Quinazolinone Histamine H3 Receptor InVerse Agonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 15 4785
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HPLC purity (98.8%). H NMR (400 MHz, CDCl3): δ 1.04 (6H,
2-Methyl-3-(4-{[3-(3-methyl-1-pyrrolidinyl)propyl]oxy}phenyl)-
4(3H)-quinazolinone (6h). Compound 6h was prepared from
3-methylpyrrolidine (racemate)33 using the procedure described for
t, J ) 7.2 Hz), 1.91-2.00 (2H, m), 2.25 (3H, s), 2.55 (4H, q, J )
6.8 Hz), 2.63 (2H, t, J ) 6.8 Hz), 4.06 (2H, t, J ) 6.4 Hz), 7.03
(2H, d, J ) 8.8 Hz), 7.13 (2H, d, J ) 8.8 Hz), 7.44 (1H, t, J ) 8.4
Hz), 7.65 (1H, d, J ) 8.0 Hz), 7.74 (1H, t, J ) 8.0 Hz), 8.25 (1H,
d, J ) 8.0 Hz). MS (ESI) m/z 366 (M + H)+. HRMS (M + H)+
calcd for C22H28N3O2, 366.2182; found, 366.2177.
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6a as a white solid (43% yield). HPLC purity (98.7%). H NMR
(400 MHz, CDCl3): δ 1.05 (3H, d, J ) 6.8 Hz), 1.38-1.42 (1H,
m), 2.02-2.09 (4H, m), 2.26 (3H, s), 2.28-2.30 (1H, m), 2.54-2.56
(1H, m), 2.63-2.72 (2H, m), 2.78-2.80 (1H, m), 2.92 (1H, t, J )
8.3 Hz), 4.09 (2H, t, J ) 6.3 Hz), 7.04 (2H, td, J ) 6.0, 3.6 Hz),
7.15 (2H, td, J ) 6.0, 3.6 Hz), 7.46 (1H, t, J ) 8.0 Hz), 7.67 (1H,
d, J ) 7.8 Hz), 7.74-7.78 (1H, m), 8.27 (1H, dd, J ) 7.8, 1.5
Hz). MS (ESI) m/z 378 (M + H)+. HRMS (M + H)+ calcd for
C23H28N3O2, 378.2182; found, 378.2187.
2-Methyl-3-(4-{[3-(1-pyrrolidinyl)propyl]oxy}phenyl)-4(3H)-
quinazolinone (6b). Compound 6b was prepared from pyrrolidine
using the procedure described for 6a as a white solid (42% yield).
HPLC purity (98.4%). 1H NMR (400 MHz, CDCl3): δ 1.78-1.82
(4H, m), 2.00-2.08 (2H, m), 2.25 (3H, s), 2.52-2.56 (4H, m),
2.64 (2H, t, J ) 7.2 Hz), 4.08 (2H, t, J ) 6.4 Hz), 7.03 (2H, d, J
) 9.2 Hz), 7.12 (2H, d, J ) 9.2 Hz), 7.44 (1H, t, J ) 8.0 Hz), 7.65
(1H, d, J ) 7.6 Hz), 7.74 (1H, t, J ) 7.2 Hz), 8.25 (1H, d, J ) 8.0
Hz). MS (ESI) m/z 364 (M + H)+. HRMS (M + H)+ calcd for
C22H26N3O2, 364.2025; found, 364.2030.
3-[4-({3-[(2R,5R)-2,5-Dimethyl-1-pyrrolidinyl]propyl}oxy)phenyl]-
4(3H)-quinazolinone (6i). Compound 6i was prepared from (2R,5R)-
2,5-dimethylpyrrolidine hydrochloride using the procedure described
for 6a as a colorless oil (66% yield). HPLC purity (99.1%).
NMR (400 MHz, CDCl3): δ 1.03 (6H, d, J ) 4.4 Hz), 1.40-1.46
(2H, br m), 2.02-2.10 (4H, br m), 2.26 (3H, s), 2.59-2.65 (1H,
br m), 2.81-2.88 (1H, br m), 3.10-3.17 (2H, br m), 4.05-4.14
(2H, m), 7.05 (2H, d, J ) 8.8 Hz), 7.15 (2H, d, J ) 8.8 Hz), 7.46
(1H, t, J ) 7.6 Hz), 7.67 (1H, d, J ) 7.8 Hz), 7.74-7.79 (1H, m),
8.27 (1H, d, J ) 8.3 Hz). MS (ESI) m/z 392 (M + H)+. HRMS
(M + H)+ calcd for C24H30N3O2, 392.2338; found, 392.2331.
2-Methyl-3-(4-{[3-(2-methyl-1-piperidinyl)propyl]oxy}phenyl)-
4(3H)-quinazolinone (6j). Compound 6j was prepared from 2-me-
thylpiperidine (racemate) using the procedure described for 6a as
1H
2-Methyl-3-(4-{[3-(1-piperidinyl)propyl]oxy}phenyl)-4(3H)-
quinazolinone (6c). Compound 6c was prepared from piperidine
using the procedure described for 6a as a white solid (50% yield).
