Saccharin Aza Bioisosteres - Synthesis and Preclinical Property Comparisons

Article abstract of DOI:10.1021/acsmedchemlett.7b00137

Saccharin is a well-known scaffold in drug discovery. Herein, we report the synthesis and preclinical property comparisons of three bioisosteres of saccharin: aza-pseudosaccharins (cluster B), and two new types of aza-saccharins (clusters C and D). We dem

Full text of DOI:10.1021/acsmedchemlett.7b00137

Letter
pubs.acs.org/acsmedchemlett
Saccharin Aza BioisosteresSynthesis and Preclinical Property
Comparisons
,
†
‡
§
∥
⊥
Yantao Chen,* Carl-Johan Aurell, Anna Pettersen, Richard J. Lewis, Martin A. Hayes,
∥
∥
∥
∥
Matti Lepisto, Anna C. Jonson, Hanna Leek, and Linda Thunberg
̈
†
‡
§
∥
Medicinal Chemistry, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca R&D
Gothenburg, 431 83 Molndal, Sweden
Large Scale Chemistry, Early Chemical Development, Pharmaceutical Sciences, AstraZeneca R&D Gothenburg, 431 83 Mo
Sweden
̈
̈
lndal,
Pharmaceutical Technology and Development, Product Development, AstraZeneca Operations Gothenburg, 431 83 Mo
Sweden
̈
lndal,
Medicinal Chemistry, Respiratory, Inflammation and Autoimmunity, Innovative Medicines and Early Development, AstraZeneca
R&D Gothenburg, 431 83 Molndal, Sweden
DMPK, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca R&D Gothenburg,
31 83 Molndal, Sweden
̈
⊥
4
̈
*
S Supporting Information
ABSTRACT: Saccharin is a well-known scaffold in drug discovery.
Herein, we report the synthesis and preclinical property comparisons of
three bioisosteres of saccharin: aza-pseudosaccharins (cluster B), and
two new types of aza-saccharins (clusters C and D). We demonstrate a
convenient protocol to selectively synthesize products in cluster C or D
when primary amines are used. Preclinical characterization of selected
matched-pair products is reported. Through comparison of two
diastereomers, we highlight how stereochemistry affects the preclinical
properties. Given that saccharin-based derivatives are widely used in many
chemistry fields, we foresee that structures exemplified by clusters C and
D offer new opportunities for novel drug design, creating a chiral center on the sulfur atom and the option of substitution at two
different nitrogens.
KEYWORDS: Pseudosaccharin, Sulfonamide, Sulfonimidamide, Regioselectivity, Chemoselectivity, Telescoping synthesis,
Functionalization, Ring-closure, N-Substitution, Chlorinating reagent, Medicinal chemistry
he saccharin scaffold has been a subject of great interest,
especially in the field of medicinal chemistry. Since
the functionalization of this heterocycle has proved difficult,
except for N- and O-alkylation, novel strategic approaches are
much sought-after and would be of great value to medicinal
chemists.
1
,2
T
N- and O-Alkylated saccharin derivatives have been
employed as key structural elements in biologically active
compounds ranging from enzyme inhibitors to receptor ligands
Figure 1. Structures of saccharin (cluster A) and three accessible
saccharin aza derivatives (clusters B−D).
2
−4
and beyond.
-N-substituted benzo[d]isothiazole 1,1-dioxide derivatives by
derivatization of the carbonyl carbon (aza-pseudosaccharins),
The saccharin motif can be transformed into
saccharin analog by replacing one sulfonamide oxygen with
3
8
alkyl groups to give the cyclic acylsulfoximines. Recently, an aza
5
−7
transformation strategy has been applied for the synthesis of
and they also have great utility.
9
,10
sulfoximinesanalogues to sulfones.
It is also possible to derivatize at the sulfonamide oxygens
to generate a chiral center and two new types of derivatives
Linear chiral sulfonimidamides have been used as chiral
ligands in organocatalytic asymmetric chemistry.
