WO2003055477A1 - Methode de traitement de troubles lies au recepteur de la melanocortine (mc), faisant intervenir un chelate et/ou un chelateur - Google Patents

Methode de traitement de troubles lies au recepteur de la melanocortine (mc), faisant intervenir un chelate et/ou un chelateur Download PDF

Info

Publication number
WO2003055477A1
WO2003055477A1 PCT/DK2002/000902 DK0200902W WO03055477A1 WO 2003055477 A1 WO2003055477 A1 WO 2003055477A1 DK 0200902 W DK0200902 W DK 0200902W WO 03055477 A1 WO03055477 A1 WO 03055477A1
Authority
WO
WIPO (PCT)
Prior art keywords
receptor
chelator
chelate
human
animal
Prior art date
Application number
PCT/DK2002/000902
Other languages
English (en)
Inventor
Birgitte Holst Lange
Thue W. Schwartz
Original Assignee
7Tm Pharma A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 7Tm Pharma A/S filed Critical 7Tm Pharma A/S
Priority to AU2002367087A priority Critical patent/AU2002367087A1/en
Publication of WO2003055477A1 publication Critical patent/WO2003055477A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a method for reducing overweight and/or treating and/or preventing overweight, obesity and/or complications to obesity.
  • the method comprises administering to an animal such as, e.g. a human and/or a domestic animal in need thereof an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with a natural metal-ion binding site in an MC receptor from an MC-R family.
  • the invention also relates to methods for treating and/or preventing diabetes mellitus type II, conditions involving the immune system, inflammation, and male or female sexual dysfunctions including erectile dysfunction.
  • the invention relates to a cosmetic method for reducing overweight and to the use of a chelate and/or a chelator for the preparation of a pharmaceutical composition.
  • Obesity is recognized as a major risk factor for coronary heart diseases, hypertension, and type II diabetes mellitus making its treatment and prevention an important health issue.
  • Body weight regulation is a complex process, where multiple environmental and genetic factors contribute to the phenotype. Identification of genes mutated in several animal models of obesity has provided an entry point into understanding the molecular basis of energy homeostasis.
  • Pro-opiomelanocortin (POMC) derived peptides have been recognized to affect food intake and obesity.
  • GPCRs G-protein coupled receptors
  • M-R melanocortin receptor
  • a specific single MC-R that may be targeted for the control of obesity has not yet been identified, although the MC-3 and MC-4 receptors are the most likely candidates.
  • the melanocortins are all derived from the precursor protein pro- opiomelanocortin. They are peptide hormones, which exert their function on the five different members of the melanocortin receptor family.
  • the receptors are widely distributed both peripherally in the body and in the central nervous system. The physiological functions of the receptors cover a correspondingly diverse spectrum ranging from regulation of pigmentation and immune functions (MC-1 receptor), adrenal cortical steroidogenesis (MC-2/ACTH receptor) and exocrine secretion (MC-5 receptor) to energy homeostasis and food intake (MC-3 and -4 receptors).
  • MC-1 R was initially characterized by dominant gain of function mutations at the Extension locus, affecting coat color by controlling phaeomelanin to eumelanin conversion through control of tyrosinase.
  • MC-1 R is mainly expressed in melanocytes and on certain cells of the immune system, such as the monocytes/macrophages, neutrophils, endothelial and mast cells.
  • MC-2R represents the ACTH receptor, responsible for the adrenocortical steroid synthesis and it is expressed in the adrenal gland.
  • MC-3R is expressed in the brain, gut, and placenta and may be involved in the control of food intake, energy homeostasis and thermogenesis.
  • MC-4R is uniquely expressed in the brain and has been shown to be strongly involved in food intake.
  • MC-5R is expressed in many tissues, including white fat, placenta, and exocrine glands. A low level of expression is also observed in the brain. MC-5R knockout mice reveal reduced sebaceous gland lipid production.
  • injection intracerebroventricularly (ICV) of the cyclic heptapeptide MT-II (a non-selective MC-1 R,-3R,-4R, and-5R agonist) or other MC receptor agonists in rodents reduces food intake in several animal feeding models (NPY, oblob, agouti, fasted) whereas injection ICV of the selective MC-3R and MC-4R antagonist SHU- 9119 can reverse this effect and induces hyperphagia.
  • the melanocortin receptors differ from most other 7TM receptors by having a very complex endogenous regulation.
  • at least three different peptide agonists ⁇ - MSH, ⁇ -MSH and ACTH
  • endogenous antagonists / inverse agonists are regulating the function with a high potency.
  • the agonist ligands exhibit certain degree of receptor selectivity: the MC-1 receptor, MC-4 receptor and MC-5 receptor all prefers ⁇ -MSH, the MC-3 receptor prefers ⁇ -MSH whereas the MC-2 receptor prefers ACTH. Similar selectivity is observed for the two different antagonists, Agouti and Agouti related peptide (AGRP).
  • the Agouti protein preferentially binds to the MC-1 , MC-2 and MC-4 but inhibit MC-2 and MC-5 to a lower extent.
  • the other antagonist, AGRP displays a higher degree of selectivity as it only inhibits MC-3 and MC-4. Due to the constitutive expression of the endogenous antagonist/inverse agonist, even a partial agonist may in the MC receptor system be sufficient to shift the balance in favor of an increased receptor activity. Thus, it is very likely that partial agonist drugs as many of those presented in the present invention will be useful drugs in the treatment of, for example obesity.
  • mice were not or only slightly overweight, but the fat mass of MC-3R KO was approximately the double of that of the wild type, whereas the lean body mass was reduced.
  • the MC-3R KO mice had a significant higher incidence of obesity compared to wild type mice on the same diet.
  • these mice did not exhibit increased food intake - they even were hypophagic in some groups.
  • the MC-3R KO mice had a lower locomotor activity, which were statistically significant compared to wild type mice.
  • the MC-3 receptor is believed to be expressed for example on the NPY / AGRP neurons in the arcuate nucleus and here be part of the system where the MSH from the POMC expressing neurons inhibits the stimulatory branch of the appetite control also in the arcuate nucleus while it acts through MC-4 receptors in the paraventricular nucleus to serve the same purpose of inhibiting food intake.
  • Synthetic melanocortin receptor agonists have been found to initiate erections in men with psychogenic erectile dysfunction. Activation of melanocortin receptors of the brain appears to cause normal stimulation of sexual arousal. It has been demonstrated that a centrally acting ⁇ -melanocyte-stimulating hormone analog, melanotan-11 (MT-II), exhibited a 75% response rate, similar to results obtained with apomorphine, when injected intramuscularly or subcutaneously to males with psychogenic erectile dysfunction. Some studies indicate that the effect of MC receptor agonists on penile erection may also occur locally in the penis. DISCLOSURE OF THE INVENTION
  • the present inventors have found that a specific class of chemical substances acts as agonists both in a MC-1 and a MC-4 receptor model.
  • the common feature of these substances is their ability to act as chelators, i.e. there ability to form a complex with a metal ion.
  • Metal ions have been applied to stabilise agonists for the MC receptor family, but there have been no suggestions or indications of any interaction between a metal ion and the receptor itself.
  • Naturally occurring metal-ion binding sites in MC receptors can be used as targets or attachment sites for metal-ion chelating compounds.
  • such natural metal-ion sites are identified functionally by studying the effect of either free metal-ions and/or by the effect of metal-ion chelators or chelates on any function of the receptor.
  • Metal-ion binding sites can also be identified or confirmed by structural means and location of the site can also be identified by careful, controlled mutagenesis, i.e. exchanging of the residues involved in metal-ion binding with residues not having this property.
  • the metal- ion site involved in the action of the metal-ion and the metal-ion chelating compounds has in this way been localized to residues in the MC-1 receptor, which are conserved among all the MC receptors.
  • the present inventors have found that Zn 2+ modulates the activity of both MC-1 receptor and MC-4 receptor. In both receptors the affinity for zinc ions were approximately 15 ⁇ M as measured in competition binding studies. Furthermore, functional studies reveal that the zinc ion binding induces an active conformation of the receptor. Not only zinc ions alone but also zinc ions chelated with metal ion chelators are able to activate both of the two receptors tested. Thus, metal ions potentially represent a novel starting point in the drug discovery for melanocortin receptor agonists. An additional advantage of the metal ion as a drug discovery lead is that it has potential as an enhancer of the ⁇ -MSH induced activation.
  • Agoutf is intended to indicate an endogenous protein which acts as an antagonist or inverse agonist at the MC-1 , MC-2, MC-4 and to a lower extent also the MC-5 receptors
  • AGRP' is intended to indicate the agouti related proyein, which is homologous to agouti and acts as an endogenous antagonist or inverse agonist preferentially at the MC-3 and MC-4 receptors.
  • body mass index or "6M/” is defined as body weight (kg)/height 2 (m 2 ).
  • Weight is intended to indicate a BMI in a range from about 25 to about 29.9.
  • “Obesity” is intended to indicate a BMI, which is at least about 30.
