• 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:
    METHOD OF OBTAINING DIHYDROCHLORIDES DERIVATIVE DI-0-H-APKSH1GLYCERINES. CHg-v CH-CH CH-OR where one, from Y and Y means h "O CHNHH and a different OK, R" and R each means Cg- or C.jj-alkyl, characterized in that the compound of the formula groove is 7, CH-Z iCHf OR, where one of Z and Z means CO h CX CN a, another OC, where R-1 has the indicated values, is subjected to catalytic hydrogenation in the presence of bo ry to Rene nickel followed by conversion of the base obtained to the dihydrochloride.
    公开号:SU1122220A3
    申请号:SU792764751
    申请日:1979-05-14
    公开日:1984-10-30
    发明作者:Ричард Краска Аллен
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of di-hydrochloride derivatives of di-0-n-alkylglycerol derivatives which can be used as a nonspecific stimulus for torocellular intermediate immunity. In particular, these compounds are suitable for stimulating antitumor activity, and could also be used in combination with known immunological substances as stimulators during vacuuming. The use of biological vaccines, synthetic levamisole, is known as an immunostimulator for Cl J. However, these compounds do not exhibit cytotoxicity to tumor formation. Known derivatives of glycerol of the formula R.-X-CH ,, i CH-2- / P1 -6. R —Y — CHj where R, R is alkyl, alkaryl, aryl cycloalkyl, substituted nitrogapogengroup aryl, X, Y, Z is O, S, SOj, 0 is alkyl, with C = 6 atoms; B-di (lower) alkylamino. piperidino, morpholino pyrolidino, lower) alkylpyr olidino-, N-alkyl piperazino, which is obtained by reacting 1,3-di (substituted) 2-propanol in the form of sodium salt with tert. aminoyl halide. These compounds are used as anesthetics in medical practice C21. The aim of the invention is to develop a method for producing di-hydrochloride derivatives of di-0-n-alkylglycerols with a wider spectrum of action compared with the known Cl. This goal is achieved in that according to the method for producing dihydrochloride derivatives of di-0-n-alkylglycerols of the general formula G CH, I cn - v CHfORi de one. From P - yi means O (CHgNHg and another OR R, and f each means Cg- or C, d-alkyl, a compound of the formula and .CHH-2 CH-Z CHj-OR where one of the 2 and 2 means O (and the other OR, where X has the indicated meanings, is subjected to catalytic hydrogenation in the presence of Rene nickel followed by translation of the obtained base to dihydrochloride. The proposed method is based on the reaction of catalytic reduction of the compound cyanide containing compound in the presence of Rene L3J nickel. Example 1. 4-Cyano-1- | 2,3- (di-n-decyloxy) -n-propyl 4-ennp-pipervdii. 1,2-Di-0- 1G-dec l- (3-0-decyl) -3-0- (p-tosyl) -glycerin (20 g, 0.0189 mol), obtained from 1,2-di-) tn-decyl-3-glycerol chloride and 4-cyano-4-phenylpiperidine (4.5 g, 0.024 mol) is combined and heated to 20 minutes. Water (50 ml) and ether (100 ml) are added to the cooled product. The ether layer is separated and washed with a saturated sodium bicarbonate solution (2 100 ml) with 1N hydrochloric acid solution (100 ml), water (2-100 sp), with a complete solution of bicarbonate n Atri (100 ml) and water (100 ml). Then the ethereal solution is dried over magnesium sulphate, treated with activated charcoal, filtered and concentrated to an oily product (10 g). The oil is absorbed by silica gel, which is then washed with hexane (3 200 ml), top with ol (3 200 ml), chloroform (3 200 ml) and ethyl acetate (3 200 ml). After concentration of ethyl acetate, a pure cyano compound is obtained: oil, an infrared spectrum (exact data) is 2220 cm. Example 2. 4-Aminomethyl-1-D, 3 (di-n-decyloxy) -n-propyl) NILE-piperidine. The nitrile prepared in Example 1 (1.2 g; 0.0022 mol) was dissolved in CHz-CH-CH-iJX 2HCl. Hjo
    OSMN-YOSiNi
    Found,%: C 66.46; H 10.56) N 4.43
      2HCt 3/4
    - CH2UH2
    (Shg-chn sn2- | (X - nsm / jno
    1yn-f y
    OSVNp OCgHn
    from m.p. 176-178 s.
