Syntheses of quinazoline-2,4-dione alkaloids and analogues from Mexican Zanthoxylum species

Article abstract of DOI:10.3390/90700609

Quinazolinone and quinazolinedione derivatives are of considerable interest due to their wide array of pharmacological properties. In this paper we report the synthesis of ten quinazolinediones. The previous isolation of two of these compounds, namely 1-methyl-3-(2′-phenylethyl)-1H,3H-quinazoline-2,4-dione and 1-methyl-3-[2′-(4′-methoxyphenyl)ethyl]-1H,3H-quinazoline-2,4- dione, from the seed husks of Mexican Zanthoxylum species has been reported.

Full text of DOI:10.3390/90700609

Molecules 2004, 9, 609-616
molecules
ISSN 1420-3049
http://www.mdpi.org
Syntheses of Quinazoline-2,4-dione Alkaloids and Analogues
from Mexican Zanthoxylum Species†
I. A. Rivero *, K. Espinoza and R. Somanathan
Centro de Graduados e Investigación, Instituto Tecnológico de Tijuana, Apartado Postal 1166. 22000.
Tijuana, B.C. México.
†
Taken in part from the Ph.D. thesis of Karla Espinoza
* To whom correspondence should be addressed: E-mail: irivero@tectijuana.mx
Received: 25 March 2004 / Accepted: 26 April 2004 / Published: 30 June 2004
Abstract: Quinazolinone and quinazolinedione derivatives are of considerable interest
due to their wide array of pharmacological properties. In this paper we report the
synthesis of ten quinazolinediones. The previous isolation of two of these compounds,
namely 1-methyl-3-(2'-phenylethyl)-1H,3H-quinazoline-2,4-dione and 1-methyl-3-[2'-(4'-
methoxyphenyl)ethyl]-lH,3H-quinazoline-2,4-dione, from the seed husks of Mexican
Zanthoxylum species has been reported
Keywords: Quinazoline-2,4-dione, alkaloids, triphosgene, anti-hypertensive activity.
Introduction
Quinazolinone and quinazolinedione derivatives are of considerable interest because of their wide
array of pharmacological properties [1-15]. We have been specifically interested in the synthesis of
novel heterocycles containing the quinazoline-2,4-dione backbone, which are known to exhibit
potential anti-hypertensive properties [16-20]. A previous report from this laboratory described an
efficient synthetic route to Pelanserine (TR 25-15), a potent anti-hypertensive [21], structurally similar
to the clinically used anti-hypertensive agent Ketanserine [22,23]. We have also extended this

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methodology to the synthesis of other quinazoline-2,4-diones with amino acids and dipeptide side
chains which when tested showed mild to no antihypertensive properties [24]. In our search for other
lead compounds containing the quinazoline-2,4-dione ring system, we encountered two simple natural
alkaloids, 1-methyl-3-(2'-phenylethyl)-1H,3H-quinazoline-2,4-dione and 1-methyl-3-[2'-(4'-methoxy-
phenyl)ethyl]-lH,3H-quinazoline-2,4-dione (1c and 1f), both isolated from the seed husks of
Zanthoxylum arborescens [25].
R
O
N
N
O
Me
1c (R=H), 1f (R=OCH3)
In order to study their antihypertensive properties in more detail, we embarked on a large scale
synthesis of 1c and 1f, and their analogues 1d,e and g (Scheme 1).