  • Erectile dysfunction is intended to indicate a disorder involving the failure of a male mammal to achieve erection, ejaculation, or both. Symptoms of erectile dysfunction include an inability to achieve or maintain an erection, ejaculatory failure, premature ejaculation, or inability to achieve an orgasm. An increase in erectile dysfunction is often associated with age and although it is generally caused by a physical disease or as a side effect of drug treatment it may also be of psychological nature.
  • a "chemical compound” is intended to indicate a small organic molecule of low molecular weight or a small organic compound, which is capable of interacting with a receptor, in particular with a protein, in such a way as to modify the biological activity thereof.
  • the term includes in its meaning metal-ion chelates of the formulas shown below.
  • the term includes in its meaning metal-ion chelates of the formulas shown below as well as chemical derivatives thereof constructed to interact with other part(s) of the receptor than the metal-ion binding site.
  • a chemical compound may also be an organic compound, which in its structure includes a metal atom via a covalent binding.
  • a “metal-ion chelator” or a “chelator” is intended to indicate a chemical compound capable of forming a complex with a metal atom or ion, and contains at least two interactions between the metal center and the chelator. Such a compound will generally contain two heteroatoms such as N, O, S, Se or P with which the metal atom or ion is capable of forming a complex.
  • a “metal-ion chelate” or a “chelate” is intended to indicate a complex of a metal ion chelator and a metal atom or ion.
  • a "ligand” is intended to indicate a functional group or a structural element that binds or coordinates a metal ion.
  • metal ion is intended to indicate a charged or neutral element. Such elements belong to the groups denoted main group metals, light metals, transition metals, semi-metals or lanthanides (according to the periodic system).
  • metal ion includes in its meaning metal atoms as well as metal ions.
  • a "metal-ion binding site" is intended to indicate a part of a receptor that comprises atoms in relative positions in such a way that they are capable of complexing with a metal atom or ion. Such atoms will typically be heteroatoms, in particular N, O, S, Se or P. With respect to proteins a metal-ion binding site is typically an amino acid residue of a protein, which comprises an atom capable of forming a complex with a metal ion. These amino acid residues are typically, but not restricted to, histidine, cysteine, glutamate and aspartate.
  • a "receptor-ligand” is intended to include any substance that binds to a receptor and thereby inhibiting or stimulating its activity.
  • An "agonist” is defined as a ligand increasing the functional activity of a receptor (e.g. signal transduction through a receptor).
  • An "antagonist” is defined as a ligand decreasing the functional activity of a receptor either by inhibiting the action of an agonist or by its own intrinsic activity.
  • An "inverse agonist” (also termed “negative antagonist”) is defined as a ligand decreasing the basal functional activity of a receptor.
  • endogenous e.g. in the sense “endogenous metal-ion site” is intended to mean that the metal-ion site occurs in the natural unmutated receptor
  • a “functional group” is intended to indicate any chemical entity which is a component part of the chemical compound and which is capable of interacting with an amino acid residue or a side chain of an amino acid residue of the receptor.
  • a functional group is also intended to indicate any chemical entity, which is a component part of the receptor and which is capable of interacting with other parts of the receptor or with a part of the chemical compound.
  • Functional groups may be involved in interactions such as, e.g., ionic interactions, ion-dipole interactions, dipole-dipole interactions, hydrogen bond interactions, hydrophobic interactions, pi-stacking interactions, edge-on aromatic interactions, dispersion and induction forces or metal complex interactions.
  • the term "in the vicinity of” is intended to include an amino acid residue or any other residue or functional group located in the space defined by the binding site of the metal ion chelate and at such a distance from the metal ion binding amino acid residue that it is possible, by attaching suitable functional groups to the chemical compound, to generate an interaction between said functional group or groups and said amino acid residue, another residue or functional group.
  • chelates and chelators of Formula I below are effective as melanocortin receptor agonists, i.e. agonist for the MC-R series such as, e.g. MC-1 R, MC-2R, MC-3R, MC-4R and MC-5R and in particular for MC-1 R and/or MC-4R.
  • MC-R series such as, e.g. MC-1 R, MC-2R, MC-3R, MC-4R and MC-5R and in particular for MC-1 R and/or MC-4R.
  • MC-1 R e.g. MC-1 R, MC-2R, MC-3R, MC-4R and MC-5R
  • MC-1 R and/or MC-4R e.g. MC-1 R, MC-2R, MC-3R, MC-4R and MC-5R
  • disorders responsive to the activation of human MC- 4R such as overweight, obesity, diabetes as well as male and/or female sexual dysfunction, in particular
  • the present invention relates to a method for reducing overweight and/or for treating of and/or preventing overweight, obesity and/or complications thereto, the method comprising administering to an animal such as, e.g. a human and/or a domestic animal in need thereof an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with a natural metal-ion binding site in an MC receptor.
  • an animal such as, e.g. a human and/or a domestic animal in need thereof an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with a natural metal-ion binding site in an MC receptor.
  • the complications to overweight and/or obesity may be diabetes type II, hypertension, hypercholesterolaemia, hypertriglyceridaemia, cardiovascular diseases and/or arthritic diseases.
  • the invention relates to a method treating and/or prevention diabetes mellitus type II, the method comprising administering to an animal such as, e.g. a human and/or a domestic animal in need thereof an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with a natural metal-ion binding site in an MC receptor.
  • an animal such as, e.g. a human and/or a domestic animal in need thereof an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with a natural metal-ion binding site in an MC receptor.
  • the invention relates to a cosmetic method for reducing overweight, the method comprising administering to an animal such as, e.g. a human and/or a domestic animal in need thereof an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with a natural metal-ion binding site in an MC receptor.
  • an animal such as, e.g. a human and/or a domestic animal in need thereof an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with a natural metal-ion binding site in an MC receptor.
  • the invention relates to a method for reducing the fat tissue mass /lean mass body mass ratio in a domestic animal, the method comprising administering to a domestic animal an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with a natural metal-ion binding site in an MC receptor.
  • the invention also relates to a method for treating and/or preventing conditions involving the immune system, the method comprising administering to a human or a domestic animal an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with the natural metal-ion binding site in an MC receptor.
  • the invention relates to a method for treating and/or preventing male or female sexual dysfunction such as, e.g. psychogenic sexual dysfunction of a mammal including a human, the method comprising administering to the mammal in need thereof an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with the natural metal-ion binding site in an MC receptor.
  • a chelate and/or a chelator which is capable of binding or otherwise interacting with the natural metal-ion binding site in an MC receptor.
  • the invention relates to a method for treating and/or preventing erectile dysfunction in a mammal including a human, the method comprising administering to the mammal in need thereof an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with the natural metal-ion binding site in an MC receptor.
  • the MC receptor may be selected from the group consisting of MC-1 , MC-2, MC-3, MC-4, MC-5 such as, e.g., MC-1 or MC-4, including homo- and heterodimers, - trimers and -oligomers thereof.
  • the MC receptor mentioned above is a mammalian MC receptor such as, e.g. a human MC receptor, a dog MC receptor, a cat MC receptor, a mouse MC receptor or a rat MC receptor.
  • the invention also relates to a method for treating and/or preventing conditions involving the immune system, the method comprising administering to an animal such as, e.g. a human in need thereof, an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with the natural metal-ion binding site in an MC-1 receptor.
  • the invention relates to a method for treating and/or preventing chronic and acute inflammation, the method comprising administering to an animal such as, e.g. a human in need thereof, an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with the natural metal-ion binding site in an MC-1 receptor.
  • the acute inflammation may be related to ischemic conditions, such as, e.g. ischemic stroke.
  • the chelate and/or chelator have agonistic and/or antagonistic activity against an MC-1 receptor, they can be used in a cosmetic method for obtaining a suitable tan of the skin of an animal including a human.
  • Such a method comprises administering to an animal such as, e.g. a human in need thereof, an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with the natural metal-ion binding site in an MC-1 receptor.
