IP Library › Granted Patent US 7,169,888
Granted Patent B2
US 7,169,888 · App. 10/283,549 · Granted Jan 30, 2007

Tetra-, penta-, hexa- and heptapeptides having antiangiogenic activity

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Quick Facts
Patent No.
US 7,169,888
App. No.
10/283,549
Granted
Jan 30, 2007
Kind
B2
Abstract

Compounds of formula (SEQ ID NO:2) and (SEQ ID NO:3), 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 (84)

1. A compound of formula (II)

Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8   (II), (SEQ ID NO:2)

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 β-alanyl, D-alloisoleucyl D-4-chlorophenylalanyl, D-homophenylalanyl, D-isoleucyl,D-leucyl, D-penicillaminyl, and D-prolyl;

Xaa 3 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);

Xaa 4 is selected from the group consisting of N-methylalanyl, allothreonyl, glutaminyl, D-glutaminyl, glycyl, homoseryl, leucyl, lysyl(N-epsilon-acetyl), norleucyl, norvalyl, D-norvalyl, N-methylnorvalyl, ornithyl(N-delta-acetyl), 3-(3-pyridyl)alanyl, sarcosyl, seryl, N-methylseryl, threonyl, tryptyl, valyl and N-methylvalyl;

Xaa 5 is selected from the group consisting of alanyl, alloisoleucyl, aspartyl, citrullyl, glutaminyl, isoleucyl, D-isoleucyl, N-methylisoleucyl, leucyl, D-leucyl, lysyl, lysyl(N-epsilon-acetyl), D-lysyl(N-epsilon-acetyl), norleucyl, norvalyl, phenylalanyl, prolyl, and D-prolyl;

Xaa 6 is selected from the group consisting of arginyl, D-arginyl, citrullyl, histidyl, lysyl, lysyl(N-epsilon-isopropyl), ornithyl, and 3-(3-pyridyl)alanyl;

Xaa 7 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 8 is selected from the group consisting of D-alanylamide, azaglycylamide, glycylamide, hydroxyl, D-lysyl(N-epsilon-acetyl)amide, 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, provided 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 of claim 1 selected from the group consisting of

N-Ac-D-Pro-Thr-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Leu-Thr-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Leu-Ser-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Hphe-Thr-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-4ClPhe-Thr-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Pen-Thr-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-bAla-Thr-Nva-Ile-Arg-ProNHCH 2 CH 3 (SEQ ID NO:49);

N-Ac-bAla-Thr-Gln-Ile-Arg-ProNHCH 2 CH 3 (SEQ ID NO:50); and

N-Ac-D-Leu-Asp-Nva-Ile-Arg-ProNHCH 2 CH 3 .

3. The compound of claim 1 wherein Xaa 2 is D-alloisoleucyl.

4. The compound of claim 3 selected from the group consisting of

N-Ac-D-aIle-Thr-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Ser-Ser-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Thr-Ser-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Tyr-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Ser-Thr-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Thr-Trp-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Ser-Ser-Lys(Ac)-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Ser-Ser-Nle-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Ser-Ser-Pro-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Ser-Ser-Nva-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Ser-Ser-Lys-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Ser-Ser-Ile-Arg-ProNHCH(CH 3 ) 2 ;

N-Ac-D-aIle-Ser-Ser-Gln-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Ser-Ser-Cit-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-aIle-Ser-Ser-Ile-Arg-NHCH 2 CH 3 ;

N-Ac-D-aIle-Thr-Nva-Ile-Arg-NHCH 2 CH 3 ; and

N-Ac-D-aIle-Ser-Nva-Lys(Ac)-Arg-NHCH 2 CH 3 .

5. The compound of claim 1 wherein Xaa 2 is D-isoleucyl.

6. The compound of claim 5 wherein Xaa 3 is selected from the group consisting of allothreonyl, aspartyl, glutaminyl, lysyl(N-epsilon-acetyl), methionyl, seryl, and tyrosyl.

7. The compound of claim 6 selected from the group consisting of

N-Ac-D-Ile-alloThr-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Ser-Gln-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Ser-Nva-Ile-Arg-Pro-D-AlaNH 2 ;

N-Ac-D-Ile-Ser-Gln-D-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Gln-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Tyr-Nva-D-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Met-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Asp-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-alloThr-Nva-Pro-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Met-Gln-Ile-Arg-ProNHCH 2 CH 3 ; and

N-Ac-D-Ile-Ser-Gln-Ile-Arg-NHCH 2 CH 3 .

8. The compound of claim 5 wherein Xaa 3 is threonyl.

9. The compound of claim 8 wherein Xaa 4 is selected from the group consisting of glutaminyl, D-glutaminyl, norleucyl, N-methylnorvalyl, seryl, and tryptyl.

10. The compound of claim 9 selected from the group consisting of

N-Ac-D-Ile-Thr-Gln-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Ser-Ile-Arg-Pro-D-AlaNH 2 ;

N-Ac-D-Ile-Thr-Trp-D-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Trp-Ile-Arg-Pro-D-AlaNH 2 ;

N-Ac-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH 2 ;

N-Ac-D-Ile-Thr-Nle-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-D-Gln-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Gln-Ile-Arg-NHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Gln-Lys(Ac)-Arg-NHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Ser-Ile-Arg-NHCH 2 CH 3 ; and

N-Ac-D-Ile-Thr-NMeNva-Ile-Arg-NHCH 2 CH 3 .

11. The compound of claim 8 wherein Xaa 4 is norvalyl.

12. The compound of claim 11 selected from the group consisting of

N-Ac-D-Ile-Thr-Nva-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Nva-Pro-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Nva-Ile-Arg-D-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH 2 ;

N-Ac-D-Ile-Thr-Nva-D-Leu-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Nva-Ile-Arg-Pro-D-Lys(Ac)NH 2 ;

N-Ac-D-Ile-Thr-Nva-D-Lys(Ac)-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Nva-Ile-His-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Nva-Ile-3-Pal-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Nva-Ile-D-Arg-ProNHCH 2 CH 3 ;

N-Ac-D-Ile-Thr-Nva-Ile-ArgNHCH 2 CH 3 ; and

N-Ac-D-Ile-Thr-Nva-Lys(Ac)-Arg-NHCH 2 CH 3 .

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 8, 2013
From: ABBOTT LABORATORIES
To: ABBVIE INC.
Reel/Frame 030167/0733 →