Treatment of Debilitating Fatigue

Abstract

The present disclosure relates to a dopamine stabilizing agent and an anti-depressive agent for use in the treatment of disorders characterized by debilitating fatigue, such as myalgic encephalomyelitis (ME)/Chronic fatigue syndrome (CFS), fibromyalgia (FM) and depression, as well as of combinations thereof. Related treatment methods, pharmaceutical compositions and combination kits are also disclosed.

1 . A method of treating a subject for a disorder characterized by debilitating fatigue, comprising administering a dopamine stabilizing agent and an anti-depressive agent, wherein said dopamine stabilizing agent is selected from the group consisting of
 i) a compound of formula I   
       
         
           
           
               
               
           
         
       
       wherein: 
       R 1  and R 2  are independently selected from the group consisting of H, provided that not more than one of R 1  and R 2  is H, CONH 2 , OH, CN, CH 2 CN, OSO 2 CH 3 , OSO 2 CF 3 , SSO 2 CF 3 , COR, SO x CH 3 , SO x CF 3 , O(CH 2 ) x CF 3 , where x is 0-2, OSO 2 N(R) 2 , CH═NOR, COCOOR, CO—COON(R) 2 , C 3-8  cycloalkyl, NRSO 2 CF 3 , phenyl at position 2, 3 or 4, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, N-pyrrolinyl, triazolyl and tetrazolyl of pyridinyl; 
       R 3  is independently selected from the group consisting of H, CF 3 , CH 2 CF 3 , C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trfluorobutyl and CH 2 SCH 3 , 
       R 4  and R are independently selected from the group consisting of H, CF 3 CH 2 CF 3 , C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trfluorobutyl and —(CH 2 )m-R 5  where m is 1-8; 
       R 5  is independently selected from the group consisting of phenyl, phenyl substituted with CN, CF 3 , CH 2 CF 3 , C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl 2 or C 2 -C 8  alkynyl substituent, 2-thiophenyl, 3-thiophenyl, —NR 6 CONR 6 R 7  and —CONR 6 R 7 ; and 
       R 6  and R 7  are independently selected from the group consisting of H, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl and C 2 -C 8  alkynyl;
 ii) a compound of formula II 
 
       
         
           
           
               
               
           
         
       
       wherein: 
       R 1  is independently selected from the group consisting of OSO 2 CF 3 , OSO 2 CH 3 , SOR 3 , SO 2 R 3 , COCH 3  and COCH 2 CH 3 , wherein R 3  is as defined below; 
       R 2  is independently selected from the group consisting of C 2 -C 4  branched or unbranched alkyls, terminal allyl, CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 F, CH 2 CF 3 , 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl, 
       R 3  is independently selected from the group consisting of C 1 -C 3  alkyls, CF 3 , and N(CH 3 ) 2 ; and
 iii) a compound of formula III 
 
       
         
           
           
               
               
           
         
       
       wherein: 
       X is independently selected from the group consisting of N, CH and C, provided that X may only be C when the compound comprises a double bond at the dotted line; 
       R 1  independently is selected from the group consisting of OSO 2 CF 3 , OSO 2 CH 3 , SOR 5 , SO 2 R 5 , COR 5 , CN, NO 2 , CONHR 5 , CF 3 , 3-thiophene, 2-thiophene, 3-furane, 2-furane, F, Cl, Br, and I, wherein R 5  is as defined below; 
       R 2  is independently selected from the group consisting of C 1 -C 4  alkyls, allyls, CH 2 SCH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 F, CH 2 CF 3 , 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and —(CH 2 )—R 6 , wherein R 6  is as defined below; 
       R 3  and R 4  are independently selected from the group consisting of H and C 1 -C 4  alkyls, provided that both R 3  and R 4  cannot be H at the same time; 
       R 5  is independently selected from the group consisting of C 1 -C 3  alkyls, CF 3  and N(R 2 ) 2 , wherein R 2  is as defined above; and 
       R 6  is independently selected from the group consisting of C 3 -C 6  cycloalkyls, 2-tetrahydrofurane and 3-tetra-hydrofuran; 
       and pharmaceutically acceptable salts of any one of the compounds of formula I, II or III. 
     
     
         2 . The method according to  claim 1 , wherein in formula I
 R 1  is independently selected from the group consisting of CN, OSO 2 CF 3  and SO 2 CH 3 ;   R 2  is H;   R 3  is C 1 -8 alkyl, such as n-propyl; and   R 4  is H.   
     
     
         3 . The method according to  claim 1 , wherein said dopamine stabilizing agent is (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine or a pharmaceutically acceptable salt thereof, such as (3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride. 
     
