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Definitions

• the instant invention involves a combination therapy comprising the administration of an 11 ?-hydroxysteroid dehydrogenase type 1 inhibitor and an antihypertensive agent for treating, preventing and reducing the risk of developing insulin resistance, dyslipidemia, obesity, hypertension and other related diseases and disorders.
• the metabolic syndrome is a major global health problem.
• the metabolic syndrome is characterized by a combination of insulin resistance, dyslipidemia, obesity and hypertension leading to increased morbidity and mortality of cardiovascular diseases.
• People with the metabolic syndrome are at increased risk of developing frank type 2 diabetes mellitus, the frequency of which is equally escalating.
• type 2 diabetes the combination of insulin resistance with obesity and dyslipidemia is also highly prevalent and around 70% of people with type 2 diabetes additionally have hypertension, once again leading to increased mortality of cardiovascular diseases.
• 11 ?-Hydroxysteroid dehydrogenase type 1 (11 ?-HSD1 ) catalyses the local generation of active glucocorticoid in several tissues and organs including predominantly the liver and adipose tissue, but also e.g. skeletal muscle, bone, pancreas, endothelium, ocular tissue and certain parts of the central nervous system.
• 11 ? ⁇ HSD1 serves as a local regulator of glucocorticoid actions in the tissues and organs where it is expressed (Tannin et al., J. Biol.
• 11 ⁇ -HSD1 in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence.
• treatment with the non-specific 11y#-HSD1 inhibitor carbenoxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes.
• 11 MHSD1 knock-out mice are resistant to insulin resistance induced by obesity and stress.
• the knock-out mice present with an anti-atherogenic lipid profile of decreased VLDL triglycerides and increased HDL-cholesterol.
• mice that over-express 11 -HSD1 in adipocytes develop insulin resistance, hyperlipidemia, visceral obesity and hypertension, a phenotype that resembles the human metabolic syndrome
• 11 MHSD1 promotes the features of the metabolic syndrome by increasing hepatic expression of the rate-limiting enzymes in gluconeogenesis, namely phosphoenolpyuvate carboxykinase and glucose-6-phosphatase, promoting the differentiation of preadipocytes into adipocytes thus facilitating obesity, directly and indirectly stimulating hepatic VLDL secretion, decreasing hepatic LDL uptake and increasing vessel contractility, presumably by decreasing the levels of endothelial nitric oxide synthase and consequently the levels of the vasodialating substance nitric oxide (Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94, 14924(1997); Morton et al., J. Biol. Chem. 276, 4
• 11 ?-HSD1 inhibitors constitute a new therapeutic principle for the treatment of insulin resistance, dyslipidemia, obesity and hypertension.
• monotherapeutic treatment of hypertension often lacks efficacy due, at least in part, to the induction of compensatory mechanisms.
• the instant invention addresses this problem by providing a combination therapy comprising an 11 ?-HSD1 inhibitor and an antihypertensive agent for the treatment of e.g. the metabolic syndrome and type 2 diabetes.
• a combination therapy comprising an 11 ?-HSD1 inhibitor and an antihypertensive agent for the treatment of e.g. the metabolic syndrome and type 2 diabetes.
• the 11 7-HSD1 inhibitor together with the antihypertensive agent provide improved control of hypertension and/or improved treatment ofthe metabolic syndrome and type 2 diabetes thereby reducing the risk for late complications, e.g. cardiovascular diseases and nephropathy.
• lesser dosage amounts of the 11 7-HSD1 inhibitor and more particularly the antihypertensive agent may be needed to achieve the desired clinical result, thereby resulting in improved safety.
• inhibitors and/or modulators of the human 1 ⁇ -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 200300569 filed 11 April 2003 DK, PA 200300565 filed 11 April 2003 DK, PA 200300571 filed 11 April 2003 DK, PA 2003 00570 filed 11 April 2003 DK, PA 2003 00566 filed 11 April 2003 DK, PA 2003 00972 filed 27 June 2003 DK, PA 200300998 filed 02 July 2003 DK, PA 2003 00988 filed 30 June 2003 DK, PA 200300989 filed 30 June 2003 DK, PA 200300990 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 comprised of a therapeutically effective amount of an antihypertensive agent in combination with an 1 ⁇ - hydroxysteroid dehydrogenase type 1 inhibitor (11 ?-HSD1) for the treatment, prevention and to reduce the risk of developing, metabolic syndrome, insulin resistance, dyslipidemia, obesity, hypertension and related diseases and disorders.
