HK1106765B - Adamantyl pyrrolidin-2-one derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors - Google Patents

Description

Adamantyl pyrrolidin-2-one derivatives as inhibitors of 11-beta hydroxysteroid dehydrogenase

Metabolic syndrome is a disease that is increasingly prevalent not only in the western world but also in asia and developing countries. It is characterized by obesity, particularly central or visceral obesity, type 2 Diabetes, hyperlipidemia, hypertension, arteriosclerosis, coronary heart disease and finally chronic renal failure (C.T. Montague et al (2000), Diabetes, 49, 883-. Glucocorticoid and 11 β -HSD1 are known to be important factors in the process of differentiating adipose stromal cells into mature adipocytes. In visceral stromal cells of obese patients, 11 β -HSD1 mRNA levels were higher than in subcutaneous tissue. In addition, overexpression of 11 β -HSD1 in adipose tissue in transgenic mice was associated with increased levels of corticosterone in adipose tissue, visceral obesity, insulin sensitivity, type 2 diabetes, hyperlipidemia, and hyperphagia (H. Masuzaki et al (2001), Science, 294, 2166-2170). Thus, 11 β -HSD1 is most likely involved in the development of visceral obesity and metabolic syndrome.

Inhibition of 11 β -HSD1 resulted in a decrease in differentiation and an increase in adipose stromal cell proliferation. In addition, glucocorticoid deficiency (adrenalectomy) increases the ability of insulin and leptin to promote anorexia and weight loss, and administration of glucocorticoids reverses this effect (p.m. stewart et al (2002), Trends endocrin. metabpol, 13, 94-96). These data suggest that increased reactivation of cortisone by 11 β -HSD1 may exacerbate obesity, and that inhibition of this enzyme in adipose tissue in obese patients may be beneficial.

Obesity is also associated with cardiovascular risk. There is an extremely important relationship between cortisol secretion rate and HDL cholesterol in both men and women, suggesting that glucocorticoids regulate key components of cardiovascular risk. Similarly, aortic sclerosis is also associated with visceral adiposity in the elderly.

Glucocorticoids and glaucoma

Glucocorticoids increase the risk of glaucoma by raising intraocular pressure when exogenous glucocorticoids are administered and in certain conditions where glucocorticoid production is increased, such as cushing's syndrome. Corticosteroid-induced increases in intraocular pressure are caused by glucocorticoid-induced changes in the trabecular meshwork and its intracellular matrix, resulting in increased impedance to water outflow. Zhou et al (Int J Mol Med (1998)1, 339-346) also reported that corticosteroids increase the content of fibronectin and collagen types I and IV in the trabecular meshwork of organ-cultured bovine forepart. 11 β -HSD1 was expressed in basal cells and non-pigmented epithelial cells of the corneal epithelium. Glucocorticoid receptor mRNA is found only in trabecular meshwork, whereas in pigment-free epithelial cells, glucocorticoid-, mineralocorticoid receptor mRNA and 11 β -HSD1 are also present. Administration of carbenoxolone to patients resulted in a significant reduction in intraocular pressure (s.rauz et al (2001), invest.ophtalmol.vis.science, 42, 2037-.

Thus, the problem to be solved by the present invention is to identify potent 11 β -HSD inhibitors with a high 11 β -HSD1 selectivity and their use in the treatment of pathologies associated with excessive cortisol formation such as obesity, diabetes, obesity-related cardiovascular diseases and glaucoma. As shown below, it was found that 3-substituted 2-pyrrolidone derivatives of formula (I) are useful as medicaments, in particular for the preparation of medicaments for the treatment of pathologies associated with excessive cortisol formation.

Blommaert A. et al (Heterocycles (2001), 55(12), 2273-.

Bausanne I. et al (Tetrahedron: asymetric (1998), 9(5), 797-804) provide for the preparation of 3-substituted pyrrolidones by alpha-alkylation of chiral non-racemic gamma-lactones (lacton), in particular 1- (2-hydroxy-1-phenylethyl) -3-benzylpyrrolidin-2-one is disclosed.

Us patent 2001/034343; us patent 6,211,199; us patent 6,194,406; WO 97/22604 and WO 97/19074 are a number of patent applications filed by Aventis Pharmaceuticals Inc and provide 4- (1H-benzimidazol-2-yl) [1, 4] diazepanes useful in the treatment of allergic diseases. In these applications, the 3-substituted pyrrolidones of the invention are disclosed as intermediates in the synthesis of the 4- (1H-benzimidazol-2-yl) [1, 4] diazepanes. These applications disclose, among other things: 2-pyrrolidone, 3- [ (4-fluorophenyl) methyl ] -1- [ (1S) -1-phenylethyl ] -and 2-pyrrolidone, 3- [ (4-fluorophenyl) methyl ] -1- [ (1R) -1-phenylethyl ] -.

However, none of the documents discloses the therapeutic use of the 3-substituted 2-pyrrolidone derivatives of the present invention. Thus, in a first aspect, the present invention relates to compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof:

wherein

n is 1 or 2;

m represents a direct bond or optionally substituted by one or two groups selected fromC substituted by substituents_1-3Alkyl linking group: c_1-4Alkyl radical, C_1-3alkoxy-C_1-4Alkyl-, hydroxy-C_1-4Alkyl-, hydroxy, C_1-3Alkoxy-or phenyl-C_1-4Alkyl-;

R¹and R²Each independently represents hydrogen, halogen, cyano, hydroxy, C optionally substituted by halogen_1-4Alkyl, C optionally substituted with one or possibly two or three substituents selected from_1-4Alkoxy-: hydroxy group, Ar¹And halogen;

R³represents hydrogen, halogen, C_1-4Alkyl radical, C_1-4Alkoxy-, cyano or hydroxy;

R⁴represents hydrogen, halogen, C_1-4Alkyl, hydroxy, cyano or C optionally substituted by one or possibly two or three substituents selected from_1-4Alkoxy-: hydroxy and halogen;

R⁵represents hydrogen, C_1-4Alkyl or Ar²-C_1-4Alkyl-;

R⁶represents hydrogen, hydroxy, halogen, C_1-4Alkyl or C_1-4Alkoxy-;

R⁷represents hydrogen, or R⁷And R⁵Together with the carbon atom to which they are attached form-C₂-an alkyl-linking group;

Ar¹and Ar²Each independently represents phenyl or naphthyl, wherein the phenyl and naphthyl are optionally substituted by C_1-4Alkyl radical, C_1-4Alkoxy-or phenyl-C_1-4Alkyl substitution.

As used in the foregoing definitions and hereinafter, halogen is typically fluorine, chlorine, bromine and iodine; c_1-3Alkyl is defined as straight and branched chain saturated hydrocarbon groups having 1 to 3 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, and the like; c_1-4Alkyl is defined as a straight chain having 1 to 4 carbon atomsAnd branched saturated hydrocarbon groups such as methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2-dimethylethyl and the like; c_1-4Alkoxy is defined as a straight or branched chain saturated hydrocarbon group having 1 to 3 carbon atoms, such as methoxy, ethoxy, propoxy, 1-methylethoxy, and the like; c_1-4Alkoxy is defined as a straight or branched chain saturated hydrocarbon group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, butoxy, 1-methylethoxy, 2-methylpropoxy, and the like.

The pharmaceutically acceptable addition salts mentioned hereinbefore will include the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter is conveniently obtained by treating the base form with a suitable acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid, and the like; or organic acids such as acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic (i.e., succinic), maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids.

The pharmaceutically acceptable addition salts mentioned hereinbefore will include 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 pharmaceutically acceptable amine salts, such as salts of ammonia, alkylamines, benzathine, N-methyl-D-glucamine, hydrabamine g (hydrabamine), amino acids such as arginine, lysine.

The salt form can be converted back by treatment with an appropriate base or acid to the free acid or base form.

The term addition salt as used hereinbefore also includes solvates which the compounds of formula (I), and 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 isomers as well as the 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 stereochemical and conformational isomeric forms, said mixture containing all diastereomers, enantiomers and/or conformational isomers of the basic molecular structure. All stereochemically isomeric forms of the compounds of formula (I), both pure or in admixture with each other, are intended to be embraced within the scope of the present invention.

N-oxide forms of the compounds of formula (I) will include those compounds of formula (I) in which one or more nitrogen atoms are oxidized to the so-called N-oxide.

