An efficient procedure for the synthesis of 5H-6-substituted-pyrazolo [1,5-d]-1,2,4-triazine-4,7-diones

Article abstract of DOI:10.1055/s-1999-3418

A new series of 5,6-dihydropyrazolo[1,5-d]-1,2,4-triazine-4,7-diones substituted in the 6-position with various phenyl substituents has been synthesized and found to have activity, owing to their acylating properties, as inhibitors of the serine protease enzymes.

Full text of DOI:10.1055/s-1999-3418

PAPER
453
An Efficient Procedure for the Synthesis of 5H-6-Substituted-pyrazolo[1,5-d]-
1,2,4-triazine-4,7-diones
Pier Giovanni Baraldi,* Barbara Cacciari, Romeo Romagnoli, Giampiero Spalluto
Dipartimento di Scienze Farmaceutiche, Via Fossato di Mortara 17/19, I-44100, Ferrara, Italy
Fax +39(532)291296; E-mail: pgb@dns.unife.it
Received 27 July 1998; revised 24 August 1998
These results prompted us to the design and synthesis of
Abstract: A new series of 5,6-dihydropyrazolo[1,5-d]-1,2,4-triaz-
some related 6-aryl-substituted-5H-pyrazolo[1,5-d]-
ine-4,7-diones substituted in the 6-position with various phenyl
1,2,4-triazine-4,7-diones of general formula 9 utilizing
substituents has been synthesized and found to have activity, owing
dipyrazolo[1,5-a; 1',5'-d]pyrazine-4,9-diones of general
formula 8 as starting material (Scheme 2). Only Rabba et
al.6 have reported an efficient method for the synthesis of
5,6-dihydropyrazolo[1,5-d]-1,2,4-triazine-4,7-diones
(with an hydrogen or bromine in the 3 position), which
were achieved submitting to cyclization the N-carbethoxy
hydrazides of the corresponding pyrazole-5-carboxylic
acids under alkaline conditions.
to their acylating properties, as inhibitors of the serine protease en-
zymes.
Key words: dioxopiperazine, 5-pyrazolecarboxhydrazides cycliza-
tion, trichloromethyl chloroformate, protease inhibitors
In several publications, we have reported the reactivity of
the 2,7-dimethyl-3,8-dinitrodipyrazolo[1,5-a; 1',5'-d]-
py-razine-4,9-dione (1)1 towards nucleophilic reagents
such as aliphatic and aryl amines/hydrazines to give the
In the course of an in vitro screening program of evalua-
tion of new molecular entities, as Human Leukocyte
elastase (HLE) inhibitors,7 we have tested all these deriv-
atives of general formula 9 as a novel class of serine pro-
tease inhibitors and more generally as a novel family of
anti-proteases, endowed with a great therapeutical poten-
tial. The acylÐpyrazole bond of these pyrazolotriazinedi-
ones is thought to be involved in the mechanism of
inhibition of the serine proteases. Therefore, on the basis
of these findings, this new series of triazinones might be
useful in the therapy of different inflammatory and im-
mune diseases, including respiratory and muscoloskeletal
pathologies. In particular, these compounds might repre-
corresponding
3-methyl-4-nitropyrazole-5-carboxam-
ides/hydrazides 2 and 3, respectively, in high yields
(Scheme 1). These latter compounds has been disclosed
by our group as key chemical intermediates in the synthe-
sis of 6-sub-stituted-3-methyl-1H-pyrazolo[4,3-d]pyrimi-
dine-7(6H)-ones 4,2 6-arylamino-substituted-3-methyl-
1H-pyraz-olo[4,3-d]pyrimidine-7(6H)-ones 53, 5-aryl-
substituted-3-methyl-6,7-dihydropyrazolo[4,3-e]-[1,4]di-
azepin-8(7H)-ones 64 and 4-substituted-7-methyl-5H-
pyrazolo[4,3-d]-1,2,3-triazin-4(3H)-ones 75.
