Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/296475811
CITATIONS READS
2 261
2 authors:
Some of the authors of this publication are also working on these related projects:
All content following this page was uploaded by Vadim Shevyrin on 01 March 2016.
The data on the chemical structures, biological effects, and use of cannabinoids on the
illegal market of new psychoactive substances were generalized. An extended classification
comprising new classes, groups, and subgroups of cannabinoids was proposed for better repre
sentation of their structural variety. The emergence of new synthetic cannabinoids which
belong to the groups of cycloalkanecarbonylindoles, indole and indazole3carboxamides,
and indole and indazole3carboxylates is closely associated with the market of new psycho
active substances.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 12491266, June, 2015.
10665285/15/64061249 2015 Springer Science+Business Media, Inc.
1250 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 Shevyrin and Morzherin
An essential milestone in the understanding of what is clinical trials, they were superior to the antiemetics
behind the psychoactive effect of cannabis was the deter employed at that time.5,6,17 Those encouraging results
mination of the structures and pharmacological charac prompted the Ministry of Health of Canada to approve
teristics of its principles:6,11 9tetrahydrocannabinol (1) the medical use of nabilone in 1982, regardless of its side
(THC), its isomeric 8tetrahydrocannabinol (2), can effects; dronabinol was allowed in the USA in 1985.
nabinol (3), and cannabidiol (4). Cannabinol, the first Much attention was also given to the use of cannab
natural cannabinoid isolated in the late XIX century, was inoids as analgesics. The results obtained were quite satis
structurally identified in the 1930s; the total synthesis of factory, and the US pharmaceutical company Pfizer Inc.
this compound was conducted in the 1940s.12,13 Using began to develop synthetic THC analogs as potential an
improved methods for extracting the principles of can algesics.11 In 1979, the Pfizer researchers synthesized
nabis, Mechoulam et al. isolated cannabidiol and deter 2[(1S,3R)3hydroxycyclohexyl]5(2methyloctan2
mined its structure in 1963.14 A year later, pure THC was yl)phenol (CP 47497) and its homologs with different
isolated, structurally characterized, and successfully syn lengths of the alkyl substituent (from dimethylhexyl to
thesized from cannabidiol15 as well as from simpler or dimethylnonyl).18,19 The testing of these compounds re
ganic matter.16 vealed desired high biological activity. However, their pro
By nearly that time, THC was found to be the main nounced narcogenic potential (several times that of THC)
psychoactive constituent of cannabis; the psychoactive was immediately noticed as well.20 The more potent anal
potential of cannabinol is much weaker, while cannabidi gesic 2[(1R,2R,5R)5hydroxy2(3hydroxypropyl)
ol is absolutely inactive in this respect.11 cyclohexyl]5(2methyloctan2yl)phenol (CP 55940)
The structural identification of the above natural can obtained by the same company shortly after21 exhibits even
nabinoids and the availability of their chemically pure sam higher narcotic activity.
ples considerably spurred the investigations of the thera
peutic potential of these compounds in the 1970s, mainly
in Great Britain, the USA, and Canada, where the restric
tions on the medical use of their preparations were partial
ly lifted by the local legislative authorities.5,11 The best
results were achieved with dronabinol (a THC stereo
isomer) and nabilone (a synthetic THC analog) used as
antiemetics in cancer patients under chemotherapy. In
new compounds with desired biological activity. When gastrointestinal tract. The uneven distribution of CB1
tritiumlabeled CP 55940 was injected into rats, this com receptors in the central nervous system may account, to
pound was found to specifically bind to certain molecular some extent, for the psychoactive effects of cannabinoids.29
structures of brain22 named cannabinoid CB1 receptors.6 Numerous data provide evidence for a direct relationship
In 1990, the results of molecular cloning of this receptor between the affinity of cannabinoids for CB1 receptors
were published.23 The receptor of second type, CB2, was and their narcogenic potential.3033 Cannabinoid CB2 re
identified in 1993.6,24 ceptors are mainly located on the surface of the cells of the
The discovery of cannabinoid receptors prompted immune system, mediate many physiological processes
searching for endogenous ligands that can bind to these involving immune responses, and influence the bodys
receptors. Main endogenous ligands (endocannabinoids) resistance to infectious, allergic, and oncological di
were found in 199219952527 and include arachidonic seases.29,34
acid derivatives: N(2hydroxyethyl)arachidonamide (an The serious interest in cannabinoids was revived by the
andamide) (5) and 2Oarachidonylglycerol (6). Later, advance in the understanding of their mechanisms of ac
some other endocannabinoids were discovered. Structur tion. The synthesis of new cannabinoids was intended to
ally, they are saturated or unsaturated acid amides (e.g., obtain compounds that would be specific for the one or
oleamide).28 The physiological properties of endocannab other type of cannabinoid receptors or would simulta
inoids are much the same as those of natural and synthetic neously affect both with different competitive abilities.
exogenous cannabinoids. The tendency to interact with receptors in the one or other
way can, in turn, predetermine the pharmacological ac
tivity of a new cannabinoid.11
(6aR,10aR)9Hydroxymethyl6,6dimethyl3(2me
thyloctan2yl)6a,7,10,10atetrahydro6Hbenzo[c]
chromen1ol obtained in 1988 was among the first pre
sumptive drugs containing synthetic cannabinoids; this
THC analog was named HU210.35 Preliminary tests of
HU210 revealed its high analgesic activity. However, the
medical use of this compound was precluded because of its
considerable narcogenic potential (more than 100 times
that of THC), regardless of some positive aspects.3639 Its
stereoisomer HU211 obtained at the same time is also an
analgesic but incapable of binding to cannabinoid recep
tors and thus showing no psychoactive properties. This
compound is currently under extensive medical examina
tion for the treatment of, e.g., craniocerebral traumas.40
properties.6,11,29,38,51 Future studies should be focused on of the time sense,66 and distinct Spice addiction (with
separation of the therapeutic and side (first of all, psycho a withdrawal syndrome). However, toxicological tests de
active) effects of CB1 receptor agonists. tected no tetrahydrocannabinol.