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

(i) n is 1 or 2;

(ii) m represents a direct bond or optionally substituted by C_1-4Alkyl, hydroxy or hydroxy-C_1-4Alkyl substituted C₁-a linking group; preferably M represents optionally substituted C_1-4Alkyl, hydroxy or hydroxy-C_1-4Alkyl substituted C₁-a linking group; in particular M represents C₁-a linking group;

(iii)R¹represents hydrogen, hydroxy, cyano, halogen, C_1-4Alkyl radical, C_1-4Alkoxy-, C substituted by one or possibly two or three halogen substituents_1-4Alkyl, or R¹Represents C substituted by halogen_1-4An alkoxy group;

(iv)R²represents hydrogen, halogen, C optionally substituted by one or possibly two or three halogen substituents_1-4Alkyl or C_1-4Alkoxy-;

(v)R³represents hydrogen, halogen, C_1-4Alkyl radical, C_1-4Alkoxy-or C substituted by one or possibly two or three halogen substituents_1-4An alkyl group;

(vi)R⁴represents hydrogen, halogen or C_1-4An alkyl group;

(vii)R⁵represents hydrogen, C_1-4Alkyl or Ar²-C_1-4An alkyl group; in particular hydrogen or methyl;

(viii)R⁶represents hydrogen or hydroxy, in particular hydrogen;

(ix)R⁷represents hydrogen, or R⁷And R⁵Together with the carbon atom to which they are attached form-C₂-an alkyl-linking group;

(x)Ar²represents optionally substituted by C_1-4Alkoxy-substituted phenyl.

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

(i) n is 1 or 2;

(ii) m represents C₁-a linking group;

(iii)R¹and R²Represents hydrogen, C_1-4Alkyl or C_1-4Alkoxy, in particular methyl or methoxy;

(iv)R³represents hydrogen or C_1-4Alkoxy, in particular hydrogen or methoxy;

(v)R⁴represents hydrogen or halogen;

(vi)R⁵represents hydrogen or C_1-4Alkyl, in particular hydrogen or methyl;

(vii)R⁶represents hydrogen or hydroxy;

(viii)R⁷represents hydrogen.

The compounds of interest are also those of formula (I) wherein one or more of the following limitations apply:

(i) n is 1 or 2;

(ii) m represents C₁-a linking group;

(iii)R¹represents hydrogen, C_1-4Alkyl or C_1-4Alkoxy, in particular methyl or methoxy;

(iv)R²represents hydrogen, C_1-4Alkyl or C_1-4Alkoxy, especially hydrogen;

(v)R³represents hydrogen or C_1-4Alkoxy, in particular hydrogen or methoxy;

(vi)R⁴represents hydrogen or halogen;

(vii)R⁵represents hydrogen or C_1-4Alkyl, in particular hydrogen or methyl;

(viii)R⁶represents hydrogen or hydroxy;

(ix)R⁷represents hydrogen.

In a preferred embodiment, the compound of formula (I) is selected from;

1)3- [ (3-methoxyphenyl) methyl group]-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

2)3- [ (3, 5-Dimethoxyphenyl) methyl]-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

3)3- [ (4-methylphenyl) methyl group]-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

4)3- [ (2-fluoro-3-methylphenyl) methyl group]-3-methyl-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

5)3- [ (3-methoxyphenyl) methyl group]-3-methyl-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

6)3- [ (3, 5-dimethylphenyl) methyl group]-3-methyl-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

7)3- [ (3-methoxyphenyl) methyl group]-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-piperidone;

8)3- [ (2-fluoro-3-methylphenyl) methyl group]-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-piperidone;

9)3- [ (4-fluorophenyl) methyl group]-3-methyl-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

10) 3-benzyl-1- (5-hydroxy-tricyclo [3.3.1.13, 7] decan-2-yl) -pyrrolidin-2-one;

11) 3-benzyl-1- (5-hydroxy-tricyclo [3.3.1.13, 7] decan-2-yl) -3-methyl-pyrrolidin-2-one;

12)3- (2-fluoro-3-methyl-benzyl) -1- (5-hydroxy-tricyclo [3.3.1.13, 7] decan-2-yl) -pyrrolidin-2-one;

13)3- (2-fluoro-3-methyl-benzyl) -1- (5-hydroxy-tricyclo [3.3.1.13, 7] decan-2-yl) -3-methyl-pyrrolidin-2-one;

an N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof.

In a more preferred embodiment, the compound of formula (I) is selected from;

1)3- [ (3, 5-Dimethoxyphenyl) methyl]-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

2)3- [ (4-methylphenyl) methyl group]-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

3)3- [ (2-fluoro-3-methylphenyl) methyl group]-3-methyl-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

4)3- [ (3-methoxyphenyl) methyl group]-3-methyl-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

5) 3-benzyl-1- (5-hydroxy-tricyclo [3.3.1.13, 7] decan-2-yl) -pyrrolidin-2-one;

6) 3-benzyl-1- (5-hydroxy-tricyclo [3.3.1.13, 7] decan-2-yl) -3-methyl-pyrrolidin-2-one;

7)3- (2-fluoro-3-methyl-benzyl) -1- (5-hydroxy-tricyclo [3.3.1.13, 7] decan-2-yl) -pyrrolidin-2-one;

8)3- (2-fluoro-3-methyl-benzyl) -1- (5-hydroxy-tricyclo [3.3.1.13, 7] decan-2-yl) -3-methyl-pyrrolidin-2-one;

an N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof.

According to a further aspect, the present invention provides a compound of formula, the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof:

wherein

n is 1 or 2;

m represents a direct bond or C optionally substituted with one or two substituents selected from_1-3Alkyl linking group: c_1-4Alkyl radical, C_1-3alkoxy-C_1-4Alkyl-, hydroxy-C_1-4Alkyl-, hydroxy, C_1-3Alkoxy-or phenyl-C_1-4An alkyl group;

R¹and R²Each independently represents hydrogen, halogen, cyano, hydroxy, C optionally substituted by halogen_1-4Alkyl, optionally substituted by one or possibly two or three of them selected from hydroxy, Ar¹And C substituted by halogen substituents_1-4Alkoxy-;

R³represents hydrogen, halogen, C_1-4Alkyl radical, C_1-4Alkoxy-, cyano or hydroxy;

R⁴represents hydrogen, halogen, C_1-4Alkyl, hydroxy, cyano or C optionally substituted by one or possibly two or three substituents selected from hydroxy and halogen_1-4Alkoxy-;

R⁵represents hydrogen, C_1-4Alkyl or Ar²-C_1-4Alkyl-;

R⁶represents hydrogen, hydroxy, halogen, C_1-4Alkyl or C_1-4Alkoxy-;

Ar¹and Ar²Each independently represents phenyl or naphthyl, wherein the phenyl and naphthyl are optionally substituted by C_1-4Alkyl radical, C_1-4Alkoxy-or phenyl-C_1-4Alkyl substitution.

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

i. n is 1 or 2;

ii, M represents C₁-a linking group;

iii.R¹and R²Represents hydrogen, C_1-4Alkyl or C_1-4Alkoxy, in particular methyl or methoxy;

iv.R³represents hydrogen or C_1-4Alkoxy, in particular hydrogen or methoxy;

v.R⁴represents hydrogen or halogen;

vi.R⁵represents hydrogen or C_1-4Alkyl, in particular hydrogen or methyl;

vii.R⁶represents hydrogen or hydroxyl.

The compounds of interest are also those of formula (I') wherein one or more of the following limitations apply:

i.n is 1 or 2;

m represents C₁-a linking group;

iii.R¹represents hydrogen, C_1-4Alkyl or C_1-4Alkoxy, in particular methyl or methoxy;

iv.R²represents hydrogen, C_1-4Alkyl or C_1-4Alkoxy, especially hydrogen;

v.R³represents hydrogen or C_1-4Alkoxy, in particular hydrogen or methoxy;

vi.R⁴represents hydrogen or halogen;

vii.R⁵represents hydrogen or C_1-4Alkyl, in particular hydrogen or methyl;

viii.R⁶represents hydrogen or hydroxyl.

Other groups of specific compounds are:

-those compounds of formula (I) wherein n is 1.

-those compounds of formula (I) in which the adamantyl substituent is attached to the rest of the molecule in the 2-position.

-wherein R is¹Or R²Those compounds of formula (I) which represent hydrogen.

-wherein R is³Those compounds of formula (I) which are in the meta position with respect to M.

-wherein R is⁶Those compounds of formula (I) wherein the substituent is located at the 4-position relative to the point of attachment of the adamantyl group to the rest of the molecule.

A further aspect of the invention provides any one of the aforementioned groups of compounds for use as a medicament. In particular for the treatment or prevention of pathologies associated with excessive cortisol formation, such as obesity, diabetes, obesity-related cardiovascular diseases and glaucoma.

