328
A. Mastrolorenzo et al. / European Journal of Pharmaceutical Sciences 11 (2000) 325–332
Val), 130.8 (Cmeta of CH3C6H4), 132.3 (NHCONH), 134.9
3JHH 5 7.8, 1H, CH2CH of Tyr), 7.21–7.69 (m, 6H, Hortho
3
]
]
]
]
(Cortho of CH3C6H4), 145.0 (Cpara of CH3C6H4), 148.4
of CH3C6H4 and Harom of Tyr), 7.98 (d, JHH 5 8.3, 2H,
]
]
]
]
]
Hmeta of CH3C6H4). 13C-NMR: 26.0 (CH3C6H4), 41.3
(Cipso of CH3C6H4), 178.8 (CO2H of Val). Analysis,
]
]
]
found: C, 49.72; H, 6.02; N, 8.80%; C13H18N2O5S (M5
314.362) requires: C, 49.67; H, 5.77; N, 8.91%.
(CH2CH of Tyr), 59.8 (CH2CH of Tyr), 130.9 (Cpara of
]
]
Tyr), 132.2 (Cmeta of CH3C6H4), 132.9 (NHCONH), 133.5
]
]
a-4-Toluenesulfonylureido-L-lysine hydrochloride, ts-
Lys?HCl (10d) (as white crystals): 1H-NMR: 1.66–2.20
(m, 6H, CH(CH2)3CH2 of Lys), 2.61 (s, 3H, CH3C6H4),
(Cmeta of Tyr), 134.8 (Cortho of Tyr), 135.5 (Cortho of
]
]
]
CH3C6H4), 145.1 (Cpara of CH3C6H4), 146.5 (Cipso of
]
]
Tyr), 148.6 (Cipso of CH3C6H4), 178.9 (CO2H of Tyr).
]
]
]
]
3
3.13 (t, JHH 5 6.7, 2H, CH2CH2NH2 of Lys), 3.84 (t,
Analysis, found: C, 53.90; H, 4.62; N, 7.25%;
C17H18N2O6S (M5378.41) requires: C, 53.96; H, 4.79;
N, 7.40%.
]
3JHH 5 6.7, 1H, CH2CH(NH)CO2H of Lys), 7.63 (d,
]
3JHH 5 8.1, 2H, Hortho of CH3C6H4), 7.98 (d, 3JHH 5 8.1,
]
2H, Hmeta of CH3C6H4). 13C-NMR: 26.0 (CH3C6H4), 26.6
4-Toluenesulfonylureido-L-2,3-dioxyphenylalanine, ts-
DOPA (10h) (as tan crystals): 1H-NMR: 2.65 (s, 3H,
CH3C6H4), 3.08–3.54 (m, 2H, CH2CH of DOPA), 4.16
]
]
(H2NCH2(CH2)3 of Lys), 31.4 (H2NCH2(CH2)3 of Lys),
]
]
34.8 (H2NCH2(CH2)3 of Lys), 43.8 (H2NCH2(CH2)3 of
]
]
]
]
(dd, 3JHH 5 5.0, 3JHH 5 7.8, 1H, CH2CH of DOPA), 7.09–
Lys), 58.8 (CH2CH(NH)CO2H of Lys), 130.8 (Cmeta of
]
]
]
CH3C6H4), 132.4 ] (NHCONH), 135.0 (Cortho of
7.66 (m, 5H, Hortho of CH3C6H4 and Harom of DOPA),
]
]
]
]
7.95 (d, JHH 5 8.3, 2H, Hmeta of CH3C6H4). 13C-NMR:
3
CH3C6H4), 144.9 (Cpara of CH3C6H4), 148.5 (Cipso of
CH3C6H4), 177.6 (CO2H of Lys). Analysis (of the free
base, obtained by neutralization of the hydrochloride with
NaHCO3), found: C, 48.61; H, 6.36; N, 12.08%;
C14H21N3O5S (M5343.404) requires: C, 48.97; H, 6.16;
N, 12.24%.
]
]
]
26.2 (CH3C6H4), 41.5 (CH2CH of Phe), 60.5 (CH2CH of
DOPA), 132.2 (Cmeta of CH3C6H4), 132.9 (NHCONH),
133.5 (Cmeta of DOPA), 134.3 (Cpara of DOPA), 134.8
]
]
]
]
]
]
]
]
(Cortho of DOPA), 135.5 (Cortho of CH3C6H4), 135.8
]
]
]
]
(Cmeta(OH) of DOPA), 145.0 (Cpara of CH3C6H4), 147.9
]
a-4-Toluenesulfonylureido-L-arginine hydrochloride, ts-
(Cipso of DOPA), 148.6 (Cipso of CH3C6H4), 180.6 (CO2H
]
]
Arg?HCl (10e) (as white crystals): 1H-NMR: 1.70–2.00
of DOPA). Analysis, found: C, 51.64; H, 4.39; N, 7.03%;
C17H18N2O7S (M5394.41) requires: C, 51.77; H, 4.60;
N, 7.10%.
(m, 2H, CHCH2CH2 of Arg), 2.50–2.58 (m, 2H,
]
CHCH2CH2 of Arg), 2.63 (s, 3H, CH3C6H4), 3.30–3.45
]
]
(m, 2H, CH2CH2NH of Arg), 3.45–3.60 (m, 1H,
4-Toluenesulfonylureido-L-tryptophan, ts-Trp (10i) (as
]
CH2CH(NH)CO2H of Arg), 7.64 (d, 3JHH 5 8.1, 2H, Hortho
]
white crystals): 1H-NMR: 2.62 (s, 3H, CH3C6H4), 3.44
]
]
of CH3C6H4), 7.98 (d, 3JHH 5 8.1, 2H, Hmeta of
3
2
(dd, JHH 5 9.0, JHH 5 14.6, 1H, CH2CH of Trp), 3.65
]
]
13C-NMR:
26.0
(CH3C6H4),
29.7
3
2
CH3C6H4).
