MX2012000708A - Inhibidores de cinasa que regulan la señal de apoptosis. - Google Patents
Inhibidores de cinasa que regulan la señal de apoptosis.Info
- Publication number
- MX2012000708A MX2012000708A MX2012000708A MX2012000708A MX2012000708A MX 2012000708 A MX2012000708 A MX 2012000708A MX 2012000708 A MX2012000708 A MX 2012000708A MX 2012000708 A MX2012000708 A MX 2012000708A MX 2012000708 A MX2012000708 A MX 2012000708A
- Authority
- MX
- Mexico
- Prior art keywords
- sup
- compounds
- apoptosis signal
- regulating kinase
- kinase inhibitors
- Prior art date
Links
- 230000006907 apoptotic process Effects 0.000 title abstract 2
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 abstract 4
- 208000023275 Autoimmune disease Diseases 0.000 abstract 1
- 208000024172 Cardiovascular disease Diseases 0.000 abstract 1
- 108091000080 Phosphotransferase Proteins 0.000 abstract 1
- 208000027866 inflammatory disease Diseases 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 230000001404 mediated effect Effects 0.000 abstract 1
- 230000004770 neurodegeneration Effects 0.000 abstract 1
- 208000015122 neurodegenerative disease Diseases 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 102000020233 phosphotransferase Human genes 0.000 abstract 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/4196—1,2,4-Triazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
- A61K31/585—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin containing lactone rings, e.g. oxandrolone, bufalin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Pain & Pain Management (AREA)
- Cardiology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Immunology (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
La presente invención se refiere a compuestos de la Fórmula (1); en donde X1, X2, X3, X4, X5, X6, X7, X8, R1, R2, R3 son tal como se definió anteriormente. Los compuestos tienen actividad inhibidora de la proteína de cinasa de regulación de la señal de apoptosis ('ASK1"), y son útiles en el tratamiento de condiciones tratadas por ASK1, incluyendo padecimientos a utoinm unes, enfermedades inflam atonas, enfermedades cardovasculares y enfermedades neurodegenerativas. La presente invención también se refiere a composiciones farmacéuticas que comprenden uno o más de los compuestos de la Fórmula (I), y a métodos de preparación de los compuestos de la Fórmula (I).
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US22507609P | 2009-07-13 | 2009-07-13 | |
US22507909P | 2009-07-13 | 2009-07-13 | |
US28926309P | 2009-12-22 | 2009-12-22 | |
PCT/US2010/041739 WO2011008709A1 (en) | 2009-07-13 | 2010-07-12 | Apoptosis signal-regulating kinase inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
MX2012000708A true MX2012000708A (es) | 2012-03-21 |
Family
ID=42670422
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
MX2012000708A MX2012000708A (es) | 2009-07-13 | 2010-07-12 | Inhibidores de cinasa que regulan la señal de apoptosis. |
Country Status (28)
Country | Link |
---|---|
US (7) | US8378108B2 (es) |
EP (4) | EP2454250B1 (es) |
JP (4) | JP5745721B2 (es) |
KR (3) | KR20170081722A (es) |
CN (1) | CN102482257B (es) |
AR (1) | AR077564A1 (es) |
AU (1) | AU2010273597B2 (es) |
BR (1) | BR112012000894A2 (es) |
CA (1) | CA2767894C (es) |
CY (1) | CY1119889T1 (es) |
DK (2) | DK2933252T3 (es) |
ES (3) | ES2854710T3 (es) |
HK (2) | HK1170482A1 (es) |
HR (2) | HRP20150185T1 (es) |
HU (1) | HUE038529T2 (es) |
