• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
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  • 优先权
    • 专利摘要:
    Novel water-soluble nitrosourea derivatives of the formula <IMAGE> WHEREIN R represents a 2', 3', 4', 5'-tetrahydroxycyclopentyl group exhibit high effectiveness in various animal tumor systems.
    公开号:SU849999A3
    申请号:SU772460622
    申请日:1977-03-05
    公开日:1981-07-23
    发明作者:Суами Тецуо
    申请人:Тецуо Суами (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING WATER-SOLUBLE DERIVATIVES The invention relates to a method for producing water-soluble nitrosourea derivatives having valuable pharmacological properties. The purpose of the invention is to obtain new useful compounds that expand the arsenal of means of influencing a living organism by synthesizing the latter, based on. data on the well-known reaction of obtaining urea derivatives fl, followed by their nitrosation. This goal is achieved by the fact that according to the method of obtaining water-soluble nitrosourea derivatives of the general formula O, R-NH0-N- &amp; H, jCH, ce, 1 where R is 21, 3, 4, 5 is tetraoxycyclo-enlenyl group 2,3,4-cyclopentane-tetrol is interacting with (action with 2-chloroethyl isociadate in an aqueous medium at temperatures from -10, after which the resulting ureid of the general formula
    O R-NH-C-K-cH, CH2Ce,
    n nitrosomavina
    权利要求:
    Claims (1)
    [1]
    b) 1,2,3,4 / 5-5-amino-1,2,3,4-CycZb, lopentanetrol where R has the above value, is subjected to nitrosation in the formic acid medium at a temperature of -10 and -f-10 c. The starting materials are known - 5-amino-1,2,3,4-cyclopentane-tetrol or its pentaacetyl derivatives. The ten possible stereo stereomers are shown below, together with the nomenclature used for various isomeric forms. The position and configuration of the hydroxyl substituents is indicated by the lines shown below and above the plane of the ring system #) cyclopentyl. a) 1,2,3,4,5 / 0-5-amino-1,2,3,4 cyclopentane tetrol Vj / MHi O c) 1,4,5 / 2,3-cyclopentane tetra / g) 1,4 / 2 , 3,5-pentanetrol d) 1,2,3,5 / 4 lopentanetrol e) 1,2,4,5 / 3 lopentanetrol O g) 1, .2,3 / 4,5 lopentanetrol g) 1, 2.4 / 3.5 lopentantetrol and) 1,2,5 / 3,4 lopentantetrol Vc) 1,3,5 / 2,4 lopemntant and the role of the a-g isomers are meso-forms, while the d-c isomers are racemic diastereoisomers, of which only one enantiomer is given. The method includes compounds of formula I, obtained from the meeo-starting materials described by formulas a-g, racemic isomers described by formulas dk, and split epimers of isomers dk. The condensation step of the described reaction is carried out in an inert solvent system. Examples of suitable inert solvents are water, (lower) alkanols, such as methanol, ethanol, propanol or butanol, a mixture of water with (lower) alkanals, such as aqueous methanol, aqueous ethanol, etc. and inert organic solvents, such as dioxane. Recommended or solvent systems are those that contain water or aqueous (lower) alkanols, for example, 50% ethanol. The condensation reaction can be conducted in a wide range of temperatures, for example, in the range from about -20 to +, but preferably, this reaction is carried out at a temperature of about with stirring. The nitrosation step is carried out in accordance with conventional methods. Thus, the ureid derivative — intermediate 1t can interact in an aqueous solvent system with nitrous acid or its source, for example, when it is formed in situ from a nitrite compound or its source, such as sodium nitrite, nitrite potassium or amyl nitrite or nitrogen trioxide and an aqueous organic acid, such as formic acid, acetic acid, propionic acid or hydrochloric acid. The reaction temperature of n rozirovanie may be in the range between about -20 to, but preferably, it is around. Example 1. (1,4 / 2,3,5) -5-Cz-Chloroethnl-3-nitrosoypeidoJ-l 2,3,4-cyclopentanethrol / TE-5U. D. (1,4 / 2,3,5) -5-Amino-1,2,3,4-cyclopentatatrol (1.0 g) is dissolved in ice water (20 kp) and to the solution with ice cooling