FI81796C - Process for the preparation of a 1,3-disubstituted 2-oxindol compound which acts as an analgesic and anti-inflammatory agent - Google Patents

Description

! 81796

Process for the preparation of a 1,3-disubstituted 2-oxindole compound as an analgesic and anti-inflammatory agent 5 This patent application discloses novel chemical compounds which are valuable as medicaments. More specifically, these novel chemical compounds are 2-oxindole-1-carboxamide derivatives and contain an acyl substituent both at the 3-position and attached to the nitrogen atom of the carboxamide group. These new chemical compounds are inhibitors of both cyclooxygenase (CO) and lipoxygenase (LO).

U.S. Patent 3,161,654 relates to a series of analgesic and anti-inflammatory 1-acylindole-2-acetic acid compounds. The above patent included a compound of the following formula

CH3 ° V ^ \ __ ^ CH2CO2H

. "UCC,

·· · J

o = c;, o.

commonly referred to as indometasUn and sold commercially in many countries.

30 GB Patent 1,158,532 describes a series of 2-oxindole-3-carboxylic acid compounds optionally having a variety of substituents at the 1-position, and these compounds have been shown to have anti-inflammatory activity. 2-Oxindole-3-carboxamide compounds optionally substituted in the 1-position and having anti-inflammatory activity are disclosed in U.S. Patent 3,634,453.

The compounds of the present application differ from the compounds of U.S. Patent 2,856,967 in that the compounds of the present application are oxindoles (i.e., have a keto group at the C-2 position), whereas the compounds of the reference publication are indole and ( that is, they have a 2,3-double bond and no keto group at the C-2 position).

The present invention relates to a process for the preparation of a therapeutically useful 2-oxindole compound of formula 1

X

Wherein V is hydrogen, fluorine, chlorine, C 1-4 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 f uranium 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 a group at 30 ° C;

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3,81796 wherein each of R 3 and R 4 may be hydrogen, fluoro, chloro, C 1-4 alkyl or C 1-4 alkoxyl; or a pharmaceutically acceptable base salt thereof.

The compounds of this invention have analgesic activity in mammals, especially humans, and are therefore suitable for acute administration to alleviate or eliminate pain, such as pain experienced by patients recovering from surgery or injury.

In addition to their suitability for acute administration in the treatment of pain, the compounds disclosed herein are suitable for long-term administration to mammals, especially humans, for the relief of symptoms of chronic diseases such as rheumatoid arthritis and osteoarthritis associated with inflammation and pain.

Said compounds of formula I are effective as analgesic and anti-inflammatory agents in the treatment of inflammatory diseases such as arthritis. They can be used to induce an analgesic response ai-20 in a mammalian subject, especially a human, and to treat an inflammatory disease in a mammal, especially a human, and in pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier.

One preferred group of compounds of formula I are those compounds of formula I wherein X is hydrogen and R 1 is a 2-furyl, 2-thienyl or (2-thienyl) methyl group. Particularly preferred compounds belonging to this first preferred group are those wherein R 2 is phenyl.

Another preferred group of compounds of formula I are those corresponding to formula I wherein X is 5-chloro and R 1 is a 2-furyl, 2-thienyl or (2-thienyl) methyl group. Particularly preferred compounds belonging to this second preferred group are those wherein R 2 is cyclohexyl.

4,81796

Particularly preferred individual compounds of the invention are: N-benzoyl-3- (2-furoyl) -2-oxindole-1-carboxamide (I: X is hydrogen; R 1 is 2-furyl; R 2 is phenyl) and N-cyclohexylcarbonyl- 5-chloro-3- (2-thienoyl) -2-oxyindole-1-carboxamide

(I; X is 5-chloro; R 1 is 2-thienyl; R 2 is cyclohexyl). Compounds of formula II

10 15 0 = C-NH-C-R2

O

wherein X and R 2 are groups as defined above are useful as intermediates in the preparation of compounds of formula I.

Also compounds corresponding to formula IV, 25 \ 0 tee · '' · '

B

Wherein X and R 1 are groups as defined above and their base salts are useful in the preparation of compounds of formula I. A preferred subgroup of compounds of formula IV consists of compounds wherein X is hydrogen, 5-fluoro or 5-chloro; 6-fluoro or 6-chloro;

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5,81796 and R1 is a benzyl, furyl, thienyl or thienylmethyl group; provided that when X is hydrogen R 1 is not a benzyl group.

The analgesic and anti-inflammatory compounds of this invention are compounds of formula I wherein X, R 1 and R 2 are as defined above. The compounds disclosed herein are thus derivatives of 2-oxindoline, a bicyclic amide of formula 10 4-13 L 2 'H 15. More specifically, these analgesic and anti-inflammatory agents contain the N-acylcarboxamide substituent -C (= O) -NH-C (= O) -R2 at the 1-position of the 2-20 oxindole backbone and the acyl substituent -C (= 0) at the 3-position. ) -R1, and the benzo ring may be further substituted with an X group. X may be certain monovalent substituents as defined above.

As will be appreciated by those skilled in the art, analgesic and anti-inflammatory compounds of formula I wherein X, R 1 and R 2 are as defined above may be enolized and thus exist in one or more tautomeric forms (enol form). The preparation of tautomeric forms (enol forms) of all such compounds of formula I is considered to be within the scope of this invention.

