FI80270B - FOERFARANDE FOER FRAMSTAELLNING AV ANALGETISKA OR ANTI-INFLAMMATORISKA 1,3-DIACYL-2-OXOINDOL-FOERENINGAR OCH MELLANPRODUKTER. - Google Patents

Description

1 80270

The invention relates to a process for the preparation of a therapeutically useful 1,3-diacyl-2-oxoindole compound of formula (I) or a pharmaceutically acceptable base salt thereof. the preparation of

x O

10 \ 11 1 0qT -

y 0 = C ~ K

Wherein X and Y are hydrogen, fluorine, chlorine or nitro; R 1 is phenyl, benzyl, pyridyl, thienyl, thienylmethyl or furyl; R 2 is C 1 -C 5 alkyl.

These new chemical compounds are inhibitors of cyclooxygenase (CO) and lipoxygenase (LO) enzymes.

The compounds of formula (I) have analgesic activity in mammals, in particular humans, and are therefore useful for the acute administration of pain to relieve or eliminate pain, such as in the treatment of pain experienced by a patient during surgery or injury.

In addition to its utility in acute drug delivery against pain, the compounds of formula (I) have utility in chronic drug delivery to mammals, especially humans, for alleviating the symptoms of chronic diseases such as ni-35 veloritis and osteoarthritis associated with inflammation and pain.

Preferred compounds of formula (I) are those wherein X and Y are each hydrogen and R 1 is 2-furyl, 2-thienyl, 3-pyridyl or (2-thienyl) methyl.

Further preferred compounds of formula (I) are those wherein X is 5-chloro, Y is hydrogen and R 1 is 2-furyl, 2-thienyl, 3-pyridyl or (2-thienyl) methyl.

Particularly preferred compounds of the invention 10 are: 1-acetyl-3- (2-thenoyl) -2-oxoindole, 1-acetyl-3 - [(2-thienyl) acetyl] -2-oxoindole and 5-chloro-1-acetyl -3- (2-thenoyl) -2-oxindole.

Useful intermediates in the preparation of analgesic and anti-inflammatory compounds of formula (I) include 1-acyl-2-oxoindole compounds of formula Y «2 OC-R * 25 wherein X, Y and R2 are as defined above. A preferred subgroup of compounds of formula II are those compounds wherein X is hydrogen, 5-fluoro or 5-chloro; Y is hydrogen, 6-fluoro or 6-chloro; and R 2 is C 1 -C 5 alkyl, provided that X and Y are not both hydrogen. The compounds of formula (II) and the compounds of said preferred subgroup are novel and thus also form part of the invention.

The compounds of formula (I) are derivatives of 2-oxoindole having the structure of 2-oxoindole as follows: 11 35 3 80270 Οα

° 'H

The analgesic and anti-inflammatory compounds of formula (I) in which X, Y, R 1 and R 2 are as defined above are capable of enolization and may then exist in one or more tautomeric (enol) forms. All such tautomeric forms (enol forms) are considered to be within the scope of the invention.

Compounds of formula (I) are prepared from a suitable 2-oxoindole compound of formula III: 15

Y H

Wherein X and Y are as defined above, by attaching a substituent -C (= O) -R2 at the 1-position and a substituent -C (= O) -R13 at the 3-position. These substituents can be attached in either order, and consequently the compounds of formula (I) can be prepared by two alternative methods. These are shown in Scheme A. However, the preferred method for preparing the compounds of formula (I) follows the order: compound 30 (H1) -> compound (IV) -> (I).

4,80270

Scheme A Y H

/ ..... \ γ 'n' 2 x H 0 = C-Rz "\ /"

X. O

ixx ‘γ’ I 2 1 0 = C-R ^ (I) il 5 80270 2

The substituent -C (= O) -R can be attached to a compound of formula 2 IV by reaction with an activated derivative of a carboxylic acid of formula R -C (= O) -OH used in a molar equivalent or slightly excess, and in the presence of 5 bases (1-4 equivalents). ) in an inert solvent. An inert solvent is one that dissolves at least one of the reactants and does not adversely affect the reactants or product. Usually, however, a polar, aprotic solvent such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide, N-methylpyrrolidone or dimethyl sulfoxide is used. Conventional methods are used to activate the acid of formula 2 R -C (= O) -OH. For example, acid halides such as acid chlorides, symmetrical acid anhydrides, R -C (= O) -O-C (= O) -R can be used; mixed anhydrides with an inhibited small, 2 nominal molecular weight carboxylic acid, R -C (= O) -330-C (= O) -R, wherein R is bulky lower alkyl such as tert-butyl; carboxylic acid mixed anhydrides, 2 4 4 R -C (= O) -O-C (= O) -OR, where R is a lower alkyl group.

In addition, N-hydroxyimide esters (such as N-hydroxysuccinimide and N-hydroxyphthalimide), 4-nitrophenyl esters, thiol esters (such as thiolphenyl esters) and 2,4,5-trichlorophenyl esters and the like can be used.

2

In the reaction between a compound of formula IV and an activated derivative of an acid of formula R -C (= O) -OH, many different substances can be used as the basic substance. However, preferred basic substances include tertiary amines such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine and 4- (Ν, Ν-dimethylamino) pyridine.

2

The reaction between a compound of formula IV and an activated derivative of an acid of formula R -C (= O) -OH is usually carried out at a temperature in the range of -20 to 25 ° C. In general, lower temperatures in this temperature range are used when using highly active derivatives of the acid of formula R -C (= O) -OH, while instead in the reaction of less active derivatives of the acid of formula R -C (= O) -OH higher temperatures. In most cases the reaction will take place fairly rapidly, with reaction times of from 30 mi to 5 minutes to some hours being common. After completion of the reaction, the reaction mixture is usually diluted with water and acidified, and the product can then be recovered by filtration. It can be purified by standard methods such as crystallization.

The side chain -C (= O) -R can be attached to a compound of formula II by reaction with an activated derivative of a carboxylic acid of formula R 1 -C (= O) -OH used in a molar equivalent or slightly more. This acylation reaction is carried out in the same manner as the reaction of a compound of formula IV described above with an activated derivative of an acid of formula R -C (= O) -OH.

