ZA200505068B - Adamantyl acetamides as 11-beta hydroxysteroid dehydrogenase inhibitors - Google Patents

Description

' ADAMANTYL ACETAMIDES AS 11-BETA HYDROXYSTEROID

DEHYDROGENASE INHIBITORS

The metabolic syndrome is a disease with increasing prevalence not only in the

Western world but also in Asia and developing countries. It is characterised by obesity in particular central or visceral obesity, type 2 diabetes, hyperlipidemia, hypertension, arteriosclerosis, coronary heart diseases and eventually chronic renal failure (C.T.

Montague et al. (2000), Diabetes, 49, 883-888).

Glucocorticoids and 113-HSD1 are known to be important factors in differentiation of adipose stromal cells into mature adipocytes. In the visceral stromal cells of obese patients, 11B3-HSD1 mRNA level is increased compared with subcutaneous tissue.

Further, adipose tissue over-expression of 113-HSD1 in transgenic mice is associated with increased corticosterone levels in the adipose tissue, visceral obesity, insulin sensitivity, Type 2 diabetes, hyperlipidemia and hyperphagia (H. Masuzaki et al (2001),

Science, 294, 2166-2170). Therefore, 11B3-HSD1 is most likely be involved in the development of visceral obesity and the metabolic syndrome.

Inhibition of 11B-HSD1 results in a decrease in differentiation and an increase in proliferation of adipose stromal cells. Moreover, glucocorticoid deficiency (adrenalectomy) enhances the ability of insulin and leptin to promote anorexia and weight loss, and this effect is reversed by glucocorticoid administration (P.M. Stewart et al (2002), Trends Endocrin. Metabol, 13, 94-96). These data suggest that enhanced reactivation of cortisone by 113-HSD1 may cxacerbate obesity and it may be beneficial to inhibit this enzyme in adipose tissue of obese patients.

Obesity is also linked to cardiovascular risks. There is a significant relationship between cortisol excretion rate and HDL cholesterol in both men and women, suggesting that glucocorticoids regulate key components of cardiovascular risk. In analogy, aortic stiffness is also associated with visceral adiposity in older adults.

Glucocorticoids and glaucoma

Glucocorticoids increase the risk of glaucoma by raising the intraocular pressure when ) administered exogenously and in certain conditions of increased production like in

Cushing’s syndrome. Corticosteroid-induced elevation of intra ocular pressure is . caused by increased resistance to aqueous outflow due to glucocorticoid induced changes in the trabecular meshwork and its intracellular matrix. Zhou et al. (Int J Mol

: Med (1998) 1, 339-346) also reported that corticosteroids increase the amounts of fibronectin as well as collagen type I and type IV in the trabecular meshwork of organ- cultured bovine anterior segments. 11B-HSD1 is expressed in the basal cells of the corneal epithelium and the non- pigmented epithelial cells. Glucocorticoid receptor mRNA was only detected in the trabecular meshwork, whereas in the non-pigmented epithelial cells mRNA for the glucocorticoid-, mineralocorticoid receptor and 11B-HSD1 was present. Carbenoxolone administration to patients resulted in a significant decrease in intra-ocular pressure (S.

Rauz et al. (2001), Invest. Ophtalmol. Vis. Science, 42, 2037-2042), suggesting a role for HSD1-inhibitors in treating glaucoma.

Accordingly, the underlying problem to be solved by the present invention was to identify potent 11B-HSD inhibitors, with a high selectivity for 113-HSD1, and the use thereof in treating pathologies associated with excess cortisol formation such as obesity, diabetes, obesity related cardiovascular diseases, and glaucoma.

This invention concerns compounds of formula (I) o rR!

Q (Ln

Je “Rd

Rr? R* O 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;

R! and R? each independently represents hydrogen, Cialkyl, NR’R", C,.qatkyloxy,

Het®-0-C) alkyl; or

R' and R? taken together with the carbon atom with which they are attached form a ’ carbonyl, or a Csscycloalkyl; and where n is 2, either R! or R? may be absent to form an unsaturated bond; . R? represents hydrogen, Ar!, Cy zalkyl, Cs.i2cycloalkyl or a monovalent radical having one of the following formulae

ON J- Ax FPN <L “by @) ® © @ @ ® > gp Wo A$ bs 7: g © 0) ®@ ® w)

ELE UNO ETRE

0] 0 ® Po) ® o /=nN —N

QUO 2 0, fi © © ® wherein said Ar’, Cg.1ocycloalkyl or monovalent radical may optionally be substituted with one, or where possible two or three substituents selected from the group consisting of C;4alkyl, Ci4alkyloxy, phenyl, halo, oxo, carbonyl, 1,3- dioxolyl or hydroxy; in particular R? represents a monovalent radical having formula a) or b) optionally substituted with one, or where possible two or three substituents selected from the group consisting of Ci4alkyl, Cy4alkyloxy, phenyl, halo, oxo, carbonyl, 1,3-dioxolyl or hydroxy;

R* represents hydrogen, C; alkyl, or C, alkenyl;

Q represents Cs scycloalkyl, Het! or Ar?, wherein said Cs_gcycloalkyl, Het' or Ar? are optionally substituted with one or where possible more substituents selected from halo, C4alkyl, C;alkyloxy, hydroxy, nitro, Het’, phenyl, phenyloxy, C;. salkyloxycarbonyl, hydroxycarbonyl, NR’RS, C,alkyloxy substituted with one or where possible two or three substituents each independently selected from C;. salkyl, hydroxycarbonyl, Het?, Ci4alkyl or NR'RS,

C,.alkenyl substituted with one substituent selected from phenyl-C; 4alkyl- oxycarbonyl, C) salkyloxycarbonyl, hydroxycarbonyl or Het’-carbonyl, and

C,4alkyl substituted with one or where possible two or three substituents independently selected from halo, dimethylamine, trimethylamine, amine, cyano, i Het’, Het’-carbonyl, C4alkyloxycarbonyl or hydroxycarbonyl;

R® and R® are each independently selected from hydrogen, C,4alkyl, C,4alkyloxyC;. salkyl, C,4alkyloxycarbonyl, C;4alkylcarbonyl, Ci4alkylcarbony! substituted with one or where possible two or three substituents each independently selected from halo, C;.4alkyl, and C;alkyloxy or R® and R® each independently represent C;. salkyl substituted with phenyl;

R’ and R® are each independently selected from hydrogen or Cyalkyl;

- R’ and R'° are each independently selected from hydrogen, C;4alkyl or C;. salkyloxycarbonyl;

L represents C; 4alkyl optionally substituted with one or where possible more substituents selected from C;.alkyl or phenyl;

Het 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, 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;

Het ? represents a monocyclic heterocycle selected from piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 2H-pyrrolyl, pyrrolyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, or morpholiny), said Het* optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, C, alkyl or Cjalkyloxy;

Het’ represents a monocyclic heterocycle selected from 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl;

Het" represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl, triazolyl, tetrazolyl or morpholinyl, said Het" optionally being substituted with one or where possible two or more substituents each idependently selected from hydroxy, carbonyl, C;.4alkyl or Cy4alkyloxy;

Het’ represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het’ optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C;4alkyl or Cj4alkyloxy; in particular piperazinyl or morpholinyl;

Het® represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C;4alkyl or Cj alkyloxy; ’ Het’ represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het optionally being - substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C;.alkyl or Cy _alkyloxy; in particular selected piperazinyl or morpholinyl;

. Ar' 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 naphthyl

Ar represents carbocyclic radicals containing one or more rings selected from the group consisting of phenyl, biphenyl, benzocyclobutenyl, benzocycloheptanyl, benzosuberenyl, indenyl, 2,3-dihydroindenyl, fluorenyl, 1,2-dihydronaphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl.

As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C,_jalkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethy] and the like; C, salkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 8 carbon atoms such as the groups defined for C; 4yalkyl and pentyl, hexyl, octyl, 2-methylbutyl 2-methylpentyl, 2,2-dimethylpentyl and the like;C; scycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Ce.1ocycloalkyl is generic to cycloheptyl and cyclo-octanyl, cyclononane, cyclodecane, cycloundecane and cyclododecane; C;alkyloxy defines straight or branched saturated hydrocarbon } radicals such as methoxy, ethoxy, propyloxy, butyloxy, 1-methylethyloxy, 2- methylpropyloxy and the like.

As used herein before, the terms oxo or carbonyl refers to (=O) that forms a carbonyl moiety with the carbon atom to which it is attached.

The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms, which the compounds of formula (I), are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for ’ example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic, tartaric, citric, methanesulfonic, - ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic base addition salt forms which the

-6~ ‘ compounds of formula (T), are able to form. Examples of such base addition salt forms are, for example, the sodium, potassium, calcium salts, and also the salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, N-methyl-D-glucamine, hydrabamine, amino acids, e.g. arginine, lysine.

Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form.

The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I), as well as the salts thereof, are able to form. Such solvates are for example hydrates, alcoholates and the like.

The term stereochemically isomeric forms as used hereinbefore defines the possible different isomeric as well as conformational forms which the compounds of formula (I), may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stercochemically and conformationally isomeric forms, said mixtures containing all diastereomers, enantiomers and/or conformers of the basic molecular structure. All stereochemically isomeric forms of the compounds of formula (I), both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.

The N-oxide forms of the compounds of formula (I), are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the : so-called N-oxide.

