Synthesis and SAR of 8-arylquinolines as potent corticotropin-releasing factor1 (CRF1) receptor antagonists

Article abstract of DOI:10.1016/S0960-894X(03)00684-X

A series of 4-substituted 8-aryl-2-methylquinolines 4 was designed and synthesized as highly potent antagonists for the human CRF₁ receptor. This series of compounds displayed parallel SAR to other bicyclic systems such as pyrazolo[1,5-a]pyrimidines, with several compounds possessing low nanomolar binding affinity. In addition to the high potency, the basicity of this 4-aminoquinoline core may offer CRF₁ antagonists with lower lipophilicity.

Full text of DOI:10.1016/S0960-894X(03)00684-X

Bioorganic & Medicinal Chemistry Letters 13 (2003) 3375–3379
Synthesis and SAR of 8-Arylquinolines as Potent
Corticotropin-Releasing Factor1 (CRF1) Receptor Antagonists
Charles Q. Huang, Keith Wilcoxen, James R. McCarthy, Mustapha Haddach,
Thomas R. Webb, Jian Gu, Yun-Feng Xie, Dimitri E. Grigoriadis and Chen Chen*
Department of Medicinal Chemistry and Department of Pharmacology, Neurocrine Biosciences, Inc., 10555 Science Centre Drive,
San Diego, CA 92121, USA
Received 6 March 2003; accepted 23 March 2003
Abstract—A series of 4-substituted 8-aryl-2-methylquinolines 4 was designed and synthesized as highly potent antagonists for the
human CRF1 receptor. This series of compounds displayed parallel SAR to other bicyclic systems such as pyrazolo[1,5-a]pyr-
imidines, with several compounds possessing low nanomolar binding affinity. In addition to the high potency, the basicity of this
4-aminoquinoline core may offer CRF1 antagonists with lower lipophilicity.
# 2003 Elsevier Ltd. All rights reserved.
Corticotrophin-releasing factor (CRF) is the key reg-
ulator of an organism’s response to stress and as such,
mediates the endocrine, autonomic, behavioral and
immune response to stressful stimuli.1 The binding of
the released hypothalamic CRF to the CRF1 receptors
in the pituitary is responsible for the increased release of
ACTH and other pro-opiomelanocortin derived pep-
tides in response to the stressful stimuli in the peri-
phery.2 On the other hand, prolonged activation of the
brain CRF receptors by the released hypothalamic CRF
is thought to be related to the psychological effects of
stress leading to anxiety and depression. Therefore,
blockade of central CRF1 receptor activation has been
proposed as a novel approach for the treatment of these
psychiatric disorders.3
very encouraging results in an open label clinical.9 Since
the pyrazolo[1,5-a]pyrimidine core is not very basic (an
estimated pKa value is less than 6),10 we successfully
incorporated a basic 4-methyl-6-dimethylamino-3-pyr-
idyl group in 3 to make the compound with suitable
water-solubility (the pKa value of 3 is 7.1, and water
solubility is >10 mg/mL at pH 4) as a drug candidate
(Fig. 1). The clinical trial was discontinued due to
unexpected liver toxicity.11
The recent discovery of non-peptide antagonists of the
CRF receptors has opened a new era for the study of
this neurotransmitter. Several small molecules have
been reported to have good CRF1 receptor antagonistic
activity.4 For example, anilinopyrimidine (such as NBI
27914),5 pyrrolo[1,2-d]pyrimidine (CP-154,526),6 imida-
zolo[3,4-d]pyrimidine (1),7 pyrazolo[1,5-a]pyrimidine (2,
NBI 30545) show good binding affinity as well as in vivo
activity.8 A recent human clinical trial with NBI 30775
(3) on a group of severely depressed patients revealed
*Corresponding author. Tel.: +1-858-658-7600; fax: +1-858-658-
7619; e-mail: cchen@neurocrine.com
Figure 1.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00684-X

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C. Q. Huang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3375–3379
In our continuing search for novel heterocyclic tem-
plates with desirable physicochemical properties, 4-sub-
stituted 8-aryl-2-methylquinolines of the general
structure 4 were designed. In addition to having a
topographical similarity to known CRF1 receptor
antagonists such as CP-154,526, 1 and 3,12 this bicyclic
nucleus should be relatively basic since the reported pKa
value of 4-aminoquinoline is 9.08,13 which matches with
the ACD calculated value (9.00). With this kind of pKa
value, this class of compounds should be charged in a
great proportion under physiological conditions (pH
ꢀ7.4). In this paper, we present the synthesis and
structure–activity relationship study around this nucleus
as a potent class of CRF1 receptor antagonists.
