TRI-, TETRA-, and penta-peptides having antiangiogenic activity

1. A compound of formula (I)

Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 (SEQ ID NO: 1)  (I),

or a therapeutically acceptable salt thereof, wherein

Xaa 1 is 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 N-methylalanyl, allothreonyl, allylglycyl, arginyl, beta-alanyl, glutaminyl, D-glutaminyl, glycyl, homoseryl, leucyl, lysyl(N-epsilon acetyl), norleucyl, norvalyl, D-norvalyl, N-methylnorvalyl, omithyl(N-delta acetyl), 3-(3-pyridyl)alanyl, sarcosyl, seryl, D-seryl, N-methylseryl, threonyl, tryptyl, D-tryptyl, valyl, and N-methylvalyl;

Xaa 3 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 4 is selected from the group consisting of arginyl, D-arginyl, citrullyl, histidyl, isoleucyl, lysyl, lysyl(N-epsilon isopropyl), ornithyl, and 3-(3-pyridyl)alanyl;

Xaa 5 is absent or selected from the group consisting of N-methyl-D-alanyl, 2-aminobutyryl, 2-aminoisobutyryl, arginyl, D-glutaminyl, homoprolyl, hydroxyprolyl, leucyl, phenylalanyl, prolyl, D-prolyl, and D-valyl;

provided that when Xaa 4 is arginyl or D-arginyl then Xaa 5 is other than arginyl; and

Xaa 6 is selected from the group consisting of hydroxyl, D-alanylamide, azaglycylamide, glycylamide, D-lysyl(N-epsilon acetyl)amide, prolylethylamide, —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 of 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 allylglycyl, arginyl, beta-alanyl, norleucyl, leucyl, lysyl(N-epsilon-acetyl), glycyl, glutaminyl, D-glutaminyl, norvalyl, D-norvalyl, seryl, D-seryl, allothreonyl, threonyl, tryptyl, and D-tryptyl;

Xaa 3 is selected from the group consisting of citrullyl, isoleucyl, D-isoleucycl, lysyl(N-epsilon-acetyl), norvalyl, and prolyl;

Xaa 4 is selected from the group consisting of arginyl and isoleucyl;

Xaa 5 is absent or selected from the group consisting of prolyl and arginyl; and

Xaa 6 is selected from the group consisting of —NHCH 2 CH 3 , —NHCH(CH 3 ) 2 , prolylethylamide, and D-alanylamide.

3. The compound of claim 1 wherein Xaa 4 is arginyl.

4. The compound of claim 3 wherein Xaa 2 is selected from the group consisting of norvalyl and D-norvalyl.

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

N-Ac-Nva-Ile-Arg-Pro-NHCH 2 CH 3 (SEQ ID NO:2);

N-(6-methylnicotinyl)-Nva-Ile-Arg-Pro-NHCH 2 CH 3 (SEQ ID NO:4);

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

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

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

N-Ac-Nva-Lys(Ac)-Arg-Pro-NHCH 2 CH 3 ; (SEQ ID NO:16)

N-Ac-Nva-Ile-Arg-Pro-NHCH(CH 3 ) 2 ; (SEQ ID NO:18)

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

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

6. The compound of claim 3 wherein Xaa 2 is selected from the group consisting of glutaminyl, D-glutaminyl, leucyl, norleucyl, D-seryl, and seryl.

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

N-Ac-Gln-Ile-Arg-Pro-NHCH 2 CH 3 (SEQ ID NO:3);

N-Ac-Ser-Ile-Arg-Pro-NHCH 2 CH 3 (SEQ ID NO:5);

N-Ac-Nle-Ile-Arg-Pro-NHCH 2 CH 3 (SEQ ID NO:6);

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

N-Ac-Leu-Ile-Arg-Pro-NHCH 2 CH 3 (SEQ ID NO:7);

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

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

N-Ac-Ser-Cit-Arg-Pro-NHCH 2 CH 3 ; (SEQ ID NO:15)

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

N-Ac-Gln-Ile-Arg-Pro-NHCH(CH 3 ) 2 ; (SEQ ID NO:19)

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

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

8. The compound of claim 3 wherein Xaa 2 is selected from the group consisting of allothreonyl, allylglycyl, arginyl, glycyl, lysyl(N-epsilon acetyl), threonyl, D-tryptyl, and tryptyl.

9. The compound of claim 8 selected from the group consisting of

N-Ac-Lys(Ac)-Ile-Arg-Pro-NHCH 2 CH 3 (SEQ ID NO:8);

N-Ac-Gly-Ile-Arg-Pro-NHCH 2 CH 3 (SEQ ID NO:9);

N-Ac-alloThr-Ile-Arg-Pro-NHCH 2 CH 3 (SEQ ID NO: 10);

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

N-Ac-Trp-Ile-Arg-Pro-NHCH 2 CH 3 (SEQ ID NO:11);

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

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

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

N-Ac-Thr-Pro-Arg-Pro-NHCH 2 CH 3 ; (SEQ ID NO:12)

N-Ac-Allylgly-Ile-Arg-Pro-NHCH 2 CH 3 ; (SEQ ID NO:13)

N-Ac-D-Trp-Ile-Arg-Pro-NHCH 2 CH 3 ;

N-Ac-Arg-Ile-Arg-Pro-NHCH 2 CH 3 ; (SEQ ID NO:14)

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

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

N-Ac-Trp-Pro-Arg-NHCH 2 CH 3 .

10. The compound of claim 1 wherein Xaa 5 is arginyl.

11. The compound of claim 10 wherein Xaa 2 is beta-alanyl.

12. The compound of claim 11 that is N-Ac-bAla-Nva-Ile-Arg-Pro-NHCH 2 CH 3 ; (SEQ ID NO:17).

13. A pharmaceutical composition comprising a compound of claim 1 , or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.