1-Alkyl-4-acylpiperazine Histamine H3 Receptor Antagonists
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 11 2837
2.72-2.98 (m, 3H), 3.04-3.28 (m, 5H), 3.42 (m, 2H), 3.63 (m,
1H), 4.14 (m, 1H), 4.41 (m, 1H), 7.61 (d, J ) 8 Hz, 2H), 7.99
(d, J ) 8 Hz, 2H), 10.80 (br s, 1H). Anal. (C20H27ClN2O2‚HCl)
C, H, N.
(m, 1H), 4.14 (m, 1H), 4.40 (m, 1H), 7.36 (t, J ) 8 Hz, 2H),
8.07 (t, J ) 8 Hz, 2H), 10.76 (br s, 1H). Anal. (C19H27FN2O2‚
HCl) C, H, N.
1-[4-(1-Eth ylp r op yl)p ip er a zin -1-yl]-4-(4-tr iflu or om eth -
ylp h en yl)bu ta n e-1,4-d ion e h yd r och lor id e (16): mp 213-
1-(4-Ch lor op h en yl)-4-(4-cycloh ep tylp ip er a zin -1-yl)bu -
ta n e-1,4-d ion e h yd r och lor id e (5): mp 240-242 °C. 1H NMR
(DMSO-d6) δ 1.35-1.78 (m, 10H), 2.12 (m, 2H), 2.73 (m, 2H),
2.90 (m, 1H), 3.08-3.36 (m, 7H), 3.68 (m, 1H), 4.13 (m, 1H),
4.42 (m, 1H), 7.59 (d, J ) 8 Hz, 2H), 7.98 (d, J ) 8 Hz, 2H),
10.85 (br s, 1H). Anal. (C21H29ClN2O2‚HCl) C, H, N.
1-(4-Ch lor op h en yl)-4-(4-cyclooct ylp ip er a zin -1-yl)b u -
ta n e-1,4-d ion e h yd r och lor id e (6): mp 248-251 °C. 1H NMR
(DMSO-d6) δ 1.41-1.76 (m, 12H), 2.02 (m, 2H), 2.75 (m, 2H),
2.92 (m, 1H), 3.06-3.45 (m, 7H), 3.64 (m, 1H), 4.13 (m, 1H),
4.41 (m, 1H), 7.61 (d, J ) 8 Hz, 2H), 7.99 (d, J ) 8 Hz, 2H),
10.85 (br s, 1H). Anal. (C22H31ClN2O2‚HCl) C, H, N.
1-(4-Ch lor op h en yl)-4-[4-(tetr a h yd r op yr a n -4-yl)p ip er -
a zin -1-yl]bu ta n e-1,4-d ion e h yd r och lor id e (7): mp 214-
217 °C. 1H NMR (DMSO-d6) δ 1.72 (m, 2H), 1.99 (m, 2H), 2.76
(m, 2H), 2.85 (m, 1H), 3.10 (m, 2H), 3.21-3.68 (m, 8H), 3.97
(m, 2H), 4.16 (m, 1H), 4.41 (m, 1H), 7.60 (d, J ) 8 Hz, 2H),
7.99 (d, J ) 8 Hz, 2H), 11.15 (br s, 1H). Anal. (C19H25ClN2O3‚
HCl‚0.25H2O) C, H, N.
1-(4-Ch lor op h en yl)-4-(4-cyclop r op ylm eth ylp ip er a zin -
1-yl)bu ta n e-1,4-d ion e h yd r och lor id e (8): mp 220-224 °C.
1H NMR (DMSO-d6) δ 0.39 (m, 2H), 0.64 (m, 2H), 1.11 (m,
1H), 2.77 (q, J ) 7 Hz, 2H), 2.80-3.18 (m, 5H), 3.22 (t, J ) 7
Hz, 2H), 3.46-3.62 (m, 3H), 4.18 (m, 1H), 4.40 (m, 1H), 7.58
(d, J ) 8 Hz, 2H), 7.98 (d, J ) 8 Hz, 2H), 10.82 (br s, 1H).
Anal. (C18H23ClN2O2‚HCl) C, H, N.
