Peptide morphine agonists - for use as analgesics, sedatives, antitussives, etc.

摘要

Peptides of formula R-(X1)m-(X2)n-X3-X4-X5-X6-(X7)r-(X8)p-(X9)q-R1(I) and their salts, esters, amides, N-alkyl - and N,N-dialkylamides and acid-addn. salts. In the formula X1 and X2 are D or L basic amino acid radicals, X3 is a D or L radical of formula R2(CH2)a-(CHW1)b-CHW-CO; R2 is phenyl or opt. substd. 1, 4-cyclohexadien-1-yl or opt. benzyloxy ring-substd. a=0-2 and b=0 or 1, provided that a=1 and b=0 when R2 is cyclohexadienyl, one of W and W1 is NR3 and the other is H, provided that W=NR3 when b=3; R3 is H, alkyl, alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl or carboxyalkynyl; X4 and X5 are glycyl or D or L C-propargylglycyl, alanyl, alpha-alkylalanyl, beta-alanyl, valyl, nor valyl, leucyl, isoleucyl, nor leucyl, prolyl, hydroxyprolyl, tryptophyl, asparaginyl or glytaminyl, each opt. N2-substd. by alkyl. X6 is e.g. glycyl or histidyl, or is as X3. X9 is e.g. D or L seryl, or Beta-homomethionyl, or as defined for X6. X8 is a F or L basic amino acid radical or D or L seryl threonyl, phenylalanyl or tyrosyl; X9 is glycyl, o D or L basic amino acid radical, or D or L seryl or threonyl; R is H, aralkyl, alkyl, alkenyl, alkynyl, carboxyalkyl, carboxyalkenyl or carboxyalkynyl; R1 is the OH gp. of the 1 - COOH radical of the C-terminal amino acid, or this 1 - COOH radical is replaced by CH2OR4 or 5-tetrazolyl opt. 1- or 2-substd. by alkyl or benzyl; R4 is H or alkanoyl; m, n, p, q and r are each 0 or 1, provided that p=q=0 and X4 is in the D form when r=0. Excluded from the above definition are peptides of formula (Ia) and their derivs. H-X3-Gly-Gly-X6-X7-OH(Ia) where X7 is L-leucyl or L-methionyl and either (a) X3 is L-tyrosyl or L-3, 5-diiodotyrosyl and X6 is L-phenylalanyl or (b) X3 is L-tyrosyl and X6 is L-4-chlorophenylalanyl. Cpds. (I) are morphine agonists useful as analgesics sedatives, antitussives of respiratory stimulants and antidiarrhoeal agents.