    Found,%; C 65.27 {H 9.90 N 4.95
    ug-ns
    CH-K X 2HC1 J // fH20
    I - Ph H2 | SyuO-en2 with so pl. 190-192 C. Found, Z: C 66.70; H 10.20, N 4.27. 2HC1 -3/4 H O Calculated, Z: C 66.53; H 10.78; N 4.43. Example 3. Reduction of tumor development on the sarco 180E model Six 106-180 kpetok 5-6 days old were intraperitoneally injected into six DM-1 males of mywei (2025 g). One day after the tumor was inoculated, the test compound {0.1 ml) was administered to the mice as a water-in-fat emulsion medium (for an Intralipid-type medication (Cutter Leibortriz) in the required dosage.
    CH211H2.
    Calculated XT; C66.59; H 10.78; N4,4 Similarly obtained dihydrochloride, formula
     Cj HjjOjN 2HC1 - 1/2 H, 0,
    Calculated,%: C65,23; H 10.42; N4.90; as well as the dihydrochloride id of formula-; 0 4 ethanol (50 ml), then the resulting solution is saturated with gaseous ammonia and hydrogenated under a pressure of 3.51 kg / cm for 3 hours using a skeletal nickel catalyst according to Reneus (0.7 g). Next, the reconstituted mixture is filtered, and the filtrate is concentrated under reduced pressure to an oil (1.1 g). This oil is chromatographed over silica gel, washed from the adsorbent with a mixture of benzene: ethanol, and converted into hydrochloric. salt and recrystallized from ethyl acetate, which gives pure hydrochloride salt (0.32 g, yield 24%); m.p. 138-140 0 Then follow up until death (within 40 days). The results are expressed in an increasing percentage of the time to live (% of ERW), determined by the formula, the average recovery of treated Z ZVW mice. . too, the average survival of the untreated controls was conducted using the for-, Tn compounds.
    where r- and
    Rj means
    results are obtained
    in tab. one.
    Example 4, Assessment of intraperitoneal activation of a macrophage.
    The mice are given intraperitoneal injections with a test solution of the test compound. Macrophages expound after 72 hours by intramuscular injection of 3 ml of 8% fetal calf serum - 92% RMI 1А60 medium (Grand Island Bio-Edichel K, New York) (leAOjjFCSg) + 5 ml heparin. The temperature of the whole medium is maintained at 37 ° C, the cavity is washed for 1-2 minutes, opened and the entire intraperitoneal fluid is removed with a sterile siliconized pipette and transfer to a plastic tube held in ice. Macrophages are counted using a hemocytometer and adjusted to a concentration of 1.5 using 1640
    Then the cells are placed in plates with numerous cells (1.5 10 cells in a cell) and incubated for 1-2 hours at 37 ° C. in an atmosphere of 5% carbon dioxide. The supernatant is discarded, and the cells are washed once with medium; macrophages stick to the bottoms of the cells. 1210 cells (grown from serous liquid transistritis in the peritoneal cavity of tiny TWO, approximately 5 days after innotation) are suspended in 1640.2 FCSj, then 1 mp of 1-10 cells / MP is added in each: cell and incubated at 37 ° C for 24-36 h in an atmosphere containing 5% dioxide. carbon. The cells then pulsate 3H-Tdr (1.0 Ci / ml, Amersham / Searlees) for 6 h at. The supernatant is separated and discarded using a Reeve Angeel filter to collect the cells. Cells are washed five times with brine. The filter discs are poured and placed in co-sedation vessels with LSC scintillating fluid (5.0 g PPO and 0.2 g POROP7 l toluene Yorktown Research). Samples were taken for 2 minutes using a Beekman tS-250 meter. When performing this procedure using compounds of the formula
    AI About CH
    RO-O-CH
    The results are shown in Table. 2
    Example 5. Evaluation of monocyte activity in peripheral blood.
    The rats were injected intravenously with the test compound. Saline solution is injected with control. Monocytes are harvested after 72 hours by taking 2 MP of blood into the EDTA tube and diluting with 2 ml of saline. The resulting mixture was thoroughly divided into layers with 3 ml of LSM (Bionetics lymphatic separation medium) and centrifuged at 800 rpm for 40 minutes at room temperature. A pipette is used to collect a cloudy central layer containing monocytes and lymphocytes. These cells are washed twice with Hanks' balanced salt solution, re-suspended in 164052FCSj, placed in gulls with cells and incubated with
    in 5% carbon dioxide for 1.5 hours. The cells are then vigorously filled with a medium to remove the adherent cells. The remaining monocytes are reintroduced into the medium and L 1210 cells are added in accordance with the procedure described in Example 4. The cells are pulsated with 3H-Tdr and counted in a scintillation counter.
    Using this procedure, it was established that 1.25 mg / kg of 4-aminomethyl- (2, 3-di-y-decyloxy) -n-propyl-4-phenylpiperidine provide 80% inhibition of DNA synthesis.
