US2024033320A1PendingUtilityA1

Immunorhelin compounds for intracellular infections

Assignee: ISR IMMUNE SYSTEM REGULATION HOLDING AB PUBLPriority: Jan 20, 2017Filed: Dec 14, 2022Published: Feb 1, 2024
Est. expiryJan 20, 2037(~10.5 yrs left)· nominal 20-yr term from priority
A61K 38/09A61K 31/565A61K 38/00A61K 31/573C07K 7/23A61K 31/568A61K 45/06A61P 31/04A61P 31/10A61P 33/02A61P 37/04A61P 43/00A61P 5/06A61P 5/26A61P 5/30Y02A50/30
67
PatentIndex Score
0
Cited by
0
References
0
Claims

Abstract

The present invention provides immune stimulating peptides (immunorhelins) capable of activating GnRH receptors when administered to animal or human patients or cells. These immunorhelins have utility in treating intracellular bacterial, fungal, and protozoal infections.

Claims

exact text as granted — not AI-modified
1 - 21 . (canceled) 
     
     
         22 . A method for treating an intracellular infection in a human or animal subject, the method comprising administering a therapeutically effective amount of a GnRH analog according to formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof to the subject in need thereof; 
         wherein
 R 1 = 
 
       
       
         
           
           
               
               
           
         
          R 2 = 
       
       
         
           
           
               
               
           
         
          R 3 = 
       
       
         
           
           
               
               
           
         
          R 4 = 
       
       
         
           
           
               
               
           
         
       
       and
  R 5 ═Me, Et, CH 2 CF 3 , iPr, nPr, nBu, iBu, sBu, tBu, cyclopropyl, CH 2 CONH 2 , or NHCONH 2 ; and
 wherein one of R 1 , R 3 , and R 4  is selected from Type I according to the list below, and two of R 1 , R 3 , and R 4  are selected from Type II according to the list below: 
 
 
       
         
           
                 
                 
                 
               
                     
                 
                   Group 
                   Type I 
                   Type II 
                 
                     
                 
                   R 1   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   R 3   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   R 4   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
               
            
           
         
       
     
     
         23 . The method according to  claim 22 , wherein the intracellular infection is selected from an intracellular bacterial, an intracellular fungal, and an intracellular protozoal infection. 
     
     
         24 . The method according to  claim 22 , wherein the intracellular infection is selected from  Mycobacterium tuberculosis , Mycobacteria causing atypical disease,  Mycobacterium avium  and  M. intracellulare  (also known as  Mycobacterium avium -intracellulare complex, or MAC),  M. kansasii, M. marinum, M. fortuitum, M. gordinae, Mycoplasma pneumoniae, M. genitalium, M. hominis, Ureaplasma urealyticum, U. parvum, Chlamydophila pneumoniae, Salmonella typhimurium, Toxoplasma gondii, Plasmodium falciparum, P. vivax, Trypanosoma cruzi, Cryptosporidium, Leishmania, Histoplasma capsulatum, Cryptococcus neoformans , and  Encephalitozoon cuniculi.    
     
     
         25 . The method according to  claim 22 , wherein R 5 =Et or CH 2 CONH 2 . 
     
     
         26 . The method according to  claim 22 , wherein R 5 ═Me, iPr, nPr, nBu, iBu, sBu, or tBu. 
     
     
         27 . The method according to  claim 22 , wherein R 1 = 
       
         
           
           
               
               
           
         
       
     
     
         28 . The method according to  claim 27 , wherein:
 R 2 =   
       
         
           
           
               
               
           
         
       
     
     
         29 . The method according to  claim 27 , wherein:
 R 1 =   
       
         
           
           
               
               
           
         
       
       R 3 = 
       
         
           
           
               
               
           
         
       
       and R 4 = 
       
         
           
           
               
               
           
         
       
     
     
         30 . The method according to  claim 27 , wherein the GnRH analog according to formula (I) is one of the following comuounds: 
       
         
           
                 
                 
                 
                 
                 
                 
               
                     
                 
                   Compound 
                     
                     
                     
                     
                     
                 
                   no. 
                   R 1   
                   R 2   
                   R 3   
                   R 4   
                   R 5   
                 
                     
                 
                   28 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   CH 2 CONH 2   
                 
                     
                 
                   35 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Et 
                 
                     
                 
                   55 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   CH 2 CONH 2   
                 
                     
                 
                   61 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Et 
                 
                     
                 
                   41 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   CH 2 CONH 2   
                 
                     
                 
                 
               
                   or 
                 
                     
                 
                 
                 
                 
                 
                 
                 
               
                   48 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Et 
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
             
                
                
               
            
             
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt of any of these. 
     
