ES2567135T3 - Derivados de hidantoína como inhibidores de necrosis celular - Google Patents

Derivados de hidantoína como inhibidores de necrosis celular Download PDF

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ES2567135T3
ES2567135T3 ES10011481.8T ES10011481T ES2567135T3 ES 2567135 T3 ES2567135 T3 ES 2567135T3 ES 10011481 T ES10011481 T ES 10011481T ES 2567135 T3 ES2567135 T3 ES 2567135T3
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carbons
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Gregory D. Cuny
Junying Yuan
Prakash Jagtap
Alexei Degterev
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Brigham and Womens Hospital Inc
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Abstract

Un compuesto de la fórmula:**Fórmula** una forma esteroisomérica del mismo, una sal de adición ácida o base farmacéuticamente aceptable del mismo; en donde X representa O; Y representa NH; R1, R2, y R3 representan independientemente H, OR8, F, Cl, Br, I, N(R8)2, CO2R8, NO2, NHC(O)R8, alquilo que tiene 1 a 10 carbonos, o alquilo sustituido que tiene 1 a 10 carbonos; R4 representa OR8, F, Cl, Br, I, N(R8)2, CO2R8, NO2, NHC(O)R8, metoxilo, alquilo que tiene 1 a 10 carbonos, o alquilo sustituido que tiene 1 a 10 carbonos; R5 y R7 representan independientemente H o alquilo que tiene 1 a 10 carbonos; R6 representa alquilo que tiene 1 a 10 carbonos; R8 representa H, alquilo que tiene 1 a 10 carbonos, alquilo sustituido que tiene 1 a 10 carbonos, alquenilo que tiene menos de 12 carbonos, o alquinilo que tiene menos de 12 carbonos; R9, R10, R9', R10', representan independientemente H, F, Cl, Br, I, alquilo que tiene 1 a 10 carbonos, alquilo sustituido que tiene 1 a 10 carbonos, o un cicloalquilo de tres a seis miembros o cicloalquilo sustituido que incluye Cn y/o Cn'; y n y n' es igual a un entero desde cero hasta cinco; y en donde los grupos sustituidos comprenden uno o más sustituyentes seleccionados de halógeno, alquilo que tiene 1 a 10 carbonos, alquenilo que tiene menos de 12 carbonos, alquinilo que tiene menos de 12 carbonos, cicloalquilo, hidroxilo, amino, nitro, sulfhidrilo, imino, amido, fosfonato, fosfinato, carbonilo, carboxilo, sililo, éter, alquiltio, sulfonilo, cetona, aldehído, éster, heterociclilo, -CF3, y -CN.

Description

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una forma esteroisomérica del mismo, una sal de adición ácida o base farmacéuticamente aceptable del mismo, en donde X representa O; Y representa NR8; G representa o NR7; R1, R2, y R3 representan independientemente H, OH, OR8, F, Cl, Br, I, N(R8)2, COOH, CO2R8, NO2, NHC(O)R8, alquilo que tiene 1 a 10 carbonos, o alquilo sustituido que tiene 1 a 10 carbonos; R4 representa OH, OR8, F, Cl, Br, I, N(R8)2, COOH, CO2R8, NO2, NHC(O)R8, metoxilo, alquilo que tiene 1 a 10 carbonos, o alquilo sustituido que tiene 1 a 10 carbonos; R5, y R7 representan independientemente H o alquilo que tiene 1 a 10 carbonos; R6 representa alquilo que tiene 1 a 10 carbonos; R8 representa alquilo que tiene 1 a 10 carbonos, alquilo sustituido que tiene 1 a 10 carbonos, alquenilo que tiene menos de 12 carbonos, alquinilo que tiene menos de 12 carbonos; R9, R10, R9’, R10’, representan independientemente H, F, Cl, Br, I, alquilo que tiene 1 a 10 carbonos, alquilo sustituido que tiene 1 a 10 carbonos, o un cicloalquilo de tres a seis miembros o cicloalquilo sustituido que incluye Cn y/o Cn’; n y n’ es igual a un entero desde cero hasta cinco, en donde los grupos sustituidos comprenden uno o más sustituyentes seleccionados de halógeno, alquilo que tiene 1 a 10 carbonos, alquenilo que tiene menos de 12 carbonos, alquinilo que tiene menos de 12 carbonos, cicloalquilo, hidroxilo, amino, nitro, sulfhidrilo, imino, amido, fosfonato, fosfinato, carbonilo, carboxilo, sililo, éter, alquiltio, sulfonilo, cetona, aldehído, éster, heterociclilo, -CF3, y -CN.
