5-Arylamino-1,2,4-triazin-6(1H)-one CRF1 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2010.04.121

A series of 5-arylamino-1,2,4-triazin-6(1H)-ones was synthesized and evaluated as antagonists at the corticotropin releasing factor receptor. Formation of CYP-mediated oxidative reactive metabolites previously observed in a related N³-phenylpyrazinone structure was minimized by incorporation of the additional ring nitrogen found in the triazinones.

Full text of DOI:10.1016/j.bmcl.2010.04.121

Bioorganic & Medicinal Chemistry Letters 20 (2010) 3579–3583
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
5-Arylamino-1,2,4-triazin-6(1H)-one CRF1 receptor antagonists
a
a
a
b
William D. Schmitz a, , Allison B. Brenner , Joanne J. Bronson , Jonathan L. Ditta , Corrine R. Griffin ,
*
Yu-Wen Li c, Nicholas J. Lodge b, Thaddeus F. Molski b, Richard E. Olson a, Xiaoliang Zhuo c, John E. Macor a
a Neuroscience Discovery Chemistry, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
b Neuroscience Discovery Biology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
c Preclinical Candidate Optimization, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 5-arylamino-1,2,4-triazin-6(1H)-ones was synthesized and evaluated as antagonists at the
corticotropin releasing factor receptor. Formation of CYP-mediated oxidative reactive metabolites previ-
ously observed in a related N3-phenylpyrazinone structure was minimized by incorporation of the addi-
tional ring nitrogen found in the triazinones.
Received 25 February 2010
Revised 23 April 2010
Accepted 27 April 2010
Available online 17 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Corticotropin releasing factor
Triazinone
Depression
Major depressive disorder treatment remains an area of unmet
medical need. Worldwide, the incidence of depression is estimated
at approximately 121 million affected people.1 Current standard of
care includes treatment with serotonin and/or norepinephrine
transporter reuptake inhibitors. However, there are several limita-
tions associated with these treatment regimens including slow
onset of action, a significant number of nonresponders and/or
recurrence of depressive events. A number of alternative treatment
paradigms have been investigated such as coupled use of
neurotransmitter receptor antagonists/reuptake inhibitors, aug-
mentation strategies, and neuropeptide modulators.2,3 This latter
category includes corticotropin releasing factor receptor antago-
nists. Corticotropin releasing factor (CRF) is a 41 amino acid
peptide released by the hypothalamus. CRF functions as the pri-
mary activator of the hypothalamic–pituitary–adrenal (HPA) axis,
which in turn regulates the body’s response to stress.4 The poten-
tial for treatment of a wide variety of disorders including depres-
sion, anxiety, ischemia, irritable bowel syndrome, Alzheimer’s
disease, immune system disorders and substance abuse via modu-
lation of CRF receptors has been hypothesized due to the broad
applicability of the HPA axis in stress related conditions that may
play a role in the etiology of these diseases.5 Some examples of
non-peptidic small molecule CRF1 antagonists that have been
investigated in clinical trials include R121919,6 CP-376395,7
BMS-5613888 and BMS-5620869 (Fig. 1). Many of the compounds
reported to be in preclinical development consist of similar bicyclic
heterocyclic core structures that generally exhibit potent activity
at the CRF1 receptor.10 A number of monocyclic heterocyclic based
CRF1 receptor antagonists have also been described5a,9,11 including
pyrazolones,12 thiazoles, pyrimidines, pyrazines and triazines.
We have recently disclosed the N3-phenylpyrazinone structure
as a competent class of potent and orally active CRF1 receptor
antagonists.13 One of the liabilities associated with certain N3-phe-
nylpyrazinones was the potential for oxidation at the pyrazinone
core and subsequent formation of reactive intermediates leading
to the formation of glutathione (GSH) adducts.14 Previous in vitro
metabolite studies in liver microsomes suggested that pyrazinone
oxidation was a primary pathway for metabolism. Detection of
glutathione adducts was consistent with formation of a reactive
species on the pyrazinone core. Additionally, in vivo studies con-
ducted in bile duct cannulated rats showed that for pyrazinones
N
NH
N
NH
N
N
N
N
N
N
N
O
N
N
N
OMe
BMS-562086
R121919
CP-376395
* Corresponding author. Tel.: +1 203 677 6562; fax: +1 203 677 7702.
