EP1768694A1 - Pharmazeutische zubereitungen mit insulin - Google Patents

Pharmazeutische zubereitungen mit insulin

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Publication number
EP1768694A1
EP1768694A1 EP05758689A EP05758689A EP1768694A1 EP 1768694 A1 EP1768694 A1 EP 1768694A1 EP 05758689 A EP05758689 A EP 05758689A EP 05758689 A EP05758689 A EP 05758689A EP 1768694 A1 EP1768694 A1 EP 1768694A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
independently selected
insulin
optionally substituted
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Withdrawn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
EP05758689A
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English (en)
French (fr)
Inventor
Helle Birk Olsen
Niels Christian Kaarsholm
Peter Madsen
Per Balschmidt
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Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP1768694A1 publication Critical patent/EP1768694A1/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present invention discloses insulin preparations comprising ligands for the His B10 -Zn 2+ sites of the R-state insulin hexamer wherein the ligand is extended by protamine.
  • Insulin AHostery The insulin hexamer is an allosteric protein that exhibits both posi ⁇ tive and negative cooperativity and half-of-the-sites reactivity in ligand binding. This allosteric behaviour consists of two interrelated allosteric transitions designated L A 0 and L B 0 , three in ⁇ ter-converting allosteric conformation states (eq. 1),
  • T 61 T 3 R 3 and R 6 and two classes of allosteric ligand binding sites designated as the phenolic pockets and the His 610 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 a-helical conformation in the R-state. This coil-to-heJix 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 R 8 ), and the new B-chain helices form 3-helix bun ⁇ dles (one in T 3 R 3 and two in R 6 ) with the bundle axis aligned along the hexamer three-fold symmetry axis.
  • the His 910 Zn 2+ in each R 3 unit is forced to change coordination geometry from octahedral to either tetrahedra! (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 B1 ° metal ion. This tunnel and the His B1 ° Zn 2+ ion form the anion binding site.
  • absorption rates vary between about 1 hour (for rapid-acting insulin analogues, such as Asp B2 ⁇ human insulin) and about 4 hours (Co 3+ - hexamer).
  • Current Approaches Toward Slow Acting Insulins The inherent limitation of the ab ⁇ sorption half-life to about 4 hours for a soluble human insulin hexamer necessitates further modifications to obtain the desired protraction. Traditionally, this has been achieved by the use of preparations wherein the constituent insulin is in the form of a crystalline and/or amor ⁇ phous precipitate.
  • NPH and Ultratente belong to this category of insulin preparations where crystallization/precipitation is effected by the addition of protamine and excessive zinc ion, respectively.
  • the present invention provides insulin preparations comprising high-affinity ligands for the His Bi0 -Zn 2+ sites of the R-state insulin hexamer, zinc ions and insulin wherein the ligand is extended by protamine.
  • the resulting ligands with protamine extensions work to modify the time action pro ⁇ file of insulin formulations.
  • These preparations may be formulated with variable insulin spe- cies over a wide range of pH from 3.0 to 8.5 and their time action profiles may be tailored by suitable adjustments of anchor affinity as well as the concentration of protami ⁇ e-extended iigand.
  • the invention also provides a method of preparing ligands for the His 810 Zn 2+ sites of the R-state insulin hexamer comprising the steps of • Identifying a starter compound that binds to the R-state His B10 -Zn z+ site
  • Also provided are methods of treating type 1 or type 2 diabetes comprising adminis ⁇ tering 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 1 Cl, Br and ⁇ .
  • C 1 -C 6 -BIkVl 11 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, tert-butyl, n- pentyl, isopentyl, neopentyl, fert-pe ⁇ tyl, n-hexyl, isohexyl and the like.
  • CrCe-alkylene represents a saturated, branched or straight bivalent hydrocarbon group having from 1 to 6 carbon atoms.
  • C 2 -Ce-alkenyr represents a branched or straight hydro ⁇ carbon 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- butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyH-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 -alkynyr represents a branched or straight hydro ⁇ carbon 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-pe ⁇ tynyl, 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 B -alkyl t wherein C r C 6 -alkyl is as defined above. Representative examples are methoxy, ethoxy, n-propoxy, iso- propoxy, butoxy, sec-butoxy, fert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • C 3 -C 8 -cycloalkyr represents a saturated, carbocyclic group having from 3 to 8 carbon atoms. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • d- ⁇ -cycloalkenyF represents a non-aromatic, carbocyclic group having from 4 to 8 carbon atoms containing one or two double bonds.
  • Representative examples are 1-cyclopente ⁇ yl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cycIohexenyl, 2-cyclo- hexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 1 ,4-cycioocta- dienyl and the like.
  • heterorocydyr as used herein represents a non-aromatic 3 to 10 membered ring containing one or more heteroatoms selected from nitrogen, oxygen and sulphur and op ⁇ tionally containing one or two double bonds.
  • Representative examples are pyrrolidinyl, piperi- dyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, tetrahydrofuranyl and the like.
  • aryl as used herein is intended to include carbocyclic, aromatic ring sys ⁇ tems such as 6 membered monocyclic and 9 to 14 membered bi- and tricyclic, carbocyclic, aromatic ring systems. Representative examples are phenyl, biphenylyl, naphthyl, anthra- cenyl, phenanthrenyl, fluorenyl, indenyl, a ⁇ lenyl and the like. Any! 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, aro-
  • ring systems such as 6 membered monocyclic and 9 to 14 raembered bi- and tricyclic, divalent, carbocyclic, aromatic ring systems.
  • Representative examples are phenylene, bi- phenylylene, naphthylene, anthracenylene, phenanthrenylene, fluorenylene, indenylene, az- ulenylene and the like.
  • Arylene is also intended to include the partially hydrogenated deriva- fives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydro ⁇ genated derivatives are 1 ,2,3,4-tetrahydronaphthyle ⁇ e, 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 sul ⁇ phur 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.
  • Representative examples are furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyra- zolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, 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.
  • Heteroaryl is also intended to include the partially hydrogenated de ⁇ rivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hy ⁇ drogenated derivatives are 2,3-dihydroben ⁇ ofuranyl, pyrrolinyl, pyrazoltnyl, indolinyl, oxazolid- tnyl, oxazo ⁇ nyl, 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, oxy ⁇ gen 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 nitro- gen, oxygen and sulphur.
  • carbazolylene azepinylene, diazepinylene, acridinylene and the like.
  • Heteroaryl is also intended to include the partially hydrogenated derivatives of the ring systems enumerated above.
  • Non-limiting examples of such partially hydrogenated deriva ⁇ tives are 2,3-dihydrobenzofuranylene, pyrrolinylene, pyrazolinylene, indolinylene, oxazolid- inylene, oxazolinylene, oxazepinylene and the like.
  • ArGI as used herein is intended to include an aryl or arylene radical as ap- plicable, where aryl or arylene are as defined above but limited to phenyl, biphenylyl, naphthyl, anthracenyl, phena ⁇ threnyl, fluorenyl, indenyl, and azulenyl as well as the co ⁇ esponding divalent radicals.
  • ArG2 as used herein is intended to include an aryl or arylene radical as ap ⁇ plicable, where aryl or arylene are as defined above but limited to phenyl, biphenylyl, naphthyl, fluorenyl, and indenyl, as well as the corresponding divalent radicals.
  • Hetr as used herein is intended to include a heteroaryl or heteroarytene radical as applicable, where heteroaryl or heteroarytene are as defined above but limited to furyl, thienyl, pyrrolyl, pyrazolyl, 3-oxopyrazolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,2,3-triazinyi, 1 ,2,4-triazinyl, 1 ,3,5- triazinyl, 1 ,2.3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxa- diazolyl, 1,3,4-oxadiazolyl, 1,2,3-thiadia
  • ⁇ et2 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, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, pyranyl. pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1 ,2,4-triazinyl.
  • 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.
  • Aryl-CrCe-alkyl "heteroaryl-C r C 6 -alkyl”, “aryl-C ⁇ -C ⁇ -alkenyP etc. is intended to mean Ci-C 8 -alkyl or C 2 -C ⁇ -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 dis ⁇ ease, 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 (cod- able) 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 phar ⁇ maceutically acceptable group that contains a positive charge at physiologically relevant pH, such as amino (primary, secondary and tertiary), ammonium and guanidino groups.
  • ⁇ amino acid as used herein is intended to mean mean any natural (cod- able) and non-natural ⁇ -aminocarboxylic acid, including D-isomers of these.
  • ⁇ amino acid as used herein is intended to mean any ⁇ -aminocarboxylic add, 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.
  • amino acid residues are indicated in the three letter amino acid code or the one letter amino code.
  • BIOS 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 carboxylates, dithiocarboxylates, phe ⁇ olates, thiophenolates, alkylthiolates, sulfonamides, imidazoles, 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 in ⁇ tended to include also derivatives of the compounds from which the groups take their name.
  • insulin refers to all variants of insulin including human in ⁇ sulin, an analogue thereof, a derivative thereof and combinations of any of these, acid- stabilised insulin, fast/rapid acting insulin and long/stow/basal acting insulin.
  • human insulin refers to naturally produced insulin or re- combinantly 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.
  • insulin analogue as used herein is meant human insulin in which at least one amino acid has been deleted and/or replaced by another amino acid 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.
  • insulin derivative refers to human insulin or an analogue thereof which has been chemically modified, i.e. at least one organic substitue ⁇ t is bound to one or more of the amino acids, e.g. by introducing a side chain in one or more positions of the insulin backbone.or by oxidizing or reducing groups of the amino acid residues in theJnsulin or by converting a free carboxylic group to an ester group or acylating a free amino group or a hydroxy group.
  • 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.
  • fast/rapid acting insulin as used herein is meant any insulin having an onset of action after injection or any other form of administration faster or equal to that of soluble and neutral formulations of human insulin.
  • long/slow/basal acting insulin as used herein is intended to include insu ⁇ lin compounds such as protamine insulin, zinc insulin, protamine zinc insulin.
  • 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.