The 1, 3-pyrrolidone (pyrrolidine) derivatives of the invention are typically prepared by alkylation of the appropriate lactam (II) with the appropriate alkyl halide (III) in the presence of a base such as (diisopropylamino) Lithium (LDA) or sec-butyllithium, optionally in the presence of a co-solvent such as N, N', N "-Hexamethylphosphoramide (HMPA) or a salt such as LiBr (scheme 1). The reaction is usually carried out in an inert solvent such as diisopropyl ether, tetrahydrofuran or dichloromethane. The reaction temperature and reaction time may vary depending on the starting materials or reagents, but are generally carried out at a low temperature (-50 ℃ C. -90 ℃ C.) within a few hours. In some cases, the coupling reaction is slow and the mixture must be maintained until the reaction is complete. In these cases, the temperature may be increased to (-10 ℃ C. -30 ℃ C.).

Scheme 1

The appropriate lactams of formula (II) above are typically prepared by reacting adamantan-2-one (IV) with the appropriate amino alkanoic acid (alkyl acid) in the presence of an acid such as formic acid (scheme 2). The reaction is typically carried out at elevated temperatures, for example in the range of 100-200 ℃ until adamantanone is undetectable. After completion of the reaction, the reaction mixture is cooled, basified with, for example, sodium carbonate and extracted with ether to give the lactam of formula (II).

Scheme 2

Further examples of the synthesis of compounds of formula (I) using any of the above synthetic methods are provided in the experimental section below.

Any one or more of the following steps may be performed in any order, if necessary or desired:

(i) removing any remaining protecting groups;

(ii) converting a compound of formula (I) or a protected form thereof to another compound of formula (I) or a protected form thereof;

(iii) converting a compound of formula (I) or a protected form thereof to an N-oxide, salt, quaternary amine, or solvate of a compound of formula (I) or a protected form thereof;

(iv) converting the N-oxide, salt, quaternary amine or solvate of the compound of formula (I) or a protected form thereof to the compound of formula (I) or a protected form thereof;

(v) converting a compound of formula (I) or a protected form of an N-oxide, salt, quaternary amine or solvate thereof to another compound of formula (I) or a protected form of an N-oxide, pharmaceutically acceptable addition salt, quaternary amine or solvate thereof;

(vi) if the compound of formula (I) is obtained as a mixture of the (R) and (S) enantiomers, the mixture is resolved to obtain the desired enantiomer.

One skilled in the art will recognize that the functional groups of the intermediate compounds may need to be protected by protecting groups in the above-described methods.

Functional groups to be protected include hydroxyl, amino and carboxylic acid. Suitable protecting groups for the hydroxyl group include trialkylsilyl groups (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for the amino group include tert-butoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acids include C_(1-6)Alkyl or benzyl esters.

The protection and deprotection of the functional groups may be performed before or after the reaction step.

The use of protecting Groups is described fully in the Protective Groups in Organic Synthesis 2 nd edition, T W Greene & PG M Wutz, Wiley Interscience (1991).

Alternatively, the N atom in the compound of formula (I) may be replaced by CH in a suitable solvent such as 2-propanone, tetrahydrofuran or dimethylformamide by methods known in the art₃-I methylation.

The compounds of formula (I) may also be interconverted according to functional group transformation methods known in the art, some examples of which are mentioned above.

The compounds of formula (I) may also be converted to the corresponding N-oxide form according to art-known methods for converting a trivalent nitrogen into its N-oxide form. The N-oxidation reaction can be generally carried out by reacting the starting material of formula (I) with 3-phenyl-2- (phenylsulfonyl) oxaziridine or with a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali or alkaline earth metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxy acids, such as perbenzoic acid or halogen-substituted perbenzoic acids, such as 3-chloroperoxybenzoic acid; peroxy alkanoic acids, such as peroxyacetic acid; alkyl hydroperoxides, such as tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol, and the like; hydrocarbons such as toluene; ketones, such as 2-butanone; halogenated hydrocarbons such as dichloromethane; and mixtures of such solvents.

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

Certain compounds of formula (I) and certain intermediates of the invention may contain asymmetric carbon atoms. Pure stereochemically isomeric forms of said compounds and of said intermediates may be obtained by employing procedures known in the art. For example, diastereomers may be separated by physical methods such as selective crystallization or chromatographic techniques, e.g., countercurrent distribution, liquid chromatography, and the like. Enantiomers can be obtained from racemic mixtures by the following process: the racemic mixture is first converted to a mixture of diastereomeric salts or compounds with a suitable resolving agent, e.g., a chiral acid; the mixture of diastereomeric salts or compounds is then physically separated by methods such as selective crystallization or chromatographic techniques, e.g., liquid chromatography; finally, the separated diastereomeric salt or compound is converted into the corresponding enantiomer. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that such an intervening (interfering) reaction occurs stereospecifically.

An alternative method of separating the enantiomers of the compounds of formula (I) and intermediates involves liquid chromatography, particularly using a chiral stationary phase.

Certain intermediates and starting materials for use in the above-mentioned reaction processes are known compounds, are commercially available or can be prepared according to methods known in the art.

The compounds of the present invention are useful because of their pharmacological properties. They are therefore useful as medicaments, in particular for the treatment of pathologies associated with excessive cortisol formation, such as obesity, diabetes, obesity-related cardiovascular diseases and glaucoma.

As described in the experimental section below, the inhibitory effect of the compounds of the invention on 11 β -HSD 1-reductase activity (conversion of cortisone (cortison) to cortisol) has been demonstrated in vitro, using recombinant 11 β -HSD1 enzyme in an enzymatic assay, the conversion of cortisone to cortisol was determined by HPLC purification and quantification methods. Inhibition of 11 β -HSD 1-reductase has also been demonstrated in vitro in a cell-based assay involving contacting cells, expressing 11 β -HSD1 with a test compound, and assessing the effect of the compound on cortisol formation in the cell culture medium of these cells. Preferred cells for use in the assay of the invention are selected from the group consisting of mouse fibroblast 3T3-L1 cells, HepG2 cells, porcine kidney cells, particularly LCC-PK1 cells and rat liver cells.

Accordingly, the present invention provides compounds of formula (I) and pharmaceutically acceptable N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof, for use in therapy. More particularly for the treatment or prevention of pathologies associated with excessive cortisol formation, such as obesity, diabetes, obesity-related cardiovascular diseases and glaucoma. The compounds of formula (I) and the pharmaceutically acceptable N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof, may hereinafter be referred to as compounds according to the present invention.

In view of the use of the compounds according to the invention, the present invention provides a method of treating animals, e.g. mammals including humans, suffering from pathologies associated with excessive cortisol formation, which method comprises administering an effective amount of a compound according to the invention. Said method comprising the systemic or topical administration to warm-blooded animals, including humans, of an effective amount of a compound according to the invention.

It is therefore an object of the present invention to provide compounds according to the invention for use as medicaments. In particular the use of a compound according to the invention in the manufacture of a medicament for the treatment of pathologies associated with excessive cortisol formation, such as obesity, diabetes, obesity-related cardiovascular diseases and glaucoma.

The amount of a compound according to the invention (also referred to herein as the active ingredient) required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular condition or disease being treated. Suitable daily dosages will be in the range of from 0.001mg/kg to 500mg/kg body weight, especially from 0.005mg/kg to 100mg/kg body weight. The method of treatment may also comprise administering the active ingredient on a regimen of one to four intakes per day.

While the active ingredients may be administered alone, they are preferably provided in a pharmaceutical composition. Accordingly, the present invention also provides a pharmaceutical composition comprising a compound according to the 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 recipient thereof.

The Pharmaceutical compositions of the present invention may be prepared by any method well known in the art of pharmacy, for example, using those methods described in Remington's Pharmaceutical Sciences, Gennaro et al (18 th edition, Mack Publishing Company, 1990), see especially section 8: Pharmaceutical preparations and the human Manufacture (Pharmaceutical preparations and preparations thereof)). A therapeutically effective amount of a particular compound, in base form or addition salt form, as the active ingredient is intimately admixed 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 preferably in unit dosage form, preferably suitable for systemic administration, e.g., oral, transdermal or parenteral administration; or topically, e.g., by inhalation, nasal spray, eye drops, or by ointment, gel, shampoo, and the like. For example, in preparing the compositions in oral dosage form, any of the conventional pharmaceutical media may be employed, e.g., water, glycols, oils, alcohols, and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, and solutions; or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like may be employed. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will typically comprise sterile water, at least in large part, although other ingredients, such as solubilizing ingredients, may be included. For example, injectable solutions 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 compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and/or a suitable wetting agent, optionally in combination with small amounts of suitable additives of any nature which do not produce any significant deleterious effect on the skin. The additives may facilitate dermal administration and/or may aid in the preparation of the desired composition. These compositions may be administered in various ways, for example as a transdermal patch, a spot-on or a cream. As suitable compositions for topical application, mention may be made of all compositions usually used for topical administration, such as ointments, gels (gellies), dressings, shampoos, tinctures, pastes, creams, salves, powders and the like. By means of, for example, aerosols with propellants such as nitrogen, carbon dioxide, freon; or propellant-free aerosols such as pump sprays; drops, lotions; or a semi-solid of a thick composition, such as may be applied with a swab. In particular, semisolid compositions such as salves, ointments, gels, creams, and the like are more convenient to use.

