IL110509A - Pyrimido Compounds [D-5,4] Pyrimidine 2,4,8-Trimot preparation preparations and pharmaceutical preparations containing them - Google Patents
Pyrimido Compounds [D-5,4] Pyrimidine 2,4,8-Trimot preparation preparations and pharmaceutical preparations containing themInfo
- Publication number
- IL110509A IL110509A IL110509A IL11050994A IL110509A IL 110509 A IL110509 A IL 110509A IL 110509 A IL110509 A IL 110509A IL 11050994 A IL11050994 A IL 11050994A IL 110509 A IL110509 A IL 110509A
- Authority
- IL
- Israel
- Prior art keywords
- piperidino
- pyrimido
- pyrimidine
- morpholino
- methyl
- Prior art date
Links
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 238000002512 chemotherapy Methods 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 7
- JOZPEVMCAKXSEY-UHFFFAOYSA-N pyrimido[5,4-d]pyrimidine Chemical class N1=CN=CC2=NC=NC=C21 JOZPEVMCAKXSEY-UHFFFAOYSA-N 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 125000001246 bromo group Chemical group Br* 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 2
- 125000004605 1,2,3,4-tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims 2
- YIWSBONCEROBAF-UHFFFAOYSA-N 1-[8-(6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-2-yl]-n,n-dimethylpiperidin-4-amine Chemical compound C1C=2C=C(OC)C(OC)=CC=2CCN1C(C1=N2)=NC=NC1=C(N1CCOCC1)N=C2N1CCC(N(C)C)CC1 YIWSBONCEROBAF-UHFFFAOYSA-N 0.000 claims 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- VSCSZOZBOUEJHV-UHFFFAOYSA-N N1=CN=CC2=NC=NC=C21.C1CC(CN(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(C)CC=3C4=CC=CC=C4C=CC=3)C2=N1 Chemical class N1=CN=CC2=NC=NC=C21.C1CC(CN(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(C)CC=3C4=CC=CC=C4C=CC=3)C2=N1 VSCSZOZBOUEJHV-UHFFFAOYSA-N 0.000 claims 1
- 239000000969 carrier Substances 0.000 claims 1
- 230000002708 enhancing effect Effects 0.000 claims 1
- KXCXDESVYWWYMK-UHFFFAOYSA-N n-benzyl-2-[4-(dimethylamino)piperidin-1-yl]-n-methyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(C)CC=3C=CC=CC=3)C2=N1 KXCXDESVYWWYMK-UHFFFAOYSA-N 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- -1 2,4,8-Trisubstituted pyrimido[5,4-d]pyrimidine compounds Chemical class 0.000 description 294
- 238000002844 melting Methods 0.000 description 80
- 230000008018 melting Effects 0.000 description 80
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 150000001875 compounds Chemical class 0.000 description 36
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- 239000000741 silica gel Substances 0.000 description 30
- 229910002027 silica gel Inorganic materials 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
- 239000013543 active substance Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000203 mixture Substances 0.000 description 17
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 235000002639 sodium chloride Nutrition 0.000 description 16
- 239000003826 tablet Substances 0.000 description 15
- 229960000583 acetic acid Drugs 0.000 description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 239000012362 glacial acetic acid Substances 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 229940009456 adriamycin Drugs 0.000 description 12
- 239000002246 antineoplastic agent Substances 0.000 description 11
- 229940127089 cytotoxic agent Drugs 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 239000008120 corn starch Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000001117 sulphuric acid Substances 0.000 description 6
