Use of a glucocorticoid receptor ii antagonist to treat depression in patients taking il-2

Abstract

The invention pertains to the discovery that type II glucocorticoid receptor antagonists can be used in methods for reversing or inhibiting the symptoms of depression in patients receiving interleukin-2 treatment.

1 . A method for ameliorating the symptoms of depression in a patient with normal levels of cortisol taking interleukin-2 (IL-2), comprising the step of administering to the patient an effective amount of a specific glucocorticoid receptor antagonist, with the proviso that the patient is not clinically depressed at the time IL-2 therapy is commenced, and is not otherwise in need of treatment with a glucocorticoid receptor antagonist. 
   
   
       2 . The method of  claim 1 , wherein the glucocorticoid receptor antagonist is administered to the patient coextensively with IL-2. 
   
   
       3 . The method of  claim 2 , wherein the glucocorticoid receptor antagonist is administered to the patient during the entire time when the patient is taking IL-2. 
   
   
       4 . The method of  claim 1 , wherein the glucocorticoid receptor antagonist is administered to the patient taking IL-2 in conjunction with other treatment methods. 
   
   
       5 . The method of  claim 1 , wherein the glucocorticoid receptor antagonist is administered via intravaginal or intrarectal routes. 
   
   
       6 . The method of  claim 5 , wherein the glucocorticoid receptor antagonist is administered by suppositories. 
   
   
       7 . The method of  claim 1 , wherein the glucocorticoid receptor antagonist comprises a steroid compound. 
   
   
       8 . The method of  claim 7 , wherein the glucocorticoid receptor antagonist has a modified cortisol steroid backbone selected from the group consisting of removal of the 11-β-hydroxy group, aryl substitution of the 11-β-hydroxy group, 11-β-phenyl-aminodimethyl steroids, 17-β-side chain modifications, alpha-keto-methane-sulfonate derivatives of cortisol, and androgen type steroids. 
   
   
       9 . The method of  claim 7 , wherein the glucocorticoid receptor antagonist is selected from the group consisting of dexamethasone-oxetanone, 4-pregnene-11-beta,17-alpha,21-triol-3,20-dione-21-methane-sulfonate, 16-methyl-9 alpha-fluoro-1,4-pregnadiene-11β,17-alpha,21-triol-3,20-dione-21-methane-sulfonate, 11-β-(4-dimethyl-aminoethoxyphenyl)-17-alpha-(propynyl-17-beta-hydroxy-4,9-estradien-3-one, and 17-β-hydroxy-11-β-(4-dimethyl-aminophenyl)17-alpha-(1-propynyl)estra-4,9-dien-3-one. 
   
   
       10 . The method of  claim 7 , wherein the glucocorticoid receptor antagonist is selected from the group consisting of (6β,11β,17β)-11-(4-(dimethyl-amino)phenyl)-6-methyl-4′,5′-dihydro[estra-4,9-diene-17,2′(3H′)-furan]-3-one, (11β,17β)-11-(1,3-benzodioxol-5-yl)-17-hydroxy-17-(1-propynyl)e-stra-4,9-dien-3-one, (11β,17α)-11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,-9,20-trien-3-one, (7β,11β,17β)-11-(4-(dimethylamino)phenyl)-7-Me-4′,5′-dihydrospiro(oestra-4,9-diene-17,2′(3′H)-furan)-3-one]-, (11β,17α)-11,21-Bis[4-(dimethylamino)phenyl]-17-hydroxy-19-norpregna-4,9,dien-20-yn-3-one, and (11β,17α)-11-[4-(dimethylamino)phenyl]-17-hydroxy-21-[4-(methylsulfonyl)phenyl-19-norpregna-4,9-dien-20-yn-3-one 
   
   
       11 . The method of  claim 7 , wherein the glucocorticoid receptor antagonist comprises a steroidal skeleton with at least one phenyl-containing moiety in the 11-beta position of the steroidal skeleton. 
   
   
       12 . The method of  claim 11 , wherein the phenyl-containing moiety in the 11-beta position of the steroidal skeleton is a dimethylaminophenyl moiety. 
   
   
       13 . The method of  claim 12 , wherein the glucocorticoid receptor antagonist comprises mifepristone. 
   
   
       14 . The method of  claim 11 , wherein the glucocorticoid receptor antagonist is selected from the group consisting of RU009 and RU044. 
   
   
       15 . The method of  claim 1 , wherein the glucocorticoid receptor antagonist comprises a non-steroidal compound. 
   
   
       16 . The method of  claim 15 , wherein the glucocorticoid receptor antagonist comprises a modified pyrimidine compound 
   
   
       17 . The method of  claim 15 , wherein the glucocorticoid receptor antagonist is 4b(S)-benzyl-7(S)-hydroxy-7-(1-propynyl)-4b,5,6,7,8,8a(R),9,10-octahydrophenanthrene-2-carboxylic acid (pyridine-4-ylmethyl)amide. 
   
