AR123791A1 - NOVEL GLP-1 / GIP DUAL AGONISTS - Google Patents

NOVEL GLP-1 / GIP DUAL AGONISTS

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Publication number
AR123791A1
AR123791A1 ARP210102841A ARP210102841A AR123791A1 AR 123791 A1 AR123791 A1 AR 123791A1 AR P210102841 A ARP210102841 A AR P210102841A AR P210102841 A ARP210102841 A AR P210102841A AR 123791 A1 AR123791 A1 AR 123791A1
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AR
Argentina
Prior art keywords
compound
lys
group
absent
attachment
Prior art date
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ARP210102841A
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Spanish (es)
Inventor
Rajamannar Thennati
Vinod Sampatrao Burade
Muthukumaran Natarajan
Dhiren Rameshchandra Joshi
Manish Harendraprasad Gandhi
Chandulal Thakarshibhai Jivani
Abhishek Tiwari
Krunal Harishbhai Soni
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Sun Pharmaceutical Ind Ltd
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Publication date
Application filed by Sun Pharmaceutical Ind Ltd filed Critical Sun Pharmaceutical Ind Ltd
Publication of AR123791A1 publication Critical patent/AR123791A1/en

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La presente invención se refiere a polipéptidos agonistas duales de acción prolongada del péptido similar al glucagón tipo 1 y el polipéptido insulinotrópico dependiente de la glucosa humano (GIP) que pueden ser útiles para tratar la diabetes mellitus tipo 2 (T2D), la diabetes con obesidad, la obesidad y la hiperlipidemia. Reivindicación 1: Un polipéptido o una sal farmacéuticamente aceptable de este que comprende la secuencia de aminoácidos: Y-X¹-E-G-T-F-T-S-D-Y-S-I-X²-L-Xₐₐ₁₅-K-I-A-Xₐₐ₁₉-X³-Xₐₐ₂₁-F-V-Xₐₐ₂₄-W-L-X⁴-A-G-G-P-S-S-G-A-P-P-P-S-X⁵-X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹ (Seq. ID 1) en donde X¹ es Aib, (L)-norvalina o (D)-norvalina; X² se selecciona de Aib, Leu, (D)-Leu, Val, (D)-Val, Ile, (D)-Ile, e isómero L o D de un aminoácido de la fórmula (17), en donde “⁻⁻⁻⁻⁻ ⁻⁻⁻” representa el punto de unión a Leu y R se selecciona de alquilo C₂₋₅, cicloalquilo C₃₋₇, cicloalquilo C₃₋₇-alquilo C₁₋₃-, alquenilo C₃₋₅, alquinilo C₃₋₅, cicloalquenilo C₅₋₇-CH₂-, y haloalquilo C₁₋₃; o R junto con el carbono al cual está unido, forma un anillo de cicloalquilo C₃₋₆; X³ es Gln o Lys; en donde, cuando X³ es Lys, el grupo amino (e amino) de la cadena lateral de la Lys está acilado con una porción: {-U-W-Y-Z en donde U es -C(O)-CH₂-O-(CH₂)₂-O-(CH₂)₂-NH-} en donde } es el punto de unión con el grupo W; W se selecciona de un grupo que consiste en -C(O)-NH-(CH₂)ₚ-NH-], -C(O)-C(CH₃)₂-NH-] y -C(O)-CH₂-O-(CH₂)₂-O-(CH₂)₂-NH-], en donde p es 3 ó 4 y en donde ] es el punto de unión con el grupo Y; Y es -C(O)-(CH₂)₂-CH(COOH)NH-- y -- es el punto de unión con el grupo Z; Z es -C(O)-(CH₂)ₙ-COOH o -C(O)-(CH₂)ₙ-CH₃, en donde n es un número entero de 14 a 20; X⁴ es Leu, Ile o Glu; X⁵ está ausente, es Arg o Lys; en donde cuando X⁵ es Lys, el grupo amino (e amino) de la cadena lateral de la Lys está acilado con una porción: {-U’-W’-Y’-Z’ en donde U’ es -C(O)-CH₂-O-(CH₂)₂-O-(CH₂)₂-NH-} en donde } es el punto de unión con el grupo W’; W’ se selecciona de un grupo que consiste en -C(O)-NH-(CH₂)q-NH-], -C(O)-C(CH₃)₂- NH-] y -C(O)-CH₂-O-(CH₂)₂-O-(CH₂)₂-NH-], en donde q es 3 ó 4 y en donde ] es el punto de unión con el grupo Y’; Y’ es -C(O)-(CH₂)₂-CH(COOH)NH-- y -- es el punto de unión con el grupo Z’; Z’ es -C(O)-(CH₂)ₘ-COOH o -C(O)-(CH₂)ₘ-CH₃ en donde m es un número entero de 14 a 20; X⁶ está ausente o es Lys; X⁷ está ausente o es Lys; X⁸ está ausente o es Lys; X⁹ está ausente o es Lys; X¹⁰ está ausente o es Lys; X¹¹ está ausente o es Lys; Xₐₐ₁₅ es Asp o Glu; Xₐₐ₁₉ es Gln o Ala; Xₐₐ₂₁ es Ala o Glu; Xₐₐ₂₄ es Gln o Asn; en donde el grupo ácido del aminoácido C terminal es un grupo de ácido carboxílico libre o se amida como una amida primaria C-terminal y al menos uno de X³ y X⁵ es Lys; y con la condición de que cuando