described in Scheme 2. Thus, 2-iodoaniline was cyclized
to the 4-hydroxyquinoline 9, in 65% yield, with ethyl
acetoacetate as described above. Compound 9 was
reacted with POCl3, followed by dipropylamine in the
presence of TsOH to afford the aminoquinoline 11
(77% yield, two steps). Compound 11 was then sub-
jected to a Suzuki coupling reaction with various aryl-
boronic acids to yield the desired products 4r–4v in 25–
80% yields.
Compound 4w was synthesized from 2-(2,4-dimethoxy-
phenyl)-4,4-dimethyl-2-oxazoline. Reaction of 12 with
4-chlorophenylmagnesium chloride gave the biphenyl 13
in good yield with a literature protocol.18 The oxazole
ring was then hydrolyzed to the acid 14, followed by a
Curtis rearrangement with (PhO)2PON3 in tertiary
butanol to afford the urethane 15, which was depro-
tected in trifluoroacetic acid to give the aniline 16 (45%
yield in three steps). Compound 16 was then converted
to the target quinoline 4w using a similar procedure to
that described earlier (Scheme 3).
The synthesis of the 4-substituted 8-aryl-2-methylquino-
lines 4a–4q is outlined in Scheme 1. Palladium catalyzed
cross coupling reaction of 2-bromo- or 2-iodoaniline
with 2,4-dichlorophenylboronic acids under Suzuki
coupling conditions gave 2-(2,4-dichlorophenyl)aniline
in 87% yield,14 which was condensed with ethyl acet-
oacetate in benzene under azeotropic conditions to give
an enamine intermediate, which was subsequently
cyclized upon heating in phenyl ether to give the 4-
hydroxyquinoline 7 (42% in two steps).15 Reaction of 7
with POCl3 at reflux afforded the corresponding 4-
chloroquinoline 8 in quantitative yield. Compound 8
was converted to 4-methoxyquinoline 4b with sodium
methoxide (1.2 equiv) in DMF at room temperature.
The corresponding methylsulfide 4c was obtained in
The CRF1 receptor binding assay was performed with
the cloned human CRF1 receptor expressed in CHO-
cells using [125I]o-CRF as the ligand in a manner similar
to that previously reported.19 Tables 1 and 2 summarize
the SAR results of the different substituents at the 4-
and 8-positions of the arylquinolines 4.
As seen in Table 1, the intermediate 4-hydroxyquinoline
7a exhibited no CRF activity (the inactivity could be
related to the acidic hydroxy group), whereas the 4-
chloroquinoline 8a had an unexpected high binding
affinity (Ki=5 nM). The small 4-methyl and 4-methoxy
analogues 4a and 4b had Ki values of 460 and 140 nM,
respectively, and the slightly larger S-methyl analogue
4c showed very good binding affinity (Ki=12 nM). This
set of data suggested a lipophilic group is favored at the
4-position of the quinoline 4, and the highly lipophilic
chlorine was able to mimic the larger-sized S-methyl
a
similar manner. The 4-aminoquinolines 4d–4q
were synthesized in very good yields (65–90%) by
reacting 8 with various mono- or di-alkylamines
promoted by toluenesulfonic acid at an elevated tem-
perature.16 Compound 4a was made from cyclization of
6 with 2,5-pentadione in heated phenyl ether in 30%
yield.17
The quinolines 4r–4v with various aromatic groups at
the 8-position were synthesized according to the route
Scheme 1. Reagents and conditions: (a) 2,4-ClPhB(OH)2, Pd(PPh3)4, Na2CO3, benzene, EtOH, H2O; (b) ethyl acetoacetate, TsOH, benzene;
then Ph2O, 260 ꢁC; (c) POCl3, reflux; (d) R1H, see text (R1=RO, RS or R2N); (e) 2,5-pentadione, Á.
Scheme 2. Reagents and conditions: (a) ethyl acetoacetate, TsOH, benzene; then Ph2O, 260 ꢁC; (b) POCl3, reflux; (c) Pr2NH, TsOH, 180 ꢁC;
(d) ArB(OH)2, Pd(PPh3)4, Na2CO3, benzene, EtOH, H2O.

