Sulfoximines from a Medicinal Chemist's Perspective: Physicochemical and in vitro Parameters Relevant for Drug Discovery

Article abstract of DOI:10.1016/j.ejmech.2016.09.091

Sulfoximines, sulfondiimides and sulfonimidamides are fascinating but not yet fully explored variants of the common sulfone or sulfonamide motif. In this study, we report the physicochemical and in vitro properties of sulfoximines and compare them with related analogs and isosteres. Furthermore, we present a matched molecular pair analysis of compounds from drug discovery projects within Boehringer Ingelheim. We demonstrate that the sulfoximine moiety is a chemically stable, comparatively polar and weakly basic functional group, often leading to favorable aqueous solubility, permeability and metabolic stability. Moreover, their additional vectors at nitrogen enable simple chemical modifications and thus facilitate exploration and fine-tuning of the molecular properties. We conclude that sulfoximines and their congeners do not exhibit any intrinsic flaw but significantly enrich the toolbox of medicinal chemists.

Full text of DOI:10.1016/j.ejmech.2016.09.091

Accepted Manuscript
Sulfoximines from a medicinal Chemist's perspective: Physicochemical and in vitro
parameters relevant for drug discovery
Marcus Frings, Carsten Bolm, Andreas Blum, Christian Gnamm
PII:
S0223-5234(16)30853-4
10.1016/j.ejmech.2016.09.091
EJMECH 8957
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 12 August 2016
Revised Date: 27 September 2016
Accepted Date: 28 September 2016
Please cite this article as: M. Frings, C. Bolm, A. Blum, C. Gnamm, Sulfoximines from a medicinal
Chemist's perspective: Physicochemical and in vitro parameters relevant for drug discovery, European
Journal of Medicinal Chemistry (2016), doi: 10.1016/j.ejmech.2016.09.091.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Sulfoximines from a Medicinal Chemist’s
Perspective: Physicochemical and in vitro
Parameters Relevant for Drug Discovery
a
a
b‡
b‡
Marcus Frings, Carsten Bolm, Andreas Blum and Christian Gnamm *
Author information
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen,
Germany
b
Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach an
der Riß, Germany
Corresponding Author
*
E-Mail: christian.gnamm@boehringer-ingelheim.com. Phone: (+49)7351-98297. Fax:
(+49)7351-545181.
1
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KEYWORDS
Synthesis, Sulfoximines, Sulfondiimides, Sulfonimidamides, Metabolic stability, Permeability,
Solubility.
1
. Introduction
Until recently, sulfoximines remained a rather unrecognized class of compounds despite the
fact that their discovery dates back to the early 1950s. [1] We realized that even experienced
chemists are surprised to learn of the high chemical stability of the sulfonimidoyl moiety, [2,3]
and many have never considered applying such compounds in their own research programs.
Although one particular compound, namely buthionine sulfoximine [4,5] (BSO, 1) has over
6
,200 SciFinder entries, [6] its recognition in the chemical community remained rather low. A
small number of other sulfoximines such as compounds 2, [7] 3, [8] 4, [9] 5, [10] 6, [11] and 7
12] were published as bioactive agents by various companies and researchers (Figure 1), but to
date no sulfoximine has been approved for a therapeutic application. [13]
[
O
S
NH
O
O
O
O
S
HN
O
S
-
O
O
Cl
CO H
2
N
S
NEt2
N
NH2
(HOCH ) CNH
2 3 3
+
N
N
N
BSO (1)
Suloxifen (2)
Gödecke)
Gö 4962 (3)
(Gödecke)
RU 31156 (Sudexanox, 4)
(
(Roussel Uclaf)
N
N
O
S
Ph
Ph
O
H
HO
O
S
NH
OH
N
CF
N
3
MeO
MeO
H
H
N
HCl
N
N
N
N
N
H
O
N
O
S
O
N
O
HIV-1 protease inhibitor 5
PYK2 inhibitor 6
α-Adrenergic receptor blocker 7
(
Pfizer)
(Eli Lilly)
2
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Figure 1. Bioactive sulfoximines – early discoveries.
About a decade ago, the interest in sulfoximines began to grow along with intensified research
activities in crop science and studies in the pharmaceutical industry. In 2005 Dow AgroSciences
reported N-cyano sulfoximine 8 (Sulfoxaflor) as a new insecticide, [14 ] which was later
approved for field applications in several countries. [15] Around the same time, Bayer Pharma
(formerly Schering) began developing pan-CDK inhibitor BAY 1000394 (9), [16] which has
entered clinical trials. More recently, other sulfoximines with potential medical applications have
been made public, such as Amgen’s GKRP disruptor 10, [17] Astra Zeneca’s ATR inhibitor 11,
[
18] and the MNK inhibitor 12 [19] and human neutrophile elastase inhibitor 13, [20] both
disclosed by Boehringer Ingelheim.
N
H
O
O
N
CF3
OH
O
S
N
N
S
NH
N
CF3
S
O
N
O
N
N
F C
N
3
S
H N
CH3
2
NH
O
1
0
Sulfoxaflor (
Dow AgroSciences)
8
)
BAY 1000394 (9)
(Bayer Pharma)
(
Amgen)
(
O
O
O
MeO
O
N
H
N
S
N
N
N
S
N O
O
O
H
O
NH
N
NH
N
S
N
N
N
F
CF3
AZD6378 (11)
Astra Zeneca)
12
(Boehringer Ingelheim)
13
(
(Boehringer Ingelheim)
Figure 2. Bioactive sulfoximines - recent discoveries.
In addition to sulfoximines, other sulfur-containing compounds with related core structures
such as sulfonimidamides [21] and sulfondiimides [22] have also recently garnered increased
attention (Figure 3).
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O
NH
R'
O
NR'
R''N NR'''
S
S
S
R
R
NR''R'''
R
R'
sulfoximines
sulfonimidamides
sulfondiimides
Figure 3. General scaffolds of sulfoximines and their congeners: sulfonimidamides and
sulfondiimides.
Although there is an increasing interest in sulfoximines and their chemistry, we felt that the
routine application of sulfoximines in drug discovery projects is still hampered by synthetic
considerations or uncertainty about their chemical stability, and also due to limited experience
about their physicochemical and in vitro parameters. Although a few scattered data can be found
in the literature, [21c,23] a comprehensive picture is still missing.
We sought to analyze from a medicinal chemist’s perspective whether sulfoximines and
related molecules implicate any principal flaws or if it could be recommended to employ them
systematically in drug discovery projects like any other functional group. In this study, we report
the physicochemical and in vitro properties of selected custom-made sulfoximines and compare
them with related analogs and isosteres. Furthermore, we present an analysis of compounds from
drug discovery projects within Boehringer Ingelheim.
2
2
. Results and discussion
.1 Selection, design and synthesis of matric compounds 15
At the outset of our studies, we defined a matrix of N-arylated sulfoximines 15 which could be
synthesized from the NH- (“free”) sulfoximines and arylboronic acids by Chan-Lam coupling
reactions (Scheme 1). [24] For the sulfoximine cores 15A-M, aliphatic residues covering a range
4
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of lipophilicity (15A-E), cyclic sulfoximines (15F-J) and derivatives with (hetero)aromatic
residues (15K-M) were selected. For the N-aryl group both neutral (a), electron rich (b) and
electron poor (c-g) aromatics as well as heteroaromatic moieties (h-j) were chosen. From this
matrix of 130 possible compounds 15Aa to 15Mj a total of 94 sulfoximines could be prepared in
satisfactory yields, utilizing the aforementioned method (for details see the Supporting
Information). With the exception of (R)-15Ke and (S)-15Ke, all chiral sulfoximines were used as
racemates.
O
NH
O N Ar
Cu(OAc) (0.1 equiv),
2
1
S
2
+
Ar B(OH)
2
1
S
2
R
R
DMF, 3 d, RT
R
R
15
9
4 examples
Variations of sulfoximine core structure 15A-M
O
S
O
S
O
S
O
S
O
O
S
O
S
N
5A
N
N
N
N
O
S
