• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    New physiologically active N-substituted lactams having the formula <IMAGE> wherein R1, R2, R3, R4, R5, R6 and R7, represent independently a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms or a phenyl group, R8 is a hydrogen atom or R8 and R3 together form the ethylene or trimethylene radical, and n is 3, 4 or 5, processes for the preparation thereof and pharmaceutical compositions containing the same.
    公开号:SU937450A1
    申请号:SU782626702
    申请日:1978-06-13
    公开日:1982-06-23
    发明作者:Родригез Людовик；Маршаль Люсьен
    申请人:за вители；
    IPC主号:
    专利说明:

    The invention relates to novel .biologically active chemical compounds, specifically to N-substituted lactams having pharmaco-hygienic activity.
    In particular, they exhibit activity in mnestic processes and defensive activity against aggressions such as HYPOXIA; They can find a use for treating memory disorders associated with cell changes caused by both age and a decrease in oxygen supply to the brain due to primary or secondary vascular injuries. They can be used in many other areas, for example, for the prevention and treatment of injuries to cerebral vessels or cardiovascular injuries, post-traumatic or toxic comatose conditions, memory disorders, difficulties caused by mental stress, etc.
    N-substituted lactams are known (for example, piracetam-2-oxo-1-pyrrolidine acetamide), having analogs. gichny therapeutic activity 11
    However, the known compound has the disadvantage that it can only be effective with lower doses.
    The purpose of the invention is to dissolve the range of compounds, showing activity in mental processes and activity against aggressions such as hypoxia and cardiac activity.
    The goal is achieved by the properties of N-substituted lactams of the general form
    (CttaU
    Kb
    Rj-C-CO- -CH-CO-N:
    to

    where R, Ri, R3fR4 5 6 tons independently of one another hydrogen, alkyl radical, or phenyl; Rg is hydrogen, or Rg and Rj together form an ethylene or trimethylene radical; n is an integer (from 3 to 5). Compounds of formula (D) are prepared in a known manner 2. They are usually condensed in an inert medium (chloroform or methylene chloride), lactam is N-acetic acid of general formula (II) with amino acid CH2 ester and R4 with o- -HH-cit -coo tg dik Hj-C-COOH 8 lots of the general formula (Y) in the presence of a condensing agent, for example dicyclohexylcarbodiimide (DCC), and the ester of the general formula (GC) thus obtained is then reacted with an amine of the general formula, in some cases in the presence of sodium methoxide as a catalyst. The reaction scheme can be represented as follows: NKbKu II Кз - С - со.-Т Г-ч; н-; оо z R. The following compounds of the formula (111) B) N- (2-oxy- l-pyropolyacyl) -glycine. M.p. 92 ° C. Yield 58%. (Formula (111):, Z-benzyl). c) N- (d-ethyl-5,5-dimethyl-2-oxo-1-pyrrolidine-acetyl-glycine ethyl ester. mp. 61 ° C. Yield 68% (formula (111):, H4-K5-5 -methyl EZ-EHYL g-ethyl. Fri-3, n -R-5-methyl, R-ethyl, Z-ethyl 1) N- (dL, 5, 5-trimethyl-2-oxo-1-pyrrolidine acetyl ethyl ester ) -g qina.T.p. Yield: 55% (formula (111):,, j-5-methyl, thyl, Z-ethyl). d) N- (o1-ethyl-2-pk ethyl ester -1-pyrrolidine acetyl) -glycine. Mp 70 ° C. Output 63% (Formula (111): p-3 Re-ethyl, Z-ethyl). e) W- (cL-methyl-2-o-co-1-pyrrolidine acetyl) -glycine ethyl ester. T. 4 ° C. Yield 66% (formula (111): n, Z-et l). g) 2- 1- (2-oxo-pyrrolidino) -cyclopropanecaroxime to-acetic acid ethyl ester. T. pl. . Yield 51% (formula (111):, Rj and Rg-ethylene, Z-ethyl). E) N- (2-OXO-1-PI Rolidine Acetyl) -sarcosine ethyl ester. Mp.160 (0.01 mmHg). Yield 67% (Formula (111):, R-methyl, Z-ethyl). m) N- (2-oxo-1-pyrrolidine acetyl) sarcosine benzyl ester. Cyro Yield 87% (formula (111), R4-m thyl, Z-benzyl). j) Methyl ether. 