C. Q. Huang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3375–3379
Table 1. Effects of 4-substituents on the quinolines 4
3377
Table 2. Effects of 8-aryl substituents on the quinolines 4
Compd
R2
R3
R1
Ki (nM)
Compd
R2
R3
Ki (nM)
7a
8a
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
H
H
H
H
H
H
H
H
H
2,4-Cl
2,4-Cl
2,4-Cl
2,4-Cl
2,4-Cl
2,4-Cl
2,4-Cl
2,4-Cl
2,4-Cl
2,4-Cl
2,4-Cl
2,4-Cl
2,4-Cl
2,4,6-Me
2,4,6-Me
2,4,6-Me
2,4,6-Me
2,4,6-Me
2,4,6-Me
OH
Cl
Me
MeO
MeS
EtNBu
Pr2N
>10,000
5.0Æ1.0
460
140
16Æ4
4r
4m
4e
4i
4s
4t
4u
4v
4w
H
H
H
Me
H
H
H
H
MeO
H
420
2,4,6-Me
2,4-Cl
2,4-Cl
2,4-MeO
4-MeO
4-Me
3.0Æ1.5
0.9Æ0.3
4.5Æ0.7
14.5Æ5.1
52
32.5Æ5.5
8.9Æ0.7
9.0Æ3.0
5.7Æ1.0
0.9Æ0.3
0.5Æ0.1
5.7Æ1.0
3.8Æ0.5
4.5Æ0.7
2.5Æ0.6
12.1Æ1.3
2.4Æ0.6
3.0Æ1.5
2.2Æ1.7
6.5Æ3.3
3.0Æ0.5
3.2Æ0.7
PrNCH2Pr-c
(MeOCH2CH2)2N
PrNBn
4-Cl
4-Cl
H
Me
Me
Me
H
H
H
H
H
H
Pr2N
PrNCH2Pr-c
(MeOCH2CH2)2N
EtNBu
4m
4n
4o
4p
4q
Pr2N
methyl compounds, which was somewhat surprised. We
expected the 7-methyl group would help the dichloro-
phenyl group to take the orthogonal position relative to
the quinoline ring.5b Additional methyl group at the
phenyl ring did not have big effect on the receptor
binding, thus, 4l–4q were also slightly less active than
4d–4h.
PrNCH2Pr-c
(MeOCH2CH2)2N
PrNBu-n
PrNBn
group. The prototypical compound in this series was 8-
(2,4-dichlorophenyl)-4-dipropylamino-2-methylquinoline
4e, which was found to have subnanomolar binding
affinity on the CRF1 receptor (Ki=0.9). Replacement of
the 4-chloro-group of quinoline 8a with N-cyclopropane-
methyl-N-propylamino group also afforded compound
with subnanomolar activity (4f, Ki=0.5 nM). Replace-
ment of the N-cyclopropanemethyl group of compound
4f with a smaller ethyl resulted in approximately 10-fold
loss in binding affinity (4d, Ki=5.7 nM). The more polar
bis(methoxyethyl)amino analogue 4g was also 10-fold
less active than 4f.
The effect of substitutions on the 8-phenyl ring of the
quinolines 4 was also examined (4r–4x, Table 2). The
non-substituted phenyl analogue 4r was moderately
active (Ki=420 nM). Introduction of a non-polar sub-
stituent on the phenyl group generally resulted in more
active compounds. Thus, the 2,4,6-trimethylphenyl
analogue had an approximately 140-fold increase in
binding (4i, Ki=3 nM), while the 2,4-dichlorophenyl
group exhibited a 460-fold increase (4e, Ki=0.9 nM).
The relatively polar 2,4-dimethoxyphenyl group had a
similar but somewhat reduced effect (4s, Ki=15 nM). A
para-substitution with methyl or methoxy resulted in
compounds with good binding affinity (4u and 4t,
Ki=33 and 52 nM, respectively). Substitution with a
The 7-methylquinoline derivatives (4i–4k), however,
were slightly less active than the corresponding des-
Scheme 3. Reagents and conditions: (a) 4-ClPhMgBr, Et2O; (b) MeI then 2 N HCl, reflux; (c) (PhO)2PON3, Et3N, t-BuOH, reflux; (d) TFA;
(e) ethyl acetoacetate, TsOH, benzene; then Ph2O, 260 ꢁC; (f) POCl3, reflux; (g) Pr2NH, TsOH, 180 ꢁC.

