CA2894399A1 - Histone demethylase inhibitors - Google Patents

Info

Publication number

CA2894399A1

CA2894399A1 CA2894399A CA2894399A CA2894399A1 CA 2894399 A1 CA2894399 A1 CA 2894399A1 CA 2894399 A CA2894399 A CA 2894399A CA 2894399 A CA2894399 A CA 2894399A CA 2894399 A1 CA2894399 A1 CA 2894399A1

Authority

CA

Canada

Prior art keywords

pyrazol

compound

formula

pyridine

hydrogen

Prior art date

2012-12-06

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.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 108010074870 Histone Demethylases Proteins 0.000 title claims abstract description 35
• 102000008157 Histone Demethylases Human genes 0.000 title claims abstract description 35
• 239000003112 inhibitor Substances 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 616
• 239000000203 mixture Substances 0.000 claims abstract description 102
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 29
• 201000011510 cancer Diseases 0.000 claims abstract description 21
• 239000008194 pharmaceutical composition Chemical class 0.000 claims abstract description 12
• 229910052739 hydrogen Inorganic materials 0.000 claims description 266
• 239000001257 hydrogen Substances 0.000 claims description 264
• 238000000034 method Methods 0.000 claims description 232
• 125000000217 alkyl group Chemical group 0.000 claims description 213
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 174
• 125000003118 aryl group Chemical group 0.000 claims description 160
• 125000001072 heteroaryl group Chemical group 0.000 claims description 151
• 125000004452 carbocyclyl group Chemical group 0.000 claims description 147
• 125000000623 heterocyclic group Chemical group 0.000 claims description 140
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 138
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 138
• 125000005884 carbocyclylalkyl group Chemical group 0.000 claims description 137
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 94
• 150000003839 salts Chemical class 0.000 claims description 91
• 125000002947 alkylene group Chemical group 0.000 claims description 85
• 229910052736 halogen Inorganic materials 0.000 claims description 79
• 150000002367 halogens Chemical group 0.000 claims description 79
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 56
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
• 230000002401 inhibitory effect Effects 0.000 claims description 16
• 239000003937 drug carrier Substances 0.000 claims description 8
• -1 pyrazolylpyrimidine derivative compounds Chemical class 0.000 abstract description 223
• 238000011282 treatment Methods 0.000 abstract description 16
• 206010005003 Bladder cancer Diseases 0.000 abstract description 9
• 206010006187 Breast cancer Diseases 0.000 abstract description 8
• 208000026310 Breast neoplasm Diseases 0.000 abstract description 8
• 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 8
• 208000000236 Prostatic Neoplasms Diseases 0.000 abstract description 8
• 208000007097 Urinary Bladder Neoplasms Diseases 0.000 abstract description 8
• 201000005202 lung cancer Diseases 0.000 abstract description 8
• 208000020816 lung neoplasm Diseases 0.000 abstract description 8
• 201000005112 urinary bladder cancer Diseases 0.000 abstract description 8
• 206010060862 Prostate cancer Diseases 0.000 abstract description 7
• 201000001441 melanoma Diseases 0.000 abstract description 7
• 150000005292 pyrazolylpyridines Chemical class 0.000 abstract description 5
• XEODJMCAUUKTEC-UHFFFAOYSA-N 3-(1h-pyrazol-5-yl)pyridazine Chemical class N1C=CC(C=2N=NC=CC=2)=N1 XEODJMCAUUKTEC-UHFFFAOYSA-N 0.000 abstract description 4
• 230000005764 inhibitory process Effects 0.000 abstract description 2
• TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 465
• 238000002360 preparation method Methods 0.000 description 238
• 238000005160 1H NMR spectroscopy Methods 0.000 description 206
• 150000002431 hydrogen Chemical group 0.000 description 158
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 138
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 129
• 101150041968 CDC13 gene Proteins 0.000 description 110
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 110
• GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 96
• 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 91
• 239000000243 solution Substances 0.000 description 88
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 84
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 79
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 63
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 63
• 239000011541 reaction mixture Substances 0.000 description 54
• 239000007787 solid Substances 0.000 description 53
• 229910001868 water Inorganic materials 0.000 description 47
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• 239000002253 acid Substances 0.000 description 43
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 40
• 150000001204 N-oxides Chemical class 0.000 description 39
• LPQCTEIJKYZMTK-UHFFFAOYSA-N OC1=CC=NN1C1=CC(C#N)=CC=N1 Chemical compound OC1=CC=NN1C1=CC(C#N)=CC=N1 LPQCTEIJKYZMTK-UHFFFAOYSA-N 0.000 description 39
• 239000000126 substance Substances 0.000 description 35
• 125000004432 carbon atom Chemical group C* 0.000 description 34
