ES2603958T3 - 4-Fenil-piridinas sustituidas para el tratamiento de enfermedades relacionadas con el receptor NK1 - Google Patents

4-Fenil-piridinas sustituidas para el tratamiento de enfermedades relacionadas con el receptor NK1 Download PDF

Info

Publication number
ES2603958T3
ES2603958T3 ES12798549.7T ES12798549T ES2603958T3 ES 2603958 T3 ES2603958 T3 ES 2603958T3 ES 12798549 T ES12798549 T ES 12798549T ES 2603958 T3 ES2603958 T3 ES 2603958T3
Authority
ES
Spain
Prior art keywords
phenyl
trifluoromethyl
dimethylpropanamide
emesis
5bis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
ES12798549.7T
Other languages
English (en)
Inventor
Luca Fadini
Peter Manini
Claudio Pietra
Claudio Giuliano
Emanuela Lovati
Roberta Cannella
Alessio Venturini
Valentino J. Stella
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Helsinn Healthcare SA
Original Assignee
Helsinn Healthcare SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=48094815&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=ES2603958(T3) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Helsinn Healthcare SA filed Critical Helsinn Healthcare SA
Application granted granted Critical
Publication of ES2603958T3 publication Critical patent/ES2603958T3/es
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • 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
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • 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
    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/76—Nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/025—Purification; Separation; Stabilisation; Desodorisation of organo-phosphorus compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Otolaryngology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Un compuesto seleccionado entre el grupo que consiste en:**Tabla** GA1**Fórmula** 4-(5-(2-(3,5-bis(trifluorometil)fenil)-N,2-dimetilpropanamido)-4- (o-tolil)piridin-2-il)-1-metil-1-((fosfonooxi)metil)piperazin-1-io, GA2**Fórmula** 1-(acetoximetil)-4-(5-(2-(3,5-bis(trifluorometil)fenil)-N,2- dimetilpropanamido)-4-(o-tolil)piridin-2-il)-1-metilpiperazin-1-io, GA3**Fórmula** 4-(5-(2-(3,5-bis(trifluorometil)fenil)-N,2-dimetilpropanamido)-4- (o-tolil)piridin-2-il)-1-((butiriloxi)metil)-1-metilpiperazin-1-io, GA4**Fórmula** 1,4-dioxido de 1-(5-(2-(3,5-bis(trifluorometil)fenil)-N,2- dimetilpropanamido)-4-(o-tolil)piridin-2-il)-4-metilpiperazina, GA6**Fórmula** 1-oxido 4-(5-(2-(3,5-bis(trifluorometil)fenil)-N,2- dimetilpropanamido)-1-oxido-4-(o-tolil)piridin-2-il)-1- metilpiperazina, o una sal farmaceuticamente aceptable del mismo.