  • Protamine as used herein refers to the generic name of a group of strongly basic proteins present in sperm cell nucleic in saltlike combination with nucleic acids. Commercially available protamines can be isolated from mature fish sperm and are usually obtained as the sulphate. The peptide composition of a specific protamine may vary depending of which fam- ily, genera or species of fish it is obtained from.
  • Protamine usually contains four major com ⁇ ponents, i.e. single-chain peptides containing about 30-32 residues of which about 21-22 are arginines.
  • the N-ternimal is praline for each of the four main components, and since no other amino groups are present in the sequence, chemical modification of protamine is expected to be homogenoues in this context.
  • protamines to be used together with insulin are obtained from e.g. salmon (salmine), rainbow trout (iridine), herring (clupeine), sturgeon (sturine) or Spanish mackerel (thynnine).
  • Protamine also refers to preparations comprising salts of the proteins.
  • an insulin derivative according to the invention is stated to be “soluble at physiological pH values” it means that the insulin derivative can be used for preparing injectable insulin compositions that are fully dissolved at physiological pH values.
  • Such favourable solubil ⁇ ity may either be due to the inherent properties of the insulin derivative alone or a result of a fa ⁇ vourable interaction between the insulin derivative and one or more ingredients contained in the vehicle.
  • physiologically relevant pH as used herein is intended to mean a pH of about 7.1 to 7.9.
  • Fig. 1 Change in plasma glucose level after subcutaneous injection of the prepara- tion: 0,6mM A21G, B28D human insulin, 0.3mM Zn2+, 3OmM phenol, 1.6% glycerol, 0.3mM 4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)naphthalen-1-yloxy]butyrylprotamine.
  • Fig. 2 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-n ⁇ trobenzoic acid (4H3N). Inserted in the upper right comer is the absorbance at 444nm vs. the co ⁇ cen- tration of ligand
  • Fig. 3 Fluorescence spectra resulting from a titration of hexameric in ⁇ sulin with 5-(3-methoxybenzylidene)thiazolidine-2,4-dione in the presence of 5-(4- dimethylaminobenzylidene)thiazolidine-2 T 4-dione (TZD). Inserted in the upper right comer is the fluorescence at 460 nm vs. the concentration of ligand
  • the present invention is based on the discovery that the His 910 Zn +* ligand binding sites of the R-state insulin hexamer wherein the ligand is extended by protamine can be used to obtain an insulin preparation having prolonged action designed for flexible injection re ⁇ gimes including once-daily, based on insulin molecules of any kind.
  • the basic concept underlying the present invention involves reversible attachment of a ligand to the His B1 ° Zn 2+ site of the R-state hexamer.
  • a suitable ligand binds to the hexamer metal site with one end while at the other end, the anchor features a carboxylate group.
  • the carboxylate group is covalently bound via an amide link to protamine.
  • the anions currently used in insulin formulations as allosteric ligands for the R-state hexamers bind only weakly to the His B1 ° anion site.
  • the present inven ⁇ tion 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 outlined above.
  • the His B1Q Zn 2* 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 oc ⁇ cupying the site, the opening can be capped over by the Asn 63 and Phe B1 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 Be . Therefore, except for the zinc ion, which is coordinated to three His B1 ° 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 B3 and with the peptide linkage to Cys B7 .
  • the present invention originates from a search for compounds with suitable binding properties 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 B10 -Zn 2+ site by the incoming ligand in question. These compounds will be referred to as "starter com ⁇ pounds" in the following. These assays are easily transformed into a high-throughput format capable of handling fibraries constructed around hits from the initial search of compound da ⁇ tabases. These starter compounds provide the starting point for the task of constructing a chemical handle that allows for attachment of the protamine group.
  • 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
  • Zinc ions A ligand which binds reversibly to a HisB10 Zn 2+ site of an R-state hexamer and wherein the ligand is extended by covalent attachment to protamine, having the following general formula (I)
  • CGr is a chemical group which reversibly binds to a His B1 ° Zn 2+ site of an insulin hexamer
  • Lnk is a linker selected from
  • B 2 is a valence bond, C ⁇ C ⁇ -alkylene.
  • C 2 -C 1B -alkenylene, C r Ci 8 -alkynylene, arylene. heteroarylene, -C t -Ci ⁇ -alkyl-aryl-, -Crde-alkenyl-aryl-. -Cz-Ci ⁇ -alkynyl-aryl-. -C( O)-
  • arylene and heteroarylene moieties are optionally substituted by halogen, -C(O)OR 6 , -C(O)H, OCOR 6 , -SO 2 , -CN, -CF 3 , -
  • Frg is a fragment consisting of O to 5 neutral ⁇ - or ⁇ -amino acids
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative exam ⁇ ples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulphuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, gly- colic, lactic, maleic, malic, malonic, ma ⁇ delic, picric, pyruvic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, , ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like.
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, magnesium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-, n-butyh sec-butyi-, tert-butyh tetramethylammonium salts and the like.
  • pharmaceutically acceptable acid addition salts are the hydrates, which the present compounds, are able to form.
  • the acid addition salts may be obtained as the direct products of compound synthe ⁇ sis, in the alternative, the free base may be dissolved in a suitable solvent containing the ap ⁇ intestinalte acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of the present invention may form solvates with standard low mo ⁇ lecular weight solvents using methods well known to the person skilled in the art. Such sol ⁇ vates are also contemplated as being within the scope of the present invention.
  • CGr is a chemical structure selected from the group consisting of carboxylates, dithiocarboxylates, phenolates, thiophe ⁇ olates, alkylthiolates, sulfonamides, imidazoles, 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 consist- ing of benzotriazoles, 3-hydroxy 2-napthoic acids, salicylic acids, tetrazoles, thiazolidin- ediones, 5-mercaptotetrazoles, or 4-cyano-1 ,2,3-triazoles.
  • R 1 and R 4 are independently selected from hydrogen or Ci-C ⁇ -alkyl
  • R 2 is hydrogen or Ci-C 6 -alkyl or aryl
  • R 1 and R 2 may optionally be combined to form a double bond
  • R 3 and R 6 are independently selected from hydrogen, halogen, aryl, C r C 6 -alkyl, or -C(O)NR 11 R 12 .
  • a and B are independently selected from d-C ⁇ -alkylene, arylene, aryl-CrC 6 -alkyl-, aryl-C 2 - C ⁇ -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 ? , 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 e is independently selected from halogen, -CN, -CF 3 , -OCF 3 , aryl, -COOH and -NH 2 ,
  • R 7 , R 8 , R B and R 10 are independently selected from • hydrogen, halogen, -CN, -CH 2 CN 1 -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 . -OS(O) 2 CF 3 , -SCF 3 . -NO 2 , -OR 11 , -NR 11 R 12 , -SR 11 , -NR 11 S(O) 2 R 12 , -S(O) 2 NR 11 R 12 , -S(O)NR 11 R 12 .
  • Ci-C ⁇ -alkyl C ⁇ -C ⁇ -alkenyl or Cz-C ⁇ -alkynyl. each of which may optionally be substi ⁇ tuted with one or more substituents independently selected from R 13 ,
  • each cyclic moiety may optionally be substituted with one or more substitu ⁇ ents independently selected from R 1 *,
  • R 11 and R 12 are independently selected from hydrogen, OH, d-Cj-o-alkyl, aryl-Ci-C fl -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 11 R 12 , and -C(O)NR 11 R 12 ,
  • R 1 " 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 d-C ⁇ -aikyl,
  • R 15 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -Od-C ⁇ -alkyl, -C(O)OC 1 -C 6 - alkyl, -COOH and -NH 2
  • R l ⁇ is independently selected from halogen, -C(O)OC 1 -Ce-SlKyI, -COOH, -CN, -CF 3 .
  • X O.
  • Y is -O- or -S-.
  • Y is -O-.
  • 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 sub ⁇ stituents, 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 ⁇ , 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 10 which may be the same or different.
  • A is selected from Het1 optionally substituted with up to four sirb- stituents, R 7 , R ⁇ , R 9 , and R 10 which may be the same or different.
  • A is selected from Het2 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 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 substitue ⁇ ts, R 7 , R 8 , R 9 , and R 10 which may be the same or different.
  • A is be ⁇ zofuranylene optionally substituted with up to four substitu- ents R 7 , R B , R 9 , and R 10 which may be the same or different.
  • R 7 , R B , R 9 , and R 10 which may be the same or different.
  • A is carbazolylidene optionally substituted with up to four substitu- ents 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 8 , R ⁇ , and R 10 which may be the same or different.
  • R 7 , R 8 , R ⁇ , and R 10 which may be the same or different.
  • R 1 is hydrogen. In another embodiment R 2 is hydrogen.
  • R 1 and R 2 are combined to form a double bond.
  • R 3 is d-C ⁇ -alkyl, halogen, or C(O)NR 18 R 17 .
  • R 3 is C r C 6 -alkyl or C(O)NR 16 R 17 .
  • R 3 is methyl.
  • R 7 , R B , R 9 , and R 10 which may be the same or different.
  • R 4 is hydrogen.
  • R 5 is hydrogen.
  • R 6 is aryl.
  • R ⁇ is phenyl.
  • R 7 , R 8 , R 9 and R 10 are independently selected from
  • R 7 , R ⁇ , R 8 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 .
  • 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 .
  • R 7 , R 8 , R 9 and R 10 are independently selected from •hydrogen, halogen, -OR 11 , -Od-C ⁇ -alkyl-qojOR 11 , or -C(O)OR 11 ,
  • R 11 and R 12 are independently selected from hydrogen, Ci-Ca-alkyl, aryl or aryKVCe-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 ie ; R 11 and R 1Z when at ⁇ tached 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 11 and R 12 are independently selected from hydrogen, CrCaralkyl, aryl or aryl-CrC ⁇ -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-C r C 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 .
  • 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)OC 1 -C 6 - alkyl.and -COOH.
  • R 15 is independently selected from halogen or -C(O)OCi-C ⁇ -alkyl.
