WO2004089470A2 - New amide derivatives and pharmaceutical use thereof - Google Patents

New amide derivatives and pharmaceutical use thereof Download PDF

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Publication number
WO2004089470A2
WO2004089470A2 PCT/DK2004/000250 DK2004000250W WO2004089470A2 WO 2004089470 A2 WO2004089470 A2 WO 2004089470A2 DK 2004000250 W DK2004000250 W DK 2004000250W WO 2004089470 A2 WO2004089470 A2 WO 2004089470A2
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WIPO (PCT)
Prior art keywords
alkyl
phenyl
methyl
methanone
bicyclo
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.)
Ceased
Application number
PCT/DK2004/000250
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English (en)
French (fr)
Other versions
WO2004089470A3 (en
Inventor
Henrik Sune Andersen
Gita Camilla Tejlgaard Kampen
Inge Thøger Christensen
John Patrick Mogensen
Annette Rosendal Larsen
John Paul Kilburn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Priority to AT04725891T priority Critical patent/ATE482747T1/de
Priority to JP2006504353A priority patent/JP2006522746A/ja
Priority to DE602004029346T priority patent/DE602004029346D1/de
Priority to EP04725891A priority patent/EP1615698B1/en
Publication of WO2004089470A2 publication Critical patent/WO2004089470A2/en
Publication of WO2004089470A3 publication Critical patent/WO2004089470A3/en
Priority to US11/265,794 priority patent/US20060111366A1/en
Anticipated expiration legal-status Critical
Priority to US12/006,765 priority patent/US20080108598A1/en
Priority to US12/493,698 priority patent/US20090264414A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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    • A61K31/16—Amides, e.g. hydroxamic acids
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to use of substituted amides and pharmaceutical compositions comprising the compounds for treating disorders where it is desirable to modulate the activity of 11 ⁇ -hydroxysteroid dehydrogenase type 1 (11 ⁇ HSDl ).
  • the present invention also relates to novel substituted amides, to their use in therapy, to pharmaceutical compositions comprising the compounds, to the use of said compounds in the manufacture of medicaments, and to therapeutic methods comprising the administration of said compounds.
  • the present compounds modulate the activity of 11 ⁇ - hydroxysteroid dehydrogenase type 1 (11 ⁇ HSDl) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.
  • the metabolic syndrome is a major global health problem. In the US, the prevalence in the adult population is currently estimated to be approximately 25%, and it continues to increase both in the US and worldwide.
  • the metabolic syndrome is characterised 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, the prevalence of which is equally escalating. In type 2 diabetes, obesity and dyslipidemia are also highly prevalent and around
  • 11 ⁇ -hydroxysteroid dehydrogenase type 1 (11 ⁇ HSDl) 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 ⁇ HSDl serves as a local regulator of glucocorticoid actions in the tissues and organs where it is expressed (Tannin et al., J. Biol.
  • 11 ⁇ HSDl in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence.
  • treatment with the non-specific 11 ⁇ HSDl inhibitor carbenoxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes.
  • 11 ⁇ HSDl knock-out mice are resistant to insulin resistance induced by obesity and stress. Additionally, the knock-out mice present with an anti-atherogenic lipid profile of decreased VLDL triglycerides and increased HDL-cholesterol.
  • mice that overexpress 11 ⁇ HSDl in adipocytes develop insulin resistance, hyperlipidemia and vis- ceral obesity, a phenotype that resembles the human metabolic syndrome (Andrews et al., J. Clin.
  • 11 ⁇ HSDl modulation and thereby modulation of intracellular levels of active glucocorticoid have been investigated in several rodent models and different cellular systems.
  • 11 ⁇ HSDl promotes the features ofthe 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 stimulat- ing hepatic VLDL secretion, decreasing hepatic LDL uptake and increasing vessel contractility (Kotelevtsev et al., Proc. Natl. Acad. Sci.
  • WO 01/90090, WO 01/90091, WO 01/90092, WO 01/90093 and WO 01/90094 dis- closes various thiazol-sulfonamides as inhibitors of the human 11 ⁇ -hydroxysteroid dehydrogenase type 1 enzyme, and further states that said compounds may be useful in treating diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders and depression.
  • the present compounds can be used to treat disorders where a decreased level of active intracellular glucocorticoid is desirable, such as e.g.
  • One object of the present invention is to provide compounds, pharmaceutical compositions and use of compounds that modulate the activity of 11 ⁇ HSDl .
  • halo includes fluorine, chlorine, bromine, and iodine.
  • trihalomethyl includes trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.
  • trihalomethoxy includes trifluorometoxy, trichlorometoxy, tribromometoxy, and triiodometoxy.
  • alkyl includes C ⁇ Cs straight chain saturated and methylene aliphatic hydrocarbon groups, C 3 -C 8 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), terf-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 -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, azepanyl, azocanyl, pyrrolinyl, pyrrolidinyl, 2- imidazolinyl, imidazolidinyl, 2-pyrazoIinyl, morpholinyl, piperidinyl, thiomorpholinyl, piperaz- inyl, phthalimide, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1,2,3,4- tetrahydro-quinoxalinyl, indolinyl, 1, 6-aza-bicyclo[3.2.1]octane, 2-aza-bicyclo[4.1.1]octane, 2-aza-bicyclo[3.2.1]octanyl, 7-aza-bicyclo[4.1.1]octanyl, 9-aza-bicyclo
  • saturated or partially saturated cyclic ring system represents but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclo- hexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, tetrahydrofuranyl ortetra- hydropyranyl.
  • 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]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like
  • cycloalkylalkyl (e.g. cyclopropylmethyl, cyclobutylethyl, adamantylmethyl and the like) represents a cycloalkyl group as defined above attached through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • cycloalkenyl (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like) represents a partially saturated, mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms.
  • cycloalkylcarbonyl e.g. cyclopropylcarbonyl, cyclohexylcarbonyl repre- sents an cycloalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
  • hetcycloalkylcarbonyl (e.g. 1-piperidin-4-yl-carbonyl, 1 -(1,2,3,4- tetrahydro-isoquinolin-6-yl)carbonyl) represents an hetcycloalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
  • cycloalkylalkylcarbonyl (e.g. cyclohexylmethylcarbonyl, cycloheptylethyl- carbonyl and the like) represents a cycloalkyl group as defined above attached through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • heteroalkyl tetrahydrofuranyl, tetrahydropyranyl, tertahydrothiopyranyl, piperidine, pyridzine and the like
  • hetcycloalkyl 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 .
  • hetcycloalkylalkyl (e.g. tetrahydrofuranylmethyl, tetrahydropyranylethyl, tertahydrothiopyranylmethyl, and the like) represents a hetcycloalkyl group as defined above attached through an alkyl group having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • 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
  • hetaryloxy represents a hetaryl group as defined below attached through an oxygen bridge.
  • arylalkyloxy e.g. phenethyloxy, naphthylmethyloxy and the like repre- sents an arylalkyl group as defined below attached through an oxygen bridge.
  • hetarylalkyloxy (e.g. 2-pyridylmethyloxy and the like) represents a hetary- lalkyl group as defined below attached through an oxygen bridge.
  • alkyloxycarbonyl e.g. methylformiat, ethylformiat and the like
  • aryloxycarbonyl e.g. phenylformiat, 2-thiazolylformiat and the like
  • arylalkyloxycarbonyl e.g. benzylformiat, phenyletylformiat and the like
  • arylalkyloxycarbonyl represents an “arylalkyloxy” group as defined above attached through a carbonyl group.
  • alkylthio (e.g. methylthio, ethylthio and the like) represents an alkyl group as defined above attached through a sulphur bridge.
  • arylthio (e.g. benzenthiol, naphthylthiol and the like) represents an aryl group as defined below attached through a sulphur bridge.
  • 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-ethylsulfanyl-isoquino- line 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
  • 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.
  • 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 or “hetaralkyl” (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) 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
  • hetarylcarbonyl e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like
  • carbonylalkyl (e.g. acetyl and the like) represents a carbonyl group at- tached 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
  • 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 a hetarylalkyl group as defined above wherein the alkyl group is in turn attached through a carbonyl.
  • 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.
  • 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
  • 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, phenylpropylcar- boxypropyl 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 indi- cated number of carbon atoms.
  • hetarylcarboxy e.g. pyridine-2-carboxylic acid and the like
  • hetarylcarboxy represents a hetarylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • hetarylalkylcarboxy e.g. (1-H-imidazol-2-yl)-acetic acid, 3-pyrimidin-2-yl- propionic acid and the like
  • hetarylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • 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, ,4-dihydronaphthyl and the like.
  • aryll includes phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, and fluorenyl.
  • aryl2 includes phenyl, biphenyl, and naphthyl.
  • 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-thiophenyl, 3-thiophenyl, 4-thiophenyl, 5-thiophenyl), furanyl (2-pyrroly
  • alkylSO m (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 m oxygen atoms.
  • 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.
  • hetarylSO m e.g. thiazol-2-sulfinyl, pyridine-2-sulfonyl and the like repre- sents 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.
  • NR 4 R 5 carbonylalkyl e.g. /V./V-dimethyl- propionamide, ⁇ /-isopropyl-W-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 represents an alkyl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above.
  • arylR 6 alkyl e.g. ethoxy-benzene, N-ethyl- N-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.
  • arylalkylR 6 alkyl e.g. benzyloxymethyl, N- ethyl-N-methyl-benzyl-amine, /V-ethyl-benzylamide and the like
  • R 6 represents an arylalkyl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above.
  • hetarylR 6 alkyl e.g. 2-ethoxy-1r7-imidazol, ethyl-quinolin-2-yl-amine, thiazole-2-carboxylic acid, methyl-propyl-amide, pyridine-3-sulfonic acid isobutyl-amide and the like
  • R 6 represents a hetaryl group as defined above, substituted by R 6 , which is substituted by an alkyl group as defined above.
  • arylcarbonylNR 15 (e.g. /V-benzyl- ⁇ /- methyl-benzamide and the like) represents an arylcarbonyl group as defined above, substituted by NR 15 .