1- (2-oxo-1-pyrrole or sodium acetate). Syrup. Yield 79% (formula (111):, Rj-Z-methyl). l) N- (2-OKCo-l-pyrrolidine acetyl) -2-phenylglycine ethyl ester. M.p. 89 ° C. Yield: 80% (formula (111, R5-phenyl, Z-ethyl). M.) N- (2-oxo-4-phenyl-1-pyrrolidine acetyl) ethyl ester, glycine, m.p. . Yield: 77% (formula (111 Rxi-4-phenyl, 2-ethyl). N) Ethyl ester of N- (2-oxo-C1-phenyl-1-pyrrolidine acetyl) -glycine. M.p. 115C. Yield 66% ((111): Rz-phenyl, Z-ethyl). o) N- (5-methyl-2-oxo-1-pyrrolidine acetyl) glycine ethyl ester. Syrup. Yield 100% (formula (Ml):, Ri-5-methyl, Z-ethyl). P) Ethyl ester of N- (hydroxyhydro-2-occo-1H-azepine-acetyl) -glycine m.p. 104С. Yield 61% (formula (111):, Z-ethyl). p) N- (eL-H-butyl-2-oxo-1-pyrrolidine acetyl) -glycine ethyl ester m.p. 79 ° C. Yield 75% (formula (111): Rz-w-butyl, Z-ethyl). c) N- (3-n-butyl-2-oxo-1-pyrrolidine acetyl) -glycine ethyl ester. Syrup. The yield is 100% (formula (111): P, R -3-n-butyl, Z-ethyl). Example 2. Synthesis of an acid of formula (IV). “) N- (2-oxo-1-pyrrolidine acetyl) -glycine. Dissolve 2, .9 g (0.01 mol) of N- (2-bx-1-pyrrolidine-acetyl) -glycine benzyl ester (product 1B) in 50 ml of acetic acid and hydrogenate the product in the presence of palladium-carbon (Pd / C) at room temperature under pressure of 4 kg / cm. The catalyst is filtered off, the filtrate is evaporated to dryness, and the syrup with anhydrous 1L4 ether thus obtained is triturated to give a white poroiac so that jB is obtained. Thus, 2 g of N- (2-oxo-1-pyrrolidine acetyl) -glycine is isolated. M.p. 149-150 ° С, ylkhod 100%. Molecular weight 200. Elemental analysis. number,%: C 48.0; H 6.0; N 14.0. C Q Found,%: C 47.6; H 6.21; N 13.88. Get N- (2-oko-l-w prolidinatsetil) -sarcosin. M.p. . Yield 67% (formula (IV):, R4-methyl). &amp;) (2-Oxo-pyrrolidino) -cyclopropanecarboxamido-acetic acid (formula (IV):, Rj and Ra-ethylene). To a solution of 20.4 g (0.08 mol) of ethyl (2-oxo-pyrrolidino) cyclopropanecarboxamido-acetic acid in 80 MP of methanol, a solution of 3.5 g of NaOH in 80 ml of water is poured. The solution thus obtained is heated at 40 ° C for 5 hours. The alcohol is evaporated, the residue is treated with water and acidified with concentrated hydrochloric acid to pH 1. The mixture is evaporated to dryness and the residue is recrystallized from water. Obtain 13 g (yield 69%) of 2-Cl- (2-oxo-pyrrolidino) -cyclopropane c-amide J-acetic acid. M.p. . Elemental analysis. Calculated,%: C 53.14; H 6.24: N 12.39. C 0 N, 04; Found: C 53.20; H, 6.30; N 12.36. Example 3. Synthesis of lactams of the formula (1). h) 2- (2-Oxo-1-pyrrolidine-acetamido) -acetamide (formula (1):, R - hydrogen). 