N
N
N
Ar
Ar
Ar
Ar
Ar
Ar
Ar
1
15B
15C
15D
15E
15F
15G
O
S
O
O
S
O
N
O
O
S
N
N
S
N
S
N
N
S N
Ar
Ar
Ar
Ar
Ar
Ar
O
N
H
15H
15I
15J
15K
15L
15M
Variations of the N-aryl substituent Ar
Cl
N
N N
F C
CF3
N
3
OMe
F
CN
CF3
a
b
c
d
e
f
g
h
i
j
Scheme 1. Initial matrix of sulfoximines 15 (rectangles emphasize the structural elements of the
subsequent template compounds 15Ae and 15He; see text for further explanation).
All synthesized compounds 15 were tested for metabolic stability in human liver microsomes
and aqueous solubility (high-throughput HPLC assay, data not shown). The N-[4-(trifluoro-
5
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methyl)phenyl]sulfoximines 15Ae and 15He were picked as reference structures, as they
exhibited suitable intermediate values allowing for the observation of trends in subsequent
measurements of analogs. To broaden the scope of our study, we intended not only to explore the
properties of the sulfoximines 15, but also to compare their properties with those of isosteres and
further analogs bearing more common structural elements. To this end, the selected sulfoximines
1
5Ae and 15He served as templates for the design of series 16 comprising of various isosteres
and of closely related analogs (Chart 1). The depicted spectrum of compounds covers not only
structural motifs commonly found in small molecule drugs, such as carboxamides, sulfoxides,
sulfones, sulfonates and sulfonamides (16a-16g), but also less common ones such as
sulfondiimides (16h, 16i), sulfonimidamides (16j-16l), sulfilimines (16o, 16q) and sulfoximines
(16m, 16n). Since series 16 is mainly focused on 4-(trifluoromethyl)phenyl as the nitrogen
substituent, a related series was designed in which the 4-(trifluoromethyl)phenyl group is
attached to sulfur. Thus, sulfoximine 17c served as template for the respective isosteres and
analogs 17 (Chart 2). Additionally, sulfoximines 18d and 19d with a N-aroyl or a N-carbamoyl
motif, respectively, served as reference structures for series of isosteres and analogs 18 and 19
(Chart 3).
Chart 1. Sulfoximines 15Ae and 15He together with isosteres and analogous compounds 16a-
6q (reference structures are highlighted).
1
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CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
N
HN
N
O
HN
N
S
S
S
S
S
S
O
O
O
O
O O
O O
O O
O O
15Ae
16a
16b
CF3
16c
16d
16e
16f
16g
CF3
CF3
CF3
CF3
CF3
CF3
N
N
N
N
N
S
N
HN
S
S
S
S
S
S
HN
O NH2
O
N
O
N
O
O
H
1
6h
16j
16k
16l
16m
16o
16p
CF3
CF3
CF3
CF3
N
O
N
NH
N
O
N
S
S
S
S
15He
16i
16n
16q
Chart 2. Sulfoximine 17c together with isosteres and analogous compounds 17a-17n (reference
structures are highlighted).
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
H
S
O
S
O
S
O
S
N
O
S
N
O
S
N
O
S
N
N
O
S
N
N
O
H
O
NH
NH
17a
17b
17c
17d
17e
17f
17g
17h
CF3
CF3
CF3
CF3
CF3
CF3
H
O
S
NH2
O
S
N
O
S
N
O
NH2
7i
O
N
O
N
H
O
O
O
1
17
17
17l
17m
17n
Chart 3. Sulfoximines 18d and 19d together with isosteres and analogous compounds 18a-18e
and 19a-19e (reference structures are highlighted).
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CF3
CF3
CF3
CF3
CF3
O
O
O
NH
O
NH
O
N
O
N
S
S
S
O
O
HN
O
1
8a
18b
CF3
18c
CF3
18d
18e
CF3
CF3
CF3
HN
O
HN
HN
O
HN
HN
O
HN
O
HN
O
O
O
NH
O
N
N
O
S
S
S
19a
19b
19c
19d
19e
2
2
.2 Chemistry
.2.1 General synthetic routes
Whilst some of the abovementioned molecules were available from commercial suppliers
25a] or accessible using standard chemistry, [25b] the majority of the envisaged compounds and
[
their synthetic precursors were unprecedented and thus required facile access. Most of them
could be synthesized following established routes, which are schematically depicted in Schemes
2
and 3.
Typically, the synthesis of sulfoximines starts by oxidation of commercially available or easily
accessible sulfides I and subsequent imination of the resulting sulfoxides II (Scheme 2). [26]
3
While Rhodium-catalyzed iminations usually result in N-protected sulfoximines V (R =
protecting group) which are then deprotected, [27] iminations using in situ generated hydrazoic
acid, [28] activated reagents such as MSH [29] or DPH [30] or ammonium carbamate in the
3
presence of diacetoxyiodobenzene, [31] lead directly to the free sulfoximines IV (R = H).
8
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3
N-Functionalized sulfoximines V (R ≠ H) can be prepared from the free NH-sulfoximines IV
3
(
R = H) by methods such as Cu-catalyzed arylations (Scheme 1), nucleophilic substitutions or
3
reductive alkylations (see next section). Alternatively, sulfoximines V (R ≠ H) can also be
obtained by oxidation of sulfilimines III, [32] which are accessible by imination of sulfides I or
transformation of sulfoxides II. [33] Sulfondiimides VI can be synthesized by imination of
sulfides I [34] or sulfilimines III. [22a]
O
oxidation
imination
1
S
2
R
R
II
3
O
N
R
1
S
2
transformation
R
R
1
S
2
R
R
I
3
R
3
N
S
IV (R = H)
N-deprotection /
N-functionalization
imination
1
2
oxidation
3
R
R
V (R = H)
III
imination
3
4
R
N N
R
imination
1
S
2
R
R
VI
Scheme 2. General synthetic routes for the preparation of sulfoximines IV/V and sulfondiimides
VI.
As opposed to sulfoximines or sulfondiimides, the synthesis of sulfonimidamides often
requires more steps, as the necessary sulfinamide precursors are usually not commercially
available (Scheme 3). Hence, the sulfinamides XII have to be prepared from sulfinic acids IX,
sulfinyl chlorides X or sulfinate esters XI, which themselves are accessible from more readily
3
5
available starting materials such as disulfides VII or sulfonyl chlorides VIII. [
]
Sulfonimidamides XV are typically prepared by oxidative chlorination of the parent sulfinamides
XII and subsequent reaction of the intermediate sulfonimidoyl chlorides XIII with amines
(Scheme 3). [21,36] Alternatively, the usually unstable sulfonimidoyl chlorides XIII can be
9
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converted into the more stable sulfonimidoyl fluorides XIV which are easier to handle and less
susceptible to reduction, e.g. by hydrazine nucleophiles. [37] Recently some of us reported that
sulfonimidamides XV can also be prepared directly from NH-sulfoximines IV. [38]
1
1
S
R
R
S
VII
reduction
2
O
S
O N
R
O
S
H NR2
2
O
Cl
3
4
2
HNR R
4
2
1
S
R
1
R
R
1
R
N
1
S
R
N
nucleophilic
substitution
oxidative
chlorination
R
N
nucleophilic
substitution
R
X
H
3
R
oxidation
IX (X = OH)
X (X = Cl)
XI (X = OR)
XII
XIII
XV
halogen-
exchange
nucleophilic
substitution
O
O
1
S
R
Cl
VIII
O
F
2
1
S
R
R
N
XIV
Scheme 3. General synthetic routes for the preparation of sulfonimidamides XV.
2
.2.2 Synthesis of derivatives 16-19
To illustrate the abovementioned general synthetic routes, some of the syntheses that were
carried out will be described below. For example, sulfoxide 17a was prepared from sulfide 21
[39] by oxidation with m-CPBA or on larger scale using in situ prepared peracetic acid (Scheme
4
). Mild imination under rhodium catalysis furnished N-trifluoroacetyl sulfoximine 22 which
could readily be deprotected to give the desired NH-sulfoximine 17c. [27] Alternatively, the
latter compound could be prepared in one step on gram scale by imination of 22 with in situ
generated hydrazoic acid. [28b] Methylation of sulfoximine 17c was accomplished under
Eschweiler-Clarke conditions to give target compound 17d. [40] For the synthesis of cyclic
sulfoximine 17e, a ring closure by intramolecular nucleophilic substitution of tosylate 24 was
envisaged. To this end, sulfoximine 17c was alkylated with 2-(3-chloropropoxy)tetrahydro-2H-
10 / 55