Cannabinoid CB2 receptor agonists showing antiin Initial attempts to explain why Spice products have
flammatory and immunosuppressive activity are also of the narcogenic effect on the body failed because it was the
great interest.29,34 For the study of the therapeutic value of herbal composition claimed by manufacturers that was
CB2 receptors, it was necessary to synthesize compounds under examination first and foremost. However, it gradu
with high affinity for receptors of this type and with low ally became clear that those exotic herbs could hardly
(or no) affinity for CB1 receptors; this is a challenging task produce such a strong psychoactive effect.64 Although
in modern pharmacology. It was postulated that CB2sel a suspicion arose that Spice products could contain syn
ective agonists could be useful for the treatment of inflam thetic compounds, the lack of analytical data precluded
matory and some other diseases, exhibiting an anesthetic their identification at the laboratories of the Ministry of
(but no unwanted psychoactive) effect. Based on this pos Health of Germany as long as several months.
tulate, research laboratories and pharmaceutical compa In December 2008, the pharmaceutical company
nies still make considerable efforts in searching for CB2 "THC Pharm" (Frankfurt, Germany) specializing in the
selective agonists and synthesize a broad spectrum of struc synthesis and study of cannabinoids published its account
turally various compounds.5261 of the compositions of several Spice brands.67 All of them
were found to contain the synthetic cannabinoid JWH018
Synthetic cannabinoids as drugs of abuse in different concentrations. Soon after, two research teams
at the Freiburg University (Freiburg, Germany)62 and the
Starting in 2004, various herbal smoking blends ("Spice National Scientific Institute of Health (Japan)68 simulta
silver", "Spice gold", "Spice diamond", "Smoke", "Smoke neously identified in some Spice products the C8 homolog
Plus", "Sence", "Skunk", "Yucatan Fire", etc.62) were sold, of the synthetic cannabinoid CP 47497 (CP 47497C8)
mostly via online shopping, in Switzerland, Austria, Ger with its transdiastereomer as a byproduct. Some smok
many, and other European countries. Further active dis ing blends contain both CP 47497C8 and JWH018.
tribution of such herbal smoking and incense blends over
Europe, North America, and New Zealand in 20042008,
as well as somewhat later over Russia, revived the fashion
(first of all, among young people) for psychoactive drugs;
they are commonly named "Spice" after the correspond
ing popular brand name. Instrumental in this "revival" was
the aggressive advertising policy by Internet shops, which
sold "Spice" products as merely relaxing herbal blends,
thereby concealing their true composition.
Originally, manufacturers promoted their Spice prod
ucts as blends of traditional legal exotic and medicinal
herbs composed to imitate the psychoactive effect of mar
ijuana. In Internet forums, users described strong hash
ishlike effects after smoking these types of herbal blends.
Being advertised and easily accessible for a number of
years, Spice products were recognized by users of these
new experimental preparations as well as by many hashish
and marijuana users who wanted for legal alternatives to
these narcotic drugs.63,64 Even though Spice products were
more expensive than illicit marijuana sold on the black The consequence was that the identified synthetic can
market, their legality and negative drug test results made nabinoids JWH018 and CP 47497C8 along with their
Spice products very popular. most closely related homologs were made illegal by the
The Spice boom reached a peak in mid2008 and German controlling bodies63 on January 22, 2009 and,
caused a broad public response, notably in Germany, for almost immediately, by some other European countries.64
their enormous popularity. First of all, this was a response However, contrary to the expectations, that decision did
to a number of accidents and mental disorders in Spice not solve the Spice problem, producing quite the reverse
users.65 Toxicologists noticed that the behavior of their effect in many respects because of imperfect legislation.
patients is typical of marijuana users. The symptoms in Having realized during the preceding years the possibility
clude red eyes, tachycardia, anxiety, paranoia, and hallu of unpunishable enrichment and formed a certain social
cinations accompanied by transient global amnesia, lack stratum of users, the illegal drug trade turned every legisla
1254 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 Shevyrin and Morzherin
tive lacuna to its advantage and marketed new kinds of tive limitations for these plants had been adopted, proce
synthetic cannabinoids similar to the already prohibited dures for their identification were developed, but none of
ones in both chemical structure and psychoactive effect. these plants were detected in smoking blends. The true
This activity has become quite deliberate in the last few origin of their psychoactive effect remained unclear until
years, involving the published data on the synthesis and first publications concerning the detection, methods of
medical tests of synthetic cannabinoids. identification, and analytical characteristics of some syn
For instance, the new synthetic cannabinoid JWH073, thetic cannabinoids appeared in foreign scientific litera
which is a butyl homolog of JWH018 and is formally not ture.6266 As in other countries, the development of nor
banned, was identified in Spice products as early as March mative documentation for the control of synthetic can
2009.63 Data for its GCMS detection were presented for nabinoids was substantially accelerated by mass media
the first time. The synthetic cannabinoid HU210 was publications (NovemberDecember 2009) regarding nu
reported that year to be found in smoking blends in the merous injuries and fatal accidents caused by mental dis
USA.69 In late 2009, two more synthetic cannabinoids of orders in people smoking such blends. The Russian Gov
the "second wave", JWH250 and JWH398,64,70,71 were ernment Resolution No. 1186 (December 31, 2009) in
identified by mass spectrometry in Europe. cluded a number of synthetic cannabinoids (e.g., the
most commonly encountered JWH018, JWH073, and
CP 47497C8) in Schedule I of the narcotic drugs prohib
ited in Russia. Immediately after the publication of this
Resolution, the expert groups encountered the lack of an
alytical techniques and published data for identification of
synthetic cannabinoids. This problem became critical after
new types of such compounds had emerged into the illicit
traffic instead of the prohibited ones.73 Moreover, new
types of cannabinoids were often detected far in advance
of first papers concerning their analytical characteristics,
and an ever increasing number of new synthetic canna
binoids was constantly reported. Subsequently, it was not
uncommon that they emerged first in Russia and, in some
period of time, elsewhere in the world. This is due to the
great capacity of the Russian market as well as to the
organized groups of illicit traffickers skilfully taking ad
vantage of the defective drug legislation in use. Synthetic
cannabinoids structurally related to, but slightly modified
against, the prohibited ones could not be legally classified
as narcotic drugs. This legal problem was partially solved
In contrast to the European countries, in which the by the Russian Government Resolutions No. 882 (Octo
distribution of synthetic cannabinoids was made illegal ber 30, 2010) and No. 1178 (November 19, 2012), in which
almost immediately upon the official accounts of their the definition "drug derivative" was introduced and then
identification, no mechanism was developed in Russia in validated. This definition partly covers compounds struc
2009 to oppose the imminent enormous threat of NPS turally related to narcotic drugs but not included in Sched
distribution among people. The global distribution of syn ule I of Narcotic Drugs as individual items. Drug traffick
thetic cannabinoids was not stopped because of the lack of ers responded to this measure by offering new synthetic
relevant normative documents and provision of expert cannabinoids manufactured through more profound struc
groups with analytical techniques and scientific informa tural modification. Therefore, the identification of syn
tion regarding identification of these compounds. The his thetic cannabinoids and the provision of experts with
tory of Spice distribution in Russia followed in many re a developed methodology including analytical techniques
spects the negative foreign experience. Clearly, the lack of and the characteristics of compounds still remain modern
the analytical characteristics and techniques for identifi challenges to drug analysts.
