BRPI0918868B1 - compostos moduladores do receptor de nmda e composições compreendendo os mesmos - Google Patents
compostos moduladores do receptor de nmda e composições compreendendo os mesmos Download PDFInfo
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- BRPI0918868B1 BRPI0918868B1 BRPI0918868-1A BRPI0918868A BRPI0918868B1 BR PI0918868 B1 BRPI0918868 B1 BR PI0918868B1 BR PI0918868 A BRPI0918868 A BR PI0918868A BR PI0918868 B1 BRPI0918868 B1 BR PI0918868B1
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- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 239000011701 zinc Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Images
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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Abstract
Description
T é, independentemente para cada ocorrência, CR4R4 e n é 0,1,2 ou 3;
A está opcionalmente presente e é selecionado de fenila ou piridi-na, em que A é opcionalmente substituído por um ou mais substituintes selecionados de Ra;
R1 é selecionado do grupo consistindo em H, hidroxila, -S(O)2-C1-C4 alquila; -SO2, C1-C4alquila, C2-C4alquenila, fenila, R7 ouem que C1-C4alquila, C2-C4alquenila ou fenila é opcionalmente substituída por um ou mais substituintes selecionados de Ra;
XéCH ou N;
R3 e R3 são independentemente selecionados do grupo consistindo em H, halogênio, hidroxila, fenila, C1-C4alquila, amido, amina ou C2-C4alquenila, em que C1-C4alquila, C2-C4alquenila e fenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R4 e R4 são independentemente selecionados do grupo consistindo em H, halogênio, hidroxila, fenila, C1-C4alquila, amido, amina, C1-C4alcóxi ou C2-C4alquenila, em que C1-C4alquila, C2-C4alquenila, C1-C4alcóxi e fenila são opcionalmente substituídos por um ou mais substituintes selecionados de Ra;
R2 é selecionado do grupo consistindo em H, R7) -S(O)2, S(O)2-C1-C4alquila, C1-C4alquila, hidroxila ou fenila em que C1-C4alquila, C2-C4 alquenila e fenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R5 e R5’ são, cada um, independentemente selecionados do grupo consistindo em H, halogênio, C1-C4alquila, C1-C4alcóxi, C2-C4alquenila, ciano, amino, fenila e hidroxila, em que C1-C4alquila, C2-C4alquenila e fenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R7 é selecionado do grupo consistindo em -C(O)-C1-C4alquila ou C(O)-O-C1-C4alquila, em que C1-C4 alquila é opcionalmente substituída por 1,2 ou 3 substituintes selecionados de Rb;
R8 é selecionado do grupo consistindo em H, -C(O)- C1-C4 alquila ou C(O)-O- C1-C4 alquila, em que C1-C4alquila é opcionalmente substituída por 1, 2 ou 3 substituintes selecionados de Ra;
Ra é selecionado, independentemente para cada ocorrência, de carbóxi, hidroxila, halogênio, amino, fenila, C1-C4 alquila e C1-C4 alcóxi;
Rb é selecionado, independentemente para cada ocorrência, do grupo consistindo em carbóxi, hidroxila, halogênio, amino, fenila, C1-C4 alquila, C1-C4 alcóxi e -NH-RC; e
Rc é selecionado, independentemente para cada ocorrência, -C(O)-O-C1-C4alquila; e -C(O)-C1-C4alquila.
