Method of producing derivatives of 2-oxoindole-1-carboxy-amide

专利摘要:
2-Oxindole-1-carboxamides of the formula: …<CHEM>… and their pharmaceutically acceptable base-salts, where X and Y are certain optional substituents or can be taken together to form certain ring structures; and R<1> is alkyl, cycloalkyl, cycloalkenyl, optionally substituted phenyl, optionally substituted phenylalkyl, optionally substituted phenoxyalkyl, (thiophenoxy) alkyl, naphthyl, bicyclo [2.2.1]heptan-2-yl, bicyclo [2.2.1]hept-5-en-2-yl or a group of the formula -(CH2)n-Q-R<0> where n is 0, 1 or 2, Q is a divalent radical which is a specified heterocycle, and R<0> is H or alkyl. …<??>The compounds are useful as analgesic and anti-inflammatory agents. …<??>Also covered are certain intermediates useful in the preparation of the compounds (I), these intermediates having H in place of -COR<1>.
公开号:SU1445556A3
申请号:SU853869754
申请日:1985-03-18
公开日:1988-12-15
发明作者:Бернард Кадин Сол
申请人:Пфайзер Инк, (Фирма)；
IPC主号:

专利说明:

The invention relates to organic chemistry, namely to a method for producing new 2-oxrin-dol-1-carboxamide derivatives of the general formula
(I)
where X is hydrogen, fluorine, chlorine, bromine,
trifluoromethyl, methyl, methoxy, methylthio, nitro, phenyl, benzoyl, thenoyl or acetyl; Y - hydrogen, fluorine, chlorine, methoxy, methyl or X and Y together form the 5,6-methylenedioxy group 4-GHi-CHi-CHi-5, 5-CH.j, -CH2 CHs, -6, b-CHg-CH -CH.-CHg-), i 5-CH CH-CH CH-6, 5-0-CH2.-CHg-, 6, 5-CHg-CH2.-0-6, 5-S-CH2-CH. J 6, 5-0-CH CH 6, 5-S-CH CH-6, 5-CH CH-S-6, where the numbers indicate the point of attachment to the benzene ring; R Furyl, thienyl, thienylmethyl, furylmethyl, phenoxymethyl, phenoxyethyl, phenylethyl, Cj-Cg-cycloalkyl, methyl, isopropyl, dicyclo- (2,2,1) heptane-2-yl, dicyclo- (2,2 , 1) hept 5-en-2-yl, phenyl, phenyl, substituted by one or two chlorine atoms or methyl, benzyl, benzyl, substituted by chlorine or trifluoromethyl, pyrlsh1, pyrimidine, trifluoromethyl, tetrahydrofuryl, isothiazole, thiazolyl, 1-methyl-5-pyrazolyl, - 5-methyl-3-isoxazolyl, 1,2,3-thiadiazolsh1-4 yl, 1,2,5-thiadiazole 3-yl, yp their pharmaceutically acceptable salts, which can be used in medicine since give anti-inflammatory and analgesic properties.
 The aim of the invention is to develop an accessible process for the preparation of compounds of formula (I) having useful pharmacological properties.
The invention is illustrated by the following examples.
Example 1. 5-Chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide.
0
five
Mixable sludge 21.1 g (0.1 mol) 5-chloro-2-oxindole-1-carboxamide and 26.9 g (0.22 mol) 4 g (H, H-dimesh1amino) pyridine in 200 ml N, N-dimethylformamide is cooled to an ice bath temperature, and then a solution of 16.1 g (0.11 mol) of 2-tenosylchloride 0 in 50 ml of N, N-dimethylformamide is added dropwise to the slurry.
Stirring is continued for approximately 30 minutes, after which the reaction mixture is poured into a mixture of 1. L of water with 75 ml of 3N. hydrochloric acid. 5 The resulting mixture is cooled in an ice bath, and then the solid is collected by filtration. This solid material is washed with water, after which it is recrystallized from 1,800 ml of acetic acid, resulting in 26.6 g of the title compound being obtained in the form of light yellow crystals with m.p. 230 C (with decomposition).
Calculated,%: C, 52.42; H 2.83; N 8.74.
Found,%: C 52.22; H 2.81; N 8.53.
Example 2. By reacting the corresponding 2-oxindole-1-carboxamide with the desired acid chloride, basically, according to the procedure of Example 1, the compounds shown in Table 2 are obtained. 1. 5. Example 3. 5-Chloro-3-acetyl-2-oxindole-1-carboxamide.
Stirring 842 mg (4.0 mmol) of 5-chloro-2-oxindol-1-carboxamide and 1.08 g (8.8 mmol) 0 4- (N, N-dimethylamino) pyridine in 15 ml of N, N- The dimethylformamide is cooled to an ice bath temperature, and then a solution of 449 mg (4.4 mmol) of acetic anhydride in 5 ml of N, N-dimethylformed is added dropwise to the slurry. Stirring is continued for approximately 30 minutes, and then the reaction mixture is poured into a mixture of 75 ml of water with 3 ml. 3N hydrochloric acid 0. The resulting mixture was cooled in an ice bath and the solid material was removed by filtration. Next, the solid material is recrystallized from acetic acid, receiving 600 mg of light 5 pale pink crystals with so pl. 237, (with decomposition).
Calculated,%: G 52,, 29; H 3.59;
N 11.09.
With „HgClNjO,
Found,%: C 52.08; H 3.63; N 11.04.
Example 4. By reacting the corresponding 2-oxindole-1-carboxamides with activated derivatives of the desired carboxylic acid of the formula R-CO-OH 3, essentially as described in Example 1 or Example 3, the compounds shown in Table 2 are obtained. 2
Example 5. The reaction of 2-thenoyl chloride and 2-furoyl chloride
556
amine. The prepared solution is cooled to 50 ° C, 65 g of decolorizing carbon is added to it, after which the solution is reheated to reflux temperature and held under these conditions for 1 hour. The hot solution is filtered through supershell 10 (diatomaceous earth) and the filtrate is cooled to 40 ° C. 392 ml of concentrated hydrochloric acid is gradually added to the filtrate gradually over 30 minutes. This mixture is cooled to 20-23 C, ne
with 5,6 methylenedioxy-2-oxindol-1-carc-15 is stirred for 30 minutes, after
a boxamide according to the procedure of Example 1 gives the compounds: 5, 6-methylenedioxy-3- (. 2-thenoyl) -2-oxindole — 1-carboxamide with mp, 215-217 C (with decomposition);
5,6-methylenedioxy-3- (2-furoyl) -2-oxindole-1-carboxamide-c. 234- 235 ° С (with decomposition).
Example 6. By reacting the corresponding acid chloride with the desired 2-oxindole-1-carboxamide according to the procedure of Example 1, the compounds listed in Table 2 can be prepared. 3
Example 7. 5-Chloro-3- (2-toosh-1) -2-oxindole-1-carboxamide.
In a stirred sludge of 429.9 g (2.04 mol) of 5-chloro-2-oxindole-1-carboxamide in 4 l of S, H-dimethylformamide, 547.9 g (4.48 mol) of 4- (N, N dimethylamino) pyridine, and then the mixture is cooled to 8 ° C. To this mixture, with stirring, add a solution of 328 g (2.23 mol) of thenoyl chloride in 800 ml of N, N-dimethylformamide over 30 minutes, the temperature being kept in the range of 8-15 ° WITH. Stirring is continued for 30 minutes and then the reaction mixture is stirred in with stirring into a mixture of 510 ml of concentrated hydrochloric acid with 12 liters of water. Stirring is then continued for 2 hours, after which the solid material is collected by filtration, washed first with water and then with methanol. The solid is dried to give 675.6g of the title compound.
A portion (673.5 g, 2.1 mol) of this compound was added to 13 L of methanol and the mixture was heated to reflux temperature. 136 g (2.22 mol) of ethanol are then added to the stirred mixture.
which solid material is collected by filtration and washed with methanol. The solid material is dried, resulting in 588 g of the title compound with a mp. 229-231,5 ° С (with decomposition).
Example 8. Ethanolamine salt of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide.
The sludge 321 mg (1.0 mmol) of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide in 25-30 ml of diisopropyl alcohol is heated to the boiling point, after which a solution is added to it
67 mg of ethanolamine in 1 ml of diisopropyl alcohol. The result is a yellow solution within 2-3 minutes. This solution is evaporated to a volume of 12-13 ml, after which it is allowed to cool.
The resulting solid was filtered, resulting in 255 mg of the indicated salt as a yellow crystal, m.p. 165.5 - 67 ° C (with weak decomposition). Calculated,%: C 50,32; H 4.22;
N 11.00.
,, C1N ,.
Found,%: C 50.52; H 4.44; N 10.88.
45 Example 9. Sodium salt of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide.
Part A. In the stirred sludge 20 g (62.4 mmol) of 5-chloro-3- (2-teno50 yl) 2-oxindole-1-carboxamide c. 400 ml of methanol was added dropwise at room temperature with 4.14 ml (68.6 mmol) of ethanolamine. In this way, a solution of
55 a solution (6.74 g, 124.7 mmol) of sodium methoxide in methanol. The mixture is then heated to a temperature of approximately 90 ° C, after which it is allowed to cool and is stirred in
night's night The resulting solid was isolated by filtration and dried at room temperature under vacuum overnight, giving 18.12 g of crude product. This crude product is recrystallized from a mixture of methanol and isopropanol, resulting in 1.73 g of the first portion and 10.36 g of the second portion of the 5-chloro-3- (2-thooyl) -2 salt of sodium salt monohydrate. carboxamide. Both portions of the product melt at 236-238 ° C.
Calculated,%: C 46.48; H 3.06; N 7.74.
C 4HgClN OjSNa-H2.0
Found,%: 1 portion; C 46.99; H 2.68; N 7.98;
2 portions: C, 46.71; H 2.70; N 7.79. ,
The remainder of the first portion is dried. The result is anhydrous sodium salt of 5-chloro-3- (2-tekoyl) -2-oxindole-1-carboxamide with so pl. 237- 238 ° C.
Elementary analysis data for the remainder of the first portion of the product.
Calculated,%: C 48.92; H 2.64; N 8.15.
C HgClN OjSNa
Found,%: C 48.23; H 2.81; N 7-, 89.
Part B. To a stirred sludge of 20 g (62.4 mmol) of 5-chloro-3- (2-theioyl) -2-oxindole-1-car-6-amamide in 400 ml of methanol was added 4.14 ml (68.6 mmol) of ethanol ( dropwise, at room temperature). In this way, a clear solution is added. 6.74 g of powdered sodium dioxide and the mixture are added. The solid material which precipitated at the 3rd was collected by filtration and dried under high vacuum for the first time. The result is a 5-chloro-3- (2-teno-1x) -2-tenoyl) -2-oxindole-1-carboxamide hemi-distillate with mp. 238–239 C.
Calculated,%: C 47.67; H 2.85; N 7.94.
C HaClN203SNa 0,
Found,%: C 47.72; H 2.73; N 7.70.
Example 10. Kaliyev salt. Z-ulor-3- (2-tenoip) -2-oxindol-1-carboxamide.
The procedure of Example 9 of Part B is repeated completely, except for that.
ten
15
20
25
p- 40 - 4455566
that instead of powdered sodium methoxide use a solution of 7.00 g of potassium hydroxide in methanol. As a result, potassium monohydrate is obtained.
thirty
-