E-mail address: william.schmitz@bms.com (W.D. Schmitz).
Figure 1. Small molecule CRF1 antagonists.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.04.121

3580
W. D. Schmitz et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3579–3583
OEt
such as BMS-665053, there was extensive metabolism with pyraz-
inone oxidation products comprising the majority of drug-related
materials in plasma.15 The pathway leading to these adducts was
proposed to occur through the intermediacy of an epoxide formed
at the C5–C6 double bond of BMS-665053 (Fig. 2). This type of met-
abolic pathway has been previously reported.16 The potential for
such reactive intermediates to participate in idiosyncratic drug
reactions17 prompted us to consider modifications to the core
structure that could potentially reduce such oxidative metabolism.
We previously reported attenuation of pyrazinone core metabo-
lism via introduction of electron-withdrawing groups such as cya-
no at C-5.14 An alternative approach in our strategy involved
modification of the electronic properties of the heterocyclic core
structure via replacement of the pyrazinone with a 1,2,4-triazine-
6-one.18
O
a
O
O
O
O
N
R
R
O
N
R
N
H
b, c
N
H
NH2
N
H
NH2
R
N
O
O
O
N
O
O
d
e
N
R
N
H
N
H
Scheme 1. Reagents and conditions: (a) EtOH, reflux (85%); (b) Pt2O, AcOH, 50 psi
H2; (c) ClCOCO2Et, Et3N, CH2Cl2; (d) NH4OH, THF/EtOH (89% c b through d); (e) 1 M
NaOH, 100 °C, 20–30 min (20–30%).
The synthesis of the 1,2,4-triazine-5,6-dione core structure was
completed as shown in Scheme 1 starting with acetylhydrazide.
Condensation with a cyclopropyl ketone gave an imine of undeter-
mined geometry which was directly reduced and treated with
chloroethyloxalate. Conversion of the ester to the primary oxamide
provided the penultimate intermediate for cyclization to the core
structure. Initial methods used to effect this cyclization included
treatment with trimethylsilyl iodide or triflate in dichloromethane
at room temperature. While these conditions did provide the de-
sired material, the yields were highly variable and these reactions
were not readily amenable to large scale preparation. An improved
procedure was realized with base induced cyclization in 1 M NaOH
using microwave heating and very short reaction times to give
modest yet reliable yields of the triazine dione suitable for use
without further purification.
Preparation of the final compounds was accomplished as shown
in Scheme 2. Activation of the dione core as the imino triflate and
displacement with a variety of substituted anilines or aminopyri-
dines under basic conditions gave 5-arylamino-1,2,4-triazin-
6(1H)-ones. Alternatively, this coupling could be carried out under
neutral conditions using palladium catalysis at elevated tempera-
tures for cases in which the prior method failed.
R
N
R
N
R
N
1
N
N
O
N
N
O
2
3
N
O
O
a
b
6
OTf
NH
Ar
5
N
H
4
Scheme 2. Reagents and condition: (a) Tf2O, 2,4,6-collidine, CH2Cl2; (b) NaHMDS,
THF or Pd(OAc)2, BINAP, K2CO3, THF, 70 °C.
all designed utilizing these top structural motifs (Table 1). Addi-
tionally, since we had shown previously with the pyrazinones
bearing either 2,4,6- or 2,4,5-anilino substitutions at the 5-position
were preferred, we focused on these analogs in the triazinone ser-
ies. Compounds were tested in a CRF1 receptor binding titration as-
say using rat frontal cortex homogenate in which inhibition of
specific binding of [125I]Tyr-ovine-CRF by our test compounds
was measured to determine their receptor binding affinity.