Compounds of formula I are prepared from suitable 2-oxindole compounds of formula 35 III, 6 81796 5 7 8 wherein X is as defined above. This is accomplished by attaching a substituent -C (-O) -NH-C (-O) -R2 at the 1-position and a substituent -Ci-OJ-R1 at the 3-position. These substituents can be attached in either order, and this results in two alternative methods for preparing compounds of formula I, as shown in the scheme. 15 Figure 20

B

(III) / \ 25 *

Xx ± ‘Ολ H I“ i 0 = C-NH-C-Ra

30 II

(IV) (II) o '\ κ I 2 0 * C-NH-Jj- and o (I)

II

7 81796

The first option involves the conversion of compound III to compound IV and the conversion of compound IV to compound I, while the second option involves the conversion of compound III to compound II and the conversion of compound II to compound I.

The method according to the invention is characterized in that

(A) a compound of formula IV

B

Reacting with an acyl isocyanate of the formula R 2 -C (= O) -N = C * O in an inert solvent; or

(B) a compound of formula II

O = C-NH-C-R2 No. 25 is reacted with a reactive derivative of a carboxylic acid of formula R1-C (= O) -OH in an inert solvent.

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 (* 0) -N = C = 0. Most usually, the reaction is carried out by contacting approximately equivalent molar amounts of the starting materials in a mutually inert solvent at a temperature of 50 to 35 ° C, preferably 100 to 130 ° C. In this context, an inert solvent means 8 81796 solvents in which at least one of the reactants is soluble and which do not adversely affect the reactants or the product. Typical useful solvents include aliphatic hydrocarbons such as octane, no-5 nane, 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 Ν, Ν-dimethylformamide, Ν, Ν-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 a solvent in the reaction of a compound of formula III and IV with an acyl isocyanate of formula R2-C (-O) -N = C = 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 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, an acyl isocyanate of the formula R 2 -C (* O) -N = 00, can be accelerated by adding a base such as a tertiary amine, for example trimethylamine, tri-ethylamine, tributylamine, N- methylpiperidine, N-methylmorpholine or Ν, Ν-dimethylaniline. The basic

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9,81796 substances are usually added in an amount of about 1 to 4 equivalents, 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 then isolated as described above.

The side chain -C (→ O) -R 1 can be attached to a compound of formula II by reacting said compound with a reactive derivative of a carboxylic acid of formula R 1 -C (= O) * OH. The reaction is carried out by treating said compound of formula II with an equivalent 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 R1 = C (* 0) * 0H. conventional methods are used to activate. For example, acid halides, for example acid chlorides, may be used; symmetrical acid anhydrides R1-C (= O) -O-C (»OJ-R1; mixed anhydrides R1-C (= 0) formed by an acid R1-C (= 0) ° 0H and a sterically hindered low molecular weight carboxylic acid -O-C (= O) -R5, where R5 is a substituent lower alkyl group such as a t-butyl group, and carboxylic acid-carbonic acid mixed anhydrides R1- (O = O) -O-C (= O) -ORR6, wherein R6 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 R1-C (* O) -OH. However, preferred basic substances are tertiary amines such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine and 4- (N, N-dimethyl-5-amino) 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 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 recirculation.

The -Ci-OJ-R1 side chain can be attached to a compound of formula III by reacting said compound with a derivative of an appropriate acid of formula R1-C (* O) -OH in a lower alkanol (e.g. ethanol) with a lower alkanol alkali metal salt (e.g. sodium ethoxide) 20 in accordance with standard procedures. Typical derivatives of the acid corresponding to the formula R1-C (»O) -OH which can be used are acid chlorides, acid anhydrides corresponding to the formula R1-C (* O) -O-C (= O) -Rx, R1-C (= O) -O-C (-O) -R 5 or R 1 -C (* O) -O-C (-O) -OR 6, and simple alkyl esters of formula R 1 -C (-O) -ORR6, 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 an amount of 1-2 equivalents, based on the molar amount of said derivative of the acid R1-C ("O) -OH. The reaction between the -OH derivative and the compound of formula III is usually started at 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. The reaction times used under these conditions are usually from a few, for example two, hours.

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il 81796 country, for example, for two, days. The reaction mixture is then 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 = C = O) 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) -C1 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 III 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 et al., Journal of the American Chemical Society 78 (1956) 25,221; 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 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 compounds of formula I are acidic and form base salts. All preparation of such base salts is within the scope of this invention and can be prepared by conventional methods. They can be prepared, for example, by simply contacting the acidic and basic compounds with one another, usually in a stoichiometric ratio, either in water or in an anhydrous or partially aqueous medium, as appropriate. The salts are isolated either by filtration, mixing, mixing with a salt-insoluble substance and then filtering or evaporating the solvent, as appropriate, or, in the case of aqueous solutions, by freeze-drying. Typical salts of the compounds of formula I which may be prepared include primary, secondary and tertiary amine salts, alkali metal salts and alkaline earth metal salts. Particularly valuable salts are the ethanolamine, diethanolamine and triethanolamine salts.

