JPH049781B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to novel compounds. More specifically, these new compounds are derivatives of 2-oxindole, which can be converted into 1-oxindole by means of an acyl group.
and 3-position. These new compounds are cyclooxygenases (CO)
and lipoxygenase (LO) enzymes. The compounds of the invention have analgesic activity in mammals, particularly humans, and are therefore useful for acute administration to reduce or eliminate pain, such as that experienced by patients recovering from surgery or trauma. The compounds of the invention are useful not only for acute administration to control pain, but also to treat inflammation and pain associated with rheumatoid arthritis and osteoarthritis.
It is useful for chronic administration to mammals, particularly humans, to alleviate symptoms of chronic diseases. (Means for solving the problem) The present invention has the following formula: [wherein ^, a phenylalkyl, or -
( _CH2 ) _o -Q- ^R0 ; n is 0, 1 or 2, Q is a divalent radical derived from a compound selected from the group consisting of furan, thiophene and pyridine, and ^R0
is hydrogen or alkyl having 1 to 3 carbon atoms; and R ² is alkyl having 1 to 5 carbon atoms] and a pharmaceutically acceptable, The basic salt thereof is provided. The above compounds of the formula are active as analgesics and as therapeutic agents for inflammatory diseases such as arthritis. In a preferred group of compounds of the present invention, X and Y are each hydrogen, and R ¹ is 2-furyl, 2-thienyl,
consisting of a compound of formula which is a group selected from the group consisting of 3-pyridyl and (2-thienyl)methyl. In a more preferred group of compounds of the present invention, X is 5-
chloro, Y is hydrogen and R ¹ is a group selected from the group consisting of 2-furyl, 2-thienyl, 3-pyridyl and (2-thienyl)methyl. Particularly preferred individual compounds of the invention are 1-acetyl-3-(2-thenoyl)-2-oxindole, 1-acetyl-3-([2-thienyl]acetyl)
-2-oxindole and 5-chloro-1-acetyl-3-(2-thenoyl)
-2-oxindole. Useful as intermediates for analgesic anti-inflammatory compounds of the formula are: (In the formula, X, Y and ^R2 are as defined above.) It is a 1-acyl-2-oxindole represented by: A preferred group of compounds of the formula are those in which X is hydrogen, 5
- fluoro, 5-chloro or 5-trifluoromethyl, and Y is hydrogen, 6-fluoro, 6-chloro or 6-trifluoromethyl, and R ² is carbon Number 1
~5 alkyl. The present invention relates to compounds of the formula, which are named as derivatives of 2-oxindole, a compound of the following structural formula: Additionally, as will be readily understood by those skilled in the art, the analgesic and anti-inflammatory compounds of the present invention (X, Y,
R ¹ and R ² as defined above) can be enolized and therefore can exist in one or more tautomeric forms (enol forms). All such tautomeric forms (enol forms) of compounds of formula are considered to be within the scope of this invention. A compound of the formula is a suitable 2-oxindole compound of the formula: (In the formula, X and Y are as defined above) by attaching a substituent -C(=O)-R ² at the 1-position and a substituent -C(=O)-R ¹ at the 3-position. Therefore, it is manufactured. Either of these substituents may be attached first, resulting in two embodiments of the method for preparing compounds of formula. This process is shown in Reaction Step A. However, preferred methods of preparing compounds of formula also include the compound-compound-compound sequence. The -C(=O) ^-R2 substituent is added to a compound of the formula in the presence of 1 to 4 equivalents of a basic agent in an inert solvent.
It can be attached by reacting one molar equivalent or some excess of the activated derivative of the carboxylic acid ^R2 -C(=O)OH. An inert solvent is a solvent that dissolves at least one of the reactants and does not adversely affect either the reactants or the products. However, in reality, for example, N,N-dimethylformamide, N,N-dimethylacetamide,
Polar aprotic solvents such as N-methylpyrrolidone or dimethylsulfoxide are commonly used. Conventional methods are used to activate acids of formula ^R2 -C(=O)OH. Acid halides such as acid chlorides, symmetrical acid anhydrides
R ² -C(=O)-O-C(=O)-R ³ ; mixture of constrained low molecular weight carboxylic acid and acid anhydride, R ²
-C(=O)-O-C(=O)-R ³ (R ³ is a bulky lower alkyl group such as t-butyl); and a carboxylic acid-carbonic anhydride mixture, R ² -C( =
O)-O-C-(=O) ^-OR4 ( ^R4 is a lower alkyl group) are all used. Additionally, N-hydroxyimide esters (such as N-hydroxysuccinimide ester and N-hydroxyphthalimide ester), 4-nitrophenyl
Esters, thiol esters (such as thiol phenyl esters), 2,4,5-trichlorophenyl esters, and the like can also be used. A wide variety of basic agents can be used in the reaction between a compound of formula and an activated derivative of an acid of formula R2 ^- C(=O)OH. However, preferred basic agents are tertiary amines such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methyl-piperidine and 4-(N,
N-dimethylamino)pyridine. The reaction between a compound of formula and an activated derivative of an acid of formula ^R2 -C(=O)-OH is normally carried out at a temperature range of -20 to 25<0>C. Generally, the formula R ² -C(=O)-
When using highly activated derivatives of acids such as OH, temperatures at the lower end of this range are used and the acid R ² −
High temperatures are used when using very lightly activated derivatives of C(=O)-OH. In most cases, the reaction proceeds very quickly, with reaction times ranging from 30 minutes to several hours being common. At the end of the reaction,
The reaction medium is usually diluted with water, acidified and the product of the formula is recovered by filtration. The product is purified by standard methods such as recrystallization. -C(=O)-R ¹ side chain is added to the compound of formula R ¹
It can be attached by reacting one molar equivalent or a slight excess of the activated derivative of the carboxylic acid -C(=O)-OH. This acylation reaction is carried out in the same manner as described above for the reaction of a compound of formula with an activated derivative of a carboxylic acid of formula ^R2 -C(=O)-OH. The -C(=O) ^-R1 side chain can be added to a compound of formula in a lower alkanol solvent (e.g., ethanol) in the presence of an alkali metal salt of the lower alkanol solvent (e.g., sodium ethoxide) by standard methods. and can be attached by reacting a suitable acid derivative of the formula R ¹ -C(=O)-OH. The formula R ¹ −C(=O) can be used.
