FI82448B - 2-oxindole derivatives - Google Patents

Abstract

The invention relates to 1-substituted 2-oxindole derivatives of the formula <IMAGE> wherein X is hydrogen, fluoro, chloro, bromo, alkyl, cycloalkyl, alkoxyl, alkylthio, trifluoromethyl, alkylsulphinyl, alkylsulphonyl, nitro, phenyl, alkanoyl, benzoyl, thenoyl, alkanamido, benzamido- or N,N- dialkylsulphamoyl, and Y is hydrogen, fluoro, chloro, bromo, alkyl, cycloalkyl, alkoxyl, alkylthio or trifluoromethyl, or X and Y together may form 4,5-, 5,6- or 6,7- methylenedioxy or 4,5-, 5,6- or 6,7- ethylenedioxy, or when bound to adjacent carbon atoms, a chain of 3 or 4 carbon atoms or 2 carbon atoms and either one oxygen or sulphur atom and optionally double bonds, and R2 is alkyl, cycloalkyl, phenoxymethyl, furyl, thienyl or pyridyl or a moiety <IMAGE> wherein R3 and R4 are hydrogen, fluoro, chloro, alkyl, alkoxyl or trifluoromethyl. The invention also relates to a compound of the formula <IMAGE> wherein X is hydrogen, 5- flouro or 5- chloro, Y is hydrogen, 6- fluoro, 6- chloro, and R1 is benzyl, furyl, thienyl or thienylmethyl; with the proviso that when both X and Y are hydrogen R1 is not benzyl. Compounds having the structural formula II and IV are useful intermediates in the preparation of therapeutically valuable compounds.

Description

1,82448 2-Oxindole derivatives

Divided separated from patent application 850,491.

The invention relates to novel compounds of the formula

"OCU

O-C-NH-C-R2 (II) 0 wherein X is hydrogen, fluorine, chlorine, C1-4 alkyl or trifluoromethyl; and R 2 is C 1-6 alkyl, C 3-7 cycloalkyl, phenoxymethyl or a group 20 wherein each of R 3 and R 4 may be hydrogen, fluoro, chloro, C 1-4 alkyl or C 1-4 alkoxyl.

The invention also relates to compounds of formula (IV)

Y B

Wherein X is hydrogen, 5-fluoro or 5-chloro; V is hydrogen, 6-fluoro or 6-chloro; and R 1 is a benzyl, furyl, thienyl or thienylmethyl group; provided that when both X and Y are hydrogen, R1 is not a Bent cause.

The compounds of formula (II) and (IV) are useful in the preparation of therapeutically valuable 2-oxindole compounds of formula (I)

X

2 82448 -1-C-R1. (n 1 2 0 = C-NH-C-R 2

It 0 wherein X is hydrogen, fluorine, chlorine, C 1-6 alkyl or trifluoromethyl; R 1 is C 1-6 alkyl, C 3-7 cycloalkyl, phenyl, phenylalkyl having 1 to 3 carbon atoms in its alkyl moiety or a group - (CH 2) n -Q-R 0; wherein n is 0, 1 or 2; Q is a divalent group derived from furan or thiophene; and R 0 is hydrogen or C 1-6 alkyl; and R 2 is C 1-6 alkyl, C 3-7 cycloalkyl, phenoxymethyl or the group R 3 -Cc 20 κ wherein each of R 3 and R 4 may be hydrogen, fluorine, chlorine, C 1-6 alkyl or C 1-6 alkoxyl? or a pharmaceutically acceptable base salt thereof, The compounds of formula (I) are effective as analgesic and anti-inflammatory agents in the treatment of inflammatory diseases such as arthritis.

The compounds of formulas (II) and (IV) are thus derivatives of 2-oxindole of formula 30: φα 'h

The compounds of formula (I) are prepared

II

35 3 82448 of indole compounds of formula (III) X 4 -13 (III) 5 6kAN ^ 0

X 'H A

wherein X and Y are groups as defined above. This is accomplished by attaching the substituent -C (= O) and -NH- 2 1 C (= O) R at the 1-position and the substituent -C (= O) -R at the 3-position. These substituents can be incorporated in either order, and this results in two alternative methods for preparing the compounds of formula (I), as shown in the scheme.

15 Figure 3 & J.

B

20 (III) / O = C-NH-C-R2

, IV> (II) S

30 (y 0 »C-NH-Cj-R2

O

(I) (Y = H) 4 82448

The first alternative comprises converting compound (III) to compound (IV) and converting compound (IV) to compound (I), while the second alternative involves converting compound (III) to compound (II) and converting compound (II) to compound (I). .

The group -C (= O) -NH-C (<O) -R 2 is attached by reacting a compound of formula III or a compound of formula IV with an acyl isocyanate of formula R 2 -C (= O) -N = C = 0. Most usually, the reaction is carried out by contacting substantially equivalent molar amounts of the starting materials in a mutually inert solvent at a temperature of 50 to 150 ° C, preferably 100 to 130 ° C. In this context, an inert solvent is one in which at least one of the reactants Liu-15 is lubricated and which does not adversely affect the reactants or the product. Typical useful solvents include aliphatic hydrocarbons such as octane, nonane, decane and decalin; aromatic hydrocarbons such as benzene, chlorobenzene, toluene, xylenes 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 dimethyl sulfoxide. The reaction time varies depending on the reaction temperature, but the reaction times used at 100 to 130 ° C are usually a few hours, for example, 5 to 10 hours.