  • arylSO m NR 8 (e.g. ⁇ /-methyl-benzene- sulfonamide 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 .
  • alkylNR 5 alkyl e.g. N-ethyl-N-isobutyl-amine, N,N-dimethylamine and the like wherein the amino group (N) is substituted with R 5 as de- fined below
  • alkylNR 5 group as defined above attached through an "alkyl” group.
  • arylalkylNR 5 alkyl e.g. N-benzyl-N-methyl- amine, N-phenethyl-N-ethyl-amine and the like wherein the amino group (N) is substituted • with R 5 as defined below
  • arylalkylNR 5 group as defined above attached through an "alkyl” group.
  • 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 present invention provides the use of a substituted amide, a pro- drug thereof, 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 for a) modulation of the activity of 11 ⁇ HSDl ;or b) inhibition of 11 ⁇ HSDl, in a patient in need thereof.
  • the present invention provides the use of a substituted amide, a prodrug thereof, 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 for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any disorder and disease where it is desirable to a) modulate the activity of 11 ⁇ HSDl ; or b) inhibit 11 ⁇ HSD1, in a patient in need thereof.
  • the invention provides the present use of substituted am- ides, or a prodrug thereof of the general formula (I)
  • R 1 is C 3 -C 10 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl or hetarylC ⁇ -C 6 alkyl, 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 r C 8 alkyl, aryl, hetaryl, arylCrCealkyl, Cs-docycloalkyld-Cealkyl, C 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 CrCealkyl, aryl, hetaryl, arylC C 6 alkyl, hetarylC ⁇ -C 6 alkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, aryld-Cealkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylC r C 6 alkylcarbonyl, hetarylC r C 6 alkylcarbonyl, d-C 6 alky
  • R 3 is CrC 8 alkyl, C C 6 alkenyl, d-C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, hetaryl, arylCrCealkyl, d-CealkyloxyCi-Cealkyl, hetarylCrC 6 alkyl, aryl-R 6 -CrC 6 alkyl, hetaryl- R 6 -d-C 6 alkyl or arylC ⁇ -C 6 alkyl-R 6 -C.-C 6 alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, al- kenyl, 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, C C 6 alkyloxy, trihalomethyl, trihalomethyloxy, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcyclo- alkyl, C 3 -C ⁇ 0 cycloalkenyl, aryl, hetaryl, hetarylSO n , arylCrC 6 alkyloxy, hetaryld-C 6 alkyloxy, C.-C 6 alkyl-R 6 -d-C 6 alkyl, aryld-C-ealkyl-R ⁇ d-Cealkyl, C C 6 alkylcarbonyl, arylcarbonyl, aryld-C 6 alkylcarbonyl, hetarylcarbonyl, hetarylC.-C 6 alky
  • R 6 is oxygen, sulphur, SO n or NR 16.
  • R 7 is hydrogen, halo, hydroxy, cyano, nitro, COOR 17 , CrC 8 alkyl, C 3 -C ⁇ ocycloalkyl, C 3 -C 10 het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylC C 6 alkyl, CrC 6 alkyloxy, CrC ⁇ alkyloxyCrCealkyl, aryloxy, arylC C 6 alkyloxy, aryloxyC C 6 alkyl, arylCrC 6 alkyloxyd- C 6 alkyl, hetaryl, hetarylCrC 6 alkyl, hetaryloxy, hetarylC ⁇ -C 6 alkyloxy, hetaryloxyd-Cealkyl, hetaryld-Cealkyl-oxyd-Cealkyl, NR 8 R 9 , S0 2 NR 8 R
  • R 8 and R 9 independently are hydrogen, C C 8 alkyl, aryl, hetaryl, aryld-C 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 halo, cyano, d-C ⁇ alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC 6 alkyl, hydroxy, oxo, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl, CrC 6 alkyl-carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylCrC 6 alkylcarbonyl, d-C 6 alkyl
  • 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 arylCrC 6 alkyl
  • R 14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, C 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, C r C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylC ⁇ -C 6 alkyl, alkylcarbonyl, arylcarbonyl, arylCrC 6 alkylcarbonyl, aryloxyd- C 6 alkyl, hetaryloxyCr Cealkyl, arylthioC C 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 is hydrogen, CrC 8 alkyl, aryl or arylCrCealkyl
  • R 8 is C C 6 alkyl, C 2 -C 6 alkenyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrC 6 alkyl, C 3 - C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, CrC 6 alkyloxy, aryloxy, arylC C 6 alkyloxy, aryld- C 6 alkyloxyCrC 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 d-Cealkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetaryl- CrC 6 alkyl;
  • n 1 or 2;
  • n 0, 1 or 2;
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the above general formula (I) wherein
  • R 1 is C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, CrCealkyl, aryl, hetaryl, arylCrCealkyl or hetaryl- CrCealkyl, 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, d-docycloalkyld-Cealkyl, d-Ce- alkylcarboxyCrC 6 alkyl wherein the alkyl, aryl and cycloalkyl groups independently are op- tionally 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, arylC C 6 alkyl, hetarylCrC 6 alkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetarylC C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C 6 alkylcarbonyl, hetarylCrC 6 alkylcarbonyl, CrC 6 alkylcarboxy,
  • R 3 is CrC 8 alkyl, CrC 6 alkenyl, CrC 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, hetaryl, arylCrC 6 alkyl, CrCealkyloxyCrCealkyl, hetarylCrC 6 alkyl, aryl-R 6 -CrC 6 alkyl, hetaryl- R 6 -d-C 6 alkyl or arylCrC 6 alkyl-R 6 -CrC 6 alkyl wherein the alkyl, cycloalkyl, hetcycloalkyl, al- kenyl, 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 , C r C 8 alkyl, d-Cealkyloxy, trihalomethyl, trihalomethyloxy, C 3 -C 10 cycloalkyl, C 3 - dohetcycloalkyl, C 3 -C 10 cycloalkenyl, aryl, hetaryl, hetarylSO n , arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyl-R ⁇ d-Cealkyl, arylCrC 6 alkyl-R 6 -CrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylcarbonyl, hetaryld-C 6 alkyl-carbonyl
  • R 7 is hydrogen, halo, hydroxyl, cyano, nitro, COOR 17 , C C 8 alkyl, C 3 -C ⁇ 0 cycloalkyl, C 3 -C 10 het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyloxy, aryl, arylCrC 6 alkyl, CrC 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl, aryloxy, aryloxyd-Cealkyl, arylCrC 6 alkyloxyCrC 6 alkyl, hetaryl, hetarylCrC 6 alkyl, hetaryloxy, hetarylCrC 6 alkyloxy, hetaryloxyCrC 6 alkyl, hetaryld-C 6 alkyl- oxyd-C 6 alkyl, NR 8 R 9 , S0 2 NR 8 R 9 , NR 4
  • R 8 and R 9 independently are hydrogen, C r C 8 alky1, 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 d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrC 6 alkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrC 6 alkyloxy, d- C 6 alkyloxyd-C 6 alkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-Ci-alkyl- carbonyl, hetarylCrC 6 alkylcarbonyl, d-C 6 alkylcarboxy,
  • R 10 and R 11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, CrC ⁇ alkyl, CrCealkyloxy, NR 12 R 13 , methylendioxo, trihalomethyl or trihalomethyloxy;
  • R 12 and R 13 independently are hydrogen, C r C 8 alkyl or arylCrC 6 alkyl;
  • R 14 is hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C 8 alkyl, d-Cealkyloxy or aryloxy;
  • R 15 is hydrogen, halo, hydroxy, oxo, nitro, cyano or COOR 17 ;
  • R 16 is hydrogen, C C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrC 6 alkyl, alkylcarbonyl, arylcarbonyl, arylCrC 6 alkylcarbonyl, aryloxyd- C 6 alkyl, hetaryloxyd-C-ealkyl, 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, C C 8 alkyl, aryl or arylCrCealkyl
  • n 1 or 2;
  • n 0, 1 or 2;
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 1 is C 3 -C 10 cycioalkyl or C 3 - dohetcycloalkyl wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 4 as defined above.
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 1 is C 3 -C 10 cycloalkyl optionally substituted with one or more of R 4 as defined above.
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 2 is hydrogen or C C 8 alkyl, wherein the the alkyl group is optionally substituted with one or more of R 5 as defined above.
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 2 is C r C 8 alkyl optionally substituted with one or more of R 5 as defined above.
  • the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R 3 is C 3 -C 10 cycloalkyl, C 3 -
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) 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.
  • the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R 3 is is phenyl optionally substituted with one or more of R 7 as defined above.
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) 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.
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) 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 .
  • the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R 6 is oxygen.
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 7 is hydrogen, halo, hydroxy, cyano, d-C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 het-cycloalkyl, trihalomethyl, aryl, arylCrC 6 alkyl, CrC 6 alkyloxy, d-C-ealkyloxyd-Cealkyl, aryloxy, arylCrC 6 alkyloxy, aryloxyd-Cealkyl, aryld- CealkyloxyCrCealkyl, hetaryl, hetarylCrC 6 alkyl, hetaryloxy, hetarylCrC 6 alkyloxy, hetary- loxyd-C 6 alkyl, hetary- loxyCrCeCe
  • the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) 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, d-C 8 alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrC 6 alkyl, hydroxy, oxo, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrC 6 alkyloxy, d-Cealkyloxyd-
  • the invention provides the present use of a substituted am- ide, or a prodrug thereof of the general formula (I) wherein R 15 is CONR 8 R 9 .