  • the invention also relates to a method for treating and/or preventing anorexia and/or other appetite disorders, the method comprising administering to an animal such as, e.g. a human and/or a domestic animal in need thereof, an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with the natural metal-ion binding site in an MC receptor.
  • an animal such as, e.g. a human and/or a domestic animal in need thereof
  • an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with the natural metal-ion binding site in an MC receptor.
  • the chelate and/or chelator must have antagonistic activity against an MC receptor such as an MC-3 and/or MC-4 receptor.
  • the chelate and/or chelator When the chelate and/or chelator have agonistic and/or antagonistic activity against an MC-2 receptor, they can be used in a method for treating and/or preventing steroidal disorders such as, e.g. Cushing's syndrome.
  • the method comprises administering to an animal such as, e.g. a human in need thereof, an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with the natural metal-ion binding site in an MC-2 receptor.
  • the invention also relates to a method for treating and/or preventing perspiration disorders such as, e.g. sweat deficiency e.g. hypohidrosis, or excessive sweating e.g. diaphoresis or hyperhidrosis, the method comprising administering to an animal such as, e.g. a human in need thereof, an effective amount of a chelate and/or a chelator which is capable of binding or otherwise interacting with the natural metal-ion binding site in an MC-5R of an MC-R family.
  • Suitable chelates and/or chelators are those with agonistic and/or antagonistic activity against an MC-5 receptor.
  • the test compounds normally fulfill certain criteria with respect to molecular weight (at the most 3000 such as, e.g., at the most 2000, at the most 1500, at the most 1000, at the most 750, at the most 500), number of hydrogen bond donors (at the most 15 such as, e.g. at the most 13, 12, 11 , 10, 8, 7, 6 or at the most 5) and number of hydrogen bond acceptors (at the most 15 such as, e.g. at the most 13, 12, 11 , 10, 8, 7, 6 or at the most 5).
  • molecular weight, number of hydrogen bond donors and/or number of hydrogen bond acceptors of a test compound of a library of the invention have other values than the above-mentioned.
  • Chemical compounds which are suitable for use in drug discovery processes involving receptors having a metal-ion site, are any compounds that are capable of forming a complex with a metal ion.
  • a chemical compound for use according to the invention has at least two heteroatoms, similar or different, selected from the group consisting of nitrogen (N), oxygen (O), sulphur (S), selenium (Se) and phosphorous (P).
  • Chemical compounds which have been found to be useful in the present invention, are typically compounds comprising a heteroalkyl, heteroalkenyl, heteroalkynyl moiety or a heterocyclyl moiety for chelating the metal ion.
  • heteroalkyl is understood to indicate a branched or straight-chain chemical entity of 1-15 carbon atoms containing at least one heteroatom.
  • heteroalkenyl is intended to indicate a branched or straight-chain chemical entity of 2-15 carbon atoms containing at least one double bond and at least one heteroatom.
  • heteroalkynyl is intended to indicate a branched or straight-chain chemical entity of 2-15 carbon atoms containing at least one triple bond and at least one heteroatom.
  • heterocyclyl is intended to indicate a cyclic unsaturated (heteroalkenyl), aromatic (“heteroaryl”) or saturated (“heterocycloalkyl”) group comprising at least one heteroatom.
  • Preferred “heterocyclyl” groups comprise 5- or 6-membered rings with 1-4 heteroatoms or fused 5- or 6-membered rings comprising 1-4 heteroatoms.
  • the heteroatom is typically N, O, S, Se or P, normally N, O or S.
  • the heteroatom is either an integrated part of the cyclic, branched or straight-chain chemical entity or it may be present as a substituent on the chemical entity such as, e.g., a thiophenol, phenol, hydroxyl, thiol, amine, carboxy, etc.
  • heteroaryl groups are indolyl, dihydroindolyl, furanyl, benzofuranyl, pyridyl, pyrimidyl, pyrazoyl, benzothiazoyl, quinolinyl, triazolyl, imidazolyl, thiazolyl, tetrazolyl and benzimidazolyl.
  • the heterocyclyl group generally includes 2-20 carbon atoms, and 1-4 heteroatoms.
  • Particularly interesting chemical compounds to use according to the present invention are those having at least two heteroatoms connected according to the general formula I abbreviated as Che-R1
  • F is N, O, S, Se or P
  • G is N, O, S, Se or P
  • X, Y and Z which are the same or different, are straight or branched C C 12 alkyl, C C 12 alkenyl, C C 12 alkynyl, C C ⁇ 2 cyclyl, aryl, C C 12 heteroalkyl, C C 12 heteroalkenyl, C ⁇ C 12 heteroalkynyl, C ⁇ -C-
  • R1 may be present anywhere on the X, Y and/or Z moiety and it may be present on X, Y and/or Z up to as many times as possible, i.e. if X is -CH2-CH2-, then R1 may be present on the first and/or second carbon atom one or several times; R1 could optionally be hydrogen;
  • X may together with Y and/or Z fuse to form a cyclic ring system;
  • Y may together with X and/or Z fuse to form a cyclic ring system;
  • X, Y and Z may together fuse to form a cyclic ring system;
  • R 1 corresponds to a structure -A-B-C, wherein the element A is a coupling or connecting moiety, B is a spacer moiety and C is a functional group; -B- may be substituted one or more times with a further C, which may be the same or different, and
  • a linked to be -A-B-C is selected from the group consisting of:
  • alk includes straight or branched alkyl, straight or branched alkenyl and straight or branched alkynyl; R' is H or lower alk, i.e. C ⁇ -C 6
  • -B- is absent or selected from the group consisting of:
  • alkyl straight or branched alkyl, alkenyl (straight or branched), alkylnyl (straight or branched), aryl, cycloalkyl, heteroaryl, heterocycloalkyl, alkyloxyalkyl, alkylaminoalkyl,
  • -C is absent or selected from the group consisting of:
  • R" and/or R' has the same meaning as given for B above optionally substituted with one or more C;
  • A may be absent and then -R is -B-C or -C, and B may be substituted one or more times with C, which may be the same or different;
  • the size of a ring is at the most 14 atoms, preferably 5 or 6 atoms.
  • X, Y and/or Z may fuse to form one or more rings.
  • X-F-Y may be part of a heterocyclyl ring system:
  • X-F-Y and Y-G-Z may be part of heterocyclyl ring systems:
  • X-F-Y-G-Z may also be part of heterocyclyl ring systems:
  • X-F-Y and X-F-Y-G-Z may be part of heterocyclyl ring systems:
  • X-F-Y and Y-G-Z and X-F-Y-G-Z may be part of heterocyclyl ring systems:
  • alkyl is intended to indicate a branched or straight-chain, saturated chemical group containing 1-15 such as, e.g. 1-12, 1-10, preferably 1-8, in particular 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tert. butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl etc.
  • 1-15 such as, e.g. 1-12, 1-10, preferably 1-8, in particular 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec. butyl, tert. butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl etc.
  • alkenyl is intended to indicate an unsaturated alkyl group having one or more double bonds.
  • alkynyl is intended to indicate an unsaturated alkyl group having one or more triple bonds.
  • cycloalkyl is intended to denote a cyclic, saturated alkyl group of 3-7 carbon atoms.
  • cycloalkenyl is intended to denote a cyclic, unsaturated alkyl group of 5-7 carbon atoms having one or more double bonds.
  • aryl is intended to denote an aromatic (unsaturated), typically 6-membered, ring, which may be a single ring (e.g. phenyl) or fused with other 5- or 6-membered rings (e.g. naphthyl or anthracyl).
  • alkoxy is intended to indicate the group alkyl-O-.
  • amino is intended to indicate the group -NR"R'" where R" and R'" which are the same or different, have the same meaning as R in formula I.
  • R" and R' are hydrogen
  • a secondary amino group either but not both R" and R'" is hydrogen
  • neither of R" and R'" is hydrogen.
  • R" and R'" may also be fused to form a ring.
  • esters is intended to indicate the group COO-R", where R" is as indicated above except hydrogen, -OCOR , or a sulfonic acid ester or a phosphonic acid ester.
  • the invention relates to the use of chemical compounds having a specific characteristic feature in common.
  • radical may be placed anywhere in the cyclic system and there may also be as many radicals as there is positions possible in the structure.
  • Other symbols employed in the formulas below have the same meaning as given under formula I above.
  • the structure of the compounds are given in different structure levels. First in a very general form and then in more and more specific forms.
  • Y' is the remainder of the group Y which also includes Y ' being absent, i.e. G being directly linked to the ring.
  • the coordinating atom F is included in a 5- or 6-membered aromatic, unsaturated or saturated heterocycle containing between one and three heteroatoms and the coordinating atom G is either included in a 5- or 6-membered aromatic, unsaturated or saturated ring or an open chain.
  • F is N, O or S
  • G is N, O or S:
  • the coordinating atom F is appended to an aromatic, unsaturated or saturated 5- or 6-memebered ring.
  • F is N, O or S
  • G is N, O or S.
  • the coordinating atom G is included in a 5-or 6- membered aromatic, unsaturated or saturated heterocycle containing between one and four heteroatoms and the coordinating atom F contained within an aromatic, unsaturated or saturated 5- or 6-memebered heterocycle containing between one and four heteroatoms.
  • F is N, O or S
  • G is N, O or S.
  • the coordinating atom G is included in a 5- or 6-membered aromatic, unsaturated or saturated heterocycle containing between one and three heteroatoms and the coordinating atom F appended to an annelated aromatic, unsaturated or saturated 5- or 6-memebered ring.
