424
M. Varga et al. / European Journal of Medicinal Chemistry 38 (2003) 421ꢀ425
/
2-Amino-3-(2-piperidin-1-ylethoxy)pyridine (3) 110.12
2-[(4-Isopropyl-6-methoxy-1,1-dioxido-3-oxo-1,2-ben-
zisothiazol-2(3H)-yl)methoxy]-9-(2-piperidin-1-
ylethoxy)-4H-pyrido[1,2-a]pyrimidin-4-one (SSR69071)
hemihydrate. 7 (13.7 g, 45 mmol) was dissolved at room
temperature in 100 mL of dry DMF, then triethylamine
(7 mL) and 8 (15.6 g, 45 mmol) were added. The
suspension was stirred for 60 h at room temperature in
argon atmosphere. The precipitate was filtered off and
the mother liquor was poured into iced water (200 mL).
The suspension was filtered and the product was
recrystallised from methanol.
g (1 mol) of 1 was dissolved in 500 mL of 40%-(w/w)
aqueous NaOH. A solution of tetrabutylammonium
iodide (2 g) in CH2Cl2 (500 mL) followed by 184.11 g (1
mol) of 2 were added to the stirred mixture. Stirring of
the dark brown mixture was continued in argon atmo-
sphere for 5 days at room temperature. CH2Cl2 (500
mL) and water (200 mL) were added. The organic layer
was separated and the water was extracted with CH2Cl2
(3ꢃ
washed with water (3ꢃ
and evaporated. The redꢀ
recrystallised from acetone.
Yield: 144.71 g (65%) of 3 (m.p. 105ꢀ
/
150 mL). The combined organic solution was
200 mL), dried over MgSO4
brown crystalline product was
/
Yield: 4.8 g (19%) of SSR69071 (m.p. 138ꢀ
C27H32N4O7S×0.5H2O Calc. C, 57.33; H, 5.88; N, 9.90;
S, 5.67. Found C, 57.41; H, 6.02; N, 9.77; S, 5.39; NMR
dH (200 MHz, CDCl3): 1.30 (d, 6H, Jꢁ6.8,
(CH3)2CHO), 1.47 (m, 2H, CH2(CH2CH2)2N), 1.62
(m, 4H, CH2(CH2CH2)2N), 2.64 (m, 4H,
CH2(CH2CH2)2N), 2.98 (t, 2H, Jꢁ5.8 NCH2CH2O),
3.96 (s, 3H, CH3O) 4.23 (m, 1H, Jꢁ6.8, (CH3)2CHO),
4.32 (t, 2H, Jꢁ5.8 NCH2CH2O), 5.90 (s 1H,), 6.23 (s
2H,), 7.05 (t, 1H, Jꢁ7.4, 7?-H), 7.14 (dd, 1H, Jꢁ7.7,
1.3, 8?-H), 7.19-7.21 (m, 2H, 5-H, 7-H), 8.72 (dd, 1H,
Jꢁ7.0, 1.3, 6?-H).
/
139 8C).
/
/
/
106 8C). NMR,
/
dH (200 MHz, DMSO-d6): 1.37 (m, 2H,
CH2(CH2CH2)2N), 1.48 (m, 4H, CH2(CH2CH2)2N),
2.42 (m, 4H, CH2(CH2CH2)2N), 2.64 (t, 2H, Jꢁ
NCH2CH2O), 4.01 (t, 2H, Jꢁ5.8, NCH2CH2O), 5.63
(s, 2H, NH2), 6.47 (dd, 1H, Jꢁ7.7; 5.0, 5-H), 7.03 (dd,
1H, Jꢁ7.7, 1.2, 6-H), 7.51 (dd, 1H, Jꢁ5.0, 1.2, 4-H).
/5.8,
/
/
/
/
/
/
/
/
/
Bis-2,4,6-trichlorophenyl malonate (6) 158.0 g (0.8
mol) of 4 and 41.6 g (0.4 mol) of 5 were added to
POCl3 (100 mL, 1.05 mol, 162 g). The mixture was
stirred with mechanical stirrer under reflux for 4 h until
the hydrogen chloride evolution ceased. The warm dense
suspension was poured into iced water (500 g). The
crystals were filtered off and added to a solution of
water (100 mL) and concentrated aqueous NaHCO3 (50
mL). After 30 min stirring the crystals were filtered,
/
The elastase assay, the determination of the kinetic
parameters of elastase inhibition, the ex vivo inhibition
of HLE activity in mice BAL and the in vivo model of
HLE-induced lung haemorrhage in mice are described in
details in ref. [2].
washed with water (3ꢃ
/
40 mL) and dried in vacuum.