Typical derivatives of OH acids are acid chlorides, formula R ¹
-C(=O)-O-C(=O)-R ¹ , R ¹ -C(=O)
-O-C(=O)-R ³ and R ¹ -C(=O)-O-C
Acid anhydride represented by (=O)-OR ⁴ and formula R ¹
Contains simple alkyl esters represented by -C(=O) ^-OR4 , where ^R3 and ^R4 are as defined above.
Usually, a slight excess of a derivative of the formula R ¹ -C(=O)-OH acid is used and the alkoxide salt is prepared with this R ¹ -C(=
An amount of 1 to 2 molar equivalents based on the derivative of O)-OH acid is used. The reaction between a derivative of the formula R ¹ -C(=O)-OH acid and a compound of the formula is usually carried out between 0°C and 25°C.
but then the reaction mixture was heated to 50°C
Heating to a temperature in the range of 130°C, preferably about 80°C, is usual to complete the reaction. Under such circumstances, reaction times ranging from several hours (eg, 2 hours) to several days (eg, 2 days) are commonly used. The reaction mixture is then cooled, diluted with excess water and acidified. The product of the formula can then be recovered by standard methods of filtration or solvent extraction. A -C(=O) ^-R2 side chain can be attached to a compound of the formula by reacting a suitable acid anhydride of the formula [ ^R2 -C(=O)] _2O . Typically, a compound of formula 1 is prepared in the absence of a solvent at a temperature in the range of 80°C to 130°C, preferably at a temperature of about 100°C.
React with ~3 equivalents, preferably 1.2-1.5 equivalents of acid anhydride for several hours (eg, about 4 hours). However, if desired, an inert solvent such as toluene can be used. At the end of the reaction, the product of formula can be recovered by removing excess acid anhydride and solvent by evaporation. The crude product is usually of sufficient purity for conversion to a compound of formula. 2-oxindole compounds of the formula are prepared by known methods or by methods analogous to known methods. The following literature may be helpful: Rodd's Chemistry of Carbon Compounds.
Compounds” 2nd edition, edited by S.
Coffey), Volume A, Elsevier Scientific Publishing Company,
1973, pp. 448-450; Gassman et al., Journal of Organic Chemistry.
Organic Chemistry) 42 1340 pages (1977); Wright et al., Journal of the American Chemical Society
78, p. 221 (1956); Beckett et al., Tetrahedron 24 , p. 6093 (1968); U.S. Pat.
No. 4160032; Walker, Journal of the
American Chemical Society (Journal)
of the American Chemical Society) 77 , 3844
(1955); Protiva et al., Collection of Czechoslovakian Chemical Communications.
Chemical Communications) 44 , p. 2108 (1979); McEvoy et al., Journal of Organic Chemistry (1979);
Organic Chemistry 38 , p. 3350 (1973); Simet, Journal of Organic Chemistry
Chemistry 28 , p. 3580 (1963); Wieland et al., Chemische Berichte 96 , p. 253 (1963); and references cited therein. The compounds of formula are acidic and form base salts. All such base salts are within the scope of this invention and can be prepared by conventional methods.
These base salts can be easily prepared, for example, by contacting normally stoichiometric amounts of acidic and basic compounds in a suitable aqueous, non-aqueous, or partially aqueous medium. can. The salt can be recovered by any suitable means, such as filtration, precipitation with a non-solvent and filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization. Typical salts of compounds of formula that can be prepared are primary, secondary and tertiary amine salts, alkali metal salts and alkaline earth metal salts. Ethanolamine, diethanolamine and triethanolamine salts are particularly desirable. Basic agents suitable for use in salt formation include both organic and inorganic types, including organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, and alkali metals. Included are alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydrides, and alkaline earth metal alkoxides. Typical examples of such bases are primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethanolamine and glucamine; diethylamine, diethanolamine, N-methyl Secondary amines such as glucamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, triethanolamine, N,N-dimethylaniline, N-ethylpiperidine and N-methylmorpholine; water hydroxides such as sodium oxide; 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. (Action) The compound of formula has analgesic activity. This activity was demonstrated in mice by the method of Siegmond et al., Proc.Soc.Exp.Biol.Med. 95 , pp. 729-731 (1957); (Milne and Twomey) Agents and Actions 10,
2-phenyl-1,4 using a method suitable for high throughput based on [1980], pp. 31-37.
- Demonstrated by showing a blockade of abdominal tone induced by administering benzoquinone (PBQ). Mice used in these experiments weighed 18~
20g Carworth male, white CF-
It was the 1st series. All mice were fasted overnight before drug administration and experiments. A compound of formula was dissolved or suspended in a vehicle consisting of ethanol (5%), Emulphor 620 (a mixture of polyoxyethylene fatty acid esters, 5%) and saline (90%). This vehicle was also used as a control. Doses were on a logarithmic scale (ie 0.32, 1.0, 3.2, 10, 32...mg/Kg). The route of administration is oral, with varying concentrations.
A constant dose of 10 ml per 1 kg of body weight was maintained. Efficacy and potency were determined using the method of Milne and Tsumei. The above compound was orally administered to mice, and 1 hour later, 2 mg/Kg of PBQ was administered intraperitoneally.
Each mouse was then placed in a warmed Lucite (clear plastic) chamber and exposed to PBQ.
