• 专利附录
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    • 专利摘要:
    Certain substituted 1-phenyl-3-(aminoalkylidene)-2(1H,3H)-indolones are highly potent gabaergic agents, valuable in the treatment of individuals suffering from schizophrenia or reversing the side effects of a previously or concurrently administered neuroleptic agent; or in the treatment of epilepsy. A wider class of substituted 1-phenyl-3-(aminoalkylidene)-2(1H,3H)-indolones, together with 1-phenyl-3-(2-pyrrolidinylidene)-2(1H,3H)-indolones, and homologs thereof, are valuable in the treatment of anxiety.
    公开号:SU1272983A3
    申请号:SU833646758
    申请日:1983-09-19
    公开日:1986-11-23
    发明作者:Ральф Говард Гарри；Сарджес Рейнхард
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    According to the procedure of Example 1 with a RUPOL use of a similar amount of reagents, but replacing iodoanisole N-iodine with toluene (5.1 ml, 40 mmol), the desired product is obtained. After crystallization from the mixture of ether / pentane, 2.1 g of product was obtained, m.p. 105-108 Elemental analysis. Calculated,%: C 77.67; H 6.52; 10.07; t / e 278. NUIDEN,%: C 77.3; H 6.46; 10.06; t / e 278. Example 5. 1- (3-Cyanophenium) -3- (dimethylaminomethylene) -2- (IIIN) -indolone. According to the procedure of Example 1, using a similar amount of p agents, but replacing n-iodoanisole with 3-bromobenzonitrile and using as a eluant a 1: 1 mixture of hen: ethyl acetate in chromatography, allowing the product to crystallize upon standing, obtain the desired product (1 , 3 g), so pl. 140-143 ° C. Elemental analysis. Calculated,%: C, 74.72; H 5.13; N 14.52; ha / e 289. s, c “o Found,%: C 74.32; H 5.30; N 14.43; t / e 289. Example 6. l- (3-Methylphenyl 3- (1-dimersh-aminoethylidene) -2 (1H, 3N) -indolone. Using the reaction time for 18 h under reflux and crystallization of the product from hexane after chromatography, 3- (1-dimethylaminoethyl lidene) -2 (1H, 3N) -indolone (4.06 g, 20 mmol) is converted into the desired product (0.45 g), mp 99-96 ° С Elemental analysis. Calculated,%: C 78.05; H 6.90; N 9.58; O 5.47; t / e 292. Lo Found,%: C 77.85; H 6.89; N 9 , 57; O 5.69; t / e 292. Example 7. 1- (3-Methoxyphensh1) -3- (1-methyl-2-pyrrolidinylidene) 2 (1H, ZN) -indolone. In a nitrogen atmosphere, 3- ( 1-methyl-2pyrrolidinylidene) -2 (1H, ZN) -in Dolon (1.0 g, 5 mmol) is added in portions to a suspension of sodium hydride (50% oil dispersion, 265 mg, 5.5 mmol suspended in 50 ml of DMF, and the mixture is stirred at 25 s for 2 h the mixtures were added (1.43 tons, 5 mmol) and then n-bromoanisol (1.9 ml, 13 mmol) was added. The mixture was heated for 3.5 days, cooled, poured into ice with ethyl acetate, basified with ammonium hydroxide and filter through a layer of diamtomite earth. The aqueous layer was separated from the filtrate and extracted with fresh ethyl acetate. The combined organic layers are washed again with water, dried over magnesium sulphate, treated with activated carbon, you are. parry dry and the residue is triturated with ether and filtered to obtain the starting material (110 mg). The ether filtrate is mixed to an oily state and chromatographed on silica gel (75 ml), eluting with chloroform. The pure product fractions were combined, evaporated to an oily state, and crystallized from chloroform / ether (320 mg), m.p. 127-129 ° C (decomposition). Elemental analysis. Calculated,%: C, 74.98; H 6.29; N 8.74; m / e 320. C, Found,%: C 74.87; H 6.28; N 8.69; m / e 320. Examples 1-7 are further used to prepare the following additional compounds. The listing of characteristics is given in the following sequence: example number, product name, name of starting materials, eluant for chromatography, solvent for crystallization, yield, melting point, C, H, and N microanalysis (calculated) found. Example 8. 