WO2019140024A1 - Polythérapie - Google Patents

Polythérapie Download PDF

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Publication number
WO2019140024A1
WO2019140024A1 PCT/US2019/012956 US2019012956W WO2019140024A1 WO 2019140024 A1 WO2019140024 A1 WO 2019140024A1 US 2019012956 W US2019012956 W US 2019012956W WO 2019140024 A1 WO2019140024 A1 WO 2019140024A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
ethoxy
seq
pharmaceutically acceptable
amino
Prior art date
Application number
PCT/US2019/012956
Other languages
English (en)
Inventor
Jorge Alsina-Fernandez
Tamer Coskun
Original Assignee
Eli Lilly And Company
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 Eli Lilly And Company filed Critical Eli Lilly And Company
Publication of WO2019140024A1 publication Critical patent/WO2019140024A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2228—Corticotropin releasing factor [CRF] (Urotensin)
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the disclosure relates to biology and medicine, and more parti clularly it relates to a combination of a urocortin-2 (UCN2) analog with a glucagon analog that agonizes a glucagon receptor, as well as methods of using the same for treating diabetes and chronic kidney disease (CKD).
  • UCN2 urocortin-2
  • CKD chronic kidney disease
  • Also provided herein is a method of treating a diabetes (including T2D) or CKD, where the method includes at least a step of administering to an individual in need thereof, an effective amount of a compound of Formula I (or pharmaceutically acceptable salts thereof) (including, for example, compounds of SEQ ID NO:4 or SEQ ID NO:7) in combination with an effective amount of a compound of Formula II (or pharmaceutically acceptable salts thereof).
  • the methods also can include administering an effective amount of one or more additional therapeutic agents.
  • ECso means a concentration of compound that results in 50% activation of the assay endpoint (e.g cAMP).
  • “in combination with” or“in combination” means administration of the compound of Formula I (or pharmaceutically acceptable salt), with a molecule of Formula II I (or pharmaceutically acceptable salt), simultaneously, or sequentially in any order, or any combination thereof.
  • the two compounds may be administered either as part of the same pharmaceutical composition or in separate pharmaceutical compositions.
  • the compound of Formula I (or pharmaceutically acceptable salt) can be administered prior to, at the same time as, or subsequent to administration of the molecule of Formula II (or pharmaceutically acceptable salt),, or in some combination thereof.
  • ACR refers to urine albumin/urine creatinine ratio
  • “amu” refers to atomic mass unit
  • “Boc” refers to tert- butoxycarbonyl
  • “cAMP” refers to cyclic adenosine monophosphate
  • “DMSO” refers to dimethyl sulfoxide
  • “EIA/RIA” refers to enzyme immunoassay/radioimmunoassay
  • “hr” refers to hour
  • HTRF refers to homogenous time-resolved fluorescent
  • “i.v” refers to intravenous
  • “kDa” refers to kilodaltons
  • “LC-MS” refers to liquid chromatography-mass spectrometry
  • “MS” refers to mass spectrometry
  • “OtBu” refers to O-tert-butyl
  • “Pbf” refers to N G -2,2,4,6,7-pentamethyldihydrobenzo
  • I at position 1 is modified at the N-terminus by methylation
  • X bb is L
  • X cc is L
  • X dd is Q
  • K at position 29 is chemically modified through conjugation to an epsilon-amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(yE) 2 - C0-(CH 2 )i 6 -C0 2 H; and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO:3).
  • SEQ ID NO:3 The structure of this sequence is shown below.
  • IVX bb SLDVPIGLLQILX cc EQEKQEKEKQQAKTNAX dd ILAQV-NH 2 where I at position 1 is modified at the N-terminus by methylation, X bb is T, X cc is L, X dd is E, and K at position 29 is chemically modified through conjugation to an epsilon- amino group of a K side chain with ([2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(yE) 2 -CO- (CH 2 )i 8 -C0 2 H; and the C-terminal amino acid is amidated as a C-terminal primary amide (SEQ ID NO:5).
  • SEQ ID NO:5 The structure of this sequence is shown below.
  • a convergent synthesis also may be used.
  • an acylated K side chain is constructed and/or obtained.
  • This acylated K side chain fragment may have the acid fragments protected orthogonally as t-butyl esters or other protecting groups commonly known in peptide synthesis. It is believed that such a method of synthesis may produce the acylated side chain in high purity, >98%, which may reduce the downstream chromatography requirements, potentially leading to improved purity and increased process efficiency.
  • each fragment could be produced sequentially or simultaneously.
  • the smaller fragments of the peptides may be easier to purify and sometimes can be isolated in crystalline form which imparts high purity.
  • an error is made in one of the fragment, only that fragment has to be discarded and re-created (rather than having to re create the entire sequence).
  • Other strategic fragment breaks are posssible to further improve purity and efficiency such as but not limited to fragment condensation to produce the 18 amino acid residue.