and by mechanical stirring, 2-chloro-ethyl isocyanate (0.84 ml) is added. After 2 hours, the presence of the starting material is not noticed in the reaction mixture, which is controlled by thin layer chromatography in 50% aqueous ethanol, which is used as a solvent system. The solution is evaporated under reduced pressure and the residue is dissolved in methanol (3.0, ml). The methanol solution is placed in a refrigerator, where 0.56 g of product is obtained by precipitation. From the mother liquor receive a second portion of the product (0.20 g). After recrystallization from ethanol, 0.53 g (yield 31%) (1.4 / 2.3.5) (2-chloroethyl) urendo -1,2,3,4-cyclopene tanthrol is obtained, melting at 126– 1290 s. Found,%: C 37, 38, H 5.85, N 10.77, - C &amp; 13.62. CgH gNjOgCg O is abundant,% with 37.73, H 5.94, N 11.0, all 13.92. B. The obtained part A disinfectant (329 m is dissolved in 99% formic acid (5.5 ml) and sodium nitrite (268 mg) is added to the solution under ice cooling at a temperature range from -10 to stirring and after stirring. After 1 Ice water is added to the solution, then the solution is deionized on amberlite 1R-120 (in H-form) and evaporated under reduced pressure. The residue is dissolved in methanol and again evaporated. This treatment is repeated several times to remove formic acid. dissolve in absolute ethanol and add diethyl ether to a weak cloud. The mixture is allowed to precipitate in a refrigerator and 148 mg (40% yield) of the product is obtained, the title of which is indicated in the title melting at IO-IZ-C (with decomposition) -, Found,%: C 32.11, H 4 , 57, N 13.85, CZ 13.19. CgH, N30 ce Calculated,%: C 33.87, H 4.98, N 14.81, C 12.50. (1,2,3,4 / 5-СЗExample 2. - (2-Chlorethyl) -3-nitrosoureido -1,2, 3,4-cyclopentanetrol / TE-b /. A, Tetra-0-acetyl- (1,2,3,4 / 5) -4-acetamido-1, 2,3,4-cyclopentane-tetro (2.14 g) is heated in hydrochloric acid (50 ml) at reflux temperature for 2 hours and then evaporated under reduced pressure. activities. The residue is dissolved in water and the solution is passed through an Amberlite 1RA-400 column (in OH-form). The exit solution was evaporated under reduced pressure to obtain 0.90 g (1,2,3,4 / 5) -5-amine -1,2,3,4-cyclopentane tetrol as a light yellow syrup. at. The product, the preparation of which is described in Part A (0.93 g), is dissolved in ice water (17.5 ml) and, when cooled with ice, at temperatures ranging from -10 to + 10 ° C and mechanically stirred and goth 2-chloroethyl isocyanate (1.05 ml). After 2 h, the reaction mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is recrystallized from methanol to obtain 636 m (yield 42%) (1,2,3,4 / 5) (2-chloroethyl) -ureido -1,2,3,4-cyclop ngantetraol melting at 124 - 28 ° WITH. Found.%: C 37.48, H 5.76, N 10.89, C "13.19. C0H 5 NjOgCe is altered,%: C 37.73, H 5.94, N 11.00, СЪ 13.92. C. The compound whose preparation is described in Part B (585 mg) is dissolved in 99% formic acid (10 ml) and sodium nitrite (467 mg) is added to the solution while cooling with ice and stirring. The reaction mixture is treated as described in example 1 (part B), dl. syrup production. The syrup is dissolved in a small volume of ethanol and the solution is placed in a refrigerator to precipitate the product in an amount of 290 mg (yield 45%), melting at (with decomposition). Found,%: C 34.82, H 5.08, N 14.13, Cfl 1-94. Calculated,%: C, 33.87; H, 4.98; 14.81; ce, 12.50. Example 3. D, L- (l, 2.4 / 3.5) (2-Chloroethyl) -3-nitrosouzeidr -1, 2, 3,4-cyclopentanetrol / TE-7 /, A. 0.1- (1,2,4 / 3,5) -5-Amino-1,2, 3,4-cyclopentantetrol (1.81 g) is dissolved in ice water (34 ml) and added to the solution while cooling with ice and stirring 2-chloroethyl isocyanate (2.04 ml). After 2 hours, the reaction mixture is filtered and the filtrate is evaporated under reduced pressure to obtain a crystalline residue. After recrystallization from methanol, 1.90 g (yield 62%) of D, L (1,2, .4 / 3.5) (2-chloroethyl) -ureido -1, 2,3,4-cyclopentantetrol, melted at 127-129c. Found,%: C 37.85, H 5.84, 11.01, ce 