WO2004089367A1 - Pharmaceutical use of substituted 1,2,4-triazoles - Google Patents

Pharmaceutical use of substituted 1,2,4-triazoles Download PDF

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Publication number
WO2004089367A1
WO2004089367A1 PCT/DK2004/000249 DK2004000249W WO2004089367A1 WO 2004089367 A1 WO2004089367 A1 WO 2004089367A1 DK 2004000249 W DK2004000249 W DK 2004000249W WO 2004089367 A1 WO2004089367 A1 WO 2004089367A1
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Prior art keywords
phenyl
triazol
ethyl
methyl
ylsulfanyl
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PCT/DK2004/000249
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French (fr)
Inventor
Henrik Sune Andersen
Gita Camilla Tejlgaard Kampen
Inge Thøger Christensen
John Patrick Mogensen
Annette Rosendal Larsen
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Novo Nordisk A/S
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Priority to EP04725885A priority Critical patent/EP1615637A1/en
Priority to JP2006504352A priority patent/JP2006522745A/en
Publication of WO2004089367A1 publication Critical patent/WO2004089367A1/en
Priority to US11/246,455 priority patent/US20060100235A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
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    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to use of substituted 1 ,2,4-triazoles and pharmaceutical compositions comprising the compounds for treating disorders where it is desirable to modulate the activity of 11 ⁇ -hydroxysteroid dehydrogenase type 1 (11 ⁇ HSDl ).
  • the present invention also relates to novel substituted 1 ,2,4-triazoles, to their use in therapy, to pharmaceutical compositions comprising the compounds, to the use of said compounds in the manufacture of medicaments, and to therapeutic methods comprising the administration of said compounds.
  • the present compounds modulate the activity of 11 ⁇ - hydroxysteroid dehydrogenase type 1 (11 ⁇ HSDl ) and are accordingly useful in the treatment of diseases in which such a modulation is beneficial, such as the metabolic syndrome.
  • the metabolic syndrome is a major global health problem. In the US, the prevalence in the adult population is currently estimated to be approximately 25%, and it continues to increase both in the US and worldwide.
  • the metabolic syndrome is characterised by a combination of insulin resistance, dyslipidemia, obesity and hypertension leading to increased morbidity and mortality of cardiovascular diseases. People with the metabolic syndrome are at increased risk of developing frank type 2 diabetes, the prevalence of which is equally escalating. In type 2 diabetes, obesity and dyslipidemia are also highly prevalent and around
  • 11 ⁇ -hydroxysteroid dehydrogenase type 1 (11 ⁇ HSDl ) catalyses the local generation of active glucocorticoid in several tissues and organs including predominantly the liver and adipose tissue,, but also e.g. skeletal muscle, bone, pancreas, endothelium, ocular tissue and certain parts of the central nervous system.
  • 11 ⁇ HSDl serves as a local regulator of glucocorticoid actions in the tissues and organs where it is expressed (Tannin et al., J. Biol.
  • 11 ⁇ HSDl in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence.
  • treatment with the non-specific 11 ⁇ HSDl inhibitor carbenoxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes.
  • 11 ⁇ HSDl knock-out mice are resistant to insulin resistance induced by obesity and stress. Additionally, the knock-out mice present with an anti-atherogenic lipid profile of decreased VLDL triglycerides and increased HDL-cholesterol.
  • mice that overexpress 11 ⁇ HSDl in adipocytes develop insulin resistance, hyperlipidemia and vis- ceral obesity, a phenotype that resembles the human metabolic syndrome (Andrews et al., J. Clin.
  • 11 ⁇ HSDl modulation and thereby modulation of intracellular levels of active glucocorticoid have been investigated in several rodent models and different cellular systems.
  • 11 ⁇ HSDl promotes the features 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 stimulat- ing hepatic VLDL secretion, decreasing hepatic LDL uptake and increasing vessel contractility (Kotelevtsev et al., Proc. Natl. Acad. Sci.
  • WO 01/90090, WO 01/90091 , WO 01/90092, WO 01/90093 and WO 01/90094 dis- closes various thiazol-sulfonamides as inhibitors of the human 11 ⁇ -hydroxysteroid dehydrogenase type 1 enzyme, and further states that said compounds may be useful in treating diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders and depression.
  • the present compounds can be used to treat disorders where a decreased level of active intracellular glucocorticoid is desirable, such as e.g.
  • One object of the present invention is to provide compounds, pharmaceutical compositions and use of compounds that modulate the activity of 11 ⁇ HSDl .
  • halo includes fluorine, chlorine, bromine, and iodine.
  • trihalomethyl includes trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.
  • trihalomethoxy includes trifluorometoxy, trichlorometoxy, tribromometoxy, and triiodometoxy.
  • alkyl includes C C 6 straight chain saturated and methylene aliphatic hydrocarbon groups, C 3 -C 6 branched saturated hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, isopropyl (i-Pr), isobutyl (i-Bu), .erf-butyl (f-Bu), sec-butyl (s-Bu), isopentyl, neopentyl, and the like.
  • alkenyl includes C 2 -C 6 straight chain unsaturated aliphatic hydrocarbon groups and branched C 3 -C 6 unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl, methylbutenyl and the like.
  • alkynyl includes C 2 -C 6 straight chain unsaturated aliphatic hydrocarbon groups and C 4 -C 6 branched unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • this definition shall include but is not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylbutynyl, and the like.
  • saturated or partially saturated cyclic, bicyclic or tricyclic ring system represents but are not limit to aziridinyl, pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, morpholinyl, piperidinyl, thiomorpholinyl, piperazinyl, phthalimide, 1 ,2,3,4- tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1 ,2,3,4-tetrahydro-quinoxalinyl, and indolinyl.
  • cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep- tyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like
  • heteroalkyl (tetrahydrofuranyl, tetrahydropyranyl, tertahydrothiopyranyl, and the like) represents a saturated mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms and one or two additional heteroatoms or groups selected from nitrogen, oxygen, sulphur, SO or S0 2 .
  • alkyloxy (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge.
  • alkyloxyalkyl (e.g. methyloxymethyl and the like) represents an alkyloxy group as defined above attached through an “alkyl” group.
  • aryloxy e.g. phenoxy, naphthyloxy and the like
  • aryloxy represents an aryl group as defined below attached through an oxygen bridge.
  • hetaryloxy e.g. 2-pyridyloxy and the like
  • hetaryloxy represents a hetaryl group as defined below attached through an oxygen bridge.
  • arylalkyloxy e.g. phenethyloxy, naphthylmethyloxy and the like
  • arylalkyloxy represents an arylalkyl group as defined below attached through an oxygen bridge.
  • hetarylalkyloxy e.g. 2-pyridylmethyloxy and the like
  • alkyloxycarbonyl e.g. methylformiat, ethylformiat and the like
  • aryloxycarbonyl e.g. phenylformiat, 2-thiazolylformiat and the like
  • aryloxycarbonyl represents an aryloxy group as defined above attached through a carbonyl group.
  • arylalkyloxycarbonyl e.g. benzylformiat, phenyletylformiat and the like
  • arylalkyloxycarbonyl represents an “arylalkyloxy” group as defined above attached through a carbonyl group.
  • arylalkyl e.g. benzyl, phenylethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like
  • arylalkyl represents an aryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • heteroarylalkyl and “hetaralkyl” (e.g.
  • (2-furyl)methyl, (3-furyl)methyl, (2- thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like) represents a hetaryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above.
  • alkylcarbonyl e.g. octylcarbonyl, pentylcarbonyl, 3-hexenylcarbonyl
  • alkylcarbonyl represents an alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
  • arylcarbonyl e.g. benzoyl
  • arylcarbonyl represents an aryl group as defined below at- tached through a carbonyl group.
  • hetarylcarbonyl e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like
  • hetarylcarbonyl represents a hetaryl group as defined below attached through a carbonyl group.
  • carbonylalkyl (e.g. acetyl and the like) represents a carbonyl group at- tached through alkyl group as defined above having the indicated number of carbon atoms.
  • alkylcarbonylalkyl e.g. propan-2-one, 4,4-dimethyl-pentan-2-one and the like
  • alkylcarbonylalkyl represents an alkylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • arylcarbonylalkyl e.g. 1-phenyl-propan-1-one, 1-(3-chloro-phenyl)-2- methyl-butan-1-one and the like
  • arylcarbonylalkyl represents a arylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
  • hetarylcarbonylalkyl e.g. 1-pyridin-2-yl-propan-1-one, 1-(1-H-imidazol-2- yl)-propan-1-one and the like
  • arylalkylcarbonyl e.g. phenylpropylcarbonyl, phenylethylcarbonyl and the like
  • hetarylalkylcarbonyl (e.g. imidazolylpentylcarbonyl and the like) represents an hetarylalkyl group as defined above wherein the alkyl group is in turn attached through a carbonyl.
  • alkylcarboxy e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy
  • alkylcarboxy represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • arylcarboxy e.g. benzoic acid and the like
  • arylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • arylalkylcarboxy e.g. benzylcarboxy, phenylpropylcarboxy and the like
  • arylalkylcarboxy represents an arylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
  • hetarylalkylcarboxy e.g. (1-H-imidazol-2-yl)-acetic acid, 3-pyrimidin-2-yl- propionic acid and the like
  • aryl includes but is not limited to a carbocyclic aromatic ring system be- ing either monocyclic, bicyclic, or polycyclic, such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like.
  • aryll includes phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, and fluorenyl.
  • aryl2 includes phenyl, biphenyl, naphthyl, and anthracenyl.
  • heteroaryl includes but is not limited to pyrrolyl (2-pyrrolyl), pyrazolyl (3- pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1 ,2,3- triazol-1 -yl, 1 ,2,3-triazol-2-yl 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4- oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl
  • NR 4 R 5 carbonylalkyl (e.g. ⁇ /, ⁇ /-dimethyl-propionamide, ⁇ /-isopropyl- ⁇ /- methyl-propionamide and the like) represents NR 4 R 5 substituted by a carbonylalkyl group as defined above.
  • arylR 8 alkyl e.g. ethoxy-benzene, ethyl-methyl-phenyl-amine, ⁇ /-ethyl- benzamide, ⁇ /-isobutyl-benzenesulfonamide and the like
  • R 8 represents an aryl group as defined above, substituted by R 8 , which is substituted by an alkyl group as defined above.
  • hetarylR 8 alkyl e.g.
  • 2-ethoxy-1/-/-imidazol, ethyl-quinolin-2-yl-amine, thia- zole-2-carboxylic acid, methyl-propyl-amide, pyridine-3-sulfonic acid isobutyl-amide and the like) represents a hetaryl group as defined above, substituted by R 8 , which is substituted by an alkyl group as defined above.
  • arylcarbonylNR 15 (e.g. A/-benzyl- ⁇ /-methyl-benzamide and the like) represents an arylcarbonyl group as defined above, substituted by NR 15 .
  • treatment is defined as the management and care of a patient for the purpose of combating or alleviating the disease, condition or disorder, and the term includes the administration of the active compound to prevent the onset of the symptoms or complica- tions, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • prodrug is defined as being suitable for administration to humans without adverse events.
  • prodrug is defined as a chemically modified form of the active drug, said prodrug being administered to the patient and subsequently being converted to the active drug. Techniques for development of prodrugs are well known in the art.
  • One aspect of the present invention is the use of a substituted 1 ,2,4-triazole, a pro- drug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms for a) modulation of the activity of 11 ⁇ HSDl ;or b) inhibition of 11 ⁇ HSDl , in a patient in need thereof.
  • Another aspect of the present invention is the use of a substituted 1 ,2,4-triazole, a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any disorder and disease where it is desirable to a) modulate the activity of 11 ⁇ HSDl ; or b) inhibit 11 ⁇ HSDl , in a patient in need thereof.
  • the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof is of the general formula (I)
  • X is O or S
  • R 1 is hydrogen, C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, arylC ⁇ -C 6 alkyl, hetarylC-rCealkyl, R 4 R 5 NcarbonylC C 6 alkyl, arylcarbonylC ⁇ -C 6 alkyl, hetarylcarbonyld-
  • R 6 is CrC ⁇ alkyl, C C 6 alkenyl, arylCrC 6 alkyl, C 3 -C 10 cycloalkyl or hetarylCrC 6 alkyl; wherein the alkyl, alkenyl, cycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 ;
  • R 3 is C 3 -Ci 0 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrC 6 alkyl, arylR 8 C C 6 alkyl or hetarylR 8 CrC 6 alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 ;
  • R 4 and R 5 independently are hydrogen, C C 6 alkyl, C 3 -C 10 cycloalkyl, C 5 -C 8 hetcycloalkyl, aryl, hetaryl, arylCrC 6 alkyl or hetarylCrC 6 alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R 11 ; or
  • R 4 and R 5 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC 6 alkyl, aryl, arylCrC 6 alkyl, hydroxy, oxo, CrC 6 alkyloxy, arylC C 6 alkyloxy, C 1 -C 6 alkyloxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, arylCrC 6 alkyl-carbonyl, CrC 6 alkylcarboxy, arylcarboxy or arylC C 6 alkylcarboxy;
  • R 6 , R 7 , R 9 and R 11 independently are hydrogen, halo, N0 2 , NH 2 , cyano, NR 4 R 5 , CONR 4 R 5 , trihalomethyl, trihalomethoxy, hydroxy, oxo, C C 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, hetaryl, arylC C 6 alkyl, hetarylC C 6 alkyl, C C 6 alkylS0 2 , R 15 R 16 NS0 2 , CrC 6 alkyloxy, aryloxy, hetaryloxy, arylCrC 6 alkyloxy, C r C 6 alkylcarbonyl, arylcarbonyl, arylC C 6 alkylcarbonyl, arylcarbonylNR 15 , carboxyC C 6 alkyl or carboxyarylC C 6 alkyl;
  • R 10 is hydrogen, C C 6 alkyl, aryl, hetaryl, ary!CrC 6 alkyl or hetarylC C 6 alkyl;
  • R 15 and R 16 independently are hydrogen, CrC 6 alkyl, C 3 -C 10 cycloalkyl, C 5 -C 8 hetcycloalkyl, aryl or hetaryl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl groups independ- ently are optionally substituted with one or more of R 11 ; or R 15 and R 16 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C C 6 alkyl, aryl, arylCrC 6 alkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrC 6 alkyloxy, CrCealkyloxyCrC ⁇ alky
  • the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof is of the above general formula (I) wherein X is O or S;
  • R 1 is hydrogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, arylCrC 6 alkyl, hetarylCrC 6 alkyl, NR 4 R 5 carbonylCrC 6 alkyl, arylcarbonylC C 6 alkyl, hetarylcarbonylCrC 6 alkyl; wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 6 ;
  • R 2 is C C 6 alkyl, C C 6 alkenyl, arylCrC 6 alkyl or hetarylC C 6 alkyl; wherein the alkyl, alkenyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 7 ;
  • R 3 is C 5 -C 8 cycloalkyl, C 5 -C 8 hetcycloalkyl, aryl, hetaryl, arylC C 6 alkyl, hetarylC C 6 alkyl, arylR 8 C C 6 alkyl or hetarylR 8 CrC 6 alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R 9 ;
  • R 4 and R 5 independently are hydrogen, CrC 6 alkyl, C 5 -C 10 cycloalkyl, C 5 -C 8 hetcycloalkyl, aryl, hetaryl, arylCrC 6 alkyl or hetarylCrC 6 alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R 11 ; or
  • R 4 and R 5 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon at- oms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC 6 alkyl, aryl, arylCrC 6 alkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrC 6 alkyloxy, CrC 6 alkyloxyCrC 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, arylCrC 6 alkylcarbonyl, CrC 6 alkylcarboxy, arylcarboxy or arylCrC 6 alkyl- carboxy;
  • R 6 , R 7 , R 9 and R 11 independently are hydrogen, halo, N0 2 , NH 2 , cyano, trihalomethyl, trihalo- methoxy, hydroxy, oxo, CrC 6 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrC 6 alkyl, S0 2 NR 15 R 16 , CrC 6 alkyloxy, aryloxy, hetaryloxy, arylC C 6 alkyloxy, CrC 6 alkylcarbonyl, arylcarbonyl, arylCrC 6 alkylcarbonyl, arylcarbonylNR 15 , carboxyC C 6 alkyl or carboxyarylCrC 6 - alkyl;
  • R 10 is hydrogen, CrC 6 alkyl, aryl, hetaryl, arylCrC 6 alkyl or hetarylCrC 6 alkyl;
  • R 15 and R 16 independently are hydrogen, CrC 6 alkyl, C 5 -C 10 cycloalkyl, C 5 -C 8 hetcycloalkyl, aryl or hetaryl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl groups independently are optionally substituted with one or more of R 11 ; or
  • the invention provides the present use of a substituted
  • the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein X is S.
  • the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R 1 is arylCrC 6 alkyl, hetarylCrCealkyl, R 4 R 5 NcarbonylCrC 6 alkyl, arylcarbonylCrC 6 alkyl, hetarylcarbonylC C 6 - alkyl; wherein aryl and hetaryl groups independently are optionally substituted with one or more of R 6 .
  • the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R 2 is CrC 6 alkyl, arylC C 6 alkyl, C 3 -C 10 cycloalkyl or hetarylCrCealkyl; all of which is optionally substituted with one or more of R 7 .
  • the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R 3 is C 3 -C 10 cycloalkyl, C 3 -Ci 0 hetcycloalkyl, aryl, hetaryl, arylC C 6 alkyl, hetarylCrCealkyl, arylR 8 C C 6 alkyl or hetarylR 8 CrC 6 alkyl, wherein all groups indenpendently are optionally substituted with one or more of R 9 .
  • the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R 3 is C 3 -C 10 hetcyclo- alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl, arylR 8 CrC 6 alkyl or hetarylR 8 C C 6 alkyl, wherein all groups indenpendently are optionally substituted with one or more of R 9 .
  • the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R 4 and R 5 independently are aryl or hetaryl wherein both groups indenpendently are optionally substituted with one or more of R 11 .
  • the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R 4 and R 5 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 addi- tional nitrogen atoms, the ring system optionally being substituted with at least one of C C 6 alkyl, aryl, arylCrC 6 alkyl, hydroxy, oxo, CrC 6 alkyloxy, arylCrC 6 alkyloxy, CrC 6 alkyloxyCr C 6 alkyl, CrC 6 alkylcarbonyl, arylcarbonyl, arylC C 6 alkyl-carbonyl, CrC 6 alkylcarboxy, arylcarboxy or a * rylCrC 6 alkylcarboxy.
  • the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R 6 , R 7 , R 9 and R 11 independently are hydrogen, halo, N0 2 , NH 2 , cyano, NR 4 R 5 , CONR 4 R 5 , trihalomethyl, triha- lomethoxy, hydroxy, oxo, CrC 6 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetcycloalkyl, aryl, hetaryl, arylC C 6 alkyl, hetarylCrCealkyl, C C 6 alkylS0 2 , R 15 R 16 NS0 2 , CrC 6 alkyloxy, aryloxy, hetary- loxy, arylCrC 6 alkyloxy, CrC 6 alkylcarbonyl, arylcarbonyl, arylcarbonyl
  • the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R 10 is hydrogen, C
  • the invention provide the present use of said substituted
  • the invention provides the present use of substituted 1 ,2,4- triazoles, or prodrugs thereof of general formula (I) selected from the group consisting of the compounds of examples 1 through 3, A1 through A444 and B1 through B24.
  • the present invention is concerned with substituted 1 ,2,4- triazoles, or prodrugs thereof of general formula (I) selected from the group consisting of the compounds of examples 1 through 3, A1 through A444 and B1 through B24.
  • 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 hydro- chloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaph- thoates, glycero
  • compositions include the pharmaceutically acceptable salts listed in J. Pharm. Sci., 66, 2 (1977), which is incorporated herein by reference.
  • metal salts include lithium, sodium, potassium, barium, calcium, magnesium, zinc, calcium salts and the like.
  • amines and organic amines include ammonium, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, propylamine, bu- tylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N- methyl-D-glucamine, guanidine and the like.
  • cationic amino acids include lysine, arginine, histidine and the like.
  • solvates with water or common organic solvents.
  • Such solvates are encompassed within the scope of the invention.
  • the pharmaceutically acceptable salts are prepared by reacting a compound of the present invention with 1 to 4 equivalents of a base such as sodium hydroxide, sodium meth- oxide, sodium hydride, potassium tert-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, fe/f-butanol, dioxane, isopropanol, ethanol etc. Mixtures of solvents may be used.
  • Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc.
  • acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
  • acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, enzymatic resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, (R)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like.
  • the compound of the present invention may be converted to a 1 :1 mixture of diastereomeric amides by treating with chiral amines, ami- noacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by frac- tional crystallization or chromatography and the stereoisomers of compound of formula I may be prepared by hydrolysing the pure diastereomeric amide.
  • polymorphs of the compounds forming part of this invention may be prepared by crystallization of said compounds under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at dif- ferent 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.
  • 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.
  • the Original compound' 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.
  • 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, .erf-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters).
  • esters for instance methyl esters, ethyl esters, .erf-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters.
  • Compounds of the invention, original compounds, such modified by attaching chemical groups are termed 'modified compounds'.
  • the invention also encompasses active metabolites of the present compounds.
  • the compounds according to the invention alter, and more specifically, reduce the level of active intracellular glucocorticoid and are accordingly useful for the treatment, 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 metabo- lism, neurodegenerative and psychiatric disorders, dysregulation of intraocular pressure including glaucoma, immune disorders, inappropriate immune responses, musculo-skeletal disorders, gastrointestinal disorders, polycystic ovarie syndrome (PCOS), reduced hair growth or other diseases, disorders or conditions that are influenced by intracellular glucocorticoid levels, adverse effects of increased blood levels of active endogenous or exogen
  • the present compounds may be applicable for the treatment, prevention and/or prophylaxis of the metabolic syndrome, type 2 diabetes, diabetes as a consequence of obesity, insulin resistance, hyperglycemia, prandial hyperglycemia, hyperinsuline- mia, inappropriately low insulin secretion, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), increased hepatic glucose production, type 1 diabetes, LADA, pediatric diabetes, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipopro- teinemia, hypercholesterolemia, decreased HDL cholesterol, impaired LDL/HDL ratio, other disorders of lipid metabolism, obesity, visceral obesity, obesity as a consequence of diabetes, increased food intake, hypertension, diabetic late complications, micro-/macroalbu- minuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia, heart in
  • asthma cystic fibrosis, emphysema, bronchitis, hypersensitivity, pneu- monitis, eosinophilic pneumonias, pulmonary fibrosis, adverse effects of glucocorticoid receptor agonist treatment of inflammatory bowel disease such as Crohn's disease and ulcera- tive colitis; adverse effects of glucocorticoid receptor agonist treatment of disorders of the immune system, connective tissue and joints e.g.
  • glucocorticoid receptor agonist treatment of cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lym- phoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea, adverse effects of glucocorticoid receptor agonist treatment of diseases of muscle and at the neuro-muscular joint e.g. myasthenia gravis and heriditary myopathies (e.g. Duchenne muscular dystrophy), adverse effects of glucocorticoid receptor agonist treatment in the context of surgery & transplantation e.g.
  • glucocorticoid receptor agonists include trauma, post-surgical stress, surgical stress, renal transplantation, liver transplantation, lung transplantation, pancreatic islet transplantation, blood stem cell transplantation, bone marrow transplantation, heart transplantation, adrenal gland transplantation, tra- cheal transplantation, intestinal transplantation, corneal transplantation, skin grafting, kerato- plasty, lens implantation 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 glucocorti- coid receptor agonist treatment in other diseases, disorders and conditions where glucocorticoid receptor agonists provide clinically beneficial effects.
  • the invention relates to a compound according to the invention for use as a pharmaceutical composition.
  • the invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or diluents.
  • the pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg/day to about 2000 mg/day, preferably from about 1 mg/day to about 500 mg/day of a compound according to the invention.
  • the patient is treated with a compound according to the invention for at least about 1 week, for at least about 2 weeks, for at least about 4 weeks, for at least about 2 months or for at least about 4 months.
  • the pharmaceutical composition is for oral, nasal, transdermal, pulmonal or parenteral administration.
  • the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 ⁇ HSDl is beneficial.
  • the invention also relates to a method for the treatment, prevention and/or prophy- laxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 ⁇ 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 dis- eases and conditions that are influenced by intracellular glucocorticoid levels as mentioned above.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of conditions and disorders where a decreased level of active intracellular glucocorticoid is desir- able, such as the conditions and diseases mentioned above.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of the metabolic syndrome including insulin resistance, dyslipidemia, hypertension and obesity.
  • the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
  • ITT impaired glucose tolerance
  • IGF impaired fasting glucose
  • the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes. In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of neurodegenerative and psychiatric disorders.
  • the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
  • the route of administration may be any route which effectively transports a compound according to the invention to the 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 (melano- cortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotro- pin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, ⁇ 3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, 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
  • the antiobesity agent is leptin; dexamphetamine or amphetamine; fenfluramine or dexfenfluramine; sibutramine; orlistat; mazindol or phen- termine.
  • Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S), e.g. N ⁇ B29 -tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), e.g. Asp 828 human insulin, US 5,504,188 (Eli Lilly), e.g.
  • Lys B28 Pro 629 human insulin EP 368 187 (Aventis), eg Lantus, which are all incorporated herein by reference, GLP-1 (glucagon like peptide-1) and GLP-1 derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorpo- rated herein by reference as well as orally active hypoglycaemic agents.
  • the orally active hypoglycaemic agents preferably comprise sulphonylureas, bigua- nides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase- IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as PPAR modulators, PPAR ⁇ modulators, cholesterol absorption inhibitors, HSL (hormone-sensitive lipase) inhibitors and HMG CoA inhibitors (statins),
  • the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human in- sulin, Asp 828 human insulin, Lys 628 Pro 629 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
  • insulin an insulin analogue or derivative, such as N ⁇ B29 -tetradecanoyl des (B30) human in- sulin, Asp 828 human insulin, Lys 628 Pro 629 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
  • the present compounds are administered in combination with a sulphonylurea e.g. tolbutamide, glibenclamide, glipizide or glicazide.
  • a sulphonylurea e.g. tolbutamide, glibenclamide, glipizide or glicazide.
  • the present compounds are administered in combination with a biguanide e.g. metformin.
  • the present compounds are administered in combination with a meglitinide e.g. repaglinide or senaglinide.
  • a meglitinide e.g. repaglinide or senaglinide.
  • the present compounds are administered in combination with a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or com- pounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazo- linyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, preferably the potassium salt.
  • a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or com- pounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazo- linyl]methoxy]phenyl-methyl]thiazolidine-2,
  • the present compounds may be administered in combination with the insulin sensitizers disclosed in WO 99/19313 such as (-) 3-[4-[2-Phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salts thereof, preferably the arginine salt.
  • the insulin sensitizers disclosed in WO 99/19313 such as (-) 3-[4-[2-Phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salts thereof, preferably the arginine salt.
  • the present compounds are administered in combination with an ⁇ -glucosidase inhibitor e.g. miglitol or acarbose.
  • an agent acting on the ATP-dependent potassium channel of the ⁇ -cells e.g. tolbu- tamide, glibenclamide, glipizide, glicazide or repaglinide.
  • the present compounds may be administered in combination with nateglinide.
  • the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, ator- vastatin, fluvastatin, lovastatin, pravastatin, simvastatin, acipimox, probucol, ezetimibe or dextrothyroxine.
  • an antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, ator- vastatin, fluvastatin, lovastatin, pravastatin,
  • the present compounds are administered in combination with more than one of the above-mentioned compounds e.g. in combination with a sulphony- lurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc.
  • the present compounds may be administered in combination with one or more antihypertensive agents.
  • antihypertensive agents are ⁇ -blockers such as alprenolol, atenolol, timolol, pindolol, propranolol, metoprolol, bisoprololfumerate, esmolol, acebutelol, metoprolol, acebutolol, betaxolol, celiprolol, nebivolol, tertatolol, oxprenolol, amusolalul, carvedilol, labetalol, ⁇ 2-receptor blockers e.g.
  • S-atenolol, OPC-1085, ACE (angiotensin converting enzyme) inhibitors such as quinapril, lisinopril, enalapril, captopril, benazepril, perindopril, trandolapril, fosinopril, ramipril, cilazapril, delapril, imidapril, moexipril, spirapril, temocapril, zofenopril, S-5590, fasidotril, Hoechst-Marion Roussel: 100240 (EP 00481522), omapatrilat, gemopatrilat and GW-660511 , calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, amlodipine, nitrendipine
  • loop-diuretics e.g. bumetanide, furosemide and torasemide
  • potassium sparing diuretics e.g. amiloride, spironolactone
  • endothelin ET-A antagonists such as ABT-546, ambrisetan, atrasentan, SB- 234551 , CM 034, S-0139 and YM-598
  • endothelin antagonists e.g. bosentan and J-104133
  • renin inhibitors such as aliskiren, vasopressin V1 antagonists e.g.
  • vasopressin V2 antagonists such as tolvaptan, SR-121463 and OPC-31260
  • B-type natriuretic peptide agonists e.g. Nesiritide, angiotensin II antagonists such as irbesartan, candesartancilexetil, losartan, valsartan, telmisartan, eprosartan, candesartan, CL-329167, eprosartan, iosartan, olmesartan, pratosartan, TA-606, and YM-358, 5-HT2 agonists e.g.
  • adenosine A1 antagonists such as naftopidil, N-0861 and FK-352
  • thromboxane A2 antagonists such as KT2-962
  • endopeptidase inhibitors e.g. ecadotril
  • nitric oxide agonists such as LP-805
  • dopamine D1 antagonists e.g. MYD-37
  • dopamine D2 agonists such as nolomirole, n-3 fatty acids e.g. omacor
  • prostacyclin agonists such as treprostinil, beraprost
  • PGE1 agonists e.g.
  • ecraprost Na+/K+ ATPase modulators e.g. PST-2238, Potassium channel activators e.g. KR-30450, vaccines such as PMD-3117, Indapamides, CGRP- unigene, guanylate cyclase stimulators, hydralazines, methyldopa, docarpamine, moxo- nidine, CoAprovel, MondoBiotech-811.
  • the present compounds may be administered in combination with one or more glucocorticoid receptor agonists.
  • glucocorticoid receptor agonists 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 be- ing 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, suspen- sions, 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 com- pound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.
  • Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds for use according to the present invention and these form a further aspect of the present invention.
  • solutions of the present compounds in sterile aqueous solution aqueous propylene glycol or sesame or peanut oil may be employed.
  • aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • the aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, syrup, phospholipids, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • 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 ingre- dominant 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.
  • 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 sorbitan monooleate.
