WO2007115935A1 - 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ACTIVE COMPOUNDS - Google Patents

11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ACTIVE COMPOUNDS Download PDF

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Publication number
WO2007115935A1
WO2007115935A1 PCT/EP2007/052929 EP2007052929W WO2007115935A1 WO 2007115935 A1 WO2007115935 A1 WO 2007115935A1 EP 2007052929 W EP2007052929 W EP 2007052929W WO 2007115935 A1 WO2007115935 A1 WO 2007115935A1
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Prior art keywords
alkyl
adamantan
hydroxy
bicyclo
carbonyl
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PCT/EP2007/052929
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French (fr)
Inventor
Søren EBDRUP
Henrik Sune Andersen
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High Point Pharmaceuticals, Llc
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Priority to US12/294,475 priority Critical patent/US8053447B2/en
Priority to EP07727402A priority patent/EP2010479A1/en
Priority to CA002648074A priority patent/CA2648074A1/en
Priority to AU2007236049A priority patent/AU2007236049A1/en
Priority to JP2009503537A priority patent/JP2009532418A/en
Priority to BRPI0710669-6A priority patent/BRPI0710669A2/en
Publication of WO2007115935A1 publication Critical patent/WO2007115935A1/en
Priority to US13/236,131 priority patent/US20120004209A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/54—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/64—One oxygen atom attached in position 2 or 6
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • 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
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    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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Definitions

  • the present invention relates to novel substituted cyclic amides, to their use in therapy, to pharmaceutical compositions comprising the compounds, to the use of said com- pounds 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 (1 1 ⁇ HSD1 ) 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 characterized by a combination of insulin resistance, dyslipidemia, obesity and hypertension leading to increased morbidity and mortality of cardiovascular diseases. People with the metabolic syndrome are at increased risk of developing frank type 2 diabetes, the prevalence of which is equally escalating.
  • type 2 diabetes obesity and dyslipidemia are also highly prevalent and around 70% of people with type 2 diabetes additionally have hypertension once again leading to increased mortality of cardiovascular diseases.
  • glucocorticoids are able to induce all of the cardinal features of the metabolic syndrome and type 2 diabetes.
  • 11 ⁇ -hydroxysteroid dehydrogenase type 1 (1 1 ⁇ HSD1 ) catalyses the local generation of active glucocorticoid in several tissues and organs including predominantly the liver and adipose tissue, but also e.g. skeletal muscle, bone, pancreas, endothelium, ocular tissue and certain parts of the central nervous system.
  • 1 1 ⁇ HSD1 serves as a local regulator of glucocorticoid actions in the tissues and organs where it is expressed (Tannin et al., J. Biol.
  • 11 ⁇ HSD1 in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence.
  • treatment with the non-specific 11 ⁇ HSD1 inhibitor carbenoxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes.
  • 11 ⁇ HSD1 knock-out mice are resistant to insulin resistance induced by obesity and stress.
  • the knock-out mice present with an anti-atherogenic lipid profile of decreased VLDL triglycerides and increased HDL-cholesterol.
  • mice that overexpress 1 1 ⁇ HSD1 in adipocytes develop insulin resistance, hyperlipidemia and visceral obesity, a phenotype that resembles the human metabolic syndrome (Andrews et al., J. CHn.
  • 1 1 ⁇ HSD1 promotes the features of the metabolic syndrome by increasing hepatic expression of the rate-limiting enzymes in gluconeogenesis, namely phosphoenolpyuvate carboxykinase and glucose-6-phosphatase, promoting the differentia- tion of preadipocytes into adipocytes thus facilitating obesity, directly and indirectly stimulating hepatic VLDL secretion, decreasing hepatic LDL uptake and increasing vessel contractility (Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94, 14924 (1997); Morton et al., J. Biol. Chem.
  • WO 01/90090, WO 01/90091 , WO 01/90092, WO 01/90093 and WO 01/90094 discloses 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.
  • WO 04/089470 discloses various substituted amides as modulators of the human 11 ⁇ -hydroxysteroid dehydrogenase type 1 enzyme, and further states that said compounds may be useful in treating medical disorders where a decreased intracellular concentration of active glucocorticoid is desirable.
  • WO 2004/089415 and WO 2004/089416 discloses various combination therapies using an 11 ⁇ -hydroxysteroid dehydrogenase type 1 inhibitor and respectively a glucocorticoid receptor agonist or an antihypertensive agent.
  • novel substituted cyclic amides that modulate the activity of
  • the present compounds can be used to treat disorders where a decreased level of active intracellular glucocorticoid is desirable, such as e.g. the metabolic syndrome, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), dyslipidemia, obesity, hypertension, diabetic late complications, cardiovascular diseases, arteriosclerosis, atherosclerosis, myopathy, muscle wasting, osteoporosis, neurodegenerative and psychiatric disorders, and adverse effects of treatment or therapy with glucocorticoid receptor agonists.
  • ITT impaired glucose tolerance
  • IGF impaired fasting glucose
  • dyslipidemia obesity
  • hypertension diabetic late complications
  • cardiovascular diseases arteriosclerosis, atherosclerosis, myopathy, muscle wasting, osteoporosis
  • neurodegenerative and psychiatric disorders and adverse effects of treatment or therapy with glucocorticoid receptor agonists.
  • Objects of the present invention are to provide compounds, pharmaceutical compositions and use of said compounds that modulate the activity of 11 ⁇ HSD1.
  • halogen or "halo” means fluorine, chlorine, bromine or iodine.
  • hydroxy shall mean the radical -OH.
  • sulfanyl shall mean the radical -S-.
  • sulfo shall mean the radical HO 3 S-.
  • amino shall mean the radical -NH 2 .
  • nitro shall mean the radical -NO 2 .
  • cyano shall mean the radical -CN.
  • perhalomethyl includes but are not limited to trifluoromethyl, difluoro- methyl, monofluoromethyl, trichloromethyl and the like.
  • trihalomethyl includes trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.
  • trihalomethoxy includes trifluorometoxy, trichlorometoxy, tribromometoxy, and triiodometoxy.
  • alkyl represents a saturated, branched or straight hydrocarbon group having the indicated number of carbon atoms, e.g. C 1-2 -alkyl, C 1-3 -alkyl, C 1-4 - alkyl, C 1-6 -alkyl, C 2-6 -alkyl, C 3-6 -alkyl, C 1-8 -alkyl, C 1-10 -alkyl, and the like.
  • Representative ex- amples are methyl, ethyl, propyl (e.g. prop-1-yl, prop-2-yl (or /so-propyl)), butyl (e.g.
  • 2- methylprop-2-yl (or terf-butyl), but-1-yl, but-2-yl), pentyl (e.g. pent-1-yl, pent-2-yl, pent-3-yl), 2-methylbut-1-yl, 3-methylbut-1-yl, hexyl (e.g. hex-1-yl), heptyl (e.g. hept-1-yl), octyl (e.g. oct- 1-yl), nonyl (e.g. non-1-yl), and the like.
  • pentyl e.g. pent-1-yl, pent-2-yl, pent-3-yl
  • 2-methylbut-1-yl 3-methylbut-1-yl
  • hexyl e.g. hex-1-yl
  • heptyl e.g. hept-1-yl
  • octyl e.g. oct- 1-
  • Ci -6 -alkyl represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms, e.g. Ci- 2 -alkyl, Ci -3 -alkyl, Ci- 4 -alkyl, C 1-6 -alkyl, C 2-6 -alkyl, C 3-6 -alkyl, and the like.
  • Representative examples are methyl, ethyl, propyl (e.g. prop-1-yl, prop-2-yl (or /so-propyl)), butyl (e.g.
  • C ⁇ -alkyl represents a saturated, branched or straight hydrocarbon group having from 1 to 4 carbon atoms, e.g. C- ⁇ - 2 -alkyl, d-3-alkyl, d- 4 -alkyl and the like. Representative examples are methyl, ethyl, propyl (e.g.
  • prop-1-yl prop-2-yl (or /so-propyl)), butyl (e.g. 2-methylprop-2- yl (or tert-butyl), but-1-yl, but-2-yl), and the like.
  • butyl e.g. 2-methylprop-2- yl (or tert-butyl), but-1-yl, but-2-yl, and the like.
  • alkenyl includes C 2 -C 6 straight chain unsaturated aliphatic hydrocarbon groups and branched C 3 -C 6 unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl, methylbutenyl and the like.
  • alkynyl includes C 2 -C 6 straight chain unsaturated aliphatic hydrocarbon groups and C 4 -C 6 branched unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylbutynyl, and the like.
  • saturated or partially saturated cyclic, bicyclic or tricyclic ring system represents but are not limited to azepanyl, azocanyl, 1 ,2,3,4-tetrahydro-quinolinyl, 1 ,2,3,4- tetrahydro-isoquinolinyl, 1 ,2,3,4-tetrahydro-quinoxalinyl, indolinyl, 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[3.3.2]decanyl, 4-aza-tricyclo[4.3.1.1 3 8 ]undecanyl, 9-aza-tricyclo[3.3.2.0 37 ]decanyl, 8- aza-spiro[4.5]decane.
  • cycloalkyl represents a saturated monocyclic carbocyclic ring having the specified number of carbon atoms, e.g. C 3-6 -alkyl, C 3-8 -alkyl, C 3- i 0 -alkyl, and the like. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo- heptyl, cyclooctyl, and the like. Cycloalkyl is also intended to represent a saturated bicyclic carbocyclic ring having from 4 to 10 carbon atoms.
  • Cycloalkyl is also intended to represent a saturated carbocyclic ring having from 3 to 10 carbon atoms and containing one or two car- bon bridges.
  • Representative examples are adamantyl, norbornanyl, nortricyclyl, bicycle-
  • Cycloalkyl is also intended to represent a saturated carbocyclic ring having from 3 to 10 carbon atoms and containing one or more spiro atoms. Representative examples are spiro[2.5]octanyl, spiro[4.5]decanyl, 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, cyclohep- tenyl, 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
  • cycloalkylcarbonyl represents 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
  • heteroalkyl e.g. tetrahydrofuranyl, tetrahydropyranyl, tertahydrothio- pyranyl, piperidine, pyridazine and the like
  • hetcycloalkyl represents a saturated mono-, bi-, tri- or spiro- carbocyclic group having the specified number of carbon atoms and one or two additional heteroatoms or groups selected from nitrogen, oxygen, sulphur, SO or SO 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.
  • aryloxy e.g. phenoxy, naphthyloxy and the like
  • aryloxy represents an aryl group as defined below attached through an oxygen bridge.
  • hetaryloxy e.g. 2-pyridyloxy and the like
  • aryloxyalkyl e.g. phenoxymethyl, naphthyloxyethyl and the like
  • alkyl e.g. phenoxymethyl, naphthyloxyethyl and the like
  • arylalkyloxy e.g. phenethyloxy, naphthylmethyloxy and the like
  • hetarylalkyloxy e.g. 2-pyridylmethyloxy and the like
  • 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.
  • arylalkyloxyalkyl (e.g. ethoxymethyl-benzene, 2-methoxymethyl-naphtha- lene and the like) represents an arylalkyloxy group as defined above attached through an "alkyl” group having the indicated number of carbon atoms.
  • alkylthio (e.g. methylthio, ethylthio and the like) represents an alkyl group as defined above attached through a sulphur bridge.
  • alkyloxycarbonyl e.g. methylformiat, ethylformiat and the like
  • alkyloxycarbonyl represents an alkyloxy group as defined above attached through a carbonyl group.
  • aryloxycarbonyl e.g. phenylformiat, 2-thiazolylformiat and the like
  • aryloxycarbonyl represents an aryloxy group as defined above attached through a carbonyl group.
  • arylalkyloxycarbonyl e.g. benzylformiat, phenyletylformiat and the like
  • arylalkyl represents an "arylalkyloxy” group as defined above attached through a carbonyl group.
  • arylalkyl e.g. benzyl, phenylethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like
  • hetarylalkyl e.g. (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3- thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like
  • hetarylalkyl represents a hetaryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • alkylcarbonyl refers to the alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group. Represen- tative examples are acetyl (methylcarbonyl), propionyl (ethylcarbonyl), butanoyl (prop-1- ylcarbonyl, prop-2-ylcarbonyl), pentylcarbonyl, 3-hexenylcarbonyl, octylcarbonyl, and the like.
  • arylcarbonyl e.g. benzoyl
  • hetarylcarbonyl e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like
  • alkylcarbonylalkyl e.g. propan-2-one, 4,4-dimethyl-pentan-2-one and the like
  • alkylcarbonylalkyl represents an alkylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • 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.
  • alkylcarboxy e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy
  • alkylcarboxy represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • arylcarboxy e.g. benzoic acid and the like
  • arylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • alkylcarboxyalkyl e.g. heptylcarboxymethyl, propylcarboxy terf-butyl, 3- pentylcarboxyethyl
  • alkylcarboxyalkyl represents an alkylcarboxy group as defined above wherein the carboxy group is in turn attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylalkylcarboxy e.g. benzylcarboxy, phenylpropylcarboxy and the like
  • 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.
  • alkylS(O) n represents an alkyl group as defined above, wherein the alkyl group is in turn attached through a sulphur bridge wherein the sulphur is substituted with n oxygen atoms.
  • arylS(O) n 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 n oxygen atoms.
  • arylalkylS(O) n repre- sents an arylalkyl group as defined above, wherein the arylalkyl group is in turn attached through a sulphur bridge wherein the sulphur is substituted with n oxygen atoms.
  • bridge represents a connection in a saturated or partly saturated ring between two atoms of such ring that are not neighbors through a chain of 1 to 3 atoms selected from carbon, nitrogen, oxygen and sulfur.
  • connecting chains are -CH 2 -, -CH 2 CH 2 -, -CH 2 NHCH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, and the like.
  • the connecting chain is selected from the group consisting Of -CH 2 -, -CH 2 CH 2 -, Or -CH 2 OCH 2 -.
  • spiro atom represents a carbon atom in a saturated or partly saturated ring that connects both ends of a chain of 3 to 7 atoms selected from carbon, nitrogen, oxygen and sulfur.
  • Representative examples are -(CH 2 ) 5 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -
  • aryl as used herein is intended to include monocyclic, bicyclic or poly- cyclic carbocyclic aromatic rings.
  • Representative examples are phenyl, naphthyl (e.g. naphth-1-yl, naphth-2-yl), anthryl (e.g. anthr-1-yl, anthr-9-yl), phenanthryl (e.g. phenanthr-1- yl, phenanthr-9-yl), and the like.
  • Aryl is also intended to include monocyclic, bicyclic or poly- cyclic carbocyclic aromatic rings substituted with carbocyclic aromatic rings.
  • Representative examples are biphenyl (e.g.
  • Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic rings with at least one unsaturated moiety (e.g. a benzo moiety).
  • Representative examples are, indanyl (e.g. indan-1-yl, indan-5-yl), in- denyl (e.g. inden-1-yl, inden-5-yl), 1 ,2,3,4-tetrahydronaphthyl (e.g.
  • fluorenyl e.g. fluo- ren-1-yl, fluoren-4-yl, fluoren-9-yl
  • Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or two bridges. Representative examples are, benzonorbornyl (e.g. benzonorborn-3-yl, benzonorborn-6-yl), 1 ,4- ethano-1 ,2,3,4-tetrahydronapthyl (e.g. 1 ,4-ethano-1 ,2,3,4-tetrahydronapth-2-yl,1 ,4-ethano- 1 ,2,3,4-tetrahydronapth-10-yl), and the like.
  • Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or more spiro atoms.
  • Repre- sentative examples are spiro[cyclopentane-1 ,1 '-indane]-4-yl, spiro[cyclopentane-1 ,1 '-indene]- 4-yl, spiro[piperidine-4,1 '-indane]-1-yl, spiro[piperidine-3,2'-indane]-1-yl, spiro[piperidine-4,2'- indane]-1-yl, spiro[piperidine-4,1 '-indane]-3'-yl, spiro[pyrrolidine-3,2'-indane]-1-yl, spiro[pyrro- lidine-3,1 '-(3',4'-dihydronaphthalene)]-1-yl, spiro[piperidine-3,1 '-(3',4'-dihydronaphthalene)]-1-yl, spiro[piper
  • Representative examples are pyrrolyl (e.g. pyrrol-1-yl, pyrrol-2- yl, pyrrol-3-yl), furanyl (e.g. furan-2-yl, furan-3-yl), thienyl (e.g. thien-2-yl, thien-3-yl), oxazolyl (e.g.
  • pyridazin-2-yl pyridazin-3-yl
  • pyrimidinyl e.g. pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl
  • pyrazinyl 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazinyl, thiadiaz- inyl, azepinyl, anovanyl, and the like.
  • indolyl e.g. indol-1-yl, indol-2- yl, indol-3-yl, indol-5-yl
  • isoindolyl e.g. benzofuranyl (e.g. benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo[b]furan-5-yl, benzo[c]furan-2-yl, benzo[c]furan-3-yl, benzo[c]furan-5-yl), benzothienyl (e.g.
  • quinazolin-2-yl quinazolin-4-yl, quinazolin-6- yl
  • cinnolinyl quinoliny (e.g. quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl), iso- quinolinyl (e.g. isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl), quinoxalinyl (e.g. quinoxa- lin-2-yl, quinoxalin-5-yl), pyrrolopyridinyl (e.g.
  • thiazolopyridinyl e.g. thiazolo[3,2-d]py ⁇ dinyl
  • thia- zolopyrimidinyl e.g. thiazolo[5,4-d]pyrimidinyl
  • Representative examples are carbazolyl (e.g. carbazol-2-yl, carbazol-3-yl, carbazol- 9-yl), phenoxazinyl (e.g. phenoxazin-10-yl), phenazinyl (e.g. phenazin-5-yl), acridinyl (e.g. acridin-9-yl, acridin-10-yl), phenothiazinyl (e.g.
  • phenothiazin-10-yl carbolinyl (e.g. pyrido- [3,4-b]indol-1-yl, pyrido[3,4-b]indol-3-yl), phenanthrolinyl (e.g. phenanthrolin-5-yl), and the like.
  • Representative examples are pyrrolinyl, pyrazolinyl, imi- dazolinyl (e.g.
  • Hetaryl or heteroaryl is also intended to include partially saturated bicyclic or polycyclic heterocyclic rings containing one or more spiro atoms.
  • Representative examples are spiro[isoquinoline-3,1 '-cyclohexan]-1-yl, spiro[piperidine-4,1 '-benzo- [c]thiophen]-1-yl, spiro[piperidine-4,1 '-benzo[c]furan]-1-yl, spiro[piperidine-4,3'-benzo[b]fu- ran]-1-yl, spiro[piperidine-4,3'-coumarin]-1-yl, and the like.
  • bicyclic hetaryl or "bicyclic heteroaryl” as used herein is intended to include bicyclic heterocyclic aromatic rings as defined above.
  • the first mentioned radical is a substituent on the subsequently mentioned radical, where the point of substitution, i.e. the point of attachment to another part of the molecule, is on the last mentioned of the radicals.
  • treatment is defined as the management and care of a patient for the purpose of combating or alleviating the disease, condition or disorder, and the term includes the administration of the active compound to prevent the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • prodrug 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. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention is based on the observation that the compounds of the general formulas (I) disclosed below are able to modulate or inhibit the activity of 1 1 ⁇ HSD1.
  • R 1 is hydrogen, Ci-C 4 alkyl or cyclopropyl and R 2 is adamantyl optionally substituted with O to 1 R 18 ;
  • R 3 is selected from -1 ,2-cyclopentyl-R 9 , -1 ,3-cyclopentyl-R 9 , -1 ,4-cyclohexyl-R 9 , -CH 2 -I ,4- cyclohexyl-R 9 , -1 ,3-cyclohexyl-R 9 , -CH 2 -1 , 3-cyclohexyl-R 9 , -3-pyrrolidin-1-yl-R 10 , -CH 2 -3- pyrrolidin-1-R 10 , 4-tetrahydro-pyran, 4-tetrahydro-pyran-2-yl-R 9 , 4-tetrahydro-pyran-3-yl-R 9 , -4-piperidin-1-yl-R 11 , -CH 2 -4-piperidin-1-yl-R 11 , -3-piperidin-1-yl-R 11 , -CH 2 -3-piperidin-1-
  • X is selected from -O-, -S(O) n -, -CR 5 R 6 -, and -NR 7 -; or
  • R 3 and R 7 are connected by a covalent bond so as to form a bicyclic or tricyclic hetcycloalkyl ring comprising the N to which R 3 and R 7 are connected; the hetcycloalky ring may further be substituted with one or more R 19 ;
  • R 4 is selected from hydrogen, CrC 4 alkyl, trifluoromethyl, halogen, d-C 4 alkyloxy, Ci-C 4 alkyl- oxyCi-C 4 alkyl and Ci-C 4 alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R 18 ;
  • R 5 and R 6 independently are selected from hydrogen, fluorine, methyl, ethyl, iso-propyl or cyclopropyl;
  • R 7 is selected from hydrogen or selected from Ci-C 6 alkyl, Ci-C 6 alkenyl, CrC 6 alkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with 0 to 2 R 19 ;
  • R 8 is selected from C-rC 6 alkyl, C-rC 6 alkenyl, C-rC 6 alkynyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl, each of which may be substituted with 0 to 2 R 19 ; or
  • R 7 and R 8 optionally are connected by a covalent bond so as to form a ring comprising the N to which R 7 and R 8 are connected; the ring may further be substituted with one or more R 19 ;
  • R 10 and R 11 independently are selected from -C(O)NR 7 R 8 , -CH 2 C(O)NR 7 R 8 , -C(O)R 17 , -S(O) 2 R 16 or -S(O) 2 NR 7 R 8 , wherein the alkyl, aryl and hetaryl groups are optionaly substituted with O to 2 R 19 ;
  • n and n independently are O, 1 or 2;
  • R 13 is selected from hydroxy, C-rC 6 alkyl, C-rC 6 alkenyl, C-rC 6 alkynyl, cycloalkyl, CrC ⁇ alkyloxy, aryl, aryloxy, aryld-C ⁇ alkyloxy, hetaryl, hetaryloxy or hetarylCrC ⁇ alkyloxy wherein the CrC 6 alkyl, cycloalkyl, aryl or hetaryl groups are optionaly substituted with one or more R 19 ;
  • R 14 and R 15 independently are selected from hydrogen, halogen, C-rC ⁇ alkyl and cycloalkyl, each of which CrC 6 alkyl and cycloalkyl may be substituted with 0 to 2 halogen, hydroxy or OXO and the carbon in CR 14 R 15 can together with the R 14 and/or R 15 groups be part of a cycloalkyl ring;
  • R 16 is selected from hydrogen, d-C ⁇ alkyl, d-C ⁇ alkenyl, d-C ⁇ alkynyl, cycloalkyl, hetcycloal- kyl, aryl or hetaryl wherein the CrC 6 alkyl, cycloalkyl, aryl or hetaryl groups are optionaly substituted with one or more R 19 ;
  • R 17 is selected from hydrogen, C r C 6 alkyl, Ci-C 6 alkylC(O)R 20 , -(CR 14 R 15 ) n NR 17 S(O) 2 R 16 , cycloalkyl, hetcycloalkyl, aryl or hetaryl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups optionaly are substituted with one or more R 21 ;
  • R 18 is halogen, hydroxy, oxo, -S(O) 2 C 1 -C 4 alkyl, -S(O) 2 NR 7 R 8 or -C(O)R 13 ;
  • R 19 is selected from halogen, hydroxy, oxo, -C(O)R 20 , C 1 -C 6 alkylC(O)R 20 , -S(O) n R 16 , -S(O) n NR 7 R 8 , cyclopropyl, -OR 16 , C r C 6 alkyl, aryl, hetaryl, -NR 22 C(O)NR 7 R 8 , -NR 22 S(O) 2 NR 7 R 8 or -NC(O)NHS(O) 2 R 16 ;
  • R 20 is selected from hydroxy, Ci-C 6 alkyl, CrC 6 alkenyl, CrC 6 alkynyl, cycloalkyl, CrC 6 alkyloxy, aryl, aryloxy, arylCrC 6 alkyloxy, hetaryl, hetaryloxy or hetarylCi-C 6 alkyloxy;
  • R 21 is halogen, cyano or hydroxy
  • n is O.
  • R 14 and R 15 are both hydrogen.
  • n is 1.
  • R 7 and R 8 are connected by a covalent bond so as to form a pyrrolidine, a piperidine, a piperazine, a substituted pyrrolidine, a substituted piperidine or a substituted piperazine.
  • R 7 and R 8 are connected by a covalent bond so as to form a piperidine, a piperazine, a substituted piperidine or a substituted piperazine.
  • R 4 is hydrogen.
  • R 1 and R 2 together with the nitrogen to which they are attached, are forming a 8-1 1 membered saturated or partially saturated bicyclic or tricyclic ring, said ring being selected from the group consisting of
  • R 22 is independently selected from Ci-C 8 alkyl, halogen, hydroxy, oxo, C(O)R 13 , -S(O) 2 NR 7 R 8 , -S(O) n CrC 4 alkyl and CrC 6 alkyloxy.
  • X is -0-. In another embodiment of the present invention, in formula (I), X is -NR 7 -.
  • R 3 and R 7 are connected by a covalent bond so as to form a bicyclic or tricyclic hetcycloalkyl ring comprising the N to which R 3 and R 7 are connected wherein the hetcycloalky ring may further be substituted with one or more R 19 .
  • R 3 and R 7 together with the N to which they are connected comprises 2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2,5- diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester or (1 S,5R)-3-(pyridin-2-yloxy)- 8-aza-bicyclo[3.2.1]oct-8-yl.
  • R 3 is -1 ,4-cyclohexyl- R 9 or -CH 2 -1 ,4-cyclohexyl-R 9 .
  • R 9 in formula (I), R 9 ; i ⁇ s In another embodiment of the present invention, in formula (I) 1 R 13 is hydroxy. In another embodiment of the present invention, in formula (I), R 9 is selected from
  • R 9 is selected from -NH-S(O) 2 -aryl, -NH-S(O) 2 -hetaryl, -NH-aryl, -NH-hetaryl, -S(O) 2 -aryl and -S(O) 2 -hetaryl, where the aryl and hetaryl groups are optionally substituted.
  • R 3 is -1 ,3-cyclohexyl- R 9 or -CH 2 -1 ,3-cyclohexyl-R 9 .
  • R 3 comprises a cyclohexyl ring and R 39 ⁇ or D R12 is attached in the c/s-configuration.
  • R 3 is -4-piperidin-1-yl- R 11 or -CH 2 -4-piperidin-1-yl-R 11 .
  • R 11 is selected from aryl, hetaryl, -S(O) 2 -aryl and -S(O) 2 -hetaryl, where each aryl and hetaryl groups are optionally substituted.
  • R 3 is -3-piperidin-1-yl- R 11 or -CH ⁇ -piperidin-i-yl-R 11 .
  • R 1 is hydrogen, Ci-C 4 alkyl or cyclopropyl.
  • R 2 is an adamantyl substituted with one, two or more substituents independently selected from halogen, hy- droxy, oxo, C(O)R 13 , C r C 6 alkyl, C r C 6 alkyloxy, -S(O) 2 NR 7 R 8 , and -S(O) n Ci-C 4 alkyl.
  • R 1 and R 2 together with the nitrogen to which they are attached, are forming a substituted 8-aza-bicyclo[3.2.1]- octane.
  • R 1 and R 2 together with the nitrogen to which they are attached is 8-aza-bicyclo[3.2.1]octan-3-yl.
  • R 1 and R 2 together with the nitrogen to which they are attached are forming 8-aza-bicyclo[3.2.1]octane substituted with one, two or more substituents independently selected from halogen, hydroxy, oxo, C(O)RI 3, C r C 6 alkyl, C r C 6 alkyloxy, -S(O) 2 NR 7 R 8 and -S(0) n C r C 4 alkyl.
  • the compound of formula (I) is
  • R 1 is hydrogen, Ci-C 4 alkyl or cyclopropyl and R 2 is a substituted or unsubstituted adamantyl;
  • R 21 is halogen, hydroxy, oxo or COOH
  • R 4 is selected from hydrogen, C ⁇ C 4 alkyl, trifluoromethyl, halogen, C-rC 4 alkyloxy, Ci-C 4 alkyloxyC ⁇ C 4 alkyl and C 1 -C 4 alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R 21 ;
  • X is selected from -O-, -S-, -CR 5 R 6 -, -NH-, and -NR 6 -;
  • R 5 is hydrogen or fluorine
  • R 6 is hydrogen, methyl, ethyl, iso-propyl or cyclo-propyl
  • R 3 is selected from -1 ,4-cyclohexyl-R 7 , -CH 2 -1 , 4-cyclohexyl-R 8 , -1 ,3-cyclohexyl-R 9 , -CH 2 -1 ,3- cyclohexyl-R 10 , -4-piperidin-1-yl-R 11 , -CH 2 -4-piperidin-1-yl-R 12 , -3-piperidin-1-yl-R 13 , -CH 2 -3- piperidin-1-yl-R 14 , -4-bicyclo[2.2.2]octan-1-yl-R 15 and -CH 2 -4-bicyclo[2.2.2]octan-1-yl-R 16 ;
  • n O, 1 or 2;
  • each R 22 and R 23 are independently selected from hydrogen, halogen, CrC 6 alkyl and cycloalkyl, each of which d-C ⁇ alkyl and cycloalkyl may be substituted with O to 2 halogen, hydroxy or oxo and the carbon in CR 22 R 23 can together with the R 22 and/or R 23 groups be part of a cycloalkyl ring;
  • R 20 is selected from halogen, hydroxy, oxo, -COOH, -S(O) 0-2 R 19 , -S(O) 0-2 NR 19 R 19 , cyclopro- pyl, -0-R 19 , Ci-C 6 alkyl, aryl, hetaryl, NR 19 CONR 19 R 19 ; NR 19 SO 2 NR 19 R 19 or NCONHSO 2 R 19 '
  • R 17 is selected from hydrogen or selected from d-C 6 alkyl, CrC 6 alkenyl, CrC 6 alkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R 20 ;
  • R 18 is selected from C-rC 6 alkyl, C-rC 6 alkenyl, C-rC 6 alkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R 20 ; where R 17 and R 18 are optionally connected by a covalent bond so as to form a ring comprising the N to which R 17 and R 18 are connected;
  • R 19 is selected from hydrogen, hydroxy, C-i-C ⁇ alkyl, d-C ⁇ alkenyl, d-C ⁇ alkynyl, cycloalkyl, CrC 6 alkyloxy, aryl or hetaryl wherein hydroxy, CrC 6 alkyl, cycloalkyl, CrC 6 alkyloxy, aryl or hetaryl are optional substituted with R 20 ;
  • R 11 , R 12 , R 13 and R 14 are independently selected from -C(O)-NR 17 R 18 , -CH 2 C(O)-NR 17 R 18 , C(O)R 19 , -S( OO)) 22 RR 1188 ,, --SS((OO)) 22 NNRR 1177 RR 1188 ,, CCi r -CC 66 aallkkyyll ssuubbssttiittuuted with O to 2 R 20 , aryl substituted with O to 2 R 20 , and hetaryl substituted with O to 2 R 20 ; or
  • R is understood to be selected from the group
  • n is 0. In another embodiment of the present invention, in formula (I) R 22 and R 23 are both hydrogen.
