HK1112618B - Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors - Google Patents

Description

Tricyclic lactam derivatives as 11-beta hydroxysteroid dehydrogenase inhibitors

Metabolic syndrome is a disease that is increasingly common not only in western countries but also in developing countries of asia. It is characterized by obesity, particularly central or visceral obesity, type II diabetes, hyperlipidemia, hypertension, arteriosclerosis, coronary heart disease and ultimately chronic renal failure (CT. Montague et al (2000), diabetes mellitus, 49, 883-. Glucocorticoid and 11 β -HSD1 are known to be important factors in the differentiation of adipose stromal cells into mature adipocytes. In visceral basal cells of obese patients, 11 β -HSD1 mRNA levels increased with subcutaneous tissue. Furthermore, overexpression of 11 β -HSD1 in adipose tissue in transgenic mice was associated with elevated corticosterone levels in adipose tissue, visceral obesity, insulin sensitivity, type II diabetes, hyperlipidemia and binge eating (H. Masuzaki et al (2001), Science, 294, 2166-2170). Therefore, 11 β -HSD1 is very likely to be involved in the development of visceral obesity and metabolic syndrome.

Inhibition of 11 β -HSD1 resulted in decreased adipocyte differentiation and increased proliferation. In addition, glucocorticoid deficiency (adrenalectomy) enhances the performance of insulin and leptin, favoring anorexia and weight loss, and this effect is reversed upon glucocorticoid administration (p.m. stewart et al (2002), Trends endocrin. metabpol, 13, 94-96). These data suggest that enhanced reactivation of corticosterone by 11 β -HSD1 may reduce obesity and may be beneficial in inhibiting this enzyme in the adipose tissue of obese patients.

Obesity is also associated with cardiovascular risk. There is an important correlation between cortisol secretion rates and HDL cholesterol in men and women, suggesting that glucocorticoids regulate key components of cardiovascular risk. Similarly, stiffness of the aorta in elderly is also associated with visceral obesity.

The effect of the reduced activity of 11 β -HSD1 was highlighted in β -HSD1 knockout mice with elevated plasma levels of endogenous active glucocorticoid, although this still protected against insulin resistance caused by stress and obesity. In addition, these knockout mice display the lipid profile of the anti-atherosclerotic plasmid and benefit from a reduction in cognitive impairment associated with aging.

Glucocorticoids and glaucoma

Glucocorticoids increase the risk of glaucoma by elevating intraocular pressure when administered exogenously or in certain diseases where production is increased, such as cushing's syndrome. Corticosteroid-induced elevation of intraocular pressure is due to increased resistance to aqueous efflux due to glucocorticoid-induced changes in the trabecular meshwork and its intracellular matrix. Zhou et al (IntJ Mol Med (1998)1, 339-346) also reported that corticosteroids increase the amount of fibronectin and type I and IV collagen in organ-cultured bovine anterior trabecular meshwork. 11 β -HSD1 was expressed in basal cells of corneal epithelium and non-stained epithelial cells. Glucocorticoid receptor mRNA was only detectable in trabecular meshwork, whereas mRNA for glucocorticoid, mineralocorticoid receptor, and 11 β -HSD1 were present in non-stained epithelial cells. Administration of carbenoxolone to patients significantly reduced intraocular pressure (s. rauz et al (2001), invest. ophtalmol. vis. science, 42, 2037-.

Therefore, the above-mentioned problem to be solved by the present invention is to identify potent 11 β -HSD inhibitors with high selectivity for 11 β -HSD1 and their use in the treatment of pathologies associated with excessive cortisol formation, i.e. diseases where a reduction of the active glucocorticoid levels is desired, such as metabolic syndrome, type II diabetes, Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), dyslipidemia, hypertension, obesity, diabetes, obesity-related cardiovascular diseases, arteriosclerosis, atherosclerosis, myopathy, osteoporosis, neurodegeneration and psychosis, stress-related diseases and glaucoma. As described below, it has been 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 3-substituted pyrrolidones via alpha alkylation of chiral non-racemic gamma-lactones and disclose, inter alia, 1- (2-hydroxy-1-phenylethyl) -3-benzylpyrrolidin-2-one.

US 2001/034343; US 6,211,199; US 6,194,406; WO 97/22604 and WO97/19074 are a number of patent applications filed by Aventis Pharmaceuticals Inc. 4- (1H-benzimidazol-2-yl) [1, 4] diazepanes are provided for the treatment of allergic diseases. In these applications, the 3-substituted pyrrolidones of the invention disclose intermediates for the synthesis of 4- (1H-benzimidazol-2-yl) [1, 4] -diazepanes. These applications disclose, inter alia: 2-pyrrolidone, 3- [ (4-fluoro-phenyl) methyl ] -1- [ (1S) -1-phenylethyl ] -and 2-pyrrolidone, 3- [ (4-fluorophenyl) -methyl ] -1- [ (1R) -1-phenylethyl ] -.

Diamondoids are also disclosed in PCT publications WO 03065983(Merck & Co., Inc.) and WO2004056744 (Janssen Pharmaceutica N.V.). With WO2004056744 as the closest prior art, the compounds of the present application differ in that the adamantine ring is attached to the cyclic amide nitrogen of the tricyclic system. Despite the fact that WO 03065983 discloses that diamond rings may be attached directly to tricyclic ring systems, it should be noted that the tricyclic ring systems are characterized by having 2-adamantyl-triazole as the core building element, and thus it was not expected that replacing triazole with imidazolinones or pyrrolidones would not lose the desired activity, i.e. be effective 11 β -HSD inhibitors, and would be selective for 11 β -HSD 1.

Therefore, none of the above documents discloses the therapeutic use of the tricyclic adamantyl amide derivatives of the present invention. Thus, in a first aspect, the present invention relates to compounds of formula (I)

N-oxide forms, pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein

X represents C or N;

y represents C or N;

l represents methyl or a direct bond;

Z¹represents a direct bond, C_1-2Alkyl-or of the formula-CH₂A divalent group of-CH ═ (a) or-CH ═ b);

Z²represents a direct bond, C_1-2Alkyl-or of the formula-CH₂A divalent group of-CH ═ (a) or-CH ═ b);

R¹represents hydrogen, halogen, cyano, amino, phenyl, hydroxy, C_1-4Alkoxycarbonyl, -O- (C ═ O) -C_1-4Alkyl, hydroxycarbonyl, NR³R⁴Or C_1-4Alkyl radical, wherein the C_1-4Alkyl or-O- (C ═ O) -C_1-4Alkyl is optionally substituted by one or more groups selected from halogen, hydroxycarbonyl, phenyl, C_1-4Alkoxy or NR⁵R⁶Is substituted by a substituent of

R¹Represents optionally substituted by one or more groups selected from halogen, hydroxycarbonyl, phenyl, C_1-4Alkoxy or NR⁷R⁸C substituted by a substituent of_1-4Alkoxy-;

R²represents hydrogen, halogen, C_1-4Alkyl or C_1-4Alkoxy-;

R³and R⁴Each independently represents hydrogen, C_1-4Alkyl or C_1-4Alkylcarbonyl-;

R²and R⁶Each independently represents hydrogen, C_1-4Alkyl or C_1-4Alkyl carbonyl-

R⁷And R⁸Each independently represents hydrogen, C_1-4Alkyl or C_1-4Alkyl carbonyl-

A represents phenyl or is selected from thienyl, furyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl

Monocyclic heterocycles of oxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl and piperazinyl.

Compounds of formula (I) as described herein refer to compounds of the invention, including compounds of formula (I)^bis)、(Iⁱ)、(Iⁱⁱ)、(Iⁱⁱⁱ)、(I^iv) And pharmaceutically acceptable N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof.