En ciertas realizaciones la invención proporciona un compuesto de la fórmula:
imagen10
una forma esteroisomérica del mismo, una sal de adición ácida o base farmacéuticamente aceptable del mismo, en donde X representa O; Y representa NH; R1, R2, y R3 representan independientemente H, OR8, F, Cl, Br, I, N(R8)2, CO2R8, NO2, NHC(O)R8, alquilo que tiene 1 a 10 carbonos, o alquilo sustituido que tiene 1 a 10 carbonos; R4 representa OR8, F, Cl, Br, I, N(R8)2, CO2R8 NO2, NHC(O)R8, metoxilo, alquilo que tiene 1 a 10 carbonos, o alquilo sustituido que tiene 1 a 10 carbonos; R5 y R7 representan independientemente H o alquilo que tiene 1 a 10 carbonos, R6 representa alquilo que tiene 1 a 10 carbonos; R8 representa H, alquilo que tiene 1 a 10 carbonos, alquilo sustituido que tiene 1 a 10 carbonos, alquenilo que tiene menos de 12 carbonos, alquinilo que tiene menos de 12 carbonos; R9, R10, R9’, R10’, representan independientemente H, F, Cl, Br, I, lower alquilo, alquilo sustituido que tiene 1 a 10 carbonos, o un cicloalquilo de tres a seis miembros o cicloalquilo sustituido que incluye Cn y/o Cn’; n y n’ es igual a un entero desde cero hasta cinco; en donde los grupos sustituidos comprenden uno o más sustituyentes seleccionados de halógeno, alquilo que tiene 1 a 10 carbonos, alquenilo que tiene menos de 12 carbonos, alquinilo que tiene menos de 12 carbonos, cicloalquilo, hidroxilo, amino, nitro, sulfhidrilo, imino, amido, fosfonato, fosfinato, carbonilo, carboxilo, sililo, éter, alquiltio, sulfonilo, cetona, aldehído, éster, heterociclilo, -CF3, y -CN.
En ciertas realizaciones, la invención proporciona un compuesto como se definió anteriormente, en donde R6 representa un grupo metilo.
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En algunos casos, con el fin de prolongar el efecto de un fármaco, es deseable ralentizar la absorción del mismo desde la inyección subcutánea o intramuscular. Esto se puede lograr mediante el uso de una suspensión líquida de material cristalino o amorfo que tiene poca solubilidad en agua. La velocidad de absorción del fármaco depende entonces de su velocidad de disolución, que a su vez, puede depender del tamaño del cristal y la forma cristalina. Alternativamente, la absorción retardada de una forma de fármaco administrada por vía parenteral se logra al disolver o suspender el fármaco en un vehículo oleoso.
Se elaboran formas de depósito inyectables al formar matrices microencapsuladas de los compuestos objeto en polímeros biodegradables tales como polilactida-poliglicólido. Dependiendo de la relación de fármaco a polímero y la naturaleza del polímero particular empleado, se puede controlar la velocidad de liberación del fármaco. Ejemplos de otros polímeros biodegradables incluyen poli(ortoésteres) y poli(anhídridos). Las formulaciones inyectables de depósito también se preparan al atrapar el fármaco en liposomas o microemulsiones que sean compatibles con el tejido corporal.
En otro aspecto, la presente invención se relaciona con un compuesto como se definió anteriormente para uso en un método para tratar una enfermedad asociada con necrosis celular. En particular, la invención proporciona un compuesto como se definió anteriormente para uso en métodos para prevenir o tratar un trastorno asociado con necrosis celular en un mamífero, que comprende la etapa de administrar a dicho mamífero una cantidad terapéuticamente efectiva de un compuesto o preparación terapéutica de la presente invención. En ciertas realizaciones, el trastorno asociado con necrosis celular es un trastorno neurológico, tal como trauma, isquemia o infarto cerebral. En otras realizaciones, el trastorno neurológico es una enfermedad neurodegenerativa, tal como enfermedad de Parkinson (PD), enfermedad de Alzheimer (AD), esclerosis lateral amiotrófica (ALS), enfermedad de Huntington (HD), y demencia asociada con VIH (HAD). En otras realizaciones, el trastorno es una enfermedad isquémica de órganos que incluyen pero no se limitan a cerebro, corazón, riñón e hígado. En ciertas realizaciones, el mamífero es un sujeto primate, canino o felino. En otras realizaciones, el mamífero es un sujeto humano.