  • R t ⁇ is independently selected from halogen
  • R 19 is hydrogen or Ci-C ⁇ -alkyl
  • R 20 is hydrogen or Ci-C 6 -alkyl
  • D and F are a valence bond or CVC ⁇ -alkylene optionally substituted with one or more sub- stituents independently selected from R 72 ,
  • R 72 is independently selected from hydroxy. Ci-C ⁇ -alkyl, or aryl,
  • E is Ci-C ⁇ -alkylene, arylene or heteroarylene, wherein the arylene or heteroarylene is option ⁇ ally substituted with up to three substituents R 21 , R 22 and R 23 ,
  • G is Ci-C ⁇ -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 z ⁇ R 22 , R 23 , R 24 , R 25 and R 26 are independently selected from
  • R 29 which may optionally be substituted with one or more substituents independently se ⁇ lected from R 29 , •aryl, aryloxy, aryloxycarbonyl, aroyl, aryl-d-C ⁇ -alkoxy, aryl-CrC ⁇ -alkyl.
  • R 27 and R 28 are independently selected from hydrogen.
  • C r C ⁇ -alkyl, aryl-d-Ce-alkyl or aryl, or R 27 and R 2 ⁇ 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 het- eroatoms 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 2r , and -NR 27 R 28 ,
  • R 30 is independently selected from halogen, -C(Q)OR 27 . -CM, -CF 3 , -OCF 3 . -NO 2 , -OR 27 , -NR 27 R za and d-C 8 -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 Ci-C 6 -alkylene optionally substituted with one or more hydroxy, d-C ⁇ -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 R 23 .
  • E is arylene optionally substituted with up to three substituents inde ⁇ pendently 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 phe ⁇ ylene optionally substituted with up to three substituents independently selected from R 21 , R 22 and R 23 .
  • CGr is
  • R 21 , R 22 and R 23 are independently selected from
  • R 21 , R 22 and R 23 are independently selected from
  • Ci-C ⁇ -alkyl optionally substituted with one or more substituents independently se ⁇ lected from R 29
  • R 21 , R 22 and R 23 are independently selected from
  • 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 1 ⁇ is hydrogen.
  • R 87 is Hydrogen, CrC ⁇ -aIkyl or aryl.
  • R 27 is hydrogen or CrC ⁇ -alkyl.
  • R 28 is hydrogen or d-Cs-alkyl.
  • F is a valence bond.
  • F is C r C ⁇ -alkylene optionally substituted with one or more hydroxy, Ci-C ⁇ -alkyl, or aryl.
  • G is CrC ⁇ -alkylene or arylene, wherein the arylene is optionally sub ⁇ stituted with up to three substituents R 24 , R 25 and R 28 .
  • G is Ci-C 6 -alkylene or ArG1, wherein the arylene is optionally substi ⁇ tuted with up to three substituents R 24 , R 28 and R 2 ⁇
  • G is Ci-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 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 24 , R 2S and R 28 are independently selected from
  • R 24 , R 25 and R 28 are independently selected from
  • ArG1-Ci-C 6 -alkyl of which the cyclic moieties optionally may be substituted with one or more substituents se ⁇ lected from R 30 .
  • R 20 is hydrogen or methyl.
  • R 20 is hydrogen
  • R 27 is hydrogen, Ci-C 6 -alkyl or aryl.
  • R 27 is hydrogen or C r C 6 -alkyl or ArG1. In another embodiment R 27 is hydrogen or C 1 -C ⁇ -alkyl.
  • R 28 is hydrogen or d-Ce-alkyl.
  • R 17 and R 18 are independently selected from
  • R 17 and R 18 are independently selected from •hydrogen, halogen, -CN. -CF 3 , -NO 2 , -OR 27 , -NR 27 R 28 , or -C(O)OR 27 ,
  • R 17 and R 1 ⁇ are independently selected from
  • R 17 and R 18 are independently selected from
  • R 17 and R 18 are independently selected from • hydrogen, halogen, -CN, -CF 3 , -NO 2 , -OR 27 . -NR 27 R 28 , or -C(O)OR 27
  • R 27 is hydrogen or C,-C ⁇ -alkyl. In another embodiment R 27 is hydrogen, methyl or ethyl. In another embodiment R 28 is hydrogen or Ci-C 6 -alkyl. In another embodiment R 28 is hydrogen, methyl or ethyl. In another embodiment R 72 is -OH or phenyl. In another embodiment 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-, and n is 1 or 2,
  • Arylene -aryloxy-. arylene-oxycarbonyl-, -aroyl, arylene-C r C ⁇ -alkoxy-, ary- lene-CrC ⁇ -alkylene, arylene-C r C 6 -alkenylene, arylene-C 2 -C a -alkynylene, heteroary- len ⁇ , heteroarylene-Ca-Ce-alkenylene or heteroary- le ⁇ e-C 2 -C 6 -alkynylene, wherein the cyclic moieties are optionally substituted with one or more substituents selected from R 37 , R 31 is independently selected from hydrogen, halogen, -CN, -CH 2 CN, -CHF 2 , -CF 3 , -OCF3, -OCHF 2 , -OCH 2 CF 3 .
  • R 32 and R 33 are independently selected from hydrogen, CrC ⁇ -alkyl or Ci-Ce-alkanoyl,
  • R 34 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 35 , and -NR 35 R 38 ,
  • R 35 and R 36 are independently selected from hydrogen, CrC e -alkyl, aryl-d-C ⁇ -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 het- eroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R 37 is independently selected from halogen, -C(OpR 35 , -C(O)H, -CN, -CF 3 , -OCF 3 , -NO 2 , - OR 35 . -NR 35 R 39 , d-Ce-alkyl or d-C ⁇ -alkanoyl.
  • t is a valence bond, -CH 2 N(R 32 )-, or -SO 2 N(R 33 )-.
  • 1 is a valence bond.
  • J is
  • J is «ArG1 or Het3, wherein the cyclic moieties are optionally substituted with one or more substituents independently selected from R 37 .
  • tn another embodiment J is
  • R 32 and R 33 are independently selected from hydrogen or Ci-C ⁇ -alkyl.
  • R 3 * is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -SCF 3 , -NO 2 , -OR 35 ,
  • Ce-BlKyI-C(O)OR 35 -Sd-C 6 -alkyl-C(O)OR 35 or -C(O)OR 35 .
  • R 34 is hydrogen, halogen, -CF 3 . -NO 2 , -OR 35 , -NR 35 R 36 , -SR 35 , -NR 35 C(O)R 38 , or -C(O)OR 35 .
  • R 34 is hydrogen, halogen, -CF 3 , -NO 2 , -OR 35 , -NR 35 R 36 , or
  • R 34 is hydrogen, halogen, or -OR 35 .
  • R 33 and R 36 are independently selected from hydrogen, CrC ⁇ -alkyl, or aryl.
  • R 35 and R 36 are independently selected from hydrogen or C
  • R 37 is halogen. -C(O)OR 35 , -CN. -CF 3 , -OR 35 , -NR 35 R 36 , Ci-C e -alkyl or
  • R 37 is halogen, -C(O)OR 35 , -OR 35 , -NR 35 R 38 , d-C ⁇ -alkyl or C 1 -C 6 - alkanoyl.
  • R 37 is halogen, -C(O)OR 35 or -OR 35 .
  • U is a valence bond, d-Ce-alkenylene, -C t -C 6 -alkyl-O- or Ci-C ⁇ -alkyJe ⁇ e wherein any C,- Ce-alkyl moiety is optionally substituted with d-C ⁇ -alkyl,
  • R 38 is CrC ⁇ -alkyl, aryl, wherein the alkyl or aryl moieties are optionally substituted with one or more substituents independently selected from R 39 ,
  • R 3B is independently selected from halogen, cyano, nitro, amino,
  • M is a valence bond, arylene or heteroaryfene, wherein (he aryl or heleroaryl moieties are optionally substituted with one or more substituents independently selected from R* 0 ,
  • R 40 is selected from
  • R 41 and R 42 are independently selected from hydrogen, -OH 1 d-C ⁇ -alkyl f d-C B -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 substi- tuted with one or more substituents independently selected from R 46 ; R 41 and R 42 when at ⁇ tached 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, - CF 3 . -OCF 3 , -NO 2 .
  • R 45 is independently selected from halogen. -CN, -CF 3 , -OCF 3 . -O-C-Ce-alkyl, -C(O)-O-C 1 - C ⁇ -alkyl, -COOH and -NH 2 ,
  • R 47 and R 48 are independently selected from hydrogen, C r C e -alkyl, aryl optionally substituted with one or more R 49 ,
  • R 49 is independently selected from halogen and -COOH
  • T is •CrC ⁇ -alkylene, C r C ⁇ -alkenylene , C 2 -C ⁇ -alkynylene, -CrC ⁇ -alkyloxy-carbonyl.
  • the alkylene, alkenylene and alkynylene moieties are optionally substituted with one or more substituents independently selected from R 50 , •arylene, -aryloxy-, -aryloxy-carbonyl-, arylene-d-C ⁇ -alkylene, -aroyl-, arylene-Ci- C ⁇ -alkoxy-, arylene-CrC ⁇ -alkenylene, arylene-C 2 -C e -alkynylene, heteroarylene, het- eroarylene-Ci-C ⁇ -alkylene, heteroarylene-C 2 -Ce-alkenylene, heteroarylene-C 2 - C ⁇ -alkynylene,
  • 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-Ce-alkyl
  • R 53 is independently selected from Ci-C 6 -alkyl. d-Ce-alkoxy, -Ci-C 6 -alkyl-COOH, -Cr
  • K is a valence bond.
  • K is a valence bond.
  • CrC ⁇ -alkyl moiety is optionally substituted with R 38 .
  • K is a valence bond or d-C ⁇ -alkylene, wherein any d-C ⁇ -alkyl moi- ety is optionally substituted with R 38 .
  • K is a valence bond
  • U is a valence bond or -C,-C e -alkyl-O-.