The side chain -C (= O) -RJ 'can be coupled to a compound of formula III by standard methods in reaction with a suitable acid derivative of formula R 1 -C (= O) -OH in a lower C 20 alkanol solvent (e.g. ethanol) in a lower alkanol solvent. in the presence of an alkali metal salt of the solvent (e.g. sodium ethoxide). Typical acid derivatives of the formula R 1 -C (= O) -OH suitable for use include acid chlorides, R1-C (= O) -O-C (= O) -R 1, R 1 -C (= O) -O -C (= O) -R 1 and 1 4 25 R -C (= O) -O-C (= O) -OR acid anhydrides, simple alkyl esters of formula 1 4 R -C (= O) -OR In formulas 4, R and R have the same meaning as above). In general, a slight excess of the acid derivative of the formula R 1 -C (O) -OH is used and the alkoxide salt is usually present in 1-2 molar equivalents per mole of the acid 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 to complete the reaction, the reaction mixture is usually then heated to 50 to 130 ° C, preferably to about 80 ° C. Under these 7 80270 conditions, the reaction time is from some hours (e.g.

2 h) for some days (eg 2 days). The reaction mixture is then cooled, diluted with water (excess) and acidified. The product of formula IV is then recovered by filtration or conventional solvent extraction.

2

The side chain -C (= O) -R can be attached to a compound of formula III by reaction with a suitable acid anhydride of formula (r) -C (= O) -O 2. The compound of formula III is usually reacted with 1-3 equivalents of a folder (preferably 1.2-1.5 eq) of anhydride without solvent at a temperature in the range of 80-130 ° C, preferably at about 100 ° C, for several hours (e.g. about 4 h). However, if desired, an inert solvent such as toluene may be used. Upon completion of the reaction, the product of formula II is recovered by removing excess anhydride and any solvent by evaporation. The crude product is usually sufficiently pure to be converted to a compound of formula I.

The 2-oxoindole compounds of formula III are prepared by known methods or analogously to known methods. References: "Rodd's Chemistry of Carbon Compounds", 2nd Edition, ed. S. Coffey, vol. Part IV A, Elsevier Scientific Publishing Company, 1973, pages 448-450, Gassman et al., Journal of Organic Chemistry, 42, 1340 (1977); Wright et al., Journal of the American Chemical Society, 78, 221 (1956); Beckett et al., Tetrahedron, 24, 6093 (1968); U.S. Patent Nos. 3,882,236, 4,006,161 and 4,160,032; Walker, Journal of the American Chemical Society, 77, 3844 (1955); Protiva et al., Collection of Czechoslovakian Chemical Communications, 44, 2108 30 (1979); McEvoy et al., Journal of Organic Chemistry, 38, 3350 (1973); Simet, Journal of Organic Chemistry, 28, 3580 (1963); Wieland et al., Chemische Berichte, 96, 253 (1963); and references therein.

The compounds of formula I are acidic and can form base salts. All such base salts are within the scope of the invention and can be prepared by conventional methods. They can be prepared, as the case may be, for example, by contacting the acidic and basic compounds with one another, usually in a stoichiometric ratio, in either an aqueous, anhydrous or partially aqueous medium. The salts are recovered, as the case may be, either by filtration, precipitation with a non-solvent and then filtration, evaporation of the solvent, or, in the case of an aqueous solution, by lyophilization. Typical salts of the compounds of formula I which may be prepared include salts of primary, secondary and tertiary amines, alkali metal salts and alkaline earth metal salts. Of particular value are the salts of ethanolamine, diethanolamine and triethanolamine-15.

The basic substances which can be used for salt formation are organic or inorganic and include, for example, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbons, alkaline earth metal carbons and alkaline earth metal alkoxides. Representative examples of such bases include primary amines such as n-propylamine, n-butylamine, aniline cyclohexyl-amine, benzylamine, p-toluidine, ethanolamine and glucamine; secondary amines such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, triethanolamine, N, N-di-methylaniline, N-ethylpiperidine and N-methylmortoline; 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 are analgesically active 980270. This activity was demonstrated in mice by inhibition of abdominal elongation due to 2-phenyl-1,4-benzoquinone (PBQ) administration; the method is based on Sieg-mund et al., Proc. Soc. Exp. 3iol. Med., 95, 729-731 5 (1957), for faster execution (see Milne and Twomey, Agents and Actions, 10, 31-37 (1980)). The mice used in these experiments were male Carworth-Albino mice, strain CF-1, weighing 18-20 g. All mice fasted overnight 10 before drug administration and experiment.

The compounds of formula I were dissolved or suspended in a medium consisting of ethanol (5%), emulphor 620 (polyoxyethylene fatty acid ester mixture (5%), and brine (90%). This medium was also used as a control. Doses were on a logarithmic scale ( so ... 0.32, 1.0, 3.2, 10, 32, ... mg / kg) The drug was administered orally at varying concentrations to give a constant dose volume of 10 ml / kg body weight. Milne and Twomey's method was used to determine potency and potency, and mice received compounds orally and one hour later PBQ 2 mg / kg intraperitoneally, and each mouse was then placed separately immediately in a heated Lucite chamber (Lucite = clear plastic), and Abdominal contractions occurring over the next 5 minutes were recorded and the degree of analgesic protection (% MPE) was calculated based on the abdominal pressure. reduced dose relative to the estimated dose of MPE ^ rn ^ that reduces abdominal contractions by 50% of the control level) to the response rates required to achieve.

The compounds of formula I also have anti-inflammatory activity. This activity has been demonstrated by a standard method based on a carrageenan-induced rat swelling test (Winter et al., Proc. 35 Soc. Exp. Biol. Med., 111, 544/19637).

10 80270

Anesthetized adult male albinoro-tat (weight 150-190 g) were numbered, weighed, and their right outer spindle was marked with ink. The legs were immersed in mercury exactly to the ink mark.

5 The mercury was in a glass cylinder connected to a Statham pressure transducer. The converter reading was fed through a control unit to a microvolt meter. The volume of mercury displaced by the embedded leg was read. Drugs were administered via a supply line. One hour after the dose of ai-10, edema was induced by injecting 0.05 ml of a 1% carrageenan solution into the plantar tissue of the marked feet. Immediately thereafter, the volume of the injected foot was measured. An increase in foot volume 3 hours after carrageenan injection gives the test animal an anti-inflammatory response. Test compounds are administered at 32 mg / kg, and activity is recorded as the percentage reduction in edema compared to the untreated control (% prevention).

The results of the experiment are shown in the following table.