3378
C. Q. Huang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3375–3379
Table 3. Inhibition of CRF-stimulated cAMP production
5. (a) Chen, C.; Dagnino, R., Jr.; De Souza, E. B.; Grigor-
iadis, D. E.; Huang, 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) Arvanitis, A.; Gilligan, P. J.;
Chorvat, R. J.; Cheeseman, R. S.; Christos, T. E.; Baktha-
vatchalam, R.; Beck, J. P.; Cocuzza, A. J.; Hobbs, F. W.;
Wilde, R. G.; Arnold, C.; Chidester, D.; Curry, M.; He, L.;
Hollis, A.; Klaczkiewicz, J. D.; Krentitsky, P.; Rescinito, J. P.;
Scholfield, E.; Culp, S.; De Souza, E. B.; Fitzgerald, L. W.;
Grigoriadis, D. E.; Tam, S. W.; Wong, Y. N.; Huang, S.-M.;
Shen, H. L. J. Med. Chem. 1999, 42, 805. (c) Gilligan, P. J.;
He, L.; Culp, S.; Fitzgerald, L.; Tam, S. W.; Wong, Y. N.
Bioorg. Med. Chem. 1999, 7, 2321. (d) Nakazato, A.; Kuma-
gai, T.; Okubo, T.; Tanaka, H.; Chaki, S.; Okuyama, S.;
Tomisawa, K. Bioorg. Med. Chem. 2000, 8, 1183.
Compd
Ki (nM)
IC50 (nM)
4d
4e
4f
4g
4m
5.7
0.9
0.5
5.7
3.0
51
17
16
14
14
lipophilic chloro group increased the binding affinity to
low nanomolar (4v, Ki=9 nM). Finally, introduction of
a methoxy group at the 7-position of the quinoline core
had no effect in binding affinity (4w, Ki=9 nM).
6. Schulz, D. W.; Mansbach, R. S.; Sprouse, J.; Braselton;
Collins, J.; Corman, M.; Dunaiskis, A.; Faraci, S.; Schmidt,
A. W.; Seeger, T.; Seymour, P.; Tingley, F. D.; Winston, E. N.,
III; Chen, Y. L.; Heym, J. Proc. Natl. Acad. Sci. U.S.A. 1996,
93, 10477.
Selective compounds from this series were further tested
for functional antagonism on the CRF1 receptor.20
Thus, in a CRF-stimulated c-AMP production assay,
compounds 4e, 4f, 4g, and 4m inhibited c-AMP accu-
mulation with low nanomolar IC50 values (about 15
nM), while compound 4d was slightly less active
(IC50=51 nM) (Table 3). None of these compounds
tested alone demonstrated any effects on basal cAMP
production, indicating that these compounds are devoid
of agonist activity at this receptor subtype. All com-
pounds were examined for activity in a CRF2-receptor
binding assay as previously described21 and none of the
listed compounds showed a does-dependent inhibition
of ligand binding and none had a greater than 40%
inhibition at a concentration of 10 mM. These data
demonstrate these compounds are selective CRF1
antagonists.
7. Chorvat, R. J.; Bakthavatchalam, R.; Beck, J. P.; Gilligan,
P. J.; Wilde, R. G.; Cocuzza, A.; Hobbs, F. W.; Cheeseman,
R. S.; Curry, M.; Rescinito, J. P.; Krenitsky, P.; Chidester, D.;
Yarem, J.; Klackewicz, J. D.; Hodge, C. N.; Aldrich, P. E.;
Wasserman, Z. R.; Fernandez, C. H.; Zaczek, R.; Fitzgerald,
L.; Huang, S.-M.; Shen, H. L.; Wong, Y. N.; Chien, B. M.;
Quon, C. Y.; Arvanitis, A. J. Med. Chem. 1999, 42, 833.
8. (a) Wustrow, D. J.; Capiris, T.; Rubin, R.; Knobelsdorf,
J. A.; Akunne, H.; Davis, M. D.; MacKenzie, R.; Pugsley,
T. A.; Zoski, K. T.; Heffner, T. G.; Wise, L. D. Bioorg. Med.
Chem. Lett. 1998, 8, 2067. (b) Wilcoxen, K.; Chen, C.; Huang,
C.; Haddach, M.; Xie, M.; Wing, L.; Grigoriadis, D. E.; De
Souza, E. B.; McCarthy, J. R. Book of Abstracts, 217th
American Chemical Society National Meeting, Anaheim, CA,
USA, March 21–25, 1999; MEDI 002.
