WO2004089415A2 - Therapie combinatoire utilisant un inhibiteur de 11$g(b)-hydroxysteroide deshydrogenase de type 1 et agoniste du recepteur de glucocorticoides pour minimiser les effets secondaires associes a la therapie a base d'agoniste du recepteur de glucocorticoides - Google Patents

Therapie combinatoire utilisant un inhibiteur de 11$g(b)-hydroxysteroide deshydrogenase de type 1 et agoniste du recepteur de glucocorticoides pour minimiser les effets secondaires associes a la therapie a base d'agoniste du recepteur de glucocorticoides Download PDF

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WO2004089415A2
WO2004089415A2 PCT/DK2004/000248 DK2004000248W WO2004089415A2 WO 2004089415 A2 WO2004089415 A2 WO 2004089415A2 DK 2004000248 W DK2004000248 W DK 2004000248W WO 2004089415 A2 WO2004089415 A2 WO 2004089415A2
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phenyl
methyl
methanone
alkyl
pyrazolo
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PCT/DK2004/000248
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WO2004089415A3 (fr
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Gita Camilla Tejlgaard Kampen
Henrik Sune Andersen
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Novo Nordisk A/S
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Priority to JP2006504351A priority Critical patent/JP2006522744A/ja
Priority to EP04725890A priority patent/EP1615667A2/fr
Publication of WO2004089415A2 publication Critical patent/WO2004089415A2/fr
Publication of WO2004089415A3 publication Critical patent/WO2004089415A3/fr
Priority to US11/246,814 priority patent/US20060094699A1/en
Priority to US12/491,659 priority patent/US20090264412A1/en

