Synthesis and neuropharmacological evaluation of 2-aryl- and alkylapomorphines

Article abstract of DOI:10.1016/j.bmc.2008.01.057

A novel synthesis has been elaborated for the pharmacologically remarkable 2-arylapomorphines described and characterized in the last few years. This new procedure contains two alternative synthetic routes and has allowed the preparation of several hither

Full text of DOI:10.1016/j.bmc.2008.01.057

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 3773–3779
Synthesis and neuropharmacological evaluation
of 2-aryl- and alkylapomorphines
b
b
b
a
Attila Sipos,a, Bela Kiss, Eva Schmidt, Istvan Greiner and Sandor Berenyi
*
´
´
´
´
´
aDepartment of Organic Chemistry, University of Debrecen, PO Box 20, H-4010 Debrecen, Hungary
bResearch Division, Richter Gedeon Ltd, PO Box 27, H-1475 Budapest, Hungary
Received 6 September 2007; revised 24 January 2008; accepted 30 January 2008
Available online 5 February 2008
Abstract—A novel synthesis has been elaborated for the pharmacologically remarkable 2-arylapomorphines described and charac-
terized in the last few years. This new procedure contains two alternative synthetic routes and has allowed the preparation of several
hitherto unknown compounds as well. The pharmacological profile of the previously published and the novel 2-alkyl- and arylapo-
morphines has been determined with the application of in vitro and in vivo techniques. For 2-phenyl- (2) and 2-(4-hydroxy-
phenyl)apomorphines (3) the superior dopamine agonist profile has been confirmed and for the novel compounds some
remarkable results have been observed.
ꢀ 2008 Elsevier Ltd. All rights reserved.
3
4
1. Introduction
R
2
5
R
6
N
H
1
1
2
3
The ability of (R)-apomorphine (1, Fig. 1) and its 2-
substituted derivatives for binding to dopamine recep-
tors has been widely studied in the last decades.1 As a
result of that, drug products are now commercially
available containing apomorphine hydrochloride as ac-
tive substance. The indications aimed are those disor-
ders which are in connection with the abnormal
functioning of dopaminergic system, especially Parkin-
son’s disease and erectile dysfunction. It is also known
that apomorphine is not dopamine-receptor subtype
selective, this feature suggests the need for the prepara-
tion of apomorphines modified in 2-position.
6a
Me
H
Ph
OH
11
7
OH
10
OH
8
9
Figure 1. Apomorphine and its 2-aryl derivatives.
On the basis of this principle, Søndergaard et al.3
synthesized 2-phenylapomorphine (2) and 2-(4-hydroxy-
phenyl)-apomorphine (3) among other 2-arylapomo-
phines. These two derivatives have superior affinity to
D2 receptors in comparison to apomorphine (1). Fur-
thermore, the D3/D2 selectivity of the above-mentioned
derivatives 2 and 3 also exceeded the same ratio for
reference compound 1.
Several studies into dopamine-receptor binding empha-
size the effect of the presence of a hydrophobic group
in the proximity of 2-position of the aporphine skele-
ton.2 This effect is in agreement with the model of dopa-
mine D2 receptors suggested by Ramsby et al.
According to this model there is a lipophilic cavity on
the surface of the receptor next to the binding site.
2. Chemistry
Our conception for the formation of new C–C bond at
2-position was based on Suzuki reaction.4 Several
papers report remarkable effectiveness of palladium
catalyzed cross-couplings in the formation of aryl–aryl
and aryl–alkyl type C–C bonds starting from aryl
halides.
Keywords: Apomorphine; Dopamine receptor subtypes; D3/D2 selec-
tivity; Suzuki–Miyaura reaction.
*
Corresponding author. Tel.: +36 52512900; fax: +36 52512836;
e-mail: asipos@puma.unideb.hu
0968-0896/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2008.01.057

3774
A. Sipos et al. / Bioorg. Med. Chem. 16 (2008) 3773–3779
In the field of aporphine chemistry Hedberg et al.5 used
this coupling reaction in the synthesis of 11-phenyl and
methyl-aporphine. Søndergaard et al.3 used Suzuki-type
reaction in the preparation of four different 2-arylapo-
morphines. These syntheses used triflates in the cross-
coupling.
hebaine (4). The average yields of the palladium-cata-
lyzed reaction were high and the products were easily
obtained from the reaction mixtures. The cross-coupling
step on the original 6-bromo-6-demethoxythebaine (4)
was also attempted (synthesis route II). The same Suzu-
ki cross-coupling conditions were applied as in the case
of 2-bromoapocodeine (5, Scheme 2).
In preliminary publications we reported the application
of Suzuki reaction for either the preparation of 2-aryla-
pomorphines from 2-bromoapocodeine (5)6a or the
application of a double strategy to obtain 3-alkyl- and
arylapomorphines.6b
In Table 1 the yields of every single 2-aryl- and alkyl-
apocodeines 6–10 prepared via either 2-bromoapoco-
deine (5) or 6-aryl- and alkyl-morphinandienes 14–18
were compared. It can be concluded that the yields for
vinyl halide type morphinandienes were lower than that
of the aryl halide, but still practically suitable for the
synthesis of the target molecules.
In this paper a successful extension of the double strat-
egy has been presented for the synthesis of 2-alkyl- and
arylapomorphines 2, 3, 11–13.
