• 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:
    The diastereoisomeric forms of N-(4-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d] -pyrimidin-6-yl)ethyl]benzoyl)-L-glutamic acid are antineoplastic agents. The compounds are prepared by separation of the diastereoisomeric form of the correspondingly protected glutamic derivatives and hydrolytic or hydrogenolytic removal of carboxylic acid and/or amino protecting groups.
    公开号:SU1627087A3
    申请号:SU874202677
    申请日:1987-06-05
    公开日:1991-02-07
    发明作者:С.Тейлор Эдуард；Питер Бердсли Джордж；Ших Чуан；Р.Флетчер Стивен
    申请人:Дзе Трастиз Оф Принстон Юниверсити (Фирма)；
    IPC主号:
    专利说明:

    where R "and RZ (identical or different) are C, g is 4-alkyl, R3 is H or C, -C6 acyl; the carbon atom configuration with the sign is a -configuration, and a chiral acid. The resulting two diastereomeric salts of this compound are separated, and the cation part is separated from this salt by the action
    bases and remove occupied groups. 1 The isolation of the base is carried out as a separate step, either before or after the removal of the protecting groups or with the removal of the protecting groups. The target products are obtained almost as individual diastereomers. 2 tab.
     and
    This invention relates to a process for the preparation of new optically active forms of N- ((2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido 2,3-dJnn-rimidin-6-yl) ethyl benzoyl -1, -glut - Minic acid with antitumor activity.
    The purpose of the invention is to develop a method for producing optically active forms of N- (4- 2- (.) - iHo-4-hydroxy-5,6,7, 8-tetrahydropyrido {2,3-dJ pyrimidin-6-yl) It is benzoyl-1, -glutamic acid, which has a higher antitumor activity.
    Example 1. A mixture of 1 g of diethyl ether (2-acetamido-4-hydroxy-5,6,7,8-tetrahydropyrndo 2,3-dJ pyrimidin-6-yl) ethyl benzoyl -1 -1 glutamic acid and 880 mg of d (+) - 10-camphorsulfonic acid in 50 ml of anhydrous ethanol is boiled for 4 hours. The reaction mixture is cooled to room temperature and left to stand for a day. The white solid that forms is separated by filtration and subjected to fractional crystallization to obtain 37 mg of disteomer B d (+) - 10-camphorsulfonate diethyl ether (2-acetamido-4-hydroxy-5,6,7,8-tetrahydropyrido 2, 3 -dj pyrimidine-6-yl) ethyl benzoyl-L-glutamic acid, m.p. 222-225 C,
    OS
    I mn-th 0.
    The solvent is removed from the mother liquor by evaporation and the resulting solid residue is recrystallized twice from ethanol to obtain the diastereomer A d (+) - 10-camphorsulone of diethyl M-H 4 -2- (2-acetamido-4-hydroxy-5, 6,7,8-tetrahydropyrido 2,3} pyrimidin-6-yl) ethyphenzoyl-L-glutamic acid, .3b.
    A solution of the diastereomer B d (+) - 10-M-{4- 2- (2-acetamido-4-hydroxy--5,6,7) diethyl ether, zpetrahydropirido (2,3-dJriH-rimidin-6-yl) ethyl benzoyl-L-glutamic acid p 50 ml of methanol containing 3 ml of 1N aqueous sodium hydroxide solution are stirred for 72 hours at room temperature. After adding 2 ml of acetic acid, the mixture is centrifuged to obtain the diastereomer B M- / 4- 2- (2-amino-4-β-hydroxy-5,6,7,8-tetrahydropyrido 2,3-cfJ pyrimidin-6-yl) ethyl benchoyl -
    -
    6270874
    -L-glutamino acid, m.p..22410
    15
    20
    25
    thirty
    CQ 227 C (with decomposition), cQJ |, MJ | - -21.0581 (C 0.636, O, IN NaOH). 5 NMR (SOSTS), 5: 1.85 (m, 2H) J 1.98 (m, 1H); 2.25 (m, 1H); 2.45 (m, 1H); 2.68 (m, 1H); 2.92 (m, 5H); 3.25 (t, J 10 Hz, 1H); 3.82 (d, J 10 Hz, 1H); 5.13 (m, 1H); 7.43 (d, J 9 Hz, 2H); 7.84 (d, L 9 Hz, 2H).