En una realización, la invención se relaciona con un compuesto para uso en un método para tratar una enfermedad celular necrótica que comprende administrar a un sujeto que tiene una enfermedad celular necrótica un compuesto de la fórmula:
imagen15
una forma esteroisomérica del mismo, una sal de adición ácida o base farmacéuticamente aceptable del mismo; en donde X representa O;
Y representa NH; R1, R2, y R3 representan independientemente H, OR8, F, Cl, Br, I, N(R8)2, CO2R8, NO2, NHC(O)R8, alquilo que tiene 1 a 10 carbonos, o alquilo sustituido que tiene 1 a 10 carbonos; R4 representa OR8, F, Cl, Br, I, N(R8)2, CO2R8, NO2, NHC(O)R8, metoxilo, alquilo que tiene 1 a 10 carbonos, o alquilo sustituido que tiene 1 a 10 carbonos;
R5 y R7 representan independientemente H o alquilo que tiene 1 a 10 carbonos; R6 representa alquilo que tiene 1 a 10 carbonos; R8 representa H, alquilo que tiene 1 a 10 carbonos, alquilo sustituido que tiene 1 a 10 carbonos, alquenilo que tiene
menos de 12 carbonos, o alquinilo que tiene menos de 12 carbonos; R9, R10, R9’, R10’, representan
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Biol. 1998, 143, 1353-1360). Los compuestos experimentales se aplicaron a las células en los intentos de rescatarlos desde esta muerte necrótica. Por lo tanto, los compuestos encontrados para restablecer la viabilidad celular utilizando este protocolo son inhibidores de la ruta de necrosis.
Se cribaron las colecciones de compuestos para la inhibición de la muerte celular inducida por TNF-α en presencia de zVAD en la estirpe celular B humana U-937. Un compuesto identificado como inhibidor de la necrosis era 1 (no de acuerdo con la invención reivindicada):
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Los compuestos se probaron también en otro ensayo de necrosis utilizando células T Jurkat humanas, ligando Fas para inducir muerte celular, y zVAD para inhibir la ruta de apoptosis. Después de 36h, se midió la viabilidad celular 10 mediante el ensayo de viabilidad celular CellTiter ATP comercial (Promega).
Un estudio de estructura-actividad-relaciones (SAR) se llevó a cabo con el fin de aumentar la actividad anti-necrosis. Los compuestos de la Tabla 1 se prepararon de acuerdo con los procedimientos descritos en las Figuras 2 y 3.
Tabla 1
naci = no de acuerdo con la invención reivindicada
Compuesto No.
R1 R2 R3 R4 X Y
893-01 (naci)
H H Me H S NH
893-02 (naci)
H Me Me H S NH
893-03 (naci)
H H Me Me S NH
893-04
H H Et H O NH
893-05 (naci)
6-F H Me H S NH
893-06 (naci)
5-OMe H Me H S NH
893-07 (naci)
5-OH H Me H S NH
893-08 (naci)
H H Me H S NMe
893-09 (naci)
7-F H Me H S NH
893-10 (naci)
7-Cl H Me H S NH
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naci = no de acuerdo con la invención reivindicada
Compuesto No.
R1 R2 R3 R4 X Y
893-11 (naci)
6-Cl H Me H S NH
893-12 (naci)
7-Br H Me H S NH
893-13 (naci)
7-OMe H Me H S NH
893-14 (naci)
5-Cl H Me H S S
893-15 (naci)
7-Cl H Me H S NMe
893-16 (naci)
6-SO2Me; 7-Cl H Me H S NH
893-17 (naci)
H H CH2CH2-morfolina H S NH
893-18 (naci)
H H H H S NH
893-19
H H H H O NH
893-20
H H Me H O NH
893-21 (naci)
H H Me H S S
893-22
H H Me H O NH
893-23
7-Me H Me H O NH
893-24
5-Cl H Me H O NH
893-25
7-OMe H Me H O NH
893-26
5-OMe H Me H O NH
893-27
6-Cl H Me H O NH
893-28
7-F H Me H O NH
Me = metilo, Et = etilo
Otros derivados también se preparan utilizando procedimientos similares:
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Tabla 3
Número de Compuesto
EC50(µM)
893-22
0.439
893-23
0.095
893-24
6.8
893-25
0.229
893-26
>300
893-27
1.12
893-28
0.324
893-31
0.303
893-32
0.078
893-33
> 10
893-34
0.154
893-35
0.448
893-36
> 10
893-37
1.8
893-38
>10
893-39
5.4
893-40
> 10
893-41
> 10
893-42
> 10
893-43
>10
893-44
> 10
893-45
> 10
893-46
5.3
893-47
> 10
893-48
> 10
893-49
4.3
893-50
> 10
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Claims (1)

