CN1070402A - 缩合的嘧啶衍生物 - Google Patents
缩合的嘧啶衍生物 Download PDFInfo
- Publication number
- CN1070402A CN1070402A CN92109669A CN92109669A CN1070402A CN 1070402 A CN1070402 A CN 1070402A CN 92109669 A CN92109669 A CN 92109669A CN 92109669 A CN92109669 A CN 92109669A CN 1070402 A CN1070402 A CN 1070402A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- compound
- pyrimidine derivatives
- phenylene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000003230 pyrimidines Chemical class 0.000 title claims abstract description 72
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title claims description 68
- 150000001875 compounds Chemical class 0.000 claims abstract description 394
- 238000002360 preparation method Methods 0.000 claims abstract description 220
- 150000003839 salts Chemical class 0.000 claims abstract description 103
- 238000000034 method Methods 0.000 claims abstract description 100
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims description 134
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 99
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 64
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 49
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 47
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 44
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 43
- 239000002253 acid Substances 0.000 claims description 42
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 41
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 39
- 125000005843 halogen group Chemical group 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 150000002148 esters Chemical class 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 20
- 125000001544 thienyl group Chemical group 0.000 claims description 19
- 125000000335 thiazolyl group Chemical group 0.000 claims description 18
- 229940041181 antineoplastic drug Drugs 0.000 claims description 13
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 13
- 230000007062 hydrolysis Effects 0.000 claims description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000001118 alkylidene group Chemical group 0.000 claims 10
- 125000000547 substituted alkyl group Chemical group 0.000 claims 9
- 239000000470 constituent Substances 0.000 claims 5
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims 4
- 239000005864 Sulphur Substances 0.000 claims 3
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 claims 1
- 125000004426 substituted alkynyl group Chemical group 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 6
- 229940034982 antineoplastic agent Drugs 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 204
- 239000000203 mixture Substances 0.000 description 183
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 162
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 159
- 239000002904 solvent Substances 0.000 description 140
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 132
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- -1 oxo compounds Chemical class 0.000 description 120
- 239000000243 solution Substances 0.000 description 112
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 97
- 238000010898 silica gel chromatography Methods 0.000 description 68
- 238000005160 1H NMR spectroscopy Methods 0.000 description 67
- 229960002989 glutamic acid Drugs 0.000 description 66
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 62
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
- 239000011541 reaction mixture Substances 0.000 description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 50
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 50
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 49
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
- 238000005481 NMR spectroscopy Methods 0.000 description 47
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 239000012044 organic layer Substances 0.000 description 43
