Patent ID: 6777535
Filing Date: 2004-08-17
Classification: A61K,C07K

Abstract:
A compound having a formula:(I)Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-â€ƒâ€ƒâ€ƒâ€ƒâ€ƒâ€ƒ1â€ƒâ€ƒâ€ƒâ€ƒ2â€ƒâ€ƒâ€ƒâ€ƒ3â€ƒâ€ƒâ€ƒâ€ƒ4â€ƒâ€ƒâ€ƒâ€ƒ5â€ƒâ€ƒâ€ƒâ€ƒ6 Xaa8-Xaa9-Xaa10-Xaa11,7â€ƒâ€ƒâ€ƒâ€ƒ8â€ƒâ€ƒâ€ƒâ€ƒâ€ƒ9â€ƒâ€ƒâ€ƒâ€ƒâ€ƒâ€ƒâ€ƒâ€ƒor a pharmaceutically acceptable salt thereof, whereinat least one amide bond of an amino acid residue represented by Xaa3, Xaa4, Xaa5, Xaa6, Xaa7, Xaa8, Xaa9, and Xaa10 is N-alkylated; Xaa1 is selected from the group consisting of N-methylprolyl, and an acyl group, wherein the acyl group is selected from the group consisting of R1â€”(CH2)nâ€”C(O)â€”, wherein n is an integer from 0 to 8 and R1 is selected from the group consisting of N-acetylamino, alkoxy, alkyl, aryl, carboxy, cycloalkenyl, cycloalkyl, heterocycle, and hydroxy; and R2â€”CH2CH2â€”Oâ€”(CH2CH2O)pâ€”CH2â€”C(O)â€”, wherein p is an integer from 1 to 8 and R2 is selected from the group consisting of hydrogen, N-acetylamino, and alkyl; Xaa2 is an N-alkylated amino acid selected from the group consisting of N-(R3)-alanyl, N-(R3)-glycyl, N-(R3)-norvalyl, and N-(R3)-prolyl, wherein R3 is C1-C5-alkyl; or Xaa2 is an N-unalkylated amino acid selected from the group consisting of &bgr;-alanyl, D-alanyl, 4-aminobutyryl, (1R,3S)-1-aminocyclopentane-3-carbonyl, (1S,3R)-1-aminocyclopentane-3-carbonyl, (1R,4S)-1-aminocyclopent-2-ene-4-carbonyl, (1S,4R)-1-aminocyclopent-2-ene-4-carbonyl, asparaginyl, 3-(4-chlorophenyl)alanyl, 3-(4-cyanophenyl)alanyl, glutaminyl, glutamyl, glycyl, 4-hydroxyprolyl, 3-(4-methylphenyl)alanyl, prolyl, seryl, and threonyl; Xaa3 is an N-alkylated amino acid selected from the group consisting of N-(R3)-alanyl, N-(R3)-glycyl, N-(R3)-leucyl, and N-(R3)-phenylalanyl, wherein R3 is as defined above; or Xaa3 is an N-unalkylated amino acid selected from the group consisting of alanyl, (1S,3R)-1-aminocyclopentane-3-carbonyl, (1S,4R)-1-aminocyclopent-2-ene-4-carbonyl, asparaginyl, aspartyl, 3-(3-cyanophenyl)alanyl, 3-(4-cyanophenyl)alanyl, glutaminyl, glycyl, leucyl, lysyl(N-epsilon-acetyl), 3-(4-methylphenyl)alanyl, norvalyl, prolyl, and phenylalanyl; Xaa4 is an N-alkylated amino acid selected from the group consisting of N-(R3)-alanyl, N-(R3)-glycyl, N-(R3)-homophenylalanyl, N-(R3)-isoleucyl, N-(R3)-leucyl, N-(R3)-norvalyl, N-(R3)-phenylalanyl, N-(R3)-D-phenylalanyl, N-(R3)-seryl, N-(R3)-tyrosyl, N-(R3)-valyl, and N-(R3)-D-valyl, wherein R3 is as defined above; or Xaa4 is an N-unalkylated amino acid selected from the group consisting of alanyl, alloisoleucyl, allylglycyl, 2-aminobutyryl, (1R,4S)-aminocyclopent-2-ene-4-carbonyl, asparaginyl, aspartyl, 3-[2-(5-bromothienyl)]alanyl, 3-(3-chlorophenyl)alanyl, 3-(4-chlorophenyl)alanyl, 