DD232916A5 - PROCESS FOR THE PREPARATION OF 2-OXINDOL-1-CARBOXAMIDES OR PHARMACEUTICAL ACCEPTABLE SALTS HEREVON - Google Patents

Abstract

Certain 2-oxindole-1-carboxamide compounds having an acyl substituent at the 3-position and also further substituted at the carboxamide nitrogen by an alkyl, cycloalkyl, phenyl or subst.-phenyl group are inhibitors of the cyclooxygenase enzymes (CO) and lipoxygenase (LO) and are useful as analgesic and antiperspirant agents in mammals. These 2-oxindole-1-carboxamide compounds are of particular value in alleviating pain in human patients recovering from surgery or trauma and alleviating the symptoms of chronic diseases such as rheumatoid arthritis and osteoarthritis in humans. Certain 2-oxindole-1-carboxamide compounds, unsubstituted at C-3 but having a substituent on the carboxamide nitrogen, are useful as intermediates in analgesic and antiperspirant agents of the invention.

Description

wherein R ³ and R ^{4 are} each hydrogen, fluorine, chlorine, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons or trifluoromethyl.

3. Method according to item 1 or item 2, characterized by reacting a compound of the formula

CR ¹

(IV)

with substantially one molar equivalent of an isocyanate of formula R ² -N = C = O in an inert solvent at a temperature in the range of 50 to 15O ⁰ C.

4. The method according to item 3, characterized in that the reaction in a solvent selected from aliphatic hydrocarbon, aromatic hydrocarbons, chlorinated hydrocarbons, ethers, N, N-dimethylformamide, N, N-

Dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide, is performed.

5. The method according to item 1 or item 2, characterized by reacting a compound of the formula

O = C-NH-R

(V)

with a Moläquivaient or a slight excess of an activated derivative of a carboxylic acid of the formula R ¹ -C (= O) -OH, in an inert solvent in the presence of 1 to 4 molar equivalents of a basic agent at a temperature in the range -10 to 25 ^0C ,

6. The method according to item 5, characterized in that the activated derivative is an acid chloride and the reaction is carried out in a polar, aprotic solvent.

7. A method according to item 1 or any one of items 3 to 6, characterized in that Y is hydrogen and X is hydrogen, 5-chloro, 6-chloro, 5-fluoro or 6-fluoro.

8. The method according to item 7, characterized in that R ^{1 is} benzyl, 2-furyl, 2-thienyl, (2-furyl) methyl or (2-thienyl) methyl.

9. The method according to item 8, characterized in that X is 5-chloro, R ^{1 is} 2-furyl and R ^{2 is} t-butyl.

Field of application of the invention

This invention relates to novel chemical compounds. In particular, these novel chemical compounds are derivatives of 2-oxindole-1-carboxamide, and are in the 3-position by an acyl group and on the carboxamide nitrogen by an alkyl, cycloalkyl, phenyl, subst.-phenyl. or heterocyclic group further substituted. These new chemical compounds are inhibitors of the two enzymes cyclooxygenase (CO) and lipoxygenase (LO).

The compounds of the present invention have analgesic activity in mammals, particularly humans, and are therefore useful for acute administration to alleviate or eliminate pain, such as pain experienced by patients recovering from surgery or trauma.

In addition to their usefulness for acute administration for pain control purposes, the compounds of this invention are useful for chronic administration to mammals, particularly humans, for the relief of the symptoms of chronic disease, inflammation and pain associated with rheumatoid arthritis and osteoarthritis.

Aim and presentation of the essence of the invention

This invention provides novel 2-oxindole-1-carboxamide compounds of the formula

X »1

* ~, CR ^X

- (D.

O = C-NH-R ²

and the pharmaceutically acceptable salts thereof, wherein

X is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, trifluoromethyl, alkylsulfinyl of 1 to 4 carbons Alkylsulfonyl of 1 to 4 carbons, nitro, phenyl, alkanoyl of 2 to 4 carbons, benzoyl, thenoyl, alkanamido of 2 to 4 carbons, benzamido and Ν, Ν-dialkylsulfamoyl of 1 to 3 carbons in each of the alkyls; and Y is selected from the group consisting of hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons and trifluoromethyl; or X and Y taken together are a 4,5, 5,6 or 6,7-methylenedioxy group or a 4,5, 5,6 or 6,7-ethylenedioxy group; or

X and Y when taken together and attached to adjacent carbon atoms form a bivalent radical Z wherein Z is selected from the group consisting of

where W is oxygen or sulfur;

R ^{1 is} selected from the group consisting of alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, cycloalkenyl of 4 to 7 carbons, phenyl, subst.-phenyl, phenylalkyl of 1 to 3 carbons in the alkyl, (subst. Phenyl) alkyl having 1 to 3 carbon atoms in the alkyl, phenoxyalkyl having 1 to 3 carbon atoms in the alkyl, (substituted phenoxy) alkyl having 1 to 3 carbon atoms in the alkyl, (thiophenoxy) alkyl having 1 to 3 carbon atoms in the alkyl, naphthyl, Bicyclo [2.2.1] heptan-2-yl, bicyclo [2.2.1] hept-5-en-2-yl and - (CH ₂ ) _n -QR °;

wherein the substituent on the substituted phenyl, the (substituted phenyl) alkyl and the (substituted phenoxy) alkyl is selected from the group consisting of fluoro, chloro, bromo, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons and trifluoromethyl; η is zero, 1 or 2; Q is a divalent radical derived from a compound selected from the group consisting of furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole , 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo [b] furan and benzo [b] thiophene; and R ° is hydrogen or alkyl of 1 to 3 carbons; and R ^{2 is} selected from the group consisting of alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, benzyl, furyl, thienyl, pyridyl, and a group of the formula

R ³

wherein R ³ and R ^{4 are} each selected from the group consisting of hydrogen, fluorine, chlorine, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, and trifluoromethyl.

The compounds of formula I are active as analgesic agents and as agents for the treatment of inflammatory diseases such as arthritis. Thus, this invention also provides a method for eliciting an analgesic response in a mammal, especially humans; a method of treating an inflammatory disease in a mammal, especially a human; and pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier.

-4- 750 30

A preferred group of compounds of this invention consists of the compounds of formula I wherein X and Y are each selected from the group consisting of hydrogen, 5-fluoro, 6-fluoro, 5-chloro, 6-chloro, 5-trifluoromethyl and 6 Trifluoromethyl, and R ¹ and R ^{2 are} as previously defined. Within this preferred group, particularly preferred compounds are those wherein R ^{1 is} selected from the group consisting of benzyl, 2-furyl, 2-thienyl, (2-furyl) methyl and

(2-thienyl) -methyl.

Particularly preferred single compounds of this invention are:

Nt-butyl-5-chloro-3- (2-furoyl) -2-oxindole-1-carboxamide (I: X is 5-chloro; Y is hydrogen; R ¹ is 2-furyl; R ² is t-butyl) ; Nt-butyl-5-fluoro-3- (2-furoyl) -2-oxindole-1-carboxamide (I: X is 5-fluoro; Y is hydrogen; R ¹ is 2-furyl; R ^{2 is} t-butyl); Nt-butyl-6-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide (I: X is 6-chloro; Y is hydrogen; R ¹ is 2-thienyl; R ² is t-

Butyl);

N- (4-methoxyphenyl) -3- (2-thenoyl) -2-oxindole-1-carboxamide (I: X is hydrogen, Y is hydrogen, R ¹ is 2-thienyl, R ² is

4-methoxyphenyl); and

N- (2,4-Difluorophenyl) -3- (2-furoyl) -2-oxindole-1-carboxamide (I: X is hydrogen, Y is hydrogen, R ¹ is 2-furyl, R ² is

2,4-Difluorophenyl).

Useful as intermediates to the compounds of formula I are the compounds of the formula

(V)

O = C-NH-R ²

wherein X, Y and R ^{2 are} as previously defined. A valuable subgroup of compounds of formula V consists of those compounds in which X and Y are each selected from the group consisting of hydrogen, 5-fluoro, 6-fluoro, 5-chloro, 6-chloro, 5-trifluoromethyl and 6- Trifluoromethyl, provided that X and Y are not both hydrogen. As such, the compounds of formula V in the latter subgroup are a part of this invention.

