AR111781A1 - Ligadores peptídicos y conjugados de criptoficina, su preparación y su uso terapéutico - Google Patents

Ligadores peptídicos y conjugados de criptoficina, su preparación y su uso terapéutico

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AR111781A1
AR111781A1 ARP180101213A ARP180101213A AR111781A1 AR 111781 A1 AR111781 A1 AR 111781A1 AR P180101213 A ARP180101213 A AR P180101213A AR P180101213 A ARP180101213 A AR P180101213A AR 111781 A1 AR111781 A1 AR 111781A1
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och2ch2
na7c
ch2ch2o
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Sanofi Sa
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    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
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    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • A61K47/6829—Bacterial toxins, e.g. diphteria toxins or Pseudomonas exotoxin A
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    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic 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
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    • C07D405/06—Heterocyclic 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 carbon chain containing only aliphatic carbon atoms
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    • C—CHEMISTRY; METALLURGY
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052—Val-amino acid

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Abstract

La revelación también se refiere a cargas útiles de criptoficina, así como a conjugados de criptoficina, a composiciones que los contienen y a su uso terapéutico, en especial como agentes anticáncer. La presente también se refiere al proceso para preparar estos conjugados. Reivindicación 1: Compuestos de la fórmula (1): RCG¹-L-P (1), en donde RCG¹ representa un grupo químico reactivo que es reactivo respecto de un grupo químico presente en un polipéptido como un anticuerpo; P representa un átomo de hidrógeno, -OH o un O activado; L representa un ligador de la fórmula (2), en donde: L¹ es de la fórmula (3), en donde cuando P representa un átomo de hidrógeno, entonces x = 0 ó 1 e y = 1 y z = 0; cuando P representa -OH, entonces x = y = z = 0; cuando P representa un O activado, entonces x = 1 e y = z = 0 o x = y = z = 1; J¹, J², J³ y J⁴ se seleccionan, de modo independiente entre sí, de CA¹ y N; ALK representa un grupo alquileno C₁₋₁₂, por ejemplo, alquileno C₁₋₆, como de la forma -(CH₂)ₙ-, siendo n un número entero que va de 1 a 12 y, por ejemplo, que va de 1 a 6; A¹, A², A³, A⁴, A⁵ y A⁶ representan, de modo independiente entre sí, un átomo de hidrógeno o un grupo alquilo C₁₋₆, como un átomo de hidrógeno o un grupo metilo; (AA)ʷ representa una secuencia de AAₛ sustituido con w o aminoácidos no sustituidos AAₙₛ, conectados juntos por medio de enlaces peptídicos; w representa un número entero que va de 1 a 12, por ejemplo, de 1 a 6, como 2 ó 3; si (AA)ʷ contiene al menos un aminoácido sustituido AAₛ, entonces L² representa un enlace simple, un grupo alquilo C₁₋₆, un grupo alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo alquil C₁₋₆-(OCH₂CH₂)ⁱ-O-alquilo C₁₋₆, un grupo (CH₂CH₂O)ⁱ-alquilo C₁₋₆, un grupo CH(SO₃H)-alquilo C₁₋₆, un grupo alquil C₁₋₆-CH(SO₃H), un grupo alquil C₁₋₆-ciclohexilo, un grupo C(=O)-alquilo C₁₋₆, un grupo C(=O)-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo C(=O)-alquil C₁₋₆-(OCH₂CH₂)ⁱ-O-alquilo C₁₋₆, un grupo C(=O)-(CH₂CH₂O)ⁱ-alquilo C₁₋₆, un grupo C(=O)-CH(SO₃H)-alquilo C₁₋₆, un grupo C(=O)-alquil C₁₋₆-CH(SO₃H), un grupo C(=O)-alquil C₁₋₆-ciclohexilo, un grupo NA⁸-alquilo C₁₋₆, un grupo NA⁸-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo NA⁸-alquil C₁₋₆-(OCH₂CH₂)ⁱ-O-alquilo C₁₋₆, un grupo NA⁸-(CH₂CH₂O)ⁱ-alquilo C₁₋₆, un grupo NA⁸-alquil C₁₋₆-CH(SO₃H), un grupo C(=O)-NA⁸-alquilo C₁₋₆, un grupo C(=O)-NA⁸-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo C(=O)-NA⁸-alquil C₁₋₆-(OCH₂CH₂)ⁱ-O-alquilo C₁₋₆, un grupo C(=O)-NA⁸-(CH₂CH₂O)ⁱ-alquilo C₁₋₆, un grupo C(=O)-NA⁸-alquil C₁₋₆-CH(SO₃H), un grupo NA⁷-alquilo C₁₋₆, un grupo alquil C₁₋₆-NA⁷, un grupo NA⁷-(CH₂CH₂O)ⁱ-alquilo C₁₋₆, un grupo NA⁷-arilo, un grupo NA⁷-heteroarilo, un grupo alquil C₁₋₆-NA⁷C(=O)-alquilo C₁₋₆, un grupo alquil C₁₋₆-NA⁷C(=O)-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo alquil C₁₋₆-C(=O)NA⁷-alquilo C₁₋₆, un grupo alquil C₁₋₆-C(=O)NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo alquil C₁₋₆-NA⁷-alquilo C₁₋₆, un grupo alquil C₁₋₆-NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo alquil C₁₋₆-(OCH₂CH₂)ⁱ-NA⁷-alquilo C₁₋₆, un grupo C(=O)-NA⁷-alquilo C₁₋₆, un grupo C(=O)-alquil C₁₋₆-NA⁷, un grupo C(=O)-NA⁷-(CH₂CH₂O)ⁱ-alquilo C₁₋₆, un grupo C(=O)-NA⁷-arilo, un grupo C(=O)-NA⁷-heteroarilo, un grupo C(=O)-alquil C₁₋₆-NA⁷C(=O)-alquilo C₁₋₆, un grupo C(=O)-alquil C₁₋₆-NA⁷C(=O)-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo C(=O)-alquil C₁₋₆-C(=O)NA⁷-alquilo C₁₋₆, un grupo C(=O)-alquil C₁₋₆-C(=O)NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo C(=O)-alquil C₁₋₆-NA⁷-alquilo C₁₋₆, un grupo C(=O)-alquil C₁₋₆-NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo C(=O)-alquil C₁₋₆-(OCH₂CH₂)ⁱ-NA⁷-alquilo C₁₋₆, un grupo NA⁸-alquil C₁₋₆-NA⁷, un grupo NA⁸-alquil C₁₋₆-NA⁷C(=O)-alquilo C₁₋₆, un grupo NA⁸-alquil C₁₋₆-NA⁷C(=O)-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo NA⁸-alquil C₁₋₆-C(=O)NA⁷-alquilo C₁₋₆, un grupo NA⁸-alquil C₁₋₆-C(=O)NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo NA⁸-alquil C₁₋₆-NA⁷-alquilo C₁₋₆, un grupo NA⁸-alquil C₁₋₆-NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo NA⁸-alquil C₁₋₆-(OCH₂CH₂)ⁱ-NA⁷-alquilo C₁₋₆, un grupo C(=O)-NA⁸-alquil C₁₋₆-NA⁷, un grupo C(=O)-NA⁸-alquil C₁₋₆-NA⁷C(=O)-alquilo C₁₋₆, un grupo C(=O)-NA⁸-alquil C₁₋₆-NA⁷C(=O)-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo C(=O)-NA⁸-alquil C₁₋₆-C(=O)NA⁷-alquilo C₁₋₆, un grupo C(=O)-NA⁸-alquil C₁₋₆-C(=O)NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo C(=O)-NA⁸-alquil C₁₋₆-NA⁷-alquilo C₁₋₆, un grupo C(=O)-NA⁸-alquil C₁₋₆-NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ o un grupo C(=O)-NA⁸-alquil C₁₋₆-(OCH₂CH₂)ⁱ-NA⁷-alquilo C₁₋₆; si (AA)ʷ representa una secuencia de aminoácidos no sustituidos con w AAₙₛ, entonces L² representa un grupo NA⁷-alquilo