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

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

Further, adipose tissue over-expression of 11ß-HSD1 in transgenic mice is associated with increased corticosterne 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, llp-HSDl is most likely be involved in the development of visceral obesity and the metabolic syndrome.

Inhibition of llp-HSDl 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 11 (3-HSD1 may exacerbate 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.

11ß-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 11ß-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.

Accordinaly, the underlying problem to be solved by the present invention was to identify potent 1 lß-HSD inhibitors, with a high selectivity for 1 lß-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) 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 ;' Rl and R2 each independently represents hydrogen, C1-4alkyl, NR9R10, C1-4alkyloxy, Het3-O-Cl 4alkyl ; or Rl and R2 taken together with the carbon atom with which they are attached form a carbonyl, or a C36cycloalkyl ; and where n is 2, either Rl or R2 may be absent to form an unsaturated bond; R3 represents hydrogen, Arl, C1-8alkyl, Cg-l2cycloalkyl or a monovalent radical having one of the following formulae

wherein said Arl, C6-l2cYcloalkyl or monovalent radical may optionally be substituted with one, or where possible two or three substituents selected from the group consisting of Cl 4alkyl, Cl4alkyloxy, phenyl, halo, oxo, carbonyl, 1, 3- dioxolyl'or hydroxy ; R4 represents hydrogen or Cl 4alkyl ; Q represents C3-8cycloalkyl, Het1 or Ar2, wherein said C3-8cycloalkyl, Hetl or Ar2 are optionally substituted with one or where possible more substituents selected from halo, C1-4alkyl, C1-4alkyloxy, hydroxy, nitro, Het4, phenyl, phenyloxy, Cl 4alkyloxycarbonyl, hydroxycarbonyl, NR5R6, Cl 4alkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het2 and NR7R8, and Cl 4alkyl substituted with one or where possible two or three halo substituents; R$ and R6 are each independently sèlected from hydrogen, C1-4alkyl, C1-4alkyloxyC1- 4alkyl, C1-4alkyloxycarbonyl, C1-4alkylcarbonyl, C1-4alkylcarbonyl substituted with one or where possible two or three substituents each independently selected from halo, C1-4alkyl, and Cl 4alkyloxy or R5and R 6each independently represent Ci- 4alkyl substituted with phenyl; R7 and R8 are each independently selected from hydrogen or Cl 4alkyl ; R9 and Rio are each independently selected from hydrogen, Cl 4alkyl or Cl- 4alkyloxycarbonyl; L represents Cl 4alkyl optionally substituted with one or where possible more substituents selected from Cl 4alkyl or phenyl; Hetl 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 2 represents a monocyclic heterocycle selected from piperidinyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl., 2H-pyrrolyl, pyrrolyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, or morpholinyl ; Het3 represents a monocyclic heterocycle selected from 2H-pyranyl, 4H-pyranyl, furanyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, or furanyl; Het4 represents a monocyclic heterocycle selected from pyridazinyl, pyrimidinyl, pyrrolidinyl, pyrazinyl, piperazinyl or morpholinyl, said Het4 optionally being substituted with one or where possible two or more substituents each idependently selected from hydroxy, carbonyl, Cl 4alkyl or Cl 4alkyloxy ; Arl represents carbocyclic radicals containing one or more rings selected from the group consisting of phenyl, biphenyl, indenyl, 2,3-dihydroindenyl, fluorenyl, 5,6, 7,8-tetrahydronaphtyl or naphtyl Ar2 represents carbocyclic radicals containing one or more rings selected from the group consisting of phenyl, biphenyl, indenyl, 2,3-dihydroindenyl, fluorenyl, 5,6, 7, 8-tetrahydronaphtyl or naphtyl.

As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo, Cl 4alkyl 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-dimethylethyl and the like; Cl 8alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 8 carbon atoms such as the groups defined for C (l 4) alkyl and pentyl, hexyl, octyl, 2-methylbutyl 2-methylpentyl, 2, 2-dimethylpentyl and the like; C36cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C6-l2cycloalkyl is generic to cycloheptyl and cyclo-octanyl, cyclononane, cyclodecane, cycloundecane and cyclododecane; Cl 4alkyloxy 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 compounds of formula (I), 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 (1), 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 stereochemically and cohformationally 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 (I) wherein one or more of the following restrictions apply:

(i) n represents an integer being 1 or 2 provided that when n represents 2, Q represents Hetl or Ar2, wherein said Hetl or Ar2 are optionally substituted with one or where possible more substituents selected from halo, C1-4alkyl, C1-4alkyloxy, hydroxy, nitro, Het4, phenyl, phenyloxy, hydroxycarbonyl, NR5R6, Cl 4alkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het2 and NR, and C1-4alkyl substituted with one or where possible two or three halo substituents; (ii) R1 and R2 each independently represents hydrogen, C1-4alkyl, NR9R10, C1- 4alkyloxy, Het3-O-C1-4alkyl ; or' Rl and R2 taken together with the carbon atom with which they are attached form a carbonyl, or a C3-6cycloalkyl; (iii) R3 represents phenyl, C6-i2cycloalkyl or a monovalent radical having one of the following formulae wherein said phenyl, C6-l2cycloalkyl or monovalent radical may optionally be substituted with or where possible two or three substituents selected from the group consisting of C1-4alkyl, C1-4alkyloxy, halo, carbonyl, phenyl or hydroxy; (iv) R4 represents hydrogen or Cl 4alkyl ; (v) Q represents Hetl or Ar2, wherein said Hetl or Ar2 are optionally substituted with one or where possible more substituents selected from halo, C1-4alkyl, C1- 4alkyloxy, hydroxy, nitro, Het4, phenyl, phenyloxy, hydroxycarbonyl, NRSR6, Cl- 4alkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het2 and NR7R8, and Cl 4alkyl substituted with one or where possible two or three halo substituents; (vi) Hetl 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) Ar2 represents phenyl or naphtyl optionally substituted with Cialkyi, Ci-4alkyloxy 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 : (i) Rl and R2 each independently represents hydrogen C1-4alkyl, NR9R10 ; or Rl and R2 taken together with the carbon atom with which they are attached form a C36cycloalkyl, and where n is 2, either Rl or R2 may be absent to form an unsaturated bond ; (ii) Represents a C6-l2cycloalkyl or a monovalent radical having one of the following formulae wherein said C6-12cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of C1-4alkyl, Cl-4alkyloxy, halo, carbonyl, hydroxy, or 1,3-dioxolyl; 3-dioxolyl ; (iii) Q represents Hetl or Ar2 wherein said Hetl or Ar2 are optionally substituted with one or where possible two or more substituents selected from halo, C 4alkyl, C1-4alkyloxy, hydroxy, C1-4alkyloxycarbonyl, NR5R6, C1-4alkyloxy substituted with one or where possible two or three substituents each independently selected from hydroxycarbonyl, Het2 and NR7R8, and Cl 4alkyl substituted with one or where possible two or three halo substituents; (iv) R5 and R6 are each independently selected from hydrogen, C1-4alkyl, C1- 4alkylcarbonyl, Cl 4alkylcarbonyl substituted with one or where possible two or three halo substituents.