  • n 1
  • n is 1 and both R ,22 and R are hydrogen.
  • R 17 and R 18 are con- nected by a covalent bond so as to form a piperidine, a piperazine, a substituted piperidine or a substituted piperazine.
  • R 17 and R 18 are connected by a covalent bond so as to form a piperidine or a substituted piperidine.
  • R 4 is hydrogen.
  • R 1 and R 2 together with the nitrogen to which they are attached are forming a 8-11 membered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitrogen, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S(O) m , where m is O, 1 or 2.
  • R 1 and R 2 together with the nitrogen to which they are attached are forming a 8-11 membered saturated or partially saturated bicyclic or tricyclic ring, said ring being selected from the group consisting of
  • R 25 is independently selected from d-C 8 alkyl, halogen, hydroxy, oxo, COOH, and C-i-C ⁇ alkyloxy.
  • R 1 and R 2 together with the nitrogen to which they are attached are forming a 8-11 membered saturated or partially saturated bicyclic or tricyclic ring, said ring being selected from the group consisting of
  • X is -O-. In another embodiment of the present invention, in formula (I) X is -S-. In another embodiment of the present invention, in formula (I) X is -CR 5 R 6 -. In another embodiment of the present invention, in formula (I) X is -NH-. In another embodiment of the present invention, in formula (I) X is -NR 6 -.
  • R 5 is hydrogen.
  • R 6 is hydrogen.
  • X is -CH 2 -.
  • R 3 is -1 ,4-cyclohexyl-
  • R 7 and R 8 are C(O)R 19 .
  • R 19 is hydroxy.
  • R 7 and R 8 are selected from -CH 2 -O-aryl, -CH 2 -O-hetaryl, -O-aryl, -O-hetaryl, -CH 2 -O-Ci -6 alkyl, -NHC(O)R 18 , where the aryl, hetaryl and Ci -6 alkyl groups are optionally substituted.
  • R 7 and R 8 are selected from -NH-S(O) 2 -aryl, -NH-S(O) 2 -hetaryl, -NH-aryl, -NH-hetaryl, -S(O) 2 -aryl and - S(O) 2 -hetaryl, where the aryl and hetaryl groups are optionally substituted.
  • R 3 is -1 ,3-cyclohexyl- R 9 or -CH 2 -1 ,3-cyclohexyl-R 10 .
  • R 3 comprises a cyclo- hexyl ring and R ⁇ >7 , D R8 , D R9 _ or D R10 is attached in the c/s-configuration.
  • R 3 comprises a cyclo- hexyl ring and R 7 , R 8 , R 9 or R 10 is attached in the frans-configuration.
  • R 3 is -4-piperidin-1-yl- R 11 or -CH 2 -4-piperidin-1-yl-R 12 .
  • R 11 and R 12 are se- lected from aryl, hetaryl, -S(O) 2 -aryl and -S(O) 2 -hetaryl, where each aryl and hetaryl groups are optionally substituted.
  • R 3 is -3-piperidin-1-yl- R 13 or -CH 2 -3-piperidin-1-yl-R 14 .
  • R 20 is halogen, hy- droxy, oxo, -COOH or cyclopropyl.
  • R 1 is hydrogen, Ci-C 4 alkyl or cyclopropyl.
  • R 2 is an unsubstituted adamantyl selected from 1-adamantyl and 2-adamantyl. In another embodiment of the present invention, in formula (I) R 2 is a substituted adamantyl.
  • R 2 is a substituted 1- adamantyl or a substituted 2-adamantyl.
  • R 2 is an adamantyl substituted with one, two or more substituent independently selected from halogen, hydroxy, oxo, COOH, Ci-C 6 alkyl and d-C 6 alkyloxy.
  • R 1 and R 2 together with the nitrogen to which they are attached, are forming a 8-11 mem- bered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitro- gen, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S(O) m , where m is 0, 1 or 2, and said ring being substituted with 0 to 3 groups independently selected from d-C 4 alkyl, halogen, hydroxy, oxo, COOH, -NHR 17 , NR 17 R 17 , Ci-C 4 alkyloxy, Ci-C 4 alkyloxyCrC 4 alkyl and Ci-C 4 alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R 21 , or
  • R 1 is hydrogen, Ci-C 4 alkyl or cyclopropyl and R 2 is a substituted or unsubstituted adamantyl;
  • R 21 is halogen, hydroxy, oxo or COOH
  • R 4 is selected from hydrogen, C ⁇ C 4 alkyl, trifluoromethyl, halogen, C-rC 4 alkyloxy,
  • X is selected from -O-, -S-, -CR 5 R 6 -, -NH-, and -NR 6 -;
  • R 5 is hydrogen or fluorine
  • R 6 is hydrogen, methyl, ethyl, iso-propyl or cyclo-propyl
  • R 3 is selected from -1 ,4-cyclohexyl-R 7 , -CH 2 -1 ,4-cyclohexyl-R 8 , -1 ,3-cyclohexyl-R 9 , -CH 2 -1 ,3- cyclohexyl-R 10 , -4-piperidin-1-yl-R 11 , -CH 2 -4-piperidin-1-yl-R 12 , -3-piperidin-1-yl-R 13 , -CH 2 -3- piperidin-1-yl-R 14 , -4-bicyclo[2.2.2]octan-1-yl-R 15 and -CH 2 -4-bicyclo[2.2.2]octan-1-yl-R 16 ;
  • n O, 1 or 2;
  • each R 22 and R 23 are independently selected from hydrogen, halogen, CrC 6 alkyl and cycloalkyl, each of which d-C ⁇ alkyl and cycloalkyl may be substituted with O to 2 halogen, hydroxy or oxo and the carbon in CR 22 R 23 can together with the R 22 and/or R 23 groups be part of a cycloalkyl ring;
  • R 20 is halogen, hydroxy, oxo, -COOH, -S(O) 0-2 R 19 , -S(O) 0-2 NR 19 R 19 , cyclopropyl, -0-R 19 or Ci-C 6 alkyl;
  • R 17 is hydrogen or selected from d-C 6 alkyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R 20 ;
  • R 18 is C-i-C ⁇ alkyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R 20 ; wwhheerree RR 1177 aanndd RR 1188 aarree ooppttiioonnaallllyy ccoonnnneecctteedd bb ⁇ y a covalent bond so as to form a ring compris- ing the N to which R 17 and R 18 are connected;
  • R 19 is selected from hydroxy, C-rC 6 alkyl, cycloalkyl, C-rC 6 alkyloxy, aryl or hetaryl wherein hydroxy, C ⁇ C 6 alkyl, cycloalkyl, d-C ⁇ alkyloxy, aryl or hetaryl are optional substituted with R 20 .
  • R 11 , R 12 , R 13 and R 14 are independently selected from -C(O)-NR 17 R 18 , -CH 2 C(O)-NR 17 R 18 , - C(O)R 19 , -S(O) 2 R 18 , -S(O) 2 NR 17 R 18 , C r C 6 alkyl substituted with O to 2 R 20 , aryl substituted with O to 2 R 20 , and hetaryl substituted with O to 2 R 20 ; or
  • R 1 and R 2 together with the nitrogen to which they are attached, are forming a 8-11 mem- bered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitrogen, 5-10 carbon atoms and from O to 1 additional heteroatoms selected from nitrogen, oxygen, and S(0) m , where m is O, 1 or 2, and said ring being substituted with O to 3 groups inde- pendently selected from Ci-C 4 alkyl, halogen, hydroxy, oxo, CrC 4 alkyloxy, Ci-C 4 alkyloxy-
  • each alkyl group is substituted with O to 1 R 21 , or R 1 is hydrogen, Ci-C 4 alkyl or cyclopropyl and R 2 is a substituted or unsubstituted adamantyl; R 21 is halogen, hydroxy, oxo or COOH;
  • R 4 is selected from hydrogen, Ci-C 4 alkyl, trifluoromethyl, halogen, Ci-C 4 alkyloxy, Ci-C 4 alkyloxyCi-C 4 alkyl and CrC 4 alkylcarbonyl, wherein each alkyl group is substituted with O to 1 R 21 ;
  • X is selected from -0-, -S-, -CR 5 R 6 -, -NH-, and -NR 6 -;
  • R 5 is hydrogen or fluorine
  • R 6 is hydrogen, methyl, ethyl, iso-propyl or cyclo-propyl
  • R 3 is selected from -1 ,4-cyclohexyl-R 7 , -CH 2 -1 , 4-cyclohexyl-R 8 , -1 ,3-cyclohexyl-R 9 , -CH 2 -1 ,3- cyclohexyl-R 10 , -4-piperidin-1-yl-R 11 , -CH 2 -4-piperidin-1-yl-R 12 , -3-piperidin-1-yl-R 13 , -CH 2 -3- piperidin-1-yl-R 14 , -4-bicyclo[2.2.2]octan-1-yl-R 15 and -CH 2 -4-bicyclo[2.2.2]octan-1-yl-R 16 ;
  • R 7 , R 8 , R 9 , R 10 , R 15 and R 16 are independently selected from CO 2 H, C(O)R 19 , OH, -C(O)- NR 17 R 18 , -NHC(O)R 18 , -CH 2 NHC(O)R 18 , -OR 18 , -SR 18 , -S(O) 2 R 18 , -NR 17 R 18 , -CH 2 OR 18 , - CH 2 SR 18 , -CH 2 NHR 18 , -C(O)R 19 , -CH 2 -O-R 19 , -CH 2 C(O)-NR 17 R 18 , aryl substituted with O to 2 R 20 , and hetaryl substituted with O to 2 R 20 ;
  • R 20 is halogen, hydroxy, oxo, COOH or C r C 6 alkyl
  • R 17 is hydrogen or selected from d-C ⁇ alkyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R 20 ;
  • R 18 is C ⁇ C 6 alkyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R 20 ; where R 17 and R 18 are optionally connected by a covalent bond so as to form a ring compris- ing the N to which R 17 and R 18 are connected;
  • R 19 is selected from hydroxy, Ci-C ⁇ alkyl, cycloalkyl, d-C ⁇ alkyloxy, aryl or hetaryl;
  • R 11 , R 12 , R 13 and R 14 are independently selected from -C(O)-NR 17 R 18 , -CH 2 C(O)-NR 17 R 18 , - C(O)R 19 , -S(O) 2 R 18 , CrC 6 alkyl substituted with O to 2 R 20 , aryl substituted with O to 2 R 20 , and hetaryl substituted with O to 2 R 20 ; or
  • the compounds of general formula (I) is selected from the group consisting of
  • Cis-Pyridine-2-sulfonic acid ⁇ 4-[4-(octahydro-quinoline-1 -carbonyl)-phenoxy]-cyclohexyl ⁇ - amide
  • the polar surface area (PSA) of said compound is in the range from 40 A 2 to 130 A 2 , preferably from 50 A 2 to 130 A 2 , more preferably from 60 A 2 to 120 A 2 , more preferably from 70 A 2 to 120 A 2 , most prefer- able from 70 A 2 to 110 A 2 .
  • the molar weight of said compound is in the range from 350D to 650D, preferably from 400D to 600D.
  • 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
  • inorganic or organic acid addition salts include the pharmaceutically accept- able 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.
  • solvates 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 terf-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, tert-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 preferred 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, [R)- 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, ami- noacids, 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; or various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound 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, terf-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters.
  • esters for instance methyl esters, ethyl esters, terf-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters.
  • 'modified compounds' for instance methyl esters, ethyl esters, terf-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, pre- vention 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, prevention 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, hyperlipoproteinemia, 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, ar- teriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia, heart insuff
  • asthma cystic fibrosis, emphysema, bronchitis, hypersensitivity, pneumonitis, eosinophilic pneumonias, pulmonary fibrosis, adverse effects of glucocorticoid receptor agonist treatment of inflammatory bowel disease such as Crohn's disease and ulcerative colitis; adverse effects of glucocorticoid receptor agonist treatment of disorders of the immune system, connective tissue and joints e.g. reactive arthritis, rheumatoid arthritis, Sjogren's syn- drome, systemic lupus erythematosus, lupus nephritis, Henoch-Schonlein purpura,
  • hemolytic anemia thrombocytopenia, paroxysmal nocturnal hemoglobinuria
  • adverse effects of glucocorticoid receptor agonist treatment of cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lymphoblastic 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. myas- thenia gravis and heriditary myopathies (e.g. Duchenne muscular dystrophy), adverse effects of glucocorticoid receptor agonist treatment in the context of surgery & transplantation e.g.
  • cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lymphoblastic 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
  • glucocorticoid receptor agonists include trauma, post-surgical stress, surgical stress, renal transplantation, liver transplantation, lung transplantation, pancreatic islet transplantation, blood stem cell transplantation, bone marrow transplantation, heart transplantation, adrenal gland transplantation, tracheal transplantation, intestinal transplantation, corneal transplantation, skin grafting, keratoplasty, lens implanta- tion and other procedures where immunosuppression with glucocorticoid receptor agonists is beneficial; adverse effects of glucocorticoid receptor agonist treatment of brain absess, nausea/vomiting, infections, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal cord diseases, saccular aneurysms or adverse effects to glucocorticoid receptor agonist treatment in other diseases, disorders and conditions where glucocorticoid receptor agonists provide clinically beneficial effects.
  • 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 invention 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 ⁇ HSD1 is beneficial.
  • the invention also relates to a method for the treatment, prevention and/or prophy- laxis of disorders and diseases wherein a modulation or an inhibition of the activity of
  • 11 ⁇ HSD1 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 dis- eases 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 desir- able, 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).
  • ITT 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. In yet another preferred embodiment of the invention 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 appro- priate or desired site of action, such as oral, nasal, buccal, transdermal, pulmonal, 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 modi- fying 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 adminis- tered in combination with one or more antiobesity agents or appetite regulating agents.
  • agents may be selected from the group consisting of CART (***e amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH
  • CART ***e amphetamine regulated transcript
  • NPY neuropeptide Y
  • MC4 melanocortin 4
  • TNF tumor necrosis factor
  • CRF corticotropin releasing factor
  • CRF BP corticotropin releasing factor binding protein
  • melanocyte-concentrating hormone CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator- activated receptor) modulators, RXR (retinoid X receptor) modulators, TR ⁇ agonists, AGRP (Agouti related protein) inhibitors, H3 histamine antagonists, opioid antagonists (such as naltrexone), exendin-4, G
  • 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 792 290 (Novo Nordisk A/S), e.g. N ⁇ B29 -tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk NS), e.g. Asp B28 human insulin, US 5,504,188 (EIi Lilly), e.g. Lys B28 Pro 629 human insulin, EP 368 187 (Aventis), e.g.
  • GLP-1 glucagon like peptide-1
  • 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 glycogenosis, 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 (statin
  • the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human in- sulin, Asp B28 human insulin, Lys B28 Pro 629 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
  • insulin an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human in- sulin, Asp B28 human insulin, Lys B28 Pro 629 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.
  • a sulphonylurea e.g. tolbutamide, glibenclamide, glipizide or glicazide.
  • the present compounds are administered in combination with a biguanide e.g. metformin.
  • the present compounds are administered in combination with a meglitinide e.g. repaglinide or senaglinide.
  • a meglitinide e.g. repaglinide or senaglinide.
  • the present compounds are administered in combination with a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or com- pounds 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 com- pounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazo- linyl]methoxy]phenyl-methyl]thiazolidine-2,
  • 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. tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells e.g. tolbutamide, 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
  • vasopressin V2 antagonists such as tolvaptan, SR-121463 and OPC-31260
  • B-type natriuretic peptide agonists e.g. Nesiritide, angiotensin Il antagonists such as irbesartan, candesartancilexetil, losartan, valsartan, tel- misartan, eprosartan, candesartan, CL-329167, eprosartan, iosartan, olmesartan, prato- sartan, 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, moxonidine, CoAprovel, Mondo- Biotech-81 1.
  • 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-41 14, RU-24858 and T-25 series.
  • the compounds of the 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 pharma- ceutically acceptable carriers or diluents as well as any other known adjuvants and excipients 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 ac- tive ingredient chosen.
  • compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sus- tained or prolonged release according to methods well-known in the art.
  • 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 ster- ile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
  • Suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
  • 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, pentaerythritol 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.
  • the pharmaceutical compositions formed by combining the compounds of the invention 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 cal- cium 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 glyceryl 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.
  • Formulations for oral use may also be presented as hard gelatine capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatine capsule wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxy- cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbi- ents, sorbi- ents, sorbi- ents, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • the pharmaceutical compositions comprising a compound for use according to the present invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, preservative and flavouring and colouring agent.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conveniently employed as solvent or suspending medium.
  • any bland fixed oil may be employed using synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be in the form of suppositories for rectal administration of the compounds of the present invention.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter and polyethylene glycols, for example.
  • topical applications For topical use, creams, ointments, jellies, solutions of suspensions, etc., containing the compounds of the present invention are contemplated.
  • topical applications shall include mouth washes and gargles.
  • the compounds for use according to the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • some of the compounds for use according to the present invention may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the present invention.
  • composition com- prising a compound for use according to the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipi- ents, or diluents.
  • the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain: Core:
  • Active compound (as free compound or salt thereof) 5.0 mg
  • the compounds of the invention may be administered to a patient which is a mammal, especially a human in need thereof.
  • mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • HPLC-MS The RP-analysis was performed on an Agilent HPLC system (1100 degasser, 1100 pump, 1 100 injector and a 1 100 DAD) fitted with an Agilent MS detector system Model VL (MW 0-1000) and a S.E.D.E.R.E Model Sedex 55 ELS detector system using a Waters X-terra MS C18 column (5 ⁇ m, 3.0 mm x 50 mm) with gradient elution, 5% to 95% solvent B (0.05% TFA in acetonitrile) in solvent A (0.05% TFA in water) within 3 min, 2.7 mL/min.
  • Agilent HPLC system 1100 degasser, 1100 pump, 1 100 injector and a 1 100 DAD
  • VL MW 0-1000
  • S.E.D.E.R.E Model Sedex 55 ELS detector system using a Waters X-terra MS C18 column (5 ⁇ m, 3.0 mm x 50 mm) with gradient e
  • DIPEA Diisopropylethylamine
  • EDAC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours
  • R is Ci-C 6 alkyl or arylCi-C 6 alkyl
  • Example 12a was made in a similar way as described for example 11 a.
  • aqueous phase was acidified to pH ⁇ 1 with 1 N HCI and extracted with EtOAc (2x10 ml_), dried (MgSO 4 ), filtered and evaporated affording 0,6 g 84 %) of 4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-benzoic acid as a solid.
  • reaction mixture was cooled to 0 0 C and DIAD (9.6 g, 47.4 mmol) was added dropwise from an addition funnel over a period of 3 h.
  • the reaction was gradually brought to room temperature and stirring continued for 3 h.
  • the solvent was removed under vacuum and ether (100 ml.) was added and cooled to 0 0 C.
  • the aqueous layer was acidified to pH ⁇ 2 with 2N HCI and the white precipitate obtained was filtered off and washed with hexane affording 4.0 g (92 %) of 4-[4-(cyclopropanecarbonyl- amino)-cyclohexyloxy]-benzoic acid as a soild.
  • N-Adamantan-2-yl-4-(4-hydroxy-cyclohexyloxy)-benzamide To a solution of N-adamantan-2-yl-4-[4-(f-butyl-diphenyl-silanyloxy)-cyclohexyloxy]- benzamide (4,73 g, 7.78 mmol) in dry THF (50 ml.) was added a 1 N TBAF solution in THF (31 ,12 ml.) and the mixture was stirred for 48 hrs. at room temperature. The volatiles were evaporated in vacuo and the residue redissolved in AcOEt (50 mL) and washed with 5 % aqous citric acid and vand.
  • N-adamantan-2-yl-4-(4-hydroxymethyl-cyclohexyloxy)-benzamide 150 mg, 0.39 mmol
  • 2-hydroxypyridine 38 mg, 0.4 mmol
  • tributyl phosphine 144 ⁇ L, 0.59 mmol
  • the resulting mixture was cooled and azodicarboxylic dipiperidide (149 mg, 0.59 mmol) dissolved in dry THF (3 mL) was added.
  • the mixture was stirred for 6 hrs. at room temperature, filtered and the volatiles evaporated in vacuo. The residue was purified on prep.
  • the crude ester was dissolved in a mixture of MeOH (100 ml.) and THF (50 ml.) and to this mixture was added 1 N NaOH (20 ml.) followed by stirring for 16 hrs. at room temperature. The volume was reduced to % and 1 N HCI was added to pH ⁇ 1 . The organic phase was separated and the aqueous phase extraxted with DCM (2x50 ml_). The combined organic phases were washed with water, dried (MgSO 4 ), filtered and the solvent evaporated in vacuo.
  • a precipiate was forme, filtered off and redissolved in DCM (25 mL) followed by addition of TFA (10 mL). The mixture was stirred at room temperature for 16 hrs and the volatiles evaporated in vacuo. The residue was dissolved in water (50 mL) and washed with diethyl ether (2x10 mL). The pH of the aqueous phase was ajusted to ⁇ 11 by addition of 32 % NaOH followed by extraction with diethyl ether (2x50 mL). The combined organic phases were dried (Na 2 SU 4 ), filtered and evaporated in vacuo. The crude residue was stirred with EtOAc (20 mL) and the precipiate formed was filtered off.
  • 3 H-cortisone and anti-rabbit Ig coated scintillation proximity assay (SPA) beads were purchased from Amersham Pharmacia Biotech, ⁇ -NADPH was from Sigma and rabbit anti- cortisol antibodies were from Fitzgerald.
  • An extract of yeast transformed with h-11 ⁇ HSD1 (HuIt et al., FEBS Lett, 441 , 25 (1998)) was used as the source of enzyme.
  • the test compounds were dissolved in DMSO (10 mM).
  • R 1 and R 2 together with the nitrogen to which they are attached, are forming a 8-11 mem- bered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitrogen, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxy- gen, and S(O) m , where m is 0, 1 or 2, and said ring being substituted with 0 to 3 groups independently selected from Ci-C 4 alkyl, halogen, hydroxy, oxo, COOH, -NHR 17 , NR 17 R 17 , Ci-C 4 alkyloxy, Ci-C 4 alkyloxyCrC 4 alkyl and Ci-C 4 alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R 21 , or R 1 is hydrogen, Ci-C 4 alkyl or cyclopropyl and R 2 is a substituted or unsubstituted adamantyl;
  • R 21 is halogen, hydroxy, oxo or COOH
  • R 4 is selected from hydrogen, Ci-C 4 alkyl, trifluoromethyl, halogen, Ci-C 4 alkyloxy, Ci-C 4 alkyloxyCi-C 4 alkyl and CrC 4 alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R 21 ;
  • X is selected from -O-, -S-, -CR 5 R 6 -, -NH-, and -NR 6 -;
  • R 5 is hydrogen or fluorine;
  • R 6 is hydrogen, methyl, ethyl, iso-propyl or cyclo-propyl
  • R 3 is selected from -1 ,4-cyclohexyl-R 7 , -CH 2 -1 , 4-cyclohexyl-R 8 , -1 ,3-cyclohexyl-R 9 , -CH 2 -1 ,3- cyclohexyl-R 10 , -4-piperidin-1-yl-R 11 , -CH 2 -4-piperidin-1-yl-R 12 , -3-piperidin-1-yl-R 13 , -CH 2 -3- piperidin-1-yl-R 14 , -4-bicyclo[2.2.2]octan-1-yl-R 15 and -CH 2 -4-bicyclo[2.2.2]octan-1-yl-R 16 ;
  • R 7 , R 8 , R 9 , R 10 , R 15 and R 16 are independently selected from CO 2 H, C(O)R 19 , OH, -(CR 22 - R 23 ) n -C(O)-NR 17 R 18 , -(CR 22 R 2 VNHC(O)R 18 , -(CR 22 R 23 ) n -OR 18 , -(CR 22 R 23 ) n -SR 18 , -(CR 22 -
  • n O, 1 or 2;
  • each R 22 and R 23 are independently selected from hydrogen, halogen, d-C ⁇ alkyl and cycloalkyl, each of which CrC 6 alkyl and cycloalkyl may be substituted with 0 to 2 halogen, hydroxy or oxo and the carbon in CR 22 R 23 can together with the R 22 and/or R 23 groups be part of a cycloalkyl ring;
  • R 20 is selected from halogen, hydroxy, oxo, -COOH, -S(O) 0-2 R 19 , -S(O) 0-2 NR 19 R 19 , cyclopro- pyl, -0-R 19 , Ci-C 6 alkyl, aryl, hetaryl, NR 19 CONR 19 R 19 ; NR 19 SO 2 NR 19 R 19 or NCONHSO 2 R 19 '
  • R 17 is selected from hydrogen or selected from C-rC 6 alkyl, C-rC 6 alkenyl, C-rC 6 alkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R 20 ;
  • R 18 is selected from d-C 6 alkyl, d-C 6 alkenyl, d-C 6 alkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R 20 ; where R 17 and R 18 are optionally connected by a covalent bond so as to form a ring comprising the N to which R 17 and R 18 are connected; R 19 is selected from hydrogen, hydroxy, CrC 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, cycloalkyl, CrC ⁇ alkyloxy, aryl or hetaryl wherein hydroxy, C-i-C ⁇ alkyl, cycloalkyl, d-C ⁇ alkyloxy, aryl or hetaryl are optional substituted with R 20 ;
  • R 11 , R 12 , R 13 and R 14 are independently selected from -C(O)-NR 17 R 18 , -CH 2 C(O)-NR 17 R 18 , - C(O)R 19 , -S(O) 2 R 18 , -S(O) 2 NR 17 R 18 , C r C 6 alkyl substituted with O to 2 R 20 , aryl substituted with O to 2 R 20 , and hetaryl substituted with O to 2 R 20 ; or
  • R 25 is independently selected from CrC ⁇ alkyl, halogen, hydroxy, oxo, COOH, and CrC ⁇ alkyloxy.
  • R 7 and R 8 are selected from -CH 2 -O- aryl, -CH 2 -O-hetaryl, -O-aryl, -O-hetaryl, -CH 2 -O-C 1-6 alkyl, -NHC(O)R 18 , where the aryl, hetaryl and C 1-6 alkyl groups are optionally substituted.
  • R 7 and R 8 are selected from -NH-S(O) 2 - aryl, -NH-S(O) 2 -hetaryl, -NH-aryl, -NH-hetaryl, -S(O) 2 -aryl and -S(O) 2 -hetaryl, where the aryl and hetaryl groups are optionally substituted.
  • R 11 and R 12 are selected from aryl, hetaryl, -S(O) 2 -aryl and -S(O) 2 -hetaryl, where each aryl and hetaryl groups are optionally substituted.
  • R 2 is an unsubstituted adamantyl selected from 1 -adamantyl and 2-adamantyl.
  • a prodrug thereof 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.
  • PSA polar surface area
  • IGF impaired fasting glucose
  • a pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the clauses 1-28 together with one ore more pharmaceutically acceptable carriers or excipients.
  • composition according to clause 36 or 37 in unit dosage form comprising from 0.05 mg to 2000 mg/day, from 0.1 mg to 1000 mg or from 0.5 mg to 500 mg per day of the compound according to anyone of the clauses 1-28.
