ES2523169T3 - Compuestos tricíclicos como moduladores de la síntesis de TNF y como inhibidores de PDE4 - Google Patents

Compuestos tricíclicos como moduladores de la síntesis de TNF y como inhibidores de PDE4 Download PDF

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ES2523169T3
ES2523169T3 ES09704760.9T ES09704760T ES2523169T3 ES 2523169 T3 ES2523169 T3 ES 2523169T3 ES 09704760 T ES09704760 T ES 09704760T ES 2523169 T3 ES2523169 T3 ES 2523169T3
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methoxy
pyrimido
quinoline
dione
ethyl
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Adnan M M Mjalli
Bapu Gaddam
Dharma Rao Polisetti
Matthew Kostura
Mustafa Guzel
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vTv Therapeutics LLC
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High Point Pharnaceuticals LLC
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Abstract

Un compuesto que es: 1-ciclopentil-3-etil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-3-etil-7-metoxi-2-tioxo-2,3-dihidro-1H-pirimido[5,4-c]quinolin-4-ona; 1,3-diciclopentil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-((3,4-dimetoxi-fenil)-3-etil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-3-Isopropil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4diona; 1-ciclopentil-7-metoxi-3-propil-1H-pirimido[5,4-c]quinolina-2,4-diona: 3-butil-1-ciclopentil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona: 1-ciclopentil-3-furan-2-ilmetil-7-metoxi-1H-pirimido-[5,4-c]quinolina-2,4-diona; 3-terc-butil-1-ciclopentil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 7-ciclopentil-7-metoxi-3-tiofen-2-il-1H-pirimido[5,4-c]quinolina-2,4-diona; etil éster del ácido 3-((1-ciclopentil-7-metoxi-2,4-dioxo-1,4-dihidro-2H-pirimido[5,4-c]quinolin-3-il)-propiónico; 1-ciclopentil-3-(2,4-dimetoxi-fenil)-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-isopropil-7-metoxi-3-propil-1H-pirimido[5,4-c]quinolina-2,4-diona; 1,3-diisopropil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 3-etil-7-metoxi-1-propil-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-butil-3-etil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 3-etil-1-isobutil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 3-etil-7-metoxi-1-(tetrahidro-furan-2-ilmetil)-1H-pirimido[5,4-c]quinolina-2,4-diona; 1,3-dietil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopropil-3-etil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclobutil-3-etil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 3-etil-1-(1-etil-propil)-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 3-etil-7-metoxi-1-(tetrahidro-furan-3-il)-1H-pirimido[5,4-c]quinolina-2,4-diona; 3-etil-7-metoxi-1-(3-metoxi-propil)-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-((2,2-Dimetil-propil)-3-etil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 8-cloro-1-ciclopentil-3-etil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-3-etil-9-fluoro-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 7-cloro-1-ciclopentil-3-etil-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-3-etil-7-isopropil-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-bencil-3-etil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 3-etil-7-metoxi-1-(tetrahidro-piran-4-ilmetil)-1H-pirimido[5,4-c]quinolina-2,4-diona; 3-etil-1-isopropil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 3-sec-butil-1-ciclopentil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-7-metoxi-3-fenil-1H-pirimido[5,4-c]quinolina-2,4-diona; 3-bencil-1-ciclopentil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona ; 3-etil-7-metoxi-1-(4-metoxi-bencil)-1H-pirimido[5,4-c]quinolina-2,4-diona; 3-etil-7-metoxi-1-(4-metil-ciclohexil)-1H-pirimido[5,4-c]quinolina-2,4-diona; etil éster del ácido (1-ciclopentil-7-metoxi-2,4-dioxo-1,4-dihidro-2H-pirimido[5,4-c]quinolin-3-il)-acético; 1-ciclopentil-7-metoxi-3-metil-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-3-(3,5-dimetil-isoxazol-4-il)-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-7-metoxi-3-tiofen-3-il-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-7-metoxi-3-(4-metil-tiofen-2-il)-1H-pirimido[5,4-c]quinolina-2,4-diona; 3-etil-7-metoxi-1-(3-pirrolidin-1-il-propil)-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclohexil-3-etil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-7-metoxi-3-m-tolil-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-7-metoxi-3-p-tolil-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-butil-3-etil-9-fluoro-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-butil-9-cloro-3-etil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-butil-8-cloro-3-etil-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-3-(4-fluoro-3-metil-fenil)-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-3-(3-fluoro-4-metil-fenil)-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-7-metoxi-3-(3-metoxi-fenil)-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-3-(3-fluoro-fenil)-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona; 1-ciclopentil-3-(4-difluorometoxi-fenil)-7-metoxi-1H-pirimido[5,4-c]quinolina-2,4-diona.