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 39
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 36
- 235000002639 sodium chloride Nutrition 0.000 description 35
- 238000001816 cooling Methods 0.000 description 34
- 125000005556 thienylene group Chemical group 0.000 description 34
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 33
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 32
- 125000004093 cyano group Chemical group *C#N 0.000 description 32
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 31
- 125000001183 hydrocarbyl group Chemical group 0.000 description 29
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 29
- 229920006395 saturated elastomer Polymers 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- LYDRKKWPKKEMNZ-UHFFFAOYSA-N tert-butyl benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1 LYDRKKWPKKEMNZ-UHFFFAOYSA-N 0.000 description 24
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 23
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 22
- 239000002585 base Substances 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 20
- 235000019270 ammonium chloride Nutrition 0.000 description 20
- 239000007864 aqueous solution Substances 0.000 description 19
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 19
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 19
- 125000002947 alkylene group Chemical group 0.000 description 18
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
- 238000006798 ring closing metathesis reaction Methods 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 16
- 206010028980 Neoplasm Diseases 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 14
- 125000005551 pyridylene group Chemical group 0.000 description 14
- 150000007942 carboxylates Chemical class 0.000 description 13
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- 108010022394 Threonine synthase Proteins 0.000 description 12
- 229910000085 borane Inorganic materials 0.000 description 12
- 102000004419 dihydrofolate reductase Human genes 0.000 description 12
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 239000005711 Benzoic acid Substances 0.000 description 11
- 125000003277 amino group Chemical group 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- WJTWHJRAPTZRNI-UHFFFAOYSA-N 5-oxocyclopentene-1-carbonitrile Chemical compound O=C1CCC=C1C#N WJTWHJRAPTZRNI-UHFFFAOYSA-N 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 235000010233 benzoic acid Nutrition 0.000 description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 9
- 235000011089 carbon dioxide Nutrition 0.000 description 9
- 125000002541 furyl group Chemical group 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 150000003138 primary alcohols Chemical class 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
- KCTZOTUQSGYWLV-UHFFFAOYSA-N N1C=NC=C2N=CC=C21 Chemical compound N1C=NC=C2N=CC=C21 KCTZOTUQSGYWLV-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- 238000007239 Wittig reaction Methods 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 8
- 150000002306 glutamic acid derivatives Chemical group 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 7
- ZFFWIOSEDOAZAY-UHFFFAOYSA-N 2-aminoprop-2-enenitrile Chemical compound NC(=C)C#N ZFFWIOSEDOAZAY-UHFFFAOYSA-N 0.000 description 7
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-Glutamic acid Natural products OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 7
- 229910002092 carbon dioxide Inorganic materials 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 7
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- 125000004494 ethyl ester group Chemical group 0.000 description 7
- 208000032839 leukemia Diseases 0.000 description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
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- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 6