This invention relates to the compounds of formula I and these compounds are referred to as derivatives of 2-oxindole, the compound of formula II:

(II)

More specifically, the analgesic and anti-inflammatory agents of Formula I have a carboxamide substituent, -C (= O) -NH-R ² , in the 1-position, and an acyl substituent, -Cf = O) -R ¹ , in U.S. Patent Nos. 4,648,931; 3-position of 2-oxindole, and the benzo ring may be further substituted by X and Y groups. X and Y may be certain monovalent substituents as previously defined, or X and Y may be when, on adjacent carbon atoms of the benzo ring, a methylenedioxy group, -OCH ₂ O-, or an ethylenedioxy group, -OCH ₂ CH ₂ O- mean. Still further, X and Y, when attached to adjacent carbon atoms of the benzo ring of the 2-oxindole, can form a divalent moiety Z such that when Z is taken together with the carbon atoms to which it is attached, it forms a fused carboxyclic or heterocyclic ring , Certain divalent groups for Z (ie Z ^ Z ⁵ ) have been listed earlier. Thus, when ZZ is ¹ , X and Y, when taken together with the carbons to which they are attached, mean a fused cyclopentene ring; and when ZZ is ^s , X and Y, when taken together with the carbons to which they are attached, mean a fused furan or thiophene ring. Further, it is clear that when ZZ is ⁴ or Z is ⁵ , the Z group may be appended in any of two possible ways. So z. For example, when X and Y are C-5 and C-6 and they are Z ⁵ , Formula I is both of the following formulas:

O = C-NH-R ²

and

In addition, as those skilled in the art will recognize, the analgesic and antiinflammatory compounds of this invention of formula I, wherein X, Y, R ¹ and R ^{2 are} as previously defined, are capable of enolization, and therefore may be expressed in one or more tautomeric (enolic ) Forms exist. All such tautomeric (enolic) forms of the compounds of the formula I are considered to be within the scope of this invention

 The compounds of the formula I are prepared from the suitable 2-oxindole compound of the formula III:

(III)

wherein X and Y are as previously defined. This is done by appending the substituent -Cf = O) -NH-R ² to the 1-position and the -C (= O) -R ¹ substituent to the 3-position. These substituents can be added in any order, and this leads to two variants of the process for the preparation of the compounds of formula I, as shown in the scheme.

O = C-NH-IT

(IV)

O = C-NH-R '

Thus, the first variant comprises the following: compound III to compound IV to compound I; the second variant comprises the sequence: compound IM to compound V to compound I.

The -CI = O) -NH-R ² group may be added by reacting a compound of formula IM or a compound of formula IV with an isocyanate of the formula R ² -N = C = O. Most commonly, the reaction by combining virtually equimolar amounts of the reaction components in a Interten solvent is carried out at a temperature in the range of 50 to 15O ⁰ C and preferably 100 to 130 ° C. In this connection, an inert solvent is one which dissolves at least one of the reaction components and which does not adversely interact with each of the reaction components or the product. Typical solvents which may be used include aliphatic hydrocarbons such as octane, nonane, decane and decalin; aromatic hydrocarbons such as benzene, chlorobenzene, toluene, xylenes and tetralin; chlorinated hydrocarbons, such as 1,2-dichloroethane; Ethers, such as tetrahydrofuran, dioxane, 1,2-

Dimethoxyethane and di (2-methoxyethyl) ether; and polar, aprotic solvents such as Ν, Ν-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide. The reaction time varies according to the reaction temperature, but at a temperature of 100 to 130 ⁰ C usually reaction times of a few hours, for example 5 to 10 hours applied.

When a relatively non-polar reaction solvent is used for the reaction of a compound of formula III or IV with an isocyanate of the formula R ² -N = C = O, the product (V or I) is usually out of solution at the end of the reaction, if the reaction mixture is cooled to room temperature. Under these circumstances, the product is usually recovered by filtration. However, if relatively polar solvents are used and the product is not out of solution at the end of the reaction, the product can be recovered by evaporation of the solvent. Alternatively, in the case of water-miscible solvents, dilution of the reaction medium with water precipitates the product and it can be recovered by filtration. The reaction product (I or V) can be purified by standard methods, for example by recrystallization.

The reaction between a compound of formula IV and an isocyanate of formula R ² -N = C = O may be effected by addition of a base such as a tertiary amine, e.g. As trimethylamine, triethylamine, tributylamine, N-methylpiperidine, N-methylmorpholine or Ν, Ν-dimethylaniline, be accelerated. About 1 to about 4 equivalents of the basic agent are usually added, and this allows the application of a reaction temperature of 20 to 50 ° C. At the end of the reaction, the reaction medium must be neutralized (or acidified) and then the product isolated as described earlier. The-C (= O) -R ¹ side chain can be added to a compound of formula V by reacting with one molar equivalent or a slight excess of an activated derivative of a carboxylic acid of formula R ¹ -C (= O) OH in the presence of one to four Equivalents of a basic agent are attached. An inert solvent is one which dissolves at least one of the reaction components and does not adversely interact with each of the reaction components or the product. In practice, however, a polar, aprotic solvent such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide is usually used. Conventional methods for activating the acid of the formula R ¹ -C (= O) OH are used. For example, acid halides, e.g. For example, acid chlorides; symmetrical acid hydrides, R ¹ -C (= O) -OC (= O) -R ¹ ; mixed acid anhydrides having a hindered, low molecular weight carboxylic acid, R ¹ -C (= O) -OC (= O) -R ⁵ , wherein R ^{5 is} a bulky lower alkyl group such as t-butyl; and mixed carboxylic / carbonic anhydrides, R ¹ -C (= O) -O - (= O) -OR ⁶ , wherein R ^{6 is} a lower alkyl group. In addition, N-hydroxyimide esters (such as N-hydroxysuccinimide and N-hydroxyphthalimide esters), 4-nitrophenyl esters, thiolesters (such as thiolphenyl esters) and 2,4,5-trichlorophenyl esters and the like can be used.

A wide variety of basic agents can be used in the reaction between a compound of formula V and the activated derivative of the acid of formula RM 1 = O) OH. However, preferred basic agents are tertiary amines such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine and 4- (N, N-dimethylamino) pyridine. The reaction between a compound of formula V and the activated derivative of the acid of formula R ¹ -C (= O) -OH is usually carried out in the temperature range from -10 to 25 ^° C. Reaction times from 30 minutes to a few hours are common. At the end of the reaction, the reaction medium is usually diluted with water and acidified, and then the product can be recovered by filtration. It can be purified by standard methods, such as recrystallization.

The-C (= O) -R ¹ side chain can be added to a compound of Formula III by reaction with a derivative of the appropriate acid of the formula R ¹ -C (= O) -OH in a lower alkanol solvent (e.g., ethanol ) in the presence of an alkali metal salt of the lower alkanol solvent (eg, sodium ethylate) according to standard procedures. Typical derivatives of the acid of the formula R ¹ ^ f = O) OH which may be used include acid chlorides, acid anhydrides of the formula R 1 Cl = O) -O-Cf = O) -R ¹ , R ¹ -C (= O ) -O - (= O) -R ⁵ and R ¹ -C (= O) -OC (= O) -OR ⁶ and simple alkyl esters of the formula R ¹ ^ f = O) -OR ⁶ , wherein R ⁵ and R ^{6 are} as defined above. Usually, a slight excess of the derivative of the acid of the formula R ¹ -C (= O) -OH is used, and the alcoholate is usually present in an amount of from 1 to 2 molar equivalents, based on the derivative of the acid of the formula R ¹ -C ( = O) OH, present. The reaction between the derivative of the acid of formula RM ^ t = O) OH and the compound of formula III is usually started at 0 to 25 ⁰ C, but it is then usual, the reaction mixture to a temperature in the range of 50 to 130 ^0th C and preferably to about 80 ° C to complete the reaction. Under these circumstances, reaction times of usually a few hours, for example 2 hours, up to a few days, for example 2 days, are used. The reaction mixture is then cooled, diluted with an excess of water and acidified. The product of formula IV may then be recovered by filtration or by the standard procedure of solvent extraction.

The isocyanates of the formula R ² -N = C = O can be prepared according to standard procedures. See, further, "Organic Functional Group Preparations" by Sandler and Karo, Part 1.2, ed., Academic Press, Inc., New York, NY, 1983, Chapter 12, pp. 364-369 A particularly useful method involves the reaction of the suitable amine of the formula R ² -NH ₂ with phosgene:

R ² -NH ₂ + COCl ₂ > · R ² -N = C = O + 2 HCl

Many of the isocyanates of the formula R ² -N = C = O) are known in the art.