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pyran using KOH as base in DMSO at room temperature. [22d,41] Removal of the THP
protecting group under acidic conditions and tosylation of the resulting alcohol delivered
substrate 24, which was now ready to be cyclized in the next step. While deprotonation of 24
with Schlosser’s base under reported conditions [41] led only to incomplete ring closure,
employing n-butyllithium afforded the desired 1,2-thiazine-1-oxide 17e in good yield.
CF3
O N
S
d
e
O
F3C
22
O
S
O NH
S
O N
S
Cl
S
a
b or c
f
g
F3C
F3C
F3C
F
C
F3C
3
20
21
17a
17c
17d
h,i
OTs
OH
N
S
O N
S
O N
S
O
k
j
F3C
F3C
F3C
17e
24
23
Scheme 4. Reagents and conditions: (a) NaSMe, DMF, 50 °C, 20 h (94%); (b) m-CPBA,
CH Cl , 0 °C, 2 h (94%); (c) H , AcOH, –5 °C to rt, 22 h (98%); (d) Rh (OAc) , PhI(OAc)
CF CONH , MgO, CH Cl , rt, 1.5 d (79%); (e) K CO , MeOH, rt, 1 h (quant.); (f) NaN , H SO ,
2
2
2
O
2
2
4
2
,
3
2
2
2
2
3
3
2
4
CHCl , –10 °C to 50 °C, 5 d (67%); (g) paraformaldehyde, formic acid, 130 °C, 4 d (75%); (h) 2-
3
(3-chloropropoxy)tetrahydro-2H-pyran, KOH, DMSO, rt, 11 h; (i) aq. HCl (90%, two steps); (j)
Et N, TsCl, CH Cl , 0 °C to rt, 14 h (78%); (k) n-BuLi, THF, –78 °C to rt, 45 h (58%).
3
2
2
For the synthesis of sulfoximine 16m, S,S-dimethylsulfoximine (25) was prepared firstly by
imination of DMSO (Scheme 5). [42] While reductive alkylations of NH-sulfoximines with
aldehydes and, in particular, ketones had proven challenging for a long time, we were delighted
to find that under adapted conditions [23,43] the reaction of sulfoximine 25 with 4-(trifluoro-
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methyl)cyclohexanone (26) proceeded smoothly and furnished the target compound 16m as a
single cis-stereoisomer in acceptable yield. [ 44 ] The imination of DMSO with
4
-(trifluoromethyl)aniline (27) failed when using either TFAA [33a] or sulfur trioxide-pyridine
complex, [45] but could successfully be achieved when switching to phosphorus pentoxide as
activator to give sulfilimine 16o. [33b]
O
CF3
a
O
S
NH
26
O
S
N
CF3
b
25
16m
O
S
CF3
CF3
N
S
H N
2
27
c
16o
Scheme 5. Reagents and conditions: (a) NaN
-(trifluoromethyl)cyclohexanone (26), NaBH(OAc)
methyl)aniline (27), P O , Et N, CHCl , 12 °C to rt, over night (56%).
3
, H
2
4 2 2
SO , CH Cl , 0 °C to 42 °C, 18 h (27%); (b)
4
3
, DCE, 42 °C, 43 h (42%); (c) 4-(trifluoro-
4
10
3
3
The synthesis of the cyclic representatives 16n and 16q started from tetrahydrothiopyran (28)
and is depicted in Scheme 6. Oxidation of 28 gave sulfoxide 29, which was then converted into
sulfilimine 16q and sulfoximine 16n, respectively, in analogous fashion as described before.
Once again, the reductive amination with cyclohexanone 26 delivered 16n as a single cis-
configured stereoisomer. [44] For the preparation of sulfondiimide 16i, thioether 28 was
iminated with MSH [29] to give sulfiliminium salt 31. Although extensive experimentation was
carried out, the following second imination under modified conditions [22a] with NCS and
aniline 27 remained troublesome and sulfondiimide 16i was isolated only in low yield. Since
12 / 55