  • the aqueous suspensions may also contain one or more colouring agents, one or more flavouring agents
  • 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, pre- servative 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.
  • 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 in- elude 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.
  • 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.
  • 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 liq- uid 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
  • 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. Any novel feature or combination of features described herein is considered essential to this invention.
  • the present invention also relate to the below methods of preparing the compounds of the invention.
  • CDCI 3 deuterio chloroform
  • EDAC 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours
  • the triazole (III) is alkylated with an alkylating agent (IV), wherein Y is halo, OS0 2 C C 6 alkyl, OS0 2 aryl or 0S0 2 arylCrC 6 alkyl and the like and R 13 is selected from the group consisting of CrC 6 alkyl, aryl, hetaryl, arylCrC 6 alkyl, hetarylCrCealkyl as defined above and wherein the alkyl, aryl and hetaryl groups optionally are substituted as defined above, in a solvent such as DMF, DMSO, NMP, acetone, THF, dichloromethane and the like under basic conditions (e.g. K 2 C0 3 , NaOH, NaH, n-BuLi and the like) affording compound (V) wherein X, R 2 , R 3 and R 13 are as defined above.
  • an alkylating agent (IV) wherein Y is halo,
  • a solvent such as MeOH, EtOH, i-PrOH, tert-BuO , DMF, DMSO, NMP, acetone, THF, dichloromethane
  • the residue was purified by silicagel chromatography using first a mixture of ethyl acetate/heptane (1 :1 , 500 ml) followed by pure ethyl acetate. Pure fractions were collected and the solvent evaporated in vacuo.
  • the solid residue was suspended in diethyl ether (5 ml) and stirred for 1 hrs. The solid product was filtered off and dried in vacuo at 50 °C affording 250 mg (45%) of the title compound as a solid.
  • the volatiles were evaporated in vacuo and the residue was purified by sili- cagel chromatography using ethyl acetate as eluent. Pure fractions were collected and the solvent evaporated in vacuo to almost dryness.
  • the wet residue was suspended in diethyl ether (10 ml) and stirred for 1 hrs. The solid product was filtered off and dried in vacuo at 50
  • A-114 403.89 ylmethylsulfanyl)-4-ethyl-5-(4-methoxy- phenyl)-4H-[1 ,2,4]triazole 3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5- (4-methoxy-phenyl)-4H-[1 ,2,4]triazole

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Abstract

The use of substituted 1,2,4-triazoles for modulating the activity of 11 β-hydroxysteroid dehydrogenase type 1 (11 βHSD1) and the use of these compounds as pharmaceutical compositions has been described. Also a novel class of substituted 1,2,4-triazoles, their use in therapy, pharmaceutical compositions comprising the compounds, as well as their use in the manufacture of medicaments has been described. The present compounds are modulators and more specifically inhibitors of the activity of 11 βHSD1 and may be useful in the treatment, prevention and/or prophylaxis of a range of medical disorders where a decreased intracellular concentration of active glucocorticoid is desirable.

Description

PHARMACEUTICAL USE OF SUBSTITUTED 1,2,4-TRIAZOLES
FIELD OF THE INVENTION
The present invention relates to use of substituted 1 ,2,4-triazoles and pharmaceutical compositions comprising the compounds for treating disorders where it is desirable to modulate the activity of 11 β-hydroxysteroid dehydrogenase type 1 (11 βHSDl ).
The present invention also relates to novel substituted 1 ,2,4-triazoles, 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 11β- hydroxysteroid dehydrogenase type 1 (11 βHSDl ) 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. 11 β-hydroxysteroid dehydrogenase type 1 (11 βHSDl ) 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, 11 βHSDl 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, 27, 375 (2000); Da- vani et al., J. Biol. Chem., 275, 34841 (2000); Brem et al., Hypertension, 31, 459 (1998); Rauz et al., invest. Ophthalmol. Vis. Sci., 42, 2037 (2001); Moisan et al., Endocrinology, 127, 1450 (1990)).
The role of 11 βHSDl in the metabolic syndrome and type 2 diabetes is supported by several lines of evidence. In humans, treatment with the non-specific 11 βHSDl inhibitor carbenoxolone improves insulin sensitivity in lean healthy volunteers and people with type 2 diabetes. Likewise, 11 βHSDl 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 11 βHSDl in adipocytes develop insulin resistance, hyperlipidemia and vis- ceral obesity, a phenotype that resembles the human metabolic syndrome (Andrews et al., J. Clin. Endocrinol. Metab., 88, 285 (2003); Walker et al., J. Clin. 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 11 βHSDl modulation and thereby modulation of intracellular levels of active glucocorticoid have been investigated in several rodent models and different cellular systems. 11 βHSDl 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 stimulat- ing 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 dis- closes various thiazol-sulfonamides as inhibitors of the human 11 β-hydroxysteroid dehydrogenase type 1 enzyme, and further states that said compounds may be useful in treating diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders and depression.
We have now found substituted 1,2,4-triazoles that modulate the activity of 11 βHSDl leading to altered intracellular concentrations of active glucocorticoid. More specifically, the present compounds inhibit the activity of 11 βHSDl 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), im- paired 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 11 βHSDl .
DEFINITIONS
In the following structural formulas and throughout the present specification, the following terms have the indicated meaning: The term "halo" includes fluorine, chlorine, bromine, and iodine.
The term "trihalomethyl" includes trifluoromethyl, trichloromethyl, tribromomethyl, and triiodomethyl.
The term "trihalomethoxy" includes trifluorometoxy, trichlorometoxy, tribromometoxy, and triiodometoxy. The term "alkyl" includes C C6 straight chain saturated and methylene aliphatic hydrocarbon groups, C3-C6 branched saturated hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, isopropyl (i-Pr), isobutyl (i-Bu), .erf-butyl (f-Bu), sec-butyl (s-Bu), isopentyl, neopentyl, and the like. The term "alkenyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and branched C3-C6 unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to ethenyl, propenyl, butenyl, pentenyl, hexenyl, methylpropenyl, methylbutenyl and the like. The term "alkynyl" includes C2-C6 straight chain unsaturated aliphatic hydrocarbon groups and C4-C6 branched unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, this definition shall include but is not limited to ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylbutynyl, and the like.
The term "saturated or partially saturated cyclic, bicyclic or tricyclic ring system" represents but are not limit to aziridinyl, pyrrolinyl, pyrrolidinyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, morpholinyl, piperidinyl, thiomorpholinyl, piperazinyl, phthalimide, 1 ,2,3,4- tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 1 ,2,3,4-tetrahydro-quinoxalinyl, and indolinyl.
The term "cycloalkyl" (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep- tyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like) represents a saturated, mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms.
The term "hetcycloalkyl" (tetrahydrofuranyl, tetrahydropyranyl, tertahydrothiopyranyl, and the like) represents a saturated mono-, bi-, tri- or spirocarbocyclic group having the specified number of carbon atoms and one or two additional heteroatoms or groups selected from nitrogen, oxygen, sulphur, SO or S02.
The term "alkyloxy" (e.g. methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. The term "alkyloxyalkyl" (e.g. methyloxymethyl and the like) represents an alkyloxy group as defined above attached through an "alkyl" group.
The term "aryloxy" (e.g. phenoxy, naphthyloxy and the like) represents an aryl group as defined below attached through an oxygen bridge.
The term "hetaryloxy" (e.g. 2-pyridyloxy and the like) represents a hetaryl group as defined below attached through an oxygen bridge.
The term "arylalkyloxy" (e.g. phenethyloxy, naphthylmethyloxy and the like) represents an arylalkyl group as defined below attached through an oxygen bridge.
The term "hetarylalkyloxy" (e.g. 2-pyridylmethyloxy and the like) represents a hetary- lalkyl group as defined below attached through an oxygen bridge. The term "alkyloxycarbonyl" (e.g. methylformiat, ethylformiat and the like) represents an alkyloxy group as defined above attached through a carbonyl group.
The term "aryloxycarbonyl" (e.g. phenylformiat, 2-thiazolylformiat and the like) represents an aryloxy group as defined above attached through a carbonyl group.
The term "arylalkyloxycarbonyl" (e.g. benzylformiat, phenyletylformiat and the like) represents an "arylalkyloxy" group as defined above attached through a carbonyl group.
The term "arylalkyl" (e.g. benzyl, phenylethyl, 3-phenylpropyl, 1-naphtylmethyl, 2-(1- naphtyl)ethyl and the like ) represents an aryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above. The term "hetarylalkyl" and "hetaralkyl" (e.g. (2-furyl)methyl, (3-furyl)methyl, (2- thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl and the like) represents a hetaryl group as defined below attached through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above. The term "alkylcarbonyl" (e.g. octylcarbonyl, pentylcarbonyl, 3-hexenylcarbonyl) represents an alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term "arylcarbonyl" (e.g. benzoyl) represents an aryl group as defined below at- tached through a carbonyl group.
The term "hetarylcarbonyl" (e.g. 2-thiophenylcarbonyl, 3-methoxy-anthrylcarbonyl, oxazolylcarbonyl and the like) represents a hetaryl group as defined below attached through a carbonyl group.
The term "carbonylalkyl" (e.g. acetyl and the like) represents a carbonyl group at- tached through alkyl group as defined above having the indicated number of carbon atoms.
The term "alkylcarbonylalkyl" (e.g. propan-2-one, 4,4-dimethyl-pentan-2-one and the like) represents an alkylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "arylcarbonylalkyl" (e.g. 1-phenyl-propan-1-one, 1-(3-chloro-phenyl)-2- methyl-butan-1-one and the like) represents a arylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "hetarylcarbonylalkyl" (e.g. 1-pyridin-2-yl-propan-1-one, 1-(1-H-imidazol-2- yl)-propan-1-one and the like) represents a hetarylcarbonyl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms. The term "arylalkylcarbonyl" (e.g. phenylpropylcarbonyl, phenylethylcarbonyl and the like) represents an arylalkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group.
The term "hetarylalkylcarbonyl" (e.g. imidazolylpentylcarbonyl and the like) represents an hetarylalkyl group as defined above wherein the alkyl group is in turn attached through a carbonyl.
The term "alkylcarboxy" (e.g. heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "arylcarboxy" (e.g. benzoic acid and the like) represents an arylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "arylalkylcarboxy" (e.g. benzylcarboxy, phenylpropylcarboxy and the like) represents an arylalkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge. The term "hetarylalkylcarboxy" (e.g. (1-H-imidazol-2-yl)-acetic acid, 3-pyrimidin-2-yl- propionic acid and the like) represents a hetarylalkyl group as defined above wherein the carbonyl is in turn attached through an oxygen bridge.
The term "aryl" includes but is not limited to a carbocyclic aromatic ring system be- ing either monocyclic, bicyclic, or polycyclic, such as phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl, biphenylenyl and the like. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic aromatic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1 ,2,3,4-tetrahydronaphthyl, 1 ,4-dihydronaphthyl and the like. The term "aryll" includes phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, and fluorenyl.
The term "aryl2" includes phenyl, biphenyl, naphthyl, and anthracenyl. The term "hetaryl" includes but is not limited to pyrrolyl (2-pyrrolyl), pyrazolyl (3- pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1 ,2,3- triazol-1 -yl, 1 ,2,3-triazol-2-yl 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4- oxazolyl, 5-oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl (2-thiophenyl, 3-thiophenyl, 4-thiophenyl, 5-thiophenyl), furanyl (2-furanyl, 3-furanyl, 4-furanyl, 5-furanyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl, 5- pyridyl), 5-tetrazolyl, pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3- quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3- isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), ben- zo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6- benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-ben- zo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro- benzo-[b]furanyl), 6-(2,3-dihydro-benzo-[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl)), ben- zo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5- benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thio- phenyl (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3- dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thio- phenyl), 7-(2,3-dihydro-benzo[b]thiophenyl)), 4,5,6,7-tetrahydro-benzo[b]thiophenyl (2- (4,5,6,7-tetrahydro-benzo[b]thiophenyl), 3-(4,5,6,7-tetrahydro-benzo[b]thiophenyl), 4-(4,5,6,7- tetrahydro-benzo[b]thiophenyl), 5-(4,5,6,7-tetrahydro-benzo[b]thiophenyl), 6-(4,5,6,7-tetra- hydro-benzo[b]thiophenyl), 7-(4,5,6,7-tetrahydro-benzo[b]thiophenyl)), 4,5,6,7-tetrahydro- thieno[2,3-c]pyridyl (4-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl), 5-4,5,6,7-tetrahydro- thieno[2,3-c]pyridyl), 6-(4,5,6,7-tetrahydro-thieno[2,3-c]pyridyl), 7-(4,5,6,7-tetrahydro- thieno[2,3-c]pyridyl)), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7- indolyl), isoindolyl (1 -isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, 6- isoindolyl, 7-isoindolyl), 1 ,3-dihydro-isoindolyl (1-(1 ,3-dihydro-isoindolyl), 2-(1,3-dihydro- isoindolyl), 3-(1 ,3-dihydro-isoindolyl), 4-(1 ,3-dihydro-isoindolyl), 5-(1 ,3-dihydro-isoindolyl), 6- (1 ,3-dihydro-isoindolyl), 7-(1 ,3-dihydro-isoindolyl)), indazole (1-indazolyl, 3-indazolyl, 4- indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benz- imidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benz- imidazolyl), benzoxazolyl (1-benz-oxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothia- zolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzo- thiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), piperidinyl (2- piperidinyl, 3-piperidinyl, 4-piperidinyl), pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrro- lidinyl).
The term "NR4R5carbonylalkyl" (e.g. Λ/,Λ/-dimethyl-propionamide, Λ/-isopropyl-Λ/- methyl-propionamide and the like) represents NR4R5 substituted by a carbonylalkyl group as defined above.
The term "arylR8alkyl" (e.g. ethoxy-benzene, ethyl-methyl-phenyl-amine, Λ/-ethyl- benzamide, Λ/-isobutyl-benzenesulfonamide and the like) represents an aryl group as defined above, substituted by R8, which is substituted by an alkyl group as defined above. The term "hetarylR8alkyl" (e.g. 2-ethoxy-1/-/-imidazol, ethyl-quinolin-2-yl-amine, thia- zole-2-carboxylic acid, methyl-propyl-amide, pyridine-3-sulfonic acid isobutyl-amide and the like) represents a hetaryl group as defined above, substituted by R8, which is substituted by an alkyl group as defined above.
The term "arylcarbonylNR15" (e.g. A/-benzyl-Λ/-methyl-benzamide and the like) represents an arylcarbonyl group as defined above, substituted by NR15.
Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.
The term "optionally substituted" as used herein means that the groups in question are either unsubstituted or substituted with one or more of the substituents specified. When the groups in question are substituted with more than one substituent the substituents may be the same or different.
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 complica- tions, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
The term "pharmaceutically acceptable" is defined as being suitable for administration to humans without adverse events. The term "prodrug" is defined as a chemically modified form of the active drug, said prodrug being administered to the patient and subsequently being converted to the active drug. Techniques for development of prodrugs are well known in the art.
DETAILED DESCRIPTION OF THE INVENTION
One aspect of the present invention is the use of a substituted 1 ,2,4-triazole, a pro- drug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms for a) modulation of the activity of 11 βHSDl ;or b) inhibition of 11 βHSDl , in a patient in need thereof. Another aspect of the present invention is the use of a substituted 1 ,2,4-triazole, a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any disorder and disease where it is desirable to a) modulate the activity of 11 βHSDl ; or b) inhibit 11 βHSDl , in a patient in need thereof.
In another embodiment, the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof is of the general formula (I)
Figure imgf000009_0001
wherein X is O or S;
R1 is hydrogen, C C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, arylCι-C6alkyl, hetarylC-rCealkyl, R4R5NcarbonylC C6alkyl, arylcarbonylCι-C6alkyl, hetarylcarbonyld-
C6alkyl; wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R6; R2 is CrCβalkyl, C C6alkenyl, arylCrC6alkyl, C3-C10cycloalkyl or hetarylCrC6alkyl; wherein the alkyl, alkenyl, cycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R3 is C3-Ci0cycloalkyl, C3-C10hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrC6alkyl, arylR8C C6alkyl or hetarylR8CrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R4 and R5 independently are hydrogen, C C6alkyl, C3-C10cycloalkyl, C5-C8hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R11; or
R4 and R5 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, arylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, arylC C6alkyloxy, C1-C6alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, arylCrC6alkyl-carbonyl, CrC6alkylcarboxy, arylcarboxy or arylC C6alkylcarboxy;
R6, R7, R9 and R11 independently are hydrogen, halo, N02, NH2, cyano, NR4R5, CONR4R5, trihalomethyl, trihalomethoxy, hydroxy, oxo, C C6alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, hetaryl, arylC C6alkyl, hetarylC C6alkyl, C C6alkylS02, R15R16NS02, CrC6alkyloxy, aryloxy, hetaryloxy, arylCrC6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, arylC C6alkylcarbonyl, arylcarbonylNR15, carboxyC C6alkyl or carboxyarylC C6alkyl;
Ra is oxygen, NRηυ, C(=0)NRιυ or SOnNRιυ; wherein n is 1 or 2;
R10 is hydrogen, C C6alkyl, aryl, hetaryl, ary!CrC6alkyl or hetarylC C6alkyl;
R15 and R16 independently are hydrogen, CrC6alkyl, C3-C10cycloalkyl, C5-C8hetcycloalkyl, aryl or hetaryl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl groups independ- ently are optionally substituted with one or more of R11; or R15 and R16 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of C C6alkyl, aryl, arylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, CrCealkyloxyCrCβalkyl, CrC6alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6alkyl- carboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof is of the above general formula (I) wherein X is O or S;
R1 is hydrogen, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, arylCrC6alkyl, hetarylCrC6alkyl, NR4R5carbonylCrC6alkyl, arylcarbonylC C6alkyl, hetarylcarbonylCrC6alkyl; wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R6;
R2 is C C6alkyl, C C6alkenyl, arylCrC6alkyl or hetarylC C6alkyl; wherein the alkyl, alkenyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R3 is C5-C8cycloalkyl, C5-C8hetcycloalkyl, aryl, hetaryl, arylC C6alkyl, hetarylC C6alkyl, arylR8C C6alkyl or hetarylR8CrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R4 and R5 independently are hydrogen, CrC6alkyl, C5-C10cycloalkyl, C5-C8hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R11; or
R4 and R5 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon at- oms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, arylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, CrC6alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6alkyl- carboxy;
R6, R7, R9 and R11 independently are hydrogen, halo, N02, NH2, cyano, trihalomethyl, trihalo- methoxy, hydroxy, oxo, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrC6alkyl, S02NR15R16, CrC6alkyloxy, aryloxy, hetaryloxy, arylC C6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, arylcarbonylNR15, carboxyC C6alkyl or carboxyarylCrC6- alkyl;
R8 is oxygen, NR10, C(=0)NR10 or SOnNR10; wherein n is 1 or 2;
R10 is hydrogen, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrC6alkyl;
R15 and R16 independently are hydrogen, CrC6alkyl, C5-C10cycloalkyl, C5-C8hetcycloalkyl, aryl or hetaryl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl groups independently are optionally substituted with one or more of R11; or
R15 and R16 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, arylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, CrC6alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, arylC C6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6alkyl- carboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the invention provides the present use of a substituted
1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein X is O.
In another embodiment, the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein X is S.
In another embodiment, the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R1 is arylCrC6alkyl, hetarylCrCealkyl, R4R5NcarbonylCrC6alkyl, arylcarbonylCrC6alkyl, hetarylcarbonylC C6- alkyl; wherein aryl and hetaryl groups independently are optionally substituted with one or more of R6.
In another embodiment, the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R2 is CrC6alkyl, arylC C6alkyl, C3-C10cycloalkyl or hetarylCrCealkyl; all of which is optionally substituted with one or more of R7.
In another embodiment, the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R3 is C3-C10cycloalkyl, C3-Ci0hetcycloalkyl, aryl, hetaryl, arylC C6alkyl, hetarylCrCealkyl, arylR8C C6alkyl or hetarylR8CrC6alkyl, wherein all groups indenpendently are optionally substituted with one or more of R9.
In another embodiment, the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R3 is C3-C10hetcyclo- alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, arylR8CrC6alkyl or hetarylR8C C6alkyl, wherein all groups indenpendently are optionally substituted with one or more of R9.
In another embodiment, the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R4 and R5 independently are aryl or hetaryl wherein both groups indenpendently are optionally substituted with one or more of R11.
In another embodiment, the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R4 and R5 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 addi- tional nitrogen atoms, the ring system optionally being substituted with at least one of C C6alkyl, aryl, arylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, CrC6alkyloxyCr C6alkyl, CrC6alkylcarbonyl, arylcarbonyl, arylC C6alkyl-carbonyl, CrC6alkylcarboxy, arylcarboxy or a*rylCrC6alkylcarboxy.
In another embodiment, the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R6, R7, R9 and R11 independently are hydrogen, halo, N02, NH2, cyano, NR4R5, CONR4R5, trihalomethyl, triha- lomethoxy, hydroxy, oxo, CrC6alkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, hetaryl, arylC C6alkyl, hetarylCrCealkyl, C C6alkylS02, R15R16NS02, CrC6alkyloxy, aryloxy, hetary- loxy, arylCrC6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, arylcarbon- ylNR15, carboxyCrC6alkyl or carboxyarylCrC6alkyl. In another embodiment, the invention provides the present use of a substituted
1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R8 is oxygen, NR10,
C(=0)NR1° or SOnNR10; wherein n is 1 or 2.
In another embodiment, the invention provides the present use of a substituted 1 ,2,4-triazole, or a prodrug thereof of the general formula (I) wherein R10 is hydrogen, C
C6alkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl.