  • the invention provides the present use of a substituted amide, or a prodrug thereof of the general formula (I) wherein R 18 is d-Cealkyl optionally substi- tuted with R 15 ;
  • the invention provides the present use of a substituted am- ide, or a prodrug thereof of general formula (I), selected from the group consisting of:
  • Adamantane-1 -carboxylic acid (3-benzyloxy-2-ethyl-6-methyl-pyridin-4-yl)-amide; (6-Fluoro-2-methyl-3,4-dihydro-2H-quinolin-1 -yl)-(3,4,5-trimethoxy-phenyl)-methanone;
  • 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 -yl)-methanone;
  • Cyclohexanecarboxylic acid [2-methyl-1-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6- carbonyl)-butyl]-amide; 3-Cyclopentyl-N-[2-methyl-1-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-bu-yl]- propionamide;
  • Furan-2-carboxylic acid [4-(4-methyl-piperidine-1 -sulfonyl)-phenyl]-amide; N-(2-Cyclohex-1 -enyl-ethyl)-2-o-tolyloxy-acetamide;
  • N-Cyclooctyl-2-p-tolyloxy-acetamide (3,5-Dimethyl-piperidin-1-yl)-(4-methyl-3-nitro-phenyl)-methanone;
  • N-Benzyl-N-cyclohex-1-enyl-isonicotinamide 1 -[4-(4-Fluoro-phenyl)-piperazin-1 -yl]-2-(2-methyl-benzylsulfanyl)-ethanone;
  • Benzo[b]thiophene-3-carboxylic acid (3,3,5-trimethyl-cyclohexyl)-amide; 2-(2,6-Dimethyl-phenoxy)-N-(2-isopropyl-phenyl)-acetamide;
  • Acetic acid 4-(4-methyl-piperidine-1-carbonyl)-phenyl ester; Acetic acid 4-(4-benzyl-piperidine-1 -carbonyl)-phenyl ester;
  • N-(4-tert-Butyl-3-nitro-phenyl)-acetamide (2,6-Dimethyl-piperidin-1-yl)-[5-(2,3,5,6-tetrafluoro-phenoxymethyl)-furan-2-yl]-methanone; N-Cyclohexyl-3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-methyl-propionamide;
  • Adamantane-1 -carboxylic acid (naphthalen-1 -ylmethyl)-amide; Adamantane-1 -carboxylic acid (benzo[1 ,3]dioxol-5-ylmethyl)-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; 2-(3,4-Difluoro-phenyl)-N-(4-hydroxy-benzyl)-N-thiophen-2-ylmethyl-acetamide;
  • the present invention is concerned the substituted amides or prodrugs thereof of the general formula (II)
  • R 1 is C 3 -C 10 cycloalkyl or C 3 -C 10 hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 4 ;
  • R 2 is hydrogen, C C 8 alkyl, arylCi -C h alky!, wherein the alkyl and aryl 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 d-C 8 alkyl, aryl, hetaryl, aryld- C 6 alkyl, hetarylCrC 6 alkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld-Cealkylcarbonyl, C C 6 alkylcarboxy
  • R 3 is C 3 -C ⁇ 0 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl or hetaryl, wherein the alkyl, cycloalkyl, hetcycloalkyl, 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, CrC 6 alkyloxy, trihalomethyl, trihalomethyloxy, C 3 -C 10 cycloalkyl, C 3 -C.
  • R 6 is oxygen, sulphur, SO n or NR 16 ;
  • R 7 is hydrogen, halo, hydroxy, cyano, nitro, COOR 17 , d-C 8 alkyl, C 3 -d 0 cycloalkyl, C 3 -C 10 het- cycloalkyl, methylendioxo, trihalomethyl, trihalomethyl, trihalomethyloxy, aryl, arylCrCealkyl, CrC 6 alkyloxy, CrCealkyloxyCrC 6 alkyl, aryloxy, arylC 1 -C 6 alkyloxy, aryloxyCrC 6 alkyl, arylCrC 6 alkyloxyCr C 6 alkyl, hetaryl, hetarylC C 6 alkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyd-Cealkyl, hetaryld-Cealkyl-oxyd-Cealkyl, NR 8
  • R 8 and R 9 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, CrC 6 alkylSO m , arylSO m , arylCrC 6 alkylSO m , arylCrC 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, d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrC 6 alkyl, hydroxy, oxo, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl, CrC 6 aIkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylCrC 6 alkylcarbonyl, CrC 6 alkylcar
  • R 10 and R 11 independently are hydrogen, hydroxy, oxo, halo, cyano, nitro, d-C 8 alkyl, d- C 6 alkyl-oxy, 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, C r C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrC 6 alkyl, alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, aryloxyd- Cealkyl, 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 17 is hydrogen, d-C 8 alkyl, aryl or arylCrCealkyl;
  • R 18 is CrCealkyl, C 2 -C 6 alkenyl, aryl, aryld-Cealkyl, hetaryl, hetarylCrC 6 alkyl, C 3 - C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, CrC 6 alkyloxy, aryloxy, arylCrC 6 alkyloxy, aryld- C 6 alkyloxyCrCealkyl, hetarylCrC 6 alkyloxyCrC 6 alkyl, hetaryloxy, hetarylCrCealkyloxy or R 8 R 9 NCrC 6 alkyl wherein the alkyl, alkenyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups are optionally substituted
  • R 19 is CrCealkyl, C 3 -C 10 cycloalkyl, C 3 -C ⁇ 0 hetcycloalkyl, aryl, arylCrC 6 alkyl, hetaryl, hetarylCrC 6 alkyl;
  • n 1 or 2;
  • n 0, 1 or 2;
  • R 1 is C 3 -C 10 cycloalkyl or C 3 -C 10 hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 4 as defined above.
  • R 2 is hydrogen or d-
  • 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-Cealkyl, hetarylC ⁇ -C 6 - alkyl, hydroxy, oxo, cyano, d-C-ealkyloxy, aryld-C 6 alkyloxy, hetarylCrCealkyloxy, d-C 6 alkyl- oxyd-Cealkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylcarbonyl,
  • R 1 and R 2 together with the nitrogen to which they are attached are 6-aza-bicyclo[3.2.1]octane.
  • R 3 is aryl or hetaryl, wherein the aryl and hetaryl groups independently are optionally substituted with one or more of R 7 as defined above.
  • R 3 is C 3 -C 10 cycloalkyl or C 3 - dohetcycloalkyl, optionally substituted with one or more of R 7 as defined above.
  • 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 as defined above.
  • R 7 is hydrogen, halo, hydroxy, cyano, CrCealkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 het-cycloalkyl, trihalomethyl, aryl, aryld- Cealkyl, CrC 6 alkyloxy, d-Cealkyloxyd-Cealkyl, aryloxy, arylCrC 6 alkyloxy, aryloxyCrC 6 alkyl, arylCrCealkyloxyd-Cealkyl, hetaryl, hetarylCrC 6 alkyl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyd-C 6 alkyl, hetarylCrC 6 alkyl-oxyCrC 6 alkyl, NR 8 R 9 , R 18 carbonylNR 8 , or R 19 SO
  • R 7 is halo, cyano, d- C 8 alkyl, C 3 -C 10 hetcycloalkyl, trihalomethyl, aryl, d-C 6 alkyloxy, aryloxy, arylCrC 6 alkyloxy, aryloxyd-Cealkyl, arylCrCealkyloxyCrC 6 alkyl, hetaryl, hetaryloxy, hetarylCrCealkyloxy, hetaryloxyd-Cealkyl, hetaryld-Cealkyloxyd-Cealkyl, NR 8 R 9 , R 18 carbonylNR 8 , or R 19 SO m NR 8 , wherein the aryl and hetaryl groups are independently optionally substituted with one or more R 10 as defined above.
  • R 7 is R 18 carbonylNR 8 or R 19 SO m NR 8 ; wherein m, R 8 , R 18 and R 19 are defined as above.
  • R 8 is CrCealkyl.
  • 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, C C 8 alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyIoxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, C Cealkyloxyd-Cealkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCr
  • R 15 is CONR 8 R 9 .
  • R 18 is CrC 6 alkyl, optionally substituted with R 15 as defined above.
  • R 18 is aryl or hetaryl.
  • R 18 is arylCrC 6 alkyl- oxyd-C 6 alkyl or hetaryld-Cealkyloxyd-Cealkyl.
  • R 18 is R 8 R 9 Nd-C 6 - alkyl; wherein R 8 and R 9 are defined as above.
  • R 19 is aryl or hetaryl
  • the aryl group is phenyl or pyridyl.
  • the hetaryl group is thienyl, imidazolyl, oxazolyl, thiazolyl, or indolyl.
  • the compounds or prodrugs thereof of the general formula (II) are selected from the group consisting of the compounds of exam- pies 4 through 8 as described under EXAMPLES, COMPOUNDS OF GENERAL FORMULAS (I) AND (II).
