Synthesis and anticonvulsant activity of acetylenic quinazolinone derivatives

Article abstract of DOI:10.1002/1521-4184(20008)333:8<261::AID-ARDP261>3.0.CO;2-O

Acetylenic derivatives of quinazolinones and quinazolinediones were synthesized and evaluated for their anticonvulsant activity. Most compounds displayed seizure-antagonizing activity in the maximal electroshock test (MES test) in most cases associated wi

Full text of DOI:10.1002/1521-4184(20008)333:8<261::AID-ARDP261>3.0.CO;2-O

Acetylenic Quinazolinone Derivatives
261
Synthesis and Anticonvulsant Activity of Acetylenic Quinazolinone
Derivatives
a)
b)
Cyril O. Usifoh and Gerhard K. E. Scriba *
a) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Benin, Nigeria
b) Department of Pharmaceutical Chemistry, University of Jena, Philosophenweg 14, D-07743 Jena, Germany
Key Words: Anticonvulsants; quinazolinone; quinazolinedione
Summary
Results and Discussion
Acetylenic derivatives of quinazolinones and quinazolinediones
were synthesized and evaluated for their anticonvulsant activity.
Most compounds displayed seizure-antagonizing activity in the
maximal electroshock test (MES test)in mostcases associated with
little or no acute neurotoxicity determined in the rotorod test. Only
three compounds exhibited significant activity in the seizure
threshold test with subcutaneous pentylenetetrazole (scMet test).
Based on the ED50 in the MES test, 1,3-bis-(prop-2-ynyl)-quin-
azoline-2,4-(1H,3H)-dione (9a) was about ten-fold less active than
phenytoin or carbamazepine but about as active as mesuximide.
Chemistry
The acetylenic derivatives of the quinazolinones were syn-
thesized according to general procedures as outlined in
Scheme 1. N-Alkylation of the quinazolinones 1a–g with
propargyl bromide in dimethylformamide in the presence of
potassium carbonate at room temperature yielded the 2-sub-
stituted quinazolinones 2a–g. In the case of the phenyl and
trifluoromethyl derivatives 2b and 2c, respectively, O-alkyl-
ation occurred as a side reaction. This is in agreement with
an earlier study on the synthesis of acetylenic quinazolinones
[6]
reporting a ratio of 36:64 and 10:90 for the N-propargyl
and O-propargyl derivatives of the phenyl and tri-
fluoromethyl compound by gas chromatography. No O-alky-
lation was observed for the benzyl derivative . When
Introduction
[6]
isolated by column chromatography we found a ratio of 32:68
for both sets of compounds 2b/3b and 2c/3c. Compounds 6a
and 6b were prepared by ring opening of isatoic acid anhy-
dride with 2-propyn-1-ylamine and 2-methyl-3-butyn-2-
ylamine, respectively, to the corresponding 2-amino
benzamides 5a and 5b followed by cyclization with triethyl-
orthoformate.
Worldwide, approximately 40–50 million people (about
0.5–1% of the population) suffer from epilepsy, a symptom
of excessive temporary neuronal discharge, characterized by
discrete recurrent episodes, in which there is a disturbance of
movement, sensation, behavior, perception, and/or con-
sciousness . 20–30% of the patients have seizures that are
resistant to the available medical therapies. This fact warrants
the search for new anticonvulsant drugs.
Quinazolinones are a large class of active chemical com-
[1]
The mono- and dialkylated quinazolinediones 8a and 9a,
and 8b and 9b, respectively, were prepared by N-alkylation
of quinazolindiones 7a and 7b with propargyl bromide using
sodium hydroxide in methanol-water (1:1). No attempt was
made to synthesize the mono and dialkylated derivatives
specifically but the resulting mixture of the mono- and dial-
kylated products was separated by alkaline extraction of the
monoalkylated derivatives. The assignment of all structures
pounds exhibiting a broad spectrum of biological activities in
[2,3]
animals as well as in humans
. The effects of 4-(3H)-quin-
azolinones on the central nervous system have been well
documented especially for the 3-aryl derivatives. The proto-
type of this series is 2-methyl-3-o-tolyl-4(3H)-quinazolin-
one, the sedative drug methaqualone. In this context
numerous derivatives, especially 2-substituted quinazolin-
ones, have been investigated for their anticonvulsant activity
1
13
was established on the basis of IR, H- and C-NMR, mass
spectrometry, and microanalysis.
Pharmacology
[2,3]
[4,5]
. Quinazolinediones have also been studied
.
Acetylenic derivatives of quinazolinones and quinazoline-
The compounds were tested for anticonvulsant activity
[6–9]
[11]
diones have been synthesized previously
but their phar- according to standard procedures
which included the
maximal electroshock seizure test (MES test) and the seizure
threshold test with subcutaneous pentylenetetrazole (scMet
test). The acute neurological toxicity was determined in the
rotorod test. The results of the screening in mice is summa-
rized in Table 1. The intermediate 2-aminobenzamides 5a
macological potential has not been fully evaluated. The
propargyl group has also been used to modify the anticonvul-
[10]
sant properties of hydantoins
a well known class of
anticonvulsants. Moreover, allyl substituted quinazoline-
[4]
diones displayed anticonvulsant activity . The present
and 5b were included as the anticonvulsant activity of 2- and
[12-14]
study was conducted in order to evaluate the anticonvulsant
4-aminobenzamides has been reported
. However, only
activity of acetylenic quinazolinones and quinazolinediones. 5a displayed an effect in the MES test at a dose of 100 mg/kg.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0365-6233/00/0808/0261 $17.50 +.50/0

262
Usifoh and Scriba
Scheme 1
Arch. Pharm. Pharm. Med. Chem. 333, 261–266 (2000)

Acetylenic Quinazolinone Derivatives
263
Table 1. Anticonvulsant activity in the MES test and the ScMet test and toxicity in the rotorod test of quinazolinones
following intraperitoneal administration to mice. The numbers are expressed as animals protected/animals tested.