- 235000011149 sulphuric acid Nutrition 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- 125000003282 alkyl amino group Chemical group 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 239000003708 ampul Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 229960004679 doxorubicin Drugs 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 230000001235 sensitizing effect Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- PXSFRIGHWCHZSU-UHFFFAOYSA-N 4-(2,8-dichloropyrimido[5,4-d]pyrimidin-4-yl)morpholine Chemical compound C=12N=CN=C(Cl)C2=NC(Cl)=NC=1N1CCOCC1 PXSFRIGHWCHZSU-UHFFFAOYSA-N 0.000 description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 125000004663 dialkyl amino group Chemical group 0.000 description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- CCMKPVQTRQFFQH-UHFFFAOYSA-N n-benzyl-2-chloro-n-methyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound N=1C=NC2=C(N3CCOCC3)N=C(Cl)N=C2C=1N(C)CC1=CC=CC=C1 CCMKPVQTRQFFQH-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- WEBTULVKHZERRR-UHFFFAOYSA-N 1-[8-[benzyl(methyl)amino]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-2-yl]piperidin-4-one Chemical compound N=1C=NC2=C(N3CCOCC3)N=C(N3CCC(=O)CC3)N=C2C=1N(C)CC1=CC=CC=C1 WEBTULVKHZERRR-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 125000005505 thiomorpholino group Chemical group 0.000 description 3
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical compound NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 2
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- XZGYPGBRTTWCGC-UHFFFAOYSA-N 4-pyrimido[5,4-d]pyrimidin-2-ylmorpholine Chemical compound C1COCCN1C1=NC=C(N=CN=C2)C2=N1 XZGYPGBRTTWCGC-UHFFFAOYSA-N 0.000 description 2
- 108010078791 Carrier Proteins Proteins 0.000 description 2
- 102000014914 Carrier Proteins Human genes 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000005236 alkanoylamino group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- JPOXNPPZZKNXOV-UHFFFAOYSA-N bromochloromethane Chemical compound ClCBr JPOXNPPZZKNXOV-UHFFFAOYSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 230000001085 cytostatic effect Effects 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 2
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 230000036457 multidrug resistance Effects 0.000 description 2
- KNAZSODFMTYDOC-UHFFFAOYSA-N n'-benzyl-n'-[2-[4-(dimethylamino)piperidin-1-yl]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-yl]propane-1,3-diamine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(CCCN)CC=3C=CC=CC=3)C2=N1 KNAZSODFMTYDOC-UHFFFAOYSA-N 0.000 description 2
- WCLULZMGEWWQNF-UHFFFAOYSA-N n-benzyl-2-[4-(2,2-diphenylethylamino)piperidin-1-yl]-n-methyl-8-morpholin-4-ylpyrimido[5,4-d]pyrimidin-4-amine Chemical compound N=1C(N2CCC(CC2)NCC(C=2C=CC=CC=2)C=2C=CC=CC=2)=NC2=C(N3CCOCC3)N=CN=C2C=1N(C)CC1=CC=CC=C1 WCLULZMGEWWQNF-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 150000007530 organic bases Chemical group 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000004983 pleiotropic effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical group C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- 125000006091 1,3-dioxolane group Chemical group 0.000 description 1
- QDVBKXJMLILLLB-UHFFFAOYSA-N 1,4'-bipiperidine Chemical compound C1CCCCN1C1CCNCC1 QDVBKXJMLILLLB-UHFFFAOYSA-N 0.000 description 1
- CQFHBHZIZNVPLT-UHFFFAOYSA-N 1-(4,8-dimorpholin-4-ylpyrimido[5,4-d]pyrimidin-2-yl)-n,n-dimethylpiperidin-4-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N3CCOCC3)C2=N1 CQFHBHZIZNVPLT-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- UJEZGRRLFQNFGM-UHFFFAOYSA-N 1-[1-[8-(5-methoxy-3,4-dihydro-1h-isoquinolin-2-yl)-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-2-yl]piperidin-4-yl]-n,n-dimethylmethanamine Chemical compound C1CC=2C(OC)=CC=CC=2CN1C(C1=N2)=NC=NC1=C(N1CCOCC1)N=C2N1CCC(CN(C)C)CC1 UJEZGRRLFQNFGM-UHFFFAOYSA-N 0.000 description 1
- GNORAVMCYOMWFM-UHFFFAOYSA-N 1-[8-(1,3-dihydroisoindol-2-yl)-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-2-yl]-n,n-dimethylpiperidin-4-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N3CC4=CC=CC=C4C3)C2=N1 GNORAVMCYOMWFM-UHFFFAOYSA-N 0.000 description 1
- AQHKGPWUIOAPHJ-UHFFFAOYSA-N 2,4,8-trichloropyrimido[5,4-d]pyrimidine Chemical compound N1=CN=C(Cl)C2=NC(Cl)=NC(Cl)=C21 AQHKGPWUIOAPHJ-UHFFFAOYSA-N 0.000 description 1
