ES2658597T3 - Inhibidores de histona desmetilasa - Google Patents

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Publication number

ES2658597T3

ES2658597T3 ES13866465.1T ES13866465T ES2658597T3 ES 2658597 T3 ES2658597 T3 ES 2658597T3 ES 13866465 T ES13866465 T ES 13866465T ES 2658597 T3 ES2658597 T3 ES 2658597T3

Authority

ES

Spain

Prior art keywords

preparation

fluoro

amino

indazol

pyridine

Prior art date

2012-12-19

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.)

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• 108010074870 Histone Demethylases Proteins 0.000 title description 11
• 102000008157 Histone Demethylases Human genes 0.000 title description 11
• 239000003112 inhibitor Substances 0.000 title description 6
• 150000001875 compounds Chemical class 0.000 claims abstract description 430
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 124
• 150000003839 salts Chemical class 0.000 claims abstract description 86
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 85
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 81
• 125000003118 aryl group Chemical group 0.000 claims abstract description 74
• 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 73
• 101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 claims abstract description 68
• 125000004452 carbocyclyl group Chemical group 0.000 claims abstract description 68
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims abstract description 68
• 125000005884 carbocyclylalkyl group Chemical group 0.000 claims abstract description 66
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 66
• 125000003342 alkenyl group Chemical group 0.000 claims abstract description 44
• 125000000304 alkynyl group Chemical group 0.000 claims abstract description 44
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 39
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 29
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 26
• 239000001257 hydrogen Substances 0.000 claims abstract description 25
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 22
• 125000004104 aryloxy group Chemical group 0.000 claims abstract description 21
• 150000002367 halogens Chemical class 0.000 claims abstract description 21
• MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims abstract description 15
• JAMULYFATHSZJM-UHFFFAOYSA-N 8-(4-dibenzothiophenyl)-2-(4-morpholinyl)-1-benzopyran-4-one Chemical compound O1C2=C(C=3C=4SC5=CC=CC=C5C=4C=CC=3)C=CC=C2C(=O)C=C1N1CCOCC1 JAMULYFATHSZJM-UHFFFAOYSA-N 0.000 claims abstract description 14
• 206010028980 Neoplasm Diseases 0.000 claims description 22
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 22
• 125000005843 halogen group Chemical group 0.000 claims description 18
• 201000011510 cancer Diseases 0.000 claims description 14
• 238000011282 treatment Methods 0.000 claims description 13
• 239000008194 pharmaceutical composition Substances 0.000 claims description 10
• 125000002431 aminoalkoxy group Chemical group 0.000 claims description 6
• 239000003937 drug carrier Substances 0.000 claims description 5
• 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
• 238000002360 preparation method Methods 0.000 description 360
• 238000000034 method Methods 0.000 description 195
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 176
• -1 aminopyridazine derivative compounds Chemical class 0.000 description 155
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 146
• 238000005481 NMR spectroscopy Methods 0.000 description 110
• 238000005160 1H NMR spectroscopy Methods 0.000 description 99
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
• XCUAIINAJCDIPM-XVFCMESISA-N N(4)-hydroxycytidine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=NO)C=C1 XCUAIINAJCDIPM-XVFCMESISA-N 0.000 description 72
• XLQIGLBALJNHKR-UHFFFAOYSA-N methyl 3-aminopyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1N XLQIGLBALJNHKR-UHFFFAOYSA-N 0.000 description 56
• 125000002947 alkylene group Chemical group 0.000 description 53
• 238000006243 chemical reaction Methods 0.000 description 50
• 238000000746 purification Methods 0.000 description 46
• 239000007787 solid Substances 0.000 description 43
• 230000007062 hydrolysis Effects 0.000 description 40
• 238000006460 hydrolysis reaction Methods 0.000 description 40
• CZUPBTJBMHZBTJ-UHFFFAOYSA-N 5-fluoro-3-iodo-2h-indazole Chemical compound FC1=CC=C2NN=C(I)C2=C1 CZUPBTJBMHZBTJ-UHFFFAOYSA-N 0.000 description 37
• 239000000243 solution Substances 0.000 description 37
