Different Classes of CB2 Ligands Potentially Useful in the Treatment of Pain

28 Pages·2013·1.37 MB·English

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42 Recent Patents on CNS Drug Discovery, 2013, 8, 42-69
Different Classes of CB2 Ligands Potentially Useful in the Treatment of
Pain
Gabriele Murineddu*, Francesco Deligia, Antonio Dore, Giovanni Pinna, Battistina Asproni and
Gerard A. Pinna
Department of Chemistry and Pharmacy, University of Sassari, Italy
Received: February 08, 2013; Revised: March 05, 2013; Accepted: March 06, 2013
Abstract: The search of new drugs and targets to treat the pain is an intriguing challenge both for several companies and
researchers from academia. In this context, since the modulation of the endocannabinoid system with the non selective
phytocannabinoid (cid:1)9-THC produces analgesia and potentiates opioid analgesia in animal models, CB ligands studies
2
aimed to explore the involvement of endocannabinoid system in management of pain were started. Several selective CB
2
receptor agonists exhibited analgesic activity in preclinical models of acute, inflammatory and neuropathic pain, therefore
this class of modulators could be useful as analgesic agents for pain, migraine, inflammation and osteoarthritis. This re-
view is an update of our previously manuscript “A survey of recent patents on CB agonists in the management of pain”
2
and provides an overview of patents and advances in CB agonist studies in the treatment of pain.
2
Keywords: Cannabinoid, CB receptors, CB receptor ligands, chronic pain, inflammatory pain, neuropathic pain.
2 2
1. INTRODUCTION The mediation of analgesia in the central nervous system
(CNS) involves the use of different types of compounds such
Pain is an unpleasant sensorial and emotional experience,
as opioids, which have been used for centuries to relieve
associated with actual or potential tissue damage. It is a ho-
pain and whose analgesic effect is due to the interaction with
meostatic and protective mechanism, but is liable to change
three types of receptors: μ, (cid:2) and (cid:3). Nowadays, opioids rep-
in disease states and thus requires treatment.
resent the only analgesics able to achieve acceptable pain
The physiopathology of pain is complex and variable and relief in more than 50% of treated patients, thus justifying
involves several mechanisms, neurotransmitters and recep- the challenge faced by different research groups to find new
tors. analgesics.
In general terms, pain may be classified as being acute or For a long time marijuana and hashish, the common
chronic. The aim of acute pain is to warn the body of the nouns for the dried blossom tips and dried resin, respec-
presence of dangerous stimuli in the surroundings or in the tively, of Cannabis sativa, have been used as drugs for me-
body itself. Chronic pain is present in degenerative, neuro- dicinal and recreational purposes. In the last decades, the
logical and oncological illness involving sensorial and emo- chemical and physiological effects of cannabinoids have
tional aspects. been investigated. Recently, this research has highlighted the
presence of an endogenous cannabinoid system (ECS) in the
Three major physiopathogenetic mechanisms are stimu-
human body whose biological organization includes two
lated in chronic pain: the nociceptive or “physiological”
subtypes of G-protein coupled membrane receptors, CB and
pain, a strong, sudden and localized pain which can derive 1
CB , their endogenous ligands anandamide (AN) and 2-
from an internal or external trauma; the neuropathic, due to 2
arachidonoyl-glycerol (2-Ara-Gl), and their multiple meta-
damage of, or a dysfunction in, peripheral or central nervous
bolic pathways for synthesis, degradation and reuptake.
system tissue, which is characterized by symptoms such as a
burning sensation, constraint, and pins and needles; finally, Animal studies have clearly demonstrated that the non-
the idiopathic pain whose cause is unknown. selective cannabinoid, (cid:1)9-tetrahydrocannabinol ((cid:1)9-THC),
the principal component of Cannabis, and synthetic cannabi-
Chronic pain represents a major health problem through-
noids, which act on the two receptors of the ECS, produce
out the world. It is estimated that, at any given time, 22% of
analgesia and potentiate opioid analgesia. Furthermore, re-
primary care patients between the ages of 18 and 65 suffer
cent studies would suggest that cannabinoids could be effec-
from chronic pain. In Europe, as in the United States, ap-
tive in specific chronic pain states.
