Improved synthesis of a new nonpeptidic inhibitor of human neutrophil elastase

Article abstract of DOI:10.1055/s-2001-10786

A practical method for the synthesis of ONO-6818 {2-(5-Amino-6-oxo-2-phenylhydropyrimidinyl)-N-[2-(5-tert-butyl-1,3,4-oxadiazo l-2-yl)-1-(methylethyl)-2-oxoethyl]acetamide} (1), the first clinical candidate for a nonpeptidic orally active inhibitor of hum

Full text of DOI:10.1055/s-2001-10786

LETTER
299
Improved Synthesis of a New Nonpeptidic Inhibitor of Human Neutrophil
Elastase
Kazuyuki Ohmoto,a Tetsuya Yamamoto,a Toshihide Horiuchi,a Tsutomu Kojima,b Katsutoshi Hachiya,b
Shinsuke Hashimoto,b Masanori Kawamura,b Hisao Nakai,*a Masaaki Todaa
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka 618-8585, Japan
a Minase Research Institute, Ono Pharmaceutical Co., Ltd.
b Fukui Research Institute, Ono Pharmaceutical Co., Ltd.
Tel. +81-75-961-1151; Fax +81-75-962-9314; E-mail: hi.nakai@ono.co.jp
Received 6 October 2000
Abstract: A practical method for the synthesis of ONO-6818 {2-
(5-Amino-6-oxo-2-phenylhydropyrimidinyl)-N-[2-(5-tert-butyl-
1,3,4-oxadiazol-2-yl)-1-(methylethyl)-2-oxoethyl]acetamide} (1),
the first clinical candidate for a nonpeptidic orally active inhibitor
of human neutrophil elastase (HNE), was developed. This method
includes a Lossen rearrangement instead of an explosive Curtius re-
arrangement and the improved preparation of the -aminoketone.
N
O
N
O
N
N
H2N
O
N
H
O
Key words: enzyme inhibitor, aminopyrimidinone, ketooxadiaz-
ole, Lossen rearrangement, anionic addition reaction
Right Half
Left Half
1 (ONO-6818)
F
Human neutrophil elastase (HNE) is a serine protease re-
leased by human neutrophils in response to inflammatory
stimuli.1 It has been implicated in the development of var-
ious diseases such as emphysema,2 adult respiratory dis-
tress syndrome (ARDS), cystic fibrosis,3 and rheumatoid
arthritis. In excess, HNE hydrolyses elastin, the structural
protein which gives the lungs their elasticity, and may
cause tissue damage and the development of the diseases
mentioned above. It has been postulated that a small mo-
lecular weight inhibitor of HNE could restore this imbal-
ance, and would be beneficial for the treatment of such
diseases. A variety of structural classes of inhibitors of
HNE have thus been studied.4 But orally active ones pos-
sessing clinical potential are very rare. In fact, peptidyl tri-
fluoromethyl ketone inhibitor reported by Zeneca5 was
the only example until recently. 2-Phenyl-pyrimidinone-
-keto-1,3,4-oxadiazole 1 (ONO-6818) is a nonpeptidic
orally active inhibitor of HNE that is currently being eval-
uated in clinical trials (phase I).6 Pharmacological data
(Table) indicate 1 to be a clinically useful drug on the ba-
sis of its excellent oral profiles relative to 2.7 Cost-effec-
tive production of 1 has been our urgent requirement
because of the remarkable increase in demand for further
clinical evaluation. Removal of the explosive Curtius re-
arrangement, which was included in the previously report-
ed method,8 was needed for the development of a cost-
effective method of synthesizing 1. The tedious reaction
process (10 18a 18b 19a 19b 19c 15: 6
steps in all) for the synthesis of 15 also had to be im-
proved.6
N
N
H2N
O
CF3
O
N
H
O
2
Figure 5-Amino-2-phenylpyrimidin-6-ones: Orally Active
Inhibitors of HNE
Table Biological data of 1 (ONO-6818) and 2
a
Inhibition of HNE-catalyzed hydrolysis of the synthetic substrate
MeO-Suc-Ala-Ala-Pro-Val-pNa. b Inhibition of HNE-induced lung
hemorrhage in hamsters. Test compounds were administered orally
1h before intratracheal instillation of HNE (10 U / lung). c See ref 7.
prepared according to the reported method,8 was convert-
ed to the corresponding hydroxamic acid 4. Lossen rear-
rangement of 5, prepared by O-acetylation of 4 followed
by the aqueous hydrolysis of the formed isocyanate, af-
forded an amine 6. Protection of the newly formed amine
group of 6 by a benzyloxy carbonyl group afforded 7.
Acidic deprotection of the dimethyl acetal of 7 produced
an aldehyde 8. Oxidation of the aldehyde 8 to a carboxylic
acid 9 was accomplished upon the treatment of 8 with so-
dium chlorite in water.
In this paper, we describe a practical method for the syn-
thesis of 1, the first clinical candidate for an orally active
nonpeptidic inhibitor of HNE. The overall reaction
schemes are outlined in Schemes 1 and 2. Compound 3,
Synlett 2001 No. 2, 299–301 ISSN 0936-5214 © Thieme Stuttgart · New York

