• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
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    • 专利摘要:

    公开号:SU969701A1
    申请号:SU792847114
    申请日:1979-11-26
    公开日:1982-10-30
    发明作者:Родригес Людовик；Маршаль Люсьен
    申请人:Юцб С.А. (Фирма)；
    IPC主号:
    专利说明:

    Products A and B. In addition, new compounds have activity in relation to heart activity. Compounds of formula (1) in which h is O or 1, and R denotes a hydroxyl group are obtained by bringing in an inert solvent a lactam alkali metal derivative , jlie,,. where He is an alkali metal with an alpha-bromo lactone of the formula, (g where n has the given values, then subjected to a lactone of alpha- (hydroxyalkyl) lactam-M-acetic acid thus obtained once again of the formula W o CJH 1 () g. n has the indicated values, hydrolysis under the action of an alkali metal hydroxide and the separated free acid by acidification of the obtained alkali metal salt of alpha- (hydroxyalkyl) lactam-M-acetic acid. To obtain the compound VIi (I) in which n is 0 or 1, and R denotes a group, first obtained in this way lacquer alpha- (hydroxyalkyl) lactam-N-hydroxy acid of formula (IV), then the specified lactone is reacted with the nitrated compound of formula (V) in which R. and R are given. of formula (I), in which | 1 p but O, and R denotes a hydroxyl group, glyoxylic acid is reacted with a lactam of the formula. Finally, to obtain a compound of formula (I), in which m is O, denotes a group driven by First, glyoxylic acid or its ether with a lactam of formula (VI), and then alpha hydroxy lactam-H-acetic acid thus obtained is condensed with the formula 4wX (CJOOH Or the corresponding ester with the nitrated compound of the formula (V). In any case, when a nitrated compound of formula (V /) with alpha-hydroxy-lactam-M-acetic acid of formula (VII) is subjected to a condensation reaction, this acid should be preliminarily activated by conventional means using a common reagent, for example, dicyclohexylcarbodiimide. The present invention also relates to pharmaceutically acceptable salts of lactam-M-acetic acids of formula (I). As examples of such salts, salts of metals, ammonium, organic bases (for example, amine salts, dicyclohexylamine) and amino acid salts can be given. These salts are prepared by methods that are widely used to prepare compounds of this kind. In the examples illustrating the invention, the position of the peaks in the NK-spectra is given in the chemical shift in the NMR spectroscopy indicated in (f (ppm) relative to tetramethylsilane, 60 MHz. Example 1. Preparation of intermediate lactones 1- (tetrapahydro-2-oco-3-fluoryl) -2-pyrrolidinone. 60.5 g (1.265 mol) of sodium hydride (50% technical suspension in paraffin, previously washed twice with benzene) are suspended in 575 ml of anhydrous benzene. 98 g (1.15 mol) of 2-pyrrolidinone are added dropwise to the suspension, and then heated under reflux until fine. of a gas evolution. A solution of 237 g (1.44 mol) of 3-bromo dihydro-2 (3N) / - furanone in 60 ml of anhydrous benzene is added dropwise and the temperature is kept in the range of 40-50 ° C. the mixture is cooled and separated by filtration of the sodium MFA. The benzene solution is evaporated under reduced pressure and the residue is distilled at il62-164 ° C (0.001 mbar). The distillate obtained in the form of syrup is quickly
    crystallized, resulting in 100.8 g of 1- (tetrahydro-2-oxo-3-furyl) -2-pyrrolidinone. Calculated,% "C 56.80; H 6.51) N, 8.28.
    , (M.S. 169}
    Found,% | C, 56.70; H 6, N 8.15
    IR spectrum (KVG) | 1785, 1770 (CO 2-oxo-furyl), 1690 (CO pyrrolidinone).
    Example 2, Preparation of alpha-hydroxy-lactam-M-acetic acid of formud (I) (i-O; R-OH).
    Alpha-hydroxy-2-oxo-1-pyrrolidinacetic acid (dicyclohexylamine salt).
    To 9.2 g (0.1 mol) of glyoxylic acid monohydrate, 8.5 g (0.1 mol) of 2-pyrrolidinone are added. The temperature rises spontaneously to 35 ° C. After the addition is complete, the reaction mixture is heated for 15 minutes at. The temperature is then lowered until 15 ml of carbon tetrachloride and 10 ml of ether are added. The mixture is stratified into two phases.