———————————————————————————————————————————————
MES
0.5 h
ScMet
0.5 h
Toxicity
0.5 h
Cmpnd
Dose
4 h
4 h
4 h
Class a)
[mg/kg]
———————————————————————————————————————————————
2a
2b
2c
2d
2e
2f
30
0/1
3/3
1/1
0/1
0/3
1/1
0/1
0/3
0/1
0/1
3/3
1/1
0/1
1/3
1/1
0/1
3/3
1/1
0/1
1/3
1/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
1/3
1/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
1/1
0/1
2/3
1/1
0/1
0/3
0/1
0/1
0/3
1/1
0/1
0/3
0/1
0/1
0/3
1/1
0/1
0/3
0/1
0/1
0/3
1/1
0/1
0/3
1/1
0/1
0/3
1/1
0/1
0/3
1/1
0/1
1/3
1/1
0/1
1/3
1/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
1/1
0/1
0/3
1/1
0/1
0/3
1/1
0/1
2/3
1/1
0/1
2/5
–
0/1
0/1
–
0/4
1/8
4/4
0/4
0/8
0/4
0/4
1/8
0/4
0/4
1/8
4/4
0/4
0/8
4/4
0/4
2/8
4/4
0/4
0/8
1/4
0/4
0/8
0/4
0/4
0/8
0/4
0/4
0/8
3/4
0/4
0/8
1/4
0/4
0/8
0/4
0/4
0/8
4/4
0/4
0/8
4/4
0/4
0/8
0/4
0/4
0/8
0/4
0/4
0/8
0/4
0/2
0/4
2/2
0/2
0/4
2/2
0/2
0/4
2/2
0/2
0/4
2/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
1
2
2
1
1
1
1
1
3
1
3
3
2
1
2
2
1
100
300
30
0/1
0/1
0/1
0/1
1/5
3/5
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
1/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
2g
3b
3c
5a
5b
6a
6b
8a
8b
9a
9b
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
———————————————————————————————————————————————
a) Classification according to reference [11]. Class 1, active at ≤ 100 mg/kg; class 2, active at 300 mg/kg;
class 3, inactive.
Arch. Pharm. Pharm. Med. Chem. 333, 261–266 (2000)

264
Usifoh and Scriba
Table 2. Median effective dose (ED50), median toxic dose (TD50) and
protective index (PI) of 9a and standard anticonvulsant drugs after intraperi-
toneal administration to mice. The values are expressed in µmol/kg; 95%
confidence intervals are given in brackets. The time of testing at the time of
peak effect is listed in square brackets.
Acknowledgments
C. O. Usifoh was supported by a stipend from the Deutscher Akademischer
Austauschdienst (DAAD). The anticonvulsant and toxicity testing by Dr. J.
P. Stables at the NINDS Epilepsy Branch, National Institutes of Health,
Rockville, MD, USA, and the financial support by the Fonds der Chemischen
Industrie are gratefully acknowledged.
——————————————————————————————
Compound
ED50
TD50
PI
(MES)
(rotorod)
(TD50/ED50)
Experimental
——————————————————————————————
General
9a
364 (299–431)
[1 h]
> 1680
> 4.6
6.9
Mp: Kofler melting point apparatus, uncorrected.– IR: Perkin-Elmer 457.–
NMR: Varian Gemini 200 (TMS), 1H: 200 MHz, 13C: 50 MHz.– MS Varian
MAT 44S, EI: 70 eV, source temp. 200 °C. TLC: Pre-coated silica gel plates
Merck (F254).– Column chromatography: Silica gel Merck Si-60 (70–230
mesh). 2-Methyl-4(3H)-quinazolinone (1a), isatoic acid anhydride (4) and
the quinazolinediones 7a and 7b were from Aldrich Chemical Co. (Deisen-
hofen, Germany). The remaining quinazolinones were synthesized from
ortho-anthranilamide according to the literature: 1b [15], 1c [16], 1d [16], 1e
[1 h]
phenytoin a)
mesuximide a)
carbamazepine a)
37.7 (32.2–41.2)
[2 h]
260 (208–286)
[2 h]
375 (310–440)
[0.5 h]
925 (780–1160)
[0.5 h]
2.5
[17], 1f [17] and 1g [18]
.
