• 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:
    A nitrosourea compound of the formula: <IMAGE> wherein R1 is alkyl of one to six carbon atoms, hydroxyalkyl of one to six carbon atoms, alkenyl of three to five carbon atoms or alkynyl of three to five carbon atoms, R2 is aldopentofuranosyl, aldo-pentopyranosyl, aldo-hexopyranosyl, O-aldo-hexopyranosyl-(1->4)-aldo-hexopyranosyl or a group of the formula: -CH2(CHOH)nCH2OH, and wherein n is zero or an integer of one to four. A method of preparation is disclosed whereby said nitrosourea compound is prepared by the nitrosation of a compound of the formula: <IMAGE> wherein R1 and R2 are the same as above. Said nitrosourea compound is useful as an anti-tumor or anti-leukemic agent.
    公开号:SU908247A3
    申请号:SU782643999
    申请日:1978-07-28
    公开日:1982-02-23
    发明作者:Цудзихара Кендзи；Озеки Масакацу；Араи Есихиса
    申请人:Танабе Сейяку Ко Лтд (Фирма)；
    IPC主号:
    专利说明:

    {54) METHOD FOR MAKING NITROCHROMINUM DERIVATIVES
    one
    The invention relates to methods for producing new nitrosourea derivatives of the general formula
    R.
    H N-CO-N-CHiCHaCe / V1ЛI
    / NO
    Ra
    al kil, alkenyl,
    where R R. oxyalkyl C, quinil al-dopentofuoanosyl, aldopeitopyranosyl, aldo-hexopyranosyl- () -aldo-hexopyranoyl, group-CH 2. (CHOH) CH, OH, p O or 1-4,
    A known method for producing (N-chlorostil-N-nitrosocarbamoyl) amino derivatives of monosaccharides, for example, 1- (2-chloroethyl) -1-nitroso-3-0-glucopyranosyl urea (GNI) and 1- (2-chloroethyl) -1-nitroso 3-P-mannopyranosyl ureas. These compounds exhibit biological activity.
    Known are also the N- (chloroethyl-M-nitrosocarbamoyl) amino derivatives of disaccharides, such as 1- (2-chloroethyl) -1-nitroso-3-O-lactosylurea and 1- (2-chloroethyl) -1-nitrozo-3-B- maltosylurea, obtained from the corresponding (fj-chloroethylcarbamoyl) aminodisaccharides in a similar way, and having antitumor activity against
    10 leukemias 2.
    The purpose of the invention is the synthesis of compounds of general formula 1, expanding the arsenal of means of influencing the living
    15 organism.
    The goal is achieved by the fact that the compound of the general formula
    VN-CO-NH-CHjCHiCe 11.
    g
    20
    where R. (and R 2 have the indicated meanings, nitrosate at (-20) -20 ° C in an inert solvent medium.  3 The starting reagent of the formula M can be obtained, for example, by condensing a primary amine of the formula R -Nll2, where R has the indicated values, with a compound of the formula, where R2 has the specified values and X is a hydroxyl group or halogen, at a temperature of about 20SO C in an inert solvent, for example methyl or ethyl alcohol, followed by condensation of the secondary amine obtained from the first condensation reaction R -NH-R, where R and R: the formulas have the indicated meanings with 2-chloro ethyl isocyanate at a suitable solvent, for example tetra rahidrofuran, methyl or lov alcohol.  The nitrosation reaction is carried out by contacting a compound of formula II with nitrous acid, nitrogen trioxide or nitrogen tetroxide in a suitable solvent.  The reaction is carried out at (-20) - 20 ° C, preferably.  As solvents, it is advisable to use lower alkanol, for example, methyl and ethyl alcohols, water, tetrahydrofuran, methylene chloride, ethyl acetate, acetic and formic acids, etc. d.  When free nitrous acid is obtained from the reaction of an alkali metal salt of nitrous acid, such as sodium nitrite, potassium nitrite, or its lower alkyl ester, such as butyl nitrite, amyl nitrite, with a mineral or organic acid, such as hydrochloric, sulfuric, formic or acetic acid and t. P.  i) - {preferably, the free nitrogenous to lot should be used for the nitrosation reaction immediately after preparation.  In the case when nitroxide or nitroxide is used as a nitrosating agent, it is advisable to carry out the nitrosation reaction by combining the starting reagent of formula f in an acceptable solvent with subsequent introduction of gaseous trioxide or nitrogen tetroxide in the presence of an acid acceptor or without it.  Sodium bicarbonate, sodium or potassium carbonate, sodium or potassium acetate, etc. can be used as the acid acceptor. P.  7 After the completion of the reaction, the compound of formula 1 can easily be recovered from the reaction mixture and, if necessary, can then be purified by silica gel chromatography.  Nitrosourea formula 1 has strong antitumor activity or anti-leukemic activity with low associated toxicity and is used to inhibit the growth of malignant tumor cells in warm-blooded animals.  For example, an antitumor effect was determined in mice infected with tumor cells (for example, mice that were implanted with Leukemia L-1210 tumor cells), by intraperitoneal administration of each drug continuously for 5 days, it was found that 1- (2-chloroethyl) - 1-nitroso-3-isobutyl-3-P-galactopyranosylurea with a daily dose of 1.0 mg / kg of body weight or l- (2-xj-opethyl) -1-nitroso-3-isobutyl-3-GO-01 ;.  -B-glucopyranosyl- (1-) -P-glucopyranosyl-urea with a daily dose of 0.9 mg / kg increases the life expectancy of mice by about 30%.  The preventive effect of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-D-glucopyranosyl urea, 1 -2-chloroethyl) - -nitroso-3-isobutyl-3-D-galactopyrazonyl urea and 1- ( -chloroethyl) -1-nitroso-3 isobutyl-3 O- oL -P-glucopyranosyl- (1-) -D-glucopyranosyl urea against Ehrlich's ascitic tumor is also about 8-16 times stronger than the prophylactic effect of 1- (2- chloroethyl) -1-nitroso-3-cyclohexylurea (CHCNM), where H-, cyclohexyl).  The nitrosourea of formula 1 has low toxicity and is characterized by greater safety when used as an anticancer drug.  For example, a therapeutic index was determined by the ratio of the optimal dose (daily dose at which the maximum increase in the life expectancy of mice infected with tumor cells) to the minimum daily dose at which the increased life expectancy in these mice in the case of Leukemia L-1210 is reached, it was found that the value of this index for 1- (2-chloroethyl) -1-nitrozo-3-iso6ytil-3-tO with / -L-glucopyranosyl- (1-J i) -D-glucopyranosyl urea is more than ten times the value therapeutic index for HCNM and GNM.  The compound of formula 1 can also be characterized by a high therapeutic index, defined as the ratio 1), (the maximum dose at which in experiments with mice, the growth of the Ehrlich ascitic tumor without death was achieved) to P / the minimum dose at which 100 % inhibition of growth of the indicated ascitic tumor.  For example, the value of the indicated therapeutic index (1- (2-chloroethyl) -1-nitroso-3-n-butyl-3B-galactopyranosylurea, 1- (2-chloroethyl) -1 -nitroso-3-isobutyl-3-O - oL -1 glucopyranosyl-G1 -) -1) -glucopyranosyl urea and 1- (2-chloroethyl) -1-nitrozo-3 (2-propenyl) - arabi nyranoyl urea more than three times greater than that of GNM and CTSNM .  The proposed compound also has low toxicity in relation to the bone marrow.  Thus, the obtained nitrosoureas of formula 1 possess strong antitumor activity in relation to various tumor cells, such as Lewes carcinoma, Voschid's sarcoma, ascitic hepatoma Rat, etc. d.  These compounds can be used to prolong the life of warm-blooded animals affected by these tumors and / or to minimize the growth of these tumors in these animals.  They can also be used in the treatment of malignant lymphomas), leukemia, gastric cancer, hepatoka and other malignant tumors.  The nitrosomes of Formula 1 can be used in the form of pharmaceutical forms suitable for either oral or parenteral administration.  They can also be used in a mixture with pharmaceutical excipients.  Suitable fillers are materials that do not react with the compound of the formula I.  Examples of acceptable fillers include, for example, gelatin, milk sugar, glucose, sodium chloride, starch, magnesium stearate, talc, vegetable oil, and the like. d.  In addition, other medical excipients may be used.  Pharmaceutical formulations can be prepared either in the form of solid dosage forms (tablets, tablets with shells, capsules or capsules), or in the form of liquid dosage forms (solutions of a suspension or emulsion).  The compounds of formula 1 can also be administered as injections or suppositories that are administered parenterally.  The pharmaceutical forms may be sterilized and / or contain adjuvants (stabilizing and preserving agents). .  The dosage of the compounds of formula 1 is determined by the chosen course of treatment, the age, weight and condition of the patient and the specific type of disease.  Usually for pharmaceutical use daily doses of O are used, 1 to 30 mg / kg of live weight, preferably 0.210 mg / kg.  PRI me R 1.  k, S g of 1- {2-chloroethyl) -3-isobutyl-3-Go-o1 -P-glucopyranosyl- (1-) -D-glucopyranosyl 3 ureas and 7.1 g of anhydration sodium acetate are suspended in 50 ml of tetrahydrofuran, and the mixture is cooled to a solution of solid carbon dioxide in methanol. 8 g of nitrogen trioxide (gaseous) are introduced into the mixture for 10 minutes at (-15) -10 ° C with simultaneous stirring.  