11−13
They have
(Figure 1). These compounds are here categorized into three
clusters: cluster B, aza-pseudosaccharin; cluster C, formed
by replacement of sulfonyl oxygen by an imino nitrogen; and
cluster D, formed by replacement of sulfonyl oxygen with
an amino nitrogen. In 1975, Stoss and Satzinger prepared a
Received: March 31, 2017
Accepted: May 1, 2017
Published: May 1, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.7b00137
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ACS Medicinal Chemistry Letters
Letter
also been proposed as a bioisosteric replacement of sulfonamides
and carboxylic acids.
First, the sulfonamide group in methyl 2-sulfamoylbenzoate
14−19
is functionalized to sulfonimidamide (products 22−38) using
2
0
We now report a novel synthetic approach to prepare
compounds in cluster B from saccharin. The core structure in
clusters C and D was prepared via an intramolecular reaction
between the ortho ester and the sulfonimidamide group using
TBS protected methyl 2-sulfamoylbenzoate as the starting
material. The chlorinating agent chloro(triphenyl)phosphonium
our previously published protocol; then intramolecular
ring-closure occurs between the ester group and a nitrogen
from either the amidic nitrogen or the imidic nitrogen in the
sulfonimidamide moiety. Acidic treatment of the TBS-protected
intermediates gave the final products 48−56 in cluster C, and
6
5−73 in cluster D.
Product 65 was prepared from 22 when the latter was treated
with aqueous ammonia.
When cyclohexylamine was used, both the open- and ring-
closed products 25 and 41 were found in the reaction mixture in
approximately a 1:1 ratio. It was hypothesized that the steric
effect of the cyclohexyl group prevented full ring-closure.
Treatment of the crude mixture with HCl gave 50 and 66.
No corresponding methyl ester 57 was found.
When an α-branched primary amine, (S)- or (R)-1-phenyl-
ethylamine, was used, only a diastereomeric mixture of esters
2a/b or 33a/b was formed, and no cyclized product was
observed. NMR indicated the dr ratio of each diastereomeric
mixture was about 1:1. Chromatographic separation afforded
stereochemically homogeneous isomers. Acidic treatment gave
the relevant products 67a, 67b, 68a, and 68b.
X-ray crystal structures of diastereomers 68a and 68b
indicated that 68a had the RcRs (RR) and 68b had the RcSs
20
chloride (Ph PCl ), which we used in our previous work, was
3
2
employed in this work for both the CO aza and SO aza
chemistries.
In order to evaluate the potential of these compounds as drug
molecules, matched-pair compounds in clusters B, C, and D and
three N-alkylated saccharin compounds in cluster A (R = H, Et,
and Bn) were screened in in vitro assays. Herein, we report
preclinical screening data, including measured pK , experimental
a
log D, in vitro metabolic stability, plasma protein binding, Caco-2
permeability, aqueous solubility, and hERG inhibition. We also
studied the property differences between diastereomers.
Although the library of compounds that we have screened is
small, the preliminary preclinical characterization results indicate
that the functionalization strategy represented in clusters C and
D potentially offers new opportunities for novel drug design,
creating a chiral center on the sulfur atom and the option of
substitution at two different nitrogens.
3
(
RS) configurations, as shown in Figure 2. Though they only
CHEMISTRY
■1
. Cluster B. The traditional method for synthesis of
differ in the configuration around the sulfur atom, they display a
very different conformation in the solid state with either a face to
face or edge to face aromatic interaction, which is also present in
solution (see Supporting Information for additional details).
The other ring-closed intermediates (39, 40, 42−47) were
obtained during the purification of the relevant precursors
(23, 24, 26−31). Finally, acidic treatment of 39−47 led to the
formation of compounds 48−56 in cluster C.