Scheme 1
Synthesis 1999, No. 3, 453Ð458 ISSN 0039-7881 © Thieme Stuttgart · New York

454
P. G. Baraldi et al.
PAPER
sent an important tool in the treatment of emphysema, condensation between isobutyl methyl ketone and diethyl
cystic fibrosis, chronic bronchitis as well as osteoarthritis oxalate in the presence of sodium ethoxide). This pyrazole
and osteoporosis.8
derivative 11 has been subsequently nitrated with a mix-
ture of fuming nitric acid and fuming sulfuric acid at
100ûC or subjected to direct halogenation (with NaClO or
Br2 in HOAC) to give rise to their 4-substituted-5-pyraz-
olecarboxylic acid 12, 13 and 14, respectively. The treat-
ment of 11 and these 4-substituted intermediates 12Ð14
with refluxing thionyl chloride for 18 h, to give the
dioxopiperazines 15Ð18, followed by the treatment with
different phenylhydrazines allowed to obtain as expected,
very high yields of the hydrazides 19aÐc, 20aÐc, 21aÐc
and 22aÐc (Table 1).
The cyclization of hydrazides 19Ð22a,c with a slight ex-
cess (1.1 equiv.) of trichloromethyl chloroformate gave
the corresponding 6-arylsubstituted-5H-pyrazolo[1,5-d]-
1,2,4-triazine-4,7-diones 23 aÐc, 24 aÐc, 25 aÐc and 26 aÐ
c in good yields (Scheme 3 and Table 2).
Scheme 2
In our synthetic strategy, triazinones of general formula 9
are obtained by a multistep process starting from the
3-isobutyl-5-pyrazolecarboxylic acid 11, easily obtained
by a well-known method which consists of the condensa-
tion between the hydrazine sulfate and the sodium enolate
of the a,g dioxo carboxylic esters 109 (prepared by Claisen
In order to demonstrate the chemical reactivity of the
acylÐpyrazole bond in this family of new pyrazolotriaz-
inones 23Ð26 a,c towards nucleophiles, we performed the
reaction of the 2-isopropyl-6-phenyl-5H-pyrazolo[1,5-d]-
1,2,4-triazine-4,7-dione 23a with benzyl amine. This re-
Scheme 3
Synthesis 1999, No. 3, 453Ð458 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 5H-6-Substituted-pyrazolo[1,5-d]-1,2,4-triazine-4,7-diones
455
1H NMR (DMSO-d6): d = 0.89 (d, 6H, J = 6.2 Hz), 1.86 (m, 1H),
2.77 (m, 2H, J = 8 Hz), 13.8 (br s, 1H), 14 (s, 1H).
IR (KBr, cmÐ1): n = 3180, 2820, 2785, 1700, 1410, 1320, 635.
action gives rise to the formation of the corresponding
product of addition, the acyl semicarbazide 27, in high
yield (Scheme 4).
4-Chloro-3-isobutylpyrazole-5-carboxylic Acid (13)
To a solution of 3-isobutylpyrazole-5-carboxylic acid 11 (3 g; 17.9
mmol) in glacial HOAc (50 mL) cooled at 0ûC was added portion-
wise aq 14% sodium hypochlorite (d = 1.25) (38 mL; 71.5 mmol of
NaClO).The solution should be acid (pH = 5), and the mixture can
be adjusted to acid pH with concentrated glacial HOAc. After being
stirred at r.t. for 4 h, the solvent was evaporated and the residue
crystallized from Et2O/petroleum ether, to give the product 13 (3.2
g, 90% yield) as white solid, m.p.=205ûC.
1H NMR (DMSO-d6) d = 0.85 (d, 6H, J = 6 Hz), 1.92 (m, 1H), 2.42
(m, 2H, J = 7 Hz), 2.49 (s, 1H), 11 (br s, 1H).
IR (KBr, cmÐ1): n = 3200, 2810, 2760, 1430, 1340, 650.