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control reactions with unsubstituted aniline or 4-iodoaniline resulted in much higher yields, the
poor yield is likely due to the low nucleophilicity of 27.
CF3
N
S
d
16q
O
S
O
NH
O
N
CF3
S
S
a
e
b
c
2
9
30
16n
S
NH
+
S
2
O
HN
N
S
CF3
2
8
-
O
S
f
O
3
1
16i
Scheme 6. Reagents and conditions: (a) NaIO , MeOH/H O, –20 °C to rt, 6.5 h (94%); (b) MSH,
4
2
CH Cl , 0 °C, 20 min, then rt, 1.5 d, then aq. NaOH, rt, 1 h (81%); (c) 26, NaBH(OAc) , DCE,
2
2
3
4
0
2 °C, 40 h (45%); (d) 27, P O , Et N, CHCl , 0 °C to rt, over night (50%); (e) MSH, DCE,
4 10 3 3
°C to rt, 2.5 h (72%); (f) 27, NCS, Na CO , DMF, 0 °C to rt, over night (12%).
2
3
The synthesis of N-arylated derivatives 16g and 16h relied on palladium catalyzed arylation
chemistry (Scheme 7). Thus, commercially available methyl(methylsulfonyl)amine (32) and
S,S-dimethylsulfondiimide (33), which was prepared by double imination of dimethylsulfide
according to Haake’s procedure, [34] were arylated with appropriate aryl halides using palladium
catalysts to give the desired products 16g and 16h in acceptable yield. The solid state structure of
sulfondiimide 16h was confirmed by X-ray crystal structure analysis. [46]
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CF3
O O
S
a
O O
S
N
N
H
1
6g
32
b
HN NH
S
c
HN
N
CF3
S
S
33
16h
Scheme 7. Reagents and conditions: (a) 4-bromobenzotrifluoride, Pd dba , Xantphos, K PO ,
2
3
3
4
1
4
,4-dioxane, 100 °C, over night (36%); (b) t-BuOCl, MeCN, NH , –20 °C to rt, 48 h (30%); (c)
3
-iodobenzotrifluoride, Pd dba , JohnPhos, NaOt-Bu, 1,4-dioxane, 80 °C, 4 h (16%).
2
3
Exemplary syntheses of sulfonimidamides are depicted in Scheme 8. Methanesulfinyl chloride
34) was freshly prepared by oxidative chlorination of dimethyl disulfide and treated with aniline
7 to give sulfinamide 16p, which was found to be sensitive towards acidic conditions (traces of
(
2
acid in CDCl , decomposition on silica gel). While this compound could be handled as an
3
intermediate for further syntheses, its instability prevented any further physicochemical
characterization. Next, sulfinamide 16p was oxidized in situ with tert-butyl hypochlorite to the
sulfonimidoyl chloride (as in Scheme 3) which was not isolated but directly treated with aqueous
ammonia leading to sulfonimidamide 16j as the main product and sulfonamide 16f as a side
product. Furthermore, sulfinamide 16p was easily converted to the analogous N-methyl
sulfonimidamide 16k in the presence of NCS, methylamine and KOt-Bu. The corresponding
N,N-dimethyl derivative 16l was obtained by double alkylation of the unsubstituted
sulfonimidamide 16j with an excess of iodomethane and Cs CO .
2
3
14 / 55

ACCEPTED MANUSCRIPT
It was also planned to prepare cyclic sulfonimidamide 16r by double alkylation of intermediate
5 with 1,3-dibromopropane. However, the envisaged double deprotonation and alkylation of
3
Boc-protected compound 35 failed to furnish compound 36, but rather resulted in the isolation of
S-cyclobutyl derivative 37. Since further attempts with other protecting groups and different
alkylation conditions remained unsuccessful, the synthesis of target compound 16r was
abandoned.
CF3
N
O
S
1
2
2
NR R
e
d
1
1
6k: R = Me, R =H
6l: R , R = Me
1
2
1
S
S
a
CF3
CF3
CF3
Cl
b
c
S
HN
N
S
O
+
HN
Me
O
S
S
O
NH2
O O
3
4
16p
16j
16f
f
CF3
N
O
S
g
NHBoc
CF3
CF3
CF3
35
N
O
N
S
N
O
O
S
S
NBoc
NH
NHBoc
3
7
16r
3
6
Scheme 8. Reagents and conditions: (a) AcOH, SO Cl , –20 °C, over night, then 2 h, rt (79%);
2
2
(
b) 27, Et N, CH Cl , –10 °C to 0 °C, 3.5 h (84%); (c) t-BuOCl, aq. NH , THF, 0 °C to rt, 5 h
3 2 2 3
15 / 55