1- (3-Chloro-4-methoxyphenyl) -3- (dimethylaminomethylene) 2 (1H, 3N) -indolone, 3- (dimethylaminomethylene) -2 (1H, 3N) -indolone, 3- (dimethylaminomethylbn) - 2 (1H, 3N) -indolone / 2chloro-4-iodoanisole, etipacetate / hexane, benzene / pentane, 38%, 148-151C, C (65.75) 66.15; H (5.21) 5.26; N (8.52) 8.47. Example 9. 1- (3-Ethylphenyl) 3- (dimethylaminomethyl) -2 (1H, 3N) -indolone, 3- (dimethylaminomethyleneU.-2 (1H, 3N) -indolone / 3-ethylphenyl iodide, ethyl acetate, ether / pentane , 34%, 112-P4s, C (78.05) 77.75; H (6.90) 6.88; N (9.58) 9.53. Example 10, 1- (3-chlorop-4- methoxy-5-methylfen w) -3- (dimethylaminomethyl) -2 (1H, 3N) -indolone, 3- (dimethylaminomethylene) -2 (1H, 3N) -indolone / 2-chloro-4-bromo-6-methylisol, 1: 1 etipacetate / hexane, ether / pentane, 33% 147-150 ° C, C (66.56) 66.48; H (5.59 5.48; N (8.17) 7.91. Example II 1- (2-Metsh1penthen) -3- (dimethylaminomethylene) -2 (1H, 3N) -indolone, 3- (dimethylaminomethylene 2- (1H, 3N) -indolone / 2-iodotoluene, ethyl acetate, hexane and then ether, 10 % 105-107 ° C C (77.67) 77.23; H (6.52 6.44; N (10.07) 10.06. Example 11 1- (4-Methoxyphenyl) -3- (dimethylaminomethylene) - 2 (W, 3N) -dolon, 3- (dimethylaminomethylene) 2 (1H, 3N) -indolone / 4-bromoanisole, without chromatography, ether / pentane, 30%, 136-138 ° C, C (73.45) 73 , 49; H (6.16 6.20; N (9.52) 9.69. Example 13. 1- (2-Chloro-5-three fluoromethylfesh) -3- (dimethylaminomethylene-2 (1H, 3N) - indolone, 3- (dimethylaminomethylene) -2 (1H, 3N) -indolone / 2-chloro-5-tri}} tormethylphene1 iodide, 1: 1 ethyl acetate: hexane, ethyl acetate / hexane, 14%, b7-165 ° C; C (58.94) 58.9 N (3.85) 3.94; N (7.64) 7.57. Example 14. 1- (3,5-Dichlorophenyl) -3- (dimethylaminomethylene) -2 (1H, 3N) -indolone, 3- (dimethylaminomethylene) -2 (1H, 3N) -indolone / 3,5-dichlorophenyl iodide, ethyl acetate, without crystallization, 72%, 147-149.5 ° C; C (61.27) 61.02; H (4.23) 4.15; N (8.41) 8.57. Example 15. 5-Chloro-1- (3-chloro fensch1) -3- (dimethylaminomethylene) -2 (1H, 3N) -indolone, 5-chloro-3- (dimethylaminomethylene) -2 (1H, 3N) -indolone / 3 -chlorophenylbromide, chloroform, without recrystallization, 24%, 165-168C, C (61.2 61.34; H (4.24) 4.26; N (8.40) 8.32 P. m and me 16. 1- (2-Nitrophenyl) -3- (dimethylaminomethylene) -2- (1H, 3N) -indolone, 3- (dimethylaminomethylene) -2 (1H, 3N) -indolone / H-bromonitrobenzene, without chromatography, ether, 29%, 213-215 ° C, C (66.01) 66.04; H (4.89) 4.91; N (13.59) 13.63. Example 17. 1- (3-Bromophenyl) -3- (dimethylaminomethylene) -2 (1H, 3N) -indolone, 3- (dimethylaminomethylene) -2 (1H, 3N) -indolone / H-dibromobenzene beta chromatography, ether, 24%, 118-121 C 1 3 C ( 59.49) 59.56; H (4.41) 4.16; (8.16) 8.06. Example 18. 1- (2-Chlorophenyl) -3- (dimethylaminomethylene) -2 (1H, 3N ) ndolon, 3- (dimethylaminomethylene) -2 (W, 3N) -indolone / O-chloroiodobenzene, without chromatography, ether / pentane, 12%, C (68.34) 67.95; H (5.06), 30; N (9.38) 9.45. Example 19. 