• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    The invention pertains to derivatives of N-[4-(N-[2-amino-4(3H)-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6- ylmethyl]a mino)benzoyl]-L-glutamic acid of the formula: <CHEM> wherein R<1> is hydrogen, methyl, ethyl, or R<5>CO-; R<2'> and R<3'> are hydrogen or a carboxylic acid protecting group; R<4'> is hydrogen or an amino protecting group; and R<5> is hydrogen or alkyl and the configuration about the carbon atom designated * is L, which derivatives are antineoplastic agents, to their preparation and use, and to intermediates useful in their preparation.
    公开号:SU1581222A3
    申请号:SU874202827
    申请日:1987-06-26
    公开日:1990-07-23
    发明作者:К.Тейлор Эдуард；Питер Бирдслей Джордж；Сих Чуан；М.Хэмби Джемс
    申请人:Дзе Трастиз Оф Принстон Юниверсити (Фирма)；
    IPC主号:
    专利说明:

    Isobenzene relates to a method for producing new pyrido derivatives of 2,3-3 pyrimidine, which have pharmacological activity and which can be used in medicine.
    The purpose of the invention is a method for producing new pyrido 2, 3-d3 pyrimidine derivatives with higher antitumor activity.
    Example 1. N-f4- (2-acetamido-4 (3N) -oxopyrido 2, 3-d pyrimidin-6-ylmethyl) amino-benzoyl glutamic acid diethyl ester.
    A mixture of 800 mg of 2-acetamido-6-formyl-4 (3N) -oxopyri-, 3-d pyrimidine in a mixture of 55 ml of glacial acetic acid and 1.2 g of diethyl ether p- aminobenzoyl-1, α-glutamic acid. Then, 0.19 ml of the borohydride-triethylamine complex is added to the mixture. The mixture is stirred

    s
    for 40 min at room temperature and then maintained at 60 ° C for 10 min. The reaction mixture is cooled and concentrated in vacuo. The resulting residue is dissolved in 90 ml of methanol and the solution is filtered. The filter residue is washed with 20 ml of methanol and 360 ml of diethyl ether. The filtrates are combined and evaporated to dryness. The residue is passed through a silica gel column (97: 3, chloroform: methanol) and 1.08 g of N-Ј4-N (2-acetamido 4 (ZN)) diethyl 2,3-d pyrimidine-6-ylmethyl) amino ether are obtained. beneroyl} -b glutamic acid,
    PRI mme R 2. Diethyl ether - (2-acetamido-4 (3N) -oxo-3, 6, 7.8 - tetrahydropyrido 2,3-d pyrimidine-6-ylmethyl) amino Zbenzoyl-L-glutamino - howl acid.
    A mixture of 340 mg of N-f4-N- (2-acetylamino-4 (3N) -oxo-pyrido 2, 3-d pyrimidin-6-ylmethyl) amino-benzoyl lL-glutamic acid diethyl ester in 80 ml of methanol and 40 ml glacial acetic acid is placed in a hydrogenation vessel (Adams). 55 mg of catalyst (platinum oxide) is added and the mixture is hydrogenated at 4.2 atm (60 pounds / sq. Inch) and room temperature for 15 minutes. The catalyst is filtered off and the filtrate is concentrated in vacuo. The residue is passed through a silica gel column using a mixture of chloroform and methanol (97: 3- 95.5: 5) as an eluting solvent, and fractions of 20 ml are collected. Fractions 62-73 contain by-product 2-acetylamino-6 methyl -4 (3N) -ox-sopirido 2,3 pyrimidine. Fractions 74-88 contain 15.4 mg of the desired product N-4-4-N- (2-acetylamino-4 (3N) oxo-5,6,7,8-tetrahydropyrido 2, 3-d pyrimidine 6-diethyl ether). ylmethyl) amino benzoyl jL-glutamic acid.
    PRI me R 3. N - ((2-aue-tamido-4 (3N) -oxo-5,6,7,8-tetrahydropyrido 2, 3-d pyrimidin-6-ylmethyl) amino benzoyl- L-glutamic acid.
