The TosMIC approach to 3-(oxazol-5-yl) indoles: Application to the synthesis of indole-based IMPDH inhibitors

Article abstract of DOI:10.1016/S0960-894X(02)00748-5

A modified approach to the synthesis of 3-(oxazolyl-5-yl) indoles is reported. This method was applied to the synthesis of series of novel indole based inhibitors of inosine monophosphate dehydrogenase (IMPDH). The synthesis and the structure-activity rel

Full text of DOI:10.1016/S0960-894X(02)00748-5

Bioorganic & Medicinal Chemistry Letters 12 (2002) 3305–3308
The TosMIC Approach to 3-(Oxazol-5-yl) Indoles: Application to
the Synthesis of Indole-Based IMPDH Inhibitors
T. G. Murali Dhar,* Zhongqi Shen, Catherine A. Fleener, Katherine A. Rouleau,
Joel C. Barrish, Diane L. Hollenbaugh and Edwin J. Iwanowicz*
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA
Received 2 July 2002; accepted 15 August 2002
Abstract—A modified approach to the synthesis of 3-(oxazolyl-5-yl) indoles is reported. This method was applied to the synthesis of
series of novel indole based inhibitors of inosine monophosphate dehydrogenase (IMPDH). The synthesis and the structure–activity
relationships (SARs), derived from in vitro studies, for this new series of inhibitors is given.
# 2002 Elsevier Science Ltd. All rights reserved.
Inosine monophosphate dehydrogenase (IMPDH), a key
enzyme in the de novo synthesis of guanosine nucleotides,
catalyzes the irreversible NAD-dependent oxidation of
inosine-50-monophosphate (IMP) to xanthosine-50-
monophosphate (XMP).1 Two distinct cDNA’s encoding
IMPDH have been identified and isolated. These tran-
scripts labeled type I and type II are of identical size (514
amino acids).2ꢀ4 IMPDH II activity is markedly upregu-
lated in actively proliferating cell types including cancers
and activated peripheral blood lymphocytes.5
In recent reports, we have described a number of che-
mical changes intended to replace the urea linkage in 1
(Fig. 1).9,12 For example, we have disclosed a new class
of inhibitors of IMPDH, exemplified by BMS-337197.9
This report describes our preliminary efforts directed
at modification of the aniline moiety common to
BMS-337197 and 1.
Our strategy was to investigate an alternative spatial
placement of the terminal oxazole moiety via replace-
ment of phenyl residue (A) with a suitable molecular
scaffold. Based on the reported protein/inhibitor
crystallographic studies, key objectives would be (i) to
maintain the hydrogen bond between the oxazole and
CellCept1 (mycophenolate mofetil, MMF), a prodrug of
mycophenolic acid (MPA), has clinical utility due to its
inhibitionofIMPDH,forthetreatmentoftransplantrejec-
tion. Dose-limiting gastrointestinal (GI) toxicity exhib-
ited from administration of either MMF or MPA limits
this drug’s potential for treatment of other autoimmune
disorders, such as psoriasis and rheumatoid arthritis.6
The formation of conjugates at either the carboxylic
acid or phenolic residues of MPA, is implicated as a
contributing factor in the poor therapeutic index
observed for MMF.7,8 Structurally related analogues,
devoid of acid and phenolic functionalities, are reputed
to have an improved therapeutic index with regard to
dose limiting GI toxicity.9,10 An alternative approach to
IMPDH inhibition has been described by Pankiewicz.11
*Corresponding authors. Tel.: +1-609-252-4158; e-mail: dharm@
bms.com (T.G.M. Dhar); tel.: +1-609-252-5416; e-mail: iwanowie@
bms.com (E.J. Iwanowicz).
Figure 1. The chemical structures of MPA, BMS-337197 and 1.
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00748-5

