ES2236317T3 - Derivados de tetrahidroñ-heterocicloacepinil pirimidina. - Google Patents
Derivados de tetrahidroñ-heterocicloacepinil pirimidina.Info
- Publication number
- ES2236317T3 ES2236317T3 ES01978247T ES01978247T ES2236317T3 ES 2236317 T3 ES2236317 T3 ES 2236317T3 ES 01978247 T ES01978247 T ES 01978247T ES 01978247 T ES01978247 T ES 01978247T ES 2236317 T3 ES2236317 T3 ES 2236317T3
- Authority
- ES
- Spain
- Prior art keywords
- methyl
- formula
- tetrahydro
- nitro
- pyrimidin
- 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.)
- Expired - Lifetime
Links
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 30
- 239000001257 hydrogen Substances 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 17
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- 239000001301 oxygen Substances 0.000 claims abstract description 6
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims abstract description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- -1 azepin-6-yl Chemical group 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 230000006870 function Effects 0.000 claims description 17
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 12
- 229940079593 drug Drugs 0.000 claims description 10
- 208000028017 Psychotic disease Diseases 0.000 claims description 9
- 230000001154 acute effect Effects 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 8
- 208000002193 Pain Diseases 0.000 claims description 8
- 208000018737 Parkinson disease Diseases 0.000 claims description 7
- VQJHFBNQMZLWTB-UHFFFAOYSA-N 2-methyl-5-nitro-6-(4,5,7,8-tetrahydrothieno[2,3-d]azepin-6-yl)-1h-pyrimidin-4-one Chemical compound O=C1NC(C)=NC(N2CCC=3SC=CC=3CC2)=C1[N+]([O-])=O VQJHFBNQMZLWTB-UHFFFAOYSA-N 0.000 claims description 6
- 229930195712 glutamate Natural products 0.000 claims description 6
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- 125000000524 functional group Chemical group 0.000 claims description 4
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- PPAHTKRIGLLFBZ-UHFFFAOYSA-N 2-methyl-5-nitro-6-(5,6,8,9-tetrahydropyrimido[4,5-d]azepin-7-yl)-1h-pyrimidin-4-one Chemical compound CC1=NC(O)=C([N+]([O-])=O)C(N2CCC3=NC=NC=C3CC2)=N1 PPAHTKRIGLLFBZ-UHFFFAOYSA-N 0.000 claims description 3
- UTJUMXNIQNTVME-UHFFFAOYSA-N 2-methyl-7-(2-methyl-5-nitro-4-oxo-1h-pyrimidin-6-yl)-5,6,8,9-tetrahydro-1h-pyrimido[4,5-d]azepin-4-one Chemical compound C1CC2=NC(C)=NC(O)=C2CCN1C1=NC(C)=NC(O)=C1[N+]([O-])=O UTJUMXNIQNTVME-UHFFFAOYSA-N 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 3
- 208000023105 Huntington disease Diseases 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 230000000926 neurological effect Effects 0.000 claims description 3
- ZIXGMFSFXIBUFN-UHFFFAOYSA-N 6-(6-ethoxy-2-methyl-5-nitropyrimidin-4-yl)-4,5,7,8-tetrahydrothieno[2,3-d]azepine Chemical compound CCOC1=NC(C)=NC(N2CCC=3SC=CC=3CC2)=C1[N+]([O-])=O ZIXGMFSFXIBUFN-UHFFFAOYSA-N 0.000 claims description 2
- 208000010496 Heart Arrest Diseases 0.000 claims description 2
- 208000020339 Spinal injury Diseases 0.000 claims description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 2
- 230000000747 cardiac effect Effects 0.000 claims description 2
- 230000006806 disease prevention Effects 0.000 claims description 2
- 125000005191 hydroxyalkylamino group Chemical group 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims 1