4-Bromo-3-isobutylpyrazole-5-carboxylic Acid (14)
To a solution of 3-isobutylpyrazole-5-carboxylic acid 11 (3 g; 17.9
mmol) in glacial HOAc (50 ml) cooled at 0ûC was added dropwise
Br2 (3.7 g; 23.21 mmol). After being stirred at r.t. for 4 h, the solvent
was evaporated and the residue crystallized from Et2O/petroleum
ether, to give the product 14 (4.14 g; 94% yield) as pale yellow sol-
id, mp = 199ûC.
1H NMR (DMSO-d6): d = 0.83 (d, 6H, J = 6 Hz), 1.98 (m, 1H), 2.46
(m, 2H, J = 8 Hz), 2.51 (s, 1H), 8.13 (br s, 1H).
IR (KBr, cmÐ1): n = 3170, 2800, 2760, 1410, 1320, 640.
Scheme 4
The general procedure here described is not necessarily
limited to the only pyrazolo-5-carboxylic acid but appears
of larger applicability, allowing us to aim at a wide num-
ber of different and closely related bicyclic and tricyclic
fused 1,2,4-triazinediones.
All reactions were carried out under an inert atmosphere of Ar, un-
less otherwise described. Standard syringe techniques were applied
for transferring anhyd solvents. Reaction courses and product mix-
tures were routinely monitored by TLC on silica gel (precoated F254
Merk plates) and visualized with aq KMnO4. 1H NMR spectra were
obtained in DMSO-d6 or CDCl3 solutions with a Bruker AC 200
spectrometer. Chemical shifts (d) are given in ppm upfield from
TMS. Mps were determined on a Buchi-Tottoli apparatus and are
uncorrected. Chromatography was performed with Merck 60Ð200
mesh silica gel. All products reported showed 1H NMR spectra in
agreement with the assigned structures. Organic solutions were
dried over anhyd MgSO4. Anhyd CH2Cl2 was distilled from CaCl2
prior to use. Elemental analyses were effected by the microanalyti-
cal laboratory of Dipartimento di Chimica, University of Ferrara.
Mass spectra were performed with Maldi-Toff Helwett Packard G
2025 A instrument.
2,7-Diisobutyl-3,8-disubstituted-dipyrazolo[1,5-a;1',5'-d]-
pyrazine-4,9-dione (15Ð18); General Procedure
A mixture of 3-isobutyl-4-substituted-pyrazole-5-carboxylic acid
(15 mmol) and thionyl chloride (10.9 ml, 150 mmol, 10 equiv.) was
heated under reflux for 18 h. The mixture was then cooled and ex-
cess thionyl chloride removed by evaporation under vacuo. The res-
idue was used without purification for the next reaction.
2,7-Diisobutyldipyrazolo[1,5-a;1',5'-d]pyrazine-4,9-dione (15)
Using a procedure similar to that described above, 15 (85% yield)
was obtained as a pale yellow solid, mp = 130ûC.
1H NMR (DMSO-d6): d = 0.92 (d, 12H, J = 6.4 Hz), 2.03 (m, 2H),
2.58 (m, 4H, J = 8 Hz), 7.40 (s, 2H).
IR (KBr, cmÐ1): n = 3000, 1780, 1470, 1420, 1290, 1090, 860, 780,
720.
FAB (Maldi-Toff): m/z = 301.6 [M+1]+.
3-Isobutylpyrazole-5-carboxylic Acid (11)
2,7-Diisobutyl-3,8-dinitrodipyrazolo[1,5-a;1',5'-d]pyrazine-4,9-
dione (16)
Using a procedure similar to that described above, 16 (88% yield)
was obtained as a yellow solid, mp = 196ûC.
1H NMR (CDCl3): d = 0.88 (d, 6H, J = 6.4 Hz), 0.99 (d, 6H, J = 6.4
Hz), 1.93 (m, 1H), 2.11 (m, 1H), 2.72 (m, 2H, J = 8 Hz), 2.93 (d,
2H, J = 8 Hz).
IR (KBr, cmÐ1): n = 3000, 1780, 1560, 1480, 1430, 1370, 1280,
1100, 865, 790, 730.
FAB (Maldi-Toff): m/z = 393.5 [M+1]+.
