ES2821407T3 - Compuestos de piperidina sustituidos con indol como agentes degradantes de los receptores de estrógenos - Google Patents

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Publication number

ES2821407T3

ES2821407T3 ES17769483T ES17769483T ES2821407T3 ES 2821407 T3 ES2821407 T3 ES 2821407T3 ES 17769483 T ES17769483 T ES 17769483T ES 17769483 T ES17769483 T ES 17769483T ES 2821407 T3 ES2821407 T3 ES 2821407T3

Authority

ES

Spain

Prior art keywords

compound

group

pmol

mmol

alkyl

Prior art date

2016-03-25

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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• -1 Indole-substituted piperidine compounds Chemical class 0.000 title description 86
• 102000015694 estrogen receptors Human genes 0.000 title description 36
• 108010038795 estrogen receptors Proteins 0.000 title description 36
• 239000003795 chemical substances by application Substances 0.000 title description 4
• 230000000593 degrading effect Effects 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 149
• 150000003839 salts Chemical class 0.000 claims abstract description 51
• 125000005842 heteroatom Chemical group 0.000 claims abstract description 47
• 229910052801 chlorine Inorganic materials 0.000 claims abstract description 36
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 35
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 34
• 229910052794 bromium Inorganic materials 0.000 claims abstract description 33
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 33
• 229910052740 iodine Inorganic materials 0.000 claims abstract description 31
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims abstract description 28
• 125000003118 aryl group Chemical group 0.000 claims abstract description 22
• 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims abstract description 18
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 16
• 150000002367 halogens Chemical class 0.000 claims abstract description 16
• 125000004404 heteroalkyl group Chemical group 0.000 claims abstract description 14
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 14
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 11
• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims abstract description 5
• 125000000896 monocarboxylic acid group Chemical group 0.000 claims abstract 21
• 125000000217 alkyl group Chemical group 0.000 claims description 60
• 229910052799 carbon Inorganic materials 0.000 claims description 38
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
• 125000003545 alkoxy group Chemical group 0.000 claims description 11
• 125000004414 alkyl thio group Chemical group 0.000 claims description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 8
• 125000004076 pyridyl group Chemical group 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
• 229910052721 tungsten Inorganic materials 0.000 claims description 7
• 125000001544 thienyl group Chemical group 0.000 claims description 6
• 125000002883 imidazolyl group Chemical group 0.000 claims description 5
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
• 125000002971 oxazolyl group Chemical group 0.000 claims description 5
• 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 5
• 125000000335 thiazolyl group Chemical group 0.000 claims description 5
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 4
• 125000001041 indolyl group Chemical group 0.000 claims description 4
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 4
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
• 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 1
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 4
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 4
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
• 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 1
• JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 abstract 1
• 108010081348 HRT1 protein Hairy Proteins 0.000 abstract 1
• 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 abstract 1
• VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 abstract 1
• 239000000243 solution Substances 0.000 description 333
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 266
• 238000006243 chemical reaction Methods 0.000 description 266
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 148
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 119
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 117
• BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 105
• 239000012043 crude product Substances 0.000 description 94
• 235000019439 ethyl acetate Nutrition 0.000 description 90
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 83
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 82
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 80
• 239000000047 product Substances 0.000 description 79
• 239000012074 organic phase Substances 0.000 description 78
• 229910052757 nitrogen Inorganic materials 0.000 description 73
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 69
• 239000000203 mixture Substances 0.000 description 64
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 63
• 239000012299 nitrogen atmosphere Substances 0.000 description 62
• 238000005160 1H NMR spectroscopy Methods 0.000 description 57
• JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 53
• 235000019253 formic acid Nutrition 0.000 description 53
• OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 52
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 52
• 238000002953 preparative HPLC Methods 0.000 description 41
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 38
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 37
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
• 210000004027 cell Anatomy 0.000 description 35
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 29
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
• YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 28
• 239000000706 filtrate Substances 0.000 description 28
• 239000007787 solid Substances 0.000 description 26