ACCEPTED MANUSCRIPT
2 2 3
(16j: 68%, 16f: 15%); (d) NCS, MeNH , KOt-Bu, MeCN, rt, over night (62%); (e) MeI, Cs CO ,
DMF, rt, 19 h (68%); (f) Boc O, Et N, DMAP, THF, rt, 18 h (66%); (g) n-BuLi, Br(CH ) Br,
2
3
2 3
THF, –78 °C to rt, over night (34%).
The synthesis of sulfonimidamide derivatives 17f-h is described in Scheme 9. For the
preparation of central sulfinamide 40, the known synthetic route by oxidative chlorination of
thiophenol acetate 38 to the sulfinyl chloride [47] and subsequent reaction with methylamine was
attempted first, but the desired product 40 could not be detected. [48] Following the protocol
reported by Harmata employing sulfonyl chloride 39 as starting material and PPh as reducing
3
agent, the preparation of the desired sulfinamide 40 proceeded smoothly, [ 49 ] and
sulfonimidamides 17f-h were prepared from this intermediate in serviceable yields. [50,51]
S
a
O
NH
S
O
c
F C
N
H
3
38
F C
3
17f
O
S
O
O
O
N
S
b
N
S
d
e
N
Cl
H
H
F C
3
F C
F C
3
3
17g
39
4
0
O
N
S
N
F C
3
17h
Scheme 9. Reagents and conditions: (a) SO Cl , Ac O, CH Cl , –20 °C to rt, then MeNH ,
2
2
2
2
2
2
CH Cl , 0 °C to rt (0%); (b) PPh , MeNH , Et N, CH Cl , 0 °C to rt, 1 h (35%); (c) t-BuOCl,
2
2
3
2
3
2
2
NH , MeCN, 30 min, 0 °C to rt (13%); (d) t-BuOCl, MeNH , MeCN, 30 min, 0 °C to rt (45%);
3
2
2
(e) t-BuOCl, Me NH, MeCN, 30 min, 0 °C to rt (72%).
16 / 55

ACCEPTED MANUSCRIPT
The synthesis of the acylated derivatives 18 was straightforward and relied on established
methods such as sulfonylation (18c) or acylations (18d, 18e) (Scheme 10). The structure of
benzoylated sulfondiimide 18e was determined by X-ray structure analysis. [46] For the
synthesis of urea derivatives 19, isocyanate 42 was treated with the appropriate nucleophiles,
which provided the desired compounds in low (19c) to good yields (19d and 19e).
O
O O
S
O
a
N
NH2
H
F C
3
F3C
17i
18c
O
S
N
S
O
b
c
F3C
1
8d
O
OH
O
F3C
N
NH
41
F3C
18e
H
N
H
N
S
d
O O
O
F3C
19c
NCO
H
N
N
O
e
f
S
F3C
O
F3C
42
19d
H
N
N
NH
S
O
F3C
19e
Scheme 10. Reagents and conditions: (a) NaH, MeSO Cl, THF, 2 h, rt (30%); (b) 25, HATU,
2
DIPEA, DMF, over night, rt (61%); (c) 33, HATU, DIPEA, DMF, over night, rt (38%); (d)
17 / 55

ACCEPTED MANUSCRIPT
MeSO
2
NH
2
, aq. NaOH (1
M
), acetone, reflux, 3 h (7%); (e) 25, DIPEA, 1,4-dioxane, over night,
rt (96%); (f) 33, DIPEA, 1,4-dioxane, over night, rt (73%).
2
.3 Analysis of physicochemical and in vitro properties
2.3.1 Physicochemical and in vitro properties for matrix compounds 15
For a subset of the obtained 94 matrix compounds 15, basic physicochemical and in vitro
pharmacokinetic parameters such as lipophilicity (logP), [ 52 ] stability in human liver
microsomes, aqueous solubility (high-throughput HPLC assay) [53] and permeability (PAMPA)
were measured (Table 1). For selected compounds, the dissociation constant (pK
a b
/pK ) and
aqueous solubility from solid material (shake flask assay) were also determined. [53]
a
Table 1. Physicochemical and in vitro pharmacokinetic parameters of selected compounds.
Stability in
pK /pKb human liver
Aqueous
Solubility
[µg/mL] [53]
Permeability
(PAMPA)
Papp [10 cm/s]
logP
52]
Entry Compound
Structure
a
[
-6
microsomes
Shake
flask
assay
T
min]
½
HPLC-
Assay
%
QH
[
O
N
S
1
2
3
4
5
15Ha
15Hb
15Hc
15Hd
15He
–0.1
–0.1
0.7
n.d.
n.d.
n.d.
n.d.
n.d.
>130 <23
>130 <23
37
n.d.
900
9.5
9.1
9.5
7.9
7.7
O
N
O
S
>51
>46
45
O
N
F
S
120
25
>1,000
n.d.
O
N
CN
CF3
S
1.1
>130 <23
O
N
S
2.8
46
6
46
87
51
70
CF3
O
N
6
15Hf
S
4.0
n.d.
<1
n.d.
3.3
CF3
18 / 55

ACCEPTED MANUSCRIPT
Cl
O
O
O
N
N
N
7
15Hg
S
S
S
2.0
n.d.
28
8
58
82
>50
500
12.0
N
b
b
8
9
15Hh
15Hi
15Hj
–2.7
–2.6
–3.9
pK
b
4.8
>75
42
n.d.
n.d.
n.d.
5.8
5.7
3.2
N
pK
b
7.2
>130 <23
>130 <23
N
N
O
S
N
1
0
n.d.
no
39
O
N
S
CF3
1
1
1
2
15Ae
15Be
1.4
2.0
c
>130 <23
>130 <23
>50
>51
900
n.d.
8.2
7.7
pK
a
/pK
b
O
S
N
CF3
n.d.
O
S
N
CF3
CF3
CF3
d
d
d
1
1
3
4
15Ce
15De
3.1
2.3
n.d.
n.d.
-
-
22
40
n.d.
n.d.
-
O
N
S
>130 <23
>130 <23
>130 <23
7.8
9.6
O
N
S
1
5
15Ee
2.5
n.d.
46
n.d.
O
O
N
CF
3
1
1
6
7
15Fe
15Ge
S
2.5
2.4
n.d.
n.d.
48
50
n.d.
9.6
8.7
O
S
N
CF3
CF3
110
26
6,000
O
N
S
1
1
8
9
15Ie
15Je
2.7
0.9
n.d.
>130 <23
>57
>57
300
8.0
8.3
O
O
N
CF3
S
e
pK
5.2
110
25
2,300
b
N
H
O
N
CF3
S
2
2
2
0
1
2
(R)-15Ke
(S)-15Ke
15Le
3.7
3.7
2.5
n.d.
>130 <23
>130 <23
>130 <23
20
17
47
n.d.
n.d.
n.d.
2.5
3.5
8.4
O
S
N
CF3
n.d.
no
O
N
N
CF3
CF3
S
S
c
a b
pK /pK
N
O
no
pK /pKb
2
3
15Me
2.6
c
56
41
44
n.d.
6.2
a
N
a
b
c
d
e
For assay details see the Supporting Information; n.d.: not determined.
Protonation on the pyridine nitrogen.
No pK /pK was detected within the measurement range of the assay (pH 2-12).
a
b
No valid results were obtained.
Protonation on the secondary amine.
19 / 55