- 208000036260 idiopathic disease Diseases 0.000 claims 1
- 230000003902 lesion Effects 0.000 claims 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 125000001425 triazolyl group Chemical group 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 2
- 125000006701 (C1-C7) alkyl group Chemical group 0.000 abstract 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- MGVLZTSOZFVVKR-UHFFFAOYSA-N 6-bromo-2-methyl-5-nitro-1h-pyrimidin-4-one Chemical compound CC1=NC(Br)=C([N+]([O-])=O)C(=O)N1 MGVLZTSOZFVVKR-UHFFFAOYSA-N 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 108010014719 metabotropic glutamate receptor type 1 Proteins 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
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- ARMSVRBUSGVGCO-UHFFFAOYSA-N 1-(5-bromo-1,2-dihydro-3-benzazepin-3-yl)ethanone Chemical compound BrC1=CN(C(=O)C)CCC2=CC=CC=C21 ARMSVRBUSGVGCO-UHFFFAOYSA-N 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- MWVMYAWMFTVYED-WYKQUDHLSA-N 4,5,5-tritritio-1,2,3,4-tetrahydro-3-benzazepine Chemical compound [3H]C1([3H])C([3H])NCCC2=CC=CC=C21 MWVMYAWMFTVYED-WYKQUDHLSA-N 0.000 description 4
- JUPMBVNRFXPRCB-UHFFFAOYSA-N 5,6,7,8-tetrahydro-4h-thieno[2,3-d]azepine Chemical class C1CNCCC2=C1SC=C2 JUPMBVNRFXPRCB-UHFFFAOYSA-N 0.000 description 4
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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| US7718647B2 (en) * | 2004-06-30 | 2010-05-18 | Athersys, Inc. | Substituted azepine derivatives as serotonin receptor modulators |
| JP5002460B2 (ja) | 2004-10-04 | 2012-08-15 | 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 | タンパク質キナーゼインヒビターとして有用なラクタム化合物 |
| BRPI0620205A2 (pt) * | 2005-12-20 | 2011-11-01 | Richter Gedeon Nyrt | novos compostos |
| PE20080145A1 (es) | 2006-03-21 | 2008-02-11 | Janssen Pharmaceutica Nv | Tetrahidro-pirimidoazepinas como moduladores de trpv1 |
| ES2380165T3 (es) * | 2007-08-02 | 2012-05-09 | Recordati Ireland Limited | Nuevos compuestos heterocíclicos como antagonistas mGlu5 |
| PE20091211A1 (es) | 2007-11-30 | 2009-09-14 | Boehringer Ingelheim Int | Derivados de pirazolopirimidina como moduladores de pde9a |
| CL2008003749A1 (es) | 2007-12-17 | 2010-01-15 | Janssen Pharmaceutica Nv | Compuestos derivados de imidazol, oxazol, y tiazol pirimidina, moduladores de trpv1, proceso de preparacion, composicion farmaceutica y su uso en el tratamiento de enfermedades, trastornos o condicion de dolor, prurito, artritis, tos, asma, trastorno del oido interno y enfermedad inflamatoria intestinal, entre otras. |
| UA105362C2 (en) | 2008-04-02 | 2014-05-12 | Бьорингер Ингельхайм Интернациональ Гмбх | 1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a modulators |
| AP2011005672A0 (en) | 2008-09-08 | 2011-04-30 | Boehringer Ingelheim Int | Pyrazolopyrimidines and their use for the treatment of CNS disorders. |
| US7998952B2 (en) | 2008-12-05 | 2011-08-16 | Millennium Pharmaceuticals, Inc. | Thiolactams and uses thereof |
| US20100317630A1 (en) * | 2009-02-04 | 2010-12-16 | Recordati Ireland Limited | Novel heterocyclic compounds as mglu5 antagonists |
| PE20120505A1 (es) | 2009-03-31 | 2012-05-09 | Boehringer Ingelheim Int | Derivados de 1-heterociclil-1,5-dihidro-pirazolo[3,4-d]pirimidin-4-ona como moduladores de pde9a |