   
       18 . The method of  claim 15 , wherein the glucocorticoid receptor antagonist is 4b(S)-benzyl-7(S)-hydroxy-7-(3,3,3-trifluoropropyl)-4b,5,6,7,8,8a(R),9,10-octahydrophenanthrene-2-carboxylic acid (2-methylpyridin-3-ylmethyl)amide. 
   
   
       19 . The method of  claim 15 , wherein the glucocorticoid receptor antagonist is selected from the group consisting of 1-(o-chloro-alpha,alpha-diphenylbenzyl)imidazole, N(triphenylmethyl)imidazole, N-([2-fluoro-9-phenyl]fluorenyl)imidazole, N-([2-pyridyl]diphenylmethyl)imidazole, N-([4,4′,4″]-trichlorotrityl)imidazole, and N((2,6 dichloro-3-methylphenyl)diphenyl)methylimidazol 
   
   
       20 . The method of  claim 15 , wherein the glucocorticoid receptor antagonist is selected from the group consisting of 6-substituted-1,2-dihydro-N protected-quinolines, octahydrophenanthrenyl carbamates, oxadiazolylalkoxyoctahydrophenanthrenes, and octahydrophenanthrene hydrazines. 
   
   
       21 . The method of  claim 15 , wherein the glucocorticoid receptor antagonist is selected from the group consisting of octahydro-2-H-naphthol[1,2,-f]indole-4 carboxamide, cyclopent[f]indazole, and benz[f]indazole. 
   
   
       22 . The method of  claim 15 , wherein the glucocorticoid receptor antagonist is selected from the group consisting of 6H-dibenzo[b,d]pyran derivatives, substituted aminobenzene derivatives, triphenylmethane derivatives, diphenyl ether derivatives, and modified pyrimidine compounds. 
   
   
       23 . The method of  claim 15 , wherein the glucocorticoid receptor antagonist is selected from the group consisting of 1-(2-chlorotrityl)-2-methylimidazole, N-(2-chlorotrityl)-L-prolinol acetate, 1-(2-chlorotrityl)-1,2,4-triazole, and 1-(2-chlorotrityl)-3,5-dimethylpyrazole. 
   
   
       24 . The method of  claim 15 , wherein the glucocorticoid receptor antagonist is selected from the group consisting of cis-1-acetyl-4-(4-((2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazine, N-(2[4,4′,4″-trichlorotrityl]oxyethyl)morpholine, 1-(2[4,4′,4″-trichlorotrityl]oxyethyl)-4(2-hydroxyethyl)piperazine dimaleate, 4-(morpholinomethyl)-A-(2-pyridyl)benzhydrol, and 1,S-bis(4,4′,4″-trichlorotrityl)-1,2,4-triazole-3-thiol. 
   
   
       25 . The method of  claim 15 , wherein the glucocorticoid receptor antagonist is selected from the group consisting of 9-(3-mercapto-1,2,4 triazolyl)-9-phenyl-2,7-difluorofluorenone, 5-(5-methoxy-2-(N-methylcarbamoyl)-phenyl)dibenzosuberol, 4a(S)-benzyl-2(R)-chloroethynyl-1,2,3,4,4a,9,10,10a(R)-octahydro-phenanthrene-2,7-diol, and 4a(S)-benzyl-2(R)-prop-1-ynyl-1,2,3,4,4a,9,10,10a(R)-octahydro-phenanthrene-2,7-diol. 
   
   
       26 . The method of  claim 15 , wherein the glucocorticoid receptor antagonist is an azadecalin compound. 
   
   
       27 . The method of  claim 15 , wherein the glucocorticoid receptor antagonist is a fused ring azadecalin compound. 
   
   
       28 . The method of  claim 1 , wherein the glucocorticoid receptor antagonist is administered once per day. 
   
   
       29 . The method of  claim 1 , wherein the glucocorticoid receptor antagonist is administered in an amount of between 0.5 mg and 20 mg per kg of body weight per day. 
   
   
       30 . The method of  claim 29 , wherein the glucocorticoid receptor antagonist is administered in an amount of between about 1 mg and 10 mg per kg of body weight per day. 
   
   
       31 . The method of  claim 30 , wherein the glucocorticoid receptor antagonist is administered in an amount of between 1 mg and 4 mg per kg of body weight per day. 
   
   
       32 . The method of  claim 1 , wherein the glucocorticoid receptor antagonist is administered orally. 
   
   
       33 . The method of  claim 1 , wherein the glucocorticoid receptor antagonist is administered by a transdermal application, by a nebulized suspension, by an aerosol spray, or by injection.