Bioorganic & Medicinal Chemistry Letters 16 (2006) 3950–3954
Amino substituted analogs of 1-phenyl-3-phenylimino-2-indolones
with potent galanin Gal3 receptor binding affinity
and improved solubility
Michael J. Konkel,* Mathivanan Packiarajan, Heidi Chen, Upendra P. Topiwala,
Hermogenes Jimenez, Ian Jamie Talisman, Heather Coateꢀ and Mary W. Walker
Lundbeck Research USA, Inc., 215 College Road, Paramus, NJ 07652, USA
Received 22 September 2005; revised 5 May 2006; accepted 8 May 2006
Available online 30 May 2006
Abstract—A series of amino analogs of 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (1) were synthe-
sized to improve aqueous solubility, while retaining high affinity for the human galanin Gal3 receptor. A very potent analog (9e, 1,3-
dihydro-1-[3-(2-pyrrolidinylethoxy)phenyl]-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one, Ki = 5 nM) shows good selectivity
and solubility of 48 lg/mL at pH 7.4.
Ó 2006 Elsevier Ltd. All rights reserved.
In the rat, galanin has been shown to have physiological
effects on feeding, insulin release, lactation, gut contrac-
tility, and growth, and has effects on central functions
such as spinal reflex, learning, memory, and in rodent
models of depression.1 These effects are presumably
through galanin’s role as a neuropeptide that activates
G-protein coupled receptors (GPCRs) to regulate a vari-
ety of functions. Three cloned galanin GPCRs have
been identified and are designated as Gal1, Gal2, and
Gal3.2 Rat mRNA encoding the galanin Gal3 receptor
has been localized in the hypothalamus, pituitary, spinal
cord, pancreas, liver, kidney, stomach, and adrenal
gland suggesting possible roles in feeding, digestion,
pituitary hormone release, nociception, insulin homeo-
stasis, and glucose homeostasis.3
some in vitro assays in our hands. In our characteriza-
tion of compound 1 and related analogs, we discovered
that compounds of this series suffer from low aqueous
solubility (<1 lg/mL). Herein are described novel ana-
logs of compound 1 that have significantly improved
aqueous solubility.
Our strategy for increasing solubility in this series of
compounds was to incorporate a basic amino function-
ality. Since we knew from previous unpublished work in
this series that the galanin Gal3 receptor was least
sensitive to substitution on the 1-phenyl group of the
1-phenyl-3-imino-2-indolones, we decided to explore
modifications on this ring.
The syntheses of these compounds are illustrated in
Schemes 1–3. The reaction conditions have not been
optimized in these studies. The hydroxyphenylindolones
7 were synthesized as key intermediates according to the
methods in Scheme 1. Isatin (2) was condensed with
m-(trifluoromethyl)aniline, giving imine 3. Imine 3 was
then arylated with substituted phenyl boronic acids
under cupric acetate catalysis, giving the intermediates
4 and 6. Alternatively, isatin (2) was arylated with p-iso-
propyloxyphenyl boronic acid under cupric acetate
catalysis5 and the resulting intermediate isatin was con-
densed with m-(trifluoromethyl)aniline, giving the inter-
mediate 5. A different phenolic protecting group was
employed for each of the isomers due to commercial
availability of the boronic acids. Each was deprotected
We had previously discovered that 1,3-dihydro-1-phen-
yl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one
(compound 1) is a potent antagonist (Ki = 17 nM, see
Table 1) selective for the human galanin Gal3 receptor.4
While this is a useful compound in some assays for
exploring the role of the galanin Gal3 receptor, its low
aqueous solubility (<1 lg/mL) has limited its utility in
Keywords: Galanin; Gal3 antagonist.
*
Corresponding author. Tel.: +1 201 350 0355; fax: +1 201 261
ꢀ
Present address: OSI Pharmaceuticals, Inc., Broadhollow Bioscience
Park, 1 Bioscience Park Drive, Farmingdale, NY 11735, USA.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.05.025