As used in the definitions herein, halogen generally refers to fluorine, chlorine, bromine, and iodine; c_1-2Alkyl defines a straight chain saturated hydrocarbon group having 1 to 2 carbon atoms, i.e., methyl or ethyl; c_1-4Alkyl defines straight and branched chain saturated hydrocarbon groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2-dimethylethyl, and the like; c_1-4Alkoxy defines 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 above definitions and the heterocycles mentioned immediately below may be suitably attached to the rest of the molecule of formula (I) via a ring carbon or a heteroatom. Thus, for example, when the heterocycle is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 3-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is thiazolyl, it may be 2-thiazolyl, 4-thiazolyl and 5-thiazolyl.

The pharmaceutically acceptable addition salts mentioned above are meant to include the therapeutically active non-toxic acid addition salts which the compounds of formula (I) are able to form. The latter can be conveniently obtained by treating the base 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, cyclohexylsulfamic, salicylic, p-aminosalicylic, pamoic and the like acids.

The pharmaceutically acceptable addition salts mentioned above are meant to comprise the therapeutically active non-toxic base addition salts which the compounds of formula (I) are able to form. Examples of base addition salt forms are, for example, sodium, potassium, calcium salts and salts with pharmaceutically acceptable amines, such as ammonia, alkylamines, benzathine, N-methyl-D-glucamine, hydrabamine, amino acids, such as arginine, lysine.

Conversely, the salts may be formed by treatment with a suitable base or acid to give the free acid or base form.

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

The term stereochemically isomeric forms as used herein defines the possible different isomers as well as conformational forms which the compounds of formula (I) may possess. Unless otherwise stated or indicated, the chemical designation of mixtures represents a mixture of all possible stereochemical and conformational isomers, said mixture comprising all diastereomers, enantiomers and/or conformational isomers of the basic molecular structure. (I) All stereochemically isomeric forms of the compounds of (a), both in pure form and in the form of mixtures, are intended to be embraced within the scope of the present invention. N-oxides of compounds of formula (I) are meant to include those compounds of formula (I) wherein one or more nitrogen atoms are oxidized to the so-called N-oxide.

The first group of compounds are those compounds of formula (I) wherein one or more of the following definitions are employed;

(i) x represents C or N;

(ii) y represents C or N;

(iii) l represents methyl or a direct bond;

(N)Z¹represents a direct bond, C_1-2Alkyl-or of the formula-CH₂A divalent group of-CH ═ (a) or-CH ═ b);

(v)Z²represents a direct bond, C_1-2Alkyl-or of the formula-CH₂A divalent group of-CH ═ (a) or-CH ═ b);

(vi)R¹represents hydrogen, halogen, cyano, amino, phenyl, hydroxy, C_1-4Alkoxycarbonyl, hydroxycarbonyl, NR³R⁴Or optionally substituted by one or more groups selected from hydroxycarbonyl, phenyl, C_1-4Alkoxy or NR⁵R⁶C substituted by a substituent of_1-4Alkyl or R¹Represents optionally substituted by one or more groups selected from hydroxycarbonyl, phenyl, C_1-4Alkoxy or NR⁷R⁸C substituted by a substituent of_1-4An alkoxy group;

(vii)R²represents hydrogen, halogen, C_1-4Alkyl or C_1-4Alkoxy-;

(viii)R³and R⁴Each independently represents hydrogen, C_1-4Alkyl or C_1-4Alkylcarbonyl-;

(ix)R⁵and R⁶Each independently represents hydrogen, C_1-4Alkyl or C_1-4Alkylcarbonyl-;

(x)R⁷and R⁸Each independently represents hydrogen, C_1-4Alkyl or C_1-4Alkylcarbonyl-;

(xi) A represents phenyl or a monocyclic heterocycle selected from thienyl, furyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl and piperazinyl.

One group of interesting compounds are those of formula (I) wherein one or more of the following definitions apply;

(i) x represents C or N;

(ii) y represents C or N;

(iii) l represents methyl or a direct bond;

(vi)Z¹represents a direct bond, C_1-2Alkyl-or of the formula-CH₂A divalent group of-CH ═ (a) or-CH ═ b);

(v)Z²represents a direct bond, C_1-2Alkyl-or of the formula-CH₂A divalent group of-CH ═ (a) or-CH ═ b);

(vi)R¹represents hydrogen, halogen, cyano, amino, phenyl, hydroxy, C_1-4Alkoxycarbonyl, hydroxycarbonyl, NR³R⁴Or optionally substituted by one or more groups selected from hydroxycarbonyl, phenyl, C_1-4Alkoxy or NR⁵R⁶C substituted by a substituent of_1-4An alkyl group;

(vii)R²represents hydrogen, halogen, C_1-4Alkyl or C_1-4Alkoxy-;

(viii)R³and R⁴Each independently represents hydrogen, C_1-4Alkyl or C_1-4Alkylcarbonyl-;

(ix)R⁵and R⁶Each independently represents hydrogen, C_1-4Alkyl or C_1-4Alkylcarbonyl-;

(x) A represents phenyl or a monocyclic heterocycle selected from thienyl, furyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl and piperazinyl.

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

(i) l represents methyl or a direct bond;

(ii)R¹represents hydrogen, halogen or hydroxy; in particular halogen or hydroxy;

(iii)R²represents hydrogen, halogen or C_1-4Alkoxy-;

(vi) a represents phenyl or a monocyclic heterocycle selected from pyridyl and thienyl;

another group of interesting compounds are those of formula (I) wherein one or more of the following definitions apply:

(i) l represents methyl or a direct bond;

(ii)R¹represents hydrogen, halogen, amino or hydroxyl; in particular fluorine, amino or hydroxyl;

(iii)R²represents hydrogen, bromo or methoxy-;

(iv)Z¹represents a direct bond, methyl, ethyl or a group of formula-CH₂-CH ═ a divalent radical of (a);

(v)Z²represents a direct bond, methyl or ethyl;

(vi) a represents phenyl or a monocyclic heterocycle selected from pyridyl and thienyl;

also of interest are those compounds of formula (I) wherein

A represents phenyl or pyridyl and wherein L represents a direct bond; and/or R¹Represents halogen, cyano, amino, phenyl, hydroxy, C_1-4Alkoxycarbonyl, hydroxycarbonyl, NR³R⁴Or optionally substituted by one or more groups selected from hydroxycarbonyl, phenyl, C_1-4Alkoxy or NR⁵R⁶C substituted by a substituent of_1-4Alkyl or R¹Represents optionally substituted by one or more groups selected from hydroxycarbonyl, phenyl, C_1-4Alkoxy or NR⁷R⁸C substituted by a substituent of_1-4An alkoxy group; in particular R¹Represents halogen, cyano, amino, phenyl, C_1-4Alkoxycarbonyl, hydroxy, hydroxycarbonyl, NR³R⁴Or optionally substituted by one or more groups selected from hydroxycarbonyl, phenyl, C_1-4Alkoxy or NR⁵R⁶C substituted by a substituent of_1-4An alkyl group.

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

2-adamantan-2-yl-2, 3, 3a, 4, 9, 9 a-hexahydro-benzo [ f ] isoindol-1-one;

2-adamantan-2-yl-2, 3, 10, 10 a-tetrahydro-5H-imidazo [1, 5-b ] isoquinolin-1-one;

2-adamantan-2-yl-1, 5, 10, 10 a-tetrahydro-2H-imidazo [1, 5-b ] isoquinolin-3-one;

2-adamantan-1-ylmethyl-1, 2, 3a, 4, 5, 9 b-hexahydro-benzo [ e ] isoindol-3-one;

7-adamantan-2-yl-7, 8, 8a, 9-tetrahydro-pyrrolo [3, 4-g ] quinolin-6-one;

2- (5-hydroxy-adamantan-2-yl) -1, 5, 6, 10 b-tetrahydro-2H-imidazo [5, 1-a ] isoquinolin-3-one;

2- (5-fluoro-adamantan-2-yl) -1, 2, 3a, 4, 5, 9 b-hexahydro-benzo [ e ] isoindol-3-one;

2- (5-hydroxy-adamantan-2-yl) -2, 3, 3a, 4, 9, 9 a-hexahydro-benzo [ f ] isoindol-1-one.

