JPH0437076B2 - - Google Patents

Description

[Detailed description of the invention]

This application relates to new chemical compounds that have value as new pharmaceuticals. More specifically, these new chemical compounds are derivatives of 2-oxindole-1-carboxamides, further substituted by an acyl group at the 3-position. These new chemical compounds are inhibitors of both cyclooxygenase (CO) and lipoxygenase (LO) enzymes. The compounds of the invention are useful as analgesics in mammals, particularly humans, and are useful in ameliorating or eliminating pain, such as pain experienced by patients recovering from surgery or trauma. In addition to being effective for acute administration to relieve pain, the compounds of the invention may also be used in mammals, particularly humans, to reduce the symptoms of chronic diseases, such as the inflammation and pain associated with rheumatoid arthritis and osteoarthritis. It is effective for administration. The present invention provides novel 2-oxindole-1-carboxamide compounds and pharmaceutically acceptable salts thereof represented by the following formula: [Wherein, ,
Alkylsulfinyl having 1 to 4 carbon atoms, 1 carbon number
~4 alkylsulfonyl nitro, nitro, phenyl, alkanoyl having 2 to 4 carbon atoms, benzoyl, thenoyl, alkanamide having 2 to 4 carbon atoms,
benzamide, and each alkyl group has 1 to 3 carbon atoms
selected from the group consisting of N,N-dialkylsulfamoyl, where Y is hydrogen, fluoro, chloro,
Brome, alkyl having 1 to 4 carbon atoms, 3 to 7 carbon atoms
cycloalkyl, alkoxy having 1 to 4 carbon atoms,
selected from the group consisting of alkylthio and trifluoromethyl having 1 to 4 carbon atoms; and when X and Y are taken together, a 4,5-, 5,6- or 6,7-methylenedioxy group or 4,5-,
5,6- or 6,7-ethylenedioxy group; R ¹ is alkyl having 1 to 6 carbon atoms, 3 carbon atoms
cycloalkyl having ~7 carbon atoms, cycloalkenyl having 4 to 7 carbon atoms, phenyl, substituted phenyl, phenylalkyl having an alkyl group having 1 to 3 carbon atoms, (substituted phenyl)alkyl having an alkyl group having 1 to 3 carbon atoms, Phenoxyalkyl in which the alkyl group has 1 to 3 carbon atoms, (substituted phenoxy)alkyl in which the alkyl group has 1 to 3 carbon atoms, (thiophenoxy)alkyl in which the alkyl group has 1 to 3 carbon atoms, naphthyl, bicyclo[ 2.2.1] Heptane-2-yl,
selected from the group consisting of bicyclo[2.2.1]hept-5-en-2-yl and -( _CH2 ) _o -Q- ^R0 , wherein said substituted phenyl, said (substituted phenyl)alkyl and said (substituted phenoxy ) Alkyl substituent is fluoro, bromo, chloro, carbon number 1-4
selected from the group consisting of alkyl, alkoxy having 1 to 4 carbon atoms and trifluoromethyl, where n is 0, 1 or 2, and Q is furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole. , oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5
- 2 based on a compound selected from the group consisting of thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzo[b]furan and benzo[b]thiophene
valence radical, R ⁰ is hydrogen or carbon number 1
~3 alkyl] The compounds of formula (1) are effective as analgesics and as therapeutic agents for inflammatory diseases, such as arthritis. Accordingly, the present invention provides a patient who is a mammal;
Provides a method to specifically elicit an analgesic response in humans, and the formula
A pharmaceutical composition comprising the compound (1) and a pharmaceutically acceptable carrier is provided. A first preferred group of compounds of the invention is in formula (1) where Y is hydrogen and X is 5-chloro, 6-chloro, 5-fluoro, 6-fluoro, 5-trifluoromethyl and 6-trifluoromethyl. It consists of a compound selected from the group consisting of fluoromethyl.
Among this first preferred group, particularly preferred compounds are compounds in which R ¹ is benzyl, 2-furyl, 2-thienyl,
A compound that is (2-furyl)methyl or (2-thienyl)methyl. A second preferred group of compounds of the invention are compounds in formula (1) in which X is selected from the group consisting of 5-chloro and 5-fluoro and Y is selected from the group consisting of 6-chloro and 6-fluoro. It consists of Within this second preferred group, particularly preferred compounds are those in which R ¹ is benzyl, 2-furyl, 2-thienyl, (2-furyl)methyl or (2-thienyl)methyl. Particularly preferred individual compounds of the invention are listed below: 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide (in formula 1, X is 5-chloro, Y is hydrogen, and R ¹ is 2-
5-trifluoromethyl-3-(2-[2-thienyl]acetyl)-2-oxindole-1-
Carboxamide (in formula 1, X is 5-trifluoromethyl, Y is hydrogen, and R ¹ is 2-[2-thienyl]acetyl); 6-fluoro-3-(2-phenylacetyl)-
2-oxindole-1-carboxamide (in formula 1, X is 6-fluoro, Y is hydrogen, and
R ¹ is benzyl); 6-chloro-5-fluoro-3-(2-phenylacetyl)-2-oxindole-1-carboxamide (in formula 1, X is 5-fluoro,
Y is 6-chloro and R ¹ is benzyl); 5,6-difluoro-3-(2-furoyl)-2
-oxindole-1-carboxamide (formula 1
in which X is 5-fluoro, Y is 6-fluoro, and R ¹ is 2-furyl); and 5,6-difluoro-3-(2-thenoyl)-oxindole-1-carboxamide (in formula 1, X is 5-fluoro, Y is 6-fluoro,
R ¹ is 2-thienyl). The compound of the invention has the following formula: (wherein X and Y are as defined above). The analgesic anti-inflammatory compounds of the present invention include X, Y and
R ₁ is a compound of formula as defined above.
The compounds of the invention are therefore derivatives of 2-oxindole, a bicyclic amide of the formula: More specifically, the analgesic anti-inflammatory agent of the present invention has a carboxamide substituent, -C(=O) _-NH2 , at the 1st position of the 2-oxindole, and an acyl substituent, -C (=O)-R ¹ and the benzene nucleus can be further substituted by X and Y groups. X and Y can be monovalent substituents as defined above, but when X and Y are bonded to adjacent carbon atoms of the benzene nucleus, a methylenedioxyl group, -OCH ₂ O- or ethylenedioxy group,
_-OCH2CH2O- can _be represented. Additionally, as will be readily understood by those skilled in the art, the analgesic anti-inflammatory compounds of the present invention (X, Y and R
(as defined above) and enolization is possible, so that the compounds of the invention may exist in one or more tautomeric forms (enol forms). All such tautomers (enol forms) of compounds of formula are considered to be within the scope of this invention. The compound of the formula is: (wherein X and Y are as defined above)
Manufactured from carboxamide compounds. This production method is carried out by bonding a substituent -C(=O)-R ¹ to the 3-position of the 2-oxindole nucleus. The -C(=O) ^-R1 substituent is attached by reacting a compound of the formula with an activated derivative of a carboxylic acid of the formula ^R1 -C(=O)OH. This reaction consists of 1 of the above compounds of formula dissolved in an inert solvent.
A molar equivalent or a slight excess of the formula R ¹ -C(=
It is carried out by reacting an activated derivative of the compound O)OH in the presence of 1 to 4 equivalents of a basic agent. An inert solvent is one that dissolves at least one of the reactants and does not react adversely with either the reactants or the products. However, in practice aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone or dimethylsulfoxide are generally used. Conventional methods are used to activate acids of formula R ¹ -C(=O)OH. Acid halides, symmetric acid anhydrides, such as acid chlorides, i.e. R ¹ -C(=O)-O-C(=
O) ^-1 , a mixture of an acid anhydride and a sterically hindered low molecular weight carboxylic acid, i.e. R1 ^- C(=O)-O
-C(=O)-R ³ (wherein R ³ represents a bulky lower alkyl group such as t-butyl) and a mixture of carboxylic acid-carbonic anhydride, i.e. R ¹ -C(=
O)-O-C(=O) ^-OR4 , where ^R4 represents a low molecular weight alkyl group, are all used. Other examples include N-hydroxyimide esters (such as N-hydroxysuccinimide and N-hydroxyphthalimide esters), 4-nitrophenyl esters, thiol esters (such as thiol phenyl esters) and 2,4,5 -Trichlorophenyl ester etc. are used. moreover,
-C at the 3-position of the 2-oxindole compound of the formula
When attaching a (=O)-R ¹ substituent, when R ¹ is a heteroaryl group (e.g. furyl), the formula R ¹ -C(=O)-O-R ⁴ (formula Sometimes simple alkyl esters of the formula R ₁ (in which R ⁴ represents a low molecular weight alkyl group, such as ethyl)
Used as an acid activated derivative of -C(=O)-OH. A wide variety of basic agents can be used in the reaction of a compound of formula with an activated derivative of an acid of formula R1 ^- C(=O)-OH. However, preferred basic agents are, for example, trimethylamine, triethylamine, tributylamine, N-methylmorpholine,
Tertiary amines such as N-methylpiperidine and 4-(N,N-dimethylamino)-pyridine. The reaction between a compound of formula and an activated derivative of an acid of formula ^R1 -C(=O)-OH is normally carried out at a temperature range of -10 to 25<0>C. The reaction time is usually 30 minutes to several hours. At the end of the reaction, the reaction medium is usually acidified by diluting with water and the product is then recovered by filtration. The product can be purified by standard methods such as recrystallization. 2-oxindole-1-carboxamides of the formula can be prepared by two methods. In the first method, a 2-(2-ureidophenyl)acetic acid compound of formula is cyclized by treatment with trifluoroacetic acid and trifluoroacetic anhydride: i.e. (wherein X and Y are as defined above). Generally, a solution of a compound of formula in trifluoroacetic acid is treated with 2 to 5 molar equivalents of trifluoroacetic anhydride, preferably about 3 molar equivalents, and the resulting solution is refluxed for 0.5 to 3 hours, usually about 1 hour. Heat. The compound of formula is then obtained by removing the solvent. Compounds of formula can be purified, if desired, by standard methods such as recrystallization. Alternatively, this compound can be used directly to form a compound of formula. Compounds of formula can be prepared by basic hydrolysis of compounds of formula: (where X and Y are as defined above,
R ² is a lower alkyl group or a lower cycloalkyl group). Particularly useful groups as R ² are isobutyl and cyclohexyl. Basic hydrolysis of a compound of formula (R ² is isobutyl or cyclohexyl) is typically carried out by treating a compound of formula with a large excess of dilute aqueous potassium hydroxide (e.g., 0.5 N ~3.0N, typically 1.0N). The reaction usually takes place fairly quickly and is usually complete within 1 to 2 hours. The reaction mixture is then acidified (HCl) and the product is isolated by filtration or by solvent extraction using a volatile, water-immiscible organic solvent. A compound of formula can optionally be purified, for example by recrystallization, or directly cyclized,
2-oxindole-1-carboxamide of the formula. Compounds of formula are prepared by reaction of the appropriate 2-oxindole of formula with an acylisocyanate of formula R ² -C(=O)-N=C=O: The conversion of the two reactants into substantially equimolar amounts of the two reactants in refluxing toluene for several hours, e.g.
This can be carried out by heating for a period of time. A second method for preparing 2-oxindole-1-carboxamide compounds of the formula
- Reacting the oxindole with chlorosulfonyl isocyanate to form an intermediate N-chlorosulfonyl-2-oxindole-1-carboxamide of the formula, followed by removal of the chlorosulfonyl group by hydrolysis: The first step in this reaction sequence, the reaction of a suitable 2-oxindole compound of formula with chlorosulfonyl isocyanate, is carried out in a solvent medium inert to the reaction, i.e. chlorosulfonyl isocyanate or N-chlorosulfonyl-2-oxindole of formula It is carried out in a solvent that does not react with any of the 1-carboxamide products. The solvent need not completely dissolve the reactants. Typical solvents are dialkyl ethers such as diethyl ether; cyclic ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, xylene and toluene; chlorinated hydrocarbons such as methylene chloride and chloroform; acetonitrile; It is a mixture of The reaction is generally carried out at temperatures ranging from ambient temperature (about 20°C) to the reflux temperature of the solvent used. Generally, temperatures of 25°C to 110°C are preferred. below 20℃,
For example, temperatures up to -70°C may be used if desired. However, in reality, temperatures below 0°C are
It is not used for economic reasons in terms of the yield of the desired product. The 2-oxindole compound of the formula and chlorosulfonyl isocyanate are generally reacted in molar ratios ranging from equimolar to 30% excess of chlorosulfonyl isocyanate, ie from 1:1 to 1:1.3. Further excess of chlorosulfonyl isocyanate appears to have no benefit;
Not used for economic reasons. The chlorosulfonyl derivative of formula thus produced can optionally be isolated or converted directly to a compound of formula in the same reaction vessel without isolation. Isolation of intermediate chlorosulfonyl compounds of formula is carried out by means well known to those skilled in the art, for example by filtration or evaporation of the solvent. Hydrolysis of a chlorosulfonyl derivative of formula with or without isolation of a compound of formula
This is carried out by treatment with an aqueous acid or base solution. Water alone or an aqueous acid solution is generally preferred as the hydrolyzing agent, even if, for example, the hydrolysis step involves a two-phase system. The rate of hydrolysis is fast enough to overcome reactant solubility problems. However, from a large scale reaction point of view, the use of water alone is more economical than other hydrolysis methods. The use of aqueous organic acids as hydrolyzing agents can sometimes overcome the occurrence of two-phase reaction systems. this is,