• an antihypertensive agent in combination with an 1 ⁇ - hydroxysteroid dehydrogenase type 1 inhibitor (11 ?-HSD1) for the treatment, prevention and to reduce the risk of developing, metabolic syndrome, insulin resistance, dyslipidemia, obesity, hypertension and related diseases and disorders.
• halo includes fluorine, chlorine, bromine, and iodine.
• trihalomethyl includes trifluoromethyl, trichloromethyl, tribromomethyl, 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 number of carbon atoms.
• this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, isopropyl (i-Pr), isobutyl (i-Bu), tert-butyl (-•Bu), sec-butyl (s-Bu), isopentyl, neopentyl, and the like.
• 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, hexenyl, 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, cydoheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl, tetrahydropyranyl, phenyl, pyridyl or pyrimidinyl.
• cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyl, 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
• arylalkyloxy represents an arylalkyl group as defined below attached through an oxygen bridge.
• hetarylalkyloxy e.g. 2-pyridylmethyIoxy and the like
• hetarylalkyloxy 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
• arylalkyloxycarbonyl e.g. benzylformiat, phenyletylformiat and the like
• arylalkyl e.g. benzyl, phenylethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like
• arylalkyl represents an aryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
• hetarylalkyl e.g. (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3- thienyl)methyl, (2-pyridyl)methyl, 1 -methyl-1 -(2-pyrimidyl)ethyl and the like
• 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
• hetarylcarbonyl e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like
• carbonylalkyl e.g. acetyl and the like
• 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-l-one, 1-(3-chloro-phenyl)-2- methyl-butan-1-one and the like
• arylcarbonylalkyl represents a arylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
• hetarylcarbonylalkyl e.g. 1-pyridin-2-yl-propan-1-one, 1-(1-H-imidazol-2-yl)- propan-1-one and the like
• arylalkylcarbonyl e.g. phenylpropylcarbonyl, phenylethylcarbonyl and the like
• hetarylalkylcarbonyl (e.g. imidazolylpentylcarbonyl and the like) represents an hetarylalkyl group as defined above wherein the 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
• arylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
• alkylcarboxyalkyl e.g. heptylcarboxymethyl, propylcarboxy tert-butyl, 3- pentylcarboxyethyl
• arylalkylcarboxy e.g. benzylcarboxy, phenylpropylcarboxy and the like
• arylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
• arylalkylcarboxyalkyl e.g. benzylcarboxymethyl, phenylpropylcarboxypropyl 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
• alkylthio e.g. methylthio, ethylthio and the like
• alkyl group as defined above attached through a sulphur bridge.
• 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
• arylthioalkyl represents an arylthio group as defined below attached through an alkyl group having the indicated number of carbon atoms.
• hetarylthioalkyl e.g. 2-methylsulfanyl-pyridine, 1-ethylsulfanyl-isoquinoline and the like
• 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
• alkyl e.g. phenoxymethyl, naphthyloxyethyl and the like
• aryloxyaryl e.g. 1-phenoxy-naphthalene, phenyloxyphenyl and the like
• aryloxyalkyl e.g. ethoxymethyl-benzene, 2-methoxymethyl- naphthalene and the like
• alkyl alkyl
• 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
• alkylcarbonylamino 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
• alkylcarbonylaminoalkyl 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
• arylalkylcarbonylaminoalkyl represents an “arylalkylcarbonylamino” 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
• 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 systems 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-yl), oxazolyl (2-oxazolyl, 4- oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl (2-thiophenyI, 3-thiophenyl, 4-thiophenyl, 5-thiophenyl), furanyl (2-
• NR R 5 carbonylalkyl e.g. ⁇ /./V-dimethyl- propionamide, ⁇ /-isopropyl- ⁇ /-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-1H-imidazol, ethyl- 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 attached 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.
