CA3110520A1 - Thyroid hormone receptor beta agonist compounds - Google Patents
Thyroid hormone receptor beta agonist compounds Download PDFInfo
- Publication number
- CA3110520A1 CA3110520A1 CA3110520A CA3110520A CA3110520A1 CA 3110520 A1 CA3110520 A1 CA 3110520A1 CA 3110520 A CA3110520 A CA 3110520A CA 3110520 A CA3110520 A CA 3110520A CA 3110520 A1 CA3110520 A1 CA 3110520A1
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- CA
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- Prior art keywords
- substituted
- compound
- alkyl
- methyl
- dichloro
- Prior art date
- 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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- 150000001875 compounds Chemical class 0.000 title claims abstract description 318
- 229940123876 Thyroid hormone receptor beta agonist Drugs 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 61
- 230000001404 mediated effect Effects 0.000 claims abstract description 12
- 102100033451 Thyroid hormone receptor beta Human genes 0.000 claims abstract description 7
- 108091008762 thyroid hormone receptors ß Proteins 0.000 claims abstract description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 140
- 125000000217 alkyl group Chemical group 0.000 claims description 113
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 98
- 150000003839 salts Chemical class 0.000 claims description 88
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 69
- 229910052757 nitrogen Inorganic materials 0.000 claims description 65
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 64
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 62
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 32
- 125000004429 atom Chemical group 0.000 claims description 28
- 125000005843 halogen group Chemical group 0.000 claims description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims description 28
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
- 125000005842 heteroatom Chemical group 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 22
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 16
- 125000000468 ketone group Chemical group 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 15
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 11
- 239000000651 prodrug Substances 0.000 claims description 11
- 229940002612 prodrug Drugs 0.000 claims description 11
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 239000012453 solvate Substances 0.000 claims description 10
- 125000001475 halogen functional group Chemical group 0.000 claims description 9
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 8
- 150000001204 N-oxides Chemical class 0.000 claims description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 101100509371 Arabidopsis thaliana CHR11 gene Proteins 0.000 claims description 3
- 239000000203 mixture Substances 0.000 abstract description 387
- 239000000556 agonist Substances 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 439
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 246
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 192
- 239000000243 solution Substances 0.000 description 157
- 235000019439 ethyl acetate Nutrition 0.000 description 147
- 229940093499 ethyl acetate Drugs 0.000 description 146
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 145
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 142
- 238000004809 thin layer chromatography Methods 0.000 description 137
- -1 cyclic phosphate esters Chemical class 0.000 description 116
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 113
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- 125000001072 heteroaryl group Chemical group 0.000 description 98
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 93
- 239000007832 Na2SO4 Substances 0.000 description 90
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 90
- 229910052938 sodium sulfate Inorganic materials 0.000 description 90
- 235000011152 sodium sulphate Nutrition 0.000 description 90
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 89
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 89
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- 239000012267 brine Substances 0.000 description 84
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 84
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 84
- 238000005481 NMR spectroscopy Methods 0.000 description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- 125000003118 aryl group Chemical group 0.000 description 61
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 58
- 229910052681 coesite Inorganic materials 0.000 description 54
- 229910052906 cristobalite Inorganic materials 0.000 description 54
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- 125000000547 substituted alkyl group Chemical group 0.000 description 54
- 229910052905 tridymite Inorganic materials 0.000 description 54
- 125000003107 substituted aryl group Chemical group 0.000 description 47
- 101150041968 CDC13 gene Proteins 0.000 description 46
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 46
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 46
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 45
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- 239000012044 organic layer Substances 0.000 description 41
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 39
- 125000003342 alkenyl group Chemical group 0.000 description 37
- 125000000304 alkynyl group Chemical group 0.000 description 37
- 238000002953 preparative HPLC Methods 0.000 description 37
- 229910052739 hydrogen Inorganic materials 0.000 description 36
- 239000001257 hydrogen Substances 0.000 description 35
- 238000005160 1H NMR spectroscopy Methods 0.000 description 34
- 229910004373 HOAc Inorganic materials 0.000 description 34
- 125000001424 substituent group Chemical group 0.000 description 34
- 125000005017 substituted alkenyl group Chemical group 0.000 description 34
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 33
- 229910017912 NH2OH Inorganic materials 0.000 description 33
- 239000012071 phase Substances 0.000 description 33
- 125000004426 substituted alkynyl group Chemical group 0.000 description 32
- 201000010099 disease Diseases 0.000 description 31
- 238000011282 treatment Methods 0.000 description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 30
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- 125000003545 alkoxy group Chemical group 0.000 description 30
- 238000000746 purification Methods 0.000 description 30
- 229910000027 potassium carbonate Inorganic materials 0.000 description 29
- 235000015320 potassium carbonate Nutrition 0.000 description 29
- 150000002431 hydrogen Chemical class 0.000 description 28
- 125000005415 substituted alkoxy group Chemical group 0.000 description 27
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 24
- 239000007858 starting material Substances 0.000 description 24
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- 208000035475 disorder Diseases 0.000 description 23
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 22
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 20
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 20
- 239000000706 filtrate Substances 0.000 description 20
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- JRZDBBCBIQEJLA-UHFFFAOYSA-N 3,6-dichloro-4-propan-2-ylpyridazine Chemical compound CC(C)C1=CC(Cl)=NN=C1Cl JRZDBBCBIQEJLA-UHFFFAOYSA-N 0.000 description 17
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 17
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 17
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 17
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- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 17
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
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- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 15
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 14
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- 125000004414 alkyl thio group Chemical group 0.000 description 12
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- 125000006310 cycloalkyl amino group Chemical group 0.000 description 12
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 12
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 125000005366 cycloalkylthio group Chemical group 0.000 description 11
- 125000005553 heteroaryloxy group Chemical group 0.000 description 11
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- 125000005110 aryl thio group Chemical group 0.000 description 10
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- 125000001769 aryl amino group Chemical group 0.000 description 9
- 125000004104 aryloxy group Chemical group 0.000 description 9
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- 125000003277 amino group Chemical group 0.000 description 8
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- ZXSBDSGRQIWJPM-UHFFFAOYSA-N dimethylcarbamothioic s-acid Chemical compound CN(C)C(S)=O ZXSBDSGRQIWJPM-UHFFFAOYSA-N 0.000 description 8
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- LGRFSURHDFAFJT-UHFFFAOYSA-N phthalic anhydride Chemical compound C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 8
- 238000012746 preparative thin layer chromatography Methods 0.000 description 8
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
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- 208000035150 Hypercholesterolemia Diseases 0.000 description 7
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 7
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
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| CN114437034A (zh) * | 2020-11-06 | 2022-05-06 | 深圳微芯生物科技股份有限公司 | 一种酞嗪类化合物的可药用盐、晶型及其制备方法 |
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| US10800767B2 (en) | 2020-10-13 |
| EP3840755A4 (en) | 2022-04-20 |
| AU2019325656B2 (en) | 2025-04-24 |
| JP2025020206A (ja) | 2025-02-12 |
| TWI837169B (zh) | 2024-04-01 |
| WO2020041741A1 (en) | 2020-02-27 |
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| AU2019325656A1 (en) | 2021-03-11 |
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