Adamantyl acetamides as 11-beta hydroxysteroid dehydrogenase inhibitors

A compound having the formula

• the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
• n represents an integer being 0, 1 or 2;
• m represents an integer being 0 or 1;
• R1 and R2 each independently represents hydrogen, C1-4alkyl, NR9R10, C1-4alkyloxy, Het3-O—C1-4alkyl;
• or
• R1 and R2 taken together with the carbon atom with which they are attached form a carbonyl, or a C3-6cycloalkyl;
• and where n is 2, either R1 or R2 may be absent to form an unsaturated bond;
• R3 represents hydrogen, Ar1, C1-8alkyl, C6-12cycloalkyl or a monovalent radical having one of the following formulae
• wherein said Ar1, C6-12cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two or three substituents selected from the group consisting of C1-4alkyl, C1-4alkyloxy, phenyl, halo, oxo, carbonyl, 1,3-dioxolyl or hydroxy;
• R4 represents hydrogen or C1-4alkyl;
• Q represents C3-8cycloalkyl, Het1 or Ar2, wherein said C3-8cycloalkyl, Het1 or Ar2 are optionally substituted with one or where possible more substituents selected from halo, C1-4alkyl, C1-4alkyloxy, hydroxy, nitro, Het4, phenyl, phenyloxy, C1-4alkyloxycarbonyl, hydroxycarbonyl, NR5R6, C1-4alkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het2 and NR7R8, and
• C1-4alkyl substituted with one or where possible two or three halo substituents;
• R5 and R6 are each independently selected from hydrogen, C1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkyloxycarbonyl, C1-4alkylcarbonyl, C1-4alkylcarbonyl substituted with one or where possible two or three substituents each independently selected from halo, C1-4alkyl, and C1-4alkyloxy or R5 and R6 each independently represent C1-4alkyl substituted with phenyl;
• R7 and R8 are each independently selected from hydrogen or C1-4alkyl;
• R9 and R10 are each independently selected from hydrogen, C1-4alkyl or C1-4alkyloxycarbonyl;
• L represents C1-4alkyl optionally substituted with one or where possible more substituents selected from C1-4alkyl or phenyl;
• Het1 represents a heterocycle selected from pyridinyl, piperinidyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, furanyl, benzofuranyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, benzothiophenyl, thiophenyl, 1,8-naphthyridinyl, 1,6-naphthyridinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, or 1,3-benzodioxolyl;
• Het2 represents a monocyclic heterocycle selected from piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 2H-pyrrolyl, pyrrolyl,
• 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, or morpholinyl;
• Het3 represents a monocyclic heterocycle selected from 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl;
• Het4 represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het4 optionally being substituted with one or where possible two or more substituents each idependently selected from hydroxy, carbonyl, C1-4alkyl or C1-4alkyloxy;
• Ar1 represents carbocyclic radicals containing one or more rings selected from the group consisting of phenyl, biphenyl, indenyl, 2,3-dihydroindenyl, fluorenyl, 5,6,7,8-tetrahydronaphtyl or naphtyl
• Ar2 represents carbocyclic radicals containing one or more rings selected from the group consisting of phenyl, biphenyl, indenyl, 2,3-dihydroindenyl, fluorenyl, 5,6,7,8-tetrahydronaphtyl or naphtyl.

A compound of formula (I′)

