WO2008101885A1 - N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase - Google Patents

N-adamantyl benzamides as inhibitors of 11-beta-hydroxysteroid dehydrogenase Download PDF

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Publication number
WO2008101885A1
WO2008101885A1 PCT/EP2008/051912 EP2008051912W WO2008101885A1 WO 2008101885 A1 WO2008101885 A1 WO 2008101885A1 EP 2008051912 W EP2008051912 W EP 2008051912W WO 2008101885 A1 WO2008101885 A1 WO 2008101885A1
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group
hydroxy
cyclopropyl
methyl
substituted
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PCT/EP2008/051912
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French (fr)
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Søren EBDRUP
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High Point Pharmaceuticals, Llc
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Priority to US12/528,231 priority Critical patent/US20110003852A1/en
Priority to JP2009550269A priority patent/JP2010519239A/en
Priority to EP08709054A priority patent/EP2146952A1/en
Publication of WO2008101885A1 publication Critical patent/WO2008101885A1/en

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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07C235/58—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 with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/62—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 with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—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
    • C07D211/08—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
    • C07D211/18—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
    • 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
    • C07D211/22—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 by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C07D213/71—Sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no 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
    • C07D309/06—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to novel substituted benzamide based inhibitors, to their use in therapy, to pharmaceutical compositions comprising the compounds, to the use of said compounds in the manufacture of medicaments, and to therapeutic methods comprising the administration of said compounds.
  • the present compounds modulate the activity of ll ⁇ - hydroxysteroid dehydrogenase type 1 (ll ⁇ HSDl) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.
  • the metabolic syndrome is a major global health problem. In the US, the prevalence in the adult population is currently estimated to be approximately 25%, and it continues to increase both in the US and worldwide.
  • the metabolic syndrome is characterised by a combination of insulin resistance, dyslipidemia, obesity and hypertension leading to increased morbidity and mortality of cardiovascular diseases. People with the metabolic syndrome are at increased risk of developing frank type 2 diabetes, the prevalence of which is equally escalating.
  • glucocorticoids are able to induce all of the cardinal features of the metabolic syndrome and type 2 diabetes.
  • ll ⁇ -hydroxysteroid dehydrogenase type 1 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.
  • ll ⁇ HSDl 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, 140, 3188 (1999); Whorwood et al., J
  • ll ⁇ HSDl in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence.
  • treatment with the non-specific ll ⁇ HSDl inhibitor carben- oxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes.
  • ll ⁇ HSDl 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 ll ⁇ HSDl in adipocytes develop insulin resistance, hyperlipidemia and visceral obesity, a phenotype that resembles the human metabolic syndrome (Andrews et al., J. Clin.
  • ll ⁇ HSDl promotes the features of the metabolic syndrome by increasing hepatic expression of the rate-limiting enzymes in gluconeogenesis, namely phosphoenolpyuvate carboxykinase and glucose-6-phosphatase, promoting the differentiation of preadipocytes into adipocytes thus facilitating obesity, directly and indirectly stimulating hepatic VLDL secretion, decreasing hepatic LDL uptake and increasing vessel contractility
  • 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 ll ⁇ -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 2004/089470 discloses various substituted amides and the use thereof for stimulating ll ⁇ - hydroxysteroid dehydrogenase type 1.
  • WO 2004/089415 and WO 2004/089416 discloses various combination therapies using an ll ⁇ -hydroxysteroid dehydrogenase type 1 inhibitor and respectively a glucocorticoid receptor agonist or an antihypertensive agent.
  • the present compounds can be used to treat disorders where a decreased level of active intracellular glucocorticoid is desirable, such as e.g.
  • One object of the present invention is to provide compounds, pharmaceutical compositions and use of compounds that modulate the activity of ll ⁇ HSDl.
  • radical shall mean a chemical group attached via a single bond.
  • halogen or halo means fluorine, chlorine, bromine or iodine.
  • hydroxy shall mean the radical -OH.
  • Ci-C 6 alkyl represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms, e.g. Ci-C 2 alkyl, Ci-C 3 alkyl, Ci-C. 4 alkyl, Ci-C 6 alkyl, C 2 -C 6 alkyl, C 3 -C 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 tert- butyl), but-l-yl, but-2-yl), pentyl (e.g.
  • Ci-Qalkyl represents a saturated, branched or straight hydrocarbon group having from 1 to 4 carbon atoms, e.g. Ci-C 2 alkyl, Ci-C 3 alkyl, Ci-C. 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-l-yl, but-2-yl), and the like.
  • 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 -, - CH 2 NHCH 2 CH 2 -, -CH 2 CH 2 NHCH 2 CH 2 -, -CH 2 NHCH 2 CH 2 CH 2 -, -CH 2 CH 2 OCH 2 -, -OCH 2 CH 2 O-, and the like.
  • C 3 -C 10 cycloalkyl represents a saturated monocyclic carbocyclic ring having from 3 to 10 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, cycloheptyl, cyclooctyl, and the like.
  • C 3 -Ci 0 cycloalkyl is also intended to represent a saturated bicyclic carbocyclic ring having from 4 to 10 carbon atoms.
  • C 3 -Ci 0 cycloalkyl is also intended to represent a saturated carbocyclic ring having from 3 to 10 carbon atoms and containing one or two carbon bridges.
  • Representative examples are adamantyl, norbornanyl, nortricyclyl, bicyclo[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.
  • C 3 -Ci 0 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.
  • aryl as used herein is intended to include monocyclic, bicyclic or polycyclic 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 polycyclic 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), indenyl (e.g. inden-1-yl, inden-5-yl), 1,2,3,4-tetrahydronaphthyl (e.g.
  • 1,2-dihydronaphthyl e.g. 1,2-dihydronaphth-l-yl, l,2-dihydronaphth-4-yl, 1,2- dihydronaphth-6-yl
  • fluorenyl e.g. fluoren-1-yl, fluoren-4-
  • 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), l,4-ethano-l,2,3,4-tetrahydronapthyl (e.g. 1,4- ethano-l,2,3,4-tetrahydronapth-2-yl,l,4-ethano-l,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.
  • Representative examples are spiro[cyclo- pentane-l,l'-indane]-4-yl, spiro[cyclopentane-l,l'-indene]-4-yl, spiro[piperidine-4,l'- indane]-l-yl, spiro[piperidine-3,2'-indane]-l-yl, spiro[piperidine-4,2'-indane]-l-yl, spiro[piperidine-4,l'-indane]-3'-yl, spiro[pyrrolidine-3,2'-indane]-l-yl, spiro[pyrrolidine-3,l'- (3',4'-dihydronaphthalene)]-l-yl, spiro[piperidine-3,l'-(3',4'-dihydronaphthalene)]-l-yl, spiro[piperidine-4,l'-
  • Representative examples are aziridinyl (e.g. aziridin-1-yl), azetidinyl (e.g. azetidin-1-yl, azetidin-3-yl), oxetanyl, pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), imidazolidinyl (e.g.
  • tetrahydrofuran-2-yl tetrahydrofuran-3-yl
  • tetrahydrothienyl tetrahydro-l,l-dioxothienyl
  • tetrahydropyranyl e.g. 2-tetrahydropyranyl
  • tetrahydrothiopyranyl e.g. 2-tetrahydrothiopyranyl
  • 1,4-dioxanyl 1,3-dioxanyl, and the like.
  • Representative examples are octahydroindolyl (e.g. octahydroindol-1-yl, octahydroindol-2-yl, octahydroindol-3-yl, octahydroindol-5-yl), decahydroquinolinyl (e.g.
  • Representative examples are 3-azabicyclo- [3.2.2]nonyl, 2-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.0]hexyl, 2,5-diazabicyclo-
  • Representative examples are 1,4- dioxaspiro[4.5]decanyl (e.g.
  • 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
  • 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, pyrazol-3-yl, pyrazol-5-yl
  • isoxazolyl e.g.
  • 1,3,4- oxadiazol-2-yl, l,3,4-oxadiazol-5-yl 1,2,3-thiadiazolyl (e.g. l,2,3-thiadiazol-4-yl, 1,2,3- thiadiazol-5-yl), 1,2,4-thiadiazolyl (e.g. l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl), 1,2,5- thiadiazolyl (e.g. l,2,5-thiadiazol-3-yl, l,2,5-thiadiazol-4-yl), 1,3,4-thiadiazolyl (e.g.
  • Representative examples are indolyl (e.g.
  • phthalazinyl e.g. phthalazin-1-yl, phthalazin-5-yl
  • purinyl e.g. purin-2-yl, purin-6-yl, purin-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
  • isoquinolinyl e.g. isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin- 4-yl
  • quinoxalinyl e.g. quinoxalin-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.
  • Representative examples are carbazolyl (e.g.
  • Representative examples are pyrrolinyl, pyrazolinyl, imidazolinyl (e.g. 4,5- dihydroimidazol-2-yl, 4,5-dihydroimidazol-l-yl), indolinyl (e.g. 2,3-dihydroindol-l-yl, 2,3- dihydroindol-5-yl), dihydrobenzofuranyl (e.g.
  • 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.
  • 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,l'-cyclohexan]-l- yl, spiro[piperidine-4,l'-benzo[c]thiophen]-l-yl, spiro[piperidine-4,l'-benzo[c]furan]-l-yl, spiro[piperidine-4,3'-benzo[b]furan]-l-yl, spiro[piperidine-4,3'-coumarin]-l-yl, and the like.
  • monocyclic heteroaryl as used herein is intended to include monocyclic heterocyclic aromatic rings as defined above.
  • bicyclic heteroaryl as used herein is intended to include bicyclic heterocyclic aromatic rings as defined above.
  • morpholin-2-yl morpholin-3-yl, morpholin-4- yl
  • thiomorpholinyl e.g. thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl
  • 1-oxo- thiomorpholinyl 1,1-dioxo-thiomorpholinyl
  • aziridinyl e.g. aziridin-1-yl
  • azetidinyl e.g. azetidin-1-yl, azetidin-3-yl
  • azetidine e.g. azetidin and the like.
  • 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.
  • pharmaceutically acceptable is defined as being suitable for administration to humans without adverse events.
  • prodrug is defined as a chemically modified form of the active drug, said prodrug being administered to the patient and subsequently being converted to the active drug. Techniques for development of prodrugs are well known in the art.
  • substituted benzamide based inhibitors that modulate the activity of ll ⁇ HSDl leading to altered intracellular concentrations of active glucocorticoid are provided. More specifically, the present compounds inhibit the activity of ll ⁇ HSDl leading to decreased intracellular concentrations of active glucocorticoid.
  • the present compounds can be used to treat disorders where a decreased level of active intracellular glucocorticoid is desirable, such as e.g.
  • 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.
  • One object of the present invention is to provide compounds, pharmaceutical compositions and use of compounds that modulate the activity of ll ⁇ HSDl.
  • the present invention furthermore relates to the use in therapy of the compounds according to the invention, to pharmaceutical compositions comprising the compounds, to the use of said compounds in the manufacture of medicaments, and to therapeutic methods comprising the administration of said compounds.
  • the invention provides for a compound of the general formula (I) :
  • R 1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and cyclopropyl and R 2 is selected from the group consisting of a monovalent radical having one of the following formulae, wherein the symbol * denotes the point of attachment:
  • R 5 is selected from the group consisting of hydrogen, cyclopropyl and Ci-C 4 alkyl, wherein said cyclopropyl and Ci-C 4 alkyl are optionally substituted with one or two independently selected R 9 ;
  • R 6 is selected from the group consisting of cyclopropyl and Ci-C 4 alkyl, wherein said cyclopropyl and Q-Qalkyl are optionally substituted with one or two independently selected R 9 ; or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4 to 6 membered ring optionally substituted with one or two independently selected R 9 ;
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, cyclopropyl and Ci-C 4 alkyl, wherein said cyclopropyl and Ci-C 4 alkyl are optionally substituted with one or two independently selected R 9 ; or R 7 and R 8 together with the nitrogen atom to which they are attached form a 4 to 6 membered ring optionally substituted with one or two independently selected R 9 ;
  • R 95 is selected from the group consisting of Ci-C 6 alkyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said Q-Csalkyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with one or two independently selected R 96 ;
  • R 97 is selected from the group consisting of hydrogen, cyclopropyl and Ci-C 4 alkyl;
  • R 9 is selected from the group consisting of hydrogen, Q-Qalkyl, cyclopropyl, hydroxy, halogen, trifluoromethyl, -CH 2 OH and carboxy;
  • R 10 and R 11 are each independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, -CH 2 OH, fluorine, isopropyl and cyclopropyl; or R 10 and R 11 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl is optionally substituted with hydroxy or fluorine;
  • n is selected from the group consisting of O, 1 and 2;
  • R 22 and R 23 are each independently selected from the group consisting of hydrogen, halogen, Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl, wherein said Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R 22 and R 23 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen;
  • R 86 and R 87 are each independently selected from the group consisting of hydrogen, halogen, Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl, wherein said Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R 86 and R 87 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen; R 88 and R 89 are each independently selected from the group consisting of hydrogen, halogen, Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl, wherein said Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl independently are optionally substituted with one or two substituents
  • n 0 or 1
  • R 15 , R 16 , R 20 , R 21 , R 24 , R 25 and R 45 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -Ci 0 heterocyclyl, C 3 -Ci 0 cycloalkyl, aryl and heteroaryl, wherein said Ci-C 6 alkyl, C 3 -Ci 0 heterocyclyl, C 3 -Ci 0 cycloalkyl, aryl and heteroaryl are optionally substituted independently with one, two or three independently selected R 41 ;
  • R 17 , R 18 and R 19 are each independently selected from the group consisting of hydrogen, Ci-Csalkyl, C 3 -C 10 cycloalkyl, phenyl and heteroaryl, wherein said Q-Csalkyl, C 3 -C 10 cycloalkyl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, ethyl and hydroxy; or R 17 and R 18 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said ring are optionally substituted with hydroxy, trifluoromethyl or halogen;
  • R 28 , R 29 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 R 98 and R 40 are each independently selected from the group consisting of hydrogen, Q-Csalkyl, phenyl, heteroaryl and C 3 -C 10 cycloalkyl, wherein said Ci-Csalkyl, phenyl, heteroaryl and C 3 -C 10 cycloalkyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, triflouromethyl, methoxy and hydroxy;
  • R 30 and R 31 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said Ci-C 6 alkyl, tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy, or R 30 and R 31 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said ring is optionally substituted with hydroxy or halogen;
  • R 42 is selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, aryl and heteroaryl, wherein said d-C 6 alkyl, C 3 -C 10 cycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, triflouromethyl, methoxy and hydroxy;
  • R 43 and R 44 are each independently selected from the group consisting of hydrogen
  • Ci-C 6 alkyl, C 3 -Ci 0 heterocyclyl, C 3 -Ci 0 cycloalkyl and heteroaryl wherein said Ci-C 6 alkyl, C 3 - Cioheterocyclyl, C 3 -Ci 0 cycloalkyl and heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy, or R 43 and R 44 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl is optionally substituted with hydroxy or halogen;
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric forms.
  • R 1 is hydrogen
  • R 1 is methyl
  • R 1 is ethyl
  • R 1 is isopropyl
  • R 1 is cyclopropyl
  • R 2 is selected from the group consisting of:
  • R 2 is selected from the group consisting of
  • R 2 is
  • R 2 i,s
  • R is In one aspect, R 2 : i,s
  • R is
  • Q is hydroxy
  • Q is -CH 2 OH.
  • Q is -C(CH 3 )HOH.
  • Q is 1-cyclopropanol.
  • Q is -C(CH 3 ) 2 OH.
  • Q is -0-CH 2 CH 2 -OH.
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, wherein said methyl, ethyl and cyclopropyl optionally are substituted with one or two independently selected R 9 .
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl.
  • R 6 is selected from the group consisting of methyl, ethyl and cyclopropyl, wherein said ethyl and cyclopropyl optionally are substituted with one or two independently selected R 9 .
  • R 6 is selected from the group consisting of methyl, ethyl and cyclopropyl.
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl ring, which ring is optionally substituted with one or two independently selected R 9 .
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl ring.
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, wherein said methyl, ethyl and cyclopropyl are optionally substituted with one or two independently selected R 9 .
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl.
  • R 8 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, wherein said methyl, ethyl and cyclopropyl are optionally substituted with one or two independently selected R 9 .
  • R 8 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl.
  • R 7 and R 8 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl ring, which ring is optionally substituted with one or two independently selected R 9 .
  • R 7 and R 8 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl ring.
  • R 95 is selected from the group consisting of methyl, ethyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said methyl, ethyl, phenyl, pyridinyl, pyrimidinvl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with one or two independently selected R 96 .
  • R 95 is selected from the group consisting of methyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said methyl, phenyl, pyridinyl, pyrimidinvl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with R 96 .
  • R 95 is selected from the group consisting of methyl, phenyl, pyridinyl, pyrimidinvl, cyclopropyl, cyclobutyl and cyclohexyl.
  • R 96 is selected from the group consisting of fluorine, chlorine, hydroxy and trifluoromethyl.
  • R 97 is hydrogen
  • R 97 is C 1 -C 4 SIkVl.
  • R 97 is selected from the group consisting of methyl, ethyl and cyclopropyl.
  • R 9 is selected from the group consisting of hydrogen, methyl, cyclopropyl, hydroxy, halogen, trifluoromethyl, -CH 2 OH and carboxy.
  • R 9 is selected from the group consisting of hydrogen, methyl, cyclopropyl, hydroxy, fluorine, chlorine and trifluoromethyl.
  • X 1 is -CR 10 R 11 -. In one aspect, X 1 is -O-.
  • X 1 is -S-.
  • X 2 is -CR 86 R 87 -
  • X is -O-.
  • X 2 is -S-.
  • X 2 is -NR 24 -.
  • X 3 is -CR 88 R 89 -
  • X 3 is -Cl ⁇
  • X 3 is -S-.
  • X 3 is -NR 25 -.
  • -X 1 -X 2 -X 3 -R 3 does not comprise one or more rings selected from the group consisting of phenyl, biphenyl, benzocyclobutenyl, benzocycloheptanyl, benzosuberenyl, indenyl, 2,3-dihydroindenyl, fluorenyl, 1,2-dihydronaphthyl, 5,6,7,8- tetrahydronaphthyl or naphthyl.
  • R 10 is selected from the group consisting of hydrogen, hydroxy, methyl, fluorine, isopropyl and cyclopropyl.
  • R 10 is selected from the group consisting of hydrogen, hydroxy, methyl and fluorine.
  • R 11 is selected from the group consisting of hydrogen, hydroxy, methyl, fluorine, isopropyl and cyclopropyl.
  • R 11 is selected from the group consisting of hydrogen, hydroxy, methyl and fluorine.
  • R 10 and R 11 together with the carbon atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl is optionally substituted with hydroxy or fluorine.
  • R 10 and R 11 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl is optionally substituted with hydroxy or fluorine.
  • R 3 is selected from the group consisting of Ci-C 4 alkyl substituted with R 13 and R 14 , C 3 -Cioheterocyclyl substituted with R 13 and R 14 , C 3 -Ci 0 cycloalkyl substituted with R 13 and R 14 , aryl substituted with R 13 and R 14 , and heteroaryl substituted with R 13 and R 14 .
  • R 3 is selected from the group consisting of C 3 -C 10 heterocyclyl substituted with R 13 and R 14 , C 3 -C 10 cycloalkyl substituted with R 13 and R 14 , aryl substituted with R 13 and R 14 , and heteroaryl substituted with R 13 and R 14 .
  • n 1
  • n is 2.
  • R 3 is selected from the group consisting of C 3 -Ci 0 heterocyclyl substituted with R 13 , C 3 -Ci 0 cycloalkyl substituted with R 13 , aryl substituted with R 13 and heteroaryl substituted with R 13 .
  • R 3 is selected from the group consisting of with R 13 substituted tetrahydro- pyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
  • R 3 is selected from the group consisting of with R 13 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.
  • R 3 is phenyl substituted with R 13 .
  • R 3 is selected from the group consisting of with R 13 substituted imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
  • R 13 is selected from the group consisting of -(CR 22 R 23 ) m -C 3 -C 10 heterocyclyl substituted with R 37 and R 38 , -(CR 22 R 23 ) m -C 3 -C 10 cycloalkyl substituted with R 37 and R 38 , - (CR 22 R 23 ) m -aryl substituted with R 39 and R 40 , Q-Csalkyl-R 98 and -(CR 22 R 23 ) m -heteroaryl substituted with R 39 and R 40 .
  • R 13 is selected from the group consisting of C 3 -Ci 0 heterocyclyl substituted with R 37 , C 3 -C 10 cycloalkyl substituted with R 37 , aryl substituted with R 39 , Q-Csalkyl-R 98 and heteroaryl substituted with R 39 .
  • R 13 is C 3 -C 10 heterocyclyl substituted with R 37 .
  • R 13 is selected from the group consisting of with R 37 substituted tetrahydro- pyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
  • R 13 is C 3 -Ci 0 cycloalkyl substituted with R 37
  • R 13 is selected from the group consisting of with R 37 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.
  • R 13 is aryl substituted with R 39 . In one aspect, R 13 is phenyl substituted with R 39 .
  • R 13 is Ci-C 6 alkyl-R 98 .
  • R 13 is selected from the group consisting of with R 98 substituted methyl, ethyl and isopropyl.
  • R 13 is heteroaryl substituted with R 39 .
  • R 13 is selected from the group consisting of with R 39 substituted imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
  • R 14 is selected from the group consisting of -(CR 22 R 23 ) m -C 3 -Ci 0 heterocyclyl substituted with R 37 and R 38 , -(CR 22 R 23 ) m -C 3 -C 10 cycloalkyl substituted with R 37 and R 38 , - (CR 22 R 23 ) m -aryl substituted with R 39 and R 40 , Q-Csalkyl-R 98 and -(CR 22 R 23 ) m -heteroaryl substituted with R 39 and R 40 .
  • R 14 is selected from the group consisting of C 3 -Ci 0 heterocyclyl substituted with R 37 , C 3 -Ciocycloalkyl substituted with R 37 , aryl substituted with R 39 , Ci-C 6 alkyl-R 98 and heteroaryl substituted with R 39 .
  • R 14 is C 3 -C 10 heterocyclyl substituted with R 37 .
  • R 14 is selected from the group consisting of with R 37 substituted tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
  • R 14 is C 3 -Ci 0 cycloalkyl substituted with R 37
  • R 14 is selected from the group consisting of with R 37 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.
  • R 14 is aryl substituted with R 39 .
  • R 14 is phenyl substituted with R 39 .
  • R 14 is Ci-Csalkyl-R 98 .
  • R 14 is selected from the group consisting of with R 98 substituted methyl, ethyl and isopropyl.
  • R 14 is heteroaryl substituted with R 39 .
  • R 14 is hydrogen
  • R 14 is selected from the group consisting of with R 39 substituted imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
  • R 22 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, isopropyl, cyclobutyl and cyclopropyl wherein said cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy. In one aspect, R 22 is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.
  • R 23 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, isopropyl, cyclobutyl and cyclopropyl wherein said cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
  • R 23 is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.
  • R 22 and R 23 together with the carbon atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl ring is optionally substituted with hydroxy or fluorine.
  • R 22 and R 23 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl ring is optionally substituted with hydroxy or fluorine.