1- (2,5-Dichlorophenyl) -3- (dimethylaminomethylene) -2 (W, | ZN) -indolone, 3- (dimethylaminomethyl) 2 (1H, ZN) -indolone / 2,5-dichlorodobenzene, ethyl acetate, ether, 19%, 161-163 ° C, C (61.27) 61.13; H (4.23) 4.28; N (8.41) 8.40. Example 20. 1- (3,4-Dichlorophenyl) -3- (dimethylaminomethylene) -2 (1H, 3N) -indolone, 3- (dimethylaminomethylene) 2 (1H, 3N) -indolone / 3,4-dichlorodobenzene, without chromatography, ether, 28%, 149-15GS, C (61.27) 61.10; H (4.23) 4.21; N (8.41) 8.33. Example 21. 1- (3-Nitrophenyl) -3- (dimethylaminomethylene) -2 (1H, ZN) -indolone, 3- (dimethylaminomethylene) 2 (1H, ZN) -indolone / h-iodonitrobenzene, without chromatography, ethyl acetate / hexane , 51%, ПЗ-Пб С, С (66.01) 65.90; H (4.89) 4.92; N (13.59) 13.53. Example 22. 1- (4-Nitrophenyl) -3- (dimethylaminomethylene) -2 (1H, 3N) -indolone, 3- (dimethylaminomethylene) 2 (IH, 3N) -indolone / n-brominitrobenzene, without chromatography, ethyl acetate / hexane , 6%, 189-192 ° С, С (64.14) 63.84; H (5.07.) 4.88; N (13.20) 13.18 with 0.5. Example 23. 1- (3-Formylphenyl) -3- (dimethylaminomethylene) -2 (W, 3N) -indolone, 3- (dimethylaminomethylene) -2 (1H, 3N) -indolone / 3-iodobenzaldehyde, ethyl acetate, ether, 18 %, 120122 ° С, С (73.95) 73.76; H (5.52) 5.66; N (9.59) 9.89. Example 24. 1- (3,4-Dimethoxyphenyl) -3- (dimethylaminomethylene) -2 (W, 3N) -indolone, 3- (dimethylaminomethylene) -2 (1H, 3N) -indolone / 3,4-dimethoxyphenyl bromide, without chromatography, ether, 6%, 164-167 ° C, C (70.35) 70.02; H (6.22) 6.06; N (8.64) 8.69. Example 25. 5-Methoxy-1- (3 chlorophenyl) -3- (dimethylaminomethylene) 2 (1H, 3N) -indolone, 5-methoxy-3- (dimethylaminomethylene) -2 (III, 3H) -indolone / m-chloroiodobenzene, chloroform, netanol / ether, 9%, 128-130 ° C, C (65.75 65.27; H (5.21) 5.19; N (8,) 8.53 Example 26. 1- (3- Dimethylcarbamoylphenyl) -3- (dimethylaminomethylene) -2 (1H, ZI) -indolor}, 3- (dimethylaminomethylene) -2 (1H, ZN) -indolone / m but-to-S, Y-dimethylbenzamide, 1: ethyl acetate: hexane , toluene / pentane, 24%, 180.5-183 ° С, С (70.67) 70.95; Н (6.38) 6.18; N (12.36) 12.35 with 0.25 НО Example 27. 4-Chloro-1- (3-chlorophenyl) -3- (dimethylaminomethyl) -2 (1H 3N) -INDSlon, 4-chloro-3- (dimethylaminomethylene) -2 (III, 3H) -indolone / m-chloroiodb Enzol, chloroform, chloroform / ether, 5%, 169-170C, C (61.28) 60.99; H (4.23) 4.13; N (8.40) 8.40. Example 28. 1- (4-Dimetsch1aminophenyl) -3- (dimethylaminomethylene) -2 (, 1H, ZN) -indolone, 3- (dimethylaminomethylene) -2 (W, 3N) -indolone / 1-1-bromo-M, Mdimetilanshtin, ethyl acetate, 32 %, 192195 ° C, C (74.24) 73.92; H (6.89) 6.84; N (13.67) 13.99. Example 29. 1- (4-Methylphenyl) 3- (dimethylaminomethylene ) -2 (1H, ZN) indolone, 3- (dimethylaminomethylene) -2 (W, 3N) -indolone / -bromotoluene, ethyl acetate, benzene / pentane, 23%, 135, 137 ° С, С (77.67) 77 , 44; H (6.52) 6.54; N (10.07) 10.29. Example 30. 1- (4-MethylDIffensI) -3- (dimethylaminomethylene) -2 (1H, 3N) -indolone, 3- (dimethylaminomethylene) -2- (1H, 3N) -indolone / c-methylthiophenylbroshch, ethyl acetate, ethyl acetate / pentane; 32%, 144-147 ° C, C (69.64 69.45; H (5.84) 5.88; N (9.03) 8.85. Example 31. 6-Chloro-1- (3- phenyl chloro) -3- (dimethylaminomethylene) -2 (1H, 3N) -indolone, 6-chloro-3- (dimethylaminomethylene) -2 (1H, 3N) -indolone / m-chloroiodobenzene, ethyl acetate, cyclohexane, 2%, 128-130 ° С, С (61.28) 61.07; Н (4.23) 4.25; N (8.40) 8.37. Example 32. 