salts of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide with so pl. 214-216 ° C. Calculated,%: C 44.30; H 2.93; N 7.41.
C, HgClNjO, SK-HtO
Found,%: C 44.29; H 2.67; N 7.22.
Example 11. The ammonium salt of 5-chloro-3- (2-tenoyl) -2-oxindole-1-carboxamide. .
Said salt is obtained essentially according to the procedure of Example 9 part B using an ammonia solution in methanol instead of powdered sodium methoxide. The result is an anhydrous salt with so pl. 203-204 S.
Calculated,%: C 49.64; H 3.86; N. 12.41 .-. C, 4H8C1N SO, -NH4
Found,%: C 49.75; H 3.53; N 12.20.
Example 12. 2-Oxindole-1-carboxamide.
B, a solution of 194 mg (1.0 mmol) of 2-C2-ureidophenyl) acetic acid in 4 ml of trifluoroacetic acid was added 630 mg (3.0 mmol) of trifluoroacetic anhydride and then the mixture was kept at 35 at reflux temperature for approximately 1 h. Next, the reaction mixture is cooled and the solvent is removed by evaporation in vacuum. The residue is dissolved in 5-8 ml of saturated sodium bicarbonate solution, and the material that precipitates from the solution is collected by filtration. The solid thus obtained was recrystallized from ethanol to obtain 61 mg of the compound as colorless crystals with m.p. 179-180 s (with weak decomposition).
Calculated,%: C, 61.36; H 4.58; 50 N 15.91.
C 9 HfftN O
Found,%: N 15.77.
Example 55 1-carboxamide.
Cyclization of 4.78 g (0.021 mol). 2- (5-chloro-2-urendophenyl) acetic acid together with 8-, O g (0.063 mol) trifluoroacetic anhydride in 75 ml
45
C, 61.40; H 4.80;
13. 5-Chloro-2-oxindol trifluoroacetic acid in accordance with the procedure of Example 12 and the subsequent recrystallization of the crude product from acetonitrile allows to obtain 80 mg of the compound with m.p. 211 C (with decomposition).
Imported,%: C, 51.32; H 3.52; N 13.30.
С,, 0, i
Found,%: C 51.37; H 3.37; N 13.53.
Example 14. 2-OXINDOL-1-carbrxamide.
1.20 g (8.4 mmol) of chlorosulfonyl isocyanate is added to a mixture of 0.94 (7.1, mmol) of 2-oxindole with 30 ml of diethyl ether and the mixture is stirred at room temperature for 20 hours. Then diethyl ether removed in vacuo and the residue is treated with 10 ml of water and 10 ml of 1N. hydrochloric acid solution. 125 ml of ethyl acetate and a mixture of the mixture are then added. According to the procedure of Example 15, the above compound is prepared from 1.0 g (6.0 mmol) of 6-fluoro-5-metsh1-2-oxindole and 1.03 g (7.3 mmol)
toluene. At the stage of hydrolysis using 5 Nm of water, resulting in a gain of 0.58 g (46% yield) of the product with so pl. 200-203 ° C.
for 1 hour. Separate the ethyl acetate-25 chlorosulfonyl isocyanate in a 30-th polymer phase, wash it with one 50-ml portion 1 and. hydrochloric acid, 2 portions of 100 ml brine each and dried over magnesium sulphate. As a result of the concentration, 0.97 g (77% yield) of crude product is obtained. Recrystallization from ethanol of N allows to obtain 0.18 g of product with m.p. 177-179 p.
Example 15. 2-Oxindol-1-car- 35 N 12.05. boxamide.
To a stirred mixture of 5.86 g (44.0 mmol) of 2-oxindole with 160 ml of dry toluene was added 7.47 g
Calculated,%: C 57.69; H 4.36; 13.46. Found,%: C 57.02; H 4.41;
Sample chlorosulfonyl prom-. before the hydrolysis, the short product is removed and subjected to mass spectrometric analysis for the purpose of accurate (52.8 mmol) chlorosulfonyl isocyanate. 40 determine the mass, as a result of which Chlorine immediately begins to emit that the molecular weight
hydrogen hydrogen. This mixture was stirred at reflux temperature for 15 minutes, after which it was cooled to room temperature. 50 ml of water are added to the cooled mixture (first, some hydrogen chloride is released), and then the mixture is stirred for 1.5 hours. Solid
C, (, HgN.i04SCl is 307.9848.
Example 17. 2-Oxindole-1-carboxamide.
45 To the sludge 13.3 g (0.10 mol) of 2-oxindole in 150 ml of toluene was added 15.6 g (0.11 mol) of chlorosulfonyl isocyanate and the reaction mixture was held over a steam bath for 10 minutes,
50 almost immediately after the formation and
the product which precipitates during the precipitation over the course of the precipitates is collected by filtration and in a short 3 minutes a clear
sew (4.10 g). The filtrate is exposed to the solution. The reaction mixture is cooled.
extracting 100 ml of ethyl water in an ice bath for 30 minutes, acetate, and the resulting extract was washed, after which the solid material was filtered out in 2 portions of 100 ml each time, brine and dried in air, dried over magnesium sulfate. In the thus obtained chlorosulfate, by evaporation of the prionyl intermediate intermediate product, under reduced pressure, 4.16 are obtained in 240 ml of an acetic acid mixture.
solid material. The combined portions of solid material are recrystallized by dissolving in 200 ml of acetonitrile, followed by concentration of the solution under reduced pressure to a residual volume of about 75 ml. A small amount of amorphous material which is separated is filtered off, the filtrate is decolorized and concentrated under reduced pressure to a residual volume of approximately 50 ml, after which seed material is added to it. As a result, 3.0 g (38% yield) of the compound is obtained in the form of dark red crystals, which are filtered and dried.
Example 16. 6-Fluoro-5-methyl-2oxindole-1-carboxamide. .
In accordance with the procedure of the prior 15, said compound is made from 1.0 g (6.0 mmol) of 6-fluoro-5-esh1-2-oxindole and 1.03 g (7.3 mmol)
chlorosulfonyl isocyanate in 30 gy
toluene. At the stage of hydrolysis using 5 Nm of water, resulting in a gain of 0.58 g (46% yield) of the product with so pl. 200-203 ° C.
Chlorosulfonyl isocyanate in 30 gy N
orsulfonyl isocyanate in 30yy
Calculated,%: C 57.69; H 4.36; 13.46. Found,%: C 57.02; H 4.41;
C, (, HgN.i04SCl is 307.9848.
Example 17. 2-Oxindole-1-carboxamide.
45 To the sludge 13.3 g (0.10 mol) of 2-oxindole in 150 ml of toluene was added 15.6 g (0.11 mol) of chlorosulfonyl isocyanate and the reaction mixture was held over a steam bath for 10 minutes,
50 almost immediately after the formation and
9144555610
with water in the ratio of 2; .1 and obtained; At 5–10 ° C, 5.66 g (0.04 mol) of chlorine sludge is kept on a water bath of sulfonyl isocyanate and added to the sludge for 10 min. Then it is cooled with 6.0 g (0.033 mol) of a 6-methylthio-2-oxine-in bath, and not completely white with a fraction of 60 ml of acetonitrile. This reacting material, which is formed, is filtered and dried in air. As a result, the concentration of the stock solution to a viscous mass and
filtering the cavity by an additional extraction treatment with 600 ml ethyl 1.2 g of the product. The combined solid acetate, after which the extract washed material is recrystallized
from about 250 ml of ethanol with
obtaining of 11.48 g (65% yield)
product.
PRI me R 18. Substituted 2-i.
sequentially with water and brine, dried over magnesium sulphate and evaporated under reduced pressure with 15 preparation of a gray solid material, which is recrystallized from
oxindole-1-carboxamide.
The reaction of the corresponding 2-oxynolides with chlorosulfonyl isocyanate with
subsequent hydrolysis, in accordance with which 20 are obtained in total
with the procedure of Example 17, the lower compounds listed in Table 1 are obtained. four.
Example 19. 5,6-Methyldioxy-2-oxindole-1-carboxamide.
5,6-Methylenedioxy-2-oxindole-1-carboxamide is prepared by reacting 5,6-methylenedioxy-2-oxindole with chlorosulfonyl isocyanate, followed by hydrolysis according to the procedure. of example 17. After recrystallization from acetic acid, a product with m.p. 237-238 C (with decomposition).
Example 20. The reaction of the corresponding 2-oxindoles with chlorosulfonyl-isocyanate, followed by hydrolysis according to the procedure of Example 17, can be obtained triticlic compounds:
-L
,
 N I
Y
0 C-SH12
where X and Y: 4-CH2-CH2.-CH2-5; e-CHi-CE-CE-CHt-J 5-CH: CH-CH CH-6, 5-0-CH2-CHi-6; 0-6; З-З-СНг-СКа-б; 5-0-t; H CH-6; ZZZ-CH CH-B; .5-CH CH-S-6 (the digit to the left of fop a5 ly indicates the point of attachment of this radical end to the 2-oxindole cycle, and the digit to the right
pointing to the point of attachment of the right-55 under reduced pressure allows the Zogh of the radical to the 2-oxindole to obtain an additional amount of ring). Recrystallization from aceplimer 21. 6-Methylthio-2-tonitrile gives an additional g of oxind-l-1-carboxyamide product.
The mixture is stirred for 1 hour. Then 100 ml of water are added and stirring is continued for 10 minutes. The aqueous solution is subjected
sequentially with water and brine, dried over magnesium sulphate and evaporated under reduced pressure with 15 preparation of a gray solid material, which is recrystallized from
acetonitrile to obtain 3, O g product. An additional .0.71 g of product is obtained from the mother liquor, after 5
3.71 g (yield 50.6%) of the product with so pl. 176-179 ° C.
Example 22. 5,6-Dimethoxy-25 oxindole-1-carboxamide.
In accordance with the procedure of Example 21, the title compound was prepared using 8.0 g (0.042 mol) of 3,6-dimethoxy-2-oxindole, 7.08 g
0 (0.05 mol) of isocyanate and 73 ml of acetonitrile. The crude product obtained after evaporation of the ethyl acetate extract was recrystallized from a mixture of acetonitrile and acetic acid in a 1: 1 ratio, resulting in the separation of 6.02 g (60% yield) of the compound with m.p. 206.5-209 C.
Example 23. 6-Trifluormetsh1-2-oxindole-1-carboxamide.
To a slurry of 8.0 g (0.04 mol) of 6-trifluoromethyl-2-oxindole, 6.65 g (0.047 mol) of chlorosulfonyl isocyanate are added to 80 ml of acetonitrile and the mixture is stirred for 45 minutes. Further, up to 5 ml of water is added to the mixture and the aqueous mixture is stirred for 1 hour. The precipitate, which is formed, is filtered off and recrystallized from acetonitrile, resulting in a yield of 0.92 g of product. Extraction and processing of the filtrate with an aqueous reaction mixture - 300 ml of ethyl acetate, followed by extracting c-ear over magnesium sulfate and then evaporation
0
0
1445556 2
An additional 1.85 g of the product with the final solution of acetic acid in the mixture is combined by combining the mother liquors according to the procedure of the example, after recrystallization from acetonite-26, respectively, of the compound is obtained and concentrated by the following: 5-acetyl-2-oxindol-1 - gbar pressure box. As a result, the amide (34% yield) with so pl. 200 C total of 4.97 g (with decomposition) is obtained (from a mixture of methanol (51% yield) of product with mp. CH, CN); 5- (2gtiensh1) -2-oxindol-1-207.5-210 ° C. carboxamide (51% yield) with m.p.
Example 24. Repeating 200 ° C (with decomposition) from the mixture of the procedure of Example 23, but using c.
By using the corresponding substituted 2-oxin-Example 28. 5-Acetamido-2-dolov, the compounds given by oxindole-1-carboxamide are obtained. the data in table. 5. Slurry 0.5 g (2.6 mmol) of 5-amino-2 Example 25, 6-Phenyl-2-oxin-15 oxindole-1-carboxamide and 0.35 g of 4-dol-1-carboxamide. (H, K-dimethylamino) pyridine mixed with 4.5 g (21.5 mmol) of 6-phenyl-2- is added and then oxindole is added to the mixture in a mixture of 100 ml of toluene and 0.20 ml (2.8 mmol) acetylchloro-25 ml of tetrahydrofuran with stirring. Stirring is continued for 5 ° C and 2.2 ml of 20 ml are added to the precipitate for 20 minutes at -10 ° C and
(25.8 mmol) of chlorosulfonyl isocyanate. at room temperature for stirring, continue for 15 minutes, then add 20 ml of 1 hour at 0-5 ° C, and then add. in 1N. hydrochloric acid solution. Top is a mixture of 100 ml of water. The solid material is separated by filtration by filtration and 25 are added and dried to obtain 0.20 g of the product in a mixture of 40 ml of glacial acetic acid as a solid, dyed with 80 ml of water. Formed cervical to cream color. The mixture was incubated at 100 ° C for 1 ° C using butanoyl chloride for 1 hour, cooled and filtered, instead of acetylchloride, when carried out. The residue is dried to give 30% of the above procedure. 3.1 g of the compound with m.p. 188-189 ° C. get 5-butanamido-2-oxindole-1 Example 26. 5-Benzoyl-2 - carboxamide. oxindole-1-carboxamide. Example 29, 5-Benzamido-2Mixed 10.1 g (42 mmol) of 5-benzoyl-oxindole-1-carboxamnd.
2-oxindole, 4.4 ml (51 mmol) of chloro-35 by acetylation of 5-amisulfonyl isocyanate and 300 ml of trano-2-oxindole-1-carboxamide hporis-hydrofuran are mixed at room temperature; temperature for 6 hours, after the procedure of Example 28, to the extent that: the solvent is evaporated in vacuo of 90% yield as colourant. The residue is added to 150 ml of ice-40 cream-colored solid acetic acid and 300 ml of water,. Duk.ta receive connection with so pl.223- after which the final mixture is hollow - 226 C.
are refluxing at about 30 ° C. 4-Methylsulfonyl-cooler for 2 hours. Next, 2-oxindole-1-carboxamvd. the reaction mixture is cooled and the top 45. The indicated compound is obtained and the liquid layer is removed by decantation. by oxidation of 2.5 g of 4-methylthio-2-oxin- Residual resinous material with a molecular weight of 2.4 mol-1-carboxamide. is equivalent to - rubbing in acetonitrile to obtain 3-chloroperbenzoic acid in a solid product, which is taken up in tetrahydrofuran at room temperature, after which its mixture is crystallized from the mixture using n-propanone procedures. 0.81 g (28% cessing with acetonitrile in the ratio of 1: 1. Stroke) of the product is altered as a solid. 4.1 g of the compound are obtained.
not in the form of a solid substance with so pl. Example 31. b-Methlsulfonyl- 210-211 C. I 55 2-OXINDOL-1-carboxamide.
Example 27. As a result of re-oxidation, 1.25 g of 6-stock of 5-acetyl-2-oxindole and 5- (2-methylthio-2-oxindole-1-carboxido-tenoyl) -2-oxindole with chlorosulfonyl- 2.1 mol. equivalent of 3-chloroperbenzoate-isocyanate, followed by hydrolysis of the acid in tetrahydrofuran at
13,144
at room temperature in accordance with standard procedures, 1.13 g of the title compound, contaminated with the corresponding sulfoxide, is obtained.
Example 32 4-Methylsulfinyl-2-oxindole-1-carboxamide.
As a result of the oxidation of t, 0 g 4-methylthio-2-oxindole-1-carboxamnd