Starting 5 minutes after administration, the number of abdominal contractions for the next 5 minutes was recorded. Analgesic protection (MPE%) was calculated based on the abdominal tightness inhibition associated with the count from the response data that yielded the MPE50, which was the best estimate of the dose that reduced abdominal tone to 50% of the control level. Compounds of formula also have anti-inflammatory activity. This activity has been demonstrated in rats by a method based on the standard carrageenan-induced rat paw edema test [Winter et al., Proc. Soc.
Exp. Biol. Med., 111, 544 [1963]]. Unanesthetized adult male white rats weighing 150-190 g were numbered, weighed, and marked with ink on the right hind ankle. Each paw was immersed in mercury exactly up to the ink mark. The mercury is placed in a glass cylinder connected to a Statum transformer whose output is fed via a control unit to a microvoltameter. The amount of mercury displaced by the immersed foot was read. Drugs were administered by gavage. One hour after drug administration, edema was induced by injecting 0.05 ml of a 1% solution of carrageenan into the plantar tissue of the labeled paws. Immediately after this, the volume of the injected paw was measured. The increase in paw volume 3 hours after carrageenan injection represents the individual inflammatory response. The compounds of the formula have analgesic activity and are therefore useful for acute administration to mammals for the control of pain, such as post-surgical pain and trauma pain. Additionally, the compounds of formula are useful for chronic administration to mammals to alleviate the symptoms of chronic diseases such as the inflammation of rheumatoid arthritis, the pain associated with osteoarthritis and other musculoskeletal disorders. When a compound of formula or a pharmaceutically acceptable salt thereof is used as either an analgesic or an anti-inflammatory agent, the compound may be added alone or preferably to a pharmaceutical composition by standard pharmaceutical means. The composition can be administered to a mammalian subject in combination with a pharmaceutically acceptable carrier or diluent. Compounds can be administered orally or parenterally. Parenteral administration includes intravenous, intramuscular, intraperitoneal, subcutaneous and topical administration. In pharmaceutical compositions containing a compound of formula or a pharmaceutically acceptable salt thereof, the weight ratio of carrier to active ingredient usually ranges from 1:4 to 4:1, preferably from 1:2 to 2:1. range. However, in each case this ratio will be selected depending on the solubility of the active ingredient, the intended dose and the precise route of administration. For oral use of a compound of the formulas of the invention, the compound can be administered, for example, as a tablet or capsule, or as an aqueous solution or suspension. Common carriers for oral tablets are lactose and cornstarch, and lubricants such as magnesium stearate are also commonly added. Useful diluents for oral use in capsules are lactose and dried cornstarch. 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 can be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredient are usually prepared, the pH of the solution being suitably adjusted and buffering agents added. For intravenous use, the total concentration of solutes must be adjusted to make the formulation isotonic. When a compound of formula or a salt thereof is used in a human patient, the daily dose will usually be determined by the attending physician. Additionally, depending on the age, weight and response of each patient as well as the severity of the patient's symptoms and efficacy of the particular compound administered, the dosage will be varied. However, in most cases, the effective amount to induce an analgesic response is 0.1 g to 1.0 g, as needed (e.g., every 4 to 6 hours).
It is thought that. An effective amount for chronic administration for alleviating (treating) inflammation and pain is in most cases 0.1 to 1.5 g/day, preferably 0.3 to 1.0 g/day, in single or divided doses. However, it may be necessary to use doses outside these limits in some cases. The following examples and preparations are presented only to further illustrate the invention. Example 1 1-Acetyl-3-(2-thenoyl)-2-oxindole 3-(2-Thenoyl)-2-oxindole dissolved in 4 ml of N,N-dimethylformamide 486
mg (2.0 mmol) of 4-(N,
538 mg (4.4 mmol) of N-dimethylamino)pyridine were added. The resulting mixture was cooled in an ice bath and a solution of 225 mg (2.2 mmol) of acetic anhydride in 2 ml of N,N-dimethylformamide was added dropwise with stirring over about 1 minute. Remove the cooling bath;
After stirring for 1 hour, the reaction mixture was mixed with 50 ml of water.
Pour onto the mixture 1.7 ml of 3N hydrochloric acid. The resulting mixture was cooled in an ice bath and the solid was collected by filtration. This gave 528 mg of a yellow solid.
This yellow solid was recrystallized from about 15 ml of ethanol to obtain 300 g of the title compound as a yellow solid (melting point 139-140).
℃). Analysis Calculated value as C ₁₅ H ₁₁ NO ₃ S: C, 63.14; H, 3.89; N, 4.91% Experimental value: C, 63.15; H, 3.90; N, 4.87% Example 2 1-acetyl-3- (2-Furoyl)-2-oxindole Acetylation of 3-(2-furoyl)-2-oxindole with acetic anhydride substantially according to the method of Example 1 yields the title compound in 73% yield. (melting point
137.5°C to 138.5°C). Analysis Calculated value as C ₁₅ H ₁₁ NO ₄ : C, 66.91; H, 4.12; N, 5.20% Experimental value: C, 66.93; H, 4.23; N, 5.12% Example 3 1-acetyl-3-( 3-pyridylcarbonyl)
-2-Oxindole Following substantially the method of Example 1, 3-(3-pyridylcarbonyl)-2-oxindole was acetylated with acetic anhydride to give the title compound (mp 141) in 53% yield. °C to 142.5 °C). Example 4 Substantially according to the method of ^Example 1, _a suitable 3-
By acylating the acyl-2-oxindole, the following compound was obtained: [Table] [Table] Example 5 1-Acetyl-3-([2-thienyl]acetyl)-2-oxindole 1.29 g (5.0 mmol) of 3-([2-thienyl]acetyl)-2-oxindole, 4-(N,N
A stirred mixture of 1.22 g (10.0 mmol) of -dimethylamino)pyridine and 15 ml of N,N-dimethylformamide was cooled in an ice bath and then acetic anhydride.