  • X-F can optionally be included in a fused ring as indicated by the dashed line.
  • F is N, O or S; and G is N, O or S.
  • the annelated derivatives may be substituted with one or more R 1 moieties.
  • a compound for use according to the present invention may be mono-, di-, tri-, tetra-, pentasubstituted derivatives.
  • Suitable heterocyclic coordinating rings could be appended with coordinating moieties G to produce other chelating scaffolds containing one or more R1 groups.
  • Typical coordinating sacffolds of this type are imine moieties appended to coordinating heterocycles.
  • the coordinating groups e.g. thiol and imine, may be attached to a ring moiety containing one or more R1 groups.
  • Suitable open-chain chelating scaffolds are hydroxamic acids or 1 ,2-diamine coordinating moieties containing one or more R1 groups.
  • Chelator scaffolds containing one or more R1 groups of particular value are:
  • 2-pyridyl systems may also be connected to other six-membered nitrogen containing rings having one nitrogen adjacent to the connecting bond, such as
  • Non-pyridyl six-membered nitrogen containing aromatic rings may also be coupled to another non-pyridyl six-membered nitrogen containing ring where both ring systems having one nitrogen adjacent to the connecting bond, form useful scaffolds
  • biheterocyclyl derivatives may be substituted with one or more R 1 moieties.
  • a compound for use according to the present invention may be mono-, di-, tri-, tetra- , pentasubstituted biheterocyclyl derivatives.
  • the biheterocyclyl system may be symmetric or asymmetric and they may be symmetricly or asymmetricly substituted with one or more R1 groups.
  • the 5-membered ring may also be annelated with e.g. a benzene ring.
  • 2,2'-bipyridine is given as an example on a common basic structural element for chemical compounds for use according to the invention, i.e. the 2,2'-bipyridine here functions as the chelator skeleton.
  • a suitable compounds for use according to the present invention may be a 2,2'- bipyridine.
  • the 2,2'-bipyridines for use according to the invention is normally substituted with one or more functional groups.
  • a compound for use according to the present invention may contain mono-, di-, tri-, tetra-, penta-, hexa- or heptasubstituted bipyridines.
  • the di-, tetra- and/or hexasubstituted bipyridines may be symmetric or asymmetric substituted bipyridines. Normally, up to 4 or at the most 5 substituents are present on the 2,2'-bipyridine skeleton.
  • the position 3' is preferably substituted with a hydrogen atom.
  • Chemical compounds of the following general formulas are of specific interest in the present context.
  • the groups of compounds are denoted i) "A-group” in those cases where the compounds have a common connecting element, -A-, and ii) "C-group” in those cases where the compounds have a common functional group, -C.
  • the group of compounds may be an AA-, AA'-, AC-, CC- or CC'-group (A' is different from A but selected from the same group as A mentioned above; the same applies to C and C).
  • the group of compounds may be an AAA-, AAA'-, AA'A"-, AAC-, AA'C-, ACC-, ACC-, AC'C"-, CCC-, CCC- or CC'C”- group (or other possible permutations; the same notation is used as above, i.e. A is different from A', and A and A' are different from A").
  • the same notation applies for tetra-, penta-, hexa- or heptasubstitued 2,2-bipyridines.
  • the 2,2'-bipyridines of an A-group have a common connecting group attached directly on the ring system and a variable B-C moiety.
  • the functionalisations are made according to well-known chemical reactions with proper considerations of chemical compatibility of the functional groups with respect to the synthetic steps. Some exemplifications will be shown in the following.
  • Che-N(B-C) 2 ; Che-S-B-C ; Che-CO-NH-B-C ; Che-CH CH-B-C ; Che-O-B-C ; Che-NH- CO-B-C ; Che-SO 2 -NH-B-C as exemplified with the Che being 2,2'-bipyridine :
  • the compounds having an amide -CONH-B-C can be obtained by reacting a suitably activated carboxylate derivative with appropriate amines as detailed in the Experimental part.
  • the amines can be obtained by reacting the bipyridyl amines with suitable B-C reagents or sequentially by reaction with a B reagent followed by a C reagent.
  • the alkenes can be obtained by forming the double bond in either direction, i.e. either having the carbonyl moiety on the bipyridyl scaffold or preferably having the carbonyl moiety located on the B moiety as indicated in the example.
  • the thiols may be obtained by alkylation of the thiol with a B-C reagent or by nucleophilic addition/elimination with a suitable sulphur-containing derivative.
  • the substituent e.g. -CONH-B-C
  • the substituent may be positioned anywhere in the 3, 4 or 5 position on the 2,2'-bipyridine skeleton.
  • Alkenes with different B and C moieties can be obtained by reacting ylides of phosphonium salts or phosphonates such as:
  • 0 means a phenyl group, with appropriate ketone or aldehyde derivatives as detailed in the Experimental part.
  • the B moiety may optionally be part of a ring appended to an exo-cyclic double bond.
  • Alkenes/amides (AA') with different B and C moieties can be obtained by reacting ylides of phosphonium salts or phosphonates containing suitably protected carboxylic functions such as:
  • 0 means a phenyl group, with appropriate ketone or aldehyde derivatives, followed by deprotection, activation and coupling with suitable amines as shown for the amides (see Experimental section).
  • the 2,2'-bipyridines of a C-group have a common functional group either directly attached on the 2,2'-biyridine skeleton or at a position at a distance from the skeleton. Irrespective its position, a characteristic feature of a C-group is that the common functional group is not further derivatized or substituted.
  • Examples are 2,2'-bipyridines of formula II wherein R 1 is -A-B-C, -A-C, -B-C or -C (and, if present, B may be further substituted with one or more C groups). Examples on such functional end groups are e.g.
  • the present invention also relates to symmetric disustituted bipyridines, i.e. the bipyhdine skeleton has been substituted in the same position in the two pyridine rings.
  • the substituent may be the same or different and it may represent the same or different functional group.
  • Metal ions forming the complex with the heteroalkyl or heterocyclyl moiety in the chemical compounds may advantageously be selected from metal ions, which have been tested for or are used for pharmaceutical purposes.
  • Such metal ions belong to the groups denoted light metals, transition metals, post- transition metals or semi-metals (according to the periodic system).
  • the metal ion is typically selected from the group consisting of aluminium, antimony, arsenic, astatine, barium, beryllium, bismuth, boron, cadmium, calcium, cerium, caesium, chromium, cobalt, copper, dysprosium, erbium, europium, gadolinium, gallium, germanium, gold, hafnium, holmium, indium, iridium, iron, lanthanum, lead, lutetium, magnesium, manganese, mercury, molybdenum, neodymium, nickel, niobium, osmium, palladium, platinum, polonium, praseodymium, promethium, rhenium, rhodium, rubidium, ruthenium, samarium, scandium, selenium, silicon, silver, strontium, tantalum, technetium, tellurium, terbium, thallium, thorium
  • chemical compound having various chelating moieties (Che) containing different spacers (A and B moieties) and functionalities (C moities) can be produced and be tested with different metal ions (e.g. Zn, Cu, Ni, Co, Gd, Mn).
  • the compounds suitable for use according to the present invention may either be in the form of a chelate or in the form of a chelator.
  • a chelate is contemplated to be formed with a metal ion administered together with the chelator of with a metal ion present in the animal to be treated.
  • a chelator may be administered together with a sufficient amount of a suitable metal ion in the form of e.g. a metal salt, complex or covalent compound.
  • the chelates or chelators for use according to the invention can be prepared by methods well known to a person skilled in the art. Specific examples are disclosed in the following co-pending Danish patent applications Nos. PA 2001 01032, PA 2001 01033, PA 2001 01034, PA 2000 01035, which are hereby incorporated by reference.
  • the chelates and chelators for use in the methods according to the invention are normally presented in the form of a pharmaceutical or a cosmetic composition comprising the specific chelate or chelator together with one or more pharmaceutically and/or cosmetically acceptable excipients.
  • the chelates or chelators may be administered to the animal including a mammal such as, e.g., a human or a domestic animal including horses, pigs, cattle, cats, dogs, sheep by any convenient administration route such as, e.g., the oral, buccal, nasal, ocular, pulmonary, topical, transdermal, vaginal, rectal, parenteral (including inter alia subcutaneous, intramuscular, and intravenous), route in a dose that is effective for the individual purposes.
  • a mammal such as, e.g., a human or a domestic animal including horses, pigs, cattle, cats, dogs, sheep by any convenient administration route such as, e.g., the oral, buccal, nasal, ocular, pulmonary, topical, transdermal, vaginal, rectal, parenteral (including inter alia subcutaneous, intramuscular, and intravenous), route in a dose that is effective for the individual purposes.
  • parenteral including inter alia subcutaneous, intra
  • the effective dosage of a chelate or chelator employed may vary depending on the particular compound employed, the mode of administration, the condition being treated, the age and condition of the animal to be treated and the severity of the condition being treated. Suitable dosages may be ascertained readily by a person skilled in the art.