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Definitions

  • the instant invention involves a combination therapy comprising the administration of an 11 ?-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist for treating some forms of cancer, diseases and disorders having inflammation as a component, and to minimize the side effects associated with glucorticoid receptor agonist therapy.
  • Glucocorticoid receptor agonists are widely used as anti-inflammatory and disease- modifying treatment in a broad spectrum of diseases with an inflammatory component. Glucocorticoid receptor agonists are also used as a component of some forms of cancer chemotherapy. However, the use of glucocorticoid receptor agonists is often limited by severe side effects caused by glucocorticoid receptor agonism in organs and tissues that are not targets for treatment. These side effects include osteoporosis, decreased linear growth (children), aseptic bone necrosis, cushingoid fat distribution, mental changes, insulin resistance, hypertension, myopathy, cataract and glaucoma (Harrison's Principles of Internal Medicine, 14 th edition, Eds. Fauci et al., McGraw-Hill, New York, USA).
  • glucocorticoid receptor agonists Like the endogenous active glucocorticoids (e.g. cortisol in humans, corticosterone in rodents), glucocorticoid receptor agonists bind to and stimulate ubiquitously expressed in- tracellular glucocorticoid receptors. Hence, the degree of receptor agonism depends on the intracellular concentration of ligand (reviewed e.g. in Yudt & Cidlowski, Mol Endocrinol; 16, 1719 (2002)).
  • 11 ?-hydroxysteroid dehydrogenase type 1 (11 ?-HSD1) is an intracellular enzyme that physiologically catalyses the conversion of biologically inactive endogenous glucocorti- coid (e.g. cortisone in man, 11-dehydrocorticosterone in rodents) to active glucocorticoid (e.g. cortisol in man, corticosterone in rodents).
  • 11 ?-HSD1 is expressed in several tissues and organs including the liver, adipose tissue, skeletal muscle, bone, pancreas, endothelium, ocular tissue and certain parts of the central nervous system.
  • 11/?-HSD1 serves to increase the local levels of active endogenous glucocorticoid in many of the tissues and or- gans that are the origin of the side effects (but not the beneficial effects) of treatment with glucocorticoid receptor agonists(Tannin et al., J. Biol. Chem., 266, 16653 (1991); Bujalska et al., Endocrinology, 140, 3188 (1999); Whorwood et al., J. Clin. Endocrinol. Metab., 86, 2296 (2001); Cooper et al., Bone, 27, 375 (2000); Davani et al., J. Biol.
  • the degree of stimulation of the glucocorticoid receptor will reflect the sum of contributions from the active endogenous glucocorticoid generated locally by 11 7-HSD1, the active endogenous glucocorticoid derived from plasma and the exogenous glucocoid receptor agonist. Consequently, inhibition of 11 ?-HSD1 decreases the total stimulation of the glucocorticoid receptor. Due to the expression pattern of 11 ?-HSD1 , levels of active glucocorticoid are decreased in the tissues and organs that are negatively affected by therapy with glucocorticoid receptor agonists while the desired therapeutic effects remain intact.
  • a clinical case report demonstrates that a partial defect in/reduced activity of 11 ?-HSD1 abolishes the obesity and hypertension normally associated with Cushing's disease, i.e. increased pituitary ACTH secretion resulting in increased synthesis of cortisol in the adrenal glands (Tomlinson et al., J. Clin. Endocrinol. Metab., 87, 57 (2002).
  • the instant invention addresses the clinical problems related to side effects of treatment with glucocorticoid receptor agonists by providing a combination therapy comprised of an 11 ?-HSD1 inhibitor and a glucocorticoid receptor agonist.
  • a combination therapy comprised of an 11 ?-HSD1 inhibitor and a glucocorticoid receptor agonist.
  • the 11 ?-HSD1 inhibitor together with the glucocorticoid receptor agonist allow for control of the disease while minimizing the side effects.
  • dosage of the glucocorticoid receptor agonist can be optimized to meet the required therapeutic effect, providing improved means of achieving the desired clinical result.
  • inhibitors and/or modulators of the human 11 ?-hydroxysteroid dehydrogenase type 1 enzyme can be found in WO 01/90090, WO 01/90091 , WO 01/90092, WO 01/90093, WO 01/90094, WO 02/72084 and WO 02/076435, as well as the following patent applications under common ownership of the present application: PA 2003 00569 filed 11 April 2003 DK, PA 2003 00565 filed 11 April 2003 DK, PA 2003 00571 filed 11 April 2003 DK, PA 200300570 filed 11 April 2003 DK, PA 2003 00566 filed 11 April 2003 DK, PA 200300972 filed 27 June 2003 DK, PA 2003 00998 filed 02 July 2003 DK, PA 2003 00988 filed 30 June 2003 DK, PA 200300989 filed 30 June 2003 DK, PA 2003 00990 filed 30 June 2003 DK, and PA 200301910 filed 22 December 2003 DK, the contents of which are hereby incorporated by reference in their entirety.
  • An object of the present invention is to provide a novel combination therapy com- prised of a therapeutically effective amount of a glucocorticoid receptor agonist in combination with an 11jff-hydroxysteroid dehydrogenase type 1 (11 jff-HSDI) inhibitor for the reduction of undesirable side effects occurring during glucocorticoid receptor agonist therapy, and for treating some forms of cancer, diseases and disorders having inflammation as a component.
  • 11jff-HSDI 11jff-hydroxysteroid dehydrogenase type 1
  • halo includes fluorine, chlorine, bromine, and iodine.
  • trihalomethyl includes trifluoromethyl, trichloromethyl, tr ibromomelhyl, and triiodomethyl.
  • trihalomethoxy includes trifluorometoxy, trichlorometoxy, tribromometoxy, and triiodometoxy.
  • alkyl includes C ⁇ -C 6 straight chain saturated and methylene aliphatic hydrocarbon groups, C 3 -C 6 branched saturated hydrocarbon groups having the specified num- ber of carbon atoms.
  • this definition shall include but is not limited to methyl
  • alkenyl includes C 2 -C 6 straight chain unsaturated aliphatic hydrocarbon groups and branched C 3 -C 6 unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyi, methylpropenyl, methylbutenyl and the like.
  • alkynyl includes C 2 -C 6 straight chain unsaturated aliphatic hydrocarbon groups and C 4 -C 6 branched unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylbutynyl, and the like.
  • saturated or partially saturated cyclic, bicyclic or tricyclic ring system represents but are not limit to aziridinyl, pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, morpholinyl, piperidinyl, thiomorpholinyl, piperazinyl, phthalimide, 1,2,3,4- tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinoxalinyl, and indolinyl.
  • saturated or partially saturated cyclic ring system represents but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cydoheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl or tetrahydropyranyl.
  • saturated or partially saturated aromatic ring system represents but are not limited to cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl or pyrimidinyl.
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep- tyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyI, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like
  • cycloalkylalkyl e.g. cyclopropylmethyl, cyclobutylethyl, adamantylmethyl and the like
  • cycloalkenyl e.g.
  • cyclobutenyl represents a partially saturated, mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms.
  • heteroalkyl (tetrahydrofuranyl, tetrahydropyranyl, tertahydrothiopyranyl, and the like) represents a saturated mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms and one or two additional heteroatoms or groups selected from nitrogen, oxygen, sulphur, SO or S0 2 .
  • alkyloxy (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
  • alkyloxyalkyl (e.g. methyloxymethyl and the like) represents an alkyloxy group as defined above attached through an “alkyl” group.
  • aryloxyhetaryl e.g. 2-phenoxy-pyridyl and the like
  • aryloxy e.g. phenoxy, naphthyloxy and the like
  • hetaryloxy e.g. 2-pyridyloxy and the like
  • arylalkyloxy e.g. phenethyloxy, naphthylmethyloxy and the like
  • hetarylalkyloxy (e.g. 2-pyridylmethyloxy and the like) represents a hetarylalkyl group as defined below attached through an oxygen bridge.
  • alkyloxycarbonyl e.g. methylformiat, ethylformiat and the like
  • alkyloxycarbonyl represents an alkyloxy group as defined above attached through a carbonyl group.
  • aryloxycarbonyl e.g. phenylformiat, 2-thiazolylformiat and the like
  • aryloxycarbonyl represents an aryloxy group as defined above attached through a carbonyl group.
  • arylalkyloxycarbonyl e.g. benzylformiat, phenyletylformiat and the like
  • arylalkyl represents an "arylalkyloxy” group as defined above attached through a carbonyl group.
  • arylalkyl e.g. benzyl, phenylethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like
  • hetarylalkyl e.g. (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3- thienyl)methyl, (2-pyridyl)methyl, 1 -methyl-1 -(2-pyrimidyI)ethyl and the like
  • hetarylalkyl represents a hetaryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • alkylcarbonyl e.g. octylcarbonyl, pentylcarbonyl, 3-hexenylcarbonyl
  • alkylcarbonyl represents an alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
  • arylcarbonyl e.g. benzoyl
  • arylcarbonyl represents an aryl group as defined below attached through a carbonyl group.
  • hetarylcarbonyl e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like
  • hetarylcarbonyl represents a hetaryl group as defined below attached through a carbonyl group.
  • carbonylalkyl e.g. acetyl and the like
  • carbonylalkyl represents a carbonyl group attached through alkyl group as defined above having the indicated number of carbon atoms.
  • alkylcarbonylalkyl e.g. propan-2-one, 4,4-dimethyl-pentan-2-one and the like
  • alkylcarbonylalkyl represents an alkylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylcarbonylalkyl e.g. 1-phenyl-propan-1-one, 1-(3-chloro-phenyl)-2- methyl-butan-1-one and the like
  • hetarylcarbonylalkyl e.g. 1-pyridin-2-yl-propan-1-one, 1-(1-H-imidazol-2- yl)-propan-1-one and the like
  • hetarylcarbonylalkyl represents a hetarylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylalkylcarbonyl e.g. phenylpropylcarbonyl, phenylethylcarbonyl and the like
  • hetarylalkylcarbonyl e.g. imidazolylpentylcarbonyl and the like
  • alkyl group is in turn attached through a carbonyl.
  • alkylcarboxy e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy
  • alkylcarboxy represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • arylcarboxy (e.g. benzoic acid and the like) represents an arylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • alkylcarboxyalkyl e.g. heptylcarboxymethyl, propylcarboxy fe/t-butyl, 3- pentylcarboxyethyl
  • arylalkylcarboxy e.g. benzylcarboxy, phenylpropylcarboxy and the like
  • arylalkylcarboxyalkyl e.g. benzylcarboxymethyl, phenylpropylcarboxypro- pyl and the like
  • arylalkylcarboxyalkyl represents an arylalkylcarboxy group as defined above wherein the carboxy group is in turn attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • hetarylcarboxy e.g. pyridine-2-carboxylic acid and the like
  • hetarylalkylcarboxy e.g. (1-H-imidazol-2-yl)-acetic acid, 3-pyrimidin-2-yl- propionic acid and the like
  • hetarylalkylcarboxy represents a hetarylalkyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • alkylthio e.g. methylthio, ethylthio and the like
  • arylthio e.g. benzenthiol, naphthylthiol and the like
  • hetarylthio e.g. pyridine-2-thiol, thiazole-2-thiol and the like
  • arylthioalkyl e.g. methylsulfanyl benzene, ethylsulfanyl naphthalene and the like
  • alkyl group having the indicated number of carbon atoms.
  • hetarylthioalkyl e.g. 2-methylsulfanyl-pyridine, 1-ethylsulfanyI-isoquinoline and the like
  • hetarylthioalkyl represents a hetarylthio group as defined below attached through an alkyl group having the indicated number of carbon atoms.
  • hetaryloxyaryl e.g. 1-phenoxy-isoquinolyl, 2-phenoxypyridyl and the like
  • aryloxyaryl represents a hetaryloxy group as defined above attached through an “aryl” group as defined below.
  • hetaryloxyhetaryl e.g. 1-(2-pyridyloxy-isoquinoline), 2-(imidazol-2-yloxy- pyridine) and the like
  • hetaryloxyhetaryl represents a hetaryloxy group as defined above attached through a "hetaryl” group as defined below.
  • aryloxyalkyl e.g. phenoxymethyl, naphthyloxyethyl and the like
  • aryloxyaryl e.g. 1-phenoxy-naphthalene, phenyloxyphenyl and the like
  • aryloxy group as defined above attached through an "aryl” group as defined below.
  • arylalkyloxyalkyl (e.g. ethoxymethyl-benzene, 2-methoxymethyl- naphthalene and the like) represents an arylalkyloxy group as defined above attached through an “alkyl” group having the indicated number of carbon atoms.
  • hetaryloxyalkyl e.g. 2-pyridyloxymethyl, 2-quinolyloxyethyl and the like