ACCEPTED MANUSCRIPT
As expected, variation of the N-aryl substituent has a significant impact on the lipophilicity of
the compounds represented by the measured partition-coefficient (logP) of the compounds that
covers a wide range between –3.9 for 15Hj up to 4.0 for 15Hf (Table 1, entries 1-10).
Surprisingly, varying the substituents at the sulfur atom modulated logP only from 0.9
(
thiomorpholine sulfoximine 15Je) to 3.7 (S-phenyl sulfoximines 15Ke, entries 5, 11-23).
Amongst the cyclic sulfoximines (entries 5, 16-19), thietane and thiolane derivatives 15Fe and
5Ge show comparable lipophilicity and the tetrahydrothiopyran 15He is only slightly more
1
lipophilic. Interestingly, the oxathiane sulfoximine 15Ie and its carbon analogue 15He are
equally lipophilic, whereas thiomorpholine sulfoximine 15Je is significantly more polar.
The basicity of most of the sulfoximines 15 is outside the scope of the assay (pK /pK 2-12)
a
b
and could therefore not be determined. Thus, only the pK of additional basic nitrogens could be
b
measured. For 3-pyridyl and 4-pyridyl sulfoximines 15Hh and 15Hi, the measured pK values of
b
4
.8 and 7.2, respectively, are comparable to those of the corresponding 3-methoxypyridine (pKb
4.9) [54] and 4-methoxypyridines (pK = 6.7), [55] thus indicating a similar electronic
=
b
influence of the sulfoximine substituent. The basicity of S-pyridyl sulfoximines 15Le and 15Me
was too low to be determined which is in line with the pK values for the corresponding sulfones
b
as calculated using the Hammet equation (pK = 1.7 for 3-methylsulfonylpyridine and pK = 1.2
b
b
5
6
for 4-methylsulfonpyridine), [ ] implicating a similar electronic effect of the sulfoximine
substituent. The pK of the thiomorpholine derivative 15Je of 5.2 is in good agreement with
b
reported pK of the corresponding 1,4-thiazinane-1,1-dioxide (pK = 5.4). [57]
b
b
20 / 55

ACCEPTED MANUSCRIPT
Most of the compounds 15 exhibit very desirable microsomal stability in human liver
microsomes beyond the scope of the assay (T > 130 min). This indicates that the sulfoximine
½
moiety per se is not intrinsically metabolically unstable. [58]
Only limited conclusions can be drawn from the solubility data from the high-throughput
HPLC assay, as many of the compounds are soluble beyond the upper detection limit of the
assay (≈200 µM). As anticipated, representatives with high lipophilicity (15Hf, 15Ce) or
additional phenyl substituents (15Ke) exhibit significantly reduced solubility. For some of the
compounds, aqueous equilibrium solubility from solid material was determined. In most of these
cases, aqueous equilibrium solubility was found to be very high, for compounds 15Hc, 15Ge and
1
5Je even higher than 1 mg/mL.
As assumed for such small molecules, the passive permeability of the compounds is generally
very high (PAMPA). Reduced permeability is detected for the pyridyl derivatives 15Hh and
5Hi as well as the pyrazole 15Hj, which is in agreement with their comparatively high polarity.
1
The reduced permeability of the most lipophilic derivatives 15Hf and 15Ke may be an artefact
caused by low solubility.
2
.3.2 Physicochemical and in vitro properties of isosteres and compounds with related
functional groups
Apart from exploring the physicochemical and in vitro properties of sulfoximines, we also
envisaged to compare their properties with those of isosteres and analogs with more common
structural elements. Hence, using sulfoximines 15Ae and 15He as templates, a series of N-aryl
sulfoximine isosteres and congeners 16a-16n (Table 2) was synthesized. Additionally, S-aryl
21 / 55

ACCEPTED MANUSCRIPT
sulfoximines 17a-17n, N-acyl sulfoximines 18a-18e and N-carbamoyl sulfoximines 19a-19e
were prepared (Tables 3 and 4).
a
Table 2. N-Aryl sulfoximines and related compounds.
Permeability
PAMPA)
Papp [10
Stability in
human liver
microsomes
Aqueous
Solubility
[µg/mL] [53]
(
Entry Compound Structure
logP [52]
pK
a
/pK
b
-6
cm/s]
Potentio-
metric
assay
Shake
HPLC-
flask
HPLC
assay
T½
%QH
[min]
Assay
assay
no
/pK
b
O
S
N
N
CF3
1
2
15Ae
15He
1.4
2.8
n.d.
n.d.
>130 <23
>50
51
900
70
8.2
7.7
[b]
pK
a
O
S
CF3
n.d.
46
60
46
39
H
N
CF3
CF3
CF3
CF3
CF3
CF3
CF3
3
4
5
6
7
8
9
16a
16b
16c
16d
16e
16f
1.8
0.8
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
10
>52
>51
n.d.
n.d.
47
100
1,300
4,300
400
6.0
9.7
6.3
O
N
O
c
c
-
-
S
S
S
S
S
–0.5
1.3
110
25
O
c
c
c
-
-
-
O
O
O
c
c
c
4.3
-
-
300
-
O
O
H
N
d
e
n.d.
2.0
pK
8.0
>130 <23
600
5.1
O
a
O
N
c
c
c
16g
16h
2.5
n.d.
n.d.
-
-
46
200
-
O
O
HN
HN
N
N
CF3
f
g
1
0
1
–0.5
1.8
pK 4.0
b
>130 <23
110 25
>51
8,400
5.6
7.3
S
S
CF3
1
1
1
16i
16j
16k
1.3
n.d.
1.6
n.d.
pK
b
4.0
44
31
500
<1
O
N
CF3
CF3
h
i
2
3
1.6
pK
a
10.3
>130 <23
>130 <23
5.3
5.0
S
NH2
O
S
N
no
n.d.
n.d.
>54
800
b
b
NH
pK /pKb
a
O
S
N
CF3
no
1
4
16l
2.4
42
48
41
70
7.6
N
pK /pKb
a
22 / 55

