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WO2011128374A1 - Conjugués insuline-arnsi - Google Patents

Conjugués insuline-arnsi Download PDF

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Publication number
WO2011128374A1
WO2011128374A1 PCT/EP2011/055823 EP2011055823W WO2011128374A1 WO 2011128374 A1 WO2011128374 A1 WO 2011128374A1 EP 2011055823 W EP2011055823 W EP 2011055823W WO 2011128374 A1 WO2011128374 A1 WO 2011128374A1
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Prior art keywords
alkyl
cycloalkyl
aryl
heterocyclyl
heteroaryl
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Werner Kramer
David William Will
Marcus Hermann Korn
Bodo Brunner
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Sanofi SA
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Sanofi SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • 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

  • This invention relates generally to therapeutic compounds and methods useful for treating disease in humans. Specifically, the present invention relates to methods and reagents useful for treating humans suffering from metabolic diseases. Specifically, the present invention relates to covalent conjugates of insulin and analogues with nucleic acid derivatives which are capable of modulating gene expression. Furthermore, this invention relates to the use of such conjugated insulins for the treatment of metabolic diseases, including diabetes mellitus.
  • pharmacodynamic properties of insulins to provide basal insulins which can provide stable control of blood glucose levels over several hours, as well as fast-acting insulins to control postprandial blood glucose excursions. This has been achieved either by formulation, by modification of the insulin amino acid sequence, or conjugation to, for example, fatty acids.
  • Insulin regulates circulating glucose levels by suppressing hepatic glucose production and increasing glucose transport into muscle and adipose tissues. At the cellular level, insulin stimulates glucose uptake by inducing the translocation of the glucose transporter 4 (GLUT4) from intracellular storage sites to the plasma membrane, where the transporter facilitates the diffusion of glucose into striated muscle and adipocytes.
  • GLUT4 glucose transporter 4
  • Insulin exerts its biological effects by binding to insulin receptor, a transmembrane receptor with intrinsic tyrosine kinase activity. Upon insulin binding the insulin receptor undergoes a conformational change which enables it to bind ATP and be autophosphorylated. This autophosphorylation increases the kinase activity of the receptor allowing it to phosphorylate a variety of intracellular substrates which initiate signalling cascades, leading to the activation of multiple downstream effectors and resulting ultimately in the biological response, including glucose uptake in muscle and adipose tissue as a consequence of the rapid translocation of GLUT4 glucose transporters from an intracellular site to the cell surface.
  • insulin-insulin receptor complex Following insulin binding and the activation of the receptor the insulin-insulin receptor complex is internalized via receptor-mediated endocytosis after translocation to clathrin-coated pits. This process depends on the presence of bound insulin ligand on the insulin receptor. Following uncoating of the clathrin-coated vesicles and fusion with endosomal compartments, insulin dissociates from its receptor and is directed to late endosomes and ultimately to lysosomal compartments where it is degraded. The ligand-free insulin receptor is recycled back to the cell membrane. (Foti, M. et al., Novartis Foundation Symposium (2004) 262, 125-147; Carpentier, J.-L, Diabetologia (1994) Suppl 2, 1 17-124.)
  • insulin conjugates have been synthesized previously. These are usually aimed at improving the pharmacokinetic and/or pharmacodynamic properties of insulin, or to facilitate alternative methods of insulin delivery, such as oral or pulmonary delivery. Examples include, but are not limited to: insulin-polyethylene glycol (PEG) conjugates (Hinds, K.D. and Kim, S.W. Advanced Drug Delivery Reviews (2002) 54, 505-530; WO2007043059A1 ; WO2007007345A1 ; Uchio, T. et al. Advanced Drug Delivery Reviews (1999) 35, 289-306.); Insulin-branched polymer conjugates
  • Insulin-Silk sericin peptide conjugates (Zhang, Y.-Q. et al. Journal of Controlled
  • Insulin-transferrin conjugates (Xia, C. Q. et al.
