TRH-like peptide derivatives as inhibitors of the TRH-degrading ectoenzyme

Abstract

Peptide derivatives useful as inhibitors of activity of thyrotropin-releasing hormone-degrading ectoenzyme (TRH-DE) disclosed.

1 . A compound of the formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is an optionally substituted 4-, 5- or 6-membered heterocyclic ring having one or more heteroatoms, in which at least one carbon atom of the ring is substituted with O or S;  
 X 1  is —CO— or —CS— or —CH 2 CO— or CH(R 4 ) wherein R 4  is H or optionally substituted alkyl or —COOH or —COOR 11  wherein R 11  is optionally substituted alkyl;  
 X 2  and X 3  (which may be the same or different) are —CO— or —CS—;  
 Z is —CH 2 — or —S— or —O— or —NH—;  
 Q is O or S;  
 R 2  is H or optionally substituted alkyl or an optionally substituted carbocyclic ring;  
 R 3  is H or optionally substituted alkyl or an optionally substituted mono- or polycyclic ring, optionally having one or more heteroatoms in the ring(s) and optionally being a fused ring; or R 2  and R 3  together form an optionally substituted mono- or polycyclic ring optionally having one or more heteroatoms in the ring(s) and optionally being a fused ring;  
 R 5  and R 6  (which may be the same or different) are H, or lower alkyl;  
 R 7  and R 8  (which may be the same or different) are H, or optionally substituted lower alkyl;  
 R 9  and R 10  (which may be the same or different) are H, or optionally substituted alkyl, or an optionally substituted carbocyclic ring;  
 Y is —(CH 2 ) n — where n is 0, 1, 2 or 3 provided that when R 2  and R 3  form part of the ring n is 0;  
 provided that when R 1  is:  
                     
 and X 1 , X 2  and X 3  are —CO— 
 and R 5 , R 6 , R 7 , R 8 , R 9 , R 10  are H  
 and Z is —CH 2 —  
 and Q is O  
 and Y is —(CH 2 ) n — where n is 0, 
 then R 2 and R 3  are not both H;  
 and pharmaceutically acceptable salts thereof.  
 
 
     
     
         2 . The compound of  claim 1 , wherein R 1 , X 1 , X 2 , X 3 , Z, Q, R 5 , R 6 , R 7 , R 8 , R 9 , R 10  and Y are as defined in  claim 1 , 
 R 2  is H or optionally substituted alkyl or an optionally substituted carbocyclic ring,    R 3  is optionally substituted alkyl or an optionally substituted mono- or polycyclic ring, optionally having one or more heteroatoms in the ring(s) and optionally being a fused ring;    or R 2  and R 3  together form an optionally substituted mono- or polycyclic ring optionally having one or more heteroatoms in the ring(s) and optionally being a fused ring; and pharmaceutically acceptable salts thereof.    
     
     
         3 . The compounds of  claim 1 , wherein R 2  or R 3 , or R 2  and R 3  together, represent an optionally substituted mono- or polycyclic ring.  
     
     
         4 . The compound of  claim 1 , wherein R 5 and R 6  are H and Q is O so that the compounds are thyrotropin-releasing hormone (TRH) derivatives having L-asparagine residue (Asn) in the P 1 ′ position.  
     
     
         5 . The compound of  claim 2 , comprising L-asparagine (Asn) in the P 1 ′ position of the peptide with the general formula:  
       R 1 —X 1 —L-Asn-L-Pro—NR 2 Y R 3 ,  
       wherein R 1 , X 1 , R 2 , Y and R 3  are as defined in  claim 1 .  
     
     
         6 . The compound of  claim 1 , wherein Z is —CH 2 — and R 7  and R 8  are H.  
     
     
         7 . The compound of  claim 1 , wherein X 1 , X 2  and X 3  are —CO— 
     
     
         8 . The compound of  claim 1 , wherein R 2  or R 3 , or R 2  and R 3  together, represent a large hydrophobic group.  
     