It is particularly advantageous to formulate the above pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein the specification and claims refer 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 sachets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls, and the like, and segregated multiples thereof.

In order to improve the solubility and/or stability of the compounds of formula (I) in the pharmaceutical composition, it may be advantageous to use α -, β -or γ -cyclodextrins or derivatives thereof. Co-solvents such as alcohols may also improve the solubility and/or stability of the compounds of formula (I) in the pharmaceutical composition. In the preparation of aqueous compositions, addition salts of the subject compounds are obviously more suitable due to their increased solubility in water.

Test section

Hereinafter, the term ' DCM ' refers to dichloromethane, "DIP E" refers to diisopropyl ether, "DMF" refers to N, N-dimethylformamide, ' Et₂O ' means diethyl ether, "EtOAc" means ethyl acetate, ' LDA ' means lithium (diisopropylamino), ' THF ' means tetrahydrofuran.

A. Preparation of intermediates

Example A1

Preparation of intermediate 1

Adamantan-2-one (5.00g, 33.28mmol), gamma-aminobutyric acid (6.86g, 66.56mmol), and 8.3ml formic acid were placed in a round bottom flask. The mixture was heated at 140 ℃ and 160 ℃ for 17 hours until adamantanone could not be monitored. TLC of intermediate 1: in Et₂O +1 drop CH₃R in COOH_fUnrolling 2 times at 0.24. The mixture was poured into crushed ice and then basified (NaHCO₃) Using Et₂O (3X 70ml) extraction and drying (MgSO₄). The solvent was distilled off to yield 4.95g of crude intermediate 1. Chromatographic purification (column h 279mm, phi 46mm, 230-400 mesh silica gel 170g, eluent Et₂O) gave 4.36g (59%) of pure intermediate 1 (colorless crystals).

Example A2

a) Preparation of intermediate 2

A mixture of 4-oxo-1-phenyl-cyclohexanecarbonitrile (0.025mol), tricyclo [3.3.1.13, 7] decan-2-amine hydrochloride (0.025mol) and potassium acetate (5g) in methanol (150ml) was hydrogenated overnight at 50 ℃ in the presence of a thiophene solution (1ml) using palladium on activated carbon (10%) (2g) as the catalyst. After absorption of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in DCM and washed with water. The organic layer was separated, dried, filtered and the solvent was evaporated to give 8g of intermediate 2.

b) Preparation of intermediate 3

A mixture of intermediate 2(0.0029mol) and potassium hydroxide (0.0145mol) in 1, 2-ethanediol (15ml) was stirred and refluxed over the weekend. The reaction mixture was cooled, poured into water and extracted with DCM. The aqueous layer was acidified with citric acid (pH: 5) and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated to give 1.8g of intermediate 3.

Example A3

a) Preparation of intermediate 4

In N₂To a mixture of α -methyl-phenylacetonitrile (0.076mol) in DMF (100ml) in a gaseous stream was added sodium hydride (0.08 mol). The mixture was stirred for 2.5 hours, then 2-bromo-1, 1-dimethoxy-ethane (0.1mol) was added dropwise and the reaction mixture was stirred for 3 hours. The mixture was poured into ice and extracted with DCM. The organic layer was separated, washed, dried, filtered and the solvent was evaporated, yielding 15g (90%) of intermediate 4.

b) Preparation of intermediate 5

A mixture of intermediate 4(0.022mol) in formic acid (25ml) was stirred at 50 ℃ for 10 minutes and then cooled. The reaction mixture was poured into ice and extracted with DIPE. Separating the organic layer with Na₂CO₃The solution was washed with water and then dried (MgSO)₄) Filtration and evaporation of the solvent gave 3g (79%) of intermediate 5.

c) Preparation of intermediate 6

A mixture of intermediate 5(0.017mol), tricyclo [3.3.1.13, 7] decan-2-amine hydrochloride (0.017mol) and potassium acetate (3g) in methanol (50ml) was hydrogenated overnight in the presence of a thiophene solution (0.5ml) using palladium on activated carbon (0.5g) as a catalyst. After absorption of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The resulting residue was stirred in DIPE, filtered and the filtrate was evaporated, yielding 3.7g (71%) of intermediate 6.

d) Preparation of intermediate 7

A mixture of intermediate 6(0.0094mol) in sulfuric acid (25ml) was stirred at room temperature overnight and the reaction mixture was poured into ice, then the mixture was neutralized with NaOH solution and extracted with EtOAc. The organic layer was separated, washed, dried, filtered and the solvent was evaporated to yield 3.7g of intermediate 7.

e) Preparation of intermediate 8

A mixture of intermediate 7(0.01mol) in hydrobromic acid (48%) (50ml) was stirred and refluxed for 2 hours, then the reaction mixture was cooled and filtered. The filter residue was washed with water and dried to yield 2.3g (57%) of intermediate 8.

Example A4

a) Preparation of intermediate 9

In N₂N- (1-methyl) was stirred under a stream of air in an ice/methanol bath (-15 ℃ C.)A mixture of ethyl) -2-propylamine (0.016mol) in THF (15ml) was added dropwise thereto a 2.5M solution of n-butyllithium in hexane (0.016mol) at (-10 ℃ C.) and the resulting mixture was stirred for 10 minutes. Dropping 1, 4-dioxaspiro [4.5 ] at-10 deg.C]A mixture of ethyl decane-8-carboxylate (0.016mol) in THF (15ml) was stirred for 30 minutes, and then a mixture of (bromomethyl) benzene (0.016mol) in THF (15ml) was added dropwise at-10 ℃. The reaction mixture was stirred for 1 hour and then at room temperature overnight. The mixture was poured into saturated NH₄Cl solution and extracted with DIPE. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was purified by flash column chromatography. The product fractions were collected and the solvent was evaporated, yielding 2.2g (46%) of intermediate 9.

b) Preparation of intermediate 10

A mixture of intermediate 9(0.0072mol) in 2-propanone (50ml) and hydrochloric acid (2.5N) (50ml) was stirred overnight and the reaction mixture was poured into DCM. The organic layer was separated, washed, dried, filtered and the solvent was evaporated to yield 1.9g of intermediate 10.

c) Preparation of intermediate 11

A mixture of intermediate 10(0.0073mol), tricyclo [3.3.1.13, 7] decan-2-amine hydrochloride (0.009mol) and potassium acetate (1g) in ethanol (50ml) was hydrogenated overnight at 50 ℃ in the presence of a thiophene solution (0.5ml) using palladium on activated carbon (0.5g) as the catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated to yield 2.9g of intermediate 11.

d) Preparation of intermediate 12

A mixture of intermediate 11(0.0043mol) and potassium hydroxide (5g) in ethanol (80ml) and water (20ml) was stirred and refluxed for 1 week, then the solvent was evaporated. The residue was dissolved in water and washed with DCM. The aqueous layer was acidified with HCl and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated to give 0.774g of intermediate 12.

Example A5

a) Preparation of intermediate 13

2, 5-dihydro-2, 5-dimethoxy-furan (0.01mol) and 4-amino- (1 α, 3 α,4 α, 5 β, 7 α) -tricyclo [3.3.1.13, 7] are stirred at room temperature]Decyl-1-ol (0.01mol) in water (50 ml). Concentrated hydrochloric acid (2ml) was added and the reaction mixture was stirred overnight. The acidic mixture is treated with NaHCO₃Neutralizing with water solution. The mixture was extracted with DCM (3 ×). The combined organic layers were dried, filtered and the solvent was evaporated to give 1.5g of intermediate 13.

b) Preparation of intermediate 14

A mixture of intermediate 13(0.0064mol) in methanol (150ml) was stirred and hydrogenated overnight using 10% palladium on activated carbon (0.5g) as catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated to yield 1.2g of intermediate 14.

B. Preparation of the Compounds

Example B1

Preparation of Compound 1

In a flame-dried Schlenk flask, a solution of 0.20g (0.92mmol) of intermediate 1 in 10ml of THF is cooled to-80 ℃. LDA (1.3 equiv., 0.59ml, ca.2M commercial THF/heptane/ethylbenzene solution) was introduced by syringe and the mixture was stirred at-80 ℃ for 30 min. 2-fluoro-3-methylbenzyl bromide (0.19g, 0.96mmol) was introduced and the reaction mixture was stirred at-80 ℃ for 1 hour. The temperature was slowly raised to-50 ℃ and held for 4 hours. The mixture was quenched with 2N HCl and then Et₂O extraction, organic layer with NaHCO₃(5% aqueous solution), H₂Washed with O and Na₂SO₄And (5) drying. After evaporation of the solvent, the crude product is chromatographed (column h 380mm,. phi. 17mm, 30g silica gel 230-400 mesh, eluent petroleum ether/Et₂O1: 1) to yield 0.22g (71%) of compound 1 (colorless crystals).