  • a method for the treatment, prevention and/or prophylaxis of any conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 1 1 ⁇ HSD1 is beneficial comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
  • R 1 and R 2 together with the nitrogen to which they are attached, are forming a 8-11 mem- bered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitrogen, 5-10 carbon atoms and from 0 to 1 additional heteroatom selected from nitrogen, oxygen, and S(O) m , where m is 0, 1 or 2, and said ring being substituted with 0 to 3 groups independently selected from d-C 4 alkyl, halogen, hydroxy, oxo, COOH, -NHR 7 , NR 7 R 8 , -S(O) 2 Cr C 4 alkyl, -S(O) 2 NR 7 R 8 , C r C 4 alkyloxy, Ci-C 4 alkyloxyC r C 4 alkyl and Ci-C 4 alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R 18 , or
  • R 1 is hydrogen, d-C 4 alkyl or cyclopropyl and R 2 is adamantyl optionally substituted with 0 to 1 R 18 ;
  • R 3 is selected from -1 ,2-cyclopentyl-R 9 , -1 ,3-cyclopentyl-R 9 , -1 ,4-cyclohexyl-R 9 , -CH 2 -1 , 4- cyclohexyl-R 9 , -1 ,3-cyclohexyl-R 9 , -CH 2 -1 , 3-cyclohexyl-R 9 , -3-pyrrolidin-1-yl-R 10 , -CH 2 -3- pyrrolidin-1-R 10 , 4-tetrahydro-pyran, 4-tetrahydro-pyran-2-yl-R 9 , 4-tetrahydro-pyran-3-yl-R 9 , -4-piperidin-1-yl-R , -CH 2 -4-piperidin-1-yl-R , -3-piperidin-1-yl-R , -CH 2 -3-piperidin-1-yl-R >
  • X is selected from -O-, -S(O) n -, -CR 5 0 ⁇ R->6-, and -NR j7- .; or
  • R 3 and R 7 are connected by a covalent bond so as to form a bicyclic or tricyclic hetcycloalkyl ring comprising the N to which R 3 and R 7 are connected; the hetcycloalky ring may further be substituted with one or more R 19 ;
  • R 4 is selected from hydrogen, Ci-C 4 alkyl, trifluoromethyl, halogen, Ci-C 4 alkyloxy, Ci-C 4 alkyloxyC-rC 4 alkyl and Ci-C 4 alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R 18 ;
  • R 5 and R 6 independently are selected from hydrogen, fluorine, methyl, ethyl, iso-propyl or cyclopropyl;
  • R 7 is selected from hydrogen or selected from CrC ⁇ alkyl, Ci-C ⁇ alkenyl, d-C ⁇ alkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with 0 to 2 R 19 ;
  • R 8 is selected from CrC 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl, each of which may be substituted with 0 to 2 R 19 ; or
  • R 7 and R 8 optionally are connected by a covalent bond so as to form a ring comprising the N to which R 7 and R 8 are connected; the ring may further be substituted with one or more R 19 ;
  • R 10 and R 11 independently are selected from -C(O)NR 7 R 8 , -CH 2 C(O)NR 7 R 8 , -C(O)R 17 , -S(O) 2 R 16 or -S(O) 2 NR 7 R 8 , wherein the alkyl, aryl and hetaryl groups are optionaly substituted with O to 2 R 19 ;
  • n and n independently are O, 1 or 2;
  • R 13 is selected from hydroxy, C ⁇ C 6 alkyl, CrC ⁇ alkenyl, d-C ⁇ alkynyl, cycloalkyl,
  • R 14 and R 15 independently are selected from hydrogen, halogen, Ci-C 6 alkyl and cycloalkyl, each of which d-C ⁇ alkyl and cycloalkyl may be substituted with O to 2 halogen, hydroxy or oxo and the carbon in CR 14 R 15 can together with the R 14 and/or R 15 groups be part of a cycloalkyl ring;
  • R 16 is selected from hydrogen, d-C 6 alkyl, Ci-C 6 alkenyl, Ci-C 6 alkynyl, cycloalkyl, hetcycloal- kyl, aryl or hetaryl wherein the Ci-C ⁇ alkyl, cycloalkyl, aryl or hetaryl groups are optionaly substituted with one or more R 19 ;
  • R 17 is selected from hydrogen, C r C 6 alkyl, Ci-C 6 alkylC(O)R 20 , -(CR 14 R 15 ) n NR 17 S(O) 2 R 16 , cycloalkyl, hetcycloalkyl, aryl or hetaryl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups optionaly are substituted with one or more R 21 ;
  • R 18 is halogen, hydroxy, oxo, -S(O) 2 Ci-C 4 alkyl, -S(O) 2 NR 7 R 8 or -C(O)R 13 ;
  • R 19 is selected from halogen, hydroxy, oxo, -C(O)R 20 , d-CealkylC ⁇ R 20 , -S(O) n R 16 , -S(O) n NR 7 R 8 , cyclopropyl, -OR 16 , C r C 6 alkyl, aryl, hetaryl, -NR 22 C(O)NR 7 R 8 , -NR 22 S(O) 2 NR 7 R 8 or -NC(O)NHS(O) 2 R 16 ;
  • R 20 is selected from hydroxy, CrC ⁇ alkyl, CrC ⁇ alkenyl, d-C ⁇ alkynyl, cycloalkyl,
  • R 21 is halogen, cyano or hydroxy
  • R 7 and R 8 are con- nected by a covalent bond so as to form a pyrrolidine, a piperidine, a piperazine, a substituted pyrrolidine, a substituted piperidine or a substituted piperazine.
  • R 22 is independently selected from Ci-C 8 alkyl, halogen, hydroxy, oxo, C(O)R 13 , -S(O) 2 NR 7 R 8 , -S(O) n CrC 4 alkyl and CrC 6 alkyloxy.
  • R 9 is selected from -CH 2 -O-aryl, -CH 2 - O-hetaryl, -O-aryl, -O-hetaryl, -CH 2 -O-Ci -6 alkyl, -NHC(O)R 16 , where the aryl, hetaryl and Ci- 6 alkyl groups are optionally substituted. 14.
  • R 9 is selected from -NH-S(O) 2 -aryl, -NH- S(O) 2 -hetaryl, -NH-aryl, -NH-hetaryl, -S(O) 2 -aryl and -S(O) 2 -hetaryl, where the aryl and hetaryl groups are optionally substituted.
  • R 11 is selected from aryl, hetaryl, -S(O) 2 - aryl and -S(O) 2 -hetaryl, where each aryl and hetaryl groups are optionally substituted.
  • R 2 is an unsubstituted adamantyl selected from 1 -adamantyl and 2-adamantyl.
  • R 2 is a substituted 1 -adamantyl or a substituted 2-adamantyl.
  • R 2 is an adamantyl substituted with one, two or more substituents independently selected from halogen, hydroxy, oxo, C(O)R 13 , Ci-C 6 alkyl, C r C 6 alkyloxy, -S(O) 2 NR 7 R 8 , and -S(O) n Ci-C 4 alkyl.
  • Cis-Pyridine-2-sulfonic acid ⁇ 4-[4-(octahydro-quinoline-1-carbonyl)-phenoxy]-cyclohexyl ⁇ - amide
  • PSA polar surface area
  • a pharmaceutical composition comprising, as an active ingredient, at least one com- pound according to any one of the clauses 1-29 together with one ore more pharmaceutically acceptable carriers or excipients.
  • composition according to clause 39 which is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration.
  • the pharmaceutical composition according to clause 39 or 40 in unit dosage form comprising from 0.05 mg to 2000 mg/day, from 0.1 mg to 1000 mg or from 0.5 mg to 500 mg per day of the compound according to anyone of the clauses 1-29. 42.
  • a method for the treatment, prevention and/or prophylaxis of any conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 1 1 ⁇ HSD1 is beneficial comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
  • the conditions, disorders or diseases are selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.

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Abstract

A novel class of compounds of the general formula (I), their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments are described. The present compounds modulate the activity of 11β-hydroxy-steroid dehydrogenase type 1 (11βHSD1) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, e.g. the metabolic syndrome.

Description

11BETA-HYDR0XYSTER0ID DEHYDROGENASE TYPE 1 ACTIVE COMPOUNDS
FIELD OF INVENTION
The present invention relates to novel substituted cyclic amides, to their use in therapy, to pharmaceutical compositions comprising the compounds, to the use of said com- pounds in the manufacture of medicaments, and to therapeutic methods comprising the administration of said compounds. The present compounds modulate the activity of 11 β- hydroxysteroid dehydrogenase type 1 (1 1 βHSD1 ) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.
BACKGROUND OF THE INVENTION 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 characterized by a combination of insulin resistance, dyslipidemia, obesity and hypertension leading to increased morbidity and mortality of cardiovascular diseases. People with the metabolic syndrome are at increased risk of developing frank type 2 diabetes, the prevalence of which is equally escalating.
In type 2 diabetes, obesity and dyslipidemia are also highly prevalent and around 70% of people with type 2 diabetes additionally have hypertension once again leading to increased mortality of cardiovascular diseases. In the clinical setting, it has long been known that glucocorticoids are able to induce all of the cardinal features of the metabolic syndrome and type 2 diabetes.
11 β-hydroxysteroid dehydrogenase type 1 (1 1 βHSD1 ) 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. Thus, 1 1 βHSD1 serves as a local regulator of glucocorticoid actions in the tissues and organs where it is expressed (Tannin et al., J. Biol. Chem., 266, 16653 (1991 ); Bujalska et al., Endocrinology, UO, 3188 (1999); Whorwood et al., J. Clin. Endocrinol. Metab., 86, 2296 (2001 ); Cooper et al., Bone, ZL, 375 (2000); Da- van i et al., J. Biol. Chem., 275, 34841 (2000); Brem et al., Hypertension, 31, 459 (1998); Rauz et al., Invest. Ophthalmol. Vis. Sci., 42, 2037 (2001 ); Moisan et al., Endocrinology, 127. 1450 (1990)).
The role of 11 βHSD1 in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence. In humans, treatment with the non-specific 11 βHSD1 inhibitor carbenoxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes. Likewise, 11 βHSD1 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. Conversely, mice that overexpress 1 1 βHSD1 in adipocytes develop insulin resistance, hyperlipidemia and visceral obesity, a phenotype that resembles the human metabolic syndrome (Andrews et al., J. CHn. Endocrinol. Metab., 88, 285 (2003); Walker et al., J. CHn. Endocrinol. Metab., 80, 3155 (1995); Morton et al., J. Biol. Chem. 276, 41293 (2001 ); Kotelevtsev et al., Proc. Natl. Acad. ScL USA, 94, 14924 (1997); Masuzaki et al., Science, 294, 2166 (2001 )). The more mechanistic aspects of 1 1 βHSD1 modulation and thereby modulation of intracellular levels of active glucocorticoid have been investigated in several rodent models and different cellular systems. 1 1 βHSD1 promotes the features of the metabolic syndrome by increasing hepatic expression of the rate-limiting enzymes in gluconeogenesis, namely phosphoenolpyuvate carboxykinase and glucose-6-phosphatase, promoting the differentia- tion of preadipocytes into adipocytes thus facilitating obesity, directly and indirectly stimulating hepatic VLDL secretion, decreasing hepatic LDL uptake and increasing vessel contractility (Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94, 14924 (1997); Morton et al., J. Biol. Chem. 276, 41293 (2001 ); Bujalska et al., Endocrinology, 140, 3188 (1999); Souness et al., Steroids, 67, 195 (2002); Brindley & Salter, Prog. Lipid Res., 30, 349 (1991 )). WO 01/90090, WO 01/90091 , WO 01/90092, WO 01/90093 and WO 01/90094 discloses various thiazol-sulfonamides as inhibitors of the human 11 β-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. WO 04/089470 discloses various substituted amides as modulators of the human 11 β-hydroxysteroid dehydrogenase type 1 enzyme, and further states that said compounds may be useful in treating medical disorders where a decreased intracellular concentration of active glucocorticoid is desirable. WO 2004/089415 and WO 2004/089416 discloses various combination therapies using an 11 β-hydroxysteroid dehydrogenase type 1 inhibitor and respectively a glucocorticoid receptor agonist or an antihypertensive agent. We have now found novel substituted cyclic amides that modulate the activity of
11 βHSD1 leading to altered intracellular concentrations of active glucocorticoid. More specifically, the present compounds inhibit the activity of 11 βHSD1 leading to decreased intracellular concentrations of active glucocorticoid. Thus, the present compounds can be used to treat disorders where a decreased level of active intracellular glucocorticoid is desirable, such as e.g. the metabolic syndrome, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), dyslipidemia, obesity, hypertension, diabetic late complications, cardiovascular diseases, arteriosclerosis, atherosclerosis, myopathy, muscle wasting, osteoporosis, neurodegenerative and psychiatric disorders, and adverse effects of treatment or therapy with glucocorticoid receptor agonists.
Objects of the present invention are to provide compounds, pharmaceutical compositions and use of said compounds that modulate the activity of 11 βHSD1.
DEFINITIONS
In the following structural formulas and throughout the present specification, the fol- lowing terms have the indicated meaning:
The term "halogen" or "halo" means fluorine, chlorine, bromine or iodine. The term "hydroxy" shall mean the radical -OH. The term "sulfanyl" shall mean the radical -S-. The term "sulfo" shall mean the radical HO3S-. The term "sulfonyl" shall mean the radical -S(=0)2-.
The term "oxo" shall mean the radical =0. The term "amino" shall mean the radical -NH2. The term "nitro" shall mean the radical -NO2. The term "cyano" shall mean the radical -CN. The term "carboxy" shall mean the radical -(C=O)OH.
The term "perhalomethyl" includes but are not limited to trifluoromethyl, difluoro- methyl, monofluoromethyl, trichloromethyl and the like.
The term "trihalomethyl" includes trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl. The term "trihalomethoxy" includes trifluorometoxy, trichlorometoxy, tribromometoxy, and triiodometoxy.
The term "alkyl" as used herein represents a saturated, branched or straight hydrocarbon group having the indicated number of carbon atoms, e.g. C1-2-alkyl, C1-3-alkyl, C1-4- alkyl, C1-6-alkyl, C2-6-alkyl, C3-6-alkyl, C1-8-alkyl, C1-10-alkyl, and the like. Representative ex- amples are methyl, ethyl, propyl (e.g. prop-1-yl, prop-2-yl (or /so-propyl)), butyl (e.g. 2- methylprop-2-yl (or terf-butyl), but-1-yl, but-2-yl), pentyl (e.g. pent-1-yl, pent-2-yl, pent-3-yl), 2-methylbut-1-yl, 3-methylbut-1-yl, hexyl (e.g. hex-1-yl), heptyl (e.g. hept-1-yl), octyl (e.g. oct- 1-yl), nonyl (e.g. non-1-yl), and the like. The term "Ci-6-alkyl" as used herein represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms, e.g. Ci- 2-alkyl, Ci-3-alkyl, Ci-4-alkyl, C1-6-alkyl, C2-6-alkyl, C3-6-alkyl, and the like. Representative examples are methyl, ethyl, propyl (e.g. prop-1-yl, prop-2-yl (or /so-propyl)), butyl (e.g. 2- methylprop-2-yl (or terf-butyl), but-1-yl, but-2-yl), pentyl (e.g. pent-1-yl, pent-2-yl, pent-3-yl), 2-methylbut-1-yl, 3-methylbut-1-yl, hexyl (e.g. hex-1-yl), and the like. The term "C^-alkyl" as used herein represents a saturated, branched or straight hydrocarbon group having from 1 to 4 carbon atoms, e.g. C-ι-2-alkyl, d-3-alkyl, d-4-alkyl and the like. Representative examples are methyl, ethyl, propyl (e.g. prop-1-yl, prop-2-yl (or /so-propyl)), butyl (e.g. 2-methylprop-2- yl (or tert-butyl), but-1-yl, but-2-yl), and the like.
The term "alkenyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and branched C3-C6 unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl, methylbutenyl and the like.
The term "alkynyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and C4-C6 branched unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylbutynyl, and the like.
The term "saturated or partially saturated cyclic, bicyclic or tricyclic ring system" represents but are not limited to azepanyl, azocanyl, 1 ,2,3,4-tetrahydro-quinolinyl, 1 ,2,3,4- tetrahydro-isoquinolinyl, 1 ,2,3,4-tetrahydro-quinoxalinyl, indolinyl, 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[3.3.2]decanyl, 4-aza-tricyclo[4.3.1.13 8]undecanyl, 9-aza-tricyclo[3.3.2.037]decanyl, 8- aza-spiro[4.5]decane.
The term "cycloalkyl" as used herein represents a saturated monocyclic carbocyclic ring having the specified number of carbon atoms, e.g. C3-6-alkyl, C3-8-alkyl, C3-i0-alkyl, and the like. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo- heptyl, cyclooctyl, and the like. Cycloalkyl is also intended to represent a saturated bicyclic carbocyclic ring having from 4 to 10 carbon atoms. Representative examples are decahydro- naphthalenyl, bicyclo[3.3.0]octanyl, and the like. Cycloalkyl is also intended to represent a saturated carbocyclic ring having from 3 to 10 carbon atoms and containing one or two car- bon bridges. Representative examples are adamantyl, norbornanyl, nortricyclyl, bicycle-
[3.2.1]octanyl, bicyclo[2.2.2]octanyl, tricyclo[5.2.1.0/2,6]decanyl, bicyclo[2.2.1]heptyl, and the like. Cycloalkyl is also intended to represent a saturated carbocyclic ring having from 3 to 10 carbon atoms and containing one or more spiro atoms. Representative examples are spiro[2.5]octanyl, spiro[4.5]decanyl, and the like. The term "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.
The term "cycloalkenyl" (e.g. cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohep- tenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like) represents a partially saturated, mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms.
The term "cycloalkylcarbonyl" (e.g. cyclopropylcarbonyl, cyclohexylcarbonyl) represents an cycloalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group. The term "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.
The term "hetcycloalkyl" (e.g. tetrahydrofuranyl, tetrahydropyranyl, tertahydrothio- pyranyl, piperidine, pyridazine and the like) represents a saturated mono-, bi-, tri- or spiro- carbocyclic group having the specified number of carbon atoms and one or two additional heteroatoms or groups selected from nitrogen, oxygen, sulphur, SO or SO2.
The term "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.
The term "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.
The term "alkyloxyalkyl" (e.g. methyloxymethyl and the like) represents an alkyloxy group as defined above attached through an "alkyl" group.
The term "aryloxy" (e.g. phenoxy, naphthyloxy and the like) represents an aryl group as defined below attached through an oxygen bridge.
The term "hetaryloxy" (e.g. 2-pyridyloxy and the like) represents a hetaryl group as defined below attached through an oxygen bridge. The term "aryloxyalkyl" (e.g. phenoxymethyl, naphthyloxyethyl and the like) represents an aryloxy group as defined above attached through an "alkyl" group having the indicated number of carbon atoms.
The term "arylalkyloxy" (e.g. phenethyloxy, naphthylmethyloxy and the like) represents an arylalkyl group as defined below attached through an oxygen bridge. The term "hetarylalkyloxy" (e.g. 2-pyridylmethyloxy and the like) represents a hetary- lalkyl group as defined below attached through an oxygen bridge.
The term "hetaryloxyalkyl" (e.g. 2-pyridyloxymethyl, 2-quinolyloxyethyl and the like) represents a hetaryloxy group as defined above attached through an "alkyl" group having the indicated number of carbon atoms.
The term "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.
The term "arylalkyloxyalkyl" (e.g. ethoxymethyl-benzene, 2-methoxymethyl-naphtha- lene and the like) represents an arylalkyloxy group as defined above attached through an "alkyl" group having the indicated number of carbon atoms.
The term "alkylthio" (e.g. methylthio, ethylthio and the like) represents an alkyl group as defined above attached through a sulphur bridge.
The term "alkyloxycarbonyl" (e.g. methylformiat, ethylformiat and the like) represents an alkyloxy group as defined above attached through a carbonyl group.
The term "aryloxycarbonyl" (e.g. phenylformiat, 2-thiazolylformiat and the like) represents an aryloxy group as defined above attached through a carbonyl group.
The term "arylalkyloxycarbonyl" (e.g. benzylformiat, phenyletylformiat and the like) represents an "arylalkyloxy" group as defined above attached through a carbonyl group. The term "arylalkyl" (e.g. benzyl, phenylethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like ) 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.
The term "hetarylalkyl" (e.g. (2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3- thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like) 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.
The term "alkylcarbonyl" as used herein refers to the alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group. Represen- tative examples are acetyl (methylcarbonyl), propionyl (ethylcarbonyl), butanoyl (prop-1- ylcarbonyl, prop-2-ylcarbonyl), pentylcarbonyl, 3-hexenylcarbonyl, octylcarbonyl, and the like.
The term "arylcarbonyl" (e.g. benzoyl) represents an aryl group as defined below attached through a carbonyl group. The term "hetarylcarbonyl" (e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like) represents a hetaryl group as defined below attached through a carbonyl group.
The term "alkylcarbonylalkyl" (e.g. propan-2-one, 4,4-dimethyl-pentan-2-one and the like) represents an alkylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "hetarylcarbonylalkyl" (e.g. 1-pyridin-2-yl-propan-1-one, 1-(1-H-imidazol-2- yl)-propan-1-one and the like) represents a hetarylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms. The term "arylalkylcarbonyl" (e.g. phenylpropylcarbonyl, phenylethylcarbonyl and the like) represents an arylalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term "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.
The term "alkylcarboxy" (e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "arylcarboxy" (e.g. benzoic acid and the like) represents an arylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "alkylcarboxyalkyl" (e.g. heptylcarboxymethyl, propylcarboxy terf-butyl, 3- pentylcarboxyethyl) represents an alkylcarboxy group as defined above wherein the carboxy group is in turn attached through an alkyl group as defined above having the indicated number of carbon atoms. The term "arylalkylcarboxy" (e.g. benzylcarboxy, phenylpropylcarboxy and the like) represents an arylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "hetarylalkylcarboxy" (e.g. (1-H-imidazol-2-yl)-acetic acid, 3-pyrimidin-2-yl- propionic acid and the like) represents a hetarylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "alkylS(O)n" (e.g. ethylsulfonyl, ethylsulfinyl and the like) represents an alkyl group as defined above, wherein the alkyl group is in turn attached through a sulphur bridge wherein the sulphur is substituted with n oxygen atoms. The term "arylS(O)n" (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 n oxygen atoms.
The term "arylalkylS(O)n" (e.g. benzylsulfinyl, phenetyl-2-sulfonyl and the like) repre- sents an arylalkyl group as defined above, wherein the arylalkyl group is in turn attached through a sulphur bridge wherein the sulphur is substituted with n oxygen atoms.
The term "bridge" as used herein represents a connection in a saturated or partly saturated ring between two atoms of such ring that are not neighbors through a chain of 1 to 3 atoms selected from carbon, nitrogen, oxygen and sulfur. Representative examples of such connecting chains are -CH2-, -CH2CH2-, -CH2NHCH2-, -CH2CH2CH2-, -CH2OCH2-, and the like. In one embodiment according to the invention, the connecting chain is selected from the group consisting Of -CH2-, -CH2CH2-, Or -CH2OCH2-.
The term "spiro atom" as used herein represents a carbon atom in a saturated or partly saturated ring that connects both ends of a chain of 3 to 7 atoms selected from carbon, nitrogen, oxygen and sulfur. Representative examples are -(CH2)5-, -(CH2)3-, -(CH2)4-, -
CH2NHCH2CH2-, -CH2CH2NHCH2CH2-, -CH2NHCH2CH2CH2-, -CH2CH2OCH2-, -OCH2CH2O-, and the like.
The term "aryl" as used herein is intended to include monocyclic, bicyclic or poly- cyclic carbocyclic aromatic rings. Representative examples are phenyl, naphthyl (e.g. naphth-1-yl, naphth-2-yl), anthryl (e.g. anthr-1-yl, anthr-9-yl), phenanthryl (e.g. phenanthr-1- yl, phenanthr-9-yl), and the like. Aryl is also intended to include monocyclic, bicyclic or poly- cyclic carbocyclic aromatic rings substituted with carbocyclic aromatic rings. Representative examples are biphenyl (e.g. biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl), phenylnaphthyl (e.g.1-phenylnaphth-2-yl, 2-phenylnaphth-1-yl), and the like. Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic rings with at least one unsaturated moiety (e.g. a benzo moiety). Representative examples are, indanyl (e.g. indan-1-yl, indan-5-yl), in- denyl (e.g. inden-1-yl, inden-5-yl), 1 ,2,3,4-tetrahydronaphthyl (e.g. 1 ,2,3,4-tetrahydronaphth- 1-yl, 1 ,2,3,4-tetrahydronaphth-2-yl, 1 ,2,3,4-tetrahydronaphth-6-yl), 1 ,2-dihydronaphthyl (e.g. 1 ,2-dihydronaphth-1-yl, 1 ,2-dihydronaphth-4-yl, 1 ,2-dihydronaphth-6-yl), fluorenyl (e.g. fluo- ren-1-yl, fluoren-4-yl, fluoren-9-yl), and the like. Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or two bridges. Representative examples are, benzonorbornyl (e.g. benzonorborn-3-yl, benzonorborn-6-yl), 1 ,4- ethano-1 ,2,3,4-tetrahydronapthyl (e.g. 1 ,4-ethano-1 ,2,3,4-tetrahydronapth-2-yl,1 ,4-ethano- 1 ,2,3,4-tetrahydronapth-10-yl), and the like. Aryl is also intended to include partially saturated bicyclic or polycyclic carbocyclic aromatic rings containing one or more spiro atoms. Repre- sentative examples are spiro[cyclopentane-1 ,1 '-indane]-4-yl, spiro[cyclopentane-1 ,1 '-indene]- 4-yl, spiro[piperidine-4,1 '-indane]-1-yl, spiro[piperidine-3,2'-indane]-1-yl, spiro[piperidine-4,2'- indane]-1-yl, spiro[piperidine-4,1 '-indane]-3'-yl, spiro[pyrrolidine-3,2'-indane]-1-yl, spiro[pyrro- lidine-3,1 '-(3',4'-dihydronaphthalene)]-1-yl, spiro[piperidine-3,1 '-(3',4'-dihydronaphthalene)]-1- yl, spiro[piperidine-4,1 '-(3',4'-dihydronaphthalene)]-1-yl, spiro[imidazolidine-4,2'-indane]-1-yl, spiro[piperidine-4,1 '-indene]-1-yl, and the like.
The term "hetaryl" or "heteroaryl" as used herein is intended to include monocyclic heterocyclic aromatic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, SO and S(=O)2. Representative examples are pyrrolyl (e.g. pyrrol-1-yl, pyrrol-2- yl, pyrrol-3-yl), furanyl (e.g. furan-2-yl, furan-3-yl), thienyl (e.g. thien-2-yl, thien-3-yl), oxazolyl (e.g. oxazol-2-yl, oxazol-4-yl, oxazol-5-yl), thiazolyl (e.g. thiazol-2-yl, thiazol-4-yl, thiazol-5-yl), imidazolyl (e.g. imidazol-2-yl, imidazol-4-yl, imidazol-5-yl), pyrazolyl (e.g. pyrazol-1-yl, pyra- zol-3-yl, pyrazol-5-yl), isoxazolyl (e.g. isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl), isothiazolyl (e.g. isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl), 1 ,2,3-triazolyl (e.g. 1 ,2,3-triazol-1-yl, 1 ,2,3-triazol-4-yl, 1 ,2,3-triazol-5-yl), 1 ,2,4-triazolyl (e.g. 1 ,2,4-triazol-1-yl, 1 ,2,4-triazol-3-yl, 1 ,2,4-triazol-5-yl), 1 ,2,3-oxadiazolyl (e.g. 1 ,2,3-oxadiazol-4-yl, 1 ,2,3-oxadiazol-5-yl), 1 ,2,4- oxadiazolyl (e.g. 1 ,2,4-oxadiazol-3-yl, 1 ,2,4-oxadiazol-5-yl), 1 ,2,5-oxadiazolyl (e.g. 1 ,2,5-oxa- diazol-3-yl, 1 ,2,5-oxadiazol-4-yl), 1 ,3,4-oxadiazolyl (e.g. 1 ,3,4-oxadiazol-2-yl, 1 ,3,4-oxadiazol-5- yl), 1 ,2,3-thiadiazolyl (e.g. 1 ,2,3-thiadiazol-4-yl, 1 ,2,3-thiadiazol-5-yl), 1 ,2,4-thiadiazolyl (e.g. 1 ,2,4-thiadiazol-3-yl, 1 ,2,4-thiadiazol-5-yl), 1 ,2,5-thiadiazolyl (e.g. 1 ,2,5-thiadiazol-3-yl, 1 ,2,5- thiadiazol-4-yl), 1 ,3,4-thiadiazolyl (e.g. 1 ,3,4-thiadiazol-2-yl, 1 ,3,4-thiadiazol-5-yl), tetrazolyl (e.g. tetrazol-1-yl, tetrazol-5-yl), pyranyl (e.g. pyran-2-yl), pyridinyl (e.g. pyridine-2-yl, pyridine-3-yl, pyridine-4-yl), pyridazinyl (e.g. pyridazin-2-yl, pyridazin-3-yl), pyrimidinyl (e.g. pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl), pyrazinyl, 1 ,2,3-triazinyl, 1 ,2,4-triazinyl, 1 ,3,5-triazinyl, thiadiaz- inyl, azepinyl, azecinyl, and the like. Hetaryl or heteroaryl is also intended to include bicyclic heterocyclic aromatic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2. Representative examples are indolyl (e.g. indol-1-yl, indol-2- yl, indol-3-yl, indol-5-yl), isoindolyl, benzofuranyl (e.g. benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo[b]furan-5-yl, benzo[c]furan-2-yl, benzo[c]furan-3-yl, benzo[c]furan-5-yl), benzothienyl (e.g. benzo[b]thien-2-yl, benzo[b]thien-3-yl, benzo[b]thien-5-yl, benzo[c]thien-2-yl, benzo[c]thien-3-yl, benzo[c]thien-5-yl), indazolyl (e.g. indazol-1-yl, indazol-3-yl, indazol-5-yl), indolizinyl (e.g. indolizin-1-yl, indolizin-3-yl), benzopyranyl (e.g. benzo[b]pyran-3-yl, benzo[b]pyran-6-yl, benzo[c]pyran-1-yl, benzo[c]pyran-7-yl), benzimidazolyl (e.g. benzimida- zol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzothiazolyl (e.g. benzothiazol-2-yl, ben- zothiazol-5-yl), benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl (e.g. 1 ,8-naphthyridin-2-yl, 1 ,7-naphthyιϊdin-2-yl, 1 ,6-naphthyridin-2-yl), phtha- lazinyl (e.g. phthalazin-1-yl, phthalazin-5-yl), pteridinyl, purinyl (e.g. purin-2-yl, purin-6-yl, pu- rin-7-yl, purin-8-yl, purin-9-yl), quinazolinyl (e.g. quinazolin-2-yl, quinazolin-4-yl, quinazolin-6- yl), cinnolinyl, quinoliny (e.g. quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl), iso- quinolinyl (e.g. isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl), quinoxalinyl (e.g. quinoxa- lin-2-yl, quinoxalin-5-yl), pyrrolopyridinyl (e.g. pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl), furopyridinyl (e.g. furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2- c]pyridinyl), thienopyridinyl (e.g. thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2- c]pyridinyl), imidazopyridinyl (e.g. imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl, imi- dazo[1 ,5-a]pyridinyl, imidazo[1 ,2-a]pyridinyl), imidazopyrimidinyl (e.g. imidazo[1 ,2- a]pyrimidinyl, imidazo[3,4-a]pyrimidinyl), pyrazolopyridinyl (e.g. pyrazolo[3,4-b]pyιϊdinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[1 ,5-a]pyridinyl), pyrazolopyrimidinyl (e.g. pyrazolo[1 ,5- a]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl), thiazolopyridinyl (e.g. thiazolo[3,2-d]pyιϊdinyl), thia- zolopyrimidinyl (e.g. thiazolo[5,4-d]pyrimidinyl), imdazothiazolyl (e.g. imidazo[2,1-b]thiazolyl), triazolopyridinyl (e.g. triazolo[4,5-b]pyridinyl), triazolopyrimidinyl (e.g. 8-azapurinyl), and the like. Hetaryl or heteroaryl is also intended to include polycyclic heterocyclic aromatic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2. Representative examples are carbazolyl (e.g. carbazol-2-yl, carbazol-3-yl, carbazol- 9-yl), phenoxazinyl (e.g. phenoxazin-10-yl), phenazinyl (e.g. phenazin-5-yl), acridinyl (e.g. acridin-9-yl, acridin-10-yl), phenothiazinyl (e.g. phenothiazin-10-yl), carbolinyl (e.g. pyrido- [3,4-b]indol-1-yl, pyrido[3,4-b]indol-3-yl), phenanthrolinyl (e.g. phenanthrolin-5-yl), and the like. Hetaryl or heteroaryl is also intended to include partially saturated monocyclic, bicyclic or polycyclic heterocyclic rings containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2. Representative examples are pyrrolinyl, pyrazolinyl, imi- dazolinyl (e.g. 4,5-dihydroimidazol-2-yl, 4,5-dihydroimidazol-1-yl), indolinyl (e.g. 2,3-dihydro- indol-1-yl, 2,3-dihydroindol-5-yl), dihydrobenzofuranyl (e.g. 2,3-dihydrobenzo[b]furan-2-yl, 2,3- dihydrobenzo[b]furan-4-yl), dihydrobenzothienyl (e.g. 2,3-dihydrobenzo[b]thien-2-yl, 2,3- dihydrobenzo[b]thien-5-yl), 4,5,6,7-tetrahydrobenzo[b]furan-5-yl), dihydrobenzopyranyl (e.g. 3,4-dihydrobenzo[b]pyran-3-yl, 3,4-dihydrobenzo[b]pyran-6-yl, 3,4-dihydrobenzo[c]pyran-1-yl, dihydrobenzo[c]pyran-7-yl), oxazolinyl (e.g. 4,5-dihydrooxazol-2-yl, 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl), isoxazolinyl, oxazepinyl, tetrahydroindazolyl (e.g. 4,5,6,7-tetrahydro- indazol-1-yl, 4,5,6,7-tetrahydroindazol-3-yl, 4,5,6,7-tetrahydroindazol-4-yl, 4,5,6,7-tetra- hydroindazol-6-yl), tetrahydrobenzimidazolyl (e.g. 4,5,6,7-tetrahydrobenzimidazol-1-yl, 4,5,6,7-tetrahydrobenzimidazol-5-yl), tetrahydroimidazo[4,5-c]pyridyl (e.g. 4,5,6,7-tetrahydro- imidazo[4,5-c]pyrid-1-yl, 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-5-yl, 4,5,6,7-tetrahydro- imidazo[4,5-c]pyrid-6-yl), tetrahydroquinolinyl (e.g. 1 ,2,3,4-tetrahydroquinolinyl, 5,6,7,8- tetrahydroquinolinyl), tetrahydroisoquinolinyl (e.g. 1 ,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8- tetrahydroisoquinolinyl), tetrahydroquinoxalinyl (e.g. 1 ,2,3,4-tetrahydroquinoxalinyl, 5,6,7,8- tetrahydroquinoxalinyl), and the like. Hetaryl or heteroaryl is also intended to include partially saturated bicyclic or polycyclic heterocyclic rings containing one or more spiro atoms. Representative examples are spiro[isoquinoline-3,1 '-cyclohexan]-1-yl, spiro[piperidine-4,1 '-benzo- [c]thiophen]-1-yl, spiro[piperidine-4,1 '-benzo[c]furan]-1-yl, spiro[piperidine-4,3'-benzo[b]fu- ran]-1-yl, spiro[piperidine-4,3'-coumarin]-1-yl, and the like.