     
         9 . The compound of  claim 1 , wherein the group —N(R 2 )Y R 3  or the group R 3  is at least one optionally substituted amino acid residue.  
     
     
         10 . The compound of  claim 1 , wherein R 1  is selected from any of the following:  
       
         
           
           
               
               
           
         
       
       wherein R 12  is hydrogen, lower alkyl or phenyl, 
 R 13  is hydrogen or lower alkyl,  
 Q is O or S.  
 
     
     
         11 . The compound of  claim 10 , wherein Q is O.  
     
     
         12 . The compound of  claim 1 , wherein R 1  is a five-membered pyrrolidinone, thiazolidinone or butyrolactone ring.  
     
     
         13 . The compound of  claim 1 , wherein R 1  is:  
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , wherein substituents present which do not interfere substantially with the function of the compounds as inhibitors of activity of  
       
         
           
           
               
               
           
         
       
       thyrotropin-releasing hormone-degrading ectoenzyrne (TRH-DE).  
     
     
         15 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         16 . A compound having the formula (Glp-L-Asn-L-Pro-L-Tyr-L-TrpAMC):  
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         18 . A novel compound selected from the group consisting of Glp-Asn-Pro-isopropylamide, Glp-Asn-Pro-cyclohexamide, Glp-Asn-Pro-piperazide, Glp-Asn-Pro-5-amidoquinoline (or 6-amidoquinoline or 8-amidoquinoline), Glp-Asn-Pro-5-amido-isoquinoline, Glp-Asn-Pro-Anilide, Glp-Asn-Pro-7-amido(trifluoromethyl)coumarin, Glp-Asn-Pro-6-amido-3,4-benzocoumarin, Glp-Asn-Pro-1,2,3,4-tetrahydro-1-naphthylamide, Glp-Asn-Pro-5,6,7,8-tetrahydro-1-naphthylamide, Glp-Asn-Pro-benzylamide, Glp-Asn-Pro-2-thiazolamide, Glp-Asn-Pro- 1-naphthylmethylamide, Glp-Asn-Pro-p-Anisidide, Glp-Asn-Pro-para amidobenzoic acid, Glp-Asn-Pro-m-anisidide, Glp-Asn-Pro-o-anisidide, Glp-Asn-Pro-5-chloro-2-methoxy anilide, Glp-Asn-Pro-3-hydroxy-4-methoxy anilide, Glp-Asn-Pro-2-hydroxy anilide, Glp-Asn-Pro-2-(hydroxymethyl-) anilide, Glp-Asn-Pro-4- trifluoromethyl anilide, Glp-Asn-Pro-Tyr-NH 2 , Glp-Asn-Pro-Trp-Ser-Tyr-NH 2 , Glp-Asn-Pro-Trp-Tyr-NH 2 , Glp-Asn-Pro-Trp-NH 2 , Glp-Asn-Pro-Tyr-Trp-NH 2 , Glp-Asn-Pro-Trp-AMC, Glp-Asn-Pro-Tyr-Trp-AMC, Glp-Asn-Pro-Trp-Trp-AMC, Glp-Asn-Pro-Tyr-Trp-Trp-AMC, Glp-Asn-Pro-Phe-TyrAMC, Glp-Asn-Pro-Ala-TrpAMC, Glp-Asn-Pro-Val-Tyr-TrpAMC and pharmaceutically acceptable salts thereof.  
     
     
         19 . The compound of  claim 18 , selected from the group consisting of Glp-Asn-Pro-1,2,3,4-tetrahydro-1-naphthylamide, Glp-Asn-Pro-5,6,7,8- tetrahydro-1-naphthylamide, Glp-Asn-Pro-benzylamide, Glp-Asn-Pro-p-anisidide, Glp-Asn-Pro-m-anisidide, Glp-Asn-Pro-o-anisidide, Glp-Asn-Pro-5-chloro-2-methoxy anilide, Glp-Asn-Pro-3-hydroxy-4-methoxy anilide, Glp-Asn-Pro-2-hydroxy anilide, Glp-Asn-Pro-2-(hydroxymethyl-) anilide, and pharmaceutically acceptable salts thereof.  
     
