Classifications

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  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/22—Bridged ring systems
  • C07D221/26—Benzomorphans
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • 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
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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
  • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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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
  • C07D401/14—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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  • 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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  • 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
  • C07D405/06—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 carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • 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
  • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/08—Bridged systems

Definitions

• the present invention relates to compounds derived from the following chemical scaffold which is structurally defined by the formula I
• the invention further relates to pharmaceutical compositions containing a compound of formula I according to the invention as well as the use of a compound according to the invention for preparing a pharmaceutical composition for the treatment of metabolic disorders.
• the invention relates to processes for preparing a pharmaceutical composition as well as a compound according to the invention.
• HSD hydroxysteroid dehydrogenase
• R 1 , R 2 , Q', and Z are as described therein.
• R 1 , R 2 , R 3 , and R 5 are as defined therein and R 4 is 2-methoxymethylfuran-3-yl or 3- methoxymethylfuran-2-yl, are described as intermediates for the preparation of the corresponding N-furanylmethyl-benzomorphanes.
• R, R 1 , R 2 , R 3 , and Y are as defined therein, are described as intermediates for the preparation of benzomorphanes that may be useful as analgesics and antitussives.
• R', R 1 , and Z are principally described as possible intermediates for the preparation of benzomorphanes that may have valuable therapeutic properties.
• R 1 , R 2 , R 4 , and Z are described as principle intermediates for the preparation of benzomorphanes that may have analgetic activity.
• R, R 1 , R 2 , X, and Y are as defined therein, that may be useful as anti-inflammatory and analgesic agents, are described.
• the aim of the present invention is to find new benzomorphanes or related compounds, particularly those which are active with regard to the enzyme 1 1 ⁇ -hydroxysteroid dehydrogenase (HSD) 1.
• a further aim of the present invention is to discover benzomorphanes or related compounds which have an inhibitory effect on the enzyme 1 1 ⁇ - hydroxysteroid dehydrogenase (HSD) 1 in vitro and/or in vivo and possess suitable pharmacological and pharmacokinetic properties to use them as medicaments.
• a further aim of the present invention is to provide new pharmaceutical compositions which are suitable for the prevention and/or treatment of metabolic disorders, particularly diabetes and dyslipidemia.
• Other aims of the present invention will become apparent to the skilled man directly from the foregoing and following remarks.
• R 1 denotes aryl or heteroaryl
• aryl is meant phenyl or naphthyl
• heteroaryl by heteroaryl is meant pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, or
• indolyl benzofuranyl, benzothiophenyl, quinolinyl, or isoquinolinyl, wherein 1 to 3 CH are replaced by N, or
• aryl or heteroaryl rings are optionally substituted with one R 4 , one to four identical or different R 5 , and one R 6 , and all heteroaryl rings are attached to the carbonyl group via a carbon atom,
• a pyrrolo, furo, thieno, pyridazino, pyrimido or pyrazino ring optionally substituted with two substituents selected from R 7 , R 8 and R 9 ,
• a 1 ,2,3-triazolo ring optionally substituted with d- 4 -alkyl or with phenyl that is optionally additionally substituted with one to three R 10 ,
• R 4 denotes fluorine, chlorine, bromine, iodine
• aminosulfonyl d- 3 -alkyl-aminosulfonyl, di-(Ci- 3 -alkyl)-aminosulfonyl, pyrrolidin-1 -yl- sulfonyl, piperidin-1 -yl-sulfonyl, morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl, 4-(Ci -3 - alkyl)-piperazin-1 -yl-sulfonyl,
• azetidin-1-yl, pyrrolidin-1-yl and piperidin-1-yl moieties are optionally substituted with one or two groups selected from methyl, ethyl, methoxymethyl, hydroxy or methoxy, and,
• (het)aryl is phenyl, naphthyl, pyrrolyl, furanyl, thienyl, tetrazolyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, or
• R 5 and R 6 which may be identical or different, denote halogen, d- 3 -alkyl, C 2 - 3 -alkynyl, trifluormethyl, hydroxy, Ci -3 -alkyloxy, cyano, or R 5 together with R 6 , if bound to adjacent carbon atoms, may additionally be methylenedioxy, difluoromethylenedioxy, ethylenedioxy, C 3-5 -alkylene, or
• R 5 together with R 6 may form together with the carbon atoms to which they are attached, a pyrazolo, imidazo, oxazolo, thiazolo, isoxazolo, or isothiazolo ring, that optionally are substituted with d-3-alkyl, trifluoromethyl, amino, Ci -3 - alkylamino, di-(Ci -3 -alkyl)amino, hydroxy, Ci -3 -alkyloxy,
• R 7 denotes fluorine, chlorine, bromine, iodine
• Ci -4 -alkyloxy-Ci -4 -alkyloxy Ci -4 -alkylsulfanyl-Ci -4 -alkyloxy, Ci -4 - alkylsulfinyl-Ci -4 -alkyloxy, Ci -4 -alkylsulfonyl-Ci -4 -alkyloxy, amino-Ci -4 -alkyloxy, Ci -4 - alkylamino-Ci -4 -alkyloxy, di-(Ci -4 -alkyl)-amino-Ci -4 -alkyloxy, pyrrolidin-1 -yl-Ci -4 -alkyloxy,
• aminosulfonyl d- 4 -alkyl-aminosulfonyl, di-(Ci. 4 -alkyl)-aminosulfonyl, pyrrolidin-1-yl- sulfonyl, piperidin-1-yl-sulfonyl, morpholin-4-yl-sulfonyl, piperazin-1-yl-sulfonyl, 4-(Ci -4 - alkyl)-piperazin-1 -yl-sulfonyl,
• R 8 and R 9 which may be identical or different, are halogen, d- 3 -alkyl, trifluormethyl, hydroxy, d- 3 -alkyloxy, cyano, or R 8 together with R 9 , if bound to adjacent carbon atoms, may additionally be methylenedioxy, difluoromethylenedioxy, ethylenedioxy, C 3-5 -alkylene, or
• R 8 together with R 9 may also form together with the carbon atoms to which they are attached, a benzo, pyrido, pyrimido, pyrazino, pyridazino, pyrazolo, imidazo, triazolo, oxazolo, thiazolo, isoxazolo, or isothiazolo ring, that all optionally are substituted with one L and/or one or two substituents independently selected from halogen, Ci -3 -alkyl, trifluoromethyl, amino, Ci -3 -alkylamino, di-(Ci -3 -alkyl)amino, hydroxy, Ci -3 - alkyloxy,
• L is L 1 or L 2 and L 1 denotes halogen, Ci -6 -alkyl, hydroxy-Ci -4 -alkyl, Ci -3 -alkyloxy-Ci -3 -alkyl, C 3- 6 -cycloalkyl, hydroxy-C 4-6 -cycloalkyl, d-s-alkyloxy-Cs-e-cycloalkyl, azetidinyl, 1-(Ci -3 -alkyl)- azetidinyl, 1-(Ci -3 -alkylcarbonyl)-azetidinyl, pyrrolidinyl, 1-(Ci -3 -alkyl)-pyrrolidinyl, 1 -(Ci -3 - alkylcarbonyl)-pyrrolidinyl, piperidinyl, 1-(Ci -3 -alkyl)-piperidinyl, 1-(Ci -3 -alkylcarbonyl)-
• L 2 denotes phenyl
• each of the groups mentioned hereinbefore under L 2 is optionally substituted with one or two groups independently selected from fluorine, chlorine, Ci -3 -alkyl, difluoromethyl, trifluoromethyl, cyano, amino, acetylamino, methylsulfonylamino, carboxy, Ci -4 -alkyl- oxycarbonyl, aminocarbonyl, Ci -3 -alkylaminocarbonyl, di-(Ci -3 -alkyl)-aminocarbonyl, hydroxy, Ci -3 -alkyloxy, difluoromethoxy, and trifluoromethoxy,
• R 10 is R 10' or R 10" and R 10 denotes halogen, d- 3 -alkyl, difluoromethyl, trifluoromethyl, cyano, nitro, amino, acetylamino, methylsulfonylamino, carboxy, Ci -4 -alkyloxycarbonyl, aminocarbonyl, Ci- 3 -alkylaminocarbonyl, di-(Ci- 3 -alkyl)-aminocarbonyl, aminosulfonyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, hydroxy, C- ⁇ -3-alkyloxy, difluoromethoxy, or trifluoromethoxy,
• R 10 denotes pyrrolyl, furanyl, thienyl, pyridyl, wherein in any of these groups 1 or 2 CH optionally are replaced by N atoms, or
• indolyl benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, wherein in any of these groups 1 to 3 CH optionally are replaced by N atoms, or
• any of the groups mentioned hereinbefore under R 10" optionally are substituted independently with one or two groups selected from halogen, d- 3 -alkyl, difluoromethyl, trifluoromethyl, cyano, nitro, amino, acetylamino, methylsulfonylamino, carboxy, Ci -4 -alkyl- oxycarbonyl, aminocarbonyl, Ci -3 -alkylaminocarbonyl, di-(Ci -3 -alkyl)-aminocarbonyl, aminosulfonyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, hydroxy, Ci -3 -alkyloxy, difluoromethoxy, and trifluoromethoxy,
• X denotes CH or N
• n, o denote 0, 1 or 2
• R 11 denotes fluorine, Ci -4 -alkyl, (het)aryl, hydroxy, Ci -4 -alkyloxy, cyano, carboxy, Ci -4 -alkyloxycarbonyl, aminocarbonyl, Ci -4 -alkylamino-carbonyl, di-(Ci -4 -alkyl)- aminocarbonyl, hydroxy-Ci -4 -alkyl or Ci -3 -alkyloxy-Ci -4 -alkyl, wherein (het)aryl is as described hereinbefore,
• R 12 denotes fluorine or Ci -4 -alkyl
• R 13 and R 14 which may be identical or different, denote Ci -4 -alkyl
• alkyl or alkylene moieties are branched or unbranched
• R is any substituent
• M 1 is d- 4 -alkyl
• M 2 and M 3 independently of each other are hydrogen or Ci -4 -alkyl
• M 4 is hydrogen or hydroxy
• M 5 is hydrogen or hydroxy
• M 6 denotes phenyl, which may be substituted with one to three substituents selected from the group consisting of halogen, hydroxy, alkyl, nitro, cyano, trifluoromethyl, methoxy, naphthyl or biphenylyl, which may be substituted with one to three substituents selected from the group consisting of halogen, alkyl, nitro, cyano, trifluoromethyl, methoxy, pyridyl, which may be substituted with halogen, alkyl, nitro, cyano, trifluoromethyl, methoxy, and NR'R", where R' and R" are each independently hydrogen or alkyl, or form together with the nitrogen atom a 3- to 7-membered alicyclic ring optionally having a double bond, quinolinyl, isoquinolinyl, 4-cyclohexylphenyl, 4-oxo-4H-chromenyl, indolyl, benzothiophenyl,
• M 1 is d- 4 -alkyl
• M 2 is hydrogen or Ci -4 -alkyl
• M 6 denotes 2-acetoxy-phenyl, 2-ethylamino-phenyl, 2-phenylamino-phenyl, 2-(2,3-dimethyl- phenylamino)-phenyl, 2-(3-methylsulfanylphenylamino)-phenyl, or pyridyl
• R is hydrogen, Ci -6 -alkyl
• M 1 is hydrogen or d- 4 -alkyl
• M 4 is hydrogen or hydroxy
• M 6 is phenyl, methylphenyl, or methoxyphenyl
• the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibitory effect on the enzyme 11 ⁇ -hydroxysteroid dehydrogenase (HSD) 1.
• HSD ⁇ -hydroxysteroid dehydrogenase
• the first aspect of the invention also relates to the physiologically acceptable salts of the compounds of general formula I with inorganic or organic acids, except for the salts of the compounds comprised by the formulae 11.1 to II.8.
• this invention relates to pharmaceutical compositions, containing at least one compound of general formula I, except for the compounds comprised by the formulae 11.1 to II.8, or a physiologically acceptable salt according to the invention, optionally together with one or more inert carriers and/or diluents.
