5208 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 25
David et al.
C8 Kromasil (5 µm, 100 Å) CH3CN/H2O (TFA) 15/85, tR ) 10.2
min. MS 421.8 ) MH+, 443.8 ) MNa+.
27: [[(2R, 3R), 3-Am in o-5-p h osp h on a te-2-su lfh yd r yl]-
pen tan oyl]-(L)Ile-(L)Asp-OH. White powder. 1H NMR (DMSO-
d6 + TFA) δ 0.75 (t, 3H, CH3δ Ile), 0.8 (d, 3H, CH3γ Ile), 1.0
and 1.4 (m, 2H, CH2γ Ile), 1.6 to 2.0 (m, 5H, CHâ Ile, CH-
CH2-CH2, CH-CH2-CH2), 2.65 (m, 2H, CH2â Asp), 3.25 (d, 1H,
SH), 3.4 (m, 1H, CH-CH2-CH2), 3.95 (m, 1H, CH-S), 4.25 (dd,
1H, CHR Ile), 4.5 (dd, 1H, CHR Asp), 8.0 (broad s, 3H, H3N+),
8.4 (d, 1H, CONH Asp), 8.55 (d, 1H, CONH Ile). HPLC C18
Kromasil (5 µm, 100 Å) CH3CN/H2O (TFA) 15/85, tR ) 3.6 min.
MS 458.3 ) MH+.
28: [[(2S, 3R), 3-Am in o-2-su lfh yd r yl-5-su lfon a te]-p en -
ta n oyl]-(L)Tyr -(L)Asp -OH. White powder. 1H NMR (DMSO-
d6 + TFA) δ 1.9 (m, 2H, CH-CH2-CH2), 2.5 to 2.7 (m, 4H, CH2â
Asp, CH2â Tyr), 2.8 (d, 1H, SH), 2.9 (m, 2H, CH-CH2-CH2),
3.5 (m, 1H, CH-CH2-CH2), 3.7 (m, 1H, CH-S), 4.5 (m, 2H, CHR
Tyr, CHR Asp), 6.6 (d, 2H, CH arom. ortho OH), 7.0 (d, 2H,
CH arom. meta OH), 8.0 (broad s, 3H, NH3+), 8.4 (d, 1H,
CONH Asp), 8.5 (d, 1H, CONH Tyr). HPLC C8 Kromasil (5
µm, 100 Å) gradient CH3CN/H2O (TFA) 10/60, tR ) 8.4 min.
MS 507.7 ) MH+, 529.6 ) MNa+. Anal. (C17H29N4O10S2F3) C,
H, N.
29: [[(2R, 3R), 3-Am in o-2-su lfh yd r yl-5-su lfon a te]-p en -
ta n oyl]-(L)Tyr -(L)Asp -OH. White powder. 1H NMR (DMSO-
d6 + TFA) δ 1.4 to 1.6 (m, 2H, CH-CH2-CH2), 2.5 to 2.7 (m,
4H, CH2â Asp, CH2â Tyr), 2.9 (m, 2H, CH-CH2-CH2), 3.2 (d,
1H, SH), 3.5 (m, 1H, CH-CH2-CH2), 3.8 (d, 1H, CH-S), 4.5 (m,
2H, CHR Tyr, CHR Asp), 6.6 (d, 2H, CH arom. ortho OH), 7.0
(d, 2H, CH arom. meta OH), 7.9 (broad s, 3H, NH3+), 8.4 (d,
1H, CONH Asp), 8.6 (d, 1H, CONH Tyr). HPLC C8 Kromasil
(5 µm, 100 Å) gradient CH3CN/H2O (TFA) 10/60, tR ) 8.0 min.
MS 507.8 ) MH+, 529.7 ) MNa+.
