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US 7,067,490 B2Granted
Hepta-, Octa-and nonapeptides having antiangiogenic activity
AssigneeAbbott Laboratories
InventorsFortuna Haviv, Michael F. Bradley
Life of this patent
Estimating the term…
Abstract
Compounds of formula (SEQ ID NO:1), which are useful for treating conditions that arise from or are exacerbated by angiogenesis, are described. Also disclosed are pharmaceutical compositions comprising these compounds, methods of treatment using these compounds, and methods of inhibiting angiogenesis.
Claims18
A compound of formula (I)
- Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10 (I), (SEQ ID NO:1)
- or a therapeutically acceptable salt thereof, wherein
- Xaa1 is selected from the group consisting of hydrogen and R—(CH2)n—C(O)—, wherein n is an integer from 0 to 8 and R is selected from the group consisting of alkoxy, alkyl, aryl, carboxyl, cycloalkenyl, and cycloalkyl;
- Xaa2 is selected from the group consisting of alanyl, D-alanyl, (1S,3R)-1-aminocyclopentane-3-carbonyl, (1S,4R)-1-aminocyclopent-2-ene-4-carbonyl, (1R,4S)-1-aminocyclopent-2-ene-4-carbonyl, asparaginyl, 3-cyanophenylalanyl, 4-cyanophenylalanyl, 3,4-dimethoxyphenylalanyl, 4-fluorophenylalanyl, 3-(2-furyl)alanyl, glutaminyl, D-glutaminyl, glycyl, lysyl(N-epsilon acetyl), 4-methylphenylalanyl, norvalyl, and sarcosyl;
- Xaa3 is selected from the group consisting of alanyl, (1R,4S)-1-aminocyclopent-2-ene-4-carbonyl, arginyl, asparaginyl, D-asparaginyl, t-butylglycyl, citrullyl, cyclohexylglycyl, glutaminyl, D-glutaminyl, glutamyl, glycyl, histidyl, isoleucyl, leucyl, lysyl(N-epsilon-acetyl), methionyl, norvalyl, phenylalanyl, N-methylphenylalanyl, prolyl, seryl, 3-(2-thienylalanyl), threonyl, valyl, and N-methylvalyl;
- Xaa4 is selected from the group consisting of D-alanyl, D-allylglycyl, D-4-chlorophenylalanyl, D-citrullyl, D-3-cyanophenylalanyl, D-homophenylalanyl, D-homoseryl, D-isoleucyl, D-leucyl, N-methyl-D-leucyl, D-norleucyl, D-norvalyl, D-penicillaminyl, D-phenylalanyl, D-prolyl, D-seryl, D-thienylalanyl, and D-threonyl;
- Xaa5 is selected from the group consisting of allothreonyl, aspartyl, glutaminyl, D-glutaminyl, N-methylglutaminyl, N-methylglutamyl, glycyl, histidyl, homoseryl, isoleucyl, lysyl(N-epsilon-acetyl), methionyl, seryl, N-methylseryl, threonyl, D-threonyl, tryptyl, tyrosyl, and tyrosyl(O-methyl);
- Xaa6 is selected from the group consisting of alanyl, N-methylalanyl, allothreonyl, glutaminyl, glycyl, homoseryl, leucyl, lysyl(N-epsilon-acetyl), norleucyl, D-norvalyl, N-methylnorvalyl, octylglycyl, ornithyl(N-delta-acetyl), 3-(3-pyridyl)alanyl, sarcosyl, seryl, N-methylseryl, threonyl, tryptyl, valyl, and N-methylvalyl;
- Xaa7 is selected from the group consisting of alanyl, alloisoleucyl, aspartyl, citrullyl, isoleucyl, D-isoleucyl, leucyl, D-leucyl, lysyl(N-epsilon-acetyl), D-lysyl(N-epsilon-acetyl), N-methylisoleucyl, norvalyl, phenylalanyl, prolyl, and D-prolyl;
- Xaa8 is selected from the group consisting of arginyl, D-arginyl, citrullyl, glutaminyl, histidyl, homoarginyl, lysyl, lysyl(N-epsilon-isopropyl), ornithyl, and 3-(3-pyridyl)alanyl;
- Xaa9 is absent or selected from the group consisting of N-methyl-D-alanyl, 2-aminobutyryl, D-glutaminyl, homoprolyl, hydroxyprolyl, leucyl, prolyl, D-prolyl, and D-valyl;
- and
- Xaa10 is selected from the group consisting of D-alanylamide, azaglycylamide, glycylamide, D-lysyl(N-epsilon-acetyl)amide, a group represented by the formula —NH—(CH2)n—CHR1R2;
- and a group represented by the formula —NHR3, wherein n is an integer from 0 to 8;R1 is selected from the group consisting of hydrogen, alkyl, cycloalkenyl, and cycloalkyl;
- R2 is selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, cycloalkenyl, cycloalkyl, heterocycle, and hydroxyl, with the proviso that when n is 0, R2 is other than alkoxy or hydroxyl;
- and R3 is selected from the group consisting of hydrogen, cycloalkenyl, cycloalkyl, and hydroxyl.
13 more elements
A compound which is N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH2CH3.