Description

imagen1
imagen2
imagen3
imagen4
imagen5
imagen6
7
o una sal o un aducto farmacéuticamente aceptables del mismo. En una realización adicional, la invención es un compuesto de fórmula GA1,
o una sal o un aducto farmacéuticamente aceptables del mismo.
imagen7
Breve descripción de los dibujos
La FIGURA 1 reproduce los datos de estabilidad para diversas sales de 4(5(2(3,5bis(trifluorometil)fenil)N,2
8
imagen8
imagen9
imagen10
imagen11
imagen12
imagen13
imagen14
imagen15
imagen16
imagen17
imagen18
imagen19
imagen20
imagen21
la emesis. La emesis retardada se refiere al segundo, tercer, cuarto y quinto período de veinticuatro horas siguientes a un acontecimiento inductor de la emesis. Cuando se dice que un tratamiento es eficaz durante la fase tardía, se entenderá en el sentido de que la eficacia del tratamiento es estadísticamente significativa durante toda la fase retardada, independientemente de si el tratamiento es eficaz durante cualquier período en particular de veinticuatro 5 horas la fase retardada. También se entenderá que el uso médico puede definirse basándose en su eficacia durante cualquiera de los períodos de veinticuatro horas de la fase retardada. Por tanto, a menos que se especifique lo contrario, cualquiera de los usos médicos para el tratamiento de las náuseas y/o vómitos durante las fases retardadas, como se describen en el presente documento, también podrían practicarse para tratar las náuseas y/o vómitos durante el segundo, tercer, cuarto y quinto período de veinticuatro horas siguientes a un acontecimiento
10 inductor de la emesis o una combinación de los mismos.
En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que están fisiopatológicamente moduladas por el receptor NK1, en los que dichas fases agudas y/o retardadas de las NVIQ son inducidas la quimioterapia moderada o altamente emetógena. "Quimioterapia altamente emetógena" se
15 refiere a la quimioterapia que tiene un alto grado de potencial emético, e incluye la quimioterapia a base de carmustina, cisplatino, ciclofosfamida ≥ 1500 mg/m2, dacarbazina, dactinomicina, mecloretamina y estreptozotocina. "Quimioterapia moderadamente emetógena" se refiere a la quimioterapia que tiene un grado moderado de potencial emético, e incluye la quimioterapia a base de carboplatino, ciclofosfamida < 1500 mg/m2, citarabina > 1 mg/m2, daunorubicina, doxorubicina, epirubicina, idarubicina, ifosfamida, irinotecán y oxaliplatino.
20 En una realización preferida, los usos médicos de la presente invención son eficaces para tratar la emesis aguda y retardada resultante de la quimioterapia moderadamente y altamente emetógena, a partir de una sola dosis del derivado de netupitant administrado antes de la quimioterapia, opcionalmente en combinación con otros principios activos.
25 Una posología particularmente preferida para el tratamiento de la emesis, especialmente la emesis inducida por la quimioterapia, implica un derivado de netupitant de la presente invención, un antagonista de 5HT3 tal como palonosetrón o una sal farmacéuticamente aceptable del mismo y un corticoesteroide tal como dexametasona. Una posología fija adecuada para el tratamiento de las NVIQ agudas y retardadas incluye una única administración del
30 derivado de netupitant el día uno (preferentemente antes de la quimioterapia), una única administración del antagonista de 5HT3 el día 1 (preferentemente antes de la quimioterapia). Se añade un corticoesteroide opcionalmente a la combinación en un día y, cuando se administra la quimioterapia altamente emetógena, en días 2, 3 y 4 también. Una dosis intravenosa preferida de HCl de palonosetrón es de 0,25 mg sobre la base del peso de la base libre. Las dosis preferidas de dexametasona son 12 mg por vía oral el día 1, seguidos de 8 mg por vía oral los
35 días 2, 3 y 4 para la quimioterapia altamente emetógena.
En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que están fisiopatológicamente moduladas por el receptor NK1, en los que dicha disfunción de la vejiga se selecciona entre urgencia, frecuencia, poliaquiuria, nicturia, bajo tiempo el aplazamiento, umbral de volumen subóptimo y vejiga
40 neurógena o una combinación de los mismos.