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
• 150000003254 radicals Chemical class 0.000 description 31
• 239000012071 phase Substances 0.000 description 27
• 239000002904 solvent Substances 0.000 description 27
• 238000003786 synthesis reaction Methods 0.000 description 27
• 239000000543 intermediate Substances 0.000 description 26
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 26
• 238000003818 flash chromatography Methods 0.000 description 25
• 229910052757 nitrogen Inorganic materials 0.000 description 25
• 239000012074 organic phase Substances 0.000 description 25
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
• 239000012267 brine Substances 0.000 description 24
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
• 125000001424 substituent group Chemical group 0.000 description 23
• PMRMKCHJLLVOQU-UHFFFAOYSA-N 2-hydrazinylpyridine-4-carbonitrile Chemical compound NNC1=CC(C#N)=CC=N1 PMRMKCHJLLVOQU-UHFFFAOYSA-N 0.000 description 22
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 22
• 108010033040 Histones Proteins 0.000 description 19
• 108090000623 proteins and genes Proteins 0.000 description 19
• REPVNSJSTLRQEQ-UHFFFAOYSA-N n,n-dimethylacetamide;n,n-dimethylformamide Chemical compound CN(C)C=O.CN(C)C(C)=O REPVNSJSTLRQEQ-UHFFFAOYSA-N 0.000 description 18
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
• 125000003944 tolyl group Chemical group 0.000 description 17
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 17
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
• 125000004450 alkenylene group Chemical group 0.000 description 16
• 239000000651 prodrug Substances 0.000 description 16
• 229940002612 prodrug Drugs 0.000 description 16
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
• 238000006243 chemical reaction Methods 0.000 description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
• 125000001207 fluorophenyl group Chemical group 0.000 description 15
• 239000003921 oil Substances 0.000 description 15
• 239000000047 product Substances 0.000 description 15
• 238000010992 reflux Methods 0.000 description 15
• 102100040584 Lysine-specific demethylase 2B Human genes 0.000 description 14
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
• 229910052799 carbon Inorganic materials 0.000 description 14
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 14
• 229940093499 ethyl acetate Drugs 0.000 description 14
• 235000019439 ethyl acetate Nutrition 0.000 description 14
• 125000003709 fluoroalkyl group Chemical group 0.000 description 14
• 239000012044 organic layer Substances 0.000 description 14
• 101000615488 Homo sapiens Methyl-CpG-binding domain protein 2 Proteins 0.000 description 13
• 102100021299 Methyl-CpG-binding domain protein 2 Human genes 0.000 description 13
• 239000007832 Na2SO4 Substances 0.000 description 13
• 230000015572 biosynthetic process Effects 0.000 description 13
• 238000002953 preparative HPLC Methods 0.000 description 13
• 235000018102 proteins Nutrition 0.000 description 13
• 102000004169 proteins and genes Human genes 0.000 description 13
• 229910052938 sodium sulfate Inorganic materials 0.000 description 13
• 235000011152 sodium sulphate Nutrition 0.000 description 13
• 150000007513 acids Chemical class 0.000 description 12
• 239000002585 base Substances 0.000 description 12
• 201000010099 disease Diseases 0.000 description 12
• 125000005843 halogen group Chemical group 0.000 description 12
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 12
• TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 12
• 239000003960 organic solvent Substances 0.000 description 12
• 235000015320 potassium carbonate Nutrition 0.000 description 12
• 229910000027 potassium carbonate Inorganic materials 0.000 description 12
• 125000003831 tetrazolyl group Chemical group 0.000 description 12
• 244000201986 Cassia tora Species 0.000 description 11
• 102100040598 Lysine-specific demethylase 2A Human genes 0.000 description 11
• 102100033247 Lysine-specific demethylase 5B Human genes 0.000 description 11
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• 125000003342 alkenyl group Chemical group 0.000 description 11
• 238000007069 methylation reaction Methods 0.000 description 11
• NCAIGTHBQTXTLR-UHFFFAOYSA-N phentermine hydrochloride Chemical compound [Cl-].CC(C)([NH3+])CC1=CC=CC=C1 NCAIGTHBQTXTLR-UHFFFAOYSA-N 0.000 description 11
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• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 10
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• 125000004122 cyclic group Chemical group 0.000 description 10
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• 230000011987 methylation Effects 0.000 description 9
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• RLCYIOZTWUVYOM-UHFFFAOYSA-N 2-hydrazinylpyridine-4-carbonitrile;hydrochloride Chemical compound Cl.NNC1=CC(C#N)=CC=N1 RLCYIOZTWUVYOM-UHFFFAOYSA-N 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 8
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• NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 6
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• 125000006279 3-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C(Br)=C1[H])C([H])([H])* 0.000 description 5
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