cation of synthetic cannabinoids diverted all Russian con
trolling bodies onto the wrong path pursued for a long Classification of cannabinoids
period of time.72 For instance, based on Internetwide
information, they limited in Russia the distribution of Biologically, cannabinoids are chemical compounds
Hawaiian rose, sage of the diviners (Salvia divinorum), that can interact, in some or other way, with cannabinoid
and blue lotus all allegedly found in smoking blends and receptors. Such compounds can be divided into can
responsible for their narcotic activity. Only after legisla nabimimetics (they exhibit cannabinoid activity and are
Cannabinoids: structures and classification Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 1255
mostly CB1 receptor agonists) and antagonists capable of indol3yl cycloalkyl ketone moiety into a new large group
binding to cannabinoid receptors (they produce no can of cycloalkanecarbonylindoles within 3carbonylindoles.
nabinoid effects, simply blocking these receptors for other Cycloalkanecarbonylindoles can be further subdivided, de
substances).4,50 pending on the cycloalkane structure, into smaller groups
The term "cannabinoids" covers compounds having di such as, e.g., adamantanecarbonylindoles and cyclo
verse chemical structures underlying the following con propanecarbonylindoles.
ventional classification.4,50,74 Along with indole3carboxamides, a new group of syn
1. Classical cannabinoids: dibenzopyran derivatives thetic cannabinoids based on indole3carboxylates should
(THC, its isomers, and structurally related synthetic ana also be referred to as 3carbonylindoles. This group will
logs such as, e.g., HU210). include indole3carboxylic acid esters identified in smok
2. Nonclassical cannabinoids: synthetic cyclohexyl ing blends in 20122014.
phenol derivatives (3arylcyclohexanols such as, e.g., CP Because the modification of synthetic cannabinoids,
47497 and CP 55940). for the synthesis of NPS as well, often involves replace
3. Hybrid cannabinoids combining the structural fea ment of the indole heterocyclic system by the indazole
tures of classical and nonclassical cannabinoids. one, an increasing number of new synthetic cannabinoids
4. Aminoalkylindoles: a large class of synthetic can contain the indazole3carbonyl moiety. The substituents
nabinoids subdivided, according to the current classifica in positions 1 and 3 of the indazole ring are the same as
tion, into naphthoylindoles, phenylacetylindoles, benzo in 3carbonylindoles. For instance, 3naphthoylind
ylindoles, and naphthylmethylindoles. It was the first three azoles,7678 indazole3carboxamides,7982 and indazole
groups of compounds that were used by criminal business 3carboxylates83 have been identified as designer drugs to
as designer drugs giving birth to the era of smoking blends. date. Therefore, 3carbonylindazoles can be regarded as
5. Eicosanoids: endocannabinoids (such as, e.g., anand a new class subdivided into much the same groups as those
amide) or their synthetic analogs. for 3carbonylindoles.
6. Others: such compounds as diarylpyrazoles (e.g., Based on the above reasoning, the current classifica
SR141716A and SR144528), naphthoylpyrroles, naph tion of cannabinoids should be recast as follows:
thylmethylindenes, and other cannabinoids constituting 1. Classical cannabinoids.
no classes in their own right. 2. Nonclassical cannabinoids.
The above classification cannot be considered exhaus 3. Hybrid cannabinoids.
tive, especially for aminoalkylindoles. A first extension75 4. 3Carbonylindoles:
to this classification was made only in mid2013 by intro 4.1. Naphthoylindoles;
ducing such groups as adamantoylindoles (or, more cor 4.2. Phenylacetylindoles;
rectly, adamantanecarbonylindoles), cyclopropanoylin 4.3. Benzoylindoles;
doles (cyclopropanecarbonylindoles), indolecarboxamides 4.4. Cycloalkanecarbonylindoles:
(indole3carboxamides), and indazolecarboxamides 4.4.1. Adamantanecarbonylindoles;
(indazole3carboxamides) widely distributed as NPS 4.4.2. Cyclopropanecarbonylindoles;
since 2011. 4.5. Indole3carboxamides;
Despite this attempt,75 the classification is still defec 4.6. Indole3carboxylates;
tive because a number of new compounds as well as the 4.7. Other 3carbonylindoles.
potential structural variety of substituents within certain 5. 3Carbonylindazoles:
groups are ignored. 5.1. Naphthoylindazoles;
First of all, it should be noted that the class name 5.2. Indazole3carboxamides;
"aminoalkylindoles" originating from compounds like 5.3. Indazole3carboxylates.
WIN552122 has lost much of its initial sense because of 6. Eicosanoids.
successful replacement of the aminoalkyl group in posi 7. Miscellaneous cannabinoids:
tion 1 of the indole ring by alkyl or aryl groups without 7.1. Diarylpyrazoles;
losing the cannabinoid activity. This class of compounds 7.2. 3Naphthoylpyrroles;
mainly consists of 3acylindole derivatives subdivided into 7.3. Naphthylmethylindoles;
groups according to the acyl substituent structure. There 7.4. 2Naphthoylbenzimidazoles;
fore, the only common structural moiety found in most of 7.5. Naphthylmethylindenes;
the compounds of this class is indole3carbonyl, and and other groups.
a new, more accurate name "3carbonylindoles" can be Of course, since new synthetic cannabinoids emerge
proposed for them. Naphthylmethylindoles should be constantly, the classification proposed above cannot be
placed in a new small class of "miscellaneous cannab "fixed for ever" and should be permanently modified and
inoids" (the former class name "other cannabinoids"). It is supplemented with new classes of compounds. Never
expedient to unite synthetic cannabinoids containing the theless, this version of classification conforms better to
1256 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 Shevyrin and Morzherin
a structural variety of synthetic cannabinoids, provides simplified and combined using a computerassisted model
their more detailed systematization, and allows elabora to reveal reactive sites in these molecules and obtain a new
tion of more definite legal measures against the distribu hybrid structure.84 Several 3naphthoylindole derivatives
tion of synthetic cannabinoids as designer drugs. Below containing normal Nalkyl substituents (C3C7) were
we will dwell on some groups of synthetic cannabinoids by synthesized. Biological tests of these compounds con
analyzing the literature data on their structures, the goals firmed the hypothesis that a necessary and sufficient con
of synthesis, and identification on the NPS market. dition for the cannabinoid activity to appear is that the
indole ring should contain the naphthoyl or similar group
3Carbonylindoles in position 3 and an Nalkyl substituent C4C6 in place of
the aminoalkyl fragment of WIN552122. For instance,
This class includes various 3acylindole derivatives the pronounced cannabinoid activity and affinity for both
containing, e.g., oxo, ester, or carboxamide groups in po types of receptors are exhibited by (2methyl1pentyl
sition 3 of the heterocycle. 1Hindol3yl)(1naphthyl)methanone (JWH007), one
of the first compounds of this series.