  • hetaryloxyalkyl represents a hetaryloxy group as defined above attached through an “alkyl” group having the indicated number of carbon atoms.
  • hetarylalkyloxyalkyl (e.g. 4-methoxymethyl-pyrimidine, 2-methoxymethyl- quinoline and the like) represents a hetarylalkyloxy group as defined above attached through an "alkyl” group having the indicated number of carbon atoms.
  • alkylcarbonylamino (e.g. methylcarbonylamino, cyclopentylcarbonyl- aminomethyl, methylcarbonylaminophenyl) represents an "alkylcarbonyl” group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen atom may itself be substituted with an alkyl or aryl group.
  • alkylcarbonylaminoalkyl e.g.N-propyl-acetamide, N-butyl-propionamide and the like
  • alkylcarbonylamino represents an "alkylcarbonylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylalkylcarbonylamino e.g. phenylacetamide, 3phenyl-propionamide and the like
  • arylalkylcarbonylamino represents an “arylalkylcarbonyl” group as defined above attached through an amino group.
  • arylalkylcarbonylaminoalkyl e.g. N-ethyl-phenylacetamide, N-butyl-3- phenyl-propionamide and the like
  • arylcarbonylamino represents an "arylcarbonylamino” group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylcarbonylamino e.g. benzamide, naphthalene-1 -carboxylic acid amide and the like
  • arylcarbonylaminoalkyl e.g. N-propyl-benzamide, N-Butyl-naphthalene-1- carboxylic acid amide and the like
  • arylcarbonylaminoalkyl represents an "arylcarbonylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • aryl includes but is not limited to a carbocyclic aromatic ring system being either monocyclic, bicyclic, or polycyclic, such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic sys- terns enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like.
  • heteroaryl includes but is not limited to pyrrolyl (2-pyrrolyl), pyrazolyl (3- pyrazolyl), imidazolyl (1 -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3- triazol-1-yl, 1 ,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yI), oxazolyl (2-oxazolyl, 4- oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl (2-thiophenyl, 3-thiophenyl, 4-thiophenyl, 5-thiophenyl), furanyl (2-fur
  • NR 4 R 5 carbonylalkyl e.g. V, V-dimethyl- propionamide, /V-isopropyl-N-methyl-propionamide and the like
  • alkylR 6 alkyl e.g. 2-ethoxymethyl, N-ethyl-N- methy amine, methyl-propyl-amide, ethanesulfonic acid methylamide and the like
  • R 6 represents an alkyl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above, wherein R 6 is as defined for Formula II herein.
  • arylR 6 alkyl e.g. ethoxy-benzene, ethyl-methyl- phenyl-amine, ⁇ /-ethyl-benzamide, ⁇ /-isobutyl-benzenesulfonamide and the like
  • R 6 represents an aryl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above, wherein R 6 is as defined for Formula II herein.
  • arylalkylR 6 alkyl e.g.
  • benzyloxymethyl, ethyl- methyl-benzyl-amine, ⁇ /-ethyl-benzylamide and the like represents an arylalkyl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above, wherein R 6 is as defined for Formula II herein.
  • R 6 is as defined for Formula II herein.
  • hetarylR 6 alkyl e.g.
  • 2-ethoxy-1 /-/-imidazol, ethyI-quinolin-2-yl-amine, thiazole-2-carboxylic acid, methyl-propyl-amide, pyridine-3-sulfonic acid isobutyl-amide and the like) represents a hetaryl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above, wherein R 6 is as defined for Formula II herein.
  • arylcarbonylNR 15 e.g. ⁇ /-benzyl- ⁇ /-methyl- benzamide and the like
  • alkylSO n (e.g. ethylsulfonyl, ethylsulfinyl and the like) represents an alkyl group as defined above, wherein the alkyl group is in turn at- tached through a sulphur bridge wherein the sulphur is substituted with n oxygen atoms, wherein n is as defined for Formula II herein.
  • arylSO m (e.g. phenylsulfinyl, naphthyl-2-sulfonyl and the like) represents an aryl group as defined above, wherein the aryl group is in turn attached through a sulphur bridge wherein the sulphur is substituted with m oxygen atoms, wherein m is as defined for Formula II herein.
  • hetarylSO m (e.g. thiazol-2-sulfinyl, pyridine-2- sulfonyl and the like) represents a hetaryl group as defined above, wherein the hetaryl group is in turn attached through a sulphur bridge wherein the sulphur is substituted with m oxygen atoms, wherein is as defined for Formula II herein.
  • arylSO m NR 8 e.g.
  • NR 4 R 5 carbonylalkyl (e.g.
  • ⁇ /, ⁇ -dimethyl- propionamide, ⁇ /-isopropyl- ⁇ /-methyl-propionamide and the like represents NR R 5 substituted by a carbonylalkyl group as defined above, wherein R 4 and R 5 are as defined for Formula V herein.
  • arylR 8 alkyl e.g. ethoxy-benzene, N-ethyl-N- methyl-phenyl-amine, ⁇ /-ethyl-benzamide, /V-isobutyl-benzenesutfonamide and the like
  • R 8 represents an aryl group as defined above, substituted by R 8 , which is substituted by an alkyl group as defined above, wherein R 8 is as defined for Formula V herein.
  • hetaryl R 8 alkyl e.g. 2-ethoxy-1H-imidazol, ethyl-quinolin-2-yl-amine, thiazole-2-carboxylic acid, methyl-propyl-amide, pyridine-3-sulfonic acid isobutyl-amide and the like
  • R 8 represents a hetaryl group as defined above, substituted by R 8 , which is substituted by an alkyl group as defined above, wherein R 8 is as defined for Formula V herein.
  • arylcarbonylNR 15 (e.g. ⁇ /-benzyl- ⁇ /-methyl- benzamide and the like) represents an arylcarbonyl group as defined above, substituted by NR 15 , wherein R 15 is as defined for Formula V herein.
  • treatment is defined as the management and care of a patient for the purpose of combating or alleviating the disease, condition or disorder, and the term includes the administration of the active compound to prevent the onset of the symptoms or complica- tions, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • pharmaceutically acceptable is defined as being suitable for administration to humans without adverse events.
  • prodrug is defined as a chemically modified form of the active drug, said prodrug being administered to the patient and subsequently being converted to the active drug. Techniques for development of prodrugs are well known in the art.
  • the term "combination therapy” is defined as the administration of a single pharmaceutical dosage formulation which comprises the 11 ?-HSD1 inhibitor and the glucocorticoid receptor agonist, as well as administration of each active agent in its own separate pharma- ceutical dosage formulation. Where separate dosage formulations are used, the 11 7-HSD1 inhibitor and the glucocorticoid receptor agonist can be administered to the patient at essentially the same time, i.e. concurrently, or at separate staggered times, i.e. sequentially. When given by different dosage formulations, the route of administration may be the same or different for each agent. Any route of administration known or contemplated for the individual agents is acceptable for the practice of the present invention.
  • the term "therapeutically effective amount” is defined as the amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system or a mammal that is sought by the treating individual, i.e. medical doctor or other clinician.
  • modulation are intended to include stimulation (e.g., increasing or upregulating a particular response or activity) and inhibition (e.g., decreasing or downregulating a particular response or activity).
  • agonist is intended to indicate a substance that activates the receptor(s).
  • glucocorticoid receptor agonist is intended to indicate a substance that activates glucocorticoid receptor(s) without dependence on prior modification of the substance by 11 ⁇ HSD1.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I)
  • R 6 and R 7 independently are C ⁇ -C ⁇ alkyl, C 3 -C 10 cycloalkyl, hetC 3 -C ⁇ 0 cycloalkyl, arylCrC 6 alkyl or hetarylC C 6 alkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R 10 ; or
  • R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC 6 alkyl, aryl, hetaryl, arylC C 6 alkyl, halo, hydroxy, oxo, C C 6 alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d- C 6 alkyloxyCrC 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy, hetarylcarboxy
  • R 8 and R 9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C 3 -C 10 cycloalkyl, C 3 - C 10 hetocycloalkyl, d-Cealkyl, d-Cealkyloxy, trihalomethyl, trihalomethoxy, aryld-Cealkyloxy, hetarylC C 6 alkyloxy, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C 6 alkylcarboxy, arylcarboxy, hetarylcarboxy, aryld-Ce- alkylcarboxy, hetarylCrC 6 alkylcarboxy, CrC 6 alkylcarbonylamino or arylCrC 6 alkylcarbonyl-
  • R 10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, Ci- Cealkyl, CrC 6 aIkyloxy, trihalomethyl, trihalometh dialkylamino oxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy or arylCrC 6 alkylcarboxy;
  • R 11 is d-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryld-Cealkyl, hetarylCrCealkyl, d-C 6 alkyl- carbonylCrC 6 alkyl, CrC 6 alkyloxy, aryloxy, CrC 6 alkyloxy, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonylCrC 6 alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 ;
  • R 2 is CrC 6 alkylcarbonyIaminoCrC 6 alkyl, arylcarbonylaminoCrC 6 alkyl or arylCrC 6 alkyl- carbonylaminoCrC 6 alkyl;
  • R 13 and R 14 independently are hydrogen, oxo, C 3 -C 10 cycloalkyl, CrC 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylCrCealkylcarbonyl;
  • R 15 is hydrogen, C 3 -C 10 cycloalkyl, CrC 6 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, CrC 6 alkyloxyalkyl or arylGrC 6 alkyloxyalkyl; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • R 3 and R 5 independently are hydrogen, NR 13 R 14 trihalomethyl, trihalomethoxy, d-Cealkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, CrC 6 alkyloxy, CrC 6 alkylthio, aryl, arylCrC 6 alkyl, hetaryl or hetarylCrCealkyl, wherein alkyl, alkynyl, alkenyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R 8 ;
  • R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC ⁇ alkyl, aryl, hetaryl, aryld- C 6 alkyl, halo, hydroxy, oxo, CrC 6 alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d-C 6 - alkyloxyd-C 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy, hetaryl
  • R 8 and R 9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C 3 -d -cycloalkyl, C 3 - dohetocycloalkyl, d-C 6 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC 6 aIkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, aryld- C 6 alkylcarboxy, hetarylCrC 6 alkylcarboxy, d-Cealkylcarbonylamino or arylCrC 6 alkyl- carbonylamino;
  • R 10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, Ci- Cealkyl, CrC 6 alkyloxy, trihalomethyl, trihalometh dialkylamino oxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C 6 alkylcarbonyl, hetarylCrC 6 alkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy or aryld- C 6 alkylcarboxy;
  • R 11 is Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, arylCrC 6 alkyl, hetaryld-Cealkyl, C C 6 alkyl- carbonylCrC 6 alkyl, d-C 6 alkyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonylCrC 6 - alkyl, wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 ;
  • R 12 is CrC 6 alkylcarbonylaminoCrC 6 alkyl, arylcarbonylaminoCrC 6 alkyl or arylCrC 6 alkyl- carbonylaminoCrC 6 alkyl;
  • R 13 and R 14 independently are hydrogen, oxo, C 3 -C 10 cycloalkyl, CrC 6 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethoxy, arylCrCealkyloxy, hetaryld-Cealkyloxy, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy;
  • R 15 is hydrogen, C 3 -C ⁇ 0 cycloalkyl, CrCealkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC 6 alkyl, CrC 6 alkyloxyalkyl or arylCrC 6 alkyloxyalkyl; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • said substituted pyrazoIo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 3 and R 5 independently are hydrogen, trihalomethyl, CrC 6 alkyl, CrC 6 alkyloxy, aryl, arylCrC 6 alkyl, hetaryl or hetaryld-Cealkyl, wherein alkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R 8 .
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 6 and R 7 independently are CrC 6 alkyl, C 3 -C ⁇ 0 cycloalkyl, hetC 3 - Ciocycloalkyl, arylCrC 6 alkyl or hetarylCrCealkyl, wherein the alkyl, cycloalkyl, hetcycloalkyl, arylalkyl, and hetarylalkyl groups independently are optionally substituted with one or more of R 10 .
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I)
  • R 6 and R 7 together with the nitrogen to which they are attached are form- ing a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of C ⁇ -C ⁇ alkyl, aryl, hetaryl, arylCrC 6 alkyl, halo, hydroxy, oxo, CrC 6 alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, d- C 6 alkyloxyCrC 6 alkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl,
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional nitrogen atoms, the ring system optionally being substituted with at least one of CrCealkyl, aryl, hetaryl, aryld-Cealkyl, halo, hydroxy, oxo, CrC 6 alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 8 and R 9 independently are hydrogen, halo, hydroxy, oxo, cyanoC 3 -C 10 cycloalkyl, G 3 -dohetocycloalkyl, d-Cealkyl, C C 6 alkyloxy, trihalomethyl, aryld- C 6 alkyloxy, hetarylCrCealkyloxy.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C 3 -d 0 cyclo- alkyl, C 3 -C ⁇ 0 hetcycloalkyl, d-Cealkyl, CrC e alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 11 is d-Cealkyl, arylCrC 6 aIkyl, hetarylCrCealkyl, CrC 6 alkyloxy, aryloxy, CrC 6 alkyIoxy, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 .