    EXAMPLE 6. Testing the validity of the VII of the most prescriptive. esters as an adjuvant for vaccine inhibition of hemagglucination.
    Influenza virus, interacting with an erythrocyte, causes hemagglutinization. If an antiviral antibody is present in the serum sample, the interaction of the virus with the crastat by the blood cells, resulting in their adhesion, is prevented. Thus, the lack of agglutination indicates the presence of antiviral antibodies. The determination of the hemagglutination titer 7 provides measurement of the level of antibodies. The test compounds were introduced into the formulation in the required dosage by dissolving in 0.3 ml of ethanol, after which 0.1 MP Tween-80 was added, and the mixture was added to 4.6 MP Intralipid (Cutter Leibortriz). Suitable media are also prepared without the addition of the test compound. The fluogen influenza virus (Park Davis and K) is removed from each of the media in order to obtain 250 CCA antigen per 0.5 MP of volume for injection. One group of female Guinea Pigs Hartgley (Kamm Leibortriz) was injected intramuscularly with 0.5 MP of the medium containing Fluogen and the test compound. A control group of guinea pigs was injected with a medium containing Fluogen, but without the test compound. 30 days after the primary sensitization, the animals4 are additionally administered intramuscularly the same antigen, the same with which they were initially immunized. Animals are bled by puncturing the heart muscle several times after initial sensitization. Separate the serum using the Korvac serum separation tube (Corning Glass Works) and store it at (-20) C until titrated during the haemagglutination test. Test serum treated 0.011 g of potassium iodide solution to remove non-specific serum factors that inhibit agglutination are poured into serial 2-fold solutions in 0.025 ml wide containers in cells | pp Scientifically Company, New Haven, Conicticut, USA (type ISHMRC-96), with 0.025 mp O, O1-m phosphate-buffered saline (FBI), at pH 7 Suspension of the test virus containing hemagglutin units by 0.025 FBI MP, added to cazidu cell. Also include a cell containing only the FBI, and control cells with antigen (FBI and virus antigen). After the plates were incubated at an external temperature for 30 minutes, each cell of the cell was added with 8 LYuYT 0.05 ml of red blood cells of the CK Film washed with 0.5% saline solution (Flow Leibortriz, Rockville, Maryland, USA). Incubation is continued until the control cell shows normal precipitation. Serum obtained from normal guinea pigs and treated with periodate include to assess the level of inhibition of nonspecific agglutination remaining in the test serum formed by potassium iodide. The haemagglutination inhibition titer is defined as the highest degree of dilution at which a completely inhibited hemagglutination takes place, taking into account the amendment to non-specific inhibition. The results obtained with the tested 4-amino-methyl-1-2,3- (di-n-dicidoxy) -n-propyl A-phenylpyridine are shown in Table. 3. The highest titer of inhibition of hemagglutination is observed after vaccination in those animals that have tested the compound for therapeutic purposes, indicating the activity of the compound as a stimulant during vaccination. The results are consistent with the results observed in each animal in the respective groups. Example 7. Cytotoxicity test against melanoma B-16 cells of a compound of the formula Ph CHiNH-j foHzt-O-CH CioH2i- (bCHQ and levamisole) was carried out as follows. Different groups of healthy mice were treated (intraperitoneally) with compound CP-46.6b5 with the norms use in the range of 0.625–20 mg / kg live weight, levamisole with application rates in the range of Oj1–10 mg / kg live weight, or not treated (control). After 72 h, mice were boiled with exudate cells and tested in vitro for ability to cytotoxicity (i.e., ability to destroy) by rel. sheniyu to cells of B-16 melanoma. Klet91122220
    ki collected from mice treated with levanisole did not show cytotoxicity compared to cells collected from the control group of mice. Cells collected from mice treated with CP-46,665 showed the following cytotoxicity relative to the control group: R.R. Before antigen
    O .0
    O 10 10 10 10 10
    Fluogen
    Sh
    Cytotoxicity,
    %
    0.625
    A 31 64 59 65 1.25 2.5 5 20
    Table 1
    40
    40
    160
    thirty
    ten
    ABOUT
    thirty
    ten
    80
    80 100
    160
    80
    1280,640
    2360% of ERW at a dose, mg / kg 0.251 114I 16 113109154 (1) 192 (4) 127 (1) 139 (1) HO108 a, mg / kg Inhibition of DNA synthesis of incubated U 1210 cells. Leuke bt (in vitro), Z 1.2576 0.62594 0.31356 The titer of inhibition of genaglutination Day I 30 1 44 T 65 Table 2 Tb l and c a 3
    n112222012
    Continued table. 3
     Day after primary sensitization (anaphylaxis). Repeated measurement after 30, 44, 65 days after primary sensitization
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING DI-O-H-APKYLGLYCERIN DERIVATIVE DIHYDROCHLORIDES OF THE FORMULA.