The acid-catalyzed rearrangement of the morphinandi-
enes and the O-demethylation of the obtained apocode-
ines by methionine/methanesulfonic acid reaction
mixture10 are routinely performed in our laboratory
and presented in several papers. The apomorphine
derivatives were prepared in HCl salt form to assure
the water solubility of the compounds in the pharmaco-
logical studies.
Both reaction routes were based on 6-bromo-6-demeth-
oxythebaine (4). The synthesis of this compound7 was
first reported by our research group in 1984. The prepa-
ration and the chemical behavior of halo-substituted
morphinandienes were extensively studied in our labora-
tory.8,9 We found that 6-chloro-6-demethoxythebaine
could also be used to give rise of the target molecules,
however, with considerably lower yield in comparison
to its bromo congener 4.
3. Results and discussion
The original conception (synthesis route I) was to
accomplish the acid-catalyzed rearrangement of 6-bro-
mo-6-demethoxythebaine (4) into 2-bromo-apocodeine
(5), a potentially suitable partner for Suzuki reaction
(Scheme 1). The obtained 2-substituted apocodeines 6–
10 were converted into the aimed 2-substituted apomor-
phines via an O-demethylation step using methanesulf-
onic acid/methionine reactant mixture.
In vitro affinity for the dopamine D2 and D3 receptors of
the hydrochloride salts of the presented 2-methyl- and
arylapomorphines (2, 3, 11–13) was determined in order
to discover their pharmacological profile. In the case of
dopamine D2 affinity rat-brain striatal membrane
homogenate was prepared and displacement of [3H]spip-
erone (0.5 nM) was determined. Membrane preparation
containing recombinant rat D3 receptors expressed in
Sf9 cells was used for the determination of D3 affinity
and the displacement of radioligand [3H]spiperone was
studied. The obtained Ki results for the characterization
The aryl halide type 2-bromoapocodeine (5), as the basic
compound of the Suzuki reaction, was prepared by acid-
catalyzed rearrangement of 6-bromo-6-demethoxyt-
7
Br
R
Br
R
6
8
14
5
N
N
N
9
(i)
N
(ii)
(iii)
Me
Me
Me
Me
O
OH
OH
OH
OH
10
3
OMe
OMe
OMe
1
2
6 - 10
5
2, 3, 11 - 13
4
R
Me
Ph
6, 11
7, 2
8, 3
OH
N(Me)2
9, 12
10, 13
O
Scheme 1. Synthesis route I. Reagents: (i) CH3SO2OH, 90 ꢁC, 30 min; (ii) R-B(OH)2, Ba(OH)2.8H2O, PdCl2(PPh3)2, 1,4-dioxane:H2O = 4:1, 90 ꢁC,
30 min; (iii) CH3SO2OH, methionine, 90 ꢁC, 2 h.

A. Sipos et al. / Bioorg. Med. Chem. 16 (2008) 3773–3779
3775
R
R
Br
R
N
N
N
(i)
N
(ii)
(iii)
Me
Me
Me
Me
O
O
OH
OH
OH
OMe
OMe
OMe
4
2, 3, 11 - 13
14 - 18
6 - 10
R
Me
Ph
14, 6, 11
15, 7, 2
16, 8, 3
OH
N(Me)2
17, 9, 12
18, 10, 13
O
Scheme 2. Synthesis route II. Reagents: (i) R-B(OH)2, Ba(OH)2.8H2O, PdCl2(PPh3)2, 1,4-dioxane:H2O = 4:1, 90 ꢁC, 30 min; (ii) CH3SO2OH, 90 ꢁC,
30 min; (iii) CH3SO2OH, methionine, 90 ꢁC, 2 h.
results. The D3/D2 binding selectivities of these com-
pounds are similar to those of the reference compound
Table 1. Comparison of yields of 2-aryl- and alkylapocodeines 6–10
(synthesis routes I & II)
1.
Compound
R
Yield* (%)
Synthesis
route I
Yield* (%)
synthesis
route II
In connection with novel compounds it could be empha-
sized that the affinity of 2-methyl- and 2-(4-dibenzofura-
nyl)-congeners to D3 receptor subtype was found to be
similar to that of the apomorphine (1). However, in case
of the presence of small methyl substituent, the binding
potency for D2 subtype was superior in comparison with
that of the reference compound 1, on the other hand in
case of the insertion of large heteroaromatic substituent
(i.e. dibenzofuranyl) at 2-position in case of compound
13 the affinity for D2 receptor was very low which
led to a remarkable increase of D3 selectivity. For (R)-
(ꢀ)-2-(4-N,N-dimethyl-aminophenyl)-apomorphine (12)
moderate binding-affinities were observed for both
dopamine-receptor subtypes. The in vivo activity of
compounds 2, 3, 11–13 was determined by the determi-
nation of dopamine turnover index in male mice. Apo-
morphine derivatives 2, 3, 11–13 were subcutaneously
given to mice at a dose of 3.29 lmol/kg (equivalent to
1.0 mg/kg apomorphine.HCl administration). After
their sacrifice dopamine (DA), dihydroxyphenylacetic
acid (DOPAC) and homovanilic acid (HVA) concentra-
tions were determined from the striatum and olfactory
6
7
Me
Ph
60
74
66
74
8
9
53
30
63
53
OH
N(Me)2
10
29
54
O
* All yields are referred to the starting 6-bromo-6-demethoxythebaine
(4) and are the averages of 3 runs.
