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EP1615667A2 - Therapie combinatoire utilisant un inhibiteur de 11beta-hydroxysteroide deshydrogenase de type 1 et agoniste du recepteur de glucocorticoides - Google Patents

Therapie combinatoire utilisant un inhibiteur de 11beta-hydroxysteroide deshydrogenase de type 1 et agoniste du recepteur de glucocorticoides

Info

Publication number
EP1615667A2
EP1615667A2 EP04725890A EP04725890A EP1615667A2 EP 1615667 A2 EP1615667 A2 EP 1615667A2 EP 04725890 A EP04725890 A EP 04725890A EP 04725890 A EP04725890 A EP 04725890A EP 1615667 A2 EP1615667 A2 EP 1615667A2
Authority
EP
European Patent Office
Prior art keywords
phenyl
methyl
methanone
alkyl
pyrazolo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04725890A
Other languages
German (de)
English (en)
Inventor
Gita Camilla Tejlgaard Kampen
Henrik Sune Andersen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Priority to EP07114939A priority Critical patent/EP1854487A3/fr
Publication of EP1615667A2 publication Critical patent/EP1615667A2/fr
Withdrawn legal-status Critical Current

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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

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.
EP04725890A 2003-04-11 2004-04-06 Therapie combinatoire utilisant un inhibiteur de 11beta-hydroxysteroide deshydrogenase de type 1 et agoniste du recepteur de glucocorticoides Withdrawn EP1615667A2 (fr)

Priority Applications (1)

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EP07114939A EP1854487A3 (fr) 2003-04-11 2004-04-06 Combinaisons d'un inhibiteur de 11-beta-hydroxystéroïde déhydrogénase, type 1, et d'un agoniste d'un récepteur glucocorticoïde

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DKPA200300565 2003-04-11
DKPA200300568 2003-04-11
DKPA200300569 2003-04-11
DKPA200300571 2003-04-11
DKPA200300566 2003-04-11
DKPA200300570 2003-04-11
US46736303P 2003-05-02 2003-05-02
US46780003P 2003-05-02 2003-05-02
US46744303P 2003-05-02 2003-05-02
US46745303P 2003-05-02 2003-05-02
US46736203P 2003-05-02 2003-05-02
US46728403P 2003-05-02 2003-05-02
DKPA200300778 2003-05-22
DKPA200300776 2003-05-22
US47515703P 2003-06-02 2003-06-02
US47519503P 2003-06-02 2003-06-02
DKPA200300972 2003-06-27
DKPA200300990 2003-06-30
DKPA200300988 2003-06-30
DKPA200300989 2003-06-30
DKPA200300998 2003-07-02
US48609403P 2003-07-10 2003-07-10
US48609703P 2003-07-10 2003-07-10
US48609803P 2003-07-10 2003-07-10
US48607803P 2003-07-10 2003-07-10
US48609503P 2003-07-10 2003-07-10
DKPA200301910 2003-12-22
DKPA200400009 2004-01-06
US53709904P 2004-01-16 2004-01-16
PCT/DK2004/000248 WO2004089415A2 (fr) 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