- MAWKNUDUKRUYMB-UHFFFAOYSA-N 2,8-dichloro-4-piperidin-1-ylpyrimido[5,4-d]pyrimidine Chemical compound C=12N=CN=C(Cl)C2=NC(Cl)=NC=1N1CCCCC1 MAWKNUDUKRUYMB-UHFFFAOYSA-N 0.000 description 1
- UOPRPCBCBQMLEB-UHFFFAOYSA-N 2,8-dichloro-n,n-diethylpyrimido[5,4-d]pyrimidin-4-amine Chemical compound N1=CN=C2C(N(CC)CC)=NC(Cl)=NC2=C1Cl UOPRPCBCBQMLEB-UHFFFAOYSA-N 0.000 description 1
- ZESYFFOWIGNGIO-UHFFFAOYSA-N 2-(2-chloro-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-yl)-3,4-dihydro-1h-isoquinoline-6,7-diol Chemical compound C1C=2C=C(O)C(O)=CC=2CCN1C(C1=NC(Cl)=N2)=NC=NC1=C2N1CCOCC1 ZESYFFOWIGNGIO-UHFFFAOYSA-N 0.000 description 1
- LSNYLERJYCQZJQ-UHFFFAOYSA-N 2-[4-(dimethylamino)piperidin-1-yl]-4-morpholin-4-yl-n-(2-phenylethyl)pyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2NCCC=3C=CC=CC=3)C2=N1 LSNYLERJYCQZJQ-UHFFFAOYSA-N 0.000 description 1
- BBWRRGBAXJNUMJ-UHFFFAOYSA-N 2-[4-(dimethylamino)piperidin-1-yl]-n-[(4-methoxyphenyl)methyl]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1=CC(OC)=CC=C1CNC1=NC=NC2=C(N3CCOCC3)N=C(N3CCC(CC3)N(C)C)N=C12 BBWRRGBAXJNUMJ-UHFFFAOYSA-N 0.000 description 1
- IYGVKKSDSOSZJV-UHFFFAOYSA-N 2-[4-(dimethylamino)piperidin-1-yl]-n-[(4-methylphenyl)methyl]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2NCC=3C=CC(C)=CC=3)C2=N1 IYGVKKSDSOSZJV-UHFFFAOYSA-N 0.000 description 1
- CHTRZHZLAMTTPH-UHFFFAOYSA-N 2-[4-(dimethylamino)piperidin-1-yl]-n-methyl-4-morpholin-4-yl-n-(naphthalen-1-ylmethyl)pyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(C)CC=3C4=CC=CC=C4C=CC=3)C2=N1 CHTRZHZLAMTTPH-UHFFFAOYSA-N 0.000 description 1
- DPXOGEZISMVCJW-UHFFFAOYSA-N 2-[4-(dimethylamino)piperidin-1-yl]-n-methyl-4-morpholin-4-yl-n-(naphthalen-2-ylmethyl)pyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(C)CC=3C=C4C=CC=CC4=CC=3)C2=N1 DPXOGEZISMVCJW-UHFFFAOYSA-N 0.000 description 1
- WZWPIQGNNNVPLT-UHFFFAOYSA-N 2-[4-(dimethylamino)piperidin-1-yl]-n-methyl-8-morpholin-4-yl-n-(naphthalen-1-ylmethyl)pyrimido[5,4-d]pyrimidin-4-amine Chemical group C1CC(N(C)C)CCN1C1=NC(N(C)CC=2C3=CC=CC=C3C=CC=2)=C(N=CN=C2N3CCOCC3)C2=N1 WZWPIQGNNNVPLT-UHFFFAOYSA-N 0.000 description 1
- DKRWHVOIJRAXHJ-UHFFFAOYSA-N 2-[4-[(dimethylamino)methyl]piperidin-1-yl]-n-methyl-4-morpholin-4-yl-n-(naphthalen-1-ylmethyl)pyrimido[5,4-d]pyrimidin-8-amine Chemical group C1CC(CN(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(C)CC=3C4=CC=CC=C4C=CC=3)C2=N1 DKRWHVOIJRAXHJ-UHFFFAOYSA-N 0.000 description 1
- FEFJCECQAKEBNA-UHFFFAOYSA-N 2-[4-[(dimethylamino)methyl]piperidin-1-yl]-n-methyl-n-(naphthalen-1-ylmethyl)-4-piperidin-1-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(CN(C)C)CCN1C1=NC(N2CCCCC2)=C(N=CN=C2N(C)CC=3C4=CC=CC=C4C=CC=3)C2=N1 FEFJCECQAKEBNA-UHFFFAOYSA-N 0.000 description 1
- KPWHMHALXRBQKK-UHFFFAOYSA-N 2-chloro-4-morpholin-4-yl-n-(3-phenylpropyl)pyrimido[5,4-d]pyrimidin-8-amine Chemical compound C=12N=CN=C(NCCCC=3C=CC=CC=3)C2=NC(Cl)=NC=1N1CCOCC1 KPWHMHALXRBQKK-UHFFFAOYSA-N 0.000 description 1
- LGUFKWLGJFXHND-UHFFFAOYSA-N 2-chloro-n-(cyclohexylmethyl)-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C=12N=CN=C(NCC3CCCCC3)C2=NC(Cl)=NC=1N1CCOCC1 LGUFKWLGJFXHND-UHFFFAOYSA-N 0.000 description 1
- SMBOFEIJKBINQD-UHFFFAOYSA-N 2-chloro-n-(cyclohexylmethyl)-n-methyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound N=1C=NC2=C(N3CCOCC3)N=C(Cl)N=C2C=1N(C)CC1CCCCC1 SMBOFEIJKBINQD-UHFFFAOYSA-N 0.000 description 1
- GYCTVWOYMAHFBV-UHFFFAOYSA-N 2-chloro-n-[(4-methoxynaphthalen-1-yl)methyl]-n-methyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C12=CC=CC=C2C(OC)=CC=C1CN(C)C(C1=NC(Cl)=N2)=NC=NC1=C2N1CCOCC1 GYCTVWOYMAHFBV-UHFFFAOYSA-N 0.000 description 1
- GUUZIICWUODTQX-UHFFFAOYSA-N 2-chloro-n-[(4-methoxyphenyl)methyl]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1=CC(OC)=CC=C1CNC1=NC=NC2=C(N3CCOCC3)N=C(Cl)N=C12 GUUZIICWUODTQX-UHFFFAOYSA-N 0.000 description 1
