US2007167376A1PendingUtilityA1
Hexa-, Hepta-, and Octapeptides Having Antiangiogenic Activity
Est. expiryOct 31, 2021(expired)· nominal 20-yr term from priority
A61K 38/00C07K 7/06
63
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Claims
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.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I)
(I)
Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -
(SEQ ID NO:1)
Xaa 8 -Xaa 9 ,
or a therapeutically acceptable salt thereof, wherein
Xaa 1 is selected from the group consisting of hydrogen and R—(CH 2 ) n —C(O)—, wherein n is an integer from 0 to 8 and R is selected from the group consisting of alkoxy, alkyl, amino, aryl, carboxyl, cycloalkenyl, cycloalkyl, and heterocycle;
Xaa 2 is selected from the group consisting of alanyl, (1R,4S)-1-aminocyclopen-2-ene-4-carbonyl, asparaginyl, D-asparaginyl, t-butylglycyl, citrullyl, cyclohexylglycyl, glutaminyl, D-glutaminyl, glutamyl, glycyl, histidyl, isoleucyl, leucyl, lysyl(N-epsilon-acetyl), methionyl, norvalyl, phenylalanyl, prolyl, 3-(3-pyridyl)alanyl, homoseryl, seryl, thienylalanyl, threonyl, D-valyl, and valyl;
Xaa 3 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, isoleucyl, 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;
Xaa 4 is selected from the group consisting of allothreonyl, aspartyl, glutaminyl, D-glutaminyl, N-methylglutaminyl, glycyl, histidyl, homoseryl, isoleucyl, lysyl(N-epsilon-acetyl), methionyl, D-norvalyl, N-methylnorvalyl, seryl, N-methylseryl, threonyl, D-threonyl, tryptyl, tyrosyl, tyrosyl(O-methyl), and N-methylvalyl;
Xaa 5 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), 3-(3-pyridyl)alanyl, sarcosyl, seryl, N-methylseryl, threonyl, tryptyl, valyl, and N-methylvalyl;
Xaa 6 is selected from the group consisting of alanyl, alloisoleucyl, aspartyl, citrullyl, isoleucyl, D-isoleucyl, N-methylisoleucyl, leucyl, D-leucyl, lysyl(N-epsilon-acetyl), D-lysyl(N-epsilon-acetyl), norvalyl, phenylalanyl, prolyl, and D-prolyl;
Xaa 7 is selected from the group consisting of arginyl, D-arginyl, citrullyl, histidyl, homoarginyl, lysyl, lysyl(N-epsilon-isopropyl), ornithyl, and 3-(3-pyridyl)alanyl;
Xaa 8 is absent or selected from the group consisting of N-methyl-D-alanyl, 2-aminobutyryl, 2-aminoisobutyryl, D-glutaminyl, homoprolyl, hydroxyprolyl, leucyl, phenylalanyl, prolyl, D-prolyl, and D-valyl; and
Xaa 9 is selected from the group consisting of D-alanylamide, azaglycylamide, glycylamide, lysyl(N-epsilon-acetyl)amide, D-lysyl(N-epsilon-acetyl)amide, —NHCH(CH 3 ) 2 , a group represented by the formula —NH—(CH 2 ) n —CHR 1 R 2 , and a group represented by the formula —NHR 3 , wherein n is an integer from 0 to 8; R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkenyl, and cycloalkyl; R 2 is selected from the group consisting of hydrogen, alkoxy, alkyl, aryl, cycloalkenyl, cycloalkyl, heterocycle, and hydroxyl, with the proviso that when n is 0, R 2 is other than alkoxy or hydroxyl; and R 3 is selected from the group consisting of hydrogen, cycloalkenyl, cycloalkyl, and hydroxyl.
2 . The compound according to claim 1 wherein
Xaa 1 is R—(CH 2 ) n —C(O)—; n is 0; R is selected from the group consisting of alkyl and heterocycle, wherein the alkyl is methyl, and wherein the heterocycle is 6-methylpyridinyl; Xaa 2 is selected from the group consisting of alanyl, (1R,4S)-1-aminocyclopent-2-ene-4-carbonyl, asparaginyl, D-asparaginyl, glutaminyl, D-glutaminyl, histidyl, homoseryl, isoleucyl, lysyl(N-epsilon-acetyl), norvalyl, phenylalanyl, prolyl, 3-(3-pyridyl)alanyl, thienylalanyl, threonyl, valyl, and D-valyl; Xaa 3 is selected from the group consisting of D-alloisoleucyl, D-isoleucyl, D-leucyl, and D-homophenylalanyl; Xaa 4 is selected from the group consisting of allothreonyl, methionyl, N-methylvalyl, N-methylnorvalyl, D-norvalyl, seryl, threonyl, and tyrosyl; Xaa 5 is selected from the group consisting of glutaminyl, norvalyl, and seryl; Xaa 6 is selected from the group consisting of isoleucyl, D-isoleucyl, lysyl(N-epsilon-acetyl), D-lysyl(N-epsilon-acetyl), and prolyl; Xaa 7 is selected from the group consisting of citrullyl and arginyl; and Xaa 8 is absent or selected from the group consisting of prolyl and D-prolyl; and Xaa 9 is selected from the group consisting of D-alanylamide, —NHCH 2 CH 3 , —NHCH(CH 3 ) 2 , NH 2 , and lysyl(N-epsilon-acetyl)amide.