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Families Citing this family (111)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL373043A1 (en) 2002-03-26 2005-08-08 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
ATE482747T1 (de) * 2003-04-11 2010-10-15 High Point Pharmaceuticals Llc Neue amide derivate und deren pharmazeutische verwendungen
SE0301232D0 (sv) * 2003-04-25 2003-04-25 Astrazeneca Ab Novel use
UY28526A1 (es) 2003-09-24 2005-04-29 Boehringer Ingelheim Pharma Miméticos de glucocorticoides, métodos de preparación composiciones farmacéuticas y usos de los mismos
WO2005090320A2 (fr) * 2004-03-12 2005-09-29 Wyeth Derives de triazole et leur methode d'utilisation pour traiter les infections par le vih
US7795272B2 (en) 2004-03-13 2010-09-14 Boehringer Ingelheim Pharmaceutical, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
EP1747199B1 (fr) 2004-05-07 2014-09-17 Janssen Pharmaceutica NV Utilisation de derives de pyrrolidin-2-one et de piperidin-2-one comme inhibiteurs de la 11-beta-hydroxysteroide deshydrogenase
JP2008510726A (ja) * 2004-08-20 2008-04-10 エントレメッド インコーポレイテッド プロテイナーゼ活性化受容体アンタゴニストを含む組成物および方法
DE602005017159D1 (de) 2004-08-30 2009-11-26 Janssen Pharmaceutica Nv Oxysteroid-dehydrogenase-inhibitoren
CN101039908B (zh) 2004-08-30 2010-06-23 詹森药业有限公司 作为11-β羟甾类脱氢酶抑制剂的三环内酰胺衍生物
MY146435A (en) * 2004-08-30 2012-08-15 Janssen Pharmaceutica Nv N-2 adamantanyl-2-phenoxy-acetamide derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors
US20090036484A1 (en) * 2004-10-29 2009-02-05 Astrazeneca Ab Use of Unsaturated Quionoline or Naphtalene Derivatives as Medicaments
EP1817295B1 (fr) 2004-11-18 2012-11-07 Synta Pharmaceuticals Corp. Composes triazole modulant l'activite de hsp90
WO2006071609A2 (fr) 2004-12-27 2006-07-06 Boehringer Ingelheim Pharmaceuticals, Inc. Composes mimetiques glucocorticoides, compositions pharmaceutiques les contenant, et methodes de fabrication et d'utilisation de ceux-ci
JP4880671B2 (ja) 2005-04-05 2012-02-22 エフ．ホフマン−ラ ロシュ アーゲー １Ｈ−ピラゾール４−カルボキシルアミドその製造方法および１１β−ヒドロキシステロイドデヒドロゲナーゼとしてのその使用
KR100970294B1 (ko) * 2005-06-08 2010-07-15 니뽄 다바코 산교 가부시키가이샤 복소환 화합물
CA2612338C (fr) * 2005-06-17 2015-02-03 Apogee Biotechnology Corporation Inhibiteurs de la sphingosine kinase
CA2618628C (fr) 2005-08-18 2014-11-18 Synta Pharmaceuticals Corp. Derives de triazole modulant l'activite de hsp90
US7622492B2 (en) 2005-08-31 2009-11-24 Hoffmann-La Roche Inc. Pyrazolones as inhibitors of 11β-hydroxysteroid dehydrogenase
TW200734313A (en) * 2006-01-17 2007-09-16 Astrazeneca Ab Piperazines and piperidines as mGluR5 potentiators
JP5068768B2 (ja) 2006-01-18 2012-11-07 エフ．ホフマン−ラ ロシュ アーゲー １１ベータ−ｈｓｄ１阻害剤としてのチアゾール
PL1999114T3 (pl) 2006-03-22 2015-12-31 Hoffmann La Roche Pirazole jako 11-Beta-HSD-1
EP1998760A2 (fr) * 2006-03-30 2008-12-10 James E. Summerton Compositions outils oncologiques et procédés d'utilisation pour détecter et traiter des tumeurs
RU2303597C1 (ru) * 2006-05-12 2007-07-27 Иващенко Андрей Александрович Фармацевтическая композиция, способы ее получения и применения
JP5410965B2 (ja) 2006-05-25 2014-02-05 シンタ ファーマシューティカルズ コーポレーション Ｈｓｐ９０活性を調節するトリアゾール化合物
EP2034995A2 (fr) 2006-05-25 2009-03-18 Synta Pharmaceuticals Corporation Procédé pour traiter des troubles proliférants associés à des produits protooncogènes
