EP1610812A1 - Preparations pharmaceutiques contenant de l'insuline stabilisee d'un point de vue acide - Google Patents

Preparations pharmaceutiques contenant de l'insuline stabilisee d'un point de vue acide

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Publication number
EP1610812A1
EP1610812A1 EP04719368A EP04719368A EP1610812A1 EP 1610812 A1 EP1610812 A1 EP 1610812A1 EP 04719368 A EP04719368 A EP 04719368A EP 04719368 A EP04719368 A EP 04719368A EP 1610812 A1 EP1610812 A1 EP 1610812A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
independently selected
pharmaceutical composition
composition according
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP04719368A
Other languages
German (de)
English (en)
Inventor
Sören ÖSTERGAARD
Helle Birk Olsen
Niels C. Kaarsholm
Peter Madsen
Palle Jakobsen
Svend Ludvigsen
Gerd Schluckebier
Dorte Bjerre Steensgaard
Anders Klarskov Petersen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP1610812A1 publication Critical patent/EP1610812A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • 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
    • A61K38/28—Insulins
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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    • 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
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    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07K14/62—Insulins

Definitions

  • the present invention discloses pharmaceutical preparations comprising ligands for the HisBlO Zn 2+ sites of the R-state insulin hexamer and acid-stabilsed insulin analogues.
  • the compositions release insulin slowly following subcutaneous injection.
  • the insulin hexamer is an allosteric protein that exhibits both positive and negative cooperativity and half-of-the-sites reactivity in ligand binding.
  • This allosteric behav- iour consists of two interrelated allosteric transitions designated L A 0 and- L B 0> three inter- converting allosteric conformation states (eq. 1),
  • T 6 , T 3 R 3 , and R 6 and two classes of allosteric ligand binding sites designated as the phenolic pockets and the His 810 anion sites. These allosteric sites are associated only with insulin subunits in the R conformation. Insulin Hexamer Structures and Ligand Binding.
  • the T- to R-transition of the insulin hexamer involves transformation of the first nine residues of the B chain from an extended conformation in the T-state to an ⁇ -helical conformation in the R-state. This coil-to-helix transition causes the N-terminal residue, Phe B1 , to undergo an ⁇ 30 A change in position.
  • This conformational change creates hydrophobic pockets (the phenolic pockets) at the sub- unit interfaces (three in T 3 R 3 , and six in Re), and the new B-chain helices form 3-helix bun- dies (one in T 3 R 3 and two in Re) with the bundle axis aligned along the hexamer three-fold symmetry axis.
  • the His 610 Zn 2+ in each R 3 unit is forced to change coordination geometry from octahedral to either tetrahedral (monodentate ligands) or pentahedral (bidentate ligands). Formation of the helix bundle creates a narrow hydrophobic tunnel in each R 3 unit that extends from the surface -12 A down to the His 810 metal ion. This tunnel and the His 610 Zn 2+ ion form the anion binding site.
  • Hexamer Ligand Binding and Stability of Insulin Formulations The in vivo role of the T to R transition is unknown. However, the addition of allosteric ligands (e.g. phenol and chloride ion) to insulin preparations is widely used. Hexamerization is driven by coordination of Zn 2+ at the His 610 sites to give T 6 , and the subsequent ligand-mediated transition of T 6 to T 3 R 3 and to Re is known to greatly enhance the physical and chemical stability of the resulting formulations.
  • allosteric ligands e.g. phenol and chloride ion
  • absorption rates vary between about 1 hour (for rapid-acting insulin analogues, such as Asp 828 human insulin) and about 4 hours (Co 3+ -hexamer).
  • Current Approaches Toward Slow Acting Insulins The inherent limitation of the absorption half-life to about 4 hours for a soluble human insulin hexamer necessitates further modifications to obtain the desired protraction.
  • this has been achieved by the use of preparations wherein the constituent insulin is in the form of a crystalline and/or amorphous precipitate. In this type of formulation, the dissolution of the precipitate in the subcutaneous depot becomes rate-limiting for the absorption.
  • NPH and Ultralente belong to this category of insulin preparations where crystallization/precipitation is effected by the addition of protamine and excessive zinc ion, respectively.
  • Another approach involves the use of insulin derivatives where the net charge is increased to shift the isoelectric point, and hence the pH of minimum solubility, from about 5.5 to the physiological range.
  • Such preparations may be injected as clear solutions at slightly acidic pH. The subsequent adjustment of the pH to neutral induces crystallization/precipitation in the subcutaneous depot and dissolution again becomes rate-limiting for the absorption.
  • Gly* 21 Arg 831 Arg 832 human insulin belongs to this category of insulin analogues.
  • soluble insulin derivatives with a hydrophobic moiety covalently attached to the side chain of Lys 829 have been synthesized. These derivatives may show prolonged action profile due to various mechanisms including albumin binding (e.g. B29-N ⁇ - myristoyl-des(B30) human insulin), extensive protein self-association and/or stickiness (e.g. B29-N ⁇ -(N-lithocholyl- ⁇ -glutamyl)-des(B30) human insulin) induced by the attached hydro- phobic group.
  • albumin binding e.g. B29-N ⁇ - myristoyl-des(B30) human insulin
  • extensive protein self-association and/or stickiness e.g. B29-N ⁇ -(N-lithocholyl- ⁇ -glutamyl)-des(B30) human insulin
  • the present invention provides a pharmaceutical preparation comprising ligands for the His 610 Zn 2+ sites of the R-state insulin hexamer, zinc ions and acid-stabilised insulin analogs.
  • the preparations form clear solutions at slightly acidic pH. When the pH is adjusted towards neutral upon subcutaneous injection, the ligands work to stabilize hexamers and modify solubility in the neutral pH range. As a result, the preparations release insulin slowly following subcutaneous injection.
  • the invention furthermore provides a method of preparing ligands for the His 810 Zn 2+ sites of the R-state insulin hexamer comprising the steps of
  • the invention also provides a method of prolonging the action of an acid-stabilised insulin preparation which comprises adding a zinc-binding ligand of the invention to the acid- stabilised insulin preparation.
  • the invention finally provides a method of treating type 1 or type 2 diabetes comprising administering to a patient in need thereof a theraputically effective amount of a pharmaceutical preparation of the invention.
  • Halogen designates an atom selected from the group consisting of F, Cl, Br and I.
  • CrCe-alkyl as used herein represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tetf-butyl, n-pentyl, isopentyl, neopentyl, ferf-pentyl, n-hexyl, isohexyl and the like.
  • CrCe-alkylene represents a saturated, branched or straight bivalent hydrocarbon group having from 1 to 6 carbon atoms. Representative examples include, but are not limited to, methylene, 1 ,2-ethylene, 1 ,3-propylene, 1 ,2-propylene, 1 ,4-butylene, 1 ,5- pentylene, 1 ,6-hexylene, and the like.
  • C 2 -C 6 -alkenyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one double bond.
  • groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-buta- dienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3- pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5- hexenyl and the like.
  • C 2 -C 6 -alkynyl represents a branched or straight hydrocarbon group having from 2 to 6 carbon atoms and at least one triple bond.
  • groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl, 2,4-hexadiynyl and the like.
  • d-Ce-alkoxy refers to the radical -O-d-C ⁇ -alkyl, wherein d-Ce-alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, terf-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • C 3 -C 8 -cycloalkyl as used herein represents a saturated, carbocyclic group having from 3 to 8 carbon atoms.
  • Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • the term as used herein represents a non-aromatic, carbocyclic group having from 4 to 8 carbon atoms containing one or two double bonds.
  • Representative examples are 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3- cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1 ,4-cyclooctadienyl and the like.
  • heterocyclyl represents a non-aromatic 3 to 10 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulphur and optionally containing one or two double bonds. Representative examples are pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.
  • aryl as used herein is intended to include carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, carbocyclic, aromatic ring systems.
  • Aryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4- dihydronaphthyl and the like.
  • arylene as used herein is intended to include divalent, carbocyclic, aromatic ring systems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, divalent, carbocyclic, aromatic ring systems.
  • Arylene is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthylene, 1 ,4-dihydronaphthylene and the like.
  • aryloxy as used herein denotes a group -O-aryl, wherein aryl is as defined above.
  • aroyl denotes a group -C(O)-aryl, wherein aryl is as defined above.
  • heteroaryl as used herein is intended to include aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as 5 to 7 membered monocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur.
  • Representative examples are furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazoiyl, isothiazolyl, 1 ,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1,3,5- triazinyl, 1,2,3- oxadiazolyl, 1 ,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, 1 ,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, t
  • Heteroaryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.
  • heteroarylene as used herein is intended to include divalent, aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxygen and sulphur such as 5 to 7 membered monocyclic and 8 to 14 membered bi- and tricyclic aromatic, heterocyclic ring systems containing one or more heteroatoms selected from nitrogen, oxy- gen and sulphur.
  • Heteroaryl is also in- tended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated derivatives are 2,3-dihydro- benzofuranylene, pyrrolinylene, pyrazolinylene, indolinylene, oxazolidinylene, oxazolinylene, oxazepinylene and the like.
  • ArG1 as used herein is intended to include an aryl or arylene radical as applicable, where aryl or arylene are as defined above but limited to phenyl, biphenylyl, naphthyl, anthra- cenyl, phenanthrenyl, fluorenyl, indenyl, and azulenyl as well as the corrresponding divalent radicals.
  • ArG2 as used herein is intended to include an aryl or arylene radical as applicable, where aryl or arylene are as defined above but limited to phenyl, biphenylyl, naphthyl, fluo- renyl, and indenyl, as well as the corrresponding divalent radicals.
  • Het1 as used herein is intended to include a heteroaryl or heteroarylene radical as applicable, where heteroaryl or heteroarylene are as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazoiyl, isothiazolyl, 1 ,2,3-triazolyl, 1,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3- triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1 ,
  • Het2 as used herein is intended to include a heteroaryl or heteroarylene radical as applicable, where heteroaryl or heteroarylene are as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazoiyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3- triazinyl, 1,2,4-triazinyl, 1,3,5- triazinyl, 1,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4
  • Het3 is intended to include a heteroaryl or heteroarylene radical as applicable, where heteroaryl or heteroarylene are as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazoiyl, isothiazolyl, 1 ,2,3-triazolyl, 1,2,4-triazolyl, pyridyl, tetrazolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzimidazolyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinolyl, isoqui- nolyl, quinoxalinyl, carbazolyl, thiazolidinyl, 2-thiooxothiazolidinyl,
  • Aryl-d-Ce-alkyl is intended to mean d-Ce- alkyl or C 2 -C 6 -alkenyl as defined above, substituted by an aryl or heteroaryl as defined above, for example:
  • treatment means the management and care of a patient for the purpose of combating a disease, disorder or condition.
  • the term is intended to include the delaying of the progression of the disease, disorder or condition, the alleviation or relief of symptoms and complications, and/or the cure or elimination of the disease, disorder or condition.
  • the patient to be treated is preferably a mammal, in particular a human being.
  • fragment as used herein is intended to mean a bivalent chemical group
  • Neutral amino acid as used herein is intended to mean any natural (codable) and non-natural amino acid, including ⁇ - or ⁇ -aminocarboxylic acids, including D-isomers of these (when applicable) without charges at physiologically relevant pH in the side chain, such as glycine, alanine, ⁇ -alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, aspargine, glutamine, cysteine, methionine, 3-aminobenzoic acid, 4-aminobenzoic acid or the like.
  • positively charged group as used herein is intended to mean any pharmaceutically acceptable group that contains a positive charge at physiologically relevant pH, such as amino (primary, secondary and tertiary), ammonium and guanidino groups.
  • a amino acid as used herein is intended to mean mean any natural (codable) and non-natural ⁇ -aminocarboxylic acid, including D-isomers of these.
  • ⁇ amino acid as used herein is intended to mean any ⁇ -aminocarboxylic acid, such as ⁇ -alanine, isoserine or the like.
  • desB30 as used herein is intended to mean meant a natural insulin B chain or an analogue thereof lacking the B30 amino acid residue.
  • the amino acid residues are indicated in the three letter amino acid code or the one letter amino code.
  • B1 is intended to mean the amino acid residue in position 1 in the B chain of insulin or analogue thereof (counted from the N-terminal end) and the amino acid residue in position 1 in the A chain of insulin or analogue thereof (counted from the N-terminal end), respectively.
  • groups of compounds such as car- boxylates, dithiocarboxylates, phenolates, thiophenolates, alkylthiolates, sulfonamides, irni- dazoles, triazoles, 4-cyano-1 ,2,3-triazoles, benzimidazoles, benzotriazoles, purines, thia- zolidinediones, tetrazoles, 5-mercaptotetrazoles, rhodanines, N-hydroxyazoles, hydantoines, thiohydantoines, naphthoic acids and salicylic acids, these groups of compounds are intended to include also derivatives of the compounds from which the groups take their name.
  • acid-stabilised insulin refers to an insulin analog that does not deamidate or dimerize at pH values below 7. Specifically, the analog cannot have Asn or Asp as a C-terminal residue.
  • human insulin refers to naturally produced insulin or recombinantly produced insulin.
  • Recombinant human insulin may be produced in any suitable host cell, for example the host cells may be bacterial, fungal (including yeast), insect, animal or plant cells.
  • the expression "insulin derivative” as used herein (and related expressions) refers to human insulin or an analogue thereof in which at least one organic substituent is bound to one or more of the amino acids.
  • analogue of human insulin as used herein (and related expressions) is meant human insulin in which one or more amino acids have been deleted and/or replaced by other amino acids, including non-codeable amino acids, or human insulin comprising additional amino acids, i.e. more than 51 amino acids, such that the resulting analogue possesses insulin activity.
  • phenolic compound or similar expressions as used herein refers to a chemical compound in which a hydroxyl group is bound directly to a benzene or substituted benzene ring. Examples of such compounds include, but are not limited to, phenol, o-cresol, m-cresol and p-cresol.
  • physiologically relevant pH as used herein is intended to mean a pH of about 7.1 to 7.9.