Later, Huffman et al. obtained a number of 3naph
Naphthoylindoles thoylindoles containing various alkyl and aminoalkyl sub
stituents.8588 Most of them show affinity for cannab
These are 3naphthoylindole derivatives having the inoid receptors of both types. However, some prefer to
general structural formula shown below. bind to CB1 receptors, while others, to CB2 ones.
The synthesized compounds with high affinity for both
types of receptors as well as with a pronounced narcogenic
potential include, apart from JWH007, (naphthalen1yl)
(1pentyl1Hindol3yl)methanone (JWH018), (1but
yl1Hindol3yl)(naphthalen1yl)methanone (JWH073),
(1hexyl1Hindol3yl)(naphthalen1yl)methanone
(JWH019), (4methylnaphthalen1yl)(1pentyl1Hin
dol3yl)methanone (JWH122), (4ethylnaphthalen1
yl)(1pentyl1Hindol3yl)methanone (JWH210),
(4methoxynaphthalen1yl)(1pentyl1Hindol3yl)
The pioneering investigations aimed at the targeted methanone (JWH081), (4methylnaphthalen1yl)[1
synthesis of a large group of cannabinoids representing (2morpholin4ylethyl)1Hindol3yl]methanone
Nalkyl3naphthoylindoles and considered a point of de (JWH193), (4methoxynaphthalen1yl)(2methyl1
parture for the development of the whole class of 3carbo pentyl1Hindol3yl)methanone (JWH098), etc.
nylindoles were effected in the 1990s at the Clemson Uni Almost simultaneously, the research team headed by
versity (USA).84 The investigations were supervised by A. Makriyannis89 at the Connecticut State University
J. W. Huffman, after whom the series of such compounds (USA) obtained a large series of compounds (convention
has been named JWH. All the synthesized "experimental" ally named AM) with the aim of studying their cannab
compounds served to study a relationship between the inoid activity. First representatives of this group included
chemical structure of cannabinoids and their affinity for 3naphthoylindole derivatives in which an aminoalkyl
CB1 and CB2 receptors as well as to gain insight into the chain as a cyclic amine is attached to the indole N atom
mechanisms by which cannabinoids interact with the through a carbon atom.90 An example is [1(1methyl
corresponding receptors. The synthetic cannabinoid piperidin2ylmethyl)1Hindol3yl](naphthalen1yl)
WIN552122 and THC were used as "parent" compounds methanone (AM1220). The 3naphthoylindole deriva
for structural modeling. Their structures were deliberately tives obtained later contain normal Nalkyl substituents
Cannabinoids: structures and classification Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 1257
Generally, these compounds are not highly selective to A great stride in this direction was made by the re
CB2 receptors. However, some of them show equally high search team at the Connecticut State University (USA).
affinity for receptors of both types. These are 2(2me Compounds of this group were investigated in parallel with
the synthesis and study of 3naphthoylindoles.9092 One
of the first representatives is [6iodo2methyl1(2mor
pholin4ylethyl)1Hindol3yl](4methoxyphenyl)
methanone (AM630, or 6iodopravadoline). This potent
CB2 receptor antagonist shows weak affinity for CB1 re
ceptors.95 Many compounds were synthesized during the
structural modeling, including (2iodo5nitrophenyl)[1
(1methylpiperidin2ylmethyl)1Hindol3yl]meth
anone (AM1241). This strong and selective CB2 receptor
agonist possesses analgesic properties, with no pronounced
1258 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 Shevyrin and Morzherin
Pravadoline
side effects on the central nervous system.96,97 The other tested for cannabinoid activity.92,93 Several structurally
synthesized compounds exhibiting very high affinity for related compounds (AM1248 and AB001)100 highly se
CB1 receptors and, consequently, having an narcogenic lective to CB1 receptors were studied later.101,102
potential include [1(5fluoropentyl)1Hindol3yl](2
iodophenyl)methanone (AM694)98 and (2iodophen
yl)[1(1methylpiperidin2ylmethyl)1Hindol3yl]
methanone (AM2233).99
Cycloalkanecarbonylindoles
an anesthetic is useful for further investigations of the CB2 MMB2201, etc.)111 are water soluble, which is a new and
receptor pharmacology.106 medically useful property.
The other synthesized compounds are not highly selec Indole3carboxamides have been widely distribut
tive; some slightly prefer CB2 receptors but display con ed as NPS in the illegal drug market since 2012. Com
siderable cannabinoid activity at receptors of both types. pounds containing Nnaphthyl, N1carbamoylalkyl, and
A series of compounds of this subgroup107,108 that are N1methoxycarbonylalkyl groups in the amide frag
modified (1Hindol3yl)(2,2,3,3tetramethylcycloprop ment79,80,82,112,113 as well as (4methylpiperazino)(1pen
yl)methanone were first identified as NPS in Russia in the tyl1Hindol3yl)methanone (MEPIRAPIM)92 have
summer of 2011. It was also found that the strained cyclo since been identified in smoking blends.