Suitable bases for salt formation include both organic and inorganic, and include organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogencarbonates, alkali metal hydrides, alkali metal oxides, alkaline earth metal alkali metal hydroxides, alkaline earth metal alkali metal, alkaline earth metal alkoxides. Typical examples of such bases include primary amines such as n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucamine; secondary amines such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, triethanolamine, N, N-dimethylaniline, N-ethylpiperidine and N-methylmorpholine; hydroxides such as sodium hydroxide; alkoxides such as sodium ethoxide and potassium methoxide; hydrides such as calcium hydride and sodium hydride; and carbonates such as potassium carbonate and sodium carbonate.

It is 81796

The compounds of formula I have an analgesic effect. This effect has been demonstrated in mice by demonstrating inhibition of 2-phenyl-1,4-benzoquinone (PBQ) -induced abdominal tension. The method 5 used was based on the method of Siegmund et al. method (Proc. Soc. Exp. Biol. Med. 95 (1957) 729-731) applied to high throughput (see further Milne and Twomey, Agents and Actions 10 (1980) 31-37). The mice used in these experiments were male Carworth, CF-1 albino strain, and weighed 10-18-20 g. All mice were fasted overnight prior to drug administration and testing.

Compounds of formula I were dissolved or suspended in a medium containing ethanol (5%), Emulphor 620 (mixture of polyoxyethylene fatty acid esters; 5%) and physiological saline (90%). This medium also served as a reference. Doses followed a logarithmic scale (i.e. ... 0.32, 1.0, 3.2, 10, 32 ... mg / kg) and were calculated based on the mass of the salt and not the mass of the acid when the salt was useful. Oral administration was performed with varying concentrations so that the dose volume was kept constant (10 ml per kg body weight). The aforementioned Milne and Twomey method was used to determine efficiency and potency. Mice were administered compounds orally and up to 25 hours later at 2 mg / kg PBQ intraperitoneally. Each mouse was then immediately placed in a heated Lucite chamber (transparent plastic), and the number of abdominal cramps over the next 5 minutes was recorded, starting 5 minutes after PBQ administration. The degree of analgesic protection (% MPE) was calculated based on the inhibition of abdominal cramps in relation to the figures obtained from parallel determinations performed on control animals on the same day. Dose-response data were obtained from at least four such assays (N £ 5) to calculate a 35 MPE50; MPES0 is the best estimate of the dose of 14,881,796 that reduces abdominal cramps to 50% of reference levels.

The compounds of formula I also have an anti-in-f Lamina Tor ine effect. This effect has been demonstrated in rats by a method based on the conventional measurement of carrageenan-induced rat swelling in the rat. (Winter et al., Proc. Soc. Exp. Biol. Med. 111 (1963) 544).

Anesthetized adult male albii norotas weighing 150-190 g were numbered and weighed, and their right lateral malleolus was marked with ink. Each paw was immersed in mercury exactly to the ink mark. Mercury was in a glass cylinder connected to a Statham pressure vessel. The signal from the sensor was fed through a control unit to a microvolt-15 meter. The volume of mercury displaced by the embedded leg was recorded. The drugs were administered through a tube. Swelling was induced one hour after drug administration by injecting 0.05 ml of a 1% carrageenan solution into the plantar tissue of the labeled paw. Immediately after this 20, the volume of the injected foot was measured. An increase in leg volume 3 hours after carrageenan injection produces an individual inflammatory response.

The analgesic effect of the compounds of formula 1 makes said compounds suitable for acute administration to mammals for the purpose of relieving pain, for example post-operative and injury pain. In addition, the compounds of formula I are suitable for long-term administration to mammals for the relief of symptoms of chronic disease, 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 mammalian subject either alone or in a preferred manner.

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As a pharmaceutical composition in association with pharmaceutically acceptable carriers or diluents in accordance with standard pharmaceutical practice. The compound can be administered orally or parenterally. Parente-5 oral administration includes intravenous, intramuscular and intraperitoneal, subcutaneous and topical administration.

In a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof, the weight ratio of carrier to active ingredient is usually in the range of 1: 4 to 4: 1, preferably 1: 2 to 2: 1. However, the ratio to be used in each case will depend on such factors as the solubility of the active ingredient, the intended dosage and the precise route of administration.

For oral administration of a compound of formula I, the compound may be administered as tablets or capsules or as an aqueous solution or suspension. In the case of tablets suitable for oral use, carriers which are commonly used include lactose and corn starch, and lubricants such as magnesium stearate are generally added. Diluents suitable for oral capsule administration include lactose and dried corn starch. In the case of aqueous suspensions suitable for oral use, the active ingredient is combined with emulsifying or suspending agents, if necessary. If desired, sweetening and / or flavoring agents may be added. For intramuscular, intraperitoneal, intravenous and subcutaneous use, sterile solutions of the active ingredient are usually prepared, the pH of which should be adjusted and buffered. For intravenous use, the total concentration of solutes should be adjusted so that the product becomes isotonic.

When a compound of formula I or a salt thereof is used in a human subject, the prescribing physician will usually prescribe a daily dose. The dosage will vary depending on the age, weight and response of each individual patient, as well as the severity of the patient's symptoms and the strength of the compound being administered. An effective dose of Anal-5 that elicits an analgesic response for acute pain relief is in most cases 0.1-1.0 g as needed (e.g., every 4-6 hours). An effective dose for long-term relief (treatment) of inflammation and pain is in most cases 0.5-3.0 g / day, preferably 0.5-1.5 g / day, in one or more doses. On the other hand, in some cases it may be necessary to use dosages outside these limits.

