Design and synthesis of a novel L-Dopa - Entacapone codrug

Article abstract of DOI:10.1021/jm010980d

A novel codrug, in which L-Dopa and entacapone are linked via a biodegradable carbamate spacer to form a single chemical entity, was synthesized and studied kinetically. This carbamate codrug provides adequate stability [t_1/2 = 12.1 h (pH 1.2); 1.4 h (pH 5.0); 1.1 h (pH 7.4)] against chemical hydrolysis but rapidly hydrolyzes to L-Dopa and entacapone in liver homogenate (t_1/2 = 7 min; pH 7.4) at 37°C. The therapeutical potential of this novel codrug is discussed.

Full text of DOI:10.1021/jm010980d

J . Med. Chem. 2002, 45, 1379-1382
1379
Brief Articles
Design a n d Syn th esis of a Novel L-Dop a -En ta ca p on e Cod r u g
J ukka Leppa¨nen,*,† J uhani Huuskonen,† Tapio Nevalainen,† J ukka Gynther,†,‡ Hannu Taipale,† and
Tomi J a¨rvinen†,‡
Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, 70211, Kuopio, Finland, and
Finncovery Ltd., Kuopio, Finland
Received J uly 10, 2001
A novel codrug, in which L-Dopa and entacapone are linked via a biodegradable carbamate
spacer to form a single chemical entity, was synthesized and studied kinetically. This carbamate
codrug provides adequate stability [t1/2 ) 12.1 h (pH 1.2); 1.4 h (pH 5.0); 1.1 h (pH 7.4)] against
chemical hydrolysis but rapidly hydrolyzes to L-Dopa and entacapone in liver homogenate (t1/2
) 7 min; pH 7.4) at 37 °C. The therapeutical potential of this novel codrug is discussed.
Sch em e 1
In tr od u ction
The prodrug approach is commonly used to improve
physicochemical, biopharmaceutical, and drug delivery
properties of therapeutic agents. Ideally, an inactive pro-
moiety is covalently attached to the parent molecule,
and the resulting prodrug is converted to the parent
drug in the body before it exhibits its pharmacological
effect.1-3 Many diseases are treated by a combination
of therapeutic agents that are coadministered in sepa-
rate dosage forms. However, there are potential advan-
tages in giving the coadministered agents as a single
chemical entity (e.g., improved delivery properties and
targeting drugs to specific sites of action). As codrugs,
at least two different synergistic drugs are linked
together and designed to release the parent drugs at
the desired site of action.4-6
L-Dopa (3,4-dihydroxyphenyl-L-alanine, 1) is a pre-
cursor to dopamine, which is deficient in the brains of
patients suffering from Parkinson’s disease (PD). Con-
ventional PD treatment consists of L-Dopa combined
with an AADC (amino acid decarboxylase) inhibitor,
such as carbidopa. During treatment, COMT (catechol-
O-methyltransferase)7 remains the main enzyme for
metabolizing L-Dopa. Entacapone [(E)-2-cyano-N,N-
diethyl-3-(3,4-dihydroxy-5-nitrophenyl)propenamide] is
a new, potent inhibitor of COMT, which is currently
used as a clinical adjunct to L-Dopa therapy in PD.8 The
administration of entacapone, together with L-Dopa and
an AADC inhibitor, leads to increased L-Dopa bioavail-
ability and its prolonged duration of action.9 However,
even after combination therapy of entacapone and
L-Dopa, the bioavailability of L-Dopa is low (5-10%).10
In addition, the bioavailability of entacapone after oral
administration is also low (29-46%).11
and entacapone, because their delivery route and rate
should be identical to improve L-Dopa brain delivery,
and they have similar doses on a molar bases. In the
present study, we describe a straightforward route of
synthesis and preliminary in vitro studies for a novel
codrug of L-Dopa and entacapone.
Resu lts a n d Discu ssion
L-Dopa (1) has four functional groups (two hydroxyls,
one primary amine, and one carboxylic acid) that can
link to entacapone via a spacer. Due to potential risk of
intramolecular hydrolysis by an unsubstituted hydroxyl
group, there were no attempts to link L-Dopa by its
hydroxyl groups to entacapone. Moreover, the chemical
similarity of the two L-Dopa hydroxyl groups could lead
to a difficult separation of the resulting 3- and 4-sub-
stituted L-Dopa derivatives.