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 36
• 238000002953 preparative HPLC Methods 0.000 description 35
• 238000003786 synthesis reaction Methods 0.000 description 33
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 32
• 125000004432 carbon atom Chemical group C* 0.000 description 32
• 150000003254 radicals Chemical class 0.000 description 31
• 239000000203 mixture Substances 0.000 description 28
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
• 239000000126 substance Substances 0.000 description 22
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
• 108010033040 Histones Proteins 0.000 description 21
• 239000000047 product Substances 0.000 description 21
• TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 20
• 210000004027 cell Anatomy 0.000 description 19
• 101001088893 Homo sapiens Lysine-specific demethylase 4C Proteins 0.000 description 18
• 102100033230 Lysine-specific demethylase 4C Human genes 0.000 description 18
• 102100033246 Lysine-specific demethylase 5A Human genes 0.000 description 18
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
• 235000019439 ethyl acetate Nutrition 0.000 description 18
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
• 238000012360 testing method Methods 0.000 description 18
• 108090000623 proteins and genes Proteins 0.000 description 17
• 239000000725 suspension Substances 0.000 description 17
• 102100033247 Lysine-specific demethylase 5B Human genes 0.000 description 16
• 150000003901 oxalic acid esters Chemical class 0.000 description 16
• 125000001424 substituent group Chemical group 0.000 description 16
• 150000003900 succinic acid esters Chemical class 0.000 description 16
• 125000003831 tetrazolyl group Chemical group 0.000 description 16
• 101001088892 Homo sapiens Lysine-specific demethylase 5A Proteins 0.000 description 15
• 101001088883 Homo sapiens Lysine-specific demethylase 5B Proteins 0.000 description 15
• 101000615488 Homo sapiens Methyl-CpG-binding domain protein 2 Proteins 0.000 description 14
• 102100021299 Methyl-CpG-binding domain protein 2 Human genes 0.000 description 14
• 239000003153 chemical reaction reagent Substances 0.000 description 14
• 239000002253 acid Substances 0.000 description 13
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 13
• 125000003709 fluoroalkyl group Chemical group 0.000 description 13
• VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 13
• 239000000651 prodrug Substances 0.000 description 13
• 229940002612 prodrug Drugs 0.000 description 13
• 238000010898 silica gel chromatography Methods 0.000 description 13
• 239000002904 solvent Substances 0.000 description 13
• 244000201986 Cassia tora Species 0.000 description 12
• 102000006947 Histones Human genes 0.000 description 12
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
• 150000001204 N-oxides Chemical class 0.000 description 12
• 229910052799 carbon Inorganic materials 0.000 description 12
• NCAIGTHBQTXTLR-UHFFFAOYSA-N phentermine hydrochloride Chemical compound [Cl-].CC(C)([NH3+])CC1=CC=CC=C1 NCAIGTHBQTXTLR-UHFFFAOYSA-N 0.000 description 12
• 235000018102 proteins Nutrition 0.000 description 12
• 102000004169 proteins and genes Human genes 0.000 description 12
• LETVJWLLIMJADE-UHFFFAOYSA-N pyridazin-3-amine Chemical class NC1=CC=CN=N1 LETVJWLLIMJADE-UHFFFAOYSA-N 0.000 description 12
• CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 12
• 125000004450 alkenylene group Chemical group 0.000 description 11
• 229910052757 nitrogen Inorganic materials 0.000 description 11
• CUYKNJBYIJFRCU-UHFFFAOYSA-N pyridine-3-amine Natural products NC1=CC=CN=C1 CUYKNJBYIJFRCU-UHFFFAOYSA-N 0.000 description 11
• 239000011541 reaction mixture Substances 0.000 description 11
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical class [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 10
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
• 125000004122 cyclic group Chemical group 0.000 description 10
• 238000001514 detection method Methods 0.000 description 10
• 201000010099 disease Diseases 0.000 description 10
• LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 10
• KPGXRSRHYNQIFN-UHFFFAOYSA-N 2-oxoglutaric acid Chemical compound OC(=O)CCC(=O)C(O)=O KPGXRSRHYNQIFN-UHFFFAOYSA-N 0.000 description 9
• 150000003929 3-aminopyridines Chemical class 0.000 description 9
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
• KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 9
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
• 230000005764 inhibitory process Effects 0.000 description 9
