JP5237799B2 - ピラゾールベースのlxrモジュレーター - Google Patents
ピラゾールベースのlxrモジュレーター Download PDFInfo
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- JP5237799B2 JP5237799B2 JP2008519444A JP2008519444A JP5237799B2 JP 5237799 B2 JP5237799 B2 JP 5237799B2 JP 2008519444 A JP2008519444 A JP 2008519444A JP 2008519444 A JP2008519444 A JP 2008519444A JP 5237799 B2 JP5237799 B2 JP 5237799B2
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- Prior art keywords
- alkyl
- haloalkyl
- halogen
- independently
- cor
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- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 525
- 229910052736 halogen Inorganic materials 0.000 claims description 376
- 150000002367 halogens Chemical class 0.000 claims description 328
- 125000000217 alkyl group Chemical group 0.000 claims description 291
- 125000003118 aryl group Chemical group 0.000 claims description 213
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 195
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 194
- 229910052739 hydrogen Inorganic materials 0.000 claims description 182
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 178
- 239000001257 hydrogen Substances 0.000 claims description 178
- 125000001072 heteroaryl group Chemical group 0.000 claims description 173
- 125000000623 heterocyclic group Chemical group 0.000 claims description 165
- 125000004076 pyridyl group Chemical group 0.000 claims description 125
- 150000002431 hydrogen Chemical class 0.000 claims description 124
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 109
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 107
- -1 C 0 -C 6 alkoxyaryl Chemical group 0.000 claims description 93
- 125000001544 thienyl group Chemical group 0.000 claims description 90
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 79
- 125000002541 furyl group Chemical group 0.000 claims description 70
- 125000000335 thiazolyl group Chemical group 0.000 claims description 65
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 64
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 64
- 125000004104 aryloxy group Chemical group 0.000 claims description 56
- 125000001188 haloalkyl group Chemical group 0.000 claims description 55
- 125000002971 oxazolyl group Chemical group 0.000 claims description 55
- 229910052799 carbon Inorganic materials 0.000 claims description 51
- 125000001931 aliphatic group Chemical group 0.000 claims description 50
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 45
- 230000000694 effects Effects 0.000 claims description 41
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 41
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 40
- 102000004311 liver X receptors Human genes 0.000 claims description 39
- 108090000865 liver X receptors Proteins 0.000 claims description 39
- 201000010099 disease Diseases 0.000 claims description 37
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 35
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 34
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 33
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 28
- 229910052757 nitrogen Inorganic materials 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 28
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 27
- 208000035475 disorder Diseases 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 26
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 20
- 125000005844 heterocyclyloxy group Chemical group 0.000 claims description 20
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 20
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 17
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- 229920006395 saturated elastomer Polymers 0.000 claims description 10
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- 208000002874 Acne Vulgaris Diseases 0.000 claims description 7
- 206010000496 acne Diseases 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 150000002632 lipids Chemical class 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
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- 235000020824 obesity Nutrition 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 208000032928 Dyslipidaemia Diseases 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 3
- 206010049287 Lipodystrophy acquired Diseases 0.000 claims description 3
- 230000037365 barrier function of the epidermis Effects 0.000 claims description 3
- 150000001721 carbon Chemical group 0.000 claims description 3
- 230000004069 differentiation Effects 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 210000002615 epidermis Anatomy 0.000 claims description 3
- 208000026278 immune system disease Diseases 0.000 claims description 3
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- 230000005856 abnormality Effects 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 99
- JFWVQXCNQINFMD-UHFFFAOYSA-N 2-[5-[2-(2-chlorophenyl)-5-(trifluoromethyl)pyrazol-3-yl]-2-(3-methylsulfonylphenyl)phenyl]propan-2-ol Chemical compound CC(C)(O)C1=CC(C=2N(N=C(C=2)C(F)(F)F)C=2C(=CC=CC=2)Cl)=CC=C1C1=CC=CC(S(C)(=O)=O)=C1 JFWVQXCNQINFMD-UHFFFAOYSA-N 0.000 description 96
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 74
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- 108020004017 nuclear receptors Proteins 0.000 description 61
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 60
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 59
- 238000000034 method Methods 0.000 description 57
- 125000003545 alkoxy group Chemical group 0.000 description 42
- 102000005962 receptors Human genes 0.000 description 38
- 108020003175 receptors Proteins 0.000 description 38
- 229940107161 cholesterol Drugs 0.000 description 37
- 125000002883 imidazolyl group Chemical group 0.000 description 35
- 125000002757 morpholinyl group Chemical group 0.000 description 31
- 239000000651 prodrug Substances 0.000 description 28
- 229940002612 prodrug Drugs 0.000 description 28
- 125000001424 substituent group Chemical group 0.000 description 25
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 22
