• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
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  • 优先权
    • 专利摘要:
    This invention relates to new oxazaphosphorin-4-thio-alkanesulphonic acids and to the neutral salts thereof corresponding to the general formula I <IMAGE> and to methods to use such compounds to control cancer diseases and to produce immunosuppression in humans and animals.
    公开号:SU1318167A3
    申请号:SU823414100
    申请日:1982-03-23
    公开日:1987-06-15
    发明作者:Шеффлер Герхард；Нимейер Ульф；Брок Норберт；Поль Йерг
    申请人:Аста-Верке Аг Хемише Фабрик (Фирма)；
    IPC主号:
    专利说明:

    113
    The invention relates to the chemistry of organophosphorus compounds, namely to a method for producing oxazaphosphorino-4-thioalkanesulfonic acid and its neutral salts of the general formula
    , 6-1
    RT, H S-X-S03
     /
    -w / w
    -CH2
    Y
     where R, and R, is hydrogen or C1-CH, CH2;
    Rj - Cl-CK.j, CH
    g
    X - C2-C5-alkylene or mercaptopropane;
    Y is a cyclohexylammonium, sodium, ammonium or guanidine cycle, which has an antitumor effect and can be used in the treatment of cancer diseases and in suppressing immunity,
    The aim of the invention is to develop a process for the preparation of oxazaphosphorino-4-thioalkanesulfonic acid and its neutral salts having antitumor activity.
    The invention is illustrated by the following examples.
    Example 1. Cyclohexylammonium BA salt of (bis) -2-chloroethyl (amino -2-oxo-tetrahydro 2H-1,3,2-oxazophosphorin-4-yl-thio zanesulfonic acid
    5.6 g (20 mmol) of 4-oxycyclophosphamide (i.e. 2- (bis) -2-chloroethyl (amino) -A-oxy-tetrahydro-2H-1,3,2-oxazaphosphorin -2-oxide) and 4.8 g (20 mmol of cyclohexylammonium-2-mercaptoethane sulfonate) are dissolved in 100 ml of distilled water, mixed with a small amount of trichloroacetic acid and left to stand for 3 days at 0 ° C in a refrigerator. This solvent is removed under high vacuum, the residue is taken up in acetone, evaporated again, crystallized from acetone and recrystallized from isopropanol. Yield 7.2 g (72% of theory), i.e. 149-151 C (cis -form) about
    Example 2. Cyclohexylammonium salt (btis) -2 chloroethyl (amino) -2-oxo-tetrahydro-2H-1, 3,2-β-oxazaphosphorin-4-yl-thio ethanesulfonic acid
    2.9 g (10 mmol) of 2- (bis) -2-chloro-ethyl (amine) -4-methoxytetrahydride-2H-l, 3,2-oxazaphosphorin-2-oxide and 2.4 g (10 mmol) cyclohexylammonium
    o
    five
    0
    five
    0
    35
    0
    five
    0
    five
    672
    -2-mercaptoethanesulfonate was dissolved with a small amount of trichloroacetic acid and 10 ml of dimethylformamide, and kept for 20 hours at -25 ° C. After an additional 3 hours of incubation at 0 ° C, they were mixed with effluent until the beginning of turbidity, triturated, and the crystallized acid was removed after it for 20 hours at 0 ° C, washed and dried.
    Output 4.7 g-1 94% of theory), so pl. 145 ° C (decomp.). Recrystallized from an alcohol / ether mixture, m.p. 149 - 151 C (cis-form).
    Example 3. Cyclohexylammonium salt of (bis) -2-x. Porethyl (amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thio-ethanesulfonic acid.
    1.4 g (5 mmol) of 4-oxycyclophosphamide and 1.2 g (5 mmol) of cyclohexyl ammonium-2-mercaptoethanesulfonate, and together with a small amount (traces) of trichloroacetic acid, are dissolved in 25 ml of methanol and left to stand. overnight at -25 C in the fridge. Immediately thereafter, the reaction solution was evaporated to approximately 5 ml, ether was added until turbidity and triturated. After 20 hours, crystallized acid is sucked off at OS, washed and dried.
    Yield 2.1 g (84% of theory), mp. 143-145 ° C (cis-form).
    Example 4. Sodium salt of (bis) -2-chlorostil (amino) 2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thio-ethanesulfonic acid.
