Synthesis and evaluation of carbamoylmethylene linked prodrugs of BMS-582949, a clinical p38α inhibitor

Article abstract of DOI:10.1016/j.bmcl.2013.03.022

A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α- aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2 mpk (equivalent to 10 mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10 mpk of 1 itself. At a suspension dose of 142 mpk (equivalent to 100 mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates.

Full text of DOI:10.1016/j.bmcl.2013.03.022

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3028–3033
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and evaluation of carbamoylmethylene linked prodrugs
of BMS-582949, a clinical p38a inhibitor
⇑
Chunjian Liu , James Lin, Gerry Everlof, Christoph Gesenberg, Hongjian Zhang, Punit H. Marathe,
Mary Malley, Michael A. Galella, Murray Mckinnon, John H. Dodd, Joel C. Barrish, Gary L. Schieven,
Katerina Leftheris
Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38
thesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and
a
inhibitor, were syn-
-aminoacyl-
Received 15 November 2012
Accepted 6 March 2013
Available online 15 March 2013
a
oxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid
derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral
conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution
dose of 14.2 mpk (equivalent to 10 mpk of 1), 2 gave essentially the same exposure of 1 compared to dos-
ing 10 mpk of 1 itself. At a suspension dose of 142 mpk (equivalent to 100 mpk of 1), 2 demonstrated that
it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our
knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could repre-
sent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug
candidates.
Keywords:
Prodrugs
Carbamoylmethylene linked prodrugs
Prodrugs of secondary amides
Ó 2013 Elsevier Ltd. All rights reserved.
We have previously disclosed 1 (BMS-582949) (Fig. 1) as a
highly selective p38 inhibitor that advanced to Phase II clinical
promoieties. However, prodrugs derived from amide NH or diaryl
NH are not well-documented in the literature except for some pio-
neering studies. These studies include investigations of Mannich
base, sulfenamide, and other typed prodrugs,4,5 which were not
attractive to us according to our specific prodrug criteria for 1.
On the other hand, it was noted that prodrugs of aliphatic amines
were more often seen in literature.6 One of the prodrug approaches
for amines is the conversion of the parent amine into acyloxymeth-
ylene or phosphoryloxymethylene carbamates. For example,
hydrophobic acyloxymethylene carbamates of pseudomycin ana-
logs were reported to improve toxicity profiles,7 while phosphoryl-
oxymethylene carbamates of paclitaxels were synthesized to
increase aqueous solubility.8 The design of these types of amine
prodrugs were based on the rationale that acyloxymethylene and
phosphoryloxymethylene carbamates would be hydrolyzed
in vivo by esterases and phosphatases, respectively, to form a
hydroxymethylene carbamate as the immediate intermediate that
would be chemically unstable and spontaneously decompose to
the parent amine, formaldehyde, and carbon dioxide.9,10 Any con-
cerns about the generation of formaldehyde during the bio-conver-
sion of these types of prodrug were lessened by the consideration
that humans produce and/or may be exposed to 31–59 g of form-
aldehyde daily and that several prodrugs that release formalde-
hyde were approved by regulatory agencies.11
a
trials for the treatment of rheumatoid arthritis (RA).1 An important
consideration for the development of 1 is its pH dependent solubil-
ity, which was determined to be 0.280 mg/mL at pH 1.2 and
0.003 mg/mL at pH 6.5. This presents a potential limit to its usage
in RA patients, who are often prescribed drugs that increase stom-
ach pH, including H2 blockers such as famotidine.2,3 Systemic
exposure of 1 can be expected to be significantly lower in patients
using such co-medications. While formulation studies were under
way, we speculated that this potential issue could be addressed by
implementing a prodrug strategy. To avoid additional development
complications, we set a high bar for the prodrug criteria. Specifi-
cally, in addition to improving the solubility profile, the prodrug
needed to be chemically stable between pH 1 and pH 7; completely
bio-converted to 1 before or during absorption; have parent drug
exposure upon prodrug administration comparable to or better
than what was observed with 1 itself; and lastly, the safety profiles
of its in vivo by-products should be known or predictable. Our
investigation yielded prodrug 2 that met all the afore-mentioned
criteria.