1.1 mol. an equivalent of 3-chlorobenzoic acid, 280 mg of the compound with an acid in tetragvdrofuran are obtained at a temperature of approximately 0 ° C.
etc .. 232-234 C.
Examples of.
0.9 g of the title compound with mp. 198.5-200 ° C.
Similarly, oxidation with 6-methylthio-2-oxindole-1-carboxamide with 3-chloroperbenzoic acid gives 6-methylsulfinyl-2-oxindole-1-carboxamide.
Example 33. 3- (2-Furoch1) - 6-chloro-2-oxindole-1-carboxamide,
In accordance with the procedure of Example 21, with a 17% yield, using 0.30 g (1.2 mmol) of 3-C2-furosh1) -6-fluoro-2 oxindole, 0.20 g (1.4 mmol) of chlorosulfonyliso cyanate, 15 ml of acetonitrile and 10 ml of water receive 60 mg of the compound with so pl. 231-235- S.
Example 34. 3- (2-Tenoyl) -5- hpor-2-ca synol-1-carboxamide.
In the stirred sludge, 1.5 g (5.4 mmol) of 3- (2-thenoyl) -5-chloro-2-oxindole in 15 ml of dry acetonitrile Example 35. 2- (2-Ureidophenyl) is acetic acid.
15 Sludge 2.9 g (0.01 mol) of N-cyclohexylcarbonyl-2-oxindole-1-carboxamide in 50 ml of 1N potassium hydroxide solution is stirred at room temperature for approximately
20 30 min, and during this period of time the solid material goes into solution. At this stage, the reaction mixture is acidified with concentrated hydrochloric acid with simultaneous cooling with ice, after which it is subjected to extraction treatment with ethyl acetate. The extracts are washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated in vacuo to give an oil-like solid. This butter-like solid is washed with diisopropyl ether, and then
recrystallized from ethanol, 0.52 ml (5.9 mmol) of xnops was added to give 70 mg of the compound, the temperature of the sulfonyl isocyanate and the reaction time of which was 174.5 ° C (and the mixture was stirred at room temperature for 2 h. A small sample of the mixture was made, filtered and evaporated in vacuo to obtain a small sample of N-chlorosul fonch1-3- (2-tenoyl) -5-chloro-2-oxivdol-1-carboxamide with mp. 166- 169 C. To the rest of the reaction mixture with stirring, gradually add
decomposition).
Calculated,%: C 55.66; H 5.19; N 14.43.
, oN203
C 55.37; H 5.33;
45
Found,% N, 14.38.
Example 36. 2- (5-Chloro-2-ureidophenyl) acetic acid.
The specified connection is obtained with the achievement of 43% yield by hydrolysis of M isobutyryl-5-chlorine, -2-oxindole-1 - carboxamide 1 n. with a solution of potassium hydroxide mainly in accordance with the procedure of Example 35. After completion of the hydrolysis, the reaction mixture is acidified and the product precipitates. It is filtered and recrystallized from ethanol in ml of water and stirring is continued for 1 hour. Then the reaction mixture is poured into 50 ml of 1N. hydrochloric acid solution containing ice chips and the resulting mixture is stirred for 20 minutes. The yellow solid is isolated by filtration, washed with water and diisopropyl ether and recrystallized from ice.
hydrochloric acid, receiving 200 mg first 55 resulting in the specified connection
get in the form of colorless crystals with so pl. 187, (with decomposition).
Some of the first batch is selected, it is possible to Calculate,%: С 47.28; H 3.97;
are added to precipitate additional N 12.26
portions of the indicated compound with m.p. 213-215 C. Uterine solutions, from co14
the amount of yellow solid. This solid was isolated to give 470 mg of a second portion of the compound. The second portion is recrystallized from glacial acetic acid and combined with the first portion, then recrystallized from glacial acetic acid. As a result, 280 mg of the compound is obtained.
etc .. 232-234 C.
Examples of.
Example 35. 2- (2-Ureidophenyl) -acetic acid.
Sludge 2.9 g (0.01 mol) of N-cyclohexylcarbonyl-2-oxindole-1-carboxamide in 50 ml of 1N potassium hydroxide solution is stirred at room temperature for approximately
30 min, and during this period of time the solid material goes into solution. At this stage, the reaction mixture is acidified with concentrated hydrochloric acid while being cooled with ice, after which it is subjected to extraction with ethyl acetate. The extracts are washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated in vacuo to give an oil-like solid. This butter-like solid is washed with diisopropyl ether, and then
recrystallized from ethanol to obtain 70 mg of a compound whose temperature is 174.5 ° C (
decomposition).
Calculated,%: C 55.66; H 5.19; N 14.43.
recrystallized from ethanol to obtain 70 mg of a compound whose temperature is 174.5 ° C (s
, oN203
C 55.37; H 5.33;
Found,% N, 14.38.
Example 36. 2- (5-Chloro-2-ureidophenyl) acetic acid.
This compound is obtained in a 43% yield by hydrolysis of M with isobutyryl-5-chloro, -2-oxindol-1-carboxamide 1N. with a solution of potassium hydroxide mainly according to the procedure of Example 35. After verifying the hydrolysis, the reaction mixture is acidified and the product precipitates. It is filtered and recrystallized from ethanol;
CgHgClN-jOj
Found,%: C 47J1; H 3.98; N 12.20.
Example 37. N-Cyclohexyl-carbonyl-2-oxindole-1-carboxamide.
To a stirred sludge of 20.0 g (0.15 mol) of 2-oxindral in 150 ml of toluene, 29.6 g (0.19 mol) of cyclohexylcarbonyl isocyanate are added. This mixture is held at reflux temperature for about 30 minutes and then cooled to room temperature. The solid material is isolated by filtration, after which it is recrystallized from ethanol. As a result, 26.5 g of the compound were obtained in the form of light colorless crystals; mp. 144.5-145 ,.
Calculated,%: C 67.11; H
6.34;
N 9.79.
C, bN, a Found,%:
N 9.77.
Example
C, 67.00; H 6.36;
38. N-Isobutyryl-5-chloro-2-oxindole-1-carboxamide.
In a sludge of 8.38 g (0.05 mol) of 5-chloro-2-oxindole in 250 ml of toluene, 6.79 g (0.06 mol) of isobutyryl isocyanate are added and the reaction mixture is kept at reflux temperature, for 5.5 hours. The reaction mixture is then cooled to room temperature and a small amount of insoluble material is removed by filtration, after which the solvent is removed by vacuum evaporation. The residue is recrystallized in vacuo to a gummy solid. This resinous solid residue is dissolved in 400 ml of water and the aqueous solution prepared in this way decolorizes the active
25 with coal, after which it is poured into a mixture of 1 l of water with 180 ml of concentrated hydrochloric acid containing ice chips. As a result, a reddish brown precipitates.
30 is a solid which is collected by filtration and thoroughly rinsed with water. This solid is then dried and washed with diethyl ether. Finally his recrystallized35
ejected from ethanol; compounds of mp. back to top).
obtaining 48.9 g of 193-195 0 (with a similar processing method, they hydrate. from acetonitrate (using the Razingdrat and then the ethoxide of the non-glossy carbon), after which the re-ethanol is converted 5 whereby in the form of pink crystals, 3.23 g of compound with a mp of 139-14 ° C are obtained.
Calculated%
methylisolove in 5-methyl-2-oxindole. The melting point of the product is 173-174 ° C.
45
C 55.62; H 4.67;
Example 40. 4,5-Dimethyl-2-oxindole and 5,6-dimethyl-2-oxindole.
The reaction with chloral hydrate and hydroxylamine converts 3,4-dimethylaniline to 3,4-dimethylisonitrosoacetanilide. Further 3,4-dimethyl-. Isonitroacetanilide is cyclized with sulfuric acid in accordance with the Baker method and others, to obtain 4 5-di methyl isatin with so pl. 225-226 C and 5,6- 5-dimetilisatin with so pl. 217-218 C.
N 9.98.
С „П„ СШ 05
Found,%: C 55.53; H 4.48; N 9.97.
Example 39. 5-Chloro-2-oxindole.
In a stirred sludge of 100 g (0.55 mol) of 5-chlorozatin in 930 ml of ethanol, 40 ml (0.826 mol) of hydrazine hydrate is added, resulting in a red solution. This solution is maintained at a temperature of
44555616
reflux for 3.5 hours, after which a precipitate appears. The reaction mixture is stirred overnight, and then the precipitate is separated by filtration, which allows to obtain 5-chloro-3-hydrazono-2-oxindole as a yellow solid, which is dried in a vacuum.
10 dryer. The dry weight is 105.4 g.
Then, in dried portions over 10 minutes, this dried solid is added to the solution of 125.1 g
15 sodium methoxide in 900 ml of absolute ethanol. The resulting solution is maintained at reflux for 10 minutes, after which its concentration
20 is vacuum drawn to a gummy solid. This resinous solid residue is dissolved in 400 ml of water and the aqueous solution prepared in this way decolorizes the active
25 with coal, after which it is poured into a mixture of 1 l of water with 180 ml of concentrated hydrochloric acid containing ice chips. As a result, a reddish brown precipitates.
30 is a solid which is collected by filtration and thoroughly rinsed with water. This solid is then dried and washed with diethyl ether. Finally his recrystallized35
ejected from ethanol; compounds of mp. back to top).
In a similar way, the treatment with hydrasinghydrate and then ethoxide nat ethanol is converted to 5-
methylisolove in 5-methyl-2-oxindole. The melting point of the product is 173-174 ° C.
40 Razingvdrata, and then ethoxide nat-ethanol is converted 5-
45
0
Example 40. 4,5-Dimethyl-2-oxindole and 5,6-dimethyl-2-oxindole.
The reaction with chloral hydrate and hydroxylamine converts 3,4-dimethylaniline to 3,4-dimethylisonitrosoacetanilide. Further 3,4-dimethyl-. Isonitroacetanilide is cyclized with sulfuric acid in accordance with the Baker method and others, to obtain 4 5-di methyl isatin with so pl. 225-226 C and 5,6- 5-dimetilisatin with so pl. 217-218 C.
By treatment with hydrazapadrate and then sodium ethoxide in ethanol, mainly according to the procedure of Preparation 5, the conversion is carried out
This 4,5-dimetilisatin in 4,5-dimethyl-2-oxindole with t.pcs. 245.5-247 ,.
Similarly, treatment with hydrazine hydrate and then sodium ethoxide in ethanol mainly followed the procedure of Example 39 to convert 5,6-dimethylisatin to 5, b-dimethyl-2-oxindole with m.p., 196.5-198 s.
Example 41. 4-Chloro-2-oxindole and 6-hpor-2 oxindole.
A.3-Chloro-nitroso-tetanilide.
 In a stirred solution of 113.23 g (0.686 mol) of chlorohydrate in 2 liters of water, 419 g (2.95 mol) of sodium sulfate is added, and then a solution prepared from 89.25 g (0.70 mol) of 3-chloroaniline , 62 ml of concentrated hydrochloric acid and 500 ml of water. As a result, a thick precipitate is formed. A solution of 155 g (2.23 mol) of hydroxylamine in 500 ml of water is then added to the reaction mixture with stirring. Stirring is continued and the reaction mixture is gradually heated, after which it is kept at 60-75 ° C for approximately 6 hours, with an additional 1 liter of water being added to simplify mixing. Then the reaction mixture is cooled and the precipitate is separated by filtration. The solid product is dried to obtain 136.1 g of 3-chlorozonitrosa-acetamine-nipid "
B, 4-chlorosatin and 6-chlorosatin.
In 775 ml of concentrated sulfuric acid, preheated to 70 ° C, 136 g of 3-chlororizonitrosa-acetanilide are added with simultaneous stirring at such a rate that the medium of the reaction medium is maintained in the range of 75-85 ° C. After the total amount of solid material is added, the reaction mixture The mixture is aggravated before and held in place for another 30 minutes. Next, the reaction mixture is cooled and gradually poured into approximately 2 l of ice while stirring. Add an additional amount of ice, taking into account the need to maintain the temperature below room temperature. A red-orange precipitate formed, which was separated by filtration, washed with water and injected. The obtained solid material is suspended in 2 liters of water, after which it is transferred to the solution.
.