• 238000000034 method Methods 0.000 description 25
• 239000000460 chlorine Substances 0.000 description 24
• 238000010898 silica gel chromatography Methods 0.000 description 24
• 125000001424 substituent group Chemical group 0.000 description 24
• 206010006187 Breast cancer Diseases 0.000 description 21
• 208000026310 Breast neoplasm Diseases 0.000 description 21
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 21
• 239000003921 oil Substances 0.000 description 19
• 238000004237 preparative chromatography Methods 0.000 description 19
• 239000002253 acid Substances 0.000 description 17
• PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 17
• 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 17
• GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 17
• 125000004429 atom Chemical group 0.000 description 16
• IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 16
• 229920006395 saturated elastomer Polymers 0.000 description 16
• GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 15
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
• 229940125797 compound 12 Drugs 0.000 description 15
• 239000012046 mixed solvent Substances 0.000 description 15
• 239000002585 base Substances 0.000 description 13
• 238000004440 column chromatography Methods 0.000 description 13
• 239000003814 drug Substances 0.000 description 13
• 230000000694 effects Effects 0.000 description 13
• 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 12
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
• NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 12
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 12
• 239000012267 brine Substances 0.000 description 11
• 229940079593 drug Drugs 0.000 description 11
• 238000012746 preparative thin layer chromatography Methods 0.000 description 11
• 229910052938 sodium sulfate Inorganic materials 0.000 description 11
• 235000011152 sodium sulphate Nutrition 0.000 description 11
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 10
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
• 229910000024 caesium carbonate Inorganic materials 0.000 description 10
• 125000000623 heterocyclic group Chemical group 0.000 description 10
• 238000002360 preparation method Methods 0.000 description 10
• 125000006239 protecting group Chemical group 0.000 description 10
• 239000000741 silica gel Substances 0.000 description 10
• 229910002027 silica gel Inorganic materials 0.000 description 10
• AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 10
• 235000019345 sodium thiosulphate Nutrition 0.000 description 10
• 239000011877 solvent mixture Substances 0.000 description 10
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 239000007864 aqueous solution Substances 0.000 description 9
• 125000004432 carbon atom Chemical group C* 0.000 description 9
• 125000001183 hydrocarbyl group Chemical group 0.000 description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 description 9
• 239000012071 phase Substances 0.000 description 9
• SYKXNRFLNZUGAJ-UHFFFAOYSA-N platinum;triphenylphosphane Chemical compound [Pt].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 SYKXNRFLNZUGAJ-UHFFFAOYSA-N 0.000 description 9
• 238000004262 preparative liquid chromatography Methods 0.000 description 9
• 239000002994 raw material Substances 0.000 description 9
• CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 8
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
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• 239000003886 aromatase inhibitor Substances 0.000 description 8
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• 125000001072 heteroaryl group Chemical group 0.000 description 8
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
• 229940095743 selective estrogen receptor modulator Drugs 0.000 description 8
• 239000000333 selective estrogen receptor modulator Substances 0.000 description 8
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• 230000000903 blocking effect Effects 0.000 description 7
• 229910052796 boron Inorganic materials 0.000 description 7
• 150000001721 carbon Chemical group 0.000 description 7
• DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 7
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• 230000005764 inhibitory process Effects 0.000 description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
• VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 6
• GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 6
• 0 C[U]CCN(C1)CC1(*)N Chemical compound C[U]CCN(C1)CC1(*)N 0.000 description 6
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• 241000699670 Mus sp. Species 0.000 description 6
• 238000004458 analytical method Methods 0.000 description 6
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• ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 6
• 239000003153 chemical reaction reagent Substances 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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• 125000004434 sulfur atom Chemical group 0.000 description 6
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• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
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• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
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• YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 4
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• OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
• 230000000259 anti-tumor effect Effects 0.000 description 4
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
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• 238000004587 chromatography analysis Methods 0.000 description 4
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• 125000000392 cycloalkenyl group Chemical group 0.000 description 4
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
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• 239000001257 hydrogen Substances 0.000 description 4
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