The parent compound 1 contains two amide NH groups and one
diaryl NH that can be considered as logical handles to install
Inspired by the literature precedents of carbamoylmethylene
linked prodrugs of aliphatic amines, we wondered if we could
⇑
Corresponding author. Tel.: +1 609 252 3682; fax: +1 609 252 7410.
E-mail address: chunjian.liu@bms.com (C. Liu).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.03.022

C. Liu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3028–3033
3029
H
N
H
N
HN
N
N
N
a
1
O
Boc
O
O
O
N
N
N
N
Prn NH
Prn NH
9
1 (BMS-582949)
H
N
N
H
N
HN
N
Boc
O
b
c
O
N
O
O
N
Prn
N
O
N
N
N
Prn
N
O
O
10
Cl
O
O
O
H
N
CO2H
HN
N
2
O
O
N
O
N
N
I
Figure 1. Clinical p38
a
inhibitor 1 and its prodrug 2.
Prn
O
11
prepare any carbamoylmethylene linked phosphate prodrugs of 1
through any of its NH groups. To our satisfaction, it was found that
all three possible isomeric prodrugs, 3, 4, and 5 (Schemes 1–3,
respectively), could be synthesized. Two of the three were derived
directly from 1 by taking advantage of the pKa differences among
the three NH groups. As shown in Scheme 1, treatment of 1 with
chloromethyl chloroformate in the presence of pyridine provided
chloromethyl carbamate 6. The latter was converted to iodomethyl
H
N
HN
d, e
O
O
N
O
N
N
O
Prn
N
O
PO(OH)2
Cl
O
H
N
a
4
O
N
N
1
O
Scheme 2. Reagents and conditions: (a) di-tert-butyl dicarbonate, DMAP, DMF,
60 °C, 70% yield; (b) 2 equiv lithium bis(trimethylsilyl)amide, THF, À45 °C, then
1 equiv chloromethyl chloroformate, À45 °C to rt, 60% yield; (c) NaI, acetone, reflux,
61%; (d) silver dibenzyl phosphate, toluene, reflux, 26% yield over two steps; (e) H2,
10% Pd/C, rt, 90% yield.
O
N
N
Prn NH
6
I
O
H
N
carbamate 7 with sodium iodide. Heating 7 with silver dibenzyl
phosphate supplied 8, which was hydrogenated to form the de-
sired prodrug 3.
O
N
b
O
O
N
N
For the preparation of 4 (Scheme 2), 1 was reacted with di-tert-
butyl dicarbonate in the presence of 4-dimethylaminopyridine
(DMAP) to afford 9. Interestingly, it was the pyrrolotriazine ring
nitrogen that was acylated instead of the anilino nitrogen. The
structure of 9 was revealed by X-ray crystallography (Fig. 2).12
Treatment of 9 with 2 equiv of lithium bis(trimethylsilyl)amide,
followed by 1 equiv of chloromethyl chloroformate, led to the for-
mation of chloromethyl carbamate 10 regioselectively. The regi-
oselectivity of this carbamoylation can be rationalized in that the
N-propyl amide NH is most likely less acidic than the N-cyclopro-
pyl benzamide NH, and therefore its conjugated base N-propyl
amide nitrogen anion is more basic and nucleophilic. When 10
was refluxed with sodium iodide in acetone to convert the chloro-
methyl carbamate to a iodomethyl carbamate, it was pleasantly
found that the Boc group was cleaved under the same conditions,
generating 11 from 10 in one pot. Prodrug 4 was then obtained
from 11 in a similar manner as in the preparation of 3 from 7.