The 2-oxindole compounds of the formula III are prepared by known methods or by known analogous methods. See.; Rodd's Chemistry of Carbon Compounds, 2nd Ed., S. Coffey, Vol. IV, Part A, Elsevier Scientific Publishing Company 1973, pp. 448-450, Gassman et al., Journal of Organic Chemistry, 42, 1340 (1977). Wright et al., Journal of the American Chemical Society, 78,221 (1956); Beckett et al., Tetrahedron, 24, 6093 (1968); U.S. Patents 3,882,236, 4,606,161 and 4,160,032; Walker, Journal of the American Chemical Society, 77, 3844 (1955); Provita et al., Collection of Czechoslovakian Chemical Communications, 44, 22108 (1979); McEvoy et al., Journal of Organic Chemistry, 38, 3350 (1973); Simet, Journal of Organic Chemistry Wieland et al., Chemische Berichte, 96, 253 (1963), and the references cited therein The compounds of formula I are acidic and form base salts All such base salts are within the scope of this invention and can be prepared by conventional methods For example, they can be easily prepared by contacting the acidic and basic units, usually in a stoichiometric ratio, in either aqueous, non-aqueous

with a non-solvent and subsequent filtration, by evaporation of the solvent, as appropriate, or obtained in the case of aqueous solutions by lyophilization. Typical salts of the compounds of formula I which can be prepared are primary, secondary and tertiary amine salts, alkali metal salts and alkaline earth metal salts. Particularly valuable are the ethanolamine, diethanolamine and triethanolamine salts.

Basic agents suitably used in salt formation include both organic and inorganic types, and include organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal carbonates, alkali metal hydrides, alkali metal alcoholates, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides and alkaline earth metal alcoholates. Representative examples of such bases include primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucamine; secondary amines such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, triethanolamine, Ν, Ν-dimethylaniline, N-ethylpiperidine and N-methylmorpholine; Hydroxides, such as sodium hydroxide; Alcoholates, such as sodium ethylate and potassium methylate; Hydrides, such as calcium hydride and sodium hydride; and carbonates such as potassium carbonate and sodium carbonate.

The compounds of the formula I have analytical activity. This activity has been demonstrated in mice by detecting blockade of the abdominal lining induced by administration of 2-phenyl-1,4-benzoquinone (PBQ). The method used was based on that of Siegmund et al., Proc. Soc. Exp. Biol. Med., 95, 729-731 (1957), adapted for high throughput (see also, Milne and Twomey, Agents and Actions, 10, 31-37 [1980]). The mice used in these experiments were Carworth males. Albino CF-i strain, weighing 18-2Og. All mice were fasted overnight prior to drug administration and testing.

The compounds of formula I were dissolved or suspended in a carrier consisting of ethanol (5%), emulsifier 620 (a mixture of polyoxyethylene fatty acid esters, 5%) and saline (90%). This carrier also served as a control.

Doses were on a logarithmic scale (i.e. 0,32,1,0,3,2,10,32 ... mg / kg). The route of administration was varied orally

Concentrations to allow a constant dose volume of 10 ml / kg body weight. The aforementioned method of Milne and Twomey was used to determine potency and potency. Mice were treated orally with compounds and received PBQ, 2 mg / kg, intraperitoneally one hour later.

Single mice were then immediately placed in a heated lucite chamber, and abdominal contractures were recorded 5 min after PBQ administration during the subsequent 5 min. The level of analgesic protection (% MPE) was calculated based on the suppression of abdominal contractility relative to counts of concurrent controls performed on the same day. At least 4 such determinations (NS 5) yielded dose-response data to form an MPE ₅₀ value, the best dose determination, which reduced abdominal contractions to 50% of control values.

The compounds of formula I also possess anti-inflammatory activity. This activity has been demonstrated in rats by a method based on the carrageenin-induced rat paw edema standard test (Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544 [1963]).

Non-anesthetized adult male albino rats of 150g to 190g body weight were numbered, weighed, and a color mark was placed on the right lateral malleolus. Each paw was dipped in mercury just to the color mark. The mercury was contained in a glass cylinder connected to a Statham pressure transducer. The output signal from the transducer was fed via a control unit to a microvoltameter. The volume of mercury displaced by the submerged paw was read. Active ingredients were given by forced feeding. One hour after the drug administration, edema was produced by injecting 0.05 ml of 1% carrageenin solution into the plantar tissue of the labeled paws. Immediately thereafter, the volume of the paw was measured by injection. The increase in foot volume 3 hours after the injection of carrageenin represents the single inflammatory reaction. The analgesic activity of the compounds of formula I makes them suitable for acute administration to mammals for the control of pain, e.g. Postoperative pain and trauma pain. In addition, the compounds of formula I are useful for chronic administration to nipples for the relief of the symptoms of chronic diseases, such as the inflammation of rheumatoid arthritis, and the pain associated with osteoarthritis and other musculoskeletal disorders. When a compound of formula I or a pharmaceutically acceptable salt thereof is to be used either as analgesic or as anti-inflammatory agent, it may be administered to a nipple either alone or preferably in combination with pharmaceutically acceptable carriers or diluents in a pharmaceutical composition according to standard pharmaceutical practice , A compound can be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration. In a pharmaceutical composition containing a compound of formula I or its pharmaceutically acceptable salt, the weight ratio of carrier to active ingredient will normally be in the range of from 1: 4 to 4: 1 and preferably from 1: 2 to 2: 1. In any given case, however, the chosen ratio will depend on such factors as the solubility of the active ingredient, the dosage considered, and the exact route of administration. For oral administration of a compound of formula I of this invention, the compound can be administered, for example, in the form of tablets or capsules, or as an aqueous solution or suspension. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch, and lubricants such as magnesium stearate are usually added. For oral administration in capsule form, useful diluents are lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring agents may be added. Intramuscular, intraperitoneal, subcutaneous and intravenous use are usually sterile. Solutions of the active ingredient prepared, and the pH of the solutions should be suitably adjusted and buffered. For intravenous use, the total solute concentration should be controlled to make the preparation isotonic. ,

When a compound of formula I or a salt of it is used in a human, the daily dosage is usually determined by the prescribing physician. Further, the dosage will vary with the age, weight and response of the individual patient as well as with the severity of the patient's symptoms and the strength of the particular compound being administered. However, for acute administration to alleviate pain, an effective analgesic response-eliciting dose in most cases will be 0.02 to 0.5 g, as needed (e.g., every four to twenty-four hours).

For chronic administration for the relief (treatment) of inflammation and pain, in most cases an effective dose of 0.02 to 1.0 g per day and preferably 0.05 to 0.5 g per day will be in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.

embodiments

The following examples and preparations are given solely for the purpose of further illustration.

example 1 N-phenyl-S-acetyl - ^ - oxindole-I-carboxamide

To a stirred slurry of 526 mg (3, OmMoI) 3-acetyl-2-oxindole in 6 mL of toluene was added 393 mg (3.3 mmol) of phenyl isocyanate, and then the mixture was refluxed for 7 h. The reaction mixture was cooled to room temperature and the precipitate collected by filtration. The solid thus obtained was recrystallized from about 20 ml of acetonitrile to give 229 mg of the title compound as near white needles, m.p. 171-173 ° ^C. Analysis for C ₁₇ H ₁₄ N ₂ O _3,%: calc .: C 69.38 H 4.79 N 9.52 Found .: C 69.31 H 4.97 N 9.59

Example 2 Nt-Butyl-6-chloro-3- (2-thenoyl) -2-oxindoM-carboxamide A solution of 667 mg (2.5 mmol) of Nt-butyl-e-chloro-1-oxindole-i-carboxamide and 684 mg (5 , 6 mmol) of 4- (N, N-dimethylamino) -pyridine in 8 ml of Ν, Ν-dimethylformamide was cooled in an ice bath and then a solution of 410 mg (2.8 mmol) of 2-thenoyl chloride in 2 ml of Ν, Ν-dimethylformamide added dropwise with stirring. Stirring was continued for 30 minutes and then the reaction mixture was poured into a mixture of 60 ml of water and 2.5 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice bath, and then the solid was collected by filtration and recrystallized from about 30 ml of acetic acid. This gave 425mg of the title compound as yellow crystals, mp. 160.5 to 161.5 ⁰ C (slight decomposition). Analysis for C ₁₈ H ₁₇ CIN ₂ O ₃ S,%: calc .: C 57.36 H 4.55 N 7.43 Found .: C 57.29 H 4.48 N 7.38

Example 3 N- (4-fluorophenyl) -3-acetyl-2-oxindole-1-carboxamide

To a stirred slurry of 811 mg (3, OmMoI) N- (4-fluorophenyl) -2-oxindole-1-carboxamide in 4 ml of Ν, Ν-dimethylformamide was added 806 mg (6.6 mmol) of 4- (N, N-dimethylamino) given pyridine. Stirring was continued for a few minutes and then the slurry was cooled in an ice-bath and a solution of 337 mg (3.3 mmol) of acetic anhydride in 2 ml of Ν, Ν-dimethylformamide was added. Stirring was continued for an hour, and then the reaction mixture was poured onto a mixture of 60 ml of ice-water and 2.2 ml of 3N hydrochloric acid. The solid which precipitated was recovered by filtration. It was recrystallized from acetonitrile to obtain 600 mg of the title compound as dark crystals, mp. 181-182 ⁰ C to give. Analysis for C ₁₇ H ₁₃ FN ₂ O ₃ ,%: calc .: C 65.38 H 4.19 N 8.97 Found: C, 65.44, H, 4.31, N, 8.97