44555618
about 700 ml 3 n. sodium hydroxide solution. The solution is filtered, and then its value
 The pH is adjusted to 8 by the addition of concentrated hydrochloric acid. At this stage, 120 ml of a mixture of 80 parts of water with 20 parts of concentrated hydrochloric acid are added. Solid material
10, which precipitates, is collected by filtration, washed with water and dried to give 50 g of crude 4-chlorosatin. The filtrate, from which 4-chlorozatin is isolated, is additionally
15 is acidified to a pH of 0 using concentrated hydrochloric acid to form an additional amount of precipitate. The latter is separated by filtration, washed with water and dried to obtain 43 g of crude b-chlorozatin. The crude 4 chloroates1 is recirculated from acetic acid, resulting in 43.3 g of material, the melting point of which is 258-259 C.
Crude 6-5 Shorizatin recrystallized from acetic acid to obtain 36.2 g of material melted 30 at 261-262 ° C.
C. 4-H.LOR-2-OXINDOL. 17.3 ml of hydrazine hydrate is added to a sludge of 43.3 g of 4-z lorizatin in 350 ml of ethanol, and then the reaction mixture is held at
35 under reflux for 2 hours. Then the reaction mixture is cooled and the precipitated precipitate is isolated by filtration, resulting in 43.5 g of 4-chloro 40 3-hydrazine-2-oxnndol with m.p. 23525
.
A stirred solution of 22 g of sodium in 450 ml of anhydrous ethanol is added in separate portions to 43.5 g.
45 4-chloro-3-hydrazono-2-oxindole and the final solution are held at reflux at reflux temperature for 30 minutes.
The cooled solution is then concentrated to a gumlike mass, which is dissolved in 400 ml of water, and discolored using activated charcoal. The resulting solution is poured into a mixture of 1 l.
55 water with 45 ml of concentrated hydrochloric acid. The precipitate which precipitates is isolated by filtration, dried and recrystallized from ethanol, whereby 22.4 g are obtained. 41 9
chlorine-2-oxindole, m.p. 216-218 ° С (with decomposition).
D. 6-Chloro-2-oxindole. As a result of the reaction of 36.2 g of 6-chlorosatin with hydrazine hydrate and then with ethoxide of sodium in ethanol mainly in accordance with the above C, 14.2 g of 6-chloro 2-oxindole with a mp of 196-198 ° C.
14
Example 42 5,6-Difluoro-2-oxindole.
As a result of the reaction of 3,4-difluoro-aniline with chloral hydrate and hydroxylamine, followed by cyclization with sulfuric acid, as described above in points to A and B of the example of preparation 41, 5,6-difluorisatin is obtained, which is then reacted with hydrazine hydrate and then with sodium methoxide in methanol in the same way as described in preparation 39, to give the compound with m.p. 187-190 ° C.
Example 43. To a stirred solution of 11.1 g (0.1 mol) of 4-fluoroaniline in 200 ml of dichloromethane at a temperature of from -60 to -65 ° C, a solution of 1 /) is added dropwise, 8 g (0 , 1 mol) tert-butyl hypochlorite in 25 ml of dichloromethane. Stirring is continued for 10 minutes at a temperature of from -60 to -6 ° C, and then a solution of 13.4 g (0.1 mol) of ethyl-2- (methylthio) -acetate in 25 ml of dichloromethane is added dropwise. .
Stirring is continued at a temperature of 35 Rene nickel, resulting in a batch of -60 ° C for 1 h, after which 5-trifluoromethyl-2-oxindole
A solution of 11.1 g (0.11 mol) of triethylamine in 25 ml of dichloromethane is added dropwise at a temperature of from -60 to -65 ° C. The cooling bath is removed, and when the reaction mixture r is heated to room temperature, 100 ml of water is added to it. Going on; separation into phases, after which the organic phase is washed with a saturated solution of sodium chloride, dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in 350 ml of distil ether and 40 ml of 2N was added to the solution. hydrochloric acid. This mixture is stirred at room temperature overnight. As a result, it is divided into phases, the ether phase being washed with water and then with an saturated sodium chloride solution. The ethereal phase, dried over sodium sulfate, is evaporated in vacuo to give 17 g of an orange-brown solid which is ground.