ACCEPTED MANUSCRIPT
O
S
N
N
CF3
CF3
f
1
1
5
6
16m
16n
n.d.
n.d.
2.4
3.5
pK
pK
b
b
4.2
5.0
>130 <23
52 43
n.d.
n.d.
300
<50
7.8
O
S
f
10.0
a
b
c
d
e
f
For assay details see the Supporting Information; n.d.: not determined.
No pK /pK was detected within the measurement range of the assay (pH 2-12).
No valid results were obtained.
Measured at pH 3.
Deprotonation of the sulfonamide NH.
Measured at pH 12.
Protonation sulfoximine.
Measured at pH 3.
a
b
g
h
i
Deprotonation of the sulfonimidamide NH.
Measured at pH 12.
j
a
Table 3. S-Aryl sulfoximines and related compounds.
Permeability
Stability in
human liver
microsomes
Aqueous
Solubility
[µg/mL] [53]
(
PAMPA)
Entry Compound Structure
logP [52]
pK
a
/pK
b
-6
Papp [10
cm/s]
Potentio-
metric
assay
Shake
flask
assay
HPLC
assay
T½
HPLC-
Assay
%QH
[min]
O
S
b
b
b
CF3
–0.3
1.5
n.d.
n.d.
n.d.
n.d.
-
-
-
-
>46
>47
>50
11,100
300
-
1
2
3
17a
17b
17c
O
b
b
b
O
S
CF
-
3
O
b
c
HN
S
CF
-
2.0
pK
2.5
>130 <23
>130 <23
9,100
6.9
3
b
O
S
no
N
N
4
5
6
7
17d
17e
17f
17g
CF
3
0.1
0.2
n.d.
n.d.
>54
>59
n.d.
n.d.
2,400
4,700
6,900
1,200
11.0
d
a
pK /pK
b
O
S
CF3
CF3
pK
3.8
2.4
>130 <23
9.2
5.7
9.8
9.5
b
O
HN
c
S
–0.5
0.4
0.9
pK
47
45
N
b
H
O
no
N
S
CF
3
n.d.
>130 <23
>130 <23
N
d
b
H
pK
a
/pK
no
O
S
N
CF3
8
9
17h
17i
17j
1.5
0.3
0.5
n.d.
n.d.
n.d.
n.d.
>44
n.d.
1,200
300
N
d
pK /pKb
a
O
b
b
b
CF3
n.d.
n.d.
-
-
-
2
H N
O
CF3
1
0
>130 <23
200
5.7
N
H
23 / 55

ACCEPTED MANUSCRIPT
O
N
CF3
1
1
1
1
2
3
17k
17l
0.2
n.d.
n.d.
n.d.
n.d.
pK 9.4
pK
>130 <23
>130 <23
n.d.
>48
>49
700
800
900
11.0
4.1
O
S
N
O
e
CF
3
1.4
a
H2
O
O
e
S
CF3
CF3
17m
2.3
a
10.7 >130 <23
6.3
N
H
O
O
b
b
b
S
1
4
17n
2.7
n.d.
n.d.
-
-
47
90
-
N
a
b
c
d
e
For assay details see the Supporting Information; n.d.: not determined.
No valid results were obtained.
Measured at pH 12.
No pK /pK was detected within the measurement range of the assay (pH 2-12).
a
b
Measured at pH 2.
a
Table 4. Acylated and carbamoylated sulfoximines and related compounds.
Permeability
Stability in
human liver
microsomes
Aqueous
Solubility
[µg/mL] [53]
(
PAMPA)
Entry Compound
Structure
logP [52]
pK
a
/pK
b
-6
Papp [10
cm/s]
Potentio-
metric
assay
Shake
flask
assay
HPLC
assay
T
[min]
½
HPLC-
Assay
%QH
O
CF3
b
b
b
1
2
3
4
5
18a
18b
18c
18d
18e
4.8
2.6
n.d.
1.8
0.4
n.d.
n.d.
n.d.
n.d.
-
-
7
20
10
-
O
O
CF3
CF3
CF3
CF3
>130 <23
>130 <23
14
7.1
0.01
11.0
9.2
N
H
O
O
c
O
1.7
pK
3.2
>62
>53
n.d.
>20,000
300
S
N
H
a
O
N
O
N
O
no
n.d.
n.d.
d
62
39
S
pK
a
/pK
b
HN
no
S
d
>130 <23
8,100
pK /pKb
a
H
N
CF3
CF3
CF3
b
b
O
6
7
8
9
19a
19b
19c
19d
19e
4.4
3.4
n.d.
1.6
0.4
n.d.
n.d.
n.d.
n.d.
-
-
<1
<1
<1
20
0.8
5.1
O
H
N
H
N
>130 <23
>130 <23
>130 <23
O
H
N
H
N
c
1.9
pK
4.2
55
11,100
40
0.04
4.3
a
S
O
O
O
H
N
CF3
no
N
n.d.
n.d.
d
44
O
S
O
pK /pKb
a
H
N
CF3
e
b
b
N
1
0
pK
b
3.3
-
-
>68
500
3.3
HN
S
O
a
For assay details see the Supporting Information; n.d.: not determined.
No valid results were obtained.
b
24 / 55

