• 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:
    N-substituted-diglycidyl-isocyanurates having the formula: <IMAGE> wherein R represents a hydrocarbon-containing radical selected from the group consisting of alkyl, aryl, aralkyl, alkaryl and cycloalkyl, optionally containing: (a) heterocycles except epoxides, and unsaturation, and (b) substituents selected from the group consisting of halogen, hydroxyl, amino, N-substituted amino, mercapto, alkylmercapto, arylmercapto, alkylsulfoxy, arylsulfoxy, alkoxy, aryloxy and acyloxy, and R1 represents a member selected from the group consisting of hydrogen and alkyl having from 1 to 4 carbon atoms, as well as the method for preparing said N-substituted-diglycidyl-isocyanurates, therapeutic compositions with cytostatic action comprising said N-substituted-diglycidyl-isocyanurates, and a method of treatment of malignant neoplasias in warm-blooded animals by administering a therapeutically effective amount of said N-substituted-diglycidyl-isocyanurate.
    公开号:SU976849A3
    申请号:SU802990883
    申请日:1980-10-03
    公开日:1982-11-23
    发明作者:Фишер Герберт；Будновски Манфред；Цейдлер Ульрих
    申请人:Хенкель Кгаа (Фирма)；
    IPC主号:
    专利说明:

    (5) METHOD FOR OBTAINING ISOCYANURIC ACID DERIVATIVES
    . The invention relates to a process for the preparation of new isocyanate acid derivatives having cytostagative activity, which can be used in medicine.
    The known reaction of opening the epoxide cycle, in particular glycidol, by nucleophilic reagents such as water, alcohols, mercaptanes SP.
    The purpose of the invention is to emit new isocyanuric acid derivatives with valuable cytostatic properties.
    The goal is achieved by the fact that according to the method for producing isocyanuric acid compounds of the general formula
    R
    JH2C-HC-H2 -ir s -CH2-CH-dH2
    VQо
    where R-2 3-disexipropyl, 2-hydroxy-3- (2-hydroxyethyl} propyl, propionyloxypropyl, 2-hydroxy-3-propoxypropyl, 2-hydroxypropyl or 2-hydroxy-3-di- (2-hydroxyethyl). aminopropyl , triglycidyl isocyanurate formula
    it is-it-o
    OZGuO (p;
    1ГгС-ЛЙ-Н2 1-ИххТ «-СН2: Р 2,
    subjected to interaction 1 with a compound of the general formula
    R-OH
    III
    where R is hydrogen, propyl, ethylcarbonyl, 2-mercaptoztil, 2-hydroxyethylaminoethyl,
    with the subsequent selection of the target
    product. In this case, the process is preferably carried out at 70 ° C, if R is hydrogen. In addition, the process is carried out at room temperature in ethanol in the presence of sodium borohydride if K is hydrogen. Moreover, the process is preferably carried out at boiling in an organic solvent, if R is propyl. In addition, the process is carried out by boiling in an organic solvent in the presence of a molecular sieve if R is ethylcarbonyl. In this case, the process is carried out by calcination in an organic solvent in the presence of a base, if R is mercaptoethyl. Moreover, the reaction is carried out at 60 ° C in an organic solvent, if R is 2-hydroxy-3-di- (2-hydroxyethyl) aminopropyl. Example. Preparation of .diglycium dil-2,3-dioxypropyl isocyanurate. 100 g of cc-triglycidyl isocyanurate is stirred in 1000 ml of water at pH for 3 h at 70 ° C. The incomplete source product was filtered out of the filter after cooling the solution and the solution was evaporated to dryness carefully in an oil pump vacuum. The mixture contains 9.1 epoxy ki (hydrogen and consists of a mixture of diglycidyl-2, dioxypropyl isocyanurate and glycidyl-di {2, -z-dioxypropyl) isocyanurate. The mixture is chromatographed on a 3 cm diameter column containing 170 g of silica gel with a particle size of 0 , OBZ0, 2 mm. As eluent, a mixture of methylene chloride and ethyl acetate (32) containing 5 methanol is used. I By chromatographing 38 g of product, 18 fractions of 100 ml each were isolated. Fractions 10–18 yielded 21 g of the desired product. .. Percent epoxy oxygen, 10.3 (theoretically 10.1), colorless syrup. The refractive index is 1.5093. PRI mme R 2. Obtaining diglitsi. Dil-2-hydroxy-3- (2-hydroxyethylthiopropyl) isocyanurate, 29.7 g (0.1 mol) oL-triglycidyl isocyanurate, 8.0 g (0.1 mol) of mercaptoethanol and 1.5 ml of triethylamine 8 500 ml of methylene chloride boil with a brother cooler for an hour. Then extract with water (3 ra. 60 ml each) by shaking, suat over sodium sulfate and. evaporated. The product is boiled in 200 ml of methanol. The precipitated starting triglycidyl cyocyanurate is aspirated. The methanol phase is evaporated and get 16.g mixture. zmono - and diglycidol connection. The percentage of epoxy oxygen is 6.1. The reaction mixture is chromatographed on a 4 cm diameter column containing 230 g of silica gel No. 60, A mixture of ethylene chloride, ethyl acetate and metaol (3: 2: 1) is used as eluent. The output of the IGLICIDYL compound was 10.5 g. The percentage of epoxy oxygen was 8.2 (theoretically 8.5). Relamenlen index Pd 1, 5207. .P. p and measures 3-. Preparation of diglycidyl (propionyloxyoxypropyl) isocyanuate. 