    2.5g (5 mmol) of cyclohexyl-ammonium-2- 2- (bis) -2-chlorostil (amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin- (4-yl) - The thio-ethanesulfonate is dissolved in 25 ml of water free from dissolved oxygen and passed through a Merck brand cation-exchange resin filled with sodium ions. The eluate is passed over nitrogen, freeze dried, and the solid residue is dried under vacuum over phosphorus pentoxide.
    Output 1.9 g (91% of theory), so pl. 78-83 ° C (decomp.), Refraction value 0.61 (elution liquid: ethyl acetate / isopropanol) N acetic acid (5: 3: 2).
    Example 5. Ammonium salt of (bis) -2-chloroethyl (amino) 2-oxo31
    -tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thio-ethanesulfonic acid.
    2.8 g (10 mmol) of 4-oxycyclophosphamide and 1.6 g (10 mmol) of ammonium-2-mercaptoethanesulfonate are dissolved together with a catalytic amount of trichloroacetic acid in 50 ml of water and left to stand for 3 days at C in the fridge. Thereafter, water is distilled off under high vacuum, the residue is added twice to acetone and evaporated in vacuo. Recrystallize from acetone / ether.
    Output 3.9 g (93% of theory), so pl. (cis form).
    Example 6. The ammonium salt of 2- 2- (bis) -2-chloro-ethyl (amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thio-ethanesulfonic acid.
    2.8 g (10 mmol) of 4-oxycyclophosphamide and 1.6 g (10 mmol) of ammonium 2-mercaptoethanesulfonate with a catalytic amount of trichloroacetic acid are dissolved in 10 ml of dimethylformamide and kept in a refrigerator at -25 ° C. for 20 hours. After additional incubation for 5 hours at 0 ° C, mix with ether before the appearance of turbidity and triturate. The crystallisate is sucked off after 1 day at 0 ° C, washed, dried and recrystallized from n-propanol.
    Output 3.2 g (77% of theory),, CIS-form, so pl. 132 C.
    Example 7. The sodium salt of (bis) -2-chloroethyl (amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thio-propane sulfonic acid.
    5.4 g (20 mmol) of 4-oxycyclophosphamide and 5.2 g (20 mmol) of cyclyhexyl ammonium-3-mercaptopropanesulfonate are dissolved in 100 ml of water, mixed with a small amount of trichloroacetic acid and left to stand for 1 day. at 0 ° C. After that, the reaction mixture is evaporated in a vacuum, the concentrated residue is passed through a cation exchange column filled with sodium ions, the eluate is evaporated in a vacuum, the residue is dissolved in dry ethanol, filtered and precipitated with ether.
    Vpsod 5.5 g (63% of theory), so pl. 7-5-79 ° C, refraction value O, 64 elution liquid: ethyl acetate — iso-propanol: 1 N acetic acid C5: 3: 2),
    74
    Example 8, Sodium salt of 2- 2- (bis) -2-chloroethyl (2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thio1-ethanesulfonic acid, 1.6 g (5 mmol ) 2- (bis) -2-chloroethyl- (amino) -4-ethoxytetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide and 0.8 g (5 mmol sodium-2-mercaptoethanesulfonate in 10 NP dimethylformamide, mixed with traces of trichloroacetic acid and left to stand overnight at -25 C. Immediately thereafter and the reaction mixture is added 20 ml of ether. The residue is filtered off with suction after 20 hours at the same O, washed and dried.
    . Yield 1.5 g (71% of theory), So pl. 145-150 C (decomp.), Refraction value: 0.56. ,
    Example 9. (bis) -2-chloroethyl (amino) -2-oxo-tetrahydro-2H-1, 3,2-oxazaphos forin-4-yl-thio} - ethanesulfonic acid.
    0.8 g (3.0 mmol) of 4-oxycyclophosphamide in 3 ml of water is mixed while cooling water with ice with 420 mg (3.0 mmol) of 2-mercaptoethanesulfonic acid. After 1 hour, evaporate under high vacuum and crystallize.
    Output 1.1 g (92% of theory), so pl. 75-78 s.
    Example 10. (bis) -2-Chloroethyl (amino) -2-oxo-tetrahydro-2H-1,3,2-oxase aphosphorin-4-yl-thio-ethanesulfonic acid.
    2.0 g (4 mmol) of cyclohexyl ammonium-2- 2- (bis) -2-chloroethyl {amnno) 2-ox-so-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thioethanesulfonate dissolved in a small amount of water and passed through a cation-exchange column filled with hydrogen ions, while cooling to 4 ° C. The eluate is immediately dried by freezing and recrystallized from dimethylformamide / chloroform.