  • the present invention is concerned the substituted amides or prodrugs thereof of the general formula (III)
  • R 1 is aryl, arylCrC 6 alkyl, hetaryl or hetarylCr -C 6 alkyl optionally substituted with one or more of R 6 independently;
  • R 2 is halo, d-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylCrC- 6 - alkyl, trihalomethyl, aryl, aryld-Cealkyl, d-C-ealkyloxyd-Cealkyl, aryld-Cealkyloxyd-Cealkyl, CrC 6 alkylNR 5 CrC 6 alkyl, arylCrC 6 alkylNR 5 CrC 6 alkyl, hetaryl or hetarylC C 6 alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R 7 ;
  • R 3 is CrC 6 alkyl optionally substituted with one or more of R 8 ;
  • R 4 is Ce-docycloalkyl, C 6 -C ⁇ ohetcycloalkyl, Ce-CiocycloalkylCrC ⁇ alkyl or C 6 -C 1Q hetcyclo- alkylCrC 6 alkyl wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 8 ; or
  • R 3 and R 4 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic/bridge ring system containing from 7 to 12 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, arylCrC 6 alkyl, hetaryl- CrC ⁇ alkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrC 6 alkyloxy or hetarylCrCealkyloxy, wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R 9 ;
  • R 5 is CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 - cycloalkylCrC 6 alkyl, C3-C 10 hetcycloalkylCrC 6 alkyl, aryl, hetaryl, arylC ⁇ -C 6 alkyl or hetaryld- C 6 alkyl wherein the alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 9 ;
  • R 6 and R 7 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC 6 alkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR 10 R 11 , arylCrC 6 alkyloxy, hetarylCrCealkyloxy, C C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrC 6 alkyloxycarbonyl, aryloxycarbonyl, aryld-C 6 alkyloxycarbonyl, CrC 6 alkylcarboxy, arylcarboxy or arylCrC 6 alkyI- carboxy;
  • R 8 and R 9 independently are hydrogen, d-C 6 alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrC 6 - alkyl, hydroxy, oxo, cyano, NR 10 R 11 , CrC 6 alkyloxy, aryloxy, arylCrC 6 alkyloxy, hetaryloxy, hetarylCrCealkyloxy, CrCealkyloxyCrCealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC 6 alkylcarbonyl, C ⁇ -C 6 alkylcarboxy, arylcarboxy or aryld-C 6 alkylcarboxy;
  • R 10 and R 11 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, C 3 -C ⁇ o- cycloalkyl, C 3 -C 0 hetcycloalkyl, C 3 -C 10 cycloalkylCrC 6 alkyl, CrC 6 alkylcarbonyl, d- C 6 alkylcarboxyCrC 6 alkyl; or
  • R 10 and R 11 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 at- oms 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, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, C C 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcar
  • the present invention is concerned with compounds or pro- drugs thereof of the general formula (III) wherein: R 1 is aryl or hetaryl optionally substituted with one or more R 6 independently;
  • R 2 is halo, d-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C ⁇ ocycloalkylCrC 6 - alkyl, aryl, arylCrCealkyl, CrC-ealkyloxyd-Cealkyl, aryld-Cealkyloxyd-Cealkyl, d-C 6 - alkylNR 5 CrC 6 alkyl, arylCrC- 6 alkylNR 5 CrC 6 alkyl, hetaryl or hetarylC C 6 alkyI wherein the alkyl, alkenyl, alkynyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R 7 ;
  • R 3 is CrC 6 alkyl optionally substituted with one or more of R 8 ;
  • R 4 is C 6 -docycloalkyl, C 6 -C 10 hetcycloalkyl, C 6 -C ⁇ ocycloalkylCrC 6 alkyl or C 6 -C ⁇ 0 hetcyclo- alkylC r C 6 alkyl wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 8 ;
  • R 5 is CrC 6 alkyl, C 2 -Cealkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 - cycloalkyICrC 6 alkyl, C3-C 10 hetcycloalkylC ⁇ -C 6 alkyl, aryl, hetaryl, aryld-Cealkyl or hetaryld- C 6 alkyl wherein the alkyl, alkenyl, alkynyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 9 ;
  • R 6 and R 7 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, C ⁇ -C 6 alkyl, d-C 6 - alkyloxy, trihalomethyl, trihalomethoxy, NR 10 R 11 , arylCrC 6 alkyloxy, hetarylCrCealkyloxy, d- C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, CrCealkyloxycarbonyl, aryloxycarbonyl, aryICrC 6 alkyloxycarbonyl, CrC 6 alkylcarboxy, arylcarboxy or arylCrC 6 aIkyl- carboxy; R 8 and R 9 independently are hydrogen, C C 6 alkyl, aryl, hetaryl, aryld-C 6 alkyl, hetarylCrCealkyl, hydroxy,
  • R 10 and R 11 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, C 3 -C 10 - cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkylCrC 6 alkyl, CrCealkylcarboxyCrC 6 alkyl; or
  • R 10 and R 11 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- C 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, aryld-C 6 alkyloxy, hetaryl d-C 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylCrC 6 alkylcarbonyl, C C 6 alkylcarboxy,
  • R 1 is aryl, aryld- Cealkyl or hetaryl optionally substituted with one or more of R 6 .
  • R 1 is aryl optionally substituted with one or more of R 6 .
  • R 1 is aryld-Cealkyl optionally substituted with one or more of R 6 .
  • R 1 is hetaryl optionally substituted with one or more of R 6 .
  • R 2 is CrC 6 alkyl, C 3 - docycloalkyl, C 3 -C 10 cycloalkylCrC 6 alkyl, trihalomethyl, arylCrCealkyl, or hetarylC C 6 alkyl wherein the alkyl, cycloalkyl and aryl groups independently are optionally substituted with one or more R 7 .
  • R 2 is CrC 6 alkyl op- tionally substituted with one or more R 7 .
  • R 2 is trihalomethyl.
  • R 3 is C C 6 alkyl optionally substituted with one or more of R 8 .
  • R 4 is C 6 -C 10 cyclo- alkyl, or C 6 -C 10 hetcycloalkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 8 .
  • R 4 is C 6 -C 10 cyclo- alkyl optionally substituted with one or more of R 8 .
  • R 4 is C 6 C 6 -C 10 het- cycloalkyl optionally substituted with one or more of R 8 .
  • R 3 and R 4 together with the nitrogen to which they are attached are forming a saturated or partially saturated bi- cyclic/bridge ring system containing from 7 to 12 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being sub- stituted with at least one of CrC 6 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrC 6 alkyloxy or hetaryld-C 6 alkyloxy, wherein the alkyl and aryl groups independently are optionally substituted with one ore more of R 9 .
  • the saturated or partially saturated bicyclic/bridge ring system is 6-aza-bicyclo[3.2.1]octane.
  • R 6 and R 7 independently are hydrogen, hydroxy, oxo, halo, cyano, CrC ⁇ alkyl, d-C 6 alkyloxy, trihalomethyl, NR 10 R 11 , arylCrC 6 alkyloxy, hetarylCrCealkyloxy, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, CrCealkyloxycarbonyl, aryloxycarbonyl or aryld- C 6 alkyloxycarbonyl.
  • R 8 and R 9 independently are hydrogen, CrC 6 alkyl, hydroxy, oxo, d-dalkyl
  • R 10 and R 11 independently are hydrogen or d-C 8 alkyl.
  • the compound of the general for- mula (III) or a prodrug thereof is 1 -(4-Chloro-phenyl)-5-propyl-1 /-/-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide 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.
  • the compounds of the general for- mula (III) or a prodrug thereof is selected from the group consisting of: 1 -(4-Chloro-phenyl)-5-trifluoromethyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; [1-(4-Methoxy-phenyl)-5-methyl- -H-pyrazol-4-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone; 1 [1-(4-Chloro-phenyl)-5-propyl-1r7-pyrazol-4-yl]-(1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1]oct-6-yl)-methanone; [1 -(3,5-Dichloro-phenyl)-5-propyl-1 H-pyrazol-4-yl]-(1 ,3,3-trimethyl-6
  • the compounds of the general formula (III) or a prodrug thereof is selected from the group consisting of: 1 -(Phenyl)-5-methyl-1 r/-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Fluoro-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Methoxy-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Chloro-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(2-Methyl-phenyl)-5-methyl-1 H-pyrazole-4-carboxylic acid cyclohexyl-methyl-amide; 1 -(4-Amino-phenyl
  • the present invention is concerned with compounds or prodrugs thereof of the general formula (IV)
  • R 1 is hydrogen, trihalomethyl, CrC 6 alkyl, d-C 6 alkyloxy, CrC 6 alkylthio, aryl, arylCrC 6 alkyl, hetaryl or hetaralkyl, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 8 ;
  • R 2 , R 3 , R 4 and R 5 independently are hydrogen, halo, nitro, cyano, hydroxy, NR 9 R 10 , trihalomethyl, CrC 6 alkyl, CrC 6 alkyloxy, CrC 6 alkylthio, aryl, arylCrC 6 alkyl, hetaryl or hetaralkyl, wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 8 ; or
  • R 2 together with R 3 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 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 CrCealkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyloxy, aryloxy, arylCrC 6 alkyloxy or hetarylCrCealkyloxy; or
  • R 3 together with R 4 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 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 6 - alkyl, aryl, hetaryl, aryld-C 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, CrCealkyloxy, aryloxy, arylCrC 6 alkyloxy or hetarylCrC 6 alkyloxy; or
  • R 4 together with R 5 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 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 CrCealkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, d-Cealkyloxy, aryloxy, aryld-C 6 alkyloxy or hetarylCrC 6 alkyloxy;
  • R 6 is aryl, hetaryl, aryld-C 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkylCr C 6 alkyl, d-Cealkylcarboxyd-Cealkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R 11 ;
  • R 7 is C r C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 - C ⁇ ocycloalkylCrC 6 alkyl, CrC 6 alkylcarboxyCrC 6 alkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R 11 ; 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 6 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, arylC C 6 alkyl, hetaryl -Cealkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C 6 alkylcar
  • R 9 and R 10 independently are hydrogen, C C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, C 3 -C 10 - cycloalkyl, C 3 -C ⁇ ohetcycloalkyl, C 3 -C ⁇ ocycloalkylCrC 6 alkyl, CrCealkylcarboxyCrCealkyl, wherein the alkyl, aryl and cycloalkyl groups independently are optionally substituted with one or more of R 11 ; or
  • R 9 and R 10 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, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C 6 al
  • R 8 and R 11 independently are hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C 8 alkyl, d-C 6 - alkyloxy or aryloxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • R 1 is hydrogen or C C 6 alkyl, wherein the alkyl group is optionally substituted with one or more of R 8 .
  • R 1 is hydrogen.
  • R 2 , R 3 , R 4 and R 5 are hydrogen.
  • R 3 together with R 4 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring sys- tem optionally being substituted with at least one of d-C 6 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyloxy, aryloxy, aryld-C 6 alkyloxy or hetarylCrCealkyloxy.
  • R 4 together with R 5 are forming a saturated or partially saturated cyclic ring system containing from 3 to 6 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-C ⁇ alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, CrC 6 alkyloxy, aryloxy, arylCrC 6 aIkyloxy or hetarylCrCealkyloxy.
  • 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 6 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 8 alkyl, aryl, hetaryl, arylCrCealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, d-C 6 alkyloxyCr C 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetaryld- C 6 alkylcarbonyl,
  • R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 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 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, C C 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, CrC 6 alkyloxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrC 6 alkyI- carbonyl, CrCealkylcar
  • R 9 and R 10 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 C C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-Cealkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d-C-ealkyloxyd- C 6 alkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C 6 alkylcarbon
  • a compound of the general formula (IV) or a prodrug thereof is pyrazolo[1,5-a]pyridin-3-yl-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct- 6-yl)-methanone; 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.