  • Fig. 1 The effect of various concentrations of the ligand 4-[3-(2H-tetrazol-5-yl)carbazol-9- ylmethyl]benzoyl-Arg 1 -NH 2 on the pH-dependence of Gly* 21 , Asp 828 insulin solubility.
  • Fig. 2 The effect of a high concentrations of the ligand 4-[3-(2H-tetrazol-5-yl)carbazol-9- ylmethyl]benzoyl-Argi 2 -NH 2 on the pH-dependence of Gly* 21 insulin solubility.
  • Fig. 3 Disappearance from the subcutaneous depot (pig model) of insulin preparations.
  • Curves a)-c) are Gly* 21 , Asp 828 human insulin formulated with an excess concentration compared to Zn 2+ of a) 4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyryl- Arg 3 -NH 2 , b) 4-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyryl-Arg 5 -NH 2 and c) 4-(2H-Tetrazol-5-yl)benzoyl-Abz-Gly 2 -Arg 5 -NH 2 .
  • Curve d) is B29-N ⁇ -myristoyl- des(B30) human insulin.
  • Curves e) and f) are Gly* 21 human insulin formulated with two dif- ferent excess concentrations compared to Zn 2+ of 4-[3-(2H-Tetrazol-5-yl)carbazol-9- ylmethy I] benzoy l-Arg 1 -N H 2.
  • Fig.4 4H3N-assay. UV/vis spectra resulting from a titration of hexameric insulin with the compound 3-hydroxy-2-naphthoic acid in the presence of 4-hydroxy-3-nitrobenzoic acid (4H3N). Inserted in the upper right corner is the absorbance at 444nm vs. the concentration of ligand
  • Fig. 5 TZD-assay. Fluorescence spectra resulting from a titration of hexameric insulin with 5-(3-methoxybenzylidene)thiazolidine-2,4-dione in the presence of 5-(4-dimethylamino- benzylidene)thiazolidine-2,4-dione (TZD). Inserted in the upper right corner is the fluorescence at 460 nm vs. the concentration of ligand
  • the present invention is based on the discovery that the His 810 Zn ++ ligand binding sites of the R-state insulin hexamer can be used to obtain an insulin preparation having prolonged action designed for flexible injection regimes including once-daily, based on acid-stabillised insulins.
  • the basic concept underlying the present invention involves reversible attachment of a ligand to the His 810 Zn 2+ site of the R-state hexamer.
  • a suitable ligand binds to the hexamer metal site with one end while other moieties are covalently attachment to the other end.
  • prolonged action via modification of preparation solubility may be obtained in a number of ways.
  • the anions currently used in insulin formulations as allosteric ligands for the R-state hexamers bind only weakly to the His 810 anion site.
  • the present invention which is based on the discovery of suitable higher affinity ligands for these anion sites, provides ligands which are extended to modify timing via changes in hexamer solubility as out- lined above.
  • the His 810 Zn + site consists of a tunnel or cavity with a triangular-shaped cross-section that extends -12 A from the surface of the hexamer down to the His 810 Zn 2+ ion.
  • the diameter of the tunnel varies along its length and, depending on the nature of the ligand occupying the site, the opening can be capped over by the Asn 83 and Phe 81 side chains.
  • the walls of the tunnel are made up of the side chains of the amino acid residues along one face each of the three ⁇ -helices.
  • the side chains from each helix that make up the lining of the tunnel are Phe B1 , Asn 83 , and Leu 86 . Therefore, except for the zinc ion, which is coordinated to three His 810 residues and is positioned at the bottom of the tunnel, the site is principally hydrophobic.
  • substituents on the ligand it may be possible for substituents on the ligand to make H-bonding interactions with Asn 83 and with the peptide linkage to Cys 87 .
  • the present invention originates from a search for compounds with suitable binding proper- ties by using UV-visible and fluorescence based competition assays described herein which are based on the displacement of chromophoric ligands from the R-state His 810 -Zn 2+ site by the incoming ligand in question. These compounds will be referred to as "starter compounds" in the following. These assays are easily transformed into a high-throughput format capable of handling libraries constructed around hits from the initial search of compound databases.
  • this chemical group can be attached (optionally using a spacer group using and synthesis procedures known to those skilled in the art) to a position on the starter compound remote from the Zn 2+ -binding functionality.
  • the invention thus provides pharmaceutical preparation comprising
  • CGr is a chemical group which reversibly binds to a His 810 Zn 2+ site of an insulin hexamer;
  • Lnk is a linker selected from
  • Frg1 is a fragment consisting of 0 to 5 neutral ⁇ - or ⁇ -amino acids
  • Frg2 is a fragment comprising 1 to 20 positively charged groups independently selected from amino or guanidino groups.
  • X is -OH, -NH 2 or a diamino group
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric forms.
  • CGr is a chemical structure selected from the group consisting of car- boxylates, dithiocarboxylates, phenolates, thiophenolates, alkylthiolates, sulfonamides, imi- dazoles, triazoles, 4-cyano-1 ,2,3-triazoles, benzimidazoles, benzotriazoles, purines, thia- zolidinediones, tetrazoles, 5-mercaptotetrazoles, rhodanines, N-hydroxyazoles, hydantoines, thiohydantoines, barbiturates, naphthoic acids and salicylic acids.
  • CGr is a chemical structure selected from the group consisting of benzotriazoles, 3-hydroxy 2-napthoic acids, salicylic acids, tetrazoles, thiazolidinediones, 5- mercaptotetrazoles, or 4-cyano-1 ,2,3-triazoles. In another embodiment CGr is
  • R 1 and R 4 are independently selected from hydrogen or CrCe-alkyl
  • R 2 is hydrogen or d-C 6 -alkyl or aryl, R 1 and R 2 may optionally be combined to form a double bond,
  • R 3 and R 5 are independently selected from hydrogen, halogen, aryl, d-C ⁇ -alkyl, or -C(O)NR 11 R 12 ,
  • a and B are independently selected from d-C 6 -alkylene, arylene, aryl-d-C 6 -alkyl-, aryl-C - Ce-alkenyl- or heteroarylene, wherein the alkylene or alkenylene is optionally substituted with one or more substituents independently selected from R 6 and the arylene or heteroarylene is optionally substituted with up to four substituents R 7 , R 8 , R 9 , and R 10 ,
  • a and R 3 may be connected through one or two valence bonds
  • B and R 5 may be connected through one or two valence bonds
  • R 6 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , aryl, -COOH and -NH 2 ,
  • R 7 , R 8 , R 9 and R 10 are independently selected from
  • each cyclic moiety may optionally be substituted with one or more substituents independently selected from R 14 ,
  • R 11 and R 12 are independently selected from hydrogen, OH, C 1 -C 20 -alkyl, aryl-d-C 6 -alkyl or aryl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R 15 , and the aryl groups may optionally be substituted one or more substituents independently selected from R 16 ; R 11 and R 12 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R 13 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 11 , -C(O)OR 11 , -NR 1 R 12 , and -C(O)NR 11 R 12 ,
  • R 14 is independently selected from halogen, -C(O)OR 11 , -CH 2 C(O)OR 11 , -CH 2 OR 11 , -CN, - CF 3 , -OCF 3 , -NO 2 , -OR 11 , -NR 11 R 12 , S(O) 2 R 11 , aryl and C C 6 -alkyl,
  • R 15 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -Od-C 6 -alkyl, -C(O)OC Ce- alkyl, -COOH and -NH 2 ,
  • Crg is arylene optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • A is selected from ArG1 optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • A is phenylene or naphtylene optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • A is phenylene
  • A is heteroarylene optionally substituted with up to four substituents
  • R 7 , R 8 , R 9 , and R 0 which may be the same or different.
  • A is selected from Het1 optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • A is selected from Het2 optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • A is selected from Het3 optionally substituted with up to four sub- stituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • A is selected from the group consisting of indolylene, benzofu- ranylidene, quinolylene, furylene, thienylene, or pyrrolylene, wherein each heteroaryl may optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • A is benzofuranylene optionally substituted with up to four substituents R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • A is
  • A is carbazolylidene optionally substituted with up to four substituents R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • A is quinolylidene optionally substituted with up to four substituents R 7 , R 8 , R 9 , and R 10 which may be the same or different. In another embodiment A is
  • A is indolylene optionally substituted with up to four substituents R 7 , R , R , and R -10 which may be the same or different.
  • R 7 , R , R , and R -10 which may be the same or different.
  • R 1 is hydrogen
  • R 2 is hydrogen
  • R 1 and R 2 are combined to form a double bond.
  • R 3 is d-Ce-alkyl, halogen, or C(O)NR 16 R 17 .
  • R 3 is d-C 6 -alkyl or C(O)NR 16 R 17 .
  • R 3 is methyl
  • B is phenylene optionally substituted with up to four substituents, R 7 ,
  • R 8 , R 9 , and R 10 which may be the same or different.
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 6 is aryl. In another embodiment R 6 is phenyl.
  • R 7 , R 8 , R 9 and R 10 are independently selected from
  • R 7 , R 8 , R 9 and R 10 are independently selected from
  • each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R 14
  • each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R 14 .
  • R 7 , R 8 , R 9 and R 10 are independently selected from
  • each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R 4 .
  • R 7 , R 8 , R 9 and R 10 are independently selected from • hydrogen, halogen, -OR 11 , -OCrC 6 -alkyl-C(O)OR 11 , or -C(O)OR 11 ,
  • R 11 and R 12 are independently selected from hydrogen, CrC 20 -alkyl, aryl or aryl-d-Ce-alkyl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R 15 , and the aryl groups may optionally be substituted one or more substituents independently selected from R 16 ; R 11 and R 12 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds.
  • R 1 and R 12 are independently selected from hydrogen, CrC 20 -alkyl, aryl or aryl-d-Ce-alkyl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R 15 , and the aryl groups may optionally be substituted one or more substituents independently selected from R 16 .
  • R 11 and R 12 are independently selected from phenyl or phenyl-CrC 6 - alkyl.
  • R 11 and R 12 are methyl.
  • R 13 is independently selected from halogen, CF 3 , OR 11 or NR 11 R 12 . In another embodiment R 13 is independently selected from halogen or OR 11 .
  • R 13 is OR 11 .
  • R 14 is independently selected from halogen, -C(O)OR 11 , -CN, -CF 3 , -
  • R 14 is independently selected from halogen, -C(O)OR 11 , or -OR 11 .
  • R 15 is independently selected from halogen, -CN, -CF 3 , -C(O)Od-C 6 - alkyl.and -COOH.
  • R 15 is independently selected from halogen or -C(O)OCrC 6 -alkyl.
  • R 16 is independently selected from halogen, -C(O)OCrC 6 -alkyl,
  • R 1 ⁇ is independently selected from halogen, -C(O)OCrC 6 -alkyl,
  • R 19 is hydrogen or d-C ⁇ -alkyl
  • R 20 is hydrogen or CrCe-alkyl
  • D and F are a valence bond or d-C 6 -alkylene optionally substituted with one or more substituents independently selected from R 72 ,
  • R 72 is independently selected from hydroxy, d-C ⁇ -alkyl, or aryl,
  • E is CrCe-alkylene, arylene or heteroarylene, wherein the arylene or heteroarylene is optionally substituted with up to three substituents R 21 , R 22 and R 23 ,
  • G is CrC 6 -alkylene, arylene or heteroarylene, wherein the arylene or heteroarylene is op- tionally substituted with up to three substituents R 24 , R 25 and R 26 ,
  • R 17 , R 18 , R 21 , R 22 , R 23 , R 24 , R 25 and R 26 are independently selected from
  • R 27 and R 28 are independently selected from hydrogen, d-Ce-alkyl, aryl-d-C 6 -alkyl or aryl, or R 27 and R 28 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 27 , and -NR 27 R 28 ,
  • R 30 is independently selected from halogen, -C(O)OR 27 , -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 27 , -NR 27 R 28 and d-Ce-alkyl, or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.
  • D is a valence bond
  • D is d-Ce-alkylene optionally substituted with one or more hydroxy, d-Ce-alkyl, or aryl.
  • E is arylene or heteroarylene, wherein the arylene or heteroarylene is optionally substituted with up to three substituents independently selected from R 21 , R 22 and
  • E is arylene optionally substituted with up to three substituents independently selected from R 21 , R 22 and R 23 .
  • E is selected from ArG1 and optionally substituted with up to three substituents independently selected from R 21 , R 22 and R 23 .
  • E is phenylene optionally substituted with up to three substituents independently selected from R 21 , R 22 and R 23 .
  • R , R and R are independently selected from
  • R 2 , R 22 and R 23 are independently selected from
  • the cyclic moieties optionally may be substituted with one or more substituents selected from R 30 .
  • R 21 , R 22 and R 23 are independently selected from
  • R 21 , R 22 and R 23 are independently selected from
  • R 19 is hydrogen or methyl.
  • R 19 is hydrogen.
  • R 27 is Hydrogen, d-C 6 -alkyl or aryl.
  • R 27 is hydrogen or d-C ⁇ -alkyl.
  • R 28 is hydrogen or d-C ⁇ -alkyl.
  • F is a valence bond.
  • F is d-C 6 -alkylene optionally substituted with one or more hydroxy, d-C ⁇ -alkyl, or aryl.
  • G is d-C e -alkylene or arylene, wherein the arylene is optionally substituted with up to three substituents R 24 , R 25 and R 26 .
  • G is CrCe-alkylene or ArG1 , wherein the arylene is optionally substituted with up to three substituents R 24 , R 25 and R 26 .
  • G is d-C ⁇ -alkylene.
  • G is phenylene optionally substituted with up to three substituents R 24 , R 25 and R 26 .
  • R 24 , R 25 and R 26 are independently selected from
  • R 29 • aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-d-C ⁇ -alkoxy, aryl-CrC 6 -alkyl, a ⁇
  • the cyclic moieties optionally may be substituted with one or more substituents selected from R 30 .
