AgNO3 mediated C-N bond forming reaction: Synthesis of 3-substituted benzothiazines as potential COX inhibitors

Article abstract of DOI:10.1016/j.tetlet.2012.09.102

AgNO₃ facilitated the intramolecular ring closure of o-(1-alkynyl)benzenesulfonamides via a regioselective C-N bond forming reaction leading to the formation of 3-substituted benzothiazine derivatives. A number of compounds were prepared in goo

Full text of DOI:10.1016/j.tetlet.2012.09.102

Tetrahedron Letters 53 (2012) 6577–6583
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
AgNO3 mediated C–N bond forming reaction: synthesis of 3-substituted
benzothiazines as potential COX inhibitors
D. Rambabu a,b, P. V. N. S. Murthy a, K. R. S. Prasad a, Ajit Kandale b, Girdhar Singh Deora b,
b,
M. V. Basaveswara Rao c, , Manojit Pal
⇑
⇑
a Department of Chemistry, K L University, Vaddeswaram, Guntur 522502, Andhra Pradesh, India
b Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra Pradesh, India
c Department of Chemistry, Krishna University, Machilipatnam 521001, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
AgNO3 facilitated the intramolecular ring closure of o-(1-alkynyl)benzenesulfonamides via a regioselec-
tive C–N bond forming reaction leading to the formation of 3-substituted benzothiazine derivatives. A
number of compounds were prepared in good yields by using this inexpensive and safe methodology.
All the compounds synthesized were evaluated for their cyclooxygenase (COX) inhibiting properties
in vitro. A number of compounds that do not contain an enolic hydroxyl group showed selectivities
toward COX-2 over COX-1 inhibition. This was further supported by the predictive binding mode of
two compounds with COX-1 and -2 proteins through molecular docking studies.
Received 8 August 2012
Revised 20 September 2012
Accepted 22 September 2012
Available online 28 September 2012
Keywords:
Benzothiazine
Benzenesulfonamides
AgNO3
Ó 2012 Elsevier Ltd. All rights reserved.
COX
Docking
Benzothiazine, an important heterocyclic compound consists of
a benzene ring attached to the six-membered heterocycle thiazine.
Compounds containing benzothiazine framework have been stud-
ied widely because of their numerous pharamacological impor-
tance. For example, various benzothiazine based compounds
have been reported as potent anti-inflammatory agents.1 Some of
these compounds, particularly oxicams2a,b have already been mar-
keted. Well known anti-inflammatory drugs such as meloxcicam
(A, Fig. 1) and piroxicam (B, Fig. 1) belong to this class of com-
pounds. Both meloxicam and piroxicam inhibit cyclooxygenase
(COX), the enzyme responsible for converting arachidonic acid into
prostaglandin H2 (the first step in the synthesis of prostaglandins)
that are mediators of inflammation. While piroxicam showed non-
selective inhibition of COX isozymes, meloxicam did show low
selectivity towards COX-2 over COX-1 especially at low therapeu-
tic dosage.2c Notably, selective inhibition of COX-2 has been re-
ported to be beneficial to avoid gastrointestinal side effects of
non-selective NSAIDs (non-steroidal anti-inflammatory drugs).
While meloxicam showed fewer gastrointestinal side effects than
diclofenac, piroxicam and naproxen, its long term use causes gas-
trointestinal toxicity and bleeding that was thought to be due to
the presence of acidic enolic OH in addition to its COX-1 inhibition.
Thus, derivatization3 of this group provided compounds that were
stable under gastric conditions and caused lower gastrointestinal
irritation.3b–e This prompted us to evaluate the COX inhibiting
properties of a library of small molecules (C, Fig. 1) based on ben-
zothiazine devoid of enolic OH to identify new COX-2 inhibitors.
The structure of the target compound C therefore was reached by
omitting the enolic OH of A or B followed by introduction of R1
and R2 to generate diversity around the core structure.