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 239000000010 aprotic solvent Substances 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 150000004820 halides Chemical class 0.000 description 6
- 150000002440 hydroxy compounds Chemical class 0.000 description 6
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 6
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 6
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
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- 238000006722 reduction reaction Methods 0.000 description 6
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- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 6
- 239000005977 Ethylene Substances 0.000 description 5
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- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
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- 239000003960 organic solvent Substances 0.000 description 5
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- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 4
- BJUPTJXRJDXLHF-UHFFFAOYSA-N 6,7-dihydro-5h-cyclopenta[d]pyrimidine Chemical class N1=CN=C2CCCC2=C1 BJUPTJXRJDXLHF-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
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- QDZHTSUAGUMODC-UHFFFAOYSA-N tert-butyl 4-[2-(2-methoxycarbonyl-3-oxocyclopentyl)ethyl]benzoate Chemical compound C1CC(=O)C(C(=O)OC)C1CCC1=CC=C(C(=O)OC(C)(C)C)C=C1 QDZHTSUAGUMODC-UHFFFAOYSA-N 0.000 description 1
- YZDSPKCGFYOLCU-UHFFFAOYSA-N tert-butyl 4-[3-(2,4-diaminopyrrolo[3,2-d]pyrimidin-5-yl)butan-2-yl]benzoate Chemical compound C1=CC2=NC(N)=NC(N)=C2N1C(C)C(C)C1=CC=C(C(=O)OC(C)(C)C)C=C1 YZDSPKCGFYOLCU-UHFFFAOYSA-N 0.000 description 1
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- SQQIOFIRIUZMIN-UHFFFAOYSA-N tert-butyl 4-[3-(2-amino-4-oxo-1h-pyrrolo[3,2-d]pyrimidin-5-yl)propyl]benzoate Chemical compound C1=CC(C(=O)OC(C)(C)C)=CC=C1CCCN1C2=C(O)N=C(N)N=C2C=C1 SQQIOFIRIUZMIN-UHFFFAOYSA-N 0.000 description 1
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- NDCQKGXMOXTZMP-UHFFFAOYSA-N tert-butyl 4-[3-(2-cyano-3-methoxycyclopent-2-en-1-yl)propyl]benzoate Chemical compound C1CC(OC)=C(C#N)C1CCCC1=CC=C(C(=O)OC(C)(C)C)C=C1 NDCQKGXMOXTZMP-UHFFFAOYSA-N 0.000 description 1
- ZLYFEYYIJLNDEF-UHFFFAOYSA-N tert-butyl 4-[3-(2-cyano-3-oxocyclopentyl)propyl]benzoate Chemical compound C1=CC(C(=O)OC(C)(C)C)=CC=C1CCCC1C(C#N)C(=O)CC1 ZLYFEYYIJLNDEF-UHFFFAOYSA-N 0.000 description 1
- QSOFPIXGDWKANX-UHFFFAOYSA-N tert-butyl 4-[3-(3-amino-2-cyanopyrrol-1-yl)propyl]benzoate Chemical compound C1=CC(C(=O)OC(C)(C)C)=CC=C1CCCN1C(C#N)=C(N)C=C1 QSOFPIXGDWKANX-UHFFFAOYSA-N 0.000 description 1
- UPEYQTBFNLMZTH-UHFFFAOYSA-N tert-butyl 4-[4-(2-cyano-3-methoxycyclopent-2-en-1-yl)butan-2-yl]benzoate Chemical compound C1CC(OC)=C(C#N)C1CCC(C)C1=CC=C(C(=O)OC(C)(C)C)C=C1 UPEYQTBFNLMZTH-UHFFFAOYSA-N 0.000 description 1
- NMOFKVHBJJHHBN-UHFFFAOYSA-N tert-butyl 4-[4-(2-cyano-3-oxocyclopentyl)butan-2-yl]benzoate Chemical compound C=1C=C(C(=O)OC(C)(C)C)C=CC=1C(C)CCC1CCC(=O)C1C#N NMOFKVHBJJHHBN-UHFFFAOYSA-N 0.000 description 1
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- GRUSXPIAJWRLRQ-UHFFFAOYSA-N tert-butyl 4-methylbenzoate Chemical compound CC1=CC=C(C(=O)OC(C)(C)C)C=C1 GRUSXPIAJWRLRQ-UHFFFAOYSA-N 0.000 description 1
- MCHIPTCUNOHZCY-UHFFFAOYSA-N tert-butyl 4-propanoylbenzoate Chemical compound CCC(=O)C1=CC=C(C(=O)OC(C)(C)C)C=C1 MCHIPTCUNOHZCY-UHFFFAOYSA-N 0.000 description 1
- VHPDUAJRKPBMSR-UHFFFAOYSA-N tert-butyl 5-[3-(2-cyano-3-methoxycyclopent-2-en-1-yl)propyl]thiophene-2-carboxylate Chemical compound C1CC(OC)=C(C#N)C1CCCC1=CC=C(C(=O)OC(C)(C)C)S1 VHPDUAJRKPBMSR-UHFFFAOYSA-N 0.000 description 1
- TYDXSUIPFVFLNU-UHFFFAOYSA-N tert-butyl 5-[3-(3-amino-2-cyanopyrrol-1-yl)propyl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC(C)(C)C)=CC=C1CCCN1C(C#N)=C(N)C=C1 TYDXSUIPFVFLNU-UHFFFAOYSA-N 0.000 description 1
