Bioisosteric hybrids of two anti-inflammatory agents, rutaecarpine and piroxicam

Article abstract of DOI:10.1016/j.tetlet.2008.07.098

Bioisosteric replacements were accomplished by building the structural elements of piroxicam, an anti-inflammatory drug, into the pentacyclic system of rutaecarpine, a quinazolinocarboline alkaloid, in order to modify activity and selectivity on COX-isoenzymes. The pentacyclic compounds were synthesized efficiently by employing 1-oxo-9,10,11,12-tetrahydro-4H-pyrido[1,2-b]1,2-benzothiazine 5,5-dioxide as a key intermediate, and prepared by alternative routes. Condensation of the tricyclic ketone with arylhydrazines and subsequent Fischer-indolization provided the first representatives of new heterocyclic ring systems 3 and 4. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2008.07.098

Tetrahedron Letters 49 (2008) 5711–5713
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Bioisosteric hybrids of two anti-inflammatory agents, rutaecarpine
and piroxicam
a
a
a
a
b
Máté Bubenyák a, , Béla Noszál , Kristóf Kóczián , Mária Takács , Szabolcs Béni , István Hermecz ,
*
József Kökösi a
a
}
Department of Pharmaceutical Chemistry, Semmelweis University, Hogyes E. u. 9., Budapest H-1092, Hungary
b Chinoin Pharmaceutical and Chemical Works Ltd, PO Box 110, Budapest H-1325, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Bioisosteric replacements were accomplished by building the structural elements of piroxicam, an anti-
inflammatory drug, into the pentacyclic system of rutaecarpine, a quinazolinocarboline alkaloid, in order
to modify activity and selectivity on COX-isoenzymes. The pentacyclic compounds were synthesized effi-
ciently by employing 1-oxo-9,10,11,12-tetrahydro-4H-pyrido[1,2-b]1,2-benzothiazine 5,5-dioxide as a
key intermediate, and prepared by alternative routes. Condensation of the tricyclic ketone with arylhydr-
azines and subsequent Fischer-indolization provided the first representatives of new heterocyclic ring
systems 3 and 4.
Received 26 May 2008
Revised 30 June 2008
Accepted 9 July 2008
Available online 24 July 2008
Keywords:
Rutaecarpine
Piroxicam
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Anti-inflammatory drug
Bioisosteric hybrid
Alkaloid analogues
New pharmacological results arising from active components of
traditional Chinese folk medicines often provide promising lead
structures for novel drug development.
Rutaecarpine 1 is a major quinazolinocarboline alkaloid isolated
from the well-known Chinese herbal drugs Wu-Chu-Yu1,2 and
Shih-Hu,3 the dried, unripe fruits of Rutaceous plants such as Evo-
dia rutaecarpa4 and Evodia officinalis. They have long been utilized
for the treatment of inflammation-related symptoms5,6 in tradi-
tional oriental medicinal practice in Japan and China.
According to an increasing number of reports, rutaecarpine 1
possesses a wide spectrum of pharmacological properties, such
as calcitonin gene-related peptide (CGRP) mediated vasodilating,
antihypertensive,7 vasorelaxing,8 antithrombotic,9 antiplatelet,10
antianoxic,11 cardioprotective,12 uterotonic,13 antinociceptive,14
analgesic,4 diuretic,4 specific 2,3,7,8-TCDD binding inhibitory,15
and cytotoxic16 activities. Recent studies have revealed that rutae-
carpine 1 exhibits strong anti-inflammatory activity, and shows
potent and selective inhibitory activity against COX-2
isoenzyme.3,17
of prostaglandins through the nonselective inhibition of COX-1/2
isoenzymes.19
As part of our interest in developing safer anti-inflammatory
drugs,20 we describe the preparation of classical (quinazoline—
benzothiazine; indole—7-azaindole) and nonclassical (amide moi-
ety—pyrrole) bioisoster substituted21 hybrid structures 3 and 4 ob-
tained by combination of the structural elements of piroxicam 2
and the quinazolinocarboline skeleton 1 (Fig. 1). Through synthetic
modifications of the pentacyclic ring system, the anti-inflamma-
tory activity of 1 and its selectivity toward COX-2 can be modified
O
O
O
N
N
N
N
N
H
S
O
H
N
HO
1
2
Oxicams containing the 1,2-benzothiazine ring system are used
as non-steroidal anti-inflammatory18 drugs (NSAIDs). Examples
such as 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxam-
ides, for example, piroxicam 2, are applied widely in the treatment
of rheumatoid arthritis. Piroxicam 2 acts by blocking the formation
O
O
N
N
N
S
N
N
H
S
O
O
H
HO
HO
4
3
* Corresponding author. Tel.: +36 1 4763600x3073; fax: +36 1 2170891.