• this invention relates to the compounds according to general formula I, including the compounds comprised by the formulae 11.1 to II.8, or the physiologically acceptable salts thereof, for treatment or prevention of diseases or conditions which can be influenced by inhibiting the enzyme 1 1 ⁇ -hydroxysteroid dehydrogenase (HSD) 1 , such as metabolic disorders.
• HSD ⁇ -hydroxysteroid dehydrogenase
• this invention relates to the use of at least one compound according to general formula I, including the compounds comprised by the formulae 11.1 to II.8, or one of the physiologically acceptable salts thereof for preparing a pharmaceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be influenced by inhibiting the enzyme 1 1 ⁇ -hydroxysteroid dehydrogenase (HSD) 1 , such as metabolic disorders.
• HSD ⁇ -hydroxysteroid dehydrogenase
• the invention relates to a process for preparing a pharmaceutical composition according to the invention, characterized in that a compound of general formula I, except for the compounds comprised by the formulae 11.1 to II.8, or one of the physiologically acceptable salts thereof is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
• the present invention relates to a process for preparing the compounds of general formula I, except for the compounds comprised by the formulae 11.1 to II.8, characterized in that in order to prepare compounds of general formula I which are defined as hereinbefore and hereinafter,
• R 1 -CO-Y is reacted with R 1 -CO-Y, optionally prepared in situ from the corresponding carboxylic acid, wherein
• Y is a leaving group and in particular
• alkyl, alkenyl, and alkynyl groups mentioned in the definition of the above groups may be mono- or polysubstituted with fluorine, chlorine, Ci -3 -alkyl, or Ci -3 -alkoxy,
• aryl groups mentioned in the definition of the above groups denote phenyl or naphthyl groups and the heteroaryl groups mentioned in the definition of the above groups, either alone or as part of another group, denote pyridinyl, pyrimidinyl, triazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, whilst both the aryl and heteroaryl groups optionally are independently mono or polysubstituted with fluorine, chlorine, bromine, Ci -3 -alkyl, Ci -3 -alkyloxy, nitro, cyano, or di-(Ci -3 -alkyl)amino groups, and R 1 is defined as hereinbefore and hereinafter,
• the present invention relates to novel compounds of formulae Ilia to INg, representing subgeneric structures of formula III, including their tautomers, their stereoisomers, and the salts thereof, which are suitable as intermediates in the synthesis of compounds of formula I, characterised by
• bicyclic substructure of formual Ilia (2-aza-bicyclo[3.3.1]non-6-ene, comprised by the core structure of formula I) is optionally substituted with one to three methyl groups and wherein A denotes an heteroarylo ring that is annelated to the polycyclic scaffold in formula Ilia via two adjacent carbon atoms of the benzo ring and wherein
• heteroarylo denotes triazolo or d-3-alkyl-triazolo or pyrido, pyrimido, pyrazino, pyridazino, each of them being optionally substituted with one L and/or one or two substituents independently selected from fluorine, chlorine, C- ⁇ -3-alkyl, trifluoromethyl, hydroxy, Ci -3 -alkyloxy, or pyrazolo, imidazo, N-d-3-alkyl-imidazo, oxazolo, thiazolo, isoxazolo, or isothiazolo, each of them being optionally substituted with one L, preferably, heteroarylo denotes triazolo or methyl-triazolo, or pyrazino optionally substituted with one L and/or one substituent selected from fluorine, methyl, and methoxy, or imidazo, N-methyl-imidazo, or oxazolo, each of them being optional
• T denotes fluorine, chlorine, hydroxy, Ci -3 -alkyl, Ci -3 -alkyloxy, preferably, fluorine, methyl, hydroxy, and methoxy,
• n denotes 0, 1 , or 2, preferably, 0 or 1 ,
• bicyclic substructure of formual INb (2-aza-bicyclo[3.3.1]non-6-ene) is optionally substituted with one to three methyl groups and wherein
• S 1 denotes fluorine, chlorine, ethyl, propyl, isopropyl, trifluoromethyl, hydroxy-Ci -3 -alkyl, cyano, carboxy, Ci -3 -alkyloxycarbonyl, aminocarbonyl, Ci -3 -alkylaminocarbonyl, di-(Ci -3 - alkyl)aminocarbonyl, Ci -3 -alkylsulfonyl,
• S 1 denotes fluorine, cyano, carboxy, Ci -3 -alkyloxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylsulfonyl,
• n denotes 0, 1 , 2, or 3, preferably, 0 or 1 ,
• bicyclic substructure of formual INc (2-aza-bicyclo[3.3.1]non-6-ene) is optionally substituted with one to three methyl groups and wherein
• S 2 denotes fluorine, Ci -3 -alkyl, amino-Ci -3 -alkyl, acetylamino-Ci -3 -alkyl, hydroxy-Ci -3 -alkyl, Ci -3 -alkylcarbonyl, cyano, carboxy, Ci -3 -alkyloxycarbonyl, aminocarbonyl, Ci -3 -alkylamino carbonyl, di-(Ci -3 -alkyl)aminocarbonyl, amino, Ci -3 -alkylcarbonylamino, Ci -3 -alkylsulfonylami no, di-(Ci -3 -alkyl)-aminosulfonyl, or phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, thiazolyl, or N-methyl-pyridin-2- onyl, each of them being
• S 2 denotes fluorine, methyl, aminomethyl, acetylaminomethyl, hydroxyethyl, methylcarbonyl, cyano, carboxy, Ci -3 -alkyloxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, amino, acetylamino, methylsulfonylamino, dimethylaminosulfonyl, or phenyl or oxadiazolyl, each of them being optionally monosubstituted with methyl,
• T and n are as defined hereinbefore;
• bicyclic substructure of formual INd (2-aza-bicyclo[3.3.1]non-6-ene) is optionally substituted with one to three methyl groups and wherein
• S 3 denotes Ci -3 -alkyl, amino-Ci -3 -alkyl, hydroxy-Ci -4 -alkyl, hydroxy-trifluromethyl-Ci -3 -alkyl,
• N-methyl-pyridin-2-onyl N-methyl-pyridazin-3-onyl, oxadiazolyl, each of them being optionally additionally substituted with methyl,
• T and n are as defined hereinbefore;
• bicyclic substructure of formual INe (2-aza-bicyclo[3.3.1]non-6-ene) is optionally substituted with one to three methyl groups and wherein
• S 4 denotes fluorine, ethyl, propyl, isopropyl, trifluoromethyl, hydroxy-Ci -3 -alkyl, cyano, carboxy, Ci -3 -alkyloxycarbonyl, aminocarbonyl, Ci -3 -alkylaminocarbonyl, di-(Ci -3 -alkyl) aminocarbonyl, nitro, amino, Ci -3 -alkylcarbonylamino, Ci -3 -alkylsulfonylamino, or phenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, oxazolyl, thiazolyl, pyrrol-1-yl, N-(Ci -3 - alkyl)-pyridin-2-onyl, each of them being optionally mono- or disubstituted with substituents independently selected from fluorine, Ci -3 -alkyl, triflu
• S 4 denotes cyano, nitro, amino, methylsulfonylamino, pyridinyl, pyrrol-1-yl,
• T and n are as defined hereinbefore;
• S 5 denotes hydrogen, Ci -4 -alkyl, preferably, hydrogen or methyl, and
• S 6 denotes hydrogen, Ci -4 -alkyl, preferably, hydrogen or methyl.
• a compound of general formula I which contains an amino, alkylamino or imino group, this may be converted by acylation or sulfonylation into a corresponding acyl or sulfonyl compound of general formula I;
• a compound of general formula I which contains an aromatic substructure, this may be derivatized with a chlorine, bromine, or iodine atom or a nitro, sulfonic acid, or acyl group to a corresponding compound of general formula I by an electrophilic substitution reaction;
• a compound of general formula I which contains an aromatic amino group, this may be transformed into a corresponding cyano, fluoro, chloro, bromo, iodo, hydroxy, mercapto, or azido compound of general formula I by diazotization and subsequent replacement of the diazo group with cyanide, fluoride, chloride, bromide, iodide, hydroxide, alkyl or hydrogen sulfide, or azide, respectively;
• a compound of general formula I which contains an aromatic chloro, bromo, iodo, trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy group, this may be converted into a corresponding aryl, alkenyl, alkynyl, or alkyl derivatized compound of general formula I by replacement of the respective group by aryl, alkenyl, alkynyl, or alkyl using a transition metal species mediated process;
• the subsequent esterification is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydro- furan, benzene/tetrahydrofuran or dioxane or particularly advantageously in the correspon- ding alcohol optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g.
• the subsequent ester formation may also be carried out by reacting a compound which contains a carboxy group with a corresponding alkyl halide.
• the subsequent acylation or sulfonylation is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane with a corresponding acyl or sulfonyl derivative optionally in the presence of a tertiary organic base or in the presence of an inorganic base or in the presence of a dehydrating agent, e.g.
• the subsequent alkylation is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g. methyl iodide, ethyl bromide, dimethylsulfate, or benzyl chloride, optionally in the presence of a tertiary organic base or in the presence of an inorganic base at temperatures between 0 and 150 0 C, preferably between 0 and 100 0 C.
• solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane with an al
• the subsequent reductive alkylation is carried out with a corresponding carbonyl compound such as e.g. formaldehyde, acetaldehyde, propionaldehyde, acetone or butyraldehyde in the presence of a complex metal hydride such as sodium borohydride, lithium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride conveniently at a pH of 6-7 and at ambient temperature or using hydrogen in the presence of a transition metal catalyst, e.g. palladium/charcoal at a hydrogen pressure of 1 to 5 bar.
• the methylation may also be carried out in the presence of formic acid as reducing agent at elevated temperature, e.g. between 60 and 120 0 C.
• the subsequent reduction of a nitro group is carried out, for example, with hydrogen and a catalyst such as palladium on carbon, platinum dioxide or Raney nickel, or using other reducing agents such as iron or zinc in the presence of an acid such as acetic acid.
• a catalyst such as palladium on carbon, platinum dioxide or Raney nickel, or using other reducing agents such as iron or zinc in the presence of an acid such as acetic acid.
• the subsequent nitrosation of an imino group followed by reduction to obtain the N-amino- imino compound is carried out, for example, with an alkyl nitrite such as isoamyl nitrite to form the N-nitroso-imino compound that is then reduced to the N-amino-imino compound using, for example, zinc in the presence of an acid such as acetic acid.
• an alkyl nitrite such as isoamyl nitrite
• the subsequent cleaving of a Ci -3 -alkyloxycarbonyl group to obtain the carboxy group is carried out, for example, by hydrolysis with an acid such as hydrochloric acid or sulfuric acid or an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide.
• an acid such as hydrochloric acid or sulfuric acid
• an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide.
• the subsequent amide formation is carried out by reacting a corresponding reactive car- boxylic acid derivative with a corresponding amine optionally in a solvent or mixture of sol- vents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, while the amine used may also serve as solvent, optionally in the presence of a tertiary organic base or in the presence of an inorganic base or with a corresponding carboxylic acid in the presence of a dehydrating agent, e.g.
• chlorine and bromine electrophiles may be e.g. N-halo- succinimide, HOCI, HOBr, te/fBuOCI, te/fBuOBr, chlorine, bromine, dibromoisocyanuric acid, pyridinium dichlorobromate, pyridinium tribromide, or sulfuryl chloride that may be used alone or in combination with an acid, e.g.
• hydrochloric acid hydrobromic acid, tetrafluoroboric acid, triflic acid, sulfuric acid, or acetic acid, or a Lewis acid, e.g. iron(lll) halide, borontri- fluoride hydrate, borontrifluoride etherate, or aluminum halide.
• Lewis acid e.g. iron(lll) halide, borontri- fluoride hydrate, borontrifluoride etherate, or aluminum halide.
• Further useful combinations may be LiBr and eerie ammonium nitrate, KCI or KBr with Oxone ® , or KBr and sodium perborate.