- SHLGAHGBEJLXLO-UHFFFAOYSA-N 2-chloro-n-[(4-methoxyphenyl)methyl]-n-methyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1=CC(OC)=CC=C1CN(C)C1=NC=NC2=C(N3CCOCC3)N=C(Cl)N=C12 SHLGAHGBEJLXLO-UHFFFAOYSA-N 0.000 description 1
- DPHFZHWBTMCYPO-UHFFFAOYSA-N 2-chloro-n-[(4-methylphenyl)methyl]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1=CC(C)=CC=C1CNC1=NC=NC2=C(N3CCOCC3)N=C(Cl)N=C12 DPHFZHWBTMCYPO-UHFFFAOYSA-N 0.000 description 1
- YCGLOZYVBRBNKR-UHFFFAOYSA-N 2-chloro-n-methyl-4-morpholin-4-yl-n-(naphthalen-1-ylmethyl)pyrimido[5,4-d]pyrimidin-8-amine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)C(C1=NC(Cl)=N2)=NC=NC1=C2N1CCOCC1 YCGLOZYVBRBNKR-UHFFFAOYSA-N 0.000 description 1
- ZFBCUYHHCKDHMW-UHFFFAOYSA-N 2-chloro-n-methyl-4-morpholin-4-yl-n-(naphthalen-2-ylmethyl)pyrimido[5,4-d]pyrimidin-8-amine Chemical compound C=1C=C2C=CC=CC2=CC=1CN(C)C(C1=NC(Cl)=N2)=NC=NC1=C2N1CCOCC1 ZFBCUYHHCKDHMW-UHFFFAOYSA-N 0.000 description 1
- IHVOAIZQPSQCIU-UHFFFAOYSA-N 2-chloro-n-methyl-n-(naphthalen-1-ylmethyl)-4-piperidin-1-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)C(C1=NC(Cl)=N2)=NC=NC1=C2N1CCCCC1 IHVOAIZQPSQCIU-UHFFFAOYSA-N 0.000 description 1
- AVKQCAIJQBKBKC-UHFFFAOYSA-N 2-chloro-n-methyl-n-[(4-methylphenyl)methyl]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound N=1C=NC2=C(N3CCOCC3)N=C(Cl)N=C2C=1N(C)CC1=CC=C(C)C=C1 AVKQCAIJQBKBKC-UHFFFAOYSA-N 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 125000001241 2-phenylethylthio group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])S* 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- MWTGBAURSCEGSL-UHFFFAOYSA-N 3-(benzylamino)propanenitrile Chemical compound N#CCCNCC1=CC=CC=C1 MWTGBAURSCEGSL-UHFFFAOYSA-N 0.000 description 1
- STBDXSALGFNTHC-UHFFFAOYSA-N 3-[benzyl-(2-chloro-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-yl)amino]propanenitrile Chemical compound C=12N=CN=C(N(CCC#N)CC=3C=CC=CC=3)C2=NC(Cl)=NC=1N1CCOCC1 STBDXSALGFNTHC-UHFFFAOYSA-N 0.000 description 1
- LEOGASIOPSSVQW-UHFFFAOYSA-N 3-[benzyl-[2-[4-(dimethylamino)piperidin-1-yl]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-yl]amino]propanenitrile Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(CCC#N)CC=3C=CC=CC=3)C2=N1 LEOGASIOPSSVQW-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- NWCMUXXOBVJKPH-UHFFFAOYSA-N 4-(2-chloro-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-yl)morpholine Chemical compound C=12N=CN=C(N3CCOCC3)C2=NC(Cl)=NC=1N1CCOCC1 NWCMUXXOBVJKPH-UHFFFAOYSA-N 0.000 description 1
- YZYXKCUCMUSEEV-UHFFFAOYSA-N 4-(2-chloro-8-phenylmethoxypyrimido[5,4-d]pyrimidin-4-yl)morpholine Chemical compound C=12N=CN=C(OCC=3C=CC=CC=3)C2=NC(Cl)=NC=1N1CCOCC1 YZYXKCUCMUSEEV-UHFFFAOYSA-N 0.000 description 1
- HHQWKZLAQJGWCH-UHFFFAOYSA-N 4-(8-benzylsulfanyl-2-chloropyrimido[5,4-d]pyrimidin-4-yl)morpholine Chemical compound C=12N=CN=C(SCC=3C=CC=CC=3)C2=NC(Cl)=NC=1N1CCOCC1 HHQWKZLAQJGWCH-UHFFFAOYSA-N 0.000 description 1
- OZSQCIRNFWOXQG-UHFFFAOYSA-N 4-[1-[8-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-2-yl]piperidin-4-yl]-1,4-thiazinane 1-oxide Chemical compound C1C=2C=C(OC)C(OC)=CC=2CCN1C(C1=N2)=NC=NC1=C(N1CCOCC1)N=C2N(CC1)CCC1N1CCS(=O)CC1 OZSQCIRNFWOXQG-UHFFFAOYSA-N 0.000 description 1
- LGFWFHVAVVEHBR-UHFFFAOYSA-N 4-[2-chloro-8-(1,3-dihydroisoindol-2-yl)pyrimido[5,4-d]pyrimidin-4-yl]morpholine Chemical compound C=12N=CN=C(N3CC4=CC=CC=C4C3)C2=NC(Cl)=NC=1N1CCOCC1 LGFWFHVAVVEHBR-UHFFFAOYSA-N 0.000 description 1
- BAOWHINZPPYCMS-UHFFFAOYSA-N 4-[8-(6,7-dimethoxy-3,4-dihydro-1h-isoquinolin-2-yl)-2-(4-morpholin-4-ylpiperidin-1-yl)pyrimido[5,4-d]pyrimidin-4-yl]morpholine Chemical compound C1C=2C=C(OC)C(OC)=CC=2CCN1C(C1=N2)=NC=NC1=C(N1CCOCC1)N=C2N(CC1)CCC1N1CCOCC1 BAOWHINZPPYCMS-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- STWODXDTKGTVCJ-UHFFFAOYSA-N 4-pyrrolidin-1-ylpiperidine Chemical compound C1CCCN1C1CCNCC1 STWODXDTKGTVCJ-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- LGYLTTHVEZGXDY-UHFFFAOYSA-N 8-[8-[benzyl(methyl)amino]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-2-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one Chemical compound N=1C=NC2=C(N3CCOCC3)N=C(N3CCC4(CC3)C(NCN4C=3C=CC=CC=3)=O)N=C2C=1N(C)CC1=CC=CC=C1 LGYLTTHVEZGXDY-UHFFFAOYSA-N 0.000 description 1
