ES2665461T3 - Moduladores del receptor esfingosina 1-fosfato y métodos de síntesis quiral - Google Patents
Moduladores del receptor esfingosina 1-fosfato y métodos de síntesis quiral Download PDFInfo
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- ES2665461T3 ES2665461T3 ES10830877.6T ES10830877T ES2665461T3 ES 2665461 T3 ES2665461 T3 ES 2665461T3 ES 10830877 T ES10830877 T ES 10830877T ES 2665461 T3 ES2665461 T3 ES 2665461T3
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A61P25/00—Drugs for disorders of the nervous system
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- 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
- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
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- 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
- C07D413/12—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 chain containing hetero atoms as chain links
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
Un compuesto que tiene la estructura de las Fórmulas I-R o I-S o una sal, un hidrato o un solvato farmacéuticamente aceptables del mismo: **(Ver fórmula)** en las que X es -NR'R" o -OR'''; Y es -CN, -Cl, -CF3, I, -COOH o -COOR1; R' es H, alquilo C1-4, n-hidroxialquilo C1-4, -SO2-R1 o -CO-R1; R" es H, -SO2-R3, alquilo C1-4 opcionalmente sustituido con 1 o más R2, o un resto de anillo opcionalmente sustituido con R4 en donde dicho resto de anillo es piperidinilo, ciclohexilo, morfolinilo, tiazolilo, pirazolilo, pirrolidinilo, imidazolilo o fenilo; o R' y R" tomados junto con el átomo de nitrógeno al que están unidos forman un anillo heterocíclico saturado de 4, 5 o 6 miembros que contiene 0 o 1 heteroátomos adicionales donde dicho heteroátomo adicional es O o N en donde dicho heterociclo está opcionalmente sustituido de forma individual o múltiple con sustituyentes seleccionados independientemente entre el grupo que consiste en -OH, oxo, -NH2, n-hidroxialquilo C1-4, - COOH, -(CH2)m-COOH, -(CH2)m-COOR1, -N(R1R1) y -(CH2)m-CO-N(R5R5); R"' es H, alquilo C1-4 o -CO-R1; cada R1 es independientemente alquilo C1-4 o H; cada R2 es independientemente H, halo, OH, oxo, >=NH, NH2, -COOH, F, -NHR1, -N(R5R5),-SO2-R1, -SO2- N(R5R5), -N(R1)-SO2-R1, -COOR1, -OCO-R1, -CO-N(R5R5), -N(R1)-COR1, alquilo C1-3, alcoxi C1-3 y un resto de anillo opcionalmente sustituido con R4 en donde dicho resto de anillo es piperazinilo, piperidinilo, morfolinilo, pirrolidinilo, pirazolilo, imidazolilo, benzoimidazolilo, azetidinilo, ciclobutinilo o fenilo; cada R3 es independientemente R2, alquilo C1-4, cicloalquilo C3-6 o alquilo C1-4 opcionalmente sustituido con 1 o más R2; cada R4 es independientemente halo, OH, -NH2, -NHR1, -N(R1R1), -COOH, -COOR1, -NHCO-R1; cada R5 es independientemente alquilo C1-4 o H, o dos R5 tomados junto con el átomo de nitrógeno al que están unidos forman un anillo heterocíclico saturado de 4, 5 o 6 miembros que contiene 0 o 1 heteroátomos adicionales donde dicho heteroátomo adicional es O o N en donde dicho heterociclo está opcionalmente sustituido con -OH, -NH2, -N(R1R1), n-hidroxialquilo C1-4, -(CH2)m-COOH, -(CH2)m-COOR1; y cada m es independientemente 0, 1, 2 o 3.