• W-methyl-benzenesulfonamide and the like represents an aryl group as defined above, wherein the aryl group is in turn attached through a SO m NR 8 group wherein the sulphur is substituted with m oxygen atoms and the nitrogen atom substituted by R 8 , wherein R 8 and m are as defined for Formula II herein.
• NR 4 R 5 carbonylalkyl e.g. ⁇ /, ⁇ /-dimethyl- propionamide, ⁇ /-isopropyl- ⁇ /-methyl-propionamide and the like
• arylR 8 alkyl e.g. ethoxy-benzene, ethyl-methyl- phenyl-amine, ⁇ /-ethyl-benzamide, ⁇ /-isobutyl-benzenesulfonamide 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.
• hetarylR 8 alkyl e.g. 2-ethoxy-1 H-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.
• arylcarbonyl NR 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 complications, 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.
• combination therapy is defined as the administration of a single pharmaceutical dosage formulation which comprises the 11 ?-HSD1 inhibitor and the antihypertensive agent, as well as administration of each active agent in its own separate pharmaceutical dosage formulation.
• the 11/?- HSD1 inhibitor and the anti-hypertensive agent can be administered to the patient at essentially the same time, i.e. concurrently, or at separate staggered times, i.e. sequentially.
• 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.
• terapéuticaally 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).
• R 3 and R 5 independently are hydrogen, NR 13 R 14 trihalomethyl, trihalomethoxy, C ⁇ -C 6 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, CrC 6 alkyloxy, C C 6 alkylthio, aryl, aryld-Cealkyl, hetaryl or hetarylCrC 6 alkyl, 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 independently are d-C ⁇ alkyl, C 3 -C 10 cycloalkyl, hetC 3 -C 10 cycloalkyl, aryld-C 6 alkyl or hetarylCrCealkyl, 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, arylCrCealkyl, halo, hydroxy, oxo, CrC 6 alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, CrC 6 alkyloxyCr C 6 alkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C 6 alkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarbox
• R 8 and R 9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C 3 -C 10 cycloalkyl, C 3 - dohetocycloalkyl, d-C 6 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethoxy, aryld-C 6 alkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy, hetaryld-Cealkylcarboxy, CrC 6 alkylcar bonylamino or aryld-C 6 alkylcarbonyl- amino;
• R 10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, CrCealkyl, CrC 6 alkyloxy, trihalomethyl, trihalometh dialkylamino oxy, aryld-C 6 alkyloxy, hetaryld- C 6 alkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-Cealkylcarboxy, arylcarboxy or aryld-C 6 alkylcarboxy;
• R 11 is d-Cealkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryld-C e alkyl, hetaryld-dalkyl, d-C 6 alkyl- carbonylCrC 6 alkyl, d-C-ealkyloxy, aryloxy, C C 6 alkyloxy, arylcarbonyl, arylCrC 6 alkyl- carbonyl, hetarylcarbonylC C 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 d-Cealkylcarbonylaminod-Cealkyl, arylcarbonylaminoCrC 6 alkyl or arylCrC 6 alkyl- carbonylaminod-C 6 alkyl;
• R 13 and R 14 independently are hydrogen, oxo, C 3 -C 10 cycloalkyl, CrC 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl;
• R 15 is hydrogen, C 3 -C 10 cycloalkyl, CrC 6 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetaryld-Cealkyl, 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.