An interesting group of compounds consists of those compounds of formula (1) wherein one or more of the following restrictions apply : (1) n represents an integer being 1 or 2 provided that when n represents 2, Q represents

Het' or Ar’, wherein said Het or Ar” are optionally substituted with one or where possible more substituents selected from halo, Cialkyl, Cy4alkyloxy, hydroxy, ’ nitro, Het®, phenyl, phenyloxy, hydroxycarbonyl, NR°R®, C 14alkyloxy substituted with one or where possible two or three substituents each independently selected - from hydroxycarbonyl, Het? and NR'R®, and

Ci.salkyl substituted with one or where possible two or three halo substituents; (ii) R'andR? each independently represents hydrogen, Cj.alkyl, NR°R', C,. salkyloxy, Het’-O-Cy alkyl; or

: R' and R? taken together with the carbon atom with which they are attached form a carbonyl, or a Cs. ¢cycloalkyl; (iii) R? represents phenyl, Cg.12cycloalkyl or a monovalent radical having one of the following formulae /

Wo A oes ® ® © ©

USE VERON

@ ® ® Nom

Woo QO ® @ ® 0

WW 0-0 ® ® To © wherein said phenyl, Cs.12cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two or three substituents selected from the group consisting of Csalkyl, Cj 4alkyloxy, halo, carbonyl, phenyl or hydroxy; in particular R® represents a monovalent radical having formula a) or b) optionally substituted with one, or where possible two or three substituents selected from the group consisting of C;_alkyl, Cysalkyloxy, halo, carbonyl, phenyl or hydroxy; (iv) R* represents hydrogen or C 14alkyl; (v) Q represents Het' or Ar’, wherein said Het’ or Ar” are optionally substituted with one or where possible more substituents selected from halo, Cy.alkyl, Ci. salkyloxy, hydroxy, nitro, Het’, phenyl, phenyloxy, hydroxycarbonyl, NR’RS, C,. salkyloxy substituted with one or where possible two or three substituents each independently selected from C;.alkyl hydroxycarbonyl, Het” and NR'R®, and

C,4alkyl substituted with one or where possible two or three halo substituents; (vi) Het' represents a heterocycle selected from piperinidyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, benzofuranyl, . benzothiophenyl, 1,8-naphthyridinyl, 1,6-naphthyridinyl, quinazolinyl, phthalazinyl, or 1,3-benzodioxolyl.; (vii) Ar? represents phenyl or naphtyl optionally substituted with Cy4alkyl, Cy alkyloxy or halo; preferably substituted with methyl or methoxy.

Another interesting group of compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply :

: {) R' and R? each independently represents hydrogen Cj4alkyl, NR’RY; or

R' and R? taken together with the carbon atom with which they are attached form a Cs 4cycloalkyl; and where n is 2, either RlorR? may be absent to form an unsaturated bond; (i) Rrepresents a Csocycloalkyl or a monovalent radical having one of the following formulae

WO A

@ ® ©

GRRE) @ ® ® 9

T x ay) 9) : ® ™) ® ®

N ~C x

LERVEPS

W ® © wherein said Cg.1ocycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of C,.4alkyl, C)4alkyloxy, halo, carbonyl, hydroxy, or 1,3-dioxolyl; in particular R? represents a monovalent radical having formula a) or b) optionally substituted with one, or where possible two or three substituents selected from the group consisting of C,4alkyl, C;_4alkyloxy, halo, carbonyl, or hydroxy; (iii) Q represents Het' or Ar* wherein said Het! or Ar® are optionally substituted with one or where possible two or more substituents selected from halo,

Ciaalkyl, Csalkyloxy, hydroxy, Cisalkyloxycarbonyl, Het, NR°R®,

Cisalkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het? and NRRS,

Czalkenyl substituted with one substituent selected from phenyl-C4alkyl- oxycarbonyl or Het*-carbonyl and

Ci.alkyl substituted with one or where possible two or three substituents each . independently selected from halo, dimethylamine, amine, cyano, Het’, Het'- carbonyl or hydroxycarbonyl; (iv) R’and RS are each independently selected from hydrogen, Cy.alkyl, C,. salkylcarbonyl, C, salkylcarbonyl substituted with one or where possible two or three halo substituents.

~) R® and R'® are each independently selected from hydrogen or C;4alkyl; (vi) L represents a C;4alkyl, preferably methyl; (vii) Het! represents a heterocycle selected from pyridinyl, pyrimidinyl, indolyl, thiophenyl, benzothiophenyl, quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 2H-benzopyranyl, 3,4-dihydro- 2H-benzopyranyl, 2H-benzothiopyranyl, 3,4-dihydro-2H-benzothiopyranyl or 1,3-benzodioxolyl; (viii) Het? represents a monocyclic heterocycle selected from piperidinyl, piperazinyl, pyridinyl, pyrrolidiny] or morpholinyl, said Het® optionally being substituted with one or where possible two or more C; 4alkyl substituents ; (ix) Het represents tetrazolyl; (x) Het’ represents morpholinyl; (xi) Het® represents a monocyclic heterocycle selected from pyrrolidinyl, piperazinyl or morpholinyl, said Het® optionally being substituted with one or where possible two or more hydroxy substituents, preferably with one hydroxy substituent; (xii) Het represents a monocyclic heterocycle selected from piperazinyl or morpholinyl, preferably morpholiny}l; (xii) Ar? represents carbocyclic radicals containing one or more rings selected from the group consisting of phenyl, benzocyclobutene, benzocycloheptanyl, benzosuberenyl, indenyl, 2,3-dihydroindenyl, 5,6,7,8-tetrahydronaphthyl or naphthyl.

A particular group of compounds of formula (I) were those compounds shown fo be highly HSD1 specific. For these compounds of formula (I) one or more of the following restrictions apply : 6) n represents an integer being 0, 1 or 2; (i) Rand R? each independently represents hydrogen, C,alkyl, NR°R'; or

R' and R? taken together with the carbon atom with which they are attached form a Cs ¢cycloalkyl; and where n is 2, either R! or R* may be absent to form an unsaturated bond; (iii) R® represents a Cs.jocycloalkyl, preferably cylo-octanyl or a monovalent radical having one of the following formulae

. /

JONPREe ® ® © wu do ©@ ® @ 9)

Ne 21 AD ~ ® 1) ® G pUNBURD (u) 0) (0) , preferably having the formula (a) or (b) above, wherein said Ce.12cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of Csalkyl,

Ci4alkyloxy, halo or hydroxy; preferably having the formula a) above optionally substituted with C; alkyl, C;salkyloxy, halo or hydroxy; (iv) Q represents Het! or Ar” wherein said Het! or Ar” are optionally substituted with one or where possible two or more substituents selected from halo, Cj alkyl, C) salkyloxy, hydroxy, NR°R,

Ciualkyloxy substituted with one or where possible two, three or more substituents each independently selected from hydroxycarbonyl, Het” or NR'R?,

C.4alkenyl substituted with one substituent selected from phenyl-C;4alkyl- oxycarbonyl or Het’-carbonyl and C;.alkyl substituted with one or where possible two or three substituents selected from halo, Het®, Cy4alkyloxycarbonyl or hydroxycarbonyl; (v) Rand RS each independently represent hydrogen or C;_salkyl; (vi) R® and R'? each independently represent hydrogen or C;alkyloxycarbonyl; (vii) L represents Ciaalkyl; (viii) Het’ represents a heterocycle selected from pyridinyl, piperidinyl, thiophenyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 2H- benzopyranyl, 3,4-dihydro-2H-benzopyranyl, 3,4-dihydro-2H-benzothiopyranyl or 1,3-benzodioxol; : (ix) Het represents pyridinyl, pyrrolidinyl or morpholinyl; x) Het? represents morpholinyl; (xi) Ar” represents phenyl, benzocyclobutene, benzocycloheptanyl, benzosuberenyl, 2,3-dihydroindenyl, 5,6,7,8-tetrahydronaphthyl, naphtyl or indenyl.

: A subgroup of these highly HSD1 specific inhibitors was shown to have a superior cellular activity and consist of compounds of formulae (I) wherein one or more of the following restrictions apply (1) n represents an integer being 0, 1 or 2; (i) R'andR?each independently represents hydrogen, C, alkyl; or

R! and R? taken together with the carbon atom with which they are attached form a Cs scycloalkyl; and where n is 2, either R* or R? may be absent to form an unsaturated bond; (iii) R® represents a Ce-12cycloalkyl, preferably cylo-octanyl or a monovalent radical having one of the following formulae

We A ® ® ©

LRN) iE © 0 0 , in particular having the formula (a) or (b) above, wherein said Cs.12cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of C; alkyl,

Ci4alkyloxy, halo or hydroxy; preferably having the formula a) above optionally substituted with C; alkyl, Calkyloxy, halo or hydroxy; (iv) Q represents Het or Ar® wherein said Het! or Ar? are optionally substituted with one or where possible two or more substituents selected from halo, Cyalkyl, C;4alkyloxy, hydroxy, NR°RS,

Cjalkyloxy substituted with one or where possible two, three or more substituents each independently selected from hydroxycarbonyl, Het? and

NR'R?,

C.salkenyl substituted with one Het>-carbonyl and Csalkyl substituted with one or where possible two or three substituents selected from halo, Het®, C4alkyloxycarbonyl or hydroxycarbonyl; : (v) R’andRS each independently represent hydrogen or C)alkyl; (vi) L represents C;salkyl; (vii) Het represents a heterocycle selected from pyridinyl, piperidinyl, thiophenyl, 2H-benzopyranyl, 3,4-dihydro-2H-benzopyranyl, 3,4-dihydro-2H- ‘ benzothiopyranyl or 1,3-benzodioxol;

(viii) Het” represents pyrrolidinyl or morpholinyl; (ix) Het’ represents morpholinyl; (x) Het® represents morpholinyl; (xi) Het’ represents morpholinyl; (ix) Ar represents phenyl, benzocyclobutene, benzocycloheptanyl, benzosuberenyl, 5,6,7,8-tetrahydronaphthyl, naphtyl or indenyl.

