Therapeutic compounds: Patent evaluation of WO2011011652A1

Article abstract of DOI:10.1517/13543776.2011.584873

A series of sulfonamide derivatives, incorporating azabicyclo[3.2.1]octane and phenyl-propyl scaffolds, were prepared by a succession of original steps. The compounds are claimed to act as antagonists of the C-C chemokine receptor 5 (CCR5) involved in the

Full text of DOI:10.1517/13543776.2011.584873

Patent Evaluation
Therapeutic compounds: patent
evaluation of WO2011011652A1
Claudiu T Supuran
University of Florence, Dipartimento di Chimica, Via della Lastruccia 3, 50019 Sesto Fiorentino,
1. Introduction
2. Chemistry
Florence, Italy
A series of sulfonamide derivatives, incorporating azabicyclo[3.2.1]octane and
phenyl-propyl scaffolds, were prepared by a succession of original steps. The
compounds are claimed to act as antagonists of the C-C chemokine receptor
5 (CCR5) involved in the entry of HIV-1 to cells, but only semi-quantitative anti-
viral data are provided. HIV entry inhibitors, including CCR5 antagonists, are
clinically used for the treatment of this viral infection; the compounds claimed
in the patent, possessing a new and original scaffold, seem to be of interest for
developing novel antiviral agents belonging to this class.
3. Biological activity
4. Expert opinion
Keywords: antiviral agent, azabicyclo[3.2.1]octane, CCR5 antagonist, HIV infection,
sulfonamide
Expert Opin. Ther. Patents (2011) 21(9):1491-1495
1. Introduction
Viral infections represent a major medical problem worldwide. HIV infection affects
millions all over the world, and although much progress has been registered in the treat-
ment of this infection by the introduction of combination, highly active antiretroviral
therapy, the massive viral replication (with > 109 virions produced daily) and the high
error rate of the reverse transcriptase (RT) lead to the emergence of drug resistant strains
and the stringent need of new therapeutic approaches [1-6]. The emergence of the AIDS
epidemic in the early 1980s fostered much research and great progress in this area, and
presently > 30 antiviral drugs are available, most of them for the management of HIV
infection and AIDS, but also for the treatment of other viral diseases such as hepatitis B,
influenza, herpes simplex, varicella-zoster and cytomegalovirus (HCMV) infections [5].
There are at least 10 steps in the HIV life cycle, most of which are amenable to
be targeted by drugs, already identified and clinically used at this moment, or cur-
rently under investigation [1-6]. They are: (i) virus adsorption inhibitors; (ii) viral
co-receptor antagonists; (iii) viral fusion inhibitors; (iv) nucleocapsid protein zinc
finger targeted compounds; (v) RT inhibitors of the nucleoside/nucleotide type, N
(t)RTIs, which target the substrate binding site of the enzyme; (vi) RT inhibitors
of the non-nucleoside type (NNRTIs), which target an allosteric, non-substrate
binding site; (vii) the IN inhibitors; (viii) transcription/transactivation inhibitors;
(ix) protease inhibitors and (x) maturation inhibitors. Steps (ii) and (iii) may be con-
sidered as those dealing with the entry of HIV within cells, one of the most promis-
ing targets for HIV drug development. Indeed, enfuvirtide, a HIV fusion inhibitor,
was the first drug with a target different from viral RT or protease to be approved
by the FDA [2-4]. However, there is still need of potent, orally bioavailable small
molecules able to make concrete the efforts made so far in this research field.
Chemokines are low molecular mass (8 -- 12 kD) proteins produced and secreted
after stimulation by several exogenous (such as viruses, bacteria and endotoxins) and
pro-inflammatory endogenous agents such as the cytokines IL-2 and TNF, whereas
IFN and glucocorticoids are potent inhibitors of their secretion [7]. Furthermore,
chemokines promote both humoral and cell-mediated immunity, regulate cellular
adhesion and angiogenesis, and contribute to lymphopoiesis and hematopoiesis [7].
10.1517/13543776.2011.584873 © 2011 Informa UK, Ltd. ISSN 1354-3776
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Therapeutic compounds -- patent evaluation of WO2011011652A1
When administered at very high concentration, chemokines
can suppress inflammatory reactions. They are produced by
several cell lines that can respond to many of them through
different pathways. Chemokines are classified into two main
categories: a-chemokines, also known as C-X-C chemokines,
possessing 10 amino-terminal cystein (C) residues separated
by another amino acid (X); they activate the neutrophils and
promote their adhesion to endothelial cells, their crossing of
the vessel wall followed by the tissue spread and migration