When secondary amines were used as nucleophilic agents,
intermediates 34−38 were obtained. After acidic cleavage of
the TBS group, the final compounds 69−73 in cluster D
were formed directly through ring-closure between the imidic
nitrogen and the ester group in the corresponding intermediates
cluster B products starts from saccharin 1. Chlorinating agents
2
1
22
23,24
such as SOCl2, POCl3, and PCl5
have been used as the
chlorinating agents. In this work, Ph PCl was used as the
3
2
chlorinating agent to give the intermediate 2. Nucleophilic
substitution of 2 with amines afforded products 3−19 in one pot
2
0
(
Scheme 1).
2
. Clusters C and D. As shown in Scheme 1, a cluster B
product was formed using saccharin as the starting material.
In order to prepare an aza analogue on the sulfur atom, i.e.
a sulfonimidamide-like product, we have developed a new
methodology to prepare the compounds in clusters C and D in a
parallel way as shown in Scheme 2.
6
0−64.
Besides aliphatic amines, other amino reagents, such as amino
Scheme 1. Synthesis of Aza Pseudosaccharin B from
a
Saccharin
alcohols, amino esters, and anilines, are also tolerated under the
reaction conditions.
In Scheme 2, when less hindered primary amines, such as
methylamine, ethylamine, or benzylamine, were used, only
the cluster C compounds were obtained. Product 74 in cluster D
had to be synthesized from the benzylated intermediate 73
(
Scheme 3).
Is it possible to prepare a cluster D compound directly using
a primary amine as the nucleophile?
First, the intermediate 24 was prepared under the same
conditions as shown in Scheme 3. Second, without evaporation, a
solution of HCl in organic solvents, such as methanol, was added
to the reaction mixture to afford 74 exclusively (Scheme 4).
In the same manner, products 77, 79, and 81 were synthesized,
which were not originally formed during the chemistry experi-
ment in Scheme 2.
The chemoselectivity is highlighted in Scheme 5. In general,
ring-closure first followed by TBS-deprotection led to a cluster C
product, while deprotection first followed by ring-closure in
one-pot afforded the regioisomer, a cluster D product.
a
Conditions: (i) fresh Ph PCl2 (1.15 equiv), TEA (2 equiv),
3
DCM/CHCl , 35 °C, 5 h; (ii) various amines (3 equiv), 1.5−6 h,
rt (reference numbers of known compounds are in parentheses).
3
2
5−30
B
DOI: 10.1021/acsmedchemlett.7b00137
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ACS Medicinal Chemistry Letters
Letter
a
Scheme 2. Synthesis of Aza Saccharin Derivatives in Clusters C and D from Methyl 2-Sulfamoylbenzoate
a
Conditions: (i) TBS-Cl (1.18 equiv), TEA (3 equiv), DCM, rt, 1 d; (ii) fresh Ph PCl (1.18 equiv), DCM/CHCl , 0−35 °C, 10 h; (iii) various
3
2
3
amines (3.0 equiv), 10 min −6 h, rt; (iv) HCl/MeOH/water, 1−2 h, rt
Scheme 5. Chemoselectivity of 49 and 74
Figure 2. X-ray diffraction structures of 68a and 68b.
Scheme 3. Synthesis of 74
compounds from the four clusters, particularly for those matched
pairs where the same substituents appear in different clusters.
Comparisons are made between the measured solubility,
Scheme 4. Synthesis of Cluster D Products from Primary
Amines
a
lipophilicity, pK , permeability, metabolic stability, and hERG
a
inhibition (Table 1). All the physicochemical and in vitro assays
in this work are standard and used to assess preclinical
31
compounds at AstraZeneca.
Compounds 1, 3, and 65 bear just a proton as the sub-
stituent. Among these three products, Table 1 shows that 3 has
excellent permeability (Papp), whereas 65 with a lower
pK (5.7) has a moderate permeability, and 1 is poorly permeable
a
(
pK 3.1). But they have quite similar profiles in terms of
a
a
solubility, plasma protein binding (PPB), and in vitro meta-
bolic stability (Cl ). Interestingly, when one nitrogen is
substituted, Table 1 showed large differences in many DMPK
properties.
Conditions: (i), (ii), (iii) same as in Scheme 3; (iv) 1.25 N HCl
solution in MeOH (6 equiv), 5 min, −10 °C, then warmed up to rt in
1
int
6 h, followed by 10 h of stirring at rt.