T é, independentemente para cada ocorrência, CR4R4 e n é 0,1,2 ou 3;
A está opcionalmente presente e é selecionado de fenila ou piridi-na, em que A é opcionalmente substituído por um ou mais substituintes sele-cionados de Ra;
R1 é selecionado do grupo consistindo em H, hidroxila, -S(O)2-C1-C4alquila; -SO2, C1-C4alquila, C2-C4alquenila, fenila, R7 ouem que C1-C4alquila, C2-C4alquenila ou fenila é opcionalmente substituída por um ou mais substituintes selecionados de Ra;
X é CH ou N;
R3 e R3 são independentemente selecionados do grupo consistindo em H, halogênio, hidroxila, fenila, C1-C4alquila, amido, amina ou C2-C4alquenila, em que C1-C4alquila, C2-C4alquenila e fenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R4 e R4 são independentemente selecionados do grupo consistindo em H, halogênio, hidroxila, fenila, C1-C4alquila, amido, amina, C1-C4alcóxi ou C2-C4alquenila, em que C1-C4alquila, C2-C4alquenila, C1-C4alcóxi e fenila são opcionalmente substituídos por um ou mais substituintes selecionados de Ra;
R2 é selecionado do grupo consistindo em H, R7, -S(O)2, S(O)2-C1-C4 alquila, C1-C4alquila, hidroxila ou fenila em que C1-C4alquila, C2-C4 alquenila e fenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R5 e R5’ são, cada um, independentemente selecionados do grupo consistindo em H, halogênio, C1-C4alquila, C1-C4alcóxi, C2-C4alquenila, ciano, amino, fenila e hidroxila, em que C1-C4alquila, C2-C4alquenila e fenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R7 é selecionado do grupo consistindo em -C(O)-C1-C4alquila ou C(O)-O-C1-C4alquila, em que C1-C4 alquila é opcionalmente substituída por 1,2 ou 3 substituintes selecionados de Rb;
R8 é selecionado do grupo consistindo em H, -C(O)- C1-C4 alquila ou C(O)-O- C1-C4 alquila, em que C1-C4alquila é opcionalmente substituída por 1, 2 ou 3 substituintes selecionados de Ra;
Ra é selecionado, independentemente para cada ocorrência, de carbóxi, hidroxila, halogênio, amino, fenila, C1-C4 alquila e C1-C4 alcóxi;
Rb é selecionado, independentemente para cada ocorrência, do grupo consistindo em carbóxi, hidroxila, halogênio, amino, fenila, C1-C4 alquila, C1-C4 alcóxi e -NH-RC; e
Rc é selecionado, independentemente para cada ocorrência, -C(O)-O-C1-C4alquila; e -C(O)-C1-C4alquila.
Por exemplo, compostos divulgados podem incluir aqueles representados por:em que R1 é C(O)-C2-C4alquila, em que C2-C4alquila é substituída em um carbono por NH2 ou -N-carbobenzilóxi e em um carbono diferente por hidroxila. Por exemplo, R1 pode ser C(O)-O-C1-C4alquila (por exemplo, metila, etila, propila, em que C1-C4alquila é substituída por fenila.
Por exemplo. R1 code ser carbobenzilóxi ou Dode ser representado por;em que X pode ser N; R5’ pode ser H; e R8 pode ser -C(O)-C2-C4alquila (por exemplo, etila, propila, n-butila ou t-butila), em que C2-C4 alquila é substituída em um carbono por NH2 ou -N-carbobenzilóxi e em um carbono diferente por hidroxila.
Em outra modalidade, compostos representados pela Fórmula II são considerados:e sais, estereoisômeros e N-óxidos farmaceuticamente aceitáveis dos mesmos; em que:
R1 é selecionado do grupo consistindo em H, hidroxila, -S(O)2-C1-C4 alquila; -SO2, C1-C4alquila; R7 ouX é CH ou N;
R3 e R3’ são, cada um, independentemente selecionados do grupo consistindo em H, halogênio, hidroxila, fenila, C1-C4alquila, amido, amina ou C2-C4 alquenila, em que C1-C4alquila, C2-C4alquenila e fenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R2 é selecionado do grupo consistindo em H, R7, -S(O)2, S(O)2-C1-C4 alquila, C1-C4 alquila, hidroxila ou fenila em que C1-C4alquila, C2-C4 alquenila e fenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R5 é selecionado do grupo consistindo em H, halogênio, C1-C4 alquila, C1-C4 alcóxi, C2-C4 alquenila, ciano, amino, fenila e hidroxila, em que C1-C4 alquila, C2-C4alquenila e fenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R6 é selecionado do grupo consistindo em H, halogênio, C1-C4 alquila, C1-C4 alcóxi, C2-C4alquenila, ciano, amino, fenila e hidroxila em que C1-C4 alquila, C2-C4alquenila e fenila são opcionalmente substituídas por 1, 2 ou 3 substituintes selecionados de Ra;
R7 é selecionado do grupo consistindo em -C(O)-C1-C4alquila ou -C(O)-O-C1-C4 aIquila, em que C1-C4 alquila é opcionalmente substituída por 1,2 ou 3 substituintes selecionados de Rb; ou
ou R1 e R6, tomados juntos com a Fórmula II, formam:R8 é selecionado do grupo consistindo em H, -C(O)- C1-C4alquila ou C(O)-O-C1-C4 alquila, em que C1-C4alquila é opcionalmente substituída por 1, 2 ou 3 substituintes selecionados de Ra;
Ra é selecionado, independentemente para cada ocorrência, de carbóxi, hidroxila, halogênio, amino, fenila, C1-C4alquila e C1-C4alcóxi;
Rb é selecionado, independentemente para cada ocorrência, do grupo consistindo em carbóxi, hidroxila, halogênio, amino, fenila, C1-C4alquila, C1-C4alcóxi e -NH-RC; e
Rc é selecionado, independentemente para cada ocorrência, -C(O)-O-C1-C4alquila; e -C(O)-C1-C4alquila.