When a relatively non-polar solvent is used as the solvent in the reaction of a compound of formula III and IV with an acyl isocyanate of formula R 2 -C (= O) -N = C 0 O, the product (I or II) is usually separated at the end of the reaction. cooling the reaction mixture from room temperature to room temperature. Under these conditions, the product is usually recovered by filtration. However, if 5,82448 relatively polar solvents are used and the product has not separated from the solution at the end of the reaction, the product can be recovered by evaporating the solvent or, in the case of water-miscible solvents, by diluting the reaction medium with water. This causes the product to precipitate and can be recovered by filtration. The reaction product (I or II) can be purified by conventional methods, for example, by recrystallization.

The reaction between a compound of formula IV and an acyl isocyanate of formula R2-C (= O) -N = C = 0 can be accelerated by adding a base such as a tertiary amine, for example trimethylamine, triethylamine to the reaction mixture. , tributylamine, N-methylpiperidine, N-methylmorpholine or Ν, Ν-dimethylaniline. About 1 to 4 equivalents of basic substance are usually added, and this allows the reaction to be carried out at a temperature of 20 to 50 ° C. Upon completion of the reaction, the reaction medium must be neutralized (or acidified), and the product is then isolated as described above.

The side chain -Ci-OJ-R1 can be attached to a compound of formula II by reacting said compound with a reactive derivative of a carboxylic acid of formula R1-C (→ O) → OH. The reaction is carried out by treating said compound of formula II with an equivalent 25 molar amount (or a small excess) of a reactive derivative of a compound of formula R 1 -C (= O) * OH in an inert solvent and in the presence of 1 to 4 equivalents of base. By inert solvent is meant a solvent in which at least one of the reactants is soluble and which does not adversely affect the reactants or the product. In practice, however, a polar aprotic solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide is usually used. An acid of formula 35 R 2 Cf-OJ'OH. Conventional methods are used to activate 6 82448. For example, acid halides, for example acid chlorides, may be used; symmetrical acid anhydrides R1-C (= O) -O-C (= O) -R1; mixed anhydrides formed by an acid and a sterically hindered low molecular weight carboxylic acid R 5 - (O) -O-C (~ O) -R 5, wherein R 5 is a bulky lower alkyl group such as a t-t> u style group; and carboxylic acid-carbonic acid mixed anhydrides R 1 -C (= O) -O-C (= O) -OR 6, wherein R 6 is a lower alkyl group. In addition, N-hydroxyimide esters (such as N-hydroxysuccinimide and N-hydroxyphthalimide esters), 4-nitrophenyl esters, thiol esters (such as thiolphenyl esters) and 2,4,5-trichlorophenyl esters and the like can be used.

Many different bases can be used in the reaction between a compound of formula II and a reactive derivative of an acid of formula R 1 -C (* O) -OH. However, preferred basic substances are tertiary amines such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine and 4- (N, N-dimethylamino) pyridine.

The reaction between a compound of formula II and a reactive derivative of an acid of formula R 1 -C (O) -OH is usually carried out at a temperature of -10 to 25 ° C. Reaction times usually range from 30 minutes to a few 25 hours. Upon completion of the reaction, the reaction medium is usually diluted with water and acidified, and the product can then be recovered by filtration. It can be purified by conventional methods, for example, by recrystallization.

The side chain -C (= O) -R 1 can be attached to a compound of formula III by reacting said compound with an appropriate acid derivative of the formula Rx-C (= O) -OH in a lower alkanol (e.g. ethanol) with a lower alkanol alkali metal salt ( e.g. sodium ethoxide 35) in accordance with conventional procedures. Typical acid derivatives of the formula 1- (3- (= O) -011) which can be used are acid chlorides, acid anhydrides of the formula R1-C (= O) -O-C (= O) -R1, R1-C (= O) -O-O (= O) -R5 or R1-C (= O) -O-C (= O) -OR6, and single alkyl esters corresponding to the formula Rx-C (= O) -OR6, wherein R5 and R6 are as defined above The derivative of the acid R1-C (= O) -OH is usually used in a slight excess, and the alkoxide salt is usually present in 1-2 equivalents of the derivative of said acid R1-C (= O) -OH. The reaction between the R1C (= O) -OH derivative of the acid and the compound corresponding to the formula is usually started at a temperature of 0 to 25 ° C, but then the reaction mixture is usually heated to 50 to 130 ° C, preferably about 80 ° C. to complete the reaction 15. The reaction times used under these conditions are usually from a few, for example two, hours to a few, for example two, days. then the reaction mixture is cooled, diluted with excess water and acidified. The product of formula IV can then be recovered by filtration or by a conventional solvent extraction procedure.

Acyl isocyanates of the formula R 2 -C (= O) -N- = 00, which are known compounds, can be prepared by published methods. Acyl isocyanates analogous to known compounds can be prepared using similar procedures. In general, the corresponding amide of formula R 2 -C (= O) -NH 2 is reacted with oxalyl chloride or the acid chloride of formula R 2 -C (= O) -Cl is reacted with silver cyanate. See Speziale et al., Journal of Organic Chemistry 28 (1963) 1805 and 30 (1965) 4306; Ramirez et al., Journal of Organic Chemistry 34 (1969) 376; and Naito et al., Journal of Antibiotics (Japan) 18 (1965) 145.

