Novel selective 5-HT3 receptor ligands: Facile generation methods for 2-amino- and 4-aminopyrido[4′,3′:4,5]thieno[2,3-d] pyrimidines

Article abstract of DOI:10.1515/znb-2006-1008

This work reports on the synthesis of new 2-amino- and 4- aminopyridothienopyrimidines, with a view to identify potent and selective ligands for the 5-HT₃ receptor, starting from derivatives of 2-aminothiophene-3-carboxylic ester, -3-carboxamide, or 2-amino-3- cyanothiophene.

Full text of DOI:10.1515/znb-2006-1008

Novel Selective 5-HT3 Receptor Ligands: Facile Generation Methods for
2-Amino- and 4-Aminopyrido[4’,3’:4,5]thieno[2,3-d]pyrimidines
Mohamed A. Ameen
Chemistry Department, Faculty of Science, El Minia University, El Minia 61519, Egypt
Reprint requests to Dr. M. A. Ameen. E-mail: m_ameen10@yahoo.com
Z. Naturforsch. 61b, 1234 – 1238 (2006); received September 16, 2005
This work reports on the synthesis of new 2-amino- and 4-aminopyridothienopyrimidines, with
a view to identify potent and selective ligands for the 5-HT3 receptor, starting from derivatives of
2-aminothiophene-3-carboxylic ester, -3-carboxamide, or 2-amino-3-cyanothiophene.
Key words: 5-HT3 Receptor, Aminopyridothienopyrimidines, Cyclodesulfurization, Diazotization
Introduction
to our work during the last few years in which we have
been interested in the synthesis of thienopyrimidines
[16 – 21]. They also prompted us to continue our long-
term research aiming to obtain more potent and selec-
tive ligands for the 5-HT3 receptor. The present work
reports on the synthesis of 2-amino- and 4-amino-
thieno[2,3-d]pyrimidine derivatives which can be re-
garded or might behave prospectively as analogues to
5-HT3 receptor ligands [22]. These compounds pos-
sess the three key pharmacophoric elements (an aro-
matic moiety, a hydrogen-bond acceptor and a basic
amino group) required for interaction with the 5-HT3
receptor [23] and are structurally related to quipazine,
a potent ligand for the 5-HT3 receptor [24].
Derivatives of 2-aminothiophene-3-carboxylicester,
-3-carboxamide, or 2-amino-3-cyanothiophene have
been found to be important intermediates in the prepa-
ration of thienopyrimidines. Therefore they attracted
much attention during recent years [1 – 9]. The ob-
tained thienopyrimidine derivatives have found wide
application in a variety of synthetic transformations
as well as biological activities. The serotonin neuro-
transmitter is involved in a number of different physi-
ological functions through its interaction with 14 types
of receptors [10]. These are G-protein-coupled recep-
tors, with the exception of the 5-HT3, which is a lig-
and gated-ion channel receptor. 5-HT3 receptor antag-
onists, such as ondansetron, granisetron, or tropisetron
[11] are used as anti-emetic drugs to prevent vomit-
ing associated with chemotherapy or radiation-induced
emesis, but literature studies [12] indicated that they
could possess numerous other potential therapeutic ap-
plications in the control of pain or in the treatment of
psychosis, memory impairment, depression, anxiety,
schizophrenia, and drugs abuse.
Results and Discussion
The reaction of 2-aminothiophene-3-carboxamide 1
with benzoyl isothiocyanate in acetone afforded the
corresponding [N-benzoyl(thiocarbamoyl)]-aminothi-
ophene derivative 2 in 67% yield (Scheme 1). The iso-
lated compound 2 was hydrolyzed to yield the corre-
sponding thiourea 3 (Scheme 1).
On the other hand, little is known about the ther-
In the accomplishment of the cyclodesulfurization
apeutic potential of 5-HT3 receptor agonists although (Scheme 1) by use of a heavy metal salt, compound
some potent and selective ligands with full agonistic 3 was added to a suspension of a slight excess of the
properties [13] were recently reported. It has been sug- metal salt in aqueous sodium hydroxide. The reaction
◦
gested that stimulation of the 5-HT3 receptor mod- was completed after heating at 100 C. Thereafter, t◦he
ulates in the central nervous system the release of temperature of the reaction mixture was kept at 50 C
dopamine, cholecystokinin, and acetylcholine [14]. for 15 min and the formed copper sulfide was then fil-
Moreover, 5-HT3 receptors are involved in the pe- tered off. Compound 4 was obtained after purification
ripheral control of acetylcholine release of the distal and recrystallization processes (see Experimental Sec-
colon [15]. These interesting results make it desirable tion). The best yields of 4 were obtained with copper
c
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M. A. Ameen · Novel Selective 5-HT3 Receptor Ligands
1235
Table 1. Effect of the metal iona, the amount and concentra-
tion of base, and the temp. on conversion of 3 to 4.