En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que están fisiopatológicamente moduladas por el receptor NK1, en los que dicho compuesto o una sal o un aducto farmacéuticamente aceptables del mismo, se administra por una o más vías seleccionadas entre el grupo que
45 consiste en la administración rectal, bucal, sublingual, intravenosa, subcutánea, intradérmica, transdérmica, intraperitoneal, oral, colirio, parenteral y tópica.
En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que están fisiopatológicamente moduladas por el receptor NK1, en los que dicha administración se realiza mediante la
50 administración por vía intravenosa de una forma líquida de dicho compuesto o una sal o un aducto farmacéuticamente aceptables del mismo.
En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que están fisiopatológicamente moduladas por el receptor NK1, en particular por los derivados de netupitant, en los que
55 dicha administración se consigue mediante la administración por vía oral de dicho compuesto o una sal o un aducto farmacéuticamente aceptables del mismo. En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que están fisiopatológicamente moduladas por el receptor NK1, en los que dicho derivado de netupitant se administra por vía oral a una dosis de aproximadamente 50 mg a aproximadamente 500 mg, de aproximadamente 100 mg a aproximadamente 400 mg, de aproximadamente 150 mg a
60 aproximadamente 350 mg o aproximadamente 300 mg, sobre la base del peso del componente netupitant de la molécula.
En algunas otras formas, se desvelan usos médicos para la prevención y/o el tratamiento de enfermedades que
23
imagen22
imagen23
imagen24
imagen25
imagen26
imagen27
imagen28
imagen29
imagen30
imagen31
imagen32
Cuando la especie de ácido parental no se almacenó en estado seco se descubrió que experimentó una degradación de más del 8 % en la primera semana y una degradación de más del 65 % en los primeros seis meses. Cuando la especie de ácido parental seca se mantuvo a 30 ºC al aire experimentó una degradación del 0,05 % en los primeros 7 días y una degradación total del 7,03 % en seis meses. Cuando la especie de ácido parental seca se mantuvo en atmósfera de argón a temperatura ambiente experimentó una degradación de hasta el 0,13 % en los primeros 7 días, pero después fue esencialmente estable durante seis meses. Se muestran resultados para diversas sales derivadas en la Tabla 1 a continuación.
Tabla 1: Resultados de degradación representativos para sales
Disolventes
Aditivos % de Rendimiento Pureza % de A por HPLC Comentarios
MeOH
LHistidina, 2 eq. 26,6 % 95,94 % Degradación: +0,70 % en 6 días (en aire) +0,46 % en 6 días (en atmósfera de argón)
MeOH
Mg(OH)2, 2 eq. 48,6 % 94,11 % Degradación: +0,81 % en 6 días (en aire) +0,29 % en 6 días (en atmósfera de argón)
MeOH + DCM, 1:1
Ácido cítrico, 2 eq. N.A. 94,40 % A partir de especie protegida.
MeOH
1. HCl de dioxano, 4 eq. 2. Ca(OH)2 > 90 % 94,50 % A partir de especie protegida.
MeOH
H3PO4, 85 %, 2 eq. > 90 % 98,81 % A partir de especie protegida y conserva el 0,39 % de esa especie.
MeOH
HBr, 48 %, 4 eq. 84,6 % 96,11 % A partir de especie protegida. El producto se degrada rápidamente.
MeOH + DCM, 1:4
CH3SO3H N.A. 61,54 % A partir de especie protegida. Producto NO estable: contiene el 32,45 % de especie de descomposición.
MeOH
NaH2PO4, 4 eq. N.A. n.d. Solo se formó 1,27 de especie parental. Reacción pobre.
MeOH
NmetilDglucamina N.A. 96,88 % Degradación: +0,87 % en 6 días (en aire)
(Meglumina), 2 eq.
+1,52 % en 11 días (en atmósfera de argón)
MeOH
NmetilDglucamina (Meglumina), 1 eq. > 99 % 97,42 % Degradación: +0,77 % en 6 días (en aire) +0,83 % en 7 días (en atmósfera de argón)
MeOH + DCM, 5:2
1. NaOH, 3 eq 2. Ácido cítrico, 1 eq. 96,5 % 97,49 % Degradación: +0,09 % en 2 días (en atmósfera de argón) +0,59 % en 89 días (en atmósfera de argón)
MeOH + DCM, 5:2
1. NaOH, 3 eq. 2. Ácido fumárico, 1 eq. 93,8 % 97,46 % Degradación: +1,95 % en 14 días (en aire) +1,80 % en 12 días (en atmósfera de argón)
MeOH
Llisina, 1 eq. > 99 % 97,62 % Degradación: +0,69 % en 14 días (en aire) +0,48 % en 12 días (en atmósfera de argón)
Una muestra más completa de los resultados de estabilidad se proporciona en la Fig. 1, donde el eje horizontal representa el número de días del ensayo y el eje vertical representa el porcentaje en masa de degradación. Se usan
35