562 mg (5.5 mmol) were added dropwise over 1 minute with stirring. Stirring was continued for 3.25 hours at ice bath temperature and the reaction mixture was filtered. When the liquid was poured onto a mixture of 3N hydrochloric acid and water, a solid and a gum formed. The solid was recovered by filtration and the gum was recovered by decantation. Trituration of the gum under isopropanol-water gave additional solid, which was also recovered by filtration. Both solids were combined and extracted with hot benzene, leaving a dark gummy residue. The benzene solution was cooled and evaporated in vacuo and the residue was recrystallized from toluene to give the title compound (melting point
136°C to 137°C) 66 mg was obtained. The recrystallization mother liquor was evaporated in vacuo and the residue was recrystallized from hexane to give a secondary yield of 90 mg of the title compound (mp 135°C-136°C). Elemental analysis was performed on this secondary yield. Analysis Calculated value as C ₁₆ H ₁₃ NO ₃ S: C, 64.20; H, 4.38; N, 4.68% Experimental value: C, 64.36; H, 4.44; N, 4.68% Example 6 1-acetyl-3- (2-pentylacetyl)-
2-Oxindole Using the method of Example 5, 3-(2-phenylacetyl)-2-oxindole was acetylated with acetic anhydride. When the reaction mixture was poured into a mixture of 3N hydrochloric acid and water, a solid was formed. The solid was collected by filtration and recrystallized from isopropanol to give the title compound in 40% yield (mp 149°C-151°C). The ultraviolet absorption spectrum of the product in methanol is
It showed absorption peaks at 238, 260 and 290 millimicrons. After adding one drop of KOH, the absorption peak is
Occurred at 238, 260 and 307 millimicrons. Analysis Calculated value as C ₁₈ H ₁₅ NO ₃ : C, 73.71; H, 5.15; N, 4.77% Experimental value: C, 73.23; H, 5.18; N, 4.62% Example 7 1-acetyl-3-( 3-pyridylcarbonyl)
-2-Oxindole A mixture of 476 mg (2.0 mmol) of 3-(3-pyridylcarbonyl)-2-oxindole and 4 ml of acetic anhydride was heated under reflux for 30 minutes. The reaction mixture was cooled to room temperature, most of the acetic anhydride was removed by vacuum evaporation, and the residue was triturated under 15 ml of water. The solid was collected by filtration, dried and triturated under isopropanol. The residue (158 mg) was recrystallized from acetonitrile to give 64 mg of the title compound as red-orange crystals (melting point 142.5°C to 143.5°C). The title compound (40 mg) was obtained from the mother liquor of recrystallization. Both yields were the same by thin layer chromatography. Elemental analysis was performed on the primary yield. Analysis Calculated value as C ₁₆ H ₁₂ N ₂ O ₃ : C, 68.56; H, 4.32; N, 10.00% Experimental value: C, 68.26; H, 4.38; N, 9.87% Example 8 1-acetyl-3 Ethanolamine salt of -(2-thenoyl)-2-oxindole To a slurry of 2.85 g of N-acetyl-3-(2-thenoyl)-2-oxindole in 40 ml of methanol is added 610 mg of ethanolamine. The resulting mixture is heated to boiling for 5 minutes and then cooled.
The solvent is removed by vacuum evaporation to give the title salt. Example 9 5-chloro-1-acetyl-3-(2-thenoyl)-2-oxindole 5-chloro-1-acetyl-2-oxy in 20 ml of N,N-dimethyl-formamide cooled to about 0°C. Indole 0.75g (3.6 mmol) and 4-
(N,N-dimethylamino)pyridine 0.96ml (7.9
0.4 ml of 2-thenoyl chloride in 5 ml of N,N-dimethylformamide to a stirred solution of
(3.7 mmol) was added dropwise over a few minutes.
The reaction mixture was stirred at about 0° C. for 30 minutes, then at room temperature for 3.5 hours before being poured into 500 ml of ice-cold 2N hydrochloric acid. The resulting solution was extracted with ethyl acetate and the extracts were washed with water and then with saturated sodium chloride solution before drying using magnesium sulfate. Evaporation of the dry ethyl acetate solution gave 1.1 g of crude product. The crude product was purified by column chromatography on silica gel using a dichloromethane-ethyl acetate mixture as eluent and then recrystallized from a small amount of toluene to give the title compound (mp 168°C-170°C).
℃) 250 mg was obtained. The above compound is 5-chloro-3-(2-thenoyl)
It was found that the compound obtained by the reaction of -2-oxindole and acetic anhydride is the same compound. Analysis Calculated value as C ₁₅ H ₁₀ ClNO ₃ S: C, 56.34; H, 3.15; N, 4.38% Experimental value: C, 56.40; H, 3.21; N, 4.32% Reference example 1 5-chloro-1- Acetyl-2-oxindole 5-chloro-2-oxindole 7.0g (42
A mixture of 5.9 ml (63 mmol) of acetic anhydride and 5.9 ml (63 mmol) of acetic anhydride was heated under reflux for 3.5 hours under nitrogen atmosphere.
The cooled reaction mixture was diluted with 300 ml of ethyl acetate,
The resulting solution was washed with aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution.
This ethyl acetate solution was then dried (Na ₂ SO ₄ ),
Evaporation in vacuo gave 8.3 g of a purple solid. This solid was purified by chromatography on silica gel using 2.5% ethyl acetate in dichloromethane as eluent to give 6.0 g of the crude title compound as a yellow solid. This solid was recrystallized from about 50 ml of ethanol to obtain 4.7 g of the title compound as a pale yellow needle-like solid (melting point 129°C to 130°C). Reference Example 2 Following substantially the method of Reference Example 1, the following compound was obtained by reacting the required acid anhydride with the appropriate 2-oxindole: 1-acetyl-2-oxindole, mp.