     
         4 . The method according to  claim 1 , wherein said anti-depressive agent is selected from the group consisting of selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), serotonin modulators and stimulators (SMSs), serotonin reuptake inhibitors (SARIs), norephinephrine reuptake inhibitors (NRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), tetracyclic antidepressants (TeCAs), noradrenergic and specific serotonergic antidepressant (NaSSAs), buprenorphine, low-dose antipsychotics and St John's wort, such as the group consisting of selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI) and tricyclic antidepressants (TCAs), such as the group consisting of selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI). 
     
     
         5 . The method according to  claim 1 , wherein said method involves concomitant or simultaneous administration of said dopamine stabilizing agent and said anti-depressive agent. 
     
     
         6 . The method according to  claim 1 , wherein said disorder is selected from the group consisting of myalgic encephalomyelitis/chronic fatigue syndrome, fibromyalgia, mental fatigue, post stroke fatigue, Huntington's disease, Parkinson's disease, multiple sclerosis, narcolepsy, post cancer fatigue, fatigue associated with cancer with or without cytostatic treatment, depression and combinations thereof. 
     
     
         7 . The method according to  claim 1 , wherein said disorder is a fatigue disorder or pain disorder characterized by at least one of the conditions selected from fibromyalgia, mental fatigue, myalgic encephalomyelitis/chronic fatigue syndrome and depression. 
     
     
         8 . The method according to  claim 1 , wherein said dopamine stabilizing agent is administered in a dose of approximately 0.1-45 mg, such as 0.1-5 mg or such as approximately 1-45 mg, such as approximately 1-30 mg, such as approximately 5-30 mg, such as approximately 10-30 mg, such as 15 mg or 30 mg. 
     
     
         9 . The method according to  claim 1 , wherein said dopamine stabilizing agent is administered once, twice or three times a day, such as once or twice a day. 
     
     
         10 . The method according to  claim 1 , wherein, upon administration, the therapeutically effective blood plasma concentration of said dopamine stabilizing agent is approximately 0.1-0.7 μM, such as approximately 0.3-0.7 μM. 
     
     
         11 . A pharmaceutical composition comprising an anti-depressive agent and a dopamine stabilizing agent selected from the group consisting of
 i) a compound of formula I   
       
         
           
           
               
               
           
         
       
       wherein: 
       R 1  and R 2  are independently selected from the group consisting of H, provided that not more than one of R 1  and R 2  is H, CONH 2 , OH, CN, CH 2 CN, OSO 2 CH 3 , OSO 2 CF 3 , SSO 2 CF 3 , COR, SO x CH 3 , SO x CF 3 , O(CH 2 ) x CF 3 , where x is 0-2, OSO 2 N(R) 2 , CH═NOR, COCOOR, CO—COON(R) 2 , C 3-8  cycloalkyl, NRSO 2 CF 3 , phenyl at position 2, 3 or 4, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, N-pyrrolinyl, triazolyl and tetrazolyl of pyridinyl; 
       R 3  is independently selected from the group consisting of H, CF 3 , CH 2 CF 3 , C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and CH 2 SCH 3 , 
       R 4  and R are independently selected from the group consisting of H, CF 3 CH 2 CF 3 , C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and —(CH 2 )m-R 5  where m is 1-8; 
       R 5  is independently selected from the group consisting of phenyl, phenyl substituted with CN, CF 3 , CH 2 CF 3 , C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl or C 2 -C 8  alkynyl substituent, 2-thiophenyl, 3-thiophenyl, —NR 6 CONR 6 R 7  and —CONR 6 R 7 ; and 
       R 6  and R 7  are independently selected from the group consisting of H, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl and C 2 -C 8  alkynyl;
 ii) a compound of formula II 
 
       
         
           
           
               
               
           
         
       
       wherein: 
       R 1  is independently selected from the group consisting of OSO 2 CF 3 , OSO 2 CH 3 , SOR 3 , SO 2 R 3 , COCH 3  and COCH 2 CH 3 , wherein R 3  is as defined below; 
       R 2  is independently selected from the group consisting of C 2 -C 4  branched or unbranched alkyls, terminal allyl, CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 F, CH 2 CF 3 , 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl, 
       R 3  is independently selected from the group consisting of C 1 -C 3  alkyls, CF 3 , and N(CH 3 ) 2 ; 
       and
 iii) a compound of formula III 
 
       
         
           
           
               
               
           
         
       
       wherein: 
       X is independently selected from the group consisting of N, CH and C, provided that X may only be C when the compound comprises a double bond at the dotted line; 
       R 1  independently is selected from the group consisting of OSO 2 CF 3 , OSO 2 CH 3 , SOR 5 , SO 2 R 5 , COR 5 , CN, NO 2 , CONHR 5 , CF 3  3-thiophene, 2-thiophene, 3-furane, 2-furane, F, Cl, Br, and I, wherein R 5  is as defined below; 
       R 2  is independently selected from the group consisting of C 1 -C 4  alkyls, allyls, CH 2 SCH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 F, CH 2 CF 3 , 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and —(CH 2 )—R 6 , wherein R 6  is as defined below; 
       R 3  and R 4  are independently selected from the group consisting of H and C 1 -C 4  alkyls, provided that both R 3  and R 4  cannot be H at the same time; 
       R 5  is independently selected from the group consisting of C 1 -C 3  alkyls, CF 3  and N(R 2 ) 2 , wherein R 2  is as defined above; and 
       R 6  is independently selected from the group consisting of C 3 -C 6  cycloalkyls, 2-tetrahydrofurane and 3-tetra-hydrofuran; 
       and pharmaceutically acceptable salts of any one of the compounds of formula I, II or III. 
     