Because of their various pharmacological significance, synthesis
of benzothiazines has attracted the particular attention of organic
and medicinal chemists. This is exemplified by the continued effort
devoted towards the development of new and better synthetic
methods for the construction of the 2H-benzo[e][1,2]thiazine
ring.4–8 Transition-metal catalyzed reactions are now considered
as a powerful tool for the construction of various carbocyclic
and heterocyclic structures. Accordingly, a Pd-mediated one-step
OH
O
R1
R2
NHR
CH3
N
N
S
S
CH3
O
O
O
O
C
R = 5-methylthiazole-2-yl (A)
= 2-pyridyl (B)
⇑
Corresponding author. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail address: manojitpal@rediffmail.com (M. Pal).
Figure 1. Meloxicam (A), piroxicam (B) and design of benzothiazine based new
COX inhibitors.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.102

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D. Rambabu et al. / Tetrahedron Letters 53 (2012) 6577–6583
R2
synthesis of benzothiazines involving the coupling of bromosulfox-
imine with terminal alkynes under Sonogashira conditions has
been reported.9 One of the major drawbacks of this methodology
is the formation of isomeric 1,2-benzoisothiazoles as side products.
Thus, a more convenient synthesis of benzothiazines was devel-
oped following a coupling-iodocyclization strategy.10 While this
methodology was free from the generation of isomeric side prod-
ucts, it required an additional step to remove the C-4 iodo group.
To overcome this problem a direct synthesis of benzothiazine
derivatives was developed that involved intramolecular cyclization
of o-(1-alkynyl)benzenesulfonamides in the presence of AgSbF6
and Et3N.11 While this reaction was found to be highly regioselec-
tive and afforded good to excellent yields of desired products the
methodology, however, involved the use of relatively expensive
and corrosive AgSbF6 catalyst. As part of our continuing effort on
the identification of biologically active small organic molecules
we required a library of benzothiazine derivatives for various
in vitro pharmacological screens. We, therefore, were in need of
an inexpensive and safer method for accessing this class of com-
pounds. Herein we report our results on AgNO3 mediated synthesis
of 3-substituted benzothiazines 2 (or C, Fig. 1) from o-(1-alky-
nyl)benzenesulfonamides (1) via a regioselective C–N bond form-
ing reaction (Scheme 1). To the best of our knowledge the use of
AgNO3 for a similar C–N bond forming reaction has not been stud-
ied extensively. We also report COX inhibiting properties of com-
pounds 2 in vitro.12
R2
R1
I
R1
10% Pd/C, PPh3, CuI
NHCH3
O
NHCH3
O
Et3N, CH3CN, 80 o
C
S
S
O
O
3
1
Scheme 2. Pd/C-mediated synthesis of o-(1-alkynyl)benzenesulfonamides (1).
Table 1
AgNO3-mediated cyclization of N-methyl-2-p-toluylethynyl benzenesulfonamide
(1a)a
CH3
CH3
AgNO3
O
N
S
CH3
solvent
S
O
O
O
NHCH3
2a
1a
Entry
Solvent
Time (h)
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
DMF
DMF
DMF
DMF
DMF
CH3CN
DCE
2
2
2
6
2
2
2
2
25
60
80
80
120
80
80
80
0
55
80
73
70
70
20
0c
The synthesis of our key starting material o-(1-alkynyl)ben-
zenesulfonamides (1) was carried out via the Pd/C mediated cou-
pling of o-iodobenzenesulfonamide (3) with terminal alkynes in
good yields (Scheme 2).10,11 The required sulfonamide (3) was pre-
pared either via treating 2-iodobenzenesulfonyl chloride13 with
MeNH2 in dioxane/THF14 or iodination of N-methyl benzene sul-
fonamide derivative15 using n-BuLi in THF according to the
literature.10
DMF
a
b
c
All the reactions were carried out with 1a with 15 mol % catalyst.
Isolated yields.
The reaction was performed without catalyst. (DCE = 1,2-dichloroethane).
To establish the optimized reaction conditions we examined the
AgNO3 mediated intramolecular cyclization of N-methyl-2-p-
toluylethynyl benzenesulfonamide (1a) under various conditions
(Table 1). Initially, the reaction was carried out in DMF at 25 °C
when no formation of product was observed (Table 1, entry 1).