80270 X_Y_R ^ _R ^ _% Prevention HH benzyl methyl 17.0 * HH 2-thienyl methyl 40.9 HH 2-furyl methyl 17.2 HH (2-thienyl) methyl methyl 36.5 HH 3-pyridyl methyl 33.0 5-C1H-benzyl methyl 9.0 5-C1H-furylmethyl 60.0 5-C1H-phenylmethyl 16.0 5-C1H2-thienylmethyl 42.0 5-FH2-furylmethyl 18.0 HH 2 -thienyl neopentyl 15.0 HH 2-furyl neopentyl 31.0 5-C 1 H 2 -furyl isopropyl 3.0 5-C 1 H benzyl neopentyl 16.0 5-FH 2-thienyl neopentyl 24.0 HH benzyl isopropyl 9 .0HH (2-thienyl) methyl neopentyl 4.0 5-C1H2-thienyl neopentyl 34.0 5-C1H2-thienyl ethyl 7.0 5-C1H (2-thienyl) methyl neopentyl 10.0 HH 2-thienyl isopropyl 3.0 5-FH 2-furyl isopropyl 3.0 5-C1H benzyl isopropyl 4.0 5-FH 2-thienyl isopropyl 6.0 5-NO2 H 2-furyl isopropyl 4.0 5-F 6-C1-2-thienyl methyl 33.0 5-C1H2-furyl ethyl 24.0 HH2-furyl neopentyl 17.0 5-F5-F2-thienyl methyl 20.0 5-FH2-furyl ethyl 17 .0 HH (2-thienyl) met yl isopropyl 17.0 '' · This compound was tested at a dose of 100 mg / kg.

i2 80270

The analgesic activity of the compounds of formula I makes them useful for administration to mammals for the acute control of pain, e.g. post-operative or post-injury pain. In addition, the compounds of formula I are useful for the chronic administration of drugs to mammals for the relief of symptoms of chronic diseases such as rheumatoid arthritis and pain associated with osteoarthritis and other musculoskeletal disorders.

When a compound of formula I or a pharmaceutically acceptable salt thereof is to be used as either an analgesic or an anti-inflammatory agent, it may be administered to a mammal either alone or more preferably in combination with a pharmaceutically acceptable carrier or diluent as a standard pharmaceutical composition. Parenteral administration includes intravenous, intramuscular, 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 ingredient is normally 1: 4-4: 1, preferably 1: 2-2: 1. However, the ratio chosen will in any case depend on such factors as the solubility of the active substance, the intended dose and the precise route of administration.

For oral use, the compound of formula I may be formulated, for example, as tablets or capsules or as water-soluble suspensions or suspensions. Tablet carriers for oral tablets usually contain lactose and corn starch, and in addition usually lubricants such as magnesium stearate. Capsules for oral use suitably contain lactose and corn starch as diluents. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying or suspending agents.

II

i3 with 80270. If desired, certain sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous use, the active ingredient is usually prepared in the form of a sterile solution 5, the pH of which should be suitably adjusted and buffered. The total concentration of solutes for intravenous use should be adjusted so that the product is isotonic.

When a compound of formula I or a salt thereof is administered to a human patient, the daily dose will normally be determined by the attending physician. In addition, the dose will vary with the age, weight and response of the patient, as well as the symptoms of the patient and the potency of the compound being administered. For acute drug administration to relieve pain, the genetic dose of Anal-15, which in most cases is effective, is 0.1-1.0 g as needed (e.g., every 4 or 6 hours). For chronic use to alleviate (treat) inflammation and pain, the effective dose is 0.1-1.5 g per day, preferably 0.3-1.0 g / day in a single dose or in divided doses. On the other hand, it may be necessary in some cases to use doses outside these limits.

The following examples and preparations are presented to illustrate the invention only.

Example 1 1-Acetyl-3- (2-thenoyl) -2-oxoindole To a stirred solution of 3- (2-thenoyl) -2-oxoindole (486 mg, 2.0 mmol) in 4 mL of Ν, Ν-dimethylformamide was added 538 mg (4.4 mmol) of 4- (Ν, Ν-dimethylamino) pyridine. The resulting mixture was cooled in an ice bath, and then a solution of acetic anhydride (225 mg, 2.2 mmol) in 2 mL of Ν, Ν-dimethylformamide was added dropwise over about 1 minute with stirring. The cooling bath was removed and stirring was continued for 1 hour, then the reaction mixture was poured into a mixture of water (50 ml) and 3M hydrochloric acid (1.7 ml). The resulting mixture was cooled in an ice bath, and the solid was filtered. 523 mg of a yellow solid were obtained. It was recrystallized from 15 ml of ethanol to give 300 mg of the title compound as yellow crystals, mp 139-140 ° C.

Analysis for C 1 H 2 NO 2 S:

Calculated: C 63.14, H 3.89, N 4.91%

Found: C 63.15, H 3.90, N 4.87%

Example 2 1-Acetyl-3- (2-furoyl) -2-oxoindole Acetylation of 3- (2-furoyl) -2-oxoindole with acetic anhydride by essentially the same procedure as in Example 1 gave the title compound in 73% yield, m.p. 137.5 to 138.5 ° C.

Analysis for c 15 H 11 NO 4: 15 Calculated: C 66.91, H 4.12, N 5.20%

Found: C 66.93, H 4.23, N 5.12%

Example 3 1-Acetyl-3- (3-pyridylcarbonyl) -2-oxoindole

Acetylation with 3- (3-pyridylcarbonyl) -2-oxoindo-20'-acetic anhydride in essentially the same manner as in Example 1 gave the title compound in 53% yield, mp 141-142.5 ° C.

Example 4

Acylation of the appropriate 3-acyl-2-oxoindole with the required acid anhydride of formula (R CO) 2 <0 in substantially the same manner as in Example 1 gave the following compounds: '2 o = c-ir 11 35 is 80270 XYR "* ~ Melting point - --—__ point (° C) 5-C1H2-thienylmethyl 167-169 5-C1H2-furylmethyl 174-175 5-C1H-phenylmethyl 164-167 5 5-C1H-benzylmethyl 167-168 5-C1H (2-thienyl) methyl methyl 170-171.5 5-FH 2-furyl methyl 161-163 HH 2-thienyl neopentyl 142-145 5-C1H 2-thienyl neopentyl 142-143.5 ^ ® 5 -FH 2-thienyl neopentyl 152-153 HH (2-thienyl) methyl neopentyl 120-122 5-Cl H benzyl neopentyl 128-130 HH benzyl isopropyl 125-128 HH 2-furyl isopropyl 112-115 5-C1H 2-furyl neopentyl 131-132 5-C1H2-thienyl isopropyl 150-151 5-FH 2-furyl isopropyl 114-116 5-NC> 2H-2-furyl isopropyl 183-185 HH 2-thienyl isopropyl 173-175 20 5-FH 2-thienyl isopropyl 147-149 5-C1H (2-thienyl) neopentyl 139-140 , 5 methyl 5-C1H benzyl isopropyl 145-146.5 5-C1H2-thienyl ethyl 180-183 25 HH (2-thienyl) methyl isopropyl 107-109 HH 2-furyl neopentyl 123-125 5-C1H2 -furyl ethyl 195-196.5 5-FH 2 -furyl ethyl 153-154.5 5-F 6 -Cl 2-thienyl methyl 183-185 30 5-F 6 -F 2-thienyl methyl 166-168