• the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof wherein
• R1 and R2 each independently represents hydrogen, C1-4alkyl, NR9R10, C1-4alkyloxy or Het3-O—C1-4alkyl;
• preferably C1-4alkyl in particular methyl;
• or
• R1 and R2 taken together with the carbon atom with which they are attached from a C3-6cycloalkyl, in particular cyclopropyl or cyclobutyl;
• R4 represents hydrogen, C1-4alkyl, C2-4alkenyl;
• U represents hydrogen, C1-4alkyl, C1-4alkyloxy, phenyl, halo, oxo, carbonyl or hydroxy
• R5 and R6 are each independently selected from hydrogen, C1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkyloxycarbonyl, C1-4alkylcarbonyl, C1-4alkylcarbonyl substituted with one or where possible two or three substituents each independently selected from halo, C1-4alkyl, and C1-4alkyloxy or R5 and R6 each independently represent C1-4alkyl substituted with phenyl;
• R7 and R8 are each independently selected from hydrogen or C1-4alkyl;
• R9 and R10 are each independently selected from hydrogen, C1-4alkyl or C1-4alkyloxycarbonyl;
• R11 and R12 are each independently selected from hydrogen, halo, C1-4alkyl, C1-4alkyloxy, hydroxy, nitro, Het4, phenyl, phenyloxy, C1-4alkyloxycarbonyl, hydroxycarbonyl, NR5R6, C1-4alkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het2 and NR7R8, C2-4alkenyl substituted with one substituent selected from phenyl-C1-4alkyl-oxycarbonyl, C1-4alkyloxycarbonyl, hydroxycarbonyl, Het5-carbonyl, and
• C1-4alkyl substituted with one or where possible two or three substituents independently selected from halo, dimethylamine, trimethylamine, amine, cyano, Het6, Het7-carbonyl, C1-4alkyloxycarbonyl or hydroxycarbonyl;
• Het1 represents a heterocycle selected from pyridinyl, piperinidyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, furanyl, benzofuranyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, benzothiophenyl, thiophenyl, 1,8-naphthyridinyl, 1,6-naphthyridinyl, quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, 2H-benzopyranyl, 3,4-dihydro-2H-benzopyranyl, 2H-benzothiopyranyl, 3,4-dihydro-2H-benzothiopyranyl or 1,3-benzodioxolyl;
• Het2 represents a monocyclic heterocycle selected from piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 2H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, or morpholinyl, said Het2 optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C1-4alkyl or C1-4alkyloxy;
• Het3 represents a monocyclic heterocycle selected from 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl;
• Het4 represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl, triazolyl, tetrazolyl or morpholinyl, said Het4 optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C1-4alkyl or C1-4alkyloxy;
• Het5 represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het5 optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C1-4alkyl or C1-4alkyloxy;
• preferably piperazinyl or morpholinyl;
• Het6 represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het6 optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C1-4alkyl or C1-4alkyloxy;
• Het7 represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het7 optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C1-4alkyl or C1-4alkyloxy;
• preferably piperazinyl or morpholinyl;
• in particular morpholinyl.

A compound of formula (I″)

• the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein
• R4 represents hydrogen, C1-4alkyl, C2-4alkenyl;
• U represents hydrogen, C1-4alkyl, C1-4alkyloxy, phenyl, halo, oxo, carbonyl or hydroxy
• Q represents Het1 or Ar2, wherein said Het1 or Ar2 are optionally substituted with one or where possible more substituents selected from halo, C1-4alkyl, C1-4alkyloxy, hydroxy, nitro, Het4, phenyl, phenyloxy, C1-4alkyloxycarbonyl, hydroxycarbonyl, NR5R6, C1-4alkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het2 and NR7R8, and
• C1-4alkyl substituted with one or where possible two or three substituents independently selected from halo or hydroxycarbonyl;
• R5 and R6 are each independently selected from hydrogen, C1-4alkyl, C1-4alkyloxyC1-4alkyl, C1-4alkyloxycarbonyl, C1-4alkylcarbonyl, C1-4alkylcarbonyl substituted with one or where possible two or three substituents each independently selected from halo, C1-4alkyl, and C1-4alkyloxy or R5 and R6 each independently represent C1-4alkyl substituted with phenyl;
• R7 and R8 are each independently selected from hydrogen or C1-4alkyl;
• R9 and R10 are each independently selected from hydrogen, C1-4alkyl or C1-4alkyloxycarbonyl;
• Het1 represents a bicyclic heterocycle selected from indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, 1,8-naphthyridinyl, 1,6-naphthyridinyl, quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, 2H-benzopyranyl, 3,4-dihydro-2H-benzopyranyl, 2H-benzothiopyranyl, 3,4-dihydro-2H-benzothiopyranyl or 1,3-benzodioxolyl;
• Het2 represents a monocyclic heterocycle selected from piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 2H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, or morpholinyl, said Het optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, C1-4alkyl or C1-4alkyloxy;
• Het3 represents a monocyclic heterocycle selected from 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl;
• Het4 represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het4 optionally being substituted with one or where possible two or more substituents each idependently selected from hydroxy, carbonyl, C1-4alkyl or C1-4alkyloxy;
• Ar2 represents carbocyclic radicals containing two rings selected from the group consisting of benzocyclobutene, benzocycloheptanyl, benzosurbenyl, indenyl, 2,3-dihydroindenyl, 5,6,7,8-tetrahydronaphtyl or naphthyl.

A method to prepare 1-hydroxy-4-aminoadamantane said method comprising

• i) reductively aminating a corresponding ketone (XIII) to obtain stereomers of an amine of formula (XVIII);
• ii) separating the thus obtained stereomers of the amine of formula (XVIII);
• and
• iii) debenzylating the compounds of formula (XVIII)