  1. imagen1
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ES10011481.8T 2003-08-29 2004-08-30 Derivados de hidantoína como inhibidores de necrosis celular Active ES2567135T3 (es)

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Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006521377A (ja) * 2003-03-27 2006-09-21 ランケナー インスティテュート フォー メディカル リサーチ 新型ｉｄｏ阻害剤とその使用方法
DK2384753T3 (en) 2003-08-29 2016-04-11 Brigham & Womens Hospital Hydantoin derivatives as inhibitors of cell necrosis
EP1723227A4 (en) * 2004-02-10 2007-09-19 Dartmouth College NICOTINAMIDRIBOSIDE KINASE COMPOSITIONS AND METHOD FOR THEIR USE
US7920101B2 (en) * 2004-10-08 2011-04-05 Sharp Laboratories Of America, Inc. Methods and systems for imaging device display standardization
US20070021421A1 (en) * 2005-07-25 2007-01-25 Hampton Thomas G Measurement of gait dynamics and use of beta-blockers to detect, prognose, prevent and treat amyotrophic lateral sclerosis
WO2007075772A2 (en) * 2005-12-20 2007-07-05 President And Fellows Of Harvard College Compounds, screens, and methods of treatment
EP2003119A1 (de) * 2007-06-13 2008-12-17 Bayer Schering Pharma Aktiengesellschaft Substituierte Acetamide als Modulatoren des EP2-Rezeptors
EP2192838A4 (en) * 2007-08-15 2011-07-27 Harvard College HETEROCYCLIC NEKROPTOSIS HEMMER
US8304421B2 (en) * 2008-09-30 2012-11-06 Vanderbilt University Indole compounds and their use as radiation sensitizing agents and chemotherapeutic agents
WO2010075290A1 (en) * 2008-12-22 2010-07-01 President And Fellows Of Harvard College Unsaturated heterocyclic inhibitors of necroptosis
CN104803986A (zh) 2008-12-23 2015-07-29 哈佛大学校长及研究员协会 坏死性凋亡的小分子抑制剂
EP2560629B1 (en) 2010-04-23 2020-06-03 Massachusetts Eye & Ear Infirmary Methods and compositions for preserving photoreceptor and retinal pigment epithelial cells
US20140024598A1 (en) 2010-11-01 2014-01-23 Demetrios Vavvas Methods and compositions for preserving retinal ganglion cells
US9643977B2 (en) 2011-03-11 2017-05-09 President And Fellows Of Harvard College Necroptosis inhibitors and methods of use therefor
WO2013059791A2 (en) * 2011-10-21 2013-04-25 Massachusetts Eye And Ear Infirmary Methods and compositions for promoting axon regeneration and nerve function
WO2014145022A1 (en) 2013-03-15 2014-09-18 President And Fellows Of Harvard College Hybrid necroptosis inhibitors
WO2014152182A1 (en) * 2013-03-15 2014-09-25 President And Fellows Of Harvard College Deuterated heterocyclic inhibitors of necroptosis
CN105394045B (zh) * 2014-09-04 2020-02-14 中国科学院上海巴斯德研究所 一种肠道病毒的小分子化合物抑制剂及其应用
EP3229807A4 (en) 2014-12-11 2018-10-17 President and Fellows of Harvard College Inhibitors of cellular necrosis and related methods
CA2972294C (en) 2014-12-24 2018-09-25 National Institute Of Biological Sciences, Beijing Necrosis inhibitors
AU2015371822B2 (en) 2014-12-24 2020-04-09 National Institute Of Biological Sciences, Beijing Necrosis inhibitors
WO2017064217A1 (en) 2015-10-13 2017-04-20 Institut National De La Sante Et De La Recherche Medicale (Inserm) Sibiriline derivatives for use for preventing and/or treating disorders associated with cellular necroptosis
ES2821971T3 (es) 2015-10-13 2021-04-28 Inst Nat Sante Rech Med Derivados de la sibirilina sustituidos en N1 y N7 y su utilización como inhibidores de la necroptosis celular
KR20180114910A (ko) 2016-02-05 2018-10-19 데날리 테라퓨틱스 인크. 수용체-상호작용 단백질 키나제 1의 억제제
WO2018073321A1 (en) 2016-10-18 2018-04-26 Institut National De La Sante Et De La Recherche Medicale (Inserm) Natural product derivatives for inhibiting cellular necroptosis, ferroptosis and oxytosis
WO2018107060A1 (en) 2016-12-09 2018-06-14 Denali Therapeutics Inc. Compounds, compositions and methods
BR112019017738A2 (pt) 2017-02-27 2020-04-07 Glaxosmithkline Ip Dev Ltd combinação, composição farmacêutica, uso de uma combinação ou composição farmacêutica, método para tratar câncer em um humano, e, composto