To synthesize 5 (Scheme 3), N-cyclopropyl benzamide 12 was
deprotonated with lithium bis(trimethylsilyl)amide and then ex-
posed to chloromethyl chloroformate to furnish 13. Chloromethyl
carbamate 13 was transformed into carbamoylmethylenephos-
phate 15 by sodium iodide, followed by silver dibenzyl phosphate.
Prn NH
N
7
(BnO)2OP
O
O
H
N
c
O
N
O
O
N
N
O
Prn NH
N
8
(HO)2OP
O
H
N
O
N
N
d
O
O
N
N
Prn NH
3
Scheme 1. Reagents and conditions: (a) chloromethyl chloroformate, pyridine,
CH2Cl2, 50 °C, 63% yield; (b) NaI, acetone, reflux; (c) silver dibenzyl phosphate,
toluene, reflux, 51% yield over two steps; (d) H2, 10% Pd/C, rt, 100% yield.

3030
C. Liu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3028–3033
Cl
O
O
H
N
a
O2N
N
O2N
O
O
13
12
I
O
O
O
b
c
N
O2N
O
14
PO(OBn)2
Figure 2. X-ray crystal structure of 9.
O
O
d
N
O2N
Table 1
O
Stability profiles of 3, 4, and 5
15
Stability at 37 °C
O
PO(OBn)2
3
4
5
O
O
T1/2 at pH 1.0 (h)
T1/2 at pH 7.4 (h)
8.5
<0.25
26.8
<0.25
20.5
<0.25
e
N
H2N
O
With 3, 4, and 5 in hand, we began our prodrug evaluations with
solution stability tests, the results of which are shown in Table 1.
Compounds 3, 4, and 5 were stable at pH 1.0 and 37 °C with their
half lives being 8.5, 26.8, and 20.5 h, respectively. However, they
were all unstable under more physiologically relevant conditions
(pH 7.4, 37 °C), as their half lives were determined to be less than
0.25 h. It was noted that the stability profiles displayed by 3, 4, and
5 at pH 7.4 were very different from that of an aliphatic amine de-
rived phosphoryloxymethylene carbamate 20, the half life of which
was reported to be 48 days at pH 7.5 and 25 °C (Fig. 3).10 Instead,
their stabilities were more similar to what was observed for phos-
phoryloxymethyl carbonate 21 (T1/2 = 58 min at pH 7.5 and 25 °C).
The short half life for 21 at neutral pH was attributed to an intra-
molecular phosphate-assisted hydrolysis or an intramolecular
nucleophilic reaction of the phosphate oxygen anion to the carbon-
ate carbonyl, which is more electrophilic than the carbamate car-
bonyl in 20. This proposal can be used to explain the instability
of 3, 4, and 5 under similar conditions. Though they are carba-
mates, the carbamate carbonyls are highly activated by either
N,N-diaryl or N-acyl groups.
16
O
PO(OBn)2
O
O
O
N
f
HN
O
N
N
Prn NH
N
17
O
PO(OH)2
O
O
O
N
HN
O
N
N
Prn NH
N
5
Cl
O
N
Attempting to obtain prodrugs of 1 with improved stability, we
O
O
g, h, i
N
NH
synthesized
a-amino aminoacyloxymethylene carbamates 22, 23,
N
N
Prn NH
N
and 26 (Scheme 4). Reaction of intermediate 6 and silver salt of
(S)-2-(benzyloxycarbonylamino)propanoic acid (27) in refluxing
toluene, followed by hydrogenation with 10% Pd/C in the presence
of 1 N hydrochloric acid, provided 22. In a similar manner, 23 was
synthesized from iodide 11. The silver salt 27 was prepared by
treating (S)-2-(benzyloxycarbonylamino)propanoic acid with so-
EtO
19
18
Scheme 3. Reagents and conditions: (a) bis(trimethylsilyl)amide, THF, À78 °C, then
chloromethyl chloroformate, 0 °C to rt, 72% yield; (b) NaI, acetone, reflux, 90%; (c)
silver dibenzyl phosphate, toluene, reflux, 83% yield; (d) Zn dust, NH4Cl, 1:1 MeOH/
THF, rt, 100% yield; (e) 18, DMF, rt, 43% yield; (f) H2, 10% Pd/C, rt, 60% yield; (g) 1 N
NaOH, MeOH, reflux, 72% yield; (h) n-PrNH2, BOP, 1-methylmorpholine; (i) POCl3, i-
Pr2NEt, toluene, reflux, 61% yield.
