D. Zuev et al. / Bioorg. Med. Chem. Lett. 15 (2005) 431–434
433
cyclobutyl led to an 8-fold decrease in binding affinity
for 6l. Analog 6m, with the bulkier cyclohexyl ring,
was nearly inactive. The introduction of b- and, espe-
cially, a-methyl branching to the nitrogen atom also
led to a decrease in potency. This is exemplified by a
3-fold loss of activity for 6n, compared to 6g, followed
by a further 40-fold decrease in activity for 6o. Homolo-
gation of the cyclopropylmethyl group resulted in a 50-
fold decrease in potency of 6p and 6q, compared to 2
and 6a. Analogs 6e (Ki = 1 3lM) and 6r (Ki = 1 9lM),
containing dimethylamino groups, were weakly active,
suggesting very little tolerance of the CRF1 receptor
for polar atoms in the side chain.
highest binding affinity was displayed by benzyl
3,3,3-trifluoropropyl amines 8m–p, which were more
potent, than our initial lead 2. These analogs were also
three to six times more potent than the corresponding
n-propyl amines 8c–g. Pyridyl-containing derivatives
8i–k were less active than benzyl amine 8a, again
suggesting that polar atoms in the side chain are not
well-tolerated by the receptor. Indeed, the more lipophi-
lic 2-thienyl compound 8g was 6-fold more potent
than 2-furanylmethyl analog 8h. Some of the phenethyl
alkyl amines 8q–v showed good binding to the CRF1
receptor. The highest potency in the series was displayed
by phenethyl n-propyl amine 8q (Ki = 28nM), and it
rapidly diminished as the size of the alkyl substituent
R2 was reduced. 5-(2-Methylthiothiazolyl) amine 8w
was nine times more potent than benzyl analog 8t.
Thiazoles 7a–g, possessing cyclic amino side chains, dis-
played significantly lower binding affinities than acyclic
amines 6 (Table 2). Olefins 7b and 7g were slightly more
potent than their saturated analogs 7a and 7f. Imidazole
derivative 7d was less active than pyrrolidine 7a and
pyrroline 7b. The introduction of an ethyl group at the
2-position of the imidazole ring led to a 10-fold enhance-
ment in activity for 7e, compared to its unsubstituted
analog 7d. This Ôbranching effectÕ could also be responsi-
ble for the marginally higher binding affinity of 7c com-
pared to that of 7a.
In summary, we have developed an efficient parallel syn-
thesis of CRF1R antagonists, 2-(2,4,6-trichlorophenyl)-
4-trifluoromethyl-5-aminomethylthiazoles, by selective
monoamination of the common chloromethyl interme-
diate. Analogs containing benzyl 3,3,3-trifluoropropyl
amino side chains were found to have the highest bind-
ing affinities.
In the course of our optimization study we prepared and
tested a number of arylalkylthiazoles 8 (Table 3). The
References and notes
1. Owens, M.; Nemeroff, C. B. Pharmacol. Rev. 1991, 43,
425.
2. Grigoriadis, D. E.; Haddach, M.; Ling, N.; Saunders, J.
Curr. Med. Chem. CNS Agents 2001, 1, 63.
Table 3. hCRF1R binding affinities of arylalkylaminomethylthiazoles
8
Ar
3. Banki, C. M.; Karmasci, L.; Bissette, G.; Nemeroff, C. B.
Eur. Neuropsychopharmacol. 1992, 2, 107.
4. Holsboer, F. J. Psychiatr. Res. 1999, 33, 181.
5. Kaskow, J. W.; Baker, D.; Geracioti, T. D. Peptides 2001,
22, 845.
6. OÕBrien, D.; Skelton, K. H.; Owens, M. J.; Nemeroff, C. B.
Hum. Psychopharmacol. Clin. Exp. 2001, 16, 81 .
7. McCarthy, J. R.; Heinrichs, C.; Grigoriadis, D. E. In
Bristol, J. A., Ed.; Annual Reports in Medicinal Chem-
istry; Academic: San Diego, CA, 1999; Vol. 34, p 11.
8. Gilligan, P. J.; Robertson, D. W.; Zaczek, R. J. Med.
Chem. 2000, 43, 1641.
9. Dubowchik, G. M.; Michne, J. A.; Zuev, D.; Schwartz,
W.; Scola, P. M.; James, C.; Ruediger, E.; Pin, S.; Burris,
K. D.; Balanda, L.; Gao, Q.; Fung, L.; Fiedler, T.;
Browman, K. E.; Taber, M. T.; Zhang, J. Bioorg. Med.
Chem. Lett. 2003, 13, 3997.
1
R
N
n
S
H
N
Cl
N
F
C
3
Cl
Cl
8
Compound
n
Ar
R1
Ki (nM)
8a
8b
8c
8d
8e
8f
1Ph
1Ph
nPr
38
201
25
Et
1
1
1
1
p-F–Ph
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
nPr
p-Cl–Ph
p-MeO–Ph
m-F–Ph
11
37
42
8g
8h
8i
12-Thiophenyl
12-Furanyl
14-Pyridyl
13-Pyridyl
12-Pyridyl
1Ph
130
770
100
290
1300
390
10. All new compounds gave satisfactory analytical data. For
6i: H NMR (CDCl3) 2.27 (m, 2H), 2.75 (ABq, 2H), 3.62
1
(s, 2H), 3.74 (s, 2H), 7.28 (m, 5H), 7.48 (s, 2H), 8.75 (br s,
1H). Mass spec.: 563.98 (MH+).
8j
8k
8l
11. General procedure for monoalkylation of amines: To a
stirred solution of the appropriate primary or secondary
amine (1mmol) and triethylamine (1mmol) in ether (3mL)
at 0ꢁC was added (5-chloromethyl-4-trifluoromethylthi-
azol-2-yl)-(2,4,6-trichlorophenyl)amine 5 (1mmol). The
reaction mixture was warmed to room temperature and
stirred for 15min. Triethylamine hydrochloride was
removed by filtration and the filtrate was concentrated in
vacuo. The final purification of the products 6 was
achieved by column chromatography.
CF 3CH2
CF 3CH2CH2
CF3CH2CH2
CF3CH2CH2
CF3CH2CH2
nPr
8m
8n
8o
8p
8q
8r
8s
8t
1Ph
6.1
1
1
1
2
2
2
2
2
2
0
p-F–Ph
m-F–Ph
p-Cl–Ph
Ph
4.8
3.7
3.2
28
Ph
Ph
Et
Me
79
560
Ph
Ph
H
>10,000
50
130
8u
8v
8w
CF3CH2
CF3CH2CH2
H
12. The purity of analogs 6 was found to be >90% by reversed
phase analytical LC–MS analysis under following condi-
tions: column–PHENOMENEX-LUNA 4.6 · 50mm S10;
Ph
5-(2-MeS-thiadiazolyl)
1100