• Suited iodine electrophiles may be generated from iodine combined with an oxidizing agent such as nitric acid, sulfur trioxide, manganese dioxide, HIO3, hydrogen peroxide, sodi- urn periodate, peroxydisulfates, and Oxone ® .
• an oxidizing agent such as nitric acid, sulfur trioxide, manganese dioxide, HIO3, hydrogen peroxide, sodi- urn periodate, peroxydisulfates, and Oxone ® .
• Further suited iodine electrophiles may be e.g. iodine chloride, dichloroiodates, and N-iodosuccinimide. These iodine electrophiles may be used without an additive or in the presence of an acid such as e.g.
• acetic acid trifluoroacetic acid, or sulfuric acid, or a Lewis acid such as borontrifluoride hydrate, or copper salts.
• a nitro group is to be introduced appropriate nitro electrophiles may be generated from, for example, nitric acid, acetyl nitrate, eerie ammonium nitrate, sodium nitrate, N 2 O 5 , alkyl nitrate, and nitronium tetrafluoroborate.
• Some of these reagents may be used without an additive, though, several of them are better used in combination with an acid, e.g.
• the SO 3 H group may be introduced by reacting the aromatic com- pound with, for example, concentrated sulfuric acid, SO 3 , CISO 3 H, or CISO 2 NMe 2 combined with indium triflate.
• Acylating the aromatic part is conducted using an acyl electrophile that may be generated from the respective acyl halide, e.g. chloride, or acyl anhydride and a Lewis acid such as e.g.
• Preferred solvents for the electrophilic substitutions described may differ depending on the electrophile employed; in the following some more generally applicable are mentioned: methylene chloride, dichloroethane, chlorobenzene, dichlorobenzene, ether, fluorinated hydrocarbons, hexanes, quinoline, or acetonitrile.
• the temperatures preferably applied range from 0 to 180 0 C.
• a nitrous acid or nitrosonium source or equivalent such as a nitrite salt combined with an acid, e.g. sodium nitrite and hydrochloric acid, nitrosonium tetrafluoroborate, or an alkylnitrite, e.g. te/fbutylnitrite or /soamylnitrite.
• the diazotization is optionally carried out in methylene chloride, dichloroethane, dimethylformamide, N-methylpyrrolidinone, benzene, toluene, chlorobenzene, tetrahydrofuran, water, ethyl acetate, alcohol, ether, dimethoxyethane, dioxane or mixtures thereof at temperatures between -10 0 C and 100 0 C (diazotization of amino groups is detailed in, for example, Angew. Chem. Int. Ed. 1976, 15, 251 ).
• the subsequent displacement of the diazo group for a cyano group, chlorine, or bromine using cuprous cyanide, chloride, or bromide, respectively, is known as the Sand- meyer reaction (see e.g. March's Advanced Organic Chemistry, Michael B. Smith and Jerry March, John Wiley & Sons Inc., 6. Ed., New Jersey, 2007 and references quoted therein); the reaction is optionally conducted between -10 0 C and 120 0 C in one of the solvents or mixtures mentioned above.
• the replacement of the diazo group for a fluorine atom may be achieved with a tetrafluoroborate salt or acid and heating to 20 to 160 0 C; the reaction is known as the Schiemann reaction.
• Iodine may be introduced by treatment of the diazo compound with an iodide salt, e.g. sodium iodide, preferably using water or an aqueous solvent mixture at temperatures between 0 and 120 0 C.
• the diazo group is replaced for hydroxy using water or an aqueous solvent mixture at temperatures between 0 and 180 0 C.
• the reaction usually works without further additives but the addition of cuprous oxide or strong acid may be advantageous.
• Mercapto or alkylmercapto may be introduced via their corresponding disulfide salts or dialkyldisulfides at temperatures between 0 and 120 0 C; depending on the sulfur species used an inert solvent or aqueous solvent system may be preferred (see e.g. Synth. Commun. 2001 , 31, 1857 and references quoted therein).
• the subsequent replacement of an aromatic amino group by an aryl group may be carried out via the corresponding diazo compound obtainable as described above.
• the reaction with an aryl nucleophile, preferably an aryl boronic acid, boronic ester, trifluoroborate, zinc halide, or stannane is conducted in the presence of a transition metal species derived from palladi- um, nickel, rhodium, copper, or iron, preferably palladium.
• the active catalyst may be a complex of the transition metal with ligands such as e.g.
• phosphines phosphites, imdiazole car- benes, imidazolidine carbenes, dibenzylideneacetone, allyl, or nitriles, an elemental form of the transition metal such as palladium on carbon or nanoparticles, or salts such as chloride, bromide, acetate, or trifluoroacetate.
• the diazo compound is preferably employed as its tetrafluoroborate salt optionally in methylene chloride, dimethylformamide, N-methylpyrrolidinone, benzene, toluene, tetrahydrofuran, water, ethyl acetate, alcohol, ether, dimethoxyethane, dioxane, or mixtures thereof at temperatures between 10 0 C and 180 0 C, preferably between 20 0 C and 140 0 C.
• the subsequent replacement of an aromatic chloro, bromo, iodo atom or an aromatic triflu- oromethylsulfonyloxy, mesyloxy, or tosyloxy group for an aryl, alkenyl, alkynyl, or alkyl residue is preferably mediated by a transition metal species derived from palladium, nickel, rhodium, copper, or iron.
• the active catalyst may be a complex of the transition metal with ligands such as e.g. phosphines (e.g.
• trite/fbutylphosphine tricyclohexylphosphine, substi- tuted biphenyldicyclohexylphosphines, substituted biphenyldite/fbutylphosphines, triphenyl- phosphine, tritolylphosphine, trifurylphosphine, 1 ,1 '-bis(diphenylphosphino)ferrocene), phosphites, imdiazole carbenes, imidazolidine carbenes, dibenzylideneacetone, allyl, or nitriles, an elemental form of the transition metal such as palladium on carbon or nanopar- ticles of iron or palladium, or a salt such as fluoride, chloride, bromide, acetate, triflate, or trifluoroacetate.
• a salt such as fluoride, chloride, bromide, acetate, triflate, or trifluoro
• the replacement is preferably conducted with a trifluoroborate, boronic acid, or boronic ester (Suzuki or Suzuki-type reaction), zinc halide (Negishi or Negishi-type reac- tion), stannane (Stille or Stille-type reaction), silane (Hiyama or Hiyama-type reaction), magnesium halide (Kumada or Kumada-type reaction) of the aryl, alkenyl, or alkyl residue to be introduced.
• the terminal alkyne is preferably used as it is or as the zinc acetylide derivative.
• additives such as halide salts, e.g.
• Copper iodide is a preferred additive in the coupling with a terminal alkyne group (Sonogashira reaction).
• the coupling reactions are optionally conducted in methylene chloride, dimethylformamide, N-methylpyrrolidinone, benzene, toluene, tetra- hydrofuran, water, ethyl acetate, alcohol, ether, dimethylsulfoxide, dimethoxyethane, diox- ane, or mixtures thereof, though, depending on the nucleophile some of them are less or not suited at all.
• Preferred temperatures are in the range from -10 0 C to 180 0 C.
• the subsequent replacement of an aromatic chlorine, bromine, iodine atom or an aromatic trifluoromethylsulfonyloxy, mesyloxy, or tosyloxy group for a hydrogen atom is preferably mediated by a transition metal species derived from palladium, nickel, platinum, rhodium, or ruthenium.
• the active catalyst may be a complex of the transition metal with ligands, an elemental form, or a salt of the transition metal as mentioned above. Raney nickel or palladium on carbon are among the preferred catalyst species.
• Suited hydrogen sources may be hydrogen, preferably at pressures of 1 to 5 bar, silanes, e.g. trialkoxysilane, boranes, hydrides, e.g.
• alkali metal borohydride formic acid, or formates, e.g. ammonium formate.
• the reactions are preferably carried out in methylene chloride, dimethylformamide, dimethylacet- amide, N-methylpyrrolidinone, benzene, toluene, tetrahydrofuran, water, ethyl acetate, alcohol, ether, dimethoxyethane, dioxane, or mixtures thereof at -10 0 C to 180 0 C, more preferably at 20 0 C to 140 0 C.
• the subsequent cyclization of two adjacent heteroatoms is optionally conducted with a carboxy equivalent such as nitrile, carboxylic chloride or fluoride, carboxylic acid, ketene, carboxylic ester, or carboxylic thioester.
• the overall transformation consists of two reaction steps: attachment of the carboxy equivalent to one of the two heteroatoms followed by cyclization with the other heteroatom.
• the first step is an amide formation with the amino functionality that may be carried out as described hereinbefore.
• the ensuing reaction step, cyclization with the second heteroatom may be accomplished by heating in the presence of an acid, e.g. acetic acid, trifluoroacetic acid, sulfuric acid, or hydrochloric acid, or a base, e.g.
• dehydrating reagents such as anhydrides, e.g. acetic anhydride, orthoesters, e.g. trimethylorthoformate, thionyl- chloride, phosgene, diphosgene, triphosgene, phosphorous oxychloride, phosphorous penta- chloride, dialkylcarbodiimides, combinations of phosphines, e.g. triphenylphosphine or trialkylphosphine with dialkyl azodicarboxylates, bromine, iodine, or 1 ,2-dihaloethanes, e.g.
• anhydrides e.g. acetic anhydride
• orthoesters e.g. trimethylorthoformate
• thionyl- chloride e.g. trimethylorthoformate
• thionyl- chloride e.g. trimethylorthoformate
• thionyl- chloride
• 1 ,2-dibromotetrafluoroethane may be advantageous.
• the reactions are preferably carried out in inert solvents or mixtures such as methylene chloride, dichloroethane, benzene, toluene, tetrahydrofuran, ether, or combinations thereof, though, cyclization in the presence of an acid or a base may also be conducted in water or an alcohol, e.g. methanol, ethanol, /sopropanol, or te/fbutanol, or combinations with these solvents.
• the reactions are carried out at temperatures between 0 0 C and 200 0 C, preferably between 20 0 C and 140 0 C.
• transition metal species may be derived from palladium, nickel, platinum, rhodium, or ruthenium such as, for example, palladium on charcoal, palladium hydroxide, platinum oxide, or Raney nickel that may be used in solvents such as ethyl acetate, alcohols, e.g.
• methanol or ethanol dichloromethane, tetrahydrofuran, ether, benzene, toluene, dimethylformamide, or N-methylpyrrolidinone at hydrogen pressures between 1 and 10 bar, preferably between 1 and 5 bar, and at temperatures between 0 and 180 0 C, preferably between 20 and 120 0 C.
• Additives such as acids, e.g. hydrochloric acid, methanesulfonic acid, sulfuric acid, or acetic acid, may be beneficial for the hydrogenation.
• Appropriate hydride sources may be selected from e.g. borohydrides, e.g.
• Some of these reagents are best used in combination with nickel chloride or cobalt chloride as sodium borohydride.
• These reagents may be used in e.g. tetrahydrofuran, ether, dioxane, 1 ,2-dimethoxyethane, dichloromethane, 1 ,2-dichloroethane, benzene, or toluene; some are also compatible with alcoholic solutions.
• Preferred reaction temperatures range from -80 0 C to 160 0 C, more preferred from -40 0 C to 60 0 C.
• the subsequent formation of a N-hydroxycarbamimidoyl group from a cyano group may be carried out by the treatment of the cyano compound with hydroxylamine.
• the reaction is preferably conducted in aqueous or alcoholic solvents at temperatures between 0 0 C and 140 0 C.
• the subsequent formation of an oxadiazole from an N-hydroxycarbamimidoyl is optionally conducted with a carboxy equivalent such as nitrile, carboxylic chloride or fluoride, carboxylic acid, ketene, carboxylic ester, or carboxylic thioester.
• the transformation is related to the formation of a ring starting from two adjacent heteroatoms described above and may be carried out analogously.
