JP5749263B2 - １１β−ヒドロキシステロイドデヒドロゲナーゼ１の環状インヒビター - Google Patents
１１β−ヒドロキシステロイドデヒドロゲナーゼ１の環状インヒビター Download PDFInfo
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- JP5749263B2 JP5749263B2 JP2012518598A JP2012518598A JP5749263B2 JP 5749263 B2 JP5749263 B2 JP 5749263B2 JP 2012518598 A JP2012518598 A JP 2012518598A JP 2012518598 A JP2012518598 A JP 2012518598A JP 5749263 B2 JP5749263 B2 JP 5749263B2
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- alkyl
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- 239000003112 inhibitor Substances 0.000 title description 23
- 102100036506 11-beta-hydroxysteroid dehydrogenase 1 Human genes 0.000 title description 4
- 101710186107 11-beta-hydroxysteroid dehydrogenase 1 Proteins 0.000 title description 2
- 125000004122 cyclic group Chemical group 0.000 title 1
- -1 -COOR 6 Chemical group 0.000 claims description 316
- 150000001875 compounds Chemical class 0.000 claims description 200
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 181
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 154
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 107
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 92
- 125000004043 oxo group Chemical group O=* 0.000 claims description 91
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 90
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 82
- 125000005843 halogen group Chemical group 0.000 claims description 76
- 108010088011 11-beta-Hydroxysteroid Dehydrogenase Type 1 Proteins 0.000 claims description 60
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 51
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 50
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 49
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 48
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 47
- 101100516563 Caenorhabditis elegans nhr-6 gene Proteins 0.000 claims description 46
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 101100516568 Caenorhabditis elegans nhr-7 gene Proteins 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 42
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 41
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 41
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 40
- 125000000623 heterocyclic group Chemical group 0.000 claims description 39
- 125000004076 pyridyl group Chemical group 0.000 claims description 39
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 37
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 35
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 33
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 31
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 30
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- 125000001425 triazolyl group Chemical group 0.000 claims description 30
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 24
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 125000003386 piperidinyl group Chemical group 0.000 claims description 22
- 230000000694 effects Effects 0.000 claims description 21
- 125000002393 azetidinyl group Chemical group 0.000 claims description 19
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 19
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 18
- 125000005366 cycloalkylthio group Chemical group 0.000 claims description 18
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- 125000001153 fluoro group Chemical group F* 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 17
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- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 claims description 15
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 15
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 14
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- 125000002971 oxazolyl group Chemical group 0.000 claims description 11
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- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 11
- 125000001544 thienyl group Chemical group 0.000 claims description 11
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 10
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- 238000004519 manufacturing process Methods 0.000 claims description 6
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 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 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 5
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 3
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical group C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004450 alkenylene group Chemical group 0.000 claims description 3
- 125000005529 alkyleneoxy group Chemical group 0.000 claims description 3