HPLC purity (98.1%). 1H NMR (400 MHz, CDCl3): δ 1.41-1.55
(2H, m), 1.50-1.64 (4H, m), 1.97-2.04 (2H, m), 2.25 (3H, s),
2.37-2.46 (4H, br m), 2.49 (2H, t, J ) 6.8 Hz), 4.06 (2H, t, J )
6.8 Hz), 7.03 (2H, d, J ) 8.4 Hz), 7.12 (2H, d, J ) 8.4 Hz), 7.44
(1H, t, J ) 8.0 Hz), 7.65 (1H, d, J ) 8.8 Hz), 7.74 (1H, t, J ) 8.0
Hz), 8.25 (1H, d, J ) 8.0 Hz). MS (ESI) m/z 378 (M + H)+. HRMS
(M + H)+ calcd for C23H28N3O2, 378.2182; found, 378.2190.
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a white solid (25% yield). HPLC purity (98.1%). H NMR (400
MHz, CDCl3): δ 1.14 (3H, d, J ) 5.5 Hz), 1.30-1.40(1H, br s),
1.55-1.65 (6H, br s), 2.01-2.05 (2H, m), 2.26 (3H, s), 2.42 (1H,
br s), 2.59 (1H, br s), 2.92-2.96 (2H, m), 4.03-4.08 (2H, m), 7.03
(2H, d, J ) 8.4 Hz), 7.12 (2H, d, J ) 8.4 Hz), 7.44 (1H, t, J ) 8.0
Hz), 7.65 (1H, d, J ) 8.8 Hz), 7.74 (1H, t, J ) 8.0 Hz), 8.25 (1H,
d, J ) 8.0 Hz). MS (ESI) m/z 392 (M + H)+. HRMS (M + H)+
calcd for C24H30N3O2, 392.2338; found, 392.2344.
2-Methyl-3-[4-({3-[(3S)-3-methyl-1-piperidinyl]propyl}oxy)phenyl]-
4(3H)-quinazolinone (6k). Compound 6k was prepared from (S)-
3-methylpiperidine (S)-(+)-mandelate salt34 using the procedure
described for 6a as a pale-pink oil (66% yield). HPLC purity
(96.6%). 1H NMR (400 MHz, CDCl3): δ 0.87-0.89 (4H, m),
1.56-1.76 (5H, m), 1.84-1.91 (1H, m), 2.02-2.06 (2H, m), 2.26
(3H, s), 2.53 (2H, t, J ) 7.2 Hz), 2.85-2.93 (2H, m), 4.07 (2H, t,
J ) 6.3 Hz), 7.04 (2H, d, J ) 9.0 Hz), 7.15 (2H, d, J ) 9.0 Hz),
7.46 (1H, t, J ) 7.6 Hz), 7.67 (1H, d, J ) 7.6 Hz), 7.76 (1H, t, J
) 7.6 Hz), 8.27 (1H, d, J ) 7.6 Hz). MS (ESI) m/z 392 (M +
H)+. HRMS (M + H)+ calcd for C24H30N3O2, 392.2338; found,
392.2330.
2-Methyl-3-[4-({3-[(3R)-3-methyl-1-piperidinyl]propyl}oxy)phenyl]-
4(3H)-quinazolinone (6l). Compound 6l was prepared from (R)-3-
methylpiperidine (R)-(-)-mandelate salt33 using the procedure
described for 6a as a pale-pink oil (37% yield). HPLC purity
(99.1%). 1H NMR (400 MHz, CDCl3): δ 0.87-0.89 (4H, m),
1.50-1.95 (6H, m), 2.00-2.05 (2H, m), 2.26 (3H, s), 2.50 (2H, t,
J ) 6.8 Hz), 2.89-2.97 (2H, m), 4.07 (2H, t, J ) 6.4 Hz), 7.05
(2H, d, J ) 8.6 Hz), 7.15 (2H, d, J ) 8.6 Hz), 7.46(1H, t, J ) 8.0
Hz), 7.67 (1H, d, J ) 8.0 Hz), 7.76 (1H, t, J ) 8.4 Hz), 8.27 (1H,
d, J ) 8.0 Hz). MS (ESI) m/z 392 (M + H)+. HRMS (M + H)+
calcd for C24H30N3O2, 392.2338; found, 392.2344.
2-Methyl-3-(4-{[3-(4-methyl-1-piperidinyl)propyl]oxy}phenyl)-
4(3H)-quinazolinone (6m). Compound 6m was prepared from
4-methylpiperidine using the procedure described for 6a as a white
solid (41% yield). HPLC purity (97.7%). 1H NMR (400 MHz,
CDCl3): δ 0.93 (3H, d, J ) 6.6 Hz), 1.22-1.26 (2H, m), 1.32-1.39
(1H, m), 1.62-1.65 (2H, m), 1.92-2.05 (4H, m), 2.25 (3H, s),
2.51 (2H, t, J ) 7.6 Hz), 2.90-2.93 (2H, m), 4.06 (2H, t, J ) 6.2
Hz), 7.02 (2H, d, J ) 6.6 Hz), 7.12 (2H, d, J ) 6.6 Hz), 7.46 (1H,
t, J ) 6.5 Hz), 7.65 (1H, d, J ) 7.7 Hz), 7.76 (1H, t, J ) 8.4 Hz),
8.26 (1H, d, J ) 8.4 Hz). MS (ESI) m/z 392 (M + H)+. HRMS
(M + H)+ calcd for C24H30N3O2, 392.2338; found, 392.2350.
