7864 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24
Smits et al.
(d, J ) 8.8 Hz, 1H), 3.62 (t, J ) 4.9 Hz, 4H), 2.37 (t, J ) 4.9 Hz,
4H), 2.20 (s, 3H); MS (ESI) m/z 279 (M + H)+.
purified over SiO2 (EtOAc 90%, Et3N 5%, MeOH 5%) to yield
186 mg (87%) of the title compound. H NMR (CDCl3) δ (ppm)
1
2,4,7-Trichloroquinazoline (25). 7-Chloroquinazolin-2,4(1H,3H)-
dione (1.03 g, 5.21 mmol), DIPEA (1.91 mL, 10.95 mmol), and
POCl3 (5.0 mL) were heated at reflux. After 4 h the hot mixture
was carefully poured onto crushed ice, causing a precipitate to form
after vigorous stirring. The formed suspension was extracted with
CH2Cl2, and the organic phases were combined. After the mixture
was washed with brine and dried over Na2SO4, the solvent was
removed and the title compound was obtained as a yellow solid
that was used in the next step without further purification. Yield:
1.124 g (96%). 1H NMR (DMSO-d6) δ (ppm) 8.17 (d, J ) 9.0 Hz,
1H), 7.96 (d, J ) 2.0 Hz), 7.66 (d, J ) 2.0 Hz, J ) 9.0 Hz, 1H).
6-Chloro-2-(4-methylpiperazin-1-yl)quinazolin-4-amine (30).
2,4,6-Trichloroquinazoline (300 mg, 1.28 mmol) was added to a
saturated solution of ammonia in MeOH (5.0 mL) and stirred at
room temperature. After 16 h the mixture was diluted with EtOAc
(50 mL) and washed with water and brine. After the mixture was
dried over Na2SO4, the organic phase was concentrated (about 3
mL) and transferred to a microwave tube containing N-methylpip-
erazine (1.0 mL). The mixture was heated at 140 °C for 5 min
using microwave irradiation. The formed suspension was then
diluted with EtOAc and washed with water and brine. Subsequent
drying over Na2SO4 and evaporation of the solvent yielded an
orange solid that was purified over SiO2 (EtOAc 90%, Et3N 5%,
MeOH 5%). The title compound was obtained as 276 mg (78%)
7.44-7.35 (m, 3H), 5.45 (d, J ) 4.2 Hz, 1H), 5.06-4.89 (m, 2H),
3.18-3.02 (m, 6H), 2.74-2.65 (m, 1H), 2.29-2.11 (m, 2 H),
2.02-1.74 (m, 4H), 1.56-1.50 (m, 1H); 13C NMR (CDCl3) δ (ppm)
159.46, 158.76, 150.50, 132.73, 127.14, 125.41, 120.07, 110.97,
62.53, 53.43, 52.00, 48.25, 43.10, 27.99, 27.14, 21.06; MS (ESI)
m/z 318 (M + H)+.
Acknowledgment. Thanks goes to Debora Granemann for
synthetic assistance. The authors also greatly appreciate the
technical assistance of Frans de Kanter.
Supporting Information Available: Purity data for compounds
5, 7, 11, and 29-64 as determined by LC-MS; experimental details
for compounds 7, 19-22, 26-29, 32, 33, 35-39, and 41-64. This
material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) de Esch, I. J. P.; Thurmond, R. L. J. A.; Jongejan, A.; Leurs, R. The
histamine H4 receptor as a new therapeutic target for inflammation.
Trends Pharmacol. Sci. 2005, 26, 462–469.
(2) Hill, S., J. Distribution, properties and functional characteristics of
three classes of histamine receptor. Pharm. ReV. 1990, 42, 45–83.
(3) Klabunde, T.; Hessler, G. Drug design strategies for targeting
G-protein-coupled receptors. ChemBioChem 2002, 3, 928–944.
(4) Black, J. W.; Garbarg, M.; Durant, G., J.; Ganellin, C., R.; Parsons,
M. E. Definition and antagonism of histamine H2-receptors. Nature
1972, 236, 385–390.