20: [[(2S, 3R), 3-Am in o-5-ca r boxyla te-2-su lfh yd r yl]-
p en ta n oyl]-(L)Ile-(L)Asp -OH. Compounds 20 and 21 were
obtained from the (2RS, 3R) isomer of IIc by procedure I and
HPLC separation. White powder. 1H NMR (DMSO-d6 + TFA)
δ 0.75 (t, 3H, CH3δ Ile), 0.85 (d, 3H, CH3γ Ile), 1.05 and 1.4
(m, 2H, CH2 Ile), 1.7 (m, 3H, CHâ Ile, CH-CH2-CH2), 2.25 (m,
2H, CH-CH2-CH2), 2.6 (m, 2H, CH2â Asp), 3.1 (m, 1H, SH),
3.4 (m, 1H, CH-CH2-CH2), 3.8 (m, 1H, CH-S), 4.2 (m, 1H, CHR
Ile), 4.5 (m, 1H, CHR Asp), 7.9 (broad s, 3H, H3N+), 8.4 (d,
1H, CONH Asp), 8.4 (d, 1H, CONH Ile). HPLC C8 Kromasil
(5 µm, 100 Å) CH3CN/H2O (TFA) 15/85, tR ) 8.9 min. MS 422.0
) MH+.
21: [[(2R, 3R), 3-Am in o-5-ca r boxyla te-2-su lfh yd r yl]-
pen tan oyl]-(L)Ile-(L)Asp-OH. White powder. 1H NMR (DMSO-
d6 + TFA) δ 0.75 (t, 3H, CH3δ Ile), 0.8 (d, 3H, CH3γ Ile), 1.0
and 1.4 (m, 2H, CH2Ile), 1.65 (m, 2H, CH-CH2-CH2), 1.8 (m,
1H, CHâ Ile), 2.35 (m, 2H, CH-CH2-CH2), 2.5 to 2.7 (m, 2H,
CH2â Asp), 3.3 (m, 1H, SH), 3.4 (m, 1H, CH-CH2-CH2), 4.0 (m,
1H, CH-S), 4.25 (m, 1H, CHR Ile), 4.5 (m, 1H, CHR Asp), 8.0
(broad s, 3H, H3N+), 8.45 (d, 1H, CONH Asp), 8.6 (d, 1H,
CONH Ile). HPLC C8 Kromasil (5 µm, 100 Å) CH3CN/H2O
(TFA) 15/85, tR ) 5.6 min. MS 422.0 ) MH+.
22: [[(2R, 3S), 3-Am in o-2-su lfh yd r yl-5-su lfon a te]-p en -
ta n oyl]-(L)Ile-(L)Asp -OH. Compounds 22 and 23 were ob-
tained from the (2RS, 3S) isomer of IIb by procedure I and
HPLC separation. White powder. 1H NMR (DMSO-d6 + TFA)
δ 0.75 (t, 3H, CH3δ Ile), 0.8 (d, 3H, CH3γ Ile), 1.05 and 1.4 (m,
2H, CH2γ Ile), 1.75 (m, 1H, CHâ Ile), 1.95 (m, 2H, CH-CH2-
CH2), 2.5 to 2.7 (m, 4H, CH-CH2-CH2, CH2â Asp), 3.5 (m, 1H,
CH-CH2-CH2), 3.9 (m, 1H, CH-S), 4.25 (dd, 1H, CHR Ile), 4.5
(dd, 1H, CHR Asp), 8.0 (broad s, 3H, H3N+), 8.3 (d, 1H, CONH
Asp), 8.6 (d, 1H, CONH Ile). HPLC C18 Kromasil (5 µm, 100
Å) CH3CN/H2O (TFA) 15/85, tR ) 6.0 min. MS 458.1 ) MH+,
480.1 ) MNa+. Anal. (C17H28N3O11S2F3) C, H, N.
30: [[(2S, 3R), 3-Am in o-2-su lfh yd r yl-5-su lfon a te]-p en -
1
ta n oyl]-(L)Ile-(L)Asp -NH2. White powder. H NMR (DMSO-
d6 + TFA) δ 0.7 (m, 6H, CH3δ Ile, CH3γ Ile), 1.0 and 1.4 (m,
2H, CH2γ Ile), 1.7 (m, 1H, CHâ Ile), 1.85 (m, 2H, CH-CH2-
CH2), 2.6 (m, 4H, CH-CH2-CH2, CH2â Asp), 3.45 (m, 1H, CH-
CH2-CH2), 3.75 (m, 1H, CH-S), 4.1 (dd, 1H, CHR Ile), 4.5 (dd,
1H, CHR Asp), 8.1 (broad s, 3H, H3N+), 8.15 (d, 1H, CONH
Asp), 8.55 (d, 1H, CONH Ile). HPLC C18 Kromasil (5 µm, 100
Å) CH3CN/H2O (TFA) 15/85, tR ) 4.9 min. MS 456.9 ) MH+,
478.9 ) MNa+. Anal. (C17H29N4O10S2F3) C, H, N.