Next, the mixture is stirred at (-10) - (-7) ° C for 20 minutes  6 ml of methanol are then added to the mixture and the mixture is stirred for 10 minutes at the same temperature.  To this mixture is added 5 g.  sodium acetate, 50 ml of ethyl acetate and 9 ml of water while stirring.  Then the organic layer is separated by filtration, dried and concentrated under reduced pressure.  The residual oil is purified by chromatography using silica gel (ethyl acetate-chloroform-methanol solvent 2: 1: 1).  Thus, 3.0 g of 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3-C-D-glucopyranosyl- (1) -B-glucopyranosy1 urea is obtained in the form of a yellow powdery product.  7 Example 2, 3.0 g of 1- (2-chloroethyl) -3 isopropyl-3-o-arabinopyranosyl urea is dissolved in 60 mp of tetrahydrofuran, and to a solution of up to 12 t C of anhydrated sodium acetate.  Kg gaseous nitrogen trioxide is introduced into the mixture for 10 minutes at 10 -.  After the reaction, 5 ml of methanol, 3 ml of water and g of sodium acetate were added to the mixture.  The mixture is concentrated under reduced pressure.  The residual product was concentrated in 20 ml of cold water and shaken together with 100 ml of ethyl acetate.  The organic layer is separated, dried and concentrated under reduced pressure.  Then, the resulting residue was purified by chromatography using silica gel (ethyl acetate-chloroform-methanol solvent 5: 2: 1).  Thus, 2.2 g of 1- (2-chloroethyl) -1-nitroso-3-isopropyl-3 s / - arabinopyranosylurea in the form of yellow caramel are obtained. EXAMPLE 1, 3.6 g is treated with D - glucose; 1.1 g of ethyl amine and 2.5 g of 2-chloroethyl isocyanate. 5.5 g of 1- (2-chloroethyl O) -3-ethyl-3 0-glucopyranosyl urea are obtained in the form of a colorless caramel.  b) In 15 ml of formic acid, 6.0 g of 1- (2-chloroethyl) -3-ethyl-3-D-glucopyraniosyl mocheve are dissolved and k, 0 g of sodium nitrite is added gradually to the solution at 1 hour while stirring .  The mixture is further stirred at the same temperature for 20 minutes. To the reaction mixture is added 100 ml: a mixture of sulfuric ether and hexane (1: 1) and the resulting oil is separated.  The oil was washed with ether and 100 ml of a mixture of methylene chloride and methyl alcohol (5: 1) were added.  Not dissolved materials filter out.  The filtrate is evaporated to remove the solvent and the resulting residue is purified by chromatography on silica gel using a mixture of chloroform, ethyl acetate and methyl alcohol (2: 1: 1) as the eluting solvent.  The result was 2.0 g of 1- (2-chloroethyl) -1-nitroso-3-ethyl-3 0-glucopyranosyl urea as a pale yellow caramel.  7 Example 4.  In a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, 3.1 g of 1- (2-chloroethyl) -3-ethyl-3-glucopyranosylmochevine are dissolved and 15 g of anhydrous sodium carbonate is added to the solution.  For 10 minutes, 5 g of nitrogen tetroxide was added to the mixture under ice-cooling.  The mixture is treated in the same way as in example 2.  As a result, 2.6 g of 1- (2-chloroethyl) -1-nitroso-3-ethyl-3-L-glucopyranosyl urea are obtained in the form of a pale yellow caramel.  , 0 ° C 0.4, methyl alcohol).  PRI me R 5.  a) A mixture of 3.6 g of D-glucose, 1.3 g of n-propylamine and 15 ml of methyl alcohol is kept at 30 minutes.  The reaction mixture is concentrated to dryness under reduced pressure, and the remainder of the fcl is taken up in ethyl ether, resulting in 4.4 g of 1 n-propylamino-1-deoxy-D-glucose as a crude product.  4.4 g of this product was dissolved in 50 ml of methyl alcohol and a solution of 2.5 g of 2-chloroethyl isocyanate in 10 ml of tetrahydrofuran was added dropwise at 0-5 ° C.  The solution is stirred at room temperature for 1 hour and then concentrated under reduced pressure.  The resulting residue is dissolved in 20 ml of formic acid, and the solution is kept at room temperature for 20 minutes.  A mixture of sulfuric ether and n-hexane (1: 1) is added to a solution of 200 MP and the resulting oily product is washed several times with sulfuric ether.  The result is 5.0 g of 1- (2-chloroethyl) 3-n-propyl-3-D-glucopyranosyl urea as a brownish caramel, which can optionally be further purified by chromatography on silica gel using chloroform as an eluting solvent. ethyl acetate and.  methyl alcohol (1: 2: 1).  After purification, the product is obtained in the form of a colorless caramel.  6), 5. g of 1- (2-chloroethyl) -3-n-propyl-3-D-glucopyranosyl urea is dissolved in 20 ml of formic acid and 2.8 g of sodium nitrite is added gradually at 0-5 ° C over 1 hour while stirring.  The mixture is further stirred at the same temperature for 1 hour.  After the reaction mixture, 20 ml of methyl alcohol is added.  The mixture is neutralized with potassium carbonate, cooled with ice.  Then 150 ml of ethyl acetate are added to the mixture and the insoluble materials are filtered off.  The filtrate is washed with aqueous sodium bicarbonate solution, dried and evaporated to remove the solvent.  The residue obtained is purified by chromatography on silica gel, using a mixture of methyl alcohol and chloroform (1: 5) as an eluting solvent.  As a result, 1.5 g of 1- (2-chloroethyl) -1-nitroso-3-n-propyl-3-D-glucopyranosyl urine are obtained in the form of pale yellow caramel.  When the coat of arms.  In a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, 3.3 g of 1- (2-chloroethyl) -3-n-propyl-3-P-glucopyranosyl urea are dissolved and 15 g of anhydrous sodium carbonate is added to it.  5 g of nitrogen tetroxide is introduced into the mixture cooled with ice for 10 minutes.  The mixture is treated in accordance with the method of example 2.  As a result, 2.6 g of 1- (2-chloroethyl) 1-nitroso-3-n-propyl-3 V glucopyranosyl alcohol was obtained in the form of yellow caramel.  d + S, Q ° (C 1.5 methyl ID-5.0 alcohol).  Example.  a) In analogy to Example 5a, 3.6 g of D-glucose, 2.0 g of iso-propylamine and 2.5 g of 2-chloroethyl isocyanate are treated.  Received, 8 g of 1 - (2-chloroethyl-3-isopropyl-3 D-glucopyr anosylmoche. ; guilt in the form of colorless caramel.  IR spectrum of yy, s | x (nujol, cm): 3350, 1535, 1070 and 1030.  NMR spectrum (with BgO) cf: 1, 38 (doublet, -CH (CH3) 2).  b) 6.0 g of 1- (2-chloroethyl) zopropyl-3 D-glucopyr anosyl urine are dissolved in 50 ml of hydrochloric acid, and 6 g of sodium nitrite is added gradually to the solution while stirring.  The mixture is further stirred at this temperature for 10 minutes.  The reaction mixture is extracted with ethyl acetate.  The extract is washed with an aqueous solution of sodium bicarbonate, dried and evaporated to remove the solvent.  The obtained residue is purified by chromatography on silica gel using a mixture of chloroform and methyl alcohol (5: 1) as an eluting solvent.  As a result, 2.0 g of 1- (2-hlc1-ethyl) -1 -nitrozo-3-isopropyl-3-D-rhukogrmenosilmocochevine was obtained in the form of a pale yellow caramel.   2 1.0 (C 1.2, methyl alcohol).  PRI me R 8.  p and me and a) 3.6 g of D-glucose; 1.7 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate are treated as in Example 5a.  As a result, 5.0 g of 1- (2-chloroethyl) -3 n-butyl-3 P-glucopyranosyl urea was obtained in the form of a colorless caramel.  IR spectrum T, o unuyol, cm: 3300, 1630, 1530, 1070 and 1030.  NMR spectrum  0.75-16.0 (multiplet, -CH. ).  b) 2.2 g of 1- (2-chloroethyl) -3-n-butyl-3-P-glucopyranosylurea is dissolved in 10 ml of formic acid, and the solution is added gradually over AO minutes with stirring and 0-5 ° C 1 g of sodium nitrite.  The mixture is further stirred at the same temperature for 1.5 hours.  After completion of the reaction, the mixture is treated as in Example 56.  As a result, 1.0 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-C-glucopyranosylurea is obtained in the form of a pale yellow caramel.  ci + 0.8 ° (, methyl alcohol).  Example A In a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, 3, g of 1- (2-chloroethyl) -3 n-butyl-3-D-glucopyranosyl urea are dissolved and 15 g of anhydrous sodium carbonate is added.  Within 10 minutes, 5 g of nitrogen gaseous methyrerchide are introduced into the mixture cooled with ice.  The mixture is treated similarly to the method of example 2.  As a result, cooked 2. 9 g of 1- (2-chloroethyl) - 1 -nitroso-3-n- (wiped 2 oL-glucopyranosyl urea in the form of yellow caramel.  o (, 8, methyl alcohol).  PRI me R 10.  a) In analogy to Example 5a, 3.6 g of D-glucose, 2.5 g of isobutylamine and 2.5 g of 2-chloroethyl-isocyanate are treated.  5.0 g of 1- (2-hporethyl) -3-isobutyl-3-D-glucopyranosyl urea as a colorless caramel was obtained.  6) In a mixture of 70 ml of tetrahydrofuran and 70 ml of methylene chloride, dissolve 3, g of 1- (2-chloroethyl) -3-isobuty-3 glucose pyramide fcl and add 15 g of anhydrous sodium carbonate to the mixture cooled with ice for 10 minutes 5 g of nitrogen tetroxide are introduced with stirring.  The mixture is treated analogously to example 2.  As a result, 2.6 g of 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3-P-glucopyranosyl urea are obtained in the form of yellow caramel.  