20 g (0, 7 mol) o-triglycidyl isocyanurate, 50 g (0.67 mol) of propionic acid and 10 g of molecular acid, and 3 A sieve in 300 ml of toluene are boiled under reflux for 5 hours. Then filtered and evaporated. The yield of the crude product is 23.5 g. The mixture is introduced into 150 ml of methanol, the precipitated triglycidyl isocyanurate is filtered off and the methanol filtrate is evaporated. After fractionation on a No.60 silica gel column, 17.2 g of the expected product are obtained in the form of a colorless syrup. The percentage of epoxy oxygen is 8.1 (theoretically 8.2). PRI me R 4. Obtaining diglycidyl (2-hydroxy-3-propoxypropyl) isocyanurate. 29.7 g (0.1 mol) of ot-triglycidyl isocyanurate and 30 g (0.5 mol) of n-propanol in 500 ml of toluene under reflux for 6 hours with stirring. The solution is then evaporated and taken up in 200 ml of methanol. The triglycidyl isocyanurate which precipitates is filtered off and the methacol filtrate is evaporated. Crude yield of the product is 15 g (in the form of oily syrupp.). The mixture is chromatographed on a column 5 cm in diameter and 50 cm in height containing 250 g of silica gel No.60. Methylene chloride and ethyl acetate (3: 2) are taken as eluent. The yield of diglycidyl alcohol is 12 g. The percentage of epoxy acid is 8.9 (theoretically 9, .0). According to thin-layer chromatogram data, the target product has a value of 35 (methylene chloride: ethyl acetate at-3: 2). Example 5. Obtaining diglycig dil-2-hydroxypropylisocyanurate. 5.9 g (0.02 mol) of cC-triglycidyl isocyanurate are dissolved in 200 ml of a mixture of ethanol and water (7: 3). Then 0.76 g (0.02 mol) of sodium borohydride is added and stirred at room temperature for 5 hours. The turbid solution is acidified with dilute hydrochloric acid, filtered and then extracted 3 times with 200 ml of methylene chloride, the methylene chloride extracts are dried and evaporated. . The yield of crude product, 8 g. The percentage of epoxy oxygen is 8.5 (ter. 10.7). The crude reaction mixture is chromatographed on a column of 5 cm in diameter: a hundredth 5 cm containing silica gel Ч4o..60. A mixture of methylene chloride, ethyl acetate and methanol (3.2: 1) is taken as eluent. The yield of diglycidyl ether is 3.7 g. Percentage of epoxy oxygen is 10.6 (terrateically 10.7). According to the thin-layer chromatogram data, the target product has a value of Rf 0.5 (methylene chloride: ethyl acetate: methanol-3: 2: 1) .. k36 P p and m e p 6. Preparation of digdycidyl (2-oxy-3-dioxyethylaminopropyl) isocyanurate. 29.7 (0.1 mol) oi-triglycidyl isocyanurate and 10.6 g (0.1 mol) of ethanol ethylene in 500 ml of toluene are heated for 6 hours, protecting from moisture. Toluene is distilled off and the residue is treated analogously to Example k. The desired product has a value of Rf 0.6 (solvent: methylene chloride methanol; 1 and k in the ratio k7k7: 6). The percentage of epoxy oxygen is 7.7 (theoretically 7.9). Exit 13 g. The cytostatic activity of the known and proposed compounds is evaluated in mice. The compounds are administered to the animals as an aqueous solution for injections, which are prepared immediately prior to use. Mice become infected with tumors. New R 388 (leukemia) (cell cell / mouse). The life span of infected animals is determined in the control group (i.). Experimental groups of infected subjects were injected with test substances in g of three different doses. The average life expectancy (t) is determined for each experimental group. The average life span of animals in experimental groups with control groups of the control groups is compared to determine the degree of life extension in% T / C, which indicates the activity of the applied Q experience of the compound. The table shows the values of T / C depending on the concentration of the test substances.