PMP refere-se a p-metoxibenzilideno; Cbz refere-se a um radical carbobenzilóxi que pode ser representado como:
Esquema A:
Claims (11)
- Composto, caracterizado pelo fato de que é representado pela Fórmula I:e sais, estereoisômeros e N-óxidos farmaceuticamente aceitáveis do mesmo; em que
T é, independentemente para cada ocorrência, CR4R4’ e n é 0, 1, 2 ou 3;
A está opcionalmente presente e é selecionado de fenila ou piridina, em que A é opcionalmente substituído por um ou mais substituintes selecionados de Ra;
R1 é selecionado do grupo consistindo em H, hidroxila, -S(O)2-C1-C4 alquila, C1-C4alquila, C2-C4alquenila, fenila, e R7, em que C1-C4 alquila e C2-C4alquenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R3 e R3 são independentemente selecionados do grupo consistindo em H, halogênio, hidroxila, C1-C4alquila, amido, amina e C2-C4alquenila, em que C1-C4alquila e C2-C4alquenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R4 e R4’ são independentemente selecionados do grupo consistindo em H, halogênio, hidroxila, fenila, C1-C4alquila, amido, amina, Ci-C4alcóxi e C2-C4 alquenila, em que C1-C4alquila, C2-C4alquenila, C1-C4alcóxi e fenila são opcionalmente substituídos por um ou mais substituintes selecionados de Ra;
R2 é selecionado do grupo consistindo em H, R7, S(O)2-C1-C4 alquila, e C1-C4alquila, em que C1-C4alquila é opcionalmente substituída por um ou mais substituintes selecionados de Ra;
R5 é selecionado do grupo consistindo em H, halogênio, C1-C4alquila, C1-C4alcóxi, C2-C4alquenila, dano, amino, fenila e hidroxila, em que C1-C4alquila, C2-C4alquenila e fenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R7 é selecionado do grupo consistindo em -C(O)-C1-C4alquila e C(O)-O-C1-C4alquila, em que C1-C4 alquila é opcionalmente substituída por 1, 2 ou 3 substituintes selecionados de Rb;
Ra é selecionado, independentemente para cada ocorrência, do grupo consistindo em hidroxila, halogênio, amino, C1-C4 alquila e C1-C4 alcoxi;
Rb é selecionado, independentemente para cada ocorrência, do grupo consistindo em carbóxi, hidroxila, halogênio, amino, C1-C4 alquila, C1-C4 alcoxi e -NH-RC; e
Rc é selecionado, independentemente para cada ocorrência, do grupo consistindo em -C(O)-O-C1-C4alquila; e -C(O)-C1-C4alquila. - Composto de acordo com a reivindicação 1, caracterizado pelo fato de que R3 é H.
- Composto de acordo a reivindicação 1 ou 2, caracterizado pelo fato de que R2 é -C(O)-C2-C4alquila substituída em um carbono por NH2 e outro carbono por hidroxila.
- Composto de acordo com qualquer uma das reivindicações 1-3, caracterizado pelo fato de que C1-C4alquila é selecionada do grupo consistindo em metila, etila, propila, n-butila e t-butila, em que C1-C4alquila é opcionalmente substituída por um, dois ou três substituintes selecionados do grupo consistindo em F, Cl e Br.
- Composto, caracterizado pelo fato de que é representado por:la oulb
e sais, estereoisômeros e N-óxidos farmaceuticamente aceitáveis do mesmo; em que
R1 é selecionado do grupo consistindo em H, hidroxila, -S(O)2-C1-C4 alquila, C1-C4alquila, C2-C4alquenila, fenila, e R7, em que C1-C4 alquila e C2-C4alquenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R3 e R3 são independentemente selecionados do grupo consistindo em H, halogênio, hidroxila, C1-C4alquila, amido, amina e C2-C4alquenila, em que C1-C4alquila e C2-C4alquenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R2 é selecionado do grupo consistindo em H, R7, S(O)2-C1-C4 alquila, e C1-C4alquila, em que C1-C4alquila é opcionalmente substituída por um ou mais substituintes selecionados de Ra;
R5 é selecionado do grupo consistindo em H, halogênio, C1-C4alquila, C1-C4alcóxi, C2-C4alquenila, dano, amino, fenila e hidroxila, em que C1-C4alquila, C2-C4alquenila e fenila são opcionalmente substituídas por um ou mais substituintes selecionados de Ra;