Analgesic Activity of 2-Oxindole Compounds A. Method 15 The pharmacological activity of 2-oxindole compounds was demonstrated using mouse experiments. The ability of the compounds to inhibit or limit the stretching response of the abdominal cavity caused by 2-phenyl-1,4-benzoquinone (PBQ) was measured. The method used was based on the method used by Sigmund 20 et al., Proc. Soc. Exp. Biol. Med., 95: 729-731, 1957, further modified (see Milne and Twomey, Agents and Actions, 10: 31-37, 1980). The mice used in these experiments were Carworth males, Albino CF-1 strain weighing 18-20 g.

25 All mice were fasted overnight prior to drug dosing and testing.

The 2-oxindole compounds were dissolved or diluted in a medium consisting of ethanol (5%), emulsifier 620 (a mixture of polyoxyethylene fatty acid esters, 5%) and brine (90%). This medium also served as a control. Doses were on a logarithmic scale (i.e., .... 0.32, 1.0, 3.2, 10, 32 ... mg / kg) and were calculated by salt weight. Dosing was oral and concentrations were allowed to vary to give a dosing volume of 10 to 35 ml / kg. In line with Milne and Twomay

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17 81 796 The above method was used to determine the effectiveness. Mice were treated with the compounds orally and after 1 hour were given PBQ, 2 mg / kg, via the peritoneal membrane. Individual mice were then placed 5 immediately in a heated Lucite (transparent plastic) chamber, and, starting 5 minutes after PBQ administration, the number of abdominal cramps was counted over the next 5 minutes. The degree of analgesic protection (% MPE) was calculated based on Suppression of abdominal cramps relative to control animals according to the following 10 formulas% MPE = mean control stretch - mean test stretch x 100 mean control stretch

When the% MPE approaches 100%, it indicates that the drug was producing the maximum possible effect; when it approaches 0%, it indicates that the drug did not produce any effect.

IB 81 79 * B. Results »" Ccx "0 = C-NH-C-R2

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0

X R1 R2 Dose% MPE

10 (mg / kg) H methyl phenyl 32 92.5 H 4-fluorophenyl phenyl 32 24.0 H benzyl phenyl 32 9.9 H 2-furyl phenyl 10 35.5 15 H (2-thienyl) methyl phenyl 32 73, 5 H 2-thienyl phenyl 32 55.6 H cyclopropyl phenyl 32 3.0 H isopropyl phenyl 32 33.6 H cyclohexyl phenyl 32 28.2 20 H 2-thienyl 4-fluorophenyl 10 57.9 H 2-furyl 4-fluorophenyl 32 97.6 H methyl 4-fluorophenyl 32 65.8 5-C1 methyl phenyl 32 31.9 5-C1 isopropyl phenyl 32 22.3 25 5-C1 cyclohexyl phenyl 32 34.0 H benzyl 4-fluorophenyl 32 20.6 H phenoxymethyl phenyl 32 9.9 H phenoxymethyl 4-fluorophenyl 32 23.9 H cyclopropyl 4-fluorophenyl 32 5.7 30 H cyclohexyl 4-fluorophenyl 32 16.3 H 2-furyl isopropyl 32 96.3 5-Cl (2- thienyl) methyl phenyl 32 77.0 H (2-thienyl) methyl 4-fluorophenyl 32 75.3 5-C1-2-furyl phenyl 32 66.9 35 H 3-furyl phenyl 32 45.4 81 796 19

- -1 R2 Dose% MPE

(mg / kg) 5-C1-2-thienyl phenyl 32 92.2 5-C1 2-furyl 4-fluorophenyl 32 66.7 5 5-C1 cyclopropyl phenyl 32 6.5 2-furyl 4-fluorophenyl 32 30.5 H 1-phenylethyl phenyl 32 45.4 H 2-thienyl isopropyl 32 98.9 H (2-thienyl) methyl isopropyl 32 81.1 10 5-C1-benzyl phenyl 32 38.2 5-C1-benzyl 4-fluorophenyl 32 35.5 5-C1-2-thienyl 4-fluorophenyl 32 96.7 5-C1 phenoxymethyl 4-fluorophenyl 32 45.3? -CH2-furyl phenyl 32 32.2 15 5-CH2 2-thienyl isopropyl 32 46.7 5- CH 2 2-furyl isopropyl 32 67.5 phenoxymethyl isopropyl 32 33.3 5-C12-thienyl isopropyl 32 100 5-C1 2-furyl isopropyl 32 94.4 20 5-C1 phenoxymethyl isopropyl 32 62.4 5-C1 benzyl isopropyl 32 100 H 2-furyl 4-chlorophenyl 100 30.3 H 2-thienyl 4-chlorophenyl 100 65.4 H 4-fluorobenzyl phenyl 32 2.6 25 H (3-thienyl) methyl phenyl 32 45.0 H methyl cyclohexyl 32 19.8 H propyl 4-chlorophenyl 32 18.3 H 2-thienyl cyclohexyl 32 78.2 H 2-furyl cyclohexyl 32 57.9 30 H 2- thienyl 2-tolyl 10 2.0 H 2-furyl 2-tolyl 32 94.7 H (2-thienyl) methyl cyclohexyl 32 89.1 5-Cl isopropyl 4-fluorophenyl 32 4.8 5-Cl (2-thienyl) methyl 4-fluorophenyl 32 98.5 35 5-Cl (2-thienyl) methyl isopropyl 10 76.1 20 81796