proximately half population seeks medical help for pain at
some point in their lives. To this end, an initial study with cannabinoid ligands was
aimed at evaluating the involvement of endogenous cannabi-

noids in the control of pain [1, 2]. The analgesic properties
*Address correspondence to this author at the Department of Chemistry and of non-selective cannabinoid receptor agonists have been
Pharmacy, University of Sassari, Via F. Muroni 23/A, 07100 Sassari, Italy; known for many years and several behavioral and electro-
Tel: + 39 079 228 749; Fax: [phone]; E-mail: [email protected]
physiological studies in animal models have shown antinoci-
2212-3954/13 $100.00+.00 © 2013 Bentham Science Publishers
CB2 Ligands and Pain Recent Patents on CNS Drug Discovery, 2013, Vol. 8, No. 1 43
ceptive and antihyperalgesic effects in different models of A plethora of reviews on CB receptors [10, 11], their
2
pain [3]. However, selective CB ligands proved not to be distribution, molecular analysis and signalling pathways
1
useful as analgesic agents in humans, because their admini- have been published [12, 13]: the present review focuses on
stration was associated with undesirable central nervous sys- recent patents, from 2009 onwards, concerning CB receptor
2
tem side effects due to the doses of cannabinoids that can be ligands acting as analgesic agents.
administered [4]: for this reason their clinical development
The review has been structured taking into account the
was limited. Recently CB agonists have been proposed as a
2 number of patents, updated to January 2013, from different
valid alternative, either because of their mainly peripheral
applicants and the related articles published recently.
distribution, so they do not cause adverse CNS effects, or
because of their capability to inhibit signs of acute nocicep- Table 1 [14-129] summarizes the classes of CB agonists
2
tive, inflammatory and neuropathic pain in preclinical stud- reviewed in this article, and shows the key compounds for
ies [5-7]. Although there is a large body of evidence support- each of the classes of derivatives presented. The table has
ing the potential utility of selective cannabinoid CB receptor been organized in the same order in which key compounds
2
agonists for the treatment of pain [8, 9], the mechanism and appear in the text.
site of action responsible for CB -mediated analgesia remain
2 When available from the patents, CB selectivity against
unexplained. 2
CB receptors is given.
1

Table 1. Classes of CB Agonists
2
Classes Key Compounds Reference
Thiazoles, isothiazoles and thiadiazoles [14-38]
O
S
N
N
O
7
(A-836339)
hCB K = 0.64 nM
2 i
Dihydropyrazoles, bicyclic pyrazoles and indazoles O [35, 39-45, 79-81, 107, 108,
125-127]
NH
HN
O
N
N
N CF
3
18
hCB K = 0.40 nM
2 i
Indoles, indole-indanes and arylsulfonylindoles [46-48, 104, 105, 113]
O
N
22
O
hCB Ki = 0.21 nM
2
44 Recent Patents on CNS Drug Discovery, 2013, Vol. 8, No. 1 Murineddu et al.
(Table 1) contd…..
Classes Key compounds Reference
Azetidines, pyrrolidines, azepanes, diazepanes and deca- [52-57, 66, 68, 97]
hydroquinolines
O
O
N N
H
N
N
CF
3
30
CB EC = 0.015 nM
2 50
Amidosulfones O [58-65]
O S
O
NH
N O
38
CB EC = 0.04 nM
2 50
Butyramides and ureas [83, 84, 87]
O
H
N N
NH
2
O
66
CB K = 0.11 nM
2 i
(Sulfamoyl)benzamides O O [88-91]
S
N
O
HN O
71
CB K = 1.7 nM
2 i
(cid:1)
CB2 Ligands and Pain Recent Patents on CNS Drug Discovery, 2013, Vol. 8, No. 1 45
(Table 1) contd…..
Classes Key compounds Reference
Pyridines and furopyridines [49, 92, 93, 98-101]
Cl
O
N Cl
N N
O
76
CB IC = 3 nM
2 50
Tetrahydroimidazoles and imidazopyridines [75-78, 94-96]
O
NH
CF COO
3
N N
H
O F
81
CB K = 1.92 nM
2 i
Triaryl derivatives Cl [102]
OMe
Cl
MeO S
OH
85
CB K = 0.27 nM
2 i
Pyrimidines, pyrazines, pyridazinones and purines [106-109, 128, 129]
O N
H
N
N N
O
OH
91
hCB K = 43 nM
2 i
Thienoderivatives O [50, 111]
N H
N
MeO S S
O O
98
(For these derivatives, patents lack of detailed binding data)

(cid:1)
46 Recent Patents on CNS Drug Discovery, 2013, Vol. 8, No. 1 Murineddu et al.
(Table 1) contd…..