156 8C). NMR dH
(200 MHz, CDCl3): 4.05 (s, 2H, CH2), 7.40 (s, 4H,
Yield: 180.9 g (98%) of 6 (m.p. 154ꢀ
/
References
[1] P. Ara´nyi, S. Batori, S. Dessilla, I. Hermecz, Z. Kapui, F. Levai,
E. Mikus, M. Pascal, L. T. Nagy, B. Simonot, K. Urban-Szabo,
M. Varga, L. Vasvari-Debreczy, Saccharin derivatives as orally
active elastase inhibators, WO 01/44245 A1 (Priority date. 17-12-
1999).
C6H2Cl3O).
2-Hydroxy-9-(2-piperidin-1-ylethoxy)-4-oxo-4H-pyr-
ido[1,2-a]pyrimidine (7) 88.50 g (0.4 mol) of 3, was
added to dry acetone (550 mL). The mixture was
refluxed and 6 (185.20 g, 0.4 mol) was carefully added
to it in small portions. Reflux was continued for 2 h and
after cooling to room temperature the suspension was
kept at 5 8C for a night. The crystals were filtered off.
After evaporating the mother liquor to half of its
volume a second generation of product was obtained.
[2] Z. Kapui, M. Varga, K. Urban-Szabo, E. Mikus, T. Szabo´, J.
Szeredi, O. Finance, P. Ara´nyi, J. Pharm. Exp. Ther. 305 (2003)
1ꢀ
[3] C. Delclaux, C. Delacourt, M. d’Ortho, V. Boyer, C. Lafuma, A.
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/
9.
/
/
895.
[5] C. Vogelmeier, R.C. Hubbard, G.A. Fells, H.P. Schnebli, R.C.
The combined raw product was washed 3 times with ꢀ
/
Thompson, H. Fritz, R.G. Crystal, J. Clin. Invest. 87 (1991) 482ꢀ
488.
[6] A. Janoff, Am. Rev. Respir. Dis. 132 (1985) 417ꢀ
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Weinbaum, N. Eng. J. Med. 304 (1981) 192ꢀ196.
[8] C.G. Llewellyn-Jones, T.A. Harris, R.A. Stockley, Am. J. Respir.
Crit. Care Med. 153 (1996) 616ꢀ621.
[9] P.D. Piccioni, J.A. Kramps, A. Rudolphus, A. Bulgheroni, M.
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[10] K.N. Cowan, A. Heilbut, T. Humpl, C. Lam, S. Ito, M.
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M.B. Prepys, Gut 26 (1985) 1306ꢀ1311.
/
30 mL of acetone. The product was purified by flash
chromatography on silica gel. The remaining 2,4,6-
trichlorophenol was eluted with CH2Cl2 and the pure
product was obtained by elution with a mixture of
/433.
/
ethanolꢀ/CH2Cl2 (1:1 v/v).
/
Yield: 69.31 g (60%) of 7 (mp 171ꢀ
/
172 8C). NMR dH
(200 MHz, DMSO-d6): 1.39 (m, 2H, CH2(CH2CH2)2N),
1.50 (m, 4H, CH2(CH2CH2)2N), 2.50 (m, 4H,
/
/
CH2(CH2CH2)2N), 2.83 (t, 2H, Jꢁ
4.27 (t, 2H, Jꢁ5.9, NCH2CH2O), 5.16 (s, 1H, 3-H) 7.13
(t, 1H, Jꢁ7.3, 7-H), 7.50 (d, 1H, Jꢁ7.3, 8-H) 8.50 (d,
1H, Jꢁ6.4, 6-H).
/5.9, NCH2CH2O)
/
/
/
/
[12] C.A. Veale, P.R. Bernstein, C.M. Bohnert, F.J. Brown, C. Bryant,
/
J.R. Damewood, R. Earley, S.W. Feeney, P.D. Edwards, B