Diverse substituents on the lower aryl ring were tolerated with
respect to steric and electronic considerations (Tables 1–3). In the
2,4,6-substituted aniline series, substitution of chlorine for methyl
in the 2- and 4-positions resulted in reduced potency (1A vs 2A).
However, compounds having chlorine in the 2- and 6-position
were more potent than their respective methyl analogs (4A and
4C vs 3A and 3C). Replacing the methyl ether in the 4-position of
Previous investigation in the pyrazinone series had shown that
preferred structural elements in the hydrophobic top region were
cyclopropyl accompanied by either a small alkyl or alkoxyalkyl
substituent; therefore the target compounds in this series were
O
O
N
N
O
N1
N
O
6
5
N
N
O
H2O
P450
3
O
NH
Cl
NH
Cl
NH
Cl
Cl
Cl
Cl
Cl
Cl
OCHF2
OCHF2
BMS-665053
OCHF2
+GSH
N
HN
O
HN
Cl
NH
GSH
HO
O
Cl
N
NH
Cl
Cl
OCHF2
OCHF2
Figure 2. Proposed core oxidative metabolic pathway of N3-phenylpyrazinones.

W. D. Schmitz et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3579–3583
3581
Table 1
Table 2
rCRF1 binding affinities of 5-(2,4,6-substituted)arylamino-1,2,4-triazin-6(1H)-onesa
rCRF1 binding affinities of 5-(2,4,5-substituted)arylamino-1,2,4-triazin-6(1H)-onesa
R
R
N
N
N
O
X
N
N
O
X
R = (A) Me; (B) Et; (C) CH2OMe
Compound
R = (A) Me; (B) Et; (C) CH2OMe
Compound
N
b
X
rCRF1 IC50
X
rCRF1 IC50
NH
NH
9A
9B
5.0 (2.5)
0.89 (0.10)
1A
2A
19 (4)
OMe
NH
NH
Cl
33 (5)
10A
28 (8)
Cl
OEt
NH
NH
3A
3C
68 (19)
51 (2)
11A
11B
60 (13)
9.3 (3.7)
OMe
NH
CN
NH
4A
4C
15 (1)
6.3 (1.6)
Cl
Cl
Cl
Cl
Cl
Cl
12A
13A
14A
270 (50)
10 (3)
Cl
OMe
CN
NH
NH
5A
5B
5C
14 (2)
6.3 (1.6)
11 (2)
Cl
Cl
CF3
NH
CN
6A
6C
39 (5)
11 (2)
NH
Cl
Cl
Cl
Cl
Cl
3300 (200)
F3C
OCF3
NH
CN
NH
7A
7B
7C
9.9 (2.5)
2.1 (0.8)
6.3 (1.2)
15A
15B
94 (25)
13 (6)
Cl
MeO
OCHF2
CN
a
NH
Cl
Values are means of three experiments, standard deviation is given in
parentheses.
8A
20 (1)
SO2Me
270 nM. Incorporation of an additional chlorine at the 6-position
as in compound 13A improved the potency by 27-fold to 10 nM.
While electron-withdrawing substituents such as –CF3, –SO2Me
and –CN were tolerated (compounds 5A–C and 8B, Table 1; com-
pounds 11–15, Table 2), aryl groups bearing multiple electron-
withdrawing groups were less active (12A vs 14A, Table 2). One
notable example from the 2,4,5-trisubstituted series was com-
pound 9B, which was the most potent compound tested at
0.89 nM.
Structures possessing a substituted 3-amino pyridyl substituent
at the 5-position of the triazinone were found to have potencies
equal to or better than the aniline-derived compounds (Table 3).
Earlier work in the pyrazinone series had shown either a 2,6- or
2,5,6-substitution pattern on the pyridine was optimal.19 Initial re-
sults for the triazinones suggested that this trend was conserved.