Claims (4)

  1. REIVINDICACIONES
    1. Un compuesto seleccionado entre el grupo que consiste en:
    GA1
    imagen1 4(5(2(3,5bis(trifluorometil)fenil)N,2dimetilpropanamido)4(otolil)piridin2il)1metil1((fosfonooxi)metil)piperazin1io,
    GA2
    imagen2 1(acetoximetil)4(5(2(3,5bis(trifluorometil)fenil)N,2dimetilpropanamido)4(otolil)piridin2il)1metilpiperazin1io,
    GA3
    imagen3 4(5(2(3,5bis(trifluorometil)fenil)N,2dimetilpropanamido)4(otolil)piridin2il)1((butiriloxi)metil)1metilpiperazin1io,
    GA4
    imagen4 1,4dióxido de 1(5(2(3,5bis(trifluorometil)fenil)N,2dimetilpropanamido)4(otolil)piridin2il)4metilpiperazina,
    GA6
    imagen5 1óxido 4(5(2(3,5bis(trifluorometil)fenil)N,2dimetilpropanamido)1oxido4(otolil)piridin2il)1metilpiperazina,
    5
    o una sal farmacéuticamente aceptable del mismo.
  2. 2. Un compuesto de acuerdo con la reivindicación 1 para su uso en un método de tratamiento de la emesis, la
    disfunción de la vejiga, la depresión o la ansiedad, en un paciente que lo necesite. 10
  3. 3. El compuesto para el uso de acuerdo con la reivindicación 2, en el que dicha emesis comprende las náuseas y vómitos inducidos por quimioterapia (NVIQ), las náuseas y vómitos inducidos por radioterapia (NVIR) o las nausea y vómitos postoperatorios (NVPO).
    15 4. El compuesto para el uso de acuerdo con cualquiera de las reivindicaciones 23, en el que dicha emesis es inducida por la quimioterapia moderadamente o altamente emetógena.
  4. 5. El compuesto para el uso de acuerdo con cualquiera de las reivindicaciones 24, en el que la emesis es la emesis
    aguda y retardada inducida por la quimioterapia moderadamente o altamente emetógena. 20
    42
    imagen6
    imagen7
    imagen8
ES12798549.7T 2011-11-29 2012-11-28 4-Fenil-piridinas sustituidas para el tratamiento de enfermedades relacionadas con el receptor NK1 Active ES2603958T3 (es)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201161564537P 2011-11-29 2011-11-29
US201161564537P 2011-11-29
US13/478,361 US8426450B1 (en) 2011-11-29 2012-05-23 Substituted 4-phenyl pyridines having anti-emetic effect
US201213478361 2012-05-23
PCT/US2012/066778 WO2013082102A1 (en) 2011-11-29 2012-11-28 Substituted 4 - phenyl - pyridines for the treatment of nk-1 receptor related diseases

Publications (1)

Publication Number Publication Date
ES2603958T3 true ES2603958T3 (es) 2017-03-02

Family

ID=48094815

Family Applications (1)

Application Number Title Priority Date Filing Date
ES12798549.7T Active ES2603958T3 (es) 2011-11-29 2012-11-28 4-Fenil-piridinas sustituidas para el tratamiento de enfermedades relacionadas con el receptor NK1

Country Status (51)

Country Link
US (7) US8426450B1 (es)
EP (1) EP2785706B1 (es)
JP (3) JP5635708B2 (es)
KR (1) KR101979050B1 (es)
CN (6) CN111662330B (es)
AP (1) AP2014007729A0 (es)
AR (1) AR089019A1 (es)
AU (1) AU2012346133B2 (es)
BR (1) BR112014012878B1 (es)
CA (1) CA2850644C (es)
CL (1) CL2014001280A1 (es)
CO (1) CO6990728A2 (es)
CR (1) CR20140312A (es)
CY (2) CY1118416T1 (es)
DK (1) DK2785706T3 (es)
DO (1) DOP2014000115A (es)
EA (1) EA026553B1 (es)
EC (1) ECSP14003642A (es)
ES (1) ES2603958T3 (es)
FI (1) FIC20200022I1 (es)
FR (1) FR20C1029I2 (es)
GE (1) GEP201706695B (es)
GT (1) GT201400102A (es)
HK (1) HK1199030A1 (es)
HR (1) HRP20161708T1 (es)
HU (2) HUE032288T2 (es)
IL (1) IL232859B (es)
IN (1) IN2014CN04907A (es)
JO (1) JO3202B1 (es)
LT (2) LT2785706T (es)
MA (1) MA35836B1 (es)
MD (1) MD4539C1 (es)
ME (1) ME02561B (es)
MX (1) MX2014006423A (es)
MY (1) MY165514A (es)
NI (1) NI201400043A (es)
NL (1) NL301047I2 (es)
PE (1) PE20141421A1 (es)
PH (1) PH12014501199A1 (es)
PL (1) PL2785706T3 (es)
PT (1) PT2785706T (es)
RS (1) RS55448B1 (es)
SG (1) SG11201402044XA (es)
SI (1) SI2785706T1 (es)
SM (1) SMT201600467B (es)
TN (1) TN2014000165A1 (es)
TW (1) TWI638806B (es)
UA (1) UA115136C2 (es)
UY (1) UY34472A (es)
WO (1) WO2013082102A1 (es)
ZA (1) ZA201404787B (es)

