AR077851A1 - Agonistas del tgr5 - Google Patents

Agonistas del tgr5

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Publication number
AR077851A1
AR077851A1 ARP100102942A ARP100102942A AR077851A1 AR 077851 A1 AR077851 A1 AR 077851A1 AR P100102942 A ARP100102942 A AR P100102942A AR P100102942 A ARP100102942 A AR P100102942A AR 077851 A1 AR077851 A1 AR 077851A1
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Argentina
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alkyl
groups
substituted
optionally substituted
independently selected
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ARP100102942A
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Exelixis Inc
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
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    • 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
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    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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    • 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
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    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • 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
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    • 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
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • 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
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
    • C07D233/84—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • 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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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Child & Adolescent Psychology (AREA)
  • Urology & Nephrology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Composiciones de éstos y el uso de los compuestos y composiciones para el tratamiento de enfermedades. También comprende el uso de los compuestos en y para la fabricacion de medicamentos, particularmente para el tratamiento de enfermedades. Asociadas a la perturbacion del metabolismo de los ácidos biliares. Reivindicacion 1: Un compuesto de formula (1) o sal farmacéuticamente aceptable de éste, en donde: X es =N- o =C(R4)-; R1 es RC; o X puede ser =C(RC) solo cuando R1 es fenilo opcionalmente sustituido con uno, dos o tres grupos RC10; RC se selecciona de fenilo, cicloalquilo C5-6, -CH2-fenilo, heteroarilo y alquil C1-4 opcionalmente sustituido con -ORC13, -N(RC13)2 o -S(RC13), en donde el grupo cíclico de RC puede opcionalmente estar sustituido con 1, 2, 3, 4 o 5 grupos RC10, en donde los 1, 2, 3, 4 o 5 grupos RC10 se seleccionan independientemente de RC10A y RC10B, con tal que RC no pueda estar sustituido con más de 2 grupos RC10B, en donde cada RC10A se selecciona independientemente de halo, ciano y alquil C1-4 opcionalmente sustituido con 1 - 3 grupos seleccionados de -OH y halo; cada RC10B se selecciona independientemente de -C(O)NH2, heterocicloalquilo de 5 a 6 miembros, -O-alquil C1-4-RC11, -C(O)ORC12, -OC(O)ORC12 y -O-alquil C1-4 opcionalmente sustituido con -OH o -C(O)OH; RC11 es ciano, nitro, -N(RC12)2, -ORC12, -SRC12, -C(O)RC12, -C(O)ORC12, -C(O)N(RC12)2, -S(O)N(RC12)2 -S(O)2N(RC12)2, -S(O)2RC12, -OC(O)RC12, OC(O)ORC12, -OC(O)N(RC12)2, -N(RC12)C(O)RC12, -N(RC12)C(O)ORC12, -N(RC12)C(O)N(RC12)2, o -N(RC12)C(=NRC12)N(RC12)2; cada RC12 se selecciona independientemente de hidrogeno, alquilo C1-4, y haloalquilo C1-4; cada RC13 se selecciona independientemente de hidrogeno, alquilo C1-4, y haloalquilo C1-4; R2 es -LD-RD1; LD es -[C(R)2]p-Y-[C(R)2]q-; p es 0 o 1; q es 0 o 1; cada R se selecciona independientemente de H, -alquil C1-3, halo, -OH, y -CH2OH; Y es un enlace, -S-, -S(O)2-, -CH(OH)-, -O-, -C(H)=C(H)-, -C(O)-alquil C1-4-, alquil C1-4-S-alquil C1-4-, alquil C1-4-N(RY)-alquil C1-4-, -C(H)(halo)-, -alquil C1-4-S(O)2-, -S(O)2-N(RY)-, -alquil C1-4-O-, o -C(O)-N(RY)-, en donde RY es H, -alquilo C1-4, hidroxilo C1-4 alquil o -CsC-alquil C1-3; RD1 se selecciona de arilo C6-10, -N(H)-fenilo, cicloalquilo, heterocicloalquilo, y heteroarilo, en donde RD1 se sustituye con 1 - 5 grupos RD10 en donde los 1 - 5 grupos RD10 independientemente se seleccionan de los grupos A y los grupos B, con tal que RD1 se sustituye con 1 - 2 grupos B; cada grupo A, cuando se producen, se selecciona independientemente de halo, -CF3, -CN, -NO2, -OH, -O-alquil C1-4- opcionalmente sustituido en el grupo alquilo con 1 - 3 sustituyentes