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 12 is CrC 6 alkylcarbonylaminoCrC 6 alkyl, arylcarbonylaminod- C 6 alkyl or arylCrCealkylcarbonylaminoCrC ⁇ alkyl.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 13 and R 14 independently are hydrogen, C 3 -C ⁇ 0 cycloalkyl, Ci- Cealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is of the general formula (I) wherein R 15 is hydrogen, C 3 -C ⁇ 0 cycloalkyl, d-C 6 alkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, d-C 6 alkyloxyalkyl or aryld-C 6 alkyloxyaIkyl.
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is selected from the group consisting of: (3-Bromo-5-thiophen-2-yl-7-trifluoromethyl-pyrazolo[1 ,5-a]pyrimidin-2-yl)-(2,6-dimethyl- piperidin-1 -yl-)methanone;
  • said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is selected from the group of
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II)
  • R 1 is C 3 -C ⁇ ocycloalkyl, C 3 -C 10 hetcycloalkyl, CrC 8 alkyl, aryl, hetaryl, aryld-C 6 alkyl or hetarylCrCealkyl, wherein the cycloalkyl, hetcycloalkyl, alkyl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R 4 .
  • R 2 is hydrogen, d-C 8 alkyI, aryl, hetaryl, arylCrCealkyl, C 3 -C ⁇ ocycloalkylCrC 6 alkyl, d- C 6 alkyl-carboxyCrC 6 alkyl wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R 5 ; or
  • R 1 and R 2 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C C 8 alkyl, aryl, hetaryl, aryld- C 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, aryld-Cealkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-Cealkylcarbox
  • R 3 is CrC 8 alkyl, d-C 6 alkenyl, C ⁇ -C 6 alkynyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, hetaryl, arylCrC 6 alkyl, d-Cealkyloxyd-Cealkyl, hetarylCrCealkyl, aryl-R 6 -CrC 6 alkyI, hetaryl- R 6 -CrC 6 alkyl or arylCrCealkyl-R ⁇ CrCealkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 ;
  • R 4 and R 5 independently are hydrogen, hydroxy, oxo, cyano, halo, methylendioxo, NR 8 R 9 , CrC 8 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethyloxy, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 0 hetcyclo- alkyl, C 3 -C ⁇ 0 cycloalkenyl, aryl, hetaryl, hetarylSO n , arylCrCealkyloxy, hetaryld-Cealkyloxy, CrC 6 alkyl-R 6 -C ⁇ -C 6 alkyl, arylCrC 6 alkyl-R 6 -CrC 6 alkyl, C r C 6 alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrC
  • R° is oxygen, sulphur, SO n or NR 16.
  • R 7 is hydrogen, halo, hydroxy, cyano, nitro, COOR 17 , d-C 8 alkyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 0 het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylCrC 6 alkyl, CrCealkyloxy, CrCealkyloxyCrCealkyl, aryloxy, arylCrCealkyloxy, aryloxyd-Cealkyl, arylCrC 6 alkyloxyCr C 6 alkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCrCealkyl, he-aryld-Ce
  • R 8 and R 9 independently are hydrogen, CrC 8 alkyl, aryl, hetaryl, aryld-C 6 alkyl or hetaryld- Cealkyl wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 11 ; or
  • R 8 and R 9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, CrC 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetaryld-Cealkyl, hydroxy, oxo, CrC 6 alkyloxy, aryld-Cealkyloxy, hetaryld- Cealkyloxy, CrC 6 alkyloxyC 1 -C 6 alkyl ) d-C 6 alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C 6 alkyl
  • R 10 and R 11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, CrC 8 alkyl, d- C 6 alkyloxy, NR 12 R 13 , methylendioxo, trihalomethyl or trihalomethyloxy;
  • R 12 and R 13 independently are hydrogen, d-C 8 alkyl or arylCrC 6 alkyl
  • R 14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C 8 alkyl, d-C 6 alkyloxy or aryloxy;
  • R 15 is hydrogen, halo, hydroxy, oxo, nitro, cyano, CONR 8 R 9 or COOR 17 ;
  • R 16 is hydrogen, CrC 8 alkyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrCealkyl, alkylcarbonyl, arylcarbonyl, arylCrC 6 alkylcarbonyl, aryloxyd- Cealkyl, hetaryloxyCrC 6 alkyl, arylthioCrCealkyl or hetarylthioCrC 6 alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 10 ;
  • R is hydrogen, CrC ⁇ alkyl, aryl or arylCrCealkyl
  • R 18 is CrCealkyl, C 2 -C 6 alkenyl, aryl, arylCrC 6 alkyI, hetaryl, hetarylCrCealkyl, C 3 - Ciocycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, CrC 6 alkyloxy, aryloxy, arylCrCealkyloxy, aryld- CealkyIoxyC ⁇ -C 6 alkyl, hetaryloxy, hetarylCrC 6 alkyloxy, hetarylCrCealkyloxyCrCealkyl or R 8 R 9 NCrC 6 alkyl wherein the alkyl, alkenyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally substituted with R 15 ;
  • R 19 is CrC 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetaryld-Cealkyl;
  • n 1 or 2;
  • n 0, 1 or 2;
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein: R 1 is C 3 -Ci 0 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, d-C 8 alkyl, aryl, hetaryl, aryld-C 6 alkyl or hetaryld-Cealkyl, wherein the cycloalkyl, hetcycloalkyl, alkyl, arylalkyl and hetarylalkyl groups independently are optionally substituted with one or more of R 4 ;
  • R 2 is hydrogen, C C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, C 3 -C ⁇ 0 cycloalkylCrC 6 alkyI, C C 6 - alkylcarboxyCrC 6 alkyl wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R 5 ; or
  • R 1 and R 2 are together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC 8 alkyl, aryl, hetaryl, aryld- C 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, aryld-C 6 alkyloxy, hetaryld- Cealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, aryl
  • R 3 is CrC 8 alkyl, CrC 6 alkenyl, CrC 6 alkynyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, hetaryl, arylCrC 6 alkyl, CrCealkyloxyCrCealkyl, hetarylCrCealkyl, aryl-R 6 -CrC 6 alkyl, hetaryl- R 6 -CrC 6 alkyl or arylC ⁇ -C6alkyl-R 6 -CrC 6 alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 ;
  • R 4 and R 5 independently are hydrogen, hydroxy, oxo, cyano, halo, methylendioxo, NR 8 R 9 , CrC 8 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethyloxy, C 3 -C ⁇ 0 cycloalkyl, C 3 -
  • Ciohetcycloalkyl C 3 -C ⁇ 0 cycloalkenyl, aryl, hetaryl, hetarylSO n , arylCrC 6 alkyloxy, he-aryld- C 6 alkyloxy, CrC 6 alkyl-R 6 -CrCealkyl, arylC ⁇ -C 6 alkyl-R 6 -CrC 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrC 6 alkyl-carbonyl, C ⁇ -C 6 alkylSO n , CrC 6 alkyl-carboxy, arylcarboxy, hetarylcarboxy, arylCrC 6 alkylcarboxy or hetarylCrC 6 alkyl- carboxy wherein the alkyl, cycloalkyl,
  • R 8 is oxygen, sulphur, SO n , NR 16 ;
  • R 7 is hydrogen, halo, hydroxyl, cyano, nitro, COOR 17 , CrC 8 alkyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 0 het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyl, trihalomethyloxy, aryl, arylCrCealkyl, CrC 6 alkyloxy, CrCealkyloxyCrCealkyl, aryloxy, aryloxyCrC 6 alkyl, arylCrCealkyloxyCrCealkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCrCealkyl, hetarylCrCealkyloxyCrCealkyl, NR 8 R 9 , S0 2 NR 8 R 9
  • C 6 alkyIR 6 CrC 6 alkyl wherein the aryl and hetaryl groups independently are optionally substituted with one or more R 10 ;
  • R 8 and R 9 independently are hydrogen, CrC 8 alkyl, aryl, hetaryl, arylCrCealkyl or hetaryld- C 6 alkyl wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 11 ; or
  • R 8 and R 9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one d-C 8 alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC 6 alkyl, hydroxy, oxo, CrC 6 alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d- CealkyloxyCrCealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC 6 alkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy,
  • R 10 and R 11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, d-Cealkyl, d-C 6 - alkyloxy, NR 12 R 13 , methylendioxo, trihalomethyl or trihalomethyloxy;
  • R 12 and R 13 independently are hydrogen, C ⁇ -C 8 alkyl or arylCrC 6 alkyl
  • R 14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, C C 8 alkyl, CrC 6 alkyloxy or aryloxy;
  • R 15 is hydrogen, halo, hydroxy, oxo, nitro, cyano or COOR 17 ;
  • R 16 is hydrogen, CrC 8 alkyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrCealkyl, alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, aryloxyd- C 6 alkyl, hetaryloxyCrCealkyl, arylthioCrC 6 alkyl or hetarylthioCrC 6 alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 10 ;
  • R 17 is hydrogen, CrC 8 alkyI, aryl or aryld-C 6 alkyl
  • n 1 or 2;
  • n 0, 1 or 2; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 1 is C 3 -C ⁇ 0 cycloalkyl or C 3 -C ⁇ ohetcycloalkyl wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 4 as defined above.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 1 is C 3 -C ⁇ 0 cycloalkyl optionally substituted with one or more of R 4 as defined above.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 2 is hydrogen or d-C 8 alkyl, wherein the the alkyl group is optionally substituted with one or more of R 5 as defined above.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 2 is d-G 8 alkyl optionally substituted with one or more of R 5 as defined above.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is o the general formula (II) wherein R 3 is C 3 -C 10 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, hetaryl, arylC C 6 alkyl, hetaryld- Cealkyl, aryl-R 6 -CrC 6 alkyl, hetaryI-R 6 -CrC 6 alkyl or arylCrC 6 alkyl-R 6 -CrC 6 alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 .
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 3 is aryl or hetaryl, wherein the aryl and hetaryl groups are optionally substituted with one or more of R 7 as defined above.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 3 is is phenyl optionally substituted with one or more of R 7 as defined above.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 3 is phenyl optionally substituted independently in position 2(ortho) or 4(para) with one or more of R 7 as defined above.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 4 and R 5 independently are hydrogen, hydroxy, oxo, halo, CrC 8 alkyl, wherein the alkyl group is optionally substituted with one ore more of R 15 .
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 6 is oxygen.
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 7 is hydrogen, halo, hydroxy, cyano, d-C 8 alkyI, C 3 -C 10 cycloalkyl, C 3 -C 10 het- cycloalkyl, trihalomethyl, aryl, arylCrC 6 alkyl, CrC 6 alkyloxy, CrCealkyloxyCrCealkyl, aryloxy, arylCrCealkyloxy, aryloxyCrC 6 alkyl, arylCrCealkyloxyCrCealkyl, hetaryl, hetaryld-Cealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCrCealkyl, hetaryld-Cealkyl-oxy, hetaryl
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 8 and R 9 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 car- bon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system optionally being substituted with at least one halo, cyano, d-C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, CrCealkyloxyd-Cealkyl, CrC 6 alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl,
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 15 is CONR 8 R 9 .
  • said substituted amides, or a pro- drug thereof, as a component of the combination therapy is of the general formula (II) wherein R 18 is d-C 6 alkyl optionally substituted with R 15 .
  • said substituted amide, or a prodrug thereof, as a component of the combination therapy is selected from the group consisting of: 3-(10, 11 -Dihydro-dibenzo[b,f]azepin-5-yl)-1 -[4-(1 H-imidazol-4-yl)-piperidin-1 -yl]-propan-1 - one; 4-(10,11-Dihydro-dibenzo[b,f]azepin-5-yl)-1-[4-(3H-imidazol-4-yl)-piperidin-1-yl]-butan-1-one;
  • Azepan-1-yl-(4-chloro-phenyl)-methanone 3-Heptylcarbamoyl-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid; Adamantan-1 -yl-azepan-1 -yl-methanone;
  • Naphthalene-2-carboxyIic acid (2-oxo-azepan-3-yl)-thiophen-3-ylmethyl-amide; 3,4,5-Trimethoxy-N-(4-methyl-benzyl)-N-[6-(pyridin-2-ylamino)-hexyl]-benzamide; 3-Cyclopentyl-N-(4-methyl-benzyl)-N-[6-(pyridin-2-ylamino)-hexyl]-propionamide;
  • Acetic acid 4-(3,5-dimethyl-piperidine-1-carbonyl)-phenyl ester; (4-Chloro-3-nitro-phenyl)-(2,6-dimethyl-piperidin-1-yl)-methanone;
  • Furan-2-carboxylic acid [4-(4-methyl-piperidine-1 -sulfonyl)-phenyl]-amide;
  • Cyclohexanecarboxylic acid (2-phenylsulfanyl-phenyl)-amide; (4-Hydroxy-4-phenyl-octahydro-quinolin-1-yl)-phenyl-methanone;
  • N-Benzyl-4-bromo-N-ethyl-benzamide (3-Methyl-piperidin-1 -yl)-[4-(naphthalen-1 -yloxymethyl)-phenyl]-methanone;
  • N-Benzyl-N-cyclohex-1-enyl-isonicotinamide 1-[4-(4-Fluoro-phenyl)-piperazin-1-yl]-2-(2-methyl-benzylsulfanyl)-ethanone; 2-(2-Bromo-4-methyl-phenoxy)-N-(2-cyclohex-1-enyl-ethyl)-acetamide;
  • Benzo[b]thiophene-3-carboxylic acid (3,3,5-trimethyl-cyclohexyl)-amide; 2-(2,6-Dimethyl-phenoxy)-N-(2-isopropyl-phenyl)-acetamide;
  • 6-Oxo-6-phenyl-hexanoic acid (4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide; 2-(3,4-Difluoro-phenyl)-N-(4-hydroxy-benzyl)-N-thiophen-2-ylmethyl-acetamide;