  • U is a valence bond
  • M is arylene or heteroarylene, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R 40 .
  • 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 ArGI 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
  • M is carbazolylene optionally substituted with one or more substitu ⁇ ents independently selected from R 40 .
  • M is
  • R 40 is selected from
  • Ci-C ⁇ -alkyl or C 2 -C 6 - alkenyl which may each optionally be substituted with one or more substituents independently selected from R 43 ,
  • 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 hafogen or -
  • Q is a valence bond, -CH 2 -. -CH 2 -CH 2 -, -CH 2 -O-, -CH 2 -CH 2 -O-,
  • R 4r and R 48 are independently selected from hydrogen, methyl and phenyl.
  • T is #Ci-C ⁇ -alkylene optionally substituted with one or more substituents independently selected from R 50 ,
  • ArGI 1 ArGI-d-C ⁇ -alkylene, Het3, wherein the alkyl, aryl and heteroaryl moieties are optionally substituted with one or more substituents independently selected from R w .
  • Ci-Ce-alkylene optionally substituted with one or more substituents independently selected from R 50 ,
  • R 50 is d-C ⁇ -alkyl, d-C ⁇ -alkoxy, aryl, aryloxy, aryl-d-C ⁇ -alkoxy , -OR 61 , -NO 2 , halogen, -COOH 1 -CF 3 , wherein any aryl moiety is optionally substituted with one or more R 53 .
  • R 50 is d-Ce-alkyl, aryloxy, aryl-Ci-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 C r C 8 -alkyl, ArGI-O-, ArG1-C r Ce-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 ⁇ -a1kylene, arylene, heteroarylene, arylene-Ci-e-alkylene or aryfene-C 2 ⁇ - 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 -hydrogen, halogen. -CN, -CH 2 CN, -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 ,
  • -OS(O) 2 R » -C(O)NR 56 R 57 , -OC(O)NR 50 R 57 , -NR 56 C(O)R 57 , -CH 2 C(O)NR 56 R 57 . -OC 1 -C 6 - 8 ⁇ yI-C(O)NR 56 R 57 , -CH 2 OR 56 , -CH 2 OC(O)R 58 , -CH 2 NR 56 R 57 . -OC(O)R 58 , -OC 1 -C 8 - alkyl-CtOJOR 59 , -SCrC ⁇ -alkyl-CCOJOR 56 , -Cz-C ⁇ -alkenyl-
  • 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, the heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R 58 is independently selected from hafoge ⁇ , -CN, -CF 3 , -OCF 3 , -OR 56 , and -NR 56 R 57 ,
  • R 59 is independently selected from halogen. -C(O)OR 56 . -CH 2 C(O)OR 56 , -CH 2 OR 59 , -CN, - CF 3 , -OCF 3 , -NO 2 , -OR 56 , -NR 56 R 57 and d-Qralkyl,
  • R 62 is d-Ce-alkyl, aryl optionally substituted with one or more substituents independently se ⁇ lected from halogen, or heteroaryl optionally substituted with one or more C r C ⁇ -alkyl inde ⁇ 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-Ci.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 inde- pendently selected from R 55 .
  • V is arylene, Het1, or aryle ⁇ e-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 inde ⁇ pendently selected from R 55 .
  • V is arylene, Het2, 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 inde ⁇ pendently selected from R 55 .
  • V is arylene, Het3, 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 Inde ⁇ pendently selected from R 55 .
  • V is arylene optionally substituted with one or more substituents in ⁇ dependently selected from R 55 .
  • V is ArG1 optionally substituted with one or more substituents inde ⁇ pendently selected from R 53 .
  • V is phenylene, naphthyle ⁇ e 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
  • Ci-C ⁇ -alkyl optionally substituted with one or more substituents independently se- lected from R 58
  • R 55 is independently selected from • halogen, d-C ⁇ -alkyl, -CN. -OCF 3 ,-CF 3 . -NO 2 , -OR 56 , -NR 58 R 57 . -NR 58 C(O)R 57
  • Ci-Ce-alkyl optionally substituted with one or more substituents independently se ⁇ lected from R 58
  • R 55 is independently selected from halogen, -OR 59 , -NR 58 R 57 , -C(O)OR 58 , -OCrC-alkyl-CfOJOR 56 , -NR 58 C(O)R 57 or C r C ⁇ -alkyl.
  • R 55 is independently selected from halogen, -OR 56 , -NR 58 R 57 . -C(O)OR 58 , -OC-C ⁇ -alkyl-qojOR 56 , -NR 58 C(O)R 57 , methyl or ethyl.
  • R 56 and R S7 are independently selected from hydrogen or d-C 12 -alkyl, R 56 and R 57 when attached to the same nitrogen atom may form a 3 to 8 mem- bered 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 Ci-C ⁇ -alkylene, arylene, heteroarylene, arylene-Ci-C 6 -alkylene or arylene-Cj.
  • 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 84 ,
  • R 63 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , aryl, -COOH and -NH 2 ,
  • R 6 * 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(O)OR 65 . -CH 2 C(O)OR 65 , -CH 2 OR 65 , -CN, - CF 3 , -OCF 3 , -NO 2 , -OR 65 , -NR 65 R 68 and d-Ce-alkyl.
  • R 69 is independently selected from Ci-C ⁇ -alkyl, aryl optionally substituted with one or more halogen, or heteroaryl optionally substituted with one or more Ci-C ⁇ -alkyl,
  • R 70 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OC r C ⁇ -afkyl, -C(O)OC 1 -Ce- alkyl, -COOH and -NH 2 ,
  • R 71 is independently selected from halogen, -C(O)OCi-C ⁇ -alkyl, -COOH, -CN, -CF 3 , -OCF 3 , -
  • AA is arylene, heteroarylene or arylene-d.C ⁇ -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 aryle ⁇ e or heteroarylene, wherein the aryiene or heteroarylen ⁇ 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 substitu ⁇ ents independently selected from R 84 .
  • AA is ArG 1 or Het3 optionally substituted with one or more substitu ⁇ ents independently selected from R 64 .
  • AA is phenylene, naphtylene, anthrylene, carbazolylene, thienylene, pyridylene, or benzodioxylene optionally substituted with one or more substituents independ ⁇ ently 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 , C-Ce-alkyl, -OC(O)R 65 , -OC 1 -C 6 -BlRyI-C(O)OR 65 , aryloxy or aryl, wherein Ci-C B -alkyl is optionally substituted with one or more substituents independ ⁇ ently selected from R 97 , and the cyclic moieties optionally are substituted with one or more substituents independently selected from R 88 .
  • R 84 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(O)OR 65 , -OCH 2 -CH 2 -C(O)OR 65 , phenoxy optionally substituted with one or more substituents independently selected from R 68 .
  • R 65 and R eB are independently selected from hydrogen, CF 3 , C ⁇ C ⁇ -alkyl, aryl, or heteroaryl optionally substituted with one or more substituents inde- pendently selected from R 71 .
  • R 65 and R 8 ⁇ are independently hydrogen, Ci-C 1z -alkyl, aryl, or het ⁇ eroaryl optionally substituted with one or more substituents independently selected from R 7 ⁇
  • 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 inde- pendently selected from R 71 .
  • R 65 and R ⁇ are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG1 or Het2 optionally substituted with one or more substituents inde ⁇ pendently selected from R 71 .
  • R 65 and R ⁇ are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG 1 or Het3 optionally substituted with one or more substituents inde ⁇ pendently selected from R 71 .
  • R 65 and R e ⁇ are independently hydrogen, methyl, ethyl, propyl, butyl,
  • R 71 is halogen or Ci-C ⁇ -alkyl.
  • R 71 is halogen or methyl.
  • Frg consists of 0 to 5 neutral amino acids independently selected from the group consisting of GIy, Ala, Thr, and Ser.
  • Frg consists of 0 to 5 GIy. In another embodiment Frg consists of O GIy.
  • Frg consists of 1 GIy.
  • Frg consists of 2 GIy.
  • Frg consists of 3 GIy.
  • Frg consists of 4 GIy. In another embodiment Frg consists of 5 GIy.
  • G B is of the formula B'-B ⁇ CKO ⁇ -, B'-B ⁇ SOz- or B 1 ⁇ -CH 2 -, wherein
  • G B is of the formula B 1 -B 2 -C(O)-.
  • G B is of the formula B 1 -B 2 -C(O)-, B ⁇ B 2 OH 2 - or B T -B 2 -NH- t wherein
  • G B 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 B is of the formula B 1 -B 2 -C(O)- or B 1 ⁇ -SO 2 -, wherein B 1 and B 2 are as defined in claim 1.
  • G B is of the formula B 1 ⁇ -C(O)- 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(O)- 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 n -B 2 -CH 2 - or B 1 -B 2 -SO 2 - , wherein B 1 and B 2 are as defined in claim 1.
  • G B is of the formula B 1 -B 2 -NH- or B 1 -B 2 -SO 2 - , wherein B 1 and B 2 are as defined in claim 1.
  • G B is of the formula B'-B ⁇ CHz- 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(O)-. In another embodiment G B is of the formula B 1 -B 2 -CH 2 -. In another embodiment G B is of the formula B 1 -B 2 -SO 2 -. In another embodiment G B is of the formula B 1 -B 2 -NH-. In another embodiment B 1 is a valence bond, -O-, or -S-. In another embodiment B 1 is a valence bond, -O-. or -N ⁇ R 6 )-. In another embodiment B 1 is a valence bond, -S-, or -N(R 6 )-.
  • B 1 is -O-, -S- or -N(R 6 )-.
  • B 1 is a valence bond or -O-.
  • B 1 is a valence bond or -S-.
  • B 1 is a valence bond or -N(R 6 )-.
  • B 1 is -O-or -S-.
  • B 1 is -O-or -N(R 6 )-.
  • B 1 is -S-or -N(R 6 )-.
  • tn another embodiment B 1 is a valence bond.
  • B 1 is -O-.
  • B 1 is -S-.
  • B 1 is -N(R 8 )-.