General Procedure for the Synthesis of 2-Substituted Quinazolinones
37.3 (23.1–59.7)
[0.25 h]
303 (194–570)
[0.25 h]
8.1
Propargyl bromide (6.0 mmol) was added to a stirred suspension of 5 mmol
of the appropriate quinazolinone 1a–g and 60 mmol potassium carbonate in
10 ml dry N,N-dimethylformamide. The reaction mixture was stirred at room
temperature till TLC (6–8 h) indicated the complete disappearance of the
quinazolinone. The reaction mixture was poured into 100 ml brine/ethyl
acetate (1:1) and the aqueous phase was extracted with ethyl acetate. The
combined organic phase was dried and evaporated in vacuo to give a crude
product which was further purified by column chromatography (dichlo-
romethane to dichloromethane/ethyl acetate 6:1).
——————————————————————————————
a) Data from reference [11]; for better comparison the data given in [11] on
a mg/kg basis were converted to µmol/kg.
Generally, most quinazolinone derivatives exhibited activity
in the MES test while a seizure antagonizing effect in the
scMet test was only observed for 2a, 2c, 2d, and 2f. However,
none of the compounds exhibited significant activity at the
lowest concentration tested. The quinazolinones 6a and 6b
which bear no substituent in position 2 displayed no activity
or only a low activity. In contrast, most 2-substituted deriva-
tives displayed activity in the MES test at a dose of
100 mg/kg. This is in accordance with structure activity rela-
3-Prop-2-ynyl-2-methyl-quinazolin-4(3H)-one (2a)
Yield 0.69 g (70%), mp 91–92 °C (CH2Cl2/hexane) (Ref.[8] 91–93 C). IR
(KBr): ν (cm–1) = 3200 (C≡CH), 2100 (C≡C), 1680 (C=O). 1H NMR
(CDCl3): δ = 2.35 (t, J = 2.5 Hz, 1H, 3′-H), 2.75 (s, 3H, 2-CH3), 4.91 (d,
J = 2.5 Hz, 2H, 1′-H), 7.44 (ddd, J = 1.4, 7.4, 8.2 Hz, 1H, 6-H), 7.62 (dd,
J = 1.4, 8.2 Hz, 1H, 8-H), 7.73 (ddd, J = 1.5, 7.1, 8.3 Hz, 1H, 7-H), 9.24 (dd,
J = 1.5, 8.3 Hz, 1H, 5-H). 13C NMR (CDCl3): δ = 22.8, 33.1, 72.7, 77.6,
120.5, 126.8, 127.0, 127.2, 134.8, 147.5 154.0, 161.6. MS: m/z = 198 [M+]
(100), 197 [M+–1] (88), 183 (22), 169 (36), 156 (6), 143 (10), 129 (14), 117
(10), 102 (14), 90 (14), 76 (16).
tionships which revealed a higher activity of 2-substituted
quinazolinones compared to the unsubstituted compounds
[3]
.
Interestingly, the O-alkylated derivative 3b is more active
than the corresponding quinazolinone 2b. All quinazoline-
diones showed activity in the MES test. Most compounds
showed no acute neurotoxicity in the rotorod test.
3-Prop-2-ynyl-2-trifluoromethyl-quinazolin-4-(3H)-one (2b)
Yield 0.38 g (30%), mp 97–98 °C (CH2Cl2/n-hexane). IR (KBr): ν (cm–1
)
= 3200 (C≡C), 2100 (C≡CH), 1680 (C=O). 1H NMR (CDCl3): δ = 2.28 (t,
J = 2.2 Hz, 1H, 3′-H), 4.93 (d, J = 2.2 Hz, 2H, 1′-H), 7.60–7.65 (ddd, J = 2.3,
7.7, 8.1 Hz, 1H, 6-H), 7.80–7.85 (m, 2H, 5-H, 7-H), 8.34 (d, J = 7.8 Hz, 1H,
8-H). 13C NMR (CDCl3): δ = 34.6, 35.5, 72.9, 77.5, 117.4, 122.2, 127.8,
129.1, 130.1, 135.7, 145.2, 161.1. MS: m/z = 252 [M+] (90), 223 (8), 210
(18), 183 (10), 155 (22), 129 (64), 102 (75), 90 (100), 69 (74), 51 (41).
C12H7N2OF3 (252.20): Calc. C 57.15 H 2.80 N 11.11; found C 57.10 H 2.76
N 11.00.
Compound 9a was selected for quantitative evaluation. The
median effective dose (ED ) in the MES test and the median
50
neurotoxic dose (TD ) in the rotorod test of 9a and the
50
anticonvulsant drugs phenytoin, carbamazepine and mesux-
imide are summarized in Table 2. Based on the ED in the
50
MES test, 9a is about ten-fold less active than phenytoin or
carbamazepine but about as active as mesuximide. 9a did not
display significant acute neurotoxicity up to a dose of
240 mg/kg (1.68 mmol/kg), resulting in a protective index (PI
4-Prop-2-ynoxy-2-trifluoromethyl-quinazoline (3b)
Yield 0.82 g (65%), mp 99–100 °C (CH2Cl2/n-hexane). IR (KBr): ν (cm–1
)
1
= 3000, 1630, 1600. H NMR (CDCl3): δ = 2.56 (t, J = 2.3 Hz, 1H, 3′-H),
5.27 (d, J = 2.3 Hz, 2H, 1′-H), 7.68 (t, J = 7.4 Hz, 1H, 7-H), 7.92 (t, J = 7.4
Hz, 1H, 6-H), 8.06 (d, J = 8.4 Hz, 1H, 5-H), 8.25 (d, J = 8.1 Hz, 1H, 8-H).