  • Insulin has also been used as a drug carrier by conjugation to cytotoxic/cytostatic drugs, such as 5-fluorouracil (Huang, J. et al. Chinese Chemical Letters (2007), 18(3), 247-250).
  • cytotoxic/cytostatic drugs such as 5-fluorouracil
  • Insulin has been used as a carrier for alpha-1 ,4-glucosidase enzyme. Poorly defined conjugates of insulin with this enzyme, or with a conjugate of enzyme with albumin were prepared and tested for their cell association, enzyme activity and intracellular and in vivo distribution (Poznansky, M. J. et al. Science (1984) 223(4642), 1304-6). A poorly characterized insulin-serum albumin conjugate was used to form an indirect, non-specific and non-covalent complex with DNA, by virtue of electrostatic and lipophilic interactions of the negatively-charged DNA with the positively-charged albumin. This was used in vitro to transfect the DNA, which coded for the neo gene, into HEPG2 cells (Huckett, B.
  • Type II Diabetes mellitus the etiology of which is more complex than simple
  • insulin underproduction of insulin.
  • This can be treated in its early stages by a variety of oral antidiabetic drugs, which, as the disease progresses, must normally be supplemented by insulin therapy.
  • type 2 diabetes has sparked interest in the development of agents other than insulins that treat and prevent the disease. It has not, so far, been possible to develop therapeutically useful insulin receptor agonists which can directly mimic and replace insulins.
  • insulin therapy there are a number of other biological targets and pathways which can be exploited for the treatment of Type II diabetes.
  • An exemplary promising approach is improving insulin sensitivity by the modulation of targets downstream of the insulin receptor.
  • the signalling cascade set in motion by the binding of insulin to its receptor is regulated by a number of enzymes, some of which inhibit transduction of the signal. Improving insulin signalling by removing or inhibiting these negative regulators is of particular interest in the development of new therapeutics for the treatment of diabetes.
  • An example of a key negative regulator of insulin signalling is protein tyrosine
  • PTP1 B belongs to the protein-tyrosine phosphatase family of enzymes that catalyze protein tyrosine dephosphorylation. Over 100 PTPs have been isolated in humans and can function either as negative or positive modulators in various signal transduction pathways. PTPs play essential roles in intracellular signal transduction by regulating the cellular level of tyrosine
  • PTP protein tyrosine phosphatase
  • PTP1 B plays a seminal role in cellular signaling and in many human diseases, including cancer, diabetes and obesity.
  • Abundant in vitro and in vivo data have established a role for PTP1 B as a key negative regulator of insulin receptor signaling and therefore insulin action.
  • PTP1 B acts as an insulin "antagonist" through the direct dephosphorylation and inactivation of the insulin receptor and possibly also by dephosphorylating downstream targets. This evidence indicates that PTP-1 B negatively regulates insulin signaling making it a prime target for enhancing insulin sensitivity. In addition it negatively regulates leptin signaling and therefore influences appetite and body mass.
  • PTP1 B inhibitors Despite intense efforts and recent progress, development of therapeutically useful orally bioavailable small-molecule PTP1 B inhibitors has so far been unsuccessful.
  • Other approaches to modulate the action of PTP1 B are inhibition of its expression using antisense oligonucleotides, and more recently in vitro siRNA knock-down of siRNA expression has been reported (WO 2004016735 A2; WO 2003099227 A2; US 2006025361 A1 ; US 2006019913 A1 ; US 2004077574 A1 ; US 2004009946 A1 ).
  • introduction of double-stranded RNA (dsRNA) induces potent and specific gene silencing.
