NO331981B1 - Tienopyrimidin forbindelser, deres anvendelse samt farmasoytisk middel - Google Patents

Info

Publication number

NO331981B1

NO331981B1 NO20053974A NO20053974A NO331981B1 NO 331981 B1 NO331981 B1 NO 331981B1 NO 20053974 A NO20053974 A NO 20053974A NO 20053974 A NO20053974 A NO 20053974A NO 331981 B1 NO331981 B1 NO 331981B1

Authority

NO

Norway

Prior art keywords

methyl

compound

phenyl

difluorobenzyl

amino

Prior art date

2003-01-29

Links

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 366
• 239000008177 pharmaceutical agent Substances 0.000 title claims description 4
• 125000001424 substituent group Chemical group 0.000 claims abstract description 183
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 67
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 46
• 150000003839 salts Chemical class 0.000 claims abstract description 46
• 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 claims abstract description 28
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 27
• 150000002367 halogens Chemical class 0.000 claims abstract description 27
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 27
• XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 claims abstract description 25
• 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 claims abstract description 24
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 18
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 2
• 125000000623 heterocyclic group Chemical group 0.000 claims description 27
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
• 230000001419 dependent effect Effects 0.000 claims description 18
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 16
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
• 201000011510 cancer Diseases 0.000 claims description 14
• 229940088597 hormone Drugs 0.000 claims description 14
• 239000005556 hormone Substances 0.000 claims description 14
• 206010028980 Neoplasm Diseases 0.000 claims description 13
• 239000003163 gonadal steroid hormone Substances 0.000 claims description 13
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 7
• 230000002980 postoperative effect Effects 0.000 claims description 7
• MNXSZYSLNRUFIA-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-ethoxyethyl(methyl)amino]methyl]-2,4-dioxo-3-pyridin-2-ylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2N=CC=CC=2)C(=O)C=2C(CN(C)CCOCC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F MNXSZYSLNRUFIA-UHFFFAOYSA-N 0.000 claims description 6
• 208000024827 Alzheimer disease Diseases 0.000 claims description 6
• 201000009273 Endometriosis Diseases 0.000 claims description 6
• 206010020880 Hypertrophy Diseases 0.000 claims description 6
• 230000002028 premature Effects 0.000 claims description 6
• 210000002307 prostate Anatomy 0.000 claims description 6
• AOMXMOCNKJTRQP-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CN(C)C)C(C(=O)N(C=2N=NC(OC)=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 AOMXMOCNKJTRQP-UHFFFAOYSA-N 0.000 claims description 5
• DUZGTINKFAHXDT-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CN(C)C)C(C(=O)N(C=2C=NC(OC)=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 DUZGTINKFAHXDT-UHFFFAOYSA-N 0.000 claims description 5
• GAQYSUJKGLPTKB-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-2,4-dioxo-3-pyridin-2-ylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical group O=C1N(C=2N=CC=CC=2)C(=O)C=2C(CN(C)CCOC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F GAQYSUJKGLPTKB-UHFFFAOYSA-N 0.000 claims description 5
• 206010046798 Uterine leiomyoma Diseases 0.000 claims description 5
• 210000001672 ovary Anatomy 0.000 claims description 5
• 208000011580 syndromic disease Diseases 0.000 claims description 5
• 208000002874 Acne Vulgaris Diseases 0.000 claims description 4
• 201000004384 Alopecia Diseases 0.000 claims description 4
• 201000000736 Amenorrhea Diseases 0.000 claims description 4
• 206010001928 Amenorrhoea Diseases 0.000 claims description 4
• 206010036618 Premenstrual syndrome Diseases 0.000 claims description 4
• 206010000496 acne Diseases 0.000 claims description 4
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 4
• 231100000360 alopecia Toxicity 0.000 claims description 4
• 231100000540 amenorrhea Toxicity 0.000 claims description 4
• 239000003433 contraceptive agent Substances 0.000 claims description 4
• 230000002254 contraceptive effect Effects 0.000 claims description 4
• 208000000509 infertility Diseases 0.000 claims description 4
• 231100000535 infertility Toxicity 0.000 claims description 4
• 230000036512 infertility Effects 0.000 claims description 4
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
• 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 4
• 208000005171 Dysmenorrhea Diseases 0.000 claims description 3
• 206010013935 Dysmenorrhoea Diseases 0.000 claims description 3
• 239000000411 inducer Substances 0.000 claims description 3
• 230000016087 ovulation Effects 0.000 claims description 3
• 208000033830 Hot Flashes Diseases 0.000 claims description 2
• 206010060800 Hot flush Diseases 0.000 claims description 2
• 206010027476 Metastases Diseases 0.000 claims description 2
• 210000000988 bone and bone Anatomy 0.000 claims description 2