127-129°C; 5-chloro-1-isobutyryl-2-oxindole, melting point 91-93°C; and 6-chloro-5-fluoro-1-acetyl-2
-oxindole, melting point 146-148°C. Preparation Example 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-oxindole at room temperature. The resulting solution was cooled to ice bath temperature and 15.7 g (0.12 moles) of 2-furoyl chloride was added dropwise over 10-15 minutes. Remove the ice bath and add more ethanol
100ml was added and the reaction mixture was allowed to stand overnight before the solids were separated. This solid was added to 400 ml of water and the resulting mixture was acidified with concentrated hydrochloric acid. The mixture was cooled with ice and the solids were collected by filtration. The solid residue was recrystallized from 150 ml of acetic acid to obtain 8.3 g of yellow crystals (melting point 209-210°C (decomposed)). Analysis Calculated value 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 2 Using the method of Production Example 1 The following products were further obtained by reacting 2-oxindole with the appropriate acid chloride using: 3-(2-thenoyl)-2-oxindole,
Melting point 189-190°C, 17% yield; 3-(2-[2-thienyl]acetyl)-2-oxindole, melting point 191-192.5°C, 38% yield; 3-(2-phenoxyacetyl) -2-oxindole, melting point 135-136°C, 42% yield; and 5-chloro-3-(2-[2-thienyl]acetyl)-2-oxindole, melting point 228-230°C,
22% yield. Preparation Example 3 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.
13.3 g (0.10 mol) was added followed by 16.8 g of ethyl 3-furoate. The mixture was heated to reflux for 47 hours, cooled and the solvent was removed by vacuum evaporation. Grind the residue under 200ml of ether,
The solid was separated and discarded. Evaporate the liquid in vacuum,
The residue was triturated under isopropyl alcohol;
It was recovered by filtration. The solid was suspended in 250ml of water and then acidified with concentrated hydrochloric acid. The mixture was stirred to yield a solid, which was collected by filtration. This solid was recrystallized from acetic acid and then from acetonitrile to give the title compound (mp 185-
186℃) 705mg was obtained. Analysis Calculated value as C ₁₃ H ₉ O ₃ N: C, 68.72; H, 3.99; N, 6.17% Experimental value: C, 68.72; H, 4.14; N, 6.14% Production Example 4 Substantially Production Example 3 According to the method of
Reaction of the oxidole with the ethyl ester of the required carboxylic acid gave the following compound: 5-chloro-3-(2-thenoyl)-2-oxindole, mp 190.5-192°C, 36% yield; 5-chloro-3-(2-furoyl)-2-oxindole, melting point 234-235°C, 54% yield; 5-chloro-3-(2-phenylacetyl)-2
-oxindole, melting point 241-243°C, 61% yield; 5-fluoro-3-(2-furoyl)-2-oxindole, melting point 222-224°C, 51% yield; 5-fluoro-3-( 2-Thenoyl)-2-oxindole, melting point 200-203°C, 26% yield; 6-fluoro-3-(2-furoyl)-2-oxindole, melting point 239-242°C, 26% yield; 6-chloro-5-fluoro-3-(2-thenoyl)-2-oxindole, melting point 212-215°C,
20% yield. In a similar manner, using the required 2-oxindole and ethyl ester, following substantially the method of Preparation Example 3, the following compounds can be prepared: 5-trifluoromethyl-3-(2- Froil)
-2-oxindole; and 5-trifluoromethyl-3-(3-thenoyl)-2-oxindole. Production example 5 3-(3-pyridicarbonyl)-2-oxindole 2.1 g of methium metal in 100 ml of ethanol
(0.090 mol) of 2-oxindole
10.0 g (0.075 mole) was added followed by 13.6 g (0.090 mole) of ethyl nicotinate. The resulting slurry was heated to reflux for 3 hours, then the mixture was cooled and filtered. The residue was discarded and the liquid was evaporated in vacuo. The residue thus obtained is diluted with approximately 150 g of water.
ml and the aqueous solution was washed with chloroform.
Next, 5.8 ml of glacial acetic acid was added to this aqueous solution, and the resulting mixture was cooled in an ice bath. The solid was collected by filtration and recrystallized from ethanol to give 3.3 g of the title compound as yellow needles (melting point 169-170°C). Analysis Calculated values for C ₁₄ H ₁₀ N ₂ O ₂ : C, 70.58; H, 4.23; N, 11.76% Experimental values: C, 70.66; H, 4.41; N, 11.73% 3-(2-pyrrolylcarbonyl)-2-oxindole can be prepared by reacting sodium ethoxide and ethylpyrrole-2-carboxylate with 2-oxindole. Production example 6 5-chloroisatin 100g in ethanol 930ml
To a stirred slurry of (0.55 mol) was added 40 ml (0.826 mol) of hydrated hydrazine to produce a red solution. This solution was heated under reflux for 3.5 hours.
During this time, a precipitate was deposited. The reaction mixture was stirred overnight and the precipitate was collected by filtration to give 5-chloro-
3-hydrazono-2-oxindole was obtained as a yellow solid, which was dried in a vacuum desiccator. The dry solid weighed 105.4g. The dry solid was then added in portions over 10 minutes to a solution of 125.1 g of sodium methoxide in 900 ml of absolute ethanol. The resulting solution was heated to reflux for 10 minutes and concentrated in vacuo to give a gummy solid. This gummy solid was dissolved in 400 ml of water, the aqueous solution thus obtained was decolorized with activated carbon and poured into a mixture of 1 ml of water and 180 ml of concentrated hydrochloric acid containing ice chips. A yellow colored solid precipitated out and 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 obtain 48.9 g of the title compound [melting point 193-195°C (decomposition)]. In a similar manner, 5-methylisatin was treated with sodium ethoxide in ethanol followed by hydrated hydrazine to produce 5-methylisatin.