Further interesting compounds according to the invention are those compounds of formulae (I) wherein one or more of the following restrictions apply n represents an integer being 1 or 2; (ii) R'andR?each independently represents hydrogen C;alkyl, NR°RY, C,. salkyloxy; or

R’ and R? taken together with the carbon atom with which they are attached form a Csecycloalkyl; and where n is 2, either R! or R2 may be absent to form an unsaturated bond; (iid) R? represents a Cs.12cycloalkyl, preferably selected from cylo-octanyl and cyclohexyl or R? represents a monovalent radical having one of the following formulae

JOR SEPCER

: N @® ® © W @ 0] ® ® § G0, 0 0) ® ® © wherein said Ce.12cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of C, alkyl, C;4alkyloxy, halo or hydroxy; in particular having the formula (a) or (b) above, wherein said Cs.12cycloalkyl or : monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of C; 4alkyl,

Ci4alkyloxy, halo or hydroxy; preferably having the formula a) above optionally substituted with C,4alkyl, C,<alkyloxy, halo or hydroxy; (iv) Qrepresents Csscycloalkyl, Het' or Ar® wherein said Cs-scycloalkyl, Het! or

Ar? are optionally substituted with one or where possible two or more substituents selected from halo, C;4alkyl, C; 4alkyloxy, hydroxy, nitro, NR°R®,

‘ Cialkyloxy substituted with one or where possible two, three or more substituents each independently selected from hydroxycarbonyl, Het” and

NRR? and C,4alkyl substituted with one or where possible two or three halo substituents, preferably trifluoromethyl; (v) R’andR®each independently represent hydrogen, Ci alkyl, or C;4alkyl substituted with phenyl; (vi) L represents C,4alkyl; (vii) Het’ represents a heterocycle selected from pyridinyl, piperidinyl, or thiophenyl; (viii) Het’ represents piperidinyl, pyrrolidinyl or morpholinyl; (ix) Ar’ represents phenyl, naphtyl or indenyl.

A particular group of compounds of formula (I) are those where one or more of the following restrictions apply : @ n represents an integer being 0, 1 or 2; (i) R'andR®each independently represents hydrogen C;_alkyl, NR°R'’, C,. salkyloxy; or

R' and R? taken together with the carbon atom with which they are attached form a Cs 4cycloalkyl; and where n is 2, either R' or R? may be absent to form an unsaturated bond; (iii) R® represents a Cs.1zcycloalkyl, preferably selected from cylo-octanyl and cyclohexyl or R? represents a monovalent radical having one of the following formulae

Gk o, ©@ o ® pt L

Lo py

Th @ *) ® preferably having the formula (a) above, wherein said Cs.j2cycloalkyl or : 25 monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of C; salkyl, } Ci4alkyloxy, halo or hydroxy; (iv) rR? represents hydrogen or C, alkyl; wv) Q represents Het’ or Ar® wherein said Csscycloalkyl, Het! or Ar? are optionally substituted with one or where possible two or more substituents selected from halo, C,4alkyl, C;alkyloxy, hydroxy, nitro, NR°R®,

. Cisalkyloxy substituted with one or where possible two, three or more substituents each independently selected from hydroxycarbonyl, Het? or NR'R®,

Cz.alkenyl substituted with phenyl-C, 4alkyl-oxycarbonyl and Cj salkyl substituted with one or where possible two or three substituents selected from, halo, Het®, Het'-carbonyl, Ci.alkyloxycarbonyl or hydroxycarbonyl; (vi) R®and R® each independently represent hydrogen, C;4alkyl, or C;4alkyl substituted with phenyl; (vii) L represents C;.4alkyl; (viii) Het! represents a heterocycle selected from pyridinyl, thiophenyl, 2H- benzopyranyl, 3,4-dihydro-2H-benzopyranyl, 3,4-dihydro-2H-benzothiopyranyl or 1,3-benzodioxolyl; (ix) Het’ represents piperidinyl, pyrrolidinyl or morpholinyl; (x) Het® represents a monocyclic heterocycle selected from piperazinyl or morpholinyl, preferably morpholinyl; (xi) Ar’ represents phenyl, benzocyclobutene, benzocycloheptanyl, benzosuberenyl, 2,3-dihydroindenyl, 1,2-dihydronaphthyl, 5,6,7,8-tetrahydronaphthyl, naphtyl or indenyl.

A preferred group of compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply : (i) Q represents phenyl, said phenyl optionally substituted with one or two substituents selected from the halo, preferably chloro or fluor, or C;4alkyloxy preferably methoxy. ; (i) nis I; (iii) m is 0; (iv) R! and R? represent Ci4alkyl, preferably methyl; or

R' and R? taken together with the carbon atom with which they are attached form a

Cs.gscycloalkyl, preferably cyclopropyl; (v) R* represents hydrogen; : (vi) R® represents a monovalent radical having one of the following formulae

. AN

Woe A oan © ® © © ©

Ne X ce @ ® ®

Door og WW Te 0 6 ® ® wherein said monovalent radical may optionally be substituted with one or where possible two or three substituents selected from halo, carbonyl, hydroxy or Cj. salkyloxy, preferably methoxy, in particular R® represents a monovalent radical having the formula (a) or (b) above optionally substituted with one, or where possible two, three or more substituents selected from the group consisting of halo, carbonyl, hydroxy or C,alkyloxy; preferably having the formula a) above optionally substituted with hydroxy or Cj4alkyloxy, preferably methoxy.

Also of interest are those compounds of formula (I) wherein one ore more of the following restrictions apply; @) Het! represents a heterocycle selected from piperinidyl, pyrimidinyl, pyrazinyl, piperazinyl, pyridazinyl, indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, 1,8-naphthyridinyl, 1,6-naphthyridinyl, quinazolinyl, phthalazinyl, or 1,3-benzodioxolyl; (ii) Q represents Het or Ar” wherein said Het' or Ar” are optionally substituted with one or where possible two or more substituents selected from halo, C;. salkyl, C,alkyloxy, hydroxy, NR°R®, C 14alkyloxy substituted with one or where possible two, three or more substituents each independently selected from hydroxycarbonyl, Het? and NR'R?, and Ci.alkyl substituted with one or where possible two or three halo substituents; or Q represents phenyl, said phenyl optionally substituted with one or two substituents selected from the halo, preferably chloro or fluor, or C,salkyloxy preferably methoxy; (ili) nrepresents an integer being 1 or 2;or nn is 1; (iv) misO; (v) Rand R® represent hydrogen C,.ialkyl, NR’R", preferably C, alkyl, in particular methyl; or

R' and R” taken together with the carbon atom with which they are attached form a C3 gcycloalkyl, preferably cyclopropyl; and where n is 2, either R! or R? may be absent to form an unsaturated double bond (vi) R*represents hydrogen;

- i) R? represents a monovalent radical having one of the following formulae [&)] ®) © @ =

Wa OO § @ ® ® ®

AN

O or 0

Te ® ® ® wherein said monovalent radical may optionally be substituted with one or where possible two or three substituents selected from halo, carbonyl, hydroxy or C,alkyloxy, preferably methoxy; or

R’ represents a Cs.12cycloalkyl, preferably cylo-octanyl or a monovalent radical having one of the following formulae ® ® A o 0 (0)

AY - @ ® © oo wherein said Cs.12cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of C.alkyl, C;4alkyloxy, halo or hydroxy; or

R? represents a Ce-12cycloalkyl or a monovalent radical having one of the following formulae

Ax

J AX

@®) ®) © (0)

AQ OO

@ ® ® (©) r ~ gE oO ®) 0) ® © wherein said Cs.1ocycloalky] or monovalent radical may optionally be } substituted with one, or where possible two, three or more substituents selected from the group consisting of C, alkyl, C,4alkyloxy, halo or hydroxy; preferably R® represents a monovalent radical having one of the following formulae

WD wherein said monovalent radical may optionally be substituted with one or where possible two or three substituents selected from halo, carbonyl, hydroxy or Cy 4alkyloxy, preferably a substituent selected from bromo, fluoro, chloro, hydroxy or methoxy; even more preferably those compounds wherein the R? substituent is 2-adamantyl optionally substituted with one, or where possible two or three substituents selected from the group consisting of C;4alkyl, Ci. salkyloxy, halo, oxo, carbonyl or hydroxy, preferably a substituent selected from bromo, fluoro, chloro, hydroxy or methoxy; (viii) R’andR®each independently represent hydrogen or C;salkyl; (ix) R’andR' each independently represent hydrogen or C;alkyloxycarbonyl; (x) L represents Cialkyl; (xi) Het represents a heterocycle selected from pyridinyl, piperidinyl, thiophenyl or 1,3-benzodioxol; (xii) Het? represents pyridinyl, pyrrolidinyl or morpholinyl; (xiii) Ar" represents phenyl, naphtyl or indenyl.