By comparison, the 2,4,6-substitution pattern on the pyridyl group
was disfavored (compare 5A, Table 1 to 16A, Table 3), thus we fo-
cused on pyridyl analogs with either the 2,6- or 2,5,6-substitution
patterns. Alkyl ethers were the preferred groups at the 6-position,
and a significant improvement in potency was observed upon
replacing the methyl ether with a difluoromethyl ether (compare
20C vs 21C, Table 3). Introduction of an additional nitrogen as in
pyrimidine 22A resulted in a substantial loss of activity which
was also consistent with observed results in the pyrazinone
series.20
a
Values are means of three experiments, standard deviation is given in
parentheses.
b
IC50 of o-CRF = 2.9 1.0 nM in this assay.
compound 4C with an electron-withdrawing substituent resulted
in similar potency for the –CF3 analogs 5A and 5C. Only a modest
decrease in potency was observed when the larger, more polar
methylsulfonyl group was introduced in compound 8A. No
improvement in potency was realized by incorporating the –CF3
phenol ether in compounds 6A and 6C. However, when a slight
change was made from a –CF3 ether to –CHF2 ether, improved
potencies were observed (compounds 7A–C). Consistent with pre-
vious observations in the pyrazinone series,13 a general rank order-
ing of compound IC50’s with respect to alkyl substitution on the
triazinone N1 position was: 1-cyclopropylethyl > 1-cyclopropyl-
2-methoxyethyl P 1-cyclopropylpropyl-1-amine. The most potent
compound in the 2,4,6-series was 7B.
For select compounds in the 2,4,5-substituted aniline series, a
significant improvement in potency was observed relative to the
2,4,6-substituted series (Table 2). For example, migration of the
6-methyl in 3A to the 5-position as in 9A gave a >10-fold increase
in potency. Interestingly, even though a diverse array of substitu-
ents were tolerated in compounds with potent rCRF1 binding affin-
ities, the relative positions and combinations of these groups
showed significant effects on binding. Compound 12A, with chlo-
rine at the 2- and 5-position, was only modestly active at
The effect of stereogenicity on the CRF1 binding profile of indi-
vidual enantiomers was also assessed. It was found that there was

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W. D. Schmitz et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3579–3583
Table 4
generally a preference for the (S-) enantiomer within the anilino
series and for the (R-) enantiomer in the 3-aminopyridine series
(Table 4) although the difference between any enantiomer pair
was no greater than 10-fold. Of particular note was that com-
rCRF1 binding affinities of individual enantiomers for select triazinones.a
Entry
Compound
(R-)
(S-)
1
2
3
4
5
6
7
8
9
4A
7A
8.3 (3.7)
13 (2)
7.5 (0.4)
7.2 (2.0)
12 (1)
pounds possessing
a 1-cyclopropyl-2-methoxyethyl fragment
17A
18A
4C
3.5 (1.0)
8.6 (0.6)
69 (10)
23 (9)
exhibited the greatest potency differences (5- to 11-fold; Table 4,
entries 5–9). This trend was in contrast to that observed previously
for pyrazinones, wherein compounds containing this functionality
showed little to no differentiation in activity across enantiomer
pairs.13b Absolute configuration was assigned based on single crys-
tal X-ray analyses for compounds 4A and 4C and subsequent corre-
lation of optically active triazinone core intermediates used for
syntheses of final products.21
23 (1)
7.2 (2.0)
4.4 (1.8)
15 (4)
27 (2)
6.5 (1.3)
7C
17C
18C
21C
2.3 (1.7)
2.4 (0.8)
1.1 (0.0)
a
Values are means of three experiments, standard deviation is given in
parentheses.
Compound 17A was chosen for further evaluation to assess its
in vitro metabolic profile, particularly with respect to core oxida-
tion. Previous experience with pyrazinone compounds bearing
the identical trifluormethyl methoxy pyridine residue found in
17A suggested that this was one of the more metabolically stable
pendant aryl groups under our assay conditions which allowed
for a more straightforward analysis of metabolism specifically at
the triazinone core.19 Accordingly, results of incubation with hu-
man and rat liver microsomes for triazinone 17A showed a signif-
icant decrease in the total percentage of metabolized compound
resulting from core oxidation (Table 5). The levels of core oxidation
products resulting from the proposed CYP-mediated epoxidation
were below the limits of detection. The levels of GSH adducts
attributed to reactive oxidative metabolites at the core structure
were estimated at <1% (detectable only by mass spectral analysis).