  • R 86 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
  • R 86 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
  • R 87 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
  • R 87 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
  • R 86 and R 87 together with the carbon atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl are optionally substituted with hydroxy or fluorine.
  • R 86 and R 87 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl are optionally substituted with hydroxy or fluorine.
  • R 88 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
  • R 88 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
  • R 89 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
  • R 89 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
  • R 88 and R 89 together with the carbon atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl are optionally substituted with hydroxy or fluorine.
  • R 88 and R 89 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl are optionally substituted with hydroxy or fluorine.
  • R 26 is selected from the group consisting of hydrogen, C 3 -C 10 heterocyclyl substituted with R 37 , C 3 -C 10 cycloalkyl substituted with R 38 , phenyl substituted with R 39 and R 40 , Ci-Csalkyl-R 98 and heteroaryl substituted with R 39 and R 40 .
  • R 26 is hydrogen
  • R 26 selected from the group consisting of with R 37 substituted tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
  • R 26 selected from the group consisting of with R 38 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl substituted with R 38 .
  • R 26 is phenyl substituted with R 39 . In one aspect, R 26 selected from the group consisting of with R 98 substituted methyl, ethyl and isopropyl.
  • R 26 selected from the group consisting of substituted with R 39 imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
  • R 27 is selected from the group consisting of hydrogen, C 3 -Ci 0 heterocyclyl substituted with R 37 , C 3 -Ci 0 cycloalkyl substituted with R 38 , phenyl substituted with R 39 and R 40 , CrCsalkyl-R 98 and heteroaryl substituted with R 39 and R 40 .
  • R 27 is hydrogen
  • R 27 selected from the group consisting of with R 37 substituted tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
  • R 27 selected from the group consisting of with R 38 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.
  • R 27 is phenyl substituted with R 39 .
  • R 27 selected from the group consisting of with R 98 substituted methyl, ethyl and isopropyl.
  • R 27 selected from the group consisting of substituted with R 39 imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
  • m 0.
  • m is 1.
  • R 15 , R 16 , R 20 , R 21 , R 24 , R 25 and R 45 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, imidazolyl, pyr
  • R 15 , R 16 , R 20 , R 21 , R 24 , R 25 and R 45 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, where
  • R 17 , R 18 and R 19 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl
  • R 17 , R 18 and R 19 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine, chlorine, methyl or hydroxy.
  • R 17 and R 18 together with the nitrogen atom to which they are attached form a cyclopropyl ring, wherein said ring are optionally substituted with hydroxy or halogen.
  • R 17 and R 18 together with the nitrogen atom to which they are attached form a cyclobutyl ring, wherein said ring are optionally substituted with hydroxy or halogen.
  • R 28 , R 29 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 R 98 and R 40 are each independently selected from the group consisting of hydrogen, Q-Qalkyl, heteroaryl and C 3 -C 10 cycloalkyl, wherein said C 1 -QaIkYl, heteroaryl and C 3 -C 10 cycloalkyl are optionally substituted with halogen, methyl, triflouromethyl, methoxy or hydroxy.
  • R 28 , R 29 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 R 98 and R 40 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrol
  • R 28 , R 29 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 R 98 and R 40 are each independently selected from the group consisting of hydrogen, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl, pyra
  • R 30 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, isopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said methyl, ethyl, cyclopropyl, isopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with halogen or hydroxy.
  • R 30 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl and isopropyl, wherein said ethyl, cyclopropyl and isopropyl are optionally substituted with halogen or hydroxy.
  • R 31 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, isopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said methyl, cyclopropyl, isopropyl tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with halogen or hydroxy.
  • R 31 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl and isopropyl, wherein said ethyl, cyclopropyl and isopropyl are optionally substituted with halogen or hydroxy.
  • R 30 and R 31 together with the nitrogen atom to which they are attached form a cyclopropyl ring, wherein said ring is optionally substituted with hydroxy or halogen.
  • R 30 and R 31 together with the nitrogen atom to which they are attached form a cyclobutyl ring, wherein said ring is optionally substituted with hydroxy or halogen.
  • R 42 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl,
  • R 42 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine, chlorine, halogen, methyl, triflouro
  • R 43 is selected from the group consisting hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl
  • R 43 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine or hydroxy.
  • R 44 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyr
  • R 44 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl and isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine or hydroxy.
  • R 43 and R 44 together with the nitrogen atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl is optionally substituted with hydroxy or halogen.
  • R 43 and R 44 together with the nitrogen atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl is optionally substituted with hydroxy or halogen.
  • the compound of the invention is selected from the group consisting of N-(5- Hydroxy-adamantan-2-yl)-4-methanesulfonylmethoxy-benzamide, N-(5-Hydroxy-tricyclo- [3,3,l,l,3,7]decan-2-yl)-4-methanesulfonylmethoxy-N-methyl-benzamide, 4-(4-methane- sulfonylmethoxy-benzoylamino)- adamantane-1-carboxylic acid, N-(5-Hydroxy-adamantan-2- yl)-N-methyl-4- ⁇ 2-[l-(pyridine-2-sulfonyl)-piperidin-4-yl]-ethoxy ⁇ -benzamide, N-(5- hydroxy-adamantan-2-yl)-4- ⁇ 2-[l-(pyridine-2-sulfonyl)-piperidin-4-yl]-ethoxy
  • the compound of the invention 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 ll ⁇ HSDl is beneficial.
  • the compound of the invention is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
  • the compound of the invention 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.
  • the compound of the invention is an agent useful 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 compound of the invention is an agent useful for the delaying or prevention of the progression from IGT into type 2 diabetes.
  • the compound of the invention is an agent useful for delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
  • the compound of the invention is an agent useful for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, at least one compound according to the invention together with one ore more pharmaceutically acceptable carriers or excipients.
  • the invention relates to a pharmaceutical composition which is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration.
  • the invention relates to a pharmaceutical composition 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 the invention.
  • the invention relates to a use of a compound according to the invention 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 ll ⁇ HSDl is beneficial.
  • the invention relates to a use of a compound according to the invention 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.
  • the compounds according to the invention have a IC 50 value as tested as described under the heading "PHARMACOLOGICAL METHODS" below 100OnM, in a further aspect below 50OnM, in yet a further aspect below 300 nM and in yet a further aspect below 200 nM.
  • Some of 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, hydroxyl- naphthoates, glycerophosphate
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci., 66, 2 (1977), which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, barium, calcium, magnesium, zinc, calcium salts and the like.
  • amines and organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, butylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenyl- ethylamine, 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 methoxide, sodium hydride, potassium te/t-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 diastereo- meric 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, amino- acids, 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.
  • 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 administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances.
  • prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the present invention.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • esters for instance methyl esters, ethyl esters, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acyloxy- methyl esters.
  • esters for instance methyl esters, ethyl esters, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acyloxy- methyl esters.
  • 'modified compounds' for instance methyl esters, ethyl esters, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acyloxy- methyl esters.
  • the invention also encompasses active metabolites of the present compounds.
  • the compounds according to the invention alter, and more specifically, reduce the level of active intracellular glucocorticoid and are accordingly useful for the treatment, prevention and/or prophylaxis of disorders and diseases in which such a modulation or reduction is beneficial.
  • the present compounds may be applicable for the treatment, prevention and/or prophylaxis of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension, obesity, type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), Latent Autoimmune Diabetes in the Adult (LADA), type 1 diabetes, diabetic late complications including cardiovascular diseases, cardiovascular disorders, disorders of lipid metabolism, neurodegenerative and psychiatric disorders, dysregulation of intraocular pressure including glaucoma, immune disorders, inappropriate immune responses, musculoskeletal 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
  • 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, hyperinsulinemia, 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- /macroalbuminuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia, heart insufficiency, congestional
  • 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.
  • 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. myasthenia 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.g
  • glucocorticoid receptor agonists include trauma, postsurgical stress, surgical stress, renal transplantation, liver transplantation, lung transplant- tation, pancreatic islet transplantation, blood stem cell transplantation, bone marrow transplantation, heart transplantation, adrenal gland transplantation, tracheal transplanttation, intestinal transplantation, corneal transplantation, skin grafting, keratoplasty, lens implant- tation 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 lmg/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 ll ⁇ HSDl is beneficial.
  • the invention also relates to a method for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of ll ⁇ HSDl is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of any diseases and conditions that are influenced by intracellular glucocorticoid levels as mentioned above.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of conditions and disorders where a decreased level of active intracellular glucocorticoid is desirable, such as the conditions and diseases mentioned above.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of the metabolic syndrome including insulin resistance, dyslipidemia, hypertension and obesity.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
  • 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.
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of neurodegenerative and psychiatric disorders.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
  • the route of administration may be any route which effectively transports a compound according to the invention to the appropriate or desired site of action, such as oral, nasal, buccal, transdermal, 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 modifying the lipid metabolism, antihypertensive agents, glucocorticoid receptor agonists, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
  • the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.
  • Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotropin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, 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
  • the antiobesity agent is leptin; dexamphetamine or amphetamine; fenfluramine or dexfenfluramine; sibutramine; orlistat; mazindol or phentermine.
  • 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 A/S), e.g. Asp B28 human insulin, US 5,504,188 (EIi Lilly), e.g.
  • Lys B28 Pro 629 human insulin EP 368 187 (Aventis), eg Lantus, which are all incorporated herein by reference, GLP-I (glucagon like peptide-1) and GLP-I 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, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-I agonists, potas- sium 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
  • the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human insulin, Asp B28 human insulin, Lys B28 Pro 829 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 insulin, Asp B28 human insulin, Lys B28 Pro 829 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
  • the present compounds are administered in combination with a sulphonylurea e.g. tolbutamide, glibenclamide, glipizide or glicazide.
  • 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 compounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]- methoxy]phenyl-methyl]thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, preferably the potassium salt.
  • a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or compounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]- methoxy]phenyl-methyl]thiazolidine-2,4-dione or a
  • 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)eth- oxy]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 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, clofibrate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin, acipimox, probucol, ezetimibe or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofibrate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin,
  • the present compounds are administered in combination with more than one of the above-mentioned compounds e.g. in combination with a sulphonylurea 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.
  • ACE angiotensin converting enzyme
  • quinapril 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, ver
  • vasopressin V2 antagonists such as tolvaptan, SR-121463 and OPC-31260
  • B-type natriuretic peptide agonists e.g. Nesiritide, angiotensin II antagonists such as irbesartan, candesartancilexetil, losartan, valsartan, telmisartan, eprosartan, candesartan, CL-329167, eprosartan, iosartan, olmesartan, pratosartan, TA-606, and YM-358, 5-HT2 agonists e.g.
  • adenosine Al 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 Dl antagonists e.g. MYD-37
  • dopamine D2 agonists such as nolomirole, n-3 fatty acids e.g. omacor
  • prostacyclin agonists such as treprostinil, beraprost, PGEl 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, MondoBiotech-811.
  • the present compounds may be administered in combination with one or more glucocorticoid receptor agonists.
  • 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-4114, 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 pharmaceutically 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 active 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 sustained 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 sterile 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.
  • compositions 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 compounds 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.
  • 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.
  • a compounds 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.
  • 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, phosphor- lipids, 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.
  • 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 calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating 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-eneoxycetanol, 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., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, 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 triglycerides.
  • 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.
  • solvates may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the present invention.
  • a pharmaceutical composition comprising 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, excipients, 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:
  • 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.
  • the present invention also relates to the below methods of preparing the compounds of the invention.
  • Preparative HPLC Column: 1.9 x 15 cm Waters XTerra RP-18. Buffer: linear gradient 5 - 95 % MeCN in water over 15 min, 0.1 % TFA, flow rate of 15 ml/min. The pooled fractions are either evaporated to dryness in vacuo, or evaporated in vacuo until the MeCN is removed, and then frozen and freeze-dried.
  • ADDP l,l'-(Azodicarbonyl)dipiperidine
  • CDCI 3 Deuterio chloroform
  • Y is -X 1 -X 2 -X 3 -R 3 .
  • Y in above formulas is -X 1 -X 2 -X 3 -R 3 .
  • an acid (I) wherein R 4 and Y are defined as above to form the corresponding acid chloride by reaction with thionyl chloride, and then reacting the acid chloride with an amine (II) wherein R 2 is defined as above under basic conditions (e.g. triethyl amine, DIPEA, K 2 CO 3 and the like) in a solvent (DCM, DMF, THF, NMP and the like) affording amide (III) wherein R 2 , R 4 , and Y are defined as above.
  • Amines (II) are used as single isomers or as mixtures of two isomers; therefore amides (III) are isolated as mixtures of two isomers or as single isomers.
  • Y is -X 1 -X 2 -X 3 -R 3 .
  • a benzoic acid ester (II) wherein R is a Ci-C 4 alkyl and R 4 is defined as above under standard Mitsunobu conditions using a phosphine reagent (e.g. triphenyl- phosphine or tributylphosphine) together with a diazocarbonyl reagent (e.g. DEAD, DIAD, ADDP) in a solvent (e.g. THF, dioxane, DCM) followed by standard alkaline hydrolysis (using a strong base such as NaH, NaOH and the like) affording acid (III) wherein Y and R 4 are defined as above.
  • a phosphine reagent e.g. triphenyl- phosphine or tributylphosphine
  • a diazocarbonyl reagent e.g. DEAD, DIAD, ADDP
  • Lithium aluminium hydride (0.711 g, 0.018 mol) was added to a solution of (5-hydroxy- adamantan-2-yl)carbamic acid tert-butyl ester (1 g, 0.0037 mol) in THF (50 ml) at 0 0 C under a nitrogen atmosphere. The slurry was heated under reflux for 5h. It was then cooled to O 0 C and quenched with 30% NaOH solution (12 ml) and filtered. The filtrate was concentrated to give 2-methylaminoadamantan-5-ol as a white solid (0.6 g, 90%). LC-MS ⁇ m/z) : 181.9 (M+l).
  • N-Boc-4-(2-piperidin-4-yl-ethoxy)-benzoic acid ethyl ester /V-Boc-4-piperidine ethanol 15 g, 65 mmol
  • ethyl 4-hydroxybenzoate 11 g, 65 mmol
  • tri-n-butylphosphine 24 ml, 98 mmol
  • ADDP 25 g, 98 mmol
  • 2-Pyridinesulfonyl chloride (hydrochloride salt, 0.85 g, 4.0 mmol) was added to a solution of benzyl 4-(2-piperidin-4-yl-ethoxy)-benzoate (1.0 g, 2.7 mmol) and DIPEA (0.93 ml, 5.3 mmol) in DCM (20 ml), and the solution was stirred overnight at 20 0 C. Removal of the solvents and purification by flash chromatography (100% DCM ⁇ 10% EtOAc in DCM) provided the desired sulfonamide.
  • Acetyl chloride (0.39 ml, 5.4 mmol) was added to a 0 0 C solution of 4- methanesulfinylmethoxy-benzoic acid ethyl ester (1.2 g, 5.0 mmol) in DCM (40 ml). The temperature is allowed to rise to 20 0 C over a period of 2 h, and the solvent is removed to give 1.2 g of the title compound.
  • R 1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and cyclopropyl and R 2 is selected from the group consisting of a monovalent radical having one of the following formulae, wherein the symbol * denotes the point of attachment:
  • R 5 is selected from the group consisting of hydrogen, cyclopropyl and Ci-C 4 alkyl, wherein said cyclopropyl and Q-Qalkyl are optionally substituted with one or two independently selected
  • R 6 is selected from the group consisting of cyclopropyl and Ci-C 4 alkyl, wherein said cyclopropyl and Ci-C 4 alkyl are optionally substituted with one or two independently selected R 9 ; or R 5 and R 6 together with the nitrogen atom to which they are attached form a 4 to 6 membered ring optionally substituted with one or two independently selected R 9 ;
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, cyclopropyl and Ci-C 4 alkyl, wherein said cyclopropyl and Ci-C 4 alkyl are optionally substituted with one or two independently selected R 9 ; or R 7 and R 8 together with the nitrogen atom to which they are attached form a 4 to 6 membered ring optionally substituted with one or two independently selected R 9 ;
  • R 95 is selected from the group consisting of Ci-C 6 alkyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said Q-Csalkyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with one or two independently selected R 96 ;
  • R 97 is selected from the group consisting of hydrogen, cyclopropyl and Ci-C 4 alkyl;
  • R 9 is selected from the group consisting of hydrogen, CVQalkyl, cyclopropyl, hydroxy, halogen, trifluoromethyl, -CH 2 OH and carboxy;
  • R 10 and R 11 are each independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, -CH 2 OH, fluorine, isopropyl and cyclopropyl; or R 10 and R 11 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl is optionally substituted with hydroxy or fluorine;
  • R 22 and R 23 are each independently selected from the group consisting of hydrogen, halogen, Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl, wherein said Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R 22 and R 23 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen;
  • R 86 and R 87 are each independently selected from the group consisting of hydrogen, halogen, Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl, wherein said Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R 86 and R 87 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen;
  • R 88 and R 89 are each independently selected from the group consisting of hydrogen, halogen, Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl, wherein said Ci-C 6 alkyl and C 3 -Ci 0 cycloalkyl independently are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R 88 and R 89 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen;
  • NR 30 C( O)-NR 30 R 31 , -(CR 22 R 23 ) m -C 3 -C 10 heterocyclyl substituted with R 37 , -(CR 22 R 23 ) m - C 3 -C 10 - cycloalkyl substituted with R 38 , -(CR 22 R 23 ) m -aryl substituted with R 39 and R 40 , Q-Csalkyl-R 98 and -(CR 22 R 23 ) m -heteroaryl substituted with R 39 and R 40 ; m is 0 or 1;
  • R 15 , R 16 , R 20 , R 21 , R 24 , R 25 and R 45 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, C 3 -Ci 0 heterocyclyl, C 3 -Ci 0 cycloalkyl, aryl and heteroaryl, wherein said Ci-C 6 alkyl, C 3 -Ci 0 heterocyclyl, C 3 -Ci 0 cycloalkyl, aryl and heteroaryl are optionally substituted independently with one, two or three independently selected R 41 ;
  • R 17 , R 18 and R 19 are each independently selected from the group consisting of hydrogen, Ci-Csalkyl, C 3 -C 10 cycloalkyl, phenyl and heteroaryl, wherein said CVCsalkyl, C 3 -C 10 cycloalkyl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, ethyl and hydroxy; or R 17 and R 18 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said ring are optionally substituted with hydroxy, trifluoromethyl or halogen;
  • R 28 , R 29 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 R 98 and R 40 are each independently selected from the group consisting of hydrogen, C 1 -C 6 SIkYl, phenyl, heteroaryl and C 3 -C 10 cycloalkyl, wherein said Ci-C 6 alkyl, phenyl, heteroaryl and C 3 -Ci 0 cycloalkyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, triflouromethyl, methoxy and hydroxy;
  • R 30 and R 31 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said Ci-C 6 alkyl, tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy, or R 30 and R 31 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said ring is optionally substituted with hydroxy or halogen;
  • R 42 is selected from the group consisting of hydrogen, d-Qalkyl, C 3 -C 10 cycloalkyl, aryl and heteroaryl, wherein said Ci-C 6 alkyl, C 3 -Ci 0 cycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, triflouromethyl, methoxy and hydroxy;
  • R 43 and R 44 are each independently selected from the group consisting of hydrogen
  • Ci-C 6 alkyl, C 3 -Ci 0 heterocyclyl, C 3 -Ci 0 cycloalkyl and heteroaryl wherein said Ci-C 6 alkyl, C 3 - C 10 heterocyclyl, C 3 -C 10 cycloalkyl and heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy, or R 43 and R 44 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl is optionally substituted with hydroxy or halogen;
  • any optical isomer or mixture of optical isomers including a racemic mixture, or any tautomeric forms.
  • R 2 is selected from the group consisting of:
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, wherein said methyl, ethyl and cyclopropyl optionally are substituted with one or two independently selected R 9 .
  • R 5 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl.
  • R 6 is selected from the group consisting of methyl, ethyl and cyclopropyl, wherein said ethyl and cyclopropyl optionally are substituted with one or two independently selected R 9 .
  • R 6 is selected from the group consisting of methyl, ethyl and cyclopropyl.
  • R 7 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, wherein said methyl, ethyl and cyclopropyl is optionally substituted with one or two independently selected R 9 .
  • R 8 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl.
  • R 95 is selected from the group consisting of methyl, ethyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said methyl, ethyl, phenyl, pyridinyl, pyrimidinvl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with one or two independently selected R 96 .
  • R 95 is selected from the group consisting of methyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said methyl, phenyl, pyridinyl, pyrimidinvl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with R 96 .
  • R 95 is selected from the group consisting of methyl, phenyl, pyridinyl, pyrimidinvl, cyclopropyl, cyclobutyl and cyclohexyl.
  • R 96 is selected from the group consisting of fluorine, chlorine, hydroxy and trifluoromethyl.
  • R 97 is selected from the group consisting of methyl, ethyl and cyclopropyl.
  • R 9 is selected from the group consisting of hydrogen, methyl, cyclopropyl, hydroxy, halogen, trifluoromethyl, - CH 2 OH and carboxy.
  • R 9 is selected from the group consisting of hydrogen, methyl, cyclopropyl, hydroxy, fluorine, chlorine and trifluoromethyl.
  • R 10 is selected from the group consisting of hydrogen, hydroxy, methyl, fluorine, isopropyl and cyclopropyl.
  • R 3 is selected from the group consisting of C 3 -Ci 0 heterocyclyl substituted with R 13 and R 14 , C 3 -Ci 0 cycloalkyl substituted with R 13 and R 14 , aryl substituted with R 13 and R 14 , heteroaryl substituted with R 13 and R 14 .
  • R 3 is selected from the group consisting of with R 13 substituted imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
  • R 13 is selected from the group consisting of -(CR 22 R 23 ) m -C 3 -C 10 heterocyclyl substituted with R 37 and R 38 , -(CR 22 R 23 ) m - C 3 -C 10 cycloalkyl substituted with R 37 and R 38 , -(CR 22 R 23 ) m -aryl substituted with R 39 and R 40 , Ci-Csalkyl-R 98 and -(CR 22 R 23 ) m -heteroaryl substituted with R 39 and R 40 .
  • R 13 is selected from the group consisting of C 3 -Ci 0 heterocyclyl substituted with R 37 , C 3 -Ci 0 cycloalkyl substituted with R 37 , aryl substituted with R 39 , Ci-C 6 alkyl-R 98 and heteroaryl substituted with R 39 .
  • R 13 is selected from the group consisting of with R 37 substituted tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
  • R 14 is selected from the group consisting of -(CR 22 R 23 ) m -C 3 -C 10 heterocyclyl substituted with R 37 and R 38 , - (CR 22 R 23 ) m -C 3 -C 10 cycloalkyl substituted with R 37 and R 38 , -(CR 22 R 23 ) m -aryl substituted with R 39 and R 40 , Q-Csalkyl-R 98 and -(CR 22 R 23 ) m -heteroaryl substituted with R 39 and R 40 .
  • R 14 is selected from the group consisting of C 3 -Ci 0 heterocyclyl substituted with R 37 , C 3 -Ci 0 cycloalkyl substituted with R 37 , aryl substituted with R 39 , Ci-C 6 alkyl-R 98 and heteroaryl substituted with R 39 .