of D2 and D3-binding affinities and the D3/D2-binding
selectivity data are presented in Table 2. The affinity
of (R)-(ꢀ)-2-phenylapomorphine (2) and (R)-(ꢀ)-2-(4-
hydroxyphenyl)-apomorphine (3) for the D2 and D3
receptors was significantly higher than those for (R)-
(ꢀ)-apomorphine (1) in accordance with Søndergaard’s
Table 2. D2 and D3-binding data for displacing [3H]spiperone
a
a
Compound
D3
D2
D2/D3 selectivity
IC-50
Ki
IC-50
Ki
(R)-(ꢀ)-ApomorphineÆHCl (1)
69.5
82.6
14.7
3.70
178
36.4
40.1
87
47.7
20.7
11.7
4.14
242
1.31
0.52
1.52
2.33
3.09
72.96
(R)-(ꢀ)-2-Methyl-apomorphineÆHCl (11)
43.0
23.3
8.5
(R)-(ꢀ)-2-Phenyl-apomorphineÆHCl (2)
7.70
1.78
78.4
22.3
(R)-(ꢀ)-2-(4-Hydroxyphenyl)-apomorphineÆHCl (3)
(R)-(ꢀ)-2-(4-N,N-Dimethylaminophenyl)-apomorphineÆ2HCl (12)
(R)-(ꢀ)-2-(4-Dibenzofuranyl)-apomorphineÆHCl (13)
484
3259
49.4
1627
Results are means for three experiments each performed in triplicate.
a IC-50 and Ki results are reported in nM.

3776
A. Sipos et al. / Bioorg. Med. Chem. 16 (2008) 3773–3779
Table 3. Effects of 2-alkyl- and arylapomorphine derivatives on the dopaminergic activity in mouse striatum and olfactory tubercle
Compound
Dopamine turnover index (% of control SEM)a
Mouse striatum
Mouse tuberculum olfactorium
(R)-(ꢀ)-ApomorphineÆHCl (1)
48.6 1.9*
42.3 1.5*
44.2 1.2*
43.6 2.4*
52.3 1.3*
92.0 3.1
57.7 5.2*
43.6 1.3*
50.9 4.0*
39.6 0.7*
84.5 6.5
106.1 7.1
(R)-(ꢀ)-2-Methyl-apomorphineÆHCl (11)
(R)-(ꢀ)-2-Phenyl-apomorphineÆHCl (2)
(R)-(ꢀ)-2-(4-Hydroxyphenyl)-apomorphineÆHCl (3)
(R)-(ꢀ)-2-(4-N,N-Dimethylaminophenyl)-apomorphineÆ2HCl (12)
(R)-(ꢀ)-2-(4-dibenzo-furanyl)-apomorphineÆHCl (13)
a Dopamine turnover index ([DOPAC] + [HVA]/[DA]) was calculated as a measure of dopamine turnover. Control values for this index varied from
0.139 to 0.193 (with SEM 1.9–4.6%) in five independent experiments.
* Differ from control (p < 0.05) (n = 5).
tubercle. The calculated dopamine turnover indices are
presented in Table 3.
pound 12 is comparable with the same property of the
reference compound 1 on the basis of the dopamine-
turnover data. It could be concluded regarding optimal
spatial size of substituents in 2-position that the size of
the hydrophobe moiety on the range from methyl to
phenyl groups is favorable. The modest to weak
in vivo agonistic properties of 13 could be explained
by either the presence of unfavorably large substituents
in 2-position or the poor penetration of these molecules
into the brain. The specific property of compound 12
regarding the in vivo activity in nigrostriatal dopaminer-
gic system and inactivity in mesolimbic system is also
noticeable. Further experiments will be based on the
introduction of spatially more fitting substituent-bearing
charges at 2-position.
These results show that (R)-(ꢀ)-2-phenylapomorphine
(2), (R)-(ꢀ)-2-(4-hydroxyphenyl)-apomorphine (3) and
(R)-(ꢀ)-2-methylapomorphine (11) are well absorbed,
enter the brain and seem to possess remarkable dopa-
mine agonistic properties over (R)-(ꢀ)-apomorphine
(1) indicated by the substantial decrease in dopamine
turnover index. The obtained results for (R)-(ꢀ)-2-(4-
N,N-dimethylaminophenyl)-apomorphine (12) con-
firmed its dopamine agonistic property only in the
nigrostriatal dopaminergic system. The 4-dibenzofura-
nyl-substituted congener 13 was found to be inactive
in both dopaminergic systems.
4. Conclusion
5. Experimental
We have established an efficient procedure for preparing
2-alkyl- and arylapomorphines 2, 3, 11–13 including two
synthesis routes differing in the target system of the Su-
zuki–Miyaura cross-coupling. It was found that this pal-
ladium-catalyzed reaction was very well applicable and
produced from high to very high yields in case of both
vinyl halide-type morphinandiene 4 and aryl halide-type
apocodeine 10. The overall yields of the syntheses of 2-
alkyl- and arylapomorphines 2, 3, 11–13 were in the
range of 29–36% referred to thebaine. In conclusion of
the in vitro and in vivo pharmacological results the
superior dopamine-binding activity of 2-phenyl- (2)
and 2-(4-hydroxyphenyl)-apomorphines (3) are in accor-
dance with the literature results3 and the high affinity of
compound 3 to D3 receptor subtype could result in ther-
apeutic application as well. These results also supported
the assumption of the existence of a lipophilic cleft on
the surface of the receptor in the proximity of 2-position
of aporphine backbone in optimal binding mode. In the
case of compound 3 an additional amplifying effect
could be the appearance of an H-bond between surface
peptides and the phenolic hydroxyl.