The sodium salt of ethyl 6-methyl-2,4-dioxoheptanoate (45 g, 0.217
mol) was added in small portions to a 2 M aq KOH (100 mL) cooled
to 0ûC. After 30 min at this temperature, hydrazine sulfate (25 g, 0.5
mol) was slowly added to this solution. After 10 min, the deposited
white precipitate was collected by filtration and dried (P2O5) to give
the pyrazole 11 (21 g, 58% yield) as a white solid. mp = 184 ûC.
1H NMR (CDCl3): d = 0.84 (d, 6H, J = 6.4 Hz), 1.86 (m, 1H), 2.47
(m, 2H), 6.48 (s, 1H), 11.5 (br s, 1H), 13 (br s, 1H).
IR (KBr, cmÐ1): n = 3200, 1710, 1356, 1210, 1015.
3,8-Dichloro-2,7-diisobutyldipyrazolo[1,5-a;1',5'-d]pyrazine-
4,9-dione (17)
Using a procedure similar to that described above, 17 (80% yield)
was obtained as a yellow solid; 80% yield; mp = 257ûC.
1H NMR (CDCl3): d = 0.99 (d, 12H, J = 6.4 Hz), 2.23 (m, 2H), 2.73
(m, 4H, J = 8 Hz).
IR (KBr, cmÐ1): n = 3000, 1770, 1550, 1480, 1400, 1300, 1100, 840,
3-Isobutyl-4-nitropyrazole-5-carboxylic Acid (12)
To a mixture of fuming H2SO4 (29 mL, 27Ð33% SO3) and 100%
HNO3 (19 mL) cooled to 0ûC, was added portionwise 11 (20 g; 19
mmol) with stirring. The solution was then heated at 100ûC for 6 h.,
cooled to ambient temperature and poured into ice. The resulting
precipitate was collected, recrystallized from water and dried to
give the product 12 as white needles (19.6 g, 84% yield), mp = 177Ð
180ûC.
750.
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456
P. G. Baraldi et al.
PAPER
FAB (Maldi-Toff): m/z = 372.3 [M+1]+.
IR (KBr, cmÐ1): n = 3000, 1780, 1550, 1450, 1430, 1280, 1050, 840,
770, 730.
3,8-Dibromo-2,7-diisobutyldipyrazolo[1,5-a;1',5'-d]pyrazine-
4,9-dione (18)
FAB (Maldi-Toff): m/z = 461.2 [M+1]+.
Using a procedure similar to that described above, 18 (88% yield)
was obtained as a yellow solid. mp = 208ûC.
1H NMR (CDCl3) d = 0.98 (d, 12H, J = 6.4 Hz), 2.11 (m, 2H), 2.69
(m, 4H, J = 7.4 Hz).
3-Isobutyl-4-substituted-pyrazole-5-carboxyhydrazides (19Ð22
a,c); General Procedure
To a stirred solution of Et3N (1.5 ml, 11 mmol, 2.2 equiv.) in 100
mL of CH2Cl2, cooled at 0ûC, was added the appropriate phenylhy-
Table 1 N2-Phenylsubstituted 3-Isobutyl-4-substituted-pyrazole-5-carboxhydrazides 19Ð22 a,c Prepared
Com-
pound
R
H
X
H
Yielda
(%)
mp
(ûC)
1H NMR (DMSO-d6)
δ
IR (KBr)
cmÐ1
19a
20a
78
83
197
189
0.89 (d, 6H, J = 6 Hz), 1.9 (m, 1H), 2.51 (d, 2H, J = 7.2 Hz),