This is often the case when aqueous acetic acid solutions are used. The amount of acid is not critical to the hydrolysis step. The amount of acid can range from less than equimolar to more than equimolar. Generally, when an aqueous acid solution is used in the hydrolysis step, about 0.1 per mole of compound of formula
From 1 mole of acid up to 3 moles of acid per mole of compound of formula are used. Acid concentrations from about 1 molar to 6 molar are commonly used for ease of handling. Aqueous acid solutions are often used when the intermediate of the formula is isolated and a single-phase hydrolysis mixture is desired. Representative acids are hydrochloric, sulfuric, nitric, phosphoric, acetic, formic, citric, and benzoic acids. Alternatively to this, compounds of formula
It can also be produced by reacting chlorosulfonyl isocyanate with a compound of the formula followed by hydrolysis. : (wherein X, Y, and R ¹ are as defined above.) The reaction of the chlorosulfonyl isocyanate with the compound of formula and the subsequent hydrolysis step converts the 2-oxindole compound of formula It is carried out in the same manner as described above, where the conversion to the compound and subsequent hydrolysis gave the compound of formula. Compounds of formula are prepared by attachment of -C(=O)-R ¹ to the 3-position of a 2-oxindole compound of the required formula. This acylation reaction is performed by standard means using an alkali metal salt (e.g., sodium ethoxide) in a lower alkanol solvent.
This is carried out by reacting a compound of the formula 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 R 1 -C(=O)-OH. Formulas that may be used: R ¹ -C(=O)OH
A typical derivative of the acid is the acid chloride, formula R ¹ −
C(=O)-O-C(=O)-R ¹ , R ¹ -C(=O)-
OC(=O)-R ³ and R ¹ -C(=O)-O-C(=
O)-OR ⁴ acid anhydride, and formula R ¹ -C(=O)-
Containing simple alkyl esters of OR ⁴ (wherein R ³
and R ⁴ are as defined above). Usually, the expression
Derivatives of acids of R ¹ -C(=O)-OH are used in slight excess; alkoxide salts are usually of the formula R ¹ -C(=
Based on said derivative of the acid O)OH, it is present in an amount of 1 to 2 molar equivalents. The reaction between a derivative of an acid of formula R ¹ -C(=O)OH and a compound of formula is usually 0
Although started at ~25 °C, the reaction mixture was heated to 50-130 °C.
Heating at a temperature in the range of, preferably about 80° C., to complete the reaction is usually carried out. Under these atmospheres, reaction times ranging from several hours (eg 2 hours) to several days (eg 2 days) are usually used.
The reaction mixture is then cooled and diluted with excess water,
acidify. The product of the formula can then be recovered by filtration or standard solvent extraction methods. Some of the 2-oxindole-1-carboxamide compounds of the formula can be conventionally prepared from other compounds of the formula by conversion from one X or Y substituent to a different X or Y substituent. For example,
Compounds of the formula in which is alkylsulfinyl or alkylsulfonyl may be prepared from suitable compounds of the formula in which X is alkylthio by oxidation. This oxidation is carried out by standard methods, for example using a peroxycarboxylic acid such as 3-chloroperbenzoic acid. To convert alkylthio to alkylsulfinyl, use 1.0 to 1.2 molar equivalents of oxidizing agent, and to convert thioalkyl to alkylsulfonyl, use 2.0 to 1.2 molar equivalents of oxidizing agent.
2.4 molar equivalents of oxidizing agent are used. moreover,
Compounds of the formula where X is alkanamide or benzamide may be prepared by acylation of the corresponding compound where X is amino. This is accomplished by acylation with alkanoyl chloride or benzoyl chloride according to standard procedures. The 2-oxindole compound of the formula is prepared by the following known method or a method similar to a known method. Reference: “Rodd’s
Chemistry of Carbon Compounds.” 2nd edition,
Editor S. Coffey. Volume 4 Part A, Elsevier Scientific
Publishing Company, (1973), pp. 448-450;
Gassman et al., Journal of Organic Chemistry,
Volume 42, page 1340 (1977); Wright et al., Journal of
the American Chemical Society, vol. 78, p. 221 (1956); Beckett et al., Tetrahedron, vol. 24;
6093 pages (1968 pages); U.S. Patent No. 3,882,236, no.
No. 4006161 and No. 4160032; Walker, Journal
of the American Chemical Society, 77, 3844
Page (1955); Protiva et al., Collection of
Czechoslovakian Chemical Communications,
Volume 44, page 2108 (1979); McEvoy et al., Journal
of Organic Chemistry, vol. 38, p. 3350 (1973
); Simet, Journal of Organic Chemistry,
Volume 28, page 3580 (1963); Wieland et al.
Chemische Berichte, vol. 96, p. 253 (1963);
and the cited documents listed therein. The compounds of formula are acidic and they form basic salts. All such basic salts are within the scope of this invention and they may be prepared by conventional methods. For example, they can be prepared by contacting acidic and basic substances, usually in stoichiometric ratios, in a suitable aqueous, nonaqueous, or partially aqueous medium, or by interconverting one salt with another. In some cases, it can simply be manufactured. The salt is recovered by filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, if appropriate, or, in the case of aqueous solutions, lyophilization. Typical salts of compounds of formula that may be prepared include primary, secondary, and tertiary amine salts,
They are alkali metal salts and alkaline earth metal salts.
Of particular interest are the sodium, potassium, ammonium, ethanolamine, diethanolamine, and triethanolamine salts. Basic agents suitably used in salt formation belong to both organic and inorganic types, they include ammonia organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, Includes alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides, and alkaline earth metal alkoxides. Typical examples of such bases are: ammonia; n-
Propylamine, n-butylamine, aniline,
Primary amines such as cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucamine; secondary amines such as diethylamine, diethanolamine, N-methylglucamine, N-methylaniline, morpholine, pyrrolidine and piperidine; triethylamine, Triethanolamine, N,N-dimethylaniline, N-
Tertiary amines such as 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. Solvates of the analgesic anti-inflammatory compound of formula also include hydrates, such as hemihydrates and monohydrates.
Included in this invention. Compounds of formula possess analgesic activity. This activity has been demonstrated in mice by showing a reduction in abdominal stretching induced by administration of 2-phenyl-1,4 benzoquinone (PBQ). The method used was adopted for high throughput as described by Siegmmnd et al., proc.
Soc.Exp.Biol.Med., vol. 95, pp. 729-731 (1957
It was based on the method of 2010). 〔moreover,
Milne and Twomey, Agents and Actions, 10 volumes,
See pages 31-37 (1980)]. Mice used in these experiments were Carworth male, (white CF-1)
strain), and weighed 18-20 g. All mice are
Animals were fasted overnight before drug administration and testing. Formula compound in ethanol (5%),
It was dissolved or suspended in a vehicle consisting of emulphor 620 (a compound of polyoxyethylene fatty acid ester, 5%) and saline (90%). This vehicle was also used as a control. Doses are on a logarithmic scale (i.e....0.32, 1.0, 3.2, 10, 32...mg/
Kg), calculated from the weight of the salt and not the weight of the acid, where applicable. The route of administration is oral and the concentration is 10
Variations were made to allow a constant dose of ml/Kg mouse. Efficacy and potency were determined using the method of Milne and Twomey, previously described. Mice were orally treated with the compound and 1 hour later PBQ, 2 mg/Kg, was administered intraperitoneally. Individual mice were then immediately placed into a warmed plastic glass chamber and, starting 5 minutes after PBQ administration, the number of abdominal contractions was recorded over the next 5 minutes. Analgesic protection (MPE%) was calculated based on the degree of abdominal contraction inhibition compared to numbers from concurrent control animals tested on the same day. At least four such measurements (N≧5) provided dose-response data for the development of MPE ₅₀ , ie the best calculation of the dose that reduces abdominal contractions by 50% of the control level. Compounds of formula also have anti-inflammatory activity. This activity was demonstrated in rats by a method based on the standard carrageen-induced rat paw edema test. [Winter et al., Proc.Soc.Exp.Biol.
Med. vol. 111, p. 544, (1963)]. Unanesthetized, adult male white rat (body weight
(150-190g), numbered, weighed, and made an ink mark on the right ankle. Each foot was immersed in mercury exactly up to the ink mark. Mercury is
It was in a glass cylinder connected to a Statham transformer. The output from the transformer is controlled by
through the unit to the microvoltmeter. The amount of mercury eliminated by foot immersion was read. Drugs were given by gavage. One hour after drug administration, edema was induced by injection of 0.05 ml of a 1% solution of carrageen into the marked plantar tissue of the paw. Immediately thereafter, the volume of the injected paw was measured. The increase in paw volume 3 hours after carrageen injection constitutes a respective inflammatory response. The analgesic activity of compounds of formula makes these compounds useful for acute administration to mammals for the treatment of pain, such as post-surgical pain and traumatic pain. moreover,
The compounds of the formula are effective for chronic administration to mammals for the alleviation of symptoms of chronic diseases such as the inflammation of rheumatoid arthritis and the pain associated with degenerative arthritis and other musculoskeletal disorders. A compound of formula or a pharmaceutically acceptable salt thereof, when used as an analgesic or an anti-inflammatory agent, makes it pharmaceutically acceptable to a mammalian subject alone or preferably according to standard pharmaceutical methods. It can be administered as a pharmaceutical composition in combination with a carrier or diluent. Compounds can be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous, and topical administration. In pharmaceutical compositions comprising a compound of formula, or a pharmaceutically acceptable salt thereof, the weight ratio of carrier to active ingredient is usually from 1:4 to 4:1, preferably:
It is in the range of 1:2 to 2:1. However, in the particular case, the ratio chosen will depend on factors such as the solubility of the active ingredient, the expected dose, and the exact oral administration. For oral use of a compound of the formulas of the invention, the compound is administered, for example, in the form of a tablet or capsule, or as an aqueous solution or dispersion. In the case of oral tablets, the carriers commonly used are lactose and cornstarch;
A lubricant such as magnesium stearate is usually added. Effective diluents for oral administration in capsules are lactose and dried cornstarch. When aqueous dispersions are required for oral use, the active ingredient is combined with emulsifying agents and precipitating and dispersing agents. If desired, certain sweetening and/or flavoring agents are added. Intramuscular, intraperitoneal, subcutaneous,
For intravenous and intravenous use, sterile solutions of the active ingredient should normally be prepared and the pH of the solution should be appropriately adjusted and buffered. For intravenous use, total solute concentrations should be adjusted to make the formulation isotonic. When a compound of formula or a salt thereof is used in human subjects, the day is usually determined by the prescribing physician. Additionally, dosage will vary depending on the age, weight, and response of the individual patient, as well as the severity of the patient's symptoms and the efficacy of the particular compound administered. but,
For acute administration to relieve pain, the effective amount in most cases is 0.01-0.5 g, as appropriate. (e.g. every 4-6 hours). For chronic administration, the effective amount will most often be 0.01 to 1.0 g/day and preferably 20 g/day in single or divided doses.
~250mg/day. On the other hand, it may be necessary to use doses outside these limits in some cases. The following examples and preparations are included solely to illustrate the invention in further detail. Example 1 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide
A stirred slurry of 21.1 g (0.1 mol) of chloro-2-oxindole-1-carboxamide and 26.9 g (0.22 mol) of 4-(N,N-dimethylamino)pyridine was cooled to ice bath temperature and then treated with N ,N-
A solution of 16.1 g (0.11 mol) of 2-thenoyl chloride in 50 ml of dimethylformamide was added dropwise. Stirring was continued for about 30 minutes, then the reaction mixture was mixed with 1 part water.
Pour into a mixture of 75 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice bath and the solids were then collected by filtration. The solid was washed with water and then recrystallized from 180 ml of acetic acid to give 26.6 g of the title compound as fluffy yellow crystals (mp 230°C, decomposed). A sample of the standard compound obtained from a similar experiment yielded the following results on elemental analysis. Analytical value: Calculated as C ₁₄ H ₉ ClN ₂ O ₃ S C, 52.42; H, 2.83; N, 8.74% Experimental value: C, 52.22; H, 2.81; N, 8.53% Example 2 According to the method of Example 1 Suitable 2-oxindole-1-carboxamides and formula R ₁ − according to practice
Reaction of CO-Cl with the appropriate acid chloride gave the following compounds:

[Table] Example 3 5-Chloro-3-acetyl-2-oxindole-1-carboxamide In 15 ml of N,N-dimethylformamide, 842 mg (4.0 mmol) of 5-chloro-2-oxindole-1-carboxamide and 4 -(N,N-dimethylformamino)pyridine 1.08 g (8.8 mmol)
The stirred slurry was cooled to ice bath temperature and then a solution of 449 mg (4.4 mmol) of acetic anhydride dissolved in 5 ml of N,N-dimethylformamide was added dropwise. Continue stirring for approximately 30 minutes, then pour the reaction mixture into 75 ml of water.
and 3 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice bath and the solids were then collected by filtration. The solid is recrystallized from acetic acid to give fluffy pale pink crystals (melting point 237.5℃ decomposed)600
I got mg. Analytical value: Calculated as C ₁₁ H ₉ ClN ₂ O ₃ C, 52.29; H, 3.59; N, 11.09% Experimental value: C, 52.08; H, 3.63; N, 11.04% Example 4 Experimental example 1 or Experimental example 3 By reaction of the appropriate 2-oxindole-1-carboxamide with the activated derivative of the required carboxylic acid of formula R ₁ -CO-OH, following the method in practice, the following compounds were obtained:

【table】

【table】

【table】

【table】

Table: Example 5 Reaction of 2-thenoyl chloride with 2-furoyl chloride using the method of Example 1 gave the following compounds, respectively: 5,6-methylenedioxy-3-(2 -thenoyl)-2-oxindole-1-carboxamide (melting point 215-217°C, decomposed) and 5,6-methylenedioxy-3-(2-furoyl)-2-oxindole-1-carboxamide (melting point 234-217°C, decomposition) 235
C, decomposition) Example 6 Reaction of the appropriate acid chloride with the required 2-oxindole-1-carboxamide using the method of Example 1 gives the following compound: X and Y ^* R ¹ 4-CH ₂ -CH ₂ -CH ₂ -5 2-furyl 5-CH ₂ -CH ₂ -CH ₂ -6 2-thienyl 6-CH ₂ -CH ₂ -CH ₂ -CH ₂ - 7
2-Frill 5-CH=CH-CH=CH-6
(2-Thienyl)-methyl 5-O-CH ₂ -CH ₂ -6 2-thienyl 5-CH ₂ CH ₂ -O-6 2-furyl 5-S-CH ₂ -CH ₂ -6 2-thienyl 5- O-CH=CH-6 2-furyl 5-S-CH=CH-6 (2-thienyl)-methyl 5-CH=CH-S-6 2-furyl *In this column, the number on the left side of the formula is The point of addition of the end of the formula to the 2-oxindole nucleus is shown, and the number on the right side of the formula shows the point of addition of the end of the formula to the 2-oxindole nucleus. Example 7 5-Chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide 429.9 g (2.04 mol) of 5-chloro-2-oxindole-1-carboxamide in 4 ml of N,N-dimethylformamide 4 to the stirred slurry
-(N,N-dimethylamino)pyridine 547.9g
(4.48 mol) was added and the mixture was then cooled to 8°C. To this mixture was added 328 mg of thenoyl chloride dissolved in 800 ml of N,N-dimethylformamide over a period of 30 minutes, maintaining the temperature between 8 and 15°C.
(2.23 mol) was added with stirring. Stirring was continued for 30 minutes and then the reaction mixture was poured into a mixture of 510 ml of concentrated hydrochloric acid and 12 ml of water with stirring. Stirring was continued for 2 hours, then the solid was collected by filtration and washed with water and then methanol. The solid was dried to obtain 675.6 g of the title compound. Part of the above title compound (673.5g, 2.1mol)
was added to methanol 13 and the mixture was heated to reflux. Ethanolamine to reflux mixture
136 g (2.22 moles) were added. 50% of the resulting solution
After cooling to 0.degree. C., 65 g of decolorizing charcoal were added and the solution was then heated again to reflux temperature and maintained at that temperature for 1 hour. The hot solution was passed through Svpercel (diatomaceous earth) and the liquid was cooled to 40°C. liquid for 30 minutes,
Gradually, 392 ml of concentrated hydrochloric acid was added. The mixture was stirred for 30 minutes and cooled to 20-23°C, then the solid was collected by filtration and washed with methanol. Dry the solid to give the title compound (mp 229-231.5°C, decomposed)
Obtained 589g. Example 8 Ethanolamine salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide 5-chloro-3-(2-thenoyl)-2-oxindole in 25-30 ml of diisopropyl alcohol - Heat a slurry of 321 mg (1.0 mmol) of 1-carboxamide to boiling, then dissolve ethanolamine in 1 ml of diisopropyl alcohol.
67 mg of solution was added. This resulted in a yellow solution within a few minutes. The solution was boiled to 12-13 ml and then cooled. The precipitated solid was collected by filtration to obtain 255 mg of the title compound as yellow crystals (melting point 165.5-167°C, slightly decomposed). Analytical value: Calculated _{as C16H16ClN3O4S} C, 50.32; H, 4.22; _N , 11.00% Experimental value: C, 50.52; H, 4.44; N, 10.88% Example 9 5 _- chloro-3- Sodium salt of (2-thenoyl)-2-oxindole-1-carboxamide Part A Stir 20 g (62.4 mmol) of 5-chloro-3-(2-tenoyl)-2-oxindole-1-carboxamide in 400 ml of methanol. Add 4.14 ml (68.6 mmol) of ethanolamine to the slurry.
was added dropwise at room temperature. A solution of 6.74 g (124.7 mmol) of sodium methoxide in methanol was added to the clear solution thus obtained.
The resulting mixture was heated to about 90°C, then cooled and stirred overnight. The solid formed was collected by filtration and dried overnight at room temperature under high vacuum;
18.12 g of crude product was obtained. The crude product was recrystallized from methanol-isopropanol to give 5-chloro-3-(2-thenoyl)-2-oxindole-
1.73 g of a first product, sodium salt of 1-carboxamide hydrate, and 10.36 g of a second product were obtained. Both products melted at 236-238°C. Analysis value:

Table: The remainder of the first product was redried. This gave the anhydrous sodium salt of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide (melting point 237-238°C). Analytical values: C ₁₄ H ₈ ClN ₂ O ₃ SNa Calculated as first re-dried Experimental value of product C 48.92 48.23 H 2.64 2.81 N 8.15 7.89 Part B 5-chloro-3-(2-thenoyl in 400 ml methanol) )-2-oxindole-1-carboxamide (20 g, 62.4 mmol) was added dropwise to the stirred slurry, and 4.14 ml (68.6 mmol) of ethanolamine was added at room temperature. 6.74 g of powdered sodium methoxide were added to the clear solution thus obtained and the mixture was stirred overnight. The solid that formed was collected by filtration and dried under high vacuum overnight. This gave a hemihydrate of 5-chloro-3-(2-thenoyl)-2-oxindole-1-carboxamide (melting point 238-239°C). Analytical value: Calculated as C ₁₄ H ₈ ClN ₂ O ₃ SNa・0.5H ₂ O Experimental value C 47.67 47.72 H 2.85 2.73 N 7.94 7.70 Example 10 5-chloro-3-(2-thenoyl)-2-oxindole- Potassium Salt of 1-Carboxamide The procedure of Part B of Example 9 was repeated except that a 7.00 g solution of potassium hydroxide in methanol was used instead of powdered sodium methoxide. This allows 5-chloro-3-(2-
Potassium salt of (2-oxindole-1-carboxamide) hydrate (melting point 214-216
°C) was obtained. Analytical value: Calculated as C ₁₄ H ₈ ClN ₂ O ₃ SK・H ₂ O Experimental value C 44.30 44.29 H 2.93 2.67 N 7.41 7.22 Example 11 5-chloro-3-(2-thenoyl)-2-oxindole-1 - Ammonium Salt of Carboxamide The title salt was prepared by actually following the method of Example 9, Part B, using a solution of ammonia in methanol instead of powdered sodium methoxide. This allows the title salt anhydride (melting point
203-204°C). Analytical value: Calculated as C ₁₄ H ₈ ClN ₂ SO ₃・NH ₄ Experimental value C 49.64 49.75 H 3.86 3.53 N 12.41 12.20 Reference example 1 2-oxindole-1-carboxamide 2-(2- 630 mg (3.0 mmol) of trifluoroacetic anhydride in a solution of 194 mg (1.0 mmol) acetic acid (ureidophenyl)
was added and the mixture was then heated under reflux for about 1 hour. The reaction mixture was cooled and the solvent was removed by vacuum evaporation. The residue was dissolved in saturated sodium bicarbonate solution 5
It was triturated under ~8 ml and the remaining undissolved material was collected by filtration. The solid thus obtained was recrystallized from ethanol to obtain 61 mg of the title compound (melting point: 179-180°C, slightly decomposed) as colorless needle-like crystals. Analytical value: Calculated _{as C9H18N2O2} C, 61.36; H, 4.58; N, 15.91% Experimental value: C, 61.40 _; H, 4.80; N, 15.77% Reference example 2 5 _- chloro-2-oxy Indole-1-carboxamide Trifluoroacetic acid 75 according to the method of Reference Example 1
8.0 g of trifluoroacetic anhydride (0.063
80 mg of the title compound (melting point 211° C. dec. Obtained. Analytical value: Calculated _{as C9H7ClN2O2} C, 51.32; H, 3.35; N, 13.30% Experimental value: C, 51.37 _; H, 3.37; N, 13.53% Reference example 3 2 _- oxindole-1- Carboxamide chlorosulfonyl isocyanate (1.20g,
2-oxindole (0.94 g, 7.1 mmol) mixed in ether (30 ml)
and the compound was stirred at room temperature for 20 hours. The ether was removed under vacuum and the residue was dissolved in water (10
ml) and 1N HCl (10 ml). Ethyl acetate (125ml) was added and the mixture was stirred for 1 hour. The ethyl acetate phase was separated, washed with 1N HCl (1 x 50ml) and brine (2 x 100ml) and dried ( _MgSO4 ). Concentration yielded 0.97 g (77%) of crude product. Recrystallization from ethanol gave 0.18 g of the title product (mp 177-179°C). Reference Example 4 2-oxindole-1-carboxamide Chlorosulfonyl isocyanate (7.47 g,
52.8 mmol) was added. Hydrogen chloride evaporated immediately. The mixture was stirred under reflux for 15 minutes, then it was cooled to room temperature. Water (50ml) was added to the cooled mixture (some HCl evaporated first) and the mixture was then stirred for 1.5 hours. The solid formed was collected by filtration and dried. (4.10g)
The liquid was extracted with ethyl acetate (100 ml), the resulting extract was washed with brine (2 x 100 ml), and (MgSO ₄ )
dried with. Evaporation of the extract under reduced pressure gave 4.16 g of solid. The combined solid was recrystallized by dissolving it in acetonitrile (200ml) and then concentrating the solution to about 75ml under reduced pressure. A small amount of separated amorphous material was separated.
The liquid was decolorized, concentrated under reduced pressure to a volume of approximately 50 ml, and then crystallized. This gave the title compound as dark red crystals which were filtered and dried. (3.0g: 38%) Reference Example 5 6-Fluoro-5-methyl-2-oxindole-1-carboxamide Following the method of Reference Example 4, the title compound was dissolved in 6-fluoro-5-6-fluoro-5-methyl in toluene (30ml). Methyl-2-
Prepared from oxindole (1.0 g, 6.0 mmol) and chlorosulfonyl isocyanate (1.03 g, 7.3 mmol). Water (5 ml) was used for the hydrolysis step. Yield = 0.58g, 46%, melting point 200-203℃ Analytical value: Calculated as C ₁₀ H ₉ N ₂ O ₂ F C, 57.69; H, 4.36; N, 13.46% Experimental value: C, 57.02; H, 4.41; N, 12.85% A sample of the chlorosulfonyl intermediate was taken before hydrolysis and subjected to mass spectrometry analysis for accurate mass determination: C ₁₀ H ₈ N ₂ O ₄ SCl: 307.9848 Reference Example 6 2-oxindole -1-Carboxamide To a slurry of 2-oxindole (13.3g, 0.10mol) in toluene (150ml) was added chlorosulfonylisocyanate (15.6g, 0.11mol) and the reaction mixture was heated in a steam bath for 10 minutes. (about 3
A clear solution formed within minutes and a precipitate formed almost immediately. ) The reaction mixture was cooled in an ice bath for 30 minutes, then the solid was separated and air-dried. The chlorosulfonyl intermediate thus obtained was added to a 2:1 mixture (240 ml) of acetic acid and water;
The resulting slurry was heated in a steam bath for 10 minutes. It was cooled in an ice bath and the yellow-white solid formed was separated and air-dried. By concentrating the mother liquor to a slurry and filtering it, further product is obtained.
Obtained 12g. Combined solids in ethanol approx.
Recrystallized from ml; Yield = 11.4 g (65%) Reference Example 7 Substituted 2-oxindole-1-carboxamide Using the method of Reference Example 6, an appropriate 2-oxindole and chlorosulfonyl isocyanate were reacted. , and then hydrolyzed to produce the following compound.