independientemente seleccionados de -OH y halo, y -alquil C1-4 opcionalmente sustituido con 1 - 3 sustituyentes seleccionados independientemente de -OH y halo; cada grupo B se selecciona de -alquil C1-4-N(RD11)RD11B, -C(O)-N(RD11D)RD11, -C(O)-alquil C1-4-QA, -C(O)O-alquil C1-4-QA, -C(O)-heterocicloalquil-RD11, -S(O)2-alquil C1-4-N(RD11B)RD11, -S(O)2-RD11, -S(O)2-N(RD11D)QR, -S(O)2-N(H)C(O)-alquil C1-4-QA, -S(O)2-N(RD11D)C(O)O-alquil C1-4-QA, -S(O)2-N(H)C(O)-N(H)RD11, -S(O)2-heterocicloalquilo-(de 4 a 6 miembros)-alquil C0-4-QA, en donde un carbono del grupo heterocicloalquilo de -S(O)2-heterocicloalquilo-(de 4 a 6 miembros)-alquil C0-4-QA puede sustituirse con RD11D, -S(O)2-alquil C1-4-QA, -O-alquil C1-4-QA sustituirse opcionalmente en el grupo alquilo con 1 o 2 grupos RD11B, -C(O)-N(RD11D)-alquilo C1-6 sustituido en el grupo alquilo con 1 o 2 grupos RD11, heterocicloalquil-QA sustituido opcionalmente con oxo o RD11D, -S(O)2-N(RD11D)RD11, -N(RD11D)-C(O)alquilo C1-4 sustituido en el grupo alquilo con 1 o 2 grupos RD11, -N(H)-C(O)-N(RD11D)alquil C1-3 sustituido en el grupo -alquil C1-3 con RD11,alquilo C1-6 sustituido con 1 o 2 grupos RD11, y -CsC-alquilo C0-3 sustituido con RD11; cada RD11 se selecciona independientemente de cicloalquilo C3-6-QA, alquil C0-6-QA sustituido opcionalmente con halo o COOH, alquil C0-6-heterocicloalquilo (de 5 a 6 miembros)-QA, y un polímero PEG sustituido con QA; RD11B selecciona de QA, H, -OH, -CF3, -N(RD11E)2, -C(O)OH, -O-alquilo C1-4, -S(O)2OH, -C(=NH)-NH2, -N(H)C(=NH)NH2, -C(H)=NC(=NH)NH2, -C(H)=NN(H)C(=NH)NH2, 1,4-diazabiciclo[2,2,2]octanilo, -N(H)C(=NH)-N(H)C(=NH)NH2, -C(O)-alquil C1-3, -O-alquil C1-4-C(O)OH, heteroarilo (de 5 a 6 miembros), alquil C1-4 opcionalmente sustituido con 1 - 3 grupos seleccionados independientemente de halo, -OH, -S(O)2OH, C(O)OH, -NH2, -N[alquil C1-3]3+, 1,4-diazabiciclo[2,2,2]octanilo, y -N(H)C(=NH)NH2, alquil C0-3-heterocicloalquilo (de 5 a 8 miembros) sustituido opcionalmente en el grupo heterocicloalquilo con 1 - 3 RD11, alquil C0-3-cicloalquilo C3-6 opcionalmente sustituido con RD11, y arilo sustituido opcionalmente con 1 - 5 halo; RD11D se selecciona de H, cicloalquilo C3-6, alquil C1-6 opcionalmente sustituido con 1 o 2 sustituyentes seleccionados de -N[alquil C1-3]3+, gem-ciclopropilo, -OH, -C(O)OH, -C(O)O-alquil C1-3, y -C(O)NH2, y -alquilfenilo C1-6 opcionalmente sustituido en el grupo fenilo con alcoxi C1-3, -C(O)OH, o -C(O)O-alquil C1-3; cada RD11E se selecciona independientemente de H, -alquil C1-3, y -haloalquilo C1-3; R4 es H, alquil C1-3 o halo; R5 es -[C(R8)2]-fenilo, -[C(R8)2]-naftalenilo, o -[C(R8)2]-heteroarilo (de 5 a 10 miembros), en donde el heteroarilo se selecciona de benzo[d][1,3]dioxolilo, benzo[d]isoxazol, quinoxalinilo, quinolinilo y 2,3,4a,8a-tetrahidrobenzo[b][1,4]dioxinilo, en donde el grupo cíclico de R5 es sustituido opcionalmente con 1 - 5 grupos RA10, en donde los 1 - 5 grupos RA10 se seleccionan independientemente de RA10A y RA10B, con tal que R5 no pueda estar sustituido con más de 2 grupos RA10B; cada RA10A, cuando se produzcan, se selecciona independientemente de halo, alcoxilo, hidroxilo, -CN, -OCF3, alquilo C1-4 y -NH2; cada RA10B, cuando se produzcan, se selecciona de -O-alquil C1-4-RA11, -S(O)2-NH2, -S(O)2CH3, -N(H)-S(O)2CH3, -S(O)2N(H)-CH3, -C(O)OH, -alquil C1-4-OH, -C(O)NH2, y -alquilo C1-4 sustituido con 1 - 3 grupos seleccionados de -OH y halo; RA11 se selecciona de -C(O)OH, heterocicloalquilo de 5 a 6 miembros, halogeno, ciano, nitro, alquilo C1-4, -N(RA12)2, -ORA12, -SRA12, -N(ORA12)RA12, -C(O)RA12, -C(O)ORA12, -C(O)N(RA12)2, -N(RA12)S(O)RA12, -N(RA12)S(O)2RA12, -S(O)2N(RA12)2, -S(O)N(RA12)2, -S(O)2N(RA12), -S(O)2RA12, -OC(O)RA12, -OC(O)ORA12, -OC(O)N(RA12)2, -N(RA12)C(O)RA12, N(RA12)S(O)2RA12, -N(RA12)C(O)ORA12, -N(RA12)C(O)N(RA12)2, -N(RA12)C(=NRA12)N(RA12)2, y heteroarilo, en donde cada RA12 es independientemente hidrogeno, -alquil C1-4 o, haloalquilo C1-4; cada R8 es independientemente hidrogeno, halogeno o metilo, o ambos R8 tomados en conjunto con el carbono al cual ambos están unidos forman un cicloalquilo C3-6 o un heterocicloalquilo (de 3 a 6 miembros); QA es QL o QR; QL es -N[alquil C1-3]3+ en donde un grupo alquilo de -N[alquil C1-3]3+ es sustituido opcionalmente con -alquil C0-6-S(O)2OH; QR se selecciona del grupo de formulas (2); RQA es alquilo C1-6; RQB es alquil C1-6 opcionalmente sustituido con -C(O)OH; y RQC es H, -OH, alquil C0-6-C(O)OH o alquil C1-6.
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