    Output 1.2 g (75% of theory), so pl. 75-78 ° C, refraction value: 0.58 elution liquid: ethyl acetate-propanol: 1N. acetic acid (5: 3: 2).
    Example 11. The ammonium salt of 2- 2- (bis) -chloroethyl (amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thio-ethanesulfonic acid.
    720 mg (1.8 mmol) (bis) -2-chloroethyl (amino) -2-oxotetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thio 5 1
    α-ethanesulfonic acid is dissolved in a small amount of water, neutralized with ammonia and mixed with 4 ml of acetone. The reaction solution is left to stand overnight at -25 ° C. The crystallisate is isolated and recrystallized from methanol / acetone,
     Primer 12, Cyclohexylammonium salt of (bis) -2-chloroethyl (amino) -6-methyl-2-oxo-tetrahydro-2H -1,3,2-oxazaphosphorin-4-yl-thio-ethane sulfonic acids.
    1.45 g. (5 mmol) 2- (bis) -2-chloroethyl (amino) -4-hydroxy-6-methyltetrahydropho-PO-2H-1,3,2-oxazaphosphorin-2-oxide and 1, 2 g (5 mmol) of cyclohexylammonium -2-mercapto ethanesulfonate is dissolved in 5 ml of water and 5 ml of acetone, acidified with trichloroacetic acid and left to stand for 20 hours at 0 ° C. Directly thereafter, the filtrate is evaporated gently in vacuo, the residue is added twice to acetone and evaporated. Again the residue is dissolved in acetone, cooled with ether, washed with ether and dried.
    Output 1.4 g (56% of theory), so pl. 120-125 C, (decomp.), BG 0.61.
    Example 13. Sodium salt of 3- 2- (bis) -2-chloroethyl (am: yno) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thio -2 methyl propanesulfonic acid you.
    27 g (1 mmol) of 4-oxyphosphamide and 192 mg (1 mmol) of sodium-3-mercapto-2-methy-1-propanesulfonate are dissolved in 4 ml of water, mixed with traces of trichloroacetic acid and left to stand for 20 hours About C. After evaporation in vacuo, the residue is dissolved twice in dry ethanol and then evaporated and then precipitated in an alcohol / ether mixture.
    Yield 420 mg (86% of theory), Rf 0.61. .
    Example 14o Sodium salt of 6-2 (bis) -2-chloroethyl (amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thio-hexanesulfonic acid.
    277 mg (1 mmol) of 1-oxycyclophosphamide and 220 mg (1 mmol) of sodium-6-mercaptohexane sulfonate, together with traces of trichloroxypercic acid, are dissolved in 4 ml of water and left to stand for 20 hours. Immediately after this, the reaction mixture was carefully evaporated in vacuo, the residue was twice dissolved in dry ethanol and
    181676
    evaporated again. The residue is taken up in alcohol and precipitated with ether.
    Yield 350 mg (70% of theory), Rf 0.58.
    Example 15. The cyclohexylammonium salt of (2-chloroethyl) - 2- (2-chloroethyl) -carboxy-2-oxy-tetrahydrop Q-2H-1,3,2-oxazaphosphorin-4-yl-thio - ethanesulfonic acid.
    fO 277 mg (1 mmol) 3- (2-chloroethyl) -2- (2-chloroethylamino) -oxytetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide and 240 mg (1 mmol) cyclohexylammonium- -2 -mercaptoethanesulfonate is dissolved
    15 in 4 ml of water, mixed with traces of trichloroacetic acid and left for 20 hours at 0 ° C. The reaction solution, evaporated in vacuo, is twice dissolved in ethanol and again evaporated. Immediately thereafter introduced into ethanol and precipitated with ether .
    Exit 340 mg (68% of theory), so pl. 115-120 ° C (decomp.), Rf 0.56. Example 16, Cyclo logexam25 monium salt of (2-chlorostil) -2- (bis) -2-chloroethyl (amino) -2-oxo-tetrahydro-2P-1,3,2-oxazaphosphorin-4-yl-thio - ethanesulfonic acid.
    340 mg (1 mmol) 3- (2-chloroethyl; 030 -2- (bis) -2-chloroethyl (amino) -4-hydroxy-tetrahydro-2H-, 3,2-oxazaphosphorin-2-oxide and 240 mg (1 mmol), cyclohexylammonium-2-mercaptoethane sulfonate in 2 ml of dimethylformamide is mixed with traces of trichloroacetic acid and kept for 2 days at -25 ° C. Immediately after this, the reaction mixture is treated with a 20-fold amount of ether, the precipitated precipitate
    40 washed and dried.