Classes Key compounds Reference
Dihydrobenzofuranes [115]
N
O
O
104
CB K = 422 nM
2 i
Imidazoles, (heteroaryl)benzimidazoles N F [117-121]
O
N
HN
OMe
O
O
108
CB K = 0.36 nM
2 i
Benzimidazolones, biphenylimidazolidine-2,4-diones O [122-124]
N
O
N
N
O
112
hCB EC < 400 nM
2 50

2. ABBOTT LABORATORIES mide (2) showed a high affinity for both human and rat CB
2
receptors, with K values of 0.74 and 0.15 nM for the former,
The compounds acting as CB agonists which were pat- i
2 and 0.30 and 0.50 nM for the latter, respectively, Fig. (1).
ented by Abbott Laboratories between 2009 and January
2013 can be classified into three different groups: the largest CF CF
3 3
group is that containing heterocyclic ring systems as thiazole O O
[14-28], and the section on this will also include a discussion S S
on the thiazole sulfonamides published by Taisho Pharma- N N
ceuticals Co. [29, 30], the isothiazoles [31-34] and the N O N O
thiadiazoles [35-38]; the second group covers dihydropyra-
NH
zole derivatives [35, 39-45]; the last encompasses indole O
[46-48], (hetero)arylcarboxamides [49] and tricyclic thio-
OH
phene compounds [50, 51].
1 2
2.1. 1,3-Thiazoles, Isothiazoles and 1,3,4-Thiadiazoles hCB K= 0.74 nM hCB K= 0.30 nM
2 i 2 i
Over the last three years Abbot has published several rCB2 Ki = 0.15 nM rCB2 Ki = 0.50 nM
patents and articles which propose different 1,3-thiazol- Fig. (1). (Z)-N-(5-tert-Butyl-3-isobutylthiazol-2(3H)-ylidene)-2-
(2-hydroxyethoxy)-5-(trifluoromethyl)benzamide (1) and (Z)-N-
2(3H)-ylidene derivatives as cannabinoid receptor ligands
(5-tert-butyl-3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-
[14-17]. In patents WO071783 (2010) [14] and WO028338
2(3H)-ylidene)-2-[(isopropylamino)oxy]-5-
(2010) [15], the authors claim that these compounds are
(trifluoromethyl)benzamide (2).
novel CB ligands. Amongst them, both (Z)-N-(5-tert-
2
butyl-3-isobutylthiazol-2(3H)-ylidene)-2-(2-hydroxyethoxy)-
The modulation of the 1,3-thiazol-2(3H)-ylidene-
5-(trifluoromethyl)benzamide (1) and (Z)-N-(5-tert-butyl-
benzamide, by condensation of 6-membered hetero(aryl)
3-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-thiazol-2(3H)-
rings to the thiazolic core [18, 19], furnished the N-[(2Z)-3-
ylidene)-2-[(isopropylamino)oxy]-5-(trifluoromethyl)benza-
CB2 Ligands and Pain Recent Patents on CNS Drug Discovery, 2013, Vol. 8, No. 1 47
butyl[1,3]thiazolo[4,5-b]pyrazin-2(3H)-ylidene]-2-{[(2S)-2- Derivative 7 demonstrated a CB receptor-mediated
2
hydroxypropyl]oxy}-5-(trifluoromethyl)benzamide (3) and broad spectrum of efficacy in in vivo animal models of noci-
N-[(2Z)-3-butyl-6-methyl-7-oxo-6,7-dihydro[1,3]thiazolo[4, ceptive pain, using complete Freund’s adjuvant (CFA) assay,
5-d]pyridazin-2(3H)-ylidene]-2-{[(2S)-2-hydroxypropyl] and of neuropathic pain, measuring allodynia in L5 and L6
oxy}-5-(trifluoromethyl)benzamide (4) which showed inter- spinal nerve ligation (SNL) and in a rat human constriction
esting KCB values, Fig. (2). The condensation of the injury (CCI) model, following systemic administration [28].
i 2
pyrazine ring to the thiazole system gave the new CB recep- Therefore, compound 7 provides a useful tool for studying
2
tor ligand 3 with K values for human CB and rat CB recep- the CB receptor pharmacology in vitro and for assessing the
i 2 2 2
tors of 2.0 and 4.1 nM, respectively, whereas the substitution biological consequences of CB receptor activation in ani-
2
of the pyrazine ring with pyridazinone (4) showed an inver- mals.
sion of affinity for human and rat CB receptors, with K val-
2 i
ues of 6.2 and 1.5 nM, respectively. O
S

N
OH OH N
O O
O O O O
N S S 7
N (A-836339)
N N
N N CF3 N N CF3 hCB2 Ki = 0.64 nM
rCB2 Ki = 0.76 nM (cid:1)
Fig. (4). (Z)-N-[3-(2-Methoxyethyl)-4,5-dimethylthiazol-2(3H)-
3 4
ylidene]-2,2,3,3-tetramethylcyclopropanecarboxamide.