Metal saltsb
Conc. of
NaOH, M
0.1
0.1
1
1
3
3
3
Temp.
[◦C]
100c
100
25
100
100
100
100
100
Time
[h]
2
1
45
1
1
0.5
2
Yield
[%]
38
74
90
97
97
89
98
Cu2+
Cu2+
Cu2+
Cu2+
Cu2+
Cu2+
Ag+
Hg2+
3
2
87
Scheme 2. Alternative method used to synthesize com-
pound 4.
a Metal salts used: Cu2(OAc)4, AgCl and HgCl2; b poor yields for
4 were obtained when the chloride salts of Pb+2, Zn+2, Bi+3 and
Fe+2 were used;
after 1 h.
at room temp. a 82% yield of 4 was obtained
c
in-4-one derivative 6 was obtained [18]. This method
has been successfully improvedherein by heating com-
◦
pound 5 at a temperature between 40 and 50 C, so that
the reaction was finished in about 10 h.
When compound 6 had reacted with hydrazine hy-
drate in the presence of pyridine, 2,3-diaminothieno
[2,3-d]pyrimidin-4-one derivative 7 was formed in
87% yield. The NMR spectra of 7 were in a good
agreement with the assigned structure. Further diazo-
tization of 7, with sodium nitrite in acetic acid [20],
gave successfully our target compound 4 (Scheme 2),
which was identical in all aspects with that obtained in
Scheme 1.
Scheme 1. Cyclodesulfurization of 3 into 4 catalyzed by cop-
per acetate in aqueous NaOH.
The elemental analysis of 4 is in accordance with
its molecular formula as C12H14N4O3S. The IR spec-
troscopy of 4 showed the absorption of the NH2,
and silver salts, while mercury salts afforded a some-
what lower yield. Bismuth, lead and zinc gave only
poor yields, and ferrous salts failed (Table 1). The mo-
lar ratio of hydroxyl ions to compound 3 turned out to
be essential for the yield of the ring closure reaction,
the preferable ratio being 6 equiv. of hydroxyl ions to
1 equiv. of compound 3 (Table 1). The molar concen-
tration of hydroxyl ions had, on the other hand, only a
small effect on the yield. It is worthy to mention that
the utility of Cu2+ in the conversion of 3 into 4 can be
enhanced using a moderately concentrated solution of
NaOH (1 M) at 100 ◦C. With higher concentrations of
NaOH, for example 3 M, the interconversion of 3 pro-
ceeds to give 4 with the same yield as for 1 M of NaOH
˜
NH and the carbonyl group at ν = 3380– 3285 and
1
1705 cm−1, respectively. The H NMR spectrum of
4 revealed a triplet and a quartet corresponding to
ester protons. Furthermore, two singlets appeared at
δ = 4.79 and 8.35 ppm corresponding to the NH2 and
NH protons. Three distinctive carbon signals were de-
tected in the 13C NMR spectrum of 4 at δ = 152.62,
156.16 and 158.24 ppm related to the C-NH2 and two
carbonyl groups (see Experimental Section).
We synthesized the novel tricyclic 4-aminothieno-
pyrimidine derivative 12 starting from the aminothio-
phene derivative 8, according to known examples of
cyclizations with an ortho-aminonitrile. For the prepa-
ration of the 4-aminopyridothienopyrimidine deriva-
tive 12, we used a method reported by Taylor and
Berger [25] and Gewald and Martin [26]. Reaction
of ammonia with the iminoester group in compound
9 [21] occurred to afford the thienopyridine-2-imino-
(see Table 1). In the case of salts of Ag+ and Hg2+
,
higher concentrations of NaOH were used. The advan-
tage of this methodology is related to the lower cost
of the available salts used, in addition to the produc-
tive yields of aminopyrimidines from the correspond-
ing 1,2-imidothiourea derivatives (Scheme 3).