    • 2 CH-Ύ ί CHg-OR, where one of Y 1 Y 2 means
    Ph ch 2 nh 2 and the other is ORj, and R 2 each means Cd or C 1o ~ alkyl, characterized in that the compound of FORMULA _ z 1, I g , cn-g g ι CHfORi where one of Z 1 and Z 2 means
    Ph.
    N
    CN and another OR ^, where R 2 has the indicated values, are subjected to catalytic hydrogenation in the presence of Raney nickel, followed by conversion of the obtained base to dihydrochloride.
    SU and , 1122220>
    1 1122220 2
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    同族专利:
    公开号 | 公开日
    DK102479A|1979-11-16|
    IN150574B|1982-11-13|
    NO791604L|1979-11-16|
    EG15252A|1986-09-30|
    JPS6139301B2|1986-09-03|
    YU41156B|1986-12-31|
    ATA356179A|1983-03-15|
    DE2919514C2|1982-06-03|
    DD144540A5|1980-10-22|
    CA1105935A|1981-07-28|
    FR2426039A1|1979-12-14|
    NO151285C|1985-03-13|
    KE3354A|1983-12-16|
    ES480565A1|1980-08-16|
    FR2426039B1|1983-12-16|
    HK13584A|1984-02-24|
    IL57268D0|1979-09-30|
    IT7922664D0|1979-05-14|
    HU180283B|1983-02-28|
    AR221724A1|1981-03-13|
    DE2919514A1|1979-11-22|
    GB2021580B|1982-09-08|
    IL57268A|1982-05-31|
    DK149946C|1987-06-15|
    GR72419B|1983-11-03|
    NO151285B|1984-12-03|
    FI791531A|1979-11-16|
    JPS55378A|1980-01-05|
    GB2021580A|1979-12-05|
    PL123910B1|1982-12-31|
    YU109479A|1983-02-28|
    IT1115217B|1986-02-03|
    JPS5924974B2|1984-06-13|
    GT197957869A|1980-11-04|
    PL215573A1|1980-07-01|
    LU81253A1|1979-12-07|
    FI69450B|1985-10-31|
    NL175524C|1984-11-16|
    AT372678B|1983-11-10|
    NL7903769A|1979-11-19|
    BE876229A|1979-11-14|
    SE7904216L|1979-11-16|
    CH639939A5|1983-12-15|
    AU513771B2|1980-12-18|
    NZ190444A|1981-05-29|
    AU4701679A|1979-11-22|
    JPS58131947A|1983-08-06|
    US4173641A|1979-11-06|
    DK149946B|1986-11-03|
    IE48229B1|1984-11-14|
    PH15256A|1982-11-02|
    SG65483G|1984-07-27|
    ZA792306B|1980-05-28|
    MY8500096A|1985-12-31|
    IE790938L|1979-11-15|
    PT69607A|1979-06-01|
    SE429966B|1983-10-10|
    FI69450C|1986-02-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
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    US4069223A|1977-05-02|1978-01-17|G. D. Searle & Co.|4-Aminomethyl-1--4-arylpiperidine and derivatives thereof|
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    US4310550A|1979-10-26|1982-01-12|Pfizer Inc.|Lipid amines formulated with fat or lipid emulsions as vaccine adjuvants|
    US4395394A|1979-10-26|1983-07-26|Pfizer Inc.|Use of lipid amines formulated with fat or lipid emulsions as vaccine adjuvants|
    JPS60105650A|1983-11-14|1985-06-11|Ono Pharmaceut Co Ltd|Glycerol derivative, production thereof and pharmaceutical containing said derivative|
    US4880626A|1985-01-18|1989-11-14|Mcmichael John|Immunotherapeutic methods and compositions for the treatment of diseases of viral origin, including acquired immune deficiency syndrome|
    JPH0588290B2|1985-12-27|1993-12-21|Nippon Steel Corp|
    US4842862A|1986-07-03|1989-06-27|International Minerals & Chemical Corp.|Immunostimulating agents|
    ZA899436B|1988-12-12|1990-08-29|Ciba Geigy|Piperidine derivatives|
    WO2005077963A1|2004-01-16|2005-08-25|Institut Superieur Agricole De Beauvais|Saccharide and itol derivatives having an o-alkyl group or an o-alkyl group and an o-n butanyl group, uses as medicines in tumoral or benign proliferative pathologies|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/906,260|US4173641A|1978-05-15|1978-05-15|Di-O-n-alkyl glycerol derivatives as immune stimulants|
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