  • R 24 , R 25 and R 26 are independently selected from
  • R 24 , R 25 and R 26 are independently selected from
  • the cyclic moieties optionally may be substituted with one or more substituents selected from R 30 .
  • R 24 , R 25 and R 26 are independently selected from
  • R 24 , R 25 and R 26 are independently selected from
  • R 24 , R 25 and R 26 are independently selected from
  • R 20 is hydrogen or methyl. In another embodiment R 20 is hydrogen.
  • R 27 is hydrogen, CrC 6 -alkyl or aryl.
  • R 27 is hydrogen or d-Ce-alkyl or ArG1.
  • R 27 is hydrogen or d-Ce-alkyl.
  • R 28 is hydrogen or d-C 6 -alkyl.
  • R 17 and R 18 are independently selected from
  • R 17 and R 18 are independently selected from • hydrogen, halogen, -CN, -CF 3 , -N ⁇ 2 , -OR 27 , -NR 27 R 28 , or -C(O)OR 27 ,
  • R 17 and R 18 are independently selected from
  • R 17 and R 18 are independently selected from
  • R 17 and R 18 are independently selected from
  • R 27 is hydrogen or d-C ⁇ -alkyl.
  • R 27 is hydrogen, methyl or ethyl.
  • R 28 is hydrogen or d-C 6 -alkyl.
  • R 28 is hydrogen, methyl or ethyl.
  • R 72 is -OH or phenyl.
  • CGr is
  • I is selected from »a valence bond
  • Z 1 is S(O) 2 or CH 2
  • Z 2 is -NH-, -O-or -S-
  • n is 1 or 2
  • R 31 is independently selected from hydrogen, halogen, -CN, -CH 2 CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3
  • R 32 and R 33 are independently selected from hydrogen, d-C 6 -alkyl or d-Ce-alkanoyl,
  • R ⁇ is independently selected from halogen, -CN, -CF 3 , -OCF 3l -OR 35 , and -NR 35 R 36 ,
  • R 35 and R 36 are independently selected from hydrogen, d-Ce-alkyl, aryl-d-C 6 -alkyl or aryl, or R 35 and R 36 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R 37 is independently selected from halogen, -C(O)OR 35 , -C(O)H, -CN, -CF 3 , -OCF 3l -NO 2 , - OR 35 , -NR 35 R 36 , d-Ce-alkyl or d-Ce-alkanoyl,
  • I is a valence bond, -CH 2 N(R 32 )-, or -SO 2 N(R 33 )-. In another embodiment I is a valence bond. In another embodiment J is
  • R 32 and R 33 are independently selected from hydrogen or d-C 6 -alkyl.
  • R 34 is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -SCF 3 , -NO 2 , -OR 35 ,
  • R 34 is hydrogen, halogen, -CF 3 , -NO 2 , -OR 35 , -NR ⁇ R 36 , -SR 35 ,
  • R 34 is hydrogen, halogen, -CF 3 , -NO 2 , -OR 35 , -NR ⁇ R 36 , or
  • R 34 is hydrogen, halogen, or -OR 35 .
  • R 35 and R 36 are independently selected from hydrogen, d-C ⁇ -alkyl, or aryl.
  • R 35 and R 36 are independently selected from hydrogen or d-C ⁇ alkyl.
  • R 37 is halogen, -C(O)OR 35 , -CN, -CF 3 , -OR 35 , -NR 35 R 36 , C C ⁇ -alkyl or CrC ⁇ -alkanoyl.
  • R 37 is halogen, -C(O)OR 35 , -OR 35 , -NR 35 R 38 , d-C 6 -alkyl or d-Ce- alkanoyl.
  • R 37 is halogen, -C(O)OR 35 or -OR 35 .
  • CGr is
  • U is a valence bond, d-C 6 -alkenylene, -d-C 6 -alkyl-O- or d-C 6 -alkylene wherein any d- Ce-alkyl moiety is optionally substituted with d-Ce-alkyl,
  • R 38 is CrCe-alkyl, aryl, wherein the alkyl or aryl moieties are optionally substituted with one or more substituents independently selected from R 39 ,
  • R 39 is independently selected from halogen, cyano, nitro, amino,
  • M is a valence bond, arylene or heteroarylene, wherein the aryl or heteroaryl moieties are optionally substituted with one or more substituents independently selected from R 40 ,
  • R 40 is selected from
  • R 41 and R 42 are independently selected from hydrogen, -OH, d-Ce-alkyl, d-Ce-alkenyl, aryl- d-C ⁇ -alkyl or aryl, wherein the alkyl moieties may optionally be substituted with one or more substituents independently selected from R 45 , and the aryl moieties may optionally be substituted with one or more substituents independently selected from R 46 ; R 41 and R 42 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R 43 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 41 , and -NR 41 R 42
  • R 44 is independently selected from halogen, -C(O)OR 41 , -CH 2 C(O)OR 41 , -CH 2 OR 41 , -CN, -
  • R 45 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -O-d-C ⁇ -alkyl, -C(O)-O-d-
  • R 49 is independently selected from halogen and -COOH
  • any alkylene, alkenylene , alkynylene, arylene and heteroarylene moiety is optionally substituted with one or more substituents independently selected from R 50 ,
  • R 51 and R 52 are independently selected from hydrogen and d-C ⁇ -alkyl
  • R 53 is independently selected from C C ⁇ -alkyl, d-C 6 -alkoxy, -CrC 6 -alkyl-COOH, -C 2 - C 6 -alkenyl-COOH, -OR 51 , -NO 2 , halogen, -COOH, -CF 3 , -CN, or -N(R 51 R 52 ),
  • CrCe-alkyl moiety is optionally substituted with R 38 .
  • K is a valence bond or d-Ce-alkylene, wherein any d-C 6 -alkyl moiety is optionally substituted with R 38 .
  • K is a valence bond
  • U is a valence bond or -d-C ⁇ -alkyl-O-.
  • M is arylene or heteroarylene, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from
  • M is ArG1 or Het1 , wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R 40 .
  • M is ArG1 or Het2, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R 40 .
  • M is ArG1 or Het3, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R 40 .
  • M is phenylene optionally substituted with one or more substituents independently selected from R 40 .
  • M is indolylene optionally substituted with one or more substituents independently selected from R 40 .
  • M is carbazolylene optionally substituted with one or more substitu- ents independently selected from R 40 .
  • M is
  • R 40 is selected from
  • R 40 is selected from
  • R 40 is selected from
  • R 41 and R 42 are independently selected from hydrogen, d-Ce-alkyl, or aryl, wherein the aryl moieties may optionally be substituted with halogen or -COOH.
  • R 41 and R 42 are independently selected from hydrogen, methyl, ethyl, or phenyl, wherein the phenyl moieties may optionally be substituted with halogen or - COOH.
  • R 47 and R 48 are independently selected from hydrogen, methyl and phenyl.
  • T is
  • R 50 is d-C ⁇ -alkyl, d-Ce-alkoxy, aryl, aryloxy, aryl-d-C 6 -alkoxy , -OR 51 , -N0 2 , halogen, -COOH, -CF 3 , wherein any aryl moiety is optionally substituted with one or more R 53 .
  • R 50 is d-Ce-alkyl, aryloxy, aryl-d-C 6 -alkoxy , -OR 51 , halogen, -COOH, -CF 3 , wherein any aryl moiety is optionally substituted with one or more R 53 .
  • R 50 is d-Ce-alkyl, ArG1-O-, ArG1-d-C 6 -alkoxy , -OR 51 , halogen, -COOH, -CF 3 , wherein any aryl moiety is optionally substituted with one or more R 53 .
  • R 50 is phenyl, methyl or ethyl.
  • R 50 is methyl or ethyl.
  • R 51 is methyl.
  • R 53 is d-Ce-alkyl, d-C 6 -alkoxy, -OR 51 , halogen.or -CF 3 .
  • V is Ci-C 6 -alkylene, arylene, heteroarylene, arylene-d-e-alkylene or arylene-C 2 - 6 - alkenylene, wherein the alkylene or alkenylene is optionally substituted with one or more substituents independently selected from R 54 , and the arylene or heteroarylene is optionally substituted with one or more substituents independently selected from R 55 ,
  • R 54 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , aryl, -COOH and -NH 2
  • R 55 is independently selected from
  • R 58 which may optionally be substituted with one or more substituents selected from R 58 , • aryl, aryloxy, aryloxycarbonyl, aroyl, arylsulfanyl, aryl-d-C ⁇ -alkoxy, aryl-d-C ⁇ -alkyl, aryl-C 2 -C 6 -alkenyl, aroyl-C 2 -C 6 -alkenyl, aryl-C 2 -C 6 -alkynyl, heteroaryl, heteroaryl-d- C ⁇ -alkyl, heteroaryl-C 2 -C 6 -alkenyl or heteroaryl-C 2 -C 6 -alkynyl,
  • R 58 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 56 , and -NR 56 R 57 ,
  • R 59 is independently selected from halogen, -C(0)OR 56 , -CH 2 C(0)OR 56 , -CH 2 OR 56 , -CN, - CF 3 , -OCF 3 , -N0 2 , -OR 56 , -NR 56 R 57 and d-C ⁇ -alkyl,
  • R 62 is d-C ⁇ -alkyl, aryl optionally substituted with one or more substituents independently selected from halogen, or heteroaryl optionally substituted with one or more d-C 6 -alkyl jnde- pendently, or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.
  • V is arylene, heteroarylene, or arylene-d.C ⁇ -alkylene, wherein the alkylene is optionally substituted with one or more substituents independently selected R 54 , and the arylene or heteroarylene is optionally substituted with one or more substituents independently selected from R 55 .
  • V is arylene, Het1, or arylene-d-C ⁇ -alkylene, wherein the alkylene is optionally substituted with one or more substituents independently selected from R 54 , and the arylene or heteroarylene moiety is optionally substituted with one or more substituents independently selected from R 55 .
  • V is arylene, Het2, or arylene-d.C 6 -alkylene, wherein the alkylene is optionally substituted with one or more substituents independently selected from R 54 , and the arylene or heteroarylene moiety is optionally substituted with one or more substituents inde- pendently selected from R 55 .
  • V is arylene, Het3, or arylene-d.C 6 -alkylene, wherein the alkylene is optionally substituted with one or more substituents independently selected from R 54 , and the arylene or heteroarylene moiety is optionally substituted with one or more substituents independently selected from R 55 .
  • V is arylene optionally substituted with one or more substituents independently selected from R 55 .
  • V is ArG1 optionally substituted with one or more substituents independently selected from R 55 .
  • V is phenylene, naphthylene or anthranylene optionally substituted with one or more substituents independently selected from R 55 .
  • V is phenylene optionally substituted with one or more substituents independently selected from R 55 .
  • R 55 is independently selected from
  • R 55 is independently selected from
  • R 55 is independently selected from halogen, -OR 56 , -NR 56 R 57 ,
  • R 55 is independently selected from halogen, -OR 56 , -NR 56 R 57 ,
  • R 56 and R 57 are independently selected from hydrogen or d-Ci 2 -alkyl, R 56 and R 57 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom.
  • R 56 and R 57 are independently selected from hydrogen or methyl, ethyl, propyl butyl, R 56 and R 57 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom.
  • AA is d-C ⁇ -alkylene, arylene, heteroarylene, arylene-Ci-C ⁇ -alkylene or arylene-C 2 .
  • C ⁇ -alkenylene wherein the alkylene or alkenylene is optionally substituted with one or more substituents independently selected from R 63 , and the arylene or heteroarylene is optionally substituted with one or more substituents independently selected from R 64 ,
  • R 63 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , aryl, -COOH and -NH 2 ,
  • R 64 is independently selected from
  • R 67 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 65 , and -NR 65 R 66 ,
  • R 68 is independently selected from halogen, -C(0)OR 65 , -CH 2 C(0)OR 65 , -CH 2 OR 65 , -CN, - CF 3 , -OCF 3 , -N0 2 , -OR 65 , -NR 65 R 66 and CrC 6 -alkyl,
  • R 69 is independently selected from d-Ce-alkyl, aryl optionally substituted with one or more halogen, or heteroaryl optionally substituted with one or more d-C ⁇ -alkyl
  • R 70 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -Od-Ce-alkyl, -C(0)OCrC 6 - alkyl, -COOH and -NH 2 ,
  • AA is arylene, heteroarylene or arylene-d-Ce-alkylene, wherein the alkylene is optionally substituted with one or more R 63 , and the arylene or heteroarylene is optionally substituted with one or more substituents independently selected from R 64 .
  • AA is arylene or heteroarylene, wherein the arylene or heteroarylene is optionally substituted with one or more substituents independently selected from R 64 .
  • AA is ArG1 or Het1 optionally substituted with one or more substitu- ents independently selected from R 64 .
  • AA is ArG1 or Het2 optionally substituted with one or more substituents independently selected from R 64 .
  • AA is ArG1 or Het3 optionally substituted with one or more substituents independently selected from R 64 .
  • AA is phenylene, naphtylene, anthrylene, carbazolylene, thienylene, pyridylene, or benzodioxylene optionally substituted with one or more substituents independently selected from R 64 .
  • AA is phenylene or naphtylene optionally substituted with one or more substituents independently selected from R 64 .
  • R 64 is independently selected from hydrogen, halogen, -CF 3 , -OCF 3 , -OR 65 , -NR 65 R 66 , d-C 6 -alkyl, -OC(0)R 65 , -Od-C 6 -alkyl-C(0)OR 65 , aryl-C 2 -C 6 -alkenyl, aryloxy or aryl, wherein d-C 6 -alkyl is optionally substituted with one or more substituents independently selected from R 67 , and the cyclic moieties optionally are substituted with one or more substituents independently selected from R 68 .
  • R 64 is independently selected from halogen, -CF 3 , -OCF 3 , -OR 65 , -NR 65 R 66 , methyl, ethyl, propyl, -OC(O)R 65 , -OCH 2 -C(0)OR 65 , -OCH 2 -CH 2 -C(0)OR 65 , phenoxy optionally substituted with one or more substituents independently selected from R 68 .