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

To a stirred solution of 682 mg of (3, OmMoI) 3- (2-furoyl) -2-oxindole in 8 mL of dimethylsulfoxide was added 668 mg (6.6 mmol) of triethylamine, then 512 mg (3.3 mmol) of 2,4-difluorophenyl isocyanate , Stirring was continued for 1 h, and then the reaction mixture was poured into 60 ml of water. The resulting mixture was acidified with 3N hydrochloric acid and then cooled in an ice bath. The solid was removed by filtration and recrystallized from ca. 35 ml of acetic acid to give 925 mg of the title compound as yellow crystals, mp 191-192 ° C. Analysis for C ₂₀ H ₁₂ F ₂ N ₂ O ₄ ,%: calc .: C 62.83 H 3.16 N 7.33 Found: C, 62.70, H, 3.07, N, 7.26

Example 5

The following compounds were prepared essentially according to the method of Example 1 (Method A), Example 2 or 3 (Method B) or Example 4 (Method C):

O = C-NH-R ²

R ¹

Production method ¹

Melting point ( ⁰ O ²

H 2-furyl ethyl B H 2-thienyl ethyl B H (2-thienyl-methyl ethyl B H methyl ethyl B 5-CI 2-furyl ethyl B 5-CI 2-thienyl ethyl B 5-CI methyl ethyl B 5-CI (2-thienyl) -methyl ethyl B 5-CI 2-thienyl isopropyl B 5-CI (2-thienyl) -methyl isopropyl B 5-CI methyl isopropyl B 5-CI 2-furyl n-butyl B 5-CI 2-thienyl n-butyl B 5-CI 2-furyl t-butyl B H 2-furyl isopropyl B H 2-thienyl isopropyl B 5-CI methyl t-butyl B H 2-furyl t-butyl B 5-CI 2-thienyl t-butyl B H (2-thienyl) -methyl t-butyl B H 2-thienyl t-butyl B H methyl t-butyl B 5-CI (2-thienyl) -methyl t-butyl B H methyl isopropyl B H 2-furyl n-butyl B 5-CI 2-thienyl n-butyl B 5-CI methyl n-butyl B H 2-thienyl n-butyl B 5-CI cyclohexyl t-butyl B 5-CI cyclopentyl t-butyl B 5-CI cyclobutyl t-butyl B 5-CF ₃ 2-thienyl t-butyl B 5-CF ₃ 2-furyl t-butyl B 5-CF ₃ (2-thienyl) -methyl t-butyl B 6-Cl 2-furyl t-butyl B 6-Cl (2-thienyl) methyl t-butyl B 5-CI 2-furyl cyclohexyl B 5-CI methyl cyclohexyl B 5-CI (2-thienyl) thienyl cyclohexyl B 5-CI 2-thienyl cyclohexyl B H methyl 3- (trifluoro-methyl) phenyl A H methyl 2,4-Difluoro-phenyl A H methyl 4-fluoro-phenyl A H benzyl phenyl A H (2-methyl-ThienyO 2,4-Difluoro-phenyl A H (2-thienyl) -methyl phenyl A H isopropyl 4-fluoro-phenyl B H cyclopropyl 4-fluoro-phenyl B H 2-thienyl phenyl C H 2-thienyl 2,4-Difluoro-phenyl C H 2-furyl 4-chloro-phenyl C H 2-furyl 2- (trifluoro-methyl) phenyl C H Trifluoro-methyl 4-chloro-phenyl A H Trifluoro-methyl 2,4-Difluoro-phenyl A H · 2-thienyl 2- (trifluoro-methyOphenyl C H 2-furyl 2,4-dichloro-phenyl C H 2-furyl 3-methoxy-phenyl C H 2-thienyl 2,4-dichloro-phenyl C H 2-furyl 4-methoxyphenyl C

201-201.5

128-129.5

130-131

157-158

134-135

154-155

173-174

154-155

129-130

155-156

186-187

100-101

152-153

171-171.5

114-115

177-178.5

219-220

160-161

178-179.5

141-142d

163-164

163-164

218-219d

162.5-163.5

87-88

123-124

167-169

137-138

239-24Od

229-23Od

226-227d

162-163

171.5-172.5

133-134

168.5-169.5

151-152

138-139

226-227

153-154

158-159

186-188

161-162

181-183

145-147

165-167

165-167

176-177

202-203

152-153

164-165

200.5-201.5d

202-203d

202-230

133.5-134.5

166.5-167.5d

235.5d

137-138

221.5-222.5d

168-169.5

- IU - / 9O SO

Example 5 (continued)

XR ¹

R ²

Production method ¹

M.p. ( ⁰ O ²

H 2-thienyl 4-methoxyphenyl C H 2-furyl 2,4-dimethylphenyl C H 2-thienyl 2,4-dimethylphenyl C H 2-furyl 4-ethylphenyl C H 2-thienyl 4-ethylphenyl C H methyl 4-chloro-phenyl A H phenyl phenyl B H phenyl 4-chloro-phenyl B H 3-pyridyl phenyl B H 4-fluoro-phenyl 4-chloro-phenyl B H 3-pyridyl 4-chloro-phenyl B H 4-fluoro-phenyl phenyl B H phenyl 2,4-Difluoro-phenyl B H benzyl 2,4-Difluoro-phenyl A H benzyl 4-chloro-phenyl A H 2-thienyl 4-fluoro-phenyl B H 2-furyl 4-fluoro-phenyl B H cyclohexyl 4-fluoro-phenyl B H 2-furyl phenyl C H 3-pyridyl 2,4-Difluoro-phenyl C H Trifluoro-methyl 4-fluoro-phenyl B H Trifluoro-methyl phenyl A H Phenoxy-methyl phenyl A H Phenoxy-methyl 4-chloro-phenyl H Phenoxy-methyl 2,4-Difluoro-phenyl A H (2-thienyl) -methyl 4 ^ -chloro-phenyl A H (2-thienyl) -methyl 4-fluoro-phenyl A H (2-thienyl) -methyl 3-tolyl A H (2-thienyl) -methyl 3-fluoro-phenyl A H (2-thienyl) -methyl 3-trifluoro-methylphenyl A H 1-phenyl-ethyl 2,4-Difluoro-phenyl C H 2-thienyl 4-chloro-phenyl C H 1-phenyl-ethyl 4-fluoro-phenyl B H 2-thienyl 3-methoxyphenyl C H 2-furyl cyclohexyl B H 2-thienyl cyclohexyl B H Phenoxy-methyl cyclohexyl B H benzyl cyclohexyl B H 4-Chloro-benzyl phenyl B H 4-Chloro-benzyl 2,4-Difluoro-phenyl B H 4-Chloro-benzyl 4-chloro-phenyl B H 4-Chloro-benzyl 4-fluoro-phenyl B H 4-fluoro-benzyl phenyl B H 4-fluoro-benzyl 2,4-Difluoro-phenyl B H 4 ^ fluoro-benzyl 4-chloro-phenyl B H 4-fluoro-benzyl 4-Fluoro-phenyl B H (3-thienyl) -methyl phenyl B H (3-methyl-ThienyO 2,4-Difluoro-phenyl B H (3-methyl-ThienyD 4-chloro-phenyl B H (3-thienyl I (-methyl 4-fluoro-phenyl B H 3-furyl phenyl B H 3-furyl 2,4-Difluoro-phenyl B H 3-furyl 4-chloro-phenyl B H 3-furyl 4-fluoro-phenyl B H 3-thienyl phenyl B H 3-thienyl 2,4-Difluoro-phenyl B H 3-thienyl 4-chloro-phenyl B H 3-thienyl 4-fluoro-phenyl B H 4-chloro-phenyl 4-fluoro-phenyl B H methyl benzyl B H 2-thienyl benzyl B H 2-furyl benzyl B H 4-pyridyl phenyl C H 4-pyridyl 2,4-Difluoro-phenyl C H 4-pyridyl 4-chloro-phenyl C