hCB2 Ki = 2.0 nM hCB2 Ki = 6.2 nM
rCB2 Ki = 4.1 nM rCB2 Ki = 1.5 nM A series of compounds with the same 1,3-thiazole core
as the structures just reviewed, were identified by Taisho
Fig. (2). N-[(2Z)-3-Butyl[1,3]thiazolo[4,5-b]pyrazin-2(3H)-
Pharmaceuticals Co. through a random screening program
ylidene]-2-{[(2S)-2-hydroxypropyl]oxy}-5-(trifluoromethyl)benza-
of their libraries. In particular, (Z)-N-[5-tert-butyl-3,4-
mide (3) and N-[(2Z)-3-butyl-6-methyl-7-oxo-6,7-dihydro[1,3]
dimethyl-1,3-thiazol-2(3H)-ylidene]phenyl-1-sulfonamide
thiazolo[4,5-d]pyridazin-2(3H)-ylidene]-2-{[(2S)-2-hydroxypropyl]
(8), acting as a full CB receptor agonist in the [35S]GTP(cid:1)S
oxy}-5-(trifluoromethyl)benzamide (4). 2
binding assay (EC CB = 7.2 nM, E = 100%), showed a
50 2 max
The introduction of a second aliphatic ring condensed moderate CB receptor affinity (IC = 340 nM) [29]. Struc-
2 50
with various heterocycles [20-22] and the synthesis of car- ture-Activity Relationship (SAR) studies, aimed at identify-
boximidamide derivatives [23-26], gave new CB2 receptor ing related compounds with a better CB2 affinity, allowed
ligands with general structures 5 and 6, some of which were to obtain the (Z)-N-[5-tert-butyl-3-(cyclopropylmethyl)-4-
shown to possess an analgesic effect in animal models of methyl-1,3-thiazol-2(3H)-ylidene]naphthalene-1-sulfona-
neuropathic and nociceptive pain, although no in vitro and in mide (9) which exhibited high CB affinity (IC = 16 nM)
2 50
vivo data were given in the patents for these derivatives Fig. and selectivity (IC CB /IC CB = 106) in comparison to 8
50 1 50 2
(3). Fig. (5) [29].
O R1 O R1
S S
N N
O O
( )n N n = 1,2,3 N O S O S
R R
S S
N N
5 6
N N
Fig. (3). Modulation of the 1,3-thiazol-2(3H)-ylidene-benzamide.
In contrast, compound 7, (Z)-N-[3-(2-methoxyethyl)-4,5-
8 9
dimethylthiazol-2(3H)-ylidene]-2,2,3,3-tetramethylcyclopro-
panecarboxamide (A-836339), has been extensively charac- CB2 IC50 = 340 nM CB2 IC50 = 16 nM
terized using in vitro binding and functional assays, in vivo
Fig. (5). (Z)-N-[5-tert-Butyl-3,4-dimethyl-1,3-thiazol-2(3H)-yli-
pain models and CNS behavior tests, and phMRI studies Fig.
dene]phenyl-1-sulfonamide (8) and (Z)-N-[5-tert-butyl-3-
(4). It was found to exhibit high affinities and agonist poten-
(cyclopropylmethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene]naphtha-
cies at both human and rat CB receptors, with K values of
2 i
lene-1-sulfonamide (9).
0.64 and 0.76 nM, respectively, and an excellent selectivity
against the CB receptors in human (KCB = 270 nM) and Modulation of the sulfonamide group, responsible for
1 i 1
rat (KCB = 143 nM), with a selectivity ratio, KCB /KCB , the poor metabolic stability of these compounds in human
i 1 i 1 i 2
of 422- and 189-fold, respectively [27]. In addition, 7 did not liver microsomes, led to the synthesis of N-alkylidenearyl-
exhibit significant species selectivity between human and rat carboxamide analogues shown in Fig. (6). In particular,
for either CB or CB receptors.
1 2
48 Recent Patents on CNS Drug Discovery, 2013, Vol. 8, No. 1 Murineddu et al.
(Z)-N-(5-tert-butyl-3-(cyclopropylmethyl)-4-methylthiazol- administration that significantly reversed the mechanical
2(3H)-ylidene)-3-(trifluoromethyl)benzamide (10) exhib- hyperalgesia in the Randall-Selitto model of inflammatory
ited a high affinity for the CB receptor and a good selec- pain in rats.
