3074 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 11
Letters
Scheme 3a
Scheme 6a
a Reagents and conditions: (a) HgCl2, triethylamine, amine, DMF, 4 h,
80%; (b) 6-(N-Boc)amino-1-hexanol or 4-(N-Boc)amino-1-butanol, Ph3P,
DIAD, THF, 0 °C to room temp, 12 h, 95-96%; (c) TFA, DCM, 12 h,
99%.
a Reagents and conditions: (a) TFA, DCM, room temp, 3-12 h,
98-100%; (b) methanesulfonic acid, dioxane, reflux, 2 h, 80-86%; (c) 12
N HCl, EtOH, 4 h at room temp, 6 h at 50 °C, 28-57%.
Scheme 4a
gave carbodiimide 9, which was in turn reacted with suitable
amines to give 10a,b, which after deprotection with trifluoro-
acetic acid furnished 11a,b as trifluoroacetates (Scheme 4).
Compound 15 was synthesized as reported in Scheme 5 from
the wholly protected guanidine 12 by alkylation, first with
cinnamic alcohol to give 13 and then with protected aminobu-
tanol to give 14, which after deprotection under standard
conditions gave 15 as a free amine.
To obtain 19a,b and 20a,b, thiourea 2b was first alkylated
with piperidine and N-methylpiperazine to give 16a,b, respec-
tively (Scheme 6). Reaction of these intermediates with 4-N-
(tert-butoxycarbonyl)amino-1-butanol and 6-N-(tert-butoxycar-
bonyl)amino-1-hexanol gave protected amines 17a,b and 18a,b,
which were then deprotected with trifluoroacetic acid to give
19a,b and 20a,b.
a Reagents and conditions: (a) p-fluorophenyl isothiocyanate, DCM, 12 h,
85%; (b) 2-chloro-N-methylpyridinium iodide, DIPEA, DCM, 12 h, 90%;
(c) suitable amine, isocyanate resin, toluol, 50 °C, 4 h, 90-99%; (d) TFA,
DCM, 3-12 h, 90-99%.
All compounds were evaluated in vivo in the widely used
diabetic db/db mice, characterized by a defect in the leptin
receptor, inducing hyperphagia, obesity, hyperglycemia, hyper-
insulinemia, and insulin resistance. Administration was per-
formed in male mice twice a day for 4 days and once on day 5,
by subcutaneous route, to overcome, in this first investigation,
any possible interference in adsorption and gastrointestinal
stability due to structural differences between the compounds.
On day 5, 8 h after last administration and in postabsorptive
conditions, improvements of glucose homeostasis, glucose
tolerance, and insulin sensitivity were evaluated using the insulin
suppression test (IST) of Greenfield et al.,7 as modified for
diabetic obese mice8 and slightly further modified (somatostatin
was substituted for propranolol and epinephrine,9 and blood was
withdrawn 60 min after the load injection, having verified that
at this time nearly steady-state plasma glucose and insulin levels
were reached). Values at time 0 can be viewed as postabsorptive
glucose levels. All the investigated molecules were given at
doses equivalent to 25 mg/kg 1a, while the antidiabetic drugs
metformin and rosiglitazone, used as reference compounds, were
administered in the same way at the respective doses, as reported
below. There was a significant reduction of glycemia with
respect to control for 1a (-31%), accompanied by a 53%
reduction of water consumption and about a 20% reduction in
food intake, while there was only a 13% reduction in glycemia
with 1b, together with a similar water consumption but a higher
(-37% vs control) reduction of food intake with respect to 1a.
During the investigation of the effects of the alkyl chain length
between amine and guanidine groups, the best antihyperglycemic
effect was produced by the six-carbon chain while the five- and
four-carbon chains (1m and 1b, respectively) seemed to be
endowed with the highest reduction in food intake. When the
double bond of the unsaturated alkyl substituent was replaced
by the corresponding saturated moiety, as in 1q, the activity
Scheme 5a
a Reagents and conditions: (a) Ph3P, DIAD, cinnamic alcohol, THF, 0
°C to reflux, 12 h, 74%; (b) Ph3P, DIAD, 4-(N-Boc)aminobutanol, THF, 0
°C to reflux, 12 h, 29%; (c) cyclohexene, 10% Pd/C, MeOH, reflux, 8 h,
88%.
Amines 4a-t were obtained by alkylation of intermediate
3a with suitable Boca-aminoalcohols (intermediates 4c,d) or by
reaction of 2b or 3b-f with different amines (intermediates
4a,b,e-t) (Scheme 2).
Deprotection of 4a-t with TFA, HCl, or CH3SO3H gave the
final compounds 1a-t as corresponding salts (Scheme 3).
Compounds 1s and 1t are two- and three-carbon superior
homologues of agmatine.
Compound 6 (see Table 1) was synthesized starting from 4n
by standard bromination with CBr4 in the presence of PPh3,
followed by deprotection with methanesulfonic acid.
Compounds 11a,b, having three substituents on guanidine,
were synthesized starting from Boc-protected 1,6-hexamethyl-
enediamine 7 and p-fluorophenyl isothiocyanate to give thiourea
8. Reaction of the thiourea with Mukaiyama’s reagent readily
a Abbreviations: Boc, tert-butoxycarbonyl; TFA, trifluoroacetic acid;
DIAD, diisopropyl azadicarboxylate; DCM, dichloromethane; DIPEA,
diisopropylethylamine.