The simplest codrug, a L-Dopa ester of entacapone
(Scheme 1), was unstable after deprotection of the amino
group, and thus the desired codrug could not be pre-
pared. An attempt was made to stabilize the L-Dopa
and entacapone ester codrug by inserting a methylene
spacer between entacapone and the carboxylic moiety
of L-Dopa.12,13 An iodomethylene linker was introduced
to the carboxylic group of a protected L-Dopa (2xPg1-O,
Pg2-N) by treating it with chloromethyl chlorosulfonic
acid and sodium iodide.14 Unfortunately, entacapone
reacted poorly with the resulting L-Dopa derivative
(RCOOCH2I).
The codrug approach was considered to be a produc-
tive way for combining the therapeutic effects of L-Dopa
Since carbamate ester prodrugs of entacapone are
chemically stable and release entacapone enzymatically
in vitro,15 carbamate was evaluated as a possible linker
for a L-Dopa-entacapone codrug. The synthesis of the
carbamate codrug (4) is outlined in Scheme 2.
* Corresponding author: Department of Pharmaceutical Chemistry,
University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Fin-
land. Tel: +358 17 162 460. Fax: +358 17 162 456. E-mail:
jukka.leppanen@uku.fi.
† Department of Pharmaceutical Chemistry.
‡ Finncovery Ltd.
10.1021/jm010980d CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/12/2002

1380 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6
Brief Articles
Sch em e 2a
Sch em e 3
Sch em e 4
a
Reagents: (a) MeOH, SOCl2; (b) AcCl, TFA; (c) diphosgene,
EtOAc; (d) entacapone, CH3CN; (e) 3 N HCl in acetone.
To prevent cyclization of isocyanate to N-carboxylic
anhydride,16 the carboxylic group of L-Dopa was esteri-
fied by treating with thionyl chloride in dry methanol.
The methyl ester was treated with trifluoroacetic acid
and acetyl chloride to give 2-amino-3-(3,4-diacetoxy-
phenyl)-propionic acid 2 in quantitative yields. The
protected L-Dopa (2) was treated with a convenient
phosgene source, diphosgene, to yield the isocyanate 3,17
which was used immediately for the next step without
purification, due to its rapid decomposition on exposure
to humidity.
The isocyanate 3 and entacapone were dissolved in
dry acetonitrile and refluxed overnight under a N2
atmosphere in the absence of light to produce the
carbamate ester 4. The reaction proceeded slowly due
to the poor nucleophilicity of entacapone, resulting from
the electron withdrawing effect of the nitro group and
the conjugated structure of entacapone. After flash
chromatography purification of 4, the acetate protecting
groups were removed by treatment with 3 N HCl in
acetone. Purification attempts by flash chromatography
on dry silica gel resulted in rapid degradation of 4. Thus,
4 was purified by preparative HPLC on reversed-phase
silica gel, providing the codrug in moderate yields (46%).
Less than 5% of 4 was converted to the Z-form during
the purification step, probably due to heat or exposure
to light.
Compound 4 was readily hydrolyzed enzymatically
(t1/2 ) 7 min) to entacapone and L-Dopa in a liver
homogenate at pH 7.4, which fulfilled the criteria of a
bioreversible codrug. Unfortunately, the direct quanti-
tation of the parent drugs was difficult, due to the low
aqueous solubility of 4 (i.e., low concentrations of the
parent compound in liver homogenate) and rapid me-
tabolism of the released L-Dopa in liver homogenate.18
Two alternative biodegradation routes of 4 are out-
lined in Scheme 4. During the hydrolysis of the car-
bamate spacer, the carboxylic residue remains either
with entacapone or L-Dopa. The subsequent release of
carbon dioxide is spontaneous.19 The carbamate may
also hydrolyze back to the unstable isocyanate,20 which
rapidly decomposes in an aqueous environment to
primary amine and carbon dioxide.
Our results suggest that 4 may release L-Dopa and
entacapone in the body after absorption. Furthermore,
biodegradation of 4 and the simultaneous release of both
L-Dopa and entacapone results in the inhibition of
COMT, which is expected to facilitate a decrease in
metabolism of L-Dopa more efficiently than if either
therapeutic agents were administered in separate dos-
age forms. Thus, the novel L-Dopa-entacapone codrug
approach warrants further studies.
Instability of 4 in even mildly basic conditions ex-
cludes the use of protective groups that are cleaved
under basic conditions. Similarly, the reductive cleavage
of protecting groups may lead to an unwanted reduction
of the functional groups present on 4. Thus, the acetate
was a simple and easily introduced protective group,
although the carbamate function was slightly hydro-
lyzed when the acetate groups were cleaved under acidic
conditions.