propane ring of these compounds undergoes thermal open
ing at T > 150 C to give stable acyclic isomers. Indole3carboxylates
Indole3carboxamides
A group of new compounds were identified as NPS on
the market of designer drugs between October 2012 and
The presence of the carboxamide group in position 3 of
the first half of 2014. Chemically, these are esters of in
an azaheterocycle is no novelty in the modeling of syn
dole3carboxylic acids (QCBL018, QCBL2201, and
thetic cannabinoids (see, e.g., diarylpyrazoles SR141716A
QCBLCHM) structurally related to wellknown and pro
and SR14452843,47); however, indole3carboxamides
hibited synthetic cannabinoids.82,83
have been synthesized only recently.109,110
Naphthoylindazoles
Naphthoylpyrroles
Thiazolylidenes
2Naphthoylbenzimidazoles
13. R. Adams, B. R. Baker, R. B. Wearn, J. Am. Chem. Soc., 40. R. Vink, A. J. Nimmo, Neurotherapeutics, 2000, 6, 28.
1940, 62, 2204. 41. M. R. Bell, T. E. DAmbra, V. Kumar, M. A. Eissenstat,
14. R. Mechoulam, Y. Shvo, Tetrahedron, 1963, 19, 2073. J. L. Herrmann, Jr., J. R. Wetzel, D. Rosi, R. E. Philion,
15. Y. Gaoni, R. Mechoulam, J. Am. Chem. Soc., 1964, 86, 1646. S. J. Daum, D. J. Hlasta, R. K. Kullnig, J. H. Ackerman,
16. R. Mechoulam, Y. Gaoni, J. Am. Chem. Soc., 1965, 87, 3273. D. R. Haubrich, D. A. Luttinger, E. R. Baizman, M. S.
17. P. Robson, Br. J. Psychiatry, 2001, 178, 107. Miller, S. J. Ward, J. Med. Chem., 1991, 34, 1099.
18. DE Pat. 2839836; https://www.google.com/patents/ 42. T. E. DAmbra, K. G. Estep, M. R. Bell, M. A. Eissens
DE2839836C2?cl=en. tat, K. A. Josef, S. J. Ward, D. A. Haycock, E. R. Baiz
19. A. Weissman, G. M. Milne, L. S. Melvin, Jr., J. Pharmacol. man, F. M. Casiano, N. C. Beglin, S. M. Chippari, J. D.
Exp. Ther., 1982, 223, 516. Grego, R. K. Kullnig, G. T. Daley, J. Med. Chem., 1992,
20. L. S. Melvin, M. R. Johnson, C. A. Harbert, G. M. Milne, 35, 124.
A. Weissman, J. Med. Chem., 1984, 27, 67. 43. M. RinaldiCarmona, F. Barth, M. Haulme, D. Shire,
21. US Pat. 4371720; http://www.google.com/patents/ B. Calandra, C. Congy, S. Martinez, J. Maruani, G. Neliat,
US4371720. D. Caput, P. Ferrara, Ph. Soubri, J. C. Brelire, G. Le Fur,
22. W. A. Devane, F. A. Dysark, M. R. Johnson, L. S. Melvin, FEBS Lett., 1994, 350, 240.
A. C. Howlett, Mol. Pharmacol., 1988, 34, 605. 44. J. De Vry, K. R. Jentzsch, Eur. J. Pharmacol., 2002,
23. L. A. Matsuda, S. J. Lolait, M. J. Brownstein, A. C. Young, 457, 147.aaa
T. I. Bonner, Nature, 1990, 346, 561. 45. M. K. Sharma, P. R. Murumkar, A. M. Kanhed, R. Girid
24. S. Munro, K. L. Thomas, M. AbuShaar, Nature, 1993, har, M. R. Yadav, Eur. J. Med. Chem., 2014, 79, 298.
365, 61. 46. M. RinaldiCarmona, F. Barth, J. Millan, J. M. Derocq,
25. E. Fride, R. Mechoulam, Eur. J. Pharmacol., 1993, 231, 313. P. Casellas, C. Congy, D. Oustric, M. Sarran,
26. R. Mechoulam, S. BenShabat, L. Hanus, M. Ligumsky, M. Bouaboula, B. Calandra, M. Portier, D. Shire, J.C.
N. E. Kaminski, A. R. Schatz, A. Gopher, S. Almog, Brelire, G. Le Fur, J. Pharmacol. Exp. Ther., 1998,
B. R. Martin, D. R. Compton, R. G. Pertwee, G. Griffin, 284, 644.aaa
M. Bayewitch, J. Barg, Z. Vogel, Biochem. Pharmacol., 1995, 47. G. Griffin, E. J. Wray, Q. Tao, S. D. McAllister, W. K.
50, 83. Rorrer, M. Aung, B. R. Martin, M. E. Abood, Eur. J. Phar
27. T. Sugiura, S. Kondo, A. Sukagawa, S. Nakane, A. Shinoda, macol., 1999, 377, 117.
K. Itoh, A. Yamashita, K. Waku, Biochem. Biophys. Res. 48. L. Hanus, A. Breuer, S. Tchilibon, S. Shiloah, D. Golden
Commun., 1995, 215, 89. berg, M. Horowitz, E. Fride, R. Mechoulam, Proc. Natl.
28. J. D. Leggett, S. Aspley, S. R. Beckett, A. M. DAntona, Acad. Sci. USA, 1999, 96, 14228.
D. A. Kendall, D. A. Kendall, Br. J. Pharmacol., 2004, 49. C. Labuda, M. Koblish, P. Little, Eur. J. Pharmacol., 2005,
141, 253. 527, 172.
29. M. V. Churyukanov, V. V. Churyukanov, Eksp. Klin. Farma 50. V. Auwrter, S. Kneisel, M. Hutter, A. Thierauf, Rechts
kol. [Experimental and Clinical Pharmacology], 2004, 67, medizin, 2012, 22, 259.
No. 2, 70 (in Russian). 51. L. N. Maslov, A. V. Krylatov, Sib. Med. Zh. [Siberian Medi
30. D. R. Compton, K. C. Rice, B. R. De Costa, R. K. Razdan, cal Journal], 2012, 27(2), 9 (in Russian).
L. S. Melvin, M. R. Johnson, B. R. Martin, J. Pharmacol. 52. V. Lucchesi, T. Parkkari, J. R. Savinainen, A. M. Malfitano,
Exp. Ther., 1993, 265, 218. M. Allara, S. Bertini, F. Castelli, S. Del Carlo, C. Laezza,
31. R. K. Razdan, Pharmacol. Rev., 1986, 38, 75. A. Ligresti, G. Saccomanni, M. Bifulco, V. Di Marzo,
32. J. L. Wiley, D. R. Compton, D. Dai, J. A. Lainton, M. Macchia, C. Manera, Eur. J. Med. Chem., 2014,
M. Phillips, J. W. Huffman, B. R. Martin, J. Pharmacol. Exp. 74, 524.aaaa
Ther., 1998, 285, 995. 53. A. Tourteau, V. Andrzejak, M. BodyMalapel, L. Lemaire,
33. M. Mereu, V. Tronci, L. E. Chun, A. M. Thomas, J. L. A. Lemoine, R. Mansouri, M. Djouina, N. Renault, J. El
Green, J. L. Katz, G. Tanda, Addict. Biol., 2015, 20, 91. Bakali, P. Desreumaux, G. G. Muccioli, D. M. Lambert,
34. E. G. Lobanova, Zdorove. Meditsinskaya ekologiya. Nauka Ph. Chavatte, B. Rigo, N. LeleuChavain, R. Millet, Bioorg.
[Health. Medical Ecology. Science], 2009, No. 45, 112 Med. Chem., 2013, 21, 5383.