Description

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E09704760
03-11-2014
Preparar los compuestos por adición a las células: Todos los compuestos eran caldos de DMSO a 20 mM. Las materias primas de trabajo para probar la célula se prepararon como material concentrado 4X en RPMI + 10 % FBS. Los compuestos se añadieron a un bloque polipropileno y después se diluyó con la cantidad adecuada de RPMI + 10 % FBS. Típicamente
5 2.6 µl del caldo 20 mM se diluyó a 650 µl volumen final para dar una concentración de inicio de 80 µM en los caldos. RPMI se añadió al caldo de DMSO mediante pipeta en el tubo o bloque. Los compuestos se diluyeron en serie con RPMI + 10 % FBS. Las concentraciones finales de DMSO no fueron mayores que 0.5 % en el ensayo.
Los compuestos se añadieron a las células como caldos de trabajo 4x. Anteriormente se prepararon 50 µl del compuesto y 10 se añaden a las células y se re-equilibra en un incubador al 5 % de CO2 humidificado a 37 °C por 30 minutos.
Una materia prima de LPS se preparó usando RPMI + 10 % FBS. Para preparar el caldo, 2.8 µl de LPS (5mg/ml; Sigma Cat # L3024) se añadió a 35 ml del media. 50 µl de LPS en el medio se añadió a las células. Los cultivos de control sin LPS recibieron sólo RPMI + 10 % de FBS. Después de una incubación durante la noche a 37 °C, el sobrenadante de cultivo
15 celular se cosechó y almacenó en una placa de polipropileno de 96 pocillos.
Las muestras se analizaron para TNF según las instrucciones del fabricante (TNF ELISA; R&D Systems, Cat # DY210). Las muestras se diluyeron de forma seriada con PBS + 1 % BSA a la condición de dilución adecuada para la preparación de la célula, por lo general a una dilución de 1:4 o 1:6.
20
La inhibición de TNF para los compuestos seleccionados de la presente invención se muestra en la tabla más abajo:
25
30
35
40
45
50
55
Ej. #
inhib. de TNF (µm) Ej. # inhib. de TNF (µm) Ej. # inhib. de TNF (µm)
1
0.18 4 14.2 5 0.27
10
0.41 16 0.68 17 0.39
18
1.1 28 3.5 29 0.92
30
2.5 32 2.6 33 20
34
3.6 37 20 38 0.45
39
1.3 41 0.5 45 0.2
46
1 47 0.9 48 1.4
51
0.03 54 0.006 55 0.163
72
0.004 73 0.009 75 0.006
78
0.001 83 0.001 84 0.002
87
0.002 88 0.001 89 0.005
90
0.002 91 0.001 92 0.0024
93
0.0004 94 0.0004 95 0.001
96
0.0004 97 0.0006 98 0.0003
99
0.02 100 0.0009 103 0.001
106
0.004 107 0.001 108 0.45
109
0.008 110 0.123 111 0.074
112
0.28 113 0.0003 114 0.031
115
0.029 116 0.002 117 1.0
118
0.029 120 0.24 124 50
126
0.002 127 0.006
56
imagen55
imagen56
imagen57

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Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5406215B2 (ja) * 2008-01-25 2014-02-05 ハイ ポイント ファーマシューティカルズ，リミティド ライアビリティ カンパニー ＴＮＦ−α合成の調節因子及びＰＤＥ４阻害剤としての三環系化合物
US8754114B2 (en) 2010-12-22 2014-06-17 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
AR090100A1 (es) * 2012-02-21 2014-10-22 Celgene Corp Procesos para la preparacion de la (s)-1-(3-etoxi-4-metoxifenil)-2-metanosulfoniletilamina
ME03300B (me) 2012-06-13 2019-07-20 Incyte Holdings Corp Supsтituisana triciklična jedinjenja као inhibiтori fgfr
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
EP3632426A1 (en) 2013-02-01 2020-04-08 Wellstat Therapeutics Corporation Amine compounds having anti-inflammatory, antifungal, antiparasitic and anticancer activity
ES2657451T3 (es) 2013-04-19 2018-03-05 Incyte Holdings Corporation Heterocíclicos bicíclicos como inhibidores del FGFR
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
MA41551A (fr) 2015-02-20 2017-12-26 Incyte Corp Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4
ES2751669T3 (es) 2015-02-20 2020-04-01 Incyte Corp Heterociclos bicíclicos como inhibidores FGFR
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
JP6827959B2 (ja) * 2015-06-17 2021-02-10 ファイザー・インク 三環式化合物およびホスホジエステラーゼ阻害剤としてのそれらの使用
WO2017089347A1 (en) 2015-11-25 2017-06-01 Inserm (Institut National De La Sante Et De La Recherche Medicale) Methods and pharmaceutical compositions for the treatment of braf inhibitor resistant melanomas
AR111960A1 (es) 2017-05-26 2019-09-04 Incyte Corp Formas cristalinas de un inhibidor de fgfr y procesos para su preparación
CR20200590A (es) 2018-05-04 2021-04-26 Incyte Corp Formas sólidas de un inhibidor de fgfr y procesos para prepararlas
JP2021523118A (ja) 2018-05-04 2021-09-02 インサイト・コーポレイションＩｎｃｙｔｅ Ｃｏｒｐｏｒａｔｉｏｎ Ｆｇｆｒ阻害剤の塩
CN109705037A (zh) * 2019-01-24 2019-05-03 广西师范大学 4-氨基喹啉-3-甲酸酯衍生物及其制备方法和应用
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
KR20210017842A (ko) 2019-08-09 2021-02-17 주식회사 엘지화학 연쇄발화 방지를 위한 에너지 드레인 저항체를 구비한 배터리 팩
IL291901A (en) 2019-10-14 2022-06-01 Incyte Corp Bicyclyl heterocycles as fgr suppressors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
JP2023505257A (ja) 2019-12-04 2023-02-08 インサイト・コーポレイション Ｆｇｆｒ阻害剤の誘導体
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CN113861189A (zh) * 2020-06-29 2021-12-31 Vtv治疗有限责任公司 喹啉衍生物，其药学上可接受的盐及其使用方法
TW202220986A (zh) * 2020-07-28 2022-06-01 美商維特衛治療有限責任公司 喹啉衍生物的鹽酸鹽的結晶形式
CA3220274A1 (en) 2021-06-09 2022-12-15 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
WO2023109909A1 (zh) * 2021-12-15 2023-06-22 上海翊石医药科技有限公司 一种芳杂环类化合物及其制备方法和用途