towards the inflamed sites. b-Chemokines, also known as
C-C chemokines, mainly activate monocytes, lymphocytes,
basophils and eosinophils and play a central role in T-cell pro-
liferation and allergies [7]. In 1995, Cocchi et al. discovered
the potent inhibitory effect of three chemokines secreted by
CD8+ T lymphocytes on HIV-1, focusing the attention on
this class of molecules which led to important discoveries
that finally unraveled the process of HIV entry within the
cells [8]. The chemokines described in this study, RANTES
(regulated on activation normal T cell expressed and secreted),
MIP (macrophage inflammatory protein)-1a and MIP-1b,
belong to the group of C-C chemokines (b chemokines)
and are soluble factors secreted by CD8+ T lymphocytes.
C-X-C chemokines (a-chemokines) include SDF (stromal
derived factor)-1a and SDF-1b among others [8]. There are
different target cells for different chemokines: MIP-1a
and MIP-1b target monocytes/macrophages, T lymphocytes
(inducing TH1 ! TH2 differentiation), basophils, immature
dendritic cells and bone marrow cells. MIP-1a and MIP-1b
interact with the C-C chemokine receptor (CCR)1 and
CCR5 receptors. RANTES targets monocyte/macrophages,
T lymphocytes (inducing memory T cells ! TH1 !
TH2 differentiation), NK cells, basophils, eosinophils and
dendritic cells. RANTES interacts with the CCR1, CCR3
and CCR5 receptors. SDF-1a and SDF-1b target CD34+
cells, dendritic cells, B lymphocytes, naive B lymphocytes
and activated CD4+ T lymphocytes. SDF-1a and SDF-1b
specifically interact with CXCR4 [7-12].
Maraviroc was the first selective CCR5 antagonist with
potent antiviral activity against all CCR5-tropic HIV-1
viruses at low nanomolar concentrations (mean 90% inhibi-
tory concentration of 2 nM) which started to be used
clinically in 2007 [17]. By acting as an antagonist at the
CCR5 co-receptor, maraviroc inhibits HIV-1 from entering
host cells. Clinical data for maraviroc were initially available
from two large, well-designed, ongoing Phase IIb -- III trials
(MOTIVATE-1 and -2) conducted in patients infected with
R5-tropic HIV-1 who had previously received at least one
agent from three of the four classes of antiretroviral drugs
and/or were triple-class resistant. According to 24-week
interim results of the MOTIVATE-1 and -2 trials, a signifi-
cantly greater reduction in viral load occurred in patients
receiving maraviroc 150 or 300 mg (depending on optimized
background therapy (OBT)) twice daily plus OBT compared
with placebo plus OBT. This significant difference was main-
tained at 48 weeks in MOTIVATE-1. The 48-week results of
MOTIVATE-1 also reported a significant difference in favor
of maraviroc for all these end points. In general, maraviroc
at dosages of up to 300 mg twice daily was well tolerated
in treatment-experienced patients infected with R5-tropic
HIV-1. Thus, this first-in-the-class drug fostered much
research in the field of CCR5 antagonists with use as antivi-
rals. The patent analyzed here is just an example of such
de novo designed CCR5 antagonists based on totally
new scaffolds.
2. Chemistry
The compounds claimed in the patent possess the
general structure I which is an original one in the field of
CCR5 antagonists as it includes:
X
A
N
H
HIV entry into host cell is a complicated process that
involves a series of molecular events that started to be
understood in detail ultimately. The T-lymphocyte cell sur-
face protein CD4 is the primary receptor involved in the
interaction with the viral glycoprotein gp120, but a cellular
co-receptor is also needed for the successful entry of the
virus within the cell [7-12]. At least two types of such co-
receptors have been identified so far, both belonging to
the chemokine family of seven-transmembrane-spanning
receptors coupled to a G-protein signaling pathway [13-16]:
the CCR5 (which binds the chemotactic chemokines,
MIP-1a, and MIP-1b, and RANTES, as already mentioned
above) and the CXC chemokine receptor 4 (CXCR4)
(which binds SDF-1 as natural ligand) [13-16]. These recep-
tors, therefore, are the gateways for HIV entry, determi-
nants of viral tropism and sensitivity. CCR5 receptor is
used by macrophage (M)-tropic viruses and CXCR4 is
used by T-lymphocyte (T)-tropic virus [13-16].
N
H
R
H
I
X = H, halogen, C1 – C6 alkyls; A = aryl,
substituted aryl, alkyl, cycloalkyl; R = heterocyclyl
(substituted eventually with one or more substituents).
i) an azabicyclo[3.2.1]octane connected to a phenyl-
propyl scaffold via the bridging nitrogen atom
ii) the same phenyl belonging to the scaffold mentioned
above is part of a phenethylamine moiety
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Expert Opin. Ther. Patents (2011) 21(9)

