Therapeutic uses of tri-, tetra-, penta-, and polypeptides

Abstract

Novel uses of certain peptides to treat patients suffering from neurological or psychiatric disorders are disclosed. The peptides include the tripeptide hormone MIF and compounds made by modifications of MIF, such as modification of amino terminus residues, carboxyl terminus residues and internal residues, including addition and substitution of amino acid residues and modification of the peptide bonds and functional side groups of respective amino acid residues. The tri-, tetra-, penta-, peptides and polypeptides may be utilized alone or in combination with other agents, to treat patients suffering from physiological, psychosomatic, neurological or psychiatric disorders.

1 . A method for treating a physiological, psychosomatic, neurological or psychiatric disorder in a patient, comprising administering to the patient at least one pentapeptide or salt thereof having a general formula (7c):
   R 1 -AA 1 -R 1 -Pro 1 -AA 1 -Gly-Trp  (7c)   
       wherein Pro 1  represents the amino acid Pro; AA 1  represents the amino acid Phe; AA 2  represents the amino acid homo-Arg; and R 1  and R 2  each independently are selected from the group consisting of a hydrogen atom, a halogen atom, and a hydroxyl group. 
     
     
         2 . The method of  claim 1 , wherein the pentapeptide is selected from the group consisting of:
 4-F-Phe-cis- or trans-4-OH-Pro-Homo-Arg-Gly-Trp (SEQ NO:74); and,   
       pharmaceutically acceptable salts thereof. 
     
     
         3 . A method for treating a physiological, psychosomatic, neurological or psychiatric disorder in a patient, comprising administering to the patient at least one pentapeptide or salt thereof having a general formula (7d):
   R 1 -AA 1 -R2-Pro 1 -AA 2 -Gly-AA 3 -R  (7d)   
       wherein Pro 1  represents an amino acid selected from the group consisting of Pro and Dehydro-Pro; AA 1  represents an amino acid selected from the group consisting of Phe, PhenylGly and Tyr; AA 2  represents the amino acid Arg; AA 3  represents an amino acid selected from the group consisting of Trp and AzaTrp; R 1  and R 2  each independently are selected from the group consisting of a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, at least one halogen atom, a hydroxyl group, a sulphydryl group, an alkylamino group, and a diakylamino group, and R is selected from the group consisting of an amino group and a hydroxylamino group. 
     
     
         4 . The method of  claim 3 , wherein the pentapeptide is selected from the group consisting of: 
       
         
           
                 
                 
               
                   (SEQ NO:80) 
                     
                 
                 
                 
                 
               
                     
                   4-F-Phe-3,4-Dehydro-ProArg-Gly-Trp-NH 2 ; 
                     
                 
                     
                     
                 
                 
                 
               
                   (SEQ NO:81) 
                     
                 
                 
                 
                 
               
                     
                   4-CH 3 O-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NH 2 ; 
                     
                 
                     
                     
                 
                 
                 
               
                   (SEQ NO:82) 
                     
                 
                 
                 
                 
               
                     
                   2,4-Di-F-Phe-3,4-Dihydro-Pro-Arg-Gly-Trp-NH 2 ; 
                     
                 
                     
                     
                 
                 
                 
               
                   (SEQ NO:83) 
                     
                 
                 
                 
                 
               
                     
                   4-CF 3 -Phe-3,4-Dehydro-ProArg-Gly-Trp-NH 2 ; 
                     
                 
                     
                     
                 
                 
                 
               
                   (SEQ NO:84) 
                     
                 
                 
                 
                 
               
                     
                   4-F-PhenylGly-3,4-Dehydro-Pro-Arg-Gly-Trp-NH 2 ; 
                     
                 
                     
                     
                 
                 
                 
               
                   (SEQ NO:85) 
                     
                 
                 
                 
                 
               
                     
                   3-F-Tyr-3,4-Dehydro-Pro-Arg-Gly-Trp-NH 2 ; 
                     
                 
                     
                     
                 
                 
                 
               
                   (SEQ NO:86) 
                     
                 
                 
                 
                 
               
                     
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-Trp-NHOH; 
                     
                 
                     
                     
                 
                 
                 
               
                   (SEQ NO:87) 
                     
                 
                 
                 
                 
               
                     
                   3,4-Di-C1-Phe-3,4-Dihydro-Pro-Arg-Gly-Trp-NH 2 ; 
                     
                 
                     
                     
                 
                 
                 
               
                   (SEQ NO:88) 
                     
                 
                 
                 
                 
               
                     
                   2-F-Tyr-3,4-Dehydro-Pro-Arg-Gly-Trp-NH 2 ; 
                     
                 
                     
                     
                 
                 
                 
               
                   (SEQ NO:89) 
                     
                 
                 
                 
                 
               
                     
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-7-AzaTrp-NH 2 ; 
                     
                 
                     
                   and, 
                 
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
           
         
       
       pharmaceutically acceptable salts thereof. 
     