  • Suitable dosage forms include powders, granules, granulates, dispersions including solid dispersions, emulsions, including nano-emulsions, suspensions, solutions including solid solutions, mixtures, syrups, drops, aerosols, liniments, ointments, creams, gels including hydrogels, vagitories, suppositories, plasters, patches, tablets, capsules, sachets, troches, devices etc.
  • the dosage form may be designed to release the chelate or chelator freely or in a controlled manner e.g. with respect to tablets by suitable coatings.
  • compositions may be prepared by any of the method well known to a person skilled in pharmaceutical or cosmetic formulation.
  • the compounds of Formula I are normally combined with a pharmaceutical excipient, i.e. a therapeutically inert substance or carrier.
  • the carrier may take a wide variety of forms depending on the desired dosage form and administration route.
  • the pharmaceutically or cosmetically acceptable excipients may be e.g. fillers, binders, disintegrants, diluents, glidants, solvents, emulsifying agents, suspending agents, stabilizers, enhancers, flavours, colors, pH adjusting agents, retarding agents, wetting agents, surface active agents, preservatives etc. Details can be found in pharmaceutical handbooks such as, .e.g. ., Remington's Pharmaceutical Science or Pharmaceutical Excipient Handbook.
  • Figure 1 represents a serpentine model of the MC-1 receptor mutated as described in Example 1.
  • the potential metal-ion binding residues, which can be reached by extracellular acting ligands, are indicated with circles with black letters on gray background.
  • Figure 2 illustrates the binding and functional properties of the Zn(ll).
  • Competition binding studies on the MC-1 and the MC-4 receptor in transiently transfected COS-7 cells using 125 l-NDP- ⁇ -MSH as a radio-ligand are shown in Figure 2A and 2B, respectively.
  • the dose-response curves for Zn(ll) induced [ 3 H]cAMP accumulation measured in transiently transfected COS-7 cells expressing MC-1 and MC-4 receptors are shown in figure 2C and 2D, respectively.
  • Figure 3 illustrates that mutations of a crucial metal-ion binding residue destroy the agonistic properties of Zn(ll).
  • the dose-response curves for Zn(ll) induced [ 3 H]cAMP accumulation measured in transiently transfected COS-7 cells expressing wild type MC-1 and the MC-1 receptor with the Cys 271 mutated into an alanine are shown in Figure 3A.
  • Figure 3B the ⁇ -MSH dose response curve for each of the two construct are shown.
  • Figure 4 shows a sequence alignment of the five different MC receptors.
  • the amino acid sequence of the five different human MC receptors are aligned using the alignment program Multiple Sequence Alignment Clustal W1.8. Equal residues are marked in white on black whereas similar residues are marked in white on gray.
  • the location of the transmembrane segments - TM-I-TM-VII - are indicated in a line above the sequence alignment.
  • the two main residues involved in the metal-ion binding - Asplll:05 corresponds to Asp119 in the mouse MC-1 receptor which was used for the mutational mapping
  • the Cys in extracellular loop III corresponds to Cys271 in the mouse MC-1 receptor
  • Figure 5 illustrates the potentiating and enhancing properties of Zn(ll) on the agonist properties of ⁇ -MSH peptide.
  • [ 3 H]cAMP accumulation is measured in transiently transfected COS-7 cells expressing MC-1 and MC-4 receptors, where a Zn(ll) dose-response curve are added on top of a sub-maximal ⁇ -MSH stimulation.
  • Figure 5C and 5D shows that the addition of a constant concentration of Zn(ll) (lO ⁇ M) shifted the dose-response curve of ⁇ -MSH and NDP- ⁇ -MSH to the left for MC-1 R and MC-4R, respectively.
  • Figure 6 indicates two different binding modes for Zn++ acting either as an agonist alone on an MC receptor (panel A) or acting as a potentiator or enhancer in the presence of an MSH peptide having the important core tetra-peptide sequence - His-Phe-Arg-Trp- (panel B).
  • an agonist Zn++ binds in between Asplll:05 (Asp119 in mouse MC-1 receptor) and Cys in EC loop III (Cys271 in the mouse MC-1 receptor), which are conserved among all MC receptors, see Fig. 4 (the numbers coresponds to those of the MC-1 receptor- the numbers differes in the different receptors).
  • the metal-ion binds in between Cys in EC loop III of the receptor and the His residue of the ligand.
  • Figure 7 shows examples of the molecular structure of the metal-ion chelating compounds used in Example 3.
  • Figure 8 shows the correlation between the binding affinities obtained in MC-1 and MC-4 receptor, respectively.
  • the affinities are determined from competition binding studies on the MC-1 and the MC-4 receptor in transiently transfected COS-7 cells using 125 l-NDP- ⁇ - MSH as a radio-ligand and displaced with various different metal ion chelates.
  • the correlation between the affinities of the chelates obtained in the two different receptors is highly significant (p ⁇ 0.001 ).
  • Figure 9 shows the increased potency and efficacy of the dose response curve of the modified metal ion chelates.
  • the dose-response curves for Zn(ll) and Zn(ll) chelates induced [ 3 H]cAMP accumulation measured in transiently transfected COS-7 cells expressing MC1 and MC4 receptors are shown in Figure 8A and 8B, respectively.
  • Figure 10 illustrates that full antagonism was obtained from those metal-ion chelates, which were unable to activate the receptor.
  • [ 3 H]cAMP accumulation measured in transiently transfected COS-7 cells expressing MC-1 receptor, where a Zn(134) dose- response curve is added on top of a sub-maximal ⁇ -MSH stimulation.
  • Formula I may be constructed by well-known synthetic steps involving coupling reactions, including Stille-, Suzuki-, Negishi-, Ullmann-couplings (C-C bond formations), condensation reactions, including heterocyclic ring-forming reactions, elimination reactions, cycloaddition reactions, and/or substitution reactions known from the common literature, as illustrated with some typical but non-limiting reaction schemes.
  • coupling reactions including Stille-, Suzuki-, Negishi-, Ullmann-couplings (C-C bond formations), condensation reactions, including heterocyclic ring-forming reactions, elimination reactions, cycloaddition reactions, and/or substitution reactions known from the common literature, as illustrated with some typical but non-limiting reaction schemes.
  • the usual considerations regarding which functional groups that are compatible with the different types of chemistries should always be taken into account when selecting synthetic routes, order of introduction of functional groups and their interconversions, etc, which accordingly will differ on a case by case basis but are evident for the skilled person.
  • Scheme II illustrates the C-C-bond forming reaction in the 2,2'-bipyridine series.
  • Coupling of functionalised heterocyclic ring systems such as chloropyndines with trialkyl tin pyridines can be performed by the Stille coupling method, and exemplified in Scheme V.
  • Typical functional group interconversions are exemplified by transforming -COOCH 3 into a -CH 2 -NH 2 moiety as exemplified with the 2,2'.bipyridine system.
  • chelator systems may be formed and manipulated.
  • a chelator which have one of the coordinating atom(s) outside the ring system is 2-(2- pyridyl)thiophenol (See Scheme XV).
  • the construction may follow different routes, i.e. the coordinating atoms may be introduced at various stages, protected or unprotected, schematically illustrated in Scheme XV.
  • H 3 C _ s - TFFH LC-MS Alumina HBTU LC-MS HPLC HBTU LC-MS HPLC
  • 5- Amino-2,2 '-bipyridine 5-Nitro-2,2'-bipyridine (0.641 mol, 129 mg) was dissolved in MeOH/THF (5ml+5ml). To the solution was added Pd/C (5 %, 50 mg) and the reaction mixture was set under an H 2 -atmosphere and stirred for 24 h at room temperature. The reaction mixture was filtered through Celite, and the filtrate was evaporated in vacuo. The residue was purified by column chromatography (neutral Al 2 0 3 , 5 % EtOH in DCM), to yield the desired product. Yield: quantitative.
  • Ethyl 4-(3-carboxypropyl)-4'-metyl-2,2'-bipyridyl (2.5 g, 13.5 mmol) was dissolved in dry THF (20 ml) under a nitrogen atmosphere, in a flame-dried flask, equipped with a stirrer. The solution was cooled to -78 °C, and a solution of LDA (10 ml, 16.8 mmol) was added. The reaction mixture was allowed to warm to room temperature for 1,5 hours.
  • Triethyl amine (78.8 mmol, 11.0 ml, 5 equiv.) was then added and the reaction mixture was allowed to warm to ambient temperature.
  • DCM 100 ml
  • sat. NaHCO 3 150 ml
  • the organic phase was separated and the aqueous phase was extracted with DCM (2x100 ml).
  • the combined organic phases were dried over MgSO 4 , and the solvent was evaporated in vacuo
  • the crude product was purified by column chromatography (DCM/MeOH/NH 3 , 100/10/1). Yield: 44 %.
  • Triphenyl phosphine (1.0 mmol, 0.262 g) was dissolved in dry benzene (7 ml). 4-(Bromomethyl)-2,2'-bipyridine (1.06 mmol, 0.265 g) was added, and the reaction solution was refluxed for 2 h. A white precipitate formed. The solvent was removed in vacuo, and DCM (7 ml) was added to the solid residue. Benzaldehyde (1.0 mmol, 0.102 ml) was added and thereafter aqueous NaOH (1.0 mmol, 0.25 ml, 4M).
  • bipyridyl alkenes have been synthesized according to Table 26-1.
  • Table 26-1 Alkene derivatives prepared according to Example 26 in a typical "A"-type group.
  • 6-Chloro- te/t-butylnicotinate (12.7 mmol, 2.7g) was dissolved in dry m-xylene (150 ml) whereupon Me 3 SnSnMe 3 (15.26 mmol, 5.0 g) was added together with PdCI 2 (PPh 3 ) 2 (1.5 mmol, 1.0g). The reaction solution was heated to 130C under an N 2 atmosphere for 4h.
  • N-(8-Hydroxy-quinolin-5-yl)-acetamide N-(8-Hydroxy-quinolin-5-yl)-acetamide.
  • 5-Amino-8-hydroxyquinoline (1 mmol, 0.233g) was stirred in ether at ambient temperature before acetic anhydride (10 mmol, 1ml), followed by sodium acetate (10 mmol, 1.36g) was added.
