NO342745B1 - Inhibitorer av E1-aktiverende enzym - Google Patents

Info

Publication number

NO342745B1

NO342745B1 NO20083581A NO20083581A NO342745B1 NO 342745 B1 NO342745 B1 NO 342745B1 NO 20083581 A NO20083581 A NO 20083581A NO 20083581 A NO20083581 A NO 20083581A NO 342745 B1 NO342745 B1 NO 342745B1

Authority

NO

Norway

Prior art keywords

hydrogen

group

mmol

pyrrolo

compound

Prior art date

2006-02-02

Links

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• 102000004190 Enzymes Human genes 0.000 title abstract description 32
• 108090000790 Enzymes Proteins 0.000 title abstract description 32
• 239000003112 inhibitor Substances 0.000 title description 16
• 150000001875 compounds Chemical class 0.000 claims abstract description 250
• -1 C1-4aliphatic group Chemical group 0.000 claims description 71
• 239000001257 hydrogen Substances 0.000 claims description 68
• 229910052739 hydrogen Inorganic materials 0.000 claims description 68
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 41
• 125000001931 aliphatic group Chemical group 0.000 claims description 24
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 21
• 150000003839 salts Chemical class 0.000 claims description 21
• 150000002431 hydrogen Chemical class 0.000 claims description 19
• 125000001153 fluoro group Chemical group F* 0.000 claims description 17
• 229910052736 halogen Inorganic materials 0.000 claims description 12
• 125000004122 cyclic group Chemical group 0.000 claims description 8
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
• 229910052702 rhenium Inorganic materials 0.000 claims description 7
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 6
• 125000003118 aryl group Chemical group 0.000 claims description 6
• 125000005843 halogen group Chemical group 0.000 claims description 6
• 150000002367 halogens Chemical class 0.000 claims description 6
• 125000001072 heteroaryl group Chemical group 0.000 claims description 6
• 229910052757 nitrogen Inorganic materials 0.000 claims description 6
• 125000000623 heterocyclic group Chemical group 0.000 claims description 5
• 125000001424 substituent group Chemical group 0.000 claims description 5
• 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 4
• 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 claims description 4
• 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 claims description 4
• 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 4
• 229910052799 carbon Inorganic materials 0.000 claims description 3
• 125000003545 alkoxy group Chemical group 0.000 claims description 2
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
• 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 claims description 2
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
• 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 claims description 2
• 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 2
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 claims description 2
• 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 2
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
• 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 claims description 2
• 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 claims description 2
• 125000000532 dioxanyl group Chemical group 0.000 claims description 2
• 125000005879 dioxolanyl group Chemical group 0.000 claims description 2
• 125000002541 furyl group Chemical group 0.000 claims description 2
• 125000006161 haloaliphatic group Chemical group 0.000 claims description 2
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 2
• 125000002883 imidazolyl group Chemical group 0.000 claims description 2
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
• 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 2
• 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 2
• 125000001041 indolyl group Chemical group 0.000 claims description 2
• 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 2
• 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
• 125000002757 morpholinyl group Chemical group 0.000 claims description 2
• 125000001624 naphthyl group Chemical group 0.000 claims description 2
• 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 claims description 2
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 2
• 125000000160 oxazolidinyl group Chemical group 0.000 claims description 2
• 125000002971 oxazolyl group Chemical group 0.000 claims description 2
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
• 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 claims description 2
• 125000004193 piperazinyl group Chemical group 0.000 claims description 2
• 125000003386 piperidinyl group Chemical group 0.000 claims description 2
• 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 claims description 2
• 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 2
• 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 2
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
• 125000004076 pyridyl group Chemical group 0.000 claims description 2
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
• 125000004929 pyrrolidonyl group Chemical group N1(C(CCC1)=O)* 0.000 claims description 2
• 125000001422 pyrrolinyl group Chemical group 0.000 claims description 2
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
• 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 2
• 125000005493 quinolyl group Chemical group 0.000 claims description 2
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
• 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 claims description 2
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 2
• 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 2
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
• 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 claims description 2
• 125000000335 thiazolyl group Chemical group 0.000 claims description 2
• 125000001544 thienyl group Chemical group 0.000 claims description 2
• 125000004306 triazinyl group Chemical group 0.000 claims description 2