Family Cites Families (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO162019C (no) * 1983-11-23 1989-10-25 Fujisawa Pharmaceutical Co Analogifremgangsmaate for fremstilling av terapeutisk aktive pyrimidoiskinolinderivater.
US4927820A (en) 1988-11-25 1990-05-22 Hoechst Roussel Pharmaceuticals Inc. Fused heterocyclic derivatives of 1,2,3,4-tetrahydroacridine
JPH0741479A (ja) * 1993-07-28 1995-02-10 Taisho Pharmaceut Co Ltd ７−アザプテリジン類およびその製造方法
EP0912519A1 (en) * 1996-05-20 1999-05-06 Darwin Discovery Limited Quinoline sulfonamides as tnf inhibitors and as pde-iv inhibitors
US6930101B1 (en) * 1999-05-17 2005-08-16 The Regents Of The University Of California Thiazolopyrimidines useful as TNFα inhibitors
US20030207845A1 (en) 2001-02-08 2003-11-06 Keating Elizabeth T. Method and compositions for treating an inflammatory disease
EA008108B1 (ru) 2001-09-19 2007-04-27 Алтана Фарма Аг Комбинация нспвлс и ингибитора pde-4
TW200306192A (en) 2002-01-18 2003-11-16 Bristol Myers Squibb Co Tricyclic 2-pyrimidone compounds useful as HIV reverse transcriptase inhibitors
PL193012B1 (pl) * 2003-06-09 2007-01-31 Univ Medyczny 3-podstawiony 1,2,3,4-tetrahydropirymido[5,4-c]cynnolin-2,4-dion i 3-podstawiony 1,2,3,4-tetrahydropirymido[5,4-c]chinolin-2,4-dion oraz sposób otrzymywania 3-podstawionego 1,2,3,4-tetrahydropirymido[5,4-c]cynnolin-2,4-dionu i 3-podstawionego 1,2,3,4-tetrahydropirymido[5,4-c]chinolin-2,4-dionu
TW200726767A (en) * 2005-07-04 2007-07-16 Astrazeneca Ab Chemical compounds 2
JP5406215B2 (ja) * 2008-01-25 2014-02-05 ハイ ポイント ファーマシューティカルズ，リミティド ライアビリティ カンパニー ＴＮＦ−α合成の調節因子及びＰＤＥ４阻害剤としての三環系化合物
CA2753604A1 (en) 2009-02-27 2010-09-02 Boehringer Ingelheim International Gmbh Drug combinations containing pde4-inhibitors and nsaids
EP2400961B1 (de) 2009-02-27 2017-11-22 Boehringer Ingelheim International GmbH Arzneimittelkombinationen enthaltend pde4-inhibitoren und nsaids
EP2555774B1 (de) 2010-04-08 2015-10-21 Boehringer Ingelheim International GmbH Arnzeimittelkombinationen enthaltend pde4-inhibitoren und ep4-rezeptor-antagonisten
WO2011124524A1 (de) 2010-04-08 2011-10-13 Boehringer Ingelheim International Gmbh Arzneimittelkombinationen enthaltend pde4-inhibitoren und ep4-rezeptor-antagonisten

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