1-(4-Ch lor oph en yl)-4-(4-isopr opylpiper azin -1-yl)bu tan e-
1,4-d ion e h yd r och lor id e (9): mp 225-227 °C. 1H NMR
(DMSO-d6) δ 1.28 (d, J ) 7 Hz, 6H), 2.73 (m, 2H), 2.85 (m,
1H), 3.09 (m, 2H), 3.22 (m, 2H), 3.33-3.67 (m, 4H), 4.16 (m,
1H), 4.42 (m, 1H), 7.60 (d, J ) 8 Hz, 2H), 7.99 (d, J ) 8 Hz,
2H), 10.75 (br s, 1H). Anal. (C17H23ClN2O2‚HCl) C, H, N.
1-(4-Ch lor op h en yl)-4-[4-(1-eth ylp r op yl)p ip er a zin -1-yl]-
bu ta n e-1,4-d ion e h yd r och lor id e (10): mp 207-209 °C. 1H
NMR (DMSO-d6) δ 0.98 (t, J ) 7 Hz, 6H), 1.62 (m, 2H), 1.85
(m, 2H), 2.74 (m, 2H), 2.88-3.26 (m, 6H), 3.39 (m, 2H), 3.68
(m, 1H), 4.12 (m, 1H), 4.39 (m, 1H), 7.59 (d, J ) 8 Hz, 2H),
7.98 (d, J ) 8 Hz, 2H), 10.45 (br s, 1H). Anal. (C19H27ClN2O2‚
HCl) C, H, N.
1
215 °C. H NMR (DMSO-d6) δ 0.97 (t, J ) 7 Hz, 6H), 1.62 (m,
2H), 1.85 (m, 2H), 2.79 (m, 2H), 2.95 (m, 1H), 3.00-3.50 (m,
7H), 3.68 (m, 1H), 4.14 (m, 1H), 4.41 (m, 1H), 7.91 (d, J ) 8
Hz, 2H), 8.18 (d, J ) 8 Hz, 2H), 10.42 (br s, 1H). Anal.
(C20H27F3N2O2‚HCl) C, H, N.
1-[4-(1-Eth ylp r op yl)p ip er a zin -1-yl]-4-(4-tr iflu or om eth -
oxyph en yl)bu tan e-1,4-dion e h ydr och lor ide (17): mp 206-
1
208 °C. H NMR (DMSO-d6) δ 0.97 (t, J ) 7 Hz, 6H), 1.63 (m,
2H), 1.85 (m, 2H), 2.77 (m, 2H), 2.95 (m, 1H), 3.00-3.31 (m,
5H), 3.35-3.55 (m, 2H), 3.68 (m, 1H), 4.14 (m, 1H), 4.41 (m,
1H), 7.52 (d, J ) 8 Hz, 2H), 8.12 (d, J ) 8 Hz, 2H), 10.47 (br
s, 1H). Anal. (C20H27F3N2O3‚HCl) C, H, N.
1-[4-(1-Eth ylp r op yl)p ip er a zin -1-yl]-4-(3-flu or o-4-m eth -
oxyph en yl)bu tan e-1,4-dion e h ydr och lor ide (18): mp 214-
217 °C. 1H NMR (DMSO-d6) δ 0.98 (t, J ) 7 Hz, 6H), 1.61 (sept,
J ) 7 Hz, 2H), 1.87 (m, 2H), 2.72 (m, 2H), 2.85-3.28 (m, 6H),
3.40 (m, 2H), 3.72 (m, 1H), 3.93 (s, 3H), 4.11 (m, 1H), 4.39 (m,
1H), 7.29 (t, J ) 7 Hz, 1H), 7.76 (br d, J ) 14 Hz, 1H), 7.84 (br
d, J ) 7 Hz, 1H), 10.75 (br s, 1H). Anal. (C20H29FN2O3‚HCl‚
0.25H2O) C, H, N.
1-(3,4-Dim eth oxyph en yl)-4-[4-(1-eth ylpr opyl)piper azin -
1-yl]bu ta n e-1,4-d ion e h yd r och lor id e (19): mp 195-196 °C.
1H NMR (DMSO-d6) δ 0.97 (t, J ) 7 Hz, 6H), 1.63 (m, 2H),
1.84 (m, 2H), 2.72 (m, 2H), 2.95 (m, 1H), 3.00-3.25 (m, 5H),
3.39 (m, 2H), 3.63 (m, 1H), 3.81 (s, 3H), 3.85 (s, 3H), 4.14 (m,
1H), 4.42 (m, 1H), 7.08 (d, J ) 8 Hz, 1H), 7.45 (s, 1H), 7.66 (d,
J ) 8 Hz, 1H), 10.12 (br s, 1H). Anal. (C21H32N2O4‚HCl) C, H,
N.