9. Zobel, A. W.; Nickel, T.; Kunzel, H. E.; Ackl, N.; Sonntag,
A.; Ising, M.; Holsboer, F. J. Psychiatr. Res. 2000, 34, 171.
10. The calculated value for 7-aminopyrazolo[1,5-a]pyr-
imidine is 5.4 (ACD/Labs, ACD Software Development,
2002).
11. Owens, M. J.; Nemeroff, C. B. CNS Drugs 1999, 12, 85.
12. Chen. C.; Wilcoxen, K.; Bozigian, H.; Chen, T. K.; Cha,
M.; McCarthy, J. R.; Huang, C. Q.: Haddach, H.; Zhu, Y. F.;
Murphy, B.; De Souza, E. B.; Grigoriadis, D. E. Book of
Abstracts, 221st ACS National Meeting, San Diego, April 1–5,
2001; MEDI 214.
In summary, a series of 8-aryl-2-methylquinolines
exemplified by 4e was designed and synthesized as low
nanomolar CRF1 receptor antagonists. The results of
the SAR study suggest that the dipropylamino, or a
group with similar size and shape on the 4-amino func-
tionality of the quinoline core structure in conjunction
with a para-substituent such as chlorine at the 8-phenyl
group are required for optimal CRF1 receptor binding
affinity. This series of compounds also demonstrated
good antagonistic function in inhibition of CRF-stimu-
lated c-AMP production on the CRF1 receptor. In
addition to the high potency, the basicity of this 4-ami-
noquinoline core may offer CRF1 antagonists with
lower lipophilicity (a calculated pKa value for 4w is 10.7,
ACD Software).
13. (a) Brown, H. C. In Determination of Organic Structure by
Physical Methods; Braude, E. A., Nachod, F. C., Eds.; Aca-
demic: New York, 1955. (b) Hawley, S. R.; Bray, P. G.;
O’Neill, P. M.; Park, B. K.; Ward, S. A. Biochem. Pharmacol.
1996, 52, 723.
14. Sollewijn Gelpke, A. E.; Veerman, J. J. N.; Schreuder
Goedheijt, M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Hiemstra, H. Tetrahedron 1999, 55, 6657.
15. Kaslow, H. J. Am. Chem. Soc. 1951, 73, 4986.
16. Synthesis of 2-methyl-4-(dipropylamino)-8-(2,4-dichloro-
phenyl)quilonine (4e). To a stirring solution of 2-bromoaniline
(4.0 g, 23.3 mmol) in 120 mL of toluene was added tetra-
kis(triphenylphosphine)-palladium(0) (2.7 g, 2.33 mmol, 10%
mol) and 2.0 M aqueous sodium carbonate solution (35 mL,
70 mmol). In a separate flask, 2,4-dichlorophenylboronic acid
(25.6 mmol) was dissolved in alcohol (35 mL). To the light
yellow boronic acid solution was added the 2-bromoaniline
mixture. The resulting brown mixture was heated to reflux
overnight. The green reaction mixture was cooled, diluted with
ethyl acetate and washed with saturated ammonium chloride
solution once. The organic layer was dried by sodium sulfate,
filtered and concentrated. The residue was purified by flash
chromatography on silica gel to provide the desired 2-(2,4-
References and Notes
1. Rivier, C. L.; Plotsky, P. M. Annu. Rev. Physiol. 1986, 48,
475.
2. Dieterich, K. D.; Lehnert, H.; De Souza, E. B. Endocrinol.,
Diabetes 1998, 105, 65.
3. Heit, S. O.; Michael, J.; Plotsky, P.; Nemeroff, C. B.
Neuroscientist 1997, 3, 186.
4. (a) Grigoriadis, D. E.; Haddach, M.; Ling, N.; Saunders, J.
Curr. Med. Chem. Central Nervous System Agents 2001, 1, 63.
(b) Gilligan, P. J.; Robertson, D. W.; Zaczek, R. J. Med.
Chem. 2000, 43, 1641.

