WO2003004010A1 - Derives carbonylamino permettant d'obtenir une immunoregulation - Google Patents

Derives carbonylamino permettant d'obtenir une immunoregulation Download PDF

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Publication number
WO2003004010A1
WO2003004010A1 PCT/DK2002/000427 DK0200427W WO03004010A1 WO 2003004010 A1 WO2003004010 A1 WO 2003004010A1 DK 0200427 W DK0200427 W DK 0200427W WO 03004010 A1 WO03004010 A1 WO 03004010A1
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phenyl
acetamide
fluoro
use according
alkyl
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PCT/DK2002/000427
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English (en)
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Lars Siim Madsen
Alex Haahr Gouliaev
Bo Skaaning Jensen
Marc Hertz
Anand Gautam
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Poseidon Pharmaceuticals A/S
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Publication of WO2003004010A1 publication Critical patent/WO2003004010A1/fr

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    • 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
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the present invention relates to the use of a particular group of carbonylamino derivatives for the treatment or alleviation of diseases or conditions relating to immune regulation.
  • Ion channels are transmembrane proteins, which catalyse the transport of inorganic ions across cell membranes.
  • the ion channels participate in processes as diverse as the generation and timing of action potentials, synaptic transmissions, secretion of hormones, contraction of muscles, etc.
  • IK Ca 2+ -activated K-channels also referred to as Gardos-channels. Resting T- lymphocytes express both SKc a and IKca, whereas B-lymphocytes only express IKc a .
  • IKc a IKc a -inhibitor Clotrimazole (which is also a blocker of the cytochrome P-450 system) has been extensively used clinically in the systemic treatment of fungal infections. No toxicity related to K-channel blockade has been described.
  • WO 00/50026 describes Gardos channel antagonists (i.e. Ca 2+ -activated K-channels), which inhibit the Gardos channel of erythrocytes, reduce sickle erythrocyte dehydration and/or delay the occurrence of erythrocyte sickling or deformation.
  • Gardos channel antagonists i.e. Ca 2+ -activated K-channels
  • IFN- ⁇ human T cell ⁇ -interferon
  • WO 01/27070 describes the use of carbonylamino derivatives for treating CNS disorders relating to metabotropic glutamate receptor antagonists and/or agonists.
  • IFN- ⁇ human T cell ⁇ -interferon
  • the present invention relates to the use of a particular group of carbonylamino derivatives for suppression of immune responses and for the treatment or alleviation of diseases, disorders or conditions relating to immune regulation, in particular immune suppression. Accordingly, in its first aspect, the invention relates to the use of a carbonylamino derivative of the general Formula I
  • A represents CH or N
  • R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, alkoxy or CF 3 ;
  • Y represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, or a group of the formula
  • R 1 , R 2 and R 3 independently of each another, represent hydrogen, halogen, CN, NO 2 or CF 3 ; I is 0, 1 , 2, 3, 4, 5 or 6; and m, n and o, independent of each another, are 0, 1 or 2; for the manufacture of a medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition relates to immune regulation.
  • the invention provides a method for of treatment, prevention or alleviation of a disease or a disorder or a condition related to immune regulation in a living animal body, including a human, which method comprises the step of administering to such a living animal body in need thereof a therapeutically effective amount of a carbonylamino derivative of the general Formula I disclosed herein.
  • the invention relates to the use of a carbonylamino derivative for the manufacture of a medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, including a human, which disease, disorder or condition relates to immune regulation, in particular immune suppression.
  • A represents CH or N;
  • R represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, alkoxy or CF3;
  • Y represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, or a group of the formula
  • R 1 , R 2 and R 3 independently of each another, represent hydrogen, halogen, CN, NO 2 or CF 3 ; l is O, 1 , 2, 3, 4, 5 or 6; and m, n and o, independent of each another, are 0, 1 or 2. In a more preferred embodiment, m, n and o, independent of each another, are 0 or 1.
  • the carbonylamino derivative is a compound represented by Formula II
  • I, m, n, Y, R, R 1 and R 2 are as defined above.
  • the carbonylamino derivative of the invention is a compound of Formula II wherein Y represents alkyl, cycloalkyl, cycloalkyl-alkyl or alkenyl;