The term "monocyclic hetaryl" or "monocyclic heteroaryl" as used herein is intended to include monocyclic heterocyclic aromatic rings as defined above.
The term "bicyclic hetaryl" or "bicyclic heteroaryl" as used herein is intended to include bicyclic heterocyclic aromatic rings as defined above.
The term "optionally substituted" as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.
Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
Certain of the defined terms may occur in combinations, and it is to be understood that the first mentioned radical is a substituent on the subsequently mentioned radical, where the point of substitution, i.e. the point of attachment to another part of the molecule, is on the last mentioned of the radicals.
The term "treatment" is defined as the management and care of a patient for the purpose of combating or alleviating the disease, condition or disorder, and the term includes the administration of the active compound to prevent the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
The term "pharmaceutically acceptable" is defined as being suitable for administration to humans without adverse events. The term "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. DETAILED DESCRIPTION OF THE INVENTION
The present invention is based on the observation that the compounds of the general formulas (I) disclosed below are able to modulate or inhibit the activity of 1 1 βHSD1.
Accordingly, the present invention is concerned with compounds or prodrugs thereof of the general formula (I)
Figure imgf000013_0001
(I) wherein R1 and R2 together with the nitrogen to which they are attached, are forming a 8-1 1 mem- bered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitrogen, 5-10 carbon atoms and from 0 to 1 additional heteroatom selected from nitrogen, oxygen, and S(O)m, where m is 0, 1 or 2, and said ring being substituted with 0 to 3 groups independently selected from d-C4alkyl, halogen, hydroxy, oxo, COOH, -NHR7, NR7R8, -S(O)2Cr C4alkyl, -S(O)2NR7R8, CrC4alkyloxy, Ci-C4alkyloxyCrC4alkyl and Ci-C4alkylcarbonyl, wherein each alkyl group is substituted with O to 1 R18, or
R1 is hydrogen, Ci-C4alkyl or cyclopropyl and R2 is adamantyl optionally substituted with O to 1 R18;
R3 is selected from -1 ,2-cyclopentyl-R9, -1 ,3-cyclopentyl-R9, -1 ,4-cyclohexyl-R9, -CH2-I ,4- cyclohexyl-R9, -1 ,3-cyclohexyl-R9, -CH2-1 , 3-cyclohexyl-R9, -3-pyrrolidin-1-yl-R10, -CH2-3- pyrrolidin-1-R10, 4-tetrahydro-pyran, 4-tetrahydro-pyran-2-yl-R9, 4-tetrahydro-pyran-3-yl-R9, -4-piperidin-1-yl-R11, -CH2-4-piperidin-1-yl-R11, -3-piperidin-1-yl-R11, -CH2-3-piperidin-1-yl-R11, -4-bicyclo[2.2.2]octan-1 -yl-R12 and -CH2-4-bicyclo[2.2.2]octan-1 -yl-R12;
X is selected from -O-, -S(O)n-, -CR5R6-, and -NR7-; or
R3 and R7 are connected by a covalent bond so as to form a bicyclic or tricyclic hetcycloalkyl ring comprising the N to which R3 and R7 are connected; the hetcycloalky ring may further be substituted with one or more R19; R4 is selected from hydrogen, CrC4alkyl, trifluoromethyl, halogen, d-C4alkyloxy, Ci-C4alkyl- oxyCi-C4alkyl and Ci-C4alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R18;
R5 and R6 independently are selected from hydrogen, fluorine, methyl, ethyl, iso-propyl or cyclopropyl;
R7 is selected from hydrogen or selected from Ci-C6alkyl, Ci-C6alkenyl, CrC6alkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with 0 to 2 R19;
R8 is selected from C-rC6alkyl, C-rC6alkenyl, C-rC6alkynyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl, each of which may be substituted with 0 to 2 R19; or
R7 and R8 optionally are connected by a covalent bond so as to form a ring comprising the N to which R7 and R8 are connected; the ring may further be substituted with one or more R19;
R9 and R12 independently are selected from hydroxy, cyano, C(O)R13, -(CR14R15)nC(O)NR7R8, -(CR14R15)nNHC(O)R16, -(CR14R15)nOR16, -(CR14R15)nS(O)mR16, -(CR14R15)nS(O)2NR7R8, - (CR14R15)nNR7R8, -(CR14R15)nNR17C(O)NR7R8, -(CR14R15)nNR17S(O)2R16, -(CR14R15)nC=C- R16, -(CR14R15)nC≡C-R16, -(CR14R15)naryl substituted with 0 to 2 R20, and -(CR14R15)nhetaryl optionaly substituted with 0 to 2 R19;
R10 and R11 independently are selected from -C(O)NR7R8, -CH2C(O)NR7R8, -C(O)R17, -S(O)2R16 or -S(O)2NR7R8, wherein the alkyl, aryl and hetaryl groups are optionaly substituted with O to 2 R19;
m and n independently are O, 1 or 2;
R13 is selected from hydroxy, C-rC6alkyl, C-rC6alkenyl, C-rC6alkynyl, cycloalkyl, CrCβalkyloxy, aryl, aryloxy, aryld-Cβalkyloxy, hetaryl, hetaryloxy or hetarylCrCβalkyloxy wherein the CrC6alkyl, cycloalkyl, aryl or hetaryl groups are optionaly substituted with one or more R19;
R14 and R15 independently are selected from hydrogen, halogen, C-rCβalkyl and cycloalkyl, each of which CrC6alkyl and cycloalkyl may be substituted with 0 to 2 halogen, hydroxy or OXO and the carbon in CR14R15 can together with the R14 and/or R15 groups be part of a cycloalkyl ring;
R16 is selected from hydrogen, d-Cβalkyl, d-Cβalkenyl, d-Cβalkynyl, cycloalkyl, hetcycloal- kyl, aryl or hetaryl wherein the CrC6alkyl, cycloalkyl, aryl or hetaryl groups are optionaly substituted with one or more R19;
R17 is selected from hydrogen, CrC6alkyl, Ci-C6alkylC(O)R20, -(CR14R15)nNR17S(O)2R16, cycloalkyl, hetcycloalkyl, aryl or hetaryl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups optionaly are substituted with one or more R21;
R18 is halogen, hydroxy, oxo, -S(O)2C1-C4alkyl, -S(O)2NR7R8 or -C(O)R13;
R19 is selected from halogen, hydroxy, oxo, -C(O)R20, C1-C6alkylC(O)R20, -S(O)nR16, -S(O)nNR7R8, cyclopropyl, -OR16, CrC6alkyl, aryl, hetaryl, -NR22C(O)NR7R8, -NR22S(O)2NR7R8 or -NC(O)NHS(O)2R16;
R20 is selected from hydroxy, Ci-C6alkyl, CrC6alkenyl, CrC6alkynyl, cycloalkyl, CrC6alkyloxy, aryl, aryloxy, arylCrC6alkyloxy, hetaryl, hetaryloxy or hetarylCi-C6alkyloxy;
R21 is halogen, cyano or hydroxy; 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.
In one embodiment of the present invention, in formula (I), n is O. In another embodiment of the present invention, in formula (I), R14 and R15 are both hydrogen.
In another embodiment of the present invention, in formula (I), n is 1. In another embodiment of the present invention, in formula (I), R7 and R8 are connected by a covalent bond so as to form a pyrrolidine, a piperidine, a piperazine, a substituted pyrrolidine, a substituted piperidine or a substituted piperazine.
In another embodiment of the present invention, in formula (I), R7 and R8 are connected by a covalent bond so as to form a piperidine, a piperazine, a substituted piperidine or a substituted piperazine. In another embodiment of the present invention, in formula (I), R4 is hydrogen.
In another embodiment of the present invention, in formula (I), R1 and R2 together with the nitrogen to which they are attached, are forming a 8-1 1 membered saturated or partially saturated bicyclic or tricyclic ring, said ring being selected from the group consisting of
Figure imgf000016_0001
where each carbon is substituted with 0 to 2 R22, and R22 is independently selected from Ci-C8alkyl, halogen, hydroxy, oxo, C(O)R13, -S(O)2NR7R8, -S(O)nCrC4alkyl and CrC6alkyloxy.
In another embodiment of the present invention, in formula (I), X is -0-. In another embodiment of the present invention, in formula (I), X is -NR7-.
In another embodiment of the present invention, in formula (I) R3 and R7 are connected by a covalent bond so as to form a bicyclic or tricyclic hetcycloalkyl ring comprising the N to which R3 and R7 are connected wherein the hetcycloalky ring may further be substituted with one or more R19. In another embodiment of the present invention, in formula (I) R3 and R7 together with the N to which they are connected comprises 2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 2,5- diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester or (1 S,5R)-3-(pyridin-2-yloxy)- 8-aza-bicyclo[3.2.1]oct-8-yl.
In another embodiment of the present invention, in formula (I), R3 is -1 ,4-cyclohexyl- R9 or -CH2-1 ,4-cyclohexyl-R9.
In another embodiment of the present invention, in formula (I), R 9 ; i~s
Figure imgf000016_0002
In another embodiment of the present invention, in formula (I)1R13 is hydroxy. In another embodiment of the present invention, in formula (I), R9 is selected from
-CH2-O- ■aarryyll,, --CCHH22--OO--hheettaarryyll,, --OO--aarryyll,, --OO--hheettaarryyll,, --CCHH2^-OO--(d-ealkyl, -NHC(O)R16, where the aryl, hetaryl and
Figure imgf000016_0003
groups are optionally substituted.
In another embodiment of the present invention, in formula (I), R9 is selected from -NH-S(O)2-aryl, -NH-S(O)2-hetaryl, -NH-aryl, -NH-hetaryl, -S(O)2-aryl and -S(O)2-hetaryl, where the aryl and hetaryl groups are optionally substituted.
In another embodiment of the present invention, in formula (I), R3 is -1 ,3-cyclohexyl- R9 or -CH2-1 ,3-cyclohexyl-R9.
In another e mmbbooddiimment of the present invention, in formula (I), R3 comprises a cyclohexyl ring and R 39 ^ or D R12 is attached in the c/s-configuration.
In another embodiment of the present invention, in formulc cyclohexyl ring and R9 or R12 is attached in the frans-configuration.
I Inn aannootthheerr eemmbbooddiimmeenrt of the present invention, in formula (I), R3 is -4-piperidin-1-yl- R11 or -CH2-4-piperidin-1-yl-R11.
In another embodiment of the present invention, in formula (I), R11 is selected from aryl, hetaryl, -S(O)2-aryl and -S(O)2-hetaryl, where each aryl and hetaryl groups are optionally substituted.
In another embodiment of the present invention, in formula (I), R3 is -3-piperidin-1-yl- R11 or -CH^-piperidin-i-yl-R11.
In another embodiment of the present invention, in formula (I), R1 is hydrogen, Ci-C4alkyl or cyclopropyl.
In another embodiment of the present invention, in formula (I), R2 is an adamantyl substituted with one, two or more substituents independently selected from halogen, hy- droxy, oxo, C(O)R13, CrC6alkyl, CrC6alkyloxy, -S(O)2NR7R8, and -S(O)nCi-C4alkyl.
In another embodiment of the present invention, in formula (I), R1 and R2 together with the nitrogen to which they are attached, are forming a substituted 8-aza-bicyclo[3.2.1]- octane.
In another embodiment of the present invention, in formula (I), R1 and R2 together with the nitrogen to which they are attached, is 8-aza-bicyclo[3.2.1]octan-3-yl.
In another embodiment of the present invention, in formula (I), R1 and R2 together with the nitrogen to which they are attached, are forming 8-aza-bicyclo[3.2.1]octane substituted with one, two or more substituents independently selected from halogen, hydroxy, oxo, C(O)RI 3, CrC6alkyl, CrC6alkyloxy, -S(O)2NR7R8 and -S(0)nCrC4alkyl. In another embodiment of the present invention, the compound of formula (I) is
Figure imgf000017_0001
wherein R1 and R2 together with the nitrogen to which they are attached, are forming a 8-11 mem- bered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitrogen, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S(O)m, where m is 0, 1 or 2, and said ring being substituted with 0 to 3 groups inde- pendently selected from d-C4alkyl, halogen, hydroxy, oxo, COOH, -NHR17, NR17R17,
Ci-C4alkyloxy, Ci-C4alkyloxyCrC4alkyl and Ci-C4alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R21, or
R1 is hydrogen, Ci-C4alkyl or cyclopropyl and R2 is a substituted or unsubstituted adamantyl;
R21 is halogen, hydroxy, oxo or COOH;
R4 is selected from hydrogen, CτC4alkyl, trifluoromethyl, halogen, C-rC4alkyloxy, Ci-C4alkyloxyCτC4alkyl and C1-C4alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R21;
X is selected from -O-, -S-, -CR5R6-, -NH-, and -NR6-;
R5 is hydrogen or fluorine;
R6 is hydrogen, methyl, ethyl, iso-propyl or cyclo-propyl;
R3 is selected from -1 ,4-cyclohexyl-R7, -CH2-1 , 4-cyclohexyl-R8, -1 ,3-cyclohexyl-R9, -CH2-1 ,3- cyclohexyl-R10, -4-piperidin-1-yl-R11, -CH2-4-piperidin-1-yl-R12, -3-piperidin-1-yl-R13, -CH2-3- piperidin-1-yl-R14, -4-bicyclo[2.2.2]octan-1-yl-R15 and -CH2-4-bicyclo[2.2.2]octan-1-yl-R16;
R7, R8, R9, R10, R15 and R16 are independently selected from CO2HR22R23)n-C(O)-NR17R18, - (CR22R23)n-NHC(O)R18, -(CR22R2VOR18, -(CR22R23)n-SR18 , C(O)R19, OH, -(C, -(CR22- R23)n-S(O)2R18, -(CR22R2VS(O)2NR17R18, -(CR22R23)n-NR17R18, -(CR22R23Jn-N R17C(O)- NR17R18, -(CR22R2VC=C-R18, -(CR22R23)n-C≡C-R18, -(CR22R23)n-aryl substituted with O to 2 R20, and -(CR22R23)n-hetaryl substituted with O to 2 R20;
n is O, 1 or 2;
each R22 and R23 are independently selected from hydrogen, halogen, CrC6alkyl and cycloalkyl, each of which d-Cβalkyl and cycloalkyl may be substituted with O to 2 halogen, hydroxy or oxo and the carbon in CR22R23 can together with the R22 and/or R23 groups be part of a cycloalkyl ring;
R20 is selected from halogen, hydroxy, oxo, -COOH, -S(O)0-2R19, -S(O)0-2NR19R19, cyclopro- pyl, -0-R19, Ci-C6alkyl, aryl, hetaryl, NR19CONR19R19; NR19SO2NR19R19 or NCONHSO2R19'
R17 is selected from hydrogen or selected from d-C6alkyl, CrC6alkenyl, CrC6alkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R20;
R18 is selected from C-rC6alkyl, C-rC6alkenyl, C-rC6alkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R20; where R17 and R18 are optionally connected by a covalent bond so as to form a ring comprising the N to which R17 and R18 are connected;
R19 is selected from hydrogen, hydroxy, C-i-Cβalkyl, d-Cβalkenyl, d-Cβalkynyl, cycloalkyl, CrC6alkyloxy, aryl or hetaryl wherein hydroxy, CrC6alkyl, cycloalkyl, CrC6alkyloxy, aryl or hetaryl are optional substituted with R20;
R11, R12, R13 and R14 are independently selected from -C(O)-NR17R18, -CH2C(O)-NR17R18, C(O)R19, -S( OO))22RR1188,, --SS((OO))22NNRR1177RR1188,, CCir-CC66aallkkyyll ssuubbssttiittuuted with O to 2 R20, aryl substituted with O to 2 R20, and hetaryl substituted with O to 2 R20; 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.
In formula (I) R is understood to be selected from the group
Figure imgf000019_0001
where * indicates the carbon whereto X is bound.
In one embodiment of the present invention, in formula (I) n is 0. In another embodiment of the present invention, in formula (I) R22 and R23 are both hydrogen.
In another embodiment of the present invention, in formula (I) n is 1.
In another embodiment of the present invention, in formula (I) n is 1 and both R ,22 and R are hydrogen.
In another embodiment of the present invention, in formula (I) R17 and R18 are con- nected by a covalent bond so as to form a piperidine, a piperazine, a substituted piperidine or a substituted piperazine.
In another embodiment of the present invention, in formula (I) R17 and R18 are connected by a covalent bond so as to form a piperidine or a substituted piperidine.
In another embodiment of the present invention, in formula (I) R4 is hydrogen. In another embodiment of the present invention, in formula (I) R1 and R2 together with the nitrogen to which they are attached, are forming a 8-11 membered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitrogen, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S(O)m, where m is O, 1 or 2. In another embodiment of the present invention, in formula (I) R1 and R2 together with the nitrogen to which they are attached, are forming a 8-11 membered saturated or partially saturated bicyclic or tricyclic ring, said ring being selected from the group consisting of
Figure imgf000020_0001
where each is substituted with 0 to 2 R25, and R25 is independently selected from d-C8alkyl, halogen, hydroxy, oxo, COOH, and C-i-Cβalkyloxy. In another embodiment of the present invention, in formula (I) R1 and R2 together with the nitrogen to which they are attached, are forming a 8-11 membered saturated or partially saturated bicyclic or tricyclic ring, said ring being selected from the group consisting of
Figure imgf000021_0001
In another embodiment of the present invention, in formula (I) X is -O-. In another embodiment of the present invention, in formula (I) X is -S-. In another embodiment of the present invention, in formula (I) X is -CR5R6-. In another embodiment of the present invention, in formula (I) X is -NH-. In another embodiment of the present invention, in formula (I) X is -NR6-.
In another embodiment of the present invention, in formula (I) R5 is hydrogen. In another embodiment of the present invention, in formula (I) R6 is hydrogen. In another embodiment of the present invention, in formula (I) X is -CH2-.
In another embodiment of the present invention, in formula (I) R3 is -1 ,4-cyclohexyl-
R7 or -CH2-1 ,4-cyclohexyl-R8.
In another embodiment of the present invention, in formula (I) R7 and R8 are C(O)R19.
In another embodiment of the present invention, in formula (I) R19 is hydroxy. In another embodiment of the present invention, in formula (I) R7 and R8 are selected from -CH2-O-aryl, -CH2-O-hetaryl, -O-aryl, -O-hetaryl, -CH2-O-Ci-6alkyl, -NHC(O)R18, where the aryl, hetaryl and Ci-6alkyl groups are optionally substituted.
In another embodiment of the present invention, in formula (I) R7 and R8 are selected from -NH-S(O)2-aryl, -NH-S(O)2-hetaryl, -NH-aryl, -NH-hetaryl, -S(O)2-aryl and - S(O)2-hetaryl, where the aryl and hetaryl groups are optionally substituted. In another embodiment of the present invention, in formula (I) R3 is -1 ,3-cyclohexyl- R9 or -CH2-1 ,3-cyclohexyl-R10.
In anot hheerr eemmbbooddiimmeent of the present invention, in formula (I) R3 comprises a cyclo- hexyl ring and R ■>7 , D R8 , D R9 _ or D R10 is attached in the c/s-configuration. In another embodiment of the present invention, in formula (I) R3 comprises a cyclo- hexyl ring and R7, R8, R9 or R10 is attached in the frans-configuration.
In another embodiment of the present invention, in formula (I) R3 is -4-piperidin-1-yl- R11 or -CH2-4-piperidin-1-yl-R12.
In another embodiment of the present invention, in formula (I) R11 and R12 are se- lected from aryl, hetaryl, -S(O)2-aryl and -S(O)2-hetaryl, where each aryl and hetaryl groups are optionally substituted.
In another embodiment of the present invention, in formula (I) R3 is -3-piperidin-1-yl- R13 or -CH2-3-piperidin-1-yl-R14.
In another embodiment of the present invention, in formula (I) R20 is halogen, hy- droxy, oxo, -COOH or cyclopropyl.
In another embodiment of the present invention, in formula (I) R1 is hydrogen, Ci-C4alkyl or cyclopropyl.
In another embodiment of the present invention, in formula (I) R2 is an unsubstituted adamantyl selected from 1-adamantyl and 2-adamantyl. In another embodiment of the present invention, in formula (I) R2 is a substituted adamantyl.
In another embodiment of the present invention, in formula (I) R2 is a substituted 1- adamantyl or a substituted 2-adamantyl.
In another embodiment of the present invention, in formula (I) R2 is an adamantyl substituted with one, two or more substituent independently selected from halogen, hydroxy, oxo, COOH, Ci-C6alkyl and d-C6alkyloxy.
In another embodiment of the present invention, the compound of formula (I) is
Figure imgf000022_0001
wherein
R1 and R2 together with the nitrogen to which they are attached, are forming a 8-11 mem- bered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitro- gen, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxygen, and S(O)m, where m is 0, 1 or 2, and said ring being substituted with 0 to 3 groups independently selected from d-C4alkyl, halogen, hydroxy, oxo, COOH, -NHR17, NR17R17, Ci-C4alkyloxy, Ci-C4alkyloxyCrC4alkyl and Ci-C4alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R21, or
R1 is hydrogen, Ci-C4alkyl or cyclopropyl and R2 is a substituted or unsubstituted adamantyl;
R21 is halogen, hydroxy, oxo or COOH;
R4 is selected from hydrogen, CτC4alkyl, trifluoromethyl, halogen, C-rC4alkyloxy,
Ci-C4alkyloxyCτC4alkyl and C1-C4alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R21;
X is selected from -O-, -S-, -CR5R6-, -NH-, and -NR6-;
R5 is hydrogen or fluorine;
R6 is hydrogen, methyl, ethyl, iso-propyl or cyclo-propyl;
R3 is selected from -1 ,4-cyclohexyl-R7, -CH2-1 ,4-cyclohexyl-R8, -1 ,3-cyclohexyl-R9, -CH2-1 ,3- cyclohexyl-R10, -4-piperidin-1-yl-R11, -CH2-4-piperidin-1-yl-R12, -3-piperidin-1-yl-R13, -CH2-3- piperidin-1-yl-R14, -4-bicyclo[2.2.2]octan-1-yl-R15 and -CH2-4-bicyclo[2.2.2]octan-1-yl-R16;
R7, R8, R9, R10, R15 and R16 are independently selected from CO2H, C(O)R19, OH, -(CR22- R23)n-C(O)-NR17R18, -(CR22R23)n-NHC(O)R18, -(CR22R23)n-OR18, -(CR22R23)n-SR18 , -(CR22- R23)n-S(O)2R18, -(CR22R2VS(O)2NR17R18, -(CR22R23)n-NR17R18, -(CR22R23)n-N R17C(O)- NR17R18, -(CR22R2VC=C-R18, -(CR22R23)n-C≡C-R18, -(CR22R23)n-aryl substituted with O to 2 R20, and -(CR22R23)n-hetaryl substituted with O to 2 R20;
n is O, 1 or 2;
each R22 and R23 are independently selected from hydrogen, halogen, CrC6alkyl and cycloalkyl, each of which d-Cβalkyl and cycloalkyl may be substituted with O to 2 halogen, hydroxy or oxo and the carbon in CR22R23 can together with the R22 and/or R23 groups be part of a cycloalkyl ring; R20 is halogen, hydroxy, oxo, -COOH, -S(O)0-2R19, -S(O)0-2NR19R19, cyclopropyl, -0-R19 or Ci-C6alkyl;
R17 is hydrogen or selected from d-C6alkyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R20;
R18 is C-i-Cβalkyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R20; wwhheerree RR1177 aanndd RR1188 aarree ooppttiioonnaallllyy ccoonnnneecctteedd bb\y a covalent bond so as to form a ring compris- ing the N to which R17 and R18 are connected;
R19 is selected from hydroxy, C-rC6alkyl, cycloalkyl, C-rC6alkyloxy, aryl or hetaryl wherein hydroxy, CτC6alkyl, cycloalkyl, d-Cβalkyloxy, aryl or hetaryl are optional substituted with R20.
R11, R12, R13 and R14 are independently selected from -C(O)-NR17R18, -CH2C(O)-NR17R18, - C(O)R19, -S(O)2R18, -S(O)2NR17R18, CrC6alkyl substituted with O to 2 R20, aryl substituted with O to 2 R20, and hetaryl substituted with O to 2 R20; 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.
In another embodiment of the present invention, the compound of formula (I) is
Figure imgf000024_0001
wherein
R1 and R2 together with the nitrogen to which they are attached, are forming a 8-11 mem- bered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitrogen, 5-10 carbon atoms and from O to 1 additional heteroatoms selected from nitrogen, oxygen, and S(0)m, where m is O, 1 or 2, and said ring being substituted with O to 3 groups inde- pendently selected from Ci-C4alkyl, halogen, hydroxy, oxo, CrC4alkyloxy, Ci-C4alkyloxy-
CrC4alkyl and Ci-C4alkylcarbonyl, wherein each alkyl group is substituted with O to 1 R21, or R1 is hydrogen, Ci-C4alkyl or cyclopropyl and R2 is a substituted or unsubstituted adamantyl; R21 is halogen, hydroxy, oxo or COOH;
R4 is selected from hydrogen, Ci-C4alkyl, trifluoromethyl, halogen, Ci-C4alkyloxy, Ci-C4alkyloxyCi-C4alkyl and CrC4alkylcarbonyl, wherein each alkyl group is substituted with O to 1 R21;
X is selected from -0-, -S-, -CR5R6-, -NH-, and -NR6-;
R5 is hydrogen or fluorine;
R6 is hydrogen, methyl, ethyl, iso-propyl or cyclo-propyl;
R3 is selected from -1 ,4-cyclohexyl-R7, -CH2-1 , 4-cyclohexyl-R8, -1 ,3-cyclohexyl-R9, -CH2-1 ,3- cyclohexyl-R10, -4-piperidin-1-yl-R11, -CH2-4-piperidin-1-yl-R12, -3-piperidin-1-yl-R13, -CH2-3- piperidin-1-yl-R14, -4-bicyclo[2.2.2]octan-1-yl-R15 and -CH2-4-bicyclo[2.2.2]octan-1-yl-R16;
R7, R8, R9, R10, R15 and R16 are independently selected from CO2H, C(O)R19, OH, -C(O)- NR17R18, -NHC(O)R18, -CH2NHC(O)R18, -OR18, -SR18 , -S(O)2R18, -NR17R18, -CH2OR18, - CH2SR18, -CH2NHR18, -C(O)R19, -CH2-O-R19, -CH2C(O)-NR17R18, aryl substituted with O to 2 R20, and hetaryl substituted with O to 2 R20;
R20 is halogen, hydroxy, oxo, COOH or CrC6alkyl;
R17 is hydrogen or selected from d-Cβalkyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R20;
R18 is CτC6alkyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R20; where R17 and R18 are optionally connected by a covalent bond so as to form a ring compris- ing the N to which R17 and R18 are connected;
R19 is selected from hydroxy, Ci-Cβalkyl, cycloalkyl, d-Cβalkyloxy, aryl or hetaryl; R11, R12, R13 and R14 are independently selected from -C(O)-NR17R18, -CH2C(O)-NR17R18, - C(O)R19, -S(O)2R18, CrC6alkyl substituted with O to 2 R20, aryl substituted with O to 2 R20, and hetaryl substituted with O to 2 R20; 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.