Scheme I
O
O
CO2
R2
O
N
2
+
H
R -NH2
i)
N
O
N
H
R1
(5)
R1
(3)
(2)
ii)
R1=CH3
Yield 50%
ii)
R1=H
O
N
O
R2
R2
O
N
iii)
N
Yield 98%
O
N
H
CH3
(4)
(1)
R1
a) -H
b) -CH3
O
R2
e)
d)
c)
O
O
g)
f)
iii) Tetramethylguanidine/Iodomethane
i) Triethylamine/DMF ii) Triphosgene/CH2Cl2

Molecules 2004, 9
611
Results and Discussion
Amines 5c-g [R2-NH2] were reacted with isatoic anhydride (2a) to give the corresponding
2-aminobenzamides 3 in excellent yields (84-93%). Following the methodology developed for the
synthesis of Pelanserine, we used triphosgene to ring close the amides 3 to give quinazolinediones 4c-g
in good yields [21]. Use of ethyl chloroformate instead of triphosgene was limited to an analytical scale
and led to a complex mixture of products in a scaled up reaction. Synthesis of N-methylquinazoline-2,4-
diones 1 from N-methylisatoic anhydride (2b) gave less than a 50% yield of the desired compounds,
however, using tetramethylguanidine as base, amides 4 were methylated with methyl iodide to give
quinazolinediones 1 in good yields (83-96%). Using this method we also synthesized analogues 1c-g,
for further biological evaluation. The methylene protons of 1 are magnetically non-equivalent and
display a AA'XX’ spin system, with the hydrogens on the same carbon splitting each other, thus leading
to a more complicated pattern than expected.
Conclusions
We have synthesized ten quinazoline-2,4-diones for biological evaluation as potential
antihypertensive agents. While up to now most of the structural modifications have been confined to the
amine R2-NH2 fragment, the basic backbone 4 now provides a target for introduction of different
heterocyclic rings on the amide –NH to diversify the quinazoline-2,4-dione structural system.
Acknowledgments
We gratefully acknowledge support for this project by the Consejo Nacional de Ciencia y
Tecnología, México (CONACyT, GRANT No. 28488-E) and the Consejo Nacional de Educación
Tecnológica, México (COSNET, GRANT No. 623.97-P). Karla Espinoza thanks CONACyT for a
graduate fellowship. The authors are indebted to Dr. Charles Perrin for encouragement.
Experimental Section
General
Melting points were measured on an Electrothermal 88629 apparatus and are uncorrected. Infrared
(IR) spectra were recorded on a Perkin Elmer FT-IR 1600 spectrometer. 1H- and 13C-NMR spectra were
recorded in CDCl3 at 200 MHz and 50.289 MHz, respectively, on a Varian Mercury 200 Spectrometer
with TMS as internal standard. Mass spectra were obtained on a Agilent 1100 series LC/MSD Trap, SL
Spectrometer by electrospray insertion.

Molecules 2004, 9
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General Method for Preparing o-Aminobenzamides 3: 2-Amino-N-(2-phenylethyl)-benzamide (3ac).
A solution of phenylethylamine (5c, 1mmol) in DMF (30 mL) was stirred while isatoic anhydride
(2a, 1.3 mmol) was added portionwise over a period of 30 minutes and then the temperature was
maintained at ~500C for an additional 30 minutes as CO2 was evolved. The mixture was stirred at room
temperature for 2 hours more, hot water (100 mL) was added and then it was kept at room temperature
without stirring for 6 hours. The solids were collected by filtration, dried under high vacuum and
purified by silica gel chromatography column using dichloromethane as eluant. Finally, the excess of
solvent was removed under reduced pressure to give compound 3ac as a pale brown solid. Yield 85%;
1
mp 83-85°C; IR (KBr): 3291, 1631, 1596, 1303, 1155, 1030 cm-1; H-NMR: δ 7.40-7.13 (m, 7H,
Ar-H), 6.67 (br, 1H, NH-CO), 6.07 (brs, 2H, NH-Ar), 5.50 (brs, 1H, NH-CO), 3.66 (q, 2H, J=6.8 Hz,
13
CH2-NH), 2.91 (t, 2H, J=6.8 Hz, CH2-Ar) ppm; C NMR: δ 164.5, 148.6, 138.9, 132.2, 128.9, 128.8,
127.0, 126.6, 117.3, 116.6, 40.8, 35.8 ppm; ESI-MS (m/e): 263[M+Na]+.