  • the resulting mixture was heated to 40 °C for 16 h before being diluted with ether (100ml) poured onto a saturated solution of ammonium chloride (50 ml).
  • the organics were separated and washed with sodium bicarbonate (50 ml), water (3 x 50 ml), brine (50 ml), dried over sodium sulphate and concentrated in vacuo.
  • N-(8-Hydroxy-quinolin-5-yl)-4-trifluoromethyl-benzamide 5-Amino-8-hydroxyquinoline (0.15mmol, 25 mg) was dissolved in dry dichloromethane (5 ml) before the sequential addition of dimethyl formamide (0.2 ml), ⁇ /, ⁇ /,-dimethylaminopyridine (1 crystal), PS- carbodiimide (750mg) and 1 -hydroxybenzotriazole monohydrate (0.6mmol, 81 mg).
  • 2-(2-Pyridyl)fluorobenzene 2-Fluorophenylboronic acid (3.0 g, 21.4 mmol) was dissolved in DME (40 ml). 2-Bromopyridine (1.64 ml, 17.2 mmol) was added followed by 2M K 2 CO 3 (20 ml). The mixture was degassed by bubbling nitrogen gas through for 34 min. Bis- (triphenylphosphine)palladium chloride (1.2 g, 1.72 mmol) was added and the mixture was heated to 80°C over night. The mixture was cooled to room temperature and filtered through celite.
  • 2-(2-Pyridyl)thiophenol S-fe/t-Butyl-2-(2-pyridyl)thiophenol (200 mg, 0.82 mmol) was dissolved in 37 % HCl (4 ml) and the mixture was heated to 110 °C over night. The mixture was cooled to room temperature. H 2 O (10 ml) was added and the mixture was extracted with EtOAc (20 ml). pH of the aqueous phase was adjusted to 7 and the mixture was extracted with EtOAc (50 ml). The organic phase was dried over MgSO 4 , filtered and evaporated. Purification by column chromatography (SiO2, EtOAc:Heptane 1 :1).
  • 2-(2-Pyridyl)pyrazine 2-Chloropyrazine (100 mg, 0.87 mmol) was dissolved in m-xylen (2 ml), 2-tri-n-butylstannylpyridin (354 mg, 0.96 mmol) was added followed by bis- (triphenylphosphine)palladium chloride (1.2 mg, 0.0017 mmol). The mixture was heated to 130 °C over night under nitrogen. The mixture was allowed to cool to room temperature. The crude mixture was purified by column chromatography (SiO2; EtOAc:Heptane 1 :1).
  • the present example describes the novel discovery that Zn(ll) can bind to the wild type MC1 receptor and to the wild type MC-4 receptor with micromolar affinity. Furthermore it is observed that Zn(II) can act as an agonist on both of the two melanocortin receptors.
  • the geometry of metal ion binding sites in general is well characterized from the crystal structure of metal-ion binding soluble proteins.
  • the metal-ion binding site in the MC1 receptor is mapped by mutational substitution of potential metal-ion binding residues (histidine, cysteine, glutamate or aspartate residues) located in suitable positions in the extracellular part of the receptor. In Fig. 1 these potential metal ion binding residues, which can be reached by extracellular acting ligands, are marked with grey.
  • the human MC-4 receptor cDNA was cloned by PCR from brain cDNA library whereas the mouse MC-1 receptor was kindly provided by Dr. R. Cone, U.S.A.. Both receptors were cloned into a eukaryotic expression vector and introduced into COS-7 cells by a standard calcium phosphate transfection method.
  • Binding assay One day after transfection the cells were transferred and seeded in multi- well plates for assay. The number of cells plated per well was chosen so as to obtain 5 to 10% binding of the radioligand added. Two days after transfection the cells were assayed in competition binding assays using 125 l- NDP- ⁇ -MSH as a tracer. Radioligand was bound in a buffer composed of 0.5 ml of 50 mM Hepes buffer, pH 7.4, supplemented with 1 mM CaCI 2 , 5 mM MgCI 2 , and 0.1 % BSA, and displaced in a dose dependent manner by unlabelled ligands. The assay was performed in duplicate for 3 hours at 25 °C and stopped by washing twice in the buffer.
  • Radioligand was determined by the addition of lysis buffer (48% urea, 2% NP-40 in 3M acetic acid). The concentration of radioligand in the assay corresponds to a final concentration of approximately 20 pM. The metal-ion chelating compounds were added in a two-fold molar excess in order to ensure that no free metal-ion was present.
  • cAMP assay Two days after transfection the cells were assayed for intracellular levels of " basal and ligand-induced cyclic AMP. The assay employed is essentially as described in Solomon et al (Anal.Biochem. (1974) 58: 541). Labelled adenine (2 ⁇ Ci, [ 3 H]adenine,
  • Amersham TRK311 was added to cells seeded in 6-well culture dishes. The following day the cells were washed twice with HBS buffer [25 mM Hepes, 0.75 mM NaH 2 PO 4 , 140 mM NaCI (pH 7.2)] and incubated in buffer supplemented with 1 mM 3-isobutyl-1- methylxanthine (Sigma I-5879). Agonists were added and the cells were incubated for 30 min at 37 °C.
  • the assay was terminated by placing the cells on ice and aspiration of the buffer followed by addition of ice-cold 5% trichloroacetic acid containing 0.1 mM unlabelled camp (Sigma A-9062) and ATP (Sigma A-9501). Cyclic AMP was then isolated by application of the supernatant to a 50W-X4 resin (BioRad) and subsequently an alumina resin (A-9003; Sigma) eluting the cyclic AMP with 0.1 M imidazole (Sigma I- 0125). Determinations were done in duplicate. Results and discussion
  • Table 45-1 Competition binding using 125 l-NDP- ⁇ -MSH as a radioligand in transiently transfected COS-7 cell expressing MC1 and MC4.
  • Zn(ll) The functional consequence of the Zn(ll) binding was evaluated by analysis of cAMP accumulation in transiently transfected COS-7 cells.
  • Zn(ll) acted as a partial agonist both in the MC-1 receptor and in the MC-4 receptor.
  • Zn(ll) On the MC-1 receptor Zn(ll) had an efficacy of approximately 50 % as compared to ⁇ -MSH, whereas on the MC-4 receptor Zn(ll) showed only 20 % efficacy compared to ⁇ -MSH (Fig. 2C, 2D).
  • the potency of Zn(ll) was 13 and 16 ⁇ M (EC50 values) for the MC-1 and the MC-4, respectively, which corresponds to the affinity for Zn(ll) determined in the competition binding experiments.
  • the affinity and potency of the metal ion interaction with the receptor indicate that the metal-ion binding site is composed of at least two metal ion coordinating residues.
  • the metal ion is coordinated between the Cys and the Asp at the extracellular end of TMIII (TMIII:05), since this residue is located close in space and since the natural agonist, ⁇ - MSH also binds to this residue.
  • TMIII metal ion coordinating residues.
  • the present example describes the discovery that metal ions not only function as agonists as described in example No. 45, but that the metal ions also are able to modulate the ⁇ - MSH function as it increases both the potency and the efficacy of the natural, endogenous agonits, ⁇ -MSH.
  • a Zn(ll) binding to the ⁇ -MSH peptide ligand as such concomitantly with its binding to the receptor may explain the modulating function of Zn(ll) on both the potency and the efficacy of ⁇ -MSH.
  • the peptide sequence of the ⁇ -MSH is Ac-Ser-Tyr- Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val and accordingly the Zn(ll) may bind with high affinity to the Histidine and / or the Glutamate residue a sequence, which previously has been demonstrated to be very importnant for the function of the peptide.
  • Zn(ll) may bind in between Asp 119 and Cys 271 when the metal-ion alone or in complex with metal-ion chelators act as a partial agonist as presented in the present invention - in accordance with the fact that the inner ace of TM-III is an interaction site for agonists in general in 7TM receptors.
  • Fig. 6A Zn(ll) may bind in between Asp 119 and Cys 271 when the metal-ion alone or in complex with metal-ion chelators act as a partial agonist as presented in the present invention - in accordance with the fact that the inner ace of TM-III is an interaction site for agonists in general in 7TM receptors.
  • the Arg of the agonist ligand is supposed to interact with Asp 119 in TM-III of the receptor and the potentiating action of the metal-ion described in the present invention could therefor be mediated through the binding of the metal-ion in between Cys 271 of the receptor andthe His residue of the core tetra-peptide sequence of the ligand.
  • Example 47 Metal ion chelators and metal ion chelates can be used as agonists in the MC-1 and the MC-4 receptor
  • metal-ion chelates can be useful compounds as MC receptor modulators and potential drugs.
  • binding of the metal-ion in a chelate also create a greater degree of specificity especially when the chelator is chemically modified and optimized for interaction with the intended receptor.
  • Table 47-1 Competition binding using 125 l-NDP- ⁇ -MSH as a Radioligand in transiently transfected COS-7 cell expressing MC1 and MC4.
  • Table 47-2 cAMP accumulation in transiently transfected COS7 cells with MC1 and MC4. The efficacies expressed as percent of maximum Zn(ll) induced stimulation for the different Zn(ll) chelates are listed. For some of the chelates the potency(EC 50 ) are measured.
  • the molecular structure of the chelator compounds was of crucial importance for the degree of activation they induced.
  • the two basic chelator compounds Zn-phenanthroline and Zn-bipyridine ( Figure 9A and Table 47-2) had a lower efficacy than the free zinc ion alone. However, when the chelates were further substituted it was possible to recover the activity.
  • One of the compounds Zn-(5-chloro-1 ,10-phenanthroline) had a higher efficacy reaching 168 % of the Zn(ll) induced efficacy and a 2 fold increased potency compared to free zinc (Figure 9A).
  • this compound is nearly as efficacious as the natural agonist MSH, as it is a full agonist on the MC-1 receptor.
  • the compounds that bind to the melanocortin receptors but do not activate the receptors are antagonists as illustrated with one of the compounds Zn(134) on the MC-1 receptor ( Figure 9).
  • metal-ion chelates or metal-ion chelators which pick up a metal-ion in the organism, can be useful compounds to regulate melanocortin receptors activity also in the whole animal and in humans.