  • I is O; m and n, independently of each another, represent 0 or 1 ; and
  • R represents hydrogen
  • N-hex-2-enyl-2,2-diphenyl-acetamide or a pharmaceutically-acceptable addition salt hereof.
  • the carbonylamino derivative of the invention is a triaryl methane represented by Formula III wherein R 1 , R 2 and R 3 are as defined above.
  • the carbonylamino derivative of the invention is a triaryl methane of Formula III wherein R 1 , R 2 and R 3 , independently of each another, represent hydrogen or fluoro.
  • the triaryl methane derivative is
  • the triaryl methane derivative of the invention is represented by Formula IV, wherein R 1 , R 2 and R 3 , independently of each another, represent hydrogen or fluoro. In a most preferred embodiment the triaryl methane derivative of the invention is
  • I, m, n, Y, R, R 1 and R 2 are as defined above.
  • the carbonylamino derivative of the invention is a compound of Formula V, wherein
  • Y represents alkyl, cycloalkyl, cycloalkyl-alkyl or alkenyl; I is 0; m and n, independently of each another, represent 0 or 1 ;
  • R represents hydrogen
  • R 1 and R 2 independently of each another, represent hydrogen or fluoro.
  • halogen represents a fluorine, a chlorine, a bromine or an iodine atom.
  • an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain.
  • the hydrocarbon chain preferably contain of from one to eighteen carbon atoms (C ⁇ -i 8 -alkyl), more preferred of from one to six carbon atoms (C-t- 6 -alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
  • alkyl represents a C- ⁇ - 4 -alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl.
  • alkyl represents a C ⁇ - 3 -alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.
  • an alkenyl group designates a carbon chain containing one or more double bonds, including di-enes, tri-enes and poly-enes.
  • the alkenyl group of the invention comprises of from two to eight carbon atoms (C 2-8 -alkenyl), more preferred of from two to six carbon atoms (C 2-6 -alkenyl), including at least one double bond.
  • the alkenyl group of the invention is ethenyl; 1- or 2-propenyl (allyl); 1-, 2- or 3- butenyl, or 1 ,3-butdienyl; 1-, 2-, 3-, 4- or 5-hexenyl, or 1 ,3-hexdienyl, or 1 ,3,5- hextrienyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-octenyl, or 1 ,3-octdienyl, or 1 ,3,5-octtrienyl, or 1 ,3,5,7-octtetraenyl.
  • an alkynyl group designates a carbon chain containing one or more triple bonds, including di-ynes, tri-ynes and poly-ynes.
  • the alkynyl group of the invention comprises of from two to eight carbon atoms (C 2-8 -alkynyl), more preferred of ram two to six carbon atoms (C 2- 6 -aIkynyl), including at least one triple bond.
  • the alkynyl group of the invention is ethynyl; 1-, or 2-propynyl; 1-, 2-, or 3-butynyl, or 1 ,3- butdiynyl; 1-, 2-, 3-, 4-pentynyl, or 1 ,3-pentdiynyl; 1-, 2-, 3-, 4-, or 5-henynyl, or 1 ,3- hexdiynyl or 1 ,3,5-hextriynyI; 1-, 2-, 3-, 4-, 5- or 6-heptynyl, or 1 ,3-heptdiynyl, or 1 ,3,5-hepttriynyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-octynyl, or 1 ,3-octdiynyl, or 1,3,5-octtriynyl, or 1 ,3,5,7-octtetraynyl.
  • a cycloalkyl group designates a cyclic alkyl group, preferably containing of from three to seven carbon atoms (C 3-7 -cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a cycloalkyl-alkyl group designates a cycloalkyl group as defined above, which cycloalkyl group is substituted on an alkyl group as also defined above.
  • Examples of preferred cycloalkyl-alkyl groups of the invention include cyclopropylmethyl and cyclopropylethyl.
  • an alkoxy group designates an "alkyl-O-" group, wherein alkyl is as defined above.
  • the chemical compound for use according to the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, or pre- or prodrug forms of the chemical compound for use according to the invention.
  • Examples of pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulfonate derived from benzensulfonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from citric acid, the embonate derived from embonic acid, the enantate derived from enanthic acid, the formate derived from formic acid, the fuma- rate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, the malonate derived from
  • Metal salts of a chemical compound for use according to the invention includes alkali metal salts, such as the sodium salt, of a chemical compound for use according to the invention containing a carboxy group.
  • onium salts of N-containing compounds are also contemplated as pharmaceutically acceptable salts.
  • Preferred “onium salts” include the alkyl-onium salts, the cycloalkyl-o ⁇ ium salts, and the cycloalkylalkyl-onium salts.
  • the chemical compounds of the present invention may exist in (+) and (-) forms as well as in racemic forms.