Table 5
Liver microsome incubation comparison of select pyrazinones and triazinonesa
N
N
O
N
N
O
N
NH
NH
Cl
Cl
CF3
N
OCHF2
OMe
17A
23
Compound Species Compound
remainingb (%)
Core
GSH core
oxidation (%) adducts (%)
17A
17A
Human 85
Rat 37
NDc
NDc
<1
<1
Table 3
rCRF1 binding affinities of 5-(di- and tri-substituted-pyridin-3-ylamino)-1,2,4-triazin-
6(1H)-onesa
23
23
Human 71
Rat 12
8
7
20
56
a
R
Data from (R)-enantiomers.
Thirty minute incubation with liver microsomes at 37 °C. For experimental
b
N
N
O
X
R = (A) Me; (B) Et; (C) CH2OMe
Compound
N
details see Ref. 15.
c
ND, not detected.
X
rCRF1 IC50
260 (10)
NH
Cl
Cl
16A
The major metabolic pathway for triazinone 17A was found to be
O-demethylation (ꢀ70% of total), along with smaller amounts of
oxidation products on the pyridyl ring (ꢀ2%). Only trace amounts
(60.1%) of GSH adducts at the pyridyl ring were detected.15 In-
cluded for reference in Table 5 is the data for pyrazinone 2315
which possesses an analogous core structure.
Finally, to further assess the viability of the triazinone chemo-
type, central target engagement was measured using an ex vivo
binding assay. Compounds 9B and 18C were shown to occupy rat
CRF1 receptors in the parietal cortex at 64% and 46%, respectively.22
The antagonist activity of the triazinones at CRF1 was confirmed by
N
5
1
CF3
NH
17A
17B
17C
6.7 (0.6)
3.7 (0.4)
3.7 (0.3)
CF3
N
OMe
NH
18A
18B
18C
12 (2)
3.6 (0.8)
3.0 (0.3)
CF3
N
OEt
NH
CF3
19B
2.7 (1.0)
evaluating both enantiomers of compound 21C in
a cAMP
N
assay, using Y79 cells in which potent antagonist activity
(7.3 nM, R-enantiomer; 29 nM, S-enantiomer) against 0.5 nM CRF
was observed.
In summary, a series of 5-arylamino-1,2,4-triazin-6(1H)-ones
was found to be potent CRF1 receptor antagonists. Additionally,
oxidative metabolism of the heterocyclic core was not detected,
thereby minimizing the potential for formation of reactive metab-
olites, improving the overall metabolic profile of triazinone-based
compounds relative to N3-phenylpyrazinones.
OMe
NH
20A
20B
20C
26 (7)
6.5 (1.6)
20 (2)
N
OMe
NH
21C
1.1 (0.0)b
N
OCHF2
NH
OMe
22A
1100 (100)
NN
OMe
Acknowledgments
a
The authors thank Richard Hartz for helpful discussions during
the preparation of the manuscript. The authors also thank Gail
Mattson for performing the in vitro CRF1 binding assay.
Values are means of three experiments, standard deviation is given in
parentheses.
b
Data from most potent single enantiomer.

W. D. Schmitz et al. / Bioorg. Med. Chem. Lett. 20 (2010) 3579–3583
3583
14. Hartz, R. A.; Ahuja, V. T.; Zhuo, X.; Mattson, R. J.; Denhart, D.; Deskus, J. A.;
Vrudhula, V. M.; Pan, S.; Ditta, J. L.; Shu, Y.-Z.; Grace, J. E.; Lentz, K. A.; Lelas, S.;
Li, Y.-W.; Molski, T. F.; Krishnananthan, S.; Wong, H.; Qian-Cutrone, J.;
Schartman, R.; Denton, R.; Lodge, N. J.; Zaczek, R.; Macor, J. E.; Bronson, J. J. J.
Med. Chem. 2009, 52, 7653.