In another embodiment, the invention provide the present use of said substituted
1 ,2,4-triazole, or a prodrug thereof of general formula (I) selected from the group consisting of: 3-(4-Allyl-5-mercapto-4H-[1 ,2,4]triazol-3-yl)-1-(2,4-dichloro-benzyl)-1 H-pyridin-2-one;
4-Methyl-3-(4-methyl-2-phenyl-thiazol-5-yl)-5-prop-2-ynylsulfanyl-4H-[1 ,2,4]triazole;
N-{1-[5-(4-tert-Butyl-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-ethyl}-4-chloro- benzenesulfonamide;
4-Methyl-3-methylsulfanyl-5-[3-(3-trifluoromethyl-benzyloxy)-thiophen-2-yl]-4H-[1 ,2,4]triazole; N-(4-Chloro-phenyl)-2-(4-methyl-5-thiophen-3-ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide;
2-[4-Methyl-5-(2-oxo-2-phenyl-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-4H- benzo[1 ,4]thiazin-3-one;
3-(4-Fluoro-benzylsulfanyl)-5-(2-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole; 3-(2-Fluoro-phenyl)-4-methyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-Methyl-3-(4-methyl-benzylsulfanyl)-5-(3-trifluoromethyl-phenyl)-4H-[1 ,2,4]triazole;
3-(2,4-Dichloro-phenyl)-4-furan-2-ylmethyl-5-methylsulfanyl-4H-[1,2,4]triazole;
3-(4-tert-Butyl-phenyl)-5-(2,6-dichloro-benzylsulfanyl)-4-furan-2-ylmethyl-4H-[1 ,2,4]triazole;
4-Methyl-3-(4-methyl-benzylsulfanyl)-5-(5-methyl-isoxazol-3-yl)-4H-[1 ,2,4]triazole; 3-(3-Methoxy-benzylsulfanyl)-4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole;
3-(4-Fluoro-benzylsulfanyl)-4-methyl-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
3-(4-tert-Butyl-benzylsulfanyl)-4-methyl-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
4-Methyl-3-(2-methyl-benzylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]triazole;
2-(5-Benzylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4H-benzo[1 ,4]thiazin-3-one; 2-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl]-4H-benzo[1 ,4]thiazin-3- one;
5-[5-(2,6-Dichloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-benzo[1 ,2,5]oxadiazole;
1-(4-Chloro-phenyl)-2-[4-methyl-5-(4-trifluoromethyl-pyridin-3-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-ethanone; 3-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-2-methyl-imidazo[1 ,2- ajpyridine;
3-[5-(2,4-Dichloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-2,8-dimethyl-imidazo[1 ,2- ajpyridine; 4-Allyl-5-(2,4-dichloro-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
3-(5-Allylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-1 -benzyl-1 H-pyridin-2-one;
3-(4-Allyl-5-methylsulfanyl-4H-[1 ,2,4]triazol-3-yl)-1-(2,4-dichloro-benzyl)-1 H-pyridin-2-one;
3-(4-Allyl-5-mercapto-4H-[1 ,2,4]triazol-3-yl)-1 -(4-chloro-benzyl)-1 H-pyridin-2-one;
3-(4-Allyl-5-prop-2-ynylsulfanyl-4H-[1 ,2,4]triazol-3-yl)-1-(4-chloro-benzyl)-1 H-pyridin-2-one; 3-(5-Allylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-1 -(2,4-dichloro-benzyl)-1 H-pyridin-2-one;
1-(2,4-Dichloro-benzyl)-3-[4-ethyl-5-(2-oxo-2-phenyl-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-1 H- pyridin-2-one;
3-(4-Allyl-5-prop-2-ynylsulfanyl-4H-[1 ,2,4]triazol-3-yl)-1-(3,4-dichloro-benzyl)-1 H-pyridin-2- one; 4-Allyl-5-(4-methyl-2-phenyl-thiazol-5-yl)-4H-[1 ,2,4]triazole-3-thiol;
3-Allylsulfanyl-4-methyl-5-(4-methyl-2-phenyl-thiazol-5-yl)-4H-[1 ,2,4]triazole;
4-Allyl-5-[2-(3,4-dimethoxy-phenyl)-thiazol-4-yl]-4H-[1 ,2,4]triazole-3-thiol;
N-[5-(4-tert-Butyl-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl]-4-methyl- benzenesulfonamide; 4-Methyl-3-[3-(4-methyl-benzyloxy)-thiophen-2-yl]-5-methylsulfanyl-4H-[1 ,2,4]triazole;
5-[3-(2,4-Dichloro-benzyloxy)-thiophen-2-yl]-4-methyl-4H-[1 ,2,4]triazole-3-thiol;
3-[3-(2,4-Dichloro-benzyloxy)-thiophen-2-yl]-4-methyl-5-methylsulfanyl-4H-[1 ,2,4]triazole;
4-Methyl-5-[3-(3-trifluoromethyl-benzyloxy)-thiophen-2-yl]-4H-[1,2,4]triazole-3-thiol;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-iodo-phenyl)-acetamide; 3-(5-Allylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-2,7-dimethyl-imidazo[1 ,2-a]pyridine;
3-(5-Benzylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-2,7-dimethyl-imidazo[1,2-a]pyridine;
3-(5-Benzylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-2-methyl-imidazo[1 ,2-a]pyridine;
4-Butyl-5-(3-chloro-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
4-Allyl-5-(3-chloro-phenyl)-4H-[1,2,4]triazole-3-thiol; N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-
4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-benzamide;
N-(5-{2-[3,5-Bis-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-4-methyl-
4H-[1 ,2,4]triazol-3-ylmethyl)-3-methoxy-benzamide;
N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}- 4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4-(pyrrolidine-1 -sulfonyl)-benzamide; N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-
4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4-(piperidine-1-sulfonyl)-benzamide;
N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-
4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4-(morpholine-4-sulfonyl)-benzamide; 4-Benzyl-3-(4-fluoro-naphthalen-1-ylmethylsulfanyl)-5-phenyl-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-naphthalen-1-yl-ethanone;
1 -(4-Fluoro-phenyl)-4-(4-methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-butan-1 -one
2-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)- ethanone; 5-(2-Carbazol-9-yl-ethyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol;
1-(4-Methoxy-phenyl)-2-[4-(2-methyl-allyl)-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl]-ethanone;
2-{2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid methyl ester;
5-(2,4-Dichloro-phenyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol; 4-Allyl-3-(4-methoxy-benzylsulfanyl)-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(9H-fluoren-2-yl)-ethanone;
3-(4-Methoxy-benzylsulfanyl)-4-methyl-5-phenyl-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-ethyl-phenyl)-ethanone;
2-(4-Allyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)-acetamide; 2-[4-Allyl-5-(4-tert-butyl-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-chloro-phenyl)-ethanone;
2-(4-Allyl-5-phenylaminomethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2,4-difluoro-phenyl)- acetamide;
2-(4-Allyl-5-phenoxymethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(4-Allyl-5-phenoxymethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-(4-bromo-phenyl)-ethanone; (4-Allyl-5-benzylsulfanyl-4H-[1 ,2,4]triazol-3-ylmethyl)-phenyl-amine;
2-(4-Allyl-5-benzotriazol-1-ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)- ethanone;
2-(4-Allyl-5-phenylaminomethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-chloro-phenyl)-acetamide;
1-(4-Methoxy-phenyl)-2-[4-(2-methyl-allyl)-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl]-ethanone; 2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide;
[5-(2-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid isopropyl ester;
N-(4-Chloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide; 2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methoxy-phenyl)- acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-
[1 ,2,4]triazol-3-ylsulfanyl]-acetamide; N-(4-Acetyl-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
4-[5-(2,6-Dichloro-benzylsulfanyl)-4-furan-2-ylmethyl-4H-[1,2,4]triazol-3-yl]-pyridine;
N-(4-Methyl-3-nitro-phenyl)-2-[4-methyl-5-(3,4,5-trimethoxy-phenyl)-4H-[1,2,4]triazol-3- ylsulfanylj-acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(4-furan-2-ylmethyl-5-pyridin-4-yl- 4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid methyl ester;
2-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide;
N-(4-Chloro-phenyl)-2-(4-ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-(4-ethyl-5-m-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-bromo-phenyl)-acetamide;
2-{5-[(2,6-Dimethyl-phenylamino)-methyl]-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-phenyl- ethanone;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-fluoro-phenyl)-acetamide; 2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -(4-methoxy-phenyl)- ethanone;
N-(4-lodo-2-methyl-phenyl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(3,4-dihydro-2H-quinolin-1-yl)- ethanone;
N-(2-Bromo-4-methyl-phenyl)-2-(4-furan-2-ylmethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3- ylsulfanyl)-acetamide;
N-(4-Chloro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(3-trifluoromethyl-phenyl)- acetamide;
2-[5-[(4-Fluoro-phenylamino)-methyl]-4-(tetrahydro-furan-2-ylmethyl)-4H-[1,2,4]triazol-3- ylsulfanyl]-1-p-tolyl-ethanone;
2-(5-Methyl-4-phenethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-naphthalen-1-yl-acetamide;
N-(5-Ethyl-[1 ,3,4]thiadiazol-2-yl)-2-(5-methyl-4-phenethyl-4H-[1,2,4]triazol-3-ylsulfanyl)- acetamide; 2-(5-Methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
[5-(4-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid cyclohexyl ester;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(3-chloro-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-chloro-phenyl)-acetamide; 2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-m-tolyl-acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-
[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)-acetamide;
3-Benzylsulfanyl-4-methyl-5-phenyl-4H-[1,2,4]triazole; 3-Butylsulfanyl-5-(4-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-ethoxy-phenyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(4-benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2,4-dimethyl-phenyl)-acetamide;
N-(3-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
N-Naphthalen-1-yl-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid cyclohexyl ester;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-acetamide;
2-[5-(4-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
3-Benzylsulfanyl-5-(4-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
2-(4,5-Dibenzyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-m-tolyl-acetamide; 2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-propionamide;
3-(5-Benzylsulfanyl-4-phenethyl-4H-[1 ,2,4]triazol-3-yl)-pyridine;
(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid ethyl ester;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-propionamide; 1-(3,4-Dihydro-2H-quinolin-1-yl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-
[1,2,4]triazol-3-ylsulfanyl}-ethanone;
2-[5-(3,4-Dimethoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-p-tolyl-ethanone;
N-(3-Chloro-2-methyl-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N,N-diphenyl-propionamide; 2-(5-Cyclohexyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide; 2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methyl-3-nitro-phenyl)-acetamide;
N-(2-Bromo-4-methyl-phenyl)-2-(4-ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone;
N-(4-Fluoro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(5-benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-chloro-phenyl)-acetamide;
N-(3-Chloro-2-methyl-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-nitro-phenyl)- acetamide;
2-[5-(2-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-propionamide;
[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid ethyl ester; 2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-naphthalen-1-yl- propionamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-propionamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-phenyl-propionamide; 2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-acetamide;
N-(3-Chloro-4-methyl-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide; 2-[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-nitro-phenyl)-acetamide;
4-{2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid ethyl ester;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-o-tolyl-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-chloro-phenyl)-acetamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methoxy-2-nitro-phenyl)- acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-nitro-phenyl)- acetamide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-{5-[(2,4-dimethyl-phenylamino)-methyl]-4-ethyl-4H- [1 ,2,4]triazol-3-ylsulfanyl}-ethanone; N-(4-Chloro-3-nitro-phenyl)-2-[5-(4-chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(3,4-dihydro-2H-quinolin-1-yl)- ethanone; 2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -p-tolyl-ethanone;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-phenyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-chloro-phenyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)- acetamide; 4-{2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid methyl ester;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-cyano-4,5,6,7-tetrahydro- benzo[b]thiophen-2-yl)-acetamide; 2-[5-(4-Chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-nitro-phenyl)-acetamide;
(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl)-(4-chloro-phenyl)-amine;
N-(2-Methoxy-phenyl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-(4-Allyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3,4-dichloro-phenyl)-acetamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-phenyl)-acetamide;
N-(5-Chloro-2-methyl-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Methoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; N-(2,4-Dimethyl-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
4-[2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid methyl ester;
N-(4-Chloro-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-bromo-4-methyl-phenyl)-acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-ethoxy-phenyl)- acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-naphthalen-1-yl-acetamide;
4-[5-(4-tert-Butyl-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine; 4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(4-fluoro-phenyl)-acetamide;
4-{2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid methyl ester;
N-(3-Chloro-phenyl)-2-(5-cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-ethoxy-phenyl)-acetamide;
2-{5-[(4-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-N-(2-nitro- phenyl)-acetamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-chloro-2-methyl-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-phenyl-acetamide;
3-Benzyl-5-(2-chloro-6-fluoro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazole;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone; 4-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-fluoro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-bromo-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide; 2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-propionamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-trifluoromethyl-phenyl)-acetamide;
{5-[(3-Chloro-4-methyl-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
3-[5-(2,4-Dichloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-pyridine; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-phenyl-acetamide;
N-(3-Chloro-4-methyl-phenyl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
N-(4-Chloro-phenyl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]- acetamide; 3-Benzyl-5-(4-chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazole; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-nitro-phenyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methoxy-phenyl)- acetamide;
{5-[(4-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
3-Benzylsulfanyl-5-(2-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
N-(2-Chloro-phenyl)-2-(4-methyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; N-(2-Methoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(3-nitro-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(3,4-dihydro-2H-quinolin-1- yl)-ethanone; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-bromo-4-methyl-phenyl)-acetamide;
N-(2-Chloro-phenyl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl)-(3-trifluoromethyl-phenyl)-amine;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy-phenyl)- ethanone;
[4-Allyl-5-(3-bromo-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-phenyl-amine;
2-(4-Furan-2-ylmethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(3-nitro-phenyl)- ethanone;
1-(4-Bromo-phenyl)-2-(4-furan-2-ylmethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone;
4-{5-[2-(2-Methoxy-phenoxy)-ethylsulfanyl]-4-methyl-4H-[1 ,2,4]triazol-3-yl}-phenylamine;
4-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-phenylamine;
[4-Allyl-5-(1 ,3-dioxo-1 H,3H-benzo[de]isoquinolin-2-ylmethyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetic acid ethyl ester; 2-{4-Allyl-5-[(4-chloro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-phenyl- ethanone;
5-(3-Bromo-phenyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol;
2-(4-Allyl-5-benzotriazol-1-ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)- acetamide; 1 -(4-Fluoro-phenyl)-2-(4-methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone; 8-(4-Methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-5-nitro-quinoline;
3-(2-Bromo-benzylsulfanyl)-4-methyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(2,4-dimethyl-phenyl)- ethanone; 1 -(4-Bromo-phenyl)-2-(5-furan-2-yl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(5-methyl-thiazol-2-yl)- acetamide;
2-[4-Ethyl-5-(p-tolylamino-methyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-p-tolyl-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-ethyl-phenyl)-acetamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -(4-methoxy-phenyl)-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-p-tolyl-ethanone;
3-(2-Bromo-phenyl)-4-methyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2,4-dimethyl-phenyl)- acetamide;
N-(4-Bromo-phenyl)-2-[5-(2-bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
2-{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-(4-methoxy- phenyl)-ethanone;
2-{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-p-tolyl- ethanone;
{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester; 2-{5-[(4-Fluoro-phenylamino)-methyl]-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -phenyl- ethanone;
2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-(4-methoxy- phenyl)-ethanone;
[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-(4-fluoro-phenyl)-amine; (5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl)-(4-fluoro-phenyl)-amine;
{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
N-(4-Chloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(4-Acetyl-phenyl)-2-(5-cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide;
N-Cyclohexyl-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(2,4-Dimethyl-phenyl)-2-[4-furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
4-[2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid ethyl ester;
2-[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro- phenyl)-acetamide; 3-lsobutylsulfanyl-4-methyl-5-p-tolyl-4H-[1 ,2,4]triazole;
2-[2-(4-Methyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid methyl ester;
2-{4-Ethyl-5-[4-(morpholine-4-sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-p-tolyl- ethanone; 4-Methyl-3-phenethylsulfanyl-5-p-tolyl-4H-[1 ,2,4]triazole;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-chloro-phenyl)-acetamide; 2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-propionamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2,5-dichloro-phenyl)-acetamide;
N-(3-Chloro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-propionamide;
N-(2-Bromo-4-methyl-phenyl)-2-[5-(3,4-dimethoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-N-(4-nitro-phenyl)- acetamide;
3-Benzylsulfanyl-5-cyclohexyl-4-ethyl-4H-[1 ,2,4]triazole;
[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid cyclohexyl ester; 2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)- acetamide;
N-(3-Chloro-4-methyl-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
[4-Benzyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid ethyl ester; 3-Benzylsulfanyl-4-methyl-5-(3,4,5-trimethoxy-phenyl)-4H-[1 ,2,4]triazole; N-(2-Chloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(2,4-Dimethoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)- acetamide; 2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
3-Cyclohexyl-4-methyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
N-(2-Bromo-phenyl)-2-(5-cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-iodo-2-methyl-phenyl)- acetamide; N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(5-cyclohexyl-4-methyl-4H-
[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(5-cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-phenyl)-acetamide;
N-(4-Chloro-phenyl)-2-(5-cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-methoxy-4-nitro-phenyl)- acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-
[1 ,2,4]triazol-3-ylsulfanyl]-acetamide; N-(4-Bromo-phenyl)-2-(5-cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-phenyl-acetamide;
N-(3-Chloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(4-Acetyl-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(4-Bromo-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide; 2-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-iodo-2-methyl-phenyl)- acetamide;
N-(2,4-Dimethyl-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
4-[5-(4-Chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol; [4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid cyclohexyl ester;
2-[5-(2-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
N-(3-Chloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-nitro-phenyl)-acetamide; 2-[4-Methyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
N-(4-Bromo-phenyl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3- ylsulfanyl}-acetamide;
N-(4-Chloro-phenyl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-N-(2-nitro-phenyl)- acetamide;
1-(4-Methoxy-phenyl)-2-[4-methyl-5-(4-nitro-phenyl)-4H-t1 ,2,4]triazol-3-ylsulfanyl]-ethanone;
[5-(4-Chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl]-(4-fluoro-phenyl)-amine; 2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-p-tolyl-ethanone;
2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-N-(4-methyl-3- nitro-phenyl)-acetamide;
N-(2-Bromo-4-methyl-phenyl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-
3-ylsulfanyl}-acetamide; 4-Allyl-5-(3-bromo-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
N-(2-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-{4-Ethyl-5-[4-(piperidine-1 -sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -p-tolyl- ethanone;
2-{4-Ethyl-5-[4-(piperidine-1 -sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -phenyl- ethanone;
N-Biphenyl-2-yl-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-chloro-4-methyl-phenyl)- acetamide;
N-(2-Bromo-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 4-Benzyl-5-cyclohexyl-4H-[1 ,2,4]triazole-3-thiol;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid cyclohexyl ester;
4-Methyl-3-(4-nitro-benzylsulfanyl)-5-phenyl-4H-[1 ,2,4]triazole; 2-(4-Methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -p-tolyl-ethanone;
2-(4-Methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
3-Benzylsulfanyl-4-methyl-5-(naphthalen-2-yloxymethyl)-4H-[1 ,2,4]triazole;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsuIfanyl)-N-p-tolyl-acetamide;
3-Benzylsulfanyl-5-cyclohexyl-4-methyl-4H-[1 ,2,4]triazole; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-3-nitro-phenyl)-acetamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methyl-3-nitro-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methoxy-4-nitro-phenyl)-acetamide;
N-(2-Bromo-4-methyl-phenyl)-2-(4-methyl-5-phenyl-4H-[1 ,2,4]triazol-3-yisulfanyl)-acetamide;
3-Benzylsulfanyl-4-ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole; 4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-p-tolyl-ethanone;
3-(4-Chloro-benzylsulfanyl)-4-ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(3,4-dimethyl-phenyl)- acetamide;
(2,4-Dimethyl-phenyl)-[4-ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-amine
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide;
2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-trifluoromethyl-phenyl)-acetamide; 2-[5-[(2,4-Dimethyl-phenylamino)-methyl]-4-(tetrahydro-furan-2-ylmethyl)-4H-[1 ,2,4]triazol-3- ylsulfanyl]-1 -p-tolyl-ethanone;
4-[5-(2,6-Dichloro-benzylsulfanyl)-4-(tetrahydro-furan-2-ylmethyl)-4H-[1,2,4]triazol-3-yl]- pyridine;
3-Benzylsulfanyl-5-(4-chloro-phenoxymethyl)-4-ethyl-4H-[1 ,2,4]triazole; 3-Butylsulfanyl-4-methyl-5-p-tolyl-4H-[1 ,2,4]triazole;
1-(5-Chloro-2-methoxy-phenyl)-2-(4-methyl-5-p-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
1-(4-Chloro-phenyl)-2-(4-methyl-5-p-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
N-(2,4-Dimethoxy-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)-acetamide; N-(4-Ethoxy-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Ethyl-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-p-tolyl-ethanone; 2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
N-(3-Chloro-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(2-Chloro-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[5-(2-Hydroxy-phenyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone;
2-[5-(2-Morpholin-4-yl-ethylsulfanyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-yl]-phenol; N-(2-Methyl-4-nitro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide;
N-(2-Methyl-5-nitro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide; N-(4-Bromo-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(3-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-fluoro-phenyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methoxy-4-nitro-phenyl)-acetamide;
N-(2,5-Dichloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide;
2-[4-Benzyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-nitro-phenyl)- acetamide;
2-(4-Phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)- acetamide;
[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4jtriazol-3-ylsulfanyl]-acetic acid cyclohexyl ester;
2-[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-ethyl-phenyl)-acetamide; 2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3,4-dichloro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-2-nitro-phenyl)-acetamide;
2-(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(5-methyl-thiazol-2-yl)-acetamide;
2-(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide; 2-(4,5-Dibenzyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
3-Benzylsulfanyl-5-(4-bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide; 2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -phenyl-ethanone;
2-(4-Benzyl-5-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(5-Methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
2-(5-Methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)- acetamide; N-(3-Chloro-phenyl)-2-(5-methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; N-(4-Chloro-phenyl)-2-(5-methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-methoxy-4-nitro-phenyl)- acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide; N-(2,3-Dichloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
N-(2,3-Dichloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy-phenyl)- ethanone;
2-[4-Benzyl-5-(2-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone;
2-[4-Benzyl-5-(2-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-acetamide;
2-{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-furan-2-ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1- phenyl-ethanone; 2-(4-Methyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
4-{4-Ethyl-5-[4-(piperidine-1-sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl}- benzonitrile;
N-(2-Methoxy-phenyl)-2-(4-methyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(4-ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methyl-3-nitro-phenyl)-acetamide;
2-[5-(4-Amino-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-nitro-phenyl)-ethanone;
N-{4-[5-(2-Chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-phenyl}-2-methoxy- benzamide;
2-(4-Allyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-fluoro-phenyl)-ethanone; 2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-fluoro-phenyl)-acetamide;
2-[5-(4-Amino-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-nitro-phenyl)-ethanone;
2-(4-Allyl-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)-acetamide;
(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid ethyl ester;
4-[5-(4-tert-Butyl-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-pyridine; 2-{5-[(3-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -phenyl- ethanone;
{5-[(2-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid isopropyl ester;
2-[4-Ethyl-5-(4-methoxy-phenoxymethyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone; 1-(4-Chloro-phenyl)-2-{5-[(2-chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3- ylsulfanylj-ethanone;
4-[5-(2-Chloro-6-fluoro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-pyridine
3-Benzyl-5-benzylsulfanyl-4-ethyl-4H-[1,2,4]triazole; 3-Benzylsulfanyl-4-methyl-5-o-tolyl-4H-[1 ,2,4]triazole;
N-(4-Chloro-3-nitro-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-p-tolyl-ethanone;
1-(4-Methoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetonitrile; [5-(2-Hydroxy-phenyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetonitrile;
1-[5-(2-Hydroxy-phenyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-propan-2-one;
N-(2,3-Dichloro-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
N-(3-Chloro-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
N-(4-Chloro-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
2-[5-(4-Methoxy-phenoxymethyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -phenyl-ethanone;
2-{5-[(2-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-piperidin-1-yl- ethanone;
2-[5-(4-Methoxy-phenoxymethyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanylj-1-(4-methoxy- phenyl)-ethanone;
N-(2,3-Dichloro-phenyl)-2-[4-furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide; 2-[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -(4-methoxy- phenyl)-ethanone;
{5-[(2-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
2-(4-Phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide; 2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methoxy-phenyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-trifluoromethyl-phenyl)-acetamide;
2-[4-Furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4- nitro-phenyl)-acetamide; N-(3-Chloro-2-methyl-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
4-Allyl-5-m-tolyl-4H-[1 ,2,4]triazole-3-thiol;
4-(2-Methyl-allyl)-5-m-tolyl-4H-[1 ,2,4]triazole-3-thiol; 2-[4-Allyl-5-(3-bromo-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-ethyl-phenyl)-acetamide;
4-Allyl-3-(3-bromo-phenyl)-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(3-bromo-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-biphenyl-4-yl-ethanone;
4-(2-Methyl-allyl)-5-(3-nitro-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
4-Allyl-5-(2-carbazol-9-yl-ethyl)-4H-[1 ,2,4]triazole-3-thiol; 5-(4-Bromo-phenyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol;
4-(2-Methyl-allyl)-5-(3-methyl-2-nitro-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
5-(4-Methoxy-phenyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol;
2-(4-Allyl-5-benzotriazol-1-ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-bromo-phenyl)- acetamide; 2-(4-Allyl-5-benzotriazol-1 -ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-pyridin-2-yl-acetamide;
{4-Allyl-5-[3-(1 ,3-dioxo-1 H,3H-benzo[de]isoquinolin-2-yl)-propyl]-4H-[1 ,2,4]triazol-3- ylsulfanyl}-acetic acid ethyl ester;
4-Allyl-5-(4-phenyl-piperazin-1 -ylmethyl)-4H-[1 ,2,4]triazole-3-thiol; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
In another embodiment, the invention provides the present use of substituted 1 ,2,4- triazoles, or prodrugs thereof of general formula (I) selected from the group consisting of the compounds of examples 1 through 3, A1 through A444 and B1 through B24.
In another embodiment, the present invention is concerned with substituted 1 ,2,4- triazoles, or prodrugs thereof of general formula (I) selected from the group consisting of the compounds of examples 1 through 3, A1 through A444 and B1 through B24.
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 hydro- chloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaph- thoates, glycerophosphates, ketoglutarates and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically 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, bu- tylamine, tetramethylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, choline, N,N'-dibenzylethylenediamine, N-benzylphenylethylamine, N- methyl-D-glucamine, guanidine and the like. Examples of cationic amino acids include lysine, arginine, histidine and the like.
Further, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention. The pharmaceutically acceptable salts are prepared by reacting a compound of the present invention with 1 to 4 equivalents of a base such as sodium hydroxide, sodium meth- oxide, sodium hydride, potassium tert-butoxide, calcium hydroxide, magnesium hydroxide and the like, in solvents like ether, THF, methanol, fe/f-butanol, dioxane, isopropanol, ethanol etc. Mixtures of solvents may be used. Organic bases like lysine, arginine, diethanolamine, choline, guandine and their derivatives etc. may also be used. Alternatively, acid addition salts wherever applicable are prepared by treatment with acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonic acid, methanesulfonic acid, acetic acid, citric acid, maleic acid salicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid, succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and the like in solvents like ethyl acetate, ether, alcohols, acetone, THF, dioxane etc. Mixture of solvents may also be used.
The stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomer form or by resolving the mixture of stereoisomers by conventional methods. Some of the preferred methods include use of microbial resolution, enzymatic resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or chiral bases such as brucine, (R)- or (S)-phenylethylamine, cinchona alkaloids and their derivatives and the like. Com- monly 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, ami- noacids, aminoalcohols derived from aminoacids; conventional reaction conditions may be employed to convert acid into an amide; the diastereomers may be separated either by frac- tional 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 dif- ferent 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, .erf-butyl, acetoxymethyl, pivaloyloxymethyl esters or other acy- loxymethyl esters). Compounds of the invention, original compounds, such modified by attaching chemical groups are termed 'modified compounds'. The invention also encompasses active metabolites of the present compounds.
The compounds according to the invention alter, and more specifically, reduce the level of active intracellular glucocorticoid and are accordingly useful for the treatment, 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 metabo- lism, neurodegenerative and psychiatric disorders, dysregulation of intraocular pressure including glaucoma, immune disorders, inappropriate immune responses, musculo-skeletal disorders, gastrointestinal disorders, polycystic ovarie syndrome (PCOS), reduced hair growth or other diseases, disorders or conditions that are influenced by intracellular glucocorticoid levels, adverse effects of increased blood levels of active endogenous or exogenous glucocorticoid, and any combination thereof, adverse effects of increased plasma levels of endogenous active glucocorticoid, Cushing's disease, Cushing's syndrome, adverse effects of glucocorticoid receptor agonist treatment of autoimmune diseases, adverse effects of glucocorticoid receptor agonist treatment of inflammatory diseases, adverse effects of glucocorticoid receptor agonist treatment of diseases with an inflammatory component, adverse ef- fects 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 bene- ficial 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, hyperinsuline- mia, inappropriately low insulin secretion, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), increased hepatic glucose production, type 1 diabetes, LADA, pediatric diabetes, dyslipidemia, diabetic dyslipidemia, hyperlipidemia, hypertriglyceridemia, hyperlipopro- teinemia, hypercholesterolemia, decreased HDL cholesterol, impaired LDL/HDL ratio, other disorders of lipid metabolism, obesity, visceral obesity, obesity as a consequence of diabetes, increased food intake, hypertension, diabetic late complications, micro-/macroalbu- minuria, nephropathy, retinopathy, neuropathy, diabetic ulcers, cardiovascular diseases, arteriosclerosis, atherosclerosis, coronary artery disease, cardiac hypertrophy, myocardial ischemia, heart insufficiency, congestional heart failure, stroke, myocardial infarction, arryth- mia, decreased blood flow, erectile dysfunction (male or female), myopathy, loss of muscle tissue, muscle wasting, muscle catabolism, osteoporosis, decreased linear growth, neurode- generative and psychiatric disorders, Alzheimers disease, neuronal death, impaired cognitive function, depression, anxiety, eating disorders, appetite regulation, migraine, epilepsia, addiction to chemical substances, disorders of intraocular pressure, glaucoma, polycystic ovary syndrome (PCOS), inappropriate immune responses, inappropriate T helper-1/T helper-2 polarisation, bacterial infections, mycobacterial infections, fungal infections, viral infections, parasitic infestations, suboptimal responses to immunizations, immune dysfunction, partial or complete baldness, or 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 respi- ratory system e.g. asthma, cystic fibrosis, emphysema, bronchitis, hypersensitivity, pneu- monitis, eosinophilic pneumonias, pulmonary fibrosis, adverse effects of glucocorticoid receptor agonist treatment of inflammatory bowel disease such as Crohn's disease and ulcera- tive colitis; adverse effects of glucocorticoid receptor agonist treatment of disorders of the immune system, connective tissue and joints e.g. reactive arthritis, rheumatoid arthritis, Sjδgren's syndrome, systemic lupus erythematosus, lupus nephritis, Henoch-Schδnlein pur- pura, Wegener's granulomatosis, temporal arteritis, systemic sclerosis, vasculitis, sarcoido- sis, dermatomyositis-polymyositis, pemphigus vulgaris; adverse effects of glucocorticoid receptor agonist treatment of endocrinological diseases such as hyperthyroidism, hypoaldos- teronism, hypopituitarism; adverse effects of glucocorticoid receptor agonist treatment of hematological diseases e.g. hemolytic anemia, thrombocytopenia, paroxysmal nocturnal he- moglobinuria; adverse effects of glucocorticoid receptor agonist treatment of cancer such as spinal cord diseases, neoplastic compression of the spinal cord, brain tumours, acute lym- phoblastic leukemia, Hodgkin's disease, chemotherapy-induced nausea, adverse effects of glucocorticoid receptor agonist treatment of diseases of muscle and at the neuro-muscular joint e.g. myasthenia gravis and heriditary myopathies (e.g. Duchenne muscular dystrophy), adverse effects of glucocorticoid receptor agonist treatment in the context of surgery & transplantation e.g. trauma, post-surgical stress, surgical stress, renal transplantation, liver transplantation, lung transplantation, pancreatic islet transplantation, blood stem cell transplantation, bone marrow transplantation, heart transplantation, adrenal gland transplantation, tra- cheal transplantation, intestinal transplantation, corneal transplantation, skin grafting, kerato- plasty, lens implantation 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 glucocorti- coid receptor agonist treatment in other diseases, disorders and conditions where glucocorticoid receptor agonists provide clinically beneficial effects.
Accordingly, in a further aspect the invention relates to a compound according to the invention for use as a pharmaceutical composition.
The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound according to the invention together with one or more pharmaceutically acceptable carriers or diluents.
The pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg/day to about 2000 mg/day, preferably from about 1 mg/day to about 500 mg/day of a compound according to the invention. In another embodiment, the patient is treated with a compound according to the invention for at least about 1 week, for at least about 2 weeks, for at least about 4 weeks, for at least about 2 months or for at least about 4 months.
In yet another embodiment, the pharmaceutical composition is for oral, nasal, transdermal, pulmonal or parenteral administration. Furthermore, the invention relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSDl is beneficial.
The invention also relates to a method for the treatment, prevention and/or prophy- laxis of disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSDl is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
In a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of any dis- eases and conditions that are influenced by intracellular glucocorticoid levels as mentioned above.
Thus, in a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of conditions and disorders where a decreased level of active intracellular glucocorticoid is desir- able, such as the conditions and diseases mentioned above.
In yet a preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of the metabolic syndrome including insulin resistance, dyslipidemia, hypertension and obesity.
In yet another preferred embodiment of the invention the present compounds are used for the preparation of a medicament for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes. In yet another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
In still another preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
In a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of neurodegenerative and psychiatric disorders. In yet a further preferred embodiment of the invention the present compounds are used for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
In another embodiment of the present invention, the route of administration may be any route which effectively transports a compound according to the invention to the 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 (melano- cortin 4) agonists, orexin antagonists, TNF (tumor necrosis factor) agonists, CRF (corticotro- pin releasing factor) agonists, CRF BP (corticotropin releasing factor binding protein) antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentrating hormone) antagonists, CCK (cholecystokinin) agonists, serotonin re-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone releasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP 2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DA agonists (bromocriptin, doprexin), lipase/amylase inhibitors, PPAR (peroxisome proliferator-activated receptor) modulators, RXR (retinoid X receptor) modulators, TR β agonists, AGRP (Agouti related protein) inhibitors, H3 histamine antagonists, opioid antagonists (such as naltrexone), exendin-4, GLP-1 and ciliary neurotrophic factor.
In one embodiment of the invention the antiobesity agent is leptin; dexamphetamine or amphetamine; fenfluramine or dexfenfluramine; sibutramine; orlistat; mazindol or phen- termine.
Suitable antidiabetic agents include insulin, insulin analogues and derivatives such as those disclosed in EP 792 290 (Novo Nordisk A/S), e.g. NεB29-tetradecanoyl des (B30) human insulin, EP 214 826 and EP 705 275 (Novo Nordisk A/S), e.g. Asp828 human insulin, US 5,504,188 (Eli Lilly), e.g. LysB28 Pro629 human insulin, EP 368 187 (Aventis), eg Lantus, which are all incorporated herein by reference, GLP-1 (glucagon like peptide-1) and GLP-1 derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S, which is incorpo- rated herein by reference as well as orally active hypoglycaemic agents. The orally active hypoglycaemic agents preferably comprise sulphonylureas, bigua- nides, meglitinides, glucosidase inhibitors, glucagon antagonists such as those disclosed in WO 99/01423 to Novo Nordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassium channel openers such as those disclosed in WO 97/26265 and WO 99/03861 to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV (dipeptidyl peptidase- IV) inhibitors, inhibitors of hepatic enzymes involved in stimulation of gluconeogenesis and/or glycogenolysis, glucose uptake modulators, compounds modifying the lipid metabolism such as antihyperlipidemic agents and antilipidemic agents as PPAR modulators, PPARδ modulators, cholesterol absorption inhibitors, HSL (hormone-sensitive lipase) inhibitors and HMG CoA inhibitors (statins), nicotinic acid, fibrates, anion exchangers, compounds lowering food intake, bile acid resins, RXR agonists and agents acting on the ATP-dependent potassium channel of the β-cells.
In one embodiment, the present compounds are administered in combination with insulin or an insulin analogue or derivative, such as NεB29-tetradecanoyl des (B30) human in- sulin, Asp828 human insulin, Lys628 Pro629 human insulin, Lantus®, or a mix-preparation comprising one or more of these.
In a further embodiment the present compounds are administered in combination with a sulphonylurea e.g. tolbutamide, glibenclamide, glipizide or glicazide.
In another embodiment the present compounds are administered in combination with a biguanide e.g. metformin.
In yet another embodiment the present compounds are administered in combination with a meglitinide e.g. repaglinide or senaglinide.
In still another embodiment the present compounds are administered in combination with a thiazolidinedione e.g. troglitazone, ciglitazone, pioglitazone, rosiglitazone or com- pounds disclosed in WO 97/41097 such as 5-[[4-[3-Methyl-4-oxo-3,4-dihydro-2-quinazo- linyl]methoxy]phenyl-methyl]thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, preferably the potassium salt.
In yet another embodiment the present compounds may be administered in combination with the insulin sensitizers disclosed in WO 99/19313 such as (-) 3-[4-[2-Phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid or a pharmaceutically acceptable salts thereof, preferably the arginine salt.
In a further embodiment the present compounds are administered in combination with an α-glucosidase inhibitor e.g. miglitol or acarbose. In another embodiment the present compounds are administered in combination with an agent acting on the ATP-dependent potassium channel of the β-cells e.g. tolbu- tamide, glibenclamide, glipizide, glicazide or repaglinide.
Furthermore, the present compounds may be administered in combination with nateglinide.
In still another embodiment the present compounds are administered in combination with an antihyperlipidemic agent or antilipidemic agent e.g. cholestyramine, colestipol, clofi- brate, gemfibrozil, fenofibrate, bezafibrate, tesaglitazar, EML-4156, LY-818, MK-767, ator- vastatin, fluvastatin, lovastatin, pravastatin, simvastatin, acipimox, probucol, ezetimibe or dextrothyroxine.