  • B 2 is a valence bond, d-C t ⁇ -alkylene, C 2 -Ci a -alkenylene, C 2 -Ci 8 - alkynylene. arylene, heteroarylene.
  • B 2 is a valence bond, Ci-d 8 -alkylene, arylene, heteroarylene, -Ci- Ci 8 -alkyl-aryl-, and the alkylene and arylene moieties are optionally substituted as defined in claim 1.
  • B 2 is a valence bond, d-Ci ⁇ -alkylene, arylene, -d-C ⁇ alkyl-aryl-, and the alkylene and arylene moieties are optionally substituted as defined in claim 1.
  • B 2 is a valence bond or and the alkylene moieties are optionally substituted as defined in claim 1.
  • the insulin is selected from the goup consisting of human in ⁇ sulin, an analogue thereof, a derivative thereof and combinations of any of these.
  • the insulin is human insulin.
  • the insulin is an analogue of human insulin.
  • the insulin is a derivative of human insulin. In another embodiment the insulin is an analogue of human insulin wherein position
  • B28 is Asp, GIu, Lys, Leu, VaI, or Ala.
  • the insulin is an analogue of human insulin wherein position B28 is Asp, GIu or Lys
  • the insulin is an analogue of human insulin wherein position B28 is Asp or GIu.
  • the insulin is an analogue of human insulin wherein position B28 is Asp.
  • the insulin is an analogue of human insulin wherein position B28 is GIu. In another embodiment the insulin is an analogue of human insulin wherein position B28 is GIu. In another embodiment the insulin is an analogue of human insulin wherein position B28 is GIu.
  • B29 is Pro, Asp or GlU/
  • the insulin is an analogue of human insulin wherein position B29 is Pro or GIu.
  • the insulin is an analogue of human insulin wherein position B29 is Pro.
  • the insulin is an analogue of human insulin wherein position B29 is GIu.
  • the insulin is an analogue of human insulin wherein position
  • B9 is Asp or GIu.
  • the insulin is an analogue of human insulin wherein position B10 is Asp or GIu.
  • the insulin is an analogue of human insulin wherein position B10 is GIu. In another embodiment the insulin is an analogue of human insulin wherein position B1 is GIy.
  • the insulin is an analogue of human insulin wherein position 83 is Lys, Thr, Ser, Ala or GIn. In another embodiment the insulin is an analogue of human insulin wherein position 83 is Lys, Thr, Ser, Ala or GIn. In another embodiment the insulin is an analogue of human insulin wherein position 83 is Lys, Thr, Ser, Ala or GIn. In another embodiment the insulin is an analogue of human insulin wherein position
  • B3 is Lys, Thr, Ser or Ala.
  • the insulin is an analogue of human insulin wherein position B3 is Lys or Ala.
  • the insulin is an analogue of human insulin wherein position B3 is Lys.
  • the insulin is an analogue of human insulin wherein position B3 is Lys and position B29 is GIu.
  • the insulin is an analogue of human insulin wherein position B25 is deleted. In another embodiment the insulin is an analogue of human insulin wherein position B25 is deleted. In another embodiment the insulin is an analogue of human insulin wherein position B25 is deleted. In another embodiment the insulin is an analogue of human insulin wherein position B25 is deleted. In another embodiment the insulin is an analogue of human insulin wherein position B25 is deleted. In another embodiment the insulin is an analogue of human insulin wherein position B25 is deleted. In another embodiment the insulin is an analogue of human insulin wherein position B25 is deleted. In another embodiment the insulin is an analogue of human insulin wherein position B25 is deleted. In another embodiment the insulin is an analogue of human insulin wherein position B25 is deleted. In another embodiment the insulin is an analogue of human insulin wherein position B25 is deleted. In another embodiment the insulin is an analogue of human insulin wherein position B25 is deleted. In another embodiment the insulin is an analogue of human insulin wherein position B25 is deleted. In another embodiment the insulin
  • the insulin is an analogue of human insulin wherein position B30 is deleted.
  • the insulin is an analogue of human insulin wherein position A18 is Gln.
  • the insulin is an analogue of human insulin wherein position A21 is Ala, GIn, GIu, GIy, His, lie, Leu, Met, Phe, Ser, Thr, Trp, Tyr, VaI or hSer.
  • the insulin is an analogue of human insulin wherein position A21 is Ala, GIy, lie, Leu, Phe, Ser, Thr, VaI or hSer. In another embodiment the insulin is an analogue of human insulin wherein position A21 is Ala, GIy, lie, Leu, Phe, Ser, Thr, VaI or hSer. In another embodiment the insulin is an analogue of human insulin wherein position A21 is Ala, GIy, lie, Leu, Phe, Ser, Thr, VaI or hSer. In another embodiment the insulin is an analogue of human insulin wherein position
  • A21 is Ala or GIy.
  • the insulin is an analogue of human insulin wherein position A21 is GIy.
  • the insulin is a derivative of human insulin or an analogue thereof having one or more lipophilic substituents.
  • the insulin is a derivative of human insulin or an analogue thereof wherein the N f -amino group in position B29Lys is modified by covalent acylation with a hydrophobic moiety such as an fatty acid derivative or an litocholic acid derivative.
  • the insulin derivative is selected from the group consisting of B29-N ⁇ -myristoyI ⁇ des(B30) human insulin, B29-N E -palmitoyl-des(B30) human insulin, B29-N ⁇ - myristoyl human insulin, B29-N ⁇ -palmitoyl human insulin, B28-N ⁇ -myristoyl Lys B2S Pro 829 hu- man insulin.
  • analogs of human insulin contain any combination of the additional stabilizing substitutions in positions B1, B3, A18 and A21.
  • the insulin is an analogue of human insulin selected from the group consisting of:
  • the insulin is an analogue of human insulin selected from the group consisting of:
  • A21G, B10E,desB30 A21G, desB25. desB30.
  • B29E B1 G, A21 G, B3K, B29E, desB30
  • the insulin is an analogue of human insulin from above three lists further modified in positions B3 and A18, eg B3T, B3S. B3Q and A18Q.
  • the insulin is an analogue of human insulin from the above three lists further modified as follows: B3T, B28D B3T, desB27.
  • the insulin is an analogue of human insulin from the above three lists further modified by deletion of B30.
  • the ratio of the protamine-exte ⁇ ded ligand of general for ⁇ mula (I) to zinc ion is 1:20 to 20:1.
  • the ratio of the protami ⁇ e-extended ligand of general for ⁇ mula (I) to zinc ion is 1:6 to 10:1.
  • the amount of zinc ions is 2-6 moles per mole of putative in- sulin hexamer.
  • the amount of zinc ions is 2.0-3.5 moles per putative insulin hexamer.
  • zinc ions are present in an amount corresponding to 10 to 40 ⁇ g Zn/100 U insulin. In another embodiment zinc ions are present in an amount corresponding to 10 to 26 ⁇ g Zn/100 U insulin.
  • the ratio between insulin and the protamine-extended ligand of the invention is in the range from 99:1 to 1:99.
  • the ratio between insulin and the protamine-extended ligand of the invention is in the range from 95:5 to 5:95.
  • the ratio between between insulin and the protamine- extended ligand of the invention is in the range from 80:20 to 20:80.
  • the ratio between between insulin and the protamine- extended ligand of the invention is in the range from 70:30 to 30:70.
  • the invention relates to a method of preparing a protamine- extended ligand of the invention comprising the steps of:
  • the invention relates to a method of prolonging the action of an in ⁇ sulin preparation which comprises adding the ligand of the invention to the insulin prepara ⁇ tion.
  • the invention in another aspect relates to a method of treating type 1 or type 2 dia- betes comprising administering to a patient in need thereof a theraputicaHy effective amount of a pharmaceutical preparation comprising
  • a ligand that binds to the R-state His B10 -Zn 2* site where said ligand may be as described in the embodiments above.
  • the invention provides an embodiment 1, which is a pharmaceuti ⁇ cal preparation comprising
  • a ligand which binds reversibly to a HisB10 Zn 2+ site of an R-state hexamer and wherein the ligand is extended by covalent attachment to protamine having the following general formula (I)
  • 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
  • R 6B and R 7B are independently H, C r C 4 -alkyl;
  • Frg is a fragment consisting of O to 5 neutral ⁇ - or ⁇ -amino acids, or
  • CGr is a chemical structure selected from the group consisting of carboxylates, dithiocarboxylates, phenolates, thiophenolates, alkylthiolates, sulfonamides, imidazoles, triazoles, 4-cyano- 1 ,2,3-triazoles, benzimidazoles, benzotriazoles, purines, thiazolidinediones, tetrazoles, 5- mercaptotetrazoles, rhodanines.
  • 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- ⁇ apthoic acids, salicylic acids, tetrazoles, thiazolidinediones, 5-mercaptotetrazoles, or A- cyano-1 ,2,3-triazoles.
  • Embodiment 4 A pharmaceutical composition according to any one of the embodiments 1 to 3 wherein CGr is
  • Y is -S-, -O- or -NH-
  • R 1 , R 1A and R 4 are independently selected from hydrogen or Ci-C 6 -alkyl
  • R 2 and R 2 * are hydrogen or CrCe-alkyl or aryl, R 1 and R 2 may optionally be combined to form a double bond, R 1A 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 substi- tuted with one or more substituents independently selected from R 16 .
  • d-Ce-alkyl, or -C(O)NR 11 R 12 , A, A 1 and B are independently selected from Ci-C 6 -alkyl, aryl, aryl-C r C fl -aIkyl, -NR 11 -ary[, aryI-C 2 -C 6 -alkenyl or heteroaryl, wherein the alkyl or alkenyl is optionally substituted with one or more substituents independently selected from R e 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 ⁇ 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 substitu ⁇ ents independently selected from R 14 ,
  • R 11 and R 12 are independently selected from hydrogen, OH, Ci-C ⁇ -alkyl, aryl-C ⁇ 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 1 ⁇ ;
  • 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 11 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 , -NR 11 C(O)R 11 . -S(O) 2 R 11 , aryl and C r C ⁇ -alkyl,
  • Embodiment 8. A pharmaceutical composition according to any one of the embodiments 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
  • Embodiment 11 A pharmaceutical composition according to embodiment 8 wherein Y is -S-.