17.1 g (0.075 mol) of N- (2-oxo-1-pyrroidine-acetyl) glycine ethyl ester are dissolved in 350 ml of methanol. NHj (approximately 2 h) is passed into a saturated solution and the mixture is stirred for 3 h at a rotate temperature. After evaporation of the reaction mixture to dryness in vacuo, the residue is rapidly crystallized. Thus, 14.9 g (yield 100%) of 2- (2-oxo-1-pyrrolidinam tamido) -acetamide are obtained. M.p. 147-148 ° C. Molecular weight 199. Elemental analysis. Calculated%: C 48.24; H 6.53; N 21.10. Found,%: C, 48.11; H 6.49; N 21.24. B) Nn-Butyl-2- (2-OXO-1-PIRROL idinacetamido) acetamide. (Formula (1):, R (, - n-butyl). Boil with reflux for 12 hours 9.12 g (0.04 mol) of N- (2-oxy-l-pyrrolidinetsetil) ethyl ester glycine with 7.7 (0.1 mol) H-butylamine. Then evaporated in vacuo to dryness and the crystallized residue is washed with ether, filtered, dusted with ether and the remaining product is dried. Thus 9.9 g are obtained (yield 97%) Mn-butyl-2- (2-OXO-1-pyrrolidine-acetamido) acetamide. T. mp 105-106 ° C, molecular weight 255. Elemental analysis, calculated: C 56.51; H 8 , 23; N 16.47. Found: C 56.66; H N N 16.36. B) N-Methyl-2- (2-oxo-1-pyrrolidine acetamido) acet Ministry of Foreign Affairs. (Formula (1):, E (5-methyl). Add 31 g (1 Mel) of methylamine to 18.24 g (0.08 mol) of ethyl N- (2-oxo-1-pyrrolidinacetyl)) glycine. The reaction mixture is kept under stirring for 8 hours, then evaporated and the residue is crystallized from absolute ethanol to give 15.7 g (yield 92%) of N-methyl-2- (2-o-co-1 -pyrrolidine acetamide 6) acetyamide So melting point 139-140 ° C, molecular mass 213. Elemental analysis: Calculated,%: C 50.74; H 7.04; N 19.72. Found,%: C 50.80 ; H, 7.10; N, 19.60. G) 2- (2-OXO-1-pyrrolidine acetam to) -N-phenylacetamide. (Formula (1): PVZ,) enyl., 23.2 g are mixed in the flask. (0.102 mol). N- (2-oxo-1-pyrrolidine acetyl) glycine ethyl ester with 51 ml of aniline (0.51 mol) and 10.5 methanol. 0.39 g (0.017 mol) of sodium was added to this solution in portions. Bring the temperature of the reaction medium to. to dissolve the sodium completely, then boil for 17 hours under reflux. Alcohol is then added and 150 Mff of anhydrous toluene is added. The precipitate formed is filtered off, washed with ether and recrystallized from absolute ethanol. Then 7.4 g (26.5% yield) of 2- (2-oxo-1-pyrrolidine-acetamido) -N-phenylacetamide is isolated. M.p. 200-201 ° C. Elemental analysis. Calculated,%: C 61.14; H 6.18; N 15.28. CmH 7N3O3 Found: C 61.12; H 6.22; N 15.30. a) 2- (N-Methyl-2-oxo-pyrrolidine-acetamido) -N-phenylacetamide. (Formula (1):, R.-methyl, K (, - phenyl). Add a solution of 3.8 g ((0.04 mol) aniline in 40 ml of methylene chloride) to a suspension of 8.6 g (0.04 mol A) N-f2-oxo-1-pyrrolidine-acetyl3-sacrosin in 60 ml of methylene chloride. The mixture is cooled to 9.2 g (0.044 mol) of DCC dissolved in 20 ml of methylene chloride and added dropwise therein. h at a temperature between 5 ° C and then for 18 h at room temperature. Then dicyclohexyl urea is filtered off and 6 ml of acetic acid is added to the filtrate, then evaporated to dryness in a vacuum. The solution is treated with ethyl acetate, the insoluble products are filtered off (dicyclohexyl urea) and the filtrate is evaporated to dryness. A syrup is obtained which is stirred in toluene to make it crystallizable. You can also carry out chromatography on a column of silica (eluant methanol-chloroform 1/9). It is filtered, washed with ether and dried. Thus, 9.5 g (82% yield) of 2-N-methyl-2-oxo-1-pyrrolidine-acetamido-N-phenylacetamide is collected. M.p. 145-14 bps, molecular weight 289. Elemental analysis. Calculated,%: C, 62.33; H 6.57; N 14.54. c gH gNaOj Found,%: C 62.50; H 6.50; N 14.48. e) s-isopropyl-2- (2-oxo-1-pyrrolidine acetamide) 5-acetamide. M.p. molecular weight 241. Elemental analysis. Listed,%: C 54.81; H 7.88; N 17.43. C H gNjOj Found,%: C 54.80; H 7.80; N 17.36. 