R7 é selecionado do grupo consistindo em -C(O)-C1-C4alquila e C(O)-O-C1-C4alquila, em que C1-C4 alquila é opcionalmente substituída por 1, 2 ou 3 substituintes selecionados de Rb;
Ra é selecionado, independentemente para cada ocorrência, do grupo consistindo em hidroxila, halogênio, amino, C1-C4 alquila e C1-C4 alcóxi;
Rb é selecionado, independentemente para cada ocorrência, do grupo consistindo em carbóxi, hidroxila, halogênio, amino, C1-C4 alquila, C1-C4 alcóxi e -NH-RC; e
Rc é selecionado, independentemente para cada ocorrência, do grupo consistindo em -C(O)-O-C1-C4alquila; e -C(O)-C1-C4alquila. - Composto, caracterizado pelo fato de que é representado pela
Fórmula II:e sais, estereoisômeros e N-óxidos farmaceuticamente aceitáveis do mesmo; em que
R1 é selecionado do grupo consistindo em H, hidroxila, -S(O)2-C1-C4 alquila, C1-C4alquila, e R7, em que C1-C4 alquila é opcionalmente substituída por um ou mais substituintes cada um independentemente selecionado de halogênio, hidroxila, e amino;
R3 e R3’ são, cada um, H;
R2 é selecionado do grupo consistindo em H e R7;
R5 é H;
R6 é selecionado do grupo consistindo em H, halogênio, C1-C4 alquila, C1-C4 alcóxi, C2-C4alquenila, ciano, amino, fenila e hidroxila em que C1-C4 alquila, C2-C4alquenila e fenila são opcionalmente substituídas por 1,2 ou 3 substituintes selecionados de Ra;
R7 é-C(O)-C1-C4alquila, em que C1-C4 alquila é opcionalmente substituída por 1, 2 ou 3 substituintes selecionados de Rb;
Ra é selecionado, independentemente para cada ocorrência, do grupo consistindo em hidroxila , halogênio, amino, fenila, C1-C4alquila e C1-C4alcóxi;
Rb é selecionado, independentemente para cada ocorrência, do grupo consistindo em carbóxi, hidroxila, halogênio, amino, fenila, C1-C4alquila, C1-C4alcóxi e -NH-RC; e
Rc é selecionado, independentemente para cada ocorrência, do grupo consistindo em -C(O)-O-C1-C4alquila e -C(O)-C1-C4alquila. - Composição farmaceuticamente aceitável, caracterizada pelo fato de que compreende um composto como definido em qualquer uma das reivindicações 1-9 e um excipiente farmaceuticamente aceitável.
- Composição de acordo com a reivindicação 10, caracterizada pelo fato de que é adequada para administração oral a um paciente.
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ES2979128T3 (es) | 2016-08-01 | 2024-09-24 | Tenacia Biotechnology Hong Kong Co Ltd | Moduladores del receptor NMDA espirolactama y bis-espirolactama y uso de los mismos |
AU2017306164B2 (en) | 2016-08-01 | 2021-10-21 | Aptinyx Inc. | Spiro-lactam NMDA modulators and methods of using same |
CN109890825B (zh) | 2016-08-01 | 2022-03-11 | 阿普廷伊克斯股份有限公司 | 螺-内酰胺nmda受体调节剂及其用途 |
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JP2012503008A (ja) | 2012-02-02 |
RU2011114982A (ru) | 2012-10-27 |
US10906913B2 (en) | 2021-02-02 |
IL211802A (en) | 2017-03-30 |
AU2009293164A1 (en) | 2010-03-25 |
US9512133B2 (en) | 2016-12-06 |
US20110306586A1 (en) | 2011-12-15 |
US20150105364A1 (en) | 2015-04-16 |
US9802946B2 (en) | 2017-10-31 |
EP2331571A4 (en) | 2012-06-20 |
IL211802A0 (en) | 2011-06-30 |
US20210332061A1 (en) | 2021-10-28 |
US20190077807A1 (en) | 2019-03-14 |
JP5702288B2 (ja) | 2015-04-15 |
RU2515615C2 (ru) | 2014-05-20 |
EP2331571B1 (en) | 2015-08-26 |
EP2331571A1 (en) | 2011-06-15 |
AU2009293164B2 (en) | 2015-07-09 |
CN102186883B (zh) | 2016-08-03 |
CA2740628A1 (en) | 2010-03-25 |
BRPI0918868B8 (pt) | 2021-05-25 |
WO2010033757A1 (en) | 2010-03-25 |
BRPI0918868A2 (pt) | 2018-05-22 |
ES2553968T3 (es) | 2015-12-15 |
US20150336969A1 (en) | 2015-11-26 |
KR20110076941A (ko) | 2011-07-06 |
KR101769999B1 (ko) | 2017-08-21 |
CA2740628C (en) | 2018-05-01 |
MX2011003015A (es) | 2011-11-18 |
CN102186883A (zh) | 2011-09-14 |
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