  • Embodiment 12 A pharmaceutical composition according to any one of the embodiments 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 B , 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 embodiments 4 to 11 wherein A is heteroaryl optionally substituted with up to four substitue ⁇ ts, R 7 . R 8 , R ⁇ , 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 ⁇ , R ⁇ , R a , 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 t 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 t0 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 ⁇ , 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 embodiments 4 to 29 wherein R 1 is hydrogen.
  • Embodiment 31 A pharmaceutical composition according to any one of the embodiments 4 to 30 wherein R 2 is hydrogen.
  • Embodiment 32 A pharmaceutical composition according to any one of the embodiments 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 embodiments 4 to 32 wherein R 3 is d-C ⁇ -alkyl, halogen, or C(O)NR 16 R 17 .
  • Embodiment 34 A pharmaceutical composition according to embodiment 33 wherein R 3 is
  • 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 embodiments 4 to 11 wherein B is phenyl optionally substituted with up to four substituents, R 7 , R s , R 9 , and R 10 which may be the same or different.
  • Embodiment 37 A pharmaceutical composition according to any one of the embodiments 4 to 11 or 36 wherein R 4 is hydrogen.
  • Embodiment 38 A pharmaceutical composition according to any one of the embodiments 4 to 11 or 36 to 37 wherein R 5 is hydrogen.
  • Embodiment 39 A pharmaceutical composition according to any one of the embodiments 4 to 38 wherein R 6 is aryl.
  • Embodiment 40 A pharmaceutical composition according to embodiment 39 wherein R ⁇ is phenyl.
  • Embodiment 41 A pharmaceutical composition according to any one of the embodiments 4 to 40 wherein R 7 , R ⁇ , R ⁇ and R 10 are independently selected from
  • Embodiment 42 A pharmaceutical composition according to embodiment 41 wherein R 7 , R ⁇ , R 9 and R 10 are independently selected from
  • Ci-Ce-alkyl or CrC ⁇ -alkenyl which may each optionally be substituted with one or more substituents independently selected from R 13 • aryl, aryloxy, aroyl, aryl-Ci-C a -alkoxy, aryl-Ci-Ce-alkyl, heteroaryl,
  • each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R 14 .
  • Embodiment 43 A pharmaceutical composition according to embodiment 42 wherein R 7 , R 8 , R B 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
  • each of the cyclic moieties optionally may be substituted with one or more substituents independently selected from R 14 .
  • Embodiment 45 A pharmaceutical composition according to embodiment 44 wherein 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 substitu- ents independently selected from R 14 .
  • 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 embodiments 4 to 46 wherein R 11 and R 12 are independently selected from hydrogen, CrC 2 o-alkyl, aryl or aryl-d-C f i-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 substi- tuted one or more substituents independently selected from R 1 ⁇ ; 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.
  • R 11 and R 12 are independently selected from hydrogen, CrC 2 o-alkyl, aryl or aryl-d-C f i-alkyl, wherein the alkyl groups may optionally be substituted with
  • Embodiment 48 A pharmaceutical composition according to embodiment 47 wherein R 11 and R 12 are independently selected from hydrogen, d-Czo-alkyl, aryl or aryl-C,-C ⁇ -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 substitu ⁇ ents independently selected from R 1 ⁇ .
  • Embodiment 49 A pharmaceutical composition according to embodiment 48 wherein R 11 and R 12 are independently selected from phenyl or phenyl-Ci-C ⁇ -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 embodiments 4 to 50 wherein R 13 is independently selected from halogen, CF 3 , OR 11 or NR 11 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 is
  • Embodiment 54 A pharmaceutical composition according to any one of the embodiments 4 to 53 wherein R 14 is independently selected from halogen, -C(O)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(O)OR 11 , or -OR 11 .
  • Embodiment 56 A pharmaceutical composition according to any one of the embodiments 4 to 55 wherein R 15 is independently selected from halogen, -CN, -CF 3 , -CfOJOCrC ⁇ -alkyl.and
  • Embodiment 57 A pharmaceutical composition according to embodiment 56 wherein R 15 is independently selected from halogen or -C(O)OCi-C ⁇ -alkyl.
  • Embodiment 5 ⁇ A pharmaceutical composition according to any one of the embodiments 4 to 57 wherein R 1 ⁇ is independently selected from halogen, -C(O)OC r C a -alkyl, -COOH, -NO 2 ,
  • Embodiment 59 A pharmaceutical composition according to embodiment 58 wherein R 19 is independently selected from halogen, -C(O)OCi-C 6 -afkyl, -COOH, -NO 2 , or d-C 6 -alkyl.
  • Embodiment 60 A pharmaceutical composition according to any one of the embodiments 1 to 3 wherein CGr is
  • R 1 ⁇ is hydrogen or C r C ⁇ -alkyK
  • R 20 is hydrogen or d-C 6 -alkyl
  • D, D 1 and F are a valence bond, d-C ⁇ -alkylene or d-C 6 -alkenylene optionally substituted with one or more substituents independently selected from R 72 ,
  • R 72 is independently selected from hydroxy.
  • E is C t -C ⁇ -alkyl, aryl or h ⁇ teroaryl, 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 2 ⁇ ,
  • R 24 , R 25 and R 26 are independently selected from
  • R 27 and R 28 are independently selected from hydrogen, Ci-C 6 -alkyl, aryl-CrC ⁇ -alkyl or aryl, or R 27 and R 23 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 het- eroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R 29 Is independently selected from halogen, -CN 1 -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 ,
  • 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
  • C-pCe-alkylene optionally substituted with one or more hydroxy, C,-Ce-alkyl, or aryl.
  • Embodiment 63 A pharmaceutical composition according to any one of the embodiments 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 substttuents 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 , R 22 and R 23 .
  • Embodiment 67 A pharmaceutical composition according to embodiment 66 wherein CGr is
  • Embodiment 68 A pharmaceutical composition according to any one of the embodiments 60 to 67 wherein R 21 , R 22 and R 23 are independently selected from
  • Embodiment 69 A pharmaceutical composition according to embodiment Error! Reference source not found, wherein R 21 , R 22 and R 23 are independently selected from
  • Embodiment 70 A pharmaceutical composition according to embodiment 69 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 2 ⁇ R 22 and R 23 are independently selected from
  • Embodiment 73 A pharmaceutical composition according to any one of the embodiments 60 to 72 wherein R 19 is hydrogen or methyl.
  • Embodiment 74 A pharmaceutical composition according to embodiment 73 wherein R 1 ⁇ is hydrogen.
  • Embodiment 75 A pharmaceutical composition according to any one of the embodiments 60 to 74 wherein R 27 is Hydrogen, Ci-Ce-alkyl or aryl.
  • Embodiment 76 A pharmaceutical composition according to embodiment 75 wherein R 27 is hydrogen or C r C e -alkyl.
  • Embodiment 77 A pharmaceutical composition according to any one of the embodiments 60 to 76 wherein R 28 is hydrogen or C r C ⁇ -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 Cr
  • Embodiment 80 A pharmaceutical composition according to any one of the embodiments 60 or 78 to 79 wherein G is Ci-C ⁇ -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 embodiments 60 or 78 to 79 wherein G is C r Ce-alkyl or ArGI 1 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
  • 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 embodiments 60 to 83 wherein R 24 , R 25 and R 28 are independently selected from
  • Embodiment 85 A pharmaceutical composition according to embodiment 84 wherein R 24 , R 25 and R 28 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 2 ⁇ R 22 and R 23 are independently selected from
  • Embodiment 88 A pharmaceutical composition according to embodiment 87 wherein R 21 , R 22 and R 23 are independently selected from
  • ArGI-d-Cs-alkyl of which the cyclic moieties optionally may be substituted with one or more substituents se ⁇ lected from R 30 .
  • Embodiment 90 A pharmaceutical composition according to any one of the embodiments 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 embodiments 60 or 78 to 91 wherein R 27 is hydrogen, Ci-C 6 -alkyl or aryi.
  • Embodiment 93 A pharmaceutical composition according to embodiment 92 wherein R 27 is hydrogen or Ci-C ⁇ -alkyl or ArG1.
  • Embodiment 94 A pharmaceutical composition according to embodiment 93 wherein R 27 is hydrogen or C r C ⁇ -alkyl.
  • Embodiment 95 A pharmaceutical composition according to any one of the embodiments 60 or 78 to 93 wherein R 28 is hydrogen or d-Ce-alkyl.
  • Embodiment 96 A pharmaceutical composition according to embodiment 60 wherein R 17 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 1 ⁇ are independently selected from
  • Embodiment 99 A pharmaceutical composition according to embodiment 98 wherein R 17 and R 18 are independently selected from
  • Ci-C ⁇ -alkyl optionally substituted with one or more substituents independently se ⁇ lected from R 29 -phenyl, phenyloxy, phenyl-d-C ⁇ -aikoxy, phenyl-Ci-C ⁇ -alkyl, of which the cyclic moieties optionally may be substituted with one or more substituents se ⁇ lected from R 30 .
  • Embodiment 101 A pharmaceutical composition according to any one of the embodiments.
  • R 27 is hydrogen or Ci-C 6 -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 embodiments
  • R 2 ⁇ is hydrogen or C r C 6 -alkyl.
  • 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 embodiments
  • 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 embodiments 1 to 3 wherein CGr is of the form H-I-J-
  • Z 1 is S(O) 2 or CH 2
  • Z 2 is -NH-, -O-or -S-
  • ⁇ is 1 or 2
  • R 31 is independently selected from hydrogen, halogen, S 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 , -SCF 3 , -NO 2 .
  • -OR 35 , -C(O)R 35 . -NR 35 R 36 , -SR 35 .