(v) R9 and Rl° are each independently selected from hydrogen or Cl 4alkyl ; (vi) L represents a Cl 4alkyl, preferably methyl ; (vii) Het1 represents a heterocycle selected from pyridinyl, pyrimidinyl, thiophenyl or 1, 3-benzodioxolyl ; (viii) Het2 represents a monocyclic heterocycle selected from piperidinyl, pyridinyl, pyrrolidinyl or morpholinyl; (ix) Ar2 represents a C6-i4aryl preferably selected from phenyl, naphtyl or indenyl.

A particular group of compounds of formula (I) were those compounds shown to be highly HSD1 specific. For these compounds of formula (I) one or more of the following restrictions apply : (i) n represents an integer being l or 2 ; (ii) Rl and R2 each independently represents hydrogen C1-4alkyl, NR9R10 ; or Rl and R2 taken together with the carbon atom with which they are attached form a C3-6cycloalkyl ; and where n'is 2, either Rl or R2 may be absent to form an unsaturated bond ; (iii) R3 represents a C6-l2Cycloalkyl, preferably cylo-octanyl or a monovalent radical having one of the following formulae wherein said C6-i2cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of Cl 4alkyl, Cl 4alkyloxy, halo or hydroxy; (iv) Q represents Hetl or Ar2 wherein said Hetl or Ar2 are optionally substituted with one or where possible two or more substituents selected from halo, C 4alkyl, C}-4alkyloxy, hydroxy, NR5R6, C1-4alkyloxy substituted with one or where possible two, three or more substituents each independently selected from

hydroxycarbonyl, Het2 and NR7R8, and Cl 4alkyl substituted with one or where possible two or three halo substituents; (v) R5 and R6 each independently represent hydrogen or Cl 4alkyl ; (vi) R9 and Rl° each independently represent hydrogen or Cl 4alkyloxyvarbonyl ; (vii) L represents Cl 4alkyl ; (viii) Hetl represents a heterocycle selected from pyridinyl, piperidinyl, thiophenyl or 1, 3-benzodioxol ; (ix) Het2 represents pyridinyl, pyrrolidinyl or morpholinyl ; (x) Ar2 represents phenyl, 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 (i) n represents an integer being 1 or 2 ; (ii) R1 and R2 each independently represents hydrogen, C1-4alkyl ; or Rl and R2 taken together with the carbon atom with which they are attached form a C36cyclòalkyl ; and where n is 2, either R1 or R2 may be absent to form an unsaturated bond; (iii) R3 represents a C6-l2cycloalkyl, preferably cylo-octanyl or a monovalent radical having one of the following formulae wherein said C6-i2cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of CI-4alkyl, Cl-4alkyloxy, halo or hydroxy; (iv) Q represents Hetl or Ar2 wherein said Hetl or Ar2 are optionally substituted with one or where possible two or more substituents selected from halo, C 4alkyl, C1-4alkyloxy, hydroxy, NR5R6, C1-4alkyloxy substituted with one or where possible two, three or more substituents each independently selected from hydroxycarbonyl, Het2 and NR7R8, and Cl 4alkyl substituted with one or where possible two or three halo substituents;

(v) Rs and R6 each independently represent hydrogen or Cl 4alkyl ; (vi) L represents Cl 4alkyl ; (vii) Het'represents a heterocycle selected from pyridinyl, piperidinyl, thiophenyl or 1,3-benzodioxol ; (viii) Het2 represents pyrrolidinyl or morpholinyl; (ix) Ar2 represents phenyl, 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 (i) n represents an integer being 1 or 2 ; (ii) R1 and R2 each independently represents hydrogen Cl 4alkyl, NR9RI0, C 4alkyloxy; or Ri and R2 taken together with the carbon atom with which they are attached form a C36cycloalkyl ; and where n is 2, either Ri or R2 may be absent to form an unsaturated bond ; (iii) R3 represents a C6-12cycloalkyl, preferably selected from cylo-octanyl and cyclohexyl or R3 represents a monovalent radical having one of the following<BR> <BR> <BR> <BR> formulae wherein said C6-l2cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of C1-4alkyl, C1-4alkyloxy, halo or hydroxy ; (iv) Q represents Cs-gcycloalkyi, Het or Ar2 wherein said C3-8cycloalkyl, Het1 or Ar2 are optionally substituted with one or where possible two or more substituents selected from halo, Cl-4alkyl, Cl-4alkyloxy, hydroxy, nitro, NR5R6, C1-4alkyloxy substituted with one or where possible two, three or more substituents each independently selected from hydroxycarbonyl, Het2 and NR7R8, and Cl 4alkyl substituted with one or where possible two or three halo substituents, preferably trifluoromethyl ;

(v) R5 and R6 each independently represent hydrogen, Cl 4alkyl, or Cl 4alkyl substituted with phenyl; (vi) L represents Cl 4alkyl ; (vii) Hetl represents a heterocycle selected from pyridinyl, piperidinyl, or thiophenyl ; (viii) Het2 represents piperidinyl, pyrrolidinyl or morpholinyl ; (ix) Ar2 represents phenyl, naphtyl or indenyl.

A particular group of compounds of formula (1) are those where one or more of the following restrictions apply : (i) n represents an integer being 1 or 2; (ii) Rl and R2 each independently represents hydrogen C1-4alkyl, NR9R10, C1- 4alkyloxy ; or Rl and R2 taken together with the carbon atom with which they are attached form a (23 6cycloalkyl, and where n is 2, either Rl or R2 may be absent to form an unsaturated bond ; (iii) R3 represents a C6-i2cycloalkyl, preferably selected from cylo-octanyl and cyclohexyl or R3 represents a monovalent radical having one of the following formulae wherein said C6-l2cycloalkyl or monovalent radical may optionally be substituted with one, or where possible two, three or more substituents selected from the group consisting of Cl-4alkyl, C1-4alkyloxy, halo or hydroxy; (iv) Q represents Hetl or Ar2 wherein said C3-8cycloalkyl, Het'or Ar2 are optionally substituted with one or where possible two or more substituents selected from halo, C1-4alkyl, C1-4alkyloxy, hydroxy, nitro, NR5R6, C1-4alkyloxy substituted with one or where possible two, three or more substituents each independently selected from hydroxycarbonyl, Het2 and NR7R8, and Cl 4alkyl substituted with one or where possible two or three halo substituents, preferably trifluoromethyl; (v) R and R6 each independently represent hydrogen, C1-4alkyl, or Cl 4alkyl substituted with phenyl; (vi) L represents Cl 4alkyl ;

(vii) Hetl represents a heterocycle selected from pyridinyl, thiophenyl, or 1,3- benzodioxolyl; (viii) Het2 represents piperidinyl, pyrrolidinyl or morpholinyl; (ix) Ar2 represents phenyl, 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 Cl-4alkyloxy preferably methoxy. ; (ii) n is 1; (iii) m is 0 ; (iv) R1 and R2 represent Cl 4alkyl, preferably'methyl ; or R'and R 2 taken together with the carbon atom with which they are attached form a C3 6cycloalkyl, preferably cyclopropyl ; (v) R4 represents hydrogen; (vi) R3 represents a monovalent radical having one of the following formulae wherein said monovalent radical may optionally be substituted with one or where possible two or three substituents selected from halo, carbonyl, hydroxy or Cl- 4alkyloxy, preferably methoxy.