c /. p -12,1 ° (C 1,4, methyl alcohol PRI me R 11.  but).  Analogously to Example 5a, g of D-glucose, 2.1 g of n-pentylamine and 2.5 g of 2-chloroethyl isocyanate are treated. 6.5 g of 1- (2-xporethyl) -3-n-pentyl-ZP-glucopyranosylurea in brownish caramel.  b).  In a mixture of 60 MP of tetrahydrofuran and 60 ml of methylene chloride, 3.5 g of 1- (2-chloroethyl) -3-n-pentyl-3 -D-glucopyranosyl urea are dissolved and 15 g of anhydrous sodium carbonate is added.  5 g of gaseous nitric anhydride (nitrogen tetroxide) are introduced into the mixture cooled with ice for 10 minutes.  The mixture is treated as in example 2.  As a result, 3.1 g of 1- (2-chloroethyl) -1- (1Trozo-3-n-pentyl-3-D-glucogranmranosyl urea in the form of yellow caramel was obtained.   3.3 ° (C 1.0, methanol).  PRI M GR 12.  a) As in Example 5a, 3.6 g of D-glucose, 2.5 g of n-hexy amine and 2.5 g of 2-chloroethyl isocyanate are treated.  6.8 g of 1- (2-chloroethyl) -3-n-hexyl-3 C-gl ") copyyrlose or urine of guilt in the form of brownish caramel was obtained.  HK-cneKTp-i) yYiax (B CHCI,): 3350,, 1520, 1080 and 1040.  b) 4.3 g of 1- (2-chloroethyl) -3-n-hexyl-3-B-glucopyranosyl urea is dissolved in 15 ml of formic acid and 2.4 g of sodium nitrite are gradually added during 1 hour while stirring. . The mixture was further stirred at the same temperature for 1.5 hours.  After the reaction, the mixture is treated as in Example 56.  The result is 1.8 g of 1- (2-chloro ethyl) -1-nitroso-3-n-hexyl-3-P-glucopyranosyl urea as a yellow oil.  , oi + 4.4 ° (, 2, methyl alcohol Example 13.  In a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, 3.7 g of 1- (2-chloroethyl) -3-n-hexyl-3 0-glucopyranosyl urea are dissolved and 15 g of anhydrous sodium carbonate is added.  5 g of nitric anhydride gas are introduced into the mixture for 10 minutes while cooling with ice.  The treatment of the mixture is carried out analogously to example 2.  As a result, 3.1 g of 1- (2-chloroethyl) -nitroso-3-n-hexyl-3-B-glucopyrano-zilurea in the form of a yellow oil, (, 2, methyl alcohol) was obtained.  PRI me R 14.  a) Analogously to example 5 and treated with 3.6 g of D-galactose; 1.5 g of n-propylamine and 2.5 g of 2-chloroethyl isocyanate.  4.5 g of 1- (2-chloro-.  ethyl) -3-n-propyl-3-g) -galactopyranosyl urea as a colorless caramel.  b).  6.0 g of 1- (2-chloroethyl) -3-n-propyl-3-D-galactopyranosylurea are dissolved in 15 ml of formic acid and 4.2 g of nitrite are added gradually over 1 hour at 0-50 ° C and stirring on three .  The mixture is further stirred at the same temperature.  After completion of the reaction, the mixture is treated as in Example 56.  As a result, 1.8 g of 1- (2-chloroethyl) -1-nitroso-3-n-propyl-3-O-galactopyranosylurea in the form of a pale yellow caramel was obtained.  „J О уо о / -JJ +18.0 (, 0, methyl alcohol).  Example 15.  In a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride are dissolved 3. 3 g of 1- (2-chloroethyl) -3-n-propyl-3-D-galactopyranosyl urea and 15 g of sodium free carbonate are added.  5 g of nitric anhydride gas are introduced into the mixture cooled with ice for 10 minutes.  The mixture is treated as in example 2.  2.8 g of 1- {2-chloroethyl) -1-nitroso-3-n-propyl-3-B-galactopyranosylurea are obtained in the form of pale yellow caramel.  0 / + 18.0 ° (, 0, methyl alcohol).  Example 16  a) As in Example 5, 3.6 g of D-galactose are treated; 2.4 g of isopropylamine and 2.5 g of 2-chloroethyl isocyanate.  Obtained 5.0 g of 1- (2-chloroethyl) -3-isopropyl-3-P-galactopyranosyl urea as a colorless caramel.  13 b) In 20 ml of formic acid, 6.0 g of 1- (2-chloroethyl-3-isopropyl-3-ga-phylopyranosyl cellulose) is dissolved and it, 2 g of sodium nitrite is added gradually at 0-5 ° C over 1 hour .  The mixture is further stirred at the same temperature for 1 hour.  After completion of the reaction, the mixture is treated as in Example 5 b.  Obtained 1.8 g of 1-G2-chloroethyl) -1-nitroso-3-y30propyl-3-D-galactopyranosyl urea in the form of pale yellow caramel.  d- +21, lCC 0, 9, methyl alcohol.  Example17.  but).  As in Example 5a, 3.6 g of D-galactose, 1.8 g of n-butylamine and 2.5 g of chloroethyl isocyanate are treated.  As a result, 5.2 g of 1- (2-chloroethyl) -3 n-butyl-3-B-galactopyranosyl urea in the form of a colorless caramel was obtained.  b) U 15 MP formic acid is dissolved in U, 8 g of 1- (2-chloroethyl) -3-n-Buty-3-B-galactopyranosylmonechemia 1, and gradually added to the solution over 1 hour while stirring and 0-5s are 2 g of sodium nitrite.  The mixture is stirred at the same temperature for 1.5 h.  After completion of the reaction, the mixture is treated as in Example 5 b.  As a result, 1.8 g of 1- (2- -chloroethyl) -1-nitroso-1-n-butyl-3-B-galactopyranosylurea in the form of a yellow powder was obtained.  The melting point of the product is kk-k6.6C (with decomposition).  , 0 + 16, (, 0, methyl alcohol) EXAMPLE 18.  In a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, 3, g of 1- (2-chloro ethyl) -3 m-butyl-3-D-galactopyranosyl urea are dissolved, and 15 g of anhydrous sodium carbonate is added to the solution.  5 g of gaseous nitric anhydride are introduced into the mixture during 10 NMH and the mixture is cooled with ice.  The mixture is treated analogously to example 2.  As a result, 2.8 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-B-galactopyranosyl urea was obtained as a yellow product.  The melting point of the product, B (with decomposition).  PRI me R 19.  a) A mixture of 3.6 g of D-galactose, 2.0 isobutylamine and 2.3 g of 2-chloroethyl isocyanate is treated in the same way as for example 7.  I measure 5 a.  As a result, 5.5 g of 1- (2-klorethyl) -3-isobutyl-3-D-galactic pyranosyl urea in the form of a colorless caramel was obtained.  b) 7.0 g of 1- (2-hl6-ethyl) -3 isobutyl-3B-galactopyranosylurea-1-s are dissolved in 15 ml of formic acid and 5 to the resulting solution gradually over 1 hour with stirring and 0-5 ° C. 0 g of sodium nitrite.  The mixture was further stirred at atcw for 1 h.  After completion of the reaction, the mixture is treated as in Example 5 b.  As a result, 2.0 g of 2- (2-chloroethyl) -nitroso-3-isobuty-3-P-halo-pyropylazochemoucheve as a pale yellow powder was obtained.  The melting point of the product is 3, 1.0, methanol).  Ex. 20.  In a mixture of 80 mi of tetrahydrofuran and 80 ml of methylene chloride, D, g of 1- (2-chloroethyl) -isobutyl-3-P-galactopyranosylurea is dissolved, and 15 g of anhydrous country carbonate is added.  5 g of nitric anhydride gas are introduced into the mixture over 10 minutes while cooling the mixture with ice.  Then the mixture is treated as in example 2.  3.0 g of 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3-D-galactolyranosylurea are obtained in the form of a yellow powder.  The melting point of the product 48-53 C.   If -3, (, 0, methanol).  PRI me R 21.  but).  Analogously to Example 5a, a mixture of 3.6 g of D-galactose, 5 g of sec-butylamine, and 3.0 g of 2-chloroethyl isocyanate is treated.  As a result, 5 g of 1- (2-chloroethyl) -3 sec-bu-, tyl-3 D-galactopyranosylurea in the form of pale brown caramel was obtained.  b) 7.0 g of 1- (2-chloroethyl) -3-sec-butyl-3-D-galactopyranosyl urea is dissolved in 20 ml of formic acid and 5.0 g of sodium nitrite is added gradually over 1 hour while stirring, maintaining the temperature mixtures within О - 5 ° С.  The mixture is further stirred at this temperature for 1 h, and is then treated as in Example 5 b.  As a result, 1- (2-hporethyl) -1-nitroso-ZVTop-butyl-3 P galactopyranosylurea is obtained in the form of a pale yellow caramel ij ° +13.8 (3, methanol).  PRI me R 22.   but). Analogously to example 5, obr. .  shake mixture 3. 6 g of P-galactose; 2.3 g of n-pentylamine and 2.5 g of 2-chloroethyl isocyanate.  5.5 g of chloroethyl) -3-n-pentyl-3-C-galactopyranosylurea are obtained in the form of a colorless caramel.  - b) In 80 ml of tetrahydrofuran and 80 methylene chloride, 3.5 1- (2-chloroethyl) -3-n-pentyl-3-D-ralactopyranosyl urea is dissolved and 15 g of anhydrous sodium carbonate is added.  5 g of gaseous nitrogenous anhydride are introduced into the mixture for 10 minutes while cooling with ice.  The mixture is treated as in example 2.  2.7 g of 1- (2-chloroethyl) -1-nitroso-3-n-pentyl-3-C-galactopyruzylurea in the form of yellow caramel is obtained. Example 23.  a) Analogously to Example 5a, a mixture of 3.6 g of D-galactose is treated; 2.3 isopentylamine and 2.5 g of 2-chloroethyl isocyanato. 5.5 g of 1- (2-chloroethyl) -3 isopentyl-3-D-galactopyrano-zylurea are obtained as colorless (caramel and.  b) 3.5 g of 1- (2-h1010 ethyl) -3-isopentyl-3-0 galactopyranosyl urea is added to a mixture of V ml of tetrahydrofuran and V MP of methylene chloride and 15 g of anhydrous sodium carbonate is added.  Gaseous nitrous anhydride is added to the mixture for 10 minutes while the mixture is cooled with ice.  The mixture is treated in the same manner as in Example 2.  As a result, 2.6 g of 1- (2-chloroethyl) -1-nitroso-3-isopentyl-3-D-galactopyranosyl urea was obtained in the form of yellow caramel.  Example 2k.  but).  