  • RNA interference This well-known, fundamental cellular mechanism of sequence-specific post-transcriptional gene silencing, known as RNA interference (RNAi), occurs in plants, animals and fungi and has roles in, for example, viral defense and transposon silencing mechanisms. Fire and Mello received the 2006 Nobel Prize for Medicine for their role in its discovery. (Ghildiyal, M. & Zamore, P.D. Nature
  • RNA-lnduced Silencing Complex RISC
  • the specific mRNA sequence to be degraded is recognized by hybridisation to the complementary short RNA sequence in the RISC complex, and on recognition the activity of the argonaute endonuclease in the RISC degrades the mRNA (Liu, J. et al. Science, (2004) 305, 1437-1441 .; song, J-J. et al. Science, (2004) 305, 1434-1437). This is a catalytic process.
  • the short RNA recognition sequence often known as the guide or antisense strand, is typically about 19 to about 25 nucleotides in length, and is normally transported to, and recognized for incorporation into the RISC as part of a duplex with a second RNA strand, known as the passenger or sense strand.
  • siRNA duplex which typically has short nucleotide overhangs of around 2 nucleotides at the 3'-end of each strand, is known as a short interfering RNA (siRNA).
  • siRNA duplex The two strands of the siRNA duplex are typically highly complementary to each other, although the presence of a small number of mismatches may be tolerated, albeit with detrimental effects on the efficiency of RNA interference.
  • the 5'-hydroxyl group of the siRNA is essential as it is phosphorylated for activity (Chiu et al., Molecular Cell, 2002, 10, 549-561 ).
  • the passenger strand On incorporation of the guide strand into the RISC, the passenger strand is typically discarded/degraded. (Tomari, Y.; Zamore P.D.
  • siRNAs are produced typically from longer endogenous or exogenous precursors which may be composed of dsRNA composed of two separate RNA strands, or sections of dsRNA within longer, partially self-complementary RNA single strands, such as stem-loop structures, for example in pre-microRNAs.
  • the processing of these precursors to form siRNA is carried out by the DICER endonuclease in the cytoplasm.
  • RNAi is, in principle, an elegantly potent and specific method of
  • siRNA sequence design is largely empirical, there are a number of generally accepted guidelines for siRNA sequence design to achieve potent and specific protein knock-down, and many of these have been formalized into computer algorithms. (Ui-Tei, K. et al. Journal of Biomedicine and Biotechnology (2006) 1-8.; Amarzguioui, M.; Prydz, H. Biochem. Biophys. Res. Commun. (2004) 316, 1050-1058.). Many of these algorithms are freely, or commercially available. In addition to the design of the primary nucleotide sequence of siRNAs, much work has been done on other structural requirements which can optimise either the stability or cost of the oligomers while maintaining or improving their potency and selectivity.
  • siRNA is prone to nuclease degradation, and requires appropriate precautions to be taken during synthesis and handling. This instability is also a major cause of the poor pharmacokinetic properties of siRNA in vivo.
  • Chemical modifications have been extensively investigated to address not only this problem, but also to investigate the mechanisms of RNAi; to improve the efficiency and specificity of protein knock-down; to reduce or eliminate immune responses related to the siRNA; to reduce the cost of the siRNA oligomers, amongst others. These chemical modifications include
  • nudeobase modifications include substitution of ribonucleotides by deoxyribonucleotides or 2'-substituted sugars; modified internucleotide linkages, including phosphorothioates and dephospho linkages; end modifications and
  • siRNAs In addition a wide variety of chemical modifications which are tolerated in specific parts of the siRNA, and which improve the properties of these siRNAs are well documented in the literature cited herein and the references cited therein. One ordinarily skilled in the art would be capable of combining this information to construct modified siRNA sequences with the potential to be potent and selective silencers of gene expression when combined with an appropriate delivery system. Synthetic methods for the solid phase synthesis of siRNAs are reviewed in (Beaucage, S. Current Opinion in Drug Discovery & Development (2008) 1 1 (2), 203-216).
  • siRNAi As a therapeutic principle, the remaining major obstacles to the utility of RNAi as a therapeutic principle are the poor cellular uptake of siRNAs into cells, and the poor pharmacokinetic and pharmacodynamic properties of siRNA in vivo.