Also of interest are those compounds of formula (1) wherein the R3 substituent is being selected from the monovalent radicals having one of the following formulae

optionally substituted with one, or where possible two or three substituents selected from the group consisting of Cl 4'alkyl, Cl 4alkyloxy,'phenyl, halof oxo, carbonyl, 1,3- dioxolyl or hydroxy; even more preferably those compounds wherein the R3 substituent is 2-adamantyl optionally substituted with one, or where possible two or three substituents selected from the group consisting of Cl 4alkyl, Cl 4alkyloxy, halo, oxo, carbonyl or hydroxy.

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 l-ethyl-3- (3'- dimethylaminopropyl) carbodiimide hydrochloride (EDCI) are used in the presence or absence of hydroxybenzotrialzole (HOBt). 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 (I), a

dehydrogenating agent such as carbodiimides, for example DCC and CDT are added to the reaction mixture.

Scheme l of couplingreagent n OH H R. R2/N (9m R2 R4 R4 R3 w l m (III) (1 (l) R A"R< R 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. 0 Scheme2 R1 11' : n OH I in" zu SOC12 SOC12 l O'/(L) m H20 gR X Q Ji R3 (L\ m NAOS R2 ; R4 3 (V) (D The carboxylic acids of formula (III) 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 <BR> <BR> 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 III..

Appropriate acids and bases in the hydrolysis are for example H2S04 and KOH. The hydrolysis reaction can be conveniently performed using microwave heating.

Scheme 3 1. KOH OH EtOH/H20 NaHMDS reflux ON 0 Q \ ^ , Q - \N N 2. HC1 Ri t12 (vit (vu) (Vil) 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 (hetero) aryl 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 (VIII) by reaction with hydroxylamine (scheme 4). In this latter case the oximes are reduced by lithium aluminium hydride or catalytic hydrogenation using an appropriate catalysator such as Rainey Nickel, said reduction being performed in an inert anhydrous solvent such as ether or tetrahydrofuran (THF).

Scheme4 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 : be performed : (i) removing any remaining protecting group (s); (ii) converting a compound of formula (1) 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; thereof ; (iv) converting a N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (1) 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) or a protected form thereof; (vi) where the compound of formula (I) is obtained as a mixture of (R) and (S) enantiomers resolving the mixture to obtain the desired enantiomer.

Compounds of formula (1), N-oxides, addition salts, quaternary amines and stereochemical isomeric forms thereof can be converted into further compounds according to the invention using procedures known in the art, for example : 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 C (6) alkyl 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 dedition, T W Greene & P G M Wutz, Wiley Interscience (1991).

Additionally, the N-atoms in compounds of formula (1) can be methylated by art- known methods using CH3-I 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. hereinabove.

The compounds of formula (1), 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 (1) 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 (1), 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 stereospecifically.

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.

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 l lb-HSD1-reductase activity (conversion of cortison into cortisol) has been demonstrated in vitro, in an enzymatic assay using the recombinant 1 lb- HSD1 enzyme, by measuring the conversion of cortison into cortisol using HPLC purification and quantification methods. 1 lb-HSD l-reductase inhibition was also demonstrated in vitro, in a cell based assay comprising contacting the cells, expressing

llb-HSDl 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-PK1 cells and rat hepatocytes.

Accordingly, the present invention provides the compounds of formula (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') 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 50 mg/kg body weight, in particular from 0.005 mg/kg to 10 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 (18th 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.

These compositions may be administered in various ways, e. g., as a transdermal patch, as a spot-on or as an ointment. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e. g. creams, gellies, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the'like. Application of said compositions may be by aerosol, e. g. with a propellant such as nitrogen, carbon dioxide, a freon, or without a propellant such as a pump spray, drops, lotions, or a semisolid such as a thickened composition which can be applied by a swab. In particular, semisolid compositions such as salves, creams, gellies, ointments and the like will conveniently be used.

It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage.

Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

In order to enhance the solubility and/or the stability of the compounds of formula (I), (I') in pharmaceutical compositions, it can be advantageous to employ oc-, ß-or y- cyclodextrins or their derivatives. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I), (I') in pharmaceutical compositions. In the preparation of aqueous compositions, addition salts of the subject compounds are obviously more suitable due to their increased water solubility.

Experimental part Hereinafter, the term'RT'means room temperature,'THF'means tetrahydrofuran, 'AcOH'means Acetic Acid,'EtOH'means ethanol,'DME'means dimethyl ether, 'DIPE'means diisopropyl ether,'TFA'means trifluoroacetic acid,'EtOAc'means ethyl acetate,'iPrOH'means dimethylformamide,'HOBt'means hydroxybenzotrialzole.

A. Preparation of the intermediates Example A1 Bicyclo [3.3. 1] non-2-ylamine (intermediate 4) and 3-aza- tricyclo [4. 3.1. 0*2,4*] decane (intermediate 5) Preparation of Preparation of (interm. 4) (interm. 5) Bicyclo [3.3. 1] nonan-2-one oxime (CAS 16473-10-2) (1.4 g) was dissolved in anhydrous THF (30 Ml) and a solution of LiAlH4 (15 Ml, 1M in diethyl ether) was added. The solution was boiled under reflux for 16h. Addition of water (0.6 Ml), 15% NaOH (0.6 MI), and water (1.8 mL), followed by filtration, drying of the filtrate (MgSO4) and evaporation gave the crude amines. The residue was dissolved in CH2C12, and extracted with 15% citric acid. The aqueous layer was basicified with 1 M KOH, and extracted with CH2Cl2. The organic layer was washed with brine, dried and evaporated to the amines 1: 1 mixture (0.5 g).