Under strongly acidic conditions, the 1,3-thiazine formamide derivative 10. Compound 10 on treat-
ring closure can be attained. On treatment of 2- ment with sodium ethoxide solution underwent en-
thioureido-3-thiophenecarboxylate 5 with conc. sulfu- suing cyclization and gave rise to 11, which under-
ric acid at r. t. for 5 d, 2-aminothieno[2,3-d][1,3]thiaz- went tautomerization to form 12. The constitution of
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1236
M. A. Ameen · Novel Selective 5-HT3 Receptor Ligands
2 NH), 3040 (arom. CH), 1708 (ester C=O), 1665 (C=O)
cm−1. – 1H NMR (300 MHz, [D6]-DMSO): δ = 1.22 (t,
3 H, OCH2CH3), 2.79 (t, 2 H, 4-H), 3.65 (t, 2 H, 5-H), 4.08
(q, 2 H, OCH2CH3), 4.54 (s, 2 H, 7-H), 7.21 (b, 2 H, NH2),
7.46 – 7.97 (m, 5 H, Ar-H), 11.68 (br, s, 1 H, NH), 14.52
(br, s, 1 H, NH). – 13C{H} NMR (75.5 MHz, [D6]-DMSO):
δ = 14.46 (CH3), 24.62 (C-4), 40.21 (C-5), 42.20 (C-7),
60.94 (CH2), 121.37 (C-3), 124.32 (C-7a), 126.11, 127.16,
131.17, 132.98 (Ar-C), 140.94 (C-3a), 154.69 (C=O), 165.58
(C-2), 166.69 (C=O), 172.83 (C=O), 174.10 (C=S). –
C19H20N4O4S2 (432.52): calcd. C 52.76, H 4.66, N 12.95;
found C 52.55, H 4.39, N 12.73.
Ethyl 2-(thiocarbamoyl)amino-3-aminocarbonyl-4,5,6,7-
tetra-hydrothieno[2,3-c]pyridine-6-carboxylate (3)
Scheme 3. Synthesis of aminopyridothienopyrimidine 12.
To compound 2 (4.32 g, 10 mmol) in acetone-methanol
(1:1, 40 ml) was added potassium carbonate (5 mmol) in wa-
ter (5 ml). The mixture was heated to reflux for 5 h, where-
upon acetic acid (12 mmol) was added. After cooling in
an ice bath the solid product was filtered off, washed with
cold water and dried to give 3. Buf◦f crystals (methanol);
3385 – 3275 (2NH2, NH), 1711 (ester C=O), 1675 (C=O)
cm−1. – 1H NMR (300 MHz, [D6]-DMSO): δ = 1.19 (t, 3 H,
OCH2CH3), 2.79 (t, 2 H, 4-H), 3.59 (t, 2 H, 5-H), 4.09 (q,
2 H, OCH2CH3), 4.47 (s, 2 H, 7-H), 4.81 (br, s, 2 H, 2 NH2),
8.32 (br, s, 1 H, NH). – 13C {H} NMR (75.5 MHz, [D6]-
DMSO): δ = 14.44 (CH3), 25.80 (C-4), 40.21 (C-5), 42.25
(C-7), 60.95 (CH2), 112.51 (C-3), 121.12 (C-7a), 129.42
(C-3a), 154.64 (C=O), 163.05 (C-2), 170.17 (C=O), 174.94
(C=S). – C12H16N4O3S2 (328.41): calcd. C 43.89, H 4.91,
N 17.06; found C 43.72, H 4.72, N 16.88.
12 is supported by independent synthesis from the o-
aminonitrile 8 with formamide under reflux and on
the basis of IR and H NMR spectra. Compound 12
1
showed no IR absorption bands for NH or CN groups
and its 1H NMR spectrum exhibited a broad singlet for
the NH2 group.
In conclusion, a new, simple and efficient synthesis
of aminopyridothienopyrimidines has been developed.
It has several merits over hitherto known methods, i. e.
fewer reaction steps, mild reaction conditions, higher
yields, and easy workup procedures.
˜
yield: 2.4 g (73%); m. p. 205 – 207 C. – IR (KBr): ν =
Experimental Section
Melting points were determined on a Boetius melting
point apparatus and are uncorrected. Elemental analyses
were performed on a Carlo Erba CHN-S Elemental Ana-
lyzer 1108. The 13C and 1H NMR spectra were obtained
using a Bruker AC 300 instrument (1H: 300.13 MHz; 13C:
75.5 MHz). The δ values are given in ppm, and the inter-
nal standard was tetramethylsilane. Mass spectra were ob-
tained on a spectrometer Perkin-Elmer SCIEX API-300 (by
ion spray using a heated nebulizer). The IR spectra were
recorded on a Nicolet 250 FT-IR spectrophotometer using
potassium bromide pellets.