US8115005B2 (en) 2006-08-04 2012-02-14 Decode Genetics Ehf. Pyrazolylphenyl and pyrrolylphenyl inhibitors of LTA4H for treating inflammation
TWI399376B (zh) 2006-08-04 2013-06-21 Merz Pharma Gmbh & Co Kgaa 經取代之吡唑並嘧啶類，製備彼等之方法及彼等作為藥物之用途
US7727978B2 (en) 2006-08-24 2010-06-01 Bristol-Myers Squibb Company Cyclic 11-beta hydroxysteroid dehydrogenase type I inhibitors
JP2010501567A (ja) 2006-08-24 2010-01-21 ノバルティス アクチエンゲゼルシャフト 代謝系、心血管系および他の障害の処置のためのステアロイル−ＣｏＡ不飽和化酵素（ＳＣＤ）阻害剤としての２−（ピラジン−２−イル）−チアゾールおよび２−（１Ｈ−ピラゾール−３−イル）チアゾール誘導体ならびに関連化合物
WO2008029168A2 (fr) * 2006-09-08 2008-03-13 Summit Corporation Plc Traitement de la dystrophie musculaire de duchenne
EP2066664A1 (fr) 2006-09-22 2009-06-10 Novartis AG Composés organiques
EP2079491B1 (fr) 2006-10-17 2013-02-27 Reva Medical, Inc. Monomères et polymères n-substitués
CN101547909A (zh) 2006-12-06 2009-09-30 贝林格尔.英格海姆国际有限公司 糖皮质激素模拟物、其制备方法、药物组合物及其用途
CN101595105B (zh) 2006-12-20 2013-01-23 诺瓦提斯公司 作为scd抑制剂的2-取代的5元杂环化合物
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
AU2008219326B2 (en) 2007-02-23 2012-12-13 Vtv Therapeutics Llc N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase
US20110003852A1 (en) 2007-02-23 2011-01-06 Soren Ebdrup N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase
MX2009010621A (es) * 2007-03-30 2009-12-11 James E Summerton Moleculas no petidicas, para detectar y tratar tumores.
WO2008121386A2 (fr) * 2007-03-30 2008-10-09 Amgen Inc. Procédés de traitement de troubles intestinaux
WO2008134036A1 (fr) * 2007-04-27 2008-11-06 Panacos Pharmaceuticals, Inc. DÉRIVÉS D'AMIDE PYRIMIDE ARYLMETHYL PYRAZOLO[1,5-α ] À SUBSTITUTION ALPHA
AU2008277783B2 (en) 2007-07-17 2012-09-20 F. Hoffmann-La Roche Ag Inhibitors of 11beta-hydroxysteroid dehydrogenase
JP2010534665A (ja) * 2007-07-25 2010-11-11 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング グルココルチコイドミメチックス、それらの製造方法、医薬組成物、及びこれらの使用
US8119658B2 (en) 2007-10-01 2012-02-21 Bristol-Myers Squibb Company Triazolopyridine 11-beta hydroxysteroid dehydrogenase type I inhibitors
FR2929851B1 (fr) 2008-04-09 2012-11-30 Centre Nat Rech Scient Molecules inhibant une voie metabolique impliquant la proteine tyrosine kinase syk et procede d'identification de ces molecules
BRPI0915680A2 (pt) 2008-06-06 2019-09-24 Boehringer Ingelheim Int miméticos de glicocorticoide, métodos de prepará-los, composições farmacêuticas, e usos dos mesmos
US8450322B2 (en) 2008-09-22 2013-05-28 Array Biopharma Inc. Substituted imidazo[1,2b]pyridazine compounds as Trk kinase inhibitors
KR20130105914A (ko) * 2008-09-22 2013-09-26 카이맨 케미칼 컴파니 인코포레이티드 Ｈ-ｐｇｄｓ 억제제로서 다중헤테로아릴 화합물 및 프로스타글란딘 ｄ2 매개된 질병의 치료를 위한 그의 용도
KR102037619B1 (ko) 2008-10-22 2019-10-28 어레이 바이오파마 인크. ＴＲＫ 키나아제 억제제로서 치환된 피라졸로［１,５­ａ］ 피리미딘 화합물
EP2348857B1 (fr) 2008-10-22 2016-02-24 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
AU2009309037A1 (en) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Novel cyclic benzimidazole derivatives useful anti-diabetic agents
EP2362730A4 (fr) 2008-11-21 2012-08-29 High Point Pharmaceuticals Llc Adamantylbenzamides
AR077468A1 (es) 2009-07-09 2011-08-31 Array Biopharma Inc Compuestos de pirazolo (1,5 -a) pirimidina sustituidos como inhibidores de trk- quinasa
US9062076B2 (en) * 2009-10-22 2015-06-23 Fibrotech Therapeutics Pty Ltd Fused ring analogues of anti-fibrotic agents