15. Zhuo, X.; Hartz, R. A.; Bronson, J. J.; Wong, H.; Ahuja, V. T.; Vrudhula, V. M.;
Leet, J. E.; Huang, S.; Macor, J. E.; Shu, Y.-Z. Drug Metab. Dispos. 2010, 38, 5.
16. Singh, R.; Elipe, M. V. S.; Pearson, P. G.; Arison, B. H.; Wong, B. K.; White, R.; Yu,
X.; Burgey, C. S.; Lin, J. H.; Baillie, T. A. Chem. Res. Toxicol. 2003, 16, 198.
17. (a) Evans, D. C.; Watt, A. P.; Nicoll-Griffith, D. A.; Baillie, T. A. Chem. Res. Toxicol
2004, 17, 3; (b) Uetrecht, J. P. Chem. Res. Toxicol 1999, 12, 387; (c) Baillie, T. A.;
Kassahun, K. Adv. Exp. Med. Biol 2001, 500, 45.
18. Compounds of this type were first disclosed in a patent application: Arvanitis,
A. G., Olson, R. E.; Arnold, C. R.; Frietze, W. E. US6159980, 2000.
19. Hartz, R. A.; Ahuja, V. T.; Schmitz, W. D.; Molski, T. F.; Lodge, N. J.; Bronson, J. J.;
Macor, J. E. Bioorg. Med. Chem. Lett. 2010, 20, 1890.
20. Pyrimidine substituted pyrazinones were generally less potent than
structurally related pyridyl analogs.19 Data shown below for closest
structurally related pyrazinones also suggested a decrease in binding at CRF1
when an additional ring nitrogen was introduced.
References and notes
1. McIntyre, J.; Moral, M. A. Drugs Future 2006, 31, 1069.
2. Rosenzweig-Lipson, S.; Beyer, C. E.; Hughes, Z. E.; Khawaja, X.; Rajarao, S. J.;
Malberg, J. E.; Rahman, Z.; Ring, R. H.; Schechter, L. E. Pharmacol. Ther. 2007,
113, 134.
3. (a) Norman, T. R.; Burrows, G. D. Expert Rev. Neurother. 2007, 7, 203; (b) Nielsen,
D. M. Life Sci. 2006, 78, 909.
4. Vale, W.; Spiess, J.; Rivier, C.; Rivier, J. Science 1981, 213, 1394.
5. (a) Dzierba, C. D., Hartz, R. A., Bronson, J. J. Annual Reports in Medicinal
Chemistry. In Macor, J. E., Ed.; Academic: San Diego, 2008; Vol. 43, pp 3–23.; (b)
Hemley, C. F.; McCluskey, A.; Keller, P. A. Curr. Drug Targets 2007, 8, 105; (c)
Chatzaki, E.; Minas, V.; Zoumakis, E.; Makrigiannakis, A. Curr. Med. Chem. 2006,
13, 2751.
6. Chen, C.; Grigoriadis, D. E. Drug Dev. Res. 2005, 65, 216.
7. Chen, Y. L.; Obach, R. S.; Braselton, J.; Corman, M. L.; Forman, J.; Freeman, J.;
Gallaschun, R. J.; Mansbach, R.; Schmidt, A. W.; Sprouse, J. S.; Tingley, F. D.;
Winston, E. I. I. I.; Schulz, D. W. J. Med. Chem. 2008, 51, 1385.
8. Gilligan, P. J.; He, L.; Clarke, T.; Tivimahaisoon, P.; Lelas, S.; Li, Y.-W.; Heman, K.;
Fitzgerald, L.; Miller, K.; Zhang, G.; Marshall, A.; Krouse, C.; McElroy, J.; Ward,
K.; Shen, H.; Wong, H.; Grossman, S.; Nemeth, G.; Zaczek, R.; Arneric, S. P.;
Hartig, P.; Robertson, D. W.; Trainor, G. J. Med. Chem. 2009, 52, 3073.