£ -1 R2 Dose% MPE

(mg / kg) 5-C1 cyclohexyl isopropyl 10 33.7 5-C1 2-furyl cyclohexyl 10 81.6 5 5-C1 2-thienyl cyclohexyl 10 98.8 5-C1 (2-thienyl) methyl cyclohexyl 32 98, 9 H 2-furyl t-butyl 32 95.7 H 2-thienyl t-butyl 32 55.5 H benzyl t-butyl 32 46.7 10 H (2-thienyl) methyl t-butyl 32 100 5-C1 5- methyl-2-furyl cyclohexyl 32 82.3 5-C1-5-methyl-2-furyl isopropyl 32 91.9 5-C1 2-furyl t-butyl 32 73.9 5-C1 methyl isopropyl 32 37.0 15 5- C1-propyl cyclohexyl 32 99.3 5-C1 isopropyl cyclohexyl 32 12.1 5-C1-5-ethyl-2-furyl isopropyl 32 59.7 5-C1-2-thienyl t-butyl 32 43.6 H 5-ethyl-2 -furyl cyclohexyl 32 18.3 20 5-C1 (2-thienyl) methyl t-butyl 10 85.5 5-C1 methyl t-butyl 32 45.2 5- C1-5-ethyl-2-furyl cyclohexyl 32 100 6- C1-2-thienyl phenyl 32 51.1 5-C1-5-ethyl-2-furyl phenyl 32 16.9 25 6-C1-2-furyl cyclohexyl 32 94.7 5-C1-5-ethyl-2-furyl t-butyl 32 19.6 H 2-thienyl phenoxymethyl 10 67.3 5-F 2-furyl phenyl 32 92.2 5-F (2-thienyl) methyl phenyl 32 100 30 5-F 2-furyl cyclohexyl 32 100 5-F 2-thienyl cyclohexyl 32 100 5-F 2-furyl t-butyl 32 80.9 5-F 2-thienyl t-butyl 32 85.9 5-F (2-thienyl) methyl t-butyl 32 92.2 35 5-F (2-thienyl) methyl cyclohexyl 32 100

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ai 81796

X R1 R2 Dose% MPE

(mg / kg) 5- C1-2-thienyl phenoxymethyl 32 94.3 6-C1 2-thienyl t-butyl 32 71.6 5 6-C1 2-thienyl cyclohexyl 32 100 6-C1 (2-thienyl) methyl cyclohexyl 32 95.0 6-C1-2-furyl isopropyl 10 97.4 6-C1 2-thienyl isopropyl 10 90.4 H 2-furyl phenoxymethyl 32 28.7 10 6-C1 2-furyl phenyl 10 91.7 5- F 2 -thienyl phenyl 32 95.0 6- F 2-furyl phenyl 10 90.1 6-Cl (2-thienyl) methyl phenyl 10 20.9 H (2-thienyl) methyl phenoxymethyl 10 47.3 15 6-C1 2- furyl phenoxymethyl 10 98.9 5-F 2-furyl phenyl 10 91.9 6-C 1 methyl phenyl 32 84.7 6-F 2-thienyl phenyl 10 18.9 20 The following examples and preparations are presented solely to illustrate the invention.

Example 1 N-Benzoyl-3- (2-furoyl) -2-oxindole-1-carboxamide A mixture of 909 mg (4.0 mmol) of 3- (2-furoyl) -2-oxindole and 706 mg of mg (4.8 mmol) of benzoyl isocyanate in 25 ml of toluene, was heated to reflux, and the mixture was then refluxed for 7 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 impure 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 C 21 H 14 O 5 N 2: 35 Calculated: C 67.37, H 3.77, N 7.49%

Found: C 66.90, H 4.02, N 7.38% 22 8 1 7 9 6

Example 2 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-dimethylamino) 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 (8.5 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) CH 2 OH 245 6,920 25 375 2,530 CH 3 OH + droplet 249 7,200 0, 1N NaOH 372 2,710 CH 3 OH + 1 droplet 241 9,070 0, 1N HCl 30

Example 3 N-benzoyl-3-acetyl-2-oxindole-1-carboxamide

To a stirred slurry of 841 mg (3.0 mmol) of N-Benzoyl-2-oxindole-1-carboxamide in 5 mL of N, N-dimethyl-35-formamide was added 806 mg (6.6 mmol) of 11 23 81 7 9 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 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 4 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:

Calculated: C 64.60, H 3.61, N 7.18% 30 Found: C 64.53, H 3.75, N 7.10%

Example 5

Reaction of the appropriate N-substituted 2-oxindole-1-carboxamide with the required acid chloride of the formula 1-CO-Cl following essentially the procedure set forth in Example 2 24 81796 gave the following compounds.

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27 81 796

Example 6 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 1.

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 in Example 1.