NMR (CDCl3) # 1.2-2.1 (m, CH), 2.45 (t, 1H), 2.9 (m, 1H)

Example A2 a) 6-Hydroxyimino-adamantan-2-yl ethylene ketal Preparation of Intermediate 16 Commercially available Spiro [1, 3-dioxolane-2, 2'-tricyclo [3.3. 1.13, 7] decan]-6'-one (CAS 50776-11-9) (2.3 g, 0.012 mol) (containing about 30% of the diketal) was dissolved in EtOH and a solution of hydroxylamine hydrochloride (1. 7 g, 0.025 mol) and NaOH (1.0 g) in water (30 ml) was added. The mixture was stirred overnight. The volatiles were evaporated in vacuo, and the residue was extracted with CH2C12. The organic layer was washed with brine, dried and evaporated to give the oxime (Intermediate 16) (2.4 g).

NMR (DMSO-d6) 8 1. 3-2.3 (m, CH), 2. 5 (bs, 1H), 3.5 (bs, 1H), 3.95 (s, 4H, CH2CH2) b) 6-Oxo-adamantan-2-ylamine ethylene ketal Preparation of Intermediate 17 6-Hydroxyimino-adamantan-2-yl ethylene ketal (2.4 g) was dissolved &M NH3/MeOH (100 mL), Raney nickel (1 g) was added and the mixture was hydrogenated at 14 °C.

The mixture was filtered, and evaporated to give 2.0 g of the title compound (Intermediate 17).

NMR (DMSO-d6) 81. 3-2.3 (m, CH), 3.23 (bs, 2H, NH2), 3.95 (s, 4H, CH2CH2).

B. Preparation of the compounds Example B 1 N-Adamantan-2-yl-2- (4-chlorophenyl)-isobutyramide Preparation of compound 1 2, 2-dimethyl- (4-chlorophenyl) acetic acid (CAS 6258-30-6) (2.0 g, 10 mmol) and 2- aminoadamantane hydrochloride (CAS 13074-39-0) (1.9 g, 10 mmol) were dissolved in CH2CL2 (50 mL), HOBt (2.7 g, 20 mol), triethylamine (2.1 g, 20 mmol), and EDCI (2.1 g, 11 mmol) were added and the mixture was stirred overnight. The reaction mixture was washed with 15% citric, acid, sat. NaHCO3 and brine, dried over MgS04, and evaporated in vacuo. The residue was recrystallised from isopropanol, yielding 2. 0 (6 mmol, 60%) of compound 1.

NMR : (DMSO-d6) 61. 4-1.8 (m, CH), 1.47 (s, 6H, (CH3) 2), 3. 79, (d, 1H, CH), 6.42 (d, 1H, NH), 7.38 (dd, Ar-H). NH), 7.38 (dd, Ar-H).

LC-MS: M+1 332.89, 334.89 Example B2<BR> <BR> <BR> <BR> N-Adamantan-2-yl-2-phenyl-isobutyramide Preparation of compound 2 Compound 1 (1.7 g, 5 mmol) was dissolved in MeOH (100 mL), 0.5 g 10% Pd-C and CaO (1 g) were added, and the mixture was hydrogenated at 50 oC, After uptake of one equivalent of hydrogen, the reaction was filtered, evaporated till dryness. The residue was dissolved in CH2C12, washed with sat. NaHCO3, dried and evaporated. The residue was crystallized from diisopropyl ether, yielding 0.65 g (60%) of the title compound.

NMR: (DMSO-d6) 8 1.4-1. 8 (m, CH), 1.49 (s, 6H, (CH3) 2), 3. 79 (d, 1H, CH), 6.21 (d, 1H, NH), 7.25-7. 37 (m, 5H, Ar-H).

LC-MS: M+1 298. 44

Example le B3 Preparation of compound 3 2,2-dimethylphenyl acetic acid (CAS 826-55-1) was dissolved in dry CH2C12, oxalyl chloride was added and one drop of DMF. After stirring for two hours, the solution was evaporated till dryness, redissolved in 10 mL CH2C12, and added to a solution of 2- amino adamantane (CAS 13074-39-0) and triethylamine in CH2C12. The mixture was stirred overnight, extracted with 15% citric acid, sat. NAHC03 and brine, dried over MgS04, and evaporated in vacuo. The residue was recrystallised from isopropyl ether.

NMR : (CDC13) 8 1.3-1. 8 (m, CH), 1.55 (s, 6H, (CH3) 2), 2.31 (s, 6H, 2 x CH3), 3.96 (d, 1H, CM, 5.50 (d, 1H, NH), 6.91 (s, 1H, Ar-H), 6.99 (s, 2H, ArH).

Example B4 a) 3-Methoxyphenyl-dimethyl adamantyl acetamide Preparation of compound 4 Intermediate 2 (2. 0 g, 10 mmol) and 2-aminoadamantane hydrochloride (CAS 13074- 39-0) (1.9 g, 10 mmol) were dissolved in CH2CL2 (50 mL), HOBt (2.7 g, 20 mol), triethylamine (2.1 g, 20 mmol), and EDCI (2.1 g, 11 mmol) were added and the mixture was stirred overnight. The reaction mixture was washed with 15% citric acid, sat. NaHCO3 and brine, dried over MgS04, and evaporated in vacuo. The residue was recrystallised from isopropanol, yielding 2.0 (6 mmol, 60%) of compound 4.

NMR: (DMSO-d6) 8 1. 4-1. 8 (m, CH), 1.48 (s, 6H, (CH3) 2), 3.75 (s, 3H, OCH3), 3.79 (d, 1H, CH), 6.23 (d, 1H, NH), 6.8-7. 3 (m, 3H, Ar-H). b) N-Adamantan-2-yl-2- (3-hydroxy-phenyl)-isobutyramide Preparation of compound 5 Compound 4 was dissolved in dry CH2C12, cooled to-78°C and boron tribromide was added. The reaction mixture was stirred at room temperature for 1 h, poured onto

aqueous ammonia and extracted with C2C12. The organic layers were washed with brine, dried and evaporated. The solid reside was crystallized from ethyl acetate.

NMR: (DMSO-d6) 8 1. 4-1.8 (m, CH), 1. 44 (s, 6H, (CH3) 2), 3 : 79 (d, 1H, CH), 6.18 (d, 1H, NH), 6.65-7. 16 (dd, 4H, Ar-H), 9.35 (s, 1H, OH). c) {3- [1- (Adamantan-2-ylcarbamoyl)-1-methyl-ethyl]-phenoxy}-acetic acid Preparation of compound 6 Compound 4 was dissolved in DMF and ethyl bromoacetate was added together with potassium carbonate. The mixture was stirred at 60 °C overnight, poured on ice, and extracted with CH2C12. The organic layer was washed with 1 M NaHCO3, and brine, and evaporated. The residue was dissoled in EtOH, 1 M KOH was added, and the mixture was stirred for 2 h. The solution was acidified with 1M HC1, extracted with EtOAc, the organic layer was dried and evaporated. The residue was crystallized from ethyl acetate.