    Optical purity 97%.
    According to the described procedure, but using the diastereomer A d (+) - 10-camphorsulfonate of diethyl ether N- {4- - 2- (2-acetamido-4-hydroxy-5,6,7,8-β-tetrahydropyrido 2,3 -I | pyrimidine-6- -yl) ethyl} benzoyl jI.-glutamic acid instead of I ichomer get diastereomer A M-G4-Ј .- (amino-4-hydroxy-5,6,7,8-tetrahydropyridoG2, 3-dJ pyrimidin-6-yl) ethyl-benzoylT-1.-glutamic acid, m.p. 25 ° -255 ° C.
    Example 2. To a solution containing 100 mg (0.187 mmol) of M-G4- 2- (2-acetamido-4-hydroxy-5,6,7,8-tetrahydropyrido Ј 2, 3 pyrimidine-6-) di-ETHYLATE ester М-Г4- 2- (2) dry ethanol, 122.7 g of (+) -3-bromo-camphor-8-sulfonic acid (0.374 mmol) is added. The resulting reaction mixture was heated under reflux for 10 minutes, cooled to room temperature, and allowed to stand overnight. The solid precipitate is collected by suction filtration; 40 mg (31%) of the corresponding salt is obtained.
    HPLC analysis of this product shows that it is enriched with a diastereomer with an enrichment factor of 3.3 (23:77 ratio) (On the other hand, the mother liquor is enriched with another diastereomer with an enrichment factor of 3.2, 7:24 ratio). Repetition of the indicated HPLC separation gives the isolated diastereomer with the required optical purity of 95.%.
    Example 3. South of N - ((2- -amino-4-hydroxy-5,6,7,8-tetrahydropyrido JJ2,3-d pyrimidin-6-yl) ethyl benzoyl} -1, -glutamic acid (B - the diastereomer) is suspended in 40 ml of water (pH 5.0). 8 ml of 5.0N aqueous solution are added dropwise with stirring to the suspension obtained.
    35
    40
    45
    sixteen
    thief gndrsh i-u and nnpi ii tiLiM p ii ii thief 1.0 ng sodium nitrate until rstr 41. it IK i t g hard material | 1vo (3, i i), pH pacr of the thief with 8. ia i ci at 50 ml of methanol and a rcc i n h of a knight in a fridge overnight. I formed was TPEFGTPЈ e i w t d UNDOF walkie, washed nep pshnm kolite- stpon MLiaHo a cold and (jiitfij in (at room 4smgerchtule g m, receiving dpugchtri-hand SGL measure dnastereo In NJ 4- 2- 2-amshyu- -rnnpnicci, - -5.6, 7, 8-1 eratg choppr c-o 2, jd, inpHMIDHN-6-Ml) i | jr, u A –Ir i g iminovoy clslog 5.1 g).
    And K (bRi): V-i O-, 1G- + 0, if, n, 1600, 1548, 15V, N02, 13e8, 1310
    H1F C, OS 1 G,, J: /, 7b (g, 2NU T - 6 Hz; O (lb, III, I - (J fi, 5 B; -J.34 CKI, 1H, i 11 Hz, 2 ON;, Q5 (MI, 111, I a 11.9 Hz),, 7 m, 24); 2, bri (rii, 1H, J 111, j,
    1, 20 (t, H.
    J - 7 n), L
    2 Hz ;, i, g m,
    1 (m, 141
    (m,
    BlT-P I-l 1, (- A, G I, I D. tO,
    N 12 / 1.3.