1
of a light-yellow solid. Mp 176.0-178.5 °C; H NMR (CDCl3) δ
(ppm) 7.46-7.34, (m, 3H), 5.30 (s, 2H), 3.86 (t, J ) 5.1 Hz, 4H),
2.44 (t, J ) 5.1 Hz, 4H), 2.31 (s, 3H); 13C NMR (CDCl3) δ (ppm)
160.59, 158.81, 151.24, 133.51, 127.37, 125.64, 120.96, 110.10,
54.98, 46.11, 43.59; MS (ESI) m/z 278 (M + H)+.
(5) Berardi, R., R.; Tankanow, R., M.; Nostrant, T., T. Comparison of
famotidine with cimetidine and ranitidine. Clin. Pharm. 1988, 7, 271–
284.
6-Chloro-N-methyl-2-(4-methylpiperazin-1-yl)quinazolin-4-
amine (40). 2,4,6-Trichloroquinazoline (300 mg, 1.28 mmol) was
dissolved in THF (5.0 mL) after which a solution of methylamine
in water (0.12 mL of 40% w/w in water) was added to the solution.
After 2 h the formed suspension was diluted with EtOAc (50 mL)
and washed with water and brine. The organic phase was dried
over Na2SO4 and concentrated (approximately 3 mL), after which
it was transferred to a microwave tube containing N-methylpip-
erazine (1.0 mL) and EtOAc (3.0 mL). The mixture was heated at
140 °C for 5 min with microwave irradiation. The product was
then diluted with EtOAc and washed with water and brine.
Subsequent drying over Na2SO4 and evaporation of the solvent
yielded a dark-yellow oil that was purified over SiO2 (EtOAc 90%,
Et3N 5%, MeOH 5%). The title compound was obtained as a light-
yellow solid. Yield: 308 mg (1.06 mmol, 82%). Mp 173.2-175.7
(6) Arrang, J., M.; Garbarg, M.; Schwartz, J., C. Auto-inhibition of brain
histamine release mediated by a novel class (H3) of histamine receptor.
Nature 1987, 302, 832–837.
(7) Lovenberg, T., W.; Roland, B., L.; Wilson, S., J.; Jiang, X.; Pyati, J.;
Huvar, A.; Jackson, M. R.; Erlander, M. E. Cloning and functional
expression of the human histamine H3 receptor. Mol. Pharmacol. 1999,
55, 1101–1107.
(8) Wijtmans, M.; Leurs, R.; de Esch, I. Histamine H3 receptor ligands
break ground in a remarkable plethora of therapeutic areas. Expert
Opin. InVest. Drugs 2007, 16, 967–985.
(9) Liu, C.; Ma, X.-J.; Jiang, X.; Wilson, S. J.; Hofstra, C. L.; Blevitt,
K.; Li, X.; Chai, W.; Carruthers, N.; Lovenberg, T. W. Cloning
and pharmacological characterization of a fourth histamine receptor
(H4) expressed in bone marrow. Mol. Pharmacol. 2001, 59, 420–
426.
(10) Morse, K. l.; Behan, J.; Laz, T. M., Jr.; Greenfender, S. A.; Anthes,
J. C.; Umland, S.; Wan, Y.; Hipkin, R. W.; Gonsiorek, W.; Shin,
N.; Gustafson, E. L.; Qiao, X.; Wang, S.; Hedrick, J. A.; Green,
J.; Bayne, M.; Monsma, F. J., Jr. Cloning and characterization of
a novel human histamine receptor. J. Pharmacol. Exp. Ther. 2001,
296, 1058–1066.
(11) Nguyen, T.; Shapiro, D. A.; George, S. R.; Setola, V.; Lee., D. K.;
Cheng, R.; Rauser, L.; Lee, S. P.; Lynch, K. R.; Roth, B. L.; O’Dowd,
B. F. Discovery of a novel member of the histamine receptor family.
Mol. Pharmacol. 2001, 59, 427–433.