US11643438B2 (en) 2018-07-20 2023-05-09 The Board Of Regents Of The University Of Oklahoma Antimicrobial peptides and methods of use
WO2020044206A1 (en) 2018-08-29 2020-03-05 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors for use in the treatment cancer
AU2019384283B2 (en) 2018-11-20 2023-10-19 Sironax Ltd RIP1 inhibitors
US10744153B1 (en) * 2019-07-01 2020-08-18 Cloudbreak Therapeutics Llc Compositions and methods for treating meibomian gland dysfunction
KR102491260B1 (ko) * 2019-12-26 2023-01-27 연세대학교 산학협력단 피롤리딘 유도체 및 이를 포함하는 베타-아밀로이드 또는 타우 단백질 관련 질병의 예방 또는 치료용 약학 조성물
EP3875086A1 (en) * 2020-03-04 2021-09-08 Technische Universität Dresden Dual-inhibitors of cellular necroptosis and ferroptosis for use in the treatment of organ transplant patients
US20230129262A1 (en) * 2020-03-31 2023-04-27 Martin Ogletree Methods and pharmaceutical compositions of thromboxane a2 receptor antagonist for the treatment of covid-19
US11654036B2 (en) 2020-05-26 2023-05-23 Elixir Medical Corporation Anticoagulant compounds and methods and devices for their use
CN112263576A (zh) * 2020-09-30 2021-01-26 浙江大学 化合物zju-37在制备肝脏疾病预防和/或治疗药物中的应用
US11999750B2 (en) 2022-01-12 2024-06-04 Denali Therapeutics Inc. Crystalline forms of (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydropyrido [3,2-B][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide

Family Cites Families (111)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE789948A (fr) * 1971-10-13 1973-04-11 Sandoz Sa Nouveaux derives du pyrazole, leur preparation et leur application comme medicaments
JPS5113156B2 (es) * 1972-10-21 1976-04-26
US4302386A (en) 1978-08-25 1981-11-24 The Ohio State University Antigenic modification of polypeptides
US4016037A (en) * 1975-10-15 1977-04-05 Ajinomoto Co., Inc. Method for producing L-amino acid
US4105776A (en) 1976-06-21 1978-08-08 E. R. Squibb & Sons, Inc. Proline derivatives and related compounds
US4110536A (en) * 1977-04-18 1978-08-29 Miles Laboratories, Inc. Derivatives of 5-(indol-3-yl)hydantoin
DE2728523C2 (de) * 1977-06-23 1986-02-27 Schering AG, 1000 Berlin und 4709 Bergkamen 4-Methyl-1,2,3-thiadiazol-5-carbonsäure-(cyclohexylmethyl)-amid, Mittel mit herbizider und wachstumsregulatorischer Wirkung enthaltend diese Verbindung sowie Verfahren zu seiner Herstellung
US4316906A (en) 1978-08-11 1982-02-23 E. R. Squibb & Sons, Inc. Mercaptoacyl derivatives of substituted prolines
IL58849A (en) 1978-12-11 1983-03-31 Merck & Co Inc Carboxyalkyl dipeptides and derivatives thereof,their preparation and pharmaceutical compositions containing them
JPS5810074B2 (ja) * 1979-07-18 1983-02-24 味の素株式会社 新規微生物
US4508729A (en) 1979-12-07 1985-04-02 Adir Substituted iminodiacids, their preparation and pharmaceutical compositions containing them
SG56656G (en) 1980-07-28 1987-03-27 Pfizer Hypoglycemic 5-substituted oxazolidine-2, 4-diones
US4332952A (en) 1980-07-28 1982-06-01 Pfizer Inc. Hypoglycemic 5-substituted oxazolidine-2,4-diones
US4344949A (en) 1980-10-03 1982-08-17 Warner-Lambert Company Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids
ZA817261B (en) 1980-10-23 1982-09-29 Schering Corp Carboxyalkyl dipeptides,processes for their production and pharmaceutical compositions containing them
US4337201A (en) 1980-12-04 1982-06-29 E. R. Squibb & Sons, Inc. Phosphinylalkanoyl substituted prolines
US4410520A (en) 1981-11-09 1983-10-18 Ciba-Geigy Corporation 3-Amino-[1]-benzazepin-2-one-1-alkanoic acids
GB2128984B (en) 1982-05-12 1985-05-22 Hoffmann La Roche Diaza-bicyclic compounds
US4780401A (en) 1984-04-09 1988-10-25 Ciba-Geigy Corporation Novel monoclonal antibodies to human renin and hybridoma cells, processes for their preparation and their applications
DE3567460D1 (en) * 1984-06-07 1989-02-16 Pfizer Ltd Dihydropyridines
JPS6122081A (ja) * 1984-07-10 1986-01-30 Mitsui Toatsu Chem Inc ヒダントイン化合物の製造法
