INTERNATIONALE PHARMACEUTICA SCIENCIA | January-March 2013 | Vol. 3 | Issue 1 | Available online http://www.ipharmsciencia.com ISSN 2231-5896 ©2013 IPS REVIEW ARTICLE
Recent progress in the chemistry of Dihydropyrimidinones ABSTRACT
1Hirenkumar
D. Shah and 2Dr. Dhrubo Jyoti Sen
This review elaborates the collective synthetic studies of a known group of Dihydropyrimidinones and their reactions. Their mechanistic studies as well as their important bioactivities have been discussed together with the synthesis of special groups of substances. The scope and limitation of the classical procedure and the synthetic applications of the catalytic variant of Biginelli reaction are also briefly summarized in this review.
1Senior
Research Associate-I, R & D Department, Oxygen Healthcare, Ahmedabad. 2Department of Pharmaceutical Chemistry, Shri Sarvajanik Pharmacy College, Gujarat Technological University, Arvind Baug, Mehsana-384001, Gujarat, India
Keywords: Dihydropyrimidinone, CVS activities, other activities.
Date of Submission: 14-03-2013 Date of Acceptance: 28-03-2013 Conflict of interest: Nil Source of support: None
INTRODUCTION
of Cytosine (1) which is found in DNA and RNA, Uracil
Pyrimidinones or Dihydropyrimidinones (DHPMs) are
(2) in RNA and Thymine (3) in DNA. Because of their
well known for their wide range of bioactivities and
involvement as bases in DNA and RNA, they have
their applications in the field of drug research have
become very important in the world of synthetic
stimulated the invention of a wide range of synthetic
organic
methods
chemical
dihydropyrimidin-2(1H)-one and their derivatives are
transformations. Out of the five major bases in Nucleic
an important class of substances in organic and
acids three are pyrimidine derivatives which comprises
medicinal chemistry.
for
their
preparation
and
N H2 N
N H
chemistry.
O
Cytosine
N H
O
O
2
N H
O
Thymine
Uracil
1 Several alkaloids containing the dihydropyrimidine
3,4-
NH
NH
O
Aryl-substituted
3 been further widen with their identification of 4-(3-
core unit have been isolated from marine sources,
hydroxyphenyl)-2-thione
which also exhibit interesting biological properties
Monastrol as a novel cell-permeable molecule for the
most notably; among these are the batzelladine
development of new anticancer drugs. Monastrol (4)
alkaloids, which were found to be potent HIV gp-120-
has been identified as a compound that specifically
CD4
inhibitors.1
The scope of this pharmacophore has
derivative
4
called
affects the cell-division (mitosis) by a new mechanism which does not involve tubulin targeting. It has been
Address for correspondence
Hirenkumar D Shah Email:
[email protected],
[email protected] 63
established that the activity of 4 consists of the specific and reversible inhibition of the motility of the
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mitotic kinesis, a motor protein required for spindle X
bipolarity.2 4
R5
OH
5
O
R2
8
NH N H
2
6 N1 H
R6
O
3 R3
1. The 1,4-DHP ring is essential for activity.
S
4 Monastrol 3,4-aryl-1,4-dihydropyridines
2. The unsaturation of the basic ring will decrease the activity. (DHPs)
of
the
3. Substitution at N1 Position or the oxidized
Nifedipine type 4 (e.g. 6) were first introduced into
(Piperidine) or reduced (pyridine) ring system
clinical medicine in 1975 and are still the most potent
greatly decreases or abolishes the activity.
group of calcium channel modulators available for the treatment
of
cardiovascular
diseases.3
4. The 2,6–Substituents of 1,4-DHP
should be
lower, alkyl, and one NH2 group is tolerated.
Dihydropyrimidines of type 7 show a very similar
5. Ester groups at C3 and C5 position shows
pharmacological profile, and in recent years, several
optimum activity .The presence of electron
related compounds were developed (e.g. 7) that are
withdrawing
equal in potency and duration of antihypertensive
antagonistic activity and may even shows agonist
activity
activity. e.g.: Isradipine
to
dihydropyridine
classical
and
second-generation
drugs.4
groups
shows
decreased
Removal or replacement by COCH3 or CN greatly reduces activity
Y
6. Ester substitution larger than COOCH3 greatly NO2 H 3CO2 C
RO 2C
CO2CH3
maintain or even increases the activity because of
CO2R
bulk tolerance in the site of 1,4-DHP. e.g.: N H
N H 6
X
7
Nifedipine
Amlodipine. C3-methyl, C5-ethyl.