  • the compounds of the general formula (IV) or a prodrug thereof are:
  • the present invention is concerned with compounds or prod- rugs thereof of the general formula (V)
  • the present invention is concerned with compounds or prodrugs thereof of the general formula (V) :
  • R 1 is hydrogen, d-C 8 alkyl, CrC 6 alkyloxyd-C 6 alkyl, aryl, hetaryl, arylCrCealkyl, hetarylC r C 6 alkyl, CrC 6 S0 2 , arylS0 2 , hetarylS0 2 , arylC C 6 alkylS0 2 or hetaryld-C 6 alkylS0 2 all of which is optionally substituted with one or more R 8 ;
  • R 2 and R 5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, CrC 6 alkyl, aryl, arylCrC 6 alkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R 9 ; and
  • R 3 is hydrogen; and R 4 is C(0)NR 7 R 8 ; or R 3 is C(0)NR 7 R 8 ; and R 4 is hydrogen; and R 6 is hydrogen, halo, cyano, trihalomethyl, NR 12 R 13 , CrC 6 alkyl, aryl, arylCrCealkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R 9 ; and
  • R 7 and R 8 independently are d-C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cyclo- alkyld-C 6 alkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 10 ; or
  • R 7 and R 8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 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-C 8 alkyl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, cyano, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd- C 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C 6 alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the
  • R 9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC 6 alkyl, d-Cealkyloxy, trihalomethyl, trihalomethoxy, NR 12 R 13 , C(0)NR 12 R 13 , aryld-C 6 alkyloxy, d-C 6 alkylcarbonyl, arylcarbonyl, aryld-C 6 alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
  • R 10 and R 1 independently are hydrogen, halo, oxo, hydroxy, CrC 6 alkyl, aryl, arylCrC 6 alkyl, hetaryl or hetarylalkyl;
  • R 12 and R 13 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, aryld-C 6 alkyl, C 3 -C 10 - cycloalkyl, C 3 -C 10 hetcycloalkyl, Cs-docycloalkyld-C-ealkyl, d-C 6 alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, hetarylcarbonyl, hetarylCrCealkylcarbonyl, d-C 6 alkylcarboxyCr C 6 alkyl; or
  • R 12 and R 13 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, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, CrC 6 alkyl-oxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarbox
  • the present invention is concerned with compounds or pro- drugs thereof of the general formula (Va)
  • R 1 is hydrogen, d-C 8 alkyl, aryl, hetaryl, aryld-Cealkyl or hetarylCrCealkyl optionally substituted with one or more R 8 ;
  • R 2 and R 5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, CrC 6 alkyl, aryl, arylCrC 6 alkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, arylalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R 8 ; and
  • R 3 is hydrogen; and R 4 is C(0)NR 6 R 7 ; or R 3 is C(0)NR 6 R 7 ; and R 4 is hydrogen;
  • R 6 and R 7 independently are C C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cyclo- alkyld-C 6 alkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 9 ; or
  • R 6 and R 7 together with the nitrogen to which they are attached, are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 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-C 8 alkyl, aryld-Cealkyl, hetarylCrCealkyl, hydroxy, cyano, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, CrC 6 alkyloxyCr C 6 alkyl, C C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C 6 alkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy wherein the
  • R 8 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C 6 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethoxy, NR 11 R 12 , arylCrC 6 alkyloxy, CrC 6 alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d-C 6 alkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
  • R 9 and R 10 independently are hydrogen, halo, oxo, hydroxy, CrC 6 alkyl, aryl, arylCrC 6 alkyl, hetaryl or hetarylalkyl;
  • R 11 and R 2 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, C 3 -C 10 - cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkylCrC 6 alkyl, CrCealkyl-carboxyCrCealkyl; or
  • R 11 and R 12 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, CrC 6 alkyloxy, arylCrQ-alkyloxy, hetaryld- C 6 alkyloxy, CrC 6 alkyl-oxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C 6 alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy,
  • R 1 is hydrogen, d-C 8 alkyl, arylCrC 6 alkyl, hetarylCrCealkyl, arylS0 2 , hetarylS0 2 , arylCrC 6 alkylSO 2 or hetarylCrCealkylS0 2 all of which is optionally substituted with one or more R 8 .
  • R 1 is hydrogen, C C 8 alkyl, aryld-Cealkyl, hetarylCrCealkyl all of which is optionally substituted with one or more R 8 .
  • R 1 is arylS0 2 , hetarylS0 2 , arylCrC 6 alkylS0 2 or hetarylCrC 6 alkylS0 2 all of which is optionally substituted with one or more R 8 .
  • R 2 is hydro- gen.
  • R 3 is hydrogen and R 4 is C(0)NR 7 R 8 .
  • R 3 is C(0)NR 7 R 8 and R 4 is hydrogen.
  • R 5 is hydrogen.
  • R 6 is hydrogen, NR 12 R 13 , CrC 6 alkyl, aryl or hetaryl wherein the alkyl, aryl and hetaryl independently are substituted with one or more R 9 .
  • R 7 and R 8 independently are C C 8 alkyl or C 3 -C 10 cycloalkyl, wherein the alkyl and cycloalkyl groups independently are optionally substituted with one or more of R 10 .
  • R 7 and R 8 together with the nitrogen to which they are attached are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 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-C 8 alkyl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, cyano, CrC 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd-Cealkyl, CrC 6 alkyl- carbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkylcarbonyl, hetarylCrC 6 alkylcarbonyl, CrCealkylcarboxy, arylcarboxy, arylcarboxy, arylcarboxy, ary
  • R 9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C 6 alkyl, d-C 6 alkyloxy, trihalomethyl, trihalomethoxy, NR 12 R 13 , C(0)NR 12 R 13 , arylC C 6 alkyloxy, d-C 6 alkylcarbonyl, arylcarbonyl, aryld- C 6 alkylcarbonyl.
  • R 10 and R 11 independently are hydrogen, halo, oxo, hydroxy, CrCealkyl, aryl, aryld-Cealkyl, hetaryl or hetarylalkyl.
  • R 11 and R 12 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-C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, hetaryld- C 6 alkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetarylCrC 6 alkyloxy, d- C 6 alkyl-oxyC C 6 alkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrC 6 alkyl-car- bonyl, hetarylC
  • the compound of the general formulas (V) and (Va), or a prodrug thereof is 1H-Benzoimidazole-5-carboxylic acid cyclohexyl- methyl-amide; 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.
  • the compounds of the general formulas (V) and (Va), or a prodrug thereof is selected from the group consisting of: 1 -Benzyl-1 rV-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide;
  • the compounds of general formulas (V) and (Va), or a prodrug thereof is sleceted from the group consisting of: lsopropyl-2-trifluoromethyl-1 H-benzoimidazole- ⁇ -carboxylic acid cyclohexyl-methyl-amide; 1 -Benzyl-1 H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 2-Methyj-l V-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 2-Hydroxymethyl-1H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; 2-(4-Amino-phenyl)-1H-benzoimidazole-5-carboxylic acid cyclohexyl-methyl-amide; (1H-Benzoimidazol-5-yl)-(1,3,3-trimethyl-6-aza-bic
  • X is oxygen or (CR 1 R 2 ) n ;
  • R 1 , R 2 , R 3 , and R 4 independently are hydrogen, C C 6 alkyl, aryl, arylCrCealkyl, hetaryl or hetarylCrCealkyl optionally substituted with one or more R 8 independently; or
  • R 1 and either R 3 or R 4 together are forming a saturated or partially saturated ring system containing from 4 to 8 carbon atoms, the ring system optionally being substituted with at least one of CrC 6 alkyl, hydroxy, oxo, aryl, hetaryl, arylCrCealkyl or hetarylCrC 6 alkyl; or
  • R 1 and either R 3 or R 4 together with the single bond are forming a carbon-carbon double bond
  • R 5 is d-C 8 alkyl optionally substituted with one or more of R 9 ;
  • R 6 is Qrdocycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkylCr Cealkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 9 ; or
  • R 5 and R 6 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 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, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, CrC 6 alkyIoxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcar
  • R 7 is hydrogen, halo, nitro, NR 12 R 13 , cyano, trihalomethyl, CrC 6 alkyl, aryl, aryld-Cealkyl, d- C 6 alkyloxy, aryloxy, arylCrC 6 alkyloxy, hetaryl, hetarylCrCealkyl, hetaryloxy or hetarylCrCealkyloxy optionally substituted with one or more R 11 independently;
  • R 8 and R 9 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C 6 alkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR 2 R 13 , arylCrC 6 alkyloxy, CrC 6 alkylcarbonyl, aryl- carbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
  • R 10 is hydrogen, d-C 8 alkyl, arylCrC 6 alkyl, hetarylCrCealkyl, CrC 6 alkyloxy, arylCrC 6 alkyl- oxy, hetarylCrCealkyloxy;
  • R 11 is hydrogen, halo, hydroxy, oxo, nitro, cyano, d-C 8 alkyl, CrC 6 alkyloxy, aryloxy or hetaryloxy;
  • R 12 and R 13 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, C 3 -C 10 cyclo- alkyl, C 3 -C 10 hetcycloalkyl, CrC 6 alkylcarbonyl, arylCrCealkylcarbonyl, C 3 -C 10 cycloalkylCrC 6 - alkyl, CrCealkyloxycarbonyl; or
  • R 12 and R 13 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 CrCealkyl, aryl, hetaryl, aryld- Cealkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrC 6 alkyloxy, hetaryld- C 6 alkyloxy, d-C-ealkyloxyd-Cealkyl, C C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarbox
  • n 1 or 2;
  • X is (CR 1 R 2 ) n , wherein R 1 , R 2 and n are as defined above.
  • n 1
  • X is oxygen.
  • R 1 , R 2 , R 3 , and R 4 independently are hydrogen, d-C 6 alkyl or aryld-Cealkyl, optionally substituted with one or more R 8 .