• a dehydrating reagent such as e.g. anhydride, e.g. acetic anhydride, triflu- oroacetic anhydride, or triflic anhydride, phosgene, thionyl chloride, oxalyl chloride, POCI 3 , PCI 5 , P 4 O 1 0, triphenylphosphite, or triphenyl- or trialkylphosphine combined with tetrachloro- methane, 1 ,2-dibromotetrafluoroethane, or bromine.
• a dehydrating reagent such as e.g. anhydride, e.g. acetic anhydride, triflu- oroacetic anhydride, or triflic anhydride, phosgene, thionyl chloride, oxalyl chloride, POCI 3 , PCI 5 , P 4 O 1 0, triphenylphosphite, or triphenyl- or
• the reactions are preferably carried out in dichloromethane, 1 ,2-dichloroethane, hexanes, ether, dioxane, benzene, toluene, aceto- nitrile, mixtures thereof, or without a solvent at temperatures between 0 0 C and 140 0 C.
• Additives such as amines, e.g. pyridine or triethylamine, or dimethylformamide may be beneficial.
• the subsequent addition of a carbon nucleophile to a keto or an aldehydic group to obtain a tertiary or secondary alcohol may be carried out with an alkyl or aryl metal compound, preferably with a lithium or magnesium derivative.
• the reactions are preferably conducted in hexa- nes, ether, dioxane, tetrahydrofuran, 1 ,2-dimethoxyethane, benzene, toluene, or mixtures thereof between -80 0 C and 50 0 C.
• the subsequent reduction of a keto or an aldehydic group to obtain a secondary or primary alcohol may be carried out with a complex metal hydride such as sodium borohydride, lithium borohydride, lithium triethylborohydride, diisobutylaluminum hydide, or lithium aluminum hydride.
• a complex metal hydride such as sodium borohydride, lithium borohydride, lithium triethylborohydride, diisobutylaluminum hydide, or lithium aluminum hydride.
• the reductions may be conducted in e.g. dichloromethane, 1 ,2-dichloroethane, hexanes, ether, dioxane, tetrahydrofuran, dimethylformamide, N-methylpyrrolidinone, benzene, toluene, alcohols, e.g.
• reducing agents are compatible with all of these solvents.
• Preferred temperatures are between -80 0 C and 140 0 C depending on the reducing power of the reagent.
• hydrogen in the presence of a transition metal catalyst may be used for the reduction.
• the subsequent conversion of a cyano into a tetrazolyl group may be achieved by reacting the cyanide with sodium azide or trimethylsilyl azide in e.g. toluene, xylene, cyclohexane, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran, dioxane,
• Beneficial additives may be ZnBr 2 , Bu 3 SnCI, NH 4 CI, Bu 2 SnO, AICI 3 , AIMe 3 , HNEt 3 CI, and NEt 3 .
• the reactions are preferably conducted between 20 0 C and 160 0 C.
• the subsequent reduction of a nitro group is carried out, for example, with hydrogen and a catalyst such as palladium on carbon, platinum dioxide, or Raney nickel, or using other reducing agents such as iron or zinc in the presence of an acid such as acetic acid.
• a catalyst such as palladium on carbon, platinum dioxide, or Raney nickel
• other reducing agents such as iron or zinc in the presence of an acid such as acetic acid.
• the subsequent formation of a pyrrolyl ring from an amino group may be accomplished, for instance, by reacting the amino compound with succinaldehyde or a derivative thereof, e.g. 2,5-dimethoxy-tetrahydrofuran or hexane-2,5-dione, in the presence of a Lewis acid, e.g. acetic acid, p-toluenesulfonic acid, or Bi(OSO 2 CF 3 ) 3 , in e.g. acetic acid, water, methanol, ethanol, acetonitrile, 1 ,4-dioxane, tetrahydrofuran, toluene, at 20 to 140 0 C.
• Additives such as molecular sieves or other dehydrating reagents such as acetic anhydride may be beneficial.
• any reactive group present such as hydroxy, car- boxy, amino, alkylamino, or imino group may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
• a protecting group for a hydroxy group may be a trimethylsilyl, terfoutyldime- thylsilyl, triisopropylsilyl, acetyl, pivaloyl, benzoyl, methyl, ethyl, te/f-butyl, allyl, trityl, benzyl, 4-methoxybenzyl, tetrahydropyranyl, methoxymethyl, ethoxymethyl, or 2-trimethylsilylethoxy- methyl group,
• protecting groups for a carboxy group may be trimethylsilyl, methyl, ethyl, te/fbutyl, allyl, benzyl, or tetrahydropyranyl,
• protecting groups for a ketone or aldehyde may be a ketal or acetal, respectively, e.g. derived from methanol, glycol, or propane-1 ,3-diol,
• protecting groups for an amino, alkylamino, or imino group may be methyl, formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxy- benzyl, or 2,4-dimethoxybenzyl and additionally, for the amino group, phthalyl, and
• protecting groups for a terminal alkyne may be trimethylsilyl, trisopropylsilyl, te/fbutyldime- thylsilyl, or 2-hydroxy-isopropyl.
• Any acyl protecting group may be cleaved, for example, hydrolytically in an aqueous solvent, e.g.
• a trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in a solvent such as acetic acid, at temperatures between 50 and 120 0 C or by treating with sodium hydroxide solution, optionally in an additional solvent such as tetrahydrofuran or methanol, at tempera- tures between 0 and 80 0 C.
• an acid such as hydrochloric acid
• a solvent such as acetic acid
• sodium hydroxide solution optionally in an additional solvent such as tetrahydrofuran or methanol
• Any acetal or ketal protecting group used may be cleaved, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water, or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 0 C, preferably between 10 and 100 0 C.
• an aqueous solvent e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water, or dioxane/water
• an acid such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid or aprotically, e.g. in the presence of iodotrimethylsilane, at
• a trimethylsilyl group is cleaved, for example, in water, an aqueous solvent mixture or an alcohol, such as methanol or ethanol, in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium carbonate, or sodium methoxide.
• Acids such as e.g. hydrochloric acid, trifluoroacetic acid, or acetic acid may also be suitable.
• the cleavage usually takes place at comparatively low temperatures, e.g. between -60 and 60 0 C.
• SiIyI groups other than trimethylsilyl are preferentially cleaved in the presence of an acid, e.g. trifluoroacetic acid, hydrochloric acid, or sulfuric acid, at temperatures between 0 0 C and 100 0 C.
• a particularly suited cleaving method for silyl groups is based on the use of fluoride salts, e.g.
• tetrabutylammonium fluoride hydrogen fluoride, or potassium fluoride
• organic solvents such as for example diethyl ether, tetrahydrofuran, dioxane, dimethoxy- ethane, toluene, benzene, dichloroethane, or dichloromethane, at temperatures between -20 and 100 0 C.
• a benzyl, methoxybenzyl, or benzyloxycarbonyl group is advantageously cleaved hydro- genolytically, e.g. with hydrogen in the presence of a catalyst such as palladium on carbon, palladium hydroxide, or platinum oxide in a solvent such as methanol, ethanol, ethyl acetate, or glacial acetic acid, optionally in the presence of an acid, such as hydrochloric acid, at temperatures between 0 and 100 0 C, preferably between 20 and 60 0 C, and at hydrogen pressures of 1 to 7 bar, preferably 3 to 5 bar.
• a catalyst such as palladium on carbon, palladium hydroxide, or platinum oxide
• a solvent such as methanol, ethanol, ethyl acetate, or glacial acetic acid
• an acid such as hydrochloric acid
• Trimethylsilyl iodide, boron trichloride, or boron trifluoride in the presence of a scavenger such as anisol, thioanisol, or pentamethylbenzene may also be used with benzylether derivatives.
• An electron-rich benzyl residue, such as methoxybenzyl may also be cleaved oxidatively with e.g. 2,3-dichloro-5,6-dicyano-1 ,4-ben- zoquinone (DDQ) or eerie ammonium nitrate (CAN) preferably in an alcoholic or aqueous solvent at temperatures between 10 and 120 0 C.
• DDQ 2,3-dichloro-5,6-dicyano-1 ,4-ben- zoquinone
• CAN eerie ammonium nitrate
• a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroace
• a terfoutyl or terfoutyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid, sulfuric acid, or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol, isopropanol, water, or diethylether.
• an acid such as trifluoroacetic acid, sulfuric acid, or hydrochloric acid
• iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol, isopropanol, water, or diethylether.
• a methyl group at an tertiary amine may be cleaved by the treatment with 1-chloroethyl chloroformate.
• Hydrobromic acid and borontribromide are particularly suited for the cleavage of methylethers.
• the compounds of general formula I may be resolved into their enantiomers and/or dia- stereomers, as mentioned before.
• cis/trans mixtures may be resolved into their cis and trans isomers, and racemic compounds may be separated into their enantiomers.
• the cis/trans mixtures may be resolved, for example, by chromatography into the cis and trans isomers thereof.
• the compounds of general formula I which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and ENeI E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 ) into their optical antipodes and dia- stereomeric mixtures of compounds of general formula I may be resolved into their dia- stereomers by taking advantage of their different physico-chemical properties using methods known per se, e.g. chromatography and/or fractional crystallization; if the compounds obtained thereafter are racemates, they may be resolved into the enantiomers as mentioned above.
• racemates are preferably resolved by column chromatography on chiral phases or by crystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives, such as e.g. esters or amides, with the racemic compound.
• Salts may be formed with enantiopure acids for basic compounds and with enantiopure bases for acidic compounds.
• Diastereomeric derivatives are formed with enantiopure auxiliary compounds such as e.g. acids, their activated derivatives, or alcohols. Separation of the diastereomeric mixture of salts or derivatives thus obtained may be achieved by taking advantage of their different physico-chemical properties, e.g.
• Optically active acids in common use for such a purpose are e.g. the D- and L-forms of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid, or quinic acid.
• Optically active alcohols applicable as auxiliary may be, for example, (+) or (-)-menthol and optically active acyl groups in amides may be, for example, (+)- or (-)-menthyloxycarbonyl.
• the compounds of formula I may be converted into salts, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids provided that compound I bears a basic residue.
• Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid.
• the compounds of formula I may be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof.
• bases for this purpose include, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, calcium isopropoxide, magnesium hydroxide, magnesium ethoxide, ammonium hydroxide, cyclohexylamine, ethanolamine, diethanolamine, triethanolamine, N-methyl-D-glucamine, L- lysine, L-arginine, and piperazine.
• a first subgeneric embodiment of this invention is directed to compounds described by general formula 1.1 wherein the bicyclic core structure of general formula 1.1 is optionally substituted with R 11 to R 14 , and wherein R 1 to R 3 and R 11 to R 14 are defined as hereinbefore and hereinafter, except for the compounds comprised by the formulae 11.1 to II.8, their tautomers, their stereoisomers, mixtures thereof and the salts thereof.
• a second subgeneric embodiment of this invention is directed to compounds described by general formula 1.2
• bicyclic core structure of general formula I.2 is optionally substituted with R to R 14 , and wherein R 1 to R 3 and R 11 to R 14 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof and the salts thereof.
• a third subgeneric embodiment of this invention is directed to compounds described by general formula 1.3
• bicyclic core structure of general formula 1.3 is optionally substituted with R to R 14 , and wherein R 1 to R 3 and R 11 to R 14 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof and the salts thereof.
• a fourth subgeneric embodiment of this invention is directed to compounds described by general formula 1.4 wherein the bicyclic core structure of general formula 1.4 is optionally substituted with R to R 14 , and wherein R 1 to R 3 and R 11 to R 14 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof and the salts thereof.
• a fifth subgeneric embodiment of this invention is directed to compounds described by general formula 1.5
• bicyclic core structure of general formula 1.5 is optionally substituted with R 11 to
• R 14 and wherein R 1 to R 3 and R 11 to R 14 are defined as hereinbefore and hereinafter, while the compounds of formulae II.7 and II.8 are excluded, their tautomers, their stereoisomers, mixtures thereof and the salts thereof.
• a sixth subgeneric embodiment of this invention is directed to compounds described by general formula 1.6
• bicyclic core structure of general formula 1.6 is optionally substituted with R 11 to R 14 , and wherein R 1 to R 3 and R 11 to R 14 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof and the salts thereof.