[Table] Reference Example 8 5,6-Methylenedioxy-2-oxindole-1-carboxamide Using the method of Reference Example 6, 5,6-methylenedioxy-2-oxindole and chlorosulfonyl isocyanate were reacted. , then by hydrolysis, 5,6-methylenedioxy-2-
Oxindole-1-carboxamide was produced. The product is heated to 237-238℃ after recrystallization from acetic acid.
It melted. (Decomposition) Reference Example 9 Using the method of Reference Example 6, the following tricyclic compound is prepared by reacting an appropriate 2-oxindole with chlorosulfonyl isocyanate and then hydrolyzing it: X and Y* 4-CH ₂ -CH ₂ -CH ₂ -5 5-CH ₂ -CH ₂ -CH ₂ -6 6-CH ₂ -CH ₂ -CH 2 _{-CH 2} -7 5-CH=CH-CH =CH-6 5-O-CH ₂ -CH ₂ -6 5-CH ₂ -CH ₂ -O-6 5-S-CH ₂ -CH ₂ -6 5-O-CH=CH-6 5-S- CH=CH-6 5-CH=CH-S-6 *In this column, the number on the left side of the formula indicates the addition point of the end of the formula to the 2-oxindole nucleus, and the number on the right side of the formula , indicating the addition of the formula end to the 2-oxindole nucleus. Reference example 10 6-methylthio-2-oxindole-1-
Carboxamide chlorosulfonyl isocyanate (5.66g,
0.04 mol) at 5° to 10°C, acetonitrile (60
ml) of 6-methylthio-2-oxindole (6.0 g, 0.033 mol). The reaction mixture was stirred for 1 hour. Water (100ml) was then added and stirring continued for 10 minutes. The aqueous solution was extracted with ethyl acetate (600ml), then the extract was effectively washed with water and brine, dried ( _MgSO4 ) and evaporated under reduced pressure to give a gray solid, which Recrystallized from acetonitrile. Yield = 3.0g. A further 0.71 g of product was obtained from the mother liquor. Total yield = 3.71g
(50.6%); Melting point 176-179°C Reference example 11 5,6-dimethoxy-2-oxindole-
1-Carboxamide According to the method of Reference Example 10, the title mixture was diluted with 5,6
-dimethoxy-2-oxindole (8.0g,
0.042 mol), chlorosulfonyl isocyanate (7.08 g, 0.05 mol) and acetonitrile (75 ml)
Manufactured from. The crude product obtained on evaporation of the ethyl acetate extract was recrystallized from acetonitrile/acetic acid (1:1). Yield = 60.2g (60
%); melting point 206.5-209°C Reference Example 12 6-Trifluoromethyl-2-oxindole-1-carboxamide Slurry of 6-trifluoromethyl-2-oxindole (8.0 g, 0.04 mol) in acetonitrile (80 ml) Hechlorosulfonyl isocyanate (6.655 g, 0.047 mol) was added and the mixture was stirred for 45 minutes. Water (100ml) was then added and the aqueous mixture was stirred for 1 hour. Separate the formed precipitate,
Recrystallization from acetonitrile gave the title product
0.92g was obtained. Further product was obtained by extracting the aqueous reaction mixture with ethyl acetate (300ml), then drying the extract over MgSO ₄ and evaporating it under reduced pressure. Further product 2.2 by recrystallization from acetonitrile
I got g. Further product (1.85 g) was recovered by combining the mother liquors from the acetonitrile recrystallization and concentrating them under reduced pressure. Total yield = 4.97 g (51%); melting point 207.5-210°C Reference Example 13 The following compound was obtained by repeating the method of Reference Example 12, except that an appropriately substituted 2-oxindole was used.

[Table] Reference example 14 6-phenyl-2-oxindole-1-carboxamide 6-phenyl-2-oxindole in a mixture of 100 ml of toluene and 25 ml of tetrahydrofuran.
4.5 g (21.5 mmol) with stirring at 5°C.
2.2 ml (25.88 mmol) of chlorosulfonyl isocyanate were added. Stirring was continued for 1 hour at 0-5°C, then 100ml of water was added. The solid was collected by filtration and added to a mixture of 40ml glacial acetic acid and 80ml water. The resulting mixture was heated at 100°C for 1 hour, cooled,
passed. Dry the residue to obtain the title compound (melting point
188-189°C) 3.1g was obtained. Reference example 15 5-benzoyl-2-oxindole-1-
Carboxamide 5-benzoyl-2-oxindole 10.1g
(42 mmol), chlorosulfonyl isocyanate
4.4 ml (51 mmol) and tetrahydrofuran 300
ml mixture was stirred for 6 hours at room temperature, then the solvent was removed by vacuum evaporation. The residue was added to 150 ml of glacial acetic acid and 300 ml of water and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was cooled and the supernatant liquid was removed by decantation. The remaining gummy residue was triturated under acetonitrile to give a solid, which was collected by filtration and recrystallized from a 1:1 mixture of n-propanol and acetonitrile. This gave 4.1 g of the title compound as a solid (melting point 210-211°C). Reference Example 16 Actually, according to the method of Reference Example 15, 5-acetyl-2-oxindole and 5-(2-thenoyl)
By reacting -2-oxindole with chlorosulfonyl isocyanate and then hydrolyzing with aqueous acetic acid, the following compounds were obtained, respectively: 5-acetyl-2-oxindole-1-carboxamide, 34% yield. (melting point 225℃ decomposition)
(from CH ₃ CN) and 5-(2-thenoyl)-2-oxindole-
1-carboxamide, 51% yield (melting point 200℃ decomposition)
(From CH ₃ OH/CH ₃ CN) Reference example 17 5-acetamido-2-oxindole-1
-carboxamide 5-amino-2-oxindole-1-carboxamide 0.5 g (2.6 mmol) and 4-(N,
A slurry of 0.35 g of N-dimethylamino)pyridine was stirred at 10°C, then 0.20 ml of acetyl chloride (2.8
mmol) was added. Stirring was continued for 20 minutes at −10° C. and 15 minutes at room temperature, then 20 ml of 1N hydrochloric acid were added.
The solid was collected by filtration and dried to give 0.20 g of the title compound as a cream colored solid. By substituting butanoyl chloride for acetyl chloride in the above method, 5-butanamido-2-oxindole-1-carboxamide is prepared. Reference example 18 5-benzamide-2-oxindole-1
-Carboxamide 5-Amino-2-oxindole-1- by benzoyl chloride according to the method of Reference Example 17 in practice.
Acylation of the carboxamide yields the title compound as a cream solid (melting point 223-226°C).
Got 90%. Reference Example 19 4-Methylsulfonyl-2-oxindole-1-carboxamide 4-Methylthio-2-oxindole-1 was prepared with 2.4 molar equivalents of 3-chloroperbenzoic acid in tetrahydrofuran at room temperature according to the title method. The title compound was prepared by oxidizing 2.5 g of 1-carboxamide. The product was isolated as a solid. (0.81 g, 28% yield) Reference Example 20 6-Methylsulfonyl-2-oxindole-1-carboxamide 6-Methylsulfonyl-2-oxindole-1-carboxamide 6- Oxidation of 1.25 g of methylthio-2-oxindole-1-carboxamide yields 1.13 g of the title compound contaminated with the corresponding sulfoxide.
I got it. Reference Example 21 4-Methylsulfinyl-2-oxindole-1-carboxamide oxidation of 4-methylthio-2-oxindole-1-carboxamide with 1.1 molar equivalents of 3-chloroperbenzoic acid in tetrahydrofuran at about 0°C. , title compound (melting point 198.5-200℃)
0.9g was obtained. In the same manner, 6-methylthio-2-oxindole-1-carboxamide was oxidized with 3-chloroperbenzoic acid to give 6-methylsulfinyl-2-oxindole-1-carboxamide. Reference example 22 3-(2-furoyl)-6-fluoro-2-oxindole-1-carboxamide Actually, according to the method of Reference example 10, 3-(2-furoyl)-6-fluoro-2-oxindole (0.30 g, 1.2 mmol), chlorosulfonyl isocyanate (0.20 g, 1.4 mmol), acetonitrile (15 ml) and water (10 ml) to prepare the title compound in 17% yield. Yield = 60 mg, melting point 231-235°C Reference example 23 3-(2-Thenoyl)-5-chloro-2-oxindole-1-carboxamide 3-(2-Thenoyl)-5-chloro-2 in 15 ml of anhydrous acetonitrile -oxindole 1.5g
To the stirred slurry of (5.4 mmol) was added 0.52 ml (5.9 mmol) of chlorosulfonyl isocyanate and the reaction mixture was stirred at room temperature for 2 hours. A small sample was removed, filtered and evaporated under vacuum to give N-chlorosulfonyl-3-(2-thenoyl)
A small sample of -5-chloro-2-oxindole-1-carboxamide (melting point 166-169°C) was obtained. 30 ml of water was slowly added to the remainder of the reaction mixture with stirring and stirring was continued for 1 hour. The reaction mixture was then poured into 50 ml of 1N hydrochloric acid containing ice chips and the resulting mixture was stirred for 20 minutes. The yellow solid was collected by filtration, washed with water and diisopropyl ether, and recrystallized from glacial acetic acid.
First product of the title compound (melting point 213-215°C) 200
I got mg. Further yellow solid precipitated from the mother liquor from which the first product was recovered. The latter solid was collected by filtration to give 470 mg of a second product of the title compound. The second product was recrystallized from glacial acetic acid, combined with the first product, and recrystallized from glacial acetic acid. This yielded 280 mg of the title compound (melting point 232-234°C)
I got it. Example 14 CA Winter et al.
Proceedings of the Society for Experimental
Biology and Medicine, Vol.111, p.544 (1962)
The following 3-acyl-2-oxindole-1-carboxamide derivatives were tested for anti-inflammatory activity in rats using the standard carrageenan-induced rat hindlimb edema test described in . The following compounds were administered orally by gavage at the dosage levels indicated below, and the results obtained were expressed as % inhibition of edema formation by each test compound as compared to the control (i.e., vehicle alone without compound).