JP2013520502A (ja) 2010-02-25 2013-06-06 メルク・シャープ・エンド・ドーム・コーポレイション 有用な抗糖尿病薬である新規な環状ベンズイミダゾール誘導体
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
ES2628418T3 (es) 2010-05-20 2017-08-02 Array Biopharma, Inc. Compuestos macrocíclicos como inhibidores de la TRK cinasa
AU2011202542A1 (en) * 2010-07-14 2012-02-02 Indian Institute Of Science Benzothiophene carboxamide compounds, composition and applications thereof
FR2962649B1 (fr) 2010-07-19 2025-10-24 Conservatoire Nat Arts Et Metiers Traitement d'une pathologie liee a un effet excessif du tnf par un compose de benzene sulfonamide
WO2012015715A1 (fr) 2010-07-27 2012-02-02 High Point Pharmaceuticals, Llc Dérivés de thiazol-2-ylamine substitués, compositions pharmaceutiques et procédés d'utilisation en tant que modulateurs de 11-bêta-hsd1
JP5728099B2 (ja) 2011-02-25 2015-06-03 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． 抗糖尿病剤として有用な新規環状アザベンゾイミダゾール誘導体
EP2773345A1 (fr) 2011-11-02 2014-09-10 Synta Pharmaceuticals Corp. Thérapie anticancéreuse utilisant une combinaison d'inhibiteurs de hsp 90 et d'inhibiteurs de topoisomérase i
JP2014534228A (ja) 2011-11-02 2014-12-18 シンタ ファーマシューティカルズ コーポレーション 白金含有剤とｈｓｐ９０阻害剤の組合せ療法
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
RU2015106909A (ru) 2012-08-02 2016-09-27 Мерк Шарп И Доум Корп. Антидиабетические трициклические соединения
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
EP2968094B1 (fr) 2013-03-13 2018-05-30 Unilever PLC Composition photoprotectrice contenant les amides de tricyclododecane
EA029547B1 (ru) 2013-03-13 2018-04-30 Юнилевер Н.В. Косметические композиции с трициклодеканамидами
MX355874B (es) 2013-03-13 2018-05-02 Unilever Nv Suministro prolongado de ciertos componentes de fragancia de composiciones de cuidado personal.
EP2970119B1 (fr) 2013-03-14 2021-11-03 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
JP6064062B2 (ja) 2013-03-15 2017-01-18 ファイザー・インク Ａｍｐｋを活性化させるインダゾール化合物
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
GB201317363D0 (en) 2013-10-01 2013-11-13 Eisai Ltd Novel compounds
WO2015051496A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
CA2930085C (fr) 2013-12-09 2021-11-02 Unilever Plc Procede de fabrication d'adamantanamides
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
AU2015261812B2 (en) 2014-05-23 2019-11-21 F. Hoffmann-La Roche Ag 5-chloro-2-difluoromethoxyphenyl pyrazolopyrimidine compounds which are JAK inhibitors
KR102529578B1 (ko) 2014-08-29 2023-05-09 (주)아모레퍼시픽 신규 아다만탄 유도체 화합물
CN107205970A (zh) 2014-11-05 2017-09-26 弗莱塞斯生物科学公司 免疫调节剂
UY36390A (es) * 2014-11-05 2016-06-01 Flexus Biosciences Inc Compuestos moduladores de la enzima indolamina 2,3-dioxigenasa (ido), sus métodos de síntesis y composiciones farmacéuticas que los contienen
CA2967951C (fr) 2014-11-16 2023-11-07 Array Biopharma, Inc. Forme cristalline d'hydrogenosulfate de (s)-n-(5-((r)-2-(2,5-difluorophenyl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
CN108697708A (zh) 2015-10-26 2018-10-23 洛克索肿瘤学股份有限公司 Trk抑制剂抗性癌症中的点突变以及与此相关的方法
US20190016680A1 (en) 2016-01-14 2019-01-17 Beth Israel Deaconess Medical Center, Inc. Mast-cell modulators and uses thereof
US10045991B2 (en) 2016-04-04 2018-08-14 Loxo Oncology, Inc. Methods of treating pediatric cancers