    4, F, c ,, 07Ma,
    Non,
    N 12.40
    II I- II L i1 i ir, 4 h 111 (, l
    RE de tt) 1 ii Oi h h
    leukemia fire i,. C (if i-n. Ri
    i i i Tt reomer with IK i i and
    chkgperins i i i ititr (i with yi i and j0 µg / mp:
    Lea g, i i and
    Пплг-, ррг, .р И)
    P i m t p j. H tchm h (i) lasi mjpa ji Lj / R1 / G ьмmt t (h n pi) i i i 1 t
    KOtHO OnV OJliJ MP O 10 R I ()
    For the same type of h) and i (no. G ny 10 Hbjic. K (che HC. I) -i j iv pHBRUSHLY P K iilM TL O1 1 I MCT i T-p.
    romera I - 2 -n - -i i -5, 6, /, -t 5t pa ini pin l (f J when
    MICIN fl - T - r, -lJOHl f T1И
    new k i p o i (L ok op u) through t i t IJT iit1 HOLI OG (i I - j J rijfi1 (iiЧ
    SHIH tt I KO ill 1CH11G} I lani
    T O V V I M N, 1 {
    n m nose cos dine ie. on osnopanin then pod "it is a percentage of ingenbiro-.
    The results are shown in t and b p. one .
    PRI me R 6. Groups of females in particular of CZN mice in the amount of 10 pcs. zfpkamt vn triburyupyno in axillary obstastts cells of limbosarcoma. and for 8 days, the test compound is injected intraperitoneally in an emulsion - 3 spo of CO, 5 ml). Control animals were treated in the same way, but without control of coenniiei rfp.
    p 1 cup d lestaty grigedy p pch 2,
    ii Rimen R 7. Groups of the SZN i mllontirmp kchetki SZN l tsmyukagtsino 0
    N i of the support tree, what you entered
     n f, n; Thyre GIROT - chig only
     in even ni (eny in tL. II t and m e p.
     inaccurate pgatm ktetok myeloma) Ztbz mitschtnr rp% nia mice, the post I-PIO is introduced sh mer r, with iiHipo ii i tsiotrye g 1 l1 -, 1-1 1b.
    The results of the tests are given in Table 4 (three, HF three) 1) Yushi - 0.6 ml / day in Zmul (ibope p ° ruiPFrfo for 10 days).
    Гииа тсрромеры, obtained according to the idea of i / gosob, about the addendum: bops you have HI i tntzooopooea swarm activity, and they belong to the group MIr TTOI sigg zhelenchenii.
    P o I m p a invention
    Cnncic golchchsii diastereomer K (2-1MINO-4-HYDROXH-5,6,7,8-сгр г in, 3-с1 pyrimidine-6 -in) oiin bonpoil - -glutamine bursa with a value of jj / 789 UM or. reomer t | -4-p- (2-ami: o-4- -g-гg01 gn-;, (, 7, 8-tet-a-idropyl1rido mrmm)) type benzoyl -, pamp (acid by treating
    ГьП 2 ч-Ч.Г °° npi them Larkar-J 5yc) im
     injitM-ipMbX solei with a base that is different in heme, which is rgst op C and ittereors are thick of the formula
    hnhn
     i; t en- n - 0 ° ° 4 | 9N SN7 SN GSOO,
      - VII
    RjNH N N, COOR,
    i
    R:
    where R and R g are the same or common - C-C-alkyl, - hydrogen or C-Cg-acyl - L-configuration of the atom
    carbon,
    are treated with chiral acid, the resulting two diastereomeric salts of this compound are separated, the cation part is separated from this salt by the action of a base, and the protecting groups are removed, and the isolation of the free base is carried out either as a separate stage before or after the removal of the protective groups, or simultaneously with the removal of the protective groups, to obtain the diastereomer M- | 4 -Ј2- (2-amnno-4-hydroxy-5,6,7,8-tetrahydropyrido 2, Z-d pyrimidin-6-yl) ethyl benzoyl} -1, -glutamic acid with an OP value
    practically free of the diastereomer of N- {4- - (2-amino-hydroxy-5,6,7,8-tetrahydropyridor, З-dJ pyrimidin-6-yl) etid benzoyl -1, -glutamic acid with the value +
    Lw
    + 31j09 ° or N-f4-2- (2-amino-4-hydroxy-5,6,7,8-tetrahydro, 3-d pyrimidin-6-yl) ethe benzyl} -L- diastereomer glutamic acid with a GoO value of But + 31.0chv, practically 5o nL
    ski-free DNA-tereomer N-J4 -G2- (2-amino-4-hydroxy-5,6,7,8-tetrahydropyridor, 3-C1 pyrimidine-6-yl) ethyl benzoyl, -T, -glutamic acid with value ga and / and
    -21.06 or converted to salt by action of the base.
