Method for treating neurocognitive dysfunction

Abstract

A method of treating corticosteroid-induced cognitive impairment comprises administering an effective amount of at least one compound of formula I, or pharmaceutically acceptable salts thereof, to a subject in need of such treatment. Formula I is: wherein: A is a bridge selected from the following radicals: —(CH 2 ) m —, —CH═CH—, —(CH 2 )—O—, —(CH 2 ) p —S—, —(CH 2 ) p —SO 2 —, —(CH 2 ) p —NR 1 — and —SO 2 —NR 2 —, and wherein: m is an integer of from 1 to 3 inclusive; p is an integer selected from 1 and 2; R 1 is selected from the group consisting of hydrogen and C 1 -C 5 alkyl; and R 2 is C 1 -C 5 alkyl; X and Y are independently selected from the group consisting of hydrogen and halogen; R and R′ are independently selected from the group consisting of hydrogen and C 1 -C 5 alkyl; n is an integer from 1 to 12 inclusive; and * denotes an asymmetric carbon.

What is claimed is: 
     
         1 . A method of treating the neurocognitive side effects associated with corticosteroid treatment as a result of a condition in a subject in need of such treatment, comprising administering to the subject an effective amount of at least one compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein: A is a bridge selected from the following radicals: —(CH  2 ) m —, —CH═CH—, —(CH 2 ) p —O—, —(CH 2 ) p —S—, —(CH 2 ) p —SO 2 —, —(CH 2 ) p —NR 1 — and —SO 2 —NR 2 —, and wherein: m is an integer of from 1 to 3 inclusive; p is an integer selected from 1 and 2; R 1  is selected from the group consisting of hydrogen and C 1 -C 5  alkyl; and R 2  is C 1 -C 5  alkyl; X and Y are independently selected from the group consisting of hydrogen and halogen; R and R′ are independently selected from the group consisting of hydrogen and C 1 -C 5  alkyl; n is an integer from 1 to 12 inclusive; and * denotes an asymmetric carbon and the bond designated by {character pullout} indicates that the absolute conformation about the asymmetric carbon can be either (R) or (S) only when all four groups attached to the asymmetric carbon are nonequivalent, or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method according to  claim 1 , wherein A is  13  SO 2 —NR 2 —. 
     
     
         3 . The method according to  claim 2 , wherein R and R′ are hydrogen. 
     
     
         4 . The method of  claim 1 , wherein the compound of formula I is tianeptine or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The method of  claim 4 , wherein the compound is (R)-tianeptine, substantially free of the corresponding (S)-enantiomer. 
     
     
         6 . The method of  claim 4 , wherein the compound is (S)-tianeptine, substantially free of the corresponding (R)-enantiomer. 
     
     
         7 . The method of  claim 1 , wherein the subject is a human. 
     
     
         8 . The method of  claim 1 , wherein the effective amount of the at least one compound of formula I administered to the subject is from about 2 to about 600 mg/day. 
     
     
         9 . The method of  claim 1 , wherein the effective amount of the at least one compound of formula I administered to the subject is from about 10 to about 400 mg/day. 
     
     
         10 . The method of  claim 1 , wherein the effective amount of the at least one compound of formula I administered to the subject is about 25 to about 300 mg/day. 
     
     
         11 . The method of  claim 1 , wherein the at least one compound of formula I is administered to the subject as a pharmaceutical composition. 
     
     
         12 . The method of  claim 11 , wherein the condition is pulmonary condition. 
     
     
         13 . The method of  claim 12 , wherein the pulmonary condition is selected from the group consisting of asthma, chronic obstructive pulmonary disease and pulmonary sarcoidosis. 
     
     
         14 . The method of  claim 11 , wherein the condition is selected from the group consisting of a cardiac condition, a gastrointestinal condition, a rheumatic condition, a collagen-vascular or dermatological condition, a renal condition, an endocrine condition. 
     
     
         15 . The method of  claim 14 , wherein the condition is pericarditis, hepatitis, ulcerative colitis or Crohn's disease, rheumatoid arthritis or psoriatic arthritis, polymyositis, polyarteritis nodosa, vasculitis, systemic dermatomyositis, eczema, cutaneous sarcoidosis, mycosis fungoides, severe seborrheic dermatitis, psoriasis, and systemic lupus erythematosus, nephritic syndrome, or lupus nephritis, a hyperthyroid state or hypercalcemia associated with malignancy and sarcoidosis. 
     
     
         16 . The method of  claim 11 , wherein the condition is the prophylaxis of the rejection of a transplanted organ. 
     
     
         17 . The method of  claim 1 , wherein the compound of formula I is administered with a systemic corticosteroid. 
     
     
         18 . The method of  claim 17 , wherein the systemic corticosteroid is prednisone. 
     
     
         19 . A pharmaceutical composition comprising a systemic corticosteroid and a compound of formula I. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the compound is tianeptine. 
     
     
         21 . The pharmaceutical composition of  claim 19 , wherein the compound is (R)-tianeptine, substantially free of the corresponding (S)-enantiomer. 
     
     
         22 . The pharmaceutical composition of  claim 19 , wherein the compound is (S)-tianeptine, substantially free of the corresponding (R)-enantiomer. 
     
     
         23 . The pharmaceutical composition of  claim 19 , wherein the systemic corticosteroid is prednisone.