(in Russian). 54. K. K. Nanda, D. A. Henze, K. D. Penna, R. Desai, M. Leitl,
35. R. Mechoulam, J. J. Feigenbaum, N. Lander, M. Segal, W. Lemaire, R. B. White, S. Yeh, J. N. Brouillette, G. D.
T. U. Jrbe, A. J. Hiltunen, P. Consroe, Experientia, 1988, Hartman, M. T. Bilodeau, B. W. Trotter, Bioorg. Med. Chem.
44, 762. Lett., 2014, 24, 1218.
36. P. J. Little, D. R. Compton, R. Mechoulam, B. R. Martin, 55. K. Kusakabe, Y. Tada, Y. Iso, M. Sakagami, Y. Morioka,
Pharmacol. Biochem. Behav., 1989, 32, 661. N. Chomei, S. Shinonome, K. Kawamoto, H. Takenaka,
37. W. A. Devane, A. Breuer, T. Sheskin, T. U. C. Jaerbe, M. S. K. Yasui, H. Hamana, K. Hanasaki, Bioorg. Med. Chem.,
Eisen, R. Mechoulam, J. Med. Chem., 1992, 35, 2065. 2013, 21, 2045.
38. B. G. Ramirez, C. Blazquez, T. G. Pulgar, M. Guzman, 56. S. Yrjl, T. Kalliokoski, T. Laitinen, A. Poso, T. Parkkari,
M. L. Ceballos, J. Neurosci., 2005, 25, 1904. T. Nevalainen, Eur. J. Pharm. Sci., 2013, 48, 9.
39. D. S. Ugdyzhekova, L. A. Maimeskulova, Yu. G. Davydova, 57. N. R. Madadi, N. R. Penthala, L. K. Brents, B. M. Ford,
Vestn. Aritmologii [Bulletin of Arrhythmology], 2000, 19, 68 P. L. Prather, P. A. Crooks, Bioorg. Med. Chem. Lett., 2013,
(in Russian). 23, 2019.
1264 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 Shevyrin and Morzherin
58. S. Yrjl, M. Sarparanta, A. J. Airaksinen, M. Hytti, 78. V. Shevyrin, V. Melkozerov, A. Nevero, O. Eltsov,
A. Kauppinen, S. PasonenSeppnen, B. Adinolfi, P. Nieri, Yu. Morzherin, Yu. Shafran, Forensic Sci. Int., 2014,
C. Manera, O. Keinnen, A. Poso, T. J. Nevalainen, 242, 72.aaa
T. Parkkari, Eur. J. Pharm. Sci., 2015, 67, 85. 79. N. Uchiyama, M. Kawamura, R. KikuraHanajiri, Y. Goda,
59. J. J. Harnett, Ch. Dolo, I. Viossat, F. Auger, E. Ferrandis, Forensic Toxicol., 2012, 30, 114.
D. Bigg, M. Auguet, S. Auvin, P.E. Chabrier, Bioorg. Med. 80. N. Uchiyama, S. Matsuda, M. Kawamura, Y. Shimokawa,
Chem. Lett., 2015, 25, 88. R. KikuraHanajiri, K. Aritake, Y. Urade, Y. Goda, Foren
60. S. Han, L. Thoresen, X. Zhu, S. Narayanan, J.K. Jung, sic Sci. Int., 2014, 243, 1.
S. StrahPleynet, M. Decaire, K. Choi, Y. Xiong, 81. N. Uchiyama, S. Matsuda, D. Wakana, R. KikuraHanaji
D. Yue, G. Semple, J. Thatte, M. Solomon, L. Fu, ri, Y. Goda, Forensic Toxicol., 2013, 31, 93.
K. Whelan, H. AlShamma, J. Gatlin, R. Chen, H. Dang, 82. N. Uchiyama, S. Matsuda, M. Kawamura, R. KikuraHa
C. Pride, I. Gaidarov, D. J. Unett, D. P. Behan, najiri, Y. Goda, Forensic Toxicol., 2013, 31, 223.
A. Sadeque, Kh. A. Usmani, Ch. Chen, J. Edwards, 83. V. Shevyrin, V. Melkozerov, A. Nevero, O. Eltsov, A. Bara
M. Morgan, R. M. Jones, Bioorg. Med. Chem. Lett., 2015, novsky, Yu. Shafran, Forensic Sci. Int., 2014, 244, 263.
25, 322. 84. J. W. Huffman, D. Dai, B. R. Martin, D. R. Compton,
61. Y. Iwata, K. Ando, K. Taniguchi, N. Koba, A. Sugiura, Bioorg. Med. Chem. Lett., 1994, 4, 563.
M. Sudo, Bioorg. Med. Chem. Lett., 2015, 25, 236. 85. J. W. Huffman, R. Mabon, M.J. Wu, J. Lu, R. Hart, D. P.
62. V. Auwrter, S. Dresen, W. Weinmann, M. Mller, M. Ptz, Hurst, P. H. Reggio, J. L. Wiley, B. R. Martin, Bioorg. Med.
N. Ferreirs, J. Mass Spectrom., 2009, 44, 832. Chem., 2003, 11, 539.
63. R. Lindigkeit, A. Boehme, I. Eiserloh, M. Luebbecke, 86. J. W. Huffman, M.J. Wu, J. Lu, J. Org. Chem., 1998,
M. Wiggermann, L. Ernst, T. Beuerle, Forensic Sci. Int., 63, 4510.
2009, 191, 58. 87. J. W. Huffman, G. Zengin, M.J. Wu, J. Lu, G. Hynd,
64. S. Dresen, N. Ferreirs, M. Ptz, F. Westphal, R. Zimmer K. Bushell, A. L. S. Thompson, S. Bushell, C. Tartal,
mann, V. Auwrter, J. Mass Spectrom., 2010, 45, 1186. D. P. Hurst, P. H. Reggio, D. E. Selley, M. P. Cassidy,
65. C. Piggee, Anal. Chem., 2009, 81, 3205. J. L. Wiley, B. R. Martin, Bioorg. Med. Chem., 2005,
66. I. Vardakou, C. Pistos, Ch. Spiliopoulou, Toxicol. Lett., 13, 89.aaa
2010, 197, 157. 88. US Pat. 20050009903; https://www.google.com/patents/
67. Ch. Steup, Untersuchung des Handelsproduktes "Spice", THC US20050009903.
PHARM GmbH, Frankfurt am Main, 2008, 6 pp. 89. T. E. DAmbra, M. A. Eissenstat, J. Abt, J. H. Ackerman,
68. N. Uchiyama, R. KikuraHanajiri, N. Kawahara, Y. Haish E. R. Bacon, M. R. Bell, P. M. Carabateas, K. A. Josef,
ima, Y. Goda, Chem. Pharm. Bull., 2009, 57, 439. V. Kumar, J. D. Weaver, R. Amold, F. M. Casiano, S. M.
