JP2014517035A5 - - Google Patents
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- JP2014517035A5 JP2014517035A5 JP2014515878A JP2014515878A JP2014517035A5 JP 2014517035 A5 JP2014517035 A5 JP 2014517035A5 JP 2014515878 A JP2014515878 A JP 2014515878A JP 2014515878 A JP2014515878 A JP 2014515878A JP 2014517035 A5 JP2014517035 A5 JP 2014517035A5
- Authority
- JP
- Japan
- Prior art keywords
- hydrogen
- compound
- hexane
- bicyclo
- benzyl
- 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.)
- Granted
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- 150000001875 compounds Chemical class 0.000 claims description 201
- -1 2,2-dimethyl-propionyloxymethyl Chemical group 0.000 claims description 94
- 239000001257 hydrogen Substances 0.000 claims description 92
- 229910052739 hydrogen Inorganic materials 0.000 claims description 92
- 125000001153 fluoro group Chemical group F* 0.000 claims description 59
- 150000003839 salts Chemical class 0.000 claims description 54
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 49
- 150000002431 hydrogen Chemical class 0.000 claims description 43
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 19
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 19
- 201000000980 schizophrenia Diseases 0.000 claims description 15
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 claims description 12
- 208000020925 Bipolar disease Diseases 0.000 claims description 11
- JAPMJSVZDUYFKL-UHFFFAOYSA-N bicyclo[3.1.0]hexane Chemical group C1CCC2CC21 JAPMJSVZDUYFKL-UHFFFAOYSA-N 0.000 claims description 11
- 208000020016 psychiatric disease Diseases 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000003440 L-leucyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C(C([H])([H])[H])([H])C([H])([H])[H] 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 208000011688 Generalised anxiety disease Diseases 0.000 claims description 7
- 208000029364 generalized anxiety disease Diseases 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 235000019000 fluorine Nutrition 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- 238000002360 preparation method Methods 0.000 description 37
- 239000000243 solution Substances 0.000 description 36
- 238000000034 method Methods 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 33
- 239000007787 solid Substances 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- 239000000203 mixture Substances 0.000 description 32
- 229940002612 prodrug Drugs 0.000 description 30
- 239000000651 prodrug Substances 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 28
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 230000000694 effects Effects 0.000 description 21
- 238000003556 assay Methods 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 20
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 241000700159 Rattus Species 0.000 description 15
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000012141 concentrate Substances 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- ANUFAWHRSIJTHW-UHFFFAOYSA-N 2-methylheptanedioic acid Chemical compound OC(=O)C(C)CCCCC(O)=O ANUFAWHRSIJTHW-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- 125000006239 protecting group Chemical group 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 108010004620 glycylsarcosine Proteins 0.000 description 11
- VYAMLSCELQQRAE-UHFFFAOYSA-N glycylsarcosine zwitterion Chemical compound OC(=O)CN(C)C(=O)CN VYAMLSCELQQRAE-UHFFFAOYSA-N 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 108091006594 SLC15A1 Proteins 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000000523 sample Substances 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- 230000036760 body temperature Effects 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 230000007062 hydrolysis Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 0 CC(C)c1nnc(*)[n]1 Chemical compound CC(C)c1nnc(*)[n]1 0.000 description 7
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 7
- 102000046014 Peptide Transporter 1 Human genes 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 229950010883 phencyclidine Drugs 0.000 description 7
- 239000000018 receptor agonist Substances 0.000 description 7
- 229940044601 receptor agonist Drugs 0.000 description 7