Abstract

L'invention concerne une méthode de réduction de la surcharge pondérale et de traitement et/ou de prévention de la surcharge pondérale, de l'obésité et/ou des complications liées à l'obésité (telles que le diabète de type 2, l'hypertension, l'hypercholestérolémie, l'hypertriglycéridémie, les pathologies cardiovasculaires et/ou les pathologies arthritiques). Cette méthode consiste à administrer à un animal, tel qu'un humain ou un animal domestique nécessitant un tel traitement, une dose efficace d'un chélate et/ou d'un chélateur capable de se fixer sur un site naturel de liaison d'ions métalliques ou d'interagir avec ce dernier dans un récepteur MC (récepteur de la mélanocortine) de la famille MC-R. L'invention concerne également des méthodes de traitement et/ou de prévention du diabète non insulino-dépendant, de troubles liés au système immunitaire, de l'inflammation, des dysfonctions sexuelles masculines ou féminines, telles que la dysfonction érectile, de l'anorexie et/ou d'autres troubles de l'appétit, des troubles stéroïdiques et des troubles de la sudation. L'invention concerne également une méthode cosmétique de réduction de la surcharge pondérale, l'utilisation d'un chélate et/ou d'un chélateur pour la préparation d'une composition pharmaceutique et l'utilisation d'un chélate et/ou d'un chélateur comme composé principal dans l'élaboration d'un médicament pour détecter les ligands qui interagissent avec un récepteur MC. Les composés de l'invention sont des composés hétérocycliques, tels que des dérivés de bipyridine.
PCT/DK2002/000902 2001-12-21 2002-12-20 Methode de traitement de troubles lies au recepteur de la melanocortine (mc), faisant intervenir un chelate et/ou un chelateur WO2003055477A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002367087A AU2002367087A1 (en) 2001-12-21 2002-12-20 Method for the treatment of mc receptor related disorders with a chelate and/or a chelator

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA200101943 2001-12-21
DKPA200101943 2001-12-21

Publications (1)

Publication Number Publication Date
WO2003055477A1 true WO2003055477A1 (fr) 2003-07-10

Family

ID=8160929

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2002/000902 WO2003055477A1 (fr) 2001-12-21 2002-12-20 Methode de traitement de troubles lies au recepteur de la melanocortine (mc), faisant intervenir un chelate et/ou un chelateur

Country Status (2)

Country Link
AU (1) AU2002367087A1 (fr)
WO (1) WO2003055477A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7326707B2 (en) 2001-08-10 2008-02-05 Palatin Technologies Incorporated Bicyclic melanocortin-specific compounds
JP2011513253A (ja) * 2008-02-27 2011-04-28 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング 糖尿病を治療するためのカルボキサミド−ヘテロアリール誘導体
WO2012117224A1 (fr) * 2011-03-02 2012-09-07 Sabrepharm Limited Dérivés de dipyridinium
JP2013501737A (ja) * 2009-08-14 2013-01-17 バイエル・クロップサイエンス・アーゲー 殺虫性カルボキサミド類
WO2013171641A1 (fr) * 2012-05-15 2013-11-21 Novartis Ag Composés et compositions pour l'inhibition de l'activité abl1, abl2 et bcr-abl1
WO2013171640A1 (fr) * 2012-05-15 2013-11-21 Novartis Ag Dérivés de benzamide pour inhiber l'activité d'abl1, d'abl2 et de bcr-abl2
US8829195B2 (en) 2012-05-15 2014-09-09 Novartis Ag Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
US9340537B2 (en) 2012-05-15 2016-05-17 Novatis Ag Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
CN108383791A (zh) * 2018-04-27 2018-08-10 上海泰禾国际贸易有限公司 一种酰胺类化合物及其制备方法和用途
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US10752594B2 (en) 2013-03-14 2020-08-25 Sumitomo Dainippon Pharma Oncology, Inc. JAK1 and ALK2 inhibitors and methods for their use
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5401746A (en) * 1980-07-11 1995-03-28 Bayer Aktiengesellschaft Substituted pyridines heptenoic acid derivatives, useful for treating arterioscleros, lipopotaemia and the like
WO2001013112A1 (fr) * 1999-08-12 2001-02-22 Palatin Technologies, Inc. Constructions de metallopeptides de melanocortine, banques combinatoires et applications
WO2001050127A2 (fr) * 1999-12-30 2001-07-12 7Tm Pharma Methode permettant d'identifier des ligands de molecules biologiques cibles
WO2001060349A2 (fr) * 2000-02-15 2001-08-23 Novactyl, Inc. Agent pharmacologique et procede de traitement
US6284795B1 (en) * 1998-09-04 2001-09-04 Warner-Lambert Company Sulfonamide compounds and methods of treating atherosclerosis and restenosis

