Patent EP-0083864-A2 (EP)
Inventor: MOMANY FRANK A
IPC: C07C/
Filed: 1982-12-22
Abstract: Novel peptides having the amino acid sequence selected from a group consisting of
     
     wherein X 1 , X 2 , and X 3  are selected from a group consisting of N-terminal and desamino alpha-carbon substitutions and a and b are 0 or 1, provided that a and b are always 0 when A 1  is a desamino residue; A and A4 are selected from a group consisting of histidyl, arginyl, lysyl, a-naphthylalanyl, β-naphthylalanyl, isoquinolyl, tyrosyl, tryptophyl, phenylalanyl, homologues and analogues thereof, and, with respect to A 1  only the desamino forms thereof; A 2  and A 5  are selected from a group consisting of D-histidyl, D-arginyl, D-lysyl, D-a-naphthylalanyl, D-β-naphthylalanyl, D-isoquinolyl, D-tyrosyl, D-tryptophyl, D-phenylalanyl, homologues and analogues thereof, and, with respect to As only, the descarboxy forms thereof; A3 is selected from a group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, prolyl, seryl, threonyl, methionyl, aspartyl, glutamyl, asparginyl, glutaminyl, histidyl, D-alanyl, D-valyl, D-leucyl, D-isoleucyl, D-prolyl, D-seryl, D-threonyl, D-methionyl, D-aspartyl, D-glutamyl, D-asparaginyl, D-glutaminyl, D-histidyl, and homologues and analogues thereof; A 6  is selected from a group consisting of amino acid residues of the L- and D- configuration, homologues and analogues thereof, and the descarboxy forms thereof; and Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions; and the pharmaceutically acceptable salts thereof; provided that (a) when (1) a is 1 and b is 0 and X, and X 2  are selected from the group consisting of tyrosyl, tryptophyl and phenylalanyl; (3) A3 is selected from the group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, prolyl, seryl, threonyl, methionyl, aspartyl, glutamyl, asparaginyl, glutaminyl, and histidyl; and (4) Y is selected from the group consisting of -NR 1 R 2 , -OR, and -CH 2 0R, wherein R, R 1  and R 2  are selcted from a group consisting of hydrogen and straight and branched chain alkyl groups containing 1-6 carbon atoms, then at least one of A 2  and As is selected such that it is not from a group consisting of D-tyrosyl, D-tryptophyl, D-phenylalanyl, and, with respect to As, the descarboxy forms thereof; (b) when (1) a is 1 and b is 0 and X, and X 2  are selected from the group consisting of -H and -CH 3 ; (2) A 2  and As are selected from the group consisting of D-tyrosyl, D-tryptophyl, D-phenylalanyl, and, with respect to As, the descarboxy forms thereof; (3) A3 is selected from the group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, prolyl, seryl, threonyl, methionyl, aspartyl, glutamyl, asparaginyl, glutaminyl and histidyl; and (4) Y is selected from a group consisting of -NR 1 R 2 , -OR, and -CH 2 0R, wherein R, R 1 , and R 2  are selected from a group consisting of hydrogen and straight and branched chain alkyl groups containing 1-6 carbon atoms; then at least one of A 1  and A4 is selected such that it is not from a group consisting of tyrosyl, tryptophyl, and phenylalanyl; (c) when (1) a is 1 and b is 0 and X' 1  and X' 2  are selected from the group consisting of -H, -CH 3 , and -CHOCH 3 ; (2) A, and A4 are selected from the group consisting of tyrosyl, tryptophyl, and phenylalanyl; (3) A3 is selected from the group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, methionyl, asparaginyl, and glutaminyl; (4) As is selected from the group consisting of asparaginyl, glutaminyl, glutamyl, arginyl, lysyl, seryl, threonyl, and the descarboxy forms thereof; and (5) Y is selected from the group consisting of -NR 1 R 2 , -OR, and -CH 2 0R, wherein R, R,, and R 2  are selected from a group consisting of hydrogen and straight and branched chain alkyl groups containing 1-6 carbon atoms; then at least one of A 2  and As is selected such that it is not from a group consisting of D-tyrosyl, D-tryptophyl, and D-phenylalanyl; and (d) when (1) a is 1 and b is 0 and X' 1  and X' 2  are selected from the group consisting of -H, PCH 3 , and -CHOCH 3 ; (2) A 2  and As are selected from the group consisting of D-tyrosyl, D-tryptophyl, and D-phenylalanyl; (3) A3 is selected from the group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, methionyl, asparaginyl, and glutaminyl; (4) A 6  is selected from the group consisting of asparaginyl, glutaminyl, glutamyl, arginyl, lysyl, seryl, threonyl, and the descarboxy forms thereof; and (5) Y is selected from the group consisting of -NR 1 R 2 , -OR, and -CH 2 OR, wherein R, R 1 , and R 2  are selected from a group consisting of hydrogen and straight and branched chain alkyl groups containing 1-6 carbon atoms; then at least one of A 1  and A4 is selected such that it is not from a group consisting of tyrosyl, tryptophyl, and phenyl. 
     In addition, this invention encompasses a combination of compounds comprising (a) at least one peptide having the formula III
     wherein X" 1 , X" 2 , and X" 3  are selected from a group consisting of N-terminal and desamino alpha-carbon substitutions; a and b are 0 or 1, provided that a and b are always 0 when A 1  is a desammo residue. A, and A 4  are selected from a group consisting of histidyl, arginyl, lysyl, a-naphthylanalyl, β-naphthylalanyl. isoquinolyl, tyrosyl, tryptophyl, phenylalanyl, homologues and analogues thereof, and, with respect to A, only, the desamino forms thereof; A 2  and A 5  are selected from a group consisting of D-histidyl, D-arginyl, D-lysyl, D-a-naphthylalanyl, D-β-naphthylalanyl, D-isoquinolyl, D-tyrosyl, D-tryptophyl, D-phenylalanyl, homologues and analogues thereof, and, with respect to A 5  only, the descrboxy forms thereof; A3 is selected from a group consisting of glycyl, alanyl, valyl, leucyl, isoleucyl, prolyl, seryl, threonyl, methionyl, aspartyl, glutamyl, asparaginyl, glutaminyl, histidyl, D-alanyl, D-valyl, D-leucyl, D-isoleucyl, D-prolyl, D-seryl, D-threonyl, D-methionyl, D-aspartyl, D-glutamyl, D-asparaginyl, D-glutaminyl, D-histidyl, and homologues and analogues thereof; A 6  is selected from a group consisting of amino acid residues of the L- and D-configuration, homologues and analogues thereof, and the descarboxy forms thereof; and Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions; and the pharmaceutically acceptable salts thereof; and (b) at least one growth promoting agent. 
     Combinations comprising at least one of the above- described peptides and at least one growth promoting agent. 
     These peptides and combinations act directly on the pituitary to release growth hormone therefrom.