A particular group of compounds are those compounds of formula (I) wherein R® is optionally substituted 2-adamantyl and wherein Q represents an optionally substituted phenyl, hereinafter referred to as the compounds of formula (I)

R'? Na il

AN "

PRpeS rR" @ the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof wherein

R'and R?each independently represents hydrogen, Ci4alkyl, NR°R'®, C 14alkyloxy or

Het’-O-C; alkyl; preferably Calkyl in particular methyl; or

R' and R? taken together with the carbon atom with which they are attached from a

Csscycloalkyl, in particular cyclopropyl! or cyclobutyl;

R* represents hydrogen, C; alkyl, C; alkenyl;

U represents hydrogen, C;4alkyl, Ci4alkyloxy, phenyl, halo, oxo, carbonyl or hydroxy

R® and R° are each independently selected from hydrogen, C;.salkyl, C,4alkyloxyC,. salkyl, Ci4alkyloxycarbonyl, C4alkylcarbonyl, C;ualkylcarbonyl substituted with

: one or where possible two or three substituents each independently selected from halo, Cy.salkyl, and C)4alkyloxy or R® and R® each independently represent C,- salkyl substituted with phenyl;

R’ and R* are each independently selected from hydrogen or C,_alkyl;

R’andR'® are each independently selected from hydrogen, C,salkyl or Ci. salkyloxycarbonyl;

R' and R'* are each independently selected from hydrogen, halo, C; alkyl, C,. salkyloxy, hydroxy, nitro, Het", phenyl, phenyloxy, C;isalkyloxycarbonyl, hydroxycarbonyl, NR°R®, C,4alkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het” and

NRR?, C;4alkenyl substituted with one substituent selected from phenyl-C,. salkyl-oxycarbonyl, C;alkyloxycarbonyl, hydroxycarbonyl, Het’-carbonyl, and

Ci4alkyl substituted with one or where possible two or three substituents independently selected from halo, dimethylamine, trimethylamine, amine, cyano,

Het®, Het’-carbonyl, Ci.alkyloxycarbonyl or hydroxycarbonyl;

Het' 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, isoquinoliny], 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.;

Het” 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, carbonyl, C;4alkyl or C,4alkyloxy;;

Het’ represents a monocyclic heterocycle selected from 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl;

Het" represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl, triazolyl, tetrazolyl or morpholinyl, said Het* ’ optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, Ciualkyl or Cj4alkyloxy; . Het” represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het’ optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C;4alkyl or Cy4alkyloxy; preferably piperazinyl or morpholinyl;

: Het® represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het’ optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C;4alkyl or Ci4alkyloxy;

Het represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het’ optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C;4alkyl or C)4alkyloxy: preferably piperazinyl or morpholinyl; in particular morpholinyl.

Also of interest are those compounds of formula (I’) wherein one or more of the following restrictions apply; i) R' and R? each independently represents hydrogen, C,4alkyl, C;4alkyloxy; preferably methyl or methoxy; (ii) R*represents hydro gen; (iii) U represents hydrogen, hydroxy or halo, in particular hydrogen, hydroxy, fluoro or chloro; (iv) R®and R® are each independently selected from hydrogen, C;alkyl, C;. salkyloxyC, salkyl, C; salkylcarbonyl, or C, 4alkylcarbonyl substituted with halo; (v) RR’ and R® represent Ci4alkyl, preferably methyl; (vi) Rand R'? are each independently selected from hydrogen, C,4alkyl, such as in particular methyl or propyl, C,_salkyloxy, hydroxy, nitro, Het®, NR’RS,

Ci4alkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het?, C, alkyl or NR'R®,

Casalkenyl substituted with one substituent selected from phenylC)alkyloxy- carbonyl, C; salkyloxycarbonyl, hydroxycarbonyl or Het’-carbonyl, and

Cisalkyl substituted with one or where possible two or three substituents independently selected from halo, dimethylaminc, trimethylamine, amine, Het?

Het -carbonyl or hydroxycarbonyl; (vii) Het” represents piperidinyl, piperazinyl, pyrrolidinyl or morpholinyl, said Het? : optionally being substituted with C;4alkyl, in particular methyl; (viii) Het" represents tetrazolyl; (ix) Het’ represents morpholinyl; : (x) Het® represents pyridazinyl, pyrrolidiny] or morpholinyl, said Het* optionally being substituted with carbonyl or C;_salkyl.

: Also of interest are those compounds of formula a)

R

0 [ 1, a the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein

R* represents hydrogen, Cjialkyl, Cz4alkenyl;

U represents hydrogen, C.salkyl, C4alkyloxy, phenyl, halo, oxo, carbonyl or hydroxy

Q represents Het’ or Ar’, wherein said Het! or Ar? are optionally substituted with one or where possible more substituents selected from halo, C)4alkyl, C;alkyloxy, hydroxy, nitro, Het", phenyl, phenyloxy, Cialkyloxycarbonyl, hydroxycarbonyl,

NR°RS,

Ci ualkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het* and NR'R?, and

C,4alkyl substituted with one or where possible two or three substituents independently selected from halo or hydroxycarbonyl;

R® and R® are each independently selected from hydrogen, C;ualkyl, C;4alkyloxyC. salkyl, C,salkyloxycarbonyl, Cialkylcarbonyl, C;4alkylcarbony! substituted with one or where possible two or three substituents each independently selected from halo, C;.4alkyl, and C, salkyloxy or R® and R® each independently represent C,. salkyl substituted with phenyl;

R” and R® are each independently selected from hydrogen or C,4alkyl;

R® and R'® are each independently selected from hydrogen, Ci4alkyl or Cy. salkyloxycarbonyl;

Het' 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-benzothiopyrany! or 1,3- benzodioxolyl.; : 30 Het” 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, Ci4alkyl or C;alkyloxy;

- Het? represents a monocyclic heterocycle selected from 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl;

Het" represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het* optionally being substituted with one or where possible two or more substituents each idependently selected from hydroxy, carbonyl, C;4alkyl or C;_alkyloxy;

Ar* 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 further group of compounds are those compounds of formula (I’’) wherein one or more of the following restrictions apply; . ® U represents hydrogen, halo or hydroxy; (i) Q represents Het' or Ar’, wherein said Het' or Ar® are optionally substituted with one or where possible two or more substituents selected from halo, C,. salkyl, Csalkyloxy, hydroxy, C;4alkyloxycarbonyl,

Ci4alkyloxy substituted with hydroxycarbonyl, and

Ciualkyl substituted with hydroxycarbonyl; (iii) Het represents a bicyclic heterocycle selected from benzothiophenyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro- isoquinolinyl, 2H-benzopyranyl, 3,4-dihydro-2H-benzopyranyl, or 2H- benzothiopyranyl; (iv) Ar” represents benzocyclobutene, benzocycloheptanyl, benzosuberenyl, indenyl, 2,3-dihydroindenyl or 5,6,7,8-tetrahydronaphthyl.

The amide compounds of this invention can be prepared by any of several standard synthetic processes commonly used by those skilled in the art of organic chemistry and described for instance in; “Introduction to organic chemistry” Streitweiser and Heathcock — Macmillan Publishing Co., Inc. — second edition - New York — Section 24.7 (partA) p 753-756. In general, the amides can be prepared through a base- catalyzed nucleophilic addition between the appropriate carboxylic acid with the corresponding amine (scheme 1), or via a nucleophilic substitution reaction wherein the : appropriate amine reacts with either the corresponding acyl halide (scheme 2), anhydride or ester, to yield the required amide.

When coupling the acids to the amines, standard chemical coupling reagents such as carbonyldiimidazole (CDI), 1.3-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-(3’-

: dimethylaminopropyl)carbodiimide hydrochloride (EDCI) are used in the presence or absence of hydroxybenzotrialzole (HOB). In general, adding of the carboxylic acids of formula (III) to the amines of formula (II) under base-catalyzed reaction conditions results in the formation of the amine salt which is in equilibrium with its weak acid and base. To force the equilibrium to the formation of the amide of formula D,a dehydrogenating agent such as carbodiimides, for example DCC and CDI are added to the reaction mixture.

Scheme 1 rR!

R! 0 coupling reagent 0 +

Q Um oo Q | 4 ~n3 oH # R RR Nn

R? R? Rr? No am ® ®

In an alternative embodiment the carboxylic acids or converted into the corresponding acyl halides by reaction with, for example, thionyl chloride or oxalyl chloride.

Subsequently said acyl halide (V) is added to the amine of formula (II) to yield the amide of formula (I) using art known reaction procedures such as the Schotten-

Baumann method. oO Scheme 2 rR’

Q n OH

Rr? 1)

SOCl, / o R' o

R' (CO H,0

Q + HN “Rr? — Q ’ cl NaOH

RB? 2 NTO . R2 Im Rr* Ns \2 oO ’ 15

The carboxylic acids of formula (IT) and the amines of formula (II) are readily available, or may be prepared using methods that are well known in the art. Many

} compounds are commercially available, for example, from Aldrich Chemicals, or when the compounds are not commercially available, they may be readily prepared from available precursors using straightforward transformations that are well known in the art.

For example the carboxylic acids are most often prepared by hydrolysis of nitriles (scheme 3), carbonation of organometallic compounds or oxidation of primary alcohols or aldehydes, see for instance in; “Introduction to organic chemistry” Streitweiser and

Heathcock — Macmillan Publishing Co., Inc. — second edition - New York — Section 19.6 p 509-511. In particular the carboxylic acids of formula (III) are prepared from the corresponding (hetero)aryl acetonitriles (VI) by conversion to the dialkyl or spiroalkyl derivative (VII) using e.g., sodium hexamethyldisilazane and methyl iodide or dibromobutane (see e.g., Trivedi et al, J. Med. Chem. 1993, 36, 3300), followed by hydrolysis under acidic or basic conditions to the desired carboxylic acid IIL

Appropriate acids and bases in the hydrolysis are for example H,SO4 and KOH. The hydrolysis reaction can be conveniently performed using microwave heating.

Many of the nitriles of formula (VI) are commercially available, or when they are not available they may be readily prepared from available (hetero)aryl-methyl derivatives (X) under art known conditions, for example by bromination using N-bromo- succinamide (NBS) followed by substitution of bromine by CN using, for example

KCN.

Scheme 3

EOB20 H . NaHMDS reflux a SAN

NN To OC °

Rj Ry

Ry R, vD ID an lo

Q Br NBS Q

NN -— ~N

I. 0

. In many cases the carboxylic acids wherein Q represents a bromo-substituted aryl (III-

A) were further modified according to reaction scheme 4. In a first step the bromo substituent was modified using the Heck reaction with acrylic esters, amides or acrylonitrile to obtain compounds of formula (XII). Reduction of double bond and functional groups yielded substituted amines of formula (XIV).

Scheme 4

R3

Br “Ra \o

H EE —. H Reduction

R1 ° Heck reaction Rt 0 (I-A) (XID

R4

R3 A . R5

Reduction

H Ee —— H

Ri oO “or Alkyl ation R1 0] (XIE av)

For those compounds of formula (I) where Q represents carbocyclic radicals containing two rings, the appropriate bicyclic carboxylic acids of formula (III-B) were synthesised, for example, by addition of trimethylsilylcyanide to corresponding ketones (XV) followed by acidic or basic hydrolysis of nitrile compounds (XVI) using standard conditions. Ketones, which were not available, were synthesised by intramolecular cyclisation of corresponding acids (XVIII) (see scheme 5).

