AR123700A1 - Preparación de derivados de benzoimidazolona como nuevos inhibidores de la diacilglicerol o-aciltransferasa 2 - Google Patents

Preparación de derivados de benzoimidazolona como nuevos inhibidores de la diacilglicerol o-aciltransferasa 2

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Publication number
AR123700A1
AR123700A1 ARP210102766A ARP210102766A AR123700A1 AR 123700 A1 AR123700 A1 AR 123700A1 AR P210102766 A ARP210102766 A AR P210102766A AR P210102766 A ARP210102766 A AR P210102766A AR 123700 A1 AR123700 A1 AR 123700A1
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alkyl
independently selected
substituted
unsubstituted
cycloalkyl
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ARP210102766A
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English (en)
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Yeon Lim
- Ashley Eric R Hee
Jianming Bao
Chen Cheng
James P Roane
Emma Helen Southgate
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Merck Sharp & Dohme
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Publication of AR123700A1 publication Critical patent/AR123700A1/es

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic 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
    • A61K31/41641,3-Diazoles
    • A61K31/41841,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/04Anorexiants; Antiobesity agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D235/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26Oxygen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic 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
    • C07D405/02Heterocyclic 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 two hetero rings
    • C07D405/12Heterocyclic 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 two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic 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
    • C07D417/14Heterocyclic 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Neurology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Biomedical Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Child & Adolescent Psychology (AREA)
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  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