In another embodiment the invention provides a compound of formula (I)^bis) Of (a) a compound

N-oxides, pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein

X represents C or N;

y represents C or N;

l represents methyl or a direct bond;

Z¹represents a direct bond, C_1-2Alkyl-or of the formula-CH₂A divalent group of-CH ═ (a) or-CH ═ b);

Z²represents a direct bond, C_1-2Alkyl-or of the formula-CH₂A divalent group of-CH ═ (a) or-CH ═ b);

R¹represents hydrogen, halogen, cyano, amino, phenyl, hydroxy, C_1-4Alkoxycarbonyl, -O- (C ═ O) -C_1-4Alkyl, hydroxycarbonyl, NR³R⁴Or C_1-4Alkyl radical, wherein the C_1-4Alkyl or-O- (C ═ O) -C_1-4Alkyl is optionally substituted by one or more groups selected from halogen, hydroxycarbonyl, phenyl, C_1-4Alkoxy or NR⁵R⁶Substituted or

R¹Represents optionally substituted by one or more groups selected from halogen, hydroxycarbonyl, phenyl, C_1-4Alkoxy or NR⁷R⁸C substituted by a substituent of_1-4Alkoxy-;

R²represents hydrogen, halogen, C_1-4Alkyl or C_1-4Alkoxy-;

R³and R⁴Each independently represents hydrogen, C_1-4Alkyl or C_1-4Alkylcarbonyl-;

R⁵and R⁶Each independently represents hydrogen, C_1-4Alkyl or C_1-4Alkylcarbonyl-;

R⁷and R⁸Each independently represents hydrogen, C_1-4Alkyl or C_1-4Alkylcarbonyl-;

a represents phenyl or a monocyclic heterocycle selected from thienyl, furyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl and piperazinyl.

In particular of the formula (I)^bis) Wherein one or more of the following definitions apply;

(i) x represents C or N;

(ii) y represents C or N;

(iii) l represents methyl or a direct bond;

(N)Z¹represents a direct bond, C_1-4Alkyl-or of the formula-CH₂A divalent group of-CH ═ (a) or-CH ═ b);

(v)Z²represents a direct bond, C_1-4Alkyl-or of the formula-CH₂A divalent group of-CH ═ (a) or-CH ═ b);

(vi)R¹represents hydrogen, halogen, cyano, amino, phenyl, hydroxy, C_1-4Alkoxycarbonyl-, hydroxycarbonyl, NR³R⁴Or optionally substituted by one or more groups selected from hydroxycarbonyl, phenyl, C_1-4Alkoxy or NR²R⁶C substituted by a substituent of_1-4An alkyl group; in particular R¹Represents hydrogen, halogen, amino or hydroxyl; even in particular fluorine, amino or hydroxyl;

(vii)R²represents hydrogen, halogen, C_1-4Alkyl or C_1-4Alkoxy-; in particular R²Represents hydrogen, halogen or C_1-4Alkoxy-;

(viii)R³and R⁴Each independently represents hydrogen, C_1-4Alkyl or C_1-4Alkylcarbonyl-;

(ix)R⁵and R⁶Each independently represents hydrogen, C_1-4Alkyl or C_1-4An alkylcarbonyl group-.

(x) A represents phenyl or a monocyclic heterocycle selected from thienyl, furyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl and piperazinyl; in particular A represents phenyl or a monocyclic heterocycle selected from pyridyl and thienyl.

In another aspect, the invention provides a compound as defined above as a medicament. Particularly in the treatment or prevention of pathologies associated with excessive cortisol formation, such as obesity, diabetes, obesity-related cardiovascular diseases, stress and glaucoma.

PCT international patent application WO 2004/089416 provides the benefit of combination therapy comprising the administration of an inhibitor of 11 β -HSD1 and an antihypertensive agent in the treatment of insulin resistance, dyslipidaemia, obesity and hypertension, in particular in the treatment of hypertension. It is therefore an object of the present invention to provide a combination therapy of any of the above-mentioned compounds with an antihypertensive drug, such as alprenolol, atenolol, timolol, pinolol, propranolol, metoprolol, bisoprolol fumarate, esmolol, acebutlol, betaxolol, celiprolol, nebivolol, terbutalol, propranolol, amunolalul, carvedilol, labetalol, S-atenolol, OPC-1085, quinapril, lisinopril, enalapril, captopril, benazepril, perindopril, trandolapril, fosinopril, ramipril, cilazapril, idapril, moxidepril, spirapril, temocapril, levofen, S-5590, fasidoionol, Hoechst-roussel: 100240(EP00481522), omapatrilat, gemopatrilat and GW-660511, nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, amlodipine, nitrendipine, verapamil, lacidipine, lercanidipine, aranidipine, clevidipine, azelnidipine, barnidipine, efonidipine, milidipine, iedipine, ieripine, menidipine, nilvadipine, prandine ipine, furnidipine, doxazosin, urapidil, prazosin, terazosin, bunazosin and OPC-28326, benflumethiazide, chlorothiadone, hydrochlorothiazide and cloperamide, bumetanide, torsemide, torasemide, amiloride, spironolactone, ABT-546, benclamenediamine, atrazine, estratriptan, 3631256, OPC-598, OPC-36638, SR-36638, OPC-36638, isb, isn, nifedipine, clevidipine, nifedipine, nif, Nesiritide, irbesartan, candesartancilexetl, losartan, valsartan, telmisartan, eprosartan, candesartan, CL-329167, eprosartan, iossartan, olmesartan, pratosartan, TA-606, YM-358, fenoldopam, ketanserin, naftopidil, N-0861, FK-352, 2-962, ecadotril, LP-805, MYD-37, nolomirol, omacor, treprolinol, beraprost, ecraprost, PST-2238, KR 304-50, Edapromide, CGRP-unigene, guanylate cyclase enhancers, hydrazinozines, methydopa, polycarbobamide, sonidine, Covelothoramide, and Mondoloth-811. In this aspect of the invention, there is provided a pharmaceutical composition comprising a combination of an inhibitor of 11 β -HSD1 of the invention and an antihypertensive agent.

PCT international patent application WO 2004/089415 provides the benefit of a combination therapy comprising the administration of a 11 β -HSD1 inhibitor and a glucocorticoid receptor agonist for the reduction of adverse side effects that occur during glucocorticoid receptor agonist therapy and for the treatment of certain forms of cancer, diseases and disorders having inflammation as a component. In particular to reduce the side effects of glucocorticoid receptor agonist therapy in indications of Cushing's disease, Cushing's syndrome, allergic inflammatory diseases; side effects in glucocorticoid receptor agonist treatment of diseases of the respiratory system, side effects in glucocorticoid receptor agonist treatment of inflammatory bowel disease; side effects in glucocorticoid receptor agonist treatment of diseases of the immune system, connective tissue and joints; side effects in glucocorticoid receptor agonist treatment of endocrine diseases; side effects in glucocorticoid receptor agonist treatment of hematological diseases; side effects in glucocorticoid receptor agonist treatment of cancer, chemotherapy-induced nausea, side effects in muscle and in neuromuscular critical glucocorticoid receptor agonist treatment; side effects in glucocorticoid receptor agonist treatment before and after surgery; transplanting; side effects in glucocorticoid receptor agonist treatment of brain absss, nausea/vomiting, infection, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal disease, cystic aneurysm.