Melting points were determined with a Kofler hot-stage
apparatus and are uncorrected. Thin layer chromatogra-
phy was performed on precoated Merck 5554 Kieselgel
60 F254 foils using chloroform/methanol = 4:1 mobile
phase. The spots were visualized with Draggendorf’s re-
agent. 1H NMR spectra were recorded on a Bruker WP
200 SY spectrometer, chemical shifts are reported in
ppm (d) from internal TMS and coupling constants (J)
are reported in Hz. Mass spectral measurements were
performed with an Automass Multi (ThermoQuest)
instrument in the EI mode (direct inlet). The source tem-
perature was 140 ꢁC, ionization was 70 eV. Optical rota-
tion was determined with a Perkin-Elmer Model 241
polarimeter. Elemental analyses (C, H, N, S) were ob-
tained on a Carlo Erba 1106 analyzer.
5.1. Acid-catalyzed rearrangement of morphinandienes
(General procedure I)
A mixture of the diene (1.48 mmol) and methanesulf-
onic acid (5 ml) was stirred for 20 min at 0 ꢁC. Then
the reaction mixture was added dropwise, with stirring
and external ice-cooling, to a solution of potassium
hydrogen carbonate (10 g) in water (50 ml). After
extraction with chloroform (3 · 15 ml), the combined
extracts were washed with saturated brine, dried
(MgSO4), and concentrated in vacuum. The residue
was submitted to purification by means of column
chromatography (Kieselgel 40, chloroform/metha-
nol = 1:1) to yield apocodeines.
The neuropharmacological profile of the newly synthe-
sized 2-substituted apomorphine derivatives 11–13 var-
ies on a wide range. In this group of novel compounds
11–13 the most remarkable binding properties were ob-
served for 2-methyl derivative 11 as it was proved to be
more potent agonist in both in vitro and in vivo studies
than apomorphine (1). The brain penetration of com-

A. Sipos et al. / Bioorg. Med. Chem. 16 (2008) 3773–3779
3777
5.2. Cross-coupling of bromo-derivatives with aryl- and
methylboronic acids (General procedure II)
(200 MHz, CDCl3) d = 151.21 (C40), 149.04 (C10),
146.78 (C11), 139.65–113.34 (15 Ar-C), 60.83 (C60),
56.05 (O–CH3), 53.32 (C5), 41.66 (N–CH3), 40.72 (N–
(CH3)2), 35.67 (C7), 34.54 (C4).
A mixture of the bromo-derivative (3.00 mmol), the
aryl- or methylboronic acid (3.00 mmol), Pd(PPh3)2Cl2
or Pd(PPh3)4 (0.15 mmol) and Ba(OH)2.8H2O
(3.00 mmol) was boiled in 1,4-dioxane/H2O = 4:1 under
reflux for 30 min. After evaporation at reduced pressure
the residue was dissolved in chloroform (20 ml) and fil-
tered. The filtrate was evaporated and the residue was
purified by flash chromatography (silica, chloroform/
methanol = 1:1) to yield aryl and alkyl derivatives.
5.2.1.6. (R)-(ꢀ)-2-(4-Dibenzofuranyl)-apocodeine (10).
Compound 10 was prepared from 2-bromoapocodeine
(5) according to General procedure II. Brown crystalline
solid; mp 98–102 ꢁC. Yield: 831 mg (62%); Anal. calcd
for C30H25NO3 (%): C, 80.51; H, 5.63; N, 3.13; O,
10.72; found (%): C, 80.48; H, 5.65; N, 3.18; O, 10.69;
25
D
1
½aꢁ ꢀ78 (c 0.12, chloroform); MS m/z (%) 447 (M+,
51); H NMR (200 MHz, CDCl3) d = 8.84 (d, 1H, H1,
J1–3 = 1.9), 8.19–7.26 (m, 8H, H3, 2-Ar), 6.84 (2d, 2H,
H8, H9, J8–9 = 8.1), 6.26 (br s, 1H, OH), 3.96 (s, 3H,
O–CH3), 3.60–2.87 (m, 5H, H4a, H5a, H5b, H6a, H7a),
2.85–2.57 (m, 5H, H4b, H7b, N–CH3); 13C NMR
(200 MHz, CDCl3) d = 158.43 (C60), 149.31 (C10),
147.78 (C40), 146.09 (C11), 136.74–111.06 (20 Ar-C),
60.66 (C60), 56.36 (O–CH3), 52.45 (C5), 41.25 (N–
CH3), 36.56 (C7), 26.29 (C4).