  • R 22 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, isopropyl, cyclobutyl and cyclopropyl wherein said cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
  • R 23 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, isopropyl, cyclobutyl and cyclopropyl wherein said cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
  • R 86 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
  • R 86 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
  • R 87 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
  • R 87 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
  • R 88 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
  • R 88 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
  • R 89 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
  • R 26 is selected from the group consisting of hydrogen, C 3 -Ci 0 heterocyclyl substituted with R 37 , C 3 -C 10 cycloalkyl substituted with R 38 , phenyl substituted with R 39 and R 40 , CrCsalkyl-R 98 and heteroaryl substituted with R 39 and R 40 .
  • R 26 selected from the group consisting of substituted with R 39 imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
  • R 27 is selected from the group consisting of hydrogen, C 3 -Ci 0 heterocyclyl substituted with R 37 , C 3 -C 10 cycloalkyl substituted with R 38 , phenyl substituted with R 39 and R 40 , Ci-Csalkyl-R 98 and heteroaryl substituted with R 39 and R 40 .
  • R 15 , R 16 , R 20 , R 21 , R 24 , R 25 and R 45 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl,
  • R 15 , R 16 , R 20 , R 21 , R 24 , R 25 and R 45 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridazinyl, pyrazinyl pyrimidinyl, wherein said ethyl
  • R 17 , R 18 and R 19 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, methyl, ethyl, isopropyl, cyclo
  • R 17 , R 18 and R 19 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine, chlorine, methyl or
  • R 28 , R 29 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 R 98 and R 40 are each independently selected from the group consisting of hydrogen, Ci-C 6 alkyl, heteroaryl and C 3 -Ci 0 cycloalkyl, wherein said Ci-C 6 alkyl, heteroaryl and C 3 -Ci 0 cycloalkyl are optionally substituted with halogen, methyl, triflouromethyl, methoxy or hydroxy.
  • R 28 , R 29 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 R 98 and R 40 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrol id iny I, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyrany
  • R 28 , R 29 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 R 98 and R 40 are each independently selected from the group consisting of hydrogen, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyridazinyl,
  • R 30 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, isopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said methyl, ethyl, cyclopropyl, isopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with halogen or hydroxy.
  • R 30 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl and isopropyl, wherein said ethyl, cyclopropyl and isopropyl are optionally substituted with halogen or hydroxy.
  • R 31 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, isopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said methyl, cyclopropyl, isopropyl tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with halogen or hydroxy.
  • R 31 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl and isopropyl, wherein said ethyl, cyclopropyl and isopropyl are optionally substituted with halogen or hydroxy.
  • R 42 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl,
  • R 42 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine, chlorine, halogen
  • R 43 is selected from the group consisting hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, methyl, ethyl, isopropyl,
  • R 43 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine or hydroxy
  • R 44 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, methyl, ethyl, isopropyl
  • R 44 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl and isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine or hydroxy.
  • a compound according to any one of the above 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 ll ⁇ HSDl is beneficial.
  • ITT impaired glucose tolerance
  • IGF impaired fasting glucose
  • a pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the clauses 1-182 together with one ore more pharmaceutically acceptable carriers or excipients.
  • composition according to clause 183 which is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration.
  • composition according to clause 183 or 184 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 1-175.
  • IGT impaired glucose tolerance
  • IGF impaired fasting glucose
  • 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 ll ⁇ HSDl is beneficial comprising administering to a subject in need thereof an effective amount of a compound according to any of the clauses 1-182.

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Abstract

Novel substituted benzamide based inhibitors, their use in therapy, pharmaceutical compositions comprising the compounds, the use of said compounds in the manufacture of medicaments, and therapeutic methods comprising the administration of said compounds are described. The present compounds modulate the activity of 11β -hydroxysteroid dehydrogenase type 1 (11βHSD1) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.

Description

N-ADAMANTYL BENZAMIDES AS INHIBITORS OF 11-BETA-HYDROXYSTEROID DEHYDROGENASE
The present invention relates to novel substituted benzamide based inhibitors, to their use in therapy, to pharmaceutical compositions comprising the compounds, to the use of said compounds in the manufacture of medicaments, and to therapeutic methods comprising the administration of said compounds. The present compounds modulate the activity of llβ- hydroxysteroid dehydrogenase type 1 (llβHSDl) 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 characterised by a combination of insulin resistance, dyslipidemia, obesity and hypertension leading to increased morbidity and mortality of cardiovascular diseases. People with the metabolic syndrome are at increased risk of developing frank type 2 diabetes, the prevalence of which is equally escalating.
In type 2 diabetes, obesity and dyslipidemia are also highly prevalent and around 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.
llβ-hydroxysteroid dehydrogenase type 1 (llβHSDl) 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, llβHSDl 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, 140, 3188 (1999); Whorwood et al., J
Clin Endocrinol Metab., 86, 2296 (2001); Cooper et al., Bone, T∑, 375 (2000); Davani et al., J. Biol. Chem., 225, 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 llβHSDl in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence. In humans, treatment with the non-specific llβHSDl inhibitor carben- oxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes. Likewise, llβHSDl 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 llβHSDl in adipocytes develop insulin resistance, hyperlipidemia and visceral obesity, a phenotype that resembles the human metabolic syndrome (Andrews et al., J. Clin. 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. Sci. USA, 94, 14924 (1997); Masuzaki et al., Science, 294, 2166 (2001)).
The more mechanistic aspects of llβHSDl modulation and thereby modulation of intra- cellular levels of active glucocorticoid have been investigated in several rodent models and different cellular systems. llβHSDl promotes the features of the metabolic syndrome by increasing hepatic expression of the rate-limiting enzymes in gluconeogenesis, namely phosphoenolpyuvate carboxykinase and glucose-6-phosphatase, promoting the differentiation of preadipocytes into adipocytes thus facilitating obesity, directly and indirectly stimulating hepatic VLDL secretion, decreasing hepatic LDL uptake and increasing vessel contractility
(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 llβ-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 2004/089470 discloses various substituted amides and the use thereof for stimulating llβ- hydroxysteroid dehydrogenase type 1. WO 2004/089415 and WO 2004/089416 discloses various combination therapies using an llβ-hydroxysteroid dehydrogenase type 1 inhibitor and respectively a glucocorticoid receptor agonist or an antihypertensive agent.
We have now found new substituted benzamide based inhibitors that modulate the activity of llβHSDl leading to altered intracellular concentrations of active glucocorticoid. More specifically, the present compounds inhibit the activity of llβHSDl 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. One object of the present invention is to provide compounds, pharmaceutical compositions and use of compounds that modulate the activity of llβHSDl.
DEFINITIONS
The term "monovalent radical" shall mean a chemical group attached via a single bond.
The term "halogen" or "halo" means fluorine, chlorine, bromine or iodine.
The term "hydroxy" shall mean the radical -OH.
The term "carboxy" shall mean the radical -(C=O)OH.
The term "Ci-C6alkyl" as used herein represents a saturated, branched or straight hydrocarbon group having from 1 to 6 carbon atoms, e.g. Ci-C2alkyl, Ci-C3alkyl, Ci-C.4alkyl, Ci-C6alkyl, C2-C6alkyl, C3-C6alkyl, 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-l-yl, but-2-yl), pentyl (e.g. pent-1-yl, pent-2-yl, pent-3-yl), 2-methylbut-l-yl, 3- methylbut-1-yl, hexyl (e.g. hex-l-yl), and the like. The term "Ci-Qalkyl" as used herein represents a saturated, branched or straight hydrocarbon group having from 1 to 4 carbon atoms, e.g. Ci-C2alkyl, Ci-C3alkyl, Ci-C.4alkyl, 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-l-yl, but-2-yl), and the like.
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 "C3-C10cycloalkyl" as used herein represents a saturated monocyclic carbocyclic ring having from 3 to 10 carbon atoms, e.g. C3.6-alkyl, C3.8-alkyl, C3.i0-alkyl, and the like. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. C3-Ci0cycloalkyl 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. C3-Ci0cycloalkyl is also intended to represent a saturated carbocyclic ring having from 3 to 10 carbon atoms and containing one or two carbon bridges. Representative examples are adamantyl, norbornanyl, nortricyclyl, bicyclo[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. C3-Ci0cycloalkyl 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 "aryl" as used herein is intended to include monocyclic, bicyclic or polycyclic 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 polycyclic 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.l-phenylnaphth-2-yl, 2-phenylnaphth-l-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), indenyl (e.g. inden-1-yl, inden-5-yl), 1,2,3,4-tetrahydronaphthyl (e.g. 1,2,3,4-tetrahydronaphth-l-yl, l,2,3,4-tetrahydronaphth-2-yl, l,2,3,4-tetrahydronaphth-6- yl), 1,2-dihydronaphthyl (e.g. 1,2-dihydronaphth-l-yl, l,2-dihydronaphth-4-yl, 1,2- dihydronaphth-6-yl), fluorenyl (e.g. fluoren-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), l,4-ethano-l,2,3,4-tetrahydronapthyl (e.g. 1,4- ethano-l,2,3,4-tetrahydronapth-2-yl,l,4-ethano-l,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. Representative examples are spiro[cyclo- pentane-l,l'-indane]-4-yl, spiro[cyclopentane-l,l'-indene]-4-yl, spiro[piperidine-4,l'- indane]-l-yl, spiro[piperidine-3,2'-indane]-l-yl, spiro[piperidine-4,2'-indane]-l-yl, spiro[piperidine-4,l'-indane]-3'-yl, spiro[pyrrolidine-3,2'-indane]-l-yl, spiro[pyrrolidine-3,l'- (3',4'-dihydronaphthalene)]-l-yl, spiro[piperidine-3,l'-(3',4'-dihydronaphthalene)]-l-yl, spiro[piperidine-4,l'-(3',4'-dihydronaphthalene)]-l-yl, spiro[imidazolidine-4,2'-indane]-l-yl, spiro[piperidine-4,l'-indene]-l-yl, and the like. The term "C3-C10heterocyclyl" as used herein represents a saturated 3 to 10 membered monocyclic ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2. Representative examples are aziridinyl (e.g. aziridin-1-yl), azetidinyl (e.g. azetidin-1-yl, azetidin-3-yl), oxetanyl, pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), imidazolidinyl (e.g. imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl), oxazolidinyl (e.g. oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl), thiazolidinyl (e.g. thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl), isothiazolidinyl, piperidinyl (e.g. piperidin- 1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), homopiperidinyl (e.g. homopiperidin-1-yl, homopiperidin-2-yl, homopiperidin-3-yl, homopiperidin-4-yl), piperazinyl (e.g. piperazin-1-yl, piperazin-2-yl), morpholinyl (e.g. morpholin-2-yl, morpholin-3-yl, morpholin-4-yl), thio- morpholinyl (e.g. thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl), 1-oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, tetrahydrofuranyl (e.g. tetrahydrofuran-2-yl, tetrahydrofuran-3-yl), tetrahydrothienyl, tetrahydro-l,l-dioxothienyl, tetrahydropyranyl (e.g. 2-tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 2-tetrahydrothiopyranyl), 1,4-dioxanyl, 1,3-dioxanyl, and the like. C3-Ci0heterocyclyl is also intended to represent a saturated 6 to 10 membered bicyclic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2. Representative examples are octahydroindolyl (e.g. octahydroindol-1-yl, octahydroindol-2-yl, octahydroindol-3-yl, octahydroindol-5-yl), decahydroquinolinyl (e.g. decahydroquinolin-1-yl, decahydroquinolin-2-yl, decahydroquinolin- 3-yl, decahydroquinolin-4-yl, decahydroquinolin-6-yl), decahydroquinoxalinyl (e.g. decahydroquinoxalin-1-yl, decahydroquinoxalin-2-yl, decahydroquinoxalin-6-yl) and the like. C3-Ci0heterocyclyl is also intended to represent a saturated 6 to 10 membered ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2 and having one or two bridges. Representative examples are 3-azabicyclo- [3.2.2]nonyl, 2-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.0]hexyl, 2,5-diazabicyclo-
[2.2.1]heptyl, atropinyl, tropinyl, quinuclidinyl, l,4-diazabicyclo[2.2.2]octanyl, and the like. C3-Ci0heterocyclyl is also intended to represent a 6 to 10 membered saturated ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, S(=O) and S(=O)2 and containing one or more spiro atoms. Representative examples are 1,4- dioxaspiro[4.5]decanyl (e.g. l,4-dioxaspiro[4.5]decan-2-yl, l,4-dioxaspiro[4.5]decan-7-yl), l,4-dioxa-8-azaspiro[4.5]decanyl (e.g. l,4-dioxa-8-azaspiro[4.5]decan-2-yl, l,4-dioxa-8- azaspiro[4.5]decan-8-yl), 8-azaspiro[4.5]decanyl (e.g. 8-azaspiro[4.5]decan-l-yl, 8- azaspiro[4.5]decan-8-yl), 2-azaspiro[5.5]undecanyl (e.g. 2-azaspiro[5.5]undecan-2-yl), 2,8- diazaspiro[4.5]decanyl (e.g. 2,8-diazaspiro[4.5]decan-2-yl, 2,8-diazaspiro[4.5]decan-8-yl), 2,8-diazaspiro[5.5]undecanyl (e.g. 2,8-diazaspiro[5.5]undecan-2-yl), 1,3,8- triazaspiro[4.5]decanyl (e.g. l,3,8-triazaspiro[4.5]decan-l-yl, l,3,8-triazaspiro[4.5]decan-3- yl, l,3,8-triazaspiro[4.5]decan-8-yl), and the like. The term "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, pyrazol-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, l,2,3-triazol-4-yl, l,2,3-triazol-5-yl), 1,2,4-triazolyl (e.g. 1,2,4-triazol-l-yl, l,2,4-triazol-3-yl, l,2,4-triazol-5-yl), 1,2,3-oxadiazolyl (e.g. l,2,3-oxadiazol-4-yl, 1,2,3- oxadiazol-5-yl), 1,2,4-oxadiazolyl (e.g. l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl), 1,2,5- oxadiazolyl (e.g. l,2,5-oxadiazol-3-yl, l,2,5-oxadiazol-4-yl), 1,3,4-oxadiazolyl (e.g. 1,3,4- oxadiazol-2-yl, l,3,4-oxadiazol-5-yl), 1,2,3-thiadiazolyl (e.g. l,2,3-thiadiazol-4-yl, 1,2,3- thiadiazol-5-yl), 1,2,4-thiadiazolyl (e.g. l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl), 1,2,5- thiadiazolyl (e.g. l,2,5-thiadiazol-3-yl, l,2,5-thiadiazol-4-yl), 1,3,4-thiadiazolyl (e.g. 1,3,4- thiadiazol-2-yl, l,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, thiadiazinyl, azepinyl, azecinyl, and the like. 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-l-yl, benzo[c]pyran-7-yl), benzimidazolyl (e.g. benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzothiazolyl (e.g. benzothiazol- 2-yl, benzothiazol-5-yl), benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl (e.g. l,8-naphthyridin-2-yl, l,7-naphthyridin-2-yl, 1,6- naphthyridin-2-yl), phthalazinyl (e.g. phthalazin-1-yl, phthalazin-5-yl), pteridinyl, purinyl (e.g. purin-2-yl, purin-6-yl, purin-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), isoquinolinyl (e.g. isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin- 4-yl), quinoxalinyl (e.g. quinoxalin-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, imidazo[l,5-a]pyridinyl, imidazo[l,2- a]pyridinyl), imidazopyrimidinyl (e.g. imidazo[l,2-a]pyrimidinyl, imidazo[3,4-a]pyrimidinyl), pyrazolopyridinyl (e.g. pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[l,5- a]pyridinyl), pyrazolopyrimidinyl (e.g. pyrazolo[l,5-a]pyrimidinyl, pyrazolo[3,4-d]pyrimi- dinyl), thiazolopyridinyl (e.g. thiazolo[3,2-d]pyridinyl), thiazolopyrimidinyl (e.g. thiazolo[5,4- d]pyrimidinyl), imdazothiazolyl (e.g. imidazo[2,l-b]thiazolyl), triazolopyridinyl (e.g. triazolo- [4,5-b]pyridinyl), triazolopyrimidinyl (e.g. 8-azapurinyl), and the like. 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), phenol- thiazinyl (e.g. phenothiazin-10-yl), carbolinyl (e.g. pyrido[3,4-b]indol-l-yl, pyrido[3,4- b]indol-3-yl), phenanthrolinyl (e.g. phenanthrolin-5-yl), and the like. 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, imidazolinyl (e.g. 4,5- dihydroimidazol-2-yl, 4,5-dihydroimidazol-l-yl), indolinyl (e.g. 2,3-dihydroindol-l-yl, 2,3- dihydroindol-5-yl), dihydrobenzofuranyl (e.g. 2,3-dihydrobenzo[b]furan-2-yl, 2,3-dihydro- benzo[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-l-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-tetrahydroindazol-l-yl, 4,5,6,7-tetrahydroindazol-3-yl, 4,5,6,7-tetrahydro- indazol-4-yl, 4,5,6,7-tetrahydroindazol-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-tetrahydroimidazo[4,5-c]pyrid-l-yl, 4,5,6,7-tetrahydroimidazo[4,5- c]pyrid-5-yl, 4,5,6,7-tetrahydroimidazo[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. 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,l'-cyclohexan]-l- yl, spiro[piperidine-4,l'-benzo[c]thiophen]-l-yl, spiro[piperidine-4,l'-benzo[c]furan]-l-yl, spiro[piperidine-4,3'-benzo[b]furan]-l-yl, spiro[piperidine-4,3'-coumarin]-l-yl, and the like.
The term "monocyclic heteroaryl" as used herein is intended to include monocyclic heterocyclic aromatic rings as defined above. The term "bicyclic heteroaryl" as used herein is intended to include bicyclic heterocyclic aromatic rings as defined above.
The term "4 to 6 membered ring" as used herein represents a saturated 4 to 6 membered monocyclic ring, containing one nitrogen and it might contain a further heteroatom selected from oxygen, sulfur, S(=O) and S(=O)2 and it is intended to include pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl), piperidinyl (e.g. piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl), morpholinyl (e.g. morpholin-2-yl, morpholin-3-yl, morpholin-4- yl), thiomorpholinyl (e.g. thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl), 1-oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, aziridinyl (e.g. aziridin-1-yl), azetidinyl (e.g. azetidin-1-yl, azetidin-3-yl), azetidine and the like.
Certain of the 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.
SUMMARY OF THE INVENTION
In one aspect of the invention substituted benzamide based inhibitors that modulate the activity of llβHSDl leading to altered intracellular concentrations of active glucocorticoid are provided. More specifically, the present compounds inhibit the activity of llβHSDl 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.
One object of the present invention is to provide compounds, pharmaceutical compositions and use of compounds that modulate the activity of llβHSDl.
The present invention furthermore relates to the use in therapy of the compounds according to the invention, to pharmaceutical compositions comprising the compounds, to the use of said compounds in the manufacture of medicaments, and to therapeutic methods comprising the administration of said compounds.
DETAILED DESCRIPTION OF THE INVENTION
The invention provides for a compound of the general formula (I) :
Figure imgf000010_0001
(I)
wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and cyclopropyl and R2 is selected from the group consisting of a monovalent radical having one of the following formulae, wherein the symbol * denotes the point of attachment:
Figure imgf000010_0002
Figure imgf000010_0004
Figure imgf000010_0003
Q is selected from the group consisting of hydroxy, -S(=O)2NR5R6, -CH2OH, -C(CH3)HOH, - C(CH3)2OH, 1-cyclopropanol, -0-CH2CH2-OH and -C(=O)NR7R8;
R5 is selected from the group consisting of hydrogen, cyclopropyl and Ci-C4alkyl, wherein said cyclopropyl and Ci-C4alkyl are optionally substituted with one or two independently selected R9;
R6 is selected from the group consisting of cyclopropyl and Ci-C4alkyl, wherein said cyclopropyl and Q-Qalkyl are optionally substituted with one or two independently selected R9; or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 6 membered ring optionally substituted with one or two independently selected R9;
R7 and R8 are each independently selected from the group consisting of hydrogen, cyclopropyl and Ci-C4alkyl, wherein said cyclopropyl and Ci-C4alkyl are optionally substituted with one or two independently selected R9; or R7 and R8 together with the nitrogen atom to which they are attached form a 4 to 6 membered ring optionally substituted with one or two independently selected R9;
R4 is selected from the group consisting of hydrogen, Ci-C4alkyl, cyclopropyl, trifluoromethyl, halogen, -S(=O)2methyl, -CH2OH, -O-cyclopropyl and -O-Ci-C4alkyl, wherein said cyclopropyl, Ci-C4alkyl, -O-cyclopropyl and -O-Ci-C4alkyl are optionally substituted with R9;
R95 is selected from the group consisting of Ci-C6alkyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said Q-Csalkyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with one or two independently selected R96;
R96 is selected from the group consisting of halogen, hydroxy, trifluoromethyl, methyl, cyclopropyl, carboxy and -S(=O)2methyl;
R97 is selected from the group consisting of hydrogen, cyclopropyl and Ci-C4alkyl;
R9 is selected from the group consisting of hydrogen, Q-Qalkyl, cyclopropyl, hydroxy, halogen, trifluoromethyl, -CH2OH and carboxy;
X1 is selected from the group consisting of -CR10R11-, -O-, -S-, -S(=O)- and -S(=O)2-;
X2 is selected from the group consisting of -CR86R87-, -O-, -S-, -S(=O)-, -S(=O)2- and -NR24-; X3 is selected from the group consisting of -CR88R89-, -O-, -S-, -S(=O)-, -S(=O)2- and -NR25-;
R10 and R11 are each independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, -CH2OH, fluorine, isopropyl and cyclopropyl; or R10 and R11 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl is optionally substituted with hydroxy or fluorine;
R3 is selected from the group consisting of Ci-C4alkyl substituted with R13 and R14, C3- C10heterocyclyl substituted with R13 and R14, C3-C10cycloalkyl substituted with R13 and R14, aryl substituted with R13 and R14, heteroaryl substituted with R13 and R14, -C(=O)R15, -CH(OH)R16, -(CR22R23)π-C(=O)-NR17R18, -(CR22R23)π-NR19C(=O)R20, -(CR22R23)π-OR21, -(CR22R23)π-SR21 , - (CR22R23)π-S(=O)2R24, -(CR22R23)π-S(=O)2NR17R18, -(CR22R23)π-NR17S( = O)2R25, -(CR22R23V NR17R18, -(CR22R23)π-NR17C(=O)-NR17R18, -(CR22R23VC=CR45R26 and -(CR22R23)π-C≡C-R27;
n is selected from the group consisting of O, 1 and 2;
R13 and R14 are each independently selected from the group consisting of hydrogen, hydroxy, halogen, -C(=O)OH, -C(=O)R28, -CH(OH)-R29, -(CR22R23)m-C(=O)-NR30R31, - (CR22R23)m-NR30C(=O)R28, -(CR22R23)m-OR32, -(CR22R23)m-SR32, -(CR22R23)m-S(=O)2R33, - (CR22R23)m-S( = O)2NR30R31, -(CR22R23)m-NR30S(=O)2R33, -(CR22R23)m-NR30R31, -(CR22R23)m- NR30C(=O)-NR30R31, -(CR22R23VC=CR34R35, -(CR22R23)m-C≡C-R36, -(CR22R23VC3- C10heterocyclyl substituted with R37 and R38, -(CR22R23)m-C3-C10cycloalkyl substituted with R37 and R38, -(CR22R23)m-aryl substituted with R39 and R40, CrQalkyl-R98 and -(CR22R23V heteroaryl substituted with R39 and R40;
R22 and R23 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl and C3-Ci0cycloalkyl, wherein said Ci-C6alkyl and C3-Ci0cycloalkyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R22 and R23 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen;
R86 and R87 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl and C3-Ci0cycloalkyl, wherein said Ci-C6alkyl and C3-Ci0cycloalkyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R86 and R87 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen; R88 and R89 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl and C3-Ci0cycloalkyl, wherein said Ci-C6alkyl and C3-Ci0cycloalkyl independently are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R88 and R89 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen;
R26 and R27 are each independently selected from the group consisting of hydrogen, -(CR22- R23)m-CO-NR30R31, -(CR22R23)m-NR30C(=O)R28, -(CR22R23)m-OR32, -(CR22R23)m-SR32, -(CR22- R23)m-S(=O)2R33, -(CR22R23)m-S(=O)2NR30R31, -(CR22R23)m-NR30S(=O)2R33, -(CR22R23)m- NR30C(=O)-NR30R31, -(CR22R23)m-C3-C10heterocyclyl substituted with R37, -(CR22R23)m-
C3-C10cycloalkyl substituted with R38, -(CR22R23)m-aryl substituted with R39 and R40, d-C6alkyl- R98 and -(CR22R23)m-heteroaryl substituted with R39 and R40;
m is 0 or 1;
R15, R16, R20, R21, R24, R25 and R45 are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, C3-Ci0heterocyclyl, C3-Ci0cycloalkyl, aryl and heteroaryl, wherein said Ci-C6alkyl, C3-Ci0heterocyclyl, C3-Ci0cycloalkyl, aryl and heteroaryl are optionally substituted independently with one, two or three independently selected R41;
R17, R18 and R19 are each independently selected from the group consisting of hydrogen, Ci-Csalkyl, C3-C10cycloalkyl, phenyl and heteroaryl, wherein said Q-Csalkyl, C3-C10cycloalkyl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, ethyl and hydroxy; or R17 and R18 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said ring are optionally substituted with hydroxy, trifluoromethyl or halogen;
R28, R29, R32, R33, R34, R35, R36, R37, R38, R39 R98 and R40 are each independently selected from the group consisting of hydrogen, Q-Csalkyl, phenyl, heteroaryl and C3-C10cycloalkyl, wherein said Ci-Csalkyl, phenyl, heteroaryl and C3-C10cycloalkyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, triflouromethyl, methoxy and hydroxy;
R30 and R31 are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said Ci-C6alkyl, tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy, or R30 and R31 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said ring is optionally substituted with hydroxy or halogen;
R41 is selected from the group consisting of halogen, hydroxy, oxo, -C(=O)OH, -S(=O)2R42, - S-NR43R44, -SC=O)2NR43R44, cyclopropyl, trifluoromethyl, -OR42, -SR42, d-C6alkyl, -C(=O)- NR43R44, -NR43C(=O)NR44R43; -NR43S(=O)2R42 and -N(C=O)R42;
R42 is selected from the group consisting of hydrogen, Ci-C6alkyl, C3-Ci0cycloalkyl, aryl and heteroaryl, wherein said d-C6alkyl, C3-C10cycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, triflouromethyl, methoxy and hydroxy;
R43 and R44 are each independently selected from the group consisting of hydrogen,
Ci-C6alkyl, C3-Ci0heterocyclyl, C3-Ci0cycloalkyl and heteroaryl, wherein said Ci-C6alkyl, C3- Cioheterocyclyl, C3-Ci0cycloalkyl and heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy, or R43 and R44 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl is optionally substituted with hydroxy or halogen;
or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
The following aspects refer to compounds that fall within the scope of Formula I:
In one aspect, R1 is hydrogen.
