BG98931A - Trisubstituted pyrimido [5,4-d]-pyrimidines for the modulation of resistence to medicaments, medicamentous formulations containing them and method for the their preparation - Google Patents
Trisubstituted pyrimido [5,4-d]-pyrimidines for the modulation of resistence to medicaments, medicamentous formulations containing them and method for the their preparation Download PDFInfo
- Publication number
- BG98931A BG98931A BG98931A BG9893194A BG98931A BG 98931 A BG98931 A BG 98931A BG 98931 A BG98931 A BG 98931A BG 9893194 A BG9893194 A BG 9893194A BG 98931 A BG98931 A BG 98931A
- Authority
- BG
- Bulgaria
- Prior art keywords
- group
- piperidino
- carbon atoms
- pyrimidine
- pyrimido
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title claims abstract description 8
- 239000003814 drug Substances 0.000 title claims description 9
- JOZPEVMCAKXSEY-UHFFFAOYSA-N pyrimido[5,4-d]pyrimidine Chemical class N1=CN=CC2=NC=NC=C21 JOZPEVMCAKXSEY-UHFFFAOYSA-N 0.000 title claims description 7
- 239000000203 mixture Substances 0.000 title description 24
- 238000009472 formulation Methods 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- -1 1,2,3,4-tetrahydroisoquinolin-2-yl Chemical group 0.000 claims description 361
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 114
- 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 109
- 150000001875 compounds Chemical class 0.000 claims description 63
- 125000004432 carbon atom Chemical group C* 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 34
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 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
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Chemical group 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 12
- 150000002431 hydrogen Chemical group 0.000 claims description 12
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000003282 alkyl amino group Chemical group 0.000 claims description 11
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 10
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 229940127089 cytotoxic agent Drugs 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 125000001624 naphthyl group Chemical group 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 238000007254 oxidation reaction Methods 0.000 claims description 6
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 150000003230 pyrimidines Chemical class 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- NDOVLWQBFFJETK-UHFFFAOYSA-N 1,4-thiazinane 1,1-dioxide Chemical group O=S1(=O)CCNCC1 NDOVLWQBFFJETK-UHFFFAOYSA-N 0.000 claims description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 4
- 230000001235 sensitizing effect Effects 0.000 claims description 4
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical group C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 230000009435 amidation Effects 0.000 claims description 3
- 238000007112 amidation reaction Methods 0.000 claims description 3
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- YFJAIURZMRJPDB-UHFFFAOYSA-N n,n-dimethylpiperidin-4-amine Chemical compound CN(C)C1CCNCC1 YFJAIURZMRJPDB-UHFFFAOYSA-N 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 238000006268 reductive amination reaction Methods 0.000 claims description 3
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 3
- YHIIJNLSGULWAA-UHFFFAOYSA-N 1,4-thiazinane 1-oxide Chemical group O=S1CCNCC1 YHIIJNLSGULWAA-UHFFFAOYSA-N 0.000 claims description 2
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 claims description 2
- CEIXWJHURKEBMQ-UHFFFAOYSA-N Heliamine Chemical group C1CNCC2=C1C=C(OC)C(OC)=C2 CEIXWJHURKEBMQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 2
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical group C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 125000005184 naphthylamino group Chemical group C1(=CC=CC2=CC=CC=C12)N* 0.000 claims description 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 2
- JHLDJOBIUVJSTG-UHFFFAOYSA-N tdiq Chemical group C1CNCC2=C1C=C1OCOC1=C2 JHLDJOBIUVJSTG-UHFFFAOYSA-N 0.000 claims description 2
- 229920000180 alkyd Polymers 0.000 claims 2
- 239000000969 carrier Substances 0.000 claims 2
- 241001024304 Mino Species 0.000 claims 1
- QQCGKIZHTJLRNN-NBRVCOCJSA-N Pipericine Chemical group CCCCCCCCCCCCC\C=C\C=C\C(=O)NCC(C)C QQCGKIZHTJLRNN-NBRVCOCJSA-N 0.000 claims 1
- PWCKZDNEYXQQGH-UHFFFAOYSA-N n-benzyl-2-[4-(dimethylamino)piperidin-1-yl]-n-methyl-4-piperidin-1-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C1CC(N(C)C)CCN1C1=NC(N2CCCCC2)=C(N=CN=C2N(C)CC=3C=CC=CC=3)C2=N1 PWCKZDNEYXQQGH-UHFFFAOYSA-N 0.000 claims 1