2
tivity (IC CB = 13 nM, IC CB = 3500 nM, selectivity
50 2 50 1 This class of compounds will be also discussed under
CB /CB = 269). Moreover, an evaluation of plasma levels
1 2 Abbot Laboratories in section 2.2.
after oral administration of compound 10 in rats gave sig-
nificant results with a good oral bioavailability [30]. Four different applications [31-34] relate to benzothia-
zolylidene derivatives. The representative compound is (Z)-
N-(1-tert-butyl-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo
O O [2,1-c]isothiazol-3(1H)-ylidene)-5-chloro-2-methoxybenza-
mide (12), with a K value of 0.24 nM for hCB receptors
i 2
S N CF3 N CF3 Fig. (7).
F
N N N Patent WO054024 (2010) [34] also describes compounds
related to (Z)-methyl 3-{[(2-tert-butyl-4-butylisothiazol-
10 11 5(2H)-ylidene)amino]carbonyl}-2,2,3-trimethylcyclopentan-
ecarboxylate (13) shown in Fig. (7). This compound showed
CB2 IC50 = 13 nM CB2 IC50 = 2.9 nM (cid:1) high affinities and agonist potencies for both human and rat
CB receptors with K values of 0.20 and 0.25 nM, respec-
2 i
Fig. (6). (Z)-N-(5-tert-Butyl-3-(cyclopropylmethyl)-4-methylthia
tively. The separation of two enantiomers showed that the
zol-2(3H)-ylidene)-3-(trifluoromethyl)benzamide (10) and (E)-N-
(1S,3R) isomer, 14, still retained high K values (hCB = 0.16
i 2
(5-tert-butyl-2-(cyclopropylmethyl)-1-methyl-1H-pyrazol-3(2H)-yli
nM and rCB = 0.10 nM), whereas its (1R,3S) enantiomer
2
dene)-2-fluoro-3-(trifluoromethyl)benzamide (11).
was less potent (K hCB = 1.6 nM and K rCB = 1.4 nM).
i 2 i 2
Further optimization of this class of compounds led to
The bioisosteric replacement of the carbon atom in the 4
the discovery of N-[5-tert-butyl-2-(cyclopropylmethyl)-
position of the thiazoline ring with a nitrogen atom enabled a
1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]-2-fluoro-3-
series of 1,3,4-thiadiazolidene derivatives to be obtained.
(trifluoromethyl)benzamide (11), which exhibited good
Within this class, compounds 15-17 Fig. (8) proved to be
affinity for CB receptors (IC CB = 2.9 nM) and good
2 50 2 potent hCB receptor ligands, with K values ranging from
2 i
metabolic stability in human and rat liver microsomes. The
0.32 to 0.60 nM [35-38], the best compound in this series
analgesic effect of compound 11 was also tested by its oral
O O O
O O O
Cl O O
N
S
N N N
S S
N N
F C
3 12 13 14
hCB2 Ki = 0.24 nM hCB2 Ki = 0.20 nM hCB2 Ki = 0.16 nM (cid:1)
Fig. (7). (Z)-N-(1-tert-Butyl-5-(trifluoromethyl)-4,5,6,7-tetrahydrobenzo[2,1-c]isothiazol-3(1H)-ylidene)-5-chloro-2-methoxybenzamide (12)
and other isothiazol-5(2H)-ylidenecarboxamides.
HN
O O
NH NH
O O O
O O O
S N CF3 S N CF3 S N CF3
N N N N N N
15 16 17
hCB2 Ki 0.32 nM hCB2 Ki 0.40 nM hCB2 Ki 0.60 nM

Fig. (8). (Z)-2-tert-Butyl-{[(2Z)-3-butyl-5-tert-butyl-1,3,4-thiadiazol-2(3H)-ylidene]carbamoyl}-4-(trifluoromethyl)phenylcarbamate (15)
and other 1,3,4-thiadiazolylidene carboxamides.
CB2 Ligands and Pain Recent Patents on CNS Drug Discovery, 2013, Vol. 8, No. 1 49
being (Z)-2-tert-butyl-{[(2Z)-3-butyl-5-tert-butyl-1,3,4-
O
thiadiazol-2(3H)-ylidene]carbamoyl}-4-(trifluoromethyl)
phenylcarbamate (15) (K hCB = 0.32 nM).