7-Chloro-1- (3-chloro-phenyl) -3 - (dimethylaminomethylene) -2- (1H ZN) -indolone, 7-chloro-3- (dimethylaminomethylene) -2 (1H, ZN) -indolonL1-chloroiodobenzene, ethyl acetate, methanol / ether, 31%, 172-175 ° С, C (61.28) 61.31; H (4.23) 4.31; N (8.40) 8.32. Example 33. 1- (3-Methyl-4-meth hydroxyphenyl) -3- (dimethylaminomethylene ) 2 (W, 3N) -indolone, 3- (dimethylaminomethylene) -2 (1H, 3N) -indolone / and-bromort methylanisol, ethyladetate, benzene / pentane, 18%, 172-174C, C (74.00) 74.09; H (6.54) 6.61; N (9.09) 9.08. Example 34. 1- (3-Biphenyl) -3 (dimethylaminomethylene) -2 (1H, 3N) -indo- (. Lon, 3- (dimethylaminomethyl) -2 (1H, 3N) -indolone / 3-bromobiphenyl, etipacetate, ether, 34%, , C g81.15) 81.55; H (5.92) 5.93; N (8.23) 8.10. Example 35. 1- (5-Chloro-2-methoxyphenyl) -3- (dimethylaminomethylene) 2 (1H, 3N) -indolone, 3- (cimethylaminomethylene) -2- (1H, 3N) -indolone / chloro-bromobenisole, ethyl acetate, ether / bent sol, 27%, 161-163 ° C, C (65.75) 65.39; H (5.2) 5.09; N (8.52) 8.39. Example .36. 1 - (3-Isopropyl-4-methoxyphenyl) -3- (dimethylaminomethylene) -2 (W, 3N) -indolone, 3- (dimethylaminomethylene) -2 (1H, 3N) -indolone / and-bromo-isopropyl anisole, ethyl acetate, ether / pentane, 7%, 133-136 ° C, C (74.97) 74.82; H (7.19) 7.23; N (8.33) 8.10. Example 37. 1- (3-Cyanofergyp) 3- (1-methyl-2-pyrrolidinylidene) -2 (1H, 3N) -indolone, 3- (1-methyl-2-pyrrolidinylidene) -2- (III, 3N) -indolone / m-bromobenzonitrile, chloroform, ether / chloroform, 16%, 172-174 ° C, C (76.17) 75.86; H (5.43) 5.19, N (13.32) 13.43. Example 38. 1 - (3-Dimethylcarbamoylphenyl) -3- (1-metip-2-pyrrolidinylidene) -2- (1H, 3N) -indolone, 3- (methyl-2-pyrrolidinsh1iden) -2 (1H, 3N) indolone / m-iodo-N, N-dimethylaniline, chloroform, ether / chloroform, 17%, 170172 C, C (72.20) 72.22; H (6.47) 6.38; N (11.48) 11.38 with 0.25 H, 0. Example 39. 6-Chloro-1- (3-chloroenyl) -3- (1-methyl-2-pyrrolidine1) (1H, 3N) -indolone, 6-chloro-3- (I-methyl-2-pyrrolidinipidene) - 2 (IL, 3N) -inolon / m-chloroiodobenzene, chloroform, firm / cyclohexane, 43%, SW-Yub S, (63.52) 63.54; H (4.49) 4.57; N (7.80) 7.86. Example 40. 1- (4-Chlorophenyl) 3- (1-methyl-2-pyrrolidinylidene) -2- (W, 3N) -indolone, 3- (1-methyl-2-pyrrolidiylidene) -2 (1H, 3N) -indolone / l-chloroiodenzene, ethyladetate, without recrystallization, 48%, 174-176 ° C, C (70.25) 69.93; H (5.28) 5.24; N (8.63) .8.52. Example 41. 1- (3-Chlorophenyl) 3- (1- (1-chlorobenzyl) -2-pyrrolidinipien -2- (1H, ZN) -indolone, 3- (1-p-chloroenzyl) -2-sh1rrolidinylidene-2 (1H, ZN) indolone / g-chloroiodobenzene, 1: 1 ethyl Deeth: hexane, ether, 29%, 115-117 C, C (67.57) 67.67; H (4.76) 4.73; N (6.30) 6.35 for 0.5. Example 42. 1- (4-Methoxyphenyl) -3- (1-methyl-2-pyrrolvindins1) 2 (1H, ZN) -indolone, 3- (1-methyl -2-pyrrolidinylidene) -2 (1H, 3N) -indolol-L-bromoanisole, ethyl acetate, ether, 8.7%, 130-132 ° C, C (74.97) 74.87; H (6.29 6.32; N (8.75) 8.73. Example 43. 1- (3-Chlorophenl) 3- (pyrrolidinomethylene) -2 (1H, 3N) indolone. Pyrrolidine (0.42 ml, 5.0 mmol) is added to the solution target compound of example 3 (0.3 g, 1.0 m mol) in 10 ml of ethanol. The mixture is stirred for 3 hours and then allowed to stand for 16 hours at 25 ° C. The reaction mixture is evaporated to dryness in vacuo, the residue is triturated with ether and filtered and washed with pentane to give the desired product 0.253 g, t. 108-112 square meters 0. Elemental analysis: Calculated,%: C, 70.25; H, 5.28; N, 8.63; m / e 326/324. C, NDOS1. Found,%: C 70.50; H 5.36; N 8.80; t / e 326/324. Example 44. 