13C NMR (CDCl3): δ = 2.56 (t, J = 2.3 Hz, 1H, 3′-H), 5.27 (d, J = 2.3 Hz,
2H, 1′-H), 7.68 (t, J = 7.4 Hz, 1H, 7-H), 7.92 (t, J = 7.4 Hz, 1H, 6-H), 8.06
(d, J = 8.4 Hz, 1H, 8-H), 8.25 (d, J = 8.1 Hz, 1H, 5-H). 13C NMR (CDCl3):
δ = 55.8, 76.4, 77.6, 116.8, 118.7, 124.2, 129.1, 129.6, 135.3,150.9, 167.4.
MS: m/z = 252 [M+] (82), 233 (7), 210 (19), 198 (13), 155 (15), 129 (100),
116 (14), 102 (85), 90 (98), 76 (73), 63 (73), 51 (30). C12H7N2OF3 (252.20):
Calc. C 57.15 H 2.80 N 11.11; found C 56.90 H 2.90 N 11.21.
= TD /ED ) of at least 4.6 which is comparable to the
50
50
approved drugs.
In conclusion, acetylenic quinazolinone derivatives were
synthesized and their anticonvulsant activity has been evalu-
[2–5]
ated. In agreement with other studies
bis-N-alkylated
quinazolinones might represent interesting structures for the
development of antiepileptic drugs.
Arch. Pharm. Pharm. Med. Chem. 333, 261–266 (2000)

Acetylenic Quinazolinone Derivatives
265
3-Prop-2-ynyl-2-phenyl-quinazolin-4(3H)-one (2c)
d6): δ = 33.1, 74.6, 78.6, 120.9, 126.4, 127.5, 128.3, 135.1, 145.8, 148.6,
159.9, 163.1. MS: m/z = 227 [M+] (100), 199 (7), 184 (60), 155 (16), 146 (9),
129 (20), 102 (16), 90 (11). C12H9N3O2 (227.22): Calc. C 63.43 H 3.99 N
18.49; found C 63.20, H 3.84 N 18.40.
Yield 0.34 g (26%), mp 171–172 °C (CH2Cl2/n-hexane) (Ref.[6] 176–
177 °C). IR (KBr): ν (cm–1) = 3215 (C≡C), 2100 (C≡CH), 1670 (C=O), 1600.
1H NMR (CDCl3): δ = 2.31 (t, J = 2.4 Hz, 1H, 3′-H), 4.65 (d, J = 2.4 Hz, 2H,
1′-H), 7.48–7.53 (m, 4H, Ar-H), 7.70–7.76 (m, 4H, Ar-H), 8.33 (d, J = 7.6
Hz, 1H, Ar-H). 13C NMR (CDCl3): δ = 34.6, 72.6, 77.4, 118.8, 124.4, 126.4,
128.2, 129.4, 130.2, 134.8, 137.8, 152.4, 159.8, 166.4. MS: m/z = 261 [M++1]
(12), 260 [M+] (99), 259 [M+–1] (100), 231 (35), 204 (7), 179 (10), 152 (6),
128 (9), 115 (15), 102 (33), 90 (35), 76 (58), 51 (39). C17H12N2O (260.30).
2-Amino-N-prop-2-ynyl-benzamide (5a)
1.65 g propargylamine (30 mmol) in 20 ml DMF were added slowly to a
solution of 3.3 g isatoic acid anhydride (20 mmol) in 20 ml DMF at 40–50 °C
and maintained at this temperature for 3 h. The reaction mixture was pored
into 200 ml water adjusted to pH 9 with NaOH. The precipitated was filtered,
washed with water, dried and recrystallized. Yield 3.1 g (89%), mp 100–
101 °C (CH2Cl2/n-hexane) (Ref.[19] 99–100.5 °C). IR (KBr) 3480, 3300
(NH2, NH), 1660. 1H NMR (CDCl3): δ = 2.24 (t, J = 2.5 Hz, 1H, 3′-H), 4.18
(dd, J = 2.5 Hz, 2H, 1′-H), 5.56 (brs, 2H, NH2), 6.35 (brs, 1H, NH), 6.63 (t,
J = 7.8 Hz, 1H, 5-H), 6.70 (d, J = 8.2 Hz, 1H, 3-H), 7.23 (ddd, J = 1.6, 7.2,
8.3 Hz, 1H, 4-H), 7.33 (dd, J = 1.5, 7.8 Hz, 1H, 6-H). 13C NMR (CDCl3): δ
= 29.5, 71.9, 80.0, 115.5, 117.0, 117.7, 127.6, 133.1, 149.4, 169.3. MS: m/z
= 174 [M+] (52), 145 (10), 130 (8), 120 (100), 105 (3), 92 (74), 77 (2), 65
(52).