【table】

【table】

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【table】

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【table】

[Table] Note that the product of Example 1, 5-chloro-
3-(2-Thenoyl)-2-oxindole-1
-carboxamide (where X=5-Cl, Y=H,
R ¹ = 2-thienyl) ED ₅₀ of CAWinter et al.
Proceedings of the Society fir Experimental
Biology and Medicine, Vol.111, p544 (1962)
According to the rat hindlimb edema test, 125mg/Kg (oral)
It was hot. This compound was obtained by oral administration to male rats.
_LD50 was 300-500 mg/Kg. This compound was obtained by oral administration to female rats.
_LD50 was 500-750mg/Kg. Production Example 1 2-(2-ureidophenyl)acetic acid A slurry of 2.9 g (0.01 mol) of N-cyclohexylcarbonyl-2-oxindole-1-carboxamide added to 50 ml of 1N potassium hydroxide solution was stirred at room temperature for about 30 minutes. During this time the solids were allowed to dissolve. At this time, the reaction mixture was acidified with concentrated hydrochloric acid while cooling on ice and then extracted with ethyl acetate. The extracts were washed with saturated sodium chloride solution, dried (Na ₂ SO ₄ ) and evaporated in vacuo to give an oily solid. This oily solid was washed with diisopropyl ether and then recrystallized from ethanol to give 70 mg of the title compound (mp 174.5°C, decomposed). Analytical value: Calculated as C ₆ H ₁₀ N ₂ O ₃ C, 55.66; H, 5.19; N, 14.43% Experimental value: C, 55.37; H, 5.33; N, 14.38% Production example 2 2-(5-chloro- 2-ureidophenyl)acetic acid N-isobutyryl-5-chloro-2-oxindole-1-
Hydrolysis of the carboxamide with 1N potassium hydroxide produced the title compound in 43% yield. After the hydrolysis was completed and the reaction mixture was acidified, the product precipitated. This was collected by filtration and recrystallized from ethanol to give the title compound as colorless crystals, melting point 187.5°C (decomposed). Analytical value: _{Calculated as C9H9ClN2O3} C, 47.28; H, 3.97; N, 12.26% Experimental value: C, 47.11; H, 3.98; N, 12.20 _% Production example 3 N-cyclohexylcarbonyl-2- Oxindole-1-carboxamide To a stirred slurry of 20.0 g (0.15 mol) of 2-oxindole in 150 ml of toluene was added 29.6 g (0.19 mol) of cyclohexyl isocyanate. The mixture was heated under reflux for about 30 minutes, then the solid was collected by cooling to room temperature and recrystallized from ethanol. This gave 26.5 g of the title compound as fluffy colorless crystals (melting point, 144.5-145.5°C). Analytical value: Calculated as C ₁₆ H ₁₈ N ₂ O ₃ C, 67.11; H, 6.34; N, 9.79% Experimental value: C, 67.00; H, 6.36; N, 9.77% Production example 4 N-isobutyryl-5-chloro -2-Oxindole-1-carboxamide To a stirred slurry of 8.38 g (0.05 mol) of 5-chloro-2-oxindole in 250 ml of toluene was added 6.79 g (0.06 mol) of isobutyryl isocyanate, and the reaction mixture was stirred for 5.5 hours. Heat under reflux. The reaction mixture was cooled to room temperature, a small amount of insoluble material was removed, and then the solvent was removed by vacuum evaporation. Recrystallization of the residue from acetonitrile (with the aid of decolorizing charcoal) and then from ethanol gave 3.23 g of the title compound as pink crystals (mp 129-141°C). Analytical value: Calculated _{as C13H13ClN2O3} C, 55.62; H, 4.67; _N , 9.98% Experimental value: C, 55.53; H, 4.48; N, 9.97% Production example 5 5 _- chloro-2-oxy Indole 5-chloroisatin 100g in 930ml ethanol
40 ml (0.826 mol) of hydrazine hydrate was added to a stirred slurry of (0.55 mol) to yield a red solution. The solution was heated under reflux for 3.5 hours, during which time a precipitate separated out. The reaction mixture was stirred overnight, then the precipitate was collected by filtration to yield 5-chloro-3-hydrazonol-2-oxindole as a yellow solid, which was dried in a vacuum oven. The dried solid weighed 105.4g. The dried solids were then soaked in absolute ethanol for 10 min.
Add portions to a solution of 125.1 g of sodium methoxide in 900 ml. The resulting solution was heated under reflux for 10 minutes, then it was concentrated under vacuum to a gummy solid. The gummy solid was dissolved in 400 ml of water, the aqueous solution thus obtained was decolorized with activated carbon, and then mixed with 1 part of water and 180 parts of concentrated hydrochloric acid containing ice chips.
ml of the mixture. A yellow and colored solid precipitates,
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 the title compound (melting point 193-195 °C decomposed)
48.9g was obtained. By the same method, 5-methylisatin was converted to 5-methyl-2- by treatment with hydrazine hydrate followed by sodium ethoxide in ethanol.
Converted to oxindole. The product is 173~
It melted at 174°C. Production Example 6 4,5-dimethyl-2-oxindole and 5,6-dimethyl-2-oxindole "Organic Syntheses", Collective Volume
1, page 327, chloral hydrate and hydroxylamine were reacted to convert 3,4-dimethylanilyl to 3,4-dimethylisonitrosoacetanilide.
Baker et al., Journal of Organic Chemistry, 17
Vol., p. 149, (1952), 3,4-dimethyl-isonitrosoacetanilide was crystallized from sulfuric acid to obtain 4,5-dimethylisatin (melting point
225-226°C) and 5,6-dimethylisatin (melting point 217-218°C) were obtained. In fact, following the method of Preparation Example 5, 4,5-dimethylisatin was converted to 4,5-dimethyl-2-oxindole by treatment with hydrazine hydrate and then sodium ethoxide in ethanol. (melting point 245.5°-247.5°C). In a similar manner, by treatment with hydrazine hydrate and then sodium ethoxide in ethanol, 5,
6-dimethylisatin to 5,6-dimethyl-2-
Converted to oxindole (melting point 196.5-198°C). Production Example 7 4-Chloro-2-oxindole and 6-chloro-2-oxindole A 3-chloro-isonitoloacetanilide 419 g of sodium sulfate was added to a stirred solution of 113.23 g (0.686 mol) of chloral hydrate in 2 parts of water.
(2.95 mol), then 89.25 g of 3-chloroaniline
(0.70 mol), a solution prepared from 62 ml of concentrated hydrochloric acid and 500 ml of water was added. A thick precipitate formed. Then add to the reaction mixture
15 g (2.23 moles) of hydroxylamine in 500 ml of water
was added with stirring. Continue stirring and gradually warm the reaction mixture, allowing it to rise for about 6 hours.
It was maintained between ~75°C, during which an additional portion of water was added to facilitate stirring. The reaction mixture was then cooled and the precipitate was collected by filtration. The wet solid was dried to yield 136.1 g of 3-chloro-isonitrosoacetanilide. B 4-chloroisatin and 6-chloroisatin 3-chloro-isonitrosoacetanilide is added to 775 ml of concentrated sulfuric acid preheated to 70°C at a rate such that the reaction medium is maintained at a temperature between 75 and 85°C.
136g was added with stirring. When all solids were added, the reaction mixture was heated at 90° C. for an additional 30 minutes. The reaction mixture was then cooled and poured slowly into approximately 2 lbs. of ice with stirring. Additional ice was added as needed to maintain the temperature below room temperature. The orange-red precipitate formed was collected by filtration, washed with water,
Dry. The resulting solid was slurried in 2 ml of water, then approximately 700 ml of 3N sodium hydroxide was added to dissolve it. The solution was filtered and then adjusted to pH 8 with concentrated hydrochloric acid. At this point, 120 ml of a mixture of 80 parts water and 20 parts concentrated hydrochloric acid was added. The precipitated solid was collected by filtration, washed with water and dried to obtain 50 g of crude 4-chloroisatin. The liquid from which 4-chloroisatin was recovered was further adjusted to pH using concentrated hydrochloric acid.
0, after which further precipitate formed.
It was collected by filtration, washed with water and dried to obtain 43 g of crude 6-chloroisatin. Crude 4-chloroisatin was recrystallized from acetic acid to yield 43.3 g of material melting at 258-259°C. Crude 6-chloroisatin was recrystallized from acetic acid to yield 36.2 g of material melting at 261-262°C. C 4-chloro-2-oxindole 4-chloroisatin 43.3 in 350 ml ethanol
Add 17.3ml of hydrazine hydrate to the slurry of stirred g
was added and the reaction mixture was then heated under reflux for 2 hours. The reaction mixture was cooled and the precipitate was collected by filtration to yield 43.5 g of 4-chloro-3-hydrazono-2-oxindole (melting point 235-236°C). 4-chloro-3-hydrazono-2 was added to a stirred solution of 22 g of sodium in 450 ml of absolute ethanol.
- 43.5 g of oxindole were added in portions and the resulting solution was heated under reflux for 30 minutes. Next, the cooled solution is concentrated until it becomes rubbery.
It was dissolved in 400 ml of water and decolorized using activated carbon. The resulting solution was poured into a mixture of 1 ml of water and 45 ml of concentrated hydrochloric acid. The precipitate formed was collected by filtration, dried and recrystallized from ethanol to give 4-
Chloro-2-oxindole (melting point 216-218℃
Decomposition) 22.4g was obtained. D 6-Chloro-2-oxindole Actually, by method C above, 36.2 g of 6-chloroisatin was reacted with hydrazine hydrate and then with sodium ethoxide in ethanol to produce 6-chloro-2-oxindole. Indole (melting point 196-198℃)
14.2g was obtained. Production Example 8 5,6-difluoro-2-oxindole In a similar manner to Parts A and B of Production Example 7, 3,
4-difluoroaniline was reacted with chloral hydrate and hydroxyamine, and then crystallized with sulfuric acid to obtain 5,6-difluoroisatin, which was reacted with hydrazine hydrate, was reacted with sodium methoxide in ethanol to give the title compound (melting point 187-190°C).
I got it. Production Example 9 5-Fluoro-2-oxindole A stirred solution of 11.1 g (0.1 mol) of 4-ethylaniline in 200 ml of dichloromethane at -60 to -65°C was added with t of hypochlorous acid in 25 ml of dichloromethane.
A solution containing 10.8 g (0.1 mol) of -butyl was added dropwise. Stirring was continued for 10 minutes at -60 to -65°C, then ethyl 2-(methylthio) was added to 25 ml of dichloromethane.
A solution containing 13.4 g (0.1 mol) of acetate was added dropwise. Stirring was continued for 1 hour at -60°C, then at 60~
At -65°C, 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 when the reaction mixture had warmed to room temperature, 100 ml of water was added. Separate the phases, wash the organic phase with saturated sodium chloride solution,
Dry (Na ₂ SO ₄ ) and evaporate under vacuum.
The residue was dissolved in 350 ml of diethyl ether, and 40 ml of 2N hydrochloric acid was added thereto. This mixture was stirred overnight at room temperature. The phases were separated and the ethereal phase was washed with water and then with saturated sodium chloride.
The ether phase, dried over (Na ₂ SO ₄ ), was evaporated under vacuum to give 17 g of an orange colored solid, which was triturated under isopropyl ether. The solid was then recrystallized from ethanol to give 5-fluoro-3-methylthio-2-oxindole (melting point 151.5-
152.5°C) 5.58g was obtained. Analytical values: Calculated _{as C9H8CNFS} : C, 54.80; H, 4.09; N, 7.10%. Experimental values: C, 54.74; H, 4.11; N, 7.11%. A sample of the above 5-fluoro-3-methylthio-2-oxindole (986 mg, 5.0 mmol) was added to 2 scoops of Raney nickel under 50 ml of absolute ethanol, and the reaction mixture was then heated under reflux for 2 hours. The catalyst was removed by decantation and washed with absolute ethanol. The combined ethanol solution was evaporated under vacuum and the residue was dissolved in dichloromethane. The dichloromethane solution was dried with (Na ₂ SO ₄ ), evaporated under vacuum and
5-fluoro-2-oxindole (melting point 121
-134°C) 475mg was obtained. In a similar manner, 4-trifluoromethylaniline is reacted with t-butyl hypochlorite, ethyl 2-(methylthio)acetate and triethylamine, and then the 3-thiomethyl-5-trifluoro Methyl-2-oxindole was reduced with Raney nickel to give 5-trifluoromethyl-2-oxindole (melting point 189.5-
190.5℃). Production Example 10 5-Methoxy-2-oxindole 5-methoxy-2-oxindole was produced from 4-methoxyaniline in a manner similar to that of Production Example 9. However, the initial chlorination step was performed using a solution of chlorine gas dissolved in dichloromethane instead of t-butyl hypochlorite. The title product is
