OA12016A - Tricyclic inhibitors of poly(adp-ribose)polymerases. - Google Patents

Info

Publication number

OA12016A

OA12016A OA1200200064A OA1200200064A OA12016A OA 12016 A OA12016 A OA 12016A OA 1200200064 A OA1200200064 A OA 1200200064A OA 1200200064 A OA1200200064 A OA 1200200064A OA 12016 A OA12016 A OA 12016A

Authority

OA

OAPI

Prior art keywords

aryl

alkynyl

heterocycloalkyl

alkyl

cycloalkyl

Prior art date

1999-08-31

Links

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• 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 title claims description 75
• 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 title claims description 74
• 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 title claims description 67
• 239000003112 inhibitor Substances 0.000 title description 12
• 150000001875 compounds Chemical class 0.000 claims abstract description 283
• 230000000694 effects Effects 0.000 claims abstract description 27
• 238000000034 method Methods 0.000 claims description 193
• 125000003118 aryl group Chemical group 0.000 claims description 180
• 125000000304 alkynyl group Chemical group 0.000 claims description 139
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 133
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 132
• 125000001072 heteroaryl group Chemical group 0.000 claims description 125
• 125000003342 alkenyl group Chemical group 0.000 claims description 124
• -1 alkeayl Chemical group 0.000 claims description 121
• 125000000217 alkyl group Chemical group 0.000 claims description 96
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 94
• 229910052736 halogen Inorganic materials 0.000 claims description 53
• 150000002367 halogens Chemical class 0.000 claims description 53
• 125000001424 substituent group Chemical group 0.000 claims description 47
• 230000005764 inhibitory process Effects 0.000 claims description 44
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 36
• 229940002612 prodrug Drugs 0.000 claims description 35
• 239000000651 prodrug Substances 0.000 claims description 35
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 33
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
• 229910052760 oxygen Inorganic materials 0.000 claims description 30
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 29
• 239000003795 chemical substances by application Substances 0.000 claims description 27
• 230000002401 inhibitory effect Effects 0.000 claims description 27
• 229910052717 sulfur Inorganic materials 0.000 claims description 27
• 102000004190 Enzymes Human genes 0.000 claims description 24
• 108090000790 Enzymes Proteins 0.000 claims description 24
• 231100000135 cytotoxicity Toxicity 0.000 claims description 21
• 230000003013 cytotoxicity Effects 0.000 claims description 21
• 125000003545 alkoxy group Chemical group 0.000 claims description 11
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 10
• 238000003556 assay Methods 0.000 claims description 9
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
• 125000004104 aryloxy group Chemical group 0.000 claims description 7
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
• 125000005842 heteroatom Chemical group 0.000 claims description 7
• 239000001301 oxygen Substances 0.000 claims description 7
• 239000008194 pharmaceutical composition Substances 0.000 claims description 7
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 6
• 108010017601 Tankyrases Proteins 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
• 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 claims 13
• 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 claims 13
• 125000005017 substituted alkenyl group Chemical group 0.000 claims 4
• 102100037664 Poly [ADP-ribose] polymerase tankyrase-1 Human genes 0.000 claims 2
• 238000004519 manufacturing process Methods 0.000 claims 2
• SGPGESCZOCHFCL-UHFFFAOYSA-N Tilisolol hydrochloride Chemical compound [Cl-].C1=CC=C2C(=O)N(C)C=C(OCC(O)C[NH2+]C(C)(C)C)C2=C1 SGPGESCZOCHFCL-UHFFFAOYSA-N 0.000 claims 1
• 239000003814 drug Substances 0.000 abstract description 8
• 206010019196 Head injury Diseases 0.000 abstract description 7
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• 208000006011 Stroke Diseases 0.000 abstract description 5
• 206010028980 Neoplasm Diseases 0.000 abstract description 3
• 239000003558 transferase inhibitor Substances 0.000 abstract 1
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• 238000005481 NMR spectroscopy Methods 0.000 description 298
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 266
• 229910052739 hydrogen Inorganic materials 0.000 description 251
• 229910052757 nitrogen Inorganic materials 0.000 description 246
• 239000007787 solid Substances 0.000 description 235
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• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 157
• 235000019439 ethyl acetate Nutrition 0.000 description 132
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 116
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• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 68
• 239000000243 solution Substances 0.000 description 68
• 150000001412 amines Chemical class 0.000 description 62
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 58
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• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 53
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• 239000000203 mixture Substances 0.000 description 31
• 150000004985 diamines Chemical class 0.000 description 30
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 27
• 235000019341 magnesium sulphate Nutrition 0.000 description 27
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
• 239000012044 organic layer Substances 0.000 description 23
• ZGLDQGIONSGJCN-UHFFFAOYSA-N diazepin-5-one Chemical compound O=C1C=CN=NC=C1 ZGLDQGIONSGJCN-UHFFFAOYSA-N 0.000 description 21
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 20
• 239000002253 acid Substances 0.000 description 20
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
• 238000000746 purification Methods 0.000 description 17
• 230000035484 reaction time Effects 0.000 description 17
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
• NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 16
• 101150041968 CDC13 gene Proteins 0.000 description 16
• 241000124008 Mammalia Species 0.000 description 16
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 16
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
• 239000012267 brine Substances 0.000 description 16
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 16
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 15
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
• 239000003921 oil Substances 0.000 description 14
• 235000019198 oils Nutrition 0.000 description 14
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
• 238000004809 thin layer chromatography Methods 0.000 description 14
• 239000012661 PARP inhibitor Substances 0.000 description 13
• 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 13
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
• 210000004027 cell Anatomy 0.000 description 13
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 12
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
• HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 12
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• 101150065749 Churc1 gene Proteins 0.000 description 11
• FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 11
• 150000002576 ketones Chemical class 0.000 description 11
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
• MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 10
• 108091026813 Poly(ADPribose) Proteins 0.000 description 10
• 229960000583 acetic acid Drugs 0.000 description 10
• 238000006268 reductive amination reaction Methods 0.000 description 10
• 238000011282 treatment Methods 0.000 description 10
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• 235000011054 acetic acid Nutrition 0.000 description 9
• 239000012043 crude product Substances 0.000 description 9
• 201000010099 disease Diseases 0.000 description 9
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• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 9
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 8
• 239000006227 byproduct Substances 0.000 description 8
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• 238000005292 vacuum distillation Methods 0.000 description 1
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
• 238000005406 washing Methods 0.000 description 1
• GDJZZWYLFXAGFH-UHFFFAOYSA-M xylenesulfonate group Chemical group C1(C(C=CC=C1)C)(C)S(=O)(=O)[O-] GDJZZWYLFXAGFH-UHFFFAOYSA-M 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1
• 239000011592 zinc chloride Substances 0.000 description 1
• 235000005074 zinc chloride Nutrition 0.000 description 1
• JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1