Example 5 1-Acetyl-3- (N-thienyl / acetyl) -2-oxoindole 3 - ((2-thienyl) acetyl) -2-oxoindole (1.29 g, 5.0 mmol), 4- (Ν, Ν- dimethylamino) pyridine (1.22 g, 35.0.0 mmol) and N, N-dimethylformamide (15 mL) were cooled in an ice bath, and 562 mg (5.5 mmol) of acetic acid was added dropwise over 1 minute with stirring. 80270 acid anhydride. Stirring at ice bath temperature was continued for 3.25 hours, then the reaction mixture was filtered. The filtrate was poured into a mixture of 3M hydrochloric acid and water to give a solid and a gum. Solid 5 was collected by filtration and decanting the gum.

The gum was triturated with isopropanol-water to give additional solid which was collected by filtration. The solids were combined and extracted with hot benzene to give a dark gum as an extraction residue. The benzene solution was cooled and evaporated in vacuo, and the residue was recrystallized from toluene to give 66 mg of the title compound, mp 136-137 ° C. The mother liquor from the recrystallization was evaporated in vacuo, and the resulting residue was recrystallized from hexane to give a second crop (90 mg) of the title compound, mp 135-136 ° C. The second batch was subjected to Elemental Analysis.

Analysis for C 16 H 13 NO 3 S;

Calculated: C 64.20, H 4.38, N 4.68% Found: C 64.36, H 4.44, N 4.68%

Example 6 1-Acetyl-3- (2-phenylacetyl) -2-oxoindole 3- (2-Phenylacetyl) -2-oxoindole was acetylated with acetic anhydride following the procedure of Example 5. When the reaction mixture was poured into a mixture of 3M hydrochloric acid and water, a solid precipitate formed. It was collected by filtration and recrystallized from isopropanol to give the title compound, mp 149-151 ° C, in 40% yield.

The ultraviolet spectrum of the product had absorption maxima of 238, 260 and 290 nm. When 1 drop of KOH solution was added, the absorption maxima were at 238, 260 and 307 nm.

Analysis for C 18 H 18 N 2 O 2: 35 Calculated: C 73.71, H 5.15, N 4.77%

Found: C 73.23, H 5.18, N 4.62% and 80270

Example 7 1-Acetyl-3- (3-pyridylcarbonyl) -2-oxoindole A mixture of 3- (3-pyridylcarbonyl) -2-oxoindole (476 mg, 2.0 mmol) and acetic anhydride (4 mL) was heated to reflux. minutes. The reaction mixture was cooled to room temperature, most of the acetic anhydride was removed by evaporation in vacuo, and the residue was triturated in 15 ml of water. The solid was collected by filtration, dried and triturated in isopropanol. The residue (158 mg) was recrystallized from acetonitrile to give 64 mg of the title compound as orange-red crystals, mp 142.5-143.5 ° C. Another batch of the title compound (40 mg) was obtained from the resuspension mother liquor. Both batches were identical by thin layer chromatography. The first batch was subjected to Elemental Analysis.

Analysis for c 18 H 12 N 2 O 3:

Calculated: C 68.56, H 4.32, N 10.00%

Found: C 68.26, H 4.38, N 9.87% Example 8 Ethanolamine salt of 1-acetyl-3- (2-thenoyl) -2-oxoindole N-acetyl-3- (2-thenoyl) - To a suspension of 2-oxoindole (2.85 g) in 40 ml of methanol was added 610 mg of ethanol-25 amine. The reaction mixture was heated at reflux for 5 minutes, then allowed to cool. The solvent was removed by evaporation in vacuo to give the title salt.

Example 9 5-Chloro-1-acetyl-3- (2-thenoyl) -2-oxoindole 5-Chloro-1-acetyl-2-oxoindole (0.75 g, 3.6 mmol) and 4- (Ν, To a solution of Ν-dimethylamino) pyridine (0.96 mL, 7.9 mmol) cooled to about 0 ° C in 20 mL of N, N-dimethylformamide was added dropwise with stirring over 2 to 10 minutes 2-tenoyl chloride (0, 4 ml, 3.7 mmol) in 5 ml of Ν, Ν-dimethylformamide. The reaction mixture was stirred for 30 minutes at about 0 ° C and then for 3.5 hours at room temperature, then the mixture was poured into 500 ml of ice-cold 2M hydrochloric acid. The resulting solution was extracted with ethyl acetate, the extracts were washed with water and then saturated sodium chloride solution, and dried over magnesium sulfate. Evaporation of the dried ethyl acetate solution gave 1.1 g of crude product. It was purified by chromatography on a silica gel column using dichloromethane-ethyl acetate mixtures as eluent, followed by crystallization from a small volume of toluene to give 250 mg of the title compound, mp 168-170 ° C.

The product obtained above was shown to be the same as that obtained in the reaction between acetic anhydride and 5-chloro-3- (2-thenoyl) -2-15 oxoindole.

Analysis for C 1 H 2 Cl 2 O 2 S:

Calculated: C 56.34, H 3.15, N 4.38%

Found: C 56.40, H 3.21, N 4.32%

Example 10 5-Chloro-1-acetyl-2-oxoindole A mixture of 5-chloro-2-oxoindole (7.0 g, 42 mmol) and acetic anhydride (5.9 mL, 63 mmol) was heated at reflux under nitrogen for 3.5 h. The cooled mixture was diluted with 300 ml of ethyl acetate, and the resulting solution was washed with aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution. The ethyl acetate solution was dried (Na 2 SO 4) and evaporated in vacuo to give 8.3 g of a purple solid. It was purified by silica gel column chromatography using 2.5% ethyl acetate in dichloromethane as the eluent to give 6.0 g of the title compound as a yellow crude solid. It was recrystallized from about 50 ml of ethanol to give 4.7 g of the title compound as pale yellow needles, mp 35-129 ° C.