The 2-oxindole compounds of formula lii are prepared by known methods or by equivalent methods. See "Rodd's Chemistry of Carbon Compounds," 2nd ed., Ed. S. Coffey, Col. Part IV A, Elsevier Scientific Publishing Company, 1973, pp. 448-450; Gassman et al., Journal of Organic Chemistry 42 (1977) 1340; Wright 5 et al. Journal of the American Chemical Society 78 (1956) 221; Beckett et al., Tetrahedron 24 (1968); U.S. Patent Nos. 3,882,236, 4,006,161 and 4,160,032; Walker, Journal of the American Chemical Society 77 (1955) 3844; Protiva et al., Collection of Czechoslovakian Chemical 10 Commucations 44 (1979) 2108; McEvoy et al., Journal of Organic Chemistry 38 (1973) 3350; Simet, Journal of Organic Chemistry 28 (1963) 3580; Wieland et al., Chemische Berichte 96 (1963) 253; and references cited therein.

The following examples are presented in more detail to illustrate the invention.

Example 1 (Compound of formula (II) N-benzoyl-2-oxindole-1-carboxamide To a stirred slurry of 399 mg (3.0 mmol) of 2-20 oxindole in 7 mL of toluene was added 485 mg (3.3 The mixture was refluxed for 2.2 h, then cooled to room temperature, the solid was isolated by filtration and then dissolved in about 10 mL of hot acetonitrile 25. The acetonitrile solution was treated with charcoal to remove color, after which the solution was allowed to cool. the precipitate was isolated by filtration, and recrystallization of the precipitate from acetonitrile gave 131 mg of the title compound, mp 183.5-184.5 ° C.

Analysis for C16H1203N2:

Calculated: C 68.56, H 4.32, N 9.99%

Found: C 68.37, H 4.58, N 10.16%

Example 2 (Compounds of formula (II)) By reacting the appropriate 2-oxindole with the required acyl isocyanate following essentially the procedure described in Example 9 82448 1, the following compounds were prepared:

0 = C-NH-C-R

II

0 X_R1_Melting point (8C) * Yield% 10 5-C1 phenyl 193-195 37 5- CH3 phenyl 202-203 68 6-C1 phenyl 206-207 59 6-F phenyl 174-175.5 5-F phenyl 187d 37 15 H 4-fluorophenyl 177-178d 21 5-CH3 4-fluorophenyl 209-211d 78 5-C1-4-fluorophenyl 198-199d 59 H 4-methoxyphenyl 180d 72 H 4-chlorophenyl. 186.5-187.5d 53 20 H 2-methylphenyl 166.5-167.5 59 H cyclohexyl 144.5-145.5 62 5-C1 cyclohexyl 172-174 63 5- CH3 cyclohexyl 140-141.5 68 6 - C1 cyclohexyl 181-182 56 25 5-F cyclohexyl 163.5-164.5 63 4- C1 cyclohexyl 173-174 69 5 CF3 cyclohexyl 177.5-178.5d 40 6- F cyclohexyl 203-206 43 H t -butyl 151-152 35 30 5-CH3 t-butyl 202.5d 34 5-C1 t-butyl 176.5-177.5d 43 5- F t-butyl 161.5-162.5d 31 6- C1 t- butyl 146-147 42 H isopropyl 114-115 23 35 5-CH3 isopropyl 169-171 38 10 8 2 448 5-Cl isopropyl 164-165 77 6-Cl isopropyl 128-129 69 H phenoxymethyl 187-188 78 5-Cl phenoxymethyl 218-219 51 5 1) In this column, the letter "d" means that it decomposed on melting

Example 3 (Compound of Formula (IV)) 3- (2-Furoyl) -2-oxindole To a stirred solution of 5.5 g (0.24 mol) of sodium in 150 ml of ethanol at room temperature was added 13 .3 g (0.10 mol) of 2-oxindole. The resulting slurry was cooled to the temperature of an ice bath, after which 15.7 g (0.12 mol) of 2-furoyl chloride was added dropwise over 10-15 minutes. The ice bath was removed and an additional 100 mL of ethanol was added, after which the reaction mixture was refluxed for 7 h. The reaction mixture was allowed to stand overnight, after which the solid was filtered off. This solid was added to 400 ml of water, and the resulting mixture was acidified with concentrated hydrochloric acid. The mixture was cooled with ice and the solid was collected by filtration. It was recrystallized from 150 ml of acetic acid to give 8.3 g of yellow crystals, mp 209 DEG-210 DEG C. (decomposition).

Analysis for C13H903N:

Calculated: C 68.72, H 3.99, N 6.17%

Found: C 68.25, H 4.05, N 6.20%

Example 4 (Compound of Formula (IV)) Reaction of 2-oxindole with the appropriate acid chloride using the procedure of Example 1 further afforded the following products: 3- (2-thienoyl) -2-oxindole, m.p. 189-190 ° C, yield 17%; 3- [2- (2-thienyl) acetyl] -2-oxindole, m.p. 191-192.5 ° C, yield 38%; 35 3- (2-phenoxyacetyl) -2-oxindole, m.p. 135-136 ° C, yield 11,82448 42%; and 5-chloro-3- [2- (2-thienyl) acetyl] -2-oxindole, m.p. 228-230 ° C, yield 22%.