  • R 65 and R 66 are independently selected from hydrogen, CF 3 , d-C 12 -alkyl, aryl, or heteroaryl optionally substituted with one or more substituents independently selected from R 71 .
  • R 85 and R 66 are independently hydrogen, d-C 12 -alkyl, aryl, or het- eroaryl optionally substituted with one or more substituents independently selected from R 71 .
  • R 65 and R 66 are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het1 optionally substituted with one or more substituents independently selected from R 71 .
  • R 65 and R 66 are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het2 optionally substituted with one or more substituents independently selected from R 71 .
  • R 65 and R 66 are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het3 optionally substituted with one or more substituents independently selected from R 71 .
  • R 65 and R 66 are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, phenyl, naphtyl, thiadiazolyl optionally substituted with one or more R 71 independently; or isoxazoiyl optionally substituted with one or more substituents independently selected from R 71 .
  • R 71 is halogen or d-C 6 -alkyl.
  • R 71 is halogen or methyl.
  • Frg1 consists of 0 to 5 neutral amino acids independently selected from the group consisting of Gly, Ala, Thr, and Ser. In another embodiment Frg1 consists of 0 to 5 Gly. In another embodiment Frg1 consists of 0 Gly. In another embodiment Frg1 consists of 1 Gly. In another embodiment Frg1 consists of 2 Gly. In another embodiment Frg1 consists of 3 Gly. In another embodiment Frg 1 consists of 4 Gly. In another embodiment Frg1 consists of 5 Gly. In another embodiment G B is of the formula B 1 -B 2 -C(0)-, B 1 -B 2 -S0 2 - or B 1 -B 2 -CH 2 -, wherein B 1 and B 2 are as defined in claim 1.
  • G 8 is of the formula B 1 -B 2 -C(0)-, B 1 -B 2 -S0 2 - or B 1 -B 2 -NH-, wherein B 1 and B 2 are as defined in claim 1.
  • G B is of the formula B 1 -B 2 -C(0)-, B 1 -B 2 -CH 2 - or B 1 -B 2 -NH-, wherein B 1 and B 2 are as defined in claim 1.
  • G 8 is of the formula B 1 -B 2 -CH 2 -, B 1 -B 2 -S ⁇ 2 - or B 1 -B 2 -NH-, wherein B 1 and B 2 are as defined in claim 1.
  • G 8 is of the formula B 1 -B 2 -C(0)- or B 1 -B 2 -S0 2 -, wherein B 1 and B 2 are as defined in claim 1.
  • G 8 is of the formula B 1 -B 2 -C(0)- or B 1 -B 2 -CH 2 -, wherein B 1 and B 2 are as defined in claim 1.
  • G B is of the formula B 1 -B 2 -C(0)- or B 1 -B 2 -NH-, wherein B 1 and B 2 are as defined in claim 1.
  • G 8 is of the formula B 1 -B 2 -CH 2 - or B 1 -B 2 -S0 2 - , wherein B 1 and B 2 are as defined in claim 1.
  • G 8 is of the formula B 1 -B 2 -NH- or B 1 -B 2 -S0 2 - , wherein B 1 and B 2 are as defined in claim 1.
  • G 8 is of the formula B 1 -B 2 -CH 2 - or B -B 2 -NH- , wherein B 1 and B 2 are as defined in claim 1.
  • G 8 is of the formula B 1 -B 2 -C(0)-.
  • G 8 is of the formula B 1 -B 2 -CH 2 -.
  • G 8 is of the formula B 1 -B 2 -S0 2 -.
  • G B is of the formula B 1 -B -NH-.
  • B 1 is a valence bond, -0-, or -S-. In another embodiment B 1 is a valence bond, -0-, or -N(R 6 )-. In another embodiment B 1 is a valence bond, -S-, or -N(R 6 )-. In another embodiment B 1 is -O-, -S- or -N(R 6 )-. In another embodiment B 1 is a valence bond or -O-. In another embodiment B 1 is a valence bond or -S-. In another embodiment B 1 is a valence bond or -N(R 6 )-. In another embodiment B 1 is -O-or -S-.
  • B 1 is -0-or -N(R 6 )-. In another embodiment B 1 is -S-or -N(R 6 )-. In another embodiment B 1 is a valence bond. In another embodiment B 1 is -0-. In another embodiment B 1 is -S-. In another embodiment B 1 is -N(R 6 )-.
  • B z is a valence bond, d-C 18 -alkylene, arylene, heteroarylene, -C
  • B 2 is a valence bond, d-da-alkylene, arylene, heteroarylene, -d- C 18 -alkyl-aryl-, and the alkylene and arylene moieties are optionally substituted as defined in claim 1.
  • B 2 is a valence bond, C C 18 -alkylene, arylene, -CrC ⁇ 8 -alkyl-aryl-, and the alkylene and arylene moieties are optionally substituted as defined in claim 1.
  • B 2 is a valence bond or -d-C 18 -alkylene, and the alkylene moieties are optionally substituted as defined in claim 1.
  • Frg2 comprises 1 to 16 positively charged groups.
  • Frg2 comprises 1 to 12 positively charged groups.
  • Frg2 comprises 1 to 10 positively charged groups.
  • Frg2 is a fragment containing basic amino acids independently selected from the group consisting of Lys and Arg and D-isomers of these.
  • the basic amino acid is Arg.
  • X is -OH or -NH 2 .
  • X is -NH 2 .
  • the pharmaceutical preparation further comprises at least 3 phenolic molecules.
  • the acid-stabilised insulin is selected from the group consisting of A21G
  • A21G, B28K, B29P A21G, B28D A21G, B28E A21G, B3K, B29E A21G, desB27
  • zinc ions are present in an amount corresponding to 10 to 40 ⁇ g
  • zinc ions are present in an amount corresponding to 10 to 26 ⁇ g
  • the ratio between insulin and the zinc-binding ligand of the invention is in the range from 99:1 to 1 :99.
  • the ratio between insulin and the zinc-binding ligand of the invention is in the range from 95:5 to 5:95
  • the ratio between between insulin and the zinc-binding ligand of the invention is in the range from 80:20 to 20:80 In another embodiment the ratio between between insulin and the zinc-binding ligand of the invention is in the range from 70:30 to 30:70
  • the invention relates to a method of preparing a zinc-binding ligand of the invention comprising the steps of
  • the invention in another aspect relates to a method of prolonging the action of an acid- stabilised insulin preparation which comprises adding a zinc-binding ligand of the invention to the acid-stabilised insulin preparation.
  • the invention in another aspect relates to a method of treating type 1 or type 2 diabetes comprising administering to a patient in need thereof a theraputically effective amount of a pharmaceutical preparation comprising 1. Acid-stabilised insulin 2. Zinc ions
  • an embodiment 1 which is a pharmaceutical prepa- ration comprising 1.
  • CGr is a chemical group which reversibly binds to a His 810 Zn 2+ site of an insulin hexamer
  • Lnk is a linker selected from
  • Frg1 is a fragment consisting of 0 to 5 neutral ⁇ - or ⁇ -amino acids
  • Frg2 is a fragment comprising 1 to 20 positively charged groups independently selected from amino or guanidino groups.
  • X is -OH, -NH 2 or a diamino group
  • Embodiment 2 A pharmaceutical preparation according to embodiment 1 wherein CGr is a chemical structure selected from the group consisting of carboxylates, dithiocarboxylates, .
  • Embodiment 3 A pharmaceutical preparation according to embodiment 2 wherein CGr is a chemical structure selected from the group consisting of benzotriazoles, 3-hydroxy 2- napthoic acids, salicylic acids, tetrazoles, thiazolidinediones, 5-mercaptotetrazoles, or 4- cyano-1 ,2,3-triazoles.
  • Embodiment 4 A pharmaceutical composition according to any one of the embodiments 1 to 3 wherein CGr is
  • R 1 , R 1 * and R 4 are independently selected from hydrogen or d-Ce-alkyl, R 2 and R 2 * are hydrogen or d-C 6 -alkyl or aryl, R 1 and R 2 may optionally be combined to form a double bond, R 1 * and R 2 * may optionally be combined to form a double bond,
  • R 3 , R 3 * and R 5 are independently selected from hydrogen, halogen, aryl optionally substituted with one or more substituents independently selected from R 16 , d-C 6 -alkyl, or -C(0)NR 11 R 12 ,
  • A, A 1 and B are independently selected from d-Ce-alkyl, aryl, aryl-d-Ce-alkyl, -NR 11 -aryl, aryl-C 2 -C 6 -alkenyl or heteroaryl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from R 6 and the aryl or heteroaryl is optionally substituted with up to four substituents R 7 , R 8 , R 9 , and R 10 , A and R 3 may be connected through one or two valence bonds, B and R 5 may be connected through one or two valence bonds,
  • R 6 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , aryl, -COOH and -NH 2
  • R 7 , R 8 , R 9 and R 10 are independently selected from
  • each cyclic moiety may optionally be substituted with one or more substituents independently selected from R 14 ,
  • R 11 and R 12 are independently selected from hydrogen, OH, CrC 20 -alkyl, aryl-d-Ce-alkyl or aryl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R 15 , and the aryl groups may optionally be substituted one or more substituents independently selected from R 16 ; R 11 and R 12 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R 13 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 11 , -C(0)OR 11 , -NR 11 R 12 , and -C(0)NR 11 R 12 ,
  • Embodiment 8. A pharmaceutical composition according to any one of the embodiment s 4 to 7 wherein Y is -O- or -S-.
  • Embodiment 9. A pharmaceutical composition according to embodiment 8 wherein Y is -O-.
  • Embodiment 10. A pharmaceutical composition according to embodiment 8 wherein Y is -NH-.
  • Embodiment 11 A pharmaceutical composition according to embodiment 8 wherein Y is -S-.
  • Embodiment 12 A pharmaceutical composition according to any one of the embodiment s 4 to 11 wherein A is aryl optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • Embodiment 13 A pharmaceutical composition according to embodiment 12 wherein A is selected from ArG1 optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • Embodiment 14 A pharmaceutical composition according to embodiment 13 wherein A is phenyl or naphtyl optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • Embodiment 15 A pharmaceutical composition according to embodiment 14 wherein A is
  • Embodiment 17 A pharmaceutical composition according to any one of the embodiment s 4 to 11 wherein A is heteroaryl optionally substituted with up to four substituents, R 7 , R a , R 9 , and R 10 which may be the same or different.
  • Embodiment 18 A pharmaceutical composition according to embodiment 17 wherein A is selected from Het1 optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • Embodiment 19 A pharmaceutical composition according to embodiment 18 wherein A is selected from Het2 optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • Embodiment 20 A pharmaceutical composition according to embodiment 19 wherein A is selected from Het3 optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • Embodiment 21 A pharmaceutical composition according to embodiment 20 wherein A is selected from the group consisting of indolyl, benzofuranyl, quinolyl, furyl, thienyl, or pyrrolyl, wherein each heteroaryl may optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • Embodiment 22 A pharmaceutical composition according to embodiment 20 wherein A is benzofuranyl optionally substituted with up to four substituents R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • Embodiment 23 A pharmaceutical composition according to embodiment 22 wherein A is
  • Embodiment 26 A pharmaceutical composition according to embodiment 20 wherein A is quinolyl optionally substituted with up to four substituents R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • Embodiment 27 A pharmaceutical composition according to embodiment 26 wherein A is
  • Embodiment 28 A pharmaceutical composition according to embodiment 20 wherein A is indolyl optionally substituted with up to four substituents R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • Embodiment 29 A pharmaceutical composition according to embodiment 28 wherein A is
  • Embodiment 30 A pharmaceutical composition according to any one of the embodiment s 4 to 29 wherein R 1 is hydrogen.
  • Embodiment 31 A pharmaceutical composition according to any one of the embodiment s 4 to 30 wherein R 2 is hydrogen.
  • Embodiment 32. A pharmaceutical composition according to any one of the embodiment s 4 to 29 wherein R 1 and R 2 are combined to form a double bond.
  • Embodiment 33 A pharmaceutical composition according to any one of the embodiment s 4 to 32 wherein R 3 is d-Ce-alkyl, halogen, or C(0)NR 16 R 17 .
  • Embodiment 34 A pharmaceutical composition according to embodiment 33 wherein R 3 is d-Ce-alkyl or C(0)NR 16 R 17 .
  • Embodiment 35 A pharmaceutical composition according to embodiment 34 wherein R 3 is methyl.
  • Embodiment 36 A pharmaceutical composition according to any one of the embodiment s 4 to 11 wherein B is phenyl optionally substituted with up to four substituents, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • Embodiment 37 A pharmaceutical composition according to any one of the embodiment s 4 to 11 or 36 wherein R 4 is hydrogen.
  • Embodiment 38. A pharmaceutical composition according to any one of the embodiment s 4 to 11 or 36 to 37 wherein R 5 is hydrogen.
  • Embodiment 39 A pharmaceutical composition according to any one of the embodiment s 4 to 38 wherein R 6 is aryl.
  • Embodiment 40. A pharmaceutical composition according to embodiment 39 wherein R 6 is phenyl.
  • Embodiment 41 A pharmaceutical composition according to any one of the embodiment s 4 to 40 wherein R 7 , R 8 , R 9 and R 10 are independently selected from
  • Embodiment 43 A pharmaceutical composition according to embodiment 42 wherein R ? , R 8 , R 9 and R 10 are independently selected from
  • Embodiment 44 A pharmaceutical composition according to embodiment 43 wherein R 7 , R 8 , R 9 and R 10 are independently selected from
  • Embodiment 45 A pharmaceutical composition according to embodiment 44 wherein R 7 , R 8 , R 9 and R 10 are independently selected from • hydrogen, halogen, -OR 11 , -Od-Ce-alkyl-C(0)OR 11 , or -C(0)OR 11 ,
  • Embodiment 46 A pharmaceutical composition according to embodiment 45 wherein R 7 , R 8 , R 9 and R 10 are independently selected from
  • Embodiment 47 A pharmaceutical composition according to any one of the embodiment s 4 to 46 wherein R 11 and R 12 are independently selected from hydrogen, CrC 20 -alkyl, aryl or aryl-d-Ce-alkyl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R 15 , and the aryl groups may optionally be substituted one or more substituents independently selected from R 16 ; R 11 and R 12 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitro- gen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds.