Ethyl 2-amino-4-oxo-1,2,3,4,5,6,7,8-octahydropyrido[4’,3’,
4,5]thieno[2,3-d]pyrimidine-7-carboxylate (4)
M e t h o d A
Compound 3 (3.28 g, 10 mmol) was dissolved in 1M
aqueous sodium hydroxide (50 ml). Copper(II) acetate-H2O
(2.2 g, 11 mmol) dissolved in water (10 ml) was added, and
the mixture was heated to 100 ◦C for 1 h. Thereafter, the tem-
perature of the reaction mixture was kept at 50 ◦C for 15 min,
the formed copper(II) sulfide was then filtered off (Whatman
GF/F). The resulting filter cake which was washed with 1M
sodium hydroxide was acidified with acetic acid to pH 5.0.
The obtained product was filtered off, washed with water and
dried to give compound 4 in 97% yield.
Ethyl 2-[N-benzoyl(thiocarbamoyl)]amino-3-aminocarbon-
yl-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine-6-carboxylate
(2)
A mixture of 1 (2.7 g, 10 mmol) and benzoyl isothiocyan-
ate (1.8 g, 11 mmol) was refluxed in acetone (30 ml) un-
der N2 for 4 h. The reaction mixture was then cooled and
M e t h o d B
To a suspension of 7 (0.31 g, 1 mmol) in acetic acid
the precipitate formed was filtered off and washed with dry (2 ml) and water (10 ml), a solution of sodium nitrite (0.28 g,
acetone (20 ml).◦Yellow needles of 2, yield 2.9 g (67%); 4 mmol) in water (1 ml) was added. After stirring for 15 min
˜
m. p. 235 – 237 C – IR (KBr): ν = 3360 – 3280 (NH2, at r. t, 40% sodium hydroxide solution was added (3 ml).
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M. A. Ameen · Novel Selective 5-HT3 Receptor Ligands
1237
The reaction mixture was warmed to form a clear solution. Ethyl 2-amidino-3-cyano-4,5,6,7-tetrahydrothieno[2,3-c]-
After cooling, 50% sulfuric acid was added dropwise un- pyridine-6-carboxylate (10)
til pH 2. The precipitated product was filtered off, washed
A suspension of 8 (0.61 g, 2 mmol) and ammonium hy-
with water, dried, and crystallized from ethanol as pale yel-
droxide solution (30%) (10 ml) was stirred at r. t. for 2 h.
◦
˜
low crystals. Yield 82%, m.p. > 300 C – IR (KBr): ν =
3380 – 3285 (NH2, NH), 1705 (ester C=O), 1665 (C=O)
cm−1. – 1H NMR (300 MHz, [D6]-DMSO): δ = 1.20 (t, 3 H,
OCH2CH3), 2.73 (t, 2 H, 5-H), 3.64 (t, 2 H, 6-H), 4.12 (q,
2 H, OCH2CH3), 4.52 (s, 2 H, 8-H), 4.79 (br, s, 2 H, NH2),
8.35 (br, s, 1 H, NH). – 13C{H} NMR (75.5 MHz, [D6]-
DMSO): δ = 14.45 (CH3), 26.08 (C-5), 40.89 (C-6), 42.69
(C-8), 60.90 (CH2), 119.77 (C-4a), 127.95 (C-4b), 129.74
(C-8a), 151.13 (C-9a), 152.62 (C-NH2), 156.16 (C=O),
158.24 (C=O). – C12H14N4O3S (294.33): calcd. C 48.97,
H 4.79, N 19.04; found C 48.72, H 4.54, N 18.86.
The product was filtered off, washed with water and re-
crystallized from ethyl acetate/acetonitrile. Compound 10
was obtained as white needles; yield 0.51 g (91%); m. p.
◦
˜
161 – 162 C – IR (KBr): ν = 3360 (NH2), 1712 (ester
C=O), 1615 (C=N) cm−1. – 1H NMR (300 MHz, [D6]-
DMSO): δ = 1.21 (t, 3 H, OCH2CH3), 2.85 (t, 2 H, 4-H),
3.65 (t, 2 H, 5-H), 4.12 (q, 2 H, OCH2CH3), 4.55 (s, 2 H,
7-H), 6.45 (br, s, 2 H, NH2), 8.35 (s, 1 H, CH). – 13C{H}
NMR (75.5 MHz, [D6]-DMSO): δ = 14.38 (CH3), 23.39
(C-4), 40.93 (C-5), 42.02 (C-7), 60.86 (CH2), 113.38 (CN),
123.99 (C-3), 129.60 (C-7a), 146.09 (C-3a), 154.55 (C=O),
159.07 (CH=N), 163.58 (C-2). – C12H14N4O2S (278.33):
calcd. C 51.78, H 5.07, N 20.13; found C 51.62, H 4.91,
N 19.98.