i 2
2.2. 1,2-Dihydro-3H-pyrazoles HN
O
The substitution of the sulfur atom of previous com-
pounds with a carbon led to the 1,2-dihydro-3H-
N
pyrazolylidene derivatives [31, 39-45]. Among them, com- N
N CF
pounds 18 and 19 Fig. (9), namely N-[(3E)-2-butyl-5-tert- 3
butyl-1-methyl-1,2-dihydro-3H-pyrazol-3-ylidene]-2-[(2,2-
dimethylpropanoyl)hydrazine]-5-(trifluoromethyl)benzamide
and (E)-N-{5-tert-butyl-1-methyl-2-[(tetrahydrofuran-2- O 20
yl)methyl]-1H-pyrazol-3(2H)-ylidene}-2-fluoro-3-(trifluoro-
methyl)benzamide, respectively, showed the best hCB2 affin- hCB2 Ki = 0.90 nM, rCB2 Ki = 0.60 nM
ity with Ki values of 0.4 nM for 18 and 0.7 nM for 19. rCB2 EC50 = 0.19 nM, rCB1 EC50 = 901 nM
O Fig. (10). N-{(3E)-5-tert-Butyl-1-methyl-2-[(2R)-tetrahydrofuran-
2-ylmethyl]-1,2-dihydro-3H-pyrazol-3-ylidene}-2-{[(2S)-tetrahyd-
NH rofuran-2-ylmethyl]amino}-5-(trifluoromethyl)benzamide.
HN F CF3
O O 2.3. Other Structures
In other patents [46-48], Abbott Laboratories claim other
N N
N N CF N N classes of CB2 receptor ligands, not related to those previ-
3 ously described, whose structures are shown in Fig. (11). In
particular, the authors assert that indole derivatives bearing a
18 19
3-keto-tetramethylcyclopropyl group, such as [1-(2-
hCB2 Ki = 0.40 nM O hCB2 Ki = 0.70 nM morpholinoethyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclo-
propyl)methanone (21) and{1-[2-(tetrahydro-2H-pyran-4-
Fig. (9). N-[(3E)-2-Butyl-5-tert-butyl-1-methyl-1,2-dihydro-3H-
yl)ethyl]-1H-indol-3-yl}-(2,2,3,3-tetramethylcyclopropyl)
pyrazol-3-ylidene]-2-[(2,2-dimethylpropanoyl)hydrazine]-5-(tri-
methanone (22), have been shown to possess high hCB re-
2
fluoromethyl)benzamide (18) and (E)-N-{5-tert-butyl-1-methyl-2-
ceptor binding affinities with K values of 4.6 and 0.21 nM,
i
[(tetrahydrofuran-2-yl)methyl]-1H-pyrazol-3(2H)-ylidene}-2-
respectively. The activity of these compounds was also as-
fluoro-3-(trifluoromethyl)benzamide (19).
sessed in human and rat cyclase assays, compound 21 being
found to be highly selective for the hCB receptors (CB /CB
Different 1,2-dihydro-3H-pyrazolidines from those just 2 1 2
= 1385). These derivatives display an analgesic effect in two
reviewed are described in patent US8188135 (2012) [45],
types of animal pain model relating to neuropathic and noci-
whose representative compound is the N-{(3E)-5-tert-
ceptive pain, that is, the complete Freund’s adjuvant and the
butyl-1-methyl-2-[(2R)-tetrahydrofuran-2-ylmethyl]-1,2-
spinal nerve ligation model, respectively.
dihydro-3H-pyrazol-3-ylidene}-2-{[(2S)-tetrahydrofuran-2-
ylmethyl]amino}-5-(trifluoromethyl)benzamide (20) shown
in Fig. (10). This derivative showed KCB values in the O O
i 2
picomolar range both in human (0.90 nM) and rat (0.60
nM) receptors. Moreover, the compounds claimed in the
patent are more potent in activating CB receptors with
2
respect to CB as resulted from cyclase assays: particularly,
1 N N
pyrazolidine 20 showed an EC = 0.19 nM for rat CB re-
50 2
ceptors, whereas only an EC value of 901 nM for rat CB
50 1
receptors. N
All compounds have been tested in different model of
21 22
pain, as incision model of postoperative pain, spinal nerve O O
ligation and chronic constriction injury model of neuropathic hCB2 Ki = 4.6 nM hCB2 Ki = 0.21 nM
pain. Tactile allodinya was measured by calibrated von Frey
Fig. (11). [1-(2-Morpholinoethyl)-1H-indol-3-yl]-(2,2,3,3-
filaments and the compounds tested showed a statistically
tetramethylcyclopropyl)methanone (21) and its tetrahydro-2H-
significant change in paw withdrawal latency versus a saline
pyran-4-yl-ethyl analogue (22).