It was converted to 2-oxindole. The melting point of the product was 173-174°C. Production example 7 4,5-dimethyl-2-oxindole and 5,6-dimethyl-2-oxindole “Organic synthesis”
3,4-dimethylaniline is converted to 3,4-dimethylisonitroacetanilide by reacting chloral hydrate with hydroxylamine using the method described in Collected Volume 1, page 327 of ``Syntheses''. Converted. 3,4 -dimethyl-isonitrosoacetanilide was cyclized with sulfuric acid to give 4,5 -dimethylisatin (melting point 225-226
°C) and 5,6-dimethylisatin (melting point 217-218
°C) was obtained. Substantially according to the method of Preparation Example 6, 4,5-dimethylisatin was prepared by treatment with chloral hydrate and subsequent treatment with sodium ethoxide in ethanol to produce 5,6-dimethyl-2-oxindole ( (melting point 196.5-198°C). Production Example 8 4-chloro-2-oxindole and 6-chloro-2-oxindole A 3-chloro-isonitrosoacetanilide Chloral hydrate 113.23 g (0.686 mol) in water 2
Add 419 g (2.95 g) of sodium sulfate to the stirred solution of
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. next,
A solution of 155 g (2.23 moles) of hydroxylamine in 500 ml of water was added to the reaction mixture with stirring. Stirring was continued and the reaction mixture was slowly heated, maintaining the temperature in the range 60-70° C. for about 6 hours, during which time an additional 1 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 To 775 ml of concentrated sulfuric acid preheated to 70°C, with stirring, 136 g of 3-chloroisonitrosoacetanilide were added at such a rate as to maintain the temperature of the reaction medium between 75 and 85°C. . When all the solids were added, the reaction mixture was heated to 90° C. for an additional 30 minutes. The reaction mixture was then cooled and added slowly to approx. 2 ml of ice with stirring. Additional ice was added as needed to maintain the temperature below room temperature. The resulting red-orange precipitate was collected by filtration, washed with water and dried. Pour the generated solid into water 2
The mixture was made into a slurry and then about 700 ml of 3N sodium hydroxide was added and dissolved. Strain the solution;
The pH was adjusted to 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 give crude 4-chloroisatin 50
I got g. When the liquid from which 4-chloroisatin was recovered is further acidified to PH0 with concentrated hydrochloric acid,
Further precipitate formed. This was collected by filtration, washed with water and dried to obtain 43 g of crude 6-chloroisatin. Crude 4-chloroisatin is recrystallized from acetic acid to produce a substance with a melting point of 258-259°C.
43.3g was obtained. Crude 6-chloroisatin was recrystallized from acetic acid to yield 36.2 g of material with a melting point of 261-262°C. C 4-Chloro-2-oxindole in 350 ml of ethanol - 43.3 g of chloroisatin
Add 17.3 ml of hydrazine hydrate to the stirred slurry of
was added and the reaction mixture was heated to 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-
Add 43.5 g of 2-oxindole little by little,
The resulting solution was heated to reflux for 30 minutes. The cooled solution was concentrated to a gum, the gum was dissolved in 400 ml of water and decolorized using activated carbon. The resulting solution was poured onto a mixture of 1 ml of water and 45 ml of concentrated hydrochloric acid. The formed precipitate was collected by filtration, dried and recrystallized from ethanol to yield 22.4 g of 4-chloro-2-oxindole (melting point 216-218°C (decomposed)). D 6-Chloro-2-oxindole Substantially according to C above, 36.2 g of 6-chloroisatin was reacted with hydrazine hydrate and then with sodium ethoxide in ethanol to form 6-chloro-2-oxindole. Indole (melting point
14.2 g (196-198°C) was obtained. Production Example 9 5,6-difluoro-2-oxindole In the same manner as Production Example 8, Parts A and B, 3,
4-difluoroaniline was reacted with chloral hydrate and hydroxylamine, and then cyclized with sulfuric acid to obtain 5,6-difluoroisatin. This was reacted with hydrazine hydrate and then with sodium methoxide in ethanol in the same manner as in Example 6 to obtain the title compound (melting point 187-190°C).
I got it. Preparation Example 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 is added t of hypochlorous acid in 25 ml of dichloromethane.
-A solution of 10.8 g (0.1 mol) of butyl was added dropwise.
Stirring was continued for 10 minutes at -60 DEG to -65 DEG C. and a solution of 13.4 g (0.1 mol) of ethyl 2-(methylthio)acetate in 25 ml of dichloromethane was added dropwise. Stirring was continued at -60 to -65 °C and dichloromethane 25
A solution of 11.1 g (0.11 mol) of triethylamine in ml was added dropwise at -60 to -65°C. Remove the cooling bath and, when the reaction mixture has reached room temperature, add 100 ml of water.
added. The phases were separated and the organic layer was washed with saturated sodium chloride solution, dried (Na ₂ SO ₄ ) and evaporated in vacuo. The residue was dissolved in 350 ml of diethyl ether, and 40 ml of 2N hydrochloric acid was added thereto. The mixture was generally stirred at room temperature. The phases were separated and the ethereal phase was washed with water and then with sodium chloride solution. The dried (Na ₂ S ₂ O ₄ ) ether phase was evaporated in vacuo to give 17 g of an orange-brown solid, which was triturated under isopropyl ether. The solid was recrystallized from ethanol to give 5-fluoro-3-methylthio-2-oxindole (mp 151.5-152.5).