A compound of formula (I)
- Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8 -Xaa9-Xaa10 (I), (SEQ ID NO:1)
- or a therapeutically acceptable salt thereof, wherein
- Xaa1 is hydrogen or R—(CH2)n—C(O)—, wherein n is an integer from 0 to 8 and R is selected from the group consisting of alkoxy, alkyl, aryl, carboxyl, cycloalkenyl, and cycloalkyl;
- Xaa2 is selected from the group consisting of alanyl, (1S,3R)-1-aminocyclopentane-3-carbonyl, (1S,4R)-1-aminocyclopent-2-ene-4-carbonyl, (1R,4S)-1-aminocyclopent-2-ene-4-carbonyl, 3-cyanophenylalanyl, 4-cyanophenylalanyl, 3,4-dimethoxyphenylalanyl, 4-fluorophenylalanyl, 3-(2-furyl)alanyl, glutaminyl, glycyl, lysyl(N-epsilon acetyl), and 4-methylphenylalanyl;
- Xaa3 is selected from the group consisting of alanyl, (1R,4S)-1-aminocyclopent-2-ene-4-carbonyl, asparaginyl, D-asparaginyl, t-butylglycyl, citrullyl, cyclohexylglycyl, glutaminyl, D-glutaminyl, glutamyl, glycyl, isoleucyl, leucyl, lysyl(N-epsilon-acetyl), methionyl, norvalyl, phenylalanyl, prolyl, seryl, 3-(2-thienylalanyl), threonyl, and valyl;
- Xaa4 is selected from the group consisting of D-alanyl, D-alloisoleucyl, D-allylglycyl, D-4-chlorophenylalanyl, D-citrullyl, D-3-cyanophenylalanyl, D-homophenylalanyl, D-homoseryl, D-isoleucyl, D-leucyl, N-methyl-D-leucyl, D-norleucyl, D-norvalyl, D-penicillaminyl, D-phenylalanyl, D-prolyl, D-seryl, D-thienylalanyl, and D-threonyl;
- Xaa5 is selected from the group consisting of allothreonyl, aspartyl, glutaminyl, D-glutaminyl, N-methylglutaminyl, glycyl, histidyl, homoseryl, isoleucyl, lysyl(N-epsilon-acetyl), methionyl, seryl, N-methylseryl, threonyl, D-threonyl, tryptyl, tyrosyl, and tyrosyl(O-methyl);
- Xaa6 is selected from the group consisting of alanyl, N-methylalanyl, allothreonyl, arginyl, glutaminyl, glycyl, homoseryl, leucyl, lysyl(N-epsilon-acetyl), norleucyl, norvalyl, D-norvalyl, N-methylnorvalyl, octylglycyl, ornithyl(N-delta-acetyl), sarcosyl, seryl, N-methylseryl, 3-(3-pyridyl)alanyl, threonyl, tryptyl, valyl, and N-methylvalyl;
- Xaa7 is selected from the group consisting of alanyl, alloisoleucyl, aspartyl, citrullyl, isoleucyl, D-isoleucyl, leucyl, D-leucyl, lysyl(N-epsilon-acetyl), D-lysyl(N-epsilon-acetyl), N-methylisoleucyl, norvalyl, phenylalanyl, prolyl, and D-prolyl;
- Xaa8 is selected from the group consisting of arginyl, D-arginyl, citrullyl, histidyl, homoarginyl, lysyl, lysyl(N-epsilon-isopropyl), ornithyl, and 3-(3-pyridyl)alanyl;
- Xaa9 is selected from the group consisting of N-methyl-D-alanyl, 2-aminobutyryl, D-glutaminyl, homoprolyl, hydroxyprolyl, leucyl, prolyl, D-prolyl, and D-valyl;
- and
- Xaa10 is selected from the group consisting of D-alanylamide, azaglycylamide, glycylamide, D-lysyl(N-epsilon-acetyl)amide, a group represented by the formula —NH—(CH2)n—CHR1R2;
- and a group represented by the formula —NHR3, wherein n is an integer from 0 to 8;
- R1 is selected from the group consisting of hydrogen, alkyl, cycloalkenyl, and cycloalkyl;
- R2 is selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, cycloalkenyl, cycloalkyl, heterocycle, and hydroxyl, with the proviso that when n is 0, R2 is other than alkoxy or hydroxyl;
- and R3 is selected from the group consisting of hydrogen, cycloalkenyl, cycloalkyl, and hydroxyl.
14 more elements
A compound selected from the group consisting of
- N-Ac-Gly-Val-D-aIle-Ser-Gln-Lys(Ac)-Arg-ProNHCH2CH3;
- N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH(CH3)2;
- N-Ac-Gly-Val-D-aIle-Tyr-Gln-Ile-Arg-ProNHCH2CH3;
- N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-Pro-D-AlaNH2;
- and
- N-Ac-Gly-Val-D-aIle-Thr-Gln-Ile-Arg-ProNHCH2CH3.
3 more elements
A compound selected from the group consisting of
- N-6MeNic-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH2CH3;
- N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-ArgNHCH2CH3;
- and
- N-Ac-Gly-Val-D-aIle-Ser-Ser-Ile-ArgNHCH2CH3.
1 more element
Dependencies are inferred from the claim text.