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK2605655T3 (en) 2010-08-19 2019-02-04 Buck Institute For Age Res METHODS OF TREATING SMALL COGNITIVE DISABILITY (MCI) AND RELATED DISORDERS
CA2820626C (en) 2010-12-07 2018-01-09 Allison Transmission, Inc. Energy storage system for hybrid electric vehicle
CA2837178C (en) 2011-06-22 2016-09-20 Purdue Pharma L.P. Trpv1 antagonists including dihydroxy substituent and uses thereof
US8426450B1 (en) 2011-11-29 2013-04-23 Helsinn Healthcare Sa Substituted 4-phenyl pyridines having anti-emetic effect
KR20160078997A (ko) 2013-11-08 2016-07-05 깃세이 야쿠힌 고교 가부시키가이샤 카복시메틸피페리딘 유도체
EP3140007A1 (en) * 2014-05-05 2017-03-15 Apicore US LLC Methods of making netupitant and intermediates thereof
TWI649307B (zh) 2014-05-07 2019-02-01 日商橘生藥品工業股份有限公司 Cyclohexylpyridine derivative
TW201613888A (en) * 2014-09-26 2016-04-16 Helsinn Healthcare Sa Crystalline forms of an NK-1 antagonist
SG10201913603QA (en) 2014-10-06 2020-02-27 Vertex Pharma Modulators of cystic fibrosis transmembrane conductance regulator
CN105061303A (zh) * 2015-08-03 2015-11-18 成都欣捷高新技术开发有限公司 一种制备奈妥吡坦关键中间体n-甲基-4-(2-甲基苯基)-6-(4-甲基-1-哌嗪基)-3-吡啶胺的新方法
US10005803B2 (en) * 2015-10-06 2018-06-26 Helsinn Healthcare Sa Crystalline forms of fosnetupitant
CN106892864A (zh) * 2015-12-21 2017-06-27 上海科胜药物研发有限公司 一种奈妥皮坦游离碱的晶型a及其制备方法
PL3436446T3 (pl) 2016-03-31 2023-09-11 Vertex Pharmaceuticals Incorporated Modulatory mukowiscydozowego przezbłonowego regulatora przewodnictwa
MD3435980T2 (ro) * 2016-06-06 2020-03-31 Helsinn Healthcare Sa Formulări injectabile de fosnetupitant echilibrate fiziologic
LT3519401T (lt) 2016-09-30 2021-11-25 Vertex Pharmaceuticals Incorporated Cistinės fibrozės transmembraninio laidumo reguliavimo moduliatorius, farmacinės kompozicijos, gydymo būdai ir moduliatoriaus gamybos būdas
US10793547B2 (en) 2016-12-09 2020-10-06 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
CN108619525B (zh) * 2017-03-15 2020-12-29 和龙 奈妥吡坦-mPEG-PLA纳米粒及其制备方法和用途
AU2018279646B2 (en) 2017-06-08 2023-04-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
MA49524A (fr) 2017-06-30 2021-05-26 Chase Therapeutics Corp Compositions d'antagoniste de nk-1 et méthodes destinées à être utilisées dans le traitement de la dépression
CA3069226A1 (en) 2017-07-17 2019-01-24 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
CN111051280B (zh) 2017-08-02 2023-12-22 弗特克斯药品有限公司 制备吡咯烷化合物的方法
CN107698500A (zh) * 2017-10-17 2018-02-16 扬子江药业集团四川海蓉药业有限公司 一种奈妥匹坦的制备方法
CA3078893A1 (en) 2017-10-19 2019-04-25 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of cftr modulators
JP7245834B2 (ja) 2017-12-08 2023-03-24 バーテックス ファーマシューティカルズ インコーポレイテッド 嚢胞性線維症膜コンダクタンス制御因子のモジュレーターを作成するためのプロセス
DK3737378T3 (da) * 2018-01-12 2023-05-30 Orion Corp Palonosetron-øjendråber til behandling eller forebyggelse af kvalme og opkastning
TWI810243B (zh) 2018-02-05 2023-08-01 美商維泰克斯製藥公司 用於治療囊腫纖化症之醫藥組合物
US11414439B2 (en) 2018-04-13 2022-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
JP7156154B2 (ja) * 2019-04-18 2022-10-19 株式会社島津製作所 培地処理システム及び培地処理方法
CN112174881B (zh) * 2019-07-04 2022-06-21 上海森辉医药有限公司 一种奈妥匹坦的衍生物及其制备方法
MX2022011545A (es) 2020-04-03 2022-11-09 Nerre Therapeutics Ltd Un antagonista de receptor de nk-1 para tratar una enfermedad que se selecciona de sepsis, choque septico, síndrome de dificultad respiratoria aguda (ards) 0 síndrome de disfunción orgánica múltiple (mcds).
CN115697332A (zh) * 2020-06-02 2023-02-03 尼尔医疗有限公司 用于治疗由肺的机械损伤促进的肺纤维化状况的神经激肽(nk)-1受体拮抗剂
US12097197B2 (en) 2021-12-21 2024-09-24 Slayback Pharma Llc Stable liquid compositions of netupitant and palonosetron