Example 5 (Compound of Formula (IV)) 3- (3-Furoyl) -2-oxindole

To a stirred solution of 2.8 g (0.12 mol) of sodium in 200 ml of ethanol was added 13.3 g (0.10 mol) of 2-oxindole followed by 16.8 g of ethyl 3-furoate. . The mixture was refluxed for 47 h, cooled, and then the solvent was removed by evaporation under reduced pressure. The residue was triturated with 200 mL of ether, and the solid was collected by filtration and discarded. The filtrate was evaporated under reduced pressure, the residue triturated with diisopropyl ether and filtered off. This material was suspended in 250 ml of water, which was then acidified with concentrated hydrochloric acid. This mixture was stirred to give a solid which was isolated by filtration. The latter solid was recrystallized from acetic acid 20 followed by acetonitrile to give 705 mg of the title compound, m.p. 185-186eC.

Analysis for C13H903N:

Calculated: C 68.72, H 3.99, N 6.17%

Found: C 68.72, H 4.14, N 6.14% Example 6 (compounds of formula (IV))

By reacting the appropriate oxindole with the required carboxylic acid ethyl ester following essentially the procedure of Example 5, the following compounds were obtained: 5-chloro-3- (2-thienoyl) -2-oxindole, m.p. 190.5192 ° 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, 35% yield 61%; i2 82448 5-fluoro-3- (2-furoyl) -2-oxindole, m.p. 222-224 ° C, yield 51%; 5-fluoro-3- (2-thienoyl) -2-oxindole, m.p. 200-203 ° C, yield 26%; 5-fluoro-3- (2-furoyl) -2-oxindole, m.p. 239-242 ° C, yield 26%; and 6-chloro-5-fluoro-3- (2-thienoyl) -2-oxindole, m.p. 212-215 ° C, yield 20%.

Example 7 (Compound of Formula (III)) 5-Chloro-2-oxindole

To a stirred slurry of 100 g (0.55 mol) of 5-chlorosatin in 930 ml of ethanol was added 40 ml (0.826 mol) of hydrazine hydrate to give a red solution. The solution was refluxed for 3.5 h during which time a precipitate formed. The reaction mixture was stirred overnight, and the precipitate was then isolated by filtration to give 5-chloro-3-hydrazono-2-oxindole as a yellow solid, which was dried in a vacuum oven. The dried solid weighed 105.4 g.

The resulting dried solid was then gradually added over 10 minutes to a solution of 125.1 g of sodium methoxide in 900 ml of absolute ethanol. The resulting solution was refluxed for 10 minutes, after which it was evaporated under reduced pressure to give 25 gummy solids. This gummy substance was dissolved in 400 ml of water, and the aqueous solution thus obtained was treated to remove color with activated carbon and then poured into a mixture of water (1 liter) and concentrated hydrochloric acid (180 ml) containing ice cubes. A golden brown precipitate formed which was collected by filtration and washed well with water. The solid was dried and then washed with diethyl ether. Finally, it was recrystallized from ethanol to give 48.9 g of the title compound, mp 193-195 ° C (dec).

In a similar manner, 5-methylisatin 13,82448 was converted to 5-methyl-2-oxindole by treatment with hydrazine hydrate followed by sodium ethoxide in ethanol. The product melted at 173-174 ° C.

Example 8 (Compound of Formula (III)) 4-Chloro-2-oxindole and 6-chloro-2-oxindole A. 3-Chloroisonitrosoacetanilide in a solution of 113.23 g (0.686 mol) of chloral hydrate in 2 L water and stirred, 419 g (2.95 mol) of sodium sulphate were added, followed by a solution of 89.25 g (0.70 mol) of 3-chloroaniline, 62 ml of concentrated hydrochloric acid and 500 ml of: water. A thick precipitate formed. A solution of 155 g (2.23 mol) of hydroxylamine in 500 ml of water was then added to the reaction mixture with stirring. Stirring was continued and the reaction mixture was slowly heated, and the mixture was maintained at 60-75 ° C for about 6 hours, during which time an additional 1 liter of water was added to facilitate stirring. The reaction mixture was then cooled and the precipitate was isolated by filtration. The wet solid was dried to give 136.1 g of 3-chloroisonitrosoacetanilide.

B. 4-Chloroisatin and 6-chloroisatin To 775 ml of concentrated sulfuric acid, preheated to 70 ° C, 136 g of 3-chloroisonitrosoacetanilide were added with stirring at such a rate that the temperature of the reaction mixture remained between 75 ° C and 85 ° C. After all the solid was added, the reaction mixture was heated at 90 ° C for an additional 30 minutes. The reaction mixture was then cooled and poured slowly while stirring into ice (about 2 L). New ice was added as needed to keep the temperature below room temperature. An orange-red precipitate formed which was isolated by filtration, washed with water and dried. The resulting solid was slurried in 2 L of water and then dissolved by the addition of about 700 mL of 35 N sodium hydroxide. The solution was filtered and adjusted to pH 8 with 84848 concentrated hydrochloric acid. In this lie, 120 ml of a mixture containing 80 parts of water and 20 parts of concentrated hydrochloric acid were added. The precipitated solid was isolated by filtration, washed with water and dried to give 50 g of crude 4-chloroisatin. The pH of the filtrate from which 4-chloroisatin was isolated was further adjusted to 0 with concentrated hydrochloric acid to form more precipitate. It was isolated by filtration, washed with water and dried to give 43 g of crude 6-chloro-10-risatin.