4-Prop-2-ynoxy-2-phenyl-quinazoline (3c)
Yield 0.72 g (55%), mp 127–128 °C (CH2Cl2/n-hexane) (Ref.[6] 135–
137 °C). IR (KBr): ν (cm–1) = 3200 (C≡C), 2995 (CH), 2115 (C≡CH), 1640
(C=O). 1H NMR (CDCl3): δ = 2.55 (t, J = 2.2 Hz, 1H, 3′-H), 5.32 (d, J = 2.1
Hz, 2H, 1′-H), 7.49–7.52 (m, 4H, Ar-H), 7.8 (t, J = 7.9 Hz, 1H, Ar-H), 8,0
(d, J = 8.4 Hz, 1H, Ar-H), 8.18 (d, J = 8.1 Hz, 1H, Ar-H), 8.59 (d, J = 7.8
Hz, 2H, Ar-H). 13C NMR (CDCl3): δ = 54.2, 75.1, 78.2, 114.9, 123.4, 126.6,
127.9, 128.4, 128.5, 130.6, 133.8, 137.8, 151.9, 159.6, 165.5. MS: m/z = 260
[M+] (34), 259 [M+–1] (100), 231 (6), 205 (6), 151 (5), 119 (6), 103 (34), 90
(88), 77 (56), 63 (59), 54 (40).
2-Amino-N-(1,1-dimethylprop-2-ynyl)-benzamide (5b)
2.5 g 1,1-Dimethyl-2-propynylamine (30 mmol) and 3.3 g isatoic acid
anhydride (20 mmol) were treated as described for 5a. Yield 2.6 g (65%),
mp 122–123 °C (CH2Cl2/n-hexane) (Ref.[20] 121–123 °C). IR (KBr): ν
(cm–1) = 3490 (NH) 3380, 3300 (NH2), 1640, 1610. 1H NMR (CDCl3): δ =
1.73 (s, 6H, 2×CH3), 2.38 (s, 1H, 3′-H), 5.34 (brs, 2H, NH2), 6.13 (brs, 1H,
NH), 6.61 (t, J = 7.9 Hz, 1H, 5-H), 6.65 (d, J = 8.2 Hz, 1H, 3-H), 7.20 (ddd,
J = 1.2, 7.4, 7.9 Hz, 1H, 4-H), 7.79 (dd, J = 1.6, 7.8 Hz, 6-H). 13C NMR
(CDCl3): δ = 29.3, 48.0, 70.0, 87.4, 116.5, 116.9, 117.7, 127.6, 132.6, 149.4,
169.3. MS: m/z = 202 [M+] (54), 174 (10), 136 (16), 119 (100), 105 (32), 92
(51), 65 (45).
3-Prop-2-ynyl-2-benzyl-quinazolin-4(3H)-one (2d)
Yield 1.23 g (90%), mp 99–99.5 °C (CH2Cl2/n-hexane) (Ref.[6] 102–
104 °C). IR (KBr): ν (cm–1) = 3210 (C≡CH), 2100 (C≡C), 1690 (C=O), 1600.
1H NMR (CDCl3): δ = 2.23 (t, J = 2.4 Hz, 1H, 3′-H), 4.36 (s, 2H, CH2ph),
4.68 (d, J = 2.4 Hz, 2H, 1′-H), 7.17–7.36 (m, 5H, Ar-H), 7.42 (t, J = 7.8 Hz,
1H, Ar-H), 7.62–7.68 (m, 2H, Ar-H), 8.20 (d, J = 8.0 Hz, 1H, Ar-H). 13C
NMR (CDCl3): δ = 32.4, 42.1, 72.6, 77.7, 120.4, 126.9, 127.0, 127.2, 127.5,
128.2, 129.2, 134.6, 134.86, 147.0, 154.5, 161.6. MS: m/z = 274 [M+] (58),
273 [M+–1] (88), 235 (5), 197 (9), 167 (6), 130 (9), 128 (18), 116 (26), 102
(33), 91 (100), 77 (50), 65 (90).
3-Prop-2-ynyl-quinazolin-4(3H)-one (6a)
3-Prop-2-ynyl-2-penta-2-olyl-quinazolin-4(3H)-one (2e)
1.7 g 5a (10 mmol), 1 g acetic acid (17 mmol) and 1.6 g triethyl orthofor-
mate (11 mmol) in 30 ml EtOH were refluxed for 4 h. Upon concentration
in vacuo and addition of 5% aqueous NaOH topH 8themixture wasextracted
with CH2Cl2. The organic phase was dried over NaSO4, evaporated under
reduced pressure and the residue was recrystallized from MeOH to yield 1.55
g (85%) of 6a. Mp 115–116 °C (MeOH) (Ref.[8] 115–116 °C) IR (KBr) ν
(cm–1) = 3210 (C≡CH), 2110 (C≡C), 1660. 1H NMR (CDCl3): δ = 2.50 (t,
J = 2.5 Hz, 1H, 3′-H), 4.83 (d, J = 2.4 Hz, 2H, 1′-H), 7.52 (ddd, J = 1.9, 6.3,
7.8 Hz, 1H, 6-H), 7.74 (s, 1H, 2-H), 7.77 (dd, J = 1.8, 8.0 Hz, 1H, 8-H),
8.27–8.32 (m, 2H, 5-H, 7-H). 13C NMR (CDCl3): δ = 35.2, 75.2, 77.8, 121.9,
126.8, 127.9, 128.1, 134.8, 145.6, 148.4, 160.8. MS: m/z = 180 [M+] (100),
155 (30), 142 (8), 129 (42), 116 (6), 102 (34), 90 (14), 76 (34), 63 (20), 51
(20).