6.45 (s, 1H), 6.59 (d, 1H, J = 7.8 Hz), 6.71 (t, 2H, J = 7.8
Hz), 7.13 (t, 2H, J = 7.8 Hz), 7.82 (s, 1H), 9.94 (s, 1H),
13.01 (s, 1H)
3340, 2820, 1720,
1630, 1520, 1400,
880, 770
H
NO2
0.92 (d, 6H, J = 6.2 Hz), 2.10 (m, 1H), 2.51 (d, 2H, J = 7.4
Hz), 6.77 (t, 1H, J = 7 Hz), 6.83 (d, 2H, J = 8.2 Hz), 7.18
(t, 2H, J = 7.8 Hz), 8.09 (s, 1H), 10.33 (s, 1H), 13.9 (br s,
1H)
3310, 2800, 1710,
1640, 1550, 1410,
880, 740
21a
22a
19b
20b
21b
22b
19c
H
Cl
Br
H
80
85
75
90
82
87
70
200Ð
202
0.89 (d, 6H, J = 6 Hz), 2.03 (m, 1H), 2.51 (d, 2H, J = 7 Hz),
6.73 (t, 1H, J = 6.8 Hz), 6.77 (d, 2H, J = 8 Hz), 7.14 (t, 2H,
J = 8 Hz), 7.84 (s, 1H), 10.02 (s, 1H), 13.43 (br s, 1H)
3350, 2900, 1700,
1600, 1520, 1380,
850, 780
H
180Ð
182
0.89 (d, 6H, J = 6 Hz), 2.05 (m, 1H), 2.51 (d, 2H, J = 7 Hz),
6.70 (t, 1H, J = 6.8 Hz), 6.76 (d, 2H, J = 7.6 Hz), 7.14 (t,
2H, J = 7.6 Hz), 7.84 (s, 1H), 10.01 (s, 1H), 13.48 (br s, 1H)
3350, 2910, 1720,
1600, 1520, 1380,
880, 780
o-CH3
o-CH3
o-CH3
o-CH3
m-Cl
75
0.93 (d, 6H, J = 6.4 Hz), 1.94 (m, 1H), 2.29 (s, 3H), 2.54 (d,
2H, J = 8 Hz), 6.14 (br s, 1H), 6.58 (s, 1H), 6.96 (m, 4H),
8.9 (br s, 1H), 14.02 (br s, 1H)
3480, 3000, 1700,
1380, 1260, 850,
770
NO2
Cl
Br
H
95
0.92 (d, 6H, J = 6.4 Hz), 2.02 (m, 1H), 2.28 (s, 3H), 2.84
(d, 2H, J = 8 Hz), 6.98 (m, 4H), 7.26 (s, 1H), 10.25 (br s,
1H), 14.02 (br s, 1H)
3420, 2820, 1720,
1620, 1550, 1430,
1220, 890, 730
135
0.89 (d, 6H, J = 6.4 Hz), 2.00 (m, 1H), 2.22 (s, 3H), 2.78
(d, 2H, J = 8.2 Hz), 7.02 (m, 4H), 7.30 (s, 1H), 10.23 (br s,
1H), 14.14 (br s, 1H)
3320, 2960, 1680,
1610, 1560, 1390,
820, 720
151Ð
153
0.92 (d, 6H, J = 6.2 Hz), 2.12 (m, 1H), 2.24 (s, 3H), 2.73
(d, 2H, J = 8 Hz), 6.88 (m, 4H), 7.29 (s, 1H), 10.33 (s, 1H),
14.08 (br s, 1H)
3370, 2980, 1690,
1620, 1580, 1390,
830, 740
140
0.88 (d, 6H, J = 6.4 Hz), 1.82 (m, 1H), 2.47 (d, 2H, J = 8
Hz), 6.59 (s, 1H), 6.73 (d, 1H, J = 7.8 Hz), 6.86 (d, 1H, J =
7.4 Hz), 7.06 (t, 2H, J = 7.8 Hz), 7.24 (br s, 1H), 9.4 (br s,
1H), 13.9 (br s, 1H)
3350, 2900, 1700,
1600, 1520, 1380,
850, 780
20c
21c
22d
m-Cl
m-Cl
m-Cl
NO2
Cl
70
82
86
216Ð
219
0.95 (d, 6H, J = 6.4 Hz), 2.02 (m, 1H), 2.81 (d, 2H, J = 8
Hz), 6.71 (d, 1H, J = 8 Hz), 6.83 (d, 1H, J = 7.8 Hz), 7.18
(t, 2H, J = 7.8 Hz), 8.35 (s, 1H), 10.41 (br s, 1H), 14.02 (br
s, 1H)
3380, 3000, 1700,
1620, 1600, 1450,
1380, 1290, 920,
790