  • Embodiment 48 A pharmaceutical composition according to embodiment 47 wherein R 11 and R 12 are independently selected from hydrogen, CrC 20 -alkyl, aryl or aryl-d-Ce-alkyl, wherein the alkyl groups may optionally be substituted with one or more substituents independently selected from R 15 , and the aryl groups may optionally be substituted one or more substituents independently selected from R 16 .
  • Embodiment 49 A pharmaceutical composition according to embodiment 48 wherein R 11 and R 12 are independently selected from phenyl or phenyl-d-C e -alkyl.
  • Embodiment 50 A pharmaceutical composition according to embodiment 48 wherein one or both of R 11 and R 12 are methyl.
  • Embodiment 51 A pharmaceutical composition according to any one of the embodiment s 4 to 50 wherein R 13 is independently selected from halogen, CF 3 , OR 11 or NR 1 R 12 .
  • Embodiment 52 A pharmaceutical composition according to embodiment 51 wherein R 13 is independently selected from halogen or OR 11 .
  • Embodiment 53 A pharmaceutical composition according to embodiment 52 wherein R 13 is
  • Embodiment 54 A pharmaceutical composition according to any one of the embodiment s 4 to 53 wherein R 14 is independently selected from halogen, -C(0)OR 11 , -CN, -CF 3 , -OR 11 ,
  • Embodiment 55 A pharmaceutical composition according to embodiment 54 wherein R 14 is independently selected from halogen, -C(0)OR 11 , or -OR 11 .
  • Embodiment 56 A pharmaceutical composition according to any one of the embodiment s 4 to 55 wherein R 15 is independently selected from halogen, -CN, -CF 3 , -C(0)Od-C 6 -alkyl,and
  • Embodiment 57 A pharmaceutical composition according to embodiment 56 wherein R 15 is independently selected from halogen or -C(0)OCrC 6 -alkyl.
  • Embodiment 58 A pharmaceutical composition according to any one of the embodiment s 4 to 57 wherein R 16 is independently selected from halogen, -C(0)OCrC 6 -alkyl, -COOH, -N0 2 ,
  • Embodiment 59 A pharmaceutical composition according to embodiment 58 wherein R 16 is independently selected from halogen, -C(0)OC Ce-alkyl, -COOH, -N0 2 , or d-C 6 -alkyl.
  • Embodiment 60 A pharmaceutical composition according to any one of the embodiment s 1 to 3 wherein CGr is
  • R 19 is hydrogen or d-C 6 -alkyl
  • R 20 is hydrogen or d-Ce-alkyl
  • D, D 1 and F are a valence bond, d-C 6 -alkylene or d-C ⁇ -alkenylene optionally substituted with one or more substituents independently selected from R 72 ,
  • R is independently selected from hydroxy, d-C 6 -alkyl, or aryl
  • E is CrC 6 -alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with up to three substituents R 21 , R 22 and R 23 ,
  • G and G 1 are d-C ⁇ -alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally sub- stituted with up to three substituents R 24 , R 25 and R 26 ,
  • R 17 , R 18 , R 21 , R 22 , R 23 , R 24 , R 25 and R 26 are independently selected from
  • R 27 and R 28 are independently selected from hydrogen, d-C ⁇ -alkyl, aryl-d-C ⁇ -alkyl or aryl, or R 27 and R 28 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds, R 29 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 27 , and -NR 27 R 28 ,
  • R 30 is independently selected from halogen, -C(0)OR 27 , -CN, -CF 3 , -OCF 3 , -N0 2 , -OR 27 , -NR 27 R 28 and d-Ce-alkyl, or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.
  • Embodiment 61 A pharmaceutical composition according to embodiment 60 wherein D is a valence bond.
  • Embodiment 62 A pharmaceutical composition according to embodiment 60 wherein D is CrC 6 -alkylene optionally substituted with one or more hydroxy, d-Ce-alkyl, or aryl.
  • Embodiment 63 A pharmaceutical composition according to any one of the embodiment s 60 to 62 wherein E is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with up to three substituents independently selected from R 21 , R 22 and R 23 .
  • Embodiment 64 A pharmaceutical composition according to embodiment 63 wherein E is aryl optionally substituted with up to three substituents independently selected from R 21 , R 22 and R 23 .
  • Embodiment 65 A pharmaceutical composition according to embodiment 64 wherein E is selected from ArG1 and optionally substituted with up to three substituents independently selected from R 21 , R 22 and R 23 .
  • Embodiment 66 A pharmaceutical composition according to embodiment 65 wherein E is phenyl optionally substituted with up to three substituents independently selected from R 21 ,
  • Embodiment 67 A pharmaceutical composition according to embodiment 66 wherein CGr is
  • Embodiment 68 A pharmaceutical composition according to any one of the embodiment s 60 to 67 wherein R 21 , R 22 and R 23 are independently selected from
  • Embodiment 69 A pharmaceutical composition according to embodiment 68 wherein R 21 , R 22 and R 23 are independently selected from
  • Embodiment 71 A pharmaceutical composition according to embodiment 70 wherein R 21 ,
  • R 22 and R 23 are independently selected from
  • Embodiment 72 A pharmaceutical composition according to embodiment 71 wherein R 21 , R 22 and R 23 are independently selected from
  • Embodiment 73 A pharmaceutical composition according to any one of the embodiment s 60 to 72 wherein R 9 is hydrogen or methyl.
  • Embodiment 74 A pharmaceutical composition according to embodiment 73 wherein R 19 is hydrogen.
  • Embodiment 75 A pharmaceutical composition according to any one of the embodiment s 60 to 74 wherein R 27 is Hydrogen, d-C 6 -alkyl or aryl.
  • Embodiment 76 A pharmaceutical composition according to embodiment 75 wherein R 27 is hydrogen or d-C 6 -alkyl.
  • Embodiment 77 A pharmaceutical composition according to any one of the embodiment s 60 to 76 wherein R 28 is hydrogen or d-C 6 -alkyl.
  • Embodiment 78 A pharmaceutical composition according to embodiment 60 wherein F is a valence bond.
  • Embodiment 79 A pharmaceutical composition according to embodiment 60 wherein F is d- C ⁇ -alkylene optionally substituted with one or more hydroxy, CrC 6 -alkyl, or aryl.
  • Embodiment 80 A pharmaceutical composition according to any one of the embodiment s 60 or 78 to 79 wherein G is d-C 6 -alkyl or aryl, wherein the aryl is optionally substituted with up to three substituents R 24 , R 25 and R 26 .
  • Embodiment 81 A pharmaceutical composition according to any one of the embodiment s 60 or 78 to 79 wherein G is d-Ce-alkyl or ArG1 , wherein the aryl is optionally substituted with up to three substituents R 24 , R 25 and R 26 .
  • Embodiment 82 A pharmaceutical composition according to embodiment 80 wherein G is d-Ce-alkyl.
  • Embodiment 83 A pharmaceutical composition according to embodiment 82 wherein G is phenyl optionally substituted with up to three substituents R 24 , R 25 and R 26 .
  • Embodiment 84 A pharmaceutical composition according to any one of the embodiment s 60 to 83 wherein R 24 , R 25 and R 26 are independently selected from
  • the cyclic moieties optionally may be substituted with one or more substituents selected from R 30 .
  • Embodiment 85 A pharmaceutical composition according to embodiment 84 wherein R 24 ,
  • R 25 and R 26 are independently selected from
  • Embodiment 86 A pharmaceutical composition according to embodiment 85 wherein R 24 ,
  • R 25 and R 26 are independently selected from
  • Embodiment 87 A pharmaceutical composition according to embodiment 86 wherein R 21 , R 22 and R 23 are independently selected from
  • Embodiment 89 A pharmaceutical composition according to embodiment 88 wherein R 21 , R 22 and R 23 are independently selected from
  • Embodiment 90 A pharmaceutical composition according to any one of the embodiment s 60 or 78 to 89 wherein R 20 is hydrogen or methyl.
  • Embodiment 91 A pharmaceutical composition according to embodiment 90 wherein R 20 is hydrogen.
  • Embodiment 92 A pharmaceutical composition according to any one of the embodiment s 60 or 78 to 91 wherein R 27 is hydrogen, d-d-alkyl or aryl.
  • Embodiment 93 A pharmaceutical composition according to embodiment 92 wherein R 27 is hydrogen or d-Ce-alkyl or ArG1.
  • Embodiment 94 A pharmaceutical composition according to embodiment 93 wherein R 27 is hydrogen or d-C 6 -alkyl.
  • Embodiment 95 A pharmaceutical composition according to any one of the embodiment s 60 or 78 to 93 wherein R 28 is hydrogen or d-C 6 -alkyl.
  • Embodiment 96 A pharmaceutical composition according to embodiment 60 wherein R l 7 and R 18 are independently selected from
  • Embodiment 97 A pharmaceutical composition according to embodiment 96 wherein R 17 and R 18 are independently selected from
  • Embodiment 98 A pharmaceutical composition according to embodiment 97 wherein R 17 and R 18 are independently selected from • hydrogen, halogen, -CN, -CF 3 , -N0 2 , -OR 27 , -NR 27 R 28 , or -C(0)OR 27 • methyl, ethyl propyl optionally substituted with one or more substituents independently selected from R 29
  • Embodiment 99 A pharmaceutical composition according to embodiment 98 wherein R 1 r and R 18 are independently selected from
  • Embodiment 100 A pharmaceutical composition according to embodiment 99 wherein R 17 and R 18 are independently selected from
  • Embodiment 101 A pharmaceutical composition according to any one of the embodiment s 60 to 100 wherein R 27 is hydrogen or d-Ce-alkyl.
  • Embodiment 102 A pharmaceutical composition according to embodiment 101 wherein R 27 is hydrogen, methyl or ethyl.
  • Embodiment 103 A pharmaceutical composition according to any one of the embodiment s
  • Embodiment 104 A pharmaceutical composition according to embodiment 103 wherein R 28 is hydrogen, methyl or ethyl.
  • Embodiment 105 A pharmaceutical composition according to any one of the embodiment s
  • R 72 is -OH or phenyl.
  • Embodiment 106 A pharmaceutical composition according to embodiment 60 wherein CGr is
  • Embodiment 107 A pharmaceutical composition according to any one of the embodiment s 1 to 3 wherein CGr is of the form H-l-J-
  • n 1 or 2
  • R 31 is independently selected from hydrogen, halogen, -CN, -CH 2 CN, -CHF 2 , -CF 3 , -OCF 3
  • R 32 and R 33 are independently selected from hydrogen, d-C 6 -alkyl or d-Ce-alkanoyl,
  • R 34 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 35 , and -NR R 36 ,
  • R 35 and R 36 are independently selected from hydrogen, d-Ce-alkyl, aryl-d-Ce-alkyl or aryl, or R 35 and R 36 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R 37 is independently selected from halogen, -C(0)OR 35 , -C(0)H, -CN, -CF 3 , -OCF 3 , -NO 2 , - OR 35 , -NR 35 R 36 , Ci-C 6 -alkyl or C C 6 -alkanoyl,
  • Embodiment 108 A pharmaceutical composition according to embodiment 107 wherein CGr is of the form H-l-J, wherein H is
  • phenyl, naphthalene or benzocarbazole rings are optionally substituted with one or more substituents independently selected from R 31 ,
  • R 31 is independently selected from hydrogen, halogen, -CN, -CH 2 CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(0) 2 CF 3 , -SCF 3 , -N0 2 , -OR 35 , -C(0)R 35 , -NR 35 R 3e , -SR 35 , -NR 35 S(0) 2 R 36 , -S(0) 2 NR 35 R 36 , -S(0)NR 35 R 36 , -S(0)R 35 , -S(0) 2 R 35 , -C(0)NR 35 R 36 , -OC(0)NR 35 R 36 , -NR 35 C(0)R 36 , -CH 2 C(0)NR 35 R 36 , -OCH 2 C(0)NR 35 R 36 , -CH 2 OR 35 , -CH 2 NR 35 R 36 , -OC(0)R 35
  • R 32 and R 33 are independently selected from hydrogen, CrCe-alkyl or d-Ce-alkanoyl,
  • R 34 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 35 , and -NR 35 R 36 ,
  • R 35 and R 36 are independently selected from hydrogen, d-Ce-alkyl, aryl-d-C 6 -alkyl or aryl, or R 35 and R 36 when attached to the same nitrogen atom together with the said nitrogen atom may form a 3 to 8 membered heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R 37 is independently selected from halogen, -C(0)OR 35 , -C(0)H, -CN, -CF 3 , -OCF 3 , -N0 2 , - OR 35 , -NR 35 R 36 , d-C e -alkyl or C,-C 6 -alkanoyl, or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base, With the proviso that R 31 and J cannot both be hydrogen.
  • Embodiment 109 A pharmaceutical composition according to any one of the embodiment s 107 or 108 wherein H is
  • Embodiment 110 A pharmaceutical composition according to embodiment 109 wherein H is
  • Embodiment 111 A pharmaceutical composition according to embodiment 109 wherein H is
  • Embodiment 112 A pharmaceutical composition according to any one of the embodiment s 107 to 111wherein I is a valence bond, -CH 2 N(R 32 )-, or -SO 2 N(R 33 )-.
  • Embodiment 113 A pharmaceutical composition according to embodiment 112 wherein I is a valence bond.
  • Embodiment 114 A pharmaceutical composition according to any one of the embodiment s 107 to 113 wherein J is
  • Embodiment 115 A pharmaceutical composition according to embodiment 114 wherein J is
  • Embodiment 116 A pharmaceutical composition according to embodiment 114 wherein J is
  • Embodiment 117 A pharmaceutical composition according to embodiment 116 wherein J is
  • Embodiment 118 A pharmaceutical composition according to embodiment 117 wherein J is hydrogen.