In one aspect, R1 is methyl.
In one aspect, R1 is ethyl.
In one aspect, R1 is isopropyl.
In one aspect, R1 is cyclopropyl.
In one aspect, R2 is selected from the group consisting of:
Figure imgf000015_0001
In one aspect, R2 is selected from the group consisting of
Figure imgf000015_0002
In one aspect, R2 is
Figure imgf000015_0003
In one aspect, R 2 : i,s
Figure imgf000015_0004
In one aspect, R is
Figure imgf000015_0005
In one aspect, R 2 : i,s
Figure imgf000016_0001
In one aspect, R is
Figure imgf000016_0002
In one aspect, Q is selected from the group consisting of hydroxy, -S(=O)2NR5R6, -CH2OH, - C(CH3)HOH, -C(CH3)2OH, 1-cydopropanol, -0-CH2CH2-OH and -C(=O)NR7R8.
In one aspect, Q is hydroxy.
In one aspect, Q is -S(=O)2NR5R6.
In one aspect, Q is -CH2OH.
In one aspect, Q is -C(CH3)HOH.
In one aspect, Q is 1-cyclopropanol.
In one aspect, Q is -C(=O)NR7R8.
In one aspect, Q is -C(CH3)2OH.
In one aspect, Q is -0-CH2CH2-OH.
In one aspect, R5 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, wherein said methyl, ethyl and cyclopropyl optionally are substituted with one or two independently selected R9.
In one aspect, R5 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl. In one aspect, R6 is selected from the group consisting of methyl, ethyl and cyclopropyl, wherein said ethyl and cyclopropyl optionally are substituted with one or two independently selected R9.
In one aspect, R6 is selected from the group consisting of methyl, ethyl and cyclopropyl.
In one aspect, R5 and R6 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl ring, which ring is optionally substituted with one or two independently selected R9.
In one aspect, R5 and R6 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl ring.
In one aspect, R7 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, wherein said methyl, ethyl and cyclopropyl are optionally substituted with one or two independently selected R9.
In one aspect, R7 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl.
In one aspect, R8 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, wherein said methyl, ethyl and cyclopropyl are optionally substituted with one or two independently selected R9.
In one aspect, R8 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl.
In one aspect, R7 and R8 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl ring, which ring is optionally substituted with one or two independently selected R9.
In one aspect, R7 and R8 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl ring.
In one aspect, R4 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, trifluoromethyl, fluorine, chlorine, -S(=O)2methyl, -CH2OH, -O- cyclopropyl and -O-methyl, wherein said methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, - S(=O)2methyl, -O-cyclopropyl and -O-methyl are optionally substituted with R9. In one aspect, R4 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, trifluoromethyl, fluorine, chlorine, -S(=O)2methyl, -CH2OH, -O- cyclopropyl and -O-methyl.
In one aspect, R4 is selected from the group consisting of hydrogen, methyl, trifluoromethyl, fluorine, chlorine, -S(=O)2methyl, -CH2OH, -O-cyclopropyl and -O-methyl.
In one aspect, R95 is selected from the group consisting of methyl, ethyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said methyl, ethyl, phenyl, pyridinyl, pyrimidinvl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with one or two independently selected R96.
In one aspect, R95 is selected from the group consisting of methyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said methyl, phenyl, pyridinyl, pyrimidinvl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with R96.
In one aspect, R95 is selected from the group consisting of methyl, phenyl, pyridinyl, pyrimidinvl, cyclopropyl, cyclobutyl and cyclohexyl.
In one aspect, R96 is selected from the group consisting of fluorine, chlorine, hydroxy, trifluoromethyl, carboxy and -S(=O)2methyl.
In one aspect, R96 is selected from the group consisting of fluorine, chlorine, hydroxy and trifluoromethyl.
In one aspect, R97 is hydrogen.
In one aspect, R97 is C1-C4SIkVl.
In one aspect, R97 is selected from the group consisting of methyl, ethyl and cyclopropyl.
In one aspect, R9 is selected from the group consisting of hydrogen, methyl, cyclopropyl, hydroxy, halogen, trifluoromethyl, -CH2OH and carboxy.
In one aspect, R9 is selected from the group consisting of hydrogen, methyl, cyclopropyl, hydroxy, fluorine, chlorine and trifluoromethyl.
In one aspect, X1 is -CR10R11-. In one aspect, X1 is -O-.
In one aspect, X1 is -S-.
In one aspect, X1 is -S(=O)-.
In one aspect, X1 is -S(=O)2-.
In one aspect, X2 is -CR86R87-
In one aspect, X is -O-.
In one aspect, X2 is -S-.
In one aspect, X2 is -S(=O)-.
In one aspect, X2 is -S(=O)2-.
In one aspect, X2 is -NR24-.
In one aspect, X3 is -CR88R89-
In one aspect, X3 is -Cl¬
in one aspect, X3 is -S-.
In one aspect, X3 is -S(=O)-.
In one aspect, X3 is -S(=O)2-.
In one aspect, X3 is -NR25-.
In one aspect, -X1-X2-X3- is selected from the group consisting of -O-CR86R87-CR88R89- and O-CR86R87-S(=O)2-.
In one aspect, -X1-X2-X3- is selected from the group consisting of -S-CR86R87-CR88R89-, - S(=O)2-NR24-CR88R89- and -S(=O)2-CR86R87-CR88R89-. In one aspect, -X1^-X3- is selected from the group consisting of -R10Rn-CR86R87-S(=O)2-,
CR l1100RRnn--CCRR8866RR8877--SS--,, --CCRR1100RRnn--CCRR8866RR8877--OO--,, -CR10Rn-CR86R87-NR25-, -CR10Rn-CR86R87-CR88R89-, CR10Rn-S(=O)2-NR25- and -CR10Rn-NR24-S(=O)2-.
In one embodiment, -X1-X2-X3-R3 does not comprise one or more rings selected from the group consisting of phenyl, biphenyl, benzocyclobutenyl, benzocycloheptanyl, benzosuberenyl, indenyl, 2,3-dihydroindenyl, fluorenyl, 1,2-dihydronaphthyl, 5,6,7,8- tetrahydronaphthyl or naphthyl.
In one aspect, R10 is selected from the group consisting of hydrogen, hydroxy, methyl, fluorine, isopropyl and cyclopropyl.
In one aspect, R10 is selected from the group consisting of hydrogen, hydroxy, methyl and fluorine.
In one aspect, R11 is selected from the group consisting of hydrogen, hydroxy, methyl, fluorine, isopropyl and cyclopropyl.
In one aspect, R11 is selected from the group consisting of hydrogen, hydroxy, methyl and fluorine.
In one aspect, R10 and R11 together with the carbon atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl is optionally substituted with hydroxy or fluorine.
In one aspect, R10 and R11 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl is optionally substituted with hydroxy or fluorine.
In one aspect R3 is selected from the group consisting of C3-C10heterocyclyl substituted with R13 and R14, C3-Ci0cycloalkyl substituted with R13 and R14, aryl substituted with R13 and R14, heteroaryl substituted with R13 and R14, -C(=O)R15, -CH(OH)R16, -(CR22R23)π-C(=O)-NR17R18, -(CR22R23)π-NR19C(=O)R20, -(CR22R23VOR21, -(CR22R23VSR21 , -(CR22R23)π-S( = O)2R24, - (CR22R23)π-S(=O)2NR17R18, -(CR22R23)π-NR17S(=O)2R25, -(CR22R23VNR17R18, -(CR22R23V NR17C(=O)-NR17R18, -(CR22R23VC=CR45R26 and -(CR22R23)π-C≡C-R27;
In one aspect, R3 is selected from the group consisting of Ci-C4alkyl substituted with R13 and R14, C3-Cioheterocyclyl substituted with R13 and R14, C3-Ci0cycloalkyl substituted with R13 and R14, aryl substituted with R13 and R14, and heteroaryl substituted with R13 and R14. In one aspect, R3 is selected from the group consisting of C3-C10heterocyclyl substituted with R13 and R14, C3-C10cycloalkyl substituted with R13 and R14, aryl substituted with R13 and R14, and heteroaryl substituted with R13 and R14.
In one aspect, R3 is selected from the group consisting of -C(=O)R15, -CH(OH)R16, -(CR22- R23)π-C(=O)-NR17R18, -(CR22R23)π-NR19C(=O)R20, -(CR22R23)π-OR21, -(CR22R23)π-SR21 , -(CR22- R23)π-S(=O)2R24, -(CR22R23)π-S( = O)2NR17R18, -(CR22R23)π-NR17S(=O)2R25, -(CR22R23)π-NR17R18, -(CR22R23)π-NR17C(=O)-NR17R18, -(CR22R23)π-C=CR45R26 and -(CR22R23)π-C≡C-R27.
In one aspect, n is 1.
In one aspect, n is 2.
In one aspect, R3 is selected from the group consisting of -C(=O)R15, -C(=O)-NR17R18, - NR19C(=O)R20, -OR21, -SR21 , -S(=O)2R24, -S(=O)2NR17R18, -NR17S(=O)2R25, -NR17C( = O)- NR17R18 and -C≡C-R27.
In one aspect, R3 is selected from the group consisting of C3-Ci0heterocyclyl substituted with R13, C3-Ci0cycloalkyl substituted with R13, aryl substituted with R13 and heteroaryl substituted with R13.
In one aspect, R3 is selected from the group consisting of with R13 substituted tetrahydro- pyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
In one aspect, R3 is selected from the group consisting of with R13 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.
In one aspect, R3 is phenyl substituted with R13.
In one aspect, R3 is selected from the group consisting of with R13 substituted imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
In one aspect, R13 is selected from the group consisting of hydrogen, hydroxy, halogen, - C( = O)OH, -C( = O)R28, -CH(OH)-R29, -(CR22R23)m-C(=O)-NR30R31, -(CR22R23)m-NR30C(=O)R28, -(CR22R23)m-OR32, -(CR22R23)m-SR32, -(CR22R23)m-S( = O)2R33, -(CR22R23)m-S(=O)2NR30R31, - (CR22R23)m-NR30S( = O)2R33, -(CR22R23)m-NR30R31, -(CR22R23)m-NR30C(=O)-NR30R31, - (CR22R23)m-C=CR34R35 and -(CR22R23)m-C≡C-R36. In one aspect, R13 is selected from the group consisting of -(CR22R23)m-C3-C10heterocyclyl substituted with R37 and R38, -(CR22R23)m-C3-C10cycloalkyl substituted with R37 and R38, - (CR22R23)m-aryl substituted with R39 and R40, Q-Csalkyl-R98 and -(CR22R23)m-heteroaryl substituted with R39 and R40.
In one aspect, R13 is selected from the group consisting of hydrogen, hydroxy, halogen, - C( = O)R28, -C( = O)-NR30R31, -NR30C(=O)R28, -OR32, -SR32, -S( = O)2R33, -S( = O)2NR30R31, - NR30S(=O)2R33, -NR30CC=O)-NR30R31, -C=CR34R35 and -C≡C-R36.
In one aspect, R13 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, -C(=O)R28, -C(=O)-NR30R31, -NR30C(=O)R28, -OR32, -S(=O)2R33, -S(=O)2NR30R31, - NR30S(=O)2R33 and -NR30C(=O)-NR30R31.
In one aspect, R13 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, methyl, trifluoromethyl, acetyl, -C(=O)-N-isopropyl, -NHC(=O)methyl, - NHC(=O)isopropyl, -O-methyl, -O-isopropyl, -O-cyclopropyl, -S(=O)2methyl, - S(=O)2cyclopropyl, -S(=O)2NH-methyl, -S(=O)2NH-isopropyl, -NHS(=O)2methyl, - NHS(=O)2cyclopropyl, -NHC(=O)NH-methyl and -NHC(=O)NH-isopropyl.
In one aspect, R13 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, methyl, trifluoromethyl, acetyl, -O-isopropyl, -O-cyclopropyl, -S(=O)2methyl and - S(=O)2cyclopropyl.
In one aspect, R13 is selected from the group consisting of C3-Ci0heterocyclyl substituted with R37, C3-C10cycloalkyl substituted with R37, aryl substituted with R39, Q-Csalkyl-R98 and heteroaryl substituted with R39.
In one aspect, R13 is C3-C10heterocyclyl substituted with R37.
In one aspect, R13 is selected from the group consisting of with R37 substituted tetrahydro- pyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
In one aspect, R13 is C3-Ci0cycloalkyl substituted with R37
In one aspect, R13 is selected from the group consisting of with R37 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.
In one aspect, R13 is aryl substituted with R39. In one aspect, R13 is phenyl substituted with R39.
In one aspect, R13 is Ci-C6alkyl-R98.
In one aspect, R13 is selected from the group consisting of with R98 substituted methyl, ethyl and isopropyl.
In one aspect, R13 is heteroaryl substituted with R39.
In one aspect, R13 is selected from the group consisting of with R39 substituted imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
In one aspect, R14 is selected from the group consisting of hydrogen, hydroxy, halogen, - C( = O)OH, -C( = O)R28, -CH(OH)-R29, -(CR22R23)m-C(=O)-NR30R31, -(CR22R23)m-NR30C(=O)R28, -(CR22R23)m-OR32, -(CR22R23)m-SR32, -(CR22R23)m-S( = O)2R33, -(CR22R23)m-S(=O)2NR30R31, - (CR22R23)m-NR30S( = O)2R33, -(CR22R23)m-NR30R31, -(CR22R23)m-NR30C(=O)-NR30R31, - (CR22R23)mC=CR34R35 and -(CR22R23)m-C≡C-R36.
In one aspect, R14 is selected from the group consisting of -(CR22R23)m-C3-Ci0heterocyclyl substituted with R37 and R38, -(CR22R23)m-C3-C10cycloalkyl substituted with R37 and R38, - (CR22R23)m-aryl substituted with R39 and R40, Q-Csalkyl-R98 and -(CR22R23)m-heteroaryl substituted with R39 and R40.
In one aspect, R14 is selected from the group consisting of hydrogen, hydroxy, halogen, - C( = O)R28, -C( = O)-NR30R31, -NR30CC=O)R28, -OR32, -SR32, -S( = O)2R33, -S( = O)2NR30R31, - NR30SC=O)2R33, -NR30CC=O)-NR30R31, -C=CR34R35 and -C≡C-R36.
In one aspect, R14 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, -C(=O)R28, -C(=O)-NR30R31, -NR30C(=O)R28, -OR32, -S(=O)2R33, -S(=O)2NR30R31, - NR30S(=O)2R33 and -NR30C(=O)-NR30R31.
In one aspect, R14 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, methyl, trifluoromethyl, acetyl, -C(=O)-N-isopropyl, -NHC(=O)metyhyl, - NHC(=O)isopropyl, -O-methyl, -O-isopropyl, -O-cyclopropyl, -S(=O)2methyl, -
S(=O)2cyclopropyl, -S(=O)2NH-methyl, -S(=O)2NH-isopropyl, -NHS(=O)2methyl, - NHS(=O)2cyclopropyl, -NHC(=O)NH-methyl and -NHC(=O)NH-isopropyl. In one aspect, R14 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, methyl, trifluoromethyl, acetyl, -O-isopropyl, -O-cyclopropyl, -S(=O)2methyl and - S(=O)2cyclopropyl.
In one aspect, R14 is selected from the group consisting of C3-Ci0heterocyclyl substituted with R37, C3-Ciocycloalkyl substituted with R37, aryl substituted with R39, Ci-C6alkyl-R98 and heteroaryl substituted with R39.
In one aspect, R14 is C3-C10heterocyclyl substituted with R37.
In one aspect, R14 is selected from the group consisting of with R37 substituted tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
In one aspect, R14 is C3-Ci0cycloalkyl substituted with R37
In one aspect, R14 is selected from the group consisting of with R37 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.
In one aspect, R14 is aryl substituted with R39.
In one aspect, R14 is phenyl substituted with R39.
In one aspect, R14 is Ci-Csalkyl-R98.
In one aspect, R14 is selected from the group consisting of with R98 substituted methyl, ethyl and isopropyl.
In one aspect, R14 is heteroaryl substituted with R39.
In one aspect, R14 is hydrogen.
In one aspect, R14 is selected from the group consisting of with R39 substituted imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
In one aspect, R22 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, isopropyl, cyclobutyl and cyclopropyl wherein said cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy. In one aspect, R22 is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.
In one aspect, R23 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, isopropyl, cyclobutyl and cyclopropyl wherein said cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
In one aspect, R23 is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.
In one aspect, R22 and R23 together with the carbon atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl ring is optionally substituted with hydroxy or fluorine.
In one aspect, R22 and R23 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl ring is optionally substituted with hydroxy or fluorine.
In one aspect, R86 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
In one aspect, R86 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
In one aspect, R87 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
In one aspect, R87 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
In one aspect, R86 and R87 together with the carbon atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl are optionally substituted with hydroxy or fluorine. In one aspect, R86 and R87 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl are optionally substituted with hydroxy or fluorine.
In one aspect, R88 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
In one aspect, R88 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
In one aspect, R89 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
In one aspect, R89 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
In one aspect, R88 and R89 together with the carbon atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl are optionally substituted with hydroxy or fluorine.
In one aspect, R88 and R89 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl are optionally substituted with hydroxy or fluorine.
In one aspect, R26 is selected from the group consisting of hydrogen, C3-C10heterocyclyl substituted with R37, C3-C10cycloalkyl substituted with R38, phenyl substituted with R39 and R40, Ci-Csalkyl-R98 and heteroaryl substituted with R39 and R40.
In one aspect, R26 is hydrogen.
In one aspect, R26 selected from the group consisting of with R37 substituted tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
In one aspect, R26 selected from the group consisting of with R38 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl substituted with R38.
In one aspect, R26 is phenyl substituted with R39. In one aspect, R26 selected from the group consisting of with R98 substituted methyl, ethyl and isopropyl.
In one aspect, R26 selected from the group consisting of substituted with R39 imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
In one aspect, R27 is selected from the group consisting of hydrogen, C3-Ci0heterocyclyl substituted with R37, C3-Ci0cycloalkyl substituted with R38, phenyl substituted with R39 and R40, CrCsalkyl-R98 and heteroaryl substituted with R39 and R40.
In one aspect, R27 is hydrogen.
In one aspect, R27 selected from the group consisting of with R37 substituted tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
In one aspect, R27 selected from the group consisting of with R38 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.
In one aspect, R27 is phenyl substituted with R39.
In one aspect, R27 selected from the group consisting of with R98 substituted methyl, ethyl and isopropyl.
In one aspect, R27 selected from the group consisting of substituted with R39 imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
In one aspect, m is 0.
In one aspect, m is 1.
In one aspect, R15, R16, R20, R21, R24, R25 and R45 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with R41. In one aspect, R15, R16, R20, R21, R24, R25 and R45 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with R41.
In one aspect, R17, R18 and R19 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine, chlorine, trifluoromethyl, methyl or hydroxy.
In one aspect, R17, R18 and R19 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine, chlorine, methyl or hydroxy.
In one aspect, R17 and R18 together with the nitrogen atom to which they are attached form a cyclopropyl ring, wherein said ring are optionally substituted with hydroxy or halogen.
In one aspect, R17 and R18 together with the nitrogen atom to which they are attached form a cyclobutyl ring, wherein said ring are optionally substituted with hydroxy or halogen.
In one aspect, R28, R29, R32, R33, R34, R35, R36, R37, R38, R39 R98 and R40 are each independently selected from the group consisting of hydrogen, Q-Qalkyl, heteroaryl and C3-C10cycloalkyl, wherein said C1-QaIkYl, heteroaryl and C3-C10cycloalkyl are optionally substituted with halogen, methyl, triflouromethyl, methoxy or hydroxy.