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69822514T2 (de) * 1997-12-31 2005-03-24 The University Of Kansas, Lawrence Wasserlösliche pro-pharmaka von arzneistoffen, die ein tertiäres amin enthalten, und verfahren zu ihrer herstellung
ATE496032T1 (de) * 1999-02-24 2011-02-15 Hoffmann La Roche 4-phenylpyridinderivate und deren verwendung als nk-1 rezeptorantagonisten
US6303790B1 (en) 1999-11-29 2001-10-16 Hoffman-La Roche Inc. Process for the preparation of pyridine derivatives
DE60006340T2 (de) * 1999-11-29 2004-09-09 F. Hoffmann-La Roche Ag 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramid
US6362172B2 (en) * 2000-01-20 2002-03-26 Bristol-Myers Squibb Company Water soluble prodrugs of azole compounds
RS50932B (sr) 2000-07-14 2010-08-31 F. Hoffmann-La Roche Ag. N-oksidi kao prolekovi 4-fenil-piridinskih derivata koji su antagonisti nk1 receptora
TWI287003B (en) * 2000-07-24 2007-09-21 Hoffmann La Roche 4-phenyl-pyridine derivatives
CA2431397C (en) 2000-12-14 2007-05-01 F. Hoffmann-La Roche Ag Self emulsifying lipid matrix (selm)
US6531597B2 (en) 2001-02-13 2003-03-11 Hoffmann-La Roche Inc. Process for preparation of 2-phenyl acetic acid derivatives
US7745625B2 (en) * 2004-03-15 2010-06-29 Bristol-Myers Squibb Company Prodrugs of piperazine and substituted piperidine antiviral agents
US20060030600A1 (en) * 2004-08-06 2006-02-09 Patrick Schnider Dual NK1/NK3 receptor antagonists for the treatment of schizophrenia
PL1863767T3 (pl) * 2005-03-23 2009-08-31 Helsinn Healthcare Sa Metabolity antagonistów NK-1 do leczenia wymiotów
JP4981673B2 (ja) * 2005-09-13 2012-07-25 エーザイ・アール・アンド・ディー・マネジメント株式会社 安定性が改善されたクロロメチルフォスフェイト誘導体を含む組成物およびその製造方法
GB0808747D0 (en) * 2008-05-14 2008-06-18 Glaxo Wellcome Mfg Pte Ltd Novel compounds
UA108077C2 (xx) * 2009-07-02 2015-03-25 Синтез динатрієвої солі n4-(2,2-диметил-4-$(дигідрофосфонокси)метил]-3-оксо-5-піридо$1,4]оксазин-6-іл)-5-фтор-n2-(3,4,5-триметоксифеніл)-2,4-піримідиндіаміну
JP5890780B2 (ja) * 2009-11-18 2016-03-22 ヘルシン ヘルスケア ソシエテ アノニム 中枢を介する悪心および嘔吐を治療するための組成物および方法
AU2010339689B2 (en) * 2010-01-07 2015-02-19 Alkermes Pharma Ireland Limited Quaternary ammonium salt prodrugs
WO2012075396A2 (en) * 2010-12-02 2012-06-07 The University Of Kansas Prodrugs of 6-cyclohexyl-1-hydroxy-4- methylpyridin-2(1h)-one and derivatives thereof
US9403772B2 (en) 2011-11-29 2016-08-02 Helsinn Healthcare Sa 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium as a neurokinin receptor modulator
US8426450B1 (en) 2011-11-29 2013-04-23 Helsinn Healthcare Sa Substituted 4-phenyl pyridines having anti-emetic effect
SG11201408284VA (en) 2012-05-22 2015-02-27 Xenon Pharmaceuticals Inc N-substituted benzamides and their use in the treatment of pain