300
K. Ohmoto et al.
LETTER
Scheme 3 Summary of the Improvement
N
O
N
a
H
N
N
N
N
HO
HO2C
N3
N
O
O
OMe
OMe
MeO
MeO
3
4
O
O
OMe
-N2
MeO
16
N
N
explosive
c
b
H
N
N
N
(previous)
AcO
H2N
N
O
O
O
O
O
OMe
OMe
6
7
3
C
MeO
MeO
N
5
6
N
(improved)
OMe
MeO
unexplosive
N
O
N
e
d
17
5
-AcOH
N
N
CHO
CbzN
CbzN
H
a) Replacement of the Explosive Curtius Rearrangement with an
Unexplosive Lossen Rearrangement: Improved Synthesis of 7
H
OMe
O
MeO
8
7
N
f
N
N
N
CO2H
R2
CbzN
H
O
BocN
R1
N
O
H
9
H
OH
19a R2 = Boc
18a R1 = CH2OH
18b R1 = CHO
Scheme 1 Unexplosive Method to Prepare the Left Half 9
Reagents: (a) 1) isobutyl chloroformate, triethylamine, THF, 0 °C, 1
h, 2) 50% hydroxylamine-H2O, 0 °C, 20 min, 91%; (b) acetic anhy-
dride, pyridine, THF, rt, 20 min; (c) 1,8-diazabicyclo[5.4.0]-7-unde-
cene, THF, H2O, reflux, 1 h; (d) benzyloxycarbonyl chloride,
NaHCO3, THF, H2O, 0 °C, overnight; (e) 1N HCl, acetic acid,
70 °C, 2 h; (f) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH, H2O,
0 °C rt, 3 h, 63% in 5 steps.
19b R2 = H
19c
(previous)
N
Ph
R2
=
10
15
N
CO
CbzN
(improved)
H
O
2 steps
2 steps
14
b) Improvement in the Synthesis of the Intermediate 15
OMe
a
b
N
BocN
H
Me
BocN
H
CO2H
10
N
N
Improved synthesis of the right half 14 starting from Boc-
valine (10) was accomplished as described in Scheme 2.
Direct coupling reaction of the Weinreb amide 11, pre-
pared from 10, with anion of 12 afforded 13, which was
converted to the right half 14 by acidic deprotection. Con-
densation of 9 with 14 was carried out by a mixed anhy-
dride method to give 15. Deprotective hydrogenation of
15 provided 1 (ONO-6818) in good yield.
O
11
O
12
N
N
N
N
c
d
O
O
BocN
H
H2N
HCl
O
N
O
13
14
The above-described synthetic improvement is summa-
rized in Scheme 3. Scale-up synthesis of 7 was problem-
atic because of the explosiveness of the Curtius
rearrangement evolving nitrogen gas. The Lossen re-
arrangement which forms acetic acid instead of nitrogen
gas is a feasible candidate as a substitute for the Curtius
rearrangement.9
e
N
O
1 (ONO-6818)
N
N
CbzN
H
O
O
N
H
15
O
Scheme 2 Synthesis of 1 (ONO-6818) Including the Improved
Synthesis of the Right Half 14
Reagents:
EDC HCl, pyridine, 0 °C
THF, -70 °C
86% in 2 steps; (d) 9, ethyl chloroformate, N-methylmorpholine,
THF, -5 °C, 1 h, 98%; (e) H2 (3 atm), 10% Pd/C (50% wet), MeOH,
rt, 25 min, 77%.
(a)
N,O-dimethylhydroxylamine
rt, 2 h, 86%; (b) 12, LDA, TMEDA,
-20 °C, 5 h; (c) 4N HCl-EtOAc, 10 ~ 20 °C, 3 h,
hydrochloride,
As shown in Scheme 3a, the explosive Curtius rearrange-
ment was replaced by an unexplosive Lossen rearrange-
ment in the synthesis of 7 whose deprotection afforded 8.
The previous method of synthesizing 7 via 16 included an
explosive rearrangement reaction of 16 to form the isocy-