• 230000009401 metastasis Effects 0.000 claims description 2
• 230000001850 reproductive effect Effects 0.000 claims description 2
• 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims 1
• 101000904177 Clupea pallasii Gonadoliberin-1 Proteins 0.000 claims 1
• -1 thienopyrimidine compound Chemical class 0.000 abstract description 463
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 28
• 229940035638 gonadotropin-releasing hormone Drugs 0.000 abstract description 23
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
• 125000003341 7 membered heterocyclic group Chemical group 0.000 abstract 1
• 230000008485 antagonism Effects 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 160
• 238000002360 preparation method Methods 0.000 description 108
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 105
• 238000006243 chemical reaction Methods 0.000 description 102
• 238000005160 1H NMR spectroscopy Methods 0.000 description 69
• 239000000243 solution Substances 0.000 description 64
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 48
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
• 239000000203 mixture Substances 0.000 description 45
• 239000013078 crystal Substances 0.000 description 44
• 239000011541 reaction mixture Substances 0.000 description 43
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
• 239000002904 solvent Substances 0.000 description 37
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
• 238000000921 elemental analysis Methods 0.000 description 34
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
• 238000000034 method Methods 0.000 description 32
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 29
• WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 28
• 125000003118 aryl group Chemical group 0.000 description 28
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
• 239000000126 substance Substances 0.000 description 27
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
• 239000000843 powder Substances 0.000 description 26
• 230000002829 reductive effect Effects 0.000 description 26
• 239000003814 drug Substances 0.000 description 25
• 239000012044 organic layer Substances 0.000 description 24
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
• 229940079593 drug Drugs 0.000 description 22
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 21
• 235000019341 magnesium sulphate Nutrition 0.000 description 21
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
• 238000005481 NMR spectroscopy Methods 0.000 description 20
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 20
• 239000003480 eluent Substances 0.000 description 20
• 238000010898 silica gel chromatography Methods 0.000 description 20
• 235000017557 sodium bicarbonate Nutrition 0.000 description 20
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
• 150000001408 amides Chemical class 0.000 description 18
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 18
• 230000003042 antagnostic effect Effects 0.000 description 17
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 17
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 17
• 239000007864 aqueous solution Substances 0.000 description 16
• 238000006467 substitution reaction Methods 0.000 description 16
• 125000005530 alkylenedioxy group Chemical group 0.000 description 15
• 239000003795 chemical substances by application Substances 0.000 description 15
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
• 102000005962 receptors Human genes 0.000 description 14
• 108020003175 receptors Proteins 0.000 description 14
• 239000002253 acid Substances 0.000 description 13
• 125000004644 alkyl sulfinyl group Chemical group 0.000 description 13
• 125000004093 cyano group Chemical group *C#N 0.000 description 13
• ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 13
• 239000000706 filtrate Substances 0.000 description 13
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 12
• IXQSZFHLLQMBAG-UHFFFAOYSA-N 2-(4-aminophenyl)propan-2-ol Chemical compound CC(C)(O)C1=CC=C(N)C=C1 IXQSZFHLLQMBAG-UHFFFAOYSA-N 0.000 description 12
• FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 12
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
• 125000004414 alkyl thio group Chemical group 0.000 description 12
• 229910052799 carbon Inorganic materials 0.000 description 12
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
• 230000000694 effects Effects 0.000 description 12
• 229960004338 leuprorelin Drugs 0.000 description 12
• 238000004519 manufacturing process Methods 0.000 description 12
• 108090000765 processed proteins & peptides Proteins 0.000 description 12
• 229940002612 prodrug Drugs 0.000 description 12
• 239000000651 prodrug Substances 0.000 description 12
• 229920006395 saturated elastomer Polymers 0.000 description 12
• 229910052717 sulfur Inorganic materials 0.000 description 12
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
• 125000003710 aryl alkyl group Chemical group 0.000 description 11
• 150000001721 carbon Chemical group 0.000 description 11
• 238000001816 cooling Methods 0.000 description 11
• 125000005842 heteroatom Chemical group 0.000 description 11
• 125000004430 oxygen atom Chemical group O* 0.000 description 11
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