In a further embodiment the present compounds are administered in combination with more than one of the above-mentioned compounds e.g. in combination with a sulphony- lurea and metformin, a sulphonylurea and acarbose, repaglinide and metformin, insulin and a sulphonylurea, insulin and metformin, insulin, insulin and lovastatin, etc. Further, the present compounds may be administered in combination with one or more antihypertensive agents. Examples of antihypertensive agents are β-blockers such as alprenolol, atenolol, timolol, pindolol, propranolol, metoprolol, bisoprololfumerate, esmolol, acebutelol, metoprolol, acebutolol, betaxolol, celiprolol, nebivolol, tertatolol, oxprenolol, amusolalul, carvedilol, labetalol, β2-receptor blockers e.g. S-atenolol, OPC-1085, ACE (angiotensin converting enzyme) inhibitors such as quinapril, lisinopril, enalapril, captopril, benazepril, perindopril, trandolapril, fosinopril, ramipril, cilazapril, delapril, imidapril, moexipril, spirapril, temocapril, zofenopril, S-5590, fasidotril, Hoechst-Marion Roussel: 100240 (EP 00481522), omapatrilat, gemopatrilat and GW-660511 , calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, amlodipine, nitrendipine, verapamil, lacidipine, lercanidipine, aranidipine, cilnidipine, clevidipine, azelnidipine, 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. bendro- flumetazide, 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 , CM 034, S-0139 and YM-598, endothelin antagonists e.g. bosentan and J-104133, renin inhibitors such as aliskiren, vasopressin V1 antagonists e.g. OPC-21268, vasopressin V2 antagonists such as tolvaptan, SR-121463 and OPC-31260, B-type natriuretic peptide agonists e.g. Nesiritide, angiotensin 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 A1 antagonists such as naftopidil, N-0861 and FK-352, thromboxane A2 antagonists such as KT2-962, endopeptidase inhibitors e.g. ecadotril, nitric oxide agonists such as LP-805, dopamine D1 antagonists e.g. MYD-37, dopamine D2 agonists such as nolomirole, n-3 fatty acids e.g. omacor, prostacyclin agonists such as treprostinil, beraprost, PGE1 agonists e.g. ecraprost, Na+/K+ ATPase modulators e.g. PST-2238, Potassium channel activators e.g. KR-30450, vaccines such as PMD-3117, Indapamides, CGRP- unigene, guanylate cyclase stimulators, hydralazines, methyldopa, docarpamine, moxo- nidine, CoAprovel, MondoBiotech-811.
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 be- ing 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, suspen- sions, 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 com- pound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion. Other salts which are not pharmaceutically acceptable may be useful in the preparation of compounds for use according to the present invention and these form a further aspect of the present invention.
For parenteral administration, solutions of the present compounds in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, syrup, phospholipids, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
The pharmaceutical compositions formed by combining the compounds of the invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy. Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.
Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingre- dient 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, pre- servative and flavouring and colouring agent. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as solvent or suspending medium. For this purpose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compositions may also be in the form of suppositories for rectal administration of the compounds of the present invention. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug. Such materials in- elude 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 liq- uid suspension or solution.
A typical tablet which may be prepared by conventional tabletting techniques may contain: Core:
Active compound (as free compound or salt thereof) 5.0 mg Lactosum Ph. Eur. 67.8 mg
Cellulose, microcryst. (Avicel) 31.4 mg
Amberlite®IRP88* 1.0 mg
Magnesii stearas Ph. Eur. q.s.
Coating: Hydroxypropyl methylcellulose approx. 9 mg
Mywacett 9-40 T** approx. 0.9 mg
* Polacrillin potassium NF, tablet disintegrant, Rohm and Haas. ** Acylated monoglyceride used as plasticizer for film coating.
The compounds of the invention may be administered to a patient which is a mammal, especially a human in need thereof. Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife. Any novel feature or combination of features described herein is considered essential to this invention.
The present invention also relate to the below methods of preparing the compounds of the invention.
The present invention is further illustrated in the following representative examples which are, however, not intended to limit the scope of the invention in any way.
EXAMPLES
The following examples and general procedures refer to intermediate compounds and final products identified in the specification and in the synthesis schemes. The preparation of the compounds 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, that 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) down field from tetramethylsilane as internal reference standard. M.p.: is melting point and is given in °C and is not corrected. Column chromatography was carried out using the technique described by W.C. Still et al., J. Org. Chem. 43: 2923 (1978) on Merck silica gel 60 (Art. 9385). HPLC 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.
The abbreviations as used in the examples have the following meaning:
TLC: thin layer chromatography
CDCI3: deuterio chloroform
CD3OD: tetradeuterio methanol
DMSO-d6: hexadeuterio dimethylsulfoxide
DMSO: dimethylsulfoxide
THF: tetrahydrofuran
DMF: N,N-dimethylformamide
HOBT: 1 -hydroxy-benzotriazole
EDAC: 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride min: minutes hrs: hours
The compounds of the invention are prepared as illustrated in the following reaction scheme 1 :
Scheme 1
ent
Figure imgf000049_0001
Method A
Method D
General method A:
By allowing a hydrazide (I), wherein R3 is as defined above, to react with a isothio- cyanate or isocyanate (II), wherein X is O or S and R2 as is defined above, in a solvent such as MeOH, EtOH, i-PrOH, tert-B O and the like catalysed by a base such as triethylamine, aq. NaOH and the like affording a 1 ,2,4-triazole (III), wherein X, R2 and R3 are as defined above. The triazole (III) is alkylated with an alkylating agent (IV), wherein Y is halo, OS02C C6alkyl, OS02aryl or 0S02arylCrC6alkyl and the like and R13 is selected from the group consisting of CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl as defined above and wherein the alkyl, aryl and hetaryl groups optionally are substituted as defined above, in a solvent such as DMF, DMSO, NMP, acetone, THF, dichloromethane and the like under basic conditions (e.g. K2C03, NaOH, NaH, n-BuLi and the like) affording compound (V) wherein X, R2, R3 and R13 are as defined above.
General method B:
By allowing a triazole (III), wherein X is O or S and R2 and R3 are as defined above, to react with a halo-ketone (VI), wherein hal is halo, n is 1 to 6 and R14 is selected from the group consisting of C5-C8cycloalkyl, aryl or hetaryl as defined above and wherein the cyclo- alkyl, aryl and hetaryl groups are optionally substituted as defined above, in a solvent such as MeOH, EtOH, i-PrOH, ferf-BuOH, DMF, DMSO, NMP, acetone, THF, dichloromethane and the like under basic conditions (e.g. triethylamine, K2C03, NaOH, NaH, n-BuLi and the like) affording 1 ,2,4-triazole (VII) ), wherein R2, R3 , X, n and R14 are as defined above.
General method C:
By allowing a triazole (III), wherein X is O or S and R2 and R3 are as defined above, to react with a halo-amide (VIII), wherein hal is halo, n is 1 to 6 and R4 and R5 are as defined above, in a solvent such as MeOH, EtOH, i-PrOH, te/t-BuOH, DMF, DMSO, NMP, acetone, THF, dichloromethane and the like under basic conditions (e.g. triethylamine, K2C03, NaOH, NaH, n-BuLi and the like) affording 1 ,2,4-triazole (XIII); wherein X, R2, R3, n, R4 and R5 are as defined above.
General method D:
By allowing a triazole (III), wherein X is O or S and R2 and R3 are defined as above, to react with a halo-ester (IX), wherein hal is halo, n is 1 to 6 and R12 is selected from the group consisting of CrC6alkyl, arylCrC6alkyl, C5-C9cycloalkyl, aryl or hetaryl as defined above and wherein the alkyl, cycloalkyl, aryl and hetaryl groups are optionally substituted as defined above, in a solvent such as MeOH, EtOH, i-PrOH, tert-BuO , DMF, DMSO, NMP, acetone, THF, dichloromethane and the like under basic conditions (e.g. triethylamine, K2C03, NaOH, NaH, n-BuLi and the like) affording 1 ,2,4-triazole (X), wherein X, n, R2, R3 and R12 are as defined above. The triazole (X) is transformed into the corresponding acid (XI), wherein X, n, R2 and R3 are as defined above, by methods known to those skilled in the art and coupled with an amine (XII), wherein R4 and R5 are as defined above, under standard amide forming conditions (e.g. HOBT, EDAC and DIPEA in dry THF) affording 1 ,2,4-triazole (XIII); wherein X, n, R2, R3, R4 and R5 are as defined above.
Example 1 (General method (A))
4-f2-(4-Ethyl-5-pyridin-4-yl-4/-/-[1 ,2,4ltriazol-3-ylsulfanyl)ethvnmorpholine
Figure imgf000050_0001
A mixture of isonicotinic acid hydrazide (22 mg, 0.16 mmol), ethyl isothiocyanoace- tate (14 mg, 0.16 mmol) and triethylamine (45 μL, 0.32 mmol) in ethanol (2 ml) was heated at 80 °C in an ampoule reaction flask for 16 hrs. The reaction mixture was cooled to 40 °C, a solution of Λ/-(chloroethyl)morpholin, hydrochloride in ethanol (0.8 ml) was added and the stirring was continued for an additional 16 hrs. at 40 °C. The cooled reaction mixture was evaporated in vacuo and the residue purified by silicagel chromatography using first a mixture of 4% triethylamine in ethyl acetate followed by a mixture of triethylamine/ethanol/ethyl acetate (5:20:75). Semi-pure fractions were collected and the solvent evaporated in vacuo affording 24 mg of crude title compound which was suspended in diethyl ether (1 ml) and stirred for 1 hrs. The solid product was filtered off and dried in vacuo at 50 °C affording 11 mg (22%) of the title compound as a solid.
1H NMR (300 MHz, CDCI3) δ 1.41 (t, 3H), 2.61 (bs, 4H), 2.90 (bs, 2H), 3.55 (t, 2H), 3.73 (m, 4H), 4.06 (q, 2H), 7.57 (m, 2H), 8.79 (m, 2H).
Example 2 (General method (B)) 1-Benzothiazol-2-yl-2-(4-ethyl-5-phenyl-4H-π ,2,4ltriazol-3-ylsulfanyl)-ethanone
Figure imgf000051_0001
A mixture of 4-ethyl-5-phenyl-4H-[1 ,2,4]triazole-3-thiol (300 mg, 1.46 mmol), 1- benzothiazol-2-yl-2-bromo-ethanone; (561 mg, 2.19 mmol), potassium carbonate (303 mg, 2.19 mmol) and potassium iodine (24 mg, 0.15 mmol) in acetone (50 ml) was heated at reflux temperature for 16 hrs. The reaction mixture was cooled, filtered and the volatiles evaporated in vacuo. The residue was purified by silicagel chromatography using first a mixture of ethyl acetate/heptane (1 :1 , 500 ml) followed by pure ethyl acetate. Pure fractions were collected and the solvent evaporated in vacuo. The solid residue was suspended in diethyl ether (5 ml) and stirred for 1 hrs. The solid product was filtered off and dried in vacuo at 50 °C affording 250 mg (45%) of the title compound as a solid.
1H NMR (300 MHz, CDCI3) δ 1.29 (t, 3H), 3.29 (d, 1 H), 3.53 (d, 1 H), 3.94 (q, 2H), 7.38 (dt, 1 H), 7.44-7.48 (m, 1 H), 7.49-7.58 (m, 5H), 7.93 (q, 2H). Calculated for
Figure imgf000051_0002
1 x C3H60; C, 60.25 %; H, 5.06 %; N, 12.78 %. Found: C, 60.45 %; H, 5.20 %; N, 12.60 %.
Example 3 (General method (D))
A/-Cvclohexyl-2-(4-ethyl-5-phenyl-4/- -π ,2,41triazol-3-ylsulfanyl)-Λ/-methyl-acetamide
Figure imgf000052_0001
A mixture of 4-ethyl-5-phenyl-4/- -[1 ,2,4]triazole-3-thiol (2 g, 9.74 mmol), chloro- acetic acid terf-butyl ester (1.61 g, 10.72 mmol) and potassium carbonate (2.02 g, 14.62 mmol) in acetone (75 ml) was heated at reflux temperature for 16 hrs. The reaction mixture was cooled, filtered and the volatiles evaporated in vacuo. The residue was purified by silicagel chromatography using first a mixture of ethyl acetate/heptane (1 :2). Pure fractions were collected and the solvent evaporated in vacuo to almost dryness. The wet residue was suspended in diethyl ether (10 ml) and stirred for 1 hrs. The solid product was filtered off and dried in vacuo at 50 °C affording 2.6 g (84%) of (4-ethyl-5-phenyl-4W-[1 ,2,4]triazol-3-ylsulfa- nyl)acetic acid terf-butyl ester as a solid. 1H NMR (300 MHz, CDCI3) δ 1.35 (t, 3H), 1.47 (s, 9H), 4.01-4.09 (m, 4H), 7.50 (m, 3H), 7.59 (m, 2H).
To a solution of the above acetic acid ferf-butyl ester (2.5 g, 7.83 mmol) in dichloromethane (25 ml) was added trifluoroacetic acid (10 ml) at room temperature. The resulting mixture was stirred for 16 hrs, the volatiles were evaporated in vacuo and to the oily residue was added ethyl acetate (15 ml) and diethyl ether (20 ml) when the crystallisation has stared. The solid precipitate was filtered off and washed with diethyl ether (20 ml) and dried in vacuo at 50 °C which afforded 1.8 g (87 %) of (4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)acetic acid as a solid.
1H NMR (300 MHz, DMSO-d6) δ 1.22 (t, 3H), 4.01 (q, 2H), 4.09 (s, 2H), 7.57 (m, 3H), 7.65 (m, 2H), 12.97 (bs, 1 H). To a solution of the above acetic acid (0.5 g, 1.9 mmol), HOBT (0.28 g, 2.09 mmol) in dry THF (40 ml) was added EDAC (0.4 g, 2.09 mmol) and the mixture was stirred for 20 minutes. Di-isopropyl ethyl amine (DIPEA) (364 μl, 2.09 mmol) and cyclohexyl-methyl-amine (0.27 ml, 2.09 mmol) was added and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were evaporated in vacuo and the residue was purified by sili- cagel chromatography using ethyl acetate as eluent. Pure fractions were collected and the solvent evaporated in vacuo to almost dryness. The wet residue was suspended in diethyl ether (10 ml) and stirred for 1 hrs. The solid product was filtered off and dried in vacuo at 50
°C affording 480 mg (70%) of the title compounds as a solid.
1H NMR (300 MHz, CDCI3) δ 1.0-1.14 (m, 1 H), 1.36 (t, 3H), 1.42-1.87 (m, 9H), 2.87 and 2.97
(2x s, 3H, N-Me rotamers), 3.68 (m, 1 H), 4.03 (dq, 2H), 4.40 and 4.49 (2x s, 2H, S-Ctf2-
C(=O) rotamers), 7.51 (m, 3H), 7.60 (m, 2H).
Calculated for
Figure imgf000053_0001
C, 63.66 %; H, 7.31 %; N, 15.63 %. Found:
C, 63.72 %; H, 7.40 %; N, 15.67 %.
The following compounds were synthesised in a similar way as described in example 1 (general method A) utilising solution phase parallel synthesis methods.
Comp.
Molecule MW IUPAC Name No.
3-[5-(2-Chloro-benzylsulfanyl)-4-ethyl-4H- [1 ,2,4]triazol-3-yl]-propan-1 -ol
4-[4-Ethyl-5-(3-hydroxy-propyl)-4H- [1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile
3-[5-(6-Chloro-benzo[1 ,3]dioxol-5- ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol- 3-yl]-propan-1-ol
3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl- 4H-[1 ,2,4]triazol-3-yl]-propan-1 -ol
3-(5-Cyclohexylmethylsulfanyl-4-et yl-4H- [1 ,2,4]triazol-3-yl)-propan-1 -ol
Figure imgf000053_0002
H
3-[4-Ethyl-5-(4-trifluoromethyl-
A-6 345.39 benzylsulfanyl)-4H-[1 ,2,4]triazoI-3-yl]- propan-1-ol
Figure imgf000054_0001
3-(5-Benzylsulfanyl-4-ethyl-4H- [1 ,2,4]triazol-3-yl)-propan-1 -ol
3-[4-Ethyl-5-(4-methanesulfonyl- benzylsuIfanyl)-4H-[1 ,2,4]triazol-3-ylj- propan-1-ol
3-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H- [1 ,2,4]triazo!-3-yI]-propan-1 -ol
3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl- 4H-[1 ,2,4]triazol-3-yl]-propan-1 -ol
Figure imgf000054_0002
3-[4-Et yi-5-(3-trifluoromet oxy-
A-11 361.39 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj- propan-1-ol
N-{4-[4-Ethyl-5-(3-hydroxy-propyI)-4H-
A-12 334.44 [1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- acetamide
3-[4-Ethyl-5-(5-methyl-2-nitro-
A-13 336.42 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]- propan-1-ol
Figure imgf000054_0003
3-[4-Ethyl-5-(2-nitro-benzylsuIfanyl)-4H- [1 ,2,4]triazol-3-yl]-propan-1 -ol
Figure imgf000054_0004
4-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-
A-15 336.42 [1 ,2,4]triazol-3-ylsulfanylmethylj-
Figure imgf000055_0001
benzonitrile
4-[5-(6-Chloro-benzo[1 ,3]dioxol-5- yimethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-
3-yl]-phenol
4-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H-
[1 ,2,4]triazol-3-yl]-phenol
4-[4-Ethyl-5-(4-trifluoromethyl- benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj- phenol
4-(5-Benzylsulfanyl-4-ethyl-4H- [1 ,2,4]triazol-3-yl)-phenol
Figure imgf000055_0002
4-[4-Ethyl-5-(4-methanesulfonyl-
A-20 389-50 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]- phenol
Figure imgf000055_0003
4-[4-Ethyl-5-(3-nitro-benzylsuIfanγI)-4H- [1 ,2,4]triazol-3-yl]-phenol
Figure imgf000055_0004
4-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-
A-22 36a45 [1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl ester
Figure imgf000055_0005
4-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-
4H-[1 ,2,4]triazol-3-yI]-phenol
Figure imgf000055_0006
N-{4-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-
A-24 368-46 [1 ,2,4]triazol-3-ylsulfanyImethyl]-phenyl}- acetamide
Figure imgf000055_0007
4-[4-EthyI-5-(4~methoxy-benzylsulfanyl)- 4H-[1 ,2,4]triazol-3-yl]-phenol
Figure imgf000056_0001
4-[4-Ethyl-5-(5-methyl-2-nitro-
A-26 370.43 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj- phenol
Figure imgf000056_0002
4-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H- [1 ,2,4]triazol-3-yl]-phenol
4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl 4H-[1 ,2,4]triazol-3-yl]-phenol
3-Benzo[1 ,3]dioxol-5-yl-5-(2-chloro- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
4-(5-Benzo[1 ,3]dioxol-5-yl-4-ethyl-4H- [1 ,2,4]triazol-3-ylsulfanylmethyl)- benzonitrile
3-Benzo[1 ,3]dioxol-5-yl-5-(6-chloro- benzo[1 ,3]dioxol-5-ylmethylsuIfanyl)-4- ethyl-4H-[1 ,2,4]triazole
3-Benzo[1 ,3]dioxol-5-yl-5-(4-bromo- benzylsulfanyl)-4-ethyI-4H-[1 ,2,4]triazole
Figure imgf000056_0003
4-[4-(5-Benzo[1 ,3]dioxol-5-yl-4-ethyl-4H-
A-33 423.52 [1 ,2,4]triazol-3-ylsulfanylmethyl)-phenylj- [1 ,2,3]thiadiazole
3-Benzo[1 ,3]dioxol-5-yl-5-
A-34 345.47 cyclohexylmethylsulfanyl-4-ethyl-4H-
Figure imgf000056_0004
[1 ,2,4]triazole 3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(4-
A-35 423.42 trifluoromethoxy-benzylsuIfanyl)-4H- [1 ,2,4]triazole
Figure imgf000057_0001
3-Benzo[1 ,3]dioxol-5-yl-5-(3,5-dimethoxy- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000057_0002
3-Benzo[1 ,3]dioxol-5-y!-4-ethyl-5-(4-
A-37 417.51 methanesulfonyl-benzylsulfanyl)-4H- [1 ,2,4]triazole
4-(5-Benzo[1 ,3]dioxol-5-yl-4-ethyl-4H-
A-38 397 ' 46 [1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl ester
A-39 408.31 3-Bβn«>[1.3]dloxol-5-yl-5-(2,Mlchloro. benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000057_0003
3-Benzo[1 ,3]dioxol-5-yl-5-(4-benzyloxy- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000057_0004
N-[4-(5-Benzo[1 ,3]dioxol-5-yl-4-ethyl-4H- A-41 396.47 [1 ,2,4]triazol-3-ylsulfanylmethyl)-phenylj- acetamide
Figure imgf000057_0005
3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(4- methoxy-benzyIsulfanyl)-4H-[1 ,2,4]triazole
Figure imgf000057_0006
3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(5-
A-43 398.44 methyI-2-nitro-benzylsulfanyl)-4H- [1 ,2,4]triazole
Figure imgf000057_0007
3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(2-nitro- benzylsulfanyl)-4H-[1 ,2,4]triazole
3-Benzo[1 ,3]dioxol-5-yl-5-(2,4-dichIoro- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000058_0001
4-[4-Ethyl-5-(2-phenoxy-phenyl)-4H- A-46 412-52 [1 ,2,4]triazol-3-ylsulfanylmethylj- benzonitrile
3-(6-Chloro-benzo[1 ,3]dioxol-5- A-47 465.96 ylmethylsulfanyl)-4-ethyl-5-(2-phenoxy- phenyl)-4H-[1 ,2,4]triazole
Figure imgf000058_0002
3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5-
(2-phenoxy-phenyl)-4H-[1 ,2,4]triazole
3-(4-Bromo-benzylsulfanyl)-4-ethyl-5-(2- phenoxy-phenyl)-4H-[1 ,2,4]triazole
Figure imgf000058_0003
4-{4-[4-Ethyl-5-(2-phenoxy-phenyl)-4H- A-50 471.61 [1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- [1 ,2,3]thiadiazole
Figure imgf000058_0004
3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl- 5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazole
Figure imgf000058_0005
4-Ethyl-3-(2-phenoxy-phenyl)-5-(4-
A-52 455.51 trifluoromethyl-benzylsιιlfanyl)-4H- [1 ,2,4]triazole
4-Ethyl-3-(4-methanesulfonyl-
A-53 465.60 benzyIsulfanyI)-5-(2-phenoxy-phenyl)-4H- [1 ,2,4]triazole
4-[4-Ethyl-5-(2-phenoxy-phenyl)-4H-
A-54 445.54 [1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl ester
Figure imgf000059_0001
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5- (2-phenoxy-phenyl)-4H-[1,2,4]triazole
3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5- (2-phenoxy-phenyl)-4H-[1,2,4]triazole
4-Ethyl-3-(4-methyl-benzyIsulfanyl)-5-(2- phenoxy-phenyl)-4H-[1 ,2,4]triazole
Figure imgf000059_0002
4-Ethyl-3-(2-phenoxy-phenyI)-5-(3-
A-58 471.51 trifluoromethoxy-benzylsulfanyl)-4H- [1 ,2,4]triazole
Figure imgf000059_0003
4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-(2- phenoxy-phenyl)-4H-[1 ,2,4]triazole
Figure imgf000059_0004
4-Ethyl-3-(2-nitro-benzylsuIfanyl)-5-(2- phenoxy-phenyl)-4H-[1 ,2,4]triazole
3-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-5- (2-phenoxy-phenyl)-4H-[1 ,2,4]triazole
3-CyclohexyImethyIsulfanyl-4-ethyl-5- naphthalen-1-yl-4H-[1 ,2,4]triazole
4-Ethyl-3-naphthalen-1 -yl-5-(4- trifluoromethyl-benzylsulfanyl)-4H- [1 ,2,4]triazole
Figure imgf000060_0001
4-Ethyl-3-(4-methanesulfonyl-
A-64 423.56 benzylsulfanyl)-5-naphthalen-1 -yl-4H- [1 ,2,4]triazole
Figure imgf000060_0002
4-Ethyl-3-naphthalen-1-yl-5-(3-nitro- benzylsulfanyl)-4H-[1 ,2,4]triazole
4-(4-Ethyl-5-naphthalen-1-yl-4H- [1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl ester
4-Ethyl-3-naphthalen-1-yl-5-(4-nitro- benzylsulfanyl)-4H-[1 ,2,4]triazole
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5- naphthalen-1 -yl-4H-[1 ,2,4]triazole
Figure imgf000060_0003
4-Ethyl-3-(4-methyl-benzylsulfanyl)-5- naphthalen-1 -yl-4H-[1 ,2,4]triazole
4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5- naphthalen-1-yl-4H-[1 ,2,4]triazole
4-Ethyl-3-(5-methyI-2-nitro-benzylsulfanyl)- 5-naphthalen-1 -yl-4H-[1 ,2,4]triazole
3-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-5- naphthalen-1-yl-4H-[1 ,2,4]triazole
[4-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H- [1 ,2,4]triazol-3-yl)-phenyl]-dimethyl-amine
Figure imgf000061_0001
{4-[5-(3,5-Dimethoxy-benzylsulfanyl)-4- 398.53 ethyl-4H-[1 ,2,4]triazol-3-yl]-phenyl}- dimethyl-amine
{4-[4-Ethyl-5-(4-trifluoromethyl- 406.48 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj- phenyl}-dimethyl-amine
4-[5-(4-Dimethylamino-phenyl)-4-ethyl-4H- 396.52 [1 ,2,4]triazol-3-ylsulfanylmethyI]-benzoic acid methyl ester
Figure imgf000061_0002
{4-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H- [1 ,2,4]triazol-3-yl]-phenyl}-dimethyl-amine
Figure imgf000061_0003
{4-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-
A-78 368.50 4H-[1 ,2,4]triazol-3-yl]-phenyl}-dimethyl-
Figure imgf000061_0004
amine {4-[4-Ethyl-5-(5-methyl-2-nitro-
A-79 397.50 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]- phenyl}-dimethyl-amine {4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyI-
A-80 407-37 4H-[1 ,2,4]triazol-3-yl]-phenyl}-dimethyl- amine
4-(4-Ethyl-5-thiophen-2-yl-4H-
A-81 326.44 [1 ,2,4]triazol-3-ylsulfanylmethyl)- benzonitrile
3-(6-Chloro-benzo[1 ,3]dioxol-5- A-82 379 ' 89 ylmethylsulfanyl)-4-ethyl-5-thiophen-2-yl-
4H-[1 ,2,4]triazole
Figure imgf000062_0001
3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5- thiophen-2-yl-4H-[1 ,2,4]triazo!e
3-(4-Bromo-benzylsulfanyl)-4-ethyl-5- thiophen-2-yl-4H-[1 ,2,4]triazole
Figure imgf000062_0002
4-[4-(4-Ethyl-5-thiophen-2-yi-4H- A-85 385'53 [1 >2,4]triazol-3-ylsulfanylmethyl)-phenylj- [1 ,2,3]thiadiazole
4-Ethyl-3-thiophen-2-yl-5-(4- A-86 385.43 trifluoromethoxy-benzyIsulfanyl)-4H- [1 ,2,4]triazoIe
Figure imgf000062_0003
3-(3,5-Dimethoxy-benzylsulfanyI)-4-ethyl-
5-thiophen-2-yl-4H-[1 ,2,4]triazole
Figure imgf000062_0004
4-Ethyl-3-thiophen-2-yl-5-(4- A-88 389.43 trifluoromethyl-benzylsulfanyl)-4H-
[1 ,2,4]triazole
Figure imgf000062_0005
3-Benzylsulfanyl-4-ethyl-5-thiophen-2-yl- 4H-[1 ,2,4]triazolβ
Figure imgf000063_0001
4-Ethyl-3-(4-methanesulfonyl-
A-90 379-52 benzylsulfanyl)-5-thiophen-2-yl-4H- [1 ,2,4]triazole
4-(4-Ethyl-5-thiophen-2-yl-4H-
A-91 359-47 [1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl ester
Figure imgf000063_0002
4-Ethyl-3-(4-nitro-benzylsulfanyl)-5- thiophen-2-yl-4H-[1 ,2,4]triazole
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5- thiophen-2-yl-4H-[1 ,2,4]triazole
Figure imgf000063_0003
N-N
X Xχ~XCX 4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-
A-94 \\ T X s 315.46
-s ^^CH3 thiophen-2-yl-4H-[1 ,2,4]triazole
CH,
4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5- thiophen-2-yl-4H-[1 ,2,4]triazole
4-Ethyl-3-(5-methyl-2-nitro-benzylsuIfanyl)- 5-thiophen-2-yl-4H-[1 ,2,4]triazole
3-(2-Chloro-benzylsulfanyl)-4-ethyl-5-(2- methoxy-phenyl)-4H-[1 ,2,4]triazole
Figure imgf000063_0004
3-(6-Chloro-benzo[1 ,3]dioxol-5- A-98 403.89 yImethylsulfanyl)-4-ethyl-5-(2-methoxy- phenyl)-4H-[1 ,2,4]triazole
Figure imgf000063_0005
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-
A-99 409.43 trifluoromethoxy-benzylsulfanyl)-4H- [1 ,2,4]triazole
Figure imgf000064_0001