The following compounds were similarly prepared:
2-Amino-N-[2-(2-methoxyphenyl)ethyl]benzamide (3ad). Yield 92%; mp 80-82°C; IR (KBr): 3468,
1
3032, 2937, 1664, 1596, 1255, 1093 cm-1; H-NMR: δ 7.21-7.16 (m, 4H, Ar-H), 6.92-6.85 (m, 2H,
Ar-H), 6.65-6.59 (m, 2H, Ar-H), 6.42 (brs, 2H, NH-Ar), 5.20 (brs, 1H, NH-CO), 3.81 (s, 3H, CH3O),
13
3.60 (q, 2H, J=6.8Hz, CH2N), 2.93 (t, 2H, J=6.8 Hz, Ar-CH2) ppm; C-NMR: δ 169.4, 157.4, 148.6,
132.1, 130.0, 127.9, 127.0, 120.94, 117.2, 116.4, 110.4, 55.3, 40.5, 29.9 ppm; ESI-MS (m/e) 263[M+
Na]+.
2-Amino-N-[2-(3-methoxyphenyl)ethyl]benzamide (3ae). Yield 84%; mp 69-71°C; (KBr): 3453, 3350,
1635,1587, 1255, 1041 cm-1; 1H-NMR: δ 7.27-7.14 (m, 3H, Ar-H), 6.84-6.71 (m, 3H, Ar-H), 6.67-6.55
(m, 3H, Ar-H), 6.11 (brs, 1H, NH-Ar), 4.5 (brs, 2H, NH-CO), 3.77 (s, 3H, CH3-O), 3.66 (q, 2H, J1=
13
J2=6.8 Hz, NH-CH2), 2.88 (t, 2H, J1= 6.8 Hz, Ar-CH2) ppm; C-NMR: δ 169.4, 159.9, 148.6, 140.6,
132.3, 129.7, 127.1, 121.2, 117.3, 116.6, 116.2, 114.4, 112.1, 55.2, 40.7, 35.7 ppm; ESI-MS (m/e):
293[M+ Na]+, 271[M+H]+.
2-Amino-N-[2-(4-methoxyphenyl)ethyl]benzamide (3af) Yield 88%; mp 98-100°C; IR (KBr): 3483,
1
3230, 2922, 1671, 1244, 1030 cm-1; H-NMR: δ 7.25-7.11 (m, 4H, Ar-H), 6.89-6.55 (m, 2H, Ar-H),
6.68-6.55 (m, 2H, Ar-H), 6.07 (brs, 2H, NH-Ar), 5.0 (brs, 1H, NH-CO) 3.79(s, 3H, CH3-O), 3.62 (q,
2H, J1=J2=6.8 Hz, CH2-N), 2.85 (t, 2H, J=6.8 Hz, CH2-Ar) ppm; 13C-NMR: δ 169.3, 158.3, 148.6,
132.2, 129.7, 129.0, 117.2, 116.6, 114.13, 55.3, 40.9, 34.9 ppm; ESI-MS (m/e): 293[M+Na]+.
o-Amino-N-benzylbenzamide (3ag) Yield 93%; mp 104-106°C; IR (KBr): 3468, 3030, 2937, 1664,
1
1251, 1063 cm-1; H-NMR: δ 7.31-7.14 (m, 7H, Ar-H), 6.67-6.60 (m, 2H, Ar-H), 6.45 (brs, 2H,

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NH-Ar), 5.45 (brs, 2H, NH-CO) 4.57 (d, 2H, J=5.4 Hz, CH2-Ar) ppm; 13C-NMR: δ 169.1, 148.7, 138.2,
132.4, 128.7, 127.8, 127.5, 127.1 117.3, 116.7, 43.7 ppm; ESI-MS (m/e): 263[M+Na]+..
General Method for Preparing Quinazolinediones 4: 3-Phenylethyl-1H-quinazoline-2,4-dione (4c).