69. DEA (US Drugs Enforcement Administration). Microgram Chippari, D. A. Haycock, J. E. Kuster, D. A. Luttinger, J. I.
Bull., 2009, 42, 23. Stevenson, S. J. Ward, W. A. Hill, A. Khanolkar, A. Mak
70. F. Westphal, T. Junge, F. Snnichsen, P. Rsner, J. Schper, riyannis, Bioorg. Med. Chem. Lett., 1996, 6, 17.
Toxichem. Krimtech., 2010, 77, 8. 90. US Pat. 7820144; https://www.google.com/patents/
71. Recommended Methods for the Identification and Analysis of US7820144.
Cannabis and Cannabis Products. A Manual for Use by 91. WO Pat. 0128557; https://www.google.com/patents/
National Drug Analysis Laboratories, United Nations, New WO2001028557B1?cl=en.
York, 2009, 56 pp. (URL: http://www.unodc.org/documents/ 92. US Pat. 20050119234; http://www.google.com.ar/patents/
scientific/STNAR40Ebook.pdf). US20050119234.
72. S. V. Nekhoroshev, A. V. Nekhorosheva, V. P. Nekhoro 93. J. W. Huffman, P. V. Szklennik, A. Almond, K. Bushell,
shev, Sud. Ekspert. [Forensic Identification], 2011, 3, 58 D. E. Selley, H. He, M. P. Cassidy, J. L. Wiley, B. R.
(in Russian). Martin, Bioorg. Med. Chem. Lett., 2005, 15, 4110.
73. N. Langer, R. Lindigkeit, H.M. Schiebel, L. Ernst, 94. M. A. Eissenstat, M. R. Bell, T. E. DAmbra, E. J. Alex
T. Beuerle, Drug Test. Anal., 2014, 6, 59. ander, S. J. Daum, J. H. Ackerman, M. D. Gruett, V. Ku
74. A. C. Howlett, F. Barth, T. I. Bonner, G. Cabral, P. Casel mar, K. G. Estep, J. Med. Chem., 1995, 38, 3094.
las, W. A. Devane, C. C. Felder, M. Herkenham, K. Mack 95. R. A. Ross, H. C. Brockie, L. A. Stevenson, V. L. Murphy,
ie, B. R. Martin, R. Mechoulam, R. G. Pertwee, Pharma F. Templeton, A. Makriyannis, R. G. Pertwee, Br. J. Phar
col. Rev., 2002, 54, 161. macol., 1999, 126, 665.
75. United Nation Office on Drugs and Crime (UNODC). Re 96. M. M. Ibrahim, H. Deng, A. Zvonok, D. A. Cockayne,
commended Methods for the Identification and Analysis of Syn J. Kwan, H. P. Mata, T. W. Vanderah, J. Lai, F. Porreca,
thetic Cannabinoid Receptor Agonists in Seized Materials, A. Makriyannis, T. P. Malan, Proc. Natl. Acad. Sci. USA,
United Nations, New York, 2013, 66 pp. 2003, 100, 10529.
76. N. Uchiyama, Y. Shimokawa, M. Kawamura, R. Kik 97. B. B. Yao, S. Mukherjee, Y. Fan, T. R. Garrison, A. V.
uraHanajiri, T. Hakamatsuka, Forensic Toxicol., 2014, Daza, G. K. Grayson, B. A. Hooker, M. J. Dart,
32, 266. J. P. Sullivan, M. D. Meyer, Br. J. Pharmacol., 2006,
77. N. Uchiyama, Y. Shimokawa, S. Matsuda, M. Kawamura, 149, 145.
R. KikuraHanajiri, Y. Goda, Forensic Toxicol., 2014, 98. P. G. Willis, R. KatochRouse, A. G. Horti, J. Label. Compd.
32, 105. Radiopharm., 2003, 46, 799.
Cannabinoids: structures and classification Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 1265
99. Ch.P. Shen, J. Ch. Xiao, H. Armstrong, W. Hagmann, 121. L. Ernst, K. Kr ger, R. Lindigkeit, H.M. Schiebel,
T. M. Fong, Eur. J. Pharmacol., 2006, 531, 41. T. Beuerle, Forensic Sci. Int., 2012, 222, 216.
100. A. Grigoryev, P. Kavanagh, A. Melnik, Drug Test. Anal., 122. V. Lucchesi, T. Parkkari, J. R. Savinainen, A. M. Malfit
2012, 4, 519. ano, M. Allara, S. Bertini, F. Castelli, S. Del Carlo,
101. J. M. Frost, M. J. Dart, K. R. Tietje, T. R. Garrison, G. K. Ch. Laezza, A. Ligresti, G. Saccomanni, M. Bifulco, V. Di
Grayson, A. V. Daza, O. F. ElKouhen, B. B. Yao, G. C. Marzo, M. Macchia, C. Manera, Eur. J. Med. Chem., 2014,
Hsieh, M. Pai, C. Z. Zhu, P. Chandran, M. D. Meyer, 74, 524.
J. Med. Chem., 2010, 53, 295. 123. A. Tourteau, V. Andrzejak, M. BodyMalapel, L. Lemaire,
102. P. Jankovics, A. Vradi, L. Tolgyesi, S. Lohner, Ju. Nmeth A. Lemoine, R. Mansouri, M. Djouina, N. Renault, J. El
Palots, J. Balla, Forensic Sci. Int., 2012, 214, 27. Bakali, P. Desreumaux, G. G. Muccioli, D. M. Lambert,
103. US Pat. 2009/0149501; http://www.google.com/patents/ Ph. Chavatte, B. Rigo, N. LeleuChavain, R. Millet, Bioorg.
US20090149501. Med. Chem., 2013, 21, 5383.
104. WO Pat. 2006069196; http://patentscope.wipo.int/search/ 124. K. K. Nanda, D. A. Henze, K. D. Penna, R. Desai, M. Leitl,
en/WO2006069196. W. Lemaire, R. B. White, S. Yeh, J. N. Brouillette, G. D.
105. US Pat. 20110065685; http://www.google.co.ug/patents/ Hartman, M. T. Bilodeau, B. W. Trotter, Bioorg. Med. Chem.
US20110065685. Lett., 2014, 24, 1218.