14.07. CgH, 5 l yOsCe H 5.94, Calculated,%: from 37.73, N 11.00, СЬ 13.92. B. The product, the preparation of which is described in Part A (776 mg), is dissolved in 99% formic acid (14 ml) and sodium atritis (641 mg) is added to the solution while cooling down in the temperature range from -10 ° C and stirring. ). The solution is treated as described in Example 1 (Part B) to obtain a remistical residue. The residue is fermented with ethanol to obtain 65 mg (yield 66%). D.L- (l, 2.4 / 3.5) 5-13- (2-chloroethyl) -3-nitrosoureido1,2, .3,4-cyclopentane tetrol ,. melt egos at 129-131 C (with decomposition) Calculated,%: C 33.87, H, 14.81, cross 12.50. SdH The proposed compounds have a wide range of efficacy against various experimental sietem tumors, for example, lymphatic leukami-P-388, Lewis lung carcinoma, and leukemia L, -1210. They can be administered either alone or in combination with other anti-tumor agents. They are usually administered parenterally, in the form of pharmaceutical preparations, for example mixtures of active agents with suitable pharmaceutical carriers or diluents. The estimated dose for humans is between 6 and 24 mg / m per day and is administered intravenously over a period of up to 10 days for each course of treatment. The invention The method of obtaining water-soluble derivatives of nitrosourea of General formula 1 O. . R-NH-C-VI-CH-GH Ce I where R is 2, 3, 4, 5-tetraoxycyclopentylene group, characterized in that 5-amino-1,2,3,4-cyclopentane tetrol is reacted with 2-chloro ethyl isocyanatrm in an aqueous medium at a temperature of from -10 to, after which the resulting ureid of the general formula II R - KN - c-NH - CHjCHjCe 1 de R has the above value, is subjected to nitrosation in the medium of formic acid at a temperature of from -10 to + 10s. Sources of information taken into account in the examination of 1- Weigand-Hilgetag, Methods of experiment in organic chemistry. M., Himi, 1968, p. 393.
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    同族专利:
    公开号 | 公开日
    AU2296877A|1978-09-14|
    SE7702519L|1977-09-09|
    BE852128A|1977-09-05|
    IE44060L|1977-09-08|
    SE8204287L|1982-07-12|
    US4039578A|1977-08-02|
    FI65234B|1983-12-30|
    CA1078868A|1980-06-03|
    FI770719A|1977-09-09|
    FR2343724A1|1977-10-07|
    SE8204287D0|1982-07-12|
    SE434263B|1984-07-16|
    CH629476A5|1982-04-30|
    JPS61165359A|1986-07-26|
    GB1524651A|1978-09-13|
    AU508346B2|1980-03-20|
    IE44060B1|1981-07-29|
    FI65234C|1984-04-10|
    DK97877A|1977-09-09|
    JPS52128357A|1977-10-27|
    SE452980B|1988-01-04|
    NL7702362A|1977-09-12|
    LU76899A1|1977-09-26|
    DE2709497C2|1986-08-28|
    FR2343724B1|1980-02-15|
    JPS6220183B2|1987-05-06|
    DE2709497A1|1977-09-22|
    DE2760351C2|1988-07-21|
    ZA771317B|1978-01-25|
    JPH0144178B2|1989-09-26|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US3859277A|1971-06-28|1975-01-07|Yamanouchi Pharma Co Ltd|D-1-1--3--1-nitrosourea|US4148921A|1977-07-13|1979-04-10|Suami T|Antitumor agents|
    FR2459231A1|1979-06-19|1981-01-09|Anvar|NOVEL CYSTAMINE DERIVATIVES USEFUL AS MEDICAMENTS|
    US4423076A|1979-08-08|1983-12-27|National Foundation For Cancer Research, Inc.|1-Branched-alkyl-3--3-nitrosoureas as novel antitumor agents|
    JPS56120662A|1980-02-28|1981-09-22|Kowa Co|Novel nitrosourea derivative and its preparation|
    JPS57116043A|1981-01-12|1982-07-19|Tetsuo Suami|New nitrosourea derivative and its preparation|
    AU3364197A|1997-04-02|1998-10-22|Tets, Victor Veniaminoich|Antitumoral drugs |
    CA2514841A1|2003-02-02|2004-08-19|Palo Alto Institute Of Molecular Medicine|Cell-killing molecules and methods of use thereof|
    WO2015089268A1|2013-12-11|2015-06-18|University Of Massachusetts|Compositions and methods for treating disease using salmonella t3ss effector protein |
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/664,844|US4039578A|1976-03-08|1976-03-08|1-Tetrahydroxycyclopentyl-3-nitroso-3--urea antitumor agents|
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