• a seventh subgeneric embodiment of this invention is directed to compounds described by general formula 1.7 wherein the bicyclic core structure of general formula 1.7 is optionally substituted with R 11 to R 14 , and wherein R 1 to R 3 and R 11 to R 14 are defined as hereinbefore and hereinafter, while the compounds comprised by the formula II.3 are excluded, their tautomers, their stereoisomers, mixtures thereof and the salts thereof.
• An eighth subgeneric embodiment of this invention is directed to compounds described by general formula 1.8
• bicyclic core structure of general formula 1.8 is optionally substituted with R 11 to
• R 14 and wherein R 1 to R 3 and R 11 to R 14 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof and the salts thereof.
• a ninth subgeneric embodiment of this invention is directed to compounds described by general formula 1.9
• bicyclic core structure of general formula 1.9 is optionally substituted with R 11 to R 14 , and wherein R 1 to R 3 and R 11 to R 14 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof and the salts thereof.
• a tenth subgeneric embodiment of this invention is directed to compounds described by general formula 1.10 wherein the bicyclic core structure of general formula 1.10 is optionally substituted with R 11 to R 14 , and wherein R 1 to R 3 and R 11 to R 14 are defined as hereinbefore and hereinafter, their tautomers, their stereoisomers, mixtures thereof and the salts thereof.
• Preferred compounds according to the invention are those of general formulae 1.1 to 1.10, wherein
• R 1 denotes aryl or heteroaryl
• aryl is meant phenyl or naphthyl
• heteroaryl by heteroaryl is meant pyrrolyl, furanyl, thienyl, pyridinyl, indolyl, benzofuranyl, benzo- thiophenyl, quinolinyl, isoquinolinyl, or
• R 1 denotes phenyl, naphthyl, furanyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, benzoxazolyl, benzo- thiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, 2,3-dihydro-2- oxo-indolyl, or 1 ,2,3,4-tetrahydro-3-oxo-quinoxalinyl, wherein any of these groups optionally are independently substituted with one R 4 , one to four identical or different R 5 , and one R 6 .
• R 1 denotes phenyl, naphthyl, pyrazolyl, pyridinyl, pyrimidinyl, naphthyl, benzofuranyl, indolyl, benzothiophenyl, benzimidazolyl, indazolyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, 2,3-dihydro-2-oxo-indolyl, or 1 ,2,3,4-tetrahydro-3-oxo-quinoxalinyl, wherein any of these groups optionally are independently substituted with one R 4 and one to four different or identical R 5 .
• R 1 denotes phenyl, pyrazolyl, pyridinyl, benzofuranyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, 2,3-dihydro-2-oxo-indolyl, or 1 ,2,3,4-tetrahydro-3-oxo-quinoxalinyl, wherein any of these groups optionally are independently substituted with one R 4 and one to four different or identical R 5 .
• R 2 and R 3 together with the double bond to which they are attached, denote a benzo or pyrido ring, optionally both independently substituted with R 7 , R 8 and R 9 , or denote a furo, pyrrolo, pyridazino, pyrimido, or pyrazino ring, wherein any of these groups optionally are independently substituted with R 7 and R 8 or R 8 and R 9 , or denote a pyrazolo, imidazo, oxazolo, thiazolo, isoxazolo, or isothiazolo ring, wherein any of these groups optionally are independently substituted with R 7 .
• R 2 and R 3 together with the double bond to which they are attached, denote a benzo or pyrido ring, both optionally independently substituted with R 7 , R 8 and R 9 , or denote a pyrrolo, pyridazino, pyrimido, or pyrazino ring, wherein any of these groups optionally are independently substituted with R 7 and R 8 or R 8 and R 9 , or denote a pyrazolo or imidazo ring, both optionally substituted with R 7 .
• R 2 and R 3 together with the double bond to which they are attached, denote a benzo or pyrido ring, both independently substituted with R 7 , R 8 and R 9 , or denote a pyrrolo ring optionally substituted independently with R 7 and R 8 or R 8 and R 9 , particularly a benzo ring optionally substituted independently with R 7 , R 8 and R 9 .
• R 4 denotes fluorine, chlorine, bromine, C- M -alkyl, hydroxy, C- M -alkyloxy,
• R 4 denotes fluorine, chlorine, d- 4 -alkyl, hydroxy, Ci -4 -alkyloxy, amino, Ci -3 - alkylamino, di-(Ci -3 -alkyl)amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, Ci -3 -alkyl- carbonylamino, aminocarbonyl, Ci -3 -alkyl-aminocarbonyl, di-(Ci -3 -alkyl)-aminocarbonyl, (N-methyl)-benzylaminocarbonyl, (N-methyl)-phenylaminocarbonyl, pyrrolidin-1 -yl- carbonyl, 2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, 3-(methoxymethyl)-pyrrolidin-1-yl- carbonyl, piperidin-1-yl-carbonyl, morpholin-4-
• R 4 denotes fluorine, chlorine, methyl, hydroxy, methoxy, methylamino, morpholin-4-yl, acetylamino, aminocarbonyl, (N-methyl)-propylaminocarbonyl, (N- methyl)-benzylaminocarbonyl, (N-methyl)-phenylaminocarbonyl, dimethylamino-carbo- nyl, diethylaminocarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, pyrrolidin-1 - yl-carbonyl, 2-(methoxymethyl)-pyrrolidin-1-yl-carbonyl, 1-hydroxy-ethyl, 1 -hydroxy-1 - methyl-ethyl, 2,2,2-trifluoro-1 -hydroxy-1 -methyl-ethyl, 2, 2, 2-trifluoro-1 -hydroxy-1 - trifluoromethyl-ethyl, acetyl,
• R 5 and R 6 are independently selected from among fluorine, chlorine, bromine, C- ⁇ -3-alkyl, C 2 -3- alkynyl, trifluoromethyl, hydroxy, Ci -3 -alkyloxy, and cyano, preferably from hydrogen, fluorine, chlorine, methyl, ethyl, ethynyl, trifluoromethyl, hydroxy, methoxy, and ethoxy, more preferably from hydrogen, fluorine, chlorine, methyl, ethynyl, hydroxy, and methoxy.
• R 5 and R 6 are bound to adjacent carbon atoms they together may additionally denote methylenedioxy, difluoromethylenedioxy, ethylenedioxy, or C3 -5 -alkylene, preferably methy- lenedioxy, ethylene-1 ,2-dioxy, propylene, or butylene, more preferably methylenedioxy or ethylene-1 ,2-dioxy, most preferably ethylene-1 ,2-dioxy.
• R 7 denotes fluorine, chlorine, C- M -alkyl, hydroxy, C- M -alkyloxy,
• R 7 denotes fluorine, chlorine, C- ⁇ - 4 -alkyl, hydroxy, C- ⁇ -alkyloxy,
• cyano-d-3-alkyloxy aminocarbonyl-d-3-alkyloxy, d-s-alkyl-aminocarbonyl-d-s-alkyl- oxy, di-(Ci-3-alkyl)-aminocarbonyl-Ci-3-alkyloxy, pyrrolidin-1 -yl-carbonyl-d-s-alkyl-oxy, piperidin-i-yl-carbonyl-d-s-alkyloxy, morpholin ⁇ -yl-carbonyl-d-s-alkyl-oxy,
• R 7 denote phenyl, furanyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl, wherein any of these groups are optionally mono- or disubstituted with R 10 .
• R 7 denotes fluorine, chlorine, Ci -3 -alkyl, hydroxy, Ci -3 -alkyloxy, amino, Ci -3 -alkyl-carbonylamino, Ci -3 -alkyl-sulfonylamino, cyano, (hydroxyimino)aminomethyl, carboxy, Ci -3 -alkyloxy-carbonyl, aminocarbonyl, d- 3 -alkyl- aminocarbonyl, di-(Ci -3 -alkyl)-aminocarbonyl, hydroxy-Ci -3 -alkyl, trifluoromethyl-hydroxy-d-3- alkyl, Ci -3 -alkyloxy-Ci -3 -alkyl, d-s-alkyl-carbonyl-amino-d-s-alkyl, hydroxy-Ci -3 -alkyloxy, Ci -3 - alkyloxy-Ci -3 -alkyloxy, trifluoromethyl
• R 7 denotes fluorine, chlorine, methyl, hydroxy, methoxy, amino, acetylamino, methylsulfonylamino, cyano, (hydroxyimino)aminomethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, acetylaminomethyl, acetyl, 1-hydroxy-ethyl, 1-hydroxy-1 -methyl-ethyl, 2,2,2-trifluoro-1- hydroxy-1 -methyl-ethyl, methylsulfonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, phenyl, pyrrol-1-yl, pyridin-3-yl, pyridin-4-yl, 1 ,2-dihydro-1-methyl-2- oxo-pyridin-5-yl, 1 ,2-di
• R 8 and R 9 which may be identical or different, denote fluorine, chlorine, bromine, d -3 -alkyl, trifluoromethyl, hydroxy, d -3 -alkyloxy, or cyano. More preferably R 8 and R 9 independently denote fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, hydroxy, methoxy, ethoxy, or cyano. Most preferably, R 8 denotes hydroxyl, or methoxy.
• R 8 and R 9 are bound to adjacent carbon atoms they together may additionally denote methylenedioxy, difluoromethylenedioxy, ethylenedioxy, C 3-5 -alkylene, or form together with the carbon atoms to which they are attached a benzo, pyrazino, pyra- zolo, imidazo, N-(Ci -3 -alkyl)-pyrazolo, N-(Ci -3 -alkyl)-imidazo, triazolo, oxazolo, thiazolo, isoxazolo, or isothiazolo ring, wherein any of the five-membered aromatics are optionally additionally monosubstituted with L and any six-membered rings are optionally mono- or disubstituted with one L and/or one substituent selected from fluorine, Ci -3 -alkyl, trifluoromethyl, amino, Ci_3-alkylamino, di-(Ci_3-alky
• R 8 and R 9 if bound to adjacent carbon atoms, together may additionally denote methylenedioxy, ethylene-1 ,2-dioxy, propylene, butylene or together with the carbon atoms to which they are attached form a benzo, pyrazino, pyrazolo, imidazo, N-(Ci -3 -alkyl)-pyrazolo, N-(Ci -3 -alkyl)-imidazo, triazolo, oxazolo, thiazolo, isoxazolo, or isothiazolo ring, wherein any of the five-membered aromatics are optionally additionally monosubstituted with L and any six-membered rings are optionally mono- or disubstituted with one L and/or one substituent selected from fluorine, methyl, trifluoromethyl, methylamino, dimethylamino, hydroxyl, or methoxy.
• R 8 and R 9 if bound to adjacent carbon atoms, together may additionally denote methylenedioxy or ethylene-, 12-dioxy or together with the carbon atoms to which they are attached form a benzo, pyrazino, imidazo, N-(Ci -3 -alkyl)-imidazo, triazolo, oxazolo, or thiazolo ring, wherein the benzo and pyrazino ring are optionally substituted with one or two methyl groups and the imidazo, N-Ci -3 -alkylimidazo, oxazolo, and thiazolo ring are optionally additionally substituted with L.
• R 8 and R 9 if bound to adjacent carbon atoms, together may additionally denote methylenedioxy or together with the carbon atoms to which they are attached form an optionally additionally with methyl, tert-butyl, cyclopropyl, tetrahydrofuran-2-yl, 1-acetyl- piperidin-4-yl, pyridin-3-yl, 1 ,2-dihydro-1-methyl-2-oxo-pyridin-5-yl, pyridazin-4-yl, pyrazinyl, or 5-methyl-pyrazin-2-yl substituted oxazolo, imidazo, or N-methyl-imidazo group, an optionally with methyl substituted triazolo group, or an optionally methyl or dimethyl substituted benzo or pyrazino ring.