Triphosgene (10 mmol) in dichloromethane (10 mL) was added with stirring at room temperature to
a solution of 2-amino-N-phenyl-ethylbenzamide (3ac, 5mmol) in dichloromethane (50 mL) and the
resulting mixture was stirred for an additional 30 minutes. This was followed by the addition of
triethylamine (30 mmol) and the mixture was refluxed for 2 hours. The reaction was quenched by
addition of aqueous acid (5% HCl, 50 mL), and the mixture was extracted into dichloromethane. The
organic phase was washed successively with saturated Na2CO3 solution (2 x 40 mL) and water (2 x 40
mL) and then dried over anhydrous Na2SO4 to give, after removal of excess solvent under reduced
pressure, compound 4c as a yellow solid. Yield 75%; mp 173-175°C; IR (KBr): 2937, 1719, 1653,
1590, 1266 cm-1; 1H-NMR: δ 10.40 (s, 1H, NH-CO), 8.15 (dd, 1H, J1=1.6, J2=8.2 Hz, H-Ar), 7.67-7.59
(ddd, J1=1.6, J2=J3= 7.4 Hz, 1H, H-Ar), 7.34-7.15 (m, 7H, H-Ar) 4.33 (ddd, J1=5.6, J2=J3=8.0 Hz, 2H,
CH2-NH), 3.05 (ddd, J1=5.6, J2=J3=8.0 Hz, 2H, CH2-Ar) ppm; 13C-NMR: δ 162.26, 151.9, 139.3, 138.6,
134.9, 128.95, 128.7, 128.6, 126.6, 115.3, 114.6, 42.3, 34.1 ppm; ESI-MS (m/e): 264.9[M- H]-.
The following compounds were similarly prepared:
3-[2-(2-Methoxyphenyl)ethyl]-lH-quinazoline-2,4-dione (4d). Yield 73%; mp 174-176°C; IR (KBr):
1
2937, 2800, 1719, 1654, 1477, 1243, 1028 cm-1; H-NMR: δ 10.65 (s, 1H, NH-Ar), 8.18 (dd, 1H,
J1=1.6, J2=8.2 Hz, H-Ar), 7.53 (ddd, J1=1.6, J2=J3=7.4 Hz, 1H, H-Ar), 7.21-6.69 (m, 6H, H-Ar), 4.34
(ddd, J1=5.6, J2=J3=8.0 Hz, 2H, NH-CH2), 3.77 (s, 3H, CH3), 3.02 (ddd, J1=5.6, J2=J3=8.0 Hz, 2H,
CH2-Ar) ppm; 13C-NMR: δ 162.4, 157.4, 151.0, 138.8, 134.3, 130.3, 127.7, 127.4, 126.9, 122.4, 120.1,
114.8, 114.2, 109.9, 55.1, 40.6, 28.5 ppm; ESI-MS (m/e): 295 [M –H]-.
3-[2-(3-Methoxyphenyl)ethyl]-lH-quinazoline-2,4-dione (4e). Yield 73%; mp 165-167°C; IR (KBr):
2928, 2593, 1728, 1671, 1604,1152 cm-1; 1H-NMR: δ 10.65 (s, 1H, NH-Ar), 7.93 (dd, J1=1.6 Hz, J2=8.2
Hz, 1H, H-Ar), 7.42 (ddd, J1=1.6, J2=J3= 7.4 Hz, 1H, H-Ar), 7.01-6.58 (m, 6H, H-Ar), 4.12 (ddd, 2H,
J1=5.6, J2=J3=7.8 Hz, CH2-NH), 3.80 (s, 3H, CH3-O) 2.82 (ddd, J1=5.6 Hz, J2=J3=7.8 Hz, 2H, CH2-Ar)
ppm; 13C-NMR: δ 159.4, 157.8, 135.2, 133.9, 130.6, 128.3, 127.7, 127.1, 126 0, 125.3, 120.9, 120.5,
118.8, 110.2, 55.5, 43.3, 28.5 ppm; ESI-MS (m/e): 295 [M –H]-.