1- (3-Chlorophenyl) 3- (morpholinomethylene) -2 (1H, 3N) -indolone. The desired product of Example 3 (0.3 g, 1.0 mmol), morpholine (0.45 ml, 5 mmol) and ethanol (10 ml) are combined and stirred for 18 hours at, then an amount of morpholine (2 ml) is added. ) and the mixture is refluxed for 4 hours. The reaction mixture is evaporated in vacuo to give an oil-like substance, chromatographed on silica gel (4.5 I B cm), diluted with ethyl acetate and initially the desired product is in the form of oil which crystallized on standing in an ether / pentane mixture (0.27 g) „so pl. 130-132.5С. Elemental analysis. Calculated,%: C, 66.96; H 5.03; N = 8.22; t / e 342/340. .WITH. Found,%: C 66.62; H 5.07; N 8.32; t / e 342/340. Example 45. 1- (3-Chlorophenyl) -3- (aminomethylene) -2 (1H, 3N) -indolone. 1 - (3-Chlorophenyl) -3-- (dimethyl aminomethylene) -2 (1H, 3N) -indolone (0.3 g 1.0 mmol) is mixed with 10 ml of this. for 3 minutes and then the mixture is doused with ammonia for 1 hour at 25 ° C, stirred for an additional 16 hours, and concentrated to an oily state, which crystallizes upon standing in vacuo. Grinding with pentane results in a purified target product (0, 5 g), m.p. 141-143 ° C. Elemental analysis. Calculated,%: C 65.46; H 4.21; N 10.18; t / e 272/270, and ° Found;%: C 65.22; H 4.40; 10.29; t / e 272-270. The following compounds are prepared analogously. The listing of characteristics is presented in the following sequence: example number, product name, starting materials, eluant in chromatography, crystallization solvent, yield, melting point. C, H and N microanalysis (calculated) found. Example 46. 1- (3-Chlorfensch1) 3- (benzylaminomethyl) -2- (1H, ZN) -indolone, the target product of example 3 / / benzylamine, without chromatography, ethanol, 90%, 97-99C, C (73 , 32) 73.65; H (4.75) 4.94; N (7.77) 7.98. Example 47. 1- (3-Chlorophenyl) 3- (methylaminomethylene) -2- (1H, ZN) -indolone, the target product of example 3 / methylamine, without chromatography, ethanol, 73%, 151.5-153С, С ( 67.49) 67.75; H (4.60) 4.77; N (9.84) 9.82. Example 48. 1- (3-Chlorophenip-3) M-methyl-m-benzylaminomethylene-2- (1H, ZN) -indolone, the target product from example 3 / N-methylbenzylamine, ethyl acetate / hexane, 3%, 118-120C , C (71.96) 71.70; H (5.25) 5.22; N (7.30) 7.26 with 0.3 H, jO. Example 49. 6-Chloro-1-fensh13- (aminoetig IDen) -2 (III, 3N) -indolone, the first target product from example 2 / ammonia, without chromatography, ethanol, 29%, 170-172, C (67 , 49) 6.21; H (4.60) 4.62; (9.84) 9.77. Example 50. 6-Chloro-1-phenylZ-pyrrolidinoethylidene-2 (IH, 3N) -indolone, the first target product of Example 2 / pyrrolidine, ethyl acetate, ether / pentane, 28%, 128-121 ° C, C (70.89) 70.75; H (5.65) 5.65; N (8.27) 8.32. D1 p and measure 51. 1- (3-chlorophenyl) 3- (piperidinomethylene) -2 (1H, 3N) -indo-on, the target product from example 3 / piperidine, ethyl acetate / hexane, 62%, 153-155 ° C, C (70.89) 7Q, 49; H (5.65 5.72; N (8.27) 8.32. Example 52. 