In another embodiment of the present invention, the compounds of general formula (I) is selected from the group consisting of
Figure imgf000026_0001
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carbox- ylic acid ethyl ester,
Figure imgf000026_0002
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carbox- ylic acid,
Figure imgf000026_0003
(3-Aza-bicyclo[3.2.2]non-3-yl)-[4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-phenyl]- methanone,
Figure imgf000026_0004
4-(1-Cyclopropanecarbonyl-piperidin-4-yloxy)-N-adamantan-2-yl-benzamide,
Figure imgf000026_0005
4-[1-(3-Methyl-butyryl)-piperidin-4-yloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000027_0001
-|.{4.[4.(3.Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-piperidin-1-yl}-3-methyl-butan-1- one,
Figure imgf000027_0002
(6-Aza-bicyclo[3.2.1]oct-6-yl)-[4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-phenyl]- methanone,
Figure imgf000027_0003
1 -{4-[4-(6-Aza-bicyclo[3.2.1 ]octane-6-carbonyl)-phenoxy]-piperidin-1 -yl}-3-methyl-butan-1 - one,
Figure imgf000027_0004
4-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000027_0005
4-[4-(Octahydro-quinoline-1 -carbonyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000027_0006
cis/trans-4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-adamantan-1-yl-benzamide,
Figure imgf000027_0007
cis/trans-4-[4-(Cyclopropane-carbonyl-amino)-cyclo-hexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000028_0001
N-Adamantan-2-yl-4-(4-hydroxy-cyclohexyloxy)-benzamide,
Figure imgf000028_0002
Cis/trans 4-[4-adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000028_0003
N-Adamantan-2-yl-4-[4-(4-methyl-1 H-imidazol-2-ylsulfanylmethyl)-cyclohexyloxy]- benzamide,
Figure imgf000028_0004
4-[4-(Pyridin-2-yloxy)-cyclohexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000028_0005
4-[4-(Pyrazol-1-yloxy)-cyclohexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000028_0006
4-[4-(Pyrazol-1-yl-oxymethyl)-cyclohexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000028_0007
4-[4-(Pyridin-2-yloxymethyl)-cyclohexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000029_0001
4-(4-Hydroxy-cyclohexyl-methoxy)-N-adamantan-2-yl-benzamide,
Figure imgf000029_0002
4-{4-[4-(Adamantan-2-yl-carbamoyl)-phenoxy]-cyclo-hexylmethoxy}-benzoic acid,
Figure imgf000029_0003
4-{4-[4-(Adamantan-2-yl-carbamoyl)-phenoxy]-cyclo-hexylmethoxy}-benzoic acid allyl ester,
Figure imgf000029_0004
Cis-4-[4-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane car- boxylic acid,
Figure imgf000029_0005
Trans-4-[4-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carboxylic acid,
Figure imgf000029_0006
Cis-N-Adamantan-2-yl-4-[4-(pyridine-2-sulfonylamino)-cyclohexyloxy]-benzamide,
Figure imgf000030_0001
Cis-Pyridine-2-sulfonic acid {4-[4-(octahydro-quinoline-1 -carbonyl)-phenoxy]-cyclohexyl}- amide,
Figure imgf000030_0002
Cis-N-Adamantan-2-yl-4-[4-(cyc oprop
Figure imgf000030_0003
Cis-Cyclopropanecarboxylic acid {4-[4-(octahydro-quinoline-1-carbonyl)-phenoxy]- cyclohexyl}-amide,
Figure imgf000030_0004
3-{3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-pyrrolidin-1-yl}-3-oxo-propionic acid,
Figure imgf000030_0005
3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-pyrrolidine-1-carboxylic acid isopro- pylamide,
Figure imgf000030_0006
{3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-pyrrolidin-1-yl}-(6-chloro-pyridin-3- yl)-methanone,
Figure imgf000031_0001
N-{3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-pyrrolidine-1-carbonyl}-4-methyl- benzenesulfonamide,
Figure imgf000031_0002
3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-cyclopentanecarboxylic acid,
Figure imgf000031_0003
3-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclopentane carbox- ylic acid,
Figure imgf000031_0004
N-(5-Hydroxy-adamantan-2-yl)-4-(4-hydroxy-cyclohexyl-oxy)-N-methyl-benzamide,
Figure imgf000031_0005
N-(5-Hydroxy-adamantan-2-yl)-4-(4-hydroxy-cyclohexyl-oxy)-N-methyl-benzamide,
Figure imgf000031_0006
N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[4-(pyridine-2-sulfonylamino)-cyclohexyloxy]- benzamide,
Figure imgf000032_0001
4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(5-hydroxy-adamantan-2-yl)-N-methyl- benzamide,
Figure imgf000032_0002
4-[4-(3-Hydroxy-adamantan-1 -ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000032_0003
4-{4-[(5-Hydroxy-adamantan-2-yl)-methyl-carbamoyl]-phen-oxy}-cyclohexanecarboxylic acid,
Figure imgf000032_0004
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carbox- ylic acid amide,
Figure imgf000032_0005
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclo-hexane carbox- ylic acid dimethylamide,
Figure imgf000032_0006
4-[4-(Octahydro-quinoline-1 -carbonyl)-phenoxy]-cyclo-hexanecarboxylic acid amide,
Figure imgf000032_0007
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carboni- trile,
Figure imgf000033_0001
Cyclopropanecarboxylic acid {4-[4-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)- phenoxy]-cyclohexyl}-amide,
Figure imgf000033_0002
Cyclopropanecarboxylic acid {4-[4-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)- phenoxy]-cyclohexyl}-amide,
Figure imgf000033_0003
4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(Z)-(5-hydroxy-adamantan-2-yl)- benzamide,
Figure imgf000033_0004
4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(E)-(5-hydroxy-adamantan-2-yl)- benzamide,
Figure imgf000033_0005
(Octahydro-quinolin-1-yl)-{4-[1-(pyridine-2-sulfonyl)-piperidin-4-ylmethoxy]-phenyl}- methanone,
Figure imgf000033_0006
{4-[1-(1-Methyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl-methoxy]-phenyl}-(octahydro-quinolin- 1-yl)-methanone,
Figure imgf000034_0001
[4-(1-Ethanesulfonyl-pipeπdin-4-yl-methoxy)-phenyl]-(octahydro-quinolin-1-yl)-methanone,
Figure imgf000034_0002
N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[1-(pyπdine-2-sulfonyl)-piperidin-4-yl-methoxy]- benzamide,
Figure imgf000034_0003
4-{4-[(5-Hydroxy-adamantan-2-yl)-methyl-carbamoyl]-phenoxy-methyl}-piperidine-1- carboxylic acid isopropylamide,
Figure imgf000034_0004
N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[1 -(1 -methyl-1 /-/-imidazole-4-sulfonyl)-piperidin-4- ylmethoxy]-benzamide,
Figure imgf000034_0005
4-(1-Ethanesulfonyl-piperidin-4-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-N-methyl- benzamide,
Figure imgf000035_0001
3-{4-[4-(Octahydro-quinoline-1-carbonyl)-phenoxymethyl]-piperidine-1-sulfonyl}-benzoic acid,
Figure imgf000035_0002
4-{4-[4-(Octahydro-quinoline-1-carbonyl)-phenoxymethyl]-piperidine-1-sulfonyl}-benzoic acid,
Figure imgf000035_0003
4-(2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-N-adamantan-2-yl-benzamide,
Figure imgf000035_0004
(1S,4S)-5-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenyl]-2,5-diaza-bicyclo[2.2.1]- heptane-2-carboxylic acid terf-butyl ester,
Figure imgf000035_0005
(Octahydro-quinolin-1-yl)-{4-[(1 phenyl}-methanone,
Figure imgf000036_0001
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.
In another embodiment of the present invention, in formula (I) the polar surface area (PSA) of said compound is in the range from 40 A2 to 130 A2, preferably from 50 A2 to 130 A2, more preferably from 60 A2 to 120 A2, more preferably from 70 A2 to 120 A2, most prefer- able from 70 A2 to 110 A2.
In another embodiment of the present invention, in formula (I) the molar weight of said compound is in the range from 350D to 650D, preferably from 400D to 600D.
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. Representative examples of 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, glycerophosphates, ketoglutarates and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically accept- able salts listed in J. Pharm. Sci., 66, 2 (1977), which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, barium, calcium, magnesium, zinc, calcium salts and the like. Examples of 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. Examples of cationic amino acids include lysine, arginine, histidine and the like.
Further, 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 terf-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, tert-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. Alternatively, 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.
The 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 preferred 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, [R)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like. Commonly used methods are compiled by Jaques et al. in "Enantiomers, Racemates and Resolu- tion" (Wiley Interscience, 1981 ). More specifically the compound of the present invention may be converted to a 1 :1 mixture of diastereomeric amides by treating with chiral amines, ami- noacids, 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. Various 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; or various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound 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. In general, such 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.
It is a well known problem in drug discovery that compounds, such as enzyme inhibitors, may be very potent and selective in biochemical assays, yet be inactive in vivo. This lack of so-called bioavailability may be ascribed to a number of different factors such as lack of or poor absorption in the gut, first pass metabolism in the liver and/or poor uptake in cells. Although the factors determining bioavailability are not completely understood, there are many examples in the scientific literature - well known to those skilled in the art - of how to modify compounds, which are potent and selective in biochemical assays but show low or no activity in vivo, into drugs that are biologically active.
It is within the scope of the invention to modify the compounds of the present inven- tion, termed the Original compound', by attaching chemical groups that will improve the bioavailability of said compounds in such a way that the uptake in cells or mammals is facilitated.
Examples of said modifications, which are not intended in any way to limit the scope of the invention, include changing of one or more carboxy groups to esters (for instance methyl esters, ethyl esters, terf-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters). Compounds of the invention, original compounds, such modified by attaching chemical groups are termed 'modified compounds'.
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, pre- vention and/or prophylaxis of disorders and diseases in which such a modulation or reduction is beneficial.
Accordingly, 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 autoimmune diseases, adverse effects of glucocorticoid receptor agonist treatment of inflammatory diseases, adverse effects of glucocorticoid receptor agonist treatment of diseases with an inflammatory component, adverse effects of glucocorticoid receptor agonist treatment as a part of cancer chemotherapy, adverse effects of glucocorticoid receptor agonist treatment for surgical/post-surgical or other trauma, adverse effects of glucocorticoid receptor agonist therapy in the context of organ or tissue transplantation or adverse effects of glucocorticoid receptor agonist treatment in other diseases, disorders or conditions where glucocorticoid receptor agonists provide clinically beneficial effects. Also the present compounds may be applicable for the treatment of visceral fat accumulation and insulin resistance in HAART (highly active antiretroviral treatment)-treated patients.
More specifically the present compounds may be applicable for the treatment, prevention 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, hyperlipoproteinemia, 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, ar- teriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia, heart insufficiency, congestional heart failure, stroke, myocardial infarction, arryth- mia, decreased blood flow, erectile dysfunction (male or female), myopathy, loss of muscle tissue, muscle wasting, muscle catabolism, osteoporosis, decreased linear growth, neurode- generative and psychiatric disorders, Alzheimers disease, neuronal death, impaired cognitive function, depression, anxiety, eating disorders, appetite regulation, migraine, epilepsia, addiction to chemical substances, disorders of intraocular pressure, glaucoma, polycystic ovary syndrome (PCOS), inappropriate immune responses, inappropriate T helper-1/T helper-2 polarisation, bacterial infections, mycobacterial infections, fungal infections, viral infections, parasitic infestations, suboptimal responses to immunizations, immune dysfunction, partial or complete baldness, or diseases, disorders or conditions that are influenced by intracellular glucocorticoid levels and any combination thereof, adverse effects of glucocorticoid receptor agonist treatment of allergic-inflammatory diseases such as asthma and atopic dermatitis, adverse effects of glucocorticoid receptor agonist treatment of disorders of the respiratory system e.g. asthma, cystic fibrosis, emphysema, bronchitis, hypersensitivity, pneumonitis, eosinophilic pneumonias, pulmonary fibrosis, adverse effects of glucocorticoid receptor agonist treatment of inflammatory bowel disease such as Crohn's disease and ulcerative colitis; adverse effects of glucocorticoid receptor agonist treatment of disorders of the immune system, connective tissue and joints e.g. reactive arthritis, rheumatoid arthritis, Sjogren's syn- drome, systemic lupus erythematosus, lupus nephritis, Henoch-Schonlein purpura,
Wegener's granulomatosis, temporal arteritis, systemic sclerosis, vasculitis, sarcoidosis, dermatomyositis-polymyositis, pemphigus vulgaris; adverse effects of glucocorticoid receptor agonist treatment of endocrinological diseases such as hyperthyroidism, hypoaldosteronism, hypopituitarism; adverse effects of glucocorticoid receptor agonist treatment of hematological diseases e.g. hemolytic anemia, thrombocytopenia, paroxysmal nocturnal hemoglobinuria; adverse effects of glucocorticoid receptor agonist treatment of cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lymphoblastic 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. myas- thenia gravis and heriditary myopathies (e.g. Duchenne muscular dystrophy), adverse effects of glucocorticoid receptor agonist treatment in the context of surgery & transplantation e.g. trauma, post-surgical stress, surgical stress, renal transplantation, liver transplantation, lung transplantation, pancreatic islet transplantation, blood stem cell transplantation, bone marrow transplantation, heart transplantation, adrenal gland transplantation, tracheal transplantation, intestinal transplantation, corneal transplantation, skin grafting, keratoplasty, lens implanta- tion and other procedures where immunosuppression with glucocorticoid receptor agonists is beneficial; adverse effects of glucocorticoid receptor agonist treatment of brain absess, nausea/vomiting, infections, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal cord diseases, saccular aneurysms or adverse effects to glucocorticoid receptor agonist treatment in other diseases, disorders and conditions where glucocorticoid receptor agonists provide clinically beneficial effects.
Accordingly, in a further aspect 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. In another embodiment, the patient is treated with a compound according to the invention 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.
In yet another embodiment, the pharmaceutical composition is for oral, nasal, transdermal, pulmonal or parenteral administration. Furthermore, 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 βHSD1 is beneficial.
The invention also relates to a method for the treatment, prevention and/or prophy- laxis of disorders and diseases wherein a modulation or an inhibition of the activity of
11 βHSD1 is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of any dis- eases and conditions that are influenced by intracellular glucocorticoid levels as mentioned above.
Thus, in a preferred embodiment of the invention 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 desir- able, such as the conditions and diseases mentioned above. In yet a preferred embodiment of the invention 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.
In yet another preferred embodiment of the invention 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).
In yet another preferred embodiment of the invention 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. In yet another preferred embodiment of the invention 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.
In still another preferred embodiment of the invention 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.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of neurodegenerative and psychiatric disorders. In yet a further preferred embodiment of the invention 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.
In another embodiment of the present invention, the route of administration may be any route which effectively transports a compound according to the invention to the appro- priate or desired site of action, such as oral, nasal, buccal, transdermal, pulmonal, or parenteral.
In still a further aspect of the invention 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 modi- fying 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.
Thus, in a further aspect of the invention the present compounds may be adminis- tered in combination with one or more antiobesity agents or appetite regulating agents. Such agents may be selected from the group consisting of CART (***e amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH
(melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator- activated receptor) modulators, RXR (retinoid X receptor) modulators, TR β agonists, AGRP (Agouti related protein) inhibitors, H3 histamine antagonists, opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor. In one embodiment of the invention 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 792 290 (Novo Nordisk A/S), e.g. NεB29-tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk NS), e.g. AspB28 human insulin, US 5,504,188 (EIi Lilly), e.g. LysB28 Pro629 human insulin, EP 368 187 (Aventis), e.g. 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 glycogenosis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as PPARα modulators, PPARδ modulators, cholesterol absorption inhibitors, HSL (hormone-sensitive lipase) inhibitors and HMG CoA inhibitors (statins), nicotinic acid, fibrates, anion exchangers, compounds lowering food intake, bile acid resins, RXR agonists and agents acting on the ATP-dependent potassium channel of the β-cells.
In one embodiment, the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as NεB29-tetradecanoyl des (B30) human in- sulin, AspB28 human insulin, LysB28 Pro629 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
In a further embodiment the present compounds are administered in combination with a sulphonylurea e.g. tolbutamide, glibenclamide, glipizide or glicazide.
In another embodiment the present compounds are administered in combination with a biguanide e.g. metformin.
In yet another embodiment the present compounds are administered in combination with a meglitinide e.g. repaglinide or senaglinide.
In still another embodiment the present compounds are administered in combination with a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or com- pounds 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.
In yet another embodiment 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.
In a further embodiment the present compounds are administered in combination with an α-glucosidase inhibitor e.g. miglitol or acarbose.
In another embodiment the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the β-cells e.g. tolbutamide, glibenclamide, glipizide, glicazide or repaglinide.
Furthermore, the present compounds may be administered in combination with nateglinide.
In still another embodiment 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.
In a further embodiment 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.
Further, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol, metoprolol, bisoprololfumerate, esmolol, acebutelol, metoprolol, acebutolol, betaxolol, celiprolol, nebivolol, tertatolol, oxprenolol, amusolalul, carvedilol, labetalol, β2-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, verapamil, lacidipine, lercanidipine, aranidipine, cilnidipine, clevidipine, azelnidipine, barni- dipine, efonodipine, iasidipine, iemildipine, iercanidipine, manidipine, nilvadipine, pranidipine, furnidipine, α-blockers such as doxazosin, urapidil, prazosin, terazosin, bunazosin and OPC- 28326, diuretics such as thiazides/sulphonamides (e.g. bendroflumetazide, chlorothalidone, hydrochlorothiazide and clopamide), loop-diuretics (e.g. bumetanide, furosemide and tora- semide) and 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. OPC-21268, vasopressin V2 antagonists such as tolvaptan, SR-121463 and OPC-31260, B-type natriuretic peptide agonists e.g. Nesiritide, angiotensin Il antagonists such as irbesartan, candesartancilexetil, losartan, valsartan, tel- misartan, eprosartan, candesartan, CL-329167, eprosartan, iosartan, olmesartan, prato- sartan, TA-606, and YM-358, 5-HT2 agonists e.g. fenoldopam and ketanserin, 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, moxonidine, CoAprovel, Mondo- Biotech-81 1.
Further reference can be made to Remington: The Science and Practice of Phar- macy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995. Furthermore, the present compounds may be administered in combination with one or more glucocorticoid receptor agonists. Examples of such glucocorticoid receptor agonists are 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-41 14, 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.
PHARMACEUTICAL COMPOSITIONS
The compounds of the 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 pharma- ceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 1995.
The pharmaceutical 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 ac- tive 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. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sus- tained or prolonged release according to methods well-known in the art.
Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.
Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as ster- ile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention.
Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.
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.
The formulations may conveniently be presented in unit dosage form by methods known 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.
For 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. The term "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. When 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. When a com- pounds for use according to the present invention, contains a free acid 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 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.
For parenteral administration, solutions of the present compounds in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such 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. Examples of 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, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, 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. The pharmaceutical compositions formed by combining the compounds of the invention 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. These excipients may be for example, inert diluents, such as cal- cium 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. For example, a time delay material such as glyceryl monostearate or glyceryl 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.
Formulations for oral use may also be presented as hard gelatine capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or a soft gelatine capsule wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyl-eneoxy- cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as su- crose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipi- ents, for example, sweetening, flavouring, and colouring agents may also be present.
The pharmaceutical compositions comprising a compound for use according to the present invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, preservative and flavouring and colouring agent. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as solvent or suspending medium. For this purpose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compositions may also be in the form of suppositories for rectal administration of the compounds of the present invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols, for example.
For topical use, creams, ointments, jellies, solutions of suspensions, etc., containing the compounds of the present invention are contemplated. For the purpose of this application, topical applications shall include mouth washes and gargles.
The compounds for use according to the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. In addition, some of the compounds for use according to the present invention may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the present invention.
Thus, in a further embodiment, there is provided a pharmaceutical composition com- prising a compound for use according to the present invention, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipi- ents, or diluents.
If a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
A typical tablet which may be prepared by conventional tabletting techniques may contain: Core:
Active compound (as free compound or salt thereof) 5.0 mg
Lactosum Ph. Eur. 67.8 mg
Cellulose, microcryst. (Avicel) 31.4 mg Amberlite®IRP88* 1.0 mg
Magnesii stearas Ph. Eur. q.s.
Coating:
Hydroxypropyl methylcellulose approx. 9 mg Mywacett 9-40 T** approx. 0.9 mg
* Polacrillin potassium NF, tablet disintegrant, Rohm and Haas. ** Acylated monoglyceride used as plasticizer for film coating.
The compounds of the invention may be administered to a patient which is a mammal, especially a human in need thereof. Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
Any novel feature or combination of features described herein is considered essential to this invention. The present invention also relate to the below methods of preparing the compounds of the invention.
The present invention is further illustrated in the following representative examples which are, however, not intended to limit the scope of the invention in any way.
EXAMPLES
The following general procedures refer to intermediate compounds and final products for general formula (I) identified in the specification and in the synthesis schemes. The preparation of the compounds of general formula (I) of the present invention is described in detail using the following. Occasionally, the reaction may not be applicable as described to each compound included within the disclosed scope of the invention. The compounds for which this occurs will be readily recognised by those skilled in the art. In these cases the reactions can be successfully performed by conventional modifications known to those skilled in the art, which is, by appropriate protection of interfering groups, by changing to other conventional reagents, or by routine modification of reaction conditions. Alternatively, other reac- tions disclosed herein or otherwise conventional will be applicable to the preparation of the corresponding compounds of the invention. In all preparative methods, all starting materials are known or may easily be prepared from known starting materials. The structures of the compounds are confirmed by either elemental analysis or nuclear magnetic resonance (NMR), where peaks assigned to characteristic protons in the title compounds are presented where appropriate. 1 H NMR shifts (δH) are given in parts per million (ppm) down field from tetramethylsilane as internal reference standard. M. p.: is melting point and is given in 0C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385).
HPLC systems:
HPLC-MS: The RP-analysis was performed on an Agilent HPLC system (1100 degasser, 1100 pump, 1 100 injector and a 1 100 DAD) fitted with an Agilent MS detector system Model VL (MW 0-1000) and a S.E.D.E.R.E Model Sedex 55 ELS detector system using a Waters X-terra MS C18 column (5 μm, 3.0 mm x 50 mm) with gradient elution, 5% to 95% solvent B (0.05% TFA in acetonitrile) in solvent A (0.05% TFA in water) within 3 min, 2.7 mL/min.
The abbreviations as used in the present application have the following meaning: TLC: Thin layer chromatography CDCI3: Deuterio chloroform
DCM: Dichloromethane
DIIC: N.N'-Diisopropylcarbodiimide
DMAP: 4-Dimethylaminopyridine
DMSO-d6: Hexadeuterio dimethylsulfoxide
DMSO: Dimethylsulfoxide
DIPEA: Diisopropylethylamine
EDAC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EtOAc: Ethyl acetate
THF: Tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1 -Hydroxy-benzotriazole
POL: Polystyrene
MeCN: Acetonitrile
NMP: N-Methylpyrrolidinone
TEA: Triethylamine
TFA: Trifluoroacetic acid
EDAC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours
The following compounds are either prepared according to the synthesis scheme 1 , scheme 2 or scheme 3 by the use of standard reactions readily recognized by those skilled in the art.
Synthesis scheme 1 :
Figure imgf000053_0001
Synthesis scheme 2:
Mitsunobu HOBT/EDAC Amine
Figure imgf000054_0001
Figure imgf000054_0002
Modified
Figure imgf000054_0003
Figure imgf000054_0004
Synthesis scheme 3:
Figure imgf000054_0005
R is Ci-C6alkyl or arylCi-C6alkyl;
General Example A
Figure imgf000054_0006
4-r4-(1 ,3,3-Tπmethyl-6-aza-bicvclor3.2.1loctane-6-carbonyl)-phenoxyl-cvclohexanecarboxylic acid
4-(4-Ethoxycarbonyl-cyclohexyloxy)-benzoic acid benzyl ester
To a solution of benzyl 4-hydroxybenzoate (50 g, 0.22 mol) and triphenylphosphine (63.2 g, 0.241 mol) dissolved in THF (800 mL) was added 4-hydroxy-cyclohexanecarboxylic acid ethyl ester (35.3 mL, 0.22 mol). The reaction mixture was cooled on an ice bath and DEAD (38 ml, 0.241 mol) was added dropwise maintaining the temperature at 0 0C. The resulting mixture was allowed slowly to reach room temperature and stirred for 16 hrs. at this temperature. The volume was reduced to app. 250 ml. by evaporation and to the resulting mixture was added water (500 ml.) followed by extraction with DCM (3x400 ml_). The combined organic phases were washed with brine (400 ml_), dried (Na2SO4), filtered and the volatiles evaporated in vacuo. Crude product ~80 g was purified on column chromatography (Flash 75) using first heptane (7.5 L) followed by a mixture of EtOAc-heptane (1 :10) (5 L) and finally a mixture of EtOAc-heptane (1 :6) (8 L). Combined fractions were evaporated in vacuo affording 18.1 g (22 %) of 4-(4-ethoxycarbonyl-cyclohexyloxy)-benzoic acid benzyl ester as an oil.
1H-NMR (300 MHz, CDCI3) δ 1.26 (t, 3H), 1.42 - 1.83 (m, 4H), 1.85 - 2.26 (m, 4H), 2.27 - 2.48 (m, 1 H), 4.14 (q, 2H), 4.22 - 4.38 (m, 0.5H), 4.55 (br.s., 0.5H), 5.33 (s, 2H), 6.89 (dd, 2H), 7.27 - 7.49 (m, 5H), 8.01 (d, 2H).
4-(4-Ethoxy-carbonyl-cyclohexyloxy)-benzoic acid
To a solution of the above benzyl ester (36.4 g; 95.2 mmol) dissolved in ethanol (250 mL) was added Pd/C (3.5 g) and the resulting mixture was hydrogenated at 1.0 atm.
The catalyst was filtered off and the filtrate evaporated in vacuo affording 26.6 g (96 %) of 4-
(4-ethoxy-carbonyl-cyclohexyloxy)-benzoic acid as an oil.
1H-NMR (400 MHz, CDCI3) δ 1.27 (t, 3H), 1.45 - 1.86 (m, 4H), 1.88 - 2.27 (m, 4H), 2.30 - 2.50
(m, 1 H), 4.09 - 4.21 (m, 2H), 4.25 - 4.40 (m, 0.5H), 4.60 (br.s., 0.5H), 6.93 (t, 2H), 8.04 (d, 2H).
To a mixture of the above benzoic acid (22 g, 75.26 mmol) and HOBt (12.2 g, 90.31 mmol) in dry THF (250 mL) was added EDAC (17.3 g, 90.31 mmol) and the resulting mixture was stirred for 10 min. at room temperature at which time 1 ,3,3-trimethyl-6-aza- bicyclo[3.2.1]-octane, HCI (17.1 g, 75.26 mmol) and DIPEA (29 mL) was added. The mixture was stirred at room temperature for 48 hrs., the volatiles evaporated and to the residue was added water (150 mL) followed by extraction with EtOAc (2x100 mL). The combined organic phases were washed with water (100 mL) and evaporated in vacuo. The residue was re- dissolved in EtOH (100 mL) and to this mixture was added 1 N NaOH (150 mL). Stirring was continued for 16 hrs. at room temperature at which time the volatiles were evaporated in vacuo followed by addition of water (100 mL) and diethyl ether (150 mL). The organic phase was separated and the aqueous phase acidified to pH ~ 1 with cone. HCI followed by extraction with diethyl ester (2x125 mL). The combined organic phases were dried (Na2SO4), filtered and left for 2 hrs. at room temperature. The precipitate was filtered off and dried in vacuo at 5O0 C affording 10.6 g (35 %) of the title compound as a solid. The filtrate was evaporated to ΛA the volume and seeded. After 16 hrs a second crop was filtered off and dried affording an additional 13.8 g (46 %) of the title compound as a solid. 1H-NMR (400 MHz, CDCI3) δ 0.94 (d, 3H), 1.03 (d, 3H), 1.12 (d, 3H), 1.17 - 1.83 (m, 10H), 1.87 - 2.31 (m, 4H), 2.31 - 2.49 (m, 1 H), 3.22 (d, 0.5H), 3.26 - 3.36 (m, 1 H), 3.58 (d, 0.5H), 3.99 - 4.11 (m, 0.5H), 4.17 - 4.31 (m, 0.5H), 4.50 (br.s., 0.5H), 4.56 - 4.67 (m, 0.5H), 6.82 - 6.94 (m, 2H), 7.35 - 7.48 (m, 2H). m/z: 400 (M+1 )+;
In a similar way as described in general example A above the following compounds 9a-40a were made.
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Example 11a
Figure imgf000058_0002
4-r4-(1 ,3,3-Tπmethyl-6-aza-bicvclor3.2.11octane-6-carbonyl)-phenoxy1-cvclohexanecarboxylic acid amide
To a solution of 4-[4-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]- cyclohexanecarboxylic acid (4 g, 10.01 mmol) in DCM (75 ml.) was added thionylchloride (1.5 ml.) and dry DMF (0.5 ml_). The resulting mixture was stirred for 16 hrs at room temperature and the volatiles evaporated in vacuo. The residue was dissolved in DCM (50 ml_), added dropwise to an ice cooled solution of cone, aqueous ammoniac (150 ml.) and TEA (7 ml.) and stirred for 1 hr. The phases were separated and the organic phase dried (Na2SO4), filtered and evaporated which afforded 3.5 g (88 %) of the title compound as a solid. m/z: 400 (M+1 )+; Rt = 1.39 min.
