Vinylogous amide analogs of methylphenidate

Article abstract of DOI:10.1016/j.bmcl.2005.04.034

In an effort to produce compounds with longer durations of action, we attempted to synthesize ketone analogs of methylphenidate which, however, appear to be highly unstable due to a highly acidic proton alpha to the ketone and phenyl groups. Nevertheless, vinylogous amide by products have been synthesized and tested for activity at dopamine, norepinephrine, and serotonin transporters. The compounds were found to be weak inhibitors of monoamine reuptake despite rigid three dimensional structures that are quite similar to the global minimum of threo-(R,R)-methylphenidate. The structures were confirmed by X-ray crystallography.

Full text of DOI:10.1016/j.bmcl.2005.04.034

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3044–3047
Vinylogous amide analogs of methylphenidate
Mark Froimowitz,a,* Yonghong Gu,a Les A. Dakin,a Charles J. Kelley,a
Damon Parrishb and Jeffrey R. Deschampsb
aMassachusetts College of Pharmacy and Health Sciences, 179 Longwood Avenue, Boston, MA 02115, USA
bThe Laboratory for the Structure of Matter, Naval Research Laboratory, 4555 Overlook Avenue, Washington, DC 20375, USA
Received 7 February 2005; revised 12 April 2005; accepted 18 April 2005
Abstract—In an effort to produce compounds with longer durations of action, we attempted to synthesize ketone analogs of meth-
ylphenidate which, however, appear to be highly unstable due to a highly acidic proton alpha to the ketone and phenyl groups.
Nevertheless, vinylogous amide by products have been synthesized and tested for activity at dopamine, norepinephrine, and sero-
tonin transporters. The compounds were found to be weak inhibitors of monoamine reuptake despite rigid three dimensional struc-
tures that are quite similar to the global minimum of threo-(R,R)-methylphenidate. The structures were confirmed by X-ray
crystallography.
Ó 2005 Elsevier Ltd. All rights reserved.
Methylphenidate (Scheme 1), which was first synthe-
sized some 60 years ago,1 is still commonly used for
the treatment of attention deficit hyperactivity disorder.
The therapeutic efficacy of methylphenidate is believed
to be due to its ability to block the reuptake of dopa-
mine and norepinephrine in the central nervous system.2
However, a less desirable aspect of the clinical use of
methylphenidate is that it typically must be administered
two or three times/day3 due to the presence of the ester
moiety, which is rapidly metabolized to the inactive
acid.4
since it is believed that such compounds will be consid-
erably less abusable than dopamine uptake blockers
with fast onsets and a short durations.6,7 Since the short
half life of methylphenidate is due to the presence of the
easily metabolized ester group, we thought that it might
be advantageous to replace the carbomethoxy with a
more stable carbonyl group. This kind of substitution
produces active, long-duration compounds in cocaine-
like analogs (Scheme 1).8,9 Since the carbomethoxy
groups in methylphenidate and in cocaine-like com-
pounds such as CFT have been found to correspond
to each other,10 the same substitution would be expected
to produce active, long-duration analogs of methylphe-
nidate. However, the synthesis of these analogs has pro-
ven to be more difficult than expected due to the highly
Our goal has been to synthesize slow onset, long-dura-
tion blockers of dopamine reuptake as possible substitu-
tion medications for the treatment of cocaine abuse5
Scheme 1.
*
Corresponding author. Tel.: +1 617 732 2851; fax: +1 617 732 2959; e-mail: mfroimowitz@bos.mcphs.edu
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.04.034

M. Froimowitz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3044–3047
3045
acidic proton that is alpha to both the phenyl ring and
the carbonyl group of the ester. A wide variety of ap-
proaches were unsuccessful but our most recent effort
has succeeded in making vinylogous amides of
methylphenidate.
Crystal structures were obtained for 8a, 9a, and all three
final products 10a–c. The crystal structure for 10c is
shown in Figure 1. The structures of all three final prod-
ucts show the presence of a double bond exocyclic to the
piperidine ring with the four atoms attached to the dou-
ble bond all lying in an approximate plane. The same
geometric isomer about the double bond appears in all
three compounds, presumably because of a favorable
attraction between the carbonyl oxygen and the amine
hydrogen. This geometric isomer corresponds to threo-
methylphenidate whereas the absent geometric isomer
corresponds to the inactive erythro isomer. The bond
The novel compounds were synthesized following the se-
quence in Scheme 2. para-Bromochlorobenzene 1 was
converted into a Grignard reagent with Mg/THF, which
was treated with pyridine-2-carboxaldehyde 2 to produce
the alcohol 3. The alcohol 3 was oxidized with pyridi-
nium chlorochromate to the ketone 4, which was then
treated with a series of Grignard reagents that contain
various R1 groups to produce the alcohols 5. The alco-
hols 5 were dehydrated with refluxing HCl to produce
Z and E olefin mixtures 6. The olefin mixtures were con-
verted to bromohydrins with N-bromosuccinimide and
water, and the bromohydrins were cyclized to a Z and
E mixture of epoxides 7 with NaOH. The epoxide mix-
tures were treated with BF3ÆOEt2 to produce the
BF2-containing compounds 8. Compounds 8 were stable
to boiling 5 N NaOH overnight. The stability of these
kinds of complexes has previously been noted.11 How-
ever, after hydrogenating the pyridine rings to 9, alkaline
hydrolysis gave vinylogous amides 10. The amide-like
character of these compounds lowers the basicity of the
nitrogen to the extent that an attempt to produce a salt
failed and led to decomposition products.
˚
lengths for the bond range from 1.395 to 1.403 A, show-
ing considerable double bond character. There appear to
be hydrogen bonds between the carbonyl oxygens and
the amine hydrogens in the three crystal structures with
˚
distances between 1.927 and 1.957 A.
All of the compounds were synthesized with a para-
chloro group since this substitution increases activity
by a considerable amount over methylphenidate itself.12
The novel synthesized compounds were tested in binding
and reuptake assays utilizing recombinant human dopa-
mine, norepinephrine, and serotonin transporters stably
expressed in human embryonic kidney 293 cells.13 The
binding studies measured the displacement of
[
125I]RTI-55 by the test compounds while the reuptake
studies measured the potency of the test compounds in
Scheme 2.