3-(4-{[3-(3,5-Dimethyl-1-piperidinyl)propyl]oxy}phenyl)-2-meth-
yl-4(3H)-quinazolinone (6n). Compound 6n was prepared from 3,5-
dimethylpiperidine using the procedure described for 6a as a pale-
3-(4-{[3-(1-Azepanyl)propyl]oxy}phenyl)-2-methyl-4(3H)-quinazoli-
none (6d). Compound 6d was prepared from azacycloheptane using
the procedure described for 6a as a white solid (58% yield). HPLC
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purity (99.3%). H NMR (400 MHz, CDCl3): δ 1.50-1.80 (8H,
m), 2.01-2.06 (2H, br m), 2.25 (3H, s), 2.73 (6H, br s), 4.08 (2H,
t, J ) 6.2 Hz), 7.03 (2H, d, J ) 8.4 Hz), 7.12 (2H, d, J ) 8.4 Hz),
7.44 (1H, t, J ) 8.0 Hz), 7.65 (1H, d, J ) 8.8 Hz), 7.74 (1H, t, J
) 8.0 Hz), 8.25 (1H, d, J ) 8.0 Hz). MS (ESI) m/z 392 (M +
H)+. HRMS (M + H)+ calcd for C24H30N3O2, 392.2338; found,
392.2336.
3-(4-{[3-(1-Azocanyl)propyl]oxy}phenyl)-2-methyl-4(3H)-quinazoli-
none (6e). Compound 6e was prepared from azacyclooctane using
the procedure described for 6a as a white solid (55% yield). HPLC
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purity (98.3%). H NMR (400 MHz, CDCl3): δ 1.57-1.63 (10H,
m), 1.92-1.99 (2H, m), 2.26 (3H, s), 2.57 (4H, br s), 2.62 (2H, t,
J ) 6.2 Hz), 4.08 (2H, t, J ) 6.2 Hz), 7.03 (2H, d, J ) 8.4 Hz),
7.12 (2H, d, J ) 8.4 Hz), 7.44 (1H, t, J ) 8.0 Hz), 7.65 (1H, d, J
) 8.8 Hz), 7.74 (1H, t, J ) 8.0 Hz), 8.25 (1H, d, J ) 8.0 Hz). MS
(ESI) m/z 406 (M + H)+. HRMS (M + H)+ calcd for C25H32N3O2,
406.2495; found, 406.2489.
2-Methyl-3-[4-({3-[(2S)-2-methyl-1-pyrrolidinyl]propyl}oxy)phenyl]-
4(3H)-quinazolinone (6f). Compound 6f was prepared from (S)-2-
methylpyrrolidine hydrobromide31 using the procedure described
for 6a as a pale-yellow oil (80% yield). HPLC purity (98.2%). 1H
NMR (400 MHz, CDCl3): δ 1.12 (3H, d, J ) 6.0 Hz), 1.40-1.50
(1H, m), 1.60-2.37 (11H, m), 2.97-3.03 (1H, m), 3.18-3.23 (1H,
m), 4.07-4.11 (2H, m), 7.05 (2H, d, J ) 9.2 Hz), 7.15 (2H, d, J
) 9.2 Hz), 7.46 (1H, t, J ) 7.6 Hz), 7.67 (1H, d, J ) 7.6 Hz), 7.76
(1H, t, J ) 7.6 Hz), 8.27 (1H, d, J ) 7.6 Hz). MS (ESI) m/z 378
(M + H)+. HRMS (M + H)+ calcd for C23H28N3O2, 378.2182;
found, 378.2182.
2-Methyl-3-[4-({3-[(2R)-2-methyl-1-pyrrolidinyl]propyl}oxy)phenyl]-
4(3H)-quinazolinone (6g). Compound 6g was prepared from (R)-2-
methylpyrrolidine benzenesulfonic acid salt32 using the procedure
described for 6a as a pale-brown oil (63% yield). HPLC purity
(98.5%). 1H NMR (400 MHz, CDCl3): δ 1.14 (3H, d, J ) 5.9 Hz),
1.43-1.55 (1H, m), 1.69-1.85 (2H, m), 1.93-2.54 (9H, m),
2.99-3.07 (1H, m), 3.21-3.26 (1H, m), 4.06-4.11 (2H, m), 7.05
(2H, d, J ) 8.8 Hz), 7.15 (2H, d, J ) 8.8 Hz), 7.46 (1H, t, J ) 7.6
Hz), 7.67 (1H, d, J ) 7.8 Hz), 7.78-7.74 (1H, m), 8.27 (1H, dd,
J ) 8.0, 1.2 Hz). MS (ESI) m/z 378 (M + H)+. HRMS (M + H)+
calcd for C23H28N3O2, 378.2182; found, 378.2190.