Examples of indications in which a combination of a 11 β -HSD1 compound of the invention and a glucocorticoid receptor agonist may be effective may be: cushing's disease, Cushing's syndrome, asthma, atopic dermatitis, cystic fibrosis, emphysema, bronchitis, allergies, pneumonia, eosinophilic pneumonia, pulmonary fibrosis, Crohn's disease, ulcerative colitis, reactive arthritis, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, lupus nephritis, Henoch-Schnlein purpura, Wegener's endobud disease, temporal arteritis, systemic sclerosis, nodular vasculitis, sarcoidosis, dermatomyositis-polymyositis, pemphigus vulgaris, hyperthyroidism, aldosteronism, hypopituitarism, hemolytic anemia, thrombocytopenia, paroxysmal nocturnal hemoglobinuria, tumor suppression of the spine, brain tumors, acute lymphocytic leukocytes, Hodgkin's disease, chemotherapy-induced nausea, myasthenia gravis, hereditary myopathy, pneumonia, eosinophilic pneumonia, Grave's pneumonia, West's syndrome, Grave's disease, temporal arteritis, systemic sclerosis, sarcoidosis, dermatomyositis-polymyositis, pemphigoiter-induced by chemotherapy, and other diseases, Duchenne muscular dystrophy, trauma, post-operative stress, surgical stress, kidney transplantation, liver transplantation, lung transplantation, pancreatic islet transplantation, blood stem cell transplantation, bone marrow transplantation, heart transplantation, adrenal gland transplantation, trachea transplantation, intestine transplantation, cornea transplantation, skin grafting, keratoplasty, lens transplantation, brain abscess, nausea/vomiting, infection, hypercalcemia, adrenal hyperplasia, autoimmune hepatitis, spinal disease, and cystic aneurysm. It is therefore an object of the present invention to provide pharmaceutical formulations comprising any of the above-mentioned compounds in combination therapy with a glucocorticoid receptor agonist and a combination comprising a compound of the present invention and a glucocorticoid receptor agonist. The glucocorticoid receptor agonist is, for example, selected from: betamethasone, dexamethasone, hydrocortisone, methylprednisolone, prednisone, beclomethasone, butixicort, clobetasol, flunisolide, flucatisone (and the like), mometasone, triamcinolone acetonide GW-685698, NXC-1015, NXC-1020, NXC-1021, NS-126, P-4112, P-4114, RU-24858 and T-25 series.

To simplify the expression of the compounds of the formula (I), radicals

Will be referred to as-D hereinafter.

The inventionA curved "tricyclic adamantyl amide derivative, hereinafter referred to as formula (I)ⁱ) Generally by reacting in a first step under known conditions a commercially available benzocyclobutane carboxylic acid (I)ⁱ) Condensation with the appropriate amine (scheme 1). Subsequently, the amide (I) thus obtained is reacted withⁱⁱ) Reduction with, for example, lithium aluminum hydride or borane-methyl sulfide complex affords the amine of formula (N). Finally, the amine is acylated with an acid chloride and subsequently subjected to a cyclization reaction using methods known in the art, such as heating the amide (V) in toluene at 190 ℃ to give a mixture of cis and trans isomers of the "bent" tricycloacrimantadine amide derivatives of the invention.

Scheme 1

Wherein R is²As defined above for the compounds of formula (I).

To obtain formula (I)ⁱ) The stereoisomer of the "curved" tricyclo adamantylamide derivative of (A), a commercially available benzocyclobutane carboxylic acid (I)ⁱ) Condensation with allyl-2-adamantan-amine (VI) to give an amide of the general formula (VII), which is subjected to cyclized ring closure to give the formula (I)ⁱⁱ) The "bent" tricyclic adamantylamide derivatives of (1) (scheme 2).

Scheme 2

Wherein R is¹And R²As defined above for the compounds of formula (I).

Those compounds of formula (I) in which X represents N are referred to hereinafter as formula (I)ⁱⁱⁱ) The ureas of (a), are generally prepared according to reaction schemes 3 and 4. In the first alternativeIn this case, the urea is prepared starting from commercial Boc-protected tetrahydroquinoline-3-carboxylic acid (both enantiomers), reacting with aminoadamantane and reducing the amide to give the diamine of formula (VIII). Subsequent cyclization is carried out according to known methods to give the formula (I)ⁱⁱⁱ) The cyclic urea of (1).

Scheme 3

In a second alternative, the urea derivative is prepared by coupling a commercially available quinoline-2-carboxylic acid or isoquinoline-1-carboxylic acid with the appropriate amine under known conditions to give the corresponding amide of formula (IX). Selective hydrogenation of the pyridine ring produces tetrahydro (iso) quinoline acetamide (X), which is reduced in toluene using, for example, BH 3. DMS to produce the diamine of formula (XI). Subsequent cyclization with, for example, Carbonyldiimidazole (CDI) to produce formula (I)ⁱⁱⁱ) The cyclic urea of (1).

Scheme 4

Wherein R is²As defined above for the compounds of formula (I), -A-A-represents-N-CH₂-or-CH₂-N-and-a ═ a-represents-N ═ CH-or-CH ═ N-.

In the case where substituted isoquinoline-1-carboxylic acids are not commercially available, the substituted tricyclic derivatives are prepared starting from phenethylamine (XII) and ethyl chloroformate (synthesis scheme 5). The resulting carbamate is cyclized by known methods, for example, by the modified Bischler-Napierelski reaction (Larsen, Robert D., et al, "a modified Bischler-Napieralski method for the synthesis of 3-aryl-3, 4-and isoquinoline-based compounds", Journal of Organic Chemistry (1991), 56(21), 6034-8.), to produce the amino-protected tetrahydroisoquinoline-1-carboxylic acid of formula (X'). Further synthesis of substituted tricyclic derivatives is described in reaction scheme 4 above.

Scheme 5

Formula (I)^N) The "linear" tricyclic adamantylamide derivatives of (a) can be prepared as described in schemes 6 and 7. According to a first alternative, the linear tricyclic adamantyl amide derivatives are prepared starting from aryl-or heteroaryl-substituted acrylic acid or acid chlorides (XIII). With an appropriate amine to give an amide of the formula (XIV) which is subjected to an electrocyclic ring closure reaction under known conditions, for example at 220 ℃ in toluene, to give the formula (I)^iv) The tricyclic system of (1).

Scheme 6

Wherein A and R are as defined above for compounds of formula (I).

In a second alternative, formula (I) wherein A represents phenyl and Y represents N^iv) The "linear" tricyclic adamantylamide derivatives of formula (XV) can be prepared by coupling amino protected D or L-phenylalanine with the appropriate amine to form the α -aminoamide of formula (XV), see for example the reaction conditions described in j. Deprotection followed by Mannich condensation with benzotriazole and formaldehyde gives the intermediate of formula (XVI). Electrical cyclization closed loop formation of formula (I)^iv) The "linear" tricyclic adamantylamide derivatives of (1).

Scheme 7

The following experimental section provides additional examples of the synthesis of compounds of formula (I) using any of the above synthetic methods.

Any one or more of the following steps may be performed in any order, as needed 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;

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

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

(vi) when the compound of formula (I) gives a mixture of the (R) and (S) enantiomers, the compound is resolved to give the desired enantiomer.

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

Functional groups to be protected include hydroxyl, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl (e.g.tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino groups 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 fully disclosed in 'Protective Groups in Organic Synthesis' 2^nd edition，T W Greene &P G M Wutz, Wiley Interscience (1991).

Furthermore, the N atom in the compounds of the formula (I) can be replaced by CH in a known manner₃-I is methylated in a suitable solvent, such as 2-propanone, tetrahydrofuran or dimethylformamide.

The compounds of formula (I) may also be interconverted by known functional group transformation methods, as described in certain examples.

The compounds of formula (I) may also be converted to the corresponding N-oxide form by known methods for converting a trivalent nitrogen to the N-oxide form. The N-oxidation reaction can generally be accomplished by reacting the starting material of formula (I) with 3-phenyl-2- (phenylsulfonyl) oxaazacyclopropene or with a suitable organic or inorganic peroxy compound. 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 peroxybenzenecarboxylic acids or halogenated peroxybenzenecarboxylic acids, such as 3-chloroperoxybenzenecarboxylic acid, peroxyalkanoic acids, such as peroxyacetic acid, alkyl hydroperoxides, such as t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, such as ethanol and the like, hydrocarbons, such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons, such as methylene chloride, and mixtures of such solvents.

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

Some compounds of formula (I) and some intermediates of the invention may contain asymmetric carbon atoms. Pure stereochemical isomers of the compounds and intermediates can be obtained by using known methods. For example, diastereomers may be separated by physical means, e.g., selective crystallization or chromatographic techniques, e.g., convective distribution, liquid chromatography, and the like. Enantiomers can be obtained from racemic mixtures by first converting the racemic mixture into a mixture of diastereomeric salts or compounds with an appropriate resolving agent, such as a chiral acid; followed by physical separation of the mixture of the diastereomeric salts or compounds, for example by selective crystallization or chromatographic techniques, such as liquid chromatography; and finally converting the separated diastereomeric salt or compound 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 the insertion occurs in a stereospecific manner.

Another method for separating the enantiomers of the compounds of formula (I) and intermediates includes liquid chromatography, particularly using a chiral stationary phase.

Some of the intermediates and starting materials used in the above reaction procedures are known compounds and are commercially available or can be prepared according to known methods.

The compounds of the present invention are useful because of their pharmacological properties. They can therefore be used as medicaments, in particular for the treatment of diseases which are associated with excessive cortisol formation, i.e. in which it is desirable to reduce the level of active glucocorticoids, such as the metabolic syndrome type II diabetes, Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), dyslipidemia, hypertension, obesity, diabetes, cardiovascular diseases associated with obesity, arteriosclerosis, atherosclerosis, myopathy, osteoporosis, neurodegeneration and psychosis, stress-related diseases and glaucoma. Particularly in the treatment of pathologies such as obesity, diabetes, type II diabetes and obesity related cardiovascular diseases, stress and glaucoma.

As described in the experimental section below, the inhibitory effect of the compounds of the present invention on 11 β -HSD 1-reductase activity (conversion of corticosterone to cortisol) has been demonstrated in an in vitro enzyme assay using recombinant 11 β -HSD1 enzyme by measuring the conversion of corticosterone to cortisol using HPLC purification and quantification methods. 11 β -HSD 1-reductase inhibition was also demonstrated in an in vitro, cell-based assay comprising contacting cells expressing 11 β -HSD1 with the compound to be tested and assessing the effect of the compound on cortisol conversion in the cell medium of these cells. The cells preferably used in the assay of the invention are selected from the group consisting of mouse fibroblast 3T3-L1 cells, HepG2 cells, porcine kidney cells, in particular LCC-PKl cells and rat liver cells.

The present invention therefore provides compounds of formula (I) and the pharmaceutically acceptable N-oxides, addition salts, quaternary amines and stereochemically isomeric forms thereof, for use in therapy. In particular for the treatment of pathologies associated with excessive cortisol formation, i.e. diseases in which it is desirable to reduce the level of active glucocorticoids, such as metabolic syndrome, type II diabetes, Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), dyslipidemia, hypertension, obesity, diabetes, cardiovascular diseases associated with obesity, arteriosclerosis, atherosclerosis, myopathy, osteoporosis, neurodegenerative and psychiatric disorders, stress-related diseases and glaucoma. More particularly, conditions such as obesity, diabetes, type II diabetes, obesity related cardiovascular diseases, stress and glaucoma. Even more particularly for the treatment or prevention of pathologies associated with excessive cortisol formation, such as obesity, diabetes, cardiovascular diseases associated with obesity and glaucoma.

For use of the compounds of the present invention, there is provided a method of treating an animal, such as a mammal, including man, suffering from a condition associated with excessive cortisol formation which comprises administering an effective amount of a compound of the present invention. The method comprises the systemic or topical administration of an effective amount of a compound of the invention to warm-blooded animals, including humans.

It is therefore an object of the present invention to provide compounds of the present invention for use as medicaments. The compounds of the invention are particularly useful for the preparation of medicaments for the treatment of pathologies associated with excessive cortisol formation, such as metabolic syndrome, type II diabetes, Impaired Glucose Tolerance (IGT), Impaired Fasting Glucose (IFG), dyslipidemia, hypertension, obesity, diabetes, cardiovascular diseases associated with obesity, arteriosclerosis, atherosclerosis, myopathy, osteoporosis, neurodegeneration and psychosis, diseases associated with stress and glaucoma, in particular obesity, diabetes, cardiovascular diseases associated with obesity, stress and glaucoma.

The amount of a compound of the invention is that amount of active ingredient required to achieve a therapeutic effect and will, of course, vary with the particular compound, the route of administration, the age and condition of the recipient, the particular disorder or disease being treated. A suitable daily dosage should be 0.001mg/kg to 500mg/kg body weight, especially 0.005mg/kg to 100mg/kg body weight. The method of treatment may also comprise administering the active ingredient on a regimen of 1-4 administrations per day.

Although the active ingredients may be administered separately, they are preferably provided in the form of a pharmaceutical composition. Accordingly, the present invention further provides pharmaceutical compositions comprising a compound of the present invention and pharmaceutically acceptable carriers and diluents. 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 can be prepared by methods well known in the Pharmaceutical art, for example, using Remington's Pharmaceutical Sciences (18) such as Gennaro^thed., mack publishing Company, 1990, see in particular Part 8: pharmaceuticals and the same manual). A therapeutically effective amount of a 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 different forms depending on the form of preparation desired for administration. It is desirable that these pharmaceutical compositions are in unit dosage forms suitable, preferably suitable, for systemic administration, e.g. oral, transdermal or parenteral administration; or apply toFor topical administration, for example, via inhalation, nasal spray, eye drops or via creams, gels, shampoos, and the like. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols and the like in the case of oral liquid preparations, e.g., 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 are the most preferred oral dosage unit form in which solid pharmaceutical carriers are obviously employed. For the preparation of parenteral compositions, the carrier will usually contain sterile water, at least in large part, and may contain other ingredients, for example, to aid solubility. Injectable solutions may be prepared in which the carrier comprises saline solution, dextrose solution, or a mixture of saline and dextrose 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 contains penetration enhancers and/or suitable wetting agents, optionally mixed with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect on the skin. The additives may facilitate application to the skin and/or may aid in the preparation of the desired composition. These compositions can be administered in a variety of ways, for example as a transdermal patch, such as a patch, or as an ointment. As compositions suitable for topical application, all compositions commonly used for topical administration may be mentioned, such as creams, gels, dressings, shampoos, tinctures, ointments, powders, and the like. The composition may be applied by aerosol, for example with a propellant, such as nitrogen, carbon dioxide, freon, or without a propellant, such as a spray pump, drops, lotion or semi-solid, such as a thickened composition which may be applied with a swab. In particular, semisolid compositions are suitable for use, such as ointments, creams, gels, salves, and the like.

It is particularly suitable to formulate the above 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 unit forms of such dosage 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 improve the solubility and/or stability of the compounds of formula (I) in the pharmaceutical composition, alpha-, beta-or gamma-cyclodextrins or derivatives thereof may suitably be used. Additionally co-solvents such as alcohols may 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 said mixtures are obviously more suitable, because of their higher aqueous solubility.

Test section

In the methods described below, the following abbreviations are used: "THF" represents tetrahydrofuran; "DIPE" represents diisopropyl ether; "EtOAc" represents ethyl acetate; "DMF" represents N, N-dimethylformamide; "BMS" stands for trihydro [ thiobis [ methane ] boron [13292-87-0 ].

Extrelut^TMIs a product of Merck KgaA (Darmstadt, Germany) and is a short column containing diatomaceous earth. Supelco is a pre-packed silica gel liquid chromatography column.

For certain chemicals, the formula is used, e.g. CH₂Cl₂Represents methylene chloride, CH₃OH for methanol, HCl for hydrochloric acid, KOH for potassium hydroxide, NaOH for sodium hydroxide, Na₂CO₃Represents sodium carbonate, NaHCO₃Represents sodium bicarbonate, MgSO₄Represents magnesium sulfate, N₂Represents nitrogen, CF₃COOH represents trifluoroacetic acid.

A. Preparation of intermediates

Example A1

Preparation of intermediate 1

Thionyl chloride (0.5ml) was added to bicyclo [4.2.0]]Octane-1, 3, 5-triene-7-carboxylic acid [14381-41-0](0.001mol) in dichloromethane. The reaction mixture was refluxed for 1 hour. Followed by stirring at room temperature overnight. The solvent was coevaporated with benzene 2 times to give bicyclo [4.2.0]]Octane-1, 3, 5-triene-7-carbonyl chloride [1473-47-478]It was dissolved in DIPE. The resulting solution was added dropwise to N-allyl-2-adamantanamine [ 24161-63-5%]And sodium carbonate in a cooled mixture (0 ℃) in DIPE. The reaction mixture was stirred on ice for 30 minutes and then at room temperature for 2 hours. The mixture was poured into water and extracted with dichloromethane. The organic layer was filtered through Extrelt (TM) and the filtrate was evaporated. The residue was purified by flash column chromatography on TRIKONEXLasttube (TM) (eluent: CH)₂Cl₂/EtOAc 90/10). The product fractions were collected and the solvent was evaporated, yielding 0.13g of intermediate 1.

Example A2

a)Preparation of intermediate 2

3-phenyl-2-propenoic acid [140-10-3 ]](0.01mol) and thionyl chloride (30ml) were refluxed for 2 hours. The solvent was co-evaporated with toluene. The residue was dissolved in DIPE (20ml) and the resulting solution was added dropwise to N-allyl-2-adamantanamine [24161-63-5 ] on ice](0.01mol) and sodium carbonate (2g) in a mixture of DIPE (50 ml). The reaction mixture was stirred overnight, poured into dichloromethane and washed with water. The organic layer was separated and dried (MgSO)₄) The solvent was filtered and evaporated. The residue was purified by column chromatography on silica gel (eluent:CH₂Cl₂). The product fractions were collected and the solvent was evaporated. The residue was triturated with DIPE and the abbreviation collected to yield 1.68g (56%) of intermediate 2.

Example A3

a)Preparation of intermediate 3

A solution of bicyclo [4.2.0] octa-1, 3, 5-triene-7-carboxylic acid [14381-41-0] (0.0033mol) in dichloromethane (25ml) and N, N-diethylethylamine (5ml) was stirred and 1-hydroxy-1H-benzotriazole (0.0035mol) was added. N' - (Ethyliminomethyl) -N, N-dimethyl-1, 3-propanediamine monohydrochloride (0.0035mol) was then added and the mixture was stirred for 10 minutes. Tricyclo [3.3.1.13, 7] decan-2-amine hydrochloride (1: 1) [10523-68-9] (0.0035mol) was added and the reaction mixture was stirred for 2 days. The mixture was washed with 15% citric acid solution and sodium carbonate solution. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated with DIPE and the desired product was collected to give 0.6g of intermediate 3.

b)Preparation of intermediate 4

Lithium aluminium hydride (0.0042mol) was stirred in ether (10ml) on ice and aluminium chloride (0.0042mol) was added, the mixture stirred for 15 min and intermediate 3(0.0021mol) was added portionwise. The reaction mixture was stirred at room temperature for 2 hours and then quenched with dilute HCl solution. Dilute KOH solution was added until pH 10 and the resulting mixture was extracted with dichloromethane. The organic layer was separated and dried, followed by filtration through extrelut (tm) and evaporation of the filtrate to give 0.489g of intermediate 4.

c)Preparation of intermediate 5

A mixture of intermediate 4(0.0018mol) and sodium carbonate (0.3g) in dichloromethane (10ml) was stirred on ice. 2-Acryloyl chloride [814-68-6] (0.002mol) was added dropwise and the reaction mixture was stirred at room temperature overnight. The mixture was washed with water (4ml) and the filtrate was filtered through Extrelut and evaporated to give 0.497g of intermediate 5.

Example A4

a)Preparation of intermediate 6

1-hydroxy-1H-benzotriazole (0.02mol) was added to a mixture of N- [ (1, 1-dimethylethoxy) carbonyl ] -D-phenylalanine [18942-49-9] (0.0075mol) and N, N-diethylethylamine (5ml) in dichloromethane (100 ml). After 5 minutes, N' - (ethylaminomethyl) -N, N-dimethyl-1, 3-propanediamine monohydrochloride [25952-53-8] (0.02mol) was stirred. After stirring for 10 minutes, tricyclo [3.3.1.13, 7] decan-2-amine hydrochloride [10523-68-9] (0.015mol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was poured into water and extracted with dichloromethane. The organic layer was dried, filtered and the solvent was evaporated, yielding 2.5g of intermediate 6.

b)Preparation of intermediate 7

A mixture of intermediate 6(0.0075mol) in dichloromethane (50ml) and trifluoroacetic acid (10ml) was stirred overnight and the solvent was evaporated. The residue was dissolved in dichloromethane and washed with sodium carbonate solution. The organic layer was dried, filtered and the solvent was evaporated. The residue was triturated with DIPE and the desired product was collected to give 1.4g of intermediate 7.

c)Preparation of intermediate 8

Intermediate 7(0.0046mol), 1H-benzotriazole [ 95-14-7%](0.0092mol), paraformaldehyde (0.0138mol) and 4-toluenesulfonic acid [ -15-4]A mixture (0.18g) in benzene (60ml) was refluxed with a Dean-Starck apparatus for 3 hours. Followed by stirring at room temperature overnight. The solvent was evaporated, toluene (60ml) was added and the mixture was refluxed for a further 2 hours with a Dean-Starck apparatus. The mixture was cooled and washed with NaOH-solution (2M). With MgSO₄The organic layer was dried, filtered and the solvent was evaporated, yielding 2.3g of intermediate 8.

Example A5

a)Preparation of intermediate 9

1-hydroxy-1H-benzotriazole (0.0012mol) and N- (ethylaminomethyl) -N, N-dimethyl-1, 3-propanediamine monohydrochloride [25952-53-8](0.0012mol) was added to (3R) -3, 4-dihydro-2, 3(1H) -isoquinolinedicarboxylic acid, 2- (1, 1-dimethylethyl) ester [2-35-1](0.001mol) in a mixture of DMF (10ml) and N, N-diethylethylamine (0.2 ml). The mixture was stirred at room temperature for 20 minutes. Addition of tricyclo [3.3.1.13, 7]]Decan-2-amine hydrochloride [10523-68-9]](0.0012mol) and the reaction mixture is stirred overnight. The mixture was poured into water and stirred for 10 minutes, after which the resulting precipitate was filtered off and dissolved in dichloromethane. The resulting solution was washed with water, MgSO₄Drying, filtration and evaporation of the solvent gave 0.38g of intermediate 9.

b)Preparation of intermediate 10

A mixture of intermediate 9(0.00087mol) in toluene (10ml) was stirred on ice (N)₂Below). BMS (0.001mol) was added dropwise, and then the reaction mixture was stirred on ice for 30 minutes. The mixture was refluxed overnight. The mixture was cooled and washed with Na₂CO₃-solution washing. The organic solvent was evaporated. The residue was dissolved in CH₂Cl₂/CF₃COOH (20%) and stirred at room temperature for 20 hours. The solvent was evaporated. The residue was dissolved in CH₂Cl₂By using Na₂CO₃And (4) washing the solution. The organic layer was concentrated and the residue was filtered over a Supelco column packed with silica gel (eluent: CH)₂C1₂/CH₃OH gradient). The product fractions were collected and the solvent was evaporated, yielding 0.120g of intermediate 10.

Example A6

a)Preparation of intermediate 11

To a stirred solution of 1-isoquinolinecarboxylic acid (0.0056mol) and N, N-diethylethylamine (0.7g) in DMF (50ml) were added 1-hydroxy-1H-benzotriazole (0.0067mol) and N- (ethylaminomethyl) -N, N-dimethyl-1, 3-propanediamine monohydrochloride [25952-53-8](0.0067 mol). The mixture was stirred at room temperature for 20 minutes. Addition of tricyclo [3.3.1.13, 7]]Decan-2-amine hydrochloride [10523-68-9]](0.0067mol) and the reaction mixture is stirred overnight. The mixture was poured into water, stirred for 10 minutes and extracted with dichloromethane. Separating the organic layer with MgSO₄Dry, filter and evaporate the solvent. The residue was dissolved in 2-propanol and converted to the hydrochloride salt (1: 1) with HCl/2-propanol. The desired product was filtered to yield 1.2g of intermediate 11.

b)Preparation of intermediate 12

A solution of intermediate 11(0.0035mol) in HCl, 2-propanol (1ml) and methanol (50ml) was hydrogenated overnight with palladium on activated carbon (0.5g) as catalyst. After uptake of hydrogen (2 eq.1), the catalyst is filtered off and the filtrate is evaporated. The residue was dissolved in dichloromethane and taken up with Na₂CO₃-solution washing. The organic layer was separated and dried (MgSO)₄) The solvent was filtered and evaporated. The residue was purified on a Supelco column packed with silica gel (eluent: CH)₂Cl₂/CH₃OH 99/1). Two product fractions were collected and the solvent was evaporated, yielding 0.370g of intermediate 12.

c)Preparation of intermediate 13

A solution of intermediate 12(0.0012mol) in toluene (10ml) was stirred on ice (N)₂). BMS (0.002mol) was added dropwise, and the reaction mixture was subsequently stirred on ice for 30 minutes and at 100 ℃. The mixture is taken up in NaHCO₃Washed with solution and CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtration and evaporation of the solvent gave 0.29g of residue. The residue was triturated with DIPE and the precipitate was filtered. The filtrate was evaporated to give 0.22g of intermediate 13.

Example A7

a)Preparation of intermediate 14

The reaction product of 7-bromo-3, 4-dihydro-1, 2(1H) -isoquinolinedicarboxylic acid, 2-ethyl ester [135335-12-5 ]]A mixture of (0.006mol) and N, N-diethylethylamine (5ml) in DMF (40ml) was stirred and 1-hydroxy-1H-benzotriazole (0.0067mol) was added. Followed by addition of N' - (ethylaminomethyl) -N, N-dimethyl-1, 3-propanediamine monohydrochloride [25952-53-8](0.0067mol) and the mixture is stirred for 20 minutes. Addition of tricyclo [3.3.1.13, 7]]Decan-2-amine hydrochloride [10523-68-9]](0.0067mol) and the reaction mixture is stirred at room temperature overnight. The mixture was poured into water and stirred for 10 minutes. The resulting precipitate was filtered and dissolved in CH₂Cl₂Over MgSO 2₄Dry, filter and evaporate the solvent. The residue was triturated with DIPE and the desired product was collected to give 1.6g of intermediate 14.

b)Preparation of intermediate 15

Intermediate 14(0.0034mol) was reacted in HBr/CH₃The solution in the COOH mixture (50ml) was stirred at room temperature for 1 week. The mixture was poured into water and stirred for 15 minutes. The precipitate was filtered and dissolved in CH₂Cl₂. With NaHCO₃Solution washing of the solution, drying (MgSO)₄) The solvent was filtered and evaporated. The residue was triturated with DIPE and the desired fraction was collected (0.7g was obtained). This fraction was dissolved in dilute HCl and washed with CH₂Cl₂The resulting solution was washed. With Na₂CO₃Basified aqueous layer with solution and CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtration and evaporation of the solvent gave 0.35g of intermediate 15.

c)Preparation of intermediate 16

A mixture of intermediate 15(0.00089mol) in toluene (50ml) and THF (20ml) was stirred under N₂Stirring until complete dissolution, and then dissolving the solution in N₂Stirring on ice. BMS (0.002mol) was added dropwise and the reaction mixture was stirred in N₂Stir for 30 minutes on ice. The mixture was further stirred at 100 ℃ overnight and then cooled. 1N HCl (50ml) was added. The mixture was stirred and refluxed for 2 hours. Cooling the resulting mixture with Na₂CO₃Neutralized in solution and with CH₂Cl₂And (4) extracting. The organic layer was separated and dried (MgSO)₄) Filtration and evaporation of the solvent gave 0.3g of intermediate 16.

B. Preparation of the Compounds

Example Bl

Preparation of Compound 1

A mixture of intermediate 1(0.00093mol) in dry toluene (10ml) was stirred at 190 ℃ for 6 hours and then at room temperature overnight. The solvent is evaporated and purified by column chromatography on silica gel (eluent: CH)₂Cl₂) And (4) residue. The product fractions were collected and the solvent was evaporated, yielding 0.19g (63%) of compound 1.

Example B2

Preparation of Compound 2

A mixture of intermediate 2(0.00031mol) and 4-methoxyphenol (catalytic amount) in toluene (10ml) was stirred at 220 ℃ for 1 hour. The solvent was evaporated. By flash chromatography on TRIKONEXFlashtube^TMPurification (2X) (eluent: CH)₂Cl₂EtOAc 90/10). The product fractions were collected to yield 0.008g of compound 2.

Example B3

Preparation of Compound 3

A solution of intermediate 5(0.0015mol) in toluene (15ml) was stirred in a pressure vessel at 190 ℃ for 6 hours. The reaction mixture was then stirred at room temperature overnight. The solvent was evaporated and the residue was purified on a Supelco column packed with silica gel (eluent: CH)₂Cl₂). Collecting fractions and evaporating solventTo obtain 0.1g of Compound 3.

Example B4

Preparation of Compound 4

Intermediate 8(0.006mol) in dichloromethane (250ml) was stirred and aluminium chloride (0.018mol) was added. The reaction mixture was refluxed for 3 hours. The mixture was cooled and washed with koh (im). The organic layer was washed, dried, filtered and the solvent was evaporated to give 0.7g of a residue. A portion (0.3g) of the residue was purified over silica gel (eluent: CH)₂Cl₂EtOAc 90/10). The product fractions were collected and the solvent was evaporated to give 0.133g of compound 4.

Example B5

Preparation of Compound 5

A solution of intermediate 10(0.00040mol) in tetrahydrofuran (10ml) was stirred and 1,1, -carbonyldi-1H-imidazole [530-62-1 ] added](0.00045 mol). The mixture was refluxed overnight. After cooling, water (2ml) was added. The mixture was extracted with dichloromethane and the organic layer was filtered through extrelut (tm). Purification by column chromatography on silica gel (Supelco) (eluent: CH)₂Cl₂) The residue obtained. The product fractions were collected and the solvent was evaporated, yielding 0.063g of Compound 5.

Example B6

Preparation of Compound 6

1, 1' -carbonyldi-1H-imidazole [530-62-1](0.00185mol) was added to a stirred solution of intermediate 13(0.00048mol) in tetrahydrofuran (15 ml). The reaction mixture was stirred at 60 ℃ for 48 hours and cooled. Water (4ml) was added. The mixture was stirred for 10 minutes and extracted with dichloromethane (10 ml). The organic layer was separated and dried (MgSO)₄) The solvent was filtered and evaporated. The residue (0.337g) was purified on a Supelco column packed with silica gel (eluent: CH)₂Cl₂). The product fractions were collected and the solvent was evaporated, yielding 0.051g of compound 6.

Example B7

Preparation of Compound 7

A mixture of intermediate 16(0.0008mol) in tetrahydrofuran (5ml) was stirred and 1, 1' -carbonylbis-1H-imidazole (0.5g) was added. The reaction mixture was stirred at room temperature overnight and the solvent was evaporated. The residue was purified by column chromatography (Supelco) on silica gel (eluent: CH)₂Cl₂EtOAc 90/10). The product fractions were collected and the solvent was evaporated, yielding 0.068g of compound 7.

Table F-1 lists the compounds prepared according to the above examples.

TABLE F-1

Table F-2 provides a mixture of the invention using CDCl3 as solvent¹H NMR and¹³CNMR chemical shift data.