vehicle. These compounds have been also tested in the uni-
lateral knee joint osteoarthritic pain model induced by a sin-
Compounds having the general structure 23 and 24 Fig.
gle intra-articular injection of sodium iodoacetate: also in
(12) were claimed in EP2176219 (2010) [49], whereas 25-27
this assay, the tested derivatives showed a statistically sig-
were claimed in US7868038 (2011) [50, 51]. The authors
nificant change in the specific test, the limb withdrawal la-
declare that some of these derivatives, which bound to CB
tency, versus a saline vehicle. 2
receptors with a K between 1 and 400 nM, showed a statisti-
i
50 Recent Patents on CNS Drug Discovery, 2013, Vol. 8, No. 1 Murineddu et al.
NR1R2 NR1R2
X
Y O O
NH NH
O R3 O R3
23 24
X = Y = CH; X = N, Y = CH; X = CH, Y = N
R and R = hydrogen, alkyl, haloalkyl, alkenyl, or linked together to form monocyclic heterocycles
1 2
R = bulky substituents
3
R1 O R3 O R1 R3 O R1 R3 O
O
N R2 N R2 O R
S H S H N 2
S H
25 26
27
X = Y = CH; X = N, Y = CH; X = CH, Y = N
R and R = alkyl, alkoxyalkyl, alkylcarbonyl, halo, haloalkyl, carbonyl, carboxamide, sulfonamide groups
1 3
R = (hetero)aryl, (hetero)cycloalkyl, alkoxy, amine groups
2
Fig. (12). Mono- bicycle aromatic carbonylamino-carboxamides (23, 24), 5,6,7,8-tetrahydro-4H-4,7- and 4,8-epoxycyclohepta[b]thiophenes
(25, 26), 4,7-epoxy-4,5,6,7-tetrahydrobenzo[b]thiophenes (27).
cally significant change in paw withdrawal latency versus a 3.1. Azacycloalkane Carboxamides
saline vehicle at less than about 300 micromol/Kg in the spi-
3.1.1. Azetidine Carboxamides
nal nerve ligation model of neuropathic pain, and showed
efficacy at less than about 50 micromol/Kg in the same The azetidine-2-carboxylic acid core [52, 53] was modu-
model. No data were provided concerning specific structures lated both at position N1 and on the C2 carboxylic function,
and activities. with the introduction of a number of aromatic and/or ali-
phatic substituents on the azetidinic N1, and the simultane-
3. BOEHRINGER INGELHEIM ous evaluation of different amine groups in the carboxylic
portion. The N-1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]
Recent Boehringer Ingelheim patents [52-57] on CB
2 group was the preferred substituent on the N1 position of the
receptor modulators have claimed aliphatic heterocyclic
azetidine, this group being present in the two most potent
compounds bearing a carboxamide moiety at the C2 posi-
derivatives claimed in the patent, namely (S)-N-(5-tert-butyl-
tion. In particular, these have covered azetidine and azepane-
isoxazol-3-yl)-1-[3-chloro-5-(trifluoromethyl)pyridin-2-
type structures, including pyrrolidine and piperidine homo-
yl]azetidine-2-carboxamide (28) and the (S)-N-(5-tert-butyl-
logues.
isoxazol-3-yl) isomer 29, Fig. (13).
All of the CB agonist derivatives claimed in the patents
2
exhibited CB -receptor-mediated modulation of cAMP syn-
2
thesis, expressed as EC (nM). However, though the inven-
50
tors identified a range of binding affinities for many com-
pounds, they did not report the binding data values of indi-
O O
vidual compounds on both the CB1 and CB2 receptors. As a O N
consequence it is difficult to assess whether any of the com- N N N O
pounds are selective for one receptor over another and to H H
N N
infer whether they are particularly well suited for the treat-
ment of pain.
Cl Cl
Seven patents [58-64] covered different sulfonyl deriva-
tives which were strictly related to amidosulfones reported in
2009 by Agmen Inc. [65] and, therefore, all of these deriva- CF3 CF3
tives will be presented in the second section on Boehringer 28 29
Ingelheim.
Finally, the last section deals with a series of 1,4- CB2 EC50 = 0.02 nM CB2 EC50 = 0.05 nM (cid:1)
diazepane carboxamides [66-68] and covers recently Fig. (13). (S)-N-(5-tert-Butyl-isoxazol-3-yl)-1-[3-chloro-5-
granted patents concerning amine [69], ether [70], triazole (trifluoromethyl)pyridin-2-yl]azetidine-2-carboxamide (28) and (S)-
and tetrazoles derivatives [71-74] which modulate CB re- N-(5-tert-butyl-isoxazol-3-yl) isomer (29).