• 239000007787 solid Substances 0.000 description 11
• 125000004434 sulfur atom Chemical group 0.000 description 11
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 10
• AGEYSCFFUDNQPS-UHFFFAOYSA-N 4-[[benzyl(methyl)amino]methyl]-2-[(2,6-difluorophenyl)methyl-ethoxycarbonylamino]-5-[4-(methoxycarbamoylamino)phenyl]thiophene-3-carboxylic acid Chemical compound S1C(C=2C=CC(NC(=O)NOC)=CC=2)=C(CN(C)CC=2C=CC=CC=2)C(C(O)=O)=C1N(C(=O)OCC)CC1=C(F)C=CC=C1F AGEYSCFFUDNQPS-UHFFFAOYSA-N 0.000 description 10
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
• 125000003277 amino group Chemical group 0.000 description 10
• 239000002585 base Substances 0.000 description 10
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 10
• 125000004122 cyclic group Chemical group 0.000 description 10
• 230000032050 esterification Effects 0.000 description 10
• 238000005886 esterification reaction Methods 0.000 description 10
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 10
• 239000007788 liquid Substances 0.000 description 10
• 229910052757 nitrogen Inorganic materials 0.000 description 10
• 125000004433 nitrogen atom Chemical group N* 0.000 description 10
• 235000011121 sodium hydroxide Nutrition 0.000 description 10
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
• QEBMIWALGQEMFR-UHFFFAOYSA-N 4-(2-methoxypropan-2-yl)aniline Chemical compound COC(C)(C)C1=CC=C(N)C=C1 QEBMIWALGQEMFR-UHFFFAOYSA-N 0.000 description 9
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 9
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
• MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
• 239000012267 brine Substances 0.000 description 9
• 239000003102 growth factor Substances 0.000 description 9
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 8
• HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 8
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 8
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 8
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 8
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
• 235000010724 Wisteria floribunda Nutrition 0.000 description 8
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
• 229910052794 bromium Inorganic materials 0.000 description 8
• 239000000460 chlorine Substances 0.000 description 8
• 229910052801 chlorine Inorganic materials 0.000 description 8
• 229910052731 fluorine Inorganic materials 0.000 description 8
• 239000011737 fluorine Substances 0.000 description 8
• 239000003112 inhibitor Substances 0.000 description 8
• 238000002347 injection Methods 0.000 description 8
• 239000007924 injection Substances 0.000 description 8
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
• 239000011630 iodine Substances 0.000 description 8
• 229910052740 iodine Inorganic materials 0.000 description 8
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 8
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
• 239000012528 membrane Substances 0.000 description 8
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 7
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
• 241001465754 Metazoa Species 0.000 description 7
• 229920002472 Starch Polymers 0.000 description 7
• 238000005917 acylation reaction Methods 0.000 description 7
• 239000003098 androgen Substances 0.000 description 7
• 239000012298 atmosphere Substances 0.000 description 7
• 210000004027 cell Anatomy 0.000 description 7
• 239000001257 hydrogen Substances 0.000 description 7
• 229910052739 hydrogen Inorganic materials 0.000 description 7
• 230000014759 maintenance of location Effects 0.000 description 7
• 235000010355 mannitol Nutrition 0.000 description 7
• 125000004943 pyrimidin-6-yl group Chemical group N1=CN=CC=C1* 0.000 description 7
• 239000008107 starch Substances 0.000 description 7
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• MRUUEMLPUDAITO-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-3-(6-methoxypyridazin-3-yl)-5-(morpholin-4-ylmethyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CN2CCOCC2)C(C(=O)N(C=2N=NC(OC)=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 MRUUEMLPUDAITO-UHFFFAOYSA-N 0.000 description 1
• QCWIVBKVSQARMH-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-3-(6-methoxypyridazin-3-yl)-5-[[methyl(2-pyridin-2-ylethyl)amino]methyl]-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CN(C)CCC=2N=CC=CC=2)C(C(=O)N(C=2N=NC(OC)=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 QCWIVBKVSQARMH-UHFFFAOYSA-N 0.000 description 1
• NDPYLJFAGLKIQA-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-(methylaminomethyl)-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2C=CC=CC=2)C(=O)C=2C(CNC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F NDPYLJFAGLKIQA-UHFFFAOYSA-N 0.000 description 1
• UALRLRPOCPDIJJ-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-(methylaminomethyl)-2,4-dioxo-3-pyridin-2-ylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2N=CC=CC=2)C(=O)C=2C(CNC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F UALRLRPOCPDIJJ-UHFFFAOYSA-N 0.000 description 1
• HZCJOTWLNONWOR-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(2-methoxyethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2N=NC(OC)=CC=2)C(=O)C=2C(CNCCOC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F HZCJOTWLNONWOR-UHFFFAOYSA-N 0.000 description 1