3-[2'-(4'-Methoxyphenyl)ethyl]-lH,3H-quinazoline-2,4-dione (4f). Yield 78%; mp 76-78°C; IR (KBr):
1
1741, 1675, cm-1; H-NMR: δ 9.80 (s, 1H, NH-Ar) 8.13 (dd, J1=1.6 Hz, J2=8.2 Hz, 1H, H-Ar) 7.61
(ddd, J1=1.6, J2=J3=7.4 Hz, 1H, H-Ar) 7.26-6.81 (m, 6H, H-Ar), 4.25 (ddd, J1=5.6, J2=J3=7.4 Hz, 2H,
CH2-NH), 3.76 (s, 3H, CH3-O), 2.95 (ddd, J1=5.6, J2=J3=7.4 Hz, 2H, CH2-Ar) ppm; 13C-NMR: δ 161.3,

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159.1, 151.2, 138.1, 134.6, 130.2, 129.6, 128.1, 123.1, 114.6, 113.6, 55.1, 42.1, 32.8 ppm; ESI-MS
(m/e): 295 [M- H]-.
3-Benzyl-1H,3H-quinazoline-2,4-dione (4g). Yield 89%; mp 163-165°C; IR (KBr): 2956, 1709, 1657,
1
1266, cm-1; H-NMR: δ 11.15 (s, 1H, NH), 7.92(d, 1H, J=8.2 Hz, H-Ar), 7.46-7.03 (m, 8H, H-Ar),
5.12(s, 2H, CH2-Ar) ppm; 13C-NMR: δ 169.9, 155.3, 144.1, 141.7, 139.2, 132.7, 132.3, 131.7.8, 127.1,
119.8, 118.6, 48.3 ppm; ESI-MS (m/e) 251 [M- H]-.
General Method for Preparing N-Methylquinazolinediones 1: 1-Methyl-3-(2'-phenylethyl)-1H,3H-
quinazoline-2,4-dione (1c).
Tetramethylguanidine (0.064 g, 0.56 mmol) was added to a solution of 3-phenylethyl-1-H-
quinazoline-2,4-dione (4c, 0.015g, 0.56 mmol) in CHCl3 (1 mL) and the mixture was stirred at room
temperature for 15 min., then methyl iodide (0.15 g, 12 mmol) was added and the reaction was heated
to 55°C for 45 minutes. Activated carbon was added and the mixture was stirred for 10 min. and then
filtered. Removal of the solvent under reduced pressure gave the title compound 1c as a yellow solid.
Yield >96%; mp 99-101°C (Lit. [25], mp. 100-102°C); IR (KBr): 3042, 2929, 1701, 1654, 1610, 1481
cm-1; 1H-NMR: δ 8.29 (dd, 1H, J1=2.6, J2=8.4 Hz, Ar-H), 7.69 (ddd, 1H, J1= 5.4, J2= J3=7.4 Hz, Ar-H),
7.34-7.23 (m, 7H, Ar-H), 4.31 (ddd, J1= 5.0, J2= J3=7.6 Hz, 2H, N-CH2), 3.62 (s, 3H, N-CH3), 2.98
(ddd, J1= 5.0, J2= J3=7.6 Hz, Ar-CH2) ppm; 13C-NMR: δ 161.3, 150.5, 140.2, 138.3, 134.8, 129.9,
128.7, 128.6, 128.2, 126.2, 122.7,120.9, 113.25, 43.3, 33.9, 30.6 ppm; ESI-MS (m/e): 289.1[M+ H]+.
The following compounds were prepared in similar fashion:
1-Methyl-3-[2'-(2'-methoxyphenyl)ethyl]-lH,3H-quinazoline-2,4-dione (1d). Yield >98%; mp 155-
163°C; IR (KBr): 2943, 1703, 1651, 1608, 1484, 1243, 1028 cm-1; 1H-NMR: δ 8.20 (dd, 1H, J1=2.2,
J2=8.4 Hz, Ar-H), 7.63 (ddd, 1H, J1= 5.4, J3= J2=7.4 Hz, 1H, Ar-H), 7.25-6.75 (m, 6H, Ar-H), 4.33
(ddd, J1= 4, J2=J3=5.8 Hz, 2H, N-CH2), 3.62 (s, 3H, N-CH3), 2.98 (ddd, J1= 4, J2=J3=5.8 Hz, Ar-CH2)
ppm; 13C-NMR: δ 161.3, 157.5, 140.2, 134.6, 130.3, 128.6, 127.48, 126.87, 122.56, 120.17, 113.16,
110.0, 55.2, 41.8, 30.6, 28.7 ppm; ESI-MS (m/e): 310.9[M+ H]+; 332 [M +Na]+.