  • the poor pharmacokinetic properties of unmodified siRNAs are related to their low in vivo stability and their fast elimination by kidney filtration (Kawakami, S. & Hashida, M. Drug Metab. Pharmacokinet. (2007) 22(3), 142-151 ).
  • siRNAs Covalent conjugation of siRNAs to lipophilic moieties such as, for example, cholesterol, cholesterol derivatives and analogues, bile acids, lipids or tocopherol has been applied with some success.
  • lipophilic siRNAs can associate to varying extents with lipoproteins, or may be used in combination with the carriers described above.
  • Covalent conjugates or complexes of siRNAs with antibodies or fragments thereof, cell surface receptor ligands, or peptides have been prepared to facilitate cellular uptake, tissue targeting, or modulate the intracellular distribution of the siRNA.
  • peptide ligands which can be modified by the addition of multiple cationic amino acids while maintaining their affinity and specificity for their receptor targets are suitable candidates for electrostatic complex formation with polyanionic siRNAs.
  • Complexes of siRNAs with antibodies or fragments thereof are often achieved by means of antibody fusion proteins with cationic peptides, such as, for example, protamine.
  • antibody conjugates are superficially attractive as delivery agents, they introduce all the issues involved in the development of therapeutic antibodies, such as species specificity, immunological stimulation, humanisation and the like.
  • Cell penetrating peptides have been conjugated to siRNA. These peptides can carry molecules to which they are conjugated across cell membranes. They typically contain domains with a high density of basic amino acids, which facilitates their uptake by cells in a receptor-independent manner.
  • Example cell penetrating peptides include Tat peptide from HIV Tat protein, Ant peptide from Drosophila antennapedia homeobox protein, Penetratin, transportan, HSV-1 protein VP22 and MPG, model amphipathic peptide (MAP) and polyarginine.
  • Tat peptide from HIV Tat protein Ant peptide from Drosophila antennapedia homeobox protein
  • Penetratin Penetratin
  • transportan HSV-1 protein VP22 and MPG
  • MAP model amphipathic peptide
  • polyarginine polyarginine.
  • Non-covalent complexes of siRNA with cell penetrating peptides (Meade, B.R. & Dowdy, S.F. Advanced Drug Delivery Reviews (2007) 59, 134-140.), as well as modified peptidic ligands for cell surface receptors have also been synthesized.
  • a streptavidin-human insulin receptor antibody conjugate has been used to form a non-covalent complex with a biotinylated siRNA (Xia, C-F. et al. Mol.
  • siRNA targeting IRS-1 designed for the treatment of breast cancer, has been successfully conjugated to small cyclic peptide mimetic of IGF-1 .
  • These conjugates were active in cellular assays without the addition of transfection reagents, and were apparently taken-up by cells specifically by receptor-mediated endocytosis of IGF-1 receptor (Cesarone, G. et al. Bioconjugate Chem. (2007) 18, 1831-1840).
  • the present invention provides covalent conjugates of insulin and analogues with nucleic acid derivatives which are capable of modulating gene expression. More specifically, the present invention relates to covalent conjugates of insulin and insulin analogues with synthetic nucleic acid molecules capable of mediating RNA
  • RNAi short interfering nucleic acid
  • siNA short interfering nucleic acid
  • dsRNA double-stranded RNA
  • miRNA micro-RNA
  • shRNA short hairpin RNA
  • the present invention relates to covalent conjugates of insulin and insulin analogues with synthetic nucleic acid molecules, capable of mediating RNA interference (RNAi), whereby the conjugate is capable of binding to, activating, and being internalised with, the insulin receptor.
  • the present invention relates to covalent conjugates of insulin and insulin analogues with synthetic nucleic acid molecules, which, by means of RNA interference (RNAi), are capable of reducing expression of proteins involved in the pathophysiology of diseases.
  • RNAi RNA interference
  • the present invention relates to covalent conjugates of insulin and insulin analogues with synthetic nucleic acid molecules, which, by means of RNA interference (RNAi), are capable of reducing expression of proteins involved in the pathophysiology of metabolic diseases.