    Output 400 mg (71% of theory), so pl. 102-107 C (decomp.). Rf 0.63.
    Example, 17, In accordance with the described examples, a 45 BUT compound was obtained, where R, IB - CX-CH CH; RJ-H; tchpl. 132-134 C.
    Example 18. The salt of cyclohexyl-silumin 3- .- (bis) -2-chloroethyl (amino) -2-oxotetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thio -2-mercaptopro- Pansulphonic acid.
    1.39 g (5 mmol) of 4-oxycyclo-losfoamide and 1.44 g (5 mmol) of the salt of cyclohexylamine 2, 3-dimercaptopropane-sulfonic acid are dissolved in 10 ml of ethanol, acidified with trichloroacetic acid and left for 2 days at about C. After that, precipitated with ether.
    50
    55
    7 1 after 20 h, decant and the remaining oil is dried in the vacuum. Oil freezes.
    Output 1.8 g (77% of theory), so pl. above 70 C (decomp.).
    Example 19. The cis-sodium salt of (bis) -2-chloroethyl (amino) -2-oxotetrahydro-2H-1,3,2-oxazaphos forin-4-yl-thio-ethanesulfonic acid.
    2.8 g (10 mmol) of 4-oxycyclophosphamide in 10 ml of acetone is mixed with 1.3 g (8 mmol) of sodium-2-mercaptoethane sulfonate in 2 ml of water and left for 3 hours at 0 ° C. Immediately thereafter, the reaction mixture was evaporated in vacuo at 25 ° C, the residue was added to dry acetone and mixed cold with dry ether until cloudy. Upon evaporation of the solution in vacuum, a precipitate is formed.
    Output 1.5 g (44% of theory) of the cis isomer, so pl. 83-85 ° C. As a result of recrystallization from acetone, a product is poorly soluble in acetone.
    Example 20. The salt of guanidine 3- 2- (bis) -2-chloroethyl (amino) -2-oxo-tetrahydro-2H-1,3,2-oxazaphosphorin-4-yl-thio 3-propanesulfonic acid.
    14 g (50 mmol) of 2-oxycyclophosphamide and 11 g (50 mmol) of 3-mercapto-propane sulfonic acid, the guanidine salt is dissolved in 100 ml of ethanol, acidified with trichloroacetic acid and maintained at 0 ° C. After 20 hours, 50 ml of ether are added. The crystallized acid is sucked off after another 20 hours, washed. And dried.
    Output 18.5 g (78% of theory), so pl. 128-132 seconds (decomp.).
    Example 21. Analogously to Example 1, 1.1 g (4 mmol) of 4-oxycyclophosphamide in 15 ml of acetone was mixed with a solution of 0.96 g (4 mmol) of 2-cyclohexylamine salt of mercaptoethanesulfonic acid in 4 ml of water and followed by trichloroacetic acid. the acids were heated to 30 ° C for 2 hours. Then cooled to 4 ° C, aspirated, stirred up crystallized glass with a small amount of solvent, sucked away, additionally washed with ether and dried using phosphoric anhydride in a vacuum.
    Output 1.2 g (60% of theory), so pl. 139-142 ° C (decomposition).
    The data of elemental analysis are presented in the table.
    678
    The compounds according to the inventive method can be used in the treatment of cancer diseases and in suppressing immunity. They have a strong antitumor effect, have high activity when administered parenterally or orally, as well as a slight overall toxicity. They have in vito high carcinotoxic selectivity and in vitro high cytotoxic specificity.
    To establish the carcinotoxic effect, substances were tested on animals in a number of tumors of various chemoresistance. For evaluation, a probit analysis was determined from the relationship between the logarithm of the dose and the frequency of the cured and surviving experimental SEVENTIONS, the average effective dose — LС 50 (mg / kg). As a comparative substance, which by chemical structure is close to the products according to the invention. , it was a cyclophosphamide trading compound
    In the case of lymphatic leukemia 1 5222 rats (strain B IX), this average effective dose for a single intravenous injection on day 5 of inoculation of leukemia was for the products in accordance with the invention, as well as for cyclophosphamide 1.5 mg / kg
    With the chemosensitive Joshida tes Karzinosarkom (line 13) rats (strain) Spragne Davley, this dose of LC 50 for the products according to the invention, as well as for the comparative substance cyclophosphamide, was 1 mg / kg.