The chemical stability of 4 increased with decreasing
pH of the solution. At pH 7.4, codrug 4 demonstrated
only adequate stability (t1/2 ) 66 min; 37 °C), which was
probably a result of entacapones’s low pKa. The ionized
hydroxyl group of entacapone may assist hydrolysis of
the carbamate ester (Scheme 3).
Con clu sion s
A novel L-Dopa-entacapone codrug was synthesized
by linking the parent compounds together via the
carbamate spacer. The presented synthetic route is
straightforward and produces the desired endproduct
in moderate yields. Codrug 4 was adequately stable
against chemical hydrolysis and released the parent
drugs by enzymatic hydrolysis in liver homogenate, thus
However, codrug 4 was more stable at acidic pH [t1/2
) 84 min (pH 5.0); t1/2 ) 726 min (pH 1.2)], which is a
desirable property for increased stability in the stomach
and small intestine.

Brief Articles
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 6 1381
130.0, 134.5, 141.3, 143.3, 143.9, 144.0, 148.1, 151.1, 152.7,
fulfilling the codrug criteria. The yield could be im-
proved if a more easily cleaved protecting group were
introduced to L-Dopa or if such a group was replaced
by biolabile groups, making the deprotection step re-
dundant.
162.9, 171.4. ESI-MS: 543.1 (M+1). Anal. (C25H26N4O10
0.25CH2Cl2) C, H, N.
‚
HP LC An a lysis. The HPLC system used for the determi-
nation of in vitro samples consisted of a Beckman System Gold
Programmable Solvent Module 126, Beckman System Gold
Detector Module 166 with variable wavelength UV detector
(set at 254 nm), and a Beckman System Gold Autosampler
507e. Separations were accomplished on a Purospher RP-18
reverse-phase column (12.5 cm × 4.0 mm i.d., 5 µm) (Merck,
Darmstadt, Germany). The chromatographic conditions were
as follows: injection volume, 50 µL; column temperature, 40
°C; flow rate, gradient/isocratic at 1.0 mL/min. The mobile
phase consisted of various proportions of methanol/water
mixture (90:10) and a citrate/phosphate buffer pH 2.2.
Exp er im en ta l Section
Rea gen ts. All solvents and reagents were of the highest
purity and used without further purification. Diphosgene was
purchased from Fluka Chemie AS. Care must be excercised in
the handling of diphosgene due to release of phosgene when
heated or activated on charcoal.
1
Ch em istr y. H and 13C NMR analyses were recorded on a
Bruker Avance 500, operating at 500.1 and 125.6 MHz,
respectively. Chemical shifts are reported in parts per million
(δ) using TMS as the internal standard. The splitting pattern
abbreviations are as follows: s ) singlet, d ) doublet, t )
triplet, q ) quartet, br ) broad. Electrospray ionization mass
spectra were acquired by an LCQ ion trap mass spectrometer
equipped with an electrospray ionization source (Finnigan
MAT, San J ose, CA). The samples were diluted with methanol
to 20 µg/mL and injected directly into the eluent flow via a 5
µL loop injector (the total amount of sample was approximately
100 ng), and full scan mass spectra were recorded. Elemental
analyses were carried out on a ThermoQuest CE Instruments
EA 1110-CHNS-O elemental analyzer. The synthetic reactions
were monitored by TLC (Kieselgel 60 F 254, DC-Alufolien,
Merck). HPLC purification was accomplished by using a
Beckmann System Gold Programmable Solvent Module 116
on reversed phase silica (Kromasil 100 Å spherical silica, C8,
16 µm, Eka Chemicals AB).
Hyd r olysis in Aqu eou s Solu tion . The rate of chemical
hydrolysis of 4 was determined in aqueous phosphate buffer
solution (0.16 M) at pH 7.4, 5.0, and 1.2 at 37 °C. An
appropriate amount of 4 was dissolved in 10 mL of preheated
buffer, and the solution was placed in a thermostatically
controlled water bath at 37 °C. At appropriate time intervals,
samples were taken and analyzed for the remaining codrug
by HPLC. Pseudo-first-order half-time (t1/2) for the hydrolysis
of 4 was calculated from the slope of the linear portion of the
plotted logarithm of remaining codrug vs time.
Hyd r olysis in 10% Ra bbit Liver Hom ogen a te. The
rabbit liver was homogenized with approximately four equiva-
lent volumes of isotonic phosphate buffer at pH 7.4 using an
X-1020 homogenizer (Ystral, Germany). The homogenate was
centrifuged for 90 min at 9000g and 4 °C with a Biofuge 28
RS-centrifuge (Heraeus Instruments, Germany). The super-
natant was stored at -80 °C until analysis. An appropriate
amount of 4 was dissolved in one volume of preheated 20%
liver homogenate. The solution was then incubated at 37 °C.