C. Q. Huang et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3375–3379
3379
dichlorophenyl)aniline in 87% yield. 1H NMR (CDCl3) d 3.54
(brs, 2H), 6.79 (d, 1H), 6.85 (d, 1H), 7.02 (d, 1H), 7.19–7.35
(m, 3H), 7.53 (d, 1H). GC/MS: m/z=237 (M+), HR-MS calcd
for C12H9NCl2: 238.0190, Found: 238.0198 (MH+).
7.53 (s, 1H), 7.63–7.65 (m, 2H), 8.26 (dd, 1H). GC/MS: m/z
321 (M+), MS (CI): m/z 322 (MH+). HR-MS calcd for
C16H10NCl3: 321.9957, Found: 321.9970 (MH+).
A
solution of 2-methyl-4-chloro-8-(2,4-dichlorophenyl)-
A solution of 2-(2,4-dichlorophenyl)aniline (19.8 mmol), ethyl
acetoacetate (2.58 g, 19.8 mmol) and p-toluenesulfonic acid
monohydrate (20 mg) in 100 mL of benzene was refluxed for
30 min. The reaction mixture was cooled, concentrated and
purified by flash chromatography on silica gel to provide a
yellow oil. A solution of the above oil (6.68 mmol) in 10 mL
diphenylether was heated to reflux for 5 min. The reaction
mixture was cooled and the solid was collected by filtration,
and rinsed with diethyl ether. The desired 2-methyl-4-hydroxy-
8-(2,4-dichlorophenyl)quilonine was obtained as a white solid
quilonine (0.31 mmol) and p-toluenesulfonic acid mono-
hydrate (0.1 g) in 0.4 mL of propylamine in a 5 mL Reacti-
Vials was heated at 160 ꢁC for 12 h. The reaction mixture was
cooled and then partitioned between ethyl acetate and water.
The organic layer was washed with brine, dried under sodium
sulfate, concentrated and purified by a preparative TLC plate
(hexane/EtOAc, 10:1). The desired 2-methyl-4-(dipropylamino)
-8-(2,4-dichlorophenyl)quilonine was isolated as pale yellow oil
1
in 67% yield. H NMR (CDCl3) d 0.89 (t, 6H), 1.56–1.66 (m,
4H), 2.52 (s, 3H), 3.25 (t, 4H), 6.73 (s, 1H), 7.33 (d, 1H),7.36 (d,
1H), 7.43 (d, 1H), 7.49 (d, 1H), 7.52 (s, 1H), 8.11 (d, 1H); GC/
MS: m/z 386 (M+), MS (ES): m/z 387 (M+H+). HR-MS calcd
for C22H24N2Cl2:MH+ 387.1395, Found: 387.1402 (MH+).
17. Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A. J. Chem.
Soc., Perkin Trans. 1 1989, 953.
in 42% yield, mp 282–284 ꢁC. H NMR (CDCl3) 2.56 (s, 3H),
1
6.11 (s, 1H), 7.34–7.44 (m, 4H), 7.58 (d, 1H), 8.38 (d, 1H), 8.82
(brs, 1H). MS (CI): m/z 304 (MH+). Anal. calcd for
C16H11NOCl2 (304.12) C, 63.18; H, 3.65; N: 4.60, Found: C,
63.34; H, 3.88; N: 4.42.
A
mixture of 2-methyl-4-hydroxy-8-(2,4-dichlorophenyl)-
18. Chew, W.; Hynes, R. C.; Harpp, D. N. J. Org. Chem.
1993, 58, 4398.
19. De Souza, E. B. J. Neurosci. 1987, 7, 88.
20. Battaglia, G.; Webster, E. L.; De Souza, E. B. Synapse
1987, 1, 572.
21. For a CRF2 binding assay, see: Grigoriadis, D. E.; Liu,
X. J.; Vaughn, J.; Palmer, S. F.; True, C. D.; Vale, W. W.;
Ling, N.; De Souza, E. B. Mol. Pharmacol. 1996, 50, 679.
quilonine (4.34 mmol) and phosphorous oxychloride (5 mL)
was refluxed for 2 h, cooled, poured onto a crack ice, neu-
tralized by 1 N NaOH. The aqueous layer was extracted by
ethyl acetate. The organic layer was washed with brine, dried
under sodium sulfate, concentrated to give the desired 2-
methyl-4-chloro-8-(2,4-dichlorophenyl)quilonine in 94% yield.
1H NMR (CDCl3) d 2.58 (s, 3H), 7.34 (s, 2H), 7.39 (s, 1H),