    For in vitro cytotoxic specificity studies, about 3–10 sterilely obtained chemoresistant Joshida – Aszites – Karzinosarkams cells (line AH13, ASTA strain) were incubated with increasing concentrations of products according to the invention at 37 ° C for 2 hours and after repeated washing implanted into the abdominal cavity of the test animals. From the ratio of the logarithms of concentrations and the number of developing tumors, the average cytotoxic doses of CE 50 (mg / ml) were determined using probit analysis. Under these conditions, experience CE 50 pro 913
    The products according to the invention are between 5 and 5 mg / ml,
    The determination of intravenous toxicity was carried out on a rat in accordance with the international formulation of the Miller and Tainter experiments.
    Toxicity is indicated as LDj-g in mg / kg. The LD50 is the dose at which 50% of experimental animals die. The test results for examples LDjo are as follows.
     Example No. for intravenous
    administering rat
    250 300 300 300

    36.0 36.0
    36.0
    25.54
    25.84 25.84 27.47 25.54 26.94 26.94 25.84 37.35 29.27 32.57 36.0
    6.45 6.45
    6.45 4.28
    5.30 5.30 4.61 4.28 4.77 4.77 5.3-0 6.66 4.91 5.47 6.45
    8167
    300 300 300 300
    Cyclophosphamide185
    For the products prepared according to the invention, the lethal dose of bDjg for a single intravenous administration is about 300 mg / kg. The average lethal dose of piclophosphamide determined by comparison with intravenous administration is 185 mg / kg.
    Thus, creeping products have approximately 20% less acute toxicity or, with TajcoM, the same curative effect, respectively, a greater therapeutic breadth.


    35.8 35.8
    35.8
    25.1
    25.7
    25.7
    27.1
    25p1
    26,8
    26,8
    25.7
    37,528, 9
    32.1
    35.6
    6.5 6.5
    6.5
    4.2
    5.3 5.3 4.6 4.2 4.8 4.8 5.3 6.8 4.8 5.4 6.4
    8.4 8.4
    8.4 6.3 10, 1 10.1 31.7 6.3 6.7 6.7 10.1 8.1 6.1 6.1 5.5 8.2
    Editor Y. Sereda
    Compiled by V. M Kusheva
    Tehred M. Morgenthal Proofreader A, Zimokosov
    Order 2441/58 Circulation 347Subscription
    VNIIPI State.Committee of the USSR
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, st. Design, 4.
    权利要求:
    Claims (1)
    [1]
    The method of producing oxazaphosphorus-4-thioalkanesulfonic acid or its neutral salts of the general formula
    where K, and - hydrogen or C1-CH g CH 2 ~; K g - C1 CH g CH g -;
    X - C 2 -C 5 - alkylene or mercaptopropane;
    Υ - cyclohexylammonium, sodium, ammonium or guanidine,
    About tl and tchayuschiy with I 'the fact that 4-hydroxy-oxazaphosphorine or 4-alkoxyoxazaphosphorine of the formula
    where H ,, E g and B 3 have the indicated meanings; Ζ-Η hydrogen or C, -C 4 -alkyl, is reacted with a compound of the formula
    Н5Х - 50 "Υ + ,
    where X and Υ have the specified values in the environment of the solvent at a temperature of + 30 ° C - minus 25 ° C, if necessary in the environment of trichloroacetic acid, followed by separation of the target product or followed by neutralization of the obtained product with an appropriate base or transferring the obtained ammonium salt to an alkali metal salt ion exchanger.
    with
    with
    Ϊ318Ϊ67 AZ
    1 '13
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE1645921C3|1966-07-11|1978-10-12|Asta-Werke Ag Chemische Fabrik, 4800 Bielefeld|2-Oxo-13,2-osazaphosphorinane, process for their preparation and pharmaceutical preparations containing them|
    DE2107936C3|1971-02-19|1978-06-08|Asta-Werke Ag Chemische Fabrik, 4800 Bielefeld|Alkyl sulfonic acid esters of 2-oxo-13,2-oxazaphosphorinanes and pharmaceutical preparations containing them|
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    FR2968662B1|2010-12-10|2013-11-22|Roussy Inst Gustave|NOVEL PRE-ACTIVE OXAZAPHOSPHORINE DERIVATIVES, USE AND METHOD OF PREPARATION|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE3111428A|DE3111428C2|1981-03-24|1981-03-24|
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