Example B2

Preparation of Compound 2

In a flame-dried Schlenk flask, a solution of 0.16g (0.47mmol) of Compound 1 in 10ml of THF is cooled to-80 ℃. LDA (1.3 equiv., 0.31ml, ca.2M commercial THF/heptane/ethylbenzene solution) was introduced by syringe and the mixture was stirred at-80 ℃ for 1 hour. Methyl iodide (0.09g, 0.66mmol) was introduced and the reaction mixture was stirred at-80 ℃ for 3 h. It was kept at-20 ℃ overnight. The mixture was quenched with 2N HCl and then Et₂O extraction, organic layer with NaHCO₃(5% Water soluble)Liquid), H₂Washed with O and Na₂SO₄And (5) drying. After evaporation of the solvent, the crude product is chromatographed (column h 460mm,. phi. 13mm, 10g silica gel 230-400 mesh, eluent petroleum ether/Et₂O1: 1) to yield 0.90g (53%) of compound 2, 0.012g of the combined components and 0.016g of by-products. (Note: it is better not to keep the reaction mixture overnight at-20 ℃).

The compounds prepared according to the above examples are listed in table 1. (in the following tables, NMR data represents NMR data; adamantane represents adamantane; and aromatic represents aromatic).

TABLE 1

Co.No.	NMR data	Melting Point (. degree.C.)
			3	CDCl(ii) a 1.55-2.23(m, 14H-adamantane, H)-CH，H-CH)；2.57-2.77(m，CH，H-CH)；2.99-3.21(m，H-CH)；3.39-3.48(m，CH)；3.77(s，CH) (ii) a 3.98(t, CH); 6.68-6.81(m, 3H-aromatic); 7.12-7.22(m, 1H-aromatic)
4	CDCl(ii) a 1.58-2.22(m, 14H-adamantane, H)-CH，H-CH)；2.62-2.78(m，CH，H-CH)；3.13-3.27(m，H-CH)；3.41-3.52(m，CH) (ii) a 3.99(t, CH); 7.02-7.10(m, 2H-aromatic); 7.12-7.19(m, 1H-aromatic); 7.25-7.36(m, 1H-aromatic)	58-59.5
			5	CDCl(ii) a 1.56-2.22(m, 14H-adamantane, H)-CH，H-CH)；2.59-2.74(m，CH，H-CH)；3.05-3.20(m，H-CH)；3.38-3.50(m，CH) (ii) a 3.97(t, CH); 7.11(m, 2H-aromatic); 7.27-7.37(m, 2H-aromatic)	83.5-85.0
6	CDCl(ii) a 1.53-2.22(m, 14H-adamantane, H)-CH，H-CH)；2.59-2.81(m，CH，H-CH)；3.04-3.21(m，H-CH)；3.38-3.48(m，CH) (ii) a 3.95(t, CH); 7.30-7.51(m, 4H-aromatic)	110.5-111.5

Co.No.	NMR data	Melting Point (. degree.C.)
			7	CDCl(ii) a 1.55-2.22(m, 14H-adamantane, H)-CH，H-CH)；2.68-2.87(m，CH，H-CH)；3.16-3.31(m，H-CH)；3.40-3.59(m，CH) (ii) a 3.98(t, CH); 7.08-7.18(t, 1H-aromatic), 7.39-7.55(m, 2H-aromatic)	103.5-105
1	CDCl(ii) a 1.57-2.22(m, 14H-adamantane, H)-CH，H-CH)；2.25(d，CH)；2.58-2.68(m，CH，H-CH)；3.13-3.29(m，H-CH)；3.48-3.57(m，CH) (ii) a 3.99(t, CH); 6.68-7.09(m, 3H-aromatic)	101-102
			8	CDCl(ii) a 1.49-2.16(m, 14H-adamantane, H)-CH，H-CH)；2.42-2.67(m，CH，H-CH)；3.00-3.09(dd，H-CH)；3.32-3.42(m，CH)；3.68(s，2xCH) (ii) a 3.91(t, CH); 6.21-6.32(m, 3H-aromatic)

9	CDCl(ii) a 1.53-2.23(m, 14H-adamantane, H)-CH，H-CH)；2.67-2.80(m，CH)；2.80-2.92(m，H-CH)；3.20-3.32(dd，H-CH)；3.42-3.57(m，CH) (ii) a 3.97(t, CH); 7.61-7.73(m, 3H-aromatic)
			10	CDCl(ii) a 1.57-2.23(m, 14H-adamantane, H)-CH，H-CH)；2.69-2.86(m，CH，H-CH)；3.13-3.29(m，H-CH)；3.42-3.54(m，CH) (ii) a 3.98(t, CH); 7.09-7.20(m, 2H-aromatic); 7.26(s, 1H-aromatic)	84-85
11	CDCl(ii) a 1.57-2.23(m, 14H-adamantane, H)-CH，H-CH)；2.27(s，2xCH)；2.51-2.73(m，CH，H-CH)；310(dd，H-CH)；3.37-3.48(m，CH)；3.99(t，CH)；6.83(m, 3H-aromatic)	85.5-87.0
			12	CDCl(ii) a 1.62-2.32(m, 14H-adamantane, H)-CH，H-CH)；2.37(s，2xCH)；2.50-2.75(m，CH，H-CH)；3.28-3.50(m，H-CH，H-CH)；3.59-3.71(m，H-CH) (ii) a 4.02(t, CH); 7.01(s, 3H-aromatic)	99-101
13	CDCl(ii) a 1.49-2.15(m, 14H-adamantane, H)-CH，H-CH)；2.54-2.69(m，CH，H-CH)；2.98-3.11(m，H-CH)；3.32-3.42(m，CH) (ii) a 3.91(t, CH); 7.02-7.21(m, 4H-aromatic)	135.5-136.5

9	CDCl(ii) a 1.53-2.23(m, 14H-adamantane, H)-CH，H-CH)；2.67-2.80(m，CH)；2.80-2.92(m，H-CH)；3.20-3.32(dd，H-CH)；3.42-3.57(m，CH) (ii) a 3.97(t, CH); 7.61-7.73(m, 3H-aromatic)
			14	CDCl(ii) a 1.55-2.20(m, 14H-adamantane, H)-CH，H-CH)；2.57-2.72(m，CH，H-CH)；3.01-3.17(m，H-CH)；3.35-3.50(m，CH) (ii) a 3.96(t, CH); 6.88-6.99(m, 2H-aromatic); 7.10-7.20(m, 2H-aromatic)	105-106
15	CDCl(ii) a 1.52-2.21(m, 14H-adamantane, H)-CH，H-CH)；2.49-2.26(m，CH，H-CH)；3.03-3.19(m，H-CH)；3.34-3.49(m，CH) (ii) a 3.96(t, CH); 7.03-7.13(m, 2H-aromatic); 7.16-7.25(m, 2H-aromatic))
			16	CDCl(ii) a 1.57-2.23(m, 14H-adamantane, H)-CH，H-CH)；2.31(s，CH)；2.55-2.72(m，CH，H-CH)；3.18-3.22(m，H-CH)；3.40-3.48(m，CH) (ii) a 3.99(t, CH); 7.08(m, 4H-aromatic)	109-110.5
17	CDCl；1.20(s，CH)1.50-2.16(m, 14H-adamantane, H)-CH，H-CH)；2.59(d，H-CH)；2.88-3.00(m，H-CH)；3.00(d，H-CH)；3.32-3.45(m，H-CH) (ii) a 3.92(t, CH); 7.08(d, 2H-aromatic); 7.22(d, 2H-aromatic)	100.5-101.5
			18	CDCl；1.20(s，CH) (ii) a 1.53-2.22(m, 14H-adamantane, H)-CH，H-CH)；2.29(s，2x CH)；2.85(d，H-CH)；3.12-3.23(m，H-CH)；3.26(d，H-CH)；3.33-3.50(m，H-CH) (ii) a 3.95(t, CH); 6.99(s, 3H-aromatic)
19	CDCl；1.18(s，CH) (ii) a 1.46-2.17(m, 14H-adamantane, H)-CH，H-CH)；2.24(s，2xCH)；2.47(d，H-CH)；2.78-2.88(m，H-CH)；2.90(d，H-CH)；3.27-3.38(m，H-CH) (ii) a 3.92(t, CH); 6.73-6.83(m, 3H-aromatic)	85-87
			20	CDCl；1.15(s，CH) (ii) a 1.42-2.23(m, 14H-adamantane, H)-CH，H-CH)；2.46(d，H-CH)；2.88(d，H-CH)；2.86-2.97(m，H-CH)；3.27-3.39(m，H-CH)；3.70(s，2xCH) (ii) a 3.88(t, CH); 6.24-6.31(m, 3H-aromatic)

