin was recrystallized from acetic acid to give 36.2 g of a melting point 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 under reflux for 2 hours, then cooled and the precipitate formed is filtered off. 43.5 g of 4-chloro-3-hydrazono-2-oxindole, m.p. 235 DEG-236 DEG C., are obtained.

To a solution of 22 g of sodium in 450 ml of anhydrous ethanol was added portionwise with stirring

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

D. 6-Chloro-2-oxindole

Analogous to Preparation 2C, 14.2 g of 6-chloro-2-oxindole, m.p. 196-198 ° C, was obtained by reaction of 6-chloroisatin with hydrazine hydrate.

Preparation 8

5,6-difluoro-2-oxindole

In analogy to paragraphs A and B of the preceding preparation, reaction of 3,4-difluoro aniline with chloral hydrate and hydroxylamine followed by cyclization with sulfuric acid yields 5,6-difluoroisatin, which is treated with hydrazine hydrate and then methoxide. sodium ethanol in ethanol in an analogous manner to Preparation 6. The title compound is obtained, m.p. 187-190 ° C.

Preparation 9

5-fluoro-2-oxindole

To a solution of 11.1 g (0.1 mol) of 4-fluoroaniline in 200 ml of dichloromethane at -60 ° C to -65 ° C was added dropwise a solution of 10.8 g (0.1 mol) of tert-butyl hypochlorite in stirring. 25 ml of dichloromethane. Stirring was continued at -60 to -65 ° C for 10 minutes, after which a solution of 13.4 g (0.1 mol) of ethyl 2- (methylthio) acetate in 25 ml of dichloromethane was added dropwise. The mixture was stirred at -60 ° C for 1 hour and then added dropwise at -60 to -65 ° C to a solution of 11.1 g (0.11 mol) of triethylamine in 25 ml of dichloromethane. The cooling bath was removed and after the reaction mixture was warmed to room temperature, 100 ml of water was added. The phases are separated, the organic phase is washed with saturated sodium chloride solution and evaporated in vacuo. The residue was dissolved in 350 ml of diethyl ether, to which 40 ml of 2N hydrochloric acid was added. The mixture is stirred at room temperature overnight, then the phases are separated and the ether phase is washed first with water and then with a 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 is triturated with isopropyl ether. The solid material was recrystallized from ethanol to give 5.58 g of 5-fluoro-3-methylthio-2-oxindole, m.p.

152.5 ° C.

H, 4.09; N, 7.10.

Found: C, 54.74; H, 4.11; N, 7.11.

986 mg (5.0 mmol) of the above-prepared 5-fluoro-3-methylthio-2-oxindole was added to a mixture of two teaspoons of Raney-nickel and 50 ml of absolute ethanol, and the reaction mixture was heated under reflux for 2 hours. The catalyst was separated by decantation and washed with absolute ethanol. The combined ethanolic 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 treated with tert-butyl hypochlorite, ethyl 2- (methylthio) acetate and triethylamine, and the resulting 3-thiomethyl-5-trifluoromethyl-2-oxindole is subjected to Raney nickel reduction. There was obtained 5-trifluoromethyl-2-oxindole, m.p. 189.5-190.5 ° C. _

Preparation 10

6-chloro-5-fluoro-2-oxindole

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

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

13.2 ml (0.166 mol) of 2-chloroacetyl chloride. The reaction mixture was stirred at room temperature for 5 hours and then extracted twice with 100 ml of 1N hydrochloric acid each and then with 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried (MgSO 4) 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 to 230 ° C for 8.5 hours. The reaction mixture was poured into a mixture of ice and 1N hydrochloric acid with stirring, and the resulting mixture was stirred for a further 30 minutes, after which the solid material was filtered off. 22.0 g of solid product are obtained, which is dissolved in a mixture of equal parts of ethyl acetate and hexane and chromatographed on 800 g of silica gel. Evaporation of the appropriate eluted fractions gave first 11.7 g of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline and then 3.0 g of 6-chloro-5-fluoro-2-oxindole. The latter product, after recrystallization from toluene, gave 1.70 g (7% yield) of the title compound, m.p. 196-206 ° C. According to NMR spectroscopy, this product is contaminated with some 4-chloro-5-fluoro-2-oxindole. 0.8 g of product is obtained as a second crop.

Preparation 11

5-acetyl-2-oxindole

To 95 ml of carbon disulfide, first 27 g (0.202 mol) of aluminum chloride were added, and then a solution of 3 ml (0.042 mol) of acetyl chloride in 5 ml of carbon disulfide was added dropwise with stirring. Stirring was continued for a further 5 minutes, then 4.4 g (0.033 mol) of 2-oxindole was added, the resulting mixture was heated under 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 of melting point 225-227 ° C is obtained.

Analogous to the above procedure, reaction of 2-oxindole with benzoyl chloride in the presence of aluminum chloride afforded 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.