• L preferably is fluorine, Ci -4 -alkyl, C 3-6 -cycloalkyl, pyrrolidinyl, 1-methyl-pyrrolidinyl, 1-acetyl- pyrrolidinyl, piperidinyl, 1-methyl-piperidinyl, 1-acetyl-piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, trifluoromethyl, cyano, amino, acetylamino, methylsulfonylamino, carboxy, Ci -3 -alkyloxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, hydroxy, Ci -3 -alkyloxy, or phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, 1 ,2-dihydro-2-oxo-pyridinyl,
• L is fluorine, methyl, ethyl, tert-butyl, C 3 _ 6 -cycloalkyl, pyrrolidinyl, 1-methyl- pyrrolidinyl, 1-acetyl-pyrrolidinyl, piperidinyl, 1-methyl-piperidinyl, 1-acetyl-piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, trifluoromethyl, cyano, amino, acetylamino, methylsulfonylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, hydroxy, methoxy, or phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, 1 ,2-dihydro-2-oxo
• L is fluorine, methyl, cyclopropyl, 1-acetyl-piperidinyl, tetrahydrofuranyl, acetylamino, methylsulfonylamino, carboxy, hydroxy, methoxy, or pyridyl, pyridazinyl, pyrazinyl, 1 ,2-dihydro-2-oxo-pyridinyl, which are optionally substituted with one or two methyl groups; particularly, L is methyl, tert-butyl, cyclopropyl, tetrahydrofuran-2-yl, 1-acetyl-piperidin-4-yl, pyrid-3-yl, pyridazin-3-yl, pyrazinyl, 5- methylpyrazin-2-yl, 1 ,2-dihydro-2-oxo-pyridin-5-yl.
• R 10 preferably denotes fluorine, chlorine, bromine, Ci -3 -alkyl, difluoromethyl, trifluoromethyl, cyano, nitro, amino, acetylamino, methylsulfonylamino, carboxy, Ci -4 -alkyloxycarbonyl, aminocarbonyl, d- 3 -alkylaminocarbonyl, di-(Ci_ 3 -alkyl)-aminocarbonyl, aminosulfonyl, methylsulfanyl, methylsulfinyl, methylsulfonyl, phenyl, hydroxy, Ci -3 -alkyloxy, difluoromethoxy, or trifluoromethoxy.
• R 10 denotes fluorine, chlorine, methyl, difluoromethyl, trifluoromethyl, cyano, hydroxy, methoxy, difluoromethoxy, or trifluoromethoxy, most preferably, R 10 denotes methyl.
• R 11 preferably denotes fluorine, Ci -3 -alkyl, phenyl, hydroxy, Ci -3 -alkyloxy, cyano, carboxy, C- ⁇ - 4 -alkyloxycarbonyl, aminocarbonyl, d- 4 -alkylamino-carbonyl, di-(Ci_ 4 -alkyl)-aminocarbonyl, hydroxy-d- 4 -alkyl, or Ci-3-alkyloxy-Ci- 4 -alkyl. More preferably R 11 denotes fluorine, Ci -3 -alkyl, hydroxyl, or Ci -3 -alkyloxy. Most preferably, R 11 denotes methyl, ethyl, propyl, hydroxy, or methoxy, particularly hydrogen, methyl, or methoxy.
• R 12 preferably denotes fluorine, or Ci -3 -alkyl, more preferably methyl or ethyl; and R 13 and R 14 , which may be identical or different, preferably denote C- ⁇ -3-alkyl. More preferably, R 13 and R 14 denote methyl.
• substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
• halogen denotes an atom selected from the group consisting of F, Cl, Br and I.
• Ci -n -alkyl wherein n may have a value of 1 to 18, denotes a saturated, branched or unbranched hydrocarbon group with 1 to n C atoms.
• examples of such groups include methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, n-hexyl, iso-hexyl, etc.
• groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl etc.
• C 2 - n -alkynyl wherein n has a value of 3 to 6, denotes a branched or unbranched hydrocarbon group with 2 to n C atoms and a C ⁇ C triple bond.
• groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl etc.
• alkynyl groups are connected to the remainder of the molecule via the C atom in position 1. Therefore terms such as 1-propynyl, 2-propynyl, 1-butynyl, etc. are equivalent to the terms 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, etc.. This also applies analogously to C 2 - n -alkenyl groups.
• Ci -n -alkoxy denotes a Ci -n -alkyl-0 group, wherein Ci -n -alkyl is as hereinbefore defined.
• groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, iso-pentoxy, neo-pentoxy, tert- pentoxy, n-hexoxy, iso-hexoxy, etc.
• groups include methylcarbonyl, ethylcarbonyl, n- propylcarbonyl, iso-propylcarbonyl, n-butylcarbonyl, iso-butylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, iso-pentylcarbonyl, neo-pentylcarbonyl, tert- pentylcarbonyl, n-hexylcarbonyl, iso-hexylcarbonyl, etc.
• C 3-n -cycloalkyl denotes a saturated mono-, bi-, tri- or spirocarbocyclic group with 3 to n C atoms.
• groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1.]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.
• C 3-7 - cycloalkyl denotes saturated monocyclic groups.
• tri-(Ci -4 -alkyl)silyl comprises silyl groups which have identical or two or three different alkyl groups.
• di-(Ci -3 -alkyl)amino comprises amino groups which have identical or two different alkyl groups.
• alkyl group is optionally mono- or polyfluorinated this comprises also alkyl residues which are part of larger groups, e.g. alkyloxy, alkylcarbonyl, alkoxyalkyl, etc. or if a (het)aryl group is optionally mono- or polysubstituted with a certain substituent or a set of substituents this also includes (het)aryl groups which are part of larger groups, e.g.
• a CH 2 group may be replaced by O, S, NR, CO, or SO 2 .
• a residue having inter alia the meaning hydroxy-Ci -3 -alkyl, in which a CH 2 group may be replaced by CO this comprises carboxy, carboxymethyl, hydroxymethylcarbonyl, carboxyethyl, hydroxymethylcarbonylmethyl, and hydroxyethyl- carbonyl.
• the compounds according to the invention may be obtained using methods of synthesis known in principle.
• the compounds are obtained by the following methods according to the invention which are described in more detail hereinafter.
• a general strategy to access compounds of the invention is delineated in Scheme 1 ;
• R 2 , R 3 , X, m, n, and o have the meanings as defined hereinbefore and hereinafter.
• the key reaction to assemble the bicyclic framework is an intramolecular merger of an amino functionality with a carboxy group that results in the formation of an amide linkage.
• the fusion of the carboxylic acid function and the amino group may be carried out with or without an additive at elevated temperatures, preferably between 20 and 200 0 C.
• Additives that remove the water forming during the reaction such as molecular sieves or orthoesters, or other additives such as ba- ses, e.g. hexamethyldisilazides, or boronic acids may facilitate the reaction.
• acyl halides are acyl chloride and acyl fluoride.
• esters and thioesters are derived from e.g.
• mixed anhydrides are derived from alkylcarboxylic acids, e.g. pivalic acid, carbonates, e.g. methyl and ethyl carbonate, carbamates, e.g. N,N-dimethyl carbamate, phosphoric acids, e.g.
• N acylated derivatives derived from azaheteroaromatics such as imidazole, triazole, tetrazole, or pyridine such as e.g. 4-dimethylaminopyridine may be used as well.
• Some of the more popular reagents used for the activation of the carboxylic acid function are N,N'-carbonyldiimidazol, dicyclohexylcarbodiimide, (benzotriazol-1-yloxy)- dipiperidinocarbenium hexafluorophospate or tetrafluoroborate, (benzotriazol-i-yloxy)dipyr- rolidinocarbenium hexafluorophospate or tetrafluoroborate, 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide methiodide, POCI 3 , SOCI 2 , (COCI) 2 , COCI 2 , arylboronic acid, TiCI 4 , (MeO) 2 POCI, cyanuric chloride, 1 -hydroxybenzotriazol, 1-hydroxy-7-azabenzotriazol, benzol- triazol-1-yloxytri
• ethyldiisopropylamine triethylamine, alkali metal carbonate, pyridine, 4-dimethylaminopyridine, imidazole, dimethylaluminum amides, lithium amides, alkali metal cyanide, or alkali metal hexamethyldisilazide.
• the reactions are preferably conducted in organic solvents but may also be carried out in aqueous solvents.
• organic solvents ordinarily used are dimethylformamide, dimethylacetamide, N-methyl- pyrrolidinone, dimethylsulfoxide, tetrahydrofuran, hexane, ether, dioxane, dimethoxyethane, dichloromethane, dichloroethane, toluene, benzene, ethyl acetate, quinoline, pyridine, or mixtures thereof.
• the reactions may be carried out at -80 0 C to 220 0 C, preferably between - 10 0 C and 120 0 C. Subsequently, the lactam group is reduced to give the secondary amine.
• This transformation is a well established reaction that may be carried out, for example, using LiAIH 4 , hydrogen in the presence of a catalyst, NaBH 4 in the presence of e.g. iodine, LiBH 4 , borane, sodium in propanol, CIsSiH, silanes, e.g. Et 3 SiH, in the presence of a transition metal such as rhenium, 9-BBN, LiBH 3 NMe 2 , or Et 3 SiH combined with LiEt 3 BH.
• Solvents such as e.g.
• tetrahydrofuran, ether, dimethoxyethane, dioxane, hexane, benzene, toluene, dichloromethane, alcohols, water, or mixtures thereof may be employed at -78 0 C to 200 0 C, preferably between -10 0 C and 120 0 C; though, in combination with some reducing reagents only a few of these solvents are usable. This strategy is well suited for the synthesis of the scaffolds 1.1 to 1.10.
• R 2 , R 3 , X, m, n, and o have the meanings as defined hereinbefore and hereinafter.
• the bicyclic framework is formed via an intramolecular reductive amination reaction of a primary amine with a ketone functionality. Reductive aminations have large precedence in organic chemistry and may be carried out e.g. using hydrogen in the presence of a transition metal catalyst such as one derived from Ni, Rh, Pd, or Pt, borohydride reagents, e.g.
• Some of these reagents are preferably used in combination with an additive such as acid, e.g. acetic acid or mineral acid.
• the reactions are preferably conducted in organic solvents or aqueous mixtures, e.g.
• the reactions may be carried out at -80 0 C to 200 0 C, preferably between -10 0 C and 100 0 C.
• Scheme 4 shows another approach to assemble the bicyclic framework.
• This approach is an intramolecular alkylation of the nitrogen group with an appropriate electrophile of the side- chain.
• the nitrogen group may be an amino group, i.e. R a denotes e.g. hydrogen, methyl, allyl, benzyl, or dimethoxybenzyl, or an amide group, i.e. R a denotes e.g.
• a base such as e.g. triethylamine, ethyldiisopropylamine, diazabicycloundecene, alkali metal carbonate, alkali metal te/fbutoxide, alkali metal diisopropylamide, butyllithium, or sodium hydride.
• the stronger bases among them are preferably used in combination with the amides in e.g.
• N-methylpyrrolidinone dimethylsulfoxide, tetrahydrofuran, hexane, ether, dioxane, dimethoxyethane, toluene, benzene, terfoutanol, isopropanol, or mixtures thereof at temperatures between -70 and 100 0 C, preferably between -30 and 60 0 C.
• the milder bases listed are preferably used in combination with the amines in dichloromethane, dimethylform- amide, N-methylpyrrolidinone, dimethylsulfoxide, tetrahydrofuran, hexane, ether, dioxane, dimethoxyethane, toluene, benzene, methanol, ethanol, te/fbutanol, isopropanol, water, or mixtures thereof at temperatures between 0 and 140 0 C, preferably between 20 and 120 0 C.
• the conditions originally reported by Mitsunobu may be used as well.
• a phosphine e.g. triphenylphosphine or tributylphosphine
• an azodicarboxylate e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, or azodi- carboxylic dipiperidide.
• Suited solvents may be selected from among dimethylformamide, N- methylpyrrolidinone, dichloromethane, tetrahydrofuran, hexane, ether, dioxane, dimethoxyethane, toluene, benzene, and mixtures thereof.
