rated when condensation of indole-3-carbaldehyde with
6
pyrrolidine gave the enamine 5 that could be transformed
Table 2. Yields, HPLC-Purities (in Parentheses), and
into the N-substituted 3-formylindole 6. Subsequent im-
mobilization gave the formylindolylmethyltriazole (FIMT)
resin 3f. Applying 3f for the model synthesis, the carbox-
amide 8 could be isolated analytically pure in 92% yield,
after cleavage with 2% TFA.
To demonstrate the utility of the click linker strategy, we
employed the FIMT resin 3f for the parallel synthesis of a
focused library of putatively dopaminergic arylcarbamides.
Whereas we followed the above-mentioned conditions for
the reductive amination, we avoided the use of the expensive
reagent HOAt for the parallel synthesis employing a TFFH
7
(
tetramethylfluoroformamidinium hexafluorophosphate) in-
duced coupling, instead (Scheme 4). Thus, subsequent
a
HPLC-purities were determined at 240 nm. Dopamine D4 affinities
3
were measured by the displacement of the radioligand [ H]spiperone from
the D4.4 receptor subtype at a concentration of the test compound of 10
-
7
mol/L. Color code: gray ) 0-33% displacement, yellow ) 34-66%
displacement, red ) 67-100% displacement.
cloned human dopamine receptors D2long, D2short, D3, and
D4. The test compounds of the focused library were not able
to substantially displace the radioligand from the D2long
,
-7
D2short, and D3 receptor subtype in 10 molar concentration
indicating poor binding affinity. In contrast, highly interesting
structure activity relationships could be observed for the D4
subtype when the 3-acylaminopyrrolidines 10i and 10s were
3
detected to displace more than 67% of [ H]spiperone. These
hit compounds can serve as leads for the development of
new dopamine D4 selective ligands, which are discussed as
valuable tools for the therapy of schizophrenia an ADHD.8
In conclusion, the 1,3-dipolar cycloaddition proved to be
an efficient and practical reaction for the linkage of SPOS
handles. Employing the BAL methodology as an example,
the FormylAryloxyMethylTriazole (FAMT) handle 3c and
the FormylIndolylMethylTriazole linker (FIMT) 3f were
developed. Application for the parallel synthesis of phar-
macological test compounds led to the selective dopamine
D4 receptor ligands 10i und 10s.
a
2 3 2 2
Reagents: (a) A(1-5)-NH , Na(OAc) BH, CH Cl , rt, 16 h;
(
b) B(1-4)-COOH, TFFH, DIPEA, DMF, rt, 24 h; (c) TFA (2%
in CH Cl ) rt, 16 h.
2
2
attachment of the primary amines A1-A5 and the aryl-
carboxylic acids B1-B4 furnished the resin-bound carbox-
amides 9a-t, which could be liberated by 2% TFA in
Acknowledgment. This work was supported by the
BMBF and the Fonds der Chemischen Industrie.
2 2
CH Cl to afford the desired test compounds 10a-t in 50-
Supporting Information Available: Experimental details
for the construction of the resins 3a-f, for parallel synthesis
of 10a-t, and for receptor binding assays including affinities
of the test compounds for the D2short, D2long, and D3 subtypes.
This material is available free of charge via the Internet at
http://pubs.acs.org.
93% yield and 77-99% purity (Table 2).
The carboxamides 10a-t were evaluated in vitro for their
3
ability to displace the radioligand [ H]spiperone from the
(5) Estep, K. G.; Neipp, C. E.; Stephens, M.; Stramiello, L.; Adam, M.
D.; Allen, M. P.; Robinson, S.; Roskamp, E. J. J. Org. Chem. 1998, 63,
5
1
5
300-5301.
6) Moriya, T.; Hagio, K.; Yoneda, N. Chem. Pharm. Bull. 1980, 28,
711-1721.
7) Carpino, L. A.; El-Faham, A. J. Am. Chem. Soc. 1995, 117, 5401-
402.
OL034520L
(
(
(8) H u¨ bner, H.; Kraxner, J.; Gmeiner, P. J. Med. Chem. 2000, 43, 4563-
4569 and references therein.
Org. Lett., Vol. 5, No. 10, 2003
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