LT (1) | LT2933252T (es) |
ME (1) | ME02104B (es) |
MX (1) | MX2012000708A (es) |
NO (1) | NO2933252T3 (es) |
NZ (1) | NZ597533A (es) |
PL (3) | PL2933252T3 (es) |
PT (3) | PT2933252T (es) |
RS (2) | RS56981B1 (es) |
SI (3) | SI3363797T1 (es) |
SM (1) | SMT201500090B (es) |
TW (3) | TWI598347B (es) |
UY (1) | UY32786A (es) |
WO (1) | WO2011008709A1 (es) |
Families Citing this family (197)
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CA2732806A1 (en) | 2008-08-04 | 2010-02-11 | John Wityak | Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
TWI598347B (zh) | 2009-07-13 | 2017-09-11 | 基利科學股份有限公司 | 調節細胞凋亡信號之激酶的抑制劑 |
WO2011091153A1 (en) | 2010-01-25 | 2011-07-28 | Chdi, Inc. | Certain kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
CA2802743C (en) * | 2010-07-02 | 2019-05-07 | Gilead Sciences, Inc. | Apoptosis signal-regulating kinase inhibitors |
EP2598661B1 (en) | 2010-07-26 | 2017-09-27 | Biomatrica, INC. | Compositions for stabilizing dna, rna and proteins in saliva and other biological samples during shipping and storage at ambient temperatures |
CA2806670A1 (en) | 2010-07-26 | 2012-02-09 | Biomatrica, Inc. | Compositions for stabilizing dna, rna and proteins in blood and other biological samples during shipping and storage at ambient temperatures |
US9045485B2 (en) | 2010-12-16 | 2015-06-02 | Convergence Pharmaceuticals Limited | ASK 1 inhibiting pyrrolopyrimidine derivatives |
US9428464B2 (en) | 2011-08-30 | 2016-08-30 | Chdi Foundation, Inc. | Kynurenine-3-monooxygenase inhibitors, pharmaceutical compositions, and methods of use thereof |
SI2750677T1 (sl) | 2011-08-30 | 2017-10-30 | Chdi Foundation, Inc. | Inhibitorji kinurenin-3-monooksigenaze, farmacevtski sestavki in postopki njihove uporabe |
AU2015201188B2 (en) * | 2012-01-27 | 2016-12-15 | Gilead Sciences, Inc. | Apoptosis signal-regulating kinase inhibitor |
UY34573A (es) * | 2012-01-27 | 2013-06-28 | Gilead Sciences Inc | Inhibidor de la quinasa que regula la señal de la apoptosis |
US9725703B2 (en) | 2012-12-20 | 2017-08-08 | Biomatrica, Inc. | Formulations and methods for stabilizing PCR reagents |
UY35212A (es) * | 2012-12-21 | 2014-06-30 | Gilead Sciences Inc | Inhibidores de la quinasa que regula la señal de la apoptosis |
JP6387488B2 (ja) | 2013-01-10 | 2018-09-12 | プルモキネ、インコーポレイテッド | 非選択的キナーゼ阻害剤 |
AU2014251038A1 (en) | 2013-04-08 | 2015-11-26 | Dennis M. Brown | Therapeutic benefit of suboptimally administered chemical compounds |
EP3632208A1 (en) | 2013-06-13 | 2020-04-08 | Biomatrica, INC. | Cell stabilization |
US9249151B2 (en) * | 2013-08-23 | 2016-02-02 | Boehringer Ingelheim International Gmbh | Bis-amido pyridines |
US9925184B2 (en) | 2013-10-11 | 2018-03-27 | Pulmokine, Inc. | Spray-dry formulations |
WO2015070366A1 (en) * | 2013-11-12 | 2015-05-21 | Merck Sharp & Dohme Corp. | Aryl linked imidazole and triazole derivatives and methods of use thereof for improving the pharmacokinetics of a drug |
EP3074016A2 (en) | 2013-11-26 | 2016-10-05 | Gilead Sciences, Inc. | Therapies for treating myeloproliferative disorders |
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US20160331754A1 (en) | 2014-01-20 | 2016-11-17 | Gilead Sciences, Inc. | Therapies for treating cancers |
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ES2891555T3 (es) | 2014-06-10 | 2022-01-28 | Biomatrica Inc | Estabilización de trombocitos a temperaturas ambiente |
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