  • the racemates of these isomers and the individual isomers themselves are within the scope of the present invention.
  • Racemic forms can be resolved into the optical antipodes by known methods and techniques. One way of separating the diastereomeric salts is by use of an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or I- (tartrates, mandelates, or camphorsulphonate) salts for example.
  • the chemical compounds of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like.
  • an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid
  • the carbonylamino derivatives for use according to the invention may be prepared by conventional methods for chemical synthesis, e.g. those described in WO 00/50026 and WO 01/27070.
  • the carbonylamino derivatives described herein are particularly useful as immune modulating agents, i.e. agents capable of regulating the immune system. More particularly, the carbonylamino derivatives may be used for reducing or inhibiting undesired immune-regulatory actions.
  • the disease, disorder or condition relates to reduction or inhibition of undesired immune-regulatory actions, including graft vs. host syndrome, transplant rejection, or transplant rejection.
  • the invention relates to the use of an IKc a inhibitory compound of the invention in a combination therapy with known immune-suppressants for the treatment or alleviation of diseases, disorders or conditions related to immune regulation, or for obtaining immune suppression.
  • Preferred immune-suppressants to combine with the compounds of the invention include Amphotericin, Busulphan, Co-trimoxazole, Chlorambucil, colony stimulating factors, corticosteroids, Cyclophosphamide, Fluconazole, folinic acid, Ganciclovir, antilymphocyte immunoglobulins, normal immunoglobulins, Methotrexate, Methylprednisolone, Octreotide, Oxpentifylline, Tacrolimus (FK506), Thalidomide, Zolimomab aritox, and the calcineurin inhibitors (protein phosphatase 2B inhibitors), in particular Cyclosporin.
  • Amphotericin Busulphan
  • Co-trimoxazole Chlorambucil
  • colony stimulating factors corticosteroids
  • Cyclophosphamide Fluconazole
  • folinic acid Ganciclovir
  • antilymphocyte immunoglobulins normal immunoglobulin
  • Other conditions which may benefit from this treatment include, but are not limited to diseases, disorders or conditions such as auto-immune diseases, e.g. Addison's disease, alopecia areata, Ankylosing spondylitis, haemolytic anemia (anemia haemolytica), pernicious anemia (anemia perniciosa), aphthae, aphthous stomatitis, arthritis, arteriosclerotic disorders, osteoarthritis, rheumatoid arthritis, aspermiogenese, asthma bronchiale, auto-immune asthma, auto-immune hemolysis, Bechet's disease, Boeck's disease, inflammatory bowel disease, Burkitt's lymphoma, Chron's disease, chorioiditis, colitis ulcerosa, Coeliac disease, cryoglobulinemia, dermatitis herpetiformis, dermatomyositis, insulin-dependent type I
  • the invention relates to pharmaceutical compositions for use in the treatment or alleviation of diseases, disorders or conditions related to immune regulation, which pharmaceutical composition comprises a therapeutically effective amount of a chemical compound having IKc a inhibitory activity, as identified by the method of the invention.
  • a chemical compound for use according to the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • the invention provides pharmaceutical compositions comprising the chemical compound for use according to the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredients.
  • the carriers must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the pharmaceutical composition of the invention may be administered by any convenient route which suite the desired therapy.
  • Preferred routes of administration include oral administration, in particular in tablet, in capsule, in drage, in powder, or in liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular, or intravenous injection.
  • the pharmaceutical composition may be prepared by the skilled person using standard and conventional techniques appropriate to the desired formulation. When desired, compositions adapted to give sustained release of the active ingredient may be employed.
  • compositions containing of from about 0.1 to about 500 mg of active ingredient per individual dose, preferably of from about 1 to about 100 mg, most preferred of from about 1 to about 10 mg, are suitable for therapeutic treatments. Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).
  • compositions containing of from about 0.1 to about 500 mg of active ingredient per individual dose, preferably of from about 1 to about 100 mg, most preferred of from about 1 to about 10 mg, are suitable for therapeutic treatments.
  • the active ingredient may be administered in one or several doses per day.
  • a satisfactory result can, in certain instances, be obtained at a dosage as low as 0.1 ⁇ g/kg i.v. and 1 ⁇ g/kg p.o.