Analogously to Example 5, a mixture of 3.6 g of D-galactose, 3.5 i-neopentylamine and 2.5 g of 2-chloroethyl isocyanate is treated. As a result, 5.0 g of 1- (2-chloroethyl) -3-neopentyl-3-P-galactopyranosyl urea is obtained in the form of a colorless caramel.  b) In a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, 3.6 g of 1- (2-chloroethyl) -3-iopentyl-3-D-halo-pyrophosphonyl moraine are dissolved and then 15 g of anhydrous sodium carbonate is added to the solution.  Under ice-cooling, 5 g of gaseous nitrogenous-sodium anhydride are introduced into the mixture for 10 minutes.  The mixture is treated as in example 2.  2.9 g of 1- (2-chloroethyl) -1-nitroso-3-neopentyl-3-D-galactopyranosyl urea are obtained in the form of yellow caramel.  , 7 ° (, 94 methanol).  P ; and measure 25.  a) In analogy to Example 5a, 3.6 g of D-galactose, 1.5 g of 2-propenylamine and 2, -5 g of 2-chloroethyl isocyanate are treated.  As a result, 4, 3 g of 1- (2-chloroethyl) -3-2-propenyl) -3-D-halo-pyropanosyl mocheve are obtained in the form of colorless caramel.  b) In a mixture of 60 MP of tetrahydrofuran and 60 ml of methylene chloride, 3.2 g of 1- (2-chloroethyl) -3- (2-propenyl) -3-D-galactopyranosylurea are dissolved and 15 g of anhydrous sodium carbonate is added to the solution.  5 g of gaseous nitrogenous anhydride are added to the mixture for 10 minutes, stirring and cooling the mixture with ice.  The mixture is treated as in example 2.  2.5 g of 1- (2-chloroethyl) -1-nitrozo-3- (2-propylene) -3-D-galactopyranosylurea are obtained in the form of yellow caramel.  xG-13.1 (, 1, methanol).  PRI me R 2b.  a) Analogously to Example 5a, a mixture of 3.6 g of D-galactose, 1, A of 2-propynylamine and 2.5 g of 2-chloro-ethyliso1-ianate is treated.  4.3 g of 1- (2-chloroethyl) -3- (2-propynyl) -3-D-galactopyranosyl urea were obtained in the form of a colorless caramel.  b) 3.2 g of i- (2-chloroethyl) -3- (2-propynyl) - are dissolved in a mixture of 70 ml of tetrahydrofuran and 60 ml of methylene chloride. Urinary 5-D-galactopyranosyl and 15 g of anhydrous sodium carbonate is added to the solution.  Then 5 g of gaseous nitric anhydride was introduced into the mixture for 10 min, while cooling with ice and stirring the mass.  Analogously to example 2, the mixture was processed.  As a result, 2.5 g of 1- (2-chloroethyl) -1-nitroso-3- (2-propynyl) - was obtained. 3-D-galactopyranosyl urea as a pale yellow powder, oi-jj -9.2 (C 1.1 methyl alcohol).  Example 27  a) 3.0 g of D-ribose, 1.0 g of methylamine and 2.5 g of 2-chloroethyl isocyanate are treated as in Example 1a.  Obtained, 0 g of 1- (2-chloroethyl) -3-methyl-3-B-ribofuranose and urea as colorless caramel b) 2 g of 1- (2-chloroethyl) -3-methyl-3 is dissolved in 10 ml of formic acid -P-ribofuranosiolurea and 1.1 g of sodium nitrite are gradually added to the solution with a stirring over 1 hour.  The mixture is further maintained at this temperature for 1 hour with stirring.  After the reaction, the mixture is treated as in Example 1 b.  Received 1, i g of 1- (2-chloroethyl) -1-nitroso-3-methyl-3-P-ribofuranosylm chevina in the form of a yellow powder.  Melting point of the product with a decomposition of 57-60 ° C.  ) 35.2 (, 1, methyl alcohol). .  Example 28.  In a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, 2.7 g of 1- (2-chloroethyl} -3-methyl-3-1) -ribofuranose and urea are dissolved and then 15 g of aqueous sodium carbonate are added.  5 g of gaseous nitric anhydride are fed into the mixture for 10 minutes, while cooling the mixture with ice.  The mixture is treated as in example 2.  2.1 g of 1- (2-chloroethyl) -1-nitroso-3-methyl-3-O-ribofuranosylurea are obtained in the form of a yellow powder.  Melting point of the product with decomposition of 57-60 0.   , 2 (, 1; methanol).  . Example 29  a) As in Example 5a, 3.0 g of D-ribose, 1.9 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate are treated.  5.0 g of 1- (2-chloroethyl) -3-n-butyl-3-B-ribofurano zilurea are obtained in the form of a colorless caramel.  b) 3.1 g of 1- (2-chloroethyl) -3 n-bugyl-3-B-ribofuranosyl urea number 1 is dissolved in 10 ml of cicaric acid and 1.5 g of nitrite is gradually added to the solution over a period of 1 hour. sodium, while maintaining the temperature of the mixture while stirring.  The mixture is further stirred at the same temperature for 1 hour.  After completion of the reaction, the mixture is treated as in Example 56.  It was obtained I, g of 1- (2-hl6etil) -1-nitroso-3-nbutyl-3-Vyuboyuoanosilurea in the form of yellow kaoamel.  , 0 (, 0, methyl alcohol).  PRI me R 30.  a) Analogously to the example of Be treated with 3.6 g of D-mannose; 1.8 g of n-butylamine and 2.5 g of chloroethyl isocyanate.  5.3 g of 1- (2-chloroethide) -3-n-butyl-3-P-mannopyranosilurea are obtained in the form of a colorless caramel.  b) In a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, D is dissolved, g of 1- (2-chloroethyl) -3-n-butyl-3-B-mannopyranosyl urea. and Then 15 g of anhydrous sodium carbonate is added.  While cooling with ice, 5 g of nitrogenous anhydride are fed into the mixture during Yumin.  The mixture is treated as in example 2. - 2.9 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-D-mannopyranosylurea are obtained in the form of yellow caramel.  PRI me R 31.  5, g of 1- (2-chloroethyl) -3-n-butyl-3-O-mannopyranosylurea are dissolved in 20 ml of formic acid, and 3.5 g of the solution is gradually added to the solution over a period of 2 hours while stirring and cooling with ice. sodium nitrite.  4 p ml of methyl alcohol and 30 g of anhydrous carbonate and potassium are then added to the mixture.  The mixture was further stirred for 10 minutes while cooling with ice.  After the reaction, the mixture is treated as in Example 56.  Received 1.6 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-Z-P-mannopyranosylurea in the form of yellow caramel.  , (, 2, methanol).  PRI me R 32.  a) Similarly to make-up artist 5a, 3.0 g of O-xylose is treated; 1.5 g of n-propylamine and 2.5 g of 2-chloroethyl isocyanate.  The obtained k, Q g 1- (2-chloroethyl) -MM-PROPYL-Z-xylopyranosylurea in the form of a colorless caramel.  b) 9.0 g of 1- (2-chloroethyl} -3-n-propyl-3-C xylopyranosyl urea is dissolved in 25 MP of formic acid and added gradually over. 1 hour with stirring and 6.0 g of sodium nitrite.  The mixture was stirred at that temperature for 30 minutes.  After completion of the reaction, the mixture is processed in the same manner as in Example 56.  As a result, 3.7 g of 1- (2-chloroethyl) -1-nitroso-3 n-propyl-3-P-xylopyranosylurea are obtained in the form of a pale yellow caramel.  about{. + 5.8 ° (, 6, methyl alcohol).  Example 33.  In a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, 3.0 g of 1-H2-chloroethyl) -3-n-propyl-3-B-xylopyranosylurea is dissolved and 15 g of anhydrous sodium carbonate is added to the solution.  5 g of nitric anhydride gas are fed into the mixture for 10 minutes, while the mixture is cooled with ice.  The mixture is processed further as in Example 2.  2.6 g of 1- (27XLorethyl) -1-nitroso-3n-propyl-3-O-xylopyrano zilmourea are obtained in the form of white caramel, 8 (, 6 methanol).  PRI me R 3.  a) 3.0 g of D-xylose, 2.5 g of isopropyl amine and 2.5 g of 2-chloroethyl isocyanta are treated as in Example 5 a.  As a result, 4.0 g of 1- (2-chloroethyl) -3-isopropyl-3-B-xy lopyranosylurea was obtained in the form of a colorless caramel.  b) In a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, 3.0 g of 1- (2-chloroethyl) -3-isopropyl-3-10-xylopyranosylurea is dissolved, and 15 g of anhydrous sodium carbonate is added to the solution.  5 g of nitric anhydride gas are introduced into the mixture for 10 minutes while cooling with ice.  The mixture is treated as in example 2.  2.5 g of 1- (2 HLOretil) -1-nitroso-3-D-xylopyre 1 ozylmochevine are obtained in the form of a yellow powder.  The melting point of the product Gs decomposition) 50-55 ° C.   4-22.2 ° (, 0, methanol).  PRI me R 35.  a) Analogously to the example b), treatment of 3.0 g of C-arabinose is carried out; 1.5 g of n-propylamine and 2.5 g of 2-chloro ethyl isocyanate.  As a result, i, 1 g of 1- (2-chloroethyl) -3-n-propyl-3-D-arabinopyranosyl urea as a colorless caramel.  2) In 25 ml of formic acid, 9.0 g of 1- (2-chloroethyl) -3-i-propyl-3-D-arabinopyranosylbenzone are dissolved and 6 are introduced gradually over 1 hour with stirring and 0-5 ° C. 0 g of sodium nitrite; The mixture is stirred at the same temperature for 7.  20 30 min.  After completion of the reaction, the procedure of Example 5 b is repeated.  As a result, 3.5 g of 1- (2-chloroethyl) -1-nitroso-3-n-propyl-3-D-arabinopyranosylurea are obtained in the form of pale yellow caramel.  D (2, methanol).  Example 36.  In a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, 3.0 g of 1- (2-chloroethyl) -3-n-propyl-3-D-arabinopyranosyl urea is dissolved and 15 g of sodium carbonate is added to the solution.  5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes, cooling it with ice.  The subsequent processing of the mixture is carried out analogously to example 2.  