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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
alkyl
substituted
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Gregory D. Cuny
Junying Yuan
Prakash Jagtap
Alexei Degterev
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Brigham and Womens Hospital Inc
Harvard University
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Harvard University
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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 Expired - Lifetime ES2567135T3 (es)

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Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2520586C (en) * 2003-03-27 2011-06-14 Lankenau Institute For Medical Research Novel ido inhibitors and methods of use
HUE027546T2 (en) 2003-08-29 2016-10-28 Brigham & Womens Hospital Inc Hydantoin derivatives as cell necrosis inhibitors
AU2005211773B2 (en) * 2004-02-10 2009-06-25 Trustees Of Dartmouth College Nicotinamide riboside kinase compositions and methods for using the same
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
CN101674826A (zh) * 2005-12-20 2010-03-17 哈佛大学校长及研究员协会 化合物、筛选和治疗方法
EP2003119A1 (de) * 2007-06-13 2008-12-17 Bayer Schering Pharma Aktiengesellschaft Substituierte Acetamide als Modulatoren des EP2-Rezeptors
CA2696349A1 (en) * 2007-08-15 2009-02-19 President And Fellows Of Harvard College Heterocyclic inhibitors of necroptosis
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
BRPI0923126A2 (pt) * 2008-12-23 2021-09-08 President And Fellows Of Harvard College Compostos inibidores de molécula pequena de necroptose, uso e composição compreendendo os mesmos e método de diminuir necroptose
WO2011133964A2 (en) * 2010-04-23 2011-10-27 Massachusetts Eye And 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
EP2773341A2 (en) * 2011-10-21 2014-09-10 Massachusetts Eye & Ear Infirmary Compositions comprising necrosis inhibitors, such as necrostatins, alone or in combination, for promoting axon regeneration and nerve function, thereby treating cns disorders
WO2014152182A1 (en) * 2013-03-15 2014-09-25 President And Fellows Of Harvard College Deuterated heterocyclic inhibitors of necroptosis
WO2014145022A1 (en) * 2013-03-15 2014-09-18 President And Fellows Of Harvard College Hybrid necroptosis inhibitors
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
EA201791289A1 (ru) * 2014-12-11 2017-12-29 Президент Энд Феллоуз Оф Гарвард Колледж Ингибиторы клеточного некроза и связанные с ними способы
HK1244792B (en) 2014-12-24 2019-07-12 北京生命科学研究所 Necrosis inhibitor
AU2015371822B2 (en) 2014-12-24 2020-04-09 National Institute Of Biological Sciences, Beijing Necrosis inhibitors
ES2885474T3 (es) 2015-10-13 2021-12-13 Inst Nat Sante Rech Med Derivados de sibirilina para la utilización en la prevención y/o tratamiento de trastornos asociados a la necroptosis celular
DK3362450T3 (da) 2015-10-13 2020-09-14 Inst Nat Sante Rech Med N1- og N7-substituerede sibirilin-derivater og anvendelse deraf som inhibitorer af cellulær nekroptose
CN118994190A (zh) 2016-02-05 2024-11-22 戴纳立制药公司 受体相互作用蛋白激酶1的抑制剂
US11224586B2 (en) 2016-10-18 2022-01-18 Institut National De La Sante Et De La Recherche Medicale (Inserm) Natural product derivatives for inhibiting cellular necroptosis, ferroptosis and oxytosis
SI3552017T1 (sl) 2016-12-09 2022-09-30 Denali Therapeutics Inc. Spojine uporabne kot zaviralci RIPK1
CA3052767A1 (en) 2017-02-27 2018-08-30 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides as kinase inhibitors
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
WO2020103859A1 (en) 2018-11-20 2020-05-28 Sironax Ltd RIP1 Inhibitors
US10744153B1 (en) * 2019-07-01 2020-08-18 Cloudbreak Therapeutics Llc Compositions and methods for treating meibomian gland dysfunction
US20230129364A1 (en) * 2019-12-26 2023-04-27 Yonsei University, University - Industry Foundation (UIF) Pyrrolidine derivative, and pharmaceutical composition for preventing or treating beta-amyloid or tau protein-associated diseases containing same
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
IL296771A (en) * 2020-03-31 2022-11-01 Martin Ogletree Methods and pharmaceutical compositions of thromboxane a2 receptor antagonist for the treatment of covid-19
EP4153582A4 (en) 2020-05-20 2024-06-19 Sironax Ltd. PIPERAZINE-TYPE CYCLIC UREAS