178.5-179.5

176-177

171-172

154.5-155.5

131-132

225-227

176-177

215-217

193-195

212-213

220-221

189-191

204-206

151-152

178-179

175-176.5

166.5-167.5d

180-181

162-163

254d

203-204

139.5-140.5

158-159

137.5-138.5

137.5-138.5

165-166

161-163

147-149

152-154

139-140

152.5-154

196.5-197.5

166-167

148.5-149.5

104-105

116-117

159-160

122-123

180-181

182-183

184-186

165-166

179-181

189-191

205-207

198-199

133-134

162-163

182-184

145-147

145-146

178-179

190-191

189-190

166-168

188-190

216-218

209.5-210.5

219-220

162-164

117-118

124-126

212.5-213.5d

229-230

211-213d

Production method ¹ Melting point

( ⁰ O ²

H H H H H

5-CF ₃ 5-CI 6-CI 5-F 5-F 5-F 6-CI 6-CI 5-CI 5-CI 5-CI 5-CI 5-CI 6-CI 6-CI 5-CI 5 -CI 5-CI 6-CI 6-CI 5-CI 5-CI 5-CI 5-CI 5-F 5-F 5-F 5-F 5-F 5-F 6-CF ₃ 6-CF ₃ 6 F 6-F 5-C ₆ H ₅ CO 5-CH ₃ CO 5-CI 5-CI 5-F 5-F

5-NO ₂ 5-C ₆ H ₆ CO 5-C ₆ H ₅ CO 5 -CH ₃ CO 5 -CH ₃ CO

2-pyridyl phenyl 2-methyl-2-furyl phenyl 2-methyl-2-furyl 2,4-Difluoro-phenyl 2-pyridyl 2,4-Difluoro-phenyl 2-pyridyl 4-chloro-phenyl Bicyclo [2.2.1.] - heptan-2-yl t-butyl Bicyclo [2.2.1] heptane-2-yl t-butyl Bicyclo [2.2.1] heptane-2-yl t-butyl 2-furyl t-butyl 2-thienyl t-butyl (2-thienyl) -methyl t-butyl 2-furyl isopropyl 2-furyl cyclohexyl 2-furyl phenyl 2-furyl 2,4-Difluoro-phenyl 2-thienyl phenyl (2-thienyl) -methyl (2-thienyl) -methyl 2,4-Difluoro-phenyl 2-thienyl isopropyl 2-thienyl cyclohexyl (3-thienyl) methyl I t-butyl 3-furyl t-butyl 3-thienyl t-butyl 2-furyl ethyl 2-thienyl ethyl 2-chloro-benzyl phenyl 2-chloro-benzyl 2,4-Difluoro-phenyl 2-thienyl 2,4-Difluoro-phenyl 4-chlorobenzyl t-butyl 2-furyl isopropyl 2-thienyl isopropyl {2-thienyl) -methyl isopropyl 3-furyl isopropyl 3-thienyl isopropyl (3-thienyl) -methyl isopropyl 2-thienyl phenyl benzyl phenyl 2-thienyl phenyl 2-thienyl 4-methoxyphenyl benzyl phenyl (2-thienyl (-methyl phenyl benzyl 4-methoxyphenyl (2-thienyl) -methyl 4-methoxyphenyl 2-thienyl phenyl 2-thienyl 4-methoxyphenyl phenoxymethyl phenyl 2-thienyl phenyl (2-thienyl) -methyl phenyl 2-thienyl phenyl benzyl phenyl 2-thienyl 4-methoxyphenyl benzyl phenyl benzyl phenyl 4-chloro-phenyl phenyl 2-tetrahydrofuran I 4-methoxyphenyl

C B B C B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B

B B B B B B B B B

¹ The letter "A" in this column indicates that the compound substantially according to Example 1 letter "B" indicates that the compound was prepared substantially according to Example 2 or 3; indicates that the compound was prepared essentially according to Example 4. In method B acid scavengers instead of 4- (N, N-dimethylamino) pyridine used in several cases.

² The letter "d" indicates that the compound melted with decomposition.

208-209

156-157

189-191

230-232d

207-208d

212.5d 235-236d 225d

184.5-185.5 183.5d 182.5-183.5 165.5-166.5 164-165 191.5-192.5. 214-215 194-195 167.5-169 211.5-212.5 118-119 145-146 222-224 181-182d 209-211d 157.5-158.5 138-139 218-219d 216d

200.5-201.5 214-216d 141-142 185-187 143-144 163-164 179-180.5 156-157 187-189 169-170 174-175 175-176 167-170 194-196 198-200 195-197 164- 166 177-179

224-225 160-163 171-173 193-195 195-198 185-187 156-158 175-177 239-240 170-172

was produced; and the letter "C" was triethylamine as

- \ -

Example 5 (continued)

Similarly, the following compounds were prepared essentially according to the method of Example 2:

O = C-NH-R

R ¹ R ' Mp. ( ⁰ o (2-thienyl) methyl phenyl 154 benzyl phenyl 203-204 2-thienyl phenyl 212-214 benzyl η-butyl 129-130 2-furyl η-butyl 122-123 benzyl 4-methoxyphenyl 194-196 2-thienyl 4-methoxyphenyl 210-212

4-CI 5-F 5-F 6-Cl 5-F 6-Cl 5-F 6-Cl 5-F 6-Cl 5-F 6-Cl 5-F 6-Cl

Example 6

The compounds in the following table can be prepared by reaction of the appropriate acid chloride with the required N-substituted-2-oxindole-1-carboxamide using the procedure of Example 2. O

* 7 R ¹ R ² Y * O = C-NH-R ² 2-furyl phenyl X and Y * 2-thienyl cyclohexyl 4-CH ₂ -CH ₂ -CH ₂ -S 2-furyl 4-fluoro-phenyl 5-CH ₂ -CH ₂ -CH ₂ -S (2-thienyl) -methyl t-butyl 6-CH 2 ~C Hj ^- CH 2 -CH 2 ~~ 7 2-thienyl isopropyl 5-CH = CH-CH = CH-6 2-furyl phenyl 5-O-CH ₂ -CH ₂ -B 2-thienyl cyclohexyl 5-CH ₂ -CH ₂ -OS 2-furyl t-butyl 5-S-CH ₂ -CH ₂ -S (2-thienyl (-methyl cyclohexyl 5-O-CH = CH-6 2-furyl phenyl 5-S-CH = CH-S 5-CH = CH-S-6

* In this column, the figure on the left of the formula indicates the point of attachment of this end of the formula with the 2-oxindole nucleus, and the number on the right indicates the point of attachment of that end of the formula with the 2-oxindole nucleus.

Example 7 Ethanolamine salt of N-t-butyl-e-chloro-3- (2-thenoxy) -2-oxindoH-carboxamide

To a slurry of 3.77 g of N-t-butyl-6-chloro-3- (2-thenoyl) -2-oxindole-1-carboxamide in 60 ml of methanol is added 610 mg of ethanolamine. The resulting mixture is boiled for 5 min and then allowed to cool. The solid is collected by filtration to give the title salt.

Example 8 N-isopropyl-Z-oxindomo-carboxamide

To a stirred suspension of 5.0 g (37.6 mmol) 2-oxindole in 50 mL toluene was added 8.0 g (94, OmMoI) isopropyl isocyanate and the mixture heated at reflux for 6 h. The reaction mixture was allowed to cool and was then stirred at room temperature overnight. The solvent was removed by evaporation in vacuo and the residue was dissolved in hot cyclohexane. The solution was allowed to cool and the solid was collected by filtration, which yielded 7.0 g of the title compound, mp. 84-85 ⁰ C as pink crystals.

Example 9

By reacting the appropriate 2-oxindole with the requisite isocyanate of the formula R ² -N = C = O essentially according to the procedure of Example 8, the following compounds were prepared:

O = C-NH-R

Reaction solvent

M.p. ( ⁰ C)

124-125 ¹

145-146 ²

98-99

121-122

164-165

67-68

153-154

60-62

49-51

116-117

139-140

¹ The product was purified by column chromatography.

² The product precipitated at the end of the reaction and was recovered by filtration.

Example 10

The N-substituted 2-oxindo! -1-carboxamides in the following table can be prepared by reacting the corresponding 2-oxindole compound with the requisite isocyanate using the procedure of Example 8.

X «♦"

6-Cl H H H H H 5-CI H 5-CI H 5-CI H 5-CI H H H H . H 5-CF ₃ H 5-CI H

t-butyl xylene 4-fluoro-phenyl toluene ethyl benzene ethyl xylene isopropyl xylene n-butyl xylene t-butyl xylene t-butyl toluene n-butyl toluene t-butyl xylene cyclohexyl xylene

O = C-NH-R

X and Y *

4-CH ₂ -CH ₂ -CH ₂ -O 5-CH ₂ -CH ₂ -CH ₂ - ^

5-CH = CH-CH = CH-6 5-0-CH ₂ -CH ₂ -O-CH ₂ -CH ₂ 5 5 -OO-S-CH ₂ -CH ₂ -O 5-O-CH = CH- 6 5-S-CH = CH-6 5-CH = CH-S-6

phenyl

cyclohexyl

4-fluoro-phenyl

t-butyl

isopropyl

phenyl

cyclohexyl

t-butyl

cyclohexyl

phenyl

* In this column, the numeral to the left of the formula indicates the juncture of this end of the formula with the 2-oxindole nucleus and the numeral to the right indicates the juncture with this end of the formula with the 2-oxindole nucleus.