5.2.1. Synthesis route I
5.2.1.1. (R)-(ꢀ)-2-Bromoapocodeine (5). Compound 5
was prepared from 6-bromo-6-demethoxythebaine (4)
according to General procedure I. White crystalline so-
lid; mp 217–219 ꢁC. Yield: 464 mg (87%); spectral data
were in agreement with previously published results.7
5.2.1.2. (R)-(ꢀ)-2-Methylapocodeine (6). Compound 6
was prepared from 2-bromoapocodeine (5) according to
General procedure II. White crystalline solid; mp 160–
163 ꢁC. Yield: 674 mg (76%); Anal. calcd for
5.2.2. Synthesis route II
5.2.2.1. 6-Methyl-6-demethoxythebaine (14). Com-
pound 14 was prepared from 6-bromo-6-demethoxyt-
hebaine (4) according to General procedure II. White
C19H21NO2 (%): C, 77.26; H, 7.17; N, 4.74; O, 10.83;
25
D
found (%): C, 77.32; H, 7.15; N, 4.75; O, 10.78; ½aꢁ
ꢀ123 (c 0.5, chloroform); MS m/z (%) 295 (M+, 100);
crystalline solid; mp 190–192 ꢁC. Yield: 743 mg (84%);
25
1H NMR (200 MHz, CDCl3) d = 8.04 (d, 1H, H1, J1–3
=
½aꢁ ꢀ247 (c 0.38, chloroform) spectral data were in
D
1.9), 6.85 (d, 1H, H3, J1–3 = 1.9), 6.72 (2d, 2H, H8, H9,
J8–9 = 7.9), 6.18 (br s, 1H, OH), 3.87 (s, 3H, O–CH3),
3.38–2.90 (m, 5H, H4a, H5a, H5b, H6a, H7a), 2.78–
2.41 (m, 5H, H4b, H7b, N–CH3), 2.3 (s, 3H, Ar–CH3);
13C NMR (200 MHz, CDCl3) d = 148.26 (C10), 146.24
(C11), 138.21–114.25 (10 Ar-C), 61.25 (C60), 55.96 (O–
CH3), 51.26 (C5), 40.84 (N–CH3), 35.19 (C7), 33.26
(C4), 32.56 (C–CH3).
agreement with previously published results.11
5.2.2.2. 6-Phenyl-6-demethoxythebaine (15). Com-
pound 15 was prepared from 6-bromo-6-demethoxyt-
hebaine (4) according to General procedure II. Yellow
crystalline solid; mp 84–87 ꢁC. Yield: 975 mg (91%);
Anal. calcd for C24H23NO2 (%): C, 80.64; H, 6.49; N,
3.92; O, 8.95; found (%): C, 80.72; H, 6.52; N, 3.99; O,
25
8.77; ½aꢁ ꢀ286 (c 0.5, chloroform); MS m/z (%) 357
D
1
5.2.1.3. (R)-(ꢀ)-2-Phenylapocodeine (7). Compound 7
was prepared from 2-bromoapocodeine (5) according to
General procedure II. White crystalline solid; mp 85–
88 ꢁC, Yield: 911 mg (85%); spectral data were in agree-
ment with previously published results.6a
(M+, 100); H NMR (200 MHz, CDCl3) d = 7.65 (m,
2H, 6-Ar), 7.52–7.10 (m, 3H, 6-Ar), 6.65 (2d, 2H, H1,
H2, J1–2 = 7.6), 6.32 (d, 1H, H8, J7–8 = 7.2), 5.95 (s,
1H, H5), 5.79 (d, 1H, H7, J7–8 = 7.2), 3.74 (s, 3H, O–
CH3), 3.45–2.75 (m, 4H, H9a, H10a, H10b, H16b), 2.52
(s, 3H, N–CH3), 2.30–2.08 (m, 2H, H15b, H16a), 1.21
(dt, 1H, H15a, J15a,15b;16a,16b 12.7, J15a,15b 5.1); 13C
NMR (200 MHz, CDCl3) d = 147.26 (C3), 146.76 (C4),
142.30 (C6), 139.21–120.85 (10 Ar-C, C14), 118.32
(C7), 116.32 (C8), 111.12 (C2), 90.43 (C5), 62.76 (C9),
57.43 (O–CH3), 51.21 (C16), 46.78 (C13), 40.80 (N–
CH3), 37.13 (C15), 30.87 (C10).
5.2.1.4. (R)-(ꢀ)-2-(4-Hydroxyphenyl)-apocodeine (8).
Compound 8 was prepared from 2-bromoapocodeine
(5) according to General procedure II. White crystalline
solid; mp 130–131 ꢁC, Yield: 806 mg (72%); spectral
data were in agreement with previously published
results.6a
5.2.1.5. (R)-(ꢀ)-2-(4-N,N-dimethylphenyl)-apocodeine
(9). Compound 9 was prepared from 2-bromoapoco-
deine (5) according to General procedure II. White crys-
talline solid; mp 108–111 ꢁC, Yield: 732 mg (61%); Anal.
5.2.2.3.