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

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

C. 4-Chloro-2-oxindole

To a slurry containing 43.3 g of 4-chloroisatin in 350 ml of ethanol and stirred was added 17.3 g of hydrazine hydrate, and then the reaction mixture was refluxed for 2 h. The reaction mixture was cooled, and the precipitate was isolated by filtration to give 43 g. 5 g of 4-chloro-3-hydrazono-2-oxindole, mp 235-236 ° C.

To a stirred solution of 22 g of sodium in 450 ml of anhydrous ethanol was added 43.5 g of 4-chloro-3-hydrazono-2-oxindole, and the resulting solution was refluxed for 30 minutes. The cooled solution was then concentrated to a gum which was dissolved in 400 mL of water and treated with charcoal to remove color. The resulting solution was poured into a mixture of water (1 liter) and concentrated hydrochloric acid (45 ml). The precipitate formed was isolated by filtration, dried and recrystallized from ethanol to give 22.4 g of 4-chloro-2-oxindole, mp 216-218 ° C (decomposes).

35 15 82448 D. 6-Chloro-2-oxindole

Reaction of 36.2 g of 6-chloroisatin with hydrazine hydrate followed by sodium ethoxide in ethanol approximately in accordance with C-5 above gave 14.2 g of 6-chloro-2-oxindole, m.p. 198 ° C.

Example 9 (Compound of Formula (III)) 5,6-Difluoro-2-oxindole

Reaction of 3,4-difluoroaniline with chloro-10 hydrate and hydroxylamine and subsequent cyclization of the product with sulfuric acid in a manner similar to Example 8 A and B gave 5,6-difluoroisatin which was reacted with hydrazine hydrate followed by sodium methoxide in ethanol. in the same manner to give the title compound, mp 187-190 ° C.

Example 10 (Compound of Formula (III)) 5-Fluoro-2-oxindole

To a solution of 11.1 g (0.1 mol) of 4-fluoro-20 aniline in 200 ml of dichloromethane and stirred at -60 to -65 ° C was added dropwise a solution containing 10.8 g (0 mol) of , 1 mol) of t-butyl hypochlorite in 25 ml of dichloromethane. Stirring was continued for 10 minutes at -60 to 65 ° C, after which a solution of 13.4 g (0.1 mol) of ethyl 2- (methylthio) acetate in 25 ml of dichloromethane was added dropwise. Stirring was continued at -60 ° C for 1 h, after which a solution of 11.1 g (0.11 mol) of triethylamine in 25 ml of dichloromethane was added dropwise. The cooling bath was removed, and after warming the reaction mixture to room temperature, 100 ml of water was added thereto. The layers were separated and the organic layer was washed with saturated sodium chloride solution, dried (Na 2 SO 4) and evaporated under reduced pressure. The residue was dissolved in 350 ml of diethyl ether, to which was added 35 40 ml of 2N hydrochloric acid. This mixture was stirred at room temperature 82448 overnight. The layers were separated, and the ether layer was washed with water and then with saturated sodium chloride solution. The dried (Na 2 SO 4) ether layer was evaporated under reduced pressure to give 17 g of an orange-brown solid which was triturated with isopropyl ether. The solid was then recrystallized from ethanol to give 5.58 g of 5-fluoro-3-methylthio-2-oxindole, mp 151.5-152.5 ° C.

Analysis for C 9 H 8 ONFS: 10 Calculated: C 54.8, H 4.09, N 7.10%

Found: C 54.74, H 4.11, N 7.11%

A small portion of the 5-fluoro-3-methylthio-2-oxindole prepared above (986 mg, 5.0 mmol) was added to a mixture of 2 teaspoons of Raney nickel in 50 mL of 15 absolute ethanol, followed by refluxing the reaction mixture. luxated for 2 h. The catalyst was removed by decantation and washed with absolute ethanol. The combined ethanol solutions were evaporated under reduced pressure and the residue was dissolved in dichloromethane. The dichloromethane solution was dried (Na 2 SO 4) and evaporated under reduced pressure to give 475 mg of 5-fluoro-2-oxindole, mp 121-134 ° C.

Similarly, 5-trifluoromethyl-2-oxindole (mp 189.5-190.5 ° C) was obtained by reacting 4-trifluoromethylaniline with t-butyl hypochlorite, ethyl 2-25 (methylthio) acetate and triethylamine, and reducing the resulting 3 -thiomethyl-5-trifluoromethyl-2-oxindole followed by Raney nickel.

Example 11 (Compound of Formula (III)) 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 and 13.5 ml (0.166 mol) pyridine. The resulting solution was cooled to about 0 ° C and 13.2 mL (0.166 mol) of 2-chloroacetyl chloride was added. The reaction mixture was stirred at room temperature for 5 h, after which it was extracted twice with 100 ml of 100 ml of 1N hydrochloric acid and then with 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried over magnesium sulfate and then evaporated under reduced pressure to give 32.6 g (88% yield) of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline.