3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl- 5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazole
Figure imgf000064_0002
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-
A-101 393.43 trifluoromethyl-benzylsulfanyl)-4H-
[1 ,2,4]triazole
Figure imgf000064_0003
3-Benzylsulfanyl-4-ethyl-5-(2-methoxy- phenyl)-4H-[1 ,2,4]triazole
Figure imgf000064_0004
4-Ethyl-3-(4-methanesulfonyl-
A-103 403.53 benzylsuifanyl)-5-(2-methoxy-phenyl)-4H- [1 ,2,4]triazole
4-[4-Ethyl-5-(2-methoxy-phenyl)-4H-
A-104 383.47 [1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl ester
Figure imgf000064_0005
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-nitro- benzylsulfanyl)-4H-[1 ,2,4]triazole
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5- (2-methoxy-phenyl)-4H-[1 ,2,4]triazole
Figure imgf000064_0006
3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5- (2-methoxy-phenyl)-4H-[1 ,2,4]triazole
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-methyl- benzylsulfany!)-4H-[1 ,2,4]triazole
4-Ethyl-3-(2-methoxy-phenyl)-5-(3- trifluoromethoxy-benzylsulfanyl)-4H-
[1 ,2,4]triazole
4-Ethyl-3-(2-methoxy-phenyl)-5-(5-methyl- 2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole
4-Ethyl-3-(2-methoxy-phenyl)-5-(2-nitro- benzylsulfanyl)-4H-[1 ,2,4]triazole
3-(2-Chloro-benzylsulfanyl)-4-ethyl-5-(4- methoxy-phenyl)-4H-[1 ,2,4]triazole
Figure imgf000065_0001
4-[4-Ethyl-5-(4-methoxy-phenyl)-4H-
A-113 350.45 [1 ,2,4]triazol-3-ylsulfanylmethylj- benzonitrile
3-(6-Chloro-benzo[1 ,3]dioxol-5-
A-114 403.89 ylmethylsulfanyl)-4-ethyl-5-(4-methoxy- phenyl)-4H-[1 ,2,4]triazole
Figure imgf000065_0002
3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5- (4-methoxy-phenyl)-4H-[1 ,2,4]triazole
3-(4-Bromo-benzylsulfanyI)-4-ethyl-5-(4- methoxy-phenyl)-4H-[1 ,2,4]triazole
Figure imgf000066_0001
4-{4-[4-Ethyl-5-(4-methoxy-phenyl)-4H- 409.54 [1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- [1 ,2,3]thiadiazole
3-Cyclohexylmethylsulfanyl-4-ethyl-5-(4- methoxy-phenyI)-4H-[1 ,2,4]triazole
4-Ethyl-3-(4-methoxy-phenyl)-5-(4- 393.43 trifluoromethyl-benzylsulfanyl)-4H- [1 ,2,4]triazole
4-Ethyl-3-(4-methanesulfonyl- 403.53 benzylsulfanyI)-5-(4-methoxy-phenyl)-4H- [1 ,2,4]triazole
4-[4-Ethyl-5-(4-methoxy-phenyl)-4H- 383.47 [1 ,2,4]triazo!-3-ylsulfanylmethyl]-benzoic
Figure imgf000066_0002
acid methyl ester
l-5-
Figure imgf000066_0003
3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5-
(4-methoxy-phenyl)-4H-[1 ,2,4]triazole
Figure imgf000066_0004
4-Ethyl-3-(4-methoxy-phenyl)-5-(3-
A-124 409.43 ttrriifflluuoorroommeetthhoo)xy- 'benzy 'lsu "lfanyl)-4 "H-
[1 ,2,4]triazole
Figure imgf000066_0005
N-{4-[4-Ethyl-5-(4-methoxy-phenyl)-4H-
A-125 382.49 ri ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- acetamide
Figure imgf000067_0001
4-Ethyl-3-(4-methoxy-benzyIsulfanyl)-5-(4- methoxy-phenyl)-4H-[1 ,2,4]triazole
4-Ethyl-3-(4-methoxy-phenyl)-5-(2-nitro- benzylsulfanyl)-4H-[1 ,2,4]triazole
4-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol- 3-ylsulfanylmethyl)-benzonitrile
4-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H- [1 ,2,4]triazol-3-yl]-pyridine
4-[5-(3,5-Dimethoxy-benzylsulfanyl)-4- ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine
4-[4-Ethyl-5-(4-methanesulfonyl- benzylsulfanyl)-4H-[1 ,2,4]triazo!-3-yl]- pyridine
Figure imgf000067_0002
4-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-
A-132 354.43 3-ylsulfanylmethyl)-benzoic acid methyl ester
Figure imgf000067_0003
4-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H- [1 ,2,4]triazol-3-yl]-pyridine
Figure imgf000067_0004
4-[4-Ethyl-5-(3-trifluoromethoxy- A-134 380.39 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]- F pyridine
Figure imgf000068_0001
4-[5-(2,4-Dichloro-benzylsuIfanyl)-4-ethyl- 4I~H1.2,4]triazol-3-yl]-pyridine
3-[5-(2-Chloro-benzylsulfanyl)-4-ethyl-4H- [1 ,2,4]triazol-3-yl]-pyridine
4-(4-Ethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol- 3-ylsulfanylmethyl)-benzonitri!e
Figure imgf000068_0002
3-[5-(6-Chloro-benzo[1 ,3]dioxol-5-
A-138 374-85 ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-
3-yl]-pyridine
Figure imgf000068_0003
3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyI- 4H-[1 ,2,4]triazol-3-yl]-pyridine
3-[5-(4-Bromo-benzylsu!fanyl)-4-ethyl-4H- [1 ,2,4]triazol-3-yl]-pyridine
Figure imgf000068_0004
3-[4-Ethyl-5-(4-[1,2,3]thiadiazol-4-yl-
A-141 380-50 benzylsulfanyl)-4H-[1,2,4]triazol-3-ylj- pyridine
3-[4-Ethyl-5-(4-trifluoromethoxy-
A-142 sso-39 benzylsu!fanyl)-4H-[1 ,2,4]triazol-3-yl]- pyridine
Figure imgf000068_0005
3-[5-(3,5-Dimethoxy-benzylsulfanyl)-4- ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine
Figure imgf000069_0001
3-[4-Ethyl-5-(4-trifluoromethyl-
A-144 364.40 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]- pyridine
Figure imgf000069_0002
3-(5-Benzylsulfanyl-4-ethyl-4H-
[1 ,2,4]triazol-3-yl)-pyridine
Figure imgf000069_0003
3-[4-Ethyl-5-(4-methanesulfonyl- A-146 374.49 benzy!sulfanyl)-4H-[1 ,2,4]triazol-3-yl]- pyridine
Figure imgf000069_0004
3-[4-Ethyl-5-(3-nitro-benzylsuIfanyl)-4H- [1 ,2,4]triazol-3-yl]-pyridine
Figure imgf000069_0005
4-(4-Ethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-
A-148 S5 .43 3-ylsulfanylmethyl)-benzoic acid methyl ester
Figure imgf000069_0006
3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl- 4H-[1 ,2,4]triazol-3-yl]-pyridine
3-[5-(4-Benzyloxy-benzylsulfanyI)-4-ethyl-
4H-[1 ,2,4]triazol-3-yl]-pyridine
3-[4-Ethyl-5-(4-methyl-benzyIsulfanyl)-4H- [1 ,2,4]triazol-3-yl]-pyridine
Figure imgf000069_0007
3-[4-Ethyl-5-(3-trifluoromethoxy- 380.39 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]- pyridine
N-[4-(4-Ethyl-5-pyridin-3-yl-4H- 353-45 [1 ,2,4]triazol-3-ylsulfanylmethyl)-phenyl]- acetamide
Figure imgf000070_0001
3-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)- 4H-[1 ,2,4]triazol-3-yl]-pyridine
Figure imgf000070_0002
3-[4-Ethyl-5-(5-methyl-2-nitro-
A-155 355.42 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yI]- pyridine
Figure imgf000070_0003
3-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-
[1 ,2,4]triazol-3-yl]-pyridine
3-[5-(2,4-Dichioro-benzylsulfanyl)-4-ethyl- 4H-[1 ,2,4]triazol-3-yl]-pyridine
3-(2-Chloro-benzyIsulfanyI)-5-(4-chloro- phenyl)-4-ethyl-4H-[1 ,2,4]triazole 4-[5-(4-Chloro-phenyl)-4-ethyl-4H-
A-159 354-86 [1 ,2,4]triazol-3-ylsulfanylmethylj-
Figure imgf000070_0005
benzonitrile
3-(4-Chloro-phenyl)-5-(3,4-dichloro- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000070_0006
4-{4-[5-(4-Chloro-phenyl)-4-ethyl-4H- A-161 413,95 [1.2,4]triazoI-3-ylsulfanylmethyl]-phenyl}- [1 ,2,3]thiadiazole
Figure imgf000070_0007
3-(4-Chloro-phenyl)-4-ethyl-5-(4-
A-162 407.94 methanesulfonyl-benzyIsuIfanyl)-4H- [1 ,2,4]triazole
Figure imgf000071_0001
3- 4-Chloro-phenyl)-4-ethyl-5- 3-nitro- benzylsulfanyl)-4H-[1 ,2,4]triazole
Figure imgf000071_0002
4-[5-(4-Chloro-phenyl)-4-ethyl-4H- 38 .89 [1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl ester
398 74 3-(4-Chloro-phenyl)-5-(2,6-dichloro- benzy!sulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000071_0003
3-(4-Benzyloxy-benzylsulfanyl)-5-(4- chIoro-phenyl)-4-ethyl-4H-[1 ,2,4]triazole
3-(4-Chloro-phenyl)-4-ethyl-5-(4-methyl- benzylsulfanyl)-4H-[1 ,2,4]triazole
Figure imgf000071_0004
3-(4-Chloro-phenyl)-4-ethyl-5-(3- A-168 413.85 trifluoromethoxy-benzylsulfanyl)-4H-
[1 ,2,4]triazole
N-{4-[5-(4-Chloro-phenyl)-4-ethyl-4H-
A-169 386.91 [1 ,2,4]triazoI-3-ylsulfanylmethyl]-phenyl}- acetamide
Figure imgf000071_0005
3-(4-Chloro-phenyl)-4-ethyl-5-(5-methyl-2- nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole
Figure imgf000071_0006
3-(4-Chloro-phenyl)-5-(2,4-dichloro- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000072_0001
A-172
A-173
A-174
A-175
A-176
5-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-
A-177 439.56 ethyl-4H-[1 ,2,4]triazol-3-yl]-4-phenyl- [1 ,2,3]thiadiazole
Figure imgf000072_0003
5-[4-EthyI-5-(4-trifluoromethyl-
A-178 447.51 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4- phenyl-[1 ,2,3]thiadiazole
5-(5-Benzylsulfanyl-4-ethyl-4H-
A-179 379.51 [1 ,2,4]triazol-3-yl)-4-phenyI- [1 ,2,3]thiadiazole
5-[4-Ethyl-5-(4-methanesulfonyl-
A-180 457.60 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4- phenyl-[1 ,2,3]thiadiazole
5-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-
A-181 424.51 [1 ,2,4]triazol-3-yl]-4-phenyl- [1 ,2,3]thiadiazole
5-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-
A-182 448.40 4H-[1 ,2,4]triazol-3-yl]-4-phenyl- [1 ,2,3]thiadiazole
Figure imgf000073_0001
A-183
Figure imgf000073_0002
5-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-
A-184 409.54 4H-[1 ,2,4]triazol-3-yl]-4-phenyl- [1 ,2,3]thiadiazole
Figure imgf000073_0003
5-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-
A-185 424.51 [1 ,2,4]triazol-3-yI]-4-phenyl- [1 ,2,3]thiadiazole
4-{5-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-
A- 186 413.55 4-ethyl-4H-[1 ,2,4]triazol-3- ylsulfanylmethyl}-benzonitrile
3-(6-Chloro-benzo[1 ,3]dioxo!-5-
A-187 466.99 ylmethylsuIfanyl)-5-[4-(2,5-dimethyl-pyrrol- 1 -yl)-phenyl]-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000074_0001
3-(3,4-Dichioro-benzylsulfanyl)-5-[4-(2,5-
A-188 457.43 dimethyl-pyrroI-1 -yI)-phenyl]-4-ethyI-4H-
CH3 A CI [1 ,2,4]triazole
CI
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4- 472.54 ethyI-5-(4-trifluoromethoxy-benzylsulfanyl)- 4H-[1 ,2,4]triazole
3-(3,5-Dimethoxy-benzylsulfanyl)-5-[4- 448.59 (2,5-dimethyl-pyrrol-1 -yl)-phenyl]-4-ethyl- 4H-[1 ,2,4]triazole
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4- 456.54 ethyl-5-(4-trifluoromethyl-benzylsulfanyl)- 4H-[1 ,2,4]triazole
Figure imgf000074_0002
3-Benzylsulfanyl-5-[4-(2,5-dimethyI-pyrrol- 1 -yl)-phenyl]-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000074_0003
3-[4-(2,5-Dimethyl-pyrrol-1-yI)-phenyl]-4-
A-193 466.63 ethyl-5-(4-methanesulfonyl- benzylsulfanyl)-4H-[1 ,2,4]triazole
Figure imgf000074_0004
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-
A-194 433.54 ethyl-5-(3-nitro-benzylsulfanyl)-4H- [1 ,2,4]triazole
4-{5-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenylj-
A-195 446.58 4-ethyI-4H-[1 ,2,4]triazol-3 ylsulfanylmethyl}-benzoic acid methyl ester
Figure imgf000075_0001
3-[4-(2,5-Dimethyl-pyrrol-1 -yl)-phenyl]-4-
433.54 ethyl-5-(4-nitro-benzylsulfanyl)-4H-
[1 ,2,4]triazole
3-(4-BenzyIoxy-benzylsulfanyl)-5-[4-(2,5- 494.66 dimethyl-pyrrol-1 -yl)-phenyl]-4-ethyl-4H-
[1 ,2,4]triazole
N-(4-{5-[4-(2,5-Dimethyl-pyrrol-1-yl)- 445.59 phenyl]-4-ethyl-4H-[1 ,2,4]triazol-3- ylsulfanylmethyl}-phenyl)-acetamide 3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4- 418.57 ethyl-5-(4-methoxy-benzylsulfanyl)-4H- [1 ,2,4]triazole 3-[4-(2,5-Dimethyl-pyrro!-1-yl)-phenyl]-4- 447-56 ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)- 4H-[1 ,2,4]triazole
3-[4-(2,5-Dimethy!-pyrrol-1-yl)-phenyl]-4- 433 54 ethyl-5-(2-nitro-benzylsuIfanyl)-4H- [1 ,2,4]triazole
3-(2,4-Dich)oro-benzyIsulfanyl)-5-[4-(2,5- 457.43 dimethyl-pyrrol-1 -yl)-phenyl]-4-ethyl-4H-
Figure imgf000075_0002
[1 ,2,4]trlazole
3-Benzo[b]thiophen-2-yl-5-(2-chloro- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000075_0003
4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4H-
[1 ,2,4]triazol-3-ylsulfanylmethyl)- benzonitrile
3-Benzo[b]thiophen-2-yl-5-(6-chloro- benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4- ethyl-4H-[1 ,2,4]triazole
3-Benzo[b]thiophen-2-yl-5-(4-bromo- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
4-[4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4H-
[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenylj-
[1 ,2,3]thiadiazole
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(3-nitro- benzylsulfanyl)-4H-[1 ,2,4]triazole
Figure imgf000076_0001
4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4H-
A-209 409.53 [1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl ester
Figure imgf000076_0002
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(4-nitro- benzylsulfanyl)-4H-[1 ,2,4]triazole
3-Benzo[b]thiophen-2-yl-5-(4-benzyloxy- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(3- trifluoromethoxy-benzylsulfanyl)-4H- [1 ,2,4]triazole
Figure imgf000076_0003
N-[4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4H-
A-213 408.55 [1 ,2,4]triazol-3-ylsulfanylmethyl)-phenylj- acetamide
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(4-
A-214 338811..5522 methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole
Figure imgf000077_0001
3-Benzo[b]thiophen-2-yl-4-ethyI-5-(2-nitro- benzylsulfanyl)-4H-[1 ,2,4]triazole
Figure imgf000077_0002
3-(2-Chloro-benzylsulfanyl)-4-ethyl-5-(1-
A-216 463.92 phenyl-5-trifluoromethyl-1 H-pyrazol-4-yl)- 4H-[1 ,2,4]triazole
Figure imgf000077_0003
ro-benzo[1 ,3]dioxol-5- uIfanyl)-4-ethyl-5-(1-phenyl-5-
A-217 ethyl-1 H-pyrazol-4-yl)-4H- zole
Figure imgf000077_0004
4-{4-[4-Ethyl-5-(1-phenyl-5-trifluoromethyl-
A-218 513-57 1 H-pyrazol-4-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethyl]-phenyl}-[1 ,2,3]thiadiazole
4-Ethyl-3-(1-phenyl-5-trifluoromethyl-1 H-
A-219 513.47 pyrazol-4-yl)-5-(4-trifluoromethoxy- benzylsulfanyl)-4H-[1 ,2,4]triazoIe
3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-
A-220 489.52 5-(1-phenyl-5-trifluoromethyl-1 H-pyrazol-4- yl)-4H-[1 ,2,4]triazole
Figure imgf000077_0005
3-Benzylsulfanyl-4-ethyl-5-(1-phenyl-5- A-221 429.47 trifluoromethyl-1 H-pyrazol-4-yI)-4H- [1 ,2,4]triazole
Figure imgf000078_0001
4-Ethyl-3-(4-methanesulfonyl- benzylsulfanyl)-5-(1 -phenyl-5- trifluoromethyl-1 H-pyrazol-4-yl)-4H- [1 ,2,4]triazole
Figure imgf000078_0002
4-Ethyl-3-(3-nitro-benzylsulfanyl)-5-(1-
A-223 474.47 phenyl-5-trifluoromethyl-1 H-pyrazol-4-yl)- 4H-[1 ,2,4]triazole
4-[4-Ethyl-5-(1-phenyl-5-.rifluoromethyl- A-224 487.51 1 H-pyrazol-4-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-benzoic acid methyl ester
Figure imgf000078_0003
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5- 498.36 (1-phenyl-5-trifluoromethyl-1 H-pyrazol-4- yl)-4H-[1 ,2,4]triazole
3-(4-Benzyloxy-benzyIsulfanyl)-4-ethyl-5- 535.60 (1-phenyl-5-trifluoromethyl-1 H-pyrazol-4- yl)-4H-[1 ,2,4]triazole
4-Ethyl-3-(4-methyI-benzyIsulfanyl)-5-(1- 443.50 phenyl-5-trifluoromethyl-1 H-pyrazol-4-yl)- 4H-[1 ,2,4]triazole
N-{4-[4-Ethyl-5-(1-phenyl-5-trifluoromethyl- 486.52 1 H-pyrazol-4-yl)-4H-[1 ,2,4]triazoI-3- ylsulfanylmethyl]-phenyl}-acetamide
Figure imgf000078_0004
4-Ethyl-3-(5-methyl-2-nitro-benzylsulfanyl)-
A-229 488.49 5-(1 -phenyl-5-trifluoromethyl-1 H-pyrazol-4- yl)-4H-[1 ,2,4]triazole
4-Ethyl-3-(2-nitro-benzyIsulfanyl)-5-(1-
A-230 474.47 phenyl-5-trifluoromethyl-1 H-pyrazol-4-yl)- 4H-[1 ,2,4]triazole
Figure imgf000079_0001
3-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-5-
A-231 498.36 (1-phenyl-5-trifluoromethyl-1 H-pyrazol-4-
A yl)-4H-[1 ,2,4]triazole
CH3 r cirΛΛ, CI
3-(2-Chloro-benzylsulfanyl)-5-(3-chloro-4-
A-232 384.35 methyl-thiophen-2-yl)-4-ethyI-4H- [1 ,2,4]triazole
4-[5-(3-Chloro-4-methyl-thiophen-2-yl)-4-
A-233 374.92 ethyl-4H-[1 ,2,4]triazol-3-yIsulfanylmethyl]- benzonitrile
Figure imgf000079_0002
3-(3-Chloro-4-methyl-thiophen-2-yl)-5-(3,4- 418.80 dichloro-benzylsulfanyl)-4-ethyl-4H- [1 ,2,4]triazole
4-{4-[5-(3-Chloro-4-methy!-thiophen-2-yl)- 434.01 4-ethyl-4H-[1 ,2,4]triazol-3- yIsulfanylmethyl]-phenyl}-[1 ,2,3]thiadiazole
3-(3-Chloro-4-methyl-thiophen-2-yl)-5- 355.95 cyclohexylmethylsulfanyl-4-ethyl-4H- [1 ,2,4]triazole
3-(3-Chloro-4-methyI-thiophen-2-yl)-4- 433.90 ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)- 4H-[1 ,2,4]triazole
Figure imgf000079_0003
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-
A-238 417.91 ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-
4H-[1 ,2,4]triazole
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-
A-239 394.90 ethy]-5-(3-nitro-benzylsulfanyl)-4H- [1 ,2,4]triazoIe
4-[5-(3-Chloro-4-methyl-thiophen-2-yI)-4- A-240 407.94 ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- benzoic acid methyl ester
3-(3-Chloro-4-methyl-thiophen-2-yl)-5-(2,6- A-241 418.80 dichloro-benzylsulfanyl)-4-ethyl-4H-
[1 ,2,4]triazole
3-(3-Chloro-4-methyl-thiophen-2-yl)-4- A-242 363.93 ethyl-5-(4-methyl-benzylsulfanyI)-4H-
[1 ,2,4]triazole
3-(3-Chloro-4-methyl-thiophen-2-yl)-4- A-243 433.90 ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-
4H-[1 ,2,4]triazole
3-(3-Chloro-4-methyl-thiophen-2-yl)-4- A-244 408.93 ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-
4H-[1 ,2,4]triazole
Figure imgf000080_0001
yl-thiophen-2-yl)-4-
A-245 zylsulfanyl)-4H
Figure imgf000080_0002
4-(4-Ethyl-5-pyridin-2-yl-4H-[1 ,2,4]triazol- 3-ylsulfanylmethyl)-benzonitrile
Figure imgf000080_0003
2-[5-(6-Chloro-benzo[1 ,3]dioxol-5-
A-247 374.85 ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol- 3-yl]-pyridine
Figure imgf000081_0001
2-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl- 4H-[1 ,2,4]triazol-3-yl]-pyridine
2-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H- [1 ,2,4]triazol-3-yl]-pyridine
Figure imgf000081_0002
2-[4-Ethyl-5-(4-[1 ,2,3]thiadiazol-4-yI-
A-250 380.50 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj-
Figure imgf000081_0003
pyridine
2-[5-(3,5-Dimethoxy-benzylsulfanyl)-4- ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine
Figure imgf000081_0004
2-[4-Ethyl-5-(4-trifluoromethyl-
A-252 364.40 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj- pyridine
2-[4-Ethyl-5-(4-methanesulfonyl-
A-253 374.49 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj- pyridine
Figure imgf000081_0005
2-[4-Ethyl-5-(3-nitro-benzylsuIfanyl)-4H- [1 ,2,4]triazol-3-yl]-pyridine
Figure imgf000081_0006
4-(4-Ethyl-5-pyridin-2-yl-4H-[1 ,2,4]triazol- 354.43 3-ylsulfanylmethyl)-benzoic acid methyl
Figure imgf000081_0007
, ester
2-[4-EthyI-5-(4-nitro-benzylsuIfanyl)-4H- [1 ,2,4]triazol-3-yl]-pyridine
Figure imgf000081_0008
2-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl- 4H-[1 ,2,4]triazol-3-yl]-pyridine
2-[4-Ethyl-5-(4-methyI-benzylsulfanyl)-4H- [1 ,2,4]triazol-3-yl]-pyridine
Figure imgf000082_0001
2-[4-EthyI-5-(3-trifluoromethoxy- 380.39 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj- pyridine
2-[4-Ethyl-5-(5-methyl-2-nitro- 355.42 benzylsulfanyl)-4H-[1 ,2,4]triazoI-3-ylj- pyridine
Figure imgf000082_0002
2-[4-Ethyl-5-(2-nitro-benzylsulfany!)-4H- [1 ,2,4]triazol-3-yl]-pyridine
Figure imgf000082_0003
3-[5-(3,4-Dichloro-benzyIsulfanyl)-4-ethyl-
A-262 411.38 4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine
3-[4-Ethyl-5-(4-[1 ,2,3]thiadiazol-4-yl-
A-263 426.59 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2- methylsulfanyl-pyridine
Figure imgf000082_0004
fanyI-4-ethyl-4H-
A-264 ylsulfanyl-
Figure imgf000082_0005
3-[4-Ethyl-5-(4-trifluoromethoxy-
A-265 426.49 benzylsulfanyl)-4H-[1 ,2,4]triazoI-3-yl]-2- methylsulfanyl-pyridine
Figure imgf000082_0006
sulfanyl)-4- 2-
Figure imgf000083_0001
3-[4-Ethyi-5-(4-trifluoromethyl- 410.49 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2- methylsulfanyl-pyridine
3-(5-Benzylsulfanyl-4-ethyl-4H- 342.49 [1 ,2,4]triazol-3-yl)-2-methylsulfanyl- pyridine
3-[4-Ethyl-5-(4-methanesulfonyl- 420.58 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2- methylsulfanyl-pyridine
4-[4-Ethyl-5-(2-methylsulfanyl-pyridin-3-yl)- 400.52 4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzoic acid methyl ester
3-[5-(2,6-Dichloro-benzylsuIfanyl)-4-ethyl- 411.38 4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine
3-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl- 448.61 4H-[1 ,2,4]triazol-3-yl]-2-methylsuIfanyl- pyridine
3-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H- 356.51 [1 ,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine
Figure imgf000083_0002
3-[4-Ethyl-5-(3-trifluoromethoxy- 426.49 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2- methylsulfanyl-pyridine
N-{4-[4-Ethyl-5-(2-methylsulfanyl-pyridin-3- 399.54 yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- phenyl}-acetamide
3-[4-Ethyl-5-(5-methyl-2-nitro- 401.51 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2- methylsulfanyl-pyridine
3-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H- 387.49 [1 ,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine
Figure imgf000084_0001
3-(2-Chloro-benzylsulfanyl)-4-ethyl-5-(5- methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole
4-[4-Ethyl-5-(5-methyl-thiophen-2-yl)-4H- [1 ,2,4]triazol-3-ylsulfanylmethylj- benzonitrile
Figure imgf000084_0002
3-(6-Chloro-benzo[1 ,3]dioxol-5- 393.92 yImethylsulfanyl)-4-ethyl-5-(5-methyl- thiophen-2-yl)-4H-[1 ,2,4]triazole
Figure imgf000084_0003
3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5- (5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole
Figure imgf000084_0004
4-{4-[4- ethyl-5-(5-methyl-thiophen-2-yl)-
A-282 385.53 4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- phenyl}-[1 ,2,3]thiadiazole
Figure imgf000084_0005
N-N
'; /N 3-CyclohexylmethylsulfanyI-4-ethyl-5-(5-
A-283 ι ~ N & 1 ] 321.51
H H3cCA \/ I s..^ A methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(4- A-284 399.46 trifluoromethoxy-benzylsulfanyl)-4H-
[1 ,2,4]triazole
Figure imgf000085_0001
3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyI- 5-(5-methyl-thiophen-2-yl)-4H-
[1 ,2,4]triazole
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(4- trifluoromethyl-benzylsulfanyl)-4H-
[1 ,2,4]triazole
3-BenzyIsulfanyl-4-ethyl-5-(5-methyl- thiophen-2-y!)-4H-[1 ,2,4]triazole
Figure imgf000085_0002
4-Ethyl-3-(4-methanesuIfonyI- 393-55 benzy!sulfanyl)-5-(5-methyl-thiophen-2-yl)- 4H-[1 ,2,4]triazole
4-EthyI-3-(5-methyl-thiophen-2-yl)-5-(3- 360. 6 y H nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole
4-[4-Ethyl-5-(5-methyl-thiophen-2-yl)-4H- 373 50 [1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl ester
Figure imgf000085_0003
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(4- nitro-benzyIsulfanyl)-4H-[1 ,2,4]triazole
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5- (5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole
Figure imgf000085_0004
4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-(5- methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole
Figure imgf000086_0001
N-{4-[4-Ethyl-5-(5-methyl-thiophen-2-yl)-
A-294 372.51 4H-[1 ,2,4]triazol-3-ylsulfanylmethyl] phenyl}-acetamide
Figure imgf000086_0002
4-Ethyl-3-(4-methoxy-benzyIsulfanyI)-5-(5- methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole
4-Ethyl-3-(5-methy!-thiophen-2-yl)-5-(2- nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole
3-(2,4-Dichloro-benzylsuIfanyl)-4-ethyl-5- (5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole
Figure imgf000086_0003
4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4H-
A-298 360-89 [ [11 ,,22,,44]]ttrriiaazzooll-3-ylsulfanylmethyl]
Figure imgf000086_0004
benzonitrile
3-(5-ChIoro-thiophen-2-yl)-5-(3,4-dichloro- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
3-(4-Bromo-benzylsulfanyl)-5-(5-chIoro- thiophen-2-yl)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000086_0005
4-{4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-
A-301 419.98 4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- phenyl}-[1 ,2,3]thiadiazole
Figure imgf000086_0006
N-N 3-(5-Chloro-thiophen-2-yl)-5-
A-302 As ϊ SAT 34 93 cyclohexylmethylsulfanyl-4-ethyl-4H- cι CH3 [1 ,2,4]triazole 3-(5-ChIoro-thiophen-2-yl)-4-ethyI-5-(4-
A-303 419,88 trifluoromethoxy-benzylsulfanyl)-4H
Figure imgf000086_0007
[1 ,2,4]triazole 3-(5-Chloro-thiophen-2-yl)-5-(3,5-
A-304 395.93 dimethoxy-benzylsulfanyl)-4-ethyl-4H- [1 ,2,4]triazole
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(4-
A-305 403.88 trifluoromethyl-benzylsulfanyl)-4H-
Figure imgf000087_0001
[1 ,2,4]triazole
3-(5-Chloro-thiophen-2-yl)-4-ethyI-5-(3- nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole
Figure imgf000087_0002
4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4H-
A-307 393.92 [1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic
Figure imgf000087_0003
H, acid methyl ester
3-(5-Chloro-thiophen-2-yl)-5-(2,6-dichloro- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(4- methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole
Figure imgf000087_0004
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(3-
A-310 419.88 trifluoromethoxy-benzylsulfanyl)-4H- [1 ,2,4]triazole
N-{4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-
A-311 392.93 4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- phenyl}-acetamide
Figure imgf000087_0005
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(4- methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole
Figure imgf000087_0006
N-N s 3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(5-
CH,
A-313 cι A»L A 394.90 methyl-2-nitro-benzylsuIfanyI)-4H- A- A^ [1 ,2,4]triazole o 3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(2- nitro-benzylsulfanyl)-4H-t1 ,2,4]triazole
3-(5-Chloro-thiophen-2-yl)-5-(2,4-dichloro- benzyIsulfanyI)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000088_0001
4-[4-Ethyl-5-(1 H-indol-3-ylmethyl)-4H-
A-316 373.48 [1 ,2,4]triazoI-3-ylsulfanylmethyl]- benzonitrile
Figure imgf000088_0002
3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-
4H-[1 ,2,4]triazol-3-ylmethyl]-1 H-indole
Figure imgf000088_0003
3-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-
A-318 408.53 ethyl-4H-[1 ,2,4]triazol-3-ylmethyl]-1 H- indole
3-[4-Ethyl-5-(4-methanesulfonyl-
A-319 426.56 benzylsulfanyl)-4H-[1 ,2,4]triazol-3- ylmethyl]-1 H-indole
Figure imgf000088_0004
3-[4-Ethyl-5-(3-nitro-benzylsulfanyI)-4H- [1 ,2,4]triazol-3-ylmethyl]-1 H-indole
3-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H- [1 ,2,4]triazol-3-ylmethyl]-1 H-indole