  • Embodiment 119 A pharmaceutical composition according to any one of the embodiment s
  • Embodiment 120 A pharmaceutical composition according to any one of the embodiment s
  • R 34 is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -SCF 3 , -N0 2 , -OR 35 ,
  • Embodiment 121 A pharmaceutical composition according to embodiment 120 wherein R 34 is hydrogen, halogen, -CF 3 , -N0 2 , -OR 35 , -NR 35 R 36 , -SR 35 , -NR 35 C(0)R 36 , or -C(0)OR 35 .
  • Embodiment 122 A pharmaceutical composition according to embodiment 121 wherein R 34 is hydrogen, halogen, -CF 3 , -N0 2 , -OR 35 , -NR 35 R 36 , or -NR 35 C(0)R 36 .
  • Embodiment 123 A pharmaceutical composition according to embodiment 122 wherein R 34 is hydrogen, halogen, or -OR 35 .
  • Embodiment 124. A pharmaceutical composition according to any one of the embodiment s
  • R 35 and R 36 are independently selected from hydrogen, d-C ⁇ -alkyl, or aryl.
  • Embodiment 125 A pharmaceutical composition according to embodiment 124 wherein R 35 and R 36 are independently selected from hydrogen or d-Ce-alkyl.
  • Embodiment 126. A pharmaceutical composition according to any one of the embodiment s
  • R 37 is halogen, -C(0)OR 35 , -CN, -CF 3 , -OR 35 , -NR 35 R 36 , d-C 6 -alkyl or d-
  • Embodiment 127 A pharmaceutical composition according to embodiment 126 wherein R 37 is halogen, -C(0)OR 35 , -OR 35 , -NR 35 R 36 , d-C 6 -alkyl or d-C 6 -alkanoyl.
  • Embodiment 128 A pharmaceutical composition according to embodiment 127 wherein R 37 is halogen, -C(0)OR 35 or -OR 35 .
  • Embodiment 129 A pharmaceutical composition according to any one of the embodiment s 1 to 3 wherein CGr is
  • U is a valence bond, d-Ce-alkenylene, -d-Ce-alkyl-O- or d-C 6 -alkylene wherein any d- Ce-alkyl moiety is optionally substituted with d-C 6 -alkyl,
  • R 38 is CrCe-alkyl, aryl, wherein the alkyl or aryl moieties are optionally substituted with one or more substituents independently selected from R 39 ,
  • R is independently selected from halogen, cyano, nitro, amino,
  • M is a valence bond, arylene or heteroarylene, wherein the aryl or heteroaryl moieties are optionally substituted with one or more substituents independently selected from R 40 ,
  • R 41 and R 42 are independently selected from hydrogen, -OH, d-Ce-alkyl, d-Ce-alkenyl, aryl- d-Ce-alkyl or aryl, wherein the alkyl moieties may optionally be substituted with one or more substituents independently selected from R 45 , and the aryl moieties may optionally be substituted with one or more substituents independently selected from R 46 ; R 41 and R 42 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom, the heterocyclic ring optionally containing one or two further heteroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R 43 is independently selected from halogen, -CN, -CF 3l -OCF 3 , -OR 41 , and -NR 41 R 42
  • R 44 is independently selected from halogen, -C(0)OR 41 , -CH 2 C(0)OR 41 , -CH 2 OR 41 , -CN, - CF 3 , -OCF 3 , -N0 2 , -OR 41 , -NR 41 R 42 and d-Ce-alkyl,
  • R 45 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -0-d-C 6 -alkyl, -C(0)-0-C Ce-alkyl, -COOH and -NH 2 ,
  • R 47 and R 48 are independently selected from hydrogen, d-Ce-alkyl, aryl optionally substituted with one or more R 49 ,
  • R is independently selected from halogen and -COOH
  • T is
  • any alkyl, alkenyl , alkynyl, aryl and heteroaryl moiety is optionally substituted with one or more substituents independently selected from R 50 ,
  • Embodiment R 50A and R 508 are independently selected from -C(0)OCrC 6 -alkyl, -COOH, -d- C 6 -alkyl-C(0)OCrC 6 -alkyl, -Ci-Ce-alkyl-COOH, or d-C 6 -alkyl
  • R 51 and R 52 are independently selected from hydrogen and d-Ce-alkyl
  • R 53 is independently selected from CrC 6 -alkyl, d-Ce-alkoxy, -d-Ce-alkyl-COOH, -C 2 - Ce-alkenyl-COOH, -OR 51 , -N0 2 , halogen, -COOH, -CF 3 , -CN, or -N(R 51 R 52 ),
  • Embodiment 133 A pharmaceutical composition according to embodiment 132 wherein K is a valence bond or C C ⁇ -alkylene, wherein any d-C e -alkyl moiety is optionally substituted with R 38 .
  • Embodiment 135. A pharmaceutical composition according to embodiment 133 wherein K is a valence bond.
  • Embodiment 136 A pharmaceutical composition according to any one of the embodiment s
  • U is a valence bond or -CrC 6 -alkyl-0-.
  • Embodiment 137 A pharmaceutical composition according to embodiment 136 wherein U is a valence bond.
  • Embodiment 138 A pharmaceutical composition according to any one of the embodiment s
  • M is arylene or heteroarylene, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from
  • Embodiment 139 A pharmaceutical composition according to embodiment 138 wherein M is ArG1 or Het1 , wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R 40 .
  • Embodiment 140 A pharmaceutical composition according to embodiment 139 wherein M is
  • Embodiment 141 A pharmaceutical composition according to embodiment 140 wherein M is
  • Embodiment 142 A pharmaceutical composition according to embodiment 141 wherein M is phenylene optionally substituted with one or more substituents independently selected from R 40 .
  • Embodiment 143 A pharmaceutical composition according to embodiment 141 wherein M is indolylene optionally substituted with one or more substituents independently selected from
  • Embodiment 144 A pharmaceutical composition according to embodiment 143 wherein M is
  • Embodiment 146. A pharmaceutical composition according to embodiment 145 wherein is
  • Embodiment 147 A pharmaceutical composition according to any one of the embodiment s 129 to 146 wherein R 40 is selected from
  • Embodiment 148 A pharmaceutical composition according to embodiment 147 wherein R 40 is selected from
  • Embodiment 150 A pharmaceutical composition according to embodiment 149 wherein R 40 is hydrogen.
  • Embodiment 151 A pharmaceutical composition according to embodiment 149 wherein R 40 is selected from .halogen, -N0 2 , -OR 41 , -NR 41 R 42 , -C(0)OR 41 , or -NR 41 C(0)R 42 ,
  • Embodiment 152 A pharmaceutical composition according to any one of the embodiment s 129 to 151 wherein R 41 and R 42 are independently selected from hydrogen, d-Ce-alkyl, or aryl, wherein the aryl moieties may optionally be substituted with halogen or -COOH.
  • Embodiment 153 A pharmaceutical composition according to embodiment 152 wherein R 41 and R 42 are independently selected from hydrogen, methyl, ethyl, or phenyl, wherein the phenyl moieties may optionally be substituted with halogen or -COOH.
  • Embodiment 154 A pharmaceutical composition according to embodiment 152 wherein R 41 and R 42 are independently selected from hydrogen, methyl, ethyl, or phenyl, wherein the phenyl moieties may optionally be substituted with halogen or -COOH.
  • Embodiment 155 Embodiment 155.
  • Q is a valence bond.
  • Embodiment 156 Embodiment 156.
  • Embodiment 157. A pharmaceutical composition according to any one of the embodiment s 129 to 156 wherein T is
  • Embodiment 158 A pharmaceutical composition according to embodiment 157 wherein T is
  • Embodiment 159 A pharmaceutical composition according to embodiment 158 wherein T is •hydrogen,
  • Embodiment 160 A pharmaceutical composition according to embodiment 159 wherein T is phenyl substituted with R 50 .
  • Embodiment 165 Embodiment 165.
  • Embodiment 166 A pharmaceutical composition according to embodiment 164 wherein R 50 is phenyl, methyl or ethyl.
  • Embodiment 167 A pharmaceutical composition according to embodiment 166 wherein R 50 is methyl or ethyl.
  • Embodiment 168 A pharmaceutical composition according to any one of the embodiment s
  • Embodiment 169 A pharmaceutical composition according to any one of the embodiment s 129 to 168 wherein R 51 is methyl.
  • Embodiment 170 A pharmaceutical composition according to any one of the embodiment s
  • R 53 is d-C ⁇ -alkyl, d-C 6 -alkoxy, -OR 51 , halogen.or -CF 3 .
  • Embodiment 171 A pharmaceutical composition according to any one of the embodiment s
  • R 50 * is -C(0)OCH 3 , -C(0)OCH 2 CH 3 -COOH, -CH 2 C(O)OCH 3 , - CH 2 C(0)OCH 2 CH 3 , -CH 2 CH 2 C(0)OCH 3 , -CH 2 CH 2 C(0)OCH 2 CH 3 , -CH 2 COOH, methyl, or ethyl.
  • Embodiment 172 A pharmaceutical composition according to any one of the embodiment s
  • R 508 is -C(0)OCH 3 , -C(0)OCH 2 CH 3 -COOH, -CH 2 C(O)OCH 3 , -
  • Embodiment 173 A pharmaceutical composition according to any one of the embodiment s 1 to 3 wherein CGr is
  • V is d-Ce-alkyl, aryl, heteroaryl, aryl-d-e-alkyl- or aryl-C 2 -e-alkenyl-, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from R 54 , and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R 55 ,
  • R 54 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , aryl, -COOH and -NH 2
  • R 55 is independently selected from • hydrogen, halogen, -CN, -CH 2 CN, -CHF 2 , -CF 3 , -OCF 3> -OCHF 2 , -OCH;>CF 3 , -OCF 2 CHF 2 , -S(0) 2 CF 3 , -OS(0) 2 CF 3 , -SCF 3 , -N0 2 .
  • R 58 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 56 , and -NR 56 R 57 ,
  • R 59 is independently selected from halogen, -C(0)OR 56 , -CH 2 C(0)OR 56 , -CH 2 OR 56 , -CN, - CF 3 , -OCF 3 , -N0 2 , -OR 56 , -NR 56 R 57 and d-Ce-alkyl
  • R 62 is CrCe-alkyl, aryl optionally substituted with one or more substituents independently selected from halogen, or heteroaryl optionally substituted with one or more d-C 6 -alkyl independently, or any enantiomer, diastereomer, including a racemic mixture, tautomer as well as a salt thereof with a pharmaceutically acceptable acid or base.
  • Embodiment 174 A pharmaceutical composition according to embodiment 173 wherein V is aryl, heteroaryl, or aryl-d-e-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected R 54 , and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R 55 .
  • Embodiment 175. A pharmaceutical composition according to embodiment 174 wherein V is aryl, Het1 , or aryl-d-e-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R 54 , and the aryl or heteroaryl moiety is optionally substituted with one or more substituents independently selected from R 55 .
  • Embodiment 176. A pharmaceutical composition according to embodiment 175 wherein V is aryl, Het2, or aryl-d-e-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R 54 , and the aryl or heteroaryl moiety is optionally substituted with one or more substituents independently selected from R 55 .
  • Embodiment 177 A pharmaceutical composition according to embodiment 176 wherein V is aryl, Het3, or aryl-d-e-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R 54 , and the aryl or heteroaryl moiety is optionally substituted with one or more substituents independently selected from R 55 .
  • Embodiment 178. A pharmaceutical composition according to embodiment 177 wherein V is aryl optionally substituted with one or more substituents independently selected from R 55 .
  • Embodiment 179. A pharmaceutical composition according to embodiment 178 wherein V is ArG1 optionally substituted with one or more substituents independently selected from R 55 .
  • Embodiment 180 A pharmaceutical composition according to embodiment 176 wherein V is aryl, Het3, or aryl-d-e-alkyl-, wherein the alkyl is optionally substituted with one or more substituents independently selected from R 54 , and the aryl or heteroaryl moiety
  • Embodiment 182. A pharmaceutical composition according to any one of the embodiment s 173 to 181 wherein R 55 is independently selected from •halogen, d-Ce-alkyl, -CN, -OCF 3 ,-CF 3 , -N0 2 , -OR 56 , -NR 56 R 57 , -NR 56 C(O)R 57
  • Embodiment 184 A pharmaceutical composition according to embodiment 183 wherein R 55 is independently selected from halogen, -OR 56 , -NR ⁇ R 57 , -C(0)OR 56 , -Od-C 8 - alkyl-C(0)OR 56 , -NR 56 C(0)R 57 or d-C 6 -alkyl.
  • Embodiment 185 A pharmaceutical composition according to embodiment 184 wherein R 55 is independently selected from halogen, -OR 56 , -NR 56 R 57 , -C(0)OR 56 , -Od-C 8 - alkyl-C(0)OR 56 , -NR 56 C(0)R 57 , methyl or ethyl.
  • Embodiment 187 A pharmaceutical composition according to embodiment 186 wherein R 56 and R 57 are independently selected from hydrogen or d-C ⁇ 2 -alkyl, R 56 and R 57 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom.
  • a pharmaceutical composition according to embodiment 187 wherein R 56 and R 57 are independently selected from hydrogen or methyl, ethyl, propyl butyl, R 56 and R 57 when attached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom.