     
         20 . The compound of  claim 1 ,  18  or  19 , or a pharmaceutically acceptable salt of any of the foregoing, for use in a method for treatment of the human or animal body by therapy or a diagnostic method optionally practised on the human or animal body.  
     
     
         21 . A compound of formula I a :  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is an optionally substituted 4-, 5- or 6-membered heterocyclic ring having one or more heteroatoms, in which at least one carbon atom of the ring is substituted with O or S;  
 X 1  is —CO— or —CS— or —CH 2 CO— or CH(R 4 ) wherein R 4  is H or optionally substituted alkyl or  
 —COOH or —COOR 11  wherein R 11  is optionally substituted alkyl;  
 X 2  and X 3  (which may be the same or different) are —CO— or —CS—;  
 Z is —CH 2 — or —S— or —O— or —NH—;  
 Q is O or S;  
 R 2  is H or optionally substituted alkyl or an optionally substituted carbocyclic ring;  
 R 3  is H or optionally substituted alkyl or an optionally substituted mono- or polycyclic ring, optionally having one or more heteroatoms in the ring(s) and optionally being a fused ring; or R 2  and R 3  together form an optionally substituted mono- or polycyclic ring optionally having one or more heteroatoms in the ring(s) and optionally being a fused ring;  
 R 5  and R 6  (which may be the same or different) are H, or lower alkyl;  
 R 7  and R 8  (which may be the same or different) are H, or optionally substituted lower alkyl;  
 R 9  and R 10  (which may be the same or different) are H, or optionally substituted alkyl, or an optionally substituted carbocyclic ring;  
 Y is —(CH 2 ) n — where n is 0, 1, 2 or 3 provided that when R 2  and R 3  form part of the ring n is 0;  
 and pharmaceutically acceptable salts thereof,  
 for use as an inhibitor of activity of thyrotropin-releasing hormone-degrading ectoenzyme (TRH-DE).  
 
     
     
         22 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, for use in potentiating thyrotropin-releasing hormone.  
     
     
         23 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, for use as an inhibitor of activity of thyrotropin-releasing hormone-degrading ectoenzyme (TRH-DE).  
     
     
         24 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, for use in inhibiting activity of TRH-DE.  
     
     
         25 . The compound of  claim 24 , for use in potentiating endogenous thyrotropin-releasing hormone (TRH) and/or in protecting exogenously administered TRH or TRH analogues from degradation by TRH-DE.  
     
     
         26 . A pharmaceutical composition comprising an effective amount of a compound of  claim 21 , or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.  
     
     
         27 . The pharmaceutical composition according to  claim 26 , further comprising a TRH or a TRH analogue.  
     
     
         28 . A compound of  claim 21 , or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for potentiating endogenous thyrotropin-releasing hormone (TRH) and/or in protecting exogenously administered TRH or TRH analogues from degradation by TRH-DE.  
     
     
         29 . The compound of  claim 21 , or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of brain or spinal injuries, or other central nervous systems disorders, or other TRH dependent disorders in tissues in which TRH-DE is the principal enzyme influencing TRH levels.  
     
     
         30 . A method of treating brain or spinal injuries, other central nervous systems disorders, or other TRE dependent disorders in tissues in which TRH-DE is the principal enzyme influencing TRH levels, which comprises administering to a patient suffering from such injuries or disorders an amount of a compound of  claim 21 , or a pharmaceutically acceptable salt thereof, effective to potentiate endogenous TRH and/or protect exogenously administered TRH or TRH analogues from degradation by TRH-DE.