EP1615667A2 - Combinations of an 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist - Google Patents

Combinations of an 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor and a glucocorticoid receptor agonist

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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
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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Withdrawn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
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German (de)
English (en)
French (fr)
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
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Novo Nordisk AS
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Priority to EP07114939A priority Critical patent/EP1854487A3/en
Publication of EP1615667A2 publication Critical patent/EP1615667A2/en
Withdrawn legal-status Critical Current

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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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