• 125000001425 triazolyl group Chemical group 0.000 claims description 2
• 125000004432 carbon atom Chemical group C* 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 151
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 40
• 206010028980 Neoplasm Diseases 0.000 abstract description 34
• 238000011282 treatment Methods 0.000 abstract description 31
• 208000035475 disorder Diseases 0.000 abstract description 25
• 201000011510 cancer Diseases 0.000 abstract description 22
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 18
• 230000002062 proliferating effect Effects 0.000 abstract description 9
• 230000000626 neurodegenerative effect Effects 0.000 abstract description 4
• 206010061218 Inflammation Diseases 0.000 abstract description 3
• 208000015181 infectious disease Diseases 0.000 abstract description 3
• 230000004054 inflammatory process Effects 0.000 abstract description 3
• 206010006895 Cachexia Diseases 0.000 abstract description 2
• 230000002757 inflammatory effect Effects 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 161
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 128
• 239000000243 solution Substances 0.000 description 125
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 122
• 239000000203 mixture Substances 0.000 description 107
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 93
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 74
• 235000019439 ethyl acetate Nutrition 0.000 description 73
• FIYXUOWXHWJDAM-UHFFFAOYSA-N methyl sulfamate Chemical compound COS(N)(=O)=O FIYXUOWXHWJDAM-UHFFFAOYSA-N 0.000 description 70
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
• 238000010898 silica gel chromatography Methods 0.000 description 63
• 238000006243 chemical reaction Methods 0.000 description 57
• 238000005481 NMR spectroscopy Methods 0.000 description 52
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
• 238000002360 preparation method Methods 0.000 description 46
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 38
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 34
• 230000000694 effects Effects 0.000 description 34
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 31
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 30
• 239000007787 solid Substances 0.000 description 30
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 28
• 235000002639 sodium chloride Nutrition 0.000 description 28
• 108090000623 proteins and genes Proteins 0.000 description 26
• FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 25
• 102000004169 proteins and genes Human genes 0.000 description 25
• 210000004027 cell Anatomy 0.000 description 24
• 239000012299 nitrogen atmosphere Substances 0.000 description 23
• 239000002904 solvent Substances 0.000 description 23
• 239000011541 reaction mixture Substances 0.000 description 22
• 230000005764 inhibitory process Effects 0.000 description 21
• 230000015572 biosynthetic process Effects 0.000 description 20
• 239000000047 product Substances 0.000 description 20
• 229920006395 saturated elastomer Polymers 0.000 description 20
• 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 20
• 239000000725 suspension Substances 0.000 description 19
• 238000003786 synthesis reaction Methods 0.000 description 19
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
• 239000002585 base Substances 0.000 description 17
• 239000003921 oil Substances 0.000 description 17
• 235000019198 oils Nutrition 0.000 description 17
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
• 239000012044 organic layer Substances 0.000 description 16
• 201000010099 disease Diseases 0.000 description 15
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 15
• 235000017557 sodium bicarbonate Nutrition 0.000 description 15
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
• 108091007790 NEDD8-activating enzyme E1 Proteins 0.000 description 14
• 102000038427 NEDD8-activating enzyme E1 Human genes 0.000 description 14
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 14
• 108010091546 Ubiquitin-Activating Enzymes Proteins 0.000 description 14
• 102000018478 Ubiquitin-Activating Enzymes Human genes 0.000 description 14
• 239000003795 chemical substances by application Substances 0.000 description 14
• 150000002009 diols Chemical class 0.000 description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
• QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 14
• 239000010410 layer Substances 0.000 description 13
• 235000018102 proteins Nutrition 0.000 description 13
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
• 239000003153 chemical reaction reagent Substances 0.000 description 12
• 239000003814 drug Substances 0.000 description 12
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
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• 229940124597 therapeutic agent Drugs 0.000 description 11
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
• 230000006663 ubiquitin-proteasome pathway Effects 0.000 description 11
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
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• 239000000758 substrate Substances 0.000 description 10
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• OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 description 9
• 238000010992 reflux Methods 0.000 description 9
• 239000011780 sodium chloride Substances 0.000 description 9
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• 230000034512 ubiquitination Effects 0.000 description 8
• 238000010798 ubiquitination Methods 0.000 description 8
• 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 7
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• 230000037361 pathway Effects 0.000 description 6
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• 230000002829 reductive effect Effects 0.000 description 6
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• ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 5
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