9. Gilligan, P. J.; Clarke, T.; He, L.; Lelas, S.; Li, Y.-W.; Heman, K.; Fitzgerald, L.;
Miller, K.; Zhang, G.; Marshall, A.; Krouse, C.; McElroy, J.; Ward, K.; Zeller, K.;
Wong, H.; Bai, S.; Saye, J.; Grossman, S.; Zaczek, R.; Arneric, S. P.; Hartig, P.;
Robertson, D. W.; Trainor, G. J. Med. Chem. 2009, 52, 3084.
N
N
O
N
N
O
N
N
O
Cl
NH
Cl
NH
Cl
NH
OMe
OMe
10. (a) Gilligan, P. J.; Robertson, D. W.; Zaczek, R. J. Med. Chem. 2000, 43, 1641; (b)
Gilligan, P. J.; Li, Y.-W. Curr. Opin. Drug Discov. Devel. 2004, 7, 487.
11. (a) Chen, C.; Dagnino, R.; De Souza, E. B.; Grigoriadis, D. E.; Huand, C. Q.; Kim,
K.-I.; Liu, Z.; Moran, T.; Webb, T. R.; Whitten, J. P.; Xie, Y. F.; McCarthy, J. R. J.
Med. Chem. 1996, 39, 4358; (b) Lanier, M.; Williams, J. P. Expert Opin. Ther.
Patents 2002, 12, 1619.
N
N
N
N
OMe
rCRF1 IC50 = 17 6 nM
21. Racemic 1,2,4-triazine-5,6,(1H, 4H)-dione cores were separated by chiral
OMe
rCRF1 IC50 = 29 12 nM
OMe
rCRF1 IC50 = 240 40 nM
chromatography. Representative conditions: Chiralcel OD column,
12. Abreu, M. E.; Rzeszotarski, W.; Kyle, D. J.; Hiner, R. N.; Elliott, R. L. U.S. Patent
5063245, 1991.
4.6 Â 250 mm, 10
lm; solvents: A = EtOH, B = heptane; 95% B for 35 min;
flow rate: 0.8 mL/min, 281 nm. Alternatively, in some cases final racemic
triazinone compounds were separated by chiral chromatography.
Representative conditions: Chiralpak AD-H column, 4.6 Â 250 mm, 5 m;
solvents: 91% CO2–9% ethanol; temperature: 35 °C; pressure: 100 bar; flow
rate: 2 mL/min; UV at 210 nm.
13. (a) Hartz, R. A.; Ahuja, V. T.; Rafalski, M.; Schmitz, W. D.; Brenner, A. B.;
Denhart, D. J.; Ditta, J. L.; Deskus, J. A.; Yue, E. W.; Arvanitis, A. G.; Lelas, S.; Li,
Y.-W.; Molski, T. F.; Wong, H.; Grace, J. E.; Lentz, K. A.; Li, J.; Lodge, N. J.; Zaczek,
R.; Combs, A. P.; Olson, R. E.; Mattson, R. J.; Bronson, J. J.; Macor, J. E. J. Med.
Chem 2009, 52, 4161; (b) Hartz, R. A.; Ahuja, V. T.; Arvanitis, A. G.; Rafalski, M.;
Yue, E. W.; Denhart, D. J.; Schmitz, W. D.; Ditta, J. L.; Deskus, J. A.; Brenner, A. B.;
Hobbs, F. W.; Payne, J.; Lelas, S.; Li, Y.-W.; Molski, T. F.; Mattson, G. K.; Peng, Y.;
Wong, H.; Grace, J. E.; Lentz, K. A.; Qian-Cutrone, J.; Zhuo, X.; Shu, Y.-Z.; Lodge,
N. J.; Zaczek, R.; Combs, A. P.; Olson, R. E.; Bronson, J. J.; Mattson, R. J.; Macor, J.
E. J. Med. Chem. 2009, 52, 4173.
22. Li, Y.-W.; Hill, G.; Wong, H.; Kelly, N.; Ward, K.; Pierdomenico, M.; Ren, S.;
Gilligan, P.; Grossman, S.; Trainor, G.; Taub, R.; McElroy, J.; Zaczek, R. J.
Pharmacol. Exp. Ther. 2003, 305, 86.