In general, the results of the substituted products in Table 1
indicate that, with the same substitutents:
DMPK
■
With all products in hand, including three reference products in
cluster A (Figure 1, compound 1, R = H; compound 82, R = Et,
and compound 83, R = Bn), herein we report physicochemical
and in vitro drug metabolism and pharmacokinetic data on
• for clogP, compounds in cluster B have the highest values;
• for pK (acidity), the compounds in cluster D are slightly
a
acidic, and pK values range from 4.1 to 6.9;
a
• for logD, compounds in cluster D have the lowest logD;
C
DOI: 10.1021/acsmedchemlett.7b00137
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ACS Medicinal Chemistry Letters
Letter
Table 1. In Vitro Physicochemical and Pharmacokinetic Properties of Selected Compounds
a
b
c
d
e
Determined by UV. Experimental logD. Dried DMSO solubility. Human plasma protein binding fraction unbound (fu%). Metabolic stability in
f
g
human liver microsomes. Apparent permeability coefficients (P ) across Caco-2 cell monolayers. The effects in percentage on ion channels by
single shot IonWorks assay; test concentration: 11 μM. Determined by potentiometric titration. Not available or not determined.
app
h
i
Table 2. In Vitro Physiochemical and Pharmacokinetic Properties of 67a, 67b
a−fSame as in Table 1.
•
for solubility, compounds in cluster A have poor solubility.
Compounds in clusters C and D are rather soluble. This
significance may be due to H-bonding between an aza
product and the solvent;
for human plasma protein binding unbound fraction,
compounds in cluster B have in general a higher unbound
fraction;
for in vitro metabolic stability in human liver microsomes, a
cluster D compound tends to have improved metabolic
stability than its analogues in clusters B and C;
for intrinsic intestinal Caco-2 permeability, although
compounds in cluster D generally have lower permeability
than the isomers in cluster C, they still exhibit moderate to
excellent permeability;
for hERG inhibition, despite different substituents in the
tested compounds, the single shot results indicated that
the hERG inhibition is usually <25%, and most of the
compounds have very low or no significant inhibition
(negative values).
Compounds 67a and 67b are diastereomeric pairs. The
differences of the physiochemical and in vitro pharmacokinetic
properties between these two compounds are shown in Table 2.
•
•
•
The results indicate that the diastereomers have similar pK and
a
Clint values. But they have different profiles, such as logD,
unbound PPB, and solubility.
OUTLOOK
■
We intend to apply the chemistry of clusters C and D in
medicinal chemistry programs, such as fragment-based hit
finding. The wide range of commercially available starting
materials that could be used means that our chemistry should
•
32
find easy applictions. Furthermore, it is also possible to install
one more variation on the imidic or amidic nitrogen atom. We
expect that structures with three possiblevariations (R, R′, and R″)
D
DOI: 10.1021/acsmedchemlett.7b00137
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(4) Reddy, Y. D.; Reddy, C. V. R.; Dubey, P. K. Green approach for
drug design and discovery of paracetamol analogues as potential
analgesic and antipyretic agents. Green Chem. Lett. Rev. 2014, 7 (1), 24−
3
1.
(5) Lai, L.; Liu, Y.; He, C.; Wu, Y.; He, S.; Shang, E. Benzoisothiazole
compounds as 5-LOX and mPGES-1 inhibitors and their preparation,
pharmaceutical compositions and use in the treatment of inflammations.
CN 103254151, Aug. 21, 2013.
(6) Toure, B. B.; Miller-Moslin, K.; Yusuff, N.; Perez, L.; Dore, M.;
Joud, C.; Michael, W.; DiPietro, L.; van der Plas, S.; McEwan, M.;
Lenoir, F.; Hoe, M.; Karki, R.; Springer, C.; Sullivan, J.; Levine, K.;
Fiorilla, C.; Xie, X. L.; Kulathila, R.; Herlihy, K.; Porter, D.; Visser, M.