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5401746A (en) * 1980-07-11 1995-03-28 Bayer Aktiengesellschaft Substituted pyridines heptenoic acid derivatives, useful for treating arterioscleros, lipopotaemia and the like
US6284795B1 (en) * 1998-09-04 2001-09-04 Warner-Lambert Company Sulfonamide compounds and methods of treating atherosclerosis and restenosis
WO2001013112A1 (fr) * 1999-08-12 2001-02-22 Palatin Technologies, Inc. Constructions de metallopeptides de melanocortine, banques combinatoires et applications
WO2001050127A2 (fr) * 1999-12-30 2001-07-12 7Tm Pharma Methode permettant d'identifier des ligands de molecules biologiques cibles
WO2001060349A2 (fr) * 2000-02-15 2001-08-23 Novactyl, Inc. Agent pharmacologique et procede de traitement

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7326707B2 (en) 2001-08-10 2008-02-05 Palatin Technologies Incorporated Bicyclic melanocortin-specific compounds
JP2011513253A (ja) * 2008-02-27 2011-04-28 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング 糖尿病を治療するためのカルボキサミド−ヘテロアリール誘導体
JP2013501737A (ja) * 2009-08-14 2013-01-17 バイエル・クロップサイエンス・アーゲー 殺虫性カルボキサミド類
WO2012117224A1 (fr) * 2011-03-02 2012-09-07 Sabrepharm Limited Dérivés de dipyridinium
JP2015520157A (ja) * 2012-05-15 2015-07-16 ノバルティス アーゲー Ａｂｌ１、ａｂｌ２およびｂｃｒ−ａｂｌ１の活性を阻害するための化合物および組成物
AU2013261129B2 (en) * 2012-05-15 2016-05-12 Novartis Ag Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
US8829195B2 (en) 2012-05-15 2014-09-09 Novartis Ag Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
CN104334529A (zh) * 2012-05-15 2015-02-04 诺华股份有限公司 用于抑制abl1、abl2和bcr-abl1的活性的化合物和组合物
KR20150014452A (ko) * 2012-05-15 2015-02-06 노파르티스 아게 Abl1, abl2 및 bcr-abl1의 활성을 억제하기 위한 화합물 및 조성물
CN104379574A (zh) * 2012-05-15 2015-02-25 诺华股份有限公司 用于抑制abl1、abl2和bcr-abl1的活性的苯甲酰胺衍生物
US20150141427A1 (en) * 2012-05-15 2015-05-21 Novartis Ag Compounds and compositions for inhibiting the activity of abl1, abl2 and bcr-abl1
JP2015516460A (ja) * 2012-05-15 2015-06-11 ノバルティス アーゲー Ａｂｌ１、ａｂｌ２およびｂｃｒ−ａｂｌ１の活性を阻害するためのベンズアミド誘導体
WO2013171641A1 (fr) * 2012-05-15 2013-11-21 Novartis Ag Composés et compositions pour l'inhibition de l'activité abl1, abl2 et bcr-abl1
US9278981B2 (en) 2012-05-15 2016-03-08 Novartis Ag Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
US9315489B2 (en) 2012-05-15 2016-04-19 Novartis Ag Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
WO2013171640A1 (fr) * 2012-05-15 2013-11-21 Novartis Ag Dérivés de benzamide pour inhiber l'activité d'abl1, d'abl2 et de bcr-abl2
US9340537B2 (en) 2012-05-15 2016-05-17 Novatis Ag Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
US9458112B2 (en) 2012-05-15 2016-10-04 Novartis Ag Compounds and compositions for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
CN104379574B (zh) * 2012-05-15 2017-03-01 诺华股份有限公司 用于抑制abl1、abl2和bcr‑abl1的活性的苯甲酰胺衍生物
EA026559B1 (ru) * 2012-05-15 2017-04-28 Новартис Аг Соединения и композиции для ингибирования активности abl1, abl2 и bcr-abl1
US9896444B2 (en) 2012-05-15 2018-02-20 Novartis Ag Benzamide derivatives for inhibiting the activity of ABL1, ABL2 and BCR-ABL1
KR102190848B1 (ko) * 2012-05-15 2020-12-15 노파르티스 아게 Abl1, abl2 및 bcr-abl1의 활성을 억제하기 위한 화합물 및 조성물
US10752594B2 (en) 2013-03-14 2020-08-25 Sumitomo Dainippon Pharma Oncology, Inc. JAK1 and ALK2 inhibitors and methods for their use
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US11603351B2 (en) 2017-07-11 2023-03-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
CN108383791A (zh) * 2018-04-27 2018-08-10 上海泰禾国际贸易有限公司 一种酰胺类化合物及其制备方法和用途
US11040038B2 (en) 2018-07-26 2021-06-22 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal ACVR1 expression and ACVR1 inhibitors for use in the same

Also Published As

Publication number Publication date
AU2002367087A1 (en) 2003-07-15

Similar Documents

Publication Publication Date Title
EP2160187B1 (fr) Spiroindalones
AU2016340264B2 (en) 2,4-dihydroxy-nicotinamides as APJ agonists
CN108473466B (zh) 爱帕琳肽受体激动剂及使用方法
EP3526198B1 (fr) Agonistes d'apj de 3-sulfonyl-5-aminopyridine -2,4-diol
JP4722851B2 (ja) キノリンカリウムチャネル阻害剤
KR102204804B1 (ko) 디히드로피라졸 gpr40 조절제
CA2555800C (fr) Piperidinylcarbonyl-pyrrolidines et leur utilisation en tant qu'agonistes de la melanocortine
EP2463276B1 (fr) Dérivé d'acylguanidine à noyau azoté
KR20180095577A (ko) Apj 수용체의 효능제로서의 헤테로아릴히드록시피리미디논
KR20070097441A (ko) 11-β 하이드록실 스테로이드 데하이드로게나제 유형 1의억제제 및 이를 사용하는 방법
EP1343761A1 (fr) Antagonistes piperidiniques de mch et leur utilisation dans le traitement de l'obesite
AU2009272486A1 (en) Benzazepine derivatives and their use as hstamine H3 antagonists
TW200815402A (en) 1,2-dihydropyridine compounds, process preparation of the same and use thereof
WO2011023812A1 (fr) Inhibiteurs de prostaglandine e synthase-1 (mpges1) microsomale
JP2008535782A (ja) ｍＧｌｕＲ５アンタゴニストとして使用するための、ピロリジンおよびピペリジンアセチレン誘導体
TW200815351A (en) Novel compounds
JPH0662565B2 (ja) Ｎ―複素環―ｎ―（４―ピペリジル）アミド及び該化合物を含む薬剤組成物
WO2003055477A1 (fr) Methode de traitement de troubles lies au recepteur de la melanocortine (mc), faisant intervenir un chelate et/ou un chelateur
US20180282320A1 (en) Triazolopyridine inhibitors of myeloperoxidase
WO2003003009A1 (fr) Utilisation de chelates a ions metalliques dans la validation de molecules biologiques utilisees comme cibles medicamenteuses dans des modeles animaux experimentaux
JP2012530136A (ja) 置換−１，３，８−トリアザスピロ［４．５］デカン−２，４−ジオン
EP2285375B1 (fr) Composés de spiro-azaindole comme inhibiteurs de HIF propylhydroxylase
US20040067955A1 (en) Pyridazinone compound and pharmaceutical use thereof
AU2017229129A1 (en) Thiazolidinone compounds and use thereof
KR20050103184A (ko) 융합된 헤테로사이클릭 화합물들

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP