BACKGROUND OF THE INVENTION A major problem with both Type 2 and Type 1 diabetes is that there is an excessive and inappropriate production of glucose by the liver. This abnormality is the primary cause of fasting hyperglycemia and occurs in addition to defects in regulation of insulin release and in peripheral sensitivity to insulin. Thus, agents that decrease liver glucose production would be beneficial for treating both Type 2 and also Type 1 diabetes.

Intensive treatment of the hyperglycemia of Type 1 diabetes mellitus has been shown to markedly decrease the development of ocular, renal and neuropathic complications, and there is evidence that intensive treatment is also beneficial for Type 2 diabetes. The available data also indicate that most patients are currently not receiving ideal and state-of-the-art treatment for either Type 2 or Type 1 diabetes. This inadequacy exists in spite of the availability of several different types of preparations of insulin for treatment of both Type 2 and Type 1 diabetes, and of a number of additional modalities, including agents that stimulate insulin release (e. g. sulfonylureas), influence liver glucose production (e. g. metformin), affect the sensitivity to insulin (e. g. compounds interacting with the PPARy such as troglitazone, rosiglitazone and pioglitazone) and glucose absorption (e. g. a-glucosidase inhibitors such as acarbose). In spite of the availability of several different orally active agents that lower blood glucose levels, many patients with Type 2 diabetes also require insulin for control of their blood sugar levels. Overall, insulin usage in Type 2 diabetes exceeds that for Type 1 diabetes, and there is general agreement that there is a need for additional orally active agents to treat Type 2 diabetes.

The glucocorticoids secreted from the adrenal gland (dominantly cortisol in humans) were so-named because of their ability to regulate glucose metabolism. These steroids stimulate the production of glucose in the liver by promoting gluconeogenesis, which is the biosynthesis of new glucose (i. e. not glucose from glycogen). Thus, in glucocorticoid insufficiency there is a tendency to hypoglycemia, with decreased liver glucose production.

Further, development of Addison's disease in the diabetic generally leads to lowered glucose levels. Conversely, glucocorticoid excess can provoke frank diabetes in individuals with latent diabetes mellitus, and generally aggravates glycemic control in established diabetics. Similar influences have been observed in various animal models.

The glucocorticoid receptor (GR) belongs to a large group of ligand dependent intracellular receptors, which regulate transcription of genes. The increased glucose production in response to glucocorticoids is due to effects of a number of proteins, which are GR regulated. Important among these proteins are various transaminases that convert amino acids to glucose precursors, glucose-6 phosphatase and phosphoenolpyruvate carboxy-kinase (PECK). Even a modest increase of PEPCK, as obtained in transgenic mice, gives rise to hyperglycemia. In mice with Type 2 diabetes and increased levels of corticosterone (the endogenous glucocorticoid of that species) there is increased expression of PEPCK. This over-expression of PEPCK can be repressed by treatment with the GR antagonist RU486 with a concomitant decrease in the hyperglycemia.

The considerations outlined above indicate that if actions of endogenous glucocorticoids on liver glucose production could be blocked in a specific manner, glycemic control could be improved for the benefit of the diabetic patients. However, to date, all means to block glucocorticoid action have been general. Thus, adrenalectomy leaves the patient with frank adrenal insufficiency and the problems of Addison's disease. Blockade of adrenal steroid production, for example by metyrapone, or of glucocorticoid action, for example with RU486 is ordinarily of limited duration of effectiveness and when it is effective also results in generalized adrenal insufficiency. Long term, compensatory ACTH hypersecretion and increased cortisol release that override the block generally overcome these treatments. By contrast, a liver-selective GR antagonist would not have these problems, but should yet counteract the increased liver glucose production in diabetes mellitus and should be useful for treatment of Type 2 diabetes.

A liver selective GR antagonist offers a number of advantages. First, it would decrease liver glucose production. This action will have a significant effect on glycemic control. In fact, excessive liver glucose production can be the major defect in Type 2 diabetes. Secondly, such a drug should enhance insulin sensitivity because of the overall improvement in the metabolic milieu and the amelioration of the hyperglycemia-induced defects in insulin action and secretion. The decreased demand on 0-cell secretion, as a result of a reduction in glycemia, would retard the progressive ß-cell dysfunction characteristic of Type 2 diabetes.

Another advantage of GR antagonist treatment compared with sulfonylurea or insulin treatment is that the patient would run a lower risk of hypoglycemia.

Previous efforts to block glucocorticoid action in diabetes have been hampered by the fact that any compounds used would generally block glucocorticoid action in all tissues and would lead to the potential problems of glucocorticoid insufficiency, such as hypotension, shock and ultimately death if the organism is exposed to sufficiently strong stress conditions. In contrast, a liver-selective GR-antagonist with minimal effects outside the liver could be used as a front line therapy for Type 2 diabetes, or could be used in conjunction with other existing therapies.

Also, glucocorticoids are known to influence the development and maintenance of inflammation, autoimmune disease, transplant rejection, neoplasm, leukemia, lymphom, Cushings disease, adrenal disease, renal disease, cerebrovascular ischemia, hypercalcemia, cerebral edema, thrombocytopenia, inflammatory bowel disease, wound healing, HIV infection, central nervous system disease, spinal cord tumour, glaucoma, sleep disorder, depression, anxiety disorder, atherosclerosis, hypertension, osteoporosis, occular hypertension, nephrotoxicity, infarction, endometriosis, pregnancy disorder, psychosis, Alzheimer disease, cocaine use disorder, asthma, allergic rhinitis, conjuctivitis, rheumatoid arthritis, dermatitis, eczema, osteoarthritis, hypoglycemia, hyperinsulinemia, hyperlipidemia and obesity.

DESCRIPTION OF THE INVENTION In accordance with the present invention, compounds are provided which are active at the glucocorticoid hormone receptor, and have the general formula 1 : wherein: R'is selected from: COOH and heteroaryl, wherein any heteroaryl residue may be optionally substituted in one or more positions independently of each other by a group selected from C, 6-alkyl, halogen, cyano, CF3, RIS, RIS (O) nX and (R9) (R'0) N; R and RI are independently of each other selected from: hydrogen, halogen, and C1 6-alkyl, provided that one of R2 or R3 is other than hydrogen; R4 is selected from: C,-6-alkyl, C3-8-cycloalkyl, C2-6-alkenyl, and C2-6-alkynyl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from A; R5 is selected from: Hydrogen, C1-12-alkyl, C2-6-alkenyl, and C2-6-alkynyl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from A; R6 and RI are independently of each other selected from: (i) aryl and heteroaryl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from C; (ii) C3-8-heterocycloalkyl, which may be optionally substituted in one or more positions independently of each other by a group selected from A; R8, R9, R10 and R11 are independently of each other selected from: (iii) hydrogen, (iv) C,-6-alkyl, C3-8-cycloalkyl, C2-6-alkenyl, Cz-6-alkynyl, and C3-s-heterocycloalkyl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from A; (v) aryl and heteroaryl, wherein any residues herein may be optionally substituted in one or more positions independently of each other by a group selected from C; or where any pair of R8, R9, R° and R11 together with the atom or atoms to which they are bound form a ring having 3-7 ring members, and which ring optionally contain 1-3 heteroatoms, or 1-3 double bonds, and which optionally is substituted by a group selected from A; A is selected from: halogen, C,-6-alkyl, Cs-8-cycloalkyl, C2-6-alkenyl, C2-6-alkynyl, aryl, C3-s-heterocycloalkyl, heteroaryl, cyano, nitro, azido, Z, R80, R'C (Z), R8C (Z) O, RSOC (Z), RIS, R'S (O) n, RIS (O) nO, RBOS (O) n, (R9)(R10)N, (R9)(R10)NC(Z), (R9)(R10(NC(Z)O, R8C (Z) N (R"), R8OC (Z) N (R11), (R9)(R10)NC (Z) N (R11), (R9)(R10)NS(O)2, R8S(O)2N(R11), (R9)(R10)NS(O)2N(R11), and RISC (Z) N (R11), wherein any C1-6alkyl, C3-8cycloalkyl, C2-6alkenyl, C2-6alkynyl, and C3-8-heterocycloalkyl residue is optionally substituted in one or more positions independently of each other by a group selected from B, and also wherein any aryl and heteroaryl residue is optionally substituted in one or more positions independently of each other by a group selected from C; provided that if A is attached to a double or to a triple bond, or to a carbon attached to a heteroatom, A is not HO, HS, R9HN, (R9) (R'°) NC (Z) NH, (R9) (R1°) NS (0) 2NH, or R8S (0) 2NH, and also provided that if A is attached to a double or to a triple bond, A is not Z; B is defined as: A, provided that if B is attached to a double or to a triple bond, or to a carbon attached to a heteroatom, B is not HO, HS, R9HN, (R9) (R10) NC (Z) NH, (R9) (R1°) NS (0) 2NH, or RIS (0) 2NH, and also provided that if B is attached to a double or to a triple bond, B is not Z; C is defined as: A, provided that C is not Z; Z is a substituent connected by a double bond, and is selected from: 0=, S=, R8N=, (R9) (R'°) NN=, R8ON=, (R9) (R1°) NS (0) 2N=, NCN=, 02NCH=, and (R9) (R10) C= ; n is 1 or 2 ; or pharmaceutical acceptable salts, stereoisomers or prodrugs thereof.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds useful as glucocorticoid receptor modulators, and have the general formula I described above.

In that formula R'may preferably be COOH.

R and RI may preferably be independently of each other, halogen, and more preferably both R2 and RI are bromine.

R4 may preferably be C1 6-alkyl or C3 8-cycloalkyl.

RI may preferably be hydrogen or C1-12-alkyl, R6 may preferably be aryl or heteroaryl, and R7 may preferably be aryl or heteroaryl.

RI and R10 may preferably be independently of each other, hydrogen or C1 6-alkyl, or RI and R'° together with the nitrogen atom to which they are bound may form a saturated heterocyclic ring having 5-6 ring members and which ring optionally contains one heteroatom, and which optionally may be substituted by C1 6-alkyl.

Compounds of the invention include, but are not limited to, the following. They are described in more detail in the Examples, i. e. compound"E1"is described in Example 1 and so on.

3, 5-Dibromo-4-{2-[(4-hydroxyphenyl)(phenyl)methyl]-5-isopropyl -4-methoxyphenoxy}- phenylacetic acid (E1) ; 3,5-Dibromo-4- {2- [ (5-fluoro-2-hydroxyphenyl) (phenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid (E2); 4- {2- [ (4-Chloro-2-hydroxyphenyl) (phenyl) methyl]-5-isopropyl-4-methoxy- phenoxy}-3,5-dibromophenylacetic acid (E3); 4-{2-[(2-Chloro-4-hydroxyphenyl) (phenyl) methyl]-5-isopropyl-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (E4); 4- {2- [ (5-Chloro-2-hydroxyphenyl) (phenyl) methyl]-5-isopropyl-4-methoxy- phenoxy}-3,5-dibromophenylacetic acid (E5) ; 3,5-Dibromo-4- {2- [ (3, 4-difluoro-2-hydroxyphenyl) (phenyl) methyl]-5-isopropyl-4-methoxyphen oxy} phenylacetic acid (E6); 3,5-Dibromo-4- {2- [ (4, 5-difluoro-2-hydroxyphenyl) (phenyl) methyl]-5-isopropyl-4-methoxyphen oxy} phenyl acetic acid (E7); 3,5-Dibromo-4- {2- [ (4, 5-dimethyl-2-hydroxyphenyl) (phenyl) methyl]-5-isopropyl-4-methoxyphe noxy} acetic acid (E8); 3,5-Dibromo-4-{2-[(2-hydroxy-4-methOxyphenyl) (phenyl) methyl]-5-isopropyl-4-methoxyphen oxy} phenylacetic acid (E9); 3,5-Dibromo-4-{2-[(3-indolyl)(phenyl)methyl]-5-isopropyl-4-m ethoxyphenoxy}phenylacetic acid (E10) ; 3,5-Dibromo-4-{2-[(4-hydroxyphenyl)(3-methylphenyl)methyl]-5 -isopropyl-4-methoxy- phenoxy} phenylacetic acid (E11) ; 3,5-Dibromo-4- {2- [ (3-fluoro-2-hydroxyphenyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxy phenoxy} phenyl acetic acid (E12); 3,5-Dibromo-4- {2- [ (4-fluoro-2-hydroxyphenyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxy phenoxy} phenylacetic acid (E13); 3,5-Dibromo-4-{2-[(5-fluoro-2-hydroxyphenyl)(3-methylphenyl) methyl]-5-isopropyl-4-methoxy phenoxy} phenyl acetic acid (E14); 4-{2-[(3-Chloro-2-hydroxyphenyl)(3-methylphenyl)methyl]-5-is opropyl-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (E15) ; 4- {2- [ (4-Chloro-2-hydroxyphenyl) (3-methylphenyl) methyl]-5-isopropy1-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (E16) ; Example 17; <BR> <BR> <BR> <BR> 4- {2- [ (5-Chloro-2-hydroxyphenyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxyphenoxy}-3, 5-dibromophenylacetic acid (E17); 4- {2- [ (3-Bromo-2-hydroxyphenyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (E18) ; 4- {2- [ (4-Bromo-2-hydroxyphenyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy}-3,5-dibromophenylacetic acid (E19); 4- {2- [ (5-Bromo-2-hydroxyphenyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (E20); 3,5-Dibromo-4- {2- [ (4, 6-dichloro-2-hydroxyphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E21); 3,5-Dibromo-4-{2-[(2-hydroxy-3-methylphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E22); 3,5-Dibromo-4- {2- [ (3, 4-dimethyl-2-hydroxyphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E23); 3,5-Dibromo-4-{2-[(3,5-dimethyl-2-hydroxyphenyl)(3-methylphe nyl) methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E24); 3,5-Dibromo-4- {2- [ (3, 6-dimethyl-2-hydroxyphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E25); 3,5-Dibromo-4- {2- [ (4, 5-dimethyl-2-hydroxyphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E26); 3,5-Dibromo-4- {2- [ (4, 6-dimethyl-2-hydroxyphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E27); 3,5-Dibromo-4- {2- [ (5-ethyl-2-hydroxyphenyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxy phenoxy} phenylacetic acid (E28); 4- {2- [ (5-tert-Butyl-2-hydroxyphenyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy}-3,5-dibromophenylacetic acid (E29); 4-[2-({5-[2-(Carboxymethyl)ethyl]-2-hydroxyphenyl}{3-methylp henyl}- methyl)-5-isopropyl-4-methoxyphenoxy]-3, 5-dibromophenylacetic acid (E30); 3,5-Dibromo-4- {2- [ (2, 4-dihydroxyphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E31) ; 3,5-Dibromo-4-{2-[(2-hydroxy-4-methoxyphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E32); 3,5-Dibromo-4-{2-[(2-hydroxy-5-methoxyphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E33) ; 3,5-Dibromo-4-{2-[(2-hydroxy-4-trifluoromethoxyphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E34); 3,5-Dibromo-4-{2-[(2-hydroxy-6-trifluoromethoxyphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E35) ; 3,5-Dibromo-4- {2- [ (5-benzyloxy-2-hydroxyphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E36); 3,5-Dibromo-4-{2-[(2-hydroxy-3-methoxy-6-methylphenyl)(3-met hyl- phenyl) methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E37); 3,5-Dibromo-4-{2-[(2-hydroxy-3, 4-dimethoxyphenyl) (3-methyl- phenyl) methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E38) ; 3,5-Dibromo-4-{2-[(2-hydroxy-4, 6-dimethoxyphenyl) (3-methyl- phenyl) methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E39); 3,5-Dibromo-4-{2-[(2-hydroxy-4,5,6-trimethoxyphenyl) (3-methyl- phenyl) methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E40); 3,5-Dibromo-4-{2-[(2-hydroxy-4,5-methylenedioxyphenyl)(3-met hyl- phenyl) methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E41); 3,5-Dibromo-4-{2-[(2-hydroxy-5,6-methylenedioxyphenyl)(3-met hyl- phenyl) methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E42); 3,5-Dibromo-4-{2-[(2, 4-dimethoxyphenyl) (3-methylphenyl) methyl]-5-iso- propyl-4-methoxyphenoxy} phenylacetic acid (E43); 3,5-Dibromo-4-(2-{[4-(dimethylamino)phenyl]-[3-methylphenyl] methyl}-5-iso- propyl-4-methoxyphenoxy) phenylacetic acid (E44); 3, 5-Dibromo-4-(2-{[2-hydroxy-5-(1-pyrrolo)phenyl]-[3-methylphe nyl]- methyl}-5-isopropyl-4-methoxyphenoxy) phenylacetic acid (E45); 4- {2- [ (3-amino-2-hydroxy-1-naphtyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (E46); 3,5-Dibromo-4- {2- [ (3-indolyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxyphenoxy}- phenylacetic acid (E47); 4- {2- [ (5-Bromo-3-indolyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxyphenoxy}-3, 5-dibro mophenylacetic acid (E48); 3,5-Dibromo-4- {2- [ (3-indolyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid (E49); 4- {2- [ (4-Carbomethoxy-3-indolyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (E50) ; 4- {2- [ (5-Carbomethoxy-3-indolyi) (3-methylphenyl) methyl]-5-isopropy1-4-methoxy- phenoxy}-3,5-dibromophenylacetic acid (E51) ; 3, 5-Dibromo-4-{5-isopropyl-2-[(3-methylphenyl)(2-thienyl)methy l]-4-methoxy- phenoxy} phenylacetic acid (E52); 3, 5-Dibromo-4-{2-[((3,5-dimethylphenyl)(4-hydroxyphenyl)methyl ]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid (E53) ; 3,5-Dibromo-4-{2-[((3, 5-dimethylphenyl) (5-fluoro-2-hydroxyphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E54); 4- {2- [ (4-Bromo-2-hydroxyphenyl) (3-methylphenyl) methyl]-5-tert-butyl-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (E55) ; 4-{2-[(B-bromo-4-hydroxyphenyl)(3-methylphenyl)methyl]-5-ter t-butyl-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (E56) ; 4- {2- [ (3-Bromo-2-hydroxyphenyl) (3-methylphenyl) methyl]-5-tert-butyl-4-methoxy- phenoxy}-3,5-dibromophenylacetic acid (57) ; 4- {5-tert-Butyl-2- [ (3, 5-dimethyl-2-hydroxyphenyl) (3-methylphenyl) methyl]-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (E58) ; 4-{5-teff-Butyl-2-[(2-hydroxy-3-methoxy-5-methylphenyl) (3-methyl- phenyl) methyl]-4-methoxyphenoxy}-3, 5-dibromophenylacetic acid (E59) ; 4-{5-Cyclopentyl-2-[(2-hydroxy-3-methoxy-4-methylphenyl)(phe nyl)methyl]-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (E60) ; 3, 5-Dibromo-4-{2-[diphenylmethyl]-5-isopropyl-4-methoxyphenoxy }phenylacetic acid (E61); 3,5-Dibromo-4- {2- [ (1-imidazolyl) (3-methylphenyl) methyl]-5-isopropyl-4-methoxyphenoxy}- phenylacetic acid (E62); 3,5-Dibromo-4-{2-[(2, 5-dihydroxyphenyl) (3-methylphenyl)- methyl]-4-hydroxy-5-isopropylphenoxy} phenylacetic acid (E63); or pharmaceutical acceptable salts, stereoisomers or prodrugs thereof.

The present invention also relates to pharmaceutical compositions comprising any of the compounds of the present invention and a pharmaceutical acceptable diluent or carrier.

The present invention also relates to processes for making the pharmaceutical compositions of the present invention.

Another embodiment of the invention is a method preventing, inhibiting or treating a disease associated with a metabolic dysfunction by administering to the mammal a therapeutical effective amount of any of the compounds or pharmaceutical compositions described herein.

Another embodiment of the invention is a method preventing, inhibiting or treating a disease, which is dependent on the expression of a glucocorticoid receptor regulated gene, by administering to the mammal a therapeutical effective amount of any of the compounds or pharmaceutical compositions described herein.

The diseases referred to comprise, but are not limited to Type 1 insulin dependent diabetes, Type 2 non-insulin dependent diabetes, Cushing's syndrome, inflammation, autoimmune disease, transplant rejection, neoplasm, leukemia, lymphom, Cushings disease, adrenal disease, renal disease, cerebrovascular ischemia, hypercalcemia, cerebral edema, thrombocytopenia, inflammatory bowel disease, wound healing, HIV infection, central nervous system disease, spinal cord tumour, glaucoma, sleep disorder, depression, anxiety disorder, atherosclerosis, hypertension, osteoporosis, occular hypertension, nephrotoxicity, infarction, endometriosis, pregnancy disorder, psychosis, Alzheimer disease, cocaine use disorder, asthma, allergic rhinitis, conjuctivitis, rheumatoid arthritis, dermatitis, eczema, osteoarthritis, hypoglycemia, hyperinsulinemia, hyperlipidemia and obesity.

Another embodiment of the invention is a method of eliciting a glucocorticoid receptor modulating effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of any of the compounds or any of the pharmaceutical compositions described herein.

One aspect of this embodiment is the method wherein the glucocorticoid receptor modulating effect is an antagonizing effect.

The compounds of the invention are glucocorticoid receptor antagonists that are preferably liver selective, and as such may be useful in the treatment of diabetes (alone or in combination with agents that stimulate insulin release such as sulfonylureas, influence liver glucose production such as metformin, affect the sensitivity to insulin such as troglitazone, or inhibit glucose absorption such as a-glucosidase inhibitors).

The compounds of the present invention in labelled form, e. g. isotopically labelled, may be used as diagnostic agents.

Further exemplifying the invention is the use of any of the compounds described above in the manufacture or preparation of a medicament for therapeutic treatment or prevention of a disease associated with a metabolism dysfunction, or a disease which is dependent on the expression of a glucocorticoid receptor regulated gene, in a mammal in need thereof. Still further exemplifying the invention is the use of any compounds described above in the manufacture or preparation of a medicament for the therapeutic treatment or prevention of Type 1 insulin dependent diabetes, Type 2 non-insulin dependent diabetes, Cushing's syndrome, inflammation, autoimmune disease, transplant rejection, neoplasm, leukemia, lymphom, Cushings disease, adrenal disease, renal disease, cerebrovascular ischemia, hypercalcemia, cerebral edema, thrombocytopenia, inflammatory bowel disease, wound healing, HIV infection, central nervous system disease, spinal cord tumour, glaucoma, sleep disorder, depression, anxiety disorder, atherosclerosis, hypertension, osteoporosis, occular hypertension, nephrotoxicity, infarction, endometriosis, pregnancy disorder, psychosis, Alzheimer disease, cocaine use disorder, asthma, allergic rhinitis, conjuctivitis, rheumatoid arthritis, dermatitis, eczema, osteoarthritis, hypoglycemia, hyperinsulinemia, hyperlipidemia and obesity.

The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powder, granules, elixirs, tinctures, suspensions, syrups and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, topical (e. g. ocular eyedrop), subcutaneous, intramuscular, or transdermal (e. g. patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts.

The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician, veterinarian or clinician can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of body weight per day (mg/kg/day) to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01,0.05,0.1,0.5,1.0,2.5,5.0,10.0,15.0,25.0, 50.0,100, and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from about 1 mg to about 100 mg of active ingredient. Intravenously, the most preferred doses will range from about 0.1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches or iontophoretic devices well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, exipients or carriers (collectively referred to herein as"carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutical acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like ; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms includes sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include without limitation starch, methylcellulose, agar, bentonite, xanthan gum and the like.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from e. g. phospholipids, cholesterol, stearylamine, or phosphatidylcholines.

The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.

The term"GR antagonist"as used herein is intended to cover any moiety that binds to a glucocorticoid receptor, or a complex of which a glucocorticoid receptor forms a part, and acts as an antagonist or a partial antagonist.

The term"halogen"and"halo", as used herein alone or as part of another group, refers to chlorine, bromine, fluorine, and iodine.

The term"heteroatom"and"hetero", as used herein, refers to nitrogen, oxygen, sulphur, and in heterocyclic rings, also selenium.

The term C1 6-alkyl, as used herein alone or as part of another group, refers to an alkyl group which may be straight or branched. Exemplary C,-6-alkyl groups include, but are not restricted to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and isohexyl.

The term C1 12-alkyl, as used herein alone or as part of another group, refers to an alkyl group which may be straight or branched. Exemplary C1 12-alkyl groups include, but are not restricted to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, isooctyl, nonyl, decyl, isodecyl, undecyl and dodecyl.

The term C3 8-cycloalkyl, as used herein alone or as part of another group, refers to a mono-, or bicyclic alkyl group, which may contain one or more unsaturations (double, and/or triple bonds). Exemplary C3-s-cycloalkyl groups include, but are not restricted to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctynyl, bicycloheptyl, bicyclooctyl, and bicyclooctenyl. It is also understood that a single carbon of the C3 8-cycloalkyl may be common to another C3 8-cycloalkyl or C3-s-heterocycloalkyl, forming a so called spiro-compounds.

The term C2 6-alkenyl, as used herein alone or as part of another group, refers to an alkenyl group which may be straight or branched. Exemplary C2 6-alkenyl groups include, but are not restricted to, vinyl, 1-propenyl, 2-propenyl, propadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 4-pentenyl, and 5-hexenyl.

The termC2-6-alkynyl, as used herein alone or as part of another group, refers to an alkynyl group which may be straight or branched. ExemplaryC2-6-alkynyl groups include, but are not restricted to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-butynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, and 5-hexynyl..

The term 8-heterocycloalkyl, as used herein alone or as part of another group, refers to a mono-, or bicyclic alkyl group which may contain one or more heteroatoms, and which may contain one or more unsaturations (double, and/or triple bonds). Exemplary C3-8-heterocycloalkyl groups include, but are not restricted to, aziridine, azetidine, pyrrolidine, pyrroline, piperidine, tetrahydropyridine, dihydropyridine, pyrazolidine, imidazolidine, imidazoline, piperazine, morpholine, thiomorpholine, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, dihydropyran, 1,3-dioxolan, 1,3-dioxane, 1,4-dioxane, thiirane, thietane, thiolane, 1,3-dithiolane, 1,4-dithiane, 1,3,5-trithiane, quinuclidine, and tropane. It is also understood that a single carbon or nitrogen of the Cs-s-heterocycloalkyl may be common to another C3-8-cycloalkyl-, or Cs-s-heterocycloalkyl-group, forming a so called spiro-compound.

The term aryl is intended to include monocyclic or bicyclic ring systems having from 6 to 10 ring carbon atoms, in which at least one ring is aromatic. Examples of such ring systems are benzene, naphtalene, 1,2,3,4-tetrahydronaphtalene, indan and indene.

The term heteroaryl refers to a mono-, bi-or tricyclic ring system having from 5 to 10 ring atoms, in which at least one ring is aromatic, and in which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur, oxygen and selenium. Examples of such heteroaryl rings include, but are not restricted to, pyrrole, furan, thiophene, pyrazol, imidazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, tetrazol, pyridine, indole, isoindole, indoline, isoindoline, quinoline, 1,2,3,4-tetrahydroquinoline, isoquinoline, 1,2,3,4-tetrahydroiso- quinoline, quinolizine, carbazole, acridine, benzofuran, isobenzofuran, chroman, isochroman, benzothiophene, pyridazine, pyrimidine, pyrazine, indazole, benzimidazole, cinnoline, quinazoline, quinoxaline, phthalazine, 1,5-naphthyridine, 1,8-naphthyridine, phenazine, benzoxazole, 3,4-dihydro-2H-1,4-benzoxazine, benzothiazole, phenothiazine, 1,3-benzodioxole, benzodioxane, 2,1,3-benzoxadiazole, 2,1,3-benzothiazole, 2,1,3-benzo- selenadiazole, purine, and pteridine. The ring system may be linked to the rest of the molecule via a carbon or nitrogen atom thereof.

The compounds of formula I in the invention may contain at least one chiral center and may therefore exist as optical isomers. The invention therefore comprises optically inactive racemic (rac) mixtures (a one to one mixture of enantiomers), optically enriched scalemic mixtures as well as optically pure individual enantiomers. The compounds in the invention also may contain more than one chiral center and therefore may exist as diastereomers.

The invention therefore comprises individual diastereomers as well as any mixture of diastereomers.

The compound of formula I in the invention may contain geometrical isomers and may therefore exist as either the E (entgegen) or Z (zusammen) isomers. The invention therefore comprises individual E or Z isomers as well as any mixture of E and Z isomers.

The compound of formula I in the invention may exist in tautomeric forms, the invention therefore comprises the individual tautomeric forms as well as any mixture thereof.

The compounds of formula I can be present as salts, in particular pharmaceutically acceptable salts. If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as C,-6-alkyl-or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane-or p-toluenesulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.

The compounds of formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di-or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl-or dimethyl-propylamine, or a mono-, di-or trihydroxy lower alkylamine, for example mono-, di-or tri-ethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included.

Preferred salts of the compounds of formula I which include a basic group include monohydrochloride, hydrogensulfate, tartrate, fumarate or maleat.

Preferred salts of the compounds of formula I which include an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.

Also included within the scope of the invention are polymorphs, hydrates, and solvates of the compounds of the instant invention.

The present invention includes within its scope prodrugs of the compounds of this invention.

In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term"administering"shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example in "Design of Prodrugs"ed. H. Bundgaard, Elsevier, 1985, which is incorporated by reference herein in its entirety.

The present invention includes within its scope metabolites of compounds of formula 1.

Metabolites of the compounds includes active species produced upon introduction of compounds of this invention into the biological milieu.

The present invention includes within its scope compounds of formula I in isotopically labelled form.

The compounds of formula I may be prepared by the exemplary processes described in the following reaction schemes. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples.

Compounds of formula I of the invention may be prepared using the sequence of steps outlined in Schemes 1 to 6 set out below. The groups R', R2, R3, R4, R5, R6, R7, R8, R9, R10, and R"in Schemes 1 to 6 are as defined in formula 1. The groups R', R2, R3, R4, R5, R6, R, R8, R9, R10, and R"may be modified one or several times, after or during the preparation of compounds of formula I by methods known in the art. Examples of such methods include, but are not restricted to, substitutions, reductions, oxidations, alkylations, hydrolysis, esterifications and etherifications. E is R', or a group that can be transformed to R'in one or several synthetic steps after or during the preparation of compounds of formula 1, by methods known by a person skilled in the art. Examples of such transformations include, but are not restricted to, nucleophilic substitutions of an alkyl group activated by a halogen or a sulphonic acid ester, hydrolysis of esters or a nitrile to give a carboxylic acid, or the transformation of a nitrile into a tetrazol.

Scheme 1 describes a synthetic route that begins with a coupling reaction between an appropriately substituted iodonium salt 2 and an appropriately substituted phenol 1 to give the diarylether 3. The coupling is preferably catalyzed by metals, preferably Cu, Ni, Pd, or suitable salts, complexes, oxides or hydroxides thereof in the presence of a base. Suitable bases include, but are not restricted to, triethylamine, pyridine, K2CO3 and Cs2CO3.

Alternatives to this ether formation include, but is not restricted to, transition metal catalyzed couplings of phenols with aryl halides or arylboronic acids, or other reactions known by a person skilled in the art. In the next step compound 3 is converted to the ketone 4 by introducing R5CO, e. g. by a Friedel-Crafts reaction of compound 3 with an appropriate acyl halid, carboxylic acid anhydrid, carboxylic acid, or ketene. The reaction is preferably performed in the presence of a Lewis or a Bnsnstedt acid. Suitable acids include, but are not restricted to, H2SO4, polyphosphoric acid, CF3SO3H, TiCl4, AICI3, ZnCl2, BF3OEt2, and the like.. Reduction of the ketone 4 by agents such as NaBH4, NaBH3CN or diisobutylaluminium hydride yields the alcohol 5. The hydroxy group of compound 5 may be converted in one or several synthetic transformations to compound 6. Examples of such conversions include, but are not restricted to, synthetic transformations known to those skilled in the art, such as alkylations, arylations, acylations, and halogenations. If E is RI in compound 6, the said compound equals compounds of formula 1 of the present invention. If E is not RI in compound 6, E is transformed to RI yielding compounds of formula I of the present invention. Such transformations may be performed in one or several synthetic steps and include, but are not restricted to, nucleophilic substitutions (e. g. by cyanides) of an alkyl group activated by a halogen or a sulphonic acid ester (e. g. by mesylate, tosylat or triflate), hydrolysis of esters or a nitrile to give a carboxylic acid, or the transformation of a nitrile into a tetrazol.

Scheme 1. Rz I BFa Rz BF RsYO R2 Y R2 Y R2 3/E R5p//R5 RSO I/R3 I/E' Ra Ra Ra 1 2 3 vil I o I E I\ o I\ I\ o I\ R O R R50 R3 E R5p Ra/E R4 R4 R4 4 6 R6 R7 R2 0 R50WR3 ß R Rua Formula I The RI and R'groups can also be introduced simultanously as depicted in Scheme 2. For example, the intermediate 3 may be allowed to react with an appropriately substituted benshydrol (7, X =OH) or benzydryl halide (7, X =halogen), or similar compounds known to those skilled in the art, to give compound 6 which is converted to compounds of formula I of the present invention, as described in Scheme 1. The reaction in Scheme 2 is preferably performed in the presence of a Lewis or a Bronstedt acid. Suitable acids include, but are not restricted to, H2SO4, polyphosphoric acid, CF3SO3H, p-toluenesulphonic acid, TiCI4, AICI3, ZnCl2, BFsOEt2, and the like. Other compounds, such as 9,10,11,12,13, and 14 (vide infra) may be analogously employed as substrates for this reaction.

Scheme 2. R2 R6 R7 R6 R7 R2 (D-r 7 0 R2 y Y R2 RO R RO R R4 R4 X = OH, halogen etc.

Scheme 3 describes an alternative synthesis to compound 3 in Scheme 1. As in Scheme 1, the synthetic route begins with a coupling reaction, in this case between the iodonium salt 8 and the phenol 1 to give the diarylether 9. The coupling is preferably catalyzed by metals, preferably Cu, Ni, Pd, or suitable salts, complexes, oxides or hydroxides thereof in the presence of a base. Suitable bases include, but are not restricted to, triethylamine, pyridine, K2CO3 and Cs2CO3. Alternatives to this ether formation include, but is not restricted to, transition metal catalyzed coupling of phenols with aryl halides or arylboronic acids, or other reactions known by a person skilled in the art. In the next step diarylether 9 is converted to the ketone 10 by introducing RACO, e. g. by a Friedel-Crafts reaction of diarylether 9 with an appropriate acyl halide, carboxylic acid anhydride, carboxylic acid, or ketene. The reaction is preferably performed in the presence of a Lewis or a Bronstedt acid.

Suitable acids include, but are not restricted to, H2SO4, polyphosphoric acid, CF3SO3H, TiCl4, AICI3, ZnCl2, BF3OEt2, and the like. Compound 10 is converted to compound 11 in one or several synthetic steps by reactions including, but not restricted to, nucleophilic substitutions, reductions, olefinations, oxidations, alkylations, hydrolysis, esterifications and etherifications. When RA, RB and RA, together with the carbon to which they are bound equals R4, compound 11 is the same as compound 3, that may be transformed to compounds of formula I of the present invention by using the synthetic sequences described in Scheme 1.

Scheme 3.

The RACO-group can also be introduced by a so called Fries rearrangement, as described in Scheme 4. In this case 12 is converted to 13 (=10, where R4 is H) in a reaction catalyzed by light or by a Lewis or a Bronstedt acid. Suitable acids include, but are not restricted to, H2SO4, polyphosphoric acid, CF3SO3H, TiCla, AICI3, ZnC12, BF3*Oet2, and the like. Compound 12 can be prepared from 8 or 9 by synthetic transformations known to those skilled in the art.

Scheme 4.

Scheme 5 describes yet another approach to introduce R4 into the molecule. The diarylether 9 is halogenated to give compound 14 (W=halogen). Suitable halogenating agents include, but are not restricted to iodine, Nal/NaOH, bromine, N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin. Compound 14 is converted to compound 3 using one or several synthetic manipulations. Such synthetic manipulations include, but are not restricted to, transition metal catalyzed alkylations, alkenylations, alkynylations, and carbonylations.

Scheme 5 also describes a sequence where the diarylether 9 is nitrated to give compound 14 (W=N02). The nitro group is then transformed in one or several synthetic steps, including, but not restricted to, reductions, diazotations, halogenations, cyanation, acylations, and transition metal catalyzed reactions (as described above) to R4 in compound 3.

Scheme 5.

Scheme 6 depicts an alternative route to synthesize compound 6. The formyl group of 15 may be introduced into 3 by reactions including, but not restricted to, electrophilic substitution reactions. Suitable electrophilic substitution reactions include, but are not restricted to the Vilsmeier reaction (i. E. a combination of an activating agent such as POCI3, COCU2 or (COCI) 2 and an amide such as DMF or N-phenyl-N-methylformamide) or the combination of MeOCHCI2 and TiC14. The Regroup in 6 is introduced by a reaction of 14 with a nucleophile. Suitable nucleophiles include, but are not restricted to Grignard, organo- cerium or organolithium reagents. Compound 6 may be transformed to compounds of formula I of the present invention by using the synthetic sequences described in Scheme 1.

Scheme 6.

Those skilled in the art will readily understand that known variations of the processes described herein and of the experimental conditions, such as solvents, temperatures and times, of the following preparative procedures, can be used to prepare compounds of the formula I of the present invention.

The following working Examples represent preferred but non-limiting embodiments of the present invention.

Synthesis of intermediate 5 in Scheme 1.

Step 1.

Bis(3-isopropyl-4-methoxyphenyl) iodonium tetrafluoroborate.

Fuming nitric acid (22.3 ml, 477 mmol) was added dropwise to 30.8 mL of acetic anhydride cooled in a dry ice/CCI4 bath. Iodine (10.3 g, 40.6 mmol) was added in one portion followed by dropwise addition of trifluoroacetic acid (37.9 mL, 492 mmol). The mixture was stirred at room temperature until the iodine was dissolved and then purged with N2 to remove nitrogen oxides. The mixture was concentrated, the residue dissolved in acetic anhydride (115 mL) and cooled in a dry ice/CC14 bath. A solution of 2-isopropylanisole (30 g, 200 mmol) in acetic anhydride (138 mL) and trifluoroacetic acid (20.5 mL) was added dropwise with stirring. The mixture was left at room temperature overnight and concentrated. The residue was taken up into MeOH (138 mL) and treated with 10% aqueous NaHSO3 (138 mL) and 2M aqueous NaBF4 (0.92 L). After the precipitate had aggregated, petroleum ether was added and the supernatant was decanted. The precipitate was triturated with petroleum ether, filtered, washed with petroleum ether and dried at room temperature under vacuum to afford 14.7 g (71 %) of the title compound.

Similarly prepared were: Bis (3-tert-butyl-4-methoxyphenyl) iodonium tetrafluoroborate and bis (3-cyclopentyl-4-methoxyphenyl) iodonium tetrafluoroborate from 2-tert-butyanisole and 2-cyclopentylanisole, respectively.

Step 2.

3,5-Dibromo-4- (3-isopropyl-4-methoxyphenoxy) phenylacetic acid methyl ester.

A solution of 3,5-dibromo-4-hydroxyphenylacetic acid methyl ester (5.27 g, 17.0 mmol) and triethylamine (1. 89 g, 18.7 mmol) in CH2Cl2 (25 mL) was added dropwise to a mixture of bis (3-isopropyl-4-methoxyphenyl) iodonium tetrafluoroborate (13.0 g, 25.5 mmol) and copper bronze (2.14 g, 33.7 mmol) in CH2CI2 (38 mL) at 0° C. The mixture was stirred in the dark for 4d and filtered through celite. The filtrate was concentrated and the residue purified by chromatography on silica gel (petroleum ether/EtOAc, 98: 2) to give 6.0g (76 %) of the title compound.

Similarly prepared were: 4- (3-tert-butyl-4-methoxyphenoxy)-3, 5-dibromophenylacetic acid methyl ester and 4- (3-cyclopentyl-4-methoxyphenoxy)-3, 5-dibromophenylacetic acid methyl ester from bis (3-tert-butyl-4-methoxyphenyl) iodonium tetrafluoroborate and bis (3-cyclo- pentyl-4-methoxyphenyl) iodonium tetrafluoroborate, respectively.

Step 3.

4- (2-Benzoyl-5-isopropyl-4-methoxyphenoxy)-3, 5-dibromophenylacetic acid methyl ester.

TiC14 (13.9 mL, 127 mmol) was added dropwise to a solution of 3,5-dibromo-4- (3-isopropyl-4-methoxyphenoxy) phenylacetic acid methyl ester (20.0 g, 42.3 mmol) and benzoyichloride (17.8 g, 127 mmol) in CH2CI2 (250 mL) at 0 °C. The mixture was stirred at room temperature for 5 d, cooled to 0 °C and quenched carefully with water (50 mL). NaHCO3 (aq., sat, 100 mL) was added, the mixture stirred at room temperature for 1 h and extracted with EtOAc (3x100 mL). The combined extracts were concentrated and purified by chromatography on silica gel to give 15.2 g (62%) of the title compound.

Similarly prepared were: 3,5-Dibromo-4- [5-isopropyl-4-methoxy-2- (3-methylbenzoyl) phenoxy] phenylacetic acid methyl ester, 3,5-dibromo-4- [2- (3, 5-dimethylbenzoyl-5-isopropyl-4-methoxy) phenoxy] phenyl- acetic acid methyl ester, 4- [5-tert-butyl-4-methoxy-2- (3-methyl- benzoyl) phenoxy]-3, 5-dibromophenylacetic acid methyl ester, and 4- [5-cyclo- pentyl-4-methoxy-2- (3-methylbenzoyl) phenoxy]-3, 5-dibromophenylacetic acid methyl ester from an appropriately substituted benzoyl chloride and 3,5-dibromo-4- (3-isopropyl-4-methoxyphenoxy) phenylacetic acid methyl ester, 4- (3-tert-butyl-4-methoxyphenoxy)-3, 5-dibromophenylacetic acid methyl ester, or 4- (3-cyclopentyl-4-methoxyphenoxy)-3, 5-dibromophenylacetic acid methyl ester respectively.

Step 4.

3,5-Dibromo-4-f2- [hydroxy (phenyl) methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid.

NaOH (2M, 43.4 mmol) was added to a stirred slurry of 4- (2-benzoyl-5-isopropyl-4-methoxyphenoxy)-3, 5-dibromophenylacetic acid methyl ester (5.5 g, 9.55 mmol) in MeOH (75 mL) at room temperature. The mixture was stirred for 19 h and NaBH4 (3.3 g, 86.8 mmol) was added in one portion. Aftyer 3 h the mixture was cooled in an ice-bathand quenched by careful addition of concentrated HCI (8 mL). Toluene (80 mL) was added and more HCI was added until pH 5. EtOAc (40 mL) was added, the layers separated and the aqueous phase extracted with EtOAC (2x50 mL). The combined organic phases were washed with 10 % HCI and brine, and concentrated to give 4.6 g (85 %) of the title compound as a white solid.

Similarly prepared were: 3,5-Dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl -4-methylphenoxy}phenyl- acetic acid, 3,5-dibromo-4- {2- [hydroxy (3,5-dimethylphenyl) methyl]-5-iso- propyl-4-methoxyphenoxy} phenylacetic acid, 4- 5-tert-butyl-2- [hydroxy (3-methyl- phenyl)methyl]-4-methoxyphenoxy}-3,5-dibromophenylacetic acid, 4- 5-cyclopentyl-2- [hydroxy (3-methylphenyl) methyl]-4-methoxyphenoxy}-3, 5-dibromophenyl acetic acid from 3,5-dibromo-4- [5-isopropyl-4-methoxy-2- (3-methylbenzoyl) phenoxy] phenyl- acetic acid methyl ester, 3,5-dibromo-4- [2- (3, 5-dimethylbenzoyl-5-isopropyl-4-methoxy)- phenoxy] phenylacetic acid methyl ester, 4-[5-tert-butyl-4-methoxy-2-(3-methyl- benzoyl) phenoxy]-3, 5-dibromophenylacetic acid methyl ester, and 4- [5-cyclo- pentyl-4-methoxy-2- (3-methylbenzoyl) phenoxy]-3, 5-dibromophenylacetic acid methyl ester, respectively.

General procedure for Examples 1-60 : An aromatic compound (1 eq.) followed by tin (II) chloride dihydrate (1 eq.) is added to a solution of 3, 5-dibromo-4- [5-alkyl-2- (aryl-hydroxymethyl)-4-methoxyphenoxy] phenylacetic acid (0.1 eq.), prepared as described above, in CH2CI2. The mixture is stirred at room temperature for two days, poured into water, and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried with Mg2SO4 and concentrated. The residue is purified by chromatography to give the title compounds.

Example 1.3. 5-Dibromo-4-{2-[(4-hydroxyphenyl)(phenyl)methyl]-5-isopropyl -4-methoxy- phenoxy}phenylacetic acid (E1).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(phenyl)methyl]-5-isopropyl-4-methoxy phenyl}- phenylacetic acid and phenol.'H NMR (CDCI3) : # 7.47 (s, 2H), 7.25-7.20 (m, 4H), 7.05 (d, 2H), 6.73 (d, 2H), 6.44 (s, 1H), 6.10 (s, 1H), 6.05 (s, 1H), 3.63 (s, 2H), 3.57 (s, 3H), 3.13 (m, 1 H), 1.01 (d, 6H). ESMS: m/z 639 (M-1).

Example 2.

3,5-Dibromo-4-{2-[(5-fluoro-2-hydroxyphenyl)(phenyl)methy l]-5-isopropyl-4-methoxyphenoxy lphenylacetic acid (E2).

Prepared from 3,5-dibromo-4-{2-[hydroxy (phenyl) methyl]-5-isopropyl-4-methoxyphenoxy}- phenylacetic acid and 4-fluorophenol. H'-NMR (DMSO-d6) : 8 7.65 (d, 2H), 7.30-7.15 (m, 5H), 6.90-6.75 (m, 2H), 6.55 (dd, 1 H), 6.40 (s, 1 H), 6.25 (s, 1 H), 6.05 (s, 1 H), 3.60 (s, 2H), 3.50 (s, 3H), 3.10-3.05 (m, 1H), 0.95 (t, 6H).

ESMS : m/z 657 (M-1).

Example 3. 4-{2-[(4-Chloro-2-hydroxyphenyl)(phenyl)methyl]-5-isopropyl- 4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (E3).

Prepared from 3,5-dibromo-4-{2-[hydroxy (phenyl) methyl]-5-isopropyl-4-methoxyphenoxy}- phenylacetic acid and 3-chlorophenol.'H NMR (DMSO-d6) : 8 9.3 (s, 1H), 7.5 (s, 2H), 7.2-7.0 (m, 5H), 6.8-6.77 (m, 2H), 6.61 (dd, 1H), 6.3 (s, 1H), 6.2 (s, 1H), 6.0 (s, 1H), 3.6 (s, 2H), 3.5 (s, 3H), 3.06 (m, 1H), 0.94 (m, 6H).

ESMS: m/z 673 (M-1).

From the reaction mixture the following compound was also isolated : Example 4. 4-12- [(2-Chloro-4-hydroxyphenyl)(phenyl)methyl]-5-isopropyl-4-met hoxy@ phenoxy}-3. 5-dibromophenylacetic acid (E4). 'H NMR (DMSO-d6) : # 9.9 (s, 1H), 7.66 (d, 2H), 7.3-7.0 (m, 5H), 6.8 (m, 3H), 6.4 (s, 1H), 6.2 (s, 1 H), 6.0 (s, 1 H), 3.6 (s, 2H), 3.4 (s, 3H), 3.07 (m, 1 H), 0.94 (m, 6H). ESMS: m/z 673 (M-1).

Example 5. 4-{2-[(5-Chloro-2-hydroxyphenvl) (phenyl) methyl]-5-isopropyl-4-methoxy- phenoxyT-3, 5-dibromophenylacetic acid (E5).

Prepared from 3,5-dibromo-4-{2-[hydroxy (phenyl) methyl]-5-isopropyl-4-methoxyphenoxy}- phenylacetic acid and 4-chlorophenol. ESMS: m/z 673 (M-1).

Example 6.

3,3,5-Dibromo-4-{2-[(3,4-difluro-2-hydroxyphenyl)(phenyl) methyl]-5-isopropyl-4-methoxyphenyl oxy} phenylacetic acid (E6).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(phenyl)methyl]-5-isopropyl-4-methoxy phenoxy}- phenylacetic acid and 2,3-difluorophenol. H1-NMR (DMSO-d6) : 8 7.65 (s, 2H), 7.40-7.10 (m, 5H), 6.80-6.60 (m, 2H), 6.40 (s, 1H), 6.15 (s, 1H), 6.05 (s, 1H), 3.60 (s, 2H), 3.55 (s, 3H), 3.15-3.00 (m, 1H), 0.95 (t, 6H). ESMS: m/z675 (M-1).

Example 7.

3,5-Dibromo-4-{2-[(4,5-difluoro-2-hydroxyphenyl)(phenyl)m ethyl]-5-isopropyl-4-methoxyphen oxy}phenylacetic acid (E7).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(phenyl)methyl]-5-isopropyl-4-methoxy phenoxy}- phenylacetic acid and 3,4-difluorophenol. H1-NMR (DMSO-d6) : 8 7.65 (d, 2H), 7.35-7.10 (m, 5H), 6.75-6.70 (m, 2H), 6.40 (s, 1H), 6.20 (s, 1H), 6.05 (s, 1H), 3.50 (s, 3H), 3.45 (s, 2H), 3.15-3.00 (m, 1H), 0.95 (t, 6H). ESMS: m/z 675 (M-1).

Example 8.

3.5-Dibromo-4-{2-[(4,5-dimethyl-2-hydroxyphenyl)(phenyl)m ethyl]-5-isopropyl-4-methoxyphe noxy}phenylacetic acid (E8).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(phenyl)methyl]-5-isopropyl-4-methoxy phenoxy}- phenylacetic acid and 2, 3-dimethylphenol. 1H NMR (DMSO-d6) : 6 8.9 (s, 1H), 7.7 (s, 2H), 7.2-7.0 (m, 5H), 6.62 (s, 1H), 6.57 (s, 1H), 6.47 (s, 1H), 6.2 (s, 1H), 6.0 (s, 1H), 3.7 (s, 2H), 3.5 (s, 3H), 3.07 (m, 1H), 2.1 (s, 3H), 2.0 (s, 3H), 0.94 (m, 6H). ESMS: m/z 667 (M-1).

Example 9.

3,5-Dibromo-4-{2-[(2-hydroxy-4-methoxyphenyl)(phenyl)meth yl]-5-isopropyl-4-methoxyphen oxy}phenylacetic acid (E9).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(phenyl)methyl]-5-isopropyl-4-methoxy phenoxy}- phenylacetic acid and 4-methoxyphenol. 1H NMR (CDCl3) : 8 7.5 (s, 2H), 7.3-7.2 (m, 5H), 6.8-6.7 (m, 2H), 6.58-6.45 (m, 2H), 6.15 (s, 1H), 6.13 (s, 1H), 3.7 (s, 3H), 3.62 (s, 2H), 3.57 (s, 3H), 3.2-3.1 (m, 1H), 1.1-0.9 (m, 6H). ESMS: m/z 669 (M-1).

Example 10.

3,5-Dibromo-4-{2-[(3-indolyl)(phenyl)methyl]-5-isopropyl- 4-methoxyphenoxy}phenylacetic acid E10).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(phenyl)methyl]-5-isopropyl-4-methoxy phenoxy}- phenylacetic acid and indole. 1H NMR (CDCI3) : # 7.9 (s, 1H), 7.5 (s, 2H), 7.35-7.1 (m, 8H), 6.6 (m, 1H), 6.7 (d, 1H), 6.6 (s, 1H), 6.25 (s, 1H), 6.1 (s, 1H), 3.6 (s, 2H), 3.5 (s, 3H), 3.1 (m, 1H), 1.0 (m, 6H). ESMS : m/z 662 (M-1).

Example 11.

3,5-Dibromo-4-{2-[(4-hydroxyphenyl)(3-methylphenyl)methyl ]-5-isopropyl-4-methoxy- phenoxy}phenylacetic acid (E11).

Prepared from 3,5-dibromo-4- {2- [hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and phenol. 1H NMR (CDCI3) : 8 7.48 (s, 2H), 7.15-6.75 (m, 8H), 4.48 (s, 1H), 6.09 (s, 1H), 6.05 (s, 1H), 363 (s, 2H), 3.57 (s, 3H), 3.13 (m, 1H), 2.28 (s, 3H), 1.05 (d, 6H). ESMS: m/z 653 (M-1).

Example 12.

3,5-Dibromo-4-{2-[(3-fluoro-2-hydroxyphenyl)(3-methylphen yl)methyl]-5-isopropyl-4-methoxy phenoxy]phenylacetic acid (E12).

Prepared from 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxyphenoxy} phenyl- acetic acid and 2-fluorophenol. ESMS: m/z 671 (M-1).

Example 13.

3,5-Dibromo-4-{2-[(4-Fluoro-2-hydroxyphenyl)(3-methylphen yl)methyl]-5-isopropyl-4-methoxy phenoxy} pheny) acetic acid (E13).

Prepared from 3,5-dibromo-4-{2-hydroxy(3-methylphenyl)methyl]-5-isopropyl- 4-methoxyphenoxy}phenyl- acetic acid and 3-fluorophenol. ESMS: m/z 671 (M-1).

Example 14.

3,5-Dibromo-4-{2-[(5-fluoro-2-hydroxyphenyl)(3-methylphen yl)methyl]-5-isopropyl-4-methoxy phenoxy}phenylacetic acid (E14).

Prepared from 3,5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl -4-methoxyphenoxy}phenyl- acetic acid and 4-fluorophenol.'H NMR (CD30D) : 8 7.57 (br. s, 2H), 7.15 (t, 1H), 6.96 (m, 3H), 6.81 (t, 1H), 6.52 (d, 1H), 6.47 (t, 1H), 6.43 (s, 1H), 6.29 (s, 1H), 6.08 (s, 1H), 3.64 (s, 2H), 3.55 (s, 3H), 3.15 (hep, 1H), 2.28 (s, 3H), 0.99 (d, 6H). ESMS: m/z 671 (M-1).

Example 15. <BR> <BR> <P>4- {2- [ (3-Chloro-2-hydroxyphenyl) (3-methylphenyi) methyl]-5-isopropyl-4-methoxyphenoxy}-3.

5-dibromophenylacetic acid (E15 !.

Prepared from 3,5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl -4-methoxyphenoxy}phenyl- acetic acid and 2-chlorophenol.'H NMR (CD30D) : # 7.57 (d, 2H), 7.17 (t, 1H), 6.98 (m, 3H), 6.75 (m, 2H), 6.53 (m, 1H), 6.42 (s, 1H), 6.31 (s, 1H), 6.11 (s, 1H), 3.62 (s, 2H), 3.55 (s, 3H), 3.15 (hep, 1 H), 2.29 (s, 3H), 1.00 (t, 6H). ESMS: m/z 687 (M-1).

Example 16.

4-{2-[(4-Chloro-2-hydroxyphenyl)(3-methylphenyl)methyl]-5 -isopropyl-4-methylphenoxy}-3, 5-dibromophenylacetic acid (E16).

Prepared from 3,5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl -4-methoxyphenoxy}phenyl- acetic acid and 3-chlorophenol. ESMS: m/z 687 (M-1).

Example 17. <BR> <BR> <P>4- {2- [(5-Chloro-2-hydroxyphenyl) 3-methylphenyl) methyl]-5-isopropyl-4-methoxyphenoxy}-3 5-dibromophenylacetic acid (E17).

Prepared from 3,5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl -4-methoxyphenoxy}phenyl- acetic acid and 4-chlorophenol. 1H NMR (CD30D) : 8 7.58 (br. s, 2H), 7.15 (t, 1H), 6.97 (m, 3H), 6.77 (m, 3H), 6.42 (s, 1H), 6.29 (s, 1H), 6.10 (s, 1H), 3.59 (s, 2H), 3.55 (s, 3H), 3.14 (hep, 1 H), 2.28 (s, 3H), 1.00 (d, 6H).

ESMS: m/z 687 (M-1).

Example 18.

4-{2-[(3-Bromo-2-hydroxyphenyl)(3-methylphenyl)methyl]-5- isopropyl-4-methoxyphenoxy}-3, 5-dibromophenylacetic acid (E18).

Prepared from 3,5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl -4-methoxyphenoxy}phenyl- acetic acid and 2-bromophenol.'H NMR (CD30D) : 8 7.57 (d, 2H), 7.17 (t, 1H), 6.87-7.09 (m, 3H), 6.75 (t, 3H), 6.40 (s, 1H), 6.27 (s, 1H), 6.10 (s, 1H), 3.61 (s, 2H), 3.55 (s, 3H), 3.16 (hep, 1H), 2.30 (s, 3H), 1.00 (t, 6H).

ESMS : m/z 732 (M-1).

Example 19.

4-{2-[(4-Bromo-2-hydroxyphenyl)(3-methylphenyl)methyl]-5- isopropyl-4-methoxyphenoxy}-3, 5-dibromophenylacetic acid (E19).

Prepared from 3,5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl -4-methoxyphenoxy}phenyl- acetic acid and 3-bromophenol.'H NMR (CD30D) : 8 7.60 (s, 2H), 7.18 (br. s, 2H), 6.99 (m, 4H), 6.83 (d, 1H), 6.46 (s, 1H), 6.12 (s, 1H), 5.95 (s, 1 H), 3.63 (s, 2H), 3.57 (s, 3H), 3.15 (hep, 1H), 2.30 (s, 3H), 1.00 (t, 6H) ESMS: m/z 732 (M-1).

Example 20.

4-{2-[(5-Bromo-2-hydroxyphenyl)(3-methylphenyl)methyl]-5- isopropyl-4-methoxyphenoxy}-3, 5-dibromophenylacetic acid (E20).

Prepared from 3,5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl -4-methoxyphenoxy}phenyl- acetic acid and 4-bromophenol.'H NMR (CDsOD) : 8 7.57 (br. s, 2H), 7.15 (t, 1H), 6.83-7.08 (m, 5H), 6.75 (d, 1H), 6.42 (s, 1H), 6.28 (s, 1H), 6.10 (s, 1H), 3.56 (s, 2H), 3.55 (s, 3H), 3.14 (hep, 1H), 2.28 (s, 3H), 0.99 (d, 6H). ESMS: m/z 732 (M-1). Example 21.3. 5-Dibromo-4-{2-[(4,6-dichloro-2-hydroxyphenyl)(3-methylpheny l)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E21).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl-4 -methoxy- phenoxy} phenylacetic acid and 3, 5-dichlorophenol. 1H NMR (CD30D) : 8 7.58 (d, 2H), 7.19 (t, 1H), 7.05 (d, H), 6.97 (s, 1H), 6.92 (s, 1H), 6.91 (s, H), 6.87 (s, H), 6.38 (s, H), 6.21 (s, H), 6.11 (s, H), 3.59 (s, H), 3.55 (s, 3H), 3.16 (hep, 1H), 2.30 (s, 3H), 1.00 (t, 6H). ESMS : m/z 722 (M-1).

Example 22. 3,5-Dibromo-4-{2-[()2-hydroxy-3-methylphenyl)(3-methylphenyl )= methyl]-5-isopropyl-4-methoxyphenoxy}phenylacetic acid E22).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl-4 -methoxy- phenoxy} phenylacetic acid and o-cresol. 1H NMR (CD30D) : 8 7.59 (s, 2H), 7.15 (t, 1H), 6.97 (br. s, 1H), 6.97 (m, 3H), 6.78 (br. s, 1H), 6.67 (d, 1H), 6.49 (s, 1H), 6.12 (s, 1H), 5.94 (s, 1H), 3.56 (s, 3H), 3.54 (s, 2H), 3.13 (hep, 1H), 2.28 (s, 3H), 2.13 (s, 3H), 1.00 (d, 6H).

ESMS: m/z 667 (M-1). Example 23. 3,5-Dibromo-4-{2-[(3,4-dimethyl-2-hydroxyphenyl)(3-methylphe nyl)- methyl]-5-isopropyl-4-methoxyphenoxy}phenylacetic acid (E23). Prepared from 3,5-dibromo-4- {2- [hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and 2,3-dimethylphenol. ESMS : m/z681 (M-1).

Example 24. 3,5-Dibromo-4-{2-[(3,5-dimethyl-2-hydroxyphenyl)(3-methylphe nyl)- methvl]-5-isopropyl-4-methoxvphenoxyyphenvlacetic acid (E24).

Prepared from 3,5-dibromo-4- {2- [hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and 2,4-dimethylphenol.'H NMR (CDsOD) : 8 7.57 (s, 2H), 7.13 (t, 1H), 6.94 (m, 3H), 6.65 (d, 1H), 6.58 (d, 1H), 6.44 (s, 1H), 6.35 (s, 1H), 6.09 (s, 1H), 3.60 (s, 2H), 3.53 (s, 3H), 3.14 (hep, 1H), 2.27 (s, 3H), 2.24 (s, 3H), 2.14 (s, 3H), 0.99 (dd, 6H).

ESMS : m/z 681 (M-1).

Example 25. 3, 5-Dibromo-4-{2-[(3,6-dimethyl-2-hydroxyphenyl)(3-methylpheny l)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E25).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl-4 -methoxy- phenoxy} phenylacetic acid and 2, 5-dimethylphenol. 1H NMR (CDsOD) : 8 7.56 (s, 2H), 7.14 (t, 1H), 6.98 (m, 2H), 6.92 (br. s, 1H), 6.80 (s, 1H), 6.52 (s, 1H), 6.44 (s, 1H), 6.35 (s, 1H), 6.09 (s, 1H), 3.63 (s, 2H), 3.53 (s, 3H), 3.14 (hep, 1H), 2.28 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 1.00 (d, 6H). ESMS: m/z 681 (M-1).

Example 26. 3,5-Dibromo-4-{2-[(4,5-dimethyl-2-hydroxyphenyl)(3-methylphe nyl)- methyl]-5-isopropyl-4-methoxyphenoxy}phenylacetic acid (E26).

Prepared from 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and 2, 3-dimethylphenol. 1H NMR (CDCI3) : 8 7.5 (s, 2H), 7.2-7.0 (m, 4H), 6.7 (s, 1H), 6.6 (s, 1H), 6.5 (s, 1H), 6.2 (s, 1H), 6.1 (s, 1H), 3.6 (m, 5H), 3.15 (m, 1H), 2.3 (s, 3H), 2.2 (s, 3H), 2.1 (s, 3H), 1.0 (m, 6H).

ESMS: m/z 681 (M-1).

Example 27. 3,5-Dibromo-4-{2-[(4,6-dimethyl-2-hydroxyphenyl)(3-methylphe nyl) methyl]-5-isopropyl-4-methoxyphenoxy}phenylacetic acid (E27).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl-4 -methoxy- phenoxy} phenylacetic acid and 3, 5-dimethylphenol. 1H NMR (CDsOD) : 8 7.57 (d, 2H), 7.15 (t, 1H), 6.81-7.06 (m, 3H), 6.60 (s, 1H), 6.57 (s, 1H), 6.40 (s, 1H), 6.09 (s, 1H), 6.02 (s, 1H), 3.63 (s, 2H), 3.53 (s, 3H), 3.15 (hep, 1H), 2.27 (s, 3H), 2.14 (s, 3H), 2.05 (s, 3H), 1.00 (t, 6H). ESMS : m/z 681 (M-1).

Example 28.

3,5-Dibromo-4-{2-[(5-ethyl-2-hydroxyphenyl)(3-methylpheny l)methyl]-5-isopropyl-4-methoxy phenoxy} pheny) acetic acid (E28).

Prepared from 3,5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl -4-methoxyphenoxy}phenyl- acetic acid and 4-ethylphenol.'H NMR (CDCI3) : 8 7.48 (s, 2H), 7.24-6.77 (m, 6H), 6.51 (m, 2H), 6.14 (s, 1H), 6.09 (s, 1H), 3.63 (s, 2H), 3.57 (s, 3H), 3.16 (m, 1H), 2.51 (q, 2H), 2.29 (s, 3H), 1.05 (t, 3H), 1.02 (m, 6H).

ESMS : m/z 681 (M-1).

Example 29.

4-{2-[(5-tert-Butyl-2-hydroxyphenyl)(3-methylphenyl)methy l]-5-isopropyl-4-methoxyphenoxy}- 315-dibromophenylacetic acid (E29).

Prepared from 3,5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl -4-methoxyphenoxy}phenyl- acetic acid and 4-tert-butylphenol.'H NMR (CDCI3) : 8 7.53 (s, 2H), 7.24-6.96 (m, 6H), 6.76 (d, 1H), 6.53 (s, 1H), 6.19 (s, 1H), 6.14 (s, 1H), 3.66 (s, 2H), 3.57 (s, 2H), 3.15 (m, 1H), 2.28 (s, 3H), 1.17 (s, 9H), 1.03 (m, 6H).

ESMS: m/z 709 (M-1).

Example 30. 4-[2-({5-[2-(Carboxymethyl)ethyl]-2-hydroxyphenyl}{3-methylp henyl}- methyl)-5-isopropyl-4-methoxyphenoxv]-3. 5-dibromophenylacetic acid (E30).

Prepared from 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxyphenoxy} phenyl- acetic acid and methyl 3- (4-hydroxyphenyl) propionate. ESMS: m/z 739 (M-1). Example 31. 3,5-Dibromo-4-{2-[(2,4-dihydroxyphenyl)(3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy}phenylacetic acid (E31).

Prepared from 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and resorcinol.'H NMR (CD30D) : 8 7.56 (s, 2 H), 7. 12 (t, 1 H), 6.94 (m, 3 H), 6.63 (d, 1 H), 6.46 (s, 1 H), 6.16-6.36 (m, 3 H), 6.08 (s, 1 H), 3.59 (s, 2 H), 3.55 (s, 3 H), 3.14 (hep, 1 H), 2.27 (s, 3 H), 0.99 (d, 6 H). ESMS: m/z 669 (M-1).

Example 32. 3,5-Dibromo-4-{2-[(2-hydroxy-4-methoxyphenyl)(3-methylphenyl )- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E32).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl-4 -methoxy- phenoxy} phenylacetic acid and 3-methoxyphenol.'H NMR (DMSO-d6) : # 9.4 (br. s, 1 H), 7.6 (s, 2H), 7.2-6.7 (m, 5H), 6.4-6.3 (m, 3H), 6.16 (s, 1H), 6.01 (s, 1H), 3.7 (s, 3H), 3.66 (s, 2H), 3.5 (s, 3H), 3.2-3.1 (m, 1H), 2.24 (s, 3H), 0.95 (m, 6H). ESMS: m/z 683 (M-1). Example 33. 3, 5-Dibromo-4- {2- [(2-hydroxy-5-methoxyphenyl (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy}phenylacetic acid (E33).

Prepared from 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} acetic acid and 4-methoxyphenol. 1H NMR (CDCI3) : 8 8.00 (s, 1H), 7.47 (s, 2H), 7.24-6.51 (m, 7H), 6.13 (s, 1H), 6.10 (s, 1H), 3.67 (s, 2H), 3.57 (s, 3H), 2.28 (s, 3H), 1.02 (d, 6H). ESMS: m/z 683 (M-1).

Example 34. 3,5-Dibromo-4-{2-[(2-hydroxy-4-trifluoromethoxyphenyl)(3-met hylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E34).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl-4 -methoxy- phenoxy} phenylacetic acid and 3-trifluoromethoxyphenol. 1H NMR (CDsOD) : 8 7.64 (s, 2H), 6.92 (s, 1H), 6.85-7.21 (m, 4H), 6.72 (s, 1H), 6.40 (s, 1H), 6.34 (s, 1H), 6.13 (s, 1H), 6.11 (s, 1H), 3.60 (s, 2H), 3.54 (s, 3H), 3.16 (hep, 1H), 2.30 (s, 3 H), 1.00 (dd, 6H). ESMS: m/z 737 (M-1).

From the reaction mixture the following compound was also isolated : Example 35.3, 5-Dibromo-4-{2-[(2-hydroxy-6-trifluoromethoxyphenyl)(3-methy lphenyl methyl]-5-isopropyl-4-methoxyphenoxy}phenylacetic acid (E35). 'H NMR (CDsOD) : 8 7.57 (s, 2H), 7.17 (t, 1H), 7.03 (d, 1H), 6.91 (m, 3H), 6.71 (m, 2H), 6.39 (s, 1H), 6.20 (s, H), 6.10 (s, 1H), 3.61 (s, 2H), 3.55 (s, 3H), 3.15 (hep, 1H), 2.28 (s, 3H), 0.99 (t, 6H). ESMS : m/z 737 (M-1). Example 36.3. 5-Dibromo-4-{2-[(5-benzyloxy-2-hydroxyphenyl)(3-methylphenyl )- methyl]-5-isopropyl-4-methoxyphenoxy}phenylacetic acid (E36).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl-4 -methoxy- phenoxy} phenylacetic acid and 4-benzyloxyphenol. 1H NMR (CD30D) : à 7.59 (d, 2H), 6.71-7.24 (m, 12H), 6.48 (s, 1H), 6.41 (s, 1H), 6.10 (d, 1H), 3.63 (s, 2H), 3.57 (s, 2H), 3.50 (s, 3H), 3.13 (hep, 1H), 2.28 (d, 3H), 0.99 (t, 6H).

ESMS : m/z 759 (M-1). Example 37. 3,5-Dibromo-4-{2-[(2-hydroxy-3-methoxy-6-methylphenyl)(3-met hyl- phenyl)methyl]-5-isopropyl-4-methoxyphenoxy}phenylacetic acid (E37).

Prepared from 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and 2-methoxy-5-methylphenol. 1H NMR (CD30D) : # 7.58 (br. s, 2H), 7.16 (t, 1H), 6.85-7.07 (m, 3H), 6.76 (s, 1H), 6.44 (s, 1H), 6.41 (s, 1H), 6.09 (s, 1H), 6.04 (s, 1H), 3.83 (s, 3H), 3.64 (s, 2H), 3.55 (s, 3H), 3.15 (hep, 1H), 2.28 (s, 3H), 2.17 (s, 3H), 1.00 (d, 6H). ESMS: m/z 697 (M-1). Example 38. 3,5-Dibromo-4-{2-[(2-hydroxy-3,4-dimethoxyphenyl)(3-methyl- phenyl) methyl]-5-isopropvl-4-methoxyphenoxy} phenylacetic acid (E38. Prepared from 3,5-dibromo-4- {2- [hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and 2,3-dimethoxyphenol. ESMS: m/z 713 (M-1). Example 39. 3,5-Dibromo-4-{2-[(2-hydroxy-4,6-dimethoxyphenyl)(3-methyl- phenyl ? methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E39).

Prepared from 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and 3,5-dimethoxyphenol. 1H NMR (CD30D) : 8 7.57 (d, 2 H), 7.15 (t, 1 H), 6.96 (m, 3 H), 6.50 (s, 1 H), 6.48 (s, 2 H), 6.27 (s, 1 H), 6.10 (s, 1 H), 3.79 (s, 3 H), 3.62 (s, 2 H), 3.58 (s, 3 H), 3.56 (s, 3 H), 3.15 (hep, 1 H), 2.28 (s, 3 H), 0.99 (d, 6 H).

ESMS: m/z 713 (M-1).

Example 40. 3,5-Dibromo-4-{2-[(2-hydroxy-4,5,6-trimethoxyphenyl)(3-methy l- phenyl)methyl]-5-isopropyl-4-methoxyphenoxy}phenylacetic acid (E40). Prepared from 3,5-dibromo-4- {2- [hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and 3,4,5-trimethoxyphenol.

ESMS: m/z 743 (M-1).

Example 41. 3,5-Dibromo-4-{2-[(2-hydroxy-4,5-methylenedioxyphenyl)(3-met hyl- phenyl)methyl]-5-isopropyl-4-methoxyphenoxy}phenylacetic acid (E41).

Prepared from 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and 3,4-methylenedioxyphenol.'H NMR (CD30D) : 8 7.58 (d, 2H), 7.06 (t, 1H), 6.92 (m, 3H), 6.76 (s, 1H), 6.46 (s, 1H), 6.11 (s, 2H), 6.05 (s, 1H), 4.80 (s, 2H), 3.59 (s, 3H), 3.47 (s, 2H), 3.13 (hep, 1H), 2.25 (s, 3H), 0.99 (dd, 6H). ESMS: m/z 697 (M-1).

From the reaction mixture the following compound was also isolated: Example 42. 3,5-Dibromo-4-{2-[(2-hydroxy-5,6-methylenedioxyphenyl)(3-met hyl- phenyl)methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (E42).

ESMS: m/z 697 (M-1).

Example 43. 3,5-Dibromo-4-{2-[(2,4-dimethoxyphenyl)(3-methylphenyl)methy l]-5-iso- propyl-4-methoxyphenoxy} phenylacetic acid (E43).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl-4 -methoxy- phenoxy} phenylacetic acid and 2,3-dimethoxybenzene.'H NMR (CDCI3) 5 7.50 (s, 2H), 7.10-7.15 (m, 1H), 6.95-7.00 (m, 2H), 6.90-6.95 (m, 1H), 6.85 (d, 1H), 6.40-6.45 (m, 2H), 6.35-6.40 (m, 1H), 6.30 (s, 1H), 6.10 (s, 1H), 3.80 (s, 3H), 3.70 (s, 3H), 3.60-3.65 (m, 5H), 3.10-3.20 (m, 1H), 2.30 (s, 3H), 1.05 (d, 6H).

ESMS: m/z 697 (M-1).

Example 44. 3, 5-Dibromo-4-(2-{[4-(dimethylamino)phenyl]-[3-methylphenyl]me thyl}-5-iso propyl-4-methoxyphenoxv) phenylacetic acid (E44).

Prepared from 3, 5-dibromo-4-{2-hydroxy(3-methylphenyl)methyl]-5-isopropyl-4- methoxy- phenoxy} phenylacetic acid and NN-dimethylaminobenzene.'H NMR (CDCl3) # 7.50 (s, 2H), 7.00-7.15 (m, 6H), 6.75 (d, 2H), 6.50 (s, 1H), 6.10 (s, 1H), 5.90 (s, 1H), 3.60 (s, 5H), 3.10-3.20 (m, 1H), 2.90 (s, 6H), 2.25 (s, 3H), 1.00 (d, 6H). ESMS: m/z 680 (M-1). Example 45.3. 5-Dibromo-4-(2-{[2-hydroxy-5-(1-pyrrolo)phenyl]-[3-methylphe nyl]- methyl}-5-isopropyl-4-methoxyphenoxy) phenvlacetic acid (E45).

Prepared from 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and 1-(4-hydroxyphenyl)pyrrole.

ESMS : m/z 718 (M-1).

Example 46.

4-{2-[(3-amino-2-hydroxy-1-naphthyl)(3-methylphenyl)methy l]-5-isopropyl-4-methoxyphenoxy -3,5-dibromophenylacetic acid (E46).

Prepared from 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxyphenoxy} phenyl- acetic acid and 3-amino-2-naphtol. ESMS: m/z 718 (M-1).

Example 47.

3,5-Dibromo-4-{2-[(3-indolyl)(3-methylphenyl)methyl]-5-is opropyl-4-methoxyphenoxy}phenyl acetic acid (E47).

Prepared from 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and indole. 1H NMR (CDCI3) : 8 7.9 (br. s, 1H), 7.5 (s, 2H), 7.4-7.2 (m, 3H), 7.2-7.1 (m, 3H), 7.0-6.9 (m, 2H), 6.7 (s, 1H), 6.6 (s, 1H), 6.2 (s, 1H), 6.1 (s, 1H), 3.6 (s, 2H), 3.5 (s, 3H), 3.1 (m, 1H), 2.3 (s, 3H), 1.0 (m, 6H). ESMS: m/z 676 (M-1).

Example 48.

4-{2-[(5-Bromo-3-indolyl)(3-methylphenyl)methyl]-5-isopro pyl-4-methoxyphenoxy}-3,5-dibro mophenylacetic acid (E48).

Prepared from 3,5-dibromo-4- {2- [hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and 5-bromoindole. 1H NMR (CDCl3) : # 8.0 (d, 1H), 7.53-7.49 (m, 3H), 7.21-6.99 (m, 6H), 6.78 (d, 1H), 6.6 (s, 1H), 6.2 (s, 1H), 6.1 (s, 1H), 3.7 (s, 2H), 3.5 (s, 3H), 3.1 (m, 1H), 2.3 (s, 3H), 1.0 (m, 6H).

ESMS: m/z 755 (M-1).

Example 49.

3.5-Dibromo-4-{2-[(3-indolyl)(3-methylphenyl)methyl]-5-is opropyl-4-methoxyphenoxy}pheny acetic acid (E49).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl-4 -methoxy- phenoxy} phenylacetic acid and 1-methylindole.'H NMR (CDCI3) : # 7.5 (m, 2H), 7.3-7.1 (m, 6H), 7.12 (t, 1H), 7.0-6.9 (m, 2H), 6.7 (s, 1H), 6.6 (s, 1H), 6.2 (s, 1H), 6.1 (s, 1H), 3.7 (s, 3H), 3.6 (s, 2H), 3.5 (s, 3H), 3.14 (m, 1H), 2.3 (s, 3H), 1.01 (dd, 6H). ESMS: m/z 690 (M-1).

Example 50.

4-{2-[(4-Carbomethoxy-3-indolyl)(3-methylphenyl)methyl]-5 -isopropyl-4-methoxyphenoxy}-3, 5-dibromophenylacetic acid (E50).

Prepared from 3,5-dibromo-4- {2- [hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and 4-carbomethoxyindole. 1H NMR (CDCI3) : 8 8.20 (d, 1 H), 7.54-7.46 (m, 3H), 7.36 (d, 1H), 7.12 (t, 1H), 7.07 (t, 1H), 7.0 (s, 1H), 6.94 (d, 1H), 6.88 (d, 1H), 6.68 (d, 1H), 6.49 (s, 1H), 6.36 (s, 1H), 6.12 (s, 1H), 3.58 (s, 2H), 3.49 (s, 3H), 3.46 (s, 3H), 3.14 (m, 1H), 2.24 (s, 3H), 1.01 (dd, 6H).

ESMS: m/z 734 (M-1).

Example 51.

4-{2-[(5-Carbomethoxy-3-indolyl)(3-methylphenyl)methyl]-5 -isopropyl-4-methoxyphenoxy}-3, 5-dibromophenylacetic acid CE51).

Prepared from 3, 5-dibromo-4-{2-[hydroxy(3-methylphenyl)methyl]-5-isopropyl-4 -methoxy- phenoxy} phenylacetic acid and 5-carbomethoxyindole. 1H NMR (CDCIs) : # 8.25 (d, 1H), 8.14 (br. s, 1H), 7.85 (dd, 1H), 7.51 (s, 2H), 7.34 (d, 1H), 7.19-7.08 (m, 3H), 7.03 (d, 1H), 6.84 (d, 1H), 6.59 (s, 1H), 6.27 (s, 1H), 6.12 (s, 1H), 3.82 (s, 3H), 3.62 (s, 2H), 3.52 (s, 3H), 3.12 (m, 1H), 2.28 (s, 3H), 1.03 (d, 6H).

ESMS : m/z 734 (M-1).

Example 52.

3,5-Dibromo-4-{5-isopropyl-2-[(3-methylphenyl)(2-thienyl) methyl]-4-methoxyphenoxy}phenyl acetic acid (E52). Prepared from 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid and thiophene. 1H NMR (CDCI3) : 8 7.5 (s, 2H), 7.2-7.0 (m, 4H), 7.02 (d, 1H), 6.7 (s, 1H), 6.3 (s, 1H), 6.1 (s, 1H), 3.6 (s, 5H), 3.14 (m, 1H), 2.3 (s, 3H), 1.02 (d, 6H). ESMS: m/z 643 (M-1).

Example 53.

3,5-Dibromo-4-{2-[((3,5-dimethylphenyl)(4-hydroxyphenyl)m ethyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid (E53).

Prepared from 3,5-dibromo-4-{2-[(3,5-dimethylphenyl)-hydroxymethyl]-5-isop ropyl-4-methoxyphenoxy}- phenylacetic acid and phenol. 1H NMR (CDCl3) : 8 7.47 (s, 2H), 7.05 (d, 2H), 6.85-6.7 (m, 5H), 6.45 (s, 1H), 6.10 (s, 1H), 5.95 (s, 1H), 3.60 (s, 5H), 3.15-3.05 (m, 1H), 2.30 (s, 6H), 1.00 (d, 6H). ESMS: m/z 667 (M-1).

Example 54. 3, 5-Dibromo-4-{2-[((3,5-dimethylphenyl)(5-fluoro-2-hydroxyphen yl)- methyl]-5-isopropyl-4-methoxyphenoxy}phenylacetic acid (E54).

Prepared from 3,5-dibromo-4-{2-[(3,5-dimethylphenyl)-hydroxymethyl]-5-isop ropyl-4-methyphenoxy}- phenylacetic acid and 4-fluorophenol. H1-NMR (DMSO-d6) : # 7.55 (d, 2H), 6.85-6.80 (m, 2H), 6.75-6.70 (m, 3H), 6.55-6.50 (m, 1H), 6.45 (s, 1H), 6.15 (s, 1H), 6.00 (s, 1H), 3.70 (s, 2H), 3.50 (s, 3H), 3.15-3.00 (m, 1H), 2.20 (s, 6H), 0.95 (d, 6H). ESMS: m/z 685 (M-1).

Example 55: 4-{2-[(4-Bromo-2-hydroxyphenyl)(3-methylphenyl)methyl]-5-ter t-butyl-4-methoxyphenoxy}-3 5-dibromophenylacetic acid (E55).

Prepared from 5-tert-butyl-4- {2- [hydroxy (3-methylphenyl) methyl]-4-methoxy- phenoxy}-3,5-dibromophenylacetic acid and 3-bromophenol.'H NMR (CDCI3) : 8 7.47 (s, 2H), 7.17 (t, 1 H), 7.09 (d, J = 3 Hz, 1 H), 7.03 (bd d, 1 H), 6.96 (bd s, 1 H), 6.88-6.95 (m, 2H), 6.71 (dd, 1H), 6.36 (s, 1H), 6.26 (s, 1H), 6.19 (s, 1H), 3.62 (s, 2H), 3.56 (s, 3H), 2.30 (s, 3H), 1.20 (s, 9H). ESMS: m/z 746 (M-1).

From the reaction mixture the two following compounds were also isolated : Example 56: 4-{2-[(B-bromo-4-hydroxyphenyl)(3-methylphenyl)methyl]-5-ter t-butyl-4-methoxyphenoxy}-3 5-dibromophenylacetic acid (E56).

'H NMR (CDCI3) : # 7. 50 (s, 2H), 7.21 (t, 1H), 6.95-7.10 (m, 5H), 6.82 (d, 1H), 6.48 (s, 1H), 6.25 (s, 1H), 6.05 (s, 1H), 3.63 (s, 2H), 3.59 (s, 3H), 2.31 (s, 3H), 1.20 (s, 9H). ESMS: m/z 746 (M-1).

Example 57: 4-{2-[(3-Bromo-2-hydroxyphenyl)(3-methylphenyl)methyl]-5-ter t-butyl-4-methoxyphenoxy}-3 5-dibromophenylacetic acid (57). H NMR (CDCI3) : # 7.42 (s, 2H), 7.11 (t, 1H), 6.90-7.05 (m, 3H), 6.84 (br. s, 1H), 6.78 (br. d, 1H), 6.45-6.53 (m, 2H), 5.94 (s, 1H), 5.62 (d, 1H), 3.60 (s, 3H), 3.58 (s, 2H), 2.24 (s, 3H), 1.37 (s, 9H). ESMS: m/z 746 (M-1).

Example 58: 4-{5-tert-Butyl-2-[(3,5-dimethyl-2-hydroxyphenyl)(3-methylph enyl)- methyl]-4-methoxyphenoxy}-3,5-dibromophenylacetic acid (E58).

Prepared from 5-tert-butyl-4-{2-[hydroxy(3-methylphenyl)methyl]-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid and 3, 5-dimethylphenol. 1H NMR (CDCI3) : 8 7.49 (s, 2H), 7.20 (t, 1H), 7.0-7.1 (m, 3H), 6.70 (s, 1H), 6.63 (s, 1H), 6.54 (s, 1H), 6.24 (s, 1H), 6.20 (s, 1H), 5.03 (br. s, 1H), 3.62 (s, 2H), 3.59 (s, 3H), 2.37 (s, 3H), 2.28 (s, 3H), 2.26 (s, 3H), 1.20 (s, 9H). ESMS: m/z 695 (M-1). Example 59 : 4-15-tert-Butyl-2-r (2-hydroxy-3-methoxy-5-methyl phenyl) (3-m ethyl- phenyl)methyl]-4-methoxyphenoxy}-3,5-dibromophenylacetic acid (E59).

Prepared from 5-tert-butyl-4- {2- [hydroxy (3-methylphenyl) methyl]-4-methoxy- phenoxy}-3,5-dibromophenylacetic acid and 3-methoxy-5-methylphenol.'H NMR (CDCI3) : 8 7.47 (s, 2H), 7.14 (t, 1H), 6.90-7.04 (m, 3H), 6.66 (s, 1H), 6.59 (s, 1H), 6.40 (s, 1H), 6.17 (s, 1 H), 6.01 (s, 1 H), 5.34 (br. s, 1 H), 3.86 (s, 3H), 3.61 (s, 2H), 3.56 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 1.19 (s, 9H). ESMS: m/z 711 (M-1).

Example 60. 4-{5-Cyclopentyl-2-[(2-hydroxy-3-methoxy-4-methylphenyl)- (phenyl)methyl]-4-methoxyphenoxy}-3,5-dibromophenylacetic acid (E60).

Prepared from 4-{5-cyclopentyl-2-[hydroxy(phenyl)methyl]-4-methoxyphenoxy} -3, 5-dibromo- phenylacetic acid and 2-methoxy-4-methylphenol.'H NMR (CDCI3) : 5 7.47 (d, 2H), 7.14 (t, 1H), 6.90-7.05 (m, 3H), 6.66 (s, 1H), 6.58 (s, 1H), 6.38 (s, 1H), 6.06 (s, 1H), 6.02 (s, 1H), 3.86 (s, 3H), 3.62 (s, 2H), 3.56 (s, 3H), 3.16 (m, 1H), 2.28 (s, 3H), 2.19 (s, 3H), 1.80-1.95 (m, 2H), 1.50-1.65 (m, 4H), 1.25-1.40 (m, 2H).

ESMS: m/z 723 (M-1). Example 61.3. 5-Dibromo-4-{2-[diphenylmethyl]-5-isopropyl-4-methoxyphenoxy }phenylacetic acid (E61).

A mixture of 3,5-dibromo-4- (3-isopropyl-4-methoxyphenoxy) phenylacetic acid methyl ester (100 mg, 0.21 mmol), benzhydrof (39.9 mg, 0.22 mmol) and p-toluenesulfonic acid monohydrate (81 mg, 0.39 mmol) in benzene (5 mL) was heated to 100° C under nitrogen.

During the reaction time, benzene was removed using a Dean-Stark trap and fresh benzene was added to the mixture. After 27 h, another batch of benhydrol and acid was added. The reaction was stopped by the addition of NaHC03 (sat.) followed by extraction four times with CH2CI2 and drying over Na2SO4. The crude mixture was dissolved in THF (5 mL) followed by addition of LiOH (1 M, 5 mL). After stirring for 1 h at ambient temperature, the mixture was treated with HCI (2 M) until pH=1. The aqueous phase was extracted four times with CH2CI2 and concentrated. 1H NMR (CDCI3) : 61. 07 (d, 6H); 3.19 (m, 1H) ; 3.59 (s, 3H); 3.60 (s, 3H); 6.16 (s, 1H) ; 6.18 (s, 1H) ; 6.50 (s, 1H) ; 7.02-7.40 (m, 10H) ; 7.51 (s, 2H).

ESMS: m/z 623 (M-1).

Example 62.

3,5-Dibromo-4-{2-[(1-imidazolyl)(3-methylphenyl)methyl]-5 -isopropyl-4-methoxy- phenoxy}phenylacetic acid (E62).

Step 1.

4-{2-[Chloro(3-methylphenyl)methyl]-5-isopropyl-4-methoxy - phenoxy}-3,5-dibromophenylacetic acid.

A mixture of 3,5-dibromo-4-{2-[hydroxy (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy} phenylacetic acid (1.9 g, 3.3 mmol), concentrated HCI (10 mL) and chloroform (10 mL) was stirred vigorously for 1 d. The organic layer was separated and washed with water, brine and concentrated to give the title compound (1.9 g, 96 %).

Step 2.

3,5-Dibromo-4-{2-[(1-imidazolyl)(3-methylphenyl)methyl]-5 -isopropyl-4-methoxy- phenoxy3phenylacetic acid.

A solution of 4- {2- [chloro (3-methylphenyl) methyl]-5-isopropyl-4-methoxy- phenoxy}-3, 5-dibromophenylacetic acid (120 mg, 0.2 mmol) and imidazole (68 mg, 1 mmol) in CHsCN (5 mL) was stirred at room temperature overnight. Water was added and the precipitate was filtered off. The solid was purified by chromatography to give the title compound, 62 mg (49 %). 1H-NMR (CD3OD) : 7.6 (m, 3H), 7.2-6.8 (m, 6H), 6.4 (s, 1 H), 6.2 (s, 1H), 3.6 (2xs, 5H), 3. 1 (m, 1H), 2.3 (s, 3H), 1.0 (d, 6H). ESMS: m/z 629 (M+1).

Example 63. 3, 5-Dibromo-4-{2-[(2,5-dihydroxyphenyl)(3-methylphenyl)- methyl]-4-hydroxy-5-isopropylphenoxy}phenylacetic acid (E63).

BBr3 (1.5 mmol, 1.5 mL, 1 M in CH2CI2) was added to a solution of 3,5-dibromo-4-{2-[(2-hydroxy-5-methoxyphenyl) (3-methylphenyl)- methyl]-5-isopropyl-4-methoxyphenoxy} phenylacetic acid (50 mg, 0.07 mmol) in CH2C12 (5 mL) at-70° C. The solution was kept at-20° C for 16h and poured into a 1: 1 mixture of 1M HCI and brine. The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic phases washed with water and brine, dried with MgS04, and concentrated. Purification by HPLC gave the title compound (10 mg, 21 %) as a white solid.

'H NMR (CDC1s) : 8 7.5 (s, 2H), 7.2-7.0 (m, 4H), 6.8-6.7 (m, 2H), 6.4-6.3 (m, 2H), 6.2 (s, 1H), 6.0 (s, 1H), 3.6 (s, 2H), 3.1 (m, 1H), 2.3 (s, 3H), 1.1 (d, 6H). ESMS: m/z 655 (M-1). The compounds of the present invention according to the general formula I exhibits an affinity for the glucocorticoid receptor in the range between 0.1 and 5000 nM.