9) 2- (e1-ethyl-5,5-dimethylg-2-oxo-1-pyrrolidine acetamido) acetamide. M.p. .151 ° C, molecular weight 255. Elemental analysis. Calculated,%: C 56.51; H 8.23; N 16.47. C fj Hii NjOj Found,%: C 56.56; H 8.29; N16 / 48. a) 2- (1-5,5-Trimethyl-2-oxo-1-pyrrolidine-acetamido) -acetam.T.p. 202 ° C, molecular weight 241. Elemental analysis. Calculated,%: C 54.82; H 7.88; N 17.42. C H gNiOj Found,%: C 54.9.0; H 7.72; N 17.45. and 2- (C1-Ethyl-5,5-dimethyl-2-oxo-1-pyrrolidineacetamido) -Y-n-propylacetamide. M.p. 177 ° C, molecular weight 297 Elemental analysis. Calculated,%: C 60.65; H 9.09; N14.14. Hij-jN Oj Found,%: C 60.59; H 9.10; N14.18. k) 2- (A-Methyl-2-oxo-1-pyrrolidine acetamido) acetamide. M.p. 119 ° C, molecular weight 213. Elemental analysis. Calculated,%: C 50.76; H 7.04; N 19.71. CgH jNjOj Found,%: C 50.80; H 7.12; N19.76. l) 2- (1-Ethyl-2-oxo-1-pyrrolidineacetamido) acetamide. M.p. 122c, molecular weight 227. Elemental analysis. Calculated,%: C, 52.90; H 7.49; (jg 51 C H N O Found, I: c53, i; H 7.60; N 18.58. (L) 2-H1- (2-OXO-Pyrrolidino) -Ciclopropanecarboxamido-acetamide. mp. 180 ° C , molecular weight 225. Elemental analysis. Calculated,%: C 53.33; H, 6.66; jg gQ C NLY About Naideno,% ° C, H 6.74; N 18.60, H) N, N-Dimethyl -2- (2-oco-l-pyprolidinecetamido) -acetamide. T.P. Molecular weight 227. Calculated,%: C, 52.8b; H 7.49; N 18,51. Cjo Hn Found: C 52.80; H 7.42; N 18.70. . O) 2- (N-Methyl-2-oxo-1-pyrroli-Idinacetamido) -acetam. T. mp. molecular weight 213, 010 Elemental analysis. Calculated,%: C 50.74; H 7.04; N 19.72. And “FoundD: C 50.85; N b; 99; N 19.80. p) N-Methyl-2- (N-methyl-2-oxo-1-pyrrolidine-acetamido) acetam. T. mp. 111 ° C, molecular weight 227. Elemental analysis, Calculated,%: C, 52.90; H 7.49; N 18,51. Found,%: C, 52.84; .H, 7.45; N 18j30. P) N, N-Dimethyl-2- (N-methyl-2-oxo-1-pyrrolidine acetamido) acetamide. M.p. molecular weight 241. Elemental analysis. Calculated,%: C 54.81; H 7.88; 17.43. Found:% C 54.84; H 7.79; N 17.36. c) 2-Methyl-2- (2-oxo-1-pyrrolidine acetamido) acetamide. M.p. 173c, molecular weight 213. Elemental analysis. Calculated,%: C 50.74; H 7.04; N 19.71. CgH 5NjOi Found:% 50.64; H 7.0; N 19.70. t) 2- (2-Oxo-1-pyrrolidine acetamide) -2-phenylacetamide. M.p. 195C, molecular weight 275. Elemental analysis. . Calculated,%: C 61.14; H 6.18; N 15.28. Found,%: C 60.47; H 6.11; N 15.07. s) 2- {2-Oxo-4-feiyl-1-pyrrolidine acetamido) acetamide. Mp.1600C, molecular weight 275. Elemental analysis. Calcd.,%: C 61.14; H 6.18; N 15.28. „A, l2 U with 00 Found: with b1.0v; H 6, -d-J; LS, C .. -o, 2- {5-Methyl-2-oko-l-pyrpolydine acetamido) acetamide. M.p. 131 "C, molecular weight 213. Elemental analysis. „, 19,72,„, in ,, .- ,, “. , 6th; H 7.10; ,, “J, X) 2- (2-Oxo-o1-phenyl-1-pyrrolidine-acetamido) acetamide. M.p. 174c, molecular weight 275. Elemental analysis. Calculated,%: C 61.14; H 6.18; N 15.29. .tTNjO3 Found,%: C 61.10; H 6.20; N 15.22.
    c) 2- {Hexahydro-1-oxo-1H-azepin-1-acetamido) acetamide. M.p. molecular weight 227.
    Elemental analysis.
    Calculated,%: C, 52, f6; H 7.50; N 18,51.
    .Oj
    Found,%: C 53.04; H 7.77; N18.45.
    h) 2 - (- n-Butyl-2-oxo-1-pyrrolidine acetamido) acetamide. M.p. molecular jes 255.
    Elemental analysis.
    Calculated,%: C 56.51; H 8.23; N 16.47.
    C-ioHij NjOj
    Found: C, 56.23; H 8.18; N 16.99.
    , U1) 2- (3-n-Butyl-2-oxy-pyr-lidinatsetamido) -acetamide. M.p. 152 ° C molecular weight 255.
    Elemental analysis.
    Calculated,%: C 56.51; H 8.23; N 16.47.