Il i9 80270

Example 11

Reaction between the appropriate 2-oxoindole and the required acid anhydride by essentially the same procedure as in Example 10 gave the following compounds: 5'-acetyl-2-oxonindole, mp 127-129 ° C, 5-chloro-1-isobutyryl-2-oxoindole, m.p. 91-93 ° C, and 6-chloro-5-fluoro-1-acetyl-2-oxoindole, mp 146-148 ° C.

Preparation 1 3- (2-Furoyl) -2-oxoindole To a stirred solution of sodium (5.5 g, 0.24 mol) in 150 mL of ethanol at room temperature was added 13.3 g (0.10 mol) of 2-oxoindole. The resulting suspension was cooled to ice bath temperature and 15.7 g (0.12 mol) of 2-furoyl-15 chloride was added dropwise over 10-15 minutes. The ice bath was removed, an additional 100 mL of ethanol was added to the reaction mixture, and the reaction mixture was then heated to reflux for 7 hours. The reaction mixture was allowed to stand overnight, then the solid was filtered. The solid was added to 400 ml of water and the resulting mixture was acidified with concentrated hydrochloric acid. The mixture was cooled with ice and the solid was filtered. It was recrystallized from 150 ml of acetic acid to give 8.3 g of yellow crystals, mp 209-210 ° C (decomposes).

Analysis for C 18 H 18 N 2 O 2 N: 25 Calculated: C 68.72, H 3.99, N 6.17%

Found: C 68.25, H 4.05, N 6.20%

Preparation 2 The reaction between 2-oxoindole and the appropriate acid chloride by the method of Preparation 1 gave the following products: 3- (2-thenoyl) -2-oxoindole, mp 189-190 ° C, yield: 17%, 3- (2- / 2 -thienyl (acetyl) -2-oxoindole, mp 191-192.5 ° C, yield: 38%, 3- (2-phenoxyacetyl) -2-oxoindole, mp 135-136 ° C, yield: 35 42%, and 5- chloro-3- (2- / 2-thienyl / acetyl) -2-oxoindole, mp 228-230 ° C, yield: 22%.

20 80270

Preparation_3 3- (3-Furoyl) -2-oxoindole

To a stirred solution of sodium (2.8 g, 0.12 mol) in 200 mL of ethanol was added 13.3 g (0.10 mol) of 2-oxo-5-dolol and then 16.8 g of ethyl 3-furoate. The mixture was heated at reflux for 47 hours, cooled and the solvent removed in vacuo. The residue was triturated in 200 ml of ether, the solid filtered and discarded. The filtrate was evaporated in vacuo and the residue was triturated in isopropyl alcohol. The filtered solid was suspended in 250 ml of water, then the suspension was acidified with concentrated hydrochloric acid. The mixture was stirred and the separated solid was collected by filtration. It was recrystallized from acetic acid and then from acetonitrile to give 705 mg of the title compound, mp 185-186 ° C.

Analysis for C 12 H 9 O 2 N:

Calculated: C 68.72, H 3.99, N 6.17%

Found: C 68.72, H 4.14, N 6.14% 20 Preparation 4

In the reaction between the appropriate 2-oxoindole and the ethyl ester of the required carboxylic acid, essentially the method of Example 3, the following compounds were prepared: 5-chloro-3- (2-thenoyl) -2-oxindole, mp 190.5-192 ° C, yield : 36%, 5-chloro-3- (2-furoyl) -2-oxoindole, mp 234-235 ° C, yield: 54%, 5-chloro-3- (2-phenylacetyl) -2-oxoindole, mp 241 -243 ° C, 20% yield: 61%, 5-fluoro-3- (2-furoyl) -2-oxoindole, mp 222-224 ° C, yield: 51%, 5-fluoro-3- (2-thenoyl) -2-oxoindole, mp 200-203 ° C, yield: 26%, 6-fluoro-3- (2-furoyl) -2-oxoindole, mp 239-242 ° C, yield: 26%, and il 2i 80270 6-chloro-5-fluoro-3- (2-thenoyl) -2-oxoindole, mp 212-215 ° C, yield: 20%.

In a similar manner, using the appropriate 2-oxoindole and ethyl ester, and essentially following the procedure of Preparation 5 3, the following compounds can be prepared: 5-trifluoromethyl-3- (2-furoyl) -2-oxoindole and 6-trifluoromethyl-2- (3-thenoyl) -2 -oksoindoli.

Preparation 5 3- (3-Pyridylcarbonyl) -2-oxoindole 10 To a solution of sodium (2.1 g, 0.090 mol) in 100 mL of ethanol was added 10.0 g (0.075 mol) of 2-oxoindole followed by 13.6 g (0.090 mol) of mol) ethyl nicotinate. The resulting suspension was heated to reflux for 3 hours, then the mixture was cooled and filtered. The precipitate was discarded and the filtrate was evaporated in vacuo. The obtained residue was dissolved in about 150 ml of water, and the aqueous solution was washed with chloroform. The aqueous solution was then added to 5.9 ml of glacial acetic acid, and the resulting mixture was cooled in an ice bath. The solid was collected by filtration and recrystallized from ethanol to give 3.3 g of the title compound as yellow needles, mp 169-170 ° C.

Analysis for c ^ 4H ^ oN2 ^ 2:

Calculated: C 70.58, H 4.23, N 11.76%

Found: C 70.66, H 4.41, N 11.73% In a similar manner, 3- (2-pyrrolylcarbonyl) -2-oxoindole can be prepared by reacting 2-oxoindole with sodium ethoxide and ethyl pyrrole-2-carboxylate in ethanol.

Preparation 6 5-Chloro-2-oxoindole To a suspension of 5-chloroisatin (100 g, 0.55 mol) in 930 mL of ethanol was added with stirring 40 mL (0.826 mol) of hydrazine hydrate to give a red solution. The solution was heated to reflux for 3.5 hours during which time a precipitate formed. The reaction mixture was stirred overnight, then the precipitate was filtered to give 5-chloro-3-2280270 hydrazono-2-oxoindole as a yellow solid which was dried in a vacuum oven. The dried solid weighed 105.4 g.