C, 54.74; H 4.11;

4555620
are in isoproxy ether. Next, the solid material is recrystallized from ethanol, resulting in a yield of 5.58 g of 5-fluoro-3-methylthio-2-oxynol with so pl. 151.5-152.5 C,
Calculated,%: C 54.80; H 4.09; N 7.10.
CqHgONFS
10 Found,%; N 7.11.
A sample weighing 986 mg (5.0 mmol) of 5-fluoro-3-methylthio-2-oxindole is added to two teaspoons of nickel.
15 Rene in 50 ml of absolute ethanol, after which the reaction mixture is held at reflux for 2 hours. The catalyst is removed by decantation.
20 and washed with absolutized ethandom. The combined ethanol solutions are evaporated in vacuo and the residue is dissolved in dichloromethane. This dichloromethane solution is dried over
25 sodium sulfate and evaporated in vacuo
to give 475 mg of 5-fluoro-2-oxindole, with so pl. 121-134 C.
In a similar way, 4-trifluorometshlaniline is reacted with tert, - 30 butyl hypochlorite, ethyl 2- (methylthio) acetate and triethylamine, followed by reduction of the obtained TA in 3-TIFORO-methyl-2-oxindole using
40
from m.p. 189.5-190 ,.
Example 44, 5-Methoxy-2-oxyindol.
5-Methoxy-2-oxindol is prepared using 4-methoxyaniline in a manner similar to that described in Preparation 43, except that the initial chlorination stage 45 is carried out using a solution of chlorine gas in dichloromethane rather than tert-butyl hypochlorite. Received the specified product with t, pl, 150.5-151.5 C.
50 Example 45. 6-Chloro-5-fluoro-2-oxindole,
24.0 g (0.165 mol) of 3-chloro-4-fluoroaniline and 13.5 ml are added in 130 ml of toluene with stirring
55 (0,166 mol) of pyridine. The resulting solution is cooled to a temperature of approximately and 13.2 ml (0.166 mol) of 2-chloroacetyl chlond is added to it. The reaction mixture is stirred from water, 280 mg of the title compound with m, pl. 168,5-
.
Example 47. 6-Bromo-2-oxindole.
195 ml of dimethyl sulfoxide is added to 9.4 g of sodium hydride, and then 22.31 ml of dimethyl-1molate are added dropwise. At the end of the addition operation, the mixture is heated to 100 ° C and above. At this stage, 25 g of 1,4-dibrom-2 are added in one portion at once at room temperature for 5 hours, after which it is subjected to two 100 ml of 1N solution of salt Acidic acid followed by 100 ml of saturated sodium chloride solution. The resulting toluene solution is dried using magnesium sulfate, after which it is concentrated in vacuo to yield 32.6 g (88% yield) of M- (2-chloroacetyl) -3-chloro-4-fluoroaniline.
A sample weighing 26.63 g of L- (2-chloro-acetyl) -3-chloro-4-fluoroaniline is thoroughly mixed with 64 g of anhydrous chloris-15 nitrobenzene. The reaction mixture was kept at 100 ° C for 4 hours, after which it was added to 1.0 liters of a saturated solution of ammonium chloride. The resulting mixture is extracted with ethyl acetate, and the extracts are washed with ammonium chloride solution, water, and saturated sodium chloride. After drying over magnesium sulfate, 25 solvent are removed and the residue is recrystallized from a mixture of ethyl acetate and hexane, to obtain 22.45 g of dimethyl-2- (4-bromo-2-nitrophenyl) -malonate.
A solution of 17.4 g of dimethyl-2- (4-bromo 30 2-nitrophenyl) maponate and 4.6 g of lithium chloride in 150 ml of dimethylsulfonic oxide is placed in an oil bath with a temperature of 100 ° C. After 3 hours, to this temperature, the reaction- (7% yield) indicated in the heading 35 U, the mixture is cooled to room temperature with so pl. 196-206 ° C. NMR spectroscopic temperature, then its vyshvagot in roskopichesky analysis shows that a mixture of 500 ml of ethyl acetate with 500 ml
saturated sodium chloride solution. The resulting layers are separated and 40 aqueous layers are subjected to extraction treatment with an additional amount
addition of aluminum and the mixture hold at 210-230 ° C for 8.5 hours. Next, the reaction mixture is poured into a mixture of ice with 1N hydrochloric acid — while stirring. After this, stirring is continued for 30 minutes and then filtered.
22.0 g of solid product is collected. This solid is dissolved in a mixture of ethyl acetate and hexane in a 1: 1 ratio and the solution is chromatographed on 800 g of silica gel. By elution of the column, followed by evaporation of the fractions, 11.7 g of N- (2-xjTOp-acetyl) -3-chloro-4-fluoroaniline, and then 3.0 g of 6-chloro-5-fluoro-2-oxindole are obtained. This last material is recrystallized from toluene to yield 1.70 g.
This product is contaminated with some 4-chloro-5-fluoro-2-oxin dol.
Example 46. 6 Fluoro-5 metsh1-2-oxindole.
A homogeneous mixture of 11.62 g (57.6 mmol) of L- (2-chloroacetyl) -3-fluoroethyl acetate. The combined organic layers are washed with a complete solution of sodium chloride, dried
4-methane with 30.6 g (229.5 mmol) 4E) using sodium sulfate, and
The dissolving aluminum chloride is heated to 210-220 ° C. After 4 hours, the reaction mixture is cooled at this temperature and then added to 100 ml of 1N hydrochloric acid and 50 ml of ice. A tan solid is formed, which is collected by filtration and recrystallized from aqueous ethanol.
Thus, three portions of the product, weighing 4.49, 2.28 and 1.0 g, respectively, are collected. Yortszho weighing 1.0.g is additionally recrystallized,
There are from water, 280 mg of the indicated compound with m, pl. 168,5-
.
Example 47. 6-Bromo-2-oxindole.
195 ml of dimethyl sulfoxide is added to 9.4 g of sodium hydride, and then 22.31 ml of dimethyl-1molate are added dropwise. At the end of the addition operation, the mixture is heated to 100 ° C and above. At this stage, 25 g of 1,4-dibrom-2 nitrobenzene are immediately added in one portion. The reaction mixture was kept at 100 ° C for 4 hours, after which it was added to 1.0 liters of a saturated solution of ammonium chloride. The resulting mixture was extracted with ethyl acetate, and the extracts were washed with a solution of ammonium chloride, water, and a saturated solution of sodium chloride. After drying over magnesium sulfate, the solvent is removed and the residue is recrystallized from a mixture of ethyl acetate and hexane to give 22.45 g of dimethyl 2- (4-bromo-2-nitrophenyl) -malonate.
ethyl acetate. The combined organic layers are washed with a complete solution of sodium chloride, dried
0
then evaporated in vacuo. The residue is chromatographed using silica gel as an adsorbent and a mixture of ethyl acetate and hexane as elto. Thus, 9.4 g of methyl 2- (4-bromo-2-ntrophenyl) acetate are obtained.
6.1 g of powdered iron are added to a solution of 7.4 g of methyl 2- (4-bromo-2-nitrophenyl) acetate in 75 ml of acetic acid. The reaction mixture is placed in an oil bath with a temperature of 100 C. After 1 hour, the solvent is removed by evaporation in aa23.
The residue is dissolved in 250 ml of ethsh-acetate. The solution is filtered, washed with a saturated sodium chloride solution, dried using sodium sulfate, decolorized with activated charcoal and evaporated in vacuo. The result is 5.3 g of 6-bromo-2-oxindole in the form of a white crystalline solid material with so pl. 213-2U ° C.
Similarly, using 1,4,5-trichloro-2-nitrobenzene, 5,6-dichloro-2-oxindole with m.p. 209-210 ° C.
Example 48. 6-Phenyl-2-oxindole.
50 ml of dimethyl sulfoxidine is added to 3.46 g (0.072 mol) of sodium hydride, and then a solution of 8.2 ml (0.072 mol) of dimethyl malonate in 10 ml of dimethyl sulfoxide with simultaneous stirring is added dropwise. After completion of the addition operation, stirring is continued for 1 hour and then a solution of 10 g (0.036 mol) of 4-bromo-3-nitrodiphenyl in 50 ml of dimethyl sulfoxide is added. This reaction mixture is kept at 100 ° C. for 1 hour, cooled and poured into an ice-water mixture containing 5 g of chloride. The mixture thus obtained was extracted with ethyl acetate, the extracts were washed with sodium chloride solution and dried over magnesium sulfate. By evaporation in vacuo, an oil-like product is obtained, which is chromatographed using silica gel and then recrystallized from methanol to give 6 g of dimethyl -1- (3-nitro-4-diphenyl) -malonate with m. square 82-83 ° C
A portion (5 g) of the specified nitro compound is reduced with hydrogen over a platinum catalyst in a mixture of 50 ml of tetrahydrofuran and 10 ml of methanol under a pressure of approximately 5 kg / sq, 1Sm, to obtain the corresponding amine. This latter compound is refluxed in ethanol for 16 hours and then the product is evaporated off the solvent and recrypted from methanol to give 1.1 g of ethyl 6-phenyl-2-oxynol-1 carboxylate with so pl. 115-117 С
45556, 24
1.0 g of the above indicated ethyl ether and 100 ml of 6N. hydrochloric acid is maintained at reflux temperature for 3 hours and then kept at room temperature for 3 days. The precipitated solid material was collected by filtration and dried, 10 to obtain 700 mg of 6-fench 1-2 oxindole with mp. 175-176 ° C. Example 49. 5-Acetyl-2-oxindole. 15 to 27 g (0.202 mol) of aluminum chloride are added to 95 ml of carbon disulfide, and then a solution of 3 ml (0.042 mol) of acetyl chloride in 5 ml of carbon disulfide is added dropwise with simultaneous stirring. Stirring 20 is continued for 5 minutes, after which 4.4 g (0.033 mol) of 2-oxindole is added. The prepared mixture is maintained at the boiling point for 4 hours under reflux, and then 2S is cooled. The carbon disulfide is removed by decantation, the residue is triturated in water and filtered. After drying, 3.2 g of compound are obtained with a mp. 225-227 ° C. 30 By reacting 2-hydroxydol with benzoyl chloride and 2-tenonyl chloride in the presence of aluminum chloride, the following compounds, respectively, are obtained, respectively, as follows: 5-benzosh 1-2-ca. Sindol with m.p. 203-205 C (and methanol) and 5- (2-tenoyl) -2-oxindole with m.p. 211-213 ° C (from CHjCN).
Example 50. 5-Brpm-2-oxine-40 dollars can be obtained by synthesizing 2-oxindole.
5-n-butyl-2-oxindole can be obtained by reacting 5-n-butyl isatin with hydrazine hydrate and then with methoxy-sodium in ethanol in accordance with the procedure of Preparation Example 5.
5-n-butyl isatin can be obtained from 4-n-butylaniline by treating it with hyralhydrate and hydroxylamine 50, followed by cyclization with sulfuric acid in accordance with Parts A and B of Preparation Example 7.
5-Ethoxy-2-oxindole can be obtained by converting 3-hydroxy-6-nitro-55 luol to 3-ethoxy-6-nitrotoluene according to
standard methods (potassium carbonate and ethyl iodide in acetone) followed by conversion of 3-ethoxy-6-nitrotoluene to 5-ethoxy-2-oxindole according to the method,
25144555626
described by Beckett et al., for a mixture of 47 hours, cooled, and then from
the solvent is removed by evaporation in vacuo. The residue is triturated in 200 ml of diethyl ether, and the solid material conversion of Z-methoxy-6-nitrotoluene to 5-methoxy-2-oxindole, 5-n-butoxy-2-oxindole can be obtained in a similar way, but using n-butoxy tiliodida instead of ethyl iodide.
Example 51. 3- (2-Furoyl) -2-oxindole.