In one aspect, R28, R29, R32, R33, R34, R35, R36, R37, R38, R39 R98 and R40 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl are optionally substituted with halogen, methyl, triflouromethyl, methoxy or hydroxy.
In one aspect, R28, R29, R32, R33, R34, R35, R36, R37, R38, R39 R98 and R40 are each independently selected from the group consisting of hydrogen, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl are optionally substituted with halogen, methyl, triflouromethyl, methoxy or hydroxy.
In one aspect, R30 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, isopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said methyl, ethyl, cyclopropyl, isopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with halogen or hydroxy.
In one aspect, R30 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl and isopropyl, wherein said ethyl, cyclopropyl and isopropyl are optionally substituted with halogen or hydroxy.
In one aspect, R31 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, isopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said methyl, cyclopropyl, isopropyl tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with halogen or hydroxy.
In one aspect, R31 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl and isopropyl, wherein said ethyl, cyclopropyl and isopropyl are optionally substituted with halogen or hydroxy.
In one aspect, R30 and R31 together with the nitrogen atom to which they are attached form a cyclopropyl ring, wherein said ring is optionally substituted with hydroxy or halogen.
In one aspect, R30 and R31 together with the nitrogen atom to which they are attached form a cyclobutyl ring, wherein said ring is optionally substituted with hydroxy or halogen.
In one aspect, R41 is selected from the group consisting of fluorine, chlorine, hydroxy, oxo, - C(=O)OH, -S(=O)2methyl, -S(=O)2NH-isopropyl, -S(=O)2NH-cyclopropyl, trifluoromethyl, - S(=O)2NH-methyl, cyclopropyl, -O-methyl, methyl, ethyl, isopropyl, -C(=O)NH-methyl, - NHC(=O)NH-methyl; -NHS(=O)2methyl and -N(C=O)methyl. In one aspect, R41 is selected from the group consisting of fluorine, chlorine, trifluoromethyl, hydroxy, oxo, -C(=O)OH, -S(=O)2methyl, -S(=O)2NH-isopropyl, -S(=O)2NH-methyl, cyclopropyl, methyl, isopropyl, -C(=O)NH-methyl, -NHC(=O)NH-methyl; -NHS(=O)2methyl and -N(C=O)methyl.
In one aspect, R42 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, are optionally substituted with one or two substituents independently selected from the group consisting of halogen, methyl, triflouromethyl, methoxy and hydroxy.
In one aspect, R42 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine, chlorine, halogen, methyl, triflouromethyl or hydroxy.
In one aspect, R43 is selected from the group consisting hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy.
In one aspect, R43 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine or hydroxy.
In one aspect, R44 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy.
In one aspect, R44 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl and isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine or hydroxy.
In one aspect, R43 and R44 together with the nitrogen atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl is optionally substituted with hydroxy or halogen.
In one aspect, R43 and R44 together with the nitrogen atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl is optionally substituted with hydroxy or halogen.
In one aspect, the compound of the invention is selected from the group consisting of N-(5- Hydroxy-adamantan-2-yl)-4-methanesulfonylmethoxy-benzamide, N-(5-Hydroxy-tricyclo- [3,3,l,l,3,7]decan-2-yl)-4-methanesulfonylmethoxy-N-methyl-benzamide, 4-(4-methane- sulfonylmethoxy-benzoylamino)- adamantane-1-carboxylic acid, N-(5-Hydroxy-adamantan-2- yl)-N-methyl-4-{2-[l-(pyridine-2-sulfonyl)-piperidin-4-yl]-ethoxy}-benzamide, N-(5- hydroxy-adamantan-2-yl)-4-{2-[l-(pyridine-2-sulfonyl)-piperidin-4-yl]-ethoxy}-benzamide, 4-(2-{4-[(5-Hydroxy-adamantan-2-yl)-methyl-carbamoyl]-phenoxy}-ethyl)-piperidine-l- carboxylic acid isopropylamide, 4-{2-[4-(5-Hydroxy-adamantan-2-ylcarbamoyl)-phenoxy]- ethyl}-piperidine-l-carboxylic acid isopropylamide, N-(5-Hydroxy-tricyclo[3.3.1.1.3.7]decan- 2-yl)-N-methyl-4-phenethyloxy-benzamide, N-(5-Hydroxy-tricyclo[3.3.1.1.3.7]decan-2-yl)-4- phenethyloxy-benzamide, 4-{2-[l-(2-Hydroxy-2-methyl-propionyl)-piperidin-4-yl]-ethoxy}- N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide, 4-{2-[l-(3-Hydroxy-2,2-dimethyl- propionyl)-piperidin-4-yl]-ethoxy}-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide, 4- {2-[l-(3-Hydroxy-2,2-dimethyl-propionyl)-piperidin-4-yl]-ethoxy}-N-(5-hydroxy-adaman- tan-2-yl)-benzamide, N-(5-Hydroxy-tricyclo[3.3.1.1.3.7]decan-2-yl)-N-methyl-4-(2-phenyl- ethanesulfonylmethoxy)-benzamide, 4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-N-(5-hydroxy- tricyclo[3.3.1.13,7]decan-2-yl)-N-methyl-benzamide, N-(5-Hydroxy-adamantan-2-yl)-N- methyl-4-[2-(tetrahydro-pyran-4-yl)-ethoxy]-benzamide, N-(5-Hydroxy-adamantan-2-yl)-4- [2-(tetrahydro-pyran-4-yl)-ethoxy]-benzamide, 4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-N-(5- hydroxy-adamantan-2-yl)-benzamide, N-(5-Hydroxy-adamantan-2-yl)-4-(pyridine-2- sulfonylmethoxy)-benzamide, and N-(5-Hydroxy-tricyclo[3.3.1.1.3.7]decan-2-yl)-N-methyl- 4-(pyridine-2-sulfonylmethoxy)-benzamide.
In one embodiment the compound of the invention 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 llβHSDl is beneficial.
In one embodiment the compound of the invention is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
In one embodiment the compound of the invention 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.
In one embodiment the compound of the invention is an agent useful for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
In one embodiment the compound of the invention is an agent useful for the delaying or prevention of the progression from IGT into type 2 diabetes.
In one embodiment the compound of the invention is an agent useful for delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
In one embodiment the compound of the invention is an agent useful for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
In one aspect, the invention relates to a pharmaceutical composition comprising, as an active ingredient, at least one compound according to the invention together with one ore more pharmaceutically acceptable carriers or excipients.
In one aspect, the invention relates to a pharmaceutical composition which is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration. In one aspect, the invention relates to a pharmaceutical composition 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 the invention.
In one aspect, the invention relates to a use of a compound according to the invention 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 llβHSDl is beneficial.
In one aspect, the invention relates to a use of a compound according to the invention 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.
In one aspect of the invention, the compounds according to the invention have a IC50 value as tested as described under the heading "PHARMACOLOGICAL METHODS" below 100OnM, in a further aspect below 50OnM, in yet a further aspect below 300 nM and in yet a further aspect below 200 nM.
Some of 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, hydroxyl- naphthoates, glycerophosphates, ketoglutarates and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable 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, butylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenyl- ethylamine, 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 methoxide, sodium hydride, potassium te/t-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 diastereo- meric 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 Resolution" (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, amino- acids, 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; 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 administration 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 invention, 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, tert-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acyloxy- methyl 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, prevention 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, musculoskeletal 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.
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, hyperinsulinemia, 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- /macroalbuminuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia, heart insufficiency, congestional heart failure, stroke, myocardial infarction, arrythmia, decreased blood flow, erectile dysfunction (male or female), myopathy, loss of muscle tissue, muscle wasting, muscle catabolism, osteoporosis, decreased linear growth, neurodegenerative 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 other 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 syndrome, systemic lupus erythematosus, lupus nephritis, Henoch-Schόnlein 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. myasthenia 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, postsurgical stress, surgical stress, renal transplantation, liver transplantation, lung transplant- tation, pancreatic islet transplantation, blood stem cell transplantation, bone marrow transplantation, heart transplantation, adrenal gland transplantation, tracheal transplanttation, intestinal transplantation, corneal transplantation, skin grafting, keratoplasty, lens implant- tation 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 lmg/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 llβHSDl is beneficial.
The invention also relates to a method for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of llβHSDl 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 diseases 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 desirable, 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 appropriate 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 modifying the lipid metabolism, antihypertensive agents, glucocorticoid receptor agonists, agents for the treatment and/or prevention of complications resulting from or associated with diabetes and agents for the treatment and/or prevention of complications and disorders resulting from or associated with obesity.
Thus, in a further aspect of the invention the present compounds may be administered in combination with one or more antiobesity agents or appetite regulating agents.
Such agents may be selected from the group consisting of CART (cocaine amphetamine regulated transcript) agonists, NPY (neuropeptide Y) antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (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-I 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 phentermine.
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 A/S), e.g. AspB28 human insulin, US 5,504,188 (EIi Lilly), e.g. LysB28 Pro629 human insulin, EP 368 187 (Aventis), eg Lantus, which are all incorporated herein by reference, GLP-I (glucagon like peptide-1) and GLP-I 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, biguanides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-I agonists, potas- sium 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 insulin, AspB28 human insulin, LysB28 Pro829 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 compounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl]- 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)eth- oxy]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, clofibrate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, atorvastatin, 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 sulphonylurea 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, barnidipine, 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 torasemide) 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 Vl 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 II antagonists such as irbesartan, candesartancilexetil, losartan, valsartan, telmisartan, eprosartan, candesartan, CL-329167, eprosartan, iosartan, olmesartan, pratosartan, TA-606, and YM-358, 5-HT2 agonists e.g. fenoldopam and ketanserin, adenosine Al 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 Dl antagonists e.g. MYD-37, dopamine D2 agonists such as nolomirole, n-3 fatty acids e.g. omacor, prostacyclin agonists such as treprostinil, beraprost, PGEl 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, MondoBiotech-811.
Further reference can be made to Remington: The Science and Practice of Pharmacy, 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-4114, RU-24858 and T-25 series.
It should be understood that any suitable combination of the compounds according to the invention with one or more of the above-mentioned compounds and optionally one or more further pharmacologically active substances are considered to be within the scope of the present invention.
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 pharmaceutically 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 active ingredient chosen.
Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules. 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 sustained 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 sterile 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 administration. 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 compounds 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 compounds 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, phosphor- lipids, 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 calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating 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-eneoxycetanol, 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 sucrose 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 excipients, 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 triglycerides. 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 comprising 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, excipients, 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
AmberliteβIRP88* 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.
The present invention also relates to the below methods of preparing the compounds of the invention.
The features disclosed in the foregoing description may, both separately and in any combination thereof, be material for realising the invention in diverse forms thereof.
All references, including publications, patent applications and patents, cited herein are hereby incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.
All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.
Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly con- tradicted by context.
The terms "a" and "an" and "the" and similar referents as used in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Unless otherwise stated, all exact values provided herein are representative of corresponding approximate values (e.g., all exact exemplary values provided with respect to a particular factor or measurement can be considered to also provide a corresponding approximate measurement, modified by "about," where appropriate).
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.
The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise indicated. No language in the specification should be construed as indicating any element is essential to the practice of the invention unless as much is explicitly stated.
The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability and/or enforceability of such patent documents,
The description herein of any aspect or embodiment of the invention using terms such as "comprising", "having", "including" or "containing" with reference to an element or elements is intended to provide support for a similar aspect or embodiment of the invention that
"consists of", "consists essentially of", or "substantially comprises" that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a formulation described herein as comprising a particular element should be understood as also describing a formulation consisting of that element, unless otherwise stated or clearly contradicted by context).
This invention includes all modifications and equivalents of the subject matter recited in the aspects or claims presented herein to the maximum extent permitted by applicable law.
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 examples and 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 examples. 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 reactions 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. 1H NMR shifts (δH) are given in parts per million (ppm) downfield from tetramethylsilane as internal reference standard. M. p. is melting point and is given in 0C and uncorrected. 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 analyses are performed using 5μm C18 4 x 250 mm column eluted with various mixtures of water and acetonitrile, flow = 1 ml/min, as described in the experimental section.
Preparative HPLC: Column: 1.9 x 15 cm Waters XTerra RP-18. Buffer: linear gradient 5 - 95 % MeCN in water over 15 min, 0.1 % TFA, flow rate of 15 ml/min. The pooled fractions are either evaporated to dryness in vacuo, or evaporated in vacuo until the MeCN is removed, and then frozen and freeze-dried.
The abbreviations as used in the examples have the following meaning :
ADDP: l,l'-(Azodicarbonyl)dipiperidine
CDCI3: Deuterio chloroform
DCM : Dichloromethane DEAD : l,l'-Diethyl azodicarboxylate
DIAD : l,l'-Disopropyl azodicarboxylate
DIC: N,N'-Diisopropylcarbodiimide
DMAP: 4-Dimethylaminopyridine
DMF: N,N-Dimethylformamide DMSO-d6: Hexadeuterio dimethylsulfoxide
DMSO: Dimethylsulfoxide DIPEA: Diisopropylethylamine
EDC: l-CB-Dimethylaminopropylj-B-ethylcarbodiimide hydrochloride
EtOAc: Ethyl acetate
EtOH : Ethanol
HOBT: 1-Hydroxy-benzotriazole hrs: hours
MCPBA: meta-Chloroperbenzoic acid
MeCN : Acetonitrile min : minutes
NMP: N-Methylpyrrolidinone
TEA: Triethylamine
TFA: Trifluoroacetic acid
THF: Tetrahydrofuran
TLC: Thin layer chromatography
General method A:
coupling reagent
R2NH, solvent
Figure imgf000052_0001
Figure imgf000052_0002
In above formulas, Y is -X1-X2-X3-R3. By allowing an acid (I) wherein R4 and Y are defined as above to be coupled with an amine (II) wherein R2 is defined as above under standard amide bond forming conditions using a coupling reagent (e.g. HOBT, EDC and DIPEA in dry DMF) affording amide (III) wherein R2, R4, and Y are defined as above. Amines (II) are used as single isomers or as mixtures of two isomers; therefore amides (III) are isolated as mixtures of two isomers or as single isomers.
General method B:
Figure imgf000052_0003
Y in above formulas is -X1-X2-X3-R3. By allowing an acid (I) wherein R4 and Y are defined as above to form the corresponding acid chloride by reaction with thionyl chloride, and then reacting the acid chloride with an amine (II) wherein R2 is defined as above under basic conditions (e.g. triethyl amine, DIPEA, K2CO3 and the like) in a solvent (DCM, DMF, THF, NMP and the like) affording amide (III) wherein R2, R4, and Y are defined as above. Amines (II) are used as single isomers or as mixtures of two isomers; therefore amides (III) are isolated as mixtures of two isomers or as single isomers.
Alternatively, the acid chloride corresponding to acid (I) wherein R4 and Y are defined as above can be used directly to react with amine (II) wherein R2 is defined as above under similar basic conditions.
General method C:
Figure imgf000053_0001
In above formulas Y is -X1-X2-X3-R3. By allowing an alcohol (I) wherein Y is defined as above to be coupled with a benzoic acid ester (II) wherein R is a Ci-C4alkyl and R4 is defined as above under standard Mitsunobu conditions using a phosphine reagent (e.g. triphenyl- phosphine or tributylphosphine) together with a diazocarbonyl reagent (e.g. DEAD, DIAD, ADDP) in a solvent (e.g. THF, dioxane, DCM) followed by standard alkaline hydrolysis (using a strong base such as NaH, NaOH and the like) affording acid (III) wherein Y and R4 are defined as above.
Compound Molecule LC-MS (m/z)
l\l-(5-Hydroxy- adamantan-2-yl)-4- methanesulfonylmethoxy- benzamide
Figure imgf000053_0002
Figure imgf000054_0001
methyl-benzamide
408
Figure imgf000054_0002
acid
l\l-(5-Hydroxy- adamantan-2-y I)-N- methyl-4-{2-[l- 554
(pyπdιne-2-sulfonyl)- (M+)
Figure imgf000054_0003
pιpeπdιn-4-yl]-ethoxy}- benzamide
l\l-(5-Hydroxy- adamantan-2-yl)-4-{2-
[l-(pyπdιne-2-sulfonyl)- pιpeπdιn-4-yl]-ethoxy}-
Figure imgf000054_0004
benzamide
4-(2-{4-[(5-Hydroxy- adamantan-2-yl)-methyl- carbamoyl]-phenoxy}- ethyl)-pιpeπdιne-l-
Figure imgf000054_0005
carboxyhc acid isopropylamide
4-{2-[4-(5-Hydroxy- adamantan-2- ylcarbamoyl)-phenoxy]- 484.2 ethyl}-pιpeπdιne-l- (M+H) carboxyhc acid
Figure imgf000054_0006
isopropylamide
N-(5-Hydroxy- m/z 406 7 tπcyclo[3 3 1 1 3 7]decan-2- ( M+1 ) yl)-N-methyl-4-phenethyloxy-
Figure imgf000054_0007
benzamide N-(5-Hydroxy- tπcyclo[3 3 1 1 3 7]decan-2- m/z 392,6 yl)-4-phenethyloxy-
Figure imgf000055_0001
( M+1 ) benzamide
4-{2-[l-(2-Hydroxy-2- methyl-propionyl)- pιpeπdιn-4-yl]-ethoxy}- 500
N-(5-hydroxy-
Figure imgf000055_0002
(M + 1) adamantan-2-y I)-N- methyl-benzamide
4-{2-[l-(3-Hydroxy-2,2- dimethyl-propionyl)- pιpeπdιn-4-yl]-ethoxy}- 514
Figure imgf000055_0003
N-(5-hydroxy- (M + 1) adamantan-2-y I)-N- methyl-benzamide
4-{2-[l-(3-Hydroxy-2,2- dimethyl-propionyl)- pιpeπdιn-4-yl]-ethoxy}- 499.8
N-(5-hydroxy- (M+H) adamantan-2-yl)-
Figure imgf000055_0004
benzamide
N-(5-Hydroxy- tπcyclo[3 3 1 1 3 7]decan-2- yl)-N-methyl-4-(2-phenyl- ethanesulfonylmethoxy)- benzamide
Figure imgf000055_0005
4-[2-(5-Ethyl-pyπdιn-2- yl)-ethoxy]-N-(5- hydroxy- 436 tπcyclo[3.3.1.13,7]decan-
Figure imgf000055_0006
(M + 1)
2-yl)-N-methyl- benzamide N-(5-Hydroxy- adamantan-2-y I)-N- methyl-4-[2-(tetrahydro- l) pyran-4-yl)-ethoxy]-
Figure imgf000056_0001
benzamide
l\l-(5-Hydroxy- adamantan-2-yl)-4-[2- 400,8 (tetrahydro-pyran-4-yl)- (M + l) ethoxy]-benzamιde
Figure imgf000056_0002
4-[2-(5-Ethyl-pyπdιn-2- yl)-ethoxy]-Λ/-(5- hydroxy-adamantan-2- yl)-benzamιde
Figure imgf000056_0003
Λ/-(5-Hydroxy- adamantan-2-yl)-4-
(pyπdιne-2- sulfonylmethoxy)-
Figure imgf000056_0004
benzamide
N-(5-Hydroxy- tπcyclo[3 3 1 1 3 7]decan-2- yl)-N-methyl-4-(pyπdιne-2- sulfonylmethoxy)-benzamιde
Figure imgf000056_0005
Example 1
4-Amino-l-hydroxyadamantane
Prepared as described in Tetrahedron 1968, 24, 5369 Example 2
4-Amino-adamantane-l-carboxylic acid methyl ester 4-Oxo-adamantane-l-carboxylic acid methyl ester (6.5 g, 31.2 mmol) (prepared following J. Org. Chem. 1983, 48, 1101) was dissolved in MeOH (75 ml). To this solution was added 10% Pd-C (Ig) followed by ammonium formate (10 g, 158 mmol). The reaction mixture was heated under reflux for Ih after which it was cooled to ambient temperature and filtered through hyflo bed. The clear filtrate was concentrated under reduced pressure and the residue was diluted with water and extracted with EtOAc. The aqueous layer was separated, basified with 10% NaOH solution and extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulphate and solvent removed under reduced pressure to give 4-aminoadamantane-l-carboxylic acid methyl ester (5g, 77%). LC-MS (m/z) \ 210 (M + l).
Example 3
(5-Hydroxyadamantan-2-yl)carbamic acid tert-butyl ester
Ammonium formate (10 g, 0.15 mol) was added to a solution of 5-hydroxyadamantan-2-one (4.5 g, 0.027 mol, prepared as described in Tetrahedron 1968, 24, 5369) in MeOH (50ml). Then 10% Pd-C (500 mg) was added carefully and the solution heated under reflux for Ih. It was then filtered through celite and to this filtrate at O0C was added triethylamine (11.2 ml, 0.081 mol) and Boc anhydride (7.06 g, 0.0324 mol). The solution was stirred for 4 h at 20 0C and then concentrated under reduced pressure. The residue was diluted with water and extracted with EtOAc. The organic layer was dried and concentrated to give (5-hydroxy- adamantan-2-yl)carbamic acid tert-butyl ester (7 g, 96%). LC-MS (m/z) : 168 (M+l). 1HNMR (300 MHz, DMSO-d6) : δ 6.8 (d, IH), 6.7 (brs, IH), 3.45 (d, IH), 2.0 (s, IH), 1.75-1.95 (m, 4H), 1.5-1.7 (m, 6H), 1.35 (s, 9H), 1.25 (t, 2H).
l-Hydroxy-4-methylamino-adamantane
Lithium aluminium hydride (0.711 g, 0.018 mol) was added to a solution of (5-hydroxy- adamantan-2-yl)carbamic acid tert-butyl ester (1 g, 0.0037 mol) in THF (50 ml) at 00C under a nitrogen atmosphere. The slurry was heated under reflux for 5h. It was then cooled to O0C and quenched with 30% NaOH solution (12 ml) and filtered. The filtrate was concentrated to give 2-methylaminoadamantan-5-ol as a white solid (0.6 g, 90%). LC-MS {m/z) : 181.9 (M+l). 1HNMR (300 MHz, DMSO-d6) : δ 4.3 (s, IH), 4.2 (s, IH), 2.4 (s, 0.7H), 2.3 (s, 0.3H), 2.2 (s, 3H), 1.8-2.0 (m, 5H), 1.5-1.6 (m, 5H), 1.4-1.5 (m, 2H), 1.2 (m, 2H).
Example 4
N-Boc-4-(2-piperidin-4-yl-ethoxy)-benzoic acid ethyl ester /V-Boc-4-piperidine ethanol (15 g, 65 mmol) and ethyl 4-hydroxybenzoate (11 g, 65 mmol) were dissolved in dry THF (750 ml) under N2. To this was added tri-n-butylphosphine (24 ml, 98 mmol) and ADDP (25 g, 98 mmol) resulting in a suspension, which was stirred overnight at 20 0C. The mixture was concentrated in vacuo to ~100 ml, filtered, and the filtrate was evaporated with silica gel. Flash chromatography (EtOAc/heptane 1 :4) afforded 24 g of the title compound. LC-MS {m/z) \ 401 (M+23).