• 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, aryld-C 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 independently are d-Cealkyl, C 3 -C 10 cycloalkyl, hetC 3 -C 10 cycloalkyl, arylCrCealkyl or hetaryld-Cealkyl, 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 d-Cealkyl, aryl, hetaryl, aryl CrC 6 al kyl, halo, hydroxy, oxo, CrCealkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd- C 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C 6 alkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetaryl
• R 8 and R 9 independently are hydrogen, halo, hydroxy, oxo, cyano, nitro, C 3 -C ⁇ 0 cycloalkyl, C 3 - dohetocycloalkyl, d-Cealkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethoxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy, hetarylCrC 6 alkylcarboxy, CrC 6 aIkylcarbonylamino or arylC ⁇ -C 6 alkylcarbonyl- amino
• R 10 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, CrCealkyl, CrC 6 alkyloxy, trihalomethyl, trihalometh dialkylamino oxy, arylCrC 6 alkyloxy, hetaryld- C 6 aIkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy or aryld-C 6 alkylcarboxy;
• R 11 is d-C ⁇ alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, arylCrC 6 alkyl, hetaryld-Cealkyl, d-C 6 alkyl- carbonylCrC 6 alkyl, CrC ⁇ 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 d-CealkylcarbonylaminoCrCealkyl, arylcarbonylaminoC C 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, aryld-C 6 alkyloxy, hetarylCrCealkyloxy, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy, hetarylcarboxy, arylCrCealkylcarboxy;
• R 15 is hydrogen, C 3 -C 10 cycloalkyl, CrC 6 alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, 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 pyrazolo[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, d-Cealkyl, CrC 6 alkyloxy, aryl, arylCrCealkyl, 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 d-Cealkyl, C 3 -C 10 cycloalkyl, hetC 3 - Ciocycloalkyl, arylCrC 6 alkyl or hetaryld-Cealkyl, 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 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 or oxygen, the ring system optionally being substituted with at least one of d-Cealkyl, aryl, hetaryl, arylCrC 6 alkyl, halo, hydroxy, oxo, CrC 6 alkyloxy, arylCrCealkyloxy, hetaryld- C 6 alkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C 6 al
• 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 d-C 6 alkyl, aryl, hetaryl, arylCrCealkyl, halo, hydroxy, oxo, CrCealkyloxy, aryld-C 6 alkyloxy, 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, C 3 -C 10 hetocycloalkyl, d-Cealkyl, C ⁇ -C 6 alkyloxy, trihalomethyl, aryld- Cealkyloxy, 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 0 is hydrogen, halo, cyano, nitro, hydroxy, oxo, C 3 -C ⁇ 0 cycloalkyl, C 3 -Ci 0 hetcycloalkyl, d-C 6 alkyl, CrCealkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, d- C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or aryld-C 6 alkylcarboxy.
• 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 1 is d-Cealkyl, arylCrC 6 alkyl, hetary!d-C 6 alkyl, d-Cealkyloxy, aryloxy, CrC 6 alkyloxy, 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 CrCealkylcarbonylaminod-Cealkyl, arylcarbonylaminod- C 6 alkyl or aryld-CealkylcarbonylaminoCrCealkyl.
• 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, CrCealkylcarbonyl, 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 10 cycloalkyl, CrC 6 alkyl, aryl, hetaryl, aryld- C 6 alkyl, hetarylCrCealkyl, d-Cealkyloxyalkyl or arylCrC 6 alkyloxyalkyl.
• said substituted pyrazolo[1 ,5- ajpyrimidines, or a prodrug thereof, as a component of the combination therapy is selected from the group consisting of:
• said substituted amides, or a prodrug thereof, as a component of the combination therapy is of the general formula (II)
• R 1 is C 3 -C 10 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, C C 8 alkyl, aryl, hetaryl, aryld-Cealkyl 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, CrC 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, C 3 -C ⁇ ocycloalkylCrC 6 alkyI, d-C 6 alkyl- carboxyd-C 6 alkyI 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 CrC 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrCealkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld- C 6 alkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, aryl
• R 3 is CrC 8 alkyl, CrC 6 alkenyl, d-C 6 alkynyl, C 3 -d 0 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, hetaryl, aryld-Cealkyl, CrCealkyloxyCrCealkyl, hetarylCrCealkyl, aryl-R 6 -CrC 6 alkyl, hetaryl- R 6 -CrC 6 alkyl or arylCrCealkyl-R ⁇ d-Cealkyl 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 , d- C 8 alkyl, Crdalkyloxy, trihalomethyl, trihalomethyloxy, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkenyl, aryl, hetaryl, hetarylSO n , arylCrCealkyloxy, hetarylCrCealkyloxy, C C 6 alkyl-R 6 -CrC 6 alkyl, arylCrC 6 alkyl-R 6 -CrC e alkyl, CrCealkylcarbonyl, arylcarbonyl, aryld- C 6 alkylcarbonyl, hetarylcarbonyl, hetarylCrC 6 alkyl-carbonyl
• R 6 is oxygen, sulphur, SO n or NR 16.