6-(4-Hydroxyphenyl)-6-demethoxythebaine
(16). Compound 16 was prepared from 6-bromo-6-
demethoxythebaine (4) according to General procedure
II. Off-white crystalline solid; mp 145–147 ꢁC. Yield:
828 mg (74%); Anal. calcd for C24H23NO3 (%): C,
calcd for C26H28N2O2 (%): C, 77.97; H, 7.05; N, 6.99; O,
25
D
1
7.99; found (%): C, 77.85; H, 7.00; N, 7.09; O, 8.06; ½aꢁ
77.19; H, 6.21; N, 3.75; O, 12.85; found (%): C, 77.35;
25
D
1
ꢀ180 (c 0.2, methanol); MS m/z (%) 400 (M+, 69); H
H, 6.20; N, 3.69; O, 12.76; ½aꢁ ꢀ516 (c 0.05, chloro-
NMR (200 MHz, CDCl3) d = 8.11 (d, 1H, H1, J1–3
=
form); MS m/z (%) 373 (M+, 85); H NMR (200 MHz,
DMSO-d6) d = 9.50 (br s, 1H, OH), 7.45 (m, 2H, 6-
Ar), 6.82–6.51 (m, 4H, H1, H2, 6-Ar), 6.30 (d, 1H,
2.3), 7.81–7.19 (m, 5H, H3, 2-Ar), 6.80 (2d, 2H, H8,
H9, J8–9 = 8.2), 6.38 (br s, 1H, OH), 3.96 (s, 3H, O–
CH3), 3.84 (dd, 1H, H6a, J6a–7b = 2.6, J6a–7a = 4.6),
3.56–3.18 (m, 10H, H4a, H5a, H5b, H7a, N–(CH3)2),
2.90–2.52 (m, 5H, H4b, H7b, N–CH3); 13C NMR
H8, J7–8 = 7.9), 5.83 (s, 1H, H5), 5.65 (d, 1H, H7, J7–8
7.9), 3.54 (s, 3H, O–CH3), 3.45–2.45 (m, 4H, H9a, H10a,
H10b, H16b), 2.35 (s, 3H, N–CH3), 2.33–2.00 (m, 2H,
=

3778
A. Sipos et al. / Bioorg. Med. Chem. 16 (2008) 3773–3779
H15b, H16a), 1.08 (dt, 1H, H15a, J15a,15b;16a,16b 12.4,
J15a,15b 4.9); 13C NMR (200 MHz, CDCl3) d = 158.89
(C40), 146.92 (C3), 146.11 (C4), 141.46 (C6), 130.13–
118.45 (8 Ar-C, C14), 117.54 (C7), 114.89 (C8), 112.56
(C2), 88.88 (C5), 61.36 (C9), 55.78 (O–CH3), 50.01
(C16), 45.11 (C13), 40.40 (N–CH3), 35.23 (C15), 29.81
(C10).
I. White crystalline solid; mp 130–131 ꢁC. Yield: 627 mg
(56%); spectral data were in agreement with previously
published results.6a
5.2.2.9.
(R)-(ꢀ)-2-(4-N,N-Dimethylphenyl)-apoco-
deine (9). Compound 9 was prepared from 6-(4-N,N-
dimethylphenyl)-6-demethoxythebaine (17) according
to General procedure I. Yield: 576 mg (48%); all the
physical and spectral data are in agreement with the de-
tails presented at Synthesis route I.
5.2.2.4. 6-(4-N,N-Dimethylphenyl)-6-demethoxytheba-
ine (17). Compound 17 was prepared from 6-bromo-6-
demethoxythebaine (4) according to General procedure
II. Yellow crystalline solid; mp 89–91 ꢁC. Yield: 756 mg
(63%); Anal. calcd for C26H28N2O2 (%): C, 77.97; H,
5.2.2.10.
(R)-(ꢀ)-2-(4-Dibenzofuranyl)-apocodeine
(10). Compound 10 was prepared from 6-(4-dibenzof-
uranyl)-6-demethoxythebaine (18) according to General
procedure I. Yield: 589 mg (44%); all the physical and
spectral data are in agreement with the details presented
at Synthesis route I.
7.05; N, 6.99; O, 7.99; found (%): C, 77.65; H, 7.09; N,
25
7.10; O, 8.16; ½aꢁ -480 (c 0.20, methanol); MS m/z (%)
D
400 (M+, 70); 1H NMR (200 MHz, CDCl3) d = 7.61 (m,
2H, 6-Ar), 6.75–6.52 (m, 4H, H1, H2, 6-Ar), 6.30 (d,
1H, H8, J7–8 = 7.8), 5.95 (s, 1H, H5), 5.82 (d, 1H, H7,
J7–8 = 7.7), 3.75 (s, 3H, O–CH3), 3.45–2.55 (m, 10H,
H9a, H10a, H10b, H16b, N–(CH3)2), 2.50 (s, 3H, N–
CH3), 2.43–2.17 (m, 2H, H15b, H16a), 1.87 (dt, 1H,
H15a, J15a,15b;16a,16b 12.6, J15a,15b 5.0); 13C NMR
(200 MHz, CDCl3) d = 149.11 (C40), 147.34 (C3), 146.65
(C4), 141.09 (C6), 134.73 (C14), 130.13–118.45 (8 Ar-C),
117.39 (C7), 115.25 (C8), 111.67 (C2), 90.12 (C5), 61.23
(C9), 56.19 (O–CH3), 50.98 (C16), 47.23 (C13), 41.56
(N–CH3), 40.23 (N–(CH3)2), 35.76 (C15), 30.30 (C10).
5.3. O-demethylation of 2-substituted apocodeines to yield
corresponding 2-substituted apomorphines (General pro-
cedure III)
A mixture of 2-substituted apocodeine (4.65 mmol),
methionine (1000 mg, 6.70 mmol) and CH3SO2OH
(4 ml) was boiled at 90 ꢁC for 2 hours. After cooling,
the pH of the mixture was set to 10 by concentrated
NH3 solution and extracted with chloroform
(3 · 15 ml). The organic layers were collected, washed
with saturated NaCl solution, dried over anhydrous
MgSO4 and evaporated. The residue was subjected to
silica-gel column chromatography. Elution with chloro-
form:methanol = 1:1 gave apomorphines.