It melted at 150.5-151.5℃. Production example 11 6-chloro-5-fluoro-2-oxindole In 130 ml of toluene, 24.0 g (0.165 mol) of 3-chloro-4-fluoroaniline and 13.5 ml of pyridine.
(0.166 mol) was added with stirring. The resulting solution was cooled to about 0°C and 2-chloroacetyl chloride
13.2 ml (0.166 mol) was added. The reaction mixture was stirred at room temperature for 5 hours, then extracted with 100 ml of 1N hydrochloric acid,
It was then extracted with 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried with magnesium sulfate and then evaporated under vacuum to N
32.6 g (yield: 83%) of -(2-chloroacetyl)-3-chloro-4-fluoroanine was obtained. N-(2-chloroacetyl)-3-chloro-4-
A 26.63 g sample of fluoroaniline was thoroughly mixed with 64 g of anhydrous aluminum chloride and the mixture was
Heated at ~230°C for 8.5 hours. The reaction mixture was then poured onto a mixture of ice and 1N hydrochloric acid with stirring. Stirring was continued for 30 minutes, then the solid was collected by filtration (22.0 g). This solid was dissolved in a 1:1 mixture of ethyl acetate-hexane and silica gel 800.
Chromatographic analysis was carried out on g. After elution of the column, the fractions were evaporated to give 11.7 g of N-(2-chloroacetyl)-3-chloro-4-fluoroaniline, then 6-chloro-5-fluoro-2
-3.0 g of oxindole was obtained. Recrystallization of the latter material from toluene yielded 170 g of the title compound.
(yield 7%), melting point 196-206°C. Analysis by NMR spectrum showed that the product was contaminated with some 4-chloro-5-fluoro-2-oxindole. Production example 12 6-fluoro-5-methyl-2-oxindole N-(2-chloroacetyl)-3-fluoro-4
- A well-mixed mixture of 11.62 g (57.6 mmol) of methylaniline and 30.6 g (229.5 mmol) of anhydrous aluminum chloride is heated to 210-220°C,
After an hour, cool the reaction mixture and add 100 ml of 1N hydrochloric acid and ice.
Added to 50ml. The yellow colored solid that formed was collected by filtration and recrystallized from aqueous ethanol. Three products were obtained, weighing 4.49 g, 2.28 g and 1.0 g wt%, respectively. The product weighing 1.0 g was further recrystallized from water to give the title compound (melting point
168.5-171°C) 280g was obtained. Production example 18 6-Bromo-2-oxindole To 9.4 g of sodium hydride, add 195 ml of dimethyl sulfoxide, then add 22.37 g of dimethyl malonate.
ml was added dropwise. At the end of this addition, pour the mixture into
It was heated to 100°C and maintained at this salinity for 40 minutes. At this point, 25 g of 1,4-dibromo-2-nitrobenzene was added all at once. Reaction mixture at 100℃
for 4 hours and then added to 1.0 saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate, and the extract was diluted with ammonium chloride solution,
Washed with water and saturated sodium chloride solution. The dried (MgSO ₄ ) solvent was evaporated and the residue was recrystallized from an ethyl acetate-hexane mixture to give dimethyl-2-(4-bromo-2-nitrophenyl).
22.45 g of malonate was obtained. A solution of 17.4 g of dimethyl 2-(4-bromo-2-nitrophenyl)malonate and 4.6 g of lithium chloride dissolved in 150 ml of dimethyl sulfoxide was heated at 100°C.
After 3 hours 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. Separate the layers;
The aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried using sodium sulphate and then evaporated under vacuum. The residue was analyzed by chromatography using silica gel as the adsorbent and an ethyl acetate-hexane mixture as the eluent. This results in methyl-
9.4 g of 2-(4-bromo-2-nitrophenyl)-acetate were obtained. Methyl-(4-bromo-2) dissolved in 75 ml of acetic acid
- in a solution of 7.4 g of nitrophenyl) acetate,
6.1g of iron powder was added. The reaction mixture was placed in a 100°C oil bath. After 1 hour, the solvent was removed by evaporation under vacuum and the residue was dissolved in 250 ml of ethyl acetate. Filter the solution and wash with saturated sodium chloride solution,
Dry with sodium sulfate, decolorize with activated charcoal and evaporate under vacuum. By this,
5.3 g of 6-bromo-2-oxindole was obtained as a white crystalline solid (melting point, 213-214 DEG C.). Similarly, using 1,4,5-trichloro-2-nitrobenzene as starting material, 5,6-
Dinitro-2-oxindole (melting point 209-210
°C) was produced. Example 14 6-phenyl-2-oxindole To 3.46 g (0.072 mol) of sodium hydride, add 50 ml of dimethyl sulfoxide, then dimethyl malonate dissolved in 10 ml of dimethyl sulfoxide.
8.2 ml (0.072 mol) of the solution was added dropwise with stirring. After the addition was complete, stirring was continued for 1 hour, 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 hour, cooled and then poured onto an ice-water mixture containing 5 g of ammonium chloride. The mixture thus obtained was extracted with ethyl acetate, the extract was extracted with sodium chloride solution and dried using magnesium sulphate. Evaporation under vacuum gave an oil which was chromatographed on silica gel and then recrystallized from methanol to give dimethyl 2-(3-nitro-4-diphenyl)-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 Kg/m ² to give the corresponding amine. The latter compound was refluxed in ethanol for 16 hours, and the product was then recovered by solvent evaporation and recrystallized from methanol to yield ethyl 6-phenyl-2-oxindole-1-carboxylate (mp, 115- 117℃)
I got it. 1.0 g of the above ethyl ester and 100 ml of 6N hydrochloric acid were heated under reflux for 3 hours, then left at room temperature for 3 days. The solid was collected by filtration and dried to give 6-phenyl-2-oxindole (melting point, 175-176°C) 700PH. Production example 15 5-acetyl-2-oxindole 27 g of aluminum chloride in 95 ml of carbon disulfide
(0.202 mol), then a solution of 3 ml (0.042 mol) of acetyl chloride dissolved in 5 ml of carbon disulfide,
Add dropwise with stirring. Stirring was continued for 5 minutes, then 4.4 g (0.033 mol) of 2-oxindole was added. The resulting mixture was heated under reflux for 4 hours and cooled. Carbon disulfide was removed by decantation, the residue was ground with water, and the solid was recovered by filtration. After drying, the title compound 3.2
g (melting point, 225-227°C) was obtained. In fact, the following compounds were obtained by reacting 2-oxindole with benzoyl chloride and 2-thenoyl chloride in the presence of aluminum chloride according to the above method: 5-benzoyl-2-oxindole, melting point
203-205°C (from ^CH3OH ) and 5-(2-thenoyl)-2-oxindole,
Melting point 211-213 °C (from _CH3CN ). Production example 16 5 by oxidation of 2-oxindole
-Bromo-2-oxindole is obtained:
Buckett et al., Tetrahedron, vol. 24, p. 6093 (1968) and Sumpter et al., Jonranal of the
See American Chemical Society, Vol. 67, p. 1956 (1945). Following the method of Example 5, 5-n-butyl-2
-5-n-butyl-2- by reacting the oxindole with hydrazine hydrate and then with sodium methoxide in ethanol.
Oxindole is produced. 5-n-Butirisatin is prepared by treating 4-n-buteraniline with chloride hydrate and then cyclizing with sulfuric acid according to the method of Parts A and B of Preparation Example 7. . 3-hydroxy-6-nitro-toluene was converted to 3-ethoxy-6-nitro-toluene by standard methods (potassium carbonate and ethyl iodide in acetone) and then Buckett et al. Regarding the conversion of -6-nitrotoluene to 5-methoxy-2-oxindole,
5-Ethoxy-2-oxindole is produced by converting 3-ethoxy-6-nitrotoluene to 5-ethoxy-2-oxindole by the method described in Tetrahedron Vol. 24, p. 6093 (1968). Ru. n- iodide instead of ethyl iodide
5-n-butoxy-6-oxindole is produced in the same manner except that butyl is used. 5,6-dimethoxy-2-oxindole was described by Walker in the Journal of the American
It is produced by the method described in Chemical Society, Vol. 77, p. 3844 (1955). 7-Chloro-2-oxindole is prepared by the method described in US Pat. No. 3,882,236. 4-thiomethyl-2-oxindole and 6-
Thiomethyl-2-oxindole is prepared by the method described in US Pat. No. 4,006,161. Similarly, but using 3-methylthioaniline instead of 4-butylthioaniline, 5
-n-butylthio-2-oxindole can be produced. 5,6-methylenedioxy-2-oxindole was reported by McEvoy et al. in the Journal of Organic
It can be produced by the method described in Chemistuy, Vol. 38, p. 3850 (1973). 5,6-
Ethylenedioxy-2-oxindole can also be produced in a similar manner. 6-fluoro-2-oxindole is
Collection of Czechoslovakian by Protiva et al.
Manufactured according to the method of Chemical Communications, Vol. 44, p. 2108 (1979) and US Pat. No. 4,160,032. 6-Trifluoromethyl-2-oxindole was reported by Simet in Journal of Organic Chemistuy28
Vol., p. 3580 (1963). 6-methoxy-2-oxindole is
It can be produced according to the method described by Wieland et al. in Chemische Berichte, Vol. 96, p. 253 (1963). 5-nitro-2-oxindole is Sumpter
etc. in the Journal of the American Chemical
It can be produced according to the method described in Society, Vol. 67, p. 499 (1945). 5-cyclopropyl-2-oxindole and 5-cycloheptyl-2-oxindole are
Produced according to the method of Preparation Example 5 by reacting 5-cyclopropylisatin and 5-cycloheptisatin with hydrazine hydrate, respectively, and then with sodium methoxide in ethanol. can do. 5-Cyclopropylisatin and 5-cycloheptilisatin were prepared by preparing 4-cyclopropylaniline and 4-cycloheptylaniline with chloral hydrate and hydroxylamine, respectively, according to the method of Preparation Parts A and B. treatment followed by cyclization with sulfuric acid. Production Example 17 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-oxindole at room temperature. The resulting slurry was cooled to ice bath temperature and then 15.7 g (0.12 mole of 2) of 2-furoyl chloride was added dropwise over 10-15 minutes. Remove the ice bath and add another 100ml of ethanol.
The reaction mixture was then heated under reflux for 7 hours. The reaction mixture was allowed to stand overnight, then the solids were separated. The solid was added to 400 ml of water and the resulting mixture was acidified using concentrated hydrochloric acid. The mixture was cooled with ice and the solid was collected by filtration. Acetic acid the solid residue
Recrystallize from 150ml to give yellow crystals (melting point 209-
210°C decomposition) 8.3g was obtained. Analytical value: Calculated as C ₁₃ H ₉ O ₃ N: C, 68.72; H, 3.99; N, 6.17% Experimental value: C, 68.25; H, 4.05; N, 6.20% Production example 18 Using the method of Production example 17 The reaction of 2-oxindole with the appropriate acid chloride further yielded the following products: 3-(2-thenoyl)-2-oxindole,
Melting point 189-190°C, yield 17%, 3-(2-[2-thienyl]acetyl)-2-oxindole, melting point 191-192.5°C, yield 38% 3-(2-phenoxyacetyl)-2- Oxindole, melting point 135-136°C, yield 42% Production example 19 3-(3-furoyl)-2-oxindole 2-oxindole was added to a stirred solution of 2.8 g (0.12 mol) of sodium in 200 ml of ethanol.
13.3g (0.10mol), then ethyl 3-furoate
Added 16.8g. The mixture was heated under reflux for 47 hours, cooled and then the solvent was removed by evaporation under vacuum. The residue was triturated under 200 ml of ether and the solid was collected by filtration and discarded.
The liquid was evaporated under vacuum and the residue was triturated under isopropyl alcohol and collected by filtration. The solid was suspended in 250ml of water, which was then acidified with concentrated hydrochloric acid. The mixture was stirred to obtain a solid, which was collected by filtration. This latter solid was recrystallized from acetic acid and then acetonitrile to give 705 mg of the title compound (mp 185-186°C). Analysis value: Calculated _{as C13H9O3N C} , 68.72; H, 3.99; _N , 6.17%. Experimental values: C, 68.72; H, 4.14; N, 6.14%. Production Example 20 5-Amino-2-oxindole-1-carboxamide 0.5 g of 10% carbon carrier catalyst was added to a solution of 5.0 g of 5-nitro-2-oxindole-1-carboxamide dissolved in 110 ml of N,N-dimethylformamide.
was added, and the resulting mixture was heated to an initial pressure of 5 in a hydrogen atmosphere.
It was shaken at Kg/cm ² until hydrogen absorption stopped. The catalyst was removed by filtration, the liquid was diluted with brine,
Extracted with ethyl acetate. The extract was dried (MgSO ₄ ) and evaporated under vacuum to give a dark oil, which solidified after trituration with water. This gave 3.0 g of the title compound as a yellow solid (melting point 189-191°C).