A 26.63 g portion of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline and 64 g of anhydrous aluminum chloride were mixed well, and the mixture was heated at 210-230 ° C for 8.5 h. The reaction mixture was then heated. poured into a mixture of ice and 1 N hydrochloric acid with stirring. Stirring was continued for 30 minutes, after which the solid was collected by filtration (22.0 g). This solid was dissolved in ethyl acetate-hexane (1: 1) and chromatographed using silica gel (800 g) as adsorbent. Elution of the column followed by evaporation gave 11.7 g of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline followed by 3.0 g of 6-chloro-5-fluoro-2-oxindole. The latter was recrystallized from toluene to give 1.80 g (7% yield) of the title compound, mp 196-206 ° C. NMR spectroscopic analysis showed the product to contain some 4-chloro-5-fluoro-2-oxindole as an impurity. A second crop of product weighing 0.8 g was obtained.

Example 12 (Compound of Formula (III)) 6-Bromo-2-oxindole To 9.4 g of sodium hydride was added 195 ml of dimethyl sulfoxide, followed dropwise by 22.37 ml of dimethyl malonate. At the end of the addition, the mixture was heated to 100 ° C and maintained at this temperature for 40-30 minutes. At this point, 25 g of 1,4-dibromo-2-nitrobenzene were added in one portion. The reaction mixture was kept at 100 ° C for 4 h, after which it was added to 1.0 L of saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate, and the extraction solutions were washed with saturated ammonium chloride solution, water and saturated sodium chloride solution. The dried (MgSO 4) solution was evaporated and the residue was recrystallized from ethyl acetate-t-hexane to give 22.45 g of dimethyl 2- (4-bromo-2-nitrophenyl) malonate.

A solution of 17.4 g of dimethyl 2- (4-bromo-2-nitrophenyl) malonate and 4.6 g of lithium chloride in 150 ml of dimethyl sulfoxide was placed in a 100 ° C oil bath. After 3 hours, the reaction mixture was cooled to room temperature and then poured into a mixture of ethyl acetate (500 ml) and saturated sodium chloride solution (500 ml). The layers were separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate and then evaporated under reduced pressure. The residue was chromatographed using silica gel as adsorbent and ethyl acetate-hexane as eluent. There was thus obtained 9.4 g of methyl 2- (4-bromo-2-nitrophenyl) acetate.

To a solution of 7.4 g of methyl 2- (4-bromo-2-nitrophenylacetate in 75 ml of acetic acid) was added 6.1 g of iron powder, and the reaction mixture was placed in an oil bath at 100 ° C. After 1 hour, the solvent was removed under reduced pressure and the residue was dissolved. To a solution of 250 ml of ethyl acetate, the solution was filtered, washed with saturated sodium chloride solution, dried over sodium sulfate, treated with decarbonated charcoal and evaporated under reduced pressure to give 5.3 g of 6-bromo-2-oxindole as a white crystalline solid, mp 213-214 ° C. .

Example 13 (Compounds of Formula (III)) 5-Bromo-2-oxindole can be prepared according to Beckett et al. [Tetrahedron 24 (1968) 6093].

5-n-Butyl-2-oxindole can be prepared by reacting 5-n-butylisatin with hydrazine hydrate followed by sodium methoxide in ethanol according to the procedure used in Example 7. 5-n-Butyl-t1992448 isatin can be prepared from 4-n-butylaniline by treating it with chloral hydrate and hydroxylamine and then cyclizing the product obtained with sulfuric acid according to the procedure of Example 8 (A) and (B).

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

6-Fluoro-2-oxindole can be prepared according to Protivan et al. [Collection of Czexhoslovak Chemical Communications 44 (1079) 2108] and in accordance with U.S. Patent No. 10,160,032.

6-Trifluoromethyl-2-oxindole can be prepared by the method of Simef [Journal of Organic Chemistry 28 (1963) 3580].

Example 14 N-Benzoyl-3- (2-furoyl) -2-oxindole-1-carboxamide

A mixture of 909 mg (4.0 nunol) of 3- (2-furoyl) -2-oxindole and 706 mg (4.8 mmol) of benzoyl isocyanate in 25 ml of toluene was heated to reflux and then refluxed for 7 hours. h. The mixture was allowed to stand at room temperature overnight, and then the precipitate formed was removed by filtration to give 1.3 g of crude product. The crude product was recrystallized from about 30 ml of acetic acid to give 920 mg of the title compound, mp 184 ° C (dec).

Analysis for C21H1405N2:

Calculated: C 67.37, H 3.77, N 7.49%

Found: C 66.90, H 4.02, N 7.38%

Example 15 N-Benzoyl-3- (2-furoyl) -2-oxindole-1-carboxamide To 30 ml of N, N-dimethylformamide was added with stirring 2.8 g (10 mmol) of N-benzoyl-2- oxindole-1-carboxamide followed by 2.9 g (24 mmol) of 4- (N, N-dimethyl-35-liaraino) pyridine. The mixture was cooled in an ice bath, and then a solution of 1.6 g (12 mmol) of 2-furoyl chloride in 10 ml of N, N-dimethylformamide was added dropwise over 10 minutes with stirring. Stirring was continued for 30 minutes, after which the reaction mixture was poured into a mixture of water (250 ml) and 3N hydrochloric acid (5 ml). The resulting mixture was cooled in an ice bath, and the solid was removed by filtration. This solid was recrystallized from about 75 ml of acetic acid to give 2.94 g of the title compound as tan crystals, m.p. 190 ° C.