As a result, 2.5 g of 1- (2-chloroethyl) -1-nitroso-3-n-propyl-3-O-arabinopyranosylurea is obtained in the form of yellow caramel.   , (, 2, methanol).  PRI me R 37.  a) Analogously to Example 5a, a mixture of 3.0 g of D-arabinose is processed; 2.5 g of isopropylamine and 2.5 g of 2-chloroethyl isocyanate.  Received C, 2 g of 1 - (2-chloroethyl) -3-i-o-propyl-3-D-arabinopyranosyl urea as a colorless caramel.  b) In a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, 3.0 g of 1- (2-chloroethyl) -3-isopropyl-3-D-arabinopyranosylurea is dissolved and 15 g of anhydrous sodium carbonate is added to the solution.  Then 5 g of nitric anhydride gas are introduced into the mixture over 10 minutes, while the mixture is cooled with ice.  The subsequent processing of the mixture is carried out analogously to example 2.  Received 2, g of 1- (2-chloroethyl) -1-nitroso-3-isopropyl-3 D-apabiopyranosylurea in the form of yellow caramel.  0.23 + 6 / 4.1 | (, 0, methanol).  Example 38.  a) Analogously to Example 5a, a mixture of 3.0 g of D-apabinose, 1.8 g of isobutylamine and 2.5 g of 2-chloroethyl isocyanate is treated.  4.3 g of 1- (2-chloroethyl) -3-isobuty-3-D-apabinopyranosylurea are obtained in the form of colorless caramel.  b) In a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, 3.1 g of 1- (2-chloroethyl) -3-itobu-3-C-ar abinopyranosyl urea is dissolved and 15 g of anhydrous sodium carbonate is added to it.  5 g of nitrogen tetroxide gas are introduced into the mixture over 10 minutes, while cooling the mixture with ice.  Subsequent processing is carried out analogously to example 2.  As a result, 2.3 g of 1- (2-chloroethyl) -1-nitroso-3-isobutyl-3-P-arabinopyrano zylurea in a pale yellow caramel were obtained.  0 35 + 28.0 ° (, it, methanol).  L r i me R 39.  a) Analogously to Example 5a, the mixture was treated with 5 g of D-arabinose, 2.5 g of 2-propylamine and 3.5 g of 2-chloroethyl isocyanate.  5.5 g of 1- (2-chloroethyl) -3- (2-propenyl) -3-G) -arabinopyranosylurea are obtained in the form of a colorless powder.  b) In a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, 3.2 g of 1 - (2-chloroethyl-3- (2-propenyl) -3-P-arabinopyranosylurea are dissolved, and 15 g of anhydrous sodium carbonate are added to the solution .  5 g of nitrogen tetroxide are introduced within 10 minutes into the mixture while stirring and cooling with ice.  The mixture is treated as in example 2.  Received 2,3 1 - (2-chloro. thyl-1-nitroso-3- (2-propenyl) -3 1 -arabinopyranosylurea in the form of yellow caramel.  d-Q +12, 8 ° (, 3, methyl with pi rt).  Example 0.  a) In analogy to Example 5a, 3.3 g of D-rhamnose, 1.8 g of n-butylamine and 2.5 g of 2 ethyl isocyanate are treated.  Received -4.2 g of 1- (2-chloroethyl) -3-n-butyl-3-b ramnopyranosyl urea in the form of a colorless caramel.  b) In 10 ml of formic acid, 3.2 g of 1- (2-chloroethyl) -3-n-butyl-3 L-ramnopyranosyl moistened are dissolved and 1.5 sodium nitrite is added to the solution gradually over 1 hour with stirring, while maintaining the mixture at. temperature 0-5 C.  The mixture is further stirred at the same temperature for 1 hour.  After completion of the reaction, the mixture is treated as in Example 56.  0.8 g of 1- (2-chloro ethyl) -1-nitroso-3-n-butyl-3-b-ramnopyranosylurea is obtained in the form of yellow caramel.   S, 2Q, (, it, methyl alcohol).  ExampleA1. 3.2 g of 1- (2-chloroethyl) -3-n-butyl-b-ramnopyranosyl are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride and 13 g of sodium carbonate is added to the solution.  Then, 5 g of nitrogen tetrachloride gas is added to the ice-cooled mixture over 10 minutes.  The mixture is treated as in example 2.  As a result, 3.5 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-b-ramnopyranosylurea are obtained in the form of yellow caramel.  CotJl; -20.1 ° (, it is methyl alcohol).  Example k2.  a) A mixture of 7.2 D-maltose monohydrate, 0.9 g of methylmine and 20 ml of methyl alcohol is kept at 60 ° C for 1 hour in a sealed tube.  The reaction mixture is concentrated to dryness under reduced pressure, and the residue is washed with ethyl ether, resulting in 7.1 g of {O-oL-P-glucopyranosyl- (1-4) -B-glucopyranosyl methylomine; t. e.  1-methylamino-1-deox-D-maltose, in the form of a crude product.  The whole product was dissolved in 50 MP of methyl alcohol, and a solution of 2.5 g of 2-chloroethyl isocyanate in 10 ml of tetrahydrofuran was added at.  The solution is stirred at room temperature for 1.5 hours.  Then, the reaction solution was concentrated under reduced pressure, and a mixture of ethyl acetate and sulfuric ether was added to the residue.  7 grams of 1- (2-chloroethyl) -3 methyl-3-o-o-B-glucopyranosyl- (1-4) -B-glucopyranosyl1 urea, m are obtained. e.  1- (2-chloroethyl) -3-methyl-3-D-maltozo l urea, in the form of an amorphous colorless powder.  b) In 10 ml of formic acid, 3.0 g of 1- (2-chloroethyl) -3-methyl-3-Go - -D-glucopir anosyl - (1-4) -B-glucopyrano is dissolved. sulphate of urea and with stirring, gradually, 1.0 g of sodium nitrite is added over kQ min. of hd while maintaining the temperature of the mixture O-5 ° C.  The mixture was further stirred at the same temperature for 1.5 hours.  After completion of the reaction, the mixture is worked up as in Example Tb, using chromatographic as an eluting solvent. cleaning the chloroform mixture,
    ethyl acetate and methyl alcohol (1: 1: 1). Obtained 1.0 I 1- (2-chloroethyl) -1-nitrozo-3-methyl-3-0-oi, -D-glucopyranosyl- (1) -B-glucopyranosyl urea, thG. 1- (2-chloroethyl) -1-nitroso-3-methyl-D-maltosylurea, as a pale yellow powder. Melting point 66-70 ° C (with degradation).
    , 9 ° (, 2, methyl
    alcohol).
    Example 3. In a mixture of 170 ml of tetrahydrofuran and 30 ml of acetic acid, 6 g of 1- (2-chloroethyl) -3-methyl-3-iO-cL-D-glucopyranosyl-3-urea-urea is dissolved and add 20 g of anhydrous sodium cabonate. 8 g of nitrogen tetroxide are introduced into the mixture during 10 minutes while stirring and cooling with ice. The mixture was further stirred at the same temperature for 20 minutes. After the reaction, 200 ml of n-hexane is added to the mixture and the mixture is filtered. The solvent is evaporated from the filtrate. 200 ml of a mixture of methyl alcohol and sulfuric ether (1:20) are added to the obtained residue, and the oily product is purified by chromatography on a silica gel. In the chromatographic purification, a mixture of ethyl acetate, chloroform and methyl alcohol (2: 1: 1) is used as an eluting solvent. 3.35 g of 1- (2-chloroethyl) -1-nitroso-3-methyl- - oL-D-ch ycopyr anosyl- (1-4) -B-glucopyranosyl Urea, i.e., is obtained. 1- (2-chloroethyl) -1-nitroso-3-methyl-3-C-maltosyl urea, as a pale yellow powder. Melting point (with decomposition) 66-70 ° C,
    ) + it2,9 ° (, 2, methyl alcohol).
    Example kk.
    a) Analogously to Example 42a, 7j2 g of D-maltose monohydrate is treated with 1.5 g of n-propylamine and 2.5 g of 2-chloroethyl isocyanate. 8.5 g of 1- (2-chloroethyl) -3-c-propi, -B-gl yucopyr anosyl- (1- .4) -B-glu copyranosyl urea, i.e. 1- (2-chloroethyl) -3-n-propyl-3-D-maltose or urine guilt, in the form of a colorless amorphous powder.
    b) In 20 MP of formic acid, 5.0 g of 1- (2-chloroethyl) -3-n-propyl-3L 0.-P-GLYuopyranosyl- (1-4) -D-glucopyranosylamine mohvine is dissolved and added gradually over 1 hour with stirring and .0-5 C 1.5 g of sodium nitrite. The mixture was further stirred at the same temperature for 1.5 hours. After stopping the reaction, the mixture was treated analogously to Example 1b using the following as an eluent solvent for chromatography on a graphical purification mixture of chloroform, ethyl acetate and methyl alcohol (1: 2: one). As a result, 0.8 g of 1- (27-chloroethyl) -1-nitroso-3-H-PROPIL-3-0 ° / 0-glucopyranosyl- (1-4) -D-glucopyranosyl2 urea, i.e. 1- (2-chloroethyl) -1-nitroso-3-n-propyl-3-P-maltosyl urea, as a pale yellow powder. Melting point (with decomposition) 59-62 ° C.
    , 3 °, 0, methyl alcohol).
    Example kS. A, 8 g of 1- (2-chloroethyl) -Z-N-PROPIL-Z-C-OO. -D-glucopyranosyl- (1-4) -B-glucopyranosyl urvins are dissolved in a mixture of 170 ml of tetrahydrofuran and 30 ml of acetic acid and 20 g of anhydrous sodium acetate is added. Under ice cooling and stirring, 8 g of nitrogen tetroxide are added to the mixture for 10 minutes. The subsequent processing of the mixture is carried out analogously to Example 43. As a result, 3.6 g of 1- (2-chloroethyl) -1-nitroz-3-H-PRopil-3-G oL-B-glucopyranosyl- (1-4) -B are obtained. -glucopyranosyl urea, i.e. 1- (2-chloroethyl-1-nitroso-3-n-propyl-3-D-maltosyl urea, as a pale yellow powder. Melting point of the product is 5962 ° C (with decomposition).
    d +62.9 (, 0, methyl alcohol).
    PRI me R 46.
    a) 7.2 g of D-maptose monohydrate, 2.0 g of i30 propyl per and 2.5 g of 2-chloroethyl isocyanate are treated analogously to example 42 a. 7.2 g of 1- (2-chloroethyl) -3-isopropyl-SO3 "0 -glucopyr anosyl- (1-4) -P-glucopyranosyl urea, i.e. 1- (2-chloroethyl) -3-isopropyl-3-D-maltosyl urea, in the form of a colorless amorphous powder.