• 235000018977 lysine Nutrition 0.000 description 9
• 238000007069 methylation reaction Methods 0.000 description 9
• 229910000027 potassium carbonate Inorganic materials 0.000 description 9
• 101100477411 Dictyostelium discoideum set1 gene Proteins 0.000 description 8
• KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 8
• 239000004472 Lysine Substances 0.000 description 8
• 238000003556 assay Methods 0.000 description 8
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
• 238000010511 deprotection reaction Methods 0.000 description 8
• 230000011987 methylation Effects 0.000 description 8
• 125000004433 nitrogen atom Chemical group N* 0.000 description 8
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
• CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 7
• ZPFBQBOZEDHSGM-UHFFFAOYSA-N 5-chloro-3-iodo-2h-indazole Chemical compound C1=C(Cl)C=CC2=NNC(I)=C21 ZPFBQBOZEDHSGM-UHFFFAOYSA-N 0.000 description 7
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
• 101000613625 Homo sapiens Lysine-specific demethylase 4A Proteins 0.000 description 7
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• 239000000543 intermediate Substances 0.000 description 7
• FASOJOLGUAUEPU-UHFFFAOYSA-N methyl 3-bromopyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC=C1Br FASOJOLGUAUEPU-UHFFFAOYSA-N 0.000 description 7
• 235000011181 potassium carbonates Nutrition 0.000 description 7
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• 229910052727 yttrium Inorganic materials 0.000 description 7
• CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 6
• ZWCIANXPJYGVEM-UHFFFAOYSA-N 3-[(5-methyl-1-propylindazol-3-yl)amino]pyridine-4-carboxylic acid Chemical compound C12=CC(C)=CC=C2N(CCC)N=C1NC1=CN=CC=C1C(O)=O ZWCIANXPJYGVEM-UHFFFAOYSA-N 0.000 description 6
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• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
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• 239000007832 Na2SO4 Substances 0.000 description 6
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
• 230000001413 cellular effect Effects 0.000 description 6
• 238000004587 chromatography analysis Methods 0.000 description 6
• JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 6
• 230000008878 coupling Effects 0.000 description 6
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• TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 6
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• NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
• SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 6
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• 235000011152 sodium sulphate Nutrition 0.000 description 6
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
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• 125000004429 atom Chemical group 0.000 description 5
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• 125000000753 cycloalkyl group Chemical group 0.000 description 5
• OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 5
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• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
• 238000010992 reflux Methods 0.000 description 5
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• 230000001225 therapeutic effect Effects 0.000 description 5
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• NVOWKWGHEKGZRF-NSHDSACASA-N 3-[[5-fluoro-1-[(3s)-pyrrolidin-3-yl]indazol-3-yl]amino]pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=C1NC(C1=CC(F)=CC=C11)=NN1[C@@H]1CNCC1 NVOWKWGHEKGZRF-NSHDSACASA-N 0.000 description 4
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• 150000001412 amines Chemical class 0.000 description 4
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• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
• 230000000069 prophylactic effect Effects 0.000 description 4
• FKGBIZLRHZTCCL-UHFFFAOYSA-N pyridine-4-carboxylic acid 2,2,2-trifluoroacetic acid Chemical compound FC(C(=O)O)(F)F.C(C1=CC=NC=C1)(=O)O FKGBIZLRHZTCCL-UHFFFAOYSA-N 0.000 description 4
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• 125000003107 substituted aryl group Chemical group 0.000 description 4
• 201000005112 urinary bladder cancer Diseases 0.000 description 4
• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
• BISRMYZLPKDLOS-UHFFFAOYSA-N 3-(1,2-benzoxazol-3-ylamino)pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC=C1NC1=NOC2=CC=CC=C12 BISRMYZLPKDLOS-UHFFFAOYSA-N 0.000 description 3
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