(12) Oda, T.; Morikawa, N.; Saito, Y.; Masuho, Y.; Matsumoto, S.
Molecular cloning and characterization of a novel type of histamine
receptor preferentially expressed in leukocytes. J. Biol. Chem. 2000,
275, 36781–36786.
(13) Zhu, Y.; Michalovich, D.; Wu, H.-L.; Tan, K. B.; Dytko, G. M.;
Mannan, I. J.; Boyce, R.; Alston, J.; Tierney, L. A.; Li, X.; Herrity,
N. C.; Vawter, L.; Sarau, H. M.; Ames, R. S.; Davenport, C. M.;
Hieble, J. P.; Wilson, S.; Bergsma, D. J.; Fitzgerald, L. R. Cloning,
expression and pharmacological characterization of a novel human
histamine receptor. Mol. Pharmacol. 2001, 59, 434–444.
(14) Dunford, P. J.; O’Donnel, N.; Riley, J.; Williams, K., N.; Karlsson,
L.; Thurmond, R., L. The histamine H4 receptor mediates allergic
airway inflammation by regulating the activation of CD4+ T cells.
J. Immunol. 2006, 176, 7062–7070.
1
°C; H NMR (CDCl3): δ (ppm) 7.42-7.24 (m, 3H), 5.42 (s, 1H),
3.92 (t, J ) 4.8 Hz, 4H), 3.10 (d, J ) 4.8 Hz, 3H), 2.46 (t, J ) 4.8
Hz, 4H), 2.32 (d, J ) 1.0 Hz, 3H); 13C NMR (CDCl3) δ (ppm)
159.47, 158.84, 150.49, 132.73, 127.27, 125.42, 119.99, 110.98,
55.03, 46.12, 43.61, 27.96; MS (ESI) m/z 292 (M + H)+.
2,6-Dichloro-N-methylquinazolin-4-amine (65). To a suspen-
sion of 2,4,6-trichloroquinazoline (4.70 g, 20.1 mmol) in EtOH (150
mL) was added methylamine (1.91 mL of 40% w/w in water). The
mixture was then stirred at room temperature for 40 min, after which
the solution was concentrated to a volume of about 30 mL. The
reaction mixture was then diluted with water (200 mL) and extracted
with EtOAc. The combined organic layers were washed with brine
and dried over Na2SO4. Evaporation of the solvent yielded 3.90 g
(17.1, 85%) of a white-yellow solid that was used in the next step
without further purification. Mp 198.2-205.0 °C. 1H NMR (DMSO-
d6) (ppm) δ 8.88 (br s, 1H), 8.35 (d, J ) 2.3 Hz, 1H), 7.81 (dd, J
) 2.3 Hz, J ) 8.9 Hz, 1H), 7.63 (d, J ) 8.9 Hz, 1H), 2.99 (s, 3H).
(S)-6-Chloro-2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl))-
N-methylquinazolin-4-amine (73). 2,6-Dichloro-N-methylquinazo-
lin-4-amine (65) (150 mg, 0.67 mmol), DIPEA (0.74 mmol, 0.13
mL), and (S)-diazabicyclo[4.3.0]nonane (0.74 mmol, 93 mg) were
added to a microwave tube with EtOAc (2.0 mL). After the mixture
was heated for 10 min at 130 °C, it was diluted with EtOAc and
washed with saturated NaHCO3 and brine. The organic layer was
dried over Na2SO4 and evapoated to dryness. The solid residue was
(15) Dunford, P. J.; Williams, K. N.; Desai, P. J.; Karlsson, L.; McQueen,
D.; Thurmond, R. L. Histamine H4 receptor antagonists are superior
to traditional antihistamines in the attenuation of experimental pruritis.
J. Allergy Clin. Immunol. 2007, 119, 176–183.
(16) Ohki, E.; Suzuki, M.; Aoe, T.; Ikawa, Y.; Negishi, E.; Ueno, K.
Expression of histamine H4 receptor in synovial cells from rheumatoid
arthritis patients. Biol. Pharm. Bull. 2007, 2217–2220.