  • the upper limit of the dosage range is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o.
  • Preferred ranges are from about 0.1 ⁇ g/kg to about 10 mg/kg/day i.v., and from about 1 ⁇ g/kg to about 100 mg/kg/day p.o.
  • the invention provides a method for treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body, including a human, which disease, disorder or condition is responsive to IKc a inhibitory compounds.
  • the invention provides a method for the treatment, prevention or alleviation of diseases, disorders or conditions relating to immune regulation in a living body, which method comprises administering to said living body an effective amount of a carbonylamino derivative of the general Formula l disclosed herein.
  • Other conditions which may benefit from this treatment include, but are not limited to diseases, disorders or conditions such as auto-immune diseases, e.g. Addison's disease, alopecia areata, Ankylosing spondylitis, haemolytic anemia (anemia haemolytica), pernicious anemia (anemia perniciosa), aphthae, aphthous stomatitis, arthritis, arteriosclerotic disorders, osteoarthritis, rheumatoid arthritis, aspermiogenese, asthma bronchiale, auto-immune asthma, auto-immune hemolysis, Bechet's disease, Boeck's disease, inflammatory bowel disease, Burkitt's lymphoma, Chron's disease, chorioiditis, colitis ulcerosa, Coeliac disease, cryoglobulinemia, dermatitis herpetiformis, dermatomyositis, insulin-dependent type I
  • the method of the invention comprises simultaneous administration of the chemical compound having selective IKc a inhibitory activity and a pharmaceutically effective amount of a conventional immune suppressing agent.
  • the immune-suppressing agent is Amphotericin, Busulphan, Co-trimoxazole, Chlorambucil, colony stimulating factors, corticosteroids, Cyclophosphamide, Fluconazole, folinic acid, Ganciclovir, antilymphocyte immunoglobulins, normal immunoglobulins, Methotrexate, Methylprednisolone, Octreotide, Oxpentifylline, Tacrolimus (FK506), Thalidomide, Zolimomab aritox, or the calcineurin inhibitors (protein phosphatase 2B inhibitors), in particular Cyclosporin.
  • the calcineurin inhibitors protein phosphatase 2B inhibitors
  • suitable dosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and especially 30-100 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
  • Lymphocytes from two individuals are mixed together in tissue culture for several days. Lymphocytes from incompatible individuals will stimulate each other to produce TH1 cytokines, whereas those from compatible individuals will not.
  • the lymphocytes from one of the individuals are inactivated (usually by treatment with Mitomycin C or by radiation) thereby allowing only the untreated remaining population of cells (the effector cells) to produce TH1 cytokines in response to foreign histocompatibility antigens.
  • the frequency of effector cells are expanded.
  • the effector cells generated in the primary MLC are restimulated with fresh responder cells, and is a much more rapid and robust immune response than the primary MLC.
  • Spleens are harvested sterilely from DBA/2 mice (available from Jackson Laboratory) and dispersed into single cell suspensions. Red blood cells are lysed with standard lysis buffer in a 12 ml test tube, using approx. 5 ml of buffer per spleen. The test tube is incubated for 2-3 minutes at room temperature.
  • DBA/2 stimulator cells are resuspended in 1 ml RPMI media (available from Life Technologies Inc.) containing 25 mg/ml Mitomycin C, and incubate for 30 minutes at 37°C. The DBA/2 stimulator cells are washed three times with media.
  • Spleens are harvested sterilely from C57/BL6 mice (available from Jackson Laboratory) and dispersed into single cell suspensions. Red blood cells are lysed with standard lysis buffer, and the pellet of spleen resuspended in lysis buffer in a 12 ml test tube, using approx. 5 ml of buffer per spleen. The test tube is incubated for 2-3 minutes at room temperature. Cell culture medium is added to fill the test tube, and the tube is spun for approx. 5 minutes at 280 x g, and the supernatant discarded. The pellet is washed again and resuspended in cell culture medium.
  • the spleen cells are counted, and the number of DBA/2 stimulator cells is adjusted to 3 x10 6 /ml in media, and the number of C57/BL6 effector cells is adjusted to 1 x10 6 /ml in media.
  • 100 ⁇ l of each cell suspension is plated in each well in a flat bottom 96- well plate, and the plate is incubated for 36 hours in a 37°C humidified 5% CO 2 incubator.
  • the supernatant is collected and the T cell production of IFN- ⁇ is measured (IFN- ⁇ ELISA).
  • % IFN- ⁇ release was calculated by comparing the IFN- ⁇ release from cells incubated with NS compounds to maximum IFN- ⁇ release cells incubated with vehicle alone (DMSO).