• R 7 is hydrogen, halo, hydroxy, cyano, nitro, COOR 17 , C r C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C ⁇ 0 het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, aryld-C 6 alkyl, CrC 6 alkyloxy, CrCealkyloxyCrCealkyl, aryloxy, aryld-Cealkyloxy, aryloxyCrC 6 alkyl, aryld-Cealkyloxyd- C 6 alkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyCrC 6 alkyl, hetarylCrCealkyloxyC ⁇ -Cealkyl, NR 8 R 9 , S
• 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, arylCrCealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrCealkyloxy, hetaryld- C 6 alkyloxy,, CrCealkyloxyCrCealkyl, CrC 6 alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy,
• R 10 and R 11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, d-C 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 aryld-Cealkyl
• R 14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, C r C 8 alkyl, C 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, C C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, aryld-Cealkyl, hetaryl, hetarylCrC 6 alkyl, alkylcarbonyl, arylcarbonyl, aryld-C 6 alkylcarbonyl, aryloxyd-C 6 alkyl, hetaryloxyCrC 6 alkyl, 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 1 ' is hydrogen, CrC 8 alkyl, aryl or aryld-Cealkyl
• R 18 is CrC 6 alkyl, C 2 -C 6 alkenyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrCealkyl, C 3 -C 10 cycloalkyl, C 3 -Ci 0 hetcycloalkyl, CrC 6 alkyloxy, aryloxy, arylCrCealkyloxy, arylCrCealkyloxyCrCealkyl, hetaryloxy, hetarylCrCealkyloxy, hetarylCrC 6 alkyloxyCrC 6 alkyl 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
• n 0, 1 or 2;
• said substituted amides, or a prodrug thereof, as a component of the combination therapy is of the general formula (II) wherein: R 1 is Qrdocycloalkyl, C 3 -C 10 hetcycloalkyl, d-C 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 alkyl, aryl, hetaryl, aryld-C 6 alkyl, C 3 -C ocycloalkylCrC 6 alkyl, d-C 6 alkyl- carboxyd-C 6 alkyI 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 d-C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrCealkyloxy, arylC C 6 alkyloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC C 6 alkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, ary
• R 3 is d-C 8 alkyl, C C 6 alkenyl, C ⁇ -C 6 alkynyl, C 3 -d 0 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, hetaryl, aryld-Cealkyl, CrC 6 alkyloxyCrC 6 alkyI, hetarylCrCealkyl, aryl-R 6 -C ⁇ -C 8 aIkyl, hetaryl- R 6 -CrC 6 alkyl or aryICrC 6 alkyI-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, methylend
• R 6 is oxygen, sulphur, SO n , NR 16 ;
• R 7 is hydrogen, halo, hydroxyl, cyano, nitro, COOR 17 , d-C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C ⁇ 0 het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, aryld-Cealkyl, CrC 6 alkyloxy, CrCealkyloxyCrCealkyl, aryloxy, aryloxyCrC 6 alkyl, arylCrCealkyloxyCrCealkyl, hetaryl, hetarylCrCealkyl, hetaryloxy, hetaryld-Cealkyloxy, hetaryloxyd-C 6 alkyl, hetarylCrCealkyloxyCrCealkyl, NR 8 R 9 , S0 2 NR 8 R 9 , NR 4
• R 8 and R 9 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl 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 C C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, d-C 6 alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d- CealkyloxyCrCealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, 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 6 is hydrogen, d-C 8 alkyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrCealkyl, alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, aryloxyd-Cealkyl, hetaryloxyCrC 6 alkyl, aryIthioCrC 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, d-C 8 alkyl, aryl or arylCrC 6 alkyl
• n 1 or 2;
• n 0, 1 or 2;
• said substituted amides, or a prodrug thereof, as a component of the combination therapy is of the general formula (II) wherein R 1 is C 3 -C 10 cycloalkyl or C 3 -C ⁇ 0 hetcycloalkyl 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 prodrug thereof, as a component of the combination therapy is of the general formula (II) wherein R 1 is C 3 -C 10 cycloalkyl optionally substituted with one or more of R 4 as defined above.