Production 1

3- (2-furoyl) -2-oxindole

To a stirred solution of 5.5 g (0.24 mol) of sodium in 150 mL of ethanol was added 13.3 g (0.10 mol) of 2-oxihdole at room temperature. The resulting slurry was cooled to ice-bath temperature and then 15.7 g (0.12 mol) of 2-furoyl chloride was added dropwise over 10-15 min. The ice-bath was removed and an additional 100 ml of ethanol was added and then the reaction mixture was refluxed for 7 hours. The reaction mixture was allowed to stand overnight and then the solid was filtered off. The solid was added to 400 ml H ₂ O and the resulting mixture was acidified using concentrated hydrochloric acid. The mixture was cooled with ice and the solid collected by filtration. The solid residue was recrystallized from 150 mL of acetic acid to yield 8.3 g of yellow crystals, m.p.

210 ° C (dec.).

Analysis for C ₁₃ H ₉ O ₃ N,%:

Calc .: C 68.72 H 3.99 N 6.17 Found: C 68.25 H 4.05 N 6.20

Production 2

The reaction of 2-oxindole with the appropriate acid chloride using the method of Preparation 1 gave the

following additional products:

3- (2-thenoyl) -2-oxindole, mp 189-190 ° C, 17% yield; 3- (2- [2-thienyllacetyl) -2-oxindole, m.p. 191-192.5 ° C, 38% yield; 3- (2-phenoxyacetyl) -2-oxindole, m.p. 135-136 ° C, 42% yield, and

-14- / t »ö yö

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, then 16.8 g of ethyl 3-furoate. The mixture was refluxed for 47h, cooled and then the solvent removed by evaporation in vacuo. The residue was triturated under 200 mL of ether and the solid was collected by filtration and discarded. The filtrate was evaporated in vacuo and the residue triturated under isopropyl alcohol and recovered by filtration. The solid 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 recovered by filtration. This latter solid was recrystallized from acetic acid, then from acetonitrile to give 705 mg of the title compound, m.p.

Analysis for C ₁₃ H ₉ O ₃ N,%:

Calculated: C 68.72 H 3.99 N 6.17

Found .: C 68.72 H 4.14 N 6.14

Production 4

Reacting the appropriate 2-oxindole with the ethyl ester of the required carboxylic acid, essentially according to the procedure of Preparation 3, gave the following compounds:

. 5-chloro-3- (2-thenoyl) -2-oxindole, mp 190.5 to 192 ⁰ C, 36% yield;

. 5-chloro-3- (2-furoyl) -2-oxindole, mp 234-235 ⁰ C, 54% yield;

. 5-chloro-3- (2-phenylacetyl) -2-oxindole, mp 241-243 ⁰ C, 61% yield; . 5-Fluoro-3- (2-furoyl) -2-oxindole, mp 222-224 ⁰ C, 51% yield;

. 5-Fluoro-3- (2-thenoyl) -2-oxindole, mp 200-203 ⁰ C, 26% yield;

. 6-Fluoro-3- (2-furoyl) -2-oxindole, mp 239-242 ⁰ C, 26% yield; and

6-Chloro-5-fluoro-3- (2-thenoyl) -2-oxindole, m.p. 212-215 ° C, 20% yield.

Similarly, using the requisite 2-oxindole and ethyl ester and essentially the method of Preparation 3, the following compounds can be prepared:

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

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

Preparation 5 S-Trifluoroacetyl-O-oxindole

Sodium (3.0 g, 0.13 mol) was dissolved in 150 ml of ethanol, and then 13.3 g (0.10 mol) of 2-oxindole was added at room temperature with stirring. The resulting mixture was cooled in an ice bath and 18.5 g (0.13 mol) of ethyl 2,2,2-trifluoroacetate was added rapidly with stirring. The cooling bath was removed and the reaction mixture heated to the reflux temperature of the solvent and held for 1 h. At this point, the reaction mixture was cooled and the bulk of the solvent removed by evaporation in vacuo. The residue was added to 300 ml of water, to which was then added 100 ml of concentrated hydrochloric acid. The resulting mixture was cooled in an ice bath and then the solid was collected by filtration. The latter solid was dissolved in ethyl acetate and the ethyl acetate solution was washed with saturated sodium chloride and then dried with magnesium sulfate. The dried solution was evaporated in vacuo and the residue was recrystallized from toluene to give 13.2 g of the title compound as yellow crystals, mp 183.5-184.5 ° C.

Analysis for C ₁₀ H ₆ F ₃ NO ₂ ,%:

Calc .: C 52.41 H 2.64 N 6.11

Found: C 52.52 H2. 75 N 6.04

Preparation 6 5-Chloro-2-oxindole

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

The dried solid was then added portionwise over 10 min to a solution of 125.1 g of sodium methylate in 900 ml of absolute ethanol. The resulting solution was heated at reflux for 10 minutes and then concentrated in vacuo to a resinous solid. The resinous solid was dissolved in 400 ml of water and the resulting aqueous solution was decolorized with activated carbon and then poured into a mixture of 11 water and 180 ml of concentrated hydrochloric acid containing ice chips. A tan solid separated, it was collected by filtration and washed thoroughly with water. The solid was dried and then washed with diethyl ether. Finally, it was recrystallized from ethanol to give 48.9g of the title compound, m.p. 193-195 ° C (dec.).

In an analogous manner, 5-methylisatin was converted to 5-methyl-2-oxindole by treatment with hydrazine hydrate followed by sodium ethylate in ethanol. The product melted at 173-174 ° C.

Production 7

4,5-dimethyl-2-oxindole and 5,6-dimethyl-2-oxindole

3,4-dimethylaniline was converted into 3,4-dimethylisonitrosoacetanilide by reaction with chloroformate and hydroxylamine using the method described in "Organic Syntheses", Vol. I, p.327. 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 (m.p. to give 217-218 ° C). Δ. R-Dimethvlisatin was dissolved in 4,5-dimethyl-2-oxindoi, mp. 245.5 to 247.5 ⁰ C) and 5,6-dimethylisatin (mp. 217-218 ° C) too

4,5-dimethylisatin was converted to 4,5-dimethyl-2-oxindole, m.p. 245.5-247.5 ° C, by treatment with hydrazine hydrate, then sodium ethyl acetate in ethanol, essentially according to the procedure of Preparation 6. Similarly, 5,6-dimethylisatin was converted to 5,6-dimethyl-2-oxindole, m.p. 196.5-198 ° ^C , by treatment with hydrazine hydrate, then sodium ethyl acetate in ethanol, essentially according to the procedure of Preparation 6.

Production 8

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

A. S-chloro-isonitrosoacetanilide

To a stirred solution of 113.23 g (0.686 mol) of chloral hydrate in 2 L water was added 419 g (2.95 mol) of sodium sulfate, then a solution prepared from 89.25 g (0.70 mol) of 3-chloroaniline, 62 mL concentrated hydrochloric acid and 500 mL water. It formed a thick precipitate. To the reaction mixture was then added with stirring a solution of 155 g (2.23 mol) of hydroxylamine in 500 ml of water. Stirring was continued and the reaction mixture was slowly warmed and maintained at between 60 and 75 ^° C for about 6 hours, during which time a further liter of water was added to facilitate stirring. The reaction mixture was then cooled and the precipitate removed by filtration. The wet solid was dried to give 136.1 g of 3-chloroisonitrosoacetanilide.