1-Methyl-3-[2'-(3'-methoxyphenyl)ethyl]-lH,3H-quinazoline-2,4-dione (1e). Yield 89%; mp 131-133°C;
IR (KBr): 2945, 2833, 1699, 1656,1604 cm-1; 1H-NMR: δ 8.21 (dd, 1H, J1=2.1, J2=8.3 Hz, Ar-H), 7.63
(ddd, 1H, J1= 5.4, J3= J2=7.5 Hz, 1H, Ar-H), 7.25-6.62 (m, 6H, Ar-H), 4.29 (ddd, J1= 5.2, J2=J3=8.2 Hz,
2H, N-CH2), 3.79 (s, 3H, O-CH3), 3.61 (s, 3H, N-CH3), 2.98 (ddd, J1=4, J2=J3=5.8 Hz, Ar-CH2) ppm;
13C-NMR: δ 169.5, 159.9, 148.5, 140.5, 132.8, 132.4, 129.7, 127.0, 126.4, 122.7, 117.4, 116.8, 116.3,
112.1, 55.1, 40.7, 35.7 ppm; ESI-MS (m/e): 332.9 [M +Na]+.

Molecules 2004, 9
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1-Methyl-3-[2'-(4'-methoxyphenyl)ethyl]-lH,3H-quinazoline-2,4-dione (1f). Yield >83%; mp. 134-
136°C. (Lit. [25] mp. 133-134°C); IR (KBr): 3301, 2928, 1700, 1647, 1600, 1400, 1261. cm-1;
1H-NMR : δ 8.210 (dd, 1H, J1=1.4, J2=7.8 Hz, Ar-H), 7.69 (ddd, 1H, J1= 1.4, J3= J2=7.4 Hz, 1H, Ar-H),
7.30-6.85 (m, 6H, Ar-H), 4.26 (ddd, J1= 5.2, J2=J3=7.8 Hz, 2H, N-CH2), 3.79 (s, 3H, O-CH3), 3.61 (s,
13
3H, N-CH3), 2.91 (ddd, J1= 5.2, J2=J3=7.8 Hz, Ar-CH2) ppm; C-NMR: δ 161.8, 158. 2, 140.5, 130.1,
129.2, 124.2, 114.0, 113.6, 55.5, 43.7, 33.4, 31.0 ppm; ESI-MS (m/e): 332.9 [M +Na]+.
1-Methyl-3-(benzyl)-1H,3H-quinazoline-2,4-dione (1g). Yield 93%; mp.103-106°C; IR (KBr): 3416,
2918, 1700, 1652, 1604, 1480, 1266, cm-1; 1H-NMR: δ 7.95 (d, 1H, J=8.0 Hz, H-Ar), 7.51 (t, 1H, J=7.9
13
Hz, H-Ar), 7.25-6.90 (m, 7H, H-Ar) 5.04 (s, 2H, CH2-Ar), 3.05 (m, 3H, CH2-NH) ppm; C-NMR: δ
161.2, 150.2, 139.8, 136.5, 134.9, 128.1, 127.9, 127.8, 126.9, 122.5, 114.7, 44.5 ppm; ESI-MS (m/e)
288.9 [M+Na]+.
References
1. Larksarp, C.; Alper, H. J. Org. Chem. 2000, 65, 2773.
2. Hermecz, I.; Kokosi, J. Podanyi, B.; Szaz, G. Heterocycles 1994, 37, 903.
3. Katritzky, A. R.; Rees, C. W. Comprehensive Heterocyclic Chemistry: The Structure, Reactions,
Synthesis and Uses of Heterocyclic Compounds, Part 2B; Pergamon Press: New York, 1984; vol. 3.