O
NH
O
MeO
MeO
O
O
O
O
O
O
O
P
Reduction of 15 with zinc dust in the presence of ammonium chlo-
ride gave 16, which was then reacted with chloropyrrolotriazine 19
to form 17. Intermediate 19 was prepared from ethyl 5-methyl-4-
oxo-3,4-dihydropyrrolo[1,2-f][1,2,4]triazine-6-carboxylate (18)13
in three steps: hydrolysis of the ester group, amide formation from
the resultant acid, and the treatment of POCl3. Hydrogenation of 17
completed the synthesis of prodrug 5.
P
HO
HO
OH
OH
21
20
T1/2 at pH 7.5 (25 oC): 48 days
T1/2 at pH 7.5 (25 oC): 58 min
Figure 3. Literature examples of phosphoryloxymethylene carbamate and phos-
phoryloxymethylene carbonate with their stability profiles10
.

C. Liu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3028–3033
3031
Table 2
O
Stability profiles of 22, 23, and 26
H2N
O
O
Stability at 37 °C
H
N
a, b
O
N
N
22
23
26
6
O
T1/2 at pH 1.0 (h)
T1/2 at pH 7.4 (h)
3.2
3.2
3.0
O
N
.
<0.25
<0.25
<0.25
2 HCl
N
Prn NH
22
Ultimately, fumaric acid derived acyloxymethylene carbamates
28, 2, and 31 were designed, with the idea that the trans configu-
ration of the fumarate would prevent the promoiety from any
intramolecular cleavage. Fumaric acid, a likely metabolic by-prod-
uct of these prodrugs, is expected to to safe, as it is among those
acids approved by FDA to form pharmaceutic salts.14 Thus, inter-
mediates 6, 10, and 30 were reacted with monosodium salt of fu-
maric acid to provide 28, 2, and 31, respectively (Scheme 5).
H
N
HN
O
c, d
O
N
11
.
2 HCl
N
Prn
N
O
N
O
O
O
O
NH2
HO2C
O
O
23
N
H
N
O
N
N
a
O
NHCbz
6
O
O
N
e
O
O
O
14
N
Prn NH
O2N
28
O
24
H
N
HN
O
NHCbz
O
b
O
N
O
f
O
O
10
N
Prn
N
O
O
N
N
H2N
O
O
O
25
CO2H
O
2
NH2
Cl
O
O
O
g, h
c
O
O
N
13
HN
N
N
H2N
O
O
N
O
.
2 HCl
26
N
Prn NH
29
Cl
Scheme 4. Reagents and conditions: (a) silver salt of (S)-2-(benzyloxycarbonyl-
amino)propanoic acid (27), toluene, reflux, 39% yield; (b) H2, 10% Pd/C, MeOH, 1 N
HCl, 80% yield; (c) 27, toluene, reflux, 19% yield; (d) H2, 10% Pd/C, MeOH, 1 N HCl,
91% yield; (e) 27, toluene, reflux, 66% yield; (f) Zn dust, NH4Cl, 1:1 MeOH/THF, rt,
39% yield; (g) 19, DMF, rt, 76% yield; (h) H2, 10% Pd/C, MeOH, 1 N HCl, 67% yield.