- 239000012047 saturated solution Substances 0.000 description 7
- 238000001890 transfection Methods 0.000 description 7
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 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 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- MWECKFISVWUYDM-UHFFFAOYSA-N bicyclo[3.1.0]hexane-2,6-dicarboxylic acid Chemical compound C1CC(C(O)=O)C2C(C(=O)O)C21 MWECKFISVWUYDM-UHFFFAOYSA-N 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
- 230000008878 coupling Effects 0.000 description 6
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- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
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- 230000004044 response Effects 0.000 description 6
- 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
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
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- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 3
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- OKSYUCYFMKATOR-UHFFFAOYSA-N 2-methylheptanedioic acid;hydrochloride Chemical compound Cl.OC(=O)C(C)CCCCC(O)=O OKSYUCYFMKATOR-UHFFFAOYSA-N 0.000 description 3
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- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 2
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| WO1993006127A1 (en) | 1991-09-17 | 1993-04-01 | Warner-Lambert Company | Novel amino acid prodrug renin inhibitors |
| US5576323A (en) | 1993-12-03 | 1996-11-19 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
| US5849525A (en) | 1994-03-09 | 1998-12-15 | Brigham And Women's Hospital, Inc. | Compositions corresponding to a proton-coupled peptide transporter and methods of making and using same |
| GB9605429D0 (en) * | 1995-11-16 | 1996-05-15 | Lilly Co Eli | Excitatory amino acid receptor antagonists |
| HUP9903459A3 (en) | 1995-11-16 | 2001-08-28 | Lilly Co Eli | Oxa- and tiabicyclo[3.1.0]hexane-carboxylic acids, process for their preparation and pharmaceutical compositions of the same |
| US5688826A (en) | 1995-11-16 | 1997-11-18 | Eli Lilly And Company | Excitatory amino acid derivatives |
| US5952294A (en) | 1996-07-31 | 1999-09-14 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Peptidyl prodrugs and methods of making and using the same |
| ZA983930B (en) * | 1997-05-14 | 1999-11-08 | Lilly Co Eli | Excitatory amino acid receptor modulators. |
| PT1052246E (pt) | 1998-01-28 | 2003-06-30 | Taisho Pharmaceutical Co Ltd | Derivados de amino-acidos contendo fluor |
| KR100469182B1 (ko) | 1998-08-31 | 2005-02-02 | 다이쇼 세이야꾸 가부시끼가이샤 | 6-플루오로비시클로[3.1.0]헥산 유도체 |
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| WO2002000605A1 (en) | 2000-06-28 | 2002-01-03 | Taisho Pharmaceutical Co., Ltd. | Novel dicarboxylic acid derivatives |
| EP1351925A1 (en) | 2001-01-11 | 2003-10-15 | Eli Lilly And Company | Prodrugs of excitatory amino acids |
| CN1267407C (zh) | 2001-01-11 | 2006-08-02 | 伊莱利利公司 | 兴奋性氨基酸前体药物 |
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| US7067507B2 (en) | 2001-06-12 | 2006-06-27 | Pharmacia & Upjohn Company | Macrocycles useful in the treatment of Alzheimer's disease |
| CN1281274C (zh) | 2001-12-27 | 2006-10-25 | 大正制药株式会社 | 6－氟双环[3.1.0]己烷衍生物 |
| WO2003084610A1 (en) | 2002-04-03 | 2003-10-16 | Eli Lilly And Company | Therapy for psychoses combining an atypical antipsychotic and an mglu2/3 receptor agonist |
| US20050192273A1 (en) | 2002-04-03 | 2005-09-01 | Johnson Bryan G. | Therapy for psychoses combining an atypical antipsychotic and an mglu2/3 receptor agonist |
| US7371872B2 (en) * | 2002-06-11 | 2008-05-13 | Eli Lilly And Company | Prodrugs of excitatory amino acids |
| CN100482680C (zh) * | 2002-06-11 | 2009-04-29 | 伊莱利利公司 | 兴奋性氨基酸前药 |
| JP4984529B2 (ja) * | 2003-06-26 | 2012-07-25 | 大正製薬株式会社 | ２−アミノビシクロ［３．１．０］ヘキサン−２，６−ジカルボン酸誘導体 |
| ES2355144T3 (es) * | 2003-06-26 | 2011-03-23 | Taisho Pharmaceutical Co., Ltd. | Derivado de éster 2-aminobiciclo 3.1.0 hexano-2,6-dicarboxílico. |
| PL2513085T3 (pl) * | 2009-11-18 | 2017-09-29 | Suven Life Sciences Limited | Związki dwupierścieniowe jako ligandy receptora nikotynowego alfa4beta2 acetylocholiny |
| JO2978B1 (en) * | 2009-12-21 | 2016-03-15 | ايلي ليلي اند كومباني | MGLU2 aids |
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