Example 14a
Figure imgf000059_0001
4-r4-(1 ,3,3-Tπmethyl-6-aza-bicvclor3.2.11octane-6-carbonyl)-phenoxy1-cvclohexane carbo- nitrile
To a solution of the above amide (2 g, 5.02 mmol) in a mixture of DMSO (570 μl_) and DCM (150 ml.) cooled in a dry ice acetone bath to -78 0C was added dropwise a solution of oxalylchloride (520 μl_, 6.02 mmol) in DCM (50 ml_). The mixture was stirred for 15 min. at -78 0C followed by dropwise addition of TEA (2.1 ml_), stirring was continued for an additional 15 min. at which time the reaction mixture was quenched by addition of water (50 ml_). The reaction was allowed to reach room temperature and the phases separated. The aqueous phase was extracted with EtOAc (2x50 ml.) and all the combined organic phases were dried (Na2SO4), filtered and the solvent evaporated in vacuo affording 1.5 g (79 %) of crude title compound.
Preparative LC/MS purification afforded after basic workup 400 mg (21 %) of the title compound. 1H-NMR (400 MHz, CDCI3) δ 0.91 (br.s., 3H), 1.10 (br.s., 6H), 1.22 - 1.33 (m, 2H), 1.41 (d, 1 H), 1.56 (br.s., 1 H), 1.69 - 1.90 (m, 4H), 1.94 - 2.23 (m, 4H), 2.62 - 2.85 (m, 1 H), 3.19 (br.s., 1 H), 3.79 (br.s., 1 H), 4.42 (br.s., 1 H), 6.89 (t, 2H), 7.26 (t, 2H). m/z: 382 (M+1 )+; Rt = 1 ,65 min.
Example 12a was made in a similar way as described for example 11 a.
General Example B
Figure imgf000059_0002
(3-Aza-bicvclor3.2.2lnon-3-ylH4-(1-cvclopropane-carbonyl-piperidin-4-yloxy)-phenyll- methanone
4-(4-Methoxycarbonyl-phenoxy)-piperidine-1-carboxylic acid f-butyl ester To a stirred solution of 4-hydroxy benzoic acid methyl ester (5.0 g, 32.86 mmol) in dry THF (400 ml.) was added triphenyl phosphine (12.93 g, 49.29 mmol) and 1-f-butoxy- carbonyl-4-hydroxypiperidine (6.61 g, 32.86 mmol). The reaction mixture was cooled to 0 0C and DEAD (7.76 ml_, 49.29 mmol) was added dropwise over a period of 1 h. The reaction was gradually brought to room temperature and stirring continued for 16 hrs. The solvent was removed under vacuum and ether (100 ml.) was added and cooled to 0 0C. The solid formed was filtered off and the clear filtrate concentrated and purified by column chromatography (100 % heptane to 35 % AcOEt in heptane). Desired fractions were pooled and the solvent evaporated in vacuo affording 6.14 g (56 %) of 4-(4-methoxycarbonyl-phenoxy)- piperidine-1-carboxylic acid f-butyl ester as an oil.
1H-NMR (400 MHz, CDCI3) δ 1.47 (s, 9H), 1.70 - 1.84 (m, 2H), 1.87 - 2.01 (m, 2H), 3.30 - 3.43 (m, 2H), 3.64 - 3.76 (m, 2H), 3.88 (s, 3H), 4.51 - 4.62 (m, 1 H), 6.91 (d, 2H), 7.99 (d, 2H).
4-(Piperidin-4-yloxy)-benzoic acid methyl ester To a solution of 4-(4-methoxycarbonyl-phenoxy)-piperidine-1-carboxylic acid f-butyl ester (6 g, 17.89 mmol) in DCM (50 ml.) was added TFA (25 ml.) and stirring was continued for 1.5 hrs at room temperature. The volatiles were removed in vacuo and the residues was crystallised from diethyl ether affording after filtration and drying 5.92 g (95 %) of 4-(piperidin- 4-yloxy)-benzoic acid methyl ester as a solid TFA salt. 1H-NMR (400 MHz, CDCI3) δ 2.06 - 2.36 (m, 4H), 3.15 - 3.29 (m, 2H), 3.29 - 3.43 (m, 2H), 3.89 (s, 3H), 4.76 (br.s., 1 H), 6.93 (d, 2H), 8.01 (d, 2H), 9.43 (br.s., 1 H), 9.70 (br.s., 1 H). m/z: 236.2 (M+1 )+;
4-(1-Cyclopropanecarbonyl-piperidin-4-yloxy)-benzoic acid methyl ester To a solution of cyclopropanecarboxylic acid (246 mg, 2.86 mmol) in DMF (20 ml.) was added HOBt (658 mg, 4.29 mmol) and EDAC (549 mg, 2.86 mmol). The mixture was stirred at room temperature for 1 hr at which time 4-(piperidin-4-yloxy)-benzoic acid methyl ester, TFA salt (1000 mg, 2.86 mmol) and DIPEA (549 μl_, 3.15 mmol) were added. After stirring for 16 hrs at room temperature the volatiles were evaporated in vacuo and the residue dissolved in AcOEt (25 ml_). The organic phase was washed with aqueous NaHCO3, dried (MgSO4), filtered and evaporated in vacuo affording 770 mg (88 %) of the 4-(1-cyclo- propanecarbonyl-piperidin-4-yloxy)-benzoic acid methyl ester as a solid. 1H-NMR (400 MHz, CDCI3) δ 0.73 - 0.83 (m, 2H), 0.95 - 1.04 (m, 2H), 1.72 - 2.10 (m, 5H), 3.60 - 3.73 (m, 2H), 3.80 (br.s., 1 H), 3.91 (s, 3H), 3.93 (br.s., 1 H), 4.61 - 4.72 (m, 1 H), 6.92 (d, 2H), 7.99 (d, 2H). 4-(1 -Cyclopropanecarbonyl-piperidin-4-yloxy)-benzoic acid
A mixture of 4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-benzoic acid methyl ester (0,75 g, 2.472 mmol), methanol (25 ml.) and 1 N NaOH (10 ml.) was stirred at room temperature for 16 hrs. The volatiles were evaporated in vacuo and the residue was redissolved in water (10 ml.) and washed with EtOAc (2x5 ml_). The aqueous phase was acidified to pH ~1 with 1 N HCI and extracted with EtOAc (2x10 ml_), dried (MgSO4), filtered and evaporated affording 0,6 g 84 %) of 4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-benzoic acid as a solid. 1H-NMR (400 MHz, CDCI3) δ 0.73 - 0.84 (m, 2H), 0.97 - 1.07 (m, 2H), 1.72 - 2.11 (m, 5H), 3.63 - 3.74 (m, 2H), 3.75 - 4.00 (m, 2H), 4.64 - 4.75 (m, 1 H), 6.96 (d, 2H), 8.06 (d, 2H).
To a solution of 4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-benzoic acid (100 mg, 0.346 mmol) in DMF (6 ml.) was added HOBt (80 mg, 0.518 mmol) and EDAC (67 mg, 0.346 mmol). The mixture was stirred at room temperature for 1 hr at which time 3-azabicyclo- [3.2.2]nonane (52 mg, 0.415 mmol) was added. After stirring for 16 hrs at room temperature the volatiles were evaporated in vacuo and the residue purified on prep-HPLC (Gilson). Pure fractions were collected and the volatiles evaporated affording 125 mg (91 %) of the title compound as an oil. 1H-NMR (400 MHz, CDCI3) δ 0.71 - 0.84 (m, 2H), 0.94 - 1.05 (m, 2H), 1.59 - 2.32 (m, 16H), 3.49 - 3.73 (m, 3H), 3.74 - 3.99 (m, 4H), 4.54 - 4.66 (m, 1 H), 6.92 (d, 2H), 7.35 (d, 2H).
In a similar way as described in general example B above the following compounds 1 b-5b were made.
Figure imgf000061_0001
Figure imgf000062_0002
General Example C
Figure imgf000062_0001
Cyclopropanecarboxylic acid {4-r4-(3-hydroxy-8-aza-bicvclor3.2.Hoctane-8-carbonyl)- phenoxyi-cyclohexyD-amide
2-(4-Hydroxy-cyclohexyl)-isoindole-1,3-dione K2CO3 (19.4 g, 140.6 mmol) was added to a solution of trans-4-aminocyclohexanol hydrochloride (9.0 g, 59.35 mmol) in water (150 ml.) followed by N-carbethoxy phthalimide (18.8 g, 85.96 mmol). A white precipitate was formed immediately. Stirring continued at RT for 1 h. The precipitate was filtered off, washed with water and dried to afford 12 g (84 %) of 2-(4-hydroxy-cyclohexyl)-isoindole-1 ,3-dione. 1H-NMR (300 MHz, DMSO-d6) δ 1.18 - 1.40 (m, 3H), 1.60 - 1.76 (m, 2H), 1.80 - 2.00 (m, 2H), 2.04 - 2.23 (dq, 2H), 3.40 - 3.50 (m, 1 H), 3.89 - 4.03 (tt,1 H), 4.6 (br.s, 1 H,), 7.15 - 7.39 (m,1 H), 7.80 (m, 3H). m/z: 246 (M+1 )+
4-[4-(1,3-Dioxo-1 , 3-dihydro-isoindol-2-yl)-cyclohexyloxy]-benzoic acid ethyl ester To a stirred solution of 2-(4-hydroxycyclohexyl)isoindole-1 ,3-dione (8.0 g, 32.6 mmol) in dry THF (100 ml.) was added triphenyl phosphine (12.8 g, 48.8 mmol) and 4- hydroxy benzoic acid ethyl ester (5.44 g, 32.7 mmol). The reaction mixture was cooled to 0 0C and DIAD (9.6 g, 47.4 mmol) was added dropwise from an addition funnel over a period of 3 h. The reaction was gradually brought to room temperature and stirring continued for 3 h. The solvent was removed under vacuum and ether (100 ml.) was added and cooled to 0 0C. The solid formed was filtered and the clear filtrate concentrated and purified by column chromatography over neutral alumina (8 % AcOEt in hexane) to give 5.13 g (42 %) of 4-[4- (I .S-dioxo-I .S-dihydro-isoindol^-ylJ-cyclohexyloxyJ-benzoic acid ethyl ester. 1H-NMR (300 MHz, CDCI3); δ 1.24 - 1.36 (m, 2H), 1.40 (t, 3H), 1.63 - 1.77 (m, 3H), 2.19 - 2.29 (m, 2H), 2.62 - 2.79 (dq, 2H), 4.15 - 4.72 (m, 1 H), 4.35 (q, 2H), 7.01 (d, 2H), 7.71 (m, 2H), 7.82 (m, 2H), 8.0 (d, 2H). m/z: 394.1 (M+1 )+
4-(4-Aminocyclohexyloxy)benzoic acid ethyl ester
To a solution of 4-[4-(1 ,3-dioxo-1 , 3-dihydro-isoindol-2-yl)-cyclohexyloxy]-benzoic acid ethyl ester (6.3 g, 16.0 mmol) in CHCI3 (50 ml.) and ethanol (60 ml.) was added hydrazine hydrate (16.0 g, 320.2 mmol). Stirring was continued at ambient temperature for 2 days. The reaction mixture was then cooled to 5-10 0C and the white precipitate was filtered off. The filtrate was washed with water, dried and the solvent evaporated under vacuum to afford 4.15 g (98 %) of 4-(4-amino-cyclohexyloxy)-benzoic acid ethyl ester. 1H-NMR (300 MHz, DMSO-d6); δ 1.30 (t, 3H), 1.39 - 1.50 (m, 2H), 1.52 - 1.70 (m, 4H), 1.84- 1.98 (m, 2H), 2.70 - 2.80 (m, 1 H), 3.20 - 3.45 (br.s, 2H), 4.25 (2H, q), 4.58 (m, 1 H), 7.0 (d, 2H), 7.9 (d, 2H).
4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-benzoic acid ethyl ester
To a solution of 4-(4-aminocyclohexyloxy)benzoic acid ethyl ester (4.15 g, 15.76 mmol) in DCM (40 ml.) at 0 0C was added TEA (1.6 g, 15.7 mmol) followed by cyclopropane carbonyl chloride (1.98 g, 18.9 mmol) over a period of 1 hr. Stirring was continued at 0-5 0C for 2 h. Water (40 ml.) was then added and extracted with EtOAc. The organic layer was washed with 2N HCI, satd. NaHCO3 and brine solution. It was dried and concentrated under vacuum affording 4.75 g (91 %) of 4-[4-(cyclopropanecarbonyl-amino)-cyclohexyloxy]- benzoic acid ethyl ester as an oil. 1H-NMR (300 MHz, CDCI3); δ 0.7 - 0.8 (m, 2H), 0.94 - 1.02 (m, 2H), 1.26 - 1.35 (m, 1 H), 1.38
(t, 3H), 1.58 - 1.64 ( m, 2H), 1.68 - 1.86 (m, 4H), 2.00 - 2.10 (m, 2H), 3.95 (m, 1 H), 4.38 (q,
2H), 4.60 (m, 1 H), 6.90 (d, 2H), 8.00 (d, 2H). m/z: 332 (M+1 )+
4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-benzoic acid
To a solution of 4-[4-(cyclopropanecarbonylamino)cyclohexyloxy]benzoic acid ethyl ester (4.75 g, 14.3 mmol) in EtOH (30 mL) and THF (10 mL) was added NaOH (2.29 g, 57.3 mmol) in 10 ml of water. Stirring was continued at ambient for 17 hrs. The solvents were re- moved under vacuum, water (50 mL) was added and the whole extracted with EtOAc. The aqueous layer was acidified to pH ~ 2 with 2N HCI and the white precipitate obtained was filtered off and washed with hexane affording 4.0 g (92 %) of 4-[4-(cyclopropanecarbonyl- amino)-cyclohexyloxy]-benzoic acid as a soild.
1H-NMR (300 MHz, DMSO-d6); δ 0.82 (m, 4H), 1.50 - 1.78 (m, 7H), 1.83 - 2.00 (m, 2H), 3.64 - 3.80 (m, 1 H), 4.58 - 4.65 (m, 1 H), 7.0 (d, 2H), 7.86 (d, 2H), 8.02 (d, 1 H), 12.6 (s, 1 H). m/z: 304 (M+1 )+
Cyclopropanecarboxylic acid {4-[4-(3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)- phenoxy]-cyclohexyl}-amide To a solution of 4-[4-(cyclopropanecarbonylamino)cyclohexyloxy]benzoic acid (150 mg, 0.494 mmol) in DMF (2 mL) was added HOBt (67 mg, 0.49 mmol) and DIEA (256 mg,1.98 mmol). The reaction mixture was cooled to 0 0C and 8-azabicyclo[3.2.1]octan-3-ol (81 mg, 0.49 mmol) was added. Stirring was continued at 0 0C for 10 min after which EDCI (107 mg, 0.543 mmol) was added to the reaction mixture. The reaction was gradually brought to room temperature and stirred for 16 hrs. It was concentrated under vacuum, water (5 mL) was added and extracted with DCM (30 mL). The organic layer was washed with 2N HCI, sat. aq. NaHCO3 solution and finally with brine and concentrated in vacuo to afford crude amide. It was recrystallized from EtOAc-pentane affording 170 mg (82 %) of the title compound as a solid. 1H-NMR (300 MHz, DMSO-d6) δ 0.80 (m, 4H), 1.50 - 2.24 (m, 17H), 3.60- 3.80 (m, 2H), 3.90- 4.20 (m, 2H), 4.40 - 4.60 (m, 2H), 6.95 (d, 2H), 7.40 (d, 2H), 8.00 (d, 1 H). m/z: 413 (M+1 )+
In a similar way as described in general example C above the following compounds 1c-11 c were made.
Figure imgf000065_0001
4-[4-(Cyclopropanecarbonyl- amino)-cyclohexyloxy]-N-(Z)- m/z: 454 (M+1 )+;
Qr TXx0C (5-hydroxy-adamantan-2-yl)- Rt = 1 ,58 min. benzamide
4-[4-(Cyclopropanecarbonyl- amino)-cyclohexyloxy]-N-(E)- m/z: 454 (M+1 )+;
J lTu (5-hydroxy-adamantan-2-yl)- Rt = 1 ,55 min. benzamide
General Example D
Figure imgf000066_0001
4-r4-(Pyridin-2-yloxy)-cvclohexyloxyl-N-adamantan-2-yl-benzamide
4-(f-Butyl-diphenyl-silanyloxy)-cis/trans-cyclohexanol
To a solution of 1 ,4-cyclohexanediole (20 g, 0.172 mol) and imidazole (11.72 g, 0.172 mol) in a mixture of DCM/DMF 2:1 (600 ml.) was added a solution of f-butyl-chloro- diphenylsilane (47.33 g, 0.172 mol) in DCM (150 ml.) and the resulting mixture was stirred for 16 hrs at room temperature. The mixture was washed with aq. sat. NH4CI (2x100 ml_), aq. sat. NaHCO3 (2x100 ml.) and water (100 ml_). The organic phase was dried (MgSO4), filtered and evaporated in vacuo affording 50.8 g (83 %) of 4-(f-butyl-diphenyl-silanyloxy)-cis/trans- cyclohexanol as an oil. 1 H-NMR (400 MHz, CDCI3) □ 1.01 (s, 1 H), 1.03 - 1.10 (m, 9H), 1.10 - 1.23 (m, 1 H), 1.28 - 1.49 (m, 2H), 1.56 - 1.67 (m, 1 H), 1.67 - 1.83 (m, 3H), 1.83 - 1.94 (m, 1 H), 3.59 - 3.77 (m, 1 H), 3.81 - 3.89 (m, 1 H), 4.12 (q, 1 H), 7.30 - 7.47 (m, 6H), 7.59 - 7.74 (m, 4H), m/z: 355 (M+1 )+;
N-Adamantan-2-yl-4-[4-(f-butyl-diphenyl-silanyloxy)-cyclohexyloxy]-benzamide
To a stirred solution of N-adamantan-2-yl-4-hydroxy-benzamide (4 g, 14.74 mmol) in dry THF (100 ml.) and DMF (75 ml.) was added triphenyl phosphine (5.8 g, 22.11 mmol) and 4-(f-butyl-diphenyl-silanyloxy)-cyclohexanol (6.27 g, 17.69 mmol). The reaction mixture was cooled to 0 0C and DEAD (3.48 ml_, 22.1 1 mmol) was added dropwise from an addition funnel over a period of 30 min. The reaction was gradually brought to room temperature and stirring continued for 16 hrs. The solvent was removed under vacuum and ether (100 ml.) was added and cooled to 0 0C. The solid formed was filtered off and the clear filtrate concen- trated and purified by column chromatography using DCM as solven to give 4.73 g (53 %) of N-adamantan-2-yl-4-[4-(f-butyl-diphenyl-silanyloxy)-cyclohexyloxy]-benzamide as an oil. m/z: 609 (M+1 )+;
N-Adamantan-2-yl-4-(4-hydroxy-cyclohexyloxy)-benzamide To a solution of N-adamantan-2-yl-4-[4-(f-butyl-diphenyl-silanyloxy)-cyclohexyloxy]- benzamide (4,73 g, 7.78 mmol) in dry THF (50 ml.) was added a 1 N TBAF solution in THF (31 ,12 ml.) and the mixture was stirred for 48 hrs. at room temperature. The volatiles were evaporated in vacuo and the residue redissolved in AcOEt (50 mL) and washed with 5 % aqous citric acid and vand. The organic phase was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was purified using a Combi Flash Sq16x with a solvent gradient starting from AcOEt/heptan (20:80) to (85:15). Desired fractions were collected and the solvent evapoarted in vacuo affording 780 mg (27 %) of N-adamantan-2-yl-4-(4-hydroxy- cyclohexyloxy)-benzamide as a solid. 1H-NMR (300 MHz, CDCI3) δ 0.78 - 1.01 (m, 1 H), 1.11 - 1.42 (m, 4H), 1.43 - 2.17 (m, 18H), 3.73 - 3.90 (m, 1 H), 4.20 - 4.29 (m, 1 H), 4.41 - 4.54 (m, 1 H), 6.34 (d, 1 H), 6.93 (d, 2H), 7.73 (d, 2H). m/z: 370 (M+1 )+;
To a stirred solution of N-adamantan-2-yl-4-(4-hydroxy-cyclohexyloxy)-benzamide (150 mg, 0.41 mmol) in dry THF (10 mL) was added triphenyl phosphine (160 mg, 0.61 mmol) and 2-hydroxypyridine (38.6 mg, 0.41 mmol). The reaction mixture was cooled to 0 0C and DEAD (96 μL, 0.61 mmol) was added. The reaction was gradually brought to room temperature and stirring continued for 16 hrs. The solvent was removed in vacuo and purified by prep. HPLC. Desired fractions were pooled and the solvent evaporated in vacuo affording 30 mg (17 %) of the title compound as a solid.
1 H-NMR (400 MHz, CDCI3) δ 1.63 - 1.81 (m, 8H), 1.81 - 1.95 (m, 8H), 2.02 (br.s., 2H), 2.17 (t, 4H), 4.15 - 4.31 (m, 1 H), 4.40 - 4.53 (m, 1 H), 5.08 - 5.21 (m, 1 H), 6.36 (d, 1 H), 6.74 (d, 1 H), 6.82 - 6.91 (m, 1 H), 6.95 (d, 2H), 7.56 - 7.65 (m, 1 H), 7.73 (d, 2H), 8.17 (d, 1 H). m/z: 447 (M+1 )+; In a similar way as described in general example D above the following compounds 1d-4d were made.
Figure imgf000068_0001
General Example E
Figure imgf000068_0002
4-r4-(Pyridin-2-yl-oxy-methyl)-cvclohexyloxyl-N-adamantan-2-yl-benzamide
4-[4-(Adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid ethyl ester
To a stirred solution of N-adamantan-2-yl-4-hydroxy-benzamide (6 g, 22.1 1 mmol) in dry THF (100 ml.) was added triphenyl phosphine (8.7 g, 33.17 mmol) and 4-hydroxy cyclo- hexane carboxylic acid ethyl ester (4.57 g, 26.53 mmol). The reaction mixture was cooled to 0 0C and DEAD (5.22 ml_, 33.17 mmol) was added dropwise from an addition funnel over a period of 30 min. The reaction was gradually brought to room temperature and stirring con- tinued for 48 hrs. The solvent was removed under vacuum and ether (100 ml.) was added and cooled to 0 0C. The solid formed was filtered off and the clear filtrate concentrated and purified by column chromatography (Gyan-flash). Desired fractions were collected and the solvent evaporated. The residue was crystallised from diethyl ether and filtered off affording 3 g (32 %) of 4-[4-(adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexane carboxylic acid ethyl ester as a solid.
1H-NMR (400 MHz, CDCI3) δ 1.27 (t, 3H), 1.41 - 2.25 (m, 22H), 2.30 - 2.47 (m, 1 H), 4.10 - 4.20 (m, 2H), 4.21 - 4.30 (m, 1 H), 4.55 (br.s., 1 H), 6.34 (d, 1 H), 6.92 (t, 2H), 7.73 (d, 2H). m/z: 427 (M+1 )+
N-Adamantan-2-yl-4-(4-hydroxymethyl-cyclohexyloxy)-benzamide
In a flame dried flask was 4-[4-(adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexane carboxylic acid ethyl ester (2 g, 4.7 mmol) dissolved in dry THF (300 ml.) and cooled to -35 0C. To this solution was added 1 M DIBAL in toluene (14 ml_, 14.1 mmol) and the mixture was stirred at -35 0C for 3 hrs. and left in a frezer at -18 0C for 16 hrs. Due to incompleate reaction an additional portion of 1 M DIBAL (5 mL) was added and the mixture was stirred at -18 0C for 1 hr. The reaction was quinched by slowly addition of sat. aq. NH4CI followed by evapoartion to % of the volume and extracted with DCM (3x50 mL). The combined organic phases were evaporated in vacuo and the residue purified using colomn chromatography (Isco, 120 gram colomn) and a solvent gradient of heptane/AcOEt from 0 to 100 %. Desired fractions were colleted and the solvent evaporated in vacuo affording 1 g (60 %) of N-adamantan-2-yl-4-(4- hydroxymethyl-cyclohexyloxy)-benzamide as an oil.
1H-NMR (400 MHz, CDCI3) δ 1.05 - 1.20 (m, 1 H), 1.29 - 1.66 (m, 7H), 1.66 - 1.85 (m, 5H), 1.85 - 1.96 (m, 6H), 1.99 - 2.1 1 (m, 3H), 2.21 (d, 1 H), 3.52 (t, 2H), 4.19 - 4.28 (m, 2H), 4.62 (br.s., 1 H), 6.34 (d, 1 H), 6.92 (t, 2H), 7.72 (d, 2H).
To a solution of N-adamantan-2-yl-4-(4-hydroxymethyl-cyclohexyloxy)-benzamide (150 mg, 0.39 mmol) in dry THF (5 mL) was added 2-hydroxypyridine (38 mg, 0.4 mmol) followed by tributyl phosphine (144 μL, 0.59 mmol). The resulting mixture was cooled and azodicarboxylic dipiperidide (149 mg, 0.59 mmol) dissolved in dry THF (3 mL) was added. The mixture was stirred for 6 hrs. at room temperature, filtered and the volatiles evaporated in vacuo. The residue was purified on prep. HPLC and the desired fractions colleted and the solvent evaporated in vacuo affording 87 mg (48 %) of the title compound as a solid. 1H-NMR (400 MHz, CDCI3) δ 1.27 (q, 1 H), 1.44 - 1.81 (m, 9H), 1.81 - 1.97 (m, 9H), 1.99 - 2.12 (m, 3H), 2.17 -2.26 (m, 1H), 4.17 (dd, 2H), 4.21 - 4.32 (m, 1H), 4.64 (br.s., 1H), 6.35 (d, 1H), 6.77 (dd, 1H), 6.87 - 6.97 (m, 3H), 7.57 - 7.66 (m, 1H), 7.72 (d, 2H), 8.15 - 8.21 (m, 1H). m/z:461 (M+1)+;
In a similar way as described in general example E above the following compounds 1e-4e were made.
Figure imgf000070_0001
General Example F
Figure imgf000070_0002
(Octahvdro-quinolin-1-ylH4-ri-(pyridine-2-sulfonyl)-piperidin-4-ylmethoxyl-phenyl>- methanone 4-(4-Methoxycarbonyl-phenoxymethyl)-piperidine-1-carboxylic acid f-butyl ester
To a stirred solution of N-Boc-4-piperidinemethanol (10 g, 46.45 mmol) in dry THF (500 ml.) was added tributyl phosphine (18.77 g, 92.9 mmol) and 4-hydroxy benzoic acid methyl ester (10.6 g, 69.67 mmol). The reaction mixture was cooled to 0 0C and ADDP
(23.41 g, 92.9 mmol) was added dropwise from an addition funnel over a period of 1 hr. The reaction was gradually brought to room temperature and stirring continued for 1 hr. The solvent was removed under vacuum and EtOAc (50 ml.) was added and cooled to 0 0C. The solid formed was filtered and the clear filtrate concentrated and purified by column chroma- tography (ISCO) using a step gradient starting with heptane going to EtOAc 100 %. Desired fractions were collected and the solvent evaporated in vacuo affording 5.9 g (36 %) of 4-(4- methoxycarbonyl-phenoxymethylj-piperidine-i-carboxylic acid f-butyl ester as an oil. 1H-NMR (400 MHz, CDCI3) δ 1.28 (q, 2H), 1.39 - 1.54 (m, 9H), 1.81 (d, 2H), 1.97 (br.s., 1 H), 3.79 - 3.94 (m, 6H), 4.17 (d, 2H), 6.89 (d, 2H), 7.99 (d, 2H).
4-(Piperidin-4-ylmethoxy)-benzoic acid methyl ester
To a solution of 4-(4-methoxycarbonyl-phenoxymethyl)-piperidine-1-carboxylic acid f-butyl ester (8.5 g, 24.61 mmol) in DCM (150 ml.) was added TFA (45 ml.) and the mixture was stirred for 2 hrs at room temperature. The volatiles were evaporated in vacuo and the residue crystallised from addition of diethyl ether. The solid was filtered off washed with a small portion of diethyl ether and dried. This afforded 8.8 g (99 %) of 4-(piperidin-4-ylmeth- oxy)-benzoic acid methyl ester as a TFA salt.
1H-NMR (400 MHz, CDCI3) δ 1.75 (q, 2H), 1.98 - 2.21 (m, 3H), 2.95 (q, 2H), 3.42 - 3.56 (m, 3H), 3.84 - 3.98 (m, 4H), 6.90 (d, 2H), 7.98 (d, 2H), 9.19 (br.s., 1 H), 9.72 (br.s., 1 H). m/z: 250 (M+1 )+;
4-[1 -(Pyridine-2-sulfonyl)-piperidin-4-ylmethoxy]-benzoic acid
To a suspension of 4-(piperidin-4-ylmethoxy)-benzoic acid methyl ester, TFA salt (1.6 g, 4.403 mmol) in DCM was added DIPEA (2.3 ml_, 13.21 mmol) followed by 2-pyridine- sulfonyl chloride HCI salt (1.89 g, 8.81 mmol). The resulting mixture was stirred for 16 hrs at room temperature and washed with 5 % aqous citric acid. The organisk phase was dried (MgSO4), filtered and the volatiles evaporated in vacuo. The crude ester was hydrolysed directly in the next step without further purification. The crude ester was dissolved in a mixture of MeOH (100 ml.) and THF (50 ml.) and to this mixture was added 1 N NaOH (20 ml.) followed by stirring for 16 hrs. at room temperature. The volume was reduced to % and 1 N HCI was added to pH ~ 1 . The organic phase was separated and the aqueous phase extraxted with DCM (2x50 ml_). The combined organic phases were washed with water, dried (MgSO4), filtered and the solvent evaporated in vacuo. The solid residue was washed in a mixture of water and diethyl ether, filtered and dried which afforded 1.45 g (87 %) of 4-[1-(pyridine-2-sulfonyl)-piperidin-4-ylmethoxy]- benzoic acid as a solid.