Claims (1)

[Claims] Primary formula: [Wherein, ,
Alkylsulfinyl having 1 to 4 carbon atoms, 1 carbon number
~4 alkylsulfonyl, nitro, phenyl,
alkanoyl having 2 to 4 carbon atoms, benzoyl, thenoyl, alkanamide having 2 to 4 carbon atoms, benzamide, or N,N-dialkylsulfamoyl in which each alkyl group has 1 to 3 carbon atoms; Y is hydrogen; Fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio or trifluoromethyl having 1 to 4 carbon atoms; X and Y are together 4,5-,5,
6- or 6,7-methylenedioxy group or 4,5-, 5,6- or 6,7-ethylenedioxy group; R ¹ is alkyl having 1 to 6 carbon atoms, 3 to 7 carbon atoms
cycloalkyl, cycloalkenyl having 4 to 7 carbon atoms, phenyl, substituted phenyl, phenylalkyl in which the alkyl group has 1 to 3 carbon atoms, (substituted phenyl) alkyl in which the alkyl group has 1 to 3 carbon atoms, alkyl group phenoxyalkyl having 1 to 3 carbon atoms, (substituted phenoxy)alkyl having 1 to 3 carbon atoms, alkyl group having 1 to 3 carbon atoms,
~3 (thiophenoxy)alkyl, naphthyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl or -( _CH2 ) _o -Q-R ⁰ and the substituents of the substituted phenyl, (substituted phenyl)alkyl and (substituted phenoxy)alkyl are fluoro, bromo, chloro, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or trifluoromethyl. Yes, n is 0, 1 or 2, Q is furan,
Thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5
R ⁰ is hydrogen or carbon number 1~
2-oxindole-1-carboxamide and a pharmaceutically acceptable base salt thereof. or , if X and Y are combined, then 4,
5-, 5,6- or 6,7-methylenedioxy group; R ¹ is alkyl having 1 to 6 carbon atoms, 3 to 7 carbon atoms
cycloalkyl, phenyl, substituted phenyl, phenylalkyl in which the alkyl group has 1 to 3 carbon atoms, phenoxyalkyl in which the alkyl group has 1 to 3 carbon atoms, and phenoxyalkyl in which the alkyl group has 1 to 3 carbon atoms (substituted phenoxy)alkyl, furyl, thienyl, pyrrolyl, alkylfuryl in which the alkyl group has 1 to 3 carbon atoms, alkylthienyl in which the alkyl group has 1 to 3 carbon atoms, furylalkyl, alkyl in which the alkyl group has 1 to 3 carbon atoms The group is thienylalkyl or bicyclo[2.2.1]heptan-2-yl having 1 to 3 carbon atoms, and the substituents of the substituted phenyl group and the substituted phenoxy group are fluoro, chloro, bromine, or 1 to 3 carbon atoms.
The compound according to claim 1, which is an alkyl group having -4 or an alkoxyl group having 1 to 4 carbon atoms. 3. The compound according to claim 2, wherein Y is hydrogen. 4. A compound according to claim 3, wherein X is 5-chloro, 6-chloro, 5-fluoro, 6-fluoro, 5-trifluoromethyl or 6-trifluoromethyl. 5 X is 5-chloro or 5-fluoro,
3. A compound according to claim 2, wherein Y is 6-chloro or 6-fluoro. 6 R ¹ is benzyl, 2-furyl, 2-thienyl,
The compound according to claim 4 or 5, which is (2-furyl)methyl or (2-thienyl)methyl. 7. The compound according to claim 1, wherein X is 5-chloro, Y is hydrogen, and R ¹ is 2-thienyl;
That is, 5-chloro-3-(2-thenoyl)-2
-oxindole-1-carboxamide. 8 The compound according to claim 1, wherein X is 5-fluoro, Y is 6-chloro, and R ¹ is benzyl, i.e., 6-chloro-5-fluoro-3-
(2-phenylacetyl)-2-oxindole-1-carboxamide. 9. A pharmaceutically acceptable carrier and the following formula: [Wherein, ,
Alkylsulfinyl having 1 to 4 carbon atoms, 1 carbon number
~4 alkylsulfonyl, nitro, phenyl,
alkanoyl having 2 to 4 carbon atoms, benzoyl, thenoyl, alkanamide having 2 to 4 carbon atoms, benzamide, or N,N-dialkylsulfamoyl in which each alkyl group has 1 to 3 carbon atoms; Y is hydrogen; Fluoro, chloro, bromo, alkyl having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio or trifluoromethyl having 1 to 4 carbon atoms; X and Y are together 4,5-,
5,6- or 6,7-methylenedioxy group or 4,5-, 5,6- or 6,7-ethylenedioxy group; R ¹ is alkyl having 1 to 6 carbon atoms, 3 to 6 carbon atoms; 7
cycloalkyl, cycloalkenyl having 4 to 7 carbon atoms, phenyl, substituted phenyl, phenylalkyl in which the alkyl group has 1 to 3 carbon atoms, (substituted phenyl) alkyl in which the alkyl group has 1 to 3 carbon atoms, alkyl group phenoxyalkyl having 1 to 3 carbon atoms, (substituted phenoxy)alkyl having 1 to 3 carbon atoms, alkyl group having 1 to 3 carbon atoms,
~3 (thiophenoxy)alkyl, naphthyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl or -( _CH2 ) _o -Q-R ⁰ and the substituents of the substituted phenyl, (substituted phenyl)alkyl and (substituted phenoxy)alkyl are fluoro, bromo, chloro, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or trifluoromethyl. Yes, n is 0, 1 or 2, Q is furan,
Thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5
R ⁰ is hydrogen or carbon number 1~
Analgesic inflammation therapeutic composition comprising 2-oxindole-1-carboxamide or a pharmaceutically acceptable base salt thereof.