• the reaction is preferably conducted at temperatures between 0 and 100 0 C.
• the opposite way around, i.e. LG denotes NHR a and NHR a denotes LG, may be applicable as well. Reaction conditions are equivalent to the original way around.
• a further generally applicable approach is based on an electrophilic aromatic substitution reaction (Scheme 5);
• R 2 , R 3 , m, n, and o have the meanings as defined hereinbefore and hereinafter.
• the aromatic part of the molecule reacts with an activated carbon atom of the azacycle to form the bicyclic framework.
• the reactive intermediate bears a (partially) positively charged carbon atom in the azacycle that may be generated by the addition of an acid to an olefinic bond or by the activation of an appropriately positioned leaving group.
• a huge number of Bronstedt and Lewis acids have been described for this classical reaction that may also be used here.
• hydrobromic acid hydroiodic acid, hydrochloric acid, sulfuric acid, phosphoric acid, P 4 Oi 0
• trifluoroacetic acid methanesulfonic acid, toluenesulfonic acid, trifluormethanesulfonic acid, Sc(OTf) 3 , SnCI 4 , FeCI 3 , AIBr 3 , AICI 3 , SbCI 5 , BCI 3 , BF 3 , ZnCI 2 , montmorillonites, POCI 3 , and PCI 5 .
• a more or less powerful acid catalyst has to be used.
• silver salts e.g. AgOTf
• Preferred solvents are hydrocarbons such as hexane or cyclohexane, chlorinated hydrocarbons such as dichloromethane or dichloro- ethane, perfluorinated hydrocarbons, nitrobenzene, chlorinated benzenes, heteroaromatics such as quinoline, dimethoxyethane, dioxane, ether, ionic liquids, or mixtures thereof.
• the reactions may be carried out between -10 0 C and 220 0 C, preferably between 20 0 C and 180 0C.
• the reactions may also be conducted under microwave irradiation. This synthetic strategy is particularly suited for the scaffolds 1.1 and 1.3 to 1.10 bearing an electron rich aromatic.
• the bicyclic scaffold may also be accessed via the route delineated in Scheme 6; m has the meaning as defined hereinbefore and hereinafter and PG and PG' are protective groups such as e.g. trialkylsilyl for PG and benzyl or methyl for PG'.
• the cyclization is realized by the addition of a radical intermediate, generated from the trichloromethyl group and a chlorine abstracting reagent, onto the double bond. Suited chlorine abstracting reagents are Bu 3 Sn* and (Me 3 Si) 3 Si* that are formed in situ by a radical initiator, such as azobisisobutyronitrile or dibenzoylperoxide, from Bu 3 SnH and (Me 3 Si) 3 SiH, respectively.
• a radical initiator such as azobisisobutyronitrile or dibenzoylperoxide
• the reaction is preferably conducted in benzene, toluene, cyclohexane, or hexanes at elevated temperature.
• This approach is reported inter alia in Tetrahedron: Asymmetry 1999, 10, 2399-2410.
• These transformations are described hereinbefore and hereinafter and are known for similar compounds from the organic chemistry literature (see e.g. Thomas L. Gilchrist, Heterocyclenchemie, VCH, Weinheim, 1995).
• the compounds according to the invention are advantageously also obtainable using the methods described in the examples that follow, which may also be combined for this purpose with methods known to the skilled man from the literature.
• the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibitory effect on the enzyme 11 ⁇ -hydroxysteroid dehydrogenase (HSD) 1.
• the biological properties of the new compounds may be investigated as follows:
• the incubation period for detection reaction was typically 2 hours.
• the amount of Cortisol is determined by reading the time-resolved fluorescence of the wells (Ex 320/75 nm; Em 615/8.5 nm and 665/7.5 nm). The ratio of the two emission signals is then calculated (Em665 * 10000/Em615).
• Each assay contained incubations with vehicle controls instead of compound as controls for non-inhibited Cortisol generation (100% CTL; 'high values') and incubations with carbenoxolone as controls for fully inhibited enzyme and Cortisol background (0% CTL; 'low values').
• Each assay also contai- ned a calibration curve with Cortisol to transform the fluorescent data into Cortisol concentrations. Percent inhibition of each compound was determined relative to the carbenoxolone signal and IC 50 curves were generated.
• the compounds of general formula I according to the invention may for example have IC 50 values below 10000 nM, particularly below 1000 nM, most preferably below 100 nM.
• IC 50 values below 10000 nM, particularly below 1000 nM, most preferably below 100 nM.
• Table 2 compounds of the invention (specified in Table 3) and their inhibitory activity determined as described above are compiled.
• the compounds of general formula I according to the invention and the corresponding pharma- ceutically acceptable salts thereof are theoretically suitable for the treatment and/or preventative treatment of all those conditions or diseases which may be affected by the inhibition of the 1 1 ⁇ -hydroxysteroid dehydrogenase (HSD) 1 activity. Therefore, compounds according to the invention are particularly suitable for the prevention or treatment of diseases, particularly metabolic disorders, or conditions such as type 1 and type 2 diabetes mellitus, complications of diabetes (such as e.g.
• retinopathy retinopathy, nephropathy or neuropathies, diabetic foot, ulcers, macroangiopathies, slow or poor wound healing
• metabolic acidosis or ketosis reactive hypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulin resistance, metabolic syndrome, dyslipidaemias of different origins, atherosclerosis and related diseases, obesity, high blood pressure, chronic heart failure, edema and hyperuricaemia.
• beta-cell degeneration such as e.g. apoptosis or necrosis of pancreatic beta cells.
• the substances are also suitable for improving or restoring the functionality of pancreatic cells, and also of increasing the number and size of pancreatic beta cells.
• the compounds according to the invention may also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute renal failure.
• HSD 11 ⁇ -hydroxysteroid dehydrogenase
• the compounds may have beneficial effects against osteoporosis.
• Cortisol has been associated with brain neuronal loss or dysfunction. Treatment with an 11 ⁇ - hydroxysteroid dehydrogenase (HSD) 1 inhibitor may result in amelioration or prevention of cognitive impairment. Such compounds may also be useful in treating anxiety or depression.
• HSD 11 ⁇ - hydroxysteroid dehydrogenase
• the dynamic interaction between the immune system and the HPA (hypothalamopituitary- adrenal) axis is known, and glucocorticoids help balance between cell-mediated responses and humoral responses.
• the immune reaction is typically biased towards a humoral res- ponse in certain disease states, such as tuberculosis, leprosy, and psoriasis. More appropriate would be a cell-based response.
• An 1 1 ⁇ -hydroxysteroid dehydrogenase (HSD) 1 inhibitor would bolster a temporal immune response in association with immunization to ensure that a cell based response would be obtained, and as such could be useful in immunomodulation.
• the compounds according to the invention are suitable for the prevention or treatment of diabetes, particularly type 1 and type 2 diabetes mellitus, and/or diabetic complications.
• the dosage required to achieve the corresponding activity for treatment or prevention usually depends on the compound which is to be administered, the patient, the nature and gravity of the illness or condition and the method and frequency of administration and is for the patient's doctor to decide.
• the dosage may be from 1 to 100 mg, preferably 1 to 30 mg, by intravenous route, and 1 to 1000 mg, preferably 1 to 100 mg, by oral route, in each case administered 1 to 4 times a day.
• the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, together with one or more inert conventional carriers and/or diluents, e.g.
• the compounds according to the invention may also be used in conjunction with other active substances, particularly for the treatment and/or prevention of the diseases and conditions mentioned above.
• Other active substances which are suitable for such combinations include for example those which potentiate the therapeutic effect of an 11 ⁇ -hydroxysteroid dehydrogenase (HSD) 1 inhibitor according to the invention with respect to one of the indications mentioned and/or which allow the dosage of an 11 ⁇ -hydroxysteroid dehydrogenase (HSD) 1 inhibitor according to the invention to be reduced.
• Therapeutic agents which are suitable for such a combination include, for example, antidiabetic agents such as metformin, sulfonylureas (e.g.
• glibenclamide tolbutamide, glimepiride
• nateglinide repaglinide
• thiazolidinediones e.g. rosiglitazone, pioglitazone
• SGLT 2 inhibitors e.g. dapagliflozin, sergliflozin
• PPAR- gamma-agonists e.g. Gl 262570
• antagonists PPAR-gamma/alpha modulators
• PPAR-gamma/alpha modulators e.g. KRP 297
• alpha-glucosidase inhibitors e.g. acarbose, voglibose
• DPPIV inhibitors e.g.
• Sitagliptin Vildagliptin, Saxagliptin, Alogliptin, BI 1356), alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin.
• the list also includes inhibitors of protein tyrosinephosphatase 1 , substances that affect deregulated glucose production in the liver, such as e.g.
• lipid lowering agents such as for example HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g.
• PPAR-alpha agonists e.g. avasimibe
• cholesterol absorption inhibitors such as, for example, ezetimibe
• bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as CETP inhibitors or ABC1 regulators or active substances for treating obesity, such as sibutramine or tetrahydrolipostatin, SDRIs, axokine, leptin, leptin mimetics, antagonists of the cannabinoidi receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or ⁇ 3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor.
• ACAT inhibitors e.g. avasimibe
• cholesterol absorption inhibitors such as, for example, ezetimibe
• bile acid-binding substances such as, for example,
• drugs for influencing high blood pressure, chronic heart failure or atherosclerosis such as e.g. A-Il antagonists or ACE inhibitors, ECE inhibitors, diuretics, ⁇ - blockers, Ca-antagonists, centrally acting antihypertensives, antagonists of the alpha-2-adre- nergic receptor, inhibitors of neutral endopeptidase, thrombocyte aggregation inhibitors and others or combinations thereof are suitable.
• angiotensin Il receptor antagonists examples include candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan, medoxomil, tasosartan, KT-3-671 , GA-0113, RU-64276, EMD-90423, BR-9701 , etc.
• Angiotensin Il receptor antagonists are preferably used for the treatment or prevention of high blood pressure and complications of diabetes, often combined with a diuretic such as hydrochlorothiazide.
• a combination with uric acid synthesis inhibitors or uricosurics is suitable for the treatment or prevention of gout.
• a combination with GABA-receptor antagonists, Na-channel blockers, topiramat, protein- kinase C inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors may be used for the treatment or prevention of complications of diabetes.
• the dosage for the combination partners mentioned above is usefully 1/5 of the lowest dose normally recommended up to 1/1 of the normally recommended dose.
• this invention relates to the use of a compound according to the invention or a physiologically acceptable salt of such a compound combined with at least one of the active substances described above as a combination partner, for preparing a pharma- ceutical composition which is suitable for the treatment or prevention of diseases or conditions which can be affected by inhibiting the enzyme 11 ⁇ -hydroxysteroid dehydrogenase (HSD) 1.
• HSD enzyme 11 ⁇ -hydroxysteroid dehydrogenase
• this invention relates to a pharmaceutical composition which comprises a compound according to the invention or a physiologically acceptable salt of such a compound and at least one of the active substances described above as combination partners, optionally together with one or more inert carriers and/or diluents.
• a pharmaceutical composition according to the invention comprises a combination of a compound of formula I according to the invention or a physiologically acceptable salt of such a compound and at least one angiotensin Il receptor antagonist optionally together with one or more inert carriers and/or diluents.
• the compound according to the invention, or a physiologically acceptable salt thereof, and the additional active substance to be combined therewith may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so-called kit-of-parts.
• Phenylacetylene (15.4 ml.) is added to a mixture of 2-bromo-4-methyl-pyridine (20.0 g), CuI
• the starting material 3,11 ,11-trimethyl-2,3,4,5-tetrahydro-1 H-2,6-methano-benzo[d]azocin-6- ol, is obtained in analogy to EP 28717 (1981 ) from 2-benzyl-1 ,3,3-trimethyl-piperidinone.
• the starting material 8-hydroxy-3-methyl-2,3,4,5-tetrahydro-1 H-2,6-methano- benzo[d]azocine-6-carboxylic acid methyl ester, may be obtained in analogy to J. Med. Chem. 1962, 5, 357-361 and US 3687957 (1972) from 8-methoxy-3-methyl-1-oxo-2,3,4,5- tetrahydro-1 H-2,6-methano-benzo[d]azocine-6-carbonitrile.