    权利要求:
    Claims (2)
    [1]
    b) 4.8 g of 1- (2-chloroethyl) -3-isopropyl-3-0-a1-B-glucopyranosyl- (1-4) -D-glucopyranosyl urea is dissolved in a mixture of 170 MP of tetrahydrofuran and 30 ml of acetic acid and add 20 g of anhydrous sodium acetate.  8 g of gaseous nitrogenous anhydride are introduced into the mixture during 10 minutes while cooling with ice and stirring.  Subsequent processing is carried out analogously to example 3.  3.6 g of 1- (2-chloroethyl) -1-nitroeo-3 isopropyl-3-Co ci B-glucopyranosyl- (1-4) -P-glucopyranosyl urea, t were obtained. e.  1- (2-chloroethyl) -1-nitroso-3-yzopropyl-3-D-maltosylurea, as a pale yellow powder.  The melting point of the product (with decomposition) is 66-71 s.  o +70.5 (, 0, methyl alcohol).  Ex. 47.  a) 7.2 g of D-maltose monohydrate, 2.2 g of n-butylamine and 2.5 g of 2-chloro-isocyanate are treated as in Example 42 a.  As a result, 8.0 g of 1- (2-chloroethyl) -3-n-butyl-3-O-oi-D-glucopyranosyl- (1) -D-glucopyranosyl urea, t was obtained. e.  1 - (2-chloroethyl) -3-n-butyl-3-C-mapytosyl urine guilt, in the form of a colorless. powder  The melting point of the product (with decomposition) is 91 ° C.  b) A, 5 g of 1- (2-l6-ethyl) -3-n-butyl-3-HO -o-D-glucopyranosyl urea is dissolved in 10 ml of formic acid and to the solution gradually over 50 minutes with stirring 1.5 g of sodium nitrite, while maintaining 0-5 C.  The mixture is further stirred at this temperature for 1.5 hours.  After completion of the reaction, the mixture is processed in the same manner as in Example 16.  Received, 1-G2-chloroethyl) -1-nitroso-3-n-butyl-3-G -o. -D-glitch pir anosyl- (1-4) -D-glucopyranosis. ilmoyche | guilt, t. e.  1- (2-chloroethyl) -1-nitro; 30-Znbutyl-3-B-maltosyl urea, as a pale yellow powder.  Melting point of the product with a decomposition of 176-804 oi +61.5 (, 7 methyl alcohol).  Example 48  In a mixture of 150 ml of terahydrofuran and 30 ml of acetic acid, 4.9 g of 1- (2-chloro-.  ethyl) -3-n-butyl-3-oo (.  Urine N-d-glucopier (1-4) -D-glucopyranosyl P-urine and 20 g of anhydrous sodium acetate is added to the solution.  Then it is introduced into the mixture for 10 minutes while cooling with ice and stirring a g of gaseous nitric anhydride.  The subsequent processing of the mixture was carried out in the same manner as the example. 3.8 g of 1- (2-chloroethyl) -1-nitroso-3H-butyl-3-O-j /, D-glucopyranosyl- (1-4) -1 glucopyranoyl urea, t were obtained. e.  1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-D-maltosyl urea, as a pale yellow powder.  Melting point product ub-BO C (with decomposition).  оС +61,6 (, 7, methyl alcohol) Example 9.  a) 7.2 g of monohydrate D-maltose; 2.9 g of issbutilamine and 2.5 g of 2-chloroethyl isocyanate are treated analogously to example a.  8.0 g of 1- (2-chloroethyl) -isobutyl-3-1 0 - o (-B-glucopyranosyl- (1-4) -B-glucopyranosyl Ureas, t were obtained. e.  1- (2-chloroethyl) -3-isobutyl-3-B-maltosyl urea, In the form of a colorless powder.  The melting point of the product with a decomposition of 86-90 ° C. - - oi-X) +72.3 (, 8 methyl alcohol).  b) In a mixture of 150 MP of tetrahydrofuran and 20 ml of acetic acid, 9 g of 1- (2-chloroethyl) -3-isobutyl-3-GO-o-P-glucopyranosyl- (1) is dissolved.  Α-D-glucopyranosyl urea and 20 g of anhydrous sodium acetate is added to the solution.  Within 10 minutes, 8 g of gaseous nitric anhydride was introduced into the mixture under stirring and cooling with ice.  Subsequent processing is carried out similarly to the example. The result is 2. 5 g of 1-H2-chloroethyl) -1-nitroso-3-isobutyl-3-O-c - -D-glucopyranosyl- (1-4) -D-glucopyranosyl urea, t. e.  1- (2-chloroethyl) -1-nitroso-3-ysobutyl-3- -B-maltosyl urea as a colorless powder.  The melting point of the product (with decomposition).  about(.  l ,, 7, 5, methyl alcohol).  Example50.  a) 7.2 g of monohydrate D-maltose; 2.5 g of n-pentylamine and 7. 5 g of 2-chloroethyl isocyanate are treated analogously to example 42 a.  8.1 g of 1 - (2-chloro-tyl l) - 3 - n-penti l - 3 {O - oi-B-glucopyranosyl- (1 - 41-1 glucopyranosyl urea, t are obtained. e.  1- (2-chloroethyl) -3-n-sctill-3-D-maltnzilmochechev, c.  as colorless porchica.  6) 5.2 g of 1- (2-chloroethyl) -3-n-pentyl- () is dissolved in 20 MP of formic acid.  -D-glucopyranosyl- (1 -h 4) -B-glucopyranosyl urea and 2 g of sodium nitrite are added to the solution over 1 hour with stirring.  The mixture is further stirred at the same temperature for 1.5 hours.  After the reaction, the mixture is treated as in Example 1 b.  1.0 g of 1- (2-chloroethyl) -1-nitrozo-3-n-pentil-3-Go-o, tB-glucopyranosyl- (1-4) -B-gluco-pyranosyl urea, t was obtained. e.  1- (2-hlbretil) -1-nitroso-3-n-pentyl-3-B-maltosyl urea, in the form of a pale yellow powder.  Melting point of the product, (with decomposition).  about(.  4-58, (, 8, methyl alcohol ;.  Example51.  In a mixture of 150 ml of tetrahydrofuran and 20 ml of acetic acid, dissolve 5.1 g of 1- (2-hl6-methyl) -3-n-pentyl-3-O-O-D-glucopyr anosyl- (1-4) -B- glucopyranosyl urea and 20 g of anhydrous sodium acetate was added.  8 g of gaseous tetroxide of nitrogen was introduced into the mixture while stirring and cooling it with ice for 10 minutes.  The subsequent processing of the mixture is carried out similarly to 3.  As a result, 3.8 g of 1- (2-chloroethyl) -1-nitroso-3-n-pentyl was obtained. -B-glucopyranosyl (1-4) -D-glucopyranosyl urea, t. e.  1- (2-chloroethyl) -1-nitroso-3-n-pentyl-3-D-maltosyl urea, as a pale yellow powder.  The melting point of the product (with decomposition) is 71-75 C.  58.4, 8, methyl alcohol).  P . REMER 52.  a) Analogously to Example 42a, 7.2 g of D-maltose monohydrate is treated; 3.0 g of n-hexylamine and 2.5 g of 2-chloroethyl isocyanate.  As a result, 8.3 g of 1- (2-chloroethyl) -3-nhexyl-3-n-hexyl-3-EO-ot-B-glucopyranosyl- (1-9 4) -B-glucopyranosyl guilt, t. e.  1- (2-Chloroethyl) -3-n-hexyl-3-B-cytosylurea, in the form of a colorless powder.  b) In a mixture of 150 ml of tetrahydrofuran and 30 MP of acetic acid, 5.2 g of 1-C2-chloroethyl) -3-n-hexyl-3-CO-01 are dissolved. -B-glucopyranosyl- (1-4-B-glucogranmranosyl urea and 20 g of anhydrous sodium acetate 728 sodium tata are added to the solution.  With stirring and ice-cooling, 8 g of gaseous nitrogenous anhydride are added to the mixture for 10 minutes.  The mixture was then processed in the same manner as in the example. 4.2 g of 1- (2-chloroethyl) -1-ft1-throzo-3-n-hexyl-3-Co-oi-D-glucopyranosyl- (1-4) -B- glucopyranosyl urea, t. e.  1- (2-chloroethyl) -1-nitroso-3-n-hexyl-3-B-maltosyl urea, as a pale yellow powder.  Melting point (with decomposition) 70-72, C.  oi + 60,3 ° (C 1.0 methyl alcohol).  Example53.  a) Analogously to Example 2a, 7.2 g of B-maltose monohydrate is treated; 1.5 g of 2-poopenylamine and 2. 5 year  2-chloroethyl isocyanate.  Received 8. 0 g of 1-H2-chloroethyl) -3- (2-propenyl) -cCo — oC-P-glucopyranosyl- (1-4) -B-glucopyranosyl momevin,), t. e.  1-H2-chloroethyl) -3- (2-propenyl) -3-B-maltosyl urea, as a colorless powder.  b) In a mixture of 150 ml of tetrahydrofuran and 20 ml of acetic acid is dissolved, 8 g of (2-chloroethyl) -3- (2 ropenip) -3-1 0-f -Q-rnmKorMpamSIL- () -B-glucopyranosyl urine VINES and 20 g of anhydrous sodium acetate are added.  With stirring and cooling with ice, 8 g of gaseous nitrogenous anhydride are added to the mixture for 10 minutes.  The mixture was processed in the same manner as in Example 43. The result was 3.2 g of 1- (2-chloroethyl) -1-nitroso-3- (2-propenyl) -3 GO-C / -B-glucopyranosyl- () -B - glucopyranosyl Urea, t. e.  1- (2-chloroethyl) -1-nitroso-3- (2-propenyl) -3-B-mal-; tosyl urea, in the form of a pale yellow powder.  Melting point (with decomposition) b7 C.   +41, (, 4, methyl alcohol).  Example 54  a) 7.2 g of B-maltose monohydrate; 2.8 g of 2-methyl-2-propenylamine and 2.5 g of 2-chloroethyl isocyanate are treated as in Example 42 a.  As a result, 7.8 g of 1- (2-chloroethyl) -3- (2-methyl-2-propenyl) -3-Go-o-B-glucopyranosyl- (4) -B-glucopyranosyl urea, t. e.  1- (2-chloroethyl) 3C2-methyl-2-propenyl) -3-B-maltosyl urea, as a colorless powder.  6) In a mixture of 150 ml of tetrahydrofuran and 20 ml of acetic acid is dissolved, 9 g of 1- (2-chloroethyl) -3- (2-methyl-2-propenyl) -3- О ci-D-glucopyranosyl- (1-4) P-glucopyranosy urea and 20 g of anhydrous sodium acetate was added to the solution.  8 g of gaseous nitric anhydride are supplied to the mixture for 10 minutes while stirring and cooling with ice.  The mixture is treated analogously to example A3.  3.6 g of 1- (2-chloroethyl) -1-nitroso-2- (2-methyl-2-propenyl) -3-fo-dl-D-glucopyranosyl- (1-4) -D-glucopyranosyl Chevine are obtained. , t e.  1- (2-chloroethyl) -1-nitro zo-3 (2-methyl-3-propenyl) -3-B-maltosyl urea, as a pale yellow powder.  Melting point (with decomposition) 76-8 (f C.  , 1 ° (, 8, methanol).  PRI me R 55.  a) Analogously to Example 2a, 7.2 g of D-maltose monohydrate, 2.1 g of 2-butenylamine and 2.5 g of 2-chloroethyl isocyanate are treated.  As a result, 8.2 g of 1- (2-chloroethyl) -3- (2-butenyl) df-D-glucopyranosyl- (1-4) -P-glucopyranosyl urea, m are obtained. e.  1- (2-chloroethyl) -3- (2-butenyl) -3-P-maltosyl urea, as a colorless powder.  The melting point of the product (with decomposition) is 71-75 C.  (b) 3 mixtures of 150 ml of tetrahydrofuran and 20 ml of acetic acid are dissolved +, 9 g of 1- (2-Yaloethyl) -3- (2-butylnyl) -3 in-oi-B-gl (okopyranosyl- (1- 4} -D-glucopyranosyl urea and 20 g of anhydrous sodium acetate is added to the solution.  8, over ice cooling and stirring, 8 g of gaseous nitric anhydride are introduced over a mixture of 10 gels.  