The following compounds were prepared by a method similar to Example 4.
N-Boc-4-(2-piperidin-4-yl-ethoxy)-benzoic acid benzyl ester
Prepared from /V-Boc-4-piperidine ethanol and benzyl 4-hydroxybenzoate. LC-MS [m/z) \ 341 (M+l).
4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy1-benzoic acid ethyl ester
Prepared from 5-ethyl-2-pyridine ethanol and ethyl 4-hydroxybenzoate. LC-MS (m/z) \ 300 (M+l)
Example 5
4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy1 -benzoic acid
4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzoic acid ethyl ester was dissolved in ethanol (25 ml), whereupon NaOH (1 N, 10 ml) was added, and the solution was stirred overnight at 20 0C. The reaction mixture was concentrated in vacuo, dissolved in HCI (1 N, 25 ml) and the resulting solution was extracted with EtOAc (3 X 25 ml). The combined organic extracts were dried (MgSO4) and evaporated to give the title compound. LC-MS (m/z) : 300 (M+l).
The following compound was prepared by a method similar to Example 5.
4-[2-(Tetrahydro-pyran-4-yl)-ethoxy1 -benzoic acid
Prepared from 4-[2-(tetrahydro-pyran-4-yl)-ethoxy]-benzoic acid.
Example 6 Ethyl 4-(2-piperidin-4-yl-ethoxy)-benzoate
TFA (25 ml) was added to a solution of N-Boc-4-(2-piperidin-4-yl-ethoxy)-benzoic acid ethyl ester (8.5 g, 22 mmol) in DCM (100 ml). Stirring overnight followed by evaporation of the solvents afforded 10 g of the title compound as the TFA salt. LC-MS {m/z) : 279 (M+l).
Ethyl 4-[2-(l-isopropylcarbamoyl-piperidin-4-yl)-ethoxyl-benzoate
Ethyl 4-(2-piperidin-4-yl-ethoxy)-benzoate (1.0 g of the TFA salt, 2.6 mmol) was dissolved in DCM (10 ml), whereupon DIPEA (1.3 ml, 7.7 mmol) and isopropyl isocyanate (0.33 g, 3.8 mmol) was added. The reaction mixture was shaken overnight at 20 0C. Silica gel (10 ml) was added, and the solvent removed in vacuo. Flash chromatography (EtOAc/heptane 35: 65 → 55:45) provided 0.67 g of the title compound. LC-MS (m/z) : 364 (M+2).
4-r2-(l-Isopropylcarbamoyl-piperidin-4-yl)-ethoxyl -benzoic acid
Ethyl 4-[2-(l-isopropylcarbamoyl-piperidin-4-yl)-ethoxy]-benzoate (0.67 g, 1.8 mmol) was dissolved in ethanol (25 ml), whereupon NaOH (1 N, 10 ml) was added, and the solution was stirred overnight at 20 0C. The reaction mixture was concentrated in vacuo, dissolved in HCI (1 N, 25 ml) and the resulting solution was extracted with EtOAc (3 X 25 ml). The combined organic extracts were dried (MgSO4) and evaporated to give 0.62 of the title compound. LC- MS {m/z) : 336 (M+2).
The following compounds were prepared by a method similar to Example 6.
4--r2-[l-(3-Hydroxy-2,2-dimethyl-propionyl)-piperidin-4-yll-ethoxy>-benzoic acid
Prepared from N-Boc-4-(2-piperidin-4-yl-ethoxy)-benzoic acid ethyl ester with the exception that ethyl 4-(2-piperidin-4-yl-ethoxy)-benzoate was converted to its corresponding carboxamide as described below before the final alkaline hydrolysis to give the title compound. LC-MS {m/z) : 351 (M+2).
Carboxamide formation
2,2-Dimethyl-3-hydroxypropionic acid (300 mg, 2.5 mmol), HOBT (583 mg, 3.8 mmol), EDC (487 mg, 2.5 mmol), and ethyl 4-(2-piperidin-4-yl-ethoxy)-benzoate (1.0 g of the TFA salt, 2.5 mmol) were suspended in DMF (2.5 ml) before DIPEA (0.44 ml, 2.5 mmol) was added. The reaction mixture was stirred at 20 0C overnight, concentrated in vacuo and purified by flash chromatography (EtOAc/heptane 30: 70 → 50: 50) to give 0.71 g of the desired carboxamide.
4--r2-[l-(2-Hydroxy-2-methyl-propionyl)-piperidin-4-yll-ethoxy>-benzoic acid
Prepared from N-Boc-4-(2-piperidin-4-yl-ethoxy)-benzoic acid ethyl ester with the exception that ethyl 4-(2-piperidin-4-yl-ethoxy)-benzoate was converted to its corresponding carboxamide with 2-hydroxy-2-methyl-propionic acid as described above before the final alkaline hydrolysis to give the title compound. LC-MS [m/z) \ 337 (M + l).
4--r2-[l-(Pyridine-2-sulfonyl)-piperidin-4-yl1-ethoxy>-benzoic acid
Prepared from N-Boc-4-(2-piperidin-4-yl-ethoxy)-benzoic acid benzyl ester with the exception that benzyl 4-(2-piperidin-4-yl-ethoxy)-benzoate was converted to its corresponding pyridine sulfonamide as described below before the final alkaline hydrolysis to give the title compound. LC-MS (m/z) : 391 (M+l).
Sulfonamide formation
2-Pyridinesulfonyl chloride (hydrochloride salt, 0.85 g, 4.0 mmol) was added to a solution of benzyl 4-(2-piperidin-4-yl-ethoxy)-benzoate (1.0 g, 2.7 mmol) and DIPEA (0.93 ml, 5.3 mmol) in DCM (20 ml), and the solution was stirred overnight at 20 0C. Removal of the solvents and purification by flash chromatography (100% DCM → 10% EtOAc in DCM) provided the desired sulfonamide.
Example 7
4-Methanesulfinylmethoxy-benzoic acid ethyl ester
NaH (60% in mineral oil, 3.4 g, 84 mmol) was added to a solution of ethyl 4-hydroxy- benzoate (10 g, 60 mmol) in dry DMF (100 ml), and the mixture was stirred at 20 0C for 30 min. Then, chloromethyl methylsulfide (6.0 ml, 72 mmol) was added, and stirring was continued at 20 0C overnight. Water (100 ml) was added, and the aqueous phase was extracted with diethyl ether. The combined organic layers were washed with ammonium chloride (sat. aq.), dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in DCM, and after cooling to 0 0C, MCPBA (12 g, 72 mmol) was added slowly. The mixture was stirred at 20 0C for 30 min, whereupon it was washed with water, stirred with another 50 ml of water and neutralized to pH ~ 8 with IN NaOH. Drying (Na2SO4) and evaporation of the solvent gave the crude material, which was purified by flash chromatography (EtOAc) to give 6.7 g of the title compound. LC-MS (m/z) : 244 (M+2).
4-Chloromethoxy-benzoic acid ethyl ester
Acetyl chloride (0.39 ml, 5.4 mmol) was added to a 0 0C solution of 4- methanesulfinylmethoxy-benzoic acid ethyl ester (1.2 g, 5.0 mmol) in DCM (40 ml). The temperature is allowed to rise to 20 0C over a period of 2 h, and the solvent is removed to give 1.2 g of the title compound.
4-(Pyridine-2-sulfonylmethoxy)-benzoic acid
NaH (60% in mineral oil, 0.56 g, 14 mmol) was added to a solution of 2-mercaptopyridine (1.1 g, 10 mmol) in dry DMF (25 ml), and the mixture was stirred at 20 0C for 10 min. After addition of 4-chloromethoxy-benzoic acid ethyl ester (2.0 g, 9.3 mmol) the reaction was stirred overnight at 20 0C. Water was added and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water and brine, whereupon they were dried (Na2SO4) and concentrated in vacuo to give the crude material. Purification by flash chromatography (EtOAc/heptane 1 :4) gave the desired sulfide.
The sulfide was dissolved in acetic acid (15 ml), and hydrogen peroxide (35% in water, 6 ml) was added in smaller portions over a period of 24 h. Evaporation and purification by flash chromatography (EtOAc/heptane 1 :4) gave 0.8 g of the ester, which was hydrolysed by treatment with NaOH (IN, 5 ml) in EtOH overnight. The solvents were removed, and the residue dissolved in water (5 ml). Washing with diethyl ether, and acidification of the aqueous layer with HCI (IN to pH ~ 4-5) gave 0.6 g of the title compound that was collected by filtration. LC-MS {m/z) : 294 (M+ 1).
Example 8
4-Methanesulfonylmethoxy-benzoic acid benzyl ester NaH (60% in mineral oil, 2.6 g, 65 mmol) was slowly added to a solution of benzyl 4- hydroxybenzoate (10 g, 44 mmol) in dry DMF (100 ml). The mixture was stirred for 30 min at 20 0C before drop wise addition of chloromethyl methylsulfide (5.9 ml, 70 mmol). After stirring overnight, water was added, and the mixture was extracted with diethyl ether. The combined organic layers were washed with ammonium chloride (sat. aq.), dried (Na2SO4) and evaporated. The crude material was dissolved in DCM (250 ml) and cooled to 00C before slow addition of MCPBA (35% in water, 27 ml, 110 mmol). The reaction mixture was stirred for 30 min at 0 0C, whereupon the temperature was allowed to reach 20 0C. After stirring for 1 h, the mixture was filtered, and the filtrate was washed with water (pH in the aqueous layer was adjusted to 6-7 with IN NaOH). The organic layer was dried (Na2SO4) and concentrated in vacuo. Flash chromatography (EtOAc/heptane 1 : 1) provided the title compound. LC-MS {m/z) : 343 (M+23 (Na)).
4-Methanesulfonylmethoxy-benzoic acid
A solution of 4-methanesulfonylmethoxy-benzoic acid benzyl ester (14 g, 44 mmol) in ethanol (200 ml) was hydrogenated overnight at 1 atm. H2 using 10% Pd/C (wet). The catalyst was removed by filtration and the solvent removed in vacuo. Addition of diethyl ether led to precipitation of the title compound (3 g). LC-MS (m/z) : 253 (M+23 (Na)).
Example 9
4-[2-(l-Isopropylcarbamoyl-piperidin-4-yl)-ethoxy]-benzoic acid (150 mg, 0.45 mmol), HOBT (103 mg, 0.67 mmol), EDC (86 mg, 0.45 mmol), and 4-amino-l-hydroxyadamantane (75 mg, 0.45 mmol) were suspended in DMF (2.5 ml) before DIPEA (0.08 ml, 0.45 mmol) was added. The reaction mixture was stirred at 20 0C overnight. The reaction mixture was purified directly by Preparative HPLC to give 149 mg of the title compound as a mixture of two isomers. LC-MS {m/z) : 484 (M).
The following compounds were prepared by a method similar to Example 9.
4-(2--r4-r(5-Hvdroxy-adamantan-2-yl)-methyl-carbamoyll-phenoxy>-ethyl)-piperidine-l- carboxylic acid isopropylamide
Prepared from 4-[2-(l-Isopropylcarbamoyl-piperidin-4-yl)-ethoxy]-benzoic acid and 1- hydroxy-4-methylaminoadamantane. LC-MS {m/z) : 498 (M).
4--r2-[l-(3-Hydroxy-2,2-dimethyl-propionyl)-piperidin-4-yl1-ethoxy>-/V-(5-hydroxy- adamantan-2-yl)-benzamide Prepared from 4-{2-[l-(3-hydroxy-2,2-dimethyl-propionyl)-piperidin-4-yl]-ethoxy}-benzoic acid and 4-amino-l-hydroxyadamantane. LC-MS (m/z) : 500 (M+H).
4--r2-[l-(2-Hydroxy-2-methyl-propionyπ-piperidin-4-yll-ethoxy>-N-(5-hydroxy-adamantan- 2-yl)-N-methyl-benzamide
Prepared from 4-{2-[l-(3-hydroxy-2,2-dimethyl-propionyl)-piperidin-4-yl]-ethoxy}-benzoic acid and l-hydroxy-4-methylaminoadamantane. LC-MS {m/z) : 514 (M+l).
4-^2-ri-(2-Hvdroxy-2-methyl-propionyl)-piperidin-4-vπ-ethoxy>-N-(5-hvdroxy-adamantan- 2-yl)-N-methyl-benzamide
Prepared from 4-{2-[l-(2-hydroxy-2-methyl-propionyl)-piperidin-4-yl]-ethoxy}-benzoic acid and l-hydroxy-4-methylaminoadamantane. LC-MS {m/z) : 500 (M+l).
4-|"2-(5-Ethyl-pyridin-2-yl)-ethoxy"l-/V-(5-hydroxy-adamantan-2-yl)-benzamide
Prepared from 4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzoic acid and 4-amino-l- hydroxyadamantane. LC-MS {m/z) : 422 (M+2).
4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy1-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide
Prepared from 4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzoic acid and l-hydroxy-4- methylaminoadamantane. LC-MS {m/z) : 436 (M + l).
/V-(5-Hydroxy-adamantan-2-yl)-4-(pyridine-2-sulfonylmethoxy)-benzamide
Prepared from 4-(pyridine-2-sulfonylmethoxy)-benzoic acid and 4-amino-l- hydroxyadamantane. LC-MS {m/z) : 443 (M).
/V-(5-Hvdroxy-adamantan-2-yl)-4-r2-(tetrahvdropyran-4-yl)-ethoxyl-benzamide
Prepared from 4-[2-(tetrahydro-pyran-4-yl)-ethoxy]-benzoic acid and 4-amino-l- hydroxyadamantane. LC-MS {m/z) : 401 (M+l).
N-(5-Hvdroxy-adamantan-2-yl)-N-methyl-4-r2-(tetrahvdro-pyran-4-yl)-ethoxyl-benzamide Prepared from 4-[2-(tetrahydro-pyran-4-yl)-ethoxy]-benzoic acid and l-hydroxy-4- methylaminoadamantane. LC-MS {m/z) : 415 (M + l).
/V-(5-Hydroxy-adamantan-2-yπ-4--r2-[l-(pyridine-2-sulfonyπ-piperidin-4-yll-ethoxy>- benzamide
Prepared from 4-{2-[l-(pyridine-2-sulfonyl)-piperidin-4-yl]-ethoxy}-benzoic acid and 4- amino-1-hydroxyadamantane. LC-MS {m/z) : 540 (M + l).
N-(5-Hvdroxy-adamantan-2-yl)-N-methyl-4--r2-ri-(pyridine-2-sulfonyl)-piperidin-4-yl"l- ethoxyVbenzamide
Prepared from 4-{2-[l-(pyridine-2-sulfonyl)-piperidin-4-yl]-ethoxy}-benzoic acid and 1- hydroxy-4-methylaminoadamantane. LC-MS {m/z) : 554 (M).
Example 10
/V-(5-Hydroxy-adamantan-2-yl)-4-methanesulfonylmethoxy-benzamide
4-Methanesulfonylmethoxy-benzoic acid (1.0 g, 4.3 mmol) was dissolved in dichloromethane (50 ml), whereupon thionylchloride (0.50 ml, 6.5 mmol) was added. The mixture was stirred at 200C under N2 overnight. The solution was evaporated to dryness and 73 mg (0.44 mmol) of the residue was suspended in DCM (10 mL) before 4-amino-l-hydroxyadamantane (74 mg, 0.44 mmol) was added. After stirring the reaction mixture at 200C for Ih, the solution was concentrated in vacuo, redissolved in methanol/water and purified by preparative HPLC to give 55 mg of the title compound as a mixture of two isomers. LC-MS {m/z) : 380 (M+l).
The following compound was prepared by a method similar to Example 10.
4-(4-Methanesulfonylmethoxy-benzoylamino)-adamantane-l-carboxylic acid
Prepared from 4-methanesulfonylmethoxy-benzoic acid and 4-amino-adamantane-l- carboxylic acid methyl ester following the method described in Example 8, followed by alkaline hydrolysis as described under Example 3. LC-MS {m/z) : 408 (M + l). PHARMACOLOGICAL METHODS
llβHSDl 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- llβHSDl (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 A/S), 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-llβHSDl, 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.
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, modifyca- tions, 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 dosages as set forth herein may be applicable as a consequence of variations in the responsiveness of the mammal being treated. 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 imgf000066_0001
(I)
wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and cyclopropyl and R2 is selected from the group consisting of a monovalent radical having one of the following formulae, wherein the symbol * denotes the point of attachment:
Figure imgf000066_0002
Figure imgf000066_0004
Figure imgf000066_0003
Q is selected from the group consisting of hydroxy, -S(=O)2NR5R6, -CH2OH, -C(CH3)HOH, - C(CH3)2OH, 1-cyclopropanol, -0-CH2CH2-OH and -C(=O)NR7R8;
R5 is selected from the group consisting of hydrogen, cyclopropyl and Ci-C4alkyl, wherein said cyclopropyl and Q-Qalkyl are optionally substituted with one or two independently selected
R9;
R6 is selected from the group consisting of cyclopropyl and Ci-C4alkyl, wherein said cyclopropyl and Ci-C4alkyl are optionally substituted with one or two independently selected R9; or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 6 membered ring optionally substituted with one or two independently selected R9;
R7 and R8 are each independently selected from the group consisting of hydrogen, cyclopropyl and Ci-C4alkyl, wherein said cyclopropyl and Ci-C4alkyl are optionally substituted with one or two independently selected R9; or R7 and R8 together with the nitrogen atom to which they are attached form a 4 to 6 membered ring optionally substituted with one or two independently selected R9;
R4 is selected from the group consisting of hydrogen, Ci-C4alkyl, cyclopropyl, trifluoromethyl, halogen, -S(=O)2methyl, -CH2OH, -O-cyclopropyl and -O-Ci-C4alkyl, wherein said cyclopropyl, Ci-C4alkyl, -O-cyclopropyl and -O-Ci-C4alkyl are optionally substituted with R9;
R95 is selected from the group consisting of Ci-C6alkyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said Q-Csalkyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with one or two independently selected R96;
R96 is selected from the group consisting of halogen, hydroxy, trifluoromethyl, methyl, cyclopropyl, carboxy and -S(=O)2methyl;
R97 is selected from the group consisting of hydrogen, cyclopropyl and Ci-C4alkyl;
R9 is selected from the group consisting of hydrogen, CVQalkyl, cyclopropyl, hydroxy, halogen, trifluoromethyl, -CH2OH and carboxy;
X1 is selected from the group consisting of -CR10R11-, -O-, -S-, -S(=O)- and -S(=O)2-;
X2 is selected from the group consisting of -CR86R87-, -O-, -S-, -S(=O)-, -S(=O)2- and -NR24-;
X3 is selected from the group consisting of -CR88R89-, -O-, -S-, -S(=O)-, -S(=O)2- and -NR25-;
R10 and R11 are each independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, -CH2OH, fluorine, isopropyl and cyclopropyl; or R10 and R11 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl is optionally substituted with hydroxy or fluorine;
R3 is selected from the group consisting of C3-Ci0heterocyclyl substituted with R13 and R14, C3-Ci0cycloalkyl substituted with R13 and R14, aryl substituted with R13 and R14, heteroaryl substituted with R13 and R14, -C(=O)R15, -CH(OH)R16, -(CR22R23)π-C(=O)-NR17R18, - (CR22R23)π-NR19C(=O)R20, -(CR22R23)π-OR21, -(CR22R23)π-SR21 , -(CR22R23)π-S( = O)2R24, - (CR22R23)π-S(=O)2NR17R18, -(CR22R23)π-NR17S(=O)2R25, -(CR22R23)π-NR17R18, -(CR22R23V NR17C(=O)-NR17R18, -(CR22R23VC=CR45R26 and -(CR22R23)π-C≡C-R27; n is selected from the group consisting of 0, 1 and 2;
R13 and R14 are each independently selected from the group consisting of hydrogen, hydroxy, halogen, -C(=O)OH, -C(=O)R28, -CH(OH)-R29, -(CR22R23)m-C(=O)-NR30R31, - (CR22R23)m-NR30C(=O)R28, -(CR22R23)m-OR32, -(CR22R23)m-SR32, -(CR22R23)m-S(=O)2R33, - (CR22R23)m-S( = O)2NR30R31, -(CR22R23)m-NR30S(=O)2R33, -(CR22R23)m-NR30R31, -(CR22R23)m- NR30C(=O)-NR30R31, -(CR22R23)m-C=CR34R35, -(CR22R23)m-C≡C-R36, -(CR22R23)m-C3- C10heterocyclyl substituted with R37 and R38, -(CR22R23)m-C3-C10cycloalkyl substituted with R37 and R38, -(CR22R23)m-aryl substituted with R39 and R40, d-C6alkyl-R98 and -(CR22R23)m- heteroaryl substituted with R39 and R40;
R22 and R23 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl and C3-Ci0cycloalkyl, wherein said Ci-C6alkyl and C3-Ci0cycloalkyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R22 and R23 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen;
R86 and R87 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl and C3-Ci0cycloalkyl, wherein said Ci-C6alkyl and C3-Ci0cycloalkyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R86 and R87 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen;
R88 and R89 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl and C3-Ci0cycloalkyl, wherein said Ci-C6alkyl and C3-Ci0cycloalkyl independently are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R88 and R89 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen;
R26 and R27 are each independently selected from the group consisting of hydrogen, -(CR22- R23)m-CO-NR30R31, -(CR22R23)m-NR30C(=O)R28, -(CR22R23)m-OR32, -(CR22R23)m-SR32, -(CR22- R23)m-S(=O)2R33, -(CR22R23)m-S(=O)2NR30R31, -(CR22R23)m-NR30S(=O)2R33, -(CR22R23)m-
NR30C(=O)-NR30R31, -(CR22R23)m-C3-C10heterocyclyl substituted with R37, -(CR22R23)m- C3-C10- cycloalkyl substituted with R38, -(CR22R23)m-aryl substituted with R39 and R40, Q-Csalkyl-R98 and -(CR22R23)m-heteroaryl substituted with R39 and R40; m is 0 or 1;
R15, R16, R20, R21, R24, R25 and R45 are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, C3-Ci0heterocyclyl, C3-Ci0cycloalkyl, aryl and heteroaryl, wherein said Ci-C6alkyl, C3-Ci0heterocyclyl, C3-Ci0cycloalkyl, aryl and heteroaryl are optionally substituted independently with one, two or three independently selected R41;
R17, R18 and R19 are each independently selected from the group consisting of hydrogen, Ci-Csalkyl, C3-C10cycloalkyl, phenyl and heteroaryl, wherein said CVCsalkyl, C3-C10cycloalkyl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, ethyl and hydroxy; or R17 and R18 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said ring are optionally substituted with hydroxy, trifluoromethyl or halogen;
R28, R29, R32, R33, R34, R35, R36, R37, R38, R39 R98 and R40 are each independently selected from the group consisting of hydrogen, C1-C6SIkYl, phenyl, heteroaryl and C3-C10cycloalkyl, wherein said Ci-C6alkyl, phenyl, heteroaryl and C3-Ci0cycloalkyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, triflouromethyl, methoxy and hydroxy;
R30 and R31 are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said Ci-C6alkyl, tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy, or R30 and R31 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said ring is optionally substituted with hydroxy or halogen;
R41 is selected from the group consisting of halogen, hydroxy, oxo, -C(=O)OH, -S(=O)2R42, - S-NR43R44, -SC=O)2NR43R44, cyclopropyl, trifluoromethyl, -OR42, -SR42, d-Qsalkyl, -C(=O)- NR43R44, -NR43C(=O)NR44R43; -NR43S(=O)2R42 and -N(C=O)R42;
R42 is selected from the group consisting of hydrogen, d-Qalkyl, C3-C10cycloalkyl, aryl and heteroaryl, wherein said Ci-C6alkyl, C3-Ci0cycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, triflouromethyl, methoxy and hydroxy;
R43 and R44 are each independently selected from the group consisting of hydrogen,
Ci-C6alkyl, C3-Ci0heterocyclyl, C3-Ci0cycloalkyl and heteroaryl, wherein said Ci-C6alkyl, C3- C10heterocyclyl, C3-C10cycloalkyl and heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy, or R43 and R44 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl is optionally substituted with hydroxy or halogen;
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 R1 is hydrogen.