  • R 1 and either R 3 or R 4 together with the single bond are forming a carbon-carbon double bond.
  • R 5 is C C 8 alkyl op- tionally substituted with one or more of R 9 .
  • R 6 is C 3 -C 10 cyclo- alkyl or C 3 -C 10 hetcycloalkyl each of which is optionally substituted with one or more of R 9 .
  • R 6 is C 3 -C 10 cyclo- alkyl optionally substituted with one or more of R 9 .
  • R 5 and R 6 together with the nitrogen to which they are attached are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 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 6 alkyl, aryl, hetaryl, aryld-Cealkyl, hetarylC C 6 - alkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy, C C 6 alkyl- oxyCrC 6 alkyl, d-C 6 alkylcarbony
  • R 7 is hydrogen, halo, NR 12 R 13 , trihalomethyl, d-C 6 alkyloxy, aryloxy, arylCrCealkyloxy or hetaryloxy optionally substituted with one or more R 11 independently.
  • R 8 and R 9 independently are hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C 6 alkyl, d-C 6 alkyloxy, trihalomethyl, or NR 12 R 13 .
  • R 10 is hydrogen or d-C 8 alkyl.
  • the bicyclic ring system is 6-aza-bicyclo[3.2.1]octane optionally substituted with one or more of CrC 6 alkyl.
  • the bicyclic ring system is 1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane.
  • a compound of the general formula (VI) or a prodrug thereof is 2,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide 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.
  • the compounds of the general formula (VI) or a prodrug thereof is selected from the group consisting of: 2,5-Dimethyl-3-phenyl-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide;
  • Benzofuran-7-carboxylic acid cyclohexyl-methyl-amide 2,3-Dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; Chroman-8-carboxylic acid cyclohexyl-methyl-amide; 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.
  • the compounds ofthe general formula (VI) or a prodrug thereof is selected from the group consisting of: 2,3-Dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; Benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2-Methyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 2-Methyl-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; 3,3-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid cyclohexyl-methyl-amide; (2,3-Dimethyl-2,3-dihydro-benzofuran-7-yl)-(2,4,4-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
  • the present invention is concerned with compounds or prodrugs thereof of the general formula (VII)
  • R 1 is hydrogen, d-C 8 alkyl, hetaryl, aryld-Cealkyl or hetarylCrCealkyl optionally substituted with one or more R 9 ;
  • R 2 , R 3 , R 4 , R 5 and R 6 independently are hydrogen, halo, nitro, cyano, trihalomethyl, carboxy, N(R 12 R 13 ), C(0)NR 7 R 8 , C r C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, N(R 12 R 13 )C C 6 alkyl, CrCealkyloxy, CrCealkyloxyCrC 6 alkyl, aryl, arylCrC 6 alkyl, aryloxy, aryloxyd- C 6 alkyl, arylCrCealkyloxy, aryld-Cealkyloxyd-C-ealkyl, CrCealkylcarboxy, arylcarboxy, arylCrCealkylcarboxy, hetaryl, hetarylCrCealkyl, hetarylCrCe
  • R 7 is hydrogen or C C 8 alkyl optionally substituted with one or more of R 10 ;
  • R 8 is C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkylCrC 6 alkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 10 ; or
  • R 7 and R 8 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 at- oms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring system optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, arylC ⁇ -C 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, aryld-C 6 alkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, d-C 6 alkyl
  • R 9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, CrC 6 alkyl, CrCealkyloxy, trihalomethyl, trihalomethoxy, NR 12 R 13 , arylC C 6 alkyloxy, d-C 6 alkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, d-C 6 alkylcarboxy, arylcarboxy or aryld-C 6 alkylcarboxy;
  • R 10 and R 11 independently are hydrogen, halo, oxo, hydroxy, CrC 6 alkyl, aryl, aryld-Cealkyl, hetaryl or hetarylalkyl;
  • R 12 and R 13 independently are hydrogen, CrC 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, C 3 -C 10 - cycloalkyl, C 3 -d 0 hetcycloalkyl, C 3 -C 10 cycloalkylCrCealkyl, CrC 6 alkylcarbonyl, arylcarbonyl, aryld-Cealkylcarbonyl, C 3 -C 10 cycloalkylcarbonyl, C 3 -C 10 hetcycloalkylcarbonyl or C 3 -C 10 cyclo- alkylCrC 6 alkylcarbonyl wherein the alkyl and aryl groups independently are optionally substituted with one or more of R 11 , wherein R 11 is as defined above; or
  • R 12 and R 13 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, hetarylCrC 6 alkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylC C 6 alkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyl-oxyd-Cealkyl, d-C 6 alkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C 6 alkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarbox
  • the present invention is concerned with compounds or pro- drugs thereof of the general formula (VII) wherein
  • R 1 is hydrogen, C C 8 aIkyl, hetaryl, arylCrCealkyl or hetarylCrCealkyl optionally substituted with one or more R 9 ;
  • R 2 and R 5 independently are hydrogen, halo, nitro, cyano, trihalomethyl, C r C 6 alkyl, CrCealkyloxy, d-Cealkyloxyd-C-ealkyl, aryl, arylCrC 6 alkyl, aryloxy, aryloxyC C 6 alkyl, arylCrCealkyloxy, arylCrCealkyloxyCrCealkyl, hetaryl or hetarylCrCealkyl wherein the alkyl, aryl, ary- lalkyl, hetaryl and hetarylalkyl groups independently are substituted with one or more R 9 ; and
  • R 3 is C(0)NR 7 R 8 , and R 4 is hydrogen; or R 3 is hydrogen, and R 4 is C(0)NR 7 R 8 ;
  • R 6 is d-C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, N(R 2 R 13 )CrC 6 alkyl, d-C 6 alkyloxyCr C 6 alkyl, aryloxyCrC 6 alkyl, aryld-Cealkyloxy or arylCrCealkyloxyCrCealkyl;
  • R 7 is d-C 8 alkyl optionally substituted with one or more of R 10 ;
  • R 8 is C 3 -C 10 cycloalkyl, C 3 -C ⁇ ohetcycloalkyl, C 3 -C 0 cycloalkylCrC 6 alkyl, wherein the cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 10 ; or
  • R 7 and R 8 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen or oxygen, the ring sys- tem optionally being substituted with at least one of d-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, aryld-Cealkyloxy, hetarylCrCealkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkyl
  • R 9 is hydrogen, hydroxy, oxo, halo, nitro, cyano, d-C 6 alkyl, CrC 6 alkyloxy, trihalomethyl, trihalomethoxy, NR 12 R 13 , arylCrC 6 alkyloxy, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, CrCealkylcarboxy, arylcarboxy or arylCrCealkylcarboxy;
  • R 10 and R 11 independently are hydrogen, halo, oxo, hydroxy, CrCealkyl, aryl, arylCrC 6 alkyl, hetaryl or hetarylalkyl;
  • R 12 and R 13 independently are hydrogen, d-C 8 alkyl, aryl, hetaryl, aryld-Cealkyl, C 3 -C ⁇ o- cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 -C 10 cycloalkylCrC 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, arylCrCealkylcarbonyl, C 3 -C 10 cycloalkylcarbonyl, C 3 -C ⁇ 0 hetcycloalkylcarbonyl or C 3 -C 10 cyclo- alkylCrC 6 alkylcarbonyl; or
  • R 12 and R 13 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, d-C 6 alkyloxy, aryld-C-ealkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyl-oxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, aryld-C-ealkyl-carbonyl, hetarylCrCealkylcarbonyl, CrCeal
  • R 2 is C(0)NR 7 R 8 and R 3 R and R 5 are hydrogen, wherein R 7 and R 8 are as defined above.
  • R 3 is C(0)NR 7 R 8 and R 2 R 4 and R 5 are hydrogen, wherein R 7 and R 8 are as defined above.
  • R 4 is C(0)NR 7 R 8 and R 2 R 3 and R 5 are hydrogen, wherein R 7 and R 8 are as defined above.
  • R 5 is C(0)NR 7 R 8 and
  • R 2 R 3 and R are hydrogen, wherein R 7 and R 8 are as defined above.
  • R 6 is C(0)NR 7 R 8 , wherein R 7 and R 8 are as defined above.
  • R 3 is C(0)NR 7 R 8 and R 4 is hydrogen, wherein R 7 and R 8 are as defined above.
  • R 3 is hydrogen and R 4 is C(0)NR 7 R 8 , wherein R 7 and R 8 are as defined above.
  • R 8 is C 3 -C 10 cycloalkyl or drdohetcycloaikyl, each of which is optionally substituted with one or more of R 10 , wherein R 10 is as defined above.
  • R 7 and R 8 together with the nitrogen to which they are attached are forming a saturated or partially saturated bicyclic or tricyclic ring system containing from 6 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-C 8 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrCealkyloxy, hetarylCrC 6 alkyl-oxy, d-C 6 alkyl- oxyCrC 6 alkyl, d-Cealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, hetarylCrCealkyl
  • the bicyclic ring system is 6-aza-bicyclo[3.2.1]octane optionally substituted with one or more CrC 6 alkyl.
  • the bicyclic ring system is 1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane.
  • the compounds of the general formula (VII) or a prodrug thereof is selected from the group consisting of: (1H-lndol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; 1H-lndole-6-carboxylic acid cyclohexyl-methyl-amide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
  • the compounds or prodrugs thereof of the general formula (VII) are selected from the group consisting of the compounds of examples 3 through 20 as described under EXAMPLES, COMPOUNDS OF GENERAL FORMULA (VII).