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Abstract

L'invention concerne une thérapie combinatoire comprenant l'administration d'un inhibiteur de 11β-hydroxystéroïde déshydrogénase de type 1 et d'un agoniste du récepteur de glucocorticoïdes destinée au traitement de certaines formes de cancer, de maladies et de troubles dont l'inflammation est une composante, et permettant de minimiser les effets secondaires associés à la thérapie à base d'agoniste du récepteur de glucocorticoïdes.
PCT/DK2004/000248 2003-04-11 2004-04-06 Therapie combinatoire utilisant un inhibiteur de 11$g(b)-hydroxysteroide deshydrogenase de type 1 et agoniste du recepteur de glucocorticoides pour minimiser les effets secondaires associes a la therapie a base d'agoniste du recepteur de glucocorticoides WO2004089415A2 (fr)

Priority Applications (4)

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JP2006504351A JP2006522744A (ja) 2003-04-11 2004-04-06 グルココルチコイド受容体アゴニスト療法に伴う副作用を最小化するための、１１β−ヒドロキシステロイドデヒドロゲナーゼ１型阻害剤およびグルココルチコイド受容体アゴニストを使用する併用療法
EP04725890A EP1615667A2 (fr) 2003-04-11 2004-04-06 Therapie combinatoire utilisant un inhibiteur de 11beta-hydroxysteroide deshydrogenase de type 1 et agoniste du recepteur de glucocorticoides
US11/246,814 US20060094699A1 (en) 2003-04-11 2005-10-07 Combination therapy using an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist to minimize the side effects associated with glucocorticoid receptor agonist therapy
US12/491,659 US20090264412A1 (en) 2003-04-11 2009-06-25 Combination Therapy Using An 11beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitor And A Glucocorticoid Receptor Agonist To Minimize The Side Effects Associated With Glucocorticoid Receptor Agonist Therapy

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DKPA200300571 2003-04-11
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DKPA200300566 2003-04-11
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DKPA200300568 2003-04-11
DKPA200300569 2003-04-11
DKPA200300565 2003-04-11
DKPA200300571 2003-04-11
DKPA200300568 2003-04-11
DKPA200300565 2003-04-11
US46736203P 2003-05-02 2003-05-02
US46744303P 2003-05-02 2003-05-02
US46780003P 2003-05-02 2003-05-02
US46736303P 2003-05-02 2003-05-02
US46745303P 2003-05-02 2003-05-02
US46728403P 2003-05-02 2003-05-02
US60/467,284 2003-05-02
US60/467,800 2003-05-02
US60/467,443 2003-05-02
US60/467,453 2003-05-02
US60/467,362 2003-05-02
US60/467,363 2003-05-02
DKPA200300776 2003-05-22
DKPA20030778 2003-05-22
DKPA200300776 2003-05-22
DKPA200300778 2003-05-22
US47519503P 2003-06-02 2003-06-02
US47515703P 2003-06-02 2003-06-02
US60/475,195 2003-06-02
US60/475,157 2003-06-02
DKPA200300972 2003-06-27
DKPA200300972 2003-06-27
DKPA200300988 2003-06-30
DKPA200300988 2003-06-30
DKPA200300990 2003-06-30
DKPA200300989 2003-06-30
DKPA200300990 2003-06-30
DKPA200300989 2003-06-30
DKPA200300998 2003-07-02
DKPA200300998 2003-07-02
US48607803P 2003-07-10 2003-07-10
US48609503P 2003-07-10 2003-07-10
US48609703P 2003-07-10 2003-07-10
US48609403P 2003-07-10 2003-07-10
US48609803P 2003-07-10 2003-07-10
US60/486,098 2003-07-10
US60/486,095 2003-07-10
US60/486,097 2003-07-10
US60/486,094 2003-07-10
US60/486,078 2003-07-10
DKPA200301910 2003-12-22
DKPA200301910 2003-12-22
DKPA200400009 2004-01-06
DKPA200400009 2004-01-06
US53709904P 2004-01-16 2004-01-16
US60/537,099 2004-01-16

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Cited By (94)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005090320A2 (fr) * 2004-03-12 2005-09-29 Wyeth Derives de triazole et leur methode d'utilisation pour traiter les infections par le vih
WO2006023844A2 (fr) * 2004-08-20 2006-03-02 Entremed, Inc. Compositions et procedes comportant des antagonistes de recepteur active par la proteinase
WO2006046915A1 (fr) * 2004-10-29 2006-05-04 Astrazeneca Ab Utilisation de derives insatures de quinoline ou de naphtalene comme medicaments
JP2006522748A (ja) * 2003-04-11 2006-10-05 ノボ　ノルディスク　アクティーゼルスカブ １１β−ヒドロキシステロイドデヒドロゲナーゼ１型化活性化合物
WO2006132436A1 (fr) * 2005-06-08 2006-12-14 Japan Tobacco Inc. Composé hétérocyclique
WO2007025892A1 (fr) 2005-08-31 2007-03-08 F. Hoffmann-La Roche Ag Inhibiteur de la 11-bêta-hydroxystéroïde déhydrogénase-1 des diabètes de type 2-1
WO2006024627A3 (fr) * 2004-08-30 2007-09-13 Janssen Pharmaceutica Nv Derives d'acetamides n-2 adamantanyl-2-phenoxy utilises en tant qu'inhibiteurs de la deshydrogenase 11-beta hydroxysteroide
WO2007117398A2 (fr) * 2006-03-30 2007-10-18 Summerton James E Compositions outils oncologiques et procédés d'utilisation pour détecter et traiter des tumeurs
WO2007139951A2 (fr) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Procédé pour traiter des troubles proliférants associés à des produits protooncogènes
WO2008019302A1 (fr) * 2006-08-04 2008-02-14 Decode Genetics Ehf Inhibiteurs pyrazolylphényliques et pyrrolylphényliques de la lta4h pour le traitement de l'inflammation
WO2008029168A2 (fr) * 2006-09-08 2008-03-13 Summit Corporation Plc Traitement de la dystrophie musculaire de duchenne
US7345058B2 (en) 2005-04-05 2008-03-18 Hoffmann-La Roche Inc. Pyrazoles
JP2008520702A (ja) * 2004-11-18 2008-06-19 シンタ ファーマスーティカルズ コーポレイション Ｈｓｐ９０活性を調節するトリアゾール化合物
WO2008101914A2 (fr) 2007-02-23 2008-08-28 High Point Pharmaceuticals, Llc Nouveaux composés
WO2008101885A1 (fr) 2007-02-23 2008-08-28 High Point Pharmaceuticals, Llc Nouveaux composés
WO2008101886A1 (fr) 2007-02-23 2008-08-28 High Point Pharmaceuticals, Llc N-adamantyl benzamides utilisés en tant qu'inhibiteurs de la 11-bêta-hydroxystéroïde déshydrogénase
WO2008121126A1 (fr) * 2007-03-30 2008-10-09 Summerton James E Molécules non-peptidiques pour la détection et le traitement des tumeurs
WO2008134035A1 (fr) * 2007-04-27 2008-11-06 Panacos Pharmaceuticals, Inc. DÉRIVÉS D'AMIDE PYRIMIDINE ARYLMETHYL PIPERAZINE PYRAZOLO[1,5-α] À SUBSTITUTION ALPHA
JP2008546714A (ja) * 2005-06-17 2008-12-25 アポジー・バイオテクノロジー・コーポレイション スフィンゴシンキナーゼ阻害剤
WO2008121386A3 (fr) * 2007-03-30 2008-12-31 Amgen Inc Procédés de traitement de troubles intestinaux
WO2009015067A2 (fr) * 2007-07-25 2009-01-29 Boehringer Ingelheim International Gmbh Mimétiques de glucocorticoïdes, leurs procédés de production, compositions pharmaceutiques et utilisations associées
FR2929851A1 (fr) * 2008-04-09 2009-10-16 Centre Nat Rech Scient Molecules inhibant une voie metabolique impliquant la proteine tyrosine kinase syk et procede d'identification de ces molecules
US7645773B2 (en) 2006-01-18 2010-01-12 Hoffmann-La Roche Inc. Thiazoles as inhibitors of 11β-hydroxysteroid dehydrogenase
US7662813B2 (en) 2005-08-18 2010-02-16 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2010059618A1 (fr) 2008-11-21 2010-05-27 High Point Pharmaceuticals, Llc Adamantylbenzamides
US7728029B2 (en) 2006-03-22 2010-06-01 Hoffmann-La Roche Inc. Adamantyl-pyrazole carboxamides as inhibitors of 11β-hdroxysteroid dehydrogenase
US7727978B2 (en) 2006-08-24 2010-06-01 Bristol-Myers Squibb Company Cyclic 11-beta hydroxysteroid dehydrogenase type I inhibitors
US7741361B2 (en) 2004-12-27 2010-06-22 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7790711B2 (en) 2007-07-17 2010-09-07 Hoffmann-La Roche Inc. Inhibitors of 11β-Hydroxysteroid Dehydrogenase
US7795272B2 (en) 2004-03-13 2010-09-14 Boehringer Ingelheim Pharmaceutical, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
WO2011006074A1 (fr) 2009-07-09 2011-01-13 Array Biopharma Inc. Composés pyrazolo[1,5-a]pyrimidines substituées en tant qu'inhibiteurs des trk kinases
US7932392B2 (en) 2002-03-26 2011-04-26 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7935703B2 (en) * 2006-01-17 2011-05-03 Astrazeneca Ab Piperazines and piperidines as Mglur5 potentiators
US7947689B2 (en) 2006-08-04 2011-05-24 Merz Pharma Gmbh & Co. Kgaa Substituted pyrazolo[1,5-a]pyrimidines as metabotropic glutamate receptor modulators
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
US20120016014A1 (en) * 2010-07-14 2012-01-19 Indian Institute Of Science Benzothiophene carboxamide compounds, composition and applications thereof
US8119658B2 (en) 2007-10-01 2012-02-21 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
US8183384B2 (en) 2006-05-25 2012-05-22 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
WO2012017166A3 (fr) * 2010-07-19 2012-07-19 Vaxconsulting Traitement d'une pathologie liee a un effet excessif du tnf par un compose de benzene sulfonamide
US8236835B2 (en) 2006-09-22 2012-08-07 Novartis Ag Heterocyclic inhibitors of stearoyl-CoA desaturase
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
US8258160B2 (en) 2006-12-20 2012-09-04 Novartis Ag SCD1 inhibitors triazole and tetrazole compounds
US8268859B2 (en) 2008-06-06 2012-09-18 Boehringer Ingelheim International Gmbh Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
US8288590B2 (en) 2006-10-17 2012-10-16 Rutgers, The State University Of New Jersey N-substituted monomers and polymers
US8314138B2 (en) 2006-08-24 2012-11-20 Novartis Ag Pyrazole derivative as SCD1 inhibitors for the treatment of diabetes
US8450322B2 (en) 2008-09-22 2013-05-28 Array Biopharma Inc. Substituted imidazo[1,2b]pyridazine compounds as Trk kinase inhibitors
US8513430B2 (en) 2010-07-27 2013-08-20 High Point Pharmaceuticals, Llc Substituted thiazol-2-ylamine derivatives, pharmaceutical compositions, and methods of use as 11-beta HSD1 modulators
US8513263B2 (en) 2008-10-22 2013-08-20 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US8563591B2 (en) 2004-08-30 2013-10-22 Janssen Pharmaceutica N.V. Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
CN103420931A (zh) * 2013-05-02 2013-12-04 范国煌 调节巨噬细胞极化并抗糖尿病的五环化合物及其应用
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
US8658637B2 (en) 2006-12-06 2014-02-25 Boehringer Ingelheim International Gmbh Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
US8741897B2 (en) 2003-09-24 2014-06-03 Boehringer Ingelheim Pharmaceuticals Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014139963A1 (fr) 2013-03-13 2014-09-18 Unilever Plc Compositions cosmétiques contenant des amides tricyclodécanes
WO2014139965A1 (fr) 2013-03-13 2014-09-18 Unilever Plc Compositions de photoprotection contenant des tricyclodécanes amides
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
US9012494B2 (en) 2004-05-07 2015-04-21 Janssen Pharmaceutica N.V. Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US9126973B2 (en) 2008-09-22 2015-09-08 Cayman Chemical Company, Incorporated Multiheteroaryl compounds as inhibitors of H-PGDS and their use for treating prostaglandin D2 mediated diseases
US9150512B2 (en) 2004-08-30 2015-10-06 Janssen Pharmaceutica N.V. Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US9205086B2 (en) 2010-04-19 2015-12-08 Synta Pharmaceuticals Corp. Cancer therapy using a combination of a Hsp90 inhibitory compounds and a EGFR inhibitor
US9346815B2 (en) 2014-05-23 2016-05-24 Genentech, Inc. 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds, compositions and methods of use thereof
US9439899B2 (en) 2011-11-02 2016-09-13 Synta Pharmaceuticals Corp. Cancer therapy using a combination of HSP90 inhibitors with topoisomerase I inhibitors
US9493476B2 (en) 2010-05-20 2016-11-15 Array Biopharma, Inc. Macrocyclic compounds as trk kinase inhibitors
US9775793B2 (en) 2013-03-13 2017-10-03 Conopco, Inc. Prolonged delivery of certain fragrance components from personal care compositions
US9782414B2 (en) 2014-11-16 2017-10-10 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US9840466B2 (en) 2013-12-09 2017-12-12 Conopco, Inc. Process of making adamantanamides
US9926312B2 (en) 2013-10-01 2018-03-27 Eisai R&D Management Co., Ltd. 4-azaindole derivatives
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
US10092574B2 (en) 2012-09-26 2018-10-09 Valorisation-Recherche, Limited Partnership Inhibitors of polynucleotide repeat-associated RNA foci and uses thereof
US10137127B2 (en) 2016-04-04 2018-11-27 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
CN109803951A (zh) * 2016-11-08 2019-05-24 正大天晴药业集团股份有限公司 作为cccDNA抑制剂的磺酰胺类化合物
US10307426B2 (en) 2017-05-22 2019-06-04 Genentech, Inc. Therapeutic compounds and compositions, and methods of use thereof
US10370727B2 (en) 2015-10-26 2019-08-06 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10500193B2 (en) 2011-11-02 2019-12-10 Synta Pharmaceuticals Corporation Combination therapy of HSP90 inhibitors with platinum-containing agents
US10688100B2 (en) 2017-03-16 2020-06-23 Array Biopharma Inc. Macrocylic compounds as ROS1 kinase inhibitors
US10696611B2 (en) 2014-08-29 2020-06-30 Amorepacific Corporation Adamantane derivative compound
WO2021045686A1 (fr) * 2019-09-04 2021-03-11 Agency For Science, Technology And Research Composés hétérocycliques en tant que modulateurs de l'interaction bêta-caténine/tcf4
AU2015342940B2 (en) * 2014-11-05 2021-04-01 Flexus Biosciences, Inc. Immunoregulatory agents
EP3576737A4 (fr) * 2017-02-06 2021-04-21 Case Western Reserve University Compositions et procédés de modulation de l'activité de la déshydrogénase à chaîne courte
WO2021092264A1 (fr) * 2019-11-05 2021-05-14 Dermira, Inc. Antagonists de mrgprx2 et leurs utilisations
US11084789B2 (en) 2016-01-14 2021-08-10 Beth Israel Deaconess Medical Center, Inc. Mast-cell modulators and uses thereof
US11084825B2 (en) 2018-12-31 2021-08-10 Biomea Fusion, Llc Substituted pyridines as irreversible inhibitors of menin-MLL interaction
US11091486B2 (en) 2016-10-26 2021-08-17 Array Biopharma, Inc Process for the preparation of pyrazolo[1,5-a]pyrimidines and salts thereof
US11174263B2 (en) 2018-12-31 2021-11-16 Biomea Fusion, Inc. Inhibitors of menin-MLL interaction
US11214571B2 (en) 2016-05-18 2022-01-04 Array Biopharma Inc. Process for the preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide and salts thereof
US11242319B2 (en) 2014-11-05 2022-02-08 Flexus Biosciences, Inc. Immunoregulatory agents
US11426420B2 (en) 2017-04-07 2022-08-30 Case Western Reserve University Inhibitors of short-chain dehydrogenase activity for treating coronary disorders
US11690847B2 (en) 2016-11-30 2023-07-04 Case Western Reserve University Combinations of 15-PGDH inhibitors with corticosteroids and/or TNF inhibitors and uses thereof