- WMCHXIVYXRICAW-UHFFFAOYSA-N 8-n-benzyl-2-chloro-4-n,4-n-diethyl-8-n-methylpyrimido[5,4-d]pyrimidine-4,8-diamine Chemical compound N1=CN=C2C(N(CC)CC)=NC(Cl)=NC2=C1N(C)CC1=CC=CC=C1 WMCHXIVYXRICAW-UHFFFAOYSA-N 0.000 description 1
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- WNOQQGROSAKPLD-UHFFFAOYSA-N ClC=1N=C(C2=C(N1)C(=NC=N2)Cl)N2CC1=CC=CC=C1CC2.ClC=2N=C(C1=C(N2)C(=NC=N1)Cl)N(C)CC1=CC=CC2=CC=CC=C12 Chemical compound ClC=1N=C(C2=C(N1)C(=NC=N2)Cl)N2CC1=CC=CC=C1CC2.ClC=2N=C(C1=C(N2)C(=NC=N1)Cl)N(C)CC1=CC=CC2=CC=CC=C12 WNOQQGROSAKPLD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 108010068250 Herpes Simplex Virus Protein Vmw65 Proteins 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 108010047230 Member 1 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241001024304 Mino Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 229940022682 acetone Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 150000008045 alkali metal halides Chemical class 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000002862 amidating effect Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 125000006842 cycloalkyleneimino group Chemical group 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- MKJDUHZPLQYUCB-UHFFFAOYSA-N decan-4-one Chemical compound CCCCCCC(=O)CCC MKJDUHZPLQYUCB-UHFFFAOYSA-N 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- WKTWNXRXMYEOJM-UHFFFAOYSA-N ethyl 2-[benzyl-(2-chloro-4-piperidin-1-ylpyrimido[5,4-d]pyrimidin-8-yl)amino]acetate Chemical compound N=1C=NC2=C(N3CCCCC3)N=C(Cl)N=C2C=1N(CC(=O)OCC)CC1=CC=CC=C1 WKTWNXRXMYEOJM-UHFFFAOYSA-N 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007154 intracellular accumulation Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229940073584 methylene chloride Drugs 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- MUIXGFADUNYAGG-UHFFFAOYSA-N n,n-dibenzyl-2-[4-(dimethylamino)piperidin-1-yl]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(CC=3C=CC=CC=3)CC=3C=CC=CC=3)C2=N1 MUIXGFADUNYAGG-UHFFFAOYSA-N 0.000 description 1
- MVOJNQIUKOCFRI-UHFFFAOYSA-N n,n-dibenzyl-2-chloro-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C=12N=CN=C(N(CC=3C=CC=CC=3)CC=3C=CC=CC=3)C2=NC(Cl)=NC=1N1CCOCC1 MVOJNQIUKOCFRI-UHFFFAOYSA-N 0.000 description 1
- SWQDHDJAIYSTRF-UHFFFAOYSA-N n,n-dimethyl-1-piperidin-4-ylmethanamine Chemical compound CN(C)CC1CCNCC1 SWQDHDJAIYSTRF-UHFFFAOYSA-N 0.000 description 1
- YFJAIURZMRJPDB-UHFFFAOYSA-N n,n-dimethylpiperidin-4-amine Chemical compound CN(C)C1CCNCC1 YFJAIURZMRJPDB-UHFFFAOYSA-N 0.000 description 1
- OKZKXIXOEFIPOX-UHFFFAOYSA-N n-(cyclohexylmethyl)-2-[4-(dimethylamino)piperidin-1-yl]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2NCC3CCCCC3)C2=N1 OKZKXIXOEFIPOX-UHFFFAOYSA-N 0.000 description 1
- QZJYGAQGDVBQMM-UHFFFAOYSA-N n-(cyclohexylmethyl)-2-[4-(dimethylamino)piperidin-1-yl]-n-methyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(C)CC3CCCCC3)C2=N1 QZJYGAQGDVBQMM-UHFFFAOYSA-N 0.000 description 1
- RDWBWBOPAWKJAZ-UHFFFAOYSA-N n-(ethylamino)-n-(methylamino)propan-1-amine Chemical compound CCCN(NC)NCC RDWBWBOPAWKJAZ-UHFFFAOYSA-N 0.000 description 1
- CXTFIHDRGAZRLY-UHFFFAOYSA-N n-[(4-chlorophenyl)methyl]-2-[4-(dimethylamino)piperidin-1-yl]-n-methyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(C)CC=3C=CC(Cl)=CC=3)C2=N1 CXTFIHDRGAZRLY-UHFFFAOYSA-N 0.000 description 1
- YNRAQBRGCBZJNS-UHFFFAOYSA-N n-[3-[benzyl-[2-[4-(dimethylamino)piperidin-1-yl]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-yl]amino]propyl]-1-phenylmethanesulfonamide Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(CCCNS(=O)(=O)CC=3C=CC=CC=3)CC=3C=CC=CC=3)C2=N1 YNRAQBRGCBZJNS-UHFFFAOYSA-N 0.000 description 1