  • this invention relates to the use of such conjugated insulins for the treatment of metabolic diseases, including, but not limited to, diabetes mellitus.
  • insulin when used in connection with the compounds of this invention, it covers insulin from any species such as porcine insulin, bovine insulin, and human insulin and salts thereof, such as zinc salts, and protamine salts as well as dimers and polymers, for example, hexamers thereof. Furthermore, the term “insulin” herein also covers "modified insulins” being what a skilled art worker generally considers derivatives of insulin, vide general texbooks, for example, insulin having a substituent not present in the parent insulin molecule.
  • Modified insulins are typically prepared by chemical and/or enzymatic manipulation of insulin, or a suitable insulin precursor such as preproinsulin, proinsulin or truncated analogues thereof.
  • insulin also covers insulin molecules acylated in one or more positions, such as in the B29 position of human insulin, desB30 human insulin, or B01 bovine insulin (Journal of Pharmaceutical Sciences (1997) 86 (1 1 ) 1264-1268). It also covers C-terminal amides of insulins.
  • insulin herein covers so-called “insulin analogues".
  • An insulin analogue is an insulin molecule having one or more mutations, substitutions, deletions and/or additions of the A and/or B amino acid chains relative to the human insulin molecule. More specifically, one or more of the amino acid residues have been exchanged with another amino acid residue and/or one or more amino acid residue has been deleted and/or one or more amino acid residue has been added with the proviso that said insulin analogue has a sufficient insulin activity.
  • insulin analogues An overview of some structure-activity relationships for insulin analogues, with examples of amino acid exchanges/deletions/additions which are tolerated is provided in Biopolymers (Peptide Science) 2007, 88 (5), 687-713 together with the references cited therein.
  • the insulin analogues are preferably such wherein one or more of the naturally occurring amino acid residues have been substituted by another amino acid residue.
  • insulin analogues are: C-terminal truncated derivatives such as des(B30) human insulin; B-chain N-terminal truncated insulin analogues such as des PheB1 insulin or des B1 -4 insulin; insulin analogues wherein the A-chain and/or B-chain have an N-terminal extension, including so-called "pre-insulins" where the B-chain has an N-terminal extension; and insulin analogues wherein the A-chain and/or the B-chain have a C-terminal extension. For example one, two or three Arg may be added to the C-terminus of the B-chain.
  • insulin analogues are composed of combinations of the substitutions, truncations and extensions described above. Examples of insulin analogues are described in the following patents and equivalents thereto: US 5,618,913, EP254,516, EP280, 534, US 5,750,497 and US 6,01 1 ,007. An overview of insulin analogues in clinical use is provided in Biopolymers (Peptide Science) 2007, 88 (5), 687-713 together with the references cited therein. Insulin analogues or their precursors are typically prepared using gene technology techniques well known to those skilled in the art, typically in bacteria or yeast, with subsequent enzymatic or synthetic manipulation if required. Alternatively, insulin analogues can be prepared chemically (Biol. Chem.
  • insulin analogues examples include insulin aspart (i.e. AspB28 human insulin); insulin lispro (i.e. LysB28, ProB29 human insulin); insulin glulisine (ie. LysB03, GluB29 human insulin); and insulin glargine (i.e. GlyA21 , ArgB31 , ArgB32 human insulin).
  • insulin also covers precursors or intermediates for other insulins, such as preproinsulin, proinsulin or derivatives of preproinsulin or proinsulin in which the C-peptide is truncated, modified or replaced.
  • insulin herein also covers compounds which can be considered to be both modified insulins and insulin analogues, for example insulins which have amino acid exchanges/deletions/additions as well as further modifications such as acylation or other chemical modification. Such insulins are also called “insulin derivatives".
  • insulin detemir ie. LysB29-tetradecanoyl, des(B30) human insulin.