X¹ es Aib, X² no es Aib. Reivindicación 54: Un polipéptido o una sal farmacéuticamente aceptable de este, seleccionado del grupo que consiste en: Compuesto (1); Compuesto (2); Compuesto (3); Compuesto (4); Compuesto (5); Compuesto (6); Compuesto (7); Compuesto (8); Compuesto (9); Compuesto (10); Compuesto (11); y Compuesto (12); en donde, la Porción A es un compuesto de fórmula (13); la Porción B es un compuesto de fórmula (14); la Porción C es un compuesto de fórmula (15); y la Porción D es un compuesto de fórmula (16).The present invention relates to long-acting dual agonist polypeptides of glucagon-like peptide 1 and human glucose-dependent insulinotropic polypeptide (GIP) that may be useful for treating type 2 diabetes mellitus (T2D), diabetes with obesity , obesity and hyperlipidemia. Sévindicicación 1: A polypeptide or a pharmaceutically acceptable salt of this that includes the amino acid sequence: Y-X¹-E-G-T-F-T-S-D-Y-S-I-X²-L-Xₐₐ₁₅-K-I-A-Xₐₐ₁₉-X³-Xₐₐ₂₁-F-V-Xₐₐ₂₄-W-W-X-X-G-G-P-P-P-P-S-S-G-G-G-G-A-P-P-P-P-P-P-P-P-P-P. -X⁶-X⁷-X⁸-X⁹-X¹⁰-X¹¹ (Seq. ID 1) where X¹ is Aib, (L)-norvaline or (D)-norvaline; X² is selected from Aib, Leu, (D)-Leu, Val, (D)-Val, Ile, (D)-Ile, and L or D isomer of an amino acid of formula (17), wherein ⁻⁻ ⁻⁻⁻ ⁻⁻⁻ represents the point of attachment to Leu and R is selected from C₂₋₅ alkyl, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyl-C₁₋₃-alkyl, C₃₋₅ alkenyl, C₃₋₅ alkynyl, C₅₋₇cycloalkenyl-CH₂-, and haloC₁₋₃alkyl; or R together with the carbon to which it is attached, forms a C₃₋₆ cycloalkyl ring; X³ is Gln or Lys; where, when X³ is Lys, the amino group (e amino) of the Lys side chain is acylated with a moiety: {-U-W-Y-Z where U is -C(O)-CH₂-O-(CH₂)₂- O-(CH₂)₂-NH-} where } is the point of attachment with the group W; W is selected from the group consisting of -C(O)-NH-(CH₂)ₚ-NH-], -C(O)-C(CH₃)₂-NH-], and -C(O)-CH₂- O-(CH₂)₂-O-(CH₂)₂-NH-], where p is 3 or 4 and where ] is the point of attachment to group Y; Y is -C(O)-(CH₂)₂-CH(COOH)NH-- and -- is the point of attachment to the Z group; Z is -C(O)-(CH₂)ₙ-COOH or -C(O)-(CH₂)ₙ-CH₃, where n is an integer from 14 to 20; X⁴ is Leu, Ile or Glu; X⁵ is absent, it is Arg or Lys; where when X⁵ is Lys, the amino group (e amino) of the Lys side chain is acylated with a moiety: {-U-W-Y-Z where U is -C(O) -CH₂-O-(CH₂)₂-O-(CH₂)₂-NH-} where } is the point of attachment with the group W; W is selected from the group consisting of -C(O)-NH-(CH₂)q-NH-], -C(O)-C(CH₃)₂-NH-], and -C(O)-CH₂ -O-(CH₂)₂-O-(CH₂)₂-NH-], where q is 3 or 4 and where ] is the point of attachment with the group Y; Y is -C(O)-(CH₂)₂-CH(COOH)NH-- and -- is the point of attachment with the group Z; Z is -C(O)-(CH₂)ₘ-COOH or -C(O)-(CH₂)ₘ-CH₃ where m is an integer from 14 to 20; X⁶ is absent or is Lys; X⁷ is absent or Lys; X⁸ is absent or Lys; X⁹ is absent or is Lys; X¹⁰ is absent or is Lys; X¹¹ is absent or is Lys; Xₐₐ₁₅ is Asp or Glu; Xₐₐ₁₉ is Gln or Ala; Xₐₐ₂₁ is Ala or Glu; Xₐₐ₂₄ is Gln or Asn; wherein the acid group of the C-terminal amino acid is a free carboxylic acid group or is amid as a C-terminal primary amide and at least one of X³ and X⁵ is Lys; and provided that when X¹ is Aib, X² is not Aib. Claim 54: A polypeptide or a pharmaceutically acceptable salt thereof, selected from the group consisting of: Compound (1); Compound (2); Compound (3); Compound (4); Compound (5); Compound (6); Compound (7); Compound (8); Compound (9); Compound(10); Compound (11); and Compound (12); wherein, Portion A is a compound of formula (13); Portion B is a compound of formula (14); Portion C is a compound of formula (15); and Portion D is a compound of formula (16).

ARP210102841A 2020-10-17 2021-10-14 NOVEL GLP-1 / GIP DUAL AGONISTS AR123791A1 (en)

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IN202021045240 2020-10-17

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AR123791A1 true AR123791A1 (en) 2023-01-11

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