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  • 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
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • 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
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  • A61P5/00—Drugs for disorders of the endocrine system
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  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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  • 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
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  • 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
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  • 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
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • 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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  • 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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  • 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
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  • 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
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  • C07D—HETEROCYCLIC COMPOUNDS
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  • 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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  • 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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• 2004
  • 2004-04-06 EP EP04725885A patent/EP1615637A1/de not_active Withdrawn
  • 2004-04-06 JP JP2006504352A patent/JP2006522745A/ja active Pending
  • 2004-04-06 WO PCT/DK2004/000249 patent/WO2004089367A1/en not_active Application Discontinuation

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