  • Embodiment 189 A pharmaceutical composition according to any one of the embodiment s 1 to 3 wherein CGr is
  • AA is d-Ce-alkyl, aryl, heteroaryl, aryl-d-e-alkyl- or aryl-C 2 - 6 -alkenyl-, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from R 63 , and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R 64 ,
  • R 63 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , aryl, -COOH and -NH 2 ,
  • R 64 is independently selected from
  • R 67 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 65 , and -NR 65 R 66 ,
  • R 68 is independently selected from halogen, -C(0)OR 65 , -CH 2 C(0)OR 65 , -CH 2 OR 65 , -CN, - CF 3 , -OCF 3 , -N0 2 , -OR 65 , -NR 65 R 66 and d-C ⁇ -alkyl,
  • R 69 is independently selected from d-Ce-alkyl, aryl optionally substituted with one or more halogen, or heteroaryl optionally substituted with one or more d-Ce-alkyl,
  • R 70 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -Od-Ce-alkyl, -C(0)OCrC 6 - alkyl, -COOH and -NH 2 ,
  • Embodiment 190 A pharmaceutical composition according to embodiment 189 wherein AA is aryl, heteroaryl or aryl-d-e-alkyl-, wherein the alkyl is optionally substituted with one or more R 63 , and the aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R 64 .
  • Embodiment 191 A pharmaceutical composition according to embodiment 190 wherein AA is aryl or heteroaryl optionally substituted with one or more substituents independently se- lected from R 64 .
  • Embodiment 192 A pharmaceutical composition according to embodiment 191 wherein AA is ArG1 or Het1 optionally substituted with one or more substituents independently selected from R 64 .
  • Embodiment 193. A pharmaceutical composition according to embodiment 192 wherein AA is ArG1 or Het2 optionally substituted with one or more substituents independently selected from R 64 .
  • Embodiment 194 A pharmaceutical composition according to embodiment 193 wherein AA is ArG1 or Het3 optionally substituted with one or more substituents independently selected from R 64 .
  • Embodiment 195 A pharmaceutical composition according to embodiment 194 wherein AA is phenyl, naphtyl, anthryl, carbazolyl, thienyl, pyridyl, or benzodioxyl optionally substituted with one or more substituents independently selected from R 64 .
  • Embodiment 196 A pharmaceutical composition according to embodiment 195 wherein AA is phenyl or naphtyl optionally substituted with one or more substituents independently se- lected from R 64 .
  • Embodiment 197 A pharmaceutical composition according to any one of the embodiment s 189 to 196 wherein R 64 is independently selected from hydrogen, halogen, -CF 3 , -OCF 3 , -OR 65 , -NR 65 R 66 , d-Ce-alkyl , -OC(0)R 65 , -OCrC 6 -alkyl-C(0)OR 65 , aryl-C 2 -C 6 -alkenyl, aryloxy or aryl, wherein d-d-alkyl is optionally substituted with one or more substituents inde- pendently selected from R 67 , and the cyclic moieties optionally are substituted with one or more substituents independently selected from R 68 .
  • R 64 is independently selected from hydrogen, halogen, -CF 3 , -OCF 3 , -OR 65 , -NR 65 R 66 , d-Ce-alkyl , -OC(0)R 65 ,
  • Embodiment 198 A pharmaceutical composition according to embodiment 197 wherein R 64 is independently selected from halogen, -CF 3 , -OCF 3 , -OR 65 , -NR 65 R 66 , methyl, ethyl, propyl, -OC(0)R 65 , -OCH 2 -C(0)OR 65 , -OCH 2 -CH 2 -C(0)OR 65 , phenoxy optionally substituted with one or more substituents independently selected from R 68 .
  • R 64 is independently selected from halogen, -CF 3 , -OCF 3 , -OR 65 , -NR 65 R 66 , methyl, ethyl, propyl, -OC(0)R 65 , -OCH 2 -C(0)OR 65 , -OCH 2 -CH 2 -C(0)OR 65 , phenoxy optionally substituted with one or more substituents independently selected from R 68 .
  • Embodiment 199 A pharmaceutical composition according to any one of the embodiment s 189 to 198 wherein R 65 and R 66 are independently selected from hydrogen, CF 3 , d-C ⁇ 2 -alkyl, aryl, or heteroaryl optionally substituted with one or more substituents independently selected from R 71 .
  • Embodiment 200 A pharmaceutical composition according to embodiment 199 wherein R 65 and R 66 are independently hydrogen, d-C 12 -alkyl, aryl, or heteroaryl optionally substituted with one or more substituents independently selected from R 71 .
  • Embodiment 201 A pharmaceutical composition according to embodiment 200 wherein R 65 and R 66 are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het1 optionally substituted with one or more substituents independently selected from R 71 .
  • Embodiment 202 A pharmaceutical composition according to embodiment 201 wherein R 65 and R 66 are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het2 optionally substituted with one or more substituents independently selected from R 71 .
  • Embodiment 203 A pharmaceutical composition according to embodiment 202 wherein R 65 and R 66 are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het3 optionally substituted with one or more substituents independently selected from R 71 .
  • Embodiment 204 A pharmaceutical composition according to embodiment 203 wherein R 65 and R 66 are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, phenyl, naphtyl, thiadiazolyl optionally substituted with one or more R 71 independently; or isoxazoiyl optionally substituted with one or more substituents independently selected from R 7 .
  • Embodiment 205 A pharmaceutical composition according to any one of the embodiment s
  • R 71 is halogen or d-d-alkyl.
  • Embodiment 206 A pharmaceutical composition according to embodiment 205 wherein R 71 is halogen or methyl.
  • Embodiment 207 A pharmaceutical preparation according to any one of the embodiment s 1 to 205 wherein Frg1 consists of 0 to 5 neutral amino acids independently selected from the group consisting of Gly, Ala, Thr, and Ser.
  • Embodiment 208 A pharmaceutical preparation according to embodiment 207 wherein Frg1 consists of 0 to 5 Gly.
  • Embodiment 209 A pharmaceutical preparation according to embodiment 208 wherein Frg1 consists of 0 Gly.
  • Embodiment 210 A pharmaceutical preparation according to embodiment 208 wherein Frg1 consists of 1 Gly.
  • Embodiment 211. A pharmaceutical preparation according to embodiment 208 wherein Frg1 consists of 2 Gly.
  • Embodiment 212 A pharmaceutical preparation according to embodiment 208 wherein Frg1 consists of 3 Gly.
  • Embodiment 213. A pharmaceutical preparation according to embodiment 208 wherein Frg1 consists of 4 Gly.
  • Embodiment 214. A pharmaceutical preparation according to embodiment 208 wherein Frg1 consists of 5 Gly.
  • Embodiment 215. A pharmaceutical preparation according to any one of the embodiment s 1 to 214 wherein G B is of the formula B 1 -B 2 -C(0)-, B -B 2 -S0 2 - or B 1 -B 2 -CH 2 -, wherein B 1 and B 2 are as defined in embodiment 1.
  • Embodiment 216 A pharmaceutical preparation according to any one of the embodiment s 1 to 214 wherein G B is of the formula B 1 -B 2 -C(0)-, B 1 -B 2 -S0 2 - or B 1 -B 2 -NH-, wherein B 1 and B 2 are as defined in embodiment 1.
  • Embodiment 217 A pharmaceutical preparation according to any one of the embodiment s 1 to 214 wherein G B is of the formula B -B -C(0)-, B 1 -B 2 -CH 2 - or B 1 -B 2 -NH-, wherein B 1 and B 2 are as defined in embodiment 1.
  • Embodiment 218 A pharmaceutical preparation according to any one of the embodiment s 1 to 214 wherein G B is of the formula B 1 -B 2 -CH 2 -, B 1 -B 2 -S0 2 - or B 1 -B 2 -NH-, wherein B 1 and B 2 are as defined in embodiment 1.
  • Embodiment 219. A pharmaceutical preparation according to any one of the embodiment s
  • G B is of the formula B 1 -B 2 -C(0)- or B 1 -B 2 -S0 2 -, wherein B 1 and B 2 are as defined in embodiment 1.
  • Embodiment 220 A pharmaceutical preparation according to any one of the embodiment s
  • G B is of the formula B 1 -B 2 -C(0)- or B 1 -B 2 -CH 2 -, wherein B 1 and B 2 are as defined in embodiment 1.
  • Embodiment 22 A pharmaceutical preparation according to any one of the embodiment s
  • G B is of the formula B 1 -B 2 -C(0)- or B 1 -B 2 -NH-, wherein B 1 and B 2 are as defined in embodiment 1.
  • Embodiment 222 A pharmaceutical preparation according to any one of the embodiment s 215 or 218 wherein G 8 is of the formula B 1 -B -CH 2 - or B 1 -B 2 -S0 2 - , wherein B 1 and B 2 are as defined in embodiment 1.
  • Embodiment 223. A pharmaceutical preparation according to any one of the embodiment s
  • G B is of the formula B 1 -B 2 -NH- or B 1 -B 2 -S0 2 - , wherein B 1 and B 2 are as defined in embodiment 1.
  • Embodiment 224 A pharmaceutical preparation according to any one of the embodiment s
  • G 8 is of the formula B 1 -B 2 -CH 2 - or B 1 -B 2 -NH- , wherein B 1 and B 2 are as defined in embodiment 1.
  • Embodiment 225 A pharmaceutical preparation according to any one of the embodiment s 219, 220, or 221 wherein G B is of the formula B 1 -B 2 -C(0)-.
  • Embodiment 226 A pharmaceutical preparation according to any one of the embodiment s
  • G B is of the formula B 1 -B 2 -CH 2 -.
  • Embodiment 227 A pharmaceutical preparation according to any one of the embodiment s
  • G B is of the formula B 1 -B 2 -NH-.
  • Embodiment 229. A pharmaceutical preparation according to any one of the embodiment s 1 to 228 wherein B 1 is a valence bond, -0-, or -S-.
  • Embodiment 230 A pharmaceutical preparation according to any one of the embodiment s 1 to 228 wherein B 1 is a valence bond, -0-, or -N(R 68 )-.
  • Embodiment 23 A pharmaceutical preparation according to any one of the embodiment s 1 to 228 wherein B 1 is a valence bond, -S-, or -N(R 68 )-.
  • Embodiment 232 A pharmaceutical preparation according to any one of the embodiment s 1 to 228 wherein B 1 is -0-, -S- or -N(R 68 )-.
  • Embodiment 233 A pharmaceutical preparation according to any one of the embodiment s
  • B 1 is a valence bond or -0-.
  • Embodiment 23 A pharmaceutical preparation according to any one of the embodiment s
  • B 1 is a valence bond or -S-.
  • Embodiment 235 A pharmaceutical preparation according to any one of the embodiment s 230 or 231 wherein B 1 is a valence bond or -N(R 68 )-.
  • Embodiment 236 A pharmaceutical preparation according to any one of the embodiment s
  • B 1 is -O-or -S-.
  • Embodiment 237 A pharmaceutical preparation according to any one of the embodiment s
  • B 1 is -S-or -N(R 68 )-.
  • Embodiment 239. A pharmaceutical preparation according to any one of the embodiment s
  • Embodiment 240 A pharmaceutical preparation according to any one of the embodiment s 233, 236 or 237 wherein B 1 is -0-.
  • Embodiment 241 A pharmaceutical preparation according to any one of the embodiment s
  • Embodiment 242 A pharmaceutical preparation according to any one of the embodiment s
  • a pharmaceutical preparation according to embodiment 246 wherein B 2 is a valence bond, d-C 18 -alkylene, arylene, heteroarylene, -CrC 18 -alkyl-aryl-, and the alkylene and arylene moieties are optionally substituted as defined in embodiment 1.
  • Embodiment 248. A pharmaceutical preparation according to embodiment 247 wherein B 2 is a valence bond, C C 18 -alkylene, arylene, -d-C 18 -alkyl-aryl-, and the alkylene and arylene moieties are optionally substituted as defined in embodiment 1.
  • Embodiment 249. A pharmaceutical preparation according to embodiment 248 wherein B 2 is a valence bond or -CrC 18 -alkylene, and the alkylene moieties are optionally substituted as defined in embodiment 1.
  • Embodiment 250. A pharmaceutical preparation according to any one of the embodiment s 1 to 249 whereiin Frg2 comprises 1 to 16 positively charged groups.
  • Embodiment 251 A pharmaceutical preparation according to embodiment 250 wherein Frg2 comprises 1 to 12 positively charged groups.
  • Embodiment 252 A pharmaceutical preparation according to embodiment 251 wherein Frg2 comprises 1 to 10 positively charged groups.
  • Embodiment 253. A pharmaceutical preparation according to any one of the embodiment s 1 to 249 wherein Frg2 comprises 10 to 20 positively charged groups.
  • Embodiment 254. A pharmaceutical preparation according to embodiment 253 wherein Frg2 comprises 12 to 20 positively charged groups.
  • Embodiment 255. A pharmaceutical preparation according to embodiment 254 wherein Frg2 comprises 16 to 20 positively charged groups.
  • Embodiment 256 A pharmaceutical preparation according to any one of the embodiment s 250 to 255 wherein the positively charged groups of Frg2 are basic amino acids independently selected from the group consisting of Lys and Arg and D-isomers of these.
  • Embodiment 257 A pharmaceutical preparation according to embodiment 256 wherein the basic amino acids are all Arg.
  • Embodiment 258 A pharmaceutical preparation according to any one of the embodiment s 250 to 257, wherein Frg2 comprises one or more neutral amino acids independently selected from the group consisting of Gly, Ala, Thr, and Ser.
  • Embodiment 259. A pharmaceutical preparation according to embodiment 258, wherein Frg2 comprises one or more Gly.
  • Embodiment 260 A pharmaceutical preparation according to any one of the embodiment s 1 to 259 wherein X is -OH or -NH 2 .
  • Embodiment 261. A pharmaceutical preparation according to embodiment 260 wherein X is - NH 2 .
  • Embodiment 262 A pharmaceutical preparation according to any one of the embodiment s 1 to 261 which further comprises at least 3 phenolic molecules per putative insulin hexamer.
  • Embodiment 263. A pharmaceutical preparation according to any one of the embodiment s 1 to 262 wherein the acid-stabilised insulin is an analogue of human insulin wherein A21 is Ala, Gin, Glu, Gly, His, He, Leu, Met, Phe, Ser, Thr, Trp, Tyr, Val, and hSer.
  • Embodiment 264 A pharmaceutical preparation according to embodiment 263 wherein the acid-stabilised insulin is an analogue of human insulin wherein A21 is Ala, Gly, He, Leu, Phe, Ser, Thr, Val, and hSer.