The following absorption peaks were observed in the ultraviolet spectrum of the title compound:

Solvent Wavelength Epsilon __ (nm) _ 15 CH 3 OH 245 6,920 375 2,530 CH 3 OH + droplet 249 7,200 O, 1N NaOH 372 2,710 CH 3 OH + 1 droplet 241 9,070 20 0, 1N HCl

Example 16 N-Benzoyl-3-acetyl-2-oxindole-1-carboxamide

To a stirred slurry of 841 mg (3.0 mmol) of N-Benz-25-soyl-2-oxindole-1-carboxamide in 5 mL of N, N-dimethylformamide was added 806 mg (6.6 mmol) of 4- (n, n-dimethylamino) pyridine. Stirring was continued for a few minutes, after which the slurry was cooled in an ice bath and a solution of 337 mg (3.3 mmol) of acetic anhydride in 2 ml of N, N-dimethylformamide was added dropwise. Stirring was continued for 1 h, after which the reaction mixture was poured into a mixture of ice water (65-70 ml) and 3N hydrochloric acid (2.2 ml). The precipitated solid was collected by filtration. It was recrystallized from ethanol to give 385 mg of the title compound 2i 82448 as golden brown crystals, mp 198 ° C. Analysis for C18H1404N2:

Calculated: C 67.07, H 4.38, N 8.69%

Found: C 66.78, H 4.65, N 8.62% Example 17 N-Benzoyl-3- (2-thienoyl) -2-oxindole-1-carboxamide

To a stirred solution of 486 mg (2.0 mmol) of 3- (2-thienoyl) -2-oxindole and 445 mg (4.4 mmol) of triethylamine in 5 mL of dimethyl sulfoxide was added 324 mg ( 2.2 mmol) benzoyl isocyanate. Stirring was continued for 1 h, after which the mixture was poured into a mixture of water (50 ml) and 3N hydrochloric acid (1.7 ml). The resulting mixture was cooled in an ice bath, and the solid was removed by filtration. This solid was recrystallized from about 30 mL of ethanol-water (2: 1) to give 190 mg of the title compound as light yellow crystals, mp 165-166 ° C (dec).

Analysis for C 21 H 14 O 4 N 2 S: 20 Calculated: C 64.60, H 3.61, N 7.18%

Found: C 64.53, H 3.75, N 7.10%

Example 18

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Example 19 N-Benzoyl-3- (2-thienoyl) -2-oxindole-1-carboxamide was also prepared by reacting 3- (2-thienoyl) -2-oxindole with benzoyl isocyanate using the method of Example 5.

N-Benzoyl-3- [2- (2-thienyl) acetyl] -2-oxindole-1-carboxamide was prepared by reacting 3- [2- (2-thienyl) acetyl] -2-oxindole with benzoyl isocyanate. using the method of Example 14.

10 Example 20

Following the procedure of Example 14 (Method A), Example 15 or 16 (Method B) or Example 17 (Method 4), the following compounds were prepared:

O

X. 11-1 OC-NH-C-R 2

II

25 82448 X R1 R2 Finished Melting point method (° C) H methyl phenyl A, B 198-200d 5 H isopropyl phenyl B 165d H cyclohexyl phenyl B 18Id 5-C methyl phenyl B 215-217d 5-C1 isopropyl phenyl B 185,5-187,5d 10 5-C1 cyclohexyl phenyl B 192-194d H 3-furyl phenyl C 187d 5-C1 cyclopropyl phenyl B 213-215d H cyclopropyl phenyl B 173d H isopropyl phenyl B 165d 15 H 1-phenylethyl phenyl B 173d 5-C1 benzyl phenyl B 239-240d 5- CH3 2-furyl phenyl B 204-205d H (3-thienyl) methyl phenyl B 195-197d 20 6-C1 2-thienyl phenyl B 192-193d 6 - F 2 -furyl phenyl B 189-190 6-F 2-thienyl phenyl B 190-194 5-C 1-5 ethyl-2- B 202-furyl phenyl B 203.5d 25 H 5-ethyl-2-furyl phenyl B 174-175 5-F 2-Furyl phenyl B 172d 5-F (2-thienyl) methyl phenyl B 189d 30 6-C1 2-furyl phenyl B 199-200 5-F (2-thienyl) methyl phenyl B 167d 6-C1 (2-thienyl) methyl phenyl B 199-200d 35 26 82 4 48 H 2-thienyl 4-fluorophenyl C 163.5-164.5d H 2-f uryl 4-fluorophenyl C 164.5d H methyl 4-fluorophenyl A 205-207d 5 H benzyl 4-fluorophenyl A 207-209d H cyclopropyl 4-fluorophenyl B 167.5d H (2-thienyl) -4-fluorophenyl A 216-217d methyl 5-CH3 2-thienyl 4-fluorophenyl B 178-179d 10 5-CH3 2-furyl 4-fluorophenyl B 197-199d 5-CH3 2-furyl 4-fluorophenyl B 179-181d 5-C1 2-thienyl 4-fluorophenyl B 191.5-1925d 15 H (2-thienyl) -4-methoxyphenyl methyl A 197-198d H 2-thienyl 4-methoxyphenyl B 173d H 2-furyl 4-methoxyphenyl B 146d H cyclopropyl 4- methoxyphenyl B 193d 20 H isopropyl 4-methoxyphenyl B 125d H 2-furyl 4-chlorophenyl B 180-181d H 2-thienyl 4-chlorophenyl B 170-171d H isopropyl 4-chlorophenyl B 164-165d H isopropyl 4-chlorophenyl B 184- 185d 25 H 2-thienyl 2-methylphenyl B 173.5d H 2-furyl 2-methylphenyl B 167-168d H (2-thienyl) -2-methylphenyl B 179.5d methyl H cyclopropyl cyclohexyl B 153-154d 30 H methyl cyclohexyl B 167-168d H 1-phenylethyl cyclohexyl B 191d H 5-methyl-2-cyclohexyl B 163-165d furyl 5-C1-5-methyl-2-cyclohexyl B 197.5d 35 furyl 27 8 2 4 4 8 5-Cl methyl cyclohexyl B 214.5d 5-Cl propyl cyclohexyl B 162-163d 5-Cl isopropyl cyclohexyl B 205-206d 5-CH3 2-furyl cyclohexyl B 170-171 5 5-CH3 2-thienyl cyclohexyl B 153-154.5d H 5-ethyl-2-cyclohexyl B 146- 147 furyl 5-CH3 5-ethyl-2-cyclohexyl B 190-191 10 furyl 5-CH3 (2-thienyl) -cyclohexyl B 158-159 methyl 5-Cl5-ethyl-2-cyclohexyl B 2110-211d furyl 15 6 -C1 2-furyl cyclohexyl B 183-184 5-F 2-furyl cyclohexyl B 186.5-187.5d 5-F 2-thienyl cyclohexyl B 145.5-201465d 5-F (2-thienyl) cyclohexyl B 164-165 methyl 6-C1 2-thienyl cyclohexyl B 172-173 6-C1 (2-thienyl) -25 methyl cyclohexyl B 173-175d 4-C1 2-thienyl cyclohexyl B 189-190 4-C1 (2-thienyl) - methyl cyclohexyl B 172-173 4-C1 methyl cyclohexyl B 131-132 30 5-CF3 2-furyl cyclohexyl B 194-195d 5-CF3 2-thienyl cyclo salhexyl B 171-172d 6- F 2 -furyl cyclohexyl B 164-166