    The lower phase (the SS is separated by decantation, washed twice with ether and distilled in vacuo. The residue (18 g) is dissolved in absolute ethanol and 18 ml of dicyclohexylamine are added to the solution. The precipitated dicyclohexylamine salt is recrystallized from ethanol containing a little ether. A little is obtained. 17.7 g of dicyclohexylamine salt of alpha oxy-2-oxo-1-pyrrolidine acetic acid, mp 139-140c., Yield 52%
    Calculated,%: C 63.58; H 3, N 8.24.
    . (Mv 340)
    Found, 63.6; H9, "; N, 8.27.
    IR spectrum (kVg): 3400 (OH); 1675 (CO pyrrolidino); 1620 (C00). Mass spectrum: M (acid) is absent, but M is COOH 114 m / e; M (dicyclohexylamine) 181 M / e.
    NMR spectrum (C OS ,,): 1.0-3.20 multiplet 28H two cyclonexyl + 6H pyr rolidinone); 5.54 singlet 1H, and Y-9 broadened MH OH.COOH) NH.
    Example 3. Obtaining alpha- (oxyalkyl) -lactam-M-acetic acid of the formula (I) (n 1; R OVi),
    Alpha- (2-hydroxyethyl) -2-oxo-1-pyrrolidine acetic acid. .
    67.6 g (0.4 mol) of 1- (Tatrahydro-2-oxo-3-furyl) -2-pyrrolidinone and 32 g (0.8 mol) of caustic soda in 210 ml of water are heated under reflux for 2 hours then cooled and acidified with hydrochloric acid to pH 1.
    The mixture is evaporated to dryness under reduced pressure, dissolved three times.
    the residue is in benzene and evaporated under vacuum. In conclusion, the precipitated residue is treated with a mixture of chloroform-9-tanol (4sl) and the insoluble matter is filtered off. The filtrate is evaporated and the residue is recrystallized in ethanol. Get 22.7 jc (yield 30%) alpha- (2-oxiztil) -2 oxo-1-pyrrolidinoacetic acid, .Т. square 123-124 S.
    0 Calculated,%: C, 51.38; H 6,9.5} N y.iie.
    . (Mb 187). Found,% i C 51.30; H 6.90; N 7.39.
    5 NMR (DMSO): 2.15 multiplet 6H pyrrolidinone + 2H ethyl; 3.37 multiplet 4H 2H pyrrolidinone ethyl; 4.62 quadruplet 1H 8.50 broad 2H OH and
    0 COOH.
    ; Examples 4-6 - preparation of amides of lactam-M-acetic acids fortiums (t) (n - 1; R N R Re). .
    Example 4. alpha-T2-oxy5 ethyl) -2-oxo-1-pyrrho olydacetamide.
    10.15 g (0.06 mol) of 1-Ttetrahydro-2-oxo-3-furyl) -21-pyrrolidinone are dissolved in 100 mol of methanol and the solution is saturated with ammonia. The temperature I spontaneously rises 1D. The reaction mixture is maintained at this temperature for 30 minutes, then left to cool to ambient temperature. Thereafter, the reaction mixture is evaporated under reduced pressure and the resulting powder is recrystallized from absolute ethanol. 10 g of alpha- (2-hydroxyethyl) -2-oxo-1-pyrrolidine acetamide are obtained.
    0 s. 164-165 ° C (yield 90%); Calculated,%: C 51.65; H 7.58; N 15.05.
    CgH "N, 3.0 (MV 186). Found,%: C, 51.70; H 7.60;
    5 N 14.86. .
    IR spectrum (KVg): 3340, 3180 (NH); 1695 (CO pyrrolidinone); 1650 (CO amide); 1075 (OH).
    NMR spectrum (DMSO): 2.15 multi 0 plet 6H 4H pyrrolidinone + 2H
    ethyl; 3.40 multiplet 4H 2H pyrrolidinone + 2H. Ethyl; 4.446 multiplet 2H OH + H; 7.08-7.30 broad 2H CONH.
     PRI me R 5. N, N-diethyl-alpha- (2-hydroxyethyl) -2-oxo-1-pyrrolidineacetamide.
    5.07 g of tO, 03 mol) of 1- (tetrahydro-2-oxo-2-furyl) -2-pyr0 rolidinone are dissolved in 20 ml of methanol and 20 ml of diethylamine are added to the solution. The mixture is heated at the boiling point of the reaction mixture at 60 ° C for 24 hours and then evaporated under.