) Scheme $ = (CH;);SiCN x

R—r -_— R=" = )a )s

X X

XV xv)

Hydrolysis

Cyclisation 0) OH 0}

IAN OH XX IRN

R= R—~ = so] FF ) n

X X

XVI) (II-B)

The amines of formula (II) are generally prepared using art known techniques, see for instance in; “Introduction to organic chemistry” Streitweiser and Heathcock —

Macmillan Publishing Co., Inc. — second edition - New York ~ Section 24.6 p 742- 753, and comprise synthesis through indirect alkylation of the appropriate (heteroaryl halides in particular by the Gabriel synthesis, through reduction of the corresponding nitro or nitrille compounds, through reductive amination using for example the Eschweiler-Clarke reaction and in particular through the reduction of oximes (IX) which may be prepared from aldehydes or ketones (VII) by reaction with hydroxylamine (scheme 6). In this latter case the oximes are reduced by lithium aluminium hydride or catalytic hydrogenation using an appropriate catalysator such as

Raney Nickel, said reduction being performed in an inert anhydrous solvent such as ether or tetrahydrofuran (THF).

) Scheme 6

Nv Rr? Nr Lia, HN _R —_— —_— CH o H,NOH ; THF (Vi (x) an

Further examples for the synthesis of compounds of formula (I) using anyone of the above mentioned synthesis methods, are provided in the experimental part hereinafter.

Where necessary or desired, any one or more of the following further steps in any order may be performed : (i) removing any remaining protecting group(s); (ii) converting a compound of formula (I) or a protected form thereof into a further compound of formula (I) or a protected form thereof: (iii) converting a compound of formula (I) or a protected form thereof into a N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof; (iv) converting a N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof into a compound of formula (I) or a protected form thereof; (v) converting a N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof into another N-oxide, a pharmaceutically acceptable addition salt a quaternary amine or a solvate of a compound of formula (I) ora protected form thereof; (vi) where the compound of formula (1) is obtained as a mixture of ®) and (S) enantiomers resolving the mixture to obtain the desired enantiomer; (vii) where the compounds of formula (T) wherein Q consists of bromo-substituted carbocyclic radicals containing one or two rings, various conversions are possible, see for example scheme 7 comprising; a) alkylation using for example, alkyliodide b) conversion to an amine using Buchwald reaction . c) arylation using Heck-reaction conditions d) alkylation using Heck reaction conditions €) conversion to nitrile using for example, potassiumcyanide and possible further conversion of the thus obtained nitrile to an amine that can be alkylated or acylated under art known conditions.

. Scheme 7 7 NS op NENG N

TAN ASIN |x Ok rR! X R' ~ Xx ’ ©

Buchwald reaction tao

RI

R!

B H n=0,1o0r2 r AN ot X=N,OorS

OR Tu p=0,1,20r3

TX Lk "0 Tk

R! x

IN Heck reaction

Heck reaction rR! H

Het Le N

UALR 0

R! Rt x

NL Tv

HAL 0

R' X rR!

H

. Rs FZ EN A , ; 2 iN

Reduction TTL 0) R 5 vu

Rr X

R!

H

HN rT N R® = ester 4 R? Tu RS = acid Hydrogenation ~ F “xP o R® = NRR7

R Rr!

H

REDE: alkylation, iy R? Tu acylation 0 ~ el ok 0 AON

R

It will be appreciated by those skilled in the art that in the processes described above the functional groups of intermediate compounds may need to be blocked by protecting groups.

Functional groups which it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl

: or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include Cq.galkyl or benzyl esters.

The protection and deprotection of functional groups may take place before or after a reaction step.

The use of protecting groups is fully described in ‘Protective Groups in Organic

Chemistry’, edited by J W F McOmie, Plenum Press (1973), and ‘Protective Groups in

Organic Synthesis’ 2™ edition, T W Greene & P G M Wutz, Wiley Interscience (1991).

Additionally, the N-atoms in compounds of formula (I) can be methylated by art- known methods using CHj-1 in a suitable solvent such as, for example 2-propanone, tetrahydrofuran or dimethylformamide.

The compounds of formula (I), can also be converted into each other following art- known procedures of functional group transformation of which some examples are mentioned hereinabove.

The compounds of formula (I), may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its

N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydro- carbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.

Pure stereochemically isomeric forms of the compounds of formula (I), may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g. counter-current distribution, liquid chromatography and the like.

: Some of the compounds of formula (I), and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stercospecifically.

An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.

A particular group of enantiomeric intermediates for the compounds of the present invention consist of the syn and anti-isomer 1-hydroxy-4-aminoadamantane, an intermediate used in the synthesis of those compounds of formula (I) where R? represents an optionally substituted 2-adamantyl. 1-hydroxy-4-aminoadamantane is generally prepared by hydroxylation of 2- aminoadamantane, for example, using a mixture of nitric and sulphuric acid (Khimiko

Farmatsevticheskii Zhurnal 1986, 20, 810; Zhurnal Organichsekoi Khimii 1976, 2369).

NH, NH; NH,

XJ HNO; /H,804 1110 ~~ J + SY anti syn

The reaction gives two stereomers of 1-hydroxy-4-aminoadamantane in ratio 3:1 to 1:1 in favour of syn-isomer. As it was found that the anti-isomers have an improved

HSD1-inhibitory activity, it would be desirable to have a synthesis method that gives a better selectivity in favour of the anti-isomer.

Alternatively 1-hydroxy-4-aminoadamantane can be obtained from the corresponding ketone after reductive amination, i.e. the cyclic ketone can be converted to the amine via an imine of oxime formation and consecutive reduction of double binding. The reduction can be done using lithium aluminium hydride, Raney-nickel or noble metals like palladium, platinum, ruthenium or rhodium supported on carbon. Reductive amination using borohydrides is a one step alternative (well know method described for example in Advanced of organic chemistry from March 2003). The selectivity of the reduction depends on the structure of substrate (ketone) and the used catalyst.

Given the fact that the two isomers of 1-hydroxy-4-aminoadamantane obtained after reduction of oxime or afier reductive amination with ammonia are not detectable in

LCMC or GCMS, it is very difficult to separate them. The coupling reaction with an acid of formula (III) gives a mixture of two coupling products of formula (I), which are separable using chromatography. However, in order to reduce the synthesis costs and to improve the yield of the anti-isomers it would be desirable to depart from the enatiomeric pure intermediates instead.

It is a object of the present invention to provide a solution for the bove mentioned problem, consisting of a method to prepare 1-hydroxy-4-aminoadamantane said method comprising the reductive amination of 5-hydroxy-adamantan-2-one with L(-)-1-phenyl- ethylamine by catalysis using for example ruthenium supported on carbon (Scheme 8).

The selectivity afforded was 3: 1 in favour of anti-stereomer. The obtained isomers are easy to separate and subsequent debenzylation of anti 4-(1-Phenyl-ethylamino)- adamantan-1-ol gives pure anti-1-hydroxy-4-aminoadamatane.

: Scheme 8

RH

0 [OY Tw N Ig LL

ROu,,,, — _ » HO, H + HO H 7 RIC = : (XVII-A) 3:1 (XVHER) a)

PIC

PIC Rp

R; 7 NH, 7 NH,

A) (+B)

In particular 1-hydroxy-4-aminoadamantane was prepared of; a) 4-(1-Phenyl-ethylamino)-adamantan-1-ol

Preparation of

H

0) ve (XVII-A) (XVII-B)

Commercially available 5-hydroxyadamantan-2-one (0.1 mol), L(-)-Alpha-methyl- benzyl amine (0.105 mol), aluminium isopropoxide (0.1mol) and Rhodium on active carbon (20 mol %) were suspended in 500ml of toluene, 20 ml of the 4% thiophene solution were added. The reaction mixture was stirred at 50 °C for 24h.

The catalyst was filtered of, the filtrate was concentrated in vacuum. The residue : containing two isomers in ratio 3:1 trans: cis, was purified by column chromatography to yield 12g of the intermediate XVIII-A and 4g of the intermediate XVIII-B.

b) 1-Hydroxy-4-aminoadamantane

Preparation of

NH, NH, (@-A) 1-B)

The amine XVII-A ( 0.05 mol) was dissolved in methanol (100 ml), palladium on active carbon (0.002 mol) was added and the mixture was hydrogenated at room temperature for 16h. The catalyst was filtered of, the filtrate was evaporated in vacuum.

The residue was triturated with dichloromethane to give the title compound (I1-A) (7.58).

Some of the intermediates and starting materials as used in the reaction procedures mentioned hereinabove are known compounds and may be commercially available or may be prepared according to art-known procedures.

The compounds of the present invention are useful because they possess pharmacological properties. They can therefore be used as medicines, in particular to treat pathologies associated with excess cortisol formation such as for example, obesity, diabetes, obesity related cardiovascular diseases, and glaucoma.

As described in the experimental part hereinafter, the inhibitory effect of the present compounds on the 11b-HSD1-reductase activity (conversion of cortison into cortisol) has been demonstrated in vitro, in an enzymatic assay using the recombinant 11b-

HSD1 enzyme, by measuring the conversion of cortison into cortisol using HPLC purification and quantification methods. 11b-HSD1-reductase inhibition was also demonstrated in vitro, in a cell based assay comprising contacting the cells, expressing 11b-HSD1 with the compounds to be tested and assessing the effect of said compounds on the formation of cortisol in the cellular medium of these cells. The cells preferably used in an assay of the present invention are selected from the group consisting of

. mouse fibroblast 3T3-L1 cells, HepG2 cells, pig kidney cell, in particular LCC-PK 1 cells and rat hepatocytes.