NMR: (DMSO-d6) 8 1. 4-1.8 (m, CH), 1.47 (s, 6H, (CH3) 2), 3.78 (d, 1H, CH), 4.67 (s, 2H, CH2COOH), 6.23 (d, 1H, NH), 6.77-7. 3 (m, 4H, Ar-H).

Example B5 N-Adamantan-2-yl-2- [3- (2-dimethylamino-ethoxy)-phenyl]-isobutyramide Preparation of compound 7 Compound 4 was dissolved in DMF, and dimethylaminoethyl chloride hydrochloride was added, followed by K2CO3. The mixture was stirred at 60 oC overnight, poured on ice, and extracted with CH2Cl2. The organic layer was washed with 1 M NaHCO3, and

brine, and evaporated. The residue was dissolved in iPrOH with heating, oxalic acid was added, and the crystallie amine was filtered.

NMR: (DMSO-d6) 8 1.4-1. 8 (m, CH), 1.49 (s, 6H, (CH3) 2), 2.78 (s, 6H, N (CH3) 2), 3.43 (t, 2H, CH2), 3.79 (d, 1H, CH), 4.27 (t, 2H, CH2), 6.29 (d, 1H, NH), 6.85-7. 35 (m, 4H, Ar-H).

Example B6 N- (trans-5-Hydroxy-adamantan-2-yl)-2-phenyl-isobutyramide (Compound 8) and N- (cis-5-Hydroxy-adamantan-2-yl)-2-phenyl-isobutyramide (Compound 9) Preparation of compound 8 Preparation of compound 9 2,2-dimethylphenyl acetic acid (CAS 826-55-1) (2.5 g, 15 mmol) was dissolved in dry CH2C12 (50 mL), oxalyl chloride (1.5 mL, 0.017 mol) was added and one drop of DMF.

After stirring for two hours, the solution was evaporated till dryness, redissolved in 50 mL of CH2C12, and added to a solution of 2-amino adamantane (CAS 13074-39-0) (2.5 g, 15 mmol) and triethylamine (3. 0 g, 30 mmol) in CH2C12 (50 mL). The mixture was stirred overnight, extracted with 15% citric acid, sat. NaHCO3 and brine, dried over MgS04, and evaporated in vacuo. The residue was chromatographed over silicagel (eluens 3-5% MeOH in CH2C12), yielding the title compounds. 1.8 g of trans-, NMR : (CDC13) 8 1.2-1. 85 (m, CH), 1.59 (s, 6H, (CH3) 2), 1.95-2. 00 (m, 2H, CH), 3.91 (dt, 1H, CH), 5.32 (d, 1H, NH), 7.25-7. 47 (m, 5H, Ar-H).

And 1.8 g of cis isomer.

NMR: (CDC13) 5 1.2-1. 7 (m, CH), 1.56 (s, 6H, (CH3) 2), 2.05-2. 10 (m, 2H, CH), 3.83 (dt, 1H, CH), 5.32 (d, 1H, NH), 7.25-7. 50 (m, 5H, Ar-H).

Example B7 N- (5-trans-fluoro-adamantan-2-yl)-2-phenyl-isobutyramide Preparation of compound 10.

Compound 8 (80 mg) was dissolved in dichloromethane (2 mL) and cooled to-78 oC under nitrogen. DAST ((diethylamino) sulfur trifluoride, 0.1 ml) was added, and the mixture was stirred and warmed to room temperature. Sat. NaHCO3 was added and the layers were separated. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was crystallized from diisopropylether to give 40 mg (50%) of the title compound.

NMR: (CDCl3) 8 1. 2-1. 85 (m, CH), 1. 59 (s, 6H, (CH3) 2), 1.95-2. 10 (m, 2H, CH), 3.93 (dt, 1H, CH), 5. 27 (d, 1H, NH), 7. 27-7. 43 (m, 5H, Ar-H).

Example le B8 N- (5-Bromo-adamantan-2-yl)-2- (3-hydroxy-phenyl)-isobutyramide Preparation of compound 11.

Compound 8 (100 mg, 0.3 mmol) was dissolved in CH2C12 (2 mL), cooled to-78 oc and boron tribromide (0.15 mL, 1. 5 mmol) was added. The reaction mixture was warmed to room temperature, diluted with CH2C12 and poured on a mixture ice and conc. Ammonia. The layers were separated, the organic layer washed with brine, dried (MgS04) and evaporated. The residue was crystallized from ethyl acetate (40 mg, 40%).

LC-MS: M+1 393.34, 395. 34 NMR : (CDC13) 8 1.25-1. 52 (m, CH), 1.57 (s, 6H, (CH3) 2), 1.90-2. 42 (m, CH), 3.97 (dt, 1H, CH), 5.37 (d, 1H, NH), 6.28-7. 30 (m, 4H, Ar-H).

Example B9 N- (6-Oxo-adamantan-2-yl)-2-phenyl-isobutyramide ethylene ketal Preparation of compound 12 2,2-dimethylphenyl acetic acid (CAS 826-55-1) (0.5 g, 2.7 mmol) was dissolved in dry CH2C12, oxalyl chloride (0.4 g) was added and one drop of DMF. After stirring for two hours, the solution was evaporated till dryness, redissolved in 10 mL CH2C12, and added to a solution of 6-oxo-adamantan-2-ylamine ethylene ketal (Intermediate 15) (0.6 g, 2. 7 mmol) and triethylamine (0. 5 mL) in CH2C12. The mixture was stirred overnight, extracted with 15% citric acid, sat. NAHC03 and brine, dried over MgS04, and evaporated in vacuo. The residue was purified over silacalgel (eluens 5% MeOH in CH2C12), and the title compound was recrystallised from isopropyl ether. 600 mg (50%) NMR : (CDC13) 8 1. 52-2.05 (m, CH), 1.60 (s, 6H, (CH3) 2), 3.85 (dt, 1H, CH), 3.85- 3.90 (m, 4H, CH2CH2), 5.45 (d, 1H, NH), 7.23-7. 42 (m, 5H, Ar-H).

Example B 10 N- (6-Oxo-adamantan-2-yl)-2-phenyl-isobutyramide Preparation of compound 13 The ketal from example B9 (450 mg) was dissolved in acetone (10 mL), 1 M HC1 (5 mL) was added and the mixture was stirred fro 3 h at 45 °C. The reaction mixture was concentrated, and extracted with dichloromethane. The organic layers were washed with sat. NaHCO3 and brine, dried and evaporated. The residue was crystallized from ethanol: 300 mg of the title compound.