5.2.2.5.
6-(4-Dibenzofuranyl)-6-demethoxythebaine
(18). Compound 18 was prepared from 6-bromo-6-
demethoxythebaine (4) according to General procedure
II. Yellow crystalline solid; mp 84–88 ꢁC. Yield:
885 mg (66%); Anal. calcd for C30H25NO3 (%): C,
80.51; H, 5.63; N, 3.13; O, 10.72; found (%): C, 80.52;
5.3.1. (R)-(ꢀ)-2-Methylapomorphine hydrochloride (11).
Compound 11 was prepared from 2-methylapocodeine
(6) according to General procedure III. Off-white crys-
talline solid; mp 208–212 ꢁC (HCl salt). Yield: 868 mg
(91%); Anal. calcd for C18H20ClNO2 (%): C, 68.03; H,
25
H, 5.72; N, 3.08; O, 10.68; ½aꢁ ꢀ346 (c 0.48, chloro-
D
form); MS m/z (%) 447 (M+, 100); 1H NMR
(200 MHz, CDCl3) d = 8.11–7.18 (m, 9H, H1, H2, 6-
Ar), 7.04 (d, 1H, H8, J7–8 = 7.2), 6.34 (s, 1H, H5a),
5.95 (d, 1H, H7, J7–8 = 7.2), 3.73 (s, 3H, O–CH3),
3.70–2.75 (m, 4H, H9a, H10a, H10b, H16eq), 2.62 (s,
3H, N–CH3), 2.52–2.20 (m, 2H, H15b, H16a), 2.01 (dt,
1H, H15a, J15a,15b;16a,16b 12.3, J15a,15b 4.8); 13C NMR
(200 MHz, CDCl3) d = 158.23 (C60), 152.32 (C40),
147.55 (C3), 146.27 (C4), 141.72 (C6), 134.87–121.18
(13 Ar-C, C14), 117.65 (C7), 115.56 (C8), 112.43 (C2),
91.39 (C5), 61.73 (C9), 56.88 (O–CH3), 50.45 (C16),
47.01 (C13), 41.45 (N–CH3), 36.83 (C15), 31.34 (C10).
6.34; Cl, 11.16; N, 4.41; O, 10.07; found (%): C, 68.11;
25
H, 6.37; N, 4.38; Cl, 11.18; O, 9.96; ½aꢁ ꢀ28 (c 0.4,
D
methanol); MS m/z (%) 318 (M+, 100); 1H NMR
(200 MHz, DMSO-d6) d = 10.75 (br s, 1H, Ar–OH),
9.85 (br s, 1H, Ar–OH), 8.85 (d, 1H, H1, J1–3 2.2),
7.25 (d, 1H, H3, J1–3 2.1), 7.82 (d, 1H, H9, J8–9 8.1),
7.75 (d, 1H, H8, J8–9 8.1), 3.78 (dd, 1H, H6a, J6a–7b
2.7, J6a–7a 4.9), 3.42–2.57 (m, 9H, H4a, H4b, H5a, H5b,
H7a, H7b, N–CH3), 2.32 (s, 3H, Ar–CH3); 13C NMR
(200 MHz, DMSO-d6) d = 145.62 (C10), 144.83 (C11),
139.01–111.85 (10 Ar–C), 60.82 (C60), 53.02 (C5),
40.13 (N–CH3), 35.54 (C7), 32.76 (C4), 32.09 (C–CH3).
5.2.2.6. (R)-(ꢀ)-2-Methylapocodeine (6). Compound 6
was prepared from 6-methyl-6-demethoxythebaine (14)
according to General procedure I. Yield: 630 mg
(71%); all the physical and spectral data are in agree-
ment with the details presented at Synthesis route I.
5.3.2. (R)-(ꢀ)-2-Phenylapomorphine hydrochloride (2).
Compound 2 was prepared from 2-phenylapocodeine
(7) according to General procedure III. Yield: 818 mg
(92.2%); mp >230 ꢁC (HCl salt); spectral data were in
agreement with previously published results.3
5.2.2.7. (R)-(ꢀ)-2-Phenylapocodeine (7). Compound 7
was prepared from 6-phenyl-6-demethoxythebaine (15)
according to General procedure I. White crystalline so-
lid; mp 85–88 ꢁC. Yield: 868 mg (81%); spectral data
were in agreement with previously published results.6a
5.3.3. (R)-(ꢀ)-2-(4-Hydroxyphenyl)-apomorphine hydro-
chloride (3). Compound 3 was prepared from 2-(4-
hydroxyphenyl)-apocodeine (8) according to General
procedure III. Yield: 762 mg (87.2%); mp > 230 ꢁC
(HCl salt); spectral data were in agreement with previ-
ously published results.3
5.2.2.8. (R)-(ꢀ)-2-(4-Hydroxyphenyl)-apocodeine (8).