1H-NMR (400 MHz, CDCI3) δ 1.39 - 1 .61 (m, 2H), 1.90 (d, 3H), 2.78 (t, 2H), 3.87 (d, 2H), 4.04 (d, 2H), 6.90 (d, 2H), 7.45 - 7.57 (m, 1 H), 7.87 - 8.00 (m, 2H), 8.05 (d, 2H), 8.74 (d, 1 H). m/z: 378 (M+1 )+;
To a solution of 4-[1 -(pyridine-2-sulfonyl)-piperidin-4-ylmethoxy]-benzoic acid (1 13 mg) in DMF (1 ,5 ml.) was added HOBt (69 mg) and EDAC (58 mg) and the resulting mixture was stired for 1 hr. cis-trans-Decahydroquinoline (42 mg) was added and stirring was continued for 16 hrs at ambient temperature. The crude reaction mixtyre was purified on a prep LC/MS and desired fractions were collected and the solvent evaporated in vacuo affording 132 mg (88 %) of the title compound as an oil.
1H-NMR (400 MHz, CDCI3) δ 1.00 - 1 .17 (m, 1 H), 1.24 - 1.99 (m, 14H), 2.28 (d, 1 H), 2.77 (t, 2H), 3.07 (br.s., 1 H), 3.27 - 3.44 (m, 1 H), 3.54 (br.s., 1 H), 3.77 - 3.86 (m, 2H), 4.02 (d, 2H), 4.52 (br.s., 1 H), 4.73 (br.s., 1 H), 6.77 - 6.93 (m, 2H), 7.28 - 7.37 (m, 2H), 7.45 - 7.55 (m, 1 H), 7.86 - 8.05 (m, 2H), 8.73 (d, 1 H). m/z: 499 (M+1 )+;
In a similar way as described in general example F above the following compounds 1f-9f were made.
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
General Example G
Figure imgf000074_0002
{3-r4-(3-Aza-bicvclor3.2.2lnonane-3-carbonyl)-phenoxyl-pyrrolidin-1-yl>-(6-chloro-pyridin-3- yl)-methanone
3-(4-Carboxy-phenoxy)-pyrrolidine-1 -carboxylic acid f-butyl ester To a stirred solution of 3-hydroxy-pyrrolidine-i-carboxylic acid f-butyl ester (3 g,
16.02 mmol) in dry THF (75 ml.) was added triphenyl phosphine (4.62 g, 17.62 mmol) and 4- hydroxy-benzoic acid benzyl ester (4.02 g, 17.62 mmol). The reaction mixture was cooled to 0 0C and DEAD (2.78 ml_, 17.62 mmol) was added dropwise over a period of 30 min. The reaction was gradually brought to room temperature and stirring continued for 16 hrs. The solvent was removed under vacuum and the residue purified by column chromatography (Flash 40) using a gradient of starting from EtOAc-heptane 1 :20 to 1 :5. Desired fractions were collected and the solvent evaporated in vacuo. The residue was dissolved in EtOH (80 ml.) and 10 % Pd/C (0.5 g) was added and the mixture was hydrogenated for 16 hrs. The mixture was filtered and the volatiles were evaporated in vacuo affording 3.4 g (69 %) of 3- ^-carboxy-phenoxyj-pyrrolidine-i-carboxylic acid f-butyl ester as a solid.
1H-NMR (400 MHz, DMSO-d6) δ 1.40 (d, 9H), 2.05 (br.s., 1 H), 2.17 (br.s., 1 H), 3.23 - 3.50 (m, 3H) 3.51 - 3.66 (m, 1 H), 5.11 (br.s., 1 H), 6.81 (d, 1 H), 7.03 (d, 1 H), 7.78 (d, 1 H), 7.90 (d, 1 H), 10.30 (br.s., 1 H).
(3-Aza-bicyclo[3.2.2]non-3-yl)-[4-(pyrrolidin-3-yloxy)-phenyl]-methanone
To a solution of 3-(4-carboxy-phenoxy)-pyrrolidine-1-carboxylic acid f-butyl ester (2.0 g, 6.53 mmol) in DMF (75 mL) was added HOBt (1.1 g, 7.83 mmol) and EDAC (1.5 g, 7.83 mmol) and the resulting mixture was stired for 10 min. 3-Aza-bicyclo-[3.2.2]nonane (1 g, 7.83 mmol) and DIPEA (1.4 mL) were added and stirring was continued for 16 hrs at ambient temperature. The volatiles were evaporated in vacuo and to the residue was added water (50 mL) and diethyl ether (25 mL). A precipiate was forme, filtered off and redissolved in DCM (25 mL) followed by addition of TFA (10 mL). The mixture was stirred at room temperature for 16 hrs and the volatiles evaporated in vacuo. The residue was dissolved in water (50 mL) and washed with diethyl ether (2x10 mL). The pH of the aqueous phase was ajusted to ~11 by addition of 32 % NaOH followed by extraction with diethyl ether (2x50 mL). The combined organic phases were dried (Na2SU4), filtered and evaporated in vacuo. The crude residue was stirred with EtOAc (20 mL) and the precipiate formed was filtered off. The filtrate was evaporated to dryness affording crude 1.1 g (55 %) of (3-aza-bicyclo[3.2.2]non-3-yl)-[4- (pyrrolidin-3-yloxy)-phenyl]-methanone wich was used without further purification. m/z: 315 (M+1 )+; To a solution of (3-aza-bicyclo[3.2.2]non-3-yl)-[4-(pyrrolidin-3-yloxy)-phenyl]- methanone (150 mg, 0.48 mmol) in DCM (20 ml.) was added TEA (130 μl_) followed by 6- chloro-nicotinoyl chloride (126 mg, 0.72 mmol). The mixture was stirred at room temperature for 16 hrs followed by evaporation of the solvent in vacuo. The residue was purified on prep. HPLC affording after drying at 50 0C 115 mg (53 %) of the title compound. 1H-NMR (400 MHz, CDCI3) δ 1.67 (br.s., 7H), 1.92 (br.s., 1 H), 2.08 - 2.29 (m, 2H), 2.28 - 2.42 (m, 1 H), 3.42 - 3.75 (m, 4H), 3.75 - 4.04 (m, 4H), 5.02 (d, 1 H), 6.82 (d, 1 H), 6.92 (d, 1 H), 7.30 - 7.48 (m, 3H), 7.81 - 7.97 (m, 1 H), 8.60 (dd, 1 H). m/z: 455 (M+1 )+;
In a similar way as described in general example G above the following compounds 1g-3g were made.
Figure imgf000076_0001
General Example H
Figure imgf000077_0001
4-(2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-N-adamantan-2-yl-benzamide
4-Fluoro-N-adamantan-2-yl-benzamide To a solution of 4-fluorobenzoic acid (15,0 g, 0.11 mol) in DMF (400 ml.) was added
HOBt (24,59 g, 0.16 mol) and EDAC (20,53 g, 0.1 1 mol). The resulting mixture was stirred for 1 hr at room temperature at which time a solution of 2-amino-adamantane.HCI (20,1 g, 0.11 mol) and DIPEA (20,52 ml.) in DMF (100 ml.) was added dropwise. The mixture was stirred at room temperature for 16 hrs and the volatiles evaporated in vacuo. The residue was dissolved in AcOEt and washed with aq. NaHCO3, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo affording 28,66 g, (98 %) of 4-fluoro-N-adamantan-2-yl- benzamide as a solid.
1 H-NMR (300 MHz, CDCI3) δ ppm 1.64 - 2.00 (m, 12H), 2.04 (br.s., 2H), 4.18 - 4.32 (m, 1 H), 6.38 (d, 1 H), 7.1 1 (t, 2H), 7.78 (dd, 2H). m/z: 274.1 (M+H)+
A solution of 4-fluoro-N-adamantan-2-yl-benzamide (0.5 g, 1.83 mmol), 2-oxa-5-aza- bicyclo[2.2.1]heptane (0.47 g, 2.01 mmol) and K2CO3 (0.5 g, 3.84 mmol) in NMP (3 ml.) was heated in a microwave owen for 3 hrs. at 200 0C. The cooled reaction mixture was added wa- ter (30 ml.) and extrachted with AcOEt (2x 30 ml_). The volatiles were evaporated in vacuo and the residue purified on column chromathrography (Flash 40) using first AcOEt-Heptan 1 :4 followed by AcOEt-Heptan 1 :1 as eluents. Pure fractions were collected and the solvent evaporated in vacuo. The solid residue was trituated with diethyl ether and filtered off affording after drying in vacuo at 50 oC 260 mg (46 %) of the title compound as a solid. 1 H-NMR (400 MHz, CDCI3) δ ppm 1.58 - 1.67 (m, 2H), 1.71 (br.s., 2H), 1.74 - 1.88 (m, 9H), 1.89 - 2.00 (m, 5H), 3.16 (d, 1 H), 3.50 (dd, 1 H), 4.13 - 4.22 (m, 1 H), 4.41 (s, 1 H), 4.62 (s, 1 H), 6.24 (d, 1 H), 6.50 (dd, 2H), 7.61 (d, 2H). m/z: 353 (M+1 )+ In a similar way as described in general example H above the following compounds 1g-3g were made.
Figure imgf000078_0001
PHARMACOLOGICAL METHODS
11βHSD1 enzyme assay
Materials
3H-cortisone and anti-rabbit Ig coated scintillation proximity assay (SPA) beads were purchased from Amersham Pharmacia Biotech, β-NADPH was from Sigma and rabbit anti- cortisol antibodies were from Fitzgerald. An extract of yeast transformed with h-11 βHSD1 (HuIt et al., FEBS Lett, 441 , 25 (1998)) was used as the source of enzyme. The test compounds were dissolved in DMSO (10 mM). All dilutions were performed in a buffer containing 50 mM TRIS-HCI (Sigma Chemical Co), 4 mM EDTA (Sigma Chemical Co), 0.1 % BSA (Sigma Chemical Co), 0.01 % Tween-20 (Sigma Chemical Co) and 0.005% bacitracin (Novo Nordisk AJS), pH=7.4. Optiplate 96 wells plates were supplied by Packard. The amount of 3H- cortisol bound to the SPA beads was measured on TopCount NXT, Packard. Methods h-11 βHSD1 , 120 nM 3H-cortisone, 4 mM β-NADPH, antibody (1 :200), serial dilutions of test compound and SPA particles (2 mg/well) were added to the wells. The reaction was initiated by mixing the different components and was allowed to proceed under shaking for 60 min at 3O0C. The reaction was stopped be the addition of 10 fold excess of a stopping buffer containing 500 μM carbenoxolone and 1 μM cortisone. Data was analysed using GraphPad Prism software.
Table 1 Inhibition of 11 βHSD1 by compounds of the invention
Figure imgf000079_0001
Figure imgf000080_0001
While the invention has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications, and substitutions can be made therein without departing from the spirit and scope of the present invention. For example, effective dosages other than the preferred dos- ages as set forth herein may be applicable as a consequence of variations in the responsiveness of the mammal being treated for the disease(s). Likewise, the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present invention. Accordingly, the invention is not to be limited as by the appended claims.
The features disclosed in the foregoing description and/or in the claims may both separately ans in any combination thereof be material for realising the invention in diverse forms thereof.
Preferred features of the invention:
1. A compound of the general formula (I):
Figure imgf000081_0001
wherein
R1 and R2 together with the nitrogen to which they are attached, are forming a 8-11 mem- bered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitrogen, 5-10 carbon atoms and from 0 to 1 additional heteroatoms selected from nitrogen, oxy- gen, and S(O)m, where m is 0, 1 or 2, and said ring being substituted with 0 to 3 groups independently selected from Ci-C4alkyl, halogen, hydroxy, oxo, COOH, -NHR17, NR17R17, Ci-C4alkyloxy, Ci-C4alkyloxyCrC4alkyl and Ci-C4alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R21, or R1 is hydrogen, Ci-C4alkyl or cyclopropyl and R2 is a substituted or unsubstituted adamantyl;
R21 is halogen, hydroxy, oxo or COOH;
R4 is selected from hydrogen, Ci-C4alkyl, trifluoromethyl, halogen, Ci-C4alkyloxy, Ci-C4alkyloxyCi-C4alkyl and CrC4alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R21;
X is selected from -O-, -S-, -CR5R6-, -NH-, and -NR6-; R5 is hydrogen or fluorine;
R6 is hydrogen, methyl, ethyl, iso-propyl or cyclo-propyl;
R3 is selected from -1 ,4-cyclohexyl-R7, -CH2-1 , 4-cyclohexyl-R8, -1 ,3-cyclohexyl-R9, -CH2-1 ,3- cyclohexyl-R10, -4-piperidin-1-yl-R11, -CH2-4-piperidin-1-yl-R12, -3-piperidin-1-yl-R13, -CH2-3- piperidin-1-yl-R14, -4-bicyclo[2.2.2]octan-1-yl-R15 and -CH2-4-bicyclo[2.2.2]octan-1-yl-R16;
R7, R8, R9, R10, R15 and R16 are independently selected from CO2H, C(O)R19, OH, -(CR22- R23)n-C(O)-NR17R18, -(CR22R2VNHC(O)R18, -(CR22R23)n-OR18, -(CR22R23)n-SR18 , -(CR22-
Figure imgf000082_0001
N JRR1177RR1188,, --((CCRR2222RR22VVCC==CC--RR1188,, --((CCRR2222RR2233))nn--CC≡≡CC--RR1188,, --((CR22R23)n-aryl substituted with O to 2 R20, and -(CR22R23)n-hetaryl substituted with O to 2 R20;
n is O, 1 or 2;
each R22 and R23 are independently selected from hydrogen, halogen, d-Cβalkyl and cycloalkyl, each of which CrC6alkyl and cycloalkyl may be substituted with 0 to 2 halogen, hydroxy or oxo and the carbon in CR22R23 can together with the R22 and/or R23 groups be part of a cycloalkyl ring;
R20 is selected from halogen, hydroxy, oxo, -COOH, -S(O)0-2R19, -S(O)0-2NR19R19, cyclopro- pyl, -0-R19, Ci-C6alkyl, aryl, hetaryl, NR19CONR19R19; NR19SO2NR19R19 or NCONHSO2R19'
R17 is selected from hydrogen or selected from C-rC6alkyl, C-rC6alkenyl, C-rC6alkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R20;
R18 is selected from d-C6alkyl, d-C6alkenyl, d-C6alkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with O to 2 R20; where R17 and R18 are optionally connected by a covalent bond so as to form a ring comprising the N to which R17 and R18 are connected; R19 is selected from hydrogen, hydroxy, CrC6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, cycloalkyl, CrCβalkyloxy, aryl or hetaryl wherein hydroxy, C-i-Cβalkyl, cycloalkyl, d-Cβalkyloxy, aryl or hetaryl are optional substituted with R20;
R11, R12, R13 and R14 are independently selected from -C(O)-NR17R18, -CH2C(O)-NR17R18, - C(O)R19, -S(O)2R18, -S(O)2NR17R18, CrC6alkyl substituted with O to 2 R20, aryl substituted with O to 2 R20, and hetaryl substituted with O to 2 R20; 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.
2. The compound according to clause 1 , wherein n is O.
3. The compound according to clause 1 , wherein R22 and R23 are both hydrogen.
4. The compound according to clause 3, wherein n is 1.
5. The compound according to any of the preceding clauses, wherein R17 and R18 are connected by a covalent bond so as to form a piperidine, a piperazine, a substituted piperidine or a substituted piperazine.
6. The compound according to any of the preceding clauses, wherein R4 is hydrogen.
7. The compound according to any of the preceding clauses, wherein R1 and R2 together with the nitrogen to which they are attached, are forming a 8-11 membered saturated or partially saturated bicyclic or tricyclic ring, said ring being selected from the group consisting of
Figure imgf000083_0001
where each carbon is substituted with 0 to 2 R25, and R25 is independently selected from CrCβalkyl, halogen, hydroxy, oxo, COOH, and CrCβalkyloxy.
8. The compound according to clause 7, wherein R1 and R2 together with the nitrogen to which they are attached, are forming a 8-1 1 membered saturated or partially saturated bi- cyclic or tricyclic ring, said ring being selected from the group consisting of
Figure imgf000084_0001
9. The compound according to any of the preceding clauses, wherein X is -0-.
10. The compound according to any of the preceding clauses, wherein R3 is -1 ,4-cyclohexyl- R7 or -CH2-1 ,4-cyclohexyl-R8.
11. The compound according to clause 10, wherein R7 and R8 are C(O)R19.
12. The compound according to clause 1 1 , wherein R19 is hydroxy.
13. The compound according to clause 10, wherein R7 and R8 are selected from -CH2-O- aryl, -CH2-O-hetaryl, -O-aryl, -O-hetaryl, -CH2-O-C1-6alkyl, -NHC(O)R18, where the aryl, hetaryl and C1-6alkyl groups are optionally substituted.
14. The compound according to clause 10, wherein R7 and R8 are selected from -NH-S(O)2- aryl, -NH-S(O)2-hetaryl, -NH-aryl, -NH-hetaryl, -S(O)2-aryl and -S(O)2-hetaryl, where the aryl and hetaryl groups are optionally substituted.
15. The compound according to any of clauses 1-9, wherein R3 is -1 ,3-cyclohexyl-R9 or -CH2- 1 ,3-cyclohexyl-R10. 16. The compound according to any of the preceding clauses, wherein R3 comprises a cyclohexyl ring and R7, R8, R9 or R10 is attached in the c/s-configu ration.
17. The compound according to any of clauses 1-15, wherein R3 comprises a cyclohexyl ring and R7, R8, R9 or R10 is attached in the frans-configuration.
18. The compound according to any of the clauses 1-9, wherein R3 is -4-piperidin-1-yl-R11 or -CH2-4-piperidin-1-yl-R12.
19. The compound according to clause 18, wherein R11 and R12 are selected from aryl, hetaryl, -S(O)2-aryl and -S(O)2-hetaryl, where each aryl and hetaryl groups are optionally substituted.
20. The compound according to any of the clauses 1-9, wherein R3 is -3-piperidin-i-yl-R13 or -CHz-S-piperidin-i-yl-R14.
21. The compound according to any of clauses 1-6, wherein R1 is hydrogen, d-C4alkyl or cyclopropyl.
22. The compound according to clause 21 , wherein R2 is an unsubstituted adamantyl selected from 1 -adamantyl and 2-adamantyl.
23. The compound according to clause 21 , wherein R2 is a substituted adamantyl.
24. The compound according to clause 23, wherein R2 is a substituted 1 -adamantyl or a substituted 2-adamantyl.
25. The compound according to any of clauses 23-24, wherein R2 is an adamantyl substi- tuted with one, two or more substituent independently selected from halogen, hydroxy, oxo,
COOH, CrC6alkyl and CrC6alkyloxy.
26. The compound according to any of the preceding clauses, which is selected from the group consisting of
Figure imgf000086_0001
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexanecarboxylic acid ethyl ester,
Figure imgf000086_0002
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000086_0003
(3-Aza-bicyclo[3.2.2]non-3-yl)-[4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-phenyl]- methanone,
Figure imgf000086_0004
4-(1-Cyclopropanecarbonyl-piperidin-4-yloxy)-N-tricyclo[3.3.1.1.3.7]decan-2-yl-benzamide,
Figure imgf000086_0005
4-[1-(3-Methyl-butyryl)-piperidin-4-yloxy]-N-tπcyclo[3.3.1.1.3.7]decan-2-yl-benzamide,
Figure imgf000086_0006
1-{4-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-piperidin-1-yl}-3-methyl-butan-1- one,
Figure imgf000086_0007
(6-Aza-bicyclo[3.2.1]oct-6-yl)-[4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-phenyl]- methanone,
Figure imgf000087_0001
1-{4-[4-(6-Aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-piperidin-1-yl}-3-methyl-butan-1- one,
Figure imgf000087_0002
4-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000087_0003
4-[4-(Octahydro-quinoline-1-carbonyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000087_0004
cis/trans-4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-tricyclo[3.3.1.1.3.7]decan-1- yl-benzamide,
Figure imgf000087_0005
cis/trans-4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-tricyclo[3.3.1.1.3.7]decan-2- yl-benzamide,
Figure imgf000087_0006
N-Adamantan-2-yl-4-(4-hydroxy-cyclohexyloxy)-benzamide,
Figure imgf000088_0001
cis/trans 4-[4-(Tricyclo[3.3.1.1.3.7]decan-2-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000088_0002
N-Adamantan-2-yl-4-[4-(4-methyl-1 H-imidazol-2-ylsulfanylmethyl)-cyclohexyloxy]-benzamide,
Figure imgf000088_0003
4-[4-(Pyridin-2-yloxy)-cyclohexyloxy]-N-tricyclo[3.3.1.1.3.7]decan-2-yl-benzamide,
Figure imgf000088_0004
4-[4-(Pyrazol-1-yloxy)-cyclohexyloxy]-N-tricyclo[3.3.1.1.3.7]decan-2-yl-benzamide,
Figure imgf000088_0005
4-[4-(Pyrazol-1-yloxymethyl)-cyclohexyloxy]-N-tricyclo[3.3.1.1.3.7]decan-2-yl-benzamide,
Figure imgf000088_0006
4-[4-(Pyridin-2-yloxymethyl)-cyclohexyloxy]-N-tricyclo[3.3.1.1.3.7]decan-2-yl-benzamide,
Figure imgf000088_0007
4-(4-Hydroxy-cyclohexylmethoxy)-N-tricyclo[3.3.1.1.3.7]decan-2-yl-benzamide,
Figure imgf000089_0001
4-{4-[4-(Tricyclo[3.3.1.1.3.7]decan-2-ylcarbamoyl)-phenoxy]-cyclohexylmethoxy}-benzoic acid, and
Figure imgf000089_0002
4-{4-[4-(Tricyclo[3.3.1.1.3.7]decan-2-ylcarbamoyl)-phenoxy]-cyclohexylmethoxy}-benzoic acid allyl ester, or
a prodrug thereof, 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.
27. The compound according to any one of the preceding clauses, wherein polar surface area (PSA) of said compound is in the range from 40 A2 to 130 A2, preferably from 50 A2 to 130 A2, more preferably from 60 A2 to 120 A2, more preferably from 70 A2 to 120 A2, most preferable from 70 A2 to 1 10 A2.
28. The compound according to any one of the preceding clauses, wherein the molar weight of said compound is in the range from 350D to 650D, preferably from 400D to 600D.
29. The compound according to any one of the preceding clauses, which is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSD1 is beneficial.
30. The compound according to any one of the clauses 1-28, which is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
31. The compound according to any one of the clauses 1-28 which is an agent useful for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
32. The compound according to any one of the clauses 1-28 which is an agent useful for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance
(IGT), impaired fasting glucose (IFG).
33. The compound according to any one of the clauses 1-28 which is an agent useful for the delaying or prevention of the progression from IGT into type 2 diabetes.
34. The compound according to any one of the clauses 1-28 which is an agent useful for delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
35. The compound according to any one of the clauses 1-28 which is an agent useful for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
36. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the clauses 1-28 together with one ore more pharmaceutically acceptable carriers or excipients.
37. The pharmaceutical composition according to clause 36 which is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration.
38. The pharmaceutical composition according to clause 36 or 37 in unit dosage form, comprising from 0.05 mg to 2000 mg/day, from 0.1 mg to 1000 mg or from 0.5 mg to 500 mg per day of the compound according to anyone of the clauses 1-28.
39. Use of a compound according to any of the clauses 1-28, for the preparation of a phar- maceutical composition for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSD1 is beneficial. 40. Use of a compound according to any of the clauses 1-28, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
41. Use of a compound according to any of the clauses 1-28, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
42. Use of a compound according to any of the clauses 1-28, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
43. Use of a compound according to any of the clauses 1-28, for the preparation of a phar- maceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
44. Use of a compound according to any of the clauses 1-28, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
45. Use of a compound according to any of the clauses 1-28, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
46. A method for the treatment, prevention and/or prophylaxis of any conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 1 1 βHSD1 is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
47. The method according to clause 46 wherein the conditions, disorders or diseases are selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
Other preferred features of the invention: 1. A compound of the general formula (I):
Figure imgf000092_0001
(I) wherein
R1 and R2 together with the nitrogen to which they are attached, are forming a 8-11 mem- bered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitrogen, 5-10 carbon atoms and from 0 to 1 additional heteroatom selected from nitrogen, oxygen, and S(O)m, where m is 0, 1 or 2, and said ring being substituted with 0 to 3 groups independently selected from d-C4alkyl, halogen, hydroxy, oxo, COOH, -NHR7, NR7R8, -S(O)2Cr C4alkyl, -S(O)2NR7R8, CrC4alkyloxy, Ci-C4alkyloxyCrC4alkyl and Ci-C4alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R18, or
R1 is hydrogen, d-C4alkyl or cyclopropyl and R2 is adamantyl optionally substituted with 0 to 1 R18;
R3 is selected from -1 ,2-cyclopentyl-R9, -1 ,3-cyclopentyl-R9, -1 ,4-cyclohexyl-R9, -CH2-1 , 4- cyclohexyl-R9, -1 ,3-cyclohexyl-R9, -CH2-1 , 3-cyclohexyl-R9, -3-pyrrolidin-1-yl-R10, -CH2-3- pyrrolidin-1-R10, 4-tetrahydro-pyran, 4-tetrahydro-pyran-2-yl-R9, 4-tetrahydro-pyran-3-yl-R9, -4-piperidin-1-yl-R , -CH2-4-piperidin-1-yl-R , -3-piperidin-1-yl-R , -CH2-3-piperidin-1-yl-R >11
-4-bicyclo[2.2.2]octan-1-yl-R l1'2^ and -CH2-4-bicyclo[2.2.2]octan-1-yl-R 12.
X is selected from -O-, -S(O)n-, -CR 50ιR->6-, and -NR j7- .; or
R3 and R7 are connected by a covalent bond so as to form a bicyclic or tricyclic hetcycloalkyl ring comprising the N to which R3 and R7 are connected; the hetcycloalky ring may further be substituted with one or more R19;
R4 is selected from hydrogen, Ci-C4alkyl, trifluoromethyl, halogen, Ci-C4alkyloxy, Ci-C4alkyloxyC-rC4alkyl and Ci-C4alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R18; R5 and R6 independently are selected from hydrogen, fluorine, methyl, ethyl, iso-propyl or cyclopropyl;
R7 is selected from hydrogen or selected from CrCβalkyl, Ci-Cβalkenyl, d-Cθalkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with 0 to 2 R19;
R8 is selected from CrC6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl, each of which may be substituted with 0 to 2 R19; or
R7 and R8 optionally are connected by a covalent bond so as to form a ring comprising the N to which R7 and R8 are connected; the ring may further be substituted with one or more R19;
R9 and R12 independently are selected from hydroxy, cyano, C(O)R13, -(CR14R15X1C(O)NR7R8, -(CR14R15)nNHC(O)R16, -(CR14R15)nOR16, -(CR14R15)nS(O)mR16, -(CR14R15)nS(O)2NR7R8, - (CR14R15XNR7R8, -(CR14R15XNR17C(O)NR7R8, -(CR14R15XNR17S(O)2R16, -(CR14R15)nC=C- R16, -(CR14R15)nC≡C-R16, -(CR14R15)naryl substituted with O to 2 R20, and -(CR14R15)nhetaryl optionaly substituted with O to 2 R19;
R10 and R11 independently are selected from -C(O)NR7R8, -CH2C(O)NR7R8, -C(O)R17, -S(O)2R16 or -S(O)2NR7R8, wherein the alkyl, aryl and hetaryl groups are optionaly substituted with O to 2 R19;
m and n independently are O, 1 or 2;
R13 is selected from hydroxy, CτC6alkyl, CrCθalkenyl, d-Cθalkynyl, cycloalkyl,
Ci-C6alkyloxy, aryl, aryloxy, arylCi-C6alkyloxy, hetaryl, hetaryloxy or hetarylCi-C6alkyloxy wherein the CτC6alkyl, cycloalkyl, aryl or hetaryl groups are optionaly substituted with one or more R19;
R14 and R15 independently are selected from hydrogen, halogen, Ci-C6alkyl and cycloalkyl, each of which d-Cθalkyl and cycloalkyl may be substituted with O to 2 halogen, hydroxy or oxo and the carbon in CR14R15 can together with the R14 and/or R15 groups be part of a cycloalkyl ring; R16 is selected from hydrogen, d-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, cycloalkyl, hetcycloal- kyl, aryl or hetaryl wherein the Ci-Cβalkyl, cycloalkyl, aryl or hetaryl groups are optionaly substituted with one or more R19;
R17 is selected from hydrogen, CrC6alkyl, Ci-C6alkylC(O)R20, -(CR14R15)nNR17S(O)2R16, cycloalkyl, hetcycloalkyl, aryl or hetaryl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups optionaly are substituted with one or more R21;
R18 is halogen, hydroxy, oxo, -S(O)2Ci-C4alkyl, -S(O)2NR7R8 or -C(O)R13;
R19 is selected from halogen, hydroxy, oxo, -C(O)R20, d-CealkylC^R20, -S(O)nR16, -S(O)nNR7R8, cyclopropyl, -OR16, CrC6alkyl, aryl, hetaryl, -NR22C(O)NR7R8, -NR22S(O)2NR7R8 or -NC(O)NHS(O)2R16;
R20 is selected from hydroxy, CrCβalkyl, CrCβalkenyl, d-Cθalkynyl, cycloalkyl,
CrC6alkyloxy, aryl, aryloxy, arylCrC6alkyloxy, hetaryl, hetaryloxy or hetarylCrC6alkyloxy;
R21 is halogen, cyano or hydroxy; 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.
2. The compound according to clause 1 , wherein n is O.
3. The compound according to clause 1 , wherein R14 and R15 are both hydrogen.
4. The compound according to clause 3, wherein n is 1.
5. The compound according to any of the preceding clauses, wherein R7 and R8 are con- nected by a covalent bond so as to form a pyrrolidine, a piperidine, a piperazine, a substituted pyrrolidine, a substituted piperidine or a substituted piperazine.