10 Example 7

Following the procedure of Example 1 (Method A), Example 2 or 3 (Method B) or Example 4 (Method 4), the following compounds were prepared: I n 0 = C-NH-C-R '20 fl 28 81 796

Preparation Melting point x_R1_R2_method (° C) 2__ H methyl phenyl A, B 198-200d H isopropyl phenyl B 165d 5 H cyclohexyl phenyl B 181d 5-C1 methyl phenyl B 215-217d 5-C1 isopropyl phenyl B 185.5-1887, 5d 5-C1 cyclohexyl phenyl B 192-194d 10 H 3-furyl phenyl C 187d 5-C1 cyclopropyl phenyl B 213-215d H cyclopropyl phenyl B 173d H isopropyl phenyl B 165d H 1-phenylethyl phenyl B 173d 15 5-C1 benzyl phenyl B 239-240d 5-CH2-furyl phenyl B 204-205d H (3-thienyl) methyl phenyl B 195-197d 6-C1 2-thienyl phenyl B 192-193d 20 6-F2-furyl phenyl B 189 -190 6-F 2-thienyl phenyl B 190-194 5-C 1-5 ethyl-2-furyl phenyl B 202-203.5d H 5-ethyl-2-furyl phenyl B 174-175 5-F 2-furyl phenyl B 172d 5-F (2-thienyl) methyl phenyl B 189d 6-C1 2-furyl phenyl B 199-200 30 5-F (2-thienyl) methyl phenyl B 167d 6-C1 (2-thienyl) - methyl phenyl B 199-200d H 2-thienyl 4-fluoro-C 163.5- 35 phenyl 164.5d H 2-furyl 4-fluorophenyl C 164.5d

II

29 81 796

Preparation- Melting point_R1_R2_method point (° C) 2 H methyl 4-fluorophenyl A 205-207d 5 H benzyl 4-fluorophenyl A 207-209d H cyclopropyl 4-fluorophenyl B 1671.5d H (2-thienyl) - 4-fluoromethylphenyl A 216-217d 2-thienyl 4-fluorophenyl B 178-179d 5-C1 2-furyl 4-fluorophenyl B 197-199d 15-CH2-furyl 4-fluoro- phenyl B 179-181d 5-C1 2-thienyl 4-fluoro-B 191,5-phenyl 192.5d H (2-thienyl) -4-methoxy-methylphenyl A 197-198d 'H 2-thienyl 4-methoxy - phenyl B 173d H 2-furyl 4-methoxyphenyl B 146d 25 H cyclopropyl 4-methoxyphenyl B 193d 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 35 H propyl 4-chlorophenyl B 184-185d 30 81 796

Preparation- Melting-1 2 X_R-_R - method point (° C) 2 H 2-thienyl 2-methyl-B 173.5d 5 phenyl H 2 -furyl 2-methyl-B 167-168d phenyl H (2-thienyl) - 2-methylmethyl phenyl B 179.5d 10 H cyclopropyl cyclohexyl B 153-154d H methyl cyclohexyl B 167-168d H 1-phenylethyl cyclohexyl B 191d H 5-methyl-2-furyl cyclohexyl B 163-165d 15 5-C1 5 -methyl-2-furyl cyclohexyl B 197,5d 5-C1 methyl cyclohexyl B 214,5d 5-C1 propyl cyclohexyl B 162-163d 5-C1 isopropyl cyclohexyl B 205-206d 20 5-CH2 2-furyl cyclohexyl B 170-171 δ-CHg 2-thienyl cyclohexyl B 153-154.5d H 5-ethyl-2-furyl cyclohexyl B 146-147 S-CHg 5-ethyl-2-furyl cyclohexyl B 190-191 δ-CHg (2-thienyl) - methyl cyclohexyl B 158-159 5-C1-5-ethyl-2-furyl cyclohexyl B 210-211d 30 6-C1 2-furyl cyclohexyl B 183-184 5-F 2-furyl cyclohexyl B 186.5-187.5d 5 -F 2-thienyl cyclohexyl B 145.5-146.5d 35 5-F (2-thienyl) methyl cyclohexyl B 164- 165

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31 81796

Preparation- Melting point (° C) 2 6-C1 2-thienyl cyclohexyl B 172-173 6-C1 (2-thienyl) -5-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 10 5-CFg 2-furyl cyclohexyl B 194-195d 5 CFg 2-thienyl cyclohexyl B 171-172d 6- F 2-furyl cyclohexyl B 164-166

6-F 2-thienyl cyclohexyl B

5-CH2 2-thienyl t-butyl B 189.5d 15 S-CH4 methyl t-butyl B 194d 5-C1 methyl t-butyl B 211.5d S-CH2 5-ethyl-2-furyl t-butyl B 214 -215 5-C 1-5 ethyl-2-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 25 6-C1 2-thienyl t-butyl B 191-192 5-CHg 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 30 5-CH8 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 35 5-C1 methyl isopropyl B 215-216 H methyl isopropyl B 170-172 32 81 796

Preparation- Melting X_R1___R2_method point (“C) 2 H cyclohexyl isopropyl B 188-189 H benzyl isopropyl B 145-146 5 5-C1-5-ethyl-2-furyl isopropyl B 209-211d 5-C1 isopropyl isopropyl B 142-143 6-C1 2-furyl isopropyl B 184-185d 6-C1 2-thienyl isopropyl B 174.5-1075 6-C1 (2-thienyl) methyl isopropyl B 157-158d H 2-thienyl phenoxyethyl B 161-162 5 -C1 2-thienyl phenoxymethyl B 182-183 15 H 2-furyl phenoxymethyl B 173-175d H (2-thienyl) methyl phenoxymethyl B 193-194 5-C1 2-furyl phenoxymethyl B 194-195.5 20 1) Here in column A, the letter A means that the compound was prepared approximately according to Example 1; the letter B means that the compound was prepared approximately according to Example 2 or 3; and the letter C means that the compound was prepared approximately according to Example 4.