Yield 9.87 g (65%), mp 109–110 °C (n-pentane). IR (KBr): ν (cm–1) =
3405 (OH), 3250 (C≡CH), 2100 (C≡C), 1670 (C=O), 1600. 1H NMR
(CDCl3): δ = 1.15–1.25 (d, J = 6.7 Hz, 3H, CH3), 1.55–1.70 (q, J = 6.7 Hz,
2H, 3′′-H), 1.95–2.18 (m, 2H, 4′′-H), 2.30 (t, J = 2.4 Hz, 1H, 3′-H), 2.90–3.10
(t, J = 7.0 Hz, 2H, 5′′-H), 3.80–3.95 (m, 1H, 2′′-H), 4.95 (d, J = 2.4 Hz, 2H,
1′-H), 7.44–7.52 (ddd, J = 1.2, 7.2, 8.0 Hz, 1H, 8-H), 7.50–7.82 (m, 2H, 6-H,
7-H), 8.24–8.32 (dd, J = 1.2, 8.0 Hz, 1H, 5-H). 13C NMR (CDCl3): δ = 22.3,
23.7, 38.6, 67.3, 72.6, 77.9, 120.3, 126.8, 126.9, 127.1, 134.6, 146.9, 156.2,
161.5. MS: m/z = 269 [M+–1] (1), 253 [M+–OH] (38) 225 (7), 211 (33), 198
(49), 197 (100), 169 (11), 130 (5), 115 (5), 92 (5), 77 (6). C16H18N2O2
(270.33): Calc. C 71.09 H 6.71 N 10.36; found C 71.02 H 6.58 N 10.30.
3-Prop-2-ynyl-2-penta-2-onyl-quinazolin-4(3H)-one (2f)
3-(1,1-Dimethylprop-2-ynyl)-quinazolin-4(3H)-one (6b)
Yield 1.02 g (80%), mp 88–89 °C (CH2Cl2/n-hexane). IR (KBr): ν (cm–1
)
2.0 g 5b (10 mmol) were treated as described for 6a. Yield 1.2 g (56%),
mp 98–99 °C (Ref.[8] 97–99 °C). IR (KBr): ν (cm–1) = 3240 (C≡CH), 2100
(C≡C), 1660. 1H NMR (CDCl3): δ = 2.10 (s, 6H, 2×CH3), 2.96 (s, 1H, 3′-H),
7.44–7.58 (ddd, J = 1.9, 6.3, 8.2 Hz, 1H, 6-H), 7.60–7.78 (m, 2H, 7-H, 8-H),
8.30 (ddd, J = 1.3,7.1, 7.9 Hz, 1H, 5-H), 8.96 (s, 1H, 2-H). 13C NMR
(CDCl3): δ = 28.5, 58.4, 77.9, 84.7, 127.1, 127.3, 127.5, 127.6, 134.6, 145.1,
148.0, 162.1. MS: m/z = 212 [M+] (58), 197 (14), 183 (8), 169 (10), 146 (100),
131 (8), 118 (28), 102 (16), 90 (26), 69 (26).
= 3200 (C≡CH), 2960 (Ar-H), 2100 (C≡C), 1740, 1685 (C=O), 1600. 1H
NMR (CDCl3): δ = 2.14 (s, 3H, CH3), 2.18–2.22(m, 2H, CH2), 2.26 (s, 1H,
3′-H), 2.62–2.69 (t, J = 6.7 Hz, 2H, 3′′-H), 2.91–3.98 (t, J = 7.3 Hz, 2H,
4′′-H), 4.96 (s, 2H, 1′-H), 7.41 (t, J = 7.0 Hz, 1H, 8-H), 759 (d, J = 7.8 Hz,
1H, 6-H), 7.66 (t, J = 7.0 Hz, 1H, 7-H), 8.20 (d, J = 7.8 Hz, 1H, 5-H). 13C
NMR (CDCl3): δ = 21.0, 30.5, 32.9, 42.7, 72.9, 110.0, 120.7, 127.1, 127.4,
134.9, 147.4, 155.9, 161.9, 208.8. MS: m/z = 254 [M+] (2), 253 [M+–1] (3),
225 (28), 211 (18), 198 (86), 197 (100), 184 (8), 169 (13), 142 (3), 130 (4),
115 (4). C16H16N2O2 (268.32): Calc. C 71.62 H 4.51 N 10.44; found C 71.56
H 4.60 N 10.50.
General Procedure for the Synthesis of Quinazoline-2,4-diones
6.0 mmol sodium hydroxide were addedto 6.0mmol of the quinazolinedio-
nes 7a or 7b in 30 ml 50% methanol and stirred at room temperature for
30 min. 0.7 mmol 3-bromo-prop-1-yne was added and the reaction mixture
was refluxed for 6 hours. After cooling to room temperature, 40 ml of 0.7 M
sodium hydroxide were added and stirred for 15 min to remove the monoal-
kylated product. The dialkylated product was filtered and dried. Precipitation
of the monoalkylated product was carried out by adjusting the filtrate to pH
5 with 0.1 M HCl. The precipitate was filtered and dried. The compounds
were further purified by column chromatography (CH2Cl2).