  • the present invention is concerned with compounds or prodrugs thereof of the general formula (VIII)
  • X is NR 4 , S or O;
  • R 1 and R 2 independently are hydrogen, halo, cyano, trihalomethyl, d-Cealkyl or CrCealkyloxy, wherein the alkyl groups independently are optionally substituted with one or more of R 7 ;
  • R 3 is hydrogen, CrC 6 alkyl, C 3 -C ⁇ 0 cycloalkyl, CrC 6 alkyloxy, CrC 6 alkylthio, aryl, arylCrCealkyl, hetaryl or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are optionally substituted with one or more of R 7 ;
  • R 4 is hydrogen, C C 8 alkyl, CrC 6 alkyloxyCrC 6 alkyl, aryl, hetaryl, hetarylCrCealkyl, aryld- Cealkyl, arylCrC 6 alkyloxyCrC 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C ⁇ ohetcycloalkyl, C 3 -C 10 cyclo- alkylCrC 6 alkyl, CrCealkylcarboxyCrCealkyl wherein the alkyl, aryl, hetaryl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 7 ;
  • R 5 is hydrogen
  • R 6 is adamantyl optionally substituted with hydroxy, CrC 6 alkyloxy, aryl, arylCrC 6 alkyl, aryloxy, aryld-C 6 alkyloxy, hetaryl, hetaryloxy or hetarylCrCealkyloxy wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 ; or
  • R 5 and R 6 are together with the nitrogen to which they are attached, forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 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, aryld- Cealkyl, hetarylalkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrCealkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, arylcar
  • R 7 are independently hydrogen, halo, hydroxy, oxo, nitro, NR 9 R 10 , cyano, COOR 8 ,
  • R 8 is hydrogen, d-C 6 alkyl, aryl, aryld-Cealkyl, hetarylalkyl, wherein the alkyl, aryl and het- arylalkyl groups independently are optionally substituted with one or more of R 7 ;
  • R 9 and R 10 independently are hydrogen, C C 8 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, C 3 - docycloalkyld-Cealkyl, wherein the alkyl, cycloalkyl and hetcycloalkyl groups independently are optionally substituted with one or more of R 7 ; or R 9 and R 10 together with the nitrogen to which they are attached, are forming a saturated or partially saturated 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 8 alkyl, arylCrC 6 alkyl, hetarylCrC 6 alkyl, hy- droxy, cyano, d-C 6 alkyloxy, arylCrCealkyloxy, hetarylCrCealkyloxy
  • R 11 is hydrogen, halo, oxo, hydroxy, d-C 6 alkyl, aryl, arylCrC 6 alkyl, hetaryl or hetarylalkyl;
  • hetcycloalkyl cannot be 7- aza[2,2, 1 jbicycleheptane.
  • the present invention is concerned with compounds or prodrugs thereof of the above general formula (VIII) wherein
  • X is NR 4 , S or O
  • R 1 and R 2 independently are hydrogen, halo, cyano, trihalomethyl, C C 6 alkyl or CrCealkyloxy, wherein the alkyl groups independently are optionally substituted with one or more of R 7 ;
  • R 3 is hydrogen, d-C 6 alkyl, C 3 -C 10 cycloalkyl, C C 6 alkyloxy, d-Cealkylthio, aryl, arylCrCealkyl, hetaryl or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are optionally substituted with one or more of R 7 ;
  • R 4 is hydrogen, CrC 8 alkyl, d-Cealkyloxyd-Cealkyl, aryl, hetaryl, arylCrC 6 alkyl, arylC C 6 alkyloxyCrC 6 alkyl, C 3 -C.
  • R 5 is hydrogen
  • R 6 is adamantyl optionally substituted with hydroxy, d-C 6 alkyloxy, aryl, arylCrCealkyl, aryloxy, arylCrCealkyloxy, hetaryl, hetaryloxy or hetarylCrCealkyloxy wherein the alkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 ; or
  • R 5 and R 6 are together with the nitrogen to which they are attached, forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 5 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, aryld- C 6 alkyl, hetarylalkyl, hydroxy, oxo, cyano, CrC 6 alkyloxy, arylCrCealkyloxy, hetaryld- C 6 alkyloxy, d-Cealkyloxyd-Cealkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetarylCrCealkylcarbonyl, CrCealkylcarboxy, aryl
  • R 7 are independently hydrogen, halo, hydroxy, oxo, nitro, NR 5 R 6 , cyano, COOR 8 , CONR 5 R 6 , d-C 8 alkyl, d-C 6 alkyloxy, aryloxy or hetaryloxy;
  • R 8 is hydrogen, CrC 6 alkyl, aryl, arylCrC 6 alkyl, hetarylalkyl, wherein the alkyl, aryl and het- arylalkyl groups independently are optionally substituted with one or more of R 7 ; 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.
  • X is NR 4 or S wherein R 4 is defined as above.
  • X is O. In another embodiment of the present invention, in formula (VIII) X is S. In another embodiment of the present invention, in formula (VIM) is NR 4 wherein R 4 is defined as above. In another embodiment of the present invention, in formula (VIII) R 1 and R 2 independently are hydrogen, halo, trihalomethyl or d-C e alkyl, wherein the alkyl groups independently are optionally substituted with one or more of R 7 .
  • R 3 is hydrogen, d- C 6 alkyl, aryl, aryld-Cealkyl, hetaryl or hetarylalkyl, wherein the alkyl, cycloalkyl, aryl, hetaryl and hetarylalkyl groups independently are optionally substituted with one or more of R 7 .
  • R 4 is hydrogen, d- C 8 alkyl, aryl, hetaryl, hetarylCrCealkyl, arylCrC 6 alkyl, wherein the alkyl, aryl, hetaryl, groups independently are optionally substituted with one or more of R 7 .
  • R 5 and R 6 are to- gether with the nitrogen to which they are attached, forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 6 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, aryld-Cealkyl, hetarylalkyl, hydroxy, oxo, cyano, d-C 6 alkyloxy, arylCrCealkyloxy, hetarylCrC 6 alkyloxy, d-C 6 alkyloxyCr C 6 alkyl, CrCealkylcarbonyl, arylcarbonyl, hetarylcarbonyl, arylCrCealkylcarbonyl, hetaryld- C 6 alkyl,
  • R 5 and R 6 together with the nitrogen to which they are attached, are azepane, azocane, 6-aza- bicyclo[3.2.1]octane, 8-aza-bicyclo[3.2.1]octane, 3-aza-bicyclo[3.2.1]octane, 2-aza- bicyclo[3.2.1]octane, 3-oxa-6-aza-bicyclo[3.2.1]octane, 6-aza-bicyclo[3.2.2]nonane, 3-aza- bicyclo[3.2.2]nonane, 4-aza-tricyclo[4.3.1.1 3,8 ]undecane.
  • the compounds of the general formulas (VIII) or a prodrug thereof is selected from the group consisting of : (4-Methyl-2-phenyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone ; (2,4-Dimethyl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; (4-Methyl-2-pyrazin-2-yl-thiazol-5-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone; [4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6- yl)-methanone;
  • the compounds of the general formulas (VIM) or a prodrug thereof is selected from the group consisting of : (1-Methyl-1H-imidazol-4-yl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone; [1-(6-Methyl-pyridin-2-yl)-1H-imidazol-4-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)- methanone;
  • the compounds of the present invention have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
  • the present invention also encompasses pharmaceutically acceptable salts of the present compounds.
  • Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts.
  • Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaph- thoates, glycero
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci., 66, 2 (1977), which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, barium, calcium, magnesium, zinc, calcium salts and the like.
  • amines and organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, bu- tylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N- methyl-D-glucamine, guanidine and the like.
  • cationic amino acids include lysine, arginine, histidine and the like.
  • some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
  • the pharmaceutically acceptable salts are prepared by reacting a compound of the present invention with 1 to 4 equivalents of a base such as sodium hydroxide, sodium meth- oxide, sodium hydride, potassium fe/f-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, tet -butanol, dioxane, isopropanol, ethanol etc. Mixtures of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the pre- ferred methods include use of microbial resolution, enzymatic resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, ( .)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like.
  • the compound of the present invention may be converted to a 1 :1 mixture of diastereomeric amides by treating with chiral amines, aminoac- ids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by fractional crystallization or chromatography and the stereoisomers of compound of formula I may be prepared by hydrolysing the pure diastereomeric amide.
  • polymorphs of the compounds forming part of this invention may be prepared by crystallization of said compounds under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the com- pound followed by gradual or fast cooling. The presence of polymorphs may be determined by solid probe nmr spectroscopy, ir spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the invention also encompasses prodrugs of the present compounds, which on ad- ministration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the present invention.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • esters for instance methyl esters, ethyl esters, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters.
  • esters for instance methyl esters, ethyl esters, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters.
  • 'modified compounds' for instance methyl esters, ethyl esters, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters.
  • the invention also encompasses active metabolites of the present compounds.
  • the compounds according to the invention alter, and more specifically, reduce the level of active intracellular glucocorticoid and are accordingly useful for the treatment, prevention and/or prophylaxis of disorders and diseases in which such a modulation or reduction is beneficial.
  • the present compounds may be applicable for the treatment, prevention and/or prophylaxis of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), Latent Autoimmune Diabetes in the Adult (LADA), type 1 diabetes, diabetic late complications including cardiovascular diseases, cardiovascular disorders, disorders of lipid metabolism, neurodegenerative and psychiatric disorders, dysregulation of intraocular pressure including glaucoma, immune disorders, inappropriate immune responses, musculo-skeletal disorders, gastrointestinal disorders, polycystic ovarie syndrome (PCOS), reduced hair growth or other diseases, disorders or conditions that are influenced by intracellular glucocorticoid levels, adverse effects of increased blood levels of active endogenous or exogenous glucocorticoid, and any combination thereof, adverse effects of increased plasma levels of endogenous active glucocorticoid, Cushing's disease, Cushing's syndrome, adverse effects of glucocorticoid receptor agonist treatment of
  • the present compounds may be applicable for the treatment, pre- vention and/or prophylaxis of the metabolic syndrome, type 2 diabetes, diabetes as a consequence of obesity, insulin resistance, hyperglycemia, prandial hyperglycemia, hyperinsuline- mia, inappropriately low insulin secretion, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), increased hepatic glucose production, type 1 diabetes, LADA, pediatric diabetes, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipopro- teinemia, hypercholesterolemia, decreased HDL cholesterol, impaired LDL/HDL ratio, other disorders of lipid metabolism, obesity, visceral obesity, obesity as a consequence of diabetes, increased food intake, hypertension, diabetic late complications, micro-/macroalbu- minuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia
  • asthma cystic fibrosis, emphysema, bronchitis, hypersensitivity, pneu- monitis, eosinophilic pneumonias, pulmonary fibrosis, adverse effects of glucocorticoid re- ceptor agonist treatment of inflammatory bowel disease such as Crohn's disease and ulcera- tive colitis; adverse effects of glucocorticoid receptor agonist treatment of disorders of the immune system, connective tissue and joints e.g.