E-mail address: bmate@gyok.sote.hu (M. Bubenyák).
Figure 1. Hybrid structures 3 and 4 of rutaecarpine 1 and piroxicam 2.
0040-4039/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.098

5712
M. Bubenyák et al. / Tetrahedron Letters 49 (2008) 5711–5713
and its undesired side effects eliminated. 11,12-Dichloro-rutaecar-
pine was recently been published as an example of a hybrid be-
tween rutaecarpine and bauerine C.22
decreases remarkably in the presence of traces of moisture in the
alcohol and leads to the formation of undesired side products or
a multicomponent gummy mixture. After the fast Gabriel–Colman
rearrangement of 9 to 10, copper(II) carbonate was added to the
reaction mixture to exclude lactone formation by preventing O-
alkylation with complex formation and to assure selective ring clo-
sure to linearly condensed tricyclic product 8.
The pyridobenzothiazinone 8 was treated with phenylhydr-
azine in ethanol at 80 °C for 3 h to form hydrazone 11 in excellent
yield (Scheme 2). Geometric isomerism around the C@N double
bond is possible in 11. NMR data showed only the existence of
the E isomer containing an @NÁÁÁH–O intramolecular H-bond. Phen-
ylhydrazone 11 was subjected to Fischer indole synthesis as re-
ported earlier.23e Thus, heating the hydrazone in polyphosphoric
acid (PPA) at 180 °C for 30 min led, through 12, to the pentacyclic
compound 3 in 78% yield.32
The 7-azaindole derivative 4 can be considered a bioisoster of
an indole moiety33 and contains the 2-amino-pyridyl part of 2.
Contrary to indole, the 7-azaindole (1H-pyrrolo[2,3-b]pyridine)
nucleus is only present in a few natural products such as alkaloids
from the variolin family.34 Nevertheless, many compounds of po-
tential pharmaceutical interest containing the 7-azaindole motif35
have been synthesized due to their improved physicochemical and
pharmacological properties.
Condensation of the tricyclic ketone 8 with 2-pyridylhydrazine
provided the 2-pyridylhydrazone 13 in 90% yield (Scheme 3). Com-
pound 13 showed different geometric isomerism from the phen-
ylhydrazone 11 due to its zwitterionic nature as identified from
the upfield shift of the NH proton signals in its 1H NMR spectrum.
The unionized 13u E isomer is in equilibrium with the seven- and
five-membered H-bond stabilized and sterically unfavorable 13z Z
isomer in chloroform (isomer ratio = 14:86). Solvent dependent
geometric isomerism exists in more polar solvents. The 13z E:13z
Z isomer ratio proved to be 68:32 in DMSO-d6 (d = 13.49 (s,
0.68H, NHE), 15.67 (s, 0.32H, NHZ), 14.32 (br s, 1H, NH+)). Fischer-
indolization of pyridylhydrazone 13 was performed in PPA at
180 °C for 1 h to give 7-azaindolopyridoquinazoline 4 as a novel
heterocyclic ring system in moderate yield (57%).36 The pyridine
nitrogen in the A-ring of compound 4 is protonated by the acidic
enolic hydroxyl group, and the enolate forms a strong intramolec-
ular hydrogen bond with the indole NH. The highly stable zwitter-
ionic form 4z is the major species in equilibrium with the
The wide pharmacological activity of rutaecarpine 1 has led to
the development of efficient methods for the total synthesis of
rutaecarpine-type compounds.23 We had earlier developed an ori-
ginal approach for the facile synthesis of rutaecarpine by B/C ring
annelation,23e,23g and extended this approach to synthesize substi-
tuted derivatives of rutaecarpine in rings A, C, and E,24 1,2,3,4-tet-
rahydro derivatives, C-ring homologues,25 C-ring opened
analogues,26 E-ring debenzo derivatives,27 and 3-aza-28 and 7-
aza-bioisosters.29
Tricyclic ketone 8 is described in the literature30 and is prepared
by alkylation of 2-acetylbenzothiadiazine with chloroacetalde-
hyde, following ring closure by condensation, then hydrogenation
of the conjugated double bond with Pd-C catalyst. An alternative
method for the synthesis of compound 8 was performed from
the intermediate 5 of piroxicam31 (Scheme 1). Alkylation of sulfon-
amide 5 with ethyl 4-chlorobutyrate was carried out in the pres-
ence of copper(II) carbonate, a complex forming agent,31 to avoid
O-alkylated product formation. Among the various bases and con-
ditions investigated, the combination of NaOEt/EtOH/DMF led to
the diester 6 in reasonable yield. Without isolation, 6 was trans-
formed to tricyclic compound 7 via a consecutive Dieckmann-con-
densation catalyzed by excess sodium ethoxide in 47% yield.