The dried solid was then added portionwise over 10 minutes to a solution of sodium methoxide (125.1 g) in 900 ml of anhydrous ethanol. The resulting solution was heated to reflux for 10 minutes, then the solution was concentrated in vacuo to a gum. The gummy substance was dissolved in 400 ml of water, the aqueous solution 10 was treated with decolorizing carbon, the carbon was filtered and the filtrate was poured into a mixture of water (1 liter) and concentrated hydrochloric acid (180 ml) containing crushed ice. A brown precipitate precipitated which was collected by filtration and washed thoroughly with water. The precipitate 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).

Similarly, 5-methylisatin was converted to 5-methyl-2-oxoindole by treatment with hydrazine hydrate 20 and then sodium ethoxide in ethanol. Mp 173-174 ° C.

Preparation 7 4,5-Dimethyl-2-oxoindole and 5,6-dimethyl-2-oxoindole 3,4-Dimethylaniline was converted to 3,4-dimethylisonitrosoacetanilide by reaction with chloral hydrate and hydroxylamine according to the method described in "Organic Syntheses", Collective Volume I, page 327, 3,4-dimethylisonitrosoacetanilide was cyclized with sulfuric acid by the method of Baker et al., Journal of Organic Chemistry, 17, 149 (1952) to give 4,5-dimethylisatin ( mp 225-226 ° C) and 5,6-dimethylisatin (mp 217-218 ° C).

4,5-Dimethylisatin was converted to 4,5-dimethyl-2-35 oxoindole, mp 245.5-247.5 ° C, by treatment with hydrazine.

II

23,80270 nihydrate and then sodium ethoxide in ethanol essentially as described in Preparation 6.

Similarly, 5,6-dimethylisatin was converted to 5,6-dimethyl-2-oxoindole, mp 196.5-198 ° C, by treatment with hydrazine hydrate and then sodium ethoxide in ethanol essentially as described in Preparation 6.

Preparation 8 4-chloro-2-oxoindole and 6-chloro-2-oxoindole 10 Δ. 3-chloro-isonitrosoacetanilide

To a stirred solution of chloral hydrate (113.23 g, 0.686 mol) in 2 liters of water was added 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 15 concentrated hydrochloric acid and 500 ml of water. A thick precipitate formed. The reaction mixture was then added with stirring to a solution of hydroxylamine (155 g, 2.23 mol) in 500 mL of water. Stirring was continued and the reaction mixture was slowly warmed to 60-75 ° C where it was stirred for about 6 hours during which time an additional 1 liter of water was added to facilitate stirring. The reaction mixture was cooled and the precipitate was filtered. It was dried to give 136.1 g of 3-chloroisonitrosoacetanilide.

B. 4-Chloroisatin and 6-chloroisatin To concentrated sulfuric acid (775 mL) heated to 70 ° C was added 136 g of 3-chloroisonitrosoacetanilide with stirring at such a rate that the temperature of the reaction mixture remained at 75-85 ° 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 onto about 2 liters of ice. Additional ice was added as needed to keep the temperature below room temperature. An orange-red precipitate formed which was filtered, washed with water and dried. The resulting solid was suspended in water (2 L), and about 700 mL of 3 M sodium hydroxide solution was added to dissolve the solid. Solution 24 80270 was filtered and the pH was adjusted to 8 with concentrated hydrochloric acid. At this point, 120 rll of a mixture of water and concentrated hydrochloric acid (80:20) was added. The precipitated solid precipitate was filtered, washed with water and dried to give 50 g of 4-chloroisatin as a crude product. The filtrate from the filtration of 4-chloroisatin was further acidified to pH Q with concentrated hydrochloric acid to form a precipitate. It was filtered, washed with water and dried to give 43 g of 6-chloroisatin as a crude product. The crude 4-chloroisatin was recrystallized from vinegar to give 43.3 g of product, m.p. 258-259 ° C.

The crude 6-chloroisatin was recrystallized from vinegar to give 36.2 g of product, mp 15,261-26 ° C.

C. 4-Chloro-2-oxoindole To a suspension of 4-chloroisatin (43.3 g) in 250 mL of ethanol was added 17.3 μL of hydrazine hydrate with stirring, then the reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled, the wand was filtered to give 43.5 g of 4-chloro-3-hydrazono-2-oxoindole, mp 235-236 ° C.

To a stirred solution of sodium (22 g) in anhydrous ethanol (450 ml) was added 3.5 g of 4-k.Loo-25R-3-hydrazono-2-oxoindole portionwise, and the resulting solution was heated under reflux for 30 minutes.

The cooled solution was concentrated to a gum which was dissolved in 400 mL of water and treated with a decolorizer. The decarbonated solution was poured into a mixture of water (1 L) and concentrated hydrochloric acid (45 mL). The precipitate formed was filtered off, dried and recrystallized from ethanol to give 22.4 g of 4-chloro-2-oxoindole, mp 216-218 ° C (decomposes).

D. 6-Chloro-2-oxoindole 6 6-Chloro-isatin (36.2 g) was reacted with hydrazine hydrate and then with sodium ethoxide.

II

80270 in ethanol essentially as in C above to give 14.2 g of 6-chloro-2-oxindole, mp 196-198 ° C.

Preparation 9 5,6-Difluoro-2-oxoindole 3,4-Difluoroaniline was reacted with chloral and hydroxylamine and the reaction product was then cyclized with sulfuric acid in analogy to Preparation 8 A and B to give 5,6-difluoro-2-oxoindole. 10 Isatin, which was reacted with hydrazine hydrate and then sodium methoxide in ethanol according to the method of Preparation 6 to give the title compound, mp 187-190 ° C.

Preparation 10 5-Fluoro-2-oxoindole To a solution of 4-fluoroaniline (11.1 g, 0.1 mol) in 200 mL of dichloromethane was added dropwise at -60 to -65 ° C dropwise tert-butyl hypochlorite (10.8 g). , 0.1 mol) in 25 ml of dichloromethane. Stirring was continued at 20-60-65 ° C for 10 minutes and then a solution of ethyl 2- (methylthio) acetate (13.4 g, 0.1 mol) in 25 ml of dichloromethane was added dropwise to the mixture. Stirring was continued at -60 ° C for 1 h, then a solution of triethylamine (11.1 g, 0.11 mol) in 25 mL of dichloromethane was added dropwise at -60-65 ° C. The cooling bath was removed, and after the reaction mixture was warmed to room temperature, 100 ml of water was added to the mixture. The phases were separated and the organic phase was washed with saturated sodium chloride solution, dried (Na 2 SO 4) and evaporated in vacuo. The residue was dissolved in 30,350 ml of diethyl ether to which 40 ml of 2M hydrochloric acid had been added. The mixture was stirred at room temperature overnight. The phases were separated and the ether phase was washed with water and then saturated sodium chloride solution. The dried (Na 2 SO 4) ether phase was evaporated in vacuo to give 17 g of an orange-brown solid which was triturated with isopropyl ether. The solid was recrystallized from ethanol to give 5.58 g of 26,80270 5-fluoro-3-methylthio-2-oxoindole, mp 151.5-152.5 ° C. Analysis for C