2
ceptors.
CB2 Ligands and Pain Recent Patents on CNS Drug Discovery, 2013, Vol. 8, No. 1 51
O O O
O N N
N N N O N O
H H H
N N N
N N N
F
CF3 Cl CF3
30 31 32
CB2 EC50 = 0.015 nM CB2 EC50 = 0.02 nM CB2 EC50 = 0.023 nM
Fig. (14). (S)-N-(5-tert-Butyl-isoxazol-3-yl)-2-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide (30) and it (S)-N-(3-tert-
butyl-isoxazol-5-yl)-1-pyridin-2-yl-pyrroldine-2-carboxamide analogs.
From this series further indications could be derived re- rolidine, and its homologation to piperidine, furnished com-
garding the carboxamidic function since the two derivatives pounds 36 and 37 which still retained a good CB affinity:
2
28 and 29, in addition to possessing the best CB receptor more precisely, the potency of pyrrolidin-1-ylsulfonyl-
2
affinity amongst related compounds, showed little difference propanamide, compound 36, was 3-fold higher than that of
in cAMP EC values, 0.020 and 0.050 nM, respectively, compound 35 (EC CB = 1.3nM), whilst the potency of the
50 50 2
indicating that the bond position of the isoxazole ring rela-
tive to the carboxylic function of the azetidine core plays a
significant role.
3.1.2. Pyrrolidine Carboxamides
O O
O O
The same trend, regarding its azetidinic homologs, is also
reported in the pyrrolidine-carboxamides series claimed in N N N N
H H
patents WO147791 (2010) [54] and US0142677 (2012) N N
[55]. Again, (S)-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-1-
[5-(trifluoromethyl)pyridin-2-yl]pyrrolidine-2-carboxamide N
CF
(30) was found to be the agonist with the highest CB recep- 3
2
tor affinity (EC = 0.015 nM), while its (S)-N-(3-tert-butyl- O
50 33 34
isoxazol-5-yl) analogs, 31 and 32, showed a slight CB re-
2
ceptor affinity decrease (cAMP, EC50 = 0.020 and 0.023 nM, CB2 EC50 = 0.093 nM CB2 EC50 = 0.03 nM
respectively) Fig. (14).
Fig. (15). (S)-N-(5-tert-Butyl-isoxazol-3-yl)-1-[5-(trifluoromethyl)
3.1.3. Piperidine and Azepane Carboxamides pyridin-2-yl]piperidine-2-carboxamide (33) and (S)-N-(5-tert-butyl-
isoxazol-3-yl)-1-(tetrahydro-pyran-4-ylmethyl)azepane-2-
(S)-N-(5-tert-Butyl-isoxazol-3-yl)-1-[5-(trifluoromethyl)
carboxamide (34).
pyridin-2-yl]piperidine-2-carboxamide (33) and (S)-N-(5-

tert-butyl-isoxazol-3-yl)-1-(tetrahydro-pyran-4-ylmethyl)
O
azepane-2-carboxamide (34) Fig. (15) are the most represen- O O
O S N O
tative derivatives of piperidine and azepane-carboxamides O S N
related to previously discussed compounds [56, 57]. The
NH
homologation of the aza-ring to piperidine, as in compound O NH
N
33, resulted in a decrease in CB receptor affinity (cAMP, O
2 N
35
EC = 0.093 nM), as compared with the pyrrolidine series,
50 36
while for the azepane derivative, 34, the N1-piperidine group
CB EC = 3.6 nM
2 50
substitution with a tetrahydro-pyran-4-ylmethyl retained a CB EC = 1.3 nM
2 50
CB receptor affinity (cAMP, EC = 0.030 nM) with respect
2 50
to pyrrolidine. O
O
O S N
3.2. Sulfonyl-Isoxazolyl-Amides and Benzensulfonyl-
Carboxamides NH
O
N
SAR studies and cannabinoidergic profiles of 2-(azetidin-
1-ylsulfonyl)-N-(5-tert-butylisoxazol-3-yl)-2-methylpropa- 37
namide (35) and related compounds were evaluated by Boe-
CB2 EC50 = 6.5 nM
hringer Ingelheim [58], Fig. (16). Compound 35 showed
agonistic activity for the CB receptor with an EC value of Fig. (16). 2-(Azetidin-1-ylsulfonyl)-N-(5-tert-butylisoxazol-3-yl)-
2 50
3.6 nM. Ring expansion of the azetidine nucleus to pyr- 2-methylpropanamide (35) and its pyrrolidine (36) and piperidine
(37) homologues.