3-[5-(2,6-Dichloro-benzy!sulfanyl)-4-ethyl- 4H-[1 ,2,4]triazol-3-yImethyl]-1 H-indole
Figure imgf000088_0005
3-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl- 4H-[1 ,2,4]triazol-3-ylmethyl]-1 H-indole
Figure imgf000089_0001
3-[4-Ethyl-5-(3-trifluoromethoxy-
A-324 432.47 benzylsulfanyl)-4H-[1 ,2,4]triazol-3- ylmethyO-1 H-indole
N-{4-[4-Ethyl-5-(1 H-indol-3-yImethyl)-4H- A-325 405.53 [1 ,2,4]triazol-3-ylsulfanylmethyI]-phenyI}- acetamide
Figure imgf000089_0002
3-[4-Ethyl-5-(4-methoxy-benzylsulfanyI)-
4H-[1 ,2,4]triazol-3-ylmethyl]-1 H-indole
Figure imgf000089_0003
(5-methyl-2-nitro-
A-327 yl)-4H-[1 ,2,4]triazol-3- -indole
Figure imgf000089_0004
3-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-
[1 ,2,4]triazol-3-ylmethyl]-1 H-indole
Figure imgf000089_0005
yl-
Figure imgf000089_0006
2-[5-(6-Chloro-benzo[1 ,3]dioxol-5-
A-330 389.86 ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol- 3-yl]-phenol
Figure imgf000089_0007
2-[4-Ethyl-5-(4-[1 ,2,3]thiadiazol-4-yl-
A-331 395.5i benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj- phenol
Figure imgf000090_0001
2-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H- [1 ,2,4]triazol-3-yl)-phenol
2-[5-(3,5-Dimethoxy-benzylsulfanyI)-4- ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol
Figure imgf000090_0002
2-[4-Ethyl-5-(4-trifluoromethyl-
A-334 379.41 benzyIsuIfanyl)-4H-[1 ,2,4]triazol-3-yl]- phenol
Figure imgf000090_0003
2-(5-Benzy!sulfanyl-4-ethyl-4H- [1 ,2,4]triazol-3-yl)-phenol
Figure imgf000090_0004
2-[4-Ethyl-5-(4-methanesulfonyl-
A-336 389.50 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]- phenol
Figure imgf000090_0005
OH fXx u % 2-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-
A-337 A ^YV^ 356.41 LJ [1 ,2,4]triazol-3-yl]-phenol
CH,
4-[4-Ethyl-5-(2-hydroxy-phenyl)-4H- A-338 369.45 [1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl ester
Figure imgf000090_0006
OH
A A-T A ^ /^ 2-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-
A-339 W AS^YA 356.41
L LAN÷°" [1 ,2,4]triazol-3-yl]-phenol
II o 2-[5-(2,6-Dichloro-benzylsulfanyI)-4-ethyl- 4H-[1 ,2,4]triazol-3-yl]-phenol
2-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H- [1 ,2,4]triazol-3-yl]-phenol
Figure imgf000091_0001
2-[4-Ethyl-5-(3-trifluoromethoxy-
A-342 395-41 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj- Pneno1
N-{4-[4-Ethyl-5-(2-hydroxy-phenyI)-4H-
A-343 368.46 [1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- acetamide
2-[4-Ethyl-5-(5-methyl-2-nitro-
A-344 370.43 benzylsuIfanyl)-4H-[1 ,2,4]triazol-3-yl]- phenol
Figure imgf000091_0002
OH X A /\ ^\ 2-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-
A-345 XX AS^ A 356.41 y '
7 ol X [1 ,2,4]triazol-3-yl]-phenol
CH3 N ^^ o
2-[5-(2,4-Dichloro-benzyIsulfanyl)-4-ethyl- 4H-[1 ,2,4]triazol-3-yl]-phenol
Figure imgf000091_0003
5-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-
A-347 386.33 4H-[1 ,2,4]triazol-3-yl]-4-methyl [1 ,2,3]thiadiazole
5-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H-
A-348 396.34 [[11 ,,22,,44]]ttrriiaazzooII--33--yylIj]--4-methyI
Figure imgf000091_0004
[1 ,2,3]thiadiazole 5-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H-
A-349 323.48 [1 ,2,4]triazol-3-yl)-4-methyl-
[1 ,2,3]thiadiazole
5-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-
A-350 377,49 ethy|-4H-[1.2.4]triazo|-3-y|]- -metny|- [1 ,2,3]thiadiazole
Figure imgf000092_0001
5-(5-Benzylsulfanyl-4-ethyl-4H-
317.44 [1 ,2,4]triazol-3-yl)-4-methyl- [1,2,3]thiadiazole 5-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-
362.43 [1 ,2,4]triazol-3-yl]-4-methyl- [1 ,2,3]thiadiazole
4-[4-Ethyl-5-(4-methyl-[1 ,2,3]thiadiazol-5- 375.47 yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- benzoic acid methyl ester
5-[4-Ethyl-5-(4-nitro-benzylsuIfanyl)-4H- 362.43 [1 ,2,4]triazol-3-yl]-4-methyl [1 ,2,3]thiadiazole
5-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl- 423.56 4H-[1 ,2,4]triazol-3-yl]-4-methyI-
[1 ,2,3]thiadiazole
5-[4-Ethyl-5-(4-methyI-benzylsulfanyl)-4H- 331.46 [1 ,2,4]triazol-3-yl]-4-methyI [1 ,2,3]thiadiazole
5-[4-Ethyl-5-(3-trifluoromethoxy- 401.43 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4- methyl-[1 ,2,3]thiadiazole
Figure imgf000092_0002
5-[4-Ethyl-5-(5-methyl-2-nitro- 376.46 benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4- methyl-[1 ,2,3]thiadiazole
5-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl- 386.33 4H-[1 ,2,4]triazol-3-yl]-4-methyl- [1 ,2,3]thiadiazole
Figure imgf000093_0001
4-(5-BenzyI-4-ethy)-4H-[1 ,2,4]triazol-3- ylsulfanylmethyl)-benzonitrile
3-Benzyl-5-(3,4-dichloro-benzylsuIfanyl)-4- ethyl-4H-[1 ,2,4]triazole
4-[4-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3- ylsulfanylmethyl)-phenyl]-[1 ,2,3]thiadiazole
3-Benzyl-5-(3,5-dimethoxy-benzylsulfanyl)- 4-ethyl-4H-[1 ,2,4]triazole
3-Benzyl-4-ethyl-5-(4-trifluoromethyl- benzylsulfanyl)-4H-[1 ,2,4]triazole
3-Benzyl-5-benzy!sulfanyl-4-ethyl-4H- [1 ,2,4]triazole
3-Benzyl-5-(2,6-dichloro-benzylsulfanyl)-4- ethyl-4H-[1 ,2,4]triazole
Figure imgf000093_0002
3-Benzyl-4-ethyl-5-(4-methyl- benzylsulfanyl)-4H-[1 ,2,4]triazoIe
3-Benzyl-4-ethyl-5-(4-methoxy- benzylsulfanyl)-4H-[1 ,2,4]triazole
3-Benzyl-4-ethyl-5-(5-methyl-2-nitro- benzylsulfanyl)-4H-[1 ,2,4]triazole
3-Benzyl-4-ethyl-5-(2-nitro-benzylsulfanyI)- 4H-[1 ,2,4]triazole
3-Benzyl-5-(2,4-dichloro-benzylsulfanyl)-4- ethyl-4H-[1 ,2,4]triazole
3-(2-Bromo-phenyl)-5-(2-chloro- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000094_0001
4-[5-(2-Bromo-phenyl)-4-ethyl-4H-
A-373 399.32 [1 ,2,4]triazol-3-ylsulfanylmethylj- benzonitrile
3-(2-Bromo-phenyl)-5-(6-chloro-
A-374 45277 benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4- ethyl-4H-[1 ,2,4]triazole
Figure imgf000094_0002
3-(2-Bromo-phenyl)-5-(3,4-dichloro- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000094_0003
3-(2-Bromo-phenyl)-5-
A-376 380'36 cyclohexylmethylsulfanyl-4-ethyl-4H- [1,2,4]triazole
Figure imgf000094_0004
3-(2-Bromo-phenyl)-4-ethyl-5-(4-
A-377 458.31 trifluoromethoxy-benzylsulfanyl)-4H- [1 ,2,4]triazole
Figure imgf000095_0001
3-(2-Bromo-phenyl)-5-(3,5-dimethoxy- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazoIe
Figure imgf000095_0002
3-(2-Bromo-phenyl)-4-ethyl-5-(4-
A-379 442.31 trifluoromethyl-benzylsulfanyl)-4H- [1 ,2,4]triazole
Figure imgf000095_0003
3-(2-Bromo-phenyI)-4-ethyl-5-(3-nitro- benzylsulfanyl)-4H-[1 ,2,4]triazole
3-(4-Benzyloxy-benzylsuIfanyl)-5-(2- bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazole
3-(2-Bromo-phenyl)-4-ethyl-5-(4-methoxy- benzylsulfanyl)-4H-[1 ,2,4]triazole
3-(2-Bromo-phenyl)-4-ethyl-5-(5-methyl-2- nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole
3-(2-Bromo-phenyl)-5-(2,4-dichloro- benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole
Figure imgf000095_0004
2-[4-(3-Methoxy-propyl)-5-(1-methyl-
A-385 385.54 piperidin-2-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-benzonitrile
Figure imgf000095_0005
2-[4-(3-Methoxy-propyl)-5-(1-methyI- 361.51 piperidin-2-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-pyridine
2-[5-(2-Methoxy-ethylsulfanyl)-4-(3- 328.48 methoxy-propyl)-4H-[1 ,2,4]triazol-3-yl]-1 - methyl-piperidine
2-[4-(2-Methoxy-ethyl)-5-(1-methyl- 371.51 piperidin-2-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-benzonitrile
2-[4-(2-Methoxy-ethyl)-5-(1-methyl- 347.49 piperidin-2-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-pyridine
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy- 314.45 ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-1 - methyl-piperidine
2-[4-Cyclopropyl-5-(1-methyl-piperidin-2- 353.49 yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile
2-[4-Cyclopropyl-5-(1-methyl-piperidin-2- 329.47 yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- pyridine
2-[4-Cyclopropyl-5-(2-methoxy- 296.44 ethylsulfanyl)-4H-[1 ,2,4]triazoI-3-yl]-1-
Figure imgf000096_0001
methyl-piperidine 2-[5-(1-Methyl-piperidin-2-yl)-4-(2-
A-394 424.62 piperidin-1 -yl-ethyl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-benzonitrile
Figure imgf000097_0001
CH,
2-[5-(1-Methyl-piperidin-2-yl)-4-(2-
A-395 X 400.59 piperidin-1 -yl-ethyl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-pyridine
CH,
"CH, ERR-265 = Senior ring system cannot be
A-396 AA 367.56 selected (implemented only up to IUPAC C.14.11.h)
CH,
2-[4-CycIopropylmethyl-5-(1-methyl-
A-397 o 367.52 piperidin-2-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-benzonitrile
2-[4-Cyclopropylmethyl-5-(1-methyl-
A-398 343.50 piperidin-2-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-pyridine
2-[4-Cyclopropylmethyl-5-(2-methoxy-
A-399 310.46 ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-1- methyl-piperidine
2-[5-(2-Hydroxy-phenyl)-4-(3-methoxy-
A-400 380.47 propyl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-benzonitrile
Figure imgf000097_0002
2-[4-(3-Methoxy-propyl)-5-(pyridin-2-
A-401 356.45 ylmethylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj- phenol
2-[5-(2-Methoxy-ethylsulfanyl)-4-(3-
A-402 323.42 methoxy-propyl)-4H-[1 ,2,4]triazol-3-ylj- phenol
2-[5-(2-Hydroxy-phenyl)-4-(2-methoxy-
A-403 366.44 ethyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyI]- benzonitrile
2-[4-(2-Methoxy-ethyl)-5-(pyridin-2-
A-404 342.42 yImethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]- phenol
Figure imgf000098_0001
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy- ethylsuIfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol
Figure imgf000098_0002
2-[4-Cyclopropyl-5-(2-hydroxy-phenyl)-4H-
A-406 348.43 [1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile
2-[4-Cyclopropyl-5-(pyridin-2-
A-407 324.41 ylmethylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj-
Figure imgf000098_0003
phenol
2-[4-Cyclopropyl-5-(2-methoxy- ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol
Figure imgf000098_0004
2-[5-(2-Hydroxy-phenyl)-4-(2-piperidin-1-
A-409 419.55 yl-ethyl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-benzonitrile
2-[4-(2-Piperidin-1-yl-ethyl)-5-(pyridin-2-
A-410 395.53 ylmethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]- phenol
Figure imgf000099_0001
2-[5-(2-Methoxy-ethylsulfanyl)-4-(2- 362.50 piperidin-1 -yl-ethyl)-4H-[1 ,2,4]triazol-3-ylj- phenol
2-[4-Cyclopropylmethyl-5-(2-hydroxy- 362.46 phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-benzonitrile
2-[4-Cyclopropylmethyl-5-(pyridin-2- 338.43 ylmethylsulfanyI)-4H-[1 ,2,4]triazol-3-yl]- phenol
Figure imgf000099_0002
2-[4-Cyclopropylmethyl-5-(2-methoxy- ethyIsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol
Figure imgf000099_0003
2-[5-(2-Methoxy-phenyl)-4-(3-methoxy-
A-415 394.50 propyl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-benzonitrile
2-[5-(2-Methoxy-phenyl)-4-(3-methoxy-
A-416 370.48 propyl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-pyridine
Figure imgf000099_0004
3-(2-Methoxy-ethylsulfanyl)-5-(2-methoxy- 337.44 phenyl)-4-(3-methoxy-propyl)-4H- [1 ,2,4]triazole
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy- 380.47 phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-benzonitrile
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy- 356.45 phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-pyridine
Figure imgf000100_0001
H,C.
4-(2-Methoxy-ethyI)-3-(2-methoxy-
A-420 X CH, 323.42 ethylsulfanyl)-5-(2-methoxy-phenyl)-4H- [1 ,2,4]triazole
CH,
2-[4-Cyclopropyl-5-(2-methoxy-phenyl)-
A-421 362.46 4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile
Figure imgf000100_0002
yl)-
A-422
Figure imgf000100_0003
4-Cyclopropyl-3-(2-methoxy-ethylsulfanyl)- 5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazole
Figure imgf000100_0004
2-[5-(2- ethoxy-phenyI)-4-(2-piperidin-1-
A-424 433.58 yl-ethyl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-benzonitrile
Figure imgf000100_0005
2-piperidin-1-
Figure imgf000101_0001
1-{2-[3-(2-Methoxy-ethyIsulfanyl)-5-(2-
A-426 376.52 methoxy-phenyl)-[1 ,2,4]triazol-4-yl]-ethyl}- piperidine
2-[4-Cyclopropylmethyl-5-(2-methoxy-
A-427 376.48 phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-benzonitrile
2-[4-CycIopropylmethyl-5-(2-methoxy-
A-428 352.46 phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethylj-pyridine
Figure imgf000101_0002
4-Cyclopropylmethyl-3-(2-methoxy- 319.43 ethyIsulfanyl)-5-(2-methoxy-phenyl)-4H- [1 ,2,4]triazole
2-[4-(3-Methoxy-propyl)-5-thiophen-2-yl- 370.50 4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile
2-[4-(3-Methoxy-propyl)-5-thiophen-2-yl- 346.48 4H-[1 ,2,4]triazol-3-ylsuIfanylmethyl]- pyridine
Figure imgf000101_0003
3-(2-Methoxy-ethylsulfanyl)-4-(3-methoxy- propyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazole
Figure imgf000101_0004
2-[4-(2-Methoxy-ethyl)-5-thiophen-2-yl-4H-
A-433 356.47 [1 ,2,4]triazol-3-ylsuIfanylmethyl]- benzonitrile
Figure imgf000102_0001
2-[4-(2-Methoxy-ethyl)-5-thiophen-2-yl-4H- [1 ,2,4]triazol-3-ylsu!fanylmethyl]-pyridine
Figure imgf000102_0002
4-(2-Methoxy-ethyl)-3-(2-methoxy-
A-435 299.42 ethylsulfanyl)-5-thiophen-2-yl-4H- [1 ,2,4]triazole
2-(4-Cyclopropyl-5-thiophen-2-yl-4H-
A-436 338.46 [1 ,2,4]triazol-3-ylsuIfanylmethyl)- benzonitrile
Figure imgf000102_0003
2-(4-Cyclopropyl-5-thiophen-2-yl-4H- [1 ,2,4]triazol-3-ylsulfanylmethyl)-pyridine
4-Cyclopropyl-3-(2-methoxy-ethyIsulfanyl)- 5-thiophen-2-yl-4H-[1 ,2,4]triazole
Figure imgf000102_0004
2-[4-(2-Piperidin-1-yI-ethyl)-5-thiophen-2-
A-439 409.58 yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile
2-[4-(2-Piperidin-1-yl-ethyl)-5-thiophen-2-
A-440 385.56 yl-4H-[1 ,2,4]triazol-3-y!sulfanylmethyl]- pyridine
1-{2-[3-(2-Methoxy-ethylsulfanyl)-5-
A-441 352.52 thiophen-2-yl-[1 ,2,4]triazol-4-yl]-ethyl}- piperidine
Figure imgf000102_0005
2-(4-CyclopropylmethyI-5-thiophen-2-yl- 352.48 4H-[1 ,2,4]triazol-3-ylsulfanylmethyI)- benzonitrile
2-(4-Cyclopropylmethyl-5-thiophen-2-yI- 328.46 4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)- pyridine
4-CyclopropyImethyl-3-(2-methoxy- 295.43 ethylsulfanyl)-5-thiophen-2-yl-4H-
Figure imgf000103_0001
[1 ,2,4]triazole
The following compounds were synthesised in a similar way as described in example 1 (general method B) utilising solution phase parallel synthesis methods.
Comp.
Molecule MW IUPAC Name No
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-1 -phenyl-ethanone
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-1-pyridin-3-yl-ethanone
Figure imgf000103_0002
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3- 401.51 ylsulfanyl)-1 -(4-methanesulfonyl-phenyI)- ethanone
Figure imgf000103_0003
2-(4-Phenethyl-5-phenyl-4H-[1 ,2,4]triazoI- 3-ylsulfanyl)-1 -phenyl-ethanone
Figure imgf000104_0001
1-(4-Methoxy-phenyl)-2-(4-phenethyl-5-
B-6 429.54 phenyI-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone
Figure imgf000104_0002
2-(4-Phenethyl-5-phenyl-4H-[1 ,2,4]triazol- 3-ylsulfanyl)-1-pyridin-3-yl-ethanone
Figure imgf000104_0003
1-(4-Methanesulfonyl-phenyl)-2-(4-
B-8 477.61 phenethyl-5-phenyl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-ethanone
Figure imgf000104_0004
2-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-1 -phenyl-ethanone
2-(4-Ethyl-5-pyridin-4-yI-4H-[1 ,2,4]triazol-3- ylsuIfanyl)-1-(4-methoxy-phenyl)-ethanone
2-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-1-pyridin-3-yl-ethanone
Figure imgf000104_0005
2-(4-Ethyl-5-pyridin-4-yI-4H-[1 ,2,4]triazol-3-
B-12 402.50 ylsulfanyl)-1 -(4-methanesuIfonyl-phenyI)- ethanone
Figure imgf000104_0006
2-(4-Phenethyl-5-pyridin-4-yl-4H-
B-13 400.51 [1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl- ethanone
,
1-(4-Methoxy-phenyl)-2-(4-phenethyl-5-
B-14 430.53 pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone
2-(4-Phenethyl-5-pyridin-4-yl-4H-
B-15 401.49 [1 ,2,4]triazoI-3-ylsulfanyl)-1-pyridin-3-yl- ethanone
Figure imgf000105_0001
1-(4-Methanesulfonyl-phenyl)-2-(4- phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-ethanone
2-(4-Ethyl-5-furan-2-yl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-1 -phenyl-ethanone
2-(4-Ethyl-5-furan-2-yl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone
2-(4-Ethyl-5-furan-2-yi-4H-[1 ,2,4]triazol-3- ylsulfanyl)-1-pyridin-3-yl-ethanone
2-(4-Ethyl-5-furan-2-yl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-1 -(4-methanesulfonyl-phenyl)- ethanone
Figure imgf000105_0002
2-(5-Furan-2-yl-4-phenethyl-4H-
B-21 389.48 [1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl- ethanone
2-(5-Furan-2-yl-4-phenethyl-4H-
B-22 419.51 [1 ,2,4]triazol-3-ylsulfanyl)-1 -(4-methoxy- phenyl)-ethanone
2-(5-Furan-2-yl-4-phenethyI-4H-
B-23 390.47 [1 ,2,4]triazol-3-ylsulfanyl)-1 -pyridin-3-yl- ethanone
Figure imgf000106_0001
2-(5-Furan-2-yl-4-phenethyl-4H- 467.57 [1 ,2,4]triazol-3-ylsulfanyl)-1 -(4- methanesulfonyl-phenyl)-ethanone
Figure imgf000106_0002
PHARMACOLOGICAL METHODS
11 βHSDl enzyme assay
Materials
3H-cortisone and anti-rabbit Ig coated scintillation proximity assay (SPA) beads were purchased from Amersham Pharmacia Biotech, β-NADPH was from Sigma and rabbit anti- cortisol antibodies were from Fitzgerald. An extract of yeast transformed with h-11 βHSDl (Hult et al., FEBS Lett, 44_1, 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-11 βHSDl , 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 30°C. The reaction was stopped be the addition of 10 fold excess of a stopping buffer containing 500 μM carbenoxolone and 1 μM cortisone. Data was analysed using GraphPad Prism software.
Table 1
Inhibition of 11 βHSDl by compounds of the invention
Figure imgf000107_0001
Comp A: 2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(3,4-dihydro-2H- quinolin-1 -yl)-ethanone;
Comp B: 2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;

Claims

1. Use of a substituted 1 ,2,4-triazole, a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture or any tautomeric forms, for a) modulation of the activity of 11 βHSDl ; or b) inhibition of 11 βHSDl , in a patient in need thereof.
2. Use of a substituted 1 ,2,4-triazole, a prodrug thereof, or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture or any tautomeric forms, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any disorder and disease where it is desirable to a) modulate the activity of 11 βHSDl ; or b) inhibit 11 βHSDl , in a patient in need thereof.
3. The use according to claim 1 or 2, wherein the substituted 1 ,2,4-triazole or a prodrug thereof is of the general formula (I)
Figure imgf000108_0001
wherein X is O or S;
R1 is hydrogen, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C10cycloalkyl, arylC C6alkyl, hetarylCrCealkyl, R4R5NcarbonylCrC6alkyl, arylcarbonylC C6alkyl, hetarylcarbonylCr C6alkyl; wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R6;
R2 is CrC6alkyl, CrC6alkenyl, arylCrC6alkyl, C3-C10cycloalkyl or hetarylCrCealkyl; wherein the alkyl, alkenyl, cycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7; R3 is C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, hetarylC C6alkyl, arylR8CrC6alkyl or hetarylR8CrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R4 and R5 independently are hydrogen, CrCealkyl, C3-C10cycloalkyl, C5-C8hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R11; or
R4 and R5 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, arylCrC6alkyl, hydroxy, oxo, C C6alkyloxy, arylCrC6alkyloxy, CrC6alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, arylCrC6alkyl-carbonyl, CrC6alkylcarboxy, arylcarboxy or arylCr C6alkylcarboxy;
R6, R7, R9 and R11 independently are hydrogen, halo, N02, NH2, cyano, NR4R5, CONR4R5, trihalomethyl, trihalomethoxy, hydroxy, oxo, CrCβalkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, CrC6alkylS02, R15R 6NS02, CrCealkyloxy, aryloxy, hetaryloxy, arylCrC6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, aryld- C6alkylcarbonyl, arylcarbonylNR15, carboxyCrC6alkyl or carboxyarylCrC6alkyl;
R8 is oxygen, NR10, C(=0)NR10 or SOnNR10; wherein n is 1 or 2;
R10 is hydrogen, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl;
R15 and R16 independently are hydrogen, CrC6alkyl, C3-C10cycloalkyl, C5-C8hetcycloalkyl, aryl or hetaryl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl groups independ- ently are optionally substituted with one or more of R11; or
R15 and R16 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, arylCrC6alkyl, hy- droxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, CrC-ealkyloxyCrCealkyl, CrC6alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6alkyl- carboxy; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
4. The use according to any of the claims 1- 3, wherein the substituted 1 ,2,4-triazole or a prodrug thereof is of the general formula (I)
Figure imgf000110_0001
wherein X is O or S;
R1 is hydrogen, CrC6alkyl, C2-C6alkenyl, C2-C6alkynyl, arylCrC6alkyl, hetarylCrCealkyl, NR4R5carbonylCrC6alkyl, arylcarbonylCrC6alkyl, hetarylcarbonylCrC6alkyl; wherein the alkyl, alkenyl, alkynyl, aryl and hetaryl groups independently are optionally substituted with one or more of R6;
R2 is CrC6alkyl, CrC6alkenyl, arylCrC6alkyl or hetarylC C6alkyl; wherein the alkyl, alkenyl, aryl and hetaryl groups independently are optionally substituted with one or more of R7;
R3 is C5-C8cycloalkyl, C5-C8hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrC6alkyl, arylR8CrC6alkyl or hetarylR8CrC6alkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl and hetaryl groups independently are optionally substituted with one or more of R9;
R4 and R5 independently are hydrogen, CrC6alkyl, C5-C10cycloalkyl, C5-C8hetcycloalkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl groups independently are optionally substituted with one or more of R11; or
R4 and R5 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, arylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, arylC C6alkyloxy, CrC6alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, C C6alkylcarboxy, arylcarboxy or arylCrC6alkyl- carboxy;
R6, R7, R9 and R11 independently are hydrogen, halo, N02, NH2, cyano, trihalomethyl, trihalo- methoxy, hydroxy, oxo, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, S02NR15R16, CrC6alkyloxy, aryloxy, hetaryloxy, arylCrC6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, arylcarbonylNR15, carboxyCrC6alkyl or carboxyarylCr C6alkyl;
R8 is oxygen, NR10, C(=0)NR1° or SOnNR10; wherein n is 1 or 2;
R10 is hydrogen, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl;
R15 and R16 independently are hydrogen, CrC6alkyl, C5-C10cycloalkyl, C5-C8hetcycloalkyl, aryl or hetaryl; wherein the alkyl, cycloalkyl, hetcycloalkyl, aryl or hetaryl groups independently are optionally substituted with one or more of R11; or
R15 and R16 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 8 carbon atoms and from 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulphur, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, arylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, CrC6alkyloxyCrC6alkyl, CrC6alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6alkyl- carboxy; 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.
5. The use according to any of the claims 1-4, wherein X is O.
6. The use according to any of the claims 1-4, wherein X is S.
7. The use according to any of the claims 1-6, wherein R1 is arylCrC6alkyl, hetarylCrCealkyl, R4R5NcarbonylC C6alkyl, arylcarbonylCrC6alkyl, hetarylcarbonylCrC6alkyl; wherein aryl and hetaryl groups independently are optionally substituted with one or more of R6.
8. The use according to any of the claims 1-7, wherein R2 is CrCealkyl, arylCrC6alkyl, C3- C10cycloalkyl or hetarylCrCealkyl; all of which is optionally substituted with one or more of R7.
9. The use according to any of the claims 1-8, wherein R3 is C3-C10cycloalkyl, C3-C10het- cycloalkyl, aryl, hetaryl, arylCrC6alkyl, hetarylCrCealkyl, arylR8CrC6alkyl or hetarylR8CrC6- alkyl, wherein all groups indenpendently are optionally substituted with one or more of R9.
10. The use according to claim 9, wherein R3 is C3-C10hetcycloalkyl, aryl, hetaryl, arylCr C6alkyl, hetarylCrCealkyl, arylR8C C6alkyl or hetarylR8CrC6alkyl, wherein all groups indenpendently are optionally substituted with one or more of R9.
11. The use according to any of the claims 1-10, wherein R4 and R5 independently are aryl or hetaryl wherein both groups indenpendently are optionally substituted with one or more of R11.
12. The use according to any of the claims 1 -10, wherein R4 and R5 together with the nitrogen to which they are attached, are forming a saturated or partially saturated cyclic, bicyclic or tricyclic ring system containing from 4 to 10 carbon atoms and from 0 to 2 additional nitrogen atoms, the ring system optionally being substituted with at least one of CrC6alkyl, aryl, arylCrC6alkyl, hydroxy, oxo, CrC6alkyloxy, arylCrC6alkyloxy, CrCealkyloxyCrCealkyl, d- C6alkylcarbonyl, arylcarbonyl, arylCrC6alkyl-carbonyl, CrC6alkylcarboxy, arylcarboxy or arylCrC6alkylcarboxy.
13. The use according to any of the claims 1-12, wherein R6, R7, R9 and R11 independently are hydrogen, halo, N02, NH2, cyano, NR4R5, CONR4R5, trihalomethyl, trihalomethoxy, hy- droxy, oxo, CrCealkyl, C3-C10cycloalkyl, C3-C10hetcycloalkyl, aryl, hetaryl, arylC C6alkyl, hetarylCrCealkyl, C1-CβalkylSO2, R15R16NS02, C C6alkyloxy, aryloxy, hetaryloxy, arylC,- C6alkyloxy, CrC6alkylcarbonyl, arylcarbonyl, arylCrC6alkylcarbonyl, arylcarbonylNR15, car- boxyCrC6alkyl or carboxyarylCrC6alkyl.
14. The use according to any of the claims 1-13, wherein R8 is oxygen, NR10, C(=0)NR10 or SOnNR10; wherein n is 1 or 2.
15. The use according to any of the claims 1-14, wherein R10 is hydrogen, CrC6alkyl, aryl, hetaryl, arylCrC6alkyl or hetarylCrCealkyl.