- TUYVEKQQQMQASM-UHFFFAOYSA-N n-[3-[benzyl-[2-[4-(dimethylamino)piperidin-1-yl]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-yl]amino]propyl]acetamide Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(CCCNC(C)=O)CC=3C=CC=CC=3)C2=N1 TUYVEKQQQMQASM-UHFFFAOYSA-N 0.000 description 1
- VWDISFJSMDADJI-UHFFFAOYSA-N n-[3-[benzyl-[2-[4-(dimethylamino)piperidin-1-yl]-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-yl]amino]propyl]benzamide Chemical group C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(CCCNC(=O)C=3C=CC=CC=3)CC=3C=CC=CC=3)C2=N1 VWDISFJSMDADJI-UHFFFAOYSA-N 0.000 description 1
- PWSDYUDGSVMQSD-UHFFFAOYSA-N n-anthracen-9-yl-2-[4-(dimethylamino)piperidin-1-yl]-n-methyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(C)C=3C4=CC=CC=C4C=C4C=CC=CC4=3)C2=N1 PWSDYUDGSVMQSD-UHFFFAOYSA-N 0.000 description 1
- BZBMUFUECZIUAD-UHFFFAOYSA-N n-anthracen-9-yl-2-chloro-n-methyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C=12C=CC=CC2=CC2=CC=CC=C2C=1N(C)C(C1=NC(Cl)=N2)=NC=NC1=C2N1CCOCC1 BZBMUFUECZIUAD-UHFFFAOYSA-N 0.000 description 1
- RQOCERXUTYMGRQ-UHFFFAOYSA-N n-benzyl-2-[4-(3,3-diphenylpropylamino)piperidin-1-yl]-n-methyl-8-morpholin-4-ylpyrimido[5,4-d]pyrimidin-4-amine Chemical compound N=1C(N2CCC(CC2)NCCC(C=2C=CC=CC=2)C=2C=CC=CC=2)=NC2=C(N3CCOCC3)N=CN=C2C=1N(C)CC1=CC=CC=C1 RQOCERXUTYMGRQ-UHFFFAOYSA-N 0.000 description 1
- JEBDHPXNELDUOI-UHFFFAOYSA-N n-benzyl-2-[4-(benzylamino)piperidin-1-yl]-n-methyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound N=1C=NC2=C(N3CCOCC3)N=C(N3CCC(CC3)NCC=3C=CC=CC=3)N=C2C=1N(C)CC1=CC=CC=C1 JEBDHPXNELDUOI-UHFFFAOYSA-N 0.000 description 1
- XEQNUBSYVFXPJR-UHFFFAOYSA-N n-benzyl-2-[4-(dimethylamino)piperidin-1-yl]-n-methyl-8-morpholin-4-ylpyrimido[5,4-d]pyrimidin-4-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N(C)CC=2C=CC=CC=2)=C(N=CN=C2N3CCOCC3)C2=N1 XEQNUBSYVFXPJR-UHFFFAOYSA-N 0.000 description 1
- LZHZYXAXDYYQLI-UHFFFAOYSA-N n-benzyl-2-[4-(ethylamino)piperidin-1-yl]-n-methyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(NCC)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(C)CC=3C=CC=CC=3)C2=N1 LZHZYXAXDYYQLI-UHFFFAOYSA-N 0.000 description 1
- OJIPANVBGSVHAE-UHFFFAOYSA-N n-benzyl-2-[4-[(dimethylamino)methyl]piperidin-1-yl]-n-methyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(CN(C)C)CCN1C1=NC(N2CCOCC2)=C(N=CN=C2N(C)CC=3C=CC=CC=3)C2=N1 OJIPANVBGSVHAE-UHFFFAOYSA-N 0.000 description 1
- UIGJQLXXEQVOBS-UHFFFAOYSA-N n-benzyl-2-chloro-4-morpholin-4-yl-n-propan-2-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound N=1C=NC2=C(N3CCOCC3)N=C(Cl)N=C2C=1N(C(C)C)CC1=CC=CC=C1 UIGJQLXXEQVOBS-UHFFFAOYSA-N 0.000 description 1
- HDCUHXOEAPCBCD-UHFFFAOYSA-N n-benzyl-2-chloro-n-ethyl-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound N=1C=NC2=C(N3CCOCC3)N=C(Cl)N=C2C=1N(CC)CC1=CC=CC=C1 HDCUHXOEAPCBCD-UHFFFAOYSA-N 0.000 description 1
- QATBPZUYTGYDPU-UHFFFAOYSA-N n-benzyl-2-chloro-n-methyl-8-morpholin-4-ylpyrimido[5,4-d]pyrimidin-4-amine Chemical compound N=1C(Cl)=NC2=C(N3CCOCC3)N=CN=C2C=1N(C)CC1=CC=CC=C1 QATBPZUYTGYDPU-UHFFFAOYSA-N 0.000 description 1
- BWCBHWZRGUKVET-UHFFFAOYSA-N n-benzylpyrimido[5,4-d]pyrimidin-2-amine Chemical compound N=1C=C2N=CN=CC2=NC=1NCC1=CC=CC=C1 BWCBHWZRGUKVET-UHFFFAOYSA-N 0.000 description 1
- 125000005184 naphthylamino group Chemical group C1(=CC=CC2=CC=CC=C12)N* 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000003395 phenylethylamino group Chemical group [H]N(*)C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229940093430 polyethylene glycol 1500 Drugs 0.000 description 1
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4325900A DE4325900A1 (de) | 1993-08-02 | 1993-08-02 | Trisubstituierte Pyrimido [5,4-d] pyrimidine zur Modulation der Multidrugresistenz, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL110509A0 IL110509A0 (en) | 1994-10-21 |