O
O
O
d
N
HN
N
O
N
N
Prn NH
30
dium hydroxide and silver nitrate sequentially. Heating 14 with 27
gave rise to 24, which was reduced with zinc dust to aniline 25.
Then, 26 was obtained by reacting 25 with chloropyrrolotriazine
19 in DMF, followed by hydrogenation to remove the Cbz protec-
tion group.
O
CO2H
O
O
O
O
e
N
HN
N
Unfortunately, like phosphoryloxymethylene carbamates 3, 4, 5,
the
a-amino aminoacyloxymethylene carbamates 22, 23, and 26
O
N
were all unstable at pH 7.4 and 37 °C with their half lives being less
than 0.25 h (Table 2). Also, they were only moderately stable at pH
1.0 (T1/2 = 3.0–3.2 h). These stability results, though disappointing,
were not too surprising considering that an amine is a good
nucleophile at neutral pH values and an intramolecular nucleo-
philic attack at the highly activated carbamoyl carbonyl by the
amino may easily occur.
N
Prn NH
31
Scheme 5. Reagents and conditions: (a) monosodium salt of fumaric acid, 115 °C,
5.5 h, DMF, 20% yield; (b) monosodium salt of fumaric acid, 105 °C, 20 h, DMF, 8.5%
yield; (c) Zn dust, NH4Cl, 1:1 MeOH/THF, rt, 7 h, 94% yield; (d) 19, rt, DMF, 20 h; (e)
monosodium salt of umaric acid, 105 °C, DMF, 5 h, 17% yield for two steps.

3032
C. Liu et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3028–3033
Table 5
Exposure of 1 after a solution dose of prodrug 2 and parent drug 1
Compd
2
1
Dosea (mpk)
14.2
10
(corresponding to 10 mpk of 1)
Tmax (h)
4
1
Cmax
AUC0–24h
(
l
M)
(lM h)
4.6
52.0
6.5
53.3
a
Vehicle: 1:1 PEG 300/water.
Table 6
Exposure of 1 after a suspension dose of prodrug 2 and parent drug 1
Compd
2
1
Figure 4. X-ray crystal structure of 28.
Dosea (mpk)
142
100
(corresponding to 100 mpk of 1)
Tmax (h)
6
1.7
0.8
5.6
Intermediate 30 was prepared by reduction of 13 with zinc dust in
the presence of ammonium chloride, followed by a subsquent reac-
tion with chloropyrrolotriazine 19. The structure of 28 was con-
firmed by X-ray crystallography (Fig. 4),15 which also provided
indirect confirmation of the structure of carbamate 6.
Cmax
(l
M)
21.1
213.9
AUC0–24h
(lM h)
a
Vehicle: 0.75% methocel suspension.
We were delighted to find that prodrugs 28, 2, and 31 were
highly stable not only under acidic conditions but also under neu-
tral conditions. Their half lives ranged from 34.5 to 129 h (at pH
1.0) and from 14.6 to 21.8 h (at pH 7.4) (Table 3). Among the three,
28 showed the highest stability at pH 1.0 but the lowest at pH 7.4.
Between prodrugs 2 and 31, 2 was noticeably more stable than 31
at both acidic and neutral pH values.
After the chemical stability goal was achieved with 28, 2, and
31, we proceeded to evaluate the aqueous solubility for these three
prodrugs. At pH 6.5, all the three were highly soluble (Table 4).