16. The use according to any of the claims 1-15, wherein the substituted 1 ,2,4-triazole or a prodrug thereof is selected from the group consisting of: 3-(4-Allyl-5-mercapto-4H-[1 ,2,4]triazol-3-yl)-1 -(2,4-dichloro-benzyl)-1 H-pyridin-2-one; 4-Methyl-3-(4-methyl-2-phenyl-thiazol-5-yl)-5-prop-2-ynylsulfanyl-4H-[1 ,2,4]triazole;
N-{1-[5-(4-tert-Butyl-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-ethyl}-4-chloro- benzenesulfonamide;
4-Methyl-3-methylsulfanyl-5-[3-(3-trifluoromethyl-benzyloxy)-thiophen-2-yl]-4H-[1 ,2,4]triazole;
N-(4-Chloro-phenyl)-2-(4-methyl-5-thiophen-3-ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide;
2-[4-Methyl-5-(2-oxo-2-phenyl-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-4H- benzo[1 ,4]thiazin-3-one;
3-(4-Fluoro-benzylsulfanyl)-5-(2-fluoro-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
3-(2-Fluoro-phenyl)-4-methyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole; 4-Methyl-3-(4-methyl-benzylsulfanyl)-5-(3-trifluoromethyl-phenyl)-4H-[1,2,4]triazole;
3-(2,4-Dichloro-phenyl)-4-furan-2-ylmethyl-5-methylsulfanyl-4H-[1 ,2,4]triazole;
3-(4-tert-Butyl-phenyl)-5-(2,6-dichloro-benzylsulfanyl)-4-furan-2-ylmethyl-4H-[1 ,2,4]triazole;
4-Methyl-3-(4-methyl-benzylsulfanyl)-5-(5-methyl-isoxazol-3-yl)-4H-[1 ,2,4]triazole;
3-(3-Methoxy-benzylsulfanyl)-4-methyl-5-thiophen-2-yl-4H-[1 ,2,4]triazole; 3-(4-Fluoro-benzylsulfanyl)-4-methyl-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
3-(4-tert-Butyl-benzylsulfanyl)-4-methyl-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
4-Methyl-3-(2-methyl-benzylsulfanyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
2-(5-Benzylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4H-benzo[1 ,4]thiazin-3-one;
2-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl]-4H-benzo[1 ,4]thiazin-3- one;
5-[5-(2,6-Dichloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-benzo[1 ,2,5]oxadiazole;
1-(4-Chloro-phenyl)-2-[4-methyl-5-(4-trifluoromethyl-pyridin-3-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-ethanone;
3-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-2-methyl-imidazo[1 ,2- ajpyridine; 3-[5-(2,4-Dichloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-2,8-dimethyl-imidazo[1 ,2- ajpyridine;
4-Allyl-5-(2,4-dichloro-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
3-(5-Allylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-1 -benzyl-1 H-pyridin-2-one; 3-(4-Allyl-5-methylsulfanyl-4H-[1 ,2,4]triazol-3-yl)-1 -(2,4-dichloro-benzyl)-1 H-pyridin-2-one;
3-(4-Allyl-5-mercapto-4H-[1 ,2,4]triazol-3-yl)-1 -(4-chloro-benzyl)-1 H-pyridin-2-one;
3-(4-Allyl-5-prop-2-ynylsulfanyl-4H-[1 ,2,4]triazol-3-yl)-1-(4-chloro-benzyl)-1 H-pyridin-2-one;
3-(5-Allylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-1-(2,4-dichloro-benzyl)-1 H-pyridin-2-one;
1-(2,4-Dichloro-benzyl)-3-[4-ethyl-5-(2-oxo-2-phenyl-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-1 H- pyridin-2-one;
3-(4-Allyl-5-prop-2-ynylsulfanyl-4H-[1 ,2,4]triazol-3-yl)-1-(3,4-dichloro-benzyl)-1 H-pyridin-2- one;
4-Allyl-5-(4-methyl-2-phenyl-thiazol-5-yl)-4H-[1 ,2,4]triazole-3-thiol;
3-Allylsulfanyl-4-methyl-5-(4-methyl-2-phenyl-thiazol-5-yl)-4H-[1 ,2,4]triazole; 4-Allyl-5-[2-(3,4-dimethoxy-phenyl)-thiazol-4-yl]-4H-[1 ,2,4]triazole-3-thiol;
N-[5-(4-tert-Butyl-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl]-4-methyl- benzenesulfonamide;
4-Methyl-3-[3-(4-methyl-benzyloxy)-thiophen-2-yl]-5-methylsulfanyl-4H-[1 ,2,4]triazole;
5-[3-(2,4-Dichloro-benzyloxy)-thiophen-2-yl]-4-methyl-4H-[1 ,2,4]triazole-3-thiol; 3-[3-(2,4-Dichloro-benzyloxy)-thiophen-2-yl]-4-methyl-5-methylsulfanyl-4H-[1 ,2,4]triazole;
4-Methyl-5-[3-(3-trifluoromethyl-benzyloxy)-thiophen-2-yl]-4H-[1 ,2,4]triazole-3-thiol;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-iodo-phenyl)-acetamide;
3-(5-Allylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-2,7-dimethyl-imidazo[1 ,2-a]pyridine;
3-(5-Benzylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-2,7-dimethyl-imidazo[1 ,2-a]pyridine; 3-(5-Benzylsulfanyl-4-methyl-4H-[1 ,2,4]triazol-3-yl)-2-methyl-imidazo[1 ,2-a]pyridine;
4-Butyl-5-(3-chloro-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
4-Allyl-5-(3-chloro-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-
4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-benzamide; N-(5-{2-[3,5-Bis-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-4-methyl-
4H-[1 ,2,4]triazol-3-ylmethyl)-3-methoxy-benzamide;
N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-
4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4-(pyrrolidine-1-sulfonyl)-benzamide;
N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}- 4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4-(piperidine-1 -sulfonyl)-benzamide; N-(5-{2-[5-(4-Methoxy-phenyl)-3-thiophen-2-yl-4,5-dihydro-pyrazol-1-yl]-2-oxo-ethylsulfanyl}-
4-methyl-4H-[1 ,2,4]triazol-3-ylmethyl)-4-(morpholine-4-sulfonyl)-benzamide;
4-Benzyl-3-(4-fluoro-naphthalen-1-ylmethylsulfanyl)-5-phenyl-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -naphthalen-1 -yl-ethanone; 1 -(4-Fluoro-phenyl)-4-(4-methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-butan-1 -one
2-(4-Methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(5,6,7,8-tetrahydro-naphthalen-2-yl)- ethanone;
5-(2-Carbazol-9-yl-ethyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol;
1-(4-Methoxy-phenyl)-2-[4-(2-methyl-allyl)-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-ethanone; 2-{2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid methyl ester;
5-(2,4-Dichloro-phenyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol;
4-Allyl-3-(4-methoxy-benzylsulfanyl)-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(9H-fluoren-2-yl)-ethanone; 3-(4-Methoxy-benzylsulfanyl)-4-methyl-5-phenyl-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-ethyl-phenyl)-ethanone;
2-(4-Allyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)-acetamide;
2-[4-Allyl-5-(4-tert-butyl-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-chloro-phenyl)-ethanone;
2-(4-Allyl-5-phenylaminomethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2,4-difluoro-phenyl)- acetamide;
2-(4-Allyl-5-phenoxymethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(4-Allyl-5-phenoxymethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-bromo-phenyl)-ethanone;
(4-Allyl-5-benzylsulfanyl-4H-[1 ,2,4]triazol-3-ylmethyl)-phenyl-amine;
2-(4-Allyl-5-benzotriazol-1 -ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -(4-methoxy-phenyl)- ethanone;
2-(4-Allyl-5-phenylaminomethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-chloro-phenyl)-acetamide;
1-(4-Methoxy-phenyl)-2-[4-(2-methyl-allyl)-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-ethanone;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide; [5-(2-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid isopropyl ester;
N-(4-Chloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methoxy-phenyl)- acetamide; N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-
[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(4-Acetyl-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
4-[5-(2,6-Dichloro-benzylsulfanyl)-4-furan-2-ylmethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine; N-(4-Methyl-3-nitro-phenyl)-2-[4-methyl-5-(3,4,5-trimethoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(4-furan-2-ylmethyl-5-pyridin-4-yl-
4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid methyl ester; 2-(4-Methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide;
N-(4-Chloro-phenyl)-2-(4-ethyl-5-m-tolyl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-(4-ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-bromo-phenyl)-acetamide; 2-{5-[(2,6-Dimethyl-phenylamino)-methyl]-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -phenyl- ethanone;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-fluoro-phenyl)-acetamide;
2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy-phenyl)- ethanone; N-(4-lodo-2-methyl-phenyl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -(3,4-dihydro-2H-quinolin-1 -yl)- ethanone;
N-(2-Bromo-4-methyl-phenyl)-2-(4-furan-2-ylmethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-acetamide;
N-(4-Chloro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(3-trifluoromethyl-phenyl)- acetamide;
2-[5-[(4-Fluoro-phenylamino)-methyl]-4-(tetrahydro-furan-2-ylmethyl)-4H-[1 ,2,4]triazol-3- ylsulfanyl]-1-p-tolyl-ethanone;
2-(5-Methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-naphthalen-1-yl-acetamide;
N-(5-Ethyl-[1 ,3,4]thiadiazol-2-yl)-2-(5-methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide;
2-(5-Methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide; [5-(4-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid cyclohexyl ester; 2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(3-chloro-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-chloro-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-m-tolyl-acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H- [1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)-acetamide;
3-Benzylsulfanyl-4-methyl-5-phenyl-4H-[1 ,2,4]triazole;
3-Butylsulfanyl-5-(4-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-ethoxy-phenyl)-acetamide; N-(4-Acetyl-phenyl)-2-(4-benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2,4-dimethyl-phenyl)-acetamide;
N-(3-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
N-Naphthalen-1-yl-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; (4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid cyclohexyl ester;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3- ylsulfanyl)-acetamide;
2-[5-(4-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -phenyl-ethanone; 3-Benzylsulfanyl-5-(4-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
2-(4,5-Dibenzyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-m-tolyl-acetamide;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-propionamide;
3-(5-Benzylsulfanyl-4-phenethyl-4H-[1 ,2,4]triazol-3-yl)-pyridine; (4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid ethyl ester;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
2-(4-Phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-propionamide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-
[1 ,2,4]triazol-3-ylsulfanyl}-ethanone; 2-[5-(3,4-Dimethoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -p-tolyl-ethanone;
N-(3-Chloro-2-methyl-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N,N-diphenyl-propionamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methyl-3-nitro-phenyl)-acetamide; N-(2-Bromo-4-methyl-phenyl)-2-(4-ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone; N-(4-Fluoro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(5-benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-chloro-phenyl)-acetamide;
N-(3-Chloro-2-methyl-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide; 2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-nitro-phenyl)- acetamide;
2-[5-(2-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-propionamide;
[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid ethyl ester;
2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide; 2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-naphthalen-1 -yl- propionamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-propionamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-phenyl-propionamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-acetamide;
N-(3-Chloro-4-methyl-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-nitro-phenyl)-acetamide; 4-{2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid ethyl ester;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-o-tolyl-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-chloro-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methoxy-2-nitro-phenyl)- acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-nitro-phenyl)- acetamide;
1-(3,4-Dihydro-2H-quinolin-1-yl)-2-{5-[(2,4-dimethyl-phenylamino)-methyl]-4-ethyl-4H-
[1 ,2,4]triazol-3-ylsulfanyl}-ethanone; N-(4-Chloro-3-nitro-phenyl)-2-[5-(4-chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(3,4-dihydro-2H-quinolin-1-yl)- ethanone; 2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -p-tolyl-ethanone;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-phenyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-chloro-phenyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)- acetamide; 4-{2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid methyl ester;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-cyano-4,5,6,7-tetrahydro- benzo[b]thiophen-2-yl)-acetamide; 2-[5-(4-Chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-nitro-phenyl)-acetamide;
(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl)-(4-chloro-phenyl)-amine;
N-(2-Methoxy-phenyl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-(4-Allyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3,4-dichloro-phenyl)-acetamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-phenyl)-acetamide;
N-(5-Chloro-2-methyl-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Methoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; N-(2,4-Dimethyl-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
4-[2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid methyl ester;
N-(4-Chloro-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-bromo-4-methyl-phenyl)-acetamide;
2-(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-ethoxy-phenyl)- acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-naphthalen-1-yl-acetamide;
4-[5-(4-tert-Butyl-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine; 4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-fluoro-phenyl)-acetamide;
4-{2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetylamino}-benzoic acid methyl ester;
N-(3-Chloro-phenyl)-2-(5-cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-ethoxy-phenyl)-acetamide;
2-{5-[(4-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-N-(2-nitro- phenyl)-acetamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-chloro-2-methyl-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-phenyl-acetamide;
3-Benzyl-5-(2-chloro-6-fluoro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazole;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -phenyl-ethanone; 4-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-fluoro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-bromo-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide; 2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-propionamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-trifluoromethyl-phenyl)-acetamide;
{5-[(3-Chloro-4-methyl-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
3-[5-(2,4-Dichloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-pyridine; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-N-phenyl-acetamide;
N-(3-Chloro-4-methyl-phenyl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
N-(4-Chloro-phenyl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide; 3-Benzyl-5-(4-chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazole; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-nitro-phenyl)-acetamide;
N-(4-Ethoxy-phenyl)-2-[5-(4-hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methoxy-phenyl)- acetamide;
{5-[(4-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
3-Benzylsulfanyl-5-(2-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
N-(2-Chloro-phenyl)-2-(4-methyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; N-(2-Methoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(3-nitro-phenyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(3,4-dihydro-2H-quinolin-1- yl)-ethanone; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-bromo-4-methyl-phenyl)-acetamide;
N-(2-Chloro-phenyl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl)-(3-trifluoromethyl-phenyl)-amine;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy-phenyl)- ethanone;
[4-Allyl-5-(3-bromo-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-phenyl-amine;
2-(4-Furan-2-ylmethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(3-nitro-phenyl)- ethanone;
1-(4-Bromo-phenyl)-2-(4-furan-2-ylmethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone;
4-{5-[2-(2-Methoxy-phenoxy)-ethylsulfanyl]-4-methyl-4H-[1 ,2,4]triazol-3-yl}-phenylamine;
4-[5-(4-Chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-phenylamine;
[4-Allyl-5-(1 ,3-dioxo-1 H,3H-benzo[de]isoquinolin-2-ylmethyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetic acid ethyl ester; 2-{4-Allyl-5-[(4-chloro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -phenyl- ethanone;
5-(3-Bromo-phenyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol;
2-(4-Allyl-5-benzotriazol-1-ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)- acetamide; 1 -(4-Fluoro~phenyl)-2-(4-methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone; 8-(4-Methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-5-nitro-quinoline;
3-(2-Bromo-benzylsulfanyl)-4-methyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(3-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(2,4-dimethyl-phenyl)- ethanone; 1 -(4-Bromo-phenyl)-2-(5-furan-2-yl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(5-methyl-thiazol-2-yl)- acetamide;
2-[4-Ethyl-5-(p-tolylamino-methyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-p-tolyl-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-ethyl-phenyl)-acetamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -(4-methoxy-phenyl)-ethanone;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-p-tolyl-ethanone;
3-(2-Bromo-phenyl)-4-methyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2,4-dimethyl-phenyl)- acetamide;
N-(4-Bromo-phenyl)-2-[5-(2-bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
2-{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-(4-methoxy- phenyl)-ethanone;
2-{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-p-tolyl- ethanone;
{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester; 2-{5-[(4-Fluoro-phenylamino)-methyl]-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -phenyl- ethanone;
2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1-(4-methoxy- phenyl)-ethanone;
[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-(4-fluoro-phenyl)-amine; (5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl)-(4-fluoro-phenyl)-amine;
{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
N-(4-Chloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(4-Acetyl-phenyl)-2-(5-cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide;
N-Cyclohexyl-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(2,4-Dimethyl-phenyl)-2-[4-furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
4-[2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid ethyl ester;
2-[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro- phenyl)-acetamide; 3-lsobutylsulfanyl-4-methyl-5-p-tolyl-4H-[1 ,2,4]triazole;
2-[2-(4-Methyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetylamino]-benzoic acid methyl ester;
2-{4-Ethyl-5-[4-(morpholine-4-sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -p-tolyl- ethanone; 4-Methyl-3-phenethylsulfanyl-5-p-tolyl-4H-[1 ,2,4]triazole;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-chloro-phenyl)-acetamide; 2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-propionamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2,5-dichloro-phenyl)-acetamide;
N-(3-Chloro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-propionamide;
N-(2-Bromo-4-methyl-phenyl)-2-[5-(3,4-dimethoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-N-(4-nitro-phenyl)- acetamide;
3-Benzylsulfanyl-5-cyclohexyl-4-ethyl-4H-[1 ,2,4]triazole;
[5-(4-Hydroxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid cyclohexyl ester; 2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(5-ethyl-[1 ,3,4]thiadiazol-2-yl)- acetamide;
N-(3-Chloro-4-methyl-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide;
[4-Benzyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid ethyl ester; 3-Benzylsulfanyl-4-methyl-5-(3,4,5-trimethoxy-phenyl)-4H-[1 ,2,4]triazole; N-(2-Chloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(2,4-Dimethoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4jtriazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)- acetamide; 2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
3-Cyclohexyl-4-methyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
N-(2-Bromo-phenyl)-2-(5-cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-iodo-2-methyl-phenyl)- acetamide; N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-(5-cyclohexyl-4-methyl-4H-
[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(5-cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-phenyl)-acetamide;
N-(4-Chloro-phenyl)-2-(5-cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-phenyl-acetamide;
2-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-methoxy-4-nitro-phenyl)- acetamide;
N-(3-Cyano-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-2-[5-(2-methoxy-phenyl)-4-methyl-4H-
[1 ,2,4]triazol-3-ylsulfanyl]-acetamide; N-(4-Bromo-phenyl)-2-(5-cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-phenyl-acetamide;
N-(3-Chloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(4-Acetyl-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide;
N-(4-Bromo-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetamide; 2-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-iodo-2-methyl-phenyl)- acetamide;
N-(2,4-Dimethyl-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
4-[5-(4-Chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol; [4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylj-acetic acid cyclohexyl ester;
2-[5-(2-Methoxy-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-phenyl-thiazol-2-yl)- acetamide;
N-(3-Chloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide; 2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-nitro-phenyl)-acetamide; 2-[4-Methyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
N-(4-Bromo-phenyl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3- ylsulfanyl}-acetamide;
N-(4-Chloro-phenyl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-N-(2-nitro-phenyl)- acetamide;
1-(4-Methoxy-phenyl)-2-[4-methyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-ethanone;
[5-(4-Chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl]-(4-fluoro-phenyl)-amine; 2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -p-tolyl-ethanone;
2-{4-Ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-N-(4-methyl-3- nitro-phenyl)-acetamide;
N-(2-Bromo-4-methyl-phenyl)-2-{4-ethyl-5-[(4-fluoro-phenylamino)-methyl]-4H-[1 ,2,4]triazol-
3-ylsulfanyl}-acetamide; 4-AI[yl-5-(3-bromo-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
N-(2-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-{4-Ethyl-5-[4-(piperidine-1 -sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -p-tolyl- ethanone;
2-{4-Ethyl-5-[4-(piperidine-1 -sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -phenyl- ethanone;
N-Biphenyl-2-yl-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-chloro-4-methyl-phenyl)- acetamide;
N-(2-Bromo-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 4-Benzyl-5-cyclohexyl-4H-[1 ,2,4]triazole-3-thiol;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
(5-Benzyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid cyclohexyl ester;
4-Methyl-3-(4-nitro-benzylsulfanyl)-5-phenyl-4H-[1 ,2,4]triazole; 2-(4-Methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -p-tolyl-ethanone;
2-(4-Methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
3-Benzylsulfanyl-4-methyl-5-(naphthalen-2-yloxymethyl)-4H-[1 ,2,4]triazole;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4jtriazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
3-Benzylsulfanyl-5-cyclohexyl-4-methyl-4H-[1 ,2,4]triazole; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-3-nitro-phenyl)-acetamide; 2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methyl-3-nitro-phenyl)-acetamide;
2-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methoxy-4-nitro-phenyl)-acetamide;
N-(2-Bromo-4-methyl-phenyl)-2-(4-methyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
3-Benzylsulfanyl-4-ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole; 4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-p-tolyl-ethanone;
3-(4-Chloro-benzylsulfanyl)-4-ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Ethyl-5-(4-nitro-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(3,4-dimethyl-phenyl)- acetamide;
(2,4-Dimethyl-phenyl)-[4-ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-amine
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide;
2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-trifluoromethyl-phenyl)-acetamide; 2-[5-[(2,4-Dimethyl-phenylamino)-methyl]-4-(tetrahydro-furan-2-ylmethyl)-4H-[1 ,2,4]triazol-3- ylsulfanyl]-1 -p-tolyl-ethanone;
4-[5-(2,6-Dichloro-benzylsulfanyl)-4-(tetrahydro-furan-2-ylmethyl)-4H-[1 ,2,4]triazol-3-ylj- pyridine;
3-Benzylsulfanyl-5-(4-chloro-phenoxymethyl)-4-ethyl-4H-[1 ,2,4]triazole; 3-Butylsulfanyl-4-methyl-5-p-tolyl-4H-[1 ,2,4]triazole;
1-(5-Chloro-2-methoxy-phenyl)-2-(4-methyl-5-p-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
1-(4-Chloro-phenyl)-2-(4-methyl-5-p-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
N-(2,4-Dimethoxy-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methyl-4-nitro-phenyl)-acetamide; N-(4-Ethoxy-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Ethyl-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-p-tolyl-ethanone; 2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
N-(3-Chloro-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(2-Chloro-phenyl)-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[5-(2-Hydroxy-phenyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-piperidin-1-yl-ethanone;
2-[5-(2-Morpholin-4-yl-ethylsulfanyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-yl]-phenol; N-(2-Methyl-4-nitro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide;
N-(2-Methyl-5-nitro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- acetamide; N-(4-Bromo-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(3-Nitro-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-fluoro-phenyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methoxy-4-nitro-phenyl)-acetamide;
N-(2,5-Dichloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide;
2-[4-Benzyl-5-(4-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4-nitro-phenyl)- acetamide;
2-(4-Phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)- acetamide;
[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetic acid cyclohexyl ester;
2-[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4jtriazol-3-ylsulfanyl]-1-phenyl-ethanone;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-ethyl-phenyl)-acetamide; 2-(5-Cyclohexyl-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3,4-dichloro-phenyl)-acetamide;
2-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methoxy-2-nitro-phenyl)-acetamide;
2-(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(5-methyl-thiazol-2-yl)-acetamide;
2-(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide; 2-(4,5-Dibenzyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-nitro-phenyl)-acetamide;
3-Benzylsulfanyl-5-(4-bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazole;
2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-methyl-3-nitro-phenyl)- acetamide; 2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -phenyl-ethanone;
2-(4-Benzyl-5-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
2-(5-Methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
2-(5-Methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)- acetamide; N-(3-Chloro-phenyl)-2-(5-methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; N-(4-Chloro-phenyl)-2-(5-methyl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-methoxy-4-nitro-phenyl)- acetamide;
2-(5-Cyclohexyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(3-nitro-phenyl)-acetamide; N-(2,3-Dichloro-phenyl)-2-[4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylj- acetamide;
N-(2,3-Dichloro-phenyl)-2-[4-ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]- acetamide;
2-[4-Ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy-phenyl)- ethanone;
2-[4-Benzyl-5-(2-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -piperidin-1 -yl-ethanone;
2-[4-Benzyl-5-(2-hydroxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-p-tolyl-acetamide;
2-{5-[(2,4-Dimethyl-phenylamino)-methyl]-4-furan-2-ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1- phenyl-ethanone; 2-(4-Methyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-p-tolyl-acetamide;
4-{4-Ethyl-5-[4-(piperidine-1-sulfonyl)-phenyl]-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl}- benzonitrile;
N-(2-Methoxy-phenyl)-2-(4-methyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
N-(4-Acetyl-phenyl)-2-(4-ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide; 2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-methyl-3-nitro-phenyl)-acetamide;
2-[5-(4-Amino-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-nitro-phenyl)-ethanone;
N-{4-[5-(2-Chloro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-phenyl}-2-methoxy- benzamide;
2-(4-Allyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-fluoro-phenyl)-ethanone; 2-(4-Benzyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-fluoro-phenyl)-acetamide;
2-[5-(4-Amino-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-nitro-phenyl)-ethanone;
2-(4-Allyl-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-chloro-phenyl)-acetamide;
(4-Benzyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetic acid ethyl ester;
4-[5-(4-tert-Butyl-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-pyridine; 2-{5-[(3-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -phenyl- ethanone;
{5-[(2-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid isopropyl ester;
2-[4-Ethyl-5-(4-methoxy-phenoxymethyl)-4H-[1 ,2,4]triazol-3-yIsulfanyl]-1-phenyl-ethanone; 1-(4-Chloro-phenyl)-2-{5-[(2-chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3- ylsulfanyl}-ethanone;
4-[5-(2-Chloro-6-fluoro-benzylsulfanyl)-4-methyl-4H-[1 ,2,4]triazol-3-yl]-pyridine
3-Benzyl-5-benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazole; 3-Benzylsulfanyl-4-methyl-5-o-tolyl-4H-[1 ,2,4]triazole;
N-(4-Chloro-3-nitro-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-acetamide;
2-(4-Methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-p-tolyl-ethanone;
1-(4-Methoxy-phenyl)-2-(4-methyl-5-o-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
[5-(2-Bromo-phenyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetonitrile; [5-(2-Hydroxy-phenyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-acetonitrile;
1-[5-(2-Hydroxy-phenyl)-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-propan-2-one;
N-(2,3-Dichloro-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
N-(3-Chloro-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
N-(4-Chloro-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
2-[5-(4-Methoxy-phenoxymethyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-phenyl-ethanone;
2-{5-[(2-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-1 -piperidin-1 -yl- ethanone;
2-[5-(4-Methoxy-phenoxymethyl)-4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-(4-methoxy- phenyl)-ethanone;
N-(2,3-Dichloro-phenyl)-2-[4-furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide; 2-[4-Furan-2-ylmethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1 -(4-methoxy- phenyl)-ethanone;
{5-[(2-Chloro-phenylamino)-methyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl}-acetic acid cyclohexyl ester;
2-(4-Phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-thiazol-2-yl-acetamide; 2-(4-Ethyl-5-m-tolyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-nitro-phenyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-methoxy-phenyl)-acetamide;
2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(2-trifluoromethyl-phenyl)-acetamide;
2-[4-Furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(2-methyl-4- nitro-phenyl)-acetamide; N-(3-Chloro-2-methyl-phenyl)-2-[4-furan-2-ylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3- ylsulfanylj-acetamide;
4-Allyl-5-m-tolyl-4H-[1 ,2,4]triazole-3-thiol;
4-(2-Methyl-allyl)-5-m-tolyl-4H-[1 ,2,4]triazole-3-thiol; 2-[4-Allyl-5-(3-bromo-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-N-(4-ethyl-phenyl)-acetamide;
4-Allyl-3-(3-bromo-phenyl)-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
2-[4-Allyl-5-(3-bromo-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanyl]-1-biphenyl-4-yl-ethanone;
4-(2-Methyl-allyl)-5-(3-nitro-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
4-Allyl-5-(2-carbazol-9-yl-ethyl)-4H-[1 ,2,4]triazole-3-thiol; 5-(4-Bromo-phenyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol;
4-(2-Methyl-allyl)-5-(3-methyl-2-nitro-phenyl)-4H-[1 ,2,4]triazole-3-thiol;
5-(4-Methoxy-phenyl)-4-(2-methyl-allyl)-4H-[1 ,2,4]triazole-3-thiol;
2-(4-Allyl-5-benzotriazol-1-ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-(4-bromo-phenyl)- acetamide; 2-(4-Allyl-5-benzotriazol-1 -ylmethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-N-pyridin-2-yl-acetamide;
{4-Allyl-5-[3-(1 ,3-dioxo-1 H,3H-benzo[de]isoquinolin-2-yl)-propyl]-4H-[1 ,2,4]triazol-3- ylsulfanyl}-acetic acid ethyl ester;
4-Allyl-5-(4-phenyl-piperazin-1 -ylmethyl)-4H-[1 ,2,4]triazole-3-thiol; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
17. The use according to any of the claims 1 -16, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
18. The use according to any of the claims 1 -16 for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
19. The use according to any of the claims 1 -16, for the preparation of a composition for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
20. The use according to any of the claims 1-16, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
21. The use according to any of the claims 1-16, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
22. The use according to any of the claims 1-16, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclerosis.
23. The use according to any of the claims 1 -16, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of neurodegenerative and psychiatric disorders.
24. The use according to any of the claims 1-16, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
25. The use according to any of the claims 1-24, wherein the pharmaceutical composition is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration.
26. The use according to any of the claims 1-25, wherein the pharmaceutical composition is preferably in unit dosage form, comprising from about 0.05 mg to about 2000 mg/day, preferably from about 0.1 mg to about 1000 mg and especially preferred from about 0.5 mg to about 500 mg per day of the compound.
27. A method for the treatment, prevention and/or prophylaxis of conditions, disorders or diseases wherein a modulation or an inhibition of the activity of 11 βHSDl is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
28. The method according to claim 26, wherein the treatment, prevention and/or prophylaxis is of any conditions, disorders and diseases that are influenced by intracellular glucocorticoid levels.
29. The method according to claim 27 or 28 wherein the condition, disorder or disease is the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
30. The method according to claim 27 or 28, wherein the condition, disorder or disease is type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
31. The method according to claim 27 or 28, for the delaying or prevention of the progression from IGT to type 2 diabetes.
32. The method according to claim 27 or 28, for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
33. The method according to claim 27 or 28, wherein the condition, disorder or disease is diabetic late complications including cardiovascular diseases; arteriosclerosis; atherosclero- sis.
34. The method according to claim 27 or 28, wherein the condition, disorder or disease is neurodegenerative and psychiatric disorders.
35. A substituted 1 ,2,4-triazole or a prodrug thereof of the general formula (I) which is: 4-[2-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)ethyl]morpholine; 1-Benzothiazol-2-yl-2-(4-ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsuϊfanyl)-ethanone; Λ/-Cyclohexyl-2-(4-ethyl-5-phenyl-4 - -[1 ,2,4]triazol-3-ylsulfanyl)-Λ/-methyl-acetamide; or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mix- ture of optical isomers, including a racemic mixture, or any tautomeric forms.