    5 deep vacuum. Get the syrup. Which is purified by the method of column chromatography on silica gel (eluent (ec1 chloroform methanol 97: 3). You run 33%. .. IR spectrum (film): 3420 (he); 16 (CO pyrrolidinone); 1635 (CO amide); 1055 (OH). NMR spectrum (CPC.): 1.1-1.18 two triplet 6H 2CH4 (diethyl) j 1.7-2.6 multiplet 6H 4H pyrrolidinone + ZN ethyl, 3.1-3.8 multiplet 9H 2C (diethyl) + 2H pyrrolidnon + honed + OH 5.18 triplet 1H Huv .. Mass spectrum: M 242 m / e. Example 6.1. 4- 4-hydroxy-2- (2-OXO-1-Pyrrolidene) 6 UTIR; | -Morpholine. Mix 5.07 g (0.03 mol) (tetrahydro-2-oxo 3-furyl) -2-pyrr Lidinone with 10.45 g (0.12 mol) of morpholine and heat the mixture at 11 for 5 hours. When cooled, the ids are distilled and the product is mercury filtered and recrystallized from ether to give 6.3 g (yield 82%). 4- | 4-hydroxy-2- (2-oxo-1-pyrrolidinyl) -butyryl-Zmorfrlin. Square 10Bg-106 Calculated,% :, C 56.25;, N 10.93 .04 (mv 256) Found,%; f 56.15; H 7.82; M 10.90. IR spectrum (KW): 3450 (OH); 1680 (CO pyrrolidinone); 1650 (CO amide); 1050 (OH). HtiP-cneKTp (CDCE5): 1.8-2.6-mn tylett bN 4H pyrrolidinone + 2H bu tyryl; multiplet 13H 2H pyrrolidinone + 8H morphrlin + 2H butyryl YUN; 5.2 triplet TN H butyryl. Mass spectrum: M 256 m / e. In a similar manner, the following compounds were prepared. . . i Example b.2. alpha- (2-hydroxy ethyl) -N-propyl-2-oxo-1-pyrrolide Acetamide. Syrup. Exit 98%. Calculated,%: C 57.89; And 8.77; N 12.28. CjiH ,,, 0, (mv 228) -. Found,%: C 56.96; H 8.60; N 12, “16. IR (film): 3420 (OH); 3300 (NH); 1650-1690 (CO) j 1535 (NH); 1055 (OH). NMR spectrum (CDCE): 0.92 CH triplet, (propyl); 1.2-2.7 multiplet jn Án-j VlitUJiJa i /, f, "-ijrrf" At -w 8H 4H pyrrolidinone + CHD (propyl en ethyl; 3.0-4.1 multiplet 7H H pyrrolidinone +. CHjj ( propyl) + 2H ethyl + OH; 4, .9 triplet 1H 7.20 triplet 1H HH. Mass spectrum: M 228 m / e. Example 6.3. 1-benzyl-4-1,4-hydroxy-2. (( 2-oxo-1-pyrrole, zined) -bu; tiryl piperazine. Syrup. Yield 67%. IR spectrum (film); 3420 (OH) s 1640-1690 (C0) 1055 (OH) f 745,700 (phenyl) NMR spectrum (CDCji): 1.6-3.8 multiplet 2lHj 5.18 triplet 1H C-butyryl; 7.28 singlet 5H 5H phenyl. Mass spectrum: M 345 m / e. Example 6.4. N-cycloneent -alpha- (2-hydroxyethyl) -2-oxo-1-pyrrolidine acetamide. Syrup obtained after evaporation; neither The reaction pressure of the reaction mixture is purified by chromatography on a silica column (eluent: chloroform: methanol 95: 5). The appropriate fractions are evaporated and the remaining syrup is triturated with ether containing a few drops of chloroform. N-cyclopentyl-alpha crystallizes (2-hydroxyethyl) -2-oxo-1-pyrrolidine acetamide. M.p. 8183 C. Yield 72%. Calculated,%: C, 61.41; H 8, N 11.02. (254) Found: C 61, Il; H 8.66; N 10.98. IR spectrum (KVg): 3450 (OH); 3260 (HH); 1680 (CO pyrrolidinone); 1650, (CO amide); 1550 (NH amide); 1060 (OH). NMR spectrum (CDCEj): 1.6-2.8 multiplet 14H 8H cyclopentyl CH. + -4H pyrrolidinone + 2H ethyl; 3.3-, 4.4. multiplet 6H “2H pyrrolidinone + 2H ethyl + cyclopentyl CH + OH; 4.85 triplet 1H H.j 7.20 doublet 1H NH. Mass spectrum: M 254 m / e. Example 6.5. N-benzyl-al: FA- (2-hydroxyethyl) -2-oxo-G-pyrr6lidine-. acetamide. The syrup obtained after evaporation of the reaction mixture crystallizes very slowly. The crystals are washed with ether. T. pl. 90-92 C. Yield 71%. Calculated,%: C b5,21; H 7, N 10.14. .0з (Mv. 276). Found,%: C 65.02; H 7, N 10.23. IR (film): 3400 (OH); 3300 (NH); 1640-1690 (CO); 1540 (NH); 1065 (OH); 710 (phenyl). NMR spectrum (CDCE,): 1.7-2.5 multiplet 6H 4H pyrrolidinone + 2H 1ETH; 3.2-3.9 The multiplet 5H 2H pyrrolidino + 2H ethyl + OH + triplet; 4.4 doublet 2Н СН. (benzyl); 4.9 triplet 1H 23 singlet 5H 5H phenyl; 7.6 triplet 1H NH. Mass spectrum: M 276 m / e. Pharmacological studies 1. Effect on mnemonic processes. one). The effect on mnemonic pro cess is shown primarily on the ability of products to improve the type of memory in rats. The definition of active