    , N ,, oj
    Found,%: C 56.61; H 8.25; N 16.42.
     y) N-tert-butyl-2- (2-oxo-1-pyrrolidine-acetamido) acetamide. M.p. 14 -150s, molecular weight 255.
    Elemental analysis.
    Calculated,%: N 16.47, Ci, (i-, N ,, O,
    Found,%: 16.02. . Pharmacological results.
    Products subjected to pharmacological tests, the results of which are reproduced below.
    1. Action on memesic processes.
    The effect on the mnezic processes is proved, first of all, by the ability of the compounds to improve the type of memory in the rat. A paw compression reaction is observed in the rat, which has experienced increasing and quantitative pressure. The pressure at which the reaction occurs is called the reaction threshold. This latter is expressed by the number of divisions into degrees of the chalices of the apparatus used (UGO BASILE-Milan analdesimeter) and corresponds, in a manner, to the minimum pressure that is applied to the paw of the animals, which causes compression. It is read directly on the scale of the apparatus used.
    Experiments carried out after 24 hours on control animals showed no visible delay in prior testing: elimination is observed for stimulation intensity, compared to wakefulness intensity. In contrast, animals that have been injected with a substance that has a positive effect on various processes (such as, for example, piracetam) show significant
    degree of delay: the irritant with which the rats react to the elimination reflex is statistically lower than the stimulus of the control animals. A minimum of 20 rats are used per pig (10 treated rats and 10 control rats) and the minimum dose that reduces the stimulus below the 11 divisions of the scale is determined as the active dose.
    Subcutaneous administration of some compounds of the formula (T), namely compounds a),), 3), m), k), l), m),) / p), p), c), t), c) ich) given in these conditions, the actions shown
    in that bl. one.
    From tab. 1 it follows that, in this experiment, all compounds exhibit an activity greater than that of piracetam, whose effect on
    The processes are well known.
    Table 1
    The effect on the mnezic processes is also proved by the reduction of the spinal fixation time. In the rat, after one-sided damage to the cerebellum, there is an asymmetry of the position of the hind legs. This asymmetry can continue even after a spinal incision, if the animal has been in a sufficiently long time in this situation. This time, called spinal fixation, under the experimental conditions used 5 here, is 45 minutes.
    On the contrary, if the spinal incision was made before this time expired, for example, 35 minutes after the asymmetry was established, this latter disappeared.
    No placebo treated animals retained asymmetry under these conditions.
    In contrast, any substance that allows rats to maintain asymmetry (therefore, performing spinal fixation) when the spinal incision is made after 35 minutes is considered active.
    Introduction intraperitoneally by substance a) gave the effects described in table. 2 Under the number of animals mean the number of animals, responding positively to the experience, in relation to the number of animals experienced at a specified dose.
    Table 2
    Ii. Protection against aggressions such as hypoxia.
    Protection against aggressions of the type: hypoxia is proved by a decrease in lethal. -. of curare with a short time of action, oxide oxypentonium. At the doses used, this curare entails respiratory depression, which, in turn, causes hypoxia-hypercapnia syndrome. BeiqecTBO, able to protect the big brain during the burden of this short period of hypoxia, ensures survival. Substances
    5 were given to rpynifaiM from 10 ml for one hour before the injection of curare, in parallel the control group of 10 mice received a physiological solution of sodium chloride before the administration of curare.
    Introduction intraperitoneally by some compounds of formula (I), namely substances a), 5), e),
    5 g), 3), and),. To), A) they) gave the results described in table. 3
    Table 3
    权利要求:
    Claims (1)
    [1]
    Claim
    - Substituted lactams of the general form -
    Kb to 7
    K 5 against anoxia.
    1U. Toxicity.
    Test connections low current
    sichny. As an example, Table 5 gives toxicity when administered internally for some compounds of the invention. retirement.! T a blitz 5 Substance 111111111 i 1 1 1 1 1 1 ol I ίΧι 1 R 1 ί ί 1 1 1 1 1 1 1 1 1 1 1 1 1 1111 mmol / kg (in rat) | mg / kg
    a) > 5 > 1000 δ> > 4 > 1020 e). > 3 > 723
    35 where R 1 , R (^, R 3 , R4, Rg, R ^ and R- | are independent of one another hydrogen, alkyl containing 1-4 carbon atoms or a phenyl group;
    R ^ is hydrogen or Rg and Rj together form an ethylene residue or trimethylene;
    η is an integer (from 3 to 5), showing meeeic, antihypoxic and cardiac activity.
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB43934/76A|GB1539817A|1976-10-22|1976-10-22|N-substituted lactams|
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