4-chloroisatin and 6-chloroisatin

To 775 ml of concentrated sulfuric acid, preheated to 7O ⁰ C, were added with stirring 136g of 3-chloro-isonitrosoacetanilid at such a rate that the reaction medium was maintained at a temperature between 75 and 85 ⁰ C. When all the solid had been added, the reaction mixture was further 30 min at 9O ⁰ C heated. The reaction mixture was then cooled and poured slowly onto ca. 2 L of ice with stirring. Additional ice was added as needed to keep the temperature below room temperature. A red-orange precipitate formed, which was removed by filtration, washed with water and dried. The resulting solid was slurried in 21% water and then solubilized by the addition of about 700 ml of 3N sodium hydroxide. The solution was filtered and then the pH was adjusted to 8 with concentrated hydrochloric acid. At this point, 120 ml of a mixture of 80 parts of H ₂ O and 20 parts of concentrated hydrochloric acid were added. The solid which separated out was recovered by filtration, washed with water and dried to give 50 g of crude 4-chloroisatin. The filtrate from which the 4-chloroisatin had been removed was further acidified to pH 0 with concentrated hydrochloric acid, whereupon a further precipitate formed. It was collected by filtration, washed with water and dried to give 43 g of crude 6-chloroisatin. The crude 4-chloroisatin was recrystallized from acetic acid to give 43,3g material melting at 258-259 ⁰ C. The crude 6-Clorisatin was recrystallized from acetic acid to give 36,2g material melting at 261-262 ⁰ 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 mL of hydrazine hydrate, and then the reaction was heated at reflux for 2 hours. The reaction mixture was cooled, and the precipitate was recovered by filtration to 43,5g 4-chloro-3-hydrazono-2-oxindole, mp. 235-236 ⁰ C, to yield. To a stirred solution of 22 g of sodium in 450 ml of anhydrous ethanol was added portionwise 43.5 g of 4-chloro-3-hydrazono-2-oxindole, and the resulting solution was refluxed for 30 minutes. The cooled solution was then concentrated to a resin which was dissolved in 400 ml of water and decolorized with charcoal. The resulting solution was poured onto a mixture of 11 water and 45 ml of concentrated hydrochloric acid. The precipitate which formed was recovered by filtration, dried and recrystallized from ethanol to give 22,4g 4-chloro-2-oxindole, mp. 216-218 ⁰ C (dec.) Yield.

D. 6-chloro-2-oxindole

Reacting 36.2 g of 6-chloroisatin with hydrazine hydrate, then with sodium ethylate in ethanol, substantially from C above, afforded 14.2 g of 6-chloro-2-oxindole, m.p. 196-198 ° C.

Production 9

5,6-difluoro-2-oxindole

Reaction of 3,4-difluoroaniline with chloral hydrate and hydroxylamine followed by cyclization with sulfuric acid in a manner analogous to parts A and B of Preparation 8 gave 5,6-difluoroisatin with hydrazine hydrate followed by sodium methylate in ethanol in a manner analogously to Preparation 6 to give the title compound, m.p. 187-19O ⁰ C.

Production 10

5-fluoro-2-oxindole

To a stirred solution of 11.1 g (0.1 mol) of 4-fluoroaniline in 200 ml of dichloromethane at -60 to -65 ° C was added a solution of 10.8 g (0.1 mol) of c-butyl hypochlorite in 25 ml Dropped dichloromethane. It was 10 me. stirred at -60 to -65 ° C, and then a solution of 13.4g (0.1 mol) of ethyl 2- (methylthio) acetate in 25ml of dichloromethane was added dropwise. Stirring was continued for one hour at -6O ⁰ C, and then ° C for one solution of 11.1 g (0.11 mol) of triethylamine in 25 ml dichloromethane was added dropwise at -60 to -65. The cooling bath was removed, and when the reaction mixture had warmed to room temperature, 100 ml of water was added. The phases were separated and the organic phase was washed with saturated sodium chloride solution, dried (over Na ₂ SCu) and evaporated in vacuo. 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 phases were separated and the ether phase was washed with water, then with saturated sodium chloride. The ether phase (dried over Na ₂ SO ₄ ) was evaporated in vacuo to give 17 g of an orange-brown solid which was triturated under isopropyl ether. The solid was then recrystallized from ethanol to give 5,58g ö-fluoro-S-methylthio ^ -oxindol, mp. 151.5 to 152.5 ⁰ C, to yield

Analysis for C ₉ H ₈ ONFS,%: calc .: C 54.80 H 4.09 N 7.10 Found: C 54.74 H 4.11 N 7.11 A sample of the above 5-fluoro-3- methylthio-2-oxindole) 986mg, 5, OmMoI) was added to 2 teaspoons full of Raney Nickel under 50ml

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absolute ethanol, and then the reaction mixture was refluxed for 2 hours. The catalyst was removed by decantation and washed with absolute ethanol. The combined ethanol solutions were evaporated in vacuo and the residue dissolved in dichloromethane. The dichloromethane solution was dried (over Na ₂ SO ₄ ) and evaporated in vacuo to give 475 mg of 5-fluoro-2-oxindole, m.p. 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-oxindole with Raney nickel to give 5 to give -trifluoromethyl-2-oxindole, mp. 189.5 to 190.5 ⁰ C.

Preparation 11 5-Methoxy-2-oxindole

5-Methoxy-2-oxindole was prepared from 4-methoxyaniline in a manner similar to the procedure of Preparation 10, except that the initial chlorination step was carried out using a solution of chlorine gas in dichloromethane instead of t-butyl hypochlorite. The title product melted at 150.5 to 151.5 ⁰ C.

Preparation 12 6-Chloro-5-fluoro-2-oxindole

To 130 ml of toluene were added with stirring 24.0 g (0.165 mol) of 3-chloro-4-fluoroaniline and 13.5 ml (0.166 mol) of pyridine. The resulting solution was cooled to ca. ⁰ ° C and 13.2 ml (0.166 mol) of 2-chloroacetyl chloride were added. The reaction mixture was stirred at room temperature for 5 hours, and then it was extracted twice with 100 ml of 1N hydrochloric acid, followed by 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried with magnesium sulfate and then concentrated in vacuo to give 32.6 g (88% yield) of N- (2-chloroacetyl) -3-chloro-4-fluoroaniline. A 26,63g sample of the N- (2-chloroacetyl) -3-chloro ~ 4-fluoroaniline was thoroughly mixed with 64g of anhydrous aluminum chloride and the mixture 8.5 h at 210-230 ⁰ C heated. The reaction mixture was then poured onto a mixture of ice and 1N hydrochloric acid with stirring. Stirring was continued for 30 minutes and then the solid was collected by filtration (22.0 g). The solid was dissolved in 1: 1 ethyl acetate / hexane and chromatographed on 800 g silica gel. Elution of the column followed by evaporation of the fractions afforded 11.7 g of the N- (2-chloroacetyl) -3-chloro-4-fluoroaniline, followed by 3.0 g of 6-chloro-5-fluoro-2-oxindole. The latter material was recrystallized from toluene to 196-206 ⁰ C to give 1.70 g (7% yield) of the title compound, mp.. Analysis by NMR spectroscopy indicated that the product was contaminated with some 4-chloro-5-fluoro-2-oxindole. A second crop, weighing 0.8g, was obtained.

Production 13

6-fluoro-5-methyl-2-oxindole

An intimate mixture of 11,62g (57,6mMol) N- (2-chloroacetyl) -3-fluoro-4-methylaniline and 30,6g (229,5mMol) of anhydrous aluminum chloride was heated to 210-220 ⁰ C. After 4 h, the reaction mixture was cooled and then added to 100 ml of 1N hydrochloric acid and 50 ml of ice. A tan solid formed, which was collected by filtration and recrystallized from aqueous ethanol. Three yields were obtained, weighing 4.49g, 2.28g and 1.0g, respectively. The yield 1.0g vast was further recrystallized from water to give 280 mg of the title compound, mp. 168.5 to 171 ⁰ C to give.

Production 14

B-Bromo-2-oxindole

To 9.4 g of sodium hydride was added 195 ml of dimethylsulfoxide, followed by the dropwise addition of 22.37 ml of dimethyl malonate. At the end of the addition, the mixture was erwämt to 100 ⁰ C and held for 40 min at this temperature. At this point, 25 g of 1,4-dibromo-2-nitrobenzene were added in one go. The reaction mixture was kept at 100 ^° C. for 4 h and then added to 1.01% 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. The solution (dried over MgSO ₄ ) was evaporated and the residue was recrystallized from ethyl acetate / hexane to give 22.45 g of dimethyl 2- (4-bromo-2-nitrophenyl) malonate.

A solution of 17.4 g dimethyl-2- (4-bromo-2 ^ nitrophenyl) malonate and 4.6 g of lithium chloride in 150 ml of dimethyl sulfoxide was placed in an oil bath at 100 ⁰ C. After 3 h, the reaction mixture was cooled to room temperature and then poured into a mixture of 500 mL of ethyl acetate and 500 mL of saturated sodium chloride solution. The layers were separated and the aqueous layer extracted with more ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried with sodium sulfate and then evaporated in vacuo. The residue was chromatographed with silica gel as the adsorbent and ethyl acetate / hexane mixture as the eluent. This provided 9.4 g of methyl 2- (4-bromo-2-nitrophenyl) acetate.