    20 mg of N- {4-ЈN - (2-acetylamino-4 (3N) -oxo-5,6,7,8-tetrahydropyrido 2, 3-d pyrimidine-6- ylmethyl) amino benzoyl .VL-glutamic acid and 0.4 ml of 1N is added. water
    five
    0
    five . Q

    with
    five
    caustic soda. The mixture was stirred at room temperature for 96 hours and then 0.1 ml of glacial acetic acid was added. The methanol is removed in vacuo and the resulting residue is dissolved in 5 ml of water. This mixture is acidified with 0.16 ml of glacial acetic acid, and the resulting solid is separated by filtration, to give 6.0 mg of the product - (2-acetamido-4 (3N) -oxo-5.6, 7.8-tetrahydropyridor, C -d pyrimidine-6-ylmethyl) amino benzoyl | - L-glutamic acid.
    PRI me R 4. Diethyl ether .4-JN - (2-acetamido-4 (3N) -oxopyri-, 3-d} pyrimidine-6-ylmethyl) -Y-formylamino-benzoyl glutamic acid,
    A mixture of 25 ml of 98% formic acid and 4.9 ml (5.25 g, 51.5 mmol) of acetic anhydride is stirred at 25 ° C for 2 hours. To the resulting solution were added 2.43 g (4.5 mmol) of diethyl ether (2-acetamido-4 (3N) -oxopyrido 2, 3-d pyrimidin-6-ylmethyl) amino benzoyl-L-glutamic acid . This mixture is stirred at 55 ° C for 15 minutes and at 25 ° C for 1 hour. The solvent is distilled off under reduced pressure and the residue is triturated with diethyl ether. The solid residue is filtered off and recrystallized from isopropanol to give 2.0 g (78%) of N- {4-M ;-( 2-acetamido-4 (ZN) oxopyrido 2, 3 pyrimidine-6-ylmethyl) diethyl ester) - amino benzoyl (glutamic acid, mp: 180-182 ° C.
    PMR spectrum: 1.05-1.33 (m, 6H); 1.95-2.10 (m, 2H); 2.16 (s., NN); 2.49 (t., IH, J 7.36 Hz); 3.97-4.10 (m, 4H); 4.36-4.39 (m. 1H); 5.24 (m, 2H); 7.51-7.54 (m, 2H, AA BB 0} 7.84-7587 (m, 2H, AA BB); 8.21 (m, 1H); 8.82 (s., 1H ).
    Calculated,%: C 57.24; H 5.34; N 14.83.
    47H3oN6 ° “Found,%: C 56.94; H 5.11;
    N 14.57.
    EXAMPLE 5 Diethyl ether - (2-pivaloyl-amino-4-(3N) oxapirido-2,3 d pyrimidin-6-yl-methyl) - N1-formylamino benoyl 1-glutamic acid.
    Analogously to example 4, using diethyl ether (2-pivaloyl
    20
    amino-4 (3N) -oxopyrido 2,3-c1 pyrimy-6-ylmethyl) -Y-formylamins benzoyl j-L glutamic acid,
    Within one and a half hours in a hydrogen atmosphere at a pressure of 2.8 atm. (40 psi) Shake a mixture of 0.743 g (0.36 mmol) of N-f4-ЈN diethyl ester g (2-acetamido-4 (ZN) -oxopyrido 2,3-d Zpyrimidine-6- H ylmethyl) -M-formyl / benzoyl JL-glutamic acid and 230 mg of platinum oxide in 75 ml of a mixture of ethanol and acetic acid (2: 1). The reaction mixture is filtered through a zeolite and the filtrate is first evaporated at a slight reduced pressure, and then at high vacuum, maintaining the lowest temperature possible. The residue is dissolved in methylene chloride and passed through a chromatographic column with a chromatron, using a 5% solution of methanol in methylene chloride as an eluting solvent; as a result, 0.684 g (93%) of diethyl ether (2-acetamido-4 (3N) -oxo-5, 6,7,8-tetrahydropyrido 2, 3-d} pyrimidin-6-ylmethyl) -K is obtained β-formylamino benzoyl-J-L-glutamic acid, so pl. 188-190 ° C.
    Spectrum of the PNR (HaE280 - d) f: 2.08 (s., 3N); 2.42 (t, 2H, J 7.46 Hz), 2.78-2.91 (m, IH); 3.09-3.19 (m, 1H); 3.89 (d, 2H, J 5.98 Hz); 3.99-4.12 (m, 4H); 4.42 (m, 1H); 6.64 (m, 1H); 7.51-7.54 (m, 2H, AA BB1); 7.91-7.94 (m., 2H, AA BB); 8.61 (s, 1H); 8.74 (d, IH, J 7.32 Hz).
    Re-chromatographic central fractions. After removal of the solvent, the sample is triturated with diethyl ether and the solid is collected.
    Calculated,%: C 56.83; H 6.01; 45 N 14.73.
    din-6-ylmethyl) amino benzene j-L-glutaminoic acid, the proposed compound is obtained.
    Spectrum of PNR (Me2SO-d6) cG: 1.09-1.16 (m, 1H); 1.21 (s, 9H); 1.90-2.10 (m, 2H); 2.39 (t, 2H, J 7.37 Hz); 3.96-4.09 (m, 4H); 4.31-4.43 (m, 1H); 5.22 (s, 2H); 7.50-7.53 (AA BB, 2H); 7.83-7.86 (AA BB); 8.21 (m, 1H); 8.71 (d. 1H, J 5.87 Hz); 8.72 (m, W); 8.80 (s, 1H).
    Example 6 N-4-C.N - (2-pivaloyl-amino-4-(3N) -oxy-sopirido 2, 3 2-pyrimidin-6-ylmethyl) -N-acetylamino-benzoyl} glutamic acid diethyl ester.
    To a stirred suspension of 0.65 g of diethyl ester of N- {4-Ng- (2-pivaloylamino-4 (ZN) -oxopyrido 2,3-d J pyrimidine-6-ylmethyl) amino 6eH3onnj glutamic acid (1.1 mmol) and 0.22 g (1.2 mmol) of acetyl chloride was added to 0.22 g (2.2 mmol) of potassium bicarbonate in 10 ml of methylene chloride, cooled to 0-5 ° C. The reaction mixture is stirred at 0-5 ° C for 10 minutes and then allowed to take room temperature. After stirring for 45 minutes at room temperature, 50 ml of methylene chloride is added. The mixture was extracted sequentially three times (25 ml portions) with water, saturated sodium bicarbonate solution, and again with water. The aqueous extracts are combined and extracted with 50 ml of methylene chloride. The organic extracts are dried with anhydrous magnesium sulfate and filtered, and the solvent is distilled off under reduced pressure. 0.7 g of N-N- (2-pivaloyl-amino-4 (3N) -oxopyrido-2,3 pyrimidin-6-ylmethyl) -K-acetylamino-benzyl-yl-glutamic acid diethyl ester is obtained.
    thirty
    35
    40
     C27K34NtO
    lUj
    Found, l: C 56.60; H 5.90; N 14.43.
    PMR spectrum (Me2SO - d), J1: 1.10-1.17 (m, 6H); 1.22 (s, 9H); 1.88 (s., NN); 1.88-2.13 (m, 2H); 2.40 (t, 2H, J 7.46 Hz); 3.97-4.08 (m, 4H); 4.30-4.42 (m, 1H); 5.02 (s., 2H 7.34-7.66 (AA BB f, 2K); 7.83-7.86 (AA BB, 2H); 8.19 (m, 1H); 8.64 (m, W); 8.75 (d, W, J 7.39 Hz).
    Example. O - (2-acetamido-4 (3N) -oxo-5,6, 7,8-tetrahydropyrido 2, 3-d pyrimidine diethyl ether
    YU
    20
    YU

    YU

    thirty

    35

    40
     C27K34NtO
    lUj
    Found, l: C 56.60; H 5.90; N 14.43.
    Example8. D-ester of K- - - -pivaloylamino O-oxo-5,6,7,8-tetrahydropyrido 2, 3-d} pyrimidin-6-ylmethyl) -K-formylamino J6enzoyl-L-glutamic acid.
    This product is obtained in a similar way by reduction of N-Ј4-N - (2-pivaloylamino-4 (3H) -oxopyrido 2,3-d} pyrimidin-6-ylmethyl) -Y-formylamino benzoyl 1-glutamic acid diethyl ester, so pl. 152-153 ° C.
    IR spectrum (KBG) D cm-3369 and 3250 (NH), 1732, G637, 1605 ().
    Spectrum PNR (- dfr), G: 1.12 1.2 (m, 6H); 1.17 (s, 9H); 1.90-2.18 (m, AH); 2.43 (t, 2H, J 7.4 Hz); 2.80-2.94 (m, W); 3.12-3.20 (m, 1H); 3.86 (d, 2H, J - 5.59 Hz); 4.0-4.11 (m, AH); 3.90- 4.47 (m, 1H); 6.40 (m, 1H); 7.52-7.55 (AA1 BB, 2H); 7.92-7.94 (AA BB,
     2H); 8.62 (s., III); 8.75 (d, 1H, J 7.33 Hz).
    Found,%: C 58.53; And 6.60; 13.61.
    N
    C3 (H40NtO (,
    20
    25
    Calculated,%: C 58.81; H 6.58, N 13.72.
    EXAMPLE 9 N- {4-N- (2-Pivaloyl Amino-4 (3N) -oxy-with-5,6,7,8-tetrahydropyrido-2,3-d J Pyrimidine-6- HnMerrmi) -N-acetylamino benzoyl1-b-glutamic acid.
    To a solution of 0.64 g (1.03 mmol) of diethyl ether - (2-pivaloylamino-4 (3N) -oxopiteido 2,3-d pyrimidin-6-ylmethyl) -Y-acetylamino benzoyl-L-glutamic acid in 96 ml of platinum oxide are added to 40 ml of glacial acetic acid. The suspension is shaken under a hydrogen atmosphere (3.2 atm; 45 psi) for 2.5 hours, the mixture is diluted with 100 ml of methylene chloride and filtered through zeolite to remove the catalyst. The filtrate is evaporated under reduced pressure, and the residue is dissolved in 100 ml of methylene chloride, extracted twice (75 ml) with a saturated solution of Bi30
    Diethyl ether (0.092 g, 0.16 mmol N- {4-N - (2-acetamido-4 (ZN) -oxo-5,6, 7,8-tetrahydropyrido (2,3} pyrimidine-6-ylmethyl) - H-Formylamino benzoyl V-L-glutamic acid in 10 ml of 0.25 N aqueous sodium hydroxide solution was stirred at 25 ° C for 72 g and then the water was evaporated under reduced pressure. The residue was dissolved in 15 ml of water, the solution was cooled to O C and acidified with acetic acid. The solid is collected by filtration after 30 minutes and 0.046 g (60.5%) of (2-amino-4 (3N) -ox-co-5,6,7 9 8-tetrahydropyrido 2,3 -d J pyrimidine-6-ylmethyl) -formylamino benzoylU-L-glutamic acid lots.
    PMR spectrum (- dt) L1: 1.81-2.2 (m, AH); 2.33 (m, 3N); 2.73 (m, 1H); 3.1 (m, W, 3.85 (m, 2H); 4.39 (m, 1H); 6.2 (m, 1H); 7.49-7.51 (m, 2H, AA BB); 7.90-7.93 (m, 2H, AA BB); 8.59-8.62 (m, 2H).
    As described above, 200 mg of N-4-L- (2-pivaloylamino-4 (3H) -oxo-5,6,7,8-tetrahydropyrido 2,3-d. Diethyl ether). Zyrimidin-6-ylmethyl) 45
    sodium carbonate. Aqueous layers of repeat-40 N-acetylamino} benzoylJ-L-glutamine.
    The acidic acid is stirred for 72 hours in 5 ml of 0.2N sodium hydroxide. The reaction mixture is neutralized with 0.5 n. hydrochloric acid, cooled to 0 ° C, the resulting solid is collected, filtered, yields N-4-N- (2-amino-4 (3N) -oxo-5,6,7,8-tetrahydropyrido 2, 3-d } pyrimidin-6-ylmethyl) -K-acetylamino benzoyl jL-glutamic acid.
    Example 11. M- {4-L- (2-amino-4 (3N) -oxo-5,6,7,8-tetrahydropyrido 2, Zd pyrimidine-6-ylmethyl) -N - formylamino benzoyl lL-glutamic acid.
    A solution of 20 mg of (2-amino-4 (ZN) -oxo-5,6,7,8-tetrahydropyrido C2, 3 pyrimidin-6-ylmethyl) -amino J benzoyl} -b-glutamic acid in
    but extracted with 75 ml of methylene chloride, the organic layers were combined and dried with anhydrous magnesium sulfate. After removing the drying agent by filtration, the solvent was distilled off under reduced pressure, to obtain 0.54 g (84%) of N- - (2-pivaloylamino-4 (ZN) -oxo-5,6,7,8-tetrahydropyrido-2,6,7-tetrahydropyrido-2,3 ether) -6- ylmethyl) -i-acetylamino-benzoyl glutamic acid, which is further purified by recrystallization from ethyl acetate, m.p. 120-123 C.
    NMR spectrum (- df) f: 1.06-1.19 (m, 6H); 1.16 (s, 9H); 1.82 55 (s., NN); 1.84-2.17 (m, 6H); 2.42 (t, 2H, j 7.40 Hz); 2.80-2.94 (m, W); 3.17-3.23 (m, W); 3.68 (d, 2H,
    50
    0
    five
    0
    five
    five
    0
    J 5.59 Hz); 3.98-4.10 (m, 4H); 4.39-4.45 (m, 1H); 6.33 (s., III); 7.43-7.46 (AA BB, 2H); 7.90-7.93 HAA BB, 2H); 8.79 (d, 1H, J 7.33 Hz).
    Example 10. N - {- 4-N (- (2-aMH-but-4 (ZN) -oxo-5,6,7,8-tetrahydropi-, 3 pymidine-6-ylmethyl) -K - formylamino benzoyl -L-glutamic acid.
    Diethyl ether (0.092 g, 0.16 mmol) N- {4-N - (2-acetamido-4 (ZN) -oxo-5,6, 7,8-tetrahydropyrido (2,3} pyrimidine-6-ylmethyl) -H-formylamino-benzoyl V-L-glutamic acid in 10 ml of 0.25 N aqueous sodium hydroxide solution was stirred at 25 ° C for 72 g and then the water was evaporated under reduced pressure. The residue was dissolved in 15 ml of water, the solution was cooled to O C and acidified with acetic acid. The solid is collected by filtration after 30 minutes and 0.046 g (60.5%) of (2-amino-4 (3N) -ox-5,6,7 9 8-tetrahydropyrido 2, 3-d J pyrimidine-6-ylmethyl) -formylamino benzoyl-L-glutamine ki lots.
    PMR spectrum (- dt) L1: 1.81-2.2 (m, AH); 2.33 (m, 3N); 2.73 (m, 1H); 3.1 (m, W, 3.85 (m, 2H); 4.39 (m, 1H); 6.2 (m, 1H); 7.49-7.51 (m, 2H, AA BB); 7.90-7.93 (m, 2H, AA BB); 8.59-8.62 (m, 2H).
    As described above, 200 mg of N-4-L- (2-pivaloylamino-4 (3N) -oxo-5,6,7,8-tetrahydropyrido 2,3-d. Diethyl ether) 3, 5 pyrimidin-6-ylmethyl) 0, 5 ml of 97% formic acid is heated at 90 ° C for 1 hour. The solvent is distilled off under reduced pressure and the residue is triturated with diethyl ether. The solid is collected by filtration; 17 mg of N- {4-N -2-amino-4 (3N) - (oxo-5,6,7,8-tetrahydropyrido-6-ylmethyl) - -formylamino j6eH3oan jL- glutamic acid, which is further purified, the solution in O, 1 n. caustic soda and precipitated by the addition of glacial acetic acid.
    ten
    formylamino benzoyl 1-glutamic acid.
    Diethyl ether (1.44 g, 2.4 mmol) of N - (2-pivaloyl-amino-4 (3N) -oxo-5,6,7,8-tetrahydropyri, Z-d pyrimidine-6-ylmethyl) -N -formylamino benzoyl-L-glutamic acid is dissolved in 1N. caustic and the solution is stirred at 25 ° C for 72 hours. Activated charcoal is added and the suspension is stirred, filtered. The filtrate is acidified with glacial acetic acid and a white precipitate is Coll and Mere 12. No.-G4-Cm- (2-amino-15 is collected by filtration after 30 minutes
    Il l
    4 (3N) -oxo-5,6,7,8-tetragndi-pyrido 2, 3-d pyrimidin-6-ylmethyl) amino} benzoyl-L-glutamic acid.
    To 32 ml of a 5% aqueous solution of hydrogen chloride in methanol (prepared by diluting with methanol 2 ml of concentrated hydrochloric acid to a volume of 60 ml) were added 0.717 g (1.3 mmol) of N-G4O - (2-acetamido-4) ethyl ester ( MH) -oxo-5,6,7,8-tetrahydropyrido-2,3 pyrimidin-6-ylmethyl) -N-formylamino-benzoyl-L-glutamic acid (prepared in accordance with Example 2). The reaction mixture was stirred at 45 ° C for 18 hours. After cooling the reaction mixture to 25 ° C, 4 ml of 6N sodium hydroxide was added and the mixture was further stirred for 72 hours at
    20
    25
    thirty
    after cooling to С.C. 0.87 g (84%) of the same product is obtained, m.p. (decomposition) above 198 ° C.
    IR spectrum (KBG) Lmo (ks, cm-: 3460-2600 (NH and COOH); 1695, 1655 and 1600 (c-0).
    PMR spectrum (), f: 1.85-2.02 (m, 6H); 2.3 (t. 2H, J 7.4 Hz 2.81-2.88 (m, IH); 3.23-3.32 (m, 2H) 4.2-4.4 (m. , 1H); 5.92 (s. 2H); 6.34 (t., IH, J 5.28 Hz); 6.55-6.57 (m,
    2n, AA BB); 7.61-7.64 (AA BB, 2H);
    8.08 (d, IH, J 7.64 Hz); 9.7 (wide s., H).
    Example 13. A solution of (2-amino-4 (3N) -oxo-5,6,7,8-tetrahydropyrido 2, 3} srimidin-6-yl-methyl) aminoZbenzoyl-l-glutamic acid in an 15% mixture is prepared acetonitrile
    40
    45
    25 ° C. The solution is concentrated at a 35% and 85% solution of 0.1% triethylamine pressure. 20 ml is added and the mixture is acidified with glacial acetic acid, added dropwise. The mixture is kept at 0 ° C for 2 hours, the solid is collected and 0.485 g (88%) is obtained (2-amino-4 (3N) -oxo -5,6,7,8-tetrahydropyrido. 2,3-d J pyrimidin-6-ylmethyl) amino} benzoyl j-L-glutamic acid, m.p. (decomposition) 198 C.
    PMR spectrum (Me, SO - dЈ): 1.86-1.1 (m, 6H); 2.31 (t, 2H, J 7.2 Hz); p2.8-2.86 (m, 1H); 3.24-. 3.28 (m, 2H); 4.2-4.4 (m, 1H); 5.94 (s, 2H); 6.29 (s, 1H); 6.34 (t., IH, J 5.24 Hz); 6.56-6.58 (AA BB (, 2H); 7.62-7.65 (AA BB, 2H); 8.06 (fl ,, J 5.15 Hz); 9.7 (broad c. , W).
    This product can be obtained by the hydrolysis of diethyl ether N - (2-pivaloylamino-4 (3N) -oxopyridido 2,3 pyrimidine-6-ylmethyl) -K 50
    55
    on in acetic acid (buffer pH 7.0) at the rate of 1 mg of glutamic acid per 1 ml of solvent. This solution is injected into a chromatographic column of a 10 cm Cyclobond 1 phase using the same solvent. Set the flow rate of 1.10 ml / min with the registration of the UV spectrum at 254 nm.
    The first diastereoisomer, substantially free from the other, is obtained with a retention time of 45.58 min (isomer A). The second diastereoisomer, substantially free of the first, is obtained with a retention time of 48.32 minutes (isomer c).
    Studies have shown that the proposed compounds exhibit cytotoxicity in cell cultures. For example, with respect to CCRF-CEM, the human T cells produced in leukemia are set to the following values (for several samples), presented in Table 1,
    formylamino benzoyl 1-glutamic acid.
    Diethyl ether (1.44 g, 2.4 mmol) N - (2-pivaloylamino-4 (3N) -oxo-5,6,7,8-tetrahydropyri-, 3-d pyrimidine-6-ylmethyl) - N -formylamino benzoyl-L-glutamic acid is dissolved in 1N. caustic and the solution is stirred at 25 ° C for 72 hours. Activated carbon is added and the suspension is stirred, filtered. The filtrate is acidified with glacial acetic acid and a white precipitate.
    0
    five
    0
    after cooling to С.C. 0.87 g (84%) of the same product is obtained, m.p. - (decomposition) above 198 ° C.
    IR spectrum (KBG) Lmo (ks, cm-: 3460-2600 (NH and COOH); 1695, 1655 and 1600 (c-0).
    PMR spectrum (), f: 1.85-2.02 (m, 6H); 2.3 (t. 2H, J 7.4 Hz). 2.81-2.88 (m, IH); 3.23-3.32 (m, 2H) 4.2-4.4 (m, 1H); 5.92 (s. 2H); 6.34 (t., IH, J 5.28 Hz); 6.55-6.57 (m.,
    2n, AA BB); 7.61-7.64 (AA BB, 2H);
    8.08 (d, IH, J 7.64 Hz); 9.7 (wide s., H).
    Example 13. A solution of (2-amino-4 (3N) -oxo-5,6,7,8-tetrahydropyrido 2, 3} srimidin-6-yl-methyl) aminoZbenzoyl-l-glutamic acid in an 15% mixture is prepared acetonitrile
    and 85% solution of 0.1% triethylamine
    on in acetic acid (buffer pH 7.0) at the rate of 1 mg of glutamic acid per 1 ml of solvent. This solution is injected into a chromatographic column of a 10 cm Cyclobond 1 phase using the same solvent. Set the flow rate of 1.10 ml / min with the registration of the UV spectrum at 254 nm.
    The first diastereoisomer, substantially free from the other, is obtained with a retention time of 45.58 min (isomer A). The second diastereoisomer, substantially free of the first, is obtained with a retention time of 48.32 minutes (isomer c).
    Studies have shown that the proposed compounds exhibit cytotoxicity in cell cultures. For example, with respect to CCRF-CEM, the human T cells produced in leukemia are set to the following values (for several samples), presented in Table 1,
    These compounds are not inhibitors of dihydrofolate reductase; therefore, the cytotoxicity of the compounds can be altered by the addition of hypoxanthine. The cytotoxicity of true dihydrofolate reductase inhibitors in the same system can be changed only by the simultaneous addition of hypoxanthine and thymidine.
    Although the compounds are not dehydrofolate reductase inhibitors, they exhibit significant neoplastic activity when tested on living organisms. This is confirmed by the data presented in Table 2 for N- (4-CN - (2-amino-4- (3N)) oxo-5, 6, 7,8-tetrahydropyrido-2, 3-C1 pyrimidine -6-ylmethyl) amino-benzoyl} -b-glutamic acid.
    Such a high level of antineoplastic activity on living tissues is quite unexpected with such
    0
    low level of activity towards dihydrofolate reductase.
    As regards toxicity, these compounds are by definition antimetabolites and their therapeutic effect is based on interference with enzyme transformations. Therefore, these compounds are potentially toxic if their administration is not carefully controlled. As can be seen from the above data, toxicity can be reduced by adhering to dosage. Moreover, the toxicity of the proposed compounds is significantly lower than that of methotrexate used in clinical practice.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    / Method for Derivative Derivatives
    4 (3N) -oxo-5,6,7,8-tetrahydropyrido-- (2, 3-d) pyrimidine of general formula I
    R., is hydrogen or a group R5CO-, in which R g is hydrogen or C, is C-alkyl; means the L-configuration relative to the specified carbon atom,
    HNK
    CH0-N- / V- CONH-CH-CH-CHnCOORIЈ Ј O
    COOR2
    R. and have the indicated meanings;
    R and R3 are the same or the differences are C, -C-alkyl;
    R4 Sa-C-alkanoyl, 50
    Rl
    sn2- сgsokn-sn-sn2nn2soon soon
    35
    or their tautomeric forms, about tl and h aa-yu and with the fact that the compound of general formula II
    subjected to catalytic hydrogenation to obtain a compound of the general formula (Na)
    SOSH - CH - CH2CH2COOR3
    COOR
    2
    where and have the specified zn a b l and c and 2
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    同族专利:
    公开号 | 公开日
    DK172896B1|1999-09-20|
    CN1014895B|1991-11-27|
    HU198482B|1989-10-30|
    JPH07116189B2|1995-12-13|
    IL82896D0|1987-12-20|
    CN87104596A|1988-01-20|
    CA1301156C|1992-05-19|
    IE871586L|1987-12-30|
    PT85090A|1987-07-01|
    EP0255228A1|1988-02-03|
    ES2031894T3|1993-01-01|
    JPS6333379A|1988-02-13|
    EG18301A|1993-02-28|
    AU7426287A|1988-01-07|
    IE60038B1|1994-05-18|
    GR870943B|1987-10-19|
    DK307387A|1987-12-31|
    DK307387D0|1987-06-17|
    PT85090B|1990-03-08|
    DE3769721D1|1991-06-06|
    NZ220871A|1989-07-27|
    AU594163B2|1990-03-01|
    ES2007064A6|1989-06-01|
    IL82896A|1991-06-10|
    KR880000432A|1988-03-25|
    KR950001017B1|1995-02-07|
    EP0255228B1|1991-05-02|
    HUT44548A|1988-03-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE3276808D1|1981-09-25|1987-08-27|Southern Res Inst|PYRIDO PYRIMIDINES|
    ZA861235B|1985-03-08|1986-10-29|Univ Princeton|Pyridopyrimidine derivatives|
    NZ219971A|1986-06-06|1989-08-29|Univ Princeton|Tetrahydropyrido (2,3-d pyrimidine derivatives and pharmaceutical compositions|GB8625019D0|1986-10-18|1986-11-19|Wellcome Found|Compounds|
    JP2830008B2|1988-04-01|1998-12-02|武田薬品工業株式会社|Condensed pyrimidine derivative|
    US5223620A|1988-04-01|1993-06-29|Takeda Chemical Industries, Ltd.|Pyrido[2,3-d]pyrimidine compounds useful as intermediates|
    DK172753B1|1988-05-25|1999-06-28|Lilly Co Eli|N--glutamic acid derivatives, their use, pharmaceutical preparations|
    US4871746A|1988-05-31|1989-10-03|The Trustees Of Princeton University|N-[N--aminomethylbenzoyl]glutamic acid derivatives as neoplastic growth inhibitors|
    JP3015957B2|1989-05-29|2000-03-06|武田薬品工業株式会社|Pyrrolo [2,3-d] pyrimidine derivatives and their production|
    US5159079A|1991-12-20|1992-10-27|Eli Lilly And Company|2-piperidones as intermediates for 5-deaza-10-oxo- and 5-deaza-10-thio-5,6,7,8-tetrahydrofolic acids|
    WO1993020075A1|1992-04-01|1993-10-14|The University Of Sydney|8-substituted-n5-deazapterins as antifolates|
    CN1962658B|2005-11-10|2010-05-12|北京大学|Tetrahydropyridine [3,2-d] pyridine compound and its uses for preparing antineoplastic drug|
    AU2016349487B2|2015-11-06|2021-09-09|Avent, Inc.|Ostomy device, apparatus, and system|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US87993586A| true| 1986-06-30|1986-06-30|
    US07/040,330|US4831037A|1987-04-20|1987-04-20|4 -oxo-5,6,7,8-tetrahydropyrido-pyrimidine derivatives|
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