3. The compound according to clause 1, wherein R1 is methyl.
4. The compound according to clause 1, wherein R1 is ethyl.
5. The compound according to clause 1, wherein R1 is isopropyl.
6. The compound gaccording to clause 1, wherein R1 is cyclopropyl.
7. The compound according to any one of the preceding clauses, wherein R2 is selected from the group consisting of:
Figure imgf000070_0001
8. The compound according to clause 7, wherein R is selected from the group consisting of
Figure imgf000070_0002
9. The compound according to clause 8, wherein R2 is
Figure imgf000071_0001
10. The compound according to clause 8, wherein R is
Figure imgf000071_0002
11. The compound according to clause 8, wherein R is
Figure imgf000071_0003
12. The compound according to clause 8, wherein R is
Figure imgf000071_0004
13. The compound according to clause 8, wherein R is
Figure imgf000071_0005
14. The compound according to any one of the preceding clauses, wherein Q is - S(=O)2NR5R6.
15. The compound according to any one of the clauses 1-13, wherein Q is -CH2OH.
16. The compound according to any one of the clauses 1-13, wherein Q is -C(CH3)HOH. 17. The compound according to any one of the clauses 1-13, wherein Q is 1-cyclopropanol.
18. The compound according to any one of the clauses 1-13, wherein Q is -C(=O)NR7R8.
19. The compound according to any one of the clauses 1-13, wherein Q is -C(CH3)2OH.
20. The compound according to any one of the clauses 1-13, wherein Q is -0-CH2CH2-OH.
21. The compound according to any one of the preceding clauses, wherein R5 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, wherein said methyl, ethyl and cyclopropyl optionally are substituted with one or two independently selected R9.
22.The compound according to clause 21, wherein R5 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl.
23.The compound according to any one of the preceding clauses, wherein R6 is selected from the group consisting of methyl, ethyl and cyclopropyl, wherein said ethyl and cyclopropyl optionally are substituted with one or two independently selected R9.
24. The compound according to clause 23, wherein R6 is selected from the group consisting of methyl, ethyl and cyclopropyl.
25. The compound according to any one of the clauses 1-20, wherein R5 and R6 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl ring, which ring is optionally substituted with one or two independently selected R9.
26. The compound according to clause 25, wherein R5 and R6 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl ring.
27. The compound according to any one of the preceding clauses, wherein R7 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, wherein said methyl, ethyl and cyclopropyl is optionally substituted with one or two independently selected R9.
28. The compound according to clause 27, wherein R7 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl. 29. The compound according to any one of the preceding clauses, wherein R8 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl, wherein said methyl, ethyl and cyclopropyl are optionally substituted with one or two independently selected R9.
30. The compound according to clause 29, wherein R8 is selected from the group consisting of hydrogen, methyl, ethyl and cyclopropyl.
31. The compound according to any one of the clauses 1-26, wherein R7 and R8 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl ring, which ring is optionally substituted with one or two independently selected R9.
32. The compound according to clause 31, wherein R7 and R8 together with the nitrogen atom to which they are attached form a piperidinyl, morpholinyl or pyrrolidinyl ring.
33. The compound according to any one of the preceding clauses, wherein R4 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, trifluoromethyl, fluorine, chlorine, -S(=O)2methyl, -CH2OH, -O-cyclopropyl and -O-methyl wherein said methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, -S(=O)2methyl, -O-cyclopropyl and -O-methyl are optionally substituted with R9.
34. The compound according to clause 33, wherein R4 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl, trifluoromethyl, fluorine, chlorine, - S(=O)2methyl, -CH2OH, -O-cyclopropyl and -O-methyl.
35. The compound according to clause 34, wherein R4 is selected from the group consisting of hydrogen, methyl, trifluoromethyl, fluorine, chlorine, -S(=O)2methyl, -CH2OH, -O-cyclopropyl and -O-methyl.
36. The compound according to any one of the preceding clauses, wherein R95 is selected from the group consisting of methyl, ethyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said methyl, ethyl, phenyl, pyridinyl, pyrimidinvl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with one or two independently selected R96.
37. The compound according to clause 36, wherein R95 is selected from the group consisting of methyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said methyl, phenyl, pyridinyl, pyrimidinvl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with R96. 38. The compound according to clause 37, wherein R95 is selected from the group consisting of methyl, phenyl, pyridinyl, pyrimidinvl, cyclopropyl, cyclobutyl and cyclohexyl.
39. The compound according to any one of the preceding clauses, wherein R96 is selected from the group consisting of fluorine, chlorine, hydroxy, trifluoromethyl, carboxy and - S(=O)2methyl.
40. The compound according to clause 39, wherein R96 is selected from the group consisting of fluorine, chlorine, hydroxy and trifluoromethyl.
41. The compound according to any one of the preceding clauses, wherein R97 is hydrogen.
42. The compound according to any one of the clauses 1-40, wherein R97 is Ci-C4alkyl.
43. The compound according to clause 42, wherein R97 is selected from the group consisting of methyl, ethyl and cyclopropyl.
44. The compound according to any one of the preceding clauses, wherein R9 is selected from the group consisting of hydrogen, methyl, cyclopropyl, hydroxy, halogen, trifluoromethyl, - CH2OH and carboxy.
45. The compound according to clause 44, wherein R9 is selected from the group consisting of hydrogen, methyl, cyclopropyl, hydroxy, fluorine, chlorine and trifluoromethyl.
46. The compound according to any one of the preceding clauses, wherein X1 is -CR10R11-.
47. The compound according to any one of the clauses 1-45, wherein X1 is -O-.
48. The compound according to any one of the clauses 1-45, wherein X1 is -S-.
49. The compound according to any one of the clauses 1-45, wherein X1 is -S(=O)-.
50. The compound according to any one of the clauses 1-45, wherein X1 is -S(=O)2-.
51. The compound according to any one of the preceding clauses, wherein X2 is -CR86R87-.
52. The compound according to any one of the clauses 1-50, wherein X2 is -O-. 53. The compound according to any one of the clauses 1-50, wherein X2 is -S-.
54. The compound according to any one of the clauses 1-50, wherein X2 is -S(=O)-.
55. The compound according to any one of the clauses 1-50, wherein X2 is -S(=O)2-.
56. The compound according to any one of the clauses 1-50, wherein X2 is -NR24-.
57. The compound according to any one of the preceding clauses, wherein X3 is -CR88R89-.
58. The compound according to any one of the clauses 1-56, wherein X3 is -O-.
59. The compound according to any one of the clauses 1-56, wherein X3 is -S-.
60. The compound according to any one of the clauses 1-56, wherein X3 is -S(=O)-.
61. The compound according to any one of the clauses 1-56, wherein X3 is -S(=O)2-.
62. The compound according to any one of the clauses 1-56, wherein X3 is -NR25-.
63. The compound according to any one of the clauses 1-62, wherein -X1-X2-X3- is selected from the group consisting of -O-CR86R87-CR88R89- and -O-CR86R87-S(=O)2-.
64. The compound according to any one of the clauses 1-63, wherein -X1-X2-X3- is selected from the group consisting of -S-CR86R87-CR88R89-, -S(=O)2-NR24-CR88R89- and -S(=O)2- CR86R87-CR88R89-.
65. The compound according to any one of the clauses 1-63, wherein -X1-X2-X3- is selected from the group consisting of -R10Rn-CR86R87-S(=O)2-, -CR10Rn-CR86R87-S-, -CR10Rn-CR86R87- O-, -CR10Rn-CR86R87-NR25-, -CR10Rn-CR86R87-CR88R89-, -CR10Rn-S(=O)2-NR25- and -CR10R11- NR24-S(=O)2-.
66. The compound according to any one of the preceding clauses, wherein R10 is selected from the group consisting of hydrogen, hydroxy, methyl, fluorine, isopropyl and cyclopropyl.
67. The compound according to clause 63, wherein R10 is selected from the group consisting of hydrogen, hydroxy, methyl and fluorine. 68. The compound according to any one of the preceding clauses, wherein R11 is selected from the group consisting of hydrogen, hydroxy, methyl, fluorine, isopropyl and cyclopropyl.
69. The compound according to clause 65, wherein R11 is selected from the group consisting of hydrogen, hydroxy, methyl and fluorine.
70. The compound according to any one of the preceding clauses, wherein R10 and R11 together with the carbon atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl is optionally substituted with hydroxy or fluorine.
71. The compound according to any one of the clauses 1-66, wherein R10 and R11 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl is optionally substituted with hydroxy or fluorine.
72. The compound according to any one of the preceding clauses, wherein R3 is selected from the group consisting of C3-Ci0heterocyclyl substituted with R13 and R14, C3-Ci0cycloalkyl substituted with R13 and R14, aryl substituted with R13 and R14, heteroaryl substituted with R13 and R14.
73. The compound according to any one of the preceding clauses, wherein R3 is selected from the group consisting of -C(=O)R15, -CH(OH)R16, -(CR22R23)π-C(=O)-NR17R18, -(CR22R23V NR19C(=O)R20, -(CR22R23VOR21, -(CR22R23VSR21 , -(CR22R23)π-S(=O)2R24, -(CR22R23V S(=O)2NR17R18, -(CR22R23VNR17St=O)2R25, -(CR22R23VNR17R18, -(CR22R23)π-NR17C(=O)- NR17R18, -(CR22R23VC=CR45R26 and -(CR22R23)π-C≡C-R27.
74. The compound according to clause 73, wherein n is 1.
75. The compound according to clause 73, wherein n is 2.
76. The compound according to clause 73, wherein R3 is selected from the group consisting of -C( = O)R15, -C(=O)-NR17R18, -NR19C(=O)R20, -OR21, -SR21 , -S(=O)2R24, -S( = O)2NR17R18, - NR17S(=O)2R25, -NR17C(=O)-NR17R18 and -C≡C-R27.
77. The compound according to any one of the clauses 1-72, wherein R3 is selected from the group consisting of C3-Ci0heterocyclyl substituted with R13, C3-Ci0cycloalkyl substituted with R13, aryl substituted with R13 and heteroaryl substituted with R13. 78. The compound according to clause 77, wherein R3 is selected from the group consisting of with R13 substituted tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
79. The compound according to clause 77, wherein R3 is selected from the group consisting of with R13 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.
80. The compound according to clause 77, wherein R3 is phenyl substituted with R13.
81. The compound according to clause 77, wherein R3 is selected from the group consisting of with R13 substituted imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
82. The compound according to any one of the preceding clauses, wherein R13 is selected from the group consisting of hydrogen, hydroxy, halogen, -C(=O)OH, -C(=O)R28, -CH(OH)-
R29, -(CR22R23)m-C(=O)-NR30R31, -(CR22R23)m-NR30C(=O)R28, -(CR22R23)m-OR32, -(CR22R23)m- SR32, -(CR22R23)m-S( = O)2R33, -(CR22R23)m-S(=O)2NR30R31, -(CR22R23)m-NR30S( = O)2R33, - (CR22R23)m-NR30R31, -(CR22R23)m-NR30C(=O)-NR30R31, -(CR22R23)m-C=CR34R35 and -(CR22R23)m- C≡C-R36.
83. The compound according to any one of the clauses 1-81, wherein R13 is selected from the group consisting of -(CR22R23)m-C3-C10heterocyclyl substituted with R37 and R38, -(CR22R23)m- C3-C10cycloalkyl substituted with R37 and R38, -(CR22R23)m-aryl substituted with R39 and R40, Ci-Csalkyl-R98 and -(CR22R23)m-heteroaryl substituted with R39 and R40.
84. The compound according to clause 82, wherein R13 is selected from the group consisting of hydrogen, hydroxy, halogen, -C(=O)R28, -C(=O)-NR30R31, -NR30C(=O)R28, -OR32, -SR32, -
S(=O)2R33, -S(=O)2NR30R31, -NR30SC=O)2R33, -NR30C(=O)-NR30R31, -C=CR34R35 and -C≡C-R36.
85. The compound according to clause 84, wherein R13 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, -C(=O)R28, -C(=O)-NR30R31, -NR30C(=O)R28, -OR32, - S(=O)2R33, -SC=O)2NR30R31, -NR30SC=O)2R33 and -NR30C(=O)-NR30R31.
86. The compound according to clause 85, wherein R13 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, methyl, trifluoromethyl, acetyl, -C(=O)-N-isopropyl, -NHC(=O)methyl, -NHC(=O)isopropyl, -O-methyl, -O-isopropyl, -O-cyclopropyl, - S(=O)2methyl, -S(=O)2cyclopropyl, -S(=O)2NH-methyl, -S(=O)2NH-isopropyl, - NHS(=O)2methyl, -NHS(=O)2cyclopropyl, -NHC(=O)NH-methyl and -NHC(=O)NH-isopropyl. 87. The compound according to clause 86, wherein R13 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, methyl, trifluoromethyl, acetyl, -O-isopropyl, -O- cyclopropyl, -S(=O)2methyl and -S(=O)2cyclopropyl.
88. The compound according to clause 83, wherein R13 is selected from the group consisting of C3-Ci0heterocyclyl substituted with R37, C3-Ci0cycloalkyl substituted with R37, aryl substituted with R39, Ci-C6alkyl-R98 and heteroaryl substituted with R39.
89. The compound according to clause 88, wherein R13 is C3-C10heterocyclyl substituted with R37.
90. The compound according to clause 89, wherein R13 is selected from the group consisting of with R37 substituted tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
91. The compound according to clause 88, wherein R13 is C3-Ci0cycloalkyl substituted with R 37
92. The compound according to clause 91, wherein R13 is selected from the group consisting of with R37 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.
93. The compound according to clause 88, wherein R13 is aryl substituted with R39.
94. The compound according to clause 93, wherein R13 is phenyl substituted with R39.
95. The compound according to clause 88, wherein R13 is Ci-C6alkyl-R98.
96. The compound according to clause 95, wherein R13 is selected from the group consisting of with R98 substituted methyl, ethyl and isopropyl.
97. The compound according to clause 88, wherein R13 is heteroaryl substituted with R39.
98. The compound according to clause 97, wherein R13 is selected from the group consisting of with R39 substituted imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
99. The compound according to any one of the preceding clauses, wherein R14 is selected from the group consisting of hydrogen, hydroxy, halogen, -C(=O)OH, -C(=O)R28, -CH(OH)- R29, -(CR22R23)m-C(=O)-NR30R31, -(CR22R23)m-NR30C(=O)R28, -(CR22R23)m-OR32, -(CR22R23)m- SR32, -(CR22R23)m-S( = O)2R33, -(CR22R23)m-S(=O)2NR30R31, -(CR22R23)m-NR30S( = O)2R33, - (CR22R23)m-NR30R31, -(CR22R23)m-NR30C(=O)-NR30R31, -(CR22R23)m-C=CR34R35 and -(CR22R23)m- C≡C-R36.
100. The compound according to any one of the clauses 1-99, wherein R14 is selected from the group consisting of -(CR22R23)m-C3-C10heterocyclyl substituted with R37 and R38, - (CR22R23)m-C3-C10cycloalkyl substituted with R37 and R38, -(CR22R23)m-aryl substituted with R39 and R40, Q-Csalkyl-R98 and -(CR22R23)m-heteroaryl substituted with R39 and R40.
101. The compound according to clause 99, wherein R14 is selected from the group consisting of hydrogen, hydroxy, halogen, -C(=O)R28, -C(=O)-NR30R31, -NR30C(=O)R28, -OR32, -SR32, - S(=O)2R33, -S(=O)2NR30R31, -NR30SC=O)2R33, -NR30C(=O)-NR30R31, -C=CR34R35 and -C≡C-R36.
102. The compound according to clause 101, wherein R14 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, -C(=O)R28, -C(=O)-NR30R31, - NR30C(=O)R28, -OR32, -S( = O)2R33, -S( = O)2NR30R31, -NR30S( = O)2R33 and -NR30C(=O)-NR30R31.
103. The compound according to clause 102, wherein R14 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, methyl, trifluoromethyl, acetyl, -C(=O)- N-isopropyl, -NHC(=O)metyhyl, -NHC(=O)isopropyl, -O-methyl, -O-isopropyl, -O-cyclopropyl, -S(=O)2methyl, -S(=O)2cyclopropyl, -S(=O)2NH-methyl, -S(=O)2NH-isopropyl, - NHS(=O)2methyl, -NHS(=O)2cyclopropyl, -NHC(=O)NH-methyl and -NHC(=O)NH-isopropyl.
104. The compound according to clause 103, wherein R14 is selected from the group consisting of hydrogen, hydroxy, fluorine, chlorine, methyl, trifluoromethyl, acetyl, -O- isopropyl, -O-cyclopropyl, -S(=O)2methyl and -S(=O)2cyclopropyl.
105. The compound according to clause 100, wherein R14 is selected from the group consisting of C3-Ci0heterocyclyl substituted with R37, C3-Ci0cycloalkyl substituted with R37, aryl substituted with R39, Ci-C6alkyl-R98 and heteroaryl substituted with R39.
106. The compound according to clause 105, wherein R14 is C3-C10heterocyclyl substituted with R37.
107. The compound according to clause 106, wherein R14 is selected from the group consisting of with R37 substituted tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
108. The compound according to clause 105, wherein R14 is C3-Ci0cycloalkyl substituted with R37 109. The compound according to clause 108, wherein R14 is selected from the group consisting of with R37 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.
110. The compound according to clause 105, wherein R14 is aryl substituted with R39.
111. The compound according to clause 110, wherein R14 is phenyl substituted with R39.
112. The compound according to clause 105, wherein R14 is Ci-C6alkyl-R98.
113. The compound according to clause 112, wherein R14 is selected from the group consisting of with R98 substituted methyl, ethyl and isopropyl.
114. The compound according to clause 105, wherein R14 is heteroaryl substituted with R39.
115. The compound according to clause 114, wherein R14 is selected from the group consisting of with R39 substituted imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
116. The compound according to any one of the preceding clauses, wherein R22 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, isopropyl, cyclobutyl and cyclopropyl wherein said cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
117. The compound according to clause 116, wherein R22 is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.
118. The compound according to any one of the preceding clauses, wherein R23 is selected from the group consisting of hydrogen, fluorine, chlorine, methyl, isopropyl, cyclobutyl and cyclopropyl wherein said cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
119. The compound according to clause 118, wherein R23 is selected from the group consisting of hydrogen, fluorine, chlorine and methyl.
120. The compound according to any one of the clauses 1-115, wherein R22 and R23 together with the carbon atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl ring is optionally substituted with hydroxy or fluorine. 121. The compound according to any one of the clauses 1-115, wherein R22 and R23 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl ring is optionally substituted with hydroxy or fluorine.
122. The compound according to any one of the preceding clauses, wherein R86 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
123. The compound according to clause 122, wherein R86 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
124. The compound according to any one of the preceding clauses, wherein R87 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
125. The compound according to clause 124, wherein R87 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
126. The compound according to any one of the clauses 1-121, wherein R86 and R87 together with the carbon atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl are optionally substituted with hydroxy or fluorine.
127. The compound according to any one of the clauses 1-121, wherein R86 and R87 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl are optionally substituted with hydroxy or fluorine.
128. The compound according to any one of the preceding clauses, wherein R88 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
129. The compound according to clause 125, wherein R88 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
130. The compound according to any one of the preceding clauses, wherein R89 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, cyclopropyl and cyclobutyl, wherein said ethyl, cyclopropyl and cyclobutyl are optionally substituted with one or two substituents independently selected from the group consisting of fluorine and hydroxy.
131. The compound according to clause 127, wherein R89 is selected from the group consisting of hydrogen, fluorine, methyl and ethyl.
132. The compound according to any one of the clauses 1-127, wherein R88 and R89 together with the carbon atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl are optionally substituted with hydroxy or fluorine.
133. The compound according to any one of the clauses 1-127, wherein R88 and R89 together with the carbon atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl are optionally substituted with hydroxy or fluorine.
134. The compound according to any one of the preceding clauses, wherein R26 is selected from the group consisting of hydrogen, C3-Ci0heterocyclyl substituted with R37, C3-C10cycloalkyl substituted with R38, phenyl substituted with R39 and R40, CrCsalkyl-R98 and heteroaryl substituted with R39 and R40.
135. The compound according to clause 134, wherein R26 is hydrogen.
136. The compound according to clause 134, wherein R26 selected from the group consisting of with R37 substituted tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
137. The compound according to clause 134, wherein R26 selected from the group consisting of with R38 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl substituted with R38.
138. The compound according to clause 134, wherein R26 is phenyl substituted with R39.
139. The compound according to clause 134, wherein R26 selected from the group consisting of with R98 substituted methyl, ethyl and isopropyl.
140. The compound according to clause 134, wherein R26 selected from the group consisting of substituted with R39 imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl. 141. The compound according to any one of the preceding clauses, wherein R27 is selected from the group consisting of hydrogen, C3-Ci0heterocyclyl substituted with R37, C3-C10cycloalkyl substituted with R38, phenyl substituted with R39 and R40, Ci-Csalkyl-R98 and heteroaryl substituted with R39 and R40.
142. The compound according to clause 141, wherein R27 is hydrogen.
143. The compound according to clause 141, wherein R27 selected from the group consisting of with R37 substituted tetrahydropyranyl, piperidinyl, pyrrolidinyl and morpholinyl.
144. The compound according to clause 141, wherein R27 selected from the group consisting of with R38 substituted cyclopropyl, cyclobutyl, cyclohexyl and cyclopentyl.
145. The compound according to clause 141, wherein R27 is phenyl substituted with R39.
146. The compound according to clause 141, wherein R27 selected from the group consisting of with R98 substituted methyl, ethyl and isopropyl.
147. The compound according to clause 124, wherein R27 selected from the group consisting of substituted with R39 imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl.
148. The compound according to clause 1, wherein m is 0.
149. The compound according to clause 1, wherein m is 1.
150. The compound according to any one of the preceding clauses, wherein R15, R16, R20, R21, R24, R25 and R45 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with R41.
151. The compound according to clause 150, wherein R15, R16, R20, R21, R24, R25 and R45 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, phenyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with R41.
152. The compound according to any one of the preceding clauses, wherein R17, R18 and R19 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine, chlorine, trifluoromethyl, methyl or hydroxy.
153. The compound according to clause 152, wherein R17, R18 and R19 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine, chlorine, methyl or hydroxy.
154. The compound according to any one of the clauses 1-151, wherein R17 and R18 together with the nitrogen atom to which they are attached form a cyclopropyl ring, wherein said ring are optionally substituted with hydroxy or halogen.