The subsequent processing of the mixture is carried out analogously to the example.  3, the result was 3, B g of 1- (2-chloroethyl) -1-nit zo-3 (2-buteyl) -3 Go-o1 glucopyranosyl- (1-4) -O-glucopyranosylCevine, t. e.  1- (2-chloroethyl) -1-nitro-3 (2-butenyl) -3-P-maltosyl urea, as a pale yellow powder.  The melting point of the product (with decomposition) C.  o1 +43, (, 9, methanol).  PRI meper 56.  a) Analogously to Example C2, a treatment was performed with 7.2 g of D-maltose monohydate, 2.0 g of 3-6 yTef. 1lamine and 2.5 g of 2-chloroethyl isioate, As a result, 0 g of 1- (2-hportil) -3- (3-butenyl) -3- {P- oL-P-glucopyranosyl- (1-4) -P -gl "okopyranosyl urea, m. e.  1- (2-Chloroethyl) -3-l-butenyl) -3-P-maltosyl urea as a colorless powder.  b) Dissolve in 150 ml of tetrahydrofuran and 20 ml of acetic acid, 1 g of 1 - (2-chloroethyl) -3- (3-6utenip) -3- | p-oL-P-glucopyranosyl- (1-t 4) - U-glucopyranosyl urea and 20 g of anhydrous sodium acetate are added.  3, the mixture was stirred for 8 minutes while stirring under ice-cooling with 8 g of gaseous nitric anhydride. The mixture was subsequently treated in the same way as in Example l3.  As a result, g of 1- (2-chloroethyl) -1-nitroso-3 (3 butenyl) -P-gl (Okopyranosyl- (1-4) -D-glucopyranosyl urea t. e.  1- (2-chloroethyl) -1-nitroso-3- (3-buteyl) -3-P-maltosylbenzo ", and in the form of a pale yellow parorje.  Point ppavleni (with decomposition) 7 C.  o1 + 59.2 ° (, 0, methanol).  PRI mep 57.  a) Analogously to the example of k2 a, treatment of 7.2 g of D-lactose monohydrate is carried out; 1.9 g of n-butylamine and 2.5 g of 2-chloroethyl isocyanate.  As a result, 8.5 g of 1- (2-chloroethyl) -3-n-butyl-3-f o-o / - -D-galactopyranosyl- (1-4) -B-gl10 pyranosyl urine, t. e.  1- (2-chlorostil) -3-n-butyl-3 P-lactosyl urea, in the form of a colorless powder.  b) 5.1 g of 1- (2-chloroethyl) -3-nbutyl-3-CO L-D-galactopyranosyl- (1-4) -P-glucopyranosyl urea is dissolved in 20 ml of formic acid and for 1 hour at stirring and 0-5 ° C, 2 g of sodium nitrite are added.  The mixture is further stirred at the same temperature for 1 hour.  After the reaction, the mixture is treated as in Example 1 b.  0.8 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3-0-oi-D-galactopyranosyl- (1) -B-glucopyranosyl urea, t, was obtained. e.  1- (2-chloroethyl) -1-nitroso-3-n-butyl-3 O lactosylurea, in the form of a pale yellow, powder.  The melt temperature of the product's laziness (with decomposition).   +8.0 (, 8, methanol).  Example 58  In a mixture of 150 ml of tetrahydrofuran and 20 ml of acetic acid, lots of 4.9 g of 1- (2-hl6-ethyl-3-n-butyl-3P-β-P-galactopyranosyl- () -0-glucopyranosyl urea) are dissolved and 20 g anhydrous sodium acetate.  Under ice cooling and stirring, 8 g of nitrogen tetroxide are added to the mixture over 10 minutes.  Analogously to example 43, the mixture is subsequently processed.  The result is 3. 8 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl-3 GO-G) -galactopyranosyl- (1 4) -D-glucopyranosyl Urea, t. e.  1 - (2-chloroethyl) -1-nitroso-3 n-butyl-3-G) -lactosyl urea, as a pale yellow powder.  The melting point of the product with decomposition) is 90-95 ° C.  , 0 (, 8, methanol).  PRI me R 59.  a) As in Example 42a, 7.2 g of P-lactose monohydrate is treated; 2.5 g of isobutylamine and 2.5 g of 2-chlorostilisocyanate.  3 The result was obtained of 8.2 g of 1- (2-hl6rat-isobutyl-3-O-O-G) -galactopyranosyl- () -D-glucopyranosyl J urea, t. e.  1- (2-chloroethyl) -3-of-6-butyl 3-P-lactosyl urea, in the form of a colorless powder.  The melting point of the product (with decomposition) is 99-103 C.  b) 4.9 g of 1- (2-chloroethyl) -3-isobutyl-3-GO-1 P-gal-actopyranyl- (1-4) -P- is dissolved in a mixture of 150 ml of tetrahydrofur on AND 20 ml of acetic acid in a mixture. glucopyranosyl urea and 20 g of anhydrous sodium acetate 8 are added to the mixture, and 10 g of nitrogen tetroxide (gas) are introduced over 10 minutes with ice-cooling and stirring.  The subsequent processing of the mixture is carried out analogously to example 43.  As a result, 4.0 1- (2-chloroethyl) -1-nitro-zo-3 isobutyl-3-GO-c-i-P-galactopyranosyl- () -P-glucopyranosyl Zmochin, t. e.  1 - (2-chloroethyl) - 1-nitroso-3-isobutyl-3 P-lactosylurea, in the form of a pale yellow) O1IK.  Melting point product; (with a depiction of 87-92 p.  .  oi.   .  S-1, 0, 1 m gchpovy with. pi 7 EXAMPLE 60.  a) 1, 5 g of N-methylethanolamine is dissolved in 30 ml of tetrahydrofuran and 2.1 g of 2-chloroethyl isocyanate are added dropwise at 0-5 ° C.  The solution is stirred at room temperature for 1.5 hours.  Then, the reaction solution is concentrated under reduced pressure, whereby 3.5 g of 1- (2-chloroethyl) -3-methyl-3- (2-hydroxyethyl) urea is obtained in the form of a colorless oil.  b) 0.9 g of 1- (2-chloroethyl) -3-methyl-3- (2-hydroxyethyl) urea is dissolved in 10 ml of acetic acid and 0.9 g of sodium nitrite is added with stirring.  The mixture is stirred at room temperature for 1 hour.  Then 0.5-g of sodium nitrite is added to the mixture again and the mixture is further stirred at the same temperature for i h.  After the reaction, the mixture is freeze-dried and the residue obtained is purified by chromatography on silica gel, using a mixture of methyl alcohol and chloroform P: 10 as the solvent.  3.7 g of 1- (2-chloroethyl) -1-nitroso-3-methyl-3- (2-hydroxyethyl) urea are obtained in the form of a pale yellow oil.  PRI me R 61.  a) 2.1 g of diethanolamine is dissolved in 30 ml of tetrahydrofuran and 2.1 g of 2-chloroethyl isocyanate is added dropwise to this solution, maintaining its temperature.  The solution was stirred for 2 hours at room temperature.  Then the reaction solution is concentrated under reduced pressure.  4.2 g of 1- (2-chloroethyl) - was obtained. 3,3-bis- (2-hydroxyethyl) urea as a colorless oil.  b) 4.0 g of 1- (2-chloroethyl) -3,3-bis- (2-hydroxyethyl) urea is dissolved in 30 ml of acetic acid and 2.5 g of sodium nitrite are added with stirring.  The mixture is stirred for 4 hours at room temperature.  After the reaction, the mixture is treated as in Example 60 b, using a mixture of chloroform and methyl alcohol (10: 1) as a solvent for chromatography. The result is 3.0 g of 1- (2-chloroethyl) -1-nitroso-3, 3-bis- (2-hydroxyethyl) urea as a yellow oil.  PRI me R 62.  a) A mixture of 3.3 g of 3-chloro-1,2-dioxy-n-propane and 20 ml of 30% methyl methanol solution is kept at room temperature for 3 days.  The reaction mass is concentrated to dryness under reduced pressure, whereby 4.2 g of N-methyl-2,3-dioxy-n-propyl amine hydrochloride are obtained as a crude product.  4.2 g of the crude product and 3 g of three ethylamine are dissolved in 30 ml of methyl alcohol.  To the solution was added dropwise 3.2 g of 2-chloroethyl isocyanate, while maintaining.  The solution is stirred at room temperature for 2 hours.  Then, the reaction solution was dried under reduced pressure, and the residue was purified by chromatography on silica gel, using a ternary mixture of chloroform, ethyl acetate and methyl alcohol (3: 1: 1) as elution solvent. 3.5 g of 1- (2 -chloroethyl) -3-methyl-Z- (2,3-dioxy-n-propyl) urea as a colorless oil.  b) 2.1 g of 1- (2-chloroethyl) -3-methyl-3 (2, 3-dioxy-n-propyl) urea is dissolved in 10 ml of acetic acid and 1.4 g of sodium nitrite are added with stirring.  The mixture is kept at room temperature for 2 hours.  Then 2 ml of concentrated hydrochloric acid and 1 g of sodium nitrite are added to the mixture.  The mixture is further stirred at this temperature for 2 hours.  After termination of the reaction. and the mixture is treated analogously to example 60 b.  8 as ag. luminous solvent for chromatographic purification using a mixture of chloroform, ethyl acetic acid and methyl alcohol (3: 1: 1).  As a result, 1.5 g of 1- (2-chloroethyl) -1-nitroso-3-methyl-3- (2,3-dioxy-n-propyl) urea was obtained as a pale yellow oil.  :-) PRI mep 63.  a) 6.1 g of 1-n-butylamino-1-deoxy-2, 4-0-ethylidene-D) erythritol prepared from 2, 4-0-ethylidene-P-spectrose according to the Zyderman method is dissolved in 20 ml of aqueous hydrochloric acid.  The solution is heated at 80 ° C for 1 hour. The reaction mixture is distilled off to dryness under reduced pressure; whereby 6, g of 1-n-butylsmino-1-deoxy-O-erythrito- hydrochloride are obtained.  la in the form of a crude product. The specified product and 3 g of triethylamine are dissolved in kQ ml of methyl alcohol.  To the solution, 3.2 g of 2-chloroethyl isocyanate are added dropwise at 0-5 ° C.  The subsequent processing of the mixture was carried out analogously to Example B2 a.  As a result, 5.0 g of 1- 2-chloroethyl) -3-n-butyl-3 (1-deoxy-D-erythritolyl) urea was obtained in the form of a colorless oil.  b) 3.1 g of 1- (2-chloroethyl) -ZH-butyl 3 (1-deoxy-P-erythritolyl) urea is dissolved in 10 ml of formic acid and 1 g of sodium nitrite is added.  The mixture is stirred for 3 hours at 0-5 C.  After completion of the reaction, the mixture is treated analogously to Example B2 b.  Obtained 2.0 g of 1- (2-hl6etil) -1-nitroso-3-n-butyl-3- (1-deoxy-B-erythritolyl) urea as a yellow oil.  o1. .  -23.5 (, 9, methyl alcohol).  PRI me R 6.  a) A mixture of 3.3 g of H-chloro-1, 2-dioxy-n-propane and 8 g of n-propylamine is kept at room temperature for 5 days.  The reaction mixture is distilled to dryness under reduced pressure, whereby 5.0 g of -n-propyl-2, 3-dioxy-n-propylamine hydrochloride are obtained as a crude product.  All of the indicated product and 3 g of triethylamine are dissolved in 40 ml of methyl alcohol.  