℃) 5.58g was obtained. Analysis Calculated value as C ₉ H ₈ ONFS: C, 54.80; H, 4.09; N, 7.10% Experimental value: C, 54.74; H, 4.11; N, 7.11% Above 5-fluoro-3-methylthio-2- A sample of oxindole (986 mg, 5.0 mmol) was added to 2 tablespoons of Raney Nickel under 50 ml of absolute ethanol, and the reaction mixture was heated to reflux for 2 hours. The catalyst was removed by decantation and washed with absolute ethanol. The ethanol solution and ethanol wash were combined and evaporated in vacuo and the residue was dissolved in dichloromethane. Dry the dichloromethane solution (Na ₂ SO ₄ ),
Evaporation in vacuo gave 475 mg of 5-fluoro-2-oxindole (melting point 121-134°C). Similarly, 4-trifluoromethylaniline was reacted with t-butyl hypochlorite, ethyl 2-(methylthio)acetate and triethylamine, and then the 3-thiomethyl-5-trifluoromethylaniline thus obtained Methyl-2-oxindole was reduced by Raney nickel to give 5-trifluoromethyl-2-oxindole (melting point
189.5-190.5°C). Production Example 11 5-Methoxy-2-oxindole In the same manner as in Production Example 10, 5-methoxy-2-oxindole
2-oxindole was prepared from 4-methoxyaniline. However, the first chlorination step was carried out using a solution of chlorine gas in dichloromethane instead of t-butyl hypochlorite. The melting point of the title compound is
The temperature was 150.5-151.5℃. Production example 12 6-chloro-5-fluoro-2-oxindole Add 3-chloro-5-fluoro-2-oxindole to 130 ml of toluene with stirring.
24.0 g (0.165 mol) of 4-fluoroaniline and pyridine (0.166 mol) were added. 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 and extracted with 100 ml of 1N hydrochloric acid and then with 100 ml of saturated sodium chloride solution. The resulting toluene solution was dried over magnesium sulfate and concentrated in vacuo to yield 32.6 g (88% yield) of N-(2-chloroacetyl)-3-chloro-4-fluoroaniline. 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 to ~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 and the solid was collected by filtration (22g). This solid was dissolved in ethyl acetate-hexane 1:1.
Dissolved in the mixture and chromatographically analyzed on 800 g of silica gel. Elute the column and evaporate the fractions to N-(2-chloroacetyl)-
117 g of 3-chloro-4-fluoroanilide was obtained,
From this, 3.0 g of 6-chloro-5-fluoro-2-oxindole was obtained. The latter material was recrystallized from toluene to give the title compound (mp 109-206
℃) 1.70 g (7% yield) was obtained. NMR spectroscopy showed that the product was contaminated with some 4-chloro-5-fluoro-2-oxindole. Production example 13 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 was heated to 210-220°C. 4
After an hour, the reaction mixture was cooled and added to a mixture of 100 ml of 1N hydrochloric acid and 50 ml of ice. The resulting tan solid was collected by filtration and recrystallized from aqueous ethanol. Three yields were obtained weighing 4.49g, 2.28g and 1.0g respectively. The yield of 1.0 g was further recrystallized from water to give the title compound (melting point 168.5-171°C).
Obtained 280 mg. Production example 14 6-Bromo-2-oxindole Add 195 ml of dimethyl sulfoxide to 9.4 g of sodium hydride, then add 22.37 ml of dimethyl malonate.
was dripped. At the end of the addition, the mixture was heated to 100°C and maintained at this temperature for 40 minutes. at this point
25 g of 1,4-dibromo-2-nitrobenzene was added all at once. The reaction mixture was maintained at 100° C. for 4 hours before being added to 1.0 ml of saturated ammonium chloride solution. The resulting mixture was extracted with ethyl acetate,
The extract was extracted with ammonium chloride solution, water and saturated sodium chloride solution. dried ( _MgSO4 )
The solvent was evaporated and the residue was recrystallized from ethyl acetate-hexane to give dimethyl-2-(4-bromo-
22.45 g of 2-nitrophenyl) malonate were obtained. 17.4 g of dimethyl 2-(4-bromo-2-nitrophenyl)malonate and dimethyl sulfoxide
A solution consisting of 4.6 g of lithium chloride in 150 ml of
After 3 hours, the reaction mixture was cooled to room temperature and poured into a mixture of 500 ml of ethyl acetate and 500 ml of saturated sodium chloride solution. The phases were separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried using sodium sulfate and then evaporated in vacuo. The residue was treated with silica gel as an adsorbent.
Chromatographic analysis was performed using an ethyl acetate-hexane mixture as eluent. This gave 9.4 g of methyl-2-(4-bromo-2-nitrophenyl)acetate. Iron powder was added to a solution of 7.4 g of methyl-2-(4-bromo-2-nitrophenyl) acetate in 75 ml of acetic acid.
Added 6.1g. The reaction mixture was placed in a 100°C oil bath. After 1 hour, the solvent was removed by vacuum evaporation and the residue was dissolved in 250 ml of ethyl acetate. The solution was filtered, washed with saturated sodium chloride solution, dried using sodium sulfate, decolorized using activated charcoal and evaporated in vacuo. This gave 5.3 g of 6-bromo-2-oxindole as a white crystalline solid (melting point 213-214 DEG C.). Similarly, starting from 1,4,5-trichloro-2-nitrobenzene, 5,6-dichloro-
2-oxindole (melting point 209-210°C) was produced. Production example 15 6-phenyl-2-oxindole To 3.46 g (0.072 mol) of sodium hydride was added 50 ml of dimethyl sulfoxide, and a solution of 8.2 ml (0.072 mol) of dimethyl malonate in 10 ml of dimethyl sulfoxide was added dropwise with stirring. . After the dropwise addition was complete, stirring was continued for 1 hour and then a solution of 10 g (0.036 mol) of 4-bromo-3-nitro-diphenyl in 50 ml of dimethylsulfoxide was added. The reaction mixture was heated to 100° C. for 1 hour, cooled and poured onto an ice-water mixture containing 5 g of ammonium chloride. The mixture thus obtained was extracted with ethyl acetate, the extracts were washed with sodium chloride solution and dried using magnesium sulphate. Evaporation in vacuo gave an oil which was chromatographed on silica gel and recrystallized from methanol to yield 6 g of dimethyl 2-(3-nitro-4-diphenyl)malonate (mp 82-83°C). Ta. 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/cm ² to give the corresponding amine. The compound was refluxed in ethanol for 16 hours and the product was recovered by solvent evaporation and recrystallized from methanol as ethyl 6-phenyl-2-oxindole-1-carboxylate (mp 115-117°C). 1.1
I got g. The above ethyl ester (1.0g) and 6N-hydrochloric acid 100%
ml was heated to reflux for 3 hours and left at room temperature for 3 hours.