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- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
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- 239000003245 coal Substances 0.000 claims 1
- 238000000034 method Methods 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 77
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- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- AKQNYQDSIDKVJZ-UHFFFAOYSA-N triphenylsilane Chemical compound C1=CC=CC=C1[SiH](C=1C=CC=CC=1)C1=CC=CC=C1 AKQNYQDSIDKVJZ-UHFFFAOYSA-N 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 208000029257 vision disease Diseases 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- KIZNQHOVHYLYHY-UHFFFAOYSA-M zinc;prop-1-ene;bromide Chemical compound [Zn+2].[Br-].[CH2-]C=C KIZNQHOVHYLYHY-UHFFFAOYSA-M 0.000 description 1
Classifications
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- C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
- C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Pregnancy & Childbirth (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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| US22231809P | 2009-07-01 | 2009-07-01 | |
| US61/222,318 | 2009-07-01 | ||
| PCT/US2010/040641 WO2011002910A1 (en) | 2009-07-01 | 2010-06-30 | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
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| JP5470557B2 (ja) | 2007-07-26 | 2014-04-16 | ヴァイティー ファーマシューティカルズ，インコーポレイテッド | １１β−ヒドロキシステロイドデヒドロゲナーゼ１型の阻害剤の合成 |
| AR069207A1 (es) | 2007-11-07 | 2010-01-06 | Vitae Pharmaceuticals Inc | Ureas ciclicas como inhibidores de la 11 beta - hidroxi-esteroide deshidrogenasa 1 |
| JP5490014B2 (ja) | 2007-12-11 | 2014-05-14 | ヴァイティー ファーマシューティカルズ，インコーポレイテッド | １１β−ヒドロキシステロイドデヒドロゲナーゼ１型の環状尿素阻害剤 |
| TW200934490A (en) | 2008-01-07 | 2009-08-16 | Vitae Pharmaceuticals Inc | Lactam inhibitors of 11 &abgr;-hydroxysteroid dehydrogenase 1 |
| US8592409B2 (en) | 2008-01-24 | 2013-11-26 | Vitae Pharmaceuticals, Inc. | Cyclic carbazate and semicarbazide inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
| CA2715290A1 (en) | 2008-02-15 | 2009-08-20 | Vitae Pharmaceuticals, Inc. | Inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
| US8138178B2 (en) | 2008-05-01 | 2012-03-20 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
| CA2723034A1 (en) | 2008-05-01 | 2009-11-05 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
| KR20110050459A (ko) | 2008-07-25 | 2011-05-13 | 비타이 파마슈티컬즈, 인코포레이티드 | 11베타-하이드록시스테로이드 탈수소효소 1의 고리형 억제제 |
| EP2323994A1 (en) | 2008-07-25 | 2011-05-25 | Boehringer Ingelheim International GmbH | Synthesis of inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 |
| TW201016691A (en) | 2008-07-25 | 2010-05-01 | Boehringer Ingelheim Int | Inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
| JP5679997B2 (ja) | 2009-02-04 | 2015-03-04 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | １１β−ヒドロキシステロイドデヒドロゲナーゼ１の環状阻害剤 |
| US8680093B2 (en) | 2009-04-30 | 2014-03-25 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
| EP2440537A1 (en) | 2009-06-11 | 2012-04-18 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 based on the 1,3 -oxazinan- 2 -one structure |
| JP5750449B2 (ja) | 2009-11-05 | 2015-07-22 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規キラルリンリガンド |
| JP2013531636A (ja) | 2010-05-26 | 2013-08-08 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ２−オキソ−１，２−ジヒドロピリジン−４−イルボロン酸誘導体 |
| EP2582698B1 (en) | 2010-06-16 | 2016-09-14 | Vitae Pharmaceuticals, Inc. | Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use |
| JP5813106B2 (ja) | 2010-06-25 | 2015-11-17 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 代謝障害の処置のための１１−β−ＨＳＤ１のインヒビターとしてのアザスピロヘキサノン |
| US8835472B2 (en) * | 2010-09-02 | 2014-09-16 | Boehringer Ingelheim International Gmbh | Compounds, pharmaceutical compositions and uses thereof |
| EA201300522A1 (ru) | 2010-11-02 | 2013-11-29 | Бёрингер Ингельхайм Интернациональ Гмбх | Фармацевтические комбинации для лечения метаболических нарушений |
| EP3235813A1 (en) | 2016-04-19 | 2017-10-25 | Cidqo 2012, S.L. | Aza-tetra-cyclo derivatives |
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-
2010
- 2010-06-30 US US13/381,123 patent/US8883778B2/en not_active Expired - Fee Related
- 2010-06-30 JP JP2012518598A patent/JP5749263B2/ja not_active Expired - Fee Related
- 2010-06-30 EP EP10731680.4A patent/EP2448928B1/en not_active Not-in-force
- 2010-06-30 WO PCT/US2010/040641 patent/WO2011002910A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011002910A1 (en) | 2011-01-06 |
| US20120232050A1 (en) | 2012-09-13 |
| EP2448928B1 (en) | 2014-08-13 |
| JP2012532139A (ja) | 2012-12-13 |
| EP2448928A1 (en) | 2012-05-09 |
| US8883778B2 (en) | 2014-11-11 |
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