R = Alkyl X = O, S, NH Y = NO2,CF 3
7. Ester at C3 and C5 are non-identical, the C4 carbon becomes chiral and stereo selectivity
The major aim of this review is to provide examples for
the
synthesis
of
Dihydropyrimidinones.
the
known
In
some
groups cases,
of the
mechanistic studies of the synthesized compounds, their reactions with different reagents and their
between the enantiomers is observed. 8. Substitution of phenyl ring at C4 position has optimum activity. 9. Substitution of small non planar alkyl or cyclo alkyl group shows decreased activity.
transformations are included.5,6 Their most important
10. Compound with ortho or meta substitution
bioactivities together with the synthesis of special
possess optimum activity, while unsubstituted or
groups of substances are also discussed. In this review
a para substitution show decrease in activity
we would like to briefly summarize the mechanistic
according to their electronic and steric effect.
data as well as the scope and limitation of the classic procedure and describe the synthetic applications of
Synthetic
the catalytic variant of Biginelli reaction.
Dihydropyrimidinones:9
methodologies
for
The first synthesis of dihydropyrimidinones was Structure Activity Relationship:7,8
reported by Biginelli in 1893, however, the synthetic
The detail study on the structural features of 1,4-DHP
potential of this heterocyclic synthesis remained
as lead compound have been described.
unexplored for quite some time. In the 1970’s interest
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Hirenkumar D Shah et al: Recent progress in the chemistry of Dihydropyrimidinones
gradually increased and the scope of the original
reaction) were conducted by Folkers and Johnson in
cyclocondensation reaction shown in scheme 1 was
1933.11
gradually extended by variation of all the building blocks, allowing access to a large number of
O
O H2N
R
NH2
-OC(NH2)2 R
is
mainly
due
multifunctionalized
to
the
fact
dihydropyrimidine
18
CH3
HN
CH3
HN
activity has again occurred, as evident by the growing
This
16 -H2O O
H N
O
CO2Et
O
O
Since the late 1980’s, a tremendous increase in
N H NH2
HN
15
multifunctionalized dihydropyrimidines of type 11.
number of publications and patents on the subject.
HN R
NH2 NH2
HN
14
10
CH3
R
H
O HO
O
O O2Et
HN
CO2Et
N H
R
NH2
HN
CO2Et
17 O
Scheme-3: Folker and Johnson mechanism the
Four possible combinations of the three reaction
scaffold
components were examined for the generation of
that
(“Biginelli compounds”) represents a heterocyclic system of remarkable pharmacological efficiency. Since then several reviews on synthesis and chemical properties of pyrimidinones have been published. The search for new and efficient methods for the synthesis of pure compounds has been an active area of research in organic synthesis. From a modern point of view, Biginelli protocol is obviously very attractive for combinatorial chemistry and has been rarely used for
dihydropyrimidine (Scheme-3): A. the
intermolecular
reaction
between
benzaldehyde, ethyl acetoacetate and urea, B. the combination of ethyl acetoacetate and benzal bisurea, C. the reaction of benzaldehyde and ethyl βcarbamidocrotonate, and D. The reaction of ethyl α-benzalacetoacetate and urea.
parallel synthesis, a new avenue could be connected with an elaboration of catalytic procedures. Here we
Folkers
present
conclusions on the reaction yields and visual
the
essential
summary
of
important
and
Johnson
based
their
mechanistic
observation. They proposed that the simultaneous
characteristics of this reaction.
combination of the three components in A was improbable. D was ruled out on the basis of the low reaction yields (2%). In contrast, B and C gave high yields of 36 (80%). The authors noted that B may Scheme-1: Classical Biginelli synthesis of DHPMs
undergo
fragmentation
of
the
benzal-bisurea,
regenerating the three reaction components, which C O Kappe reported the synthesis of 2-methoxy-1,4dihydropyrimidines (13) which was obtained by condensation of ethylacetoacetate, O-methylisourea (12) and an appropriate aldehyde.10
may then form the product by another pathway. Further,
the
authors
posit
that
the
β-
carbamidocrotonate in C hydrolyses to the original three reaction components. Therefore, they concluded that 36 is likely formed from the cyclization of 35, which was generated from either B or C. Again in 1973, a second mechanistic proposal was suggested by Sweet and Fissekis, forty years after Folkers’ pioneering work.12 The proposal involved an
Scheme-2: Kappe synthesis
aldol condensation between benzaldehyde and ethyl
Mechanistic Studies
acetoacetate to form a stabilized carbenium ion (20
Forty years after Biginelli’s initial report, the first
and 21). Trapping with N-methyl urea gave 22, which
mechanism for the synthesis of DHPMs (Biginelli
cyclized to form 11 (Scheme 4). The observation that
65
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Hirenkumar D Shah et al: Recent progress in the chemistry of Dihydropyrimidinones
independently prepared 19 reacted with urea under acidic conditions to generate 11, provided evidence in
H
support of this mechanism. Evidence against this
8
O
O
H
O CH3
O O
OEt
O
9
CH3
HO
O CH3
OEt
O
21
20
19
CH3
OEt O
mechanism was provided by Kappe 44, who found
H2N O
that reaction of 37 with N-methyl thiourea produces
EtO2C
thiazine and not N-methyl dihydropyridine 11, which
N H
CH3 O NH2
HN
O
O 22
11
was the observed product under standard Biginelli
NH2
OEt
-H2O
N
H3C
OEt
Scheme-4: Sweet and Fissekis Mechanism
conditions (catalytic amounts of HCl, refluxing Pharmacological Activities:13
ethanol).