Se inventan compuestos de fórmula [1] y sales farmacéuticamente aceptables, ésteres y profármacos de los mismos, que son inhibidores de DGAT2. También se proporcionan métodos de preparación de compuestos de fórmula [1], composiciones farmacéuticas que comprenden compuestos de fórmula [1] y métodos de uso de estos compuestos para tratar la esteatosis hepática, esteatohepatitis no alcohólica (EHNA), fibrosis, diabetes mellitus de tipo 2, obesidad, hiperlipidemia, hipercolesterolemia, ateroesclerosis, declive cognitivo, demencia, enfermedades cardiorrenales tales como enfermedades renales crónicas e insuficiencia cardíaca y enfermedades y afecciones relacionadas, que comprenden administrar un compuesto de fórmula [1] a un paciente que lo necesita. Reivindicación 1: Un compuesto de fórmula [1], o una sal farmacéuticamente aceptable del mismo en donde: X, Y y Z se seleccionan independientemente entre N o C(R⁵); R¹ es (1) fenilo sin sustituir o sustituido con 1, 2 ó 3 R⁶, o (2) heteroarilo de 5 ó 6 miembros que contiene 1, 2, 3 ó 4 heteroátomos seleccionados independientemente entre N, O y S, en donde el heteroarilo está sin sustituir o sustituido con 1, 2 ó 3 R⁶, o (3) heteroarilo condensado de 8 a 10 miembros que contiene 1, 2, 3 heteroátomos seleccionados independientemente entre N, O y S, en donde el heteroarilo está sin sustituir o sustituido con 1, 2 ó 3 R⁶; R² es (1) fenilo sin sustituir o sustituido con 1, 2 ó 3 R⁷, (2) heteroarilo de 5 ó 6 miembros que contiene 1, 2 ó 3 heteroátomos seleccionados independientemente entre N, O y S, en donde el heteroarilo está sin sustituir o sustituido con 1, 2 ó 3 R⁷, (3) alquilo C₁₋₆ sin sustituir u opcionalmente monosustituido o disustituido con halógeno, OH, CF₃ o CN, (4) cicloalquilo (C₃₋₆) sin sustituir u opcionalmente monosustituido o disustituido con alquilo C₁₋₃, halógeno, OH, CF₃ o -CN, (5) -alquil (C₃₋₆)C(O)NH₂, (6) heterociclilo de 4 a 6 miembros que contiene 1 ó 2 heteroátomos seleccionados independientemente entre N, O y S en donde el heterociclilo está sin sustituir o sustituido con 1, 2 ó 3 R⁷, (7) -CH₂-arilo sin sustituir o sustituido con 1, 2 ó 3 R⁷, (8) -SO₂alquilo (C₁₋₆) sin sustituir o sustituido con 1, 2 ó 3 R⁷, o (9) -SO₂-arilo sin sustituir o sustituido con 1, 2 ó 3 R⁷; R³ es (1) heterociclilo de 4 a 7 miembros que contiene 1, 2 ó 3 heteroátomos seleccionados independientemente entre N, O y S, (2) heteroarilo de 5 ó 6 miembros que contiene 1, 2 ó 3 heteroátomos seleccionados independientemente entre N, O y S, (3) -alquil (C₁₋₆)-heteroarilo, en donde el heteroarilo es un heteroarilo de 5 ó 6 miembros que contiene 1, 2 ó 3 heteroátomos seleccionados independientemente entre N, O y S, (4) -alquil(C₁₋₆)-arilo, (5) -alquil (C₁₋₆)-heterociclilo, en donde el heterociclilo es un anillo de 3 a 6 miembros que contiene 1 ó 2 heteroátomos seleccionados independientemente entre N, O y S, (6) -alquilo (C₁₋₆), (7) -cicloalquilo (C₃₋₆), (8) -hidroxialquilo (C₁₋₆), (9) -alquil (C₁₋₆)-S(O)₂-NR⁸ᵃR⁸ᵇ, (10) -alquil (C₁₋₆)-S(O)₂-alquilo (C₁₋₃), en donde cada arilo, arilo condensado, heteroarilo, cicloalquilo o heterociclilo está sin sustituir o sustituido con 1, 2 ó 3 R⁹, y en donde cada alquilo está sin sustituir o sustituido con 1, 2 ó 3 R¹⁰; R⁴ es (1) hidrógeno, (2) alquilo (C₁₋₃), o R³ y R⁴ se combinan junto con el átomo de nitrógeno al que están unidos para formar un anillo heterociclilo mono- o bicíclico que contiene 1 ó 2 heteroátomos seleccionados independientemente entre N, O y S, en donde el anillo heterociclilo está sin sustituir o sustituido con 1, 2 ó 3 R¹¹; cuando está presente, cada R⁵ se selecciona entre (1) hidrógeno, (2) alquilo (C₁₋₆), (3) cicloalquilo (C₃₋₆), (4) haloalquilo (C₁₋₆), (5) ciano, (6) halógeno; cuando está presente, cada R⁶ se selecciona independientemente entre (1) ciano, (2) halógeno, (3) -O-alquilo C₁₋₆, (4) cicloalquilo (C₃₋₆), opcionalmente sustituido con halógeno, alquilo C₁₋₃, haloalquilo C₁₋₆ u OH, (5) -C(=O)NH₂, (6) -O-cicloalquilo (C₃₋₆) en donde el cicloalquilo está opcionalmente sustituido con halógeno, alquilo C₁₋₃ u OH, (7) hidroxi, (8) N(R¹¹)₂, (9) haloalquil (C₁₋₆)-, (10) -O-haloalquil (C₁₋₆)-, (11) -SO₂alquilo (C₁₋₆), (12) -SO₂NHalquilo (C₁₋₆), (14) -S-alquilo C₁₋₆, (15) N(R¹¹)C(O)R¹¹, (16) -S-haloalquilo C₁₋₆, o (17) alquilo (C₁₋₆); cuando está presente, cada R⁷ se selecciona independientemente entre (1) alquilo (C₁₋₃), (2) halógeno, (3) alcoxi (C₁₋₆)-, (4) haloalquil (C₁₋₆)-, o (5) hidroxi; cuando están presentes, R⁸ᵃ y R⁸ᵇ se seleccionan independientemente entre (1) hidrógeno, (2) alquilo (C₁₋₃), o (3) cicloalquilo (C₃₋₇); cuando está presente, cada R⁹ se selecciona independientemente entre (1) alquilo (C₁₋₃), (2) haloalquil (C₁₋₃)-, (3) oxo, (4) cicloalquilo (C₃₋₆), (5) N(R¹¹)₂, (6) hidroxi, (7) alcoxil (C₁₋₃)-, (8) ciano, o (9) halógeno; cuando está presente, R¹⁰ se selecciona independientemente entre (1) alcoxi (C₁₋₃)-, (2) hidroxi, (3) halógeno, (4) haloalquil (C₁₋₃)-, o (5) N(R¹¹)₂; R¹¹, cuando está presente, es independientemente (1) hidrógeno, o (2) alquilo (C₁₋₃).
ARP210102766A 2020-10-08 2021-10-06 Preparación de derivados de benzoimidazolona como nuevos inhibidores de la diacilglicerol o-aciltransferasa 2 AR123700A1 (es)

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EP (1) EP4225739A1 (es)
JP (1) JP2023545741A (es)
KR (1) KR20230084258A (es)
CN (1) CN116685577A (es)
AR (1) AR123700A1 (es)
AU (1) AU2021356589A1 (es)
CA (1) CA3195014A1 (es)
CL (1) CL2023000997A1 (es)
CO (1) CO2023004365A2 (es)
CR (1) CR20230159A (es)
DO (1) DOP2023000069A (es)
EC (1) ECSP23033936A (es)
IL (1) IL301791A (es)
MX (1) MX2023003842A (es)
PE (1) PE20240216A1 (es)
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US20240254114A1 (en) 2022-12-02 2024-08-01 Merck Sharp & Dohme Llc Preparation of fused azole derivatives as novel diacylglyceride 0-acyltransferase 2 inhibitors

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US11976061B2 (en) 2024-05-07
ECSP23033936A (es) 2023-06-30
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CN116685577A (zh) 2023-09-01
KR20230084258A (ko) 2023-06-12
PE20240216A1 (es) 2024-02-16
CL2023000997A1 (es) 2023-10-06
MX2023003842A (es) 2023-04-14
WO2022076495A1 (en) 2022-04-14
JP2023545741A (ja) 2023-10-31
EP4225739A1 (en) 2023-08-16
AU2021356589A1 (en) 2023-05-25
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