SG183260A1 - Triazolones as fatty acid synthase inhibitors - Google Patents

Info

Publication number

SG183260A1

SG183260A1 SG2012059291A SG2012059291A SG183260A1 SG 183260 A1 SG183260 A1 SG 183260A1 SG 2012059291 A SG2012059291 A SG 2012059291A SG 2012059291 A SG2012059291 A SG 2012059291A SG 183260 A1 SG183260 A1 SG 183260A1

Authority

SG

Singapore

Prior art keywords

dihydro

cyclopropylcarbonyl

triazol

mmol

methyl

Prior art date

2010-02-22

Links

• Espacenet
• Global Dossier
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• 102000015303 Fatty Acid Synthases Human genes 0.000 title abstract description 18
• 108010039731 Fatty Acid Synthases Proteins 0.000 title abstract description 18
• 239000003112 inhibitor Substances 0.000 title description 37
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 51
• 201000011510 cancer Diseases 0.000 claims abstract description 33
• 150000001875 compounds Chemical class 0.000 claims description 327
• 238000000034 method Methods 0.000 claims description 134
• 150000003839 salts Chemical class 0.000 claims description 60
• -1 chloro, hydroxyl Chemical group 0.000 claims description 42
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 239000008194 pharmaceutical composition Substances 0.000 claims description 19
• 125000003118 aryl group Chemical group 0.000 claims description 16
• 125000005842 heteroatom Chemical group 0.000 claims description 15
• 125000001424 substituent group Chemical group 0.000 claims description 15
• 125000001072 heteroaryl group Chemical group 0.000 claims description 11
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 10
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
• 125000003545 alkoxy group Chemical group 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 229910052736 halogen Inorganic materials 0.000 claims description 7
• 150000002367 halogens Chemical class 0.000 claims description 7
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
• SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 6
• 125000002619 bicyclic group Chemical group 0.000 claims description 6
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
• BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 4
• YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Chemical compound C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 4
• HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims description 4
• UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
• 125000003282 alkyl amino group Chemical group 0.000 claims description 4
• 210000001072 colon Anatomy 0.000 claims description 4
• AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
• RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 3
• 210000000481 breast Anatomy 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 3
• PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 3
• RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 3
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
• 210000004072 lung Anatomy 0.000 claims description 3
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
• JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 3
• HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
• GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 2
• 208000008383 Wilms tumor Diseases 0.000 claims description 2
• 125000001153 fluoro group Chemical group F* 0.000 claims description 2
• 210000003128 head Anatomy 0.000 claims description 2
• PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 2
• LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 claims description 2
• VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical compound C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 claims description 2
• 210000003734 kidney Anatomy 0.000 claims description 2
• 208000032839 leukemia Diseases 0.000 claims description 2
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
• 210000003739 neck Anatomy 0.000 claims description 2
• 210000002307 prostate Anatomy 0.000 claims description 2
• 150000003222 pyridines Chemical class 0.000 claims description 2
• 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 2
• 208000008770 Multiple Hamartoma Syndrome Diseases 0.000 claims 3
• 201000002847 Cowden syndrome Diseases 0.000 claims 2
• 201000007815 Bannayan-Riley-Ruvalcaba syndrome Diseases 0.000 claims 1
• 208000012609 Cowden disease Diseases 0.000 claims 1
• 206010014967 Ependymoma Diseases 0.000 claims 1
• 208000006168 Ewing Sarcoma Diseases 0.000 claims 1
• 208000002966 Giant Cell Tumor of Bone Diseases 0.000 claims 1
• 206010018338 Glioma Diseases 0.000 claims 1
• 208000005726 Inflammatory Breast Neoplasms Diseases 0.000 claims 1
• 206010021980 Inflammatory carcinoma of the breast Diseases 0.000 claims 1
• 208000022010 Lhermitte-Duclos disease Diseases 0.000 claims 1
• 208000000172 Medulloblastoma Diseases 0.000 claims 1
• 206010039491 Sarcoma Diseases 0.000 claims 1
• 201000011143 bone giant cell tumor Diseases 0.000 claims 1
• 210000004556 brain Anatomy 0.000 claims 1
• 208000005017 glioblastoma Diseases 0.000 claims 1
• 201000004653 inflammatory breast carcinoma Diseases 0.000 claims 1
• 210000004185 liver Anatomy 0.000 claims 1
• 201000001441 melanoma Diseases 0.000 claims 1
• 201000008968 osteosarcoma Diseases 0.000 claims 1
• 230000002611 ovarian Effects 0.000 claims 1
• 210000001685 thyroid gland Anatomy 0.000 claims 1
• 208000013076 thyroid tumor Diseases 0.000 claims 1
• 238000011282 treatment Methods 0.000 abstract description 59
• 230000000694 effects Effects 0.000 abstract description 34
• 230000005764 inhibitory process Effects 0.000 abstract description 8
• FFSJPOPLSWBGQY-UHFFFAOYSA-N triazol-4-one Chemical class O=C1C=NN=N1 FFSJPOPLSWBGQY-UHFFFAOYSA-N 0.000 abstract description 4
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 465
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 364
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 355
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 240
• 239000007787 solid Substances 0.000 description 223
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 221
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 185
• 239000000243 solution Substances 0.000 description 159
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 130
• 238000006243 chemical reaction Methods 0.000 description 127
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 122
• 235000019439 ethyl acetate Nutrition 0.000 description 120
• 239000000047 product Substances 0.000 description 115
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 106
• 239000000203 mixture Substances 0.000 description 99
• 239000011541 reaction mixture Substances 0.000 description 99
• 238000004007 reversed phase HPLC Methods 0.000 description 97
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 96
• 239000012044 organic layer Substances 0.000 description 85
• 239000010410 layer Substances 0.000 description 80
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 76
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 73
• 229910052757 nitrogen Inorganic materials 0.000 description 61
• 238000004458 analytical method Methods 0.000 description 55
• 229910000027 potassium carbonate Inorganic materials 0.000 description 53
• 235000002639 sodium chloride Nutrition 0.000 description 52
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 50
• 238000000746 purification Methods 0.000 description 50
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 48
• 235000019341 magnesium sulphate Nutrition 0.000 description 48
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 43
• 235000011114 ammonium hydroxide Nutrition 0.000 description 43
• 239000003921 oil Substances 0.000 description 38
• 235000019198 oils Nutrition 0.000 description 37
• KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 37
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 36
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• 235000011152 sodium sulphate Nutrition 0.000 description 36
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
• 239000012071 phase Substances 0.000 description 34
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
• 239000012267 brine Substances 0.000 description 33
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
• 230000015572 biosynthetic process Effects 0.000 description 31
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• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
• 239000007858 starting material Substances 0.000 description 27
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
• 238000004128 high performance liquid chromatography Methods 0.000 description 24
• 239000000543 intermediate Substances 0.000 description 24
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 23
• UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 22
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• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 14
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