b-Keto-ester 7, which existed in its enol form, was decarboethoxy-
lated to afford 1-oxo-9,10,11,12-tetrahydro-4H-pyrido[1,2-b]1,2-
benzothiazine 5,5-dioxide 8 in 81% yield. The reaction was carried
out by heating 7 at 130 °C in DMSO solution in the presence of cat-
alytic lithium chloride.
Tricyclic compound 8 was also prepared in satisfactory yield
starting from commercially available saccharin and 1,5-dichlorop-
entan-2-one in a one-pot procedure (alkylation, Gabriel–Colman
rearrangement, and base catalyzed ring closure) under basic condi-
tions using excess sodium ethoxide in anhydrous ethanol. Moisture
plays a key role in the ring expansion step. The yield of the product
OH
O
O
COOEt
N
NH
S
S
O
9
O
Cl
O
O
5
i
iv
OH
OH
O
COOEt
H
N
NH
OH
S
O
O
N
N
NH
COOEt
S
S
i
ii
O
O
O
O
10
Cl
N
6
S
O
O
O
O
v
ii
11
8
OH
O
OH
OH
COOEt
H
iii
H
N
O
HN
O
N
N
N
S
S
N
S
O
O
O
O
O
H
8
7
N
HO
S
Scheme 1. Synthesis of 1-oxo-9,10,11,12-tetrahydro-4H-pyrido[1,2-b]1,2-benzo-
thiazine 5,5-dioxide 8. Reagents and conditions: (i) Cl–(CH2)3–COOEt, NaOEt/EtOH,
CuCO3, DMF; (ii) NaOEt/EtOH, DMF, 65 °C, 8 h (47%); (iii) LiCl, DMSO, 130 °C, 3 h
(81%); (iv) NaOEt/EtOH, 80 °C, 40 min; (v) NaOEt/EtOH, CuCO3, DMF, 70 °C, 5 h
(42%).
O
O
3
12
Scheme 2. Synthesis of indolopyrido-1,2-benzothiazine 5,5-dioxide 3. Reagents
and conditions: (i) Ph–NHNH2, EtOH, 80 °C, 3 h (94%); (ii) PPA, 180 °C, 30 min (78%).

M. Bubenyák et al. / Tetrahedron Letters 49 (2008) 5711–5713
5713
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N
H
N
NH
OH
S
O
O
S
N
i
N
O
O
O
O
13u E
8
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N
O
N
N
S
O
O
O
O
13z Z
13z E
ii
O
O
+
N
N
N
N
S
N
N
H
S
O
O
H
H
HO
4u
O-
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4z
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Reagents and conditions: (i) 2-NHNH2–C5H4N, EtOH, 80 °C, 5 h (90%); (ii) PPA,
180 °C, 1 h (57%).
26. Hermecz, I.; Kökösi, J.; Vasvári-Debreczy, L.; Horváth, Á.; Podányi, B.; Szász, G.;
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unionized form 4u. The ionization process is similar to oxicam pro-
tonation,37,38 as published earlier by us, but the characteristic dy-
namic structural features of oxicam 2 are abolished by the highly
conjugated, rigid pentacyclic structure.
In conclusion, a short and efficient synthesis has been devel-
oped for bioisosteric analogues 3 and 4 of rutaecarpine 1 by build-
ing the pharmacophoric structural elements of piroxicam 2 into
the pentacyclic system of the alkaloid. These hybrid structures
were prepared in two alternative routes in five or preferably three
synthetic steps. The synthesized pentacylic compounds 3 and 4 are
the first representatives of new heterocyclic ring systems.