US4845079A (en) 1985-01-23 1989-07-04 Luly Jay R Peptidylaminodiols
US5066643A (en) 1985-02-19 1991-11-19 Sandoz Ltd. Fluorine and chlorine statine or statone containing peptides and method of use
CA1292840C (en) 1985-09-26 1991-12-03 David Harry Hawke Sequencing of peptides
US4894437A (en) 1985-11-15 1990-01-16 The Upjohn Company Novel renin inhibiting polypeptide analogs containing S-aryl-D- or L- or DL-cysteinyl, 3-(arylthio)lactic acid or 3-(arylthio)alkyl moieties
US4885292A (en) 1986-02-03 1989-12-05 E. R. Squibb & Sons, Inc. N-heterocyclic alcohol renin inhibitors
US4816463A (en) 1986-04-01 1989-03-28 Warner-Lambert Company Substituted diimidazo [1,5-a: 4',5'-d]pyridines having antihypertensive activity
CA1334092C (en) 1986-07-11 1995-01-24 David John Carini Angiotensin ii receptor blocking imidazoles
US4772684A (en) 1987-01-20 1988-09-20 Triton Biosciences, Inc. Peptides affecting blood pressure regulation
US4980283A (en) 1987-10-01 1990-12-25 Merck & Co., Inc. Renin-inhibitory pepstatin phenyl derivatives
US5089471A (en) 1987-10-01 1992-02-18 G. D. Searle & Co. Peptidyl beta-aminoacyl aminodiol carbamates as anti-hypertensive agents
US5034512A (en) 1987-10-22 1991-07-23 Warner-Lambert Company Branched backbone renin inhibitors
US5063207A (en) 1987-10-26 1991-11-05 Warner-Lambert Company Renin inhibitors, method for using them, and compositions containing them
US5055466A (en) 1987-11-23 1991-10-08 E. R. Squibb & Sons, Inc. N-morpholino derivatives and their use as anti-hypertensive agents
US5081127A (en) 1988-01-07 1992-01-14 E. I. Du Pont De Nemours And Company Substituted 1,2,3-triazole angiotensin II antagonists
US5036054A (en) 1988-02-11 1991-07-30 Warner-Lambert Company Renin inhibitors containing alpha-heteroatom amino acids
IE940525L (en) 1988-05-25 1989-11-25 Warner Lambert Co Known and selected novel arylmethylenyl derivatives of¹thiazolidinones, imidazolidinones and oxazolidinones useful¹as antiallergy agents and antiinflammatory agents
US5036053A (en) 1988-05-27 1991-07-30 Warner-Lambert Company Diol-containing renin inhibitors
JPH0219363A (ja) * 1988-07-06 1990-01-23 Fujisawa Pharmaceut Co Ltd イミダゾリジン誘導体
WO1990004183A1 (en) * 1988-10-07 1990-04-19 Commonwealth Scientific And Industrial Research Organisation Method for preparation of thiohydantoins and for protein sequence analysis
DE3841520A1 (de) 1988-12-09 1990-06-13 Hoechst Ag Enzymhemmende harnstoffderivate von dipeptiden, verfahren zu ihrer herstellung, diese enthaltende mittel und ihre verwendung
US5106835A (en) 1988-12-27 1992-04-21 American Cyanamid Company Renin inhibitors
EP0377083B1 (de) 1989-01-02 1993-09-22 Rütgerswerke Aktiengesellschaft Verfahren zur Herstellung von L-alpha-Aminosäuren
DE4004820A1 (de) 1989-08-05 1991-04-25 Bayer Ag Renininhibitoren, verfahren zur herstellung und ihre verwendung in arzneimitteln
US5064825A (en) 1989-06-01 1991-11-12 Merck & Co., Inc. Angiotensin ii antagonists
US5063208A (en) 1989-07-26 1991-11-05 Abbott Laboratories Peptidyl aminodiol renin inhibitors
US5098924A (en) 1989-09-15 1992-03-24 E. R. Squibb & Sons, Inc. Diol sulfonamide and sulfinyl renin inhibitors
US5104869A (en) 1989-10-11 1992-04-14 American Cyanamid Company Renin inhibitors
US5114937A (en) 1989-11-28 1992-05-19 Warner-Lambert Company Renin inhibiting nonpeptides
US5073566A (en) 1989-11-30 1991-12-17 Eli Lilly And Company Angiotensin ii antagonist 1,3-imidazoles and use thereas
US5095119A (en) 1990-03-08 1992-03-10 American Home Products Corporation Renin inhibitors
US5064965A (en) 1990-03-08 1991-11-12 American Home Products Corporation Renin inhibitors
US5075451A (en) 1990-03-08 1991-12-24 American Home Products Corporation Pyrrolimidazolones useful as renin inhibitors
US5085992A (en) 1990-07-19 1992-02-04 Merck & Co., Inc. Microbial transformation process for antihypertensive products