| IL110509A true IL110509A (en) | 1998-01-04 |
Family
ID=6494272
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL110509A IL110509A (en) | 1993-08-02 | 1994-07-29 | Pyrimido Compounds [D-5,4] Pyrimidine 2,4,8-Trimot preparation preparations and pharmaceutical preparations containing them |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5618814A (fr) |
| EP (1) | EP0645390A1 (fr) |
| JP (1) | JPH0789963A (fr) |
| KR (1) | KR950005828A (fr) |
| CN (1) | CN1041091C (fr) |
| AU (1) | AU683888B2 (fr) |
| BG (1) | BG98931A (fr) |
| CA (1) | CA2129179A1 (fr) |
| CZ (1) | CZ184594A3 (fr) |
| DE (1) | DE4325900A1 (fr) |
| EE (1) | EE9400255A (fr) |
| FI (1) | FI943574A (fr) |
| HU (1) | HUT70957A (fr) |
| IL (1) | IL110509A (fr) |
| NO (1) | NO301479B1 (fr) |
| NZ (1) | NZ264133A (fr) |
| PL (1) | PL304512A1 (fr) |
| RO (1) | RO113557B1 (fr) |
| RU (1) | RU94028278A (fr) |
| SK (1) | SK91594A3 (fr) |
| TW (1) | TW251286B (fr) |
| ZA (1) | ZA945689B (fr) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW414798B (en) * | 1994-09-07 | 2000-12-11 | Thomae Gmbh Dr K | Pyrimido (5,4-d) pyrimidines, medicaments comprising these compounds, their use and processes for their preparation |
| DE19608653A1 (de) * | 1996-03-06 | 1997-09-11 | Thomae Gmbh Dr K | Pyrimido[5,4-d]pyrimidine, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| USRE37234E1 (en) * | 1996-11-01 | 2001-06-19 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiestrase inhibitor compounds, compositions and their uses |
| US6331543B1 (en) | 1996-11-01 | 2001-12-18 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use |
| US5958926A (en) * | 1996-11-01 | 1999-09-28 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitor compounds, compositions and their uses |
| US6472425B1 (en) | 1997-10-31 | 2002-10-29 | Nitromed, Inc. | Methods for treating female sexual dysfunctions |
| US8309562B2 (en) * | 2003-07-03 | 2012-11-13 | Myrexis, Inc. | Compounds and therapeutical use thereof |
| US7618975B2 (en) * | 2003-07-03 | 2009-11-17 | Myriad Pharmaceuticals, Inc. | 4-arylamino-quinazolines and analogs as activators of caspases and inducers of apoptosis and the use thereof |
| DE102004002557A1 (de) * | 2004-01-17 | 2005-08-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von substituierten Pyrimido(5,4-d)pyrimidinen zur Behandlung von Atemwegserkrankungen |
| US8258145B2 (en) * | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
| CA2592900A1 (fr) | 2005-01-03 | 2006-07-13 | Myriad Genetics Inc. | Composes et utilisation therapeutique associee |
| CN115650827B (zh) * | 2022-10-27 | 2024-03-15 | 戊言医药科技（上海）有限公司 | 用于一类蒽环类毒素衍生物的制备方法、中间体化合物及合成方法 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3069211D1 (en) * | 1979-07-03 | 1984-10-25 | Thomae Gmbh Dr K | 2-(perhydro-1,4-diazino)-pyrimido(5,4-d)pyrimidines, their preparation and medicaments containing them |
| DE2931573A1 (de) * | 1979-08-03 | 1981-02-26 | Thomae Gmbh Dr K | Mittel zur bekaempfung des wachstums von krebszellen und dessen herstellung |
| DE3049207A1 (de) * | 1980-12-27 | 1982-07-29 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue trisubstituierte pyrimido (5,4-d) pyrimidine, ihre herstellung und ihre verwendung als arzneimittel |
| DE3423092A1 (de) * | 1984-06-22 | 1986-01-02 | Dr. Karl Thomae Gmbh, 7950 Biberach | Neue 8-alkylthio-2-piperazino-pyrimido(5,4-d) pyrimidine, ihre herstellung und diese verbindungen enthaltende arzneimittel |
| DE3833392A1 (de) * | 1988-10-01 | 1990-04-05 | Thomae Gmbh Dr K | Verwendung von pyrimido(5,4-d)pyrimidinen zur verhinderung der primaeren und sekundaeren resistenz bei der chemotherapie und diese verbindungen enthaltende arzneimittel |
-
1993
- 1993-08-02 DE DE4325900A patent/DE4325900A1/de not_active Withdrawn
-
1994