1- (3-Chlorophenyl) 3- (1-aminoethipidene) -2 (1H, ZN) -indolone, the second target product according to Example 2 / ammonia, without chromatography, ethanol, 70%, 200–202 ° C, C (67.49) 67.37; H (4.60) 4.67; N (9.84) 9.95 For gabaergic studies The activities used were male Swiss-CD swine lines weighing 17–21 g, held without food for 18 hours prior to testing.The compounds were applied subcutaneously or orally in a diluent consisting of 5% ethanol, 5% emulphor 620 and 90% saline which he himself had served as a control about the work. The compounds were tested On the 0.5x log dose scale, in order to obtain data for determining the ED values, the concentrations of the solutions were varied at different doses to obtain a constant injection volume of 10 ml / kg. The mice divided into groups were treated with the test compounds and after 1 h thereafter 3-mercaptopropionic acid (MPA) was administered intraperitoneally at a dose of 32 mg / kg, after which the mice were observed continuously for 10 minutes. In the untreated MPA, MPA causes convulsions within 4 min of treatment. Protection against convulsions caused by MPA for a given mouse, as determined, occurs if no convulsions are observed for 10 min of the test period. In this test, the compounds of formula (I) showed strong activity. For example, the EDj values for subcutaneous administration are in the range from 6.6 for I (3-fluoro-4-methoxyphensh1) -3- (dimethylaminomethylene) -2 (III, 3N) -indolone to 56 mg / kg for other compounds corresponding to 1- (4-metsh1phenyl) - and I- (4-methylthiophenes1) analogues. 1-Phenyl-3- (dimethyl aminomethylene) -2 (1H, 3N) indoles and a large number of similar compounds showed no activity in this test even at doses of 100 mg / kg Only a very small number of compounds showed such activity, for example, 1- ( 3-fluoro-4-methoxyphenyl) -3- (2-pyrrolidinide) -2 (1H, 3N) -indolone, its N-methyl analog, and, in particular, 1- (4-methoxyphenyl) -3- (1- methyl 2-pyrrolidine 1) 2- (1H, 3N) -indolone, which showed EDgg3.2-5.6 mg / kg when given subcutaneously and 18-32 mg / kg when administered orally. Studies of the compounds of the invention to combat paranoia are reflected in their strong in vivo effects on the binding of 3H-flunitrazepam. Groups of five types of the described type were injected subcutaneously with 320 µmol / kg of the test compound or diluent 1 h before intravenous injection of 200 µI Ci / kg. Twenty minutes after the injection of H-FNP, the mice were euthanized and their medulla was removed and immediately frozen. Each brain was quickly weighed and homogenized in 40 vol. (mass per volume) of ice-cooled 50 mM Tris-HC1 pI 7.7 buffer using Brinkman Polytron. Three samples of 1.0 ml each of the samples were filtered through Whatman GF / B glass filters under vacuum and flush with two 5 ml aliquots of buffer-; ra cooled by ice. Bound was measured by adding filters to puffs with a capacity of 10 mp. Aquasol-2 and radioactivity measured. Bound H-FNP for drug-treated mice was calculated as a percentage of bound H-FNP for mice treated with diluent only. In this trial, compounds of formula (II) or (III) exhibit enhanced binding of H-FNF, for example, in the range from 126% for 1- (3-chlorophenyl) -3- (morpholinomethylene) -2 (1H, 3N) -indolone and 1- (3-cyanophenyl) -3 (1-metsh1-2-pyrrolidinylidene) -2 (1H, 3N) -indolone, up to more than 250% for the most active compounds, such as 1- (3-chloro-4-methoxyphenip ) -3- (dimethyl aminomethylene) -2 (1 H, ZN) -indole it and 1- (3-fluoro-4-methoxy) -3- (1-metsh12-pyrrolidinsh1Iden) -2- (1H, ZN) - indolone .... An effective dose, inhibiting 50% of mercaptopropionic acid (gabaergic activity), convulsing in mice, bring on table one.