Their aqueous solubilities were measured to be 1.154, 0.883, and
1.570 mg/mL, dramatically better than that of the parent drug 1
(0.003 mg/mL) at the same pH value. However, at pH 1.0, the sol-
ubilities were very different among the three. Prodrug 28 was
poorly soluble (0.008 mg/mL). Prodrug 2 exhibited a solubility of
1.178 mg/mL, which was seven fold higher compared to what
was observed for 31 (0.166 mg/mL). For 2, we also determined
its solubility at pH 3.1 and 4.6 to be 0.105 and 0.367 mg/mL,
respectively. The decrease in solubility at these pH values is most
likely due to the formation of zwitter-ion.
of 1 in plasma. As shown in Table 5, after a PEG solution dose of
14.2 mpk (equivalent to 10 mpk of 1), prodrug 2 gave almost iden-
tical exposure of 1 compared to what was observed with 10 mpk of
1 itself. The AUC0–24h of 1 after dosing 2 was 52.0
53.3 M h after dosing 1. The Cmax values were also comparable
(4.6 vs 6.5 M). More impressively, after higher dose of
142 mpk (equivalent to 100 mpk of 1) with a methocel suspension
(Table 6), prodrug 2 provided an AUC0–24h of 213.9 M h of 1,
lM h versus
l
l
a
l
which is 38-fold higher than what was obtained by dosing
100 mpk of 1 itself. The Cmax of 1 was also much higher after dosing
2 compared to dosing 1 itself (21.1 vs 0.8 lM) due to solubility-
limited absorption of the parent. It was noticed that in both the
solution and suspension doses, the Tmax values after the prodrug
dosing were 3–4 h longer than the parent drug dosing. This may
suggest that the prodrug bio-conversion rate is lower than the par-
ent drug absorption rate. In both studies, prodrug 2 was not de-
tected in plasma.
In summary, to address the issue of pH dependent solubility
and absorption associated with the clinical p38
a inhibitor 1, a
number of carbamoylmethylene linked prodrugs of 1 were synthe-
sized and evaluated. The phosphoryloxymethylene carbamates (3,
With the measurement of the chemical stability and aqueous
solubility, prodrug 2 emerged as a leading candidate. Evaluation
of the bio-conversion of 2 into its parent drug 1 was then con-
ducted by oral dosing to rats and then determining the exposure
4, and 5) and
a-aminoacyloxymethylene carbamates (22, 23, and
26) were unstable at neutral pH values. However, fumaric acid de-
rived acyloxymethylene carbamates (28, 2, and 31) were highly
stable under both acidic and neutral conditions. Prodrugs 2 and
30 also dispayed good aqueous solubility at both acidic and neutral
pH values. Prodrug 2 was evaluated in vivo for its bio-conversion to
1. It gave essentially the same exposure of 1 at a solution dose of
14.2 mpk (equivalent to 10 mpk of 1). At a suspension dose of
142 mpk (equivalent to 100 mpk of 1), 2 provided a much higher
exposure of 1 compared to what was obtained by dosing 1 itself.
To our knowledge, the carbamoylmethylene linked prodrugs such
as 28, 2, and 31 have not been previously reported and represent
a novel prodrug approach for secondary amides, a class of mole-
cules frequently identified as drug candidates.
Table 3
Stability profiles of 28, 2, and 31
Stability at 37 °C
28
2
31
T1/2 at pH 1.0 (h)
T1/2 at pH 7.4 (h)
129
14.6
79.4
38.5
34.5
21.8
Table 4
Solubility profiles of 28, 1, and 31
Aqueous stability (mg/mL)
References and notes
28
2
31
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S.; McKinnon, M.; Dodd, J. H.; Barrish, J. C.; Schieven, G. L.; Leftheris, K. J. Med.
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pH 1.0
pH 3.1
pH 4.6
pH 6.5
0.008
1.178
0.105
0.367
0.883
0.166
1.154
1.570

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Kanner, S. B.; Lonial, H.; Loo, D.; McIntyre, K. W.; Pitt, S.; Shen, D. R.; Shuster, D.
J.; Yang, X.; Zhang, R.; Behnia, K.; Zhang, H.; Marathe, P. H.; Doweyko, A. M.;
Tokarski, J. S.; Sack, J. S.; Pokross, M.; Kiefer, S. E.; Newitt, J. A.; Barrish, J. C.;
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15. CCDC deposition number: 910690.
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