3-(4-Ch lor op h en oxy)-1-[4-(1-eth ylp r op yl)p ip er a zin -1-
1
yl]p r op a n -1-on e h yd r och lor id e (20): mp 206-208 °C. H
NMR (DMSO-d6) δ 0.96 (t, J ) 7 Hz, 6H), 1.62 (m, 2H), 1.85
(m, 2H), 2.87 (t, J ) 7 Hz, 2H), 2.90-3.28 (m, 4H), 3.41 (m,
2H), 3.65 (m, 1H), 4.08 (m, 1H), 4.20 (t, J ) 7 Hz, 2H), 4.47
(m, 1H), 6.96 (d, J ) 8 Hz, 2H), 7.33 (d, J ) 8 Hz, 2H), 10.45
(br s, 1H). Anal. (C18H27ClN2O2‚HCl) C, H, N.
4-{3-[4-(1-Eth ylp r op yl)p ip er a zin -1-yl]-3-oxo-p r op oxy}-
ben zon itr ile h yd r och lor id e (21): mp 198-201 °C. 1H NMR
(DMSO-d6) δ 0.96 (t, J ) 7 Hz, 6H), 1.61 (m, 2H), 1.83 (m,
2H), 2.91 (t, J ) 7 Hz, 2H), 2.92-3.45 (m, 6H), 3.71 (m, 1H),
4.07 (m, 1H), 4.30 (t, J ) 7 Hz, 2H), 4.46 (m, 1H), 7.10 (d, J )
8 Hz, 2H), 7.77 (d, J ) 8 Hz, 2H), 10.76 (br s, 1H). Anal.
(C19H27N3O2‚HCl‚0.25H2O) C, H, N.
1-[4-(1-Eth ylp r op yl)p ip er a zin -1-yl]-3-(4-tr iflu or om eth -
ylp h en yl)p r op a n -1-on e h yd r och lor id e (22): mp 218-220
°C. 1H NMR (DMSO-d6) δ 0.95 (t, J ) 7 Hz, 6H), 1.62 (m, 2H),
1.84 (m, 2H), 3.04 (m, 1H), 2.75 (m, 2H), 2.80-3.50 (m, 7H),
3.64 (m, 1H), 4.05 (m, 1H), 4.43 (m, 1H), 7.48 (d, J ) 8 Hz,
2H), 7.64 (d, J ) 8 Hz, 2H), 10.71 (br s, 1H). Anal.
(C19H27F3N2O2‚HCl) C, H, N.
1-[4-(1-Eth ylp r op yl)p ip er a zin -1-yl]-2-(4-tr iflu or om eth -
oxyp h en oxy)eth a n on e h yd r och lor id e (23): mp 219-222
°C. 1H NMR (DMSO-d6) δ 0.97 (t, J ) 7 Hz, 6H), 1.61 (m, 2H),
1.86 (m, 2H), 2.90-3.10 (m, 2H), 3.22 (m, 2H), 3.39 (m, 2H),
3.69 (m, 1H), 3.98 (m, 1H), 4.40 (m, 1H), 4.94 (s, 2H), 7.04 (m,
2H), 7.29 (m, 2H), 10.61 (br s, 1H). Anal. (C18H25F3N2O3‚HCl‚
H2O) C, H, N.
1-(4-Ch lor op h en yl)-4-[4-(1-p r op ylbu tyl)p ip er a zin -1-yl]-
bu ta n e-1,4-d ion e h yd r och lor id e (11): mp 223-226 °C. 1H
NMR (DMSO-d6) δ 0.92 (t, J ) 7 Hz, 6H), 1.28-1.60 (m, 6H),
1.80 (m, 2H), 2.76 (m, 2H), 2.93 (m, 1H), 3.05-3.55 (m, 7H),
3.64 (m, 1H), 4.15 (m, 1H), 4.42 (m, 1H), 7.61 (d, J ) 8 Hz,
2H), 8.00 (d, J ) 8 Hz, 2H), 10.24 (m, 1H). Anal. (C21H31
ClN2O2‚HCl‚0.5H2O) C, H, N.