106. B. B. Yao, G. C. Hsieh, J. M. Frost, Y. Fan, T. R. Garrison, 125. P. G. Baraldi, G. Saponaro, A. R. Moorman, R. Romag
A. V. Daza, G. K. Grayson, C. Z. Zhu, M. Pai, P. Chan noli, D. Preti, S. Baraldi, E. Ruggiero, K. Varani, M. Tar
dran, A. K. Salyers, E. J. Wensink, P. Honore, J. P. Sul ga, F. Vincenzi, P. A. Borea, M. A. Tabrizi, J. Med. Chem.,
livan, M. J. Dart, M. D. Meyer, Br. J. Pharmacol., 2008, 2012, 55, 6608.
153, 390. 126. S. Han, L. Thoresen, X. Zhu, S. Narayanan, J.K. Jung,
107. V. A. Shevyrin, V. P. Melkozerov, Yu. Yu. Morzherin, O. S. S. StrahPleynet, M. Decaire, K. Choi, Y. Xiong, D. Yue,
Eltsov, Sud. Ekspert. [Forensic Identification], 2012, 4, 87 G. Semple, J. Thatte, M. Solomon, L. Fu, K. Whelan,
(in Russian). H. AlShamma, J. Gatlin, R. Chen, H. Dang, C. Pride,
108. V. Shevyrin, V. Melkozerov, A. Nevero, O. Eltsov, I. Gaidarov, D. J. Unett, D. P. Behan, A. Sadeque, Kh. A.
Yu. Morzherin, Yu. Shafran, Forensic Sci. Int., 2013, Usmani, Ch. Chen, J. Edwards, M. Morgan, R. M. Jones,
226, 62.aaa Bioorg. Med. Chem. Lett., 2015, 25, 322.
109. A. R. Blaazer, J. H. M. Lange, M. A. W. van der Neut, 127. S. Bertini, T. Parkkari, J. R. Savinainen, Ch. Arena,
A. Mulder, F. S. den Boon, T. R. Werkman, C. G. Kruse, G. Saccomanni, S. Saguto, A. Ligresti, M. Allar, A. Bruno,
W. J. Wadman, Eur. J. Med. Chem., 2011, 46, 5086. L. Marinelli, V. Di Marzo, E. Novellino, C. Manera,
110. J. M. Adam, J. Cairns, W. Caulfield, P. Cowley, I. Cum M. Macchia, Eur. J. Med. Chem., 2015, 90, 526.
ming, M. Easson, D. Edwards, M. Ferguson, R. Goodwin, 128. S. Yrjl, T. Kalliokoski, T. Laitinen, A. Poso, T. Parkkari,
F. Jeremiah, T. Kiyoi, A. Mistry, E. Moir, R. Morphy, T. Nevalainen, Eur. J. Pharm. Sci., 2013, 48, 9.
J. Tierney, M. York, J. Baker, J. E. Cottney, A. K. Hough 129. K.I. Kusakabe, Y. Tada, Y. Iso, M. Sakagami, Y. Morioka,
ton, P. J. Westwood, G. Walker, MedChemComm, 2010, N. Chomei, S. Shinonome, K. Kawamoto, H. Takenaka,
1, 54. K. Yasui, H. Hamana, K. Hanasaki, Bioorg. Med. Chem.,
110. R. Zhao, B. Wang, H. Wu, J. Hynes, Jr., K. Leftheris, 2013, 21, 2045.
B. Balasubramanian, J. C. Barrish, B.Ch. Chen, ARKIVOC, 130. G. M. P. Giblin, A. Billinton, M. Briggs, A. J. Brown, I. P.
2010, VI, 89. Chessell, N. M. Clayton, A. J. Eatherton, P. Goldsmith,
112. V. Shevyrin, V. Melkozerov, A. Nevero, O. Eltsov, Yu. Shaf C. Haslam, M. R. Johnson, W. L. Mitchell, A. Naylor,
ran, Forensic Sci. Int., 2013, 232, 1. A. Perboni, B. P. Slingsby, A. W. Wilson, J. Med. Chem.,
113. V. A. Shevyrin, Yu. Yu. Morzherin, V. P. Melkozerov, A. S. 2009, 52, 5785.
Nevero, Khim. Geterotsikl. Soedin., 2014, 50, 634 [Chem. 131. A. R. Blaazer, J. H. M. Lange, M. A. W. van der Neut,
Heterocycl. Compd. (Engl. Transl.), 2014, 50, 583]. A. Mulder, F. S. den Boon, T. R. Werkman, Ch. G. Kruse,
114. V. A. Shevyrin, M. A. Gofenberg, V. P. Melkozerov, A. S. W. J. Wadman, Eur. J. Med. Chem., 2011, 46, 5086.
Nevero, O. S. Eltsov, O. V. Kupriyanova, Yu. Yu. Mor 132. J. J. Harnett, Ch. Dolo, I. Viossat, F. Auger, E. Ferrandis,
zherin, Butlerovskie soobshcheniya [Butlerov Communica D. Bigg, M. Auguet, S. Auvin, P.E. Chabrier, Bioorg. Med.
tions], 2014, 37, No. 1, 156 (in Russian). Chem. Lett., 2015, 25, 88.
115. WO Pat. 2003035005; http://www.google.com/patents/ 133. J. Bostr ma, R. I. Olsson, J. Tholander, P. J. Greasley,
WO2003035005A3?cl=en. E. Ryberg, H. Nordberg, S. Hjorth, L. Cheng, Bioorg. Med.
116. WO Pat./2009/106982; http://patentscope.wipo.int. Chem. Lett., 2010, 20, 479.
117. WO Pat./2009/106980; http://patentscope.wipo.int. 134. Sh. Han, F.F. Zhang, X. Xie, J.Zh. Chen, Eur. J. Med.
118. V. A. Shevyrin, V. P. Melkozerov, Yu. Yu. Morzherin, But Chem., 2014, 74, 73.
lerovskie soobshcheniya [Butlerov Communications], 2012, 30, 135. P. Yogeeswari, M. Sharma, G. Samala, M. Gangadhar,
No. 4, 93 (in Russian). S. Karthick, S. Mallipeddi, A. Semwal, Dh. Sriram, Eur. J.
119. J. A. H. Lainton, J. W. Huffman, Tetrahedron Lett., 1995, Med. Chem., 2013, 66, 211.
36, 1401. 136. L. N. Franks, B. M. Ford, N. R. Madadi, N. R. Pen
120. J. W. Huffman, L. W. Padgett, M. L. Isherwood, J. L. Wiley, thala, P. A. Crooks, P. L. Prather, Eur. J. Pharm., 2014,
B. R. Martin, Bioorg. Med. Chem. Lett., 2006, 16, 5432. 737, 140.
1266 Russ.Chem.Bull., Int.Ed., Vol. 64, No. 6, June, 2015 Shevyrin and Morzherin