The Role of the Acidity of N-Heteroaryl Sulfonamides as Inhibitors of
Bcl-2 Family Protein-Protein Interactions. ACS Med. Chem. Lett. 2013, 4
Figure 3. Further derivatization possibilities.
as shown in Figure 3 will expand the application beyond
conventional areas in which a saccharin scaffold has been applied
in medicinal chemistry and other fields.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acsmedchemlett.7b00137.
■
*
S
(
2), 186−190.
(
7) Elsayed, M. S.; El-Araby, M. E.; Serya, R. A.; El-Khatib, A. H.;
Linscheid, M. W.; Abouzid, K. A. Structure-based design and synthesis
of novel pseudosaccharine derivatives as antiproliferative agents and
kinase inhibitors. Eur. J. Med. Chem. 2013, 61, 122−31.
Synthetic procedures, NMR study of 75a and 75b,
computational chemistry, NMR spectra (pdf); X-ray
data for 68a and 68b (PDF)
(8) Stoss, P.; Satzinger, G. Cyclic sulfoximides. IV. 3-Imino-3H-1λ4,2-
benzisothiazole 1-oxides. Chem. Ber. 1975, 108 (12), 3855−63.
(
̈
9) Lucking, U. Sulfoximines: A Neglected Opportunity in Medicinal
AUTHOR INFORMATION
Corresponding Author
E-mail: yantao.chen@astrazeneca.com.
■
Chemistry. Angew. Chem., Int. Ed. 2013, 52, 9399−9408.
(10) Frings, M.; Bolm, C.; Blum, A.; Gnamm, C. Sulfoximines from a
*
Medicinal Chemist’s Perspective: Physicochemical and in vitro
Parameters Relevant for Drug Discovery. Eur. J. Med. Chem. 2017,
ORCID
1
(
26, 225−245.
11) Worch, C.; Bolm, C. Use of Prolyl Sulfonimidamides in Solvent-
Free Organocatalytic Asymmetric Aldol Reactions. Synlett 2009, 15,
425−2428.
12) Steurer, M.; Bolm, C. Synthesis of amino-functionalized
sulfonimidamides and their application in the enantioselective Henry
reaction. J. Org. Chem. 2010, 75 (10), 3301−10.
Yantao Chen: 0000-0001-5364-8263
Martin A. Hayes: 0000-0002-2640-8464
Author Contributions
2
(
Y.C. conceived the project, Y.C. designed the experiments, Y.C.
and C.-J.A. performed the synthetic experiments, C.-J.A.
measured melting points for novel solids. A.P. contributed the
crystal structure determination and elucidation, M.L. contributed
the computational study, R.L. contributed to NMR analysis,
M.H. contributed the DMPK characterization, A.J., H.L., and
L.T. contributed chiral separation.
(13) Patureau, F. W.; Worch, C.; Siegler, M. A.; Spek, A. L.; Bolm, C.;
Reek, J. N. H. SIAPhos: Phosphorylated Sulfonimidamides and their
Use in Iridium-Catalyzed Asymmetric Hydrogenations of Sterically
Hindered Cyclic Enamides. Adv. Synth. Catal. 2012, 354 (1), 59−64.
(14) Pemberton, N.; Graden, H.; Evertsson, E.; Bratt, E.; Lepisto, M.;
Notes
Johannesson, P.; Svensson, P. H. Synthesis and functionalization of
cyclic sulfonimidamides: a novel chiral heterocyclic carboxylic Acid
bioisostere. ACS Med. Chem. Lett. 2012, 3 (7), 574−8.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(15) Sehgelmeble, F.; Janson, J.; Ray, C.; Rosqvist, S.; Gustavsson, S.;
Nilsson, L. I.; Minidis, A.; Holenz, J.; Rotticci, D.; Lundkvist, J.;
Arvidsson, P. I. Sulfonimidamides as sulfonamides bioisosteres: rational
evaluation through synthetic, in vitro, and in vivo studies with gamma-
secretase inhibitors. ChemMedChem 2012, 7 (3), 396−9.