• VALZLGOIRXPQKE-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[(2-methoxy-1-phenylethyl)-methylamino]methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C=1C=CC=CC=1C(COC)N(C)CC(C=1C(=O)N(C=2C=CC=CC=2)C2=O)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=1N2CC1=C(F)C=CC=C1F VALZLGOIRXPQKE-UHFFFAOYSA-N 0.000 description 1
• WSXDGOMPQYGHFC-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[1-methoxypropan-2-yl(methyl)amino]methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2C=CC=CC=2)C(=O)C=2C(CN(C)C(C)COC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F WSXDGOMPQYGHFC-UHFFFAOYSA-N 0.000 description 1
• JDGHKCGXFRQIEQ-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-hydroxyethyl(methyl)amino]methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CN(C)CCO)C(C(=O)N(C=2N=NC(OC)=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 JDGHKCGXFRQIEQ-UHFFFAOYSA-N 0.000 description 1
• CVAJTLPIHLLNIS-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-2,4-dioxo-3-(6-oxo-1h-pyridazin-3-yl)thieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2N=NC(O)=CC=2)C(=O)C=2C(CN(C)CCOC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F CVAJTLPIHLLNIS-UHFFFAOYSA-N 0.000 description 1
• SWHNSEWTUCDIMK-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-2,4-dioxo-3-pyrazin-2-ylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2N=CC=NC=2)C(=O)C=2C(CN(C)CCOC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F SWHNSEWTUCDIMK-UHFFFAOYSA-N 0.000 description 1
• VDGNECREFSFFAT-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-2,4-dioxo-3-pyridazin-3-ylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2N=NC=CC=2)C(=O)C=2C(CN(C)CCOC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F VDGNECREFSFFAT-UHFFFAOYSA-N 0.000 description 1
• RKGKLSLHZOPNHU-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-3-(1-methylimidazol-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2N(C=CN=2)C)C(=O)C=2C(CN(C)CCOC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F RKGKLSLHZOPNHU-UHFFFAOYSA-N 0.000 description 1
• YWICDZLBOJKJSV-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-3-(3-methoxy-6-methylpyridin-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2C(=CC=C(C)N=2)OC)C(=O)C=2C(CN(C)CCOC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F YWICDZLBOJKJSV-UHFFFAOYSA-N 0.000 description 1
• FHAIIDXJZJKIFR-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-3-(3-methoxypyridin-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2C(=CC=CN=2)OC)C(=O)C=2C(CN(C)CCOC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F FHAIIDXJZJKIFR-UHFFFAOYSA-N 0.000 description 1
• HCJYDJMLQMLSAN-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-3-(5-methylpyridin-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2N=CC(C)=CC=2)C(=O)C=2C(CN(C)CCOC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F HCJYDJMLQMLSAN-UHFFFAOYSA-N 0.000 description 1
• IDQKFYZNDFRPKP-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-3-(6-methoxypyridin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2C=NC(OC)=CC=2)C(=O)C=2C(CN(C)CCOC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F IDQKFYZNDFRPKP-UHFFFAOYSA-N 0.000 description 1
• PFYDSXDBOAVIIH-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-3-(6-methylpyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2N=NC(C)=CC=2)C(=O)C=2C(CN(C)CCOC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F PFYDSXDBOAVIIH-UHFFFAOYSA-N 0.000 description 1
• BWQUDWQBENUWSL-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[2-methoxyethyl(methyl)amino]methyl]-3-(6-methylpyridin-2-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound O=C1N(C=2N=C(C)C=CC=2)C(=O)C=2C(CN(C)CCOC)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=2N1CC1=C(F)C=CC=C1F BWQUDWQBENUWSL-UHFFFAOYSA-N 0.000 description 1
• CUFNVSIQGMZTAB-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[methyl(1-phenylpropyl)amino]methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C=1C=CC=CC=1C(CC)N(C)CC(C=1C(=O)N(C=2C=CC=CC=2)C2=O)=C(C=3C=CC(NC(=O)NOC)=CC=3)SC=1N2CC1=C(F)C=CC=C1F CUFNVSIQGMZTAB-UHFFFAOYSA-N 0.000 description 1
• AGJIXNWSBLCRDL-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[methyl(1-pyridin-2-ylethyl)amino]methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CN(C)C(C)C=2N=CC=CC=2)C(C(=O)N(C=2C=CC=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 AGJIXNWSBLCRDL-UHFFFAOYSA-N 0.000 description 1
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• KOIHXOMPQRDDNC-UHFFFAOYSA-N 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[[methyl(pyridin-2-ylmethyl)amino]methyl]-2,4-dioxo-3-pyridin-2-ylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CN(C)CC=2N=CC=CC=2)C(C(=O)N(C=2N=CC=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 KOIHXOMPQRDDNC-UHFFFAOYSA-N 0.000 description 1
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• YEGNNDNPVUNYHA-UHFFFAOYSA-N 1-[4-[5-(chloromethyl)-1-[(2,6-difluorophenyl)methyl]-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea Chemical compound C1=CC(NC(=O)NOC)=CC=C1C1=C(CCl)C(C(=O)N(C=2C=CC=CC=2)C(=O)N2CC=3C(=CC=CC=3F)F)=C2S1 YEGNNDNPVUNYHA-UHFFFAOYSA-N 0.000 description 1
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