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0301232D0 (sv) * 2003-04-25 2003-04-25 Astrazeneca Ab Novel use
EP2947073B1 (fr) * 2009-10-22 2019-04-03 Fibrotech Therapeutics Pty Ltd Analogues cycliques fusionnés d'agents antifibrotiques
CA2854188A1 (fr) 2011-11-14 2013-05-23 Synta Pharmaceuticals Corp. Association therapeutique d'inhibiteurs de hsp90 et d'inhibiteurs de braf
US8889730B2 (en) 2012-04-10 2014-11-18 Pfizer Inc. Indole and indazole compounds that activate AMPK
JO3407B1 (ar) 2012-05-31 2019-10-20 Eisai R&D Man Co Ltd مركبات رباعي هيدرو بيرازولو بيريميدين
CA2905242C (fr) 2013-03-15 2016-11-29 Pfizer Inc. Composes indoliques activant l'ampk
US9381171B2 (en) 2013-12-19 2016-07-05 Samsung Electronics Co., Ltd. Composition including dapsone for preventing or treating side effect of steroid in subject and use of the composition

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072084A2 (fr) * 2001-03-08 2002-09-19 Sterix Limited Utilisation
WO2002076435A2 (fr) * 2001-03-23 2002-10-03 The University Of Edinburgh Modulation d'un profile lipidique

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1615697A2 (fr) * 2003-04-11 2006-01-18 Novo Nordisk A/S Utilisation pharmaceutique de pyrazolo 1,5-a]pyrimidines substituees

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002072084A2 (fr) * 2001-03-08 2002-09-19 Sterix Limited Utilisation
WO2002076435A2 (fr) * 2001-03-23 2002-10-03 The University Of Edinburgh Modulation d'un profile lipidique