138
156
0.86 (d, 6H, J = 6.2 Hz), 2.08 (m, 1H), 2.88 (d, 2H, J = 7.6
Hz), 6.72 (d, 1H, J = 8 Hz), 6.94 (d, 1H, J = 7.8 Hz), 7.14
(t, 2H, J = 7.8 Hz), 8.46 (s, 1H), 10.40 (br s, 1H), 13.8 (br
s, 1H)
3360, 2860, 1710,
1600, 1480, 1330,
870, 780
Br
0.90 (d, 6H, J = 6.4 Hz), 2.11 (m, 1H), 2.90 (d, 2H, J = 7.6
Hz), 6.64 (d, 1H, J = 8 Hz), 6.86 (d, 1H, J = 7.8 Hz), 7.12
(t, 2H, J = 7.8 Hz), 8.36 (s, 1H), 10.24 (br s, 1H), 13.98 (br
s, 1H)
3360, 2920, 1710,
1610, 1530, 1430,
880, 760
a Yield of isolated, purified products after crystallization
Synthesis 1999, No. 3, 453Ð458 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of 5H-6-Substituted-pyrazolo[1,5-d]-1,2,4-triazine-4,7-diones
457
drazine hydrochloride (2.2 equiv.). The suspension was then stirred
for 1 h and to this ice-cooled suspension was added the appropriate
dioxo-piperazine (5 mmol) and the resulting solution was stirred
overnight at r.t. At the end of the reaction, the system was washed
with H2O (25 mL), the organic phase separated, dried (Na2SO4),
concentrated under reduced pressure to give a residue which was
purified by crystallization.
equiv.) and the system heated to reflux for 1 h. After this time, the
reaction was cooled, stirred for 1 h. at r.t. and concentrated in vacuo.
The residue was purified by coloumn chromatography using
EtOAc:petroleum ether as mobile phase (starting with 1:4 v/v and
then with 1:1 v/v).
3-Isobutylpyrazole-5-(N2-benzylcarbamoyl, N2-phenyl) car-
boxyhydrazide (27)
6-Aryl-substituted-5H-pyrazolo[1,5-d]-1,2,4-triazine-4,7-di-
ones (23-26a,c); General Procedure
To a suspension of 19Ð22a,c (2 mmol) in anhyd toluene (5 mL) was
added trichloromethylchloroformate (266 mL, 2.2 mmol, 1.1
To a solution of 23a (285 mg, 1 mmol) in anhyd CH2Cl2 (5 mL) at
r.t. was added benzyl amine (107 mg, 1 mmol). After being stirred
at r.t. for 2 h, the mixture was concentrated in vacuo and the residue
was chromatographed with EtOAc:petroleum ether (1:2, v/v) to
Table 2 2-Isobutyl-3-substituted-5H-6-phenylsubstituted-pyrazolo[1,5-d]-1,2,4-triazine-4,7-diones 23Ð26 a,c Prepared
Com-
pound
R
H
X
H
Yield a
(%)
m.p
(ûC)
1H NMR (DMSO-d6) d
δ
IR (KBr)
cm−1
23a
24a
25a
26a
23b
24b
56
67
58
59
53
61
84Ð
86
0.95 (d, 6H, J = 6 Hz), 1.9 (m, 1H), 2.62 (d, 2H, J = 7 Hz),
6.61 (s, 1H), 7.28 (d, 2H, J = 7.6 Hz), 7.45 (m, 2H), 7.90
(d, 2H, J = 7.6 Hz).