To a stirred solution of 5.5 g (0.24 mol) of sodium in 150 ml of ethanol, 13.3 g (0.10 mol) of 2-oxindole are added at room temperature. The slurry is cooled to ice bath temperature and then dropwise 15.7 g (0.12 mol) of 2-furoyl chloride are added over 10-15 minutes. The ice bath is removed and an additional 100 ml of ethanol is added, after which the reaction mixture is held at reflux for 7 hours. The reaction mixture is then allowed to stand overnight and then the solid is filtered off. This solid is added to 400 ml of water and the prepared mixture is acidified using concentrated hydrochloric acid. The mixture is cooled with ice and the solid is collected by filtration. This solid is recrystallized from 150 ml of acetic acid, resulting in 8.3 g of yellow crystals with a mp. 209 - 210 ° С (with decomposition).
Calculated,%: C 68.72; H 3.99; N 6.17.
C, 5H, 0, N
Found% N 6.20.
Example 52. As a result of re-. Stocks of 2-oxindole with an appropriate acid chloride according to the method of Preparation 51 receive additional compounds: 3- (2-tenoyl) -2-oxindole with m.p. l89-t90 c, 17% yield; (2-thienyl) -acetyl -2-oxindole with m.p. 191-192 ,, 38% yield and 3- (2-phenoxyacetyl)
C 68.25; H 4.05;
Al collected by filtration and discarded. The filtrate is evaporated in vacuo, and the residue is triturated in isopropyl alcohol and removed by filtration. The solid material is suspended in 250 ml of water, which is then acidified with concentrated hydrochloric acid. This mixture is stirred to obtain a solid product, which
15 is filtered. The product is recaptured from acetic acid, and then from acetonitrile, to obtain 705 mg of the compound with m.p. 185-186 ° C. Calculated,%: C 68.72; H 3.99;
20 N 6.17.
C ,, N
Found,%: C 68.72; H 4.14; . N 6.14. / Example 54. 5-amino-2-6xin25 dol-1-carboxamide,
In a solution of 5.0 g of 5-nitro-2-oxynol-1-carboxamide in 110 ml of S, H-dimethylformamide, 0.5 g of 10% palladium on carbon is added and the prepared mixture is shaken in hydrogen atmosphere at an initial pressure of 5 kg / sq. cm until the process of hydrogen absorption ceases. The catalyst is removed by filtration.
35, the filtrate is diluted with brine and extracted with ethyl acetate. The extracts are dried over magnesium sulphate and evaporated in vacuo to give an oil-like dark colored product, which after solidification in water hardens. As a result, 3.0 g of the compound are obtained as a yellow solid; mp. 189-191 0.
45 Compounds of formula I have an analgesic effect. This effect has been demonstrated in mice by blocking the peritoneal contraction caused by the introduction into op45. Compounds of formula I have an analgesic effect. This effect was demonstrated on the brain by blocking the peritoneal contraction caused by the injection into or2-oxindole with mp. 135-136 C, 42% 50% of 2-phenyl-1,4-benzoquinone (PVH).
output.
Example 53. 3- (3 Furoyl) -2-oxindole.
To a stirred solution of 2.8 g (0.12 mol) of sodium in 200 ml of ethanol, 13.3 g (0.10 mol) of 2-oxindole and then 16.8 g of ethyl-3-furoate are added. This mixture is boiled at reflux temperature.
Al collected by filtration and discarded. The filtrate is evaporated in vacuo, and the residue is triturated in isopropyl alcohol and removed by filtration. The solid material is suspended in 250 ml of water, which is then acidified with concentrated hydrochloric acid. This mixture is stirred to obtain a solid product, which
filtered. The product is recaptured from acetic acid, and then from acetonitrile, to obtain 705 mg of the compound with m.p. 185-186 ° C. Calculated,%: C 68.72; H 3.99;
 N 6.17.
C ,, N
Found,%: C 68.72; H 4.14; . N 6.14. Example 54. 5-Amino-2-6xindole-1-carboxamide,
To a solution of 5.0 g of 5-nitro-2-oxynol-1-carboxamide in 110 ml of S, H-dimethylformamide, 0.5 g of 10% palladium on carbon is added and the prepared mixture is shaken in an atmosphere hydrogen at an initial pressure of 5 kg / sq. cm until termination of the hydrogen absorption process. The catalyst is removed by filtration.
the filtrate is diluted with brine and extracted with ethyl acetate. The extracts are dried over magnesium sulphate and evaporated in vacuo to give a dark oil-like product, which solidifies after being ground in water. As a result, 3.0 g of the compound are obtained as a yellow solid; mp. 189-191 0.
The compounds of formula I have an analgesic effect. This effect was demonstrated on the brain by blocking the peritoneal contraction caused by the introduction of the technique used in this case, based on the method of Zygmund and others, adapted for high flow per unit time. In the course of these experiments, male Carworth mice, CF-1 albinos, WESOM 18-20 g, were used as experimental animals. Before administration of drugs
and testing all animals overnight was not given feed.
The compounds of formula I were dissolved or suspended in a base for the preparation of drugs, which included 5% ethanol, 5% emulsion product 260 (a mixture of polyoxy methyl fatty acid esters) and 90% salt.
This basis for the preparation of drugs by juvenile feeding. After 1 h
also served as a control material. Dosages were prepared according to a logarithmic scale, i.e. ... 0.32, - 1.0 | 3.2j 10.32 ... mg / kg, and was calculated by the weight of the salt when acid was used or not. They were orally administered in concentrations that were changed to ensure a constant dosage of 10 mg / kg of animal weight. The aforementioned method used by Milna and Tumi was used to determine efficacy and potency. The compounds were administered orally to mice after 1 hour after intraperitoneal administration of PBH in the amount of 2 mg / kg of live weight. After this, the number of peritoneal peritoneum was counted for the next 5 min. The degree of analgesic protection (SAS,%) was calculated taking into account the effectiveness of suppression of peritoneal peritoneum compared to their number in parallel animals of the control group on the same day. At least four such determinations (NS 5) made it possible to obtain these reactions to the dosage and calculate the SAS, i.e. The calculated dosage that reduces the number of peritoneal resuspension by 50% compared with the number in animals of the control group.
The compounds of formula I also have anti-inflammatory effects. This effect was demonstrated on rats according to a method based on the standard test for edema of a rat paw caused by administration of corragenin.
Non-anesthetized adult white rat males weighing 150-190 g were counted, weighed, and ink marks were applied to the right side ankles of animals. Each paw was immersed in mercury exactly to the level of the ink mark. Mercury was contained in
a glass cylinder connected to a Stathem pressure transmitter. The output of the converter through a regulating device is connected to a microvoltmeter. This made it possible to note the volume of mercury displaced by the paw immersed in it. Drugs were given to animals after they were injected with a drug in their bodies, they were edematic by injecting 0.05 ml of a 1% solution of carrageenin into the sole's tissue.
labeled paw. Immediately thereafter, the volume of the paw was measured with swelling as a result of the injection. The increase in paw volume, 3 hours after the injection of carragenin, was individual
inflammatory response.
The results obtained are given as in% inhibition of the formation of edema caused by each test compound compared
with a control (i.e., only a carrier that does not contain any compound) (Table 6).
The analgesic effect of the compounds of Formash, I confirms the i-rx usefulness for the immediate introduction into the body of 1 shekopitshshihshah to alleviate the pain, such as surgical pain and injury pain. In addition, the compounds of the formula I can be used for the continuous introduction into the body of mecnopathies in order to relieve the symptoms of chronic diseases, in particular inflammation in rheumatoid arthritis, and pain,
associated with osteoarthritis and other mini-skeletal disorders.
In the case when the compound of formula I or its pharmaceutically acceptable salt is necessary to use
as either an analgesic agent or an anti-inflammatory agent, it can be administered in mammals either individually or, preferably, in combination
Research institutes with pharmaceutically acceptable carriers (excipients) or diluents in a pharmaceutical composition according to standard pharmaceutical practice. These compounds should be administered by oral or parenteral route. The parenteral route includes intravenous, intramuscular, intraperitoneal, subcutaneous, and local methods of administration.
For oral administration of compounds of the formula I, such a compound can be administered, in particular, in the form of tablets or capsules, g or in the form of aqueous solutions or suspensions. In the case of tablets for oral use, carriers which are usually used for this purpose are include lactose and corn starch. 10 In addition, lubricating agents, in particular magnesium stearate, are typically added. For oral administration in capsule form, diluents are lactose and dry corn starch. If it is necessary to prepare aqueous suspensions for oral administration, the active component is combined with emulsifying and suspending agents. 20 If desired, it is possible to add sweetening and / or flavoring substances. For intramuscular, intraperitoneal, paradigm, and intravenous administration, sterile diluents of the active components are usually prepared and the pH should be adjusted accordingly. and add a buffer. When administered intravenously into the body, the total concentration of solutes should be adjusted to form isotonic solutions.
In the case of the use of the compound of formula 35 I or its salt in the treatment of humans, the daily dosage is usually determined by the attending physician. In addition, this dosage varies depending on the age, weight, and response of the individual patient, as well as on the severity of the patient's symptoms and the potency of the particular compound that is provided for the treatment. However, in case of emergency administration in order to reduce pain-45 / Geni of pain, the effective dosage in most examples is in the range from 0.01 to 0.5 g, depending on need (for example, every 4-6 hours). For continuous administration of 50, the body in most cases is effective dosage is in the range from 0.01 to 1.0 g per day, preferably from 20 to 250 mg per day in single or fractional portions, 55
Therapeutic indicator / t. LDjg wED jo) for this compound will lie in the range from 24 to 60.
Biological data.
The value of 5-chloro-3- (2-tano-yl) -2-oxindole-1-carboxamide (where X is chlorine and the molecule is in the 5th position, Y is hydrogen, and R is 2-thienyl) of the product of example 1, when Paw puffiness tests in rats according to S.A. Winter et al. equal to 125 mg / kg (oral).
The value of bB-pDl for 5-chloro-3- (I-teno-un) -2-oxindole-1-carboxamide, a product of example 1, in male rats is equal to 300-500 mg / kg after oral administration.
The value of B before D for 5-chloro-3- (2-teno-yl) -2-oxindole-1-carboxamide, a product of example 1, for rat females is 500-750 mg / kg when administered orally.