To a solution of 7.4 g of methyl 2- (4-bromo-2-nitrophenyl) acetate in 75 ml of acetic acid was added 6.1 g of iron powder. The reaction mixture was placed in an oil bath at 100 ⁰ C. After 1 h, 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, dried with sodium sulfate, decolorized with charcoal and evaporated in vacuo. This provided 5.3 g of 6-bromo-2-oxindole as a white, crystalline solid, m.p. 213-214 ° C

Was prepared similarly starting from lAS ^ trichloro-nitrobenzene, 5,6-dichloro-2-oxindole, mp. 209-210 ⁰ C was prepared.

Preparation 15 6-Phenyl-2-oxindole

To 3.46 g (0.072 mol) of sodium hydride was added 50 ml of dimethyl sulfoxide, followed by the dropwise addition of a solution of 8.2 ml (0.072 mol) of dimethyl malonate in 10 ml of dimethyl sulfoxide with stirring. After completion of the addition, stirring was continued for 1 h, and then a solution of 10 g (0.036 mol) of 4-bromo-3-nitrodiphenyl in 50 ml of dimethyl sulfoxide was added. The reaction mixture was heated at 100 ^° C. for 1 h, cooled and poured onto a mixture of ice / water containing 5 g of ammonium chloride. The resulting mixture was extracted with ethyl acetate, and the extracts were washed with sodium chloride solution and dried with magnesium sulfate. Evaporate in vacuo to an oil containing

diphenylyd-malonate, mp 82-83 ° C. A portion (5 g) of the above nitro compound was reduced with hydrogen over a platinum catalyst in a mixture of 50 ml of tetrahydrofuran and 10 ml of methanol at a pressure of about 5 bar (5 kg / cm ² ) to the corresponding amine. The latter compound was refluxed in ethanol for 16 h, and then the product was recovered by evaporation of the solvent and recrystallized from methanol to give 1.1 g of ethyl 6-phenyl-2-oxindole-1-carboxylate, m.p. 115-117 ° C to surrender.

The above ethyl ester (1.0 g) and 100 ml of 6N hydrochloric acid were refluxed for 3 h and allowed to stand at room temperature for 3 days. The solid was collected by filtration and dried to give 700 mg of 6-phenyl-2-oxindole, m.p. 175-176 ° C.

Preparation 16 5-Acetyl-2-oxindole

To 95 ml of carbon disulfide was added 27 g (0.202 mol) of aluminum chloride, followed by the dropwise addition of a solution of 3 ml (0.042 mol) of acetyl chloride in 5 ml of carbon disulfide with stirring. Stirring was continued for 5 minutes and then 4.4 grams (0.033 moles) of 2-oxindole were added. The resulting mixture was refluxed for 4 hours and cooled. The carbon disulfide was removed by decantation and the residue triturated under water and recovered by filtration. After drying, 3.2 g of the title compound were obtained, mp 225-227 ° C.

Reacting the 2-oxindole with benzoyl chloride and with 2-thenoyl chloride in the presence of aluminum chloride essentially as in the above procedure afforded the following compounds:

5-benzoyl-2-oxindole, mp. 203-205 ⁰ C (from CH ₃ OH) and 5- (2-thenoyl) -2-oxindole, mp. 221-213X (from _CH3 CN).

Production 17

5-Bromo-2-oxindole, 5-nitro-2-oxindole and 5-amino-2-oxindole can be prepared as described in Beckett et al., Tetrahedron, 24, 6093 (1968). 5-Amino-2-oxindole can be acylated to give 5-alkanamido-2-oxindole and 5-benzamido-2-oxindole using standard procedures.

5-n-Butyl-2-oxindole can be prepared by reacting 5-n-butylisatin with hydrazine hydrate followed by sodium methylate in ethanol, following the procedure of Preparation 6. 5-n-butylisatin can be prepared from 4-n-butylaniline by treatment with chloral hydrate and hydroxylamine, followed by cyclization with sulfuric acid, following the procedure of Parts A and B of Preparation 8.

5-Ethoxy-2-oxindole can be prepared by converting 3-hydroxy-6-nitrotoluene into 3-ethoxy-6-nitrotoluene by standard methods (potassium carbonate and ethyl iodide in acetone) followed by conversion of 3-ethoxy-6-nitrotoluene into 5-ethoxy-6-oxotoluene. Ethoxy-2-oxindole according to the Beckett et al. (Tetrahedron 24, 6093 [1968]) for the conversion of 3-methoxy-6-nitrotoluene in 5-methoxy-2-oxindole described method. 5-n-butoxy-2-oxindole can be prepared in a similar manner but substituting n-butyl iodide for the ethyl iodide.

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

7-Chloro-2-oxindole can be prepared by the method described in US Pat. No. 3,882,236.

4-Thiomethyl-2-oxindole and 6-thiomethyl-2-oxindole can be prepared by the method described in US Patent No. 4,406,161. 5-n-Buutylthio-2-oxindole can be prepared similarly but replacing 3-methylthioaniline with 4-butylthioaniline.

5,6-Methylenedioxy-2-oxindole can be prepared by the method of McEvoy et al., Journal of Organic Chemistry, 38, 3350 (1973). 5,6-ethylenedioxy-2-oxindole can be prepared in an analogous manner.

6-Fluoro-2-oxindole can be prepared according to Protiva et al. Collection of Czechoslovakian Chemical Communications, 44, 22108 (1979) and U.S. Patent 4160032.

6-Trifluoromethyl-2-oxindole can be prepared according to Simet, Journal of Organic Chemistry, 28, 3580 (1963).

6-Methoxy-2-oxindole can be prepared according to Wieland et al. Chemische Berichte 96,253 (1963).

5-Cyclopropyl-2-oxindole and 5-cycloheptyl-2-oxindole can be prepared by reacting 5-cyclopropyl isatin or 5-cycloheptyl isatin with hydrazine hydrate, followed by sodium methylate in ethanol, following the procedure of Preparation 6. 5-Cyclopropylisatin and 5-cycloheptylisatin 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 Parts A and B of Preparation 8.

Claims (1)

Invention claim: or a pharmaceutically acceptable salt thereof, wherein X is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, trifluoromethyl, alkylsulfinyl of 1 to 4 carbons, alkylsulfonyl of 1 to 4 carbons, nitro, phenyl, alkanoyl of 2 to 4 carbons, benzoyl, thenoyl, alkanamido of 2 to 4 carbons, benzamido or Ν, Ν-dialkylsulfamoyl of 1 to 3 carbons in each of the alkyls; and Y is hydrogen, fluoro, chloro, bromo, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 7 carbons, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons or trifluoromethyl; or X and Y when taken together, a 4,5-, 5,6- or 6,7-iylethylenedioxy group or a 4,5-, 5,6- or 6,7- Ethylenedioxy group; or X and Y taken together and when attached to adjacent carbon atoms, a bivalent radical Z form, wherein Z is selected under and where W is oxygen or sulfur; R ^{1 is} alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, cycloalkenyl of 4 to 7 carbons, phenyl, substituted phenyl, phenylalkyl of 1 to 3 carbons in the alkyl, (substituted phenyl) alkyl of 1 to 3 carbons in the Alkyl, Phenoxyalkylmiti to 3 carbons in the alkyl, (substituted phenoxy) alkyl having 1 to 3 carbons in the alkyl, (thiophenoxy) alkyl having 1 to 3 carbons in the alkyl, naphthyl, bicyclo [2.2.1.] Heptan-2-yl , Bicyclo [2.2.1] hept-5-en-2-yl or (CH ₂ J _n -QR ⁰ is; wherein the substituent on the substituted phenyl, the (sub-phenyl) alkyl and the (substituted phenoxy) alkyl is fluoro, chloro, bromo, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons or trifluoromethyl; η is zero, 1 or 2; Q is a divalent radical derived from a compound selected from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2 , 5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo [b] furan and benzo [b] thiophene; and R ^{0 is} hydrogen or is alkyl of 1 to 3 carbons; and R ^{2 is} alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons, benzyl, furyl, thienyl, pyridyl or a group of Formula. » wherein R ³ and R ^{4 are} each hydrogen, fluorine, chlorine, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons or trifluoromethyl; marked by
(A) Reacting a compound of the formula (IV) with an isocyanate of the formula R ² -N = C = O in an inert solvent or (B) reacting a compound of the formula (V) YO = C-NH-R ² with an activated derivative of a carboxylic acid of the formula R ¹ -C (= O) -OH in an inert solvent. 2. Method according to item 1, wherein X is the 5-position or the 6-position and is hydrogen, fluorine, chlorine, bromine or trifluoromethyl, and Y is hydrogen; R ^{1 is} alkyl of 1 carbon, 3 to 7 carbon cycloalkyl, furyl, thienyl, 1 to 3 carbon phenylalkyl in alkyl, furylmethyl, thienylmethyl or trifluoromethyl; and
R ^{2 is} alkyl of 1 to 6 carbons, cycloalkyl of 3 to 7 carbons or a group of the formula