Calculated: C 54.80, H 4.09, N 7.10%

Found: C 54.74, H 4.11, N 7.11% 5-The 5-fluoro-3-methylthio-2-oxoindole (986 mg, 5.0 mmol) obtained above was added to Raney nickel (2 teaspoons) and anhydrous. ethanol (50 ml), and the reaction mixture was heated to reflux for 2 hours. The catalyst was removed by decantation and washed with anhydrous ethanol. The combined ethanol solutions were evaporated in vacuo and the residue was dissolved in dichloromethane. The dichloromethane solution was dried (Na 2 SO 4) and evaporated in vacuo to give 475 mg of 5-fluoro-2-oxindole, mp 121-134 ° C.

In an analogous manner, 4-trifluoromethylaniline was reacted with tert-butyl hypochlorite, ethyl 2- (methylthio) acetate and triethylamine, followed by reduction of the resulting 3-thiomethyl-5-trifluoromethyl-2-oxoindole with Raney nickel to 5-trifluoromethyl-20-l 2-oxoindole, mp 189.5-190.5 ° C.

Preparation 11 5-Methoxy-2-oxoindole 5-Methoxy-2-oxoindole was prepared from 4-methoxyaniline as described in Preparation 10, except that the initial chlorination was performed with a solution of chlorine gas in dichloromethane and not tert-butyl hypochlorite. Mp 150.5-151.5 ° C of the title compound.

Preparation 12 6-Chloro-5-fluoro-2-oxoindole 30 To 130 ml of toluene were added with stirring 24.0 g (Q, 165 mol) of 3-chloro-4-fluoroaniline and 13.5 ml (0.166 mol) of 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 hours, then extracted with 1 M hydrochloric acid (2 x 100 ml) and then with 100 ml of saturated sodium chloride solution. The toluene solution was dried over magnesium sulfate and evaporated in vacuo to give 32.6 g (88% yield) of N- (2-chloroacetyl) -3-5 chloro-4-fluoroaniline.

26.63 g of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline were mixed well with anhydrous aluminum chloride (64 g), and the mixture was heated at 210-230 ° C for 8.5 hours. The reaction mixture was then poured with stirring into a mixture of ice and 10 L of hydrochloric acid. Stirring was continued for 30 minutes, then the solid was filtered (22.0 g).

It was dissolved in ethyl acetate / hexane 1: 1 and chromatographed on 800 g of silica gel. Elution of the column and evaporation of the fractions gave 11.7 g of N- (2-15 chloroacetyl) -3-chloro-4-fluoroaniline and then 3.0 g of 6-chloro-5-fluoro-2-oxoindole. The latter compound was recrystallized from toluene to give 1.70 g (7% yield) of the title compound, mp 196-206 ° C. The NMR spectrum showed that the product contained some 4-chloro-5-fluoro-2-oxoindole as an impurity.

Preparation 13 6-Fluoro-5-methyl-2-oxoindole: ·: N- (2-chloroacetyl) -3-fluoro-4-methylaniline (11.62 g, 57.6 mmol) and anhydrous aluminum chloride (30.6 g). 229.5 mmol) of the uniform mixture was heated at 210-220 ° C.

After 4 hours, the reaction mixture was cooled and then added to a mixture of 1M hydrochloric acid (100 ml) and ice (50 ml). A tan solid precipitated which was filtered and recrystallized from aqueous ethanol. 3 batches of product weighing 4.49 g, 2.28 g and 1.0 g were obtained. A 1.0 g portion was recrystallized from water to give 280 mg of the title compound, mp 168.5-171 ° C.

35 28 80270

Preparation 14 6-Bromo-2-oxoindole

To sodium hydride (9.4 g) was added 195 ml of dimethyl sulfoxide and then dropwise 22.37 ml of dimethyl malonate. After the addition was complete, the reaction mixture was heated to 100 ° C and maintained at this temperature for 40 minutes. 25 g of 1,4-dibromo-2-nitrobenzene were then added in one portion. The reaction mixture was kept at 100 ° C for 4 hours, then the mixture was added to 1.0 liter of saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate, and the extracts were washed with ammonium chloride solution, water and saturated sodium chloride solution. The solution was dried (MgSO 4), the solvent evaporated and the residue recrystallized from ethyl acetate / hexane to give 22.45 g of dimethyl 2- (4-bromo-2-nitrophenyl) malonate.

A solution of dimethyl 2- (4-bromo-2-nitrophenyl) malonate (17.4 g) and lithium chloride (4.6 g) in 150 ml of dimethyl sulfoxide heated in an oil bath at 100 ° C.

After 3 hours, the reaction mixture was cooled to room temperature and then poured into a mixture of 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 extracts were washed with brine, dried over sodium sulfate and then evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate / hexane as eluent. 9.4 g of methyl 2- (4-bromo-2-nitrophenyl) acetate were obtained.

To a solution of methyl 2- (4-bromo-2-nitrophenyl) acetate (7.4 g) in 75 ml of acetic acid was added 6.1 g of iron powder. The reaction mixture was heated in an oil bath at 100 ° C. After 1 hour, the solvent was evaporated in vacuo and the residue was dissolved in 250 ml of ethyl acetate.

The solution was filtered, washed with saturated sodium chloride solution 2980270, dried over sodium sulfate, treated with decolorizing carbon, and evaporated in vacuo to remove carbon. There were thus obtained 5.3 g of 6-bromo-2-oxoindole as white crystals, mp 213-214 ° C.

In a similar manner, 5,6-dichloro-2-oxoindole, mp 209-210 ° C, was prepared using 1,4,5-trichloro-2-nitrobenzene as starting material.