     
         31 . The method according to  claim 27 , wherein:
 R 1 =   
       
         
           
           
               
               
           
         
       
       R 3 = 
       
         
           
           
               
               
           
         
       
       and R 4 = 
       
         
           
           
               
               
           
         
       
     
     
         32 . The method according to  claim 31 , wherein the GnRH analog according to formula (I) is one of the following compounds: 
       
         
           
                 
                 
                 
                 
                 
                 
               
                     
                 
                   Compound 
                     
                     
                     
                     
                     
                 
                   no. 
                   R 1   
                   R 2   
                   R 3   
                   R 4   
                   R 5   
                 
                     
                 
                   27 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   CH 2 CONH 2   
                 
                     
                 
                   34 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Et 
                 
                     
                 
                   54 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   CH 2 CONH 2   
                 
                     
                 
                   60 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Et 
                 
                     
                 
                   40 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   CH 2 CONH 2   
                 
                     
                 
                 
               
                   or 
                 
                     
                 
                 
                 
                 
                 
                 
                 
               
                   47 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Et 
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
               
            
             
                
                
               
            
             
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt of any of these. 
     
     
         33 . The method according to  claim 27 , wherein R 2 = 
       
         
           
           
               
               
           
         
       
     
     
         34 . The method according to  claim 33 , wherein the GnRH analog according to formula (I) is one of the following compounds: 
       
         
           
                 
                 
                 
                 
                 
                 
               
                     
                 
                   Compound 
                     
                     
                     
                     
                     
                 
                   no. 
                   R 1   
                   R 2   
                   R 3   
                   R 4   
                   R 5   
                 
                     
                 
                     
                 
                 
                 
                 
                 
                 
                 
               
                   5 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   CH 2 CONH 2   
                 
                     
                 
                   11 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Et 
                 
                     
                 
                   4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   CH 2 CONH 2   
                 
                     
                 
                 
               
                   or 
                 
                     
                 
                 
                 
                 
                 
                 
                 
               
                   10 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Et 
                 
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
               
            
             
                
                
               
            
             
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt of any of these. 
     
     
         35 . The method according to  claim 22 , wherein:
 R 1 =   
       
         
           
           
               
               
           
         
       
       R 3 = 
       
         
           
           
               
               
           
         
       
       and R 4 = 
       
         
           
           
               
               
           
         
       
     
     
         36 . The method according to  claim 35 , wherein the GnRH analog according to formula (I) is one of the following compounds: 
       
         
           
                 
                 
                 
                 
                 
                 
               
                     
                 
                   Compound 
                     
                     
                     
                     
                     
                 
                   no. 
                   R 1   
                   R 2   
                   R 3   
                   R 4   
                   R 5   
                 
                     
                 
                     
                 
                 
                 
                 
                 
                 
                 
               
                   7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   CH 2 CONH 2   
                 
                     
                 
                   12 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Et 
                 
                     
                 
                   30 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   CH 2 CONH 2   
                 
                     
                 
                   36 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Et 
                 
                     
                 
                   62 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Et 
                 
                     
                 
                   43 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   CH 2 CONH 2   
                 
                     
                 
                 
               
                   or 
                 
                     
                 
                 
                 
                 
                 
                 
                 
               
                   49 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   
                     
                       
                       
                           
                           
                       
                     
                   
                   Et 
                 
                     
                 
             
                
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
               
            
             
                
                
               
            
             
                
                
               
            
           
         
       
       or a pharmaceutically acceptable salt of any of these. 
     