ACCEPTED MANUSCRIPT
c
d
e
Measured at pH 2.
No pK /pK was detected within the measurement range of the assay (pH 2-12).
Protonation of S=N.
a
b
2.3.2.1 logP [52]
Within the series of N-[4-(trifluoromethyl)phenyl]sulfoximines and isosteric and related
compounds 16, the measured partition coefficients (HPLC assay) indicate that sulfoximines and
related sulfondiimides and sulfonimidamides are relatively polar functional groups with the
following order of logP: sulfondiimide (16h) ≈ sulfoxide (16c) << N-methylamide (16b) <
sulfone (16d) ≈ sulfoximine (15Ae) < N-methylsulfonimidamide (16k) < amide (16a) <
N,N-dimethylsulfonimidamide (16l) ≈ N-methylsulfonamide (16g) << sulfonate (16e). This
suggests that as a rule of thumb for lipophilicity, sulfondiimides are comparable to sulfoxides
and sulfoximines are comparable to sulfones and amides. NH-Sulfondiimides 16h and 16i were
found to be more polar than their respective sulfoximine counterparts 1Ea and 1Eh by 1.5 to 2
logP units.
Within the series of S-[4-(trifluoromethyl)phenyl]sulfoximines 17, unfortunately, no valid data
could be obtained for NH-sulfoximine 17c in the HPLC assay. Analyzing the available data from
this assay, the following trend for logP is obtained: N-methylsulfonimidamide (17f) ≈ sulfoxide
(17a) < N-alkylsulfoximines (17d, 17e) ≈ N,N-dimethylamide (17k) ≈ amide (17i) <
N,N’-dimethylsulfonimidamide (17g) < N-methylamide (17j) << sulfone (17b)
≈
N,N’,N’-trimethylsulfonimidamide (17h). Based on the available data from the potentiometric
assay, the sulfonimidamide 17f and the sulfonamide 17l are ranked as more polar than
sulfoximine 17c, which is slightly less polar than methylsulfonamide 17m.
For the series of N-acyl and N-carbamoylsulfoximines 18 and 19, and their isosteres the trends
for lipophilicity as expressed by logP are comparable to the series of compounds 16: sulfon-
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diimides (18e, 19e) << sulfoximines (18d, 19d) ≈ sulfones (18c, 19c) << tert-butyl amide (18b)
<
tert-butyl urea (19b) < tert-butyl carbamate (19a) < tert-butyl ester (18a).
2
.3.2.2 Dissociation constants (pK /pK )
a b
In accordance to literature data of related compounds, measurements of the dissociation
constants confirmed that the sulfoximines 17c, 17e, 16m and 16n are weak bases [59] whereas
the basicity of the N-[4-(trifluoromethyl)phenyl]sulfoximine 15Ae was too low to be detected
within the assay window (pK
a
/pK
b
2-12). S-(4-Trifluoromethylphenyl)sulfoximines 17c (pK
b
=
=
2
5
.5) and 17e (pK
b
= 3.8) are less basic than S-alkyl derivatives 16m (pK
b
= 4.2) and 16n (pK
b
.0), the latter of which is approximately as basic as pyridine. Interestingly, no dissociation
constant could be measured for N-methylsulfoximine 17d within the assay window, and
remarkably, sulfondiimide 16h is significantly more basic (pK = 4.0) than its sulfoximine
b
analogue 15Ae (pK < 2). While sulfonimidamides 16k, 16l, 17g and 17h did not exhibit a
b
pK /pK value within the scope of the assay, derivatives 16j was found to be weakly acidic in the
a
b
a b
range of ethyl acetoacetate (pK = 10.3) and 17f was determined to be a weak base (pK = 2.4).
Within the series 18 and 19 of acyl- and carbamoyl derivatives, carbamoylsulfondiimide 19e was
detected as weak base (pK = 3.3), acyl- and carbamoylsulfonamides 18c and 19c were found to
b
be acidic in the range of carboxylic acids (pK = 3.2 and 4.2, respectively), and N-arylated
a
methanesulfonamide 16f was weakly acidic (pK = 8.0).
a
2.3.2.3 Microsomal stability
As already observed for series 15, the majority of the sulfoximines, sulfondiimides and sulfon-
imidamides from series 16, 17, 18 and 19 exhibited very high microsomal stability, often beyond
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the scope of the assay (T1/2 > 130 min). This underlines that sulfoximines and related functional
groups have favorable metabolic stability.
2.3.2.4 Aqueous solubility
The solubility data from the HPLC assay for the compounds 17, 18 and 19 cannot be fully
analyzed, as many of the compounds are too soluble (>200 µM) to be precisely measured in this
assay. The only clear trend is that the most lipophilic compounds 18a, 19a and 19b are poorly
soluble.
The data from the aqueous equilibrium solubility (shake flask assay) confirm that for most of
the compounds, the solubility is high, often greater than 1 mg/mL. The solubility of the
sulfoximines is usually high (15Ae, 16m) or very high (17c, 17d, 17e) and only two examples
show moderate solubility (16n, 19d). Interestingly, the solubility of S-aryl sulfoximine 17c is
tenfold higher than for the corresponding N-aryl derivative 15Ae. It is noteworthy, that S-aryl
sulfoximine 17c exhibits a very high solubility, comparable to sulfoxide 17a, but a much higher
(10-100 fold) solubility than sulfone 17b or the corresponding amides (17i, 17j, 17k) or
sulfonamides (17l, 17m, 17n).
For N-aryl sulfoximine 15Ae, the solubility is inferior to the isosteric sulfoxide 16c,
comparable to N-methylamide 16b and superior to amide 16a, sulfone 16d, sulfonate 16e and
sulfonamide 16g. The sulfondiimides revealed high (16i, 19e) or very high solubility (16h, 18e).
Interestingly, sulfondiimides 16h and 18e are by far more soluble than their sulfoximine analogs
1
5Ea and 18d. Within the class of sulfonimidamides, the solubilities are more diverse: while the
N-arylated sulfonimidamides demonstrate a low (16j) or medium solubility (16l), S-arylated
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analogs 17f, 17g and 17h display a very high solubility, also higher than the corresponding
sulfones 17l, 17m and 17n.
2.3.2.5 Permeability
As expected for such small molecules, the permeability of the compounds 16a-16n and 17a-
7n is very high. Amongst the acylated compounds 18a-18e, the acidic sulfonamide 18c exhibits
1
very low solubility, presumably caused by ionization as indicated by pH dependant permeability
measurements (data not shown). For the carbamoyl derivatives 19a-19e, permeability is
generally slightly lower compared to compounds 16a-16e, 17a-17e and 18a-18e, acidic
sulfonamide 19c showing again the lowest permeability.
2.3.2.6 Chemical stability
To assess the chemical stability of the functional groups, the degradation of a number of
representative compounds was studied for seven days in aqueous solution at pH <1 and pH >10.
[60] Generally, only minor decomposition was observed. Only benzoyl derivatives 18d and 18e
completely decomposed under acidic conditions, however, this instability was not observed in
the synthesis, purification and routine handling of this compound type. [61] Overall, the
observations indicate that chemical stability in the range usually relevant for drug discovery is
not problematic. Notably, only for the compounds 16i and 19e traces of the corresponding
aniline as the decomposition product could be detected. Sulfilimines 16o and 16q as well as
sulfinamide 16p (Chart 2) were synthesized and could spectroscopically be characterized by
NMR, however, their limited chemical stability impeded the determination of any further
physicochemical data.
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