23: [[(2S, 3S), 3-Am in o-2-su lfh yd r yl-5-su lfon a te]-p en -
1
ta n oyl]-(L)Ile-(L)Asp -OH. White powder. H NMR (DMSO-
d6 + TFA) δ 0.75 (t, 3H, CH3δ Ile), 0.8 (d, 3H, CH3γ Ile), 1.05
and 1.4 (m, 2H, CH2γ Ile), 1.75 (m, 1H, CHâ Ile), 1.95 (m, 2H,
CH-CH2-CH2), 2.5 to 2.7 (m, 4H, CH-CH2-CH2, CH2â Asp), 3.5
(m, 1H, CH-CH2-CH2), 3.9 (m, 1H, CH-S), 4.25 (dd, 1H, CHR
Ile), 4.5 (dd, 1H, CHR Asp), 8.0 (broad s, 3H, H3N+), 8.3 (d,
1H, CONH Asp), 8.6 (d, 1H, CONH Ile). HPLC C18 Kromasil
(5 µm, 100 Å) CH3CN/H2O (TFA) 15/85, tR ) 3.7 min. MS 458.0
) MH+, 480.0 ) MNa+.
24: [[(2S, 3R), 3-Am in o-2-su lfh yd r yl-5-su lfon a te]-p en -
ta n oyl]-(L)Ile-(L)Asp -OH. Compounds 24 and 25 were ob-
tained from the (2RS, 3R) isomer of IIb by procedure I and
HPLC separation. White powder. 1H NMR (DMSO-d6 + TFA)
δ 0.7 to 0.9 (m, 6H, 2 × CH3 Ile), 1.0 and 1.4 (m, 2H, CH2γ
Ile), 1.7 to 2.0 (m, 3H, CHâ Ile, CH-CH2-CH2), 2.5 to 2.8 (m,
4H, CH2â Asp, CH-CH2-CH2), 3.0 (d, 1H, 5H), 3.4 (m, 1H, CH-
CH2-CH2), 3.7 (m, 1H, CH-S), 4.2 (dd, 1H, CHR Ile), 4.5 (dd,
1H, CHR Asp), 8.0 (broad s, 3H, NH3+), 8.3 (d, 1H, CONH Asp),
8.5 (d, 1H, CONH Ile). MS 458.1 ) MH+.
31: [[(2R, 3R), 3-Am in o-2-su lfh yd r yl-5-su lfon a te]-p en -
1
ta n oyl]-(L)Ile-(L)Asp -NH2. White powder. H NMR (DMSO-
d6 + TFA) δ 0.8 (m, 6H, CH3δ Ile, CH3γ Ile), 1.05 and 1.4 (m,
2H, CH2γ Ile), 1.7 (m, 1H, CHâ Ile), 1.8 to 2.0 (m, 2H, CH-
CH2-CH2), 2.6 (m, 4H, CH-CH2-CH2, CH2â Asp), 3.5 (m, 1H,
CH-CH2-CH2), 3.9 (m, 1H, CH-S), 4.1 (dd, 1H, CHR Ile), 4.5
(dd, 1H, CHR Asp), 8.0 (broad s, 3H, H3N+), 8.15 (d, 1H, CONH
Asp), 8.5 (d, 1H, CONH Ile). HPLC C18 Kromasil (5 µm,100
Å) CH3CN/H2O (TFA) 15/85, tR ) 3.5 min. MS 456.9 ) MH+,
478.9 ) MNa+.
32: [[(2S, 3R), 3-Am in o-2-su lfh yd r yl-5-su lfon a te]-p en -
1
ta n oyl]-(D)Ile-(L)Asp -OH. White powder. H NMR (DMSO-
d6 + TFA) δ 0.8 (m, 6H, 2 × CH3 Ile), 1.1 and 1.4 (m, 2H,
CH2γ Ile), 1.75 (m, 1H, CHâ Ile), 1.95 (m, 2H, CH-CH2-CH2),
2.6 to 2.8 (m, 4H, CH-CH2-CH2, CH2â Asp), 3.55 (m, 1H, CH-
CH2-CH2), 3.8 (m, 1H, CH-S), 4.25 (dd, 1H, CHR Ile), 4.6 (dd,
1H, CHR Asp), 8.0 (broad s, 3H, H3N+), 8.35 (d, 1H, CONH
Asp), 8.45 (d, 1H, CONH Ile). HPLC C18 Kromasil (5 µm, 100
Å) CH3CN/H2O (TFA) 10/90, tR ) 6.5 min.