Ethyl 2-amino-4-oxo-5,6,7,8-tetrahydropyrido[4’,3’:4,5]-
thieno[2,3-d][1,3]thiazine-7-carboxylate (6)
A suspension of compound 5 (6.0 g, 13 mmol) in 98%
sulfuric acid (60 ml) and few drops of water was stirred at
40 – 50 ◦C for 10 h. The resultant clear solution was slowly
poured on ice-water and sodium bicarbonate (300 ml). The
precipitate was collected, washed with ethanol and dried to
give compound 6. M. p. 254 – 256 ◦C [18].
Ethyl 4-amino-3,4,5,6,7,8-hexahydropyrido[4’,3’:4,5]-
thieno[2,3-d]pyrimidine-7-carboxylate (12)
M e t h o d A
A mixture of 10 (1.0 g) and a solution of 1M alcoholic
potassium hydroxide (10 ml) was refluxed for 1 h. The re-
action mixture was acidified with 1M hydrochloric acid. The
product was collected by filtration, washed with water, dried
and recrystallized from DMF/n-hexane as colorless crystals
in 91% yield.
Ethyl 2,3-diamino-4-oxo-1,2,3,4,5,6,7,8-octahydropyrido-
[4’,3’:4,5]thieno[2,3-d]pyrimidine-7-carboxylate (7)
To a stirred suspension of 6 (0.62 g, 2 mmol) in pyridine
(10 ml), hydrazine hydrate (2.5 mmol) was added. The re-
action mixture was refluxed for 4 h. The precipitate was fil-
tered off, washed with ethanol and recrystallized from ethyl
acetate. Pale yellow needles; yield 0.54 g (87%); m. p. 297 –
M e t h o d B
Compound 8 (1.2 g, 4 mmol) in formamide (10 ml) was
refluxed for 5 h. The product that formed after cooling was
filtered off and ◦washed with ethanol. Yield 0.69 g (62%);
˜
1
m. p. 272 – 274 C. – IR (KBr): ν = 3375 (NH2), 1707 (es-
◦
˜
299 C – IR (KBr): ν = 3350 – 3390 (2 NH2), 1710 (es-
ter C=O), 1618 (C=N) cm−1. – H NMR (300 MHz, [D6]-
1
ter C=O), 1685 (C=O) cm−1. – H NMR (300 MHz, [D6]-
DMSO): δ = 1.19 (t, 3 H, OCH2CH3), 2.81 (t, 2 H, 5-H),
3.68 (t, 2 H, 6-H), 4.10 (q, 2 H, OCH2CH3), 4.57 (s, 2 H,
8-H), 7.55 (br, s, 2 H, NH2), 9.12 (s, 1 H, CH). – 13C{H}
NMR (75.5 MHz, [D6]-DMSO): δ = 14.42 (CH3), 26.18
(C-5), 40.76 (C-6), 42.68 (C-8), 60.95 (CH2), 119.71 (C-4a),
127.93 (C-4b), 129.76 (C-8a), 151.14 (C-9a), 155.75 (C-2),
157.14 (C-NH2), 158.27 (C=O). – C12H14N4O2S (278.30):
calcd. C 51.78, H 5.07, N 20.13; found C 51.62, H 4.91,
N 19.98.
DMSO): δ = 1.18 (t, 3 H, OCH2CH3), 2.86 (t, 2 H, 5-H),
3.74 (t, 2 H, 6-H), 4.11 (q, 2 H, OCH2CH3), 4.61 (s, 2 H,
8-H), 4.85 (br, s, 2 H, NH2), 7.31 (br, s, 2 H, N-NH2). –
13C {H} NMR (75.5 MHz, [D6]-DMSO): δ = 14.48 (CH3),
26.18 (C-5), 40.78 (C-6), 42.71 (C-8), 60.86 (CH2), 118.98
(C-4a), 126.95 (C-4b), 129.15 (C-8a), 151.09 (C-9a), 152.52
(C-NH2), 156.07 (C=O), 158.18 (C=O). – C12H15N5O3S
(309.35): calcd. C 46.59, H 4.89, N 22.64; found C 46.42,
H 4.71, N 22.43.
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