     
         5 . A method for treating a physiological, psychosomatic, neurological or psychiatric disorder in a patient, comprising administering to the patient at least one pentapeptide or salt thereof having a general formula (7e):
   R 1 -AA 1 -R 2 —Pro 1 -AA 2 -Gly-R 4 -Trp-NH 2   (7e)   
       wherein Pro 1  represents the amino acid Pro; AA 1  represents the amino acid Phe; AA 2  represents the amino acid Arg; R 1  and R 2  each independently are selected from the group consisting of a hydrogen atom; at least one halogen atom and a hydroxyl group; and the tryptophan residue is modified at one of C4, C5, C6 and C7, with R 4  selected from the group consisting of a halogen atom, a hydroxyl group, and an alkyl group. 
     
     
         6 . The method of  claim 5 , wherein the pentapeptide is selected from the group consisting of: 
       
         
           
                 
                 
                 
               
                   4-F-Phe-cis- or trans-4-OH-Pro-Arg-Gly-4-F-Trp-NH 2 ; 
                   (SEQ NO:107) 
                     
                 
                     
                 
                   4-F-Phe-cis- or trans-4-OH-Pro-Arg-Gly-7-Methyl-Trp-NH 2 ; 
                   (SEQ NO:108) 
                 
             
                
                
                
               
            
           
         
       
       and, 
       pharmaceutically acceptable salts thereof. 
     
     
         7 . A method for treating a physiological, psychosomatic, neurological or psychiatric disorder in a patient, comprising administering to the patient at least one pentapeptide or salt thereof having a general formula (7f):
   R 1 -AA 1 -R 2 —Pro 1 -R 5 -AA 2 -Gly-Trp-NH 2   (7f)   
       wherein Pro 1  represents the amino acid Pro; AA 1  represents the amino acid Phe; AA 2  represents the amino acid Leu; R 1  and R 2  each independently are selected from the group consisting of a hydrogen atom, at least one halogen atom and a hydroxyl group; and R 5  represents at least one halogen atom. 
     
     
         8 . The method of  claim 7 , wherein the pentapeptide is selected from the group consisting of 4-F-Phe-cis- or trans-4-OH-Pro-5,5,5-Trifluoro-Leu-Gly-Trp-NH 2  (SEQ NO: 109); and pharmaceutically acceptable salts thereof. 
     
     
         9 . A method for treating a physiological, psychosomatic, neurological or psychiatric disorder in a patient, comprising administering to the patient at least one pentapeptide or salt thereof having a general formula (7g):
   R 1 -AA 1 -R 2 —Pro 1 -AA 2 -Gly-R 4 -AA 3 -R  (7g)   
       wherein Pro 1  represents an amino acid selected from the group consisting of Pro and Dehydro-Pro; AA 1  represents the amino acid Phe; AA 2  represents the amino acid Arg; AA 3  represents the amino acid Trp; R 1  and R 2  each independently are selected from the group consisting of a hydrogen atom and at least one halogen atom; and R 4  is selected from the group consisting of at least one halogen atom, a hydroxyl group, a methyl group, and a methoxy group. 
     
     
         10 . The method of  claim 9 , wherein the pentapeptide is selected from the group consisting of: 
       
         
           
                 
                 
               
                   (SEQ NO:90) 
                     
                 
                 
                 
               
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-4-F-Trp-NH 2 ; 
                     
                 
                     
                 
                 
                 
               
                   (SEQ NO:91) 
                     
                 
                 
                 
               
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-F-Trp-NH 2 ; 
                     
                 
                     
                 
                 
                 
               
                   (SEQ NO:92) 
                     
                 
                 
                 
               
                   4-F-Phe-3,4-Dihydro-Pro-Arg-Gly-6-F-Trp-NH 2 ; 
                     
                 
                     
                 
                 
                 
               
                   (SEQ NO:93) 
                     
                 
                 
                 
               
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-3-CH 3 O-Trp-NH 2 ; 
                     
                 
                     
                 
                 
                 
               
                   (SEQ NO:94) 
                     
                 
                 
                 
               
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-N-Methyl-Trp-NH 2 ; 
                     
                 
                     
                 
                 
                 
               
                   (SEQ NO:95) 
                     
                 
                 
                 
               
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-1-Methyl-Trp-NH 2 ; 
                     
                 
                     
                 
                 
                 
               
                   (SEQ NO:96) 
                     