权利要求:
Claims (1)
[1]
Formula invented and.
The method of obtaining 2-oxo-indole-1-carboxamide derivatives of the general formula
ABOUT
OtC-NHj
de X - hydrogen, fluorine, chlorine, bromine,
trifluoromethyl, methyl, methoxy, methylthio, nitro, phenyl, benzoyl, thenoyl or acetyl; . Y is hydrogen, fluorine, chlorine, methoxy, methyl, or X and Y together form; 5, 6-methyl enoxy,
4-CH; g-CH2., 5-CHg-CH2-, 6-CHg: -CHG-CH2-CHg-7, 5-CH CH-CH CH-6.5-0-CH1-CHg-6, 5-CH2-CH2., 5-S-CH2-CH2-6, 5-0-CH CH-6, 5-S-CH CH-6, 5-CH CH-S-6, where the numbers indicate the point of attachment to benzene ring; R - FURh, thienyl, thienylmethyl, furylmethyl, phenoxymethyl, phenoxyethr, phenylethyl, Cj-Cg-cycloalkyl, methyl, isopropyl, dicyclo- (2,2,1) heptane-2-yl, (2, 2,1) hept-5-en-2-yl, phenyl, phenyl, substituted by one or two chlorine atoms or methyl, benzyl, benzyl, substituted by chlorine or trifluorometip, pyrrolyl, pyrimidinyl, trifluoromethane-1 ,
methyl
234 (decomp.) 56.59 3.48 8.80 56.76 3.48 8.81
0 C - NH,
All compounds were crystallized from acetic acid, unless otherwise indicated.
table 2
35
144555636
Continued table. 2
39
c:

,
 ,
2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6-C1
6-C1
H
H
1G
, n
N N N N N
H N
i ::::: i :::::::::::::
2-thienyl
Phenyl
4-Chlorfensht
2-pyrrolcle
2-pyrrolyl
3-Tienil
3-thienyl
3-furyl
3-furyl
3-furyl
3-furip
(3-Thienyl) -methyl
(3-thienyl) metrsh
(3-Thienyl) -methyl
(3-Thienyl) -methyl
2-thienyl
(2-thienyl) -methyl
2-thienyl
(2-thienyl) -methyl
2,4-Dichlorophenyl
Trifluoromethyl
2-FSH1
Benzyl
2-thienyl
(2-thienyl) -methyl
Dicycdo (2,2,1) heptane-2-Ш1
Trifluoromethyl Benzyl Methyl 3-Thienyl (3-Thienyl) -methyl 5-Pyrimidinyl
Dicyclo (2.2.1) hept-5-en-2-yl
Dicyclo (2.2.1) hept-5-en-2-yl
eh n
H N N
H
144555640
Continued table. 2
:::: i :::::::::::
188-189 (decomp.) 236-237 (decomp.) 247-248 (decomp.) 214-215 (decomp.) 217-218 (decomp.) 236.5 (decomp.) 238 (decomp.) 229.5 (decomp.) 231.5 (decomp.) 223.5 (decomp.)
214 (decomp.) 239.5 (decomp.) 237 (decomp.) 220.5 (decomp.) 210.5 (decomp.) 227 (decomp.) 243 (decomp.) 212 (decomp.)
215 (dec.) 221 (dec.) 224-225 (dec.) 214-215 (dec.) 249-250 (dec.) 221-222 (dec.) 239-242 (dec.)
219-221 (decomp.) 217-219 (decomp.) 240-241 (decomp.) 233-234 (decomp.) 225 (decomp.) 220.5 (decomp.) 238-240 (decomp.)
211.5 (decomp.). 210.5 (decomp.)
Baseline racemic
2-Fennpropionyl chloride is a compound.
45
: 1445556
The number to the left of the formula indicates the point of attachment of this end of the radical to the 2-oxindole cycle, and the figure on the right indicates the point of attachment of this end of the radical to the 2-oxindole cycle.
46 Table 3
Table 4
about-with-ъзнг
3.3513.3051.043.2613.24
3.3513.3051.143.4813.21
3,3513,3051,073,30,13,31
3,6414,4356,253,7914,53
Melting point
with

H
5-СНз b-СН, 6-С1
214.5 222 d 214.5 245 d
 - Recrystallization from ethanol; - Recrystallization from acetonitrile; - Recrystallization from acetic acid.
XY Temperature
melting, ° C
4-СНз Н.181-184
6-F H191.5-194
6-Vg H205-208
5-N02 H201-205
5-F6-С1229-231
5-F6-F198-201
The reaction is carried out in toluene as a solvent. Both the starting material and the contamination product with a quantity of the corresponding 4-chloro-5-fluoroisomer.
Table 6
 XYR Dosage,% Inhibition / kg
H N
H
2-Four1 2-Furil 2-Furil
Data analysis
Calculated
Found
:P
N
H
N
49,192.8911.4848.90 3.0511.50
64,695,9213,7264,575 9413 64
64,695,9213,7264,526,6713,68
44,112,4711,4343,982,5511,58
Table 5
OSMN
32 18
sixteen
40 23 13
49
1445556
50
PREVIEW IT BL.6
55
144555656
Continuation of the table. ° 6
57
1445556
 58
Continuation of table 6
Continued table. b
H
H
heptan-2-il32
Biculo2,2,1) heptan-2-yl10
Bicyclo (2.2.1) Continued table. 6
66
39
Continued table. 6
Continued table. 6
y-
H2-Chloro-6-ftsr-phenyl
6-C2-Tenil
H2-Furil
H2-Tenil
NZ-Nitrobenail
H4-Nitrobenzyl
Continued table. 6
6
56
59
35
five
9
11 10 32

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引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

FR3986M|1963-06-06|

---

US3462450A|1966-06-29|1969-08-19|Merck & Co Inc|Chemical compounds|

---

GB1158532A|1967-01-05|1969-07-16|Centre Nat Rech Scient|2-Oxoindoline-3-Carboxylic Acids and Esters thereof|

---

US3631177A|1967-04-18|1971-12-28|Smith Kline French Lab|3-phenacyl-2-oxoindolines|

---

US3519592A|1967-04-18|1970-07-07|Smithkline Corp|Indole compounds|

---

BE714717A|1967-05-12|1968-09-30|

---

FR7337M|1968-01-11|1969-10-13|

---

BE756447A|1969-10-15|1971-03-22|Pfizer|OXINDOLECARBOXAMIDES|

---

US3767653A|1971-06-28|1973-10-23|Squibb & Sons Inc|Thiazines|

---

US3749731A|1971-07-08|1973-07-31|Warner Lambert Co|2-oxo-n--3-indoline-carboxamide|

---

DE2306374A1|1973-02-09|1974-08-15|Bayer Ag|2-Oxo-4-hydroxy tetrahydro quinazoline-4-carboxamides - prepd by reacting isatin-N-carboxamides with amines and useful as dyes|

---

US4012394A|1973-02-16|1977-03-15|Labaz|Indole derivatives|

---

DE2314242A1|1973-03-22|1974-09-26|Bayer Ag|Dyestuffs and heterocycles inters - ie 3-substd 2-keto-4-hydroxy-1,2,3,4-tetra hydro quinazoline-4-carboxylic acid hydrazides|

---

US3975531A|1973-10-02|1976-08-17|A. H. Robins Company, Incorporated|4-benzoylindolin-2-ones and pharmaceutical uses thereof|

---

JP4614898B2|2006-02-27|2011-01-19|京セラミタ株式会社|Developing device and image forming apparatus|

---

JP4814667B2|2006-03-24|2011-11-16|Ｈｏｙａ株式会社|Electronic endoscope device|GR850310B|1984-02-07|1985-06-05|Pfizer|

---

US4686224A|1984-10-31|1987-08-11|Pfizer Inc.|Oxindole antiinflammatory agents|

---

DE3681358D1|1985-07-09|1991-10-17|Pfizer|SUBSTITUTED OXINDOL-3-CARBOXAMINE AS AN ANTI-INFLAMMATORY AND PAIN-RELEASING AGENT.|