3046
M. Froimowitz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3044–3047
Figure 1. Stereoscopic image of crystallographic structure of 10c.
Table 1. Binding affinity (Ki, nM) and reuptake inhibition potency (IC50, nM) of compounds with recombinant human dopamine, serotonin, and
norepinephrine transporters expressed in human embryonic kidney 293 cellsa
Dopamine
Serotonin
5HT Reuptake
Norepinephrine
[I125]-RTI-55
binding
DA Reuptake
[I125]-RTI-55
binding
[I125]-RTI-55
binding
NE Reuptake
Cocaine
RR/SS-Methylphenidatea
RR/SS-para-Cl-Methylphenidate
459 69
180 40
244 28
190 50
522 42
40,000 8000
6000 100
9000 200
>10 lM
314 44
55,000 16,000
>9800
1970 130
1800 800
110 40
238 33
38
11
4
3
25
8
11
2
10a
10b
10c
9a
2200 800
2200 700
1900 700
4800 700
6300 1100
1800 600
1100 80
>10 lM
7100 1200
>10 lM
>10 lM
>9500
>10 lM
>10 lM
6900 1400
>10 lM
a Ref. 13.
inhibiting the reuptake of the tritiated monoamine neu-
rotransmitters. The results of the binding assays for the
vinylogous analogs along with those for cocaine, RR/
SS-methylphenidate, and RR/SS-para-chloromethyl-
phenidate in the same assay system are presented in
Table 1.
about 1/6 of the potency of threo-(RR/SS)-methylpheni-
date at the dopamine transporter and 1/100 of the po-
tency of the para-chloro (RR/SS) analog. This is
somewhat unexpected since the compounds 10 are rig-
idly held by the double bond in a conformation that is
similar to the global minimum of threo-(R,R)-methyl-
phenidate as computed with molecular mechanics calcu-
lations10 and this conformation is also observed in a
number of crystal structures of methylphenidate ana-
logs.14 As can be seen by comparing Figures 1 and 2,
the three dimensional structures of the vinylogous
amides are quite similar to the three dimensional struc-
ture of the biologically active threo-(R,R)-methylpheni-
date. Superimposing the heavy atoms of the piperidine
and phenyl rings and the carbonyl group of 10c with the
As can be seen from Table 1, cocaine has considerable
activity at all three monoamine transporters whereas
methylphenidate has significant activity at just the dopa-
mine and norepinephrine sites. As found previously,12
the para-chloro analog of methylphenidate is consider-
ably more potent than methylphenidate itself. The three
vinylogous amide analogs proved to have weak activity
at all three sites with the best compound, 10c, having
Figure 2. Stereoscopic image of the global minimum of threo-(R,R)-methylphenidate as computed by 6-31G* ab initio quantum mechanical
calculations.

M. Froimowitz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3044–3047
3047
Figure 3. Stereoscopic image of the least squares superimposition of the crystal structure of 10c (blue) with the global minimum of threo-(R,R)-
methylphenidate (green).
corresponding atoms of the global minimum of threo-
(R,R)-methylphenidate (as represented by a 6-31G* ab
initio quantum mechanical calculation) in a least squares
sense, one again sees the close three dimensional corre-
spondence between the structures (Fig. 3), while the pres-
ence of the double bond in the vinylogous amides does
reduce the basicity of the amine group, it has been shown
that replacement of the nitrogen in methylphenidate by
either an oxygen or carbon atom does not preclude good
activity and that a basic nitrogen is not required for the
activity of methylphenidate analogs.15 Thus, the weak
activity of the vinylogous amides tends to cast doubt that
the biologically active conformer of threo-(R,R)-methyl-
phenidate is similar to the global minimum of the com-
pound. The intermediate 9a was also tested for activity
against the monoamine transporters since the boron-con-
taining rings also forces the compound into a similar con-
formation. However, this compound also proved to have
relatively weak activity, presumably due tothe presence of
the BF2 group.
Supplementary data
An experimental section is available as supplementary
material comprising experimental details for the synthe-
ses and crystallographic studies, combustion analyses,
and NMR, melting point, and crystallographic data.
Supplementary data associated with this article can be
found in the online version at doi:10.1016/
j.bmcl.2005.04.034.
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Crystallographic data (excluding structure factors) for
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ited with the Cambridge Crystallographic Data Centre
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This work was supported by grant DA015795 from the
National Institute on Drug Abuse to M.F. X-ray crys-
tallographic studies were provided by contract Y1-
DA1002-04 from the National Institute on Drug Abuse.
Monoamine transporter binding and uptake studies
were provided by the Cocaine Treatment Discovery Pro-
gram, Division of Treatment Research and Develop-
ment, the National Institute on Drug Abuse under
contract Y1 DA 0107-05.