Abstract

L'invention concerne une polythérapie pour traiter le diabète ou une maladie rénale chronique par l'administration, à un patient ayant besoin d'un tel traitement, d'une quantité efficace d'un composé de l'urocortine-2 (ou d'un sel pharmaceutiquement acceptable de celui-ci) avec un analogue d'agoniste du récepteur du glucagon (ou un sel pharmaceutiquement acceptable de celui-ci), et des méthodes d'utilisation de celle-ci pour traiter le diabète (y compris le diabète de type 2) et une maladie rénale chronique.
PCT/US2019/012956 2018-01-12 2019-01-10 Polythérapie WO2019140024A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862616451P 2018-01-12 2018-01-12
US62/616,451 2018-01-12

Publications (1)

Publication Number Publication Date
WO2019140024A1 true WO2019140024A1 (fr) 2019-07-18

Family

ID=65269079

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/012956 WO2019140024A1 (fr) 2018-01-12 2019-01-10 Polythérapie

Country Status (1)

Country Link
WO (1) WO2019140024A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007022123A2 (fr) * 2005-08-11 2007-02-22 Amylin Pharmaceuticals, Inc. Polypeptides hybrides presentant des proprietes selectionnables
WO2008047241A2 (fr) * 2006-10-16 2008-04-24 Conjuchem Biotechnologies Inc. Peptides du facteur libérateur de corticotrophine modifiés et leurs utilisations
WO2015094878A1 (fr) 2013-12-18 2015-06-25 Eli Lilly And Company Nouveau composé pour le traitement de l'hypoglycémie sévère
WO2015094875A1 (fr) 2013-12-18 2015-06-25 Eli Lilly And Company Nouveau composé pour le traitement de l'hypoglycémie grave
WO2015094876A1 (fr) 2013-12-18 2015-06-25 Eli Lilly And Company Nouveau composé pour le traitement de l'hypoglycémie grave
US20170114115A1 (en) 2015-10-26 2017-04-27 Eli Lilly And Company Glucagon receptor agonists
WO2018013803A1 (fr) * 2016-07-15 2018-01-18 Eli Lilly And Company Nouveaux analogues d'urocortine-2 modifiés par acides gras pour le traitement du diabète et de maladies rénales chroniques

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007022123A2 (fr) * 2005-08-11 2007-02-22 Amylin Pharmaceuticals, Inc. Polypeptides hybrides presentant des proprietes selectionnables
WO2008047241A2 (fr) * 2006-10-16 2008-04-24 Conjuchem Biotechnologies Inc. Peptides du facteur libérateur de corticotrophine modifiés et leurs utilisations
WO2015094878A1 (fr) 2013-12-18 2015-06-25 Eli Lilly And Company Nouveau composé pour le traitement de l'hypoglycémie sévère
WO2015094875A1 (fr) 2013-12-18 2015-06-25 Eli Lilly And Company Nouveau composé pour le traitement de l'hypoglycémie grave
WO2015094876A1 (fr) 2013-12-18 2015-06-25 Eli Lilly And Company Nouveau composé pour le traitement de l'hypoglycémie grave
US20170114115A1 (en) 2015-10-26 2017-04-27 Eli Lilly And Company Glucagon receptor agonists
WO2018013803A1 (fr) * 2016-07-15 2018-01-18 Eli Lilly And Company Nouveaux analogues d'urocortine-2 modifiés par acides gras pour le traitement du diabète et de maladies rénales chroniques

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2006
BERGE ET AL., J. PHARMA SCI., vol. 66, 1977, pages 1 - 19
GREEN; WUTS: "Protecting Groups in Organic Synthesis", 1991, JOHN WILEY & SONS
MACKAY ET AL., EURO. J. PHARMACOL., vol. 469, 2003, pages 111 - 115
MEI HUA GAO ET AL: "One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance", JCI INSIGHT, vol. 1, no. 15, 22 September 2016 (2016-09-22), XP055410687, DOI: 10.1172/jci.insight.88322 *
STAHL ET AL.: "Handbook of Pharmaceutical Salts: Properties", 2011, WILEY-VCH

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