While increasing the temperature to 60 °C improved the product
yield, the best result was achieved when the reaction was
performed at 80 °C (Table 1, entry 3). Increasing the reaction time
(Table 1, entry 4) or temperature (Table 1, entry 5) did not improve
the product yield. The use of other solvents, for example, CH3CN
(Table 1, entry 6) and DCE (Table 1, entry 7) was examined and
all other solvents were found to be less effective. Notably, the reac-
tion did not proceed in the absence of catalyst (Table 1, entry 8)
indicating the key role played by AgNO3 in the present C–N bond
forming reaction.
1–9). Both aryl and alkyl substituents present in the alkyne 1 were
well tolerated.
Mechanistically, the reaction proceeds (Scheme 3) via activation
of the triple bond of 1 by coordination to the Ag-salt to form the
r-
complex E-1. DMF being a Lewis base form a S–N–Hꢀ ꢀ ꢀO@C hydro-
gen bond which enhances the nucleophilicity of the sulfonamide
nitrogen. Regioselective nucleophilic attack of the sulfonamide
group to the Ag-coordinated triple bond through its nitrogen in a
‘6-endo dig’ fashion provides the Ag-vinyl species E-2. On subse-
quent protonation of the complex E-2 regenerates the catalyst
affording the desired product 2. While the reason for observed
selectivity towards the six-membered ring formation was not
clearly understood the longer S-N bond length perhaps favored
endo ring closure due to the less geometric constraint.
All the synthesized products were evaluated for their COX inhi-
bition potential and selectivity by using biochemical COX (COX-1 &
COX-2) enzyme based assay. The COX-1 enzyme was isolated from
Ram seminal vesicles whereas the recombinant human COX-2 was
expressed in insect cell expression system. These enzymes were
purified by employing conventional chromatographic techniques.
Enzymatic activities of COX-1 and COX-2 were measured according
to the method reported earlier,17 with slight modifications using a
chromogenic assay based on the oxidation of N,N,N0,N0-tetra-
methyl-p-phenylene diamine (TMPD) during the reduction of
PGG2 to PGH2.18,19 The known non-selective inhibitor indometha-
cin and COX-2 inhibitor celecoxib were used as reference com-
pounds in this assay. The IC50 values determined for all the
compounds along with their selectivity (COX-2/COX-1 ratio) are
listed in Table 3. Among all the compounds tested 2a–c and 2g
showed COX-2 selectivity. While all the compounds showed COX
Using the optimized reaction conditions we examined the gen-
erality and scope of the AgNO3 mediated synthesis of benzothia-
zines. Accordingly, a number of alkynes were employed in the
present reaction16 and the results are summarized in Table 2. It
is evident from Table 2 that the reaction proceeded well in all these
cases affording good yields of the desired product (Table 2, entries
R2
R1
R2
R1
AgNO3
NHCH3
O
N
DMF, 80 o
C
S
CH3
S
O
O
O
2
1
Scheme 1. AgNO3 mediated synthesis of 3-substituted benzothiazines.

D. Rambabu et al. / Tetrahedron Letters 53 (2012) 6577–6583
6579
Table 2
Synthesis of 3-substituted benzothiazines (2) via AgNO3 mediated cyclization of o-(1-alkynyl)benzenesulfonamides (1)a
Entry
Alkynes (1)
Benzothiazines (2)
Time (h)
Yieldb,c (%)
CH3
CH3
N
1
2
80
77
79
S
S
CH3
O
O
O
O
S
NHCH3
O
O
2a
1a
N
CH3
2
1.5
O
O
S
NHCH3
2b
1b
CH3
CH3
H3C
H3C
N
3
2
S
CH3
O
O
O
S
O
NHCH3
2c
1c
O
S
NHCH3
4
2.5
79
O
N
S
CH3
1d
O
O
2d
O
5
6
7
2
2
2
80
S
S
N
NHCH3
S
S
O
CH3
O
O
O
1e
2e
Cl
Cl
O
NHCH3
75
O
N
CH3
1f
O
2f
H3C
H3C
O
77
S
O
N
NHCH3
S
CH3
O
O
1g
2g
(continued on next page)

6580
D. Rambabu et al. / Tetrahedron Letters 53 (2012) 6577–6583
Table 2 (continued)
Entry
Alkynes (1)
Benzothiazines (2)
Time (h)
Yieldb,c (%)
CN
CN
H3C
H3C
O
8
2.5
78
S
N
NHCH3
S
CH3
O
O
O
1h
2h
OH
OH
F
F
9
2.5
80
O
S
O
N
NHCH3
S
CH3
O
O
1i
2i
a
All the reactions were carried out at 80 °C with 15 mol % of AgNO3 in DMF.