  • R 32 and R 33 are independently selected from hydrogen, Ci-C ⁇ -alkyl or CrC 6 -alkanoyl,
  • R 34 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 35 , and -NR 35 R 38 ,
  • R 35 and R 3 ⁇ are independently selected from hydrogen, d-C ⁇ -alkyl. aryl-Ci-C 6 -alkyl or aryl, or R 35 and R 3 ⁇ 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 het- eroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R 37 is independently selected from halogen, -C(O)OR 33 , -C(O)H, -CN, -CF 3 , -OCF 3 , -NO 2 . - OR 35 . -NR 35 R 36 , d-C ⁇ -alkyl or C r Ce-alkanoyl,
  • Embodiment 108 A pharmaceutical composition according to embodiment 107 wherein CGr is of the form H-I-J, wherein H is
  • phenyl, naphthalene or benzocarbazole rings are optionally substituted with one or more substituents independently selected from R 31 ,
  • I is selected from *a valence bond
  • n 1 or 2
  • J is • d-C ⁇ -alkyl, CjrC ⁇ -alkenyl or Cz-C ⁇ -alkynyl, which may each optionally be substituted with one or more substituents selected from R 34 ,
  • R 31 is independently selected from hydrogen, halogen, -CN, -CH 2 CN 1 -CHF 2 , -CF 3 , -OCF 3 , -OCHF 2 , -OCH 2 CF 3 , -OCF 2 CHF 2 , -S(O) 2 CF 3 , -SCF 3 , -NO 2 , -OR 35 , -C(O)R 35 , -NR 35 R 36 , -SR 35 , -NR 35 S(O) 2 R 38 , -S(O) 2 NR 35 R 38 , -S(O)NR 35 R 36 .
  • R 32 and R 33 are independently selected from hydrogen. d-Cg-alkyl or CrC ⁇ -alkanoyl,
  • R 34 Js independently selected from halogen, -CN, -CF 3 , -OCF 3 , -OR 35 , and -NR 35 R 38 ,
  • R 35 and R 3 ⁇ are independently selected from hydrogen, Ci-C ⁇ -alkyl, aryl-Ci-C ⁇ -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 het- eroatoms 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 3 , -NO 2 , - OR 35 , -NR 35 R 38 , d-Ce-alkyl or Ci-C B -alkanoyl,
  • Embodiment 109 A pharmaceutical composition according to any one of the embodiments 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 embodiments 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 embodiments
  • Ci-Ce-alkyl Ca-Ce-alkenyl or C 2 -C ⁇ -alkynyl, which may optionally be substituted with one or more substituents selected from halogen.
  • -CN, -CF 3 , -OCF 3 , -OR 35 , and -NR 35 R 36
  • 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 • hydrogen,
  • Embodiment 118 A pharmaceutical composition according to embodiment 117 wherein J is hydrogen.
  • Embodiment 119 A pharmaceutical composition according to any one of the embodiments
  • R 32 and R 33 are independently selected from hydrogen or d-C E -alkyl.
  • Embodiment 120 A pharmaceutical composition according to any one of the embodiments.
  • R 34 is hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -SCF 3 , -NO 2 , -OR 35 .
  • Embodiment 121 A pharmaceutical composition according to embodiment 120 wherein R 34 is hydrogen, halogen, -CF 3 . -NO 2 , -OR 35 , -NR 35 R 36 , -SR 35 , -NR 35 C(O)R 38 , Or-C(O)OR 35 .
  • Embodiment 122 A pharmaceutical composition according to embodiment 121 wherein R 34 is hydrogen, halogen, -CF 3 , -NO 2 , -OR 35 , -NR 35 R 38 . or -NR 35 C(O)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 embodiments
  • R 35 and R 3 ⁇ are independently selected from hydrogen, d-C ⁇ -alkyl, or aryl.
  • Embodiment 125 A pharmaceutical composition according to embodiment 124 wherein R 35 and R 39 are independently selected from hydrogen or Ci-C ⁇ -alkyl.
  • Embodiment 126 A pharmaceutical composition according to any one of the embodiments
  • R 37 is halogen, -C(O)OR 35 . -CN, -CF 3 , -OR 33 , -NR 35 R 36 , d-C ⁇ -alkyl or C 1 - C 6 -alkanoyl.
  • Embodiment 127 A pharmaceutical composition according to embodiment 126 wherein R 37 is halogen, -C(O)OR 35 , -OR 35 , -NR 35 R 36 , CrC ⁇ -alkyl or C r C ⁇ -alkanoyl.
  • Embodiment 128 A pharmaceutical composition according to embodiment 127 wherein R 37 is halogen, -C(O)OR 35 or -OR 35 .
  • Embodiment 129. A pharmaceutical composition according to any one of the embodiments 1 to 3 wherein CGr is
  • U is a valence bond, d-C ⁇ -alkenylene, -d-C 6 -alkyl-O- or Ci-C ⁇ -alkylene wherein any C 1 - Ce-alkyl moiety is optionally substituted with Ci-Ce-alkyl, R 38 is CrC ⁇ -alky], aryl, wherein the alky] or aryl moieties are optionally substituted with one or more substituents independently selected from R 3 ⁇ ,
  • R 39 is independently selected from halogen, cyano, ⁇ itro, amino,
  • M is a valence bond, afylene 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 •hydrogen, halogen, -CN, -CH 2 CN, -CHF 2 , -CF 3 , -OCF 3 . -OCHF 2 , -OCH 2 CF 3 .
  • R 41 and R 42 are independently selected from hydrogen, -OH 1 Ci-C ⁇ -alkyl, CrC 6 -alkenyl, aryl- Ci-C ⁇ -afkyl 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 substi ⁇ tuted with one or more substituents independently selected from R 46 ; R 41 and R 42 when at ⁇ tached 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, - CF 3 , -OCF 3 , -NO 2 , -OR 41 , -NR 41 R 42 and C r C 6 -alkyl,
  • R 45 is independently selected from halogen, -CN, -CF 3 , -OCF 3 , -O-d-C ⁇ -alkyl, -C(O)-O-C 1 -
  • R 46 is independently selected from halogen, -C(O)OCi-C ⁇ -alkyl, -COOH, -CN, -CF 3 , -OCF 3 , -
  • Q is a valence bond, d-C ⁇ -alkyle ⁇ e. -d-Ce-alkyl-O-, -d-C ⁇ -alkyl-NH-, -NH-C-C ⁇ -alkyl,
  • R 47 and R 4 ⁇ are independently selected from hydrogen, d-C ⁇ -alkyl, aryl optionally substituted with one or more R 49 .
  • R 49 is independently selected from halogen and -COOH
  • Ci-C ⁇ -alkyl C 2 -C 6 -alkenyl , C 2 -C ⁇ -alkynyl, d-C ⁇ -alkyloxy-carbonyl, wherein the alkyl, alkenyl and alkynyl moieties are optionally substituted with one or more substituents independently selected from R 50 ,
  • any alkyl, alkenyl , alkynyl, aryl and heteroaryl moiety is optionally substituted with one or more substituents independently selected from R 50 ,
  • Embodiment R 50 * and R 50B are independently selected from -C(O)OC r C ⁇ -alkyl, -COOH, -C 1 - C ⁇ -alkyl-CtOOC-Ce-alkyl, -C r C ⁇ -aikyUCOOH. or C,-C ⁇ -alkyl,
  • R 51 and R 52 are independently selected from hydrogen and d-C ⁇ -alkyl
  • R 53 Is independently selected from C-rC e -alkyl, d-C ⁇ -alkoxy, -d-C ⁇ -alkyl-COOH, -C 2 -
  • a pharmaceutical composition according to embodiment 130 wherein K is a valence bond, d-C B -alkylene, -NH-C( O)-U-, -Ci-C ⁇ -alkyl-S-, or -d-C 6 -alkyl-O, wherein any d-C ⁇ -alkyl moiety is optionally substituted with R 38 .
  • Embodiment 133 A pharmaceutical composition according to embodiment 132 wherein K is a valence bond or d-C a -alkylene, wherein any d-C ⁇ -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 embodiments
  • 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 embodiments
  • Embodiment 139 A pharmaceutical composition according to embodiment 138 wherein M is arylene or heteroarylene, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R 40 .
  • Embodiment 139 A pharmaceutical composition according to embodiment 138 wherein M is
  • Embodiment 140 A pharmaceutical composition according to embodiment 139 wherein M is ArG1 or Het2, wherein the arylene or heteroarylene moieties are optionally substituted with one or more substituents independently selected from R 40 .
  • Embodiment 141 A pharmaceutical composition according to embodiment 140 wherein M is
  • Embodiment 143 A pharmaceutical composition according to embodiment 141 wherein M is indolylene optionally substituted with one or more substituents independently selected from R 40 .
  • Embodiment 144 A pharmaceutical composition according to embodiment 143 wherein M is
  • Embodiment 146 A pharmaceutical composition according to embodiment 145 wherein M is
  • Embodiment 147 A pharmaceutical composition according to any one of the embodiments 129 to 146 wherein R 40 is selected from -hydrogen, halogen, -CN, -CF 3 , -OCF 3 , -NO 2 , -OR 41 , -NR 41 R 42 , -SR 41 , -S(O) 2 R 41 .
  • CrC ⁇ -alkyl or C 2 -C 8 - alkenyl which may each optionally be substituted with one or more substituents independently selected from R 43 , • aryl, aryloxy, ary]-Ci-C ⁇ -alkoxy, aryl-d-C ⁇ -alkyl, aryl-C ⁇ Ce-alkenyl, heteroaryl, het- eroaryl-CrCe-alkyl, or heteroaryt-C 2 -C e -alkenyl, wherein the cyclic moieties optionally may be substituted with one or more substitue ⁇ ts selected from R 44 .
  • Embodiment 148 A pharmaceutical composition according to embodiment 147 wherein R* 0 is selected from
  • Embodiment 149 A pharmaceutical composition according to embodiment 148 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, -NO 2 , -OR 41 , -NR 41 R 42 , -C(O)OR 41 , or -NR 41 C(O)R 42 ,
  • Embodiment 152 A pharmaceutical composition according to any one of the embodiments 129 to 151 wherein R 41 and R 42 are independently selected from hydrogen, d-C ⁇ -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 156 A pharmaceutical composition according to any one of the embodiments 129 to 155 wherein R 47 and R 48 are independently selected from hydrogen, methyl and phenyl.