3 . The compound of claim 1 wherein Xaa 7 is arginyl.
4 . The compound of claim 3 wherein Xaa 9 is D-alanylamide.
5 . The compound of claim 4 selected from the group consisting of
N-Ac-Thi-D-Leu-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2 ;
N-Ac-Phe-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2 ;
N-Ac-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2 ;
N-Ac-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2 ;
N-Ac-Val-D-Ile-Met-Nva-Ile-Arg-Pro-D-AlaNH 2 ;
and
N-Ac-Gln-D-aIle-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2 .
6 . The compound of claim 3 wherein Xaa 9 is selected from the group consisting of —NHCH 2 CH 3 , —NHCH(CH 3 ) 2 , NH 2 , and lysyl(N-epsilon-acetyl)amide.
7 . The compound of claim 6 wherein Xaa 2 is selected from the group consisting of valyl and D-valyl.
8 . The compound of claim 7 selected from the group consisting of
N-Ac-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-aIle-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-Ile-alloThr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-(6-Me-nicotinyl)-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-
NHCH 2 CH 3 ;
N-Ac-D-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-aIle-Ser-Gln-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-Ile-Thr-Gln-Ile-Arg-NHCH 2 CH 3 ;
N-Ac-Val-D-Ile-D-Nva-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-Ile-D-Nva-Gln-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-Leu-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH(CH 3 ) 2 ;
N-Ac-Val-D-aIle-Ser-Ser-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-Lys(Ac)NH 2 ;
N-Ac-Val-D-Ile-Thr-Nva-Lys(Ac)-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-Ile-alloThr-Nva-Pro-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-aIle-Tyr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-Ile-Thr-NMeVal-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-aIle-Ser-Thr-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-Ile-Thr-Nva-Ile-Arg-D-Pro-NH 2 ;
N-Ac-Val-D-Ile-Thr-Nva-Ile-Arg-NHCH 2 CH 3 ;
N-Ac-Val-D-aIle-Ser-Gln-Pro-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-aIle-Ser-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-aIle-Thr-Nva-Lys(Ac)-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-Ile-Thr-Nva-Pro-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Val-D-Ile-Thr-NMeNva-Ile-Arg-Pro-NHCH 2 CH 3 ;
and
N-Ac-Val-D-Ile-Thr-Nva-Lys(Ac)-Arg-NHCH 2 CH 3 .
9 . The compound of claim 6 wherein Xaa 2 is selected from the group consisting of asparaginyl, D-asparaginyl, lysyl(N-epsilon-acetyl), norvalyl, prolyl, and thienylalanyl.
10 . The compound of claim 9 selected from the group consisting of
N-Ac-Pro-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Thi-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Lys(Ac)-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-DAsn-D-Ile-Thr-Nva-Lys(Ac)-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Nva-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Asn-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Asn-D-Ile-Thr-Gln-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Asn-D-Ile-Thr-Nva-Pro-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Asn-D-Leu-Ser-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Asn-D-aIle-Thr-Nva-Pro-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Pro-D-aIle-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Nva-D-aIle-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
and
N-Ac-Asn-D-Hphe-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 .
11 . The compound of claim 6 wherein Xaa 2 is selected from the group consisting of alanyl, (1R,4S)-1-aminocyclopent-2-ene-4-carbonyl, glutaminyl, D-glutaminyl, histidyl, homoseryl, isoleucyl, phenylalanyl, 3-(3-pyridyl)alanyl, and threonyl.
12 . The compound of claim 11 selected from the group consisting of
N-Ac-D-Gln-D-Ile-Thr-Nva-Lys(Ac)-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-D-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-[(1R,4S)-1-aminocyclopent-2-ene-4-carbonyl]-
D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Thr-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Phe-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Hser-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Gln-D-Ile-Tyr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-3-Pal-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Gln-D-Ile-alloThr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Gln-D-aIle-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Gln-D-Ile-Thr-Nva-D-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Ile-D-Ile-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-His-D-Leu-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Ala-D-Leu-Thr-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Gln-D-Ile-Thr-Nva-D-Lys(Ac)-Arg-Pro-NHCH 2 CH 3 ;
N-Ac-Gln-D-Ile-Thr-Nva-D-Lys(Ac)-Arg-NHCH 2 CH 3 ;
and
N-Ac-Gln-D-Ile-Thr-Nva-Lys(Ac)-Arg-NHCH 2 CH 3 .
13 . (canceled)
14 . (canceled)
15 . (canceled)
16 . A pharmaceutical composition comprising a compound of claim 1 , or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
17 . A method of inhibiting angiogenesis in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of claim 1 or a therapeutically acceptable salt thereof.
18 . A method of treating cancer in a mammal in recognized need of such treatment comprising administering to the mammal a therapeutically acceptable amount of a compound of claim 1 or a therapeutically acceptable salt thereof.Join the waitlist — get patent alerts
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