Cited By (177)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8212040B2 (en) 2002-03-26 2012-07-03 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and thereof
US7932392B2 (en) 2002-03-26 2011-04-26 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
JP2006522748A (ja) * 2003-04-11 2006-10-05 ノボ　ノルディスク　アクティーゼルスカブ １１β−ヒドロキシステロイドデヒドロゲナーゼ１型化活性化合物
US8741897B2 (en) 2003-09-24 2014-06-03 Boehringer Ingelheim Pharmaceuticals Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
WO2005090320A2 (fr) * 2004-03-12 2005-09-29 Wyeth Derives de triazole et leur methode d'utilisation pour traiter les infections par le vih
WO2005090320A3 (fr) * 2004-03-12 2006-04-27 Wyeth Corp Derives de triazole et leur methode d'utilisation pour traiter les infections par le vih
US7563905B2 (en) 2004-03-12 2009-07-21 Wyeth Triazole derivatives and method of using the same to treat HIV infections
US7795272B2 (en) 2004-03-13 2010-09-14 Boehringer Ingelheim Pharmaceutical, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
US9302987B2 (en) 2004-05-07 2016-04-05 Janssen Pharmaceutica N.V. Pyrrolidinyl derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US9776965B2 (en) 2004-05-07 2017-10-03 Janssen Pharmaceutica Nv Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US9012494B2 (en) 2004-05-07 2015-04-21 Janssen Pharmaceutica N.V. Pyrrolidin-2-one and piperidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
WO2006023844A3 (fr) * 2004-08-20 2007-04-19 Entremed Inc Compositions et procedes comportant des antagonistes de recepteur active par la proteinase
WO2006023844A2 (fr) * 2004-08-20 2006-03-02 Entremed, Inc. Compositions et procedes comportant des antagonistes de recepteur active par la proteinase
EA012263B1 (ru) * 2004-08-30 2009-08-28 Янссен Фармацевтика Н.В. Производные n-2-адамантанил-2-феноксиацетамида в качестве ингибиторов 11-бета-гидроксистероид-дегидрогеназы
WO2006024627A3 (fr) * 2004-08-30 2007-09-13 Janssen Pharmaceutica Nv Derives d'acetamides n-2 adamantanyl-2-phenoxy utilises en tant qu'inhibiteurs de la deshydrogenase 11-beta hydroxysteroide
JP2008511580A (ja) * 2004-08-30 2008-04-17 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ １１−ベータヒドロキシステロイドデヒドロゲナーゼ阻害剤としてのｎ−２アダマンタニル−２−フェノキシ−アセトアミド誘導体
US9150512B2 (en) 2004-08-30 2015-10-06 Janssen Pharmaceutica N.V. Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US8344181B2 (en) 2004-08-30 2013-01-01 Janssen Pharmaceutica N.V. N-2 adamantanyl-2-phenoxy-acetamide derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US9422284B2 (en) 2004-08-30 2016-08-23 Janssen Pharmaceutica N.V. Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US9630921B2 (en) 2004-08-30 2017-04-25 Janssen Pharmaceutica Nv Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US8563591B2 (en) 2004-08-30 2013-10-22 Janssen Pharmaceutica N.V. Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
WO2006046915A1 (fr) * 2004-10-29 2006-05-04 Astrazeneca Ab Utilisation de derives insatures de quinoline ou de naphtalene comme medicaments
US9090569B2 (en) 2004-11-18 2015-07-28 Synta Pharmaceuticals Corp. Triazone compounds that modulate HSP90 activity
US8362055B2 (en) 2004-11-18 2013-01-29 Synta Pharmaceuticals, Inc. Triazole compounds that modulate HSP90 activity
JP2008520702A (ja) * 2004-11-18 2008-06-19 シンタ ファーマスーティカルズ コーポレイション Ｈｓｐ９０活性を調節するトリアゾール化合物
US7825148B2 (en) 2004-11-18 2010-11-02 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
US8901308B2 (en) 2004-11-18 2014-12-02 Synta Pharmaceuticals Corp. Triazole compounds that modulate Hsp90 activity
US7741361B2 (en) 2004-12-27 2010-06-22 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7345058B2 (en) 2005-04-05 2008-03-18 Hoffmann-La Roche Inc. Pyrazoles
WO2006132436A1 (fr) * 2005-06-08 2006-12-14 Japan Tobacco Inc. Composé hétérocyclique
JP2008546714A (ja) * 2005-06-17 2008-12-25 アポジー・バイオテクノロジー・コーポレイション スフィンゴシンキナーゼ阻害剤
US7662813B2 (en) 2005-08-18 2010-02-16 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
WO2007025892A1 (fr) 2005-08-31 2007-03-08 F. Hoffmann-La Roche Ag Inhibiteur de la 11-bêta-hydroxystéroïde déhydrogénase-1 des diabètes de type 2-1
US7622492B2 (en) 2005-08-31 2009-11-24 Hoffmann-La Roche Inc. Pyrazolones as inhibitors of 11β-hydroxysteroid dehydrogenase
US7935703B2 (en) * 2006-01-17 2011-05-03 Astrazeneca Ab Piperazines and piperidines as Mglur5 potentiators
US7645773B2 (en) 2006-01-18 2010-01-12 Hoffmann-La Roche Inc. Thiazoles as inhibitors of 11β-hydroxysteroid dehydrogenase
US7728029B2 (en) 2006-03-22 2010-06-01 Hoffmann-La Roche Inc. Adamantyl-pyrazole carboxamides as inhibitors of 11β-hdroxysteroid dehydrogenase
WO2007117398A2 (fr) * 2006-03-30 2007-10-18 Summerton James E Compositions outils oncologiques et procédés d'utilisation pour détecter et traiter des tumeurs
WO2007117398A3 (fr) * 2006-03-30 2007-12-06 James E Summerton Compositions outils oncologiques et procédés d'utilisation pour détecter et traiter des tumeurs
US8183384B2 (en) 2006-05-25 2012-05-22 Synta Pharmaceuticals Corp. Triazole compounds that modulate HSP90 activity
US8969396B2 (en) 2006-05-25 2015-03-03 Synta Pharmaceuticals Corp. Method for treating a B-raf associated cancer with an Hsp90 inhibitor
WO2007139951A2 (fr) * 2006-05-25 2007-12-06 Synta Pharmaceuticals Corp. Procédé pour traiter des troubles proliférants associés à des produits protooncogènes
US8034834B2 (en) 2006-05-25 2011-10-11 Synta Pharmaceuticals Corp. Method for treating proliferative disorders with HSP90 inhibitors
WO2007139951A3 (fr) * 2006-05-25 2008-12-24 Synta Pharmaceuticals Corp Procédé pour traiter des troubles proliférants associés à des produits protooncogènes
US7947689B2 (en) 2006-08-04 2011-05-24 Merz Pharma Gmbh & Co. Kgaa Substituted pyrazolo[1,5-a]pyrimidines as metabotropic glutamate receptor modulators
US7985753B2 (en) 2006-08-04 2011-07-26 Merz Pharma Gmbh & Co. Kgaa Substituted pyrazolo[1,5-A]pyrimidines as metabotropic glutamate receptor modulators
WO2008019302A1 (fr) * 2006-08-04 2008-02-14 Decode Genetics Ehf Inhibiteurs pyrazolylphényliques et pyrrolylphényliques de la lta4h pour le traitement de l'inflammation
US8115005B2 (en) 2006-08-04 2012-02-14 Decode Genetics Ehf. Pyrazolylphenyl and pyrrolylphenyl inhibitors of LTA4H for treating inflammation
US7727978B2 (en) 2006-08-24 2010-06-01 Bristol-Myers Squibb Company Cyclic 11-beta hydroxysteroid dehydrogenase type I inhibitors
US8314138B2 (en) 2006-08-24 2012-11-20 Novartis Ag Pyrazole derivative as SCD1 inhibitors for the treatment of diabetes
US8299054B2 (en) 2006-08-24 2012-10-30 Bristol-Myers Squibb Company Cyclic 11-beta hydroxysteroid dehydrogenase type 1 inhibitors
WO2008029168A2 (fr) * 2006-09-08 2008-03-13 Summit Corporation Plc Traitement de la dystrophie musculaire de duchenne
WO2008029168A3 (fr) * 2006-09-08 2008-05-02 Summit Corp Plc Traitement de la dystrophie musculaire de duchenne
US8236835B2 (en) 2006-09-22 2012-08-07 Novartis Ag Heterocyclic inhibitors of stearoyl-CoA desaturase
RU2470040C2 (ru) * 2006-10-17 2012-12-20 Ратджерс, Те Стейт Юниверсити Оф Нью Джерси N-замещенные мономеры и полимеры
US8288590B2 (en) 2006-10-17 2012-10-16 Rutgers, The State University Of New Jersey N-substituted monomers and polymers
US8658637B2 (en) 2006-12-06 2014-02-25 Boehringer Ingelheim International Gmbh Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
US8258160B2 (en) 2006-12-20 2012-09-04 Novartis Ag SCD1 inhibitors triazole and tetrazole compounds
WO2008101885A1 (fr) 2007-02-23 2008-08-28 High Point Pharmaceuticals, Llc Nouveaux composés
WO2008101886A1 (fr) 2007-02-23 2008-08-28 High Point Pharmaceuticals, Llc N-adamantyl benzamides utilisés en tant qu'inhibiteurs de la 11-bêta-hydroxystéroïde déshydrogénase
WO2008101914A2 (fr) 2007-02-23 2008-08-28 High Point Pharmaceuticals, Llc Nouveaux composés
WO2008121386A3 (fr) * 2007-03-30 2008-12-31 Amgen Inc Procédés de traitement de troubles intestinaux
AU2008233088B2 (en) * 2007-03-30 2013-09-26 Amgen Inc. Calcimimetic compounds for use in the treatment of bowel disorders
US8093299B2 (en) 2007-03-30 2012-01-10 Amgen Inc. Methods of treating bowel disorders
WO2008121126A1 (fr) * 2007-03-30 2008-10-09 Summerton James E Molécules non-peptidiques pour la détection et le traitement des tumeurs
WO2008134035A1 (fr) * 2007-04-27 2008-11-06 Panacos Pharmaceuticals, Inc. DÉRIVÉS D'AMIDE PYRIMIDINE ARYLMETHYL PIPERAZINE PYRAZOLO[1,5-α] À SUBSTITUTION ALPHA
US7790711B2 (en) 2007-07-17 2010-09-07 Hoffmann-La Roche Inc. Inhibitors of 11β-Hydroxysteroid Dehydrogenase
WO2009015067A2 (fr) * 2007-07-25 2009-01-29 Boehringer Ingelheim International Gmbh Mimétiques de glucocorticoïdes, leurs procédés de production, compositions pharmaceutiques et utilisations associées
WO2009015067A3 (fr) * 2007-07-25 2009-09-11 Boehringer Ingelheim International Gmbh Mimétiques de glucocorticoïdes, leurs procédés de production, compositions pharmaceutiques et utilisations associées
US8119658B2 (en) 2007-10-01 2012-02-21 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
US8541444B2 (en) 2007-10-01 2013-09-24 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
WO2009133294A3 (fr) * 2008-04-09 2010-04-08 Centre National De La Recherche Scientifique Molecules inhibant une voie metabolique impliquant la proteine tyrosine kinase syk et procede d'identification de ces molecules
WO2009133294A2 (fr) * 2008-04-09 2009-11-05 Centre National De La Recherche Scientifique Molecules inhibant une voie metabolique impliquant la proteine tyrosine kinase syk et procede d'identification de ces molecules
US9504676B2 (en) 2008-04-09 2016-11-29 Centre National De La Recherche Scientifique Molecules inhibiting a metabolic pathway involving the Syk protein tyrosine kinase and method for identifying said molecules
FR2929851A1 (fr) * 2008-04-09 2009-10-16 Centre Nat Rech Scient Molecules inhibant une voie metabolique impliquant la proteine tyrosine kinase syk et procede d'identification de ces molecules
US8268859B2 (en) 2008-06-06 2012-09-18 Boehringer Ingelheim International Gmbh Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
US10590139B2 (en) 2008-09-22 2020-03-17 Array Biopharma Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US8450322B2 (en) 2008-09-22 2013-05-28 Array Biopharma Inc. Substituted imidazo[1,2b]pyridazine compounds as Trk kinase inhibitors
US9795611B2 (en) 2008-09-22 2017-10-24 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US9796723B2 (en) 2008-09-22 2017-10-24 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US9227975B2 (en) 2008-09-22 2016-01-05 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2B]pyridazine compounds