6. The compound according to any of the preceding clauses, wherein R7 and R8 are connected by a covalent bond so as to form a piperidine, a piperazine, a substituted piperidine or a substituted piperazine. 7. The compound according to any of the preceding clauses, wherein R4 is hydrogen.
8. The compound according to any of the preceding clauses, wherein R1 and R2 together with the nitrogen to which they are attached, are forming a 8-1 1 membered saturated or partially saturated bicyclic or tricyclic ring, said ring being selected from the group consisting of
Figure imgf000095_0001
where each carbon is substituted with 0 to 2 R22, and R22 is independently selected from Ci-C8alkyl, halogen, hydroxy, oxo, C(O)R13, -S(O)2NR7R8, -S(O)nCrC4alkyl and CrC6alkyloxy.
9. The compound according to any of the preceding clauses, wherein X is -O-.
10. The compound according to any of the preceding clauses, wherein R3 is -1 ,4-cyclohexyl- R9 or -CH2-1 ,4-cyclohexyl-R9.
11. The compound according to clause 10, wherein R9 is C(O)R13.
12. The compound according to clause 1 1 , wherein R13 is hydroxy.
13. The compound according to clause 10, wherein R9 is selected from -CH2-O-aryl, -CH2- O-hetaryl, -O-aryl, -O-hetaryl, -CH2-O-Ci-6alkyl, -NHC(O)R16, where the aryl, hetaryl and Ci- 6alkyl groups are optionally substituted. 14. The compound according to clause 10, wherein R9 is selected from -NH-S(O)2-aryl, -NH- S(O)2-hetaryl, -NH-aryl, -NH-hetaryl, -S(O)2-aryl and -S(O)2-hetaryl, where the aryl and hetaryl groups are optionally substituted.
15. The compound according to any of clauses 1-9, wherein R3 is -1 ,3-cyclohexyl-R9 or -CH2- 1 ,3-cyclohexyl-R9.
16. The compound according to any of the preceding clauses, wherein R3 comprises a cyclohexyl ring and R9 or R12 is attached in the c/s-configuration.
17. The compound according to any of clauses 1-15, wherein R3 comprises a cyclohexyl ring and R9 or R12 is attached in the frans-configu ration.
18. The compound according to any of the clauses 1-9, wherein R3 is -4-piperidin-1-yl-R11 or -CH2-4-piperidin-1-yl-R11.
19. The compound according to clause 18, wherein R11 is selected from aryl, hetaryl, -S(O)2- aryl and -S(O)2-hetaryl, where each aryl and hetaryl groups are optionally substituted.
20. The compound according to any of the clauses 1-9, wherein R3 is -3-piperidin-i-yl-R11 or -CH2-3-piperidin-1-yl-R11.
21. The compound according to any of clauses 1-6, wherein R1 is hydrogen, Ci-C4alkyl or cyclopropyl.
22. The compound according to clause 21 , wherein R2 is an unsubstituted adamantyl selected from 1 -adamantyl and 2-adamantyl.
23. The compound according to clause 21 , wherein R2 is a substituted adamantyl.
24. The compound according to clause 23, wherein R2 is a substituted 1 -adamantyl or a substituted 2-adamantyl. 25. The compound according to any of clauses 23-24, wherein R2 is an adamantyl substituted with one, two or more substituents independently selected from halogen, hydroxy, oxo, C(O)R13, Ci-C6alkyl, CrC6alkyloxy, -S(O)2NR7R8, and -S(O)nCi-C4alkyl.
26. The compound according to clauses 1-6, wherein R1 and R2 together with the nitrogen to which they are attached, are forming a substituted 8-aza-bicyclo[3.2.1]octane.
27. The compound according to clause 26, wherein the substituted 8-aza- bicyclo[3.2.1]octane is 8-aza-bicyclo[3.2.1]octan-3-yl.
28. The compound according to clauses 26-27, wherein the substituted 8-aza- bicyclo[3.2.1]octane is substituted with one, two or more substituents independently selected from halogen, hydroxy, oxo, C(O)RI 3, CrC6alkyl, CrC6alkyloxy, -S(O)2NR7R8 and -S(O)nC1- C4alkyl.
29. The compound according to any of the preceding clauses, which is selected from the group consisting of
Figure imgf000097_0001
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carbox- ylic acid ethyl ester,
Figure imgf000097_0002
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carbox- ylic acid,
Figure imgf000097_0003
(3-Aza-bicyclo[3.2.2]non-3-yl)-[4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-phenyl]- methanone,
Figure imgf000098_0001
4-(1-Cyclopropanecarbonyl-piperidin-4-yloxy)-N-adamantan-2-yl-benzamide,
Figure imgf000098_0002
4-[1-(3-Methyl-butyryl)-pipeπdin-4-yloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000098_0003
1-{4-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-piperidin-1-yl}-3-methyl-butan-1- one,
Figure imgf000098_0004
(6-Aza-bicyclo[3.2.1]oct-6-yl)-[4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-phenyl]- methanone,
Figure imgf000098_0005
1-{4-[4-(6-Aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-piperidin-1-yl}-3-methyl-butan-1- one,
Figure imgf000098_0006
4-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000098_0007
4-[4-(Octahydro-quinoline-1-carbonyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000099_0001
cis/trans-4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-adamantan-1-yl-benzamide,
Figure imgf000099_0002
cis/trans-4-[4-(Cyclopropane-carbonyl-amino)-cyclo-hexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000099_0003
N-Adamantan-2-yl-4-(4-hydroxy-cyclohexyloxy)-benzamide,
Figure imgf000099_0004
Cis/trans 4-[4-adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000099_0005
N-Adamantan-2-yl-4-[4-(4-methyl-1 H-imidazol-2-ylsulfanylmethyl)-cyclohexyloxy]- benzamide,
Figure imgf000099_0006
4-[4-(Pyridin-2-yloxy)-cyclohexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000099_0007
4-[4-(Pyrazol-1-yloxy)-cyclohexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000100_0001
4-[4-(Pyrazol-1-yl-oxymethyl)-cyclohexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000100_0002
4-[4-(Pyridin-2-yloxymethyl)-cyclohexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000100_0003
4-(4-Hydroxy-cyclohexyl-methoxy)-N-adamantan-2-yl-benzamide,
Figure imgf000100_0004
4-{4-[4-(Adamantan-2-yl-carbamoyl)-phenoxy]-cyclo-hexylmethoxy}-benzoic acid,
Figure imgf000100_0005
4-{4-[4-(Adamantan-2-yl-carbamoyl)-phenoxy]-cyclo-hexylmethoxy}-benzoic acid allyl ester,
Figure imgf000100_0006
Cis-4-[4-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane car- boxylic acid,
Figure imgf000101_0001
Trans-4-[4-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carboxylic acid,
Figure imgf000101_0002
Cis-N-Adamantan-2-yl-4-[4-(pyridine-2-sulfonylamino)-cyclohexyloxy]-benzamide,
Figure imgf000101_0003
Cis-Pyridine-2-sulfonic acid {4-[4-(octahydro-quinoline-1-carbonyl)-phenoxy]-cyclohexyl}- amide,
Figure imgf000101_0004
Cis-N-Adamantan-2-yl-4-[4-(cyclopropanecarbonyl-amino)-cyclohexyloxy]-benzamide,
Figure imgf000101_0005
Cis-Cyclopropanecarboxylic acid {4-[4-(octahydro-quinoline-1-carbonyl)-phenoxy]- cyclohexyl}-amide,
Figure imgf000101_0006
3-{3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-pyrrolidin-1-yl}-3-oxo-propionic acid,
Figure imgf000102_0001
3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-pyrrolidine-1 -carboxylic acid isopro- pylamide,
Figure imgf000102_0002
{3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-pyrrolidin-1-yl}-(6-chloro-pyridin-3- yl)-methanone,
Figure imgf000102_0003
N-{3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-pyrrolidine-1-carbonyl}-4-methyl- benzenesulfonamide,
Figure imgf000102_0004
3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-cyclopentanecarboxylic acid,
Figure imgf000102_0005
3-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclopentane carbox- ylic acid,
Figure imgf000102_0006
N-(5-Hydroxy-adamantan-2-y
Figure imgf000103_0001
N-(5-Hydroxy-adamantan-2-yl)-4-(4-hydroxy-cyclohexyl-oxy)-N-methyl-benzamide,
Figure imgf000103_0002
N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[4-(pyridine-2-sulfonylamino)-cyclohexyloxy]- benzamide,
Figure imgf000103_0003
4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(5-hydroxy-adamantan-2-yl)-N-methyl- benzamide,
Figure imgf000103_0004
4-[4-(3-Hydroxy-adamantan-1-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000103_0005
4-{4-[(5-Hydroxy-adamantan-2-yl)-methyl-carbamoyl]-phen-oxy}-cyclohexanecarboxylic acid,
Figure imgf000103_0006
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carbox- ylic acid amide,
Figure imgf000104_0001
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclo-hexane carbox- ylic acid dimethylamide,
Figure imgf000104_0002
4-[4-(Octahydro-quinoline-1-carbonyl)-phenoxy]-cyclo-hexanecarboxylic acid amide,
Figure imgf000104_0003
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carboni- trile,
Figure imgf000104_0004
Cyclopropanecarboxylic acid {4-[4-(3-hydroxy-8-aza-bicyclo[3.2.1 ]octane-8-carbonyl)- phenoxy]-cyclohexyl}-amide,
Figure imgf000104_0005
Cyclopropanecarboxylic acid {4-[4-(3-hydroxy-8-aza-bicyclo[3.2.1 ]octane-8-carbonyl)- phenoxy]-cyclohexyl}-amide,
Figure imgf000104_0006
4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(Z)-(5-hydroxy-adamantan-2-yl)- benzamide,
Figure imgf000104_0007
4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(E)-(5-hydroxy-adamantan-2-yl)- benzamide,
Figure imgf000105_0001
(Octahydro-quinolin-1-yl)-{4-[1-(pyπdine-2-sulfonyl)-piperidin-4-ylmethoxy]-phenyl}- methanone,
Figure imgf000105_0002
{4-[1-(1-Methyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl-methoxy]-phenyl}-(octahydro-quinolin- 1-yl)-methanone,
Figure imgf000105_0003
[4-(1 -Ethanesulfonyl-pipendin-4-yl-methoxy)-phenyl]-(octahydro-quinolin-1 -yl)-methanone,
Figure imgf000105_0004
N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[1-(pyridine-2-sulfonyl)-piperidin-4-yl-methoxy]- benzamide,
Figure imgf000105_0005
4-{4-[(5-Hydroxy-adamantan-2-yl)-methyl-carbamoyl]-phenoxy-methyl}-piperidine-1- carboxylic acid isopropylamide,
Figure imgf000106_0001
N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[1 -(1 -methyl-1 /-/-imidazole-4-sulfonyl)-piperidin-4- ylmethoxy]-benzamide,
Figure imgf000106_0002
4-(1-Ethanesulfonyl-piperidin-4-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-N-methyl- benzamide,
Figure imgf000106_0003
S^-^-^ctahydro-quinoline-i-carbonylJ-phenoxymethyO-piperidine-i-sulfonylJ-benzoic acid,
Figure imgf000106_0004
4-{4-[4-(Octahydro-quinoline-1-carbonyl)-phenoxymethyl]-piperidine-1-sulfonyl}-benzoic acid,
Figure imgf000106_0005
4-(2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-N-adamantan-2-yl-benzamide,
Figure imgf000107_0001
(1S,4S)-5-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenyl]-2,5-diaza- bicyclo[2.2.1]heptane-2-carboxylic acid terf-butyl ester,
Figure imgf000107_0002
(Octahydro-quinolin-1-yl)-{4-[(1 S,5R)-3-(pyridin-2-yloxy)-8-aza-bicyclo[3.2.1]oct-8-yl]-phenyl}- methanone,
Figure imgf000107_0003
4-[(1 S,5R)-3-(Pyridin-2-yloxy)-8-aza-bicyclo[3.2.1]oct-8-yl]-N-adamantan-2-yl-benzamide; or a prodrug thereof, 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.
30. The compound according to any one of the preceding clauses, wherein polar surface area (PSA) of said compound is in the range from 40 A2 to 130 A2, preferably from 50 A2 to 130 A2, more preferably from 60 A2 to 120 A2, more preferably from 70 A2 to 120 A2, most preferable from 70 A2 to 1 10 A2.
31. The compound according to any one of the preceding clauses, wherein the molar weight of said compound is in the range from 350D to 650D, preferably from 400D to 600D.
32. The compound according to any one of the preceding clauses, which is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSD1 is beneficial. 33. The compound according to any one of the clauses 1-29, which is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
34. The compound according to any one of the clauses 1-29 which is an agent useful for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
35. The compound according to any one of the clauses 1-29 which is an agent useful for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
36. The compound according to any one of the clauses 1-29 which is an agent useful for the delaying or prevention of the progression from IGT into type 2 diabetes.
37. The compound according to any one of the clauses 1-29 which is an agent useful for delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
38. The compound according to any one of the clauses 1-29 which is an agent useful for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
39. A pharmaceutical composition comprising, as an active ingredient, at least one com- pound according to any one of the clauses 1-29 together with one ore more pharmaceutically acceptable carriers or excipients.
40. The pharmaceutical composition according to clause 39 which is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration.
41. The pharmaceutical composition according to clause 39 or 40 in unit dosage form, comprising from 0.05 mg to 2000 mg/day, from 0.1 mg to 1000 mg or from 0.5 mg to 500 mg per day of the compound according to anyone of the clauses 1-29. 42. Use of a compound according to any of the clauses 1-29, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSD1 is beneficial.
43. Use of a compound according to any of the clauses 1-29, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
44. Use of a compound according to any of the clauses 1-29, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
45. Use of a compound according to any of the clauses 1-29, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
46. Use of a compound according to any of the clauses 1-29, for the preparation of a phar- maceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
47. Use of a compound according to any of the clauses 1-29, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
48. Use of a compound according to any of the clauses 1-29, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
49. A method for the treatment, prevention and/or prophylaxis of any conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 1 1 βHSD1 is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention. 50. The method according to clause 49 wherein the conditions, disorders or diseases are selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.

Claims

1. A compound of the general formula (I):
Figure imgf000111_0001
(I) wherein
R1 and R2 together with the nitrogen to which they are attached, are forming a 8-11 mem- bered saturated or partially saturated bicyclic or tricyclic ring consisting of the shown nitrogen, 5-10 carbon atoms and from 0 to 1 additional heteroatom selected from nitrogen, oxygen, and S(O)m, where m is 0, 1 or 2, and said ring being substituted with 0 to 3 groups inde- pendently selected from d-C4alkyl, halogen, hydroxy, oxo, COOH, -NHR7, NR7R8, -S(O)2Cr C4alkyl, -S(O)2NR7R8, CrC4alkyloxy, Ci-C4alkyloxyCrC4alkyl and Ci-C4alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R18, or
R1 is hydrogen, CrC4alkyl or cyclopropyl and R2 is adamantyl optionally substituted with 0 to 1 R18;
R3 is selected from -1 ,2-cyclopentyl-R9, -1 ,3-cyclopentyl-R9, -1 ,4-cyclohexyl-R9, -CH2-1 , 4- cyclohexyl-R9, -1 ,3-cyclohexyl-R9, -CH2-1 , 3-cyclohexyl-R9, -3-pyrrolidin-1-yl-R10, -CH2-3- pyrrolidin-1-R10, 4-tetrahydro-pyran, 4-tetrahydro-pyran-2-yl-R9, 4-tetrahydro-pyran-3-yl-R9, -4-piperidin-1 -yl-R11 , -CH2-4-piperidin-1 -yl-R11 , -3-piperidin-1 -yl-R11 , -CH2-3-piperidin-1 -yl-R1 -4-bicyclo[2.2.2]octan-1-yl-R12 and -CH2-4-bicyclo[2.2.2]octan-1-yl-R12;
X is selected from -O-, -S(O)n-, -CR5R6-, and -NR7-; or
R3 and R7 are connected by a covalent bond so as to form a bicyclic or tricyclic hetcycloalkyl ring comprising the N to which R3 and R7 are connected; the hetcycloalky ring may further be substituted with one or more R19;
R4 is selected from hydrogen, Ci-C4alkyl, trifluoromethyl, halogen, Ci-C4alkyloxy, CrC4alkyl- oxyCrC4alkyl and CrC4alkylcarbonyl, wherein each alkyl group is substituted with 0 to 1 R 18. ; R5 and R6 independently are selected from hydrogen, fluorine, methyl, ethyl, iso-propyl or cyclopropyl;
R7 is selected from hydrogen or selected from CrCβalkyl, Ci-Cβalkenyl, d-Cθalkynyl, cycloalkyl, aryl or hetaryl, each of which may be substituted with 0 to 2 R19;
R8 is selected from CrC6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl, each of which may be substituted with 0 to 2 R19; or
R7 and R8 optionally are connected by a covalent bond so as to form a ring comprising the N to which R7 and R8 are connected; the ring may be further substituted with one or more R19;
R9 and R12 independently are selected from hydroxy, cyano, C(O)R13, -(CR14R15X1C(O)NR7R8, -(CR14R15)nNHC(O)R16, -(CR14R15)nOR16, -(CR14R15)nS(O)mR16, -(CR14R15)nS(O)2NR7R8, - (CR14R15XNR7R8, -(CR14R15XNR17C(O)NR7R8, -(CR14R15XNR17S(O)2R16, -(CR14R15)nC=C- R16, -(CR14R15)nC≡C-R16, -(CR14R15)naryl substituted with O to 2 R20, and -(CR14R15)nhetaryl optionaly substituted with O to 2 R19;
R10 and R11 independently are selected from -C(O)NR7R8, -CH2C(O)NR7R8, -C(O)R17, -S(O)2R16 or -S(O)2NR7R8, wherein the alkyl, aryl and hetaryl groups are optionaly substituted with O to 2 R19;
m and n independently are O, 1 or 2;
R13 is selected from hydroxy, CrC6alkyl, CrC6alkenyl, CrC6alkynyl, cycloalkyl, CrC6alkyl- oxy, aryl, aryloxy, arylCi-C6alkyloxy, hetaryl, hetaryloxy or hetarylCi-C6alkyloxy wherein the CτC6alkyl, cycloalkyl, aryl or hetaryl groups are optionaly substituted with one or more R19;
R14 and R15 independently are selected from hydrogen, halogen, d-Cθalkyl and cycloalkyl, each of which CrC6alkyl and cycloalkyl may be substituted with O to 2 halogen, hydroxy or oxo and the carbon in CR14R15 can together with the R14 and/or R15 groups be part of a cycloalkyl ring; R16 is selected from hydrogen, d-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, cycloalkyl, hetcycloal- kyl, aryl or hetaryl wherein the Ci-Cβalkyl, cycloalkyl, aryl or hetaryl groups are optionaly substituted with one or more R19;
R17 is selected from hydrogen, CrC6alkyl, Ci-C6alkylC(O)R20, -(CR14R15)nNR17S(O)2R16, cycloalkyl, hetcycloalkyl, aryl or hetaryl, wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups optionaly are substituted with one or more R21;
R18 is halogen, hydroxy, oxo, -S(O)2Ci-C4alkyl, -S(O)2NR7R8 or -C(O)R13;
R19 is selected from halogen, hydroxy, oxo, -C(O)R20, d-CealkylC^R20, -S(O)nR16, -S(O)nNR7R8, cyclopropyl, -OR16, CrC6alkyl, aryl, hetaryl, -NR22C(O)NR7R8, -NR22S(O)2NR7R8 or -NC(O)NHS(O)2R16;
R20 is selected from hydroxy, Ci-C6alkyl, CrC6alkenyl, CrC6alkynyl, cycloalkyl, CrC6alkyl- oxy, aryl, aryloxy, arylCi-C6alkyloxy, hetaryl, hetaryloxy or hetarylCi-C6alkyloxy;
R21 is halogen, cyano or hydroxy; 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.
2. The compound according to claim 1 , wherein n is O.
3. The compound according to claim 1 or 2, wherein R4 is hydrogen.
4. The compound according to any of the preceding claims, wherein R1 and R2 together with the nitrogen to which they are attached, are forming a 8-1 1 membered saturated or partially saturated bicyclic or tricyclic ring, said ring being selected from the group consisting of
Figure imgf000114_0001
where each carbon is substituted with 0 to 2 R22, and R22 is independently selected from CrC8alkyl, halogen, hydroxy, oxo, C(O)R13, -S(O)2NR7R8, -S(O)nCrC4alkyl and CrC6alkyloxy.
5. The compound according to any of the preceding claims, wherein X is -O-.
6. The compound according to any of the preceding claims, wherein R1 and R2 together with the nitrogen to which they are attached, are forming a substituted 8-aza-bicyclo[3.2.1]octane.
7. The compound according to any of the preceding claims, which is selected from the group consisting of
Figure imgf000114_0002
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carbox- ylic acid ethyl ester,
Figure imgf000114_0003
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carbox- ylic acid,
Figure imgf000114_0004
(3-Aza-bicyclo[3.2.2]non-3-yl)-[4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-phenyl]- methanone,
Figure imgf000115_0001
4-(1-Cyclopropanecarbonyl-piperidin-4-yloxy)-N-adamantan-2-yl-benzamide,
Figure imgf000115_0002
4-[1-(3-Methyl-butyryl)-pipeπdin-4-yloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000115_0003
1-{4-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-piperidin-1-yl}-3-methyl-butan-1- one,
Figure imgf000115_0004
(6-Aza-bicyclo[3.2.1]oct-6-yl)-[4-(1-cyclopropanecarbonyl-piperidin-4-yloxy)-phenyl]- methanone,
Figure imgf000115_0005
1-{4-[4-(6-Aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-piperidin-1-yl}-3-methyl-butan-1- one,
Figure imgf000115_0006
4-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000115_0007
4-[4-(Octahydro-quinoline-1-carbonyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000116_0001
cis/trans-4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-adamantan-1-yl-benzamide,
Figure imgf000116_0002
cis/trans-4-[4-(Cyclopropane-carbonyl-amino)-cyclo-hexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000116_0003
N-Adamantan-2-yl-4-(4-hydroxy-cyclohexyloxy)-benzamide,
Figure imgf000116_0004
Cis/trans 4-[4-adamantan-2-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000116_0005
N-Adamantan-2-yl-4-[4-(4-methyl-1 H-imidazol-2-ylsulfanylmethyl)-cyclohexyloxy]- benzamide,
Figure imgf000116_0006
4-[4-(Pyridin-2-yloxy)-cyclohexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000117_0001
4-[4-(Pyrazol-1-yloxy)-cyclohexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000117_0002
4-[4-(PyrazoM-yl-oxymethyl)-cyclohexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000117_0003
4-[4-(Pyridin-2-yloxymethyl)-cyclohexyloxy]-N-adamantan-2-yl-benzamide,
Figure imgf000117_0004
4-(4-Hydroxy-cyclohexyl-methoxy)-N-adamantan-2-yl-benzamide,
Figure imgf000117_0005
4-{4-[4-(Adamantan-2-yl-carbamoyl)-phenoxy]-cyclo-hexylmethoxy}-benzoic acid,
Figure imgf000117_0006
4-{4-[4-(Adamantan-2-yl-carbamoyl)-phenoxy]-cyclo-hexylmethoxy}-benzoic acid allyl ester,
Figure imgf000118_0001
Cis-4-[4-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane car- boxylic acid,
Figure imgf000118_0002
Trans-4-[4-(1 ,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carboxylic acid,
Figure imgf000118_0003
Cis-N-Adamantan-2-yl-4-[4-(pyridine-2-sulfonylamino)-cyclohexyloxy]-benzamide,
Figure imgf000118_0004
Cis-Pyridine-2-sulfonic acid {4-[4-(octahydro-quinoline-1-carbonyl)-phenoxy]-cyclohexyl}- amide,
Figure imgf000118_0005
Cis-N-Adamantan-2-yl-4-[4-(cyclopropanecarbonyl-amino)-cyclohexyloxy]-benzamide,
Figure imgf000118_0006
Cis-Cyclopropanecarboxylic acid {4-[4-(octahydro-quinoline-1-carbonyl)-phenoxy]- cyclohexyl}-amide,
Figure imgf000119_0001
3-{3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-pyrrolidin-1-yl}-3-oxo-propionic acid,
Figure imgf000119_0002
3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-pyrrolidine-1 -carboxylic acid isopro- pylamide,
Figure imgf000119_0003
{3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-pyrrolidin-1-yl}-(6-chloro-pyridin-3- yl)-methanone,
Figure imgf000119_0004
N-{3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-pyrrolidine-1-carbonyl}-4-methyl- benzenesulfonamide,
Figure imgf000119_0005
3-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenoxy]-cyclopentanecarboxylic acid,
Figure imgf000119_0006
3-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclopentane carboxylic acid,
Figure imgf000119_0007
N-(5-Hydroxy-adamantan-2-yl)-4-(4-hydroxy-cyclohexyl-oxy)-N-methyl-benzamide,
Figure imgf000120_0001
N-(5-Hydroxy-adamantan-2-yl)-4-(4-hydroxy-cyclohexyl-oxy)-N-methyl-benzamide,
Figure imgf000120_0002
N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[4-(pyridine-2-sulfonylamino)-cyclohexyloxy]- benzamide,
Figure imgf000120_0003
4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(5-hydroxy-adamantan-2-yl)-N-methyl- benzamide,
Figure imgf000120_0004
4-[4-(3-Hydroxy-adamantan-1-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid,
Figure imgf000120_0005
4-{4-[(5-Hydroxy-adamantan-2-yl)-methyl-carbamoyl]-phen-oxy}-cyclohexanecarboxylic acid,
Figure imgf000120_0006
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carbox- ylic acid amide,
Figure imgf000121_0001
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclo-hexane carbox- ylic acid dimethylamide,
Figure imgf000121_0002
4-[4-(Octahydro-quinoline-1-carbonyl)-phenoxy]-cyclo-hexanecarboxylic acid amide,
Figure imgf000121_0003
4-[4-(1 ,3,3-Trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenoxy]-cyclohexane carboni- trile,
Figure imgf000121_0004
Cyclopropanecarboxylic acid {4-[4-(3-hydroxy-8-aza-bicyclo[3.2.1 ]octane-8-carbonyl)- phenoxy]-cyclohexyl}-amide,
Figure imgf000121_0005
Cyclopropanecarboxylic acid {4-[4-(3-hydroxy-8-aza-bicyclo[3.2.1 ]octane-8-carbonyl)- phenoxy]-cyclohexyl}-amide,
Figure imgf000121_0006
4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(Z)-(5-hydroxy-adamantan-2-yl)- benzamide,
Figure imgf000121_0007
4-[4-(Cyclopropanecarbonyl-amino)-cyclohexyloxy]-N-(E)-(5-hydroxy-adamantan-2-yl)- benzamide,
Figure imgf000122_0001
(Octahydro-quinolin-1-yl)-{4-[1-(pyπdine-2-sulfonyl)-piperidin-4-ylmethoxy]-phenyl}- methanone,
Figure imgf000122_0002
{4-[1-(1-Methyl-1 H-imidazole-4-sulfonyl)-piperidin-4-yl-methoxy]-phenyl}-(octahydro-quinolin- 1-yl)-methanone,
Figure imgf000122_0003
[4-(1 -Ethanesulfonyl-pipendin-4-yl-methoxy)-phenyl]-(octahydro-quinolin-1 -yl)-methanone,
Figure imgf000122_0004
N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[1-(pyridine-2-sulfonyl)-piperidin-4-yl-methoxy]- benzamide,
Figure imgf000122_0005
4-{4-[(5-Hydroxy-adamantan-2-yl)-methyl-carbamoyl]-phenoxy-methyl}-piperidine-1- carboxylic acid isopropylamide,
Figure imgf000123_0001
N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[1 -(1 -methyl-1 /-/-imidazole-4-sulfonyl)-piperidin-4- ylmethoxy]-benzamide,
Figure imgf000123_0002
4-(1-Ethanesulfonyl-piperidin-4-ylmethoxy)-N-(5-hydroxy-adamantan-2-yl)-N-methyl- benzamide,
Figure imgf000123_0003
S^-^-^ctahydro-quinoline-i-carbonylJ-phenoxymethyO-piperidine-i-sulfonylJ-benzoic acid,
Figure imgf000123_0004
4-{4-[4-(Octahydro-quinoline-1-carbonyl)-phenoxymethyl]-piperidine-1-sulfonyl}-benzoic acid,
Figure imgf000123_0005
4-(2-Oxa-5-aza-bicyclo[2.2.1]hept-5-yl)-N-adamantan-2-yl-benzamide,
Figure imgf000124_0001
(1S,4S)-5-[4-(3-Aza-bicyclo[3.2.2]nonane-3-carbonyl)-phenyl]-2,5-diaza- bicyclo[2.2.1]heptane-2-carboxylic acid terf-butyl ester,
Figure imgf000124_0002
(Octahydro-quinolin-1-yl)-{4-[(1 S,5R)-3-(pyridin-2-yloxy)-8-aza-bicyclo[3.2.1]oct-8-yl]-phenyl}- methanone,
Figure imgf000124_0003
4-[(1 S,5R)-3-(Pyridin-2-yloxy)-8-aza-bicyclo[3.2.1]oct-8-yl]-N-adamantan-2-yl-benzamide; or a prodrug thereof, 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.
8. The compound according to any one of the preceding claims, which is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSD1 is beneficial.
9. The compound according to any one of the claims 1-7, which is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
10. The compound according to any one of the claims 1-7 which is an agent useful for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
11. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the claims 1-7 together with one ore more pharmaceutically acceptable carriers or excipients.
12. Use of a compound according to any of the claims 1-7, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases wherein a modulation or an inhibition of the activity of 1 1 βHSD1 is beneficial.
13. Use of a compound according to any of the claims 1-7, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
14. Use of a compound according to any of the claims 1-7, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
15. A method for the treatment, prevention and/or prophylaxis of any conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 1 1 βHSD1 is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
PCT/EP2007/052929 2006-04-07 2007-03-27 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ACTIVE COMPOUNDS WO2007115935A1 (en)

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