• said substituted amides, or a prodrug 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 prodrug thereof, as a component of the combination therapy is of the general formula (II) wherein R 2 is CrC 8 alkyl optionally substituted with one or more of R 5 as defined above.
• said substituted amides, or a prodrug thereof, as a component of the combination therapy is of the general formula (II) wherein R 3 is C 3 -Ci 0 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, hetaryl, arylCrCealkyl, hetaryld-Cealkyl, aryl-R 6 - d-Cealkyl, hetaryl-R 6 -C C 6 alkyl or aryld-Cealkyl-R ⁇ d-Cealkyl 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 prodrug 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 prodrug 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 prodrug 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 prodrug 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, d-C 8 alkyl, wherein the alkyl group is optionally substituted with one ore more of R 15 .
• said substituted amides, or a prodrug thereof, as a component of the combination therapy is of the general formula (II) wherein R 6 is oxygen.
• said substituted amides, or a prodrug 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 alkyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -d 0 het-cycloalkyl, trihalomethyl, aryl, aryld-Cealkyl, CrC 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl, aryloxy, aryld- Cealkyloxy, aryloxyd-Cealkyl, arylCrCealkyloxyCrCealkyl, hetaryl, hetarylCrCealkyl, hetaryl, hetarylCr
• NR 8 R 9 NR 4 R 5 carbonyICrC 6 alkyI, R 18 carbonylNR 8 , R 19 SO m NR 8 , wherein the aryl and hetaryl groups independently are optionally substituted with one or more R 10 .
• said substituted amides, or a prodrug 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 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, arylCrCealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrCealkyloxy, hetaryld-
• said substituted amides, or a prodrug thereof, as a component of the combination therapy is of the general formula (II) wherein R 5 is CONR 8 R 9 .
• said substituted amides, or a prodrug thereof, as a component of the combination therapy is of the general formula (II) wherein R 18 is C 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-(1H-imidazol-4-yl)-piperidin-1-yl]-propan-1-one;
• Adamantane-1 -carboxylic acid 4-[(adamantane-1 -carbonyl)-amino]-2,6-dimethyl-pyridin-3-yl ester; 2-Phenyl-1 -(3-phenyI-pyrrolidin-1 -yl)-ethanone;
• Biphenyl-4-yl-piperidin-1 -yl-methanone Azepan-1 -yl-(3,5-dichloro-phenyl)-methanone;
• N,N-Dibenzyl-4-methyl-benzamide (2-Chloro-phenyl)-(2-methyl-piperidin-1 -yI)-methanone;
• N,N-Dibenzyl-2-fluoro-benzamide (2-ChIoro-phenyl)-piperidin-1 -yl-methanone;
• Furan-2-carboxylic acid [4-(4-methyl-piperidine-1 -sulfonyl)-phenyl]-amide; N-(2-Cyclohex-1 -enyI-ethyI)-2-o-tolyloxy-acetamide;
• N-Cycloheptyl-2,4-dimethoxy-benzamide N-(3-Chloro-phenyl)-2-(8,11 ,11-trimethyl-3,4,6-triaza-tricydo[6.2.1.0 2 ' 7 ]undeca-2(7),3,5-trien-5- ylsulfanyl)-acetamide;
• N-Benzyl-4-bromo-N-ethyl-benzamide (3-Methyl-piperidin-1 -yl)-[4-(naphthalen-1 -yloxymethyl)-phenyl]-methanone;
• N-Cyclooctyl-2-p-tolyloxy-acetamide (3,5-Dimethyl-piperidin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone;
• Adamantane-1 -carboxylic acid (2,6-dihydroxy-pyrimidin-4-yl)-amide; Adamantane-1 -carboxylic acid [3-(1 H-benzoimidazol-2-ylsulfanyl)-5-nitro-phenyl]-amide;
• Dec-3-enoic acid (4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide; 6-Oxo-6-phenyl-hexanoic acid (4-hydroxy-benzyl)-(4-trifluoromethyl-benzyl)-amide;

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