The authors thank Mark E. Light at University of Southampton
for the support of crystal structure examination and elucidation.
The authors thank Siavash Tavakoli, Jan Holmgren, Martin L
Svensson, Linda Fredlund, Nikola Sarnowska, Johan Hulthe,
Claire Landqvist, Ia Hultman, Linette L Ruston, Ann Woods,
(16) Borhade, S. R.; Svensson, R.; Brandt, P.; Artursson, P.; Arvidsson,
P. I.; Sandstrom, A. Preclinical characterization of acyl sulfonimida-
mides: potential carboxylic acid bioisosteres with tunable properties.
ChemMedChem 2015, 10 (3), 455−60.
̊
Johanna Malm, Martina Furasen, Dan Addison, and Sunil Sarda
for the generation of screening data.
(17) Lassalas, P.; Gay, B.; Lasfargeas, C.; James, M. J.; Tran, V.;
ABBREVIATIONS
■
Vijayendran, K. G.; Brunden, K. R.; Kozlowski, M. C.; Thomas, C. J.;
Smith, A. B., 3rd; Huryn, D. M.; Ballatore, C. Structure Property
Relationships of Carboxylic Acid Isosteres. J. Med. Chem. 2016, 59 (7),
3183−203.
(18) Chinthakindi, P. K.; Naicker, T.; Thota, N.; Govender, T.; Kruger,
H. G.; Arvidsson, P. I. Gaining Momentum: Sulfonimidamides in
Medicinal- and Agrochemistry. Angew. Chem., Int. Ed. 2017, 56, 4100−9.
(19) Ballatore, C.; Huryn, D. M.; Smith, A. B., 3rd Carboxylic acid
(bio)isosteres in drug design. ChemMedChem 2013, 8 (3), 385−95.
(20) Chen, Y.; Gibson, J. A convenient synthetic route to
sulfonimidamides from sulfonamides. RSC Adv. 2015, 5 (6), 4171−
4174.
CCDC, Cambridge Crystallographic Data Centre; DCM,
dichloromethane; FA, formic acid; MeCN, acetonitrile; rt,
room temperature; TBS, tert-butyldimethylsilyl; TEA, triethyl-
amine
REFERENCES
■
(
1) Ivanova, J.; Leitans, J.; Tanc, M.; Kazaks, A.; Zalubovskis, R.;
Supuran, C. T.; Tars, K. X-ray crystallography-promoted drug design of
carbonic anhydrase inhibitors. Chem. Commun. (Cambridge, U. K.) 2015,
5
(
1 (33), 7108−7111.
2) Mahon, B. P.; Hendon, A. M.; Driscoll, J. M.; Rankin, G. M.;
Poulsen, S. A.; Supuran, C. T.; McKenna, R. Saccharin: a lead compound
for structure-based drug design of carbonic anhydrase IX inhibitors.
Bioorg. Med. Chem. 2015, 23 (4), 849−54.
(21) Differding, E.; Lang, R. W. New fluorinating reagents. Part II.
Preparation and Synthetic Application of a Saccharin DerivedN-
Fluorosultam. Helv. Chim. Acta 1989, 72 (6), 1248−1252.
(22) Kim, S. H.; Tran, M. T.; Ruebsam, F.; Xiang, A. X.; Ayida, B.;
McGuire, H.; Ellis, D.; Blazel, J.; Tran, C. V.; Murphy, D. E.; Webber, S.
E.; Zhou, Y.; Shah, A. M.; Tsan, M.; Showalter, R. E.; Patel, R.; Gobbi, A.;
(
3) Csakai, A.; Smith, C.; Davis, E.; Martinko, A.; Coulup, S.; Yin, H.
Saccharin derivatives as inhibitors of interferon-mediated inflammation.