SI3439662T1 (sl) 2016-04-04 2024-11-29 Loxo Oncology, Inc. Tekoče formulacije (s)-n-(5-((r)-2-(2,5-difluorofenil)-pirolidin -1-il)-pirazološ1,5-aćpirimidin-3-il)-3-hidroksipirolidin-1-karboksamida
DK3458456T3 (da) 2016-05-18 2020-12-14 Array Biopharma Inc Fremstilling af (s)-n-(5-((r)-2-(2,5-difluorphenyl)pyrrolidin-1-yl)pyrazol[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidin-1-carboxamid
JOP20190092A1 (ar) 2016-10-26 2019-04-25 Array Biopharma Inc عملية لتحضير مركبات بيرازولو[1، 5-a]بيريميدين وأملاح منها
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
EP3551176A4 (fr) 2016-12-06 2020-06-24 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
AU2018215678A1 (en) * 2017-02-06 2019-08-22 Board Of Regents Of The University Of Texas System Compositions and methods of modulating short-chain dehydrogenase activity
JOP20190213A1 (ar) 2017-03-16 2019-09-16 Array Biopharma Inc مركبات حلقية ضخمة كمثبطات لكيناز ros1
CA3059255A1 (fr) 2017-04-07 2018-10-11 Case Western Reserve University Inhibiteurs de l'activite de la deshydrogenase a chaine courte pour le traitement des troubles coronaires
JP7256757B2 (ja) 2017-05-22 2023-04-12 エフ． ホフマン－ラ ロシュ アーゲー 処置用化合物及び組成物、並びにその使用方法
MA55147A (fr) 2018-11-21 2021-09-29 Univ Texas Compositions et procédés de modulation de l'activité de la déshydrogénase à chaîne courte
US11174263B2 (en) 2018-12-31 2021-11-16 Biomea Fusion, Inc. Inhibitors of menin-MLL interaction
CN114040760B (zh) 2018-12-31 2025-05-09 拜欧米富士恩公司 Menin-mll相互作用的不可逆抑制剂
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
CN114845709B (zh) 2019-11-05 2024-10-01 德米拉公司 用于治疗炎性病症的mrgprx2拮抗剂
WO2021092264A1 (fr) * 2019-11-05 2021-05-14 Dermira, Inc. Antagonists de mrgprx2 et leurs utilisations
EP4384179A1 (fr) 2021-08-11 2024-06-19 Biomea Fusion, Inc. Inhibiteurs covalents de l'interaction ménine-mll pour le diabète sucré
JP2024534014A (ja) 2021-08-20 2024-09-18 バイオメア フュージョン，インコーポレイテッド 癌の処置のための不可逆的メニン－ＭＬＬ阻害剤、Ｎ－［４－［４－（４－モルホリニル）－７Ｈ－ピロロ［２，３－ｄ］ピリミジン－６－イル］フェニル］－４－［［３（Ｒ）－［（１－オキソ－２－プロペン－１－イル）アミノ］－１－ピペリジニル］メチル］－２－ピリジンカルボキサミドの結晶形態
WO2024155710A1 (fr) 2023-01-18 2024-07-25 Biomea Fusion, Inc. Formes cristallines de n-[4-[4-(4-morpholinyl)-7h-pyrrolo[2,3-d]pyrimidin-6-yl]phényl]-4-[[3(r)-[(l-oxo-2-propen-l-yl)amino]-l-pipéridinyl]méthyl]-2- pyridinecarboxamide en tant qu'inhibiteur covalent de l'interaction ménine-mll
KR102863193B1 (ko) * 2023-03-13 2025-09-22 대구가톨릭대학교산학협력단 리도카인 유도체를 유효성분으로 포함하는 항염증용 조성물
EP4458358A1 (fr) * 2023-05-02 2024-11-06 Tietze Chemical Consulting UG Composés de pyridazine pour thérapie antifibrotique
WO2025002289A1 (fr) * 2023-06-29 2025-01-02 湖南九典制药股份有限公司 Composé pyrazolohétéroaryle, son procédé de préparation et son utilisation
WO2025213050A1 (fr) * 2024-04-05 2025-10-09 Albert Einstein College Of Medicine Inhibiteurs de l'autophagie médiée par les chaperonnes et leurs utilisations thérapeutiques

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0105772D0 (en) * 2001-03-08 2001-04-25 Sterix Ltd Use
GB0107383D0 (en) * 2001-03-23 2001-05-16 Univ Edinburgh Lipid profile modulation
EP1615697A2 (fr) * 2003-04-11 2006-01-18 Novo Nordisk A/S Utilisation pharmaceutique de pyrazolo 1,5-a]pyrimidines substituees

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

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