9	CDCl(ii) a 1.53-2.23(m, 14H-adamantane, H)-CH，H-CH)；2.67-2.80(m，CH)；2.80-2.92(m，H-CH)；3.20-3.32(dd，H-CH)；3.42-3.57(m，CH) (ii) a 3.97(t, CH); 7.61-7.73(m, 3H-aromatic)
			2	CDCl；1.16(s，CH) (ii) a 1.47-2.18(m, 14H-adamantane, H)-CH，H-CH)；2.23(s，CH)；2.81(d，CH)；3.05-3.18(m，H-CH)；3.34-3.47(m，H-CH) (ii) a 3.93(t, CH); 6.83-7.06(m, 3H-aromatic)	120.5-122.0
21	CDCl(ii) a 1.31-2.23(m, 14H-adamantane, 2 xCH))；2.51-2.73(m，CH，H-CH)；3.28-3.40(m，H-CH)；3.40-3.59(m，CH)；3.77(s，CH) (ii) a 4.37(t, CH); 6.19-6.81(m, 3H-aromatic); 7.12-7.21(t, 1H-aromatic)

22	CDCl(ii) a 1.42-2.27(m, 14H-adamantane, 2 xCH))；2.38(s，2xCH)；2.43-2.59(m，CH)；2.64-2.78(m，H-CH)；3.47-3.60(m，CH，H-CH) (ii) a 4.42(t, CH); 7.01(s, 3H-aromatic)	145-149
			23	CDCl(ii) a 1.28-2.24(m, 14H-adamantane, 2 xCH))；2.46-2.62(m，CH)；2.68-2.82(m，H-CH)；3.21-3.36(dd，H-CH)；3.36-3.61(m，CH) (ii) a 4.35(t, CH); 7.03-7.27(m, 4H-aromatic)
24	CDCl(ii) a 1.30-2.26(m, 14H-adamantane, 2 xCH))；2.27(s，2xCH)；2.47-2.62(m，CH)；2.60-2.72(m，H-CH)；3.29-3.31(dd，H-CH)；3.37-3.59(m，CH) (ii) a 4.39(t, CH); 6.81(m, 3H-aromatic)	116-118.5
			25	CDCl(ii) a 1.31-2.21(m, 14H-adamantane, 2 xCH))；2.52-2.67(m，CH，H-CH)；3.23-3.38(m，H-CH)；3.38-3.58(m，CH)；3.74(s，2xCH) (ii) a 4.36(t, CH); 6.23-6.31(m, 1H-aromatic); 6.31-6.39(m, 2H-aromatic)	166.5-168
26	CDCl(ii) a 1.30-2.22(m, 14H-adamantane, 2 XCH))；2.23(d，CH)；2.48-2.63(m，CH)；2.64-2.79(m，H-CH)；3.29-3.41(dd，H-CH)；3.41-3.58(m，CH) (ii) a 4.34(t, CH); 6.82-7.04(m, 3H-aromatic)	99-100
			27	CDCl；1.24(s，CH) (ii) a 1.35-2.22(m, 14H-adamantane, 2 xCH))；2.51(d，H-CH)；3.19-3.30(m，H-CH，H-CH)；3.39-3.49(m，H-CH)；3.74(s，CH) (ii) a 4.31(t, CH); 6.70(m, 3H-aromatic); 7.11 (1H-aromatic)	79-81.5

22	CDCl(ii) a 1.42-2.27(m, 14H-adamantane, 2 xCH))；2.38(s，2xCH)；2.43-2.59(m，CH)；2.64-2.78(m，H-CH)；3.47-3.60(m，CH，H-CH) (ii) a 4.42(t, CH); 7.01(s, 3H-aromatic)	145-149
			28	CDCl；1.26(s，CH) (ii) a 1.48-2.22(m, 14H-adamantane, 2 xCH))；2.47(d，H-CH)；3.18-3.32(m，H-CH，H-CH)；3.40-3.52(m，H-CH)；3.74(s，2xCH) (ii) a 4.33(t, CH); 6.33(m, 3H-aromatic)
29	CDCl(ii) a 1.17(s, CH 3); 1.42-2.28(m, 14H-adamantane, 2 xCH))；2.54(d，H-CH)；2.84-2.95(m，H-CH)；2.93(d，H-CH)；3.28-3.40(m，H-CH) (ii) a 3.75(s, CH 3); 3.91(t, CH); 6.19-6.30(m, 3H-aromatic); 7.09-7.18(t, 1H-aromatic)	89.5-92.0
			30	CDCl(ii) a 1.16(s, CH 3); 1.44-2.17(m, 14H-adamantane, CH))；2.53(d，H-CH)；2.88-3.00(m，H-CH，H-CH)；3.31-3.42(m，H-CH)；3.90(t, CH); 6.85-6.97(m, 2H-aromatic); 7.08-7.18(m, 2H-aromatic); 7.08-7.18(m, 2H-aromatic)	162-163
31	CDCl(ii) a 1.68-2.15(m, 14-adamantane, 2 xCH))；2.54(d，2xH-CH)；3.08(m，CH)；3.40(d，2xH-CH)；3.75(s，2xCH) (ii) a 4.35(t, CH); 6.68-6.79(m, 6H-aromatic); 7.08-7.18(m, 2H-aromatic)
			32	CDCl(ii) a 1.19(s, CH 3); 1.49-2.14(m, 14H-adamantane, CH))；2.60(d，1H，H-CH)；2.91(m，H-NCH)；2.98(d，1H，H-CH)；3.37(m，H-NCH) (ii) a 3.93(s, CH); 7.18-7.26(m, 5H-aromatic)
33	CDCl(ii) a 1.57-1.94(m, 12H-adamantane, H)-CH)；1.99-2.09(m，1H，H-CH) (ii) a 2.19(brs, 2H-adamantane); 2.63-2.75(m, CH, H)-CH)；3.15-3.24(m，H-CH)；3.42-3.48(m，CH) (ii) a 3.99(s, CH); 7.18-7.32(m, 5H-aromatic)
			34	1.56-2.26(m, 20H, 12H-adamantane, 4 xCH)) (ii) a 2.30(brs, 2H-adamantane); 4.12(s, CH); 4.16(brs, CH); 7.20-7.40(m, 5H-aromatic)
35	1.52(s, 3H, CH 3); 1.61-2.05(m, 12H-adamantane); 2.08-2.18(m, 1H, H)-CH) (ii) a 2.21 and 2.35 (2xbrs, 2H-adamantane); 2.38-2.46(m, 1H, H)-CH)；3.48-3.64(m，2H，H and H-CH) (ii) a 4.08(s, CH); 7.19-7.41(m, 5H-aromatic)

36	1.50-1.96(m, 20H, 12H-adamantane, 4 xCH)) (ii) a 2.27(brs, 2H-adamantane); 2.98(s, 2H, CH)) (ii) a 4.04 and 4.14(2x s, 2 xch); 7.17-7.30(m, 5H-aryl)Group)
			37	CDCl(ii) a 1.34-1.93(m, 11H-adamantane, H)-CH)；1.99-2.09(m，1H，H-CH) (ii) a 2.15(brs, 2H-adamantane); 2.42(d, 2H-adamantane); 2.63-2.75(m, CH, H)-CH)；3.15-3.24(m，H-CH)；3.42-3.48(m，CH) (ii) a 3.90(s, 1H-adamantane); 7.18-7.32(m, 5H-aromatic)
38	CDCl；1.20(s，CH) (ii) a 1.34-1.93(m, 11H-adamantane, H)-CH)；2.05-2.14(1H，CH) (ii) a 2.27(s, 1H-adamantane); 2.37(s, 1H-adamantane); 2.60(d, 1H, CH)-Ph)；2.85(m，H-NCH)；2.98(d，1H，CH-Ph)；3.32(m，H-NCH) (ii) a 3.83(s, 1H-adamantane); 7.18-7.26(m, 5H-aromatic)
			39	CDCl(ii) a 1.57-1.95(m, 11H-adamantane, H)-CH)；2.05(m，H-CH) (ii) a 2.17(s, 1H-Diamond)An alkane); 2.25(d, CH)) (ii) a 2.45(d, 2H-adamantane); 2.58-2.68(m, CH, H)-CH)；3.13-3.29(m，H-CH)；3.48-3.57(m，CH) (ii) a 3.90(s, 1H-adamantane); 6.90-7.09(m, 3H-aromatic)
40	CDCl；1.20(s，CH) (ii) a 1.37-2.18(m, 12H-adamantane, H)-CH，H-CH)；2.25(s，CH) (ii) a 2.35(d, 2H-adamantane); 2.81(d, CH))；3.05-3.18(m，H-CH)；3.34-3.47(m，H-CH) (ii) a 3.87(s, 1H-adamantane); 6.85-7.06(m, 3H-aromatic)

Example B3

Preparation of Compound 34

A mixture of intermediate (3) (0.00028mol) and phosphorus pentachloride (0.1g) in phosphorus oxychloride (1ml) was stirred at 100 ℃ for 45 minutes, then the reaction mixture was cooled, poured into ice and washed with Na₂CO₃The solution was neutralized and extracted with DCM. The organic layer was filtered with Extrelut and the solvent was evaporated. Flash column chromatography of the residue using a Triconex flash tubePurification (eluent: DCM). The product fractions were collected and the solvent was evaporated, yielding 0.051g (54%) of compound 34.