J. Med. Chem. 2014, 57 (12), 5348−55.
E
DOI: 10.1021/acsmedchemlett.7b00137
ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX

ACS Medicinal Chemistry Letters
Letter
LeBrun, L. A.; Bartkowski, D. M.; Nolan, T. G.; Norris, D. A.; Sergeeva,
M. V.; Kirkovsky, L.; Zhao, Q.; Han, Q.; Kissinger, C. R. Structure-based
design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and
benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of
hepatitis C virus NS5B polymerase. Bioorg. Med. Chem. Lett. 2008, 18
(
14), 4181−5.
(
23) Davis, F. A.; Towson, J. C.; Vashi, D. B.; Thimmareddy, R.;
Mccauley, J. P.; Harakal, M. E.; Gosciniak, D. J. Chemistry of
Oxaziridines 0.13. Synthesis, Reactions, and Properties of 3-Substituted
1
1
(
,2-Benzisothiazole 1,1-Dioxide Oxides. J. Org. Chem. 1990, 55 (4),
254−1261.
24) Bulman Page, P.; Bethell, D.; Stocks, P.; Heer, J.; Graham, A.;
Vahedi, H.; Healy, M.; Collington, E.; Andrews, D. Sulfur Oxidation
Mediated by Imine Derivatives. Synlett 1997, 12, 1355−1358.
(
25) Almeida, R.; Gomez-Zavaglia, A.; Kaczor, A.; Ismael, A.;
Cristiano, M. L. S.; Fausto, R. Matrix-isolation FTIR, theoretical
structural analysis and reactivity of amino-saccharins: N-(1,1-dioxo-1,2-
benzisothiazol-3-yl)-N-methyl amine and -N,N-dimethyl amine. J. Mol.
Struct. 2009, 938 (1−3), 198−206.
(
26) Brigas, A. F.; Clegg, W.; Dillon, C. J.; Fonseca, C. F. C.; Johnstone,
R. A. W. Metal-assisted reactions. Part 29. Structure and hydrogenolysis
of C-N bonds in derivatives of aromatic amines. Bond length and
electronegativity changes from X-ray crystallographic data. J. Chem. Soc.,
Perkin Trans. 2 2001, No. 8, 1315−1324.
(
27) Gross, W.; Nemitz, R.; Kroos, A. Saccharin derivatives as
bleaching activators for cosmetic hair preparations. DE 102010043497,
Sep. 22, 2011.
(
28) Rode, H. B.; Sprang, T.; Besch, A.; Loose, J.; Otto, H. H.
Pseudosaccharin amine derivatives: synthesis and elastase inhibitory
activity. Pharmazie 2006, 60 (10), 723−31.
(
29) Fonseca, C. Metal-Assisted Reactions, Part 32. Crystal Structure
and Reactivity of 3-Benzylamino-1,2-Benzisothiazole 1,1-Dioxide. Catal.
Lett. 2009, 130 (3−4), 608−612.
(
30) Salman, S. R.; Subber, A. K.; Hussein, F. A.; Shubber, S. K.
Synthesis and spectroscopic properties of some new substituted
saccharin anils. J. Chem. Eng. Data 1987, 32 (3), 391−393.
(
31) Lemurell, M.; Ulander, J.; Winiwarter, S.; Dahlen, A.; Davidsson,
O.; Emtenas, H.; Broddefalk, J.; Swanson, M.; Hovdal, D.; Plowright, A.
T.; Pettersen, A.; Ryden-Landergren, M.; Barlind, J.; Llinas, A.; Herslof,
M.; Drmota, T.; Sigfridsson, K.; Moses, S.; Whatling, C. Discovery of
AZD6642, an inhibitor of 5-lipoxygenase activating protein (FLAP) for
the treatment of inflammatory diseases. J. Med. Chem. 2015, 58 (2),
8
(
97−911.
32) Proudfoot, J. R.; Patel, U. R.; Dyatkin, A. B. Synthesis of 7-
substituted saccharins and 8-substituted oxicams, and a novel saccharin
to oxicam transformation. J. Org. Chem. 1997, 62 (6), 1851−1853.
F
DOI: 10.1021/acsmedchemlett.7b00137
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