Synlett 2001, No. 2, 299–301 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Improved Synthesis of a New Nonpeptidic Inhibitor of Human Neutrophil Elastase
301
Expert. Opin. Ther. Pat. 1999, 9, 869-895 and the literature
cited therein.
anate 17 followed by the addition reaction of benzyl alco-
hol to the formed isocyanate 17.8
(5) Veale, C. A.; Bernstein, P. R.; Bohnert, C. M.; Brown, F. J.;
Bryant, C.; Damewood, Jr. J. R.; Early, R.; Feeney, S. W.;
Edwards, P. D.; Gomes, B.; Hulsizer, J. M.; Kosmider, B. J.;
Krell, R. D.; Moore, G.; Salcedo, T. W.; Shaw, A.; Silberstein,
D. S.; Steelman, G. B.; Stein, M.; Strimpler, A.; Thomas, R.
M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S.
J. Med. Chem. 1997, 40, 3173-3181.
Synthesis of 15 from 10 was also improved as described
in Scheme 3b. The previous method consisting of 6 steps
via 18 and 19 was replaced by a new 4 step-synthesis via
aminoketone 14 as described in Scheme 2.
All the steps were carried out without column chromatog-
raphy on silica gel. Thus, practical synthesis of ONO-
6818 (1), the first clinical candidate for an orally active
non-peptidic inhibitor of HNE, was successfully carried
out. This method involves the unexplosive Lossen
rearrangement of 5 instead of an explosive Curtius re-
arrangement and the direct coupling reaction of Weinreb
amide 11 and the anion of 12 to form the right half 14.
(6) A communication and a full paper are being submitted to J.
Med. Chem.
(7) Brown, F. J.; Andisik, D. W.; Bernstein, P. R.; Bryant C. B.;
Ceccarelli, C.; Damewood, Jr. J. R.; Edwards, P. D.; Earley,
R. A.; Feeney, S.; Green, R. C.; Gomes, B.; Kosmider, B. J.;
Krell, R. D.; Shaw, A.; Steelman, G. B.; Thomas, R. M.;
Vacek, E. P.; Veale, C. A.; Tuthill, P. A.; Warner, P.;
Williams, J. C.; Wolanin, D. J.; Woolson S. A. J. Med. Chem.
1994, 37, 1259-1261.
(8) Veale, C. J.; Bernstein, P. R.; Bryant, C.; Ceccarelli, C.;
Damewood, Jr. J. R.; Earley, R.; Feeney, S. W.; Gomes, B.;
Kosmider, B. J.; Steelman, G. B.; Thomas, R. M.; Vacek, E.
P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. J. Med.
Chem. 1995, 38, 98-108.
Full details regarding the right half will be reported in due
course.9
References and Notes
(1) Travis, J.; Dubin, A.; Potempa, J.; Watorek, W.; Kurdowska,
A. Ann. N.Y. Acad. Sci. 1991, 624, 81-86.
(9) Full details regarding the right half will be reported in J.
Heterocycl. Chem.
(2) Janoff, A. Am. Rev. Respir. Dis. 1985, 132, 417-433.
(3) Jackson, A. H.; Hill, S. L.; Afford, S. C.; Stockley, R. A. J.
Respir. Dis. 1984, 65, 114-124.
Article Identifier:
(4) For a comprehensive review of synthetic HNE inhibitors, see:
Metz W. A.; Peet N. P. Exp. Opin. Ther. Patents 1999, 9, 851-
868 and the literature cited therein. Skiles J. W.; Jeng A. Y.
1437-2096,E;2001,0,02,0299,0301,ftx,en;Y17100ST.pdf
Synlett 2001, No. 2, 299–301 ISSN 0936-5214 © Thieme Stuttgart · New York