Example B4

Preparation of Compound 35

A mixture of intermediate 8(0.00024mol) in thionyl chloride (2ml) was stirred and refluxed for 2 hours, then stirred at room temperature overnight. The solvent was evaporated and the residue was purified by flash column chromatography using a Triconex flash tube (eluent: CH)₂Cl₂EtOAc 95/5). The product fractions were collected and the solvent was evaporated, yielding 0.0183g (7.5%) of compound 35.

Example B5

Preparation of Compound 36

A mixture of intermediate 12(0.00027mol) and phosphorus pentachloride (0.1g) in phosphorus oxychloride (1ml) was stirred at 100 ℃ for 1 hour, after cooling, the reaction mixture was poured into ice and extracted with dichloromethane. Na for organic layer₂CO₃The solution was washed, dried, filtered and the solvent was evaporated. The residue was purified by flash column chromatography using a Triconex flash tube (eluent: CH)₂Cl₂EtOAc 90/10). The product fractions were collected and the solvent was evaporated to give 0.027g of Compound 36.

Example B6

Preparation of Compound 37

Reaction in N₂Is carried out in an atmosphere. A mixture of intermediate 14(0.005mol) in dry THF (25ml) and 1, 4-dioxane (10ml) was stirred under sonication until complete dissolution. The mixture was cooled to-78 ℃. 1.3M sec-butyllithium in hexane (0.013mol) was added, and the mixture was stirred at-30 ℃ for 12 hours and then cooled to-78 ℃. (bromomethyl) -benzene (0.01mol) was added dropwise and the reaction mixture was stirred at-78 ℃ for 1 hour and then at room temperature overnight. The mixture was poured into saturated NH₄Aqueous Cl, then DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (Biotage; eluent: DCM/CH)₃OH 99/1). The product fractions were collected and the solvent was evaporated, yielding 0.8g (50%) of compound 37.

Example B7

Preparation of Compound 38

Reaction in N₂Is carried out in an atmosphere. A mixture of compound 37(0.0006mol) in THF (10ml) was stirred at-78 ℃. 1.3M sec-butyllithium in hexane (0.0026mol) was added and the mixture was stirred at-78 ℃ for 2 hours. Methyl iodide (0.0012mol) was added dropwise at-78 ℃ and the resulting reaction mixture was stirred over the weekend and the temperature was slowly raised from-78 ℃ to room temperature. The mixture is poured into NH₄Cl solution (4 ml). The mixture was extracted with DCM. The separated organic layer was dried with Extrelut. The filtrate was evaporated. The residue was purified by column chromatography over silica gel (Supelco; eluent: DCM/CH)₃OH 99/2). The product fractions were collected and the solvent was evaporated to give 0.153g of compound 38.

Example B8

Preparation of Compound 39

Reaction in N₂Is carried out in an atmosphere. A mixture of intermediate 14(0.005mol) in THF (50ml) was stirred at-78 deg.C. A1.3M solution of sec-butyllithium in hexane (0.013mol) was added dropwise thereto, and the mixture was stirred at-78 ℃ for 3 hours. 1- (bromomethyl) -2-fluoro-3-methyl-benzene (0.01mol) was added dropwise at-78 ℃ and the resulting reaction mixture was stirred at-78 ℃ for 1 hour and then at room temperature overnight. The mixture was poured into saturated NH₄In an aqueous Cl solution. The mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (Biotage; eluent; DCM/CH)₃OH 99/1). The product fractions were collected and the solvent was evaporated. The residue (0.4g) was dissolved in THF. Evaporation of the solvent gave 0.4g of Compound 39.

Example B9

Preparation of Compound 40

In N₂A mixture of Compound 39(0.0011mol) in THF (25ml) was stirred at-78 deg.C under an atmosphere, a 1.3M hexane solution of sec-butyllithium (0.0022mol) was added dropwise, the mixture was then stirred at-78 deg.C for 2 hours, and methyl iodide (0.005mol) was added dropwise. The reaction mixture was stirred at-78 ℃ for 1 hour and then at room temperature overnight. Saturated NH is added dropwise₄Cl solution (5ml), then the resulting mixture was stirred for 10 min and extracted with DCM. The organic layer was washed, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM/CH)₃OH 98/2). The product fractions were collected and the solvent was evaporated. The residue (0.242g) was dissolved in diethyl ether and the solvent was evaporated (in vacuo) at 80 ℃ to give 0.221g of Compound 40.

C. Pharmacological examples

Example c.1: test Compounds on 11 beta-hydroxysteroid dehydrogenases type 1 and type 2 Enzymatic assay of the action of

The effect of compounds on 11 β -HSD 1-dependent conversion of cortisone to cortisol (reductase activity) was studied in a reaction mixture containing 30mM Tris-HCl buffer pH7.2, 180 μ M ADPH, 1mM EDTA, 2 μ M cortisone, 1 μ l drug and/or solvent and 11 μ g recombinant protein in a final volume of 100 μ l.

The effect on 11 β -HSD 1-dehydrogenase activity (conversion of cortisol to cortisone) was determined in a reaction mixture containing 0.1M sodium phosphate buffer pH9.0, 300 μ M NADP, 25 μ M cortisol, 1 μ l drug and/or solvent and 3.5 μ g recombinant protein in a final volume of 100 μ l.

The effect on 11 β -HSD 2-dependent dehydrogenase activity was determined in a reaction mixture containing 0.1M sodium phosphate buffer pH7.5, 300 μ M NAD, 100nM cortisol (of which 2nM is 3H-radiolabel), 1 μ l drug and/or solvent and 2.5 μ g recombinant protein in a final volume of 100 μ l.

All incubations were carried out at 37 ℃ for 45 minutes in a water bath. The reaction was stopped by adding 100. mu.l acetonitrile containing 20. mu.g of corticosterone internal standard. After centrifugation, the supernatant was analyzed by HPLC for product formation, Hypersyl BDS-C18 column, 0.05mM ammonium acetate/methanol (50/50) solvent. In all of the above tests, the drug to be tested was removed from the stock solution and tested at-10^-5Final concentration test in the range of M-3.10-9M. From the dose response curve thus obtained, pIC50 values were calculated and scored as follows: a score of 1 ═ pIC50 value < 5, a score of 2 ═ pIC50 value in the range 5 to 6, and a score of 3 ═ pIC50 value > 6. Some of the results obtained are summarized in the following table (NT means not tested in this table).

Example C2: test Compounds on 11 beta-hydroxysteroid dehydrogenases type 1 and type 2 Cells of (4)Test of

The effect on 11 β -HSD1 activity was determined 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 in DMEM medium (supplemented with 10% heat-inactivated fetal bovine serum, 2mM glutamine and 25mg gentamicin) at 37 ℃ in 5% CO₂The growth was carried out in a humid atmosphere for 7 days. The medium was refreshed twice weekly. At 37 ℃ in 5% CO₂Fibroblasts differentiated into adipocytes in a humidified atmosphere in growth medium containing 2. mu.g/ml insulin, 55. mu.g/ml IBMX and 39.2. mu.g/ml dexamethasone.

Primary male rat hepatocytes were seeded at 250000 cells/well in BD-Biocoat Matrigel matrix multi-well plates and incubated at 37 ℃ in 5% CO₂Incubate for 10 days in a humidified atmosphere in DMEM-HAM F12 medium containing 5% Nu-serum, 100U/ml penicillin, 100. mu.g/ml streptomycin, 0.25. mu.g/ml amphotericin B, 50. mu.g/ml gentamicin sulfate, 5. mu.g/ml insulin, and 392ng/ml dexamethasone. The medium was refreshed 3 times per week.

After 4 hours of preincubation of test compounds, 0.5. mu. Ci was added to the medium³H-cortisone or dehydrocorticosterone. After one hour, the medium was in Extrelt³The column was extracted with 15ml of diethyl ether and analyzed by HPLC as described above.