- 1994-07-07 TW TW083106205A patent/TW251286B/zh active
- 1994-07-26 EP EP94111739A patent/EP0645390A1/fr not_active Withdrawn
- 1994-07-27 RO RO94-01270A patent/RO113557B1/ro unknown
- 1994-07-28 BG BG98931A patent/BG98931A/bg unknown
- 1994-07-29 SK SK915-94A patent/SK91594A3/sk unknown
- 1994-07-29 IL IL110509A patent/IL110509A/en not_active IP Right Cessation
- 1994-07-29 NZ NZ264133A patent/NZ264133A/en unknown
- 1994-07-29 CA CA002129179A patent/CA2129179A1/fr not_active Abandoned
- 1994-08-01 HU HU9402253A patent/HUT70957A/hu unknown
- 1994-08-01 ZA ZA945689A patent/ZA945689B/xx unknown
- 1994-08-01 AU AU68813/94A patent/AU683888B2/en not_active Ceased
- 1994-08-01 PL PL94304512A patent/PL304512A1/xx unknown
- 1994-08-01 RU RU94028278/04A patent/RU94028278A/ru unknown
- 1994-08-01 FI FI943574A patent/FI943574A/fi unknown
- 1994-08-01 KR KR1019940018961A patent/KR950005828A/ko not_active Application Discontinuation
- 1994-08-01 NO NO942853A patent/NO301479B1/no unknown
- 1994-08-01 CN CN94114910A patent/CN1041091C/zh not_active Expired - Fee Related
- 1994-08-01 JP JP6179359A patent/JPH0789963A/ja active Pending
- 1994-08-02 CZ CZ941845A patent/CZ184594A3/cs unknown
- 1994-08-02 US US08/284,325 patent/US5618814A/en not_active Expired - Fee Related
- 1994-11-23 EE EE9400255A patent/EE9400255A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU9402253D0 (en) | 1994-09-28 |
| CN1106405A (zh) | 1995-08-09 |
| AU683888B2 (en) | 1997-11-27 |
| JPH0789963A (ja) | 1995-04-04 |
| PL304512A1 (en) | 1995-02-06 |
| KR950005828A (ko) | 1995-03-20 |
| BG98931A (en) | 1995-09-29 |
| ZA945689B (en) | 1996-02-01 |
| IL110509A0 (en) | 1994-10-21 |
| CA2129179A1 (fr) | 1995-02-03 |
| FI943574A (fi) | 1995-02-03 |
| NZ264133A (en) | 1996-05-28 |
| NO301479B1 (no) | 1997-11-03 |
| FI943574A0 (fi) | 1994-08-01 |
| SK91594A3 (en) | 1995-04-12 |
| EE9400255A (et) | 1996-02-15 |
| EP0645390A1 (fr) | 1995-03-29 |
| AU6881394A (en) | 1995-02-09 |
| DE4325900A1 (de) | 1995-02-09 |
| TW251286B (fr) | 1995-07-11 |
| NO942853L (no) | 1995-02-03 |
| RO113557B1 (ro) | 1998-08-28 |
| US5618814A (en) | 1997-04-08 |
| CN1041091C (zh) | 1998-12-09 |
| HUT70957A (en) | 1995-11-28 |
| NO942853D0 (fr) | 1994-08-01 |
| RU94028278A (ru) | 1996-08-27 |
| CZ184594A3 (en) | 1995-02-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4571969B2 (ja) | キナーゼインヒビターとしてのピラゾロトリアジン | |
| JP4845379B2 (ja) | サイクリン依存性キナーゼインヒビターとしてのイミダゾピリジン | |
| JP4790265B2 (ja) | サイクリン依存性キナーゼインヒビターとしての新規ピラゾロピリミジン | |
| AU2013343550B2 (en) | Substituted tricyclic benzimidazoles as kinase inhibitors | |
| US5977102A (en) | Pyrimido [5, 4-d] pyrimidines, pharmaceuticals containing these compounds, their use and processes for their preparation | |
| KR20190099209A (ko) | 8,9-디하이드로이미다졸[1,2-a]피리미도[5,4-e]피리미딘-5(6H)-케톤계 화합물 | |
| JP2006507253A (ja) | サイクリン依存性キナーゼインヒビターとしてのイミダゾピラジン | |
| US20090275593A1 (en) | 3 Substituted N-(aryl- or heteroaryl)-pyrazolo[1,5-a]pyrimidines as Kinase Inhibitors | |
| US5618814A (en) | Trisubstituted pyrimido [5,4-d] pyrimidines for modulating multi-drug resistance and pharmaceutical compositions containing these compounds | |
| EP1742937B1 (fr) | Derives de pyrrolopyrimidine servant a traiter des maladies proliferatives | |
| JP6457523B2 (ja) | 医薬組成物のためのスルホキシイミン置換キナゾリン | |
| TW553945B (en) | Triazolopurine derivatives, medicinal composition containing the derivatives, adenosine A3 receptor compatibilizing agent, and asthmatic remedy | |
| EP3098222B1 (fr) | Dérivé d'acridine fondue et composition pharmaceutique, méthode de préparation et utilisation de celui-ci | |
| HU203347B (en) | Process for producing new condensed diazepines and pharmaceutical compositions comprising same | |
| DE19502179A1 (de) | Trisubstituierte Pyrimido[5,4-d]pyrimidine, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FF | Patent granted | ||
| KB | Patent renewed | ||
| RH | Patent void |