3-Prop-2-ynyl-quinazolin-4(3H)-one Carboxamide (2g)
Yield 0.85 g (75%), mp 203–205 °C (ethyl acetate/n-hexane). IR (KBr): ν
(cm–1) = 3415, 3395 (NH2), 1680, 1670 (C=O). 1H NMR (DMSO-d6): δ =
3.30 (t, J = 2.3 Hz, 1H, 3′-H), 5.05 (d, J = 2.4 Hz, 2H, 1′-H), 7.58–7.69 (ddd,
J = 1.4, 7.2, 8.0 Hz, 1H, 8-H), 7.70–7.78 (dd, J = 1.2, 8.2 Hz, 1H, 6-H),
7.86–7.96 (ddd, J = 1.5, 7.4, 8.2 Hz, 1H, 7-H), 8.14–8.24 (dd, J = 1.6, 8.0
Hz, 5-H), 8.18 (s, 1H, CONH2), 8.46 (s, 1H, CONH2). 13C NMR ( DMSO-
Arch. Pharm. Pharm. Med. Chem. 333, 261–266 (2000)

266
Usifoh and Scriba
3-Prop-2-ynyl-quinazoline-2,4-(1H)-dione (8a)
elevation of the pentylenetetrazole-induced seizure threshold. The acute
neurological toxicity was determined in the rotorod test where the animal
was placed on a rod rotating at 6 rpm. Neurological deficiency was indicated
by inability to maintain equilibrium for 1 min in each of 3 trials. For all these
evaluations the compounds were dissolved or suspended in 0.5% aqueous
methyl cellulose.
Yield 0.86 g (60%), mp 240–241 °C (EtOH) (Ref.[19] 239–240.5 °C). IR
(KBr) ν (cm–1) = 3310 (NH), 1705, 1680, 1640, 1290, 700. 1H NMR
(DMSO-d6): δ = 3.10 (t, J = 2.4 Hz, 1H, 3′-H), 4.65 (d, J = 2.4 Hz, 2H, 1′-H),
7.21 (d, J = 7.9 Hz, 1H, 8-H), 7.42 (t, J = 8.0 Hz, 1H, 6-H), 7.67 (ddd, J = 1.4,
7.6, 7.9 Hz, 1H, 7-H), 7.98 (dd, J = 1.6, 7.9 Hz, 1H, 5-H). 13C NMR
(DMSO-d6): δ = 29.3, 72.7, 79.2, 113.6, 115.3, 122.8, 127.5, 135.4, 139.5,
149.0, 161.3. MS: m/z = 200 [M+] (100), 171 (16), 158 (10), 146 (76), 130
(26), 119 (46), 104 (6), 92 (64), 76 (12), 64 (36), 51 (18).
References
[1] T. W. Rall, L. S. Schleifer in The Pharmacological Basis of Therapeu-
tics (Eds.: A. Goodman Gilman, T. W. Rall, A. S. Nies, P. Taylor),
Pergamon, New York, 8th ed., 1990, chapter 19.
1,3-Bis-(prop-2-ynyl)-quinazoline-2,4-(1H,3H)-dione (9a)
Yield 0.45 g (32%), mp 168–170 °C (ethanol) (Ref.[7] 169–171 °C). IR
(KBr): ν (cm–1) = 3270, 2120 (C≡CH) 1697, 1650. 1H NMR (CDCl3): δ =
2.21 (t, J = 2.5 Hz, 1H, 3′-H), 2.31 (t, J = 2.5 Hz, 1H, 3′′-H), 4.88 (d, J = 2.5
Hz, 2H, 1′-H), 4.97 (d, J = 2.5 Hz, 2H, 1′′-H), 7.20–7.50 (m, 2H, 6-H, 7-H),
7.71–7.86 (ddd, J = 1.5, 7.5, 8.0 Hz, 8-H), 8.30–8.38 (dd, J = 1.6, 7.9 Hz,
1H, 5-H). 13C NMR (CDCl3): δ = 30.9, 33.2, 70.7, 73.2, 77.4, 78.1, 114.0,
115.5, 123.4, 129.3, 135.3, 138.9, 149.8, 160.7. MS: m/z = 239 [M++1] (12),
238 [M+] (8), 237 [M+–1] (12), 199 [M+–C3H3] (100), 172 (10), 156 (26),
146 (20), 129 (20), 102 (34).
[2] J. F. Wolfe, T. L. Rathman, M. C. Sheri, J. A. Campbell, T. D.
Greenwood, J. Med. Chem. 1990, 33, 161–166.
[3] S. Sinha, M. Sritastava, in Progress in Drug Research (Ed.: E. Jucker),
Birkhäuser Verlag, 1994, Vol. 43, 143–238.
[4] C. Montginoul, G. Pastor, C. Vigne, L. Giral, Ann. Pharm. Franc. 1988,
46, 223–232.
[5] M. J. Kornet, T. Varia, W. Beaven, J. Heterocyclic Chem. 1984, 21,
1533–1535.
6,7-Dimethoxy-3-prop-2-ynyl-quinazoline-2,4-(3H)-dione (8b)
[6] C. Bogentoft, L. Krongberg, B. Danielsson, Acta Pharm. Suecica 1969,
6, 489–500.