Description
TABLA 1
- ESTRUCTURA
- NÚMERO DE COMPUESTO TIEMPO DE RETENCIÓN LCMS (min)
- imagen69
- 1 9,32
- imagen70
- 2 9,32
- imagen71
- 3 6,35
- imagen72
- 4 6,34
- imagen73
- 5 9,21
- imagen74
- 6 9,20
70 71 72 73 74 75 76 77 78 79 80 81
- imagen75
- 7 8,09
- imagen76
- 8 8,08
- imagen77
- 9 8,25
- imagen78
- 10 8,26
- imagen79
- 11 9,53
- imagen80
- 12 9,53
- imagen81
- 13 8,16
- imagen82
- 14 8,16
- imagen83
- 15 9,01
- imagen84
- 16 9,03
- imagen85
- 17 8,55
- imagen86
- 18 8,56
- imagen87
- 19 8,31
- imagen88
- 20 6,45
- imagen89
- 21 8,90
- imagen90
- 22 8,89
- imagen91
- 23 9,37
- imagen92
- 24 9,36
- imagen93
- 25 6,56
- imagen94
- 26 8,82
- imagen95
- 27 8,8
- imagen96
- 28 9,41
- imagen97
- 29 9,36
- imagen98
- 30 9,87
- imagen99
- 31 9,83
- imagen100
- 32 9,68
- imagen101
- 33 9,66
- imagen102
- 34 8,83
- imagen103
- 35 8,84
- imagen104
- 36 8,73
- imagen105
- 37 8,76
- imagen106
- 38 8,47
- imagen107
- 39 8,49
- imagen108
- 40 9,09
- imagen109
- 41 9,07
- imagen110
- 42 9,00
- imagen111
- 43 9,02
- imagen112
- 44 6,74
- imagen113
- 45 6,82
- imagen114
- 46 6,69
- imagen115
- 47 6,58
- imagen116
- 48 6,55
- imagen117
- 49 6,54
- imagen118
- 50 6,36
- imagen119
- 51 6,40
- imagen120
- 52 6,13
- imagen121
- 53 6,52
- imagen122
- 54 6,71
- imagen123
- 55 6,76
- imagen124
- 56 8,63
- imagen125
- 57 6,16
- imagen126
- 58 6,34
- imagen127
- 59 5,85
- imagen128
- 60 8,56
- imagen129
- 61 6,07
- imagen130
- 62 6,22
- imagen131
- 63 6,33
- imagen132
- 64 6,43
- imagen133
- 65 6,00
- imagen134
- 66 6,23
- imagen135
- 67 7,40
- imagen136
- 68 9,66
- imagen137
- 69 10,74
- imagen138
- 70 8,81
- imagen139
- 71 7,44
Ensayos biológicos
5
Generación de la inhibición mediada por S1P1 del ensayo indicador de AMPc
Un plásmido de expresión en mamífero que contiene S1P1/EDG1 clonado pcDNA3.1 se adquirió del Missouri S&T cDNA Resource Centre. La secuencia de nucleótidos y de aminoácidos del S1P1/EDG1 humano se ha publicado en 10 Hla y Maciag (J Biol Chem, 265(1990), 9308-9313). S1P1/pcDNA3.1 se transfectó en la línea de células CRE-bla CHO K1 (Invitrogen), y los clones monocelulares estables se seleccionaron usando técnicas convencionales. La expresión del receptor S1P1/EDG1 funcional se confirmó mediante FACS de la superficie celular con un anticuerpo dirigido contra S1P1 (R&D Systems, clone 218713) y la inhibición de AMPc inducida por forskolina mediada por S1P.
15 Ensayo indicador de S1P1 CRE-bla CHOK1 -caracterización de agonistas de S1P1
Las células se sembraron en placas de 384 pocillos de paredes negras y fondo transparente a 104 células/pocillo/19,5 µl de medio de ensayo exento de eDMEM-fenol, carbón activo al 0,5 %/suero desprovisto de dextrano, glutamina 2 mM, NEAA 0,1 mM, Na-Piruvato 1 mM, Hepes 25 mM) y se incubaron durante 18 h a 37°C en 20 CO2 al 5 %. Se generaron curvas de respuesta a la dosis (10 puntos) en HEPES 10 mM, Pluronic F127 al 0,1 %, en presencia de forskolina. Las células se trataron con 0,5 µl de compuesto en presencia de forskolina 2 µM durante 4 h a 37°C. El sustrato fluorescente de β-lactamasa basado en FRET (LiveBLAzer™-FRET B/G Loading Kit CC4-AM; Invitrogen) se preparó de acuerdo con las directrices del fabricante, y se incubó con las células durante 2 horas a
82
temperatura ambiente. Las placas se leyeron a Ex:410/Em:458 y Ex:410/Em:522, y se determinó la relación de respuesta. Los datos se analizaron mediante regresión no lineal para determinar la CE50 para la inhibición de AMPc inducido por forskolina.
5 Especificidad respecto de otros receptores S1P
Para evaluar la especificidad del compuesto sobre otros receptores S1P, se usaron las siguientes líneas celulares: S1P2 CRE-bla CHOK1, S1P3-Gα15 NFAT-bla HEK293T (Invitrogen), S1P4-bla TANGO U2OS (Invitrogen), S1P5-bla TANGO U2OS (Invitrogen). Se usó el mismo ensayo configurado para S1P1 pero sin forskolina. Los ensayos con
10 S1P4 y S1P5 se realizaron en medio FreeStyle Expression (Invitrogen). Las células S1P5 se incubaron durante 48 h antes del tratamiento con el compuesto.
