CA2466170A1 - Hexa-, hepta-, and octapeptides having antiangiogenic activity - Google Patents

Hexa-, hepta-, and octapeptides having antiangiogenic activity Download PDF

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CA2466170A1
CA2466170A1 CA002466170A CA2466170A CA2466170A1 CA 2466170 A1 CA2466170 A1 CA 2466170A1 CA 002466170 A CA002466170 A CA 002466170A CA 2466170 A CA2466170 A CA 2466170A CA 2466170 A1 CA2466170 A1 CA 2466170A1
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gln
gly
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CA2466170C (en
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Fortuna Haviv
Michael F. Bradley
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AbbVie Inc
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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, method s of treatment using these compounds, and methods of inhibiting angiogenesis.< /SDOAB>

Claims (22)

1. A compound of formula (1) 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, amino, aryl, carboxyl, cycloalkenyl, cycloalkyl, and heterocycle;
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, Beryl, 3-(2-thienylalanyl), threonyl, valyl, and N-methylvalyl;
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, isoleucyl, D-isoleucyl, D-leucyl, N-methyl-D-leucyl, D-norleucyl, D-norvalyl, D-penicillaminyl, D-phenylalanyl, D-prolyl, D-Beryl, 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, norvalyl, D-norvalyl, N-methylnorvalyl, octylglycyl, ornithyl(N-delta-acetyl), 3-(3-pyridyl)alanyl, sarcosyl, Beryl, N-methylseryl, threonyl, tryptyl, valyl, and N-methylvalyl;
Xaa7 is selected from the group consisting of alanyl, alloisoleucyl, aspartyl, citralyl, 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; R2 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.
2. The compound of claim 1 wherein Xaa2 is selected from the group consisting of alanyl, D-alanyl, asparaginyl, 4-cyanophenylalanyl, 4-methylphenylalanyl, and norvalyl.
3. The compound of claim 2 selected from the group consisting of N-Ac-(4CH3)Phe-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-(4CN)Phe-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Ala-Gln-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Asn-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Ala-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Asn-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Nva-Val-D-Ile-Thr-Nva-Ile-ArgNHCH2CH3;
N-Ac-Nva-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Ala-Gln-D-Ile-Thr-Nva-Ile-ArgNHCH2CH3;
N-Ac-DAla-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH2CH3;
N-Ac-Ala-Gln-D-Ile-Thr-Ser-Ile-Arg-ProNHCH2CH3;
N-Ac-Ala-Val-D-alle-Ser-Gln-Ile-Arg-ProNHCH2CH3;
N-Ac-Ala-Val-D-aIle-Ser-Gln-Ile-ArgNHCH2CH3;
N-Ac-(4CH3)Phe-Gln-D-Ile-Thr-Nva-Ile-ArgNHCH2CH3; and N-Ac-(4CH3)Phe-Gln-D-Ile-Thr-Gln-Ile-Arg-ProNHCH2CH3.
4. The compound of claim 1 wherein Xaa2 is selected from the group consisting of glutaminyl and D-glutaminyl.
5. The compound of claim 4 selected from the group consisting of N-Ac-Gln-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gln-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Gln-Val-D-Ile-Thr-Nva-Pro-Arg-Pro-D-AlaNH2;
N-Ac-Gln-Gln-D-Ile-Thr-Nva-Lys(Ac)-Arg-Pro-D-AlaNH2;
N-Ac-Gln-Val-D-Ile-Thr-Nva-Ile-ArgNHCH2CH3;
N-Ac-D-Gln-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-D-Gln-Val-DIle-Thr-Gln-Ile-Arg-ProNHCH2CH3;
N-Ac-Gln-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH2CH3;
N-Ac-Gln-Val-D-aIle-Ser-Ser-Ile-Arg-ProNHCH2CH3;
N-Ac-D-Gln-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH2CH3;
N-Ac-D-Gln-Val-D-aIle-Ser-Gln-Ile-ArgNHCH2CH3;
N-Ac-Gln-Val-D-aIle-Ser-Gln-Ile-ArgNHCH2CH3;

N-Ac-Gln-Val-D-Ile-Thr-Nva-Pro-ArgNHCH2CH3; and N-Ac-Gln-Val-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH2CH3.
6. The compound of claim 1 wherein Xaa2 is glycyl.
7. The compound of claim 6 wherein Xaa3 is selected from the group consisting of arginyl, asparaginyl, D-asparaginyl, citrullyl, lysyl(N-epsilon-acetyl), and histidyl.
8. The compound of claim 7 selected from the group consisting of N-Ac-Gly-Asn-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Cit-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Lys(Ac)-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-His-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-His-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Asn-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-D-Asn-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH2CH3;
N-Ac-Gly-Arg-D-Ile-Thr-Nva-Ile-Gln-Pro-D-AlaNH2; and N-Ac-Gly-His-D-aIle-Ser-Gln-Ile-Arg-ProNHCH2CH3.
9. The compound of claim 6 wherein Xaa3 is selected from the group consisting of valyl and N-methylvalyl.
10. The compound of claim 9 wherein Xaa6 is selected from the group consisting of norvalyl and N-methylnorvalyl.
11. The compound of claim 10 selected from the group consisting of N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-aIle-Thr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-Ile-alloThr-Nva-Ile-Arg-ProNHCH2CH3;
N-(6-Me-nicotinyl)-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-Ile-Thr-Nva-D-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-Ile-Thr-Nva-Pro-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-Ile-Thr-Nva-Lys(Ac)-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-NMeVal-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-Ile-Thr-NMeNva-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-Ile-NMeGlu-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-ArgNHCH2CH3;
N-(6-Me-nicotinyl)-Gly-Val-D-Ile-Thr-Nva-Ile-ArgNHCH2CH3;