- HBDDRESWUAFAHY-UHFFFAOYSA-N thiomorpholin-3-one Chemical class O=C1CSCCN1 HBDDRESWUAFAHY-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 4
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 238000000921 elemental analysis Methods 0.000 description 68
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 59
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- 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 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 239000000741 silica gel Substances 0.000 description 29
- 229910002027 silica gel Inorganic materials 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000013543 active substance Substances 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 229960000583 acetic acid Drugs 0.000 description 15
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 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
- 210000004027 cell Anatomy 0.000 description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-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
- 239000002253 acid Substances 0.000 description 10
- 239000012362 glacial acetic acid Substances 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000011780 sodium chloride Substances 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000002512 chemotherapy Methods 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 239000008298 dragée Substances 0.000 description 6
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 229940099112 cornstarch Drugs 0.000 description 5
- 229960004679 doxorubicin Drugs 0.000 description 5
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 239000002585 base Substances 0.000 description 4
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- 239000001963 growth medium Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 3
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- 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 3
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 3
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- NQXGOCGVXULVRY-UHFFFAOYSA-N 2-(4-bromo-3,5-diphenyltetrazol-2-yl)-4,5-dimethyl-1,3-thiazole Chemical compound S1C(C)=C(C)N=C1N1N(C=2C=CC=CC=2)N(Br)C(C=2C=CC=CC=2)=N1 NQXGOCGVXULVRY-UHFFFAOYSA-N 0.000 description 2
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- SWQDHDJAIYSTRF-UHFFFAOYSA-N n,n-dimethyl-1-piperidin-4-ylmethanamine Chemical compound CN(C)CC1CCNCC1 SWQDHDJAIYSTRF-UHFFFAOYSA-N 0.000 description 1
- WEJQQLAAKOHJRQ-UHFFFAOYSA-N n-[2-(2-chloro-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-yl)-3,4-dihydro-1h-isoquinolin-5-yl]acetamide Chemical compound C1CC=2C(NC(=O)C)=CC=CC=2CN1C(C1=NC(Cl)=N2)=NC=NC1=C2N1CCOCC1 WEJQQLAAKOHJRQ-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
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- XYQALCZKBXGKAD-UHFFFAOYSA-N n-benzyl-2-chloro-4-morpholin-4-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound C=12N=CN=C(NCC=3C=CC=CC=3)C2=NC(Cl)=NC=1N1CCOCC1 XYQALCZKBXGKAD-UHFFFAOYSA-N 0.000 description 1
- MHOWPDAVWDXATH-UHFFFAOYSA-N n-benzyl-2-chloro-n-methyl-4-piperidin-1-ylpyrimido[5,4-d]pyrimidin-8-amine Chemical compound N=1C=NC2=C(N3CCCCC3)N=C(Cl)N=C2C=1N(C)CC1=CC=CC=C1 MHOWPDAVWDXATH-UHFFFAOYSA-N 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
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- 235000005985 organic acids Nutrition 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- RLZZZVKAURTHCP-UHFFFAOYSA-N phenanthrene-3,4-diol Chemical compound C1=CC=C2C3=C(O)C(O)=CC=C3C=CC2=C1 RLZZZVKAURTHCP-UHFFFAOYSA-N 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
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
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- 229960003171 plicamycin Drugs 0.000 description 1
- 229940093430 polyethylene glycol 1500 Drugs 0.000 description 1
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- 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
- 238000002203 pretreatment Methods 0.000 description 1
- 230000001902 propagating effect Effects 0.000 description 1
- 125000006235 propyl amino ethyl group Chemical group [H]N(C([H])([H])C([H])([H])*)C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
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- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000008163 sugars Chemical class 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
- 239000003826 tablet Substances 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 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