The effect on 11 β -HSD2 activity was studied in HepG2 and LCC-PK 1-cells, HepG 2-cells (ATCC HB-8065) were seeded in 12-well plates at a density of 100,000 cells/ml and at 37 ℃ in 5% CO₂Growth was performed in MEM-Rcga-3 medium (supplemented with 10% heat-inactivated fetal bovine serum, 2mM L-glutamine and sodium bicarbonate) in a humid atmosphere. The medium was refreshed twice weekly.

Porcine kidney cells (LCC-PK1, ATCC CRL-1392) were seeded at a density of 150,000 cells/ml in 12-well plates and at 37 ℃ in 5% CO₂In a humid atmosphere, supplemented with a modified Earls salt solution100U/ml penicillin, 100. mu.g/ml streptomycin and 10% fetal bovine serum 199. The medium was refreshed twice weekly. 24 hours before the start of the experiment, the medium was changed to fetal bovine serum medium containing 10% charcoal adsorption (stripeped). After 4 hours of preincubation of test compounds, 0.5. mu. Ci was added to the medium³H-cortisol or corticosterone. After one hour, the medium was in Extrelt³The column was extracted with 15ml of diethyl ether and analyzed by HPLC as described above.

For enzymatic assays, the test compound is removed from the stock solution and tested at-10^-5M-3.10^-9Final concentration test in the M range. From the dose response curve thus obtained, pIC50 values were calculated and scored as follows: a score of 1 ═ pIC50 value < 5, a score of 2 ═ pIC50 value in the range 5 to 6, and a score of 3 ═ pIC50 value > 6. Some of the results obtained are summarized in the following table (NT means not tested in this table).

D. Composition examples

The following formulations illustrate typical pharmaceutical compositions according to the invention suitable for systemic or topical administration to animal and human patients.

The "active ingredient" (a.i.) used in all these examples refers to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

Example d.1: film coated tablet

Preparation of the tablet core

A mixture of a.i. (100g), lactose (570g) and starch (200g) was mixed thoroughly and then moistened with an approximately 200ml aqueous solution of sodium dodecyl sulfate (5g) and polyvinylpyrrolidone (10 g). The wet powder mixture was sieved, dried and sieved again. Then microcrystalline cellulose (100g) and hydrogenated vegetable oil (15g) were added. Mixed well and compressed into tablets to give 10.000 tablets each containing 10mg of active ingredient.

Coating film

To a solution of methylcellulose (10g) in denatured ethanol (75ml) was added CH of ethylcellulose (5g)₂Cl₂(150ml) solution. Then adding CH₂Cl₂(75ml) and 1, 2, 3-propanetriol (2.5 ml). Polyethylene glycol (10g) was melted and dissolved in dichloromethane (75 ml). The latter solution was added to the former, followed by magnesium stearate (2.5g), polyvinylpyrrolidone (5g) and concentrated pigment suspension (30ml) and mixed well. The tablet cores are coated with the mixture thus obtained in a coating apparatus.

Claims (15)

1. A compound having the formula, pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof

Wherein

n is 1 or 2;

m represents a direct bond or C_1-3An alkyl linking group;

R¹and R²Each independently represents hydrogen, halogen, C optionally substituted by halogen_1-4Alkyl, C optionally substituted by one halogen or by two or three halogens_1-4Alkoxy-;

R³represents hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy;

R⁴represents hydrogen, halogen or C1-4 alkyl;

R⁵represents hydrogen, C1-4 alkyl or Ar2-C1-4 alkyl-;

R⁶represents hydrogen or hydroxy;

R⁷represents hydrogen, or R⁷And R⁵Together with the carbon atom to which they are attached form a-C2-alkyl-linking group;

ar2 independently represents phenyl or naphthyl, wherein the phenyl and naphthyl are optionally C1-4 alkyl-or C1-4 alkoxy-substituted.

2. A compound having the formula, pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof:

wherein

n is 1 or 2;

m represents a C1-3 alkyl linking group;

R¹and R²Each independently represents hydrogen, halogen, C1-4 alkyl optionally substituted by halogen, C1-4 alkoxy-optionally substituted by one halogen or by two or three halogens;

R³represents hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy-;

R⁴represents hydrogen, halogen or C1-4 alkyl;

R⁵represents hydrogen, C1-4 alkyl or Ar2-C1-4 alkyl-;

R⁶represents hydrogen or hydroxy;

ar2 independently represents phenyl or naphthyl, wherein the phenyl and naphthyl are optionally C1-4 alkyl-or C1-4 alkoxy-substituted.

3. A compound having the formula, pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof

Wherein

n is 1 or 2;

m represents a C1-alkyl linking group;

R¹represents hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy-, C1-4 alkyl substituted by one or two or three halogen substituents, or R¹Represents C1-4 alkoxy substituted by halogen;

R²represents hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy-optionally substituted by one or two or three halogen substituents;

R³represents hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy-or C1-4 alkyl substituted by one or two or three halogen substituents;

R⁴represents hydrogen, halogen or C1-4 alkyl;

R⁵represents hydrogen, C1-4 alkyl or Ar2-C1-4 alkyl;

R⁶represents hydrogen or hydroxy;

R⁷represents hydrogen, or R⁷And R⁵Together with the carbon atom to which they are attached form a-C2-alkyl-linking group;

ar2 represents phenyl optionally substituted by C1-4 alkoxy.

4. The compound of claim 1 or 2, wherein:

n is 1 or 2;

m represents a C1-alkyl linking group;

R¹represents hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy-, C1-4 alkyl substituted by one or two or three halogen substituents, or R¹Represents C1-4 alkoxy substituted by one or two or three halogen;

R²represents hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy-optionally substituted by one or two or three halogen substituents;

R³represents hydrogen, halogen, C1-4 alkyl or C1-4 alkoxy-;

R⁴represents hydrogen, halogen or C1-4 alkyl;

R⁵represents hydrogen, C1-4 alkyl or Ar2-C1-4 alkyl;

R⁶represents hydrogen or hydroxy;

ar2 represents phenyl optionally substituted by C1-4 alkoxy.

5. The compound of claim 3, wherein R⁵Represents hydrogen or methyl, R⁶Represents hydrogen.

6. The compound of claim 4, wherein R⁵Represents hydrogen or methyl, R⁶Represents hydrogen.

7. A compound of claim 1, 2 or 3, wherein;

n is 1 or 2;

m represents a C1-alkyl linking group;

R¹and R²Represents hydrogen, C1-4 alkyl or C1-4 alkoxy;

R³represents hydrogen or C1-4 alkoxy;

R⁴represents hydrogen or halogen;

R⁵represents hydrogen or C1-4 alkyl;

R⁶represents hydrogen or hydroxyl.

8. The compound of claim 7, wherein R¹And R²Represents methyl or methoxy.

9. The compound of claim 7, wherein R³Represents hydrogen or methoxy.

10. The compound of claim 7, wherein R⁵Represents hydrogen or methyl.

11. The compound of claim 1 selected from the group consisting of:

3- [ (3, 5-Dimethoxyphenyl) methyl]-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

3- [ (4-methylphenyl) methyl group]-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

3- [ (2-fluoro-3-methylphenyl) methyl group]-3-methyl-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

3- [ (3-methoxyphenyl) methyl group]-3-methyl-1-tricyclo [3.3.1.1^3，7]Decan-2-yl-2-pyrrolidone;

3-benzyl-1- (5-hydroxy-tricyclo [ 3.3.1.1)^3，7]Decan-2-yl) -pyrrolidin-2-one;

3-benzyl-1- (5-hydroxy-tricyclo [ 3.3.1.1)^3，7]Decan-2-yl) -3-methyl-pyrrolidin-2-one;

3- (2-fluoro-3-methyl-benzyl) -1- (5-hydroxy-tricyclo [3.3.1.1^3，7]Decan-2-yl) -pyrrolidin-2-one;

3- (2-fluoro-3-methyl-benzyl) -1- (5-hydroxy-tricyclo [3.3.1.1^3，7]Decan-2-yl) -3-methyl-pyrrolidin-2-one;

a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, an effective 11 β -HSD1 inhibiting amount of a compound as described in any one of claims 1-11.

13. A process for preparing a pharmaceutical composition as defined in claim 12, characterized in that a pharmaceutically acceptable carrier is intimately mixed with an effective 11 β -HSD1 inhibiting amount of a compound as described in any one of claims 1 to 11.

14. Use of a compound according to any one of claims 1 to 11 in the manufacture of a medicament for the treatment of a condition associated with excessive cortisol formation.

15. The use of claim 14, wherein the disorder associated with excessive cortisol formation is obesity, diabetes, obesity-related cardiovascular disease, dementia, cognitive disorders, osteoporosis or glaucoma.