NMR : (CDCl3) 8 1. 52-1.75 (m, CH), 1.60 (s, 6H, (CH3) 2), 1.95-2. 15 (m, 2H, CH), 2.30 (d, 2H, CH), 2.50 (s, 2H, CH), 4.12 (dt, 1H, CH), 5.45 (d, 1H, NH), 7.27-7. 47 (m, 5H, Ar-H).

Example B 11 N- (6-Hydroxy-adamantan-2-yl)-2-phenyl-isobutyramide Preparation of compound 14 Compound 13 (50 mg) was dissolved in MeOH and NaBH4 (50 mg) was added. The mixture was stirred at room temperature for 6 h. 1M HCl was added, and the mixture was extracted with dichloromethane. The organic phase was washed with brine, dried and evaporated. Chromatography over silicagel (5% MeOH in CH2C12) gave the alcohol (20 mg, 40%) NMR: (CDC13) b, 1. 52-2, 00 (m, CH), 1.60 (s, 6H, (CH3) 2), 3.85 (dt, 1H, CH), 5. 45 (d, 1H, NH), 7.23-7. 42 (m, 5H, Ar-H).

Example B 13 Preparation of compound 17 1-Phenylcyclopropanecarboxylic acid (0.00028 mol); was added to a mixture of PS-N- cyclohexylcarbodiimide (0.0004 mol) in CH2C12 (5 ml). The mixture was stirred for 15 min. 2-methyl-2-Propanamine (0.0002 mol) was added and the reaction mixture was stirred overnight at room temperature. The resin was filtered off and the filtrate was evaporated. The residue was purified over Supelclean LC-SI (14 ml ; eluent: CH2C12).

The product fractions were collected and the solvent was evaporated, yielding compound 17.

Example B 14 Preparation of compound 31 PS-carbodiimide (0.0004 mol) was suspended in CEI2Cl2 (5 ml). Then, 1-phenyl- cyclopropanecarboxylic acid (0.00028 mol) and N, N-dimethyl-4-pyridinamine

(O. OOOOlmol) were added and the mixture was stirred for 20 min.

Tricyclo [3.3. 1.13, 7] decane-1-methanamine (0.0002 mol; 6 variables) was added and the reaction mixture was stirred overnight at room temperature. The mixture was filtered. The filter residue was washed with CH2C12 and the filtrate's solvent was evaporated. The residue was purified by flash column chromatography on Triconex flash tubes (eluent: hexane/EtOAc 9/2). The product fractions were collected and then extracted and the extracts were evaporated. Yielding 0.037 of compound 31 Tables 1, 2 and 3 list compounds of the present invention as prepared according to one of the above examples.

Table 1 Co. Ex Ri R2 1',-Physical pi R2 R R.... R3 No. No. data 16 B3-(CH2) 3-@ 17 B 13-(CH2) 2--C (CH3) 3 - C (CH3) 2-CH2-- 18 B 13--- (CHz) z--. C (CH3) s 19 B 13 _-_ (CHz) z-- CH3 20 B 13-(CH2) 2-t3 y 21 B 13-(CH2) 4--C (CH3) 3 22 B 13-(CH2) 4-4 Co. Ex Physical Roi 2 3 No. No. data 23 B13- (CH2) 4- 3 n f 24 B13--- (CH2) 4- JL 25 B 13- (CH2) 5- 26 B 13--- (CHz) s--, 1 B 1 CH3. CH3-4-Cl 27 B 1-_- (CHz) z- . 4-Cl 28 B1 CH3 + + 2 B2 CH3 CH3-_____- 29 B 1 Czgs-_ 30 Bl 31 B14-(CHz cH2 H.. : 3 Bl- (CH2) 2- 33 B14-(CH) 2- 34 B14-(CH) 3 3 - CH2- (IJ 35 B14--(CH. ß-CH2 _ 36 B 14- (CH2) 4- U 37 B14-(CH2) 6-_cH2 C Co. Ex 2 3 Physical R'R R T No., No. data 38 B 1-(CH2 ? 4-g 39 Bl- (CH2) 3- 4-Cl 40 B2-.-(CH2) 3-1+. 41 B 1 CH3 CH3 4_F- C (CH3) 3 42 Bl C=0--, n7 42 Bl C=O , ITH, 43 Bl CH30 C (CH3) 3 °,-c (eH3) 3-o_ 44 B 1 C-p-_ NH CONS 45 Bl CH3 CH3- ta 46 Bl CH3 CH3 4 B4 CH3 CH3 3-OCH3 \-"\ 47 B4 CH3 CH3 OCH3 B4 CH 48 B4 CH3 CH3- 49 Bl- (CH2) 2 _ _., 5 B4 CH3 CH3-3-OH 50 Bl-NH2 isomeric 51 B 1-NH2---form of comp 50 Co. Ex 1 2 3 Physical R R Ff----R T No. No. data 52 B 1 CH3 CH3 4-N (CH3) 2 53 B5 CH3 CH3 3-0- (CH2) 2-CH3 54 B5 CH3 $ ; S 4 55 B 14- (CH2) 2- 56 B14--- (CH- -Ic> '13 57 B 14- (CH2) 4- , Y1 58 B 14- (CH2) 4- " 59 B 14 :-(CH2) 3-H. 60 B 14--_CHz) s-. 61 B 1- (CH2) 2- 62 B 1 CH3 Cg3 _ 63 bol CH3 CH3' 64 B 1--(CH2) 2-< 6 B4 CH3 CH3. 3-O (CHz) 2-COOH 65 B5 CH3 CH3 H 9 B6 CH3 CH3 OH OH CHZ-O-- () 66 B1 --- Co. Ex Physical R'R2 f----R3 T No. No. data H AH CH2 0 H 67 B 1 CH3 CH3-H u OH 68'B 1 CH3, _ . 4 NO 69 B 1 ; t t. 69 BI CHEZ/ KA 69 B 1--H 70 B4. CH3 CH3 > 4-OH 71 B5 CH3 CH 3 3--O- (CH2) 7-ND 3-Q (z N-C- 7 B5 CH3 CH.-0% 72 Bl CH3 CH3 4-0-CH2-COOH 73 B, 5 CH3 _ CH3-. 74 B4. CH3 CH3 X 3-O-CH3 75 B4 CH3 CH3 3-0-CH3 76 B 1 CH3 CH3 3-NH2 77 B 1 CH3 CH3- 3--CH3. 78 B 1 CH3 CH3 3-N (CH3) 2 79 B 1 CH3 CH3-J 4-NH2 80 B 1 CH3 CH3 LJ 4-NH-CH3 81 Bl CH3 CH3-t\3 4-N (CH3)- (CH2)-C6H5 " Co. Ex Ri R2 R3 T Physical 1 2 R .... 3 rp No. No data 82 B i _N (CH3)-z--- 83 B 1 CH3 CH3 _ 3-Cl 84 Bl CH3 CH3-, 13-F 85 Bl C CH3- 3-CF3 86 B 1 CH3 CH3 < 3, 4 (-OCH3) 2 :.. v"- 87 B 1 CH3 CH3-,-2 4-FZ 88 Bl CH3 CH3-\\. ' 89 B 1 CH3 CH3-3-CH3 r 90 B 1 CH3 _ zS 91 B 1 CH3 CH3 f. 92. B5 CH3 CH3 3-0- (CH2) 3-N (CH3) 2 8 B6 CH3 CH3) Q-OH' 93 B1 CH3 CH3 X 2, 5 (-O-CH3) / 94 Bl CH3 CH3 2-0-C6H5 95 B1 CH3 CH3 3, 5 F2 isomeric 96 B3 CH3 CH3 form of com 90 fT 97 B3 CH3 » CH3 =/ Co. Ex Physical Ri R2 Ff-... R3 T No. No. data ., os isomeric 98 B3 CH3 CH3/ya form of com 97 99 B3 CH3 CH3-/y isomeric 100 B3 CH3 CH3 \-form of com 99 101 B3 CH3 CH3, _ isomeric 102 B3 CH3 form of com 101 isomeric 103 B3 CH3 CH3 form of com 102 isomeric 104 B3 CH3 CH3 form of com'103 --CH-C' 105 B3 CH3 CH3- _, H n 106 B 1 CH3 CH3-H 2, 4 C12 H-4 3 B1 CH3 CH3 < 3, 5 (CH3) 2 V-\ 107 B 1 CH3 CH3-3-NH-CO- (CH2) 3-Cl 108 B6 CH3 CH3 XoX H g 109 B6 CH3 Cl3-- o Co. Ex -1',-Physical Rl R2 R R.... 3 No. No. data mixture of 110 B3 CH3 CH3 and lez., n JL j 111 B3 CH3 CH3 _C _ CHCH3 3 12 B9 CH3 CH3. a 112 B 4 CH3 CH3 NJ 3-NH-CO-CH3 113 Bl CH3 CH3 y o 3-N 114 B5 CH3 CH3- _ (CH2) 2 'H-0-CH 115 B5 CH3 CH3 0 CH3 3-nez 116 B5 CH3 CH3 LDO .. E Tt 13 B 10 CH3 CH3, 0" TO 14 Bll CH3 CH3 OH 117 B6 CH3., CH3-OH 3_p_Cg3 118 B6 CH3 CH3-3-0-CH3 HO 119 B6 CH3 CH3- 3-CH3 pound HO 120 B6 CH3 CH3-oH g-Cg3