Also Published As

Publication number Publication date
FR20C1029I2 (fr) 2023-12-29
PL2785706T3 (pl) 2017-03-31
US20130231315A1 (en) 2013-09-05
PH12014501199B1 (en) 2014-09-08
MD4539C1 (ro) 2018-07-31
RS55448B1 (sr) 2017-04-28
TN2014000165A1 (en) 2015-09-30
NI201400043A (es) 2015-09-21
FIC20200022I1 (fi) 2020-06-24
US20180194788A1 (en) 2018-07-12
ECSP14003642A (es) 2015-12-31
SG11201402044XA (en) 2014-09-26
PT2785706T (pt) 2016-12-16
CN112979543A (zh) 2021-06-18
MX2014006423A (es) 2014-09-08
US10208073B2 (en) 2019-02-19
US20200399240A1 (en) 2020-12-24
CN111662330A (zh) 2020-09-15
BR112014012878A2 (pt) 2017-06-13
MD20140059A2 (en) 2014-11-30
SMT201600467B (it) 2017-03-08
AU2012346133B2 (en) 2016-10-06
HUE032288T2 (hu) 2017-09-28
US10717721B2 (en) 2020-07-21
CN111662330B (zh) 2023-05-12
JP2014507446A (ja) 2014-03-27
CN106518924B (zh) 2019-10-08
CA2850644A1 (en) 2013-06-06
CR20140312A (es) 2014-08-27
PH12014501199A1 (en) 2014-09-08
MD4539B1 (ro) 2017-12-31
HRP20161708T1 (hr) 2017-02-10
US8895586B2 (en) 2014-11-25
NL301047I2 (nl) 2023-08-01
KR20140103991A (ko) 2014-08-27
US9908907B2 (en) 2018-03-06
WO2013082102A1 (en) 2013-06-06
GEP201706695B (en) 2017-07-10
JP2016147868A (ja) 2016-08-18
CN112961104A (zh) 2021-06-15
US20190177296A1 (en) 2019-06-13
BR112014012878B1 (pt) 2022-05-31
NL301047I1 (es) 2020-06-24
AU2012346133A1 (en) 2014-04-17
HUS2000032I1 (hu) 2020-09-28
IN2014CN04907A (es) 2015-09-18
CY2020017I2 (el) 2020-11-25
US20220401463A1 (en) 2022-12-22
EP2785706A1 (en) 2014-10-08
LTPA2020510I1 (lt) 2020-07-10
AR089019A1 (es) 2014-07-23
MA35836B1 (fr) 2014-12-01
BR112014012878A8 (pt) 2021-06-15
PE20141421A1 (es) 2014-10-03
DK2785706T3 (en) 2016-12-12
JP2015017121A (ja) 2015-01-29
LT2785706T (lt) 2016-12-12
CN106518924A (zh) 2017-03-22
CN104053652A (zh) 2014-09-17
JP6023146B2 (ja) 2016-11-09
KR101979050B1 (ko) 2019-05-15
JP5635708B2 (ja) 2014-12-03
UA115136C2 (uk) 2017-09-25
IL232859A0 (en) 2014-07-31
JO3202B1 (ar) 2018-03-08
HK1199030A1 (zh) 2015-06-19
UY34472A (es) 2013-06-28
US20170050993A1 (en) 2017-02-23
US12071421B2 (en) 2024-08-27
GT201400102A (es) 2015-12-07
CY2020017I1 (el) 2020-11-25
MY165514A (en) 2018-03-28
JP6074083B2 (ja) 2017-02-01
TWI638806B (zh) 2018-10-21
AP2014007729A0 (en) 2014-06-30
IL232859B (en) 2018-01-31
US11312698B2 (en) 2022-04-26
EP2785706B1 (en) 2016-09-14
NZ623746A (en) 2016-07-29
TW201331181A (zh) 2013-08-01
CN106986822A (zh) 2017-07-28
CN112979543B (zh) 2024-09-24
CA2850644C (en) 2020-08-11
ZA201404787B (en) 2015-12-23
SI2785706T1 (sl) 2017-01-31
EA201400624A1 (ru) 2015-01-30
US8426450B1 (en) 2013-04-23
ME02561B (me) 2017-02-20
LTC2785706I2 (lt) 2023-07-10
FR20C1029I1 (fr) 2020-10-02
CY1118416T1 (el) 2017-06-28
CN106986822B (zh) 2020-04-21
CO6990728A2 (es) 2014-07-10
CL2014001280A1 (es) 2014-11-07
EA026553B1 (ru) 2017-04-28
DOP2014000115A (es) 2014-07-15