• the methoxy group on the aromatic ring may be cleaved by using boron tribromide in dichloromethane or hydrobromic acid in acetic acid (see e.g. J. Med. Chem. 1992, 35, 4135-4142; J. Med. Chem. 2004, 47, 165-174).
• the starting material may also be obtained by reacting compound Example XXII(I ) with boron tribromide according to Procedure J.
• the starting material 3,11 ,1 1-trimethyl-6-phenyl-1 ,2,3,4,5,6-hexahydro-2,6-methano- benzo[d]azocin-8-ol, may be obtained as described in DE 2027077 (1970).
• 3-methyl-6-propyl-1 ,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin- 8-ol may be obtained as described in J. Med. Chem. 1963, 6, 322-5.
• the starting material 3,6-Dimethyl-1 ,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-8-ol, may be obtained as described in J. Org. Chem. 1960, 25, 1386-8.
• the compound is prepared from (2/?,6S)-9-methoxy-6,1 1 ,1 1 -trimethyl-1 , 2, 3,4,5, 6-hexahydro- 2,6-methano-benzo[d]azocine [tartaric acid salt, for preparation see WO 9959976 (1999)] and isolated as the hydrogen bromide salt.
• Di-te/fbutyl dicarbonate (8.7 g) is added to a solution of 6, 1 1 , 1 1 -trimethyl-1 ,2, 3, 4, 5, 6- hexahydro-2,6-methano-benzo[d]azocin-9-ol (12.0 g) and triethylamine (8 ml) in dioxane (100 ml.) and water (100 ml_). The solution is stirred at room temperature overnight. Then, ethyl acetate is added and the organic phase is separated. The aqueous phase is extracted with ethyl acetate and the organic extract and phase are combined.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase or by using the enantiomerically pure starting material that in turn may be obtained as described in Example XIII(I ) or by resolution of the racemic mixture by HPLC on chiral phase.
• the synthesis of the racemic starting material is described in EP 521422 (1993).
• Trifluoro-methanesulfonic acid 3-(benzothiazole-6-carbonyl)-6-methyl-1 ,2,3 ,4,5,6-hexahvdro- 2,6-methano-benzo[d1azocin-8-yl ester
• Trifluoromethanesulfonic anhydride (0.77 mL) is added to a solution of benzothiazol-6-yl-(8- hydroxy-6-methyl-1 ,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-methanone (1.24 g; for synthesis see Example 92), triethylamine (3.4 mL), and 4-dimethylaminopyridine (10 mg) in dichloromethane (12 mL) chilled to -10 0 C under argon atmosphere. The solution is stirred at ca. -5 0 C for 30 min and then at room temperature overnight.
• Tetrakis(triphenylphosphine)palladium(0) (2.79 g) is added to a mixture of (2/?,6S)-trifluoro- methanesulfonic acid 3-benzyl-6,1 1 ,1 1-trimethyl-1 ,2,3,4,5,6-hexahydro-2,6-methano- benzo[d]azocin-10-yl ester (7.30 g) and zinc cyanide (2.85 g) in dimethylformamide (35 ml.) kept in argon atmosphere. The resulting mixture is stirred at 100 0 C for 6 h.
• the compound is prepared from 6,11 ,1 1-trimethyl-1 ,2,3,4,5,6-hexahydro-2,6-methano- benzo[d]azocine-9-carbonitrile applying the procedure described above.
• the compound is prepared from (2R,6R11 S)-6,11-dimethyl-1 , 2,3,4, 5,6-hexahydro-2,6- methano-benzo[d]azocine-8-carbonitrile applying the procedure described above.
• the compound may be prepared from 1-hydroxy-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1 H- 2,6-methano-benzo[d]azocine-6-carbonitrile [for synthesis see US 3687957 (1972)] as described above using methanol instead of ethanol.
• Pd(OH) 2 (0.20 g) is added to a solution of (2R,6S)-3-benzyl-6,1 1 ,1 1-trimethyl-1 ,2,3,4,5,6- hexahydro-2,6-methano-benzo[d]azocine-10-carboxylic acid ethyl ester (1.13 g) in ethanol
• the debenzylation is carried out in the presence of 1 equivalent of 1 M hydrochloric acid as described above.
• Aqueous 2 M Na 2 CC>3 solution (5 ml.) is added to a mixture of 6, 1 1 ,11 -trimethyl-9-trifluoro- methanesulfonyloxy-I ⁇ -tetrahydro ⁇ H ⁇ -methano-benzotdlazocine-S-carboxylic acid tert-butyl ester (1.00 g) and phenylboronic acid (0.34 g) in dimethylformamide (5 ml.) in argon atmosphere.
• the compound is obtained as its trifluoroacetic acid salt.
• the compound is obtained as its double trifluoroacetic acid salt.
• the compound is obtained as its double trifluoroacetic acid salt.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase or by using the enantiomerically pure (2S,6R)-8-methoxy-6,9,11 ,1 1-tetramethyl- I ⁇ -tetrahydro ⁇ H ⁇ -methano-benzotdJazocine-S-carboxylic acid tert-butyl ester.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase or by using the enantiomerically pure (2/?,6S)-8-methoxy-6,9,1 1 ,11-tetramethyl- 1 ,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase or by using the enantiomerically pure (2S,6R)-9-methoxy-6,8,1 1 ,1 1-tetramethyl- 1 ,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase or by using the enantiomerically pure (2/?,6S)-9-methoxy-6,8,1 1 ,11-tetramethyl- I ⁇ -tetrahydrc ⁇ lH ⁇ -rnethano-benzotdJazocine-S-carboxylic acid tert-butyl ester. (9) 8,9-Dimethoxy-6,1 1 ,11-trimethyl-1 ,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine
• the compound is obtained as its trifluoroacetic acid salt.
• the compound may be obtained from the racemic mixture by separation from the enantiomer by HPLC on chiral phase.
• the compound is isolated as its trifluoroacetic acid salt.
• the compound may be obtained from 1-hydroxy-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1 H- 2,6-methano-benzo[d]azocine-6-carboxylic acid methyl ester employing the procedure described above.
• the reduction may be conducted in analogy to J. Org. Chem. 1987, 52, 5233-5239.
• a mixture of 8, 9-dihydroxy-6,1 1 ,11 -trimethyl-1 ,2,5, 6-tetrahydro-4H-2,6-methano-benzo[d]- azocine-3-carboxylic acid tert-butyl ester (0.21 g), K 2 CO 3 (0.19 g) and diiodomethane (54 ⁇ l_) in dimethylformamide (5 ml.) is heated to 100 0 C and stirred at this temperature for 2 h. Then, another portion of diiodomethane (54 ⁇ l_) and K 2 CO 3 (0.18 g) is added and the mixture is further stirred at 100 0 C for 5 h.
• the racemic product mixture is resolved into its enantiomers by using HPLC on chiral phase.
• the compound may also be obtained in analogy to the procedure described in J. Med. Chem. 1997, 40, 2922-2930.
• the compound is isolated as its trifluoroacetic acid salt
• the compound is isolated as its trifluoroacetic acid salt
• the compound is isolated as its trifluoroacetic acid salt
• the compound is isolated as its trifluoroacetic acid salt
• the compound is isolated as its trifluoroacetic acid salt
• the compound is isolated as its trifluoroacetic acid salt
• (2R6S)-6,1 1 ,11-Trimethyl-1 ,2,3,4,5,6-hexahvdro-2,6-methano-benzordlazocine 10% Pd/C (0.20 g) is added to a solution of (2R,6S)-trifluoro-methanesulfonic acid 3-benzyl- 6,1 1 ,1 1-trimethyl-1 ,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-10-yl ester (0.50 g) in ethanol (10 ml_). The resulting mixture is shaken under hydrogen atmosphere (50 psi) at room temperature overnight.
• Trifluoroacetic anhydride (5.0 ml.) is added to a solution of the hydrobromic acid salt of
• Nitric acid (0.4 ml.) is slowly added to a solution of 2,2,2-trifluoro-1-[(2R,6S)-10-hydroxy- 6,1 1 ,1 1-trimethyl-1 ,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (2.9 g) in acetic acid (5 ml.) chilled in an ice bath. The ice bath is removed and the solution is stirred at ambient temperature overnight. The solution is poured into ice-cold water and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine and dried (Na 2 SC> 4 ).
• the compound is obtained in a mixture with compound Example XXXI 11(3) that is separated by chromatography as described above.
• Methyl iodide (80 ⁇ l_) is added to a mixture of (2R,6S)-2,2,2-trifluoro-1-(10-hydroxy-6,1 1 ,1 1- trimethyl-9-nitro-1 ,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl)-ethanone (0.40 g) and potassium carbonate (0.17 g) in dimethylformamide (5 ml_). The mixture is stirred at room temperature overnight, before another portion of methyl iodide (80 ⁇ l_) and potassium carbonate (0.16 g) are added. The mixture is stirred for another 6 h at room temperature.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase or by using the enantiomerically pure (2S,6R)-8-hydroxy-6,9,1 1 ,11-tetramethyl- 1 ,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase or by using the enantiomerically pure (2/?,6S)-8-hydroxy-6,9,11 ,1 1-tetramethyl- 1 ,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase or by using the enantiomerically pure (2S,6R)-9-hydroxy-6,8,1 1 ,11-tetramethyl- I ⁇ -tetrahydrc ⁇ lH ⁇ -rnethano-benzotdJazocine-S-carboxylic acid tert-butyl ester.
• the compound may be obtained by resolution of the racemic mixture by HPLC on chiral phase or by using the enantiomerically pure (2/?,6S)-9-hydroxy-6,8,11 ,1 1-tetramethyl- I ⁇ -tetrahydrc ⁇ lH ⁇ -rnethano-benzotdJazocine-S-carboxylic acid tert-butyl ester.
• the compound is obtained in a mixture with 8-hydroxy-9-methoxy-6,1 1 ,11 -trimethyl-1 , 2,5,6- tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester and 8,9- dimethoxy-6,1 1 ,11 -trimethyl-1 ,2,5, 6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3- carboxylic acid tert-butyl ester from 8, 9-dihydroxy-6, 1 1 ,1 1 -trimethyl-1 ,2, 5, 6-tetrahydro-4H- 2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester that may be separated by HPLC on reversed phase.
• the compound is obtained in a mixture with 9-hydroxy-8-methoxy-6,1 1 ,11 -trimethyl-1 , 2,5,6- tetrahydro-4H-2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester and 8,9- dimethoxy-6,1 1 ,11 -trimethyl-1 ,2,5, 6-tetrahydro-4H-2,6-methano-benzo[d]azocine-3- carboxylic acid tert-butyl ester from 8,9-dihydroxy-6,1 1 ,1 1 -trimethyl-1 ,2,5,6-tetrahydro-4H- 2,6-methano-benzo[d]azocine-3-carboxylic acid tert-butyl ester that may be separated by HPLC on reversed phase.
• the compound may be obtained from the racemic mixture by HPLC on chiral phase.
• the reaction mixture is stirred at 170 0 C for 5 h.
• Dimethylamine (3.3 mL, 2 M in THF) is added to a mixture of (2R6S)-6,1 1 ,1 1-trimethyl-3- (2,2,2-trifluoro-acetyl)-1 ,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine-8-sulfonyl chloride and (2R !
• Acetyl chloride (0.25 mL) is added to a suspension of AICI3 (1.3 g) in dichloromethane (5 ml.) chilled in an ice bath. After stirring the mixture for 5 min, 2,2,2-trifluoro-1 -[(2R,6S)-6,1 1 ,11 - trimethyl-1 ,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-ethanone (1.0 g) dissolved in dichloromethane (5 mL) is added dropwise. The mixture is stirred at ambient temperature overnight and then poured into ice-cold half-concentrated hydrochloric acid (20 mL).

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