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Abstract

La présente invention concerne l'utilisation d'un groupe particulier de dérivés carbonylamino destinés au traitement ou au soulagement de maladies ou d'états associés à l'immunorégulation.
PCT/DK2002/000427 2001-07-06 2002-06-26 Derives carbonylamino permettant d'obtenir une immunoregulation WO2003004010A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2004026333A1 (fr) * 2002-09-20 2004-04-01 The University Of Adelaide Traitement et diagnostic d'un trouble de la reproduction par mesure ou inhibition de l'interferon-$g(g)
EP1968563A2 (fr) * 2005-12-20 2008-09-17 Icagen, Inc. Procédés de traitement utilisant des composés de triarylméthane
WO2009027292A1 (fr) * 2007-08-24 2009-03-05 Neurosearch A/S Dérivés de carbonylamino utiles pour le traitement de certains troubles inflammatoires
US9428568B2 (en) 2008-11-10 2016-08-30 Boehringer Ingelheim International Gmbh Compositions and methods for modulating cell-cell fusion via intermediate-conductance calcium-activated potassium channels

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WO2000050026A1 (fr) * 1999-02-23 2000-08-31 Icagen, Inc. Antagonistes du canal de gardos
WO2001027070A1 (fr) * 1999-10-12 2001-04-19 F. Hoffmann-La Roche Ag Utilisation de derives carbonylamino contre les troubles du systeme nerveux central

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WO2000050026A1 (fr) * 1999-02-23 2000-08-31 Icagen, Inc. Antagonistes du canal de gardos
WO2001027070A1 (fr) * 1999-10-12 2001-04-19 F. Hoffmann-La Roche Ag Utilisation de derives carbonylamino contre les troubles du systeme nerveux central

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004026333A1 (fr) * 2002-09-20 2004-04-01 The University Of Adelaide Traitement et diagnostic d'un trouble de la reproduction par mesure ou inhibition de l'interferon-$g(g)
EP1968563A2 (fr) * 2005-12-20 2008-09-17 Icagen, Inc. Procédés de traitement utilisant des composés de triarylméthane
EP1968563A4 (fr) * 2005-12-20 2010-05-19 Icagen Inc Procédés de traitement utilisant des composés de triarylméthane
WO2009027292A1 (fr) * 2007-08-24 2009-03-05 Neurosearch A/S Dérivés de carbonylamino utiles pour le traitement de certains troubles inflammatoires
EP2322164A2 (fr) 2007-08-24 2011-05-18 NeuroSearch A/S Dérivés de carbonylamino utiles pour le traitement d'une maladie intestinale inflammatoire
EP2322164A3 (fr) * 2007-08-24 2011-12-07 NeuroSearch A/S Dérivés de carbonylamino utiles pour le traitement d'une maladie intestinale inflammatoire
US8455549B2 (en) 2007-08-24 2013-06-04 Aniona Aps Carbonylamino derivatives useful for the treatment of certain inflammatory disorders
US9428568B2 (en) 2008-11-10 2016-08-30 Boehringer Ingelheim International Gmbh Compositions and methods for modulating cell-cell fusion via intermediate-conductance calcium-activated potassium channels

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