    Table 1
    G (a l and c 3.
    Table 4
    权利要求:
    Claims (5)
    [1]
    The method of producing diastereomer
    N- ^ 4- [] [2]
    2- (2-amino-4-hydroxy and-5,6,7,8-tsgrahydhydric odirido [ .,
    [3]
    3-s1] pyrimidin-6-ip) ethyl benzoyl ^ -1.-glutamic acid lot with a value of (j / J “21.06 or diastereomer n £ -
    [4]
    4- [2- (2-amino-4-hydroxy-5,6,7,8-tetparidropyrido [_2, 3-d] pyrminidin-6-yl) ethyl] benzoyl ^ -L-glutaminespy acid with Go-'P g '+ 31.09 ° or their
    J 589 NM by the pharmacist • zoil] --Ϊ value. - r 1 at Г ag.-eomer А and)) г ря!!! 1 YaSG : one of the evil ones (semi · ···, 55 pacif the formula on the base, heme, that of the most acceptable salts, with a higher concentration of cm and zk - ^ - COMB ^ H-CH ^ CHgCOOA,
    COOR, with animal tumors, and
    < 1 ί '!'. 1'4 X '
    Ί R 3 *
    - identical or different - C ^ -C ^ -alkyl,
    - hydrogen or C, -C ^ acyl,
    - The L-configuration of the carbon atom, is subjected to treatment with chiral acid, the two diastereomeric salts of the indicated compound are separated, the cationic part is isolated from the indicated salt by the action of the base and the protective groups are removed, and the free base is isolated as a separate step before or removal of the protective groups, or temporarily by removing the N- ^ 4- ^ 2- (2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido [2,3-H] pyrimidin-6-yl) ethyl] benzoyl] -L protective diastereomer -glutamic acid with a value of ~ 1 »θ6 °, • * · either after one groups
    Compound
    The dose, mg / kg, is practically free (its diastereomer is N- ^ 4- [ .- (2-amino-4-hydroxy-5,6,7,3-tetrahydropyridor, 3-d] pyrimidin-6-yl) ethyl7benzoyl ^ -E- glutamic acid with the value Γλ / Ί 2 ® +
    L W J 669y + 31.09 ° or diastereomer N- £ 4- £ 2- (2-amino-4-hydroxy-5,6,7,8-tetrahydro, 3-D]] pyrimilin-6-yl) ethyl ] benzoyl} -L-glutamic acid with a value of 75 ^ +31, 09 е , which practically does not contain the diastereomer N- ^ 4-p- (2-amino-4-hydroxy-5,6,7,8-tetra hydropyrido [ ”2,3-I]] pyrimidini1 | -T.-glutamine
    [5]
    5ВЭ НМ in the salt of action-6-yl) ethyl]] benzoyl ^ acid with the value
    -21.06 ° or translate it base.
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    引用文献:
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    ZA861235B|1985-03-08|1986-10-29|Univ Princeton|Pyridopyrimidine derivatives|IE60038B1|1986-06-30|1994-05-18|Univ Princeton|4-oxo-5, 6, 7, 8-tetrahydropyrido-[2, 3-d]pyrimidine derivatives|
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    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|
    US5008391A|1989-07-07|1991-04-16|Eli Lilly And Company|Enantioselective synthesis of antifolates|
    US5066828A|1990-04-12|1991-11-19|Merrell Dow Pharmaceuticals Inc.|Difluoroglutamic acid conjugates with folates and anti-folates for the treatment of neoplastic diseases|
    US6426417B1|1998-02-11|2002-07-30|Eli Lilly And Company|Processes and intermediates useful to make antifolates|
    法律状态:
    2007-09-20| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20050606 |
    优先权:
    申请号 | 申请日 | 专利标题
    US87153986A| true| 1986-06-06|1986-06-06|
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