Accordingly, the present invention provides the compounds of formula (I), (I"), (I’*) and their pharmaceutically acceptable N-oxides, addition salts, quaternary amines and stereochemically isomeric forms for use in therapy. More particular in the treatment or prevention of cell proliferation mediated diseases. The compounds of formula (I), (I°), (I’) and their pharmaceutically acceptable N-oxides, addition salts, quaternary amines and the stereochemically isomeric forms may hereinafter be referred to as compounds according to the invention.

In view of the utility of the compounds according to the invention, there is provided a method for the treatment of an animal, for example, a mammal including humans, suffering from a cell proliferative disorder such as atherosclerosis, restinosis and cancer, which comprises administering an effective amount of a compound according to the present invention.

Said method comprising the systemic or topical administration of an effective amount of a compound according to the invention, to warm-blooded animals, including humans.

It is thus an object of the present invention to provide a compound according to the present invention for use as a medicine. In particular to use the compound according to the present invention in the manufacture of a medicament for treating pathologies associated with excess cortisol formation such as for example, obesity, diabetes, obesity related cardiovascular diseases, and glaucoma.

In yet a further aspect, the present invention provides the use of the compounds according to the invention in the manufacture of a medicament for treating any of the aforementioned cell proliferative disorders or indications. : The amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutical effect will be, of . course, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated. A suitable daily dose would be from 0.001 mg/kg to 500 mg/kg body weight, in particular from 0.005 mg/kg to 100 mg/kg body weight. A method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per

- day.

While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent. The carrier or diluent must be “acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.

The pharmaceutical compositions of this invention may be prepared by any methods well known in the art of pharmacy, for example, using methods such as those described in Gennaro et al. Remington’s Pharmaceutical Sciences (18° ed., Mack Publishing

Company, 1990, see especially Part 8 : Pharmaceutical preparations and their

Manufacture). A therapeutically effective amount of the particular compound, in base form or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous, or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharma- ceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the - compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.

Claims (17)

: Claims

1. A compound having the formula 0] rR’ Q L J PEN R* Rf 0) 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; R! and R? each independently represents hydrogen, Cualkyl, NR’R', C,alkyloxy, Het’-0-C) alkyl; or R'! and R” taken together with the carbon atom with which they are attached form a carbonyl, or a Cs. ¢cycloalkyl; and where n is 2, either R! or R? may be absent to form an unsaturated bond, R’ represents hydrogen, Ar’, C; salkyl, Cs.12cycloalkyl or a monovalent radical having one of the following formulae 0 A an © Aram QL Mh @® ® © @ @ © Jo PINE ~~ Z [IS J) J NE © ® ® © ®) ® BU Lr X ~~ ~~ dr EQ» aA 0} ® ® o I) ® SSN QUO 0, NS 4X ® o © ® . 20 wherein said Ar’, Cs.12cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two or three substituents selected from the group consisting of Cjalkyl, C;.salkyloxy, phenyl, halo, oxo, carbonyl, 1,3-dioxolyl or hydroxy;

: R* represents hydrogen, Cialkyl, or C, alkenyl;

Q represents Cs scycloalkyl, Het! or Ar?, wherein said Cs.scycloalkyl, Het' or Ar” are optionally substituted with one or where possible more substituents selected from halo, C, alkyl, C, 4alkyloxy, hydroxy, nitro, Het’, phenyl, phenyloxy, C, salkyl-

oxycarbonyl, hydroxycarbonyl, NR’R®, C;salkyloxy substituted with one or where possible two or three substituents each independently selected from C;salkyl, hydroxycarbonyl, Het’, C, salkyl or NR'R®,

C;aalkenyl substituted with one substituent selected from pheny}-C, salkyl- oxycarbonyl, C, salkyloxycarbonyl, hydroxycarbonyl or Het"-carbonyl, and

C, 4alkyl substituted with one or where possible two or three substituents independently selected from halo, dimethylamine, trimethylamine, amine, cyano, Het®, Het'-carbonyl, Cialkyloxycarbonyl or hydroxycarbonyl;

R® and R® are each independently selected from hydrogen, C, 4alkyl, C,.salkyloxy- Ciaalkyl, Cj4alkyloxycarbonyl, Ci4alkylcarbonyl, Ci4alkylcarbonyl substituted with one or where possible two or three substituents each independently selected from halo, C; alkyl, and C,_salkyloxy or R® and RS each independently represent Ci4alkyl substituted with phenyl;

R’ and R® are each independently selected from hydrogen or C;4alkyl;

R® and R'? are each independently selected from hydrogen, Cyualkyl or Calkyl-

oxycarbonyl;

L represents C; salkyl optionally substituted with one or where possible more substituents selected from C;4alkyl or phenyl;

Het' 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, 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;

Het? represents 2 monocyclic heterocycle selected from piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 2H-pyrrolyl, pyrrolyl,

’ 2-pyrrolinyl, 3-pyrroliny}, pyrrolidinyl, or morpholinyl, said Het” optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, Ci4alkyl or Cisalkyloxy;

Het? represents a monocyclic heterocycle selected from 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl;

Het" represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl, triazolyl, tetrazolyl or morpholinyl, said Het*

’ optionally being substituted with one or where possible two or more substituents each idependently selected from hydroxy, carbonyl, C;4alkyl or C;4alkyloxy; Het’ represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het’ optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C;4alkyl or C;alkyloxy; in particular piperazinyl or morpholinyl; Het® represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het® optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C; alkyl or C 4alkyloxy; Het’ represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het’ optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C, alkyl or C,4alkyloxy; in particular selected piperazinyl or morpholinyl; } Ar! 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 naphthyl Ar represents carbocyclic radicals containing one or more rings selected from the group consisting of phenyl, biphenyl, benzocyclobutenyl, benzocycloheptanyl, benzosuberenyl, indenyl, 2,3-dihydroindenyl, fluorenyl, 1,2-dihydronaphthyl, 5,6,7,8-tetrahydronaphthyl or naphthyl.

2. A compound having the formula 0} R! NA Bh ae Rr? L om ) 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; R! and R? each independently represents hydrogen, Cjalkyl, NR°RY, C,alkyloxy, Het’-O-Cyalkyl; or

‘ R' and R? taken together with the carbon atom with which they are attached form a carbonyl, or a Cs cycloalkyl; and where n is 2, either R!'orR? may be absent to form an unsaturated bond; rR’ represents hydrogen, Ar! C,salkyl, Cg.12cycloalkyl or a monovalent radical having one of the following formulae WD Ax oan LC (a) ©) © @ @ ® > go 0 A$ ~~ I~ N” ® (eo) 0) ® ® ©) EA AED ERSTE ® ® ® 0) ® ® a a Ow ~0, NS SCAN ED ~ © ) D © © wherein said Ar’, Cs.icycloalkyl or monovalent radical may optionally be substituted with one, or where possible two or three substituents selected from the group consisting of C; alkyl, C; 4alkyloxy, phenyl, halo, oxo, carbonyl, 1,3- dioxolyl or hydroxy; R* represents hydrogen or C,alkyl; Q represents Cs gcycloalkyl, Het! or Ar, wherein said Cs scycloalkyl, Het! or Ar” are optionally substituted with one or where possible more substituents selected from halo, C;.4alkyl, Ci4alkyloxy, hydroxy, nitro, Het®, phenyl, phenyloxy, Ci. salkyloxycarbonyl, hydroxycarbonyl, NR’R®, C,_salkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het* and NR'R?, and

Ci .salkyl substituted with one or where possible two or three halo substituents; R®and RS are each independently selected from hydrogen, C;4alkyl, C,alkyloxyC,. satkyl, Cj salkyloxycarbonyl, C;4alkylcarbonyl, Cisalkylcarbonyl substituted with one or where possible two or three substituents each independently selected from halo, C, salkyl, and C;4alkyloxy or R> and RS each independently represent Ci. salkyl substituted with phenyl; R’ and R® are each independently selected from hydrogen or C; alkyl; R® and R'° are each independently selected from hydrogen, C;alkyl or C;. salkyloxycarbonyl;

: L represents C;4alkyl optionally substituted with one or where possible more substituents selected from C,4alky) or phenyl; Het' 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.; Het ? represents a monocyclic heterocycle selected from piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 2H-pyrrolyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, or morpholinyl; Het’ represents a monocyclic heterocycle selected from 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl; Het represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het* optionally being substituted with one or where possible two or more substituents each idependently selected from hydroxy, carbonyl, C, salkyl or C;4alkyloxy; Ar! 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-tetrahydronaphty! or naphtyl Ar’ 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.

3. A compound according to claims 1 or 2 wherein; n represents an integer being 1 or 2 provided that when n represents 2, Q represents Het" or Ar®, wherein said Het" or Ar” are optionally substituted with one or where possible more substituents selected from halo, Ci4alkyl, Cy4alkyloxy, hydroxy, nitro, Het®, phenyl, phenyloxy, hydroxycarbonyl, NR°R®, C; salkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het* and NR'R?, and Ci4alky] substituted with one or where possible two or three halo substituents

4. A compound according to any one of claims 1 to 3 wherein; : R' and R* each independently represents hydrogen Cy salkyl, NR’R'; or R' and R? taken together with the carbon atom with which they are attached form a Cs gcycloalkyl; and where n is 2, either R' or R* may be absent to form an unsaturated bond;

) rR? represents a Cg.1acycloalkyl or a monovalent radical having one of the following formulae WoL A @®@ ®) © TW @ ® ® 0) TF Oy ~<) o () ® ® Www ok (u) ® (0) wherein said Cg.12cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of C,_salkyl, C,4alkyloxy, halo, carbonyl, hydroxy, or 1,3-dioxolyl;

Q represents Het’ or Ar® wherein said Het! or Ar? are optionally substituted with one or where possible two or more substituents selected from halo, C,4alkyl, C;.

salkyloxy, hydroxy, C;alkyloxycarbonyl, NR°R®, C|_alkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het” and NRR?, and C) alkyl substituted with one or where possible two or three substituents each independently selected from halo, dimethylamine, amine, cyano, Het’, Het'-carbonyl or hydroxycarbonyl;

R® and R® are each independently selected from hydrogen, C;4alkyl, C,. salkylcarbonyl, C)4alkylcarbonyl substituted with one or where possible two or three halo substituents.