---

US4678802A|1985-07-09|1987-07-07|Pfizer Inc.|1-acylcarbamoyloxindole-3-carboxamides as antiinflammatory agents|

---

GB8623819D0|1986-10-03|1986-11-05|Glaxo Group Ltd|Heterocyclic compounds|

---

RO105052B1|1987-02-02|1994-12-01|Pfizer|Producing process for the crystalline sodium salt, anhydre, of 5-chlorine-3--2-oxindol-1-carboxamide|

---

US4885370A|1987-03-11|1989-12-05|Pfizer Inc.|Synthetic method for indol-2-ones|

---

US4761485A|1987-03-11|1988-08-02|Pfizer Inc.|Synthetic method for indol-2-ones|

---

GB8720693D0|1987-09-03|1987-10-07|Glaxo Group Ltd|Chemical compounds|

---

DE3803775A1|1988-02-09|1989-08-17|Boehringer Mannheim Gmbh|NEW SUBSTITUTED LACTAME, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS|

---

US4861794A|1988-04-13|1989-08-29|Pfizer Inc.|3-substituted-2-oxindole-1-carboxamides as inhibitors of interleukin-1 biosynthesis|

---

US4853409A|1988-04-13|1989-08-01|Pfizer Inc.|3-substituted-2-oxindole-1-carboxamides for suppressing T-cell function|

---

DE68923673T2|1988-10-18|1996-01-18|Pfizer|Pro-drugs of anti-inflammatory 3-acyl-2-oxindole-1-carboxamides.|

---

RO109195B1|1988-10-18|1994-12-30|Pfizer|3-acyl-2-oxindole-1-carboxamide derivates|

---

HU215112B|1989-01-10|1998-12-28|Pfizer Inc.|Process for producing antiphlogistic 1-heteroaryl-3-acyl-2-oxindole derivatives|

---

US5300655A|1989-04-18|1994-04-05|Pfizer Inc.|2-carboxy-thiophene derivatives|

---

US5047554A|1989-04-18|1991-09-10|Pfizer Inc.|3-substituted-2-oxindole derivatives|

---

US5059693A|1989-10-06|1991-10-22|Pfizer Inc.|Process for making 3-aroyl-2-oxindole-1-carboxamides|

---

IL95880A|1989-10-13|1995-12-31|Pfizer|Use of 3-substituted-2-oxindole derivatives for the preparation of a pharmaceutical preparation for inhibiting interleukin-1 biosynthesis|

---

WO1991009598A1|1990-01-05|1991-07-11|Pfizer Inc.|Azaoxindole derivatives|

---

US5008283A|1990-03-19|1991-04-16|Pfizer Inc.|Use of tenidap to inhibit activation of collagenase and to inhibit the activity of myeloperoxidase|

---

US5006547A|1990-03-19|1991-04-09|Pfizer Inc.|Tenidap as an inhibitor of the release of elastase by neutrophils|

---

US5064851A|1990-07-24|1991-11-12|Pfizer Inc.|3--2-oxindole derivatives, compositions and use|

---

US5095031A|1990-08-20|1992-03-10|Abbott Laboratories|Indole derivatives which inhibit leukotriene biosynthesis|

---

US5122534A|1991-02-08|1992-06-16|Pfizer Inc.|Use of tenidap to reduce total serum cholesterol, ldl cholesterol and triglycerides|

---

DE4111305C2|1991-04-08|1994-12-01|Mack Chem Pharm|Pharmaceutical preparation for rectal administration, which contains a 2-oxindole-1-carboxamide derivative|

---

DE4111306C2|1991-04-08|1994-06-01|Mack Chem Pharm|Pharmaceutical preparations containing a 2-oxindole-1-carboxamide derivative and intended for injection|

---

US5210212A|1991-06-25|1993-05-11|Pfizer Inc|Process for 5-fluoro-6-chlorooxindole|

---

US5166401A|1991-06-25|1992-11-24|Pfizer Inc|Intermediates for 5-fluoro-6-chlorooxindole|

---

TW438798B|1992-10-07|2001-06-07|Pfizer|3-substituted 2-oxindole-1-carboxamide pharmaceutical compositions|

---

US5288743A|1992-11-20|1994-02-22|Abbott Laboratories|Indole carboxylate derivatives which inhibit leukotriene biosynthesis|

---

US5298522A|1993-01-22|1994-03-29|Pfizer Inc.|6-chloro-5-fluoro-3--2-oxindole-1-carboxamide as an analgesic and anti-inflammatory agent while maintaining a normal urine protein/creatinine ratio|

---

CA2153050C|1993-01-22|1998-12-29|Kelvin Cooper|Lysine salt of 6-chloro-5-fluoro-3--2-oxindole-1-carboxamide|

---

US5270331A|1993-01-26|1993-12-14|Pfizer, Inc.|Prodrugs of antiinflammatory 3-acyl-2-oxindole-1-carboxamides|

---

ES2097025T3|1993-02-09|1997-03-16|Pfizer|OXINDOL 1- ) CARBOXAMIDES AND 1-CARBOXAMIDES AS ANTI-INFLAMMATORY AGENTS.|

---

ES2076106B1|1993-08-26|1996-06-16|Pfizer|PHARMACEUTICAL COMPOSITIONS BASED ON 2-OXINDOL-1-CARBOXAMIDES 3-SUBSTITUTED|

---

US5449788A|1994-01-28|1995-09-12|Catalytica, Inc.|Process for preparing 2-oxindole-1-carboxamides|

---

EP0679396A1|1994-03-02|1995-11-02|Pfizer Inc.|Use of 3-substituted-2-oxidole-1-carboxamides for the manufacture of a medicament in the treatment and prevention of ischemia induced myocardial injury and cytokine mediated myocardial injury|

---

US6469181B1|1995-01-30|2002-10-22|Catalytica, Inc.|Process for preparing 2-oxindoles and N-hydroxy-2-oxindoles|

---

US5545656A|1995-04-05|1996-08-13|Pfizer Inc.|2-Oxidole-1-carboxamide pharmaceutical agents for the treatment of alzheimer's disease|

---

US6051588A|1995-04-19|2000-04-18|Nitromed Inc|Nitroso esters of β-oxo-amides and aryl propionic acid derivatives of non-steroidal antiinflammatory drugs|

---

US5703073A|1995-04-19|1997-12-30|Nitromed, Inc.|Compositions and methods to prevent toxicity induced by nonsteroidal antiinflammatory drugs|

---

AU7503496A|1995-12-19|1997-07-14|Pfizer Inc.|Stable, long acting salts of indole derivatives for the treatment of joint diseases|

---

HU9600855A3|1996-04-03|1998-04-28|Egyt Gyogyszervegyeszeti Gyar|Process for producing tenidap|

---

EP0826685A1|1996-08-21|1998-03-04|Pfizer Inc.|Stable, long acting salts of carboxamides for the treatment of joint disease|

---

US6043232A|1997-07-23|2000-03-28|Nitromed, Inc.|Nitroso esters of beta-oxo-amides and aryl propionic acid derivatives of non-steroidal antiinflammatory drugs|

---

AU763000B2|1998-10-30|2003-07-10|Nicox S.A.|Nitrosated and nitrosylated nonsteroidal antiinflammatory compounds, compositions and methods of use|

---

US6153634A|1998-12-17|2000-11-28|Hoffmann-La Roche Inc.|4,5-azolo-oxindoles|

---

DE69906152T2|1998-12-17|2004-02-12|F. Hoffmann-La Roche Ag|4-ALKENYLOXOINDOLE AS INHIBITORS CYCLINE-DEPENDENT KINASES, ESPECIALLY CDK2|

---

TR200101858T2|1998-12-17|2001-12-21|F.Hoffmann-La Roche Ag|4-aryloxindoles as JNK protein kinase inhibitors|

---

AU767138B2|1998-12-17|2003-10-30|F. Hoffmann-La Roche Ag|4,5-pyrazinoxindoles as protein kinase inhibitors|

---

IT1308633B1|1999-03-02|2002-01-09|Nicox Sa|NITROSSIDERIVATI.|

---

WO2001030151A1|1999-10-26|2001-05-03|The University Of Texas Southwestern Medical Center|Methods of treating hair loss comprising administering indoline compound|

---

US6313310B1|1999-12-15|2001-11-06|Hoffmann-La Roche Inc.|4-and 5-alkynyloxindoles and 4-and 5-alkenyloxindoles|

---

IT1318673B1|2000-08-08|2003-08-27|Nicox Sa|DRUGS FOR SEXUAL DYSFUNCTIONS.|

---

IT1318674B1|2000-08-08|2003-08-27|Nicox Sa|DO IT FOR INCONTINENCE.|

---

AU2002322720B2|2001-07-25|2008-11-13|Raptor Pharmaceutical Inc.|Compositions and methods for modulating blood-brain barrier transport|

---

JP2008539047A|2005-04-28|2008-11-13|プロテウスバイオメディカルインコーポレイテッド|Pharma Informatics System|

---

WO2008036682A2|2006-09-18|2008-03-27|Raptor Pharmaceutical Inc.|Treatment of liver disorders by administration of receptor-associated protein -conjugates|

---

CN104208718B|2009-02-20|2017-12-29|2-Bbb医疗股份有限公司|drug delivery system based on glutathione|

---

US20120077778A1|2010-09-29|2012-03-29|Andrea Bourdelais|Ladder-Frame Polyether Conjugates|

---

CN102911105B|2012-11-12|2013-12-04|辽宁科技大学|3-aroyl indole compound synthesis method|

---

US10239857B2|2015-03-31|2019-03-26|Monsanto Technology Llc|Processes for the preparation of 2-thiophenecarbonyl chloride|

---

US10537552B2|2015-05-05|2020-01-21|Carafe Drug Innovation, Llc|Substituted 5-hydroxyoxindoles and their use as analgesics and fever reducers|

---

BR112018069255A2|2016-03-24|2019-01-22|Monsanto Technology Llc|processes for the preparation of heteroaryl carboxylic acids|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US59065984A| true| 1984-03-19|1984-03-19|

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US06/684,634|US4556672A|1984-03-19|1984-12-21|3-Substituted 2-oxindole-1-carboxamides as analgesic and anti-inflammatory agents|LV931200A| LV5618A3|1984-03-19|1993-11-11|A panacea for obtaining 2-oxoindole-1-carboxamide derivatives|