  • Another example may be insulins in which unnatural amino acids or amino acids which are normally non-coding in eukaryotes, such as D-amino acids, have been incorporated (Hoppe Seylers Z. Physiol. Chem. (1976) 357,
  • insulin analogues in which the C-terminal carboxylic acid of either the A-chain or the B-chain, or both, are replaced by an amide.
  • linker herein is used in connection with the compounds of this invention, it covers chemical moieties used to connect two biomolecules or modified biomolecules to each other. These linkers are well known to those skilled in the art. A description of many of these linkers, together with the reagents and methods used to introduce them, is given in Hermanson, G.T., Bioconjugate Techniques (Second edition) Academic Press 2008 pages 215-342. However the term “linker” herein is not limited to those described in this reference, but also covers analogues, homologues, regioisomers and combinations thereof. Of particular relevance to this invention are the heterobifunctional linkers described in Hermanson, G.T.
  • Such in vivo cleavable linkers include those containing appropriately functionalized disulfide bridges which can be cleaved under reducing conditions intracellularly, and those containing appropriately functionalized ester functions which can be cleaved either enzymatically or in a pH dependent manner intracellularly (Oishi, M., Biomacromolecules 2003, 4, 1426-1432; Oishi, M., J. Am. Chem. Soc. 2005, 127, 1624-1625).
  • linker herein also covers chemical moieties which result from the application of the chemical reactions described in Hermanson, G.T. Bioconjugate Techniques (Second edition) Academic Press 2008 pages 169-21 1 , using appropriate starting materials obvious to a practitioner of the art.
  • RNA When the term “siRNA” herein is used in connection with this invention, it covers oligomers comprised of, or containing, ribonucleotides, which are capable of modulating gene expression by means of RNA interference. It is also by extension used to cover ribonucleotide-containing precursors which require processing by intracellular enzymes, such as DICER, to be capable of modulating gene expression by means of RNA interference.
  • oligomers include short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), DICER substrate RNA (DsiRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules.
  • the invention is a chimeric compound comprising an insulin and an siRNA.
  • the chimeric compound may be defined by formula I: Ins - Lin - siRNA (formula I), wherein the insulin (Ins) is attached to the siRNA by a linker (Lin).
  • the linker (Lin) is a moiety with the structure
  • X1 is a moiety selected from a group comprising -C(O)-; -O-C(O) -; -C(O)-O-;
  • L1 is selected from a group comprising (Ci-Cis)-alkyl, (O-(Ci-C8)-alkyl) n ,
  • L2 is selected from a group comprising (Ci-Ci 8 )-alkyl, (O-(Ci-C 8 )-alkyl) n ,
  • X2 is a moiety selected from a group comprising -C(O)-; -O-C(O) -; -C(O)-O-,
  • Z is selected from a group comprising a direct bond, (CrCi 4 )-alkyl, (O-(Ci-C 8 )-alkyl) n , ((Ci-C 8 )-alkyl-0) n> (Ci-Ci 4 )-alkyl-C(0)-, (C 3 -C 6 )-cycloalkyl-C(O)-, (C 6 -Ci 4 )-aryl-C(0)-, (CrCi 4 )-alkyl-(C 6 -Ci 4 )-aryl-C(O)-, (C 6 -Ci 4 )-aryl-(Ci-Ci 4 )-alkyl-C(O)-, (C 6 -Ci 4 )-aryl-(Ci-Ci 4 )-alkyl-C(O)-,
  • n is an integer between 1 and 1 1 ;
  • n 0, 1 or 2;
  • q, p, r, s, t are independently from each other 0, 1 or 2;
  • R1 is H, (Ci-C 6 )-alkyl
  • R2 and R3 are independently H, (CrC 6 )-alkyl, whereby R2 and R3 together with the nitrogen atom to which they are bonded may form a saturated 5- to 6-membered monocyclic heterocyclyl group.