  • glucocorticoid receptor agonist treatment of cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lym- phoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea, adverse effects of glucocorticoid receptor agonist treatment of diseases of muscle and at the neuro-muscular joint e.g. myasthenia gravis and heriditary myopathies (e.g. Duchenne muscular dystrophy), adverse effects of glucocorticoid receptor agonist treatment in the context of surgery & trans- plantation e.g.
  • cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lym- phoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea, adverse effects of glucocorticoid receptor agonist treatment of diseases of muscle and at the neuro-muscular joint e.g. myasthenia gravis and heriditary myopathies (e.
  • the invention relates to a compound according to the invention for use as a pharmaceutical composition.
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg/day to about 2000 mg/day, preferably from about 1 mg/day to about 500 mg/day of a compound according to the invention.
  • the patient is treated with a compound according to the in- vention for at least about 1 week, for at least about 2 weeks, for at least about 4 weeks, for at least about 2 months or for at least about 4 months.
  • the pharmaceutical composition is for oral, nasal, transdermal, pulmonal or parenteral administration.
  • the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 ⁇ HSDl is beneficial.
  • the invention also relates to a method for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 ⁇ HSDl is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of any diseases and conditions that are influenced by intracellular glucocorticoid levels as mentioned above.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of conditions and disorders where a decreased level of active intracellular glucocorticoid is desirable, such as the conditions and diseases mentioned above.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of the metabolic syndrome including insulin resistance, dyslipidemia, hypertension and obesity.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
  • IGT impaired glucose tolerance
  • IGF impaired fasting glucose
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of neurodegenerative and psychiatric disorders.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
  • the route of administration may be any route which effectively transports a compound according to the invention to the appropriate or desired site of action, such as oral, nasal, buccal, transdermal, pulmonai, or parenteral.
  • the present compounds are administered in combination with one or more further active substances in any suitable ratios.
  • Such further active substances may e.g. be selected from antiobesity agents, antidiabetics, agents modifying the lipid metabolism, antihypertensive agents, glucocorticoid receptor agonists, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotro- pin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, se- rotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds
  • CART cocaine amp
  • the antiobesity agent is leptin; dexamphetamine or amphetamine; fenfluramine or dexfenfluramine; sibutramine; orlistat; mazindol or phen- termine.
  • Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792290 (Novo Nordisk A/S), e.g. N ⁇ B29 -tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705275 (Novo Nordisk A/S), e.g. Asp B28 human insulin, US 5,504,188 (Eli Lilly), e.g.
  • Lys B28 Pro B29 human insulin EP 368 187 (Aventis), eg Lantus, which are all incorporated herein by reference, GLP-1 (glucagon like peptide-1 ) and GLP-1 derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorporated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise sulphonylureas, bigua- nides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase- IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as PPAR ⁇ modulators, PPAR ⁇ modulators, cholesterol absorption inhibitors, HSL (hormone-sensitive lipase) inhibitors and HMG CoA inhibitors (statins
  • the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp 628 human insulin, Lys B28 Pro 829 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
  • an insulin analogue or derivative such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp 628 human insulin, Lys B28 Pro 829 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
  • the present compounds are administered in combination with a sulphonylurea e.g. tolbutamide, glibenclamide, glipizide or glicazide.
  • present compounds are administered in combination with a biguanide e.g. metformin.
  • present compounds are administered in combination with a meglitinide e.g. repaglinide or senaglinide.
  • the present compounds are administered in combination with a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or compounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazo- linyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, preferably the potassium salt.
  • a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or compounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazo- linyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione or
  • the present compounds may be administered in combination with the insulin sensitizers disclosed in WO 99/19313 such as (-) 3-[4-[2-Phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salts thereof, preferably the arginine salt.
  • the insulin sensitizers disclosed in WO 99/19313 such as (-) 3-[4-[2-Phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salts thereof, preferably the arginine salt.
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor e.g. miglitol or acarbose.
  • an ⁇ -glucosidase inhibitor e.g. miglitol or acarbose.
  • the present compounds are administered in combination with an, agent acting on the ATP-dependent potassium channel of the ⁇ -cells e.g. tolbu- tamide, glibenclamide, glipizide, glicazide or repaglinide.
  • an, agent acting on the ATP-dependent potassium channel of the ⁇ -cells e.g. tolbu- tamide, glibenclamide, glipizide, glicazide or repaglinide.
  • the present compounds may be administered in combination with nateglinide.
  • the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, ator- vastatin, fluvastatin, lovastatin, pravastatin, simvastatin, acipimox, probucol, ezetimibe or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, ator- vastatin, fluvastatin, lovastatin, pravastatin,
  • the present compounds are administered in combination with more than one of the above-mentioned compounds e.g. in combination with a sulphony- lurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol, metoprolol, bisoprololfumerate, esmolol, acebutelol, metoprolol, acebutolol, betaxolol, celiprolol, nebivolol, tertatolol, oxprenolol, amusolalul, carvedilol, labetalol, ⁇ 2-receptor blockers e.g.
  • S-atenolol, OPC-1085, ACE (angiotensin converting enzyme) inhibitors such as quinapril, lisinopril, enalapril, captopril, benazepril, perindopril, trandolapril, fosinopril, ramipril, cilazapril, delapril, imidapril, moexipril, spirapril, temocapril, zofenopril, S-5590, fasidotril, Hoechst-Marion Roussel: 100240 (EP 00481522), omapatrilat, gemopatrilat and GW-660511 , calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, amlodipine, nitrendipine
  • loop-diuretics e.g. bumetanide, furosemide and torasemide
  • potassium sparing diuretics e.g. amiloride, spironolactone
  • endothelin ET-A antagonists such as ABT-546, ambrisetan, atrasentan, SB- 234551, CI-1034, S-0139 and YM-598
  • endothelin antagonists e.g. bosentan and J-104133
  • renin inhibitors such as aliskiren, vasopressin V1 antagonists e.g.
  • vasopressin V2 antagonists such as tolvaptan, SR-121463 and OPC-31260
  • B-type natriuretic peptide agonists e.g. Nesiritide, angiotensin II antagonists such as irbesartan, candesartancilexetil, losartan, valsartan, telmisartan, eprosartan, candesartan, CL-329167, eprosartan, iosartan, olmesartan, pratosartan, TA-606, and YM-358, 5-HT2 agonists e.g.
  • adenosine A1 antagonists such as naftopidil, N-0861 and FK-352
  • thromboxane A2 antagonists such as KT2-962
  • endopeptidase inhibitors e.g. ecadotril
  • nitric oxide agonists such as LP-805
  • dopamine D1 antagonists e.g. MYD-37
  • dopamine D2 agonists such as nolomirole, n-3 fatty acids e.g. omacor
  • prostacyclin agonists such as treprostinil, beraprost
  • PGE1 agonists e.g.
  • ecraprost Na+/K+ ATPase modulators e.g. PST-2238, Potassium channel activators e.g. KR-30450, vaccines such as PMD-3117, Indapamides, CGRP- unigene, guanylate cyclase stimulators, hydralazines, methyldopa, docarpamine, moxo- nidine, CoAprovel, MondoBiotech-811.
  • the present compounds may be administered in combination with one or more glucocorticoid receptor agonists.
  • glucocorticoid receptor agonists examples include betametasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, beclomethasone, butixicort, clobetasol, flunisolide, flucatisone (and analogues), momethasone, triamcinolonacetonide, triamcinolonhexacetonide GW-685698, NXC-1015, NXC-1020, NXC-1021, NS-126, P-4112, P-4114, RU-24858 and T-25 series. It should be understood that any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or more further pharmacologically active substances are considered to be within the scope of the present invention.
  • the compounds ofthe present invention may be administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and ex- cipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy,19 th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
  • compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.
  • Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules.
  • Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.
  • De- pot injectable formulations are also contemplated as being within the scope of the present invention.
  • a typical oral dosage is in the range of from about 0.001 to about 100 mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kg body weight per day, and more preferred from about 0.05 to about 10 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages.
  • the exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
  • a typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from 0.05 to about 2000 mg, e.g. from about 0.1 to about 1000 mg, from about 0.5 mg to about 500 mg., from about 1 mg to about 200 mg, e.g. about 100 mg.
  • parenteral routes such as intravenous, intrathecal, intramuscular and similar administration
  • typically doses are in the order of about half the dose employed for oral administra- tion.
  • the compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof.
  • examples are an acid addition salt of a compound having the utility of a free base and a base addition salt of a compound having the utility of a free acid.
  • pharmaceutically acceptable salts refers to non-toxic salts of the com- pounds for use according to the present invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base.
  • a compound for use according to the present invention contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable acid.
  • salts are prepared in a conventional manner by treating a solution or suspension of the compound with a chemical equivalent of a pharmaceutically acceptable base.
  • Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
  • Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds for use according to the present invention and these form a further aspect of the present invention.
  • solutions of the present compounds in sterile aqueous solution aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, syrup, phospholipids, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaery-hritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • compositions formed by combining the compounds of the inven- tion and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
  • compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulat- ing and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatine or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyc- eryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,356,108; 4,166,452; and 4,265,874, incorporated herein by reference, to form osmotic therapeutic tablets for controlled release.

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EP04725891A EP1615698B1 (en) 2003-04-11 2004-04-06 New amide derivatives and pharmaceutical use thereof
US11/265,794 US20060111366A1 (en) 2003-04-11 2005-10-11 Pharmaceutical use of substituted amides
US12/006,765 US20080108598A1 (en) 2003-02-07 2008-01-03 Pharmaceutical use of substituted amides
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