Yield 0.68 (50%), mp 289–290 °C (EtOH). IR (KBr): ν (cm–1) = 3340
cm–1 (NH), 1680, 1640 (C=O). 1H NMR (CF3 COOH/CDCl3): δ = 2.24 (t,
J = 2.4 Hz, 1H, 3′-H), 3.99 (s, 3H, OCH3), 4.03 (s, 3H, OCH3), 4.88 (d,
J = 2.4 Hz, 2H, 1′-H), 6.70 (s, 1H, 8-H), 7.59 (s, 1H, 5-H), 10.36 (brs, 1H,
NH). 13C NMR (CF3 COOD): δ = 31.4, 56.7, 56.8, 72.3, 98.1, 106.7, 108.6,
112.6, 134.8, 147.3, 152.7, 157.2, 163.0. MS: m/z = 260 [M+] (100), 222 (84),
207 (56), 190 (20), 164 (94), 150 (12), 136 (67), 120 (14), 108 (30), 77 (16).
C13H12N2O4 (260.25) calc. C 60.00 H 4.65 N 10.76. Found C 59.94 H 4.62
N 10.66.
[7] B. Danielsson, E. Skoglund, Acta Pharm. Suecica 1965, 2, 167–174.
[8] J. Reisch, C. O. Usifoh, J. O. Oluwadiya, J. Heterocyclic Chem. 1990,
27, 1953–1956.
[9] J. Reisch, A. R. R. Rao, C. O. Usifoh, Monatsh. Chem. 1993, 124,
1217–1220.
[10] R. Danielsson, S. Johansson, L. Paalzow, Acta Pharm. Suecica 1965,
2, 155–166.
1,3-Bis-(prop-2-ynyl)-6,7-dimethoxy-quinazoline-2,4-(1H,3H)-dione (9b)
[11] R. J. Porter, J. J. Cereghino, G. D. Gladding, B. J. Hessie, H. J.
Kupferberg, B. Scoville, B. G. White, Cleveland Clin. Q. 1984, 51,
293–305.
Yield 0.73 g (40%), mp 226–227 °C (EtOH) (Ref.[9] 225–227 °C). IR
(KBr):ν (cm–1)=3265, 2125(C≡CH), 1690, 1662 (C=O). 1H NMR (CDCl3):
δ = 2.22 (t, J = 2.4 Hz, 1H, 3′-H), 2.32 (t, J = 2.4 Hz, 1H, 3′′-H), 3.92 (s, 3H,
OCH3), 4.02 (s, 3H, OCH3), 4.86 (d, J = 2.4 Hz, 2H, 1′-H), 4.96 (d, J = 2.4
Hz, 2H, 1′′-H), 6.85 (s, 1H, 8-H), 7.63 (s, 1H, 5-H). 13C NMR (CDCl3): δ =
30.9, 32.4, 56.2, 70.6, 73.8, 77.4, 78.4, 97.2, 108.2, 109.1, 134.6, 146.0,
150.2, 155.7, 160.2. MS: m/z = 299 [M++1] (20), 298 [M+] (100), 297 [M+–1]
(21), 260 (9), 259 [M+–C3H3] (50), 216 (10), 202 (15), 186 (16), 146 (16).
[12] C. R. Clark, M. J. M. Wells, R. T. Sansom, G. N. Norris, R. C. Dockens,
W. R. Ravis, J. Med. Chem. 1984, 27, 779–782.
[13] C. R. Clark, R. T. Sansom, C.-M. Lin, G. N. Norris, J. Med. Chem.
1985, 28, 1259–1262.
[14] C.R. Clark, C.-M. Lin, R.T. Sansom, J. Med. Chem. 1986, 29, 1524–
1537.
Pharmacology
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[16] H. Stephen, G. Wadge, J. Chem. Soc. 1956, 4420–4421.
Anticonvulsant testing was provided by the Antiepileptic Drug Develop-
ment Program, Epilepsy Branch, Division of Convulsive, Developmental
and Neuromuscular Disorders, National Institutes of Health, according to
standard procedures[11] and included the MES test and the seizure scMet test.
In the MES test, an electrical stimulus of 50 mA was delivered for 0.2 s via
corneal electrodes to male CF1 mice at 30 min and 4 h after the administra-
tion of the compounds. Blockade of the tonic extension of the hind limbs was
considered protection against seizures. For the scMet test a convulsant dose
of 85 mg/kg of pentylenetetrazole dissolved in saline was injected in a loose
fold of skin on the back of the neck and the animals were isolated and
observed for 30 min. Absence of clonic spasms for at least 5 s indicated the
[17] J.-W. Chern, H.-T. Chen, N.-Y. Lai, K.-R. Wu, Y.-C. Chern, Chem.
Pharm. Bull. 1998, 46, 928–933.
[18] B. R. Baker, P. I. Almaular, J. Org. Chem. 1962, 27, 4672–4674.
[19] R.L. Jacobs, J. Heterocyclic Chem. 1970, 7, 1337–1345.
[20] J. Reisch, C. O. Usifoh, J. O. Oluwadiya, J. Heterocyclic Chem. 1989,
26, 1495–1498.
Received: April 4, 2000 [FP475]
Arch. Pharm. Pharm. Med. Chem. 333, 261–266 (2000)