C₁₋₆, un grupo alquil C₁₋₆-NA⁷, un grupo NA⁷-(CH₂CH₂O)ⁱ-alquilo C₁₋₆, un grupo NA⁷-arilo, un grupo NA⁷-heteroarilo, un grupo alquil C₁₋₆-NA⁷C(=O)-alquilo C₁₋₆, un grupo alquil C₁₋₆-NA⁷C(=O)-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo alquil C₁₋₆-C(=O)NA⁷-alquilo C₁₋₆, un grupo alquil C₁₋₆-C(=O)NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo alquil C₁₋₆-NA⁷-alquilo C₁₋₆, un grupo alquil C₁₋₆-NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo alquil C₁₋₆-(OCH₂CH₂)ⁱ-NA⁷-alquilo C₁₋₆, un grupo C(=O)-NA⁷-alquilo C₁₋₆, un grupo C(=O)-alquil C₁₋₆-NA⁷, un grupo C(=O)-NA⁷-(CH₂CH₂O)ⁱ-alquilo C₁₋₆, un grupo C(=O)-NA⁷-arilo, un grupo C(=O)-NA⁷-heteroarilo, un grupo C(=O)-alquil C₁₋₆-NA⁷C(=O)-alquilo C₁₋₆, un grupo C(=O)-alquil C₁₋₆-NA⁷C(=O)-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo C(=O)-alquil C₁₋₆-C(=O)NA⁷-alquilo C₁₋₆, un grupo C(=O)-alquil C₁₋₆-C(=O)NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo C(=O)-alquil C₁₋₆-NA⁷-alquilo C₁₋₆, un grupo C(=O)-alquil C₁₋₆-NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo C(=O)-alquil C₁₋₆-(OCH₂CH₂)ⁱ-NA⁷-alquilo C₁₋₆, un grupo NA⁸-alquil C₁₋₆-NA⁷, un grupo NA⁸-alquil C₁₋₆-NA⁷C(=O)-alquilo C₁₋₆, un grupo NA⁸-alquil C₁₋₆-NA⁷C(=O)-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo NA⁸-alquil C₁₋₆-C(=O)NA⁷-alquilo C₁₋₆, un grupo NA⁸-alquil C₁₋₆-C(=O)NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo NA⁸-alquil C₁₋₆-NA⁷-alquilo C₁₋₆, un grupo NA⁸-alquil C₁₋₆-NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo NA⁸-alquil C₁₋₆-(OCH₂CH₂)ⁱ-NA⁷-alquilo C₁₋₆, un grupo C(=O)-NA⁸-alquil C₁₋₆-NA⁷, un grupo C(=O)-NA⁸-alquil C₁₋₆-NA⁷C(=O)-alquilo C₁₋₆, un grupo C(=O)-NA⁸-alquil C₁₋₆-NA⁷C(=O)-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo C(=O)-NA⁸-alquil C₁₋₆-C(=O)NA⁷-alquilo C₁₋₆, un grupo C(=O)-NA⁸-alquil C₁₋₆-C(=O)NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ, un grupo C(=O)-NA⁸-alquil C₁₋₆-NA⁷-alquilo C₁₋₆, un grupo C(=O)-NA⁸-alquil C₁₋₆-NA⁷-alquil C₁₋₆-(OCH₂CH₂)ⁱ o un grupo C(=O)-NA⁸-alquil C₁₋₆-(OCH₂CH₂)ⁱ-NA⁷-alquilo C₁₋₆; donde A⁷ representa una cadena hidrocarbonada C₁₋₁₆₀ opcionalmente sustituida, lineal o ramificada, saturada o insaturada, en donde opcionalmente al menos una unidad de metileno está independientemente reemplazada por -NHC(=O)-, -N(alquil)C(=O)-, -C(=O)NH-C(=O)N(alquilo)-, -OC(=O)-, -C(=O)O-, -OC(=O)O-, -CH(OH)-, -CH(SO₃H)-, -O-, -C(=O)-, -S(=O)-, -S(=O)₂-, -NHS(=O)₂-, -N(alquil)S(=O)₂-, -S(=O)₂NH-, -S(=O)₂N(alquilo)-, -P(=O)(OH)-, -P(=O)(OH)O-, -O-P(=O)(OH)-, -O-P(=O)(OH)-O- o un grupo heterocicloalquilo opcionalmente sustituido con al menos un sustituyente, igual o diferente, seleccionado de -OH, -O-alquilo, -alquilo, un átomo de halógeno, -NH₂, -NH-alquilo y -N(alquilo)₂, entendiendo que cada A⁷ que comprende una función SO₃H puede estar bajo formas salinas tales como sales de metal alcalino, por ejemplo, sales de sodio (SO₃⁻ ⁺Na); A⁸ representa un átomo de hidrógeno o un grupo alquilo C₁₋₆, por ejemplo, un átomo de hidrógeno o un grupo metilo; i representa un número entero que va de 1 a 50, por ejemplo, que va de 1 a 35.
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