3.2 g of 2-chloroethyl isocyanate is added to the solution at 0-5 ° C.  Then the reaction mixture is treated analogously to example B2 and.  3.0 g of 1- (2-chloro-ethyl) -3 n-propyl-3- (2-zdioxy-n-propyl) urea are obtained in the form of a colorless oil.  b) In 1 ml of acetic acid, 3 1- (2-chloroethyl) -7) -myl-propyl-3- (2,3-dioxy-n-propyl) urine are dissolved and 1.5 g of sodium nitrite are added with stirring. .  The mixture is stirred for 4 hours.  After completion of the reaction, the mixture is treated as in Example 62 b.  Obtained 1.7 g of 1- (2-chloroethyl) -1-nitrosyl-3 n-propyl-3- (2,3-dioxy-propyl) urea as a yellow oil.  PRI me R b5.  a) To 50 ml of a solution in methyl alcohol, 2.9 g of N-methylglucamine, while cooling it with ice, add 1,6 g of 2-lorethyl isocyanate in 5 ml of tetrahydrofuran.  The mixture is stirred at room temperature for 1 hour.  After completion of the reaction, the mixture is concentrated under reduced pressure.  The resulting residue is recrystallized from a mixture of ethyl alcohol and ethyl acetate.  As a result of the floor.  3.5 g of 1 - (2-chloroethyl) -3 methyl-3 - (1-deoxy-0-glucitolyl) urea as colorless crystals was found.  The melting point of the product is 88-90 ° C.  b) 1.9 g of 1- (2-chloroethyl) -3-methyl-3- (1-dioxy-P-glucitolyl) urea is dissolved in 10 ml of formic acid, and gradually over 1 hour with stirring, 0 is added, 9 g of sodium nitrite.  The mixture is further stirred at this temperature for 30 minutes.  After completion of the reaction, the mixture is freeze-dried.  The residue obtained is purified by chromatography on silica gel using a ternary mixture of chloroform, ethyl acetate and methyl alcohol as the eluting solvent (O2: 1: 1). 0.7 g of 1 - (2-chloroethyl) -1-nitroso-3-methyl is obtained -3 (1-deoxy-P-glY cytolyl) urea in the form of pale yellow caramel.  di -1it, 7 ° (, 1, methanol).  Example 66  a) Analogously to Example 5a, 2.4 g of Nn-butyl-glucamine prepared by hydrogenolysis of 1-n-butylamino-1-deoxy-L-glucose and 1.1 g of 2-chloroethyl isocyanate are treated.  As a result, 3.5 g of 1- (2-chloroethyl) -ZH-butyl-3- (1-deoxy-D-glucitolyl) urea were obtained in the form of a colorless caramel.   IR spectrum - cm: 3350, 1b20, 1540 and 1080. .   b) g 1- (2-chloroethyl) -3-n-butyl 3 (1-deoxy-O-glucitolyl) urea is dissolved in 15 ml of formic acid and 2.5 g of sodium nitrite are gradually added over 1 hour with oh ice creep.  The mixture is stirred.  within 30 min.  After the reaction, the mixture is treated in the same manner as in Example 5b, using a binary mixture of chloroform and methyl alcohol as eluent on 36 solvent (). 1.8 g of 1- (2-chloroethyl) -1-nitroso-3-n-butyl is obtained. -3- (1-deoxy-O-glucitolyl) urea as a pale yellow powder.  The melting point of the product (with decomposition).  oCj) -17) 8, 5, methyl alcohol) The invention The method of producing nitrosourea derivatives of the general formula N-CO-N-CMiCHiC o / 1 - Ra N0 alkyl C - C, alkenyl St, - Q, oxyalkyl C, 2, alkynyl aldopentofuranosyl, aldo.   Pentopyranosyl, aldohexopyranosyl, o-aldo-hexopyranosyl-P-4) aldo-hexopyranosyl group —CH 2. (CHOH: |, or 1-, characterized in that the compound of the formula N-CO-NH-CHjCHCe 2 has the indicated meanings, is nitrosated at (. -20) - in an inert solvent.  Priority on the grounds; 29. 07-77 with alkyl C, -C / oxyalkyl 22. 09-77 with Rj-Q; oxyalkyl C, R2.  - group (CHOH), Ol20il, -0,1,2 and nitrosating agent nitrous acid acid 02. 02 78 at R - alkyl C ,, - Cg; sixteen. 05-78 with R aldopentofuraosyl, aldopentopyranosyl, aldohecopyrano. Eyl-, or o-aldo-hexoyranosyl- () aldohexopyranoyl, nitrosating agent - nitric oxide;
    379082i 738
    2b.05.78 with Rj - alkenyl 1. Japan patent No. 5217.8, and alkynyl Cz-.cl. 16 B 33 1976.
    Information sources
    [2]
    2. PaT (Japan 1nt №,
    taken into account in the examination of cl. 16 B 33 1976.
    类似技术:
    公开号 | 公开日 | 专利标题
    EP0181154B1|1990-08-08|Galactose-c-6 nitrogen mustard compounds and their uses
    HUT70765A|1995-10-30|Immunregulator rapamycin derivatives of activity, pharmaceutical compositions containing them and process for preparing them
    JP2002523495A|2002-07-30|Triptolide prodrug with high water solubility
    SU908247A3|1982-02-23|Process for preparing nitroso urea derivatives
    EP0100499A2|1984-02-15|Phospholipid derivatives, processes for preparation thereof and pharmaceutical composition of the same
    DK173952B1|2002-03-04|Use of spergualin derivatives for the preparation of drugs with immunosuppressive effect
    SU1054352A1|1983-11-15|N-glycosyl derivatives of daunorubicine having antibiotic effect
    US3920630A|1975-11-18|2,2{40 -Anhydro-ara-cytidine compounds and process of preparation
    US4039578A|1977-08-02|1-Tetrahydroxycyclopentyl-3-nitroso-3-|-urea antitumor agents
    SU1384202A3|1988-03-23|Method of producing substituted thiazolidinyl esters of phosphoric acid
    JP3650144B2|2005-05-18|Cell adhesion inhibitor
    US4021542A|1977-05-03|Derivatives of hydrazino-monosaccharides and aldohexoses which are useful as intermediates for preparing compounds or as compounds which lower the uric acid
    US4241052A|1980-12-23|Novel nitrosourea compounds and process for preparing the same
    EP0056458B1|1985-05-02|Nitrosourea derivatives, a process for preparing same and therapeutic compositions
    EP0062329B1|1985-02-20|Novel nitrosourea derivative, process for preparing same and therapeutic composition containing said derivate
    US4241053A|1980-12-23|Novel nitrosourea compounds and process for preparing the same
    US4371535A|1983-02-01|Method of and composition for delivering 5-fluorouracil to tumors
    KR810000556B1|1981-06-01|Process for preparation of nitrosourea compounds
    GB2028795A|1980-03-12|Novel nitrosourea compounds and process for preparing the same
    JP2004505899A|2004-02-26|5&#39;-Deoxy-N- | -5-fluorocytosine and derivatives thereof, method for producing the same, and anticancer composition containing the same as an active ingredient
    EP0071374A1|1983-02-09|Nitrosourea derivatives having anti-tumour and anti-bacterial activity
    US7956039B2|2011-06-07|Use of amygdalin analogues for the treatment of psoriasis
    KR820001234B1|1982-07-07|Process for the preparation of nitroso urea compounds
    CA1245644A|1988-11-29|Galactose-c-6 nitrogen mustard compounds and theiruses
    FR2471386A1|1981-06-19|PROCESS FOR THE PRODUCTION OF GLUCOPYRANOSIS-NITROSOUREE COMPOUNDS, NOVEL PRODUCTS OBTAINED WITH ANTI-TUMOR ACTIVITY AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM
    同族专利:
    公开号 | 公开日
    NL7808036A|1979-01-31|
    FR2475040A1|1981-08-07|
    CH636626A5|1983-06-15|
    GB2002370A|1979-02-21|
    SE435501B|1984-10-01|
    PH13936A|1980-11-04|
    FR2485541A1|1981-12-31|
    ATA546178A|1980-06-15|
    PL208701A1|1979-06-04|
    PT68359A|1978-08-01|
    FR2475040B1|1984-11-16|
    FI65439C|1984-05-10|
    DE2858078C2|1983-12-15|
    IT7868797D0|1978-07-27|
    FI782215A|1979-01-30|
    GB2002370B|1982-03-03|
    CA1097624A|1981-03-17|
    AU525239B2|1982-10-28|
    US4182757A|1980-01-08|
    FR2403994A1|1979-04-20|
    SE7808162L|1979-01-30|
    FR2499577A1|1982-08-13|
    AR219331A1|1980-08-15|
    FI65439B|1984-01-31|
    CS216918B2|1982-12-31|
    DE2832127C2|1983-07-28|
    IT1160450B|1987-03-11|
    HU176891B|1981-05-28|
    PL111784B1|1980-09-30|
    AU3849178A|1980-02-07|
    DE2832127A1|1979-02-08|
    FR2499577B1|1984-07-13|
    DK331978A|1979-01-30|
    AT360553B|1981-01-26|
    FR2485541B1|1986-06-06|
    BE869352A|1979-01-29|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3577406A|1968-05-23|1971-05-04|Upjohn Co|Process for preparing the antibiotic streptozotocin|
    JPS4843333B1|1970-04-25|1973-12-18|
    JPS5230491B2|1974-07-05|1977-08-09|
    IL47842A|1974-08-08|1980-07-31|Suami T|Nitroso urea glycosides and related compounds,their preparation and pharmaceutical compositions containing them|
    JPS565239B2|1974-08-08|1981-02-04|
    US3940383A|1974-12-12|1976-02-24|Stanford Research Institute|Streptozotocin analogs|US4241052A|1978-06-10|1980-12-23|Tanabe Seiyaku Co., Ltd.|Novel nitrosourea compounds and process for preparing the same|
    US4241053A|1978-08-25|1980-12-23|Tanabe Seiyaku Co., Ltd.|Novel nitrosourea compounds and process for preparing the same|
    EP0058665B1|1980-05-09|1986-02-26|LEFFLER, Hakon|Carbohydrate derivatives for inhibiting bacterial adherence|
    JPS5775993A|1980-10-30|1982-05-12|Tetsuo Suami|Novel nitrosourea derivative and its preparation|
    JPS6310958B2|1981-04-02|1988-03-10|Tanabe Seiyaku Co|
    JPS6125707B2|1981-07-21|1986-06-17|Kureha Chemical Ind Co Ltd|
    US4656259A|1983-06-29|1987-04-07|Institut Organicheskoy Khimii Akademii Nauk Kirgizskoi|Method for preparing N-alkyl-N'-glycosyl-N-nitrosourea|
    DE3436670A1|1984-10-05|1986-04-10|Kangaroos U.S.A. Inc., Maryland Heights, Mo.|Foot support for foot covering, in particular for shoes|
    US8853284B2|2008-06-02|2014-10-07|Honeywell International Inc.|Wax dispersion formulations, method of producing same, and uses|
    US10941111B2|2018-10-16|2021-03-09|Purdue Research Foundation|On-demand rapid synthesis of lomustine under continuous flow conditions|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP9167477A|JPS5427526A|1977-07-29|1977-07-29|Nitrosourea compounds and their preparation|
    JP11425977A|JPS5715110B2|1977-09-22|1977-09-22|
    JP1122578A|JPS5647192B2|1978-02-02|1978-02-02|
    JP5856078A|JPS6026120B2|1978-05-16|1978-05-16|
    JP6345978A|JPS5919555B2|1978-05-26|1978-05-26|
    [返回顶部]