Compound 8 was prepared from 6-(4-hydroxyphenyl)-6-
demethoxythebaine (16) according to General procedure

A. Sipos et al. / Bioorg. Med. Chem. 16 (2008) 3773–3779
3779
5.3.4. (R)-(ꢀ)-2-(4-N,N-Dimethylphenyl)-apomorphine
dihydrochloride (12). Compound 12 was prepared from
2-(4-N,N-dimethylphenyl)-apocodeine (9) according to
General procedure III. Brown crystalline solid; mp
>230 ꢁC (HCl salt). Yield: 1239 mg (90%); Anal. calcd
for C25H28Cl2N2O2 (%): C, 65.36; H, 6.14; Cl, 15.34;
itated, striatum and tuberculum olfactorium were
dissected and the concentration of dopamine and its
metabolites (dihydroxyphenylacetic acid and homovan-
ilic acid) were determined by reverse phase-HPLC cou-
pled with electrochemical detection essentially by the
method for Saller and Salama.18 Dopamine turnover in-
dex ([DOPAC] + [HVA]/[DA]) was calculated as a mea-
sure of dopamine-turnover.
N, 6.10; O, 6.97; found (%): C, 65.44; H, 6.18; Cl,
25
15.22; N, 6.10; O, 7.06; ½aꢁ ꢀ129 (c 0.2, methanol);
D
MS m/z (%) 459 (M+, 78); 1H NMR (200 MHz,
DMSO-d6) d = 10.65 (br s, 2H, 10-OH, 11-OH), 8.62
(d, 1H, H1, J1–3 = 2.1), 7.42 (d, 1H, H3, J1–3 2.1), 6.81
(d, 1H, H8, J8–9 7.9), 6.76 (d, 1H, H9, J8–9 7.9), 4.32
(dd, 1H, H6a, J6a–7b 2.4, J6a–7a 4.6), 3.81–2.51 (m,
15H, H4a, H4b, H5a, H5b, H7a, H7b, N–CH3, N–
(CH3)2); 13C NMR (200 MHz, DMSO-d6) d = 150.06
(C40), 146.87 (C10), 145.49 (C11), 138.48–112.92 (15
Ar–C), 61.28 (C60), 53.82 (C5), 42.66 (N–CH3), 41.05
(N–(CH3)2), 36.68 (C7), 33.81 (C4).
Acknowledgments
The authors are grateful for the substantial discussion to
´
Prof. Sandor Antus and for the financial support to the
National Science Foundation (Grant OTKA Reg. No.
T049436, K072987 and NI61336). A.S. is indebted to
the Eo¨tvo¨s Scholarship of the Hungarian State.
References and notes
5.3.5. (R)-(ꢀ)-2-(4-Dibenzofuranyl)-apomorphine hydro-
chloride (13). Compound 13 was prepared from 2-(4-dib-
enzofuranyl)-apocodeine (10) according to General
procedure III. Brown crystalline solid; mp >230 ꢁC
(HCl salt). Yield: 1113 mg (79%); Anal. calcd for
C29H24ClNO3 (%): C, 74.12; H, 5.15; Cl 7.54; N, 2.98;
1. Sit, S. Y. Curr. Pharma. Design 2000, 6, 1211.
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Berenyi, S.; Csutoras, Cs.; Kula, N. S.; Zhang, K.;
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O, 10.21; found (%): C, 74.20; H, 5.10; Cl 7.62; N,
25
3.03; O, 10.05; ½aꢁ ꢀ182 (c 0.20, methanol); MS m/z
D
(%) 470 (M+, 58); 1H NMR (200 MHz, DMSO-d6)
d = 9.01 (s, 1H, H1, J1–3 2.1), 8.32–7.20 (m, 8H, H3, 2-
Ar), 6.84 (2d, 2H, H8, H9, J8–9 8.4), 3.90–2.72 (m, 7H,
H4a, H4b, H5a, H5b, H6a, H7a, H7b), 2.57 (s, 3H, N–
CH3); 13C NMR (200 MHz, DMSO-d6) d = 156.11
(C60), 148.21 (C40), 147.27 (C10), 146.46 (C11),
137.24–113.00 (20 Ar-C), 61.19 (C60), 53.45 (C5), 40.92
(N–CH3), 37.24 (C7), 26.55 (C4).
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6.1. In vitro pharmacology
´
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6. (a) Berenyi, S.; Sipos, A.; Szabo, I.; Kalai, T. Synth.
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In vitro pharmacology involved determinations of affinity
(Ki, nM) of test compounds for dopamine D2 and D3
receptors in radioligand competition assays, using mem-
brane preparations from dopamine-rich corpus striatum
(caudatoputamen) tissue from rat forebrain and recombi-
nant rat D3 receptors expressed in Sf9 cells, respectively.
The applied radioligand was in both cases [3H]spiperone,
while non-specific bindings were determined in the pres-
ence of 2 mM (+)-butaclamol. Binding assays were per-
formed in accordance with the literature procedures.12–16
IC-50 (the concentration of the compound causes 50%
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´
´
7. Berenyi, S.; Makleit, S.; Szilagyi, L. Acta Chim. Hung.
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´ ´
Makleit, S. Med. Chem. Res. 1995, 5, 26.
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6.2. In vivo pharmacology
In vivo pharmacology involved the determination of
monoamine and metabolite levels. Male, CD-1 mice
(20–22 g) were treated with the test compounds subcuta-
neously at a dose of 3.29 lmol/kg (equivalent to 1.0 mg/
kg apomorphine.HCl administration). Each group con-
sisted of 5 mice. One hour later the animals were decap-
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