At appropriate time intervals, samples (300 µL) were with-
drawn. Samples were pretreated with 300 µL of methanol to
terminate enzymatic activity. After mixing and centrifugation,
400 µL of the supernatant was evaporated to dryness under a
stream of air. The residue was redissolved in 400 µL of the
mobile phase buffer and analyzed by HPLC.
2-Am in o-3-(3,4-d ia cetoxy-p h en yl)-p r op ion ic Acid (2).
L-Dopa methyl ester was prepared by treatment of L-Dopa (2
g, 10 mmol) with thionyl chloride (5 mL) in dry methanol (10
mL).21 The resulting white solid was stirred with trifluoroacetic
acid (4 mL) and acetyl chloride (1.5 mL) at room temperature
to give the desired product with quantitative yield and high
purity.22 The procedures are described in detail in the refer-
1
ences. H NMR (CD3OD) δ: 2.32 (6H, s, CH3CO), 3.24 (1H, q,
J ) 7.5 and 14.2 Hz, CHACH), 3.34 (1H, q, J ) 5.8 and 14.2
Hz, CHBCH), 3.86 (3H, s, OCH3), 4.24 (1H, q, J ) 5.8 and 7.5
Hz, CH2CH), 7.14 (1H, d, J ) 1.3 Hz, ArH), 7.20 (1H, d, J )
1.3 Hz, ArH), 7.21 (1H, d, ArH). ESI-MS: 296.3 (M+1).
3-(3,4-Dia cetoxy-p h en yl)-2-isocya n a to-p r op ion ic Acid
(3). The HCl salt of compound 2 (1.5 g, 4.5 mmol) was dissolved
in dry ethyl acetate, and diphosgene (1.1 mL, 9.0 mmol) was
added while stirring at -10 °C under N2 atmosphere. The
mixture was allowed to warm to room temperature, then
refluxed for 5 h and evaporated to dryness under high vacuum.
The product was used immediately in the following reaction
without further purification.
Ack n ow led gm en t. This work was supported by the
Academy of Finland and The National Technology
Agency of Finland. Orion Pharma is gratefully acknowl-
edged for donation of entacapone. The authors are
grateful to Ms. Miia-Liisa Ra¨sa¨nen and Mrs. Helly
Rissanen for their skillful technical assistance. A grant
from the Emil Aaltonen Foundation to J .L. is gratefully
acknowledged.
(S)-2-[5-((E)-2-Cya n o-2-d ieth ylca r ba m oyl-vin yl)-2-h y-
d r oxy-3-n itr o-p h en oxyca r bon yla m in o]-3-(3,4-d ih yd r oxy-
p h en yl)-p r op ion ic Acid Meth yl Ester (4). The isocyanate
3 was dissolved in dry acetonitrile (10 mL) with entacapone
(553 mg, 1.81 mmol) under N2 atmosphere in the absence of
light. The mixture was refluxed for 20 h and evaporated to
dryness. The product was purified by flash chromatography
on silica gel using dichloromethane/methanol (100:1) as an
eluent. Acetate protecting groups were removed by treating
with an acetone/3 N HCl (20:1) solution for 2 h at 50 °C. The
resulting clear yellow mixture was evaporated to dryness and
purified by preparative HPLC using acetonitrile/water (50:50)
as an eluent. Evaporation of solvents yielded a yellow solid
(436 mg, 46%). mp (decomposed). 1H NMR (CDCl3) δ: 1.26 (6H,
br, CH2CH3), 2.95 (1H, q, J ) 6.1 and 13.7 Hz, CHACH), 3.11
(1H, q, J ) 4.7 and 13.7 Hz, CHBCH), 3.50 (4H, br, CH2CH3),
3.77 (3H, s, OCH3), 4.59 (1H, q, J ) 5.9 and 7.0 Hz, CH2CH),
6.14 (1H, d, J ) 7.5 Hz, NH) 6.15 (1H, d, J ) 8.0 Hz, ArH),
6.66 (1H, s, ArH) 6.72 (1H, d, J ) 8.0 Hz, ArH), 7.52 (1H, s,
CH)C), 7.92 (1H, s, J ) 1.8 Hz, ArH), 8.32 (1H, s, J ) 1.8 Hz,
ArH). 13C NMR (125.8 MHz, CD3OD) δ: 12.5, 13.6, 37.0, 41.1,
43.6, 52.7, 55.4, 107.0, 115.5, 116.6, 121.4, 122.9, 124.9, 127.6,
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