4. Pelletier, S. W. Alkaloids: Chemical and Biological Perspectives; John Wiley & Sons Ltd.: New
York, 1985; vol. 1.
5. Scovill, J.; Blank, E.; Konnick, M.; Nenortas, E.; Shapiro, T. Antimicrob. Agents Chemother. 2002,
46, 882.
6. Penn, J.; Mantle, P. G.; Bilton, J. N.; Sheppard, R. N. J. Chem. Soc. Perkin Trans. I 1992, 1495.
7. Wong, S-M.; Musza, L. L.; Kydd, G. C.; Kulnig, R.; Gillum, A. M.; Cooper. R. J. Antibiot. 1993,
46, 545.
8. Fujimoto, H.; Negishi, E.; Yamaguchi, K.; Nishi, N.; Yamazaki, M. Chem. Pharm. Bull. 1996, 44,
1843.
9. Numata, A.; Takahashi, C.; Matsushita, T.; Miyamoto, T.; Kawai, K.; Usami. Y.; Matsumura, E.;
Inove, M.; Ohishi, H.; Shingu, T. Tetrahedron Lett, 1992, 37, 1621.
10. Takahashi, C.; Matsushita, T.; Doi, M.; Minoura, K.; Shingu, T.; Kumeda, Y.; Numata, A. J. Chem.
Soc. Perkin Trans I 1995, 2345.
11. Karwowski, J. P.; Jackson, M.; Rasmussen, R. R.; Humphrey, P. E.; Poddig, J. B.; Kohl, W. L.;
Scherr, M. H.; Kadam, S.; McAlpine, J. B. J. Antibiot. 1993, 46, 374.
12. Hochlowski, J. E.; Mullally, M. M.; Spanton, S. G.; Whitten, D. N.; Hill, P.; Mc Alpine. J. B. J.
Antibiot. 1993, 46, 380.
13. Larsen, T. O.; Frydenvang, K.; Frisvad, J. C.; Christopherson, C. J. Nat. Prod. 1998, 61, 1154.
14. Barrow, C. J.; Sun, H. H. J. Nat. Prod. 1994, 57, 471.

Molecules 2004, 9
616
15. Hernandez, F.; Buenadicha, F. L.; Avendaño, C.; Söllhuber, M. Tetrahedron: Asymmetr. 2001, 12,
3387.
16. Hayao, S.; Havera, H. J.; Strycker, W. G.; Hong, E. J. Med. Chem. 1969, 12, 936.
17. Shiau, C. V.; Chem, J. W.; Tien, J. H.; Liang, K .C. J. Hetrocycl. Chem. 1989, 26, 595.
18. Nishikawa, Y.; Shindo, T.; Ishi, K.; Nakamura, H.; Kon, T.; Uno, H. J. Med. Chem. 1989, 32, 583.
19. Hayao, S.; Havera, H. J.; Strycker, W. G.; Leipzig, T. T.; Kulp, R. A.; Hartzle, H. E. J. Med. Chem.
1965, 8, 807.
20. Hayao, S. (Miles Lab., Inc.) US Patent 3,274,194, 1965.
21. Cortez R.; Rivero, I. A.; Somanathan R.; Aguirre G.; Rámirez F. Synth. Commun. 1991, 21, 285.
22. Leysen, J. E.; Niemegeers, J. E.; Neuten, J. M.; Laduron, P. M. Mol. Pharmacol. 1982, 21, 301.
23. Darchen, F.; Scherman, D.; Laduron, P. M.; Henry, J. P. Mol. Pharmacol. 1988, 33, 672.
24. Rivero, I. A.; Somanathan, R. Synth. Commun. 1998, 28, 2077.
25. Dreyer, D.L.; Bayer, R.C. Phytochemistry 1980, 19, 935.
Sample availability: Available from the authors
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