Actividad de S1P1 indicada
15 Los datos de actividad de agonistas de S1P1 seleccionados se muestra en la Tabla 2. El intervalo de actividad se denota de la siguiente forma: ++++ representa actividad agonista <0,05 nM. +++ representa actividad agonista entre 0,05 y 0,50 nM, y ++ representa actividad agonista entre 0,50-5,00 nM, y + representa actividad agonista > 5,00 nM. N/A representa no disponible.
20 TABLA 2
- NÚMERO DE COMPUESTO
- ACTIVIDAD S1P1 NÚMERO DE COMPUESTO ACTIVIDAD S1P1
- 1
- +++ 36 ++++
- 2
- ++++ 37 ++++
- 3
- ++ 38 ++++
- 4
- +++ 39 ++++
- 5
- +++ 40 ++++
- 6
- +++ 41 ++++
- 7
- +++ 42 ++++
- 8
- +++ 43 ++++
- 9
- +++ 44 +++
- 10
- +++ 45 ++
- 11
- +++ 46 ++
- 12
- +++ 47 +++
- 13
- +++ 48 +++
- 14
- +++ 49 +++
- 15
- +++ 50 +++
- 16
- ++ 51 +++
- 17
- ++ 52 ++++
- 18
- ++ 53 +++
- 19
- ++ 54 ++
- 20
- ++ 55 +++
- 21
- +++ 56 ++
- 22
- +++ 57 ++
- 23
- ++ 58 +
- 24
- +++ 59 +
- 25
- ++ 60 +
- 26
- +++ 61 +
83
Claims (1)
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imagen1 imagen2 imagen3 imagen4 imagen5 imagen6 imagen7 imagen8 imagen9 imagen10
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26128209P | 2009-11-13 | 2009-11-13 | |
| US261282P | 2009-11-13 | ||
| US26247409P | 2009-11-18 | 2009-11-18 | |
| US262474P | 2009-11-18 | ||
| PCT/US2010/056757 WO2011060389A1 (en) | 2009-11-13 | 2010-11-15 | Sphingosine 1 phosphate receptor modulators and methods of chiral synthesis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2665461T3 true ES2665461T3 (es) | 2018-04-25 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES10830877.6T Active ES2665461T3 (es) | 2009-11-13 | 2010-11-15 | Moduladores del receptor esfingosina 1-fosfato y métodos de síntesis quiral |
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| Country | Link |
|---|---|
| US (3) | US8357706B2 (es) |
| EP (1) | EP2498611B1 (es) |
| JP (1) | JP5988379B2 (es) |
| KR (1) | KR101781233B1 (es) |
| CN (1) | CN102724880B (es) |
| AU (1) | AU2010320041B2 (es) |
| BR (1) | BR112012011430A8 (es) |
| CA (1) | CA2780433C (es) |
| CY (1) | CY1120427T1 (es) |
| DK (1) | DK2498611T3 (es) |
| EA (1) | EA023183B1 (es) |
| ES (1) | ES2665461T3 (es) |
| HR (1) | HRP20180527T1 (es) |
| HU (1) | HUE036391T2 (es) |
| IL (1) | IL219690B (es) |
| LT (1) | LT2498611T (es) |
| MX (1) | MX2012005562A (es) |
| MY (1) | MY160907A (es) |
| NZ (1) | NZ599913A (es) |
| PL (1) | PL2498611T3 (es) |
| PT (1) | PT2498611T (es) |
| RS (1) | RS57070B1 (es) |
| SI (1) | SI2498611T1 (es) |
| WO (1) | WO2011060389A1 (es) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG10201407357PA (en) | 2009-11-13 | 2014-12-30 | Receptos Inc | Selective sphingosine 1 phosphate receptor modulators and methods of chiral synthesis |
| KR101781233B1 (ko) | 2009-11-13 | 2017-09-22 | 셀진 인터내셔널 Ii 에스에이알엘 | 스핑고신 1 포스페이트 수용체 조절자 및 카이랄 합성 방법 |
| EP2706999B1 (en) | 2011-05-13 | 2019-08-28 | Celgene International II Sàrl | Selective heterocyclic sphingosine 1 phosphate receptor modulators |
| CN103251950B (zh) * | 2012-02-16 | 2018-10-02 | 中国人民解放军军事科学院军事医学研究院辐射医学研究所 | S1p受体调节剂防治肠型放射病及放射性肠炎的用途 |
| SI2920150T1 (sl) * | 2012-11-16 | 2017-10-30 | F. Hoffman-La Roche Ag | Postopek za pripravo izotonične kisline in estrov 2-trifluorometila |
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