                 
                 
                 
               
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-4-Methyl-Trp-NH 2 ; 
                     
                 
                     
                 
                 
                 
               
                   (SEQ NO:97) 
                     
                 
                 
                 
               
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-Methyl-Trp-NH 2 ; 
                     
                 
                     
                 
                 
                 
               
                   (SEQ NO:98) 
                     
                 
                 
                 
               
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-6-Methyl-Trp-NH 2 ; 
                     
                 
                     
                 
                 
                 
               
                   (SEQ NO:99) 
                     
                 
                 
                 
               
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-5-Hydroxy-Trp-NH 2 ; 
                     
                 
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
                
               
            
             
                
               
            
             
                
               
            
           
         
       
       and, pharmaceutically acceptable salts thereof. 
     
     
         11 . A method for treating a physiological, psychosomatic, neurological or psychiatric disorder in a patient, comprising administering to the patient at least one pentapeptide or salt thereof having a general formula (12):
   R 1 -Phe-R 2 -Arg-Gly-Trp-NH 2   (12)   
       wherein R 1  represents a halogen atom and R 2  represents a carboxylic acid of a monocyclic organic compound, with a three to six member ring structure having a hetero nitrogen atom. 
     
     
         12 . The method of  claim 11 , wherein the pentapeptide is selected from the group consisting of: 4-F-Phe-isonipecotic acid-Arg-Gly-Trp-NH2 (4-pyridinecarboxylic acid) (SEQ NO:100); 4-F-Phe-2-Carboxy-Azetidine-Arg-Gly-Trp-NH2 (SEQ NO: 101); 
       4-F-Phe-2-carboxy-Aziridine-Arg-Gly-Trp-NH 2  (SEQ NO:103); 
       4-F-Phe-3-Carboxy-1,4,5,6-Tetrahydropyridine-Arg-Gly-Trp-NH 2  (SEQ NO:105); 
       4-F-Phe-2-Carboxypyrrole-Arg-Gly-Trp-NH 2  (SEQ NO:106); and, 
       pharmaceutically acceptable salts thereof. 
     
     
         13 . A method for treating a physiological, psychosomatic, neurological or psychiatric disorder in a patient, comprising administering to the patient at least one pentapeptide or salt thereof having a general formula (13):
   R 1 -Phe-AA 1 -Arg-Gly-Trp-NH 2   (13)   
       wherein R 1  represents a halogen atom, and AA 1  represents an amino acid selected from the group consisting of 1-amino-1-carboxycyclopentane and 1-amino-1-carboxycyclopropane. 
     
     
         14 . The method of  claim 13 , wherein the pentapeptide is selected from the group consisting of: 
       
         
           
                 
                 
                 
               
                   4-F-Phe-1-Amino-1-Carboxycyclopentane-Arg-Gly-Trp-NH 2 ; 
                   (SEQ NO:102) 
                     
                 
                     
                 
                   4-F-Phe-1-Amino-1-Carboxy-Cyclopropyl-Arg-Gly-Trp-NH 2 ; 
                   (SEQ NO:104) 
                 
                     
                 
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Sar-Trp-NH 2 ; 
                   (SEQ NO:110) 
                 
                   and 
                 
             
                
                
                
                
                
                
               
            
           
         
       
       pharmaceutically acceptable salts thereof. 
     
     
         15 . A method for treating a physiological, psychosomatic, neurological or psychiatric disorder in a patient, comprising administering to the patient at least one a pentapeptide having a general formula (10):
   R 1 -AA 1 -R 2 —Pro 1 -AA 2 -AA 4 -Gly-AA 3 -R  (10)   
       where Pro 1  represents the amino acid dehydro-Pro; AA 1  represents the amino acid Phe; AA 2  represents the amino acid Arg; AA 3  represents the amino acid Trp; AA 4  represents the amino acid Gly; R is selected from the group consisting of a carboxyl group, a hydroxyalkyl group, a carbamyl group, an alkylcarbamyl group, and an alkoxycarbonyl group; and, R′ and R2 each independently are selected from the group consisting of a hydrogen atom, a lower alkyl group, a halogen atom, a hydroxyl group, a sulphydryl group, an alkylamino and a dialkylamino group. 
     
     
         16 . The method of  claim 15 , wherein the pentapeptide is selected from the group consisting of: 
       
         
           
                 
                 
               
                   (SEQ NO:80) 
                     
                 
                 
                 
                 
               
                     
                   4-F-Phe-3,4-Dehydro-Pro-Arg-Gly-Gly-Trp-NH2; 
                     
                 
             
                
               
            
             
                
               
            
           
         
       
       and,
 pharmaceutically acceptable salts thereof.