  • Embodiment 157 A pharmaceutical composition according to any one of the embodiments 129 to 156 wherein T is
  • Ci-C 6 -alkyl optionally substituted with one or more substituents independently se ⁇ lected from R 50 ,
  • Embodiment 158 A pharmaceutical composition according to embodiment 157 wherein T is
  • Ci-C 6 -alkyl optionally substituted with one or more substituents independently se ⁇ lected from R 50 , »ArG1, ArG1-Ci-C e -atkyl, Het3, wherein the alkyl, aryl and heteroaryl moieties are op- tionally substituted with one or more substituents independently selected from R .
  • Embodiment 159 A pharmaceutical composition according to embodiment 158 wherein T is
  • Embodiment 160 A pharmaceutical composition according to embodiment 159 wherein T is phenyl substituted with R 50 .
  • Embodiment 163 A pharmaceutical composition according to embodiment 162 wherein R 50 is CrC ⁇ -alkyl, aryloxy, aryl-Ct-C ⁇ -alkoxy, -OR 51 , halogen, -COOH 1 -CF 3 , wherein any aryl moiety is optionally substi ⁇ tuted with one or more R 53 .
  • Embodiment 165 A pharmaceutical composition according to embodiment 164 wherein R 50 is Embodiment 166.
  • 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 embodiments 129 to 167 wherein m is 1 or 2.
  • Embodiment 169 A pharmaceutical composition accord ⁇ hg to any one of the embodiments 129 to 168 wherein R 51 is methyl.
  • Embodiment 170 A pharmaceutical composition according to any one of the embodiments 129 to 169 wherein R 53 is Ci-C ⁇ -alkyl, Ci-C 6 -alkoxy, -OR 51 , halogen.or -CF 3 .
  • Embodiment 172 A pharmaceutical composition according to any one of the embodiments 129 to 171 wherein R MB is -C(O)OCH 3 , -C(O)OCH 2 CH 3 -COOH, -CH 2 C(O)OCH 3 , - CH 2 C(O)OCH 2 CH 3 , -CH 2 CH 2 C(O)OCH 3 , -CH 2 CH 2 C(O)OCH 2 CH 3 , -CH 2 COOH, methyl, or ethyl.
  • V is CrC 6 -alkyl, aryl, heteroaryl, aryl-C 1-8 -alkyl- or aryl-C 2- ⁇ -alkenyl-, wherein the al- kyl 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 5S ,
  • 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 2 CF 3 ,
  • alkyl groups may optionally be substituted with one or more substituents independently selected from R ao
  • the aryl groups may option ⁇ ally be substituted with one or more substituents independently selected from R 61 ;
  • 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, the heterocyclic ring optionally containing one or two further het- eroatoms selected from nitrogen, oxygen and sulphur, and optionally containing one or two double bonds,
  • R 59 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(O)OR 56 , -CH 2 C(O)OR 56 , -CH 2 OR 56 , -CN, - CF 3 , -OCF 3 , -NO 2 , -OR 56 , -NR 56 R 57 and C r C ⁇ -alkyl,
  • R 62 is CrC ⁇ -alkyl, aryl optionally substituted with one or more substituents independently se ⁇ lected from halogen, or heteroaryl optionally substituted with one or more inde ⁇ pendently, 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-C 1-8 -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 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 179 wherein V is phenyl, naphthyl or anthranyl optionally substituted with one or more substituents independ ⁇ ently selected from R 55 .
  • Embodiment 181 A pharmaceutical composition according to embodiment 180 wherein V is phenyl optionally substituted with one or more substituents independently selected from R 55 .
  • Embodiment 182. A pharmaceutical composition according to any one of the embodiments 173 to 181 wherein R 55 is independently selected from
  • Ci-C e -alkyl optionally substituted with one or more substituents independently se- lected from R 58
  • Embodiment 183 A pharmaceutical composition according to embodiment 182 wherein R 55 is independently selected from
  • Ci-C ⁇ -alkyl optionally substituted with one or more substituents independently se ⁇ lected from R 58 • ArG1.
  • Embodiment 184 A pharmaceutical composition according to embodiment 183 wherein R 55 is independently selected from halogen, -OR 56 , -NR 56 R 57 , -C(O)OR 56 , -OC 1 -C 8 - alkyl-CfOJOR 56 , -NR 56 C(O)R 57 or C r C e -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(O)OR 56 , -OC 1 -Ca- alkyl-C(O)OR 58 , -NR 56 C(O)R 57 , methyl or ethyl.
  • R 55 is independently selected from halogen, -OR 56 , -NR 56 R 57 , -C(O)OR 56 , -OC 1 -Ca- alkyl-C(O)OR 58 , -NR 56 C(O)R 57 , methyl or ethyl.
  • Embodiment 186 Embodiment 186.
  • a pharmaceutical composition according to any one of the embodiments 173 to 185 wherein R 58 and R 57 are independently selected from hydrogen, CF 3 , Ci-Ci2-alkyI, or -C( O)-C 1 -Ca-alkyl; R 59 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 187 A pharmaceutical composition according to embodiment 186 wherein R 56 and R 57 are independently selected from hydrogen or C r CiralkyL R 5 ⁇ and R 57 when at- tached to the same nitrogen atom may form a 3 to 8 membered heterocyclic ring with the said nitrogen atom.
  • Embodiment 188 A pharmaceutical composition according to embodiment 187 wherein R 56 and R 57 are independently selected from hydrogen or methyl, ethyl, propyl butyl, R 58 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 embodiments 1 to 3 wherein CGr is
  • AA is Ci-C 6 -alkyl, aryl, heteroaryl, 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 ⁇ 7 is independently selected from halogen, -CN, -CF 3 , -OCF 3 . -OR 85 , and -NR 65 R 68 ,
  • R 6B is independently selected from halogen, -C(O)OR 65 , -CH 2 C(O)OR 65 , -CH 2 OR 65 , -CN, - CF 3 , -OCF 3 , -NO 2 , -OR 65 , -NR 65 R 66 and Ci-C ⁇ -alkyl,
  • R ⁇ is independently selected from C t -C ⁇ -alkyl, aryl optionally substituted with one or more halogen, or heteroaryl optionally substituted with one or more Ci-C ⁇ -alkyl,
  • R 70 is independently selected from halogen, -CN. -CF 3 , -OCF 3 , -OC r C ⁇ -alkyl, -C(O)OC 1 -C 6 - alkyl, -COOH and -NH 2 ,
  • Embodiment 190 A pharmaceutical composition according to embodiment 189 wherein AA is aryl, heteroaryl or aryl-C 1-8 -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 84 .
  • 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 ⁇ 4 .
  • Embodiment 192 A pharmaceutical composition according to embodiment 191 wherein AA is ArG 1 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 84 .
  • 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 embodiments 189 to 196 wherein R 84 is independently selected from hydrogen, halogen, -CF 3 , -OCF 3 , -OR 65 . -NR 6S R ⁇ , d-Ce-alkyl , -OC(O)R 65 , -OCi-C 6 -alkyl-C(O)OR e5 .
  • 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 86 , methyl, ethyl, propyl, -OC(O)R 65 , -OCH r C(O)OR 65 . -OCHrCH 2 -C(O)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 embodiments 189 to 198 wherein R 65 and R ⁇ are independently selected from hydrogen, CF 3 , Ci-Cu-alkyl, aryl, or heteroaryl optionally substituted with one or more substituents independently se ⁇ lected from R 71 .
  • Embodiment 200 A pharmaceutical composition according to embodiment 199 wherein R 85 and R 88 are independently hydrogen, C r C 12 -aIkyl, 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 ⁇ are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-d ⁇ methyl-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 ⁇ are independently hydrogen, methyl, ethyl, propyl, butyl, 2,2-dimethyl-propyl, ArG 1 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 ⁇ 5 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 isoxazolyl optionally substituted with one or more substituents independently selected from R 71 .
  • Embodiment 205 A pharmaceutical composition according to any one of the embodiments
  • R 71 is halogen or d-C ⁇ -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 embodiments 1 to 205 wherein Frg consists of 0 to 5 neutral amino acids independently selected from the group consisting of GIy 1 Ala, Thr, and Ser.
  • Embodiment 208 A pharmaceutical preparation according to embodiment 207 wherein Frg consists of 0 to 5 GIy.
  • Embodiment 209 A pharmaceutical preparation according to embodiment 208 wherein Frg consists of 0 GIy.
  • Embodiment 210 A pharmaceutical preparation according to embodiment 208 wherein Frg consists of 1 GIy.
  • Embodiment 211. A pharmaceutical preparation according to embodiment 208 wherein Frg consists of 2 GIy.
  • Embodiment 212 A pharmaceutical preparation according to embodiment 208 wherein Frg consists of 3 GIy.
  • Embodiment 213. A pharmaceutical preparation according to embodiment 208 wherein Frg consists of 4 GIy.
  • Embodiment 214. A pharmaceutical preparation according to embodiment 208 wherein Frg consists of 5 GIy.
  • Embodiment 215. A pharmaceutical preparation according to any one of the embodiments 1 to 214 wherein G B is of the formula B 1 -B 2 -C(O)-, B 1 -B 2 -SOz- or B 1 ⁇ -CHz- . wherein B 1 and B 2 are as defined in embodiment 1.
  • Embodiment 216 A pharmaceutical preparation according to any one of the embodiments 1 to 214 wherein G B is of the formula B 1 -B 2 -C(OK B 1 ⁇ -SO 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 embodiments 1 to 214 wherein G B is of the formula B'-B ⁇ CfO)-, B 1 ⁇ -CH 2 - or B 1 -B 2 -NH-, wherein B 1 and B 2 are as defined in embodiment 1.
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