The solid was collected by filtration and dried to give 6-phenyl-2-oxindole (melting point 175-176°C).
Got 700mg. Production example 16 5-acetyl-2-oxindole 27 g of aluminum chloride in 95 ml of carbon disulfide
(0.202 mol) and then a solution of 3 ml (0.042 mol) acetyl chloride in 5 ml carbon disulfide was added dropwise with stirring. Continue stirring for 5 minutes, then 2-
4.4 g (0.033 mol) of oxindole was added.
The resulting mixture was heated to reflux for 4 hours and cooled.
removing carbon disulfide by decantation;
The residue was triturated under water and collected by filtration. After drying, the title compound (melting point 225-227
℃) 3.2g was obtained. 2-oxindole was reacted with benzoyl chloride and 2-thenoyl chloride in the presence of aluminum chloride in accordance with the method substantially described above to give the following compound: 5-benzoyl-2-oxindole , melting point
203-205°C, (from _CH3OH ) and 5-(2-thenoyl)-2-oxindole,
Melting point 211-213 °C (from _CH3OH ). Preparation Example 17 5-Bromo-2-oxindole can be prepared by bromination of 2-oxindole; see also Beckett et al., Tetrahedron 24 , 6093 (1968) and Sumpter. (Sumpter) et al., Journal of the American Chemical Society.
See also 67, p. 1956 (1945). 5-n-Butyl-2-oxindole can be prepared by reacting 5-n-butylisatin with hydrazine hydrate and then sodium methoxide in ethanol according to the method of Preparation Example 6. . 5-n-butylisatin is 4-n-
It can be produced from butylisatin according to the methods of Parts A and B of Preparation Example 8 by treatment with chloral hydrate and hydroxylamine and subsequent cyclization with sulfuric acid. 5-Ethoxy-2-oxindole was prepared by standard method (ethyl iodide in potassium carbonate and acetone).
3-hydroxy-6-nitrotoluene was converted to 3-ethoxy-6-nitrotoluene by Beckett et al. in Tetrahedron 24 , p. 6093 (1968). 5-methoxy from nitrotoluene
It can be prepared by converting 3-ethoxy-6-nitrotoluene to 5-ethoxy-2-oxindole by the method described for the conversion to 2-oxindole. 5,6-dimethoxy-2-oxindole is from Waker's Journal of the
American Chemical Society (Journal)
of the American Chemical Society) 77, 3844
(1955). 7-Chloro-2-oxine indole can be made by the method described in US Pat. No. 3,882,236. 4-thiomethyl-2-oxindole and 6-
Thiomethyl-2-oxindole can be made by the method described in US Pat. No. 4,006,161. 5-n-Butylthio-2-oxindole can be prepared in a similar manner, but by substituting 4-butylthioaniline for 3-methylthioaniline. 6-Fluoro-2-oxindole is available from the Collection of Czechoslovakian chemicals such as Protiva.
Communications) 44 , p. 2108 (1979) and US Pat. No. 4,160,032. 6-Trifluoromethyl-2-oxindole is available from Simet's Journal of
Organic Chemistry (Journal of
Organic Chemistry) 28 , p. 3580 (1963). 6-Methoxy-2-oxindole can be prepared according to Wieland et al., Chemischs Berichte 96 , p. 253 (1963). 5-Nitro-2-oxindole has been described by Sampter et al. in the Journal of the American Chemical Society.
67 , p. 499 (1945). 5-cyclopropyl-2-oxindole and 5-cycloheptyl-2-oxindole are
According to the method of Production Example 6, 5-cyclopropyloxindole and 5-cycloheptylisatin can be produced by reacting each with hydrazine hydrate and then sodium methoxide in ethanol. 5-Cyclopropylisatin and 5-cycloheptylisatin are prepared from 4-cyclopropylaniline and 4-cycloheptylaniline, respectively, using chloral hydrate and hydroxylamine according to Parts A and B of Production Example 8. and then cyclization with sulfuric acid.

Claims (1)

[Claims] Primary formula: [wherein ^, a phenylalkyl, or -
( _CH2 ) _o -Q- ^R0 ; n is 0, 1 or 2, Q is a divalent radical derived from a compound selected from the group consisting of furan, thiophene and pyridine, and ^R0
is hydrogen or alkyl having 1 to 3 carbon atoms; and R ² is alkyl having 1 to 5 carbon atoms] and its pharmaceutically acceptable Basic salts that can be made. 2 X is at the 5-position or 6-position and is hydrogen, fluoro, chloro or bromine; Y is hydrogen and R ¹ is alkyl having 1 to 6 carbon atoms, phenyl, furyl, thienyl, pyridyl, alkyl The compound according to claim 1, which is phenylalkyl, furylmethyl or thienylmethyl having 1 to 3 carbon atoms. 3. The compound according to claim 2, wherein X is hydrogen or 5-chloro. 4. A compound according to claim 3, wherein ^R1 is selected from the group consisting of 2-furyl, 2-thienyl, 3-pyridyl and (2-thienyl)methyl. 5. The compound according to claim 4, wherein R ² is methyl. 6. The compound according to claim 5, wherein X is hydrogen and ^R1 is 2-thienyl. 7. The compound according to claim 5, wherein X is 5-chloro and ^R1 is 2-thienyl.