3-(3-cyanophenyl)alanyl, cyclohexylalanyl, 3-(3,4-dimethoxyphenyl)alanyl, 3-(3-fluorophenyl)alanyl, 3-(4-fluorophenyl)alanyl, glutaminyl, glycyl, histidyl, homophenylalanyl, homoseryl, isoleucyl, leucyl, lysyl(N-epsilon-acetyl), methionyl, methionyl(sulfone), 3-(4-methylphenyl)alanyl, 3-(naphth-1-yl)alanyl, 3-(naphth-2-yl)alanyl, norornithyl, norvalyl, phenyalanyl, phenylglycyl, prolyl, 3-(3-pyridyl)alanyl, 3-(4-thiazolyl)alanyl, 3-(2-thienyl)alanyl, seryl, seryl(O-benzyl), styrylalanyl, tryptyl, tyrosyl, valyl, and D-valyl; Xaa5 is an N-alkylated amino acid selected from the group consisting of N-(R3)-D-homophenylalanyl, N-(R3)-D-isoleucyl, N-(R3)-D-leucyl, and N-(R3)-D-phenylalanyl, wherein R3 is as defined above; or Xaa5 is an N-unalkylated amino acid selected from the group consisting of D-alanyl, alloisoleucyl, D-alloisoleucyl, D-2-aminobutyryl, D-3-(4-aminophenyl)alanyl, D-asparaginyl, D-3-(3-benzothienyl)alanyl, D-t-butylglycyl, D-(chlorophenyl)alanyl, D-citrullyl, D-3-(3-cyanophenyl)alanyl, D-cyclohexylalanyl, cyclohexylglycyl, D-cysteinyl(S-acetamidomethyl), D-cysteinyl(S-t-butyl), D-3-(3,4-difluorophenyl)alanyl, D-(3,4-dimethoxyphenyl)alanyl, D-glutaminyl, glycyl, D-homophenylalanyl, D-homoseryl, isoleucyl, D-isoleucyl, D-leucyl, D-lysyl(N-epsilon-nicotinyl), D-lysyl, D-methionyl, D-3-(4-methylphenyl)alanyl, D-3-(naphth-1-yl)alanyl, D-3-(naphth-2-yl)alanyl, D-3-(4-nitrophenyl)alanyl, D-norleucyl, D-ornithyl, D-penicillaminyl(S-acetamidomethyl), D-penicillaminyl(S-benzyl), D-penicillaminyl(S-methyl), D-penicillaminyl, D-3-(pentafluorophenyl)alanyl, D-phenylalanyl, D-prolyl, D-seryl(O-benzyl), D-seryl, D-(2-thienyl)alanyl, D-threonyl(O-benzyl), D-threonyl, D-3-(3-trifluoromethylphenyl)alanyl, D-(3,4,5-trifluorophenyl)alanyl, D-tryptyl, D-tyrosyl(O-ethyl), D-tyrosyl, and D-valyl; Xaa6 is an N-alkylated amino acid selected from the group consisting of N-(R3)-aspartyl, N-(R3)-glutamyl, N-(R3)-glycyl, N-(R3)-seryl, N-(R3)-threonyl, N-(R3)-threonyl(O-benzyl), and N-(R3)-tyrosyl, wherein R3 is as defined above; or Xaa6 is an N-unalkylated amino acid selected from the group consisting of alanyl, allothreonyl, D-allothreonyl, allylglycyl, asparaginyl, aspartyl, glutaminyl, glycyl, histidyl, homoseryl, D-homoseryl, 3-(4-hydroxymethylphenyl)alanyl, isoleucyl, lysyl(N-epsilon-acetyl), methionyl, 3-(naphth-2-yl)alanyl, norvalyl, octylglycyl, prolyl, 3-(3-pyridyl)alanyl, seryl, D-seryl, threonyl, D-threonyl, tryptyl, tyrosyl, and tyrosyl(O-methyl); Xaa7 is an N-alkylated amino acid selected from the group consisting of N-(R3)-alanyl, N-(R3)-glycyl, N-(R3)-isoleucyl, N-(R3)-leucyl, N-(R3)-D-leucyl, N-(R3)-norleucyl, N-(R3)-norvalyl, N-(R3)-seryl, N-(R3)-threonyl, and N-(R3)-valyl, wherein R3 is as defined above; or