- 125000001041 indolyl group Chemical group 0.000 description 19
- 239000000126 substance Substances 0.000 description 19
- 125000004171 alkoxy aryl group Chemical group 0.000 description 18
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 18
- 235000012000 cholesterol Nutrition 0.000 description 17
- 229910052801 chlorine Inorganic materials 0.000 description 16
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 16
- 229910052731 fluorine Inorganic materials 0.000 description 16
- 125000004193 piperazinyl group Chemical group 0.000 description 16
- 125000003386 piperidinyl group Chemical group 0.000 description 16
- 125000003226 pyrazolyl group Chemical group 0.000 description 16
- 229910052794 bromium Inorganic materials 0.000 description 13
- 230000014509 gene expression Effects 0.000 description 13
- 239000000556 agonist Substances 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 12
- 108090000623 proteins and genes Proteins 0.000 description 12
- 238000011282 treatment Methods 0.000 description 12
- 230000004060 metabolic process Effects 0.000 description 11
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 125000005325 aryloxy aryl group Chemical group 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 125000001624 naphthyl group Chemical group 0.000 description 10
- 241000124008 Mammalia Species 0.000 description 9
- 108010038912 Retinoid X Receptors Proteins 0.000 description 9
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 9
- 125000005247 tetrazinyl group Chemical group N1=NN=NC(=C1)* 0.000 description 9
- 125000003831 tetrazolyl group Chemical group 0.000 description 9
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- 125000001425 triazolyl group Chemical group 0.000 description 9
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- 125000005647 linker group Chemical group 0.000 description 7
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- 125000002947 alkylene group Chemical group 0.000 description 6
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- 125000005553 heteroaryloxy group Chemical group 0.000 description 6
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- 238000001727 in vivo Methods 0.000 description 6
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- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 6
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- 125000004450 alkenylene group Chemical group 0.000 description 5
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- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 5
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 4
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Classifications
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| SA05260357B1 (ar) | 2004-11-19 | 2008-09-08 | ارينا فارماسيتو تيكالز ، أنك | مشتقات 3_فينيل_بيرازول كمعدلات لمستقبل سيروتينين 5_ht2a مفيدة في علاج الاضطرابات المتعلقه به |
| US8703805B2 (en) | 2005-06-27 | 2014-04-22 | Exelixis Patent Company Llc | Modulators of LXR |
| AU2013200480B2 (en) * | 2006-02-28 | 2016-06-09 | Dart Neuroscience (Cayman) Ltd. | Therapeutic compounds |
| EP2562168B1 (en) | 2006-02-28 | 2014-04-16 | Dart Neuroscience (Cayman) Ltd | Therapeutic piperazines as pde4 inhibitors |
| CN101484424B (zh) | 2006-02-28 | 2014-05-14 | 达特神经科学(开曼)有限公司 | 治疗化合物 |
| JP5286254B2 (ja) | 2006-05-18 | 2013-09-11 | アリーナ ファーマシューティカルズ, インコーポレイテッド | 5−ht2aセロトニンレセプター活性のモジュレーターとして有用なフェニルピラゾールの結晶形態および調製方法 |
| CA2646076C (en) | 2006-05-18 | 2015-06-30 | Arena Pharmaceuticals, Inc. | Ethers, secondary amines and derivatives thereof as modulators of the 5-ht2a serotonin receptor useful for the treatment of disorders related thereto |
| ES2536762T3 (es) | 2006-05-18 | 2015-05-28 | Arena Pharmaceuticals, Inc. | Aminas primarias y sus derivados como moduladores del receptor de la serotonina 5-HT2A útiles para el tratamiento de trastornos relacionados con este |
| CA2655933C (en) | 2006-06-23 | 2014-09-09 | Alethia Biotherapeutics Inc. | Polynucleotides and polypeptide sequences involved in cancer |
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| TWI415845B (zh) | 2006-10-03 | 2013-11-21 | Arena Pharm Inc | 用於治療與5-ht2a血清素受體相關聯病症之作為5-ht2a血清素受體之調節劑的吡唑衍生物 |
| US8193225B2 (en) * | 2006-10-13 | 2012-06-05 | The Board Of Regents Of The University Of Texas System | Isoxazole amides, derivatives and methods of chemical induction of neurogenesis |
| KR20090094125A (ko) * | 2006-12-08 | 2009-09-03 | 엑셀리시스, 인코포레이티드 | Lxr 및 fxr 조절자 |
| UY30892A1 (es) | 2007-02-07 | 2008-09-02 | Smithkline Beckman Corp | Inhibidores de la actividad akt |
| CN103087043A (zh) * | 2007-03-16 | 2013-05-08 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | 具有抗增殖活性的苯甲酰胺类衍生物及其药用制剂 |
| CA2687306A1 (en) | 2007-05-18 | 2008-11-27 | Bayer Schering Pharma Aktiengesellschaft | Heteroaryl substituted pyrazole derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
| TWI443090B (zh) | 2007-05-25 | 2014-07-01 | Abbvie Deutschland | 作為代謝性麩胺酸受體2(mglu2 受體)之正向調節劑之雜環化合物 |
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| EP2178852B9 (en) | 2007-08-03 | 2016-06-22 | Romark Laboratories, L.C. | Alkylsulfonyl-substituted thiazolide compounds |
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| JP5581219B2 (ja) | 2008-01-25 | 2014-08-27 | ミレニアム ファーマシューティカルズ, インコーポレイテッド | チオフェンおよびホスファチジルイノシトール3−キナーゼ(pi3k)阻害薬としてのその使用 |
| DE102008015032A1 (de) | 2008-03-17 | 2009-09-24 | Aicuris Gmbh & Co. Kg | Substituierte Pyrazolamide und ihre Verwendung |
| DE102008015033A1 (de) | 2008-03-17 | 2009-09-24 | Aicuris Gmbh & Co. Kg | Substituierte (Pyrazolyl-carbonyl)imidazolidinone und ihre Verwendung |
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| DE102008057343A1 (de) | 2008-11-14 | 2010-05-20 | Bayer Schering Pharma Aktiengesellschaft | Heterocyclisch substituierte Aryl-Verbindungen und ihre Verwendung |
| DE102008057364A1 (de) | 2008-11-14 | 2010-05-20 | Bayer Schering Pharma Aktiengesellschaft | Substituierte Aryl-Verbindungen und ihre Verwendung |
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