t Co. Ex Physical Ri 2 3 No. No. data 121 B6 CH3 CH3-3, 5 (-CH3) 2 HO isomeric 122 B6 CH3 : CH3 SJ 3, 5 (-CH3) 2 form of HO com 121 10 B7 CH3 CH3 XF --/'' 123, B 1 CH3 CH3 3-N (CH3)-CO-CH3 XT 1 ; t X St o. f X 11 B CH3 CH3 3-OH Table 2 0. R3 Ri Q t/. 4 R2 R4 _. Co. Ex. physical Q 1 R2 No. No. data No. No. data CH3 124 4B3 0 H CL 125 B3 fT" 126 B 1 0 H '"'3""T 127 Bl 1 0 H _ U _ H N 128 B6 I CH3 CH3 H H H 144 B CH3 2CH3 CH3 H 145 B, l 0-H 146 bu 1 I/1-O-H- 145 B1. 9 0 H a N 147 B 1 i CH3 CH3 H CH3-0-3 3 148 B6 Cll < l CH3 CH3 H X 2 149 B (HzNs 1 CH3 CH3 OY% CH3'" 150 B4 0 H I w,. i X 172 B 1 2, 5 methoxy-phenyl 1 CH3 CH3, H '--

Table Table 3 Ex. No. Q R1 R2 R3 R4 Physical data No. 151 B, I H CH3 H 151 Bl H H H 153 B 1 CH3 H H 153 B1 153 B1 > CH3 H H X C. Pharmacological examples <BR> <BR> Example C. 1 : Enzymatic assays to test the effect of compounds on 1 lb-hydroxysteroid<BR> <BR> <BR> <BR> <BR> dehydrogenase type 1 and type 2 The effects of compounds on 1 lb-HSD1 dependent conversion of cortisone into cortisol (reductase activity) was studied in a reaction mixture containing 30 mM Tris- HCl buffer pH 7.2, 180 I1M NADPH, lmM EDTA, 2 µM cortisone, 1 ul drug and/or solvent and 11 I gg recombinant protein in a final volume of 100 µl.

The effect on the 11b-HSDl-dehydrogenase activity (conversion of cortisol into cortisone) was measured in a reaction mixture containing O. 1M sodium phosphate buffer pH 9. 0, 300 µM NADP, 25 ZM cortisol, 1 1 drug and/or solvent and 3.5 gag recombinant protein in a final volume of 100 ul.

The effects on the 11b-HSD2 dependent dehydrogenase activity was studied in a reaction mixture containing 0. 1M sodium phosphate buffer pH 7.5, 300 FM NAD, 100 nM cortisol (of which 2 nM is 3H-radio labelled), 1 µl drug and/or solvent and 2. 5 µg recombinant protein in a final volume of 100 1.

All incubations were performed for 45 min at 37C in a water bath. The reaction was stopped by adding 100 u, l acetonitrile containing 20 ßg corticosterone as internal standard. After centrifugation, the product formation was analysed in the supernatant by HPLC on a Hypersyl BDS-C18 column using 0. 05 mM ammonium acetate/ methanol (50/50) as solvent. In all of the aforementioned assays, the drugs to be tested were taken from a stock solution and tested at a final concentration ranging from-10- SM to 3. 10-9M. From the thus obtained dose response curves, the pIC50 value was calculated and scored as follows; Score 1 = pIC50 value < 5, Score 2 = pIC50 value in the range of 5 to 6, Score 3 ='pIC50 value >6. Some of the thus obtained results are summarized in the table below. (in this table NT stands for Not Tested). <BR> <BR> <BR> <BR> <BR> <BR> <BR> <P> Example C2 : Cellular assays to test the effect of compounds on 1 lb-hydroxysteroid<BR> <BR> <BR> <BR> <BR> <BR> dehydrogenase type 1 and type 2 The effects on 11b-HSD1 activity was measured in differentiated 3T3-L1 cells and rat hepatocytes.

