Hepta-, Octa-and nonapeptides having antiangiogenic activity

1. A compound of formula (I)

Xaa 1 -Xaa 2 -Xaa 3 -Xaa4-Xaa 5 -Xaa 6 -Xaa 7 - Xaa 8 -Xaa 9 -Xaa 10 (I),  (SEQ ID NO:1)

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, aryl, carboxyl, cycloalkenyl, and cycloalkyl;

Xaa 2 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;

Xaa 3 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;

Xaa 4 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;

Xaa 5 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);

Xaa 6 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;

Xaa 7 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;

Xaa 8 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;

Xaa 9 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

Xaa 10 is selected from the group consisting of D-alanylamide, azaglycylamide, glycylamide, 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, 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 2 is glycyl.

3. The compound of claim 2 wherein Xaa 3 is selected from the group consisting of valyl and N-methylvalyl.

4. The compound of claim 3 wherein Xaa 6 is selected from the group of glutaminyl, seryl, and threonyl.

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

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

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

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

N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-ArgNHCH 2 CH 3 ; and

N-Ac-Gly-Val-D-Ile-Thr-Ser-Ile-ArgNHCH 2 CH 3 .

6. A compound which is N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2 CH 3 .

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

8. 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.

9. 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.

10. A compound of formula (I)

Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 (I),  (SEQ ID NO:1)

or a therapeutically acceptable salt thereof, wherein

Xaa 1 is hydrogen or 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, aryl, carboxyl, cycloalkenyl, and cycloalkyl;

Xaa 2 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;

Xaa 3 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;

Xaa 4 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;

Xaa 5 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 6 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;

Xaa 7 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;

Xaa 8 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 9 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

Xaa 10 is selected from the group consisting of D-alanylamide, azaglycylamide, glycylamide, 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, 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.

11. The compound of claim 10 wherein Xaa 2 is glycyl and Xaa 8 is arginyl.

12. The compound of claim 11 wherein Xaa 3 is valyl.

13. The compound of claim 12 wherein Xaa 6 is selected from the group of glutaminyl, seryl, and threonyl.

14. The compound of claim 13 selected from the group consisting of

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

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

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

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

N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2 CH 3 ; and

N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH 2 .

15. A pharmaceutical composition comprising a compound of claim 10 , or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.

16. 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 10 or a therapeutically acceptable salt thereof.

17. A compound selected from the group consisting of

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

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

N-Ac-Gly-Val-D-aIle-Tyr-Gln-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-Pro-D-AlaNH 2 ; and

N-Ac-Gly-Val-D-aIle-Thr-Gln-Ile-Arg-ProNHCH 2 CH 3 .

18. A compound selected from the group consisting of

N-6MeNic-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH 2 CH 3 ;

N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-ArgNHCH 2 CH 3 ; and

N-Ac-Gly-Val-D-aIle-Ser-Ser-Ile-ArgNHCH 2 CH 3 .