N-Ac-Gly-Val-D-Ile-alloThr-Nva-Ile-ArgNHCH2CH3;
N-Ac-Gly-Val-D-Ile-Thr-Nva-Ile-ArgNHCH2CH3;
N-Ac-Gly-Val-D-Ile-Thr-Nva-D-Ile-ArgNHCH2CH3; and N-(6Me-nicotinyl)-Gly-Val-DIle-Thr-Nva-Ile-ArgNHCH2CH3.
12. The compound of claim 9 wherein Xaa6 is selected from the group of glutaminyl, seryl, and threonyl.
13. The compound of claim 12 selected from the group consisting of N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-aIle-Ser-Ser-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-aIle-Thr-Ser-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-aIle-Ser-Thr-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH2CH3; and N-Ac-Gly-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH2.
N-Ac-Gly-Val-D-Ile-Ser-Gln-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-Leu-Ser-Gln-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-aIle-Ser-Gln-Lys(Ac)-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-alle-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;
N-Ac-Gly-Val-D-aIle-Thr-Gln-Ile-Arg-ProNHCH2CH3;
N-6MeNic-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-ArgNHCH2CH3;
N-Ac-Gly-Val-D-aIle-Ser-Ser-Ile-ArgNHCH2CH3;
N-Ac-Gly-Val-D-Ile-Thr-Gln-Ile-ArgNHCH2CH3; and N-Ac-Gly-Val-D-Ile-Thr-Ser-Ile-ArgNHCH2CH3.
14. The compound of claim 6 wherein Xaa3 is selected from the group consisting of glutaminyl, D-glutaminyl, phenylalanyl, and N-methylphenylalanyl.
15. The compound of claim 14 wherein Xaa7 is isoleucyl.
16. The compound of claim 15 selected from the group consisting of N-Ac-Gly-Phe-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Gln-D-aIle-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Ile-alloThr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Ile-Thr-Ser-Ile-Arg-Pro-D-AlaNH2;

N-Ac-Gly-D-Gln-D-Ile-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Ile-Tyr-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Gln-D-Ile-Met-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Ile-Thr-Gln-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Ile-Tyr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Leu-Thr-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Leu-Ser-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-aIle-Thr-Ser-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Ile-Asp-Nva-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Ile-Thr-Trp-Ile-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Phe-D-Ile-Ser-Gln-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Gln-D-aIle-Ser-Nva-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Gln-D-aIle-Ser-Gln-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-NMePhe-D-Ile-Thr-Nva-Ile-Arg-ProNHCH2CH3; and N-Ac-Gly-Gln-D-Ile-Thr-Nva-Ile-ArgNHCH2CH3.
17. The compound of claim 14 wherein Xaa7 is selected from the group consisting of D-isoleucyl, lysyl(N-epsilon acetyl), and D-prolyl.
18. The compound of claim 17 selected from the group consisting of N-Ac-Gly-Gln-D-Ile-Thr-Nva-D-Ile-Arg-ProNHCH2CH3;
N-Ac-Gly-Gln-D-Ile-Thr-Nva-D-Pro-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Ile-Thr-Nva-Lys(Ac)-Arg-Pro-D-AlaNH2;
N-Ac-Gly-Gln-D-Ile-Thr-Nva-D-Ile-Arg-Pro-D-AlaNH2; and N-Ac-Gly-Gln-D-aIle-Thr-Nva-Lys(Ac)-Arg-Pro-D-AlaNH2.
19. A compound which is N-Ac-Gly-Val-D-aIle-Ser-Gln-Ile-Arg-ProNHCH2CH3.
20. A pharmaceutical composition comprising a compound of claim 1, or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.
21. 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.
22. 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.
CA2466170A 2001-10-31 2002-10-30 Hexa-, hepta-, and octapeptides having antiangiogenic activity Expired - Fee Related CA2466170C (en)

Applications Claiming Priority (5)

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US10/000,681 2001-10-31
US10/000,681 US20030125259A1 (en) 2001-10-31 2001-10-31 Octa- and nonapeptides having antiangiogenic activity
US10/263,812 2002-10-04
US10/263,812 US20030096758A1 (en) 2001-10-31 2002-10-04 HEPTA-, OCTA- and nonapeptides having antiangiogenic activity
PCT/US2002/034811 WO2003037268A2 (en) 2001-10-31 2002-10-30 Hepta-, octa- and nonapeptides having antiangiogenic activity

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CN (1) CN1639188A (en)
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CA (1) CA2466170C (en)
IL (1) IL161527A0 (en)
MX (1) MXPA04004131A (en)
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PL (1) PL374238A1 (en)
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US5932545A (en) * 1997-03-17 1999-08-03 Abbott Laboratories Antiangiogenic drug to treat cancer, arthritis and retinopathy
US6433149B1 (en) * 1998-05-05 2002-08-13 Adherex Technologies, Inc. Compounds and methods for inhibiting cancer metastasis
ES2307337T3 (en) * 1998-05-22 2008-11-16 Abbott Laboratories ANTI-ANGIOGENIC PEPTIDIC MEDICINES.

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IL161527A0 (en) 2004-09-27
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TW200302832A (en) 2003-08-16
MXPA04004131A (en) 2004-07-08
WO2003037268A3 (en) 2003-09-12
CN1639188A (en) 2005-07-13
PL374238A1 (en) 2005-10-03
CA2466170C (en) 2011-04-05
EP1451210A2 (en) 2004-09-01
EP1451210A4 (en) 2009-05-27
JP2005512981A (en) 2005-05-12
TWI268934B (en) 2006-12-21
WO2003037268A2 (en) 2003-05-08

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