JPH054910A (ja) * 1990-07-31 1993-01-14 Nikka Chem Co Ltd 化粧料組成物
JPH06502627A (ja) 1990-08-31 1994-03-24 ワーナー―ランバート・コンパニー 新規コレシストキニンアンタゴニスト、その製造および治療用使用
GB9019812D0 (en) 1990-09-11 1990-10-24 Scotgen Ltd Novel antibodies for treatment and prevention of infection in animals and man
US5087634A (en) 1990-10-31 1992-02-11 G. D. Searle & Co. N-substituted imidazol-2-one compounds for treatment of circulatory disorders
US5071837A (en) 1990-11-28 1991-12-10 Warner-Lambert Company Novel renin inhibiting peptides
NZ286242A (en) * 1991-03-26 1997-11-24 Csl Ltd Use of veterinary implant as a single dose vaccination system: rupturable polymer film coating around core of active agent and water soluble excipient
US5693643A (en) 1991-09-16 1997-12-02 Merck & Co., Inc. Hydantoin and succinimide-substituted derivatives of spiroindanylcamphorsulfonyl oxytocin antagonists
US5604260A (en) 1992-12-11 1997-02-18 Merck Frosst Canada Inc. 5-methanesulfonamido-1-indanones as an inhibitor of cyclooxygenase-2
US5543297A (en) 1992-12-22 1996-08-06 Merck Frosst Canada, Inc. Human cyclooxygenase-2 cDNA and assays for evaluating cyclooxygenase-2 activity
US5474995A (en) 1993-06-24 1995-12-12 Merck Frosst Canada, Inc. Phenyl heterocycles as cox-2 inhibitors
GB9602877D0 (en) 1996-02-13 1996-04-10 Merck Frosst Canada Inc 3,4-Diaryl-2-hydroxy-2,5- dihydrofurans as prodrugs to cox-2 inhibitors
CA2180651A1 (en) 1994-01-10 1995-07-13 Yves Ducharme Phenyl heterocycles as cox-2 inhibitors
US5521213A (en) 1994-08-29 1996-05-28 Merck Frosst Canada, Inc. Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2
US5849943A (en) 1994-10-27 1998-12-15 Merck Frosst Canada, Inc. Stilbene derivatives useful as cyclooxygenase-2 inhibitors
US5552422A (en) 1995-01-11 1996-09-03 Merck Frosst Canada, Inc. Aryl substituted 5,5 fused aromatic nitrogen compounds as anti-inflammatory agents
WO1996030393A1 (en) 1995-03-27 1996-10-03 Warner-Lambert Company A method for the synthesis of mixtures of compounds
US6166054A (en) * 1995-03-31 2000-12-26 Nihon Nohyaku Co., Ltd. Agricultural and horticultural disease controller and a method for controlling the diseases
US5691374A (en) 1995-05-18 1997-11-25 Merck Frosst Canada Inc. Diaryl-5-oxygenated-2-(5H) -furanones as COX-2 inhibitors
US5604253A (en) 1995-05-22 1997-02-18 Merck Frosst Canada, Inc. N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors
US5643933A (en) 1995-06-02 1997-07-01 G. D. Searle & Co. Substituted sulfonylphenylheterocycles as cyclooxygenase-2 and 5-lipoxygenase inhibitors
US6846839B1 (en) * 1995-06-07 2005-01-25 Sugen, Inc. Methods for treating diseases and disorders related to unregulated angiogenesis and/or vasculogenesis
US5962478A (en) * 1995-09-19 1999-10-05 Margolin; Solomon B. Inhibition of tumor necrosis factor α
US5789413A (en) 1996-02-01 1998-08-04 Merck Frosst Canada, Inc. Alkylated styrenes as prodrugs to COX-2 inhibitors
US5733909A (en) 1996-02-01 1998-03-31 Merck Frosst Canada, Inc. Diphenyl stilbenes as prodrugs to COX-2 inhibitors
GB9607503D0 (en) 1996-04-11 1996-06-12 Merck Frosst Canada Inc Bisaryl cyclobutenes derivatives as cyclooxygenase inhibitors
US5922742A (en) 1996-04-23 1999-07-13 Merck Frosst Canada Pyridinyl-2-cyclopenten-1-ones as selective cyclooxygenase-2 inhibitors
US5677318A (en) 1996-07-11 1997-10-14 Merck Frosst Canada, Inc. Diphenyl-1,2-3-thiadiazoles as anti-inflammatory agents
US5861419A (en) 1996-07-18 1999-01-19 Merck Frosst Canad, Inc. Substituted pyridines as selective cyclooxygenase-2 inhibitors
AU725138B2 (en) * 1996-09-30 2000-10-05 Nihon Nohyaku Co., Ltd. 1,2,3-thiadiazole derivatives and salts thereof, disease controlling agents for agricultural and horticultural use, and method for the use thereof
TR199902124T2 (xx) 1997-03-03 2000-06-21 Boehringer Ingelheim Pharmaceuticals, Inc. �ltihapl� hastal�klar�n tedavisinde yararl� k���k molek�ller.