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
AU2023206890A1 (en) 2022-01-12 2024-08-22 Denali Therapeutics Inc. Crystalline forms of (s)-5-benzyl-n-(5-methyl-4-oxo-2, 3,4,5- tetrahydropyrido [3,2-b] [l,4]oxazepin-3-yl)-4h-l,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
US4332952A (en) * 1980-07-28 1982-06-01 Pfizer Inc. Hypoglycemic 5-substituted oxazolidine-2,4-diones
GB2080803B (en) 1980-07-28 1984-01-18 Pfizer 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
EP0164247B1 (en) * 1984-06-07 1989-01-11 Pfizer Limited 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
EP0217634B1 (en) 1985-09-26 1992-06-10 Beckman Research Institute of the City of Hope 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
IE62214B1 (en) 1988-05-25 1995-01-11 Warner Lambert Co Arylmethylenyl derivatives of thiazolidinones, imidazolidinones and oxazolidinones useful as 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
DE58905691D1 (de) 1989-01-02 1993-10-28 Ruetgerswerke Ag 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
US5075451A (en) 1990-03-08 1991-12-24 American Home Products Corporation Pyrrolimidazolones useful as renin inhibitors
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
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
CA2088195A1 (en) 1990-08-31 1992-03-01 David C. Horwell Cholecystokinin antagonists, their preparation and therapeutic use
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
NZ242065A (en) * 1991-03-26 1996-06-25 Csl Ltd Delayed release implant having a degradable or rupturable polymeric coating
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
EP0739340A1 (en) 1994-01-10 1996-10-30 Merck Frosst Canada Inc. 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
AU4424496A (en) 1995-03-27 1996-10-16 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
US5733909A (en) 1996-02-01 1998-03-31 Merck Frosst Canada, Inc. Diphenyl stilbenes as prodrugs to COX-2 inhibitors
US5789413A (en) 1996-02-01 1998-08-04 Merck Frosst Canada, Inc. Alkylated styrenes 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
CA2268129C (en) * 1996-09-30 2003-03-11 Nihon Nohyaku Co., Ltd. 1,2,3-thiadiazole derivatives or salts thereof and agrohorticultural disease controller and method for using the same
BR9811260A (pt) 1997-03-03 2000-08-08 Boehringer Ingelheim Pharma Pequenas moléculas úteis no tratamento de doença inflamatória
EP0976326B1 (en) * 1998-07-30 2003-05-02 Nihon Nohyaku Co., Ltd. Fungicidal composition containing a 1,2,3-tiadiazole derivative and its use
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
HUP0500027A2 (hu) 2001-11-22 2005-04-28 Ono Pharmaceutical Co., Ltd. Piperidin-2-on-származékok és hatóanyagként ezeket tartalmazó gyógyászati készítmények
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
HUE027546T2 (en) * 2003-08-29 2016-10-28 Brigham & Womens Hospital Inc Hydantoin derivatives as cell necrosis inhibitors
WO2005028664A2 (en) 2003-09-17 2005-03-31 University Of Massachusetts Modulation of programmed necrosis
US6887993B1 (en) * 2003-11-12 2005-05-03 Kosan Biosciences, Inc. 11-O-methylgeldanamycin compounds
ES2367699T3 (es) * 2004-02-19 2011-11-07 Bayer Pharma Aktiengesellschaft Derivados de dihidropiridinona.
PT1773768T (pt) * 2004-07-30 2018-11-30 Exelixis Inc Derivados de pirrol como agentes farmacêuticos
CN101115745A (zh) 2005-02-10 2008-01-30 默克公司 有丝分裂驱动蛋白抑制剂
CA2628259A1 (en) * 2005-11-01 2007-05-10 Janssen Pharmaceutica N.V. Dihydroisoindolones as allosteric modulators of glucokinase
CN101674826A (zh) 2005-12-20 2010-03-17 哈佛大学校长及研究员协会 化合物、筛选和治疗方法
AR056882A1 (es) 2006-02-01 2007-10-31 Bayer Cropscience Sa Derivados del fungicida n- cicloalquil- bencil- amida
JP2009542777A (ja) 2006-07-13 2009-12-03 ４エスツェー アクチェンゲゼルシャフト ベンゾピラノピラゾール
JP5366812B2 (ja) * 2006-10-10 2013-12-11 プレジデント アンド フェロウズ オブ ハーバード カレッジ 化合物、スクリーニング、および治療方法
CA2696349A1 (en) * 2007-08-15 2009-02-19 President And Fellows Of Harvard College Heterocyclic inhibitors of necroptosis
WO2010075290A1 (en) 2008-12-22 2010-07-01 President And Fellows Of Harvard College Unsaturated heterocyclic inhibitors of necroptosis
BRPI0923126A2 (pt) 2008-12-23 2021-09-08 President And Fellows Of Harvard College Compostos inibidores de molécula pequena de necroptose, uso e composição compreendendo os mesmos e método de diminuir necroptose

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