Supuran
CN
COOEt
KCN
+ PhCH = O
COOEt
COOEt
OH
EtOH/
water
70°C
COOEt
1
2
4
3
Dess-Martin
oxydation
H
N
N
H
1.
N
H2N
CN
H
H
6
O
N
N
NaBH(OAc)3
H
5
N
2. Ni Raney
H
H
7
Base
RSO2Cl
O
S
R
N
H
O
N
N
H
N
H
H
8
Scheme 1. General scheme for the preparation of compounds of type I, exemplified for the derivative 8.
iii) the amine belonging to the phenethylamine
fragment is in turn derivatized, most of the time,
via sulfonamide or carboxamide functionalities. As
as benzaldehyde 2, the benzylidene derivative 3 was obtained,
which was reacted with sodium cyanide in ethanol-- water,
leading to 3-phenyl-3-cyano-propanol 4. This intermediate
has been oxidized to the corresponding aldehyde 4, which
was reacted with the secondary amine 6 incorporating the
main feature of these compounds, that is, the azabicyclo
[3.2.1]octane scaffold. This condensation has been achieved
in reducing conditions, in the presence of sodium borohy-
dride derivatives, and was followed by a nickel Raney reduc-
tion of the nitrile to the corresponding primary amine 7.
This was the key intermediate for the many compounds
sulfonamides possess
a rather wide range of
biological and pharmacological properties [18-22], it
is not unusual that most of the claimed compounds
of the patent belong to this class.
A general procedure for the preparation of some of these
compounds is shown in Scheme 1. Starting from diethyl
malonate 1, by condensation with aromatic aldehydes, such
Expert Opin. Ther. Patents (2011) 21(9)
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Therapeutic compounds -- patent evaluation of WO2011011652A1
claimed in the patent, and 7 was further derivatized primarily
by reaction with alkyl/cycloalkyl/aryl sulfonyl halides, leading
to the sulfonamides 8 (Scheme 1). Some other derivatives were
obtained by reaction of amine 7 with acyl halides, leading to
the corresponding carboxamides. The claimed compounds
have been extensively characterized by means of physicochem-
ical methods which confirmed their structure. The prepara-
tion of the heterocyclic amine 6 and some of its congeners
is also presented in the patent, being achieved by routine
chemistry described in the literature.
fragment is derivatized, most of the time via sulfonamide or
carboxamide functionalities. A large number of such derivatives
has been claimed, in which a number of these three structural
elements are changed by the usual medicinal chemistry proce-
dures (most of the time, the groups substituting the phenyl
moiety and the sulfonamide part of the molecule are variable,
whereas the heterocyclic moiety present on the azabicyclo
[3.2.1]octane fragment has also been changed but less compared
to the remaining structural elements).
The compounds claimed in the patent have been evaluated
as antivirals by using just one in vitro assay, the so-called
‘HOS assay’, but few details regarding this assay are provided.
This assay afforded information on the range of activity of the
new compounds claimed in this patent, which showed IC50
values in the range of 1 -- < 0.01 µM. Thus, apparently
many of the new compounds claimed in the patent show
significant antiviral activity in the low nanomolar range.
However, these data seem to be very raw and preliminary, as
very little information is provided in the patent and no
in vivo data are available so far.
3. Biological activity
The antiviral activity of the synthesized compounds has been
evaluated by the so-called ‘HOS assay’ with little or no details
at all regarding what HOS represents. This assay afforded
information on the range of activity of the new compounds,
with IC50 values between 1 and < 0.01 µM. Thus, apparently
many of the new compounds claimed in this patent show
significant antiviral activity in the low nanomolar range.
However, these data seem to be very raw and preliminary, as
very little information is provided in the patent.
We appreciate that the structural elements present in
these molecules are innovative and the chemical part pre-
sented in this patent is appropriately developed and origi-
nal. However, the biological details regarding the antiviral
activity of these compounds is rather scarce and it is thus
difficult to assess the significance of these compounds for
developing novel CCR5 antagonists with applications as
anti-HIV therapeutical agents.
4. Expert opinion
The patent describes a series of interesting compounds incorpo-
rating a scaffold not investigated earlier for its antiviral proper-
ties. Indeed, these derivatives contain at least three main
structural features which makes them original, that is, an azabi-
cyclo[3.2.1]octane fragment connected to a phenyl-propyl scaf-
fold via the bridging nitrogen atom; the same phenyl belonging
to the scaffold mentioned above is also part of a phenethylamine
moiety; and the amine belonging to the phenethylamine
Declaration of interest
The author states no conflict of interest and has received no
payment in preparation of this manuscript.
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Expert Opin. Ther. Patents (2011) 21(9)

Supuran
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