R® and R® are each independently selected from hydrogen or Cj4alkyl;

L represents a Ci4alkyl, preferably methyl;

Het' represents a heterocycle selected from pyridinyl, pyrimidinyl, thiophenyl, benzothiophenyl, quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, isoquinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 2H-benzopyranyl, 3,4-dihydro-2H-benzo- pyranyl, 2H-benzothiopyranyl, 3,4-dihydro-2H-benzothiopyranyl or

1,3-benzodioxolyl;

) Het? represents a monocyclic beterocycle selected from piperidinyl, piperazinyl, pyridinyl, pyrrolidinyl or morpholinyl, said Het” optionally being substituted with one or where possible two or more C; alkyl substituents ; Het represents tetrazolyl; Het’ represents morpholinyl; Het" represents a monocyclic heterocycle selected from pyrrolidinyl, piperazinyl or morpholinyl, said Het® optionally being substituted with one or where possible two or more hydroxy substituents, preferably with one hydroxy substituent; Ar? represents carbocyclic radicals containing one or more rings selected from the group consisting of phenyl, benzocyclobutene, benzocyclobeptanyl, benzosuberenyl, indenyl, 2,3-dihydroindenyl, 5,6,7,8-tetrahydronaphthyl or naphthyl.

5. A compound according to any one of claims 1 to 3 wherein; R! and R* each independently represents hydrogen Ci4alkyl, NR’R'; or R' and R? taken together with the carbon atom with which they are attached form a Cs ¢cycloalkyl; and where n is 2, either R! or R? may be absent to form an unsaturated bond; R3represents a Cs.12Cycloalkyl or a monovalent radical having one of the following formulae LONPR ® ® © AQ ~~ @ ©) ® 9 J 0x J) ~ o ©) (0) ® JUGRUEe NS pa ' () ® © wherein said C.12cycloalkyl or monovalent radical may optionally be substituted \ with one, or where possible two, three or more substituents selected from the group consisting of Cy4alkyl, C,4alkyloxy, halo, carbonyl, hydroxy, or

25 . 1,3-dioxolyl; Q represents Het! or Ar? wherein said Het’ or Ax” are optionally substituted with one or where possible two or more substituents selected from halo,

) Ciualkyl, C,4alkyloxy, hydroxy, Ci4alkyloxycarbonyl, Het, NR? R®, Ciualkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het” and NR'RS, Casalkenyl substituted with one substituent selected from phenyl-Cialkyl- oxycarbonyl or Het*-carbonyl and Ci4alkyl substituted with one or where possible two or three substituents each independently selected from halo, dimethylamine, amine, cyano, Het’, Het’-carbonyl or hydroxycarbonyl; R? and R° are each independently selected from hydrogen, C; alkyl, C,. salkylcarbonyl, Ci4alkylcarbonyl substituted with one or where possible two or three halo substituents. R’ and R' are each independently selected from hydrogen or C;_salkyl; L represents a Cj4alkyl, preferably methyl; Het’ represents a heterocycle selected from pyridinyl, pyrimidinyl, indolyl, thiophenyl, benzothiophenyl, quinolinyl, 1,2,3,4-tetrahydro-quinolinyl, isoquinoliny}, 1,2,3 4-tetrahydro-isoquinolinyl, 2H-benzopyranyl, 3,4-dihydro-2H-benzopyranyl, 2H-benzothiopyranyl, 3,4-dihydro- 2H-benzothiopyranyl or 1,3-benzodioxolyl; Het® represents a monocyclic heterocycle selected from piperidinyl, piperazinyl, pyridinyl, pyrrolidinyl or morpholinyl, said Het” optionally being substituted with one or where possible two or more C;_salkyl substituents ; Het" represents tetrazolyl; Het’ represents morpholinyl; Het® represents a monocyclic heterocycle selected from pyrrolidinyl, piperazinyl or morpholinyl, said Het® optionally being substituted with one or where possible two or more hydroxy substituents, preferably with one hydroxy substituent; Het’ represents a monocyclic heterocycle selected from piperazinyl or morpholinyl, preferably morpholinyl; Ar? represents carbocyclic radicals containing one or more rings selected from the ’ group consisting of phenyl, benzocyclobutene, benzocycloheptanyl, benzosuberenyl, indenyl, 2,3-dihydroindenyl, 5,6,7,8-tetrahydronaphthyl or

. naphthyl.

6. A compound according to any one of claims 1 to 3 wherein; n represents an integer being 0, 1 or 2; R' and R? each independently represents hydrogen, Ciaalkyl, NR’R'®; or i

’ R! and R? taken together with the carbon atom with which they are attached form a Cscycloalkyl; and where n is 2, either R! or R* may be absent to form an unsaturated bond;

R3 represents a Cg.jacycloalkyl, preferably cylo-octanyl or a monovalent radical having one of the following formulae oa A ® ® A @ A J 9 Na 38 OD ® CO) @ ® pM pLape 0) © © . preferably having the formula (a) or (b) above, wherein said Cs. 12cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of Cy4alkyl, C,4alkyloxy, halo or hydroxy; Q represents Het or Ar’ wherein said Het! or Ar” are optionally substituted with one or where possible two or more substituents selected from halo, C.4alkyl, Cy 4alkyloxy, hydroxy, NRR®, Cialkyloxy substituted with one or where possible two, three or more substituents each independently selected from hydroxycarbonyl, Het? or NR'RY, Calkenyl substituted with one substituent selected from pheny}-C, 4alkyl- oxycarbonyl or Het-carbony} and Cj.alky! substituted with one or where possible two or three substituents selected from halo, Het®, C;4alkyloxycarbonyl or hydroxycarbonyl; R® and R® each independently represent hydrogen or Cy.salkyl; . R® and R'° each independently represent hydrogen or Cialkyloxycarbonyl; L represents Ci4alkyl; Het' represents a heterocycle selected from pyridinyl, piperidinyl, thiophenyl, 1,2,3,4-tetrahydro-quinolinyl, 1,2,3,4-tetrahydro-isoquinolinyl, 2H-

’ benzopyranyl, 3,4-dihydro-2H-benzopyranyl, 3,4-dihydro-2H- benzothiopyrany! or 1,3-benzodioxol; Het” represents pyridinyl, pyrrolidinyl or morpholinyl; Het represents morpholinyl; Ar? represents phenyl, benzocyclobutene, benzocyclobeptanyl, benzosuberenyl, 2,3-dihydroindenyl, 5,6,7,8-tetrahydronaphthyl, naphtyl or indenyl.

7. A compound as claimed in claim 1 wherein on represents an integer being 0, 1 or 2; (R' and R? each independently represents hydrogen C, alkyl, NR’R", C,. salkyloxy; or R! and R? taken together with the carbon atom with which they are attached form a C3 gcycloalkyl; and where n is 2, either R! or R* may be absent to form an unsaturated bond; R® represents a Cg.12cycloalkyl, preferably selected from cylo-octanyl and cyclohexyl! or R? represents a monovalent radical having one of the following formulae Woe A ® N © X70 @ ® j=l pu L Loo AL Ne (0) ®) ® , preferably having the formula (a) above, wherein said Cs.12cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of Ci4alkyl, C;salkyloxy, halo or hydroxy; R* represents hydrogen or C;atkyl; Q represents Het! or Ar’ wherein said Cs scycloalkyl, Het! or Ar? are optionally . 25 substituted with one or where possible two or more substituents selected from halo, Cy4alky), C, salkyloxy, hydroxy, nitro, NR’R, Ci4alkyloxy substituted with one or where possible two, three or more substituents each independently selected from hydroxycarbonyl, Het? or NR'R, Cz4alkenyl substituted with phenyl-C;salkyl-oxycarbonyl and C)4alkyl substituted with one or where possible two or three

: substituents selected from, halo, Het®, Het’ -carbonyl, Ci.alkyloxycarbonyl or hydroxycarbonyl; R® and R® each independently represent hydrogen, Ci4alkyl, or C,4alkyl substituted with phenyl; L represents Cy salkyl; Het represents a heterocycle selected from pyridinyl, thiophenyl, 2H- benzopyranyl, 3,4-dihydro-2H-benzopyranyl, 3,4-dihydro-2H- benzothiopyranyl or 1,3-benzodioxolyl; Het” represents piperidinyl, pyrrolidinyl or morpholinyl: Het® represents a monocyclic heterocycle selected from piperazinyl or morpholinyl, preferably morpholinyl; Ar? represents phenyl, benzocyclobutene, benzocycloheptanyl, benzosuberenyl, 2,3-dihydroindenyl, 1,2-dihydronaphthyl, 5,6,7,8-tetrahydronaphthy], naphtyl or indenyl.