-
1-(4-Ch lor oph en yl)-4-[4-(1,1-dim eth ylpr opyl)piper azin -
1-yl]bu ta n e-1,4-d ion e h yd r och lor id e (12): mp 222-224 °C.
1H NMR (DMSO-d6) δ 0.92 (t, J ) 7 Hz, 3H), 1.31 (s, 6H),
1.72 (q, J ) 7 Hz, 2H), 2.76 (t, J ) 7 Hz, 2H), 2.88 (m, 1H),
3.15 (m, 2H), 3.24 (q, J ) 7 Hz, 2H), 3.47 (m, 2H), 3.68 (m,
1H), 4.14 (m, 1H), 4.43 (m, 1H), 7.61 (d, J ) 8 Hz, 2H), 7.99
(d, J ) 8 Hz, 2H), 10.22 (br s, 1H). Anal. (C19H27ClN2O2‚HCl‚
0.75H2O) C, H, N.
1-(4-Ch lor op h en yl)-4-[4-(1,1-d im eth ylp r op -2-yn yl)p ip -
er azin -1-yl]bu tan e-1,4-dion e h ydr och lor ide (13): mp 217-
1
220 °C. H NMR (DMSO-d6) δ 1.69 (br s, 6H), 2.70-2.93 (m,
3H), 3.02-3.29 (m, 3H), 3.64 (m, 4H), 4.03 (br s, 1H), 4.19 (m,
1H), 4.48 (m, 1H), 7.60 (d, J ) 8 Hz, 2H), 7.99 (d, J ) 8 Hz,
2H), 12.05 (br s, 1H). Anal. (C19H23ClN2O2‚HCl) C, H, N.
1-[4-(2-Ch lor oa llyl)p ip er a zin -1-yl]-4-(4-ch lor op h en yl)-
bu ta n e-1,4-d ion e h yd r och lor id e (14): mp 205-207 °C. 1H
NMR (DMSO-d6) δ 2.75 (m, 2H), 2.80-3.15 (m, 2H), 3.24 (t, J
) 7 Hz, 2H), 3.30-3.80 (m, 6H), 4.11 (m, 2H), 5.81 (br s, 1H),
5.94 (br s, 1H), 7.61 (d, J ) 8 Hz, 2H), 8.00 (d, J ) 8 Hz, 2H),
11.14 (br s, 1H). Anal. (C17H20Cl2N2O2‚HCl) C, H, N.
1-[4-(1-Eth ylp r op yl)p ip er a zin -1-yl]-4-(4-flu or op h en yl)-
bu ta n e-1,4-d ion e h yd r och lor id e (15): mp 207-209 °C. 1H
NMR (DMSO-d6) δ 0.97 (t, J ) 7 Hz, 6H), 1.62 (m, 2H), 1.88
(m, 2H), 2.75 (m, 2H), 2.85-3.30 (m, 5H), 3.38 (m, 2H), 3.73
1-[4-(1-Eth ylp r op yl)p ip er a zin -1-yl]-2-(4-tr iflu or om eth -
ylp h en yl)eth a n on e h yd r och lor id e (24): mp 264-266 °C.
1H NMR (DMSO-d6) δ 0.96 (t, J ) 7 Hz, 6H), 1.61 (m, 2H),
1.85 (m, 2H), 2.90-3.50 (m, 6H), 3.69 (m, 1H), 3.90 (m, 2H),
4.15 (m, 1H), 4.45 (m, 1H), 7.45 (d, J ) 8 Hz, 2H), 7.68 (d, J
) 8 Hz, 2H), 10.71 (br s, 1H). Anal. (C18H25F3N2O‚HCl) C, H,
N.
1-[4-(1-Eth ylp r op yl)p ip er a zin -1-yl]-2-(4-tr iflu or om eth -
oxyp h en yl)eth a n on e h yd r och lor id e (25): mp 263-265 °C.
1H NMR (DMSO-d6) δ 0.96 (t, J ) 7 Hz, 6H), 1.62 (m, 2H),
1.84 (m, 2H), 2.85-3.46 (m, 6H), 3.65 (m, 1H), 3.82 (m, 2H),
4.14 (m, 1H), 4.43 (m, 1H), 7.32 (m, 4H), 10.53 (br s, 1H). Anal.
(C18H25F3N2O2‚HCl) C, H, N.