6-F 2-thienyl cyclohexyl B

5-CH3 2-thienyl t-butyl B 189.5d 35 5-CH3 methyl t-butyl B 194d 28 82448 5-C1 methyl t-butyl B 211.5d 5-CH3 5-ethyl-2-furyl t-butyl B 214-215 5-C1-5-ethyl-2-5 furyl t-butyl B 224-225 5-F 2-furyl t-butyl B 212.5d 5-F 2-thienyl t-butyl B 183.5d 5-F (2-thienyl) methyl t-butyl B 161d 10 6-C1 2-thienyl t-butyl B 191-192 5-CH3 2-thienyl isopropyl B 146-147d 5-CH3 2-furyl isopropyl B 166-167d 5- C1 benzyl isopropyl B 184-185 5-C1 cyclohexyl isopropyl B 206-208d 15 5-CH3 5-methyl-2-furyl isopropyl B 194d 5-CH3 methyl isopropyl B 158-159 5-C1-5-methyl-2-isopropyl B 198,5-furyl 199,5 20 5-C1 methyl isopropyl B 215-216 H methyl isopropyl B 170-172 H cyclohexyl isopropyl B 188-189 H benzyl isopropyl B 145-146 5-C1-5-ethyl-2-isopropyl 25 furyl B 209-211d 5-C1 isopropyl isopropyl B 142-143 6- C1 2-furyl isopropyl B 184-185d 6-C1 2-thienyl isopropyl B 174.5-175 30 6-C1 (2-thienyl) methyl isopropyl over B 157-158d H 2-thienyl phenoxymethyl B 161-162 5-C1 2-thienyl phenoxymethyl B 182-183 H 2-furyl phenoxymethyl B 173-175d 35 11 29 82448 H (2-thienyl) phenoxymethyl methyl B 193- 194 5-C 1-2 furyl phenoxymethyl B 194-195.5 5 1) In this column, the letter A means that the compound was prepared approximately according to Example 14; the letter B means that the compound was prepared approximately according to Example 15 or 16; 10 and the letter C mean that the compound was prepared roughly according to Example 17.

2) The letter "d" means that the compound decomposed on melting.

15

Claims (3)

A compound or a base salt thereof, characterized in that it has the formula 5-NH-C-R 2 (ID 10 »wherein X is hydrogen, fluorine, chlorine, C 1-4 alkyl or trifluoromethyl; and R 2 is Cl. 6-alkyl, C 3-7 cycloalkyl, phenoxymethyl or a group R 3 wherein each of R 3 and R 4 may be hydrogen, fluorine, chlorine, C 1-4 alkyl or C 1-4 alkoxyl. 2. A compound or a base salt thereof, characterized in that it has the formula 25. O * H 30 wherein X is hydrogen, 5-fluoro or 5-chloro; Y is hydrogen, 6-fluoro or 6-chloro; and R 1 is a benzyl, furyl, thienyl or thienylmethyl group; provided that when both X and Y are hydrogen, R 1 is not a benzyl group. A compound according to claim 2, characterized in that X is 5-chloro, Y is hydrogen and R 1 is a 2-thienyl group. Il 31 82448