(dd, JHH 5 4.1, JHH 5 15.0, 1H, CH2CH of Trp), 4.14
(dd, JHH 5 4.3, JHH 5 8.0, 1H, CH2CH of Trp), 7.22–
]
]
3
3
(CH2CH2CH2 of Arg), 35.4 (CHCH2CH2 of Arg), 45.7
]
]
]
]
(CH2CH2NH of Arg), 59.8 (CH2CH(NH)CO2H of Arg),
7.82 (m, 7H, Hortho of CH3C6H4 and Harom of Trp), 7.92
]
]
]
130.8 (Cmeta of CH3C6H4), 131.5 ](NHCONH), 134.9
(d, JHH 5 8.2, 2H, Hmeta of CH3C6H4). 13C-NMR: 26.0
3
]
]
]
(Cortho of CH3C6H4), 145.0 (Cpara of CH3C6H4), 148.4
(Cipso of CH3C6H4), 161.5 (NHC(NH)NH2 of Arg), 183.2
(CO2H of Arg). Analysis (of the free base, obtained by
neutralization of the hydrochloride with NaHCO3), found:
C, 45.51; H, 5.49; N, 18.66%; C14H21N5O5S (M5
371.417) requires: C, 45.27; H, 5.70; N, 18.86%.
(CH3C6H4), 31.6 (CH2CH of Trp), 58.8 (CH2CH of Trp),
113.9 (C-2 of Trp), 116.9 (C-7 of Trp), 123.4 (C-5 of Trp),
124.3 (C-6 of Trp), 126.8 (C-4 of Trp), 129.0 (C-1 of Trp),
130.9 (Cmeta of CH3C6H4), 132.1 (C-8 of Trp), 132.2
(NHCONH), 135.0 (Cortho of CH3C6H4), 141.2 (C-3 of
Trp), 145.0 (Cpara of CH3C6H4), 148.6 (Cipso of
CH3C6H4), 179.0 (CO2H of Trp). Analysis, found: C,
56.93; H, 4.54; N, 10.31%; C19H19N3O5S (M5401.443)
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
]
4-Toluenesulfonylureido-L-phenylalanine, ts-Phe (10f)
]
(as white crystals): 1H-NMR: 2.65 (s, 3H, CH3C6H4),
]
3.10–3.55 (m, 2H, CH2CH of Phe), 4.08 (dd, 3JHH 5 5.0,
requires: C, 56.85; H, 4.77; N, 10.47%.
]
3JHH 5 7.8, 1H, CH2CH of Phe), 7.29–7.58 (m, 7H, Hortho
4-Toluenesulfonylureido-glycylglycine,
ts-Gly–Gly
]
]
3
1
of CH3C6H4 and Harom of Phe), 7.95 (d, JHH 5 8.3, 2H,
(10j) (as white crystals): H-NMR: 2.49 (s, 4H, 2 CH2),
]
]
Hmeta of CH3C6H4). 13C-NMR: 26.2 (CH3C6H4), 41.7
(CH2CH of Phe), 59.3 (CH2CH of Phe), 130.9 (Cpara of
Phe), 132.3 (Cmeta of CH3C6H4), 132.7 (NHCONH), 133.8
(Cmeta of Phe), 134.4 (Cortho of Phe), 135.1 (Cortho of
2.73 (s, 3H, CH3C6H4), 7.75 (d, 3JHH 5 8.2, 2H, Hortho of
]
]
]
]
CH3C6H4), 8.08 (d, 3JHH 5 8.2, 2H, Hmeta of CH3C6H4).
]
]
]
]
13C-NMR: 26.0 (CH3C6H4), 35.7 (CH2 of Gly), 130.8
]
]
]
]
(Cmeta of CH3C6H4), 134.9 (Cortho of CH3C6H4), 145.0
]
]
]
]
]
]
CH3C6H4), 141.5 (Cipso of Phe), 145.0 (Cpara of
(Cipso of CH3C6H4), 148.4 (Cpara of CH3C6H4). Analysis,
]
]
]
CH3C6H4), 148.6 (Cipso of CH3C6H4), 178.6 (CO2H of
found: C, 43.70; H, 4.82; N, 12.54%; C12H15N3O6S (M5
329.334) requires: C, 43.76; H, 4.59; N, 12.76%.
4-Toluenesulfonylureido-carnosine, ts-b-Ala–His (ts-
]
]
Phe). Analysis, found: C, 56.41; H, 4.85; N, 7.60%;
C17H18N2O5S (M5349.39) requires: C, 56.34; H, 5.01;
N, 7.73%.
1
carnosine) (10k) (as white crystals): H-NMR: 2.63 (s, 3H,
4-Toluenesulfonylureido-L-tyrosine, ts-Tyr (10g) (as
CH3C6H4), 2.79–2.88 (m, 2H, CH2 of b-Ala), 3.11–3.26
]
]
pale tan crystals): 1H-NMR: 2.61 (s, 3H, CH3C6H4),
(m, 2H, CH2 of b-Ala), 3.34–3.45 (m, 2H, CHCH2 of
]
]
]
3
3.12–3.59 (m, 2H, CH2CH of Tyr), 4.13 (dd, JHH 5 5.0,
His), 4.57–4.63 (m, 1H, CHCH2 of His), 7.32 (s, 1H, CH-5
]
]
]