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

Example 8 Ethanolamine salt of N-benzoyl-3- (2-furoyl) -2-oxindole-1-carbox-30-amide

To a slurry of 562 g (1.5 mmol) of N-benzoyl-3- (2-furoyl) -2-oxindole-1-carboxamide in 10 mL of methanol was added 101 mg (1.65 mmol) of ethanolamine. nia. The resulting mixture was heated to reflux for a few minutes and then allowed to cool. The precipitated solid was isolated by filtration,

II

33 81 796 to give 524 mg of the title salt, mp 165-166 ° C. Yield: 80%.

Analysis for c23H21O6N3:

Calculated C 63.44, H 4.86, N 9.65% Found: C 63.27, H 4.95, N 9.58%

Example 9 The diethanolamine salt of N-benzoyl-3- (2-furoyl) -2-oxindole-1-carboxamide was prepared by replacing ethanolamine with diethanol-10 amine in the procedure of Example 8. The product melted at 157-158 ° C. Yield: 74%. Analysis for C25H2507N3:

Calculated: C 62.62, H 5.26, N 8.76%

Found: C 62.53, H 5.31, N 8.74%

Example 10 The triethanolamine salt of N-benzoyl-3- (2-furoyl) -2-oxindole-1-carboxamide was prepared by substituting triethanolamine for ethanolamine in the procedure of Example 8. The product melted at 154-155 ° C. Yield: 60%. Analysis for C 27 H 29 O 5 N 3: 20 Calculated: C 61.94, H 5.58, N 8.03%

Found: C 61.84, H 5.61, N 7.99%

Example 11 N-Benzoyl-2-oxindole-1-carboxamide To a stirred slurry of 399 mg (3.0 mmol) of 2-oxo-25-indole in 7 mL of toluene was added 485 mg (3.3 mmol) of benzoyl. isocyanates. The mixture was refluxed for 2.2 h, after which it was cooled to room temperature. The solid was isolated by filtration and then dissolved in about 10 mL of hot acetonitrile. The acetonitrile solution was treated with activated carbon to remove color, after which the solution was allowed to cool and the precipitate was isolated by filtration. Recrystallization of the precipitate from acetonitrile gave 131 mg of the title compound, mp 183.5-184.5 ° C.

35 34 8 1 7 9 6

Analysis for C16Hx203N2:

Calculated: C 68.56, H 4.32, N 9.99%

Found: C 68.37, H 4.58, N 10.16%

Example 12 By reacting the appropriate 2-oxindole with the required acyl isocyanate approximately following the procedure set forth in Example 11, the following compounds were prepared: = C-NH-C-R2 no X R2 Melting point (C *) 1 Yield% 20 - 5-C1-phenyl 193-195 43 5-CH8 phenyl 202-203 68 6-C1-phenyl 206-207 59 6-F-phenyl 174-175.5 25 5-F-phenyl 187d 37 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 30 H 4-chlorophenyl 186.5-187.5d 53 H 2-methylphenyl 166.5-167.5 59 H cyclohexyl 144.5-145.5 62 5-C1 cyclohexyl 172-174 63 5-CHg cyclohexyl 140-141.5 68 35 6-C1 cyclohexyl 181-182 56

II

35 81 796 X_R2_Melting point (C **) 1 Yield% 5-F cyclohexyl 163.5-164.5 63 4- C1 cyclohexyl 173-174 69 5 CF3 cyclohexyl 177.5-178.5d 40 5 6-F cyclohexyl 203 -206 43 H t-butyl 151-152 35 5-CH3 t-butyl 202.5d 34 5-C1 t-butyl 176.5-177.5d 43 5-T-butyl 161.5-162.5d 31 10 6-C1 t-butyl 146-147 42 H isopropyl 114-115 23 5-CH3 isopropyl 169-171 38 5- C1 isopropyl 164-165 77 6- C1 isopropyl 128-129 69 15 H phenoxymethyl 187-188 78 5-C1 phenoxymethyl 218-219 51 1) In this column, the letter "d" means that it decomposed on melting 20 Preparation 1 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 ice bath temperature, 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 209-210 ° C (decomposes).

36 8 1 7 9 6

Analysis for C 13 H 10 N:

Calculated: C 68.72, H 3.99, N 6.17%

Found: C 68.25, H 4.05, N 6.20%

Preparation 2 By reacting 2-oxindole with the appropriate acid chloride using the method of Preparation 1, the following products were further obtained: 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%; 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 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 3-20 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 was 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 followed by acetonitrile to give 705 mg of the title compound, m.p. 185-186 ° C.