Isolated yields.
All the compounds synthesized are known and well characterized by NMR, MS and IR.
b
c
Ag (I)
R2
Ag(I)
R2
R1
R2
R1
R1
AgNO3
Me2N
H
H
O
O
N
Me2NCHO
S
CH3
S
S
N
O
O
O
NHCH3
O
O
CH3
1
E-2
E-1
Me2N
H
R1
R2
OH
- Ag(I)
N
S
CH3
O
O
2
Scheme 3. Probable mechanism for the AgNO3 mediated formation of benzothiazine ring.
inhibiting properties in vitro only four of them were found to be
COX-2 selective. Compounds 2a–c and 2g (Table 3, entries 1–3
and 7) showed selectivity towards COX-2 inhibition among which
2g was found to have the best activity as well as selectivity. It is
better than indomethacin though inferior to celecoxib in terms of
that of piroxicam was found to be 4.4 l
M.20 Compound 2g, which
lacks of an enolic hydroxyl group, is therefore of high interest.
In silico docking studies were performed to understand the
interaction of compounds 2a and 2g as well as meloxicam with
both the COX isoforms. The PDB ID 1EQG (COX1) and 1CX2
(COX2) were used for the docking study and all these molecules
were docked into COX-1 and COX-2 (see Tables 1 and 2 in Supple-
mentary data). Both 2a and 2g showed good dock score, that is,
ꢁ8.45 and ꢁ8.37, respectively, when docked into the COX-2 by
selectivity. Notably, meloxicam showed an IC50 value of 4.7 lM
for COX-2 inhibition (with COX-2/COX-1 ratio of 0.12) whereas
Table 3
In vitro COX inhibition by 3-substituted benzothiazine derivatives (2)
making good p–p stacking and sitting well within the hydrophobic
pocket. These are comparable to the standard drug meloxicam (see
Table 1 in Supplementary data). When docked into the COX-1, both
2a and 2g showed comparatively lower score than that of COX-2,
for example, ꢁ7.86 and ꢁ7.55, respectively, indicating the selectiv-
ity of these molecules towards COX-2 over COX-1 (see Supplemen-
tary data, Table 1 versus 2). Notably, a similar trend was observed
in case of meloxicam.
Entry
Compound
IC50
(l
M)a
COX-2/COX-1 Selectivity ratio
COX-1
COX-2
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
11.52
13.95
14.63
12.27
15.60
15.13
20.76
17.26
22.98
0.0067
15.0
4.91
5.29
6.83
0.43
0.38
0.47
1.53
1.30
1.33
0.15
1.35
0.91
7.16
0.0028
18.71
20.25
20.09
3.25
23.27
21.02
0.048
0.042
The interaction of 2a with COX-1 was mainly contributed by a
p
–
p
stacking between the phenyl ring of 2a and tyrosine 385 res-
idue (Fig. 2) whereas that of 2g was contributed by a stacking
between its phenyl ring and the tyrosine 355 residue of COX-1
(Fig. 3). Meloxicam showed a stacking between its (i) phenyl
p–p
9
10
11
2i
Indomethacin
Celecoxib
p–p
ring and tyrosine 385 as well tryptophan 387 and (ii) thiazole ring
and tyrosine 355 residue of COX-1 (see Supplementary data).
a
The result is the mean value of two determinations, and the deviation from the
mean is <10% of the mean value.

D. Rambabu et al. / Tetrahedron Letters 53 (2012) 6577–6583
6581
Figure 2. Docking of 2a at the active site of COX-1.
Figure 3. Docking of 2g at the active site of COX-1.