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 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)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material 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 (1)
| Publication Number | Publication Date |
|---|---|
| BG98931A true BG98931A (en) | 1995-09-29 |
Family
ID=6494272
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BG98931A BG98931A (en) | 1993-08-02 | 1994-07-28 | Trisubstituted pyrimido [5,4-d]-pyrimidines for the modulation of resistence to medicaments, medicamentous formulations containing them and method for the their preparation |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5618814A (cs) |
| EP (1) | EP0645390A1 (cs) |
| JP (1) | JPH0789963A (cs) |
| KR (1) | KR950005828A (cs) |
| CN (1) | CN1041091C (cs) |
| AU (1) | AU683888B2 (cs) |
| BG (1) | BG98931A (cs) |
| CA (1) | CA2129179A1 (cs) |
| CZ (1) | CZ184594A3 (cs) |
| DE (1) | DE4325900A1 (cs) |
| EE (1) | EE9400255A (cs) |
| FI (1) | FI943574A (cs) |
| HU (1) | HUT70957A (cs) |
| IL (1) | IL110509A (cs) |
| NO (1) | NO301479B1 (cs) |
| NZ (1) | NZ264133A (cs) |
| PL (1) | PL304512A1 (cs) |
| RO (1) | RO113557B1 (cs) |
| RU (1) | RU94028278A (cs) |
| SK (1) | SK91594A3 (cs) |
| TW (1) | TW251286B (cs) |
| ZA (1) | ZA945689B (cs) |
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 |
| US6331543B1 (en) * | 1996-11-01 | 2001-12-18 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use |
| USRE37234E1 (en) * | 1996-11-01 | 2001-06-19 | Nitromed, Inc. | Nitrosated and nitrosylated phosphodiestrase inhibitor compounds, compositions and their uses |
| 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 |
| CN1984660B (zh) | 2003-07-03 | 2010-12-15 | 美瑞德生物工程公司 | 作为天冬氨酸特异性半胱氨酸蛋白酶活化剂和细胞程序死亡诱导剂的4-芳基氨基-喹唑啉 |
| 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 |
| CA2592900A1 (en) | 2005-01-03 | 2006-07-13 | Myriad Genetics Inc. | Nitrogen containing bicyclic compounds and therapeutical use thereof |
| US8258145B2 (en) * | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
| 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 |
|---|---|---|---|---|
| EP0023559B1 (de) * | 1979-07-03 | 1984-09-19 | Dr. Karl Thomae GmbH | 2-(Perhydro-1,4-diazino)-pyrimido(5,4-d)pyrimidine, ihre Herstellung und diese Verbindungen enthaltenden Arzneimittel |
| 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/de 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 IL IL110509A patent/IL110509A/en not_active IP Right Cessation
- 1994-07-29 CA CA002129179A patent/CA2129179A1/en not_active Abandoned
- 1994-07-29 NZ NZ264133A patent/NZ264133A/en unknown
- 1994-07-29 SK SK915-94A patent/SK91594A3/sk unknown
- 1994-08-01 PL PL94304512A patent/PL304512A1/xx unknown
- 1994-08-01 ZA ZA945689A patent/ZA945689B/xx unknown
- 1994-08-01 CN CN94114910A patent/CN1041091C/zh not_active Expired - Fee Related
- 1994-08-01 KR KR1019940018961A patent/KR950005828A/ko not_active Application Discontinuation
- 1994-08-01 HU HU9402253A patent/HUT70957A/hu unknown
- 1994-08-01 FI FI943574A patent/FI943574A/fi unknown
- 1994-08-01 JP JP6179359A patent/JPH0789963A/ja active Pending
- 1994-08-01 RU RU94028278/04A patent/RU94028278A/ru unknown
- 1994-08-01 AU AU68813/94A patent/AU683888B2/en not_active Ceased
- 1994-08-01 NO NO942853A patent/NO301479B1/no unknown
- 1994-08-02 US US08/284,325 patent/US5618814A/en not_active Expired - Fee Related
- 1994-08-02 CZ CZ941845A patent/CZ184594A3/cs unknown
- 1994-11-23 EE EE9400255A patent/EE9400255A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CN1041091C (zh) | 1998-12-09 |
| HU9402253D0 (en) | 1994-09-28 |
| US5618814A (en) | 1997-04-08 |
| IL110509A (en) | 1998-01-04 |
| CN1106405A (zh) | 1995-08-09 |
| AU683888B2 (en) | 1997-11-27 |
| FI943574A0 (fi) | 1994-08-01 |
| SK91594A3 (en) | 1995-04-12 |
| AU6881394A (en) | 1995-02-09 |
| CA2129179A1 (en) | 1995-02-03 |
| DE4325900A1 (de) | 1995-02-09 |
| ZA945689B (en) | 1996-02-01 |
| CZ184594A3 (en) | 1995-02-15 |
| EP0645390A1 (de) | 1995-03-29 |
| NO942853D0 (cs) | 1994-08-01 |
| PL304512A1 (en) | 1995-02-06 |
| IL110509A0 (en) | 1994-10-21 |
| RO113557B1 (ro) | 1998-08-28 |
| NZ264133A (en) | 1996-05-28 |
| NO942853L (no) | 1995-02-03 |
| KR950005828A (ko) | 1995-03-20 |
| FI943574A (fi) | 1995-02-03 |
| HUT70957A (en) | 1995-11-28 |
| EE9400255A (et) | 1996-02-15 |
| TW251286B (cs) | 1995-07-11 |
| NO301479B1 (no) | 1997-11-03 |
| JPH0789963A (ja) | 1995-04-04 |
| RU94028278A (ru) | 1996-08-27 |
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