AR106314A1 - COMPUESTOS DE ESPIRO[3H-INDOL-3,2-PIRROLIDIN]-2(1H)-ONA Y DERIVADOS COMO INHIBIDORES DE MDM2 - p53 - Google Patents
COMPUESTOS DE ESPIRO[3H-INDOL-3,2-PIRROLIDIN]-2(1H)-ONA Y DERIVADOS COMO INHIBIDORES DE MDM2 - p53Info
- Publication number
- AR106314A1 AR106314A1 ARP160103098A ARP160103098A AR106314A1 AR 106314 A1 AR106314 A1 AR 106314A1 AR P160103098 A ARP160103098 A AR P160103098A AR P160103098 A ARP160103098 A AR P160103098A AR 106314 A1 AR106314 A1 AR 106314A1
- Authority
- AR
- Argentina
- Prior art keywords
- alkyl
- haloalkyl
- aryl
- independently
- independently selected
- Prior art date
Links
- 239000012819 MDM2-Inhibitor Substances 0.000 title 1
- VTDPFQIZFVORRI-UHFFFAOYSA-N spiro[1h-indole-3,2'-pyrrolidine]-2-one Chemical compound O=C1NC2=CC=CC=C2C11CCCN1 VTDPFQIZFVORRI-UHFFFAOYSA-N 0.000 title 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 abstract 12
- 125000001424 substituent group Chemical group 0.000 abstract 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 10
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 abstract 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 abstract 10
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 abstract 10
- 125000000392 cycloalkenyl group Chemical group 0.000 abstract 10
- 229910052739 hydrogen Inorganic materials 0.000 abstract 10
- 239000001257 hydrogen Substances 0.000 abstract 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 9
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 abstract 9
- 229910052736 halogen Inorganic materials 0.000 abstract 9
- 150000002367 halogens Chemical class 0.000 abstract 9
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 abstract 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 7
- 229910052799 carbon Inorganic materials 0.000 abstract 7
- 125000006714 (C3-C10) heterocyclyl group Chemical group 0.000 abstract 6
- 125000000623 heterocyclic group Chemical group 0.000 abstract 6
- 229910052757 nitrogen Inorganic materials 0.000 abstract 5
- 125000006574 non-aromatic ring group Chemical group 0.000 abstract 5
- 125000001072 heteroaryl group Chemical group 0.000 abstract 4
- 150000001875 compounds Chemical class 0.000 abstract 3
- 150000002431 hydrogen Chemical class 0.000 abstract 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 abstract 2
- 239000000543 intermediate Substances 0.000 abstract 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 abstract 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 abstract 1
- 101100518413 Caenorhabditis elegans orc-2 gene Proteins 0.000 abstract 1
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 abstract 1
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 abstract 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 125000000217 alkyl group Chemical group 0.000 abstract 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 125000001188 haloalkyl group Chemical group 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 230000003993 interaction Effects 0.000 abstract 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 1
- 230000000771 oncological effect Effects 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 abstract 1
- 239000001301 oxygen Substances 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 229910052717 sulfur Chemical group 0.000 abstract 1
- 239000011593 sulfur Chemical group 0.000 abstract 1
Classifications
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- 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
- C07D487/22—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 four or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—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
- A61K31/415—1,2-Diazoles