36. A substituted 1 ,2,4-triazole or a prodrug thereof of the general formula (I) which is: 2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone; 2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone; 2-(4-Ethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -pyridin-3-yl-ethanone;
2-(4-Ethyl-5-phenyl-4/- -[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methanesulfonyl-phenyl)-ethanone; 2-(4-Phenethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone; 1-(4-Methoxy-phenyl)-2-(4-phenethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone; 2-(4-Phenethyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanyl)-1-pyridin-3-yl-ethanone; 1-(4-Methanesulfonyl-phenyl)-2-(4-phenethyl-5-phenyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone;
2-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone; 2-(4-Ethyl-5-pyridin-4-yl-4 -/-[1 ,2,4]triazol-3-ylsulfanyl)-1 -pyridin-3-yl-ethanone;
2-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methanesulfonyl-phenyl)- ethanone;
2-(4-Phenethyl-5-pyridin-4-yl-4 -/-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
1-(4-Methoxy-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone; 2-(4-Phenethyl-5-pyridin-4-yl-4 - -[1 ,2,4]triazol-3-ylsulfanyl)-1 -pyridin-3-yl-ethanone;
1-(4-Methanesulfonyl-phenyl)-2-(4-phenethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)- ethanone;
2-(4-Ethyl-5-furan-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-phenyl-ethanone;
2-(4-Ethyl-5-furan-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone; 2-(4-Ethyl-5-furan-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -pyridin-3-yl-ethanone;
2-(4-Ethyl-5-furan-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methanesulfonyl-phenyl)-ethanone;
2-(5-Furan-2-yl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -phenyl-ethanone;
2-(5-Furan-2-yl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-(4-methoxy-phenyl)-ethanone;
2-(5-Furan-2-yl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1-pyridin-3-yl-ethanone; 2-(5-Furan-2-yl-4-phenethyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-1 -(4-methanesulfonyl-phenyl)- ethanone;
1 -Adamantan-1 -yl-2-(4-methyl-4H-[1 ,2,4]triazol-3-ylsulfanyl)-ethanone;
3-[5-(2-Chloro-benzylsulfanyl)-4-ethyl-4ry-[1 ,2,4]triazol-3-ylj-propan-1-ol;
4-[4-Ethyl-5-(3-hydroxy-propyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile; 3-[5-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-propan-1 -ol;
3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol;
3-(5-Cyclohexylmethylsulfanyl-4-ethyl-4 - -[1 ,2,4]triazol-3-yl)-propan-1-ol;
3-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol;
3-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-propan-1-ol; 3-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-propan-1 -ol;
3-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol;
3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol;
3-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-propan-1-ol;
N-{4-[4-Ethyl-5-(3-hydroxy-propyl)-4/- -[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide; 3-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-propan-1 -ol; 3-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylj-propan-1-ol;
4-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
4-[5-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol; 4-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-(5-Benzylsulfanyl-4-ethyl-4r -[1 ,2,4]triazol-3-yl)-phenol;
4-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4/-/-[1 ,2,4]triazol-3-yl]-phenol;
4-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-[4-Ethyl-5-(4-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl et- ser;
4-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4 -/-[1 ,2,4]triazol-3-yl]-phenol;
N-{4-[4-Ethyl-5-(4-hydroxy-phenyl)-4r/-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide;
4-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol; 4-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
3-Benzo[1 ,3]dioxol-5-yl-5-(2-chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-(5-Benzo[1 ,3]dioxol-5-yl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
3-Benzo[1 ,3]dioxol-5-yl-5-(6-chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4 - - [1 ,2,4]triazole;
3-Benzo[1 ,3]dioxol-5-yl-5-(4-bromo-benzylsulfanyl)-4-ethyl-4 -/-[1 ,2,4]triazole;
4-[4-(5-Benzo[1 ,3jdioxol-5-yl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenylj-
[1 ,2,3]thiadiazole;
3-Benzo[1 ,3]dioxol-5-yl-5-cyclohexylmethylsulfanyl-4-ethyl-4 - -[1 ,2,4]triazole; 3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-Benzo[1 ,3]dioxol-5-yl-5-(3,5-dimethoxy-benzylsuIfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4 - -[1 ,2,4]triazole;
4-(5-Benzo[1 ,3]dioxol-5-yl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser; 3-Benzo[1 ,3]dioxol-5-yl-5-(2,6-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-Benzo[1 ,3]dioxol-5-yl-5-(4-benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
N-[4-(5-Benzo[1 ,3]dioxol-5-yl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenyl]-acetamide;
3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4 - -[1 ,2,4]triazole;
3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-Benzo[1 ,3]dioxol-5-yl-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-Benzo[1 ,3]dioxol-5-yl-5-(2,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-[4-Ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-
[1 ,2,4]triazole; 3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazole;
3-(4-Bromo-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4 - -[1 ,2,4]triazole;
4-{4-[4-Ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-
[1 ,2,3]thiadiazole;
3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4 -/-[1 ,2,4]triazole; 4-Ethyl-3-(2-phenoxy-phenyl)-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(2-phenoxy-phenyl)-4 -/-[1 ,2,4]triazole;
4-[4-Ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazole; 3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-(2-phenoxy-phenyl)-4/- -[1 ,2,4]triazole;
4-Ethyl-3-(2-phenoxy-phenyl)-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-(2-phenoxy-phenyl)-4/- -[1 ,2,4]triazole;
4-Ethyl-3-(2-nitro-benzylsuϊfanyl)-5-(2-phenoxy-phenyl)-4H-[1 ,2,4]triazole; 3-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(2-phenoxy-phenyl)-4 - -[1 ,2,4]triazole;
3-Cyclohexylmethylsulfanyl-4-ethyl-5-naphthalen-1-yl-4/- -[1 ,2,4]triazole;
4-Ethyl-3-naphthalen-1-yl-5-(4-trifluoromethyl-benzylsulfanyl)-4r-/-[1 ,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-naphthalen-1-yl-4 -/-[1 ,2,4]triazole;
4-Ethyl-3-naphthalen-1-yl-5-(3-nitro-benzylsulfanyl)-4 - -[1 ,2,4]triazole; 4-(4-Ethyl-5-naphthalen-1 -yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
4-Ethyl-3-naphthalen-1-yl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-naphthalen-1-yl-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-naphthalen-1-yl-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-naphthalen-1-yl-4H-[1 ,2,4]triazole; 4-Ethyl-3-(5-methyl-2-nitro-benzylsulfanyl)-5-naphthalen-1 -yl-4H-[1 ,2,4jtriazole;
3-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-5-naphthalen-1-yl-4H-[1 ,2,4]triazole;
[4-(5-Cyclohexylmethylsulfanyl-4-ethyl-4 -/-[1 ,2,4]triazol-3-yl)-phenyl]-dimethyl-amine
{4-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenyl}-dimethyl-amine
{4-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenyl}-dimethyl-amine 4-[5-(4-Dimethylamino-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
{4-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenyl}-dimethyl-amine;
{4-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-4 -/-[1 ,2,4]triazol-3-yl]-phenyl}-dimethyl-amine; {4-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-phenyl}-dimethyl-amine;
{4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4 - -[1 ,2,4]triazol-3-yl]-phenyl}-dimethyl-amine;
4-(4-Ethyl-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5-thiophen-2-yl-4H-[1 ,2,4]triazole; 3-(4-Bromo-benzylsulfanyl)-4-ethyl-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
4-[4-(4-Ethyl-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenyl]-[1 ,2,3jthiadiazole;
4-Ethyl-3-thiophen-2-yl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-thiophen-2-yl-4 - -[1 ,2,4]triazole;
4-Ethyl-3-thiophen-2-yl-5-(4-trifluoromethyl-benzylsulfanyl)-4 - -[1 ,2,4]triazole; 3-Benzylsulfanyl-4-ethyl-5-thiophen-2-yl-4 - -[1 ,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
4-(4-Ethyl-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
4-Ethyl-3-(4-nitro-benzylsulfanyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-thiophen-2-yl-4H-[1 ,2,4]triazole; 4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
4-Ethyl-3-(5-methyl-2-nitro-benzylsulfanyl)-5-thiophen-2-yl-4 -/-[1 ,2,4]triazole;
3-(2-Chloro-benzylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4 - -[1 ,2,4]triazole;
3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4H- [1 ,2,4]triazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-trifluoromethoxy-benzylsulfanyl)-4 - -[1 ,2,4]triazole;
3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4 - -[1 ,2,4]triazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-Benzylsulfanyl-4-ethyl-5-(2-methoxy-phenyl)-4/- -[1 ,2,4]triazole; 4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(2-methoxy-phenyl)-4 - -[1 ,2,4]triazole;
4-[4-Ethyl-5-(2-methoxy-phenyl)-4 - -[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
4-Ethyl-3-(2-methoxy-phenyl)-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazole; 3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazole; 4-Ethyl-3-(2-methoxy-phenyl)-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(3-trifluoromethoxy-benzylsulfanyl)-4 - -[1 ,2,4]triazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(2-methoxy-phenyl)-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(2-Chloro-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazole;
4-[4-Ethyl-5-(4-methoxy-phenyl)-4/-/-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4H-
[1 ,2,4]triazole;
3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4 - -[1 ,2,4]triazole; 3-(4-Bromo-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4 -/-[1 ,2,4]triazole;
4-{4-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-
[1 ,2,3]thiadiazole;
3-Cyclohexylmethylsulfanyl-4-ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methoxy-phenyl)-5-(4-trifluoromethyl-benzylsulfanyl)-4r- -[1 ,2,4]triazole; 4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazole;
4-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4 -/-[1 ,2,4]triazole;
3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5-(4-methoxy-phenyl)-4 - -[1 ,2,4]triazole; 4-Ethyl-3-(4-methoxy-phenyl)-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole;
N-{4-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide;
4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-(4-methoxy-phenyl)-4ry-[1 ,2,4]triazole;
4-Ethyl-3-(4-methoxy-phenyl)-5-(2-nitro-benzylsulfanyl)-4/-/-[1 ,2,4]triazole;
4-(4-Ethyl-5-pyridin-4-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile; 4-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
4-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4/-/-[1 ,2,4]triazol-3-yl]-pyridine;
4-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
4-(4-Ethyl-5-pyridin-4-yl-4 - -[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
4-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4 -/-[1 ,2,4]triazol-3-yl]-pyridine; 4-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4 -/-[1 ,2,4]triazol-3-yl]-pyridine;
4-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[5-(2-Chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
4-(4-Ethyl-5-pyridin-3-yl-4ry-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
3-[5-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine; 3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine; 3-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(4-[1 ,2,3]thiadiazol-4-yl-benzylsulfanyl)-4H-[1 ,2,4jtriazol-3-yl]-pyridine;
3-[4-Ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4 - -[1 ,2,4]triazol-3-yl]-pyridine;
3-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4f -[1 ,2,4]triazol-3-yl]-pyridine; 3-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4 -/-[1 ,2,4]triazol-3-yl]-pyridine;
3-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-pyridine;
3-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4 - -[1 ,2,4]triazol-3-ylj-pyridine;
3-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
4-(4-Ethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser; 3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4 - -[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4W-[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4 -/-[1 ,2,4]triazol-3-yl]-pyridine;
N-[4-(4-Ethyl-5-pyridin-3-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenyl]-acetamide; 3-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4/-/-[1 ,2,4]triazol-3-yl]-pyridine;
3-(2-Chloro-benzylsulfanyl)-5-(4-chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazole; 4-[5-(4-Chloro-phenyl)-4-ethyl-4 - -[1 ,2,4]triazol-3-ylsulfanylmethylj-benzonitrile;
3-(4-Chloro-phenyl)-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-{4-[5-(4-Chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-
[1 ,2,3]thiadiazole;
3-(4-Chloro-phenyl)-4-ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4 -/-[1 ,2,4]triazole; 3-(4-Chloro-phenyl)-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-[5-(4-Chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
3-(4-Chloro-phenyl)-5-(2,6-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-(4-Benzyloxy-benzylsulfanyl)-5-(4-chloro-phenyl)-4-ethyl-4 - -[1 ,2,4]triazole;
3-(4-Chloro-phenyl)-4-ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(4-Chloro-phenyl)-4-ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4 -/-[1 ,2,4]triazole;
N-{4-[5-(4-Chloro-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide;
3-(4-Chloro-phenyl)-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(4-Chloro-phenyl)-5-(2,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
5-[5-(2-Chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole; 4-[4-Ethyl-5-(4-phenyl-[1 ,2,3]thiadiazol-5-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile; 5-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1,2,3]thiadiazole;
5-[4-Ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-
[1 ,2,3]thiadiazole;
5-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole; 5-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-
[1 ,2,3]thiadiazole;
5-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-4-phenyl-[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4/-/-[1 ,2,4]triazol-3-yl]-4-phenyl-
[1 ,2,3]thiadiazole; 5-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole;
5-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4 - -[1 ,2,4]triazol-3-yl]-4-phenyl-
[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole; 5-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-phenyl-[1 ,2,3]thiadiazole;
4-{5-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl}- benzonitrile;
3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4- ethyl-4H-[1 ,2,4]triazole; 3-(3,4-Dichloro-benzylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-
[1 ,2,4]triazole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4 - -
[1 ,2,4]triazole;
3-(3,5-Dimethoxy-benzylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4 - - [1 ,2,4]triazole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-Benzylsulfanyl-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-[1 ,2,4]triazole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H- [1 ,2,4]triazole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-{5-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl}-benzoic acid methyl etser;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(4-nitro-benzylsulfanyl)-4 -/-[1 ,2,4]triazole; 3-(4-Benzyloxy-benzylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-
[1 ,2,4]triazole;
N-(4-{5-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl}- phenyl)-acetamide; 3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-[4-(2,5-Dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(2,4-Dichloro-benzylsulfanyl)-5-[4-(2,5-dimethyl-pyrrol-1-yl)-phenyl]-4-ethyl-4H-
[1 ,2,4]triazole;
3-Benzo[b]thiophen-2-yl-5-(2-chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4 - -[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
3-Benzo[b]thiophen-2-yl-5-(6-chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4 -/- [1 ,2,4]triazole;
3-Benzo[b]thiophen-2-yl-5-(4-bromo-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-[4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4/-/-[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenylj-
[1 ,2,3]thiadiazole;
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole; 4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-Benzo[b]thiophen-2-yl-5-(4-benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4/-/-[1 ,2,4]triazole; N-[4-(5-Benzo[b]thiophen-2-yl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenylj- acetamide;
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4 -/-[1 ,2,4]triazole;
3-Benzo[b]thiophen-2-yl-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(2-Chloro-benzylsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4 -/- [1 ,2,4]triazole;
3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H- pyrazol-4-yl)-4H-[1 ,2,4]triazole;
4-{4-[4-Ethyl-5-(1 -phenyl-5-trifluoromethyl-1 H-pyrazol-4-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethyl]-phenyl}-[1 ,2,3]thiadiazole; 4-Ethyl-3-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-5-(4-trifluoromethoxy-benzylsulfanyl)-
4H-[1 ,2,4]triazole;
3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H-
[1 ,2,4]triazole; 3-Benzylsulfanyl-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1 -/-pyrazol-4-yl)-
4H-[1 ,2,4]triazole;
4-Ethyl-3-(3-nitro-benzylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4 -/-
[1 ,2,4jtriazole; 4-[4-Ethyl-5-(1-phenyl-5-trifluoromethyl-1 H-pyrazol-4-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- benzoic acid methyl etser;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4 - -
[1 ,2,4]triazole;
3-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H- [1 ,2,4]triazole;
4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4 - -
[1 ,2,4]triazole;
N-{4-[4-Ethyl-5-(1 -phenyl-5-trifluoromethyl-1 H-pyrazol-4-yl)-4H-[1 ,2,4]triazol-3- ylsulfanylmethyl]-phenyl}-acetamide; 4-Ethyl-3-(5-methyl-2-nitro-benzylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H-
[1 ,2,4]triazole;
4-Ethyl-3-(2-nitro-benzylsulfanyl)-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H-
[1 ,2,4]triazole;
3-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-4H- [1 ,2,4]triazole;
3-(2-Chloro-benzylsulfanyl)-5-(3-chloro-4-methyl-thiophen-2-yl)-4-ethyl-4H-[1 ,2,4]triazole;
4-[5-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-4r/-[1 ,2,4]triazol-3-ylsulfanylmethylj- benzonitrile;
3-(3-Chloro-4-methyl-thiophen-2-yl)-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole; 4-{4-[5-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- phenyl}-[1 ,2,3]thiadiazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-5-cyclohexylmethylsulfanyl-4-ethyl-4H-[1 ,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-
[1 ,2,4jtriazole; 3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-[5-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-4 - -[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
3-(3-Chloro-4-methyl-thiophen-2-yl)-5-(2,6-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4jtriazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-
[1 ,2,4]triazole; 3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-
[1 ,2,4]triazole;
3-(3-Chloro-4-methyl-thiophen-2-yl)-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-(4-Ethyl-5-pyridin-2-yl-4r -[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
2-[5-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4ry-[1 ,2,4]triazol-3-yl]-pyridine 2-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(4-[1 ,2,3]thiadiazol-4-yl-benzylsulfanyl)-4ry-[1 ,2,4]triazol-3-yl]-pyridine;
2-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4 -/-[1 ,2,4]triazol-3-yl]-pyridine; 2-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
4-(4-Ethyl-5-pyridin-2-yl-4 -/-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzoic acid methyl etser;
2-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4 - -[1 ,2,4]triazol-3-yl]-pyridine; 2-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4 -/-[1 ,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4 - -[1 ,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
2-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-pyridine;
3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4 - -[1 ,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine; 3-[4-Ethyl-5-(4-[1 ,2,3]thiadiazol-4-yl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine;
3-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-2-methylsulfanyl-pyridine;
3-[4-Ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4 -/-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine; 3-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine; 3-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-2-methylsulfanyl-pyridine;
3-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4/-/-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine; 4-[4-Ethyl-5-(2-methylsulfanyl-pyridin-3-yl)-4 - -[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4/-/-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine; 3-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl- pyridine;
N-{4-[4-Ethyl-5-(2-methylsulfanyl-pyridin-3-yl)-4H-[1 ,2,4jtriazol-3-ylsulfanylmethyl]-phenyl}- acetamide;
3-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4 - -[1 ,2,4]triazol-3-ylj-2-methylsulfanyl-pyridine; 3-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-2-methylsulfanyl-pyridine;
3-(2-Chloro-benzylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-[4-Ethyl-5-(5-methyl-thiophen-2-yl)-4 -/-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-
[1 ,2,4]triazole; 3-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-{4-[4-Methyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-
[1 ,2,3]thiadiazole;
3-Cyclohexylmethylsulfanyl-4-ethyl-5-(5-methyl-thiophen-2-yl)-4ry-[1 ,2,4]triazole;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(4-trifluoromethyl-benzylsulfanyl)-4 -/-[1 ,2,4]triazole;
3-Benzylsulfanyl-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methanesulfonyl-benzylsulfanyl)-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole; 4-[4-Ethyl-5-(5-methyl-thiophen-2-yl)-4/- -[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(4-nitro-benzylsulfanyl)-4 - -[1 ,2,4]triazole;
3-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(4-methyl-benzylsulfanyl)-5-(5-methyl-thiophen-2-yl)-4r -[1 ,2,4]triazole; N-{4-[4-Ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- acetamide;
4-Ethyl-3-(4-methoxy-benzylsulfanyl)-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-Ethyl-3-(5-methyl-thiophen-2-yl)-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1 ,2,4]triazole;
4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-(5-Chloro-thiophen-2-yl)-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-(4-Bromo-benzylsulfanyl)-5-(5-chloro-thiophen-2-yl)-4-ethyl-4 -/-[1 ,2,4]triazole;
4-{4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}- [1 ,2,3]thiadiazole;
3-(5-Chloro-thiophen-2-yl)-5-cyclohexylmethylsulfanyl-4-ethyl-4H-[1 ,2,4]triazole;
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4r- -[1 ,2,4]triazole;
3-(5-Chloro-thiophen-2-yl)-5-(3,5-dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4 -/-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
3-(5-Chloro-thiophen-2-yl)-5-(2,6-dichloro-benzylsulfanyl)-4-ethyl-4 -/-[1 ,2,4]triazole;
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(4-methyl-benzylsulfanyl)-4 -/-[1 ,2,4]triazole; 3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole;
N-{4-[5-(5-Chloro-thiophen-2-yl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj-phenyl}- acetamide;
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(5-Chloro-thiophen-2-yl)-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(5-Chloro-thiophen-2-yl)-5-(2,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-[4-Ethyl-5-(1ry-indol-3-ylmethyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
3-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4r/-[1 ,2,4]triazol-3-ylmethyl]-1H-indole;
3-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl]-1H-indole; 3-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethylj-1 H-indole;
3-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-1H-indole;
3-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-1H-indole;
3-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl]-1ry-indole;
3-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl]-1 - -indole; 3-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-1 H-indole; N-{4-[4-Ethyl-5-(1H-indol-3-ylmethyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide;
3-[4-Ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-1H-indole;
3-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-1H-indole;
3-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-ylmethyl]-1H-indole; 3-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylmethyl]-1 H-indole;
2-[5-(6-Chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[4-Ethyl-5-(4-[1 ,2,3]thiadiazol-4-yl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-phenol;
2-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1,2,4]triazol-3-yl]-phenol; 2-[4-Ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-phenol;
2-[4-Ethyl-5-(4-methanesulfonyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
4-[4-Ethyl-5-(2-hydroxy-phenyl)-4H-[1 ,2,4jtriazol-3-ylsulfanylmethyl]-benzoic acid methyl et- ser;
2-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[5-(2,6-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol; N-{4-[4-Ethyl-5-(2-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-phenyl}-acetamide;
2-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[4-Ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-phenol;
5-[5-(3,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-methyl-[1 ,2,3]thiadiazole; 5-[5-(4-Bromo-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-methyl-[1 ,2,33thiadiazole;
5-(5-Cyclohexylmethylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-4-methyl-[1 ,2,3]thiadiazole;
5-[5-(3,5-Dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4jtriazol-3-yl]-4-methyl-[1 ,2,3]thiadiazole;
5-(5-Benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazol-3-yl)-4-methyl-[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-methyl-[1 ,2,3]thiadiazole; 4-[4-Ethyl-5-(4-methyl-[1 ,2,3]thiadiazol-5-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzoic acid methyl etser;
5-[4-Ethyl-5-(4-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-methyl-[1 ,2,3]thiadiazole;
5-[5-(4-Benzyloxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-methyl-[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1,2,4]triazol-3-yl]-4-methyl-[1,2,3]thiadiazole; 5-[4-Ethyl-5-(3-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-methyl-
[1 ,2,3]thiadiazole;
5-[4-Ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-4-methyl-
[1 ,2,3]thiadiazole; 5-[5-(2,4-Dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazol-3-yl]-4-methyl-[1 ,2,3jthiadiazole;
4-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
3-Benzyl-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-[4-(5-Benzyl-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-phenyl]-[1 ,2,3]thiadiazole;
3-Benzyl-5-(3,5-dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole; 3-Benzyl-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-Benzyl-5-benzylsulfanyl-4-ethyl-4H-[1 ,2,4]triazole;
3-Benzyl-5-(2,6-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-Benzyl-4-ethyl-5-(4-methyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-Benzyl-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-Benzyl-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-Benzyl-4-ethyl-5-(2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-Benzyl-5-(2,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-(2-Bromo-phenyl)-5-(2-chloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
4-[5-(2-Bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile; 3-(2-Bromo-phenyl)-5-(6-chloro-benzo[1 ,3]dioxol-5-ylmethylsulfanyl)-4-ethyl-4H-
[1 ,2,4]triazole;
3-(2-Bromo-phenyl)-5-(3,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-(2-Bromo-phenyl)-5-cyclohexylmethylsulfanyl-4-ethyl-4H-[1 ,2,4jtriazole;
3-(2-Bromo-phenyl)-4-ethyl-5-(4-trifluoromethoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(2-Bromo-phenyl)-5-(3,5-dimethoxy-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-(2-Bromo-phenyl)-4-ethyl-5-(4-trifluoromethyl-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(2-Bromo-phenyl)-4-ethyl-5-(3-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(4-Benzyloxy-benzylsulfanyl)-5-(2-bromo-phenyl)-4-ethyl-4H-[1 ,2,4]triazole;
3-(2-Bromo-phenyl)-4-ethyl-5-(4-methoxy-benzylsulfanyl)-4H-[1 ,2,4]triazole; 3-(2-Bromo-phenyl)-4-ethyl-5-(5-methyl-2-nitro-benzylsulfanyl)-4H-[1 ,2,4]triazole;
3-(2-Bromo-phenyl)-5-(2,4-dichloro-benzylsulfanyl)-4-ethyl-4H-[1 ,2,4]triazole;
2-[4-(3-Methoxy-propyl)-5-(1-methyl-piperidin-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- benzonitrile;
2-[4-(3-Methoxy-propyl)-5-(1-methyl-piperidin-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- pyridine; 2-[5-(2-Methoxy-ethylsulfanyl)-4-(3-methoxy-propyl)-4H-[1 ,2,4]triazol-3-yl]-1 -methyl- piperidine;
2-[4-(2-Methoxy-ethyl)-5-(1-methyl-piperidin-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile; 2-[4-(2-Methoxy-ethyl)-5-(1 -methyl-piperidin-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- pyridine;
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-1-methyl-piperidine;
2-[4-Cyclopropyl-5-(1-methyl-piperidin-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-Cyclopropyl-5-(1-methyl-piperidin-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-pyridine; 2-[4-Cyclopropyl-5-(2-methoxy-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-1 -methyl-piperidine;
2-[5-(1-Methyl-piperidin-2-yl)-4-(2-piperidin-1-yl-ethyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- benzonitrile;
2-[5-(1-Methyl-piperidin-2-yl)-4-(2-piperidin-1-yl-ethyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- pyridine; 2-[4-Cyclopropylmethyl-5-(1 -methyl-piperidin-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile;
2-[4-Cyclopropylmethyl-5-(1-methyl-piperidin-2-yl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- pyridine;
2-[4-Cyclopropylmethyl-5-(2-methoxy-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-1-methyl- piperidine;
2-[5-(2-Hydroxy-phenyl)-4-(3-methoxy-propyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile;
2-[4-(3-Methoxy-propyl)-5-(pyridin-2-ylmethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[5-(2-Methoxy-ethylsulfanyl)-4-(3-methoxy-propyl)-4H-[1 ,2,4]triazol-3-yl]-phenol; 2-[5-(2-Hydroxy-phenyl)-4-(2-methoxy-ethyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-(2-Methoxy-ethyl)-5-(pyridin-2-ylmethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy-ethylsulfanyl)-4H-[1 ,2,4jtriazol-3-yl]-phenol;
2-[4-Cyclopropyl-5-(2-hydroxy-phenyl)-4H-[1 ,2,4jtriazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-Cyclopropyl-5-(pyridin-2-ylmethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol; 2-[4-Cyclopropyl-5-(2-methoxy-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[5-(2-Hydroxy-phenyl)-4-(2-piperidin-1-yl-ethyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile;
2-[4-(2-Piperidin-1-yl-ethyl)-5-(pyridin-2-ylmethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[5-(2-Methoxy-ethylsulfanyl)-4-(2-piperidin-1-yl-ethyl)-4H-[1 ,2,4]triazol-3-yl]-phenol; 2-[4-Cyclopropylmethyl-5-(2-hydroxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile;
2-[4-Cyclopropylmethyl-5-(pyridin-2-ylmethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol;
2-[4-Cyclopropylmethyl-5-(2-methoxy-ethylsulfanyl)-4H-[1 ,2,4]triazol-3-yl]-phenol; 2-[5-(2-Methoxy-phenyl)-4-(3-methoxy-propyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- benzonitrile;
2-[5-(2-Methoxy-phenyl)-4-(3-methoxy-propyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj-pyridine;
3-(2-Methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-4-(3-methoxy-propyl)-4H-[1 ,2,4]triazole;
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- benzonitrile;
2-[4-(2-Methoxy-ethyl)-5-(2-methoxy-phenyl)-4H-[1 ,2,4jtriazol-3-ylsulfanylmethyl]-pyridine;
4-(2-Methoxy-ethyl)-3-(2-methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazole;
2-[4-Cyclopropyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-Cyclopropyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-pyridine; 4-Cyclopropyl-3-(2-methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazole;
2-[5-(2-Methoxy-phenyl)-4-(2-piperidin-1-yl-ethyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- benzonitrile;
2-[5-(2-Methoxy-phenyl)-4-(2-piperidin-1-yl-ethyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]- pyridine; 1-{2-[3-(2-Methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-[1 ,2,4]triazol-4-yl]-ethyl}-piperidine;
2-[4-Cyclopropylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj- benzonitrile;
2-[4-Cyclopropylmethyl-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-pyridine;
4-Cyclopropylmethyl-3-(2-methoxy-ethylsulfanyl)-5-(2-methoxy-phenyl)-4H-[1 ,2,4]triazole; 2-[4-(3-Methoxy-propyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-(3-Methoxy-propyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-pyridine;
3-(2-Methoxy-ethylsulfanyi)-4-(3-methoxy-propyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
2-[4-(2-Methoxy-ethyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile;
2-[4-(2-Methoxy-ethyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethylj-pyridine; 4-(2-Methoxy-ethyl)-3-(2-methoxy-ethylsulfanyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
2-(4-Cyclopropyl-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile;
2-(4-Cyclopropyl-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-pyridine;
4-Cyclopropyl-3-(2-methoxy-ethylsulfanyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazole;
2-[4-(2-Piperidin-1-yl-ethyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-benzonitrile; 2-[4-(2-Piperidin-1-yl-ethyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl]-pyridine; 1-{2-[3-(2-Methoxy-ethylsulfanyl)-5-thiophen-2-yl-[1 ,2,4]triazol-4-yl]-ethyl}-piperidine; 2-(4-Cyclopropylmethyl-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-benzonitrile; 2-(4-Cyclopropylmethyl-5-thiophen-2-yl-4H-[1 ,2,4]triazol-3-ylsulfanylmethyl)-pyridine; 4-Cyclopropylmethyl-3-(2-methoxy-ethylsulfanyl)-5-thiophen-2-yl-4H-[1 ,2,4]triazole; 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.
37. A compound according to claim 35 or 36, which is an agent useful for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases wherein a modula- tion or an inhibition of the activity of 11 βHSDl is beneficial.
38. A compound according to claim 35 or 36, 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.
39. A compound according to claim 35 or 36, 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.
40. A compound according to claim 35 or 36, which is an agent useful for the treatment, prevention and/or prophylaxis of type 2 diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG).
41. A compound according to claim 35 or 36, which is an agent useful for the delaying or prevention of the progression from IGT into type 2 diabetes.
42. A compound according to claim 35 or 36, which is an agent useful for delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
43. A compound according to claim 35 or 36, which is an agent useful for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
44. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to claim 35 or 36 together with one ore more pharmaceutically acceptable carriers or excipients.
45. The pharmaceutical composition according to claim 44 which is for oral, nasal, buccal, transdermal, pulmonal or parenteral administration.
46. The pharmaceutical composition according to claim 44 or 45 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 claim 35 or 36.
47. A use of a compound according to claim 35 or 36, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of any conditions, disorders and diseases wherein a modulation or an inhibition of the activity of 11 βHSDl is beneficial.
48. A use of a compound according to claim 35 or 36, 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.
49. A use of a compound according to claim 35 or 36, 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.
50. A use of a compound according to claim 35 or 36, 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).
51. A use of a compound according to claim 35 or 36, for the preparation of a pharmaceuti- cal composition for the delaying or prevention of the progression from IGT to type 2 diabetes.
52. A use of a compound according to claim 35 or 36, for the preparation of a pharmaceutical composition for the delaying or prevention of the progression of the metabolic syndrome into type 2 diabetes.
53. A use of a compound according to claim 35 or 36, for the preparation of a pharmaceutical composition for the treatment, prevention and/or prophylaxis of adverse effects of glucocorticoid receptor agonist treatment or therapy.
54. 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 11 βHSDl is beneficial, the method comprising administering to a subject in need thereof an effective amount of a compound according to the invention.
55. The method according to claim 54 wherein the conditions, disorders or diseases are selected from the group consisting of the metabolic syndrome, insulin resistance, dyslipidemia, hypertension and obesity.
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