3250, 3150, 2990,
1790, 1650, 1500,
1370, 1080, 750
H
NO2
Cl
97
0.92 (d, 6H, J = 6 Hz), 2.06 (m, 1H), 2.46 (d, 2H, J = 7.2
Hz), 7.30 (m, 2H,), 7.48 (d, 2H, J = 7.4 Hz), 7.92 (d, 2H,
J = 8.2 Hz)
3270, 2780, 1700,
1670, 1550, 1380,
1020, 860
H
133
0.97 (d, 6H, J = 6 Hz), 2.10 (m, 1H), 2.65 (d, 2H, J = 7 Hz),
7.32 (m, 2H), 7.50 (d, 2H, J = 8.2 Hz), 7.94 (d, 2H, J = 7.8
Hz)
3210, 3000, 1820,
1660, 1590, 1380,
1280, 1180, 890
H
Br
144Ð
147
0.91 (d, 6H, J = 6.1 Hz), 1.96 (m, 1H), 2.62 (d, 2H,
J = 7.2 Hz), 7.52 (m, 2H), 7.74 (d, 2H, J = 7.4 Hz), 7.92
(d, 2H, J = 7.8 Hz)
3380, 2900, 1670,
1520, 1430, 840,
770
o-CH3
o-CH3
H
125
0.99 (d, 6H, J = 6.4 Hz), 2.04 (m, 1H), 2.35 (s, 3H), 2.69
(d, 2H, J = 8 Hz), 6.64 (s, 1H), 7.35 (m, 5H)
3150, 3000, 1800,
1740, 1390, 1240,
1090, 970, 780
NO2
159Ð
161
1.02 (d, 6H, J = 6.4 Hz), 2.15 (m, 1H), 2.41 (s, 3H), 2.98
(d, 2H, J = 7.8 Hz), 7.37 (m, 5H)
3285, 1770, 1650,
1520, 1480, 1390,
1140, 1040, 950,
810
25b
26b
23c
24c
o-CH3
o-CH3
m-Cl
Cl
63
59
56
59
141
98
0.96 (d, 6H, J = 6.2 Hz), 2.06 (m, 1H), 2.13 (s, 3H), 2.68
(d, 2H, J = 8 Hz), 7.32 (m, 5H).
3180, 2860, 1690,
1620, 1540, 1360,
800, 730
Br
0.96 (d, 6H, J = 6 Hz), 2.08 (m, 1H), 2.20 (s, 3H), 2.58 (d,
2H, J = 8 Hz), 7.29 (m, 5H)
3370, 2980, 1690,
1620, 1580, 1390,
830, 740
H
145
0.97 (d, 6H, J = 6.2 Hz), 1.94 (m, 1H), 2.59 (d, 2H, J = 8.2
Hz), 6.62 (s, 1H), 7.22 (d, 1H, J = 7.4 Hz), 7.46 (d, 1H, J
= 7.4 Hz), 7.76 (m, 2H), 7.98 (s, 1H)
3150, 3000, 1660,
1500, 1280, 1160,
1000, 800, 760
m-Cl
NO2
155Ð
158
0.94 (d, 6H, J = 6.2 Hz), 1.98 (m, 1H), 2.67 (d, 2H, J = 7.8
Hz), 7.23 (d, 1H, J = 8 Hz), 7.38 (d, 1H, J = 7.6 Hz), 7.68
(m, 2H), 8.12 (s, 1H)
3220, 3150, 1810,
1660, 1530, 1380,
1180, 1100, 890,
760
25c
26c
m-Cl
m-Cl
Cl
Br
63
68
112
139
0.88 (d, 6H, J = 6.2 Hz), 2.02 (m, 1H), 2.72 (d, 2H, J = 6.8
Hz), 7.24 (d, 1H, J = 8 Hz), 7.45 (d, 1H, J = 7.8 Hz), 7.64
(m, 2H), 8.02 (s, 1H)
3260, 1780, 1630,
1505, 1360, 890,
780
0.97 (d, 6H, J = 6.4 Hz), 1.94 (m, 1H), 2.59 (d, 2H, J = 7.8
Hz), 7.23 (d, 1H, J = 7.8 Hz), 7.38 (d, 1H, J = 7.8 Hz), 7.72
(m, 2H), 8.02 (s, 1H)
3220, 3150, 1800,
1660, 1620, 1380,
1180, 1160, 890,
760
a Yield of isolated, purified products after crystallization from EAOAc-petroleum ether
Synthesis 1999, No. 3, 453Ð458 ISSN 0039-7881 © Thieme Stuttgart · New York

458
P. G. Baraldi et al.
PAPER
give 27 (305 mg, 78% yield) as a brown solid, mp (EtOAc/petro-
(3) Baraldi, P.G.; Guarneri, M.; Moroder, F.; Simoni, D.;
leum ether) = 158 ûC.