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T. G. M. Dhar et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3305–3308
the NH of Gly326 while maintaining the contribution to
binding from inhibitor/protein interactions at the
methyl binding pocket and (ii) preserve the hydrogen
bond between the NH of the inhibitor and the
carboxylate of Asp 274 (Fig. 2).13 The use of an indole
core offered the opportunity to suitably position the
terminal oxazole residue and the flexibility to probe the
methyl binding pocket.
corresponding aldehydes.17 Consistent with a previous
report, we have observed no reaction of the anion
derived from TosMIC with either indole-3-carbox-
aldehyde or 6-nitro indole-3-carboxaldehyde.18 The
reaction of TosMIC with N-methyl-6-nitro indole-3-
carboxaldehyde with potassium carbonate (reflux/
MeOH) or DBN (DME/RT) as the base, gave us the
corresponding 2-oxazoline (Table 1, 4) as reported in
the literature.18 However, we were surprised to find that
the desired 3-(oxazol-5-yl) indole was isolated in 60%
yield when the reaction was carried out at 80 ꢁC in the
presence of DBU (Table 1, 5). These results clearly indi-
cate that as long as the nitrogen moiety of the indole is
suitably derivatized the reaction with the anion of Tos-
MIC will occur. Subsequent elimination of the tosyl
group from the 2-oxazolines will depend on a variety of
factors and the stability of the protecting group to the
reaction conditions. These results are summarized in
Table 1. As Table 1 indicates, reaction of TosMIC with
an indole, the nitrogen of which is protected as a urea
(Table 1, entry 10) and DBU at 80 ꢁC leads to the for-
mation of the desired 3-(oxazol-5-yl) indoles.19 These
optimized conditions were used to prepare a variety of
substituted 3-(oxazol-5-yl) indoles (Table 2). Although
the yields are moderate, this procedure offers an attrac-
tive alternative to the toxic and hazardous methyl
Literature reports for the synthesis of 3-(oxazol-5-yl)in-
doles are sparse with the reported methods based upon
the Schollkopf reaction of indole-3-carboxylates with
isocyanomethyllithium.14ꢀ16
Tosylmethyl isocyanide (TosMIC) is a widely used
reagent to prepare 5-substituted oxazoles from the
Table 2.
Entry
R
H
Yield (%)
47
19a
19b5-OMe
19c
19d
41
Figure 2. A comparison of binding modes for 2, an analogue of BMS-
337197 and an indole-based inhibitor, 3.
5-Br
6-Me
51
40
Reagents and conditions: (a) TosMIC, DME, DBU, 80 ꢁC, 2.5 h.
Table 1. Reaction of TosMIC with N-protected indoles
Entry
R1
Rxn conditions
Product
Yield (%)
37
4
5
Me
Me
a
b12
11
60
6
7
8
9
10
SO2Me
SO2Me
CO2Me
CONMe2
CONMe2
a
b14 and 16
b15 and 17
a
b18
13
1:1
2:1
75
a
a
No Rxnb
46
Reagents and conditions: (a) TosMIC, MeOH, K2CO3, 80 ꢁC, 2.5 h;
(b) TosMIC, DME, DBU, 80 ꢁC, 2.5 h.
aRatio of products based upon LC/MS analysis.
Scheme 1. Synthesis of 22–27. Reagents and conditions: (a) K2CO3,
MeOH, H2O, 80 ꢁC, 1.5 h, (84%); (b) H2/Pd/C, MeOH (78%); (c) A,
dioxane, 100 ꢁC, (30–70%).

T. G. M. Dhar et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3305–3308
3307
Table 3. SARs of the five-membered heterocyclic inhibitors of
IMPDH
Compd
R2
R1
IMPDH II
IC50 (mM)
CEM
IC50 (mM)
1
NA
H
NA (UREA STD)
19
1.0
22
0.040
>10
23
24
25
26
27
3
H
H
0.035
0.20
9.7
>10
>10
NT
H
0.011
>5
Scheme 2. Synthesis of 3, 30–33. Reagents and conditions: (a)
1,10thiocarbonyldi-2(1H)-pyridone, CH2Cl2, rt, (96%); (b) 29a–d,
PPh3, CH2Cl2, rt or dioxane 80 ꢁC (50–60%); (c) LiOH, MeOH, H2O,
rt, (63%); (d) pyridine, MsCl, then morpholine (31%).
Me
Me
H
isocyanide in the synthesis of 3-(oxazol-5-yl) indoles.20
This methodology was applied to a variety of indole
based IMPDH inhibitors (Schemes 1 and 2).
>5
NT
Table 3 reports the in vitro inhibitor potencies against
IMPDH II for a series of inhibitors featuring 3-(oxazol-
5-yl) indole derived analogues.
0.093
0.038
0.205
0.077
>10
>10
>10
1.5
30
31
32
H
Replacement of the 3-oxazol-5-yl aniline moiety in urea
1 with 3-(oxazol-5-yl) indole, giving 22, resulted in a
minimal loss in potency. The potential for substitution
about the phenyl ring was investigated through the
incorporation of a methyl residue at the ortho, meta and
para positions, 23, 24, and 25. As Table 3 indicates there
is an clear preference for substitution at the ortho and
para over the meta postions. Surprisingly, methylation
of the indole nitrogen of analogues 26 and 27 led to a
considerable loss in potency. Based upon the binding
model, this loss in binding affinity is likely due to steric
repulsion and not due a disruption of a hydrogen bond
to the NH. SAR in the 5-phenyl-2-aminooxazole series
(3, 30–34) suggests that the ortho position is most pre-
ferred. It is of interest to note that compound (34) which
has the same morpholino side chain as BMS-337197
(Fig. 1) is significantly less potent in inhibiting the T-cell
proliferation response in a CEM cell line (BMS-337197,
CEM IC50=590 nM versus compound 34, CEM
IC50=3.0 mM).21
H
H
33
H
0.007
1.0
34
H
0.035
3.0
In summary, we have demonstrated that the 3-(oxazol-
5-yl) indole group serves as a excellent replacement of
the aniline moiety of the urea derivative (1) and BMS-
337197 (Fig. 1) while maintaining potency. Efforts to
improve the in vitro cell potency and evaluate the
compounds in a T-cell mediated pharmacodynamic
model are underway and will be reported in due
course.
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1.05 mmol) in 3 mL of anhydrous DMF was added sodium
hydride (0.042 g, 1.56 mmol) at 0 ꢁC. The reaction mixture is
warmed to room temperature over 10 min and dimethylcar-
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1
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(5 mL) followed by TosMIC (0.075 g, 0.383 mmol) and DBU
(0.064 g, 0.42 mmol). The reaction mixture was heated at
80 ꢁC for 90 min, cooled to room temperature and con-
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1
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