155. The compound according to any one of the clauses 1-151, wherein R17 and R18 together with the nitrogen atom to which they are attached form a cyclobutyl ring, wherein said ring are optionally substituted with hydroxy or halogen.
156. The compound according to any one of the preceding clauses, wherein R28, R29, R32, R33, R34, R35, R36, R37, R38, R39 R98 and R40 are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, heteroaryl and C3-Ci0cycloalkyl, wherein said Ci-C6alkyl, heteroaryl and C3-Ci0cycloalkyl are optionally substituted with halogen, methyl, triflouromethyl, methoxy or hydroxy.
157. The compound according to clause 156, wherein R28, R29, R32, R33, R34, R35, R36, R37, R38, R39 R98 and R40 are each independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrol id iny I, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl are optionally substituted with halogen, methyl, triflouromethyl, methoxy or hydroxy.
158. The compound according to clause 157, wherein R28, R29, R32, R33, R34, R35, R36, R37, R38, R39 R98 and R40 are each independently selected from the group consisting of hydrogen, hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl, pyrimidinyl and pyridinyl are optionally substituted with halogen, methyl, triflouromethyl, methoxy or hydroxy.
159. The compound according to any one of the preceding clauses, wherein R30 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, isopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said methyl, ethyl, cyclopropyl, isopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with halogen or hydroxy.
160. The compound according to clause 146, wherein R30 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl and isopropyl, wherein said ethyl, cyclopropyl and isopropyl are optionally substituted with halogen or hydroxy.
161. The compound according to any one of the preceding clauses, wherein R31 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, isopropyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said methyl, cyclopropyl, isopropyl tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with halogen or hydroxy.
162. The compound according to clause 161, wherein R31 is selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl and isopropyl, wherein said ethyl, cyclopropyl and isopropyl are optionally substituted with halogen or hydroxy.
163. The compound according to any one of the clauses 1-150, wherein R30 and R31 together with the nitrogen atom to which they are attached form a cyclopropyl ring, wherein said ring is optionally substituted with hydroxy or halogen. 164. The compound according to any one of the clauses 1-150, wherein R30 and R31 together with the nitrogen atom to which they are attached form a cyclobutyl ring, wherein said ring is optionally substituted with hydroxy or halogen.
165. The compound according to any one of the preceding clauses, wherein R41 is selected from the group consisting of fluorine, chlorine, hydroxy, oxo, -C(=O)OH, -S(=O)2methyl, -
S(=O)2NH-isopropyl, -S(=O)2NH-cyclopropyl, trifluoromethyl, -S(=O)2NH-methyl, cyclopropyl, -O-methyl, methyl, ethyl, isopropyl, -C(=O)NH-methyl, -NHC(=O)NH-methyl; - NHS(=O)2methyl and -N(C=O)methyl.
166. The compound according to clause 165, wherein R41 is selected from the group consisting of fluorine, chlorine, trifluoromethyl, hydroxy, oxo, -C(=O)OH, -S(=O)2methyl, - S(=O)2NH-isopropyl, -S(=O)2NH-methyl, cyclopropyl, methyl, isopropyl, -C(=O)NH-methyl, - NHC(=O)NH-methyl; -NHS(=O)2methyl and -N(C=O)methyl.
167. The compound according to any one of the preceding clauses, wherein R42 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, are optionally substituted with one or two substituents independently selected from the group consisting of halogen, methyl, triflouromethyl, methoxy and hydroxy.
168. The compound according to clause 167, wherein R42 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine, chlorine, halogen, methyl, triflouromethyl or hydroxy.
169. The compound according to any one of the preceding clauses, wherein R43 is selected from the group consisting hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy.
170. The compound according to clause 169, wherein R43 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine or hydroxy.
171. The compound according to any one of the preceding clauses, wherein R44 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, imidazolyl, pyrazolyl, isoxazolyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy.
172. The compound according to clause 171, wherein R44 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl, wherein said methyl, ethyl and isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, phenyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, pyridazinyl, pyrazinyl pyrimidinyl and pyridinyl are optionally substituted with fluorine or hydroxy.
173. The compound according to any one of the clauses 1-168, wherein R43 and R44 together with the nitrogen atom to which they are attached form a cyclopropyl ring, wherein said cyclopropyl is optionally substituted with hydroxy or halogen.
174. The compound according to any one of the clauses 1-168, wherein R43 and R44 together with the nitrogen atom to which they are attached form a cyclobutyl ring, wherein said cyclobutyl is optionally substituted with hydroxy or halogen.
175. The compound selected from the group consisting of N-(5-Hydroxy-adamantan-2-yl)-4- methanesulfonylmethoxy-benzamide, N-(5-Hydroxy-tricyclo[3,3,l,l,3,7]decan-2-yl)-4- methanesulfonylmethoxy-N-methyl-benzamide, 4-(4-Methanesulfonylmethoxy- benzoylamino)- adamantane-1-carboxylic acid, N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4- {2-[l-(pyridine-2-sulfonyl)-piperidin-4-yl]-ethoxy}-benzamide, N-(5-Hydroxy-adamantan-2- yl)-4-{2-[l-(pyridine-2-sulfonyl)-piperidin-4-yl]-ethoxy}-benzamide, 4-(2-{4-[(5-Hydroxy- adamantan-2-yl)-methyl-carbamoyl]-phenoxy}-ethyl)-piperidine-l-carboxylic acid isopropylamide, 4-{2-[4-(5-Hydroxy-adamantan-2-ylcarbamoyl)-phenoxy]-ethyl}-piperidine- 1-carboxylic acid isopropylamide, N-(5-Hydroxy-tricyclo[3.3.1.1.3.7]decan-2-yl)-N-methyl-4- phenethyloxy-benzamide, N-(5-Hydroxy-tricyclo[3.3.1.1.3.7]decan-2-yl)-4-phenethyloxy- benzamide, 4-{2-[l-(2-Hydroxy-2-methyl-propionyl)-piperidin-4-yl]-ethoxy}-N-(5-hydroxy- adamantan-2-yl)-N-methyl-benzamide, 4-{2-[l-(3-Hydroxy-2,2-dimethyl-propionyl)- piperidin-4-yl]-ethoxy}-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide, 4-{2-[l-(3- Hydroxy-2,2-dimethyl-propionyl)-piperidin-4-yl]-ethoxy}-N-(5-hydroxy-adamantan-2-yl)- benzamide, N-(5-Hydroxy-tricyclo[3.3.1.1.3.7]decan-2-yl)-N-methyl-4-(2-phenyl- ethanesulfonylmethoxy)-benzamide, 4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-N-(5-hydroxy- tricyclo[3.3.1.13,7]decan-2-yl)-N-methyl-benzamide, N-(5-Hydroxy-adamantan-2-yl)-N- methyl-4-[2-(tetrahydro-pyran-4-yl)-ethoxy] -benzamide, N-(5-Hydroxy-adamantan-2-yl)-4- [2-(tetrahydro-pyran-4-yl)-ethoxy] -benzamide, 4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-N-(5- hydroxy-adamantan-2-yl)-benzamide, N-(5-Hydroxy-adamantan-2-yl)-4-(pyridine-2- sulfonylmethoxy)-benzamide, and N-(5-Hydroxy-tricyclo[3.3.1.1.3.7]decan-2-yl)-N-methyl- 4-(pyridine-2-sulfonylmethoxy)-benzamide.
176. A compound according to any one of the above 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 llβHSDl is beneficial.
177. A compound according to any one of the clauses 1-175, 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.
178. A compound according to any one of the clauses 1-175, 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.
179. A compound according to any one of the clauses 1-175, which is an agent useful for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
180. A compound according to any one of the clauses 1-175, which is an agent useful for the delaying or prevention of the progression from IGT into type 2 diabetes. 181. A compound according to any one of the clauses 1-175, which is an agent useful for delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
182. A compound according to any one of the clauses 1-175, which is an agent useful for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
183. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the clauses 1-182 together with one ore more pharmaceutically acceptable carriers or excipients.
184. The pharmaceutical composition according to clause 183 which is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration.
185. The pharmaceutical composition according to clause 183 or 184 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 1-175.
186. A use of a compound according to any of the clauses 1-182, 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 llβHSDl is beneficial.
187. A use of a compound according to any of the clauses 1-182, 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.
188. A use of a compound according to any of the clauses 1-182, 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.
189. A use of a compound according to any of the clauses 1-182, 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). 190. A use of a compound according to any of the clauses 1-182, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
191. A use of a compound according to any of the clauses 1-182, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
192. A use of a compound according to any of the clauses 1-182, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
193. 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 llβHSDl is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to any of the clauses 1-182.
194. The method according to clause 193 wherein the conditions, disorders or diseases are selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
195. The compound according to any one of the clauses 1-182, wherein Q is selected from the group consisting of -S(=O)2NR5R6, -CH2OH, -C(CH3)HOH, -C(CH3)2OH, 1-cyclopropanol, - 0-CH2CH2-OH and -C(=O)NR7R8.
196. The compound according to any one of the clauses 1-182, wherein Q is hydroxy.

Claims

1. A compound of the general formula (I) :
Figure imgf000091_0001
(I)
wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl and cyclopropyl and R2 is selected from the group consisting of a monovalent radical having one of the following formulae, wherein the symbol * denotes the point of attachment:
Figure imgf000091_0002
Figure imgf000091_0004
Figure imgf000091_0003
Q is selected from the group consisting of hydroxy, -S(=O)2NR5R6, -CH2OH, -C(CH3)HOH, - C(CH3)2OH, 1-cyclopropanol, -0-CH2CH2-OH and -C(=O)NR7R8;
R5 is selected from the group consisting of hydrogen, cyclopropyl and Ci-C4alkyl, wherein said cyclopropyl and Ci-C4alkyl are optionally substituted with one or two independently selected
R9;
R6 is selected from the group consisting of cyclopropyl and Ci-C4alkyl, wherein said cyclopropyl and Ci-C4alkyl are optionally substituted with one or two independently selected R9; or R5 and R6 together with the nitrogen atom to which they are attached form a 4 to 6 membered ring optionally substituted with one or two independently selected R9;
R7 and R8 are each independently selected from the group consisting of hydrogen, cyclopropyl and C1-C4SIkVl, wherein said cyclopropyl and C!-C4alkyl are optionally substituted with one or two independently selected R9; or R7 and R8 together with the nitrogen atom to which they are attached form a 4 to 6 membered ring optionally substituted with one or two independently selected R9;
R4 is selected from the group consisting of hydrogen, Ci-C4alkyl, cyclopropyl, trifluoromethyl, halogen, -S(=O)2methyl, -CH2OH, -O-cyclopropyl and -O-Ci-C4alkyl, wherein said cyclopropyl, Ci-C4alkyl, -O-cyclopropyl and -O-Ci-C4alkyl are optionally substituted with R9;
R95 is selected from the group consisting of Ci-C6alkyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl, wherein said Q-Csalkyl, phenyl, pyridinyl, pyrimidinyl, cyclopropyl, cyclobutyl and cyclohexyl are optionally substituted with one or two independently selected R96;
R96 is selected from the group consisting of halogen, hydroxy, trifluoromethyl, methyl, cyclopropyl, carboxy and -S(=O)2methyl;
R97 is selected from the group consisting of hydrogen, cyclopropyl and Ci-C4alkyl;
R9 is selected from the group consisting of hydrogen, CVQalkyl, cyclopropyl, hydroxy, halogen, trifluoromethyl, -CH2OH and carboxy;
X1 is selected from the group consisting of -CR10R11-, -O-, -S-, -S(=O)- and -S(=O)2-;
X2 is selected from the group consisting of -CR86R87-, -O-, -S-, -S(=O)-, -S(=O)2- and -NR24-;
X3 is selected from the group consisting of -CR88R89-, -O-, -S-, -S(=O)-, -S(=O)2- and -NR25-;
R10 and R11 are each independently selected from the group consisting of hydrogen, hydroxy, methyl, ethyl, -CH2OH, fluorine, isopropyl and cyclopropyl; or R10 and R11 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl is optionally substituted with hydroxy or fluorine;
R3 is selected from the group consisting of Ci-C4alkyl substituted with R13 and R14, C3- Cioheterocyclyl substituted with R13 and R14, C3-Ci0cycloalkyl substituted with R13 and R14, aryl substituted with R13 and R14, heteroaryl substituted with R13 and R14, -C(=O)R15, -CH(OH)R16, -(CR22R23)π-C(=O)-NR17R18, -(CR22R23)π-NR19C(=O)R20, -(CR22R23)π-OR21, -(CR22R23)π-SR21 , - (CR22R23)π-S(=O)2R24, -(CR22R23)π-S(=O)2NR17R18, -(CR22R23)π-NR17S( = O)2R25, -(CR22R23),- NR17R18, -(CR22R23)π-NR17C(=O)-NR17R18, -(CR22R23)π-C=CR45R26 and -(CR22R23)π-C≡C-R27; n is selected from the group consisting of 0, 1 and 2;
R13 and R14 are each independently selected from the group consisting of hydrogen, hydroxy, halogen, -C(=O)OH, -C(=O)R28, -CH(OH)-R29, -(CR22R23)m-C(=O)-NR30R31, - (CR22R23)m-NR30C(=O)R28, -(CR22R23)m-OR32, -(CR22R23)m-SR32, -(CR22R23)m-S(=O)2R33, - (CR22R23)m-S( = O)2NR30R31, -(CR22R23)m-NR30S(=O)2R33, -(CR22R23)m-NR30R31, -(CR22R23)m- NR30C(=O)-NR30R31, -(CR22R23)m-C=CR34R35, -(CR22R23)m-C≡C-R36, -(CR22R23)m-C3-C10hetero- cyclyl substituted with R37 and R38, -(CR22R23)m-C3-C10cycloalkyl substituted with R37 and R38, - (CR22R23)m-aryl substituted with R39 and R40, Q-Csalkyl-R98 and -(CR22R23)m-heteroaryl substituted with R39 and R40;
R22 and R23 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl and C3-Ci0cycloalkyl, wherein said Ci-C6alkyl and C3-Ci0cycloalkyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R22 and R23 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen;
R86 and R87 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl and C3-Ci0cycloalkyl, wherein said Ci-C6alkyl and C3-Ci0cycloalkyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R86 and R87 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen;
R88 and R89 are each independently selected from the group consisting of hydrogen, halogen, Ci-C6alkyl and C3-Ci0cycloalkyl, wherein said Ci-C6alkyl and C3-Ci0cycloalkyl independently are optionally substituted with one or two substituents independently selected from the group consisting of halogen, hydroxy and oxo; or R88 and R89 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl are optionally substituted with hydroxy or halogen;
R26 and R27 are each independently selected from the group consisting of hydrogen, -(CR22- R23)m-CO-NR30R31, -(CR22R23)m-NR30C(=O)R28, -(CR22R23)m-OR32, -(CR22R23)m-SR32, -(CR22- R23)m-S(=O)2R33, -(CR22R23)m-S(=O)2NR30R31, -(CR22R23)m-NR30S(=O)2R33, -(CR22R23)m-NR30- C(=O)-NR30R31, -(CR22R23)m-C3-C10heterocyclyl substituted with R37, -(CR22R23)m- C3-C10cyclo- alkyl substituted with R38, -(CR22R23)m-aryl substituted with R39 and R40, Q-Csalkyl-R98 and - (CR22R23)m-heteroaryl substituted with R39 and R40; m is 0 or 1;
R15, R16, R20, R21, R24, R25 and R45 are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, C3-Ci0heterocyclyl, C3-Ci0cycloalkyl, aryl and heteroaryl, wherein said Ci-C6alkyl, C3-Ci0heterocyclyl, C3-Ci0cycloalkyl, aryl and heteroaryl are optionally substituted independently with one, two or three independently selected R41;
R17, R18 and R19 are each independently selected from the group consisting of hydrogen, Ci-Csalkyl, C3-C10cycloalkyl, phenyl and heteroaryl, wherein said CVCsalkyl, C3-C10cycloalkyl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, ethyl and hydroxy; or R17 and R18 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said ring are optionally substituted with hydroxy, trifluoromethyl or halogen;
R28, R29, R32, R33, R34, R35, R36, R37, R38, R39 R98 and R40 are each independently selected from the group consisting of hydrogen, C1-C6SIkYl, phenyl, heteroaryl and C3-C10cycloalkyl, wherein said Ci-C6alkyl, phenyl, heteroaryl and C3-Ci0cycloalkyl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, triflouromethyl, methoxy and hydroxy;
R30 and R31 are each independently selected from the group consisting of hydrogen, Ci-C6alkyl, tetrahydropyrane, cyclohexyl and cyclopentyl, wherein said Ci-C6alkyl, tetrahydropyrane, cyclohexyl and cyclopentyl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy, or R30 and R31 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said ring is optionally substituted with hydroxy or halogen;
R41 is selected from the group consisting of halogen, hydroxy, oxo, -C(=O)OH, -S(=O)2R42, - S-NR43R44, -SC=O)2NR43R44, cyclopropyl, trifluoromethyl, -OR42, -SR42, d-Qsalkyl, - C(=O)NR43R44, -NR43CC=O)NR44R43; -NR43S(=O)2R42 and -N(C=O)R42;
R42 is selected from the group consisting of hydrogen, d-Qalkyl, C3-C10cycloalkyl, aryl and heteroaryl, wherein said Ci-C6alkyl, C3-Ci0cycloalkyl, aryl and heteroaryl are optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, methyl, triflouromethyl, methoxy and hydroxy;
R43 and R44 are each independently selected from the group consisting of hydrogen,
Ci-C6alkyl, C3-Ci0heterocyclyl, C3-Ci0cycloalkyl and heteroaryl, wherein said Ci-C6alkyl, C3- C10heterocyclyl, C3-C10cycloalkyl and heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of halogen and hydroxy, or R43 and R44 together with the nitrogen atom to which they are attached form a cyclopropyl or cyclobutyl ring, wherein said cyclopropyl or cyclobutyl is optionally substituted with hydroxy or halogen;
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 claim 1, wherein R2 is selected from the group consisting of:
Figure imgf000095_0001
3. The compound according to any one of the preceding claims, wherein -X1-X2-X3- is selected from the group consisting of -O-CR86R87-CR88R89- and -O-CR86R87-S(=O)2-.
4. The compound according to any one of the claims 1-3, wherein -X1-X2-X3- is selected from the group consisting of -R10Rn-CR86R87-S(=O)2-, -CR10Rn-CR86R87-S-, -CR10Rn-CR86R87-O-, - CR10Rn-CR86R87-NR25-, -CR10Rn-CR86R87-CR88R89-, -CR10Rn-S(=O)2-NR25- and -CR10Rn-NR24- SC=O)2-.
5. The compound according to any one of the preceding claims, wherein R3 is selected from the group consisting of Ci-C4alkyl substituted with R13 and R14, C3-Ci0heterocyclyl substituted with R13 and R14, C3-Ci0cycloalkyl substituted with R13 and R14, aryl substituted with R13 and R14, heteroaryl substituted with R13 and R14.
6. The compound according to any one of the preceding claims, wherein R3 is selected from the group consisting of -C(=O)R15, -CH(OH)R16, -(CR22R23)π-C(=O)-NR17R18, -(CR22R23V
NR19C(=O)R20, -(CR22R23VOR21, -(CR22R23)π-SR21 , -(CR22R23)π-S(=O)2R24, -(CR22R23V S(=O)2NR17R18, -(CR22R23)π-NR17S(=O)2R25, -(CR22R23VNR17R18, -(CR22R23)π-NR17C(=O)- NR17R18, -(CR22R23VC=CR45R26 and -(CR22R23)π-C≡C-R27.
7. The compound selected from the group consisting of N-(5-Hydroxy-adamantan-2-yl)-4- methanesulfonylmethoxy-benzamide, N-(5-Hydroxy-tricyclo[3,3,l,l,3,7]decan-2-yl)-4- methanesulfonylmethoxy-N-methyl-benzamide, 4-(4-Methanesulfonylmethoxy-benzoyl- amino)- adamantane-1-carboxylic acid, N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-{2-[l- (pyridine-2-sulfonyl)-piperidin-4-yl]-ethoxy}-benzamide, N-(5-Hydroxy-adamantan-2-yl)-4- {2-[l-(pyridine-2-sulfonyl)-piperidin-4-yl]-ethoxy}-benzamide, 4-(2-{4-[(5-Hydroxy- adamantan-2-yl)-methyl-carbamoyl]-phenoxy}-ethyl)-piperidine-l-carboxylic acid isopro- pylamide, 4-{2-[4-(5-Hydroxy-adamantan-2-ylcarbamoyl)-phenoxy]-ethyl}-piperidine-l- carboxylic acid isopropylamide, N-(5-Hydroxy-tricyclo[3.3.1.1.3.7]decan-2-yl)-N-methyl-4- phenethyloxy-benzamide, N-(5-Hydroxy-tricyclo[3.3.1.1.3.7]decan-2-yl)-4-phenethyloxy- benzamide, 4-{2-[l-(2-Hydroxy-2-methyl-propionyl)-piperidin-4-yl]-ethoxy}-N-(5-hydroxy- adamantan-2-yl)-N-methyl-benzamide, 4-{2-[l-(3-Hydroxy-2,2-dimethyl-propionyl)-piperi- din-4-yl]-ethoxy}-N-(5-hydroxy-adamantan-2-yl)-N-methyl-benzamide, 4-{2-[l-(3-Hydroxy- 2,2-dimethyl-propionyl)-piperidin-4-yl]-ethoxy}-N-(5-hydroxy-adamantan-2-yl)-benzamide, N-(5-Hydroxy-tricyclo[3.3.1.1.3.7]decan-2-yl)-N-methyl-4-(2-phenyl-ethanesulfonylmeth- oxy)-benzamide, 4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-N-(5-hydroxy-tricyclo[3.3.1.13,7]de- can-2-yl)-N-methyl-benzamide, N-(5-Hydroxy-adamantan-2-yl)-N-methyl-4-[2-(tetrahydro- pyran-4-yl)-ethoxy]-benzamide, N-(5-Hydroxy-adamantan-2-yl)-4-[2-(tetrahydro-pyran-4- yl)-ethoxy]-benzamide, 4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-N-(5-hydroxy-adamantan-2-yl)- benzamide, N-(5-Hydroxy-adamantan-2-yl)-4-(pyridine-2-sulfonylmethoxy)-benzamide, and N-(5-Hydroxy-tricyclo[3.3.1.1.3.7]decan-2-yl)-N-methyl-4-(pyridine-2-sulfonylmethoxy)- benzamide.
8. A compound according to any one of the above 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 llβHSDl is beneficial.
9. A 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. A 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 compound according to any one of the claims 1-7, which is an agent useful for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance
(IGT), impaired fasting glucose (IFG).
12. A compound according to any one of the claims 1-7, which is an agent useful for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
13. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of the claims 1-12 together with one ore more pharmaceutically acceptable carriers or excipients.
14. A use of a compound according to any of the claims 1-12, 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 llβHSDl is beneficial.
15. A use of a compound according to any of the claims 1-12, 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.
16. A use of a compound according to any of the claims 1-12, 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.
17. A use of a compound according to any of the claims 1-12, 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).
18. A use of a compound according to any of the claims 1-12, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
19. 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 llβHSDl is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to any of the claims 1-12.
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