DE69907331T2 (de) * 1998-07-30 2003-10-23 Nihon Nohyaku Co Ltd Fungizide Zusammensetzung enthaltend ein 1,2,3-Thiadiazolderivat sowie deren Verwendung
WO2001028493A2 (en) * 1999-10-15 2001-04-26 President And Fellows Of Harvard College Small molecule inhibitors of necrosis
US6756394B1 (en) * 1999-10-15 2004-06-29 President And Fellow Of Harvard College Small molecule inhibitors of necrosis
US6706766B2 (en) * 1999-12-13 2004-03-16 President And Fellows Of Harvard College Small molecules used to increase cell death
WO2001074807A1 (fr) 2000-03-30 2001-10-11 Sagami Chemical Research Center Derives indolylpyrrole et inhibiteurs de mort cellulaire
GB0011071D0 (en) * 2000-05-08 2000-06-28 Novartis Ag Organic compounds
JP4529338B2 (ja) * 2001-03-08 2010-08-25 味の素株式会社 ヒダントイナーゼをコードするｄｎａ、ｎ−カルバミル−ｌ−アミノ酸ハイドロラーゼをコードするｄｎａ、組み換えｄｎａ、形質転換された細胞、タンパク質の製造方法および光学活性アミノ酸の製造方法
MXPA04004830A (es) 2001-11-22 2004-07-30 Ono Pharmaceutical Co Compuestos derivados de piperidin-2-ona, y composiciones farmaceuticas que los contienen como ingredientes activos.
US6797708B2 (en) * 2001-12-03 2004-09-28 Wyeth Inhibitors of cytosolic phospholipase A2
JP3659224B2 (ja) 2001-12-26 2005-06-15 村田機械株式会社 インターネットファクシミリ装置
FR2850652B1 (fr) 2003-01-31 2008-05-30 Aventis Pharma Sa Nouveaux derives d'uree cyclique, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de kinases
GB0302671D0 (en) * 2003-02-06 2003-03-12 Astrazeneca Ab Pharmaceutical formulations
US7320986B2 (en) * 2003-03-07 2008-01-22 Abbott Labortories Fused tri and tetra-cyclic pyrazole kinase inhibitors
DK2384753T3 (en) 2003-08-29 2016-04-11 Brigham & Womens Hospital Hydantoin derivatives as inhibitors of cell necrosis
US20080019909A1 (en) 2003-09-17 2008-01-24 Francis Ka-Ming Chan Modulation of Programmed Necrosis
US6887993B1 (en) * 2003-11-12 2005-05-03 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
WO2005080372A1 (en) * 2004-02-19 2005-09-01 Bayer Healthcare Ag Dihydropyridinone derivatives
BRPI0513677B8 (pt) * 2004-07-30 2021-05-25 Exelixis Inc derivados de pirrol como agentes farmacêuticos
AU2006212863A1 (en) 2005-02-10 2006-08-17 Merck Sharp & Dohme Corp. Mitotic kinesin inhibitors
JP2009518286A (ja) * 2005-11-01 2009-05-07 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ グルコキナーゼのアロステリックモジュレーターとしてのジヒドロイソインドロン
WO2007075772A2 (en) 2005-12-20 2007-07-05 President And Fellows Of Harvard College Compounds, screens, and methods of treatment
AR056882A1 (es) 2006-02-01 2007-10-31 Bayer Cropscience Sa Derivados del fungicida n- cicloalquil- bencil- amida
AU2007274283A1 (en) 2006-07-13 2008-01-17 4Sc Ag Benzopyranopyrazoles
CA2666060C (en) 2006-10-10 2015-02-03 President And Fellows Of Harvard College Thieno[2,3-d]pyrimidin-4-one compounds and methods of using the same
EP2192838A4 (en) * 2007-08-15 2011-07-27 Harvard College HETEROCYCLIC NEKROPTOSIS HEMMER
WO2010075290A1 (en) 2008-12-22 2010-07-01 President And Fellows Of Harvard College Unsaturated heterocyclic inhibitors of necroptosis
CN104803986A (zh) 2008-12-23 2015-07-29 哈佛大学校长及研究员协会 坏死性凋亡的小分子抑制剂

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