- AXGWEMGJOUIUMX-UHFFFAOYSA-N tert-butyl 5-formylthiophene-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CC=C(C=O)S1 AXGWEMGJOUIUMX-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 239000005460 tetrahydrofolate Substances 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004187 tetrahydropyran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005557 thiazolylene group Chemical group 0.000 description 1
- 239000003734 thymidylate synthase inhibitor Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- SCHLFXXEFZSLSD-UHFFFAOYSA-M triethyl(methyl)phosphanium;bromide Chemical compound [Br-].CC[P+](C)(CC)CC SCHLFXXEFZSLSD-UHFFFAOYSA-M 0.000 description 1
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- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20925291 | 1991-08-21 | ||
| JP209252/91 | 1991-08-21 | ||
| JP25154891 | 1991-09-30 | ||
| JP251548/91 | 1991-09-30 | ||
| JP21767092A JP3144903B2 (ja) | 1991-08-21 | 1992-08-17 | 縮合ピリミジン誘導体 |
| JP217670/92 | 1992-08-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1070402A true CN1070402A (zh) | 1993-03-31 |
Family
ID=27328976
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92109669A Pending CN1070402A (zh) | 1991-08-21 | 1992-08-21 | 缩合的嘧啶衍生物 |
Country Status (9)
| Country | Link |
|---|---|
| JP (1) | JP3144903B2 (enExample) |
| KR (1) | KR950011740B1 (enExample) |
| CN (1) | CN1070402A (enExample) |
| AU (1) | AU655051B2 (enExample) |
| CA (1) | CA2076431A1 (enExample) |
| FI (1) | FI923697A7 (enExample) |
| HU (1) | HUT70180A (enExample) |
| NO (1) | NO923249L (enExample) |
| TW (1) | TW202451B (enExample) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2127274C1 (ru) * | 1992-09-25 | 1999-03-10 | Эли Лилли Энд Компани | СПОСОБ ПОЛУЧЕНИЯ 5-ЗАМЕЩЕННЫХ ПИРРОЛО (2,3-α)ПИРИМИДИНОВ |
| US8252804B2 (en) | 2008-10-01 | 2012-08-28 | Duquesne University Of The Holy Spirit | Selective proton coupled folate transporter and folate receptor, and GARFTase inhibitor compounds and methods of using the same |
| US20110082158A1 (en) * | 2008-10-01 | 2011-04-07 | Aleem Gangjee | Selective proton coupled folate transporter and folate receptor, and garftase and/or other folate metabolizing enzymes inhibitor compounds and methods of using the same |
| CN106188060A (zh) * | 2015-04-29 | 2016-12-07 | 厦门大学 | 嘧啶并吡咯类化合物、其制备方法、药用组合物及其应用 |
| CN113788834B (zh) * | 2021-09-18 | 2022-11-29 | 河南奥思恩医药科技有限公司 | 2,4-二氯-6,7-二氢-5H-吡咯并[3,4-d]嘧啶盐酸盐的制备方法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0438261A3 (en) * | 1990-01-16 | 1992-02-26 | Takeda Chemical Industries, Ltd. | Condensed heterocyclic glutamic acid derivatives, their production and use |
-
1992
- 1992-08-17 JP JP21767092A patent/JP3144903B2/ja not_active Expired - Fee Related
- 1992-08-18 FI FI923697A patent/FI923697A7/fi not_active Application Discontinuation
- 1992-08-18 TW TW081106523A patent/TW202451B/zh active
- 1992-08-19 CA CA002076431A patent/CA2076431A1/en not_active Abandoned
- 1992-08-19 NO NO92923249A patent/NO923249L/no unknown
- 1992-08-19 HU HU9202699A patent/HUT70180A/hu unknown
- 1992-08-20 AU AU21157/92A patent/AU655051B2/en not_active Ceased
- 1992-08-21 CN CN92109669A patent/CN1070402A/zh active Pending
- 1992-08-21 KR KR1019920015043A patent/KR950011740B1/ko not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| HUT70180A (en) | 1995-09-28 |
| JP3144903B2 (ja) | 2001-03-12 |
| KR950011740B1 (ko) | 1995-10-09 |
| JPH05186437A (ja) | 1993-07-27 |
| FI923697A0 (fi) | 1992-08-18 |
| TW202451B (enExample) | 1993-03-21 |
| AU655051B2 (en) | 1994-12-01 |
| KR930004307A (ko) | 1993-03-22 |
| NO923249L (no) | 1993-02-22 |
| AU2115792A (en) | 1993-02-25 |
| NO923249D0 (no) | 1992-08-19 |
| FI923697A7 (fi) | 1993-02-22 |
| CA2076431A1 (en) | 1993-02-22 |
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| AD01 | Patent right deemed abandoned | ||
| C20 | Patent right or utility model deemed to be abandoned or is abandoned |