While interacting with COX-2 both 2a (Fig. 4) and 2g (Fig. 5)
showed good stacking with tyrosine 355, tyrosine 385 and
tryptophan 387 (not shown in 2D interaction diagram, due to de-
fault software parameters). Additionally, their hydrophobic parts
occupied the hydrophobic region of the receptor site. Meloxicam
An inexpensive and safer method has been developed for their syn-
thesis which involved AgNO3 mediated intramolecular ring closure
of o-(1-alkynyl)benzenesulfonamides via a regioselective C–N bond
forming reaction. A number of compounds were prepared by using
this methodology in good yields. All the compounds synthesized
were evaluated for their cyclooxygenase (COX) inhibiting proper-
ties in vitro some of which showed selectivities toward COX-2 over
COX-1 inhibition. This was further supported by the predictive
binding mode of two compounds with COX-1 and -2 proteins
through molecular docking studies. Overall, the benzothiazine
framework presented here could be an attractive template for the
identification of novel cyclooxygenase inhibitors. Due to the atom
economic nature, functional group tolerance and efficiency, the
p–p
showed a (i)
385 as well tryptophan 387, (ii)
p
–
p
stacking between its phenyl ring and tyrosine
-cation interaction between its
p
thiazole ring and arginine 120 and (iii) H-bonding between its
sulphoxide oxygen and the side chain of serine 530 (see Supple-
mentary data).
In conclusion, 3-substituted benzothiazine derivatives devoid of
enolic hydroxyl group were designed based on oxicam family of
anti-inflammatory agents and explored as potential COX inhibitors.

6582
D. Rambabu et al. / Tetrahedron Letters 53 (2012) 6577–6583
Figure 4. Docking of 2a at the active site of COX-2.
Figure 5. Docking of 2g at the active site of COX-2.
2. (a) Engelhardt, G.; Homma, D.; Schlegel, K.; Utzmann, R.; Schnitzler, C. Inflamm.
Res. 1995, 44, 423; (b) Olkkola, K. T.; Brunetto, A. V.; Mattila, M. J. Clin.
Pharmacokinet. 1994, 26, 107; (c) Noble, S.; Balfour, J. A. Drugs 1996, 51, 431.
3. (a) Jayaselli, J.; Cheemala, J. M. S.; Rani, D. P. G.; Pal, S. J. Braz. Chem. Soc. 2008,
19, 509; (b) Hopkins, S. J.; Rabasseda, X. Drugs Today 1994, 30, 557; (c) Marfat,
A. U.S. Patent Application No US4551452, Nov. 5, 1985.; (d) Farre, A. J.;
Colombo, M.; Fort, A.; Gutierrez, B.; Rodriguez, L.; Roser, R. Meth. Find. Exp. Clin.
Pharmacol. 1986, 8, 407; (e) Cherie-Ligniere, G.; Montagnani, G.; Alberici, M.;
Acerbi, D. Arzneim.-Forsch./Drug Res. 1987, 37, 560.
present methodology could find application in the construction of
diverse benzothiazine based small molecules of potential pharma-
cological interest.
Acknowledgment
The authors thank the management of Institute of Life Sciences
for encouragement and support.
4. Layman, W. J., Jr.; Greenwood, T. D.; Downey, A. L.; Wolfe, J. F. J. Org. Chem.
2005, 70, 9147.
5. Sianesi, E.; Redaelli, R.; Magistretti, M. J.; Massarani, E. J. Med. Chem. 1973, 16,
1133.
Supplementary data
6. Lombardino, J. G.; Wiseman, E. H. J. Med. Chem. 1971, 14, 973.
7. Catsoulacos, P. J. Heterocycl. Chem. 1971, 8, 947.
8. Hauser, C. R.; Wantanabe, H.; Mao, C.-L.; Barnish, I. T. J. Org. Chem. 1969, 34,
919.
9. Harmata, M.; Rayanil, K.-o.; Gomes, M. G.; Zheng, P.; Calkins, N. L.; Kim, S.-Y.;
Fan, Y.; Bumbu, V.; Lee, D. R.; Wacharasindhu, S.; Hong, X. Org. Lett. 2005, 7,
143.
10. Barange, D. K.; Batchu, V. R.; Gorja, D.; Pattabiraman, V. R.; Tatini, L. K.; Babu, J.
M.; Pal, M. Tetrahedron 2007, 63, 1775.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.
102.
References and notes
1. (a) Lombardino, J. G.; Wiseman, E. H. Med. Res. Rev. 1982, 2, 127; (b) Lazer, E. S.;
Miao, C. K.; Cywin, C. L.; Sorcek, R.; Wong, H.-C.; Meng, Z.; Potocki, I.;
Hoermann, M.; Snow, R. J.; Tschantz, M. A.; Kelly, T. A.; McNeil, D. W.; Coutts, S.