- A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A—HUMAN NECESSITIES
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- 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
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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- Urology & Nephrology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
La presente solicitud divulga compuestos como inhibidores de la interacción entre MDM2 y p53, composiciones farmacéuticas que contienen compuestos de este tipo, su uso como medicamentos, especialmente, como agentes para el tratamiento y/o la prevención de enfermedades oncológicas e intermediarios sintéticos. Reivindicación 1: Un compuesto caracterizado por la fórmula (1), en donde R¹ es un grupo opcionalmente sustituido con uno o más Rᵇ¹ y/o Rᶜ¹, idénticos o diferentes, seleccionados de C₁₋₆ alquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ haloalquilo, C₃₋₇ cicloalquilo, C₄₋₇ cicloalquenilo, C₆₋₁₀ arilo, heteroarilo de 5 a 10 miembros y heterociclilo de 3 a 10 miembros; cada Rᵇ¹ se selecciona independientemente de -ORᶜ¹, -NRᶜ¹Rᶜ¹, halógeno, -CN, -C(O)Rᶜ¹, -C(O)ORᶜ¹, -C(O)NRᶜ¹Rᶜ¹, -S(O)₂Rᶜ¹, -S(O)₂NRᶜ¹Rᶜ¹, -NHC(O)Rᶜ¹, -N(C₁₋₄ alquil)C(O)Rᶜ¹ y el sustituyente bivalente =O, mientras que =O puede ser únicamente un sustituyente en sistemas de anillos no aromáticos; cada Rᶜ¹, independientemente entre sí, indica hidrógeno o un grupo opcionalmente sustituido con uno o más Rᵈ¹ y/o Rᵉ¹, idénticos o diferentes, seleccionados de C₁₋₆ alquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ haloalquilo, C₃₋₇ cicloalquilo, C₄₋₇ cicloalquenilo, C₆₋₁₀ arilo, heteroarilo de 5 a 10 miembros y heterociclilo de 3 a 10 miembros; cada Rᵈ¹ se selecciona independientemente de -ORᵉ¹, -NRᵉ¹Rᵉ¹, halógeno, -CN, -C(O)Rᵉ¹, -C(O)ORᵉ¹, -C(O)NRᵉ¹Rᵉ¹, -S(O)₂Rᵉ¹, -S(O)₂NRᵉ¹Rᵉ¹, -NHC(O)Rᵉ¹, -N(C₁₋₄ alquil)C(O)Rᵉ¹ y el sustituyente bivalente =O, mientras que =O puede ser únicamente un sustituyente en sistemas de anillos no aromáticos; cada Rᵉ¹, independientemente entre sí, indica hidrógeno o un grupo opcionalmente sustituido con uno o más Rᶠ¹ y/o Rᵍ¹, idénticos o diferentes, seleccionados de C₁₋₆ alquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ haloalquilo, C₃₋₇ cicloalquilo, C₄₋₇ cicloalquenilo, C₆₋₁₀ arilo, heteroarilo de 5 a 10 miembros y heterociclilo de 3 a 10 miembros; cada Rᶠ¹ se selecciona independientemente de -ORᵍ¹, -NRᵍ¹Rᵍ¹, halógeno, -CN, -C(O)Rᵍ¹, -C(O)ORᵍ¹, -C(O)NRᵍ¹Rᵍ¹, -S(O)₂Rᵍ¹, -S(O)₂NRᵍ¹Rᵍ¹, -NHC(O)Rᵍ¹, -N(C₁₋₄ alquil)C(O)Rᵍ¹ y el sustituyente bivalente =O, mientras que =O puede ser únicamente un sustituyente en sistemas de anillos no aromáticos; cada Rᵍ¹ se selecciona independientemente de hidrógeno, C₁₋₆ alquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ haloalquilo, C₃₋₇ cicloalquilo, C₄₋₇ cicloalquenilo, C₆₋₁₀ arilo, heteroarilo de 5 a 10 miembros y heterociclilo de 3 a 10 miembros; R² y R³, cada uno independientemente, se selecciona de hidrógeno, C₆₋₁₀ arilo, heteroarilo de 5 a 10 miembros y heterociclilo de 3 a 10 miembros, en donde C₆₋₁₀ arilo, heteroarilo de 5 a 10 miembros y heterociclilo de 3 a 10 miembros están opcionalmente sustituidos con uno o más, Rᵇ² y/o Rᶜ² idénticos o diferentes; cada Rᵇ² se selecciona independientemente de -ORᶜ², -NRᶜ²Rᶜ², halógeno, -CN, -C(O)Rᶜ², -C(O)ORᶜ², -C(O)NRᶜ²Rᶜ², -S(O)₂Rᶜ², -S(O)₂NRᶜ²Rᶜ², -NHC(O)Rᶜ², -N(C₁₋₄ alquil)C(O)Rᶜ² y el sustituyente bivalente =O, mientras que =O puede ser únicamente un sustituyente en sistemas anulares no aromáticos; cada Rᶜ², independientemente entre sí, indica hidrógeno o un grupo opcionalmente sustituido con uno o más Rᵈ² y/o Rᵉ² idénticos o diferentes seleccionados de C₁₋₆ alquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ haloalquilo, C₃₋₆ cicloalquilo, C₄₋₆ cicloalquenilo, C₆₋₁₀ arilo, heteroarilo de 5 a 10 miembros y heterociclilo de 3 a 10 miembros; cada Rᵈ² se selecciona independientemente de -ORᵉ², -NRᵉ²Rᵉ², halógeno, -CN, -C(O)Rᵉ², -C(O)ORᵉ², -C(O)NRᵉ²Rᵉ², -S(O)₂Rᵉ², -S(O)₂NRᵉ²Rᵉ², -NHC(O)Rᵉ², -N(C₁₋₄ alquil)C(O)Rᵉ² y el sustituyente bivalente =O, mientras que =O puede ser únicamente un sustituyente en sistemas de anillos no aromáticos; cada Rᵉ², independientemente entre sí, indica hidrógeno o un grupo seleccionado de C₁₋₆ alquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ haloalquilo, C₃₋₆ cicloalquilo, C₄₋₆ cicloalquenilo, C₆₋₁₀ arilo, heteroarilo de 5 a 10 miembros y heterociclilo de 3 a 10 miembros; A se selecciona de fenilo y heteroarilo de 5 a 6 miembros si F es carbono o A es heteroarilo de 5 a 6 miembros que contiene nitrógeno si F es nitrógeno; cada R⁴ se selecciona independientemente de Rᵃ⁴ y Rᵇ⁴; cada Rᵃ⁴, independientemente entre sí, es un grupo opcionalmente sustituido con uno o más Rᵇ⁴ y/o Rᶜ⁴, idénticos o diferentes, seleccionados de C₁₋₆ alquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ haloalquilo, C₃₋₇ cicloalquilo, C₄₋₇ cicloalquenilo, C₆₋₁₀ arilo, heteroarilo de 5 a 10 miembros y heterociclilo de 3 a 10 miembros; cada Rᵇ⁴ se selecciona independientemente de -ORᶜ⁴, -NRᶜ⁴Rᶜ⁴, halógeno, -CN, -C(O)Rᶜ⁴, -C(O)ORᶜ⁴, -C(O)NRᶜ⁴Rᶜ⁴, -C(O)NRᵍ⁴ORᶜ⁴, -S(O)₂Rᶜ⁴, -S(O)₂NRᶜ⁴Rᶜ⁴, -NHSO₂Rᶜ⁴, -N(C₁₋₄ alquil)SO₂Rᶜ⁴, -NHC(O)Rᶜ⁴ y -N(C₁₋₄ alquil)C(O)Rᶜ⁴; cada Rᶜ⁴, independientemente entre sí, indica hidrógeno o un grupo opcionalmente sustituido con uno o más Rᵈ⁴ y/o Rᵉ⁴, idénticos o diferentes, seleccionados de C₁₋₆ alquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ haloalquilo, C₃₋₇ cicloalquilo, C₄₋₇ cicloalquenilo, C₆₋₁₀ arilo, heteroarilo de 5 a 10 miembros y heterociclilo de 3 a 10 miembros; cada Rᵈ⁴ se selecciona independientemente de -ORᵉ⁴, -NRᵉ⁴Rᵉ⁴, halógeno, -CN, -C(O)Rᵉ⁴, -C(O)ORᵉ⁴, -C(O)NRᵉ⁴Rᵉ⁴, -C(O)NRᵍ⁴ORᵉ⁴, -S(O)₂Rᵉ⁴, -S(O)₂NRᵉ⁴Rᵉ⁴, -NHC(O)Rᵉ⁴ y -N(C₁₋₄ alquil)C(O)Rᵉ⁴; cada Rᵉ⁴, independientemente entre sí, indica hidrógeno o un grupo opcionalmente sustituido con uno o más Rᶠ⁴ y/o Rᵍ⁴, idénticos o diferentes, seleccionados de C₁₋₆ alquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ haloalquilo, C₃₋₇ cicloalquilo, C₄₋₇ cicloalquenilo, C₆₋₁₀ arilo, heteroarilo de 5 a 10 miembros y heterociclilo de 3 a 10 miembros; cada Rᶠ⁴ se selecciona independientemente de -ORᵍ⁴, -NRᵍ⁴Rᵍ⁴, halógeno, -CN, -C(O)Rᵍ⁴, -C(O)ORᵍ⁴, -C(O)NRᵍ⁴Rᵍ⁴, -C(O)NRᵍ⁴ORᵍ⁴, -S(O)₂Rᵍ⁴, -S(O)₂NRᵍ⁴Rᵍ⁴, -NHC(O)Rᵍ⁴ y -N(C₁₋₄ alquil)C(O)Rᵍ⁴; cada Rᵍ⁴ se selecciona independientemente de hidrógeno, C₁₋₆ alquilo, C₂₋₆ alquenilo, C₂₋₆ alquinilo, C₁₋₆ haloalquilo, C₃₋₇ cicloalquilo, C₄₋₇ cicloalquenilo, C₆₋₁₀ arilo, heteroarilo de 5 a 10 miembros y heterociclilo de 3 a 10 miembros; r indica el número 0, 1, 2 ó 3; n indica el número 1, 2 ó 3; cada R⁷ se selecciona independientemente de halógeno, C₁₋₄ alquilo, -CN, C₁₋₄ haloalquilo, -OC₁₋₄ alquilo y -OC₁₋₄ haloalquilo; q indica el número 0, 1, 2 ó 3; W, X e Y se seleccionan, cada uno independientemente, de -N= y -CH= siempre que el hidrógeno en cada -CH= se pueda reemplazar por un sustituyente R⁷ si está presente y que un máximo de dos W, X e Y puedan ser -N=; V es oxígeno o azufre; D es nitrógeno, E es carbono y F es carbono; o D es carbono, E es nitrógeno y F es carbono; o D es carbono, E es carbono y F es nitrógeno; o una sal de aquel. Reivindicación 16: Intermediarios sintéticos caracterizados por la fórmula (2), en donde R², R³, R⁴, R⁷, A, V, W, X, Y, r y q son como se definen en cualquiera de las reivindicaciones 1 a 14.
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2016
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