Vicentini, C.B. Synthesis 1982, 70.
Baraldi, P.G.; Menziani, M.; Simoni, D.; Vicentini, C.B. Il
Farmaco 1983, 7, 508.
1H NMR (CDCl3): d = 0.82 (d, 6H, J = 6.4 Hz), 1.81 (m, 1H), 2.37
(d, 2H, J = 7.2 Hz), 4.44 (d, 2H, J = 5.8 Hz), 5.30 (t, 1H, J = 4.8 Hz),
6.53 (s, 1H), 7.30 (m, 10H), 7.48 (d, 1H, J = 6.6 Hz), 11.1 (s, 1H).
(4) Baraldi, P.G.; Simoni, D.; Periotto, V.; Manfredini, S.;
Guarneri, M.; Borea P.A. J.Med. Chem. 1985, 28, 683.
(5) Baraldi, P.G.; Cacciari, B.; Leoni, A.; Recanatini, M.; Roberti,
M.; Rossi, M.; Manfredini, S.; Periotto, V.; Simoni, D.
Il Farmaco 1991, 46, 1337.
IR (KBr, cmÐ1): n = 3320, 3180, 3050, 1670, 1610, 890, 720, 630.
Acknowledgement
Manfredinbi,S.; Bazzanini, R.; Baraldi, P.G.; Guarneri, M.;
Simoni, D.; Marongiu, M.E.; Pani, A.;Tramontano, E.;
La Colla, P. J. Med. Chem. 1992, 35, 917.
These investigations were supported (in part) by Ministero Univer-
sitˆ e Ricerca Scientifica (MURST) (40 and 60%) with the financial
aid from the Domp• Pharmaceuticals S.p.A.
Baraldi, P.G.; Cacciari, B.; Dalpiaz, A.; Dionisotti, S.; Zocchi,
C.; Pineda de las Infantas, M.J.; Spalluto, G. Varani, K.
Arzneimittel-Forschung Drug Research 1996, 46, 365.
(6) Lancelot, J.C.; Maume, D.; Robba, M. J. Heterocyclic Chem.
1982, 19, 817.
References
(1) Musante, C. Gazz. Chim. Ital. 1945, 75, 121.
(2) Baraldi, P.G.; Guarneri, M.; Moroder, F.; Simoni, D. Synthe-
sis 1981, 727.
(7) Polgar, L. Mechanisms of Protease Action, CRC Press: Boca
Raton, 1989, 87.
For recent publications related to HNE inhibitors see:
Burkhart, J.P.; Mehdi, S.; Koehl, J.R.; Angelastro, M.R.; Bey,
P.; Peet, N.P. Bioorg. Med. Chem. Lett. 1998, 8, 63.
(8) unpublished results
(9) Burch, H.A.; Gray, J.E. J. Med. Chem. 1972, 15, 429.
Borsche, W.; Thiele, K. Chem. Ber. 1923, 56, 2132.
Keskin. Instanbul Univ. Fen. Fak. Mecm. Seri A. 1944, 9, 64;
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Baraldi, P.G.; Vicentini, C.B.; Simoni, D.; Guarneri, M. Il
Farmaco 1983, 6, 369.
Baraldi, P.G.; Simoni, D.; Periotto, V.; Manfredini, S.;
Guarneri, M.; Manservigi, R.;Cassai, E.; Bertolasi, V. J. Med.
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Baraldi, P.G.; Casolari, A.; Manfredini, S.; Periotto, V.;
Zanirato, V.; Florio, C.; Traversa, V.; Bertelli, G.M.; Borea,
P.A. Arzneimittel-Forschung Drug Research 1988, 9, 1262.
Synthesis 1999, No. 3, 453Ð458 ISSN 0039-7881 © Thieme Stuttgart · New York