Xaa7 is an N-unalkylated amino acid selected from the group consisting of alanyl, allothreonyl, allylglycyl, 3-(4-amidophenyl)alanyl, 2-aminobutyryl, arginyl, asparaginyl, cyclohexylalanyl, glutaminyl, D-glutaminyl, glycyl, homoalanyl, homoseryl, 4-hydroxyprolyl, leucyl, D-leucyl, lysyl(N-epsilon-acetyl), methionyl sulfone, methionyl sulfoxide, methionyl, norleucyl, norvalyl, D-norvalyl, octylglycyl, ornithyl(N-delta-acetyl), phenylalanyl, propargylglycyl, seryl, D-seryl, threonyl, tryptyl, tyrosyl, and valyl; Xaa8 is an N-alkylated amino acid selected from the group consisting of N-(R3)-alanyl, N-(R3)-D-alanyl, N-(R3)-isoleucyl, and N-(R3)-leucyl, wherein R3 is as defined above; or Xaa8 is an N-unalkylated amino acid selected from the group consisting of alanyl, alloisoleucyl, D-alloisoleucyl, allylglycyl, citrullyl, glycyl, isoleucyl, D-isoleucyl, leucyl, D-leucyl, lysyl(N-epsilon-acetyl), D-lysyl(N-epsilon-acetyl), methionyl, 3-(naphth-1-yl)alanyl, norvalyl, prolyl, D-prolyl, and valyl; Xaa9 is the N-alkylated amino acid N-(R3)-arginyl, wherein R3 is as defined above; or Xaa9 is an N-unalkylated amino acid selected from the group consisting of [(4-amino-N-isopropyl)cyclohexyl]alanyl, 3-(4-amino-N-isopropylphenyl)alanyl, arginyl(NGNGâ€² diethyl), arginyl, D-arginyl, citrullyl, glutaminyl, 3-(4-guanidinophenyl)alanyl, histidyl, homoarginyl, lysyl(N-epsilon-isopropyl), lysyl(N-epsilon-nicotinyl), lysyl, norarginyl, ornithyl, ornithyl[N-delta-(2-imidazolinyl)], ornithyl(N-delta-isopropyl), and 3-(3-pyridyl)alanyl; Xaa10 is an N-alkylated amino acid selected from the group consisting of N-(R3)-alanyl, N-(R3)-D-alanyl, N-(R3)-glycyl, N-(R3)-homoalanyl, and N-(R3)-norvalyl, wherein R3 is as defined above; or Xaa10 is an N-unalkylated amino acid selected from the group consisting of D-alanyl, 2-aminobutyryl, D-2-aminobutyryl, 2-aminoisobutyryl, 3,4-dehydroprolyl, 4-hydroxyprolyl, phenylalanyl, prolyl, D-prolyl, 1,2,3,4-tetrahydroisoquinoline-3-carbonyl, and D-valyl; and Xaa11 is a hydroxy group or an amino acid amide selected from the group consisting of: alanylamide, D-alanylamide, alanylethylamide, D-alanylethylamide, azaglycylamide, glycylamide, glycylethylamide, lysyl(N-epsilon-acetyl), D-lysyl(N-epsilon-acetyl), N-methyl-D-alanylamide, sarcosylamide, serylamide, D-serylamide, a residue represented by the formula â€ƒand a group represented by the formula â€”NHâ€”R6; wherein s is an integer from 0 to 8; R4 is selected from the group consisting of hydrogen, alkyl, and a 5- to 6-membered cycloalkyl ring; R5 is selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, cycloalkenyl, cycloalkyl, heterocycle, and hydroxy; provided that s is not zero when R5 is hydroxy or alkoxy; and R6 is selected from hydrogen and hydroxy.