  • X1 is a moiety selected from a group comprising -C(O)-; -O-C(O) -; -C(O)-O-;
  • L1 is selected from a group comprising (Ci-Cio)-alkyl, (O-(C 2 -C3)-alkyl) n ,
  • L2 is selected from a group comprising (Ci-Cio)-alkyl, (0-(C2-C3)-alkyl) n ,
  • X2 is a moiety selected from a group comprising -C(O)-; -O-C(O) -; -C(O)-O-,
  • Z is selected from a group comprising a direct bond, (Ci-Cio)-alkyl, (O-(C2-C3)-alkyl) n , ((C 2 -C 3 )-alkyl-O)n, (Ci-Ci 0 )-alkyl-C(O)-, (C 3 -C 6 )-cycloalkyl-C(O)-, (C 6 -Ci 0 )-aryl-C(O)-, (Ci-C 6 )-alkyl-(C 6 -Cio)-aryl-C(O)-, (C 6 -Ci 0 )-aryl-(Ci-C 6 )-alkyl-C(O)-, (C 6 -Ci 0 )-aryl-(Ci-C 6 )-alkyl-C(O)-, (C 6 -Ci 0 )-aryl-(Ci-C 6 )-alkyl
  • n is an integer between 1 and 1 1 ;
  • n 0, 1 or 2;
  • q, p, r, s, t are independently from each other 0, 1 or 2;
  • R1 is H, (Ci-C 6 )-alkyl
  • R2 and R3 are independently H, (CrC 6 )-alkyl, whereby R2 and R3 together with the nitrogen atom to which they are bonded may form a saturated 5- to 6-membered monocyclic heterocyclyl group.
  • X1 is a moiety selected from a group comprising -C(O)-; -O-C(O) -; -C(O)-O-;
  • L1 is selected from a group comprising (Ci-Cio)-alkyl, (O-(C2-C3)-alkyl) n ,
  • L2 is selected from a group comprising (Ci-Cio)-alkyl, (O-(C2-C3)-alkyl) n ,
  • X2 is a moiety selected from a group comprising -C(O)-; -O-C(O) -; -C(O)-O-,
  • Z is selected from a group comprising a direct bond, (Ci-Cio)-alkyl, (O-(C2-C 3 )-alkyl) n , ((C 2 -C 3 )-alkyl-O) n ,
  • n is an integer between 1 and 1 1 ;
  • n 0, 1 or 2;
  • q, p, r, s, t are independently from each other 0, 1 or 2;
  • R1 is H, (Ci-C 6 )-alkyl
  • R2 and R3 are independently H, (Ci-C 6 )-alkyl, whereby R2 and R3 together with the nitrogen atom to which they are bonded may form a saturated 5- to 6-membered monocyclic heterocyclyl group.
  • X1 is a moiety selected from a group comprising -C(O)-; -O-C(O) -; -C(O)-O-;
  • L1 is selected from a group comprising (Ci-Cio)-alkyl, (O-(C2-C3)-alkyl) n , ((C 2 -C 3 )-alkyl-O)n, (C 3 -C 6 )-cycloalkyl, (O-(C 3 -C 6 )-cycloalkyl)n, ((C 3 -C 6 )-cycloalkyl-O)n, (Ci-C 6 )-al kyl-(C 3 -C 6 )-cycloalkyl , (C 3 -C 6 )-cycloal kyl-(Ci-C 6 )-al kyl , (C 6 -Ci 0 )-aryl ,
  • L2 is selected from a group comprising (Ci-Cio)-alkyl, (O-(C2-C3)-alkyl) n ,
  • X2 is a moiety selected from a group comprising -C(O)-; -O-C(O) -; -C(O)-O-,
  • phosphorus atom of Z is attached to a 3'-, or 5'-oxygen atom of the siRNA; d is an integer between 0 and 10; n is an integer between 1 and 1 1 ;
  • n 0, 1 or 2;
  • q, p, r, s, t are independently from each other 0, 1 or 2;
  • R1 is H, (Ci-C 6 )-alkyl
  • R2 and R3 are independently H, (CrC 6 )-alkyl, whereby R2 and R3 together with the nitrogen atom to which they are bonded may form a saturated 5- to 6-membered monocyclic heterocyclyl group.