8. A compound as claimed in claim 1 wherein the compound is (10,,2B,3B,5B,7B)-N-(5-hydroxytricyclo[3.3.1.13,7]dec-2-y})-0,0.-dimethyl- benzeneacetamide; (10,2B,3B,5B,7B)-N-(5-hydroxytricyclo[3.3.1.13,7]dec-2-yl)-a,0-dimethyl-3- methyl-benzeneacetamide;

(10.,2B,3P,5B,7B)-N-(5-hydroxytricyclo[3.3.1.13,7]dec-2-yl)-c,0.-dimethyl-3- methoxy-benzeneacetamide; (10,2B,3B,58,7B)-N-(5-hydroxytricyclo[3.3.1.13,7]dec-2-yl)-o, at-dimethyl-3- hydroxy-benzeneacetamide; (10,,2,38,5B,7B)-N-(5-hydroxytricyclo[3.3.1.13,7]dec-2-yl)-0, 0-dimethyl-3,5- dimethyl-benzeneacetamide); (10,,2B,3B,5B8,7B)-N-(5-hydroxytricyclo[3.3.1.13,7}dec-2-yl)-3- (phenylmethoxy)benzeneacetamide; (10,2B,3B,5B,78)-N-(5-hydroxytricyclo[3.3.1.13,7]dec-2-yl)-o,at-dimethyl-3- {carboxymethoxy)-benzeneacetamide;

(10.,2B,3B,5B,7B)-N-(5-hydroxytricyclo[3.3.1.13,7]dec-2-yl)-ot,0-dimethyl-3- [2-(4-morpholinyl)ethoxy]-benzeneacetamide; (10,,2B,3B,5B,7B)-N-(5-fluorotricyclof3.3.1.13,7]dec-2-yl)-0, 0-dimethyl-

. benzeneacetamide; (12,2B,3B,5pB,7B)-N-(5-methoxytricyclo[3.3.1.13,7}dec-2-y})-0, a-dimethyl- benzeneacetamide;

(10.,20,,38,5B,7B)-N-(5-methoxytricyclo[3.3.1.13,7]dec-2-yl)-a, o-dimethyl- benzeneacetamide;

N-(tricyclo[3.3.1.13,7]}dec-2-yl)-a, 0-dimethyl-benzeneacetamide; N-(tricyclo[3.3.1.13,7]}dec-2-y)-a, a-dimethyl-3-(carboxymethoxy)- benzeneacetamide; N-(tricyclo[3.3.1.13,7]dec-2-yl)-a, a-dimethyl-3-[2-(4-morpholinyl)ethoxy]- benzeneacetamide; N-(tricycio[3.3.1.13,7]dec-2-yl)-o, ¢-dimethyl-3,5-dimethoxy- benzeneacetamide; N-(tricyclo[3.3.1.13,7]dec-2-y])-0, ~-dimethyl-3-methyl-benzeneacetamide; N-(tricyclo[3.3.1.13,7]dec-2-y])-o, o-dimethyl-3-methox y-benzeneacetamide; N-(tricyclo[3.3.1.13,7)dec-2-yD)-o, a-dimethyl-3-hydroxy-benzeneacetamide; N-(tricyclof3.3.1.13,7]dec-2-yD)-o, 0-dimethyl-3,5-dimethyl-benzeneacetamide; N-(tricyclo[3.3.1.13,7]}dec-2-y])-o, -dimethyl-4-fluoro-benzencacetamide; N-(tricyclo[3.3.1.13,7]dec-2-yl)-1-phenyl-cyclopropanecarboxamide; N-(tricyclo[3.3.1.13,7]dec-2-yl)-a,a-dimethyl-2,6-difluoro-benzeneacetamide; : N-(tricyclo[3.3.1.13,7]dec-2-yD)-o, -dimethyl-2-thiopheneacetamide; N-(5-hydroxy-2-adamantyl)-2-methyl-2-(5-methylpyridin-3-yl)propanamide; N-(5-hydroxy-2-adamantyl)-2-methyl-2-(6-methylpyridin-2-y})propanamide; 3-(3-{2-[(5-fluoro-2-adamantyf)amino}-1,1-dimethyl-2-oxoethyl}-5- methylphenyl)propanoic acid; 4-(3-{2-[(5-hydroxy-2-adamantyl)amino]-1,1-dimethyl-2-oxoethyl}-5- methylphenyl)butanoic acid; tert-butyl-4-[3-(3-{2-[(5-hydroxy-2-adamantyl)amino]-1,1-dimethy}-2- oxoethyl}-5-methylphenyl)propanoyl]-1,4-diazepane- I -carboxylate; N-(5-hydroxy-2-adamantyl)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1- carboxamide; N-2-adamantyl-1,2,3,4-tetrahydroisoquinoline- 1-carboxamide; N-(5-hydroxy-2-adamantyl)-3,4-dihydroquinoline- 1(2H)-carboxamide; or a N- oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof.

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, an effective 113-HSD1 inhibitory amount of a compound as described in any one of claims 1 to 8.

10. A process of preparing a pharmaceutical composition as defined in claim 8, characterized in that, a pharmaceutically acceptable carrier is intimately mixed with an effective 11B-HSD1 inhibitory amount of a compound as described in any one of claims 1 to 8.

11. A compound as claimed in any one of claims 1 to 8 for use as a medicine.

12. Use of a compound as claimed in any one of claims 1 to 8 in the manufacture of a medicament for treating pathologies associated with excess cortisol formation such as for example, obesity, diabetes, obesity related cardiovascular diseases, dementia, cognition, osteoporosis and glaucoma.

13. A compound of formula (I’) R12 rR! FR? x AN " Dt jer rH m the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof wherein R! and R* each independently represents hydrogen, C;4alkyl, NR’R", C,_alkyloxy or Het?-0-C, alkyl; preferably C; alkyl in particular methyl; or R! and R? taken together with the carbon atom with which they are attached from a Cs gcycloalkyl, in particular cyclopropyl or cyclobutyl; R* represents hydrogen, C4alkyl, C,4alkenyl; U represents hydrogen, Ci4alkyl, Cisalkyloxy, phenyl, halo, oxo, carbonyl or hydroxy R® and RS are each independently selected from hydrogen, C;4alkyl, C, salkyloxyC). salkyl, Cy salkyloxycarbonyl, Cyalkylcarbonyl, C;.salkylcarbonyl substituted with one or where possible two or three substituents each independently selected from halo, C;4alkyl, and C;.4alkyloxy or R® and R® each independently represent Ci. salkyl substituted with phenyl; R’ and R® are each independently selected from hydrogen or C,4alkyl; R® and R'° are each independently selected from hydrogen, C; alkyl or C,. salkyloxycarbonyl; R'! and R™ are each independently selected from hydrogen, halo, Ciualkyl, C,. salkyloxy, hydroxy, nitro, Het", phenyl, phenyloxy, C;4alkyloxycarbonyl, hydroxycarbonyl, NR’R®, C;_salkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het’ and NR'RE, C, 4alkenyl substituted with one substituent selected from phenyl-C,. salkyl-oxycarbonyl, Cy alkyloxycarbonyl, hydroxycarbonyl, Het’-carbonyl, and

\

* C4alkyl substituted with one or where possible two or three substituents independently selected from halo, dimethylamine, trimethylamine, amine, cyano, Het®, Het’-carbonyl, Ci4alkyloxycarbonyl or hydroxycarbonyl;

Het' 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.;

Het? 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, carbonyl, C; alkyl or Ci4alkyloxy;;

Het? represents a monocyclic heterocycle selected from 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl;

Het" represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl, triazolyl, tetrazolyl or morpholinyl, said Het*

optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, Ci alkyl or C; 4alkyloxy;

Het’ represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het’ optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C,4alkyl or Cialkyloxy; preferably piperazinyl or morpholinyl;

Het’ represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het® optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, C;4alkyl or Cj4alkyloxy; Het’ represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het’ optionally being substituted with one or where possible two or more substituents each independently selected from hydroxy, carbonyl, Ciualkyl or Cialkyloxy; preferably piperazinyl or morpholinyl; in particular morpholinyl.

14. A compound of formula (I"*) \

0 [ 1, @) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein

R* represents hydrogen, C,_alkyl, Csaalkenyl;

U represents hydrogen, C, alkyl, C;.4alkyloxy, phenyl, halo, oxo, carbonyl or hydroxy

Q represents Het or Ar’, wherein said Het! or Ar? are optionally substituted with one or where possible more substituents selected from halo, C;4alkyl, C,salkyloxy,

: hydroxy, nitro, Het*, phenyl, phenyloxy, C, 4alkyloxycarbonyl, hydroxycarbonyl, NR'RS, C,ualkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het” and NR'R?, and

Ci4alkyl substituted with one or where possible two or three substituents independently selected from halo or hydroxycarbonyl;

R® and RS are each independently selected from hydrogen, Cy salkyl, Cy satkyloxyCi. alkyl, Ci4alkyloxycarbonyl, Cialkylcarbonyl, C;alkylcarbonyl substituted with one or where possible two or three substituents each independently selected from halo, C,.4alkyl, and C;alkyloxy or R® and R® each independently represent Cj. salkyl substituted with phenyl;

R’ and R® are each independently selected from hydrogen or C;4alkyl;

R’ and R'? are each independently selected from hydrogen, C4alkyl or C,.

salkyloxycarbonyl;

Het" 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- . 30 benzodioxolyl;

Het * 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, C; alkyl or Cyalkyloxy; Het? represents a monocyclic heterocycle selected from 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl; Het! represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het* optionally being substituted with one or where possible two or more substituents each idependently selected from hydroxy, carbonyl, C; alkyl or C;4alkyloxy; Ar’ 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.

15. A compound of formula (I") or (I"’) for use as a medicine.

16. Use of a compound of formula (I’) or (I’’) in the manufacture of a medicament for treating pathologies associated with excess cortisol formation such as for example, obesity, diabetes, obesity related cardiovascular diseases, dementia, cognition, osteoporosis and glaucoma.

17. A method to prepare 1-hydroxy-4-aminoadamantane said method comprising i) the reductive amination of the corresponding ketone (XIII); ii) separating the thus obtained stercomers of the amine of formula (XVIII); and iii) debenzylating the compounds of formula (XVIII) AF 7 ° 7 JJ 7 LL) HOY, (7 Reductive amination ~[ J i + [J i : Zz OOVIR-A) 3:1 (vim-5) (xn) H,, PIC Ry, PU/C NH, a NH;

, . (A) @-B)