     
         37 . A method for treating an intracellular infection in a human or animal subject, the method comprising administering a therapeutically effective amount of a GnRH analog or a pharmaceutically acceptable salt thereof to the subject in need thereof, wherein the GnRH analog is one of the following compounds:
 1: pGlu-His-Trp-Ser-His-D-Ser(tBu)-Leu-Arg-Pro-Gly-NH 2 ,   2: pGlu-His-Trp-Ser-Tyr-D-Ser(tBu)-Trp-Arg-Pro-Gly-NH 2 ,   3: pGlu-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Tyr-Pro-Gly-NH 2 ,   6: pGlu-His-Trp-Ser-His-D-Ser(tBu)-Leu-Arg-Pro-NHEt,   8: pGlu-His-Trp-Ser-Tyr-D-Ser(tBu)-Trp-Arg-Pro-NHEt,   9: pGlu-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Tyr-Pro-NHEt,   23: pGlu-His-Trp-Ser-His-D-Nal-Leu-Arg-Pro-Gly-NH 2 ,   24: pGlu-His-Trp-Ser-Tyr-D-Nal-Trp-Arg-Pro-Gly-NH 2 ,   25: pGlu-His-Trp-Ser-Tyr-D-Nal-Leu-Tyr-Pro-Gly-NH 2 ,   26: pGlu-His-Trp-Ser-Tyr-D-Nal-Leu-Arg-Pro-NHEt,   29: pGlu-His-Trp-Ser-His-D-Nal-Leu-Arg-Pro-NHEt,   31: pGlu-His-Trp-Ser-Tyr-D-Nal-Trp-Arg-Pro-NHEt,   32: pGlu-His-Trp-Ser-Tyr-D-Nal-Leu-Tyr-Pro-NHEt   33: pGlu-His-Trp-Ser-His-D-Nal-Trp-Tyr-Pro-Gly-NH 2 ,   37: pGlu-His-Trp-Ser-His-D-Leu-Leu-Arg-Pro-Gly-NH 2 ,   38: pGlu-His-Trp-Ser-Try-D-Leu-Trp-Arg-Pro-Gly-NH 2 ,   39: pGlu-His-Trp-Ser-Tyr-D-Leu-Leu-Tyr-Pro-Gly-NH 2 ,   42: pGlu-His-Trp-Ser-His-D-Leu-Leu-Arg-Pro-NHEt,   44: pGlu-His-Trp-Ser-Tyr-D-Leu-Trp-Arg-Pro-NHEt,   45: pGlu-His-Trp-Ser-Tyr-D-Leu-Leu-Tyr-Pro-NHEt,   50: pGlu-His-Trp-Ser-His-D-Leu-Trp-Tyr-Pro-NHEt,   51: pGlu-His-Trp-Ser-His-D-Bhi-Leu-Arg-Pro-Gly-NH 2 ,   52: pGlu-His-Trp-Ser-Tyr-D-Bhi-Trp-Arg-Pro-Gly-NH 2 ,   53: pGlu-His-Trp-Ser-Tyr-D-Bhi-Leu-Tyr-Pro-Gly-NH 2 ,   56: pGlu-His-Trp-Ser-His-D-Bhi-Leu-Arg-Pro-NHEt,   57: pGlu-His-Trp-Ser-Tyr-D-Bhi-Trp-Arg-Pro-Gly-NH 2 ,   58: pGlu-His-Trp-Ser-Tyr-D-Bhi-Trp-Arg-Pro-Gly-NH 2 ,   59: pGlu-His-Trp-Ser-Tyr-D-Bhi-Leu-Tyr-Pro-NHEt,   63: pGlu-His-Trp-Ser-His-D-Bhi-Trp-Tyr-Pro-NHEt, or   67: pGlu-His-Trp-Ser-Tyr-D-Bhi-Trp-Arg-Pro-NHEt.   
     
     
         38 . The method according to  claim 37 , wherein the intracellular infection is selected from an intracellular bacterial, an intracellular fungal, and an intracellular protozoal infection, 
     
     
         39 . The method according to  claim 37 , wherein the intracellular infection is selected from  Mycobacterium tuberculosis , Mycobacteria causing atypical disease,  Mycobacterium avium  and  M. intracellulare  (also known as  Mycobacterium avium -intracellulare complex, or MAC),  M. kansasii, M. marinum, M. fortuitum, M. gordinae, Mycoplasma pneumoniae, M. genitalium, M. hominis, Ureaplasma urealyticum, U. parvum, Chlamydophila pneumoniae, Salmonella typhimurium, Toxoplasma gondii, Plasmodium falciparum, P. vivax, Trypanosoma cruzi, Cryptosporidium, Leishmania, Histoplasma capsulatum, Cryptococcus neoformans , and  Encephalitozoon cuniculi.

Join the waitlist — get patent alerts

Track US2024033320A1 — get alerts on status changes and closely related new filings.

We store only your email — no account needed. See our privacy policy.