25: [[(2R, 3R), 3-Am in o-2-su lfh yd r yl-5-su lfon a te]-p en -
1
ta n oyl]-(L)Ile-(L)Asp -OH. White powder. H NMR (DMSO-
d6 + TFA) δ 0.7 to 0.9 (m, 6H, 2 × CH3 Ile), 1.0 and 1.45 (m,
2H, CH2γ Ile), 1.7 to 2.2 (m, 3H, CHâ Ile, CH-CH2-CH2), 2.5
to 2.9 (m, 4H, CH2â Asp, CH-CH2-CH2), 3.2 (d, 1H, SH), 3.5
(m, 1H, CH-CH2-CH2), 3.95 (m, 1H, CH-S), 4.25 (m, 1H, CHR
Ile), 4.5 (m, 1H, CHR Asp), 8.0 (broad s, 3H, NH3+), 8.3 (d,
1H, CONH Asp), 8.5 (d, 1H, CONH Ile). MS 458.2 ) MH+.
26: [[(2S, 3R), 3-Am in o-5-p h osp h on a te-2-su lfh yd r yl]-
pen tan oyl]-(L)Ile-(L)Asp-OH. White powder. 1H NMR (DMSO-
d6 + TFA) δ 0.75 (t, 3H, CH3δ Ile), 0.8 (d, 3H, CH3γ Ile), 1.05
and 1.4 (m, 2H, CH2γ Ile), 1.65 to 2.0 (m, 5H, CHâ Ile, CH-
CH2-CH2, CH-CH2-CH2), 2.6 (m, 2H, CH2â Asp), 3.1 (d, 1H,
SH), 3.4 (m, 1H, CH-CH2-CH2), 3.8 (m, 1H, CH-S), 4.2 (dd,
1H, CHR Ile), 4.5 (dd, 1H, CHR Asp), 8.0 (broad s, 3H, H3N+),
8.4 (2d, 2H, CONH Asp, CONH Ile). HPLC C18 Kromasil (5
µm, 100 Å) CH3CN/H2O (TFA) 15/85, tR ) 5.97 min. MS 458.4
) MH+. Anal. (C17H29N3O11SPF3) C, H, N.
33: [[(2R, 3R), 3-Am in o-2-su lfh yd r yl-5-su lfon a te]-p en -
1
ta n oyl]-(D)Ile-(L)Asp -OH. White powder. H NMR (DMSO-
d6 + TFA) δ 0.8 (m, 6H, 2 × CH3 Ile), 1.1 and 1.4 (m, 2H,
CH2γ Ile), 1.8 (m, 1H, CHâ Ile), 2.05 (m, 2H, CH-CH2-CH2),
2.6 to 2.9 (m, 4H, CH-CH2-CH2), 3.55 (m, 1H, CH-CH2-CH2),
3.9 (m, 1H, CH-S), 4.2 (dd, 1H, CHR Ile), 4.55 (dd, 1H, CHR
Asp), 8.0 (broad s, 3H, H3N+), 8.2 (d, 1H, CONH Asp), 8.4 (d,
1H, CONH Ile). HPLC C18 Kromasil (5 µm, 100 Å) CH3CN/
H2O (TFA) 10/90, tR ) 17.6 min.
34: [[(2S, 3R), 3-a m in o-2-su lfh yd r yl-5-su lfon a te]-p en -
1
ta n oyl]-(L)Ile-(D)Asp -OH. White powder. H NMR (DMSO-
d6 + TFA) δ 0.8 (m, 6H, 2 × CH3 Ile), 1.1 and 1.45 (m, 2H,
CH2γ Ile), 1.7 (m, 1H, CHâ Ile), 1.9 (m, 2H, CH-CH2-CH2), 2.5
to 2.7 (m, 4H, CH-CH2-CH2, CH2â Asp), 3.45 (m, 1H, CH-CH2-