Similar Documents

Publication Publication Date Title
ES2603958T3 (es) 4-Fenil-piridinas sustituidas para el tratamiento de enfermedades relacionadas con el receptor NK1
AR124662A2 (es) Formulaciones inmunosupresoras
NZ610312A (en) 6-amino-2-phenylamino-1h-benzimidazole-5-carboxamide- derivatives and their use as microsomal prostaglandin e2 synthase-1 inhibitors
RU2014140739A (ru) Соединения на основе имидазо[1, 2-b]пиридазина, композиции таких соединений и способы их применения
BRPI1006812B8 (pt) Forma cristalina de l-malato de n-(4-{[6,7-bis(metiloxi)-quinolin-4-il]oxi}fenil)-n&#39;-(4-fluorfenil)ciclopropano-1,1-dicarboxamida, composições farmacêuticas e usos do mesmo
RU2012144317A (ru) Противоинфекционные соединения
AR058287A1 (es) Derivados de isoquinolina y composicion farmaceutica
WO2008115098A3 (fr) 2,3,4,5-tétrahydro-1h-pyrido[4,3-b]indoles substitués ainsi que procédés de leur fabrication et leur utilisation
JP2013529196A5 (es)
PE20081549A1 (es) Derivados de n-(amino-heteroaril)-1h-pirrolopiridin-2-carboxamida y su preparacion
AR082046A1 (es) Compuesto heterociclico conteniendo nitrogeno y fungicida para el uso en agricultura y jardineria
AR086357A1 (es) Derivados de indazol sustituidos activos como inhibidores de quinasas
RU2014129742A (ru) Производные бензолсульфонамида в качестве модуляторов rorc
AR076435A1 (es) Compuestos de indazoles sustituidos, composiciones farmaceuticas que los contienen y procesos de obtencion de los mismos
ES2571449T3 (es) Derivados de piridazinona herbicidas
AR053195A1 (es) Compuestos inhibidores de dipeptidil peptidasa-iv metodos para preparar los mismos y composiciones farmaceuticas que los contienen como un agente activo
EA201390888A1 (ru) Бензимидазоловые ингибиторы респираторно-синцитиального вируса
NO20084129L (no) Pyridin(3,4-B)Pyrazinoner
AR075447A1 (es) Sales y polimorfos de un compuesto de tetraciclina, metodo de obtencion y composiciones farmaceuticas
WO2008078196A3 (en) Substituted heteroaryl pyridopyrimidone derivatives
MX344276B (es) Compuesto de piperidina novedoso o sal del mismo.
AR054272A1 (es) Derivados de 3- aminopirrilidinas tri, tetra - sustituidos
AR077534A1 (es) Derivados de isoxazol, un proceso para su obtencion, composiciones farmaceuticas que los contienen y su uso en el tratamiento de enfermedades relacionadas con el receptor gaba aalfa5
AR063577A1 (es) Derivados 8- piperidinil - pirimido [1 2 a] pirimidin -6-ona y 8- piperidinil-2- pirimidinil- pirimido [1,2-a] pirimidin -6- ona sustituidos
AR052301A1 (es) Procedimiento de preparacion de un monoclorhidrato. formas cristalinas y composiciones farmaceuticas