J.; Churchill, L.; Graham, A. G.; David, E.; Grob, P. M.; Engel, W.; Meier, H.;
Trummlitz, G. J. Med. Chem. 1997, 40, 980.
11. Barange, D. K.; Nishad, T. C.; Swamy, N. K.; Bandameedi, V.; Kumar, D.;
Sreekanth, B. R.; Vyas, S. K.; Pal, M. J. Org. Chem. 2007, 72, 8547.
12. For our earlier effort on COX-2 inhibitors, see: (a) Pal, M.; Madan, M.;
Padakanti, S.; Pattabiraman, V. R.; Kalleda, S.; Vanguri, A.; Mullangi, R.;
Mamidi, N. V. S. R.; Casturi, S. R.; Yeleswarapu, K. R. J. Med. Chem. 2003, 46,

D. Rambabu et al. / Tetrahedron Letters 53 (2012) 6577–6583
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3975; (b) Pal, M.; Veeramaneni, V. R.; Nagabelli, M.; Kalleda, S. R.; Misra, P.;
Casturi, S. R.; Yeleswarapu, K. R. Bioorg. Med. Chem. Lett. 2003, 13, 1639; (c) Pal,
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19. Enzyme assay: Microsomal fraction of ram seminal vesicles were used as a
source of COX-1 enzyme and microsomes from sf-9 cells infected with
baculovirus containing human COX-2 c-DNA were used as a source of COX-2
enzyme. Enzyme activity was measured using a chromogenic assay based on
oxidation of N,N,N0,N0-tetramethyl-p-phenylenediamine (TMPD) during the
reduction of PGG2 to PGH2 as per the procedure described by Copeland et al17
13. Gilman, M. J. Am. Chem. Soc. 1952, 74, 5317.
14. Rabai, J. Synthesis 1989, 523.
15. Nozu, R.; Osaka, T.; Kitano, H.; Fukui, K.-i. Nippon Kagaku Zasshi 1955, 76, 775
16. Typical procedure for the preparation of 2a: To
a mixture of 1a (0.27 g,
0.94 mmol), and triethylamine (0.28 g, 0.39 mL, 2.8 mmol) in ethanol
(5.4 mL) was added AgNO3 (0.031 g, 0.18 mmol, 0.2 equiv) and the mixture
was stirred at 80 °C for 5 min. After completion of the reaction (indicated by
TLC), the mixture was filtered through celite and washed with EtOAc. The
filtrate was collected and concentrated under vacuum. The residue was
purified by column chromatography (SiO2) to afford the desired product as a
white solid; mp 119–120 °C; 1H NMR (400 MHz, CDCl3): d 7.90 (dd, J = 7.7 and
with the following modifications. The assay mixture (1000
lL) contained
100 mM Tris pH 8.0, 3 mM EDTA, 15 M hematin, 150 units enzyme and 8%
l
DMSO. The mixture was pre-incubated at 25 °C for 15 min before initiation of
enzymatic reaction in the presence of compound/vehicle. The reaction was
initiated by the addition of 100 lM arachidonic acid and 120 lM TMPD. The
enzyme activity was measured by estimation of the initial velocity of TMPD
oxidation over the first 25 s of the reaction followed from increase in
absorbance at 603 nM. The IC50 values were calculated using non-linear
regression analysis.
0.6 Hz, 1H), 7.63–7.26 (m, 7H), 6.69 (s, 1H), 3.01 (s, 3H), 2.41 (s, 3H); IR (cmꢁ1
,
CHCl3) 1346, 1184; m/z (ES Mass) 286 (M+1, 100%); 13C NMR (100 MHz,
CDCl3): d 144.7, 140.1, 132.9, 132.1, 131.7, 131.3, 129.6 (2C), 128.0 (2C), 127.6,
127.5, 122.4, 111.5, 35.7, 21.3.
20. Blanco, F. J.; Guitian, R.; Moreno, J.; de Toro, F. J.; Galdo, F. J. Rheumatol. 1999,
26, 1366.