Analysis for C13H903N:

Calculated: C 68.72, H 3.99, N 6.17% 35 Found: C 68.72, H 4.14, N 6.14%

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37 81 796

Preparation 3A

By reacting the appropriate oxindole with the necessary carboxylic acid ethyl ester following essentially the procedure of Preparation 3, the following compounds were obtained: 5-chloro-3- (2-thienoyl) -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-thienoyl) -2-oxindole, m.p. 200-203 ° C, yield 26%; 6-fluoro-3- (2-furoyl) -2-oxindole, m.p. 239-242 ° C, yield 26%.

Preparation 4 5-Chloro-2-oxindole 20 To a slurry containing 100 g (0.55 mol) of 5-chloroisatin in 930 ml of ethanol and stirred 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 added 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 refluxed for 10 minutes, after which it was evaporated under reduced pressure to give a gummy solid. 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).

Similarly, 5-methylisatin 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.

Preparation 5 4-Chloro-2-oxindole and 6-chloro-2-oxindole 15 A. 3-Chloroisonitrosoacetanilide

To a stirred solution of 113.23 g (0.686 mol) of chloral hydrate in 2 L of water was added 419 g (2.95 mol) of sodium sulfate, followed by a solution prepared from 89.25 g (0 .70 mol) of 3-chloro-20 ryaniline, 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 at 60-75 ° C for about 6 h, 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-chloroiso-nitrosoacetanilide.

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.

Il 39 81 796

After the addition of lime solid, 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 10 3 N sodium hydroxide. The solution was filtered and the pH was adjusted to 8 with concentrated hydrochloric acid. At this point, 120 ml of a mixture of 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-20-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 material, melting at 261-262 ° C.

C. 4-Chloro-2-oxindole

To a stirred slurry of 43.3 g of 4-chloroisatin in 350 ml of ethanol 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 35 anhydrous ethanol was added 43.5 g of 4-chloro-3-hydrazono-2-oxindole from at least 40 81 796 bogies, 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).

10 D. 6-chloro-2-oxindole

Reaction of 36.2 g of 6-chloroisatin with hydrazine hydrate followed by sodium ethoxide in ethanol approximately according to C above gave 14.2 g of 6-chloro-2-oxindole, mp 196-198 ° C. .

Preparation 6 5-Fluoro-2-oxindole

To a solution of 11.1 g (0.1 mol) of 4-fluoroaniline in 200 ml of dichloromethane and stirred at 20-60 to -65 ° C was added dropwise a solution of 10.8 g (0 mol) of , 1 mol) of t-butyl hypochlorite in 25 ml of dichloromethane. Stirring was continued for 10 minutes at -60-65 ° 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 40 ml of 2N hydrochloric acid. This mixture was stirred at room temperature overnight. The layers were separated and the ether layer was washed

II

4i 81796 with water followed by 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 C9HBONFS:

Calculated: C 54.80, H 4.09, N 7.10% 10 Found: C 54.74, H 4.11, N 7.11%

A small portion of the 5-fluoro-3-methyl-thio-2-oxindole prepared above (986 mg, 5.0 mmol) was added to a mixture of 2 teaspoons of Raney nickel in 50 mL of absolute ethanol, followed by re-reaction. was fluxed 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 g of 5-fluoro-2-oxindole, mp 121-134 ° C.

In a similar manner, 5-trifluoromethyl-2-oxindole (mp 189.5-190, 5 ° C) was reacted with 4-trifluoromethylaniline with t-butyl hypochlorite, ethyl 2- (methylthio) acetate and triethylamine and reduced-25-trifluoromethylaniline. by 3-thiomethyl-5-trifluoromethyl-2-oxindole thus obtained with Raney nickel.

Preparation 7 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 Preparation 4. 5-n-Butylisatin can be prepared from 4-n-butylaniline by treating it with chloral hydrate and hydroxylamine and then cyclizing the product obtained with sulfuric acid by a procedure corresponding to Parts 6 A and B of Preparation 6.

81796 6-Fluoro-2-oxindole can be prepared according to Protivan et al. [Collection of Czechoslovakian Chemical Communcations 44 (1079) 2108] and in accordance with U.S. Patent 4,160,032.

6-Trifluoromethyl-2-oxindole can be prepared

By the method of Simet [Journal of Organic Chemistry 28 (1963) 3580].

Il

Claims (3)

43 8 1 7 9 6 A process for the preparation of a therapeutically useful 2-oxindole compound of formula I wherein O is hydrogen, fluoro, chloro, C 1-4 alkyl or tri-fluoromethyl; 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 f uranium or thiophene; and R 0 is hydrogen or C 1-3 alkyl; and R 2 is C 1-4 alkyl, C 3-7 cycloalkyl, phenoxymethyl or a group wherein each of R 3 and R 4 may be hydrogen, fluoro, chloro, C 1-4 alkyl or C 1-4 alkoxyl; or a pharmaceutically acceptable base salt thereof, characterized in that a compound of formula (A) corresponding to formula IV is reacted with an acyl isocyanate of formula R 2 -C (= O) -N = C = O , in an inert solvent, or (B) a compound of formula II 10 X 0 = C-NH-C-R 2 II 15 O is reacted with a reactive derivative of a carboxylic acid of formula ^ -O (= O) -011 in an inert solvent. Process according to Claim 1, characterized in that the compound of the formula I in which X is hydrogen, R 1 is 2-furyl and R 2 is phenyl. 45 81 796