  • Embodiment 265. A pharmaceutical preparation according to embodiment 264 wherein the acid-stabilised insulin is an analogue of human insulin wherein A21 is Ala or Gly.
  • Embodiment 266 A pharmaceutical preparation according to embodiment 265 wherein the acid-stabilised insulin is an analogue of human insulin wherein A21 is Gly.
  • Embodiment 267 A pharmaceutical preparation according to any one of the embodiment s 263 to 266 wherein the acid-stabilised insulin is an analogue of human insulin further modi- fied by exchange or deletion of one or more amino acid residues according to the following: B3 is selected from Thr, Ser, Lys or Ala
  • B28 is Lys, Asp or Glu
  • B29 is Pro or Glu B9 is Glu or Asp
  • Embodiment 268 A pharmaceutical preparation according to embodiment 267 wherein the acid-stabilised insulin is an analogue of human insulin further modified by exchange of B28 to Lys or Asp.
  • Embodiment 269. A pharmaceutical preparation according to embodiment 268 wherein the acid-stabilised insulin is an analogue of human insulin further modified by exchange of B28 to Asp.
  • Embodiment 270. A pharmaceutical preparation according to embodiment 268 wherein the acid-stabilised insulin is an analogue of human insulin further modified by exchange of B28 to Lys.
  • Embodiment 271 A pharmaceutical preparation according any one of the embodiment s 263 to 270 wherein the acid-stabilised insulin is an analogue of human insulin further modified by exchange of B29 to Pro.
  • Embodiment 272 A pharmaceutical preparation according any one of the embodiment s 263 to 271 wherein the acid-stabilised insulin is an analogue of human insulin further modified by exchange of B3 to Lys or Ala.
  • Embodiment 273 A pharmaceutical preparation according any one of the embodiment s 263 to 272 wherein the acid-stabilised insulin is an analogue of human insulin further modified by exchange of A18 to Gin.
  • Embodiment 274 A pharmaceutical preparation according any one of the embodiment s 263 to 273 wherein the acid-stabilised insulin is an analogue of human insulin further modified by deletion of B25.
  • Embodiment 275 A pharmaceutical preparation according any one of the embodiment s 263 to 274 wherein the acid-stabilised insulin is an analogue of human insulin further modified by deletion of B30.
  • Embodiment 276 A pharmaceutical preparation according to embodiment 263 wherein the acid-stabilised insulin is selected from the group A21G A21G, B28K, B29P
  • A21G, B3K, B29E, desB30 A21G, desB27, desB30
  • Embodiment 277 A pharmaceutical preparation according to any one of the embodiment s 1 to 276 wherein zinc ions are present in an amount corresponding to 10 to 40 ⁇ g Zn/100 U insulin.
  • Embodiment 278 A pharmaceutical preparation according to embodiment 277 wherein zinc ions are present in an amount corresponding to 10 to 26 ⁇ g Zn/100 U insulin.
  • Embodiment 280 A pharmaceutical preparation according to embodiment 279 wherein the ratio between insulin and the zinc-binding ligand according to any one of the embodiment s 1 to 261 is in the range from 95:5 to 5:95.
  • Embodiment 281. A pharmaceutical preparation according to embodiment 280 wherein the ratio between between insulin and the zinc-binding ligand according to any one of the embodiment s 1 to 261 is in the range from 80:20 to 20:80. Embodiment 282. A pharmaceutical preparation according to embodiment 281 wherein the ratio between between insulin and the zinc-binding ligand according to any one of the embodiment s 1 to 261 is in the range from 70:30 to 30:70.
  • Embodiment 283 A pharmaceutical preparation according to any one of the embodiment s 1 to 282 wherein the concentration of insulin is 60 to 3000 nmol/ml.
  • Embodiment 284. A pharmaceutical preparation according to embodiment 283 wherein the concentration of insulin is 240 to 1200 nmol/ml.
  • Embodiment 285. A pharmaceutical preparation according to embodiment 284 wherein the concentration of insulin is about 600 nmol/ml.
  • Embodiment 286. A method of preparing a zinc-binding ligand according to embodiment 1 comprising the steps of
  • Embodiment 287 Method of prolonging the action of an acid-stabilised insulin preparation which comprises adding a zinc-binding ligand according to any of embodiment s 1 to 261 to the acid-stabilised insulin preparation.
  • Embodiment 288 A method of treating type 1 or type 2 diabetes comprising administering to a patient in need thereof a theraputically effective amount of a pharmaceutical preparation according to any one of the embodiment s 1 to 282.
  • Embodiment 28 Use of a preparation according to any one of the embodiment s 1 to 282 for the preparation of a medicament for treatment of type 1 or type 2 diabetes.
  • the present invention also relates to a pharmaceutical preparation for the treatment of diabetes in a patient in need of such a treatment comprising an R-state hexamer of insulin according to the invention together with a pharmaceutically acceptable carrier.
  • the insulin preparation comprises 60 to 3000 nmol/ml of insulin.
  • the insulin preparation comprises 240 to 1200 nmol/ml of insulin. In another embodiment of the invention the insulin preparation comprises about 600 nmol/ml of insulin.
  • Zinc ions may be present in an amount corresponding to 10 to 40 ⁇ g Zn/100 U insulin, more preferably 10 to 26 ⁇ g Zn/100 U insulin.
  • Insulin formulations of the invention are usually administered from multi-dose containers where a preservative effect is desired. Since phenolic preservatives also stabilize the R-state hexamer the formulations may contain up to 50 mM of phenolic molecules.
  • the phenolic molecules in the insulin formulation may be selected from the group consisting of phenol, m- cresol, chloro-cresol, thymol, 7-hydroxyindole or any mixture thereof. In one embodiment of the invention 0.5 to 4.0 mg/ml of phenolic compound may be employed.
  • 0.6 to 4.0 mg/ml of m-cresol may be employed.
  • 0.5 to 4.0 mg/ml of phenol may be employed.
  • 0.5 to 4.0 mg/ml of a mixture of m-cresol or phenol may be employed.
  • the pharmaceutical preparation may further comprises a buffer substance, such as a TRIS, phosphate, glycine or glycylglycine (or another zwitterionic substance) buffer, an isotonicity agent, such as NaCl, glycerol, mannitol and/or lactose.
  • a buffer substance such as a TRIS, phosphate, glycine or glycylglycine (or another zwitterionic substance) buffer
  • an isotonicity agent such as NaCl, glycerol, mannitol and/or lactose.
  • Chloride would be used at moderate concentrations (e.g. up to 50 mM) to avoid competition with the zinc-site ligands of the present invention.
  • the action of insulin may further be slowed down in vivo by the addition of physiologically acceptable agents that increase the viscosity of the pharmaceutical preparation.
  • the pharmaceutical preparation according to the invention may furthermore comprise an agent which increases the viscosity, such as polyethylene glycol, polypropylene glycol, copolymers thereof, dextrans and/or polylactides.
  • the insulin preparation of the invention comprises between 0.001
  • a non-ionic surfactant for example tween 20 or Polox 188.
  • a nonionic detergent can be added to stabilise insulin against fibrillation during storage and handling.
  • the insulin preparation of the present invention may have a pH value in the range of 2.5 to
  • the preparations of the invention are used in connection with insulin pumps.
  • the insulin pumps may be prefilled and disposable, or the insulin preparations may be supplied from a reservoir which is removable. Insulin pumps may be skin-mounted or carried, and the path of the insulin preparation from the storage compartment of the pump to the patient may be more or less tortuous.
  • Non-limiting examples of insulin pumps are disclosed in US 5,957,895, US 5,858,001 , US 4,468,221, US 4,468,221 , US 5,957,895, US 5,858,001 , US 6,074,369, US 5,858,001 , US 5,527,288, and US 6,074,369.
  • the preparations of the invention are used in connection with pen-like injection devices, which may be prefilled and disposable, or the insulin preparations may be supplied from a reservoir which is removable.
  • pen-like injection devices are FlexPen ® , InnoLet ® , InDuoTM, Innovo ® .
  • preparations of the invention are used in connection with devices for pulmonary administration of aqueous insulin preparations, a non-limiting example of which is the AerX ® device.
  • the invention furthermore relates to treatment of a patient in which the pharmaceutical preparation of the invention, i.e. comprising zinc ions, acid-stabilised insulin analogue and a ligand for the R-state His 810 Zn 2+ site, is combined with another form of treatment.
  • the pharmaceutical preparation of the invention i.e. comprising zinc ions, acid-stabilised insulin analogue and a ligand for the R-state His 810 Zn 2+ site
  • treatment of a patient with the pharmaceutical preparation of the invention is combined with diet and/or exercise.
  • the pharmaceutical preparation of the invention is administered in combination with one or more further active substances in any suitable ratios.
  • Such further active substances may e.g. be selected from antiobesity agents, antidiabetics, antihypertensive agents, agents for the treatment of complications resulting from or associated with diabetes and agents for the treatment of complications and disorders resulting from or associated with obesity.
  • the pharmaceutical preparation of the invention may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melano- cortin 4) agonists, MC3 (melanocortin 3) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releas- ing factor binding protein) antagonists, urocortin agonists, ⁇ 3 adrenergic agonists such as CL-316243, AJ-9677, GW-0604, LY362884, LY377267 or AZ-40140, MSH (melanocyte- stimulating hormone) agonists, MCH (melanocyte-concentrating hormone
  • the antiobesity agent is leptin.
  • the antiobesity agent is dexamphetamine or amphetamine. In another embodiment the antiobesity agent is fenfluramine or dexfenfluramine.
  • the antiobesity agent is sibutramine.
  • the antiobesity agent is orlistat.
  • the antiobesity agent is mazindol or phentermine.
  • the antiobesity agent is phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate or ecopipam.
  • the orally active hypoglycemic agents comprise imidazolines, sulphonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, insulin sensitizers, insulin secretagogues such as glimepride, ⁇ -glucosidase inhibitors, agents acting on the ATP- dependent potassium channel of the ⁇ -cells eg potassium channel openers such as those disclosed in WO 97/26265, WO 99/03861 and WO 00/37474 (Novo Nordisk A/S) which are incorporated herein by reference, or mitiglinide, or a potassium channel blocker, such as BTS-67582, nateglinide, glucagon antagonists such as those disclosed in WO 99/01423 and WO 00/39088 (Novo Nordisk A/S and Agouron Pharmaceuticals, Inc.), which are incorpo- rated herein by reference, GLP-1 agonists such as those
  • the pharmaceutical preparation of the invention is administered in combination with a sulphonylurea e.g. tolbutamide, chlorpropa- mide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide.
  • a sulphonylurea e.g. tolbutamide, chlorpropa- mide, tolazamide, glibenclamide, glipizide, glimepiride, glicazide or glyburide.
  • the pharmaceutical preparation of the invention is administered in combination with a biguanide, e.g. metformin.
  • a biguanide e.g. metformin.
  • the pharmaceutical preparation of the invention is administered in combination with a meglitinide eg repaglinide or nateglinide.
  • the pharmaceutical preparation of the invention is administered in combination with a thiazolidinedione insulin sensitizer, e.g. trogli- tazone, ciglitazone, pioglitazone, rosiglitazone, isaglitazone, darglitazone, englitazone, CS- 011/CI-1037 or T 174 or the compounds disclosed in WO 97/41097, WO 97/41119, WO 97/41120, WO 00/41121 and WO 98/45292 (Dr. Reddy's Research Foundation), which are incorporated herein by reference.
  • the pharmaceutical preparation of the invention may be administered in combination with an insulin sensitizer, e.g. such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414, WO 00/63191 , WO 00/63192, WO 00/63193 (Dr.
  • an insulin sensitizer e.g. such as GI 262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 or the compounds disclosed in WO 99/19313, WO 00/50414,
  • the pharmaceutical preparation of the in- vention is administered in combination with an ⁇ -glucosidase inhibitor, e.g. voglibose, emigli- tate, miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor e.g. voglibose, emigli- tate, miglitol or acarbose.
  • the pharmaceutical preparation of the invention is administered in combination with an agent acting on the ATP-dependent potassium channel of the ⁇ -cells, e.g. tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or re- paglinide.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells e.g. tolbutamide, glibenclamide, glipizide, glicazide, BTS-67582 or re- paglinide.
  • the pharmaceutical preparation of the invention may be administered in combination with nateglinide.
  • the pharmaceutical preparation of the invention is administered in combination with an antilipidemic agent, e.g. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • an antilipidemic agent e.g. cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol or dextrothyroxine.
  • the pharmaceutical preparation of the invention is administered in combination with more than one of the above-mentioned compounds, e.g. in combination with metformin and a sulphonylurea such as glyburide; a sulphonylurea and acarbose; nateglinide and metformin; acarbose and metformin; a sulphonylurea, metformin and troglitazone; metformin and a sulphonylurea; etc.
  • metformin and a sulphonylurea such as glyburide
  • a sulphonylurea and acarbose such as glyburide
  • a sulphonylurea and acarbose such as glyburide
  • a sulphonylurea and acarbose such as glyburide
  • the pharmaceutical preparation of the invention may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and ⁇ - blockers such as doxazosin, urapidil, prazosin and terazosin.
  • ⁇ -blockers such as alprenolol, atenolol, timolo
  • the pharmaceutical preparation of the invention may also be combined with NEP inhibitors such as candoxatril. Further reference can be made to Remington: The Science and Practice of Pharmacy, 19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.

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Abstract

L'invention concerne de nouveaux ligands des sites HisB10 Zn2+ de l'héxamère d'insuline R, pouvant prolonger l'action des préparations d'insuline.
EP04719368A 2003-03-11 2004-03-11 Preparations pharmaceutiques contenant de l'insuline stabilisee d'un point de vue acide Withdrawn EP1610812A1 (fr)

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NO20054555D0 (no) 2005-10-04
NO20054555L (no) 2005-11-17
BRPI0408229A (pt) 2006-02-21

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