  • X1 is a moiety selected from a group comprising -C(O)-; -C(O)-O-; -C(O)-N(R1 )-; -S-; -N(R1 )-; -O-; and heterocyclyl;
  • L1 is selected from a group comprising (Ci-Cio)-alkyl, (O-(C2-C3)-alkyl) n ,
  • D is independently selected from a group comprising -C(O)-, -C(O)O-, -O-C(O)-, -N(R1 )-C(O)-, -C(O)-N(R1 )-, -N(R1 )C(O)-N(R1 )-, -N(R1 )-, -O-, -S-, -S-S-, -O-(CH 2 )-, -(CH 2 )-O-, (O-(C 2 -C 3 )-alkyl) nj ((C 2 -C 3 )-alkyl-O) n , (N(R1 )-(Ci-C 6 )-alkyl),
  • L2 is selected from a group comprising (Ci-Cio)-alkyl, (O-(C2-C3)-alkyl) n ,
  • X2 is a moiety selected from a group comprising -C(O)-; -O-C(O) -; -C(O)-O-,
  • Z is selected from a group comprising a direct bond, -O-P(O)(OH)-,

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Abstract

L'invention concerne généralement des composés thérapeutiques et des procédés utiles pour traiter une maladie chez des humains. Spécifiquement, la présente invention concerne des procédés et des réactifs utiles pour traiter des humains souffrant de maladies métaboliques. Spécifiquement, la présente invention concerne des conjugués covalents d'insuline et d'analogues avec des dérivés d'acide nucléique qui sont capables de moduler l'expression génique. De plus, cette invention concerne l'utilisation de telles insulines conjuguées pour le traitement de maladies métaboliques, comprenant le diabète sucré.
PCT/EP2011/055823 2010-04-14 2011-04-13 Conjugués insuline-arnsi Ceased WO2011128374A1 (fr)

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US9364519B2 (en) 2011-09-01 2016-06-14 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition for use in the treatment of a neurodegenerative disease
US9408893B2 (en) 2011-08-29 2016-08-09 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
US9526764B2 (en) 2008-10-17 2016-12-27 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1-agonist
US9707176B2 (en) 2009-11-13 2017-07-18 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist and methionine
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
US9908908B2 (en) 2012-08-30 2018-03-06 Jiangsu Hansoh Pharmaceutical Co., Ltd. Tenofovir prodrug and pharmaceutical uses thereof
US9950039B2 (en) 2014-12-12 2018-04-24 Sanofi-Aventis Deutschland Gmbh Insulin glargine/lixisenatide fixed ratio formulation
US9981013B2 (en) 2010-08-30 2018-05-29 Sanofi-Aventis Deutschland Gmbh Use of AVE0010 for the treatment of diabetes mellitus type 2
US10029011B2 (en) 2009-11-13 2018-07-24 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist, an insulin and methionine
US10092513B2 (en) 2013-04-03 2018-10-09 Sanofi Treatment of diabetes mellitus by long-acting formulations of insulins
US10159713B2 (en) 2015-03-18 2018-12-25 Sanofi-Aventis Deutschland Gmbh Treatment of type 2 diabetes mellitus patients
US10434147B2 (en) 2015-03-13 2019-10-08 Sanofi-Aventis Deutschland Gmbh Treatment type 2 diabetes mellitus patients
US11597744B2 (en) 2017-06-30 2023-03-07 Sirius Therapeutics, Inc. Chiral phosphoramidite auxiliaries and methods of their use
US11981703B2 (en) 2016-08-17 2024-05-14 Sirius Therapeutics, Inc. Polynucleotide constructs

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US9950039B2 (en) 2014-12-12 2018-04-24 Sanofi-Aventis Deutschland Gmbh Insulin glargine/lixisenatide fixed ratio formulation
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