avoidance; the rat paw withdrawal reaction, is observed. which have increased pressure is quantified. The pressure at which the paw withdrawal reaction occurs is called the response threshold. It is measured by the number of tick marks on the scale of the instrument used and, consequently, corresponds to the minimum pressure causing paw withdrawal. Pressure is read off directly on the scale of the instrument used. When repeating the experiment after 24 hours, no visible memory of the previous test is observed in the controllers of the animals: the paw withdrawal occurs at stimulation rates comparable to the intensity of the previous day. On the other hand, animals that received a substance that have a positive effect on mnemonic processes (for example, piracetam), have a significant degree of memorization: the irritant to which rats react with the withdrawal reflex | Paws, is statistically less irritant, to which counter-rats react . In each experiment, use at least 20 rats (10 receive the test substance and 10 controls), the active dose is the minimum dose that reduces the stimulus below 11 divisions. Under these conditions, subcutaneous administration of some compounds of the formula gives the following results: Active dose. Product mmol / kg of example 0.0002 0.002 Product A (comparison) Product B (comparison) 0.005 Comparative product C (2-oxo-1-pyrrolidine- acetic acid) non-. active at a dose of 0.1 mmol / kg. The data show that in this experiment all the compounds according to the invention show greater activity than the products A and B, whose effect on the mnemonic processes is well known. 2). The effect on mnemonic processes was also shown by the shortening of the duration of spinal fixation. In rats with unilateral defeat of the cerebellum, postural asymmetry of the zgchnych paws is observed. The asymmetry can be maintained even after the spinal cross section, if the animal has been long enough in this position. The time interval, called the duration of spinal fixation, is 45 minutes under the accepted experimental conditions. On the contrary, if the spinal section is done before this time interval has elapsed, for example, 35 minutes after the establishment of aspirametry, the latter disappears. None of the placebo-treated animals maintained asymmetry under these conditions. On the contrary, any product that contributes to the preservation of asymmetry in rats, i.e. preserving spinal fixation (spinal section made after 35 min) is considered active. value in the United States., pr. “one number of those who showed the experience, IS, IC-,
    From the table it can be seen that the compounds according to the invention have the same activity as the products taken for comparison, but at definitely lower doses. 2. Action on the work of the heart.
    The compounds according to the invention have been found to exhibit marked activity in relation to work. This can be shown in experience.
    with sosochka 1 "1ShTsAA".
    The effect is on the papillary heart valve prolate, extracted from the cat's heart and immersed in physiological saline, to which the substance to be tested is then added.
    In this experiment, the compound of Example 4 shows greater inotropic activity (stimulation of muscle function) than caffeine. Thus, at a dose of 10 µg / kg, the increase in strength, reduction in mass, is respectively 7% for the compound according to the invention and 4% for caffeine.
    3. Toxicity
    Compounds of the Invention According to the Invention of Mass Shothoxy. Their toxicity when administered intraperitoneally to mice is:
    mg / kg 5 102
    i2i2 111b
    1452
    153b
    1368
     345
    762
     822
    权利要求:
    Claims (2)
    [1]
    1.Patent UK No. 103911 Cl. G 2 C; .rpublik. 08.08.64
    [2]
    2. The UK patent 1309692 .kl. 02 C, published. 14.03.73.
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    法律状态:
    优先权:
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