    100
    50
    25 12.5
    100
    50
    25 12.5
    226 17 167
    300
    197 17V
    R - 2,3 dioxypropyl, 2-hydroxy-3
    - (2-hydroxyethylthio) propyl, propionyloxypropyl, 2-hydroxy-3-propoxypropyl, 2-hydroxypropyl or 2-hydroxy-3 A- (2-hydroxyethyl) aminopropyl.
    8 Continuation of the table
    R -OH
    where R is hydrogen, propyl, ethylcarbo NIL, 2-mercaptoethyl, 2-hydroxyethyl aminoethyl
    with the subsequent selection of the target
    product.
    2. Method according to Clause Kotlichayu-.
    u and with the fact that the process is carried out with if R is hydrogen.
    3. The method according to claim 1, wherein the process is carried out at room temperature in ethanol in the presence of sodium borohydride, if R is hydrogen.
    . The method according to claim 1, in which it is carried out with the fact that the process is carried out by boiling in an organic solvent, if R is propyl.
    5. A method according to claim 1, in which it is carried out by boiling in an organic solvent in the presence of a molecular sieve, if R is ethylcarbonyl.
    6. The method according to claim 1, characterized by the fact that the process is carried out by boiling in an organic solvent in the presence of a base, if R is 2-mercaptoethyl.
    7. The method according to claim 1, wherein the process is carried out in an organic solvent, if R is 2-hydroxy (ox ethyl) aminopropyl.
    Sources of information taken .80 attention during examination
    1. The chemistry of Heter cycUc cpmpouir.ds 1 n f. publ. I. Wiley, 196 N. Y. vol 19 part 1, 276.
    权利要求:
    Claims (7)
    [1]
    Claim
    1. A method of obtaining derivatives of • isocyanuric acid of the general formula where R is 2,3-dioxipropyl, 2-hydroxy-3- (2-hydroxyethylthio) propyl, propionyloxyoxypropyl, 2-hydroxy-3- 35 -propoxypropyl, 2-hydroxypropyl or 2- hydroxy-Z-di- (2-hydroxyethyl) aminopropyl, with a l of h and with the fact that, triglycidyl isocyanurate of the formula II
    CH 2 - <! H-CK2 * l 0
    ΟγΚ'γ-Ο 'H 2 C-HC-S g <1 - ^> ^ ~ sn 2 · is reacted with a compound of the general formula C1
    R —OH where R is hydrogen, propyl, ethylcarbonyl, 2-mercaptoethyl, 2-hydroxyethyl aminoethyl, followed by isolation of the target product.
    9 976849
    [2]
    2. The method according to π. 1. On the basis of the fact that the process is carried out at 70 ° C, if R is hydrogen.
    [3]
    3. The method according to π. 1, characterized in that the process is carried out 5 at room temperature in ethanol in the presence of sodium borohydride, if R is hydrogen.
    [4]
    4. The method according to n. J, due to the fact that the process is carried out by boiling in an organic solvent, if R is propyl.
    [5]
    5 · The method according to claim 1, characterized in that the process is carried out by boiling in an organic solvent 15 in the presence of a molecular sieve, if R is ethylcarbonyl.
    [6]
    6. The method of pop. 1, due to the fact that the process is carried out by boiling in an organic solvent in the presence of a base, if R is 2-mercaptoethyl.
    [7]
    7. The method according to π. 1, the fact that the process is carried out at 60 ° C in an organic solvent, if R is 2-hydroxy-di- (oxy- * ethyl) aminopropyl.
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