32. Compound 3: Mp: 238–241 °C. UV: in EtOH kmax (log e: 379. 4.30), 374 (4.42),
362 (4.32), 328 (3.86), 296 (3.80), 226 (4.41) nm. 1H NMR (600 MHz, DMSO-d6,
Aldrich) d 3.21 (t, J = 7.0 Hz, 2H), 4.25 (t, J = 7.0 Hz, 2H), 7.12 (ddd, J = 1.0, 7.9,
8.0 Hz, 1H), 7.30 (dd, J = 1.2, 7.9, Hz, 1H), 7.49 (dd, J = 1.0, 7.1 Hz, 1H), 7.67 (dd,
J = 1.2, 7.9 Hz, 1H), 7.71 (ddd, J = 1.2, 8.0, 8.2 Hz, 1H), 7.77 (ddd, J = 1.3, 7.1,
8.0 Hz, 1H), 7.84 (dd, J = 1.3, 8.2 Hz, 1H), 8.10 (dd, J = 1.2, 7.1 Hz, 1H), 10.67 (s,
1H, OH), 12.26 (s, 1H, NH). 13C NMR (150 MHz, DMSO-d6) d 22.31, 40.17, 105.5,
112.3, 119.1, 119.6, 119.7, 122.2, 122.4, 124.3, 125.0, 126.9, 129.9, 131.9, 135.8,
138.4, 143.9, 135.3. HRMS (ESI): calcd for (M+H)+ (C18H15N2O3S) requires m/z
339.0803, found 339.0812.
33. Popowycz, F.; Routier, S.; Joseph, B.; Mérour, J.-Y. Tetrahedron 2007, 63, 1031.
34. Joseph, B.; Meijer, L.; Liger, F. PCT int. Appl. WO 06/040451, 2006; Chem. Abstr.,
2006, 144, 390900.
Acknowledgment
35. (a) Bignan, G. C.; Battista, K.; Connolly, P. J.; Orsini, M. J.; Liu, J.; Middleton, S. A.;
Reitz, A. B. Bioorg. Med. Chem. Lett. 2006, 16, 3524; (b) Wang, X.; Zhi, B.; Baum,
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M.; Reider, P. J. Org. Chem. 2006, 71, 4021; (c) O’Neill, D. J.; Shen, L.; Prouty, C.;
Conway, B. R.; Westover, L.; Xu, J. Z.; Zhang, H.; Maryanoff, B. E.; Murray, W. V.;
Demarest, K. T.; Kuo, G. Bioorg. Med. Chem. 2004, 12, 3167; (d) Wang, T.; Zhang,
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This work was supported by the Hungarian Scientific Founda-
tion (OTKA T048554, OTKA K73804).
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36. Compound 4: Mp: 289–291 °C. UV: in EtOH kmax (loge: 390 (4.27), 385 (4.38),
373 (4.28), 334 (3.91), 218 (4.41) nm. 1H NMR (600 MHz, DMSO-d6, Aldrich) d
3.23 (t, J = 6.8 Hz, 2H), 4.18 (t, J = 6.8 Hz, 2H), 7.04 (dd, J = 7.7, 4.8 Hz, 1H), 7.73
(ddd, J = 1.2, 8.0, 8.2 Hz, 1H), 7.75 (ddd, J = 1.3, 7.1, 8.0 Hz, 1H), 7.87 (dd, J = 7.7,
1.7 Hz, 1H), 7.98 (dd, J = 1.3, 8.2 Hz, 1H), 8.25 (dd, J = 4.8, 1.7 Hz, 1H), 8.33 (dd,
J = 1.2, 7.1 Hz, 1H), 10.89 (s, 1H, NH), 13.38 (s, 1H, NH), 14.32 (s, 1H, H-bonded
NH).13C NMR (150 MHz, DMSO-d6) d 22.3, 42.1, 103.7, 119.8, 120.8, 123.1,
124.3, 127.5, 127.8, 128.6, 130.4, 131.6, 136.5, 142.5, 145.5, 146.5, 134.8. HRMS
(ESI): calcd for (M+H)+ (C17H14N3O3S) requires m/z 340.0755, found 340.0760.
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