Mouse fibroblast 3T3-L1 cells (ATCC-CL-173) were seeded at a density of 16500 cells /ml in 12 well plates and grown for 7 days in DMEM medium (supplemented with 10 % heat inactivated foetal calf serum, 2mM glutamine and 25 mg gentamycin) at 37C in a humidified 5% C02 atmosphere. Medium was refreshed twice a week. Fibroblasts were differentiated into adipocytes at 37C in a 5% C02 humidified atmosphere in growth medium containing 2Fgiml insulin, 55 gg/ml 113MX and 39.2 ktg/ml dexamethasone.

Primary hepatocytes from male rats were seeded on BD-Biocoat Matrigel matrix multiwell plates at a density of 250000 cells/well and incubated for 10 days at 37C in a 5% C02 humidified atmosphere in DMEM-HAM's F12 medium containing 5% Nu- serum, 100 U/ml penicillin, 100 ug/ml streptomycin, 0.25 jug/ml amphotericin B, 50 Fg/ml gentamycin sulfate, 5µg/ml insulin and 392 ng/ml dexamethasone. Medium was refreshed 3 times a week.

Following a 4 hour pre-incubation with test compound, 0. 5 µCi 3H-cortisone or dehydrocorticosterone, was added to the cultures. One hour later, the medium was extracted on Extrelut3-columns with 15 ml diethyl ether and the extract was analysed by HPLC as described above.

The effects on 11b-HSD2 activity was studied in HepG2 and LCC-PKl-cells

HepG2-cells (ATCC HB-8065) were seeded in 12 well plates at a density of 100,000 cells/ml and grown at 37C in a humidified 5% C02 atmosphere in MEM-Rega-3 medium supplemented with 10% heat inactivated foetal calf serum, 2 mM L-glutamine and sodium bicarbonate). Medium was refreshed twice a week.

Pig kidney cells (LCC-PK1, ATCC CRL-1392) were seeded at a density of 150,000 cells/ml in 12 well plates and grown at 37C in a humidified 5% C02 atmosphere in Medium 199 supplemented with Earls modified salt solution, 100 U/ml penicillin, 100 Zg/ml streptomycin and 10 % foetal calf serum. Medium was refreshed twice a week.

Twenty four hours prior to the onset of the experiment, medium was changed by medium containing 10% charcoal stripped foetal calf serum.

Following a 4 hour pre-incubation with test compound, 0. 5 uCi 3H-cortisol or corticosterone, was added to the cultures. One hour later, the medium was extracted on Extrelut3-columns with 15 ml diethyl ether and the extract was analysed by HPLC as described above.

As for the enzymatic assays, the compounds to be tested were taken from a stock solution and tested at a final concentration ranging from-10-5M to 3. 10-9M. From the thus obtained dose response curves, the pIC50 value was calculated and scored as follows; Score 1 = pIC50 value < 5, Score 2 = pIC50 value in the range of 5 to 6, Score <BR> <BR> <BR> 3 = pIC50 value >6. Some of the thus obtained results are summarized in the table<BR> <BR> <BR> <BR> below. (in this table NT stands for Not Tested). N C F 77 E p. Q x S N 0 *- Q-co Q- Z Z o U _ U o, m O O O x m = a 0 a i S , 3 S 8 8 u :-z I z W S E I M M M uj o-, r 3 : I : 0 f-M (N Score Score Score Score B3 16 NT 1 2 1 B13 19 NT 1 2 1 B13 22 NT 1 2 1 B1 1 NT 1 3 1 C\l 04 g p 2 -- _-_ a' Q 0 lux. l (D Q) CL : 3 0 C\l C\l E CL cz x E 3 : U) C/) LU 0-3 :-r ". Score Score Score Score B1 28 NT NT 3 1 B1 29 NT NT 3 1 B1 30 NT NT 3 1 B14 31 NT 1 3 1 B14 35 NT 1 2 B1 41 3 1 3 1 BI 43 3 1 2 B1 46 1'1 3 1 B4 47 3 1 3 1 B4 48 1 1 3. 1 B1 126 31 3 1 B1 127 1 1 3 1 B4 5 3 1 3 1 B1 50 1 1 2 1 B1 51 1 1 2 1 B1 52 1 1 3 1 B5 53 1 1 3 1 B5 54 2 1 3 1 B14 55 NT 1 3 B14 56 NT 1 2 1 8 B14 57 NT 1 2 1 B1 64 NT 1 2 1 B4 6 2 1 3 1 B6 128 3 1 3 1 B1 129 2 1 2 1 B1 68 2 1 2 1 B5 71 3 NT 3 1 B5 7 1 NT 3 1 B1 72 2 1 3 1 B5 73 1 1 3 1 B4 74 3 1 3 1 C\l C\l CL C () a) a) ? <D)-Q) E Er E ca w Z, 0-5 75 . S c . u a S D po 7ffi c : 9- -3 0 N C\l 0 )'T ; 7 cm Score Score Score Score B1 133 1 1 3 1 Bl 77 1 2 3 1 B1 78 3 2 3 1 B1 81 3 NT 2 1 B1 84 1 1 3 1 B1 85 1 1 31 B1 86 1 1 3 1 B1 87 1 1 3 1 B1 88 1 1 3 1. B1 89 3 1 3 1 B1 137 3 1 3 3 1 B1 138 1 1 3 1 B1. 91 1 1 3 1 B1 151 2 1 3 1 B1 153 2 1 3 1 B1 140 3 1 3 1 B1 141 3 1 3 1 B1 92 3 1 3 1 B1 93 3 NT 3 1 B1 173 1 NT 3 1 B1 95 1 NT 3 1 bol 144 3 NT 3 1 B1 106 1 NT 3 1 B1 3 3 NT 3 1 B6 109 3 NT 3 1

D. Composition examples The following formulations exemplify typical pharmaceutical compositions suitable for systemic or topical administration to animal and human subjects in accordance with the present invention.

"Active ingredient" (A. I.) as used throughout these examples relates to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

Example D. 1 : film-coated le D.1 : film-coated tablets Preparation, of tablet core A mixture of A. I. (100 g), lactose (570 g) and starch (200 g) was mixed well and thereafter humidified with a solution of sodium dodecyl sulfate (5 g) and polyvinyl- pyrrolidone (10 g) in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added microcrystalline cellulose (100 g) and hydrogenated vegetable oil (15 g). The whole was mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient.

Coating To a solution of methyl cellulose (10 g) in denaturated ethanol (75 ml) there was added a solution of ethyl cellulose (5 g) in CH2C12 (150 ml). Then there were added CH2C12 (75 ml) and 1,2, 3-propanetriol (2.5 ml). Polyethylene glycol (10 g) was molten and dissolved in dichloromethane (75 ml). The latter solution was added to the former and then there were added magnesium octadecanoate (2.5 g), polyvinyl-pyrrolidone (5 g) and concentrated color suspension (30 ml) and the whole was homogenated. The tablet cores were coated with the thus obtained mixture in a coating apparatus.