TABLE F-2

C. Pharmacological examples

Example C1: testing the Effect of Compounds on 11 b-hydroxysteroid dehydrogenase type 1 and 2 Enzyme assay

The effect of compounds on 11b-HSD 1-dependent conversion of corticosterone to cortisol (reductase activity) was studied in a reaction mixture containing 30mM Tris-HCl buffer pH 7.2, 180. mu.M NADPH, 1. mu.M DTA, 2. mu.M corticosterone, 1. mu.l drug and/or solvent and 11. mu.g recombinant protein in a final volume of 100. mu.l.

The effect of 11b-HSD 1-dehydrogenase activity (converting cortisol to corticosterone) was determined in a reaction mixture containing 0.1M sodium phosphate buffer pH 9.0, 300. mu.M NADP, 25. mu.M cortisol, 1. mu.l drug and/or solvent and 3.5. mu.g recombinant protein in a final volume of 100. mu.l.

The 11b-HSD 2-dependent dehydrogenase activity was determined in a buffer containing 0.1M sodium phosphate buffer pH7.5, 300. mu.M NAD, 100nM cortisol (2 nM of which is³H-radiolabelled), 1. mu.l drug and/or solvent 2.5. mu.g recombinant protein in a reaction mixture at a final volume of 100. mu.l.

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

Example C2: testing the Effect of Compounds on 11 b-hydroxysteroid dehydrogenase type 1 and 2 Cell assay

The effect on 1b-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 humidified 5% CO at 37 ℃ in DMEM medium₂Growth was carried out in atmosphere for 7 days (supplemented with 10% heat-inactivated fetal bovine serum, 2mM glutamic acid and 25mg gentamicin). The medium was refreshed 2 times per week. Fibroblasts at 37 ℃ and humidified 5% CO₂In an atmosphere containing 2. mu.g/ml insulin, 55. mu.g/mDifferentiation into adipocytes in growth medium of lIBMX and 39.2. mu.g/ml dexamethasone.

Primary hepatocytes from male rats were seeded in conventional Falcon 12-well plates at a density of 250000 cells/well and at 37 ℃ in 5% CO₂The cells were cultured in DMEM-HAM's 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 for 16 hours in a humidified atmosphere. After 4 hours of pre-incubation with test compound, 0.5. mu. Ci was added³H-corticosterone or dehydrocorticosterone was added to 3T3-L1 cultures. After 1 hour, the medium was maintained in Extrelut³The column was extracted with 15ml of ether and the extracts were analyzed by HPLC as described above. Then use 0.5 mu Ci³After 90 min incubation of H-dehydrocorticosterone, the effect of JNJ-compounds on HSD1 activity in rat hepatocytes was determined. Corticosterone formation was analyzed by HPLC.

The effect on 11b-HSD2 activity was performed in HepG2 and LCC-PKl-cells. HepG 2-cells (ATCC HB-8065) were seeded at a density of 100,000 cells/ml in 12-well plates and at 37 ℃ at 5% CO₂Growth in MEM-Rega-3 medium supplemented with 10% heat-inactivated fetal bovine serum, 2mM 1-glutamic acid and sodium bicarbonate was performed in a humidified atmosphere. The medium was refreshed 2 times per week. Porcine kidney cells (LCC-PKl, ATCC CRL-1392) were seeded at a density of 150,000 cells/ml in 12-well plates and at 37 ℃ in 5% CO₂Growth was carried out in a humidified atmosphere in medium 199 supplemented with Earls modified saline solution, 100U/ml penicillin, 100 μ g/ml streptomycin and 10% fetal bovine serum. The medium was refreshed 2 times per week. At 24 hours before the start of the experiment, the medium was changed to medium containing 10% carbon-extracted fetal bovine serum. After 4 hours of pre-incubation with test compound, 0.5. mu. Ci will be added³H-Cortisol or Cortisone is added to the culture. After 1 hour, the medium was maintained in Extrelut³The column was extracted with 15ml of ether and the extracts were analyzed by HPLC as described above.

For enzyme assays, the compounds testedThe substances are taken from stock solutions and are in 10^-5M to 3.10^-9M was tested in the final concentration range. From the dose response curve thus obtained, pIC50 values can be calculated and scored as follows; score 1 ═ pIC50 value < 5, score 2 ═ pIC50 value in the range 5-6, score 3 ═ pIC50 value > 6. Some of the results thus obtained are summarized in the following table (NT means not tested in this table).

D. Composition examples

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

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

Example D1: film coated tablet

Preparation of the tablet core

A.i. (100g), lactose (570g) and starch (200g) were mixed well and thereafter moistened with a solution of sodium lauryl sulfate (5g) and polyvinylpyrrolidone (10g) in about 200ml of water. The wet powder mixture was sieved, dried and sieved again. Subsequently microcrystalline cellulose (100g) and hydrogenated vegetable oil (15g) were added. All the ingredients were mixed well and compressed into tablets to give 10.000 tablets, each containing 10mg of the active ingredient.

Coating film

To a solution of methylcellulose (10g) in denatured ethanol (75ml) was added ethylcellulose (5g) in CH₂Cl₂(150 ml). Followed by addition of 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 solution followed by magnesium octadecanoate (2.5g), polyvinylpyrrolidone (5g) and concentrated coloured suspension (30ml) and the whole was homogenised. The tablet cores are coated with the mixture thus obtained in a coating apparatus.

Claims (9)

1. A compound of formula (I)

Pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein

X represents CH or N;

y represents CH;

l represents a methylene group or a direct bond;

Z¹represents a direct bond, C_1-2Alkylene-or a group of formula-CH ═ c;

Z²represents a direct bond or C_1-2An alkylene group;

R¹represents hydrogen, halogen or hydroxy;

R²represents hydrogen, halogen or C_1-4Alkoxy-;

a represents phenyl or a monocyclic heterocycle selected from thienyl and pyridyl.

2. The compound of claim 1, wherein:

a represents phenyl or pyridyl, wherein L represents a direct bond; and wherein R¹Represents halogen or hydroxyl.

3. The compound of claim 1, wherein the compound is selected from the group consisting of:

2-adamantan-2-yl-2, 3, 3a, 4, 9, 9 a-hexahydro-benzo [ f ] isoindol-1-one;

2-adamantan-2-yl-1, 5, 10, 10 a-tetrahydro-2H-imidazo [1, 5-b ] isoquinolin-3-one;

2-adamantan-1-ylmethyl-1, 2, 3a, 4, 5, 9 b-hexahydro-benzo [ e ] isoindol-3-one;

7-adamantan-2-yl-7, 8, 8a, 9-tetrahydro-pyrrolo [3, 4-g ] quinolin-6-one;

2- (5-hydroxy-adamantan-2-yl) -1, 5, 6, 10 b-tetrahydro-2H-imidazo [5, 1-a ] isoquinolin-3-one;

2- (5-fluoro-adamantan-2-yl) -1, 2, 3a, 4, 5, 9 b-hexahydro-benzo [ e ] isoindol-3-one; and

2- (5-hydroxy-adamantan-2-yl) -2, 3, 3a, 4, 9, 9 a-hexahydro-benzo [ f ] isoindol-1-one.

4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a potent 11 β -HSD1 inhibiting amount of a compound as claimed in any one of claims 1-3.

5. A process for the preparation of a pharmaceutical composition as defined in claim 4, characterized in that said pharmaceutically acceptable carrier is intimately mixed with an effective 11 β -HSD1 inhibiting amount of a compound according to any one of claims 1 to 3.

6. Use of a compound according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of a condition associated with excessive cortisol formation.

7. The use of claim 6, wherein the pathology associated with excessive cortisol formation is selected from the group consisting of obesity, diabetes, cardiovascular diseases associated with obesity, dementia, cognition, osteoporosis, stress and glaucoma.

8. Use of a compound as claimed in any one of claims 1 to 3 in combination with an antihypertensive agent in the manufacture of a medicament for the treatment of insulin resistance, dyslipidemia, obesity and hypertension.

9. Use of a compound according to any one of claims 1-3 in combination with a glucocorticoid receptor agonist for the manufacture of a medicament for reducing side effects occurring during glucocorticoid receptor agonist therapy and for the treatment of cancers, diseases and disorders of which inflammation is a component.