| US20120028931A1 (en) | 2009-09-14 | 2012-02-02 | Recordati Ireland Limited | Heterocyclic m-glu5 antagonists |
| EP2590985B1 (en) | 2010-07-09 | 2014-05-14 | Recordati Ireland Limited | Novel spiroheterocyclic compounds as mglu5 antagonists |
| HUE033378T2 (en) | 2010-08-12 | 2017-11-28 | Boehringer Ingelheim Int | 6-cycloalkyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a inhibitors |
| US8809345B2 (en) | 2011-02-15 | 2014-08-19 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders |
| US8822464B2 (en) | 2011-11-28 | 2014-09-02 | Boehringer Ingelheim International Gmbh | N-aryl-piperazine derivatives and their use as positive allosteric modulators of mGluR5 receptors |
| US8741892B2 (en) | 2011-12-05 | 2014-06-03 | Boehringer Ingelheim International Gmbh | Compounds |
| US8796467B2 (en) * | 2011-12-13 | 2014-08-05 | Boehringer Ingelheim International Gmbh | Compounds |
| US8846948B2 (en) | 2011-12-13 | 2014-09-30 | Boehringer Ingelheim International Gmbh | Compounds |
| US8883789B2 (en) | 2011-12-14 | 2014-11-11 | Boehringer Ingelheim International Gmbh | Piperazine derivatives and their use as positive allosteric modulators of mGluR5 receptors |
| US8716277B2 (en) | 2011-12-14 | 2014-05-06 | Boehringer Ingelheim International Gmbh | Substituted imidazole compounds useful as positive allosteric modulators of mGlu5 receptor activity |
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| US8889677B2 (en) | 2012-01-17 | 2014-11-18 | Boehringer Ingellheim International GmbH | Substituted triazoles useful as mGlu5 receptor modulators |
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| US3940395A (en) * | 1969-08-29 | 1976-02-24 | American Home Products Corporation | 4-Amino-2-phenyl-6-thiopryimidines |
| BG17786A3 (bg) * | 1970-08-14 | 1973-12-25 | Dr. Karl Thomae Gmbh | Метод за получаване на нови производни на азепина |
| BE790287A (fr) * | 1971-10-28 | 1973-04-19 | Delalande Sa | Acides pyrimidin-6yl acethydroxamiques, leur procede de preparation et leur application en therapeutique |
| FR2608607B1 (fr) | 1986-12-23 | 1989-04-28 | Sanofi Sa | Procede de preparation de thienylethylamines et dithienylethylamines ainsi obtenues |
| DE3820775A1 (de) | 1988-06-20 | 1989-12-21 | Thomae Gmbh Dr K | Neue 4,5,7,8-tetrahydro-6h-thiazolo(5,4,-d)azepine, ihre herstellung und ihre verwendung als arzneimittel |
| ES2074867T3 (es) * | 1990-11-06 | 1995-09-16 | Pfizer | Derivados de quinazolina para potenciar la actividad antitumoral. |
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| JP2004504324A (ja) | 2004-02-12 |
| CA2415966A1 (en) | 2002-01-24 |
| ZA200300163B (en) | 2004-04-07 |
| EP1303521A1 (en) | 2003-04-23 |
| US20020045635A1 (en) | 2002-04-18 |
| ATE288437T1 (de) | 2005-02-15 |
| BR0112586A (pt) | 2003-05-20 |
| WO2002006288A1 (en) | 2002-01-24 |
| KR100525214B1 (ko) | 2005-11-01 |
| DE60108759T2 (de) | 2006-05-11 |
| PT1303521E (pt) | 2005-05-31 |
| JP4060705B2 (ja) | 2008-03-12 |
| DK1303521T3 (da) | 2005-06-13 |
| DE60108759D1 (de) | 2005-03-10 |
| EP1303521B1 (en) | 2005-02-02 |
| CN1187358C (zh) | 2005-02-02 |
| MXPA03000428A (es) | 2003-06-24 |
| AU2002210418B2 (en) | 2006-08-17 |
| CA2415966C (en) | 2009-10-27 |
| KR20030015397A (ko) | 2003-02-20 |
| CN1441804A (zh) | 2003-09-10 |
| US6369222B1 (en) | 2002-04-09 |
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