    13
    Table 1
    1272983
    four
    Continued table. 2 No toxicity was detected for all studied compounds. Formulalabing,. The method for preparing the 1-fe derivatives. Nile-2 (1H, ZN) -indolone of the general formula where L 2 is H or CH; In | - H or C, - H or -CH C ln - H or CH QI, taken together with the B atom of the nitrogen to which they are attached, form a pyrrolidine, piperidine or Mo ring with another ring; A and B - together mean 1,4-butilen; C, -CH3 or -CHjCgHg; W is hydrogen, C-C -alkoxy, chlorine; X and Y. each independently different, l and V from each other means hydrogen, coxy, C, -C-alkyl or C-C-alkylthio, chlorine, fluorine, trifluoromethyl, formyl, cyano, nitro, di-C -C - alkylcarboxyamide group, di-C-C-alkylamino group, o t-l and that the alkali metal salt of a compound of the general formula where W, L, B and C, have the indicated meanings, is reacted with a phenyl halide of the general formula where X is iodine or bromine; X, -, and Y have the indicated meanings; in the presence of CUjBrj in a reaction-inert solvent followed by separation of the target product or, if necessary, when in B. and C are both lower alkyl groups, the latter is transferred to another specified amino group by an excess of the corresponding amine in the reaction-inert solvent.
    权利要求:
    Claims (1)
    [1]
    The claims of $
    The method of obtaining derivatives of 1-phenyl-2 (1H, 3H) -indolone of the general formula thio group, chlorine, fluorine, trifluoromethyl group, formyl, cyano-, nitro groups, di-СУ-С 2 ~ alkylcarbokeamido group, di-С ( -С а - alkylamino group, characterized in that the alkali metal salt of the compound of general formula (II) (III) where W, L 2 , B 4 and C, have the indicated meanings, is reacted with a phenyl-loid of the general formula l
    where Λ 2- n or CH; 20 IN - n or sn 3 ; from, - n or - CI W 5 ; OR Λ G- n or CH; C 1 ' taken with an atom 25
    the nitrogen to which they are attached form a pyrrolidine, piperidine or morpholine ring;
    or
    A and B < - together mean 1,4-butylene;
    C f -CH 3 or -CH a C e Hg;
    W is hydrogen, C 1 -C 2 alkoxy group, chlorine;
    W, X, and Y ( each independently 35 from each other means hydrogen, C ^ -C-alkoxy, C, -C 2 -alkyl or Cy-C 2 -alkyl- where X is iodine or bromine;
    W, X, · and Υ have the indicated meanings;
    in the presence of CUjBTj in a reaction-inert solvent, followed by isolation of the target product, or, if necessary, when the group -nC with 1 группе ν and С, both lower alkyl, the latter is transferred to the other specified amino group by the action of an excess of the corresponding amine in the reaction-inert solvent.
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    NO161557B|1989-05-22|
    PH18297A|1985-05-24|
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    KR840006239A|1984-11-22|
    NO161557C|1989-08-30|
    PL141876B1|1987-09-30|
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    HU189747B|1986-07-28|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/420,544|US4476307A|1982-09-20|1982-09-20|Heteroylidene indolone compounds|
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