     
         12 . A kit comprising an anti-depressive agent and a dopamine stabilizing agent selected from the group consisting of
 i) a compound of formula I   
       
         
           
           
               
               
           
         
       
       wherein: 
       R 1  and R 2  are independently selected from the group consisting of H, provided that not more than one of R 1  and R 2  is H, CONH 2 , OH, CN, CH 2 CN, OSO 2 CH 3 , OSO 2 CF 3 , SSO 2 CF 3 , COR, SO x CH 3 , SO x CF 3 , O(CH 2 ) x CF 3 , where x is 0-2, OSO 2 N(R) 2 , CH═NOR, COCOOR, CO— COON(R) 2 , C 3-8  cycloalkyl, NRSO 2 CF 3 , phenyl at position 2, 3 or 4, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, N-pyrrolinyl, triazolyl and tetrazolyl of pyridinyl; 
       R 3  is independently selected from the group consisting of H, CF 3 , CH 2 CF 3 , C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and CH 2 SCH 3 , 
       R 4  and R are independently selected from the group consisting of H, CF 3 CH 2 CF 3 , C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and —(CH 2 )m-R 5  where m is 1-8; 
       R 5  is independently selected from the group consisting of phenyl, phenyl substituted with CN, CF 3 , CH 2 CF 3 , C 1 -C 3  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl or C 2 -C 8  alkynyl substituent, 2-thiophenyl, 3-thiophenyl, —NR 6 CONR 6 R 7  and —CONR 6 R 7 ; and 
       R 6  and R 7  are independently selected from the group consisting of H, C 1 -C 8  alkyl, C 3 -C 8  cycloalkyl, C 4 -C 9  cycloalkyl-methyl, C 2 -C 8  alkenyl and C 2 -C 8  alkynyl;
 ii) a compound of formula II 
 
       
         
           
           
               
               
           
         
       
       wherein: 
       R 1  is independently selected from the group consisting of OSO 2 CF 3 , OSO 2 CH 3 , SOR 3 , SO 2 R 3 , COCH 3  and COCH 2 CH 3 , wherein R 3  is as defined below; 
       R 2  is independently selected from the group consisting of C 2 -C 4  branched or unbranched alkyls, terminal allyl, CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 F, CH 2 CF 3 , 3,3,3-trifluoropropyl and 4,4,4-trifluorobutyl, 
       R 3  is independently selected from the group consisting of C 1 -C 3  alkyls, CF 3 , and N(CH 3 ) 2 ; 
       and
 iii) a compound of formula III 
 
       
         
           
           
               
               
           
         
       
       wherein: s 
       X is independently selected from the group consisting of N, CH and C, provided that X may only be C when the compound comprises a double bond at the dotted line; 
       R 1  independently is selected from the group consisting of OSO 2 CF 3 , OSO 2 CH 3 , SOR 5 , SO 2 R 5 , COR 5 , CN, NO 2 , CONHR 5 , CF 3  3-thiophene, 2-thiophene, 3-furane, 2-furane, F, Cl, Br, and I, wherein R 5  is as defined below; 
       R 2  is independently selected from the group consisting of C 1 -C 4  alkyls, allyls, CH 2 SCH 3 , CH 2 CH 2 OCH 3 , CH 2 CH 2 CH 2 F, CH 2 CF 3 , 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and —(CH 2 )—R 6 , wherein R 6  is as defined below; 
       R 3  and R 4  are independently selected from the group consisting of H and C 1 -C 4  alkyls, provided that both R 3  and R 4  cannot be H at the same time; 
       R 5  is independently selected from the group consisting of C 1 -C 3  alkyls, CF 3  and N(R 2 ) 2 , wherein R 2  is as defined above; and 
       R 6  is independently selected from the group consisting of C 3 -C 6  cycloalkyls, 2-tetrahydrofurane and 3-tetra-hydrofuran; 
       and pharmaceutically acceptable salts of any one of the compounds of formula I, II or III. 
     
     
         13 . A method of treating a subject for a disorder characterized by debilitating fatigue, comprising administering the pharmaceutical composition according to  claim 11  to the subject. 
     
     
         14 . A method of treating a subject for a disorder characterized by debilitating fatigue, comprising administering the dopamine stabilizing agent and the anti-depressive agent of the kit of  claim 12  to the patient. 
     
     
         15 . (canceled)