AR084408A1 - Compuestos de purina y 7-deazapurina substituidos - Google Patents

Compuestos de purina y 7-deazapurina substituidos

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Publication number
AR084408A1
AR084408A1 ARP110104537A ARP110104537A AR084408A1 AR 084408 A1 AR084408 A1 AR 084408A1 AR P110104537 A ARP110104537 A AR P110104537A AR P110104537 A ARP110104537 A AR P110104537A AR 084408 A1 AR084408 A1 AR 084408A1
Authority
AR
Argentina
Prior art keywords
alkyl
cycloalkyl
aryl
halo
alkynyl
Prior art date
Application number
ARP110104537A
Other languages
English (en)
Inventor
Richard Cheswort
Kevin W Kuntz
Victoria M Richon
Edward J Olhava
Roy M Pollock
Scoot R Daigle
Original Assignee
Epizyme Inc
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
Application filed by Epizyme Inc filed Critical Epizyme Inc
Publication of AR084408A1 publication Critical patent/AR084408A1/es

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • 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
    • 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
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/14—Pyrrolo-pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/167—Purine radicals with ribosyl as the saccharide radical

Abstract

La presente se refiere a compuestos de purina y 7-deazapurina substituidos. La presente también se refiere a composiciones farmacéuticas que contienen estos compuestos y a métodos para tratar trastornos en los cuales la metilación de proteínas mediada por DOT1 juega un rol, tales como cáncer y trastornos neurológicos, mediante la administración de estos compuestos y composiciones farmacéuticas a sujetos que lo necesitan.Reivindicación 1: Un compuesto de fórmula (1) o su N-óxido o una sal farmacéuticamente aceptable de los mismos, donde: A es O ó CH2; Q es H, NH2, NHRb, NRbRc, OH, Rb, u ORb, donde cada uno de Rb y Rc es independientemente alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 7miembros, heteroarilo de 5 a 10 miembros o -M1-T1, donde M1 es una ligadura o un grupo de enlace alquilo C1-6 opcionalmente substituido con halo, ciano, hidroxilo o alcoxilo C1-6 y T1 es cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 6 miembros o heteroarilo de 5 a 10 miembros, o Rb y Rc, conjuntamente con el átomo de N al cual están unidos, forman un heterocicloalquilo de 4 a 7 miembros que tiene 0 ó 1 heteroátomos adicionales al átomo de N opcionalmente substituidos con alquilo C1-6, alquenilo C2-6, alquinilo C2-6, halo, hidroxilo, carboxilo, C(O)OH, C(O)O-alquilo C1-6, OC(O)-alquilo C1-6, ciano, alcoxilo C1-6, amino, mono-alquil C1-6amino, di-alquil C1-6amino, cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 6 miembros o heteroarilo de 5 a 6 miembros, y cada uno de Rb, Rc y T1 está opcionalmente substituido con uno o más substituyentes seleccionados del grupo formado por alquilo C1-6, alquenilo C2-6, alquinilo C2-6, halo, hidroxilo, carboxilo, ciano, alcoxilo C1-6, amino, mono-alquil C1-6amino, dialquil C1-6amino, cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 6 miembros y heteroarilo de 5 a 6 miembros; X es N o CRx, donde Rx es H, halo, hidroxilo, carboxilo, ciano o RS1, siendo RS1 amino, alcoxilo C1-6, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 6 miembros o heteroarilo de 5 a 6 miembros, y estando RS1 opcionalmente substituido con uno o más substituyentes seleccionados del grupo formado por halo, hidroxilo, carboxilo, ciano, alcoxilo C1-6, amino, mono-alquil C1-6amino, di-alquil C1-6amino, cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 6 miembros y heteroarilo de 5 a 6 miembros; Y es H, Rd, SO2Rd o CORd, siendo Rd alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 6 miembros o heteroarilo de 5 a 6 miembros, y estando Rd opcionalmente substituido con uno o más substituyentes seleccionados, del grupo formado por alquilo C1-6, alquenilo C2-6, alquinilo C2-6, halo, hidroxilo, carboxilo, ciano, alcoxilo C1-6, alquilsulfonilo C1-6, amino, mono-alquil C1-6amino, dialquil C1-6amino, cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 6 miembros, y heteroarilo de 5 a 6 miembros, y estando cada uno de los substituyentes sobre Rd cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 6 miembros y heteroarilo de 5 a 6 miembros adicionalmente opcionalmente substituido con alquilo C1-6, alquenilo C2-6, alquinilo C2-6, halo, hidroxilo, carboxilo, C(O)OH, C(O)O-alquilo C1-6, OC(O)-alquilo C1-6, ciano, alcoxilo C1-6, amino, mono-alquil C1-6amino, di-alquil C1-6amino, cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 6 miembros o heteroarilo de 5 a 6 miembros; cada uno de R1 y R2 es independientemente H, halo, hidroxilo, carboxilo, ciano, RS2, siendo RS2 amino, alcoxilo C1-6, alquilo C1-6, alquenilo C2-6 o alquinilo C2-6 y estando cada RS2 opcionalmente substituido con uno o más substituyentes seleccionados del grupo formado por halo, hidroxilo, carboxilo, ciano, alcoxilo C1-6, amino, mono-alquil C1-6amino, di-alquil C1-6amino, cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 6 miembros y heteroarilo de 5 a 6 miembros; cada uno de Re, Rf, Rg y Rh, es independientemente -M2-T2, donde M2 es una ligadura, SO2, SO, S, CO, CO2, O, un grupo de enlace O-alquilo C1-4, un grupo de enlace alquilo C1-4, NH, o N(Rt), siendo Rt alquilo C1-6, y T2 es H, halo o RS4, siendo RS4 alquilo C1-6, alquenilo C2-6, alquinilo C2-6, cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 8 miembros o heteroarilo de 5 a 10 miembros, y estando cada uno del enlace O-alquilo C1-4, enlace alquilo C1-4, Rt y RS4 opcionalmente substituido con uno o más substituyentes seleccionados del grupo formado por halo, hidroxilo, carboxilo, ciano, alquilo C1-6, alquenilo C2-6, alquinilo C2-6, alcoxilo C1-6, amino, mono-alquil C1-6amino, di-alquil C1-6amino, cicloalquilo C3-8, arilo C6-10, heterocicloalquilo de 4 a 6 miembros y heteroarilo de 5 a 6 miembros; y m es 0, 1 ó 2.
ARP110104537A 2010-12-03 2011-12-05 Compuestos de purina y 7-deazapurina substituidos AR084408A1 (es)

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US (5) US8580762B2 (es)
EP (1) EP2646444B1 (es)
JP (1) JP5931905B2 (es)
KR (1) KR101923746B1 (es)
CN (1) CN103391939B (es)
AR (1) AR084408A1 (es)
AU (1) AU2011336415B2 (es)
BR (1) BR112013013659B8 (es)
CA (1) CA2819648C (es)
DK (1) DK2646444T3 (es)
ES (1) ES2577027T3 (es)
HK (1) HK1189596A1 (es)
HR (1) HRP20160655T1 (es)
IL (1) IL226651A (es)
MX (1) MX2013006251A (es)
RU (1) RU2606514C2 (es)
SI (1) SI2646444T1 (es)
TW (1) TWI537271B (es)
WO (1) WO2012075381A1 (es)

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