Antihypertensive agents:
Figure 1 to
selective antagonists as attractive drug candidates for
possess α1a antagonistic action in the cardiovascular
the treatment of hypertension with fewer undesirable
systems
synthetic
side effects that may be associated with the other
attention.14 α1a antagonists inhibit the binding of α1a
subtypes. Soon after the cloning and expression of the
receptor through plasma membrane channels and
three different α1 receptor subtypes, the DHP calcium
thus dilate vascular smooth muscle and alleviate the
channel blocker niguldipine was shown to be a potent
force of cardiac muscle contraction. Some α1a
antagonist of the α1a-receptor subtype.16,17
antagonists such as niguldipine have been used as
NO2
Dihydropyrimidinone which
derivatives
have
attracted
are
known
much
antihypertensive agents. However, nifedipine and verapamil have a serious disadvantage in the
O N
treatment of hypertension. Since their plasma half-
dihydropyrimidones
which
is
suitable
for
α1a
Antagonists with Potent and long-lasting Vasodilative, hypotensive or antihypertensive activity.15
OMe Me
N H
Me
S (+) Niguldipine
administered repeatedly to achieve enough clinical Therefore, the fore mentioned drugs were replaced by
O
Ph
lives are relatively short, these drugs must be efficacy, and the multiple dosages lower compliance.
O
Ph
In a further modification step, the DHP core was therefore replaced by a DHPM scaffold, as in SNAP 6201 in order to avoid problems derived from the propensity of DHPs towards oxidation. The difluoro analog SNAP 6201 showed good binding affinity and excellent subtype selectivity 300 fold for the α1a receptor, no cardiovascular effects and a
However, that the functional potency of a number of
good pharmacodynamic profile.18
α1 antagonists correlates well with the binding affinity for α1a subtype at the cloned human receptors. Therefore, efforts are being made to develop α1aInternationale Pharmaceutica Sciencia
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Hirenkumar D Shah et al: Recent progress in the chemistry of Dihydropyrimidinones NO2
O
O
Ph N
N H
MeO2C
N
NH2
O
N H
Me
SNAP 6201 F F
O
O
Figure-3
Ph N
N H
Me
N O
OMe N H
A variety of such drugs that bind to tubulin and thus
OMe
inhibit spindle assembly are currently used in cancer
SNAP 6201 metabolite: 4-methoxycarbonyl-4phenylpiperidine
therapy (e.g. paclitaxel, docetaxel). Recently identified
However, in-vitro and in-vivo evaluation of SNAP 6201
showed
its
major
metabolite,
4-
methoxycarbonyl-4-phenylpiperidine, to be a potent m-opioid agonist. Modification of the linker in SNAP 6201 gave several compounds with good a1a binding affinity and selectivity. DHPMs of this type were shown to generally have good binding affinity and excellent subtype selectivity (100 fold) for the α1areceptor. In-vivo testing of these compounds in both
the structurally rather simple DHPM as a novel cellpermeable molecule, that blocks normal bipolar mitotic spindle assembly in mammalian cells and therefore, causes cell cycle arrest. By combining several screening assays, it was established that DHPM 43 termed monastrol — blocks mitosis by specifically inhibiting the motor activity of the mitotic kinesin Eg5, a motor protein required for spindle bipolarity. OH
rat and dog models confirmed the results from receptor studies and suggest that DHPMs of this type have significant potential to relieve the symptoms of EtO2 C
BPH without eliciting effects on the cardiovascular
NH
system. N H
S
Monastrol
Anticancer agents:19,20 A common strategy for cancer therapy is the
Monastrol is the only cell-permeable molecule
development of drugs that interrupt the cell cycle
currently known to specifically inhibit mitotic kinesin
during the mitosis stage. Compounds that perturb
Eg5 and can therefore be considered as a lead for the
microtubule
or
development of new anticancer drugs. Interestingly,
lengthening (polymerization) cause arrest of the cell
the closely related DHPM did not affect mitotic
cycle in mitosis due to perturbation of the normal
kinesin Eg5 or arrest cells in mitosis. Although the
microtubule dynamics necessary for chromosome
antimitotic activity of monastrol itself is not very high
movement.
being a micromolar inhibitor of Eg5 — structural
shortening
(depolymerization)
variants could prove to have better activity. Racemic monastrol has been resolved into its individual enantiomers, but pharmacological data on these have not been reported. Conclusion: The chemistry of Dihydropyrimidones has been Figure-2 67
synthesized as early as 1893s, but the most Internationale Pharmaceutica Sciencia
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Hirenkumar D Shah et al: Recent progress in the chemistry of Dihydropyrimidinones
considerable
advances
in
both
the
synthetic
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