Preparation 15 6-Phenyl-2-oxindole 10 To 3.46 g (Q, 072 mol) of sodium hydride was added 50 ml of dimethyl sulfoxide and then dropwise with stirring a solution of dimethyl malonate (8.2 ml, 0.072 mol) in 10 ml of dimethyl sulfoxide. After the addition was complete, stirring was continued for 1 hour, and then a solution of 4-bromo-3-nitrodiphenyl (10 g, 0.036 mol) in 50 mL of dimethyl sulfoxide was added. The reaction mixture was heated at 100 ° C for 1 hour, cooled and poured into a mixture of ice water and ammonium chloride (5 g). The mixture thus obtained was extracted with ethyl acetate, the extracts were washed with sodium chloride solution and dried over magnesium sulfate. Evaporation in vacuo gave an oil which was chromatographed on silica gel and then crystallized from methanol to give 6 g of dimethyl 2- (3-nitro-4-diphenyl) malonate, mp 82-83 ° C.

A portion (5 g) of the nitro compound obtained above was reduced with hydrogen using a platinum catalyst in 50 ml of tetrahydrofuran and 10 ml of methanol at a pressure of about 25 kg / cm to give the corresponding amine. This was refluxed in ethanol for 16 hours, the solvent was evaporated, and the residue was recrystallized from methanol to give 1.1 g of ethyl 6-phenyl-2-oxoindole-1-carboxylate, mp 115-117 ° C.

The ethyl ester obtained above (1.0 g) and 100 ml of 6-M hydrochloric acid were heated under reflux for 3 hours, then the mixture was allowed to stand at room temperature for 3 days. The solid was filtered off and dried, yielding 700 mg of 6-phenyl-2-oxoindole, mp 175-176 ° C.

Preparation 16 5-Acetyl-2-oxoindole To 95 ml of carbon disulphide was added 27 g (0.202 mol) of 5 aluminum chloride and then dropwise with stirring a solution of acetyl chloride (3 ml, 0.042 mol) in 5 ml of carbon disulphide. Stirring was continued for 5 minutes, then 4.4 g (0.033 mol) of 2-oxoindole were added. The resulting mixture was heated to reflux for 4 hours, then the mixture was cooled. Sulfur carbon was removed by decantation and the residue was triturated in water. The residue was filtered and dried to give 3.2 g of the title compound, mp 225-227 ° C.

When 2-oxoindole was reacted with benzoyl chloride and 2-thenoyl chloride in the presence of aluminum chloride essentially following the above procedure, the following compounds were obtained: 5-benzoyl-2-oxoindole, mp 203-205 ° C (from CH 2 OH), and 5- (2-thenoyl) -2-oxoindole, mp 211-213 ° C (CH 2 Cl 2).

Preparation 17 3-Bromo-2-oxoindole can be prepared with bromoamole-2-oxoindole; see Becket et al., Tetrahedron, 24, 6093 (1968) and Sumpter et al., Journal of the American Chemical Society, 67, 1656 (1945).

5-n-Butyl-2-oxoindole can be prepared by reacting 5-n-butylisatin with hydrazine hydrate and then with sodium methoxide in ethanol following the procedure of Preparation 6. 5-n-Butylisatin can be prepared by treating 4-n-butylan-30 with chloral hydrate and hydroxylamine, then cyclizing with sulfuric acid following the procedure of Preparation 8 A and B.

5-Ethoxy-2-oxoindole can be prepared by converting 3-hydroxy-6-nitrotoluene by conventional method 35 (potassium carbonate and ethyl iodide in acetone) to 3-ethoxy-6-nitrotoluene, which is converted to 5-ethoxy-2-oxoindole by the method of Tl 3i 80270 by Becket et al., Tetrahedron 24 6093 (1963), have described the conversion of 3-methoxy-6-nitrotoluene to 5-methoxy-2-oxoindole. 5-n-Butoxy-2-oxoindole can be prepared in a similar manner using n-butyl iodide instead of ethyl iodide.

5,6-Dimethoxy-2-oxoindole can be prepared by the method of Walker, In, Journal of the American Chemical Society, 77, 3844 (1955).

7-Chloro-2-oxoindole can be prepared by the method disclosed in U.S. Patent No. 3,882,236.

4-Thiomethyl-2-oxoindole and 6-thiomethyl-2-oxoindole can be prepared by the method described in U.S. Patent 4,006,161. 5-n-Butylthio-2-oxoindole can be prepared in a similar manner, but substituting 4-butylthioaniline for 3-methylthioaniline.

6-Fluoro-2-oxoindole can be prepared by the method of Protivan et al., Collection of Czechoslovakian Chemical Communications, 44, 2108 (1979) and described in U.S. Patent 4,160,032.

2 ° 6-Trifluoromethyl-2-oxoindole can be prepared

Simet, Journal of Organic Chemistry, 28, 3580 (1963).

6-Methoxy-2-oxoindole can be prepared by the method described by Wieland et al., Chemische Berichte, 96, 253 (1963).

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

5-Cyclopropyl-2-oxoindole and 5-cycloheptyl-2-oxoindole can be prepared by reacting 5-cyclopropylisatin and 5-cycloheptylisatin, respectively, with hydrazine hydrate and then with sodium methoxide in ethanol according to the method of Preparation 6. 5-Cyclopropylisatin and 5-cycloheptylisatine can be prepared from 4-cyclopropylaniline and 4-cycloheptylaniline, respectively, by treatment with chloral hydrate and hydroxylamine, followed by cyclization with sulfuric acid according to Preparation 8, according to Preparation 8.

Claims (4)

A process for the preparation of therapeutically useful 1,3-diacyl-2-oxoindole compound of formula (I) or a pharmaceutically acceptable base salt thereof, γ 'O = CR 2 where X and Y represent hydrogen, fluorine, chlorine or nitro ; R 1 is phenyl, benzyl, pyridyl, thienyl, thienylmethyl or furyl; and R 2 is C 1 -C 5 alkyl, characterized in that (A) a compound of the formula "fci" ·· YH is acylated with an activated derivative of a carboxylic acid of the formula R 2 -C (= O) -0H in an inert solvent or (B) a compound of the formula Y 0 = C-R2 is acylated with an activated derivative of a carboxylic acid of the formula - (2 (= O) -011 in an inert solvent. A process according to claim 1, characterized in that a compound of formula (I) is prepared, wherein X is 5-chloro, Y is hydrogen, R 1 is 2-thienyl 5 and R 2 is methyl. Compound, characterized in that it has the formula * O = CR 2 where X is hydrogen, 5-fluoro or 5-chloro, Y is hydrogen, 6-fluoro or 6-chloro, and R 2 is C 1 -C 5 alkyl ; provided that X and Y bed are not hydrogen. A compound according to claim 3, characterized in that X is 5-chloro, Y is hydrogen and R 2 is methyl.