US9126973B2 (en) 2008-09-22 2015-09-08 Cayman Chemical Company, Incorporated Multiheteroaryl compounds as inhibitors of H-PGDS and their use for treating prostaglandin D2 mediated diseases
US10011604B2 (en) 2008-09-22 2018-07-03 Array Biopharma, Inc. Method of treatment using substituted imidazo[1,2b]pyridazine compounds
US9447104B2 (en) 2008-10-22 2016-09-20 Array Biopharma, Inc. Method of treatment using substituted pyrazolo[1,5-a]pyrimidine compounds
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
US8513263B2 (en) 2008-10-22 2013-08-20 Array Biopharma Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US10005783B2 (en) 2008-10-22 2018-06-26 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US10774085B2 (en) 2008-10-22 2020-09-15 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-A] pyrimidine compounds
US9676783B2 (en) 2008-10-22 2017-06-13 Array Biopharma, Inc. Method of treatment using substituted pyrazolo[1,5-A] pyrimidine compounds
US11267818B2 (en) 2008-10-22 2022-03-08 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US8865698B2 (en) 2008-10-22 2014-10-21 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a]pyrimidine compounds
US10047097B2 (en) 2008-10-22 2018-08-14 Array Biopharma Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
US9127013B2 (en) 2008-10-22 2015-09-08 Array Biopharma, Inc. Method of treatment using substituted pyrazolo[1,5-a] pyrimidine compounds
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2010059618A1 (fr) 2008-11-21 2010-05-27 High Point Pharmaceuticals, Llc Adamantylbenzamides
US9682979B2 (en) 2009-07-09 2017-06-20 Array Biopharma, Inc. Substituted pyrazolo [1,5-A] pyrimidine compounds as TRK kinase inhibitors
US10251889B2 (en) 2009-07-09 2019-04-09 Array BioPharm Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
WO2011006074A1 (fr) 2009-07-09 2011-01-13 Array Biopharma Inc. Composés pyrazolo[1,5-a]pyrimidines substituées en tant qu'inhibiteurs des trk kinases
US9782415B2 (en) 2009-07-09 2017-10-10 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US8791123B2 (en) 2009-07-09 2014-07-29 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
US9796724B2 (en) 2009-07-09 2017-10-24 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyrimidine compounds as Trk kinase inhibitors
EP3299372A1 (fr) 2009-07-09 2018-03-28 Array Biopharma, Inc. Composés intermediares pour la préparation des composés de pyrazolo[1,5-a] pyrimidine substitués en tant qu'inhibiteurs de kinases trk
US10758542B2 (en) 2009-07-09 2020-09-01 Array Biopharma Inc. Substituted pyrazolo[l,5-a]pyrimidine compounds as Trk kinase inhibitors
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
US9205086B2 (en) 2010-04-19 2015-12-08 Synta Pharmaceuticals Corp. Cancer therapy using a combination of a Hsp90 inhibitory compounds and a EGFR inhibitor
US9840519B2 (en) 2010-05-20 2017-12-12 Array Biopharma, Inc. Macrocyclic compounds as TRK kinase inhibitors
US9493476B2 (en) 2010-05-20 2016-11-15 Array Biopharma, Inc. Macrocyclic compounds as trk kinase inhibitors
US10647730B2 (en) 2010-05-20 2020-05-12 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
US9718822B2 (en) 2010-05-20 2017-08-01 Array Biopharma, Inc. Macrocyclic compounds as Trk kinase inhibitors
US9750744B2 (en) 2010-05-20 2017-09-05 Array Biopharma, Inc. Macrocyclic compounds as Trk kinase inhibitors
US9902741B2 (en) 2010-05-20 2018-02-27 Array Biopharma Inc. Macrocyclic compounds as TRK kinase inhibitors
US20120016014A1 (en) * 2010-07-14 2012-01-19 Indian Institute Of Science Benzothiophene carboxamide compounds, composition and applications thereof
US8975399B2 (en) 2010-07-19 2015-03-10 Jean-Francois Zagury Benzenesulfon amide-compound treatment of a pathological condition linked to an excessive effect of TNF
WO2012017166A3 (fr) * 2010-07-19 2012-07-19 Vaxconsulting Traitement d'une pathologie liee a un effet excessif du tnf par un compose de benzene sulfonamide
US8513430B2 (en) 2010-07-27 2013-08-20 High Point Pharmaceuticals, Llc Substituted thiazol-2-ylamine derivatives, pharmaceutical compositions, and methods of use as 11-beta HSD1 modulators
EP3243385A1 (fr) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
US10500193B2 (en) 2011-11-02 2019-12-10 Synta Pharmaceuticals Corporation Combination therapy of HSP90 inhibitors with platinum-containing agents
US9439899B2 (en) 2011-11-02 2016-09-13 Synta Pharmaceuticals Corp. Cancer therapy using a combination of HSP90 inhibitors with topoisomerase I inhibitors
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
US10092574B2 (en) 2012-09-26 2018-10-09 Valorisation-Recherche, Limited Partnership Inhibitors of polynucleotide repeat-associated RNA foci and uses thereof
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
US9682028B2 (en) 2013-03-13 2017-06-20 Conopco, Inc. Personal care photoprotective compositions with tricyclodecane amides
US9883997B2 (en) 2013-03-13 2018-02-06 Conopco, Inc. Cosmetic compositions with tricyclodecane amides
US9775793B2 (en) 2013-03-13 2017-10-03 Conopco, Inc. Prolonged delivery of certain fragrance components from personal care compositions
WO2014139963A1 (fr) 2013-03-13 2014-09-18 Unilever Plc Compositions cosmétiques contenant des amides tricyclodécanes
WO2014139965A1 (fr) 2013-03-13 2014-09-18 Unilever Plc Compositions de photoprotection contenant des tricyclodécanes amides
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
CN103420931B (zh) * 2013-05-02 2015-07-08 范国煌 调节巨噬细胞极化并抗糖尿病的五环化合物及其应用
CN103420931A (zh) * 2013-05-02 2013-12-04 范国煌 调节巨噬细胞极化并抗糖尿病的五环化合物及其应用
US10072005B2 (en) 2013-10-01 2018-09-11 Eisai R&D Management Co., Ltd. 4-azaindole derivatives
US9926312B2 (en) 2013-10-01 2018-03-27 Eisai R&D Management Co., Ltd. 4-azaindole derivatives
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
US9840466B2 (en) 2013-12-09 2017-12-12 Conopco, Inc. Process of making adamantanamides
US9346815B2 (en) 2014-05-23 2016-05-24 Genentech, Inc. 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds, compositions and methods of use thereof
US9604984B2 (en) 2014-05-23 2017-03-28 Genentech, Inc. 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds, compositions and methods of use thereof
US10696611B2 (en) 2014-08-29 2020-06-30 Amorepacific Corporation Adamantane derivative compound
AU2015342940B2 (en) * 2014-11-05 2021-04-01 Flexus Biosciences, Inc. Immunoregulatory agents
US11932601B2 (en) 2014-11-05 2024-03-19 Flexus Biosciences, Inc. Immunoregulatory agents
US11242319B2 (en) 2014-11-05 2022-02-08 Flexus Biosciences, Inc. Immunoregulatory agents
US10172861B2 (en) 2014-11-16 2019-01-08 Array Biopharma Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10285993B2 (en) 2014-11-16 2019-05-14 Array Biopharma Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10813936B2 (en) 2014-11-16 2020-10-27 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-YL)-pyrazolo[1,5-A]pyrimidin-3-YL)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10799505B2 (en) 2014-11-16 2020-10-13 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US9782414B2 (en) 2014-11-16 2017-10-10 Array Biopharma, Inc. Crystalline form of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide hydrogen sulfate
US10655186B2 (en) 2015-10-26 2020-05-19 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10907215B2 (en) 2015-10-26 2021-02-02 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10370727B2 (en) 2015-10-26 2019-08-06 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10378068B2 (en) 2015-10-26 2019-08-13 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US10724102B2 (en) 2015-10-26 2020-07-28 Loxo Oncology, Inc. Point mutations in TRK inhibitor-resistant cancer and methods relating to the same
US11084789B2 (en) 2016-01-14 2021-08-10 Beth Israel Deaconess Medical Center, Inc. Mast-cell modulators and uses thereof
US10588908B2 (en) 2016-04-04 2020-03-17 Loxo Oncology, Inc. Methods of treating pediatric cancers
US11484535B2 (en) 2016-04-04 2022-11-01 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
US10668072B2 (en) 2016-04-04 2020-06-02 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US11191766B2 (en) 2016-04-04 2021-12-07 Loxo Oncology, Inc. Methods of treating pediatric cancers
US10137127B2 (en) 2016-04-04 2018-11-27 Loxo Oncology, Inc. Liquid formulations of (S)-N-(5-((R)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-A]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
US11214571B2 (en) 2016-05-18 2022-01-04 Array Biopharma Inc. Process for the preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide and salts thereof
US11091486B2 (en) 2016-10-26 2021-08-17 Array Biopharma, Inc Process for the preparation of pyrazolo[1,5-a]pyrimidines and salts thereof
CN109803951A (zh) * 2016-11-08 2019-05-24 正大天晴药业集团股份有限公司 作为cccDNA抑制剂的磺酰胺类化合物
CN109803951B (zh) * 2016-11-08 2020-12-04 正大天晴药业集团股份有限公司 作为cccDNA抑制剂的磺酰胺类化合物
US11690847B2 (en) 2016-11-30 2023-07-04 Case Western Reserve University Combinations of 15-PGDH inhibitors with corticosteroids and/or TNF inhibitors and uses thereof
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
EP3576737A4 (fr) * 2017-02-06 2021-04-21 Case Western Reserve University Compositions et procédés de modulation de l'activité de la déshydrogénase à chaîne courte
US11718589B2 (en) 2017-02-06 2023-08-08 Case Western Reserve University Compositions and methods of modulating short-chain dehydrogenase
US10966985B2 (en) 2017-03-16 2021-04-06 Array Biopharma Inc. Macrocyclic compounds as ROS1 kinase inhibitors
US10688100B2 (en) 2017-03-16 2020-06-23 Array Biopharma Inc. Macrocylic compounds as ROS1 kinase inhibitors
US11426420B2 (en) 2017-04-07 2022-08-30 Case Western Reserve University Inhibitors of short-chain dehydrogenase activity for treating coronary disorders
US10307426B2 (en) 2017-05-22 2019-06-04 Genentech, Inc. Therapeutic compounds and compositions, and methods of use thereof
US11084825B2 (en) 2018-12-31 2021-08-10 Biomea Fusion, Llc Substituted pyridines as irreversible inhibitors of menin-MLL interaction
US11702421B2 (en) 2018-12-31 2023-07-18 Biomea Fusion, Llc Substituted pyridines as irreversible inhibitors of menin-MLL interaction
US11174263B2 (en) 2018-12-31 2021-11-16 Biomea Fusion, Inc. Inhibitors of menin-MLL interaction
US11845753B2 (en) 2018-12-31 2023-12-19 Biomea Fusion, Inc. Inhibitors of menin-mll interaction
CN114286677A (zh) * 2019-09-04 2022-04-05 新加坡科技研究局 作为β-连环蛋白/TCF4相互作用调节剂的杂环化合物
WO2021045686A1 (fr) * 2019-09-04 2021-03-11 Agency For Science, Technology And Research Composés hétérocycliques en tant que modulateurs de l'interaction bêta-caténine/tcf4
WO2021092264A1 (fr) * 2019-11-05 2021-05-14 Dermira, Inc. Antagonists de mrgprx2 et leurs utilisations

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